WO1998009987A1 - Inhibiteurs lactame de la thrombine - Google Patents
Inhibiteurs lactame de la thrombine Download PDFInfo
- Publication number
- WO1998009987A1 WO1998009987A1 PCT/US1997/015312 US9715312W WO9809987A1 WO 1998009987 A1 WO1998009987 A1 WO 1998009987A1 US 9715312 W US9715312 W US 9715312W WO 9809987 A1 WO9809987 A1 WO 9809987A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- acetamide
- benzyl
- ethyl
- phenyl
- oxo
- Prior art date
Links
- 108090000190 Thrombin Proteins 0.000 title abstract description 25
- 239000003112 inhibitor Substances 0.000 title abstract description 8
- 229960004072 thrombin Drugs 0.000 title description 24
- 150000003951 lactams Chemical class 0.000 title description 6
- 150000001875 compounds Chemical class 0.000 claims abstract description 83
- 125000000623 heterocyclic group Chemical group 0.000 claims abstract description 25
- 208000007536 Thrombosis Diseases 0.000 claims abstract description 20
- 238000011282 treatment Methods 0.000 claims abstract description 12
- 238000011321 prophylaxis 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 4
- 208000010378 Pulmonary Embolism Diseases 0.000 claims abstract description 3
- 206010008118 cerebral infarction Diseases 0.000 claims abstract description 3
- 208000026106 cerebrovascular disease Diseases 0.000 claims abstract description 3
- 208000010125 myocardial infarction Diseases 0.000 claims abstract description 3
- -1 C3.7 cycloalkyi Chemical group 0.000 claims description 93
- 125000006201 3-phenylpropyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 73
- 125000000217 alkyl group Chemical group 0.000 claims description 55
- DLFVBJFMPXGRIB-UHFFFAOYSA-N thioacetamide Natural products CC(N)=O DLFVBJFMPXGRIB-UHFFFAOYSA-N 0.000 claims description 38
- 125000003118 aryl group Chemical group 0.000 claims description 34
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 20
- 238000000034 method Methods 0.000 claims description 19
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 17
- 229920006395 saturated elastomer Polymers 0.000 claims description 16
- 229910052739 hydrogen Inorganic materials 0.000 claims description 15
- 150000001413 amino acids Chemical class 0.000 claims description 14
- 229910052736 halogen Inorganic materials 0.000 claims description 14
- 125000005842 heteroatom Chemical group 0.000 claims description 14
- 239000001257 hydrogen Substances 0.000 claims description 14
- 150000002367 halogens Chemical class 0.000 claims description 13
- 125000006282 2-chlorobenzyl group Chemical group [H]C1=C([H])C(Cl)=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 11
- 229910052717 sulfur Inorganic materials 0.000 claims description 11
- 125000004217 4-methoxybenzyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1OC([H])([H])[H])C([H])([H])* 0.000 claims description 10
- 125000003710 aryl alkyl group Chemical group 0.000 claims description 10
- 125000002837 carbocyclic group Chemical group 0.000 claims description 10
- 229910052757 nitrogen Inorganic materials 0.000 claims description 10
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 9
- 229910052760 oxygen Inorganic materials 0.000 claims description 9
- 108090000765 processed proteins & peptides Proteins 0.000 claims description 9
- 229910052799 carbon Inorganic materials 0.000 claims description 8
- 125000001165 hydrophobic group Chemical group 0.000 claims description 8
- 125000000539 amino acid group Chemical group 0.000 claims description 7
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 7
- 241000124008 Mammalia Species 0.000 claims description 6
- SIKJAQJRHWYJAI-UHFFFAOYSA-N benzopyrrole Natural products C1=CC=C2NC=CC2=C1 SIKJAQJRHWYJAI-UHFFFAOYSA-N 0.000 claims description 6
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 6
- 125000006512 3,4-dichlorobenzyl group Chemical group [H]C1=C(Cl)C(Cl)=C([H])C(=C1[H])C([H])([H])* 0.000 claims description 5
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 5
- 125000003545 alkoxy group Chemical group 0.000 claims description 5
- 125000002947 alkylene group Chemical group 0.000 claims description 5
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 5
- 230000002209 hydrophobic effect Effects 0.000 claims description 5
- 125000006283 4-chlorobenzyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1Cl)C([H])([H])* 0.000 claims description 4
- HQABUPZFAYXKJW-UHFFFAOYSA-N butan-1-amine Chemical compound CCCCN HQABUPZFAYXKJW-UHFFFAOYSA-N 0.000 claims description 4
- 150000002431 hydrogen Chemical class 0.000 claims description 4
- PZOUSPYUWWUPPK-UHFFFAOYSA-N indole Natural products CC1=CC=CC2=C1C=CN2 PZOUSPYUWWUPPK-UHFFFAOYSA-N 0.000 claims description 4
- RKJUIXBNRJVNHR-UHFFFAOYSA-N indolenine Natural products C1=CC=C2CC=NC2=C1 RKJUIXBNRJVNHR-UHFFFAOYSA-N 0.000 claims description 4
- DPBLXKKOBLCELK-UHFFFAOYSA-N pentan-1-amine Chemical compound CCCCCN DPBLXKKOBLCELK-UHFFFAOYSA-N 0.000 claims description 4
- 229940080818 propionamide Drugs 0.000 claims description 4
- 125000004189 3,4-dichlorophenyl group Chemical group [H]C1=C([H])C(Cl)=C(Cl)C([H])=C1* 0.000 claims description 3
- 125000000738 acetamido group Chemical group [H]C([H])([H])C(=O)N([H])[*] 0.000 claims description 3
- 150000001408 amides Chemical class 0.000 claims description 3
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 3
- JUMYSVYVTVINJF-UHFFFAOYSA-N 2-[2-[(benzylsulfonylamino)methyl]-4-butyl-3,6-dioxopiperazin-1-yl]-n-[3-(1-carbamimidoylpiperidin-3-yl)-1-oxo-1-(1,3-thiazol-2-yl)propan-2-yl]acetamide Chemical compound C=1C=CC=CC=1CS(=O)(=O)NCC1C(=O)N(CCCC)CC(=O)N1CC(=O)NC(C(=O)C=1SC=CN=1)CC1CCCN(C(N)=N)C1 JUMYSVYVTVINJF-UHFFFAOYSA-N 0.000 claims description 2
- HZKVXDSVIMRLTI-UHFFFAOYSA-N 2-[2-benzyl-3,6-dioxo-4-(3-phenylpropyl)piperazin-1-yl]-n-[3-(3-carbamimidoylphenyl)-1-oxo-1-(1,3-thiazol-2-yl)propan-2-yl]acetamide Chemical compound NC(=N)C1=CC=CC(CC(NC(=O)CN2C(CN(CCCC=3C=CC=CC=3)C(=O)C2CC=2C=CC=CC=2)=O)C(=O)C=2SC=CN=2)=C1 HZKVXDSVIMRLTI-UHFFFAOYSA-N 0.000 claims description 2
- KWERQAONXGOPNU-UHFFFAOYSA-N 2-[2-benzyl-3,6-dioxo-4-(3-phenylpropyl)piperazin-1-yl]-n-[5-(diaminomethylideneamino)-1-oxo-1-(1,3-thiazol-2-yl)pentan-2-yl]acetamide Chemical compound N=1C=CSC=1C(=O)C(CCCN=C(N)N)NC(=O)CN(C(CN(CCCC=1C=CC=CC=1)C1=O)=O)C1CC1=CC=CC=C1 KWERQAONXGOPNU-UHFFFAOYSA-N 0.000 claims description 2
- GSRWMFGBDLHGBU-UHFFFAOYSA-N 2-[4-(benzenesulfonyl)-2-oxopiperazin-1-yl]-n-[5-(diaminomethylideneamino)-1-oxo-1-(1,3-thiazol-2-yl)pentan-2-yl]acetamide Chemical compound N=1C=CSC=1C(=O)C(CCCN=C(N)N)NC(=O)CN(C(C1)=O)CCN1S(=O)(=O)C1=CC=CC=C1 GSRWMFGBDLHGBU-UHFFFAOYSA-N 0.000 claims description 2
- OUDVJZIAKCWJNU-UHFFFAOYSA-N 2-[4-benzyl-2-[(4-methoxyphenyl)methyl]-3,6-dioxopiperazin-1-yl]-N-[3-(1-carbamimidoylpiperidin-4-yl)-1-oxo-1-(1,3-thiazol-2-yl)propan-2-yl]acetamide Chemical compound C(C1=CC=CC=C1)N1C(C(N(C(C1)=O)CC(=O)NC(C(C=1SC=CN=1)=O)CC1CCN(CC1)C(N)=N)CC1=CC=C(C=C1)OC)=O OUDVJZIAKCWJNU-UHFFFAOYSA-N 0.000 claims description 2
- CGWBIHLHAGNJCX-UHFFFAOYSA-N 2-butylguanidine Chemical compound CCCCNC(N)=N CGWBIHLHAGNJCX-UHFFFAOYSA-N 0.000 claims description 2
- 125000001931 aliphatic group Chemical group 0.000 claims description 2
- 150000002475 indoles Chemical class 0.000 claims description 2
- PWMRLNWGBVVJQG-UHFFFAOYSA-N n-[3-(1-carbamimidoylpiperidin-3-yl)-1-oxo-1-(1,3-thiazol-2-yl)propan-2-yl]-2-[2,5-dioxo-4-(3-phenylpropyl)piperazin-1-yl]acetamide Chemical compound C1N(C(=N)N)CCCC1CC(C(=O)C=1SC=CN=1)NC(=O)CN1C(=O)CN(CCCC=2C=CC=CC=2)C(=O)C1 PWMRLNWGBVVJQG-UHFFFAOYSA-N 0.000 claims description 2
- DTMPCWANZJBGJV-UHFFFAOYSA-N n-[5-(diaminomethylideneamino)-1-oxo-1-(1,3-thiazol-2-yl)pentan-2-yl]-2-(2-oxo-3,4-dihydroquinoxalin-1-yl)acetamide Chemical compound O=C1CNC2=CC=CC=C2N1CC(=O)NC(CCCN=C(N)N)C(=O)C1=NC=CS1 DTMPCWANZJBGJV-UHFFFAOYSA-N 0.000 claims description 2
- 229940100684 pentylamine Drugs 0.000 claims description 2
- 125000003275 alpha amino acid group Chemical group 0.000 claims 2
- LTXIGNPLSOBQMV-UHFFFAOYSA-N 2-(4-benzhydrylsulfonyl-2-oxopiperazin-1-yl)-n-[(4-carbamimidoylphenyl)methyl]acetamide Chemical compound C1=CC(C(=N)N)=CC=C1CNC(=O)CN1C(=O)CN(S(=O)(=O)C(C=2C=CC=CC=2)C=2C=CC=CC=2)CC1 LTXIGNPLSOBQMV-UHFFFAOYSA-N 0.000 claims 1
- XRSVMUVWNUNKAV-UHFFFAOYSA-N 2-(4-benzylsulfonyl-2-oxopiperazin-1-yl)-n-[3-(1-carbamimidoylpiperidin-3-yl)-1-oxo-1-(1,3-thiazol-2-yl)propan-2-yl]acetamide Chemical compound C1N(C(=N)N)CCCC1CC(C(=O)C=1SC=CN=1)NC(=O)CN1C(=O)CN(S(=O)(=O)CC=2C=CC=CC=2)CC1 XRSVMUVWNUNKAV-UHFFFAOYSA-N 0.000 claims 1
- YWBNCUIGYUMOLP-UHFFFAOYSA-N 3-(1-carbamimidoylpiperidin-3-yl)-2-[[2-[2-[(2-chlorophenyl)methyl]-3,6-dioxo-4-(3-phenylpropyl)piperazin-1-yl]acetyl]amino]-n-methylpropanamide Chemical compound C=1C=CC=C(Cl)C=1CC1C(=O)N(CCCC=2C=CC=CC=2)CC(=O)N1CC(=O)NC(C(=O)NC)CC1CCCN(C(N)=N)C1 YWBNCUIGYUMOLP-UHFFFAOYSA-N 0.000 claims 1
- 125000004203 4-hydroxyphenyl group Chemical group [H]OC1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims 1
- DBUMLGUZNUTCBH-UHFFFAOYSA-N N-[1-(1,3-benzothiazol-2-yl)-3-(1-carbamimidoylpiperidin-3-yl)-1-oxopropan-2-yl]-2-[2-benzyl-3,6-dioxo-4-(3-phenylpropyl)piperazin-1-yl]acetamide Chemical compound S1C(=NC2=C1C=CC=C2)C(C(CC1CN(CCC1)C(N)=N)NC(CN1C(C(N(CC1=O)CCCC1=CC=CC=C1)=O)CC1=CC=CC=C1)=O)=O DBUMLGUZNUTCBH-UHFFFAOYSA-N 0.000 claims 1
- BKDPZKHTSBSZGS-UHFFFAOYSA-N N-[1-(4-aminocyclohexyl)-2-oxo-2-(1,3-thiazol-2-yl)ethyl]-2-[2-benzyl-4-[3-(3,4-dichlorophenyl)propyl]-3,6-dioxopiperazin-1-yl]acetamide Chemical compound NC1CCC(CC1)C(C(C=1SC=CN=1)=O)NC(CN1C(C(N(CC1=O)CCCC1=CC(=C(C=C1)Cl)Cl)=O)CC1=CC=CC=C1)=O BKDPZKHTSBSZGS-UHFFFAOYSA-N 0.000 claims 1
- YPTNJQBPRXNVTD-YMXDCFFPSA-N N-[3-[(3S)-1-carbamimidoylpiperidin-3-yl]-1-oxo-1-(1,3-thiazol-2-yl)propan-2-yl]-2-[4-[3-(3,4-dichlorophenyl)propanoyl]-2-oxopiperazin-1-yl]acetamide Chemical compound C(N)(=N)N1C[C@@H](CCC1)CC(C(C=1SC=CN=1)=O)NC(CN1C(CN(CC1)C(CCC1=CC(=C(C=C1)Cl)Cl)=O)=O)=O YPTNJQBPRXNVTD-YMXDCFFPSA-N 0.000 claims 1
- 101150052863 THY1 gene Proteins 0.000 claims 1
- 125000003342 alkenyl group Chemical group 0.000 claims 1
- 125000000304 alkynyl group Chemical group 0.000 claims 1
- 125000005843 halogen group Chemical group 0.000 claims 1
- SULRXLGAQSKHRU-UHFFFAOYSA-N n-[(4-aminocyclohexyl)methyl]-2-[4-(2,2-diphenylethylsulfonyl)-2-oxopiperazin-1-yl]acetamide Chemical compound C1CC(N)CCC1CNC(=O)CN1C(=O)CN(S(=O)(=O)CC(C=2C=CC=CC=2)C=2C=CC=CC=2)CC1 SULRXLGAQSKHRU-UHFFFAOYSA-N 0.000 claims 1
- XVSJMYQZEYMPLO-UHFFFAOYSA-N n-[1-(1-carbamimidoylpiperidin-3-yl)-3-(1,3-thiazol-2-yl)propan-2-yl]-2-[2-methyl-3,6-dioxo-4-(3-phenylpropyl)piperazin-1-yl]acetamide Chemical compound O=C1CN(CCCC=2C=CC=CC=2)C(=O)C(C)N1CC(=O)NC(CC=1SC=CN=1)CC1CCCN(C(N)=N)C1 XVSJMYQZEYMPLO-UHFFFAOYSA-N 0.000 claims 1
- JDWMHLZPZMETMY-UHFFFAOYSA-N n-[1-(4-aminocyclohexyl)-2-oxo-2-(1,3-thiazol-2-yl)ethyl]-2-(4-benzylsulfonyl-2-oxopiperazin-1-yl)acetamide Chemical compound C1CC(N)CCC1C(C(=O)C=1SC=CN=1)NC(=O)CN1C(=O)CN(S(=O)(=O)CC=2C=CC=CC=2)CC1 JDWMHLZPZMETMY-UHFFFAOYSA-N 0.000 claims 1
- RDLVGARUIUOEQM-UHFFFAOYSA-N n-[3-(1-carbamimidoylpiperidin-3-yl)-1-oxo-1-(1,3-thiazol-2-yl)propan-2-yl]-2-[2-(naphthalen-2-ylmethyl)-3,6-dioxo-4-(3-phenylpropyl)piperazin-1-yl]acetamide Chemical compound C1N(C(=N)N)CCCC1CC(C(=O)C=1SC=CN=1)NC(=O)CN1C(=O)CN(CCCC=2C=CC=CC=2)C(=O)C1CC1=CC=C(C=CC=C2)C2=C1 RDLVGARUIUOEQM-UHFFFAOYSA-N 0.000 claims 1
- VADHIQCYDRQPNN-UHFFFAOYSA-N n-[3-(1-carbamimidoylpiperidin-3-yl)-1-oxo-1-(1,3-thiazol-2-yl)propan-2-yl]-2-[2-[(3-chlorophenyl)methyl]-3,6-dioxo-4-(3-phenylpropyl)piperazin-1-yl]acetamide Chemical compound C1N(C(=N)N)CCCC1CC(C(=O)C=1SC=CN=1)NC(=O)CN1C(=O)CN(CCCC=2C=CC=CC=2)C(=O)C1CC1=CC=CC(Cl)=C1 VADHIQCYDRQPNN-UHFFFAOYSA-N 0.000 claims 1
- VTQJRINODAZATN-UHFFFAOYSA-N n-[3-(1-carbamimidoylpiperidin-3-yl)-1-oxo-1-(1,3-thiazol-2-yl)propan-2-yl]-2-[2-[(4-chlorophenyl)methyl]-3,6-dioxo-4-(3-phenylpropyl)piperazin-1-yl]acetamide Chemical compound C1N(C(=N)N)CCCC1CC(C(=O)C=1SC=CN=1)NC(=O)CN1C(=O)CN(CCCC=2C=CC=CC=2)C(=O)C1CC1=CC=C(Cl)C=C1 VTQJRINODAZATN-UHFFFAOYSA-N 0.000 claims 1
- XCRPPBNJIUJGIQ-UHFFFAOYSA-N n-[5-(diaminomethylideneamino)-1-oxo-1-(1,3-thiazol-2-yl)pentan-2-yl]-2-[2-oxo-4-(3-phenylpropanoyl)piperazin-1-yl]acetamide Chemical compound N=1C=CSC=1C(=O)C(CCCN=C(N)N)NC(=O)CN(C(C1)=O)CCN1C(=O)CCC1=CC=CC=C1 XCRPPBNJIUJGIQ-UHFFFAOYSA-N 0.000 claims 1
- 125000003854 p-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Cl 0.000 claims 1
- 125000000547 substituted alkyl group Chemical group 0.000 claims 1
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- 239000000243 solution Substances 0.000 description 64
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- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 7
- 239000011734 sodium Substances 0.000 description 7
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- 239000002244 precipitate Substances 0.000 description 6
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- UPSFMJHZUCSEHU-JYGUBCOQSA-N n-[(2s,3r,4r,5s,6r)-2-[(2r,3s,4r,5r,6s)-5-acetamido-4-hydroxy-2-(hydroxymethyl)-6-(4-methyl-2-oxochromen-7-yl)oxyoxan-3-yl]oxy-4,5-dihydroxy-6-(hydroxymethyl)oxan-3-yl]acetamide Chemical compound CC(=O)N[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@H]1O[C@H]1[C@H](O)[C@@H](NC(C)=O)[C@H](OC=2C=C3OC(=O)C=C(C)C3=CC=2)O[C@@H]1CO UPSFMJHZUCSEHU-JYGUBCOQSA-N 0.000 description 1
- QSQBYNZMYUYOLO-UHFFFAOYSA-N n-[(4-aminocyclohexyl)methyl]-2-[2-benzyl-3,6-dioxo-4-(3-phenylpropyl)piperazin-1-yl]acetamide Chemical compound C1CC(N)CCC1CNC(=O)CN1C(=O)CN(CCCC=2C=CC=CC=2)C(=O)C1CC1=CC=CC=C1 QSQBYNZMYUYOLO-UHFFFAOYSA-N 0.000 description 1
- ZJNVMDMTEDRWBN-UHFFFAOYSA-N n-[(6-amino-2-chloropyridin-3-yl)methyl]-2-[4-benzyl-2-[(4-methoxyphenyl)methyl]-3,6-dioxopiperazin-1-yl]acetamide Chemical compound C1=CC(OC)=CC=C1CC1C(=O)N(CC=2C=CC=CC=2)CC(=O)N1CC(=O)NCC1=CC=C(N)N=C1Cl ZJNVMDMTEDRWBN-UHFFFAOYSA-N 0.000 description 1
- TXKQCYXJRUODLH-UHFFFAOYSA-N n-[1-(1,3-benzothiazol-2-yl)-5-(diaminomethylideneamino)-1-oxopentan-2-yl]-2-[2-oxo-4-(3-phenylpropanoyl)piperazin-1-yl]acetamide;2,2,2-trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F.N=1C2=CC=CC=C2SC=1C(=O)C(CCCN=C(N)N)NC(=O)CN(C(C1)=O)CCN1C(=O)CCC1=CC=CC=C1 TXKQCYXJRUODLH-UHFFFAOYSA-N 0.000 description 1
- CSAQZUOUYMGDBU-UHFFFAOYSA-N n-[1-(1-carbamimidoylpiperidin-4-yl)-2-oxo-2-(1,3-thiazol-2-yl)ethyl]-2-[4-methyl-2-(naphthalen-2-ylmethyl)-3,6-dioxopiperazin-1-yl]acetamide Chemical compound C=1C=C2C=CC=CC2=CC=1CC1C(=O)N(C)CC(=O)N1CC(=O)NC(C(=O)C=1SC=CN=1)C1CCN(C(N)=N)CC1 CSAQZUOUYMGDBU-UHFFFAOYSA-N 0.000 description 1
- VXDOTXLGFXRLQB-UHFFFAOYSA-N n-[4-[[2-[4-(benzenesulfonyl)-2-oxopiperazin-1-yl]acetyl]amino]butyl]-n-carbamimidoyl-1,3-benzothiazole-2-carboxamide Chemical compound N=1C2=CC=CC=C2SC=1C(=O)N(C(=N)N)CCCCNC(=O)CN(C(C1)=O)CCN1S(=O)(=O)C1=CC=CC=C1 VXDOTXLGFXRLQB-UHFFFAOYSA-N 0.000 description 1
- CUDXSHIKWVJPHQ-UHFFFAOYSA-N n-[5-(diaminomethylideneamino)-1-oxo-1-(1,3-thiazol-2-yl)pentan-2-yl]-2-(2-oxopiperazin-1-yl)acetamide Chemical compound N=1C=CSC=1C(=O)C(CCCN=C(N)N)NC(=O)CN1CCNCC1=O CUDXSHIKWVJPHQ-UHFFFAOYSA-N 0.000 description 1
- QJQAMHYHNCADNR-UHFFFAOYSA-N n-methylpropanamide Chemical compound CCC(=O)NC QJQAMHYHNCADNR-UHFFFAOYSA-N 0.000 description 1
- 125000001624 naphthyl group Chemical group 0.000 description 1
- 239000006225 natural substrate Substances 0.000 description 1
- 230000003472 neutralizing effect Effects 0.000 description 1
- 125000004433 nitrogen atom Chemical group N* 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- 238000005457 optimization Methods 0.000 description 1
- 210000000056 organ Anatomy 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 230000008506 pathogenesis Effects 0.000 description 1
- 230000037361 pathway Effects 0.000 description 1
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 125000000286 phenylethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])C([H])([H])* 0.000 description 1
- ABOYDMHGKWRPFD-UHFFFAOYSA-N phenylmethanesulfonamide Chemical compound NS(=O)(=O)CC1=CC=CC=C1 ABOYDMHGKWRPFD-UHFFFAOYSA-N 0.000 description 1
- 229910052698 phosphorus Inorganic materials 0.000 description 1
- QUUYRYYUKNNNNS-UHFFFAOYSA-N piperidine-1-carboximidamide Chemical compound NC(=N)N1CCCCC1 QUUYRYYUKNNNNS-UHFFFAOYSA-N 0.000 description 1
- 125000003367 polycyclic group Chemical group 0.000 description 1
- 229920000573 polyethylene Polymers 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 238000002953 preparative HPLC Methods 0.000 description 1
- 238000003825 pressing Methods 0.000 description 1
- 150000003141 primary amines Chemical class 0.000 description 1
- 230000035755 proliferation Effects 0.000 description 1
- 230000002035 prolonged effect Effects 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000006239 protecting group Chemical group 0.000 description 1
- 230000017854 proteolysis Effects 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 125000006513 pyridinyl methyl group Chemical group 0.000 description 1
- 102000005962 receptors Human genes 0.000 description 1
- 108020003175 receptors Proteins 0.000 description 1
- 108091006091 regulatory enzymes Proteins 0.000 description 1
- 230000008439 repair process Effects 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 230000007017 scission Effects 0.000 description 1
- 150000003335 secondary amines Chemical class 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 230000019491 signal transduction Effects 0.000 description 1
- 238000010898 silica gel chromatography Methods 0.000 description 1
- 210000000329 smooth muscle myocyte Anatomy 0.000 description 1
- URGAHOPLAPQHLN-UHFFFAOYSA-N sodium aluminosilicate Chemical compound [Na+].[Al+3].[O-][Si]([O-])=O.[O-][Si]([O-])=O URGAHOPLAPQHLN-UHFFFAOYSA-N 0.000 description 1
- 239000011780 sodium chloride Substances 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
- 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
- 238000012453 sprague-dawley rat model Methods 0.000 description 1
- 230000006641 stabilisation Effects 0.000 description 1
- 238000011105 stabilization Methods 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 230000000707 stereoselective effect Effects 0.000 description 1
- 239000008174 sterile solution Substances 0.000 description 1
- 125000004962 sulfoxyl group Chemical group 0.000 description 1
- 239000011593 sulfur Substances 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- 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
- 229940095064 tartrate Drugs 0.000 description 1
- BNWCETAHAJSBFG-UHFFFAOYSA-N tert-butyl 2-bromoacetate Chemical compound CC(C)(C)OC(=O)CBr BNWCETAHAJSBFG-UHFFFAOYSA-N 0.000 description 1
- UIYOVVYZPVVUMJ-UHFFFAOYSA-N tert-butyl carbamoyl carbonate Chemical compound CC(C)(C)OC(=O)OC(N)=O UIYOVVYZPVVUMJ-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
- OSBSFAARYOCBHB-UHFFFAOYSA-N tetrapropylammonium Chemical compound CCC[N+](CCC)(CCC)CCC OSBSFAARYOCBHB-UHFFFAOYSA-N 0.000 description 1
- 125000001544 thienyl group Chemical group 0.000 description 1
- 229930192474 thiophene Natural products 0.000 description 1
- 229960003766 thrombin (human) Drugs 0.000 description 1
- 230000002885 thrombogenetic effect Effects 0.000 description 1
- DSNBHJFQCNUKMA-SCKDECHMSA-N thromboxane A2 Chemical compound OC(=O)CCC\C=C/C[C@@H]1[C@@H](/C=C/[C@@H](O)CCCCC)O[C@@H]2O[C@H]1C2 DSNBHJFQCNUKMA-SCKDECHMSA-N 0.000 description 1
- 230000000699 topical effect Effects 0.000 description 1
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 1
- 230000005945 translocation Effects 0.000 description 1
- HGBOYTHUEUWSSQ-UHFFFAOYSA-N valeric aldehyde Natural products CCCCC=O HGBOYTHUEUWSSQ-UHFFFAOYSA-N 0.000 description 1
- 230000002792 vascular 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
- 229920002554 vinyl polymer Polymers 0.000 description 1
- 230000003612 virological effect Effects 0.000 description 1
- 239000003039 volatile agent Substances 0.000 description 1
Classifications
-
- 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
-
- 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
- C07K5/06139—Dipeptides with the first amino acid being heterocyclic
Definitions
- This invention relates to compounds useful for the treatment of thrombotic disorders, and more particularly to novel lactam inhibitors of serine proteases such as factor Vila, Xa and thrombin.
- This application is a continuation- in-part of USSN 60/025,599 and GB 9618687.9 filed 6 September 1996 incorporated herein by reference.
- thrombus formation on blood vessel walls precipitates acute cardiovascular disease states that are the chief cause of death in economically developed societies .
- Plasma proteins such as fibrinogen, proteases and cellular receptors participating in hemostasis have emerged as important factors that play a role in acute and chronic coronary disease as well as cerebral artery disease by contributing to the formation of thrombus or blood clots that effectively diminish normal blood flow and supply.
- Vascular aberrations stemming from primary pathologic states such as hypertension, rupture of atherosclerotic plaques or denuded endothelium, activate biochemical cascades that serve to respond and repair the injury site.
- Thrombin is a key regulatory enzyme in the coagulation cascade; it serves a pluralistic role as both a positive and negative feedback regulator. However, in pathologic conditions the former is amplified through catalytic activation of cofactors required for thrombin generation as well as activation of factor XIII necessary for fibrin cross-linking and stabilization.
- thrombin In addition to its direct effect on hemostasis, thrombin exerts direct effects on diverse cell types that support and amplify pathogenesis of arterial thrombus disease.
- the enzyme is the strongest activator of platelets causing them to aggregate and release substances (e.g. ADP TXA 2 NE) that urt er propagate t e t rom otic cyc e.
- Platelets in a fibrin mesh comprise the principal framework of a white thrombus.
- Thrombin also exerts direct effects on endothelial cells causing release of vasoconstrictor substances and translocation of adhesion molecules that become sites for attachment of immune cells.
- the enzyme causes mitogenesis of smooth muscle cells and proliferation of fibroblasts .
- ATIII antithrombin III
- heparin has shown clinical efficacy in alleviating venous thrombosis by enhancing ATIII/thrombin binding through catalysis. However, heparin also catalyzes inhibition of other proteases in the coagulation cascade and its efficacy m platelet -dependent thrombosis is largely reduced or abrogated due to inaccessibility of thrombus -bound enzyme. Also, adverse side effects such as thrombocytopema, osteoporosis and triglyceridemia have been observed following prolonged treatment with heparin.
- thrombin activity can be inhibited by compounds that compete with fibrinogen for thrombi 's catalytic site, thereby inhibiting proteolysis of that protein or other protein substrates such as the thrombin receptor.
- a common strategy for designing enzyme inhibitory compounds relies on mimicking the specificity inherent m the primary and secondary structure of the enzyme's natural substrate.
- Thrombin inhibitors have been modeled upon the partial sequence of the fibrinogen A chain comprising its proteolyt cally susceptible region (Blomback, et al . , J. Clin. Lab. Invest., 24_, 59, 1969).
- This region of fibrinogen minimally includes the residues commencing with phenylalanine: a- sp- er- y- u- y- sp- e - eu- a- u- y -Gly-Gly-Val -Arg-Gly- Pro-Arg t scissile bond
- the present invention provides novel compounds that are useful for inhibiting thrombin activity, represented by formula (I):
- W and X are independently selected from CH-R 4 , C-R 4 , N-R 4 , N,
- R ⁇ is a polar amino acid residue or derivative or analogue thereof optionally substituted with an amino acid, a peptide or a heterocycle
- R 2 and R 2 ' are independently selected from H, halogen, C 1 - 16 alkyl optionally substituted with C 6 _ 16 aryl, heterocycle or a 3 - 7 cycloalkyi group
- R 3 and R 4 are independently selected from H; NR S R 6 ; carboxyl; c e-i 6 aryl or C 3 , 7 cycloalkyi optionally substituted with C ⁇ g alkyl; C ⁇ _ 16 alkyl optionally interrupted by one or more heteroatom or carbonyl group and optionally substituted with OH, SH, NR 5 R 6 or a C 6 _ 16 aryl, heterocycle or C 3 .
- R 7 cycloalkyi group optionally substituted with halogen, hydroxyl, carboxyl, C . - alkyl; an amino acid side chain; and a hydrophobic group; or when Y is CH-R 4 or C-R 4 then R 3 and R 4 together with Y form a 5 or 6 member saturated or unsaturated carbocyclic ring; R 5 and R 6 are independently selected from H and C x _ 4 alkyl.
- compositions comprising compounds of the formula (I) in combination with pharmaceutically acceptable carriers, diluents or adjuvants.
- a method for the treatment or prophylaxis of thrombotic disorders in a mammal comprising administering to said mammal an effective amount of a compound according to formula (I) .
- the present invention relates to compounds which inhibit the enzyme, thrombin. These molecules are characterized by a lactam moiety as illustrated in formula (I) :
- hydrophobic group refers to any group which lacks affinity for, or displaces water.
- Hydrophobic groups include but are not limited to C ⁇ Q alkyl, C 2 _ 20 alkenyl (e.g. vinyl, allyl) or C 2 - 20 alkynyl (e.g. propargyl) optionally interrupted by a carbonyl group, (e.g. forming an acyl group); C 6 . ⁇ e aryl, C 3 _ 7 cycloalkyi, C 6 .
- aralkyl C 6 _ 20 cycloalkyi substituted C 1 _ 2Q alkyl, wherein the aliphatic portion is optionally interrupted by a carbonyl group (e.g. forming an acyl group) and the ring portion is optionally substituted with C ⁇ g alkyl such as methyl ethyl or t-butyl; or a hydrophobic amino acid side chain.
- Preferred hydrophobic groups include cyclohexyl, benzyl, benzoyl , phenylmethyl , phenethyl and para-t-butyl-phenylmethyl .
- an analogue or derivative of the natural residue may incorporate a longer or shorter methylene chain from the alpha carbon (i.e. ethylene or butylene chain); replacement of the guanidino group with a hydrogen bond donating or accepting group (i.e. ammo, amid o or methoxy) ; replacement of the methylene chain with a constrained group (i.e. an aryl, cycloalkyi or heterocyclic ring) ; elimination of the terminal carboxyl (i.e. des-carboxy) or hydroxyl (i.e. an aldehyde) ; or a combination thereof.
- alkyl represents a straight or branched, saturated or unsaturated chain having a specified total number of carbon atoms .
- aromatic or aryl represents an unsaturated carbocyclic rmg(s) of 6 to 16 carbon atoms which is optionally mono- or di-substituted with OH, SH, ammo (i.e. NR 5 R 6 ) halogen or C-_ 6 alkyl.
- Aromatic rings include benzene, biphenyl, napththalene, phenanthrene and anthracene. Preferred aromatic rings are benzene and naphthalene . -
- cycloalkyi represents a mono- or poly- (including bridged) carbocyclic ring of 3 to 7 carbon atoms which is optionally mono- or di-substituted with OH, SH, ammo (i.e. NR 5 R 6 ) , halogen, carboxy (and esters thereof) or C 2 6 alkyl.
- Cycloalkyi groups are generally saturated but may be partially unsaturated and include cyclo-propyl, butyl, pentyl, hexyl and heptyl .
- a preferred cycloalkyi group is cyclohexyl .
- aralkyl represents a substituent comprising an aryl moiety attached via an alkylene chain (e.g. benzyl, phenethyl) wherem the sum total of carbon atoms for the aryl moiety and the alkylene chain is as specified.
- the aryl or chain portion of the group is optionally mono- or di-substituted with OH, SH, ammo (i.e. NR 5 R 6 ) halogen or C-. 6 alkyl
- heteroatom represents oxygen, nitrogen or sulfur (0, N or S) as well as sulfoxyl or sulfonyl (SO or S0 2 ) unless otherwise indicated.
- alkyl chains interrupted by one or more heteroatoms means that a carbon atom of the chain is replaced with a heteroatom having the appropriate valency.
- an alkyl chain is interrupted by 0 to 4 heteroatoms.
- two adjacent carbon atoms are not both replaced with a heteroatom except for example to form a sulfona ide group.
- heterocycle represents a saturated or unsaturated mono- or polycyclic (i.e. bicyclic, bridged) ring incorporating 1 or more (i.e. 1-4) heteroatoms selected from N, O and S. It is understood that a heterocycle is optionally mono- or di-substituted with OH, SH, amino (i.e. NR S R 6 ) , halogen, CF 3 , oxo or C ⁇ _ 6 alkyl.
- Suitable monocyclic heterocycles include but are not limited to pyridine, piperidine, pyrazine, piperazine, pyrimidine, imidazole, thiazole, oxazole, furan, pyran and thiophene .
- suitable bicyclic heterocycles include but are not limited to indole, quinoline, isoquinoline, purine, and carbazole .
- hydrophobic amino acid represents an amino acid residue that bears an alkyl or aryl group attached to the ⁇ - carbon atom.
- the alkyl or aryl group can be substituted, provided that the substituent or substituents do not detract from the overall hydrophobic character of the amino acid.
- hydrophobic amino acids include natural amino acid residues such as alanine; isoleucine; leucine; phenylalanine; and non-naturally occurring amino acids such as those described in "The Peptides", vol. 5, 1983, Academic Press, Chapter 6 by D.C. Roberts and F. Vellaccio. Suitable non- naturally occurring amino acids include cyclohexylalanme and l-aminocyclohexane-carboxylic .
- amino acid side chain is meant the substituent attached to the carbon which is ⁇ to the amino group.
- side chain of the amino acid alanine is a methyl group while benzyl is the side chain for phenylalanine.
- W is CH-R 4 or C-R 4 while X is N-R 4 , N, O, S, SO or S0 2 , wherein R 4 is as previously defined. More preferably, W is CH-R 4 or C-R 4 while X is N-R 4 or N. More preferably, W is CH-R 4 while X is N-R 4 .
- W is CH 2 while X is N-R 4 .
- Y is CH-R 4 wherein R 4 is as previously defined.
- Y is CH-R 4 wherein R 4 is H.
- R 2 and R 2 ' are independently H; halogen such as F or
- R 2 and R 2 ' are H. Most preferably, both R 2 and R 2 ' are both H.
- R 3 and R 4 are independently a carboxyl group or a hydrophobic group such as a saturated or unsaturated carbocycle of 5 or 6 members optionally fused to another carbocyclic group.
- the carboxyl group or hydrophobic group may be linked via a spacer such as a C ⁇ alkyl chain optionally interrupted with 1 or more (i.e. 1-4) heteroatoms, carbonyl or sulfonyl (S0 2 ) groups.
- R 4 substituent is an optionally substituted aromatic ring such as phenyl , biphenyl , cyclohexyl, indole, thienyl, quinoline, tetrahydroisoquinoline, naphthyl or benzodioxolane linked via c ⁇ -i 6 alkyl optionally interrupted with a heteroatom or sulfonyl or carbonyl; while R 3 is selected from H, C 1 - 16 alkyl, and an optionally substituted aromatic ring linked via alkyl.
- Optional aromatic ring substituents include OH, carboxyl (and esters thereof), C- ⁇ alkyl and halogen.
- R 3 is other than 3 , 5-bis (trifluoromethyl) benzoyl when R 4 is 3-indolyl- methyl .
- Y is -CH 2 - or carbonyl and R 3 is H, saturated or unsaturated carbocycle or heterocycle of 5 or 6 members optionally fused to another carbocyclic group.
- the carbocycle or heterocycle group is optionally linked via a spacer such as a C ⁇ _. 16 alkyl chain optionally interrupted with 1 or more (i.e. 1-4) heteroatoms, carbonyl or sulfonyl (S0 2 ) groups.
- Particularly preferred R 3 groups include H, methyl, isopropyl, butyl, 2°butyl, benzyl (optionally substituted i.e.
- R 3 is-H or optionally substituted benzyl and most preferably is benzyl optionally substituted i.e. 2-Cl, 3-C1, 4-C1, 3,4-diCl, 4-methyl, 4-methoxy.
- R 3 and R 4 are independently an optionally substituted phenyl or cyclohexyl ring linked via C ⁇ _ 4 alkyl optionally interrupted with carbonyl or sulfonyl.
- one of the R 4 substituents is phenylpropionyl , phenylpropyl , benzylsulfonyl , 2 , 3-dichlorophenylpropionyl , phenylethyl or cyclohexyl -methyl while R 3 is H, isopropyl or benzyl.
- R 3 and the R 4 from Y together form a 5 or 6 member saturated or unsaturated carbocyclic ring.
- said ring is a phenyl or cyclohexyl ring and more preferably a phenyl ring fused to the ring containing W, X and Y.
- R- and R 6 are independently hydrogen, methyl or ethyl . More preferably R 5 and R 6 are independently hydrogen or methyl and most preferably are both hydrogen.
- R x is represented by one of formula Ha to He: wherein :
- R 7 is hydrogen or C x - 6 alkyl
- K is a bond or -NR 7 -;
- G is C x _ 4 alkoxy; cyano; -NHR 8 ; -CH 2 -NHR 8 ; -C(NH)-NHR 8 ;
- G is other than unsubstituted indole and when G is C 6 _ 12 cycloalkyi or aryl then G is substituted with at least one group selected from -NHR 8 , -CH 2 -NHR 8 , -C(NH)-NHR 8 , -NH-C(NH) -NHR 8 or -CH 2 -NH-C (NH) -NHR 8 ;
- U is cyano, -NHR 8 , -C(NH)-NHR 8 or -NH-C (NH) -NHR 8 ;
- R 8 is H, OH or NH 2 ;
- P is a bond, -C(O)-, - C (S ) - or a bivalent group:
- J is alkylene optionally substituted with OH, NH 2 and C-__ - alkyl and optionally interrupted by a heteroatom selected from O, S and N; n is 0 or 1; and
- T is H, OH, 0-R 4 , carboxyl, amino, a peptide chain, C ⁇ g alkyl, c ⁇ -i 6 alkoxy, Cg. 20 aralkyl , or heterocycle optionally substituted; provided that R x is other than -NHNH 2 .
- R x incorporates an amino acid or derivative of the formula Ha (wherein P is a carbonyl)
- the carbon atom alpha to the nitrogen may adopt one of two stereo configurations.
- the alpha carbon will be oriented such that the amino acid or derivative will be in the L configuration.
- R 7 is H or methyl and most preferably H.
- K is a bond
- G is -NH-C (NH) -NH 2 attached via a methylene chain of
- a phenyl or piperidine attached via a methylene chain of 0 to 3 carbons wherein the phenyl or piperidine is substituted with -C(NH)-NH 2 ; or cyclohexyl attached via a methylene chain of 0 to 3 carbons wherein the cyclohexyl is substituted with -NH 2 .
- G is -NH-C (NH) -NH 2 attached via a methylene chain of 3 atoms.
- More preferably G is piperdin-3-yl N-substituted with -C(N)-NH 2 .
- G is a piperidine ring attached via a methylene chain of 0-3 carbons wherein the piperidine ring is substituted with one or two of the groups selected from cyano, -NH 2 , -C(NH)-NH 2 , -C(NH) -NH-NH 2 , -C (NH) -NH-OH and -NH-C (NH) -NH 2 .
- the piperidine ring is attached via one methylene group at the 3 position of the ring.
- the ring is mono-substituted at the 1 position (the nitrogen atom) and is one of -C(NH)-NH 2 , -C (NH) -NH-NH 2 or -C (NH) -NH-NH-OH . More preferably the substituent is -C(NH)-NH 2 .
- P is -C(0)-.
- J is selected from: -CH 2 -S-CH ? -CH 2 - ; -CH 2 -0-CH 2 -CH 2 - ;
- R- is selected from the following amino acid derivatives prepared according to the procedures described in Bioorg. Med. Chem., 1995, 3:1145 and PCT application WO 96/19483 (published 27 June 1996) incorporated herein by reference .
- R x may be selected from include :
- R- is a group represented by formula Ilia or Illb:
- R 7 , R B , P, J, n, n 2 and T are as previously defined.
- P is a bond n is 0 and T is H.
- P is C(O) and n is 0. More preferably nl is 2. More preferably n2 is 0-3 and most preferably 1. More preferably R 7 is H. More preferably R 8 is H. More preferably R 8 is NH 2 . More preferably R 8 is OH.
- T is a peptide of 1 to 4 amino acid residues in length and preferably fibrinogen' s A or B chain or fragment or derivative thereof.
- T is H while P is a bond and n is 0.
- T is selected from H, and amino such as N(R 9 ) (R 10 ) , N(R 9 ) (OR 10 ) wherein R 9 and R l0 are independently H or C- L -g alkyl .
- R 9 and R 10 together with the N from which they depend form a 3-8 member heterocyclic ring (preferably 5 or 6 member) such as piperidine.
- T is a heterocycle selected from the group consisting of :
- X 5 , X 10 , X X1 and X 12 are each independently selected from N, and
- X 6 and X 13 are each independently selected from the group consisting of C, O, N, S, N-X 7 , and CH-X 7 ;
- R' is hydrogen, C 1 . 16 alkyl optionally carboxyl substituted, carboxyl, -C 0 . 16 alkyl-C0 2 -C 1 . 16 alkyl , C 6 _ 20 aralkyl , C 3 _ 7 cycloalkyi, aryl or an aromatic heterocycle. Preparation of heterocycles according to the definition of T is described in PCT application WO 96/19483.
- T is selected from the group consisting of:
- R' is as defined above.
- T is selected from the group consisting of : wherein R' is as defined above
- T is selected from the group consisting of
- R * is as defined above.
- R' is H or C 1 .
- t alkyl such as methyl, ethyl, propyl or butyl and most preferably wherein R * is hydrogen, .
- T is a 1,2 thiazole optionally substituted with R * and/or is attached to J at the 2, 3, 4 or 5 position of the ring.
- Preferred compounds of the invention include: (1)
- R 3 and R 4 from substituent Y together form a 5 or 6 member saturated or unsaturated carbocyclic ring include:
- Particularly preferred compounds of the present invention include : (3 ⁇ 2- [2 -Benzyl -3 , 6-dioxo-4- (3 -phenyl -propyl) -piperazin-1- yl] -N- [4-guanidino-l- (thiazole-2-carbonyl ) -butyl] - acetamide ;
- Compounds of the invention may be used the treatment and/or prophylaxis of disorders mediated by serme proteases such as viral serine proteases i.e. HSV, CMV, HCV; those serine proteases involved in coagulatioin pathways i.e. thrombin, protein C / activated protein C, factor Vila, IXa and Xa .
- serme proteases such as viral serine proteases i.e. HSV, CMV, HCV; those serine proteases involved in coagulatioin pathways i.e. thrombin, protein C / activated protein C, factor Vila, IXa and Xa .
- Compounds of the invention may also be used in the treatment and prophylaxis of angiogenesis and tumour metastasis.
- the compounds are used in the prophylaxis and/or treatment of thrombotic disorders mediated by the activity of thrombin.
- Such thrombotic disorders include venous thrombosis, pulmonary embolism, arterial thrombosis, myocardial infarction and cerebral infarction.
- Methods of treatment or prophylaxis according to the invention comprise administering to a mammal, more particularly human, an effective amount of compounds of the present invention.
- effective is meant an amount of the compound sufficient to alleviate or reduce the severity of the disorder as measured by parameters established for the particular indication i.e. blood flow (patency) , clot size or density.
- the compounds of the present invention may be used as anticoagulants in vi tro or ex vivo as in the case of contact activation with foreign thrombogenic surfaces such as is found in tubing used in extracorporeal shunts.
- the compounds of the invention may also be used to coat the surface of such conduits.
- the compounds of the invention are obtained as lyophilized powders, redissolved in isotonic saline and added in an amount sufficient to maintain blood in an anticoagulated state.
- the therapeutic agents of the present invention may be administered alone or in combination with pharmaceutically acceptable carriers, diluents or adjuvants.
- the proportion of each carrier, diluent or adjuvant is determined by the solubility and chemical nature of the compound, the route of administration, and standard pharmaceutical practice.
- the compounds may be injected parenterally; this being intramuscularly, intravenously, or subcutaneously.
- the compound may be used in the form of sterile solutions containing other solutes, for example, sufficient saline or glucose to make the solution isotonic.
- the compounds may be administered orally in the form of tablets, capsules, or granules containing suitable excipients such as starch, lactose, white sugar and the like.
- the compounds may also be administered sublingually in the form of troches or .lozenges in which each active ingredient is mixed with sugar or corn syrups, flavouring agents and dyes, and then dehydrated sufficiently to make the mixture suitable for pressing into solid form.
- the compounds may be administered orally in the form of solutions which may contain colouring and/or flavouring agents.
- Dosages may vary with the mode of administration and the particular compound chosen.
- the dosage may vary with the particular patient under treatment .
- typical dosage is about 0.01 to 500 mg/kg body weight per day, and preferably about 0.5 to 10 mg/kg body weight per day.
- composition When the composition is administered orally, a larger quantity of the active agent will typically be required to produce the same effect as caused with a smaller quantity given parenterally .
- Prodrugs of the present invention are prepared according to established organic synthetic techniques and include for example esters of carboxyl groups . Prodrug selection and preparation are described in detail in "The
- salts of the compounds of the invention particularly pharmaceutically acceptable salts such as inorganic salts i.e. chloride, bromide, sodium, calcium, and potassium; and organic salts i.e. acetate, citrate, maleate, tartrate and mesylate.
- inorganic salts i.e. chloride, bromide, sodium, calcium, and potassium
- organic salts i.e. acetate, citrate, maleate, tartrate and mesylate.
- Pharmaceutically acceptable salts and their preparation are described in detail in Wermuth (supra) incorporated herein by reference.
- lactam portion of the molecule is 1) reacted with t-Bu bromoacetate followed by 2) ester hydrogenolysis to give monocyclic acid intermediate which is in turn 3) coupled by routine amidation to the polar amino acid residue R x to achieve the final compound.
- Various substituents may be introduced on the lactam or the polar amino acid residue R 1 either prior or subsequent to coupling.
- monoprotected diaminopropane may be substituted with a group according to R 4 , for example alkylated (reductive animation: J. Org. Chem., 1996, 61:3849) with hydrocinnamaldehyde .
- the protecting group of the primary amine is removed and the di-am e is cyclized into a urea using t ⁇ phosgene.
- the urea is alkylated with benzyl bromoacetate, followed by ester hydrogenolysis to give an acid intermediate which may then be coupled by amidation to an R x substituent.
- substituents may also be introduced on the cyclic urea prior to coupling with R ⁇ using conventional techniques in the art.
- the compound of formula (I) is desired as a single isomer, it may be obtained either by resolution of the final product or by stereospecific synthesis from isomerically pure starting material or any convenient intermediate. Resolution of the final product, or an intermediate or starting material therefor, may be effected by any suitable method known in the art: see for example, “Stereochemistry of Carbon Compounds”, by E.L. Eliel (McGraw Hill, 1962), and “Tables of Resolving Agents", by S.H. Wilen. Resolution of the final compound can also be achieved using established chiral HPLC techniques as described in “Chiral Separations", Eds. D. Stevenson and I.D. Wilson; "Chromatographic
- Step 1 To Boc-Arg(MTR) -OH (6.61g, 13.6mmol, Bache ) in dichloro ethane (33mL) at 0°C was added N-methyl morpholine (1.65mL, 15.0mmol) then isobutyl chlorofornate (1.95mL, 15.0mmol) and stirred at 0°C for 30 minutes. N,0-dimethyl amine HCl (1.5g, 15.4mmol) and N-methyl morpholine (1.65mL, 15.0mmol) was added and stirred at 0°C for 45 minutes.
- Step 2 To thiazole (1.95mL, 27.5mmol) and TMEDA (3.8mL, 25.2mmol, distilled from sodium) in THF (65mL, freshly distilled from potassium) at -78°C was added nBuLi in hexane (13.7mL, 24.7mmol, 1.8M) at a rate that raised the internal temperature to -50°C. Reaction flask was placed in dry ice/acetonitrile bath to give an internal temperature of 41°C. The solution was stirred for 25 minutes, cooled to
- Step 3 To BOC-Arg-CO-thiazol-2-yl was added ethyl methyl sulfide (2.3mL, 25.4mmol) then 4M HCl in dioxane (20mL) and stirred at room temperature for 40 minutes. A yellow, gummy precipitate formed and the supernatant was decanted. Ethyl acetate (40mL) was added and the gummy precipitate was stirred to change it to a fine granular precipitate. Precipitate was isolated by filtration and washed thoroughly with ethyl acetate (150mL) to give 3.
- the intermediate benzothiazolo-Arg (MTR) .HCl may be prepared by incorporating benzothiazole instead of thiazole in step 2.
- Step 1 To N ⁇ Boc-3 -pyridylalanine (I) (10.5g, 39.5mmol) in methylene chloride (106mL) was added BOP reagent [ (benzotriazol-1-yloxy tris- (dimethylamino) phosphonium hexafluorophosphate), 18.3g, 41.48mmol] and DIEA (7.56mL, 43.45mmol) . The reaction mixture was stirred at room temperature for twenty minutes and then was added N,0- dimethylhydroxylamine hydrochloride (3.85g, 39.5mmol) followed by DIEA (7.56mL). The reaction mixture stirred four hours and the solvents removed in vacuo.
- Step 2 To (II) (4.4g, 14.2mmol)in acetic acid (lOOmL) was added Pt0 2 (0.44g) and hydrogen gas in a Parr reactor. The reation was complete in twenty three hours. The catalyst was filtered and the reaction mixture concentrated in vacuo. The product was dissolved in water and lyophylized to yield 5.9g of the desired product as a sticky oil (III) .
- Step 3 To (III) (6.75g, 17.9mmol) in DMF ( 9mL) was added [ (lH-pyrazole-1-carboxamidine hydrochloride) 2.6g, 17.9mmol] followed by DIEA (6.25mL, 35mmol). The reaction mixture was stirred four hours at room temp, then the sovents removed in vacuo. The product was triturated with ether several times and the ether layer decanted. The product (IV) was used unpurified in the subsequent reaction.
- Step 4 To (IV) (0.56g, 1.56mmol) in acetone (6.8mL) at 0°C was added 4N NaOH (1.7mL) and PmcCl [ (4methyloxy-2 , 3 , 6 - trimethylbenzenesulfonyl chloride, 0.679g, 2.73mmol] in acetone (1.7mL) .
- the reaction mixture was stirred at 0°C for 2.5 hours. 10% citric acid was added until pH 6.0.
- the solvents were removed in vacuo.
- the residue was extracted with ethyl acetate several times and the combined organic phases were washed with brine, dried over magnesium sulfate, filtered and the solvents removed in vacuo.
- the product was purified on silica gel eluted with ethyl acetate to yield 396mg (V) R-isomer and 211mg (V) S-isomer.
- Step 5 To a solution of (V) (l.OOg, 1.6mmol) in THF (5mL) at -78°C, was added IM lithium aluminum hydride in THF (6.4mL, 6.4mmol) drop wise over 10 minutes. The reaction was stirred at -78°C for an additioinal 30 minutes. IM KHS0 4 (5.0mL) was added. The resulting solution was poured into a separatory funnel containing ethyl acetate and water (50mL each) . The organic layer was separated, washed with brine (50mL) and dried with sodium sulfate. Evaporation to dryness gave 0.93g of (VI) as a white solid.
- Step 6 To a solution of (VI) (0.90g, 1.58mmol) in methanol/acetonitrile at 0°C, was added NaCl0 2 (0.40g, 3.53mmol), KHP0 4 (0.066g, 0.48mmol) and 30% aqueous H 2 0 2 . The reaction was then warmed to room temperature and stirred for an additional 4 hours. The reaction mixture was evaporated, the residue was taken up in H 2 0, acidified with 10% HCl to pH 2.5 and extracted with ethyl acetate (2X50mL) . The organic layer was washed with brine (50mL) and dried with sodium sulfate. After removal of solvent under reduced pressure, (VII) was obtained after crystallization with ethyl acetate/hexane (0.83g).
- Step 7 A solution of (VII) (0.13g, 0.224mmol) , HATU [(0-(7- azabenzotriazol-1-yl) -1,1,3, 3-tetramethyluronium hexafluorophosphate), 0.085g, 0.225mmol], methylamine hydrochloride (0.020g, 0.31mmol) and DIEA (0.080mL, 0.46mmol) in DMF (2.0mL) was stirred at room temperature for 2 hours. The reaction mixture was poured into a separatory funnel containing ethyl acetate and saturated NaHC0 3 (20mL each) . The organic layer was separated, washed with brine (50mL) and dried with sodium sulfate. After removal of solvent under reduced pressure, the residue was purified by silica gel column chromatography (ethyl acetate) to give 0.130g of (VIII) .
- Step 1 To a suspension of NaH 60%/oil (256 mg, 1.5 eq) in dry THF (43 ml), at 0°C, under N 2 , was added the oxo-piperazine carbamate (1.0 g, 4.27 mmols, Maybridge) in small portions. The reaction mixture was stirred at 0°C for 30 min and t-Bu bromoacetate (693 ⁇ L, 1.1 eq) was added. The ice bath was removed and the solution was stirred for 15 hr . Water (2 mL) was added carefully (to destroy the excess of NaH) and the solution was poured in EtOAc/H 2 0. The phases were separated and the aqueous layer was extracted with EtOAc (2x) .
- Step 2 To a solution of the carbamate from step 1 (1.43 g, 4.12 mmols n dry MeOH 41 mL , at r.t., under N 2 , was added Pd/C 10% (357 mg, 25% wt) . The reaction mixture was placed under an H 2 atmosphere and stirred at r.t. for 60 min. The catalyst was filtered through Celite and the solvent was evaporated to give the amine (880 mg, 4.12 mmols, 100%) as a white solid.
- Step 3 To a solution of the amine of step 2 (880 mg, 4.12 mmols) in dry DMF (41 mL) , at r.t., under N 2 , were added successively iPr 2 NEt (1.43 mL, 2 eq) , 3-phenylpropionic acid (648 mg, 1.05 eq) and BOP (2.72 g, 1.5 eq) . The solution was stirred at r.t. for 15 hr and was poured in EtOAc/H 2 0. The phases were separated and the aqueous layer was extracted with EtOAc (2x) . The combined organic extracts were washed with 10% citric acid (lx) , sat.aq.
- Step 4 To a solution of the amidolactam t-butyl ester from step 3 (1.27 g, 3.65 mmols) in dry CH 2 C1 2 (18 mL) , at 0°C, under N 2 , was added CF 3 COOH (18 mL) .
- MTR l-methoxy-2 , 3 , 6- trimethylbenylsulfonyl
- Step 6 To a solution of the guanidino-protected product from step 5 (211 mg, 0.29 mmol) in CF 3 C00H (4 mL) , at 0°C, under N 2 , was added MeSPh (10% vol of TFA) . The solution was stirred at 0°C for 30 min, then at r.t. for 4 hr . The TFA was evaporated down to a minimum volume and Et 2 0 (20 mL) was added. The suspension was stirred vigorously for 10 min. The solids were filtered, rinsed with Et 2 0 and dried in vaccuo . The crude product was purified by HPLC (15% CH 3 CN/H 2 0 -> 50% CH 3 CN/H 2 0, 180 min) . The salt of compound (1) was obtained as a white solid (70 mg, 0.094 mmol, 24%).
- Step 1 2-OXO-4- (3 -phenyl -propionyl) -piperazin-1-yl] -acetic acid was coupled with benzothiazoloarginine-MTR-HCl according to the procedures described in step 5 of example 2 to give the guanidino-protected final compound.
- Step 2 The guanidino-protected product of step 1 was deprotected according to the procedures described in step 6 of example 2 (omitting addition of MeSPh) to give the final compound (2) .
- Step 1 To a solution of the glycine-OEt-HCl (499 mg, 3.58 mmol) in anh. EtOH (36 mL) , at r.t., under N 2 , were added hydrocynnamaldehyde (471 ⁇ L, 1 eq) and NaBH 3 CN (225 mg, 1 eq)
- Step 3 To a solution of the BOC-carbamate from step 2 (776 mg, 1.66 mmol) in anh. dioxanne (8 mL) , at r.t., under N 2 , was added 4N HCl/dioxanne (0.1 M: 16 mL) . The solution was stirred at r.t. for 4 hr. The solvent was evaporated and the oil dried under reduced pressure. The oil obtained was dissolved in H 2 0 (15 mL) and NaHC0 3 (700 mg, 5 eq) was added. The solution was heated at 60°C for 15 hr. A white precipitate was formed. The suspension was cooled to r.t. and the solid was filtered and then dried under vacuum to get 437 mg (82%) of the pure bi-lactam.
- 4N HCl/dioxanne 0.1 M: 16 mL
- Step 4 To a suspension of 60% NaH/oil (81 mg, 1.5 eq) in anh. THF (13.5 mL) , at 0°C, under N 2 , was added the bi-lactam of step 3 (437 mg, 1.36 mmol), in small portions. The suspension was stirred at 0°C for 10 min, then at r.t. for 20 min. BrCH 2 C0 2 Bn (236 ⁇ L, 1.1 eq) was added and the reaction mixture was stirred at r.t. for 18 hr. Water (10 mL) was added carefully to destroy the excess NaH and the reaction mixture was poured in EtOAc/H 2 0. The layers were separated and the aqueous phase was extracted with EtOAc (2x) .
- Step 5 To a solution of the ester from step 4 (427 mg, 0.91 mmol) in anh. MeOH (9.0 L) , at r.t., under N 2 , was added Pd/C 10% (100 mg, 25% wt . ) . The black suspension was placed under an atmosphere of H 2 and was stirred for 60 min. The catalyst was filtered through Celite and was rinsed with MeOH. The solvent was evaporated and the resulting white solid was dried under vacuum: 338 mg (98%) .
- Step 6 The acid from step 5 was coupled with thiazolo- arginine-MTR-HCl according to the procedures described in step 5 of example 2 to give the guanidino-protected final compound.
- Step 7 The guanidino-protected final compound of step 6 was deprotected using standard HF cleavage to give final compound (3) as a crude oil. The brown oil obtained was dissolved in 10% AcOH/H 2 0. The. aqueous phase was washed with Et 2 0 (2x) and evaporated to drynes ⁇ .
- Step 1 To a NaH suspension (0.24g, 5.9mmol ) in THF (50mL) at 0°C was added compound a (l.Og, 3.96mmol, Maybridge) in small portions. The reaction was stirred for 30 minutes followed by addition of tert-butyl -2-bromoacetate (0.7mL, 4.0mmol) . The reaction was allowed to stir overnight at ambient termperature followed by standard workup to give compound b.
- Step 2 To compound b (0.67mg, l,83mmol) was added EtSMe (0.3mL) followed by TFA (lOmL) at ambient temperature. The reaction was allowed to stir for 3h. The solvent was removed then added 10% aq.NaOH. The mixture was extracted with EtOAc and the aqueous layer acidified with powdered KHS0 4 , followed by extraction with DCM. Drying the organic layer with MgS0 4 followed by evaporation of solvent yeilded the acid c.
- Step 3 A mixture of c_ (0.235g, 0.758mmol) and thiazoloarginine-MTR.HCl (0.4g, 0.755mmol) was dissolved in DMF (20mL) .
- Step 4 A mixture of e (0.14g, 0.19mmol) was dissolved in TFA (2mL) and thioanisole (0.2mL) was added. The reaction stirred at room temperature for 6 hours then ether was added to precipitate the white powder which was purified by RP-TLC (0.5mm, Sigma; H2)/MeOH/TFA 80/80/5mL, v/v) to give 30mg of final compound (17) .
- Step 1' To starting compound a (l.Og, 6.75mmol, Maybridge) at 0 C was added hydrocinnamoyl chloride (l.lmL, 3.96mmol) slowly then stirred at RT for 2h then added brine (50mL) to precipitate the light brown solid which was filtered and washed repeatedly with ether and hexane to give compound b. Subsequent step were performed in the same manner as steps 1-4 of example 5 to yield final compound (18) .
- Step 1 To a mixture of the alcohol (21.7 g; 0.686 mol) and powdered molecular sieves 4A (40 g) in methylene chloride (500 mL) was added NMO (N-methyl morpholine oxide 17 g; 0.14 mol) followed by TPAP (tetrapropyl ammonium perruthenate 2.0 g) .
- NMO N-methyl morpholine oxide 17 g; 0.14 mol
- TPAP tetrapropyl ammonium perruthenate 2.0 g
- Step 2 To a solution of the amide (1.16 g, 2.21 mmols) in THF (30 mL) was added at -40 °C a 1.0 M solution of LAH in ether (2.9 mL) . The solution was warmed to -5 °C - 10 °C and stirred for 50 minutes. The solution was cooled to ⁇ -25 °C and quenched with 1 M aqueous solution of KHS0 4 (10 mL) . The mixture was stirred at 0 °C for 40 minutes then brine was added (30 mL) . The organic phase was separated and the aqueous layer extracted with ether (2 x 30 mL) .
- Step 3 To a solution of ethyl orthothioformate (2.7 mL; 14 mmols) in THF (30 mL) was added at - 60 °C - 55 °C n-BuLi in hexanes (1.3 M, 9.0 mL, 12 mmols) . The solution was stirred at - 60 °C - 55 °C for 30 minutes then a solution of the aldehyde (932 g; 2.00 mmols) in THF (10 mL) was added so that the temperature was maintained at - 60 °C - 55 °C.
- Step 4 To a solution of the orthothioformate (2.56 g; 3.85 mmols) in methanol (69 mL) and water (4 mL) was added HgO (732 mg) and mercuric chloride (2.69 g) . The mixture was stirred at room temperature for 2 hours then at 60 °C for 30 minutes. The mixture was filtered on a celite pad and washed with methanol (2 x 4 mL) , and dichloromethane (3 x 20 mL) . Water (80 L) and dichloromethane (40 mL) was added to the filtrate and the organic layer was separated. The aqueous phase was extracted with dichloromethane (2 x 80 mL) .
- Step 5 To a solution of the alcohol (812 mg; 1.54 mmols) in dichloromethane ( 100 mL) was added Dess-Martm reagent (3.0 g, 7.0 mmols) . The resulting mixture was stirred at room temperature for 30 minutes then quenched with solution of sodium thiosulphate (15 g) in a saturated aqueous solution of NaHC0 3 (150 mL) . The mixture was stirred for about 10 minutes and the organic layer was separated. The aqueous layer was extracted with ethyl acetate (3 x 100 mL) and the combined organic layers were washed with a saturated aqueous solution of NaHC0 3 then dried (MgS0 4 ) .
- Step 6 To a solution of the acid (200 mg, 0.640 mmol) in dry DMF (7 mL) was added the amine (380 mg, 0.819 mmols) followed by collidine (0.8 mL) and by HATU (320 mg, 0.842 mmols). The solution was stirred at room temperature for 23 hours, poured into a 10% citric acid solution, extracted with ethyl acetate (3 times) . The combined organic layers were washed successsively with a saturated solution of NaHC0 3 , a 10 % citric acid solution, brine then fried (MgS0 4 ) . The residue was purified on silica gel (EtOAC 100%) to afford the coupled product (265 mg, 57%) .
- EtOAC silica gel
- Step 7 To a solution of the ester (265 mg, 0.367 mmols) in THF (10 mL) was added LiOH-H 2 0 (35 mg; 0.833 mmols) in water (10 mL) . The solution was stirred at room temperature for one hour then poured into 5 % HCl (50 L) and extracted with dichloromethane (3 x 50 mL) . The combined organic layers were dried (MgS0 4 ) and evaporated to afford the acid (215 mg, 83 which was used in the next step without further purification.
- Step 11 To a solution of the protected compound (207 mg, 0.292 mmols) in TFA (10 mL) was added thioanisole (1 mL) and methanesulfonic acid (30 ml. 0.46 mmols) . The solution was stirred overnight and TFA was evaporated. Ether was added to the residue and the resulting solid was filtered and washed several times with ether. This solid was purified by preparative HPLC to afford, after lyophilization, compound
- Step 1 To a solution of the amine (2.04 g, 16.24 mmol) in anh. MeOH (81 mL) , at 0°C, under N 2 , was added butyraldehyde (732 ⁇ L, 0.5 eq) and NaBH 3 CN (561 mg, 0.55 eq) . The solution was stirred at 0°C for 30 min, then at r.t. for 18 hr . The MeOH was evaporated and the residue was poured in sat.aq. NaHC0 3 /CH 2 Cl 2 . The phases were separated and the aqueous layer was extracted with CH 2 C1 2 (2x) .
- Step 2 To a solution of the amine (512 mg, 3.53 mmol) in anh. DMF (35 L) , at r.t., under N 2 , was added the were added the acid (2.20 g, 1.2 eq) , the NMM (776 ⁇ L, 2 eq) and HATU (1.61 g, 1.2 eq) . The yellow solution was stirred at r.t. for 18 hr. The solvent was evaporated and the residue poured in EtOAc/H 2 0. The phases were separated and the aqueous layer was extracted with EtOAc (2x) . The combined organic extracts were washed with 10% citric acid (lx) , sat.aq.
- Step 3 1) The ester-dicarbamate (1.21 g, 2.61 mmol) was dissolved in 4N HCl/dioxane. The solution was stirred at r.t for 3 hr. The solvent was evaporated and the residue was dried in vaccuo. 2 ) The amine salt was dissolved in H 2 0 (26 mL) and NaHC0 3 (1.1 g, 5 eq) was added. A white solid precipitated im ediatly. The suspension was heated at 60°C for 18 hr. It was brought down to r.t. and extracted with CH 2 CL 2 (3x) .
- Step 4 To a suspension of NaH 60%/oil (64 mg . 1.1 eq) , in dry THF (10.6 mL) , at 0°C, under N2 , was added a solution of the dioxopiperazine (486 mg, 1.46 mmol, in 2 mL of anh. THF). The flask was rinced with another 2 mL of anh. THF. The suspension was stirred at 0°C for 30 min, and then at r.t. for 30 min. BrCH2C02tBu (30 ⁇ L, 1.1 eq) was then added and the solution/suspension was stirred at r.t. for 2 hr .
- Step 5 To a solution of the carbamate (463 mg, 1.04 mmol) in anh. MeOH (10 mL) , at r.t., under N 2 , was added Pd/C 10% (115 mg, 25% wt) . The black suspension was placed under an H 2 atmosphere and stirred at t.p. for 60 min. The catalyst was filtered through Celite and the Celite cake was rinced with MeOH. The solvent was evaporated and the residue was dried under vacuum to give the amine as a clear oil (333 mg, 0.96 mmol, 93%) .
- Step 6 To a solution of the am e (333 mg, 0.96 mmol) in anh. CH 2 C1 2 (9.6 mL) , at t.p., under N 2 , were added NMM (159 ⁇ L, 1.5 eq) and BnS0 2 Cl (193 mg, 1.05 eq) . The solution was stirred at r.t. for 2 hr . It was then poured m 10% citric acid/CH 2 Cl 2 . The phases were separated and the aqueous layer was extracted with CH 2 C1 2 (2x) .
- Step 7 To a solution of the ester (396 mg, 0.85 mmol) in anh. CH2C12 (4.25 mL) , at 0°C, under N2 , was added trifluoroacetic acid (4.25 mL) . The solution was stirred at 0°C for 15 min, and then at r.t. for 2 hr. The solvents were evaporated and the residue dried under vacuum. The acid was obtainded in 100% yield as a yellow solid (349 mg, 0.85 mmol) ,
- Step 8 To a solution of the acid (270 mg, 0.66 mmol) in anh. DMF (6.5 mL) , at r.t., under N2 , were added successively the arginine-mimic-HCl (382 mg, 1.1 eq) , 2 , 4 , 6-collidine (347 ⁇ L, 4 eq) and HATU (299 mg, 1.2 eq) .
- the solution was stirred at r.t. for 15 hr and was then poured in EtOAc/H20. The phases were separated and the aqueous layer was extracted with EtOAc (2x) . The combined organic extracts were washed with 10% citric acid (lx), sat.aq.
- Step 9 To a solution of the protected guanidine (349 mg, 0.39 mmol) in trifluoroacetic acid (10 mL) , at r.t., under N 2 , was added thioanisole (1 mL, 10% vol of TFA) . The solution was stirred at r.t. for 3 hr. The TFA was evaporated and Et 2 0 (20 mL) was added to precipitate the guanidine salt. The solid was scraped off the wall of the flask and the suspension was stirred vigorously for 10 min. The solids were then filtered and dried under vacuum.
- the reaction reached a steady-state within 3 minutes after mixing thrombin with the substrate and an inhibitor. The steady-state velocity was then measured for a few minutes.
- the compounds of this invention were also pre-incubated with thrombin for 20 minutes at room temperature before adding the substrate. The steady-state was achieved within 3 min and measured for a few min.
- the kinetic data (the steady-state velocity at various concentrations of the substrate and the inhibitors) of the competitive inhibition was analyzed using the methods described by Segel (1975) .
- a non-linear regression program, RNLIN in the IMSL library (IMSL, 1987), LMDER in MINPACK library (More et al., 1980) or MicrosoftTM ExcellTM was used to estimate the kinetic parameters (K_, V max and K .
- the FeCl 3 induced injury to the carotid artery in rats was induced according to the method described by Kurz , K.D., Main, R.W., Sandusky, G.E., Thrombosis Research 60; 269-280, 1990 and Schumacher, W.A. et al . J. Pharmacology and Experimental Therapeutics 267; 1237-1242, 1993.
- Vessel temperature changes were recorded on a thermister (Cole-Palmer * Model 08533-41) .
- Inhibitor compounds were given as an i.v. bolus (0.75 mg/kg) followed immediately by an i.v. infusion (50 ⁇ g/kg/min. via femoral vein) .
- Blood (ImL) was collected in to sodium citrate (1:9; 3.8%) as an anticoagulant prior to treatment, 30 and 90 min. after the start of the infusion. All anticoagulated blood samples were centrifuged (12,000 x g for 3 min.) to obtain plasma for same day analysis.
- Activated partial thromboplastin time (aPTT) and thrombin time (TT) were measured at 37°C using a coagulometer (ST4 from Diagnostica Stago, Asnieres, France; American Bioproducts Company, Parsipanny, NJ) .
- citrated plasma 50uL was incubated with reagent 1 (PTTAutomate; 00480, ST4 BIO; Diagnostica Stago) at 37°C for 180 sec. Clotting was initiated by adding 25mM CaCl 2 (50uL) .
- citrated plasma 200uL was incubated at 37°C for 2 min. and the clotting time was initiated by adding Thrombin Prest (titrated calcium thrombin; 200uL; Diagnostica Stago) . The time taken for the plasma to clot was then determined. Table 1
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Abstract
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
AU41723/97A AU4172397A (en) | 1996-09-06 | 1997-09-05 | Lactam inhibitors of thrombin |
Applications Claiming Priority (4)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US2559996P | 1996-09-06 | 1996-09-06 | |
GBGB9618687.9A GB9618687D0 (en) | 1996-09-06 | 1996-09-06 | Lactam inhibitors of thrombin |
US60/025,599 | 1996-09-06 | ||
GB9618687.9 | 1996-09-06 |
Publications (1)
Publication Number | Publication Date |
---|---|
WO1998009987A1 true WO1998009987A1 (fr) | 1998-03-12 |
Family
ID=26309992
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/US1997/015312 WO1998009987A1 (fr) | 1996-09-06 | 1997-09-05 | Inhibiteurs lactame de la thrombine |
Country Status (3)
Country | Link |
---|---|
AU (1) | AU4172397A (fr) |
WO (1) | WO1998009987A1 (fr) |
ZA (1) | ZA978049B (fr) |
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WO1998046626A1 (fr) * | 1997-04-14 | 1998-10-22 | Cor Therapeutics, Inc. | INHIBITEURS SELECTIFS DU FACTEUR Xa |
WO1998046627A1 (fr) * | 1997-04-14 | 1998-10-22 | Cor Therapeutics, Inc. | INHIBITEURS SELECTIFS DU FACTEUR Xa |
WO1999064446A1 (fr) * | 1998-06-11 | 1999-12-16 | 3-Dimensional Pharmaceuticals, Inc. | Inhibiteurs de protease a base de pyrazinone |
WO2000008005A3 (fr) * | 1998-08-08 | 2000-05-18 | Merck Patent Gmbh | Derives de piperazinone |
US6133256A (en) * | 1997-04-14 | 2000-10-17 | Cor Therapeutics Inc | Selective factor Xa inhibitors |
FR2795072A1 (fr) * | 1999-06-15 | 2000-12-22 | Adir | Nouveaux derives bicycliques d'amino-pyrazinones, leur procede de preparation et les compositions pharmaceutiques qui les contiennent |
US6180627B1 (en) | 1998-08-14 | 2001-01-30 | Pfizer Inc. | Antithrombotic agents |
US6194435B1 (en) | 1996-10-11 | 2001-02-27 | Cor Therapeutics, Inc. | Lactams as selective factor Xa inhibitors |
US6218382B1 (en) | 1997-08-11 | 2001-04-17 | Cor Therapeutics, Inc | Selective factor Xa inhibitors |
US6228854B1 (en) | 1997-08-11 | 2001-05-08 | Cor Therapeutics, Inc. | Selective factor Xa inhibitors |
US6262047B1 (en) | 1996-10-11 | 2001-07-17 | Cor Therapeutics, Inc. | Selective factor Xa inhibitors |
US6323219B1 (en) | 1998-04-02 | 2001-11-27 | Ortho-Mcneil Pharmaceutical, Inc. | Methods for treating immunomediated inflammatory disorders |
US6333321B1 (en) | 1997-08-11 | 2001-12-25 | Cor Therapeutics, Inc. | Selective factor Xa inhibitors |
US6369080B2 (en) | 1996-10-11 | 2002-04-09 | Cor Therapeutics, Inc. | Selective factor Xa inhibitors |
US6403583B1 (en) * | 1998-12-23 | 2002-06-11 | Patrick Y. S. Lam | Thrombin or factor Xa inhibitors |
EP1051176A4 (fr) * | 1998-01-27 | 2002-06-12 | Aventis Pharm Prod Inc | COMPOSES OXOAZAHETEROCYCLYLE SUBSTITUES INHIBITEURS DU FACTEUR Xa |
US6469036B1 (en) | 1999-01-27 | 2002-10-22 | Ortho-Mcneil Pharmaceutical, Inc. | Peptidyl heterocyclic ketones useful as tryptase inhibitors |
US6476016B2 (en) | 2000-07-17 | 2002-11-05 | 3-Dimensional Pharmaceuticals, Inc. | Cyclic oxyguanidine pyrazinones as protease inhibitors |
US6525076B1 (en) | 1996-10-11 | 2003-02-25 | Millennium Pharmaceuticals, Inc. | Selective factor Xa inhibitors |
US6534495B1 (en) * | 1997-05-02 | 2003-03-18 | Akzo Nebel | Serine protease inhibitors |
WO2002042272A3 (fr) * | 2000-11-20 | 2003-07-24 | Pharmacia Corp | Aryl-et-heteroaryl-pyridines polycycliques substituees utiles dans l'inhibition selective de la cascade de la coagulation |
US6642225B2 (en) | 2000-10-02 | 2003-11-04 | Novartis Ag | Diazacycloalkanedione derivatives |
US6653316B1 (en) | 1999-05-19 | 2003-11-25 | Pharmacia Corporation | Substituted polycyclic aryl and heteroaryl pyrimidinones useful for selective inhibition of the coagulation cascade |
US6660885B2 (en) | 2000-03-13 | 2003-12-09 | Pharmacia Corporation | Polycyclic aryl and heteroaryl substituted benzenes useful for selective inhibition of the coagulation cascade |
US6664255B1 (en) | 1999-05-19 | 2003-12-16 | Pharmacia Corporation | Substituted polycyclic aryl and heteroaryl pyrazinones useful for selective inhibition of the coagulation cascade |
US6686484B2 (en) | 2000-04-17 | 2004-02-03 | Pharmacia Corporation | Polycyclic aryl and heteroaryl substituted 1,4-quinones useful for selective inhibition of the coagulation cascade |
US6693121B2 (en) | 2000-04-05 | 2004-02-17 | Pharmacia Corporation | Polycyclic aryl and heteroaryl substituted 4-pyridones useful for selective inhibition of the coagulation cascade |
US6710058B2 (en) | 2000-11-06 | 2004-03-23 | Bristol-Myers Squibb Pharma Company | Monocyclic or bicyclic carbocycles and heterocycles as factor Xa inhibitors |
US6716838B1 (en) | 1999-05-19 | 2004-04-06 | Pharmacia Corporation | Substituted polycyclic aryl and heteroaryl uracils as anticoagulative agents |
US6750342B1 (en) | 1999-05-19 | 2004-06-15 | Pharmacia Corporation | Substituted polycyclic aryl and heteroaryl pyrimidinones useful for selective inhibition of the coagulation cascade |
US6867217B1 (en) | 1999-05-19 | 2005-03-15 | Pharmacia Corporation | Substituted polycyclic aryl and heteroaryl pyridones useful for selective inhibition of the coagulation cascade |
US6875791B2 (en) | 2000-04-05 | 2005-04-05 | Pharmacia Corporation | Polycyclic aryl and heteroaryl substituted 4-pyrones useful for selective inhibition of the coagulation cascade |
US6906068B1 (en) | 1999-05-19 | 2005-06-14 | Pharmacia Corporation | Substituted polycyclic aryl and heteroaryl 1,2,4 - triazinones useful as anticoagulants |
US6908919B2 (en) * | 1999-05-19 | 2005-06-21 | Pharmacia Corporation | Substituted polycyclic aryl and heteroaryl pyrazinones useful for selective inhibition of the coagulation cascade |
US6969715B2 (en) | 2001-10-03 | 2005-11-29 | Pharmacia Corporation | 6-membered heterocyclic compounds useful for selective inhibition of the coagulation cascade |
US7015223B1 (en) | 2000-11-20 | 2006-03-21 | Pharmacia Corporation | Substituted polycyclic aryl and heteroaryl 1,2,4-triazinones useful for selective inhibition of the coagulation cascade |
US7015230B1 (en) | 1999-05-19 | 2006-03-21 | Pharmacia Corporation | Substituted polycyclic aryl and heteroaryl uracils useful for selective inhibition of the coagulation cascade |
US7105559B2 (en) | 2001-10-03 | 2006-09-12 | Pharmacia Corporation | Substituted 5-membered polycyclic compounds useful for selective inhibition of the coagulation cascade |
US7119094B1 (en) | 2000-11-20 | 2006-10-10 | Warner-Lambert Company | Substituted polycyclic aryl and heteroarpyl pyrazinones useful for selective inhibition of the coagulation cascade |
US7192615B2 (en) | 2001-02-28 | 2007-03-20 | J&J Consumer Companies, Inc. | Compositions containing legume products |
US7309688B2 (en) | 2000-10-27 | 2007-12-18 | Johnson & Johnson Consumer Companies | Topical anti-cancer compositions and methods of use thereof |
US7629318B2 (en) | 2002-03-22 | 2009-12-08 | Gpc Biotech Ag | Immunosuppressant compounds, methods and uses related thereto |
US8093293B2 (en) | 1998-07-06 | 2012-01-10 | Johnson & Johnson Consumer Companies, Inc. | Methods for treating skin conditions |
US8106094B2 (en) | 1998-07-06 | 2012-01-31 | Johnson & Johnson Consumer Companies, Inc. | Compositions and methods for treating skin conditions |
US8431550B2 (en) | 2000-10-27 | 2013-04-30 | Johnson & Johnson Consumer Companies, Inc. | Topical anti-cancer compositions and methods of use thereof |
EP2982668A2 (fr) | 2002-12-03 | 2016-02-10 | Pharmacyclics LLC | Dérivés de 2-(2-hydroxybiphényl-3-yl)-1h-benzoimidazole-5-carboxamidine en tant qu'inhibiteurs du facteur viia inhibitors pour le traitement de maladies thromboemboliques |
US9758473B2 (en) | 2014-10-06 | 2017-09-12 | Cortexyme, Inc. | Inhibitors of lysine gingipain |
US10730826B2 (en) | 2016-09-16 | 2020-08-04 | Cortexyme, Inc. | Ketone inhibitors of lysine gingipain |
US10751417B2 (en) | 2017-04-20 | 2020-08-25 | Novartis Ag | Sustained release delivery systems comprising traceless linkers |
US10906881B2 (en) | 2015-11-09 | 2021-02-02 | Cortexyme, Inc. | Inhibitors of arginine gingipain |
US11389541B2 (en) | 2018-10-03 | 2022-07-19 | Novartis Ag | Sustained delivery of angiopoetin-like 3 polypeptides |
US12433949B2 (en) | 2022-11-11 | 2025-10-07 | Novartis Ag | Sustained release delivery systems comprising traceless linkers |
Citations (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5120718A (en) * | 1991-06-13 | 1992-06-09 | Abbott Laboratories | Candida acid protease inhibiting compounds |
WO1995035313A1 (fr) * | 1994-06-17 | 1995-12-28 | Corvas International, Inc. | Derives d'acide 3-amino-2-oxo-piperidineacetique contenant un analogue de l'arginine utilises en tant qu'inhibiteurs d'enzyme |
WO1995035311A1 (fr) * | 1994-06-17 | 1995-12-28 | Corvas International, Inc. | Derives de l'acide 3-amino-2-oxo-1-piperidineacetique |
WO1996018644A1 (fr) * | 1994-12-13 | 1996-06-20 | Corvas International, Inc. | Derives aromatiques heterocycliques utilisables comme inhibiteurs d'enzymes |
WO1996019483A1 (fr) * | 1994-12-22 | 1996-06-27 | Biochem Pharma Inc. | Inhibiteurs de la thrombine bicyclique a faible poids moleculaire |
WO1996019491A1 (fr) * | 1994-12-22 | 1996-06-27 | Biochem Pharma Inc. | Peptides de cetoarginine heterocycliques utilises comme inhibiteurs de thrombine |
-
1997
- 1997-09-05 WO PCT/US1997/015312 patent/WO1998009987A1/fr active Application Filing
- 1997-09-05 AU AU41723/97A patent/AU4172397A/en not_active Abandoned
- 1997-09-08 ZA ZA978049A patent/ZA978049B/xx unknown
Patent Citations (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5120718A (en) * | 1991-06-13 | 1992-06-09 | Abbott Laboratories | Candida acid protease inhibiting compounds |
WO1995035313A1 (fr) * | 1994-06-17 | 1995-12-28 | Corvas International, Inc. | Derives d'acide 3-amino-2-oxo-piperidineacetique contenant un analogue de l'arginine utilises en tant qu'inhibiteurs d'enzyme |
WO1995035311A1 (fr) * | 1994-06-17 | 1995-12-28 | Corvas International, Inc. | Derives de l'acide 3-amino-2-oxo-1-piperidineacetique |
WO1996018644A1 (fr) * | 1994-12-13 | 1996-06-20 | Corvas International, Inc. | Derives aromatiques heterocycliques utilisables comme inhibiteurs d'enzymes |
WO1996019483A1 (fr) * | 1994-12-22 | 1996-06-27 | Biochem Pharma Inc. | Inhibiteurs de la thrombine bicyclique a faible poids moleculaire |
WO1996019491A1 (fr) * | 1994-12-22 | 1996-06-27 | Biochem Pharma Inc. | Peptides de cetoarginine heterocycliques utilises comme inhibiteurs de thrombine |
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US6525076B1 (en) | 1996-10-11 | 2003-02-25 | Millennium Pharmaceuticals, Inc. | Selective factor Xa inhibitors |
US6262047B1 (en) | 1996-10-11 | 2001-07-17 | Cor Therapeutics, Inc. | Selective factor Xa inhibitors |
US6369080B2 (en) | 1996-10-11 | 2002-04-09 | Cor Therapeutics, Inc. | Selective factor Xa inhibitors |
US6194435B1 (en) | 1996-10-11 | 2001-02-27 | Cor Therapeutics, Inc. | Lactams as selective factor Xa inhibitors |
US6133256A (en) * | 1997-04-14 | 2000-10-17 | Cor Therapeutics Inc | Selective factor Xa inhibitors |
US6369063B1 (en) | 1997-04-14 | 2002-04-09 | Cor Therapeutics, Inc. | Selective factor Xa inhibitors |
WO1998046626A1 (fr) * | 1997-04-14 | 1998-10-22 | Cor Therapeutics, Inc. | INHIBITEURS SELECTIFS DU FACTEUR Xa |
US6204268B1 (en) | 1997-04-14 | 2001-03-20 | Cor Therapeutics, Inc | Selective factor Xa inhibitors |
WO1998046627A1 (fr) * | 1997-04-14 | 1998-10-22 | Cor Therapeutics, Inc. | INHIBITEURS SELECTIFS DU FACTEUR Xa |
US6534495B1 (en) * | 1997-05-02 | 2003-03-18 | Akzo Nebel | Serine protease inhibitors |
US6218382B1 (en) | 1997-08-11 | 2001-04-17 | 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 |
EP1051176A4 (fr) * | 1998-01-27 | 2002-06-12 | Aventis Pharm Prod Inc | COMPOSES OXOAZAHETEROCYCLYLE SUBSTITUES INHIBITEURS DU FACTEUR Xa |
US7612075B2 (en) | 1998-01-27 | 2009-11-03 | Aventis Pharmaceuticals Inc. | Substituted oxoazaheterocyclyl compounds |
US6323219B1 (en) | 1998-04-02 | 2001-11-27 | Ortho-Mcneil Pharmaceutical, Inc. | Methods for treating immunomediated inflammatory disorders |
US6204263B1 (en) | 1998-06-11 | 2001-03-20 | 3-Dimensional Pharmaceuticals, Inc. | Pyrazinone protease inhibitors |
EP1589029A3 (fr) * | 1998-06-11 | 2006-01-18 | Johnson & Johnson Pharmaceutical Research & Development L.L.C. | Inhibiteurs de protéase à base de pyrazine |
WO1999064446A1 (fr) * | 1998-06-11 | 1999-12-16 | 3-Dimensional Pharmaceuticals, Inc. | Inhibiteurs de protease a base de pyrazinone |
US6514978B2 (en) | 1998-06-11 | 2003-02-04 | 3-Dimensional Pharmaceuticals, Inc. | Thromboresistant materials incorporating pyrazinone protease inhibitors |
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 |
WO2000008005A3 (fr) * | 1998-08-08 | 2000-05-18 | Merck Patent Gmbh | Derives de piperazinone |
US6180627B1 (en) | 1998-08-14 | 2001-01-30 | Pfizer Inc. | Antithrombotic agents |
US6403583B1 (en) * | 1998-12-23 | 2002-06-11 | Patrick Y. S. Lam | Thrombin or factor Xa inhibitors |
US6602871B2 (en) | 1998-12-23 | 2003-08-05 | Bristol-Myers Squibb Pharma Company | Thrombin or factor Xa inhibitors |
US7132418B2 (en) | 1999-01-27 | 2006-11-07 | Ortho-Mcneil Pharmaceutical, Inc. | Peptidyl heterocyclic ketones useful as tryptase inhibitors |
US6469036B1 (en) | 1999-01-27 | 2002-10-22 | Ortho-Mcneil Pharmaceutical, Inc. | Peptidyl heterocyclic ketones useful as tryptase inhibitors |
US6870056B1 (en) | 1999-05-19 | 2005-03-22 | Pharmacia Corporation | Substitituted polycyclic aryl and heteroaryl pyridones useful for selective inhibition of the coagulation cascade |
US6653316B1 (en) | 1999-05-19 | 2003-11-25 | Pharmacia Corporation | Substituted polycyclic aryl and heteroaryl pyrimidinones useful for selective inhibition of the coagulation cascade |
US6664255B1 (en) | 1999-05-19 | 2003-12-16 | Pharmacia Corporation | Substituted polycyclic aryl and heteroaryl pyrazinones useful for selective inhibition of the coagulation cascade |
US7015230B1 (en) | 1999-05-19 | 2006-03-21 | Pharmacia Corporation | Substituted polycyclic aryl and heteroaryl uracils useful for selective inhibition of the coagulation cascade |
US6908919B2 (en) * | 1999-05-19 | 2005-06-21 | Pharmacia Corporation | Substituted polycyclic aryl and heteroaryl pyrazinones useful for selective inhibition of the coagulation cascade |
US6716838B1 (en) | 1999-05-19 | 2004-04-06 | Pharmacia Corporation | Substituted polycyclic aryl and heteroaryl uracils as anticoagulative agents |
US6750342B1 (en) | 1999-05-19 | 2004-06-15 | Pharmacia Corporation | Substituted polycyclic aryl and heteroaryl pyrimidinones useful for selective inhibition of the coagulation cascade |
US6906068B1 (en) | 1999-05-19 | 2005-06-14 | Pharmacia Corporation | Substituted polycyclic aryl and heteroaryl 1,2,4 - triazinones useful as anticoagulants |
US6867217B1 (en) | 1999-05-19 | 2005-03-15 | Pharmacia Corporation | Substituted polycyclic aryl and heteroaryl pyridones useful for selective inhibition of the coagulation cascade |
FR2795072A1 (fr) * | 1999-06-15 | 2000-12-22 | Adir | Nouveaux derives bicycliques d'amino-pyrazinones, leur procede de preparation et les compositions pharmaceutiques qui les contiennent |
EP1069132A1 (fr) * | 1999-06-15 | 2001-01-17 | Adir Et Compagnie | Dérivés bicycliques d'amino-pyrazinones, leur procédé de préparation et les compositions pharmaceutiques qui les contiennent |
US6852761B2 (en) | 2000-03-13 | 2005-02-08 | Pharmacia Corporation | Polycyclic aryl and heteroaryl substituted benzenes useful for selective inhibition of the coagulation cascade |
US6660885B2 (en) | 2000-03-13 | 2003-12-09 | Pharmacia Corporation | Polycyclic aryl and heteroaryl substituted benzenes useful for selective inhibition of the coagulation cascade |
US6693121B2 (en) | 2000-04-05 | 2004-02-17 | Pharmacia Corporation | Polycyclic aryl and heteroaryl substituted 4-pyridones useful for selective inhibition of the coagulation cascade |
US6875791B2 (en) | 2000-04-05 | 2005-04-05 | Pharmacia Corporation | Polycyclic aryl and heteroaryl substituted 4-pyrones useful for selective inhibition of the coagulation cascade |
US6916847B2 (en) | 2000-04-05 | 2005-07-12 | Pharmacia Corporation | Polycyclic aryl and heteroaryl substituted 4-pyrones useful for selective inhibition of the coagulation cascade |
US6686484B2 (en) | 2000-04-17 | 2004-02-03 | Pharmacia Corporation | Polycyclic aryl and heteroaryl substituted 1,4-quinones useful for selective inhibition of the coagulation cascade |
US7030110B2 (en) | 2000-07-17 | 2006-04-18 | Ortho-Mcneil Pharmaceuticals, Inc. | Cyclic oxyguanidine pyrazinones as protease inhibitors |
US6476016B2 (en) | 2000-07-17 | 2002-11-05 | 3-Dimensional Pharmaceuticals, Inc. | Cyclic oxyguanidine pyrazinones as protease inhibitors |
US6642225B2 (en) | 2000-10-02 | 2003-11-04 | Novartis Ag | Diazacycloalkanedione derivatives |
US8431550B2 (en) | 2000-10-27 | 2013-04-30 | Johnson & Johnson Consumer Companies, Inc. | Topical anti-cancer compositions and methods of use thereof |
US7309688B2 (en) | 2000-10-27 | 2007-12-18 | Johnson & Johnson Consumer Companies | Topical anti-cancer compositions and methods of use thereof |
US6710058B2 (en) | 2000-11-06 | 2004-03-23 | Bristol-Myers Squibb Pharma Company | Monocyclic or bicyclic carbocycles and heterocycles as factor Xa inhibitors |
US6951872B2 (en) | 2000-11-06 | 2005-10-04 | Bristol-Myers Squibb Pharma Company | Monocyclic or bicyclic carbocycles and heterocycles as factor Xa inhibitors |
WO2002042272A3 (fr) * | 2000-11-20 | 2003-07-24 | Pharmacia Corp | Aryl-et-heteroaryl-pyridines polycycliques substituees utiles dans l'inhibition selective de la cascade de la coagulation |
US7119094B1 (en) | 2000-11-20 | 2006-10-10 | Warner-Lambert Company | Substituted polycyclic aryl and heteroarpyl pyrazinones useful for selective inhibition of the coagulation cascade |
US7015223B1 (en) | 2000-11-20 | 2006-03-21 | Pharmacia Corporation | Substituted polycyclic aryl and heteroaryl 1,2,4-triazinones useful for selective inhibition of the coagulation cascade |
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US7192615B2 (en) | 2001-02-28 | 2007-03-20 | J&J Consumer Companies, Inc. | Compositions containing legume products |
US7897144B2 (en) | 2001-02-28 | 2011-03-01 | Johnson & Johnson Comsumer Companies, Inc. | Compositions containing legume products |
US6969715B2 (en) | 2001-10-03 | 2005-11-29 | Pharmacia Corporation | 6-membered heterocyclic compounds useful for selective inhibition of the coagulation cascade |
US7105559B2 (en) | 2001-10-03 | 2006-09-12 | Pharmacia Corporation | Substituted 5-membered polycyclic compounds useful for selective inhibition of the coagulation cascade |
US7629318B2 (en) | 2002-03-22 | 2009-12-08 | Gpc Biotech Ag | Immunosuppressant compounds, methods and uses related thereto |
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US10730826B2 (en) | 2016-09-16 | 2020-08-04 | Cortexyme, Inc. | Ketone inhibitors of lysine gingipain |
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US10751417B2 (en) | 2017-04-20 | 2020-08-25 | Novartis Ag | Sustained release delivery systems comprising traceless linkers |
US11389541B2 (en) | 2018-10-03 | 2022-07-19 | Novartis Ag | Sustained delivery of angiopoetin-like 3 polypeptides |
US12433949B2 (en) | 2022-11-11 | 2025-10-07 | Novartis Ag | Sustained release delivery systems comprising traceless linkers |
Also Published As
Publication number | Publication date |
---|---|
ZA978049B (en) | 1998-09-10 |
AU4172397A (en) | 1998-03-26 |
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