NO20023921L - Derivater av thiazepinylhydroksamisk syre som inhibitorer av matriks metalloproteinase - Google Patents

Info

Publication number

NO20023921L

NO20023921L NO20023921A NO20023921A NO20023921L NO 20023921 L NO20023921 L NO 20023921L NO 20023921 A NO20023921 A NO 20023921A NO 20023921 A NO20023921 A NO 20023921A NO 20023921 L NO20023921 L NO 20023921L

Authority

NO

Norway

Prior art keywords

optionally substituted

alkanoyl

alkoxy

substituted

group containing

Prior art date

2000-02-21

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• 102000002274 Matrix Metalloproteinases Human genes 0.000 title claims abstract description 19
• 108010000684 Matrix Metalloproteinases Proteins 0.000 title claims abstract description 19
• 239000003112 inhibitor Substances 0.000 title claims abstract description 6
• -1 Thiazepinyl hydroxamic Chemical compound 0.000 title claims description 2007
• 239000002253 acid Substances 0.000 title description 22
• 125000003545 alkoxy group Chemical group 0.000 claims abstract description 244
• 238000004519 manufacturing process Methods 0.000 claims abstract description 171
• 125000000623 heterocyclic group Chemical group 0.000 claims abstract description 136
• 150000003839 salts Chemical class 0.000 claims abstract description 75
• 125000003118 aryl group Chemical group 0.000 claims abstract description 64
• 125000002252 acyl group Chemical group 0.000 claims abstract description 42
• 125000004104 aryloxy group Chemical group 0.000 claims abstract description 35
• 125000000304 alkynyl group Chemical group 0.000 claims abstract description 20
• 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 claims abstract description 15
• 125000003107 substituted aryl group Chemical group 0.000 claims abstract description 14
• 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims abstract description 13
• 239000001257 hydrogen Substances 0.000 claims abstract description 13
• 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 13
• 125000002947 alkylene group Chemical group 0.000 claims abstract description 10
• UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims abstract description 7
• 241000534944 Thia Species 0.000 claims abstract description 5
• 125000000475 sulfinyl group Chemical group [*:2]S([*:1])=O 0.000 claims abstract description 5
• 125000001589 carboacyl group Chemical group 0.000 claims description 158
• 125000000217 alkyl group Chemical group 0.000 claims description 153
• 150000001875 compounds Chemical class 0.000 claims description 142
• 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 138
• 125000002911 monocyclic heterocycle group Chemical group 0.000 claims description 132
• 125000004433 nitrogen atom Chemical group N* 0.000 claims description 110
• 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 claims description 89
• 125000004356 hydroxy functional group Chemical group O* 0.000 claims description 70
• 125000004434 sulfur atom Chemical group 0.000 claims description 63
• 238000006243 chemical reaction Methods 0.000 claims description 61
• 125000004430 oxygen atom Chemical group O* 0.000 claims description 61
• 229920006395 saturated elastomer Polymers 0.000 claims description 57
• 125000004453 alkoxycarbonyl group Chemical group 0.000 claims description 54
• 125000005115 alkyl carbamoyl group Chemical group 0.000 claims description 54
• 125000005236 alkanoylamino group Chemical group 0.000 claims description 52
• 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 48
• 125000004390 alkyl sulfonyl group Chemical group 0.000 claims description 45
• 229910052736 halogen Inorganic materials 0.000 claims description 38
• 150000002367 halogens Chemical group 0.000 claims description 38
• 125000005843 halogen group Chemical group 0.000 claims description 34
• 238000000034 method Methods 0.000 claims description 33
• 125000004471 alkyl aminosulfonyl group Chemical group 0.000 claims description 31
• 125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 claims description 29
• 125000001544 thienyl group Chemical group 0.000 claims description 29
• 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 claims description 27
• 125000004466 alkoxycarbonylamino group Chemical group 0.000 claims description 27
• 125000003435 aroyl group Chemical group 0.000 claims description 27
• 125000003342 alkenyl group Chemical group 0.000 claims description 26
• 125000004170 methylsulfonyl group Chemical group [H]C([H])([H])S(*)(=O)=O 0.000 claims description 24
• 125000002619 bicyclic group Chemical group 0.000 claims description 23
• 125000006254 cycloalkyl carbonyl group Chemical group 0.000 claims description 23
• 125000000041 C6-C10 aryl group Chemical group 0.000 claims description 21
• 125000005400 pyridylcarbonyl group Chemical group N1=C(C=CC=C1)C(=O)* 0.000 claims description 21
• 125000006263 dimethyl aminosulfonyl group Chemical group [H]C([H])([H])N(C([H])([H])[H])S(*)(=O)=O 0.000 claims description 20
• 125000005037 alkyl phenyl group Chemical group 0.000 claims description 19
• 125000006125 ethylsulfonyl group Chemical group 0.000 claims description 19
• 125000003170 phenylsulfonyl group Chemical group C1(=CC=CC=C1)S(=O)(=O)* 0.000 claims description 19
• 125000004076 pyridyl group Chemical group 0.000 claims description 19
• 125000003088 (fluoren-9-ylmethoxy)carbonyl group Chemical group 0.000 claims description 18
• 125000001501 propionyl group Chemical group O=C([*])C([H])([H])C([H])([H])[H] 0.000 claims description 18
• YQTCQNIPQMJNTI-UHFFFAOYSA-N 2,2-dimethylpropan-1-one Chemical group CC(C)(C)[C]=O YQTCQNIPQMJNTI-UHFFFAOYSA-N 0.000 claims description 17
• 125000004949 alkyl amino carbonyl amino group Chemical group 0.000 claims description 17
• 125000001584 benzyloxycarbonyl group Chemical group C(=O)(OCC1=CC=CC=C1)* 0.000 claims description 17
• 125000004093 cyano group Chemical group *C#N 0.000 claims description 17
• 125000006255 cyclopropyl carbonyl group Chemical group [H]C1([H])C([H])([H])C1([H])C(*)=O 0.000 claims description 17
• UYWQUFXKFGHYNT-UHFFFAOYSA-N phenylmethyl ester of formic acid Natural products O=COCC1=CC=CC=C1 UYWQUFXKFGHYNT-UHFFFAOYSA-N 0.000 claims description 17
• 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 16
• 125000004414 alkyl thio group Chemical group 0.000 claims description 15
• 125000000753 cycloalkyl group Chemical group 0.000 claims description 15
• 125000002541 furyl group Chemical group 0.000 claims description 15
• 125000003104 hexanoyl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 15
• 125000001624 naphthyl group Chemical group 0.000 claims description 15
• 125000003630 glycyl group Chemical group [H]N([H])C([H])([H])C(*)=O 0.000 claims description 14
• 230000002401 inhibitory effect Effects 0.000 claims description 14
• 125000001999 4-Methoxybenzoyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1OC([H])([H])[H])C(*)=O 0.000 claims description 13
• 125000000242 4-chlorobenzoyl group Chemical group ClC1=CC=C(C(=O)*)C=C1 0.000 claims description 13
• 108060008682 Tumor Necrosis Factor Proteins 0.000 claims description 13
• 125000003754 ethoxycarbonyl group Chemical group C(=O)(OCC)* 0.000 claims description 13
• 125000001160 methoxycarbonyl group Chemical group [H]C([H])([H])OC(*)=O 0.000 claims description 13
• 125000003816 2-hydroxybenzoyl group Chemical group OC1=C(C(=O)*)C=CC=C1 0.000 claims description 12
• 125000006637 cyclobutyl carbonyl group Chemical group 0.000 claims description 12
• 125000006639 cyclohexyl carbonyl group Chemical group 0.000 claims description 12
• 125000006638 cyclopentyl carbonyl group Chemical group 0.000 claims description 12
• 125000005929 isobutyloxycarbonyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])OC(*)=O 0.000 claims description 12
• 125000006678 phenoxycarbonyl group Chemical group 0.000 claims description 12
• 125000005493 quinolyl group Chemical group 0.000 claims description 12
• 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims description 10
• 125000001038 naphthoyl group Chemical group C1(=CC=CC2=CC=CC=C12)C(=O)* 0.000 claims description 10
• 125000004397 aminosulfonyl group Chemical group NS(=O)(=O)* 0.000 claims description 9
• 125000001255 4-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1F 0.000 claims description 8
• 125000000499 benzofuranyl group Chemical group O1C(=CC2=C1C=CC=C2)* 0.000 claims description 8
• 125000004802 cyanophenyl group Chemical group 0.000 claims description 8
• 125000004860 4-ethylphenyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)C([H])([H])C([H])([H])[H] 0.000 claims description 7
• 125000004861 4-isopropyl phenyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)C([H])(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 7
• 125000000590 4-methylphenyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)C([H])([H])[H] 0.000 claims description 7
• 125000001841 imino group Chemical group [H]N=* 0.000 claims description 7
• 239000000463 material Substances 0.000 claims description 7
• 125000003854 p-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Cl 0.000 claims description 7
• 125000001424 substituent group Chemical group 0.000 claims description 7
• 125000001216 2-naphthoyl group Chemical group C1=C(C=CC2=CC=CC=C12)C(=O)* 0.000 claims description 6
• 125000004172 4-methoxyphenyl group Chemical group [H]C1=C([H])C(OC([H])([H])[H])=C([H])C([H])=C1* 0.000 claims description 6
• 102100037205 Sal-like protein 2 Human genes 0.000 claims description 6
• 101710192308 Sal-like protein 2 Proteins 0.000 claims description 6
• 102100040247 Tumor necrosis factor Human genes 0.000 claims description 6
• 125000005036 alkoxyphenyl group Chemical group 0.000 claims description 6
• 125000005059 halophenyl group Chemical group 0.000 claims description 6
• 150000002431 hydrogen Chemical group 0.000 claims description 6
• 125000006239 protecting group Chemical group 0.000 claims description 6
• 102000003390 tumor necrosis factor Human genes 0.000 claims description 6
• 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 claims description 6
• 125000002941 2-furyl group Chemical group O1C([*])=C([H])C([H])=C1[H] 0.000 claims description 5
• 125000001622 2-naphthyl group Chemical group [H]C1=C([H])C([H])=C2C([H])=C(*)C([H])=C([H])C2=C1[H] 0.000 claims description 5
• 125000000175 2-thienyl group Chemical group S1C([*])=C([H])C([H])=C1[H] 0.000 claims description 5
• 239000004480 active ingredient Substances 0.000 claims description 5
• 125000003983 fluorenyl group Chemical group C1(=CC=CC=2C3=CC=CC=C3CC12)* 0.000 claims description 5
• 125000002485 formyl group Chemical group [H]C(*)=O 0.000 claims description 5
• LJGHYPLBDBRCRZ-UHFFFAOYSA-N 3-(3-aminophenyl)sulfonylaniline Chemical group NC1=CC=CC(S(=O)(=O)C=2C=C(N)C=CC=2)=C1 LJGHYPLBDBRCRZ-UHFFFAOYSA-N 0.000 claims description 4
• 125000004199 4-trifluoromethylphenyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)C(F)(F)F 0.000 claims description 4
• 125000005161 aryl oxy carbonyl group Chemical group 0.000 claims description 4
• 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 4
• 239000003814 drug Substances 0.000 claims description 4
• 231100000252 nontoxic Toxicity 0.000 claims description 4
• 230000003000 nontoxic effect Effects 0.000 claims description 4
• 229920002554 vinyl polymer Polymers 0.000 claims description 4
• 125000004801 4-cyanophenyl group Chemical group [H]C1=C([H])C(C#N)=C([H])C([H])=C1* 0.000 claims description 3
• 125000004442 acylamino group Chemical group 0.000 claims description 3
• 229940079593 drug Drugs 0.000 claims description 3
• 239000000546 pharmaceutical excipient Substances 0.000 claims description 3
• 125000003277 amino group Chemical group 0.000 claims description 2
• ODIGIKRIUKFKHP-UHFFFAOYSA-N (n-propan-2-yloxycarbonylanilino) acetate Chemical compound CC(C)OC(=O)N(OC(C)=O)C1=CC=CC=C1 ODIGIKRIUKFKHP-UHFFFAOYSA-N 0.000 claims 1
• 125000004179 3-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C(Cl)=C1[H] 0.000 claims 1
• 125000002373 5 membered heterocyclic group Chemical group 0.000 claims 1
• 125000004070 6 membered heterocyclic group Chemical group 0.000 claims 1
• 241001465754 Metazoa Species 0.000 claims 1
• 230000010933 acylation Effects 0.000 claims 1
• 238000005917 acylation reaction Methods 0.000 claims 1
• 229940059260 amidate Drugs 0.000 claims 1
• NPUKDXXFDDZOKR-LLVKDONJSA-N etomidate Chemical compound CCOC(=O)C1=CN=CN1[C@H](C)C1=CC=CC=C1 NPUKDXXFDDZOKR-LLVKDONJSA-N 0.000 claims 1
• CMWTZPSULFXXJA-VIFPVBQESA-N naproxen Chemical group C1=C([C@H](C)C(O)=O)C=CC2=CC(OC)=CC=C21 CMWTZPSULFXXJA-VIFPVBQESA-N 0.000 claims 1
• GBXQPDCOMJJCMJ-UHFFFAOYSA-M trimethyl-[6-(trimethylazaniumyl)hexyl]azanium;bromide Chemical compound [Br-].C[N+](C)(C)CCCCCC[N+](C)(C)C GBXQPDCOMJJCMJ-UHFFFAOYSA-M 0.000 claims 1
• 125000001475 halogen functional group Chemical group 0.000 abstract 1
• 230000017074 necrotic cell death Effects 0.000 abstract 1
• DLFVBJFMPXGRIB-UHFFFAOYSA-N Acetamide Chemical compound CC(N)=O DLFVBJFMPXGRIB-UHFFFAOYSA-N 0.000 description 196
• XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 165
• 238000002360 preparation method Methods 0.000 description 163
• HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 102
• 239000000243 solution Substances 0.000 description 98
• OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 87
• IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 84
• 239000000203 mixture Substances 0.000 description 81
• ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 58
• HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 56
• CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 54
• LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 51
• VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 46
• QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 42
• VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 42
• WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 40
• XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 35
• 238000001816 cooling Methods 0.000 description 34
• YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 30
• 239000012267 brine Substances 0.000 description 28
• HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 28
• JUJWROOIHBZHMG-UHFFFAOYSA-N pyridine Substances C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 26
• 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 26
• 229910052943 magnesium sulfate Inorganic materials 0.000 description 25
• 235000019341 magnesium sulphate Nutrition 0.000 description 25
• WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 24
• 239000011541 reaction mixture Substances 0.000 description 23
• UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 22
• 239000002904 solvent Substances 0.000 description 22
• HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 21
• ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 21
• 239000000843 powder Substances 0.000 description 20
• YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 20
• KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 18
• 239000012044 organic layer Substances 0.000 description 18
• 239000007787 solid Substances 0.000 description 18
• RTZKZFJDLAIYFH-UHFFFAOYSA-N ether Substances CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 17
• 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 17
• 125000004432 carbon atom Chemical group C* 0.000 description 16
• 239000005457 ice water Substances 0.000 description 16
• CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 15
• CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 14
• DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 14
• 235000011054 acetic acid Nutrition 0.000 description 14
• 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 14
• UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 14
• 238000003756 stirring Methods 0.000 description 14
• 238000010898 silica gel chromatography Methods 0.000 description 13
• KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 12
• 229910052783 alkali metal Inorganic materials 0.000 description 12
• 239000003480 eluent Substances 0.000 description 12
• BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 12
• FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 12
• RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 11
• 239000012230 colorless oil Substances 0.000 description 11
• 150000002148 esters Chemical class 0.000 description 11
• 238000001704 evaporation Methods 0.000 description 11
• 230000008020 evaporation Effects 0.000 description 11
• XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 description 11
• BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical compound [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 description 11
• 239000000725 suspension Substances 0.000 description 11
• QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 10
• 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 10
• RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 10
• VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 9
• 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 9
• 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 9
• ASOKPJOREAFHNY-UHFFFAOYSA-N 1-Hydroxybenzotriazole Chemical compound C1=CC=C2N(O)N=NC2=C1 ASOKPJOREAFHNY-UHFFFAOYSA-N 0.000 description 8
• ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 8
• FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 8
• 125000005116 aryl carbamoyl group Chemical group 0.000 description 8
• 239000003054 catalyst Substances 0.000 description 8
• 239000000460 chlorine Substances 0.000 description 8
• 229910052801 chlorine Inorganic materials 0.000 description 8
• 125000000068 chlorophenyl group Chemical group 0.000 description 8
• CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 description 8
• 125000002971 oxazolyl group Chemical group 0.000 description 8
• 229910000030 sodium bicarbonate Inorganic materials 0.000 description 8
• 235000017557 sodium bicarbonate Nutrition 0.000 description 8
• 102000029816 Collagenase Human genes 0.000 description 7
• 108060005980 Collagenase Proteins 0.000 description 7
• PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 7
• 230000002411 adverse Effects 0.000 description 7
• 239000003795 chemical substances by application Substances 0.000 description 7
• 229960002424 collagenase Drugs 0.000 description 7
• 201000010099 disease Diseases 0.000 description 7
• 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 7
• 229910052731 fluorine Inorganic materials 0.000 description 7
• 239000011737 fluorine Substances 0.000 description 7
• 238000010438 heat treatment Methods 0.000 description 7
• 229910052757 nitrogen Inorganic materials 0.000 description 7
• 239000003921 oil Substances 0.000 description 7
• 229910000029 sodium carbonate Inorganic materials 0.000 description 7
• 238000010998 test method Methods 0.000 description 7
• LMDZBCPBFSXMTL-UHFFFAOYSA-N 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide Chemical compound CCN=C=NCCCN(C)C LMDZBCPBFSXMTL-UHFFFAOYSA-N 0.000 description 6
• FPQQSJJWHUJYPU-UHFFFAOYSA-N 3-(dimethylamino)propyliminomethylidene-ethylazanium;chloride Chemical compound Cl.CCN=C=NCCCN(C)C FPQQSJJWHUJYPU-UHFFFAOYSA-N 0.000 description 6
• NIXOWILDQLNWCW-UHFFFAOYSA-M Acrylate Chemical compound [O-]C(=O)C=C NIXOWILDQLNWCW-UHFFFAOYSA-M 0.000 description 6
• IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 6
• XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 description 6
• XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 description 6
• 229920000388 Polyphosphate Polymers 0.000 description 6
• KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 6
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• YUQACHZFSVKJGM-BOXHHOBZSA-N tert-butyl 2-[(7s)-1,1-dioxo-7-[5-[4-(trifluoromethoxy)phenyl]thiophen-2-yl]-1,4-thiazepan-7-yl]acetate;hydrochloride Chemical compound Cl.C=1C=C(C=2C=CC(OC(F)(F)F)=CC=2)SC=1[C@@]1(CC(=O)OC(C)(C)C)CCNCCS1(=O)=O YUQACHZFSVKJGM-BOXHHOBZSA-N 0.000 description 1
• KTQQEMHRNDYEFW-VWLOTQADSA-N tert-butyl 2-[(7s)-4-methylsulfonyl-1,1-dioxo-7-[5-(4-propylphenyl)thiophen-2-yl]-1,4-thiazepan-7-yl]acetate Chemical compound C1=CC(CCC)=CC=C1C1=CC=C([C@]2(CC(=O)OC(C)(C)C)S(CCN(CC2)S(C)(=O)=O)(=O)=O)S1 KTQQEMHRNDYEFW-VWLOTQADSA-N 0.000 description 1
• BNRZKCQOADFPHP-HNNXBMFYSA-N tert-butyl 2-[(7s)-7-(5-bromothiophen-2-yl)-1,1-dioxo-1,4-thiazepan-7-yl]acetate Chemical compound C=1C=C(Br)SC=1[C@@]1(CC(=O)OC(C)(C)C)CCNCCS1(=O)=O BNRZKCQOADFPHP-HNNXBMFYSA-N 0.000 description 1
• HQZDGLUZICPBNK-FQEVSTJZSA-N tert-butyl 2-[(7s)-7-(5-bromothiophen-2-yl)-1,1-dioxo-4-(thiophene-3-carbonyl)-1,4-thiazepan-7-yl]acetate Chemical compound C([C@](S(CC1)(=O)=O)(CC(=O)OC(C)(C)C)C=2SC(Br)=CC=2)CN1C(=O)C=1C=CSC=1 HQZDGLUZICPBNK-FQEVSTJZSA-N 0.000 description 1
• HKUJJAIECIWZNZ-KRWDZBQOSA-N tert-butyl 2-[(7s)-7-(5-bromothiophen-2-yl)-4-(dimethylsulfamoyl)-1,1-dioxo-1,4-thiazepan-7-yl]acetate Chemical compound O=S1(=O)CCN(S(=O)(=O)N(C)C)CC[C@]1(CC(=O)OC(C)(C)C)C1=CC=C(Br)S1 HKUJJAIECIWZNZ-KRWDZBQOSA-N 0.000 description 1
• WXKMABZGOPJMMW-NRFANRHFSA-N tert-butyl 2-[(7s)-7-[5-(4-chlorophenyl)thiophen-2-yl]-1,1-dioxo-1,4-thiazepan-7-yl]acetate Chemical compound C=1C=C(C=2C=CC(Cl)=CC=2)SC=1[C@@]1(CC(=O)OC(C)(C)C)CCNCCS1(=O)=O WXKMABZGOPJMMW-NRFANRHFSA-N 0.000 description 1
• VXXNTDRTDUUHQQ-QHCPKHFHSA-N tert-butyl 2-[(7s)-7-[5-(4-ethylphenyl)thiophen-2-yl]-1,1-dioxo-1,4-thiazepan-7-yl]acetate Chemical compound C1=CC(CC)=CC=C1C1=CC=C([C@]2(CC(=O)OC(C)(C)C)S(CCNCC2)(=O)=O)S1 VXXNTDRTDUUHQQ-QHCPKHFHSA-N 0.000 description 1
• XOJSOFMUZKBLNB-MHZLTWQESA-N tert-butyl 2-[(7s)-7-[5-(4-methoxyphenyl)thiophen-2-yl]-1,1-dioxo-4-(thiophene-3-carbonyl)-1,4-thiazepan-7-yl]acetate Chemical compound C1=CC(OC)=CC=C1C1=CC=C([C@]2(CC(=O)OC(C)(C)C)S(CCN(CC2)C(=O)C2=CSC=C2)(=O)=O)S1 XOJSOFMUZKBLNB-MHZLTWQESA-N 0.000 description 1
• ZGUUJKXMNYUTMF-UHFFFAOYSA-N tert-butyl 2-[7-(5-naphthalen-2-ylthiophen-2-yl)-1,1-dioxo-1,4-thiazepan-7-yl]acetate Chemical compound C=1C=C(C=2C=C3C=CC=CC3=CC=2)SC=1C1(CC(=O)OC(C)(C)C)CCNCCS1(=O)=O ZGUUJKXMNYUTMF-UHFFFAOYSA-N 0.000 description 1
• QTPYLKAMTHPFJR-UHFFFAOYSA-N tert-butyl 2-[7-[5-(4-cyanophenyl)thiophen-2-yl]-1,1-dioxo-1,4-thiazepan-7-yl]acetate Chemical compound C=1C=C(C=2C=CC(=CC=2)C#N)SC=1C1(CC(=O)OC(C)(C)C)CCNCCS1(=O)=O QTPYLKAMTHPFJR-UHFFFAOYSA-N 0.000 description 1
• DJWQDYGQTWFOKQ-UHFFFAOYSA-N tert-butyl 2-[7-[5-(4-ethoxyphenyl)thiophen-2-yl]-1,1-dioxo-1,4-thiazepan-7-yl]acetate;hydrochloride Chemical compound Cl.C1=CC(OCC)=CC=C1C1=CC=C(C2(CC(=O)OC(C)(C)C)S(CCNCC2)(=O)=O)S1 DJWQDYGQTWFOKQ-UHFFFAOYSA-N 0.000 description 1
• NHGSMAGVPVURCC-UHFFFAOYSA-N tert-butyl 2-[7-[5-(4-fluorophenyl)thiophen-2-yl]-1,1-dioxo-1,4-thiazepan-7-yl]acetate Chemical compound C=1C=C(C=2C=CC(F)=CC=2)SC=1C1(CC(=O)OC(C)(C)C)CCNCCS1(=O)=O NHGSMAGVPVURCC-UHFFFAOYSA-N 0.000 description 1
• ZODZXGBMXXLPMR-UHFFFAOYSA-N tert-butyl 2-[7-[5-(4-methylphenyl)thiophen-2-yl]-1,1-dioxo-1,4-thiazepan-7-yl]acetate Chemical compound C1=CC(C)=CC=C1C1=CC=C(C2(CC(=O)OC(C)(C)C)S(CCNCC2)(=O)=O)S1 ZODZXGBMXXLPMR-UHFFFAOYSA-N 0.000 description 1
• RLBJVYHAAAHBFE-UHFFFAOYSA-N tert-butyl 2-[7-[5-(4-methylsulfanylphenyl)thiophen-2-yl]-1,1-dioxo-1,4-thiazepan-7-yl]acetate Chemical compound C1=CC(SC)=CC=C1C1=CC=C(C2(CC(=O)OC(C)(C)C)S(CCNCC2)(=O)=O)S1 RLBJVYHAAAHBFE-UHFFFAOYSA-N 0.000 description 1
• YIIKOXFGPQXWDI-UHFFFAOYSA-N tert-butyl 2-[7-[5-(5-chlorothiophen-2-yl)thiophen-2-yl]-1,1-dioxo-1,4-thiazepan-7-yl]acetate Chemical compound C=1C=C(C=2SC(Cl)=CC=2)SC=1C1(CC(=O)OC(C)(C)C)CCNCCS1(=O)=O YIIKOXFGPQXWDI-UHFFFAOYSA-N 0.000 description 1
• KUHPRALEZHEVIH-UHFFFAOYSA-N tert-butyl 2-[7-[5-[4-(1,3-oxazol-2-yl)phenyl]thiophen-2-yl]-1,1-dioxo-4-(thiophene-3-carbonyl)-1,4-thiazepan-7-yl]acetate Chemical compound C1CS(=O)(=O)C(CC(=O)OC(C)(C)C)(C=2SC(=CC=2)C=2C=CC(=CC=2)C=2OC=CN=2)CCN1C(=O)C=1C=CSC=1 KUHPRALEZHEVIH-UHFFFAOYSA-N 0.000 description 1
• FCQUTRVCRRYXLN-UHFFFAOYSA-N tert-butyl 2-[7-[5-[4-(methoxymethyl)phenyl]thiophen-2-yl]-1,1-dioxo-1,4-thiazepan-7-yl]acetate Chemical compound C1=CC(COC)=CC=C1C1=CC=C(C2(CC(=O)OC(C)(C)C)S(CCNCC2)(=O)=O)S1 FCQUTRVCRRYXLN-UHFFFAOYSA-N 0.000 description 1
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• ZLWCVPBRZFOAIW-UHFFFAOYSA-N tert-butyl 7-(4-phenoxyphenyl)-1,4-thiazepane-4-carboxylate Chemical compound C1CN(C(=O)OC(C)(C)C)CCSC1C(C=C1)=CC=C1OC1=CC=CC=C1 ZLWCVPBRZFOAIW-UHFFFAOYSA-N 0.000 description 1
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• 229910052718 tin Inorganic materials 0.000 description 1
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• 125000005023 xylyl group Chemical group 0.000 description 1
• 239000011701 zinc Substances 0.000 description 1
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