BG105986A - Пролекарства на тромбинови инхибитори - Google Patents

Пролекарства на тромбинови инхибитори Download PDF

Info

Publication number: BG105986A
Authority: BG; Bulgaria
Prior art keywords: alkyl; cycloalkyl; ooc; radicals; phenyl
Prior art date: 1999-04-09

Application number

BG105986A

Other languages

Bulgarian (bg)

English (en)

Inventor

Dorit Baucke

Helmut Mack

Werner Seitz

Wilfried Hornberger

Gisela Backfisch

Juergen DELZER

Original Assignee

Abbott Gmbh & Co. Kg

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

1999-04-09

Filing date

2001-10-05

Publication date

2002-06-28

2001-10-05 Application filed by Abbott Gmbh & Co. Kg filed Critical Abbott Gmbh & Co. Kg

2002-06-28 Publication of BG105986A publication Critical patent/BG105986A/bg

Links

229940002612 prodrug Drugs 0.000 title claims abstract description 20
239000000651 prodrug Substances 0.000 title claims abstract description 20
229940122388 Thrombin inhibitor Drugs 0.000 title abstract description 12
239000003868 thrombin inhibitor Substances 0.000 title abstract description 12
-1 heterocyclic amidines Chemical class 0.000 claims abstract description 260
150000001875 compounds Chemical class 0.000 claims abstract description 112
238000002360 preparation method Methods 0.000 claims abstract description 68
108090000190 Thrombin Proteins 0.000 claims abstract description 39
229960004072 thrombin Drugs 0.000 claims abstract description 38
239000003814 drug Substances 0.000 claims abstract description 18
125000000217 alkyl group Chemical group 0.000 claims description 77
125000006552 (C3-C8) cycloalkyl group Chemical group 0.000 claims description 67
125000003118 aryl group Chemical group 0.000 claims description 46
229910052801 chlorine Inorganic materials 0.000 claims description 46
229910052799 carbon Inorganic materials 0.000 claims description 43
125000000753 cycloalkyl group Chemical group 0.000 claims description 41
229910052739 hydrogen Inorganic materials 0.000 claims description 41
125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 26
125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 26
125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 22
150000001602 bicycloalkyls Chemical group 0.000 claims description 21
125000000000 cycloalkoxy group Chemical group 0.000 claims description 16
239000002253 acid Substances 0.000 claims description 14
239000001257 hydrogen Substances 0.000 claims description 14
150000003839 salts Chemical class 0.000 claims description 13
125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 12
UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 11
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 description 11
230000001419 dependent effect Effects 0.000 claims description 11
208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 11
238000011282 treatment Methods 0.000 claims description 11
125000003545 alkoxy group Chemical group 0.000 claims description 10
210000004027 cell Anatomy 0.000 claims description 7
210000001035 gastrointestinal tract Anatomy 0.000 claims description 7
125000006414 CCl Chemical group ClC* 0.000 claims description 6
238000010521 absorption reaction Methods 0.000 claims description 6
125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 6
230000007246 mechanism Effects 0.000 claims description 6
229910052760 oxygen Inorganic materials 0.000 claims description 6
125000004817 pentamethylene group Chemical group [H]C([H])([*:2])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[*:1] 0.000 claims description 6
230000036470 plasma concentration Effects 0.000 claims description 6
230000002265 prevention Effects 0.000 claims description 6
229910052717 sulfur Inorganic materials 0.000 claims description 6
125000000383 tetramethylene group Chemical group [H]C([H])([*:1])C([H])([H])C([H])([H])C([H])([H])[*:2] 0.000 claims description 6
125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 5
208000005189 Embolism Diseases 0.000 claims description 5
125000005073 adamantyl group Chemical group C12(CC3CC(CC(C1)C3)C2)* 0.000 claims description 5
125000000582 cycloheptyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 claims description 5
125000003392 indanyl group Chemical group C1(CCC2=CC=CC=C12)* 0.000 claims description 5
230000001575 pathological effect Effects 0.000 claims description 5
125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 4
150000007513 acids Chemical class 0.000 claims description 4
230000009471 action Effects 0.000 claims description 4
125000004855 decalinyl group Chemical group C1(CCCC2CCCCC12)* 0.000 claims description 4
125000002868 norbornyl group Chemical group C12(CCC(CC1)C2)* 0.000 claims description 4
210000000329 smooth muscle myocyte Anatomy 0.000 claims description 4
SNOOUWRIMMFWNE-UHFFFAOYSA-M sodium;6-[(3,4,5-trimethoxybenzoyl)amino]hexanoate Chemical compound [Na+].COC1=CC(C(=O)NCCCCCC([O-])=O)=CC(OC)=C1OC SNOOUWRIMMFWNE-UHFFFAOYSA-M 0.000 claims description 4
125000000229 (C1-C4)alkoxy group Chemical group 0.000 claims description 3
206010027476 Metastases Diseases 0.000 claims description 3
238000009825 accumulation Methods 0.000 claims description 3
230000004663 cell proliferation Effects 0.000 claims description 3
208000009190 disseminated intravascular coagulation Diseases 0.000 claims description 3
150000002431 hydrogen Chemical class 0.000 claims description 3
230000009401 metastasis Effects 0.000 claims description 3
230000035699 permeability Effects 0.000 claims description 3
230000002797 proteolythic effect Effects 0.000 claims description 3
230000010410 reperfusion Effects 0.000 claims description 3
208000037803 restenosis Diseases 0.000 claims description 3
229960000103 thrombolytic agent Drugs 0.000 claims description 3
230000002537 thrombolytic effect Effects 0.000 claims description 3
210000004881 tumor cell Anatomy 0.000 claims description 3
230000004913 activation Effects 0.000 claims description 2
230000004075 alteration Effects 0.000 claims description 2
238000011278 co-treatment Methods 0.000 claims description 2
210000002919 epithelial cell Anatomy 0.000 claims description 2
230000014509 gene expression Effects 0.000 claims description 2
230000005764 inhibitory process Effects 0.000 claims description 2
230000002297 mitogenic effect Effects 0.000 claims description 2
238000007911 parenteral administration Methods 0.000 claims description 2
GJVFBWCTGUSGDD-UHFFFAOYSA-L pentamethonium bromide Chemical compound [Br-].[Br-].C[N+](C)(C)CCCCC[N+](C)(C)C GJVFBWCTGUSGDD-UHFFFAOYSA-L 0.000 claims description 2
239000000546 pharmaceutical excipient Substances 0.000 claims description 2
108020003175 receptors Proteins 0.000 claims description 2
102000005962 receptors Human genes 0.000 claims description 2
230000009467 reduction Effects 0.000 claims description 2
230000019491 signal transduction Effects 0.000 claims description 2
230000000638 stimulation Effects 0.000 claims description 2
230000004614 tumor growth Effects 0.000 claims description 2
229910052727 yttrium Inorganic materials 0.000 claims description 2
125000000008 (C1-C10) alkyl group Chemical group 0.000 claims 1
125000006519 CCH3 Chemical group 0.000 claims 1
229910003844 NSO2 Inorganic materials 0.000 claims 1
239000012050 conventional carrier Substances 0.000 claims 1
108060005987 Kallikrein Proteins 0.000 abstract description 3
102000001399 Kallikrein Human genes 0.000 abstract description 3
239000003146 anticoagulant agent Substances 0.000 abstract description 3
229940127219 anticoagulant drug Drugs 0.000 abstract description 3
239000003112 inhibitor Substances 0.000 abstract description 3
239000002260 anti-inflammatory agent Substances 0.000 abstract description 2
229940121363 anti-inflammatory agent Drugs 0.000 abstract description 2
230000002860 competitive effect Effects 0.000 abstract description 2
238000001727 in vivo Methods 0.000 abstract description 2
239000008194 pharmaceutical composition Substances 0.000 abstract description 2
MTCFGRXMJLQNBG-UHFFFAOYSA-N serine Chemical compound OCC(N)C(O)=O MTCFGRXMJLQNBG-UHFFFAOYSA-N 0.000 abstract 2
108091005804 Peptidases Proteins 0.000 abstract 1
102000035195 Peptidases Human genes 0.000 abstract 1
239000004365 Protease Substances 0.000 abstract 1
241001522306 Serinus serinus Species 0.000 abstract 1
YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 414
239000000243 solution Substances 0.000 description 206
RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 202
VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 198
OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 198
YTPLMLYBLZKORZ-UHFFFAOYSA-N Divinylene sulfide Natural products C=1C=CSC=1 YTPLMLYBLZKORZ-UHFFFAOYSA-N 0.000 description 195
XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 165
229930192474 thiophene Natural products 0.000 description 124
WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 90
XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 89
239000000047 product Substances 0.000 description 79
CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 78
150000003254 radicals Chemical class 0.000 description 77
238000004992 fast atom bombardment mass spectroscopy Methods 0.000 description 74
239000000203 mixture Substances 0.000 description 67
239000007787 solid Substances 0.000 description 65
KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 63
239000002904 solvent Substances 0.000 description 60
238000006243 chemical reaction Methods 0.000 description 59
238000003756 stirring Methods 0.000 description 59
239000011541 reaction mixture Substances 0.000 description 57
LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 56
125000006239 protecting group Chemical group 0.000 description 54
239000012043 crude product Substances 0.000 description 53
WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 48
RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 47
QTBSBXVTEAMEQO-UHFFFAOYSA-N acetic acid Substances CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 46
239000012074 organic phase Substances 0.000 description 44
ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 43
CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 42
229910052943 magnesium sulfate Inorganic materials 0.000 description 39
235000019341 magnesium sulphate Nutrition 0.000 description 39
238000005160 1H NMR spectroscopy Methods 0.000 description 33
230000032050 esterification Effects 0.000 description 33
238000005886 esterification reaction Methods 0.000 description 33
JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 32
238000004440 column chromatography Methods 0.000 description 32
IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 32
229910000041 hydrogen chloride Inorganic materials 0.000 description 32
238000000746 purification Methods 0.000 description 32
QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 31
VLKZOEOYAKHREP-UHFFFAOYSA-N hexane Substances CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 31
239000003921 oil Substances 0.000 description 31
JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 30
FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 30
238000005809 transesterification reaction Methods 0.000 description 29
239000000460 chlorine Substances 0.000 description 27
239000012071 phase Substances 0.000 description 25
ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 24
239000000843 powder Substances 0.000 description 24
229920006395 saturated elastomer Polymers 0.000 description 22
OMGHIGVFLOPEHJ-UHFFFAOYSA-N 2,5-dihydro-1h-pyrrol-1-ium-2-carboxylate Chemical compound OC(=O)C1NCC=C1 OMGHIGVFLOPEHJ-UHFFFAOYSA-N 0.000 description 21
FZWLAAWBMGSTSO-UHFFFAOYSA-N Thiazole Chemical compound C1=CSC=N1 FZWLAAWBMGSTSO-UHFFFAOYSA-N 0.000 description 21
238000001816 cooling Methods 0.000 description 21
NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical class [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 20
239000008346 aqueous phase Substances 0.000 description 20
125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 20
239000000126 substance Substances 0.000 description 20
YLQBMQCUIZJEEH-UHFFFAOYSA-N Furan Chemical compound C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 19
239000000725 suspension Substances 0.000 description 19
VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 18
PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 18
HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 18
230000006870 function Effects 0.000 description 18
239000002244 precipitate Substances 0.000 description 18
QAEDZJGFFMLHHQ-UHFFFAOYSA-N trifluoroacetic anhydride Chemical compound FC(F)(F)C(=O)OC(=O)C(F)(F)F QAEDZJGFFMLHHQ-UHFFFAOYSA-N 0.000 description 18
238000001035 drying Methods 0.000 description 17
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229910052938 sodium sulfate Inorganic materials 0.000 description 17
235000011152 sodium sulphate Nutrition 0.000 description 17
UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 16
UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 16
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230000015572 biosynthetic process Effects 0.000 description 15
UAOMVDZJSHZZME-UHFFFAOYSA-N diisopropylamine Chemical compound CC(C)NC(C)C UAOMVDZJSHZZME-UHFFFAOYSA-N 0.000 description 15
238000004809 thin layer chromatography Methods 0.000 description 15
WTDHULULXKLSOZ-UHFFFAOYSA-N Hydroxylamine hydrochloride Chemical compound Cl.ON WTDHULULXKLSOZ-UHFFFAOYSA-N 0.000 description 14
229960000583 acetic acid Drugs 0.000 description 14
RWSOTUBLDIXVET-UHFFFAOYSA-N Dihydrogen sulfide Chemical compound S RWSOTUBLDIXVET-UHFFFAOYSA-N 0.000 description 13
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230000035602 clotting Effects 0.000 description 13
125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 13
QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 12
OXCZROVJFNJEGL-UHFFFAOYSA-N NCC1=NC(C(NO)=N)=CS1.Cl Chemical compound NCC1=NC(C(NO)=N)=CS1.Cl OXCZROVJFNJEGL-UHFFFAOYSA-N 0.000 description 12
238000001914 filtration Methods 0.000 description 12
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238000003786 synthesis reaction Methods 0.000 description 12
239000003456 ion exchange resin Substances 0.000 description 11
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238000000034 method Methods 0.000 description 11
238000012360 testing method Methods 0.000 description 11
NWUYHJFMYQTDRP-UHFFFAOYSA-N 1,2-bis(ethenyl)benzene;1-ethenyl-2-ethylbenzene;styrene Chemical compound C=CC1=CC=CC=C1.CCC1=CC=CC=C1C=C.C=CC1=CC=CC=C1C=C NWUYHJFMYQTDRP-UHFFFAOYSA-N 0.000 description 10
IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 10
229940079593 drug Drugs 0.000 description 10
239000000706 filtrate Substances 0.000 description 10
239000007789 gas Substances 0.000 description 10
HJUGFYREWKUQJT-UHFFFAOYSA-N tetrabromomethane Chemical compound BrC(Br)(Br)Br HJUGFYREWKUQJT-UHFFFAOYSA-N 0.000 description 10
RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 10
235000001014 amino acid Nutrition 0.000 description 9
238000005859 coupling reaction Methods 0.000 description 9
238000010511 deprotection reaction Methods 0.000 description 9
239000002274 desiccant Substances 0.000 description 9
238000002330 electrospray ionisation mass spectrometry Methods 0.000 description 9
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229910052757 nitrogen Inorganic materials 0.000 description 9
XCAQIUOFDMREBA-UHFFFAOYSA-N tert-butyl n-[(2-methylpropan-2-yl)oxycarbonyl]carbamate Chemical compound CC(C)(C)OC(=O)NC(=O)OC(C)(C)C XCAQIUOFDMREBA-UHFFFAOYSA-N 0.000 description 9
230000008878 coupling Effects 0.000 description 8
238000010168 coupling process Methods 0.000 description 8
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125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 8
DTQVDTLACAAQTR-UHFFFAOYSA-N trifluoroacetic acid Substances OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 8
KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 description 7
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KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 7
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239000012312 sodium hydride Substances 0.000 description 7
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239000007858 starting material Substances 0.000 description 7
TVPJJKGFBGKYGU-UHFFFAOYSA-N 2-(aminomethyl)-1,3-thiazole-4-carbonitrile Chemical compound NCC1=NC(C#N)=CS1 TVPJJKGFBGKYGU-UHFFFAOYSA-N 0.000 description 6
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AVXURJPOCDRRFD-UHFFFAOYSA-N Hydroxylamine Chemical compound ON AVXURJPOCDRRFD-UHFFFAOYSA-N 0.000 description 6
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239000008280 blood Substances 0.000 description 6
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229910000027 potassium carbonate Inorganic materials 0.000 description 6
238000010992 reflux Methods 0.000 description 6
125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 description 6
USFZMSVCRYTOJT-UHFFFAOYSA-N Ammonium acetate Chemical compound N.CC(O)=O USFZMSVCRYTOJT-UHFFFAOYSA-N 0.000 description 5
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238000003820 Medium-pressure liquid chromatography Methods 0.000 description 5
108010000499 Thromboplastin Proteins 0.000 description 5
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235000019257 ammonium acetate Nutrition 0.000 description 5
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125000001584 benzyloxycarbonyl group Chemical group C(=O)(OCC1=CC=CC=C1)* 0.000 description 5
230000023555 blood coagulation Effects 0.000 description 5
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229940043279 diisopropylamine Drugs 0.000 description 5
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150000002148 esters Chemical group 0.000 description 5
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238000003818 flash chromatography Methods 0.000 description 5
239000000543 intermediate Substances 0.000 description 5
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YBRBMKDOPFTVDT-UHFFFAOYSA-N tert-butylamine Chemical compound CC(C)(C)N YBRBMKDOPFTVDT-UHFFFAOYSA-N 0.000 description 1
YBRBMKDOPFTVDT-UHFFFAOYSA-O tert-butylammonium Chemical group CC(C)(C)[NH3+] YBRBMKDOPFTVDT-UHFFFAOYSA-O 0.000 description 1
150000003512 tertiary amines Chemical class 0.000 description 1
RWRDLPDLKQPQOW-UHFFFAOYSA-N tetrahydropyrrole Natural products C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 description 1
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238000012546 transfer Methods 0.000 description 1
UCPYLLCMEDAXFR-UHFFFAOYSA-N triphosgene Chemical compound ClC(Cl)(Cl)OC(=O)OC(Cl)(Cl)Cl UCPYLLCMEDAXFR-UHFFFAOYSA-N 0.000 description 1
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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
- C07K5/06—Dipeptides
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
- C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
- C07K5/06—Dipeptides
- C07K5/06008—Dipeptides with the first amino acid being neutral
- C07K5/06078—Dipeptides with the first amino acid being neutral and aromatic or cycloaliphatic
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
- A61P35/04—Antineoplastic agents specific for metastasis
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
- 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
- A61P9/06—Antiarrhythmics
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B43/00—Formation or introduction of functional groups containing nitrogen
- 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
- C07K5/022—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing at least one abnormal peptide link containing the structure -X-C(=O)-(C)n-N-C-C(=O)-Y-; X and Y being heteroatoms; n being 1 or 2
- C07K5/0222—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing at least one abnormal peptide link containing the structure -X-C(=O)-(C)n-N-C-C(=O)-Y-; X and Y being heteroatoms; n being 1 or 2 with the first amino acid being heterocyclic, e.g. Pro, Trp
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides

Landscapes

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

BG105986A 1999-04-09 2001-10-05 Пролекарства на тромбинови инхибитори BG105986A (bg)

Applications Claiming Priority (4)

Application Number	Priority Date	Filing Date	Title
DE19915930		1999-04-09
DE19934123		1999-07-23
DE19947920		1999-10-06
PCT/EP2000/003009 WO2000061609A2 (de)	1999-04-09	2000-04-05	Prodrugs von thrombininhibitoren

Publications (1)

Publication Number	Publication Date
BG105986A true BG105986A (bg)	2002-06-28

Family

ID=27219075

Family Applications (1)

Application Number	Title	Priority Date	Filing Date
BG105986A BG105986A (bg)	1999-04-09	2001-10-05	Пролекарства на тромбинови инхибитори

Country Status (18)

Country	Link
US (1)	US7144902B1 (de)
EP (1)	EP1165601A2 (de)
JP (1)	JP2002542165A (de)
KR (1)	KR20010108481A (de)
CN (1)	CN1355810A (de)
AU (1)	AU765244B2 (de)
BG (1)	BG105986A (de)
BR (1)	BR0009674A (de)
CA (1)	CA2370267A1 (de)
HK (1)	HK1046289A1 (de)
HU (1)	HUP0202401A3 (de)
IL (1)	IL145772A0 (de)
NO (1)	NO20014875L (de)
NZ (1)	NZ515026A (de)
PL (1)	PL352824A1 (de)
SK (1)	SK14222001A3 (de)
TR (1)	TR200102912T2 (de)
WO (1)	WO2000061609A2 (de)

Families Citing this family (16)

* Cited by examiner, † Cited by third party
Publication number	Priority date	Publication date	Assignee	Title
DE10064797A1 (de) *	2000-12-22	2002-06-27	Knoll Ag	Orale und parenterale pharmazeutische Formulierung, umfassend eine niedermolekulare Thrombininhibitor-Pro-Pharmakon
WO2004002985A1 (en) *	2002-06-27	2004-01-08	Lg Life Sciences Ltd.	Peptidic thrombin inhibitor compound
CA2525940A1 (en) *	2003-05-16	2004-11-25	National Institute For Biological Standards And Control (Nibsc)	Mixture
PT1737889E (pt)	2004-10-19	2010-12-13	Lonza Ag	Método para síntese de péptidos em fase sólida
AU2006243000B2 (en) *	2005-05-05	2011-05-26	Macrophage Pharma Limited	Alpha aminoacid ester-drug conjugates hydrolysable by carboxylesterase
PL1879573T3 (pl)	2005-05-10	2013-05-31	Incyte Holdings Corp	Modulatory 2,3-dioksygenazy indoloaminy i sposoby ich zastosowania
US8450351B2 (en)	2005-12-20	2013-05-28	Incyte Corporation	N-hydroxyamidinoheterocycles as modulators of indoleamine 2,3-dioxygenase
CL2007002650A1 (es)	2006-09-19	2008-02-08	Incyte Corp	Compuestos derivados de heterociclo n-hidroxiamino; composicion farmaceutica, util para tratar cancer, infecciones virales y desordenes neurodegenerativos entre otras.
WO2008036642A2 (en) *	2006-09-19	2008-03-27	Incyte Corporation	N-hydroxyamidinoheterocycles as modulators of indoleamine 2,3-dioxygenase
JP5465720B2 (ja)	2008-07-08	2014-04-09	インサイト・コーポレイション	インドールアミン２，３−ジオキシゲナーゼの阻害剤としての１，２，５−オキサジアゾール
US9206123B2 (en)	2009-12-18	2015-12-08	Activesite Pharmaceuticals, Inc.	Prodrugs of inhibitors of plasma kallikrein
AU2010330743A1 (en) *	2009-12-18	2012-07-05	Activesite Pharmaceuticals, Inc.	Prodrugs of inhibitors of plasma kallikrein
WO2012142308A1 (en)	2011-04-13	2012-10-18	Activesite Pharmaceuticals, Inc.	Prodrugs of inhibitors of plasma kallikrein
ES2799582T3 (es)	2013-11-08	2020-12-18	Incyte Holdings Corp	Proceso para la síntesis de un inhibidor de indoleamina 2,3-dioxigenasa
US10081624B2 (en) *	2014-08-26	2018-09-25	Takeda Pharmaceutical Company Limited	Heterocyclic compound
CN106674190B (zh) *	2016-12-13	2019-05-10	台州市创源工业技术有限公司	一种2-噻吩甲胺的合成方法

Family Cites Families (8)

* Cited by examiner, † Cited by third party
Publication number	Priority date	Publication date	Assignee	Title
IL112795A (en)	1994-03-04	2001-01-28	Astrazeneca Ab	Peptide derivatives as antithrombic agents their preparation and pharmaceutical compositions containing them
TWI238827B (en) *	1995-12-21	2005-09-01	Astrazeneca Ab	Prodrugs of thrombin inhibitors
TW523513B (en)	1996-03-01	2003-03-11	Akzo Nobel Nv	Serine protease inhibitors
DE19632773A1 (de)	1996-08-14	1998-02-19	Basf Ag	Neue Thrombininhibitoren
EP1049673A1 (de)	1998-01-26	2000-11-08	Basf Aktiengesellschaft	Heterocyclische amidine als kallikrein protease inhibitoren
JP2002501081A (ja)	1998-01-26	2002-01-15	ビーエーエスエフアクチェンゲゼルシャフト	トロンビンインヒビター
KR20000047461A (ko) *	1998-12-29	2000-07-25	성재갑	트롬빈 억제제
JP4489976B2 (ja) *	1999-04-09	2010-06-23	ビーエーエスエフソシエタス・ヨーロピア	補体プロテアーゼの低分子インヒビター

2000
- 2000-04-05 PL PL00352824A patent/PL352824A1/xx unknown
- 2000-04-05 IL IL14577200A patent/IL145772A0/xx unknown
- 2000-04-05 CA CA002370267A patent/CA2370267A1/en not_active Abandoned
- 2000-04-05 WO PCT/EP2000/003009 patent/WO2000061609A2/de not_active Ceased
- 2000-04-05 HK HK02107849.6A patent/HK1046289A1/zh unknown
- 2000-04-05 US US09/958,349 patent/US7144902B1/en not_active Expired - Fee Related
- 2000-04-05 SK SK1422-2001A patent/SK14222001A3/sk not_active Application Discontinuation
- 2000-04-05 JP JP2000611551A patent/JP2002542165A/ja active Pending
- 2000-04-05 KR KR1020017012870A patent/KR20010108481A/ko not_active Ceased
- 2000-04-05 EP EP00920661A patent/EP1165601A2/de not_active Withdrawn
- 2000-04-05 NZ NZ515026A patent/NZ515026A/en unknown
- 2000-04-05 HU HU0202401A patent/HUP0202401A3/hu unknown
- 2000-04-05 BR BR0009674-1A patent/BR0009674A/pt not_active IP Right Cessation
- 2000-04-05 CN CN00807958A patent/CN1355810A/zh active Pending
- 2000-04-05 AU AU41156/00A patent/AU765244B2/en not_active Ceased
- 2000-04-05 TR TR2001/02912T patent/TR200102912T2/xx unknown
2001
- 2001-10-05 BG BG105986A patent/BG105986A/bg unknown
- 2001-10-08 NO NO20014875A patent/NO20014875L/no not_active Application Discontinuation

Also Published As

Publication number	Publication date
WO2000061609A2 (de)	2000-10-19
EP1165601A2 (de)	2002-01-02
JP2002542165A (ja)	2002-12-10
TR200102912T2 (tr)	2002-03-21
HUP0202401A3 (en)	2003-11-28
NO20014875D0 (no)	2001-10-08
CA2370267A1 (en)	2000-10-19
WO2000061609A3 (de)	2001-03-15
WO2000061609B1 (de)	2001-04-26
IL145772A0 (en)	2002-07-25
BR0009674A (pt)	2002-01-15
PL352824A1 (en)	2003-09-08
NZ515026A (en)	2003-10-31
HK1046289A1 (zh)	2003-01-03
HUP0202401A2 (en)	2002-10-28
KR20010108481A (ko)	2001-12-07
AU4115600A (en)	2000-11-14
SK14222001A3 (sk)	2002-07-02
CN1355810A (zh)	2002-06-26
US7144902B1 (en)	2006-12-05
NO20014875L (no)	2001-11-13
AU765244B2 (en)	2003-09-11

Publication	Publication Date	Title
AU772024B2 (en)	2004-04-08	Inhibitors of urokinase and blood vessel formation
EP1808440B1 (de)	2011-07-27	Nicht-kovalente Inhibitoren von Urokinase und Blutgefäßbildung
BG105986A (bg)	2002-06-28	Пролекарства на тромбинови инхибитори
US6114358A (en)	2000-09-05	Thrombin inhibitors
CA2193844A1 (en)	1996-02-08	Thrombin inhibitors
US6740647B1 (en)	2004-05-25	Thrombin inhibitors
WO1999037611A1 (de)	1999-07-29	Heterocyclische amidine als kallikrein protease inhibitoren
AU3659200A (en)	2000-11-14	Prodrugs of thrombin inhibitors
MXPA01010119A (en)	2002-06-05	Prodrugs of thrombin inhibitors
MXPA01010118A (en)	2002-06-05	Prodrugs of thrombin inhibitors
CZ20002463A3 (cs)	2000-10-11	Nové inhibitory trombinu
CZ2001276A3 (cs)	2001-06-13	Inhibitory urokinázy a farmaceutický prostředek, který je obsahuje