NZ624874B2 - Substituted tetrahydroisoquinoline compounds as factor xia inhibitors - Google Patents
Substituted tetrahydroisoquinoline compounds as factor xia inhibitors Download PDFInfo
- Publication number
- NZ624874B2 NZ624874B2 NZ624874A NZ62487412A NZ624874B2 NZ 624874 B2 NZ624874 B2 NZ 624874B2 NZ 624874 A NZ624874 A NZ 624874A NZ 62487412 A NZ62487412 A NZ 62487412A NZ 624874 B2 NZ624874 B2 NZ 624874B2
- Authority
- NZ
- New Zealand
- Prior art keywords
- alkyl
- racemic
- enantiomer
- phcooh
- group
- Prior art date
Links
- 230000002401 inhibitory effect Effects 0.000 title abstract description 91
- 239000003112 inhibitor Substances 0.000 title abstract description 70
- 108010080805 Factor XIa Proteins 0.000 title abstract description 59
- 125000003039 tetrahydroisoquinolinyl group Chemical class C1(NCCC2=CC=CC=C12)* 0.000 title description 7
- 150000001875 compounds Chemical class 0.000 claims abstract description 261
- 239000003814 drug Substances 0.000 claims abstract description 47
- 200000000018 inflammatory disease Diseases 0.000 claims abstract description 6
- 125000000217 alkyl group Chemical group 0.000 claims description 436
- 229910052739 hydrogen Inorganic materials 0.000 claims description 219
- -1 NR Inorganic materials 0.000 claims description 194
- 201000010099 disease Diseases 0.000 claims description 84
- 229910052799 carbon Inorganic materials 0.000 claims description 83
- 239000011780 sodium chloride Substances 0.000 claims description 79
- 125000000623 heterocyclic group Chemical group 0.000 claims description 72
- 150000003839 salts Chemical class 0.000 claims description 68
- 125000005843 halogen group Chemical group 0.000 claims description 59
- 125000004432 carbon atoms Chemical group C* 0.000 claims description 52
- 238000000034 method Methods 0.000 claims description 44
- 125000003545 alkoxy group Chemical group 0.000 claims description 41
- 229910052757 nitrogen Inorganic materials 0.000 claims description 38
- 229910052760 oxygen Inorganic materials 0.000 claims description 37
- 125000005842 heteroatoms Chemical group 0.000 claims description 36
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 35
- 229910052731 fluorine Inorganic materials 0.000 claims description 34
- 208000007536 Thrombosis Diseases 0.000 claims description 33
- 239000012453 solvate Substances 0.000 claims description 33
- 125000003754 ethoxycarbonyl group Chemical group C(=O)(OCC)* 0.000 claims description 32
- 150000003536 tetrazoles Chemical group 0.000 claims description 29
- 239000008194 pharmaceutical composition Substances 0.000 claims description 28
- 210000004369 Blood Anatomy 0.000 claims description 27
- 239000008280 blood Substances 0.000 claims description 27
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 24
- 125000006297 carbonyl amino group Chemical group [H]N([*:2])C([*:1])=O 0.000 claims description 23
- GLUUGHFHXGJENI-UHFFFAOYSA-N piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 claims description 19
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 19
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 18
- 239000003937 drug carrier Substances 0.000 claims description 18
- 208000005189 Embolism Diseases 0.000 claims description 17
- 206010003210 Arteriosclerosis Diseases 0.000 claims description 15
- 201000001320 atherosclerosis Diseases 0.000 claims description 15
- 208000004476 Acute Coronary Syndrome Diseases 0.000 claims description 14
- 208000006011 Stroke Diseases 0.000 claims description 14
- 125000004429 atoms Chemical group 0.000 claims description 14
- 201000002674 obstructive nephropathy Diseases 0.000 claims description 14
- 206010047249 Venous thrombosis Diseases 0.000 claims description 13
- 229910052801 chlorine Inorganic materials 0.000 claims description 13
- 238000004519 manufacturing process Methods 0.000 claims description 13
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 13
- 208000010125 Myocardial Infarction Diseases 0.000 claims description 11
- 230000000271 cardiovascular Effects 0.000 claims description 11
- 125000001188 haloalkyl group Chemical group 0.000 claims description 11
- 229920000089 Cyclic olefin copolymer Polymers 0.000 claims description 10
- 206010051055 Deep vein thrombosis Diseases 0.000 claims description 10
- 125000004438 haloalkoxy group Chemical group 0.000 claims description 10
- 239000007943 implant Substances 0.000 claims description 10
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 10
- 125000004076 pyridyl group Chemical group 0.000 claims description 10
- 206010003178 Arterial thrombosis Diseases 0.000 claims description 9
- 206010003658 Atrial fibrillation Diseases 0.000 claims description 9
- 208000010378 Pulmonary Embolism Diseases 0.000 claims description 9
- OKTJSMMVPCPJKN-UHFFFAOYSA-N carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 9
- 206010002388 Angina unstable Diseases 0.000 claims description 8
- 206010060963 Arterial disease Diseases 0.000 claims description 8
- 206010044390 Transient ischaemic attack Diseases 0.000 claims description 8
- 208000007814 Unstable Angina Diseases 0.000 claims description 8
- 200000000007 arterial disease Diseases 0.000 claims description 8
- 125000001072 heteroaryl group Chemical group 0.000 claims description 8
- 201000004332 intermediate coronary syndrome Diseases 0.000 claims description 8
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 claims description 8
- 230000002093 peripheral Effects 0.000 claims description 8
- 229920000728 polyester Polymers 0.000 claims description 8
- 125000003003 spiro group Chemical group 0.000 claims description 8
- 201000010875 transient cerebral ischemia Diseases 0.000 claims description 8
- 150000003852 triazoles Chemical group 0.000 claims description 8
- 206010008088 Cerebral artery embolism Diseases 0.000 claims description 7
- 206010008092 Cerebral artery thrombosis Diseases 0.000 claims description 7
- 210000002216 Heart Anatomy 0.000 claims description 7
- 210000003734 Kidney Anatomy 0.000 claims description 7
- 206010037437 Pulmonary thrombosis Diseases 0.000 claims description 7
- 125000001309 chloro group Chemical group Cl* 0.000 claims description 7
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 claims description 7
- 125000001041 indolyl group Chemical group 0.000 claims description 7
- 201000010849 intracranial embolism Diseases 0.000 claims description 7
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 7
- 201000005060 thrombophlebitis Diseases 0.000 claims description 7
- 125000006367 bivalent amino carbonyl group Chemical group [H]N([*:1])C([*:2])=O 0.000 claims description 6
- 125000004674 methylcarbonyl group Chemical group CC(=O)* 0.000 claims description 6
- WPYMKLBDIGXBTP-UHFFFAOYSA-N Benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 claims description 5
- 206010042434 Sudden death Diseases 0.000 claims description 5
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 5
- 238000001631 haemodialysis Methods 0.000 claims description 5
- 230000000322 hemodialysis Effects 0.000 claims description 5
- 230000000302 ischemic Effects 0.000 claims description 5
- 125000003386 piperidinyl group Chemical group 0.000 claims description 5
- 230000000306 recurrent Effects 0.000 claims description 5
- JFDZBHWFFUWGJE-UHFFFAOYSA-N Benzonitrile Chemical compound N#CC1=CC=CC=C1 JFDZBHWFFUWGJE-UHFFFAOYSA-N 0.000 claims description 4
- 125000005275 alkylenearyl group Chemical group 0.000 claims description 4
- 125000004458 methylaminocarbonyl group Chemical group [H]N(C(*)=O)C([H])([H])[H] 0.000 claims description 4
- 125000004193 piperazinyl group Chemical group 0.000 claims description 4
- 125000004414 alkyl thio group Chemical group 0.000 claims description 3
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 3
- 230000002612 cardiopulmonary Effects 0.000 claims description 3
- 125000003453 indazolyl group Chemical group N1N=C(C2=C1C=CC=C2)* 0.000 claims description 3
- 125000006569 (C5-C6) heterocyclic group Chemical group 0.000 claims description 2
- 239000005711 Benzoic acid Substances 0.000 claims description 2
- 235000010233 benzoic acid Nutrition 0.000 claims description 2
- CWXPZXBSDSIRCS-UHFFFAOYSA-N tert-butyl piperazine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CCNCC1 CWXPZXBSDSIRCS-UHFFFAOYSA-N 0.000 claims description 2
- 125000003647 acryloyl group Chemical group O=C([*])C([H])=C([H])[H] 0.000 claims 1
- WPYMKLBDIGXBTP-UHFFFAOYSA-M benzoate Chemical compound [O-]C(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-M 0.000 claims 1
- 108090000113 Plasma kallikrein Proteins 0.000 abstract description 22
- 102000003827 Plasma kallikrein Human genes 0.000 abstract description 22
- 230000000069 prophylaxis Effects 0.000 abstract description 20
- DGIYUTOQJDQDST-IZZDOVSWSA-N 4-[[2-[(E)-3-[5-chloro-2-(tetrazol-1-yl)phenyl]prop-2-enoyl]-5-piperazin-1-yl-3,4-dihydro-1H-isoquinoline-1-carbonyl]amino]benzoic acid Chemical compound C1=CC(C(=O)O)=CC=C1NC(=O)C1C(C=CC=C2N3CCNCC3)=C2CCN1C(=O)\C=C\C1=CC(Cl)=CC=C1N1N=NN=C1 DGIYUTOQJDQDST-IZZDOVSWSA-N 0.000 abstract 2
- 239000000543 intermediate Substances 0.000 description 235
- 239000000203 mixture Substances 0.000 description 115
- XEKOWRVHYACXOJ-UHFFFAOYSA-N acetic acid ethyl ester Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 102
- DTQVDTLACAAQTR-UHFFFAOYSA-N trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 81
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 80
- 239000000243 solution Substances 0.000 description 73
- 238000006243 chemical reaction Methods 0.000 description 67
- 239000003795 chemical substances by application Substances 0.000 description 66
- 235000002639 sodium chloride Nutrition 0.000 description 65
- 239000002904 solvent Substances 0.000 description 54
- WYURNTSHIVDZCO-UHFFFAOYSA-N tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 54
- 239000007787 solid Substances 0.000 description 52
- 239000003146 anticoagulant agent Substances 0.000 description 50
- 235000019439 ethyl acetate Nutrition 0.000 description 48
- OKKJLVBELUTLKV-UHFFFAOYSA-N methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 48
- YMWUJEATGCHHMB-UHFFFAOYSA-N methylene dichloride Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 43
- 239000012267 brine Substances 0.000 description 35
- 238000004128 high performance liquid chromatography Methods 0.000 description 31
- 239000011541 reaction mixture Substances 0.000 description 29
- HEMHJVSKTPXQMS-UHFFFAOYSA-M sodium hydroxide Inorganic materials [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 29
- 239000000047 product Substances 0.000 description 28
- VEXZGXHMUGYJMC-UHFFFAOYSA-N HCl Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 27
- 239000004480 active ingredient Substances 0.000 description 27
- 108090000190 Thrombin Proteins 0.000 description 25
- 230000015271 coagulation Effects 0.000 description 25
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 25
- NKCXQMYPWXSLIZ-PSRDDEIFSA-N (2S)-2-[[(2S)-1-[(2S)-5-amino-2-[[2-[[(2S)-6-amino-2-[[2-[[(2S)-2-[[(2S)-4-amino-2-[[(2S)-2-[[(2S,3R)-2-[[(2S)-2-[[(2S,3R)-2-amino-3-hydroxybutanoyl]amino]-3-(1H-indol-3-yl)propanoyl]amino]-3-hydroxybutanoyl]amino]propanoyl]amino]-4-oxobutanoyl]amino]-3-m Chemical compound O=C([C@H](CCC(N)=O)NC(=O)CNC(=O)[C@H](CCCCN)NC(=O)CNC(=O)[C@@H](NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](C)NC(=O)[C@@H](NC(=O)[C@H](CC=1C2=CC=CC=C2NC=1)NC(=O)[C@@H](N)[C@@H](C)O)[C@@H](C)O)C(C)C)N1CCC[C@H]1C(=O)N[C@@H](CO)C(O)=O NKCXQMYPWXSLIZ-PSRDDEIFSA-N 0.000 description 24
- 238000010511 deprotection reaction Methods 0.000 description 24
- 229960004072 thrombin Drugs 0.000 description 24
- 230000015572 biosynthetic process Effects 0.000 description 23
- 230000004913 activation Effects 0.000 description 22
- 238000004166 bioassay Methods 0.000 description 22
- FAPWRFPIFSIZLT-UHFFFAOYSA-M sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 22
- 238000004296 chiral HPLC Methods 0.000 description 21
- 238000000746 purification Methods 0.000 description 21
- 108010074864 Factor XI Proteins 0.000 description 20
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 20
- 238000002360 preparation method Methods 0.000 description 20
- 239000000463 material Substances 0.000 description 19
- 125000000896 monocarboxylic acid group Chemical group 0.000 description 19
- 239000012071 phase Substances 0.000 description 19
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 19
- UIIMBOGNXHQVGW-UHFFFAOYSA-M NaHCO3 Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 18
- 238000006058 Ugi-reaction Methods 0.000 description 18
- 230000000694 effects Effects 0.000 description 18
- 239000003826 tablet Substances 0.000 description 18
- 241000282414 Homo sapiens Species 0.000 description 17
- 239000002775 capsule Substances 0.000 description 17
- 229940079593 drugs Drugs 0.000 description 17
- 210000002381 Plasma Anatomy 0.000 description 16
- QTBSBXVTEAMEQO-UHFFFAOYSA-N acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 16
- 229960001138 acetylsalicylic acid Drugs 0.000 description 16
- 230000002429 anti-coagulation Effects 0.000 description 16
- BSYNRYMUTXBXSQ-UHFFFAOYSA-N aspirin Chemical compound CC(=O)OC1=CC=CC=C1C(O)=O BSYNRYMUTXBXSQ-UHFFFAOYSA-N 0.000 description 16
- 210000004027 cells Anatomy 0.000 description 16
- 239000002552 dosage form Substances 0.000 description 16
- KDLHZDBZIXYQEI-UHFFFAOYSA-N palladium Substances [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 16
- 238000000634 powder X-ray diffraction Methods 0.000 description 16
- 230000002265 prevention Effects 0.000 description 16
- 239000002253 acid Substances 0.000 description 15
- 238000005755 formation reaction Methods 0.000 description 15
- 239000000651 prodrug Substances 0.000 description 15
- 229940002612 prodrugs Drugs 0.000 description 15
- 230000002829 reduced Effects 0.000 description 15
- 239000000126 substance Substances 0.000 description 15
- 239000005552 B01AC04 - Clopidogrel Substances 0.000 description 14
- 206010009802 Coagulopathy Diseases 0.000 description 14
- 108010054265 Factor VIIa Proteins 0.000 description 14
- 229940012414 Factor VIIa Drugs 0.000 description 14
- 230000000702 anti-platelet Effects 0.000 description 14
- 230000035602 clotting Effects 0.000 description 14
- 239000007788 liquid Substances 0.000 description 14
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 14
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 14
- 239000003921 oil Substances 0.000 description 14
- 235000019198 oils Nutrition 0.000 description 14
- 239000012044 organic layer Substances 0.000 description 14
- 125000001424 substituent group Chemical group 0.000 description 14
- 239000000758 substrate Substances 0.000 description 14
- 238000002560 therapeutic procedure Methods 0.000 description 14
- 229960003009 Clopidogrel Drugs 0.000 description 13
- 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 13
- 229920000669 heparin Polymers 0.000 description 13
- KWYUFKZDYYNOTN-UHFFFAOYSA-M potassium hydroxide Inorganic materials [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 13
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 13
- 210000001772 Blood Platelets Anatomy 0.000 description 12
- ZMANZCXQSJIPKH-UHFFFAOYSA-N N,N-Diethylethanamine Substances CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 12
- 239000000969 carrier Substances 0.000 description 12
- 238000002425 crystallisation Methods 0.000 description 12
- 239000010410 layer Substances 0.000 description 12
- 238000003786 synthesis reaction Methods 0.000 description 12
- 230000001732 thrombotic Effects 0.000 description 12
- 108010074860 Factor Xa Proteins 0.000 description 11
- 241000699670 Mus sp. Species 0.000 description 11
- 238000007792 addition Methods 0.000 description 11
- 230000003042 antagnostic Effects 0.000 description 11
- 239000005557 antagonist Substances 0.000 description 11
- 125000003118 aryl group Chemical group 0.000 description 11
- 238000005345 coagulation Methods 0.000 description 11
- 230000005712 crystallization Effects 0.000 description 11
- 239000003527 fibrinolytic agent Substances 0.000 description 11
- 230000000051 modifying Effects 0.000 description 11
- 239000000523 sample Substances 0.000 description 11
- 108091005771 Peptidases Proteins 0.000 description 10
- 239000004365 Protease Substances 0.000 description 10
- 229920002472 Starch Polymers 0.000 description 10
- 108010000499 Thromboplastin Proteins 0.000 description 10
- 102000002262 Thromboplastin Human genes 0.000 description 10
- NIXOWILDQLNWCW-UHFFFAOYSA-N acrylic acid Chemical compound OC(=O)C=C NIXOWILDQLNWCW-UHFFFAOYSA-N 0.000 description 10
- 201000011510 cancer Diseases 0.000 description 10
- 230000001808 coupling Effects 0.000 description 10
- 238000010168 coupling process Methods 0.000 description 10
- 238000005859 coupling reaction Methods 0.000 description 10
- 230000002354 daily Effects 0.000 description 10
- 239000007884 disintegrant Substances 0.000 description 10
- 238000000926 separation method Methods 0.000 description 10
- 235000019698 starch Nutrition 0.000 description 10
- 238000001356 surgical procedure Methods 0.000 description 10
- YXFVVABEGXRONW-UHFFFAOYSA-N toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 10
- 102000033147 ERVK-25 Human genes 0.000 description 9
- 108010048049 Factor IXa Proteins 0.000 description 9
- 102100011311 KNG1 Human genes 0.000 description 9
- GUBGYTABKSRVRQ-UUNJERMWSA-N Lactose Natural products O([C@@H]1[C@H](O)[C@H](O)[C@H](O)O[C@@H]1CO)[C@H]1[C@@H](O)[C@@H](O)[C@H](O)[C@H](CO)O1 GUBGYTABKSRVRQ-UUNJERMWSA-N 0.000 description 9
- 229940032147 Starch Drugs 0.000 description 9
- 238000002441 X-ray diffraction Methods 0.000 description 9
- WEVYAHXRMPXWCK-UHFFFAOYSA-N acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 9
- 230000037396 body weight Effects 0.000 description 9
- 238000004587 chromatography analysis Methods 0.000 description 9
- 238000000113 differential scanning calorimetry Methods 0.000 description 9
- 239000008101 lactose Substances 0.000 description 9
- GUBGYTABKSRVRQ-XLOQQCSPSA-N lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 9
- 229920000642 polymer Polymers 0.000 description 9
- 239000000843 powder Substances 0.000 description 9
- 239000002002 slurry Substances 0.000 description 9
- BZKBCQXYZZXSCO-UHFFFAOYSA-N sodium hydride Inorganic materials [H-].[Na+] BZKBCQXYZZXSCO-UHFFFAOYSA-N 0.000 description 9
- 239000008107 starch Substances 0.000 description 9
- 235000000346 sugar Nutrition 0.000 description 9
- 239000003765 sweetening agent Substances 0.000 description 9
- 108010080865 Factor XII Proteins 0.000 description 8
- 102000000429 Factor XII Human genes 0.000 description 8
- 241000283973 Oryctolagus cuniculus Species 0.000 description 8
- 238000010928 TGA analysis Methods 0.000 description 8
- 108090000373 Tissue plasminogen activator Proteins 0.000 description 8
- 230000017531 blood circulation Effects 0.000 description 8
- 239000007891 compressed tablet Substances 0.000 description 8
- 239000012043 crude product Substances 0.000 description 8
- RTZKZFJDLAIYFH-UHFFFAOYSA-N diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 8
- LYCAIKOWRPUZTN-UHFFFAOYSA-N glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 8
- 150000002466 imines Chemical class 0.000 description 8
- 239000000314 lubricant Substances 0.000 description 8
- 238000005259 measurement Methods 0.000 description 8
- 125000002950 monocyclic group Chemical group 0.000 description 8
- 238000010992 reflux Methods 0.000 description 8
- 238000004007 reversed phase HPLC Methods 0.000 description 8
- 230000002194 synthesizing Effects 0.000 description 8
- 238000002411 thermogravimetry Methods 0.000 description 8
- HVYWMOMLDIMFJA-DPAQBDIFSA-N (3β)-Cholest-5-en-3-ol Chemical compound C1C=C2C[C@@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)CCCC(C)C)[C@@]1(C)CC2 HVYWMOMLDIMFJA-DPAQBDIFSA-N 0.000 description 7
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 description 7
- PJVWKTKQMONHTI-UHFFFAOYSA-N 4-hydroxy-3-(3-oxo-1-phenylbutyl)-1-benzopyran-2-one Chemical compound OC=1C2=CC=CC=C2OC(=O)C=1C(CC(=O)C)C1=CC=CC=C1 PJVWKTKQMONHTI-UHFFFAOYSA-N 0.000 description 7
- 229960004676 ANTITHROMBOTIC AGENTS Drugs 0.000 description 7
- 101700042506 HIRUD Proteins 0.000 description 7
- 206010018987 Haemorrhage Diseases 0.000 description 7
- 229940006607 Hirudin Drugs 0.000 description 7
- 229920002594 Polyethylene Glycol 8000 Polymers 0.000 description 7
- 102000012479 Serine Proteases Human genes 0.000 description 7
- 108010022999 Serine Proteases Proteins 0.000 description 7
- 102000003978 Tissue plasminogen activator Human genes 0.000 description 7
- 239000011230 binding agent Substances 0.000 description 7
- 238000001816 cooling Methods 0.000 description 7
- 238000005384 cross polarization magic-angle spinning Methods 0.000 description 7
- 230000002950 deficient Effects 0.000 description 7
- 239000003085 diluting agent Substances 0.000 description 7
- 238000002474 experimental method Methods 0.000 description 7
- 230000003480 fibrinolytic Effects 0.000 description 7
- 235000003599 food sweetener Nutrition 0.000 description 7
- 238000009472 formulation Methods 0.000 description 7
- 230000023597 hemostasis Effects 0.000 description 7
- 125000004435 hydrogen atoms Chemical group [H]* 0.000 description 7
- 238000006460 hydrolysis reaction Methods 0.000 description 7
- 238000001990 intravenous administration Methods 0.000 description 7
- WMFOQBRAJBCJND-UHFFFAOYSA-M lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 7
- 239000003055 low molecular weight heparin Substances 0.000 description 7
- 235000019359 magnesium stearate Nutrition 0.000 description 7
- 230000003000 nontoxic Effects 0.000 description 7
- 231100000252 nontoxic Toxicity 0.000 description 7
- 238000001144 powder X-ray diffraction data Methods 0.000 description 7
- 239000002464 receptor antagonist Substances 0.000 description 7
- 230000001603 reducing Effects 0.000 description 7
- 238000010898 silica gel chromatography Methods 0.000 description 7
- 238000003756 stirring Methods 0.000 description 7
- 229960000187 tissue plasminogen activator Drugs 0.000 description 7
- WQZGKKKJIJFFOK-VFUOTHLCSA-N β-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 7
- 108010058207 Anistreplase Proteins 0.000 description 6
- CZMRCDWAGMRECN-UGDNZRGBSA-N D-sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 6
- HTTJABKRGRZYRN-UHFFFAOYSA-N Enoxaparin 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 6
- 102000004190 Enzymes Human genes 0.000 description 6
- 108090000790 Enzymes Proteins 0.000 description 6
- 108010071241 Factor XIIa Proteins 0.000 description 6
- 229960002897 Heparin Drugs 0.000 description 6
- ZFGMDIBRIDKWMY-PASTXAENSA-N Heparin Chemical compound CC(O)=N[C@@H]1[C@@H](O)[C@H](O)[C@@H](COS(O)(=O)=O)O[C@@H]1O[C@@H]1[C@@H](C(O)=O)O[C@@H](O[C@H]2[C@@H]([C@@H](OS(O)(=O)=O)[C@@H](O[C@@H]3[C@@H](OC(O)[C@H](OS(O)(=O)=O)[C@H]3O)C(O)=O)O[C@@H]2O)CS(O)(=O)=O)[C@H](O)[C@H]1O ZFGMDIBRIDKWMY-PASTXAENSA-N 0.000 description 6
- 108010000487 High-Molecular-Weight Kininogen Proteins 0.000 description 6
- 206010020772 Hypertension Diseases 0.000 description 6
- CGIGDMFJXJATDK-UHFFFAOYSA-N Indometacin Chemical compound CC1=C(CC(O)=O)C2=CC(OC)=CC=C2N1C(=O)C1=CC=C(Cl)C=C1 CGIGDMFJXJATDK-UHFFFAOYSA-N 0.000 description 6
- 241000124008 Mammalia Species 0.000 description 6
- 241001465754 Metazoa Species 0.000 description 6
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 6
- GEHJYWRUCIMESM-UHFFFAOYSA-L Sodium sulfite Chemical compound [Na+].[Na+].[O-]S([O-])=O GEHJYWRUCIMESM-UHFFFAOYSA-L 0.000 description 6
- CZMRCDWAGMRECN-GDQSFJPYSA-N Sucrose Natural products O([C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@H](CO)O1)[C@@]1(CO)[C@H](O)[C@@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-GDQSFJPYSA-N 0.000 description 6
- 229960005356 Urokinase Drugs 0.000 description 6
- 108090000435 Urokinase-type plasminogen activator Proteins 0.000 description 6
- 102000003990 Urokinase-type plasminogen activator Human genes 0.000 description 6
- 229960005080 Warfarin Drugs 0.000 description 6
- CSCPPACGZOOCGX-UHFFFAOYSA-N acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 6
- 150000001408 amides Chemical class 0.000 description 6
- 150000001412 amines Chemical class 0.000 description 6
- 230000002785 anti-thrombosis Effects 0.000 description 6
- XKRFYHLGVUSROY-UHFFFAOYSA-N argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 6
- 235000010980 cellulose Nutrition 0.000 description 6
- 229920002678 cellulose Polymers 0.000 description 6
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 6
- 230000000875 corresponding Effects 0.000 description 6
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 6
- 239000000706 filtrate Substances 0.000 description 6
- 239000007903 gelatin capsule Substances 0.000 description 6
- PEDCQBHIVMGVHV-UHFFFAOYSA-N glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 6
- VLKZOEOYAKHREP-UHFFFAOYSA-N hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 6
- 239000004615 ingredient Substances 0.000 description 6
- RLOWWWKZYUNIDI-UHFFFAOYSA-N phosphinic chloride Chemical compound ClP=O RLOWWWKZYUNIDI-UHFFFAOYSA-N 0.000 description 6
- DNIAPMSPPWPWGF-UHFFFAOYSA-N propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 6
- 239000011734 sodium Substances 0.000 description 6
- 239000011877 solvent mixture Substances 0.000 description 6
- 241000894007 species Species 0.000 description 6
- 239000005720 sucrose Substances 0.000 description 6
- 230000002459 sustained Effects 0.000 description 6
- 230000001225 therapeutic Effects 0.000 description 6
- 238000001757 thermogravimetry curve Methods 0.000 description 6
- 239000003868 thrombin inhibitor Substances 0.000 description 6
- 206010000891 Acute myocardial infarction Diseases 0.000 description 5
- WQZGKKKJIJFFOK-GASJEMHNSA-N D-Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 5
- 206010012601 Diabetes mellitus Diseases 0.000 description 5
- 229950003499 FIBRIN Drugs 0.000 description 5
- 102000009123 Fibrin Human genes 0.000 description 5
- BWGVNKXGVNDBDI-UHFFFAOYSA-N Fibrin Chemical compound CNC(=O)CNC(=O)CN BWGVNKXGVNDBDI-UHFFFAOYSA-N 0.000 description 5
- 108010073385 Fibrin Proteins 0.000 description 5
- MFRIHAYPQRLWNB-UHFFFAOYSA-N Sodium tert-butoxide Chemical compound [Na+].CC(C)(C)[O-] MFRIHAYPQRLWNB-UHFFFAOYSA-N 0.000 description 5
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 5
- 125000003342 alkenyl group Chemical group 0.000 description 5
- 150000001413 amino acids Chemical class 0.000 description 5
- 239000002220 antihypertensive agent Substances 0.000 description 5
- 235000020127 ayran Nutrition 0.000 description 5
- 239000002585 base Substances 0.000 description 5
- 125000002618 bicyclic heterocycle group Chemical group 0.000 description 5
- 230000023555 blood coagulation Effects 0.000 description 5
- 235000012970 cakes Nutrition 0.000 description 5
- 239000001913 cellulose Substances 0.000 description 5
- 239000003153 chemical reaction reagent Substances 0.000 description 5
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 5
- 150000002148 esters Chemical class 0.000 description 5
- 239000008103 glucose Substances 0.000 description 5
- 230000012010 growth Effects 0.000 description 5
- 239000012535 impurity Substances 0.000 description 5
- 238000000338 in vitro Methods 0.000 description 5
- 229910052740 iodine Inorganic materials 0.000 description 5
- KFZMGEQAYNKOFK-UHFFFAOYSA-N iso-propanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 5
- 150000002632 lipids Chemical class 0.000 description 5
- VASIZKWUTCETSD-UHFFFAOYSA-N manganese(II) oxide Inorganic materials [Mn]=O VASIZKWUTCETSD-UHFFFAOYSA-N 0.000 description 5
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 5
- 150000002829 nitrogen Chemical group 0.000 description 5
- 229920002866 paraformaldehyde Polymers 0.000 description 5
- 239000003182 parenteral nutrition solution Substances 0.000 description 5
- 239000002245 particle Substances 0.000 description 5
- 230000037361 pathway Effects 0.000 description 5
- 239000000106 platelet aggregation inhibitor Substances 0.000 description 5
- 102000005962 receptors Human genes 0.000 description 5
- 108020003175 receptors Proteins 0.000 description 5
- 239000000725 suspension Substances 0.000 description 5
- 125000001544 thienyl group Chemical group 0.000 description 5
- 229960000103 thrombolytic agents Drugs 0.000 description 5
- 210000001519 tissues Anatomy 0.000 description 5
- 230000001131 transforming Effects 0.000 description 5
- 230000002792 vascular Effects 0.000 description 5
- 239000003981 vehicle Substances 0.000 description 5
- LNAZSHAWQACDHT-XIYTZBAFSA-N (2R,3R,4S,5R,6S)-4,5-dimethoxy-2-(methoxymethyl)-3-[(2S,3R,4S,5R,6R)-3,4,5-trimethoxy-6-(methoxymethyl)oxan-2-yl]oxy-6-[(2R,3R,4S,5R,6R)-4,5,6-trimethoxy-2-(methoxymethyl)oxan-3-yl]oxyoxane Chemical compound CO[C@@H]1[C@@H](OC)[C@H](OC)[C@@H](COC)O[C@H]1O[C@H]1[C@H](OC)[C@@H](OC)[C@H](O[C@H]2[C@@H]([C@@H](OC)[C@H](OC)O[C@@H]2COC)OC)O[C@@H]1COC LNAZSHAWQACDHT-XIYTZBAFSA-N 0.000 description 4
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 4
- LMDZBCPBFSXMTL-UHFFFAOYSA-N 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide Substances CCN=C=NCCCN(C)C LMDZBCPBFSXMTL-UHFFFAOYSA-N 0.000 description 4
- XRZWVSXEDRYQGC-UHFFFAOYSA-N 4-cyclohexylpyrrolidin-1-ium-2-carboxylate Chemical compound C1NC(C(=O)O)CC1C1CCCCC1 XRZWVSXEDRYQGC-UHFFFAOYSA-N 0.000 description 4
- CYJZJGYYTFQQBY-UHFFFAOYSA-N 5-bromoisoquinoline Chemical compound N1=CC=C2C(Br)=CC=CC2=C1 CYJZJGYYTFQQBY-UHFFFAOYSA-N 0.000 description 4
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonium chloride Substances [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 4
- 229960000983 Anistreplase Drugs 0.000 description 4
- KXNPVXPOPUZYGB-XYVMCAHJSA-N Argatroban Chemical compound OC(=O)[C@H]1C[C@H](C)CCN1C(=O)[C@H](CCCN=C(N)N)NS(=O)(=O)C1=CC=CC2=C1NC[C@H](C)C2 KXNPVXPOPUZYGB-XYVMCAHJSA-N 0.000 description 4
- 239000005528 B01AC05 - Ticlopidine Substances 0.000 description 4
- 102000015081 Blood Coagulation Factors Human genes 0.000 description 4
- 108010039209 Blood Coagulation Factors Proteins 0.000 description 4
- YSHOWEKUVWPFNR-UHFFFAOYSA-N Burgess reagent Chemical compound CC[N+](CC)(CC)S(=O)(=O)N=C([O-])OC YSHOWEKUVWPFNR-UHFFFAOYSA-N 0.000 description 4
- FERIUCNNQQJTOY-UHFFFAOYSA-N Butanoic acid Chemical compound CCCC(O)=O FERIUCNNQQJTOY-UHFFFAOYSA-N 0.000 description 4
- DKPFZGUDAPQIHT-UHFFFAOYSA-N Butyl acetate Natural products CCCCOC(C)=O DKPFZGUDAPQIHT-UHFFFAOYSA-N 0.000 description 4
- OSGAYBCDTDRGGQ-UHFFFAOYSA-L Calcium sulfate Chemical compound [Ca+2].[O-]S([O-])(=O)=O OSGAYBCDTDRGGQ-UHFFFAOYSA-L 0.000 description 4
- 206010061592 Cardiac fibrillation Diseases 0.000 description 4
- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 description 4
- FBPFZTCFMRRESA-JGWLITMVSA-N D-glucitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-JGWLITMVSA-N 0.000 description 4
- 206010014522 Embolism venous Diseases 0.000 description 4
- 229940088598 Enzyme Drugs 0.000 description 4
- 229960004468 Eptifibatide Drugs 0.000 description 4
- GLGOPUHVAZCPRB-LROMGURASA-N Eptifibatide Chemical compound N1C(=O)[C@H](CC(O)=O)NC(=O)CNC(=O)[C@H](CCCCNC(=N)N)NC(=O)CCSSC[C@@H](C(N)=O)NC(=O)[C@@H]2CCCN2C(=O)[C@@H]1CC1=CN=C2[C]1C=CC=C2 GLGOPUHVAZCPRB-LROMGURASA-N 0.000 description 4
- 102100015239 F2 Human genes 0.000 description 4
- 102100006624 F9 Human genes 0.000 description 4
- 210000001035 Gastrointestinal Tract Anatomy 0.000 description 4
- 239000007995 HEPES buffer Substances 0.000 description 4
- 229940088597 Hormone Drugs 0.000 description 4
- 102000004311 Liver X Receptors Human genes 0.000 description 4
- 108090000865 Liver X Receptors Proteins 0.000 description 4
- 229960002900 Methylcellulose Drugs 0.000 description 4
- LXCFILQKKLGQFO-UHFFFAOYSA-N Methylparaben Chemical group COC(=O)C1=CC=C(O)C=C1 LXCFILQKKLGQFO-UHFFFAOYSA-N 0.000 description 4
- 102000032744 PAR-1 Receptor Human genes 0.000 description 4
- 108010070519 PAR-1 Receptor Proteins 0.000 description 4
- QYSPLQLAKJAUJT-UHFFFAOYSA-N Piroxicam Chemical compound OC=1C2=CC=CC=C2S(=O)(=O)N(C)C=1C(=O)NC1=CC=CC=N1 QYSPLQLAKJAUJT-UHFFFAOYSA-N 0.000 description 4
- 229920000954 Polyglycolide Polymers 0.000 description 4
- 229940039716 Prothrombin Drugs 0.000 description 4
- 108010094028 Prothrombin Proteins 0.000 description 4
- 229910019023 PtO Inorganic materials 0.000 description 4
- QIQXTHQIDYTFRH-UHFFFAOYSA-N Stearic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 4
- 108010023197 Streptokinase Proteins 0.000 description 4
- 229960005202 Streptokinase Drugs 0.000 description 4
- FYSNRJHAOHDILO-UHFFFAOYSA-N Thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 4
- 229960005001 Ticlopidine Drugs 0.000 description 4
- PHWBOXQYWZNQIN-UHFFFAOYSA-N Ticlopidine Chemical compound ClC1=CC=CC=C1CN1CC(C=CS2)=C2CC1 PHWBOXQYWZNQIN-UHFFFAOYSA-N 0.000 description 4
- 208000004043 Venous Thromboembolism Diseases 0.000 description 4
- 125000000304 alkynyl group Chemical group 0.000 description 4
- 230000004075 alteration Effects 0.000 description 4
- 239000003524 antilipemic agent Substances 0.000 description 4
- 229960003856 argatroban Drugs 0.000 description 4
- 239000012298 atmosphere Substances 0.000 description 4
- 125000003785 benzimidazolyl group Chemical group N1=C(NC2=C1C=CC=C2)* 0.000 description 4
- 125000002527 bicyclic carbocyclic group Chemical group 0.000 description 4
- 125000002619 bicyclic group Chemical group 0.000 description 4
- 230000000740 bleeding Effects 0.000 description 4
- 231100000319 bleeding Toxicity 0.000 description 4
- 239000003114 blood coagulation factor Substances 0.000 description 4
- UXVMQQNJUSDDNG-UHFFFAOYSA-L cacl2 Chemical compound [Cl-].[Cl-].[Ca+2] UXVMQQNJUSDDNG-UHFFFAOYSA-L 0.000 description 4
- 239000001110 calcium chloride Substances 0.000 description 4
- 229910001628 calcium chloride Inorganic materials 0.000 description 4
- 238000007906 compression Methods 0.000 description 4
- 229920001577 copolymer Polymers 0.000 description 4
- 230000001419 dependent Effects 0.000 description 4
- 238000011161 development Methods 0.000 description 4
- 230000018109 developmental process Effects 0.000 description 4
- 238000006073 displacement reaction Methods 0.000 description 4
- 230000002600 fibrillogenic Effects 0.000 description 4
- WSFSSNUMVMOOMR-UHFFFAOYSA-N formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 description 4
- 238000004108 freeze drying Methods 0.000 description 4
- 125000002541 furyl group Chemical group 0.000 description 4
- 229910052736 halogen Inorganic materials 0.000 description 4
- 150000002367 halogens Chemical class 0.000 description 4
- 239000008079 hexane Substances 0.000 description 4
- 239000005556 hormone Substances 0.000 description 4
- 239000001257 hydrogen Substances 0.000 description 4
- 125000002883 imidazolyl group Chemical group 0.000 description 4
- 125000003392 indanyl group Chemical group C1(CCC2=CC=CC=C12)* 0.000 description 4
- 230000000977 initiatory Effects 0.000 description 4
- 125000000842 isoxazolyl group Chemical group 0.000 description 4
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 4
- 230000001404 mediated Effects 0.000 description 4
- 229920000609 methyl cellulose Polymers 0.000 description 4
- 235000010981 methylcellulose Nutrition 0.000 description 4
- 239000001923 methylcellulose Substances 0.000 description 4
- 125000001624 naphthyl group Chemical group 0.000 description 4
- 125000004433 nitrogen atoms Chemical group N* 0.000 description 4
- 125000002971 oxazolyl group Chemical group 0.000 description 4
- GEIAQOFPUVMAGM-UHFFFAOYSA-N oxozirconium Chemical compound [Zr]=O GEIAQOFPUVMAGM-UHFFFAOYSA-N 0.000 description 4
- 125000004430 oxygen atoms Chemical group O* 0.000 description 4
- 229960002702 piroxicam Drugs 0.000 description 4
- 239000002797 plasminogen activator inhibitor Substances 0.000 description 4
- 229920003023 plastic Polymers 0.000 description 4
- 229920000747 poly(lactic acid) polymer Polymers 0.000 description 4
- 229920001223 polyethylene glycol Polymers 0.000 description 4
- 239000004633 polyglycolic acid Substances 0.000 description 4
- 239000004626 polylactic acid Substances 0.000 description 4
- WCUXLLCKKVVCTQ-UHFFFAOYSA-M potassium chloride Chemical compound [Cl-].[K+] WCUXLLCKKVVCTQ-UHFFFAOYSA-M 0.000 description 4
- 238000002953 preparative HPLC Methods 0.000 description 4
- 239000003755 preservative agent Substances 0.000 description 4
- 230000002035 prolonged Effects 0.000 description 4
- 125000006239 protecting group Chemical group 0.000 description 4
- 239000008213 purified water Substances 0.000 description 4
- 125000003373 pyrazinyl group Chemical group 0.000 description 4
- 125000003226 pyrazolyl group Chemical group 0.000 description 4
- 239000007909 solid dosage form Substances 0.000 description 4
- 239000000600 sorbitol Substances 0.000 description 4
- 235000010356 sorbitol Nutrition 0.000 description 4
- 238000001228 spectrum Methods 0.000 description 4
- 238000009987 spinning Methods 0.000 description 4
- 150000008163 sugars Chemical class 0.000 description 4
- 125000004434 sulfur atoms Chemical group 0.000 description 4
- 239000006188 syrup Substances 0.000 description 4
- 235000020357 syrup Nutrition 0.000 description 4
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 description 4
- 125000003831 tetrazolyl group Chemical group 0.000 description 4
- 125000000335 thiazolyl group Chemical group 0.000 description 4
- 125000004306 triazinyl group Chemical group 0.000 description 4
- 125000005955 1H-indazolyl group Chemical group 0.000 description 3
- TYMLOMAKGOJONV-UHFFFAOYSA-N 4-Nitroaniline Chemical compound NC1=CC=C([N+]([O-])=O)C=C1 TYMLOMAKGOJONV-UHFFFAOYSA-N 0.000 description 3
- 229940035674 ANESTHETICS Drugs 0.000 description 3
- 108010004463 Abciximab Proteins 0.000 description 3
- OZAIFHULBGXAKX-VAWYXSNFSA-N Azobisisobutyronitrile Chemical compound N#CC(C)(C)\N=N\C(C)(C)C#N OZAIFHULBGXAKX-VAWYXSNFSA-N 0.000 description 3
- MUALRAIOVNYAIW-UHFFFAOYSA-N BINAP Chemical compound C1=CC=CC=C1P(C=1C(=C2C=CC=CC2=CC=1)C=1C2=CC=CC=C2C=CC=1P(C=1C=CC=CC=1)C=1C=CC=CC=1)C1=CC=CC=C1 MUALRAIOVNYAIW-UHFFFAOYSA-N 0.000 description 3
- 238000006407 Bischler-Napieralski reaction Methods 0.000 description 3
- 210000001736 Capillaries Anatomy 0.000 description 3
- 208000008787 Cardiovascular Disease Diseases 0.000 description 3
- 206010007688 Carotid artery thrombosis Diseases 0.000 description 3
- 229940107161 Cholesterol Drugs 0.000 description 3
- 206010070954 Congenital hypercoagulation Diseases 0.000 description 3
- 229960000913 Crospovidone Drugs 0.000 description 3
- FBPFZTCFMRRESA-KAZBKCHUSA-N D-Mannitol Natural products OC[C@@H](O)[C@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KAZBKCHUSA-N 0.000 description 3
- OEHFRZLKGRKFAS-UHFFFAOYSA-N Droxicam Chemical compound C12=CC=CC=C2S(=O)(=O)N(C)C(C2=O)=C1OC(=O)N2C1=CC=CC=N1 OEHFRZLKGRKFAS-UHFFFAOYSA-N 0.000 description 3
- 108010056764 Eptifibatide Proteins 0.000 description 3
- 108010076282 Factor IX Proteins 0.000 description 3
- HEFNNWSXXWATRW-UHFFFAOYSA-N Ibuprofen Chemical compound CC(C)CC1=CC=C(C(C)C(O)=O)C=C1 HEFNNWSXXWATRW-UHFFFAOYSA-N 0.000 description 3
- 229960000905 Indomethacin Drugs 0.000 description 3
- 206010061255 Ischaemia Diseases 0.000 description 3
- AWJUIBRHMBBTKR-UHFFFAOYSA-N Isoquinoline Chemical compound C1=NC=CC2=CC=CC=C21 AWJUIBRHMBBTKR-UHFFFAOYSA-N 0.000 description 3
- 206010058467 Lung neoplasm malignant Diseases 0.000 description 3
- 238000005004 MAS NMR spectroscopy Methods 0.000 description 3
- FBPFZTCFMRRESA-KVTDHHQDSA-N Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 3
- 229940103185 Mefenamate Drugs 0.000 description 3
- HYYBABOKPJLUIN-UHFFFAOYSA-N Mefenamic acid Chemical compound CC1=CC=CC(NC=2C(=CC=CC=2)C(O)=O)=C1C HYYBABOKPJLUIN-UHFFFAOYSA-N 0.000 description 3
- KXKVLQRXCPHEJC-UHFFFAOYSA-N Methyl acetate Natural products COC(C)=O KXKVLQRXCPHEJC-UHFFFAOYSA-N 0.000 description 3
- 229920000881 Modified starch Polymers 0.000 description 3
- JRNVZBWKYDBUCA-UHFFFAOYSA-N N-Chlorosuccinimide Substances ClN1C(=O)CCC1=O JRNVZBWKYDBUCA-UHFFFAOYSA-N 0.000 description 3
- WHNWPMSKXPGLAX-UHFFFAOYSA-N N-Vinylpyrrolidone Chemical compound C=CN1CCCC1=O WHNWPMSKXPGLAX-UHFFFAOYSA-N 0.000 description 3
- 238000005481 NMR spectroscopy Methods 0.000 description 3
- CMWTZPSULFXXJA-VIFPVBQESA-N Naproxen Chemical compound C1=C([C@H](C)C(O)=O)C=CC2=CC(OC)=CC=C21 CMWTZPSULFXXJA-VIFPVBQESA-N 0.000 description 3
- 206010028980 Neoplasm Diseases 0.000 description 3
- 102000012132 Peroxisome proliferator-activated receptor gamma Human genes 0.000 description 3
- SCVFZCLFOSHCOH-UHFFFAOYSA-M Potassium acetate Chemical compound [K+].CC([O-])=O SCVFZCLFOSHCOH-UHFFFAOYSA-M 0.000 description 3
- QELSKZZBTMNZEB-UHFFFAOYSA-N Propylparaben Chemical compound CCCOC(=O)C1=CC=C(O)C=C1 QELSKZZBTMNZEB-UHFFFAOYSA-N 0.000 description 3
- 241000700159 Rattus Species 0.000 description 3
- 206010059054 Shunt thrombosis Diseases 0.000 description 3
- 229940083542 Sodium Drugs 0.000 description 3
- 229960003329 Sulfinpyrazone Drugs 0.000 description 3
- 229960000894 Sulindac Drugs 0.000 description 3
- MLKXDPUZXIRXEP-MFOYZWKCSA-N Sulindac Chemical compound CC1=C(CC(O)=O)C2=CC(F)=CC=C2\C1=C/C1=CC=C(S(C)=O)C=C1 MLKXDPUZXIRXEP-MFOYZWKCSA-N 0.000 description 3
- UWYZHKAOTLEWKK-UHFFFAOYSA-N Tetrahydroisoquinoline Chemical compound C1=CC=C2CNCCC2=C1 UWYZHKAOTLEWKK-UHFFFAOYSA-N 0.000 description 3
- 206010053648 Vascular occlusion Diseases 0.000 description 3
- 210000003462 Veins Anatomy 0.000 description 3
- 229960000446 abciximab Drugs 0.000 description 3
- 238000002835 absorbance Methods 0.000 description 3
- 125000001931 aliphatic group Chemical group 0.000 description 3
- 125000002947 alkylene group Chemical group 0.000 description 3
- 235000019270 ammonium chloride Nutrition 0.000 description 3
- 230000003444 anaesthetic Effects 0.000 description 3
- 238000004458 analytical method Methods 0.000 description 3
- 239000012296 anti-solvent Substances 0.000 description 3
- 239000003529 anticholesteremic agent Substances 0.000 description 3
- 229910052786 argon Inorganic materials 0.000 description 3
- 125000005605 benzo group Chemical group 0.000 description 3
- 125000001164 benzothiazolyl group Chemical group S1C(=NC2=C1C=CC=C2)* 0.000 description 3
- WVDDGKGOMKODPV-UHFFFAOYSA-N benzyl alcohol Chemical compound OCC1=CC=CC=C1 WVDDGKGOMKODPV-UHFFFAOYSA-N 0.000 description 3
- VEXZGXHMUGYJMC-UHFFFAOYSA-M chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 3
- 235000012000 cholesterol Nutrition 0.000 description 3
- 239000003593 chromogenic compound Substances 0.000 description 3
- 229940075614 colloidal silicon dioxide Drugs 0.000 description 3
- 239000003086 colorant Substances 0.000 description 3
- 238000007796 conventional method Methods 0.000 description 3
- 239000010949 copper Substances 0.000 description 3
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 3
- NLUNLVTVUDIHFE-UHFFFAOYSA-N cyclooctylcyclooctane Chemical compound C1CCCCCCC1C1CCCCCCC1 NLUNLVTVUDIHFE-UHFFFAOYSA-N 0.000 description 3
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 3
- DCOPUUMXTXDBNB-UHFFFAOYSA-N diclofenac Chemical compound OC(=O)CC1=CC=CC=C1NC1=C(Cl)C=CC=C1Cl DCOPUUMXTXDBNB-UHFFFAOYSA-N 0.000 description 3
- 229960001259 diclofenac Drugs 0.000 description 3
- 238000004821 distillation Methods 0.000 description 3
- 229960001850 droxicam Drugs 0.000 description 3
- 239000003995 emulsifying agent Substances 0.000 description 3
- 238000001704 evaporation Methods 0.000 description 3
- 229960004222 factor IX Drugs 0.000 description 3
- 201000007219 factor XI deficiency Diseases 0.000 description 3
- BDAGIHXWWSANSR-UHFFFAOYSA-N formic acid Chemical compound OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 3
- 239000012458 free base Substances 0.000 description 3
- 239000003193 general anesthetic agent Substances 0.000 description 3
- 150000002334 glycols Chemical class 0.000 description 3
- 239000008187 granular material Substances 0.000 description 3
- 230000003179 granulation Effects 0.000 description 3
- 230000036541 health Effects 0.000 description 3
- 238000010438 heat treatment Methods 0.000 description 3
- 150000002430 hydrocarbons Chemical group 0.000 description 3
- UFHFLCQGNIYNRP-UHFFFAOYSA-N hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 3
- 239000002471 hydroxymethylglutaryl coenzyme A reductase inhibitor Substances 0.000 description 3
- 229960001680 ibuprofen Drugs 0.000 description 3
- 125000002632 imidazolidinyl group Chemical group 0.000 description 3
- 230000001976 improved Effects 0.000 description 3
- 125000003387 indolinyl group Chemical group N1(CCC2=CC=CC=C12)* 0.000 description 3
- 238000001802 infusion Methods 0.000 description 3
- 230000003993 interaction Effects 0.000 description 3
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical compound II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 description 3
- 239000011630 iodine Substances 0.000 description 3
- 125000002183 isoquinolinyl group Chemical group C1(=NC=CC2=CC=CC=C12)* 0.000 description 3
- 201000005202 lung cancer Diseases 0.000 description 3
- 239000000594 mannitol Substances 0.000 description 3
- 235000010355 mannitol Nutrition 0.000 description 3
- 239000002609 media Substances 0.000 description 3
- 239000004292 methyl p-hydroxybenzoate Substances 0.000 description 3
- 235000010270 methyl p-hydroxybenzoate Nutrition 0.000 description 3
- 229960002216 methylparaben Drugs 0.000 description 3
- 150000007522 mineralic acids Chemical class 0.000 description 3
- 235000019426 modified starch Nutrition 0.000 description 3
- QDHHCQZDFGDHMP-UHFFFAOYSA-N monochloramine Chemical compound ClN QDHHCQZDFGDHMP-UHFFFAOYSA-N 0.000 description 3
- 125000002757 morpholinyl group Chemical group 0.000 description 3
- 230000035772 mutation Effects 0.000 description 3
- IMNFDUFMRHMDMM-UHFFFAOYSA-N n-heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 3
- 229960002009 naproxen Drugs 0.000 description 3
- PVNIIMVLHYAWGP-UHFFFAOYSA-N nicotinic acid Chemical compound OC(=O)C1=CC=CN=C1 PVNIIMVLHYAWGP-UHFFFAOYSA-N 0.000 description 3
- 229940021182 non-steroidal anti-inflammatory drugs Drugs 0.000 description 3
- 230000003287 optical Effects 0.000 description 3
- 239000012074 organic phase Substances 0.000 description 3
- 125000001715 oxadiazolyl group Chemical group 0.000 description 3
- 125000000160 oxazolidinyl group Chemical group 0.000 description 3
- 230000003647 oxidation Effects 0.000 description 3
- 238000007254 oxidation reaction Methods 0.000 description 3
- 239000000123 paper Substances 0.000 description 3
- 238000007911 parenteral administration Methods 0.000 description 3
- 239000003208 petroleum Substances 0.000 description 3
- 239000000546 pharmaceutic aid Substances 0.000 description 3
- 239000004033 plastic Substances 0.000 description 3
- 200000000002 platelet activation Diseases 0.000 description 3
- 125000003367 polycyclic group Polymers 0.000 description 3
- 235000013809 polyvinylpolypyrrolidone Nutrition 0.000 description 3
- 229920000523 polyvinylpolypyrrolidone Polymers 0.000 description 3
- 230000035935 pregnancy Effects 0.000 description 3
- 230000002335 preservative Effects 0.000 description 3
- 230000000019 pro-fibrinolytic Effects 0.000 description 3
- BDERNNFJNOPAEC-UHFFFAOYSA-N propanol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 3
- XBDQKXXYIPTUBI-UHFFFAOYSA-M propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 description 3
- 235000010232 propyl p-hydroxybenzoate Nutrition 0.000 description 3
- 239000004405 propyl p-hydroxybenzoate Substances 0.000 description 3
- 229960003415 propylparaben Drugs 0.000 description 3
- PAQZWJGSJMLPMG-UHFFFAOYSA-N propylphosphonic anhydride Substances CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1 PAQZWJGSJMLPMG-UHFFFAOYSA-N 0.000 description 3
- 230000002633 protecting Effects 0.000 description 3
- 102000004169 proteins and genes Human genes 0.000 description 3
- 108090000623 proteins and genes Proteins 0.000 description 3
- 230000002797 proteolythic Effects 0.000 description 3
- 239000003586 protic polar solvent Substances 0.000 description 3
- 125000000714 pyrimidinyl group Chemical group 0.000 description 3
- 125000000168 pyrrolyl group Chemical group 0.000 description 3
- 125000002294 quinazolinyl group Chemical group N1=C(N=CC2=CC=CC=C12)* 0.000 description 3
- 125000002943 quinolinyl group Chemical group N1=C(C=CC2=CC=CC=C12)* 0.000 description 3
- 238000001953 recrystallisation Methods 0.000 description 3
- 238000011160 research Methods 0.000 description 3
- KEAYESYHFKHZAL-UHFFFAOYSA-N sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 3
- 229910052708 sodium Inorganic materials 0.000 description 3
- 239000012064 sodium phosphate buffer Substances 0.000 description 3
- 229920003109 sodium starch glycolate Polymers 0.000 description 3
- 239000008109 sodium starch glycolate Substances 0.000 description 3
- 229940079832 sodium starch glycolate Drugs 0.000 description 3
- 235000010265 sodium sulphite Nutrition 0.000 description 3
- 238000000371 solid-state nuclear magnetic resonance spectroscopy Methods 0.000 description 3
- 239000003381 stabilizer Substances 0.000 description 3
- 230000001954 sterilising Effects 0.000 description 3
- 238000004659 sterilization and disinfection Methods 0.000 description 3
- 238000007920 subcutaneous administration Methods 0.000 description 3
- AUMHDRMJJNZTPB-UHFFFAOYSA-N sulfinpyrazone Chemical compound O=C1N(C=2C=CC=CC=2)N(C=2C=CC=CC=2)C(O)=C1CCS(=O)C1=CC=CC=C1 AUMHDRMJJNZTPB-UHFFFAOYSA-N 0.000 description 3
- NINIDFKCEFEMDL-UHFFFAOYSA-N sulfur Chemical group [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 3
- 229910052717 sulfur Inorganic materials 0.000 description 3
- FCMLWBBLOASUSO-UHFFFAOYSA-N tert-butyl 3-oxopiperazine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CCNC(=O)C1 FCMLWBBLOASUSO-UHFFFAOYSA-N 0.000 description 3
- ISXSCDLOGDJUNJ-UHFFFAOYSA-N tert-butyl prop-2-enoate Chemical compound CC(C)(C)OC(=O)C=C ISXSCDLOGDJUNJ-UHFFFAOYSA-N 0.000 description 3
- 125000003718 tetrahydrofuranyl group Chemical group 0.000 description 3
- 230000002537 thrombolytic Effects 0.000 description 3
- COKMIXFXJJXBQG-NRFANRHFSA-N tirofiban Chemical compound C1=CC(C[C@H](NS(=O)(=O)CCCC)C(O)=O)=CC=C1OCCCCC1CCNCC1 COKMIXFXJJXBQG-NRFANRHFSA-N 0.000 description 3
- 229960003425 tirofiban Drugs 0.000 description 3
- 238000000844 transformation Methods 0.000 description 3
- 125000001425 triazolyl group Chemical group 0.000 description 3
- ITMCEJHCFYSIIV-UHFFFAOYSA-M triflate Chemical compound [O-]S(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-M 0.000 description 3
- CYPYTURSJDMMMP-WVCUSYJESA-N (1E,4E)-1,5-diphenylpenta-1,4-dien-3-one;palladium Chemical compound [Pd].[Pd].C=1C=CC=CC=1\C=C\C(=O)\C=C\C1=CC=CC=C1.C=1C=CC=CC=1\C=C\C(=O)\C=C\C1=CC=CC=C1.C=1C=CC=CC=1\C=C\C(=O)\C=C\C1=CC=CC=C1 CYPYTURSJDMMMP-WVCUSYJESA-N 0.000 description 2
- 125000004514 1,2,4-thiadiazolyl group Chemical group 0.000 description 2
- LVEYOSJUKRVCCF-UHFFFAOYSA-N 1,3-Bis(diphenylphosphino)propane Chemical compound C=1C=CC=CC=1P(C=1C=CC=CC=1)CCCP(C=1C=CC=CC=1)C1=CC=CC=C1 LVEYOSJUKRVCCF-UHFFFAOYSA-N 0.000 description 2
- CYSGHNMQYZDMIA-UHFFFAOYSA-N 1,3-Dimethyl-2-imidazolidinone Chemical compound CN1CCN(C)C1=O CYSGHNMQYZDMIA-UHFFFAOYSA-N 0.000 description 2
- VFNJIWJRUXUBDK-UHFFFAOYSA-N 1-fluoro-2-isocyanobenzene Chemical compound FC1=CC=CC=C1[N+]#[C-] VFNJIWJRUXUBDK-UHFFFAOYSA-N 0.000 description 2
- DFPYXQYWILNVAU-UHFFFAOYSA-N 1-hydroxybenzotriazole Chemical compound C1=CC=C2N(O)N=NC2=C1.C1=CC=C2N(O)N=NC2=C1 DFPYXQYWILNVAU-UHFFFAOYSA-N 0.000 description 2
- BPXKZEMBEZGUAH-UHFFFAOYSA-N 2-(chloromethoxy)ethyl-trimethylsilane Chemical compound C[Si](C)(C)CCOCCl BPXKZEMBEZGUAH-UHFFFAOYSA-N 0.000 description 2
- BTANRVKWQNVYAZ-UHFFFAOYSA-N 2-Butanol Chemical compound CCC(C)O BTANRVKWQNVYAZ-UHFFFAOYSA-N 0.000 description 2
- VUKAUDKDFVSVFT-UHFFFAOYSA-N 2-[6-[4,5-bis(2-hydroxypropoxy)-2-(2-hydroxypropoxymethyl)-6-methoxyoxan-3-yl]oxy-4,5-dimethoxy-2-(methoxymethyl)oxan-3-yl]oxy-6-(hydroxymethyl)-5-methoxyoxane-3,4-diol Chemical compound COC1C(OC)C(OC2C(C(O)C(OC)C(CO)O2)O)C(COC)OC1OC1C(COCC(C)O)OC(OC)C(OCC(C)O)C1OCC(C)O VUKAUDKDFVSVFT-UHFFFAOYSA-N 0.000 description 2
- CPXFMJZURXTLMQ-UHFFFAOYSA-N 2-bromo-4-chloro-3-fluorobenzoic acid Chemical compound OC(=O)C1=CC=C(Cl)C(F)=C1Br CPXFMJZURXTLMQ-UHFFFAOYSA-N 0.000 description 2
- LRDFRRGEGBBSRN-UHFFFAOYSA-N 2-methylpropanenitrile Chemical compound CC(C)C#N LRDFRRGEGBBSRN-UHFFFAOYSA-N 0.000 description 2
- AUUIARVPJHGTSA-UHFFFAOYSA-N 3-(aminomethyl)chromen-2-one Chemical compound C1=CC=C2OC(=O)C(CN)=CC2=C1 AUUIARVPJHGTSA-UHFFFAOYSA-N 0.000 description 2
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 2
- XTWYTFMLZFPYCI-KQYNXXCUSA-N 5'-adenylphosphoric acid Chemical compound C1=NC=2C(N)=NC=NC=2N1[C@@H]1O[C@H](COP(O)(=O)OP(O)(O)=O)[C@@H](O)[C@H]1O XTWYTFMLZFPYCI-KQYNXXCUSA-N 0.000 description 2
- FCDBLDCTWLKSRQ-UHFFFAOYSA-N 5-bromo-3,3-dimethyl-2,4-dihydro-1H-isoquinoline Chemical compound C1=CC=C2CNC(C)(C)CC2=C1Br FCDBLDCTWLKSRQ-UHFFFAOYSA-N 0.000 description 2
- FRNLODWJIKMPDY-UHFFFAOYSA-N 5-chloro-2-(difluoromethoxy)benzaldehyde Chemical compound FC(F)OC1=CC=C(Cl)C=C1C=O FRNLODWJIKMPDY-UHFFFAOYSA-N 0.000 description 2
- 239000005541 ACE inhibitor Substances 0.000 description 2
- 101700077954 APOA1 Proteins 0.000 description 2
- 102000007469 Actins Human genes 0.000 description 2
- 108010085238 Actins Proteins 0.000 description 2
- VSCWAEJMTAWNJL-UHFFFAOYSA-K Aluminium chloride Chemical compound Cl[Al](Cl)Cl VSCWAEJMTAWNJL-UHFFFAOYSA-K 0.000 description 2
- 229960005348 Antithrombin III Drugs 0.000 description 2
- 108090000935 Antithrombin-III Proteins 0.000 description 2
- 102000004411 Antithrombin-III Human genes 0.000 description 2
- 210000001367 Arteries Anatomy 0.000 description 2
- 239000005465 B01AC22 - Prasugrel Substances 0.000 description 2
- 108060001001 BRK1 Proteins 0.000 description 2
- 229960000686 Benzalkonium Chloride Drugs 0.000 description 2
- 210000004204 Blood Vessels Anatomy 0.000 description 2
- ILAHWRKJUDSMFH-UHFFFAOYSA-N Boron tribromide Chemical compound BrB(Br)Br ILAHWRKJUDSMFH-UHFFFAOYSA-N 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
- 238000007125 Buchwald synthesis reaction Methods 0.000 description 2
- 229940084030 CARBOXYMETHYLCELLULOSE CALCIUM Drugs 0.000 description 2
- 125000006414 CCl Chemical group ClC* 0.000 description 2
- YQEZLKZALYSWHR-UHFFFAOYSA-N Calypsol Chemical compound C=1C=CC=C(Cl)C=1C1(NC)CCCCC1=O YQEZLKZALYSWHR-UHFFFAOYSA-N 0.000 description 2
- 241000282472 Canis lupus familiaris Species 0.000 description 2
- 210000001715 Carotid Arteries Anatomy 0.000 description 2
- ZAIPMKNFIOOWCQ-UEKVPHQBSA-N Cefalexin Chemical compound C1([C@@H](N)C(=O)N[C@H]2[C@@H]3N(C2=O)C(=C(CS3)C)C(O)=O)=CC=CC=C1 ZAIPMKNFIOOWCQ-UEKVPHQBSA-N 0.000 description 2
- OSASVXMJTNOKOY-UHFFFAOYSA-N Chlorobutanol Chemical compound CC(C)(O)C(Cl)(Cl)Cl OSASVXMJTNOKOY-UHFFFAOYSA-N 0.000 description 2
- 229960004926 Chlorobutanol Drugs 0.000 description 2
- OROGSEYTTFOCAN-DNJOTXNNSA-N Codeine Chemical compound C([C@H]1[C@H](N(CC[C@@]112)C)C3)=C[C@H](O)[C@@H]1OC1=C2C3=CC=C1OC OROGSEYTTFOCAN-DNJOTXNNSA-N 0.000 description 2
- 229920002676 Complementary DNA Polymers 0.000 description 2
- OPQARKPSCNTWTJ-UHFFFAOYSA-L Copper(II) acetate Chemical compound [Cu+2].CC([O-])=O.CC([O-])=O OPQARKPSCNTWTJ-UHFFFAOYSA-L 0.000 description 2
- FXHOOIRPVKKKFG-UHFFFAOYSA-N DMA Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 2
- GUVUOGQBMYCBQP-UHFFFAOYSA-N DMPU Chemical compound CN1CCCN(C)C1=O GUVUOGQBMYCBQP-UHFFFAOYSA-N 0.000 description 2
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N DMSO-d6 Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 2
- NEFBYIFKOOEVPA-UHFFFAOYSA-K Dicalcium phosphate Chemical compound [Ca+2].[Ca+2].[O-]P([O-])([O-])=O NEFBYIFKOOEVPA-UHFFFAOYSA-K 0.000 description 2
- 235000019739 Dicalciumphosphate Nutrition 0.000 description 2
- CSJLBAMHHLJAAS-UHFFFAOYSA-N Diethylaminosulfur trifluoride Chemical compound CCN(CC)S(F)(F)F CSJLBAMHHLJAAS-UHFFFAOYSA-N 0.000 description 2
- MTHSVFCYNBDYFN-UHFFFAOYSA-N Diethylene glycol Chemical compound OCCOCCO MTHSVFCYNBDYFN-UHFFFAOYSA-N 0.000 description 2
- IZEKFCXSFNUWAM-UHFFFAOYSA-N Dipyridamole Chemical compound C=12N=C(N(CCO)CCO)N=C(N3CCCCC3)C2=NC(N(CCO)CCO)=NC=1N1CCCCC1 IZEKFCXSFNUWAM-UHFFFAOYSA-N 0.000 description 2
- 229960002768 Dipyridamole Drugs 0.000 description 2
- 241000196324 Embryophyta Species 0.000 description 2
- KBNIFDASRCWYGC-GXNXWABVSA-J Evans blue Chemical compound [Na+].[Na+].[Na+].[Na+].C\1=CC2=C(S([O-])(=O)=O)C=C(S([O-])(=O)=O)C(N)=C2C(=O)C/1=N/NC(C(C)=C1)=CC=C1C1=CC=C(N\N=C/2C(C3=C(N)C(=CC(=C3C=C\2)S([O-])(=O)=O)S([O-])(=O)=O)=O)C(C)=C1 KBNIFDASRCWYGC-GXNXWABVSA-J 0.000 description 2
- 206010015866 Extravasation Diseases 0.000 description 2
- 102100009906 F7 Human genes 0.000 description 2
- 108010023321 Factor VII Proteins 0.000 description 2
- 108010014173 Factor X Proteins 0.000 description 2
- 210000001105 Femoral Artery Anatomy 0.000 description 2
- 210000003191 Femoral Vein Anatomy 0.000 description 2
- 229940012952 Fibrinogen Drugs 0.000 description 2
- 108010049003 Fibrinogen Proteins 0.000 description 2
- 102000008946 Fibrinogen Human genes 0.000 description 2
- 229940019698 Fibrinogen containing hemostatics Drugs 0.000 description 2
- 108010010803 Gelatin Proteins 0.000 description 2
- 229940093915 Gynecological Organic acids Drugs 0.000 description 2
- JNWBBCNCSMBKNE-UHFFFAOYSA-N HATU Chemical compound F[P-](F)(F)(F)(F)F.C1=CN=C2N(OC(N(C)C)=[N+](C)C)N=NC2=C1 JNWBBCNCSMBKNE-UHFFFAOYSA-N 0.000 description 2
- 208000009429 Hemophilia B Diseases 0.000 description 2
- 241000282412 Homo Species 0.000 description 2
- 206010061218 Inflammation Diseases 0.000 description 2
- 210000000936 Intestines Anatomy 0.000 description 2
- 102000001399 Kallikreins Human genes 0.000 description 2
- 108060005987 Kallikreins Proteins 0.000 description 2
- TYQCGQRIZGCHNB-JLAZNSOCSA-N L-ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(O)=C(O)C1=O TYQCGQRIZGCHNB-JLAZNSOCSA-N 0.000 description 2
- 102000007330 LDL Lipoproteins Human genes 0.000 description 2
- 108010007622 LDL Lipoproteins Proteins 0.000 description 2
- OTQCKZUSUGYWBD-BRHMIFOHSA-N Lepirudin Chemical compound C([C@@H](C(=O)N[C@H](C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CS)C(=O)N[C@H](C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CO)C(=O)NCC(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CS)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CS)C(=O)N[C@@H](CCC(O)=O)C(=O)NCC(=O)N[C@@H](CO)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@H](C(=O)N[C@@H](CS)C(=O)NCC(=O)N[C@@H](CCC(N)=O)C(=O)NCC(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CS)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CC(C)C)C(=O)NCC(=O)N[C@@H](CO)C(=O)N[C@@H](CC(O)=O)C(=O)NCC(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CS)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H]([C@@H](C)O)C(=O)NCC(=O)N[C@@H](CCC(O)=O)C(=O)NCC(=O)N[C@@H]([C@@H](C)O)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CCCCN)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CO)C(=O)N[C@@H](CC=1NC=NC=1)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC(O)=O)C(=O)NCC(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(N)=O)C(O)=O)C(C)C)[C@@H](C)O)[C@@H](C)O)NC(=O)[C@@H](NC(=O)[C@@H](N)CC(C)C)[C@@H](C)O)C1=CC=C(O)C=C1 OTQCKZUSUGYWBD-BRHMIFOHSA-N 0.000 description 2
- YNESATAKKCNGOF-UHFFFAOYSA-N Lithium bis(trimethylsilyl)amide Chemical compound [Li+].C[Si](C)(C)[N-][Si](C)(C)C YNESATAKKCNGOF-UHFFFAOYSA-N 0.000 description 2
- KWGKDLIKAYFUFQ-UHFFFAOYSA-M Lithium chloride Chemical compound [Li+].[Cl-] KWGKDLIKAYFUFQ-UHFFFAOYSA-M 0.000 description 2
- 230000036223 MICHAELIS CONSTANT Effects 0.000 description 2
- BZLVMXJERCGZMT-UHFFFAOYSA-N MeOtBu Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 2
- NHQDETIJWKXCTC-UHFFFAOYSA-N Meta-Chloroperoxybenzoic acid Chemical compound OOC(=O)C1=CC=CC(Cl)=C1 NHQDETIJWKXCTC-UHFFFAOYSA-N 0.000 description 2
- BDNKZNFMNDZQMI-UHFFFAOYSA-N N,N'-Diisopropylcarbodiimide Chemical compound CC(C)N=C=NC(C)C BDNKZNFMNDZQMI-UHFFFAOYSA-N 0.000 description 2
- 150000001204 N-oxides Chemical class 0.000 description 2
- KPSSIOMAKSHJJG-UHFFFAOYSA-N Neopentyl alcohol Chemical compound CC(C)(C)CO KPSSIOMAKSHJJG-UHFFFAOYSA-N 0.000 description 2
- LQNUZADURLCDLV-UHFFFAOYSA-N Nitrobenzene Chemical compound [O-][N+](=O)C1=CC=CC=C1 LQNUZADURLCDLV-UHFFFAOYSA-N 0.000 description 2
- 208000008589 Obesity Diseases 0.000 description 2
- 108010015181 PPAR delta Proteins 0.000 description 2
- 108010016731 PPAR gamma Proteins 0.000 description 2
- YJVFFLUZDVXJQI-UHFFFAOYSA-L Palladium(II) acetate Chemical compound [Pd+2].CC([O-])=O.CC([O-])=O YJVFFLUZDVXJQI-UHFFFAOYSA-L 0.000 description 2
- 241001504519 Papio ursinus Species 0.000 description 2
- VLTRZXGMWDSKGL-UHFFFAOYSA-N Perchloric acid Chemical compound OCl(=O)(=O)=O VLTRZXGMWDSKGL-UHFFFAOYSA-N 0.000 description 2
- 102000003728 Peroxisome Proliferator-Activated Receptors Human genes 0.000 description 2
- 108090000029 Peroxisome Proliferator-Activated Receptors Proteins 0.000 description 2
- XHXFXVLFKHQFAL-UHFFFAOYSA-N Phosphoryl chloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 description 2
- 239000002202 Polyethylene glycol Substances 0.000 description 2
- 229920001710 Polyorthoester Polymers 0.000 description 2
- 229940068968 Polysorbate 80 Drugs 0.000 description 2
- 239000004793 Polystyrene Substances 0.000 description 2
- LPNYRYFBWFDTMA-UHFFFAOYSA-N Potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 2
- 206010060862 Prostate cancer Diseases 0.000 description 2
- 102000002298 Purinergic P2Y Receptors Human genes 0.000 description 2
- 108010000818 Purinergic P2Y Receptors Proteins 0.000 description 2
- 229940030915 Refludan Drugs 0.000 description 2
- 206010038563 Reocclusion Diseases 0.000 description 2
- 210000002966 Serum Anatomy 0.000 description 2
- WXMKPNITSTVMEF-UHFFFAOYSA-M Sodium benzoate Chemical compound [Na+].[O-]C(=O)C1=CC=CC=C1 WXMKPNITSTVMEF-UHFFFAOYSA-M 0.000 description 2
- LPXPTNMVRIOKMN-UHFFFAOYSA-M Sodium nitrite Chemical compound [Na+].[O-]N=O LPXPTNMVRIOKMN-UHFFFAOYSA-M 0.000 description 2
- 229940091252 Sodium supplements Drugs 0.000 description 2
- AKHNMLFCWUSKQB-UHFFFAOYSA-L Sodium thiosulphate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=S AKHNMLFCWUSKQB-UHFFFAOYSA-L 0.000 description 2
- 235000021355 Stearic acid Nutrition 0.000 description 2
- 239000005864 Sulphur Substances 0.000 description 2
- 206010051379 Systemic inflammatory response syndrome Diseases 0.000 description 2
- 101710034269 TFPI Proteins 0.000 description 2
- 102100008880 TFPI Human genes 0.000 description 2
- CXWXQJXEFPUFDZ-UHFFFAOYSA-N Tetralin Chemical compound C1=CC=C2CCCCC2=C1 CXWXQJXEFPUFDZ-UHFFFAOYSA-N 0.000 description 2
- 102000003938 Thromboxane Receptors Human genes 0.000 description 2
- 108090000300 Thromboxane Receptors Proteins 0.000 description 2
- PYOKUURKVVELLB-UHFFFAOYSA-N Trimethyl orthoformate Chemical compound COC(OC)OC PYOKUURKVVELLB-UHFFFAOYSA-N 0.000 description 2
- ONDSBJMLAHVLMI-UHFFFAOYSA-N Trimethylsilyldiazomethane Chemical compound C[Si](C)(C)[CH-][N+]#N ONDSBJMLAHVLMI-UHFFFAOYSA-N 0.000 description 2
- LWIHDJKSTIGBAC-UHFFFAOYSA-K Tripotassium phosphate Chemical compound [K+].[K+].[K+].[O-]P([O-])([O-])=O LWIHDJKSTIGBAC-UHFFFAOYSA-K 0.000 description 2
- 102000010861 Type 3 Cyclic Nucleotide Phosphodiesterases Human genes 0.000 description 2
- 108010037543 Type 3 Cyclic Nucleotide Phosphodiesterases Proteins 0.000 description 2
- MWOOGOJBHIARFG-UHFFFAOYSA-N Vanillin Chemical compound COC1=CC(C=O)=CC=C1O MWOOGOJBHIARFG-UHFFFAOYSA-N 0.000 description 2
- BPICBUSOMSTKRF-UHFFFAOYSA-N Xylazine Chemical compound CC1=CC=CC(C)=C1NC1=NCCCS1 BPICBUSOMSTKRF-UHFFFAOYSA-N 0.000 description 2
- 229960001600 Xylazine Drugs 0.000 description 2
- 238000010521 absorption reaction Methods 0.000 description 2
- 230000002378 acidificating Effects 0.000 description 2
- NIXOWILDQLNWCW-UHFFFAOYSA-M acrylate Chemical compound [O-]C(=O)C=C NIXOWILDQLNWCW-UHFFFAOYSA-M 0.000 description 2
- 239000012190 activator Substances 0.000 description 2
- 239000008186 active pharmaceutical agent Substances 0.000 description 2
- 125000005073 adamantyl group Chemical group C12(CC3CC(CC(C1)C3)C2)* 0.000 description 2
- 230000002776 aggregation Effects 0.000 description 2
- 238000004220 aggregation Methods 0.000 description 2
- 150000001298 alcohols Chemical class 0.000 description 2
- 125000004450 alkenylene group Chemical group 0.000 description 2
- 125000004419 alkynylene group Chemical group 0.000 description 2
- 230000000172 allergic Effects 0.000 description 2
- 229940024142 alpha 1-Antitrypsin Drugs 0.000 description 2
- 102000015395 alpha 1-Antitrypsin Human genes 0.000 description 2
- 108010050122 alpha 1-Antitrypsin Proteins 0.000 description 2
- VHUUQVKOLVNVRT-UHFFFAOYSA-N ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 2
- 235000011114 ammonium hydroxide Nutrition 0.000 description 2
- 230000003321 amplification Effects 0.000 description 2
- 239000002333 angiotensin II receptor antagonist Substances 0.000 description 2
- PAYRUJLWNCNPSJ-UHFFFAOYSA-N aniline Chemical compound NC1=CC=CC=C1 PAYRUJLWNCNPSJ-UHFFFAOYSA-N 0.000 description 2
- 239000003242 anti bacterial agent Substances 0.000 description 2
- 230000000111 anti-oxidant Effects 0.000 description 2
- 230000003064 anti-oxidating Effects 0.000 description 2
- 239000003416 antiarrhythmic agent Substances 0.000 description 2
- 239000003429 antifungal agent Substances 0.000 description 2
- 239000003963 antioxidant agent Substances 0.000 description 2
- 235000006708 antioxidants Nutrition 0.000 description 2
- 239000004019 antithrombin Substances 0.000 description 2
- 229940019336 antithrombotic Enzymes Drugs 0.000 description 2
- 235000010323 ascorbic acid Nutrition 0.000 description 2
- 239000011668 ascorbic acid Substances 0.000 description 2
- 229960005070 ascorbic acid Drugs 0.000 description 2
- 201000008937 atopic dermatitis Diseases 0.000 description 2
- 125000004604 benzisothiazolyl group Chemical group S1N=C(C2=C1C=CC=C2)* 0.000 description 2
- 125000004603 benzisoxazolyl group Chemical group O1N=C(C2=C1C=CC=C2)* 0.000 description 2
- 125000000499 benzofuranyl group Chemical group O1C(=CC2=C1C=CC=C2)* 0.000 description 2
- 125000004196 benzothienyl group Chemical group S1C(=CC2=C1C=CC=C2)* 0.000 description 2
- 125000004935 benzoxazolinyl group Chemical group O1C(=NC2=C1C=CC=C2)* 0.000 description 2
- 125000004541 benzoxazolyl group Chemical group O1C(=NC2=C1C=CC=C2)* 0.000 description 2
- 125000005512 benztetrazolyl group Chemical group 0.000 description 2
- 239000003613 bile acid Substances 0.000 description 2
- 239000004621 biodegradable polymer Substances 0.000 description 2
- 229920002988 biodegradable polymer Polymers 0.000 description 2
- 230000033228 biological regulation Effects 0.000 description 2
- 229920001400 block copolymer Polymers 0.000 description 2
- CPELXLSAUQHCOX-UHFFFAOYSA-M bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 description 2
- 229910052794 bromium Inorganic materials 0.000 description 2
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
- 239000000480 calcium channel blocker Substances 0.000 description 2
- 239000001506 calcium phosphate Substances 0.000 description 2
- 235000011132 calcium sulphate Nutrition 0.000 description 2
- 238000004364 calculation method Methods 0.000 description 2
- KXDHJXZQYSOELW-UHFFFAOYSA-M carbamate Chemical compound NC([O-])=O KXDHJXZQYSOELW-UHFFFAOYSA-M 0.000 description 2
- 125000000609 carbazolyl group Chemical group C1(=CC=CC=2C3=CC=CC=C3NC12)* 0.000 description 2
- 125000002837 carbocyclic group Chemical group 0.000 description 2
- 239000011203 carbon fibre reinforced carbon Substances 0.000 description 2
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 2
- 239000001768 carboxy methyl cellulose Substances 0.000 description 2
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 2
- 150000001735 carboxylic acids Chemical group 0.000 description 2
- 239000011111 cardboard Substances 0.000 description 2
- 230000003197 catalytic Effects 0.000 description 2
- 230000001413 cellular Effects 0.000 description 2
- 239000007795 chemical reaction product Substances 0.000 description 2
- 239000007810 chemical reaction solvent Substances 0.000 description 2
- 238000002512 chemotherapy Methods 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- LKYXEULZVGJVTG-UHFFFAOYSA-N chloromethane Chemical compound Cl[CH] LKYXEULZVGJVTG-UHFFFAOYSA-N 0.000 description 2
- 125000003016 chromanyl group Chemical group O1C(CCC2=CC=CC=C12)* 0.000 description 2
- 238000004440 column chromatography Methods 0.000 description 2
- 238000002648 combination therapy Methods 0.000 description 2
- 230000002860 competitive Effects 0.000 description 2
- 230000000295 complement Effects 0.000 description 2
- 239000000470 constituent Substances 0.000 description 2
- 230000001276 controlling effect Effects 0.000 description 2
- 238000007887 coronary angioplasty Methods 0.000 description 2
- 125000004122 cyclic group Chemical group 0.000 description 2
- 125000001162 cycloheptenyl group Chemical group C1(=CCCCCC1)* 0.000 description 2
- 239000008121 dextrose Substances 0.000 description 2
- 238000010586 diagram Methods 0.000 description 2
- 229940038472 dicalcium phosphate Drugs 0.000 description 2
- 229910000390 dicalcium phosphate Inorganic materials 0.000 description 2
- 229910001873 dinitrogen Inorganic materials 0.000 description 2
- 238000004090 dissolution Methods 0.000 description 2
- KCXVZYZYPLLWCC-UHFFFAOYSA-N edta Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 description 2
- 239000000839 emulsion Substances 0.000 description 2
- XBSGYVHOINMTIM-UHFFFAOYSA-N ethyl 3-isocyanatopropanoate Chemical compound CCOC(=O)CCN=C=O XBSGYVHOINMTIM-UHFFFAOYSA-N 0.000 description 2
- 239000000284 extract Substances 0.000 description 2
- 230000036251 extravasation Effects 0.000 description 2
- 229940012413 factor VII Drugs 0.000 description 2
- 201000003542 factor VIII deficiency Diseases 0.000 description 2
- 229940012426 factor X Drugs 0.000 description 2
- 230000020764 fibrinolysis Effects 0.000 description 2
- 239000012065 filter cake Substances 0.000 description 2
- 239000000796 flavoring agent Substances 0.000 description 2
- 125000001153 fluoro group Chemical group F* 0.000 description 2
- 235000013355 food flavoring agent Nutrition 0.000 description 2
- ZHNUHDYFZUAESO-UHFFFAOYSA-N formamide Chemical compound NC=O ZHNUHDYFZUAESO-UHFFFAOYSA-N 0.000 description 2
- 230000002496 gastric Effects 0.000 description 2
- 239000008273 gelatin Substances 0.000 description 2
- 229920000159 gelatin Polymers 0.000 description 2
- 235000019322 gelatine Nutrition 0.000 description 2
- 235000011852 gelatine desserts Nutrition 0.000 description 2
- 239000011521 glass Substances 0.000 description 2
- 235000001727 glucose Nutrition 0.000 description 2
- 239000003292 glue Substances 0.000 description 2
- 238000005469 granulation Methods 0.000 description 2
- OAKJQQAXSVQMHS-UHFFFAOYSA-N hydrazine Chemical compound NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 0.000 description 2
- 239000000017 hydrogel Substances 0.000 description 2
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 description 2
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 description 2
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 description 2
- 230000001939 inductive effect Effects 0.000 description 2
- 230000004054 inflammatory process Effects 0.000 description 2
- 238000001361 intraarterial administration Methods 0.000 description 2
- 238000007918 intramuscular administration Methods 0.000 description 2
- 238000007912 intraperitoneal administration Methods 0.000 description 2
- 125000004936 isatinoyl group Chemical group N1(C(=O)C(=O)C2=CC=CC=C12)C(=O)* 0.000 description 2
- 125000000904 isoindolyl group Chemical group C=1(NC=C2C=CC=CC12)* 0.000 description 2
- 238000002955 isolation Methods 0.000 description 2
- 150000002527 isonitriles Chemical class 0.000 description 2
- 229940011051 isopropyl acetate Drugs 0.000 description 2
- OSILBMSORKFRTB-UHFFFAOYSA-N isoquinolin-1-amine Chemical compound C1=CC=C2C(N)=NC=CC2=C1 OSILBMSORKFRTB-UHFFFAOYSA-N 0.000 description 2
- 125000001786 isothiazolyl group Chemical group 0.000 description 2
- GWYFCOCPABKNJV-UHFFFAOYSA-M isovalerate Chemical compound CC(C)CC([O-])=O GWYFCOCPABKNJV-UHFFFAOYSA-M 0.000 description 2
- 229960003299 ketamine Drugs 0.000 description 2
- 150000002576 ketones Chemical class 0.000 description 2
- 230000003907 kidney function Effects 0.000 description 2
- 230000000670 limiting Effects 0.000 description 2
- 239000002502 liposome Substances 0.000 description 2
- HPQVWDOOUQVBTO-UHFFFAOYSA-N lithium aluminum hydride Chemical compound [Li+].[Al-] HPQVWDOOUQVBTO-UHFFFAOYSA-N 0.000 description 2
- 230000003908 liver function Effects 0.000 description 2
- 239000011777 magnesium Substances 0.000 description 2
- 230000014759 maintenance of location Effects 0.000 description 2
- 238000004949 mass spectrometry Methods 0.000 description 2
- 229960002137 melagatran Drugs 0.000 description 2
- DKWNMCUOEDMMIN-PKOBYXMFSA-N melagatran Chemical compound C1=CC(C(=N)N)=CC=C1CNC(=O)[C@H]1N(C(=O)[C@H](NCC(O)=O)C2CCCCC2)CC1 DKWNMCUOEDMMIN-PKOBYXMFSA-N 0.000 description 2
- CERQOIWHTDAKMF-UHFFFAOYSA-M methacrylate Chemical compound CC(=C)C([O-])=O CERQOIWHTDAKMF-UHFFFAOYSA-M 0.000 description 2
- AFVFQIVMOAPDHO-UHFFFAOYSA-N methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 2
- UAVOCTDYPKOULU-UHFFFAOYSA-N methylchloranuidyl formate Chemical compound C[Cl-]OC=O UAVOCTDYPKOULU-UHFFFAOYSA-N 0.000 description 2
- CSNNHWWHGAXBCP-UHFFFAOYSA-L mgso4 Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 2
- 238000003801 milling Methods 0.000 description 2
- LRHPLDYGYMQRHN-UHFFFAOYSA-N n-butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 2
- MZRVEZGGRBJDDB-UHFFFAOYSA-N n-butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 2
- SJRJJKPEHAURKC-UHFFFAOYSA-N n-methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 description 2
- SECXISVLQFMRJM-UHFFFAOYSA-N n-methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 description 2
- 235000001968 nicotinic acid Nutrition 0.000 description 2
- 229960003512 nicotinic acid Drugs 0.000 description 2
- 239000011664 nicotinic acid Substances 0.000 description 2
- 150000002825 nitriles Chemical class 0.000 description 2
- 239000012454 non-polar solvent Substances 0.000 description 2
- 238000010899 nucleation Methods 0.000 description 2
- 238000003199 nucleic acid amplification method Methods 0.000 description 2
- 235000020824 obesity Nutrition 0.000 description 2
- 125000004930 octahydroisoquinolinyl group Chemical group C1(NCCC2CCCC=C12)* 0.000 description 2
- 239000006186 oral dosage form Substances 0.000 description 2
- 150000007524 organic acids Chemical class 0.000 description 2
- 235000005985 organic acids Nutrition 0.000 description 2
- 210000000056 organs Anatomy 0.000 description 2
- 239000007800 oxidant agent Substances 0.000 description 2
- 125000004095 oxindolyl group Chemical group N1(C(CC2=CC=CC=C12)=O)* 0.000 description 2
- 239000001301 oxygen Substances 0.000 description 2
- LXNAVEXFUKBNMK-UHFFFAOYSA-N palladium(II) acetate Substances [Pd].CC(O)=O.CC(O)=O LXNAVEXFUKBNMK-UHFFFAOYSA-N 0.000 description 2
- 230000036961 partial Effects 0.000 description 2
- 230000001575 pathological Effects 0.000 description 2
- 230000003285 pharmacodynamic Effects 0.000 description 2
- 125000004592 phthalazinyl group Chemical group C1(=NN=CC2=CC=CC=C12)* 0.000 description 2
- 239000006187 pill Substances 0.000 description 2
- RFIOZSIHFNEKFF-UHFFFAOYSA-M piperazine-1-carboxylate Chemical compound [O-]C(=O)N1CCNCC1 RFIOZSIHFNEKFF-UHFFFAOYSA-M 0.000 description 2
- 229940096701 plain lipid modifying drugs HMG CoA reductase inhibitors Drugs 0.000 description 2
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical compound [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 description 2
- 239000003880 polar aprotic solvent Substances 0.000 description 2
- 239000002798 polar solvent Substances 0.000 description 2
- 229920001610 polycaprolactone Polymers 0.000 description 2
- 125000005575 polycyclic aromatic hydrocarbon group Chemical group 0.000 description 2
- 229920000656 polylysine Polymers 0.000 description 2
- 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 description 2
- 239000000244 polyoxyethylene sorbitan monooleate Substances 0.000 description 2
- 229920000053 polysorbate 80 Polymers 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- 239000003450 potassium channel blocker Substances 0.000 description 2
- 230000003389 potentiating Effects 0.000 description 2
- 229960004197 prasugrel Drugs 0.000 description 2
- DTGLZDAWLRGWQN-UHFFFAOYSA-N prasugrel Chemical compound C1CC=2SC(OC(=O)C)=CC=2CN1C(C=1C(=CC=CC=1)F)C(=O)C1CC1 DTGLZDAWLRGWQN-UHFFFAOYSA-N 0.000 description 2
- 230000003405 preventing Effects 0.000 description 2
- 230000003449 preventive Effects 0.000 description 2
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
- 102000004885 protease-activated receptor 4 Human genes 0.000 description 2
- 108090001010 protease-activated receptor 4 Proteins 0.000 description 2
- 230000004224 protection Effects 0.000 description 2
- 230000003331 prothrombotic Effects 0.000 description 2
- 125000000561 purinyl group Chemical group N1=C(N=C2N=CNC2=C1)* 0.000 description 2
- 125000002098 pyridazinyl group Chemical group 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- 230000001105 regulatory Effects 0.000 description 2
- 230000004044 response Effects 0.000 description 2
- 230000028327 secretion Effects 0.000 description 2
- 239000003001 serine protease inhibitor Substances 0.000 description 2
- QZAYGJVTTNCVMB-UHFFFAOYSA-N serotonin Chemical compound C1=C(O)C=C2C(CCN)=CNC2=C1 QZAYGJVTTNCVMB-UHFFFAOYSA-N 0.000 description 2
- LIVNPJMFVYWSIS-UHFFFAOYSA-N silicon monoxide Inorganic materials [Si-]#[O+] LIVNPJMFVYWSIS-UHFFFAOYSA-N 0.000 description 2
- 150000003384 small molecules Chemical class 0.000 description 2
- VMHLLURERBWHNL-UHFFFAOYSA-M sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 description 2
- 239000004299 sodium benzoate Substances 0.000 description 2
- 235000010234 sodium benzoate Nutrition 0.000 description 2
- DWAQJAXMDSEUJJ-UHFFFAOYSA-M sodium bisulfite Chemical compound [Na+].OS([O-])=O DWAQJAXMDSEUJJ-UHFFFAOYSA-M 0.000 description 2
- 229940001607 sodium bisulfite Drugs 0.000 description 2
- YOQDYZUWIQVZSF-UHFFFAOYSA-N sodium borohydride Substances [BH4-].[Na+] YOQDYZUWIQVZSF-UHFFFAOYSA-N 0.000 description 2
- 229910000033 sodium borohydride Inorganic materials 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L sodium carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- 235000010267 sodium hydrogen sulphite Nutrition 0.000 description 2
- WQDUMFSSJAZKTM-UHFFFAOYSA-N sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 2
- 229940001482 sodium sulfite Drugs 0.000 description 2
- 235000019345 sodium thiosulphate Nutrition 0.000 description 2
- ODGROJYWQXFQOZ-UHFFFAOYSA-N sodium;boron(1-) Chemical compound [B-].[Na+] ODGROJYWQXFQOZ-UHFFFAOYSA-N 0.000 description 2
- 230000003595 spectral Effects 0.000 description 2
- 150000003413 spiro compounds Chemical class 0.000 description 2
- 230000002269 spontaneous Effects 0.000 description 2
- 239000008117 stearic acid Substances 0.000 description 2
- 230000000638 stimulation Effects 0.000 description 2
- 238000000547 structure data Methods 0.000 description 2
- 235000021092 sugar substitutes Nutrition 0.000 description 2
- 239000000375 suspending agent Substances 0.000 description 2
- DPKBAXPHAYBPRL-UHFFFAOYSA-M tetrabutylazanium;iodide Chemical compound [I-].CCCC[N+](CCCC)(CCCC)CCCC DPKBAXPHAYBPRL-UHFFFAOYSA-M 0.000 description 2
- 125000000147 tetrahydroquinolinyl group Chemical group N1(CCCC2=CC=CC=C12)* 0.000 description 2
- UEUXEKPTXMALOB-UHFFFAOYSA-J tetrasodium;2-[2-[bis(carboxylatomethyl)amino]ethyl-(carboxylatomethyl)amino]acetate Chemical compound [Na+].[Na+].[Na+].[Na+].[O-]C(=O)CN(CC([O-])=O)CCN(CC([O-])=O)CC([O-])=O UEUXEKPTXMALOB-UHFFFAOYSA-J 0.000 description 2
- 125000004525 thiadiazinyl group Chemical group S1NN=C(C=C1)* 0.000 description 2
- 125000001113 thiadiazolyl group Chemical group 0.000 description 2
- FWPIDFUJEMBDLS-UHFFFAOYSA-L tin dichloride dihydrate Chemical compound O.O.Cl[Sn]Cl FWPIDFUJEMBDLS-UHFFFAOYSA-L 0.000 description 2
- 230000000699 topical Effects 0.000 description 2
- 230000001988 toxicity Effects 0.000 description 2
- 231100000419 toxicity Toxicity 0.000 description 2
- 230000032258 transport Effects 0.000 description 2
- 108010036927 trypsin-like serine protease Proteins 0.000 description 2
- 238000001622 two pulse phase modulation pulse sequence Methods 0.000 description 2
- 238000004450 types of analysis Methods 0.000 description 2
- 239000002691 unilamellar liposome Substances 0.000 description 2
- AINNWLIGRJYURO-LZCJLJQNSA-N (2,5-dioxopyrrolidin-1-yl) (E)-3-[5-chloro-2-(tetrazol-1-yl)phenyl]prop-2-enoate Chemical compound C=1C(Cl)=CC=C(N2N=NN=C2)C=1\C=C\C(=O)ON1C(=O)CCC1=O AINNWLIGRJYURO-LZCJLJQNSA-N 0.000 description 1
- XSNMGLZVFNDDPW-ZWKOTPCHSA-N (2S)-1-[(2R)-2-[3-chloro-5-(difluoromethoxy)phenyl]-2-hydroxyacetyl]-N-[[4-(N'-methoxycarbamimidoyl)phenyl]methyl]azetidine-2-carboxamide Chemical compound C1=CC(C(/N)=N/OC)=CC=C1CNC(=O)[C@H]1N(C(=O)[C@H](O)C=2C=C(OC(F)F)C=C(Cl)C=2)CC1 XSNMGLZVFNDDPW-ZWKOTPCHSA-N 0.000 description 1
- LJCBAPRMNYSDOP-LVCYMWGESA-N (2S)-3-(7-carbamimidoylnaphthalen-2-yl)-2-[4-[(3S)-1-ethanimidoylpyrrolidin-3-yl]oxyphenyl]propanoic acid;hydron;chloride;pentahydrate Chemical compound O.O.O.O.O.Cl.C1N(C(=N)C)CC[C@@H]1OC1=CC=C([C@H](CC=2C=C3C=C(C=CC3=CC=2)C(N)=N)C(O)=O)C=C1 LJCBAPRMNYSDOP-LVCYMWGESA-N 0.000 description 1
- GVVCHDNSTMEUCS-MUGJNUQGSA-N (2S,5S)-1-[2-[(2S,5S)-2,5-diethylphospholan-1-yl]phenyl]-2,5-diethylphospholane Chemical compound CC[C@H]1CC[C@H](CC)P1C1=CC=CC=C1P1[C@@H](CC)CC[C@@H]1CC GVVCHDNSTMEUCS-MUGJNUQGSA-N 0.000 description 1
- PQLBJVPZXNPVOS-HLBWOJLBSA-N (3R,3aS,4S,4aR,8aS,9aR)-3-methyl-4-[(E)-2-[5-[3-(trifluoromethyl)phenyl]pyridin-2-yl]ethenyl]-3a,4,4a,5,6,7,8,8a,9,9a-decahydro-3H-benzo[f][2]benzofuran-1-one Chemical compound C(/[C@H]1[C@@H]2CCCC[C@H]2C[C@H]2C(=O)O[C@@H]([C@@H]12)C)=C\C(N=C1)=CC=C1C1=CC=CC(C(F)(F)F)=C1 PQLBJVPZXNPVOS-HLBWOJLBSA-N 0.000 description 1
- FJLGEFLZQAZZCD-JUFISIKESA-N (3S,5R)-fluvastatin Chemical compound C12=CC=CC=C2N(C(C)C)C(\C=C\[C@H](O)C[C@H](O)CC(O)=O)=C1C1=CC=C(F)C=C1 FJLGEFLZQAZZCD-JUFISIKESA-N 0.000 description 1
- JOGKWALAFPNFPR-VURMDHGXSA-N (4Z)-cycloocta-1,4-diene Chemical group [CH]1CC\C=C/CC=C1 JOGKWALAFPNFPR-VURMDHGXSA-N 0.000 description 1
- 229920000160 (ribonucleotides)n+m Polymers 0.000 description 1
- KZPYGQFFRCFCPP-UHFFFAOYSA-N 1,1'-Bis(diphenylphosphino)ferrocene Chemical compound [Fe+2].C1=CC=C[C-]1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=C[C-]1P(C=1C=CC=CC=1)C1=CC=CC=C1 KZPYGQFFRCFCPP-UHFFFAOYSA-N 0.000 description 1
- SSUJUUNLZQVZMO-UHFFFAOYSA-N 1,2,3,4,8,9,10,10a-octahydropyrimido[1,2-a]azepine Chemical compound C1CCC=CN2CCCNC21 SSUJUUNLZQVZMO-UHFFFAOYSA-N 0.000 description 1
- 125000004607 1,2,3,4-tetrahydroquinolinyl group Chemical group N1(CCCC2=CC=CC=C12)* 0.000 description 1
- 125000004502 1,2,3-oxadiazolyl group Chemical group 0.000 description 1
- 125000004511 1,2,3-thiadiazolyl group Chemical group 0.000 description 1
- 125000001399 1,2,3-triazolyl group Chemical group N1N=NC(=C1)* 0.000 description 1
- 125000004504 1,2,4-oxadiazolyl group Chemical group 0.000 description 1
- 125000001376 1,2,4-triazolyl group Chemical group N1N=C(N=C1)* 0.000 description 1
- 125000004506 1,2,5-oxadiazolyl group Chemical group 0.000 description 1
- 125000004517 1,2,5-thiadiazolyl group Chemical group 0.000 description 1
- WJUKOGPNGRUXMG-UHFFFAOYSA-N 1,2-dibromo-1,1,2,2-tetrachloroethane Chemical compound ClC(Cl)(Br)C(Cl)(Cl)Br WJUKOGPNGRUXMG-UHFFFAOYSA-N 0.000 description 1
- DDMOUSALMHHKOS-UHFFFAOYSA-N 1,2-dichloro-1,1,2,2-tetrafluoroethane Chemical compound FC(F)(Cl)C(F)(F)Cl DDMOUSALMHHKOS-UHFFFAOYSA-N 0.000 description 1
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 description 1
- IOEPOEDBBPRAEI-UHFFFAOYSA-N 1,2-dihydroisoquinoline Chemical compound C1=CC=C2CNC=CC2=C1 IOEPOEDBBPRAEI-UHFFFAOYSA-N 0.000 description 1
- 125000001781 1,3,4-oxadiazolyl group Chemical group 0.000 description 1
- 125000004520 1,3,4-thiadiazolyl group Chemical group 0.000 description 1
- COVZYZSDYWQREU-UHFFFAOYSA-N 1,4-Butanediol, dimethanesulfonate Chemical compound CS(=O)(=O)OCCCCOS(C)(=O)=O COVZYZSDYWQREU-UHFFFAOYSA-N 0.000 description 1
- KCCOVPPONJFFDS-UHFFFAOYSA-N 1-(2-bromo-3-chlorophenyl)ethanone Chemical compound CC(=O)C1=CC=CC(Cl)=C1Br KCCOVPPONJFFDS-UHFFFAOYSA-N 0.000 description 1
- NOJYTLBGSSNAQV-UHFFFAOYSA-N 1-(2-bromo-4-chloro-3-fluorophenyl)ethanone Chemical compound CC(=O)C1=CC=C(Cl)C(F)=C1Br NOJYTLBGSSNAQV-UHFFFAOYSA-N 0.000 description 1
- FPIRBHDGWMWJEP-UHFFFAOYSA-N 1-Hydroxy-7-azabenzotriazole Chemical compound C1=CN=C2N(O)N=NC2=C1 FPIRBHDGWMWJEP-UHFFFAOYSA-N 0.000 description 1
- LZSYGJNFCREHMD-UHFFFAOYSA-N 1-bromo-2-(bromomethyl)benzene Chemical compound BrCC1=CC=CC=C1Br LZSYGJNFCREHMD-UHFFFAOYSA-N 0.000 description 1
- NNQDMQVWOWCVEM-UHFFFAOYSA-N 1-bromoprop-1-ene Chemical compound CC=CBr NNQDMQVWOWCVEM-UHFFFAOYSA-N 0.000 description 1
- MICMHFIQSAMEJG-UHFFFAOYSA-N 1-bromopyrrolidine-2,5-dione Chemical compound BrN1C(=O)CCC1=O.BrN1C(=O)CCC1=O MICMHFIQSAMEJG-UHFFFAOYSA-N 0.000 description 1
- JLPULHDHAOZNQI-ZTIMHPMXSA-N 1-hexadecanoyl-2-(9Z,12Z-octadecadienoyl)-sn-glycero-3-phosphocholine Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCCCCCC\C=C/C\C=C/CCCCC JLPULHDHAOZNQI-ZTIMHPMXSA-N 0.000 description 1
- 125000006432 1-methyl cyclopropyl group Chemical group [H]C([H])([H])C1(*)C([H])([H])C1([H])[H] 0.000 description 1
- 125000006017 1-propenyl group Chemical group 0.000 description 1
- 238000004293 19F NMR spectroscopy Methods 0.000 description 1
- OZAIFHULBGXAKX-UHFFFAOYSA-N 2,2'-azo-bis-isobutyronitrile Substances N#CC(C)(C)N=NC(C)(C)C#N OZAIFHULBGXAKX-UHFFFAOYSA-N 0.000 description 1
- RHQDFWAXVIIEBN-UHFFFAOYSA-N 2,2,2-trifluoroethyl alcohol Chemical compound OCC(F)(F)F RHQDFWAXVIIEBN-UHFFFAOYSA-N 0.000 description 1
- 125000004206 2,2,2-trifluoroethyl group Chemical group [H]C([H])(*)C(F)(F)F 0.000 description 1
- LTMRRSWNXVJMBA-UHFFFAOYSA-L 2,2-diethylpropanedioate Chemical compound CCC(CC)(C([O-])=O)C([O-])=O LTMRRSWNXVJMBA-UHFFFAOYSA-L 0.000 description 1
- XXJWXESWEXIICW-UHFFFAOYSA-N 2-(2-Ethoxyethoxy)ethanol Chemical compound CCOCCOCCO XXJWXESWEXIICW-UHFFFAOYSA-N 0.000 description 1
- SBASXUCJHJRPEV-UHFFFAOYSA-N 2-(2-Methoxyethoxy)ethanol Chemical compound COCCOCCO SBASXUCJHJRPEV-UHFFFAOYSA-N 0.000 description 1
- YRULUXDRMGWMDA-UHFFFAOYSA-K 2-(2-ethylhexanoyloxy)ethanethiolate;methyltin(3+) Chemical compound CCCCC(CC)C(=O)OCCS[Sn](C)(SCCOC(=O)C(CC)CCCC)SCCOC(=O)C(CC)CCCC YRULUXDRMGWMDA-UHFFFAOYSA-K 0.000 description 1
- ZNQVEEAIQZEUHB-UHFFFAOYSA-N 2-Ethoxyethanol Chemical compound CCOCCO ZNQVEEAIQZEUHB-UHFFFAOYSA-N 0.000 description 1
- GGDYAKVUZMZKRV-UHFFFAOYSA-N 2-Fluoroethanol Chemical compound OCCF GGDYAKVUZMZKRV-UHFFFAOYSA-N 0.000 description 1
- AFABGHUZZDYHJO-UHFFFAOYSA-N 2-Methylpentane Chemical class CCCC(C)C AFABGHUZZDYHJO-UHFFFAOYSA-N 0.000 description 1
- JYVLIDXNZAXMDK-UHFFFAOYSA-N 2-Pentanol Chemical compound CCCC(C)O JYVLIDXNZAXMDK-UHFFFAOYSA-N 0.000 description 1
- JWAZHODZSADEHB-UHFFFAOYSA-M 2-[4-(4-chlorobenzoyl)phenoxy]-2-methylpropanoate;2-hydroxyethyl(trimethyl)azanium Chemical class C[N+](C)(C)CCO.C1=CC(OC(C)(C)C([O-])=O)=CC=C1C(=O)C1=CC=C(Cl)C=C1 JWAZHODZSADEHB-UHFFFAOYSA-M 0.000 description 1
- 125000005273 2-acetoxybenzoic acid group Chemical group 0.000 description 1
- LENZDBCJOHFCAS-UHFFFAOYSA-N 2-amino-2-(hydroxymethyl)propane-1,3-diol Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 1
- CDMGNVWZXRKJNS-UHFFFAOYSA-N 2-benzylphenol Chemical compound OC1=CC=CC=C1CC1=CC=CC=C1 CDMGNVWZXRKJNS-UHFFFAOYSA-N 0.000 description 1
- VEJPLARLFWIYNM-UHFFFAOYSA-N 2-bromo-3-chlorobenzaldehyde Chemical compound ClC1=CC=CC(C=O)=C1Br VEJPLARLFWIYNM-UHFFFAOYSA-N 0.000 description 1
- IIXYZMJRCIPQDN-UHFFFAOYSA-N 2-bromo-4-chloro-3-fluorobenzamide Chemical compound NC(=O)C1=CC=C(Cl)C(F)=C1Br IIXYZMJRCIPQDN-UHFFFAOYSA-N 0.000 description 1
- RZFIPXFHCDUXHO-UHFFFAOYSA-N 2-bromo-4-chloro-3-fluorobenzonitrile Chemical compound FC1=C(Cl)C=CC(C#N)=C1Br RZFIPXFHCDUXHO-UHFFFAOYSA-N 0.000 description 1
- 125000004974 2-butenyl group Chemical group C(C=CC)* 0.000 description 1
- 229940093475 2-ethoxyethanol Drugs 0.000 description 1
- 125000006040 2-hexenyl group Chemical group 0.000 description 1
- YCIRHAGYEUJTFH-UHFFFAOYSA-N 2-imidazol-1-ylethanamine Chemical compound NCCN1C=CN=C1 YCIRHAGYEUJTFH-UHFFFAOYSA-N 0.000 description 1
- KIPMDPDAFINLIV-UHFFFAOYSA-N 2-nitroethanol Chemical compound OCC[N+]([O-])=O KIPMDPDAFINLIV-UHFFFAOYSA-N 0.000 description 1
- 125000006024 2-pentenyl group Chemical group 0.000 description 1
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 description 1
- VSCBATMPTLKTOV-UHFFFAOYSA-N 2-tert-butylimino-N,N-diethyl-1,3-dimethyl-1,3,2$l^{5}-diazaphosphinan-2-amine Chemical compound CCN(CC)P1(=NC(C)(C)C)N(C)CCCN1C VSCBATMPTLKTOV-UHFFFAOYSA-N 0.000 description 1
- VUGRPJUREUOUIO-UHFFFAOYSA-N 2H-benzotriazol-4-yloxy-tris(dimethylamino)phosphanium;hexafluorophosphate Chemical compound F[P-](F)(F)(F)(F)F.CN(C)[P+](N(C)C)(N(C)C)OC1=CC=CC2=C1N=NN2 VUGRPJUREUOUIO-UHFFFAOYSA-N 0.000 description 1
- LTJQRZGEPZQDLX-UHFFFAOYSA-N 3,3-dimethyl-2,4-dihydro-1H-isoquinoline Chemical compound C1=CC=C2CNC(C)(C)CC2=C1 LTJQRZGEPZQDLX-UHFFFAOYSA-N 0.000 description 1
- IDTLXHTXEHPDLT-UHFFFAOYSA-N 3-(2-bromophenyl)-2,2-dimethylpropanenitrile Chemical compound N#CC(C)(C)CC1=CC=CC=C1Br IDTLXHTXEHPDLT-UHFFFAOYSA-N 0.000 description 1
- PXLOONGLASJSGK-UHFFFAOYSA-N 3-(2-bromophenyl)-2,2-dimethylpropanoic acid Chemical compound OC(=O)C(C)(C)CC1=CC=CC=C1Br PXLOONGLASJSGK-UHFFFAOYSA-N 0.000 description 1
- AQIXEPGDORPWBJ-UHFFFAOYSA-N 3-Pentanol Chemical compound CCC(O)CC AQIXEPGDORPWBJ-UHFFFAOYSA-N 0.000 description 1
- BBPRUNPUJIUXSE-DXKRWKNPSA-N 3-[2-[[(1S,2R,3S,4R)-3-[4-(pentylcarbamoyl)-1,3-oxazol-2-yl]-7-oxabicyclo[2.2.1]heptan-2-yl]methyl]phenyl]propanoic acid Chemical compound CCCCCNC(=O)C1=COC([C@H]2[C@H]([C@@H]3CC[C@H]2O3)CC=2C(=CC=CC=2)CCC(O)=O)=N1 BBPRUNPUJIUXSE-DXKRWKNPSA-N 0.000 description 1
- WUGQZFFCHPXWKQ-UHFFFAOYSA-N 3-aminopropanol Chemical compound NCCCO WUGQZFFCHPXWKQ-UHFFFAOYSA-N 0.000 description 1
- 125000004975 3-butenyl group Chemical group C(CC=C)* 0.000 description 1
- 125000006041 3-hexenyl group Chemical group 0.000 description 1
- XJMMNTGIMDZPMU-UHFFFAOYSA-N 3-methylglutaric acid Chemical compound OC(=O)CC(C)CC(O)=O XJMMNTGIMDZPMU-UHFFFAOYSA-N 0.000 description 1
- LWCIBYRXSHRIAP-UHFFFAOYSA-N 3-phenylmethoxypropane-1,2-diol Chemical compound OCC(O)COCC1=CC=CC=C1 LWCIBYRXSHRIAP-UHFFFAOYSA-N 0.000 description 1
- JVVRCYWZTJLJSG-UHFFFAOYSA-N 4-Dimethylaminophenol Substances CN(C)C1=CC=C(O)C=C1 JVVRCYWZTJLJSG-UHFFFAOYSA-N 0.000 description 1
- RKSMVPNZHBRNNS-UHFFFAOYSA-N 4-[2,6-ditert-butyl-4-[2-(3,5-ditert-butyl-4-hydroxyphenyl)sulfanylpropan-2-ylsulfanyl]phenoxy]-4-oxobutanoic acid Chemical compound CC(C)(C)C1=C(O)C(C(C)(C)C)=CC(SC(C)(C)SC=2C=C(C(OC(=O)CCC(O)=O)=C(C=2)C(C)(C)C)C(C)(C)C)=C1 RKSMVPNZHBRNNS-UHFFFAOYSA-N 0.000 description 1
- MXNQOXJLUJUCGE-UHFFFAOYSA-N 4-amino-2-(4,4-dimethyl-2-oxoimidazolidin-1-yl)-N-[3-(trifluoromethyl)phenyl]pyrimidine-5-carboxamide;hydrochloride Chemical compound Cl.O=C1NC(C)(C)CN1C(N=C1N)=NC=C1C(=O)NC1=CC=CC(C(F)(F)F)=C1 MXNQOXJLUJUCGE-UHFFFAOYSA-N 0.000 description 1
- ZLPXBWMVZANJJQ-UHFFFAOYSA-N 4-chloro-2-fluorobenzoic acid Chemical compound OC(=O)C1=CC=C(Cl)C=C1F ZLPXBWMVZANJJQ-UHFFFAOYSA-N 0.000 description 1
- WULIZEOAYMSIHS-UHFFFAOYSA-N 4-chloro-5-methylpyrrolo[3,2-d]pyrimidine-6-carbaldehyde Chemical compound C1=NC(Cl)=C2N(C)C(C=O)=CC2=N1 WULIZEOAYMSIHS-UHFFFAOYSA-N 0.000 description 1
- ZAPMJTYDMYNERA-UHFFFAOYSA-N 4-chloro-N-fluoroaniline Chemical compound FNC1=CC=C(Cl)C=C1 ZAPMJTYDMYNERA-UHFFFAOYSA-N 0.000 description 1
- 229960000549 4-dimethylaminophenol Drugs 0.000 description 1
- 125000006042 4-hexenyl group Chemical group 0.000 description 1
- CBJLBXCGJVTODE-UHFFFAOYSA-N 4-isocyanoaniline Chemical compound NC1=CC=C([N+]#[C-])C=C1 CBJLBXCGJVTODE-UHFFFAOYSA-N 0.000 description 1
- CIROOWQVERYDSK-UHFFFAOYSA-N 4-isocyanobenzonitrile Chemical compound [C-]#[N+]C1=CC=C(C#N)C=C1 CIROOWQVERYDSK-UHFFFAOYSA-N 0.000 description 1
- KVIZTDNKHOCNAM-UHFFFAOYSA-N 4-methylpiperazin-2-one Chemical group CN1CCNC(=O)C1 KVIZTDNKHOCNAM-UHFFFAOYSA-N 0.000 description 1
- 125000005986 4-piperidonyl group Chemical group 0.000 description 1
- STWODXDTKGTVCJ-UHFFFAOYSA-N 4-pyrrolidin-1-ylpiperidine Chemical compound C1CCCN1C1CCNCC1 STWODXDTKGTVCJ-UHFFFAOYSA-N 0.000 description 1
- 125000002471 4H-quinolizinyl group Chemical group C=1(C=CCN2C=CC=CC12)* 0.000 description 1
- BOSOTGBFJJEBMR-UHFFFAOYSA-N 5-(4-methylpiperazin-1-yl)-3,4-dihydroisoquinoline Chemical compound C1CN(C)CCN1C1=CC=CC2=C1CCN=C2 BOSOTGBFJJEBMR-UHFFFAOYSA-N 0.000 description 1
- AVBZQZPGIVMEPM-UHFFFAOYSA-N 5-(4-methylpiperazin-1-yl)isoquinoline Chemical compound C1CN(C)CCN1C1=CC=CC2=CN=CC=C12 AVBZQZPGIVMEPM-UHFFFAOYSA-N 0.000 description 1
- OCPDWZMOVWWQRW-UHFFFAOYSA-N 5-(4-pyrrolidin-1-ylpiperidin-1-yl)-3,4-dihydroisoquinoline Chemical compound C1CCCN1C1CCN(C=2C=3CCN=CC=3C=CC=2)CC1 OCPDWZMOVWWQRW-UHFFFAOYSA-N 0.000 description 1
- OUAZSWRXVXIZNW-UHFFFAOYSA-N 5-(4-pyrrolidin-1-ylpiperidin-1-yl)isoquinoline Chemical compound C1CCCN1C1CCN(C=2C3=CC=NC=C3C=CC=2)CC1 OUAZSWRXVXIZNW-UHFFFAOYSA-N 0.000 description 1
- OKRUMSWHDWKGHA-UHFFFAOYSA-N 5-bromopentanoyl chloride Chemical compound ClC(=O)CCCCBr OKRUMSWHDWKGHA-UHFFFAOYSA-N 0.000 description 1
- 125000006043 5-hexenyl group Chemical group 0.000 description 1
- 125000006163 5-membered heteroaryl group Chemical group 0.000 description 1
- MUBNVVQOLQPCFS-UHFFFAOYSA-N 5-piperazin-1-ylisoquinoline Chemical compound C1CNCCN1C1=CC=CC2=CN=CC=C12 MUBNVVQOLQPCFS-UHFFFAOYSA-N 0.000 description 1
- 101700064369 A2M Proteins 0.000 description 1
- 102100000684 A2M Human genes 0.000 description 1
- 101710037523 ACAT1 Proteins 0.000 description 1
- 101710037511 ACAT2 Proteins 0.000 description 1
- 229940005513 ANTIDEPRESSANTS Drugs 0.000 description 1
- 229940116904 ANTIINFLAMMATORY THERAPEUTIC RADIOPHARMACEUTICALS Drugs 0.000 description 1
- 229940022659 Acetaminophen Drugs 0.000 description 1
- 206010001052 Acute respiratory distress syndrome Diseases 0.000 description 1
- 102000019632 Acyl transferases Human genes 0.000 description 1
- 108091022082 Acyl transferases Proteins 0.000 description 1
- YKIOKAURTKXMSB-UHFFFAOYSA-N Adams's catalyst Chemical compound O=[Pt]=O YKIOKAURTKXMSB-UHFFFAOYSA-N 0.000 description 1
- 229920001817 Agar Polymers 0.000 description 1
- 229940023476 Agar Drugs 0.000 description 1
- QNZCBYKSOIHPEH-UHFFFAOYSA-N Apixaban Chemical compound C1=CC(OC)=CC=C1N1C(C(=O)N(CC2)C=3C=CC(=CC=3)N3C(CCCC3)=O)=C2C(C(N)=O)=N1 QNZCBYKSOIHPEH-UHFFFAOYSA-N 0.000 description 1
- 239000004475 Arginine Substances 0.000 description 1
- 229940104697 Arixtra Drugs 0.000 description 1
- IAOZJIPTCAWIRG-QWRGUYRKSA-N Aspartame Chemical compound OC(=O)C[C@H](N)C(=O)N[C@H](C(=O)OC)CC1=CC=CC=C1 IAOZJIPTCAWIRG-QWRGUYRKSA-N 0.000 description 1
- 229960003438 Aspartame Drugs 0.000 description 1
- 108010011485 Aspartame Proteins 0.000 description 1
- 241000416162 Astragalus gummifer Species 0.000 description 1
- 206010048632 Atrial thrombosis Diseases 0.000 description 1
- MGEVGECQZUIPSV-UHFFFAOYSA-N BOP reagent Chemical compound F[P-](F)(F)(F)(F)F.C1=CC=C2N(O[P+](N(C)C)(N(C)C)N(C)C)N=NC2=C1 MGEVGECQZUIPSV-UHFFFAOYSA-N 0.000 description 1
- 238000006237 Beckmann rearrangement reaction Methods 0.000 description 1
- 229940092782 Bentonite Drugs 0.000 description 1
- BNBQRQQYDMDJAH-UHFFFAOYSA-N Benzodioxan Chemical compound C1=CC=C2OCCOC2=C1 BNBQRQQYDMDJAH-UHFFFAOYSA-N 0.000 description 1
- HSDAJNMJOMSNEV-UHFFFAOYSA-N Benzyl chloroformate Chemical compound ClC(=O)OCC1=CC=CC=C1 HSDAJNMJOMSNEV-UHFFFAOYSA-N 0.000 description 1
- 229940096699 Bile acid sequestrants Drugs 0.000 description 1
- 108010007539 Blocking Antibodies Proteins 0.000 description 1
- 230000036868 Blood Concentration Effects 0.000 description 1
- 241000283690 Bos taurus Species 0.000 description 1
- 208000003174 Brain Neoplasms Diseases 0.000 description 1
- 210000000481 Breast Anatomy 0.000 description 1
- 206010006187 Breast cancer Diseases 0.000 description 1
- 229940009550 C1 esterase inhibitor Drugs 0.000 description 1
- 102100007260 C1S Human genes 0.000 description 1
- 229940030609 CALCIUM CHANNEL BLOCKERS Drugs 0.000 description 1
- 102100003147 CCDC85B Human genes 0.000 description 1
- 101710009963 CCDC85B Proteins 0.000 description 1
- FJDQFPXHSGXQBY-UHFFFAOYSA-L Caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 description 1
- 102000003922 Calcium Channels Human genes 0.000 description 1
- 108090000312 Calcium Channels Proteins 0.000 description 1
- 229960001080 Cangrelor Drugs 0.000 description 1
- 229920002134 Carboxymethyl cellulose Polymers 0.000 description 1
- 229940105329 Carboxymethylcellulose Drugs 0.000 description 1
- 108090000201 Carboxypeptidase B2 Proteins 0.000 description 1
- 102000003847 Carboxypeptidase B2 Human genes 0.000 description 1
- 102000005367 Carboxypeptidases Human genes 0.000 description 1
- 108010006303 Carboxypeptidases Proteins 0.000 description 1
- 229920001268 Cholestyramine Polymers 0.000 description 1
- RRGUKTPIGVIEKM-UHFFFAOYSA-N Cilostazol Chemical compound C=1C=C2NC(=O)CCC2=CC=1OCCCCC1=NN=NN1C1CCCCC1 RRGUKTPIGVIEKM-UHFFFAOYSA-N 0.000 description 1
- 230000037250 Clearance Effects 0.000 description 1
- HEMJJKBWTPKOJG-UHFFFAOYSA-N Clearol Chemical compound CC1=CC=C(C)C(OCCCC(C)(C)C(O)=O)=C1 HEMJJKBWTPKOJG-UHFFFAOYSA-N 0.000 description 1
- KNHUKKLJHYUCFP-UHFFFAOYSA-N Clofibrate Chemical compound CCOC(=O)C(C)(C)OC1=CC=C(Cl)C=C1 KNHUKKLJHYUCFP-UHFFFAOYSA-N 0.000 description 1
- 229940093530 Coenzyme A Drugs 0.000 description 1
- 229920002911 Colestipol Polymers 0.000 description 1
- GMRWGQCZJGVHKL-UHFFFAOYSA-N Colestipol Chemical compound ClCC1CO1.NCCNCCNCCNCCN GMRWGQCZJGVHKL-UHFFFAOYSA-N 0.000 description 1
- 108010048623 Collagen Receptors Proteins 0.000 description 1
- 102000005911 Complement C1 Inhibitor Protein Human genes 0.000 description 1
- 108010005563 Complement C1 Inhibitor Protein Proteins 0.000 description 1
- 108010028774 Complement C1s Proteins 0.000 description 1
- 229940072645 Coumadin Drugs 0.000 description 1
- 238000006969 Curtius rearrangement reaction Methods 0.000 description 1
- 229940109275 Cyclamate Drugs 0.000 description 1
- HPXRVTGHNJAIIH-UHFFFAOYSA-N Cyclohexanol Chemical compound OC1CCCCC1 HPXRVTGHNJAIIH-UHFFFAOYSA-N 0.000 description 1
- 229940030606 DIURETICS Drugs 0.000 description 1
- UZZWBUYVTBPQIV-UHFFFAOYSA-N DME dimethoxyethane Chemical compound COCCOC.COCCOC UZZWBUYVTBPQIV-UHFFFAOYSA-N 0.000 description 1
- CETRZFQIITUQQL-UHFFFAOYSA-N DMSO dimethylsulfoxide Chemical compound CS(C)=O.CS(C)=O CETRZFQIITUQQL-UHFFFAOYSA-N 0.000 description 1
- 229960003850 Dabigatran Drugs 0.000 description 1
- NNBZCPXTIHJBJL-UHFFFAOYSA-N Decalin Chemical compound C1CCCC2CCCCC21 NNBZCPXTIHJBJL-UHFFFAOYSA-N 0.000 description 1
- XYWBJDRHGNULKG-OUMQNGNKSA-N Desirudin Chemical compound C([C@@H](C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(N)=O)C(O)=O)NC(=O)[C@H](CC(O)=O)NC(=O)CNC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CC=1NC=NC=1)NC(=O)[C@H](CO)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H]1N(CCC1)C(=O)[C@H](CCCCN)NC(=O)[C@H]1N(CCC1)C(=O)[C@@H](NC(=O)CNC(=O)[C@H](CCC(O)=O)NC(=O)CNC(=O)[C@@H](NC(=O)[C@@H](NC(=O)[C@H]1NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CCCCN)NC(=O)[C@H](CCC(O)=O)NC(=O)CNC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CO)NC(=O)CNC(=O)[C@H](CC(C)C)NC(=O)[C@H]([C@@H](C)CC)NC(=O)[C@@H]2CSSC[C@@H](C(=O)N[C@@H](CCC(O)=O)C(=O)NCC(=O)N[C@@H](CO)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@H](C(=O)N[C@H](C(NCC(=O)N[C@@H](CCC(N)=O)C(=O)NCC(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CCCCN)C(=O)N2)=O)CSSC1)C(C)C)NC(=O)[C@H](CC(C)C)NC(=O)[C@H]1NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CCC(N)=O)NC(=O)CNC(=O)[C@H](CO)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H]([C@@H](C)O)NC(=O)[C@@H](NC(=O)[C@H](CC(O)=O)NC(=O)[C@@H](NC(=O)[C@H](CC=2C=CC(O)=CC=2)NC(=O)[C@@H](NC(=O)[C@@H](N)C(C)C)C(C)C)[C@@H](C)O)CSSC1)C(C)C)[C@@H](C)O)[C@@H](C)O)C1=CC=CC=C1 XYWBJDRHGNULKG-OUMQNGNKSA-N 0.000 description 1
- 238000006646 Dess-Martin oxidation reaction Methods 0.000 description 1
- NKLCNNUWBJBICK-UHFFFAOYSA-N Dess–Martin periodinane Chemical compound C1=CC=C2I(OC(=O)C)(OC(C)=O)(OC(C)=O)OC(=O)C2=C1 NKLCNNUWBJBICK-UHFFFAOYSA-N 0.000 description 1
- 229940087091 Dichlorotetrafluoroethane Drugs 0.000 description 1
- HPNMFZURTQLUMO-UHFFFAOYSA-N Diethylamine Chemical compound CCNCC HPNMFZURTQLUMO-UHFFFAOYSA-N 0.000 description 1
- MKRTXPORKIRPDG-UHFFFAOYSA-N Diphenylphosphoryl azide Chemical compound C=1C=CC=CC=1P(=O)(N=[N+]=[N-])C1=CC=CC=C1 MKRTXPORKIRPDG-UHFFFAOYSA-N 0.000 description 1
- 229940019337 Direct thrombin inhibitors Drugs 0.000 description 1
- 230000036947 Dissociation constant Effects 0.000 description 1
- 206010013710 Drug interaction Diseases 0.000 description 1
- 102100003966 ELANE Human genes 0.000 description 1
- 238000002965 ELISA Methods 0.000 description 1
- 206010014476 Elevated cholesterol Diseases 0.000 description 1
- 206010014498 Embolic stroke Diseases 0.000 description 1
- 206010048653 Enzyme inhibition Diseases 0.000 description 1
- 241000283086 Equidae Species 0.000 description 1
- OJCSPXHYDFONPU-UHFFFAOYSA-N EtOAc EtOAc Chemical compound CCOC(C)=O.CCOC(C)=O OJCSPXHYDFONPU-UHFFFAOYSA-N 0.000 description 1
- 210000002744 Extracellular Matrix Anatomy 0.000 description 1
- OLNTVTPDXPETLC-XPWALMASSA-N Ezetimibe Chemical compound N1([C@@H]([C@H](C1=O)CC[C@H](O)C=1C=CC(F)=CC=1)C=1C=CC(O)=CC=1)C1=CC=C(F)C=C1 OLNTVTPDXPETLC-XPWALMASSA-N 0.000 description 1
- 102100000368 F8 Human genes 0.000 description 1
- 101700070229 F8 Proteins 0.000 description 1
- 101700074227 F9 Proteins 0.000 description 1
- 206010016077 Factor IX deficiency Diseases 0.000 description 1
- 108010014172 Factor V Proteins 0.000 description 1
- 229960002297 Fenofibrate Drugs 0.000 description 1
- YMTINGFKWWXKFG-UHFFFAOYSA-N Fenofibrate Chemical compound C1=CC(OC(C)(C)C(=O)OC(C)C)=CC=C1C(=O)C1=CC=C(Cl)C=C1 YMTINGFKWWXKFG-UHFFFAOYSA-N 0.000 description 1
- 238000003547 Friedel-Crafts alkylation reaction Methods 0.000 description 1
- 238000005727 Friedel-Crafts reaction Methods 0.000 description 1
- 102100008842 GH1 Human genes 0.000 description 1
- 208000009471 Gastroesophageal Reflux Diseases 0.000 description 1
- 206010017885 Gastrooesophageal reflux disease Diseases 0.000 description 1
- 208000004104 Gestational Diabetes Diseases 0.000 description 1
- 102000003886 Glycoproteins Human genes 0.000 description 1
- 108090000288 Glycoproteins Proteins 0.000 description 1
- 108010051696 Growth Hormone Proteins 0.000 description 1
- 102100013175 HCAR2 Human genes 0.000 description 1
- 102100013173 HCAR3 Human genes 0.000 description 1
- JKMHFZQWWAIEOD-UHFFFAOYSA-N HEPES Chemical compound OCC[NH+]1CCN(CCS([O-])(=O)=O)CC1 JKMHFZQWWAIEOD-UHFFFAOYSA-N 0.000 description 1
- 229910004373 HOAc Inorganic materials 0.000 description 1
- 229940030482 HORMONAL CONTRACEPTIVES FOR SYSTEMIC USE Drugs 0.000 description 1
- 230000036499 Half live Effects 0.000 description 1
- 210000003709 Heart Valves Anatomy 0.000 description 1
- 208000009292 Hemophilia A Diseases 0.000 description 1
- 108090000481 Heparin cofactor II Proteins 0.000 description 1
- 102000004032 Heparin cofactor II Human genes 0.000 description 1
- DOJXGHGHTWFZHK-UHFFFAOYSA-N Hexachloroacetone Chemical compound ClC(Cl)(Cl)C(=O)C(Cl)(Cl)Cl DOJXGHGHTWFZHK-UHFFFAOYSA-N 0.000 description 1
- GNOIPBMMFNIUFM-UHFFFAOYSA-N Hexamethylphosphoramide Chemical compound CN(C)P(=O)(N(C)C)N(C)C GNOIPBMMFNIUFM-UHFFFAOYSA-N 0.000 description 1
- 210000001624 Hip Anatomy 0.000 description 1
- 206010020243 Hodgkin's disease Diseases 0.000 description 1
- 201000006743 Hodgkin's lymphoma Diseases 0.000 description 1
- 208000009576 Hypercholesterolemia Diseases 0.000 description 1
- 206010020850 Hyperthyroidism Diseases 0.000 description 1
- QWPPOHNGKGFGJK-UHFFFAOYSA-N Hypochlorous acid Chemical compound ClO QWPPOHNGKGFGJK-UHFFFAOYSA-N 0.000 description 1
- SYJRVVFAAIUVDH-UHFFFAOYSA-N IPA isopropanol Chemical compound CC(C)O.CC(C)O SYJRVVFAAIUVDH-UHFFFAOYSA-N 0.000 description 1
- 102100019336 ITGA2 Human genes 0.000 description 1
- 102100019332 ITGA2B Human genes 0.000 description 1
- 101710044247 ITGA2B Proteins 0.000 description 1
- 229950004274 Ifetroban Drugs 0.000 description 1
- 206010056997 Impaired fasting glucose Diseases 0.000 description 1
- 206010061216 Infarction Diseases 0.000 description 1
- 206010022114 Injury Diseases 0.000 description 1
- RBTARNINKXHZNM-UHFFFAOYSA-K Iron(III) chloride Chemical compound Cl[Fe](Cl)Cl RBTARNINKXHZNM-UHFFFAOYSA-K 0.000 description 1
- 206010061256 Ischaemic stroke Diseases 0.000 description 1
- ZXEKIIBDNHEJCQ-UHFFFAOYSA-N Isobutanol Chemical compound CC(C)CO ZXEKIIBDNHEJCQ-UHFFFAOYSA-N 0.000 description 1
- 210000004731 Jugular Veins Anatomy 0.000 description 1
- 102100005678 KLKB1 Human genes 0.000 description 1
- 101700062538 KLKB1 Proteins 0.000 description 1
- 101700056073 KNG Proteins 0.000 description 1
- 101700036456 KNG1 Proteins 0.000 description 1
- OZWKMVRBQXNZKK-UHFFFAOYSA-N Ketorolac Chemical compound OC(=O)C1CCN2C1=CC=C2C(=O)C1=CC=CC=C1 OZWKMVRBQXNZKK-UHFFFAOYSA-N 0.000 description 1
- 210000003127 Knee Anatomy 0.000 description 1
- ODKSFYDXXFIFQN-BYPYZUCNSA-P L-argininium(2+) Chemical compound NC(=[NH2+])NCCC[C@H]([NH3+])C(O)=O ODKSFYDXXFIFQN-BYPYZUCNSA-P 0.000 description 1
- QUOGESRFPZDMMT-YFKPBYRVSA-N L-homoarginine Chemical compound OC(=O)[C@@H](N)CCCCNC(N)=N QUOGESRFPZDMMT-YFKPBYRVSA-N 0.000 description 1
- AHLPHDHHMVZTML-BYPYZUCNSA-N L-ornithine Chemical compound NCCC[C@H](N)C(O)=O AHLPHDHHMVZTML-BYPYZUCNSA-N 0.000 description 1
- 101710009221 LD Proteins 0.000 description 1
- 102100004193 LIPG Human genes 0.000 description 1
- 101700058972 LIPG Proteins 0.000 description 1
- 229950010645 Lanoteplase Drugs 0.000 description 1
- 229940067606 Lecithin Drugs 0.000 description 1
- 235000010643 Leucaena leucocephala Nutrition 0.000 description 1
- 240000007472 Leucaena leucocephala Species 0.000 description 1
- 108010028275 Leukocyte Elastase Proteins 0.000 description 1
- 210000000265 Leukocytes Anatomy 0.000 description 1
- PCZOHLXUXFIOCF-BXMDZJJMSA-N Lovastatin Chemical compound C([C@H]1[C@@H](C)C=CC2=C[C@H](C)C[C@@H]([C@H]12)OC(=O)[C@@H](C)CC)C[C@@H]1C[C@@H](O)CC(=O)O1 PCZOHLXUXFIOCF-BXMDZJJMSA-N 0.000 description 1
- 229940118179 Lovenox Drugs 0.000 description 1
- 210000004072 Lung Anatomy 0.000 description 1
- 208000009856 Lung Disease Diseases 0.000 description 1
- 239000004472 Lysine Substances 0.000 description 1
- NCBZRJODKRCREW-UHFFFAOYSA-N M-Anisidine Chemical compound COC1=CC=CC(N)=C1 NCBZRJODKRCREW-UHFFFAOYSA-N 0.000 description 1
- 101710027709 MAGEE2 Proteins 0.000 description 1
- 102100019305 MTTP Human genes 0.000 description 1
- COTNUBDHGSIOTA-UHFFFAOYSA-N MeOH methanol Chemical compound OC.OC COTNUBDHGSIOTA-UHFFFAOYSA-N 0.000 description 1
- 230000036740 Metabolism Effects 0.000 description 1
- 206010027476 Metastasis Diseases 0.000 description 1
- 229920000168 Microcrystalline cellulose Polymers 0.000 description 1
- 229920001410 Microfiber Polymers 0.000 description 1
- 206010061532 Mitral valve disease Diseases 0.000 description 1
- 238000006751 Mitsunobu reaction Methods 0.000 description 1
- 239000004368 Modified starch Substances 0.000 description 1
- 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 description 1
- 210000000214 Mouth Anatomy 0.000 description 1
- 208000002089 Myocardial Stunning Diseases 0.000 description 1
- MBHINSULENHCMF-UHFFFAOYSA-N N,N-dimethylpropanamide Chemical compound CCC(=O)N(C)C MBHINSULENHCMF-UHFFFAOYSA-N 0.000 description 1
- PEECTLLHENGOKU-UHFFFAOYSA-N N,N-dimethylpyridin-4-amine Chemical compound CN(C)C1=CC=NC=C1.CN(C)C1=CC=NC=C1 PEECTLLHENGOKU-UHFFFAOYSA-N 0.000 description 1
- DAKZISABEDGGSV-UHFFFAOYSA-N N-(2-aminoethyl)acetamide Chemical compound CC(=O)NCCN DAKZISABEDGGSV-UHFFFAOYSA-N 0.000 description 1
- CHMBIJAOCISYEW-UHFFFAOYSA-N N-(4-aminophenyl)acetamide Chemical compound CC(=O)NC1=CC=C(N)C=C1 CHMBIJAOCISYEW-UHFFFAOYSA-N 0.000 description 1
- VYNKVNDKAOGAAQ-RUZDIDTESA-N N-[(1R)-2-[4-(1-methylpiperidin-4-yl)piperazin-1-yl]-2-oxo-1-phenylethyl]-1H-indole-6-carboxamide Chemical compound C1CN(C)CCC1N1CCN(C(=O)[C@H](NC(=O)C=2C=C3NC=CC3=CC=2)C=2C=CC=CC=2)CC1 VYNKVNDKAOGAAQ-RUZDIDTESA-N 0.000 description 1
- 125000003047 N-acetyl group Chemical group 0.000 description 1
- GSCCALZHGUWNJW-UHFFFAOYSA-N N-cyclohexyl-N-methylcyclohexanamine Chemical compound C1CCCCC1N(C)C1CCCCC1 GSCCALZHGUWNJW-UHFFFAOYSA-N 0.000 description 1
- WOOWBQQQJXZGIE-UHFFFAOYSA-N N-ethyl-N-propan-2-ylpropan-2-amine Chemical compound CCN(C(C)C)C(C)C.CCN(C(C)C)C(C)C WOOWBQQQJXZGIE-UHFFFAOYSA-N 0.000 description 1
- NQTADLQHYWFPDB-UHFFFAOYSA-N N-hydroxy-Succinimide Chemical compound ON1C(=O)CCC1=O NQTADLQHYWFPDB-UHFFFAOYSA-N 0.000 description 1
- OHLUUHNLEMFGTQ-UHFFFAOYSA-N N-methylacetamide Chemical compound CNC(C)=O OHLUUHNLEMFGTQ-UHFFFAOYSA-N 0.000 description 1
- ATHHXGZTWNVVOU-UHFFFAOYSA-N N-methylformamide Chemical compound CNC=O ATHHXGZTWNVVOU-UHFFFAOYSA-N 0.000 description 1
- 229940097496 Nasal Spray Drugs 0.000 description 1
- 229940033757 Niaspan Drugs 0.000 description 1
- 108070000019 Nicotinic acid receptor Proteins 0.000 description 1
- LYGJENNIWJXYER-UHFFFAOYSA-N Nitromethane Chemical compound C[N+]([O-])=O LYGJENNIWJXYER-UHFFFAOYSA-N 0.000 description 1
- 206010029592 Non-Hodgkin's lymphomas Diseases 0.000 description 1
- DQGOXYCNTXUQCL-UHFFFAOYSA-N O=C(O[N+]#[C-])c1ccccc1 Chemical compound O=C(O[N+]#[C-])c1ccccc1 DQGOXYCNTXUQCL-UHFFFAOYSA-N 0.000 description 1
- ZADPBFCGQRWHPN-UHFFFAOYSA-N OBO Chemical compound OBO ZADPBFCGQRWHPN-UHFFFAOYSA-N 0.000 description 1
- GUBGYTABKSRVRQ-DCSYEGIMSA-N OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)[C@H](O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O Chemical compound OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)[C@H](O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-DCSYEGIMSA-N 0.000 description 1
- 229940074726 OPHTHALMOLOGIC ANTIINFLAMMATORY AGENTS Drugs 0.000 description 1
- 229940012843 Omega-3 Fatty Acids Drugs 0.000 description 1
- 230000035536 Oral bioavailability Effects 0.000 description 1
- 229960003104 Ornithine Drugs 0.000 description 1
- 206010033128 Ovarian cancer Diseases 0.000 description 1
- 210000001672 Ovary Anatomy 0.000 description 1
- 241000283898 Ovis Species 0.000 description 1
- 102100005352 PCSK9 Human genes 0.000 description 1
- 101700000651 PCSK9 Proteins 0.000 description 1
- 108010028924 PPAR alpha Proteins 0.000 description 1
- 101700002274 PZP Proteins 0.000 description 1
- 208000008443 Pancreatic Carcinoma Diseases 0.000 description 1
- 241000282520 Papio Species 0.000 description 1
- 229940049954 Penicillin Drugs 0.000 description 1
- JGSARLDLIJGVTE-MBNYWOFBSA-N Penicillin G Chemical compound N([C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)C(=O)CC1=CC=CC=C1 JGSARLDLIJGVTE-MBNYWOFBSA-N 0.000 description 1
- 102000035443 Peptidases Human genes 0.000 description 1
- CPJSUEIXXCENMM-UHFFFAOYSA-N Phenacetin Chemical compound CCOC1=CC=C(NC(C)=O)C=C1 CPJSUEIXXCENMM-UHFFFAOYSA-N 0.000 description 1
- 229960003893 Phenacetin Drugs 0.000 description 1
- 229940067631 Phospholipids Drugs 0.000 description 1
- 229960005235 Piperonyl Butoxide Drugs 0.000 description 1
- 229940012957 Plasmin Drugs 0.000 description 1
- 108010077971 Plasminogen Inactivators Proteins 0.000 description 1
- 102000010752 Plasminogen Inactivators Human genes 0.000 description 1
- 229940020573 Plavix Drugs 0.000 description 1
- 239000004698 Polyethylene (PE) Substances 0.000 description 1
- 206010051077 Post procedural haemorrhage Diseases 0.000 description 1
- 229960002965 Pravastatin Drugs 0.000 description 1
- TUZYXOIXSAXUGO-PZAWKZKUSA-N Pravastatin Chemical compound C1=C[C@H](C)[C@H](CC[C@@H](O)C[C@@H](O)CC(O)=O)[C@H]2[C@@H](OC(=O)[C@@H](C)CC)C[C@H](O)C=C21 TUZYXOIXSAXUGO-PZAWKZKUSA-N 0.000 description 1
- 241000288906 Primates Species 0.000 description 1
- FYPMFJGVHOHGLL-UHFFFAOYSA-N Probucol Chemical compound C=1C(C(C)(C)C)=C(O)C(C(C)(C)C)=CC=1SC(C)(C)SC1=CC(C(C)(C)C)=C(O)C(C(C)(C)C)=C1 FYPMFJGVHOHGLL-UHFFFAOYSA-N 0.000 description 1
- FVSKHRXBFJPNKK-UHFFFAOYSA-N Propionitrile Chemical compound CCC#N FVSKHRXBFJPNKK-UHFFFAOYSA-N 0.000 description 1
- 102000000033 Purinergic Receptors Human genes 0.000 description 1
- 108010080192 Purinergic Receptors Proteins 0.000 description 1
- VIAFLMPQBHAMLI-UHFFFAOYSA-N PyBOP Chemical compound F[P-](F)(F)(F)(F)F.C1CCCN1[P+](N1CCCC1)(N1CCCC1)ON1C2=CC=CC=C2N=N1 VIAFLMPQBHAMLI-UHFFFAOYSA-N 0.000 description 1
- 229940086526 Renin-inhibitors Drugs 0.000 description 1
- 208000004124 Rheumatic Heart Disease Diseases 0.000 description 1
- KGFYHTZWPPHNLQ-AWEZNQCLSA-N Rivaroxaban Chemical compound S1C(Cl)=CC=C1C(=O)NC[C@@H]1OC(=O)N(C=2C=CC(=CC=2)N2C(COCC2)=O)C1 KGFYHTZWPPHNLQ-AWEZNQCLSA-N 0.000 description 1
- YASAKCUCGLMORW-UHFFFAOYSA-N Rosiglitazone Chemical compound C=1C=CC=NC=1N(C)CCOC(C=C1)=CC=C1CC1SC(=O)NC1=O YASAKCUCGLMORW-UHFFFAOYSA-N 0.000 description 1
- BPRHUIZQVSMCRT-VEUZHWNKSA-N Rosuvastatin Chemical compound CC(C)C1=NC(N(C)S(C)(=O)=O)=NC(C=2C=CC(F)=CC=2)=C1\C=C\[C@@H](O)C[C@@H](O)CC(O)=O BPRHUIZQVSMCRT-VEUZHWNKSA-N 0.000 description 1
- 239000005092 Ruthenium Substances 0.000 description 1
- 102100019388 SOAT1 Human genes 0.000 description 1
- 101700025022 SOAT1 Proteins 0.000 description 1
- 102100019390 SOAT2 Human genes 0.000 description 1
- 101700032213 SOAT2 Proteins 0.000 description 1
- YGSDEFSMJLZEOE-UHFFFAOYSA-N Salicylic acid Chemical compound OC(=O)C1=CC=CC=C1O YGSDEFSMJLZEOE-UHFFFAOYSA-N 0.000 description 1
- 229940076279 Serotonin Drugs 0.000 description 1
- BNRNXUUZRGQAQC-UHFFFAOYSA-N Sildenafil Chemical compound CCCC1=NN(C)C(C(N2)=O)=C1N=C2C(C(=CC=1)OCC)=CC=1S(=O)(=O)N1CCN(C)CC1 BNRNXUUZRGQAQC-UHFFFAOYSA-N 0.000 description 1
- RYMZZMVNJRMUDD-HGQWONQESA-N Simvastatin Chemical compound C([C@H]1[C@@H](C)C=CC2=C[C@H](C)C[C@@H]([C@H]12)OC(=O)C(C)(C)CC)C[C@@H]1C[C@@H](O)CC(=O)O1 RYMZZMVNJRMUDD-HGQWONQESA-N 0.000 description 1
- LGJMUZUPVCAVPU-JFBKYFIKSA-N Sitostanol Natural products O[C@@H]1C[C@H]2[C@@](C)([C@@H]3[C@@H]([C@H]4[C@@](C)([C@@H]([C@@H](CC[C@H](C(C)C)CC)C)CC4)CC3)CC2)CC1 LGJMUZUPVCAVPU-JFBKYFIKSA-N 0.000 description 1
- 229940005550 Sodium alginate Drugs 0.000 description 1
- UDIPTWFVPPPURJ-UHFFFAOYSA-M Sodium cyclamate Chemical compound [Na+].[O-]S(=O)(=O)NC1CCCCC1 UDIPTWFVPPPURJ-UHFFFAOYSA-M 0.000 description 1
- BCKXLBQYZLBQEK-KVVVOXFISA-M Sodium oleate Chemical compound [Na+].CCCCCCCC\C=C/CCCCCCCC([O-])=O BCKXLBQYZLBQEK-KVVVOXFISA-M 0.000 description 1
- RYYKJJJTJZKILX-UHFFFAOYSA-M Sodium stearate Chemical compound [Na+].CCCCCCCCCCCCCCCCCC([O-])=O RYYKJJJTJZKILX-UHFFFAOYSA-M 0.000 description 1
- 239000004133 Sodium thiosulphate Substances 0.000 description 1
- 102000037245 Sodium–hydrogen antiporter Human genes 0.000 description 1
- 108091006587 Sodium–hydrogen antiporter Proteins 0.000 description 1
- 208000010110 Spontaneous Platelet Aggregation Diseases 0.000 description 1
- 102000005782 Squalene Monooxygenase Human genes 0.000 description 1
- 108020003891 Squalene Monooxygenase Proteins 0.000 description 1
- 238000006619 Stille reaction Methods 0.000 description 1
- 210000002784 Stomach Anatomy 0.000 description 1
- 241000282887 Suidae Species 0.000 description 1
- HXJUTPCZVOIRIF-UHFFFAOYSA-N Sulfolane Chemical compound O=S1(=O)CCCC1 HXJUTPCZVOIRIF-UHFFFAOYSA-N 0.000 description 1
- 238000006069 Suzuki reaction reaction Methods 0.000 description 1
- WROMPOXWARCANT-UHFFFAOYSA-N TFA trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F.OC(=O)C(F)(F)F WROMPOXWARCANT-UHFFFAOYSA-N 0.000 description 1
- 229960000216 Tenecteplase Drugs 0.000 description 1
- 108010039185 Tenecteplase Proteins 0.000 description 1
- MSXVEPNJUHWQHW-UHFFFAOYSA-N Tert-Amyl alcohol Chemical compound CCC(C)(C)O MSXVEPNJUHWQHW-UHFFFAOYSA-N 0.000 description 1
- WMOVHXAZOJBABW-UHFFFAOYSA-N Tert-Butyl acetate Chemical compound CC(=O)OC(C)(C)C WMOVHXAZOJBABW-UHFFFAOYSA-N 0.000 description 1
- JRMUNVKIHCOMHV-UHFFFAOYSA-M Tetra-n-butylammonium bromide Chemical compound [Br-].CCCC[N+](CCCC)(CCCC)CCCC JRMUNVKIHCOMHV-UHFFFAOYSA-M 0.000 description 1
- 241001061127 Thione Species 0.000 description 1
- 229960003766 Thrombin (Human) Drugs 0.000 description 1
- 208000001435 Thromboembolism Diseases 0.000 description 1
- 210000001685 Thyroid Gland Anatomy 0.000 description 1
- 208000005057 Thyrotoxicosis Diseases 0.000 description 1
- OEKWJQXRCDYSHL-FNOIDJSQSA-N Ticagrelor Chemical compound C1([C@@H]2C[C@H]2NC=2N=C(N=C3N([C@H]4[C@@H]([C@H](O)[C@@H](OCCO)C4)O)N=NC3=2)SCCC)=CC=C(F)C(F)=C1 OEKWJQXRCDYSHL-FNOIDJSQSA-N 0.000 description 1
- AXZWODMDQAVCJE-UHFFFAOYSA-L Tin(II) chloride Chemical compound [Cl-].[Cl-].[Sn+2] AXZWODMDQAVCJE-UHFFFAOYSA-L 0.000 description 1
- 102000019400 Tissue-type plasminogen activator Human genes 0.000 description 1
- 229940116362 Tragacanth Drugs 0.000 description 1
- 229920001615 Tragacanth Polymers 0.000 description 1
- IMFACGCPASFAPR-UHFFFAOYSA-N Tributylamine Chemical compound CCCCN(CCCC)CCCC IMFACGCPASFAPR-UHFFFAOYSA-N 0.000 description 1
- 239000007983 Tris buffer Substances 0.000 description 1
- HWKQNAWCHQMZHK-UHFFFAOYSA-N Trolnitrate Chemical compound [O-][N+](=O)OCCN(CCO[N+]([O-])=O)CCO[N+]([O-])=O HWKQNAWCHQMZHK-UHFFFAOYSA-N 0.000 description 1
- 206010058990 Venous occlusion Diseases 0.000 description 1
- ZBGXUVOIWDMMJE-QHNZEKIYSA-N Vorapaxar Chemical compound C(/[C@@H]1[C@H]2[C@H](C(O[C@@H]2C)=O)C[C@H]2[C@H]1CC[C@H](C2)NC(=O)OCC)=C\C(N=C1)=CC=C1C1=CC=CC(F)=C1 ZBGXUVOIWDMMJE-QHNZEKIYSA-N 0.000 description 1
- HEBKCHPVOIAQTA-SCDXWVJYSA-N Xylitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)CO HEBKCHPVOIAQTA-SCDXWVJYSA-N 0.000 description 1
- 229960002675 Xylitol Drugs 0.000 description 1
- 240000008042 Zea mays Species 0.000 description 1
- 235000002017 Zea mays subsp mays Nutrition 0.000 description 1
- WGOBPPNNYVSJTE-HSZRJFAPSA-N [(2R)-1-diphenylphosphanylpropan-2-yl]-diphenylphosphane Chemical compound C([C@@H](C)P(C=1C=CC=CC=1)C=1C=CC=CC=1)P(C=1C=CC=CC=1)C1=CC=CC=C1 WGOBPPNNYVSJTE-HSZRJFAPSA-N 0.000 description 1
- DGEZNRSVGBDHLK-UHFFFAOYSA-N [1,10]phenanthroline Chemical compound C1=CN=C2C3=NC=CC=C3C=CC2=C1 DGEZNRSVGBDHLK-UHFFFAOYSA-N 0.000 description 1
- HGMSJMJPXGGEBP-UHFFFAOYSA-N [4-[3-(4-ethylphenyl)butyl]phenyl]-trimethylazanium Chemical compound C1=CC(CC)=CC=C1C(C)CCC1=CC=C([N+](C)(C)C)C=C1 HGMSJMJPXGGEBP-UHFFFAOYSA-N 0.000 description 1
- SORGEQQSQGNZFI-UHFFFAOYSA-N [azido(phenoxy)phosphoryl]oxybenzene Chemical compound C=1C=CC=CC=1OP(=O)(N=[N+]=[N-])OC1=CC=CC=C1 SORGEQQSQGNZFI-UHFFFAOYSA-N 0.000 description 1
- PAEBIVWUMLRPSK-IDTAVKCVSA-N [dichloro-[[[(2R,3S,4R,5R)-3,4-dihydroxy-5-[6-(2-methylsulfanylethylamino)-2-(3,3,3-trifluoropropylsulfanyl)purin-9-yl]oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-hydroxyphosphoryl]methyl]phosphonic acid Chemical compound C1=NC=2C(NCCSC)=NC(SCCC(F)(F)F)=NC=2N1[C@@H]1O[C@H](COP(O)(=O)OP(O)(=O)C(Cl)(Cl)P(O)(O)=O)[C@@H](O)[C@H]1O PAEBIVWUMLRPSK-IDTAVKCVSA-N 0.000 description 1
- BIABKPAXSLKGLN-UHFFFAOYSA-N [dimethylamino(2H-triazolo[4,5-b]pyridin-7-yloxy)methylidene]-dimethylazanium;hexafluorophosphate Chemical compound F[P-](F)(F)(F)(F)F.CN(C)C(=[N+](C)C)OC1=CC=NC2=C1N=NN2 BIABKPAXSLKGLN-UHFFFAOYSA-N 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-M acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 125000000641 acridinyl group Chemical group C1(=CC=CC2=NC3=CC=CC=C3C=C12)* 0.000 description 1
- 229920002877 acrylic styrene acrylonitrile Polymers 0.000 description 1
- 230000004658 acute-phase response Effects 0.000 description 1
- 125000002252 acyl group Chemical group 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- 239000000362 adenosine triphosphatase inhibitor Substances 0.000 description 1
- 230000000240 adjuvant Effects 0.000 description 1
- 239000002671 adjuvant Substances 0.000 description 1
- 239000000674 adrenergic antagonist Substances 0.000 description 1
- 230000001058 adult Effects 0.000 description 1
- 201000000028 adult respiratory distress syndrome Diseases 0.000 description 1
- 239000008272 agar Substances 0.000 description 1
- 235000010419 agar Nutrition 0.000 description 1
- 239000003741 agents affecting lipid metabolism Substances 0.000 description 1
- 235000010443 alginic acid Nutrition 0.000 description 1
- 229920000615 alginic acid Polymers 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 125000006177 alkyl benzyl group Chemical group 0.000 description 1
- 229910052782 aluminium Inorganic materials 0.000 description 1
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminum Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 description 1
- QGZKDVFQNNGYKY-UHFFFAOYSA-N ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 1
- 239000000908 ammonium hydroxide Substances 0.000 description 1
- 239000004037 angiogenesis inhibitor Substances 0.000 description 1
- 239000000587 angiogenesis modulating agent Substances 0.000 description 1
- 230000003288 anthiarrhythmic Effects 0.000 description 1
- 125000002178 anthracenyl group Chemical group C1(=CC=CC2=CC3=CC=CC=C3C=C12)* 0.000 description 1
- 230000001396 anti-anti-diuretic Effects 0.000 description 1
- 230000000879 anti-atherosclerotic Effects 0.000 description 1
- 230000001093 anti-cancer Effects 0.000 description 1
- 230000001430 anti-depressive Effects 0.000 description 1
- 230000003110 anti-inflammatory Effects 0.000 description 1
- 239000002260 anti-inflammatory agent Substances 0.000 description 1
- 230000002253 anti-ischaemic Effects 0.000 description 1
- 230000000845 anti-microbial Effects 0.000 description 1
- 239000000883 anti-obesity agent Substances 0.000 description 1
- 230000003262 anti-osteoporosis Effects 0.000 description 1
- 230000001028 anti-proliferant Effects 0.000 description 1
- 230000000767 anti-ulcer Effects 0.000 description 1
- 108090001123 antibodies Proteins 0.000 description 1
- 102000004965 antibodies Human genes 0.000 description 1
- 239000000935 antidepressant agent Substances 0.000 description 1
- 239000003472 antidiabetic agent Substances 0.000 description 1
- 239000004599 antimicrobial Substances 0.000 description 1
- 239000002246 antineoplastic agent Substances 0.000 description 1
- 239000000164 antipsychotic agent Substances 0.000 description 1
- 239000003443 antiviral agent Substances 0.000 description 1
- 239000002249 anxiolytic agent Substances 0.000 description 1
- 229960003886 apixaban Drugs 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 239000007900 aqueous suspension Substances 0.000 description 1
- 125000000511 arginine group Chemical group N[C@@H](CCCNC(N)=N)C(=O)* 0.000 description 1
- 125000006615 aromatic heterocyclic group Chemical group 0.000 description 1
- 125000005418 aryl aryl group Chemical group 0.000 description 1
- 239000000605 aspartame Substances 0.000 description 1
- 235000010357 aspartame Nutrition 0.000 description 1
- 229960005370 atorvastatin Drugs 0.000 description 1
- XUKUURHRXDUEBC-KAYWLYCHSA-N atorvastatin Chemical compound C=1C=CC=CC=1C1=C(C=2C=CC(F)=CC=2)N(CC[C@@H](O)C[C@@H](O)CC(O)=O)C(C(C)C)=C1C(=O)NC1=CC=CC=C1 XUKUURHRXDUEBC-KAYWLYCHSA-N 0.000 description 1
- 125000002393 azetidinyl group Chemical group 0.000 description 1
- 125000004931 azocinyl group Chemical group N1=C(C=CC=CC=C1)* 0.000 description 1
- 201000005008 bacterial sepsis Diseases 0.000 description 1
- 239000000440 bentonite Substances 0.000 description 1
- 229910000278 bentonite Inorganic materials 0.000 description 1
- 235000012216 bentonite Nutrition 0.000 description 1
- 125000004618 benzofuryl group Chemical group O1C(=CC2=C1C=CC=C2)* 0.000 description 1
- 125000003354 benzotriazolyl group Chemical group N1N=NC2=C1C=CC=C2* 0.000 description 1
- QUMFBQOZYANIQN-UHFFFAOYSA-N benzyl 3,3-dimethyl-5-[4-[(2-methylpropan-2-yl)oxycarbonyl]piperazin-1-yl]-1,4-dihydroisoquinoline-2-carboxylate Chemical compound C1CN(C(=O)OC(C)(C)C)CCN1C1=CC=CC2=C1CC(C)(C)N(C(=O)OCC=1C=CC=CC=1)C2 QUMFBQOZYANIQN-UHFFFAOYSA-N 0.000 description 1
- JVEFLZRXBZVTHA-UHFFFAOYSA-N benzyl 5-bromo-3,3-dimethyl-1,4-dihydroisoquinoline-2-carboxylate Chemical compound CC1(C)CC2=C(Br)C=CC=C2CN1C(=O)OCC1=CC=CC=C1 JVEFLZRXBZVTHA-UHFFFAOYSA-N 0.000 description 1
- 235000019445 benzyl alcohol Nutrition 0.000 description 1
- 125000001584 benzyloxycarbonyl group Chemical group C(=O)(OCC1=CC=CC=C1)* 0.000 description 1
- 229960000626 benzylpenicillin Drugs 0.000 description 1
- 102000012740 beta Adrenergic Receptors Human genes 0.000 description 1
- 108010079452 beta Adrenergic Receptors Proteins 0.000 description 1
- 239000002876 beta blocker Substances 0.000 description 1
- 229920000080 bile acid sequestrant Polymers 0.000 description 1
- 230000000975 bioactive Effects 0.000 description 1
- 239000012472 biological sample Substances 0.000 description 1
- 230000000903 blocking Effects 0.000 description 1
- 239000001045 blue dye Substances 0.000 description 1
- 150000001642 boronic acid derivatives Chemical class 0.000 description 1
- 201000005216 brain cancer Diseases 0.000 description 1
- 125000001246 bromo group Chemical group Br* 0.000 description 1
- 239000006172 buffering agent Substances 0.000 description 1
- 125000000480 butynyl group Chemical group [*]C#CC([H])([H])C([H])([H])[H] 0.000 description 1
- 239000007963 capsule composition Substances 0.000 description 1
- 150000004657 carbamic acid derivatives Chemical class 0.000 description 1
- 125000004623 carbolinyl group Chemical group 0.000 description 1
- 235000010948 carboxy methyl cellulose Nutrition 0.000 description 1
- 239000008112 carboxymethyl-cellulose Substances 0.000 description 1
- 230000000747 cardiac effect Effects 0.000 description 1
- HEDRZPFGACZZDS-MICDWDOJSA-N cdcl3 Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 1
- 230000004640 cellular pathway Effects 0.000 description 1
- 150000001780 cephalosporins Chemical class 0.000 description 1
- 238000003889 chemical engineering Methods 0.000 description 1
- 125000003636 chemical group Chemical group 0.000 description 1
- HGAZMNJKRQFZKS-UHFFFAOYSA-N chloroethene;ethenyl acetate Chemical compound ClC=C.CC(=O)OC=C HGAZMNJKRQFZKS-UHFFFAOYSA-N 0.000 description 1
- 230000001906 cholesterol absorption Effects 0.000 description 1
- 239000003354 cholesterol ester transfer protein inhibitor Substances 0.000 description 1
- 125000004230 chromenyl group Chemical group O1C(C=CC2=CC=CC=C12)* 0.000 description 1
- 230000001684 chronic Effects 0.000 description 1
- 229960004588 cilostazol Drugs 0.000 description 1
- 125000000259 cinnolinyl group Chemical group N1=NC(=CC2=CC=CC=C12)* 0.000 description 1
- 230000004087 circulation Effects 0.000 description 1
- 230000035512 clearance Effects 0.000 description 1
- 238000003776 cleavage reaction Methods 0.000 description 1
- 229960001214 clofibrate Drugs 0.000 description 1
- FDEODCTUSIWGLK-RSAXXLAASA-N clopidogrel sulfate Chemical compound [H+].OS([O-])(=O)=O.C1([C@H](N2CC=3C=CSC=3CC2)C(=O)OC)=CC=CC=C1Cl FDEODCTUSIWGLK-RSAXXLAASA-N 0.000 description 1
- 239000011248 coating agent Substances 0.000 description 1
- 238000000576 coating method Methods 0.000 description 1
- 229960004126 codeine Drugs 0.000 description 1
- 239000005516 coenzyme A Substances 0.000 description 1
- 229960002604 colestipol Drugs 0.000 description 1
- 201000011231 colorectal cancer Diseases 0.000 description 1
- 238000004040 coloring Methods 0.000 description 1
- 239000002299 complementary DNA Substances 0.000 description 1
- 235000008504 concentrate Nutrition 0.000 description 1
- 239000012141 concentrate Substances 0.000 description 1
- 235000005822 corn Nutrition 0.000 description 1
- 235000005824 corn Nutrition 0.000 description 1
- 201000008739 coronary artery disease Diseases 0.000 description 1
- 235000012343 cottonseed oil Nutrition 0.000 description 1
- 239000002385 cottonseed oil Substances 0.000 description 1
- 239000006071 cream Substances 0.000 description 1
- 239000011549 crystallization solution Substances 0.000 description 1
- 238000010192 crystallographic characterization Methods 0.000 description 1
- XFXPMWWXUTWYJX-UHFFFAOYSA-N cyanide Chemical compound N#[C-] XFXPMWWXUTWYJX-UHFFFAOYSA-N 0.000 description 1
- 125000001047 cyclobutenyl group Chemical group C1(=CCC1)* 0.000 description 1
- 125000000582 cycloheptyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- UVCMYJYTEVWUCV-UHFFFAOYSA-N cyclononylcyclononane Chemical compound C1CCCCCCCC1C1CCCCCCCC1 UVCMYJYTEVWUCV-UHFFFAOYSA-N 0.000 description 1
- RRKODOZNUZCUBN-UHFFFAOYSA-N cycloocta-1,3-diene Chemical compound C1CCC=CC=CC1 RRKODOZNUZCUBN-UHFFFAOYSA-N 0.000 description 1
- 125000000522 cyclooctenyl group Chemical group C1(=CCCCCCC1)* 0.000 description 1
- 125000000640 cyclooctyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C([H])([H])C1([H])[H] 0.000 description 1
- 125000002433 cyclopentenyl group Chemical group C1(=CCCC1)* 0.000 description 1
- HTJDQJBWANPRPF-UHFFFAOYSA-N cyclopropylamine Chemical compound NC1CC1 HTJDQJBWANPRPF-UHFFFAOYSA-N 0.000 description 1
- 230000009089 cytolysis Effects 0.000 description 1
- YBSJFWOBGCMAKL-UHFFFAOYSA-N dabigatran Chemical compound N=1C2=CC(C(=O)N(CCC(O)=O)C=3N=CC=CC=3)=CC=C2N(C)C=1CNC1=CC=C(C(N)=N)C=C1 YBSJFWOBGCMAKL-UHFFFAOYSA-N 0.000 description 1
- 230000034994 death Effects 0.000 description 1
- 125000004856 decahydroquinolinyl group Chemical group N1(CCCC2CCCCC12)* 0.000 description 1
- XEKSTYNIJLDDAZ-JASSWCPGSA-D decasodium;(2S,3S,4R,5R,6R)-6-[(2R,3R,4R,5R,6R)-6-[(2R,3S,4S,5R,6R)-2-carboxylato-4-hydroxy-6-[(2R,3S,4R,5R,6S)-4-hydroxy-6-methoxy-5-(sulfonatoamino)-2-(sulfonatooxymethyl)oxan-3-yl]oxy-5-sulfonatooxyoxan-3-yl]oxy-5-(sulfonatoamino)-4-sulfonatooxy-2-(sul Chemical compound [Na+].[Na+].[Na+].[Na+].[Na+].[Na+].[Na+].[Na+].[Na+].[Na+].O[C@@H]1[C@@H](NS([O-])(=O)=O)[C@@H](OC)O[C@H](COS([O-])(=O)=O)[C@H]1O[C@H]1[C@H](OS([O-])(=O)=O)[C@@H](O)[C@H](O[C@@H]2[C@@H]([C@@H](OS([O-])(=O)=O)[C@H](O[C@H]3[C@@H]([C@@H](O)[C@H](O[C@@H]4[C@@H]([C@@H](O)[C@H](O)[C@@H](COS([O-])(=O)=O)O4)NS([O-])(=O)=O)[C@H](O3)C([O-])=O)O)[C@@H](COS([O-])(=O)=O)O2)NS([O-])(=O)=O)[C@H](C([O-])=O)O1 XEKSTYNIJLDDAZ-JASSWCPGSA-D 0.000 description 1
- 230000003247 decreasing Effects 0.000 description 1
- 238000007872 degassing Methods 0.000 description 1
- 230000003111 delayed Effects 0.000 description 1
- 229920003013 deoxyribonucleic acid Polymers 0.000 description 1
- 239000007933 dermal patch Substances 0.000 description 1
- 108010073652 desirudin Proteins 0.000 description 1
- 230000001809 detectable Effects 0.000 description 1
- 229910052805 deuterium Inorganic materials 0.000 description 1
- YZCKVEUIGOORGS-OUBTZVSYSA-N deuterium Chemical compound [2H] YZCKVEUIGOORGS-OUBTZVSYSA-N 0.000 description 1
- 235000005911 diet Nutrition 0.000 description 1
- 230000000378 dietary Effects 0.000 description 1
- 235000014113 dietary fatty acids Nutrition 0.000 description 1
- FRSRBEPZCGVXTH-UHFFFAOYSA-N diethyl 2-[(2-bromo-4-chloro-3-fluorophenyl)-hydroxymethylidene]propanedioate Chemical compound CCOC(=O)C(C(=O)OCC)=C(O)C1=CC=C(Cl)C(F)=C1Br FRSRBEPZCGVXTH-UHFFFAOYSA-N 0.000 description 1
- 229940075557 diethylene glycol monoethyl ether Drugs 0.000 description 1
- 125000001028 difluoromethyl group Chemical group [H]C(F)(F)* 0.000 description 1
- 230000001079 digestive Effects 0.000 description 1
- ROSDSFDQCJNGOL-UHFFFAOYSA-N dimethylamine Chemical compound CNC ROSDSFDQCJNGOL-UHFFFAOYSA-N 0.000 description 1
- UXGNZZKBCMGWAZ-UHFFFAOYSA-N dimethylformamide DMF Chemical compound CN(C)C=O.CN(C)C=O UXGNZZKBCMGWAZ-UHFFFAOYSA-N 0.000 description 1
- PWEGVZDXTQLFLQ-UHFFFAOYSA-N dioxidoboron Chemical compound [O-][B][O-] PWEGVZDXTQLFLQ-UHFFFAOYSA-N 0.000 description 1
- 229940042399 direct acting antivirals Protease inhibitors Drugs 0.000 description 1
- 239000006185 dispersion Substances 0.000 description 1
- 239000002612 dispersion media Substances 0.000 description 1
- 238000009826 distribution Methods 0.000 description 1
- 239000002934 diuretic Substances 0.000 description 1
- 231100000673 dose–response relationship Toxicity 0.000 description 1
- 238000009510 drug design Methods 0.000 description 1
- 238000009509 drug development Methods 0.000 description 1
- 229960000622 edoxaban Drugs 0.000 description 1
- PSMMNJNZVZZNOI-SJILXJHISA-N edoxaban tosylate hydrate Chemical compound O.CC1=CC=C(S(O)(=O)=O)C=C1.N([C@H]1CC[C@@H](C[C@H]1NC(=O)C=1SC=2CN(C)CCC=2N=1)C(=O)N(C)C)C(=O)C(=O)NC1=CC=C(Cl)C=N1 PSMMNJNZVZZNOI-SJILXJHISA-N 0.000 description 1
- 238000002330 electrospray ionisation mass spectrometry Methods 0.000 description 1
- 230000003073 embolic Effects 0.000 description 1
- 238000005538 encapsulation Methods 0.000 description 1
- 230000002708 enhancing Effects 0.000 description 1
- 239000002702 enteric coating Substances 0.000 description 1
- 238000009505 enteric coating Methods 0.000 description 1
- 239000002329 esterase inhibitor Substances 0.000 description 1
- OTMSDBZUPAUEDD-UHFFFAOYSA-N ethane Chemical compound CC OTMSDBZUPAUEDD-UHFFFAOYSA-N 0.000 description 1
- PSLIMVZEAPALCD-UHFFFAOYSA-N ethanol;ethoxyethane Chemical compound CCO.CCOCC PSLIMVZEAPALCD-UHFFFAOYSA-N 0.000 description 1
- HHFAWKCIHAUFRX-UHFFFAOYSA-N ethoxide Chemical class CC[O-] HHFAWKCIHAUFRX-UHFFFAOYSA-N 0.000 description 1
- OYQVQWIASIXXRT-UHFFFAOYSA-N ethyl 2,4-dioxopentanoate Chemical compound CCOC(=O)C(=O)CC(C)=O OYQVQWIASIXXRT-UHFFFAOYSA-N 0.000 description 1
- AUCNDAZBLKMEEM-UHFFFAOYSA-N ethyl 4-isocyanobenzoate Chemical compound CCOC(=O)C1=CC=C([N+]#[C-])C=C1 AUCNDAZBLKMEEM-UHFFFAOYSA-N 0.000 description 1
- XNWFRZJHXBZDAG-UHFFFAOYSA-N ethylene glycol monomethyl ether Chemical compound COCCO XNWFRZJHXBZDAG-UHFFFAOYSA-N 0.000 description 1
- 125000002534 ethynyl group Chemical group [H]C#C* 0.000 description 1
- 230000005284 excitation Effects 0.000 description 1
- 229960000815 ezetimibe Drugs 0.000 description 1
- 108010091897 factor V Leiden Proteins 0.000 description 1
- 239000000194 fatty acid Substances 0.000 description 1
- 239000002319 fibrinogen receptor antagonist Substances 0.000 description 1
- 229940049370 fibrinolysis inhibitor Drugs 0.000 description 1
- 239000000945 filler Substances 0.000 description 1
- 238000011049 filling Methods 0.000 description 1
- 239000012530 fluid Substances 0.000 description 1
- 125000003983 fluorenyl group Chemical group C1(=CC=CC=2C3=CC=CC=C3CC12)* 0.000 description 1
- 239000007850 fluorescent dye Substances 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- YCKRFDGAMUMZLT-UHFFFAOYSA-N fluorine atom Chemical compound [F] YCKRFDGAMUMZLT-UHFFFAOYSA-N 0.000 description 1
- 125000003709 fluoroalkyl group Chemical group 0.000 description 1
- 125000004216 fluoromethyl group Chemical group [H]C([H])(F)* 0.000 description 1
- 229960003765 fluvastatin Drugs 0.000 description 1
- 239000011888 foil Substances 0.000 description 1
- 229960001318 fondaparinux Drugs 0.000 description 1
- 235000013305 food Nutrition 0.000 description 1
- 235000019253 formic acid Nutrition 0.000 description 1
- 238000001640 fractional crystallisation Methods 0.000 description 1
- 125000000524 functional group Chemical group 0.000 description 1
- 238000007306 functionalization reaction Methods 0.000 description 1
- 125000003838 furazanyl group Chemical group 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 201000006860 gastroesophageal reflux disease Diseases 0.000 description 1
- 239000000499 gel Substances 0.000 description 1
- 229960003627 gemfibrozil Drugs 0.000 description 1
- 238000010363 gene targeting Methods 0.000 description 1
- 230000002068 genetic Effects 0.000 description 1
- 238000007446 glucose tolerance test Methods 0.000 description 1
- 239000000122 growth hormone Substances 0.000 description 1
- 239000003324 growth hormone secretagogue Substances 0.000 description 1
- 125000004995 haloalkylthio group Chemical group 0.000 description 1
- 125000001475 halogen functional group Chemical group 0.000 description 1
- 239000002874 hemostatic agent Substances 0.000 description 1
- 125000006343 heptafluoro propyl group Chemical group 0.000 description 1
- 125000005980 hexynyl group Chemical group 0.000 description 1
- 238000004896 high resolution mass spectrometry Methods 0.000 description 1
- 230000013632 homeostatic process Effects 0.000 description 1
- 239000008240 homogeneous mixture Substances 0.000 description 1
- 239000012456 homogeneous solution Substances 0.000 description 1
- 238000002657 hormone replacement therapy Methods 0.000 description 1
- 150000004677 hydrates Chemical class 0.000 description 1
- 150000004680 hydrogen peroxides Chemical class 0.000 description 1
- UMGDCJDMYOKAJW-UHFFFAOYSA-O hydron;thiourea Chemical class NC(N)=[SH+] UMGDCJDMYOKAJW-UHFFFAOYSA-O 0.000 description 1
- 230000002209 hydrophobic Effects 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-M hydroxyl anion Chemical compound [OH-] XLYOFNOQVPJJNP-UHFFFAOYSA-M 0.000 description 1
- UWYVPFMHMJIBHE-OWOJBTEDSA-N hydroxymaleic acid group Chemical group O/C(/C(=O)O)=C/C(=O)O UWYVPFMHMJIBHE-OWOJBTEDSA-N 0.000 description 1
- 230000001631 hypertensive Effects 0.000 description 1
- 239000005457 ice water Substances 0.000 description 1
- 238000003384 imaging method Methods 0.000 description 1
- 125000002636 imidazolinyl group Chemical group 0.000 description 1
- 125000001841 imino group Chemical group [H]N=* 0.000 description 1
- 210000002865 immune cell Anatomy 0.000 description 1
- 238000000099 in vitro assay Methods 0.000 description 1
- 230000000937 inactivator Effects 0.000 description 1
- 238000010348 incorporation Methods 0.000 description 1
- 125000004926 indolenyl group Chemical group 0.000 description 1
- 125000003406 indolizinyl group Chemical group C=1(C=CN2C=CC=CC12)* 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 125000002346 iodo group Chemical group I* 0.000 description 1
- 150000002500 ions Chemical class 0.000 description 1
- 230000002530 ischemic preconditioning Effects 0.000 description 1
- 125000001977 isobenzofuranyl group Chemical group C=1(OC=C2C=CC=CC12)* 0.000 description 1
- 125000003384 isochromanyl group Chemical group C1(OCCC2=CC=CC=C12)* 0.000 description 1
- CZALJDQHONFVFU-UHFFFAOYSA-N isocyanatocyclopentane Chemical compound O=C=NC1CCCC1 CZALJDQHONFVFU-UHFFFAOYSA-N 0.000 description 1
- 125000005438 isoindazolyl group Chemical group 0.000 description 1
- 125000004594 isoindolinyl group Chemical group C1(NCC2=CC=CC=C12)* 0.000 description 1
- 125000001972 isopentyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000003253 isopropoxy group Chemical group [H]C([H])([H])C([H])(O*)C([H])([H])[H] 0.000 description 1
- 125000005956 isoquinolyl group Chemical group 0.000 description 1
- 125000001810 isothiocyanato group Chemical group *N=C=S 0.000 description 1
- 125000000468 ketone group Chemical group 0.000 description 1
- 229960004752 ketorolac Drugs 0.000 description 1
- 150000003951 lactams Chemical class 0.000 description 1
- 108010051044 lanoteplase Proteins 0.000 description 1
- 235000010445 lecithin Nutrition 0.000 description 1
- 239000000787 lecithin Substances 0.000 description 1
- 231100000518 lethal Toxicity 0.000 description 1
- 230000001665 lethal Effects 0.000 description 1
- 239000008297 liquid dosage form Substances 0.000 description 1
- 238000006138 lithiation reaction Methods 0.000 description 1
- OCZDCIYGECBNKL-UHFFFAOYSA-N lithium;alumanuide Chemical compound [Li+].[AlH4-] OCZDCIYGECBNKL-UHFFFAOYSA-N 0.000 description 1
- 239000010807 litter Substances 0.000 description 1
- 230000004777 loss-of-function mutation Effects 0.000 description 1
- 229960004844 lovastatin Drugs 0.000 description 1
- 125000003588 lysine group Chemical group [H]N([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])(N([H])[H])C(*)=O 0.000 description 1
- 230000002934 lysing Effects 0.000 description 1
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 1
- 235000019341 magnesium sulphate Nutrition 0.000 description 1
- 230000036210 malignancy Effects 0.000 description 1
- 235000013310 margarine Nutrition 0.000 description 1
- 239000003264 margarine Substances 0.000 description 1
- 239000003550 marker Substances 0.000 description 1
- 238000001819 mass spectrum Methods 0.000 description 1
- 239000011159 matrix material Substances 0.000 description 1
- 230000035800 maturation Effects 0.000 description 1
- 239000000155 melt Substances 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 239000012528 membrane Substances 0.000 description 1
- 230000004060 metabolic process Effects 0.000 description 1
- 230000035786 metabolism Effects 0.000 description 1
- NBTOZLQBSIZIKS-UHFFFAOYSA-N methoxide Chemical class [O-]C NBTOZLQBSIZIKS-UHFFFAOYSA-N 0.000 description 1
- 125000004184 methoxymethyl group Chemical group [H]C([H])([H])OC([H])([H])* 0.000 description 1
- RAPITQBKYHYOEF-UHFFFAOYSA-N methyl 5-bromo-3,3-dimethyl-1,4-dihydroisoquinoline-2-carboxylate Chemical compound C1=CC(Br)=C2CC(C)(C)N(C(=O)OC)CC2=C1 RAPITQBKYHYOEF-UHFFFAOYSA-N 0.000 description 1
- UFDGMXHPQNDESO-UHFFFAOYSA-N methyl N-(4-aminophenyl)carbamate Chemical compound COC(=O)NC1=CC=C(N)C=C1 UFDGMXHPQNDESO-UHFFFAOYSA-N 0.000 description 1
- LQWIPKMGHDPMPA-UHFFFAOYSA-N methyl N-(4-formamidophenyl)carbamate Chemical compound COC(=O)NC1=CC=C(NC=O)C=C1 LQWIPKMGHDPMPA-UHFFFAOYSA-N 0.000 description 1
- ACUAVTXQUIOSTP-UHFFFAOYSA-N methyl N-(4-isocyanophenyl)carbamate Chemical compound COC(=O)NC1=CC=C([N+]#[C-])C=C1 ACUAVTXQUIOSTP-UHFFFAOYSA-N 0.000 description 1
- KQSSATDQUYCRGS-UHFFFAOYSA-N methyl glycinate Chemical compound COC(=O)CN KQSSATDQUYCRGS-UHFFFAOYSA-N 0.000 description 1
- BAVYZALUXZFZLV-UHFFFAOYSA-N methylamine Chemical compound NC BAVYZALUXZFZLV-UHFFFAOYSA-N 0.000 description 1
- 229940016286 microcrystalline cellulose Drugs 0.000 description 1
- 235000019813 microcrystalline cellulose Nutrition 0.000 description 1
- 239000008108 microcrystalline cellulose Substances 0.000 description 1
- 239000003658 microfiber Substances 0.000 description 1
- 108010038232 microsomal triglyceride transfer protein Proteins 0.000 description 1
- 230000003278 mimic Effects 0.000 description 1
- 239000002394 mineralocorticoid antagonist Substances 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000006011 modification reaction Methods 0.000 description 1
- 239000003607 modifier Substances 0.000 description 1
- 229960005181 morphine Drugs 0.000 description 1
- 229930014694 morphine Natural products 0.000 description 1
- ZQHJAAMMKABEBS-UHFFFAOYSA-N morpholin-2-one Chemical group O=C1CNCCO1 ZQHJAAMMKABEBS-UHFFFAOYSA-N 0.000 description 1
- AMQJEAYHLZJPGS-UHFFFAOYSA-N n-pentanol Chemical compound CCCCCO AMQJEAYHLZJPGS-UHFFFAOYSA-N 0.000 description 1
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000003506 n-propoxy group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])O* 0.000 description 1
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- PMZURENOXWZQFD-UHFFFAOYSA-L na2so4 Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 1
- 125000004593 naphthyridinyl group Chemical group N1=C(C=CC2=CC=CN=C12)* 0.000 description 1
- 239000007922 nasal spray Substances 0.000 description 1
- 230000017570 negative regulation of blood coagulation Effects 0.000 description 1
- 230000014508 negative regulation of coagulation Effects 0.000 description 1
- 125000001971 neopentyl group Chemical group [H]C([*])([H])C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 230000001264 neutralization Effects 0.000 description 1
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 1
- 239000012457 nonaqueous media Substances 0.000 description 1
- 125000002868 norbornyl group Chemical group C12(CCC(CC1)C2)* 0.000 description 1
- 238000005016 nuclear Overhauser enhanced spectroscopy Methods 0.000 description 1
- 230000000414 obstructive Effects 0.000 description 1
- 239000004006 olive oil Substances 0.000 description 1
- 235000008390 olive oil Nutrition 0.000 description 1
- 235000020660 omega-3 fatty acid Nutrition 0.000 description 1
- 239000006014 omega-3 oil Substances 0.000 description 1
- 230000036220 oral bioavailability Effects 0.000 description 1
- 239000003539 oral contraceptive agent Substances 0.000 description 1
- 239000007935 oral tablet Substances 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 230000000399 orthopedic Effects 0.000 description 1
- MYMOFIZGZYHOMD-UHFFFAOYSA-N oxygen Chemical compound O=O MYMOFIZGZYHOMD-UHFFFAOYSA-N 0.000 description 1
- RZVAJINKPMORJF-UHFFFAOYSA-N p-acetaminophenol Chemical compound CC(=O)NC1=CC=C(O)C=C1 RZVAJINKPMORJF-UHFFFAOYSA-N 0.000 description 1
- 235000019629 palatability Nutrition 0.000 description 1
- PIBWKRNGBLPSSY-UHFFFAOYSA-L palladium(II) chloride Chemical compound Cl[Pd]Cl PIBWKRNGBLPSSY-UHFFFAOYSA-L 0.000 description 1
- 125000001312 palmitoyl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 201000002528 pancreatic cancer Diseases 0.000 description 1
- 229960005489 paracetamol Drugs 0.000 description 1
- 239000008188 pellet Substances 0.000 description 1
- 125000006340 pentafluoro ethyl group Chemical group FC(F)(F)C(F)(F)* 0.000 description 1
- 125000002255 pentenyl group Chemical group C(=CCCC)* 0.000 description 1
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 1
- 125000005981 pentynyl group Chemical group 0.000 description 1
- 238000005897 peptide coupling reaction Methods 0.000 description 1
- 239000000137 peptide hydrolase inhibitor Substances 0.000 description 1
- 239000002304 perfume Substances 0.000 description 1
- 230000003836 peripheral circulation Effects 0.000 description 1
- 230000035699 permeability Effects 0.000 description 1
- 239000008024 pharmaceutical diluent Substances 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 230000000275 pharmacokinetic Effects 0.000 description 1
- 125000004934 phenanthridinyl group Chemical group C1(=CC=CC2=NC=C3C=CC=CC3=C12)* 0.000 description 1
- 125000004625 phenanthrolinyl group Chemical group N1=C(C=CC2=CC=C3C=CC=NC3=C12)* 0.000 description 1
- 125000001791 phenazinyl group Chemical group C1(=CC=CC2=NC3=CC=CC=C3N=C12)* 0.000 description 1
- 125000001484 phenothiazinyl group Chemical group C1(=CC=CC=2SC3=CC=CC=C3NC12)* 0.000 description 1
- 125000005954 phenoxathiinyl group Chemical group 0.000 description 1
- 125000001644 phenoxazinyl group Chemical group C1(=CC=CC=2OC3=CC=CC=C3NC12)* 0.000 description 1
- 150000008105 phosphatidylcholines Chemical class 0.000 description 1
- 239000002570 phosphodiesterase III inhibitor Substances 0.000 description 1
- 239000002590 phosphodiesterase V inhibitor Substances 0.000 description 1
- 150000003904 phospholipids Chemical class 0.000 description 1
- 229920000406 phosphotungstic acid polymer Polymers 0.000 description 1
- 125000001557 phthalyl group Chemical group C(=O)(O)C1=C(C(=O)*)C=CC=C1 0.000 description 1
- 150000004885 piperazines Chemical class 0.000 description 1
- 150000003053 piperidines Chemical class 0.000 description 1
- 125000004928 piperidonyl group Chemical group 0.000 description 1
- 125000004591 piperonyl group Chemical group C(C1=CC=2OCOC2C=C1)* 0.000 description 1
- 230000000896 plasminic Effects 0.000 description 1
- 230000033885 plasminogen activation Effects 0.000 description 1
- 229910052697 platinum Inorganic materials 0.000 description 1
- 229920002721 polycyanoacrylate Polymers 0.000 description 1
- 201000010065 polycystic ovary syndrome Diseases 0.000 description 1
- 229920000573 polyethylene Polymers 0.000 description 1
- 229920002223 polystyrene Polymers 0.000 description 1
- 239000004810 polytetrafluoroethylene Substances 0.000 description 1
- 229920001343 polytetrafluoroethylene Polymers 0.000 description 1
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 1
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 1
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 1
- 230000002980 postoperative Effects 0.000 description 1
- 230000001323 posttranslational Effects 0.000 description 1
- 235000011056 potassium acetate Nutrition 0.000 description 1
- 239000001184 potassium carbonate Substances 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 102000004257 potassium channel family Human genes 0.000 description 1
- 108020001213 potassium channel family Proteins 0.000 description 1
- 229910000160 potassium phosphate Inorganic materials 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 229960003912 probucol Drugs 0.000 description 1
- 230000000644 propagated Effects 0.000 description 1
- 230000001902 propagating Effects 0.000 description 1
- OGHBATFHNDZKSO-UHFFFAOYSA-N propan-2-olate Chemical class CC(C)[O-] OGHBATFHNDZKSO-UHFFFAOYSA-N 0.000 description 1
- NSETWVJZUWGCKE-UHFFFAOYSA-N propylphosphonic acid Chemical compound CCCP(O)(O)=O NSETWVJZUWGCKE-UHFFFAOYSA-N 0.000 description 1
- 125000002568 propynyl group Chemical group [*]C#CC([H])([H])[H] 0.000 description 1
- 230000001681 protective Effects 0.000 description 1
- 201000005660 protein C deficiency Diseases 0.000 description 1
- 239000012268 protein inhibitor Substances 0.000 description 1
- 229940121649 protein inhibitors Drugs 0.000 description 1
- 125000001042 pteridinyl group Chemical group N1=C(N=CC2=NC=CN=C12)* 0.000 description 1
- 238000010926 purge Methods 0.000 description 1
- 125000004309 pyranyl group Chemical group O1C(C=CC=C1)* 0.000 description 1
- 150000003217 pyrazoles Chemical class 0.000 description 1
- 125000003072 pyrazolidinyl group Chemical group 0.000 description 1
- 125000002755 pyrazolinyl group Chemical group 0.000 description 1
- 125000000719 pyrrolidinyl group Chemical group 0.000 description 1
- 125000001422 pyrrolinyl group Chemical group 0.000 description 1
- 150000003242 quaternary ammonium salts Chemical class 0.000 description 1
- 125000005493 quinolyl group Chemical group 0.000 description 1
- 125000001567 quinoxalinyl group Chemical group N1=C(C=NC2=CC=CC=C12)* 0.000 description 1
- 125000004621 quinuclidinyl group Chemical group N12C(CC(CC1)CC2)* 0.000 description 1
- 239000012429 reaction media Substances 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 235000020095 red wine Nutrition 0.000 description 1
- 230000011514 reflex Effects 0.000 description 1
- 230000020964 regulation of blood coagulation Effects 0.000 description 1
- 230000029865 regulation of blood pressure Effects 0.000 description 1
- 239000002461 renin inhibitor Substances 0.000 description 1
- 200000000008 restenosis Diseases 0.000 description 1
- 230000004141 reverse cholesterol transport Effects 0.000 description 1
- 238000004366 reverse phase liquid chromatography Methods 0.000 description 1
- 229910052703 rhodium Inorganic materials 0.000 description 1
- 239000010948 rhodium Substances 0.000 description 1
- MHOVAHRLVXNVSD-UHFFFAOYSA-N rhodium Chemical compound [Rh] MHOVAHRLVXNVSD-UHFFFAOYSA-N 0.000 description 1
- 238000007363 ring formation reaction Methods 0.000 description 1
- 229960001148 rivaroxaban Drugs 0.000 description 1
- 229960004586 rosiglitazone Drugs 0.000 description 1
- 229960000672 rosuvastatin Drugs 0.000 description 1
- 229910052707 ruthenium Inorganic materials 0.000 description 1
- KJTLSVCANCCWHF-UHFFFAOYSA-N ruthenium Chemical compound [Ru] KJTLSVCANCCWHF-UHFFFAOYSA-N 0.000 description 1
- 238000005070 sampling Methods 0.000 description 1
- 108010073863 saruplase Proteins 0.000 description 1
- 239000012047 saturated solution Substances 0.000 description 1
- 239000008299 semisolid dosage form Substances 0.000 description 1
- 231100000486 side effect Toxicity 0.000 description 1
- 238000007873 sieving Methods 0.000 description 1
- 229960003310 sildenafil Drugs 0.000 description 1
- 239000000377 silicon dioxide Substances 0.000 description 1
- 229960002855 simvastatin Drugs 0.000 description 1
- MSXHSNHNTORCAW-UHFFFAOYSA-M sodium 3,4,5,6-tetrahydroxyoxane-2-carboxylate Chemical compound [Na+].OC1OC(C([O-])=O)C(O)C(O)C1O MSXHSNHNTORCAW-UHFFFAOYSA-M 0.000 description 1
- 239000001632 sodium acetate Substances 0.000 description 1
- 235000017281 sodium acetate Nutrition 0.000 description 1
- 235000010413 sodium alginate Nutrition 0.000 description 1
- 239000000661 sodium alginate Substances 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 239000001187 sodium carbonate Substances 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 description 1
- 229920001027 sodium carboxymethylcellulose Polymers 0.000 description 1
- 235000010288 sodium nitrite Nutrition 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
- WGRULTCAYDOGQK-UHFFFAOYSA-M sodium;sodium;hydroxide Chemical compound [OH-].[Na].[Na+] WGRULTCAYDOGQK-UHFFFAOYSA-M 0.000 description 1
- 239000008247 solid mixture Substances 0.000 description 1
- 238000007614 solvation Methods 0.000 description 1
- 238000000638 solvent extraction Methods 0.000 description 1
- VIDRYROWYFWGSY-UHFFFAOYSA-N sotalol hydrochloride Chemical compound Cl.CC(C)NCC(O)C1=CC=C(NS(C)(=O)=O)C=C1 VIDRYROWYFWGSY-UHFFFAOYSA-N 0.000 description 1
- 239000003549 soybean oil Substances 0.000 description 1
- 235000012424 soybean oil Nutrition 0.000 description 1
- 238000004611 spectroscopical analysis Methods 0.000 description 1
- 238000005507 spraying Methods 0.000 description 1
- 239000004059 squalene synthase inhibitor Substances 0.000 description 1
- 238000011105 stabilization Methods 0.000 description 1
- 229910001220 stainless steel Inorganic materials 0.000 description 1
- 239000010935 stainless steel Substances 0.000 description 1
- 235000011150 stannous chloride Nutrition 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- REYJJPSVUYRZGE-UHFFFAOYSA-N stearylamine Chemical compound CCCCCCCCCCCCCCCCCCN REYJJPSVUYRZGE-UHFFFAOYSA-N 0.000 description 1
- 239000011550 stock solution Substances 0.000 description 1
- 238000003860 storage Methods 0.000 description 1
- 238000000859 sublimation Methods 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 238000000967 suction filtration Methods 0.000 description 1
- GGCSSNBKKAUURC-UHFFFAOYSA-N sufentanil Chemical group C1CN(CCC=2SC=CC=2)CCC1(COC)N(C(=O)CC)C1=CC=CC=C1 GGCSSNBKKAUURC-UHFFFAOYSA-N 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-L sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 1
- 239000011593 sulfur Substances 0.000 description 1
- 239000004094 surface-active agent Substances 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- DKGAVHZHDRPRBM-UHFFFAOYSA-N t-BuOH Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- NYJCYQYANPADQE-SOFGYWHQSA-N tert-butyl (E)-3-(6-acetyl-3-chloro-2-fluorophenyl)prop-2-enoate Chemical compound CC(=O)C1=CC=C(Cl)C(F)=C1\C=C\C(=O)OC(C)(C)C NYJCYQYANPADQE-SOFGYWHQSA-N 0.000 description 1
- GCMIHVIJDVSYMT-QPJJXVBHSA-N tert-butyl (E)-3-[5-chloro-2-(difluoromethoxy)phenyl]prop-2-enoate Chemical compound CC(C)(C)OC(=O)\C=C\C1=CC(Cl)=CC=C1OC(F)F GCMIHVIJDVSYMT-QPJJXVBHSA-N 0.000 description 1
- DHNGBXPHBAGWCQ-UHFFFAOYSA-N tert-butyl 2-[(4-aminophenyl)carbamoyloxy]acetate Chemical compound CC(C)(C)OC(=O)COC(=O)NC1=CC=C(N)C=C1 DHNGBXPHBAGWCQ-UHFFFAOYSA-N 0.000 description 1
- SAZYDWOWLRDDRQ-UHFFFAOYSA-N tert-butyl 2-dimethoxyphosphorylacetate Chemical compound COP(=O)(OC)CC(=O)OC(C)(C)C SAZYDWOWLRDDRQ-UHFFFAOYSA-N 0.000 description 1
- KYORUZMJUKHKFS-UHFFFAOYSA-N tert-butyl 4-aminobenzoate Chemical compound CC(C)(C)OC(=O)C1=CC=C(N)C=C1 KYORUZMJUKHKFS-UHFFFAOYSA-N 0.000 description 1
- DZBLVKGXRPGFAL-UHFFFAOYSA-N tert-butyl 4-formamidobenzoate Chemical compound CC(C)(C)OC(=O)C1=CC=C(NC=O)C=C1 DZBLVKGXRPGFAL-UHFFFAOYSA-N 0.000 description 1
- RGQKDBWDGMIOCX-UHFFFAOYSA-N tert-butyl 4-isocyanobenzoate Chemical compound CC(C)(C)OC(=O)C1=CC=C([N+]#[C-])C=C1 RGQKDBWDGMIOCX-UHFFFAOYSA-N 0.000 description 1
- WIVYTYZCVWHWSH-UHFFFAOYSA-N tert-butyl N-(4-aminophenyl)carbamate Chemical compound CC(C)(C)OC(=O)NC1=CC=C(N)C=C1 WIVYTYZCVWHWSH-UHFFFAOYSA-N 0.000 description 1
- WHRNULOCNSKMGB-UHFFFAOYSA-N tetrahydrofuran THF Chemical compound C1CCOC1.C1CCOC1 WHRNULOCNSKMGB-UHFFFAOYSA-N 0.000 description 1
- 150000003526 tetrahydroisoquinolines Chemical class 0.000 description 1
- 125000001712 tetrahydronaphthyl group Chemical group C1(CCCC2=CC=CC=C12)* 0.000 description 1
- 125000004627 thianthrenyl group Chemical group C1(=CC=CC=2SC3=CC=CC=C3SC12)* 0.000 description 1
- 239000002175 thienopyridine Substances 0.000 description 1
- 238000004809 thin layer chromatography Methods 0.000 description 1
- 125000005309 thioalkoxy group Chemical group 0.000 description 1
- 125000005403 thiohaloalkoxy group Chemical group 0.000 description 1
- 229960002528 ticagrelor Drugs 0.000 description 1
- 238000004448 titration Methods 0.000 description 1
- 235000010487 tragacanth Nutrition 0.000 description 1
- 239000000196 tragacanth Substances 0.000 description 1
- 230000037317 transdermal delivery Effects 0.000 description 1
- FAQYAMRNWDIXMY-UHFFFAOYSA-N trichloroborane Chemical compound ClB(Cl)Cl FAQYAMRNWDIXMY-UHFFFAOYSA-N 0.000 description 1
- 125000003866 trichloromethyl group Chemical group ClC(Cl)(Cl)* 0.000 description 1
- 125000002827 triflate group Chemical group FC(S(=O)(=O)O*)(F)F 0.000 description 1
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 1
- HYUFXBPAIGJHRY-UHFFFAOYSA-L triphenylphosphane;dichloride Chemical compound [Cl-].[Cl-].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 HYUFXBPAIGJHRY-UHFFFAOYSA-L 0.000 description 1
- 235000019798 tripotassium phosphate Nutrition 0.000 description 1
- 229910052722 tritium Inorganic materials 0.000 description 1
- YZCKVEUIGOORGS-NJFSPNSNSA-N tritium Chemical compound [3H] YZCKVEUIGOORGS-NJFSPNSNSA-N 0.000 description 1
- 230000001810 trypsinlike Effects 0.000 description 1
- 210000002229 urogenital system Anatomy 0.000 description 1
- 238000001291 vacuum drying Methods 0.000 description 1
- 235000012141 vanillin Nutrition 0.000 description 1
- 229940117960 vanillin Drugs 0.000 description 1
- 230000024883 vasodilation Effects 0.000 description 1
- 230000002861 ventricular Effects 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
- 229960005044 vorapaxar Drugs 0.000 description 1
- 238000010792 warming Methods 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
- 239000001993 wax Substances 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
- 230000029663 wound healing Effects 0.000 description 1
- 239000000230 xanthan gum Substances 0.000 description 1
- 235000010493 xanthan gum Nutrition 0.000 description 1
- 229920001285 xanthan gum Polymers 0.000 description 1
- 229940082509 xanthan gum Drugs 0.000 description 1
- 125000001834 xanthenyl group Chemical group C1=CC=CC=2OC3=CC=CC=C3C(C12)* 0.000 description 1
- 229960001522 ximelagatran Drugs 0.000 description 1
- ZXIBCJHYVWYIKI-PZJWPPBQSA-N ximelagatran Chemical compound C1([C@@H](NCC(=O)OCC)C(=O)N2[C@@H](CC2)C(=O)NCC=2C=CC(=CC=2)C(\N)=N\O)CCCCC1 ZXIBCJHYVWYIKI-PZJWPPBQSA-N 0.000 description 1
- 239000000811 xylitol Substances 0.000 description 1
- 235000010447 xylitol Nutrition 0.000 description 1
- RSDOASZYYCOXIB-UHFFFAOYSA-N β-alaninamide Chemical compound NCCC(N)=O RSDOASZYYCOXIB-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/47—Quinolines; Isoquinolines
- A61K31/472—Non-condensed isoquinolines, e.g. papaverine
- A61K31/4725—Non-condensed isoquinolines, e.g. papaverine containing further heterocyclic rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene
-
- 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
- A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
- A61K31/5375—1,4-Oxazines, e.g. morpholine
- A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
-
- 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
- A61K31/54—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame
- A61K31/541—Non-condensed thiazines containing further heterocyclic rings
-
- 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
- A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
-
- 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
- A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
- A61K31/551—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having two nitrogen atoms, e.g. dilazep
-
- 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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/13—Crystalline forms, e.g. polymorphs
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
- C07D217/22—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the nitrogen-containing ring
- C07D217/26—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/10—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing aromatic rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/10—Spiro-condensed systems
-
- 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
- C07D487/04—Ortho-condensed systems
-
- 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
-
- 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
- C07D487/10—Spiro-condensed systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
- C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
- C07D491/10—Spiro-condensed systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
- C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
- C07D491/10—Spiro-condensed systems
- C07D491/107—Spiro-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
- C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
- C07D491/10—Spiro-condensed systems
- C07D491/113—Spiro-condensed systems with two or more oxygen atoms as ring hetero atoms in the oxygen-containing ring
Abstract
Disclosed are compounds of formula (I), wherein the substituents are as defined in the specification. The disclosed compounds are inhibitors of factor XIa and/or plasma kallikrein which may be used as medicaments for the treatment or prophylaxis of thromboembolic inflammatory disorders. An example of a compound of formula (I) is: (E)-4-(2-(3-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)acryloyl)-5-(piperazin-1-yl)-1,2,3,4-tetrahydroisoquinoline-1-carboxamido)benzoic acid e of a compound of formula (I) is: (E)-4-(2-(3-(5-chloro-2-(1H-tetrazol-1-yl)phenyl)acryloyl)-5-(piperazin-1-yl)-1,2,3,4-tetrahydroisoquinoline-1-carboxamido)benzoic acid
Description
SUBSTITUTED TETRAHYDROISOQUINOLINE COMPOUNDS AS FACTOR XIA
INHIBITORS
FIELD OF THE INVENTION
[0001] The present invention provides novel substituted tetrahydroisoquinoline
(THQ) compounds, and their analogues thereof, which are inhibitors of factor XIa or
plasma kallikrein, compositions containing them, and methods of using them, for
example, for the treatment or prophylaxis of thromboembolic disorders.
BACKGROUND OF THE INVENTION
Thromboembolic diseases remain the leading cause of death in developed
countries despite the availability of anticoagulants such as warfarin (COUMADIN ),
heparin, low molecular weight heparins (LMWH), and synthetic pentasaccharides and
antiplatelet agents such as aspirin and clopidogrel (PLAVIX ). The oral anticoagulant
warfarin, inhibits the post-translational maturation of coagulation factors VII, IX, X and
prothrombin, and has proven effective in both venous and arterial thrombosis. However,
its usage is limited due to its narrow therapeutic index, slow onset of therapeutic effect,
numerous dietary and drug interactions, and a need for monitoring and dose adjustment.
Thus discovering and developing safe and efficacious oral anticoagulants for the
prevention and treatment of a wide range of thromboembolic disorders has become
increasingly important.
One approach is to inhibit thrombin generation by targeting the inhibition of
coagulation factor XIa (FXIa). Factor XIa is a plasma serine protease involved in the
regulation of blood coagulation, which is initiated in vivo by the binding of tissue factor
(TF) to factor VII (FVII) to generate factor VIIa (FVIIa). The resulting TF:FVIIa
complex activates factor IX (FIX) and factor X (FX) that leads to the production of factor
Xa (FXa). The generated FXa catalyzes the transformation of prothrombin into small
amounts of thrombin before this pathway is shut down by tissue factor pathway inhibitor
(TFPI). The process of coagulation is then further propagated via the feedback activation
of Factors V, VIII and XI by catalytic amounts of thrombin. (Gailani, D. et al.,
Arterioscler. Thromb. Vasc. Biol., 27:2507-2513 (2007).) The resulting burst of thrombin
converts fibrinogen to fibrin that polymerizes to form the structural framework of a blood
clot, and activates platelets, which are a key cellular component of coagulation (Hoffman,
M., Blood Reviews, 17:S1-S5 (2003)). Therefore, factor XIa plays a key role in
propagating this amplification loop and is thus an attractive target for anti-thrombotic
therapy.
SUMMARY OF THE INVENTION
The present invention provides novel substituted tetrahydroisoquinoline
compounds, and their analogues thereof, including stereoisomers, tautomers,
pharmaceutically acceptable salts, or solvates thereof, which are useful as selective
inhibitors of serine protease enzymes, especially factor XIa and/or plasma kallikrein.
The present invention also provides processes and intermediates for making
the compounds of the present invention.
The present invention also provides pharmaceutical compositions comprising
a pharmaceutically acceptable carrier and at least one of the compounds of the present
invention or stereoisomers, tautomers, pharmaceutically acceptable salts, or solvates
thereof.
The compounds of the invention may be used in the treatment and/or
prophylaxis of thromboembolic disorders.
The compounds of the present invention may be used in therapy.
[0009] The compounds of the present invention may be used for the manufacture of a
medicament for the treatment and/or prophylaxis of a thromboembolic disorder.
The compounds of the invention can be used alone, in combination with other
compounds of the present invention, or in combination with one or more, preferably one
to two, other agent(s).
[0011] These and other features of the invention will be set forth in expanded form as
the disclosure continues.
BRIEF DESCRIPTION OF THE DRAWINGS
The invention is illustrated by reference to the accompanying drawings
described below.
Figure 1 shows the observed and calculated (room temperature) powder X-ray
diffraction patterns (CuKα λ=1.5418 Å) of Form HCl:SA-1 of crystalline (S,E)(2-(3-
(3-chlorofluoro(1H-tetrazolyl)phenyl)acryloyl)(4-methyloxopiperazin
yl)-1,2,3,4-tetrahydroisoquinolinecarboxamido)benzoic acid.
Figure 2 shows the observed and calculated (room temperature) powder X-ray
diffraction patterns (CuKα λ=1.5418 Å) of Form H.5-1 of crystalline (S,E)(2-(3-(3-
chlorofluoro(1H-tetrazolyl)phenyl)acryloyl)(4-methyloxopiperazinyl)-
1,2,3,4-tetrahydroisoquinolinecarboxamido)benzoic acid.
Figure 3 shows the observed powder X-ray diffraction patterns (CuKα
λ=1.5418 Å) of Form P13 of crystalline (S,E)(2-(3-(3-chlorofluoro(1H-tetrazol-
1-yl)phenyl)acryloyl)(4-methyloxopiperazinyl)-1,2,3,4-tetrahydroisoquinoline
carboxamido)benzoic acid.
Figure 4 is a differential scanning calorimetry thermogram of Form HCl:SA-
1of crystalline (S,E)(2-(3-(3-chlorofluoro(1H-tetrazolyl)phenyl)acryloyl)
(4-methyloxopiperazinyl)-1,2,3,4-tetrahydroisoquinolinecarboxamido)benzoic
acid.
[0017] Figure 5 is a differential scanning calorimetry thermogram of Form P13 of
crystalline (S,E)(2-(3-(3-chlorofluoro(1H-tetrazolyl)phenyl)acryloyl)(4-
methyloxopiperazinyl)-1,2,3,4-tetrahydroisoquinolinecarboxamido)benzoic acid.
Figure 6 is a differential scanning calorimetry thermogram of Form H.5-1 of
crystalline (S,E)(2-(3-(3-chlorofluoro(1H-tetrazolyl)phenyl)acryloyl)(4-
methyloxopiperazinyl)-1,2,3,4-tetrahydroisoquinolinecarboxamido)benzoic acid.
Figure 7 is a thermogravimetric analysis thermogram of Form HCl:SA-1 of
crystalline (S,E)(2-(3-(3-chlorofluoro(1H-tetrazolyl)phenyl)acryloyl)(4-
methyloxopiperazinyl)-1,2,3,4-tetrahydroisoquinolinecarboxamido)benzoic acid.
Figure 8 is a thermogravimetric analysis thermogram of Form P13 of
crystalline (S,E)(2-(3-(3-chlorofluoro(1H-tetrazolyl)phenyl)acryloyl)(4-
methyloxopiperazinyl)-1,2,3,4-tetrahydroisoquinolinecarboxamido)benzoic acid.
Figure 9 is a thermogravimetric analysis thermogram of Form H.5-1 of
crystalline (S,E)(2-(3-(3-chlorofluoro(1H-tetrazolyl)phenyl)acryloyl)(4-
methyloxopiperazinyl)-1,2,3,4-tetrahydroisoquinolinecarboxamido)benzoic acid.
[0022] Figure 10 is a C-13 CPMASA spectrum diagram of Form P13 of crystalline
(S,E)(2-(3-(3-chlorofluoro(1H-tetrazolyl)phenyl)acryloyl)(4-methyl
oxopiperazinyl)-1,2,3,4-tetrahydroisoquinolinecarboxamido)benzoic acid. The
spinning sidebands are labeled with “ssb.”
Figure 11 is a F-19 CPMAS spectrum (with proton decoupling) diagram of
Form P13 of crystalline (S,E)(2-(3-(3-chlorofluoro(1H-tetrazol
yl)phenyl)acryloyl)(4-methyloxopiperazinyl)-1,2,3,4-tetrahydroisoquinoline
carboxamido)benzoic acid. The spinning side bands are labeled and were confirmed by
varying the spinning speed.
DETAILED DESCRIPTION OF THE INVENTION
I. COMPOUNDS OF THE INVENTION
In a first aspect, the present invention provides compounds of Formula (I):
(R )
(R )
or stereoisomers, tautomers, pharmaceutically acceptable salts, or solvates thereof,
wherein:
ring A is C carbocycle;
ring B is 4- to 7-membered heterocycle containing carbon atoms and 0-3
additional heteroatoms selected from the group consisting of N, NR , O, and S(O) ;
optionally, ring B forms a fused ring or spiro ring with a 4- to 7-membered heterocycle
containing carbon atoms and 1-3 heteroatoms selected from the group consisting of NR ,
O, and S(O) ; ring B, including the fused ring or spiro ring is substituted with 1-3 R ;
10 10 10
L is selected from the group consisting of: -CHR CHR -, -CR =CR -,
10
-C≡C-, -CHR NH-, -NHCHR -, -SCH -, -CH S-, -SO CH -, - CH SO -, -NHCH -,
2 2 2 2 2 2 2
and -CH NH-;
R , at each occurrence, is selected from the group consisting of: H, halo, C
alkyl, C alkoxy, C alkylthio, OH, SH, CHF , CF , OCF , CN, NH , COC alkyl,
2 3 3 2
1-4 1-4 1-4
CO (C alkyl), -CH CO H, -CH CO (C alkyl), -CH NH ,
2 2 2 2 2 2 2
1-4 1-4
-CONH , -CONH(C alkyl), -NHCO(C alkyl), -NHCO (C alkyl),
1-4 1-4 1-4
-NHSO (C alkyl), and -SO NH , and -C(=NH)NH ;
2 2 2 2
R is selected from the group consisting of: H, halo, CN, OH,
C alkyl, C alkoxy, C haloalkyl, C haloalkoxy, CO(C alkyl), CONH , CO H,
1-6 1-4 1-6 1-6 1-4
CH NH , and a 5- to 7-membered heterocycle comprising carbon atoms and 1-4
heteroatoms selected from N, NR , O, and S(O) , wherein said heterocycle is substituted
with 0-2 R ;
R , at each occurrence, is selected from the group consisting of: H, halo, C
alkyl, -CH OH, C alkoxy, OH, CF , OCF , CN, NH , CO H,
3 3 2 2
2 1-4
CO (C alkyl), CO(C alkyl), -CONH , -CH OH, -CH OC alkyl, -CH NH -,
2 2 1-4
2 2 2 2
1-4 1-4
CONH(C alkyl), -CON(C alkyl) , -SO (C alkyl), -SO NH , -SO NH(C
2 2 2 2 2
1-4 1-4 1-4 1-4
alkyl), and -SO N(C alkyl) ;
3 3a
R is selected from the group consisting of: C alkyl substituted with 1-3 R , -
(CH ) -C carbocycle substituted with 0-3 R or -(CH ) 10 membered heterocycle
2 n 3-10 2 n
containing carbon atoms and 1-4 heteroatoms selected from the group consisting of N,
7 3a
NR , O, and S(O) ; wherein said heterocycle is substituted with 0-3 R ;
R , at each occurrence, is selected from the group consisting of: =O, halo, C
alkyl, OH, C alkoxy, CN, NH , CO H, CO (C alkyl), CONH CONH(C alkyl),
2 2 2 2,
1-4 1-4 1-6
CON(C alkyl) -CONH-C alkylene-CO (C alkyl),
2, 2
1-4 1-4 1-4
-CONHCO C alkyl, -CONH-C alkylene-NHCO(C alkyl),
2 1-4 1-4 1-4
-CONH-C alkylene-CONH , -NHCOC alkyl, -NHCO (C alkyl),
1-4 1-4 1-4
f f f
-C alkylene-NHCO C alkyl, R , CONHR , and -CO R ;
1-4 2 1-4
R , at each occurrence, is selected from the group consisting of: H, halo and C
alkyl;
R , at each occurrence, is selected from the group consisting of: H, =O, halo, C
alkyl, OH, CN, NH , -N(C alkyl) , NO , C alkoxy, -OCO(C alkyl), -O-C
2 1-4 2 1-4 1-4 1-4
alkylene-O(C alkyl), -O-C alkylene-N(C alkyl) , -CO H, -CO (C alkyl), -
1-4 1-4 1-4 2 2 2 1-4
CONH , -(CH ) CONH , -CONR (C alkyl), -CONR -C alkylene-O(C alkyl), -
2 2 2
2 1-4 1-4 1-4
CON(C alkyl) , -CONR -C alkylene-N(C alkyl) , -CON(C alkyl)-C
1-4 2 1-4 1-4 1-4 1-4
alkylene-O(C alkyl), -CONR -C alkylene-CO (C alkyl), -NR COC alkyl, -
1-4 1-4 2 1-4 1-4
9 9 9 9
NR CO C alkyl, -NR CONH(C alkyl), -NR CONR -C alkylene-CO C alkyl, -
2 1-4 1-4 1-4 2 1-4
8 8 8 8 8
NR -C alkylene-N(C alkyl) , R , -OR , -O-C alkylene-R , -COR , -CO R , -
1-4 1-4 1-4 2
9 9 9 9 9
8 8 8 8
CONR R , -NR COR , -NR CO R , and -NR CON R R ;
R is selected from the group consisting of: H, C alkyl, -CO (C alkyl), -
1-4 2 1-4
CO(C alkyl), -CONH , -CO-C alkylene-N(C alkyl) , -(CH ) N(C alkyl) , -
1-4 2 1-4 1-4 1-4
9 9 9
CONR (C alkyl), -CONR -C alkylene-O(C alkyl), -CONR -C alkylene-N(C
1-4 1-4 1-4 1-4 1-
alkyl) , -CONR -C alkylene-CO (C alkyl), -CON(C alkyl) , R , -COR , -
4 1-4 2 1-4 1-4 2
CO R , and -CONR R ;
R , at each occurrence, is selected from the group consisting of: H, C alkyl,
COC alkyl, CO (C alkyl), CO Bn, -CONH-C alkylene-CO C alkyl, phenyl,
1-4 2 1-4 2 1-4 2 1-4
benzyl, and -CO -C alkylene-aryl;
2 1-4
R , at each occurrence, is selected from the group consisting of:
-(CH ) -C carbocycle substituted with 0-3 R and -(CH ) 10 membered
2 n 3-10 2 n
heterocycle containing carbon atoms and 1-4 heteroatoms selected from the group
consisting of N, NR , O, and S(O) ; wherein said carbocycle and heterocycle are
optionally substituted with =O;
R , at each occurrence, is selected from the group consisting of: H and C alkyl;
R , at each occurrence, is selected from the group consisting of: H, halo, OH,
and C alkyl;
R is, independently at each occurrence, selected from the group consisting of: H,
C alkyl, COC alkyl, CO C alkyl, and CO Bn;
1-4 1-4 2 1-4 2
R is, independently at each occurrence, selected from the group consisting of:
H, C alkyl, CO(C alkyl), COCF , CO (C alkyl),
1-4 1-4 1-4
-CONH-C alkylene-CO C alkyl, CO Bn, R , and CONHR ;
1-4 2 1-4
R is, independently at each occurrence, selected from the group consisting of:
=O, halo, C alkyl, C alkoxy, OCF , NH , NO , N(C alkyl) , CO(C alkyl),
3 2 2 2
1-4 1-4 1-4 1-4
CO(C haloalkyl), CO (C alkyl), CONH , -CONH(C alkyl), -CONHPh, -
1-4 2 1-4 1-4
CON(C alkyl) , -CONH-C alkylene-O(C alkyl), -CONH-C alkylene-N(C
1-4 1-4 1-4 1-4 1-4
f f f
alkyl) , -CONH-C alkylene-CO (C alkyl), -NHCO (C alkyl), R , COR , CO R
1-4 2 1-4 1-4
and CONHR ;
R is, independently at each occurrence, selected from the group consisting of:
-(CH ) -C cycloalkyl, -(CH ) -phenyl, and -(CH ) to 6- membered heterocycle
2 n 3-6 2 n 2 n
containing carbon atoms and 1-4 heteroatoms selected from the group consisting of N,
NR , O, and S(O) ; wherein each ring moiety is substituted with 0-2 R ;
R is, independently at each occurrence, selected from the group consisting of:
=O, halo, C alkyl, OH, C alkoxy, and NHCO(C alkyl);
1-4 1-4 1-4
n, at each occurrence, is selected from 0, 1, 2, 3, and 4; and
p, at each occurrence, is selected from 0, 1, and 2.
In a second aspect, the present invention provides compounds of Formula (I)
or stereoisomers, tautomers, pharmaceutically acceptable salts thereof, within the scope
of the first aspect, wherein:
ring A is C carbocycle;
ring B is 4- to 7-membered heterocycle containing carbon atoms and 0-3
additional heteroatoms selected from the group consisting of N, NR , O, and S(O) ;
optionally, ring B forms a fused ring or spiro ring with a 4- to 7-membered heterocycle
containing carbon atoms and 1-3 heteroatoms selected from the group consisting of NR ,
O, and S(O) ; ring B, including the fused ring or spiro ring is substituted with 1-3 R ;
10 10 10
L is selected from the group consisting of: -CHR CHR -, -CR =CR -, and -
C≡C-;
R , at each occurrence, is selected from the group consisting of: H, halo, C
alkyl, -O(C alkyl), CN, -CH NH , and -C(=NH)NH ;
1-4 2 2
R is independently selected from the group consisting of: H, halo, CN, OH
C alkyl, C alkoxy, C haloalkyl, C haloalkoxy, CO(C alkyl), CONH , CO H
1-6 1-4 1-6 1-6 1-4
and a 5- to 7-membered heterocycle comprising carbon atoms and 1-4 heteroatoms
selected from N, NH, N(C alkyl), O, and S(O) , wherein said heterocycle is substituted
with 1-2 R ;
R , at each occurrence, is selected from the group consisting of: H, halo, C
alkyl, CO H, -CO (C alkyl), -CONH , -CH OH, -CH OC alkyl, and -CH NH ;
2 2 1-4 2 2 2 1-4
3 3a
R is selected from the group consisting of: C alkyl substituted with 1-3 R ,
C carbocycle substituted with 1-3 R , and 5-10 membered heterocycle containing
3-10
carbon atoms and 1-4 heteroatoms selected from the group consisting of N, NR , O, and
S(O) ; wherein said heterocycle is substituted with 1-3 R ;
R , at each occurrence, is selected from the group consisting of: halo, C alkyl,
-OH, C alkoxy, -CN, -NH , -CO H, - -CO (C alkyl), -CONH -CONH(C
2 2 2 2,
1-4 1-4 1-6
alkyl), -CON(C alkyl) -CONH-C alkylene-CO (C alkyl), -CONHCO C
2, 2
1-4 1-4 1-4 2 1-4
alkyl, -CONH-C alkylene-NHCO(C alkyl), -CONH-C alkylene-CONH , -
1-4 1-4 1-4
8 8 8
NHCOC alkyl, -NHCO (C alkyl), R , -CONHR , and -CO R ;
1-4 1-4
R , at each occurrence, is selected from the group consisting of: H, halo, and C
alkyl;
R , at each occurrence, is selected from the group consisting of: H, =O, halo, C
alkyl, OH, CN, NH , -N(C alkyl) , NO , C alkoxy, -OCO(C alkyl), -O-C
2 1-4 2 1-4 1-4 1-4
alkylene-O(C alkyl), -O-C alkylene-N(C alkyl) , -CO H, -CO (C alkyl), -
1-4 1-4 1-4 2 2 2 1-4
CONH , -(CH ) CONH , -CONR (C alkyl), -CONR -C alkylene-O(C alkyl), -
2 2 2
2 1-4 1-4 1-4
CON(C alkyl) , -CONR -C alkylene-N(C alkyl) , -CON(C alkyl)-C
1-4 2 1-4 1-4 1-4 1-4
alkylene-O(C alkyl), -CONR -C alkylene-CO (C alkyl), -NR COC alkyl, -
1-4 1-4 2 1-4 1-4
9 9 9 9
NR CO C alkyl, -NR CONH(C alkyl), -NR CONR -C alkylene-CO C alkyl, -
2 1-4 1-4 1-4 2 1-4
8 8 8 8 8
NR -C alkylene-N(C alkyl) , R , -OR , -O-C alkylene-R , -COR , -CO R , -
1-4 1-4 1-4 2
9 9 9 9 9
8 8 8 8
CONR R , -NR COR , -NR CO R , and -NR CON R R ;
R is selected from the group consisting of: H, C alkyl, -CO (C alkyl), -
1-4 2 1-4
CO(C alkyl), -CONH , -CO-C alkylene-N(C alkyl) , -(CH ) N(C alkyl) , -
1-4 2 1-4 1-4 1-4
9 9 9
CONR (C alkyl), -CONR -C alkylene-O(C alkyl), -CONR -C alkylene-N(C
1-4 1-4 1-4 1-4 1-
alkyl) , -CONR -C alkylene-CO (C alkyl), -CON(C alkyl) , R , -COR , -
4 1-4 2 1-4 1-4 2
CO R , and -CONR R ;
R , at each occurrence, is selected from the group consisting of: H, C alkyl, -
CO (C alkyl), and -CO -C alkylene-aryl;
2 1-4 2 1-4
R , at each occurrence, is selected from the group consisting of:
-(CH ) -C carbocycle and -(CH ) 10 membered heterocycle containing carbon
2 n 3-10 2 n
atoms and 1-4 heteroatoms selected from the group consisting of N, NH, N(C alkyl),
O, and S(O) ; wherein said carbocycle and heterocycle are substituted with =O;
R , at each occurrence, is selected from the group consisting of: H and C alkyl;
R , at each occurrence, is selected from the group consisting of: H and F;
n, at each occurrence, is selected from 0, 1, 2, 3, and 4; and
p, at each occurrence, is selected from 0, 1, and 2.
In a third aspect, the present invention includes compounds of Formula (II):
q 5a
(R )
(II)
or stereoisomers, tautomers, pharmaceutically acceptable salts, or solvates thereof, within
the scope of the second aspect, wherein:
5b 5c 6
W is selected from the group consisting of CR R , O, S(O) , and NR ;
4a 4b 4c 4d
R , R , R , and R are independently selected from the group consisting of:
H, F, and C alkyl;
R is selected from the group consisting of: H and =O;
5b 5c
R and R are independently selected from the group consisting of: H, halo, C
alkyl, OH, CN, NH , -N(C alkyl) , C alkoxy, -OCO-C alkyl, -O-C alkylene-
4 2 1-4 1-4 1-4 1-4
N(C alkyl) , -O-C alkylene-O(C alkyl), -CO H, -CO (C alkyl), -CONH , -
1-4 1-4 1-4 2 2 1-4 2
8 8 8 8
CONR (C alkyl), -CON(C alkyl) , R , -OR , -COR , and -CO R ;
1-4 1-4 2
5b 5c
optionally, R and R together with the carbon atom to which they are attached
form a 4-7 membered heterocyclic ring containing carbon atoms and 1-3 heteroatoms
selected from the group consisting of NR , O, and S(O) ; wherein said heterocycle is
unsubstituted or substituted with =O.
q, at each occurrence, is selected from 0, 1, and 2; and
r, at each occurrence, is selected from 0, 1, and 2.
In a fourth aspect, the present invention includes compounds of Formula (III):
q 5a
(III)
or stereoisomers, tautomers, pharmaceutically acceptable salts, or solvates thereof, within
the scope of the third aspect, wherein:
R is selected from the group consisting of: H, halo, C alkyl, and methoxy;
R is selected from the group consisting of: H and halo;
R is independently selected from the group consisting of: H, F, CN, OH, C
alkoxy, -CHF , -CF , -OCHF , -CO(C alkyl), triazole substituted with R , and
2 3 2 1-4
tetrazole substituted with R ;
3 3a
R is selected from the group consisting of: phenyl substituted with 1-2 R , C
3a 3a
cycloalkyl substituted with 1-2 R , heterocycle substituted with 1-2 R ; wherein said
heterocycle is selected from the group consisting of: piperidinyl, pyridyl, indolyl, and
indazolyl.
In a fifth aspect, the present invention includes compounds of Formula (IV):
q 5a
(IV)
or stereoisomers, tautomers, pharmaceutically acceptable salts, or solvates thereof, within
the scope of the fourth aspect, wherein:
q 6 6 0-2
0-2 O
R R R
W N N
N N N
0-2 0-2
is selected from the group consisting of: ,
5b 5b
6 0-2
N O O S
5c 5c
N N N N N N
0-2 0-2
, , , , , , and
3 3a
R is selected from the group consisting of: phenyl substituted with 1-2 R ,
3a 3a
pyridyl substituted with 1-2 R , C cycloalkyl substituted with 1-2 R , ,
and ;
R is selected from the group consisting of: C alkyl.
In a sixth aspect, the present invention includes compounds of Formula (V):
R 4d
H 1b
or stereoisomers, tautomers, pharmaceutically acceptable salts, or solvates thereof, within
the scope of the fifth aspect, wherein:
3 3a
R is selected from the group consisting of: phenyl substituted with 1-2 R
and pyridyl substituted with 1-2 R ;
q 5a
is selected from the group consisting of: , ,
5b 5b
6 R R
5c 5c
N N N
, , , , ,
O O S
N N N N N
, , , , , , and
R , at each occurrence, is selected from the group consisting of: halo, C alkyl,
OH, C alkoxy, CN, NH , -CO H, -CO (C alkyl), -CONH CONH(C alkyl), -
2 2 2 2,
1-4 1-4 1-4
f f f
CON(C alkyl) ; , -NHCO (C alkyl), R , -CONHR , and -CO R ;
2 2 2
1-4 1-4
5b 5c
R and R are independently selected from the group consisting of: H, C
alkyl, OH, CN, NH , -N(C alkyl) , C alkoxy, -OCO-C alkyl, -CO H, -CO (C
2 1-4 1-4 1-4 2 2 1-4
8 8 8
alkyl), -CONH , -CONR (C alkyl), -CON(C alkyl) , R , -OR , -COR , and -
2 1-4 1-4
CO R ;
5b 5c
optionally, R and R together with the carbon atom to which they are both
attached form a 5-6 membered heterocyclic ring containing carbon atoms and 1-3
heteroatoms selected from the group consisting of NR , O, and S(O) ; wherein said
heterocycle is unsubstituted or substituted with =O; and
R is selected from the group consisting of: H, C alkyl, -CO (C alkyl), -
1-4 2 1-4
CO(C alkyl), -CO-C alkylene-N(C alkyl) , -CONH , -(CH ) N(C alkyl) , -
2 2 2 2
1-4 1-4 1-4 2 1-4
CONH(C alkyl), -CONH-C alkylene-O(C alkyl), -CONH-C alkylene-N(C
1-4 1-4 1-4 1-4 1-4
alkyl) , -CONH-C alkylene-CO (C alkyl), -CON(C alkyl) , R , -COR , and -
1-4 2 1-4 1-4 2
CO R .
In a seventh aspect, the present invention includes compounds of Formula
(VI):
(VI)
or stereoisomers, tautomers, pharmaceutically acceptable salts thereof, within the scope
of the sixth aspect, wherein:
R is independently selected from the group consisting of: H and F;
R is selected from the group consisting of: halo, CN, CO H, -CO (C
2 2 1-4
alkyl), -CONH CONH(C alkyl), -NHCO (C alkyl), -CO (C cycloalkyl), -
2, - 2 2
1-4 1-4 3-6
CO (CH ) Ph, and -CO (CH ) triazole.
2 2 1-2 2 1-2
In an eighth aspect, the present invention includes compounds of Formula
(VI), or stereoisomers, tautomers, pharmaceutically acceptable salts, or solvates thereof,
within the scope of the seventh aspect, wherein:
0-2 5a
is selected from the group consisting of :, , , ,
N N NC
N N N
, , , ,
C alkyl C alkyl
1-4 1-4
OC alkyl
N N N N N
, , , , ,
C alkyl
C alkyl
C alkyl
C alkylene-N(C alkyl) C alkylene-O(C alkyl)
1-4 1-4 2 1-4 1-4 N
C alkyl
N N N N
, , , ,
C alkyl
O N N N
C alkyl O
O O O
N O N N N N
, , , , ,
C alkyl
C alkyl
N N N N
, , , ,
N N N N
, , , ,
N N N
, , , ,
C alkyl
C alkyl
N N N
, , , , ,
O O S S
N N N N
, , , , and
[0034] R is independently selected from the group consisting of: F, Cl, CN, CO H,
-CO Me, -CO Et , -CO (i-Pr), -CO (t-Bu), -CO (n-Bu), -CO (i-Bu), --NHCO Me, -
2 2 2 2 2 2 2
CO CH (phenyl), -CO (C cycloalkyl) and -CO (CH ) -triazole; and
2 2 , 2 2
R is selected from the group consisting of: H, C alkyl, -CO (C alkyl), -
1-4 2 1-4
CO(C alkyl), -COCH N(C alkyl) , -(CH ) N(C alkyl) , -CONH(C alkyl), -
2 2 2 1-2 2
1-4 1-4 1-4 1-4
CONH-C alkylene-O(C alkyl), -CONH-C alkylene-N(C alkyl) , -CONH-C
1-4 1-4 1-4 1-4 1-4
alkylene-CO (C alkyl), -CH Ph, and -CO -C alkylene-Ph.
2 1-4 2 1-4
In a ninth aspect, the present invention includes compounds of Formula (VII):
H 1b
(VII)
or stereoisomers, tautomers, pharmaceutically acceptable salts, or solvates thereof,
within the scope of the second aspect, wherein:
R is selected from the group consisting of: H and F;
5a 6 6
is selected from the group consisting of: ,
5b 5b
6 6 O
5c 5c
R R O
N N N N N
, , , , ,
O O S S
N N N N N N
, , , , ,
5c 6
R N 5b
N N N
, , , , ,
and ;
R is selected from the group consisting of: H, F, CN, COMe, OH, OMe, OCHF ,
CHF , CF , and tetrazole;
3 3a
R is selected from the group consisting of: phenyl substituted with 1-2 R ,
cyclohexyl, , and ;
R is independently selected from the group consisting of: F, Cl, CN, CO H, -
CO Me, -CO Et, -CO (i-Pr), -CO (t-Bu), -CO (n-Bu), -CO (i-Bu), - -NHCO Me, -
2 2 2 2 2 2 2
CO (CH ) -triazole, and -CO (cyclopentyl);
2 2 2
4c 4d
R and R are independently selected from the group consisting of: H and Me;
5b 5c
R and R are, independently selected from the group consisting of: H, F, Me,
Et, i-propyl, CN, OH, -OMe, -CO Me, -CO Et, -CON(Me) , NH , -N(Me) , -
O(CH )N(Me) , -O(CH )OMe, , , , ,
2 2 2
O HN
, , , and ;
R is selected from the group consisting of: H, Me, -CO Me, -CO (t-butyl), -
COMe, -CONHMe, -CONH(CH ) CO Et, CONH(CH ) N(Me) , -CO CH Ph, -
2 2 2 2 2 2
(CH ) N(Me) , and -CH Ph; and
2 2 2 2
R is Me;
q, at each occurrence, is selected from 0, 1, and 2; and
r, at each occurrence, is selected from 0, 1, and 2.
In a tenth aspect, the present invention includes compounds of Formula (VIII):
O 3a
(VIII)
or stereoisomers, tautomers, pharmaceutically acceptable salt thereof, within the scope of
the ninth aspect wherein:
R is selected from the group consisting of: H, F, CN, COMe, OH, OMe, OCHF ,
CHF , CF , and tetrazole;
R is selected from the group consisting of: F, Cl, CN, CO H, CO Me, -CO Et, -
2 2 2
CO (i-Pr), -CO (t-Bu), -CO (n-Bu), -CO (i-Bu), and -NHCO Me;
2 2 2 2 2
R is selected from the group consisting of: H, Me, -CO Me, -CO (t-butyl), -
COMe, and –CONHMe;
q is 1or 2; and
r is 1 or 2.
In an eleventh aspect, the present invention includes compounds of Formula
(VIII):
O 3a
(VIII)
or stereoisomers, tautomers, pharmaceutically acceptable salts thereof, wherein:
R is selected from the group consisting of: H, Cl, C alkyl, and methoxy;
R is selected from the group consisting of: H and F;
R is selected from the group consisting of: H, C alkyl, -CO(C alkyl),
1-4 1-4
CO H, -CO (C alkyl), -CONH(C alkyl), and -CO(CH ) N(C alkyl) ;
2 2 1-4 1-4 2 0-2 1-4 2
R is selected from the group consisting of: H, F, Cl, CN, CO H, -CO Et, and -
CO (t-Bu).
In a twelfth aspect, the present invention includes compounds of Formula (I)
or stereoisomers, tautomers, pharmaceutically acceptable salts thereof, within the scope
of the first aspect, wherein:
ring B is heteroaryl or bridged heterocycle, each containing carbon atoms and 0-2
additional heteroatoms selected from the group consisting of N, NH, O, and S(O)p, and
each substituted with 1-3 R ;
R is selected from the group consisting of: H, F, CN, -CO(C alkyl), OH, -
O(C alkyl), -OCHF , -CHF , -CF , triazole, and tetrazole, wherein said triazole and
1-4 2 2 3
tetrazole are substituted with 0-2 R ; and
R , at each occurrence, is selected from the group consisting of: H, =O, halo, C
alkyl, OH, CN, NH , -N(C alkyl) , C alkoxy, -CO H, -CO (C alkyl), -CONH , -
2 1-4 1-4 2 2 1-4 2
CONR (C alkyl), -CON(C alkyl) , R , and -COR .
1-4 1-4 2
In another embodiment, ring A is phenyl.
[0041] In another embodiment, ring A is cyclohexyl.
In another aspect, ring A is wherein R is, independently at each
occurrence, selected from the group consisting of: halogen, C alkyl, OH, C alkoxy,
1-4 1-4
CO(C alkyl), CN, CH F, CHF , OCHF , and -CH NHCO (C alkyl), a 5- to 7-
2 2 2 2 2
1-4 1-4
membered heterocycle comprising carbon atoms and 1-4 heteroatoms selected from N,
c 2a
NR , O, and S(O) , wherein said heterocycle is substituted with 0-2 R .
In another aspect, ring A is is independently selected from the
C alkoxy CO(C alkyl)
1-4 1-4
halo halo
group consisting of: , ,
CHF OCHF CN
halo halo halo
, , ,
C alkyl
1-4 halo
halo
C alkyl
halo
halo
halo
, , ,
C alkoxy
CN 1-4 halo
halo HO halo
halo
halo
halo halo halo halo
, , , , and
CO(C alkyl)
halo
halo
In another embodiment, L is independently selected from the group consisting
of: a bond, -CH CH -, -CH=CH-, -C(Me)=CH-, -C≡C-, and -CH NH-.
2 2 2
In another embodiment, L is independently selected from the group consisting
of: a bond, -CH CH -, -CH=CH-, and -C(Me)=CH.
In another embodiment, L is independently selected from the group consisting
of: a bond, -CH CH - and -CH=CH-.
In another embodiment, L is -CH=CH-.
In another embodiment, ring B is
, wherein R is methyl or ethyl; q and r are independently selected
from 0, 1, and 2.
In another embodiment, ring B is
In another embodiment, ring B is substituted pyrazole.
In another embodiment, ring B is
(R )
3 3a
[0051] In another embodiment, R is C alkyl substituted with R .
3 3a
In another embodiment, R is phenyl substituted with R .
3 3a
In another embodiment, R is cyclohexyl substituted with R .
3 3a
In another embodiment, R is a heterocycle substituted with R and selected
from: , and .
3 3a
[0055] In another embodiment, R is substituted with R .
In another embodiment, ring B is
wherein R is methyl or ethyl, q and r are independently an integer selected from 1 and 2;
R is selected from the group consisting of: H, F, CN, COMe, OH, OMe, OCHF , CHF ,
3 3a 3a
CF , and tetrazole; R is phenyl substituted with R , wherein R is selected from the
group consisting of: H, F, Cl, CN, CO H, - CH CO H, CO Me, -CO Et, -CO (i-Pr), -
2 2 2 2 2
CO (t-Bu), -CO (n-Bu), -CO (i-Bu), - and NHCO Me;
2 2 2 2
In another aspect, the present invention provides a compound selected from
the exemplified examples or a stereoisomer, a tautomer, a pharmaceutically acceptable
salt, or a solvate thereof.
In another aspect, the present invention provides a compound selected from
any subset list of compounds within the scope of the exemplified examples or a
stereoisomer, a tautomer, a pharmaceutically acceptable salt, or a solvate thereof.
In another aspect, the invention provides a compound, or a tautomer,
pharmaceutically acceptable salt or solvate thereof, wherein the compound is selected
from:
N R'
wherein R and R’ are:
Stereochemistry R R’
S-enantiomer PhCOOCH2CON(CH )
S-enantiomer
.
In another embodiment, the compounds of the present invention have Factor
XIa Ki values ≤ 10 µM.
In another embodiment, the compounds of the present invention have Factor
XIa Ki values ≤ 1 µM.
In another embodiment, the compounds of the present invention have Factor
XIa Ki values ≤ 0.5 µM.
[0062] In another embodiment, the compounds of the present invention have Factor
XIa Ki values ≤ 0.1 µM.
II. OTHER EMBODIMENTS OF THE INVENTION
In another embodiment, the present invention provides a composition
comprising at least one of the compounds of the present invention or a stereoisomer, a
tautomer, a pharmaceutically acceptable salt, or a solvate thereof.
In another embodiment, the present invention provides a pharmaceutical
composition comprising a pharmaceutically acceptable carrier and at least one of the
compounds of the present invention or a stereoisomer, a tautomer, a pharmaceutically
acceptable salt, or a solvate, thereof.
In another embodiment, the present invention provides a pharmaceutical
composition, comprising: a pharmaceutically acceptable carrier and a therapeutically
effective amount of at least one of the compounds of the present invention or a
stereoisomer, a tautomer, a pharmaceutically acceptable salt, or a solvate thereof.
[0066] Also described herein is a process for making a compound of the present
invention.
Also described herein is an intermediate for making a compound of the
present invention.
In another embodiment, the present invention provides a pharmaceutical
composition further comprising additional therapeutic agent(s). In a preferred
embodiment, the present invention provides pharmaceutical composition, wherein the
additional therapeutic agent(s) are an anti-platelet agent or a combination thereof.
Preferably, the anti-platelet agent(s) are clopidogrel and/or aspirin, or a combination
thereof.
[0069] Also described herein is a method for the treatment and/or prophylaxis of a
thromboembolic disorder comprising administering to a patient in need of such treatment
and/or prophylaxis a therapeutically effective amount of at least one of the compounds of
the present invention or a stereoisomer, a tautomer, a pharmaceutically acceptable salt, or
a solvate thereof.
In another embodiment, the present invention provides a compound of the
present invention or a stereoisomer, a tautomer, a pharmaceutically acceptable salt, or a
solvate thereof, for use in therapy.
In another embodiment, the present invention provides a compound of the
present invention or a stereoisomer, a tautomer, a pharmaceutically acceptable salt, or a
solvate thereof, for use in therapy for the treatment and/or prophylaxis of a
thromboembolic disorder.
[0072] In another embodiment, the present invention also provides the use of a
compound of the present invention or a stereoisomer, a tautomer, a pharmaceutically
acceptable salt, or a solvate thereof, for the manufacture of a medicament for the
treatment and/or prophylaxis of a thromboembolic disorder.
Also described herein is a method for treatment and/or prophylaxis of a
thromboembolic disorder, comprising: administering to a patient in need thereof a
therapeutically effective amount of a first and second therapeutic agent, wherein the first
therapeutic agent is a compound of the present invention or a stereoisomer, a tautomer, a
pharmaceutically acceptable salt, or a solvate thereof, and the second therapeutic agent is
at least one agent selected from a second factor XIa inhibitor, an anti-coagulant agent, an
anti-platelet agent, a thrombin inhibiting agent, a thrombolytic agent, and a fibrinolytic
agent. Preferably, the second therapeutic agent is at least one agent selected from
warfarin, unfractionated heparin, low molecular weight heparin, synthetic
pentasaccharide, hirudin, argatroban, aspirin, ibuprofen, naproxen, sulindac,
indomethacin, mefenamate, droxicam, diclofenac, sulfinpyrazone, piroxicam, ticlopidine,
clopidogrel, tirofiban, eptifibatide, abciximab, melagatran, desulfatohirudin, tissue
plasminogen activator, modified tissue plasminogen activator, anistreplase, urokinase,
and streptokinase. Preferably, the second therapeutic agent is at least one anti-platelet
agent. Preferably, the anti-platelet agent(s) are clopidogrel and/or aspirin, or a
combination thereof.
[0074] The thromboembolic disorder includes arterial cardiovascular thromboembolic
disorders, venous cardiovascular thromboembolic disorders, arterial cerebrovascular
thromboembolic disorders, and venous cerebrovascular thromboembolic disorders.
Examples of the thromboembolic disorder include, but are not limited to, unstable angina,
an acute coronary syndrome, atrial fibrillation, first myocardial infarction, recurrent
myocardial infarction, ischemic sudden death, transient ischemic attack, stroke,
atherosclerosis, peripheral occlusive arterial disease, venous thrombosis, deep vein
thrombosis, thrombophlebitis, arterial embolism, coronary arterial thrombosis, cerebral
arterial thrombosis, cerebral embolism, kidney embolism, pulmonary embolism, and
thrombosis resulting from medical implants, devices, or procedures in which blood is
exposed to an artificial surface that promotes thrombosis.
Also described herein is a method for the treatment and/or prophylaxis of an
inflammatory disorder comprising: administering to a patient in need of such treatment
and/or prophylaxis a therapeutically effective amount of at least one of the compounds of
the present invention or a stereoisomer, a tautomer, a pharmaceutically acceptable salt, or
a solvate thereof. Examples of the inflammatory disorder include, but are not limited to,
sepsis, acute respiratory distress syndrome, and systemic inflammatory response
syndrome.
In another embodiment, the present invention provides a combined
preparation of a compound of the present invention and additional therapeutic agent(s) for
simultaneous, separate or sequential use in therapy.
In another embodiment, the present invention provides a combined
preparation of a compound of the present invention and additional therapeutic agent(s) for
simultaneous, separate or sequential use in treatment and/or prophylaxis of a
thromboembolic disorder.
The present invention may be embodied in other specific forms without
departing from the spirit or essential attributes thereof. This invention encompasses all
combinations of preferred aspects of the invention noted herein. It is understood that any
and all embodiments of the present invention may be taken in conjunction with any other
embodiment or embodiments to describe additional embodiments. It is also to be
understood that each individual element of the embodiments is its own independent
embodiment. Furthermore, any element of an embodiment is meant to be combined with
any and all other elements from any embodiment to describe an additional embodiment.
III. CHEMISTRY
Throughout the specification and the appended claims, a given chemical
formula or name shall encompass all stereo and optical isomers and racemates thereof
where such isomers exist. Unless otherwise indicated, all chiral (enantiomeric and
diastereomeric) and racemic forms are within the scope of the invention. Many
geometric isomers of C=C double bonds, C=N double bonds, ring systems, and the like
can also be present in the compounds, and all such stable isomers are contemplated in the
present invention. Cis- and trans- (or E- and Z-) geometric isomers of the compounds of
the present invention are described and may be isolated as a mixture of isomers or as
separated isomeric forms. The present compounds can be isolated in optically active or
racemic forms. Optically active forms may be prepared by resolution of racemic forms or
by synthesis from optically active starting materials. All processes used to prepare
compounds of the present invention and intermediates made therein are considered to be
part of the present invention. When enantiomeric or diastereomeric products are
prepared, they may be separated by conventional methods, for example, by
chromatography or fractional crystallization. Depending on the process conditions the
end products of the present invention are obtained either in free (neutral) or salt form.
Both the free form and the salts of these end products are within the scope of the
invention. If so desired, one form of a compound may be converted into another form. A
free base or acid may be converted into a salt; a salt may be converted into the free
compound or another salt; a mixture of isomeric compounds of the present invention may
be separated into the individual isomers. Compounds of the present invention, free form
and salts thereof, may exist in multiple tautomeric forms, in which hydrogen atoms are
transposed to other parts of the molecules and the chemical bonds between the atoms of
the molecules are consequently rearranged. It should be understood that all tautomeric
forms, insofar as they may exist, are included within the invention.
The term “stereoisomer” refers to isomers of identical constitution that differ
in the arrangement of their atoms in space. Enantiomers and diastereomers are examples
of stereoisomers. The term “enantiomer” refers to one of a pair of molecular species that
are mirror images of each other and are not superimposable. The term “diastereomer”
refers to stereoisomers that are not mirror images. The term “racemate” or “racemic
mixture” refers to a composition composed of equimolar quantities of two enantiomeric
species, wherein the composition is devoid of optical activity.
The symbols “R” and “S” represent the configuration of substituents around a
chiral carbon atom(s). The isomeric descriptors “R” and “S” are used as described herein
for indicating atom configuration(s) relative to a core molecule and are intended to be
used as defined in the literature (IUPAC Recommendations 1996, Pure and Applied
Chemistry, 68, 2193-2222 (1996)).
The term “chiral” refers to the structural characteristic of a molecule that
makes it impossible to superimpose it on its mirror image. The term “homochiral” refers
to a state of enantiomeric purity. The term “optical activity” refers to the degree to which
a homochiral molecule or nonracemic mixture of chiral molecules rotates a plane of
polarized light.
As used herein, the term “alkyl” or “alkylene” is intended to include both
branched and straight-chain saturated aliphatic hydrocarbon groups having the specified
number of carbon atoms. For example, “C to C alkyl” or “C alkyl” (or alkylene),
1 10 1-10
is intended to include C , C , C , C , C , C , C , C , C , and C alkyl groups.
1 2 3 4 5 6 7 8 9 10
Additionally, for example, “C to C alkyl” or “C -C alkyl” denotes alkyl having 1 to 6
1 6 1 6
carbon atoms. Alkyl group can be unsubstituted or substituted with at least one hydrogen
being replaced by another chemical group. Example alkyl groups include, but are not
limited to, methyl (Me), ethyl (Et), propyl (e.g., n-propyl and isopropyl), butyl (e.g., n-
butyl, isobutyl, t-butyl), and pentyl (e.g., n-pentyl, isopentyl, neopentyl). When “C
alkyl” or “C alkylene” is used, it is intended to denote a direct bond.
Alkenyl” or “alkenylene” is intended to include hydrocarbon chains of either
straight or branched configuration having the specified number of carbon atoms and one
or more, preferably one to two, carbon-carbon double bonds that may occur in any stable
point along the chain. For example, “C to C alkenyl” or “C alkenyl” (or alkenylene),
2 6 2-6
is intended to include C , C , C , C , and C alkenyl groups. Examples of alkenyl
2 3 4 5 6
include, but are not limited to, ethenyl, 1-propenyl, 2-propenyl, 2-butenyl, 3-butenyl,
2-pentenyl, 3, pentenyl, 4-pentenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl,
2-methylpropenyl, and 4-methylpentenyl.
“Alkynyl” or “alkynylene” is intended to include hydrocarbon chains of either
straight or branched configuration having one or more, preferably one to three,
carbon-carbon triple bonds that may occur in any stable point along the chain. For
example, “C to C alkynyl” or “C alkynyl” (or alkynylene), is intended to include C ,
2 6 2-6 2
C , C , C , and C alkynyl groups; such as ethynyl, propynyl, butynyl, pentynyl, and
3 4 5 6
hexynyl.
The term “alkoxy” or “alkyloxy” refers to an –O-alkyl group. “C to C
alkoxy” or “C alkoxy” (or alkyloxy), is intended to include C , C , C , C , C , and C
1-6 1 2 3 4 5 6
alkoxy groups. Example alkoxy groups include, but are not limited to, methoxy, ethoxy,
propoxy (e.g., n-propoxy and isopropoxy), and t-butoxy. Similarly, “alkylthio” or
“thioalkoxy” represents an alkyl group as defined above with the indicated number of
carbon atoms attached through a sulphur bridge; for example methyl-S- and ethyl-S-.
“Halo” or “halogen” includes fluoro, chloro, bromo, and iodo. “Haloalkyl” is
intended to include both branched and straight-chain saturated aliphatic hydrocarbon
groups having the specified number of carbon atoms, substituted with 1 or more
halogens. Examples of haloalkyl include, but are not limited to, fluoromethyl,
difluoromethyl, trifluoromethyl, trichloromethyl, pentafluoroethyl, pentachloroethyl,
2,2,2-trifluoroethyl, heptafluoropropyl, and heptachloropropyl. Examples of haloalkyl
also include “fluoroalkyl” that is intended to include both branched and straight-chain
saturated aliphatic hydrocarbon groups having the specified number of carbon atoms,
substituted with 1 or more fluorine atoms.
“Haloalkoxy” or “haloalkyloxy” represents a haloalkyl group as defined above
with the indicated number of carbon atoms attached through an oxygen bridge. For
example, “C to C haloalkoxy” or “C haloalkoxy”, is intended to include C , C , C ,
1 6 1-6 1 2 3
C , C , and C haloalkoxy groups. Examples of haloalkoxy include, but are not limited
4 5 6
to, trifluoromethoxy, 2,2,2-trifluoroethoxy, and pentafluorothoxy. Similarly,
“haloalkylthio” or “thiohaloalkoxy” represents a haloalkyl group as defined above with
the indicated number of carbon atoms attached through a sulphur bridge; for example
trifluoromethyl-S-, and pentafluoroethyl-S-.
The term “cycloalkyl” refers to cyclized alkyl groups, including mono-, bi- or
poly-cyclic ring systems. “C to C cycloalkyl” or “C cycloalkyl” is intended to
3 7 3-7
include C , C , C , C , and C cycloalkyl groups. Example cycloalkyl groups include,
3 4 5 6 7
but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and norbornyl.
Branched cycloalkyl groups such as 1-methylcyclopropyl and 2-methylcyclopropyl are
included in the definition of “cycloalkyl”.
As used herein, “carbocycle” or “carbocyclic residue” is intended to mean any
stable 3-, 4-, 5-, 6-, 7-, or 8-membered monocyclic or bicyclic or 7-, 8-, 9-, 10-, 11-, 12-,
or 13-membered bicyclic or tricyclic hydrocarbon ring, any of which may be saturated,
partially unsaturated, unsaturated or aromatic. Examples of such carbocycles include, but
are not limited to, cyclopropyl, cyclobutyl, cyclobutenyl, cyclopentyl, cyclopentenyl,
cyclohexyl, cycloheptenyl, cycloheptyl, cycloheptenyl, adamantyl, cyclooctyl,
cyclooctenyl, cyclooctadienyl, [3.3.0]bicyclooctane, [4.3.0]bicyclononane,
[4.4.0]bicyclodecane (decalin), [2.2.2]bicyclooctane, fluorenyl, phenyl, naphthyl, indanyl,
adamantyl, anthracenyl, and tetrahydronaphthyl (tetralin). As shown above, bridged rings
are also included in the definition of carbocycle (e.g., [2.2.2]bicyclooctane). Preferred
carbocycles, unless otherwise specified, are cyclopropyl, cyclobutyl, cyclopentyl,
cyclohexyl, phenyl, and indanyl. When the term “carbocycle” is used, it is intended to
include “aryl”. A bridged ring occurs when one or more carbon atoms link two non-
adjacent carbon atoms. Preferred bridges are one or two carbon atoms. It is noted that a
bridge always converts a monocyclic ring into a tricyclic ring. When a ring is bridged,
the substituents recited for the ring may also be present on the bridge.
As used herein, the term “bicyclic carbocycle” or “bicyclic carbocyclic group”
is intended to mean a stable 9- or 10-membered carbocyclic ring system that contains two
fused rings and consists of carbon atoms. Of the two fused rings, one ring is a benzo ring
fused to a second ring; and the second ring is a 5- or 6-membered carbon ring which is
saturated, partially unsaturated, or unsaturated. The bicyclic carbocyclic group may be
attached to its pendant group at any carbon atom which results in a stable structure. The
bicyclic carbocyclic group described herein may be substituted on any carbon if the
resulting compound is stable. Examples of a bicyclic carbocyclic group are, but not
limited to, naphthyl, 1,2-dihydronaphthyl, 1,2,3,4-tetrahydronaphthyl, and indanyl.
“Aryl” groups refer to monocyclic or polycyclic aromatic hydrocarbons,
including, for example, phenyl, naphthyl, and phenanthranyl. Aryl moieties are well
known and described, for example, in Hawley’s Condensed Chemical Dictionary (13th
Ed.), Lewis, R.J., ed., J. Wiley & Sons, Inc., New York (1997). “C or C aryl” or “C
6 10 6-
aryl” refers to phenyl and naphthyl. Unless otherwise specified, “aryl”, “C or C
6 10
aryl” or “C aryl” or “aromatic residue” may be unsubstituted or substituted with 1 to 5
6-10
groups, preferably 1 to 3 groups, OH, OCH , Cl, F, Br, I, CN, NO , NH , N(CH )H,
3 2 2 3
N(CH ) , CF , OCF , C(=O)CH , SCH , S(=O)CH , S(=O) CH , CH , CH CH ,
3 2 3 3 3 3 3 2 3 3 2 3
CO H, and CO CH .
2 2 3
The term “benzyl,” as used herein, refers to a methyl group on which one of
the hydrogen atoms is replaced by a phenyl group, wherein said phenyl group may
optionally be substituted with 1 to 5 groups, preferably 1 to 3 groups, OH, OCH , Cl, F,
Br, I, CN, NO , NH , N(CH )H, N(CH ) , CF , OCF , C(=O)CH , SCH , S(=O)CH ,
2 2 3 3 2 3 3 3 3 3
S(=O) CH , CH , CH CH , CO H, and CO CH .
2 3 3 2 3 2 2 3
As used herein, the term “heterocycle” or “heterocyclic group” is intended to
mean a stable 3-, 4-, 5-, 6-, or 7-membered monocyclic or bicyclic or 7-, 8-, 9-, 10-, 11-,
12-, 13-, or 14-membered polycyclic heterocyclic ring that is saturated, partially
unsaturated, or fully unsaturated, and that contains carbon atoms and 1, 2, 3 or 4
heteroatoms independently selected from the group consisting of N, O and S; and
including any polycyclic group in which any of the above-defined heterocyclic rings is
fused to a benzene ring. The nitrogen and sulfur heteroatoms may optionally be oxidized
(i.e., N→O and S(O) , wherein p is 0, 1 or 2). The nitrogen atom may be substituted or
unsubstituted (i.e., N or NR wherein R is H or another substituent, if defined). The
heterocyclic ring may be attached to its pendant group at any heteroatom or carbon atom
that results in a stable structure. The heterocyclic rings described herein may be
substituted on carbon or on a nitrogen atom if the resulting compound is stable. A
nitrogen in the heterocycle may optionally be quaternized. It is preferred that when the
total number of S and O atoms in the heterocycle exceeds 1, then these heteroatoms are
not adjacent to one another. It is preferred that the total number of S and O atoms in the
heterocycle is not more than 1. When the term “heterocycle” is used, it is intended to
include heteroaryl.
[0095] Examples of heterocycles include, but are not limited to, acridinyl, azetidinyl,
azocinyl, benzimidazolyl, benzofuranyl, benzothiofuranyl, benzothiophenyl,
benzoxazolyl, benzoxazolinyl, benzthiazolyl, benztriazolyl, benztetrazolyl,
benzisoxazolyl, benzisothiazolyl, benzimidazolinyl, carbazolyl, 4aH-carbazolyl,
carbolinyl, chromanyl, chromenyl, cinnolinyl, decahydroquinolinyl, 2H,6H-1,5,2-
dithiazinyl, dihydrofuro[2,3-b]tetrahydrofuran, furanyl, furazanyl, imidazolidinyl,
imidazolinyl, imidazolyl, 1H-indazolyl, imidazolopyridinyl, indolenyl, indolinyl,
indolizinyl, indolyl, 3H-indolyl, isatinoyl, isobenzofuranyl, isochromanyl, isoindazolyl,
isoindolinyl, isoindolyl, isoquinolinyl, isothiazolyl, isothiazolopyridinyl, isoxazolyl,
isoxazolopyridinyl, methylenedioxyphenyl, morpholinyl, naphthyridinyl,
octahydroisoquinolinyl, oxadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-
oxadiazolyl, 1,3,4-oxadiazolyl, oxazolidinyl, oxazolyl, oxazolopyridinyl,
oxazolidinylperimidinyl, oxindolyl, pyrimidinyl, phenanthridinyl, phenanthrolinyl,
phenazinyl, phenothiazinyl, phenoxathiinyl, phenoxazinyl, phthalazinyl, piperazinyl,
piperidinyl, piperidonyl, 4-piperidonyl, piperonyl, pteridinyl, purinyl, pyranyl, pyrazinyl,
pyrazolidinyl, pyrazolinyl, pyrazolopyridinyl, pyrazolyl, pyridazinyl, pyridooxazolyl,
pyridoimidazolyl, pyridothiazolyl, pyridinyl, pyrimidinyl, pyrrolidinyl, pyrrolinyl,
2-pyrrolidonyl, 2H-pyrrolyl, pyrrolyl, quinazolinyl, quinolinyl, 4H-quinolizinyl,
quinoxalinyl, quinuclidinyl, tetrazolyl, tetrahydrofuranyl, tetrahydroisoquinolinyl,
tetrahydroquinolinyl, 6H-1,2,5-thiadiazinyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-
thiadiazolyl, 1,3,4-thiadiazolyl, thianthrenyl, thiazolyl, thienyl, thiazolopyridinyl,
thienothiazolyl, thienooxazolyl, thienoimidazolyl, thiophenyl, triazinyl, 1,2,3-triazolyl,
1,2,4-triazolyl, 1,2,5-triazolyl, 1,3,4-triazolyl, and xanthenyl. Also included are fused
ring and spiro compounds containing, for example, the above heterocycles.
Examples of 5- to 10-membered heterocycles include, but are not limited to,
pyridinyl, furanyl, thienyl, pyrrolyl, pyrazolyl, pyrazinyl, piperazinyl, piperidinyl,
imidazolyl, imidazolidinyl, indolyl, tetrazolyl, isoxazolyl, morpholinyl, oxazolyl,
oxadiazolyl, oxazolidinyl, tetrahydrofuranyl, thiadiazinyl, thiadiazolyl, thiazolyl,
triazinyl, triazolyl, benzimidazolyl, 1H-indazolyl, benzofuranyl, benzothiofuranyl,
benztetrazolyl, benzotriazolyl, benzisoxazolyl, benzoxazolyl, oxindolyl, benzoxazolinyl,
benzthiazolyl, benzisothiazolyl, isatinoyl, isoquinolinyl, octahydroisoquinolinyl,
tetrahydroisoquinolinyl, tetrahydroquinolinyl, isoxazolopyridinyl, quinazolinyl,
quinolinyl, isothiazolopyridinyl, thiazolopyridinyl, oxazolopyridinyl, imidazolopyridinyl,
and pyrazolopyridinyl.
Examples of 5- to 6-membered heterocycles include, but are not limited to,
pyridinyl, furanyl, thienyl, pyrrolyl, pyrazolyl, pyrazinyl, piperazinyl, piperidinyl,
imidazolyl, imidazolidinyl, indolyl, tetrazolyl, isoxazolyl, morpholinyl, oxazolyl,
oxadiazolyl, oxazolidinyl, tetrahydrofuranyl, thiadiazinyl, thiadiazolyl, thiazolyl,
triazinyl, and triazolyl. Also included are fused ring and spiro compounds containing, for
example, the above heterocycles.
As used herein, the term “bicyclic heterocycle” or “bicyclic heterocyclic
group” is intended to mean a stable 9- or 10-membered heterocyclic ring system which
contains two fused rings and consists of carbon atoms and 1, 2, 3, or 4 heteroatoms
independently selected from the group consisting of N, O and S. Of the two fused rings,
one ring is a 5- or 6-membered monocyclic aromatic ring comprising a 5-membered
heteroaryl ring, a 6-membered heteroaryl ring or a benzo ring, each fused to a second
ring. The second ring is a 5- or 6-membered monocyclic ring which is saturated, partially
unsaturated, or unsaturated, and comprises a 5-membered heterocycle, a 6-membered
heterocycle or a carbocycle (provided the first ring is not benzo when the second ring is a
carbocycle).
The bicyclic heterocyclic group may be attached to its pendant group at any
heteroatom or carbon atom which results in a stable structure. The bicyclic heterocyclic
group described herein may be substituted on carbon or on a nitrogen atom if the
resulting compound is stable. It is preferred that when the total number of S and O atoms
in the heterocycle exceeds 1, then these heteroatoms are not adjacent to one another. It is
preferred that the total number of S and O atoms in the heterocycle is not more than 1.
Examples of a bicyclic heterocyclic group are, but not limited to, quinolinyl,
isoquinolinyl, phthalazinyl, quinazolinyl, indolyl, isoindolyl, indolinyl, 1H-indazolyl,
benzimidazolyl, 1,2,3,4-tetrahydroquinolinyl, 1,2,3,4-tetrahydroisoquinolinyl,5,6,7,8-
tetrahydro-quinolinyl, 2,3-dihydro-benzofuranyl, chromanyl, 1,2,3,4-tetrahydro-
quinoxalinyl, and 1,2,3,4-tetrahydro-quinazolinyl.
As used herein, the term “aromatic heterocyclic group” or “heteroaryl” is
intended to mean stable monocyclic and polycyclic aromatic hydrocarbons that include at
least one heteroatom ring member such as sulfur, oxygen, or nitrogen. Heteroaryl groups
include, without limitation, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, furyl,
quinolyl, isoquinolyl, thienyl, imidazolyl, thiazolyl, indolyl, pyrroyl, oxazolyl,
benzofuryl, benzothienyl, benzthiazolyl, isoxazolyl, pyrazolyl, triazolyl, tetrazolyl,
indazolyl, 1,2,4-thiadiazolyl, isothiazolyl, purinyl, carbazolyl, benzimidazolyl, indolinyl,
benzodioxolanyl, and benzodioxane. Heteroaryl groups are substituted or unsubstituted.
The nitrogen atom is substituted or unsubstituted (i.e., N or NR wherein R is H or another
substituent, if defined). The nitrogen and sulfur heteroatoms may optionally be oxidized
(i.e., N→O and S(O) , wherein p is 0, 1 or 2).
Bridged rings are also included in the definition of heterocycle. A bridged
ring occurs when one or more atoms (i.e., C, O, N, or S) link two non-adjacent carbon or
nitrogen atoms. Examples of bridged rings include, but are not limited to, one carbon
atom, two carbon atoms, one nitrogen atom, two nitrogen atoms, and a carbon-nitrogen
group. It is noted that a bridge always converts a monocyclic ring into a tricyclic ring.
When a ring is bridged, the substituents recited for the ring may also be present on the
bridge.
The term “counterion” is used to represent a negatively charged species such
as chloride, bromide, hydroxide, acetate, and sulfate.
[00104] When a dotted ring is used within a ring structure, this indicates that the ring
structure may be saturated, partially saturated or unsaturated.
As referred to herein, the term “substituted” means that at least one hydrogen
atom is replaced with a non-hydrogen group, provided that normal valencies are
maintained and that the substitution results in a stable compound. When a substituent is
keto (i.e., =O), then 2 hydrogens on the atom are replaced. Keto substituents are not
present on aromatic moieties. When a ring system (e.g., carbocyclic or heterocyclic) is
said to be substituted with a carbonyl group or a double bond, it is intended that the
carbonyl group or double bond be part (i.e., within) of the ring. Ring double bonds, as
used herein, are double bonds that are formed between two adjacent ring atoms (e.g.,
C=C, C=N, or N=N).
In cases wherein there are nitrogen atoms (e.g., amines) on compounds of the
present invention, these may be converted to N-oxides by treatment with an oxidizing
agent (e.g., mCPBA and/or hydrogen peroxides) to afford other compounds of this
invention. Thus, shown and claimed nitrogen atoms are considered to cover both the
shown nitrogen and its N-oxide (N→O) derivative.
When any variable occurs more than one time in any constituent or formula
for a compound, its definition at each occurrence is independent of its definition at every
other occurrence. Thus, for example, if a group is shown to be substituted with 0-3 R
groups, then said group may optionally be substituted with up to three R groups, and at
each occurrence R is selected independently from the definition of R. Also, combinations
of substituents and/or variables are permissible only if such combinations result in stable
compounds.
When a bond to a substituent is shown to cross a bond connecting two atoms
in a ring, then such substituent may be bonded to any atom on the ring. When a
substituent is listed without indicating the atom in which such substituent is bonded to the
rest of the compound of a given formula, then such substituent may be bonded via any
atom in such substituent. Combinations of substituents and/or variables are permissible
only if such combinations result in stable compounds.
The phrase “pharmaceutically acceptable” is employed herein to refer to those
compounds, materials, compositions, and/or dosage forms that are, within the scope of
sound medical judgment, suitable for use in contact with the tissues of human beings and
animals without excessive toxicity, irritation, allergic response, and/or other problem or
complication, commensurate with a reasonable benefit/risk ratio.
As used herein, “pharmaceutically acceptable salts” refer to derivatives of the
disclosed compounds wherein the parent compound is modified by making acid or base
salts thereof. Examples of pharmaceutically acceptable salts include, but are not limited
to, mineral or organic acid salts of basic groups such as amines; and alkali or organic salts
of acidic groups such as carboxylic acids. The pharmaceutically acceptable salts include
the conventional non-toxic salts or the quaternary ammonium salts of the parent
compound formed, for example, from non-toxic inorganic or organic acids. For example,
such conventional non-toxic salts include those derived from inorganic acids such as
hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, and nitric; and the salts
prepared from organic acids such as acetic, propionic, succinic, glycolic, stearic, lactic,
malic, tartaric, citric, ascorbic, pamoic, maleic, hydroxymaleic, phenylacetic, glutamic,
benzoic, salicylic, sulfanilic, 2-acetoxybenzoic, fumaric, toluenesulfonic,
methanesulfonic, ethane disulfonic, oxalic, and isethionic.
[00111] The pharmaceutically acceptable salts of the present invention can be
synthesized from the parent compound that contains a basic or acidic moiety by
conventional chemical methods. Generally, such salts can be prepared by reacting the
free acid or base forms of these compounds with a stoichiometric amount of the
appropriate base or acid in water or in an organic solvent, or in a mixture of the two;
generally, nonaqueous media like ether, ethyl acetate, ethanol, isopropanol, or acetonitrile
are preferred. Lists of suitable salts are found in Remington’s Pharmaceutical Sciences,
18th Edition, Mack Publishing Company, Easton, PA (1990), the disclosure of which is
hereby incorporated by reference.
In addition, compounds of formula I may have prodrug forms. Any
compound that will be converted in vivo to provide the bioactive agent (i.e., a compound
of formula I) is a prodrug within the scope and spirit of the invention. Various forms of
prodrugs are well known in the art. For examples of such prodrug derivatives, see:
a) Design of Prodrugs, Bundgaard, H., ed., Elsevier (1985), and Methods in
Enzymology, 112:309-396, Widder, K. et al., eds., Academic Press (1985);
b) Bundgaard, H., Chapter 5, “Design and Application of Prodrugs,” A
Textbook of Drug Design and Development, pp. 113-191, Krosgaard-Larsen, P. et al.,
eds., Harwood Academic Publishers (1991);
c) Bundgaard, H., Adv. Drug Deliv. Rev., 8:1-38 (1992);
d) Bundgaard, H. et al., J. Pharm. Sci., 77:285 (1988); and
e) Kakeya, N. et al., Chem. Pharm. Bull., 32:692 (1984).
Compounds containing a carboxy group can form physiologically
hydrolyzable esters that serve as prodrugs by being hydrolyzed in the body to yield
formula I compounds per se. Such prodrugs are preferably administered orally since
hydrolysis in many instances occurs principally under the influence of the digestive
enzymes. Parenteral administration may be used where the ester per se is active, or in
those instances where hydrolysis occurs in the blood. Examples of physiologically
hydrolyzable esters of compounds of formula I include C alkyl, C alkylbenzyl, 4-
1-6 1-6
methoxybenzyl, indanyl, phthalyl, methoxymethyl, C alkanoyloxy-C alkyl (e.g.,
acetoxymethyl, pivaloyloxymethyl or propionyloxymethyl), C alkoxycarbonyloxy-C
1-6 1-
alkyl (e.g., methoxycarbonyl-oxymethyl or ethoxycarbonyloxymethyl, glycyloxymethyl,
phenylglycyloxymethyl, (5-methyloxo-1,3-dioxolenyl)-methyl), and other well
known physiologically hydrolyzable esters used, for example, in the penicillin and
cephalosporin arts. Such esters may be prepared by conventional techniques known in
the art.
[00114] Preparation of prodrugs is well known in the art and described in, for example,
Medicinal Chemistry: Principles and Practice, King, F.D., ed. The Royal Society of
Chemistry, Cambridge, UK (1994); Testa, B. et al., Hydrolysis in Drug and Prodrug
Metabolism. Chemistry, Biochemistry and Enzymology, VCHA and Wiley-VCH, Zurich,
Switzerland (2003); The Practice of Medicinal Chemistry, Wermuth, C.G., ed., Academic
Press, San Diego, CA (1999).
The present invention is intended to include all isotopes of atoms occurring in
the present compounds. Isotopes include those atoms having the same atomic number but
different mass numbers. By way of general example and without limitation, isotopes of
13 14
hydrogen include deuterium and tritium. Isotopes of carbon include C and C.
Isotopically-labeled compounds of the invention can generally be prepared by
conventional techniques known to those skilled in the art or by processes analogous to
those described herein, using an appropriate isotopically-labeled reagent in place of the
non-labeled reagent otherwise employed. Such compounds have a variety of potential
uses, e.g., as standards and reagents in determining the ability of a potential
pharmaceutical compound to bind to target proteins or receptors, or for imaging
compounds of this invention bound to biological receptors in vivo or in vitro.
[00116] “Stable compound” and “stable structure” are meant to indicate a compound
that is sufficiently robust to survive isolation to a useful degree of purity from a reaction
mixture, and formulation into an efficacious therapeutic agent. It is preferred that
compounds of the present invention do not contain a N-halo, S(O) H, or S(O)H group.
The term “solvate” means a physical association of a compound of this
invention with one or more solvent molecules, whether organic or inorganic. This
physical association includes hydrogen bonding. In certain instances the solvate will be
capable of isolation, for example when one or more solvent molecules are incorporated in
the crystal lattice of the crystalline solid. The solvent molecules in the solvate may be
present in a regular arrangement and/or a non-ordered arrangement. The solvate may
comprise either a stoichiometric or nonstoichiometric amount of the solvent molecules.
“Solvate” encompasses both solution-phase and isolable solvates. Exemplary solvates
include, but are not limited to, hydrates, ethanolates, methanolates, and isopropanolates.
Methods of solvation are generally known in the art.
Abbreviations as used herein, are defined as follows: “1 x” for once, “2 x” for
twice, “3 x” for thrice, “ °C” for degrees Celsius, “eq” for equivalent or equivalents, “g”
for gram or grams, “mg” for milligram or milligrams, “L” for liter or liters, “mL” for
milliliter or milliliters, “μL” for microliter or microliters, “N” for normal, “M” for molar,
“mmol” for millimole or millimoles, “min” for minute or minutes, “h” for hour or hours,
“rt” for room temperature, “RT” for retention time, “atm” for atmosphere, “psi” for
pounds per square inch, “conc.” for concentrate, “sat” or “sat’d “ for saturated, “MW” for
molecular weight, “mp” for melting point, “ee” for enantiomeric excess, “MS” or “Mass
Spec” for mass spectrometry, “ESI” for electrospray ionization mass spectroscopy, “HR”
for high resolution, “HRMS” for high resolution mass spectrometry, “LCMS” for liquid
chromatography mass spectrometry, “HPLC” for high pressure liquid chromatography,
“RP HPLC” for reverse phase HPLC, “TLC” or “tlc” for thin layer chromatography,
“NMR” for nuclear magnetic resonance spectroscopy, “nOe” for nuclear Overhauser
effect spectroscopy, “ H” for proton, “δ” for delta, “s” for singlet, “d” for doublet, “t” for
triplet, “q” for quartet, “m” for multiplet, “br” for broad, “Hz” for hertz, and “α”, “β”,
“R”, “S”, “E”, and “Z” are stereochemical designations familiar to one skilled in the art.
Me Methyl
Et Ethyl
Pr Propyl
i-Pr Isopropyl
Bu Butyl
i-Bu Isobutyl
t-Bu tert-butyl
Ph Phenyl
Bn Benzyl
Boc or BOC tert-butyloxycarbonyl
AcOH or HOAc acetic acid
AlCl aluminum chloride
AIBN Azobisisobutyronitrile
BBr boron tribromide
BCl boron trichloride
BEMP 2-tert-butyliminodiethylamino-1,3-dimethylperhydro-1,3,2-
diazaphosphorine
BOP reagent benzotriazolyloxytris(dimethylamino)phosphonium
hexafluorophosphate
Burgess reagent 1-methoxy-N-triethylammoniosulfonyl-methanimidate
CBz Carbobenzyloxy
DCM or CH Cl Dichloromethane
CH CN or ACN Acetonitrile
CDCl deutero-chloroform
CHCl Chloroform
mCPBA or m- meta-chloroperbenzoic acid
CPBA
Cs CO cesium carbonate
Cu(OAc) copper (II) acetate
Cy NMe N-cyclohexyl-N-methylcyclohexanamine
DBU 1,8-diazabicyclo[5.4.0]undecene
DCE 1,2 dichloroethane
DEA Diethylamine
Dess-Martin 1,1,1-tris(acetyloxy)-1,1-dihydro-1,2-beniziodoxol(1H)-one
DIC or DIPCDI Diisopropylcarbodiimide
DIEA, DIPEA diisopropylethylamine (Hunig’s base)
DMAP 4-dimethylaminopyridine
DME 1,2-dimethoxyethane
DMF dimethyl formamide
DMSO dimethyl sulfoxide
cDNA complimentary DNA
Dppp (R)-(+)-1,2-bis(diphenylphosphino)propane
DuPhos (+)-1,2-bis((2S,5S)-2,5-diethylphospholano)benzene
EDC N-(3-dimthylaminopropyl)-N΄-ethylcarbodiimide
EDCI N-(3-dimthylaminopropyl)-N΄-ethylcarbodiimide hydrochloride
EDTA ethylenediaminetetraacetic acid
(S,S)- (+)-1,2-bis((2S,5S)-2,5-diethylphospholano)benzene(1,5-
EtDuPhosRh(I) cyclooctadiene)rhodium(I) trifluoromethanesulfonate
Et N or TEA Triethylamine
EtOAc ethyl acetate
Et O diethyl ether
EtOH Ethanol
GMF glass microfiber filter
Grubbs (II) (1,3-bis(2,4,6-trimethylphenyl)
imidazolidinylidene)dichloro(phenylmethylene)
(triycyclohexylphosphine)ruthenium
HCl hydrochloric acid
HATU O-(7-azabenzotriazolyl)-N,N,N′,N′-tetramethyluronium
hexafluorophosphate
HEPES 4-(2-hydroxyethyl)piperaxineethanesulfonic acid
Hex Hexane
HOBt or HOBT 1-hydroxybenzotriazole
H SO sulfuric acid
K CO potassium carbonate
KOAc potassium acetate
K PO potassium phosphate
LAH lithium aluminum hydride
LG leaving group
LiOH lithium hydroxide
MeOH Methanol
MgSO magnesium sulfate
MsOH or MSA methylsulfonic acid
NaCl sodium chloride
NaH sodium hydride
NaHCO sodium bicarbonate
Na CO sodium carbonate
NaOH sodium hydroxide
Na SO sodium sulfite
Na SO sodium sulfate
NBS N-bromosuccinimide
NCS N-chlorosuccinimide
NH Ammonia
NH Cl ammonium chloride
NH OH ammonium hydroxide
OTf triflate or trifluoromethanesulfonate
Pd (dba) tris(dibenzylideneacetone)dipalladium(0)
Pd(OAc) palladium(II) acetate
Pd/C palladium on carbon
Pd(dppf)Cl [1,1΄-bis(diphenylphosphino)-ferrocene]dichloropalladium(II)
Ph PCl triphenylphosphine dichloride
PG protecting group
POCl phosphorus oxychloride
i-PrOH or IPA Isopropanol
PS Polystyrene
SEM-Cl 2-(trimethysilyl)ethoxymethyl chloride
SiO silica oxide
SnCl tin(II) chloride
TBAI tetra-n-butylammonium iodide
TFA trifluoroacetic acid
THF tetrahydrofuran
TMSCHN trimethylsilyldiazomethane
T3P propane phosphonic acid anhydride
TRIS tris (hydroxymethyl) aminomethane
The compounds of the present invention can be prepared in a number of ways
known to one skilled in the art of organic synthesis. The compounds of the present
invention can be synthesized using the methods described below, together with synthetic
methods known in the art of synthetic organic chemistry, or by variations thereof as
appreciated by those skilled in the art. Preferred methods include, but are not limited to,
those described below. The reactions are performed in a solvent or solvent mixture
appropriate to the reagents and materials employed and suitable for the transformations
being effected. It will be understood by those skilled in the art of organic synthesis that
the functionality present on the molecule should be consistent with the transformations
proposed. This will sometimes require a judgment to modify the order of the synthetic
steps or to select one particular process scheme over another in order to obtain a desired
compound of the invention.
[00120] It will also be recognized that another major consideration in the planning of
any synthetic route in this field is the judicious choice of the protecting group used for
protection of the reactive functional groups present in the compounds described in this
invention. An authoritative account describing the many alternatives to the trained
practitioner is Greene et al. (Protective Groups in Organic Synthesis, 3rd Ed., Wiley-
Interscience (1999)).
IV. BIOLOGY
While blood coagulation is essential to the regulation of an organism’s
hemostasis, it is also involved in many pathological conditions. In thrombosis, a blood
clot, or thrombus, may form and obstruct circulation locally, causing ischemia and organ
damage. Alternatively, in a process known as embolism, the clot may dislodge and
subsequently become trapped in a distal vessel, where it again causes ischemia and organ
damage. Diseases arising from pathological thrombus formation are collectively referred
to as thromboembolic disorders which include acute coronary syndrome, unstable angina,
myocardial infarction, thrombosis in the cavity of the heart, ischemic stroke, deep vein
thrombosis, peripheral occlusive arterial disease, transient ischemic attack, and
pulmonary embolism. In addition, thrombosis occurs on artificial surfaces in contact with
blood, including catheters, stents, artificial heart valves, and hemodialysis membranes.
Some conditions contribute to the risk of developing thrombosis, for example,
alterations of the vessel wall, changes in the flow of blood, and alterations in the
composition of the vascular compartment. These risk factors are collectively known as
Virchow’s triad. (Hemostasis and Thrombosis, Basic Principles and Clinical Practice,
5th Ed., p. 853, Colman, R.W. et al., eds., Lippincott Williams & Wilkins (2006))
Antithrombotic agents are frequently given to patients at risk of developing
thromboembolic disease because of the presence of one or more predisposing risk factors
from Virchow’s triad to prevent formation of an occlusive thrombus (primary
prevention). For example, in an orthopedic surgery setting (e.g., hip and knee
replacement), an antithrombotic agent is frequently administered prior to a surgical
procedure. The antithrombotic agent counterbalances the prothrombotic stimulus exerted
by vascular flow alterations (stasis), potential surgical vessel wall injury, as well as
changes in the composition of the blood due to the acute phase response related to
surgery. Another example of the use of an antithrombotic agent for primary prevention is
dosing with aspirin, a platelet activation inhibitor, in patients at risk for developing
thrombotic cardiovascular disease. Well recognized risk factors in this setting include
age, male gender, hypertension, diabetes mellitus, lipid alterations, and obesity.
Antithrombotic agents are also indicated for secondary prevention, following
an initial thrombotic episode. For example, patients with mutations in factor V (also
known as factor V Leiden) and additional risk factors (e.g., pregnancy) are dosed with
anticoagulants to prevent the reoccurrence of venous thrombosis. Another example
entails secondary prevention of cardiovascular events in patients with a history of acute
myocardial infarction or acute coronary syndrome. In a clinical setting, a combination of
aspirin and clopidogrel (or other thienopyridines) may be used to prevent a second
thrombotic event.
Antithrombotic agents are also given to treat the disease state (i.e., by
arresting its development) after it has already started. For example, patients presenting
with deep vein thrombosis are treated with anticoagulants (i.e., heparin, warfarin, or
LMWH) to prevent further growth of the venous occlusion. Over time, these agents also
cause a regression of the disease state because the balance between prothrombotic factors
and anticoagulant/profibrinolytic pathways is changed in favor of the latter. Examples on
the arterial vascular bed include the treatment of patients with acute myocardial infarction
or acute coronary syndrome with aspirin and clopidogrel to prevent further growth of
vascular occlusions and eventually leading to a regression of thrombotic occlusions.
Thus, antithrombotic agents are used widely for primary and secondary
prevention (i.e., prophylaxis or risk reduction) of thromboembolic disorders, as well as
treatment of an already existing thrombotic process. Drugs that inhibit blood coagulation,
or anticoagulants, are “pivotal agents for prevention and treatment of thromboembolic
disorders” (Hirsh, J. et al., Blood, 105:453-463 (2005)).
An alternative way of initiation of coagulation is operative when blood is
exposed to artificial surfaces (e.g., during hemodialysis, “on-pump” cardiovascular
surgery, vessel grafts, bacterial sepsis), on cell surfaces, cellular receptors, cell debris,
DNA, RNA, and extracellular matrices. This process is also termed contact activation.
Surface absorption of factor XII leads to a conformational change in the factor XII
molecule, thereby facilitating activation to proteolytic active factor XII molecules (factor
XIIa and factor XIIf). Factor XIIa (or XIIf) has a number of target proteins, including
plasma prekallikrein and factor XI. Active plasma kallikrein further activates factor XII,
leading to an amplification of contact activation. Alternatively, the serine protease
prolylcarboxylpeptidase can activate plasma kallikrein complexed with high molecular
weight kininogen in a multiprotein complex formed on the surface of cells and matrices
(Shariat-Madar et al., Blood, 108:192-199 (2006)). Contact activation is a surface
mediated process responsible in part for the regulation of thrombosis and inflammation,
and is mediated, at least in part, by fibrinolytic, complement, kininogen/kinin, and other
humoral and cellular pathways (for review, Coleman, R., “Contact Activation Pathway”,
Hemostasis and Thrombosis, pp. 103-122, Lippincott Williams & Wilkins (2001);
Schmaier, A.H., “Contact Activation”, Thrombosis and Hemorrhage, pp. 105-128
(1998)). The biological relevance of the contact activation system for thromboembolic
diseases is supported by the phenotype of factor XII deficient mice. More specifically,
factor XII deficient mice were protected from thrombotic vascular occlusion in several
thrombosis models as well as stroke models and the phenotype of the XII deficient mice
was identical to XI deficient mice (Renne et al., J. Exp. Med., 202:271-281 (2005);
Kleinschmitz et al., J. Exp. Med., 203:513-518 (2006)). The fact that factor XI is down-
stream from factor XIIa, combined with the identical phenotype of the XII and XI
deficient mice suggest that the contact activation system could play a major role in factor
XI activation in vivo.
[00128] Factor XI is a zymogen of a trypsin-like serine protease and is present in
plasma at a relatively low concentration. Proteolytic activation at an internal R369-I370
bond yields a heavy chain (369 amino acids) and a light chain (238 amino acids). The
latter contains a typical trypsin-like catalytic triad (H413, D464, and S557). Activation of
factor XI by thrombin is believed to occur on negatively charged surfaces, most likely on
the surface of activated platelets. Platelets contain high affinity (0.8 nM) specific sites
(130-500/platelet) for activated factor XI. After activation, factor XIa remains surface
bound and recognizes factor IX as its normal macromolecular substrate. (Galiani, D.,
Trends Cardiovasc. Med., 10:198-204 (2000))
In addition to the feedback activation mechanisms described above, thrombin
activates thrombin activated fibrinolysis inhibitor (TAFI), a plasma carboxypeptidase that
cleaves C-terminal lysine and arginine residues on fibrin, reducing the ability of fibrin to
enhance tissue-type plasminogen activator (tPA) dependent plasminogen activation. In
the presence of antibodies to FXIa, clot lysis can occur more rapidly independent of
plasma TAFI concentration. (Bouma, B.N. et al., Thromb. Res., 101:329-354 (2001)).
Thus, inhibitors of factor XIa are expected to be anticoagulant and profibrinolytic.
[00130] Further evidence for the anti-thromboembolic effects of targeting factor XI is
derived from mice deficient in factor XI. It has been demonstrated that complete fXI
deficiency protected mice from ferric chloride (FeCl )-induced carotid artery thrombosis
(Rosen et al., Thromb. Haemost., 87:774-777 (2002); Wang et al., J. Thromb. Haemost.,
3:695-702 (2005)). Also, factor XI deficiency rescues the perinatal lethal phenotype of
complete protein C deficiency (Chan et al., Amer. J. Pathology, 158:469-479 (2001)).
Furthermore, baboon cross-reactive, function blocking antibodies to human factor XI
protect against baboon arterial – venous shunt thrombosis (Gruber et al., Blood, 102:953-
955 (2003)). Evidence for an antithrombotic effect of small molecule inhibitors of factor
XIa is also disclosed in published U.S. Patent Application No. 2004/0180855A1. Taken
together, these studies suggest that targeting factor XI will reduce the propensity for
thrombotic and thromboembolic diseases.
Genetic evidence indicates that factor XI is not required for normal
homeostasis, implying a superior safety profile of the factor XI mechanism compared to
competing antithrombotic mechanisms. In contrast to hemophilia A (factor VIII
deficiency) or hemophilia B (factor IX deficiency), mutations of the factor XI gene
causing factor XI deficiency (hemophilia C) result in only a mild to moderate bleeding
diathesis characterized primarily by postoperative or posttraumatic, but rarely
spontaneous hemorrhage. Postoperative bleeding occurs mostly in tissue with high
concentrations of endogenous fibrinolytic activity (e.g., oral cavity, and urogenital
system). The majority of the cases are fortuitously identified by preoperative
prolongation of aPTT (intrinsic system) without any prior bleeding history.
The increased safety of inhibition of XIa as an anticoagulation therapy is
further supported by the fact that Factor XI knock-out mice, which have no detectable
factor XI protein, undergo normal development, and have a normal life span. No
evidence for spontaneous bleeding has been noted. The aPTT (intrinsic system) is
prolonged in a gene dose-dependent fashion. Interestingly, even after severe stimulation
of the coagulation system (tail transection), the bleeding time is not significantly
prolonged compared to wild-type and heterozygous litter mates. (Gailani, D., Frontiers in
Bioscience, 6:201-207 (2001); Gailani, D. et al., Blood Coagulation and Fibrinolysis,
8:134-144 (1997).) Taken together, these observations suggest that high levels of
inhibition of factor XIa should be well tolerated. This is in contrast to gene targeting
experiments with other coagulation factors, excluding factor XII.
In vivo activation of factor XI can be determined by complex formation with
either C1 inhibitor or alpha 1 antitrypsin. In a study of 50 patients with acute myocardial
infarction (AMI), approximately 25% of the patients had values above the upper normal
range of the complex ELISA. This study can be viewed as evidence that at least in a
subpopulation of patients with AMI, factor XI activation contributes to thrombin
formation (Minnema, M.C. et al., Arterioscler. Thromb. Vasc. Biol., 20:2489-2493
(2000)). A second study establishes a positive correlation between the extent of coronary
arteriosclerosis and factor XIa in complex with alpha 1 antitrypsin (Murakami, T. et al.,
Arterioscler. Thromb. Vasc. Biol., 15:1107-1113 (1995)). In another study, Factor XI
levels above the 90th percentile in patients were associated with a 2.2-fold increased risk
for venous thrombosis (Meijers, J.C.M. et al., N. Engl. J. Med., 342:696-701 (2000)).
Plasma kallikrein is a zymogen of a trypsin-like serine protease and is present
in plasma at 35 to 50 μg/mL. The gene structure is similar to that of factor XI. Overall,
the amino acid sequence of plasma kallikrein has 58% homology to factor XI.
Proteolytic activation by factor XIIa at an internal I389- R390 bond yields a heavy chain
(371 amino acids) and a light chain (248 amino acids). The active site of plasma
kallikrein is contained in the light chain. The light chain of plasma kallikrein reacts with
protease inhibitors, including alpha 2 macroglobulin and C1- inhibitor. Interestingly,
heparin significantly accelerates the inhibition of plasma kallikrein by antithrombin III in
the presence of high molecular weight kininogen (HMWK). In blood, the majority of
plasma kallikrein circulates in complex with HMWK. Plasma kallikrein cleaves HMWK
to liberate bradykinin. Bradykinin release results in increase of vascular permeability and
vasodilation (for review, Coleman, R., “Contact Activation Pathway”, Hemostasis and
Thrombosis, pp. 103-122, Lippincott Williams & Wilkins (2001); Schmaier A.H.,
“Contact Activation”, Thrombosis and Hemorrhage, pp. 105-128 (1998)).
[00135] Also, it is preferred to find new compounds with improved activity in in vitro
clotting assays, compared with known serine protease inhibitors, such as the activated
partial thromboplastin time (aPTT) or prothrombin time (PT) assay. (for a description of
the aPTT and PT assays see, Goodnight, S.H. et al., “Screening Tests of Hemostasis”,
Disorders of Thrombosis and Hemostasis: A Clinical Guide, 2nd Ed., pp. 41-51,
McGraw-Hill, New York (2001)).
It is also desirable and preferable to find compounds with advantageous and
improved characteristics compared with known serine protease inhibitors, in one or more
of the following categories that are given as examples, and are not intended to be
limiting: (a) pharmacokinetic properties, including oral bioavailability, half life, and
clearance; (b) pharmaceutical properties; (c) dosage requirements; (d) factors that
decrease blood concentration peak-to-trough characteristics; (e) factors that increase the
concentration of active drug at the enzyme; (f) factors that decrease the liability for
clinical drug-drug interactions; (g) factors that decrease the potential for adverse side-
effects, including selectivity versus other biological targets; and (h) factors that improve
manufacturing costs or feasibility, (i) factors that are ideal for use as a parenteral agent
such as solubility profile and pharmocokinetics.
Pre-clinical studies demonstrated significant antithrombotic effects of small
molecule factor XIa inhibitors in rabbit and rat model of arterial thrombosis, at doses that
preserved hemostasis. (Wong P.C. et al., American Heart Association Scientific Sessions,
Abstract No. 6118, November 12-15, 2006; Schumacher, W. et al., Journal of
Thrombosis and Haemostasis, Vol. 3 (Suppl. 1):P1228 (2005); Schumacher, W.A. et al.,
European Journal of Pharmacology, pp. 167-174 (2007)). Furthermore, it was observed
that in vitro prolongation of the aPTT by specific XIa inhibitors is a good predictor of
efficacy in our thrombosis models. Thus, the in vitro aPTT test can be used as a
surrogate for efficacy in vivo.
As used herein, the term “patient” encompasses all mammalian species.
As used herein, “treating” or “treatment” cover the treatment of a disease-state
in a mammal, particularly in a human, and include: (a) inhibiting the disease-state, i.e.,
arresting it development; and/or (b) relieving the disease-state, i.e., causing regression of
the disease state.
[00140] As used herein, “prophylaxis” or “prevention” covers the preventive treatment
of a subclinical disease-state in a mammal, particularly in a human, aimed at reducing the
probability of the occurrence of a clinical disease-state. Patients are selected for
preventative therapy based on factors that are known to increase risk of suffering a
clinical disease state compared to the general population. “Prophylaxis” therapies can be
divided into (a) primary prevention and (b) secondary prevention. Primary prevention is
defined as treatment in a subject that has not yet presented with a clinical disease state,
whereas secondary prevention is defined as preventing a second occurrence of the same
or similar clinical disease state.
As used herein, “risk reduction” covers therapies that lower the incidence of
development of a clinical disease state. As such, primary and secondary prevention
therapies are examples of risk reduction.
“Therapeutically effective amount” is intended to include an amount of a
compound of the present invention that is effective when administered alone or in
combination to inhibit factor XIa and/or plasma kallikrein and/or to prevent or treat the
disorders listed herein. When applied to a combination, the term refers to combined
amounts of the active ingredients that result in the preventive or therapeutic effect,
whether administered in combination, serially, or simultaneously.
The term “thrombosis”, as used herein, refers to formation or presence of a
thrombus (pl. thrombi); clotting within a blood vessel that may cause ischemia or
infarction of tissues supplied by the vessel. The term “embolism”, as used herein, refers
to sudden blocking of an artery by a clot or foreign material that has been brought to its
site of lodgment by the blood current. The term “thromboembolism”, as used herein,
refers to obstruction of a blood vessel with thrombotic material carried by the blood
stream from the site of origin to plug another vessel. The term “thromboembolic
disorders” entails both “thrombotic” and “embolic” disorders (defined above).
The term “thromboembolic disorders” as used herein includes arterial
cardiovascular thromboembolic disorders, venous cardiovascular or cerebrovascular
thromboembolic disorders, and thromboembolic disorders in the chambers of the heart or
in the peripheral circulation. The term “thromboembolic disorders” as used herein also
includes specific disorders selected from, but not limited to, unstable angina or other
acute coronary syndromes, atrial fibrillation, first or recurrent myocardial infarction,
ischemic sudden death, transient ischemic attack, stroke, atherosclerosis, peripheral
occlusive arterial disease, venous thrombosis, deep vein thrombosis, thrombophlebitis,
arterial embolism, coronary arterial thrombosis, cerebral arterial thrombosis, cerebral
embolism, kidney embolism, pulmonary embolism, and thrombosis resulting from
medical implants, devices, or procedures in which blood is exposed to an artificial surface
that promotes thrombosis. The medical implants or devices include, but are not limited
to: prosthetic valves, artificial valves, indwelling catheters, stents, blood oxygenators,
shunts, vascular access ports, ventricular assist devices and artificial hearts or heart
chambers, and vessel grafts. The procedures include, but are not limited to:
cardiopulmonary bypass, percutaneous coronary intervention, and hemodialysis. In
another embodiment, the term “thromboembolic disorders” includes acute coronary
syndrome, stroke, deep vein thrombosis, and pulmonary embolism.
Also described herein is a method for the treatment of a thromboembolic
disorder, wherein the thromboembolic disorder is selected from unstable angina, an acute
coronary syndrome, atrial fibrillation, myocardial infarction, transient ischemic attack,
stroke, atherosclerosis, peripheral occlusive arterial disease, venous thrombosis, deep
vein thrombosis, thrombophlebitis, arterial embolism, coronary arterial thrombosis,
cerebral arterial thrombosis, cerebral embolism, kidney embolism, pulmonary embolism,
and thrombosis resulting from medical implants, devices, or procedures in which blood is
exposed to an artificial surface that promotes thrombosis. Also described herein is a
method for the treatment of a thromboembolic disorder, wherein the thromboembolic
disorder is selected from acute coronary syndrome, stroke, venous thrombosis, atrial
fibrillation, and thrombosis resulting from medical implants and devices.
Also described herein is a method for the primary prophylaxis of a
thromboembolic disorder, wherein the thromboembolic disorder is selected from unstable
angina, an acute coronary syndrome, atrial fibrillation, myocardial infarction, ischemic
sudden death, transient ischemic attack, stroke, atherosclerosis, peripheral occlusive
arterial disease, venous thrombosis, deep vein thrombosis, thrombophlebitis, arterial
embolism, coronary arterial thrombosis, cerebral arterial thrombosis, cerebral embolism,
kidney embolism, pulmonary embolism, and thrombosis resulting from medical implants,
devices, or procedures in which blood is exposed to an artificial surface that promotes
thrombosis. Also described herein is a method for the primary prophylaxis of a
thromboembolic disorder, wherein the thromboembolic disorder is selected from acute
coronary syndrome, stroke, venous thrombosis, and thrombosis resulting from medical
implants and devices.
Also described herein is a method for the secondary prophylaxis of a
thromboembolic disorder, wherein the thromboembolic disorder is selected from unstable
angina, an acute coronary syndrome, atrial fibrillation, recurrent myocardial infarction,
transient ischemic attack, stroke, atherosclerosis, peripheral occlusive arterial disease,
venous thrombosis, deep vein thrombosis, thrombophlebitis, arterial embolism, coronary
arterial thrombosis, cerebral arterial thrombosis, cerebral embolism, kidney embolism,
pulmonary embolism, and thrombosis resulting from medical implants, devices, or
procedures in which blood is exposed to an artificial surface that promotes thrombosis.
Also described herein is a method for the secondary prophylaxis of a thromboembolic
disorder, wherein the thromboembolic disorder is selected from acute coronary syndrome,
stroke, atrial fibrillation and venous thrombosis.
The term “stroke”, as used herein, refers to embolic stroke or
atherothrombotic stroke arising from occlusive thrombosis in the carotid communis,
carotid interna, or intracerebral arteries.
It is noted that thrombosis includes vessel occlusion (e.g., after a bypass) and
reocclusion (e.g., during or after percutaneous transluminal coronary angioplasty). The
thromboembolic disorders may result from conditions including but not limited to
atherosclerosis, surgery or surgical complications, prolonged immobilization, arterial
fibrillation, congenital thrombophilia, cancer, diabetes, effects of medications or
hormones, and complications of pregnancy.
Thromboembolic disorders are frequently associated with patients with
atherosclerosis. Risk factors for atherosclerosis include but are not limited to male
gender, age, hypertension, lipid disorders, and diabetes mellitus. Risk factors for
atherosclerosis are at the same time risk factors for complications of atherosclerosis, i.e.,
thromboembolic disorders.
Similarly, arterial fibrillation is frequently associated with thromboembolic
disorders. Risk factors for arterial fibrillation and subsequent thromboembolic disorders
include cardiovascular disease, rheumatic heart disease, nonrheumatic mitral valve
disease, hypertensive cardiovascular disease, chronic lung disease, and a variety of
miscellaneous cardiac abnormalities as well as thyrotoxicosis.
Diabetes mellitus is frequently associated with atherosclerosis and
thromboembolic disorders. Risk factors for the more common type 2 include but are not
limited to are family history, obesity, physical inactivity, race / ethnicity, previously
impaired fasting glucose or glucose tolerance test, history of gestational diabetes mellitus
or delivery of a “big baby”, hypertension, low HDL cholesterol, and polycystic ovary
syndrome.
Risk factors for congenital thrombophilia include gain of function mutations
in coagulation factors or loss of function mutations in the anticoagulant- or fibrinolytic
pathways.
[00154] Thrombosis has been associated with a variety of tumor types, e.g., pancreatic
cancer, breast cancer, brain tumors, lung cancer, ovarian cancer, prostate cancer,
gastrointestinal malignancies, and Hodgkins or non-Hodgkins lymphoma. Recent studies
suggest that the frequency of cancer in patients with thrombosis reflects the frequency of
a particular cancer type in the general population (Levitan, N. et al., Medicine
(Baltimore), 78(5):285-291 (1999); Levine M. et al., N. Engl. J. Med., 334(11):677-681
(1996); Blom, J.W. et al., JAMA, 293(6):715-722 (2005)). Hence, the most common
cancers associated with thrombosis in men are prostate, colorectal, brain, and lung cancer,
and in women are breast, ovary, and lung cancer. The observed rate of venous
thromboembolism (VTE) in cancer patients is significant. The varying rates of VTE
between different tumor types are most likely related to the selection of the patient
population. Cancer patients at risk for thrombosis may possess any or all of the following
risk factors: (i) the stage of the cancer (i.e., presence of metastases), (ii) the presence of
central vein catheters, (iii) surgery and anticancer therapies including chemotherapy, and
(iv) hormones and antiangiogenic drugs. Thus, it is common clinical practice to dose
patients having advanced tumors with heparin or low molecular heparin to prevent
thromboembolic disorders. A number of low molecular heparin preparations have been
approved by the FDA for these indications.
There are three main clinical situations when considering the prevention of
VTE in a medical cancer patient: (i) the patient is bedridden for prolonged periods of
time; (ii) the ambulatory patient is receiving chemotherapy or radiation; and (iii) the
patient is with indwelling central vein catheters. Unfractionated heparin (UFH) and low
molecular weight heparin (LMWH) are effective antithrombotic agents in cancer patients
undergoing surgery. (Mismetti, P. et al., British Journal of Surgery, 88:913-930 (2001).)
A. In Vitro Assays
The effectiveness of compounds of the present invention as inhibitors of the
coagulation factors XIa, VIIa, IXa, Xa, XIIa, plasma kallikrein or thrombin, can be
determined using a relevant purified serine protease, respectively, and an appropriate
synthetic substrate. The rate of hydrolysis of the chromogenic or fluorogenic substrate by
the relevant serine protease was measured both in the absence and presence of
compounds of the present invention. Hydrolysis of the substrate resulted in the release of
pNA (para nitroaniline), which was monitored spectrophotometrically by measuring the
increase in absorbance at 405 nm, or the release of AMC (amino methylcoumarin), which
was monitored spectrofluorometrically by measuring the increase in emission at 460 nm
with excitation at 380 nm. A decrease in the rate of absorbance or fluorescence change in
the presence of inhibitor is indicative of enzyme inhibition. Such methods are known to
one skilled in the art. The results of this assay are expressed as the inhibitory constant, K .
Factor XIa determinations were made in 50 mM HEPES buffer at pH 7.4
containing 145 mM NaCl, 5 mM KCl, and 0.1% PEG 8000 (polyethylene glycol; JT
Baker or Fisher Scientific). Determinations were made using purified human Factor XIa
at a final concentration of 75-200 pM (Haematologic Technologies) and the synthetic
substrate S-2366 (pyroGlu-Pro-Arg-pNA; CHROMOGENIX or AnaSpec) at a
concentration of 0.0002-0.001 M.
Factor VIIa determinations were made in 0.005 M calcium chloride, 0.15 M
sodium chloride, 0.05 M HEPES buffer containing 0.1 % PEG 8000 at a pH of 7.5.
Determinations were made using purified human Factor VIIa (Haematologic
Technologies) or recombinant human Factor VIIa (Novo Nordisk) at a final assay
concentration of 1-5 nM, recombinant soluble tissue factor at a concentration of 10-40
nM and the synthetic substrate H-D-Ile-Pro-Arg-pNA (S-2288; CHROMOGENIX or
BMPM-2; AnaSpec) at a concentration of 0.001-0.0075 M.
Factor IXa determinations were made in 0.005 M calcium chloride, 0.1 M
sodium chloride, 0.0001 M Refludan (Berlex), 0.05 M TRIS base and 0.5% PEG 8000 at
a pH of 7.4. Refludan was added to inhibit small amounts of thrombin in the commercial
preparations of human Factor IXa. Determinations were made using purified human
Factor IXa (Haematologic Technologies) at a final assay concentration of 20-100 nM and
the synthetic substrate PCIXA2100-B (CenterChem) or Pefafluor IXa 3688 (H-D-Leu-
Ph′Gly-Arg-AMC; CenterChem) at a concentration of 0.0004-0.0005 M.
[00160] Factor Xa determinations were made in 0.1 M sodium phosphate buffer at a
pH of 7.5 containing 0.2 M sodium chloride and 0.5% PEG 8000. Determinations were
made using purified human Factor Xa (Haematologic Technologies) at a final assay
concentration of 150-1000 pM and the synthetic substrate S-2222 (Bz-Ile-Glu (gamma-
OMe, 50%)-Gly-Arg-pNA; CHROMOGENIX ) at a concentration of 0.0002-0.00035
M.
Factor XIIa determinations were made in 50 mM HEPES buffer at pH 7.4
containing 145 mM NaCl, 5 mM KCl, and 0.1% PEG 8000. Determinations were made
using purified human Factor XIIa at a final concentration of 4 nM (American
Diagnostica) and the synthetic substrate SPECTROZYME #312 (pyroGlu-Pro-Arg-
pNA; American Diagnostica) at a concentration of 0.00015 M.
Plasma kallikrein determinations were made in 0.1 M sodium phosphate
buffer at a pH of 7.5 containing 0.1-0.2 M sodium chloride and 0.5% PEG 8000.
Determinations were made using purified human kallikrein (Enzyme Research
Laboratories) at a final assay concentration of 200 pM and the synthetic substrate S-2302
(H-(D)-Pro-Phe-Arg-pNA; CHROMOGENIX ) at a concentration of 0.00008-0.0004 M.
The K value used for calculation of K was 0.00005 to 0.00007 M.
Thrombin determinations were made in 0.1 M sodium phosphate buffer at a
pH of 7.5 containing 0.2 M sodium chloride and 0.5% PEG 8000. Determinations were
made using purified human alpha thrombin (Haematologic Technologies or Enzyme
Research Laboratories) at a final assay concentration of 200-250 pM and the synthetic
substrate S-2366 (pyroGlu-Pro-Arg-pNA; CHROMOGENIX ) at a concentration of
0.0002-0.00026 M.
The Michaelis constant, K , for substrate hydrolysis by each protease, was
determined at 25 °C using the method of Lineweaver and Burk. Values of K were
determined by allowing the protease to react with the substrate in the presence of the
inhibitor. Reactions were allowed to go for periods of 20-180 minutes (depending on the
protease) and the velocities (rate of absorbance or fluorescence change versus time) were
measured. The following relationships were used to calculate K values:
(v -v )/v = I/(K (1 + S/K )) for a competitive inhibitor with one binding site; or
o s s i m
v /v A + ((B-A)/1 + ((IC /(I) ))); and
s o 50
K = IC /(1 + S/K ) for a competitive inhibitor
i 50
where:
v is the velocity of the control in the absence of inhibitor;
v is the velocity in the presence of inhibitor;
I is the concentration of inhibitor;
A is the minimum activity remaining (usually locked at zero);
B is the maximum activity remaining (usually locked at 1.0);
n is the Hill coefficient, a measure of the number and cooperativity of potential
inhibitor binding sites;
IC is the concentration of inhibitor that produces 50% inhibition under the assay
conditions;
K is the dissociation constant of the enzyme:inhibitor complex;
S is the concentration of substrate; and
K is the Michaelis constant for the substrate.
The selectivity of a compound may be evaluated by taking the ratio of the K
value for a given protease with the K value for the protease of interest (i.e., selectivity for
FXIa versus protease P = K for protease P/ K for FXIa). Compounds with selectivity
ratios >20 are considered selective. Compounds with selectivity ratios >100 are
preferred, and compounds with selectivity ratios > 500 are more preferred.
The effectiveness of compounds of the present invention as inhibitors of
coagulation can be determined using a standard or modified clotting assay. An increase
in the plasma clotting time in the presence of inhibitor is indicative of anticoagulation.
Relative clotting time is the clotting time in the presence of an inhibitor divided by the
clotting time in the absence of an inhibitor. The results of this assay may be expressed as
IC1.5x or IC2x, the inhibitor concentration required to increase the clotting time by 50 or
100 percent, respectively. The IC1.5x or IC2x is found by linear interpolation from
relative clotting time versus inhibitor concentration plots using inhibitor concentration
that spans the IC1.5x or IC2x.
Clotting times are determined using citrated normal human plasma as well as
plasma obtained from a number of laboratory animal species (e.g., rat, or rabbit). A
compound is diluted into plasma beginning with a 10 mM DMSO stock solution. The
final concentration of DMSO is less than 2%. Plasma clotting assays are performed in an
automated coagulation analyzer (Sysmex, Dade-Behring, Illinois). Similarly, clotting
times can be determined from laboratory animal species or humans dosed with
compounds of the invention.
Activated Partial Thromboplastin Time (aPTT) is determined using
ALEXIN (Trinity Biotech, Ireland) or ACTIN (Dade-Behring, Illinois) following the
directions in the package insert. Plasma (0.05 mL) is warmed to 37°C for 1 minute.
ALEXIN or ACTIN (0.05 mL) is added to the plasma and incubated for an additional
2 to 5 minutes. Calcium chloride (25 mM, 0.05 mL) is added to the reaction to initiate
coagulation. The clotting time is the time in seconds from the moment calcium chloride
is added until a clot is detected.
Prothrombin Time (PT) is determined using thromboplastin (Thromboplastin
C Plus, Dade-Behring, Illinois) following the directions in the package insert. Plasma
(0.05 mL) is warmed to 37°C for 1 minute. Thromboplastin (0.1 mL) is added to the
plasma to initiate coagulation. The clotting time is the time in seconds from the moment
thromboplastin is added until a clot is detected.
The Examples disclosed below were tested in the Factor XIa assay described
above and found having Factor XIa inhibitory activity. A range of Factor XIa inhibitory
activity (Ki values) of ≤ 10 μM (10000 nM) was observed. The results are shown in
Tables 1 and A. The activity ranges in Table A are: A is 500 – 5000 nanocromolar (nM);
B is 100 - 500 nM; C is 5-10 nM; D is < 5 nM. Note that by using the Example Number
in the tables the structures of the compounds can be found herein.
Table 1
Example No. Factor XIa Ki (nM)
1 <5.00
4 10.26
7 49.73
13 <5.00
2440.00
16 2294.00
22 <5.00
28 1217.00
37 86.45
41 5641.00
43 20.60
52 <5.00
63 34.46
71 491.50
81 <5.00
90 314.00
94 <5.00
98 632.4
106 <5.00
119 <5.00
125 1006.00
128 132.70
131 <5.00
155 <5.00
169 516.80
175 <5.00
184 <5.00
189 1690.00
191 1051.00
Example No. Factor XIa Ki (nM)
193 107.30
196 843.70
198 5736.00
215 <5.00
216 955.00
228 <5.00
235 74.48
237 4617.00
240 47.10
250 <5.00
257 2570.00
266 <5.00
Table A
Example No. Factor XIa Ki (nM)
C
11 D
12 C
14 D
17 C
18 D
19 C
C
Example No. Factor XIa Ki (nM)
21 D
23 C
24 C
C
26 C
27 D
29 C
B
31 D
32 B
33 C
34 D
D
36 B
38 C
39 C
40 D
42 C
44 C
45 C
46 D
47 D
48 B
49 D
50 B
51 C
53 D
54 D
55 B
56 C
Example No. Factor XIa Ki (nM)
57 C
58 B
59 C
60 D
61 C
62 D
64 D
65 C
66 C
67 B
68 B
69 B
70 B
72 A
73 A
74 B
75 B
76 A
77 B
78 D
79 D
80 D
82 D
83 D
84 D
85 D
86 D
87 D
88 C
89 D
Example No. Factor XIa Ki (nM)
91 C
92 D
93 C
95 D
96 D
97 D
99 D
100 D
101 D
102 C
103 D
104 D
105 D
107 C
108 D
109 C
110 C
111 A
112 D
113 B
114 D
115 D
116 D
117 D
118 C
120 D
121 D
122 D
123 D
124 D
Example No. Factor XIa Ki (nM)
126 D
127 D
129 D
130 D
132 B
133 D
134 D
135 D
136 D
137 D
138 D
139 D
140 D
141 D
142 D
143 D
144 D
145 D
146 D
147 D
148 D
149 D
150 D
151 D
152 D
153 C
154 D
156 C
157 C
158 D
Example No. Factor XIa Ki (nM)
159 D
160 C
161 D
162 D
163 C
164 D
165 C
166 C
167 C
168 D
170 D
171 C
172 D
173 C
174 D
176 D
177 C
178 D
179 B
180 D
181 C
182 C
183 B
185 C
186 A
187 B
188 D
190 C
192 C
194 D
Example No. Factor XIa Ki (nM)
195 D
197 C
199 D
200 B
201 D
202 B
203 C
204 D
205 C
206 D
207 C
208 D
209 D
210 D
211 D
212 D
213 D
214 D
217 D
218 D
219 D
220 D
221 C
222 D
223 D
224 C
225 D
226 C
227 D
229 B
Example No. Factor XIa Ki (nM)
230 B
231 B
232 C
233 C
234 C
236 C
238 C
239 D
241 D
242 B
243 D
244 D
245 D
246 D
247 D
248 D
249 D
251 D
252 D
253 C
254 D
255 D
256 D
258 D
259 D
260 D
261 D
262 D
263 D
264 D
Example No. Factor XIa Ki (nM)
265 D
267 D
268 D
269 D
270 D
B. In Vivo Assays
The effectiveness of compounds of the present invention as antithrombotic
agents can be determined using relevant in vivo thrombosis models, including In Vivo
Electrically-induced Carotid Artery Thrombosis Models and In Vivo Rabbit Arterio-
venous Shunt Thrombosis Models.
a. In Vivo Electrically-induced Carotid Artery Thrombosis (ECAT) Model
[00172] The rabbit ECAT model, described by Wong et al. (J. Pharmacol. Exp. Ther.,
295:212-218 (2000)), can be used in this study. Male New Zealand White rabbits are
anesthetized with ketamine (50 mg/kg + 50 mg/kg/h IM) and xylazine (10 mg/kg + 10
mg/kg/h IM). These anesthetics are supplemented as needed. An electromagnetic flow
probe is placed on a segment of an isolated carotid artery to monitor blood flow. Test
agents or vehicle will be given (i.v., i.p., s.c., or orally) prior to or after the initiation of
thrombosis. Drug treatment prior to initiation of thrombosis is used to model the ability
of test agents to prevent and reduce the risk of thrombus formation, whereas dosing after
initiation is used to model the ability to treat existing thrombotic disease. Thrombus
formation is induced by electrical stimulation of the carotid artery for 3 min at 4 mA
using an external stainless-steel bipolar electrode. Carotid blood flow is measured
continuously over a 90-min period to monitor thrombus-induced occlusion. Total carotid
blood flow over 90 min is calculated by the trapezoidal rule. Average carotid flow over
90 min is then determined by converting total carotid blood flow over 90 min to percent
of total control carotid blood flow, which would result if control blood flow had been
maintained continuously for 90 min. The ED (dose that increased average carotid
blood flow over 90 min to 50% of the control) of compounds are estimated by a nonlinear
least square regression program using the Hill sigmoid E equation (DeltaGraph; SPSS
Inc., Chicago, IL).
b. In Vivo Rabbit Arterio-venous (AV) Shunt Thrombosis Model
[00173] The rabbit AV shunt model, described by Wong et al. (Wong, P.C. et al., J.
Pharmacol. Exp. Ther. 292:351-357 (2000)), can be used in this study. Male New
Zealand White rabbits are anesthetized with ketamine (50 mg/kg + 50 mg/kg/h IM) and
xylazine (10 mg/kg + 10 mg/kg/h IM). These anesthetics are supplemented as needed.
The femoral artery, jugular vein and femoral vein are isolated and catheterized. A saline-
filled AV shunt device is connected between the femoral arterial and the femoral venous
cannulae. The AV shunt device consists of an outer piece of tygon tubing (length = 8 cm;
internal diameter = 7.9 mm) and an inner piece of tubing (length = 2.5 cm; internal
diameter = 4.8 mm). The AV shunt also contains an 8-cm-long 2-0 silk thread (Ethicon,
Somerville, NJ). Blood flows from the femoral artery via the AV-shunt into the femoral
vein. The exposure of flowing blood to a silk thread induces the formation of a
significant thrombus. Forty minutes later, the shunt is disconnected and the silk thread
covered with thrombus is weighed. Test agents or vehicle will be given (i.v., i.p., s.c., or
orally) prior to the opening of the AV shunt. The percentage inhibition of thrombus
formation is determined for each treatment group. The ID values (dose that produces
50% inhibition of thrombus formation) are estimated by a nonlinear least square
regression program using the Hill sigmoid E equation (DeltaGraph; SPSS Inc.,
Chicago, IL).
The anti-inflammatory effect of these compounds can be demonstrated in an
Evans Blue dye extravasation assay using C1-esterase inhibitor deficient mice. In this
model, mice are dosed with a compound of the present invention, Evans Blue dye is
injected via the tail vein, and extravasation of the blue dye is determined by
spectrophotometric means from tissue extracts.
The ability of the compounds of the current invention to reduce or prevent the
systemic inflammatory response syndrome, for example, as observed during on-pump
cardiovascular procedures, can be tested in in vitro perfusion systems, or by on-pump
surgical procedures in larger mammals, including dogs and baboons. Read-outs to assess
the benefit of the compounds of the present invention include for example reduced
platelet loss, reduced platelet / white blood cell complexes, reduced neutrophil elastase
levels in plasma, reduced activation of complement factors, and reduced activation and/or
consumption of contact activation proteins (plasma kallikrein, factor XII, factor XI, high
molecular weight kininogen, C1-esterase inhibitors).
[00176] The compounds of the present invention may also be useful as inhibitors of
additional serine proteases, notably human thrombin, human plasma kallikrein and human
plasmin. Because of their inhibitory action, these compounds are indicated for use in the
prevention or treatment of physiological reactions, including blood coagulation,
fibrinolysis, blood pressure regulation and inflammation, and wound healing catalyzed by
the aforesaid class of enzymes. Specifically, the compounds have utility as drugs for the
treatment of diseases arising from elevated thrombin activity of the aforementioned serine
proteases, such as myocardial infarction, and as reagents used as anticoagulants in the
processing of blood to plasma for diagnostic and other commercial purposes.
V. PHARMACEUTICAL COMPOSITIONS, FORMULATIONS AND
COMBINATIONS
The compounds of this invention can be administered in such oral dosage
forms as tablets, capsules (each of which includes sustained release or timed release
formulations), pills, powders, granules, elixirs, tinctures, suspensions, syrups, and
emulsions. They may also be administered in intravenous (bolus or infusion),
intraperitoneal, subcutaneous, or intramuscular form, all using dosage forms well known
to those of ordinary skill in the pharmaceutical arts. They can be administered alone, but
generally will be administered with a pharmaceutical carrier selected on the basis of the
chosen route of administration and standard pharmaceutical practice.
[00178] The term “pharmaceutical composition” means a composition comprising a
compound of the invention in combination with at least one additional pharmaceutically
acceptable carrier. A “pharmaceutically acceptable carrier” refers to media generally
accepted in the art for the delivery of biologically active agents to animals, in particular,
mammals, including, i.e., adjuvant, excipient or vehicle, such as diluents, preserving
agents, fillers, flow regulating agents, disintegrating agents, wetting agents, emulsifying
agents, suspending agents, sweetening agents, flavoring agents, perfuming agents,
antibacterial agents, antifungal agents, lubricating agents and dispensing agents,
depending on the nature of the mode of administration and dosage forms.
Pharmaceutically acceptable carriers are formulated according to a number of factors well
within the purview of those of ordinary skill in the art. These include, without limitation:
the type and nature of the active agent being formulated; the subject to which the agent-
containing composition is to be administered; the intended route of administration of the
composition; and the therapeutic indication being targeted. Pharmaceutically acceptable
carriers include both aqueous and non-aqueous liquid media, as well as a variety of solid
and semi-solid dosage forms. Such carriers can include a number of different ingredients
and additives in addition to the active agent, such additional ingredients being included in
the formulation for a variety of reasons, e.g., stabilization of the active agent, binders,
etc., well known to those of ordinary skill in the art. Descriptions of suitable
pharmaceutically acceptable carriers, and factors involved in their selection, are found in
a variety of readily available sources such as, for example, Remington’s Pharmaceutical
Sciences, 18th Ed. (1990).
[00179] The dosage regimen for the compounds of the present invention will, of
course, vary depending upon known factors, such as the pharmacodynamic characteristics
of the particular agent and its mode and route of administration; the species, age, sex,
health, medical condition, and weight of the recipient; the nature and extent of the
symptoms; the kind of concurrent treatment; the frequency of treatment; the route of
administration, the renal and hepatic function of the patient, and the effect desired. A
physician or veterinarian can determine and prescribe the effective amount of the drug
required to prevent, counter, or arrest the progress of the thromboembolic disorder.
By way of general guidance, the daily oral dosage of each active ingredient,
when used for the indicated effects, will range between about 0.001 to about 1000 mg/kg
of body weight, preferably between about 0.01 to about 100 mg/kg of body weight per
day, and most preferably between about 0.1 to about 20 mg/kg/day. Intravenously, the
most preferred doses will range from about 0.001 to about 10 mg/kg/minute during a
constant rate infusion. Compounds of this invention may be administered in a single
daily dose, or the total daily dosage may be administered in divided doses of two, three,
or four times daily.
Compounds of this invention can also be administered by parenteral
administration (e.g., intra-venous, intra-arterial, intramuscularly, or subcutaneously.
When administered intra-venous or intra-arterial, the dose can be given continuously or
intermittent. Furthermore, formulation can be developed for intramuscularly and
subcutaneous delivery that ensure a gradual release of the active pharmaceutical
ingredient.
[00182] Compounds of this invention can be administered in intranasal form via
topical use of suitable intranasal vehicles, or via transdermal routes, using transdermal
skin patches. When administered in the form of a transdermal delivery system, the
dosage administration will, of course, be continuous rather than intermittent throughout
the dosage regimen.
[00183] The compounds are typically administered in admixture with suitable
pharmaceutical diluents, excipients, or carriers (collectively referred to herein as
pharmaceutical carriers) suitably selected with respect to the intended form of
administration, e.g., oral tablets, capsules, elixirs, and syrups, and consistent with
conventional pharmaceutical practices.
[00184] For instance, for oral administration in the form of a tablet or capsule, the
active drug component can be combined with an oral, non-toxic, pharmaceutically
acceptable, inert carrier such as lactose, starch, sucrose, glucose, methyl cellulose,
magnesium stearate, dicalcium phosphate, calcium sulfate, mannitol, sorbitol and the like;
for oral administration in liquid form, the oral drug components can be combined with
any oral, non-toxic, pharmaceutically acceptable inert carrier such as ethanol, glycerol,
water, and the like. Moreover, when desired or necessary, suitable binders, lubricants,
disintegrating agents, and coloring agents can also be incorporated into the mixture.
Suitable binders include starch, gelatin, natural sugars such as glucose or beta-lactose,
corn sweeteners, natural and synthetic gums such as acacia, tragacanth, or sodium
alginate, carboxymethylcellulose, polyethylene glycol, waxes, and the like. Lubricants
used in these dosage forms include sodium oleate, sodium stearate, magnesium stearate,
sodium benzoate, sodium acetate, sodium chloride, and the like. Disintegrators include,
without limitation, starch, methyl cellulose, agar, bentonite, xanthan gum, and the like.
The compounds of the present invention can also be administered in the form
of liposome delivery systems, such as small unilamellar vesicles, large unilamellar
vesicles, and multilamellar vesicles. Liposomes can be formed from a variety of
phospholipids, such as cholesterol, stearylamine, or phosphatidylcholines.
Compounds of the present invention may also be coupled with soluble
polymers as targetable drug carriers. Such polymers can include polyvinylpyrrolidone,
pyran copolymer, polyhydroxypropylmethacrylamide-phenol,
polyhydroxyethylaspartamidephenol, or polyethyleneoxide-polylysine substituted with
palmitoyl residues. Furthermore, the compounds of the present invention may be coupled
to a class of biodegradable polymers useful in achieving controlled release of a drug, for
example, polylactic acid, polyglycolic acid, copolymers of polylactic and polyglycolic
acid, polyepsilon caprolactone, polyhydroxy butyric acid, polyorthoesters, polyacetals,
polydihydropyrans, polycyanoacylates, and crosslinked or amphipathic block copolymers
of hydrogels.
Dosage forms (pharmaceutical compositions) suitable for administration may
contain from about 1 milligram to about 1000 milligrams of active ingredient per dosage
unit. In these pharmaceutical compositions the active ingredient will ordinarily be
present in an amount of about 0.1-95% by weight based on the total weight of the
composition.
Gelatin capsules may contain the active ingredient and powdered carriers,
such as lactose, starch, cellulose derivatives, magnesium stearate, stearic acid, and the
like. Similar diluents can be used to make compressed tablets. Both tablets and capsules
can be manufactured as sustained release products to provide for continuous release of
medication over a period of hours. Compressed tablets can be sugar coated or film coated
to mask any unpleasant taste and protect the tablet from the atmosphere, or enteric coated
for selective disintegration in the gastrointestinal tract.
Liquid dosage forms for oral administration can contain coloring and flavoring
to increase patient acceptance.
[00190] In general, water, a suitable oil, saline, aqueous dextrose (glucose), and related
sugar solutions and glycols such as propylene glycol or polyethylene glycols are suitable
carriers for parenteral solutions. Solutions for parenteral administration preferably
contain a water soluble salt of the active ingredient, suitable stabilizing agents, and if
necessary, buffer substances. Antioxidizing agents such as sodium bisulfite, sodium
sulfite, or ascorbic acid, either alone or combined, are suitable stabilizing agents. Also
used are citric acid and its salts and sodium EDTA. In addition, parenteral solutions can
contain preservatives, such as benzalkonium chloride, methyl-or propyl-paraben, and
chlorobutanol.
Suitable pharmaceutical carriers are described in Remington’s Pharmaceutical
Sciences, Mack Publishing Company, a standard reference text in this field.
[00192] Where the compounds of this invention are combined with other anticoagulant
agents, for example, a daily dosage may be about 0.1 to about 100 milligrams of the
compound of the present invention and about 0.1 to about 100 milligrams per kilogram of
patient body weight. For a tablet dosage form, the compounds of this invention generally
may be present in an amount of about 5 to about 100 milligrams per dosage unit, and the
second anti-coagulant in an amount of about 1 to about 50 milligrams per dosage unit.
Where the compounds of the present invention are administered in
combination with an anti-platelet agent, by way of general guidance, typically a daily
dosage may be about 0.01 to about 25 milligrams of the compound of the present
invention and about 50 to about 150 milligrams of the anti-platelet agent, preferably
about 0.1 to about 1 milligrams of the compound of the present invention and about 1 to
about 3 milligrams of antiplatelet agents, per kilogram of patient body weight.
Where the compounds of the present invention are administered in
combination with thrombolytic agent, typically a daily dosage may be about 0.1 to about
1 milligrams of the compound of the present invention, per kilogram of patient body
weight and, in the case of the thrombolytic agents, the usual dosage of the thrombolytic
agent when administered alone may be reduced by about 50-80% when administered with
a compound of the present invention.
Particularly when provided as a single dosage unit, the potential exists for a
chemical interaction between the combined active ingredients. For this reason, when the
compound of the present invention and a second therapeutic agent are combined in a
single dosage unit they are formulated such that although the active ingredients are
combined in a single dosage unit, the physical contact between the active ingredients is
minimized (that is, reduced). For example, one active ingredient may be enteric coated.
By enteric coating one of the active ingredients, it is possible not only to minimize the
contact between the combined active ingredients, but also, it is possible to control the
release of one of these components in the gastrointestinal tract such that one of these
components is not released in the stomach but rather is released in the intestines. One of
the active ingredients may also be coated with a material that affects a sustained-release
throughout the gastrointestinal tract and also serves to minimize physical contact between
the combined active ingredients. Furthermore, the sustained-released component can be
additionally enteric coated such that the release of this component occurs only in the
intestine. Still another approach would involve the formulation of a combination product
in which the one component is coated with a sustained and/or enteric release polymer,
and the other component is also coated with a polymer such as a low viscosity grade of
hydroxypropyl methylcellulose (HPMC) or other appropriate materials as known in the
art, in order to further separate the active components. The polymer coating serves to
form an additional barrier to interaction with the other component.
These as well as other ways of minimizing contact between the components of
combination products of the present invention, whether administered in a single dosage
form or administered in separate forms but at the same time by the same manner, will be
readily apparent to those skilled in the art, once armed with the present disclosure.
[00197] In another embodiment, the present invention provides a pharmaceutical
composition further comprising additional therapeutic agent(s) selected from potassium
channel openers, potassium channel blockers, calcium channel blockers, sodium
hydrogen exchanger inhibitors, antiarrhythmic agents, antiatherosclerotic agents,
anticoagulants, antithrombotic agents, prothrombolytic agents, fibrinogen antagonists,
diuretics, antihypertensive agents, ATPase inhibitors, mineralocorticoid receptor
antagonists, phospodiesterase inhibitors, antidiabetic agents, anti-inflammatory agents,
antioxidants, angiogenesis modulators, antiosteoporosis agents, hormone replacement
therapies, hormone receptor modulators, oral contraceptives, antiobesity agents,
antidepressants, antianxiety agents, antipsychotic agents, antiproliferative agents,
antitumor agents, antiulcer and gastroesophageal reflux disease agents, growth hormone
agents and/or growth hormone secretagogues, thyroid mimetics, anti-infective agents,
antiviral agents, antibacterial agents, antifungal agents, cholesterol/lipid lowering agents
and lipid profile therapies, and agents that mimic ischemic preconditioning and/or
myocardial stunning, or a combination thereof.
[00198] In another embodiment, the present invention provides a pharmaceutical
composition further comprising additional therapeutic agent(s) selected from an anti-
arrhythmic agent, an anti-hypertensive agent, an anti-coagulant agent, an anti-platelet
agent, a thrombin inhibiting agent, a thrombolytic agent, a fibrinolytic agent, a calcium
channel blocker, a potassium channel blocker, a cholesterol/lipid lowering agent, or a
combination thereof.
In another embodiment, the present invention provides a pharmaceutical
composition further comprising additional therapeutic agent(s) selected from warfarin,
unfractionated heparin, low molecular weight heparin, synthetic pentasaccharide, hirudin,
argatroban, aspirin, ibuprofen, naproxen, sulindac, indomethacin, mefenamate,
dipyridamol, droxicam, diclofenac, sulfinpyrazone, piroxicam, ticlopidine, clopidogrel,
tirofiban, eptifibatide, abciximab, melagatran, ximelagatran, disulfatohirudin, tissue
plasminogen activator, modified tissue plasminogen activator, anistreplase, urokinase,
and streptokinase, or a combination thereof.
In another embodiment, the present invention provides a pharmaceutical
composition wherein the additional therapeutic agent is an antihypertensive agent
selected from ACE inhibitors, AT-1 receptor antagonists, beta-adrenergic receptor
antagonists, ETA receptor antagonists, dual ETA/AT-1 receptor antagonists, renin
inhibitors (alliskerin) and vasopepsidase inhibitors, an antiarrythmic agent selected from
IKur inhibitors, an anticoagulant selected from thrombin inhibitors, antithrombin-III
activators, heparin co-factor II activators, other factor XIa inhibitors, other kallikrein
inhibitors, plasminogen activator inhibitor (PAI-1) antagonists, thrombin activatable
fibrinolysis inhibitor (TAFI) inhibitors, factor VIIa inhibitors, factor IXa inhibitors, and
factor Xa inhibitors, or an antiplatelet agent selected from GPIIb/IIIa blockers, GP Ib/IX
blockers, protease activated receptor 1 (PAR-1) antagonists, protease activated receptor4
(PAR-4) antagonists, prostaglandin E2 receptor EP3 antagonists, collagen receptor
antagonists, phosphodiesterase-III inhibitors, P2Y receptor antagonists, P2Y
1 12
antagonists, thromboxane receptor antagonists, cyclooxygense-1 inhibitors, and aspirin,
or a combination thereof.
In another embodiment, the present invention provides pharmaceutical
composition, wherein the additional therapeutic agent(s) are an anti-platelet agent or a
combination thereof.
[00202] In another embodiment, the present invention provides a pharmaceutical
composition, wherein the additional therapeutic agent is the anti-platelet agent
clopidogrel.
The compounds of the present invention can be administered alone or in
combination with one or more additional therapeutic agents. By “administered in
combination” or “combination therapy” it is meant that the compound of the present
invention and one or more additional therapeutic agents are administered concurrently to
the mammal being treated. When administered in combination, each component may be
administered at the same time or sequentially in any order at different points in time.
Thus, each component may be administered separately but sufficiently closely in time so
as to provide the desired therapeutic effect.
Compounds that can be administered in combination with the compounds of
the present invention include, but are not limited to, anticoagulants, anti-thrombin agents,
anti-platelet agents, fibrinolytics, hypolipidemic agents, antihypertensive agents, and anti-
ischemic agents.
Other anticoagulant agents (or coagulation inhibitory agents) that may be used
in combination with the compounds of this invention include warfarin, heparin (either
unfractionated heparin or any commercially available low molecular weight heparin, for
example LOVENOX ), synthetic pentasaccharide, direct acting thrombin inhibitors
including hirudin and argatroban, as well as other factor VIIa inhibitors, factor IXa
inhibitors, factor Xa inhibitors (e.g., ARIXTRA , apixaban, rivaroxaban, LY-517717,
DU-176b, DX-9065a, and those disclosed in WO 98/57951, WO 03/026652, WO
01/047919, and WO 00/076970), factor XIa inhibitors, and inhibitors of activated TAFI
and PAI-1 known in the art.
The term anti-platelet agents (or platelet inhibitory agents), as used herein,
denotes agents that inhibit platelet function, for example, by inhibiting the aggregation,
adhesion or granule-content secretion of platelets. Such agents include, but are not
limited to, the various known non-steroidal anti-inflammatory drugs (NSAIDs) such as
acetaminophen, aspirin, codeine, diclofenac, droxicam, fentaynl, ibuprofen,
indomethacin, ketorolac, mefenamate, morphine, naproxen, phenacetin, piroxicam,
sufentanyl, sulfinpyrazone, sulindac, and pharmaceutically acceptable salts or prodrugs
thereof. Of the NSAIDs, aspirin (acetylsalicylic acid or ASA) and piroxicam are
preferred. Other suitable platelet inhibitory agents include glycoprotein IIb/IIIa
antagonists (e.g., tirofiban, eptifibatide, abciximab, and integrelin), thromboxane-A2-
receptor antagonists (e.g., ifetroban), thromboxane-A-synthetase inhibitors,
phosphodiesterase-III (PDE-III) inhibitors (e.g., dipyridamole, cilostazol), and PDE-V
inhibitors (such as sildenafil), protease-activated receptor 1 (PAR-1) antagonists (e.g., E-
5555, SCH-530348, SCH-203099, SCH-529153 and SCH-205831), and pharmaceutically
acceptable salts or prodrugs thereof.
[00207] Other examples of suitable anti-platelet agents for use in combination with the
compounds of the present invention, with or without aspirin, are ADP (adenosine
diphosphate) receptor antagonists, preferably antagonists of the purinergic receptors
P2Y and P2Y , with P2Y being even more preferred. Preferred P2Y receptor
1 12 12 12
antagonists include clopidogrel, ticlopidine, prasugrel, ticagrelor, and cangrelor, and
pharmaceutically acceptable salts or prodrugs thereof. Ticlopidine and clopidogrel are
also preferred compounds since they are known to be more gentle than aspirin on the
gastro-intestinal tract in use. Clopidogrel is an even more preferred agent.
A preferred example is a triple combination of a compound of the present
invention, aspirin, and another anti-platelet agent. Preferably, the anti-platelet agent is
clopidogrel or prasugrel, more preferably clopidogrel.
The term thrombin inhibitors (or anti-thrombin agents), as used herein,
denotes inhibitors of the serine protease thrombin. By inhibiting thrombin, various
thrombin-mediated processes, such as thrombin-mediated platelet activation (that is, for
example, the aggregation of platelets, and/or the secretion of platelet granule contents
including serotonin) and/or fibrin formation are disrupted. A number of thrombin
inhibitors are known to one of skill in the art and these inhibitors are contemplated to be
used in combination with the present compounds. Such inhibitors include, but are not
limited to, boroarginine derivatives, boropeptides, heparins, hirudin, argatroban,
dabigatran, AZD-0837, and those disclosed in WO 98/37075 and WO 02/044145, and
pharmaceutically acceptable salts and prodrugs thereof. Boroarginine derivatives and
boropeptides include N-acetyl and peptide derivatives of boronic acid, such as C-terminal
a-aminoboronic acid derivatives of lysine, ornithine, arginine, homoarginine and
corresponding isothiouronium analogs thereof. The term hirudin, as used herein, includes
suitable derivatives or analogs of hirudin, referred to herein as hirulogs, such as
disulfatohirudin.
The term thrombolytic (or fibrinolytic) agents (or thrombolytics or
fibrinolytics), as used herein, denotes agents that lyse blood clots (thrombi). Such agents
include tissue plasminogen activator (TPA, natural or recombinant) and modified forms
thereof, anistreplase, urokinase, streptokinase, tenecteplase (TNK), lanoteplase (nPA),
factor VIIa inhibitors, thrombin inhibitors, inhibitors of factors IXa, Xa, and XIa, PAI-I
inhibitors (i.e., inactivators of tissue plasminogen activator inhibitors), inhibitors of
activated TAFI, alphaantiplasmin inhibitors, and anisoylated plasminogen
streptokinase activator complex, including pharmaceutically acceptable salts or prodrugs
thereof. The term anistreplase, as used herein, refers to anisoylated plasminogen
streptokinase activator complex, as described, for example, in European Patent
Application No. 028,489, the disclosure of which is hereby incorporated herein by
reference herein. The term urokinase, as used herein, is intended to denote both dual and
single chain urokinase, the latter also being referred to herein as prourokinase.
Examples of suitable cholesterol/lipid lowering agents and lipid profile
therapies for use in combination with the compounds of the present invention include
HMG-CoA reductase inhibitors (e.g., pravastatin, lovastatin, simvastatin, fluvastatin,
atorvastatin, rosuvastatin, and other statins), low-density lipoprotein (LDL) receptor
activity modulators (e.g., HOE-402, PCSK9 inhibitors), bile acid sequestrants (e.g.,
cholestyramine and colestipol), nicotinic acid or derivatives thereof (e.g., NIASPAN ),
GPR109B (nicotinic acid receptor) modulators, fenofibric acid derivatives (e.g.,
gemfibrozil, clofibrate, fenofibrate and benzafibrate) and other peroxisome proliferator-
activated receptors (PPAR) alpha modulators, PPARdelta modulators (e.g., GW-501516),
PPARgamma modulators (e.g., rosiglitazone), compounds that have multiple
functionality for modulating the activities of various combinations of PPARalpha,
PPARgamma and PPARdelta, probucol or derivatives thereof (e.g., AGI-1067),
cholesterol absorption inhibitors and/or Niemann-Pick C1-like transporter inhibitors
(e.g., ezetimibe), cholesterol ester transfer protein inhibitors (e.g., CP-529414), squalene
synthase inhibitors and/or squalene epoxidase inhibitors or mixtures thereof, acyl
coenzyme A: cholesteryl acyltransferase (ACAT) 1 inhibitors, ACAT2 inhibitors, dual
ACAT1/2 inhibitors, ileal bile acid transport inhibitors (or apical sodium co-dependent
bile acid transport inhibitors), microsomal triglyceride transfer protein inhibitors, liver-
X-receptor (LXR) alpha modulators, LXR beta modulators, LXR dual alpha/beta
modulators, FXR modulators, omega 3 fatty acids (e.g., 3-PUFA), plant stanols and/or
fatty acid esters of plant stanols (e.g., sitostanol ester used in BENECOL margarine),
endothelial lipase inhibitors, and HDL functional mimetics which activate reverse
cholesterol transport (e.g., apoAI derivatives or apoAI peptide mimetics).
The compounds of the present invention are also useful as standard or
reference compounds, for example as a quality standard or control, in tests or assays
involving the inhibition of thrombin, Factor VIIa, IXa, Xa, XIa, and/or plasma kallikrein.
Such compounds may be provided in a commercial kit, for example, for use in
pharmaceutical research involving thrombin, Factor VIIa, IXa, Xa, XIa, and/or plasma
kallikrein. XIa. For example, a compound of the present invention could be used as a
reference in an assay to compare its known activity to a compound with an unknown
activity. This would ensure the experimentor that the assay was being performed
properly and provide a basis for comparison, especially if the test compound was a
derivative of the reference compound. When developing new assays or protocols,
compounds according to the present invention could be used to test their effectiveness.
The compounds of the present invention may also be used in diagnostic assays
involving thrombin, Factor VIIa, IXa, Xa, XIa, and/or plasma kallikrein. For example, the
presence of thrombin, Factor VIIa, IXa, Xa XIa, and/or plasma kallikrein in an unknown
sample could be determined by addition of the relevant chromogenic substrate, for
example S2366 for Factor XIa, to a series of solutions containing test sample and
optionally one of the compounds of the present invention. If production of pNA is
observed in the solutions containing test sample, but not in the presence of a compound of
the present invention, then one would conclude Factor XIa was present.
Extremely potent and selective compounds of the present invention, those
having K values less than or equal to 0.001 μM against the target protease and greater
than or equal to 0.1 μM against the other proteases, may also be used in diagnostic assays
involving the quantitation of thrombin, Factor VIIa, IXa, Xa, XIa, and/or plasma
kallikrein in serum samples. For example, the amount of Factor XIa in serum samples
could be determined by careful titration of protease activity in the presence of the relevant
chromogenic substrate, S2366, with a potent and selective Factor XIa inhibitor of the
present invention.
[00215] The present invention also encompasses an article of manufacture. As used
herein, article of manufacture is intended to include, but not be limited to, kits and
packages. The article of manufacture of the present invention, comprises: (a) a first
container; (b) a pharmaceutical composition located within the first container, wherein
the composition, comprises: a first therapeutic agent, comprising: a compound of the
present invention or a pharmaceutically acceptable salt form thereof; and, (c) a package
insert stating that the pharmaceutical composition can be used for the treatment of a
thromboembolic and/or inflammatory disorder (as defined previously). In another
embodiment, the package insert states that the pharmaceutical composition can be used in
combination (as defined previously) with a second therapeutic agent to treat a
thromboembolic and/or inflammatory disorder. The article of manufacture can further
comprise: (d) a second container, wherein components (a) and (b) are located within the
second container and component (c) is located within or outside of the second container.
Located within the first and second containers means that the respective container holds
the item within its boundaries.
The first container is a receptacle used to hold a pharmaceutical composition.
This container can be for manufacturing, storing, shipping, and/or individual/bulk selling.
First container is intended to cover a bottle, jar, vial, flask, syringe, tube (e.g., for a cream
preparation), or any other container used to manufacture, hold, store, or distribute a
pharmaceutical product.
The second container is one used to hold the first container and, optionally,
the package insert. Examples of the second container include, but are not limited to,
boxes (e.g., cardboard or plastic), crates, cartons, bags (e.g., paper or plastic bags),
pouches, and sacks. The package insert can be physically attached to the outside of the
first container via tape, glue, staple, or another method of attachment, or it can rest inside
the second container without any physical means of attachment to the first container.
Alternatively, the package insert is located on the outside of the second container. When
located on the outside of the second container, it is preferable that the package insert is
physically attached via tape, glue, staple, or another method of attachment. Alternatively,
it can be adjacent to or touching the outside of the second container without being
physically attached.
The package insert is a label, tag, marker, etc. that recites information relating
to the pharmaceutical composition located within the first container. The information
recited will usually be determined by the regulatory agency governing the area in which
the article of manufacture is to be sold (e.g., the United States Food and Drug
Administration). Preferably, the package insert specifically recites the indications for
which the pharmaceutical composition has been approved. The package insert may be
made of any material on which a person can read information contained therein or
thereon. Preferably, the package insert is a printable material (e.g., paper, plastic,
cardboard, foil, adhesive-backed paper or plastic, etc.) on which the desired information
has been formed (e.g., printed or applied).
Other features of the invention will become apparent in the course of the
following descriptions of exemplary embodiments that are given for illustration of the
invention and are not intended to be limiting thereof. The following Examples have been
prepared, isolated and characterized using the methods disclosed herein.
VI. GENERAL SYNTHESIS INCLUDING SCHEMES
The compounds of the present invention may be synthesized by many
methods available to those skilled in the art of organic chemistry (Maffrand, J. P. et al.,
Heterocycles, 16(1):35-7 (1981)). General synthetic schemes for preparing compounds
of the present invention are described below. These schemes are illustrative and are not
meant to limit the possible techniques one skilled in the art may use to prepare the
compounds disclosed herein. Different methods to prepare the compounds of the present
invention will be evident to those skilled in the art. Additionally, the various steps in the
synthesis may be performed in an alternate sequence in order to give the desired
compound or compounds.
Examples of compounds of the present invention prepared by methods
described in the general schemes are given in the intermediates and examples section set
out hereinafter. Example compounds are typically prepared as racemic mixtures.
Preparation of homochiral examples may be carried out by techniques known to one
skilled in the art. For example, homochiral compounds may be prepared by separation of
racemic products by chiral phase preparative HPLC. Alternatively, the example
compounds may be prepared by methods known to give enantiomerically enriched
products. These include, but are not limited to, the incorporation of chiral auxiliary
functionalities into racemic intermediates which serve to control the diastereoselectivity
of transformations, providing enantio-enriched products upon cleavage of the chiral
auxiliary.
Scheme 1 illustrates a few approaches to the synthesis of compounds of
Formula (I). Amide 1c can be prepared by amide coupling of commercially available or
readily accessible acid 1a and readily accessible aniline 1b using methods commonly
used in the literature, such as T3P/base, HOAt/EDC/base and/or POCl , pyridine.
Deprotection of the protecting group PG using appropriate conditions known to those in
the art of organic synthesis, followed by coupling with acid 1e can yield compounds of
formula 1g. Alternatively, coupling of amine 1d with acid 1e followed by deprotection
can give acid 1f. The coupling of acid 1f with amine 1b under standard peptide coupling
procedures can yield compounds of formula 1g. Appropriate functionalization of
intermediates used in this invention to prepare compounds of formula 1g can be achieved
through the Suzuki, Buchwald, Ullman or Mitsunobu reactions or simple reactions known
to those in the art.
Scheme 1:
1. deprotection
amide coupling
R N R
R NH 2. amide coupling O
PG O
PG O
Cl 1g
PG = H/protecting group
R = halo or carbocyclic amine
COOH
1. amide coupling amide coupling
2. deprotection R NH
O 1f
[00223] Scheme 2 describes an alternative method to access compounds of this
invention. Reaction of acid 1e, isocyanide 2a, and imine 2b can give Ugi product 2d
(Schuster, I. et al., Letters in Organic Chemistry, 4(2):102-108 (2007)). Selective
oxidation of tetrahydroisoquinoline 2c using known methods such as MnO (Aoyama, T.
et al., Synlett, 1:35-36 (1998)) can yield imine 2b, which can then be used via the three
component Ugi coupling procedures described above. The Ugi coupling procedures can
be used extensively with other imino derived intermediates contained in this invention.
Further manipulations of the Ugi derived products can afford compounds of this
invention.
Scheme 2:
(R )
(R )
1-4 N
Ugi reaction
COOH
R N R
R NC
2a O
Cl 2b
Oxidation
(R )
Scheme 3 describes methods for preparing the tetrahydroisoquinoline
intermediate 3c and 3e. Method A uses Bischler-Napieralski cyclization to access
compounds such as intermediate 3c (Al-Hiari, Y. M. et al., Journal of Heterocyclic
Chemistry, 42(4): 647-659 (2005)) or 3e (Zalan, Z. et al., Tetrahedron, 62(12): 2883-
2891 (2006)). Method B uses the Friedel-Crafts alkylation reaction to access compounds
such as intermediate 3c (Topsom, R. D. et al., Journal of the Chemical Society [Section]
D: Chemical Communications, 15:799 (1971)). Alternatively, as described in Method C,
cyclization of intermediate 3h and 3-aminopropanol (3i) can afford 3j. Reduction with
NaBH , followed by PCC oxidation gave β-amino aldehyde, which can be converted to
3c under basic conditions (Umetsu, K.; Asao, N., Tetrahedron Letters, 49(17): 2722-2725
(2008)). In Method D, lactam 3l can be synthesized from ketone 3k by the Beckmann
rearrangement. Reduction of 3l can afford intermediates such as 3c (Vernier, J. et al.,
WO 2008024398 (2008)). In Method E, the dihydroisoquinoline carbaldehyde (3m) was
converted to 3c under basic conditions (Martin, S. et al., WO 2006134143 (2006)). In
Method F, dihydroisoquinolinethione was converted to 3c treating the thione 3o with
bromopropene followed by treatment with perchloric acid and sodium borohydride
(Mohinder, B, et al., Indian Journal of Chemistry, Section B: Organic Chemistry
Including Medicinal Chemistry, 18B (4); 312-15 (1979)).
Scheme 3:
POCl
Bischler-Napieralski reaction NaBH , EtOH
200-220 C
(Regiochemistry: same as Friedel-Crafts)
R = nitro, halogen, Subst. Aryl/heteroaryl 3b
1. reflux
2. POCl (Bischler-Napieralski cyclization)
CO Et
(CO Et) 2
3. H
R NH
2 NH
1. BrCH CH OH
2 2 NH
AlCl
3 NH
2. HBr
Friedel-Crafts
R Br
R 3c
1. NaBH , EtOH R
2. AcONa, PCC
Dioxane, 100 C
3. KOH, MeOH, THF
1. MeSO H, NaN
2. NaOH
B H , THF
D) NH
O R O
HCHO,
CF COOH, 4-5 h
KOH, EtOH
2-3 h, reflux
NH reflux
HClO
Br NH
F) N
NaBH
Preparation of substituted THQ analogs is shown in Scheme 4. Bromide 4a
can be converted to nitrile 4b under lithiation conditions. Hydrolysis under basic
conditions should lead to acid 4c, which can be converted to carbamate 4e via Curtius
rearrangement. Formation of the THQ intermediate 4f can then be accomplished by
treatment with paraformaldehyde in a mixture of acetic and sulfuric acid (Bigge, C. F. et
al, Bioorganic & Medicinal Chemistry Letters, 3(1): 39-42 (1993)). Deprotection of
carbamate 4f followed by protection with Boc O should afford intermediate 4h, which
can be subjected to the Suzuki cross coupling reaction with an appropriate boronate or
boronic acid or the Stille coupling procedures known to those in the art.
Scheme 4:
Isobutyronitrile,
DPPA/TEA,
NaH (60%),
LiHMDS/THF, aq KOH
Toluene,
Br Br
o MeOH/THF,
0 C to rt, Ethyleneglycole, 0 C, 1 h,
CH CH CH
0 C to rt, 3 h.
CH 150 C, 48 h. 110 C, 4 h.
3 CH CH
Br 3 3
CN COOH N
4b 4c
4a 4d
(Boc) O, TEA,
(CH )nO, 2
aq KOH Br
Br Br
Br o
AcOH:H SO (3:1) THF, 0 C to rt,
CH Ethylene glycol, CH
2 4 3
CH 3
rt, 68 h. o o.n.
150 C, 48 h CH
CH CH 3
NBoc
N O NH
NHCOOMe CH
Purification of intermediates and final products was carried out via either
normal or reverse phase chromatography. Normal phase chromatography was carried out
using prepacked SiO cartridges eluting with either gradients of hexanes and EtOAc or
DCM and MeOH unless otherwise indicated. Reverse phase preparative HPLC was
carried out using C18 columns eluting with gradients of Solvent A (90% water, 10%
MeOH, 0.1% TFA) and Solvent B (10% water, 90% MeOH, 0.1% TFA, UV 220 nm) or
with gradients of Solvent A (90% water, 10% ACN, 0.1% TFA) and Solvent B (10%
water, 90% ACN, 0.1% TFA, UV 220 nm) or with gradients of Solvent A (98% water,
2% ACN, 0.05% TFA) and Solvent B (98% ACN, 2% water, 0.05% TFA, UV 220 nm).
Unless otherwise stated, analysis of final products was carried out by reverse
phase analytical HPLC.
Method A: A majority of analytical HPLC runs were: SunFire (4.6 x 150mm)
(15 min gradient - 95:5 H O / ACN-to 95:5ACN/H O-0.05% TFA).
Method B: A minority of analytical HPLC runs were: Zorbax (4.6 x 75 mm)
(8 min gradient -10:90 MeOH / H O to 90:10 MeOH / H O, 0.2% H PO )
2 2 3 4
A majority of mass spectra runs were run using Phenomenex Luna C18 (2 x
30mm) (2 min gradient 90% H O /10% MeOH / 0.1%TFA to 90% MeOH / 10% H O
/0.1% TFA)
Intermediate 1: (E)-2,5-Dioxopyrrolidinyl 3-(5-chloro(1H-tetrazol
yl)phenyl)acrylate
[00231] The synthesis was described as Intermediate 1 in PCT International
Application, published 09/17/09.
Intermediate 2: (E)(5-chlorotetrazolyl-phenyl)-acrylic acid
[00232] The synthesis was described as Intermediate 1B in PCT International
Application, published 09/17/09.
Intermediate 3: (E)(3-Chlorofluorotetrazolyl-phenyl)-acrylic acid 2,5-dioxo-
pyrrolidinyl ester
Intermediate 3A: (E)(3-chlorofluoro(1H-tetrazolyl)phenyl)acrylic
acid: The synthesis of Intermediate 3A was described as Intermediate 7 in PCT
International Application, published 09/17/09.
Intermediate 3: To a slightly turbid mixture of Intermediate 3A (1.0 g, 3.72
mmol) in THF (18.70 mL) and DMF (1.870 mL) was added 1-hydroxypyrrolidine-2,5-
dione (0.471 g, 4.09 mmol) and DIC (0.638 mL, 4.09 mmol). The reaction was stirred at
rt and a white precipitate formed overtime. The solid was collected by suction filtration
and washed with MeOH and H O. The crude product was then air-dried and finally dried
under vacuum to give Intermediate 3 (0.98 g, 72%), as a white solid. H NMR (500
MHz, DMSO-d6) δ 9.92 (s, 1H), 8.06 (t, J = 8.12 Hz, 1H), 7.72 (d, J = 8.80 Hz, 1H), 7.36
(d, J = 16.23 Hz, 1H), 6.81 (d, J = 16.51 Hz, 1H), 2.84 (s, 4 H) ppm. MS (ESI) m/z:
366.2 (M+H) .
Intermediate 4: (E)(2-acetylchlorophenyl)acrylic acid
H C O
Intermediate 4A: (E)-tert-butyl 3-(2-acetylchlorophenyl)acrylate: To a
degassed solution of 1-(2-bromochlorophenyl)ethanone (1.0 g, 4.28 mmol),
tributylamine (2.041 mL, 8.57 mmol), and tert-butyl acrylate (1.255 mL, 8.57 mmol) in
DMF (10 mL) was added palladium on carbon (0.456 g, 0.428 mmol) and palladium (II)
acetate (0.096 g, 0.428 mmol). The reaction mixture was warmed to 100 ºC. After 16 h,
the reaction was cooled to rt and filtered. The solid was rinsed with DMF and the filtrate
was diluted with EtOAc and washed with H O (2x) followed by brine. The crude product
was then dried over Na SO , filtered and concentrated. Purification by normal phase
chromatography afforded Intermediate 4A (0.760 g, 63%), as a brown oil. MS (ESI) m/z:
225.0 (M-C4H8+H) .
Intermediate 4: A solution of Intermediate 4A (0.048 g, 0.171 mmol) in 50%
TFA/DCM (2 mL) was stirred at rt. After 1 h, the reaction was concentrated to give
Intermediate 4 (0.038 g, 100%) as a yellow solid. The material was carried onto the next
step without further purification. MS (ESI) m/z: 225.1 (M+H) .
Intermediate 5: (E)(5-chlorofluoro(1H-tetrazolyl)phenyl)acrylic acid
Intermediate 5A: 4-chlorofluoroiodoaniline: To 4-chlorofluoroaniline
(25g, 0.17 mmol) in 250 mL of H O was added NaHCO (21.6g, 0.25 mmol). After
cooling to 0 C, iodine (43.5g, 0.17 mmol) was added. After 18 h at rt, an additional 10.8
g of iodine was added and the reaction was stirred overnight. The reaction was extracted
with DCM (4x250 mL), the combined organics were washed with sodium thiosulfate
solution (2x250 mL) and brine (2x250 mL) and dried (Na SO ). Purification by silica gel
chromatography gave 47 g of Intermediate 5A. MS (ESI) m/z: 145.2 (M+H) .
Intermediate 5B: 1-(4-chlorofluoroiodophenyl)-1H-tetrazole: To
Intermediate 5A (47g, 17.3 mmol) in AcOH (470 mL) was added NaN (33.76g, 51.9
mmol) and trimethyl orthoformate (56.8 mL, 51.9 mmol). After 30 h, the reaction was
poured into ice H O, the solids were filtered-off and washed with petroleum ether to
afford 49 g Intermediate 5B. MS (ESI) m/z: 324.8 (M+H) .
Intermediate 5C: (E)-methyl 3-(5-chlorofluoro(1H-tetrazol
yl)phenyl)acrylate: A solution of Intermediate 5B (100g, 324.4 mmol) in ACN (1000
mL) was degassed with N . TEA (64 mL) and methyl acrylate (60 mL) were added and
the reaction was further degassed. Pd(OAc) (8 g, 11.8 mmol) was added and the
reaction was heated to 85 C for 18 h. The reaction was concentrated and the residue was
diluted with H O. The aqueous layer was extracted with EtOAc and the combined
organics were washed with brine. Purification by silica gel chromatography gave 25 g
Intermediate 5C. MS (ESI) m/z: 283.0 (M+H) .
Intermediate 5: (E)(5-chlorofluoro(1H-tetrazolyl)phenyl)acrylic
acid: To Intermediate 5C (5g, 17.7 mmol) in MeOH (50 mL) and THF (25 mL) was
added 10% NaOH solution (25 mL). After 2 h, the reaction was concentrated and the
residue was diluted with H O. The pH was adjusted to 2 to 3 with 1.5N HCl and the
resultant solid was filtered and washed with petroleum ether to afford 2 g of Intermediate
. MS (ESI) m/z: 269.0 (M+H) .
Intermediate 6: tert-Butyl 4-isocyanobenzoate
Intermediate 6A: tert-Butyl 4-formamidobenzoate: Combined tert-butyl 4-
aminobenzoate (15.3g, 79 mmol), DMAP (1.935 g, 15.84 mmol), N-methylmorpholine
(15.67 mL, 143 mmol) in DCM (120 mL) and, after cooling to 0 C, slowly added formic
acid (9.11 mL, 238 mmol). After stirring for 18 h, the reaction was concentrated and then
partitioned with 1N HCl (100 mL) and EtOAc (200 mL). The aqueous layer was
extracted with EtOAc (100 mL). The combined organic layer was washed with brine (50
mL) and dried (MgSO ). The desired product was collected as yellow syrup (16 g).
Intermediate 6: To Intermediate 6A in THF (300 mL) was added TEA (33 mL,
238 mmol) and the after cooling to 0 C, POCl (7.3 mL, 79 mmol) was slowly added and
the reaction was stirred at room temperature. After 24 h, the reaction was partitioned
between EtOAc (200 mL) and aqueous NaHCO (100 mL). The aqueous layer was
extracted with EtOAc (100 mL). The combined organic layer was washed with brine (50
mL) and dried (MgSO ). Purification by normal phase chromatography afforded 10.4 g
(64.6%) of intermediate 6 as a green solid. H NMR (400 MHz, CDCl ) δ 8.02 (d, J =
8.59 Hz, 2 H), 7.41 (d, J = 8.34 Hz, 2 H), 1.60 (s, 9 H) ppm.
Intermediate 7: 4-Isocyanobenzonitrile
NC NC
Intermediate 7 was prepared in a similar manner as Intermediate 6 from 4-
isocyanoaniline. H NMR (400 MHz, CDCl ) δ 7.68 - 7.84 (m, 2 H) 7.51 (d, J = 8.34 Hz,
2 H) ppm.
Intermediate 8: tert-Butyl 6-isocyano-1H-indazolecarboxylate
Intermediate 8 was prepared in a similar manner as Intermediate 6 from tert-
butyl 6-amino-1H-indazolecarboxylate. H NMR (400 MHz, CDCl ) δ 8.28 (1 H, s),
8.20 (1 H, s), 7.76 (1 H, d, J = 8.34 Hz), 7.28 - 7.40 (1 H, m), 1.74 (9 H, s) ppm. MS
(ESI) m/z: 144 (M+H-Boc) .
Intermediate 9: Ethyl 4-isocyanobenzoate
Intermediate 9 was prepared in a similar manner as Intermediate 6. H NMR
(400 MHz, CDCl ) δ 1.40 (t, J = 7.20 Hz, 3 H) 4.40 (q, J = 7.24 Hz, 2 H) 7.44 (d, J =
8.59 Hz, 2 H) 8.00 - 8.17 (m, 2 H) ppm. MS (ESI) m/z: 176 (M+H) .
Intermediate 10: Methyl 4-isocyanophenylcarbamate
[00246] Intermediate 10A: 1- Boc-methyl 4-aminophenylcarbamate: To tert-butyl 4-
aminophenylcarbamate (2.1 g, 10.08 mmol) in a separatory funnel with DCM (75mL)
and saturated aqueous NaHCO (25mL) was added methyl chloroformate (0.937 mL,
12.10 mmol). After shaking for 10 min a thick pink gel formed. The solid was filtered
off and dried. The aqueous layer was extracted with DCM (50 mL) and dried (MgSO ).
All solids collected were combined to afford 2.6 g of Intermediate 10A. H NMR (400
MHz, MeOD) δ 7.32 (4 H, s), 3.73 (3 H, s), 1.53 (9 H, s) ppm.
Intermediate 10B: methyl 4-aminophenylcarbamate: Intermediate 10A (2.6g,
9.77 mmol) was deprotected with 30% TFA in DCM (40 mL). After 2 h, the reaction
was concentrated and the residue was partitioned with EtOAc (75 mL) and saturated
NaHCO (50 mL). The organic layer was washed with brine (20 mL) and dried
(MgSO ). Crude Intermediate 10B was carried onto the next step. H NMR (400 MHz,
DMSO-d ) δ 9.86 (1 H, s), 7.56 (2 H, d, J = 8.84 Hz), 7.28 (2 H, d, J = 8.84 Hz), 6.90 (2
H, s), 3.68 (3 H, s) ppm.
Intermediate 10C: methyl 4-formamidophenylcarbamate: Crude Intermediate
10B was heated to reflux in ethyl formate for several days. The solvent was removed and
the residue was purified by silica gel chromatography to afford 2.9 g of Intermediate 10C
as brown oil. MS (ESI) m/z: 195.0 (M+H) .
Intermediate 10 was made in a similar manner as Intermediate 6 to afford 0.31
g (17.8%) of a tan solid. H NMR (400 MHz, CDCl ) δ 7.45 (2 H, d, J = 8.8 Hz), 7.33 -
7.41 (2 H, m), 6.73 (1 H, br. s.), 3.82 (3 H, s) ppm.
Intermediate 11: benzyl 6-isocyano-1H-indazolecarboxylate:
Intermediate 11 was made in a similar manner as Intermediate 6 and
Intermediate 8 starting from benzyl 6-amino-1H-indazolecarboxylate: H NMR (400
MHz, CDCl ) δ 8.31 (1 H, s), 8.21 (1 H, s), 7.76 (1 H, d, J = 8.34 Hz), 7.54 (2 H, d, J =
6.82 Hz), 7.30 - 7.47 (4 H, m), 5.56 (2 H, s) ppm. MS (ESI) m/z: 234 (M+H-CO2) .
Intermediate 12: (E)(6-acetylchlorofluorophenyl)acrylic acid:
H C O
[00251] Intermediate 12A: 2-bromochlorofluorobenzoic acid: To a cooled (-78
°C) solution of DIEA (4.9 mL, 48 mmol) in THF was added dropwise n-BuLi (132 mL,
2.3 eq, 2.5 M ). The mixture was stirred at -30 °C for 30 min. Again the reaction mixture
was cooled to -78 °C, and a solution of 4-chlorofluorobenzoic acid (25 g, 143 mmol)
in THF was added over 1 h. The reaction was stirred at -78 °C overnight. The next day a
solution of 1,2-dibromo-1,1,2,2-tetrachloroethane (87 g, 267 mmol) in THF was added
and the reaction was stirred at -78 °C for further 2 h and then rt for 4 h. The reaction
mixture was quenched with H O, organic layer was separated and aqueous layer washed
with Et O. Aqueous layer acidified with 1.5 N HCl and extracted in EtOAc (2 x 200
mL), dried over anhydrous Na SO , filtered and concentrated to afford Intermediate 12A
(30 g, 83.3%). MS (ESI) m/z: 252.6 (M-H) .
Intermediate 12B: Diethyl 2-((2-bromochlorofluorophenyl)
(hydroxy)methylene)malonate: To a suspension of Intermediate 12A (14.6 g, 57 mmol)
in DCM (200 mL) was added thionyl chloride (6.6 mL, 88 mmol). The mixture was
stirred at reflux for 3 h. Solvent was removed and the residue was dried in vacuum to
give the acid chloride as a light brown solid. To a cooled (0 °C) suspension of sodium
hydride (3.66 g (60%), 91.5 mmol) in THF was added a solution of diethyl malonate
(0.612 g, 3.82 mmol) in THF (5 mL). After 10 min, a solution of the acid chloride (16.4
g, 60 mmol) in THF (160 mL) was added slowly. Following the addition, the reaction
was warmed to rt. After 30 min, the solvent was removed and the residue was treated
with cold (0 °C) 1.2 M HCl (150 mL). The mixture was extracted with EtOAc (3 x 250
mL). The combined organic layers were washed with brine, dried over Na SO , filtered,
and concentrated to give Intermediate 12B (20 g, 87%) as a solid. MS (ESI) m/z: 395
(M+H) .
Intermediate 12C: 1-(2-Bromochlorofluorophenyl)ethanone:
A solution of Intermediate 12B (18.6 g, 47 mmol) in AcOH (200 mL), H O (150 mL) and
H SO (2.0 mL) was stirred at 110 °C for 4 h. Most of the solvent was removed and the
residue was diluted with EtOAc (400 mL), washed with H O (5 x 20 mL), saturated
NaHCO , 1N NaOH, and brine. The solvent was removed to give Intermediate 12C (10
g, 84% yield) as a low melting solid. H NMR (400 MHz, DMSO-d ) δ 7.42 (q, J = 6.8,
6.4 Hz, 1 H), 7.24 (q, J = 6.4, 5.2 Hz, 1 H), 2.5 (s, 3H) ppm.
Intermediate 12D: (E)-tert-Butyl 3-(6-acetylchloro
fluorophenyl)acrylate: To a mixture of Intermediate 12C (50 g, 198 mmol), tert-butyl
acrylate (50.9 g, 397 mmol) and TEA (55 mL, 397 mmol) in DMF (500 mL) was added
Pd(OAc) (8.9 g, 39.7 mmol). The resulting mixture was stirred at 90 °C overnight. The
reaction was cooled to rt, filtered, and the filtrate was concentrated. Purification by
column chromatography gave Intermediate 12D (30 g, 51%) as a light yellow solid. MS
(ESI) m/z: 242.7 (M+H) .
Intermediate 12: A solution of Intermediate 12D (25 g, 84 mmol) in DCM
(330 mL) and TFA (330 mL) was stirred at rt. After 1.5 h, the solvent was concentrated
to give Intermediate 12 (19.5 g, 97%) as a white solid. H NMR (400 MHz, DMSO-d ) δ
12.69 (bs, 1 H), 7.80-7.76 (m, 2 H), 7.62 (d, J = 12.1 Hz, 1 H), 6.30 (dd, J = 2.4, 2.0 Hz,
1 H), 2.6 (s, 3H) ppm. MS (ESI) m/z: 241 (M-H) .
Intermediate 13: (E)(3-Chlorocyanofluorophenyl)acrylic acid:
CN O
Intermediate 13: 2-Bromochlorofluorobenzamide: To a solution of 2-
bromochlorofluorobenzoic acid (20 g, 0.078 mol) in DCM (200 mL) was added
thionyl chloride (14.7 g, 0.125 mol) followed by DMF (29.5 g, 0.5 moles) and the
reaction was heated to reflux for 4 h. The reaction was then cooled to 0 C and NH gas
was bubbled in until the pH was basic. After 30 min, the reaction mixture was quenched
with H O and extracted with DCM. The combined organics were washed with H O,
brine, dried over Na SO , filtered and concentrated to yield the crude product. The crude
product was finally suspended in petroleum ether and filtered to afford 16.5 g of
Intermediate 13A. MS (ESI) m/z: 250.0 (M+H) .
Intermediate 13B: 2-Bromochlorofluorobenzonitrile: To Intermediate
13A (10 g, 39 mmol) was added POCl (100 mL) and NaOH (5 g, 87 mmol) and the
reaction was heated to 110 C for 2 h. The reaction mixture was concentrated and the
residue was quenched with ice water. Extracted with EtOAc and the combined organics
were washed with 10% NaHCO , brine, dried over Na SO , filtered, and concentrated to
3 2 4
afford 8.5 g of 13B. MS (ESI) m/z: 232.9 (M+H) .
Intermediate 13C: (E)-Methyl 3-(3-chlorocyanofluorophenyl)acrylate:
Combined Intermediate 13B (7 g, 29.9 mmol), tetrabutylammonium bromide (9.6 g, 29.9
mmol), NaHCO (6.2 g, 74.8 mmol), methyl acrylate (5.2 g, 59.8 mmol) and Pd(OAc) in
DMF (50 mL). After stirring at rt for 18 h, the reaction was heated to 90 C for 4 h. The
reaction was then cooled to rt and filtered through Celite . Purification by normal phase
chromatography afforded 3.5 g of Intermediate 13C. MS (ESI) m/z: 257 (M+H O) .
Intermediate 13: To Intermediate 13C (0.5 g, 2.0 mmol) in THF (15 mL) and
MeOH (5 mL) was added 1N LiOH (5 mL, 5 mmol). After 2 h, the volatile solvents were
removed and the aqueous layer was extracted with EtOAc. The aqueous layer was
acidified and extracted with EtOAc and the combined organics were washed with H O,
brine, dried over Na SO , filtered and concentrated to afford 0.3 g of Intermediate 13.
MS (ESI) m/z: 226.2 (M+2+H) .
Intermediate 14: (E)(5-Chloro(difluoromethyl)phenyl)acrylic acid
CHF O
Intermediate 14A: 2-Bromochloro(difluoromethyl)benzene: To a
solution of 2-bromochlorobenzaldehyde (1 g, 4.56 mmol) in DCM (15 mL) was added
DAST (0.903 mL, 6.83 mmol) at 0 °C. The reaction was allowed to warm to rt and
stirred overnight. The reaction mixture was diluted with EtOAc, washed with saturated
NaHCO and brine. The organic phase was dried over MgSO , filtered and concentrated
to give Intermediate 14A (0.88 g. 80%) as a clear oil. MS (ESI) m/z: 261.2 (M+Na) .
Intermediate 14B: (E)-tert-Butyl 3-(5-chloro(difluoromethyl)phenyl)
acrylate: To a solution of Intermediate 14A (0.88 g, 3.64 mmol) in DMF (10 mL) was
added tert-butyl acrylate (1.401 g, 10.93 mmol), TEA (1.270 mL, 9.11 mmol) and
Pd(OAc) (0.082 g, 0.364 mmol). The reaction was warmed to 90 °C. After 5 h, the
reaction was cooled to rt and then filtered to remove the solid. The filtrate was diluted
with EtOAc, washed with 1M HCl, saturated NaHCO , and brine. The organic phase was
dried over MgSO , filtered and concentrated. Purification by normal phase
chromatography gave Intermediate 14B (232 mg, 22%) as a tan oil. MS (ESI) m/z:
233.1(M-tBu) .
Intermediate 14: To a solution of Intermediate 14B (232 mg, 0.804 mmol) in
DCM (2.0 mL) was added TFA (2.0 mL, 26.0 mmol). The reaction was stirred under
argon at rt. After 1 h, the solvent was removed and residue was dried to give
Intermediate 14 (191 mg, 100 %) as tan solid. H NMR (400 MHz, MeOD) δ 7.99 (dt, J
= 15.8, 1.5 Hz, 1H), 7.83 (s, 1H), 7.60 (d, J = 8.3 Hz, 1H), 7.55 - 7.48 (m, 1H), 7.01 (t, J
= 54.6 Hz, 1H), 6.51 (d, J = 15.8 Hz, 1H). 19F NMR (376 MHz, MeOD) δ -111.67 ( s,
2F) ppm. MS (ESI) m/z: 233.1(M+H) .
Intermediate 15: (E)(5-Chloro(difluoromethoxy)phenyl)acrylic acid:
F O O
Intermediate 15A (E)-tert-Butyl 3-(5-chloro(difluoromethoxy)phenyl)
acrylate: To a solution of potassium tert-butoxide (0.407 g, 3.63 mmol) in THF (10 mL)
were added tert-butyl 2-(dimethoxyphosphoryl)acetate (0.528 mL, 2.66 mmol) and 5-
chloro(difluoromethoxy)benzaldehyde (0.50 g, 2.420 mmol) at 0 °C. After 4 h, NH Cl
solution was added and the reaction mixture was diluted with EtOAc, washed with
saturated NH Cl solution, saturated NaHCO , and brine. The organic phase was dried
over Na SO , filtered and concentrated. The crude product was purified by normal phase
chromatography to yield Intermediate 15A as a white solid (550 mg, 74%). MS (ESI)
+ 19
m/z: 327.0 (M+Na) . F NMR (376 MHz, CDCl ) δ -81.11 (1 F, s) ppm.
Intermediate 15: To a solution of (E)-tert-butyl 3-(5-chloro
(difluoromethoxy) phenyl)acrylate (458 mg, 1.503 mmol) in DCM (4 mL) was added
TFA (2.0 mL, 26.0 mmol). After 1h, the solvent was removed to give Intermediate 15 as
a white solid. MS (ESI) m/z: 249.0 (M+H) .
Intermediate 16: (E)(3-chlorofluoro(trifluoromethyl)phenyl)acrylic acid
CF O
[00265] Intermediate 16 was made in a similar manner as Intermediate 15 substituting
3-chlorofluoro(trifluoromethyl)benzaldehyde for 5-chloro(difluoromethoxy)
benzaldehyde followed by TFA deprotection. MS (ESI) m/z: 292 (M+Na) . H NMR
(400 MHz, CDCl ) δ 7.87 (1 H, dd, J = 16.17, 2.02 Hz), 7.49 - 7.62 (2 H, m), 6.67 (1 H,
dd, J = 16.30, 1.39 Hz) ppm.
Intermediate 17: 1-cyclopentyl(3,4-dihydroisoquinolinyl)urea:
Intermediate 17A: 1-Cyclopentyl(isoquinolinyl)urea: To isoquinolin
amine (0.23 g, 1.595 mmol) in DCM (5 mL) was added DIEA (0.557 mL, 3.19 mmol)
and isocyanatocyclopentane (0.180 mL, 1.595 mmol). After 24 h, the reaction was
quenched with H O (15 mL) and extracted with EtOAc (3 x 30 mL). The combined
organic layers were washed with brine (10 mL) and dried (MgSO ). The impure yellow
solid was collected and was carried onto the next step. MS (ESI) m/z: 256 (M+H) .
[00267] Intermediate 17B: 1-Cyclopentyl(1,2,3,4-tetrahydroisoquinolinyl)urea:
17A was hydrogenated at 55 psi in EtOH (25mL) in the presence of PtO (30 mg). After
24 h, the reaction was filtered through Celite and filtrate concentrated to give 0.389 g of
Intermediate 17B as a white oily solid. MS (ESI) m/z: 260.1 (M+H) .
Intermediate 17: Intermediate 17B was oxidized with MnO (2.496 g, 28.7
mmol) in DCM (20 mL). After 24 h, the reaction was filtered through Celite and
concentrated to 0.34 g (83%) of brown solid. MS (ESI) m/z: 258.1 (M+H) .
Intermediate 18: tert-butyl 4-(3,4-dihydroisoquinolinyl)piperazinecarboxylate
[00269] Intermediate 18A: tert-butyl 4-(1,2,3,4-tetrahydroisoquinolinyl)piperazine-
1-carboxylate: To 5-(piperazinyl)isoquinoline, HCl (0.58 g, 2.322 mmol) and NaOH
(5.11 mL, 5.11 mmol) in dioxane (6 mL), cooled in ice bath, was added Boc O (0.539
mL, 2.322 mmol) in dioxane (6 mL). The organics were stripped and the reaction was
partitioned with H O (30mL) and EtOAc (100 mL). The organic layer was washed with
brine (15 mL) and dried (MgSO ). Collected Boc-protected compound as a yellow oil
(0.86 g) which was then hydrogenated at 55 psi with PtO in EtOH. The crude product
was then filtered through Celite and collected 0.73g (99%) of the desired product as a
off-white solid. MS (ESI) m/z: 318.1 (M+H) .
[00270] Intermediate 18: Intermediate 18A was reduced and then oxidized in a similar
manner as described for Intermediate 17. MS (ESI) m/z: 316.1 (M+H) .
Intermediate 19: 5-(4-Methylpiperazinyl)-3,4-dihydroisoquinoline:
[00271] Intermediate 19A: 5-(4-Methylpiperazinyl)isoquinoline: To 5-(piperazin
yl) isoquinoline, HCl (0.28 g, 1.121 mmol) in MeOH (10 mL) was added sodium
methoxide (1.026 mL, 4.48 mmol) and paraformaldehyde (0.040 g, 1.332 mmol). After
min, sodium borohydride (0.424 g, 11.21 mmol) was added to the above mixture. The
reaction was quenched with 1N NaOH (15 mL) and extracted with EtOAc (3 x 30 mL).
The combined organic layers were washed with brine (15 mL) and dried (MgSO ) to
afford 0.267 g of Intermediate 19A as yellow oil. MS (ESI) m/z: 228.1 (M+H) .
Intermediate 19: Intermediate 19A was reduced and then oxidized in a similar
manner as described for Intermediate 17. MS (ESI) m/z: 230.0 (M+H) .
Intermediate 20: Ethyl 3-(4-(3,4-dihydroisoquinolinyl)piperazinecarboxamido)
propanoate:
20A: Ethyl 3-(4-(isoquinolinyl)piperazinecarboxamido)propanoate: To
-(piperazinyl)isoquinoline, HCl (0.216 g, 0.865 mmol) in DCM (5 mL) was added
DIEA (0.302 mL, 1.730 mmol) and ethyl 3-isocyanatopropanoate (0.124 g, 0.865 mmol).
The reaction was quenched with H O (10 mL) and extracted with DCM (3 x 20 mL). The
combined organic layers were washed with brine (10 mL) and dried (MgSO ) which
afforded Intermediate 20A as a white solid (0.39 g). MS (ESI) m/z: 357.0 (M+H) .
Intermediate 20: Intermediate 20A was reduced and then oxidized in a similar
manner as described for Intermediate 18. MS (ESI) m/z: 359.0 (M+H) .
Intermediate 21: tert-butyl 4-(3,4-dihydroisoquinolinyl)oxopiperazine
carboxylate:
Intermediate 21A: tert-Butyl 4-(isoquinolinyl)oxopiperazine
carboxylate: To 5-bromoisoquinoline (0.3 g, 1.442 mmol) and tert-butyl 3-oxopiperazine-
1-carboxylate (0.289 g, 1.442 mmol) was added DMSO (4 mL), 1,10-phenanthroline
(0.026 g, 0.144 mmol) and K CO (0.498 g, 3.60 mmol). The mixture was degassed for
min and then was added CuI (0.055 g, 0.288 mmol). The reaction was heated in a
sealed tube in oil bath at 130 °C. After 24 h, the reaction was incomplete. After cooling
and degassing with argon, more CuI was added and heating was repeated. After 24 h, the
reaction was quenched with dilute NH OH (15 mL) and extracted with EtOAc (3 x 30
mL). The combined organic layers were washed with brine (15 mL) and dried (MgSO ).
The crude product was purified by normal phase chromatography followed by HPLC.
After partitioning with saturated NaHCO (15 mL) and EtOAc (50 mL), organic layer
was washed with brine and dried (MgSO ) to afford 0.157 g (54%) of Intermediate 21A
as a white solid. MS (ESI) m/z: 328 (M+H) .
Intermediate 21 was prepared from Intermediate 21A as described for
Intermediate 18. MS (ESI) m/z: 330.1 (M+H) .
Intermediate 22: 1-(3,4-dihydroisoquinolinyl)methylpiperazinone:
Intermediate 22 was prepared in a similar manner as Intermediate 21
substituting 4-methylpiperazinone for tert-butyl 3-oxopiperazinecarboxylate. MS
(ESI) m/z: 244.1 (M+H) .
Intermediate 23: 4-(3,4-dihydroisoquinolinyl)morpholinone:
Intermediate 23 was prepared in the same manner as Intermediate 22
substituting morpholinone for tert-butyl 3-oxopiperazinecarboxylate. MS (ESI)
m/z: 231.1 (M+H) .
Intermediate 24: 5-Bromo-3,3-dimethyl-1,2,3,4-tetrahydroisoquinoline:
[00279] Intermediate 24A: 3-(2-Bromophenyl)-2,2-dimethylpropanenitrile: To a
solution of isobutyronitrile (3.58 g, 52 mmol) in dry THF (30 mL) was added LiHMDS
(1.0 M in THF) (80 mL, 80 mmol) at 0 C, stirred for 20 min, and to this solution was
added 1-bromo(bromomethyl)benzene (10 g, 40 mmol) in dry THF (70 mL). After 3 h
at rt, the reaction mixture was quenched with saturated NH Cl solution, extracted with
EtOAc (2 x), the combined organics were washed with H O, brine, dried over Na SO ,
2 2 4
filtered and concentrated to give 9.5 g (99%) of Intermediate 24A as red wine liquid. H
NMR (400 MHz, CDCl ) δ 7.57-7.60 (2 H, m), 7.30-7.34 (1 H, m), 7.12-7.17 (1 H, m),
3.08 (2 H, s), 1.4 (6 H, s) ppm.
Intermediate 24B: 3-(2-Bromophenyl)-2,2-dimethylpropanoic acid: To a
solution of 24A (19 g, 79.83 mmol) in ethylene glycol (100 mL) was added potassium
hydroxide pellets (20 g, 359.24 mmol) and the reaction was heated at 150 C for 48 h.
The reaction mixture was cooled, diluted with H O and the aqueous layer was washed
with EtOAc (2 x). The aqueous layer was acidified with 1.5 N HCl, extracted with
EtOAc (2 x) and the combined organics were washed with H O, brine, dried over
Na SO , filtered and concentrated. The crude product was then purified by silica gel
column chromatography to give 18.0 g, (87.8%) of Intermediate 24B as a white solid.
MS (ESI) m/z: 257 (M+H) .
Intermediate 24C: 1-Bromo(2-isocyanatomethylpropyl)benzene: To a
solution of Intermediate 24B (9.0 g, 35.0 mmol) in toluene (80 mL) at 0 C, was added
TEA (4.7 mL, 33.2 mmol) and, slowly, diphenylphosphoryl azide (9.17 g, 33.2 mmol).
After 45 min at 0 C, the reaction was heated to reflux for 4 h. The reaction mixture was
cooled to rt, quenched with H O, and extracted with EtOAc (2 x). The combined
organics were washed with saturated NaHCO solution, H O, brine, dried over Na SO ,
3 2 2 4
filtered and concentrated to give 8.0 g of Intermediate 24C as colorless liquid. H NMR
(400 MHz, CDCl ) δ 7.37-7.59 (2 H, m), 7.30 (1 H, m), 7.14 (1 H, m), 3.03 (2 H, s), 1.41
(6 H, s) ppm.
Intermediate 24D: Methyl 1-(2-bromophenyl)methylpropan
ylcarbamate: To a stirred solution of Intermediate 24C (8.0 g, 31.5 mmol) in dry THF (80
mL) at 0 C, was added MeOH (5.0 mL, 157.5 mmol) and, slowly, NaH (60% in oil) (3.8
g, 94.5 mmol). After 3 h at rt, the reaction was quenched with ice cold water and
extracted with EtOAc twice. The combined organics were washed with H O, brine, dried
over Na SO , filtered and concentrated to give Intermediate 24D (8.5 g, 94.5%) as white
solid. MS (ESI) m/z: 286.0 (M+H) .
Intermediate 24E: Methyl 5-bromo-3,3-dimethyl-3,4-dihydroisoquinoline-
2(1H)-carboxylate: To a solution of 24D (5.0 g, 17.5 mmol) in AcOH/H SO (3:1; 15 + 5
mL) at 0 C was, slowly, added paraformaldehyde (0.524 g, 17.5 mmol). After 48 h at rt,
the reaction mixture was quenched with H O, extracted with EtOAc (2 x). The combined
organics were washed with saturated NaHCO solution, H O, brine, dried over Na SO ,
3 2 2 4
filtered and concentrated to give 4.6 g of Intermediate 24E as a brown liquid. MS (ESI)
m/z: 300.0 (M+H) .
Intermediate 24: 5-Bromo-3,3-dimethyl-1,2,3,4-tetrahydroisoquinoline: To a
solution of Intermediate 24E (4.6 g) in ethylene glycol (50 mL) was added 50% aqueous
KOH solution (23 mL) and the reaction was heated at 150 C for 3 days. The reaction
mixture was cooled, diluted with H O, extracted with EtOAc twice. The combined
organics were extracted with 1.5 N HCl solution, the aqueous layer was basified with
% NaOH solution, extracted with EtOAc twice and the combined organics were
washed with H O, brine, dried over Na SO , filtered and concentrated to give
2 2 4
Intermediate 24 (1.5 g, 39.4%) as a brown liquid. MS (ESI) m/z: 242.2 (M+H) .
Example 1: (E)(2-(3-(5-chloro(1H-tetrazolyl)phenyl)acryloyl)(piperazin
yl)-1,2,3,4-tetrahydroisoquinolinecarboxamido)benzoic acid, TFA
O OH
A mixture of Intermediate 18 (0.1 g, 0.317 mmol), Intermediate 6 (0.064 g,
0.317 mmol) and Intermediate 2 (0.079 g, 0.317 mmol) were heated in EtOH (3mL) to
reflux for 24 h. The reaction mixture was then cooled to rt and concentrated, followed by
treatment with TFA/DCM to give the desired product as a yellow solid (0.018 g, 7.5 %).
H NMR (400 MHz, DMSO-d ) δ 12.64 (1 H, br. s.), 10.68 (1 H, s), 9.79 (1 H, s), 8.60 (2
H, br. s.), 8.32 (1 H, d, J = 2.02 Hz), 7.75 - 7.89 (2 H, m), 7.63 - 7.71 (2 H, m), 7.60 (1
H, d, J = 8.84 Hz), 7.43 (1 H, d, J = 15.41 Hz), 7.32 (1 H, d, J = 7.58 Hz), 7.20 (1 H, t, J
= 7.83 Hz), 6.97 (1 H, d, J = 8.08 Hz), 6.91 (1 H, d, J = 15.41 Hz), 5.72 (1 H, s), 4.23 (1
H, d, J = 5.56 Hz), 3.60 - 3.70 (1 H, m), 3.21 (4 H, br. s.), 2.85 - 3.11 (6 H, m) ppm. MS
(ESI) m/z: 613.1 (M+H) . Analytical HPLC: RT = 5.54 min.
The following examples in Table 2 were made by the Ugi reaction as
described in Example 1, using Intermediate 1, Intermediate 2 or Intermediate 3A; the
corresponding imine intermediates, made in a similar manner as Intermediate 18, from
commercially available piperazines and 5-bromoisoquinoline; and the appropriate
isocyano benzoate intermediates.
N N R"
Table 2
Example # R R’ R” M+H RT
2 H Piperazine 587.0 5.54
3 F Piperazine 631.0 5.62
COOH
4 F Piperazine 660.1 5.40
NHCOOCH
F Piperazine 605.1 6.06
6 F Piperazine 612.1 5.88
7 F Piperazine 687.2 7.08
COOtBu
8 F Piperazine 587.3 5.93
9 F Piperazine 6-indazoleCBz 761.2 6.63
F Boc- 6-indazoletBoc 827.1 12.14
piperazine
11 F Piperazine 6-indazole 627.2 5.51
The following examples in Table 3 were obtained from HPLC chiral
separation of corresponding examples, or their intermediates followed by deprotection, in
Table 2.
N N R'
Table 3
Example # Stereochem R R’ M+H RT
12 R enantiomer 2-F 631.1 5.16
COOH
13 S enantiomer 2-F 631.1 5.16
COOH
14 S enantiomer 4-F 6-indazole 627.1 5.75
R enantiomer 4-F 6-indazole 627.1 5.70
16 R enantiomer 4-F 631.0 5.30
COOH
17 S enantiomer 4-F 630.9 5.27
COOH
a: Chiral HPLC Methods: a: Chiralcel OJ-H, 250 X 21 mm ID, 5 μm using 25/25/50
MeOH-IPA-Heptane-0.1% DEA, then 50/50 EtOH-IPA-0.1% DEA at 18 mL/min.
b: Chiracel OD 5 cm x 50 cm column and 20% Heptane/ 80% (1:1 EtOH/MeOH) at 50
mL/min.
c: Chiralpak AS-H, 2 X 15 cm using 30% IPA-0.1% DEA/CO (100 bar) at 60 mL/min.
The following examples in Table 4 were made by the Ugi reaction, as shown
in Example 1, using the corresponding imine intermediate such as Intermediates 18, 19 or
or an imine made in a similar manner as Intermediate 20 by substituting methyl
chloroformate for ethyl 3-isocyanatopropanoate. The acids, Intermediates 1, 2 or 3A and
the isonitriles, Intermediates 6, 7, 8, 9, 10, 11 or commercially available 1-fluoro
isocyanobenzene were used as required. Final deprotection of the t-butyl esters or
carbamates with TFA/DCM yielded the final desired products as described previously.
N N R'
Table 4
Example # R R’ R” M+H RT
18 F PhCOOH CH 645.1 5.24
19 H PhNHCOO CH CH 656.1 5.8
F PhCN CH 626.2 5.10*
21 H PhCOOH 756.1 7.87
22 H PhCOOH CH3OOC- 671.1 8.49
23 H PhNHCOO CH 785.1 8.20
24 F PhNHCOO CH CH OOC- 660.1 5.43
F PhF CH OOC- 663.4 9.50
26 F PhCN CH OOC- 670.1 9.93
27 F 6-indazole CH 641.2 6.21
*method B
The examples in Table 5 were made in a similar manner as Example 18 (Table
4) and separated by chiral HPLC.
Table 5
Example # R’ Stereochemistry M+H RT
28 COOEt R-enatiomer 673.3 6.47
29 COOEt S-enatiomer 673.3 6.46
COOH R-enatiomer 645.3 5.20
31 COOH S-enatiomer 645.3 5.20
a: Chiralpak IA SFC (250x21mm) using 40% EtOH-0.1% DEA/ 60% CO at 60 mL/min,
150 bar, 35 C.
Example 32:
(E)(2-(3-(2-(Aminomethyl)chlorophenyl)acryloyl)(piperazinyl)-1,2,3,4-
tetrahydroisoquinolinecarboxamido)benzoic acid, tri TFA salt:
H N N
O OH
Example 32 was prepared in a similar manner as Example 1, using
Intermediate (E)(2-((tert-butoxycarbonylamino)methyl)chlorophenyl)acrylic acid
in the Ugi reaction. H NMR (400 MHz, MeOD) δ 7.98 (3 H, d, J = 8.84 Hz), 7.87 (1 H,
d, J = 15.41 Hz), 7.69 (2 H, d, J = 8.84 Hz), 7.48 - 7.58 (2 H, m), 7.29 - 7.45 (3 H, m),
7.16 (1 H, d, J = 7.83 Hz), 5.86 (1 H, s), 4.38 - 4.47 (1 H, m), 4.30 (2 H, s), 3.66 - 3.77 (1
H, m), 3.38 - 3.52 (4 H, m), 3.23 - 3.29 (4 H, m), 3.15 (2 H, d, J = 177 Hz) ppm. MS
(ESI) m/z: 574.1 (M+H) . Analytical HPLC: RT = 3.55 min.
Example 33:
(E)(2-(3-(5-Chloro(1H-tetrazolyl)phenyl)acryloyl)(2-oxopiperidinyl)-
1,2,3,4-tetrahydroisoquinolinecarboxamido)benzoic acid:
O OH
33A: 1-(Isoquinolinyl)piperidinone: To isoquinolinamine (0.24 g,
1.665 mmol) in THF (5 mL) was added 5-bromopentanoyl chloride (0.223 mL, 1.665
mmol) followed by addition of THF (3 mL). The reaction was cooled with ice bath and
to the above solution was added 1M KOtBu in THF (3.66 mL, 3.66 mmol). After 24 h,
the reaction was quenched with H O (10 mL) and extracted with EtOAc (3 x 20 mL).
The combined organic layers were washed with brine (10 mL) and dried (MgSO ) to
afford 0.4 g of 33A as a dark solid. MS (ESI) m/z: 227 (M+H) .
33B: 1-(1,2,3,4-Tetrahydroisoquinolinyl)piperidinone: 33A was
hydrogenated at 55 psi in EtOH (20 mL) in the presence of PtO (30 mg). After 24 h, the
reaction was filtered through Celite and concentrated to afford 0.4 g of dark oil as
desired product. MS (ESI) m/z: 231.3 (M+H) .
33C: 1-(3,4-Dihydroisoquinolinyl)piperidinone: 33B (0.38 g, 1.650
mmol) was oxidized with MnO to afford 0.36 g of 33C as a dark oil. MS (ESI) m/z:
229.0 (M+H) .
Example 33 was made by the Ugi reaction combining 33C and Intermediates 2
and 6 as previously described for Example 1 followed by TFA deprotection. H NMR
(400 MHz, MeOD) δ 9.54 (1 H, s), 8.17 (1 H, t, J = 2.78 Hz), 7.90 - 8.03 (2 H, m), 7.61 -
7.73 (3 H, m), 7.56 - 7.60 (1 H, m), 7.52 (1 H, d, J = 7.83 Hz), 7.29 - 7.44 (2 H, m), 7.14
- 7.27 (2 H, m), 5.87 - 5.94 (1 H, m), 4.19 - 4.32 (1 H, m), 3.82 - 3.98 (1 H, m), 3.63 -
3.73 (1 H, m), 3.45 - 3.54 (1 H, m), 2.98 - 3.11 (1 H, m), 2.76 - 2.89 (1 H, m), 2.50 - 2.62
(2 H, m), 2.02 (4 H, br. s) ppm. MS (ESI) m/z: 626.0 (M+H) . Analytical HPLC: RT =
7.46 min.
The following examples in Table 6 were made by Ugi reaction as described in
Example 1 using intermediate 33C and intermediates 1, 2, 3, 5 and 12 as appropriate.
Deprotection with TFA/DCM was carried out where necessary. Single enantiomers were
isolated by chiral HPLC.
O R"
TABLE 6
Example # Stereochemistry R R’ R” M+H RT
34 Racemic tetrazole 2-F COOH 644.1 7.50
S-enantiomer tetrazole 2-F COOH 644.1 7.62
36 R-enantiomer tetrazole 2-F COOH 644.1 7.69
37 S-enantiomer tetrazole 2-F COOtBu 700.1 10.65
38 Racemic -COMe 2-F COOH 618.0 8.10
39 R-enantiomer -COMe 2-F COOH 618.0 5.68
40 S-enantiomer -COMe 2-F COOH 618.0 5.68
41 R-enantiomer tetrazole 4-F COOH 643.9 7.75
42 S-enantiomer tetrazole 4-F COOH 643.9 7.76
43 Racemic tetrazole 2-F COOEt 672.3 9.35
44 R-enantiomer tetrazole 2-F COOEt 672.3 9.02
45 S-enantiomer tetrazole 2-F COOEt 672.3 9.06
a: Chiral HPLC using Chiralcel OD 5x50 cm using 20% heptane and 80%
(1:1MeOH/EtOH) at 50 mL/min.
b: Chiralpak IA SFC, 150 X 30 mm using 55% EtOH-0.1% DEA/45% CO at 70
mL/min, 100 Bar, 35 C.
c: Chiralpak AD-H, 250 X 21 mm 30 mm using 45% (4:1 IPA-EtOH-0.1%DEA+3%
H O)/55% CO at 60 mL/min, 100 Bar, 35 C.
The following examples in Table 7 were made by Ugi reaction as described in
Example 1 using imine intermediates 19, 21, 22 or 23 and intermediates 6, 7, 8, 9, 10 or
11 as appropriate. Deprotection with TFA/DCM was carried out where necessary.
Single enantiomers were isolated by chiral HPLC at a protected late stage intermediate
and then, deprotected where indicated.
N N R'
Table 7
Example # Stereochemistry R R’ M+H RT
46 Racemic PhCOOH 646.0 7.04
47 Racemic 642.6 7.15
48 R-enantiomer PhCOOH 646.0 7.15
49 S-enantiomer PhCOOH 646.0 7.15
50 S-enantiomer PhCOOtBu 701.9 9.90
51 Racemic PhCOOEt 674.0 8.61
52 Racemic PhCOOH 779.1 8.76
HN H
53 Racemic 655.2 5.28
54 Racemic PhCOOH 645.0 5.20
Boc-N
55 Racemic PhCOOtBu 801.5 11.25
Boc-N
56 Racemic PhCOOEt 773.5 10.3
57 Racemic PhCOOtBu 715.3 6.82
58 Racemic PhNHCOOCH 661.0 9.33
59 Racemic PhCOOtBu 688.3 10.8
60 Racemic 4-PhCOOH 632.2 8.40
61 R-enantiomer 4-PhCOOH 632.3 8.44
62 S-enantiomer 4-PhCOOH 632.3 8.44
63 Racemic PhCOOEt 660.3 10.6
64 Diastereomer 4-PhCOOH 643.2 5.49
a: Chiracel OD 5 x 50 cm using 20% Heptane/80% 1:1 EtOH/MeOH at 50 mL/min.
b: Chiralpak 250x21mm, using AD-H using 45% (1:1EtOH-IPA-0.1%DEA)/55% CO at
60 mL/min, 100 bar, 35 C.
Example 65:
(E)(2-(3-(5-chlorofluoro(1H-tetrazolyl)phenyl)acryloyl)(piperazinyl)-
1,2,3,4-tetrahydroisoquinolinecarboxamido)benzoic acid, bis TFA Salt
Example 65 was prepared in a similar manner as Example 1 substituting
Intermediate 5 for Intermediate 2. H NMR (500 MHz, MeOD) δ 10.22 - 10.48 (1 H, m),
9.37 - 9.51 (1 H, m), 8.11 - 8.28 (1 H, m), 7.75 - 7.96 (2 H, m), 7.45 - 7.66 (2 H, m), 7.15
- 7.34 (2 H, m), 6.97 - 7.18 (3 H, m), 5.63 - 5.75 (1 H, m), 4.09 - 4.32 (2 H, m), 3.48 -
3.61 (2 H, m), 3.24 - 3.43 (4 H, m), 2.97 - 3.19 (4 H, m) ppm. MS (ESI) m/z: 631
(M+H) . Analytical HPLC: RT = 5.55 min.
Example 66:
(E)-N-(4-carbamoylphenyl)(3-(5-chlorofluoro(1H-tetrazol
yl)phenyl)acryloyl)(piperazinyl)-1,2,3,4-tetrahydroisoquinolinecarboxamide,
bis-TFA Salt:
O NH
66A: (E)-tert-butyl 4-(1-(4-carbamoylphenylcarbamoyl)(3-(5-chloro
fluoro(1H-tetrazolyl)phenyl)acryloyl)-1,2,3,4-tetrahydroisoquinolin
yl)piperazinecarboxylate: To Boc-protected Compound 65 (piperazine as Boc
protected) (0.2 g, 0.274 mmol) in DMF (2 mL) was added ammonium chloride (0.022 g,
0.410 mmol), PyBOP (0.142 g, 0.274 mmol) and DIEA (0.072 mL, 0.410 mmol). After
24 h, the reaction was partitioned with H O (15 mL) and EtOAc (40 mL). The organic
layer was washed with H O (2 x 10 mL), 10% LiCl (10 mL), brine (10 mL) and dried
(MgSO ). MS (ESI) m/z: 730.0 (M+H) .
Example 66: 66A was deprotected with 30% TFA/DCM (10 mL). After 2 h,
the reaction was concentrated and purified by reverse phase HPLC and freeze-dried to
afford 4.6 mg (1.8%) of example 66 as a tan solid. H NMR (400 MHz, MeOD) δ 9.46 (1
H, s), 8.14 - 8.26 (1 H, m), 7.72 (2 H, d, J = 8.84 Hz), 7.49 - 7.63 (4 H, m), 7.17 - 7.30 (2
H, m), 7.00 - 7.14 (2 H, m), 5.69 (1 H, s), 4.14 - 4.28 (1 H, m), 3.50 - 3.67 (1 H, m), 3.27
- 3.42 (4 H, m), 2.99 - 3.17 (6 H, m) ppm. MS (ESI) m/z: 630.0 (M+H) . Analytical
HPLC: RT = 5.26 min.
The examples in Table 8 were prepared in a similar manner as Example 66
using the appropriate amines in place of ammonium chloride.
Table 8
Example # R M+H RT
67 Cyclopropanamine 670.07 1.87*
68 2-(1H-imidazolyl)ethanamine 724.13 1.66*
69 Aniline 706.11 2.25*
70 N-(4-aminophenyl)acetamide 763.26 1.88*
71 Ethyl 658.11 1.85*
72 N-(2-aminoethyl)acetamide 715.23 1.67*
73 3-aminopropanamide 701.14 1.64*
74 methyl 2-aminoacetate 702.12 1.83*
75 3-methoxyaniline 736.20 2.30*
76 Dimethylamine 658.1 5.52
77 Methylamine 643.9 5.38
* Column used: Supelco Ascentis Express 4.6 x 50mm 2.7uM C18. Mobile Phase:
A = 5:95 Acetonitrile:H O; B = 95:5 Acetrile:H O; Modifier = 0.05% TFA
Wavelength: 220 nm. The remaining samples used method A.
Example 78:
(E)(2-(3-(3-chlorofluoro(1H-tetrazolyl)phenyl)acryloyl)-3,3-dimethyl
(piperazinyl)-1,2,3,4-tetrahydroisoquinolinecarboxamido)benzoic acid, bis-TFA
Salt:
78A: Benzyl 5-bromo-3,3-dimethyl-3,4-dihydroisoquinoline-2(1H)-
carboxylate: To intermediate 24 (900 mg, 3.75 mmol) in dry THF (9 mL), at 0 C, was
added 10% aqueous NaOH (5.4 mL) followed by drop-wise addition of benzyl
chloroformate (0.6 mL, 4.12 mmol). After 48 h, the reaction was quenched with ice cold
H O, extracted with EtOAc (2 x), the combined organics were washed with H O, brine,
dried over Na SO and concentrated. Purification by silica gel column chromatography
afforded 78A (0.6 g, 42.8%) as a white liquid. MS (ESI) m/z: 347.0 (M+H) .
78B: Benzyl 5-(4-(tert-butoxycarbonyl)piperazinyl)-3,3-dimethyl-3,4-
dihydroisoquinoline-2(1H)-carboxylate: To 78A (600 mg, 1.60 mmol) in toluene (5 mL)
was added NaOtBu (215 mg, 2.24 mmol), tert-butyl piperazinecarboxylate (358 mg,
1.92 mmol), Pd (dba) (3.6 mg, 0.004 mmol) and BINAP (7.4 mg, 0.012 mmol). The
reaction mixture was heated at 100 C in a sealed tube. After 18 h, the reaction was
cooled to rt, quenched with H O, extracted with EtOAc twice, the combined organics
were washed with H O, brine, dried over anhydrous Na SO , filtered and concentrated.
2 2 4
Purification by silica gel column chromatography afforded 78B (500 mg, 67%) as a green
liquid. MS (ESI) m/z: 480.4 (M+H) .
78C: tert-Butyl(3,3-dimethyl-1,2,3,4-tetrahydroisoquinolin
yl)piperazinecarboxylate: To 78B (340 mg) in EtOH (4 mL) was added 10% Pd/C (68
mg, 20 vol) and the reaction was hydrogenated under 14 psi of H . After 3 h, the reaction
was filtered through Celite and washed twice with MeOH. The combined organics were
evaporated to afford 78C (170 mg, 69.6%) as a white solid. MS (ESI) m/z: 346.2
(M+H) .
78D: tert-Butyl(3,3-dimethyl-3,4-dihydroisoquinolinyl)piperazine
carboxylate: To a solution of 78C (170 mg, 0.49 mmol) in EtOH (2 mL) was added
iodine (281 mg, 2.21 mmol) and NaOAc (60 mg, 0.73 mmol) and the reaction mixture
was heated to 80 C. After 3 h, the solvent was evaporated and the residue was quenched
with 10% sodium thiosulphate solution and extracted twice with EtOAc and the
combined organics were washed with H O. The organic layer was extracted with 2 mL
of 0.5 N HCl solution and the combined aqueous layers were basified with ammonia
solution and extracted with EtOAc twice. The combined organics were washed with
H O, brine and dried over Na SO , filtered and concentrated to give 78D (90 mg, 53.2%).
2 2 4
MS (ESI) m/z: 344.2 (M+H) .
Example 78 was prepared in an Ugi reaction in a similar manner as Example 1
using 78D, Intermediate 3, and Intermediate 6 followed by TFA deprotection and HPLC
purification. H NMR (400 MHz, DMSO-d ) δ 12.77 (1 H, s), 10.48 (1 H, s), 9.86 (1 H,
s), 8.63 (2 H, bs), 7.88-7.97 (3 H, m), 7.66 (3 H, d, J = 8.8 Hz), 7.53 (1 H, d, J = 7.6 Hz),
7.29 (1 H, t, J = 8.0 Hz), 7.07-7.11 (3.0 H, m), 5.74 (1 H, bs), 3.20- 3.23 (2 H, m), 3.06-
3.10 (2 H, m), 2.94 (3 H, bs), 1.81 (3 H, s), 1.11 (3 H, s) ppm. LCMS m/z: 659.4
(M+H) . Analytical HPLC: RT = 7.62 min.
Example 79:
(E)(2-(3-(6-acetylchlorofluorophenyl)acryloyl)(4-methylpiperazinyl)-
1,2,3,4-tetrahydroisoquinolinecarboxamido)benzoic acid, bis-TFA Salt
Example 79 was prepared in a similar manner as Example 1 using
Intermediate 19, Intermediate 6 and Intermediate 12 followed by TFA deprotection. H
NMR (500 MHz, DMSO-d ) δ 10.83 (1 H, s), 9.51 - 9.65 (1 H, m), 7.88 (2 H, d, J = 8.80
Hz), 7.73 - 7.79 (1 H, m), 7.70 (2 H, d, J = 8.80 Hz), 7.56 (1 H, d, J = 15.68 Hz), 7.44 (1
H, d, J = 7.70 Hz), 7.28 (1 H, t, J = 7.84 Hz), 7.03 - 7.12 (2 H, m), 5.85 (1 H, s), 4.21 (1
H, ddd, J = 12.04, 5.16, 4.81 Hz), 3.59 - 3.67 (1 H, m), 3.47 - 3.56 (2 H, m), 3.18 - 3.31
(5 H, m), 3.09 - 3.17 (1 H, m), 2.99 - 3.05 (2 H, m), 2.85 - 2.93 (4 H, m), 2.59 (3 H, s)
ppm. MS (ESI) m/z: 619 (M+H) . Analytical HPLC: RT = 5.0 min.
Example 80:
(E)(2-(3-(3-Chlorofluoro(1H-tetrazolyl)phenyl)acryloyl)(4-(pyrrolidin
yl)piperidinyl)-1,2,3,4-tetrahydroisoquinolinecarboxamido)benzoic acid, bis TFA
Salt
O OH
80A: 5-(4-(Pyrrolidinyl)piperidinyl)isoquinoline: To 5-
bromoisoquinoline (1 g, 4.81 mmol), 4-(pyrrolidinyl)piperidine (1.112 g, 7.21 mmol),
and sodium tert-butoxide (0.647 g, 6.73 mmol), was added toluene (10 mL) and the
mixture was degassed with argon. BINAP (0.090 g, 0.144 mmol) and Pd (dba) (0.044 g,
0.048 mmol) were added and the reaction was heated to 130 °C in a microwave for 20
min. Purification by normal phase chromatography afforded 0.84g (62.7%) of 80A as a
tan solid. MS (ESI) m/z: 282.1 (M+H) .
80B: 5-(4-(Pyrrolidinyl)piperidinyl)-3,4-dihydroisoquinoline: 80A was
hydrogenated in the presence of PtO and then oxidized with MnO to afford 0.85g
(62.8%) of 80B as a yellow oil. MS (ESI) m/z: 284.2 (M+H) .
Example 80 was prepared by the Ugi reaction as in Example 1 using 80B and
Intermediates 3A and 6 followed by TFA deprotection. H NMR (400 MHz, MeOD) δ
9.56 (1 H, s), 7.95 (2 H, d, J = 8.59 Hz), 7.72 - 7.85 (1 H, m), 7.64 (2 H, dd, J = 8.72,
1.39 Hz), 7.49 (1 H, dd, J = 8.72, 1.39 Hz), 7.23 - 7.42 (2 H, m), 7.14 - 7.23 (1 H, m),
7.07 (1 H, d, J = 7.58 Hz), 6.91 - 7.05 (1 H, m), 5.76 (1 H, s), 4.12 (1 H, ddd, J = 11.75,
4.67, 4.55 Hz), 3.72 (2 H, br. s.), 3.41 - 3.57 (1 H, m), 3.07 - 3.32 (7 H, m), 2.90 (1 H, t,
J = 11.24 Hz), 2.57 - 2.71 (1 H, m), 2.14 - 2.38 (4 H, m), 1.83 - 2.11 (4 H, m) ppm. MS
(ESI) m/z: 699.4 (M+H) . Analytical HPLC: RT = 5.51 min.
The following examples in Table 9 were prepared in a similar manner as
Example 80 starting with the appropriate substituted piperidine and isonitriles
(Intermediates 6, 7, 8, 9, 10 or 11 or commercial). Chiral separation was carried out
using chiral HPLC on late stage intermediates followed by deprotection and purification
where indicated.
N N R'
Table 9
Example # stereochemistry R R’ M+H RT
81 Racemic PhCOOH 630.3 7.46
82 Racemic Ph-F 673.4 6.83
83 Racemic PhCOOEt 727.4 6.70
84 Racemic PhCOOtBu 755.4 8.73
85 Racemic 4-PhCN 680.4 6.47
86 S-enantiomer Ph-F 673.5 6.69
87 S-enantiomer PhCOOH 699.4 5.90
88 R-enantiomer PhCOOH 699.4 5.91
89 Racemic PhNHCOOCH 728.5 6.10
90 R-enantiomer Ph-F 673.5 6.85
91 Racemic PhCOOtBu 729.5 7.28
92 Racemic PhCOOH 673.5 5.65
93 R-enantiomer Ph-COOEt 727.6 6.88
94 S-enantiomer Ph-COOEt 727.6 6.85
95 Racemic PhCOOH 706.3 9.61
96 Racemic PhCOOH 713.3 7.45
97 Racemic PhCOOH 645.4 5.19
98 R-enantiomer PhNHCOOCH3 728.6 5.84
99 S-enantiomer PhNHCOOCH 728.6 5.89
100 Racemic PhCOOH 701.2 7.20
101 S-enantiomer PhCOOH 701.2 7.26
102 R-enantiomer PhCOOH 673.5 5.39
103 S-enantiomer PhCOOH 673.5 5.37
104 Racemic Ph-Cl 689.5 6.94
105 Racemic PhCOOnBu 755.6 7.65
106 Racemic PhCOOH 713.5 7.02
107 R-enantiomer PhCOOH 713.5 6.98
108 S-enantiomer PhCOOH 713.5 6.97
109 Racemic PhCOOEt 741.6 8.45
110 S-enantiomer PhCOOEt 741.3 9.20
111 R-enantiomer Ph-Cl 689.5 7.36
112 S-enantiomer Ph-Cl 689.5 6.95
113 R-enantiomer PhCOOnBu 755.6 8.03
114 S-enantiomer PhCOOnBu 755.7 8.05
115 Racemic PhCOOH 713.5 6.70
116 Racemic PhCOOH 672.5 9.62
117 Racemic 4-PhCOOH 658.5 9.21
118 R-enantiomer PhCOOH 713.5 7.27
119 S-enantiomer PhCOOH 713.5 7.82
120 Racemic 709.3 5.76
121 Racemic PhCOOH 789.6 8.55
122 Racemic PhCOOiPr 741.6 7.26
123 Racemic PhCOOiBu 755.6 7.69
124 Racemic 767.6 7.61
125 R-enantiomer Ph-COOEt 741.5 9.13
126 S-enantiomer Ph-COOEt 741.5 9.09
127 Racemic 709.6 7.01
128 R-enantiomer PhCOOEt 701.5 7.45
129 S-enantiomer PhCOOEt 701.5 7.45
130 Racemic PhCOOH 727.5 8.86
131 Racemic PhCOOH 727.5 8.37
132 R-enantiomer PhCOOH 727.6 7.08
133 S-enantiomer PhCOOH 727.6 10.69
134 Racemic PhCOOEt 755.5 8.56
135 S-enantiomer PhCOOEt 755.3 9.3
136 Racemic PhCOOH 702.0 13.02
137 Racemic PhCOOH 688.3 10.47
138 Racemic PhCOOH 715.3 6.19
139 S-enantiomer PhCOOH 715.4 6.20
140 Racemic PhCOOH 743.3 6.75
141 S-enantiomer PhCOOH 743.3 7.24
142 Racemic PhCOOH 688.4 10.36
143 S-enantiomer PhCOOH 688.2 9.33
144 S-enantiomer PhCOOMe 702.3 2.18*
145 Racemic PhCOOH 700.2 8.75
146 Racemic HN PhCOOH 699.4 5.61
147 Racemic PhCOOH 655.3 9.54
148 Racemic PhCOOH 646.3 6.94
149 S-enantiomer PhCOOH 646.2 7.38
150 Racemic PhCOOH 660.3 9.37
151 S-enantiomer PhCOOH 660.3 8.45
152 Racemic PhCOOH 741.4 7.89
a: Chiralpak AD-H, 250 X 21 mm ID, 5µm, using 55/45 CO /(1:1) EtOH-IPA-0.1% DEA
at 60 mL/min, 150 bar BP, 40 C.
b: Chiralpak AD-H, 250 X 21 mm ID, 5µm, using 50/50 CO /(1:1) EtOH-IPA-0.1% DEA
at 90 mL/min, 150 bar BP, 40 C.
c: Chiralpak AD-H, 250 X 21 mm ID, 5µm, using 40/60 CO /(1:1) EtOH-IPA-0.1% DEA
at 60 mL/min, 125 bar BP, 40 C.
d: Chiralpak AD-H, 150 X 20 mm ID, 5µm, using 50/50 CO /IPA-0.1% DEA
at 55 mL/min, 150 bar BP, 35 C.
e: Chiralpak AS-H, 150 X 20 mm ID, 5µm, using 60/40 CO /MeOH-0.1% DEA
at 60 mL/min, 100 bar BP, 35 C.
f: Chiralpak AD-H, 250 X 30 mm ID, 5µm, using 50/50 CO /(1:1) EtOH-0.1% DEA
at 100 mL/min, 150 bar BP, 40 C.
g: Chiralpak AD-H, 150 X 21 mm ID, 5µm, using 55/45 CO /(1:1) EtOH-IPA-0.1% DEA
at 45 mL/min, 150 bar BP, 40 C.
h: Chiralpak AD-H, 150 X 21 mm ID, 5µm, using 50/50 CO /(1:1) EtOH-IPA-0.1% DEA
at 50 mL/min, 150 bar BP, 50 C.
i: Chiralpak OD-H, 250 X 30 cm ID, 5µm, using 65/35 CO /EtOH-0.1%DIPA
at 90 mL/min, 150 bar BP, 45 C.
j: Chiralpak AD-H, 25 X 2 cm ID, 5µm, using 60/40 CO /IPA-20 mM NH OH
at 50 mL/min, 100 bar BP.
k: Chiralcel OJ-H, 25 X 2 cm ID, 5µm, using 70/30 CO /IPA-0.1% DEA
at 70 mL/min, 100 bar BP.
** LCMS retention time.
[00311] The following examples in Table 10 were prepared in a similar manner as
Example 80 substituting Intermediate 3A for the appropriate carboxylic acid listed and
were separated by chiral HPLC on late stage intermediates followed by deprotection and
purification where indicated.
N R'
Table 10
Example Stereochemistry R R’ M+H RT
153 Racemic PhCOOtBu 729.4 7.76
154 Racemic PhCOOH 673.5 6.07
155 Racemic PhCOOH 656.5 6.18
156 Racemic PhCOOH 613.4 6.31
157 Racemic PhCOOH 647.5 7.45
158 Racemic PhCOOH 663.5 6.39
159 Racemic PhCOOH 679.6 6.47
160 Racemic PhCOOEt 701.6 7.07
161 Racemic PhCOOH 661.2 6.99
162 Racemic PhCOOH 647.2 7.16
163 R-enantiomer PhCOOH 656.4 5.99
164 S-enantiomer PhCOOH 656.4 5.97
165 Racemic PhCOOEt 684.5 9.90
166 S-enantiomer PhCOOEt 684.3 7.39
167 R-enantiomer PhCOOH 673.4 5.83
168 S-enantiomer PhCOOH 673.4 5.82
169 R-enantiomer PhCOOEt 701.4 7.05
170 S-enantiomer PhCOOEt 701.4 7.06
171 S-enantiomer PhCOOBzl 763.2 6.72*
172 S-enantiomer PhCOOCH2CON(CH ) 758.2 6.74
173 S-enantiomer 768.2 6.53
174 S-enantiomer 731.2 7.59
175 Racemic PhCOOCH 687.1 7.53
176 Racemic PhCOOH 699.5 8.26
177 S-enantiomer PhCOOEt 727.5 9.14
178 S-enantiomer PhCOOH 699.5 6.81
179 R-enantiomer PhCOOH 699.5 6.84
180 Racemic PhCOOH 649.5 7.86
181 Racemic PhCOOH 597.5 6.08
182 Racemic PhCOOH 633.5 6.87
a: Chiralpak AD-H, 250 X 21 cm ID, 5µm, using 50/50 CO /EtOH-IPA-0.1% DEA at 60
mL/min, 125 bar BP, 40 C.
b: Chiralpak AD-H, 250 X 21 cm ID, 5µm, using 60/40 CO /EtOH-IPA-0.1% DEA at 45
mL/min, 150 bar BP, 50 C.
c: Chiralcel OD-H, 250 X 30 mm ID, 5µm, using 55/45 CO /EtOH-IPA-0.1% DEA at 85
mL/min, 100 bar BP, 40 C.
• *Method B
Example 183:
(R,E)(2-(3-(3-chlorofluoro(1H-tetrazolyl)phenyl)acryloyl)(4-methyl
oxopiperazinyl)-1,2,3,4-tetrahydroisoquinolinecarboxamido)benzoic acid, TFA salt
Example 57 (Table 7): (E)-tert-butyl 4-(2-(3-(3-chlorofluoro(1H-
tetrazolyl)phenyl)acryloyl)(4-methyloxopiperazinyl)-1,2,3,4-
tetrahydroisoquinolinecarboxamido)benzoate: Intermediate 3A (0.320 g, 1.192 mmol)
and Intermediate 22 (0.29 g, 1.192 mmol) were combined in a vial in EtOH (5mL) and
after 10 min., Intermediate 6 (0.315 g, 1.550 mmol) in EtOH (3mL) was added and
reaction was heated at 55 °C for 24 h. The reaction was concentrated and the residue was
purified by silica gel column chromatography followed by reverse phase HPLC and
freeze-dried to afford 0.339g (32.6%) of Example 57 (Table 7) as a white solid. H NMR
(400 MHz, MeOD) δ: 9.44 (1 H, s), 7.74 - 7.84 (2 H, m), 7.62 - 7.73 (1 H, m), 7.43 - 7.58
(3 H, m), 7.37 (1 H, dd, J = 8.72, 1.64 Hz), 7.31 (1 H, td, J = 7.83, 2.78 Hz), 7.19 (1 H, t,
J = 6.82 Hz), 6.98 - 7.11 (1 H, m), 6.79 - 6.94 (1 H, m), 5.80 (1 H, s), 3.94 - 4.20 (3 H,
m), 3.84 - 3.95 (1 H, m), 3.62 - 3.80 (3 H, m), 3.53 - 3.64 (1 H, m), 2.99 (3 H, s), 2.92 -
2.96 (1 H, m), 2.61 - 2.77 (1 H, m), 1.47 (9 H, d, J = 2.02 Hz) ppm. MS (ESI) m/z: 715.3.
Analytical HPLC: RT = 6.82 min.
Example 183 was prepared from Example 57 (Table 7) and isolated as the first
eluting peak after chiral HPLC separation using Chiralpak AD-H, 250 X 30 mm, 5µm,
using 60/40 CO /1:1 EtOH-IPA-0.1% DEA at 90 mL/min, 150 bar BP, 35 C followed by
deprotection with TFA/DCM and HPLC purification to afford 96.8 mgs (25.8%) of a
white solid. H NMR (400 MHz, MeOD) δ: 9.44 (1 H, s), 7.78 - 7.95 (2 H, m), 7.69 (1 H,
td, J=8.08, 2.53 Hz), 7.44 - 7.60 (3 H, m), 7.27 - 7.41 (2 H, m), 7.15 - 7.25 (1 H, m), 6.98
- 7.11 (1 H, m), 6.77 - 6.98 (1 H, m), 5.78 - 5.88 (1 H, m), 3.83 - 4.19 (4 H, m), 3.64 -
3.80 (3 H, m), 3.54 - 3.64 (1 H, m), 3.03 (3 H, s), 2.93 - 3.00 (1 H, m), 2.63 - 2.78 (1 H,
m) ppm MS (ESI) m/z: 659.3 (M+H) . Analytical HPLC: RT = 4.90 min.
Example 184:
(S,E)(2-(3-(3-chlorofluoro(1H-tetrazolyl)phenyl)acryloyl)(4-methyl
oxopiperazinyl)-1,2,3,4-tetrahydroisoquinolinecarboxamido)benzoic acid, TFA salt
Example 184 was isolated as the second eluting enantiomer from Example 57
(Table 7) and deprotected and purified as described in Example 183 to afford 104 mgs
(27.7%) of a white solid. H NMR (400 MHz, MeOD) δ: 9.45 (1 H, s), 7.79 - 7.92 (2 H,
m), 7.64 - 7.74 (1 H, m), 7.44 - 7.62 (3 H, m), 7.27 - 7.43 (2 H, m), 7.15 - 7.24 (1 H, m),
6.97 - 7.12 (1 H, m), 6.72 - 6.90 (1 H, m), 5.77 - 5.88 (1 H, m), 3.82 - 4.17 (4 H, m), 3.53
- 3.82 (4 H, m), 2.99 - 3.03 (1 H, m), 2.98 (3 H, s), 2.60 - 2.77 (1 H, m) ppm. MS (ESI)
m/z: 659.3 (M+H) . Analytical HPLC: RT = 4.94 min.
The following compounds listed in Table 11 were isolated following chiral
HPLC separation of the appropriate racemic example listed.
O R'
TABLE 11
Example # Racemic Stereo- R R’ M+H RT
Example # chemistry
185 63 S-enantiomer -COOEt 660.4 10.13
186 63 R-enantiomer -COOEt 660.4 10.14
187 54 R-enantiomer -COOH 645.3 4.85
188 54 S-enantiomer -COOH 645.3 4.87
189 56 R-enantiomer -COOEt 672.3 5.80
190 56 S-enantiomer -COOEt 672.3 5.77
a: Chiralpak IA, 250 X 30 mm, 5µm, using 60/40 CO /1:1EtOH-IPA-0,1% DEA at 90
mL/min, 150 bar BP, 35 C.
b: Chiralpak IA, 250 X 21 mm, 5µm, using 55/45 to 60/40 CO /1:1EtOH-ACN at 40
mL/min, 150 bar BP, 35 C.
c: Chiralpak AD-H, 250 X 21 mm, 5µm, using 55/45 to 60/40 CO /1:1EtOH-ACN at 40
mL/min, 150 bar BP, 35 C
Example 191:
(R,E)-Ethyl 4-(2-(3-(3-chlorofluoro(1H-tetrazolyl)phenyl)acryloyl)(4-methyl-
2-oxopiperazinyl)-1,2,3,4-tetrahydroisoquinolinecarboxamido)benzoate, TFA Salt
Example 191 was prepared as in Example 189 (Table 11) using Intermediate
22, Intermediate 9 and Intermediate 3A to afford 84.4mg (43%) as the first peak after
chiral HPLC separation using Chiralpak IA, 250 X 30 mm, 5µm, using 60 / 40 CO /1:1
EtOH-IPA-0,1% DEA at 100 mL/min, 150 bar BP, 40 C. H NMR (400 MHz, MeOD) δ
9.50 (1 H, s), 7.85 - 7.96 (2 H, m), 7.72 - 7.77 (1 H, m), 7.61 (2 H, dd, J = 8.79, 6.05 Hz),
7.48 - 7.56 (1 H, m), 7.44 (1 H, d, J = 8.79 Hz), 7.35 (1 H, td, J = 7.83, 3.02 Hz), 7.16 -
7.27 (1 H, m), 7.05 - 7.14 (1 H, m), 6.94 - 7.05 (1 H, m), 5.84 (1 H, d, J = 7.70 Hz), 4.22
- 4.33 (2 H, m), 4.09 (1 H, s), 3.51 - 3.82 (2 H, m), 3.43 (2 H, br. s.), 2.94 - 3.07 (4 H,
m), 2.70 - 2.81 (1 H, m), 2.55 (3 H, br. s.), 1.25 (3 H, t, J = 7.42 Hz) ppm. MS (ESI)
m/z: 687.3 (M+H) . Analytical HPLC: RT = 5.91 min.
Example 192:
(S,E)-Ethyl 4-(2-(3-(3-chlorofluoro(1H-tetrazolyl)phenyl)acryloyl)(4-methyl-
2-oxopiperazinyl)-1,2,3,4-tetrahydroisoquinolinecarboxamido)benzoate, TFA Salt
Example 192 was prepared as in Example 190 (Table 11) using Intermediate
22, Intermediate 9 and Intermediate 3A to afford 84.4mg (43%) as the second peak after
chiral HPLC separation using Chiralpak IA, 250 X 30 mm, 5µm, using 60/40 CO /1:1
EtOH-IPA-0,1% DEA at 100 mL/min, 150 bar BP, 40 C. H NMR (400 MHz, MeOD)
δ: 9.54 (1 H, s), 7.90 - 7.99 (2 H, m), 7.74 - 7.82 (1 H, m), 7.61 - 7.70 (2 H, m), 7.56 (1
H, dd, J = 19.24, 7.70 Hz), 7.47 (1 H, d, J = 8.79 Hz), 7.38 (1 H, td, J = 7.70, 3.85 Hz),
7.24 (1 H, t, J = 6.87 Hz), 6.98 - 7.16 (2 H, m), 5.88 (1 H, d, J = 8.24 Hz), 4.26 - 4.38 (2
H, m), 4.06 - 4.16 (1 H, m), 3.60 - 3.81 (3 H, m), 3.47 - 3.58 (1 H, m), 3.02 - 3.16 (2 H,
m), 2.83 - 2.95 (2 H, m), 2.75 - 2.85 (1 H, m), 2.45 (3 H, s), 1.36 (3 H, t, J = 7.15 Hz)
ppm. MS (ESI) m/z: 687.3 (M+H) . Analytical HPLC: RT = 5.90 min.
Example 193:
(R,E)(2-(3-(3-Chlorofluoro(1H-tetrazolyl)phenyl)acryloyl)-3,3-dimethyl
(piperazinyl)-1,2,3,4-tetrahydroisoquinolinecarboxamido) benzoic acid, bis-TFA
salt.
Example 193 was prepared from Example 78 tert-butyl ester intermediate by
chiral HPLC separation using Chiralpak IA (250 x 4.6) mm eluting with hexane:EtOH
(50:50) and 0.2% DEA at 1 mL/min. H NMR (400 MHz, DMSO-d ) δ 12.77 (1 H, s),
.48 (1 H, s), 9.86 (1 H, s), 8.67 (2 H, q), 7.95 (2 H, t, J = 8.4 Hz), 7.88 (1 H, bs), 7.64
(3 H, d, J = 9.2 Hz), 7.53 (1 H, d, J = 7.6 Hz), 7.29 (1 H, t, J = 8.0 Hz), 7.07-7.11 (3.0 H,
m), 5.74 (1 H, bs), 3.23 (2 H, q), 3.08 (2 H, t, J = 12.4 Hz), 2.91-2.95 (3 H, m), 1.81 (3 H,
s), 1.11 (3 H, s) ppm. MS (ESI) m/z: 659.2 (M+H) . Analytical HPLC: RT = 11.26 min.
Example 194:
(S,E)(2-(3-(3-Chlorofluoro(1H-tetrazolyl)phenyl)acryloyl)-3,3-dimethyl
(piperazinyl)-1,2,3,4-tetrahydroisoquinolinecarboxamido) benzoic acid, bis-TFA
salt
Example 194 was prepared from Example 78 tert-butyl ester intermediate by
chiral HPLC separation using Chiralpak IA (250 x 4.6) mm eluting with hexane:EtOH
(50:50) and 0.2% DEA at 1 mL/min. H NMR (400 MHz, DMSO-d ) δ 12.77 (1 H, s),
10.51 (1 H, s), 9.86 (1 H, s), 8.68 (2 H, bs), 7.95 (2 H, t, J = 8.4 Hz), 7.88 (1 H, bs), 7.65
(3 H, d, J = 8.8 Hz), 7.52 (1 H, d, J = 7.6 Hz), 7.29 (1 H, t, J = 8.0 Hz), 7.09 (3 H, t, J =
9.2 Hz), 6.82 (1 H, bs), 5.79 (1 H, bs), 3.15-3.35 (2 H, m), 3.10-2.80 (5 H, m), 1.80 (3 H,
s), 1.10 (3 H, s). MS (ESI) m/z: 659.2 (M+H) . Analytical HPLC: RT = 11.28 min.
[00320] The following compounds listed in Table 12 were isolated following chiral
HPLC separation of the appropriate racemic example listed.
TABLE 12
Example # Stereochemistry R R’ M+H RT
195 S-enantiomer -COOH 658.2 2.093
196 R-enantiomer -COOH 658.2 2.094
197 S-enantiomer -COOEt 688.2 2.141
198 R-enantiomer -COOEt 688.2 2.142
199 S-enantiomer -COOH 660.2 1.974
200 R-enantiomer -COOH 660.2 1.973
201 S-enantiomer -COOH 673.2 1.515
202 R-enantiomer -COOH 673.2 1.509
203 S-enantiomer -COOEt 701.2 1.746
204 S-enantiomer -COOH 701.2 1.859
205 R-enantiomer -COOH 701.2 1.858
1. a: Chiralpak AD-H, 250 X 30 mm, 5µm, using 40/60 CO /1:1EtOH-IPA-0,1%
DEA at 90.0 mL/min, 150 bar BP, 35 C.
2. b: Chiralpak IA, 250 X 30 mm, 5µm, using 60/40 CO /1:1EtOH-IPA-0,1% DEA
at 90.0 mL/min, 150 bar BP, 35 C.
3. c: Chiralpak IA, 250 X 21 mm, 5µm, using 55/45 to 60/40 CO /1:1EtOH-ACN at
40.0 mL/min, 150 bar BP, 35 C.
4. d: Chiralpak AD-H, 250 X 21 mm, 5µm, using 55/45 to 60/40 CO /1:1EtOH-
ACN at 40.0 mL/min, 150 bar BP, 35 C
Example 206:
4-((S)((E)(3-Chlorofluoro(1H-tetrazolyl)phenyl)acryloyl)((S)
(dimethylamino)pyrrolidinyl)-1,2,3,4-tetrahydroisoquinolinecarboxamido)benzoic
acid, bis-TFA salt
206A: (S)(3,4-Dihydroisoquinolinyl)-N,N-dimethylpyrrolidinamine:
To 5-bromoisoquinoline (0.60 g, 2.88 mmol), (S)-N,N-dimethylpyrrolidinamine
(0.428 g, 3.75 mmol), Pd (dba) (0.053 g, 0.058 mmol), BINAP (0.072 g, 0.115 mmol),
and sodium tert-butoxide (0.39 g, 4.04 mmol) was added degassed toluene (10 mL) and
the mixture was heated to 85 °C overnight. The reaction mixture was dissolved in
EtOAc, washed with brine, dried over Na SO , filtered, and concentrated. This
intermediate was reduced and then, oxidized as described in Example 1 to afford 206A
(577 mg, 82%).
Example 206: 206A (0.25 g, 1.03 mmol), Intermediate 3A (0.28 g, 1.03
mmol), and Intermediate 6 (0.23 g, 1.13 mmol) were combined in an Ugi reaction as
described in Example 1 and then, deprotected by TFA. Purification by reverse phase
HPLC afforded Example 206 as the first of two diastereomers. The compound was
obtained as a light yellow solid after lyophilization. H NMR (500 MHz, DMSO-d ) δ
.78 (1 H, s), 9.88 (1 H, s), 7.97 (1 H, t, J = 8.12 Hz), 7.87 (2 H, d, J = 8.80 Hz), 7.68 (3
H, d, J = 8.80 Hz), 7.30 (1 H, d, J = 7.70 Hz), 7.22 (1 H, t, J = 7.84 Hz), 7.03 - 7.09 (1 H,
m), 6.93 - 7.02 (2 H, m), 5.75 (1 H, s), 3.94 - 4.10 (1 H, m), 3.20 - 3.55 (9 H, m), 2.79 -
3.06 (5 H, m), 2.27 - 2.40 (1 H, m), 2.06 - 2.21 (1 H, m) ppm. MS (ESI) m/z: 659.3
(M+H) . Analytical HPLC: RT = 4.53 min.
Example 207:
tert-butyl 4-((S)((E)(3-chlorofluoro(1H-tetrazolyl)phenyl)acryloyl)((S)-
3-(dimethylamino)pyrrolidinyl)-1,2,3,4-tetrahydroisoquinoline
carboxamido)benzoate, bis TFA salt:
Example 207: 206A (0.25 g, 1.03 mmol), Intermediate 3A (0.28 g, 1.03 mmol), and
Intermediate 6 (0.23 g, 1.13 mmol) were combined in an Ugi reaction as described in
Example 1. Purification by reverse phase HPLC afforded Example 207. H NMR (500
MHz, DMSO-d ) δ 10.77 (1 H, s), 9.86 (1 H, s), 7.96 (1 H, t, J = 8.25 Hz), 7.82 (2 H, d, J
= 8.80 Hz), 7.67 (3 H, d, J = 9.08 Hz), 7.29 (1 H, d, J = 7.43 Hz), 7.17 - 7.25 (1 H, m),
6.87 - 7.08 (3 H, m), 5.75 (1 H, s), 3.92 - 4.07 (2 H, m), 3.23 - 3.54 (4 H, m), 2.80 - 3.05
(9 H, m), 2.26 - 2.37 (1 H, m), 2.09 - 2.19 (1 H, m), 1.50 - 1.55 (9 H, m) ppm. MS (ESI)
m/z: 715.5 (M+H) . Analytical HPLC: RT = 8.68 min
Example 208:
4-((R)((E)(3-Chlorofluoro(1H-tetrazolyl)phenyl)acryloyl)((S)
(dimethylamino)pyrrolidinyl)-1,2,3,4-tetrahydroisoquinolinecarboxamido)benzoic
acid, bis-TFA salt
Example 208 was obtained as the second eluting diastereomer during the
synthesis and purification of Example 206. The compound was obtained as a light yellow
solid after lyophilization. H NMR (500 MHz, DMSO-d ) δ 12.73 (1 H, br. s.), 10.75 (1
H, s), 9.88 (1 H, s), 7.97 (1 H, t, J = 8.12 Hz), 7.81 - 7.93 (2 H, m), 7.63 - 7.72 (2 H, m),
7.31 (1 H, d, J = 7.70 Hz), 7.21 (1 H, t, J = 7.84 Hz), 7.03 - 7.12 (1 H, m), 6.91 - 7.00 (2
H, m), 5.72 (1 H, s), 4.03 - 4.19 (1 H, m), 3.86 - 3.98 (1 H, m), 3.37 - 3.49 (3 H, m), 3.07
- 3.30 (5 H, m), 2.81 - 2.92 (7 H, m) ppm. MS (ESI) m/z: 659.3 (M+H) . Analytical
HPLC: RT = 4.64 min.
Example 209:
4-((R)((E)(3-Chlorofluoro(1H-tetrazolyl)phenyl)acryloyl)((R)
(dimethylamino)pyrrolidinyl)-1,2,3,4-tetrahydroisoquinolinecarboxamido)benzoic
acid, bis TFA salt
Example 209 was prepared in a similar manner as Example 206 substituting
(R)-N,N-dimethylpyrrolidinamine instead of (S)-N,N-dimethylpyrrolidinamine in
Buchwald reaction. The compound was the first eluting diastereomer during purification
by reverse phase prep HPLC. H NMR (500 MHz, DMSO-d ) δ 12.74 (1 H, br. s.),
.78 (1 H, s), 9.88 (1 H, s), 7.97 (1 H, t, J = 8.12 Hz), 7.87 (1 H, d, J = 8.80 Hz), 7.67 (1
H, d, J = 8.80 Hz), 7.30 (1 H, d, J = 7.43 Hz), 7.21 (1 H, t, J = 7.84 Hz), 7.03 - 7.09 (1 H,
m), 6.94 - 7.01 (2 H, m), 5.75 (1 H, s), 3.90 - 4.18 (2 H, m), 3.40 - 3.56 (3 H, m), 3.19 -
3.33 (5 H, m), 2.80 - 2.98 (7 H, m) ppm. MS (ESI) m/z: 659.3 (M+H) . Analytical
HPLC: RT = 4.57 min.
Example 210:
4-((S)((E)(3-Chlorofluoro(1H-tetrazolyl)phenyl)acryloyl)((R)
(dimethylamino)pyrrolidinyl)-1,2,3,4-tetrahydroisoquinolinecarboxamido)benzoic
acid, bis-TFA salt
Example 210 was prepared in a similar manner as Example 206 substituting
(R)-N,N-dimethylpyrrolidinamine instead of (S)-N,N-dimethylpyrrolidinamine in
Buchwald reaction. The compound was the second eluting diastereomer during
purification by reverse phase prep HPLC. H NMR (500 MHz, DMSO-d ) δ 10.74 (1 H,
s), 9.87 (1 H, s), 7.96 (1 H, t, J = 8.12 Hz), 7.83 - 7.88 (2 H, m), 7.63 - 7.70 (3 H, m),
7.27 - 7.34 (1 H, m), 7.17 - 7.23 (1 H, m), 7.02 - 7.10 (1 H, m), 6.90 - 7.01 (2 H, m), 5.71
(1 H, s), 4.07 - 4.20 (1 H, m), 3.84 - 3.98 (1 H, m), 3.35 - 3.44 (3 H, m), 3.09 - 3.29 (5 H,
m), 2.79 - 2.92 (7 H, m) ppm. MS (ESI) m/z: 659.3 (M+H) . Analytical HPLC: RT =
4.64 min.
The following examples in Table 13 were made by Ugi reaction as described
in Example 1 using appropriate imine intermediates and carboxylic acids (Intermediates
3A, 12, or 16). Deprotection with TFA/DCM was carried out where necessary. Single
enantiomers were isolated by chiral HPLC at a protected late stage intermediate and then,
deprotected where indicated.
N N R'
Table 13
Example# Stereochemistry R R’ M+H RT
211 Racemic PhCOOH 648.3 9.53
212 S-enantiomer PhCOOH 648.2 10.61
213 Racemic O PhCOOH 680.4 11.28
214 S-enantiomer PhCOOH 680.4 7.80
a: Chiralpak AD-H, 250 x 21 mm ID, 45% (1:1EtOH-IPA-0.1%DEA)/55% CO at
45mL/min, 120 bar, 45 C.
b: Chiralpak AD-H, 250 x 21 mm ID, 45% (1:1EtOH-IPA-0.1%DEA)/55% CO at 60
mL/min, 100 bar, 35 C.
[00327] The following examples in Table 14 were made by Ugi reaction as described
in Example 18 using appropriate imine intermediates. Deprotection with TFA/DCM was
carried out where necessary. Single enantiomers were isolated by chiral HPLC at a
protected late stage intermediate and then, deprotected where indicated.
N R"
Table 14
Example # Stereochemistry R R’ R” M+H RT
215 Racemic PhCOOH 655.4 8.19
216 R-enantiomer O PhCOOH 654.3 9.43
217 S-enantiomer PhCOOH 654.3 8.19
218 Racemic PhCOOH 675.3 7.97
219 S-enantiomer PhCOOH 675.3 8.31
220 Racemic PhCOOH 689.3 7.15
221 R-enantiomer PhCOOH 687.5 8.50
222 S-enantiomer PhCOOH 687.3 10.88
223 Racemic PhCOOH 673.5 6.67
224 Racemic PhCOOH 639.5 6.33
225 Racemic PhCOOH 680.4 10.55
226 Racemic N N O PhCOOEt 708.4 10.51
227 Racemic PhCOOH 685.4 6.92
228 Racemic PhCOOH 714.3 9.77
a: Chiralpak IA-H, 150 x 21 cm ID, 45% (1:1 EtOH-IPA-0.1% DEA)/55% CO at 70
mL/min, 100 bar, 35 C.
b: Chiralcel OD-H, 2 x 20 cm ID, 30% MeOH-0.1% DEA)/70% CO at 70 mL/min, 100
bar, 35 C.
c: Chiralpak AD-H, 250 x 21 cm ID, 45% (1:1 EtOH-IPA-0.1% DEA)/55% CO at 60
mL/min, 150 bar, 35 C.
The following examples in Table 15 were made by Ugi reaction as described
in Example 1 using appropriate nitrile intermediates. Deprotection with TFA/DCM was
carried out where necessary. Single enantiomers were isolated by chiral HPLC at a
protected late stage intermediate and then, deprotected where indicated.
N N R
Table 15
Example # Stereochemistry R M+H RT
229 Racemic 651.5 5.71
230 Racemic 707.6 6.69
231 Racemic 651.5 5.54
232 Racemic 719.6 6.38
233 Racemic 719.4 6.13
234 Racemic O 705.4 5.34
235 Racemic 676.4 4.41
236 Racemic 677.6 5.32
237 Racemic 662.5 4.27
238 Racemic 734.6 6.70
239 Racemic 661.5 6.45
240 Racemic 621.4 4.64
Example 241:
(E)(2-(3-(3-Chlorofluoro(1H-tetrazolyl)phenyl)acryloyl)(3-
(ethoxycarbonyl)methyl-1H-pyrazolyl)-1,2,3,4-tetrahydroisoquinoline
carboxamido)benzoic acid:
241A: A solution of isoquinolinamine (1.442 g, 10 mmol) in H O (10 mL)
containing concentrated HCl (3.0 mL, 36.5 mmol) at 0 °C was treated dropwise with a
solution of sodium nitrite (0.759 g, 11.00 mmol) in H O (3 mL). After stirring for an
additional hour at 0 °C, the contents were transferred to an addition funnel and added
drop wise to a vigorously stirred solution of tin(II) chloride dihydrate (5.64 g, 25.00
mmol) in concentrated HCl (25 mL) at 0 °C. After stirring for 1 h, the pH was adjusted
to 7-8 by adding 10 N NaOH with cooling in an ice bath. The mixture was extracted with
CHCl /MeOH (9:1). The combined organic extracts were dried over MgSO , filtered,
and concentrated to give a light brown solid. Ethyl 2,4-dioxovalerate (1.582 g, 10.00
mmol) was added to a solution of the hydrazine in EtOH and heated at 80 °C. After
cooling to rt, the reaction mixture was concentrated. The residue was dissolved in EtOAc
(75 mL) and washed with saturated NaHCO solution, H O, brine, dried over Na SO ,
3 2 2 4
filtered, and concentrated. The crude material was purified by column chromatography.
The desired product was isolated as a brown solid. MS(ESI) m/z: 282.0 (M+H) .
[00330] 241B: Adam's Catalyst (0.061 g, 0.267 mmol) was added to a solution of
241A (1.5 g, 5.33 mmol) in EtOH (50 mL) and stirred under a hydrogen atmosphere (55
psi) overnight. The reaction mixture was filtered through a plug of Celite , the filter-
cake rinsed with EtOH, and the combined filtrate concentrated. The residue was
dissolved in DCM (50 mL), treated with MnO (8.34 g, 96 mmol), and left to stir
overnight. The reaction mixture was filtered through a plug of Celite and the filter cake
rinsed with DCM/MeOH (9:1). The combined filtrate was concentrated to yield the
desired product. MS(ESI) m/z: 284.1(M+H)
241C: 241B (0.150 g, 0.529 mmol) was dissolved in EtOH (10 mL), treated
with intermediate 3A (0.142 g, 0.529 mmol) and intermediate 6 (0.108 g, 0.529 mmol)
and heated at 60 °C overnight. The reaction mixture was concentrated, dissolved in
EtOAc, washed with 1.5M K PO solution, brine, dried over Na SO , filtered, and
3 4 2 4
concentrated. The t-butyl ester was converted into the corresponding carboxylic acid by
treatment with 50% TFA/DCM for 2 h. The reaction mixture was concentrated and
purified by reverse phase HPLC. H NMR (400MHz, DMSO-d ) δ 10.89 (s, 1H), 9.85 (s,
1H), 8.00 - 7.80 (m, 4H), 7.75 - 7.62 (m, 3H), 7.55 - 7.46 (m, 1H), 7.41 (s, 1H), 7.14 -
7.05 (m, 1H), 7.01 - 6.91 (m, 1H), 6.78 (s, 1H), 5.96 (s, 1H), 4.29 (q, J = 7.1 Hz, 2H),
4.11 - 3.99 (m, 1H), 3.77 - 3.59 (m, 1H), 2.81 - 2.67 (m, 1H), 2.44 - 2.30 (m, 1H), 2.11 (s,
3H), 1.29 (t, J = 6.9 Hz, 3H) ppm. MS(ESI) m/z: 699.1 (M+H) Analytical HPLC: RT =
9.10 min
Example 242:
(E)-Ethyl 1-(2-(3-(3-chlorofluoro(1H-tetrazolyl)phenyl)acryloyl)(4-
fluorophenylcarbamoyl)-1,2,3,4-tetrahydroisoquinolinyl)methyl-1H-pyrazole
carboxylate:
241B (0.150 g, 0.529 mmol) was dissolved in EtOH (10 mL), treated with
intermediate 3A (0.142 g, 0.529 mmol) and 1-fluoroisocyanobenzene (0.064 g, 0.529
mmol) and heated at 60°C overnight. The reaction mixture was concentrated, dissolved
in EtOAc, washed with 1.5 M K PO solution, brine, dried over Na SO , filtered, and
3 4 2 4
concentrated. The reaction mixture was concentrated and purified by reverse phase
HPLC. H NMR (400 MHz, DMSO-d ) δ 10.63 (1 H, s), 9.85 (1 H, s), 7.94 (1 H, t, J =
8.08 Hz), 7.81 (1 H, d, J = 7.83 Hz), 7.56 - 7.70 (3 H, m), 7.49 (1 H, t, J = 7.83 Hz), 7.35
- 7.42 (1 H, m), 7.04 - 7.22 (3 H, m), 6.91 - 7.02 (1 H, m), 6.78 (1 H, s), 5.93 (1 H, s),
4.28 (2 H, q, J = 7.07 Hz), 4.00 - 4.11 (1 H, m), 3.62 - 3.75 (1 H, m), 2.64 - 2.78 (1 H,
m), 2.29 - 2.41 (1 H, m), 2.11 (2 H, s), 1.29 (3 H, t, J = 7.07 Hz) ppm. MS (ESI) m/z:
673.1(M+H) Analytical HPLC: RT = 10.54 min.
The following examples in Table 16 were made by Ugi reaction as described
in Example 1 using appropriate intermediates. Deprotection with TFA/DCM was carried
out where necessary. Single enantiomers were isolated by chiral HPLC at a protected late
stage intermediate and then, deprotected where indicated.
O OH
Table 16
Example # Stereochemistry R M+H RT
243 Diastereomer 671.5 9.04
244 Diastereomer 671.5 9.12
245 Diastereomer 671.2 5.3*
246 Diastereomer 671.5 5.97
247 Diastereomer 657.1 6.62
248 Diastereomer 715.4 9.72
249 Diastereomer 699.4 8.25
250 Diastereomer 714.4 7.90
251 Diastereomer 742.4 5.87
252 Racemate 685.2 4.98*
*Method B
The following examples in Table 17 were made by Ugi reaction as described
in Example 1 using appropriate intermediates. Deprotection with TFA/DCM was carried
out where necessary. Single enantiomers were isolated by chiral HPLC at a protected late
stage intermediate and then, deprotected where indicated.
N N R'
Table 17
Example # Stereochemistry R R’ M+H RT
253 S-enantiomer 4-PhCOOEt 699.3 7.79
254 S-enantiomer 4-PhCOOH 671.3 6.64
255 Racemic 706.3 9.37
[00335] a: Kromasil cellulocoat, 250 x 4.6 mm ID, 40% (MeOH-0.1% DEA)/60% CO
at 45 mL/min, 100 bar, 40 C.
The following examples in Table 18 were made by Ugi reaction as described
in Example 1 using appropriate intermediates. Deprotection with TFA/DCM was carried
out where necessary. Single enantiomers were isolated by chiral HPLC at a protected late
stage intermediate and then, deprotected where indicated.
N N R'
Table 18
Example # Stereochemistry R R’ M+H RT
256 Racemic 4-PhCOOH 645.2 5.42
257 Racemic 4-PhCOOtBu 801.4 13.15
258 Racemic 4-PhCOOH 644.3 7.82
259 Racemic 4-PhCOOH 702.3 8.14
260 S-enantiomer 4-PhCOOH 645.2 5.02*
261 Racemic 4-PhCOOH 759.3 5.46*
262 Racemic 4-PhCOOH 659.2 4.90*
263 Racemic 4-PhCOOH 730.3 5.06*
264 Racemic 4-PhCOOH 673.3 8.36
265 S-enantiomer 4-PhCOOH 659.2 6.75
266 S-enantiomer 4-PhCOOH 730.4 6.33
a: Chiralpak AD-H, 150 x 21 mm ID, 45% (1:1 EtOH-IPA-0.1% DEA)/55% CO at 45
mL/min, 150 bar, 40 C.
• *Method B
The following examples in Table 19 were made by Ugi reaction as described
in Example 206 using appropriate intermediates. Deprotection with TFA/DCM was
carried out where necessary. Single enantiomers were isolated by chiral HPLC at a
protected late stage intermediate and then, deprotected where indicated.
O OH
Table 19
Example Stereochemistry R R’ M+H RT
267 S-enantiomer 691.3 5.86
268 S-enantiomer 660.2 6.68
269 Racemic 678.2 8.44
N N F
270 S-enantiomer 648.2 9.91
a: Chiralpak AD-H, 250 x 21 mm ID, 45% (1:1 EtOH-IPA-0.1% DEA)/55% CO at 65
mL/min, 150 bar, 45 C.
b: Chiralpak AD-H, 250 x 21 mm ID, 40% (1:1 EtOH-IPA-0.1% DEA)/60% CO at 65
mL/min, 150 bar, 45 C.
VII. POLYMORPHS
The compounds of the present invention may exist as polymorphs. As used
herein “polymorph” refers to crystalline forms having the same chemical composition but
different spatial arrangements of the molecules, and/or ions forming the crystal. The
present invention provides crystalline forms as a pharmaceutically acceptable form. The
term “pharmaceutically acceptable”, as used herein, refers to those compounds, materials,
compositions, and/or dosage forms which are, within the scope of sound medical
judgment, suitable for contact with the tissues of human beings and animals without
excessive toxicity, irritation, allergic response, or other problem complications
commensurate with a reasonable benefit/risk ratio.
In one embodiment, a compound of the present invention is in substantially
pure form. The term “substantially pure”, as used herein, means a compound having a
purity greater than about 90% including greater than 90, 91, 92, 93, 94, 95, 96, 97, 98,
and 99 weight %, and also including equal to about 100 weight % of the compound,
based on the weight of the compound. The remaining material comprises other form(s)
of the compound, and/or reaction impurities and/or processing impurities arising from its
preparation. For example, a crystalline form of a compound may be deemed substantially
pure in that it has a purity greater than 90 weight %, as measured by means that are at this
time known and generally accepted in the art, where the remaining less than 10 weight %
of material comprises other form(s) of the compound and/or reaction impurities and/or
processing impurities.
Samples of the crystalline forms may be provided with substantially pure
phase homogeneity, indicating the presence of a dominant amount of a single crystalline
form and optionally minor amounts of one or more other crystalline forms. The presence
of more than one crystalline form in a sample may be determined by techniques such as
powder X-ray diffraction (PXRD) or solid state nuclear magnetic resonance spectroscopy
(SSNMR). For example, the presence of extra peaks in the comparison of an
experimentally measured PXRD pattern with a simulated PXRD pattern may indicate
more than one crystalline form in the sample. The simulated PXRD may be calculated
from single crystal X-ray data. see Smith, D.K., “A FORTRAN Program for Calculating
X-Ray Powder Diffraction Patterns,” Lawrence Radiation Laboratory, Livermore,
California, UCRL-7196, April 1963. Preferably, the crystalline form has substantially
pure phase homogeneity as indicated by less than 10%, preferably less than 5 %, and
more preferably less than 2 % of the total peak area in the experimentally measured
PXRD pattern arising from the extra peaks that are absent from the simulated XRPD
pattern. Most preferred is a crystalline form having substantially pure phase homogeneity
with less than 1% of the total peak area in the experimentally measured PXRD pattern
arising from the extra peaks that are absent from the simulated PXRD pattern.
The crystalline forms may be prepared by a variety of methods, including for
example, crystallization or recrystallization from a suitable solvent, sublimation, growth
from a melt, solid state transformation from another phase, crystallization from a
supercritical fluid, and jet spraying. Techniques for crystallization or recrystallization of
crystalline forms from a solvent mixture include, for example, evaporation of the solvent,
decreasing the temperature of the solvent mixture, crystal seeding a supersaturated
solvent mixture of the molecule and/or salt, freeze drying the solvent mixture, and
addition of antisolvents (countersolvents) to the solvent mixture. High throughput
crystallization techniques may be employed to prepare crystalline forms including
polymorphs.
Crystals of drugs, including polymorphs, methods of preparation, and
characterization of drug crystals are discussed in Solid-State Chemistry of Drugs, S.R.
Byrn, R.R. Pfeiffer, and J.G. Stowell, 2 Edition, SSCI, West Lafayette, Indiana, 1999.
For crystallization techniques that employ solvent, the choice of solvent or
solvents is typically dependent upon one or more factors, such as solubility of the
compound, crystallization technique, and vapor pressure of the solvent. Combinations of
solvents may be employed, for example, the compound may be solubilized into a first
solvent to afford a solution, followed by the addition of an antisolvent to decrease the
solubility of the compound in the solution and to afford the formation of crystals. An
antisolvent is a solvent in which the compound has low solubility. Suitable solvents for
preparing crystals include polar and nonpolar solvents.
In one method to prepare crystals, the compound of the present invention is
suspended and/or stirred in a suitable solvent to afford a slurry, which may be heated to
promote dissolution. The term “slurry”, as used herein, means a saturated solution of the
compound and a solvent at a given temperature. Suitable solvents in this regard include,
for example, polar aprotic solvents, and polar protic solvents, and nonpolar solvents, and
mixtures of two or more of these.
[00345] Suitable polar aprotic solvents include, for example, dicholomethane (CH Cl
or DCM), tetrahydrofuran (THF), acetone, methyl ethyl ketone (MEK),
dimethylformamide (DMF), dimethylacetamide (DMAC), 1,3-dimethyl-3,4,5,6-
tetrahydro-2(1H)-pyrimidinone (DMPU), 1,3-dimethylimidazolidinone (DMI), N-
methylpyrrolidinone (NMP), formamide, N-methylacetamide, N-methylformamide,
acetonitrile (ACN or MeCN), dimethylsulfoxide (DMSO), propionitrile, ethyl formate,
methyl acetate (MeOAc), ethyl acetate (EtOAc), isopropyl acetate (IpOAc), butyl acetate
(BuOAc), t-butyl acetate, hexachloroacetone, dioxane, sulfolane, N,N-
dimethylpropionamide, nitromethane, nitrobenzene and hexamethylphosphoramide.
Suitable polar protic solvents include, for example, alcohols and glycols, such
as H O, methanol, ethanol, 1-propanol, 2-propanol, isopropanol (IPA), 1-butanol (1-
BuOH), 2-butanol (2-BuOH), i-butyl alcohol, t-butyl alcohol, 2-nitroethanol, 2-
fluoroethanol, 2,2,2-trifluoroethanol, ethylene glycol, 2-methoxyethanol, 2-
ethoxyethanol, diethylene glycol, 1-, 2-, or 3-pentanol, neo-pentyl alcohol, t-pentyl
alcohol, diethylene glycol monomethyl ether, diethylene glycol monoethyl ether,
cyclohexanol, benzyl alcohol, phenol, glycerol and methyl t-butyl ether (MTBE).
Preferred solvents include, for example, acetone, H O, CH Cl , methanol,
2 2 2
ethanol, MEK, IPA, and EtOAc.
Other solvents suitable for the preparation of slurries, in addition to those
exemplified above, would be apparent to one skilled in the art, based on the present
disclosure.
Seed crystals may be added to any crystallization mixture to promote
crystallization. As will be clear to the skilled artisan, seeding is used as a means of
controlling growth of a particular crystalline form or as a means of controlling the particle
size distribution of the crystalline product. Accordingly, calculation of the amount of
seeds needed depends on the size of the seed available and the desired size of an average
product particle as described, for example, in “Programmed cooling of batch
crystallizers,” J. W. Mullin and J. Nyvlt, Chemical Engineering Science, 1971, 26, 369-
377. In general, seeds of small size are needed to effectively control the growth of
crystals in the batch. Seeds of small size may be generated by sieving, milling, or
micronizing of larger crystals, or by micro-crystallization of solutions. Care should be
taken that milling or micronizing of crystals does not result in any change in crystallinity
of the desired crystal form or form conversions (i.e. change to amorphous or to another
polymorph).
A cooled mixture may be filtered under vacuum, and the isolated solids may
be washed with a suitable solvent, such as cold recrystallization solvent, and dried under
a nitrogen purge to afford the desired crystalline form. The isolated solids may be
analyzed by a suitable spectroscopic or analytical technique, such as SSNMR, DSC,
PXRD, or the like, to assure formation of the preferred crystalline form of the product.
The resulting crystalline form is typically produced in an amount of greater than about 70
weight % isolated yield, but preferably greater than 90 weight % based on the weight of
the compound originally employed in the crystallization procedure. The product may be
comilled or passed through a mesh screen to delump the product, if necessary.
[00351] Crystalline forms may be prepared directly from the reaction medium of the
final process step for preparing the compound of the present invention. This may be
achieved, for example, by employing in the final process step a solvent or mixture of
solvents from which the compound may be crystallized. Alternatively, crystalline forms
may be obtained by distillation or solvent addition techniques. Suitable solvents for this
purpose include any of those solvents described herein, including protic polar solvents
such as alcohols, and aprotic polar solvents such as ketones.
By way of general guidance, the reaction mixture may be filtered to remove
any undesired impurities, inorganic salts, and the like, followed by washing with reaction
or crystallization solvent. The resulting solution may be concentrated to remove excess
solvent or gaseous constituents. If distillation is employed, the ultimate amount of
distillate collected may vary, depending on process factors including, for example, vessel
size, stirring capability, and the like, by way of general guidance, the reaction solution
may be distilled to about {fraction (1/10)} the original volume before solvent
replacement is carried out. The reaction may be sampled and assayed to determine the
extent of the reaction and the wt % product in accordance with standard process
techniques. If desired, additional reaction solvent may be added or removed to optimize
reaction concentration. Preferably, the final concentration is adjusted to about 50 wt % at
which point a slurry typically results.
It may be preferable to add solvents directly to the reaction vessel without
distilling the reaction mixture. Preferred solvents for this purpose are those which may
ultimately participate in the crystalline lattice as discussed above in connection with
solvent exchange. Although the final concentration may vary depending on desired
purity, recovery and the like, the final concentration of the in solution is preferably about
4% to about 7%. The reaction mixture may be stirred following solvent addition and
simultaneously warmed. By way of illustration, the reaction mixture may be stirred for
about 1 hour while warming to about 70° C. The reaction is preferably filtered hot and
washed with either the reaction solvent, the solvent added or a combination thereof.
Seed crystals may be added to any crystallization solution to initiate crystallization.
The various forms described herein may be distinguishable from one another
through the use of various analytical techniques known to one of ordinary skill in the art.
Such techniques include, but are not limited to, solid state nuclear magnetic resonance
(SSNMR) spectroscopy, X-ray powder diffraction (PXRD), differential scanning
calorimetry (DSC), and/or thermogravimetric analysis (TGA).
One of ordinary skill in the art will appreciate that an X-ray diffraction pattern
may be obtained with a measurement error that is dependent upon the measurement
conditions employed. In particular, it is generally known that intensities in a X-ray
diffraction pattern may fluctuate depending upon measurement conditions employed. It
should be further understood that relative intensities may also vary depending upon
experimental conditions and, accordingly, the exact order of intensity should not be taken
into account. Additionally, a measurement error of diffraction angle for a conventional
X-ray diffraction pattern is typically about 5% or less, and such degree of measurement
error should be taken into account as pertaining to the aforementioned diffraction angles.
Consequently, it is to be understood that the crystal forms of the instant invention are not
limited to the crystal forms that provide X-ray diffraction patterns completely identical to
the X-ray diffraction patterns depicted in the accompanying Figures disclosed herein.
Any crystal forms that provide X- ray diffraction patterns substantially identical to those
disclosed in the accompanying Figures fall within the scope of the present invention. The
ability to ascertain substantial identities of X-ray diffraction patterns is within the
purview of one of ordinary skill in the art.
The crystalline forms of the compound of the present invention may be
formulated into pharmaceutical compositions and/or employed in therapeutic and/or
prophylactic methods. These methods include, but are not limited to, the administration
of the crystalline compound, alone or in combination with one or more other
pharmaceutically active agents, including agents that may be useful in the treatment of
the disorders mentioned herein.
The crystalline forms of the compound of the present invention and
pharmaceutical composition thereof may be useful in inhibiting Factor XIa. Accordingly,
the present invention provides methods for the treatment and/or prevention of
thromboembolic disorders in mammals (i.e., factor XIa-associated disorders). In general,
a thromboembolic disorder is a circulatory disease caused by blood clots (i.e., diseases
involving fibrin formation, platelet activation, and/or platelet aggregation). The term
“thromboembolic disorders” as used herein includes arterial cardiovascular
thromboembolic disorders, venous cardiovascular thromboembolic disorders, and
thromboembolic disorders in the chambers of the heart. The term "thromboembolic
disorders" as used herein also includes specific disorders selected from, but not limited to,
unstable angina or other acute coronary syndromes, atrial fibrillation, first or recurrent
myocardial infarction, ischemic sudden death, transient ischemic attack, stroke,
atherosclerosis, peripheral occlusive arterial disease, venous thrombosis, deep vein
thrombosis, thrombophlebitis, arterial embolism, coronary arterial thrombosis, cerebral
arterial thrombosis, cerebral embolism, kidney embolism, pulmonary embolism, and
thrombosis resulting from (a) prosthetic valves or other implants, (b) indwelling
catheters, (c) stents, (d) cardiopulmonary bypass, (e) hemodialysis, or (f) other
procedures in which blood is exposed to an artificial surface that promotes thrombosis. It
is noted that thrombosis includes occlusion (e.g. after a bypass) and reocclusion (e.g.,
during or after percutaneous transluminal coronary angioplasty). The thromboembolic
disorders may result from conditions including but not limited to atherosclerosis, surgery
or surgical complications, prolonged immobilization, arterial fibrillation, congenital
thrombophilia, cancer, diabetes, effects of medications or hormones, and complications of
pregnancy. The anticoagulant effect of compounds of the present invention is believed to
be due to inhibition of factor XIa or thrombin.
The methods preferably comprise administering to a patient a
pharmaceutically effective amount of the novel crystals of the present invention,
preferably in combination with one or more pharmaceutically acceptable carriers and/or
excipients. The relative proportions of active ingredient and carrier and/or excipient may
be determined, for example, by the solubility and chemical nature of the materials, chosen
route of administration and standard pharmaceutical practice.
The crystalline forms of the compound may be administered to a patient in
such oral dosage forms as tablets, capsules (each of which includes sustained release or
timed release formulations), pills, powders, granules, elixirs, tinctures, suspensions,
syrups, and emulsions. They may also be administered in intravenous (bolus or infusion),
intraperitoneal, subcutaneous, or intramuscular form, all using dosage forms well known
to those of ordinary skill in the pharmaceutical arts. They may be administered alone, but
generally will be administered with a pharmaceutical carrier selected on the basis of the
chosen route of administration and standard pharmaceutical practice.
The dosage regimen for the crystalline forms of the compound will, of course,
vary depending upon known factors, such as the pharmacodynamic characteristics of the
particular agent and its mode and route of administration; the species, age, sex, health,
medical condition, and weight of the recipient; the nature and extent of the symptoms; the
kind of concurrent treatment; the frequency of treatment; the route of administration, the
renal and hepatic function of the patient, and the effect desired. A physician or
veterinarian can determine and prescribe the effective amount of the drug required to
prevent, counter, or arrest the progress of the thromboembolic disorder. Obviously,
several unit dosage forms may be administered at about the same time. The dosage of the
crystalline form of the compound that will be most suitable for prophylaxis or treatment
may vary with the form of administration, the particular crystalline form of the compound
chosen and the physiological characteristics of the particular patient under treatment.
Broadly, small dosages may be used initially and, if necessary, increased by small
increments until the desired effect under the circumstances is reached.
[00361] By way of general guidance, in the adult, suitable doses may range from about
0.001 to about 1000 mg/Kg body weight, and all combinations and subcombinations of
ranges and specific doses therein. Preferred doses may be from about 0.01 to about 100
mg/kg body weight per day by inhalation, preferably 0.1 to 70, more preferably 0.5 to 20
mg/Kg body weight per day by oral administration, and from about 0.01 to about 50,
preferably 0.01 to 10 mg/Kg body weight per day by intravenous administration. In each
particular case, the doses may be determined in accordance with the factors distinctive to
the subject to be treated, such as age, weight, general state of health and other
characteristics which can influence the efficacy of the medicinal product. The crystalline
forms of the compound may be administered in a single daily dose, or the total daily
dosage may be administered in divided doses of two, three, or four times daily.
For oral administration in solid form such as a tablet or capsule, the crystalline
forms of the compound can be combined with a non-toxic, pharmaceutically acceptable
inert carrier, such as lactose, starch, sucrose, glucose, methylcellulose, magnesium
stearate, dicalcium phosphate, calcium sulfate, mannitol, sorbitol and the like.
Preferably, in addition to the active ingredient, solid dosage forms may
contain a number of additional ingredients referred to herein as "excipients". These
excipients include among others diluents, binders, lubricants, glidants and disintegrants.
Coloring agents may also be incorporated. "Diluents", as used herein, are agents which
impart bulk to the formulation to make a tablet a practical size for compression.
Examples of diluents are lactose and cellulose. "Binders", as used herein, are agents used
to impart cohesive qualities to the powered material to help ensure the tablet will remain
intact after compression, as well as improving the free-flowing qualities of the powder.
Examples of typical binders are lactose, starch and various sugars. "Lubricants", as used
herein, have several functions including preventing the adhesion of the tablets to the
compression equipment and improving the flow of the granulation prior to compression
or encapsulation. Lubricants are in most cases hydrophobic materials. Excessive use of
lubricants is undesired, however, as it may result in a formulation with reduced
disintegration and/or delayed dissolution of the drug substance. “Glidants”, as used
herein, refer to substances which may improve the flow characteristics of the granulation
material. Examples of glidants include talc and colloidal silicon dioxide.
"Disintegrants", as used herein, are substances or a mixture of substances added to a
formulation to facilitate the breakup or disintegration of the solid dosage form after
administration. Materials that may serve as disintegrants include starches, clays,
celluloses, algins, gums and cross-linked polymers. A group of disintegrants referred to
as "super-disintegrants" generally are used at a low level in the solid dosage form,
typically 1% to 10% by weight relative to the total weight of the dosage unit.
Croscarmelose, crospovidone and sodium starch glycolate represent examples of a cross-
linked cellulose, a cross-linked polymer and a cross-linked starch, respectively. Sodium
starch glycolate swells seven- to twelve-fold in less than 30 seconds effectively
disintegrating the granulations that contain it.
The disintegrant preferably used in the present invention is selected from the
group comprising modified starches, croscarmallose sodium, carboxymethylcellulose
calcium and crospovidone. A more preferred disintegrant in the present invention is a
modified starch such as sodium starch glycolate.
Preferred carriers include capsules or compressed tablets which contain the
solid pharmaceutical dosage forms described herein. Preferred capsule or compressed
tablet forms generally comprise a therapeutically effective amount of the crystalline
forms of the compound and one or more disintegrants in an amount greater than about
% by weight relative to the total weight of the contents of the capsule or the total
weight of the tablet.
Preferred capsule formulations may contain the crystalline forms of the
compound in an amount from about 5 to about 1000 mg per capsule. Preferred
compressed tablet formulations contain the crystalline forms of the compound in an
amount from about 5 mg to about 800 mg per tablet. More preferred formulations
contain about 50 to about 200 mg per capsule or compressed tablet. Preferably, the
capsule or compressed tablet pharmaceutical dosage form comprises a therapeutically
effective amount of the crystalline forms; a surfactant; a disintegrant; a binder; a
lubricant; and optionally additional pharmaceutically acceptable excipients such as
diluents, glidants and the like; wherein the disintegrant is selected from modified
starches; croscarmallose sodium, carboxymethylcellulose calcium and crospovidone.
For oral administration in liquid form, the crystalline forms of the compound
can be combined with any oral, non-toxic pharmaceutically acceptable inert carrier such
as ethanol, glycerol, water and the like. The liquid composition may contain a
sweetening agent which to make the compositions more palatable. The sweetening agent
can be selected from a sugar such as sucrose, mannitol, sorbitol, xylitol, lactose, etc. or a
sugar substitute such as cyclamate, saccaharin, aspartame, etc. If sugar substitutes are
selected as the sweetening agent the amount employed in the compositions of the
invention will be substantially less than if sugars are employed. Taking this into account,
the amount of sweetening agent may range from about 0.1 to about 50% by weight, and
all combinations and subcombinations of ranges and specific amounts therein. Preferred
amounts range from about 0.5 to about 30% by weight.
The more preferred sweetening agents are the sugars and particularly sucrose.
The particle size of the powdered sucrose used has been found to have a significant
influence in the physical appearance of the finished composition and its ultimate
acceptance for taste. The preferred particle size of the sucrose component when used is
in the range of from 200 to less than 325 mesh US Standard Screen, and all combinations
and subcombinations of ranges and specific particle sizes therein.
Sterile injectable solutions may be prepared by incorporating the crystalline
forms of the compound in the required amounts, in the appropriate solvent, with various
of the other ingredients enumerated herein, as required, followed by filtered sterilization.
Generally, dispersions may be prepared by incorporating the sterilized active ingredient
into a sterile vehicle which contains the dispersion medium and any other required
ingredients. In the case of sterile powders for the preparation of sterile injectable
solutions, the preferred methods of preparation may include vacuum drying and the
freeze drying technique which may yield a powder of the active ingredient, plus any
additional desired ingredient from the previously sterile-filtered solution thereof.
As would be apparent to a person of ordinary skill in the art, once armed with
the teachings of the present disclosure, when dissolved, a crystalline compound loses its
crystalline structure, and is therefore considered to be a solution of the compound . All
forms of the present invention, however, may be used for the preparation of liquid
formulations in which the compound may be, for example, dissolved or suspended. In
addition, the crystalline forms of the compound may be incorporated into solid
formulations.
[00371] The liquid compositions may also contain other components routinely utilized
in formulating pharmaceutical compositions. One example of such components is
lecithin. Its use in compositions of the invention as an emulsifying agent in the range of
from 0.05 to 1% by weight, and all combinations and subcombinations of ranges and
specific amounts therein. More preferably, emulsifying agents may be employed in an
amount of from about 0.1 to about 0.5% by weight. Other examples of components that
may be used are antimicrobial preservatives, such as benzoic acid or parabens;
suspending agents, such as colloidal silicon dioxide; antioxidants; topical oral anesthetics;
flavoring agents; and colorants.
The selection of such optional components and their level of use in the
compositions of the invention is within the level of skill in the art and will be even better
appreciated from the working examples provided hereinafter.
The crystalline forms of the compound may also be coupled with soluble
polymers as targetable drug carriers. Such polymers can include polyvinylpyrrolidine
pyran copolymer, polyhydroxypropylmethacrylamide-phenol, polyhydroxyethyl-
aspartamidephenol or polyethylene oxide-polylysine substituted with palmitolyl residues.
Furthermore, the crystalline compound may be coupled to a class of biodegradable
polymers useful in achieving controlled release of a drug, for example, polylactic acid,
polyglycolic acid, copolymers of polylactic and polyglycolic acid, polyepsilon
caprolactone, polyhydroxy butyric acid, polyorthoesters, polyacetals, polydihydropyrans,
polycyanoacrylates and crosslinked or amphipathic block copolymers of hydrogels.
[00374] Gelatin capsules of the crystalline forms of the compound may contain the
crystalline compound and the liquid or solid compositions described herein. Gelatin
capsules may also contain powdered carriers such as lactose, starch, cellulose derivatives,
magnesium stearate, stearic acid and the like. Similar diluents can be used to make
compressed tablets. Both tablets and capsules can be manufactured as sustained release
products to provide for continuous release of medication over a period of hours. Tablets
can be sugar coated or film coated to mask any unpleasant taste and to protect the tablet
from the atmosphere or enteric coated for selective disintegration in the gastrointestinal
track.
In general, water, a suitable oil, saline, aqueous dextrose (glucose), and related
sugar solutions and glycols, such as propylene glycol or polyethylene glycols are suitable
carriers for parenteral solutions. Solutions for parenteral solutions are prepared by
dissolving the crystalline compound in the carrier and, if necessary, adding buffering
substances. Anti-oxidizing agents such as sodium bisulfite, sodium sulfite, or ascorbic
acid either alone or combined, are suitable stabilizing agents. Citric acid and its salts and
sodium EDTA may also be employed. Parenteral solutions may also contain
preservatives, such as benzalkonium chloride, methyl- or propyl-paraben and
chlorobutanol.
Suitable pharmaceutical carriers are described in Remington's Pharmaceutical
Sciences, Mack Publishing Co., the disclosures of which are hereby incorporated herein
by reference, in their entireties. Useful pharmaceutical dosage-forms for administration
of the compounds of this invention can be illustrated as follows:
Capsules
A large number of unit capsules can be prepared by filling standard two-piece
hard gelatin capsules each with 100 mg of powdered active ingredient (i.e., Factor XIa
inhibitor), 150 mg of lactose, 50 mg of cellulose, and 6 mg magnesium stearate.
Soft Gelatin Capsules
A mixture of active ingredient in a digestible oil such as soybean oil,
cottonseed oil or olive oil can be prepared and injected by means of a positive
displacement pump into gelatin to form soft gelatin capsules containing 100 mg of the
active ingredient. The capsules should then be washed and dried.
Tablets
A large number of tablets can be prepared by conventional procedures so that
the dosage unit is 100 mg of active ingredient, 0.2 mg of colloidal silicon dioxide, 5 mg
of magnesium stearate, 275 mg of microcrystalline cellulose, 11 mg of starch and 98.8
mg of lactose. Appropriate coatings may be applied to increase palatability or delay
absorption.
Suspension
[00380] An aqueous suspension can be prepared for oral administration so that each 5
mL contain 25 mg of finely divided active ingredient, 200 mg of sodium carboxymethyl
cellulose, 5 mg of sodium benzoate, 1.0 g of sorbitol solution, U.S.P., and 0.025 mg of
vanillin.
Injectable
A parenteral composition suitable for administration by injection can be
prepared by stirring 1.5% by weight of active ingredient in 10% by volume propylene
glycol and water. The solution is sterilized by commonly used techniques.
Nasal Spray
An aqueous solution is prepared such that each 1 mL contains 10 mg of active
ingredient, 1.8 mg methylparaben, 0.2 mg propylparaben and 10 mg methylcellulose.
The solution is dispensed into 1 mL vials.
Lung Inhaler
A homogeneous mixture of the active ingredient in polysorbate 80 is prepared
such that the final concentration of the active ingredient will be 10 mg per container and
the final concentration of polysorbate 80 in the container will be 1% by weight. The
mixture is dispensed into each can, the valves are crimped onto the can and the required
amount of dichlorotetrafluoroethane is added under pressure.
The preferred crystalline form of the compound may serve as component (a)
of this invention and can independently be in any dosage form, such as those described
above, and can also be administered in various combinations, as described above. In the
following description component (b) is to be understood to represent one or more agents
as described herein suitable for combination therapy.
Thus, the crystalline forms of the compound may be used alone or in
combination with other diagnostic, anticoagulant, antiplatelet, fibrinolytic,
antithrombotic, and/or profibrinolytic agents. For example, adjunctive administration of
Factor XIa inhibitors with standard heparin, low molecular weight heparin, direct
thrombin inhibitors (i.e. hirudin), aspirin, fibrinogen receptor antagonists, streptokinase,
urokinase and/or tissue plasminogen activator may result in improved antithrombotic or
thrombolytic efficacy or efficiency. The crystals described herein may be administered to
treat thrombotic complications in a variety of animals, such as primates, including
humans, sheep, horses, cattle, pigs, dogs, rats and mice. Inhibition of Factor XIa may be
useful not only in the anticoagulant therapy of individuals having thrombotic conditions,
but also when inhibition of blood coagulation may be required, such as to prevent
coagulation of stored whole blood and to prevent coagulation in other biological samples
for testing or storage. Thus, any Factor XIa inhibitor, including the crystalline forms of
the compound as described herein, can be added to or contacted with any medium
containing or suspected of containing Factor XIa and in which it may be desired to inhibit
blood coagulation.
The crystalline forms of the compound may be used in combination with any
antihypertensive agent or cholesterol or lipid regulating agent, or concurrently in the
treatment of restenosis, atherosclerosis or high blood pressure. Some examples of agents
that may be useful in combination with a novel form of the compound according to the
present invention in the treatment of high blood pressure include, for example,
compounds of the following classes: beta-blockers, ACE inhibitors, calcium channel
antagonists and alpha-receptor antagonists. Some examples of agents that may be useful
in combination with a compound according to the invention in the treatment of elevated
cholesterol levels or disregulated lipid levels include compounds known to be HMGCoA
reductase inhibitors, or compounds of the fibrate class.
Accordingly, components (a) and (b) of the present invention may be
formulated together, in a single dosage unit (that is, combined together in one capsule,
tablet, powder, or liquid, etc.) as a combination product. When component (a) and (b) are
not formulated together in a single dosage unit, the component (a) may be administered at
the same time as component (b) or in any order; for example component (a) of this
invention may be administered first, followed by administration of component (b), or they
may be administered in the reverse order. If component (b) contains more than one agent,
these agents may be administered together or in any order. When not administered at the
same time, preferably the administration of component (a) and (b) occurs less than about
one hour apart. Preferably, the route of administration of component (a) and (b) is oral.
Although it may be preferable that component (a) and component (b) both be
administered by the same route (that is, for example, both orally) or dosage form, if
desired, they may each be administered by different routes (that is, for example, one
component of the combination product may be administered orally, and another
component may be administered intravenously) or dosage forms.
Pharmaceutical kits which may be useful for the treatment of various
disorders, and which comprise a therapeutically effective amount of a pharmaceutical
composition comprising a novel form of the compound in one or more sterile containers,
are also within the ambit of the present invention. The kits may further comprise
conventional pharmaceutical kit components which will be readily apparent to those
skilled in the art, once armed with the present disclosure. Sterilization of the container
may be carried out using conventional sterilization methodology well known to those
skilled in the art.
Example 271:
Preparation of Single Crystal Forms H.5-1 and HCl:SA-1
[00389] 271A: Single Crystal X-Ray Measurement of Forms H.5-1 and HCl:SA-1
Single crystal X-ray data were collected on a Bruker AXS APEX II
diffractometer with MicroStarH generator using Cu Kα radiation (λ = 1.5418 Å).
Indexing and processing of the measured X-ray intensity data were carried out with the
APEX2 software suite (Bruker AXS, Inc., Madison, Wisconsin, USA). The structure was
solved by direct methods and refined on the basis of observed reflections using
SHELXTL crystallographic package (Bruker AXS, Inc., Madison, Wisconsin, USA). The
derived atomic parameters (coordinates and temperature factors) were refined through
full matrix least-squares. The function minimized in the refinements was Σ (|F | - |F |) .
w o c
2 1/2
R is defined as Σ ||F | - |F ||/Σ |F |, while R = [Σ (|F | - |F |) /Σ |F | ] , where w is
o c o w w o c w o
an appropriate weighting function based on errors in the observed intensities. Difference
Fourier maps were examined at all stages of refinement. All non-hydrogen atoms were
refined with anisotropic thermal displacement parameters. Hydrogen atoms were
calculated from an idealized geometry with standard bond lengths and angles and refined
using a riding model.
271B: Preparation of Single Crystal Form H.5-1
Crystal form H.5-1 (hemi-hydrate) was prepared by adding 3 mg of (S,E)
(2-(3-(3-chlorofluoro(1H-tetrazolyl)phenyl)acryloyl)(4-methyl
oxopiperazinyl)-1,2,3,4-tetrahydroisoquinolinecarboxamido)benzoic acid to 0.7 mL
of ethyl acetate and methanol solution (1:1). Yellow prism shaped crystals were obtained
after one day of slow evaporation of solution at room temperature.
Crystal Structure Data:
Unit cell dimensions:
a = 13.6547(3) Å
b = 18.7590(3) Å
c = 24.7370(5) Å
α= 90°
β= 90°
γ = 90°
Volume = 6336.3(2) Å
Crystal system: Orthorhombic
Space group: I2(1)2(1)2(1)
Molecules/asymmetric unit: 1
Density (calculated) = 1.401 Mg/m
Measurement of the crystalline form is at a temperature of about 23°C.
Table 20. Atomic coordinates (x 10 ) and equivalent isotropic displacement parameters
(Å x 10 ) for Compound (I) H.5-1.
________________________________________________________________________________
x y z U(eq)
________________________________________________________________________________
Cl(1) 1142(1) 8638(1) 1383(1) 89(1)
F(1) 1133(2) 7271(1) 862(1) 67(1)
O(1) 1102(2) 5533(1) -724(1) 52(1)
O(2) -779(1) 4373(1) 15(1) 48(1)
O(3) -4534(2) 4606(1) -1807(1) 62(1)
O(4) -3952(2) 3964(2) -2477(1) 109(1)
O(5) 3532(2) 3748(1) 1408(1) 63(1)
N(1) 1127(2) 8164(1) -968(1) 56(1)
N(2) 1654(2) 7703(2) -1270(1) 73(1)
N(3) 1416(3) 7825(2) -1768(2) 91(1)
N(4) 759(3) 8363(2) -1810(1) 97(1)
N(5) 1100(2) 5019(1) 102(1) 35(1)
N(6) -311(2) 4095(1) -837(1) 46(1)
N(7) 2057(2) 3304(1) 1616(1) 43(1)
N(8) 2218(2) 3810(1) 2664(1) 57(1)
C(1) 1203(2) 8493(2) 699(1) 57(1)
C(2) 1257(2) 9049(2) 342(2) 59(1)
C(3) 1267(2) 8920(2) -203(2) 54(1)
C(4) 1218(2) 8232(2) -398(1) 46(1)
C(5) 1210(2) 7639(1) -54(1) 41(1)
C(6) 1193(2) 7804(2) 496(1) 49(1)
C(7) 593(3) 8565(2) -1310(2) 81(1)
C(8) 1150(2) 6900(1) -250(1) 42(1)
C(9) 1279(2) 6305(1) 22(1) 45(1)
C(10) 1151(2) 5598(1) -230(1) 38(1)
C(11) 947(2) 4321(1) -154(1) 33(1)
C(12) 1229(2) 3707(1) 214(1) 36(1)
C(13) 1543(2) 3812(1) 746(1) 35(1)
C(14) 1604(2) 4554(1) 977(1) 38(1)
C(15) 912(2) 5043(1) 686(1) 39(1)
C(16) 1171(2) 3021(1) 5(1) 50(1)
C(17) 1412(2) 2438(2) 321(1) 59(1)
C(18) 1711(2) 2537(2) 845(1) 55(1)
C(19) 1785(2) 3214(1) 1053(1) 41(1)
C(20) -134(2) 4263(1) -318(1) 35(1)
C(21) -1221(2) 4098(2) -1108(1) 42(1)
C(22) -1223(3) 3919(2) -1650(1) 76(1)
C(23) -2072(3) 3948(2) -1947(1) 78(1)
C(24) -2943(2) 4163(2) -1711(1) 47(1)
C(25) -2940(2) 4313(1) -1170(1) 40(1)
C(26) -2096(2) 4271(1) -864(1) 42(1)
C(27) -3846(3) 4228(2) -2041(1) 57(1)
C(28) 2912(2) 3605(2) 1747(1) 45(1)
C(29) 3099(2) 3770(2) 2335(1) 56(1)
C(30) 1304(2) 3112(2) 2016(1) 59(1)
C(31) 1666(3) 3151(2) 2584(1) 67(1)
C(32) 2477(4) 3923(2) 3236(1) 90(1)
O(1S) 1006(2) 5000 2500 50(1)
* U(eq) is defined as one third of the trace of the orthogonalized U tensor.
271C: Preparation of Single Crystal Form HCl:SA-1
Crystal form HCl:SA-1(solvated mono-HCl salt) was prepared by adding 2
mg of Compound (I) to 0.7 mL of methanol, 2-butanone and butyl acetate solution
(2:1:1). Yellow prism shaped crystals were obtained after one day of slow evaporation of
solution at room temperature.
Crystal Structure Data:
Unit cell dimensions:
a = 8.3746(2) Å
b = 20.2236(5) Å
c = 21.3099(6) Å
α= 90°
β= 90°
γ = 90°
Volume = 3609.14(16) Å
Crystal system: Orthorhombic
Space group: P2(1)2(1)2(1)
Molecules/asymmetric unit: 1
Density (calculated) = 1.368 Mg/m
wherein measurement of the crystalline form is at a temperature of about 23°C.
Table 21. Atomic coordinates ( x 10 ) and equivalent isotropic displacement
parameters (Å x 10 ) for Compound (I) HCl:SA-1
________________________________________________________________________________
x y z U(eq)
________________________________________________________________________________
Cl(2) 4183(3) 7590(1) 7388(1) 73(1)
C(1) 5350(8) 5357(3) -5(3) 58(2)
C(2) 5189(9) 5113(3) 606(3) 62(2)
C(3) 6122(9) 4563(3) 743(3) 62(2)
C(4) 7131(8) 4259(3) 322(4) 63(2)
C(5) 7186(9) 4508(4) -278(4) 71(2)
C(6) 6312(9) 5055(4) -435(3) 72(2)
C(7) 3624(12) 6026(4) -680(4) 87(2)
C(8) 4120(11) 5408(4) 1083(3) 76(2)
C(9) 3311(10) 5137(4) 1500(4) 78(2)
C(10) 2308(8) 5511(3) 1938(3) 57(2)
C(11) 481(11) 4538(3) 1991(4) 79(2)
C(12) -331(9) 4186(3) 2541(4) 71(2)
C(13) -1725(8) 4599(3) 2754(3) 56(2)
C(14) -1568(8) 5294(3) 2755(3) 51(2)
C(15) 41(8) 5604(3) 2612(3) 50(2)
C(16) -3161(9) 4326(3) 2946(3) 59(2)
C(17) -4444(9) 4719(4) 3106(3) 69(2)
C(18) -4286(9) 5400(4) 3088(4) 70(2)
C(19) -2842(8) 5689(3) 2911(3) 60(2)
C(20) 938(8) 5679(3) 3244(3) 54(2)
C(21) 971(8) 6440(3) 4151(3) 53(2)
C(22) 2064(8) 6122(3) 4526(3) 61(2)
C(23) 2282(8) 6336(4) 5147(3) 62(2)
C(24) 1416(8) 6856(3) 5378(3) 54(2)
C(25) 315(9) 7169(3) 4999(3) 64(2)
C(26) 103(9) 6969(3) 4387(3) 62(2)
C(27) 1629(9) 7122(4) 6032(3) 67(2)
C(28) -4232(14) 3275(4) 2493(4) 101(3)
C(29) -3869(13) 2532(4) 2464(4) 96(3)
C(30) -2699(9) 2550(3) 3483(3) 66(2)
C(31) -2625(9) 3285(3) 3458(3) 60(2)
C(32) -5588(10) 2286(4) 3384(5) 102(3)
Cl(1) 8255(3) 3595(1) 563(1) 95(1)
F(1) 6062(6) 4310(2) 1340(2) 93(1)
N(1) 4510(8) 5920(3) -180(3) 71(2)
N(2) 4579(11) 6492(3) 148(3) 96(2)
N(3) 3701(14) 6911(4) -149(5) 123(3)
N(4) 3089(12) 6638(4) -679(4) 116(3)
N(5) 1037(7) 5207(2) 2179(2) 58(1)
N(6) 645(7) 6263(2) 3524(2) 58(1)
N(7) -3312(7) 3606(2) 2977(3) 60(1)
N(8) -3972(7) 2250(3) 3097(3) 68(2)
O(1) 2620(6) 6081(2) 2096(2) 70(1)
O(2) 1744(6) 5235(2) 3465(2) 63(1)
O(3) 971(7) 7602(3) 6233(2) 91(2)
O(4) 2705(7) 6777(2) 6357(2) 81(2)
O(5) -1867(7) 3575(2) 3864(3) 80(2)
O(1S) 8222(7) 5981(2) 1227(2) 70(1)
O(2S) 489(6) 5435(3) 69(3) 103(2)
O(3SB) 9450(30) 6486(13) 631(17) 126(8)
O(3SA) 9170(30) 6463(11) 1022(13) 136(7)
O(3SC) 9560(30) 6237(13) 140(14) 137(8)
________________________________________________________________________________
* U(eq) is defined as one third of the trace of the orthogonalized U tensor.
Example 272:
272A: Preparation of Form HCl:SA-1
In a reactor, 415 g of dried crude Compound (I) was dissolved in 9.0 kg of a
solution of 200 Proof Ethanol and purified water (70:30). The batch was heated to 66 °C
and polish filtered into another reactor. 708 g of the Ethanol/water solution was used to
rinse the first reactor and transferred through the filter into the reactor containing the
solution mixture. The temperature of the batch was lowered to 50 °C and 2.24 g of
Compound (I) was added in one portion. After 30 minutes the batch was cooled to 0 °C
over 4 h and allowed to age at that temperature for 60 minutes. The temperature of the
batch was then increased to 50 °C over a 2 h period and held for an additional 30
minutes. Again, the batch temperature was then reduced to 0 °C over 4 h and 2.9 L of
200 Proof ethanol was added to the batch. The slurry was filtered at 0 °C and the wet
cake was washed twice with 0.9 L of 200 Proof ethanol. The wet cake was dried in a
vacuum oven at 40 °C for a minimum of 12 h and until the ethanol content is <6.6 weight
percent. The obtained crystal was subjected to PXRD (GADDS-NB), hybrid PXRD
(from isostructural analog), DSC and TGA analyses and the results are shown in Figures
1, 4, and 7.
PXRD data were obtained using a Bruker C2 GADDS. The radiation was Cu
Kα (40 KV, 40mA). The sample-detector distance was 15 cm. Powder samples were
placed in sealed glass capillaries of 1mm or less in diameter; the capillary was rotated
during data collection. Data were collected approximately for 2≤2θ≤35° with a sample
exposure time of at least 1000 seconds. The resulting two-dimensional diffraction arcs
were integrated to create a traditional 1-dimensional PXRD pattern with a step size of
0.05 degrees 2θ in the approximate range of 2 to 35 degrees 2θ.
“Hybrid” simulated powder X-ray patterns were generated as described in the
literature (Yin. S.; Scaringe, R. P.; DiMarco, J.; Galella, M. and Gougoutas, J. Z.,
American Pharmaceutical Review, 2003, 6,2, 80). The room temperature cell parameters
were obtained by performing a cell refinement using the CellRefine.xls program. Input to
the program includes the 2-theta position of ca. 10 reflections, obtained from the
experimental room temperature powder pattern; the corresponding Miller indices, hkl,
were assigned based on the single-crystal data collected for an isostructural analog. A
crystal structure for the molecule of interest was generated in a two step process: (1) by
replacing the analog molecule in the experimental analog crystal structure with the
molecule of interest. This step fixes the orientation and position of the molecule of
interest in the unit cell of the analog compound; (2) Inserting the molecule of interest into
the room temperature cell obtained from the experimental PXRD of the molecule of
interest, as described above. In this step, the molecules are inserted in a manner that
retains the size and shape of the molecule and the position of the molecules with respect
to the cell origin, but, allows intermolecular distances to expand/contract with the cell. A
new (hybrid) PXRD was calculated (by either of the software programs, Alex or
LatticeView) based on the crystal structure generated as described above.
DSC (open pan)
DSC experiments were performed in a TA INSTRUMENTS® model Q2000,
Q1000 or 2920. The sample (about 2-10 mg) was weighed in an aluminum pan and
recorded accurately recorded to a hundredth of a milligram, and transferred to the DSC.
The instrument was purged with nitrogen gas at 50mL/min. Data were collected between
room temperature and 300 °C at 10 °C/min heating rate. The plot was made with the
endothermic peaks pointing down.
TGA (open pan)
[00400] TGA experiments were performed in a TA INSTRUMENTS® model Q5000,
Q500 or 2950. The sample (about 4-30 mg) was placed in a platinum pan previously
tared. The weight of the sample was measured accurately and recorded to a thousandth of
a milligram by the instrument. The furnace was purged with nitrogen gas at 100 mL/min.
Data were collected between room temperature and 300 °C at 10 °C/min heating rate.
Example 273:
[00401] 273A: Preparation of Form H.5-1
60 g of dried crude Compound (I) was dissolved in 240 mL of 200 Proof
ethanol (4 mL/g) at room temperature. In one portion, 13.25 mL of triethylamine (1.1
equiv) was added and the reaction mixture was aged for a minimum of 3 h. The solution
was cooled to 0 °C and remained at that temperature for a minimum of 30 min. The
slurry was filtered and the solids were washed with 30 mL of 200 Proof ethanol (0.5
mL/g). The wet cake was dissolved in 600 mL of purified water (10 mL/g) and stirred
for a minimum of 30 min at room temperature. The slurry was filtered and the solids
were washed with 120 mL of purified water (2 mL/g) and then 180 mL of purified water
(3 mL/g). The wet cake was dried at 45 ºC under vacuum for a minimum of 12 h. The
obtained crystal was subjected to further analyses and the results are shown in Figures 2,
6, and 9.
Example 274:
274A: Preparation of Form P13
[00404] A slurry of 6.8 g of Example 271 in 33 mL of methanol (4.9 mL/g) and 102
mL of dichlormethane (15 mL/g) was heated to 40 °C and became a homogeneous
solution. Atmospheric distillation with constant volume addition of dichloromethane
(136 mL) was performed over the next hour with batch temperature maintained at 40 °C.
The batch was cooled to 15 °C, and a solvent swap from dichloromethane/methanol
solution to ethyl acetate at constant volume was initiated under reduced pressure (150
mmHg). The batch temperature was raised to 37 °C, 400 mL of ethyl acetate was used to
complete the solvent swap with a remainder of 136 mL of ethyl acetate in the reactor.
The batch was cooled to 20 °C and allowed to age for 12 h. The slurry was filtered and
the resulting wet cake was dried at 50 °C under reduced pressure for 6 h. The dried
material was subjected to PXRD, Solid-State Nuclear Magnetic Resonance (SSNMR) and
the results are shown in Figures 3, 5, 8, 10, and 11.
Carbon cross polarization magic angle spinning (CPMAS) solid state NMR
experiments were conducted on a Bruker AV III instrument operating at a proton
frequency of 400.1 MHz. Solid samples were spun at 13 KHz in a 4 mm ZrO rotor. The
contact time was 3 miliseconds and was ramped on the proton channel from 50 to
100%.(A.E. Bennett et al, J. Chem. Phys.,1995, 103, 6951),(G. Metz, X. Wu and S.O.
Smith, J. Magn. Reson. A,. 1994, 110, 219-227). The relaxation delay was maintained at
seconds. Proton decoupling was applied using a TPPM sequence with a 4
microsecond pulse (62.5KHz nominal band width). The spectral sweep width was 300
ppm centered at 100 ppm. 4096 data points were acquired and zero filled to 8192 prior to
apodization with 20 Hz line broadening. Typically 2096 free induction decays were
coadded. The spectra were referenced indirectly to TMS using 3-methylglutaric acid (D.
Barich, E. Gorman, M. Zell, and E. Munson, Solid State Nuc. Mag. Res., 2006, 30, 125-
129). Approximately 70 mg of sample was used for each experiment.
Fluorine magic angle spinning (MAS) solid state and cross polarization magic
angle spinning (CPMAS) solid state NMR experiments were conducted on a Bruker AV
III instrument operating at a proton frequency of 400.1 MHz. Solid samples were spun at
11, 12 and 13 KHz in a 4 mm ZrO rotor. Data collected at 13KHz is reported. The
relaxation delay was maintained at 30 seconds for the MAS and 5 seconds for the
CPMAS experiments. Proton decoupling was applied to the CPMAS experiments using a
TPPM sequence with a 4 microsecond pulse (62.5KHz nominal band width). The
spectral sweep width was 500 ppm centered at -100 ppm. 4096 data points were acquired
and zero filled to 8192 prior to apodization with 20 Hz line broadening. Typically 256
free induction decays were coadded. The spectra were referenced indirectly to CCl F
using PTFE (at -122 ppm).
Various crystalline forms of (S,E)(2-(3-(3-chlorofluoro(1H-tetrazol-
1-yl)phenyl)acryloyl)(4-methyloxopiperazinyl)-1,2,3,4-tetrahydroisoquinoline
carboxamido)benzoic acid and its solvates were prepared and their characteristic peak
positions are tabulated in Table 22. The unit cell data and other properties for these
examples are tabulated in Tables 23-25. The unit cell parameters were obtained from
single crystal X-ray crystallographic analysis. A detailed account of unit cells can be
found in Chapter 3 of Stout & Jensen, “X-Ray Structure Determination: A Practical
Guide”, (MacMillian, 1968).
Table 22. Characteristic diffraction peak positions (degrees 2θ±0.1) @ RT, based on a
high quality pattern collected with a diffractometer (CuKα) with a spinning capillary with
2θ calibrated with a NIST other suitable standard.
HCl:SA-1 Free Base H.5-1 Free Base P13
6.0 5.9 8.4
8.3 7.2 8.9
8.7 12.0 12.7
12.3 15.7 17.9
16.2 17.2
16.7 18.9
17.5 20.3
19.9 24.2
.4 26.1
Table 23. Cell Parameters for Single crystal (input) and hybrid (refined) for Form HCl:
SA-1
Cell Parameter Input Refined
a (Å) 8.3746 8.2562
b(Å) 20.2236 20.2918
21.3099 21.2423
c(Å)
α° 90 90
β° 90 90
γ° 90 90
3609.14 3558.77
Volume (Å )
Table 24. Carbon Chemical Shifts (referenced to external TMS) for P13
No. (ppm)
1 23.8
2 24.8
3 41.1
4 43.0
45.1
6 45.9
7 48.5
8 49.0
9 51.0
52.4
11 56.8
12 57.6
13 58.6
14 61.7
118.1
16 121.7
17 122.0
18 122.5
19 123.0
124.2
21 126.1
22 127.1
23 127.9
24 129.0
129.9
26 130.5
27 130.6
28 131.8
29 132.6
133.3
31 135.0
32 139.9
33 140.4
34 143.6
146.1
36 147.3
37 156.6
38 157.9
39 159.2
40 160.4
41 165.7
42 166.3
43 168.7
44 169.7
45 171.4
Table 25. F-19 Chemical Shifts (referenced to external CCl F) for P13
No. (ppm)
40 1 -109.8
2 -106.3
Numerous modifications and variations of the present invention are possible in
light of the above teachings. It is therefore to be understood that within the scope of the
45 appended claims, the invention may be practiced otherwise than as specifically described
herein.
12027 PCT
Claims (21)
1. A compound according to formula (I): (R ) (R ) or a stereoisomer, tautomer, pharmaceutically acceptable salt thereof, wherein: ring A is C carbocycle; ring B is 4- to 7-membered heterocycle containing carbon atoms and 0-3 additional heteroatoms selected from the group consisting of N, NR , O, and S(O) ; optionally, ring B forms a fused ring or spiro ring with a 4- to 7-membered heterocycle containing carbon atoms and 1-3 heteroatoms selected from the group consisting of NR , O, and S(O) ; ring B, including the fused ring or spiro ring is substituted with 1-3 R ; 10 10 10 10 L is selected from the group consisting of: -CHR CHR -, -CR =CR -, 10 10 -C≡C-, -CHR NH-, -NHCHR -, -SCH -, -CH S-, -SO CH -, - CH SO -, -NHCH -, 2 2 2 2 2 2 2 and -CH NH-; R , at each occurrence, is selected from the group consisting of: H, halo, C alkyl, C alkoxy, C alkylthio, OH, SH, CHF , CF , OCF , CN, NH , COC alkyl, 2 3 3 2 1-4 1-4 1-4 CO (C alkyl), -CH CO H, -CH CO (C alkyl), -CH NH , 2 2 2 2 2 2 2 1-4 1-4 -CONH , -CONH(C alkyl), -NHCO(C alkyl), -NHCO (C alkyl), 1-4 1-4 1-4 -NHSO (C alkyl), and -SO NH , and -C(=NH)NH ; 2 2 2 2 R is selected from the group consisting of: H, halo, CN, OH, C alkyl, C alkoxy, C haloalkyl, C haloalkoxy, CO(C alkyl), CONH , CO H, 1-6 1-4 1-6 1-6 1-4 CH NH , and a 5- to 7-membered heterocycle comprising carbon atoms and 1-4 12027 PCT heteroatoms selected from N, NR , O, and S(O) , wherein said heterocycle is substituted with 0-2 R ; R , at each occurrence, is selected from the group consisting of: H, halo, C alkyl, -CH OH, C alkoxy, OH, CF , OCF , CN, NH , CO H, 3 3 2 2 2 1-4 CO (C alkyl), CO(C alkyl), -CONH , -CH OH, -CH OC alkyl, -CH NH -, 2 2 1-4 2 2 2 2 1-4 1-4 CONH(C alkyl), -CON(C alkyl) , -SO (C alkyl), -SO NH , -SO NH(C 2 2 2 2 2 1-4 1-4 1-4 1-4 alkyl), and -SO N(C alkyl) ; 3 3a R is selected from the group consisting of: C alkyl substituted with 1-3 R , - (CH ) -C carbocycle substituted with 0-3 R or -(CH ) 10 membered heterocycle 2 n 3-10 2 n containing carbon atoms and 1-4 heteroatoms selected from the group consisting of N, 7 3a NR , O, and S(O) ; wherein said heterocycle is substituted with 0-3 R ; R , at each occurrence, is selected from the group consisting of: =O, halo, C alkyl, OH, C alkoxy, CN, NH , CO H, CO (C alkyl), CONH CONH(C alkyl), 2 2 2 2, 1-4 1-4 1-6 CON(C alkyl) -CONH-C alkylene-CO (C alkyl), 2, 2 1-4 1-4 1-4 -CONHCO C alkyl, -CONH-C alkylene-NHCO(C alkyl), 2 1-4 1-4 1-4 -CONH-C alkylene-CONH , -NHCOC alkyl, -NHCO (C alkyl), 1-4 1-4 1-4 f f f -C alkylene-NHCO C alkyl, R , CONHR , and -CO R ; 1-4 2 1-4 R , at each occurrence, is selected from the group consisting of: H, halo and C alkyl; R , at each occurrence, is selected from the group consisting of: H, =O, halo, C alkyl, OH, CN, NH , -N(C alkyl) , NO , C alkoxy, -OCO(C alkyl), -O-C 2 1-4 2 1-4 1-4 1-4 alkylene-O(C alkyl), -O-C alkylene-N(C alkyl) , -CO H, -CO (C alkyl), - 1-4 1-4 1-4 2 2 2 1-4 CONH , -(CH ) CONH , -CONR (C alkyl), -CONR -C alkylene-O(C alkyl), - 2 2 2 2 1-4 1-4 1-4 CON(C alkyl) , -CONR -C alkylene-N(C alkyl) , -CON(C alkyl)-C 1-4 2 1-4 1-4 1-4 1-4 alkylene-O(C alkyl), -CONR -C alkylene-CO (C alkyl), -NR COC alkyl, - 1-4 1-4 2 1-4 1-4 9 9 9 9 NR CO C alkyl, -NR CONH(C alkyl), -NR CONR -C alkylene-CO C alkyl, - 2 1-4 1-4 1-4 2 1-4 8 8 8 8 8 NR -C alkylene-N(C alkyl) , R , -OR , -O-C alkylene-R , -COR , -CO R , - 1-4 1-4 1-4 2 9 9 9 9 9 8 8 8 8 CONR R , -NR COR , -NR CO R , and -NR CON R R ; 12027 PCT R is selected from the group consisting of: H, C alkyl, -CO (C alkyl), - 1-4 2 1-4 CO(C alkyl), -CONH , -CO-C alkylene-N(C alkyl) , -(CH ) N(C alkyl) , - 1-4 2 1-4 1-4 1-4 9 9 9 CONR (C alkyl), -CONR -C alkylene-O(C alkyl), -CONR -C alkylene-N(C 1-4 1-4 1-4 1-4 1- alkyl) , -CONR -C alkylene-CO (C alkyl), -CON(C alkyl) , R , -COR , - 4 1-4 2 1-4 1-4 2 CO R , and -CONR R ; R , at each occurrence, is selected from the group consisting of: H, C alkyl, COC alkyl, CO (C alkyl), CO Bn, -CONH-C alkylene-CO C alkyl, phenyl, 1-4 2 1-4 2 1-4 2 1-4 benzyl, and -CO -C alkylene-aryl; 2 1-4 R , at each occurrence, is selected from the group consisting of: -(CH ) -C carbocycle substituted with 0-3 R and -(CH ) 10 membered 2 n 3-10 2 n heterocycle containing carbon atoms and 1-4 heteroatoms selected from the group consisting of N, NR , O, and S(O) ; wherein said carbocycle and heterocycle are optionally substituted with =O; R , at each occurrence, is selected from the group consisting of: H and C alkyl; R , at each occurrence, is selected from the group consisting of: H, halo, OH, and C alkyl; R is, independently at each occurrence, selected from the group consisting of: H, C alkyl, COC alkyl, CO C alkyl, and CO Bn; 1-4 1-4 2 1-4 2 R is, independently at each occurrence, selected from the group consisting of: H, C alkyl, CO(C alkyl), COCF , CO (C alkyl), 1-4 1-4 1-4 -CONH-C alkylene-CO C alkyl, CO Bn, R , and CONHR ; 1-4 2 1-4 R is, independently at each occurrence, selected from the group consisting of: =O, halo, C alkyl, C alkoxy, OCF , NH , NO , N(C alkyl) , CO(C alkyl), 3 2 2 2 1-4 1-4 1-4 1-4 CO(C haloalkyl), CO (C alkyl), CONH , -CONH(C alkyl), -CONHPh, - 1-4 2 1-4 1-4 CON(C alkyl) , -CONH-C alkylene-O(C alkyl), -CONH-C alkylene-N(C 1-4 1-4 1-4 1-4 1-4 f f f alkyl) , -CONH-C alkylene-CO (C alkyl), -NHCO (C alkyl), R , COR , CO R 2 1-4 2 1-4 2 1-4 and CONHR ; R is, independently at each occurrence, selected from the group consisting of: 12027 PCT -(CH ) -C cycloalkyl, -(CH ) -phenyl, and -(CH ) to 6- membered heterocycle 2 n 3-6 2 n 2 n containing carbon atoms and 1-4 heteroatoms selected from the group consisting of N, NR , O, and S(O) ; wherein each ring moiety is substituted with 0-2 R ; R is, independently at each occurrence, selected from the group consisting of: =O, halo, C alkyl, OH, C alkoxy, and NHCO(C alkyl); 1-4 1-4 1-4 n, at each occurrence, is selected from 0, 1, 2, 3, and 4; and p, at each occurrence, is selected from 0, 1, and 2.
2. The compound of claim 1, or a stereoisomer, tautomer, pharmaceutically acceptable salt thereof, wherein: ring A is C carbocycle; ring B is 4- to 7-membered heterocycle containing carbon atoms and 0-3 additional heteroatoms selected from the group consisting of N, NR , O, and S(O) ; optionally, ring B forms a fused ring or spiro ring with a 4- to 7-membered heterocycle containing carbon atoms and 1-3 heteroatoms selected from the group consisting of NR , O, and S(O) ; ring B, including the fused ring or spiro ring is substituted with 1-3 R ; 10 10 10 10 L is selected from the group consisting of: -CHR CHR -, -CR =CR -, and - C≡C-; R , at each occurrence, is selected from the group consisting of: H, halo, C alkyl, -O(C alkyl), CN, -CH NH , and -C(=NH)NH ; 1-4 2 2 R is independently selected from the group consisting of: H, halo, CN, OH C alkyl, C alkoxy, C haloalkyl, C haloalkoxy, CO(C alkyl), and a 5- to 7- 1-6 1-4 1-6 1-6 1-4 membered heterocycle comprising carbon atoms and 1-4 heteroatoms selected from N, NH, N(C alkyl), O, and S(O) , wherein said heterocycle is substituted with 1-2 R ; R , at each occurrence, is selected from the group consisting of: H, halo, C alkyl, CO H, -CO (C alkyl), -CONH , -CH OH, -CH OC alkyl, and -CH NH ; 2 2 1-4 2 2 2 1-4 3 3a R is selected from the group consisting of: C alkyl substituted with 1-3 R , C carbocycle substituted with 1-3 R , and 5-10 membered heterocycle containing 3-10 carbon atoms and 1-4 heteroatoms selected from the group consisting of N, NR , O, and S(O) ; wherein said heterocycle is substituted with 1-3 R ; 12027 PCT R , at each occurrence, is selected from the group consisting of: halo, C alkyl, -OH, C alkoxy, -CN, -NH , -CO H, -CO (C alkyl), -CONH -CONH(C alkyl), 2 2 2 2, 1-4 1-4 1-6 -CON(C alkyl) -CONH-C alkylene-CO (C alkyl), -CONHCO C alkyl, - 2, 2 1-4 1-4 1-4 2 1-4 CONH-C alkylene-NHCO(C alkyl), -CONH-C alkylene-CONH , -NHCOC 1-4 1-4 1-4 1-4 f f f alkyl, -NHCO (C alkyl), R , -CONHR , and -CO R ; R , at each occurrence, is selected from the group consisting of: H, halo, and C alkyl; R , at each occurrence, is selected from the group consisting of: H, =O, halo, C alkyl, OH, CN, NH , -N(C alkyl) , NO , C alkoxy, -OCO(C alkyl), -O-C 2 1-4 2 2 1-4 1-4 1-4 alkylene-O(C alkyl), -O-C alkylene-N(C alkyl) , -CO H, -CO (C alkyl), - 1-4 1-4 1-4 2 2 2 1-4 CONH , -(CH ) CONH , -CONR (C alkyl), -CONR -C alkylene-O(C alkyl), - 2 2 2 2 1-4 1-4 1-4 CON(C alkyl) , -CONR -C alkylene-N(C alkyl) , -CON(C alkyl)-C 1-4 2 1-4 1-4 1-4 1-4 alkylene-O(C alkyl), -CONR -C alkylene-CO (C alkyl), -NR COC alkyl, - 1-4 1-4 2 1-4 1-4 9 9 9 9 NR CO C alkyl, -NR CONH(C alkyl), -NR CONR -C alkylene-CO C alkyl, - 2 1-4 1-4 1-4 2 1-4 8 8 8 8 8 NR -C alkylene-N(C alkyl) , R , -OR , -O-C alkylene-R , -COR , -CO R , - 1-4 1-4 1-4 2 9 9 9 9 9 8 8 8 8 CONR R , -NR COR , -NR CO R , and -NR CON R R ; R is selected from the group consisting of: H, C alkyl, -CO (C alkyl), - 1-4 2 1-4 CO(C alkyl), -CONH , -CO-C alkylene-N(C alkyl) , -(CH ) N(C alkyl) , - 1-4 2 1-4 1-4 1-4 9 9 9 CONR (C alkyl), -CONR -C alkylene-O(C alkyl), -CONR -C alkylene-N(C 1-4 1-4 1-4 1-4 1- alkyl) , -CONR -C alkylene-CO (C alkyl), -CON(C alkyl) , R , -COR , - 4 1-4 2 1-4 1-4 2 CO R , and -CONR R ; R , at each occurrence, is selected from the group consisting of: H, C alkyl, - CO (C alkyl), and -CO -C alkylene-aryl; 2 1-4 2 1-4 R , at each occurrence, is selected from the group consisting of: -(CH ) -C carbocycle and -(CH ) 10 membered heterocycle containing carbon 2 n 3-10 2 n atoms and 1-4 heteroatoms selected from the group consisting of N, NH, N(C alkyl), O, and S(O) ; wherein said carbocycle and heterocycle are optionally substituted with R , at each occurrence, is selected from the group consisting of: H and C alkyl; 12027 PCT R , at each occurrence, is selected from the group consisting of: H and F; R , at each occurrence, is selected from the group consisting of: -(CH ) -C cycloalkyl, -(CH ) -phenyl, and -(CH ) to 6- membered heterocycle; 2 n 3-6 2 n 2 n wherein each ring moiety is substituted with 0-2 R ; R is, independently at each occurrence, selected from the group consisting of: =O, halo, C alkyl, OH, C alkoxy, and NHCO(C alkyl); 1-4 1-4 1-4 n, at each occurrence, is selected from 0, 1, 2, 3, and 4; and p, at each occurrence, is selected from 0, 1, and 2.
3. The compound of claim 2 having formula (II): q 5a (R ) (II) or a stereoisomer, tautomer, pharmaceutically acceptable salt thereof, wherein: 5b 5c 6 W is selected from the group consisting of CR R , O, S(O) , and NR ; 4a 4b 4c 4d R , R , R , and R are independently selected from the group consisting of: H, F, and C alkyl; R is selected from the group consisting of: H and =O; 5b 5c R and R are independently selected from the group consisting of: H, halo, C alkyl, OH, CN, NH , -N(C alkyl) , C alkoxy, -OCO-C alkyl, -O-C alkylene- 4 2 1-4 1-4 1-4 1-4 N(C alkyl) , -O-C alkylene-O(C alkyl), -CO H, -CO (C alkyl), -CONH , - 1-4 2 1-4 1-4 2 2 1-4 2 8 8 8 8 CONR (C alkyl), -CON(C alkyl) , R , -OR , -COR , and -CO R ; 1-4 1-4 2 5b 5c optionally, R and R together with the carbon atom to which they are attached form a 4-7 membered heterocyclic ring containing carbon atoms and 1-3 heteroatoms 12027 PCT selected from the group consisting of NR , O, and S(O) ; wherein said heterocycle is unsubstituted or substituted with =O. q, at each occurrence, is selected from 0, 1, and 2; and r, at each occurrence, is selected from 0, 1, and 2.
4. The compound of claim 3 having formula (III): q 5a (III) or a stereoisomer, tautomer, pharmaceutically acceptable salt thereof, wherein: R is selected from the group consisting of: H, halo, C alkyl, and methoxy; R is selected from the group consisting of: H and halo; R is independently selected from the group consisting of: H, F, CN, OH, C alkoxy, -CHF , -CF , -OCHF , -CO(C alkyl), triazole substituted with R , and 2 3 2 1-4 tetrazole substituted with R ; 3 3a R is selected from the group consisting of: phenyl substituted with 1-2 R , C 3a 3a cycloalkyl substituted with 1-2 R , heterocycle substituted with 1-2 R ; wherein said heterocycle is selected from the group consisting of: piperidinyl, pyridyl, indolyl, and indazolyl.
5. A compound of claim 4 having formula (IV): 12027 PCT q 5a (IV) or a stereoisomer, tautomer, pharmaceutically acceptable salt thereof, wherein: q 5a 6 6 0-2 R 0-2 R N N N 0-2 0-2 is selected from the group consisting of: , 5b 5b 6 0-2 R R N O O S 5c 5c N N N N N N , , , , , , and 3 3a R is selected from the group consisting of: phenyl substituted with 1-2 R , 3a 3a pyridyl substituted with 1-2 R , C cycloalkyl substituted with 1-2 R , , and ; R is selected from the group consisting of: C alkyl.
6. The compound of claim 5 having formula (V): 12027 PCT q 5a or a stereoisomer, tautomer, pharmaceutically acceptable salt thereof, wherein: 3 3a R is selected from the group consisting of: phenyl substituted with 1-2 R and pyridyl substituted with 1-2 R ; q 5a is selected from the group consisting of: , , 5b 5b 6 R R 5c 5c N N N , , , , R 5b O O S N N N N N , , , , , , and R , at each occurrence, is selected from the group consisting of: halo, C alkyl, OH, C alkoxy, CN, NH , -CO H, -CO (C alkyl), -CONH CONH(C alkyl), - 2 2 2 2, 1-4 1-4 1-4 f f f CON(C alkyl) ; , -NHCO (C alkyl), R , -CONHR and CO R ; 1-4 1-4 5b 5c R and R are independently selected from the group consisting of: H, C alkyl, OH, CN, NH , -N(C alkyl) , C alkoxy, -OCO-C alkyl, -CO H, -CO (C 2 1-4 1-4 1-4 2 2 1-4 12027 PCT 8 8 8 alkyl), -CONH , -CONR (C alkyl), -CON(C alkyl) , R , -OR , -COR , and - 2 1-4 1-4 CO R ; 5b 5c optionally, R and R together with the carbon atom to which they are both attached form a 5-6 membered heterocyclic ring containing carbon atoms and 1-3 heteroatoms selected from the group consisting of NR , O, and S(O) ; wherein said heterocycle is unsubstituted or substituted with =O; and R is selected from the group consisting of: H, C alkyl, -CO (C alkyl), - 1-4 2 1-4 CO(C alkyl), -CO-C alkylene-N(C alkyl) , -CONH , -(CH ) N(C alkyl) , - 2 2 2 2 1-4 1-4 1-4 2 1-4 CONH(C alkyl), -CONH-C alkylene-O(C alkyl), -CONH-C alkylene-N(C 1-4 1-4 1-4 1-4 1-4 alkyl) , -CONH-C alkylene-CO (C alkyl), -CON(C alkyl) , R , -COR , and - 1-4 2 1-4 1-4 2 CO R .
7. The compound of claim 6, having formula (VI): (VI) or a stereoisomer, tautomer, pharmaceutically acceptable salt thereof, wherein: R is independently selected from the group consisting of: H and F; R is selected from the group consisting of: halo, CN, CO H, -CO (C alkyl), - CONH CONH(C alkyl), -NHCO (C alkyl), -CO (C cycloalkyl), -CO (CH ) 2 2 1- 2, - 2 2 1-4 1-4 3-6 Ph, and -CO (CH ) triazole. 2 2 1-2
8. The compound of claim 7, wherein: 12027 PCT 0-2 5a 6 is selected from the group consisting of :, , , , N N N N , , , , , C alkyl C alkyl OC alkyl 1-4 1-4 HO 2 N N N N N , , , , C alkyl C alkyl C alkyl 1-4 C alkylene-N(C alkyl) C alkylene-O(C alkyl) 1-4 1-4 2 1-4 1-4 C alkyl , , , C alkyl O N N N C alkyl O O O O O N O N N N , , , , , C alkyl C alkyl N N N N , , , , N N N N , , , , N N N , , , , 12027 PCT C alkyl C alkyl N N N , , , , , O O S S N N N N , , , , and ; R is independently selected from the group consisting of: F, Cl, CN, CO H, - CO Me, -CO Et , -CO (i-Pr), -CO (t-Bu), -CO (n-Bu), -CO (i-Bu), -NHCO Me, - 2 2 2 2 2 2 2 CO CH (phenyl), -CO (C cycloalkyl) and -CO (CH ) -triazole; and 2 2 , 2 2 R is selected from the group consisting of: H, C alkyl, -CO (C alkyl), - 1-4 2 1-4 CO(C alkyl), -COCH N(C alkyl) , -(CH ) N(C alkyl) , -CONH(C alkyl), - 2 2 2 2 2 1-4 1-4 1-4 1-4 CONH-C alkylene-O(C alkyl), -CONH-C alkylene-N(C alkyl) , -CONH-C 1-4 1-4 1-4 1-4 1-4 alkylene-CO (C alkyl), -CH Ph, and -CO -C alkylene-Ph. 2 1-4 2 1-4
9. The compound of claim 3 having Formula (VII): (VII) or a stereoisomer, tautomer, pharmaceutically acceptable salt thereof, wherein: R is selected from the group consisting of: H and F; 5a 6 6 is selected from the group consisting of: , 5b 5b 6 6 O 5c 5c R R O N N N N N , , , , , 12027 PCT O O S S N N N N N N , , , , , 5c 6 R 5b N N N N N N , , , , , and ; R is selected from the group consisting of: H, F, CN, COMe, OH, OMe, OCHF , CHF , CF , and tetrazole; 3 3a R is selected from the group consisting of: phenyl substituted with 1-2 R , cyclohexyl, , and ; R is independently selected from the group consisting of: F, Cl, CN, CO H, - CO Me, -CO Et, -CO (i-Pr), -CO (t-Bu), -CO (n-Bu), -CO (i-Bu), -NHCO Me, - 2 2 2 2 2 2 2 CO (CH ) -triazole, and -CO (cyclopentyl); 2 2 2 4c 4d R and R are independently selected from the group consisting of: H and Me; 5b 5c R and R are, independently selected from the group consisting of: H, F, Me, Et, i-propyl, CN, OH, -OMe, -CO Me, -CO Et, -CON(Me) , NH , -N(Me) , - O(CH )N(Me) , -O(CH )OMe, , , , , 2 2 2 O HN , , , and ; 12027 PCT R is selected from the group consisting of: H, Me, -CO Me, -CO (t-butyl), - COMe, -CONHMe, -CONH(CH ) CO Et, CONH(CH ) N(Me) , -CO CH Ph, - 2 2 2 2 2 2 (CH ) N(Me) , and -CH Ph; 2 2 2 2 R is Me; q, at each occurrence, is selected from 0, 1, and 2; and r, at each occurrence, is selected from 0, 1, and 2.
10. The compound of claim 9 having Formula (VIII): O 3a (VIII) or a stereoisomer, tautomer, pharmaceutically acceptable salt thereof, wherein: R is selected from the group consisting of: H, F, CN, COMe, OH, OMe, OCHF , CHF , CF , and tetrazole; R is selected from the group consisting of: F, Cl, CN, CO H, CO Me, -CO Et, - 2 2 2 CO (i-Pr), -CO (t-Bu), -CO (n-Bu), -CO (i-Bu), - and NHCO Me; 2 2 2 2 2 R is selected from the group consisting of: H, Me, -CO Me, -CO (t-butyl), - COMe, and –CONHMe; q is 1or 2; and r is 1 or 2.
11. The compound of claim 1 having formula (IX): 12027 PCT H 1b (IX) or a stereoisomer, tautomer, pharmaceutically acceptable salt thereof, wherein: R is selected from the group consisting of: H, Cl, C alkyl, and methoxy; R is selected from the group consisting of: H and F; R is selected from the group consisting of: H, C alkyl, -CO(C alkyl), 1-4 1-4 CO H, -CO (C alkyl), -CONH(C alkyl), and -CO(CH ) N(C alkyl) ; and 2 2 1-4 1-4 2 0-2 1-4 2 R is selected from the group consisting of: F, Cl, CN, CO H, -CO Et, and - CO (t-Bu).
12. The compound of claim 1, wherein: ring B is heteroaryl or bridged heterocycle, each containing carbon atoms and 0-2 additional heteroatoms selected from the group consisting of N, NH, O, and S(O) , and each substituted with 1-3 R ; R is selected from the group consisting of: H, F, CN, -CO(C alkyl), OH, - O(C alkyl), -OCHF , -CHF , -CF , triazole, and tetrazole, wherein said triazole and 1-4 2 2 3 tetrazole are substituted with 0-2 R ; and R , at each occurrence, is selected from the group consisting of: H, =O, halo, C alkyl, OH, CN, NH , -N(C alkyl) , C alkoxy, -CO H, -CO (C alkyl), -CONH , - 2 1-4 1-4 2 2 1-4 2 CONR (C alkyl), -CON(C alkyl) , R , and -COR . 1-4 1-4 2 12027 PCT
13. A compound according to claim 1 or a stereoisomer, tautomer, pharmaceutically acceptable salt or solvate thereof, wherein the compound is selected from N N R" wherein R, R’ and R’’ are: R R’ R” H Piperazine F Piperazine COOH F Piperazine NHCOOCH F Piperazine F Piperazine F Piperazine COOtBu F Piperazine F Piperazine 6-indazoleCBz 12027 PCT R R’ R” F Boc-piperazine 6-indazoletBoc F Piperazine 6-indazole N N R' wherein R and R’ are: Stereochemistry R R’ R enantiomer 2-F COOH S enantiomer 2-F COOH S enantiomer 4-F 6-indazole R enantiomer 4-F 6-indazole R enantiomer 4-F COOH S enantiomer 4-F COOH 12027 PCT N N R' wherein R, R’ and R’’ are: R R’ R” F PhCOOH CH H PhNHCOO CH CH F PhCN CH H PhCOOH H PhCOOH CH OOC- H PhNHCOO CH F PhNHCOO CH CH OOC- F PhF CH OOC- F PhCN CH OOC- F 6-indazole CH wherein R' is 12027 PCT R’ Stereochemistry COOEt R-enantiomer COOEt S-enantiomer COOH R-enantiomer COOH S-enantiomer O R" wherein R, R’ and R’’ are: Stereochemistry R R’ R” Racemic tetrazole 2-F COOH S-enantiomer tetrazole 2-F COOH R-enantiomer tetrazole 2-F COOH S-enantiomer tetrazole 2-F COOtBu Racemic -COMe 2-F COOH R-enantiomer -COMe 2-F COOH S-enantiomer -COMe 2-F COOH R-enantiomer tetrazole 4-F COOH S-enantiomer tetrazole 4-F COOH Racemic tetrazole 2-F COOEt R-enantiomer tetrazole 2-F COOEt S-enantiomer tetrazole 2-F COOEt 12027 PCT N N R' wherein R and R’ are: Stereochemistry R R’ Racemic PhCOOH Racemic R-enantiomer PhCOOH S-enantiomer PhCOOH S-enantiomer PhCOOtBu Racemic PhCOOEt Racemic PhCOOH HN H Racemic 12027 PCT Stereochemistry R R’ Racemic PhCOOH Boc-N Racemic PhCOOtBu Boc-N Racemic PhCOOEt Racemic PhCOOtBu Racemic PhNHCOOCH Racemic PhCOOtBu Racemic 4-PhCOOH R-enantiomer 4-PhCOOH S-enantiomer 4-PhCOOH Racemic PhCOOEt Diastereomer 4-PhCOOH 12027 PCT wherein R is selected from: Cyclopropanamine 2-(1H-imidazolyl)ethanamine Aniline N-(4-aminophenyl)acetamide Ethyl N-(2-aminoethyl)acetamide 3-aminopropanamide methyl 2-aminoacetate 3-methoxyaniline Dimethylamine Methylamine N N R' wherein R and R’ are: 12027 PCT Stereochemistry R R’ Racemic PhCOOH Racemic Ph-F Racemic PhCOOEt Racemic PhCOOtBu Racemic 4-PhCN S-enantiomer Ph-F S-enantiomer PhCOOH R-enantiomer PhCOOH 12027 PCT Stereochemistry R R’ Racemic PhNHCOOCH R-enantiomer Ph-F Racemic PhCOOtBu Racemic PhCOOH R-enantiomer Ph-COOEt S-enantiomer Ph-COOEt Racemic PhCOOH Racemic PhCOOH Racemic PhCOOH 12027 PCT Stereochemistry R R’ R-enantiomer PhNHCOOCH S-enantiomer PhNHCOOCH3 Racemic PhCOOH S-enantiomer PhCOOH R-enantiomer PhCOOH S-enantiomer PhCOOH Racemic Ph-Cl Racemic PhCOOnBu 12027 PCT Stereochemistry R R’ Racemic PhCOOH R-enantiomer PhCOOH S-enantiomer PhCOOH Racemic PhCOOEt S-enantiomer PhCOOEt R-enantiomer Ph-Cl S-enantiomer Ph-Cl R-enantiomer PhCOOnBu S-enantiomer PhCOOnBu 12027 PCT Stereochemistry R R’ Racemic PhCOOH Racemic PhCOOH Racemic 4-PhCOOH R-enantiomer PhCOOH S-enantiomer PhCOOH Racemic Racemic PhCOOH Racemic PhCOOiPr 12027 PCT Stereochemistry R R’ Racemic PhCOOiBu Racemic R-enantiomer Ph-COOEt S-enantiomer Ph-COOEt Racemic R-enantiomer PhCOOEt S-enantiomer PhCOOEt Racemic PhCOOH 12027 PCT Stereochemistry R R’ Racemic PhCOOH R-enantiomer PhCOOH S-enantiomer PhCOOH Racemic PhCOOEt S-enantiomer PhCOOEt Racemic PhCOOH Racemic PhCOOH 12027 PCT Stereochemistry R R’ Racemic PhCOOH S-enantiomer PhCOOH Racemic PhCOOH S-enantiomer PhCOOH Racemic PhCOOH S-enantiomer PhCOOH S-enantiomer PhCOOMe Racemic PhCOOH 12027 PCT Stereochemistry R R’ Racemic HN PhCOOH Racemic PhCOOH Racemic PhCOOH S-enantiomer PhCOOH Racemic PhCOOH S-enantiomer PhCOOH Racemic PhCOOH N R' wherein R and R’ are: 12027 PCT Stereochemistry R R’ Racemic PhCOOtBu Racemic PhCOOH Racemic PhCOOH Racemic PhCOOH Racemic PhCOOH Racemic PhCOOH Racemic PhCOOH Racemic PhCOOEt 12027 PCT Stereochemistry R R’ Racemic PhCOOH Racemic PhCOOH R-enantiomer PhCOOH S-enantiomer PhCOOH Racemic PhCOOEt S-enantiomer PhCOOEt R-enantiomer PhCOOH S-enantiomer PhCOOH 12027 PCT Stereochemistry R R’ R-enantiomer PhCOOEt S-enantiomer PhCOOEt S-enantiomer PhCOOBzl S-enantiomer Racemic PhCOOCH3 Racemic PhCOOH S-enantiomer PhCOOEt S-enantiomer PhCOOH 12027 PCT Stereochemistry R R’ R-enantiomer PhCOOH Racemic PhCOOH Racemic PhCOOH Racemic PhCOOH O R' wherein R and R’ are: Stereochemistry R R’ S-enantiomer -COOEt R-enantiomer -COOEt R-enantiomer -COOH 12027 PCT Stereochemistry R R’ S-enantiomer -COOH R-enantiomer -COOEt S-enantiomer -COOEt wherein R and R’ are: Stereochemistry R R’ S-enantiomer -COOH R-enantiomer -COOH S-enantiomer -COOEt R-enantiomer -COOEt S-enantiomer -COOH R-enantiomer -COOH 12027 PCT Stereochemistry R R’ S-enantiomer -COOH R-enantiomer -COOH S-enantiomer -COOEt S-enantiomer -COOH R-enantiomer -COOH N N R' wherein R and R’ are: Stereochemistry R R’ Racemic PhCOOH S-enantiomer PhCOOH 12027 PCT Stereochemistry R R’ Racemic PhCOOH S-enantiomer PhCOOH N R" wherein R, R’ and R’’ are: Stereochemistry R R’ R” Racemic PhCOOH R-enantiomer PhCOOH S-enantiomer PhCOOH 12027 PCT Stereochemistry R R’ R” Racemic PhCOOH S-enantiomer PhCOOH Racemic PhCOOH R-enantiomer PhCOOH S-enantiomer PhCOOH Racemic PhCOOH Racemic PhCOOH 12027 PCT Stereochemistry R R’ R” Racemic PhCOOH N N O Racemic PhCOOEt N O S Racemic PhCOOH Racemic PhCOOH N N R wherein R is selected from: Stereochemistry R 12027 PCT Racemic Racemic Racemic Racemic Racemic Racemic Racemic Racemic Racemic Racemic Racemic Racemic 12027 PCT O OH wherein R is selected from: Stereochemistry R Diastereomer Diastereomer Diastereomer Diastereomer Diastereomer Diastereomer Diastereomer 12027 PCT Diastereomer Diastereomer Racemate N N R' wherein R and R’ are: Stereochemistry R R’ S-enantiomer 4-PhCOOEt S-enantiomer 4-PhCOOH Racemic 12027 PCT N N R' wherein R and R’ are: Stereochemistry R R’ Racemic 4-PhCOOH Racemic 4-PhCOOtBu Racemic 4-PhCOOH Racemic 4-PhCOOH S-enantiomer 4-PhCOOH Racemic 4-PhCOOH Racemic 4-PhCOOH Racemic 4-PhCOOH 12027 PCT Stereochemistry R R’ Racemic 4-PhCOOH S-enantiomer 4-PhCOOH S-enantiomer 4-PhCOOH O OH wherein R and R’ are: Stereochemistry R R’ S-enantiomer S-enantiomer Racemic 12027 PCT Stereochemistry R R’ N N F S-enantiomer (E)(2-(3-(5-chloro(1H-tetraz22 olyl)phenyl)acryloyl)(piperazinyl) -1,2,3,4-tetrahydroisoquinolinecarboxamido)benzoic acid; (E)(2-(3-(2-(aminomethyl)chlorophenyl)acryloyl)(piperazinyl) -1,2,3,4-tetrahydroisoquinolinecarboxamido)benzoic acid; (E)(2-(3-(5-chloro(1H-tetrazolyl)phenyl)acryloyl)(2-oxopiperidin yl)-1,2,3,4-tetrahydroisoquinolinecarboxamido)benzoic acid; (E)(2-(3-(5-chlorofluoro(1H-tetrazolyl)phenyl)acryloyl)-5 -(piperazinyl)-1,2,3,4-tetrahydroisoquinolinecarboxamido)benzoic acid; (E)-N-(4-carbamoylphenyl)(3-(5-chlorofluoro(1H-tetrazol-1 -yl)phenyl)acryloyl)(piperazinyl)-1,2,3,4-tetrahydroisoquinolinecarboxamide; (E)(2-(3-(3-chlorofluoro(1H-tetrazolyl)phenyl)acryloyl)-3,3 -dimethyl(piperazinyl)-1,2,3,4-tetrahydroisoquinolinecarboxamido)benzoic acid; (E)(2-(3-(6-acetylchlorofluorophenyl)acryloyl)(4-methylpiperazin yl)-1,2,3,4-tetrahydroisoquinolinecarboxamido)benzoic acid; (E)(2-(3-(3-chlorofluoro(1H-tetrazolyl)phenyl)acryloyl)(4 -(pyrrolidinyl)piperidinyl)-1,2,3,4-tetrahydroisoquinolinecarboxamido)benzoic acid; (R,E)(2-(3-(3-chlorofluoro(1H-tetrazolyl)phenyl)acryloyl)(4 -methyloxopiperazinyl)-1,2,3,4-tetrahydroisoquinolinecarboxamido)benzoic acid; (S,E)(2-(3-(3-chlorofluoro(1H-tetrazolyl)phenyl)acryloyl)(4 -methyloxopiperazinyl)-1,2,3,4-tetrahydroisoquinolinecarboxamido)benzoic acid; (R,E)-ethyl 4-(2-(3-(3-chlorofluoro(1H-tetrazolyl)phenyl)acryloyl)-5 12027 PCT -(4-methyloxopiperazinyl)-1,2,3,4-tetrahydroisoquinolinecarboxamido)benzoate; (S,E)-ethyl 4-(2-(3-(3-chlorofluoro(1H-tetrazolyl)phenyl)acryloyl)-5 -(4-methyloxopiperazinyl)-1,2,3,4-tetrahydroisoquinolinecarboxamido)benzoate; (R,E)(2-(3-(3-chlorofluoro(1H-tetrazolyl)phenyl)acryloyl)-3,3 -dimethyl(piperazinyl)-1,2,3,4-tetrahydroisoquinolinecarboxamido) benzoic acid; (S,E)(2-(3-(3-chlorofluoro(1H-tetrazolyl)phenyl)acryloyl)-3,3 -dimethyl(piperazinyl)-1,2,3,4-tetrahydroisoquinolinecarboxamido) benzoic acid; 4-((S)((E)(3-chlorofluoro(1H-tetrazolyl)phenyl)acryloyl)-5 -((S)(dimethylamino)pyrrolidinyl)-1,2,3,4-tetrahydroisoquinoline-1 -carboxamido)benzoic acid; tert-butyl 4-((S)((E)(3-chlorofluoro(1H-tetrazol-1 -yl)phenyl)acryloyl)((S)(dimethylamino)pyrrolidinyl)-1,2,3,4 -tetrahydroisoquinolinecarboxamido)benzoate; 4-((R)((E)(3-chlorofluoro(1H-tetrazolyl)phenyl)acryloyl)-5 -((S)(dimethylamino)pyrrolidinyl)-1,2,3,4-tetrahydroisoquinoline-1 -carboxamido)benzoic acid; 4-((R)((E)(3-chlorofluoro(1H-tetrazolyl)phenyl)acryloyl)-5 -((R)(dimethylamino)pyrrolidinyl)-1,2,3,4-tetrahydroisoquinoline-1 -carboxamido)benzoic acid; 4-((S)((E)(3-chlorofluoro(1H-tetrazolyl)phenyl)acryloyl)-5 -((R)(dimethylamino)pyrrolidinyl)-1,2,3,4-tetrahydroisoquinoline-1 -carboxamido)benzoic acid; (E)(2-(3-(3-chlorofluoro(1H-tetrazolyl)phenyl)acryloyl)(3 -(ethoxycarbonyl)methyl-1H-pyrazolyl)-1,2,3,4-tetrahydroisoquinoline-1 -carboxamido)benzoic acid; and (E)-ethyl 1-(2-(3-(3-chlorofluoro(1H-tetrazolyl)phenyl)acryloyl)-1 -(4-fluorophenylcarbamoyl)-1,2,3,4-tetrahydroisoquinolinyl)methyl-1H-pyrazole-3 -carboxylate. 12027 PCT
14. A compound according to claim 13 or a stereoisomer, tautomer, pharmaceutically acceptable salt or solvate thereof, wherein the compound is
15. A compound, or a tautomer, pharmaceutically acceptable salt or solvate thereof, wherein the compound is selected from: N R' wherein R and R’ are: Stereochemistry R R’ S-enantiomer PhCOOCH2CON(CH ) 12027 PCT Stereochemistry R R’ S-enantiomer
16. A pharmaceutical composition, comprising: a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound of any one of claims 1-15.
17. The use of a compound of any one of claims 1-15, or a pharmaceutically acceptable salt or solvate form thereof, for the manufacture of a medicament for treating a thromboembolic or an inflammatory disorder.
18. A use according to claim 17, wherein the thromboembolic disorder is selected from the group consisting of arterial cardiovascular thromboembolic disorders, venous cardiovascular thromboembolic disorders, and thromboembolic disorders in the chambers of the heart.
19. A use according to claim 18, wherein the thromboembolic disorder is selected from unstable angina, an acute coronary syndrome, atrial fibrillation, first myocardial infarction, recurrent myocardial infarction, ischemic sudden death, transient ischemic attack, stroke, atherosclerosis, peripheral occlusive arterial disease, venous thrombosis, deep vein thrombosis, thrombophlebitis, arterial embolism, coronary arterial thrombosis, cerebral arterial thrombosis, cerebral embolism, kidney embolism, pulmonary embolism, and thrombosis resulting from (a) prosthetic valves or other implants, (b) indwelling catheters, (c) stents, (d) cardiopulmonary bypass, (e) hemodialysis, or (f) other procedures in which blood is exposed to an artificial surface that promotes thrombosis.
20. A pharmaceutical composition according to claim 16 substantially as herein descried with reference to any example thereof. 12027 PCT
21. A use according to claim 17 substantially as herein described with reference to any example thereof.
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US201161547292P | 2011-10-14 | 2011-10-14 | |
US61/547,292 | 2011-10-14 | ||
PCT/US2012/059969 WO2013056060A1 (en) | 2011-10-14 | 2012-10-12 | Substituted tetrahydroisoquinoline compounds as factor xia inhibitors |
Publications (2)
Publication Number | Publication Date |
---|---|
NZ624874A NZ624874A (en) | 2016-07-29 |
NZ624874B2 true NZ624874B2 (en) | 2016-11-01 |
Family
ID=
Similar Documents
Publication | Publication Date | Title |
---|---|---|
US10208021B2 (en) | Substituted tetrahydroisoquinoline compounds as factor XIa inhibitors | |
EP2906541B1 (en) | Guanidine and amine substituted tetrahydroisoquinoline compounds as factor xia inhibitors | |
EP2906552B1 (en) | Guanidine substituted tetrahydroisoquinoline compounds as factor xia inhibitors | |
EP2899183B1 (en) | Substituted Tetrahydroisoquinoline Compounds as Factor Xia Inhibitors | |
EP2766347B1 (en) | Substituted tetrahydroisoquinoline compounds as factor xia inhibitors | |
EP3189047B1 (en) | Diamide macrocycles that are fxia inhibitors | |
EP3868753B1 (en) | Factor xia macrocyclic inhibitors bearing a non-aromatic p2' group | |
NZ624874B2 (en) | Substituted tetrahydroisoquinoline compounds as factor xia inhibitors | |
BR112014008807B1 (en) | SUBSTITUTED TETRAHYDROISOQUINOLINE COMPOUNDS AS FACTOR XIA INHIBITORS |