JPH11508535A - 低分子量２環式トロンビン阻害剤 - Google Patents

低分子量２環式トロンビン阻害剤

Info

Publication number: JPH11508535A
Authority: JP; Japan
Prior art keywords: group; carbon atoms; alkyl; alkyl group; substituted
Prior art date: 1994-12-22
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.): Pending

Application number

JP8519383A

Other languages

English (en)

Japanese (ja)

Inventor

ジマイオ，ジョン

シッジキ，エム，アルシャド

ダブリュ．ジラード，ジョン

エスティー−デニス，イーベス

ダラジ，ミッチェリン

プレビッレ，パトリス

レベスケ，ソフィー

バカン，ブノワ

ジョンエドマンズ，ジェレミィ

マリアンドハーティ，アンネット

Original Assignee

バイオケムファーマインコーポレイテッド

Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)

1994-12-22

Filing date

1995-12-21

Publication date

1999-07-27

1994-12-22 Priority claimed from GBGB9426038.7A external-priority patent/GB9426038D0/en

1995-05-22 Priority claimed from GBGB9510267.9A external-priority patent/GB9510267D0/en

1995-05-22 Priority claimed from GBGB9510266.1A external-priority patent/GB9510266D0/en

1995-05-22 Priority claimed from GBGB9510265.3A external-priority patent/GB9510265D0/en

1995-12-21 Application filed by バイオケムファーマインコーポレイテッド filed Critical バイオケムファーマインコーポレイテッド

1999-07-27 Publication of JPH11508535A publication Critical patent/JPH11508535A/ja

Status Pending legal-status Critical Current

Links

125000002619 bicyclic group Chemical group 0.000 title description 13
229940122388 Thrombin inhibitor Drugs 0.000 title description 12
239000003868 thrombin inhibitor Substances 0.000 title description 12
101000712605 Theromyzon tessulatum Theromin Proteins 0.000 title description 7
150000001875 compounds Chemical class 0.000 claims abstract description 150
125000000623 heterocyclic group Chemical group 0.000 claims abstract description 51
238000000034 method Methods 0.000 claims abstract description 26
208000007536 Thrombosis Diseases 0.000 claims abstract description 16
238000004519 manufacturing process Methods 0.000 claims abstract description 8
206010003178 Arterial thrombosis Diseases 0.000 claims abstract description 4
206010047249 Venous thrombosis Diseases 0.000 claims abstract description 3
208000010378 Pulmonary Embolism Diseases 0.000 claims abstract 2
206010008118 cerebral infarction Diseases 0.000 claims abstract 2
208000026106 cerebrovascular disease Diseases 0.000 claims abstract 2
208000010125 myocardial infarction Diseases 0.000 claims abstract 2
125000004432 carbon atom Chemical group C* 0.000 claims description 220
125000000217 alkyl group Chemical group 0.000 claims description 173
-1 3-phenyl-propionyl Chemical group 0.000 claims description 124
125000003118 aryl group Chemical group 0.000 claims description 78
125000000753 cycloalkyl group Chemical group 0.000 claims description 54
125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 53
229910052757 nitrogen Inorganic materials 0.000 claims description 51
229920006395 saturated elastomer Polymers 0.000 claims description 45
229910052799 carbon Inorganic materials 0.000 claims description 42
108090000765 processed proteins & peptides Proteins 0.000 claims description 36
125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 31
150000001413 amino acids Chemical class 0.000 claims description 28
125000005842 heteroatom Chemical group 0.000 claims description 28
150000001721 carbon Chemical group 0.000 claims description 26
229910052760 oxygen Inorganic materials 0.000 claims description 21
125000004093 cyano group Chemical group *C#N 0.000 claims description 20
229910052717 sulfur Inorganic materials 0.000 claims description 20
150000001408 amides Chemical class 0.000 claims description 19
125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 15
125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 14
125000001165 hydrophobic group Chemical group 0.000 claims description 14
125000003545 alkoxy group Chemical group 0.000 claims description 12
125000003277 amino group Chemical group 0.000 claims description 11
125000005843 halogen group Chemical group 0.000 claims description 11
125000003710 aryl alkyl group Chemical group 0.000 claims description 10
230000002209 hydrophobic effect Effects 0.000 claims description 8
125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 7
OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 6
125000000637 arginyl group Chemical group N[C@@H](CCCNC(N)=N)C(=O)* 0.000 claims description 6
125000004429 atom Chemical group 0.000 claims description 6
241001465754 Metazoa Species 0.000 claims description 3
125000006615 aromatic heterocyclic group Chemical group 0.000 claims description 3
125000004043 oxo group Chemical group O=* 0.000 claims description 3
125000004070 6 membered heterocyclic group Chemical group 0.000 claims description 2
241000124008 Mammalia Species 0.000 claims description 2
125000001931 aliphatic group Chemical group 0.000 claims description 2
125000003342 alkenyl group Chemical group 0.000 claims description 2
125000000304 alkynyl group Chemical group 0.000 claims description 2
229910052736 halogen Inorganic materials 0.000 claims description 2
150000002367 halogens Chemical class 0.000 claims description 2
NIPZZXUFJPQHNH-UHFFFAOYSA-N pyrazine-2-carboxylic acid Chemical compound OC(=O)C1=CN=CC=N1 NIPZZXUFJPQHNH-UHFFFAOYSA-N 0.000 claims description 2
125000003275 alpha amino acid group Chemical group 0.000 claims 6
125000002947 alkylene group Chemical group 0.000 claims 5
125000004169 (C1-C6) alkyl group Chemical group 0.000 claims 1
XKZPAFDSBPIWQW-UHFFFAOYSA-N 6-oxo-7-(2-phenylethyl)-3,4,7,8,9,9a-hexahydro-1h-pyrido[2,1-c][1,4]thiazine-4-carboxylic acid Chemical compound O=C1N2C(C(=O)O)CSCC2CCC1CCC1=CC=CC=C1 XKZPAFDSBPIWQW-UHFFFAOYSA-N 0.000 claims 1
MFIVTLRKPIECMQ-UHFFFAOYSA-N 7-benzyl-n-[5-(diaminomethylideneamino)-1-oxo-1-(1,3-thiazol-2-yl)pentan-2-yl]-6-oxo-3,4,7,8,9,9a-hexahydro-1h-pyrido[2,1-c][1,4]thiazine-4-carboxamide Chemical compound N=1C=CSC=1C(=O)C(CCCNC(=N)N)NC(=O)C(N1C2=O)CSCC1CCC2CC1=CC=CC=C1 MFIVTLRKPIECMQ-UHFFFAOYSA-N 0.000 claims 1
OKRPZSRSKUDYSP-UHFFFAOYSA-N N(C(=N)N)CCCC(C(=O)C=1SC(=CN1)C)NC(=O)C1=CN=CC=N1 Chemical compound N(C(=N)N)CCCC(C(=O)C=1SC(=CN1)C)NC(=O)C1=CN=CC=N1 OKRPZSRSKUDYSP-UHFFFAOYSA-N 0.000 claims 1
SNOOUWRIMMFWNE-UHFFFAOYSA-M sodium;6-[(3,4,5-trimethoxybenzoyl)amino]hexanoate Chemical compound [Na+].COC1=CC(C(=O)NCCCCCC([O-])=O)=CC(OC)=C1OC SNOOUWRIMMFWNE-UHFFFAOYSA-M 0.000 claims 1
239000000203 mixture Substances 0.000 abstract description 103
108090000190 Thrombin Proteins 0.000 abstract description 33
239000003112 inhibitor Substances 0.000 abstract description 20
238000011282 treatment Methods 0.000 abstract description 8
239000003146 anticoagulant agent Substances 0.000 abstract description 7
239000003814 drug Substances 0.000 abstract description 5
230000001225 therapeutic effect Effects 0.000 abstract description 5
230000001154 acute effect Effects 0.000 abstract description 4
229940127219 anticoagulant drug Drugs 0.000 abstract description 4
206010053567 Coagulopathies Diseases 0.000 abstract description 3
229940079593 drug Drugs 0.000 abstract description 3
238000000338 in vitro Methods 0.000 abstract description 3
230000002265 prevention Effects 0.000 abstract description 3
230000002860 competitive effect Effects 0.000 abstract description 2
201000010099 disease Diseases 0.000 abstract description 2
208000037265 diseases, disorders, signs and symptoms Diseases 0.000 abstract description 2
238000001727 in vivo Methods 0.000 abstract description 2
238000002399 angioplasty Methods 0.000 abstract 1
230000000302 ischemic effect Effects 0.000 abstract 1
230000002107 myocardial effect Effects 0.000 abstract 1
239000008194 pharmaceutical composition Substances 0.000 abstract 1
208000037803 restenosis Diseases 0.000 abstract 1
238000001356 surgical procedure Methods 0.000 abstract 1
XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 270
239000000243 solution Substances 0.000 description 184
WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 170
VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 144
235000019439 ethyl acetate Nutrition 0.000 description 92
230000002829 reductive effect Effects 0.000 description 89
YLQBMQCUIZJEEH-UHFFFAOYSA-N Furan Chemical compound C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 86
NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 66
VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 62
YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 57
ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 48
QTBSBXVTEAMEQO-UHFFFAOYSA-N acetic acid Substances CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 48
238000006243 chemical reaction Methods 0.000 description 46
LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 43
OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 42
239000000741 silica gel Substances 0.000 description 41
229910002027 silica gel Inorganic materials 0.000 description 41
IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 38
239000012267 brine Substances 0.000 description 36
HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 36
239000007787 solid Substances 0.000 description 35
239000002904 solvent Substances 0.000 description 35
RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 31
UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 30
HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 30
238000003756 stirring Methods 0.000 description 30
229960004072 thrombin Drugs 0.000 description 29
239000012074 organic phase Substances 0.000 description 28
235000019270 ammonium chloride Nutrition 0.000 description 27
KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 27
239000000047 product Substances 0.000 description 27
239000007858 starting material Substances 0.000 description 25
VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 24
229940024606 amino acid Drugs 0.000 description 23
235000001014 amino acid Nutrition 0.000 description 23
239000000543 intermediate Substances 0.000 description 22
XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 22
YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 21
238000003786 synthesis reaction Methods 0.000 description 21
230000015572 biosynthetic process Effects 0.000 description 20
SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 description 19
239000003153 chemical reaction reagent Substances 0.000 description 19
239000012043 crude product Substances 0.000 description 19
238000003818 flash chromatography Methods 0.000 description 19
FZWLAAWBMGSTSO-UHFFFAOYSA-N Thiazole Chemical compound C1=CSC=N1 FZWLAAWBMGSTSO-UHFFFAOYSA-N 0.000 description 18
239000002253 acid Substances 0.000 description 18
KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 17
PJMFBWZUYOKPSW-UHFFFAOYSA-N 4-oxo-2-(3-phenylpropanoyl)-1,3,6,7,8,8a-hexahydropyrrolo[1,2-a]pyrazine-6-carboxylic acid Chemical compound C1C(=O)N2C(C(=O)O)CCC2CN1C(=O)CCC1=CC=CC=C1 PJMFBWZUYOKPSW-UHFFFAOYSA-N 0.000 description 16
UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 16
239000000706 filtrate Substances 0.000 description 16
239000011734 sodium Substances 0.000 description 16
WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 15
UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 14
FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 14
125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 14
239000001257 hydrogen Substances 0.000 description 14
229910052739 hydrogen Inorganic materials 0.000 description 14
125000004430 oxygen atom Chemical group O* 0.000 description 13
239000003054 catalyst Substances 0.000 description 12
238000001914 filtration Methods 0.000 description 12
238000000746 purification Methods 0.000 description 12
125000004434 sulfur atom Chemical group 0.000 description 12
239000007864 aqueous solution Substances 0.000 description 11
239000000284 extract Substances 0.000 description 11
150000003839 salts Chemical class 0.000 description 11
239000008346 aqueous phase Substances 0.000 description 10
239000012141 concentrate Substances 0.000 description 10
235000008504 concentrate Nutrition 0.000 description 10
238000004090 dissolution Methods 0.000 description 10
230000000694 effects Effects 0.000 description 10
239000003921 oil Substances 0.000 description 10
125000006239 protecting group Chemical group 0.000 description 10
239000000126 substance Substances 0.000 description 10
AGRIQBHIKABLPJ-UHFFFAOYSA-N 1-Pyrrolidinecarboxaldehyde Chemical compound O=CN1CCCC1 AGRIQBHIKABLPJ-UHFFFAOYSA-N 0.000 description 9
108090000790 Enzymes Proteins 0.000 description 9
102000004190 Enzymes Human genes 0.000 description 9
PMMYEEVYMWASQN-DMTCNVIQSA-N Hydroxyproline Chemical compound O[C@H]1CN[C@H](C(O)=O)C1 PMMYEEVYMWASQN-DMTCNVIQSA-N 0.000 description 9
229940088598 enzyme Drugs 0.000 description 9
239000007789 gas Substances 0.000 description 9
230000002401 inhibitory effect Effects 0.000 description 9
239000011541 reaction mixture Substances 0.000 description 9
JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 8
150000001732 carboxylic acid derivatives Chemical class 0.000 description 8
230000003197 catalytic effect Effects 0.000 description 8
238000004587 chromatography analysis Methods 0.000 description 8
125000004122 cyclic group Chemical group 0.000 description 8
150000002148 esters Chemical group 0.000 description 8
150000002466 imines Chemical class 0.000 description 8
229910052763 palladium Inorganic materials 0.000 description 8
239000002244 precipitate Substances 0.000 description 8
235000017557 sodium bicarbonate Nutrition 0.000 description 8
229910000030 sodium bicarbonate Inorganic materials 0.000 description 8
HIIOOJGGMVEBBE-UHFFFAOYSA-N 6-oxo-8-(3-phenylpropanoyl)-1,3,4,7,9,9a-hexahydropyrazino[2,1-c][1,4]thiazine-4-carboxylic acid Chemical compound C1C(=O)N2C(C(=O)O)CSCC2CN1C(=O)CCC1=CC=CC=C1 HIIOOJGGMVEBBE-UHFFFAOYSA-N 0.000 description 7
WTDHULULXKLSOZ-UHFFFAOYSA-N Hydroxylamine hydrochloride Chemical compound Cl.ON WTDHULULXKLSOZ-UHFFFAOYSA-N 0.000 description 7
150000001299 aldehydes Chemical class 0.000 description 7
125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 7
125000001424 substituent group Chemical group 0.000 description 7
RWRDLPDLKQPQOW-UHFFFAOYSA-N tetrahydropyrrole Substances C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 description 7
NGNBDVOYPDDBFK-UHFFFAOYSA-N 2-[2,4-di(pentan-2-yl)phenoxy]acetyl chloride Chemical compound CCCC(C)C1=CC=C(OCC(Cl)=O)C(C(C)CCC)=C1 NGNBDVOYPDDBFK-UHFFFAOYSA-N 0.000 description 6
PECYZEOJVXMISF-UHFFFAOYSA-N 3-aminoalanine Chemical compound [NH3+]CC(N)C([O-])=O PECYZEOJVXMISF-UHFFFAOYSA-N 0.000 description 6
ZAQFUFHPCDFIOR-UHFFFAOYSA-N 5-methoxy-5-oxopentanoic acid;hydrochloride Chemical compound Cl.COC(=O)CCCC(O)=O ZAQFUFHPCDFIOR-UHFFFAOYSA-N 0.000 description 6
QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 6
108010049003 Fibrinogen Proteins 0.000 description 6
102000008946 Fibrinogen Human genes 0.000 description 6
PVNIIMVLHYAWGP-UHFFFAOYSA-N Niacin Chemical compound OC(=O)C1=CC=CN=C1 PVNIIMVLHYAWGP-UHFFFAOYSA-N 0.000 description 6
JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 6
PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 6
238000004458 analytical method Methods 0.000 description 6
238000001035 drying Methods 0.000 description 6
229940012952 fibrinogen Drugs 0.000 description 6
238000005984 hydrogenation reaction Methods 0.000 description 6
CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 description 6
238000002360 preparation method Methods 0.000 description 6
239000011780 sodium chloride Substances 0.000 description 6
229910052938 sodium sulfate Inorganic materials 0.000 description 6
235000011152 sodium sulphate Nutrition 0.000 description 6
239000000725 suspension Substances 0.000 description 6
JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 6
238000010792 warming Methods 0.000 description 6
CWLUFVAFWWNXJZ-UHFFFAOYSA-N 1-hydroxypyrrolidine Chemical compound ON1CCCC1 CWLUFVAFWWNXJZ-UHFFFAOYSA-N 0.000 description 5
DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 5
FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 5
229910001115 Zinc-copper couple Inorganic materials 0.000 description 5
CWNKMHIETKEBCA-UHFFFAOYSA-N alpha-Ethylaminohexanophenone Chemical compound CCCCC(NCC)C(=O)C1=CC=CC=C1 CWNKMHIETKEBCA-UHFFFAOYSA-N 0.000 description 5
210000001367 artery Anatomy 0.000 description 5
239000012298 atmosphere Substances 0.000 description 5
238000006664 bond formation reaction Methods 0.000 description 5
BULLHNJGPPOUOX-UHFFFAOYSA-N chloroacetone Chemical compound CC(=O)CCl BULLHNJGPPOUOX-UHFFFAOYSA-N 0.000 description 5
TVZPLCNGKSPOJA-UHFFFAOYSA-N copper zinc Chemical compound [Cu].[Zn] TVZPLCNGKSPOJA-UHFFFAOYSA-N 0.000 description 5
239000012153 distilled water Substances 0.000 description 5
238000000605 extraction Methods 0.000 description 5
125000001570 methylene group Chemical group [H]C([H])([*:1])[*:2] 0.000 description 5
239000012299 nitrogen atmosphere Substances 0.000 description 5
125000004433 nitrogen atom Chemical group N* 0.000 description 5
238000010647 peptide synthesis reaction Methods 0.000 description 5
239000003208 petroleum Substances 0.000 description 5
125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 5
102000004196 processed proteins & peptides Human genes 0.000 description 5
238000007363 ring formation reaction Methods 0.000 description 5
QZAYGJVTTNCVMB-UHFFFAOYSA-N serotonin Chemical compound C1=C(O)C=C2C(CCN)=CNC2=C1 QZAYGJVTTNCVMB-UHFFFAOYSA-N 0.000 description 5
229910052708 sodium Inorganic materials 0.000 description 5
239000000758 substrate Substances 0.000 description 5
238000009210 therapy by ultrasound Methods 0.000 description 5
COIOYMYWGDAQPM-UHFFFAOYSA-N tris(2-methylphenyl)phosphane Chemical compound CC1=CC=CC=C1P(C=1C(=CC=CC=1)C)C1=CC=CC=C1C COIOYMYWGDAQPM-UHFFFAOYSA-N 0.000 description 5
AKPKCGPBMNLFPF-VWMHFEHESA-N 1,3-benzothiazole (2S)-5-(diaminomethylideneamino)-2-nitrosopentanoic acid Chemical compound C1=CC=C2SC=NC2=C1.NC(=N)NCCC[C@H](N=O)C(O)=O AKPKCGPBMNLFPF-VWMHFEHESA-N 0.000 description 4
VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 4
HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 4
YXHKONLOYHBTNS-UHFFFAOYSA-N Diazomethane Chemical compound C=[N+]=[N-] YXHKONLOYHBTNS-UHFFFAOYSA-N 0.000 description 4
102000009123 Fibrin Human genes 0.000 description 4
108010073385 Fibrin Proteins 0.000 description 4
BWGVNKXGVNDBDI-UHFFFAOYSA-N Fibrin monomer Chemical compound CNC(=O)CNC(=O)CN BWGVNKXGVNDBDI-UHFFFAOYSA-N 0.000 description 4
HTTJABKRGRZYRN-UHFFFAOYSA-N Heparin Chemical compound OC1C(NC(=O)C)C(O)OC(COS(O)(=O)=O)C1OC1C(OS(O)(=O)=O)C(O)C(OC2C(C(OS(O)(=O)=O)C(OC3C(C(O)C(O)C(O3)C(O)=O)OS(O)(=O)=O)C(CO)O2)NS(O)(=O)=O)C(C(O)=O)O1 HTTJABKRGRZYRN-UHFFFAOYSA-N 0.000 description 4
SIKJAQJRHWYJAI-UHFFFAOYSA-N Indole Chemical compound C1=CC=C2NC=CC2=C1 SIKJAQJRHWYJAI-UHFFFAOYSA-N 0.000 description 4
ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 4
XBDQKXXYIPTUBI-UHFFFAOYSA-N Propionic acid Substances CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 4
SMWDFEZZVXVKRB-UHFFFAOYSA-N Quinoline Chemical compound N1=CC=CC2=CC=CC=C21 SMWDFEZZVXVKRB-UHFFFAOYSA-N 0.000 description 4
125000000539 amino acid group Chemical group 0.000 description 4
HAMNKKUPIHEESI-UHFFFAOYSA-N aminoguanidine Chemical compound NNC(N)=N HAMNKKUPIHEESI-UHFFFAOYSA-N 0.000 description 4
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DLEDOFVPSDKWEF-UHFFFAOYSA-N lithium butane Chemical compound [Li+].CCC[CH2-] DLEDOFVPSDKWEF-UHFFFAOYSA-N 0.000 description 1
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238000011068 loading method Methods 0.000 description 1
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LXTFTWWNOQJKIF-UHFFFAOYSA-N n-[5-amino-1-oxo-1-(1,3-thiazol-2-yl)pentan-2-yl]-4-oxo-2-(3-phenylpropanoyl)-1,3,6,7,8,8a-hexahydropyrrolo[1,2-a]pyrazine-6-carboxamide Chemical compound N=1C=CSC=1C(=O)C(CCCN)NC(=O)C(N1C(=O)C2)CCC1CN2C(=O)CCC1=CC=CC=C1 LXTFTWWNOQJKIF-UHFFFAOYSA-N 0.000 description 1
OBFFPANYANKHAQ-UHFFFAOYSA-N n-[5-methoxy-1-oxo-1-(1,3-thiazol-2-yl)pentan-2-yl]-4-oxo-2-(3-phenylpropanoyl)-1,3,6,7,8,8a-hexahydropyrrolo[1,2-a]pyrazine-6-carboxamide Chemical compound N=1C=CSC=1C(=O)C(CCCOC)NC(=O)C(N1C(=O)C2)CCC1CN2C(=O)CCC1=CC=CC=C1 OBFFPANYANKHAQ-UHFFFAOYSA-N 0.000 description 1
VVGGLDJLHQJCKX-UHFFFAOYSA-N n-[6-(diaminomethylideneamino)-1-oxo-1-(1,3-thiazol-2-yl)hexan-2-yl]-4-oxo-2-(3-phenylpropanoyl)-1,3,6,7,8,8a-hexahydropyrrolo[1,2-a]pyrazine-6-carboxamide Chemical compound N=1C=CSC=1C(=O)C(CCCCNC(=N)N)NC(=O)C(N1C(=O)C2)CCC1CN2C(=O)CCC1=CC=CC=C1 VVGGLDJLHQJCKX-UHFFFAOYSA-N 0.000 description 1
XCVNDBIXFPGMIW-UHFFFAOYSA-N n-ethylpropan-1-amine Chemical compound CCCNCC XCVNDBIXFPGMIW-UHFFFAOYSA-N 0.000 description 1
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CMWTZPSULFXXJA-VIFPVBQESA-N naproxen Chemical group C1=C([C@H](C)C(O)=O)C=CC2=CC(OC)=CC=C21 CMWTZPSULFXXJA-VIFPVBQESA-N 0.000 description 1
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238000005457 optimization Methods 0.000 description 1
238000000643 oven drying Methods 0.000 description 1
230000001590 oxidative effect Effects 0.000 description 1
238000005949 ozonolysis reaction Methods 0.000 description 1
PIBWKRNGBLPSSY-UHFFFAOYSA-L palladium(II) chloride Chemical compound Cl[Pd]Cl PIBWKRNGBLPSSY-UHFFFAOYSA-L 0.000 description 1
230000036961 partial effect Effects 0.000 description 1
230000002093 peripheral effect Effects 0.000 description 1
230000002085 persistent effect Effects 0.000 description 1
239000000546 pharmaceutical excipient Substances 0.000 description 1
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229910052698 phosphorus Inorganic materials 0.000 description 1
SIOXPEMLGUPBBT-UHFFFAOYSA-N picolinic acid Chemical compound OC(=O)C1=CC=CC=N1 SIOXPEMLGUPBBT-UHFFFAOYSA-N 0.000 description 1
239000006187 pill Substances 0.000 description 1
IUGYQRQAERSCNH-UHFFFAOYSA-N pivalic acid Chemical compound CC(C)(C)C(O)=O IUGYQRQAERSCNH-UHFFFAOYSA-N 0.000 description 1
125000003367 polycyclic group Chemical group 0.000 description 1
235000019446 polyethylene glycol 8000 Nutrition 0.000 description 1
229940085678 polyethylene glycol 8000 Drugs 0.000 description 1
239000000843 powder Substances 0.000 description 1
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239000002243 precursor Substances 0.000 description 1
150000003141 primary amines Chemical class 0.000 description 1
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230000002062 proliferating effect Effects 0.000 description 1
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IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 1
239000002683 reaction inhibitor Substances 0.000 description 1
230000009257 reactivity Effects 0.000 description 1
102000005962 receptors Human genes 0.000 description 1
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238000011084 recovery Methods 0.000 description 1
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230000008439 repair process Effects 0.000 description 1
238000011160 research Methods 0.000 description 1
238000007788 roughening Methods 0.000 description 1
150000003335 secondary amines Chemical class 0.000 description 1
238000013207 serial dilution Methods 0.000 description 1
229940076279 serotonin Drugs 0.000 description 1
230000019491 signal transduction Effects 0.000 description 1
239000004460 silage Substances 0.000 description 1
150000003384 small molecules Chemical class 0.000 description 1
210000000329 smooth muscle myocyte Anatomy 0.000 description 1
239000001632 sodium acetate Substances 0.000 description 1
235000017281 sodium acetate Nutrition 0.000 description 1
BEOOHQFXGBMRKU-UHFFFAOYSA-N sodium cyanoborohydride Chemical compound [Na+].[B-]C#N BEOOHQFXGBMRKU-UHFFFAOYSA-N 0.000 description 1
HRZFUMHJMZEROT-UHFFFAOYSA-L sodium disulfite Chemical compound [Na+].[Na+].[O-]S(=O)S([O-])(=O)=O HRZFUMHJMZEROT-UHFFFAOYSA-L 0.000 description 1
229940001584 sodium metabisulfite Drugs 0.000 description 1
235000010262 sodium metabisulphite Nutrition 0.000 description 1
AKHNMLFCWUSKQB-UHFFFAOYSA-L sodium thiosulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=S AKHNMLFCWUSKQB-UHFFFAOYSA-L 0.000 description 1
235000019345 sodium thiosulphate Nutrition 0.000 description 1
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229960002317 succinimide Drugs 0.000 description 1
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239000006188 syrup Substances 0.000 description 1
235000020357 syrup Nutrition 0.000 description 1
230000009897 systematic effect Effects 0.000 description 1
239000003826 tablet Substances 0.000 description 1
239000011269 tar Substances 0.000 description 1
125000003039 tetrahydroisoquinolinyl group Chemical group C1(NCCC2=CC=CC=C12)* 0.000 description 1
125000000383 tetramethylene group Chemical group [H]C([H])([*:1])C([H])([H])C([H])([H])C([H])([H])[*:2] 0.000 description 1
229940124597 therapeutic agent Drugs 0.000 description 1
125000001544 thienyl group Chemical group 0.000 description 1
SRVJKTDHMYAMHA-WUXMJOGZSA-N thioacetazone Chemical compound CC(=O)NC1=CC=C(\C=N\NC(N)=S)C=C1 SRVJKTDHMYAMHA-WUXMJOGZSA-N 0.000 description 1
150000003568 thioethers Chemical class 0.000 description 1
229930192474 thiophene Natural products 0.000 description 1
206010043554 thrombocytopenia Diseases 0.000 description 1
230000002885 thrombogenetic effect Effects 0.000 description 1
230000001732 thrombotic effect Effects 0.000 description 1
230000036964 tight binding Effects 0.000 description 1
125000002088 tosyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1C([H])([H])[H])S(*)(=O)=O 0.000 description 1
230000005945 translocation Effects 0.000 description 1
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230000001960 triggered effect Effects 0.000 description 1
GETQZCLCWQTVFV-UHFFFAOYSA-N trimethylamine Chemical compound CN(C)C GETQZCLCWQTVFV-UHFFFAOYSA-N 0.000 description 1
229910052721 tungsten Inorganic materials 0.000 description 1
230000002792 vascular Effects 0.000 description 1
230000006496 vascular abnormality Effects 0.000 description 1
239000005526 vasoconstrictor agent Substances 0.000 description 1
125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
229910052727 yttrium Inorganic materials 0.000 description 1
150000004799 α-ketoamides Chemical class 0.000 description 1

Classifications

- 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
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
- A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/08—Vasodilators for multiple indications
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
- C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
- C07D513/04—Ortho-condensed systems
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
- C07K5/02—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing at least one abnormal peptide link
- C07K5/0202—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing at least one abnormal peptide link containing the structure -NH-X-X-C(=0)-, X being an optionally substituted carbon atom or a heteroatom, e.g. beta-amino acids
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
- C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
- C07K5/06—Dipeptides
- C07K5/06008—Dipeptides with the first amino acid being neutral
- C07K5/06078—Dipeptides with the first amino acid being neutral and aromatic or cycloaliphatic
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
- C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
- C07K5/06—Dipeptides
- C07K5/06139—Dipeptides with the first amino acid being heterocyclic
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
- C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
- C07K5/08—Tripeptides
- C07K5/0802—Tripeptides with the first amino acid being neutral
- C07K5/0812—Tripeptides with the first amino acid being neutral and aromatic or cycloaliphatic
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
- C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
- C07K5/08—Tripeptides
- C07K5/0821—Tripeptides with the first amino acid being heterocyclic, e.g. His, Pro, Trp
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides

Landscapes

Chemical & Material Sciences (AREA)
Health & Medical Sciences (AREA)
Organic Chemistry (AREA)
Medicinal Chemistry (AREA)
General Health & Medical Sciences (AREA)
Life Sciences & Earth Sciences (AREA)
Engineering & Computer Science (AREA)
Bioinformatics & Cheminformatics (AREA)
Veterinary Medicine (AREA)
Public Health (AREA)
General Chemical & Material Sciences (AREA)
Pharmacology & Pharmacy (AREA)
Chemical Kinetics & Catalysis (AREA)
Animal Behavior & Ethology (AREA)
Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
Biochemistry (AREA)
Biophysics (AREA)
Proteomics, Peptides & Aminoacids (AREA)
Molecular Biology (AREA)
Genetics & Genomics (AREA)
Cardiology (AREA)
Heart & Thoracic Surgery (AREA)
Pulmonology (AREA)
Hematology (AREA)
Diabetes (AREA)
Vascular Medicine (AREA)
Urology & Nephrology (AREA)
Crystallography & Structural Chemistry (AREA)
Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Plural Heterocyclic Compounds (AREA)
Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Peptides Or Proteins (AREA)

JP8519383A 1994-12-22 1995-12-21 低分子量２環式トロンビン阻害剤 Pending JPH11508535A (ja)

Applications Claiming Priority (11)

Application Number	Priority Date	Filing Date	Title
GBGB9426038.7A GB9426038D0 (en)	1994-12-22	1994-12-22	Low molecular weight bicyclic thrombin inhibitors
GBGB9503136.5A GB9503136D0 (en)	1994-12-22	1995-02-17	Low molecular weight bicyclic thrombin inhibitors
GB9510265.3		1995-05-22
GB9510267.9		1995-05-22
GBGB9510267.9A GB9510267D0 (en)	1995-05-22	1995-05-22	Low molecular weight thiobicyclic thrombin inhibitors
GBGB9510266.1A GB9510266D0 (en)	1995-05-22	1995-05-22	Low molecular weight bicyclic thrombin inhibitors
GB9510266.1		1995-05-22
GBGB9510265.3A GB9510265D0 (en)	1995-05-22	1995-05-22	Low molecular weight diaminobicyclic thrombin inhibitors
GB9503136.5		1995-05-22
GB9426038.7		1995-05-22
PCT/CA1995/000708 WO1996019483A1 (en)	1994-12-22	1995-12-21	Low molecular weight bicyclic thrombin inhibitors

Publications (1)

Publication Number	Publication Date
JPH11508535A true JPH11508535A (ja)	1999-07-27

Family

ID=27517273

Family Applications (1)

Application Number	Title	Priority Date	Filing Date
JP8519383A Pending JPH11508535A (ja)	1994-12-22	1995-12-21	低分子量２環式トロンビン阻害剤

Country Status (22)

Country	Link
EP (1)	EP0802916A1 (is)
JP (1)	JPH11508535A (is)
CN (1)	CN1175259A (is)
AP (1)	AP9701004A0 (is)
AU (2)	AU4250596A (is)
BG (1)	BG101647A (is)
CA (1)	CA2208772A1 (is)
CZ (1)	CZ189997A3 (is)
EE (1)	EE9700113A (is)
FI (1)	FI972466L (is)
HU (1)	HUT77651A (is)
IL (1)	IL116503A0 (is)
IS (1)	IS4504A (is)
LV (1)	LV12019B (is)
MD (1)	MD970253A (is)
MX (1)	MX9704718A (is)
NO (1)	NO972892L (is)
NZ (1)	NZ297360A (is)
OA (1)	OA10493A (is)
PL (1)	PL320965A1 (is)
SK (1)	SK83897A3 (is)
WO (1)	WO1996019483A1 (is)

Families Citing this family (47)

* Cited by examiner, † Cited by third party
Publication number	Priority date	Publication date	Assignee	Title
US6699869B1 (en)	1995-03-24	2004-03-02	Myriad Genetics Inc.	β-sheet mimetics and use thereof as inhibitors of biologically active peptides or proteins
US6245764B1 (en)	1995-03-24	2001-06-12	Molecumetics Ltd.	β-sheet mimetics and use thereof as inhibitors of biologically active peptides or proteins
US6020331A (en) *	1995-03-24	2000-02-01	Molecumetics, Ltd.	β-sheet mimetics and use thereof as protease inhibitors
IT1277405B1 (it) *	1995-08-01	1997-11-10	Menarini Farma Ind	Derivati di lattami biciclici come inibitori della trombina
IL119466A (en)	1995-11-03	2001-08-26	Akzo Nobel Nv	Thrombin inhibitors, their preparation and pharmaceutical compositions containing them
BR9707501A (pt) *	1996-02-13	1999-07-27	Akzo Nobel Nv	Composto composição farmacêutica e uso do composto
TW523513B (en) *	1996-03-01	2003-03-11	Akzo Nobel Nv	Serine protease inhibitors
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1995
- 1995-12-21 AU AU42505/96A patent/AU4250596A/en not_active Abandoned
- 1995-12-21 AP APAP/P/1997/001004A patent/AP9701004A0/en unknown
- 1995-12-21 EE EE9700113A patent/EE9700113A/xx unknown
- 1995-12-21 PL PL95320965A patent/PL320965A1/xx unknown
- 1995-12-21 CN CN95197614A patent/CN1175259A/zh active Pending
- 1995-12-21 JP JP8519383A patent/JPH11508535A/ja active Pending
- 1995-12-21 SK SK838-97A patent/SK83897A3/sk unknown
- 1995-12-21 MD MD97-0253A patent/MD970253A/ro unknown
- 1995-12-21 CA CA002208772A patent/CA2208772A1/en not_active Abandoned
- 1995-12-21 NZ NZ297360A patent/NZ297360A/xx unknown
- 1995-12-21 WO PCT/CA1995/000708 patent/WO1996019483A1/en not_active Application Discontinuation
- 1995-12-21 HU HU9800216A patent/HUT77651A/hu unknown
- 1995-12-21 CZ CZ971899A patent/CZ189997A3/cs unknown
- 1995-12-21 EP EP95940923A patent/EP0802916A1/en not_active Ceased
- 1995-12-22 AU AU40628/95A patent/AU715378B2/en not_active Ceased
- 1995-12-22 IL IL11650395D patent/IL116503A0/xx unknown
1997
- 1997-06-11 IS IS4504A patent/IS4504A/is unknown
- 1997-06-11 FI FI972466A patent/FI972466L/fi unknown
- 1997-06-18 OA OA70029A patent/OA10493A/en unknown
- 1997-06-20 BG BG101647A patent/BG101647A/xx unknown
- 1997-06-20 NO NO972892A patent/NO972892L/no unknown
- 1997-06-23 MX MX9704718A patent/MX9704718A/es unknown
- 1997-07-15 LV LVP-97-141A patent/LV12019B/en unknown

Also Published As

Publication number	Publication date
AU4250596A (en)	1996-07-10
FI972466A0 (fi)	1997-06-11
MD970253A (ro)	1999-05-31
IL116503A0 (en)	1996-03-31
NO972892L (no)	1997-08-20
NZ297360A (en)	2000-03-27
BG101647A (en)	1998-03-31
LV12019A (lv)	1998-04-20
AP9701004A0 (en)	1997-07-31
WO1996019483A1 (en)	1996-06-27
FI972466L (fi)	1997-08-19
LV12019B (en)	1998-07-20
SK83897A3 (en)	1998-05-06
NO972892D0 (no)	1997-06-20
AU715378B2 (en)	2000-02-03
AU4062895A (en)	1996-07-04
CN1175259A (zh)	1998-03-04
CZ189997A3 (cs)	1998-09-16
PL320965A1 (en)	1997-11-24
EP0802916A1 (en)	1997-10-29
CA2208772A1 (en)	1996-06-27
MX9704718A (es)	1998-06-28
EE9700113A (et)	1997-12-15
IS4504A (is)	1997-06-11
OA10493A (en)	2002-04-10
HUT77651A (hu)	1998-07-28

Publication	Publication Date	Title
JPH11508535A (ja)	1999-07-27	低分子量２環式トロンビン阻害剤
RU2142469C1 (ru)	1999-12-10	Пептидные производные, их стереоизомеры или физиологически приемлемые соли, обладающие противотромбозной, противосвертывающей или противовоспалительной активностью, способ их получения, фармацевтическая композиция, способ подавления тромбина, способ подавления кининогеназ, применение соединений в качестве исходных в синтезе ингибитора тромбина
JP3353297B2 (ja)	2002-12-03	新規なアイソステリックペプチド
JP3486412B2 (ja)	2004-01-13	トロンビン阻害剤
EP2518067B1 (fr)	2014-03-05	Dérives de n-[(1h-pyrazol-1-yl)aryl]-1h-indole ou 1h- indazole-3-carboxamide et leurs applications en thérapeutique comme antagonistes de p2y12.
WO1998009987A1 (en)	1998-03-12	Lactam inhibitors of thrombin
JP4152900B2 (ja)	2008-09-17	βシート模倣物およびプロテアーゼインヒビターとしてのその使用
JPH11503455A (ja)	1999-03-26	トロンビン阻害剤
JPH10503204A (ja)	1998-03-24	トロンビン阻害剤
JP2001504810A (ja)	2001-04-10	選択的第Ｘａ因子阻害剤
HUE034856T2 (en)	2018-03-28	Substituted pyrrolidines as factor xia inhibitors for the treatment of thromboembolic diseases
JP2001518932A (ja)	2001-10-16	トロンビン阻害薬
JPH10513151A (ja)	1998-12-15	トロンビン阻害剤としての複素環式ケトアルギニンペプチド
JP2011511018A (ja)	2011-04-07	Ｐａｒ１阻害剤としてのｓｆ５誘導体、その製造、及び薬剤としての使用
JP2001502691A (ja)	2001-02-27	トロンビン阻害剤
US6124291A (en)	2000-09-26	Pyrrolo[1,2-a]pyrazine-1,4-dione serine protease inhibitors
JP2000512631A (ja)	2000-09-26	新規なアミノ酸誘導体およびトロンビン阻害剤としてのその使用
JPH07278093A (ja)	1995-10-24	抗血栓物質
JPH07278091A (ja)	1995-10-24	抗血栓症剤
JPH11505260A (ja)	1999-05-18	低分子量２環式尿素型トロンビン阻害剤
AU7463496A (en)	1997-05-15	Thrombin inhibitors
JPH09509936A (ja)	1997-10-07	抗血栓剤
JP2002504490A (ja)	2002-02-12	トロンビン受容体アンタゴニストとしてのアゾールペプチド模倣体
WO1998028326A1 (en)	1998-07-02	Bicyclic thrombin inhibitors
US6057314A (en)	2000-05-02	Low molecular weight bicyclic thrombin inhibitors