RU2002125671A - НОВЫЕ ПРОИЗВОДНЫЕ МАЛОНОВОЙ КИСЛОТЫ, СПОСОБЫ ИХ ПОЛУЧЕНИЯ, ИХ ПРИМЕНЕНИЕ В КАЧЕСТВЕ ИНГИБИТОРА АКТИВНОСТИ ФАКТОРА Xa И СОДЕРЖАЩИЕ ИХ ФАРМАЦЕВТИЧЕСКИЕ КОМПОЗИЦИИ - Google Patents
НОВЫЕ ПРОИЗВОДНЫЕ МАЛОНОВОЙ КИСЛОТЫ, СПОСОБЫ ИХ ПОЛУЧЕНИЯ, ИХ ПРИМЕНЕНИЕ В КАЧЕСТВЕ ИНГИБИТОРА АКТИВНОСТИ ФАКТОРА Xa И СОДЕРЖАЩИЕ ИХ ФАРМАЦЕВТИЧЕСКИЕ КОМПОЗИЦИИ Download PDFInfo
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- RU2002125671A RU2002125671A RU2002125671/04A RU2002125671A RU2002125671A RU 2002125671 A RU2002125671 A RU 2002125671A RU 2002125671/04 A RU2002125671/04 A RU 2002125671/04A RU 2002125671 A RU2002125671 A RU 2002125671A RU 2002125671 A RU2002125671 A RU 2002125671A
- Authority
- RU
- Russia
- Prior art keywords
- alkyl
- formula
- compound
- represents hydrogen
- acid salt
- Prior art date
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- 239000003112 inhibitor Substances 0.000 title claims 3
- 108010074860 Factor Xa Proteins 0.000 title claims 2
- 238000000034 method Methods 0.000 title claims 2
- 239000008194 pharmaceutical composition Substances 0.000 title claims 2
- 150000004701 malic acid derivatives Chemical class 0.000 title 1
- -1 4-carbamimidoylbenzyl Chemical group 0.000 claims 62
- 150000001875 compounds Chemical class 0.000 claims 52
- 229910052739 hydrogen Inorganic materials 0.000 claims 52
- 239000001257 hydrogen Substances 0.000 claims 52
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims 43
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical class OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 claims 34
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims 32
- 150000003839 salts Chemical class 0.000 claims 18
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims 16
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims 14
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims 13
- 125000004210 cyclohexylmethyl group Chemical group [H]C([H])(*)C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C1([H])[H] 0.000 claims 11
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 claims 9
- 125000000041 C6-C10 aryl group Chemical group 0.000 claims 9
- 150000002431 hydrogen Chemical group 0.000 claims 9
- 239000000203 mixture Substances 0.000 claims 8
- 125000003118 aryl group Chemical group 0.000 claims 7
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims 7
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims 6
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 claims 6
- 125000000094 2-phenylethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])C([H])([H])* 0.000 claims 5
- 150000001450 anions Chemical class 0.000 claims 5
- 125000002057 carboxymethyl group Chemical group [H]OC(=O)C([H])([H])[*] 0.000 claims 5
- 125000006239 protecting group Chemical group 0.000 claims 5
- 125000006526 (C1-C2) alkyl group Chemical group 0.000 claims 4
- 125000006273 (C1-C3) alkyl group Chemical group 0.000 claims 4
- 125000004042 4-aminobutyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])N([H])[H] 0.000 claims 4
- 125000000217 alkyl group Chemical group 0.000 claims 4
- 125000003710 aryl alkyl group Chemical group 0.000 claims 4
- 125000003739 carbamimidoyl group Chemical group C(N)(=N)* 0.000 claims 4
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims 4
- 125000002147 dimethylamino group Chemical group [H]C([H])([H])N(*)C([H])([H])[H] 0.000 claims 4
- 125000004356 hydroxy functional group Chemical group O* 0.000 claims 4
- 125000004029 hydroxymethyl group Chemical group [H]OC([H])([H])* 0.000 claims 4
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims 4
- 125000005344 pyridylmethyl group Chemical group [H]C1=C([H])C([H])=C([H])C(=N1)C([H])([H])* 0.000 claims 4
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims 4
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims 4
- YCWRFIYBUQBHJI-UHFFFAOYSA-N 2-(4-aminophenyl)acetonitrile Chemical group NC1=CC=C(CC#N)C=C1 YCWRFIYBUQBHJI-UHFFFAOYSA-N 0.000 claims 3
- 125000000143 2-carboxyethyl group Chemical group [H]OC(=O)C([H])([H])C([H])([H])* 0.000 claims 3
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical class Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims 3
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims 3
- 125000004923 naphthylmethyl group Chemical group C1(=CC=CC2=CC=CC=C12)C* 0.000 claims 3
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims 3
- 230000002265 prevention Effects 0.000 claims 3
- 238000001356 surgical procedure Methods 0.000 claims 3
- APCJUHZGIFNYHW-AKQSQHNNSA-N (2s)-2-[[(2s)-2-[[2-[(4-carbamimidoylphenyl)methyl]-3-(dimethylamino)-3-oxopropanoyl]amino]-2-cyclohexylacetyl]amino]-5-(diaminomethylideneamino)pentanoic acid Chemical compound N([C@@H](C1CCCCC1)C(=O)N[C@@H](CCCNC(N)=N)C(O)=O)C(=O)C(C(=O)N(C)C)CC1=CC=C(C(N)=N)C=C1 APCJUHZGIFNYHW-AKQSQHNNSA-N 0.000 claims 2
- 125000004916 (C1-C6) alkylcarbonyl group Chemical group 0.000 claims 2
- 125000006272 (C3-C7) cycloalkyl group Chemical group 0.000 claims 2
- 125000001622 2-naphthyl group Chemical group [H]C1=C([H])C([H])=C2C([H])=C(*)C([H])=C([H])C2=C1[H] 0.000 claims 2
- UYHZKOFBXUHRRZ-DCYPJBMNSA-N C1CCC(CC1)[C@@H](C(=O)N[C@@H](CCCN=C(N)N)C(=O)O)NC(=O)C(CC2=CC=C(C=C2)C(=N)N)C(=O)NCCC3=CC=CC=C3 Chemical compound C1CCC(CC1)[C@@H](C(=O)N[C@@H](CCCN=C(N)N)C(=O)O)NC(=O)C(CC2=CC=C(C=C2)C(=N)N)C(=O)NCCC3=CC=CC=C3 UYHZKOFBXUHRRZ-DCYPJBMNSA-N 0.000 claims 2
- 125000000882 C2-C6 alkenyl group Chemical group 0.000 claims 2
- 208000024172 Cardiovascular disease Diseases 0.000 claims 2
- 208000007536 Thrombosis Diseases 0.000 claims 2
- 239000002253 acid Substances 0.000 claims 2
- 125000004466 alkoxycarbonylamino group Chemical group 0.000 claims 2
- 238000010511 deprotection reaction Methods 0.000 claims 2
- 125000000524 functional group Chemical group 0.000 claims 2
- ZSEZTFLKIPFUSF-MNNMKWMVSA-N n-[(2s)-1-[[(2s)-1-amino-5-(diaminomethylideneamino)-1-oxopentan-2-yl]amino]-1-oxohexan-2-yl]-2-[(4-carbamimidoylphenyl)methyl]-n',n'-dimethylpropanediamide Chemical compound NC(N)=NCCC[C@@H](C(N)=O)NC(=O)[C@H](CCCC)NC(=O)C(C(=O)N(C)C)CC1=CC=C(C(N)=N)C=C1 ZSEZTFLKIPFUSF-MNNMKWMVSA-N 0.000 claims 2
- 125000001624 naphthyl group Chemical group 0.000 claims 2
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims 2
- WGYKZJWCGVVSQN-UHFFFAOYSA-N propylamine Chemical group CCCN WGYKZJWCGVVSQN-UHFFFAOYSA-N 0.000 claims 2
- 208000037803 restenosis Diseases 0.000 claims 2
- FFSIKGOCCSHQFC-QIFDKBNDSA-N (2s)-2-[[(2s)-2-[[2-[(4-carbamimidoylphenyl)methyl]-3-(dimethylamino)-3-oxopropanoyl]amino]-3-cyclohexylpropanoyl]amino]-5-(diaminomethylideneamino)pentanoic acid Chemical compound N([C@@H](CC1CCCCC1)C(=O)N[C@@H](CCCN=C(N)N)C(O)=O)C(=O)C(C(=O)N(C)C)CC1=CC=C(C(N)=N)C=C1 FFSIKGOCCSHQFC-QIFDKBNDSA-N 0.000 claims 1
- UFGRDLFQIRCQQP-WIXBZOCESA-N (2s)-2-[[(2s)-2-[[3-(benzylamino)-2-[(4-carbamimidoylphenyl)methyl]-3-oxopropanoyl]amino]-2-cyclohexylacetyl]amino]-5-(diaminomethylideneamino)pentanoic acid Chemical compound N([C@H](C(=O)N[C@@H](CCCN=C(N)N)C(O)=O)C1CCCCC1)C(=O)C(C(=O)NCC=1C=CC=CC=1)CC1=CC=C(C(N)=N)C=C1 UFGRDLFQIRCQQP-WIXBZOCESA-N 0.000 claims 1
- GLZOSBAYSOEXSG-BSOSBYQFSA-N (4s)-5-[[(2s)-1-amino-5-(diaminomethylideneamino)-1-oxopentan-2-yl]amino]-4-[[2-[(4-carbamimidoylphenyl)methyl]-3-(dimethylamino)-3-oxopropanoyl]amino]-5-oxopentanoic acid Chemical compound NC(=N)NCCC[C@@H](C(N)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)C(C(=O)N(C)C)CC1=CC=C(C(N)=N)C=C1 GLZOSBAYSOEXSG-BSOSBYQFSA-N 0.000 claims 1
- 125000004191 (C1-C6) alkoxy group Chemical group 0.000 claims 1
- 125000004454 (C1-C6) alkoxycarbonyl group Chemical group 0.000 claims 1
- 206010001052 Acute respiratory distress syndrome Diseases 0.000 claims 1
- 206010002383 Angina Pectoris Diseases 0.000 claims 1
- 125000004399 C1-C4 alkenyl group Chemical group 0.000 claims 1
- 208000005189 Embolism Diseases 0.000 claims 1
- 208000013616 Respiratory Distress Syndrome Diseases 0.000 claims 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-N Succinic acid Natural products OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 claims 1
- 208000001435 Thromboembolism Diseases 0.000 claims 1
- DTQVDTLACAAQTR-UHFFFAOYSA-M Trifluoroacetate Chemical compound [O-]C(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-M 0.000 claims 1
- DGYIJVNZSDYBOE-UHFFFAOYSA-N [CH2]C1=CC=NC=C1 Chemical group [CH2]C1=CC=NC=C1 DGYIJVNZSDYBOE-UHFFFAOYSA-N 0.000 claims 1
- 208000011341 adult acute respiratory distress syndrome Diseases 0.000 claims 1
- 201000000028 adult respiratory distress syndrome Diseases 0.000 claims 1
- 230000029936 alkylation Effects 0.000 claims 1
- 238000005804 alkylation reaction Methods 0.000 claims 1
- 230000023555 blood coagulation Effects 0.000 claims 1
- 238000006243 chemical reaction Methods 0.000 claims 1
- 239000003638 chemical reducing agent Substances 0.000 claims 1
- 210000004351 coronary vessel Anatomy 0.000 claims 1
- 125000004093 cyano group Chemical group *C#N 0.000 claims 1
- 208000009190 disseminated intravascular coagulation Diseases 0.000 claims 1
- 239000003937 drug carrier Substances 0.000 claims 1
- 125000004185 ester group Chemical group 0.000 claims 1
- 150000002148 esters Chemical class 0.000 claims 1
- 125000004494 ethyl ester group Chemical group 0.000 claims 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims 1
- 208000015181 infectious disease Diseases 0.000 claims 1
- WRIRWRKPLXCTFD-UHFFFAOYSA-N malonamide Chemical compound NC(=O)CC(N)=O WRIRWRKPLXCTFD-UHFFFAOYSA-N 0.000 claims 1
- 150000004702 methyl esters Chemical class 0.000 claims 1
- 208000010125 myocardial infarction Diseases 0.000 claims 1
- OOWHMVOOPWACHD-YPJRHXLCSA-N n-[(1s)-2-[[(2s)-1-amino-5-(diaminomethylideneamino)-1-oxopentan-2-yl]amino]-1-cyclohexyl-2-oxoethyl]-2-[(4-carbamimidoylphenyl)methyl]-n'-methylpropanediamide Chemical compound N([C@@H](C1CCCCC1)C(=O)N[C@@H](CCCN=C(N)N)C(N)=O)C(=O)C(C(=O)NC)CC1=CC=C(C(N)=N)C=C1 OOWHMVOOPWACHD-YPJRHXLCSA-N 0.000 claims 1
- QSFAZZLQRGSOIV-DCYPJBMNSA-N n-[(1s)-2-[[(2s)-1-amino-5-(diaminomethylideneamino)-1-oxopentan-2-yl]amino]-1-cyclohexyl-2-oxoethyl]-n'-benzyl-2-[(4-carbamimidoylphenyl)methyl]-n'-methylpropanediamide Chemical compound C=1C=C(C(N)=N)C=CC=1CC(C(=O)N[C@@H](C1CCCCC1)C(=O)N[C@@H](CCCN=C(N)N)C(N)=O)C(=O)N(C)CC1=CC=CC=C1 QSFAZZLQRGSOIV-DCYPJBMNSA-N 0.000 claims 1
- VHIRWQRNWJKCFG-AKQSQHNNSA-N n-[(1s)-2-[[(2s)-1-amino-5-(diaminomethylideneamino)-1-oxopentan-2-yl]amino]-2-oxo-1-phenylethyl]-2-[(4-carbamimidoylphenyl)methyl]-n',n'-dimethylpropanediamide Chemical compound N([C@H](C(=O)N[C@@H](CCCN=C(N)N)C(N)=O)C=1C=CC=CC=1)C(=O)C(C(=O)N(C)C)CC1=CC=C(C(N)=N)C=C1 VHIRWQRNWJKCFG-AKQSQHNNSA-N 0.000 claims 1
- CKLLYBCEMQDQDW-YPJRHXLCSA-N n-[(1s)-2-[[(2s)-1-amino-5-(diaminomethylideneamino)-1-oxopentan-2-yl]amino]-2-oxo-1-phenylethyl]-2-[(4-carbamimidoylphenyl)methyl]-n'-methylpropanediamide Chemical compound N([C@H](C(=O)N[C@@H](CCCN=C(N)N)C(N)=O)C=1C=CC=CC=1)C(=O)C(C(=O)NC)CC1=CC=C(C(N)=N)C=C1 CKLLYBCEMQDQDW-YPJRHXLCSA-N 0.000 claims 1
- DHIDNHDWZIHXTE-KXNJDZORSA-N n-[(2s)-1-[[(2s)-1-amino-5-(diaminomethylideneamino)-1-oxopentan-2-yl]amino]-1-oxo-3-phenylmethoxypropan-2-yl]-2-[(4-carbamimidoylphenyl)methyl]-n',n'-dimethylpropanediamide Chemical compound N([C@@H](COCC=1C=CC=CC=1)C(=O)N[C@@H](CCCN=C(N)N)C(N)=O)C(=O)C(C(=O)N(C)C)CC1=CC=C(C(N)=N)C=C1 DHIDNHDWZIHXTE-KXNJDZORSA-N 0.000 claims 1
- BSENJLGKIKMSRC-QIFDKBNDSA-N n-[(2s)-1-[[(2s)-1-amino-5-(diaminomethylideneamino)-1-oxopentan-2-yl]amino]-1-oxo-3-phenylpropan-2-yl]-2-[(4-carbamimidoylphenyl)methyl]-n',n'-dimethylpropanediamide Chemical compound N([C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](CCCN=C(N)N)C(N)=O)C(=O)C(C(=O)N(C)C)CC1=CC=C(C(N)=N)C=C1 BSENJLGKIKMSRC-QIFDKBNDSA-N 0.000 claims 1
- OMHSNBZGQMZQKZ-KXNJDZORSA-N n-[(2s)-1-[[(2s)-1-amino-5-(diaminomethylideneamino)-1-oxopentan-2-yl]amino]-1-oxo-4-phenylbutan-2-yl]-2-[(4-carbamimidoylphenyl)methyl]-n',n'-dimethylpropanediamide Chemical compound N([C@@H](CCC=1C=CC=CC=1)C(=O)N[C@@H](CCCN=C(N)N)C(N)=O)C(=O)C(C(=O)N(C)C)CC1=CC=C(C(N)=N)C=C1 OMHSNBZGQMZQKZ-KXNJDZORSA-N 0.000 claims 1
- NALXCZRJYTWWMA-FQECFTEESA-N n-[(2s)-1-[[(2s)-1-amino-5-(diaminomethylideneamino)-1-oxopentan-2-yl]amino]-1-oxohexan-2-yl]-2-[(4-carbamimidoylphenyl)methyl]-n'-methylpropanediamide Chemical compound NC(N)=NCCC[C@@H](C(N)=O)NC(=O)[C@H](CCCC)NC(=O)C(C(=O)NC)CC1=CC=C(C(N)=N)C=C1 NALXCZRJYTWWMA-FQECFTEESA-N 0.000 claims 1
- RCGGFHVLGOLVPU-QIFDKBNDSA-N n-[(2s)-1-[[(2s)-1-amino-5-(diaminomethylideneamino)-1-oxopentan-2-yl]amino]-3-(4-aminophenyl)-1-oxopropan-2-yl]-2-[(4-carbamimidoylphenyl)methyl]-n',n'-dimethylpropanediamide Chemical compound N([C@@H](CC=1C=CC(N)=CC=1)C(=O)N[C@@H](CCCN=C(N)N)C(N)=O)C(=O)C(C(=O)N(C)C)CC1=CC=C(C(N)=N)C=C1 RCGGFHVLGOLVPU-QIFDKBNDSA-N 0.000 claims 1
- ZYWOWIGUGVTUSM-QIFDKBNDSA-N n-[(2s)-1-[[(2s)-1-amino-5-(diaminomethylideneamino)-1-oxopentan-2-yl]amino]-3-cyclohexyl-1-oxopropan-2-yl]-2-[(4-carbamimidoylphenyl)methyl]-n',n'-dimethylpropanediamide Chemical compound N([C@@H](CC1CCCCC1)C(=O)N[C@@H](CCCN=C(N)N)C(N)=O)C(=O)C(C(=O)N(C)C)CC1=CC=C(C(N)=N)C=C1 ZYWOWIGUGVTUSM-QIFDKBNDSA-N 0.000 claims 1
- DAGPGMDRZQMZMY-WIXBZOCESA-N n-[(2s)-1-[[(2s)-1-amino-5-(diaminomethylideneamino)-1-oxopentan-2-yl]amino]-3-naphthalen-1-yl-1-oxopropan-2-yl]-2-[(4-carbamimidoylphenyl)methyl]-n',n'-dimethylpropanediamide Chemical compound N([C@@H](CC=1C2=CC=CC=C2C=CC=1)C(=O)N[C@@H](CCCN=C(N)N)C(N)=O)C(=O)C(C(=O)N(C)C)CC1=CC=C(C(N)=N)C=C1 DAGPGMDRZQMZMY-WIXBZOCESA-N 0.000 claims 1
- HROPZXWHNXUUCL-WIXBZOCESA-N n-[(2s)-1-[[(2s)-1-amino-5-(diaminomethylideneamino)-1-oxopentan-2-yl]amino]-3-naphthalen-2-yl-1-oxopropan-2-yl]-2-[(4-carbamimidoylphenyl)methyl]-n',n'-dimethylpropanediamide Chemical compound N([C@@H](CC=1C=C2C=CC=CC2=CC=1)C(=O)N[C@@H](CCCN=C(N)N)C(N)=O)C(=O)C(C(=O)N(C)C)CC1=CC=C(C(N)=N)C=C1 HROPZXWHNXUUCL-WIXBZOCESA-N 0.000 claims 1
- 230000008816 organ damage Effects 0.000 claims 1
- 239000000546 pharmaceutical excipient Substances 0.000 claims 1
- 239000000825 pharmaceutical preparation Substances 0.000 claims 1
- 150000003254 radicals Chemical class 0.000 claims 1
- 239000011347 resin Substances 0.000 claims 1
- 229920005989 resin Polymers 0.000 claims 1
- 238000007127 saponification reaction Methods 0.000 claims 1
- 238000011477 surgical intervention Methods 0.000 claims 1
- 230000009424 thromboembolic effect Effects 0.000 claims 1
- 230000002792 vascular Effects 0.000 claims 1
- 210000003462 vein Anatomy 0.000 claims 1
- 0 CCN(*)C(C(C*)C(N(*)C(*)C(*)=O)=O)=O Chemical compound CCN(*)C(C(C*)C(N(*)C(*)C(*)=O)=O)=O 0.000 description 6
- KCFKTDOLJYVDKB-UHFFFAOYSA-N CC(C)[O](C(C)C(N1C2CCC1)=O)=C2N Chemical compound CC(C)[O](C(C)C(N1C2CCC1)=O)=C2N KCFKTDOLJYVDKB-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D213/54—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D213/56—Amides
-
- 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
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
-
- 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
- A61P9/10—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
-
- 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
- A61P9/14—Vasoprotectives; Antihaemorrhoidals; Drugs for varicose therapy; Capillary stabilisers
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C257/00—Compounds containing carboxyl groups, the doubly-bound oxygen atom of a carboxyl group being replaced by a doubly-bound nitrogen atom, this nitrogen atom not being further bound to an oxygen atom, e.g. imino-ethers, amidines
- C07C257/10—Compounds containing carboxyl groups, the doubly-bound oxygen atom of a carboxyl group being replaced by a doubly-bound nitrogen atom, this nitrogen atom not being further bound to an oxygen atom, e.g. imino-ethers, amidines with replacement of the other oxygen atom of the carboxyl group by nitrogen atoms, e.g. amidines
- C07C257/18—Compounds containing carboxyl groups, the doubly-bound oxygen atom of a carboxyl group being replaced by a doubly-bound nitrogen atom, this nitrogen atom not being further bound to an oxygen atom, e.g. imino-ethers, amidines with replacement of the other oxygen atom of the carboxyl group by nitrogen atoms, e.g. amidines having carbon atoms of amidino groups bound to carbon atoms of six-membered aromatic rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C279/00—Derivatives of guanidine, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups
- C07C279/04—Derivatives of guanidine, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of guanidine groups bound to acyclic carbon atoms of a carbon skeleton
- C07C279/14—Derivatives of guanidine, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of guanidine groups bound to acyclic carbon atoms of a carbon skeleton being further substituted by carboxyl groups
-
- 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
- C07K5/06017—Dipeptides with the first amino acid being neutral and aliphatic
- C07K5/06026—Dipeptides with the first amino acid being neutral and aliphatic the side chain containing 0 or 1 carbon atom, i.e. Gly or Ala
-
- 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
- C07K5/06017—Dipeptides with the first amino acid being neutral and aliphatic
- C07K5/06034—Dipeptides with the first amino acid being neutral and aliphatic the side chain containing 2 to 4 carbon atoms
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2601/00—Systems containing only non-condensed rings
- C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
- C07C2601/14—The ring being saturated
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Medicinal Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Molecular Biology (AREA)
- Genetics & Genomics (AREA)
- Biophysics (AREA)
- Biochemistry (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Cardiology (AREA)
- Heart & Thoracic Surgery (AREA)
- Crystallography & Structural Chemistry (AREA)
- Vascular Medicine (AREA)
- Hematology (AREA)
- Communicable Diseases (AREA)
- Oncology (AREA)
- Diabetes (AREA)
- Urology & Nephrology (AREA)
- Pulmonology (AREA)
- Immunology (AREA)
- Epidemiology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Pyrrole Compounds (AREA)
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| EP00104041.9 | 2000-02-26 | ||
| EP00104041A EP1127884A1 (en) | 2000-02-26 | 2000-02-26 | Novel malonic acid derivatives, processes for their preparation, their use as inhibitor of factor XA activity and pharmaceutical compositions containing them |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| RU2002125671A true RU2002125671A (ru) | 2004-01-10 |
Family
ID=8167968
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| RU2002125671/04A RU2002125671A (ru) | 2000-02-26 | 2001-02-21 | НОВЫЕ ПРОИЗВОДНЫЕ МАЛОНОВОЙ КИСЛОТЫ, СПОСОБЫ ИХ ПОЛУЧЕНИЯ, ИХ ПРИМЕНЕНИЕ В КАЧЕСТВЕ ИНГИБИТОРА АКТИВНОСТИ ФАКТОРА Xa И СОДЕРЖАЩИЕ ИХ ФАРМАЦЕВТИЧЕСКИЕ КОМПОЗИЦИИ |
Country Status (23)
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|---|---|
| US (1) | US6794365B2 (enExample) |
| EP (2) | EP1127884A1 (enExample) |
| JP (1) | JP2003524001A (enExample) |
| KR (1) | KR20020079892A (enExample) |
| CN (1) | CN1406226A (enExample) |
| AR (1) | AR027533A1 (enExample) |
| AT (1) | ATE314350T1 (enExample) |
| AU (1) | AU2001235486A1 (enExample) |
| BR (1) | BR0108694A (enExample) |
| CA (1) | CA2400871C (enExample) |
| CZ (1) | CZ20022862A3 (enExample) |
| DE (1) | DE60116272T2 (enExample) |
| ES (1) | ES2254370T3 (enExample) |
| HK (1) | HK1052696A1 (enExample) |
| HU (1) | HUP0300080A3 (enExample) |
| IL (1) | IL151459A0 (enExample) |
| MX (1) | MXPA02007398A (enExample) |
| NO (1) | NO20024040L (enExample) |
| NZ (1) | NZ520982A (enExample) |
| PL (1) | PL357183A1 (enExample) |
| RU (1) | RU2002125671A (enExample) |
| WO (1) | WO2001062735A1 (enExample) |
| ZA (1) | ZA200206581B (enExample) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| RU2368610C2 (ru) * | 2005-03-24 | 2009-09-27 | УОРНЕР-ЛАМБЕРТ КОМПАНИ Эл-Эл-Си | Кристаллические формы известного пирролидинового ингибитора фактора xa |
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|---|---|---|---|---|
| US20030224023A1 (en) * | 2002-05-29 | 2003-12-04 | Unilever Home & Personal Care Usa, Division Of Conopco, Inc. | Cosmetic compositions with hydroxy amine salts of malonic acid |
| US20040202689A1 (en) * | 2003-03-17 | 2004-10-14 | Unilever Home & Personal Care Usa, Division Of Conopco, Inc. | Terpenoid fragrance components stabilized with malonic acid salts |
| US20040185015A1 (en) * | 2003-03-17 | 2004-09-23 | Unilever Home & Personal Care Usa, Division Of Conopco, Inc. | Sunscreen cosmetic compositions storage stabilized with malonate salts |
| US20040185074A1 (en) * | 2003-03-17 | 2004-09-23 | Unilever Home & Personal Care Usa, Division Of Conopco, Inc. | Odor control in amine salt containing cosmetic compositions |
| US20040185073A1 (en) * | 2003-03-17 | 2004-09-23 | Unilever Home & Personal Care Usa, Division Of Conopco, Inc. | Cosmetic compositions containing salts of malonic acid |
| US9249265B1 (en) | 2014-09-08 | 2016-02-02 | Sirrus, Inc. | Emulsion polymers including one or more 1,1-disubstituted alkene compounds, emulsion methods, and polymer compositions |
| EP2630191A4 (en) | 2010-10-20 | 2015-05-20 | Sirrus Inc | SYNTHESIS SUBSTANTIALLY CLEANING METHYLENE MALONATES |
| US9279022B1 (en) | 2014-09-08 | 2016-03-08 | Sirrus, Inc. | Solution polymers including one or more 1,1-disubstituted alkene compounds, solution polymerization methods, and polymer compositions |
| US9828324B2 (en) | 2010-10-20 | 2017-11-28 | Sirrus, Inc. | Methylene beta-diketone monomers, methods for making methylene beta-diketone monomers, polymerizable compositions and products formed therefrom |
| US10414839B2 (en) | 2010-10-20 | 2019-09-17 | Sirrus, Inc. | Polymers including a methylene beta-ketoester and products formed therefrom |
| EP3339301A3 (en) | 2011-10-19 | 2018-08-08 | Sirrus, Inc. | Methods for making methylene beta-diketone monomers |
| CA2869108A1 (en) | 2012-03-30 | 2013-10-03 | Bioformix Inc. | Methods for activating polymerizable compositions, polymerizable systems, and products formed thereby |
| EP3626784A1 (en) | 2012-03-30 | 2020-03-25 | Sirrus, Inc. | Ink and coating formulations and polymerizable systems for producing the same |
| US10913875B2 (en) | 2012-03-30 | 2021-02-09 | Sirrus, Inc. | Composite and laminate articles and polymerizable systems for producing the same |
| US10047192B2 (en) | 2012-06-01 | 2018-08-14 | Sirrus, Inc. | Optical material and articles formed therefrom |
| CN105008438B (zh) | 2012-11-16 | 2019-10-22 | 拜奥福米克斯公司 | 塑料粘结体系及方法 |
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| WO2014110388A1 (en) | 2013-01-11 | 2014-07-17 | Bioformix Inc. | Method to obtain methylene malonate via bis(hydroxymethyl) malonate pathway |
| US9315597B2 (en) | 2014-09-08 | 2016-04-19 | Sirrus, Inc. | Compositions containing 1,1-disubstituted alkene compounds for preparing polymers having enhanced glass transition temperatures |
| US9416091B1 (en) | 2015-02-04 | 2016-08-16 | Sirrus, Inc. | Catalytic transesterification of ester compounds with groups reactive under transesterification conditions |
| US10501400B2 (en) | 2015-02-04 | 2019-12-10 | Sirrus, Inc. | Heterogeneous catalytic transesterification of ester compounds with groups reactive under transesterification conditions |
| US9334430B1 (en) | 2015-05-29 | 2016-05-10 | Sirrus, Inc. | Encapsulated polymerization initiators, polymerization systems and methods using the same |
| US9217098B1 (en) | 2015-06-01 | 2015-12-22 | Sirrus, Inc. | Electroinitiated polymerization of compositions having a 1,1-disubstituted alkene compound |
| US9518001B1 (en) | 2016-05-13 | 2016-12-13 | Sirrus, Inc. | High purity 1,1-dicarbonyl substituted-1-alkenes and methods for their preparation |
| US9617377B1 (en) | 2016-06-03 | 2017-04-11 | Sirrus, Inc. | Polyester macromers containing 1,1-dicarbonyl-substituted 1 alkenes |
| US9567475B1 (en) | 2016-06-03 | 2017-02-14 | Sirrus, Inc. | Coatings containing polyester macromers containing 1,1-dicarbonyl-substituted 1 alkenes |
| US10196481B2 (en) | 2016-06-03 | 2019-02-05 | Sirrus, Inc. | Polymer and other compounds functionalized with terminal 1,1-disubstituted alkene monomer(s) and methods thereof |
| US10428177B2 (en) | 2016-06-03 | 2019-10-01 | Sirrus, Inc. | Water absorbing or water soluble polymers, intermediate compounds, and methods thereof |
| CN106501472A (zh) * | 2016-11-29 | 2017-03-15 | 昆明理工大学 | 一种基于抗凝血生化指数评价三七活血作用的方法 |
| CN111018734B (zh) * | 2019-12-13 | 2020-12-22 | 福建海西新药创制有限公司 | 一种盐酸西那卡塞中间体的合成方法 |
| IL316963A (en) * | 2022-05-20 | 2025-01-01 | Radius Health Inc | Process for preparing avalopretide |
| CN115299636B (zh) * | 2022-08-17 | 2025-02-14 | 中国烟草总公司郑州烟草研究院 | 一种卷烟滤嘴用功能吸附丸芯及其制备方法和烟支 |
Family Cites Families (13)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| AU8866882A (en) * | 1981-09-25 | 1983-03-31 | Wellcome Foundation Limited, The | 2-(n-hydroxycarbamoyl)phenylpropanoyl amino acids |
| WO1992008709A1 (de) * | 1990-11-15 | 1992-05-29 | Pentapharm Ag | Meta-substituierte phenylalanin-derivate |
| JPH07509731A (ja) * | 1993-02-10 | 1995-10-26 | ペンタファルム アクチェンゲゼルシャフト | トロンビン阻害剤としての置換されたフェニルアラニン誘導体のピペラジド |
| NZ284977A (en) * | 1994-04-26 | 1998-09-24 | Selectide Corp | Factor xa enzyme inhibitor |
| WO1996005189A1 (de) * | 1994-08-09 | 1996-02-22 | Pentapharm Ag | Neue inhibitoren vom benzamidintyp |
| UA48993C2 (uk) * | 1995-12-20 | 2002-09-16 | Авентіс Фармасьютікалз, Інк | СПОСІБ ОТРИМАННЯ N-АЦЕТИЛ-(L)-4-ЦІАНОФЕНІЛАЛАНІНУ Аc-(L)-Phe(4-CN)-OH І N-АЦЕТИЛ-(L)-П-АМІДИНФЕНІЛАЛАНІН-ЦИКЛОГЕКСИЛГЛІЦИН-<font face="Symbol">b</font>-(3-N-МЕТИЛПІРИДИН)-АЛАНІНУ Аc-(L)-pАph-Сhg-PalMe(3)-NH<sub>2</sub> |
| ES2218827T3 (es) * | 1997-05-02 | 2004-11-16 | Akzo Nobel N.V. | Inhibidores de la serina proteasa. |
| ATE344246T1 (de) * | 1997-11-26 | 2006-11-15 | Ortho Mcneil Pharm Inc | Heteroaryl aminoguanidin- und alkoxyguanidinderivate und ihre verwendung als proteasehemmer |
| PT1042287E (pt) | 1997-12-24 | 2005-08-31 | Aventis Pharma Gmbh | Derivados de indole como inibidores do factor xa |
| JP3283485B2 (ja) * | 1998-04-10 | 2002-05-20 | 日本たばこ産業株式会社 | アミジン化合物 |
| NZ512669A (en) | 1999-01-02 | 2003-11-28 | Aventis Pharma Gmbh | Arylalkanoyl derivatives, processes for their preparation, their use and pharmaceutical compositions containing them |
| CA2358578A1 (en) * | 1999-01-02 | 2000-07-13 | Aventis Pharma Deutschland Gmbh | Novel malonic acid derivatives, processes for their preparation, their use and pharmaceutical compositions containing them (inhibition of factor xa activity) |
| EP1016663A1 (en) * | 1999-01-02 | 2000-07-05 | Aventis Pharma Deutschland GmbH | Novel malonic acid derivatives, processes for their preparation, their use and pharmaceutical compositions containing them (inhibition of factor Xa activity) |
-
2000
- 2000-02-26 EP EP00104041A patent/EP1127884A1/en not_active Withdrawn
-
2001
- 2001-02-21 ES ES01907546T patent/ES2254370T3/es not_active Expired - Lifetime
- 2001-02-21 DE DE60116272T patent/DE60116272T2/de not_active Expired - Lifetime
- 2001-02-21 HU HU0300080A patent/HUP0300080A3/hu unknown
- 2001-02-21 RU RU2002125671/04A patent/RU2002125671A/ru not_active Application Discontinuation
- 2001-02-21 NZ NZ520982A patent/NZ520982A/en unknown
- 2001-02-21 HK HK03104942.8A patent/HK1052696A1/zh unknown
- 2001-02-21 WO PCT/EP2001/001928 patent/WO2001062735A1/en not_active Ceased
- 2001-02-21 KR KR1020027011004A patent/KR20020079892A/ko not_active Withdrawn
- 2001-02-21 EP EP01907546A patent/EP1265867B1/en not_active Expired - Lifetime
- 2001-02-21 JP JP2001562517A patent/JP2003524001A/ja active Pending
- 2001-02-21 PL PL01357183A patent/PL357183A1/xx not_active Application Discontinuation
- 2001-02-21 CN CN01805589A patent/CN1406226A/zh active Pending
- 2001-02-21 AT AT01907546T patent/ATE314350T1/de not_active IP Right Cessation
- 2001-02-21 CA CA2400871A patent/CA2400871C/en not_active Expired - Fee Related
- 2001-02-21 IL IL15145901A patent/IL151459A0/xx unknown
- 2001-02-21 MX MXPA02007398A patent/MXPA02007398A/es active IP Right Grant
- 2001-02-21 CZ CZ20022862A patent/CZ20022862A3/cs unknown
- 2001-02-21 AU AU2001235486A patent/AU2001235486A1/en not_active Abandoned
- 2001-02-21 BR BR0108694-4A patent/BR0108694A/pt not_active Application Discontinuation
- 2001-02-22 AR ARP010100806A patent/AR027533A1/es not_active Application Discontinuation
- 2001-02-23 US US09/790,641 patent/US6794365B2/en not_active Expired - Lifetime
-
2002
- 2002-08-16 ZA ZA200206581A patent/ZA200206581B/en unknown
- 2002-08-23 NO NO20024040A patent/NO20024040L/no not_active Application Discontinuation
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| RU2368610C2 (ru) * | 2005-03-24 | 2009-09-27 | УОРНЕР-ЛАМБЕРТ КОМПАНИ Эл-Эл-Си | Кристаллические формы известного пирролидинового ингибитора фактора xa |
Also Published As
| Publication number | Publication date |
|---|---|
| NO20024040D0 (no) | 2002-08-23 |
| NO20024040L (no) | 2002-09-24 |
| IL151459A0 (en) | 2003-04-10 |
| AR027533A1 (es) | 2003-04-02 |
| MXPA02007398A (es) | 2002-12-09 |
| CZ20022862A3 (cs) | 2002-11-13 |
| EP1265867B1 (en) | 2005-12-28 |
| AU2001235486A1 (en) | 2001-09-03 |
| KR20020079892A (ko) | 2002-10-19 |
| ES2254370T3 (es) | 2006-06-16 |
| HUP0300080A3 (en) | 2004-07-28 |
| ZA200206581B (en) | 2003-07-28 |
| ATE314350T1 (de) | 2006-01-15 |
| EP1265867A1 (en) | 2002-12-18 |
| PL357183A1 (en) | 2004-07-26 |
| US20020022596A1 (en) | 2002-02-21 |
| US6794365B2 (en) | 2004-09-21 |
| CN1406226A (zh) | 2003-03-26 |
| BR0108694A (pt) | 2002-12-10 |
| HK1052696A1 (zh) | 2003-09-26 |
| CA2400871A1 (en) | 2001-08-30 |
| JP2003524001A (ja) | 2003-08-12 |
| DE60116272D1 (de) | 2006-02-02 |
| DE60116272T2 (de) | 2006-08-17 |
| HUP0300080A2 (hu) | 2003-06-28 |
| WO2001062735A1 (en) | 2001-08-30 |
| NZ520982A (en) | 2004-05-28 |
| CA2400871C (en) | 2011-04-26 |
| EP1127884A1 (en) | 2001-08-29 |
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