NO329349B1 - Himbacinanalogforbindelser, farmasoytiske preparater som omfatter minst en slik forbindelse, samt anvendelse av forbindelsene til fremstilling av medikamenter for hemming av trombinreseptorer - Google Patents
Himbacinanalogforbindelser, farmasoytiske preparater som omfatter minst en slik forbindelse, samt anvendelse av forbindelsene til fremstilling av medikamenter for hemming av trombinreseptorer Download PDFInfo
- Publication number
- NO329349B1 NO329349B1 NO20042021A NO20042021A NO329349B1 NO 329349 B1 NO329349 B1 NO 329349B1 NO 20042021 A NO20042021 A NO 20042021A NO 20042021 A NO20042021 A NO 20042021A NO 329349 B1 NO329349 B1 NO 329349B1
- Authority
- NO
- Norway
- Prior art keywords
- alkyl
- phenyl
- compounds
- mmol
- group
- Prior art date
Links
- 150000001875 compounds Chemical class 0.000 title claims abstract description 70
- 229940079593 drug Drugs 0.000 title claims description 12
- 239000003814 drug Substances 0.000 title claims description 12
- 102000003790 Thrombin receptors Human genes 0.000 title claims description 9
- 108090000166 Thrombin receptors Proteins 0.000 title claims description 9
- 230000002401 inhibitory effect Effects 0.000 title claims description 3
- 239000008194 pharmaceutical composition Substances 0.000 title abstract 2
- 238000002360 preparation method Methods 0.000 title description 23
- 150000003839 salts Chemical class 0.000 claims abstract description 13
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 10
- 208000007536 Thrombosis Diseases 0.000 claims abstract description 5
- 206010002383 Angina Pectoris Diseases 0.000 claims abstract description 4
- 201000001320 Atherosclerosis Diseases 0.000 claims abstract description 4
- 206010019280 Heart failures Diseases 0.000 claims abstract description 4
- 206010020772 Hypertension Diseases 0.000 claims abstract description 4
- 206010003119 arrhythmia Diseases 0.000 claims abstract description 4
- 230000006793 arrhythmia Effects 0.000 claims abstract description 4
- 208000037803 restenosis Diseases 0.000 claims abstract description 4
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 21
- 229910052739 hydrogen Inorganic materials 0.000 claims description 15
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 13
- 229910052799 carbon Inorganic materials 0.000 claims description 9
- 125000004076 pyridyl group Chemical group 0.000 claims description 8
- 125000001424 substituent group Chemical group 0.000 claims description 7
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical group [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 6
- 208000027866 inflammatory disease Diseases 0.000 claims description 6
- 238000004519 manufacturing process Methods 0.000 claims description 6
- 125000006272 (C3-C7) cycloalkyl group Chemical group 0.000 claims description 5
- 201000006474 Brain Ischemia Diseases 0.000 claims description 5
- 206010008120 Cerebral ischaemia Diseases 0.000 claims description 5
- 206010008118 cerebral infarction Diseases 0.000 claims description 5
- 208000023504 respiratory system disease Diseases 0.000 claims description 5
- 125000001544 thienyl group Chemical group 0.000 claims description 5
- 239000001257 hydrogen Substances 0.000 claims description 4
- 239000000825 pharmaceutical preparation Substances 0.000 claims description 4
- 206010014498 Embolic stroke Diseases 0.000 claims description 3
- 206010018364 Glomerulonephritis Diseases 0.000 claims description 3
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 3
- 208000018262 Peripheral vascular disease Diseases 0.000 claims description 3
- 206010043647 Thrombotic Stroke Diseases 0.000 claims description 3
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 3
- 239000003937 drug carrier Substances 0.000 claims description 3
- 229910052736 halogen Inorganic materials 0.000 claims description 3
- 150000002367 halogens Chemical class 0.000 claims description 3
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 3
- 208000010125 myocardial infarction Diseases 0.000 claims description 3
- 125000000335 thiazolyl group Chemical group 0.000 claims description 3
- 125000006273 (C1-C3) alkyl group Chemical group 0.000 claims description 2
- 125000006274 (C1-C3)alkoxy group Chemical group 0.000 claims description 2
- 125000004890 (C1-C6) alkylamino group Chemical group 0.000 claims description 2
- 125000006528 (C2-C6) alkyl group Chemical group 0.000 claims description 2
- MDFFNEOEWAXZRQ-UHFFFAOYSA-N aminyl Chemical compound [NH2] MDFFNEOEWAXZRQ-UHFFFAOYSA-N 0.000 claims description 2
- 208000013557 cerebral hemisphere cancer Diseases 0.000 claims description 2
- 201000008860 cerebrum cancer Diseases 0.000 claims description 2
- 125000002541 furyl group Chemical group 0.000 claims description 2
- 125000000719 pyrrolidinyl group Chemical group 0.000 claims description 2
- 125000002393 azetidinyl group Chemical group 0.000 claims 1
- 238000000034 method Methods 0.000 abstract description 29
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 abstract description 8
- -1 carboxy, sulfinyl Chemical group 0.000 abstract description 6
- 201000010099 disease Diseases 0.000 abstract description 4
- 229940124530 sulfonamide Drugs 0.000 abstract description 3
- 150000003456 sulfonamides Chemical class 0.000 abstract description 3
- 125000001072 heteroaryl group Chemical group 0.000 abstract description 2
- 150000003862 amino acid derivatives Chemical class 0.000 abstract 1
- 201000010235 heart cancer Diseases 0.000 abstract 1
- 208000024348 heart neoplasm Diseases 0.000 abstract 1
- 125000005017 substituted alkenyl group Chemical group 0.000 abstract 1
- 125000000547 substituted alkyl group Chemical group 0.000 abstract 1
- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 abstract 1
- 239000000203 mixture Substances 0.000 description 70
- 239000000243 solution Substances 0.000 description 65
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 60
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 36
- 239000000047 product Substances 0.000 description 31
- 239000012074 organic phase Substances 0.000 description 25
- 238000006243 chemical reaction Methods 0.000 description 23
- 239000012267 brine Substances 0.000 description 22
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 22
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 21
- 235000019439 ethyl acetate Nutrition 0.000 description 18
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 15
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 15
- 238000005481 NMR spectroscopy Methods 0.000 description 15
- 210000004369 blood Anatomy 0.000 description 15
- 239000008280 blood Substances 0.000 description 15
- 239000002253 acid Substances 0.000 description 12
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical class CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 12
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 11
- 230000002776 aggregation Effects 0.000 description 10
- 238000004220 aggregation Methods 0.000 description 10
- 239000012528 membrane Substances 0.000 description 10
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 9
- 239000008346 aqueous phase Substances 0.000 description 9
- 239000000725 suspension Substances 0.000 description 9
- 239000003856 thrombin receptor antagonist Substances 0.000 description 9
- GQHTUMJGOHRCHB-UHFFFAOYSA-N 2,3,4,6,7,8,9,10-octahydropyrimido[1,2-a]azepine Chemical compound C1CCCCN2CCCN=C21 GQHTUMJGOHRCHB-UHFFFAOYSA-N 0.000 description 8
- NGNBDVOYPDDBFK-UHFFFAOYSA-N 2-[2,4-di(pentan-2-yl)phenoxy]acetyl chloride Chemical compound CCCC(C)C1=CC=C(OCC(Cl)=O)C(C(C)CCC)=C1 NGNBDVOYPDDBFK-UHFFFAOYSA-N 0.000 description 8
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 8
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 8
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 8
- CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 description 8
- 230000008569 process Effects 0.000 description 8
- 108090000765 processed proteins & peptides Proteins 0.000 description 8
- 239000011347 resin Substances 0.000 description 8
- 229920005989 resin Polymers 0.000 description 8
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 8
- 150000001299 aldehydes Chemical class 0.000 description 7
- 150000001412 amines Chemical class 0.000 description 7
- 239000007787 solid Substances 0.000 description 7
- 150000003462 sulfoxides Chemical class 0.000 description 7
- QKNYBSVHEMOAJP-UHFFFAOYSA-N 2-amino-2-(hydroxymethyl)propane-1,3-diol;hydron;chloride Chemical compound Cl.OCC(N)(CO)CO QKNYBSVHEMOAJP-UHFFFAOYSA-N 0.000 description 6
- 239000005909 Kieselgur Substances 0.000 description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- 230000027455 binding Effects 0.000 description 6
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 6
- 239000004615 ingredient Substances 0.000 description 6
- YNESATAKKCNGOF-UHFFFAOYSA-N lithium bis(trimethylsilyl)amide Chemical compound [Li+].C[Si](C)(C)[N-][Si](C)(C)C YNESATAKKCNGOF-UHFFFAOYSA-N 0.000 description 6
- 239000003921 oil Substances 0.000 description 6
- UEZVMMHDMIWARA-UHFFFAOYSA-M phosphonate Chemical compound [O-]P(=O)=O UEZVMMHDMIWARA-UHFFFAOYSA-M 0.000 description 6
- CSRZQMIRAZTJOY-UHFFFAOYSA-N trimethylsilyl iodide Chemical compound C[Si](C)(C)I CSRZQMIRAZTJOY-UHFFFAOYSA-N 0.000 description 6
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 5
- YZCKVEUIGOORGS-NJFSPNSNSA-N Tritium Chemical group [3H] YZCKVEUIGOORGS-NJFSPNSNSA-N 0.000 description 5
- 125000004432 carbon atom Chemical group C* 0.000 description 5
- 230000000694 effects Effects 0.000 description 5
- KDLHZDBZIXYQEI-UHFFFAOYSA-N palladium Substances [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 5
- 238000000746 purification Methods 0.000 description 5
- 238000010898 silica gel chromatography Methods 0.000 description 5
- 239000007858 starting material Substances 0.000 description 5
- 238000012360 testing method Methods 0.000 description 5
- 229910052722 tritium Inorganic materials 0.000 description 5
- KCXVZYZYPLLWCC-UHFFFAOYSA-N EDTA Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 description 4
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 4
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 4
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 4
- 208000006011 Stroke Diseases 0.000 description 4
- 108090000190 Thrombin Proteins 0.000 description 4
- 239000003146 anticoagulant agent Substances 0.000 description 4
- 208000035475 disorder Diseases 0.000 description 4
- 239000012039 electrophile Substances 0.000 description 4
- DEFVIWRASFVYLL-UHFFFAOYSA-N ethylene glycol bis(2-aminoethyl)tetraacetic acid Chemical compound OC(=O)CN(CC(O)=O)CCOCCOCCN(CC(O)=O)CC(O)=O DEFVIWRASFVYLL-UHFFFAOYSA-N 0.000 description 4
- 239000012458 free base Substances 0.000 description 4
- 239000007789 gas Substances 0.000 description 4
- 239000008187 granular material Substances 0.000 description 4
- 239000012948 isocyanate Substances 0.000 description 4
- 150000002513 isocyanates Chemical class 0.000 description 4
- 102000005962 receptors Human genes 0.000 description 4
- 108020003175 receptors Proteins 0.000 description 4
- 150000003457 sulfones Chemical class 0.000 description 4
- 229960004072 thrombin Drugs 0.000 description 4
- LWIHDJKSTIGBAC-UHFFFAOYSA-K tripotassium phosphate Chemical compound [K+].[K+].[K+].[O-]P([O-])([O-])=O LWIHDJKSTIGBAC-UHFFFAOYSA-K 0.000 description 4
- 229960000549 4-dimethylaminophenol Drugs 0.000 description 3
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 description 3
- OFOBLEOULBTSOW-UHFFFAOYSA-N Malonic acid Chemical compound OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 3
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 3
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 3
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 description 3
- 125000003342 alkenyl group Chemical group 0.000 description 3
- 238000004458 analytical method Methods 0.000 description 3
- 239000004305 biphenyl Substances 0.000 description 3
- 235000010290 biphenyl Nutrition 0.000 description 3
- 125000006267 biphenyl group Chemical group 0.000 description 3
- 229930003827 cannabinoid Natural products 0.000 description 3
- 239000003557 cannabinoid Substances 0.000 description 3
- 239000003054 catalyst Substances 0.000 description 3
- 210000004027 cell Anatomy 0.000 description 3
- 150000001805 chlorine compounds Chemical class 0.000 description 3
- OAYLNYINCPYISS-UHFFFAOYSA-N ethyl acetate;hexane Chemical compound CCCCCC.CCOC(C)=O OAYLNYINCPYISS-UHFFFAOYSA-N 0.000 description 3
- 125000005843 halogen group Chemical group 0.000 description 3
- 238000000338 in vitro Methods 0.000 description 3
- 230000005764 inhibitory process Effects 0.000 description 3
- 239000011981 lindlar catalyst Substances 0.000 description 3
- 239000007788 liquid Substances 0.000 description 3
- 239000012071 phase Substances 0.000 description 3
- ZUOUZKKEUPVFJK-UHFFFAOYSA-N phenylbenzene Natural products C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 description 3
- 238000012746 preparative thin layer chromatography Methods 0.000 description 3
- 102000004169 proteins and genes Human genes 0.000 description 3
- 108090000623 proteins and genes Proteins 0.000 description 3
- 239000011734 sodium Substances 0.000 description 3
- 208000010110 spontaneous platelet aggregation Diseases 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- YBBRCQOCSYXUOC-UHFFFAOYSA-N sulfuryl dichloride Chemical class ClS(Cl)(=O)=O YBBRCQOCSYXUOC-UHFFFAOYSA-N 0.000 description 3
- 239000003826 tablet Substances 0.000 description 3
- GRWFGVWFFZKLTI-IUCAKERBSA-N (-)-α-pinene Chemical compound CC1=CC[C@@H]2C(C)(C)[C@H]1C2 GRWFGVWFFZKLTI-IUCAKERBSA-N 0.000 description 2
- CYPYTURSJDMMMP-WVCUSYJESA-N (1e,4e)-1,5-diphenylpenta-1,4-dien-3-one;palladium Chemical compound [Pd].[Pd].C=1C=CC=CC=1\C=C\C(=O)\C=C\C1=CC=CC=C1.C=1C=CC=CC=1\C=C\C(=O)\C=C\C1=CC=CC=C1.C=1C=CC=CC=1\C=C\C(=O)\C=C\C1=CC=CC=C1 CYPYTURSJDMMMP-WVCUSYJESA-N 0.000 description 2
- GBBJBUGPGFNISJ-YDQXZVTASA-N (4as,7r,8as)-9,9-dimethyltetrahydro-4h-4a,7-methanobenzo[c][1,2]oxazireno[2,3-b]isothiazole 3,3-dioxide Chemical group C1S(=O)(=O)N2O[C@@]32C[C@@H]2C(C)(C)[C@]13CC2 GBBJBUGPGFNISJ-YDQXZVTASA-N 0.000 description 2
- 238000005160 1H NMR spectroscopy Methods 0.000 description 2
- IKHGUXGNUITLKF-UHFFFAOYSA-N Acetaldehyde Chemical compound CC=O IKHGUXGNUITLKF-UHFFFAOYSA-N 0.000 description 2
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 2
- PAYRUJLWNCNPSJ-UHFFFAOYSA-N Aniline Chemical compound NC1=CC=CC=C1 PAYRUJLWNCNPSJ-UHFFFAOYSA-N 0.000 description 2
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- 206010006458 Bronchitis chronic Diseases 0.000 description 2
- 102000009135 CB2 Cannabinoid Receptor Human genes 0.000 description 2
- 108010073376 CB2 Cannabinoid Receptor Proteins 0.000 description 2
- KXDHJXZQYSOELW-UHFFFAOYSA-M Carbamate Chemical compound NC([O-])=O KXDHJXZQYSOELW-UHFFFAOYSA-M 0.000 description 2
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 description 2
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 2
- TWRXJAOTZQYOKJ-UHFFFAOYSA-L Magnesium chloride Chemical compound [Mg+2].[Cl-].[Cl-] TWRXJAOTZQYOKJ-UHFFFAOYSA-L 0.000 description 2
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 2
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 2
- 208000001132 Osteoporosis Diseases 0.000 description 2
- NFHFRUOZVGFOOS-UHFFFAOYSA-N Pd(PPh3)4 Substances [Pd].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 NFHFRUOZVGFOOS-UHFFFAOYSA-N 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- 102000002020 Protease-activated receptors Human genes 0.000 description 2
- 108050009310 Protease-activated receptors Proteins 0.000 description 2
- SMWDFEZZVXVKRB-UHFFFAOYSA-N Quinoline Chemical compound N1=CC=CC2=CC=CC=C21 SMWDFEZZVXVKRB-UHFFFAOYSA-N 0.000 description 2
- 206010063897 Renal ischaemia Diseases 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 2
- 150000007513 acids Chemical class 0.000 description 2
- 239000000654 additive Substances 0.000 description 2
- 239000000556 agonist Substances 0.000 description 2
- 125000003545 alkoxy group Chemical group 0.000 description 2
- 125000000304 alkynyl group Chemical group 0.000 description 2
- 150000001408 amides Chemical class 0.000 description 2
- 229940127219 anticoagulant drug Drugs 0.000 description 2
- 238000003556 assay Methods 0.000 description 2
- 239000011230 binding agent Substances 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 230000037396 body weight Effects 0.000 description 2
- 206010006451 bronchitis Diseases 0.000 description 2
- 239000007975 buffered saline Substances 0.000 description 2
- 239000011575 calcium Substances 0.000 description 2
- 229910052791 calcium Inorganic materials 0.000 description 2
- 239000002775 capsule Substances 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- AOGYCOYQMAVAFD-UHFFFAOYSA-N chlorocarbonic acid Chemical class OC(Cl)=O AOGYCOYQMAVAFD-UHFFFAOYSA-N 0.000 description 2
- 238000004587 chromatography analysis Methods 0.000 description 2
- 208000023819 chronic asthma Diseases 0.000 description 2
- 208000007451 chronic bronchitis Diseases 0.000 description 2
- 238000004440 column chromatography Methods 0.000 description 2
- 238000007796 conventional method Methods 0.000 description 2
- 125000000753 cycloalkyl group Chemical group 0.000 description 2
- 206010012601 diabetes mellitus Diseases 0.000 description 2
- 210000003238 esophagus Anatomy 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- 238000009472 formulation Methods 0.000 description 2
- 238000010438 heat treatment Methods 0.000 description 2
- 238000004128 high performance liquid chromatography Methods 0.000 description 2
- 210000004072 lung Anatomy 0.000 description 2
- IVSZLXZYQVIEFR-UHFFFAOYSA-N m-xylene Chemical group CC1=CC=CC(C)=C1 IVSZLXZYQVIEFR-UHFFFAOYSA-N 0.000 description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 2
- 201000006417 multiple sclerosis Diseases 0.000 description 2
- 201000008383 nephritis Diseases 0.000 description 2
- 230000009871 nonspecific binding Effects 0.000 description 2
- YJVFFLUZDVXJQI-UHFFFAOYSA-L palladium(ii) acetate Chemical compound [Pd+2].CC([O-])=O.CC([O-])=O YJVFFLUZDVXJQI-UHFFFAOYSA-L 0.000 description 2
- 230000001575 pathological effect Effects 0.000 description 2
- 230000002093 peripheral effect Effects 0.000 description 2
- 239000000546 pharmaceutical excipient Substances 0.000 description 2
- 229910052700 potassium Inorganic materials 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- 229910000160 potassium phosphate Inorganic materials 0.000 description 2
- 235000011009 potassium phosphates Nutrition 0.000 description 2
- LJCNRYVRMXRIQR-OLXYHTOASA-L potassium sodium L-tartrate Chemical compound [Na+].[K+].[O-]C(=O)[C@H](O)[C@@H](O)C([O-])=O LJCNRYVRMXRIQR-OLXYHTOASA-L 0.000 description 2
- 102000004196 processed proteins & peptides Human genes 0.000 description 2
- 125000006239 protecting group Chemical group 0.000 description 2
- 238000003653 radioligand binding assay Methods 0.000 description 2
- 239000011541 reaction mixture Substances 0.000 description 2
- 230000002441 reversible effect Effects 0.000 description 2
- 206010039073 rheumatoid arthritis Diseases 0.000 description 2
- YGSDEFSMJLZEOE-UHFFFAOYSA-N salicylic acid Chemical compound OC(=O)C1=CC=CC=C1O YGSDEFSMJLZEOE-UHFFFAOYSA-N 0.000 description 2
- 229920006395 saturated elastomer Polymers 0.000 description 2
- 235000017557 sodium bicarbonate Nutrition 0.000 description 2
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 2
- 239000011780 sodium chloride Substances 0.000 description 2
- 235000011006 sodium potassium tartrate Nutrition 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- 201000000596 systemic lupus erythematosus Diseases 0.000 description 2
- 238000010998 test method Methods 0.000 description 2
- 230000001732 thrombotic effect Effects 0.000 description 2
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 2
- WJKHJLXJJJATHN-UHFFFAOYSA-N triflic anhydride Chemical compound FC(F)(F)S(=O)(=O)OS(=O)(=O)C(F)(F)F WJKHJLXJJJATHN-UHFFFAOYSA-N 0.000 description 2
- 210000003462 vein Anatomy 0.000 description 2
- GRWFGVWFFZKLTI-RKDXNWHRSA-N (+)-α-pinene Chemical compound CC1=CC[C@H]2C(C)(C)[C@@H]1C2 GRWFGVWFFZKLTI-RKDXNWHRSA-N 0.000 description 1
- BJEPYKJPYRNKOW-REOHCLBHSA-N (S)-malic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O BJEPYKJPYRNKOW-REOHCLBHSA-N 0.000 description 1
- FZAQRZMQRIJLKM-UHFFFAOYSA-N 1,1,1-trichloro-3-methoxypropane Chemical compound COCCC(Cl)(Cl)Cl FZAQRZMQRIJLKM-UHFFFAOYSA-N 0.000 description 1
- OZCUQZUMOUQYNG-UHFFFAOYSA-N 1-o-ethyl 5-o-methyl 3,6-dihydro-2h-pyridine-1,5-dicarboxylate Chemical compound CCOC(=O)N1CCC=C(C(=O)OC)C1 OZCUQZUMOUQYNG-UHFFFAOYSA-N 0.000 description 1
- RKXCKEHBMLDWET-UHFFFAOYSA-N 3,6-dihydro-2h-pyran-5-carbaldehyde Chemical compound O=CC1=CCCOC1 RKXCKEHBMLDWET-UHFFFAOYSA-N 0.000 description 1
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 1
- 208000000884 Airway Obstruction Diseases 0.000 description 1
- 102000007347 Apyrase Human genes 0.000 description 1
- 108010007730 Apyrase Proteins 0.000 description 1
- 208000026310 Breast neoplasm Diseases 0.000 description 1
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 description 1
- 238000006443 Buchwald-Hartwig cross coupling reaction Methods 0.000 description 1
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
- 102000018208 Cannabinoid Receptor Human genes 0.000 description 1
- 108050007331 Cannabinoid receptor Proteins 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 1
- 238000005698 Diels-Alder reaction Methods 0.000 description 1
- JOYRKODLDBILNP-UHFFFAOYSA-N Ethyl urethane Chemical group CCOC(N)=O JOYRKODLDBILNP-UHFFFAOYSA-N 0.000 description 1
- KRHYYFGTRYWZRS-UHFFFAOYSA-M Fluoride anion Chemical compound [F-] KRHYYFGTRYWZRS-UHFFFAOYSA-M 0.000 description 1
- 102000003688 G-Protein-Coupled Receptors Human genes 0.000 description 1
- 108090000045 G-Protein-Coupled Receptors Proteins 0.000 description 1
- FMPNFDSPHNUFOS-HQEQRHKESA-N Himbacine Natural products C(/[C@@H]1[C@H]2CCCC[C@@H]2C[C@@H]2C(=O)O[C@H]([C@H]12)C)=C\[C@@H]1CCC[C@H](C)N1C FMPNFDSPHNUFOS-HQEQRHKESA-N 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- 206010061218 Inflammation Diseases 0.000 description 1
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 1
- 238000003231 Lowry assay Methods 0.000 description 1
- 238000009013 Lowry's assay Methods 0.000 description 1
- 241000282567 Macaca fascicularis Species 0.000 description 1
- 102000018697 Membrane Proteins Human genes 0.000 description 1
- 108010052285 Membrane Proteins Proteins 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- 241000699660 Mus musculus Species 0.000 description 1
- 229940121948 Muscarinic receptor antagonist Drugs 0.000 description 1
- FMPNFDSPHNUFOS-UHFFFAOYSA-N N-Methyl-himandravin Natural products C12C(C)OC(=O)C2CC2CCCCC2C1C=CC1CCCC(C)N1C FMPNFDSPHNUFOS-UHFFFAOYSA-N 0.000 description 1
- MBBZMMPHUWSWHV-BDVNFPICSA-N N-methylglucamine Chemical compound CNC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO MBBZMMPHUWSWHV-BDVNFPICSA-N 0.000 description 1
- 206010028980 Neoplasm Diseases 0.000 description 1
- 101100030361 Neurospora crassa (strain ATCC 24698 / 74-OR23-1A / CBS 708.71 / DSM 1257 / FGSC 987) pph-3 gene Proteins 0.000 description 1
- ABLZXFCXXLZCGV-UHFFFAOYSA-N Phosphorous acid Chemical class OP(O)=O ABLZXFCXXLZCGV-UHFFFAOYSA-N 0.000 description 1
- 229920002873 Polyethylenimine Polymers 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- 238000006619 Stille reaction Methods 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-N Succinic acid Natural products OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 description 1
- 238000006069 Suzuki reaction reaction Methods 0.000 description 1
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 1
- 101000712605 Theromyzon tessulatum Theromin Proteins 0.000 description 1
- 229940122388 Thrombin inhibitor Drugs 0.000 description 1
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 1
- ZCLSQRQRWNDNLV-UHFFFAOYSA-N acetic acid;dichloromethane;methanol Chemical compound OC.ClCCl.CC(O)=O ZCLSQRQRWNDNLV-UHFFFAOYSA-N 0.000 description 1
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 102000030621 adenylate cyclase Human genes 0.000 description 1
- 108060000200 adenylate cyclase Proteins 0.000 description 1
- 150000001336 alkenes Chemical class 0.000 description 1
- 125000004450 alkenylene group Chemical group 0.000 description 1
- 150000001345 alkine derivatives Chemical class 0.000 description 1
- 150000003973 alkyl amines Chemical class 0.000 description 1
- 125000002947 alkylene group Chemical group 0.000 description 1
- 125000004419 alkynylene group Chemical group 0.000 description 1
- BJEPYKJPYRNKOW-UHFFFAOYSA-N alpha-hydroxysuccinic acid Natural products OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 description 1
- MVNCAPSFBDBCGF-UHFFFAOYSA-N alpha-pinene Natural products CC1=CCC23C1CC2C3(C)C MVNCAPSFBDBCGF-UHFFFAOYSA-N 0.000 description 1
- 229910052782 aluminium Inorganic materials 0.000 description 1
- 239000004411 aluminium Substances 0.000 description 1
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 150000001413 amino acids Chemical group 0.000 description 1
- 229910021529 ammonia Inorganic materials 0.000 description 1
- 239000005557 antagonist Substances 0.000 description 1
- 230000000879 anti-atherosclerotic effect Effects 0.000 description 1
- 230000000702 anti-platelet effect Effects 0.000 description 1
- 230000002769 anti-restenotic effect Effects 0.000 description 1
- 230000002785 anti-thrombosis Effects 0.000 description 1
- 230000000259 anti-tumor effect Effects 0.000 description 1
- 239000003963 antioxidant agent Substances 0.000 description 1
- 235000006708 antioxidants Nutrition 0.000 description 1
- 150000001499 aryl bromides Chemical class 0.000 description 1
- 125000003118 aryl group Chemical group 0.000 description 1
- 239000011668 ascorbic acid Substances 0.000 description 1
- 235000010323 ascorbic acid Nutrition 0.000 description 1
- 229960005070 ascorbic acid Drugs 0.000 description 1
- 239000002585 base Substances 0.000 description 1
- MUALRAIOVNYAIW-UHFFFAOYSA-N binap Chemical group C1=CC=CC=C1P(C=1C(=C2C=CC=CC2=CC=1)C=1C2=CC=CC=C2C=CC=1P(C=1C=CC=CC=1)C=1C=CC=CC=1)C1=CC=CC=C1 MUALRAIOVNYAIW-UHFFFAOYSA-N 0.000 description 1
- 239000012148 binding buffer Substances 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- SIPUZPBQZHNSDW-UHFFFAOYSA-N bis(2-methylpropyl)aluminum Chemical compound CC(C)C[Al]CC(C)C SIPUZPBQZHNSDW-UHFFFAOYSA-N 0.000 description 1
- 210000001772 blood platelet Anatomy 0.000 description 1
- KGBXLFKZBHKPEV-UHFFFAOYSA-N boric acid Chemical compound OB(O)O KGBXLFKZBHKPEV-UHFFFAOYSA-N 0.000 description 1
- 239000004327 boric acid Substances 0.000 description 1
- MCQRPQCQMGVWIQ-UHFFFAOYSA-N boron;methylsulfanylmethane Chemical compound [B].CSC MCQRPQCQMGVWIQ-UHFFFAOYSA-N 0.000 description 1
- 239000000872 buffer Substances 0.000 description 1
- KDYFGRWQOYBRFD-NUQCWPJISA-N butanedioic acid Chemical compound O[14C](=O)CC[14C](O)=O KDYFGRWQOYBRFD-NUQCWPJISA-N 0.000 description 1
- 201000011510 cancer Diseases 0.000 description 1
- 150000004657 carbamic acid derivatives Chemical class 0.000 description 1
- 235000013877 carbamide Nutrition 0.000 description 1
- 150000001721 carbon Chemical group 0.000 description 1
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 1
- 150000001735 carboxylic acids Chemical class 0.000 description 1
- 210000003169 central nervous system Anatomy 0.000 description 1
- 238000005119 centrifugation Methods 0.000 description 1
- 229910052681 coesite Inorganic materials 0.000 description 1
- 239000003086 colorant Substances 0.000 description 1
- 239000012230 colorless oil Substances 0.000 description 1
- TUFGVZMNGTYAQD-UHFFFAOYSA-N comins' reagent Chemical compound FC(F)(F)S(=O)(=O)N(S(=O)(=O)C(F)(F)F)C1=CC=C(Cl)C=N1 TUFGVZMNGTYAQD-UHFFFAOYSA-N 0.000 description 1
- 239000012141 concentrate Substances 0.000 description 1
- 230000008602 contraction Effects 0.000 description 1
- 229910052906 cristobalite Inorganic materials 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- 125000002993 cycloalkylene group Chemical group 0.000 description 1
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 1
- 125000004186 cyclopropylmethyl group Chemical group [H]C([H])(*)C1([H])C([H])([H])C1([H])[H] 0.000 description 1
- 238000006264 debenzylation reaction Methods 0.000 description 1
- NKLCNNUWBJBICK-UHFFFAOYSA-N dess–martin periodinane Chemical compound C1=CC=C2I(OC(=O)C)(OC(C)=O)(OC(C)=O)OC(=O)C2=C1 NKLCNNUWBJBICK-UHFFFAOYSA-N 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- LGTLXDJOAJDFLR-UHFFFAOYSA-N diethyl chlorophosphate Chemical compound CCOP(Cl)(=O)OCC LGTLXDJOAJDFLR-UHFFFAOYSA-N 0.000 description 1
- SXZIXHOMFPUIRK-UHFFFAOYSA-N diphenylmethanimine Chemical compound C=1C=CC=CC=1C(=N)C1=CC=CC=C1 SXZIXHOMFPUIRK-UHFFFAOYSA-N 0.000 description 1
- VHJLVAABSRFDPM-QWWZWVQMSA-N dithiothreitol Chemical compound SC[C@@H](O)[C@H](O)CS VHJLVAABSRFDPM-QWWZWVQMSA-N 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 238000001647 drug administration Methods 0.000 description 1
- 238000010828 elution Methods 0.000 description 1
- 239000003995 emulsifying agent Substances 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- RIFGWPKJUGCATF-UHFFFAOYSA-N ethyl chloroformate Chemical compound CCOC(Cl)=O RIFGWPKJUGCATF-UHFFFAOYSA-N 0.000 description 1
- FMVJYQGSRWVMQV-UHFFFAOYSA-N ethyl propiolate Chemical compound CCOC(=O)C#C FMVJYQGSRWVMQV-UHFFFAOYSA-N 0.000 description 1
- 239000000284 extract Substances 0.000 description 1
- 210000002950 fibroblast Anatomy 0.000 description 1
- 230000000893 fibroproliferative effect Effects 0.000 description 1
- 239000000945 filler Substances 0.000 description 1
- 239000000796 flavoring agent Substances 0.000 description 1
- 235000019634 flavors Nutrition 0.000 description 1
- 125000001153 fluoro group Chemical group F* 0.000 description 1
- 125000003709 fluoroalkyl group Chemical group 0.000 description 1
- 239000006260 foam Substances 0.000 description 1
- 238000004108 freeze drying Methods 0.000 description 1
- 239000001530 fumaric acid Substances 0.000 description 1
- 229960002598 fumaric acid Drugs 0.000 description 1
- 235000011087 fumaric acid Nutrition 0.000 description 1
- 238000003304 gavage Methods 0.000 description 1
- 239000007903 gelatin capsule Substances 0.000 description 1
- PCHJSUWPFVWCPO-UHFFFAOYSA-N gold Chemical compound [Au] PCHJSUWPFVWCPO-UHFFFAOYSA-N 0.000 description 1
- 229910052737 gold Inorganic materials 0.000 description 1
- 239000010931 gold Substances 0.000 description 1
- 125000000262 haloalkenyl group Chemical group 0.000 description 1
- 125000001188 haloalkyl group Chemical group 0.000 description 1
- 125000005347 halocycloalkyl group Chemical group 0.000 description 1
- FMPNFDSPHNUFOS-LPJDIUFZSA-N himbacine Chemical compound C(/[C@@H]1[C@H]2CCCC[C@@H]2C[C@@H]2C(=O)O[C@H]([C@H]12)C)=C\[C@H]1CCC[C@H](C)N1C FMPNFDSPHNUFOS-LPJDIUFZSA-N 0.000 description 1
- 229940106780 human fibrinogen Drugs 0.000 description 1
- 150000002431 hydrogen Chemical class 0.000 description 1
- 150000004806 hydroxypyridines Chemical class 0.000 description 1
- 230000002519 immonomodulatory effect Effects 0.000 description 1
- 230000002757 inflammatory effect Effects 0.000 description 1
- 230000004054 inflammatory process Effects 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 150000007529 inorganic bases Chemical class 0.000 description 1
- 229910052500 inorganic mineral Inorganic materials 0.000 description 1
- 150000002596 lactones Chemical group 0.000 description 1
- 229910052744 lithium Inorganic materials 0.000 description 1
- DLEDOFVPSDKWEF-UHFFFAOYSA-N lithium butane Chemical compound [Li+].CCC[CH2-] DLEDOFVPSDKWEF-UHFFFAOYSA-N 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 229910001629 magnesium chloride Inorganic materials 0.000 description 1
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 1
- 235000019341 magnesium sulphate Nutrition 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
- 239000011976 maleic acid Substances 0.000 description 1
- 229940098895 maleic acid Drugs 0.000 description 1
- 239000001630 malic acid Substances 0.000 description 1
- 235000011090 malic acid Nutrition 0.000 description 1
- 229940099690 malic acid Drugs 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 239000002207 metabolite Substances 0.000 description 1
- 229940098779 methanesulfonic acid Drugs 0.000 description 1
- CTSAXXHOGZNKJR-UHFFFAOYSA-N methyl 2-diethoxyphosphorylacetate Chemical compound CCOP(=O)(OCC)CC(=O)OC CTSAXXHOGZNKJR-UHFFFAOYSA-N 0.000 description 1
- 235000010755 mineral Nutrition 0.000 description 1
- 239000011707 mineral Substances 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 239000003149 muscarinic antagonist Substances 0.000 description 1
- 230000014508 negative regulation of coagulation Effects 0.000 description 1
- 230000001537 neural effect Effects 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- 238000011580 nude mouse model Methods 0.000 description 1
- 239000006186 oral dosage form Substances 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- 235000006408 oxalic acid Nutrition 0.000 description 1
- 239000007800 oxidant agent Substances 0.000 description 1
- FJKROLUGYXJWQN-UHFFFAOYSA-N papa-hydroxy-benzoic acid Natural products OC(=O)C1=CC=C(O)C=C1 FJKROLUGYXJWQN-UHFFFAOYSA-N 0.000 description 1
- 239000008188 pellet Substances 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 230000000704 physical effect Effects 0.000 description 1
- XOKSLPVRUOBDEW-UHFFFAOYSA-N pinane of uncertain configuration Natural products CC1CCC2C(C)(C)C1C2 XOKSLPVRUOBDEW-UHFFFAOYSA-N 0.000 description 1
- 229930000732 piperidine alkaloid Natural products 0.000 description 1
- 150000003053 piperidines Chemical class 0.000 description 1
- 230000036470 plasma concentration Effects 0.000 description 1
- 210000004623 platelet-rich plasma Anatomy 0.000 description 1
- 239000002798 polar solvent Substances 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 235000015320 potassium carbonate Nutrition 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 238000000039 preparative column chromatography Methods 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 238000010791 quenching Methods 0.000 description 1
- 230000000171 quenching effect Effects 0.000 description 1
- GRWFGVWFFZKLTI-UHFFFAOYSA-N rac-alpha-Pinene Natural products CC1=CCC2C(C)(C)C1C2 GRWFGVWFFZKLTI-UHFFFAOYSA-N 0.000 description 1
- 239000002287 radioligand Substances 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 210000002345 respiratory system Anatomy 0.000 description 1
- 230000004044 response Effects 0.000 description 1
- 238000007363 ring formation reaction Methods 0.000 description 1
- 229960004889 salicylic acid Drugs 0.000 description 1
- 210000003752 saphenous vein Anatomy 0.000 description 1
- 239000000377 silicon dioxide Substances 0.000 description 1
- 235000012239 silicon dioxide Nutrition 0.000 description 1
- 150000003378 silver Chemical class 0.000 description 1
- 239000002002 slurry Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000001476 sodium potassium tartrate Substances 0.000 description 1
- 230000009870 specific binding Effects 0.000 description 1
- 238000010561 standard procedure Methods 0.000 description 1
- 229910052682 stishovite Inorganic materials 0.000 description 1
- 239000011550 stock solution Substances 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 239000002562 thickening agent Substances 0.000 description 1
- 238000004809 thin layer chromatography Methods 0.000 description 1
- 239000003868 thrombin inhibitor Substances 0.000 description 1
- 239000003634 thrombocyte concentrate Substances 0.000 description 1
- 230000009466 transformation Effects 0.000 description 1
- GYUURHMITDQTRU-UHFFFAOYSA-N tributyl(pyridin-2-yl)stannane Chemical compound CCCC[Sn](CCCC)(CCCC)C1=CC=CC=N1 GYUURHMITDQTRU-UHFFFAOYSA-N 0.000 description 1
- DBGVGMSCBYYSLD-UHFFFAOYSA-N tributylstannane Chemical compound CCCC[SnH](CCCC)CCCC DBGVGMSCBYYSLD-UHFFFAOYSA-N 0.000 description 1
- 229910052905 tridymite Inorganic materials 0.000 description 1
- HHLJUSLZGFYWKW-UHFFFAOYSA-N triethanolamine hydrochloride Chemical compound Cl.OCCN(CCO)CCO HHLJUSLZGFYWKW-UHFFFAOYSA-N 0.000 description 1
- GGUBFICZYGKNTD-UHFFFAOYSA-N triethyl phosphonoacetate Chemical compound CCOC(=O)CP(=O)(OCC)OCC GGUBFICZYGKNTD-UHFFFAOYSA-N 0.000 description 1
- ITMCEJHCFYSIIV-UHFFFAOYSA-M triflate Chemical compound [O-]S(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-M 0.000 description 1
- 125000004950 trifluoroalkyl group Chemical group 0.000 description 1
- SUPFGDFDIDGUKL-UHFFFAOYSA-K trisodium;hydrogen carbonate;sulfite Chemical compound [Na+].[Na+].[Na+].OC([O-])=O.[O-]S([O-])=O SUPFGDFDIDGUKL-UHFFFAOYSA-K 0.000 description 1
- 150000003672 ureas Chemical class 0.000 description 1
- 210000003556 vascular endothelial cell Anatomy 0.000 description 1
- 210000004509 vascular smooth muscle cell Anatomy 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
- C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
- C07D491/04—Ortho-condensed systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
- C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
- C07D491/04—Ortho-condensed systems
- C07D491/044—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
- C07D491/048—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring the oxygen-containing ring being five-membered
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P13/00—Drugs for disorders of the urinary system
- A61P13/12—Drugs for disorders of the urinary system of the kidneys
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
- A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
-
- 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
- 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
-
- 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
- A61P9/04—Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
-
- 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
-
- 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
- A61P9/12—Antihypertensives
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D493/00—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system
- C07D493/02—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system in which the condensed system contains two hetero rings
- C07D493/04—Ortho-condensed systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
- C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
- C07D495/04—Ortho-condensed systems
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Engineering & Computer Science (AREA)
- Cardiology (AREA)
- Heart & Thoracic Surgery (AREA)
- Rheumatology (AREA)
- Urology & Nephrology (AREA)
- Physical Education & Sports Medicine (AREA)
- Immunology (AREA)
- Vascular Medicine (AREA)
- Pain & Pain Management (AREA)
- Diabetes (AREA)
- Hospice & Palliative Care (AREA)
- Orthopedic Medicine & Surgery (AREA)
- Hematology (AREA)
- Pulmonology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US33035901P | 2001-10-18 | 2001-10-18 | |
| PCT/US2002/032936 WO2003033501A1 (en) | 2001-10-18 | 2002-10-16 | Himbacine analogues as thrombin receptor antagonists |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| NO20042021L NO20042021L (no) | 2004-05-14 |
| NO329349B1 true NO329349B1 (no) | 2010-10-04 |
Family
ID=23289411
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| NO20042021A NO329349B1 (no) | 2001-10-18 | 2004-05-14 | Himbacinanalogforbindelser, farmasoytiske preparater som omfatter minst en slik forbindelse, samt anvendelse av forbindelsene til fremstilling av medikamenter for hemming av trombinreseptorer |
Country Status (23)
| Country | Link |
|---|---|
| US (2) | US7037920B2 (hu) |
| EP (1) | EP1436298B1 (hu) |
| JP (2) | JP4307260B2 (hu) |
| KR (1) | KR100960170B1 (hu) |
| CN (1) | CN100369917C (hu) |
| AR (1) | AR036832A1 (hu) |
| AT (1) | ATE525378T1 (hu) |
| AU (1) | AU2002335031C1 (hu) |
| BR (1) | BR0213967A (hu) |
| CA (1) | CA2463628A1 (hu) |
| CO (1) | CO5570668A2 (hu) |
| EC (1) | ECSP045064A (hu) |
| HU (1) | HUP0500443A3 (hu) |
| IL (1) | IL160918A0 (hu) |
| MX (1) | MXPA04003610A (hu) |
| MY (1) | MY139335A (hu) |
| NO (1) | NO329349B1 (hu) |
| NZ (1) | NZ531869A (hu) |
| PE (1) | PE20030808A1 (hu) |
| PL (1) | PL371948A1 (hu) |
| RU (1) | RU2319704C9 (hu) |
| WO (1) | WO2003033501A1 (hu) |
| ZA (1) | ZA200402849B (hu) |
Families Citing this family (46)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6346510B1 (en) | 1995-10-23 | 2002-02-12 | The Children's Medical Center Corporation | Therapeutic antiangiogenic endostatin compositions |
| US7488742B2 (en) * | 2000-06-15 | 2009-02-10 | Schering Corporation | Thrombin receptor antagonists |
| US7235567B2 (en) * | 2000-06-15 | 2007-06-26 | Schering Corporation | Crystalline polymorph of a bisulfate salt of a thrombin receptor antagonist |
| SI2065384T1 (sl) | 2002-04-16 | 2011-05-31 | Schering Corp | Tricikliäśni trombin receptor antagonist |
| US7790362B2 (en) * | 2003-07-08 | 2010-09-07 | Accumetrics, Inc. | Controlled platelet activation to monitor therapy of ADP antagonists |
| US20070243632A1 (en) * | 2003-07-08 | 2007-10-18 | Coller Barry S | Methods for measuring platelet reactivity of patients that have received drug eluting stents |
| JP4558788B2 (ja) * | 2004-05-28 | 2010-10-06 | シェーリング コーポレイション | トロンビンレセプターアンタゴニストとしての条件付きヒンバシンアナログ |
| WO2006023844A2 (en) * | 2004-08-20 | 2006-03-02 | Entremed, Inc. | Compositions and methods comprising proteinase activated receptor antagonists |
| AU2005294265A1 (en) * | 2004-10-06 | 2006-04-20 | University Of Rochester | Treatment of pulmonary hypertension using an agent that inhibits a tissue factor pathway |
| MX2007004197A (es) * | 2004-10-08 | 2007-06-15 | Schering Corp | Antagonistas del receptor de trombina. |
| EP1853592B1 (en) * | 2005-01-14 | 2011-03-02 | Schering Corporation | Synthesis of himbacine analogs |
| ES2374379T3 (es) * | 2005-01-14 | 2012-02-16 | Schering Corporation | Síntesis exo y diastereoselectiva de análogos de himbacina. |
| MX2007008622A (es) * | 2005-01-14 | 2007-09-11 | Schering Corp | Una sintesis exo-selectiva de analogos de himbacina. |
| AU2006230292A1 (en) * | 2005-03-31 | 2006-10-05 | Schering Corporation | Spirocyclic thrombin receptor antagonists |
| US7595169B2 (en) * | 2005-04-27 | 2009-09-29 | Accumetrics, Inc. | Method for determining percent platelet aggregation |
| US20070219154A1 (en) * | 2005-12-20 | 2007-09-20 | Suxing Liu | Methods for preventing and/or treating a cell proliferative disorder |
| EP1971336A2 (en) * | 2005-12-22 | 2008-09-24 | Shering Corporation | Thrombin receptor antagonists as phophylaxis to complications from cardiopulmonary surgery |
| AU2006331703A1 (en) * | 2005-12-22 | 2007-07-05 | Schering Corporation | Oxazoloisoquinoline derivatives as thrombin receptor antagonists |
| WO2007126771A2 (en) * | 2006-03-29 | 2007-11-08 | Schering Corporation | Monocyclic and bicyclic himbacine derivatives useful as thrombin receptor antagonists |
| AU2007238756A1 (en) * | 2006-04-13 | 2007-10-25 | Schering Corporation | Fused ring thrombin receptor antagonists |
| US8022088B2 (en) * | 2006-06-29 | 2011-09-20 | Schering Corporation | Substituted bicyclic and tricyclic thrombin receptor antagonists |
| AR061727A1 (es) * | 2006-06-30 | 2008-09-17 | Schering Corp | Sintesis de dietil [[ 5- ( 3-fluorofenil) -piridin -2il] metil] fosfonato |
| TWI367112B (en) | 2006-06-30 | 2012-07-01 | Schering Corp | Immediate-release tablet formulations of a thrombin receptor antagonist |
| TWI343262B (en) * | 2006-09-26 | 2011-06-11 | Schering Corp | Rapidly disintegrating lyophilized oral formulations of a thrombin receptor antagonist |
| AR063095A1 (es) * | 2006-10-04 | 2008-12-30 | Schering Corp | Antagonistas del receptor de trombina basados en la unidad triciclica modificada de himbacina |
| AU2007305269A1 (en) * | 2006-10-04 | 2008-04-10 | Schering Corporation | Bicyclic and tricyclic derivatives as thrombin receptor antagonists |
| CA2673228A1 (en) * | 2006-12-22 | 2008-07-03 | Schering Corporation | Disintegration promoters in solid dose wet granulation formulations |
| BRPI0809095A2 (pt) * | 2007-03-23 | 2014-09-09 | Schering Corp | Redução de eventos adversos após intervenção percutânea através de uso de um antagonista de receptor de trombina |
| WO2008137673A1 (en) * | 2007-05-03 | 2008-11-13 | Accumetrics, Inc. | Methods of measuring inhibition of platelet aggregation by thrombin receptor antagonists |
| CN101981034B (zh) | 2008-02-05 | 2013-08-14 | 赛诺菲-安万特 | 作为par1抑制剂的三唑并哒嗪、其制备及其制备药物的用途 |
| WO2009143039A2 (en) | 2008-05-19 | 2009-11-26 | Schering Corporation | Heterocyclic compounds as factor ixa inhibitors |
| US8575351B2 (en) | 2009-06-04 | 2013-11-05 | Merck Sharp & Dohme Corp. | Active metabolite of a thrombin receptor antagonist |
| JP2012529431A (ja) | 2009-06-08 | 2012-11-22 | メルク・シャープ・アンド・ドーム・コーポレーション | トロンビン受容体アンタゴニストおよびクロピドグレルの固定用量錠剤 |
| TWI393716B (zh) | 2009-08-04 | 2013-04-21 | Merck Sharp & Dohme | 作為ｉｘａ因子抑制劑之雜環化合物 |
| EP2822557B1 (en) | 2012-03-06 | 2017-08-23 | Merck Sharp & Dohme Corp. | Preparation and use of bicyclic himbacine derivatives as par-receptor antagonists |
| US9808473B2 (en) | 2013-08-22 | 2017-11-07 | Merck Sharp & Dohme Corp. | Preparation and use of 3-pyridyl substituted-6,6-difluoro bicyclic himbacine derivatives as par-1 receptor antagonists |
| EP3035929B1 (en) | 2013-08-22 | 2024-07-03 | Merck Sharp & Dohme LLC | 7a-amide substituted-6,6-difluoro bicyclic himbacine derivatives |
| WO2015026685A1 (en) | 2013-08-22 | 2015-02-26 | Merck Sharp & Dohme Corp. | 7a-heterocycle substituted- 6, 6-difluoro bicyclic himbacine derivatives |
| US9969724B2 (en) | 2014-04-16 | 2018-05-15 | Merck Sharp & Dohme Corp. | Factor IXa inhibitors |
| CN104610330A (zh) * | 2015-02-25 | 2015-05-13 | 成都安斯利生物医药有限公司 | 一种制备(e)-3-丙烯酸乙酯频呐硼酸酯的方法 |
| WO2022018156A1 (en) | 2020-07-22 | 2022-01-27 | Janssen Pharmaceutica Nv | Compounds useful as factor xia inhibitors |
| US11845748B2 (en) | 2021-03-18 | 2023-12-19 | Janssen Pharmaceutica Nv | Bicyclic pyridine N-oxide derivatives useful as a factor XIa inhibitors |
| US11919881B2 (en) | 2021-03-18 | 2024-03-05 | Janssen Pharmaceutica Nv | Substituted pyridine N-oxide derivatives useful as a factor XIa inhibitors |
| US11814364B2 (en) | 2021-03-18 | 2023-11-14 | Janssen Pharmaceutica Nv | Pyridine N-oxide derivatives useful as factor XIa inhibitors |
| US11897880B2 (en) | 2021-04-30 | 2024-02-13 | Janssen Pharmaceutica Nv | 7,8-dihydrobenzo[e]pyrido[3,4-c]azocine-2,5(3H,6H)-dione derivatives useful as a factor XIa inhibitors |
| US11958856B2 (en) | 2021-07-22 | 2024-04-16 | Janssen Pharmaceutica Nv | Substituted 1,2,3,8,9,9a-hexahydro-5H-pyrrolo[1,2-a]azepin-5-ones as factor XIa inhibitors |
Family Cites Families (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5716952A (en) * | 1992-03-18 | 1998-02-10 | Allergan | Method for reducing intraocular pressure in the mammalian eye by administration of muscarinic antagonists |
| IL106197A (en) | 1992-07-30 | 1999-11-30 | Cor Therapeutics Inc | Agagonists for the rhombin receptors and pharmaceutical preparations containing them |
| JP2000229961A (ja) * | 1998-12-11 | 2000-08-22 | Sagami Chem Res Center | ヒドロナフト［２，３−ｃ］フラン誘導体およびその製造方法 |
| US6063847A (en) * | 1997-11-25 | 2000-05-16 | Schering Corporation | Thrombin receptor antagonists |
| DE19801636A1 (de) * | 1998-01-17 | 1999-07-22 | Bayer Ag | Substituierte bicyclische Lactone |
| PE20020235A1 (es) | 2000-06-15 | 2002-04-02 | Schering Corp | Derivados de nor-seco himbacina como antagonistas de los receptores de trombina |
-
2002
- 2002-10-16 HU HU0500443A patent/HUP0500443A3/hu unknown
- 2002-10-16 PE PE2002001022A patent/PE20030808A1/es not_active Application Discontinuation
- 2002-10-16 AU AU2002335031A patent/AU2002335031C1/en not_active Ceased
- 2002-10-16 KR KR1020047005435A patent/KR100960170B1/ko not_active IP Right Cessation
- 2002-10-16 CA CA002463628A patent/CA2463628A1/en not_active Abandoned
- 2002-10-16 BR BR0213967-7A patent/BR0213967A/pt not_active IP Right Cessation
- 2002-10-16 PL PL02371948A patent/PL371948A1/xx not_active Application Discontinuation
- 2002-10-16 MY MYPI20023859A patent/MY139335A/en unknown
- 2002-10-16 AT AT02801732T patent/ATE525378T1/de not_active IP Right Cessation
- 2002-10-16 AR ARP020103876A patent/AR036832A1/es unknown
- 2002-10-16 US US10/271,715 patent/US7037920B2/en not_active Expired - Fee Related
- 2002-10-16 MX MXPA04003610A patent/MXPA04003610A/es active IP Right Grant
- 2002-10-16 NZ NZ531869A patent/NZ531869A/en not_active IP Right Cessation
- 2002-10-16 WO PCT/US2002/032936 patent/WO2003033501A1/en active IP Right Grant
- 2002-10-16 RU RU2004115114/04A patent/RU2319704C9/ru not_active IP Right Cessation
- 2002-10-16 CN CNB028206665A patent/CN100369917C/zh not_active Expired - Fee Related
- 2002-10-16 EP EP02801732A patent/EP1436298B1/en not_active Expired - Lifetime
- 2002-10-16 JP JP2003536240A patent/JP4307260B2/ja not_active Expired - Fee Related
- 2002-10-16 IL IL16091802A patent/IL160918A0/xx not_active IP Right Cessation
-
2004
- 2004-04-15 ZA ZA200402849A patent/ZA200402849B/xx unknown
- 2004-04-15 EC EC2004005064A patent/ECSP045064A/es unknown
- 2004-04-16 CO CO04034781A patent/CO5570668A2/es not_active Application Discontinuation
- 2004-05-14 NO NO20042021A patent/NO329349B1/no not_active IP Right Cessation
-
2005
- 2005-12-19 US US11/311,083 patent/US20060106050A1/en not_active Abandoned
-
2008
- 2008-09-17 JP JP2008238716A patent/JP2009029820A/ja not_active Withdrawn
Also Published As
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| NO329349B1 (no) | Himbacinanalogforbindelser, farmasoytiske preparater som omfatter minst en slik forbindelse, samt anvendelse av forbindelsene til fremstilling av medikamenter for hemming av trombinreseptorer | |
| AU2002335031A1 (en) | Himbacine analogues as thrombin receptor antagonists | |
| AU2001266900B2 (en) | Thrombin receptor antagonists | |
| JP4558331B2 (ja) | 三環式トロンビンレセプターアンタゴニスト | |
| EP1751144B1 (en) | Constrained himbacine analogs as thrombin receptor antagonists | |
| RU2408594C2 (ru) | Антагонисты рецептора тромбина | |
| CN101541782A (zh) | 作为凝血酶受体拮抗剂的二环和三环衍生物 | |
| MXPA06003379A (es) | Antagonistas del receptor de trombina. | |
| JP2008534604A (ja) | スピロ環式トロンビンレセプターアンタゴニスト | |
| TWI236476B (en) | Thrombin receptor antagonists | |
| JPH0443917B2 (hu) | ||
| EP2007755B1 (en) | Fused ring thrombin receptor antagonists | |
| BG65162B1 (bg) | Бензизоксазоли и фенони като алфа 2-антагонисти | |
| HRP960296A2 (en) | Chemical compounds |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| MM1K | Lapsed by not paying the annual fees |