EP1023295A1 - Promedicaments antagonistes de recepteur de fibrinogene - Google Patents
Promedicaments antagonistes de recepteur de fibrinogeneInfo
- Publication number
- EP1023295A1 EP1023295A1 EP98906092A EP98906092A EP1023295A1 EP 1023295 A1 EP1023295 A1 EP 1023295A1 EP 98906092 A EP98906092 A EP 98906092A EP 98906092 A EP98906092 A EP 98906092A EP 1023295 A1 EP1023295 A1 EP 1023295A1
- Authority
- EP
- European Patent Office
- Prior art keywords
- alkyl
- aryl
- substituted
- mammal
- hydroxy
- Prior art date
- Legal status (The legal status 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 status listed.)
- Withdrawn
Links
- 229940002612 prodrug Drugs 0.000 title abstract description 9
- 239000000651 prodrug Substances 0.000 title abstract description 9
- 239000002319 fibrinogen receptor antagonist Substances 0.000 title abstract description 8
- 125000000217 alkyl group Chemical group 0.000 claims description 156
- 125000003118 aryl group Chemical group 0.000 claims description 79
- -1 amino, amino Chemical group 0.000 claims description 74
- 150000001875 compounds Chemical class 0.000 claims description 49
- 210000001772 blood platelet Anatomy 0.000 claims description 37
- 125000003545 alkoxy group Chemical group 0.000 claims description 30
- 239000000203 mixture Substances 0.000 claims description 28
- 230000002401 inhibitory effect Effects 0.000 claims description 25
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 22
- 108010049003 Fibrinogen Proteins 0.000 claims description 21
- 102000008946 Fibrinogen Human genes 0.000 claims description 21
- 241000124008 Mammalia Species 0.000 claims description 21
- 229940012952 fibrinogen Drugs 0.000 claims description 21
- 150000003839 salts Chemical class 0.000 claims description 18
- 125000003282 alkyl amino group Chemical group 0.000 claims description 17
- 230000027455 binding Effects 0.000 claims description 15
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- 238000004220 aggregation Methods 0.000 claims description 14
- 229910052757 nitrogen Inorganic materials 0.000 claims description 14
- 229910052717 sulfur Inorganic materials 0.000 claims description 13
- 125000004453 alkoxycarbonyl group Chemical group 0.000 claims description 12
- 125000004663 dialkyl amino group Chemical group 0.000 claims description 12
- 239000001257 hydrogen Substances 0.000 claims description 12
- 229910052739 hydrogen Inorganic materials 0.000 claims description 12
- 125000003107 substituted aryl group Chemical group 0.000 claims description 12
- 125000005842 heteroatom Chemical group 0.000 claims description 11
- 238000000034 method Methods 0.000 claims description 11
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- 125000004457 alkyl amino carbonyl group Chemical group 0.000 claims description 7
- 125000005195 alkyl amino carbonyloxy group Chemical group 0.000 claims description 7
- 125000004471 alkyl aminosulfonyl group Chemical group 0.000 claims description 7
- 125000004448 alkyl carbonyl group Chemical group 0.000 claims description 7
- 125000004390 alkyl sulfonyl group Chemical group 0.000 claims description 7
- 125000004656 alkyl sulfonylamino group Chemical group 0.000 claims description 7
- 125000006570 (C5-C6) heteroaryl group Chemical group 0.000 claims description 6
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- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 6
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 6
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 6
- 125000000547 substituted alkyl group Chemical group 0.000 claims description 6
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- 229910052799 carbon Inorganic materials 0.000 claims description 5
- 125000004432 carbon atom Chemical group C* 0.000 claims description 5
- 125000004122 cyclic group Chemical group 0.000 claims description 5
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- 125000001769 aryl amino group Chemical group 0.000 claims description 4
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- 125000006552 (C3-C8) cycloalkyl group Chemical group 0.000 claims description 3
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 3
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- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 6
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- CHKVPAROMQMJNQ-UHFFFAOYSA-M potassium bisulfate Chemical compound [K+].OS([O-])(=O)=O CHKVPAROMQMJNQ-UHFFFAOYSA-M 0.000 description 6
- 108010067306 Fibronectins Proteins 0.000 description 5
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- GJOMACBKKXCRRD-LJQANCHMSA-N ethyl (2r)-3-[[5-[[4-[(z)-n'-hydroxycarbamimidoyl]phenyl]carbamoyl]thiophene-2-carbonyl]amino]-2-[(4-methylphenyl)sulfonylamino]propanoate Chemical compound C([C@H](C(=O)OCC)NS(=O)(=O)C=1C=CC(C)=CC=1)NC(=O)C(S1)=CC=C1C(=O)NC1=CC=C(C(\N)=N\O)C=C1 GJOMACBKKXCRRD-LJQANCHMSA-N 0.000 description 1
- XBFRKVVHUKMGCL-LLVKDONJSA-N ethyl (2r)-3-amino-2-[(4-methylphenyl)sulfonylamino]propanoate Chemical compound CCOC(=O)[C@@H](CN)NS(=O)(=O)C1=CC=C(C)C=C1 XBFRKVVHUKMGCL-LLVKDONJSA-N 0.000 description 1
- RJYNKHXDNVWWHC-UHFFFAOYSA-N ethyl 2-[(4-methylphenyl)sulfonylamino]propanoate Chemical compound CCOC(=O)C(C)NS(=O)(=O)C1=CC=C(C)C=C1 RJYNKHXDNVWWHC-UHFFFAOYSA-N 0.000 description 1
- 125000002534 ethynyl group Chemical group [H]C#C* 0.000 description 1
- 238000011156 evaluation Methods 0.000 description 1
- 210000002744 extracellular matrix Anatomy 0.000 description 1
- 229950003499 fibrin Drugs 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- 125000004175 fluorobenzyl group Chemical group 0.000 description 1
- 235000013305 food Nutrition 0.000 description 1
- 239000012458 free base Substances 0.000 description 1
- 229940050411 fumarate Drugs 0.000 description 1
- 210000005095 gastrointestinal system Anatomy 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 239000008273 gelatin Substances 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 235000011852 gelatine desserts Nutrition 0.000 description 1
- 238000002523 gelfiltration Methods 0.000 description 1
- 229960001731 gluceptate Drugs 0.000 description 1
- KWMLJOLKUYYJFJ-VFUOTHLCSA-N glucoheptonic acid Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)[C@@H](O)C(O)=O KWMLJOLKUYYJFJ-VFUOTHLCSA-N 0.000 description 1
- 229940050410 gluconate Drugs 0.000 description 1
- 235000001727 glucose Nutrition 0.000 description 1
- 229930195712 glutamate Natural products 0.000 description 1
- 229940049906 glutamate Drugs 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
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- 125000002795 guanidino group Chemical group C(N)(=N)N* 0.000 description 1
- 230000002439 hemostatic effect Effects 0.000 description 1
- 125000000623 heterocyclic group Chemical group 0.000 description 1
- IPCSVZSSVZVIGE-UHFFFAOYSA-M hexadecanoate Chemical compound CCCCCCCCCCCCCCCC([O-])=O IPCSVZSSVZVIGE-UHFFFAOYSA-M 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- XGIHQYAWBCFNPY-AZOCGYLKSA-N hydrabamine Chemical compound C([C@@H]12)CC3=CC(C(C)C)=CC=C3[C@@]2(C)CCC[C@@]1(C)CNCCNC[C@@]1(C)[C@@H]2CCC3=CC(C(C)C)=CC=C3[C@@]2(C)CCC1 XGIHQYAWBCFNPY-AZOCGYLKSA-N 0.000 description 1
- 150000004677 hydrates Chemical class 0.000 description 1
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-M hydrogensulfate Chemical compound OS([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-M 0.000 description 1
- 230000001771 impaired effect Effects 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 125000001041 indolyl group Chemical group 0.000 description 1
- 208000014674 injury Diseases 0.000 description 1
- 108010044426 integrins Proteins 0.000 description 1
- 102000006495 integrins Human genes 0.000 description 1
- 238000007912 intraperitoneal administration Methods 0.000 description 1
- 239000006207 intravenous dosage form Substances 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- 125000001972 isopentyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- CTAPFRYPJLPFDF-UHFFFAOYSA-N isoxazole Chemical compound C=1C=NOC=1 CTAPFRYPJLPFDF-UHFFFAOYSA-N 0.000 description 1
- 230000003907 kidney function Effects 0.000 description 1
- 229940001447 lactate Drugs 0.000 description 1
- 229940099584 lactobionate Drugs 0.000 description 1
- JYTUSYBCFIZPBE-AMTLMPIISA-N lactobionic acid Chemical compound OC(=O)[C@H](O)[C@@H](O)[C@@H]([C@H](O)CO)O[C@@H]1O[C@H](CO)[C@H](O)[C@H](O)[C@H]1O JYTUSYBCFIZPBE-AMTLMPIISA-N 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 229940070765 laurate Drugs 0.000 description 1
- 239000003446 ligand Substances 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 230000003908 liver function Effects 0.000 description 1
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 1
- 229940049920 malate Drugs 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- BJEPYKJPYRNKOW-UHFFFAOYSA-N malic acid Chemical compound OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 description 1
- IWYDHOAUDWTVEP-UHFFFAOYSA-M mandelate Chemical compound [O-]C(=O)C(O)C1=CC=CC=C1 IWYDHOAUDWTVEP-UHFFFAOYSA-M 0.000 description 1
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- 102000006240 membrane receptors Human genes 0.000 description 1
- 238000006241 metabolic reaction Methods 0.000 description 1
- 125000001160 methoxycarbonyl group Chemical group [H]C([H])([H])OC(*)=O 0.000 description 1
- QKPFIXQIWOZEML-UHFFFAOYSA-N methyl 5-[(4-cyanophenyl)carbamoyl]thiophene-2-carboxylate Chemical compound S1C(C(=O)OC)=CC=C1C(=O)NC1=CC=C(C#N)C=C1 QKPFIXQIWOZEML-UHFFFAOYSA-N 0.000 description 1
- 229940102396 methyl bromide Drugs 0.000 description 1
- LRMHVVPPGGOAJQ-UHFFFAOYSA-N methyl nitrate Chemical compound CO[N+]([O-])=O LRMHVVPPGGOAJQ-UHFFFAOYSA-N 0.000 description 1
- JZMJDSHXVKJFKW-UHFFFAOYSA-M methyl sulfate(1-) Chemical compound COS([O-])(=O)=O JZMJDSHXVKJFKW-UHFFFAOYSA-M 0.000 description 1
- 229940016286 microcrystalline cellulose Drugs 0.000 description 1
- 235000019813 microcrystalline cellulose Nutrition 0.000 description 1
- 239000008108 microcrystalline cellulose Substances 0.000 description 1
- 239000002480 mineral oil Substances 0.000 description 1
- 235000010446 mineral oil Nutrition 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 229930014626 natural product Natural products 0.000 description 1
- 230000014399 negative regulation of angiogenesis Effects 0.000 description 1
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 1
- 229940049964 oleate Drugs 0.000 description 1
- ZQPPMHVWECSIRJ-KTKRTIGZSA-N oleic acid Chemical compound CCCCCCCC\C=C/CCCCCCCC(O)=O ZQPPMHVWECSIRJ-KTKRTIGZSA-N 0.000 description 1
- 239000007935 oral tablet Substances 0.000 description 1
- 210000000056 organ Anatomy 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 229910052763 palladium Inorganic materials 0.000 description 1
- RGSFGYAAUTVSQA-UHFFFAOYSA-N pentamethylene Natural products C1CCCC1 RGSFGYAAUTVSQA-UHFFFAOYSA-N 0.000 description 1
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 1
- 239000000863 peptide conjugate Substances 0.000 description 1
- 230000002093 peripheral effect Effects 0.000 description 1
- 239000008177 pharmaceutical agent Substances 0.000 description 1
- 239000008024 pharmaceutical diluent Substances 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- 125000000286 phenylethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000004344 phenylpropyl group Chemical group 0.000 description 1
- 208000001297 phlebitis Diseases 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- 239000006187 pill Substances 0.000 description 1
- 125000004193 piperazinyl group Chemical group 0.000 description 1
- 125000003386 piperidinyl group Chemical group 0.000 description 1
- 210000002381 plasma Anatomy 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 125000001500 prolyl group Chemical group [H]N1C([H])(C(=O)[*])C([H])([H])C([H])([H])C1([H])[H] 0.000 description 1
- 235000019260 propionic acid Nutrition 0.000 description 1
- 125000005470 propylenyl group Chemical group 0.000 description 1
- 125000002568 propynyl group Chemical group [*]C#CC([H])([H])[H] 0.000 description 1
- 238000005086 pumping Methods 0.000 description 1
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 1
- 150000003254 radicals Chemical class 0.000 description 1
- 230000004044 response Effects 0.000 description 1
- 239000011369 resultant mixture Substances 0.000 description 1
- 238000007363 ring formation reaction Methods 0.000 description 1
- YGSDEFSMJLZEOE-UHFFFAOYSA-M salicylate Chemical compound OC1=CC=CC=C1C([O-])=O YGSDEFSMJLZEOE-UHFFFAOYSA-M 0.000 description 1
- 229960001860 salicylate Drugs 0.000 description 1
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 239000002002 slurry Substances 0.000 description 1
- 239000001632 sodium acetate Substances 0.000 description 1
- 235000017281 sodium acetate Nutrition 0.000 description 1
- 235000010413 sodium alginate Nutrition 0.000 description 1
- 239000000661 sodium alginate Substances 0.000 description 1
- 229940005550 sodium alginate Drugs 0.000 description 1
- WXMKPNITSTVMEF-UHFFFAOYSA-M sodium benzoate Chemical compound [Na+].[O-]C(=O)C1=CC=CC=C1 WXMKPNITSTVMEF-UHFFFAOYSA-M 0.000 description 1
- 239000004299 sodium benzoate Substances 0.000 description 1
- 235000010234 sodium benzoate Nutrition 0.000 description 1
- RYYKJJJTJZKILX-UHFFFAOYSA-M sodium octadecanoate Chemical compound [Na+].CCCCCCCCCCCCCCCCCC([O-])=O RYYKJJJTJZKILX-UHFFFAOYSA-M 0.000 description 1
- 239000000600 sorbitol Substances 0.000 description 1
- 235000010356 sorbitol Nutrition 0.000 description 1
- 241000894007 species Species 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 230000000638 stimulation Effects 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 229960005202 streptokinase Drugs 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 235000000346 sugar Nutrition 0.000 description 1
- 150000008163 sugars Chemical class 0.000 description 1
- 239000011593 sulfur Substances 0.000 description 1
- 238000001356 surgical procedure Methods 0.000 description 1
- 238000013268 sustained release Methods 0.000 description 1
- 239000012730 sustained-release form Substances 0.000 description 1
- 239000003765 sweetening agent Substances 0.000 description 1
- 229940095064 tartrate Drugs 0.000 description 1
- 229950002757 teoclate Drugs 0.000 description 1
- WAQSULGLJFOMOZ-RUZDIDTESA-N tert-butyl (2R)-3-[[4-(4-cyanophenoxy)benzoyl]amino]-2-[(4-methylphenyl)sulfonylamino]propanoate Chemical compound C1=CC(C)=CC=C1S(=O)(=O)N[C@@H](C(=O)OC(C)(C)C)CNC(=O)C(C=C1)=CC=C1OC1=CC=C(C#N)C=C1 WAQSULGLJFOMOZ-RUZDIDTESA-N 0.000 description 1
- JAELLLITIZHOGQ-UHFFFAOYSA-N tert-butyl propanoate Chemical compound CCC(=O)OC(C)(C)C JAELLLITIZHOGQ-UHFFFAOYSA-N 0.000 description 1
- 125000005301 thienylmethyl group Chemical group [H]C1=C([H])C([H])=C(S1)C([H])([H])* 0.000 description 1
- 150000003568 thioethers Chemical class 0.000 description 1
- 229930192474 thiophene Natural products 0.000 description 1
- YCGAZNXXGKTASZ-UHFFFAOYSA-N thiophene-2,5-dicarboxylic acid Chemical compound OC(=O)C1=CC=C(C(O)=O)S1 YCGAZNXXGKTASZ-UHFFFAOYSA-N 0.000 description 1
- QERYCTSHXKAMIS-UHFFFAOYSA-N thiophene-2-carboxylic acid Chemical compound OC(=O)C1=CC=CS1 QERYCTSHXKAMIS-UHFFFAOYSA-N 0.000 description 1
- 229960004072 thrombin Drugs 0.000 description 1
- 210000001519 tissue Anatomy 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 1
- 230000000699 topical effect Effects 0.000 description 1
- 235000010487 tragacanth Nutrition 0.000 description 1
- 239000000196 tragacanth Substances 0.000 description 1
- 229940116362 tragacanth Drugs 0.000 description 1
- 230000037317 transdermal delivery Effects 0.000 description 1
- 108010060000 trigramin Proteins 0.000 description 1
- 238000003828 vacuum filtration Methods 0.000 description 1
- 229940070710 valerate Drugs 0.000 description 1
- NQPDZGIKBAWPEJ-UHFFFAOYSA-N valeric acid Chemical compound CCCCC(O)=O NQPDZGIKBAWPEJ-UHFFFAOYSA-N 0.000 description 1
- 229960004295 valine Drugs 0.000 description 1
- 239000004474 valine Substances 0.000 description 1
- 230000006439 vascular pathology Effects 0.000 description 1
- 239000003981 vehicle Substances 0.000 description 1
- 239000002435 venom Substances 0.000 description 1
- 210000001048 venom Anatomy 0.000 description 1
- 231100000611 venom Toxicity 0.000 description 1
- 239000007966 viscous suspension Substances 0.000 description 1
- 239000001993 wax Substances 0.000 description 1
- 239000000230 xanthan gum Substances 0.000 description 1
- 235000010493 xanthan gum Nutrition 0.000 description 1
- 229920001285 xanthan gum Polymers 0.000 description 1
- 229940082509 xanthan gum Drugs 0.000 description 1
- 229930195724 β-lactose Natural products 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- 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
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/04—Indoles; Hydrogenated indoles
- C07D209/30—Indoles; Hydrogenated indoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to carbon atoms of the hetero ring
- C07D209/42—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
- C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
- C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
- C07D333/26—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D333/38—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
Definitions
- the invention relates generally to inhibiting the binding of fibrinogen and other proteins to blood platelets, and inhibiting the aggregation of blood platelets specifically to the gp Hb/IIIa fibrinogen receptor site.
- Fibrinogen is a glycoprotein present in blood plasma that participates in platelet aggregation and in fibrin formation. Platelets are cell-like anucleated fragments, found in the blood of all mammals, that also participate in blood coagulation. Interaction of fibrinogen with the Hb/IIIa receptor site is known to be essential for normal platelet function.
- platelets When a blood vessel is damaged by an injury or other causative factor, platelets adhere to the disrupted subendothethial surface. The adherent platelets subsequently release biologically active constituents and aggregate. Aggregation is initiated by the binding of agonists, such as thrombin, epinephrine, or ADP to specific platelet membrane receptors. Stimulation by agonists results in exposure of latent fibrinogen receptors on the platelet surface, and binding of fibrinogen to the glycoprotein Hb/IIIa receptor complex.
- agonists such as thrombin, epinephrine, or ADP
- arginine- glycine-aspartic acid containing tripeptides are recognized by at least one member of a family of structurally related receptors, integrins, which are heterodimeric proteins with two membrane-spanning subunits.
- integrins structurally related receptors
- the authors state that the conformation of the tripeptide sequence in the individual proteins may be critical to recognition specificity.
- Cheresh in Proc. Nat'l Acad. Sci. U.S.A., 84, 6471-6475, (1987) describes an Arg-Gly-Asp directed adhesion receptor expressed by human endothelial cells that is structurally similar to the Hb/IIIa complex on platelets but is antigenically and functionally distinct. This receptor is directly involved in endothelial cell attachment to fibrinogen, von Willebrand factor, and vitronectin.
- a number of low molecular weight polypeptide factors have been isolated from snake venom. These factors apparently have high affinity for the gp Hb/IIIa complex.
- Huang et al. J. Biol Chem., 262, 16157-16163 (1987); Huang et al., Biochemistry, 28, 661-666 (1989) describe the primary structure of the venom trigramin which is a 72 amino acid polypeptide that contains the RGD subunit.
- Echistatin is another compound which has high affinity for the gp Hb/IIIa complex. This polypeptide contains 49 amino acids and has the RGD subunit and various disulfide bridges.
- Gan et al. J. Biol. Chem., 263, 19827-19832 (1988).
- 5,037,808 discloses the use of indolyl platelet-aggregation inhibitors which are believed to act by antagonizing interactions between fibrinogen and/or extracellular matrix proteins and the platelet gp Hb/IIIa receptor.
- U.S. Pat. No. 5,037,808 discloses guanidino peptide mimetic compounds that retain an Asp residue which inhibit platelet aggregation.
- WO9014103 describes the use of antibody-poly-peptide conjugates wherein said polypeptides contain the Arg-Gly-Asp (RGD) sequence.
- W09111458 discloses the use of large cyclic peptides containing RGD flanked by proline residues which are platelet aggregation inhibitors.
- WO9101331 discloses small cyclic platelet aggregation inhibitors which are synthetic cyclic pentapeptides containing the tripeptide sequence Arg-Gly-Asp and a thioether linkage in the cycle.
- U.S. Patent No. 5,051,405 also discloses the use of peptides and pseudopeptides such as N-amidino-piperidine-3-carboxylglycyl-L- aspartyl-L-valine that inhibit platelet aggregation and thrombus formation in mammalian blood.
- EP 445 796 discloses linear compounds which can include internal piperazinyl or piperidinyl derivatives.
- EP437 367 discloses linear polypeptide fibrinogen receptor antagonists.
- U.S. Patent No. 5,256,812 discloses compounds of the Rl-A-(W) a -X-(CH2)b- (Y) c -B-Z-COOR wherein Rl is a guandidino or amidino moiety and A and B are chosen from specific monosubstituted aryl or heterocyclic moieties.
- Fibrinogen receptor antagonist prodrugs having the structure, for example, of
- Compounds of the invention, or pharmaceutically acceptable salts thereof, are useful in the manufacture of a medicament for inhibiting the aggregation of blood platelets, inhibiting angiogenesis, inhibiting osteoclast mediated bone resorption, preventing platelet thrombosis, preventing thrombo embolism or preventing reocclusion, in a mammal.
- the invention relates to compounds having the formula
- m and p are integers independently chosen from 0-6, q is an integer chosen from 1-6, and R ⁇ is selected from the group consisting of hydrogen, hydro xyl,
- D and E are independently chosen from C, NH, N(CH3), N(CH2CH3), N(CHCH2CH2), O and S
- R ⁇ is independently selected from the group consisting of hydrogen, Ci-io alkyl, aryl, aryl C 1-8 alkyl-, oxo, thio, amino, amino Ci-8 alkyl-,
- Ci-6 dialkylamino- Ci-6 dialkylamino Cl-8 alkyl-, Ci-4 alkoxy Ci-4 alkoxy Ci-6 alkyl-, carboxy, carboxy Ci-6 alkyl-, Ci-3 alkoxycarbonyl-, C ⁇ -3 alkoxycarbonyl C ⁇ -6 alkyl-, carboxyoxy-, carboxy C ⁇ _6 alkyloxy-, hydroxy, and hydroxy C ⁇ _6 alkyl;
- a and B which form a fused ring system sharing adjacent carbon and nitrogen atoms, are defined as follows:
- A is a 5, 6 or 7 membered saturated, partially saturated, or unsaturated ring containing 1, 2 or 3 heteroatoms selected from O, S or N;
- B is a 5, 6 or 7 membered saturated, partially saturated, or unsaturated ring containing 1, 2 or 3 heteroatoms selected from 0, S or N;
- Rl is hydrogen
- Ci-6 alkyl carboxy, carboxy Ci-6 alkyl-, Ci-6 alkylcarboxy -,
- Ci-8 alkyloxycarbonylamino- Ci-8 alkyloxycarbonylamino-, Ci-8 alkyloxycarbonylamino Ci-8 alkyl-, aryloxycarbonylamino- , aryloxycarbonylamino Cl-8 alkyl-, aryl Cl-8 alkyloxycarbonylamino-, aryl Cl-8 alkyloxycarbonylamino Cl-8 alkyl-, Cl-8 alkylcarbonylamino-,
- R4 IS hydrogen
- One class of compounds of the invention has the formula
- R5 is independently selected from the group consisting of hydrogen
- V 1 and V 2 is N or CR e and G is CH 2 , CH 2 -CH 2 ,
- R" is H, branched or straight chain Ci-4 substituted or unsubstituted alkyl, branched or straight chain lower alkenyl, Ci-4 alkylaryl, substituted aryl, or 5 or 6 membered heteroaryl containing 1, 2, or 3 N, S, or O heteroatoms wherein substituted alkyl is hydroxy- substituted or Cl-4 alkoxy- substituted alkyl, and wherein substituted aryl is substituted by one, two or three of the following groups: halogen, Cl-4 alkoxy, hydroxy, or C 1-4 alkyl; R ' is H, branched or straight chain Cl-4 substituted or unsubstituted alkyl, branched or straight chain lower alkenyl, Cl-4 alkylaryl, substituted aryl, or 5 or 6 membered heteroaryl containing 1, 2, or 3 N, S, or O 5 heteroatoms wherein substituted alkyl is hydroxy- substituted or Cl-4 alkoxy-substituted alkyl, and where
- R° is is H, branched or straight chain Cl-4 substituted or unsubstituted alkyl, branched or straight chain lower alkenyl, Cl-4 alkylaryl, substituted aryl, or 5 or 6 membered heteroaryl containing 1, 2, or 3 N, S, or 0 heteroatoms 20 wherein substituted alkyl is hydroxy- substituted or Cl-4 alkoxy-substituted alkyl, and wherein substituted aryl is substituted by one, two or three of the following groups: halogen, Cl-4 alkoxy, hydroxy, or Cl-4 alkyl;
- RlO is H, branched or straight chain Cl-4 alkyl
- n and n' are 0-7;
- n" is 0-3.
- X is -CH2-, -0-, -CH2-0-, or -NH-C(O)-;
- R4 is -CH2CH3 or -C(CH3)3.
- the prodrugs may be administered in low amounts relative to the amounts of antagonist that would ordinarily be administered.
- the prodrugs may be administered orally.
- the prodrugs retain structural integrity while passing though the gastrointestinal system, and are effectively delivered to cells. They are subjected to metabolic reactions to form the active acid which then interacts with the platelet receptor site.
- a number of very serious diseases and disorders involve hyperthrombotic complications which lead to intravascular thrombi and emboli. Myocardial infarction, stroke, phlebitis and a number of other serious conditions create the need for novel and effective fibrinogen receptor antagonists.
- fibrinogen receptor antagonist activity is based on evaluation of inhibition of ADP- stimulated platelets. Aggregation requires that fibrinogen bind to and occupy the platelet fibrinogen receptor site. Inhibitors of fibrinogen binding inhibit aggregation.
- human platelets are isolated from fresh blood, collected into acid citrate/dextrose by differential centrifugation followed by gel filtration on Sepharose 2B in divalent ion- free Tyrode's buffer (pH 7.4) containing 2% bovine serum albumin.
- Platelet aggregation is measured at 37°C in a Chronolog aggregometer.
- the reaction mixture contains gel-filtered human platelets (2 x 108 per ml), fibrinogen (100 micrograms per ml (ug/ml)), Ca2+ (1 mM), and the compound to be tested.
- the aggregation is initiated by adding 10 mM ADP 1 minute after the other components are added.
- the reaction is then allowed to proceed for at least 2 minutes.
- the extent of inhibition of aggregation is expressed as the percentage of the rate of aggregation observed in the absence of inhibitor.
- the IC50 i* 3 the dose of a particular compound inhibiting aggregation by 50% relative to a control lacking the compound.
- the active amidine-acids of these compounds have been evaluated in vitro and found to have an IC50 for inhibiting platelet aggregation of between about 1.0 nM and 10,000 nM.
- these compounds are useful for treating mammals suffering from a bone condition caused or mediated by increased bone resorption, who are in need of such therapy.
- Pharmacologically effective amounts of the compounds, including pharmaceutically acceptable salts thereof, are administered to the mammal, to inhibit the activity of mammalian osteoclasts.
- these compounds are useful for treating angiogenesis (formation of new blood vessels). It has been postulated that the growth of tumors depends on an adequate blood supply, which in turn is dependent on the growth of new vessels into the tumor. Inhibition of angiogenesis can cause tumor regression in animal models. (See, Harrison's Principles of Internal Medicine. 12th ed., 1991). These compounds are therefore useful in the treatment of cancer for inhibiting tumor growth. (See e.g., Brooks et al., Cell, 79:1157-1164 (1994)).
- salts shall mean non-toxic salts of the compounds of this invention which are generally prepared by reacting the free base with a suitable organic or inorganic acid.
- Representative salts include the following salts: acetate, benzenesulfonate, benzoate, bicarbonate, bisulfate, bitartrate, borate, bromide, calcium edetate, camsylate, carbonate, chloride, clavulanate, citrate, dihydrochloride, edetate, edisylate, estolate, esylate, fumarate, gluceptate, gluconate, glutamate, glycollylarsanilate, hexylresorcinate, hydrabamine, hydrobromide, hydrochloride, hydroxynapthoate, iodide, isothionate, lactate, lactobionate, laurate, malate, maleate, mandelate, mesylate, methylbromide, methyl
- compositions and polymorphs of the general formula are within the present invention.
- pharmaceutically effective amount shall mean that amount of a drug or pharmaceutical agent that will elicit the biological or medical response of a tissue, system or animal that is being sought by a researcher or clinician.
- anti-coagulant shall include heparin, and warfarin.
- thrombolytic agent shall include agents such as streptokinase and tissue plasminogen activator.
- platelet anti-aggregation agent shall include agents such as aspirin and dipyridamole.
- alkyl means straight or branched alkane containing 1 to about 10 carbon atoms, e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, iso-amyl, hexy, octyl radicals and the like, straight or branched alkene containing 2 to about 10 carbon atoms, e.g., propylenyl, buten-1-yl, isobutenyl, pentenylen-1-yl, 2,2-methylbuten-l-yl, 3-methylbuten-l-yl, hexen-1-yl, hepten-1-yl, and octen-1-yl radicals and the like, or straight or branched alkyne containing 2 to about 10 carbon atoms, e.g., ethynyl
- aryl means a 5- or 6-membered aromatic ring containing 0, 1, or 2 heteroatoms selected from 0, N, and S, e.g. phenyl, pyridine, pyrimidine, imidazole, thiophene, oxazole, isoxazole, thiazole, and amino- and halogen- substituted derivatives thereof.
- alkyloxy or “alkoxy” include an alkyl portion where alkyl is as defined above, e.g., methyloxy, propyloxy, and butyloxy.
- arylalkyl and “alkylaryl” include an alkyl portion where alkyl is as defined above and to include an aryl portion where aryl is as defined above.
- arylalkyl examples include benzyl, fluorobenzyl, chlorobenzyl, phenylethyl, phenylpropyl, fluorophenylethyl, chlorophenylethyl, thienylmethyl, thienylethyl, and thienylpropyl.
- alkylaryl examples include toluene, ethylbenzene, propylbenzene, methylpyridine, ethylpyridine, propylpyridine, butylpyridine, butenylpyridine, and pentenylpyridine.
- halogen includes fluorine, chlorine, iodine and bromine.
- oxy means an oxygen (O) atom.
- thio means a sulfur (S) atom.
- Oxone potassium peroxymonosulfate
- LDA Lithium diisopropylamide
- PYCLU Chloro-N,N,N',N'-bis(pentamethylene)formamidinium hexafluorophosphate
- the compounds of the present invention can be administered in such oral forms as tablets, capsules (each of which includes sustained release or timed release formulations), pills, powders, granules, elixirs, tinctures, suspensions, syrups, and emulsions. Likewise, they may be administered in intravenous (bolus or infusion), intraperitoneal, subcutaneous, or intramusculsar form, all using forms well known to those of ordinary skill in the pharmaceutical arts. An effective but non-toxic amount of the compound desired can be employed as an anti-aggregation agent.
- Compounds of the invention are useful in the manufacture of a medicament for inhibiting binding of fibrinogen to the platelet membrane glycoprotein complex Hb/IIIa receptor, preventing platelet thrombosis, thromboembolism and reocclusion during and after thrombolytic therapy or after angioplasty or coronary artery bypass procedures, and preventing myocardial infarction in a mammal.
- Compounds of the invention may be administered to patients where prevention of thrombosis by inhibiting binding of fibrinogen to the platelet membrane glycoprotein complex Hb/IIIa receptor is desired.
- peripheral arteries arterial grafts, carotid endarterectomy
- cardiovascular surgery where manipulation of arteries and organs, and/or the interaction of platelets with artificial surfaces, leads to platelet aggregation and consumption.
- the aggregated platelets may form thrombi and thromboemboli.
- Compounds of this invention may be administered to these surgical patients to prevent the formation of thrombi and thromboemboli.
- Extracorporeal circulation is routinely used for cardiovascular surgery in order to oxygenate blood. Platelets adhere to surfaces of the extracorporeal circuit. Adhesion is dependent on the interaction between gp Hb/IIIa on the platelet membranes and fibrinogen adsorbed to the surface of the circuit. (Gluszko et al., Amer. J. Physiol, 252(H), 615-621 (1987)). Platelets released from artificial surfaces show impaired hemostatic function. Compounds of the invention may be administered to prevent adhesion.
- the dosage regimen utilizing the compounds of the present invention is selected in accordance with a variety of factors including type, species, age, weight, sex and medical condition of the patient; the severity of the condition to be treated; the route of administration; the renal and hepatic function of the patient; and the particular compound or salt thereof employed.
- Oral dosages of the present invention when used for the indicated effects, will range between about 0.01 mg per kg of body weight per day (mg/kg/day) to about 100 mg kg/day and preferably 0.01-100 mg kg/day and most preferably 0.01-20 mg/kg/day.
- a typical 90 kg patient would receive oral dosages ranging between about 0.9 mg/day and about 9 g/day, most preferably between about 0.9 mg/day and 1.8 g/day.
- Suitable pharmaceutical oral compositions such as tablets or capsules may contain , for example, 10 mg, 100 mg, 200 mg and 500 mg. Intravenously, the most preferred doses will range from about 1 to about 10 mg/kg/minute during a constant rate infusion.
- compounds of the present invention may be administered in divided doses of two, three, or four times daily.
- preferred compounds for the present invention can be administered in intranasal form via topical use of suitable intranasal vehicles, or via transdermal routes, using those forms of transdermal skin patches well known to those of ordinary skill in that art.
- the dosage administration will, or course, be continuous rather that intermittent throughout the dosage regime.
- the compounds herein described in detail are typically administered in admixture with suitable pharmaceutical diluents, excipients or carriers (collectively referred to herein as "carrier” materials) suitably selected with respect to the intended form of administration, that is, oral tablets, capsules, elixirs, syrups and the like, and consistent with convention pharmaceutical practices.
- carrier suitable pharmaceutical diluents, excipients or carriers
- the compound for oral administration in the form of a tablet or capsule, can be combined with an oral, non-toxic, pharmaceutically acceptable, inert carrier such as lactose, starch, sucrose, glucose, methyl cellulose, magnesium stearate, dicalcium phosphate, calcium sulfate, mannitol, sorbitol and the like;
- an oral, non-toxic, pharmaceutically acceptable, inert carrier such as lactose, starch, sucrose, glucose, methyl cellulose, magnesium stearate, dicalcium phosphate, calcium sulfate, mannitol, sorbitol and the like
- the oral prodrug components can be combined with any oral, non-toxic, pharmaceutically acceptable inert carrier such as ethanol, glycerol, water and the like.
- suitable binders, lubricants, distintegrating agents and coloring agents can also be incorporated into the mixture.
- Suitable binders include starch, gelatin, natural sugars such as glucose or beta-lactose, corn-sweeteners, natural and synthetic gums such as acacia, tragacanth or sodium alginate, carboxymethylcellulose, polyethylene glycol, waxes and the like.
- Lubricants used in these dosage forms include sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride and the like.
- Disintegrators include, without limitation, starch methyl cellulose, agar, bentonite, xanthan gum and the like.
- Active drug can also be co-administered with the usual doses of suitable anticoagulation agents, such as heparin or warfarin (typically given in tablet doses between 1 and 20 mg daily during administration of the active drug), or thrombolytic agents such as tissue plasminogen activator (typically given in i.v. doses of between 20 and 150 mg over two hour period prior to or during administration of the active drug), to achieve beneficial effects in the treatment of various vascular pathologies.
- suitable anticoagulation agents such as heparin or warfarin (typically given in tablet doses between 1 and 20 mg daily during administration of the active drug), or thrombolytic agents such as tissue plasminogen activator (typically given in i.v. doses of between 20 and 150 mg over two hour period prior to or during administration of the active drug)
- Example 3-4 was prepared in a manner substantially the same as for example - Rf (EtOAc): 0.56.
- Example 3 ⁇ 7 was prepared in a manner substantially the same as for example 1-5.
- Rf 80% EtOAc / hexane: 0.40.
- 4-6 was prepared substantially the same as for example 1-5.
- iH NMR 400 MHz; DMSO-d 6 ) d 10.90 (bs, IH); 8.33 (t, IH); 8.27-8.25 (d, IH); 7.70-7.69 (m, 4H); 7.62-7.61 (m, 4H); 7.29-7.27 (d, 2H); 7.05-7.07 (d, 2H); 5.27 (s, 2H); 4.05 (m, IH); 3.49 (m, IH); 3.45 (m, IH); 2.3 (s, 3H); 0.96- 0.93 (t, 3H).
- 5-5 was prepared in a manner substantially similiar as for example 1-5.
- An intravenous dosage form of the above-indicated active compound is prepared as follows:
- the active compound is dissolved at room temperature in a previously prepared solution of sodium chloride, citric acid, and sodium citrate in Water for Injection (USP, see page 1636 of United States Pharmacopeia/National Formulary for 1995, published by United States Pharmacopeial Convention, Inc., Rockville, Maryland, copyright 1994.
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Abstract
Applications Claiming Priority (5)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US3690197P | 1997-02-06 | 1997-02-06 | |
US36901P | 1997-02-06 | ||
GB9707489 | 1997-04-14 | ||
GBGB9707489.2A GB9707489D0 (en) | 1997-04-14 | 1997-04-14 | Fibrinogen receptor antagonist prodrugs |
PCT/US1998/001998 WO1998034935A1 (fr) | 1997-02-06 | 1998-02-02 | Promedicaments antagonistes de recepteur de fibrinogene |
Publications (2)
Publication Number | Publication Date |
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EP1023295A1 true EP1023295A1 (fr) | 2000-08-02 |
EP1023295A4 EP1023295A4 (fr) | 2001-01-24 |
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ID=26311371
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Application Number | Title | Priority Date | Filing Date |
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EP98906092A Withdrawn EP1023295A4 (fr) | 1997-02-06 | 1998-02-02 | Promedicaments antagonistes de recepteur de fibrinogene |
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EP (1) | EP1023295A4 (fr) |
JP (1) | JP2001512439A (fr) |
AU (1) | AU747293B2 (fr) |
CA (1) | CA2279927A1 (fr) |
WO (1) | WO1998034935A1 (fr) |
Families Citing this family (7)
Publication number | Priority date | Publication date | Assignee | Title |
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ES2263179T3 (es) | 1996-06-14 | 2006-12-01 | Biocryst Pharmaceuticals Inc. | Compuestos de clopentano sustituido como inhibidores de la neuraminidasa. |
JP4102022B2 (ja) | 1997-12-17 | 2008-06-18 | バイオクリスト・ファマシューティカルズ インク. | ノイラミニダーゼ阻害剤として有用な置換シクロペンタン及びシクロペンテン化合物 |
US6025358A (en) * | 1998-06-11 | 2000-02-15 | G. D. Searle & Co. | Double prodrugs of potent GP IIb/IIIa antagonists |
AU1520300A (en) | 1998-11-05 | 2000-05-29 | Biocryst Pharmaceuticals, Inc. | New cyclopentane and cyclopentene compounds and use for detecting influenza virus |
WO2000075129A1 (fr) * | 1999-06-07 | 2000-12-14 | Shire Biochem Inc. | Inhibiteurs d'integrine thiophene |
ES2394550T3 (es) * | 2008-02-21 | 2013-02-01 | Sanofi | Clorotiofen-amidas como inhibidores de los factores Xa de coagulación y trombina |
CN111943818B (zh) * | 2020-09-16 | 2023-01-24 | 天津均凯农业科技有限公司 | 一种制备4,4′-双三氟甲基二苯醚的方法 |
Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1994008962A1 (fr) * | 1992-10-14 | 1994-04-28 | Merck & Co., Inc. | Antagonistes des recepteurs du fibrinogene |
WO1994008577A1 (fr) * | 1992-10-14 | 1994-04-28 | Merck & Co., Inc. | Antagonistes des recepteurs du fibrinogene |
WO1994012181A1 (fr) * | 1992-12-01 | 1994-06-09 | Merck & Co., Inc. | Antagonistes des recepteurs du fibrinogene |
WO1994018981A1 (fr) * | 1993-02-22 | 1994-09-01 | Merck & Co., Inc. | Antagonistes des recepteurs de fibrinogene |
EP0656348A2 (fr) * | 1993-12-03 | 1995-06-07 | F. Hoffmann-La Roche Ag | Dérivés d'acide acérique comme médicaments |
-
1998
- 1998-02-02 JP JP53482498A patent/JP2001512439A/ja active Pending
- 1998-02-02 AU AU61413/98A patent/AU747293B2/en not_active Ceased
- 1998-02-02 WO PCT/US1998/001998 patent/WO1998034935A1/fr active IP Right Grant
- 1998-02-02 EP EP98906092A patent/EP1023295A4/fr not_active Withdrawn
- 1998-02-02 CA CA002279927A patent/CA2279927A1/fr not_active Abandoned
Patent Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1994008962A1 (fr) * | 1992-10-14 | 1994-04-28 | Merck & Co., Inc. | Antagonistes des recepteurs du fibrinogene |
WO1994008577A1 (fr) * | 1992-10-14 | 1994-04-28 | Merck & Co., Inc. | Antagonistes des recepteurs du fibrinogene |
WO1994012181A1 (fr) * | 1992-12-01 | 1994-06-09 | Merck & Co., Inc. | Antagonistes des recepteurs du fibrinogene |
WO1994018981A1 (fr) * | 1993-02-22 | 1994-09-01 | Merck & Co., Inc. | Antagonistes des recepteurs de fibrinogene |
EP0656348A2 (fr) * | 1993-12-03 | 1995-06-07 | F. Hoffmann-La Roche Ag | Dérivés d'acide acérique comme médicaments |
Non-Patent Citations (1)
Title |
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See also references of WO9834935A1 * |
Also Published As
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JP2001512439A (ja) | 2001-08-21 |
AU6141398A (en) | 1998-08-26 |
WO1998034935A1 (fr) | 1998-08-13 |
EP1023295A4 (fr) | 2001-01-24 |
AU747293B2 (en) | 2002-05-16 |
CA2279927A1 (fr) | 1998-08-13 |
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