CN1168673A - 具有n-末端磺酰基或氨基磺酰基的新颖二肽对-脒基苄基酰胺 - Google Patents
具有n-末端磺酰基或氨基磺酰基的新颖二肽对-脒基苄基酰胺 Download PDFInfo
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- CN1168673A CN1168673A CN95196669A CN95196669A CN1168673A CN 1168673 A CN1168673 A CN 1168673A CN 95196669 A CN95196669 A CN 95196669A CN 95196669 A CN95196669 A CN 95196669A CN 1168673 A CN1168673 A CN 1168673A
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- alkyl
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- 108010016626 Dipeptides Proteins 0.000 title description 4
- CHOGNBXWAZDZBM-UHFFFAOYSA-N 4-(aminomethyl)benzenecarboximidamide Chemical class NCC1=CC=C(C(N)=N)C=C1 CHOGNBXWAZDZBM-UHFFFAOYSA-N 0.000 title 1
- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 title 1
- 150000001875 compounds Chemical class 0.000 claims abstract description 34
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 5
- 201000010099 disease Diseases 0.000 claims abstract description 4
- 239000002253 acid Substances 0.000 claims description 31
- 150000003839 salts Chemical class 0.000 claims description 27
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 23
- 125000003118 aryl group Chemical group 0.000 claims description 22
- 125000001072 heteroaryl group Chemical group 0.000 claims description 9
- 125000006552 (C3-C8) cycloalkyl group Chemical group 0.000 claims description 5
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 5
- 125000000217 alkyl group Chemical group 0.000 claims description 4
- 125000005982 diphenylmethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])(*)C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 claims description 4
- 125000005842 heteroatom Chemical group 0.000 claims description 4
- 229910052760 oxygen Inorganic materials 0.000 claims description 4
- 229910052717 sulfur Inorganic materials 0.000 claims description 4
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical group [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 3
- 239000000654 additive Substances 0.000 claims description 2
- 230000000996 additive effect Effects 0.000 claims description 2
- 238000002360 preparation method Methods 0.000 abstract description 9
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- -1 amidino benzyl acid amides Chemical class 0.000 description 28
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- 150000001408 amides Chemical class 0.000 description 20
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 17
- 238000004992 fast atom bombardment mass spectroscopy Methods 0.000 description 17
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- 238000006243 chemical reaction Methods 0.000 description 13
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- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 8
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 8
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- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 6
- 125000001711 D-phenylalanine group Chemical group [H]N([H])[C@@]([H])(C(=O)[*])C([H])([H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 6
- WTDHULULXKLSOZ-UHFFFAOYSA-N Hydroxylamine hydrochloride Chemical compound Cl.ON WTDHULULXKLSOZ-UHFFFAOYSA-N 0.000 description 6
- COLNVLDHVKWLRT-QMMMGPOBSA-N L-phenylalanine Chemical compound OC(=O)[C@@H](N)CC1=CC=CC=C1 COLNVLDHVKWLRT-QMMMGPOBSA-N 0.000 description 6
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- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 6
- 150000001409 amidines Chemical class 0.000 description 6
- 239000002585 base Substances 0.000 description 6
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 6
- 238000001953 recrystallisation Methods 0.000 description 6
- 238000005160 1H NMR spectroscopy Methods 0.000 description 5
- 239000004471 Glycine Substances 0.000 description 5
- IADUEWIQBXOCDZ-UHFFFAOYSA-N azetidine-2-carboxylic acid Chemical compound OC(=O)C1CCN1 IADUEWIQBXOCDZ-UHFFFAOYSA-N 0.000 description 5
- 229910052799 carbon Inorganic materials 0.000 description 5
- KZNQNBZMBZJQJO-YFKPBYRVSA-N glyclproline Chemical compound NCC(=O)N1CCC[C@H]1C(O)=O KZNQNBZMBZJQJO-YFKPBYRVSA-N 0.000 description 5
- 108010077515 glycylproline Proteins 0.000 description 5
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 5
- 239000000047 product Substances 0.000 description 5
- WHUUTDBJXJRKMK-VKHMYHEASA-N L-glutamic acid Chemical compound OC(=O)[C@@H](N)CCC(O)=O WHUUTDBJXJRKMK-VKHMYHEASA-N 0.000 description 4
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 4
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Chemical compound NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 description 4
- 235000003704 aspartic acid Nutrition 0.000 description 4
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 4
- WGQKYBSKWIADBV-UHFFFAOYSA-N benzylamine Chemical compound NCC1=CC=CC=C1 WGQKYBSKWIADBV-UHFFFAOYSA-N 0.000 description 4
- OQFSQFPPLPISGP-UHFFFAOYSA-N beta-carboxyaspartic acid Natural products OC(=O)C(N)C(C(O)=O)C(O)=O OQFSQFPPLPISGP-UHFFFAOYSA-N 0.000 description 4
- 230000000903 blocking effect Effects 0.000 description 4
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 4
- 239000012043 crude product Substances 0.000 description 4
- 238000001035 drying Methods 0.000 description 4
- 238000001914 filtration Methods 0.000 description 4
- 238000005984 hydrogenation reaction Methods 0.000 description 4
- UFWIBTONFRDIAS-UHFFFAOYSA-N naphthalene-acid Natural products C1=CC=CC2=CC=CC=C21 UFWIBTONFRDIAS-UHFFFAOYSA-N 0.000 description 4
- 125000001624 naphthyl group Chemical group 0.000 description 4
- 239000011541 reaction mixture Substances 0.000 description 4
- 235000017557 sodium bicarbonate Nutrition 0.000 description 4
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 4
- FYCRNRZIEVLZDO-BYPYZUCNSA-N (2s)-morpholin-4-ium-2-carboxylate Chemical compound OC(=O)[C@@H]1CNCCO1 FYCRNRZIEVLZDO-BYPYZUCNSA-N 0.000 description 3
- ODHCTXKNWHHXJC-VKHMYHEASA-N 5-oxo-L-proline Chemical compound OC(=O)[C@@H]1CCC(=O)N1 ODHCTXKNWHHXJC-VKHMYHEASA-N 0.000 description 3
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- DZLNHFMRPBPULJ-VKHMYHEASA-N L-thioproline Chemical compound OC(=O)[C@@H]1CSCN1 DZLNHFMRPBPULJ-VKHMYHEASA-N 0.000 description 3
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 3
- MTCFGRXMJLQNBG-UHFFFAOYSA-N Serine Natural products OCC(N)C(O)=O MTCFGRXMJLQNBG-UHFFFAOYSA-N 0.000 description 3
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 3
- 229960000583 acetic acid Drugs 0.000 description 3
- 239000013543 active substance Substances 0.000 description 3
- 125000004397 aminosulfonyl group Chemical group NS(=O)(=O)* 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 3
- 125000003739 carbamimidoyl group Chemical group C(N)(=N)* 0.000 description 3
- 238000002425 crystallisation Methods 0.000 description 3
- 230000008025 crystallization Effects 0.000 description 3
- 125000004093 cyano group Chemical group *C#N 0.000 description 3
- 238000000354 decomposition reaction Methods 0.000 description 3
- UAOMVDZJSHZZME-UHFFFAOYSA-N diisopropylamine Chemical compound CC(C)NC(C)C UAOMVDZJSHZZME-UHFFFAOYSA-N 0.000 description 3
- 238000000605 extraction Methods 0.000 description 3
- 239000012362 glacial acetic acid Substances 0.000 description 3
- 229910052739 hydrogen Inorganic materials 0.000 description 3
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- 125000005956 isoquinolyl group Chemical group 0.000 description 3
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- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 3
- 125000004076 pyridyl group Chemical group 0.000 description 3
- 239000007787 solid Substances 0.000 description 3
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- MTCFGRXMJLQNBG-REOHCLBHSA-N (2S)-2-Amino-3-hydroxypropansäure Chemical compound OC[C@H](N)C(O)=O MTCFGRXMJLQNBG-REOHCLBHSA-N 0.000 description 2
- DWNBOPVKNPVNQG-LURJTMIESA-N (2s)-4-hydroxy-2-(propylamino)butanoic acid Chemical compound CCCN[C@H](C(O)=O)CCO DWNBOPVKNPVNQG-LURJTMIESA-N 0.000 description 2
- UKAUYVFTDYCKQA-UHFFFAOYSA-N -2-Amino-4-hydroxybutanoic acid Natural products OC(=O)C(N)CCO UKAUYVFTDYCKQA-UHFFFAOYSA-N 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- IADUEWIQBXOCDZ-VKHMYHEASA-N Azetidine-2-carboxylic acid Natural products OC(=O)[C@@H]1CCN1 IADUEWIQBXOCDZ-VKHMYHEASA-N 0.000 description 2
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 description 2
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Abstract
本发明涉及式I化合物，其中R1，A，和B具有说明书中的定义，并且说明了其制备。本发明新的化合物适于治疗疾病。
Description
本发明涉及具有N-末端磺酰基或氨基磺酰基的二肽对-脒基苄基酰胺，涉及其制备方法，并且涉及其作为凝血酶抑制剂的用途。
EP601459公开了具有氨磺酰基团的杂环凝血酶抑制剂。
本发明涉及式I化合物及其立体异构体和生理耐受酸的盐其中取代基具有下面的定义：R1是C1-C20烷基，C1-C3氟代烷基，C3-C8环烷基，芳基-C1-C10烷基；芳基，杂芳基，OH或R3R2N，其中R2和R3相同或不同，是氢原子，C1-C10烷基，芳基，芳基-C1-C10烷基，或一起是芳基或杂芳基可以与之稠和的、或可以含有一个杂原子(O，S，NH或取代的N)的C2-C7亚烷基链，A是式IIα-氨基酸残基
其中R4是氢原子，C1-C8烷基，C3-C7环烷基，芳基，或芳基-C1-C3烷基，R5是氢原子，C1-C8烷基，C3-C7环烷基，C3-C7环烷基-C1-3-烷基，芳基，芳基-C1-C3烷基，二(C3-C7环烷基)-甲基或二苯基甲基或，如果R4＝H，则是C1-C8烷基，其中一个氢原子被OR6或CO-OR6(其中R6＝氢原子，C1-C8烷基或芳基-C1-C3烷基)替代，或R4和R5一起是可以含有一个稠合烷基的C2-C6亚烷基链，B是式III环状α-氨基酸残基
其中m是2，3或4，且环上的一个氢原子可以被羟基或C1-C3烷基替代，而且，如果m＝3或4，则环中的一个CH2基团可以被氧原子，硫原子，NH-，或N-C1-C4烷基替代，和/或两个相邻的氢原子可以被双键替代。
下面四组化合物是优选的：1.式I化合物，其中取代基具有下面的定义：
R1是OH或R3R2N，其中R2和R3相同或不同，是氢原子，C1-C10烷基，芳基，芳基-C1-C10烷基，或一起是芳基或杂芳基可以与之稠合的或可以含有一个杂原子(O，S，NH或取代的N)的C2-C7亚烷基链，A是式IIα-氨基酸残基
其中R4是C1-C8烷基，C3-C7环烷基，芳基，芳基-C1-C3烷基，R5是氢原子，C1-C8烷基，C3-C7环烷基，C3-C7环烷基-C1-3-烷基，芳基，芳基-C1-C3烷基，二(C3-C7环烷基)-甲基或二苯基甲基或，如果R4＝H，则是C1-C8烷基，其中一个氢原子被OR6或CO-OR6(其中R6＝氢原子，C1-C8烷基或芳基-C1-C3烷基)替代，或R4和R5一起是可以含有一个稠合芳基的C2-C6亚烷基链，B是式III环状α-氨基酸残基其中m是2，3或4，且环上的一个氢原子可以被羟基或C1-C3烷基替代，而且-如果m＝3或4-则环中的一个CH2基团可以被氧原子，硫原子，NH-，或N-C1-C4烷基替代，和/或两个相邻的氢原子可以被双键替代。
2.式I化合物，其中取代基具有下面的定义：R1是C1-C20烷基，C1-C3氟代烷基，C3-C8环烷基，芳基-C1-C10烷基，芳基，杂芳基，A是式IIα-氨基酸残基其中R4是C1-C8烷基，C3-C7环烷基，芳基，芳基-C1-C3烷基，R5是C1-C8烷基，C3-C7环烷基，C3-C7环烷基-C1-3-烷基，芳基，芳基-C1-C3烷基，二(C3-C7环烷基)-甲基或二苯基甲基或R4和R5一起是可以含有一个稠合芳基的C2-C6亚烷基链，B是一个下面的基团
3.式I化合物，其中取代基具有下面的定义：R1是C1-C20烷基，C1-C3氟代烷基，C3-C8环烷基，芳基-C1-C10烷基，芳基，杂芳基，或OH，A是下式α-氨基酸残基
其中R5是C1-C8烷基，其中一个氢原子被OR6或CO-OR6(其中R6＝氢原子，C1-C8烷基或芳基-C1-C3烷基)替代，B是一个下面的基团
4.式I化合物，其中取代基具有下面的定义：R1是C1-C20烷基，C1-C3氟代烷基，C3-C8环烷基，芳基-C1-C10烷基，芳基，杂芳基，或OH，A是下式α-氨基酸残基
其中R5是C1-C8烷基，其中一个氢原子被OR6或CO-OR6(其中R6＝氢原子，或C1-C8烷基)替代，B是式III环状α-氨基酸残基其中m是2，3或4，且环上的一个氢原子可以被羟基或C1-C3烷基替代。
术语“芳基”指环系中含有6-10碳原子的单-或双环芳香基团，例如苯基或萘基，并且可以含有至多三个相同或不同的取代基。
术语“杂芳基”指含有1或2个杂原子如N，O或S、并且有一个芳环可以与之稠合的5-或6-元芳环。
1-4组化合物I中，特别好的化合物具有下面的取代基R1，A和B：第1组化合物R1为NH2，C1-4单-或-二烷基氨基或哌啶基A为下面氨基酸的残基：缬氨酸，亮氨酸，异亮氨酸，苯基甘氨酸，环己基甘氨酸，苯丙氨酸，环己基丙氨酸，二苯基丙氨酸，二环己基丙氨酸，其中的苯环可以被至多三个相同或不同的C1-C4烷基，C1-C4烷氧基，OH，F，Cl或COOR6基团取代，B为下列氨基酸的残基：氮杂环丁烷-2-羧酸，脯氨酸，2-哌啶酸，二氢脯氨酸，4-羟基脯氨酸，氧代脯氨酸，硫代脯氨酸，4-C1-4-烷基-2-哌啶酸，吗啉-2-羧酸，哌嗪-2-羧酸，4-C1-4烷基哌嗪-2-羧酸残基第二组化合物R1为C1-4烷基，CF3CH2-，苯基，萘基，苯基-C1-4-亚烷基(特别是苄基和苯乙基)，萘基-C1-4-亚烷基，吡啶基，异喹啉基A为下面氨基酸的残基：α-甲基苯丙氨酸，α-甲基环己基丙氨酸，α-甲基苯基甘氨酸，α-甲基环己基甘氨酸残基，B为下面氨基酸的残基：二氢脯氨酸，氧代脯氨酸，硫代脯氨酸，2-哌啶酸，4-C1-4-烷基-2-哌啶酸，吗啉-2-羧酸，哌嗪-2-羧酸，4-C1-4烷基-哌嗪-2-羧酸，第三组化合物R1为C1-4烷基，CF3CH2-，苯基，萘基，苯基-C1-4-亚烷基(特别是苄基和苯乙基)，萘基-C1-4-亚烷基，吡啶基，异喹啉基，A为下面氨基酸的残基：天冬氨酸，谷氨酸，丝氨酸，高丝氨酸，苏氨酸，其中未键联羧酸或羟基可以分别被C1-8烷基酯化或醚化(特别是丝氨酸叔丁酯和苏氨酸叔丁酯)，B为下面氨基酸的残基：二氢脯氨酸，氧代脯氨酸，硫代脯氨酸，吗啉-2-羧酸，第四组化合物R1为C1-4烷基，CF3CH2-，苯基，萘基，苯基-C1-4-亚烷基(特别是苄基和苯乙基)，萘基-C1-4-亚烷基，吡啶基，异喹啉基，A为下面氨基酸的残基：丝氨酸，高丝氨酸，苏氨酸，其中OH可以被C1-8烷基醚化，或者天冬氨酸，谷氨酸，其中未键联羧基可以被C1-8烷基酯化，B为4-羟基脯氨酸，4-C1-4-烷基-2-哌啶酸的残基，基团R1，A，B如结构式I所示键联在一起，优选地，氨基酸残基A具有(D)构型，并且优选地氨基酸残基B具有(L)构型。优选地提到下面的物质
CF3-CH2-SO2-(D)Phe-Pro-NH-pAmb
C4H9-SO2-(D)Phe-Pro-NH-pAmb
C8H17-SO2-(D)Phe-Pro-NH-pAmb
C16H33-SO2-(D)Phe-Pro-NH-pAmb
异丙基 -SO2-(D)Phe-Pro-NH-pAmb
苯基 -SO2-(D)Phe-Pro-NH-pAmb
2-萘基 -SO2-(D)Phe-Pro-NH-pAmb
3-吡啶基 -SO2-(D)Phe-Pro-NH-pAmb
2-噻吩基 -SO2-(D)Phe-Pro-NH-pAmb
N-哌啶基 -SO2-(D)Phe-Pro-NH-pAmb
H2N-SO2-(D)Phe-Pro-NH-pAmb
Me2N-SO2-(D)Phe-Pro-NH-pAmb
EtHN-SO2-(D)Phe-Pro-NH-pAmb
Me-SO2-(D)Phe(4-OMe)-Pro-NH-pAmb
Me-SO2-(D)Phe(3-OMe)-Pro-NH-pAmb
Me-SO2-(D)Phe(2-Cl)-Pro-NH-pAmb
Me-SO2-(D)Dpa-Pro-NH-pAmb
Me-SO2-(L)Dpa-Pro-NH-pAmb
Me-SO2-(D)Dpa(4，4′-OMe)-Pro-NH-pAmb
Me-SO2-(L)Dpa(4，4′-OMe)-Pro-NH-pAmb
Me-SO2-(D)Dpa(4，4′-Cl)-Pro-NH-pAmb
Me-SO2-(L)Dpa(4，4′-Cl)-Pro-NH-pAmb
Me-SO2-(D，L)Phg(3，4-Cl)-Pro-NH-pAmb
Me-SO2-(D)Asp(OH)-Pro-NH-pAmb
Me-SO2-(L)Asp(OH)-Pro-NH-pAmb
Me-SO2-(D)Asp(OMe)-Pro-NH-pAmb
Me-SO2-(L)Asp(OMe)-Pro-NH-pAmb
Me-SO2-(D)Asp(OtBu)-Pro-NH-pAmb
Me-SO2-(L)Asp(OtBu)-Pro-NH-pAmb
Me-SO2-(D)Phe-Aze-NH-pAmb
Me-SO2-(D)Phe-Pip-NH-pAmb
l-萘基 -SO2-Gly-Pro-NH-pAmb上表中的缩写具有下面的意义：Phe＝苯丙氨酸，pAmb＝对脒基苯甲基，Pro＝脯氨酸，Cpa＝二苯基丙氨酸，Phg＝苯基甘氨酸，Asp＝天冬氨酸，Aze＝氮杂环丁烷-2-羧酸，Pip＝2-哌啶酸式I化合物可以以结构式所示的形式存在或者以其生理耐受酸的加成盐的形式存在。这些酸的例子是：盐酸，柠檬酸，酒石酸，乳酸，磷酸，甲磺酸，乙酸，甲酸，马来酸，富马酸，马来酸，琥珀酸，羟基琥珀酸，硫酸，戊二酸，天冬氨酸，丙酮酸，苯甲酸，葡糖醛酸，草酸，抗坏血酸和乙酰甘氨酸。本发明进一步涉及式IV中间体
其中R1，A和B具有上述定义，它可被用来制备化合物I。化合物I可以根据反应模式I或II由α-氨基酸H-A-OH或由N-保护的环状氨基酸B-OH起始而制备。反应式I反应式II
在上面的反应模式中，R7是H或C1-C4烷基，R8是C1-C4烷基，优选甲基或叔丁基，R9是CN或
且P是保护基团，优选叔丁氧羰基(Boc)，或苄氧羰基(Cbz)。或者，被保护的氨基酸P-A-OH和H-B-OR8可以偶联，从而得到二肽P-A-B-OR8，接着在消去P后与R1SO2Cl反应或者在消去R8后与对-氰基-或对-脒基苯甲胺反应，任何反应顺序都可以。R1-SO2-A-OH也可以直接与对-H-B-NHCH2C6H4R9偶连，得到终产物I或中间体IV。所需的偶连反应在标准的肽化学条件下进行(参见M.Bodansky，A.Bodansky“肽合成的实践”，Springer出版社，1084)。Boc保护基团用HCl/二噁烷或CF3COOH/二氯甲烷消去，而Cbz保护基团通过氢解或用HF消去。酯功能基在醇溶剂如甲醇或乙醇中用NaOH或LiOH水解。叔丁酯用酸例如CF3COOH水解。在有机碱如三乙胺，吡啶或N，N-二异丙基乙胺存在下与磺酰氯R1-SO2Cl的反应在有机溶剂如CH2Cl2，THF或DMF中发生。在游离羧酸功能基的情况下，反应在碱金属氢氧化物或碳酸盐水溶液存在下进行。脒由腈前体通过常规的Pinner合成(R.Roger和.G.Neilson，化学综述61，1961，179)而制备，或者优选地通过改良的Pinner合成法、通过硫代酯亚胺盐为中间体进行(H.Vieweg等，药物学39，1994，226)而制备。通过在阮内镍或Pd/C在醇溶剂等的存在下，将羟胺加成到氰基上而获得的N-羟基脒的催化氢化产生脒(B.J.Broughton等，“药物化学”18，1975，1117).本发明新的化合物可以用来治疗和预防所有的与凝血酶相关的疾病，特别是血栓栓塞疾病如心肌梗塞，外周动脉闭合疾病，深部静脉血栓形成，肺栓塞和休克。另外，其可以用来防止通过机械方法或溶解而使动脉血管开通后的再闭合。它们特别的优点是它们在口服给药后也是有效的。根据本发明的化合物可以口服或经常规途径肠胃外给药(皮下，静脉内，肌内，腹膜内，直肠)。也可以通过鼻咽腔用蒸气或喷雾给药。剂量取决于患者的年龄，症状和体重以及给药方式。总的原则是每人日剂量活性物质是口服大约10-2000mg，肠胃外给药大约1-200mg。该剂量可以以2-4单剂给药或一天一次以缓释剂型形式给药。本发明新的化合物可以以常规固体或液体药物形式使用，例如作为未包衣的或(膜)包衣的片剂，胶囊剂，粉剂，颗粒剂，栓剂，溶液，软膏，乳悬液，或喷雾剂。这些制剂可以常规生产。在这些制剂中，活性物质可以与常规药物助剂一起加工，如片剂粘合剂，填料，防腐剂，片剂崩解剂，流动调节剂，增韧剂，湿润剂，分散剂，乳化剂，溶剂，缓释剂，抗氧化剂和/或喷射气体(参见H.Sucker等：制药技术，席默出版社，斯图加特，1978)。以这些常规的方法获得的药物制剂含有0.1-99％重量的活性物质。
实施例1N-异丙基磺酰-D-苯丙氨酰脯氨酸(对-脒基苯甲基)酰胺乙酸盐a)Boc-D-苯丙氨酰脯氨酸(对-脒基苯甲基)酰胺在-15℃在2分钟内将2.0g(14.6mmol)氯甲酸异丁酯加入到5.1g(14.2mmol)Boc-D-Phe-Pro-OH和1.53g(15.2mmol)N-甲基吗啉于15ml DMF中的溶液中，混合物搅拌10分钟后，加入1.9g(14.2mmol)对-氰基苄胺(W.Walter等，年鉴(Ann.)660，1962，60)和1.53g N-甲基吗啉于3mlDMF中的溶液。-15℃搅拌3小时后，TLC检测(CH2Cl2/MeOH，9/1)显示没有可测得的起始化合物。为了分离，将反应混合物倒入200ml水中，分离出油状物，短时间后固化，破碎并抽滤。将还潮湿的残余物溶解于250ml乙酸乙酯和50ml乙醚的混合物中，连续用5％浓度的柠檬酸水溶液，碳酸氢钠和饱和的氯化钠溶液洗涤。硫酸钠干燥后，减压蒸馏去除溶剂，残余物与正己烷混合后抽滤。从50ml乙酸乙酯中重结晶，得到5.6g TLC-纯的产物。熔点156-157℃。b)D-苯丙氨酰脯氨酸(对-氰基苯甲基)酰胺盐酸盐将上面的化合物溶解于100ml 5N盐酸于二噁烷中的溶液中，并在室温下搅拌3小时，其间沉淀出盐酸盐。抽滤，用乙醚洗涤直到无游离的HCl，减压下用KOH干燥。得到4.6g(95％理论值)白色结晶，熔点220-222℃。c)N-异丙基磺酰基-D-苯丙氨酰脯氨酸(对-氰基苯甲基)酰胺将2.05g(6.05mmol)上述盐酸盐悬浮于50ml CH2Cl2。加入1.35g(13.5mmol)三乙胺，得到一溶液，在0-5℃向该溶液中滴加0.9g(6.1mmol)丙烷-2-磺酰氯溶解于10ml CH2Cl2中的溶液。反应混合物在室温下搅拌5小时后用水，5％浓度的柠檬酸和5％浓度的NaHCO3溶液摇荡萃取。用硫酸钠干燥后蒸馏去除溶剂，粘稠油状残余物从乙酸乙酯/乙醚(1∶1)混合物中重结晶。d)N-异丙基磺酰基-D-苯丙氨酰脯氨酸(对-硫代脒基苄基)酰胺在0℃，将4.1g上面的化合物和4ml三乙胺溶解于用H2S饱和的40ml吡啶中；并在室温下静置过夜。TLC检测(CH2Cl2/MeOH，9/1)表明，转化为硫代酰胺的反应已经完全。为了分离，减压蒸馏去除大部分吡啶，残余物溶解于250ml乙酸乙酯，并用氯化钠、5％浓度的柠檬酸和NaHCO3溶液洗涤。干燥并蒸馏去除溶剂，得到4.1g纯的结晶硫代酰胺。e)N-异丙基磺酰基-D-苯丙氨酰脯氨酸(对-脒基苄基)酰胺乙酸盐所述硫代酰胺溶解于150ml丙酮中，加入7ml碘甲烷后在室温下静置过夜。去除溶剂后，无定形残余物与无水乙醚一起搅拌后干燥。将S-甲基硫代亚氨酸甲酯氢碘酸盐溶解于50ml乙醇中，加入15ml 10％乙酸铵溶液，混合物在60℃加热3小时。为了分离，去除溶剂，残余物溶解于100ml CH2Cl2，过滤去除不溶成分后，蒸馏去除CH2Cl2。用乙酸乙酯/乙醚混合物溶解，去除溶解于其中的杂质。保留的碘盐/乙酸盐混合盐溶解于丙酮/水(3/2)中，并用IRA乙酸根离子交换树脂转化为纯的乙酸盐，其在乙腈中加热后呈白色结晶粉末形式，熔点148-152℃(分解)。FAB-MS(M+H)+＝500。实施例2N-(噻吩基-2-磺酰基)-D-苯丙氨酰脯氨酸(对-脒基苄基)酰胺乙酸盐a)Boc-D-苯丙氨酰脯氨酸(对-脒基苄基)酰胺通过1c的方法，用H2S将Boc-D-苯丙氨酰脯氨酸(对-氰基苄基)酰胺(参见制备实施例1a)转化为硫代酰胺后，按照1d的方法转化为脒。脒以白色结晶的形式获得，熔点237-239℃。FAB-MS(M-H)+＝347。b)D-苯丙氨酰脯氨酸(对-脒基苄基)酰胺二盐酸盐按照实施例1b的方法，用5N HCl的二噁烷溶液从上述化合物中消去Boc保护基团。分离的二盐酸盐是高吸湿性粉末，熔点130-140℃。FAB-MS(M-H)+＝247。c)N-(噻吩基-2-磺酰基)-D-苯丙氨酰脯氨酸(对-脒基苄基)酰胺乙酸盐加入1.9g(12.6mmol)1-羟基苯并三唑和3.3g(25mmol)二环己基碳化二亚胺后将3.9g(12.6mmol)N-苯基磺酰基-D-苯丙氨酸(埃及化学期刊，23，1981，273)于40ml THF中的溶液在室温下搅拌4小时。抽滤沉淀的脲并用少量的THF洗涤。在5℃向滤液中加入4.1g(12.6mmol)N-(对-脒基苄基)脯氨酸酰胺二盐酸盐和1.6g碳酸氢钠于6ml水中的溶液。室温下搅拌48小时后，蒸馏去除大部分溶剂，残留物溶解于乙醇，过滤去除不溶物并再次浓缩。残余物在硅胶柱上纯化，CH2Cl2/MeOH/50％浓度的乙酸混合物(45/5/1.5)洗脱。蒸馏纯级分洗脱液，向终了产物中加入甲苯，残余物从50ml加入了少量水的丙酮中重结晶。分离得到白色结晶形式的3.3g(48％理论值)的脒乙酸盐。熔点95-98℃。FAB-MS(M-H)+＝540.5。实施例3N-(2-萘基磺酰基)-D-苯丙氨酰脯氨酸(对-脒基苄基)酰胺乙酸盐a)Boc-脯氨酸(对-氰基苄基)酰胺在0℃将276g Boc-Pro-OSu(0.88mol)加入到2升二氯甲烷中。向该溶液中连续加入163.9g 4-氰基苄胺盐酸盐(0.97mol)和230ml二异丙基乙胺(1.34mol)。悬浮液在溶化的冰浴中搅拌48小时后过滤。滤液用20％浓度的碳酸氢钠溶液(4X)，饱和的碳酸氢钠溶液(3X)，和饱和的氯化钠溶液(2X)洗涤，干燥并在旋转蒸发器中蒸发。残余物从甲基叔丁基醚中重结晶，得到261g(90％)白色结晶，熔点124-125℃。b)N-(4-氰基苄基)脯氨酸酰胺盐酸盐将260g(0.79mol)上面Boc保护的化合物溶解于1升乙醚中，加入过量的醚制盐酸溶液后，搅拌过夜，过滤沉淀出的盐酸盐。用乙醚洗涤直到无游离的HCl，然后用乙醇重结晶。得到200g(95％)白色结晶，熔点209-211℃。c)N-(2-萘基磺酰基)-D-苯丙氨酰脯氨酸(对-氰基苄基)酰胺将5.9g(21.3mmol)上述脯氨酸酰胺盐酸盐溶解于100ml DMF。连续加入7.8g(21.3mmol)N-(2-萘基磺酰基)-D-苯丙氨酸(A.Bernat等，法国专利2593812)，2.15g(21.3mmol)三乙胺和3.25g(21.3mmol)1-羟基苯并三唑(HOBT)。在0-5℃搅拌的同时，向该溶液中加入4.4g(21.3mmol)二环己基碳化二亚胺溶解于30ml乙酸乙酯中的溶液。反应混合物在室温下搅拌48小时。抽滤沉淀的脲后，减压蒸馏去除大部分溶剂，残余物溶解于200ml乙酸乙酯中，连续用5％浓度的碳酸氢钠，4％浓度的柠檬酸溶液和水洗涤。干燥后，蒸馏去除乙酸乙酯，油状残余物溶解于30mlCH2Cl2并加入50ml乙醚结晶，分离得到9.1g(76％)所需的化合物。d)N-(2-萘基磺酰基)-D-苯丙氨酰脯氨酸(对-脒基苄基)酰胺乙酸盐排除水分，用HCl气体在0℃饱和80ml甲醇，将5.6g(10mmol)上述化合物溶解其中，溶液在0℃静置48小时。然后在20℃去除溶剂，将残余物溶解于20ml甲醇并在0-5℃加入到80ml NH3饱和的甲醇溶液中。溶液回流3小时后冷却并过滤，蒸馏去除溶剂，用乙酸根离子交换树脂将残余物转化为脒的乙酸盐。用加了少量水的丙酮重结晶，得到白色结晶的标题化合物5.1g(80％)，熔点221-225℃，FAB-MS(M+H+)＝584.5。实施例4N-(吡啶基-3-磺酰基)-D-苯丙氨酰脯氨酸(对-脒基苄基)酰胺乙酸盐a)N-(吡啶基-3-磺酰基)-D-苯丙氨酰脯氨酸(对-氰基苄基)酰胺根据实施例1c的方法，使D-苯丙氨酰脯氨酸(对-氰基苄基)酰胺盐酸盐(类似于1a和b制备)与吡啶-3-磺酰氯反应。RF＝0.57(CH2Cl2/MeOH，9/1)。b)N-(吡啶基-3-磺酰基)-D-苯丙氨酰脯氨酸(对-羟基脒基苄基)酰胺乙酸盐2g上述化合物，0.74g羟胺盐酸盐和2.2g三乙胺溶解于30ml乙醇中，并在60-70℃、氮气下搅拌2小时。TLC检测显示检测不到起始物。向反应混合物中加入水，用冰醋酸调节pH为3-4。水相用CH2Cl2萃取几次，将合并的CH2Cl2萃取液干燥并蒸馏去除二氯甲烷。仍含有乙酸的残余物直接用于下面的反应。RF＝0.1(CH2Cl2/MeOH，9/1)。c)N-(吡啶基-3-磺酰基)-D-苯丙氨酰脯氨酸(对-脒基苄基)酰胺乙酸盐在50℃、在0.4g 10％Pd/C存在下，将2.4g(5mmol)上述化合物于40ml甲醇中的溶液氢化7小时。然后抽滤掉催化剂，蒸馏去除溶剂，残余物与乙酸乙酯混合并加热。加入丙酮和少量水并冷却，得到澄清的溶液，结晶出酰胺乙酸盐。分离出1.3g(49.5％)白色粉末。熔点201-202℃，RF＝0.28(CH2Cl2/MeOH/50％浓度的乙酸，8/2/0.5)。实施例5N-(2-萘基磺酰基)甘氨酰脯氨酸(对-脒基苄基)酰胺乙酸盐a)Boc-甘氨酰脯氨酸(对-氰基苄基)酰胺在0℃，连续向7.0g(40mmol)Boc-甘氨酸于240ml二氯甲烷中的溶液中加入30ml二异丙基乙胺，10.6g(40mmol)N-(对-氰基苄基)脯氨酰酰胺盐酸盐和32ml(44mmol)丙烷膦酸苷(50％浓度的乙酸乙酯溶液)。在0℃搅拌2小时后，有机相用1N氢氧化钠，水和饱和的氯化钠溶液洗涤，干燥并蒸馏去除溶剂。分离得14.8g(96％)白色粉末，RF＝0.57(CH2Cl2/MeOH，9/1)。
1H-NMR(DMSO-d6)，δin ppm：1.4(s，9H，(CH3)3)，1.7-2.2
(m，4H，CH2-CH2)，3.3-3.6(m，2H，
脯氨酸的N-CH2)，3.8(m，2H，
甘氨酸的N-CH2，4.3-45(m，3H，
CH和N-CH2-Ar)，6.8(m，1H，
BOC-)7.4-7.5(m(因为存在第二
旋转异物体而明显三重线)，
2H，Ar-H)，7.8(d，2H，Ar-H)8.5
和18.8(每个m，与1H一起(两个
旋转异构体)，NH)b)H-甘氨酰脯氨酸(对-氰基苄基)酰胺盐酸盐根据1b，从上面的化合物中消除Boc基团，分离得到8g(64％)白色粉末。
1H-NMR(DMSO-d6)，δin ppm：1.7-2.2(m，4H，CH2-CH2)，3.4-4.0
(m，4H，脯氨酸和甘氨酸的N-CH2-
)，4.2-4.5(m，3H，CH
和N-CH2-Ar)，7.5(d，2H，Ar)，
7.8(d，2H，Ar)，8.3(s，br，3H，
NH3 +)，8.9和9.2(每个m，
与1H一起(两个旋转异构体)，NH)c)N-(2-萘磺酰基)甘氨酰脯氨酸(对-氰基苄基)酰胺根据1c，上面的化合物与2-萘磺酰氯反应，得到3.3g白色粉末
RF＝0.59(CH2Cl2/MeOH，9/1).
1H-NMR(DMSO-d6)，δin ppm：1.6-2.0(m，4H，CH2-CH2)，3.3-3.5
(m，2H，N-CH2(脯氨酸))，3.7
(m，2H，N-CH2(甘氨酸))，4.1-4.4
(m，3H，CH和N-CH2-Ar)，7.4-8.5
(13H，芳香H和2NH)d)N-(2-萘磺酰基)甘氨酰脯氨酸(对-硫代酰胺基苄基)酰胺根据1d，将上面的化合物转化为硫代酰胺。产量：3.0g(85％)，亮黄色粉末。
1H-NMR(DMSO-d6)，δin ppm：1.5-2.0(m，4H，CH2-CH2)，3.3-3.5
(m，2H，N-CH2(脯氨酸))，3.7
(m，2H，N-CH2(甘氨酸))，4.1-4.4
(m，3H，CH and N-CH2-Ar)，9.5
(s，1H，硫代酰胺)，9.8(s，1H，
硫代酰胺)e)N-(2-萘磺酰基)甘氨酰脯氨酸(对-脒基苄基)酰胺乙酸盐根据1e进行制备，分离得2.5g(68％)氢碘酸盐，RF＝0.09(CH2Cl2/MeOH，9/1)。然后用乙酸根离子交换树脂(Amberlite)转化为乙酸盐，HPLC纯度99％。FAB-MS(M-H)+＝493.5
1H-NMR(DMSO-d6)，δin ppm：1.6-2.0(m，4H，CH2-CH2)，～3.5
((m，2H，N-CH2(脯氨酸)-部分被
H2O信号覆盖)，3.7
(m，2H，N-CH2(甘氨酸)，4.1-4.4
(m，3H，CH和N-CH2-Ar)，7.3-8.5
(13H，芳香H和NH)，
～8.4-9.2(4H，脒)实施例6N-(1-萘磺酰基)甘氨酰脯氨酸(对-脒基苄基)酰胺根据实施例5，用1-萘基磺酰氯得到标题化合物。FAB-MS(M-H)+＝493。实施例7N-(正十六烷基磺酰基)-D-苯丙氨酰脯氨酸(对-脒基苄基)酰胺乙酸盐根据实施例1进行制备，得到白色粉末，熔点194-201℃，FAB-MS(M-H)+＝695。实施例8N-(正丁基磺酰基)-D-苯丙氨酰脯氨酸(对-脒基苄基)酰胺乙酸盐根据实施例1进行制备，得到白色粉末，熔点203-211℃，FAB-MS(M-H)+＝526.5。实施例9N-(异丙基氨基磺酰基)-D-苯丙氨酰脯氨酸(对-脒基苄基)酰胺乙酸盐a)N-(异丙基氨基磺酰基)-D-苯丙氨酰脯氨酸(对-氰基苄基)酰胺根据实施例1c，D-苯丙氨酰脯氨酸(对-氰基苄基)酰胺盐酸盐与异丙基氨基磺酰氯反应。b)N-(异丙基氨基磺酰基)-D-苯丙氨酰脯氨酸(对-羟基脒基苄基)酰胺根据实施例4b，使9a与羟胺盐酸盐反应，制备该化合物。c)N-(异丙基氨基磺酰基)-D-苯丙氨酰脯氨酸(对-脒基苄基)酰胺乙酸盐在40℃、在Pd/C催化下，在甲醇/冰醋酸/THF溶剂混合物中氢化9b(13小时)。然后抽滤去除催化剂，减压浓缩溶液，与乙醇共馏几次，残余物溶解于水，水相用乙酸乙酯萃取3次，然后冻干含有所需产物的水相(白色固体，熔点199-205℃，FAB-MS：M+H：515)。实施例10N-(二甲基氨基磺酰基)-D-苯丙氨酰脯氨酸(对-脒基苄基)酰胺乙酸盐根据实施例9进行制备(白色固体，熔点高于90℃分解，FAB-MS：M+H：501)。实施例11N-羟基磺酰基-D-苯丙氨酰脯氨酸(对-脒基苄基)酰胺在20℃、冷却下，将0.58g(0.33ml，5mmol)氯磺酸于10ml DCM中的溶液缓慢滴加到1.8g(4.36mmol)D-苯丙氨酰脯氨酸(对-氰基苄基)酰胺盐酸盐和1.68g(13.0mmol)二异丙基乙胺于20ml DCM中的溶液中。室温下搅拌30分钟后，混合物用DCM稀释到100ml，开始用2M HCl萃取，然后用10ml水萃取两次，有机相用硫酸镁干燥并在旋转蒸发器中蒸发溶剂。得到2.0g N-羟基磺酰基-D-苯丙氨酰脯氨酸(对-氰基苄基)酰胺粗产物，其不用进一步纯化即可用于下面的反应。2.0g所述的粗产物与0.9g(13mmol)羟胺盐酸盐和2.5ml二异丙胺于50ml乙醇中的溶液在室温下搅拌过夜后浓缩，在50℃高真空下去除挥发组分1小时。产物极易溶于水，因此使得不可能萃取。粗产物(1.8g)直接用于下面的氢化反应。上面粗产物在50℃、在稍高于大气压的氢气中，在40ml甲醇和5ml冰醋酸混合物中氢化，一刮勺尖10％Pd/C催化。5.5小时后过滤掉催化剂，在旋转蒸发器中浓缩溶液，与甲醇和甲苯共馏几次。所得产物与DCM搅拌几次，得到1.5g(三阶段理论值为73％)纯的N-羟基磺酰基-D-苯丙氨酰脯氨酸(对-脒基苄基)酰胺，根据NMR，其是甜菜碱形式。熔点220-224℃，白色粉末，FAB-MS：474(M-N)+。根据实施例4制备下面的化合物：实施例12N-三氟甲基磺酰基-D-苯丙氨酰脯氨酸(对-脒基苄基)酰胺乙酸盐白色结晶，熔点240-242℃(分解)，FAB-MS：526(M-H)+。实施例13N-(β，β，β-三氟乙基磺酰基)-D-苯丙氨酰脯氨酸(对-脒基苄基)酰胺乙酸盐白色结晶，熔点87-89℃(无定形)，FAB-MS：540(M-H)+。实施例14N-(正-辛基磺酰基)-D-苯丙氨酰脯氨酸(对-脒基苄基)酰胺乙酸盐白色无定形结晶，FAB-MS：570(M-H)+。实施例15N-甲基磺酰基-(D，L)-二苯丙氨酰脯氨酸(对-脒基苄基)酰胺乙酸盐白色无定形结晶，FAB-MS：548(M-H)+。实施例16N-甲基磺酰基-二(4-氯苯基)丙氨酰脯氨酸(对-脒基苄基)酰胺乙酸盐白色无定形结晶，FAB-MS：617(M-H)+。实施例a用常规方法在压片机中制备下面组合物的片剂：100mg实施例2的物质240mg玉米淀粉27mg明胶90mg乳糖4.5mg Aerosil(亚微观细分散的化学纯二氧化硅)0.5mg硬脂酸镁4.5mg滑石实施例b用常规方法制备下面组合物的包衣片剂：200mg实施例3的物质300mg芯组合物350mg糖包衣组合物所述芯组合物由9份玉米淀粉，3份乳糖，和1份Luviskol(60：40乙烯吡咯烷酮/乙酸乙烯酯共聚物，参考“制药工业”(1962)586)组成。所述糖包衣组合物由5份蔗糖，2份玉米淀粉，2份碳酸钙和1份滑石组成。用该方法制备的片剂接着用肠包衣。实施例c100g实施例1的物质溶解于5000ml加有氯化钠的水中，用0.1N NaOH调节pH为6.0，得到与血液等张的溶液。将5ml一份的该溶液分配到安瓿中并灭菌。
Claims (2)
1.式I化合物及其立体异构体和其与生理耐受酸的加成盐
其中取代基具有下面的定义：R1是C1-C20烷基，C1-C3氟代烷基，C3-C8环烷基，芳基-C1-C10烷基，芳基，杂芳基，OH或R3R2N，其中R2和R3相同或不同，是氢原子，C1-C10烷基，芳基，芳基-C1-C10烷基，或一起是芳基或杂芳基可以与之稠和的、或可以含有一个杂原子(O，S，NH或取代的N)的C2-C7亚烷基链，A是式IIα-氨基酸残基其中R4是氢原子，C1-C8烷基，C3-C7环烷基，芳基，芳基-C1-C3烷基，R5是氢原子，C1-C8烷基，C3-C7环烷基，C3-C7环烷基-C1-3-烷基，芳基，芳基-C1-C3烷基，二(C3-C7环烷基)-甲基或二苯基甲基或，如果R4＝H，则为C1-C8烷基，其中一个氢原子被OR6或CO-OR6(其中R6＝氢原子，C1-C8烷基或基-C1-C3烷基)替代，或R4和R5一起是可以含有一个稠合烷基的C2-C6亚烷基链，B是式III环状α-氨基酸残基
其中m是2，3或4，且环上的一个氢原子可以被羟基或C1-C3烷基替代，而且，如果m＝3或4，则环中的一个CH2基团可以被氧原子，硫原子，NH-，或N-C1-C4烷基替代，和/或两个相邻的氢原子可以被双键替代。
2.权利要求1的式I化合物用于治疗疾病的用途。
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| DEP4443390.5 | 1994-12-06 | ||
| DE4443390A DE4443390A1 (de) | 1994-12-06 | 1994-12-06 | Neue dipeptidische p-Amidinobenzylamide mit N-terminalen Sulfonyl- bzw. Aminosulfonylresten |
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| AU (1) | AU699579B2 (zh) |
| BR (1) | BR9509970A (zh) |
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| DE (2) | DE4443390A1 (zh) |
| ES (1) | ES2143666T3 (zh) |
| FI (1) | FI972384A0 (zh) |
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| SE9900043D0 (sv) * | 1999-01-11 | 1999-01-11 | Astra Ab | New use |
| US5726159A (en) * | 1994-03-04 | 1998-03-10 | Eli Lilly And Company | Antithrombotic agents |
| US5705487A (en) * | 1994-03-04 | 1998-01-06 | Eli Lilly And Company | Antithrombotic agents |
| US5707966A (en) * | 1994-03-04 | 1998-01-13 | Eli Lilly And Company | Antithrombotic agents |
| US5710130A (en) * | 1995-02-27 | 1998-01-20 | Eli Lilly And Company | Antithrombotic agents |
| US5914319A (en) * | 1995-02-27 | 1999-06-22 | Eli Lilly And Company | Antithrombotic agents |
| SE9602263D0 (sv) | 1996-06-07 | 1996-06-07 | Astra Ab | New amino acid derivatives |
| US6200967B1 (en) | 1996-06-25 | 2001-03-13 | Eli Lilly And Company | Anticoagulant agents |
| CA2258915A1 (en) * | 1996-06-25 | 1997-12-31 | Michael Robert Wiley | Anticoagulant agents |
| AR013084A1 (es) | 1997-06-19 | 2000-12-13 | Astrazeneca Ab | Derivados de amidino utiles como inhibidores de la trombina, composicion farmaceutica, utilizacion de dichos compuestos para la preparacion demedicamentos y proceso para la preparacion de los compuestos mencionados |
| SE9704543D0 (sv) | 1997-12-05 | 1997-12-05 | Astra Ab | New compounds |
| MXPA01010114A (es) | 1999-04-09 | 2002-07-30 | Basf Ag | Inhibidores de peso molecular bajo de las proteasas complemento. |
| ATE517910T1 (de) | 2000-08-11 | 2011-08-15 | Wilex Ag | NICHT-KOVALENTE INHIBITOREN VON UROKINASE UND BLUTGEFÄßBILDUNG |
| IL149042A0 (en) * | 2000-08-11 | 2002-11-10 | Corvas Int Inc | Non-covalent inhibitors of urokinase and blood vessel formation |
| DE10049937A1 (de) * | 2000-10-06 | 2002-04-11 | Knoll Ag | Niedermolekulare Inhibitoren von Serinproteasen mit Polyhydroxyalkyl- und Polyhydroxycycloalkylresten |
| CH695999A5 (de) * | 2002-02-28 | 2006-11-15 | Wilex Ag | Verfahren zur Herstellung von 3- Amidinophenylalanin-Derivaten. |
| DE102004029812A1 (de) * | 2004-06-19 | 2006-05-24 | Clariant Gmbh | Verfahren zur Herstellung von Nitrilen aus Aldehydoximen durch Umsetzung mit Alkylphosphonsäureanhydriden |
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| AU675981B2 (en) * | 1992-12-02 | 1997-02-27 | Bristol-Myers Squibb Company | Guanidinyl-substituted heterocyclic thrombin inhibitors |
| SE9301916D0 (sv) * | 1993-06-03 | 1993-06-03 | Ab Astra | New peptides derivatives |
| AU1025795A (en) * | 1994-01-27 | 1995-08-03 | Mitsubishi Chemical Corporation | Prolineamide derivatives |
| IL112795A (en) * | 1994-03-04 | 2001-01-28 | Astrazeneca Ab | Derivatives of peptides as antithrombotic drugs, their preparation, and pharmaceutical preparations containing them |
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| BR9509970A (pt) | 1997-11-25 |
| FI972384A (fi) | 1997-06-05 |
| ZA9510295B (en) | 1997-06-05 |
| CZ153797A3 (cs) | 1998-02-18 |
| JPH10509727A (ja) | 1998-09-22 |
| EP0796271B1 (de) | 2000-02-02 |
| DE59507755D1 (de) | 2000-03-09 |
| AU4255996A (en) | 1996-06-26 |
| NO972559D0 (no) | 1997-06-05 |
| AU699579B2 (en) | 1998-12-10 |
| ATE189458T1 (de) | 2000-02-15 |
| HU222353B1 (hu) | 2003-06-28 |
| TW336222B (en) | 1998-07-11 |
| RU2152953C1 (ru) | 2000-07-20 |
| IL116231A0 (en) | 1996-03-31 |
| HUT77289A (hu) | 1998-03-30 |
| NO972559L (no) | 1997-08-05 |
| FI972384A0 (fi) | 1997-06-05 |
| IL116231A (en) | 2001-01-28 |
| EP0796271A1 (de) | 1997-09-24 |
| WO1996017860A1 (de) | 1996-06-13 |
| CA2207874A1 (en) | 1996-06-13 |
| ES2143666T3 (es) | 2000-05-16 |
| MX9704050A (es) | 1997-08-30 |
| US5852051A (en) | 1998-12-22 |
| DE4443390A1 (de) | 1996-06-13 |
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