JP2002502852A5 - - Google Patents
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- Publication number
- JP2002502852A5 JP2002502852A5 JP2000530517A JP2000530517A JP2002502852A5 JP 2002502852 A5 JP2002502852 A5 JP 2002502852A5 JP 2000530517 A JP2000530517 A JP 2000530517A JP 2000530517 A JP2000530517 A JP 2000530517A JP 2002502852 A5 JP2002502852 A5 JP 2002502852A5
- Authority
- JP
- Japan
- Prior art keywords
- thiazol
- methylthiothiophene
- carboxamidine
- acid
- alkyl
- 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.)
- Pending
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- -1 amino, hydroxy Chemical group 0.000 description 194
- 150000001875 compounds Chemical class 0.000 description 108
- OKKJLVBELUTLKV-UHFFFAOYSA-N methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 104
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 94
- YXFVVABEGXRONW-UHFFFAOYSA-N toluene Substances CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 89
- 239000002253 acid Substances 0.000 description 71
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 68
- 125000000217 alkyl group Chemical group 0.000 description 68
- 239000002904 solvent Substances 0.000 description 53
- 239000000243 solution Substances 0.000 description 52
- 150000001409 amidines Chemical class 0.000 description 46
- 239000000377 silicon dioxide Substances 0.000 description 46
- 230000015572 biosynthetic process Effects 0.000 description 44
- 239000000460 chlorine Substances 0.000 description 44
- 238000006243 chemical reaction Methods 0.000 description 43
- 229910052739 hydrogen Inorganic materials 0.000 description 43
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 42
- 239000001257 hydrogen Substances 0.000 description 41
- 125000003545 alkoxy group Chemical group 0.000 description 39
- HEDRZPFGACZZDS-UHFFFAOYSA-N chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 34
- 238000003786 synthesis reaction Methods 0.000 description 33
- 125000003118 aryl group Chemical group 0.000 description 32
- 125000004093 cyano group Chemical group *C#N 0.000 description 32
- 230000002194 synthesizing Effects 0.000 description 32
- VEXZGXHMUGYJMC-UHFFFAOYSA-N HCl Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 31
- YMWUJEATGCHHMB-UHFFFAOYSA-N methylene dichloride Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 30
- 150000001412 amines Chemical class 0.000 description 28
- 239000000203 mixture Substances 0.000 description 28
- 239000003153 chemical reaction reagent Substances 0.000 description 27
- 102000003990 Urokinase-type plasminogen activator Human genes 0.000 description 26
- 108090000435 Urokinase-type plasminogen activator Proteins 0.000 description 26
- 229910052736 halogen Inorganic materials 0.000 description 26
- 150000002367 halogens Chemical class 0.000 description 26
- 239000002585 base Substances 0.000 description 25
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonium chloride Substances [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 24
- CSCPPACGZOOCGX-UHFFFAOYSA-N acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 24
- 238000005160 1H NMR spectroscopy Methods 0.000 description 23
- 229910052757 nitrogen Inorganic materials 0.000 description 23
- 239000007787 solid Substances 0.000 description 23
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Natural products CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 22
- 229960005356 Urokinase Drugs 0.000 description 22
- 235000019270 ammonium chloride Nutrition 0.000 description 22
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 22
- 150000002431 hydrogen Chemical class 0.000 description 22
- 238000001819 mass spectrum Methods 0.000 description 22
- QDHHCQZDFGDHMP-UHFFFAOYSA-N monochloramine Chemical compound ClN QDHHCQZDFGDHMP-UHFFFAOYSA-N 0.000 description 22
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 21
- 150000002148 esters Chemical class 0.000 description 21
- VEXZGXHMUGYJMC-UHFFFAOYSA-M chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 20
- KDLHZDBZIXYQEI-UHFFFAOYSA-N palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 20
- JUJWROOIHBZHMG-UHFFFAOYSA-N pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 20
- WYURNTSHIVDZCO-UHFFFAOYSA-N tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 20
- DTQVDTLACAAQTR-UHFFFAOYSA-N trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 20
- 239000011541 reaction mixture Substances 0.000 description 19
- CTSLXHKWHWQRSH-UHFFFAOYSA-N Oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 description 18
- JLTRXTDYQLMHGR-UHFFFAOYSA-N Trimethylaluminium Chemical compound C[Al](C)C JLTRXTDYQLMHGR-UHFFFAOYSA-N 0.000 description 18
- 150000001408 amides Chemical class 0.000 description 18
- 210000004027 cells Anatomy 0.000 description 18
- 238000001840 matrix-assisted laser desorption--ionisation time-of-flight mass spectrometry Methods 0.000 description 18
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 18
- 125000004414 alkyl thio group Chemical group 0.000 description 17
- 125000005110 aryl thio group Chemical group 0.000 description 17
- 125000004104 aryloxy group Chemical group 0.000 description 17
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 17
- UFHFLCQGNIYNRP-UHFFFAOYSA-N hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 17
- 239000002002 slurry Substances 0.000 description 17
- 239000011521 glass Substances 0.000 description 16
- 125000000623 heterocyclic group Chemical group 0.000 description 16
- 125000004356 hydroxy functional group Chemical group O* 0.000 description 16
- 239000011159 matrix material Substances 0.000 description 16
- 239000011780 sodium chloride Substances 0.000 description 16
- 239000000725 suspension Substances 0.000 description 16
- AFVLVVWMAFSXCK-VMPITWQZSA-N α-cyano-4-hydroxycinnamic acid Chemical compound OC(=O)C(\C#N)=C\C1=CC=C(O)C=C1 AFVLVVWMAFSXCK-VMPITWQZSA-N 0.000 description 16
- 108010088842 Fibrinolysin Proteins 0.000 description 15
- 229940012957 Plasmin Drugs 0.000 description 15
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 15
- 230000000896 plasminic Effects 0.000 description 15
- 229910052717 sulfur Inorganic materials 0.000 description 15
- ONDSBJMLAHVLMI-UHFFFAOYSA-N Trimethylsilyldiazomethane Chemical compound C[Si](C)(C)[CH-][N+]#N ONDSBJMLAHVLMI-UHFFFAOYSA-N 0.000 description 14
- 125000004442 acylamino group Chemical group 0.000 description 14
- 125000000266 alpha-aminoacyl group Chemical group 0.000 description 14
- 125000004663 dialkyl amino group Chemical group 0.000 description 14
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 14
- 150000003839 salts Chemical class 0.000 description 14
- 239000012043 crude product Substances 0.000 description 13
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 13
- 125000006239 protecting group Chemical group 0.000 description 13
- 238000010992 reflux Methods 0.000 description 13
- 108091005771 Peptidases Proteins 0.000 description 12
- 102000035443 Peptidases Human genes 0.000 description 12
- 125000004682 aminothiocarbonyl group Chemical group NC(=S)* 0.000 description 12
- 239000003054 catalyst Substances 0.000 description 12
- 238000005755 formation reaction Methods 0.000 description 12
- HEMHJVSKTPXQMS-UHFFFAOYSA-M sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 12
- 125000001424 substituent group Chemical group 0.000 description 12
- 239000004365 Protease Substances 0.000 description 11
- 125000004453 alkoxycarbonyl group Chemical group 0.000 description 11
- 125000004390 alkyl sulfonyl group Chemical group 0.000 description 11
- 125000003710 aryl alkyl group Chemical group 0.000 description 11
- 125000004657 aryl sulfonyl amino group Chemical group 0.000 description 11
- 230000001808 coupling Effects 0.000 description 11
- 238000010168 coupling process Methods 0.000 description 11
- 238000005859 coupling reaction Methods 0.000 description 11
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 11
- 230000000694 effects Effects 0.000 description 11
- NINIDFKCEFEMDL-UHFFFAOYSA-N sulfur Chemical group [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 11
- 125000000335 thiazolyl group Chemical group 0.000 description 11
- 125000004466 alkoxycarbonylamino group Chemical group 0.000 description 10
- 125000004391 aryl sulfonyl group Chemical group 0.000 description 10
- 201000010099 disease Diseases 0.000 description 10
- 238000003756 stirring Methods 0.000 description 10
- 239000011593 sulfur Chemical group 0.000 description 10
- FZWLAAWBMGSTSO-UHFFFAOYSA-N thiazole Chemical compound C1=CSC=N1 FZWLAAWBMGSTSO-UHFFFAOYSA-N 0.000 description 10
- ZMANZCXQSJIPKH-UHFFFAOYSA-N triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 10
- 206010027476 Metastasis Diseases 0.000 description 9
- XEKOWRVHYACXOJ-UHFFFAOYSA-N acetic acid ethyl ester Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 9
- 125000005140 aralkylsulfonyl group Chemical group 0.000 description 9
- 125000004659 aryl alkyl thio group Chemical group 0.000 description 9
- 125000001164 benzothiazolyl group Chemical group S1C(=NC2=C1C=CC=C2)* 0.000 description 9
- 125000005202 dialkylaminocarbonyloxy group Chemical group 0.000 description 9
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 9
- 150000002576 ketones Chemical class 0.000 description 9
- 229910052760 oxygen Inorganic materials 0.000 description 9
- 229910052763 palladium Inorganic materials 0.000 description 9
- BZKBCQXYZZXSCO-UHFFFAOYSA-N sodium hydride Inorganic materials [H-].[Na+] BZKBCQXYZZXSCO-UHFFFAOYSA-N 0.000 description 9
- 125000000437 thiazol-2-yl group Chemical group [H]C1=C([H])N=C(*)S1 0.000 description 9
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 9
- FPIRBHDGWMWJEP-UHFFFAOYSA-N 1-Hydroxy-7-azabenzotriazole Chemical compound C1=CN=C2N(O)N=NC2=C1 FPIRBHDGWMWJEP-UHFFFAOYSA-N 0.000 description 8
- 206010004446 Benign prostatic hyperplasia Diseases 0.000 description 8
- 239000002841 Lewis acid Substances 0.000 description 8
- 206010060862 Prostate cancer Diseases 0.000 description 8
- 235000011054 acetic acid Nutrition 0.000 description 8
- 125000003282 alkyl amino group Chemical group 0.000 description 8
- 125000005162 aryl oxy carbonyl amino group Chemical group 0.000 description 8
- 125000004181 carboxyalkyl group Chemical group 0.000 description 8
- 230000000875 corresponding Effects 0.000 description 8
- 238000010438 heat treatment Methods 0.000 description 8
- 230000002401 inhibitory effect Effects 0.000 description 8
- 239000000543 intermediate Substances 0.000 description 8
- 150000007517 lewis acids Chemical class 0.000 description 8
- MZRVEZGGRBJDDB-UHFFFAOYSA-N n-butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 8
- SJRJJKPEHAURKC-UHFFFAOYSA-N n-methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 description 8
- 125000002971 oxazolyl group Chemical group 0.000 description 8
- 238000002360 preparation method Methods 0.000 description 8
- 230000017854 proteolysis Effects 0.000 description 8
- 201000004681 psoriasis Diseases 0.000 description 8
- 239000012453 solvate Substances 0.000 description 8
- NKCXQMYPWXSLIZ-PSRDDEIFSA-N (2S)-2-[[(2S)-1-[(2S)-5-amino-2-[[2-[[(2S)-6-amino-2-[[2-[[(2S)-2-[[(2S)-4-amino-2-[[(2S)-2-[[(2S,3R)-2-[[(2S)-2-[[(2S,3R)-2-amino-3-hydroxybutanoyl]amino]-3-(1H-indol-3-yl)propanoyl]amino]-3-hydroxybutanoyl]amino]propanoyl]amino]-4-oxobutanoyl]amino]-3-m Chemical compound O=C([C@H](CCC(N)=O)NC(=O)CNC(=O)[C@H](CCCCN)NC(=O)CNC(=O)[C@@H](NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](C)NC(=O)[C@@H](NC(=O)[C@H](CC=1C2=CC=CC=C2NC=1)NC(=O)[C@@H](N)[C@@H](C)O)[C@@H](C)O)C(C)C)N1CCC[C@H]1C(=O)N[C@@H](CO)C(O)=O NKCXQMYPWXSLIZ-PSRDDEIFSA-N 0.000 description 7
- 108090000790 Enzymes Proteins 0.000 description 7
- 102000004190 Enzymes Human genes 0.000 description 7
- 108010074860 Factor Xa Proteins 0.000 description 7
- 206010028980 Neoplasm Diseases 0.000 description 7
- 108090000190 Thrombin Proteins 0.000 description 7
- 125000004656 alkyl sulfonylamino group Chemical group 0.000 description 7
- 239000003795 chemical substances by application Substances 0.000 description 7
- 125000004473 dialkylaminocarbonyl group Chemical group 0.000 description 7
- 239000007789 gas Substances 0.000 description 7
- CPELXLSAUQHCOX-UHFFFAOYSA-N hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 7
- 125000002816 methylsulfanyl group Chemical group [H]C([H])([H])S[*] 0.000 description 7
- 239000008194 pharmaceutical composition Substances 0.000 description 7
- 230000002797 proteolythic Effects 0.000 description 7
- 239000003638 reducing agent Substances 0.000 description 7
- 125000001544 thienyl group Chemical group 0.000 description 7
- 229960004072 thrombin Drugs 0.000 description 7
- XSQUKJJJFZCRTK-UHFFFAOYSA-N urea Chemical compound NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 description 7
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 description 6
- 210000002469 Basement Membrane Anatomy 0.000 description 6
- 210000002744 Extracellular Matrix Anatomy 0.000 description 6
- FYSNRJHAOHDILO-UHFFFAOYSA-N Thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 6
- 108090000631 Trypsin Proteins 0.000 description 6
- 102000004142 Trypsin Human genes 0.000 description 6
- 125000005078 alkoxycarbonylalkyl group Chemical group 0.000 description 6
- 238000005804 alkylation reaction Methods 0.000 description 6
- QGZKDVFQNNGYKY-UHFFFAOYSA-N ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 6
- 239000012131 assay buffer Substances 0.000 description 6
- UHOVQNZJYSORNB-UHFFFAOYSA-N benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 6
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 description 6
- QGJOPFRUJISHPQ-UHFFFAOYSA-N carbon bisulphide Chemical compound S=C=S QGJOPFRUJISHPQ-UHFFFAOYSA-N 0.000 description 6
- 230000003197 catalytic Effects 0.000 description 6
- 125000004671 dialkylaminothiocarbonyl group Chemical group 0.000 description 6
- 125000001072 heteroaryl group Chemical group 0.000 description 6
- 125000002883 imidazolyl group Chemical group 0.000 description 6
- 239000000047 product Substances 0.000 description 6
- 125000004076 pyridyl group Chemical group 0.000 description 6
- 229960001322 trypsin Drugs 0.000 description 6
- 239000012588 trypsin Substances 0.000 description 6
- 125000006700 (C1-C6) alkylthio group Chemical group 0.000 description 5
- DOBRDRYODQBAMW-UHFFFAOYSA-N Copper(I) cyanide Chemical compound [Cu+].N#[C-] DOBRDRYODQBAMW-UHFFFAOYSA-N 0.000 description 5
- FXHOOIRPVKKKFG-UHFFFAOYSA-N DMA Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 5
- 229940110715 ENZYMES FOR TREATMENT OF WOUNDS AND ULCERS Drugs 0.000 description 5
- AEOCXXJPGCBFJA-UHFFFAOYSA-N Ethionamide Chemical compound CCC1=CC(C(N)=S)=CC=N1 AEOCXXJPGCBFJA-UHFFFAOYSA-N 0.000 description 5
- 239000004793 Polystyrene Substances 0.000 description 5
- 238000007792 addition Methods 0.000 description 5
- 125000003342 alkenyl group Chemical group 0.000 description 5
- 239000002168 alkylating agent Substances 0.000 description 5
- 229940019336 antithrombotic Enzymes Drugs 0.000 description 5
- 201000011510 cancer Diseases 0.000 description 5
- 238000009903 catalytic hydrogenation reaction Methods 0.000 description 5
- 239000003814 drug Substances 0.000 description 5
- 229940020899 hematological Enzymes Drugs 0.000 description 5
- FZRKAZHKEDOPNN-UHFFFAOYSA-N nitroxyl anion Chemical compound O=[N-] FZRKAZHKEDOPNN-UHFFFAOYSA-N 0.000 description 5
- 239000001301 oxygen Substances 0.000 description 5
- MYMOFIZGZYHOMD-UHFFFAOYSA-N oxygen Chemical group O=O MYMOFIZGZYHOMD-UHFFFAOYSA-N 0.000 description 5
- 239000002797 plasminogen activator inhibitor Substances 0.000 description 5
- 229920002223 polystyrene Polymers 0.000 description 5
- 229920005989 resin Polymers 0.000 description 5
- 200000000008 restenosis Diseases 0.000 description 5
- 125000000547 substituted alkyl group Chemical group 0.000 description 5
- 239000000758 substrate Substances 0.000 description 5
- ITMCEJHCFYSIIV-UHFFFAOYSA-M triflate Chemical compound [O-]S(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-M 0.000 description 5
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 4
- VSCWAEJMTAWNJL-UHFFFAOYSA-K Aluminium chloride Chemical compound Cl[Al](Cl)Cl VSCWAEJMTAWNJL-UHFFFAOYSA-K 0.000 description 4
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Carbodicyclohexylimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 description 4
- 108090000317 Chymotrypsin Proteins 0.000 description 4
- RAXXELZNTBOGNW-UHFFFAOYSA-N Imidazole Chemical compound C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 4
- 210000000440 Neutrophils Anatomy 0.000 description 4
- 108010051456 Plasminogen Proteins 0.000 description 4
- 102000013566 Plasminogen Human genes 0.000 description 4
- YBBRCQOCSYXUOC-UHFFFAOYSA-N Sulfuryl chloride Chemical compound ClS(Cl)(=O)=O YBBRCQOCSYXUOC-UHFFFAOYSA-N 0.000 description 4
- 125000002252 acyl group Chemical group 0.000 description 4
- 229910052782 aluminium Inorganic materials 0.000 description 4
- 125000004397 aminosulfonyl group Chemical group NS(=O)(=O)* 0.000 description 4
- 230000033115 angiogenesis Effects 0.000 description 4
- 150000001450 anions Chemical class 0.000 description 4
- 230000003110 anti-inflammatory Effects 0.000 description 4
- 230000003262 anti-osteoporosis Effects 0.000 description 4
- XKRFYHLGVUSROY-UHFFFAOYSA-N argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 4
- 125000006297 carbonyl amino group Chemical group [H]N([*:2])C([*:1])=O 0.000 description 4
- KFMGJBDNOZUQON-UHFFFAOYSA-M chloro(trimethyl)alumanuide Chemical compound [Cl-].C[Al](C)C KFMGJBDNOZUQON-UHFFFAOYSA-M 0.000 description 4
- 229960002376 chymotrypsin Drugs 0.000 description 4
- XFXPMWWXUTWYJX-UHFFFAOYSA-N cyanide Chemical compound N#[C-] XFXPMWWXUTWYJX-UHFFFAOYSA-N 0.000 description 4
- 125000000753 cycloalkyl group Chemical group 0.000 description 4
- 230000001419 dependent Effects 0.000 description 4
- RWSOTUBLDIXVET-UHFFFAOYSA-N dihydrogen sulfide Chemical compound S RWSOTUBLDIXVET-UHFFFAOYSA-N 0.000 description 4
- 239000000706 filtrate Substances 0.000 description 4
- 125000002541 furyl group Chemical group 0.000 description 4
- ZRALSGWEFCBTJO-UHFFFAOYSA-N guanidine Chemical compound NC(N)=N ZRALSGWEFCBTJO-UHFFFAOYSA-N 0.000 description 4
- VLKZOEOYAKHREP-UHFFFAOYSA-N hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 4
- OAKJQQAXSVQMHS-UHFFFAOYSA-N hydrazine Chemical compound NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 0.000 description 4
- 125000004435 hydrogen atoms Chemical group [H]* 0.000 description 4
- 229910000037 hydrogen sulfide Inorganic materials 0.000 description 4
- 125000005647 linker group Chemical group 0.000 description 4
- 150000004702 methyl esters Chemical class 0.000 description 4
- 150000002825 nitriles Chemical class 0.000 description 4
- 125000004433 nitrogen atoms Chemical group N* 0.000 description 4
- 239000003960 organic solvent Substances 0.000 description 4
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Substances [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 description 4
- 239000011347 resin Substances 0.000 description 4
- 239000000126 substance Substances 0.000 description 4
- 125000005346 substituted cycloalkyl group Chemical group 0.000 description 4
- 125000004495 thiazol-4-yl group Chemical group S1C=NC(=C1)* 0.000 description 4
- 150000003573 thiols Chemical class 0.000 description 4
- 210000001519 tissues Anatomy 0.000 description 4
- KAKQVSNHTBLJCH-UHFFFAOYSA-N trifluoromethanesulfonimidic acid Chemical compound NS(=O)(=O)C(F)(F)F KAKQVSNHTBLJCH-UHFFFAOYSA-N 0.000 description 4
- LOVPHSMOAVXQIH-UHFFFAOYSA-M (4-nitrophenyl) carbonate Chemical compound [O-]C(=O)OC1=CC=C([N+]([O-])=O)C=C1 LOVPHSMOAVXQIH-UHFFFAOYSA-M 0.000 description 3
- LBLYYCQCTBFVLH-UHFFFAOYSA-M 2-methylbenzenesulfonate Chemical compound CC1=CC=CC=C1S([O-])(=O)=O LBLYYCQCTBFVLH-UHFFFAOYSA-M 0.000 description 3
- 125000004208 3-hydroxyphenyl group Chemical group [H]OC1=C([H])C([H])=C([H])C(*)=C1[H] 0.000 description 3
- OMMIMDGHTTXEFT-UHFFFAOYSA-N 4-[4-(4-chlorophenyl)-1,3-thiazol-2-yl]-5-methylsulfanylthiophene-2-carboximidamide Chemical compound S1C(C(N)=N)=CC(C=2SC=C(N=2)C=2C=CC(Cl)=CC=2)=C1SC OMMIMDGHTTXEFT-UHFFFAOYSA-N 0.000 description 3
- TVQSONUSFKVUHY-UHFFFAOYSA-N 5-methylsulfanyl-4-[4-(4-phenylphenyl)-1,3-thiazol-2-yl]thiophene-2-carboximidamide;hydrochloride Chemical compound Cl.S1C(C(N)=N)=CC(C=2SC=C(N=2)C=2C=CC(=CC=2)C=2C=CC=CC=2)=C1SC TVQSONUSFKVUHY-UHFFFAOYSA-N 0.000 description 3
- 206010003210 Arteriosclerosis Diseases 0.000 description 3
- 125000005914 C6-C14 aryloxy group Chemical group 0.000 description 3
- MOIPGXQKZSZOQX-UHFFFAOYSA-N Carbonyl bromide Chemical compound BrC(Br)=O MOIPGXQKZSZOQX-UHFFFAOYSA-N 0.000 description 3
- 108090000617 Cathepsin G Proteins 0.000 description 3
- 102000004173 Cathepsin G Human genes 0.000 description 3
- 102100003966 ELANE Human genes 0.000 description 3
- 206010014561 Emphysema Diseases 0.000 description 3
- 229950003499 FIBRIN Drugs 0.000 description 3
- BWGVNKXGVNDBDI-UHFFFAOYSA-N Fibrin Chemical compound CNC(=O)CNC(=O)CN BWGVNKXGVNDBDI-UHFFFAOYSA-N 0.000 description 3
- 108010073385 Fibrin Proteins 0.000 description 3
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- 125000001425 triazolyl group Chemical group 0.000 description 1
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- 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 description 1
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US7411098P | 1998-02-09 | 1998-02-09 | |
US60/074,110 | 1998-02-09 | ||
PCT/US1999/002784 WO1999040088A1 (en) | 1998-02-09 | 1999-02-09 | Heteroaryl amidines, methylamidines and guanidines as protease inhibitors, in particular as urokinase inhibitors |
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JP2002502852A JP2002502852A (ja) | 2002-01-29 |
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JP2000530517A Pending JP2002502852A (ja) | 1998-02-09 | 1999-02-09 | プロテアーゼ阻害剤、特にウロキナーゼ阻害剤としてのヘテロアリールアミジン、メチルアミジンおよびグアニジン |
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US6291514B1 (en) | 1998-02-09 | 2001-09-18 | 3-Dimensional Pharmaceuticals, Inc. | Heteroaryl amidines, methylamidines and guanidines, preparation thereof, and use thereof as protease inhibitors |
JP2003529536A (ja) * | 1999-02-09 | 2003-10-07 | 3−ディメンショナル ファーマシューティカルズ, インコーポレイテッド | C1s介在疾患および状態の処置法、およびそれのための化合物および組成物 |
NZ513701A (en) * | 1999-02-09 | 2001-09-28 | Dimensional Pharm Inc | Heteroaryl amidines, methylamidines and guanidines as protease inhibitors |
WO2002057273A1 (en) * | 2001-01-20 | 2002-07-25 | Trigen Limited | Serine protease inhibitors comprising a hydrogen-bond acceptor |
WO2002070517A2 (en) * | 2001-03-02 | 2002-09-12 | Merck Frosst Canada & Co. | Cathepsin cysteine protease inhibitors |
US7838560B2 (en) * | 2002-03-11 | 2010-11-23 | The Medicines Company (Leipzig) Gmbh | Urokinase inhibitors, production and use thereof |
AU2003251384B2 (en) * | 2002-05-28 | 2009-01-29 | 3-Dimensional Pharmaceuticals, Inc. | Novel thiophene amidines, compositions thereof, and methods of treating complement-mediated diseases and conditions |
EP1394159A1 (fr) * | 2002-08-13 | 2004-03-03 | Warner-Lambert Company LLC | Nouveaux dérivés de thiophène, leur procédé de préparation et les compositions pharmaceutiques qui les contiennent |
GB0315111D0 (en) | 2003-06-27 | 2003-07-30 | Cancer Rec Tech Ltd | Substituted 5-membered ring compounds and their use |
US7482376B2 (en) * | 2003-07-03 | 2009-01-27 | 3-Dimensional Pharmaceuticals, Inc. | Conjugated complement cascade inhibitors |
NZ544674A (en) * | 2003-07-10 | 2009-03-31 | Achillion Pharmaceuticals Inc | Substituted arylthiourea derivatives useful as inhibitors of viral replication |
US7674822B2 (en) | 2004-11-24 | 2010-03-09 | Wyeth | PTP1b inhibitors |
WO2006136419A2 (en) * | 2005-06-24 | 2006-12-28 | Wilex Ag | Use of urokinase inhibitors for the treatment and/or prevention of neuropathological diseases |
RU2425045C2 (ru) * | 2005-12-27 | 2011-07-27 | Ф. Хоффманн-Ля Рош Аг | Производные арил-изоксазол-4-ил-имидазола |
US20090324581A1 (en) | 2006-05-09 | 2009-12-31 | Daiichi Sankyo Company Limited | Heteroarylamide lower carboxylic acid derivative |
US7985763B2 (en) | 2007-04-10 | 2011-07-26 | National Health Research Institutes | Hepatitis C virus inhibitors |
WO2008154091A1 (en) | 2007-06-08 | 2008-12-18 | National Health Research Institutes | Thiourea derivatives |
TWI361808B (en) | 2008-01-08 | 2012-04-11 | Nat Health Research Institutes | Imidazolidinone and imidazolidinethione derivatives |
US8198284B2 (en) | 2008-04-30 | 2012-06-12 | National Health Research Institutes | Treatment of neurodegenerative disorders with thiourea compounds |
CA2766643C (en) | 2009-07-08 | 2017-01-03 | Dermira (Canada), Inc. | Tofa analogs useful in treating dermatological disorders or conditions |
SG10201806370QA (en) * | 2013-08-28 | 2018-08-30 | Medivation Tech Llc | Heterocyclic compounds and methods of use |
JP2018507235A (ja) | 2015-03-04 | 2018-03-15 | メディベイション テクノロジーズ エルエルシー | ステロール調節エレメント結合タンパク質(srebp)阻害剤 |
CA2978627A1 (en) | 2015-03-04 | 2016-09-09 | Medivation Technologies, Inc. | Srebp blockers for use in treating liver fibrosis, elevated cholesterol and insulin resistance |
Family Cites Families (11)
Publication number | Priority date | Publication date | Assignee | Title |
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US4220654A (en) * | 1979-06-04 | 1980-09-02 | Merck & Co., Inc. | Cyclic imidazole cyanoguanidines |
US5340833A (en) * | 1992-05-01 | 1994-08-23 | Eisai Co., Ltd. | Urokinase inhibitors |
GB9312761D0 (en) * | 1993-06-21 | 1993-08-04 | Wellcome Found | Amino acid derivatives |
EP0724435B1 (en) * | 1993-10-21 | 2002-08-14 | G.D. Searle & Co. | Amidino derivatives useful as nitric oxide synthase inhibitors |
IL112795A (en) * | 1994-03-04 | 2001-01-28 | Astrazeneca Ab | Derivatives of peptides as antithrombotic drugs, their preparation, and pharmaceutical preparations containing them |
US5612353A (en) * | 1995-06-07 | 1997-03-18 | Rhone-Poulenc Rorer Pharmaceuticals Inc. | Substituted (sulfinic acid, sulfonic acid, sulfonylamino or sulfinylamino) N-[(aminoiminomethyl)phenylalkyl]-azaheterocyclylamide compounds |
TW414795B (en) * | 1996-07-01 | 2000-12-11 | Yamanouchi Pharma Co Ltd | A thiophene derivative and the pharmaceutical composition |
DE19632773A1 (de) * | 1996-08-14 | 1998-02-19 | Basf Ag | Neue Thrombininhibitoren |
PE121699A1 (es) * | 1997-02-18 | 1999-12-08 | Boehringer Ingelheim Pharma | Heterociclos biciclicos disustituidos como inhibidores de la trombina |
KR100689923B1 (ko) * | 1998-01-26 | 2007-03-09 | 애보트 게엠베하 운트 콤파니 카게 | 트롬빈 억제제 |
JP2002501044A (ja) * | 1998-01-26 | 2002-01-15 | ビーエーエスエフ アクチェンゲゼルシャフト | カリクレインプロテアーゼ阻害剤としての複素環アミジン |
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- 1999-02-09 DE DE69902754T patent/DE69902754T2/de not_active Expired - Lifetime
- 1999-02-09 CA CA002321025A patent/CA2321025A1/en not_active Abandoned
- 1999-02-09 EP EP99906845A patent/EP1054886B1/en not_active Expired - Lifetime
- 1999-02-09 NZ NZ506507A patent/NZ506507A/en unknown
- 1999-02-09 AT AT99906845T patent/ATE223408T1/de not_active IP Right Cessation
- 1999-02-09 WO PCT/US1999/002784 patent/WO1999040088A1/en active IP Right Grant
- 1999-02-09 JP JP2000530517A patent/JP2002502852A/ja active Pending
- 1999-02-09 AU AU26665/99A patent/AU765072B2/en not_active Ceased
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