DE69902754T2 - Heteroaryl-amidinen,-methylamidinen und -guanidinen als protease inhibitoren, insbesondere als urokinase inhibitoren - Google Patents
Heteroaryl-amidinen,-methylamidinen und -guanidinen als protease inhibitoren, insbesondere als urokinase inhibitorenInfo
- Publication number
- DE69902754T2 DE69902754T2 DE69902754T DE69902754T DE69902754T2 DE 69902754 T2 DE69902754 T2 DE 69902754T2 DE 69902754 T DE69902754 T DE 69902754T DE 69902754 T DE69902754 T DE 69902754T DE 69902754 T2 DE69902754 T2 DE 69902754T2
- Authority
- DE
- Germany
- Prior art keywords
- carboxamidine
- thiazol
- methylthiothiophene
- alkyl
- amino
- 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.)
- Expired - Lifetime
Links
- 239000002797 plasminogen activator inhibitor Substances 0.000 title description 10
- 150000002357 guanidines Chemical class 0.000 title description 4
- 229940042399 direct acting antivirals protease inhibitors Drugs 0.000 title description 3
- 239000000137 peptide hydrolase inhibitor Substances 0.000 title description 3
- 150000001875 compounds Chemical class 0.000 claims abstract description 165
- 238000000034 method Methods 0.000 claims abstract description 42
- 108090000435 Urokinase-type plasminogen activator Proteins 0.000 claims abstract description 31
- 229960005356 urokinase Drugs 0.000 claims abstract description 27
- 229910052717 sulfur Inorganic materials 0.000 claims abstract description 25
- 102000003990 Urokinase-type plasminogen activator Human genes 0.000 claims abstract description 24
- 150000003839 salts Chemical class 0.000 claims abstract description 22
- 108010088842 Fibrinolysin Proteins 0.000 claims abstract description 21
- 229940012957 plasmin Drugs 0.000 claims abstract description 21
- 102000035195 Peptidases Human genes 0.000 claims abstract description 18
- 108091005804 Peptidases Proteins 0.000 claims abstract description 18
- 239000004365 Protease Substances 0.000 claims abstract description 11
- 229910052760 oxygen Inorganic materials 0.000 claims abstract description 11
- 108090000317 Chymotrypsin Proteins 0.000 claims abstract description 9
- 229960002376 chymotrypsin Drugs 0.000 claims abstract description 9
- 108090000631 Trypsin Proteins 0.000 claims abstract description 7
- 102000004142 Trypsin Human genes 0.000 claims abstract description 7
- 239000012588 trypsin Substances 0.000 claims abstract description 7
- 229960001322 trypsin Drugs 0.000 claims abstract description 6
- 239000012453 solvate Substances 0.000 claims abstract description 5
- -1 amino, hydroxy Chemical group 0.000 claims description 347
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Natural products CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 146
- 125000000217 alkyl group Chemical group 0.000 claims description 74
- 239000001257 hydrogen Substances 0.000 claims description 73
- 229910052739 hydrogen Inorganic materials 0.000 claims description 73
- 239000007787 solid Substances 0.000 claims description 69
- 238000011282 treatment Methods 0.000 claims description 63
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 claims description 53
- 125000003118 aryl group Chemical group 0.000 claims description 53
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 52
- 238000010992 reflux Methods 0.000 claims description 52
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 42
- 229910052736 halogen Inorganic materials 0.000 claims description 38
- 150000002367 halogens Chemical group 0.000 claims description 38
- 150000002431 hydrogen Chemical group 0.000 claims description 38
- 239000000203 mixture Substances 0.000 claims description 38
- 125000004432 carbon atom Chemical group C* 0.000 claims description 35
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 35
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 34
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 34
- 125000003545 alkoxy group Chemical group 0.000 claims description 32
- 125000000623 heterocyclic group Chemical group 0.000 claims description 30
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 29
- 238000003756 stirring Methods 0.000 claims description 29
- 125000004414 alkyl thio group Chemical group 0.000 claims description 28
- 235000019270 ammonium chloride Nutrition 0.000 claims description 28
- JLTRXTDYQLMHGR-UHFFFAOYSA-N trimethylaluminium Chemical compound C[Al](C)C JLTRXTDYQLMHGR-UHFFFAOYSA-N 0.000 claims description 28
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 27
- 125000005110 aryl thio group Chemical group 0.000 claims description 26
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 26
- 239000000725 suspension Substances 0.000 claims description 25
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 24
- 125000004442 acylamino group Chemical group 0.000 claims description 24
- 125000004104 aryloxy group Chemical group 0.000 claims description 24
- 229910052757 nitrogen Inorganic materials 0.000 claims description 24
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 24
- 125000003710 aryl alkyl group Chemical group 0.000 claims description 23
- 150000002148 esters Chemical class 0.000 claims description 23
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 23
- 125000000266 alpha-aminoacyl group Chemical group 0.000 claims description 22
- 125000004453 alkoxycarbonyl group Chemical group 0.000 claims description 21
- 125000003282 alkyl amino group Chemical group 0.000 claims description 21
- 125000000335 thiazolyl group Chemical group 0.000 claims description 21
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 20
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical group [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 20
- 125000001424 substituent group Chemical group 0.000 claims description 20
- 125000004682 aminothiocarbonyl group Chemical group NC(=S)* 0.000 claims description 19
- 201000010099 disease Diseases 0.000 claims description 19
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 19
- 125000004191 (C1-C6) alkoxy group Chemical group 0.000 claims description 18
- 125000004657 aryl sulfonyl amino group Chemical group 0.000 claims description 18
- 125000004663 dialkyl amino group Chemical group 0.000 claims description 18
- 125000004466 alkoxycarbonylamino group Chemical group 0.000 claims description 17
- 125000005162 aryl oxy carbonyl amino group Chemical group 0.000 claims description 17
- 125000002971 oxazolyl group Chemical group 0.000 claims description 17
- 206010028980 Neoplasm Diseases 0.000 claims description 16
- 239000011593 sulfur Substances 0.000 claims description 16
- 125000001544 thienyl group Chemical group 0.000 claims description 16
- 125000000304 alkynyl group Chemical group 0.000 claims description 15
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 15
- 125000004076 pyridyl group Chemical group 0.000 claims description 15
- 125000003342 alkenyl group Chemical group 0.000 claims description 14
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims description 14
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 14
- 125000000437 thiazol-2-yl group Chemical group [H]C1=C([H])N=C(*)S1 0.000 claims description 14
- 125000004390 alkyl sulfonyl group Chemical group 0.000 claims description 13
- 125000004391 aryl sulfonyl group Chemical group 0.000 claims description 13
- 125000004656 alkyl sulfonylamino group Chemical group 0.000 claims description 12
- 125000005140 aralkylsulfonyl group Chemical group 0.000 claims description 12
- 239000000460 chlorine Substances 0.000 claims description 12
- 229910052801 chlorine Inorganic materials 0.000 claims description 12
- 125000001072 heteroaryl group Chemical group 0.000 claims description 12
- 125000002883 imidazolyl group Chemical group 0.000 claims description 12
- 125000002816 methylsulfanyl group Chemical group [H]C([H])([H])S[*] 0.000 claims description 12
- 125000000229 (C1-C4)alkoxy group Chemical group 0.000 claims description 11
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 11
- 206010027476 Metastases Diseases 0.000 claims description 11
- 125000004196 benzothienyl group Chemical group S1C(=CC2=C1C=CC=C2)* 0.000 claims description 11
- 125000004181 carboxyalkyl group Chemical group 0.000 claims description 11
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 11
- 230000009401 metastasis Effects 0.000 claims description 11
- 150000003254 radicals Chemical class 0.000 claims description 11
- 125000006700 (C1-C6) alkylthio group Chemical group 0.000 claims description 10
- 239000002841 Lewis acid Substances 0.000 claims description 10
- 101100311330 Schizosaccharomyces pombe (strain 972 / ATCC 24843) uap56 gene Proteins 0.000 claims description 10
- 125000005078 alkoxycarbonylalkyl group Chemical group 0.000 claims description 10
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 10
- 239000003814 drug Substances 0.000 claims description 10
- 239000007789 gas Substances 0.000 claims description 10
- 150000007517 lewis acids Chemical class 0.000 claims description 10
- 101150018444 sub2 gene Proteins 0.000 claims description 10
- 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 claims description 9
- LKDMKWNDBAVNQZ-UHFFFAOYSA-N 4-[[1-[[1-[2-[[1-(4-nitroanilino)-1-oxo-3-phenylpropan-2-yl]carbamoyl]pyrrolidin-1-yl]-1-oxopropan-2-yl]amino]-1-oxopropan-2-yl]amino]-4-oxobutanoic acid Chemical compound OC(=O)CCC(=O)NC(C)C(=O)NC(C)C(=O)N1CCCC1C(=O)NC(C(=O)NC=1C=CC(=CC=1)[N+]([O-])=O)CC1=CC=CC=C1 LKDMKWNDBAVNQZ-UHFFFAOYSA-N 0.000 claims description 9
- 206010004446 Benign prostatic hyperplasia Diseases 0.000 claims description 9
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims description 9
- 125000000041 C6-C10 aryl group Chemical group 0.000 claims description 9
- 108090000617 Cathepsin G Proteins 0.000 claims description 9
- 206010060862 Prostate cancer Diseases 0.000 claims description 9
- 208000004403 Prostatic Hyperplasia Diseases 0.000 claims description 9
- 208000000236 Prostatic Neoplasms Diseases 0.000 claims description 9
- 201000004681 Psoriasis Diseases 0.000 claims description 9
- 108090000190 Thrombin Proteins 0.000 claims description 9
- 125000005202 dialkylaminocarbonyloxy group Chemical group 0.000 claims description 9
- 125000002541 furyl group Chemical group 0.000 claims description 9
- 230000002401 inhibitory effect Effects 0.000 claims description 9
- 239000008194 pharmaceutical composition Substances 0.000 claims description 9
- 230000008569 process Effects 0.000 claims description 9
- 125000002252 acyl group Chemical group 0.000 claims description 8
- 125000005195 alkyl amino carbonyloxy group Chemical group 0.000 claims description 8
- 125000000842 isoxazolyl group Chemical group 0.000 claims description 8
- 229960004072 thrombin Drugs 0.000 claims description 8
- 125000005915 C6-C14 aryl group Chemical group 0.000 claims description 7
- 102100033174 Neutrophil elastase Human genes 0.000 claims description 7
- 125000003277 amino group Chemical group 0.000 claims description 7
- 125000004659 aryl alkyl thio group Chemical group 0.000 claims description 7
- 125000004473 dialkylaminocarbonyl group Chemical group 0.000 claims description 7
- 125000004671 dialkylaminothiocarbonyl group Chemical group 0.000 claims description 7
- 238000010438 heat treatment Methods 0.000 claims description 7
- 125000001786 isothiazolyl group Chemical group 0.000 claims description 7
- 238000004519 manufacturing process Methods 0.000 claims description 7
- 125000001624 naphthyl group Chemical group 0.000 claims description 7
- 125000005968 oxazolinyl group Chemical group 0.000 claims description 7
- 125000003226 pyrazolyl group Chemical group 0.000 claims description 7
- 125000000714 pyrimidinyl group Chemical group 0.000 claims description 7
- 125000000168 pyrrolyl group Chemical group 0.000 claims description 7
- 229920006395 saturated elastomer Polymers 0.000 claims description 7
- 125000003831 tetrazolyl group Chemical group 0.000 claims description 7
- 125000004890 (C1-C6) alkylamino group Chemical group 0.000 claims description 6
- NPTFSUUZGYDTPV-UHFFFAOYSA-N 5-methylsulfanyl-4-phenylthiophene-2-carboximidamide Chemical compound S1C(C(N)=N)=CC(C=2C=CC=CC=2)=C1SC NPTFSUUZGYDTPV-UHFFFAOYSA-N 0.000 claims description 6
- 125000005914 C6-C14 aryloxy group Chemical group 0.000 claims description 6
- 206010014561 Emphysema Diseases 0.000 claims description 6
- 108010074860 Factor Xa Proteins 0.000 claims description 6
- 102000016387 Pancreatic elastase Human genes 0.000 claims description 6
- 108010067372 Pancreatic elastase Proteins 0.000 claims description 6
- 125000004397 aminosulfonyl group Chemical group NS(=O)(=O)* 0.000 claims description 6
- 125000004472 dialkylaminosulfonyl group Chemical group 0.000 claims description 6
- ZUOUZKKEUPVFJK-UHFFFAOYSA-N diphenyl Chemical group C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 claims description 6
- 125000005842 heteroatom Chemical group 0.000 claims description 6
- 125000004430 oxygen atom Chemical group O* 0.000 claims description 6
- 125000003373 pyrazinyl group Chemical group 0.000 claims description 6
- 125000000547 substituted alkyl group Chemical group 0.000 claims description 6
- 125000004434 sulfur atom Chemical group 0.000 claims description 6
- GFTDFOYLMGQHFH-UHFFFAOYSA-N 4-(4-cyclohexyl-1,3-thiazol-2-yl)-5-methylsulfanylthiophene-2-carboximidamide Chemical compound S1C(C(N)=N)=CC(C=2SC=C(N=2)C2CCCCC2)=C1SC GFTDFOYLMGQHFH-UHFFFAOYSA-N 0.000 claims description 5
- GARVNVZOSLSGOA-UHFFFAOYSA-N 4-[4-(2-chloropyridin-3-yl)-1,3-thiazol-2-yl]-5-methylsulfanylthiophene-2-carboximidamide Chemical compound S1C(C(N)=N)=CC(C=2SC=C(N=2)C=2C(=NC=CC=2)Cl)=C1SC GARVNVZOSLSGOA-UHFFFAOYSA-N 0.000 claims description 5
- QGSDCVGMOUWGJT-UHFFFAOYSA-N 4-[4-(2-chloropyridin-4-yl)-1,3-thiazol-2-yl]-5-methylsulfanylthiophene-2-carboximidamide Chemical compound S1C(C(N)=N)=CC(C=2SC=C(N=2)C=2C=C(Cl)N=CC=2)=C1SC QGSDCVGMOUWGJT-UHFFFAOYSA-N 0.000 claims description 5
- UZGWXXYKZGJHJY-UHFFFAOYSA-N 5-methylsulfanyl-4-(4-methyl-1,3-thiazol-2-yl)thiophene-2-carboximidamide Chemical compound S1C(C(N)=N)=CC(C=2SC=C(C)N=2)=C1SC UZGWXXYKZGJHJY-UHFFFAOYSA-N 0.000 claims description 5
- AIGVJMZDTQIJIQ-UHFFFAOYSA-N 5-methylsulfanyl-4-propan-2-ylsulfonylthiophene-2-carboximidamide Chemical compound CSC=1SC(C(N)=N)=CC=1S(=O)(=O)C(C)C AIGVJMZDTQIJIQ-UHFFFAOYSA-N 0.000 claims description 5
- 108010028275 Leukocyte Elastase Proteins 0.000 claims description 5
- 125000001769 aryl amino group Chemical group 0.000 claims description 5
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 5
- 125000002950 monocyclic group Chemical group 0.000 claims description 5
- 239000001301 oxygen Substances 0.000 claims description 5
- 208000037803 restenosis Diseases 0.000 claims description 5
- 125000002769 thiazolinyl group Chemical group 0.000 claims description 5
- 125000003441 thioacyl group Chemical group 0.000 claims description 5
- 125000004845 (C1-C6) alkylsulfonylamino group Chemical group 0.000 claims description 4
- HNTSNHYPGXXIFN-UHFFFAOYSA-N 4-[2-(2,3-dichloroanilino)-1,3-thiazol-4-yl]-5-methylsulfanylthiophene-2-carboximidamide Chemical compound S1C(C(N)=N)=CC(C=2N=C(NC=3C(=C(Cl)C=CC=3)Cl)SC=2)=C1SC HNTSNHYPGXXIFN-UHFFFAOYSA-N 0.000 claims description 4
- BBZQWPQSGQXDJT-UHFFFAOYSA-N 4-[2-(2-bromo-4-methylanilino)-1,3-thiazol-4-yl]-5-methylsulfanylthiophene-2-carboximidamide Chemical compound S1C(C(N)=N)=CC(C=2N=C(NC=3C(=CC(C)=CC=3)Br)SC=2)=C1SC BBZQWPQSGQXDJT-UHFFFAOYSA-N 0.000 claims description 4
- ZUWAYNCFFNVIBJ-UHFFFAOYSA-N 4-[2-(2-fluoroanilino)-1,3-thiazol-4-yl]-5-methylsulfanylthiophene-2-carboximidamide Chemical compound S1C(C(N)=N)=CC(C=2N=C(NC=3C(=CC=CC=3)F)SC=2)=C1SC ZUWAYNCFFNVIBJ-UHFFFAOYSA-N 0.000 claims description 4
- LIRPGSNQMOFUBQ-UHFFFAOYSA-N 4-[2-(3-chloro-2-methylanilino)-1,3-thiazol-4-yl]-5-methylsulfanylthiophene-2-carboximidamide Chemical compound S1C(C(N)=N)=CC(C=2N=C(NC=3C(=C(Cl)C=CC=3)C)SC=2)=C1SC LIRPGSNQMOFUBQ-UHFFFAOYSA-N 0.000 claims description 4
- FDRDCAYYXVHESU-UHFFFAOYSA-N 4-[2-(3-methoxyanilino)-1,3-thiazol-4-yl]-5-methylsulfanylthiophene-2-carboximidamide Chemical compound COC1=CC=CC(NC=2SC=C(N=2)C2=C(SC(=C2)C(N)=N)SC)=C1 FDRDCAYYXVHESU-UHFFFAOYSA-N 0.000 claims description 4
- KSJUFIPSZGIVLF-UHFFFAOYSA-N 4-[2-(4-chloro-2-methylanilino)-1,3-thiazol-4-yl]-5-methylsulfanylthiophene-2-carboximidamide Chemical compound S1C(C(N)=N)=CC(C=2N=C(NC=3C(=CC(Cl)=CC=3)C)SC=2)=C1SC KSJUFIPSZGIVLF-UHFFFAOYSA-N 0.000 claims description 4
- QJRTVZFPEDJWOS-UHFFFAOYSA-N 4-[2-(4-methoxyanilino)-1,3-thiazol-4-yl]-5-methylsulfanylthiophene-2-carboximidamide Chemical compound C1=CC(OC)=CC=C1NC1=NC(C2=C(SC(=C2)C(N)=N)SC)=CS1 QJRTVZFPEDJWOS-UHFFFAOYSA-N 0.000 claims description 4
- ABEISAYFSWNEFB-UHFFFAOYSA-N 4-[2-(benzhydrylamino)-1,3-thiazol-4-yl]-5-methylsulfanylthiophene-2-carboximidamide Chemical compound S1C(C(N)=N)=CC(C=2N=C(NC(C=3C=CC=CC=3)C=3C=CC=CC=3)SC=2)=C1SC ABEISAYFSWNEFB-UHFFFAOYSA-N 0.000 claims description 4
- WHGZPVSQCGFYBQ-UHFFFAOYSA-N 4-[4-(2,4-dichlorophenyl)-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)Cl)=C1SC WHGZPVSQCGFYBQ-UHFFFAOYSA-N 0.000 claims description 4
- KLVFDMVKNCAXRG-UHFFFAOYSA-N 4-[4-(3-hydroxyphenyl)-1,3-thiazol-2-yl]-5-methylsulfanylthiophene-2-carboximidamide Chemical compound S1C(C(N)=N)=CC(C=2SC=C(N=2)C=2C=C(O)C=CC=2)=C1SC KLVFDMVKNCAXRG-UHFFFAOYSA-N 0.000 claims description 4
- CKYREKXNBZFCFF-UHFFFAOYSA-N 5-methylsulfanyl-4-(4-naphthalen-2-yl-1,3-thiazol-2-yl)thiophene-2-carboximidamide Chemical compound S1C(C(N)=N)=CC(C=2SC=C(N=2)C=2C=C3C=CC=CC3=CC=2)=C1SC CKYREKXNBZFCFF-UHFFFAOYSA-N 0.000 claims description 4
- YCMAPLMAEQZHAF-UHFFFAOYSA-N 5-methylsulfanyl-4-[2-(2,4,5-trimethylanilino)-1,3-thiazol-4-yl]thiophene-2-carboximidamide Chemical compound S1C(C(N)=N)=CC(C=2N=C(NC=3C(=CC(C)=C(C)C=3)C)SC=2)=C1SC YCMAPLMAEQZHAF-UHFFFAOYSA-N 0.000 claims description 4
- YNLXACABVDXVBV-UHFFFAOYSA-N 5-methylsulfanyl-4-[2-(2-propan-2-ylanilino)-1,3-thiazol-4-yl]thiophene-2-carboximidamide Chemical compound S1C(C(N)=N)=CC(C=2N=C(NC=3C(=CC=CC=3)C(C)C)SC=2)=C1SC YNLXACABVDXVBV-UHFFFAOYSA-N 0.000 claims description 4
- VCMYKMXIDILKGK-UHFFFAOYSA-N 5-methylsulfanyl-4-[2-(3,4,5-trimethoxyanilino)-1,3-thiazol-4-yl]thiophene-2-carboximidamide Chemical compound COC1=C(OC)C(OC)=CC(NC=2SC=C(N=2)C2=C(SC(=C2)C(N)=N)SC)=C1 VCMYKMXIDILKGK-UHFFFAOYSA-N 0.000 claims description 4
- WWYYVQSACHTSIU-UHFFFAOYSA-N 5-methylsulfanyl-4-[2-(3-phenylpropylamino)-1,3-thiazol-4-yl]thiophene-2-carboximidamide Chemical compound S1C(C(N)=N)=CC(C=2N=C(NCCCC=3C=CC=CC=3)SC=2)=C1SC WWYYVQSACHTSIU-UHFFFAOYSA-N 0.000 claims description 4
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 claims description 4
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- 125000004457 alkyl amino carbonyl group Chemical group 0.000 claims description 4
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- 239000012298 atmosphere Substances 0.000 claims description 4
- 125000003785 benzimidazolyl group Chemical group N1=C(NC2=C1C=CC=C2)* 0.000 claims description 4
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- 125000001188 haloalkyl group Chemical group 0.000 claims description 4
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- UYWQUFXKFGHYNT-UHFFFAOYSA-N phenylmethyl ester of formic acid Natural products O=COCC1=CC=CC=C1 UYWQUFXKFGHYNT-UHFFFAOYSA-N 0.000 claims description 4
- 125000000719 pyrrolidinyl group Chemical group 0.000 claims description 4
- 206010039073 rheumatoid arthritis Diseases 0.000 claims description 4
- 125000005346 substituted cycloalkyl group Chemical group 0.000 claims description 4
- KAKQVSNHTBLJCH-UHFFFAOYSA-N trifluoromethanesulfonimidic acid Chemical compound NS(=O)(=O)C(F)(F)F KAKQVSNHTBLJCH-UHFFFAOYSA-N 0.000 claims description 4
- 125000006624 (C1-C6) alkoxycarbonylamino group Chemical group 0.000 claims description 3
- 125000004209 (C1-C8) alkyl group Chemical group 0.000 claims description 3
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims description 3
- 125000006272 (C3-C7) cycloalkyl group Chemical group 0.000 claims description 3
- XVPMAUVOZSXQSE-UHFFFAOYSA-N 4-[2-(2,6-dichloroanilino)-1,3-thiazol-4-yl]-5-methylsulfanylthiophene-2-carboximidamide Chemical compound S1C(C(N)=N)=CC(C=2N=C(NC=3C(=CC=CC=3Cl)Cl)SC=2)=C1SC XVPMAUVOZSXQSE-UHFFFAOYSA-N 0.000 claims description 3
- AEBZRNXDNPAWQV-UHFFFAOYSA-N 4-[2-(2-bromoanilino)-1,3-thiazol-4-yl]-5-methylsulfanylthiophene-2-carboximidamide Chemical compound S1C(C(N)=N)=CC(C=2N=C(NC=3C(=CC=CC=3)Br)SC=2)=C1SC AEBZRNXDNPAWQV-UHFFFAOYSA-N 0.000 claims description 3
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
- C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
- C07D409/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
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- 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
- A61P13/08—Drugs for disorders of the urinary system of the prostate
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P15/00—Drugs for genital or sexual disorders; Contraceptives
- A61P15/18—Feminine contraceptives
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
- A61P17/06—Antipsoriatics
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- 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
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- 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
- A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
- A61P19/10—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease for osteoporosis
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- A—HUMAN NECESSITIES
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- 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]
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
- A61P35/04—Antineoplastic agents specific for metastasis
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- 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
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- 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
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- 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
- 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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
- C07D413/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
- C07D417/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
- C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
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- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Public Health (AREA)
- Animal Behavior & Ethology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Veterinary Medicine (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Physical Education & Sports Medicine (AREA)
- Rheumatology (AREA)
- Orthopedic Medicine & Surgery (AREA)
- Urology & Nephrology (AREA)
- Heart & Thoracic Surgery (AREA)
- Cardiology (AREA)
- Oncology (AREA)
- Dermatology (AREA)
- Pain & Pain Management (AREA)
- Vascular Medicine (AREA)
- Gynecology & Obstetrics (AREA)
- Endocrinology (AREA)
- Reproductive Health (AREA)
- Immunology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
- Thiazole And Isothizaole Compounds (AREA)
- Enzymes And Modification Thereof (AREA)
- Heterocyclic Compounds Containing Sulfur Atoms (AREA)
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US7411098P | 1998-02-09 | 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 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| DE69902754D1 DE69902754D1 (de) | 2002-10-10 |
| DE69902754T2 true DE69902754T2 (de) | 2003-08-07 |
Family
ID=22117801
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| DE69902754T Expired - Lifetime DE69902754T2 (de) | 1998-02-09 | 1999-02-09 | Heteroaryl-amidinen,-methylamidinen und -guanidinen als protease inhibitoren, insbesondere als urokinase inhibitoren |
Country Status (8)
| Country | Link |
|---|---|
| EP (1) | EP1054886B1 (https=) |
| JP (1) | JP2002502852A (https=) |
| AT (1) | ATE223408T1 (https=) |
| AU (1) | AU765072B2 (https=) |
| CA (1) | CA2321025A1 (https=) |
| DE (1) | DE69902754T2 (https=) |
| NZ (1) | NZ506507A (https=) |
| WO (1) | WO1999040088A1 (https=) |
Families Citing this family (23)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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 |
| HUP0201475A2 (hu) * | 1999-02-09 | 2003-10-28 | 3-Dimensional Pharmaceuticals, Inc. | Heteroarilamidin-, metilamidin- és guanidinszármazékok, előállításuk és alkalmazásuk, valamint e vegyületeket tartalmazó gyógyászati készítmények |
| EP1152759A2 (en) * | 1999-02-09 | 2001-11-14 | 3-Dimensional Pharmaceuticals, Inc. | METHODS OF TREATING C1s-MEDIATED DISEASES AND CONDITIONS, AND COMPOUNDS AND COMPOSITIONS THEREFOR |
| US20040235792A1 (en) * | 2001-01-20 | 2004-11-25 | Deadman John J | Serine protease inhibitors compromising a hydrogen-bond acceptor |
| AU2002242500A1 (en) * | 2001-03-02 | 2002-09-19 | Merck Frosst Canada And Co. | Cathepsin cysteine protease inhibitors |
| US7838560B2 (en) * | 2002-03-11 | 2010-11-23 | The Medicines Company (Leipzig) Gmbh | Urokinase inhibitors, production and use thereof |
| HRP20041220A2 (hr) * | 2002-05-28 | 2006-04-30 | 3-Dimensional Pharmaceuticals | Novi tiofen amidini, njihovi pripravci i postupci liječenja komplementom posredovanih bolesti i stanja |
| 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 |
| CA2531068A1 (en) * | 2003-07-10 | 2005-01-27 | Achillion Pharmaceuticals, Inc. | Substituted arylthiourea derivatives useful as inhibitors of viral replication |
| US7674822B2 (en) | 2004-11-24 | 2010-03-09 | Wyeth | PTP1b inhibitors |
| MX2007016439A (es) | 2005-06-24 | 2008-03-04 | Wilex Ag | Uso de inhibidores de urocinasa para el tratamiento y/o prevencion de enfermedades neuropatologicas. |
| ATE527255T1 (de) * | 2005-12-27 | 2011-10-15 | Hoffmann La Roche | Aryl-isoxazol-4-yl-imidazol-derivate |
| JPWO2007129745A1 (ja) | 2006-05-09 | 2009-09-17 | 第一三共株式会社 | ヘテロアリールアミド低級カルボン酸誘導体 |
| WO2008124300A1 (en) | 2007-04-10 | 2008-10-16 | National Health Research Institutes | Hepatitis c virus inhibitors |
| TW200848016A (en) | 2007-06-08 | 2008-12-16 | Nat Health Research Institutes | Thiourea compound and composition of treating hepatitis C virus infection |
| 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 |
| CN102482249B (zh) | 2009-07-08 | 2016-06-08 | 德米拉(加拿大)公司 | 用于治疗皮肤病症或疾病状态的tofa类似物 |
| 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 |
| JP2018507234A (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 | 肝臓線維症、コレステロールの上昇およびインスリン抵抗性を処置する際における使用のためのｓｒｅｂｐ遮断薬 |
Family Cites Families (11)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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 |
| WO1995011014A1 (en) * | 1993-10-21 | 1995-04-27 | G.D. Searle & Co. | Amidino derivatives useful as nitric oxide synthase inhibitors |
| ZA951617B (en) * | 1994-03-04 | 1997-02-27 | Lilly Co Eli | Antithrombotic agents. |
| 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 |
| AU2424499A (en) * | 1998-01-26 | 1999-08-09 | Basf Aktiengesellschaft | Heterocyclic amidines as callicrein protease inhibitors |
| EP1051431A1 (de) * | 1998-01-26 | 2000-11-15 | Basf Aktiengesellschaft | Thrombininhibitoren |
-
1999
- 1999-02-09 NZ NZ506507A patent/NZ506507A/en unknown
- 1999-02-09 CA CA002321025A patent/CA2321025A1/en not_active Abandoned
- 1999-02-09 JP JP2000530517A patent/JP2002502852A/ja active Pending
- 1999-02-09 AT AT99906845T patent/ATE223408T1/de not_active IP Right Cessation
- 1999-02-09 DE DE69902754T patent/DE69902754T2/de not_active Expired - Lifetime
- 1999-02-09 EP EP99906845A patent/EP1054886B1/en not_active Expired - Lifetime
- 1999-02-09 AU AU26665/99A patent/AU765072B2/en not_active Ceased
- 1999-02-09 WO PCT/US1999/002784 patent/WO1999040088A1/en not_active Ceased
Also Published As
| Publication number | Publication date |
|---|---|
| WO1999040088A1 (en) | 1999-08-12 |
| DE69902754D1 (de) | 2002-10-10 |
| EP1054886B1 (en) | 2002-09-04 |
| NZ506507A (en) | 2003-08-29 |
| ATE223408T1 (de) | 2002-09-15 |
| CA2321025A1 (en) | 1999-08-12 |
| EP1054886A1 (en) | 2000-11-29 |
| AU765072B2 (en) | 2003-09-11 |
| AU2666599A (en) | 1999-08-23 |
| JP2002502852A (ja) | 2002-01-29 |
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| 8364 | No opposition during term of opposition |