NO309268B1 - Azolderivat, farmasöytisk preparat inneholdende dette, og mellomprodukter for dets fremstilling - Google Patents

Info

Publication number

NO309268B1

NO309268B1 NO971685A NO971685A NO309268B1 NO 309268 B1 NO309268 B1 NO 309268B1 NO 971685 A NO971685 A NO 971685A NO 971685 A NO971685 A NO 971685A NO 309268 B1 NO309268 B1 NO 309268B1

Authority

NO

Norway

Prior art keywords

group

propyl

formula

chlorophenylsulfonyl

thiazolyl

Prior art date

1994-10-14

Links

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• Global Dossier
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• 150000007980 azole derivatives Chemical class 0.000 title claims abstract description 20
• 239000000825 pharmaceutical preparation Substances 0.000 title claims description 8
• 238000002360 preparation method Methods 0.000 title description 18
• 239000000543 intermediate Substances 0.000 title description 3
• -1 cyano, tetrazolyl Chemical group 0.000 claims abstract description 71
• 125000000217 alkyl group Chemical group 0.000 claims abstract description 42
• 150000003839 salts Chemical class 0.000 claims abstract description 37
• 125000002947 alkylene group Chemical group 0.000 claims abstract description 17
• 125000000753 cycloalkyl group Chemical group 0.000 claims abstract description 11
• DSNBHJFQCNUKMA-SCKDECHMSA-N thromboxane A2 Chemical compound OC(=O)CCC\C=C/C[C@@H]1[C@@H](/C=C/[C@@H](O)CCCCC)O[C@@H]2O[C@H]1C2 DSNBHJFQCNUKMA-SCKDECHMSA-N 0.000 claims abstract description 9
• 150000002617 leukotrienes Chemical class 0.000 claims abstract description 7
• 229910052717 sulfur Inorganic materials 0.000 claims abstract description 7
• 208000026935 allergic disease Diseases 0.000 claims abstract description 6
• 239000004480 active ingredient Substances 0.000 claims abstract description 5
• 125000004450 alkenylene group Chemical group 0.000 claims abstract description 5
• 230000003042 antagnostic effect Effects 0.000 claims abstract description 5
• 208000031225 myocardial ischemia Diseases 0.000 claims abstract description 4
• 230000000302 ischemic effect Effects 0.000 claims abstract 2
• 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 30
• 125000005843 halogen group Chemical group 0.000 claims description 25
• 239000012453 solvate Substances 0.000 claims description 19
• 208000006673 asthma Diseases 0.000 claims description 16
• 125000003277 amino group Chemical group 0.000 claims description 14
• 125000003545 alkoxy group Chemical group 0.000 claims description 12
• 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 9
• 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 8
• 125000004390 alkyl sulfonyl group Chemical group 0.000 claims description 6
• 125000001434 methanylylidene group Chemical group [H]C#[*] 0.000 claims description 6
• 125000004434 sulfur atom Chemical group 0.000 claims description 6
• 125000002252 acyl group Chemical group 0.000 claims description 5
• 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 5
• 125000004093 cyano group Chemical group *C#N 0.000 claims description 5
• 208000030603 inherited susceptibility to asthma Diseases 0.000 claims description 5
• 125000004453 alkoxycarbonyl group Chemical group 0.000 claims description 4
• 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims description 4
• 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 4
• 150000001732 carboxylic acid derivatives Chemical class 0.000 claims description 4
• 125000001570 methylene group Chemical group [H]C([H])([*:1])[*:2] 0.000 claims description 4
• 125000004430 oxygen atom Chemical group O* 0.000 claims description 4
• 125000003170 phenylsulfonyl group Chemical group C1(=CC=CC=C1)S(=O)(=O)* 0.000 claims description 4
• 230000003449 preventive effect Effects 0.000 claims description 4
• 125000003831 tetrazolyl group Chemical group 0.000 claims description 4
• GXKYEUMGFUVOPM-UHFFFAOYSA-N 2-[2-[[3-[(4-tert-butyl-1,3-thiazol-2-yl)methoxy]benzoyl]amino]-4-[3-(4-chlorophenyl)sulfonylpropyl]phenoxy]acetic acid Chemical compound CC(C)(C)C1=CSC(COC=2C=C(C=CC=2)C(=O)NC=2C(=CC=C(CCCS(=O)(=O)C=3C=CC(Cl)=CC=3)C=2)OCC(O)=O)=N1 GXKYEUMGFUVOPM-UHFFFAOYSA-N 0.000 claims description 3
• ZEZUDOUQZAREDI-UHFFFAOYSA-N 3-[(4-tert-butyl-1,3-thiazol-2-yl)methoxy]-n-[5-[3-(4-chlorophenyl)sulfonylpropyl]-2-(2h-tetrazol-5-ylmethoxy)phenyl]benzamide Chemical compound CC(C)(C)C1=CSC(COC=2C=C(C=CC=2)C(=O)NC=2C(=CC=C(CCCS(=O)(=O)C=3C=CC(Cl)=CC=3)C=2)OCC2=NNN=N2)=N1 ZEZUDOUQZAREDI-UHFFFAOYSA-N 0.000 claims description 3
• 206010039085 Rhinitis allergic Diseases 0.000 claims description 3
• 208000024780 Urticaria Diseases 0.000 claims description 3
• 201000010105 allergic rhinitis Diseases 0.000 claims description 3
• 201000010435 allergic urticaria Diseases 0.000 claims description 3
• 239000003814 drug Substances 0.000 claims description 3
• CDAWCLOXVUBKRW-UHFFFAOYSA-N 2-aminophenol Chemical class NC1=CC=CC=C1O CDAWCLOXVUBKRW-UHFFFAOYSA-N 0.000 claims description 2
• 125000005115 alkyl carbamoyl group Chemical group 0.000 claims description 2
• 229910052736 halogen Inorganic materials 0.000 claims description 2
• 229910052757 nitrogen Inorganic materials 0.000 claims description 2
• 125000004433 nitrogen atom Chemical group N* 0.000 claims description 2
• 229940124597 therapeutic agent Drugs 0.000 claims 2
• CYOUETMLRDNEJT-UHFFFAOYSA-N 2-[4-[3-(4-chlorophenyl)sulfonylpropyl]-2-[[3-[(4-cyclobutyl-1,3-thiazol-2-yl)methoxy]benzoyl]amino]phenoxy]acetic acid Chemical compound C1=C(NC(=O)C=2C=C(OCC=3SC=C(N=3)C3CCC3)C=CC=2)C(OCC(=O)O)=CC=C1CCCS(=O)(=O)C1=CC=C(Cl)C=C1 CYOUETMLRDNEJT-UHFFFAOYSA-N 0.000 claims 1
• KFKFSHXKMXWCHA-UHFFFAOYSA-N 3-(1,3-benzothiazol-2-ylmethoxy)-n-[5-[3-(4-chlorophenyl)sulfonylpropyl]-2-(2h-tetrazol-5-ylmethoxy)phenyl]benzamide Chemical compound C1=CC(Cl)=CC=C1S(=O)(=O)CCCC(C=C1NC(=O)C=2C=C(OCC=3SC4=CC=CC=C4N=3)C=CC=2)=CC=C1OCC1=NNN=N1 KFKFSHXKMXWCHA-UHFFFAOYSA-N 0.000 claims 1
• 208000018152 Cerebral disease Diseases 0.000 claims 1
• 239000003937 drug carrier Substances 0.000 claims 1
• 229910052739 hydrogen Inorganic materials 0.000 abstract description 697
• 239000000203 mixture Substances 0.000 abstract description 73
• 125000002924 primary amino group Chemical group [H]N([H])* 0.000 abstract description 7
• 239000001257 hydrogen Substances 0.000 abstract description 6
• UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 abstract description 5
• 208000014644 Brain disease Diseases 0.000 abstract description 3
• 150000002431 hydrogen Chemical class 0.000 abstract 2
• NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 abstract 1
• QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 abstract 1
• 229910052760 oxygen Inorganic materials 0.000 abstract 1
• 239000001301 oxygen Substances 0.000 abstract 1
• 239000011593 sulfur Substances 0.000 abstract 1
• 150000001875 compounds Chemical class 0.000 description 177
• 239000000243 solution Substances 0.000 description 122
• 238000006243 chemical reaction Methods 0.000 description 103
• 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 84
• ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 69
• XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 64
• XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 60
• OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 58
• HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 55
• 101150041968 CDC13 gene Proteins 0.000 description 53
• HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 53
• YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 51
• WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 48
• WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 48
• 238000004949 mass spectrometry Methods 0.000 description 45
• LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 43
• HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 42
• KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 39
• 238000000034 method Methods 0.000 description 37
• VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 36
• 238000001816 cooling Methods 0.000 description 35
• 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 35
• 238000004519 manufacturing process Methods 0.000 description 33
• YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 31
• 238000000921 elemental analysis Methods 0.000 description 31
• 239000012267 brine Substances 0.000 description 30
• HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 30
• RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 29
• LCPDWSOZIOUXRV-UHFFFAOYSA-N phenoxyacetic acid Chemical compound OC(=O)COC1=CC=CC=C1 LCPDWSOZIOUXRV-UHFFFAOYSA-N 0.000 description 28
• UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 27
• 239000013078 crystal Substances 0.000 description 26
• CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 24
• 238000002844 melting Methods 0.000 description 24
• 230000008018 melting Effects 0.000 description 24
• 239000012044 organic layer Substances 0.000 description 24
• YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 24
• 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 22
• 239000003795 chemical substances by application Substances 0.000 description 21
• VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical group CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 21
• 239000000047 product Substances 0.000 description 21
• IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 20
• JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 20
• UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 20
• BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 20
• 238000010992 reflux Methods 0.000 description 20
• 239000007787 solid Substances 0.000 description 20
• 235000019441 ethanol Nutrition 0.000 description 19
• 238000003756 stirring Methods 0.000 description 19
• CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 18
• 238000001914 filtration Methods 0.000 description 17
• 230000000694 effects Effects 0.000 description 16
• IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 15
• 239000003480 eluent Substances 0.000 description 15
• 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 15
• 238000010898 silica gel chromatography Methods 0.000 description 15
• KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 14
• 125000000043 benzamido group Chemical group [H]N([*])C(=O)C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 14
• TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 description 14
• 235000015165 citric acid Nutrition 0.000 description 13
• 230000009467 reduction Effects 0.000 description 13
• 238000006722 reduction reaction Methods 0.000 description 13
• 125000002887 hydroxy group Chemical group [H]O* 0.000 description 12
• RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 11
• 230000005764 inhibitory process Effects 0.000 description 11
• 229910000027 potassium carbonate Inorganic materials 0.000 description 10
• UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 10
• 235000017557 sodium bicarbonate Nutrition 0.000 description 10
• 229910000030 sodium bicarbonate Inorganic materials 0.000 description 10
• 239000002904 solvent Substances 0.000 description 10
• LQANGKSBLPMBTJ-BRSNVKEHSA-N (z)-7-[(1s,2s,3r,4r)-3-[(e,3s)-3-hydroxyoct-1-enyl]-5-oxabicyclo[2.2.1]heptan-2-yl]hept-5-enoic acid Chemical compound C1[C@@H]2CO[C@H]1[C@H](/C=C/[C@@H](O)CCCCC)[C@H]2C\C=C/CCCC(O)=O LQANGKSBLPMBTJ-BRSNVKEHSA-N 0.000 description 9
• KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 9
• ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 9
• 239000002253 acid Substances 0.000 description 9
• 238000002425 crystallisation Methods 0.000 description 9
• 230000008025 crystallization Effects 0.000 description 9
• 238000010438 heat treatment Methods 0.000 description 9
• PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 8
• PXIPVTKHYLBLMZ-UHFFFAOYSA-N Sodium azide Chemical compound [Na+].[N-]=[N+]=[N-] PXIPVTKHYLBLMZ-UHFFFAOYSA-N 0.000 description 8
• 239000005457 ice water Substances 0.000 description 8
• 125000006239 protecting group Chemical group 0.000 description 8
• 238000011282 treatment Methods 0.000 description 8
• 239000000427 antigen Substances 0.000 description 7
• 102000036639 antigens Human genes 0.000 description 7
• 108091007433 antigens Proteins 0.000 description 7
• 125000004432 carbon atom Chemical group C* 0.000 description 7
• 230000007062 hydrolysis Effects 0.000 description 7
• 238000006460 hydrolysis reaction Methods 0.000 description 7
• 239000003112 inhibitor Substances 0.000 description 7
• UKVIEHSSVKSQBA-UHFFFAOYSA-N methane;palladium Chemical compound C.[Pd] UKVIEHSSVKSQBA-UHFFFAOYSA-N 0.000 description 7
• 229920006395 saturated elastomer Polymers 0.000 description 7
• 239000000126 substance Substances 0.000 description 7
• WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 6
• QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 6
• NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 6
• CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 6
• DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 6
• 238000007112 amidation reaction Methods 0.000 description 6
• QSKWJTXWJJOJFP-UHFFFAOYSA-N chloroform;ethoxyethane Chemical compound ClC(Cl)Cl.CCOCC QSKWJTXWJJOJFP-UHFFFAOYSA-N 0.000 description 6
• 238000006266 etherification reaction Methods 0.000 description 6
• YEESKJGWJFYOOK-IJHYULJSSA-N leukotriene D4 Chemical compound CCCCC\C=C/C\C=C/C=C/C=C/[C@H]([C@@H](O)CCCC(O)=O)SC[C@H](N)C(=O)NCC(O)=O YEESKJGWJFYOOK-IJHYULJSSA-N 0.000 description 6
• 239000003960 organic solvent Substances 0.000 description 6
• 239000011343 solid material Substances 0.000 description 6
• 241000700199 Cavia porcellus Species 0.000 description 5
• CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 5
• 239000000706 filtrate Substances 0.000 description 5
• 229960004592 isopropanol Drugs 0.000 description 5
• 239000000463 material Substances 0.000 description 5
• 125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 description 5
• 230000002265 prevention Effects 0.000 description 5
• 230000003381 solubilizing effect Effects 0.000 description 5
• 239000000725 suspension Substances 0.000 description 5
• 238000010998 test method Methods 0.000 description 5
• 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 5
• 229920002554 vinyl polymer Polymers 0.000 description 5
• 239000008096 xylene Substances 0.000 description 5
• ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 description 4
• QLNHAPDKHQUIOD-UHFFFAOYSA-N 2-amino-4-[3-(4-chlorophenyl)sulfonylpropyl]phenol;hydrochloride Chemical compound Cl.C1=C(O)C(N)=CC(CCCS(=O)(=O)C=2C=CC(Cl)=CC=2)=C1 QLNHAPDKHQUIOD-UHFFFAOYSA-N 0.000 description 4
• VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 4
• WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 4
• XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 description 4
• QUSNBJAOOMFDIB-UHFFFAOYSA-N Ethylamine Chemical compound CCN QUSNBJAOOMFDIB-UHFFFAOYSA-N 0.000 description 4
• KRHYYFGTRYWZRS-UHFFFAOYSA-N Fluorane Chemical compound F KRHYYFGTRYWZRS-UHFFFAOYSA-N 0.000 description 4
• OAKJQQAXSVQMHS-UHFFFAOYSA-N Hydrazine Chemical compound NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 0.000 description 4
• JLTDJTHDQAWBAV-UHFFFAOYSA-N N,N-dimethylaniline Chemical compound CN(C)C1=CC=CC=C1 JLTDJTHDQAWBAV-UHFFFAOYSA-N 0.000 description 4
• JRNVZBWKYDBUCA-UHFFFAOYSA-N N-chlorosuccinimide Chemical compound ClN1C(=O)CCC1=O JRNVZBWKYDBUCA-UHFFFAOYSA-N 0.000 description 4
• JLCHNBRGUPQWKF-UHFFFAOYSA-J [OH-].[C+4].[OH-].[OH-].[OH-] Chemical compound [OH-].[C+4].[OH-].[OH-].[OH-] JLCHNBRGUPQWKF-UHFFFAOYSA-J 0.000 description 4
• 230000008485 antagonism Effects 0.000 description 4
• 239000012298 atmosphere Substances 0.000 description 4
• 230000015572 biosynthetic process Effects 0.000 description 4
• 230000037396 body weight Effects 0.000 description 4
• GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 4
• 229910052794 bromium Inorganic materials 0.000 description 4
• 150000002148 esters Chemical group 0.000 description 4
• ZKQFHRVKCYFVCN-UHFFFAOYSA-N ethoxyethane;hexane Chemical compound CCOCC.CCCCCC ZKQFHRVKCYFVCN-UHFFFAOYSA-N 0.000 description 4
• 150000004820 halides Chemical class 0.000 description 4
• 239000003701 inert diluent Substances 0.000 description 4
• 239000007924 injection Substances 0.000 description 4
• 238000002347 injection Methods 0.000 description 4
• 150000007529 inorganic bases Chemical class 0.000 description 4
• 239000011259 mixed solution Substances 0.000 description 4
• 229910052763 palladium Inorganic materials 0.000 description 4
• 210000004623 platelet-rich plasma Anatomy 0.000 description 4
• NROKBHXJSPEDAR-UHFFFAOYSA-M potassium fluoride Chemical compound [F-].[K+] NROKBHXJSPEDAR-UHFFFAOYSA-M 0.000 description 4
• 239000011734 sodium Substances 0.000 description 4
• WBHQBSYUUJJSRZ-UHFFFAOYSA-M sodium bisulfate Chemical compound [Na+].OS([O-])(=O)=O WBHQBSYUUJJSRZ-UHFFFAOYSA-M 0.000 description 4
• 229910000342 sodium bisulfate Inorganic materials 0.000 description 4
• PUZPDOWCWNUUKD-UHFFFAOYSA-M sodium fluoride Chemical compound [F-].[Na+] PUZPDOWCWNUUKD-UHFFFAOYSA-M 0.000 description 4
• 239000007858 starting material Substances 0.000 description 4
• 125000001273 sulfonato group Chemical group [O-]S(*)(=O)=O 0.000 description 4
• FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 4
• SCYULBFZEHDVBN-UHFFFAOYSA-N 1,1-Dichloroethane Chemical compound CC(Cl)Cl SCYULBFZEHDVBN-UHFFFAOYSA-N 0.000 description 3
• ASOKPJOREAFHNY-UHFFFAOYSA-N 1-Hydroxybenzotriazole Chemical compound C1=CC=C2N(O)N=NC2=C1 ASOKPJOREAFHNY-UHFFFAOYSA-N 0.000 description 3
• LMDZBCPBFSXMTL-UHFFFAOYSA-N 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide Chemical compound CCN=C=NCCCN(C)C LMDZBCPBFSXMTL-UHFFFAOYSA-N 0.000 description 3
• BRZUSLILZCEYJF-UHFFFAOYSA-N 4-[3-(4-chlorophenyl)sulfonylpropyl]-2-nitrophenol Chemical compound C1=C([N+]([O-])=O)C(O)=CC=C1CCCS(=O)(=O)C1=CC=C(Cl)C=C1 BRZUSLILZCEYJF-UHFFFAOYSA-N 0.000 description 3
• QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
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• IWJKVHQKCPXHPQ-UHFFFAOYSA-N ethyl 2-[2-[[3-(1,3-benzoxazol-2-ylmethoxy)benzoyl]amino]-4-[3-(4-chlorophenyl)sulfonylpropyl]phenoxy]acetate Chemical compound C1=C(NC(=O)C=2C=C(OCC=3OC4=CC=CC=C4N=3)C=CC=2)C(OCC(=O)OCC)=CC=C1CCCS(=O)(=O)C1=CC=C(Cl)C=C1 IWJKVHQKCPXHPQ-UHFFFAOYSA-N 0.000 description 1
• GZHLRMBYGYNTGI-UHFFFAOYSA-N ethyl 2-[2-[[3-(1,3-benzoxazol-2-ylmethylsulfanyl)benzoyl]amino]-4-[3-(4-chlorophenyl)sulfonylpropyl]phenoxy]acetate Chemical compound C1=C(NC(=O)C=2C=C(SCC=3OC4=CC=CC=C4N=3)C=CC=2)C(OCC(=O)OCC)=CC=C1CCCS(=O)(=O)C1=CC=C(Cl)C=C1 GZHLRMBYGYNTGI-UHFFFAOYSA-N 0.000 description 1
• DDZKSOYAEYMTJR-UHFFFAOYSA-N ethyl 2-[2-[[3-[(4-tert-butyl-1,3-thiazol-2-yl)methoxy]-4-chlorobenzoyl]amino]-4-[3-(4-chlorophenyl)sulfonylpropyl]phenoxy]acetate Chemical compound C1=C(NC(=O)C=2C=C(OCC=3SC=C(N=3)C(C)(C)C)C(Cl)=CC=2)C(OCC(=O)OCC)=CC=C1CCCS(=O)(=O)C1=CC=C(Cl)C=C1 DDZKSOYAEYMTJR-UHFFFAOYSA-N 0.000 description 1
• ISDNNIIZXKMZBK-UHFFFAOYSA-N ethyl 2-[2-[[3-[(4-tert-butyl-1,3-thiazol-2-yl)methoxy]-4-methoxybenzoyl]amino]-4-[3-(4-chlorophenyl)sulfonylpropyl]phenoxy]acetate Chemical compound C1=C(NC(=O)C=2C=C(OCC=3SC=C(N=3)C(C)(C)C)C(OC)=CC=2)C(OCC(=O)OCC)=CC=C1CCCS(=O)(=O)C1=CC=C(Cl)C=C1 ISDNNIIZXKMZBK-UHFFFAOYSA-N 0.000 description 1
• MVPASEKQPUSICS-UHFFFAOYSA-N ethyl 2-[2-[[3-[(4-tert-butyl-1,3-thiazol-2-yl)methoxy]-4-methylbenzoyl]amino]-4-[3-(4-chlorophenyl)sulfonylpropyl]phenoxy]acetate Chemical compound C1=C(NC(=O)C=2C=C(OCC=3SC=C(N=3)C(C)(C)C)C(C)=CC=2)C(OCC(=O)OCC)=CC=C1CCCS(=O)(=O)C1=CC=C(Cl)C=C1 MVPASEKQPUSICS-UHFFFAOYSA-N 0.000 description 1
• BAUYHBQYTHPONS-UHFFFAOYSA-N ethyl 2-[2-[[3-[(4-tert-butyl-1,3-thiazol-2-yl)methoxy]-4-nitrobenzoyl]amino]-4-[3-(4-chlorophenyl)sulfonylpropyl]phenoxy]acetate Chemical compound C1=C(NC(=O)C=2C=C(OCC=3SC=C(N=3)C(C)(C)C)C(=CC=2)[N+]([O-])=O)C(OCC(=O)OCC)=CC=C1CCCS(=O)(=O)C1=CC=C(Cl)C=C1 BAUYHBQYTHPONS-UHFFFAOYSA-N 0.000 description 1
• GTGDWMXBABMGII-UHFFFAOYSA-N ethyl 2-[2-[[3-[(4-tert-butyl-1,3-thiazol-2-yl)methoxy]-5-chlorobenzoyl]amino]-4-[3-(4-chlorophenyl)sulfonylpropyl]phenoxy]acetate Chemical compound C1=C(NC(=O)C=2C=C(OCC=3SC=C(N=3)C(C)(C)C)C=C(Cl)C=2)C(OCC(=O)OCC)=CC=C1CCCS(=O)(=O)C1=CC=C(Cl)C=C1 GTGDWMXBABMGII-UHFFFAOYSA-N 0.000 description 1
• VUPUKQYIXOPPOG-UHFFFAOYSA-N ethyl 2-[2-[[3-[(4-tert-butyl-1,3-thiazol-2-yl)methoxy]benzenecarbothioyl]amino]-4-[3-(4-chlorophenyl)sulfonylpropyl]phenoxy]acetate Chemical compound C1=C(NC(=S)C=2C=C(OCC=3SC=C(N=3)C(C)(C)C)C=CC=2)C(OCC(=O)OCC)=CC=C1CCCS(=O)(=O)C1=CC=C(Cl)C=C1 VUPUKQYIXOPPOG-UHFFFAOYSA-N 0.000 description 1
• YCSCHKXKZQFVCB-UHFFFAOYSA-N ethyl 2-[2-[[3-[(4-tert-butyl-1,3-thiazol-2-yl)methoxy]benzoyl]-methylamino]-4-[3-(4-chlorophenyl)sulfonylpropyl]phenoxy]acetate Chemical compound C1=C(N(C)C(=O)C=2C=C(OCC=3SC=C(N=3)C(C)(C)C)C=CC=2)C(OCC(=O)OCC)=CC=C1CCCS(=O)(=O)C1=CC=C(Cl)C=C1 YCSCHKXKZQFVCB-UHFFFAOYSA-N 0.000 description 1
• UPWNQNLQQNVHND-UHFFFAOYSA-N ethyl 2-[2-[[3-[(4-tert-butyl-1,3-thiazol-2-yl)methoxy]benzoyl]amino]-6-chloro-4-[3-(4-chlorophenyl)sulfonylpropyl]phenoxy]acetate Chemical compound C1=C(NC(=O)C=2C=C(OCC=3SC=C(N=3)C(C)(C)C)C=CC=2)C(OCC(=O)OCC)=C(Cl)C=C1CCCS(=O)(=O)C1=CC=C(Cl)C=C1 UPWNQNLQQNVHND-UHFFFAOYSA-N 0.000 description 1
• RQEFUKKJNAPNMA-UHFFFAOYSA-N ethyl 2-[2-[[3-[(4-tert-butyl-5-methyl-1,3-thiazol-2-yl)methoxy]benzoyl]amino]-4-[3-(4-chlorophenyl)sulfonylpropyl]phenoxy]acetate Chemical compound C1=C(NC(=O)C=2C=C(OCC=3SC(C)=C(N=3)C(C)(C)C)C=CC=2)C(OCC(=O)OCC)=CC=C1CCCS(=O)(=O)C1=CC=C(Cl)C=C1 RQEFUKKJNAPNMA-UHFFFAOYSA-N 0.000 description 1
• HFPWWLJUBDCBQP-UHFFFAOYSA-N ethyl 2-[2-[[3-[(5-chloro-1,3-benzothiazol-2-yl)methoxy]benzoyl]amino]-4-[3-(4-chlorophenyl)sulfonylpropyl]phenoxy]acetate Chemical compound C1=C(NC(=O)C=2C=C(OCC=3SC4=CC=C(Cl)C=C4N=3)C=CC=2)C(OCC(=O)OCC)=CC=C1CCCS(=O)(=O)C1=CC=C(Cl)C=C1 HFPWWLJUBDCBQP-UHFFFAOYSA-N 0.000 description 1
• HPZSJOKHDBLBLM-UHFFFAOYSA-N ethyl 2-[2-[[3-[(6-chloro-1,3-benzothiazol-2-yl)methoxy]benzoyl]amino]-4-[3-(4-chlorophenyl)sulfonylpropyl]phenoxy]acetate Chemical compound C1=C(NC(=O)C=2C=C(OCC=3SC4=CC(Cl)=CC=C4N=3)C=CC=2)C(OCC(=O)OCC)=CC=C1CCCS(=O)(=O)C1=CC=C(Cl)C=C1 HPZSJOKHDBLBLM-UHFFFAOYSA-N 0.000 description 1
• UMODLGUQGCHOIY-UHFFFAOYSA-N ethyl 2-[2-[[3-[2-(1,3-benzothiazol-2-yl)ethyl]benzoyl]amino]-4-[3-(4-chlorophenyl)sulfonylpropyl]phenoxy]acetate Chemical compound C1=C(NC(=O)C=2C=C(CCC=3SC4=CC=CC=C4N=3)C=CC=2)C(OCC(=O)OCC)=CC=C1CCCS(=O)(=O)C1=CC=C(Cl)C=C1 UMODLGUQGCHOIY-UHFFFAOYSA-N 0.000 description 1
• OCGMXMGKQMTSRC-UHFFFAOYSA-N ethyl 2-[2-[[3-[2-(4-tert-butyl-1,3-thiazol-2-yl)ethyl]benzoyl]amino]-4-[3-(4-chlorophenyl)sulfonylpropyl]phenoxy]acetate Chemical compound C1=C(NC(=O)C=2C=C(CCC=3SC=C(N=3)C(C)(C)C)C=CC=2)C(OCC(=O)OCC)=CC=C1CCCS(=O)(=O)C1=CC=C(Cl)C=C1 OCGMXMGKQMTSRC-UHFFFAOYSA-N 0.000 description 1
• CRWDBKJXBOPUNJ-UHFFFAOYSA-N ethyl 2-[2-[[3-[2-(5-chloro-1,3-benzothiazol-2-yl)ethenyl]benzoyl]amino]-4-[3-(4-chlorophenyl)sulfonylpropyl]phenoxy]acetate Chemical compound C1=C(NC(=O)C=2C=C(C=CC=3SC4=CC=C(Cl)C=C4N=3)C=CC=2)C(OCC(=O)OCC)=CC=C1CCCS(=O)(=O)C1=CC=C(Cl)C=C1 CRWDBKJXBOPUNJ-UHFFFAOYSA-N 0.000 description 1
• BYBBAPDPGSPCAB-UHFFFAOYSA-N ethyl 2-[2-[[3-amino-5-[(4-tert-butyl-1,3-thiazol-2-yl)methoxy]benzoyl]amino]-4-[3-(4-chlorophenyl)sulfonylpropyl]phenoxy]acetate Chemical compound C1=C(NC(=O)C=2C=C(OCC=3SC=C(N=3)C(C)(C)C)C=C(N)C=2)C(OCC(=O)OCC)=CC=C1CCCS(=O)(=O)C1=CC=C(Cl)C=C1 BYBBAPDPGSPCAB-UHFFFAOYSA-N 0.000 description 1
• YHBYEFGMZNPOFW-UHFFFAOYSA-N ethyl 2-[2-[[4-[2-(1,3-benzothiazol-2-yl)ethenyl]benzoyl]amino]-4-[3-(4-chlorophenyl)sulfonylpropyl]phenoxy]acetate Chemical compound C1=C(NC(=O)C=2C=CC(C=CC=3SC4=CC=CC=C4N=3)=CC=2)C(OCC(=O)OCC)=CC=C1CCCS(=O)(=O)C1=CC=C(Cl)C=C1 YHBYEFGMZNPOFW-UHFFFAOYSA-N 0.000 description 1
• QCAKVSBEXLPVMB-UHFFFAOYSA-N ethyl 2-[2-[[6-[(4-tert-butyl-1,3-thiazol-2-yl)methoxy]pyridine-2-carbonyl]amino]-4-[3-(4-chlorophenyl)sulfonylpropyl]phenoxy]acetate Chemical compound C1=C(NC(=O)C=2N=C(OCC=3SC=C(N=3)C(C)(C)C)C=CC=2)C(OCC(=O)OCC)=CC=C1CCCS(=O)(=O)C1=CC=C(Cl)C=C1 QCAKVSBEXLPVMB-UHFFFAOYSA-N 0.000 description 1
• CVNIKNBIKUFMCI-UHFFFAOYSA-N ethyl 2-[4-[3-(4-chlorophenyl)sulfonylpropyl]-2-[[3-[(4-phenyl-1,3-thiazol-2-yl)methoxy]benzoyl]amino]phenoxy]acetate Chemical compound C1=C(NC(=O)C=2C=C(OCC=3SC=C(N=3)C=3C=CC=CC=3)C=CC=2)C(OCC(=O)OCC)=CC=C1CCCS(=O)(=O)C1=CC=C(Cl)C=C1 CVNIKNBIKUFMCI-UHFFFAOYSA-N 0.000 description 1
• PXZHUHLSJFWQAT-UHFFFAOYSA-N ethyl 2-[4-[3-(4-chlorophenyl)sulfonylpropyl]-2-[[3-[2-(4-cyclopropyl-1,3-thiazol-2-yl)ethenyl]benzoyl]amino]phenoxy]acetate Chemical compound C1=C(NC(=O)C=2C=C(C=CC=3SC=C(N=3)C3CC3)C=CC=2)C(OCC(=O)OCC)=CC=C1CCCS(=O)(=O)C1=CC=C(Cl)C=C1 PXZHUHLSJFWQAT-UHFFFAOYSA-N 0.000 description 1
• RLXQTXKPFSJUOW-UHFFFAOYSA-N ethyl 2-[4-[3-(4-chlorophenyl)sulfonylpropyl]-2-[[3-[2-[4-(4-methylphenyl)-1,3-thiazol-2-yl]ethenyl]benzoyl]amino]phenoxy]acetate Chemical compound C1=C(NC(=O)C=2C=C(C=CC=3SC=C(N=3)C=3C=CC(C)=CC=3)C=CC=2)C(OCC(=O)OCC)=CC=C1CCCS(=O)(=O)C1=CC=C(Cl)C=C1 RLXQTXKPFSJUOW-UHFFFAOYSA-N 0.000 description 1
• HGBNSZFJEWCDTI-UHFFFAOYSA-N ethyl 2-[4-[3-(4-chlorophenyl)sulfonylpropyl]-2-[[3-[[5-(trifluoromethyl)-1,3-benzothiazol-2-yl]methoxy]benzoyl]amino]phenoxy]acetate Chemical compound C1=C(NC(=O)C=2C=C(OCC=3SC4=CC=C(C=C4N=3)C(F)(F)F)C=CC=2)C(OCC(=O)OCC)=CC=C1CCCS(=O)(=O)C1=CC=C(Cl)C=C1 HGBNSZFJEWCDTI-UHFFFAOYSA-N 0.000 description 1
• NLIHMEONDFZKAE-UHFFFAOYSA-N ethyl 2-[6-[[3-[(4-tert-butyl-1,3-thiazol-2-yl)methoxy]benzoyl]amino]-2,3-dichloro-4-[3-(4-chlorophenyl)sulfonylpropyl]phenoxy]acetate Chemical compound C1=C(CCCS(=O)(=O)C=2C=CC(Cl)=CC=2)C(Cl)=C(Cl)C(OCC(=O)OCC)=C1NC(=O)C(C=1)=CC=CC=1OCC1=NC(C(C)(C)C)=CS1 NLIHMEONDFZKAE-UHFFFAOYSA-N 0.000 description 1
• MVEAAGBEUOMFRX-UHFFFAOYSA-N ethyl acetate;hydrochloride Chemical compound Cl.CCOC(C)=O MVEAAGBEUOMFRX-UHFFFAOYSA-N 0.000 description 1
• FAMRKDQNMBBFBR-UHFFFAOYSA-N ethyl n-ethoxycarbonyliminocarbamate Chemical compound CCOC(=O)N=NC(=O)OCC FAMRKDQNMBBFBR-UHFFFAOYSA-N 0.000 description 1
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