SK83897A3 - Low molecular weight bicyclic thrombin inhibitors - Google Patents

Low molecular weight bicyclic thrombin inhibitors Download PDF

Info

Publication number: SK83897A3
Authority: SK; Slovakia
Prior art keywords: alkyl; oxo; optionally substituted; carbonyl; amide
Prior art date: 1994-12-22

Application number

SK838-97A

Other languages

English (en)

Slovak (sk)

Inventor

John Dimaio

M Arshad Siddiqui

John W Gillard

Yves St-Denis

Micheline Tarazi

Patrice Preville

Sophie Levesque

Benoit Bachand

Jeremy J Edmunds

Annette M Doherty

Original Assignee

Iaf Biochem Int

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

1998-05-06

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 Iaf Biochem Int filed Critical Iaf Biochem Int

1998-05-06 Publication of SK83897A3 publication Critical patent/SK83897A3/sk

Links

229940122388 Thrombin inhibitor Drugs 0.000 title description 15
239000003868 thrombin inhibitor Substances 0.000 title description 15
125000002619 bicyclic group Chemical group 0.000 title description 13
150000001875 compounds Chemical class 0.000 claims abstract description 121
125000000623 heterocyclic group Chemical group 0.000 claims abstract description 39
125000000217 alkyl group Chemical group 0.000 claims description 89
229920006395 saturated elastomer Polymers 0.000 claims description 53
229910052739 hydrogen Inorganic materials 0.000 claims description 42
229910052757 nitrogen Inorganic materials 0.000 claims description 41
125000003118 aryl group Chemical group 0.000 claims description 39
108090000765 processed proteins & peptides Proteins 0.000 claims description 33
239000001257 hydrogen Substances 0.000 claims description 32
150000001413 amino acids Chemical class 0.000 claims description 27
125000005842 heteroatom Chemical group 0.000 claims description 23
229910052760 oxygen Inorganic materials 0.000 claims description 23
229910052799 carbon Inorganic materials 0.000 claims description 21
125000000753 cycloalkyl group Chemical group 0.000 claims description 19
229910052717 sulfur Inorganic materials 0.000 claims description 19
125000001165 hydrophobic group Chemical group 0.000 claims description 17
125000006272 (C3-C7) cycloalkyl group Chemical group 0.000 claims description 16
150000002431 hydrogen Chemical class 0.000 claims description 16
UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 15
125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 14
125000003710 aryl alkyl group Chemical group 0.000 claims description 13
125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 13
229910005965 SO 2 Inorganic materials 0.000 claims description 12
125000004093 cyano group Chemical group *C#N 0.000 claims description 12
125000003275 alpha amino acid group Chemical group 0.000 claims description 10
229910052736 halogen Inorganic materials 0.000 claims description 10
125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 9
125000000637 arginyl group Chemical group N[C@@H](CCCNC(N)=N)C(=O)* 0.000 claims description 8
230000002209 hydrophobic effect Effects 0.000 claims description 8
125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 7
125000000539 amino acid group Chemical group 0.000 claims description 5
DFWYZYVGPSECMA-BYPYZUCNSA-N (2s)-5-(diaminomethylideneamino)-2-nitrosopentanoic acid Chemical compound NC(=N)NCCC[C@H](N=O)C(O)=O DFWYZYVGPSECMA-BYPYZUCNSA-N 0.000 claims description 4
MRKWCHOGYWOFMG-NSHDSACASA-N CCCCOC(=O)[C@](C(O)=O)(N=O)CCCNC(N)=N Chemical compound CCCCOC(=O)[C@](C(O)=O)(N=O)CCCNC(N)=N MRKWCHOGYWOFMG-NSHDSACASA-N 0.000 claims description 4
125000003545 alkoxy group Chemical group 0.000 claims description 4
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 description 3
125000003161 (C1-C6) alkylene group Chemical group 0.000 claims description 2
125000006649 (C2-C20) alkynyl group Chemical group 0.000 claims description 2
125000003358 C2-C20 alkenyl group Chemical group 0.000 claims description 2
125000001931 aliphatic group Chemical group 0.000 claims description 2
125000005843 halogen group Chemical group 0.000 claims 3
150000004945 aromatic hydrocarbons Chemical class 0.000 claims 2
125000004169 (C1-C6) alkyl group Chemical group 0.000 claims 1
125000002947 alkylene group Chemical group 0.000 claims 1
GBXQPDCOMJJCMJ-UHFFFAOYSA-M trimethyl-[6-(trimethylazaniumyl)hexyl]azanium;bromide Chemical compound [Br-].C[N+](C)(C)CCCCCC[N+](C)(C)C GBXQPDCOMJJCMJ-UHFFFAOYSA-M 0.000 claims 1
239000000203 mixture Substances 0.000 abstract description 105
108090000190 Thrombin Proteins 0.000 abstract description 35
239000003112 inhibitor Substances 0.000 abstract description 20
208000007536 Thrombosis Diseases 0.000 abstract description 15
239000003146 anticoagulant agent Substances 0.000 abstract description 10
206010053567 Coagulopathies Diseases 0.000 abstract description 8
229940127219 anticoagulant drug Drugs 0.000 abstract description 7
238000011282 treatment Methods 0.000 abstract description 7
206010003178 Arterial thrombosis Diseases 0.000 abstract description 4
230000001154 acute effect Effects 0.000 abstract description 4
238000001727 in vivo Methods 0.000 abstract description 4
238000002360 preparation method Methods 0.000 abstract description 4
238000000338 in vitro Methods 0.000 abstract description 3
230000001225 therapeutic effect Effects 0.000 abstract description 3
208000010378 Pulmonary Embolism Diseases 0.000 abstract description 2
206010008118 cerebral infarction Diseases 0.000 abstract description 2
230000002860 competitive effect Effects 0.000 abstract description 2
230000000302 ischemic effect Effects 0.000 abstract description 2
208000010125 myocardial infarction Diseases 0.000 abstract description 2
230000002265 prevention Effects 0.000 abstract description 2
238000011321 prophylaxis Methods 0.000 abstract description 2
206010047249 Venous thrombosis Diseases 0.000 abstract 1
238000002399 angioplasty Methods 0.000 abstract 1
208000026106 cerebrovascular disease Diseases 0.000 abstract 1
239000003795 chemical substances by application Substances 0.000 abstract 1
239000008194 pharmaceutical composition Substances 0.000 abstract 1
XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 327
-1 arginine amide compound Chemical class 0.000 description 230
WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 214
239000000243 solution Substances 0.000 description 200
VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 181
YLQBMQCUIZJEEH-UHFFFAOYSA-N Furan Chemical compound C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 109
230000002829 reductive effect Effects 0.000 description 88
QTBSBXVTEAMEQO-UHFFFAOYSA-N acetic acid Substances CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 78
NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 76
YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 75
VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 66
IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 50
LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 50
ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 45
239000000741 silica gel Substances 0.000 description 43
229910002027 silica gel Inorganic materials 0.000 description 43
OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 42
238000006243 chemical reaction Methods 0.000 description 39
235000019270 ammonium chloride Nutrition 0.000 description 36
239000002904 solvent Substances 0.000 description 36
239000012267 brine Substances 0.000 description 35
HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 35
238000003756 stirring Methods 0.000 description 34
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
KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 30
239000007787 solid Substances 0.000 description 30
229960004072 thrombin Drugs 0.000 description 30
RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 29
FZWLAAWBMGSTSO-UHFFFAOYSA-N Thiazole Chemical compound C1=CSC=N1 FZWLAAWBMGSTSO-UHFFFAOYSA-N 0.000 description 24
YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 24
229940024606 amino acid Drugs 0.000 description 24
235000001014 amino acid Nutrition 0.000 description 24
238000003818 flash chromatography Methods 0.000 description 24
239000012044 organic layer Substances 0.000 description 24
239000007858 starting material Substances 0.000 description 24
UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 23
239000000543 intermediate Substances 0.000 description 23
230000015572 biosynthetic process Effects 0.000 description 20
MZRVEZGGRBJDDB-UHFFFAOYSA-N n-Butyllithium Substances [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 20
239000000047 product Substances 0.000 description 20
238000003786 synthesis reaction Methods 0.000 description 20
238000000034 method Methods 0.000 description 19
DLEDOFVPSDKWEF-UHFFFAOYSA-N lithium butane Chemical compound [Li+].CCC[CH2-] DLEDOFVPSDKWEF-UHFFFAOYSA-N 0.000 description 17
VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 16
239000013058 crude material Substances 0.000 description 15
238000010438 heat treatment Methods 0.000 description 15
PMMYEEVYMWASQN-DMTCNVIQSA-N Hydroxyproline Chemical class O[C@H]1CN[C@H](C(O)=O)C1 PMMYEEVYMWASQN-DMTCNVIQSA-N 0.000 description 14
WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 14
150000001408 amides Chemical class 0.000 description 14
230000000694 effects Effects 0.000 description 14
XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 14
FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 13
RROBIDXNTUAHFW-UHFFFAOYSA-N benzotriazol-1-yloxy-tris(dimethylamino)phosphanium Chemical compound C1=CC=C2N(O[P+](N(C)C)(N(C)C)N(C)C)N=NC2=C1 RROBIDXNTUAHFW-UHFFFAOYSA-N 0.000 description 13
239000000706 filtrate Substances 0.000 description 13
JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 12
239000003054 catalyst Substances 0.000 description 12
BULLHNJGPPOUOX-UHFFFAOYSA-N chloroacetone Chemical compound CC(=O)CCl BULLHNJGPPOUOX-UHFFFAOYSA-N 0.000 description 12
238000004809 thin layer chromatography Methods 0.000 description 12
SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 description 11
150000001299 aldehydes Chemical class 0.000 description 11
150000001732 carboxylic acid derivatives Chemical class 0.000 description 11
230000002401 inhibitory effect Effects 0.000 description 11
KDLHZDBZIXYQEI-UHFFFAOYSA-N palladium Substances [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 11
235000017557 sodium bicarbonate Nutrition 0.000 description 11
229910000030 sodium bicarbonate Inorganic materials 0.000 description 11
IDWXUMYXKUIJLL-UHFFFAOYSA-N O=C1CN(CC2N1CCC2)C(CCC2=CC=CC=C2)=O Chemical compound O=C1CN(CC2N1CCC2)C(CCC2=CC=CC=C2)=O IDWXUMYXKUIJLL-UHFFFAOYSA-N 0.000 description 10
PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 10
238000007792 addition Methods 0.000 description 10
239000008346 aqueous phase Substances 0.000 description 10
230000003197 catalytic effect Effects 0.000 description 10
239000012043 crude product Substances 0.000 description 10
125000006239 protecting group Chemical group 0.000 description 10
239000011541 reaction mixture Substances 0.000 description 10
229910052938 sodium sulfate Inorganic materials 0.000 description 10
235000011152 sodium sulphate Nutrition 0.000 description 10
125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 10
239000004475 Arginine Substances 0.000 description 9
108090000790 Enzymes Proteins 0.000 description 9
102000004190 Enzymes Human genes 0.000 description 9
239000002253 acid Substances 0.000 description 9
ODKSFYDXXFIFQN-UHFFFAOYSA-N arginine Natural products OC(=O)C(N)CCCNC(N)=N ODKSFYDXXFIFQN-UHFFFAOYSA-N 0.000 description 9
239000003153 chemical reaction reagent Substances 0.000 description 9
RCTYPNKXASFOBE-UHFFFAOYSA-M chloromercury Chemical compound [Hg]Cl RCTYPNKXASFOBE-UHFFFAOYSA-M 0.000 description 9
229940088598 enzyme Drugs 0.000 description 9
102000004196 processed proteins & peptides Human genes 0.000 description 9
125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 8
238000001704 evaporation Methods 0.000 description 8
230000008020 evaporation Effects 0.000 description 8
238000001914 filtration Methods 0.000 description 8
125000001570 methylene group Chemical group [H]C([H])([*:1])[*:2] 0.000 description 8
238000000746 purification Methods 0.000 description 8
125000004944 pyrazin-3-yl group Chemical group [H]C1=C([H])N=C(*)C([H])=N1 0.000 description 8
239000000725 suspension Substances 0.000 description 8
JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 8
AGRIQBHIKABLPJ-UHFFFAOYSA-N 1-Pyrrolidinecarboxaldehyde Chemical compound O=CN1CCCC1 AGRIQBHIKABLPJ-UHFFFAOYSA-N 0.000 description 7
WTDHULULXKLSOZ-UHFFFAOYSA-N Hydroxylamine hydrochloride Chemical compound Cl.ON WTDHULULXKLSOZ-UHFFFAOYSA-N 0.000 description 7
CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 7
230000035602 clotting Effects 0.000 description 7
238000000605 extraction Methods 0.000 description 7
150000002367 halogens Chemical group 0.000 description 7
239000003921 oil Substances 0.000 description 7
239000011734 sodium Substances 0.000 description 7
239000000758 substrate Substances 0.000 description 7
CWLUFVAFWWNXJZ-UHFFFAOYSA-N 1-hydroxypyrrolidine Chemical compound ON1CCCC1 CWLUFVAFWWNXJZ-UHFFFAOYSA-N 0.000 description 6
QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 6
XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 6
IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 6
102000009123 Fibrin Human genes 0.000 description 6
108010073385 Fibrin Proteins 0.000 description 6
BWGVNKXGVNDBDI-UHFFFAOYSA-N Fibrin monomer Chemical compound CNC(=O)CNC(=O)CN BWGVNKXGVNDBDI-UHFFFAOYSA-N 0.000 description 6
108010049003 Fibrinogen Proteins 0.000 description 6
102000008946 Fibrinogen Human genes 0.000 description 6
GEZDNKVNPSUCSU-UHFFFAOYSA-N N-[5-(diaminomethylideneamino)-1-oxo-1-(1,3-thiazol-2-yl)pentan-2-yl]pyrazine-2-carboxamide Chemical compound N(C(=N)N)CCCC(C(=O)C=1SC=CN=1)NC(=O)C1=CN=CC=N1 GEZDNKVNPSUCSU-UHFFFAOYSA-N 0.000 description 6
JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 6
ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 6
238000004458 analytical method Methods 0.000 description 6
125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 6
238000001816 cooling Methods 0.000 description 6
239000010949 copper Substances 0.000 description 6
239000007822 coupling agent Substances 0.000 description 6
125000004122 cyclic group Chemical group 0.000 description 6
238000001035 drying Methods 0.000 description 6
229950003499 fibrin Drugs 0.000 description 6
229940012952 fibrinogen Drugs 0.000 description 6
239000007789 gas Substances 0.000 description 6
230000007062 hydrolysis Effects 0.000 description 6
238000006460 hydrolysis reaction Methods 0.000 description 6
ZLIIGTFTLSZBJF-UHFFFAOYSA-N lithium;1,3-thiazole Chemical compound [Li].C1=CSC=N1 ZLIIGTFTLSZBJF-UHFFFAOYSA-N 0.000 description 6
125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 6
239000012074 organic phase Substances 0.000 description 6
CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 description 6
229910052763 palladium Inorganic materials 0.000 description 6
YVOFTMXWTWHRBH-UHFFFAOYSA-N pentanedioyl dichloride Chemical compound ClC(=O)CCCC(Cl)=O YVOFTMXWTWHRBH-UHFFFAOYSA-N 0.000 description 6
239000002244 precipitate Substances 0.000 description 6
QZAYGJVTTNCVMB-UHFFFAOYSA-N serotonin Chemical compound C1=C(O)C=C2C(CCN)=CNC2=C1 QZAYGJVTTNCVMB-UHFFFAOYSA-N 0.000 description 6
239000000126 substance Substances 0.000 description 6
239000011701 zinc Substances 0.000 description 6
QMPCRVWNUNHDDQ-UHFFFAOYSA-N 2-[4-amino-5-oxo-5-(1,3-thiazol-2-yl)pentyl]guanidine Chemical compound NC(N)=NCCCC(N)C(=O)C1=NC=CS1 QMPCRVWNUNHDDQ-UHFFFAOYSA-N 0.000 description 5
PECYZEOJVXMISF-REOHCLBHSA-N 3-amino-L-alanine Chemical compound [NH3+]C[C@H](N)C([O-])=O PECYZEOJVXMISF-REOHCLBHSA-N 0.000 description 5
OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical group [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 5
HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 5
RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 description 5
YXHKONLOYHBTNS-UHFFFAOYSA-N Diazomethane Chemical compound C=[N+]=[N-] YXHKONLOYHBTNS-UHFFFAOYSA-N 0.000 description 5
FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 5
KYQCOXFCLRTKLS-UHFFFAOYSA-N Pyrazine Chemical compound C1=CN=CC=N1 KYQCOXFCLRTKLS-UHFFFAOYSA-N 0.000 description 5
HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 5
HSDAJNMJOMSNEV-UHFFFAOYSA-N benzyl chloroformate Chemical compound ClC(=O)OCC1=CC=CC=C1 HSDAJNMJOMSNEV-UHFFFAOYSA-N 0.000 description 5
238000006664 bond formation reaction Methods 0.000 description 5
125000004432 carbon atom Chemical group C* 0.000 description 5
229910052802 copper Inorganic materials 0.000 description 5
239000012153 distilled water Substances 0.000 description 5
239000000284 extract Substances 0.000 description 5
ZRALSGWEFCBTJO-UHFFFAOYSA-N guanidine group Chemical group NC(=N)N ZRALSGWEFCBTJO-UHFFFAOYSA-N 0.000 description 5
238000005984 hydrogenation reaction Methods 0.000 description 5
150000002466 imines Chemical class 0.000 description 5
239000010410 layer Substances 0.000 description 5
238000007363 ring formation reaction Methods 0.000 description 5
239000011780 sodium chloride Substances 0.000 description 5
125000001424 substituent group Chemical group 0.000 description 5
229910052725 zinc Inorganic materials 0.000 description 5
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 4
ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 description 4
SIKJAQJRHWYJAI-UHFFFAOYSA-N Indole Chemical compound C1=CC=C2NC=CC2=C1 SIKJAQJRHWYJAI-UHFFFAOYSA-N 0.000 description 4
GPKRQFAJHRSDPW-UHFFFAOYSA-N N-[1-(1,3-benzothiazol-2-yl)-5-(diaminomethylideneamino)-1-oxopentan-2-yl]pyridine-3-carboxamide Chemical compound C1=CC=C2C(=C1)N=C(S2)C(=O)C(CCCN=C(N)N)NC(=O)C3=CN=CC=C3 GPKRQFAJHRSDPW-UHFFFAOYSA-N 0.000 description 4
UFWIBTONFRDIAS-UHFFFAOYSA-N Naphthalene Chemical compound C1=CC=CC2=CC=CC=C21 UFWIBTONFRDIAS-UHFFFAOYSA-N 0.000 description 4
PVNIIMVLHYAWGP-UHFFFAOYSA-N Niacin Chemical compound OC(=O)C1=CC=CN=C1 PVNIIMVLHYAWGP-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
239000007864 aqueous solution Substances 0.000 description 4
238000003556 assay Methods 0.000 description 4
125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 4
239000000872 buffer Substances 0.000 description 4
XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 4
150000002148 esters Chemical group 0.000 description 4
239000012442 inert solvent Substances 0.000 description 4
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229940040692 lithium hydroxide monohydrate Drugs 0.000 description 1
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UJTKESHOTXVYPV-UHFFFAOYSA-N n-[3-[4-(diaminomethylideneamino)cyclohexyl]-1-oxo-1-(1,3-thiazol-2-yl)propan-2-yl]-4-oxo-2-(3-phenylpropanoyl)-1,3,6,7,8,8a-hexahydropyrrolo[1,2-a]pyrazine-6-carboxamide Chemical compound C1CC(NC(=N)N)CCC1CC(C(=O)C=1SC=CN=1)NC(=O)C1N2C(=O)CN(C(=O)CCC=3C=CC=CC=3)CC2CC1 UJTKESHOTXVYPV-UHFFFAOYSA-N 0.000 description 1
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UCMGNZDFXFVZPC-UHFFFAOYSA-N n-[6-amino-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(CCCCN)NC(=O)C(N1C(=O)C2)CCC1CN2C(=O)CCC1=CC=CC=C1 UCMGNZDFXFVZPC-UHFFFAOYSA-N 0.000 description 1
UUIQMZJEGPQKFD-UHFFFAOYSA-N n-butyric acid methyl ester Natural products CCCC(=O)OC UUIQMZJEGPQKFD-UHFFFAOYSA-N 0.000 description 1
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125000003367 polycyclic group Chemical group 0.000 description 1
229920000573 polyethylene Polymers 0.000 description 1
IUBQJLUDMLPAGT-UHFFFAOYSA-N potassium bis(trimethylsilyl)amide Chemical compound C[Si](C)(C)N([K])[Si](C)(C)C IUBQJLUDMLPAGT-UHFFFAOYSA-N 0.000 description 1
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238000001556 precipitation Methods 0.000 description 1
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230000002035 prolonged effect Effects 0.000 description 1
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229940121649 protein inhibitor Drugs 0.000 description 1
125000004307 pyrazin-2-yl group Chemical group [H]C1=C([H])N=C(*)C([H])=N1 0.000 description 1
NIPZZXUFJPQHNH-UHFFFAOYSA-N pyrazine-2-carboxylic acid Chemical compound OC(=O)C1=CN=CC=N1 NIPZZXUFJPQHNH-UHFFFAOYSA-N 0.000 description 1
238000010791 quenching Methods 0.000 description 1
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
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239000000377 silicon dioxide Substances 0.000 description 1
150000003384 small molecules Chemical class 0.000 description 1
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239000001632 sodium acetate Substances 0.000 description 1
235000017281 sodium acetate Nutrition 0.000 description 1
239000012279 sodium borohydride Substances 0.000 description 1
229910000033 sodium borohydride Inorganic materials 0.000 description 1
239000001509 sodium citrate Substances 0.000 description 1
NLJMYIDDQXHKNR-UHFFFAOYSA-K sodium citrate Chemical compound O.O.[Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O NLJMYIDDQXHKNR-UHFFFAOYSA-K 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
GEHJYWRUCIMESM-UHFFFAOYSA-L sodium sulfite Chemical class [Na+].[Na+].[O-]S([O-])=O GEHJYWRUCIMESM-UHFFFAOYSA-L 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
239000012321 sodium triacetoxyborohydride Substances 0.000 description 1
239000012265 solid product Substances 0.000 description 1
208000010110 spontaneous platelet aggregation Diseases 0.000 description 1
238000012453 sprague-dawley rat model Methods 0.000 description 1
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239000008174 sterile solution Substances 0.000 description 1
238000007920 subcutaneous administration Methods 0.000 description 1
125000004962 sulfoxyl group Chemical group 0.000 description 1
FWMUJAIKEJWSSY-UHFFFAOYSA-N sulfur dichloride Chemical compound ClSCl FWMUJAIKEJWSSY-UHFFFAOYSA-N 0.000 description 1
239000006188 syrup Substances 0.000 description 1
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GZHRJEYBUUYERI-UHFFFAOYSA-N tert-butyl 2-(phenylmethoxycarbonylamino)hex-4-enoate Chemical compound CC=CCC(C(=O)OC(C)(C)C)NC(=O)OCC1=CC=CC=C1 GZHRJEYBUUYERI-UHFFFAOYSA-N 0.000 description 1
FXRLWSYREBUSNL-UHFFFAOYSA-N tert-butyl 4-hydroxy-2-(phenylmethoxycarbonylamino)butanoate Chemical compound CC(C)(C)OC(=O)C(CCO)NC(=O)OCC1=CC=CC=C1 FXRLWSYREBUSNL-UHFFFAOYSA-N 0.000 description 1
JOHVKIPGBIKFLE-UHFFFAOYSA-N tert-butyl 4-iodo-2-(phenylmethoxycarbonylamino)butanoate Chemical compound CC(C)(C)OC(=O)C(CCI)NC(=O)OCC1=CC=CC=C1 JOHVKIPGBIKFLE-UHFFFAOYSA-N 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
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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 1
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229920002554 vinyl polymer Polymers 0.000 description 1
238000010792 warming Methods 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

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Chemical & Material Sciences (AREA)
Health & Medical Sciences (AREA)
Organic Chemistry (AREA)
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Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
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SK838-97A 1994-12-22 1995-12-21 Low molecular weight bicyclic thrombin inhibitors SK83897A3 (en)

Applications Claiming Priority (6)

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
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
GBGB9510265.3A GB9510265D0 (en)	1995-05-22	1995-05-22	Low molecular weight diaminobicyclic thrombin inhibitors
PCT/CA1995/000708 WO1996019483A1 (en)	1994-12-22	1995-12-21	Low molecular weight bicyclic thrombin inhibitors

Publications (1)

Publication Number	Publication Date
SK83897A3 true SK83897A3 (en)	1998-05-06

Family

ID=27517273

Family Applications (1)

Application Number	Title	Priority Date	Filing Date
SK838-97A SK83897A3 (en)	1994-12-22	1995-12-21	Low molecular weight bicyclic thrombin inhibitors

Country Status (22)

Country	Link
EP (1)	EP0802916A1 (cs)
JP (1)	JPH11508535A (cs)
CN (1)	CN1175259A (cs)
AP (1)	AP9701004A0 (cs)
AU (2)	AU4250596A (cs)
BG (1)	BG101647A (cs)
CA (1)	CA2208772A1 (cs)
CZ (1)	CZ189997A3 (cs)
EE (1)	EE9700113A (cs)
FI (1)	FI972466A7 (cs)
HU (1)	HUT77651A (cs)
IL (1)	IL116503A0 (cs)
IS (1)	IS4504A (cs)
LV (1)	LV12019B (cs)
MD (1)	MD970253A (cs)
MX (1)	MX9704718A (cs)
NO (1)	NO972892L (cs)
NZ (1)	NZ297360A (cs)
OA (1)	OA10493A (cs)
PL (1)	PL320965A1 (cs)
SK (1)	SK83897A3 (cs)
WO (1)	WO1996019483A1 (cs)

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US6194435B1 (en)	1996-10-11	2001-02-27	Cor Therapeutics, Inc.	Lactams as selective factor Xa inhibitors
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US6369063B1 (en)	1997-04-14	2002-04-09	Cor Therapeutics, Inc.	Selective factor Xa inhibitors
AU6896298A (en)	1997-04-14	1998-11-11	Cor Therapeutics, Inc.	Selective factor xa inhibitors
WO1998046628A1 (en) *	1997-04-14	1998-10-22	Cor Therapeutics, Inc.	SELECTIVE FACTOR Xa INHIBITORS
US6228854B1 (en)	1997-08-11	2001-05-08	Cor Therapeutics, Inc.	Selective factor Xa inhibitors
US6333321B1 (en)	1997-08-11	2001-12-25	Cor Therapeutics, Inc.	Selective factor Xa inhibitors
US6218382B1 (en)	1997-08-11	2001-04-17	Cor Therapeutics, Inc	Selective factor Xa inhibitors
AU740447B2 (en) *	1997-09-23	2001-11-01	Merck & Co., Inc.	Thrombin inhibitors
AU748887B2 (en) *	1998-02-12	2002-06-13	Myriad Genetics, Inc.	Beta-sheet mimetics and methods relating to the use thereof
US6323219B1 (en)	1998-04-02	2001-11-27	Ortho-Mcneil Pharmaceutical, Inc.	Methods for treating immunomediated inflammatory disorders
US8106094B2 (en)	1998-07-06	2012-01-31	Johnson & Johnson Consumer Companies, Inc.	Compositions and methods for treating skin conditions
US8093293B2 (en)	1998-07-06	2012-01-10	Johnson & Johnson Consumer Companies, Inc.	Methods for treating skin conditions
CA2348740A1 (en)	1998-12-23	2000-07-06	Ruth R. Wexler	Thrombin or factor xa inhibitors
TR200102766T2 (tr)	1999-01-27	2001-12-21	Ortho-Mcneil Pharmaceutical, Inc.	Triptaz inhibitörü olarak kullanılan peptidil heterosiklik ketonlar
FR2795072B1 (fr) *	1999-06-15	2001-07-27	Adir	Nouveaux derives bicycliques d'amino-pyrazinones, leur procede de preparation et les compositions pharmaceutiques qui les contiennent
US7309688B2 (en)	2000-10-27	2007-12-18	Johnson & Johnson Consumer Companies	Topical anti-cancer compositions and methods of use thereof
DE60124080T2 (de) *	2000-03-23	2007-03-01	Elan Pharmaceuticals, Inc., San Francisco	Verbindungen und verfahren zur behandlung der alzheimerschen krankheit
AU2001275857A1 (en)	2000-06-29	2002-01-14	Bristol-Myers Squibb Pharma Company	Thrombin or factor xa inhibitors
US8431550B2 (en)	2000-10-27	2013-04-30	Johnson & Johnson Consumer Companies, Inc.	Topical anti-cancer compositions and methods of use thereof
FR2818277B1 (fr) *	2000-12-14	2003-01-24	Servier Lab	Nouveaux derives bicycliques d'amino-pyrazinones, leur procede de preparation et les compositions pharmaceutiques qui les contiennent
US7192615B2 (en)	2001-02-28	2007-03-20	J&J Consumer Companies, Inc.	Compositions containing legume products
JP2005526722A (ja)	2002-02-14	2005-09-08	ミリアド・ジェネティックス・インコーポレイテッド	β−シートミメティックならびにそれに関連する組成物および方法
MXPA04009228A (es)	2002-03-22	2005-08-16	Gpc Biotech Ag	Compuestos inmunosupresores, metodos y usos relacionados con los mismos.
PT3204352T (pt)	2014-10-06	2020-09-23	Cortexyme Inc	Inibidores de lisina-gingipaína
JO3637B1 (ar)	2015-04-28	2020-08-27	Janssen Sciences Ireland Uc	مركبات بيرازولو- وترايازولو- بيريميدين مضادة للفيروسات rsv
CA3004095A1 (en)	2015-11-09	2017-05-18	Cortexyme, Inc.	Inhibitors of arginine gingipain
ES2992410T3 (es)	2016-09-16	2024-12-12	Lighthouse Pharmaceuticals Inc	Inhibidores cetónicos de la lisina gingipaína
TW201932470A (zh)	2017-11-29	2019-08-16	愛爾蘭商健生科學愛爾蘭無限公司	具有抗ｒｓｖ活性之吡唑并嘧啶
SG11202006141RA (en)	2018-01-31	2020-07-29	Janssen Sciences Ireland Unlimited Co	Cycloalkyl substituted pyrazolopyrimidines having activity against rsv
US11708369B2 (en)	2018-04-23	2023-07-25	Janssen Sciences Ireland Unlimited Company	Heteroaromatic compounds having activity against RSV

1995
- 1995-12-21 WO PCT/CA1995/000708 patent/WO1996019483A1/en not_active Ceased
- 1995-12-21 PL PL95320965A patent/PL320965A1/xx unknown
- 1995-12-21 EP EP95940923A patent/EP0802916A1/en not_active Ceased
- 1995-12-21 NZ NZ297360A patent/NZ297360A/xx unknown
- 1995-12-21 CA CA002208772A patent/CA2208772A1/en not_active Abandoned
- 1995-12-21 FI FI972466A patent/FI972466A7/fi unknown
- 1995-12-21 AP APAP/P/1997/001004A patent/AP9701004A0/en unknown
- 1995-12-21 CZ CZ971899A patent/CZ189997A3/cs unknown
- 1995-12-21 SK SK838-97A patent/SK83897A3/sk unknown
- 1995-12-21 AU AU42505/96A patent/AU4250596A/en not_active Abandoned
- 1995-12-21 JP JP8519383A patent/JPH11508535A/ja active Pending
- 1995-12-21 CN CN95197614A patent/CN1175259A/zh active Pending
- 1995-12-21 MD MD97-0253A patent/MD970253A/ro unknown
- 1995-12-21 HU HU9800216A patent/HUT77651A/hu unknown
- 1995-12-21 EE EE9700113A patent/EE9700113A/xx unknown
- 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
- 1997-06-18 OA OA70029A patent/OA10493A/en unknown
- 1997-06-20 NO NO972892A patent/NO972892L/no unknown
- 1997-06-20 BG BG101647A patent/BG101647A/xx 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
AP9701004A0 (en)	1997-07-31
CZ189997A3 (cs)	1998-09-16
CN1175259A (zh)	1998-03-04
FI972466L (fi)	1997-08-19
CA2208772A1 (en)	1996-06-27
IL116503A0 (en)	1996-03-31
FI972466A0 (fi)	1997-06-11
LV12019A (lv)	1998-04-20
NO972892L (no)	1997-08-20
JPH11508535A (ja)	1999-07-27
HUT77651A (hu)	1998-07-28
IS4504A (is)	1997-06-11
EE9700113A (et)	1997-12-15
OA10493A (en)	2002-04-10
FI972466A7 (fi)	1997-08-19
NO972892D0 (no)	1997-06-20
WO1996019483A1 (en)	1996-06-27
LV12019B (en)	1998-07-20
NZ297360A (en)	2000-03-27
EP0802916A1 (en)	1997-10-29
AU715378B2 (en)	2000-02-03
MX9704718A (es)	1998-06-28
BG101647A (bg)	1998-03-31
AU4250596A (en)	1996-07-10
AU4062895A (en)	1996-07-04
MD970253A (ro)	1999-05-31
PL320965A1 (en)	1997-11-24

Publication	Publication Date	Title
SK83897A3 (en)	1998-05-06	Low molecular weight bicyclic thrombin inhibitors
CN101429232B (zh)	2012-08-29	丙型肝炎病毒蛋白酶抑制剂
TWI454264B (zh)	2014-10-01	喹啉基巨環ｃ型肝炎病毒絲胺酸蛋白酶抑制劑
CN101580535B (zh)	2012-10-03	丙型肝炎病毒蛋白酶抑制剂
AU716934B2 (en)	2000-03-09	Growth-hormone secretagogues
US6534510B2 (en)	2003-03-18	Thrombin inhibitors
WO1998009987A1 (en)	1998-03-12	Lactam inhibitors of thrombin
AU715305B2 (en)	2000-01-20	Thrombin inhibitors
JPH10513462A (ja)	1998-12-22	トロンビンインヒビター
JP2011102312A (ja)	2011-05-26	テトラペプチド類似体
EP0923372A1 (en)	1999-06-23	Pyridinone thrombin inhibitors
ITMI951688A1 (it)	1997-02-01	Derivati di lattami biciclici come inibitori della trombina
WO1997048706A1 (en)	1997-12-24	Pyrrolo[1,2-a]pyrazine-1,4-dione serine protease inhibitors
HU201961B (en)	1991-01-28	Process for producing 2,3-disubstituted isoxazolidines and pharmaceutical compositions comprising same
JP2885682B2 (ja)	1999-04-26	ジオキソピロロ−ピロール誘導体
CA2218816A1 (en)	1996-11-28	Low molecular weight bicyclic-urea type thrombin inhibitors
WO1997015190A1 (en)	1997-05-01	Thrombin inhibitors
US6057314A (en)	2000-05-02	Low molecular weight bicyclic thrombin inhibitors
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
JPWO1999006402A1 (ja)	2001-02-27	Ｎ−アシルアミノ酸アミド化合物及びその製造中間体
EP1020467A1 (en)	2000-07-19	N-acylamino acid amide compounds and intermediates for preparation thereof
CA2222960A1 (en)	1996-12-05	Imidazo 1,5a pyridine derived serine protease inhibitors
LT4368B (lt)	1998-08-25	Mažos molekulinės masės bicikliniai trombino inhibitoriai
WO1995003278A1 (en)	1995-02-02	Pyrrolidine derivative or pharmaceutically acceptable salt thereof