US20010036944A1 - Certain benzothiazine dioxide endothelin antagonists and processes for their preparation - Google Patents
Certain benzothiazine dioxide endothelin antagonists and processes for their preparation Download PDFInfo
- Publication number
- US20010036944A1 US20010036944A1 US09/818,394 US81839401A US2001036944A1 US 20010036944 A1 US20010036944 A1 US 20010036944A1 US 81839401 A US81839401 A US 81839401A US 2001036944 A1 US2001036944 A1 US 2001036944A1
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- US
- United States
- Prior art keywords
- benzo
- thiazine
- dioxo
- carboxylic acid
- dihydro
- 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.)
- Granted
Links
- 108050009340 Endothelin Proteins 0.000 title claims abstract description 12
- 102000002045 Endothelin Human genes 0.000 title claims abstract description 12
- ZUBDGKVDJUIMQQ-UBFCDGJISA-N endothelin-1 Chemical compound C([C@@H](C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(O)=O)NC(=O)[C@H]1NC(=O)[C@H](CC=2C=CC=CC=2)NC(=O)[C@@H](CC=2C=CC(O)=CC=2)NC(=O)[C@H](C(C)C)NC(=O)[C@H]2CSSC[C@@H](C(N[C@H](CO)C(=O)N[C@@H](CO)C(=O)N[C@H](CC(C)C)C(=O)N[C@@H](CCSC)C(=O)N[C@H](CC(O)=O)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCC(O)=O)C(=O)N2)=O)NC(=O)[C@@H](CO)NC(=O)[C@H](N)CSSC1)C1=CNC=N1 ZUBDGKVDJUIMQQ-UBFCDGJISA-N 0.000 title claims abstract description 12
- 238000000034 method Methods 0.000 title claims description 66
- 238000002360 preparation method Methods 0.000 title claims description 42
- 230000008569 process Effects 0.000 title claims description 26
- 239000005557 antagonist Substances 0.000 title abstract description 12
- GHNLJDPNIAIWOQ-UHFFFAOYSA-N 2h-1$l^{6},2-benzothiazine 1,1-dioxide Chemical compound C1=CC=C2S(=O)(=O)NC=CC2=C1 GHNLJDPNIAIWOQ-UHFFFAOYSA-N 0.000 title abstract description 3
- 150000001875 compounds Chemical class 0.000 claims abstract description 125
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- 206010008120 Cerebral ischaemia Diseases 0.000 claims abstract description 5
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- 230000003211 malignant effect Effects 0.000 claims abstract description 4
- 201000005857 malignant hypertension Diseases 0.000 claims abstract description 4
- 239000000243 solution Substances 0.000 claims description 75
- WYURNTSHIVDZCO-UHFFFAOYSA-N tetrahydrofuran Substances C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 57
- 229910052739 hydrogen Inorganic materials 0.000 claims description 48
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-dimethylformamide Substances CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 37
- 239000002253 acid Substances 0.000 claims description 29
- 239000002552 dosage form Substances 0.000 claims description 27
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 26
- -1 aryl zinc bromide Chemical compound 0.000 claims description 25
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 24
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 claims description 21
- 238000010992 reflux Methods 0.000 claims description 20
- 239000002904 solvent Substances 0.000 claims description 20
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 claims description 18
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 18
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 17
- 238000005859 coupling reaction Methods 0.000 claims description 13
- YDCHPLOFQATIDS-UHFFFAOYSA-N methyl 2-bromoacetate Chemical compound COC(=O)CBr YDCHPLOFQATIDS-UHFFFAOYSA-N 0.000 claims description 13
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 13
- VNDYJBBGRKZCSX-UHFFFAOYSA-L zinc bromide Chemical compound Br[Zn]Br VNDYJBBGRKZCSX-UHFFFAOYSA-L 0.000 claims description 13
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 claims description 12
- 125000000217 alkyl group Chemical group 0.000 claims description 12
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 12
- 238000006243 chemical reaction Methods 0.000 claims description 11
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims description 10
- 125000003545 alkoxy group Chemical group 0.000 claims description 10
- 150000002148 esters Chemical class 0.000 claims description 10
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 claims description 9
- 229960000549 4-dimethylaminophenol Drugs 0.000 claims description 8
- PAYRUJLWNCNPSJ-UHFFFAOYSA-N Aniline Chemical compound NC1=CC=CC=C1 PAYRUJLWNCNPSJ-UHFFFAOYSA-N 0.000 claims description 8
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 claims description 8
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 claims description 8
- 239000001257 hydrogen Substances 0.000 claims description 8
- 229910000104 sodium hydride Inorganic materials 0.000 claims description 8
- 229940102001 zinc bromide Drugs 0.000 claims description 8
- CSKNSYBAZOQPLR-UHFFFAOYSA-N benzenesulfonyl chloride Chemical compound ClS(=O)(=O)C1=CC=CC=C1 CSKNSYBAZOQPLR-UHFFFAOYSA-N 0.000 claims description 7
- 239000003054 catalyst Substances 0.000 claims description 7
- 230000003197 catalytic effect Effects 0.000 claims description 7
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- 229930194542 Keto Natural products 0.000 claims description 6
- ZADPBFCGQRWHPN-UHFFFAOYSA-N boronic acid Chemical compound OBO ZADPBFCGQRWHPN-UHFFFAOYSA-N 0.000 claims description 6
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 6
- 238000010791 quenching Methods 0.000 claims description 6
- WJKHJLXJJJATHN-UHFFFAOYSA-N triflic anhydride Chemical compound FC(F)(F)S(=O)(=O)OS(=O)(=O)C(F)(F)F WJKHJLXJJJATHN-UHFFFAOYSA-N 0.000 claims description 6
- 150000002085 enols Chemical class 0.000 claims description 5
- 229910052736 halogen Inorganic materials 0.000 claims description 5
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- 150000004702 methyl esters Chemical class 0.000 claims description 5
- 230000000171 quenching effect Effects 0.000 claims description 5
- LOFRBHZYZCIOJO-UHFFFAOYSA-N 7-methoxy-1,3-benzodioxole-5-carbaldehyde Chemical compound COC1=CC(C=O)=CC2=C1OCO2 LOFRBHZYZCIOJO-UHFFFAOYSA-N 0.000 claims description 4
- KAESVJOAVNADME-UHFFFAOYSA-N Pyrrole Chemical group C=1C=CNC=1 KAESVJOAVNADME-UHFFFAOYSA-N 0.000 claims description 4
- 206010040070 Septic Shock Diseases 0.000 claims description 4
- 229910003074 TiCl4 Inorganic materials 0.000 claims description 4
- 230000001154 acute effect Effects 0.000 claims description 4
- 239000003937 drug carrier Substances 0.000 claims description 4
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 4
- 229940098779 methanesulfonic acid Drugs 0.000 claims description 4
- 229910052763 palladium Inorganic materials 0.000 claims description 4
- 239000008194 pharmaceutical composition Substances 0.000 claims description 4
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 4
- IUBQJLUDMLPAGT-UHFFFAOYSA-N potassium bis(trimethylsilyl)amide Chemical compound C[Si](C)(C)N([K])[Si](C)(C)C IUBQJLUDMLPAGT-UHFFFAOYSA-N 0.000 claims description 4
- 229940124530 sulfonamide Drugs 0.000 claims description 4
- 150000003456 sulfonamides Chemical class 0.000 claims description 4
- XJDNKRIXUMDJCW-UHFFFAOYSA-J titanium tetrachloride Chemical compound Cl[Ti](Cl)(Cl)Cl XJDNKRIXUMDJCW-UHFFFAOYSA-J 0.000 claims description 4
- 238000010626 work up procedure Methods 0.000 claims description 4
- IISCGVRQYYMFRH-UHFFFAOYSA-N 2-(2-chlorophenyl)-4-(3,5-dimethoxyphenyl)-1,1-dioxo-1$l^{6},2-benzothiazine-3-carboxylic acid Chemical compound COC1=CC(OC)=CC(C=2C3=CC=CC=C3S(=O)(=O)N(C=3C(=CC=CC=3)Cl)C=2C(O)=O)=C1 IISCGVRQYYMFRH-UHFFFAOYSA-N 0.000 claims description 3
- AMQWLQQHYSWEKW-UHFFFAOYSA-N 2-(2-chlorophenyl)-4-(7-methoxy-1,3-benzodioxol-5-yl)-1,1-dioxo-1$l^{6},2-benzothiazine-3-carboxylic acid Chemical compound C=1C=2OCOC=2C(OC)=CC=1C(C1=CC=CC=C1S1(=O)=O)=C(C(O)=O)N1C1=CC=CC=C1Cl AMQWLQQHYSWEKW-UHFFFAOYSA-N 0.000 claims description 3
- 125000006276 2-bromophenyl group Chemical group [H]C1=C([H])C(Br)=C(*)C([H])=C1[H] 0.000 claims description 3
- YMRUIRRQMVWHTM-UHFFFAOYSA-N 3-bromo-5-(2-hydroxyethyl)phenol Chemical compound OCCC1=CC(O)=CC(Br)=C1 YMRUIRRQMVWHTM-UHFFFAOYSA-N 0.000 claims description 3
- SWOWNAALUBWJMY-UHFFFAOYSA-N 4-(1,3-benzodioxol-5-yl)-2-(2,6-dimethylphenyl)-1,1-dioxo-1$l^{6},2-benzothiazine-3-carboxylic acid Chemical compound CC1=CC=CC(C)=C1N1S(=O)(=O)C2=CC=CC=C2C(C=2C=C3OCOC3=CC=2)=C1C(O)=O SWOWNAALUBWJMY-UHFFFAOYSA-N 0.000 claims description 3
- BRLVMBSIWOVEPW-UHFFFAOYSA-N 4-(1,3-benzodioxol-5-yl)-2-(2-chloro-4-methoxyphenyl)-1,1-dioxo-1$l^{6},2-benzothiazine-3-carboxylic acid Chemical compound ClC1=CC(OC)=CC=C1N1S(=O)(=O)C2=CC=CC=C2C(C=2C=C3OCOC3=CC=2)=C1C(O)=O BRLVMBSIWOVEPW-UHFFFAOYSA-N 0.000 claims description 3
- KNBXCNUDTCRKBB-UHFFFAOYSA-N 4-(1,3-benzodioxol-5-yl)-2-(2-ethylphenyl)-1,1-dioxo-1$l^{6},2-benzothiazine-3-carboxylic acid Chemical compound CCC1=CC=CC=C1N1S(=O)(=O)C2=CC=CC=C2C(C=2C=C3OCOC3=CC=2)=C1C(O)=O KNBXCNUDTCRKBB-UHFFFAOYSA-N 0.000 claims description 3
- WSXNRJXPTNQJBH-UHFFFAOYSA-N 5,6-dihydro-4h-thiazine Chemical compound C1CSN=CC1 WSXNRJXPTNQJBH-UHFFFAOYSA-N 0.000 claims description 3
- 239000002841 Lewis acid Substances 0.000 claims description 3
- 239000012670 alkaline solution Substances 0.000 claims description 3
- 150000001499 aryl bromides Chemical class 0.000 claims description 3
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- 208000001286 intracranial vasospasm Diseases 0.000 claims description 3
- 150000007517 lewis acids Chemical class 0.000 claims description 3
- CWLGPSLYTMAPLI-UHFFFAOYSA-N methyl 4-(7-methoxy-1,3-benzodioxol-5-yl)-2-(2-methylphenyl)-1,1-dioxo-1$l^{6},2-benzothiazine-3-carboxylate Chemical compound COC(=O)C1=C(C=2C=C(OC)C=3OCOC=3C=2)C2=CC=CC=C2S(=O)(=O)N1C1=CC=CC=C1C CWLGPSLYTMAPLI-UHFFFAOYSA-N 0.000 claims description 3
- XAEFZNCEHLXOMS-UHFFFAOYSA-M potassium benzoate Chemical compound [K+].[O-]C(=O)C1=CC=CC=C1 XAEFZNCEHLXOMS-UHFFFAOYSA-M 0.000 claims description 3
- WMOVHXAZOJBABW-UHFFFAOYSA-N tert-butyl acetate Chemical compound CC(=O)OC(C)(C)C WMOVHXAZOJBABW-UHFFFAOYSA-N 0.000 claims description 3
- FNFVXWQEIZDWFQ-UHFFFAOYSA-N 2-(2-bromophenyl)-4-(3,5-dimethoxyphenyl)-1,1-dioxo-1$l^{6},2-benzothiazine-3-carboxylic acid Chemical compound COC1=CC(OC)=CC(C=2C3=CC=CC=C3S(=O)(=O)N(C=3C(=CC=CC=3)Br)C=2C(O)=O)=C1 FNFVXWQEIZDWFQ-UHFFFAOYSA-N 0.000 claims description 2
- DCHMSSPUFCVFEF-UHFFFAOYSA-N 4-(1,3-benzodioxol-5-yl)-2-(2-benzylphenyl)-1,1-dioxo-1$l^{6},2-benzothiazine-3-carboxylic acid Chemical compound OC(=O)C1=C(C=2C=C3OCOC3=CC=2)C2=CC=CC=C2S(=O)(=O)N1C1=CC=CC=C1CC1=CC=CC=C1 DCHMSSPUFCVFEF-UHFFFAOYSA-N 0.000 claims description 2
- DZRKBTOLNPQETC-UHFFFAOYSA-N 4-(1,3-benzodioxol-5-yl)-2-(2-butylphenyl)-1,1-dioxo-1$l^{6},2-benzothiazine-3-carboxylic acid Chemical compound CCCCC1=CC=CC=C1N1S(=O)(=O)C2=CC=CC=C2C(C=2C=C3OCOC3=CC=2)=C1C(O)=O DZRKBTOLNPQETC-UHFFFAOYSA-N 0.000 claims description 2
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- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 2
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- LVTJOONKWUXEFR-FZRMHRINSA-N protoneodioscin Natural products O(C[C@@H](CC[C@]1(O)[C@H](C)[C@@H]2[C@]3(C)[C@H]([C@H]4[C@@H]([C@]5(C)C(=CC4)C[C@@H](O[C@@H]4[C@H](O[C@H]6[C@@H](O)[C@@H](O)[C@@H](O)[C@H](C)O6)[C@@H](O)[C@H](O[C@H]6[C@@H](O)[C@@H](O)[C@@H](O)[C@H](C)O6)[C@H](CO)O4)CC5)CC3)C[C@@H]2O1)C)[C@H]1[C@H](O)[C@H](O)[C@H](O)[C@@H](CO)O1 LVTJOONKWUXEFR-FZRMHRINSA-N 0.000 claims description 2
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- 159000000000 sodium salts Chemical class 0.000 claims description 2
- IQFZCCCFDPHKPJ-UHFFFAOYSA-N tert-butyl 2-(2-chlorophenyl)-4-hydroxy-1,1-dioxo-1$l^{6},2-benzothiazine-3-carboxylate Chemical compound CC(C)(C)OC(=O)C1=C(O)C2=CC=CC=C2S(=O)(=O)N1C1=CC=CC=C1Cl IQFZCCCFDPHKPJ-UHFFFAOYSA-N 0.000 claims description 2
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 2
- DIXQNPMNNNHBJM-UHFFFAOYSA-N 2-(2-benzylphenyl)-4-(7-methoxy-1,3-benzodioxol-5-yl)-1,1-dioxo-1$l^{6},2-benzothiazine-3-carboxylic acid Chemical compound C=1C=2OCOC=2C(OC)=CC=1C(C1=CC=CC=C1S1(=O)=O)=C(C(O)=O)N1C1=CC=CC=C1CC1=CC=CC=C1 DIXQNPMNNNHBJM-UHFFFAOYSA-N 0.000 claims 2
- TZKOBJCQNUBVFU-UHFFFAOYSA-N 4-(1,3-benzodioxol-5-yl)-1,1-dioxo-2-(2-propan-2-ylphenyl)-1$l^{6},2-benzothiazine-3-carboxylic acid Chemical compound CC(C)C1=CC=CC=C1N1S(=O)(=O)C2=CC=CC=C2C(C=2C=C3OCOC3=CC=2)=C1C(O)=O TZKOBJCQNUBVFU-UHFFFAOYSA-N 0.000 claims 2
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- 150000002431 hydrogen Chemical group 0.000 claims 2
- OBVZSUMIYCNREA-UHFFFAOYSA-M sodium;2-(2,6-dimethylphenyl)-4-(7-methoxy-1,3-benzodioxol-5-yl)-1,1-dioxo-1$l^{6},2-benzothiazine-3-carboxylate Chemical compound [Na+].C=1C=2OCOC=2C(OC)=CC=1C(C1=CC=CC=C1S1(=O)=O)=C(C([O-])=O)N1C1=C(C)C=CC=C1C OBVZSUMIYCNREA-UHFFFAOYSA-M 0.000 claims 2
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- GDBQQVLCIARPGH-ULQDDVLXSA-N leupeptin Chemical compound CC(C)C[C@H](NC(C)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@H](C=O)CCCN=C(N)N GDBQQVLCIARPGH-ULQDDVLXSA-N 0.000 description 1
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- ZLNQQNXFFQJAID-UHFFFAOYSA-L magnesium carbonate Chemical compound [Mg+2].[O-]C([O-])=O ZLNQQNXFFQJAID-UHFFFAOYSA-L 0.000 description 1
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- NXPHGHWWQRMDIA-UHFFFAOYSA-M magnesium;carbanide;bromide Chemical compound [CH3-].[Mg+2].[Br-] NXPHGHWWQRMDIA-UHFFFAOYSA-M 0.000 description 1
- IMYZQPCYWPFTAG-IQJOONFLSA-N mecamylamine Chemical compound C1C[C@@H]2C(C)(C)[C@@](NC)(C)[C@H]1C2 IMYZQPCYWPFTAG-IQJOONFLSA-N 0.000 description 1
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- OSLPZWRYUCGDSI-UHFFFAOYSA-N methyl 1,1-dioxo-2-(2-phenylmethoxyphenyl)-4-(trifluoromethylsulfonyloxy)-1$l^{6},2-benzothiazine-3-carboxylate Chemical compound COC(=O)C1=C(OS(=O)(=O)C(F)(F)F)C2=CC=CC=C2S(=O)(=O)N1C1=CC=CC=C1OCC1=CC=CC=C1 OSLPZWRYUCGDSI-UHFFFAOYSA-N 0.000 description 1
- LLYZFMNXQONPGT-UHFFFAOYSA-N methyl 1,1-dioxo-2-[2-(trifluoromethyl)phenyl]-1$l^{6},2-benzothiazine-3-carboxylate Chemical compound COC(=O)C1=CC2=CC=CC=C2S(=O)(=O)N1C1=CC=CC=C1C(F)(F)F LLYZFMNXQONPGT-UHFFFAOYSA-N 0.000 description 1
- ABZLYBWZIARWPY-UHFFFAOYSA-N methyl 1,1-dioxo-2h-1$l^{6},2-benzothiazine-3-carboxylate Chemical compound C1=CC=C2S(=O)(=O)NC(C(=O)OC)=CC2=C1 ABZLYBWZIARWPY-UHFFFAOYSA-N 0.000 description 1
- VCGIHFKLXHXZDF-UHFFFAOYSA-N methyl 2-(2,6-dimethylphenyl)-4-(7-methoxy-1,3-benzodioxol-5-yl)-1,1-dioxo-1$l^{6},2-benzothiazine-3-carboxylate Chemical compound COC(=O)C1=C(C=2C=C(OC)C=3OCOC=3C=2)C2=CC=CC=C2S(=O)(=O)N1C1=C(C)C=CC=C1C VCGIHFKLXHXZDF-UHFFFAOYSA-N 0.000 description 1
- KEGAZPVTRNVIII-UHFFFAOYSA-N methyl 2-(2-benzylphenyl)-1,1-dioxo-4-(trifluoromethylsulfonyloxy)-1$l^{6},2-benzothiazine-3-carboxylate Chemical compound COC(=O)C1=C(OS(=O)(=O)C(F)(F)F)C2=CC=CC=C2S(=O)(=O)N1C1=CC=CC=C1CC1=CC=CC=C1 KEGAZPVTRNVIII-UHFFFAOYSA-N 0.000 description 1
- TUTFAOVNXXDRIE-UHFFFAOYSA-N methyl 2-(2-benzylphenyl)-4-(7-methoxy-1,3-benzodioxol-5-yl)-1,1-dioxo-1$l^{6},2-benzothiazine-3-carboxylate Chemical compound COC(=O)C1=C(C=2C=C(OC)C=3OCOC=3C=2)C2=CC=CC=C2S(=O)(=O)N1C1=CC=CC=C1CC1=CC=CC=C1 TUTFAOVNXXDRIE-UHFFFAOYSA-N 0.000 description 1
- AHXDWQCCAYBCKL-UHFFFAOYSA-N methyl 2-(2-benzylphenyl)-4-hydroxy-1,1-dioxo-1$l^{6},2-benzothiazine-3-carboxylate Chemical compound COC(=O)C1=C(O)C2=CC=CC=C2S(=O)(=O)N1C1=CC=CC=C1CC1=CC=CC=C1 AHXDWQCCAYBCKL-UHFFFAOYSA-N 0.000 description 1
- ZJGKSLMLQYHBAU-UHFFFAOYSA-N methyl 2-(2-bromophenyl)-4-(7-methoxy-1,3-benzodioxol-5-yl)-1,1-dioxo-1$l^{6},2-benzothiazine-3-carboxylate Chemical compound COC(=O)C1=C(C=2C=C(OC)C=3OCOC=3C=2)C2=CC=CC=C2S(=O)(=O)N1C1=CC=CC=C1Br ZJGKSLMLQYHBAU-UHFFFAOYSA-N 0.000 description 1
- CFGVNPDHWLUWMY-UHFFFAOYSA-N methyl 2-(2-bromophenyl)-4-hydroxy-1,1-dioxo-1$l^{6},2-benzothiazine-3-carboxylate Chemical compound COC(=O)C1=C(O)C2=CC=CC=C2S(=O)(=O)N1C1=CC=CC=C1Br CFGVNPDHWLUWMY-UHFFFAOYSA-N 0.000 description 1
- LBZGJDXTHLJVNB-UHFFFAOYSA-N methyl 2-(2-butylphenyl)-1,1-dioxo-4-(trifluoromethylsulfonyloxy)-1$l^{6},2-benzothiazine-3-carboxylate Chemical compound CCCCC1=CC=CC=C1N1S(=O)(=O)C2=CC=CC=C2C(OS(=O)(=O)C(F)(F)F)=C1C(=O)OC LBZGJDXTHLJVNB-UHFFFAOYSA-N 0.000 description 1
- CXGOPTURDFSXRV-UHFFFAOYSA-N methyl 2-(2-chloro-4-methoxyphenyl)-1,1-dioxo-4-(trifluoromethylsulfonyloxy)-1$l^{6},2-benzothiazine-3-carboxylate Chemical compound COC(=O)C1=C(OS(=O)(=O)C(F)(F)F)C2=CC=CC=C2S(=O)(=O)N1C1=CC=C(OC)C=C1Cl CXGOPTURDFSXRV-UHFFFAOYSA-N 0.000 description 1
- KLEGTBPZJSEEQE-UHFFFAOYSA-N methyl 2-(2-chloro-4-methoxyphenyl)-4-hydroxy-1,1-dioxo-1$l^{6},2-benzothiazine-3-carboxylate Chemical compound COC(=O)C1=C(O)C2=CC=CC=C2S(=O)(=O)N1C1=CC=C(OC)C=C1Cl KLEGTBPZJSEEQE-UHFFFAOYSA-N 0.000 description 1
- DKOYRWGNQDOKLA-UHFFFAOYSA-N methyl 2-(2-chlorophenyl)-1,1-dioxo-4-(trifluoromethylsulfonyloxy)-1$l^{6},2-benzothiazine-3-carboxylate Chemical compound COC(=O)C1=C(OS(=O)(=O)C(F)(F)F)C2=CC=CC=C2S(=O)(=O)N1C1=CC=CC=C1Cl DKOYRWGNQDOKLA-UHFFFAOYSA-N 0.000 description 1
- IVPINAOFLBGOBR-UHFFFAOYSA-N methyl 2-(2-chlorophenyl)-4-(7-methoxy-1,3-benzodioxol-5-yl)-1,1-dioxo-1$l^{6},2-benzothiazine-3-carboxylate Chemical compound COC(=O)C1=C(C=2C=C(OC)C=3OCOC=3C=2)C2=CC=CC=C2S(=O)(=O)N1C1=CC=CC=C1Cl IVPINAOFLBGOBR-UHFFFAOYSA-N 0.000 description 1
- KRSJMUYADZOGQV-UHFFFAOYSA-N methyl 2-(2-chlorophenyl)-4-hydroxy-1,1-dioxo-1$l^{6},2-benzothiazine-3-carboxylate Chemical compound COC(=O)C1=C(O)C2=CC=CC=C2S(=O)(=O)N1C1=CC=CC=C1Cl KRSJMUYADZOGQV-UHFFFAOYSA-N 0.000 description 1
- OHAHMUHZXHTLQW-UHFFFAOYSA-N methyl 2-(2-ethylphenyl)-1,1-dioxo-4-(trifluoromethylsulfonyloxy)-1$l^{6},2-benzothiazine-3-carboxylate Chemical compound CCC1=CC=CC=C1N1S(=O)(=O)C2=CC=CC=C2C(OS(=O)(=O)C(F)(F)F)=C1C(=O)OC OHAHMUHZXHTLQW-UHFFFAOYSA-N 0.000 description 1
- YELDXQCGSRBVAX-UHFFFAOYSA-N methyl 2-(2-ethylphenyl)-4-hydroxy-1,1-dioxo-1$l^{6},2-benzothiazine-3-carboxylate Chemical compound CCC1=CC=CC=C1N1S(=O)(=O)C2=CC=CC=C2C(O)=C1C(=O)OC YELDXQCGSRBVAX-UHFFFAOYSA-N 0.000 description 1
- QDFUYPHTIGWHNN-UHFFFAOYSA-N methyl 2-(2-fluorophenyl)-1,1-dioxo-4-(trifluoromethylsulfonyloxy)-1$l^{6},2-benzothiazine-3-carboxylate Chemical compound COC(=O)C1=C(OS(=O)(=O)C(F)(F)F)C2=CC=CC=C2S(=O)(=O)N1C1=CC=CC=C1F QDFUYPHTIGWHNN-UHFFFAOYSA-N 0.000 description 1
- BDDFNMLBTAKFRC-UHFFFAOYSA-N methyl 2-(2-fluorophenyl)-4-hydroxy-1,1-dioxo-1$l^{6},2-benzothiazine-3-carboxylate Chemical compound COC(=O)C1=C(O)C2=CC=CC=C2S(=O)(=O)N1C1=CC=CC=C1F BDDFNMLBTAKFRC-UHFFFAOYSA-N 0.000 description 1
- DEONWIJPUKSVPN-UHFFFAOYSA-N methyl 2-(n-[2-(7-methoxy-1,3-benzodioxole-5-carbonyl)phenyl]sulfonyl-2-methylanilino)acetate Chemical compound C=1C=CC=C(C(=O)C=2C=C(OC)C=3OCOC=3C=2)C=1S(=O)(=O)N(CC(=O)OC)C1=CC=CC=C1C DEONWIJPUKSVPN-UHFFFAOYSA-N 0.000 description 1
- FCLLEMCWICMRRP-UHFFFAOYSA-N methyl 2-(n-[2-[hydroxy-(7-methoxy-1,3-benzodioxol-5-yl)methyl]phenyl]sulfonyl-2-methylanilino)acetate Chemical compound C=1C=CC=C(C(O)C=2C=C(OC)C=3OCOC=3C=2)C=1S(=O)(=O)N(CC(=O)OC)C1=CC=CC=C1C FCLLEMCWICMRRP-UHFFFAOYSA-N 0.000 description 1
- BDPWPMNPIJSYGN-UHFFFAOYSA-N methyl 2-[(2,3-dichlorophenyl)sulfamoyl]benzoate Chemical compound COC(=O)C1=CC=CC=C1S(=O)(=O)NC1=CC=CC(Cl)=C1Cl BDPWPMNPIJSYGN-UHFFFAOYSA-N 0.000 description 1
- OBMTXQQOGKSBCC-UHFFFAOYSA-N methyl 2-[(2,4-dichlorophenyl)sulfamoyl]benzoate Chemical compound COC(=O)C1=CC=CC=C1S(=O)(=O)NC1=CC=C(Cl)C=C1Cl OBMTXQQOGKSBCC-UHFFFAOYSA-N 0.000 description 1
- TWAHIWMZQIWNTB-UHFFFAOYSA-N methyl 2-[(2-butylphenyl)sulfamoyl]benzoate Chemical compound CCCCC1=CC=CC=C1NS(=O)(=O)C1=CC=CC=C1C(=O)OC TWAHIWMZQIWNTB-UHFFFAOYSA-N 0.000 description 1
- HUABTSYNGSIJKC-UHFFFAOYSA-N methyl 2-[(2-chloro-4-methoxyphenyl)sulfamoyl]benzoate Chemical compound COC(=O)C1=CC=CC=C1S(=O)(=O)NC1=CC=C(OC)C=C1Cl HUABTSYNGSIJKC-UHFFFAOYSA-N 0.000 description 1
- ALCYDMLVBOENHW-UHFFFAOYSA-N methyl 2-[(2-chlorophenyl)-(2-methoxy-2-oxoethyl)sulfamoyl]benzoate Chemical compound C=1C=CC=C(C(=O)OC)C=1S(=O)(=O)N(CC(=O)OC)C1=CC=CC=C1Cl ALCYDMLVBOENHW-UHFFFAOYSA-N 0.000 description 1
- FYHQRDRKPBZHFB-UHFFFAOYSA-N methyl 2-[(2-ethylphenyl)sulfamoyl]benzoate Chemical compound CCC1=CC=CC=C1NS(=O)(=O)C1=CC=CC=C1C(=O)OC FYHQRDRKPBZHFB-UHFFFAOYSA-N 0.000 description 1
- XVEGPFXNAZLEBW-UHFFFAOYSA-N methyl 2-[(2-fluorophenyl)sulfamoyl]benzoate Chemical compound COC(=O)C1=CC=CC=C1S(=O)(=O)NC1=CC=CC=C1F XVEGPFXNAZLEBW-UHFFFAOYSA-N 0.000 description 1
- VKARTMCBQGZWAJ-UHFFFAOYSA-N methyl 2-[(2-methoxy-2-oxoethyl)-(2-phenylmethoxyphenyl)sulfamoyl]benzoate Chemical compound C=1C=CC=C(C(=O)OC)C=1S(=O)(=O)N(CC(=O)OC)C1=CC=CC=C1OCC1=CC=CC=C1 VKARTMCBQGZWAJ-UHFFFAOYSA-N 0.000 description 1
- AXVBHTJOOOGJHO-UHFFFAOYSA-N methyl 2-[(2-methoxy-2-oxoethyl)-(2-propylphenyl)sulfamoyl]benzoate Chemical compound CCCC1=CC=CC=C1N(CC(=O)OC)S(=O)(=O)C1=CC=CC=C1C(=O)OC AXVBHTJOOOGJHO-UHFFFAOYSA-N 0.000 description 1
- AAVSWVQCNHMBHA-UHFFFAOYSA-N methyl 2-[(2-methoxy-2-oxoethyl)-(2-pyrrol-1-ylphenyl)sulfamoyl]benzoate Chemical compound C=1C=CC=C(C(=O)OC)C=1S(=O)(=O)N(CC(=O)OC)C1=CC=CC=C1N1C=CC=C1 AAVSWVQCNHMBHA-UHFFFAOYSA-N 0.000 description 1
- IUUXXHLKAFKHFA-UHFFFAOYSA-N methyl 2-[(2-methylphenyl)sulfamoyl]benzoate Chemical compound COC(=O)C1=CC=CC=C1S(=O)(=O)NC1=CC=CC=C1C IUUXXHLKAFKHFA-UHFFFAOYSA-N 0.000 description 1
- SXYQKSVFJCOYBQ-UHFFFAOYSA-N methyl 2-[(2-phenylmethoxyphenyl)sulfamoyl]benzoate Chemical compound COC(=O)C1=CC=CC=C1S(=O)(=O)NC1=CC=CC=C1OCC1=CC=CC=C1 SXYQKSVFJCOYBQ-UHFFFAOYSA-N 0.000 description 1
- XFFYBTFUSWJUPZ-UHFFFAOYSA-N methyl 2-[(2-propan-2-ylphenyl)sulfamoyl]benzoate Chemical compound COC(=O)C1=CC=CC=C1S(=O)(=O)NC1=CC=CC=C1C(C)C XFFYBTFUSWJUPZ-UHFFFAOYSA-N 0.000 description 1
- STLOMWCRUIROQT-UHFFFAOYSA-N methyl 2-[(2-propylphenyl)sulfamoyl]benzoate Chemical compound CCCC1=CC=CC=C1NS(=O)(=O)C1=CC=CC=C1C(=O)OC STLOMWCRUIROQT-UHFFFAOYSA-N 0.000 description 1
- MJLLOSPTWYKWHG-UHFFFAOYSA-N methyl 2-[(2-pyrrol-1-ylphenyl)sulfamoyl]benzoate Chemical compound COC(=O)C1=CC=CC=C1S(=O)(=O)NC1=CC=CC=C1N1C=CC=C1 MJLLOSPTWYKWHG-UHFFFAOYSA-N 0.000 description 1
- TYTOIJWZHIBEQU-UHFFFAOYSA-N methyl 2-[(3,4-dimethyl-1,2-oxazol-5-yl)sulfamoyl]benzoate Chemical compound COC(=O)C1=CC=CC=C1S(=O)(=O)NC1=C(C)C(C)=NO1 TYTOIJWZHIBEQU-UHFFFAOYSA-N 0.000 description 1
- UTNPFUHICJEHBE-UHFFFAOYSA-N methyl 2-[(3-chloro-2-methylphenyl)sulfamoyl]benzoate Chemical compound COC(=O)C1=CC=CC=C1S(=O)(=O)NC1=CC=CC(Cl)=C1C UTNPFUHICJEHBE-UHFFFAOYSA-N 0.000 description 1
- MNPSKHCORNCHRL-UHFFFAOYSA-N methyl 2-[(6-chloro-1,3-benzodioxol-5-yl)sulfamoyl]benzoate Chemical compound COC(=O)C1=CC=CC=C1S(=O)(=O)NC(C(=C1)Cl)=CC2=C1OCO2 MNPSKHCORNCHRL-UHFFFAOYSA-N 0.000 description 1
- GGLQVSROKKLOIG-UHFFFAOYSA-N methyl 2-[[2-[(2,4-dichlorophenyl)methoxy]-2-oxoethyl]sulfamoyl]benzoate Chemical compound COC(=O)C1=CC=CC=C1S(=O)(=O)NCC(=O)OCC1=CC=C(Cl)C=C1Cl GGLQVSROKKLOIG-UHFFFAOYSA-N 0.000 description 1
- NHFCOGQOUZETIP-UHFFFAOYSA-N methyl 2-[[2-[(2,6-dimethylphenyl)methoxy]-2-oxoethyl]sulfamoyl]benzoate Chemical compound COC(=O)C1=CC=CC=C1S(=O)(=O)NCC(=O)OCC1=C(C)C=CC=C1C NHFCOGQOUZETIP-UHFFFAOYSA-N 0.000 description 1
- IMIXBTJWMMXJSE-UHFFFAOYSA-N methyl 2-[[2-[(2-butylphenyl)methoxy]-2-oxoethyl]sulfamoyl]benzoate Chemical compound CCCCC1=CC=CC=C1COC(=O)CNS(=O)(=O)C1=CC=CC=C1C(=O)OC IMIXBTJWMMXJSE-UHFFFAOYSA-N 0.000 description 1
- LIQJUTAXWZZDBS-UHFFFAOYSA-N methyl 2-[[2-[(2-fluorophenyl)methoxy]-2-oxoethyl]sulfamoyl]benzoate Chemical compound COC(=O)C1=CC=CC=C1S(=O)(=O)NCC(=O)OCC1=CC=CC=C1F LIQJUTAXWZZDBS-UHFFFAOYSA-N 0.000 description 1
- YORGRQNVPBWBKG-UHFFFAOYSA-N methyl 2-[[2-[(3,4-dimethyl-1,2-oxazol-5-yl)methoxy]-2-oxoethyl]sulfamoyl]benzoate Chemical compound COC(=O)C1=CC=CC=C1S(=O)(=O)NCC(=O)OCC1=C(C)C(C)=NO1 YORGRQNVPBWBKG-UHFFFAOYSA-N 0.000 description 1
- DAUCGXUGHYZMSB-UHFFFAOYSA-N methyl 2-[[2-[(3-chloro-2-methylphenyl)methoxy]-2-oxoethyl]sulfamoyl]benzoate Chemical compound COC(=O)C1=CC=CC=C1S(=O)(=O)NCC(=O)OCC1=CC=CC(Cl)=C1C DAUCGXUGHYZMSB-UHFFFAOYSA-N 0.000 description 1
- YWTJWMBUTBIRCE-UHFFFAOYSA-N methyl 2-[[2-oxo-2-[(2-propan-2-ylphenyl)methoxy]ethyl]sulfamoyl]benzoate Chemical compound COC(=O)C1=CC=CC=C1S(=O)(=O)NCC(=O)OCC1=CC=CC=C1C(C)C YWTJWMBUTBIRCE-UHFFFAOYSA-N 0.000 description 1
- QVNAUWXKTOKOGD-UHFFFAOYSA-N methyl 2h-thiazine-3-carboxylate Chemical compound COC(=O)C1=CC=CSN1 QVNAUWXKTOKOGD-UHFFFAOYSA-N 0.000 description 1
- NHDSVFZQGDMYTJ-UHFFFAOYSA-N methyl 4-(1,3-benzodioxol-5-yl)-1,1-dioxo-2-(2-pyrrol-1-ylphenyl)-1$l^{6},2-benzothiazine-3-carboxylate Chemical compound COC(=O)C1=C(C=2C=C3OCOC3=CC=2)C2=CC=CC=C2S(=O)(=O)N1C1=CC=CC=C1N1C=CC=C1 NHDSVFZQGDMYTJ-UHFFFAOYSA-N 0.000 description 1
- OTBPZDAGPSFNID-UHFFFAOYSA-N methyl 4-(1,3-benzodioxol-5-yl)-1,1-dioxo-2-[2-(trifluoromethyl)phenyl]-1$l^{6},2-benzothiazine-3-carboxylate Chemical compound COC(=O)C1=C(C=2C=C3OCOC3=CC=2)C2=CC=CC=C2S(=O)(=O)N1C1=CC=CC=C1C(F)(F)F OTBPZDAGPSFNID-UHFFFAOYSA-N 0.000 description 1
- CUHXQIPRKZZPCP-UHFFFAOYSA-N methyl 4-(1,3-benzodioxol-5-yl)-2-(2-benzylphenyl)-1,1-dioxo-1$l^{6},2-benzothiazine-3-carboxylate Chemical compound COC(=O)C1=C(C=2C=C3OCOC3=CC=2)C2=CC=CC=C2S(=O)(=O)N1C1=CC=CC=C1CC1=CC=CC=C1 CUHXQIPRKZZPCP-UHFFFAOYSA-N 0.000 description 1
- UMOMBZFFLJEQMS-UHFFFAOYSA-N methyl 4-(1,3-benzodioxol-5-yl)-2-(2-chloro-4-methoxyphenyl)-1,1-dioxo-1$l^{6},2-benzothiazine-3-carboxylate Chemical compound COC(=O)C1=C(C=2C=C3OCOC3=CC=2)C2=CC=CC=C2S(=O)(=O)N1C1=CC=C(OC)C=C1Cl UMOMBZFFLJEQMS-UHFFFAOYSA-N 0.000 description 1
- SJHCKBGVTQZJMA-UHFFFAOYSA-N methyl 4-(1,3-benzodioxol-5-yl)-2-(2-ethylphenyl)-1,1-dioxo-1$l^{6},2-benzothiazine-3-carboxylate Chemical compound CCC1=CC=CC=C1N1S(=O)(=O)C2=CC=CC=C2C(C=2C=C3OCOC3=CC=2)=C1C(=O)OC SJHCKBGVTQZJMA-UHFFFAOYSA-N 0.000 description 1
- RQLIYFCCEGKDIK-UHFFFAOYSA-N methyl 4-(1,3-benzodioxol-5-yl)-2-(2-hydroxyphenyl)-1,1-dioxo-1$l^{6},2-benzothiazine-3-carboxylate Chemical compound COC(=O)C1=C(C=2C=C3OCOC3=CC=2)C2=CC=CC=C2S(=O)(=O)N1C1=CC=CC=C1O RQLIYFCCEGKDIK-UHFFFAOYSA-N 0.000 description 1
- ORKJARJKDARTBS-UHFFFAOYSA-N methyl 4-(1,3-benzodioxol-5-yl)-2-(3-chloro-2-methylphenyl)-1,1-dioxo-1$l^{6},2-benzothiazine-3-carboxylate Chemical compound COC(=O)C1=C(C=2C=C3OCOC3=CC=2)C2=CC=CC=C2S(=O)(=O)N1C1=CC=CC(Cl)=C1C ORKJARJKDARTBS-UHFFFAOYSA-N 0.000 description 1
- GCEJRGXIMWIJCU-UHFFFAOYSA-N methyl 4-(7-methoxy-1,3-benzodioxol-5-yl)-1,1-dioxo-2-[2-(trifluoromethyl)phenyl]-1$l^{6},2-benzothiazine-3-carboxylate Chemical compound COC(=O)C1=C(C=2C=C(OC)C=3OCOC=3C=2)C2=CC=CC=C2S(=O)(=O)N1C1=CC=CC=C1C(F)(F)F GCEJRGXIMWIJCU-UHFFFAOYSA-N 0.000 description 1
- GJNJQTKJYIGRNJ-UHFFFAOYSA-N methyl 4-hydroxy-1,1-dioxo-2-(2-phenylmethoxyphenyl)-1$l^{6},2-benzothiazine-3-carboxylate Chemical compound COC(=O)C1=C(O)C2=CC=CC=C2S(=O)(=O)N1C1=CC=CC=C1OCC1=CC=CC=C1 GJNJQTKJYIGRNJ-UHFFFAOYSA-N 0.000 description 1
- FLDNYTCEDRUCEE-UHFFFAOYSA-N methyl 4-hydroxy-1,1-dioxo-2-(2-propylphenyl)-1$l^{6},2-benzothiazine-3-carboxylate Chemical compound CCCC1=CC=CC=C1N1S(=O)(=O)C2=CC=CC=C2C(O)=C1C(=O)OC FLDNYTCEDRUCEE-UHFFFAOYSA-N 0.000 description 1
- UNFAOCKILFSLIW-UHFFFAOYSA-N methyl 4-hydroxy-1,1-dioxo-2-(2-pyrrol-1-ylphenyl)-1$l^{6},2-benzothiazine-3-carboxylate Chemical compound COC(=O)C1=C(O)C2=CC=CC=C2S(=O)(=O)N1C1=CC=CC=C1N1C=CC=C1 UNFAOCKILFSLIW-UHFFFAOYSA-N 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
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- 229910000402 monopotassium phosphate Inorganic materials 0.000 description 1
- BIZZAMCVUWYVCZ-UHFFFAOYSA-N n-(2-methylphenyl)benzenesulfonamide Chemical compound CC1=CC=CC=C1NS(=O)(=O)C1=CC=CC=C1 BIZZAMCVUWYVCZ-UHFFFAOYSA-N 0.000 description 1
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
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- BWSDNRQVTFZQQD-AYVHNPTNSA-N phosphoramidon Chemical compound O([P@@](O)(=O)N[C@H](CC(C)C)C(=O)N[C@H](CC=1[C]2C=CC=CC2=NC=1)C(O)=O)[C@H]1O[C@@H](C)[C@H](O)[C@@H](O)[C@@H]1O BWSDNRQVTFZQQD-AYVHNPTNSA-N 0.000 description 1
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- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 239000000377 silicon dioxide Substances 0.000 description 1
- 210000000329 smooth muscle myocyte Anatomy 0.000 description 1
- URGAHOPLAPQHLN-UHFFFAOYSA-N sodium aluminosilicate Chemical compound [Na+].[Al+3].[O-][Si]([O-])=O.[O-][Si]([O-])=O URGAHOPLAPQHLN-UHFFFAOYSA-N 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 235000009518 sodium iodide Nutrition 0.000 description 1
- PYWBTFHUCPUVCJ-UHFFFAOYSA-M sodium;2-(2-bromophenyl)-4-(7-methoxy-1,3-benzodioxol-5-yl)-1,1-dioxo-1$l^{6},2-benzothiazine-3-carboxylate Chemical compound [Na+].C=1C=2OCOC=2C(OC)=CC=1C(C1=CC=CC=C1S1(=O)=O)=C(C([O-])=O)N1C1=CC=CC=C1Br PYWBTFHUCPUVCJ-UHFFFAOYSA-M 0.000 description 1
- SLZHLQUFNFXTHB-UHFFFAOYSA-M sodium;5-butan-2-yl-5-ethyl-2-sulfanylidenepyrimidin-3-ide-4,6-dione Chemical compound [Na+].CCC(C)C1(CC)C([O-])=NC(=S)NC1=O SLZHLQUFNFXTHB-UHFFFAOYSA-M 0.000 description 1
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- ZYKMANOOKYSDMJ-UHFFFAOYSA-N tert-butyl 1,1-dioxo-2h-1$l^{6},2-benzothiazine-3-carboxylate Chemical compound C1=CC=C2S(=O)(=O)NC(C(=O)OC(C)(C)C)=CC2=C1 ZYKMANOOKYSDMJ-UHFFFAOYSA-N 0.000 description 1
- DXPRGLBKWGVWNI-UHFFFAOYSA-N tert-butyl 2-bromo-3-[2-[(2-bromophenyl)sulfamoyl]phenyl]-3-oxopropanoate Chemical compound CC(C)(C)OC(=O)C(Br)C(=O)C1=CC=CC=C1S(=O)(=O)NC1=CC=CC=C1Br DXPRGLBKWGVWNI-UHFFFAOYSA-N 0.000 description 1
- HCOOCLOHUZNQAW-UHFFFAOYSA-N tert-butyl 2-bromo-3-[2-[(2-chlorophenyl)sulfamoyl]phenyl]-3-oxopropanoate Chemical compound CC(C)(C)OC(=O)C(Br)C(=O)C1=CC=CC=C1S(=O)(=O)NC1=CC=CC=C1Cl HCOOCLOHUZNQAW-UHFFFAOYSA-N 0.000 description 1
- AGQGMDBXCAPLER-UHFFFAOYSA-N tert-butyl 2-bromo-3-[2-[(2-methylphenyl)sulfamoyl]phenyl]-3-oxopropanoate Chemical compound CC1=CC=CC=C1NS(=O)(=O)C1=CC=CC=C1C(=O)C(Br)C(=O)OC(C)(C)C AGQGMDBXCAPLER-UHFFFAOYSA-N 0.000 description 1
- UYSZFXOJCPOLGI-UHFFFAOYSA-N tert-butyl 2-bromo-3-[2-[(6-chloro-1,3-benzodioxol-5-yl)sulfamoyl]phenyl]-3-oxopropanoate Chemical compound CC(C)(C)OC(=O)C(Br)C(=O)C1=CC=CC=C1S(=O)(=O)NC(C(=C1)Cl)=CC2=C1OCO2 UYSZFXOJCPOLGI-UHFFFAOYSA-N 0.000 description 1
- HGAQQLXIKUDLOE-UHFFFAOYSA-N tert-butyl 2h-1,2-benzothiazine-3-carboxylate Chemical compound C1=CC=C2SNC(C(=O)OC(C)(C)C)=CC2=C1 HGAQQLXIKUDLOE-UHFFFAOYSA-N 0.000 description 1
- VOBJXEPSLWSEQZ-UHFFFAOYSA-N tert-butyl 2h-thiazine-3-carboxylate Chemical compound CC(C)(C)OC(=O)C1=CC=CSN1 VOBJXEPSLWSEQZ-UHFFFAOYSA-N 0.000 description 1
- KJSNHAXAIGDMEF-UHFFFAOYSA-N tert-butyl 3-[2-[(6-methyl-1,3-benzodioxol-5-yl)sulfamoyl]phenyl]-3-oxopropanoate Chemical compound CC1=CC=2OCOC=2C=C1NS(=O)(=O)C1=CC=CC=C1C(=O)CC(=O)OC(C)(C)C KJSNHAXAIGDMEF-UHFFFAOYSA-N 0.000 description 1
- DJXQBXDUGONRMQ-UHFFFAOYSA-N tert-butyl 3-oxopropanoate Chemical compound CC(C)(C)OC(=O)CC=O DJXQBXDUGONRMQ-UHFFFAOYSA-N 0.000 description 1
- IZVJUOBTWRDQKC-UHFFFAOYSA-N tert-butyl 4-(1,3-benzodioxol-5-yl)-2-(2-chlorophenyl)-1,1-dioxo-1$l^{6},2-benzothiazine-3-carboxylate Chemical compound CC(C)(C)OC(=O)C1=C(C=2C=C3OCOC3=CC=2)C2=CC=CC=C2S(=O)(=O)N1C1=CC=CC=C1Cl IZVJUOBTWRDQKC-UHFFFAOYSA-N 0.000 description 1
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- 125000002948 undecyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
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Classifications
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- 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
-
- A—HUMAN NECESSITIES
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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- A61P11/06—Antiasthmatics
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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
- A61P13/00—Drugs for disorders of the urinary system
- A61P13/12—Drugs for disorders of the urinary system of the kidneys
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
- A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
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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
- 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
- A61P9/04—Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
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- A—HUMAN NECESSITIES
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/06—Antiarrhythmics
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- A—HUMAN NECESSITIES
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/12—Antihypertensives
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C303/00—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides
- C07C303/36—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides of amides of sulfonic acids
- C07C303/40—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides of amides of sulfonic acids by reactions not involving the formation of sulfonamide groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D279/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom and one sulfur atom as the only ring hetero atoms
- C07D279/02—1,2-Thiazines; Hydrogenated 1,2-thiazines
-
- 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
- C07D417/10—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 carbon chain containing aromatic rings
Definitions
- the present invention relates to improved syntheses of known and novel benzothiazine dioxide which are potent and selective endothelin antagonists.
- the processes of the instant invention are improved over those recited in U.S. Pat. No. 5,599,811 which is hereby incorporated by reference.
- the compounds of the instant invention exhibit very significant improvements over those described in U.S. Pat. No. 5,599,811. These improvements include: binding affinity to the ETA receptor, ETA selectivity, functional activity, long pharmacokinetic halflife, high bioavailability, in vivo activity in inhibiting the pressor effect caused by bET 1, oral activity with relatively long duration of action, and efficacy in acute hypoxic pulmonary hypertension in rats.
- the present invention also relates to antagonists of endothelin useful as pharmaceutical agents, to pharmaceutical compositions which include these compounds and a pharmaceutically acceptable carrier, and to pharmaceutical methods of treatment. More particularly, the compounds of the present invention are antagonists of endothelin useful in treating elevated levels of endothelin, acute and chronic renal failure, essential renovascular malignant and pulmonary hypertension, cerebral infarction and cerebral ischemia, cerebral vasospasm, cirrhosis, septic shock, congestive heart failure, endotoxic shock, subarachnoid hemorrhage, arrhythmias, asthma, preeclampsia, atherosclerotic disorders including Raynaud's disease and restenosis, angina, cancer, benign prostatic hyperplasia, ischemic disease, gastric mucosal damage, hemorrhagic shock, ischemic bowel disease, and diabetes.
- the compounds will be useful in cerebral ischemia or cerebral infarction resulting from a range of conditions such as thromboembolic or hemorrhagic stroke, cerebral vasospasm, head injury, hypoglycemia, cardiac arrest, status epilepticus, perinatal asphyxia, anoxia such as from drowning, pulmonary surgery, and cerebral trauma.
- R 1 is hydrogen, alkyl, or alkoxy
- R 2 is hydrogen or alkoxy
- R 3 is alkyl or alkoxy
- R 2 and R 3 may be joined to form a ring
- R 4 is hydrogen or alkyl
- R 5 is hydrogen, alkyl, alkoxy, halogen at the 2 or 3, or 4, or 5 positions or R 5 is a 3,4-methylenedioxo;
- R 6 is CF 3 , halogen, alkyl, benzyl, phenyl, hydroxy, or pyrrole comprising:
- the free acid of Formula 1 is obtained by sponification of the ester with, for example, LiOH in THF/MeOH or in dioxane. Any strongly alkaline solution in methanol can be used.
- Compounds of the invention are those prepared by the above process, especially those selected from:
- the invention is also a process for the preparation of a compound of
- the invention is also a process for the preparation of a compound of formula B
- step b) lithiating the product of step a) above at low temperatures and quenching with CO 2 to form a compound of formula G
- step b) treating the product of step b) above with acetic anhydride and a catalytic amount of methanesulfonic acid to produce a compound of formula H
- step d) treating the product of step c) above with NaOMe followed by methyl bromoacetate to produce a compound B as above.
- Compound B is carried over to Formula 1 as described before.
- Compounds of the invention are those prepared from the above process, especially 4-(7Ethylbenzo[-1,3]dioxol-5-yl) 1,1-dioxo-2-(2-trifluoromethyl phenyl)-1,2dihydro-1 ⁇ 6 -benzo-[e][1,2]-thiazine-3-carboxylic acid methyl ester.
- the invention is also a process for the preparation of a compound of Formula 1 which comprises
- Compounds of the invention are those prepared by the above process and especially those selected from:
- the invention is also a process for the preparation of a compound of Formula I comprising:
- step b) treating the product of step a) above with n-butyl lithium and then with 3methoxy4,5methylenedioxybenzaldehyde to produce a compound of formula M
- step b) treating the product of step b) above with sodium hydride followed by methyl bromoacetate to produce a compound of formula N
- step d) cyclizing the product of step d) above by treating with a base or a Lewis acid in an appropriate solvent to produce the corresponding ester of Formula 1
- Compounds of the invention are those prepared by the above process, especially 4-(7Methoxybenzo[1,3]dioxol-5-yl) 1,1 dioxo-2-otolyl 1,2dihydro 1 ⁇ 6 -benzo[e][1,2]thiazine-3carboxylic acid methyl ester.
- the invention is also a pharmaceutical composition of the compounds of Formula 1 above comprising a therapeutically effective amount of a compound of Formula 1 in admixture with a pharmaceutically acceptable carrier.
- the compounds of the invention are useful in inhibiting elevated levels of endothelin comprising administering to a host in need thereof a therapeutically effective amount of a compound of Formula I in unit dosage form. They are also useful in treating subarachnoid hemorrhage, essential, renovascular, malignant and pulmonary hypertension, congestive heart failure, cerebral ischemia, or cerebral infarction.
- alkyl means a straight or branched hydrocarbon radical having from 1 to 12 carbon atoms unless otherwise specified and includes, for example, methyl, ethyl, npropyl, isopropyl, n-butyl, secbutyl, isobutyl, tertbutyl, allyl, npentyl, nhexyl, nheptyl, noctyl, nnonyl, ndecyl, undecyl, and dodecyl.
- Halogen is fluorine, chlorine, bromine or iodine.
- alkoxy is an alkyl group as described above attached by oxygen to the rest of the molecule.
- Preferred alkoxy group are from 1 to 4 carbon atoms.
- the host receiving a compound of the invention is a mammal, particularly a human.
- Scheme 1 illustrates the general procedure for the preparation of the compounds of Formula 1.
- Synthesis of the intermediate A was described in U.S. Pat. No. 5,599,811. Reaction of methyl-2-(chlorosulfonyl)benzoate with an aniline in methylene chloride with 1 to 2 equivalents of pyridine and a catalytic amount of DMAP at room temperature overnight affords the sulfonamide A. The reaction can also be run using neat pyridine as the solvent. Alkylation of A was achieved by treatment of A with sodium hydride in DMF followed by reaction with methyl bromoacetate to give intermediate B. B can be converted to the key intermediate C via Claisen cyclization which were found to be promoted by at least two different catalysts.
- condition I the intermediate B in methylene chloride was added to a solution of 2 equivalents of TiCl 4 in methylene chloride at 78° C. followed by the treatment with 2.2 equivalents of triethyl amine. The reaction was quenched with IN HCl followed by aqueous work up and recrystallization.
- condition II is similar to condition I with the use of 1.2 equivalents of TiCl 2 -(OTf) 2 -( Bull. Chem. Soc. Jpn, 1989;62:1917) followed by quench with pH 7 phosphate buffer and extractive workup.
- the cyclized enol C was treated with triflic anhydride in solvents such as methylene chloride in the presence of 2 to 5 equivalents of pyridine for 1 to 5 hours to afford the triflate D quantitatively.
- the coupling reaction was carried out between the triflate D and the corresponding boronic acid in DMF and toluene (ratio of 1:4) in the presence of 10 mole % tetrakis(triphenyl phosphine)palladium as the catalyst and 1 to 2 equivalents of potassium carbonate under reflux for 2 hours.
- the reaction mixture was filtered, and the product was purified by column chromatography or by recrystallization.
- the free acid of the Formula 1 was obtained by sponification of the ester with aqueous LiOH in THF/MeOH or in dioxane.
- the free acid can be converted, for example, to a sodium or potassium salts, which are much more soluble in H 2 O, by treating it with one equivalent of NaOH or KOH in MeOH followed by recrystallization.
- Scheme la indicates an alternative assembly reaction for the formation of the 4aryl benzothiazine derivatives exemplified by intermediate E.
- the coupling reaction was conducted by reacting an aryl zinc bromide, prepared by treating an aryl bromide with one equivalent of n-butyl lithium in THF followed by zinc bromide, with the intermediate D in the presence of 10% tetrakis(triphenylphosphine)palladium as the catalyst under reflux for 2 hours.
- the Scheme 1 was further modified to replace a relatively expensive starting material, methyl-2-(chlorosulfonyl)benzoate, with phenyl sulfonyl chloride.
- the process (Scheme 1 b) is proven to be more economical and workable in large scale.
- the sulfonamide F was formed by reacting the phenyl sulfonyl chloride with one equivalent of aniline under similar condition as described for A or using an equal amount of saturated sodium bicarbonate solution in THF. It was lithiated with nBuLi at low temperature and quenched with C0 2 to form the intermediate G in 92% yield.
- the acid G was then treated with acetic anhydride with a catalytic amount of methanesulfonic acid to form the intermediate H.
- This cyclic compound was treated with NaOMe followed by quenching with methyl bromoacetate to form B directly in 71% yield.
- Scheme 3 illustrates an alternative synthesis that has been successfully utilized in the synthesis of certain analogs. This is illustrated by the synthesis of Example 8.
- Intermediate F was treated with 2 equivalents of n-butyl lithium at ⁇ 78° C. to generate the dianion.
- a solution of 3-methoxy-4,5methylenedioxybenzaldehyde in tetrahydrofaran was added to the reaction mixture. It was then warmed to 0° C. over 1.5 hours.
- Aqueous work up afforded M which was treated with sodium hydride followed by methyl bromoacetate to give N. Jones oxidation of N was carried out in acetone to afford the keto ester O in 60% yield.
- the cyclization of O can be promoted by a base or a Lewis acid such as titanium bischlorobistriflate in an appropriate solvent such as methylene chloride.
- the ester E was purified by column chromatography to provide pure sample in 53% yield.
- the esters synthesized through this route were sponified according to procedures described in Scheme 1.
- Pharmaceutically acceptable base addition salts are formed with metals or amines, such as alkali and alkaline earth metals or organic amines.
- metals used as cations are sodium, potassium, magnesium, calcium, and the like.
- suitable amines are N,N′-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, dicyclohexylamine, ethylenediamine, Nmethylglucamine, and procaine (see, for example, Berge SM, et al., “Pharmaceutical Salts,” Journal of Pharmaceutical Science, 1977;66:1-19).
- the base addition salts of said acidic compounds are prepared by contacting the free acid form with a sufficient amount of the desired base to produce the salt in the conventional manner.
- Certain of the compounds of the present invention can exist in unsolvated forms as well as solvated forms, including hydrated forms.
- the solvated forms, including hydrated forms are equivalent to unsolvated forms and are intended to be encompassed within the scope of the present invention.
- Certain of the compounds of the present invention possess one or more chiral centers and each center may exist in the R or S configuration.
- the present invention includes all enantiomeric and epimeric forms as well as the appropriate diastereomeric mixtures thereof.
- the compounds of Formula 1 are valuable antagonists of endothelin.
- the tests employed indicate that compounds of the invention possess endothelin antagonist activity.
- the compounds were tested for their ability to inhibit [ 125 I]ET-1([ 125 I]Endothelin-1) binding in a receptor assay.
- Selected compounds were also tested for antagonist activity by inhibition of ET-1 stimulated arachidonic acid release and ET1 stimulated vasoconstriction. The following testing procedures were used (Doherty AM, et al., “Design of C-Terminal Peptide Antagonists of Endothelin: StructureActivity Relationships of ET-1 [16-21, D-His 16 ]”, Bioorganic and Medicinal Chemistry Letters, 1993;3:497-502).
- Membranes were prepared from cultured cells by lysing cells in cold lysis buffer (5 mM HEPES, 2 mM EDTA, pH 7.4) and homogenizing with a Dounce “A” homogenizer. The homogenate was centrifuged at 30,000 ⁇ g for 20 minutes at 40° C. Membrane pellets were suspended in cold buffer containing 20 mM Tris, 2 mM EDTA, 200 ⁇ M Pefabloc, 10 ⁇ M phosphoramidon, 10 ⁇ M leupeptin, 1 ⁇ M pepstatin at pH 7.4 and frozen at 80° C. until use.
- Membranes were thawed and homogenized with a Brinkmann Polytron then diluted in tissue buffer containing 20 mM Tris, 2 mM EDTA, 200 ⁇ M Pefabloc, and 100 ⁇ M bacitracin (pH 7.4). Radioligand and competing ligands were prepared in binding buffer containing 20 mM Tris, 2 mM EDTA, and 0.1% BSA.
- Competing binding assays were initiated by combining membranes, [1251]ET-1 -(40 ⁇ M) and the competing ligand in a final volume of 250 ⁇ L and incubating for 2 hours at 37° C. The assay was terminated by filtration over Whatman GF/B filters which were presoaked with 50 mM Tris, pH 7.4 containing 0.2% BSA and 100 ⁇ M bacitracin. Nonspecific binding was defined as binding in the presence of 100 nM ET-1.
- Antagonist activity is measured by the ability of added compounds to reduce endothelinstimulated arachidonic acid release in cultured vascular smooth muscle cells.
- LM Alkaline
- FCS 0.5% FCS ⁇ 0.25 mCi/mL
- 3 H]arachidonic acid (Amersham). Confluent monolayers of cultured rabbit renal artery vascular smooth muscle cells were incubated in 0.5 mL of the LM over 18 hours, at 37° C., in 5% CO 2 .
- the LM was aspirated and the cells were washed once with the assay buffer (Hank's BSS +10 mM HEPES +fatty acidfree BSA (1 mg/mL)), and incubated for 5 minutes with 1 mL of the prewarmed assay buffer. This solution was aspirated, followed by an additional 1 mL of prewarmed assay buffer, and further incubated for another 5 minutes. A final 5minute incubation was carried out in a similar manner. The same procedure was repeated with the inclusion of 10 ⁇ L of the test compound (1 nM to 1 ⁇ M) and 10 ⁇ L ET-1 -(0.3 nM) and the incubation was extended for 30 minutes. This solution was then collected, 10 mL of scintillation cocktail was added, and the amount of [ 3 H]arachidonic acid was determined in a liquid scintillation counter.
- Denuded rings were mounted in 20 mL organ baths containing Krebsbicarbonate buffer (composition in mM: NaCl, 118.2; NaHCO 3 , 24.8; KCl, 4.6; MgSO 4 7H 2 O, 1.2; KH 2 PO 4 , 1.2; CaCl 2 2H 2 O; CaNa 2 EDTA, 0.026;, dextrose, 10.0), that was maintained at 37° C. and gassed continuously with 5% CO 2 in oxygen (pH 7.4). Resting tension was adjusted to 3.0 g for femoral and 4.0 g pulmonary arteries; the rings were left for 90 minutes to equilibrate.
- Krebsbicarbonate buffer composition in mM: NaCl, 118.2; NaHCO 3 , 24.8; KCl, 4.6; MgSO 4 7H 2 O, 1.2; KH 2 PO 4 , 1.2; CaCl 2 2H 2 O; CaNa 2 EDTA, 0.026;
- Vascular rings were tested for lack of functional endothelium (ie, lack of an endotheliumdependent relaxation response to carbachol (1.0 nM) in norepinephrine (0.03 nM) contracted rings.
- the ET antagonists were added 30 minutes prior to adding the agonist.
- ETA blockade with oral Example 10 was demonstrated through inhibition of bETI pressor response in the rat (10 mg/kg produced 44% inhibition at 8 hours postdose and 30 mg/kg produced a 48% inhibition at 24 hours postdose) and dog (15 mg/kg produced 25% inhibition at 24 hours postdose).
- Example 10 was well absorbed orally both in rat and dog. Terminal elimination tl/ 2 's were determined to be 8.5 and 2.2 hours in rat and dog, respectively, and bioavailability is 77% and 100% in rat and dog.
- the compounds of the present invention can be prepared and administered in a wide variety of oral and parenteral dosage forms.
- the compounds of the present invention can be administered by injection, that is, intravenously, intramuscularly, intracutaneously, subcutaneously, intraduodenally, or intraperitoneally.
- the compounds of the present invention can be administered by inhalation, for example, intranasally.
- the compounds of the present invention can be administered transdermally. It will be obvious to those skilled in the art that the following dosage forms may comprise as the active component, either a compound of Formula 1 or a corresponding pharmaceutically acceptable salt of a compound of Formula 1.
- pharmaceutically acceptable carriers can be either solid or liquid.
- Solid form preparations include powders, tablets, pills, capsules, cachets, suppositories, and dispersible granules.
- a solid carrier can be one or more substances which may also act as diluents, flavoring agents, binders, preservatives, tablet disintegrating agents, or an encapsulating material.
- the carrier is a finely divided solid which is in a mixture with the finely divided active component.
- the active component is mixed with the carrier having the necessary binding properties in suitable proportions and compacted in the shape and size desired.
- the powders and tablets preferably contain from five or ten to about seventy percent of the active compound.
- Suitable carriers are magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose, a low melting wax, cocoa butter, and the like.
- the term “preparation” is intended to include the formulation of the active compound with encapsulating material as a carrier providing a capsule in which the active component with or without other carriers, is surrounded by a carrier, which is thus in association with it.
- cachets and lozenges are included. Tablets, powders, capsules, pills, cachets, and lozenges can be used as solid dosage forms suitable for oral administration.
- a low melting wax such as a mixture of fatty acid glycerides or cocoa butter
- the active component is dispersed homogeneously therein, as by stirring.
- the molten homogeneous mixture is then poured into convenient sized molds, allowed to cool, and thereby to solidify.
- Liquid form preparations include solutions, suspensions, and emulsions, for example, water or water propylene glycol solutions.
- liquid preparations can be formulated in solution in aqueous polyethylene glycol solution.
- Aqueous solutions suitable for oral use can be prepared by dissolving the active component in water and adding suitable colorants, flavors, stabilizing and thickening agents as desired.
- Aqueous suspensions suitable for oral use can be made by dispersing the finely divided active component in water with viscous material, such as natural or synthetic gums, resins, methylcellulose, sodium carboxymethylcellulose, and other wellknown suspending agents.
- viscous material such as natural or synthetic gums, resins, methylcellulose, sodium carboxymethylcellulose, and other wellknown suspending agents.
- solid form preparations which are intended to be converted, shortly before use, to liquid form preparations for oral administration.
- liquid forms include solutions, suspensions, and emulsions.
- These preparations may contain, in addition to the active component, colorants, flavors, stabilizers, buffers, artificial and natural sweeteners, dispersants, thickeners, solubilizing agents, and the like.
- the pharmaceutical preparation is preferably in unit dosage form.
- the preparation is subdivided into unit doses containing appropriate quantities of the active component.
- the unit dosage form can be a packaged preparation, the package containing discrete quantities of preparation, such as packeted tablets, capsules, and powders in vials or ampoules.
- the unit dosage form can be a capsule, table, cachet, or lozenge itself, or it can be the appropriate number of any of these in packaged form.
- the quantity of active component in a unit dose preparation may be varied or adjusted from 0.1 mg to 100 mg preferably 0.5 mg to 100 mg according to the particular application and the potency of the active component.
- the composition can, if desired, also contain other compatible therapeutic agents.
- the compounds utilized in the pharmaceutical method of this invention are administered at the initial dosage of about 0.01 mg to about 100 mg/kg daily.
- a daily dose range of about 0.01 mg to about 10 mg/kg is preferred.
- the dosages may be varied depending upon the requirements of the patient, the severity of the condition being treated, and the compound being employed. Determination of the proper dosage for a particular situation is within the skill of the art. Generally, treatment is initiated with smaller dosages which are less than the optimum dose of the compound. Thereafter, the dosage is increased by small increments until the optimum effect under the circumstances is reached. For convenience, the total daily dosage may be divided and administered in portions during the day, if desired.
- the ether layer was separated, washed 2 ⁇ 500 mL with 1N HCl, 1 ⁇ 1 L with brine, 1 ⁇ 1 L with saturated sodium bicarbonate, and once more with 1 L of brine. It was then dried over magnesium sulfate, filtered with suction, and concentrated on the rotary evaporator without heat. The product formed fine crystals as the ether evaporated, and when most of the ether was gone, the crystals were slurried with hexane (2 L), collected with suction and dried. Yield 571 g, 84%.
- the aqueous layer was acidified to pH 1 with concentrated HCl and extracted into ethyl ether, washed with brine, dried over anhydrous magnesium sulfate, filtered, and evaporated to a foam.
- the residue was chromatographed on 50 g silica gel eluted with chloroform, and the appropriate fractions were concentrated in vacuo and evaporated from ethyl ether giving a solid foam, 1.4 g, 66% yield. NMR spectra and elemental analysis were consistent with the structure.
- Example 4E was prepared in the same way as illustrated in Example 1E in
- the aqueous layer was acidified to pH 1 with concentrated HCl and extracted into ethyl ether, washed with brine, dried over anhydrous magnesium sulfate, filtered, and evaporated to a solid, 0.70 g.
- the material was chromatographed on 15 g silica gel eluted with chloroform. The appropriate fractions were combined and evaporated in vacuo from ethyl ether giving a solid, 0.272 g.
- NMR spectra was consistent with the structure. Elemental analysis was consistent for the structure as a hydrate, holding an additional 0.25 moles of water.
- the aqueous layer was acidified to pH 1 with 6N HCl and extracted into ethyl ether, washed with brine, dried over anhydrous magnesium sulfate, filtered, and evaporated to a yellow solid.
- methanol 4 mL was added the solid (0.652 g, followed by 0.985N NaOH (1.22 mL). The mixture was evaporated to a glassy solid, redissolved in 30 mL water, and filtered at 45 microns. The filtrate was lyophilized to a white solid, 0.65 g.
- NMR spectra was consistent with the structure. Elemental analysis was consistent for the structure as a hydrate, holding an additional 1.25 mol of water.
- reaction mixture was brought to a pH of 5.0 by addition of acetic acid.
- acetic acid was added to the tetrahydrofuran
- the tetrahydrofuran was removed under vacuum, then the aqueous mixture was extracted twice with 300 mL portions of methyl t-butyl ether.
- the ether solution was dried over magnesium sulfate, filtered, and concentrated to a dark oil (54.8 g). This material was not further purified, but used directly in the next reaction.
- a 2 L, 3 neck round bottom flask was equipped with an overhead stirrer, heating mantle, condenser, and nitrogen inlet.
- the flask was flushed with nitrogen and charged with acetonitrile (700 mL), followed by 5bromo-2,3dihydroxyethylbenzene (54.5 g, assumed to be 0.25 mol), then anhydrous cesium carbonate (121 g, 0.37 mol) and bromochloromethane (57 g, 0.44 mol).
- the mixture was stirred and heated to reflux (74° C.). At that point, sodium iodide (5 g, 0.03 mol) was added, and the mixture was boiled for 90 minutes. The mixture was then cooled and filtered with suction.
- the filter cake was rinsed with acetonitrile, then the solvent was removed under vacuum.
- the residue was treated with water (700 mL), and the mixture was extracted twice with 400 mL portions of hexane.
- the hexane was removed under vacuum, then the residue (36 g) was distilled under high vacuum.
- the distillate, collected at a head temperature of 84° C. (0.8 mm Hg) weighed 24 g (0.10 mol, 41% for the two steps).
- the product thus obtained has NMR characteristics consistent with the title compound and is greater than 95% pure by gas chromatography.
- the aqueous layer was acidified to pH 1 with 6N HCl and extracted into ethyl ether, washed with brine, dried over anhydrous magnesium sulfate, filtered, and evaporated to a yellow foam, 0.51 g.
- To methanol (4 mL) was added the solid (0.465 g), followed by 0.985N NaOH (0.91 mL). The mixture was evaporated to a glassy solid, redissolved in 30 mL water, and filtered at 45 ⁇ . The filtrate was lyophilized to a white solid, 0.448 g, 70% yield.
- NMR spectra was consistent with the structure. Elemental analysis was consistent for the structure as a hydrate, holding an additional 1.5 moles of water.
- the triflate was prepared according to procedures described in Example 1D. Then, a solution of 1.14 g (4.39 mmol) of the crude triflate in toluene/DMF (10 mL/3 mL) was treated with 0.55 g (3.29 mmol, 1.5 eq) of boronic acid, 0.45 g (3.29 mmol, 1.5 eq) of K2CO 3, and 0.25 g (0.2 mmol, 0.1 eq) of Pd(PPh 3 ) 4 , and the reaction mixture heated to reflux for 2 hours.
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Abstract
The instant invention is a series of benzothiazine dioxides, or a pharmaceutically acceptable salt thereof, which are potent endothelin A antagonists with profound in vitro activity, and improved syntheses for the Formula 1
The compounds are useful in treating elevated levels of endothelin, essential renovascular malignant and pulmonary hypertension, cerebral infarction, cerebral ischemia, congestive heart failure, and subarachnoid hemorrhage.
Description
- The present invention relates to improved syntheses of known and novel benzothiazine dioxide which are potent and selective endothelin antagonists. The processes of the instant invention are improved over those recited in U.S. Pat. No. 5,599,811 which is hereby incorporated by reference.
- The compounds of the instant invention exhibit very significant improvements over those described in U.S. Pat. No. 5,599,811. These improvements include: binding affinity to the ETA receptor, ETA selectivity, functional activity, long pharmacokinetic halflife, high bioavailability, in vivo activity in inhibiting the pressor effect caused by bET 1, oral activity with relatively long duration of action, and efficacy in acute hypoxic pulmonary hypertension in rats.
- The processes of the instant invention provide more facile syntheses with higher yields. They are short, clean, reproducible and no tedious chromatography is needed. Moreover, the processes are scaleable and therefore useful for large scale development.
- The present invention also relates to antagonists of endothelin useful as pharmaceutical agents, to pharmaceutical compositions which include these compounds and a pharmaceutically acceptable carrier, and to pharmaceutical methods of treatment. More particularly, the compounds of the present invention are antagonists of endothelin useful in treating elevated levels of endothelin, acute and chronic renal failure, essential renovascular malignant and pulmonary hypertension, cerebral infarction and cerebral ischemia, cerebral vasospasm, cirrhosis, septic shock, congestive heart failure, endotoxic shock, subarachnoid hemorrhage, arrhythmias, asthma, preeclampsia, atherosclerotic disorders including Raynaud's disease and restenosis, angina, cancer, benign prostatic hyperplasia, ischemic disease, gastric mucosal damage, hemorrhagic shock, ischemic bowel disease, and diabetes.
- Also, the compounds will be useful in cerebral ischemia or cerebral infarction resulting from a range of conditions such as thromboembolic or hemorrhagic stroke, cerebral vasospasm, head injury, hypoglycemia, cardiac arrest, status epilepticus, perinatal asphyxia, anoxia such as from drowning, pulmonary surgery, and cerebral trauma.
-
- or a pharmaceutically acceptable salt thereof wherein
- R1 is hydrogen, alkyl, or alkoxy;
- R2 is hydrogen or alkoxy;
- R3 is alkyl or alkoxy;
-
- ;
- R4 is hydrogen or alkyl;
- R5 is hydrogen, alkyl, alkoxy, halogen at the 2 or 3, or 4, or 5 positions or R5 is a 3,4-methylenedioxo; and
- R6 is CF3, halogen, alkyl, benzyl, phenyl, hydroxy, or pyrrole comprising:
-
-
-
-
-
- in DMF and toluene in the presence of a palladium catalyst and potassium carbonate at about 100° C. to produce a compound of Formula 1.
- The free acid of Formula 1 is obtained by sponification of the ester with, for example, LiOH in THF/MeOH or in dioxane. Any strongly alkaline solution in methanol can be used.
- Compounds of the invention are those prepared by the above process, especially those selected from:
- 4-(3,5-Dimethoxy-phenyl)-2-(2trifluoromethyl-phenyl) 1,1 dioxo-1,2dihydro-1λ6benzo[e][1,2]thiazine-3-carboxylic acid;
- 2-(2-Chloro-phenyl)-4-(3,5-dimethoxy-phenyl) 1,1-dioxo 1,2-dihydro-1λ6benzo[e][1,2]thiazine-3-carboxylic acid;
- 2-(2-Bromo-phenyl)-4-(3,5-dimethoxy-phenyl)- 1,1-dioxo 1,2dihydro-1λ6benzo[e][1,2]thiazine-3-carboxylic acid;
- 2-(2-Chloro-phenyl)-4-(7-methoxy-benzo[1,3]dioxol5-yl)-1,1-dioxo-1,2-dihydro 1λ6 -benzo [e][1,2]thiazine-3-carboxylic acid;
- 2-(2-Benzyl-phenyl)-4-(7-methoxy-benzo[1,3]dioxol-5-yl)-1,1dioxo-1,2-dihydro 1λ6-benzo[e][1,2]thiazine-3-carboxylic acid;
- 2-(2,6-Dimethyl-phenyl)-4-(7-methoxy-benzo[1,3]dioxol5-yl) 1,1 dioxo-1,2-dihydro 1λ6-benzo[e][1,2]thiazine-3carboxylic acid monosodium salt;
- 4-(7-Methoxy-benzo[1,3]-dioxol-5-yl)-1,1-dioxo-2-(2-trifluoromethyl phenyl)-1,2dihydro-1λ6-benzo[e][1,2]thiazine-3carboxylic acid;
- 4-Benzo-[1,3]dioxol-5-yl1,1 dioxo2-(2trifluoromethyl-phenyl) 1,2dihydro-1λ6-benzo[e] [1,2]thiazine-3carboxylic acid;
- 4-Benzo-[1,3]dioxol-5-yl-2-(2ethylphenyl) 1,1 dioxo 1,2dihydro 1 6 benzo[e][1,2]thiazine-3carboxylic acid;
- 4-Benzo-[1,3]dioxol-5-yl-2-(2propylphenyl) 1,1 dioxo 1,2dihydro 1 6 benzo[e][1,2]thiazine-3carboxylic acid;
- 4-Benzo[1,3]dioxol-5-yl-2-(2isopropylphenyl) 1,1 dioxo 1,2dihydro 1λ6-benzo[e][1,2]thiazine-3carboxylic acid;
- 4-Benzo[1,3]dioxol-5-yl-2-(2butylphenyl) 1,1 dioxo 1,2dihydro 1 6 benzo[e][1,2]thiazine-3carboxylic acid;
- 4-Benzo[1,3]dioxol-5-yl-2-(2fluorophenyl) 1,1 dioxo 1,2dihydro 1λ6 benzo [e][1,2]thiazine-3carboxylic acid;
- 4-Benzo[1,3]dioxol-5-yl-2-(2-hydroxyphenyl) 1,1dioxo1,2dihydro 1λ6-benzo[e][1,2]thiazine-3carboxylic acid;
- 4-Benzo[1,3]dioxol-5-yl-2-(2,3-dichlorophenyl) 1,1 dioxo1,2dihydro ,16-benzo[e][1,2]thiazine-3 carboxylic acid;
- 4-Benzo[1,3]dioxol-5-yl-2-(2,4dichlorophenyl) 1,1 dioxo 1,2dihydro 1)X6-benzo[e][1,2]thiazine-3carboxylic acid;
- 4-Benzo[1,3]dioxol-5-yl-2-(2chloro4methoxyphenyl) 1,1 dioxo 1,2dihydro 16-benzo[e][1,2]thiazine-3carboxylic acid;
- 4-Benzo[1,3]dioxol-5-yl-2-(3chloro2methyl-phenyl)1,1 dioxo 1,2dihydro 1 λ6-benzo [e][1,2]thiazine-3 carboxylic acid;
- 4-Benzo[1,3]dioxol-5-yl-2-(2,6dimethyl-phenyl) 1,1 dioxo 1,2dihydro 16-benzo[e][1,2]thiazine-3carboxylic acid;
- 4-Benzo[1,3]dioxol-5-yl 1,1 dioxo2-(2pyrrol 1 -ylphenyl)1,2dihydro 16-benzo[e][1,2]thiazine-3 carboxylic acid;
- 4-Benzo [1,3]dioxol-5-yl-2-(3 ,4dimethylisoxazol5-yl) 1,1 dioxo 1,2dihydro1λ6-benzo[e][1,2]thiazine-3carboxylic acid;
- 4-(6Methoxybenzo [1,3]dioxol-5-yl) 1,1 dioxo2-(2trifluoromethyl phenyl) 1,2dihydro 1λ6-benzo[e][1,2]thiazine-3carboxylic acid; and
- 4-(3,5-Dimethyl-phenyl)-2-(2-trifluoromethyl-phenyl)-1,1-dioxo-1,2-dihydro-1λ6-benzo[e][1,2]thiazine-3-carboxylic acid.
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- comprising:
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- The free acid of Formula 1 is obtained by sponification of the ester.
- The following three compounds are obtained by the above process:
- 2-(2Bromophenyl)4-(7methoxy-benzo[1,3]dioxol-5-yl) 1,1 dioxo 1,2dihydro 1λ6-benzo[e][1,2]thiazine-3carboxylic acid monosodium salt;
- 4-(7Ethylbenzo[1,3]dioxol-5-yl) 1,1-dioxo-2-(2trifluoromethyl-phenyl) 1,2dihydro1λ6-benzo[e][1,2]thiazine-3carboxylic acid, potassium salt; and
- 4-Benzo[1,3]dioxol-5-yl-2-(2benzylphenyl)1,1dioxo1,2dihydro I?6-benzo[e][1,2]thiazine-3carboxylic acid.
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- comprising:
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- d) treating the product of step c) above with NaOMe followed by methyl bromoacetate to produce a compound B as above. Compound B is carried over to Formula 1 as described before.
- Compounds of the invention are those prepared from the above process, especially 4-(7Ethylbenzo[-1,3]dioxol-5-yl) 1,1-dioxo-2-(2-trifluoromethyl phenyl)-1,2dihydro-1λ6-benzo-[e][1,2]-thiazine-3-carboxylic acid methyl ester.
- The sodium and potassium salts of the above compound are preferred.
- The invention is also a process for the preparation of a compound of Formula 1 which comprises
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- b) treating the product of Step a) above with potassium hexamethyldisilylazide followed by tbutyl acetate in THF to produce
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- d) cyclizing the product of Step c) above using potassium carbonate in
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- The enol is then used to produce a compound of Formula I above.
- Compounds of the invention are those prepared by the above process and especially those selected from:
- 2-(6Methylbenzo[1,3]dioxol-5-yl)4hydroxy 1,1 dioxo 1,2dihydro 1λ6-benzo[e][1,2]thiazine-3carboxylic acid tertbutyl ester;
- 2-(2Bromophenyl)4hydroxy 1,1 dioxo 1,2dihydro 1 ,6 benzo[e][l1,2]thiazine-3carboxylic acid tertbutyl ester;
- 2-(2Chlorophenyl)4hydroxy 1,1 dioxo 1,2dihydro 1 6 benzo[e]l [1,2]thiazine-3 carboxylic acid tertbutyl ester; and
- 2-(6Chlorobenzo [1, 3 ]dioxol 5 -yl)4hydroxy 1,1 dioxo 1,2dihydro 1λ6-benzo[e][1,2]thiazine-3carboxylic acid tertbutyl ester.
- The invention is also a process for the preparation of a compound of Formula I comprising:
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- Compounds of the invention are those prepared by the above process, especially 4-(7Methoxybenzo[1,3]dioxol-5-yl) 1,1 dioxo-2-otolyl 1,2dihydro 1λ6-benzo[e][1,2]thiazine-3carboxylic acid methyl ester.
- The invention is also a pharmaceutical composition of the compounds of Formula 1 above comprising a therapeutically effective amount of a compound of Formula 1 in admixture with a pharmaceutically acceptable carrier.
- The compounds of the invention are useful in inhibiting elevated levels of endothelin comprising administering to a host in need thereof a therapeutically effective amount of a compound of Formula I in unit dosage form. They are also useful in treating subarachnoid hemorrhage, essential, renovascular, malignant and pulmonary hypertension, congestive heart failure, cerebral ischemia, or cerebral infarction.
- In the compounds of Formula I, the term “alkyl” means a straight or branched hydrocarbon radical having from 1 to 12 carbon atoms unless otherwise specified and includes, for example, methyl, ethyl, npropyl, isopropyl, n-butyl, secbutyl, isobutyl, tertbutyl, allyl, npentyl, nhexyl, nheptyl, noctyl, nnonyl, ndecyl, undecyl, and dodecyl.
- “Halogen” is fluorine, chlorine, bromine or iodine.
- The term “alkoxy” is an alkyl group as described above attached by oxygen to the rest of the molecule. Preferred alkoxy group are from 1 to 4 carbon atoms.
- The host receiving a compound of the invention is a mammal, particularly a human.
- The compounds of Formula I above may be prepared by several methods. These methods are illustrated in Schemes 1 through 3 and in a detailed manner by way of illustration in the example section of the specification.
- Scheme 1 illustrates the general procedure for the preparation of the compounds of Formula 1. Synthesis of the intermediate A was described in U.S. Pat. No. 5,599,811. Reaction of methyl-2-(chlorosulfonyl)benzoate with an aniline in methylene chloride with 1 to 2 equivalents of pyridine and a catalytic amount of DMAP at room temperature overnight affords the sulfonamide A. The reaction can also be run using neat pyridine as the solvent. Alkylation of A was achieved by treatment of A with sodium hydride in DMF followed by reaction with methyl bromoacetate to give intermediate B. B can be converted to the key intermediate C via Claisen cyclization which were found to be promoted by at least two different catalysts. In condition I, the intermediate B in methylene chloride was added to a solution of 2 equivalents of TiCl4 in methylene chloride at 78° C. followed by the treatment with 2.2 equivalents of triethyl amine. The reaction was quenched with IN HCl followed by aqueous work up and recrystallization. The condition II is similar to condition I with the use of 1.2 equivalents of TiCl2-(OTf)2 -(Bull. Chem. Soc. Jpn, 1989;62:1917) followed by quench with pH 7 phosphate buffer and extractive workup. The cyclized enol C was treated with triflic anhydride in solvents such as methylene chloride in the presence of 2 to 5 equivalents of pyridine for 1 to 5 hours to afford the triflate D quantitatively. The coupling reaction was carried out between the triflate D and the corresponding boronic acid in DMF and toluene (ratio of 1:4) in the presence of 10 mole % tetrakis(triphenyl phosphine)palladium as the catalyst and 1 to 2 equivalents of potassium carbonate under reflux for 2 hours. The reaction mixture was filtered, and the product was purified by column chromatography or by recrystallization. The free acid of the Formula 1 was obtained by sponification of the ester with aqueous LiOH in THF/MeOH or in dioxane. The free acid can be converted, for example, to a sodium or potassium salts, which are much more soluble in H2O, by treating it with one equivalent of NaOH or KOH in MeOH followed by recrystallization.
- Scheme la indicates an alternative assembly reaction for the formation of the 4aryl benzothiazine derivatives exemplified by intermediate E. The coupling reaction was conducted by reacting an aryl zinc bromide, prepared by treating an aryl bromide with one equivalent of n-butyl lithium in THF followed by zinc bromide, with the intermediate D in the presence of 10% tetrakis(triphenylphosphine)palladium as the catalyst under reflux for 2 hours.
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- Several compounds in the Examples were synthesized through a synthesis outlined in Scheme 2. Compound A, obtained as described in Scheme 1 was refluxed in xylene for 16 hours with 1 equivalent of pyridine and a catalytic amount of DMAP to afford the cyclic intermediate H. This compound was treated with potassium hexamethyldisilylazide followed by t-butyl acetate in THF at −78° C. to yield the keto ester I. Bromination of I was carried out with NBS in carbon tetrachloride to obtain J which is in turn cyclized via treatment with potassium carbonate in DMF. The enol K was converted to the ester L with similar procedures illustrated in Scheme 1. Finally, the t-butyl ester was removed by treatment with TFA in methylene chloride at room temperature to give the free acid.
- Scheme 3 illustrates an alternative synthesis that has been successfully utilized in the synthesis of certain analogs. This is illustrated by the synthesis of Example 8. Intermediate F was treated with 2 equivalents of n-butyl lithium at −78° C. to generate the dianion. Then a solution of 3-methoxy-4,5methylenedioxybenzaldehyde in tetrahydrofaran was added to the reaction mixture. It was then warmed to 0° C. over 1.5 hours. Aqueous work up afforded M which was treated with sodium hydride followed by methyl bromoacetate to give N. Jones oxidation of N was carried out in acetone to afford the keto ester O in 60% yield. The cyclization of O can be promoted by a base or a Lewis acid such as titanium bischlorobistriflate in an appropriate solvent such as methylene chloride. The ester E was purified by column chromatography to provide pure sample in 53% yield. The esters synthesized through this route were sponified according to procedures described in Scheme 1.
- Some of the compounds of Formula 1 are capable of further forming both pharmaceutically acceptable base salts. All of these forms are within the scope of the present invention.
- Pharmaceutically acceptable base addition salts are formed with metals or amines, such as alkali and alkaline earth metals or organic amines. Examples of metals used as cations are sodium, potassium, magnesium, calcium, and the like. Examples of suitable amines are N,N′-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, dicyclohexylamine, ethylenediamine, Nmethylglucamine, and procaine (see, for example, Berge SM, et al., “Pharmaceutical Salts,”Journal of Pharmaceutical Science, 1977;66:1-19).
- The base addition salts of said acidic compounds are prepared by contacting the free acid form with a sufficient amount of the desired base to produce the salt in the conventional manner.
- Certain of the compounds of the present invention can exist in unsolvated forms as well as solvated forms, including hydrated forms. In general, the solvated forms, including hydrated forms, are equivalent to unsolvated forms and are intended to be encompassed within the scope of the present invention.
- Certain of the compounds of the present invention possess one or more chiral centers and each center may exist in the R or S configuration. The present invention includes all enantiomeric and epimeric forms as well as the appropriate diastereomeric mixtures thereof.
- The compounds of Formula 1 are valuable antagonists of endothelin. The tests employed indicate that compounds of the invention possess endothelin antagonist activity. Thus, the compounds were tested for their ability to inhibit [125I]ET-1([125I]Endothelin-1) binding in a receptor assay. Selected compounds were also tested for antagonist activity by inhibition of ET-1 stimulated arachidonic acid release and ET1 stimulated vasoconstriction. The following testing procedures were used (Doherty AM, et al., “Design of C-Terminal Peptide Antagonists of Endothelin: StructureActivity Relationships of ET-1 [16-21, D-His16]”, Bioorganic and Medicinal Chemistry Letters, 1993;3:497-502).
- The following cultured cells were used in binding experiments: Ltk-cells expressing recombinant human ETAR (HETA), and CHOKI cells expressing recombinant human ETBR (HETB).
- Membranes were prepared from cultured cells by lysing cells in cold lysis buffer (5 mM HEPES, 2 mM EDTA, pH 7.4) and homogenizing with a Dounce “A” homogenizer. The homogenate was centrifuged at 30,000×g for 20 minutes at 40° C. Membrane pellets were suspended in cold buffer containing 20 mM Tris, 2 mM EDTA, 200 μM Pefabloc, 10 μM phosphoramidon, 10 μM leupeptin, 1 μM pepstatin at pH 7.4 and frozen at 80° C. until use. Membranes were thawed and homogenized with a Brinkmann Polytron then diluted in tissue buffer containing 20 mM Tris, 2 mM EDTA, 200 μM Pefabloc, and 100 μM bacitracin (pH 7.4). Radioligand and competing ligands were prepared in binding buffer containing 20 mM Tris, 2 mM EDTA, and 0.1% BSA.
- Competing binding assays were initiated by combining membranes, [1251]ET-1 -(40 μM) and the competing ligand in a final volume of 250 μL and incubating for 2 hours at 37° C. The assay was terminated by filtration over Whatman GF/B filters which were presoaked with 50 mM Tris, pH 7.4 containing 0.2% BSA and 100 μM bacitracin. Nonspecific binding was defined as binding in the presence of 100 nM ET-1.
- In Vitro Inhibition of ET-1 Stimulated Arachidonic Acid Release (AAR) in Cultured Rabbit Vascular Smooth Muscle Cells (ETA) by the Compounds of the Invention
- Antagonist activity is measured by the ability of added compounds to reduce endothelinstimulated arachidonic acid release in cultured vascular smooth muscle cells. [3H]Arachidonic Acid Loading Media (LM) is DME/F12+0.5% FCS×0.25 mCi/mL [3H]arachidonic acid (Amersham). Confluent monolayers of cultured rabbit renal artery vascular smooth muscle cells were incubated in 0.5 mL of the LM over 18 hours, at 37° C., in 5% CO2. The LM was aspirated and the cells were washed once with the assay buffer (Hank's BSS +10 mM HEPES +fatty acidfree BSA (1 mg/mL)), and incubated for 5 minutes with 1 mL of the prewarmed assay buffer. This solution was aspirated, followed by an additional 1 mL of prewarmed assay buffer, and further incubated for another 5 minutes. A final 5minute incubation was carried out in a similar manner. The same procedure was repeated with the inclusion of 10 μL of the test compound (1 nM to 1 μM) and 10 μL ET-1 -(0.3 nM) and the incubation was extended for 30 minutes. This solution was then collected, 10 mL of scintillation cocktail was added, and the amount of [3H]arachidonic acid was determined in a liquid scintillation counter.
- In Vitro Antagonism of ET-1 Stimulated Vasoconstriction (VERAA) in the Rabbit Femoral Arterv (ETA) and Sarafotoxin 6C Stimulated Vasoconstriction in the Rabbit Pulmonarv Artery (ETB)
- Male New Zealand rabbits were killed by cervical dislocation and exsanguination. Femoral and pulmonary arteries were isolated, cleaned of connective tissue, and cut into 4mm rings. The endothelium was denuded by placing the rings over hypodermic tubing (32 gauge for femoral rings and 28 gauge for pulmonary rings, Small Parts, Inc., Miami, Fla.) and gently rolling them. Denuded rings were mounted in 20 mL organ baths containing Krebsbicarbonate buffer (composition in mM: NaCl, 118.2; NaHCO3, 24.8; KCl, 4.6; MgSO4 7H2O, 1.2; KH2PO4, 1.2; CaCl2 2H2O; CaNa2 EDTA, 0.026;, dextrose, 10.0), that was maintained at 37° C. and gassed continuously with 5% CO2 in oxygen (pH 7.4). Resting tension was adjusted to 3.0 g for femoral and 4.0 g pulmonary arteries; the rings were left for 90 minutes to equilibrate. Vascular rings were tested for lack of functional endothelium (ie, lack of an endotheliumdependent relaxation response to carbachol (1.0 nM) in norepinephrine (0.03 nM) contracted rings. Agonist peptides, ET-1 -(femoral), and S6c (pulmonary), were cumulatively added at 10-minute intervals. The ET antagonists were added 30 minutes prior to adding the agonist.
- Inhibition of bETI Induced Pressor Effect in Rat
- Male Sprague-Dawley (Charles River Laboratories, Kingston, Ontario, Canada) weighing 250 to 350 g are anesthetized (Inactin, 120 mg/kg, I.P.) and acutely instrumented with a carotid artery catheter to monitor arterial blood pressure and with a jugular vein catheters to administer intravenous drugs. Once instrumented, the rats are ganglionicblocked with mecamylamine (1.25 mg/kg, I.V.) to prevent hemodynamic reflexes and then challenged with big endothelin-1 (bET-1) (1.0 nmol/kg, I.V.). The peak arterial pressor response in rats pre-treated with selected compounds of invention compared to vehicletreated rats is used to determine activity expressed as % inhibition. For I.V. activity selected compounds of invention was dose 10 minutes before the bET-1 challenge, and for oral activity selected compounds of invention was administered via oral gavage 8 or 24 hours before the bET-1 challenge.
TABLE 1 Example/Structure Example R1 R2 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 -
TABLE 2 ET Receptor Binding and Functional Activities HETA HETB AARA VERAA Example (IC50, μM) (IC50, μM) (IC50, μM) (pA2) 1 0.003 >2.5 6.6 2 0.002 7.3 6.6 3 0.003 >2.5 6.8 4 0.003 5.6 5 0.004 2 6 0.004 >2.5 7.1 7 0.003 2.5 0.0045 7.0 8 0.008 3.9 6.5 9 0.002 >2.5 6.9 10 0.0006 2.2 7.7 11 0.011 11 6.6 12 0.061 >25 0.1 13 0.023 >2.5 14 0.035 >2.5 5.8 15 0.09 11 16 0.026 >2.5 17 0.03 >25 0.031 60 18 0.036 >25 0.032 5.8 19 0.11 >25 20 0.06 >2.5 21 0.03 13 22 0.05 13 23 0.021 6.2 24 0.03 17 25 0.11 >25 0.05 6.0 26 0.017 >25 27 0.04 19 28 0.09 >25 29 0.04 >2.5 30 0.095 >2.5 31 0.006 >2.5 5.7 - For example, Example 10 is a potent inhibitor (IC50=0.6 nM) of ET-1 binding to human ETA receptors. It also has potent functional antagonist activity in human pulmonary artery smooth muscle cells blocking ET-1 induced Ca++ transients via the ETA receptor (IC50=0.2 nM). It exhibits antagonism to ET-1 stimulated vasoconstriction in rabbit femoral artery with pA2 value of 7.7. In vivo, ETA blockade with oral Example 10 was demonstrated through inhibition of bETI pressor response in the rat (10 mg/kg produced 44% inhibition at 8 hours postdose and 30 mg/kg produced a 48% inhibition at 24 hours postdose) and dog (15 mg/kg produced 25% inhibition at 24 hours postdose).
- Oral Example 10 inhibited acute hypoxic pulmonary hypertension in the rat in a dose dependent manner with the ED50=0.8 mg/kg (the plasma EC50=0.046 μg/mL). Example 10 was well absorbed orally both in rat and dog. Terminal elimination tl/2's were determined to be 8.5 and 2.2 hours in rat and dog, respectively, and bioavailability is 77% and 100% in rat and dog.
- The compounds of the present invention can be prepared and administered in a wide variety of oral and parenteral dosage forms. Thus, the compounds of the present invention can be administered by injection, that is, intravenously, intramuscularly, intracutaneously, subcutaneously, intraduodenally, or intraperitoneally. Also, the compounds of the present invention can be administered by inhalation, for example, intranasally. Additionally, the compounds of the present invention can be administered transdermally. It will be obvious to those skilled in the art that the following dosage forms may comprise as the active component, either a compound of Formula 1 or a corresponding pharmaceutically acceptable salt of a compound of Formula 1.
- For preparing pharmaceutical compositions from the compounds of the present invention, pharmaceutically acceptable carriers can be either solid or liquid. Solid form preparations include powders, tablets, pills, capsules, cachets, suppositories, and dispersible granules. A solid carrier can be one or more substances which may also act as diluents, flavoring agents, binders, preservatives, tablet disintegrating agents, or an encapsulating material.
- In powders, the carrier is a finely divided solid which is in a mixture with the finely divided active component.
- In tablets, the active component is mixed with the carrier having the necessary binding properties in suitable proportions and compacted in the shape and size desired.
- The powders and tablets preferably contain from five or ten to about seventy percent of the active compound. Suitable carriers are magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose, a low melting wax, cocoa butter, and the like. The term “preparation” is intended to include the formulation of the active compound with encapsulating material as a carrier providing a capsule in which the active component with or without other carriers, is surrounded by a carrier, which is thus in association with it. Similarly, cachets and lozenges are included. Tablets, powders, capsules, pills, cachets, and lozenges can be used as solid dosage forms suitable for oral administration.
- For preparing suppositories, a low melting wax, such as a mixture of fatty acid glycerides or cocoa butter, is first melted and the active component is dispersed homogeneously therein, as by stirring. The molten homogeneous mixture is then poured into convenient sized molds, allowed to cool, and thereby to solidify.
- Liquid form preparations include solutions, suspensions, and emulsions, for example, water or water propylene glycol solutions. For parenteral injection liquid preparations can be formulated in solution in aqueous polyethylene glycol solution.
- Aqueous solutions suitable for oral use can be prepared by dissolving the active component in water and adding suitable colorants, flavors, stabilizing and thickening agents as desired.
- Aqueous suspensions suitable for oral use can be made by dispersing the finely divided active component in water with viscous material, such as natural or synthetic gums, resins, methylcellulose, sodium carboxymethylcellulose, and other wellknown suspending agents.
- Also included are solid form preparations which are intended to be converted, shortly before use, to liquid form preparations for oral administration. Such liquid forms include solutions, suspensions, and emulsions. These preparations may contain, in addition to the active component, colorants, flavors, stabilizers, buffers, artificial and natural sweeteners, dispersants, thickeners, solubilizing agents, and the like.
- The pharmaceutical preparation is preferably in unit dosage form. In such form the preparation is subdivided into unit doses containing appropriate quantities of the active component. The unit dosage form can be a packaged preparation, the package containing discrete quantities of preparation, such as packeted tablets, capsules, and powders in vials or ampoules. Also, the unit dosage form can be a capsule, table, cachet, or lozenge itself, or it can be the appropriate number of any of these in packaged form.
- The quantity of active component in a unit dose preparation may be varied or adjusted from 0.1 mg to 100 mg preferably 0.5 mg to 100 mg according to the particular application and the potency of the active component. The composition can, if desired, also contain other compatible therapeutic agents.
- In therapeutic use as antagonists of endothelin, the compounds utilized in the pharmaceutical method of this invention are administered at the initial dosage of about 0.01 mg to about 100 mg/kg daily. A daily dose range of about 0.01 mg to about 10 mg/kg is preferred. The dosages, however, may be varied depending upon the requirements of the patient, the severity of the condition being treated, and the compound being employed. Determination of the proper dosage for a particular situation is within the skill of the art. Generally, treatment is initiated with smaller dosages which are less than the optimum dose of the compound. Thereafter, the dosage is increased by small increments until the optimum effect under the circumstances is reached. For convenience, the total daily dosage may be divided and administered in portions during the day, if desired.
- The following nonlimiting examples illustrate the preferred methods for preparing the compounds of the invention.
- Following are prepared according to Scheme 1.
- 2-(2-Trifluoromethyl-phenylsulfamoyl)-benzoic acid methyl ester
- Methyl 2-(chlorosulfonyl)benzoate (23.5 g, 0.1 mol) was dissolved in 150 mL of anhydrous pyridine in a 500 mL flask. Catalytic amount of DMAP (4-dimethylaminopyridine) (0.04 eq) was added. 2-Trifluoromethylaniline (20 g, 0.12 mol) was added to the reaction mixture, and it was allowed to stir at room temperature overnight. Pyridine was removed, and the residue was diluted with 250 mL of EtOAc. It was then washed with IN HCl solution followed by brine. After drying with MgSO4, the EtOAc was removed in vacuo to give a thick red oil. The crude product was recrystallized from hexane/Et2O to give the product IA as white crystals (17.63 g, 49% yield).
- Analysis calculated for C15H12F3N1O4S1: C, 50.14; H, 3.37; N, 3.90.
- Found: C, 50.02; H, 3.28; N, 3.82.
- MS (CI) M/E 359.8 (M+)
- 2-[Methoxycarbonylmethyl-(2-trifluoromethyl-phenyl)-sulfamoyl]-benzoic acid methyl ester
- To the suspension of NaH (60% in mineral oil, 2.0 g, 50 mmol) in 45 mL of DMF at 0° C. was added a solution of 2-(2-trifluoromethyl-phenylsulfamoyl) benzoic acid methyl ester (12.0 g, 33.3 mmol) in 22 mL of DMF dropwise. After about 10 minutes, 11.22 g (66.8 mmol) of methyl bromoacetate was added, and reaction solution was warmed to room temperature in 3 hours. The light yellow reaction mixture was poured into ice water. The mixture was then extracted with EtOAc 3×(400 mL) and washed with brine. The organic layer was dried over MgSO4 and evaporated down to a sick light orange oil. White crystals were formed upon treatment with Et2O and hexane. It was collected and dried over the vacuum oven to give pure 2-[methoxycarbonylmethyl-(2-trifluoromethyl-phenyl)-sulfamoyl]-benzoic acid methyl ester (13.85 g, 96%).
- MS (CI) M/E 431.7 (M+)
- Alternative procedure: To dimethylformamide (220 mL) was added 2-(2-trifluoromethyl-phenylsulfamoyl)-benzoic acid methyl ester, (8.0 g, 22.2 mmol). After cooling to 0° C., a solution of potassium hexamethyl-disilazide (0.5 M, 44.5 mL) in toluene was added. Methyl bromoacetate (4.32 mL, 45.6 mmol) was added, followed by stirring at 70° C. overnight. The solvent was evaporated in vacuo, and the residue was suspended in ethyl ether and washed with saturated sodium bicarbonate, brine, and 1N citric acid solutions. The ether was dried over anhydrous magnesium sulfate, filtered, and evaporated to give a crystalline solid, 5.59 g, 58% yield. NMR spectra and elemental analysis were consistent with the structure.
- Compound 1B can also be synthesized using procedures outlined in Scheme lb with benzenesulfonyl chloride. Following is the experimental detail:
- a. Preparation of 1F: N-(2-Trifluoromethyl-phenyl)-benzenesulfonamide Benzenesulfonyl chloride (400 g, 2.26 moles) was dissolved in dichloromethane (2 L). To this was added otrifluoromethylaniline (250 mL, 320 g, 1.99 mol), pyridine (222 mL), and DMAP (7.5 g). The resulting solution was stirred at room temperature for 3 days (72 h), then heated to reflux for 1 hour. The cooled solution was then concentrated on the rotary evaporator, with the bath temperature gradually raised to 70° C. The residue was taken up in ether (3 L) and 1N HCl (1.5 L). The ether layer was separated, washed 2×500 mL with 1N HCl, 1×1 L with brine, 1×1 L with saturated sodium bicarbonate, and once more with 1 L of brine. It was then dried over magnesium sulfate, filtered with suction, and concentrated on the rotary evaporator without heat. The product formed fine crystals as the ether evaporated, and when most of the ether was gone, the crystals were slurried with hexane (2 L), collected with suction and dried. Yield 571 g, 84%.
- b. Preparation of 1G: 2-(2-Trifluoromethyl-phenylsulfamoyl)-benzoic acid A 22L flask was equipped with an overhead stirrer, nitrogen inlet and thermocouple, and placed in an acetone bath. The flask was charged with 1F (544.5 g, 1.807 mol) and THF (10 L, from freshly opened bottles) and stirred. When a solution had formed, dry ice was added to the bath until the temp was <70° C. n-Butyllithium (2.4 L of 1.6M, 3.84 mol) was added in portions, keeping the temperature below 55° C. (30 minutes). The reaction mixture was then stirred at 70° C. to 72° C. for 3 hours, then bonedry carbon dioxide was bubbled in, keeping the temperature below 55° C. This was continued until no fuirther exotherm was observed, then about 10 minutes longer. The mixture was then warmed to room temperature over 1 hour, transferred to a rotary evaporator, and stripped at 50° C. until no more THF came off. The residue was dissolved in water (5 L), and the basic solution was washed with 3×1 L ether. The solution was then acidified by addition of 330 mL concentrated HCl. The acid product was extracted from the aqueous layer with 3×1 L ether. The combined ether layers were dried over magnesium sulfate, filtered, and stripped on the rotary evaporator. The solid residue was broken up and agitated with hot tap water (4 L, at about 60° C. ) for 20 minutes, then collected with suction and dried in vacuo (1 mm Hg) for 24 hours. Yield: 575 g, 92%. This material contained traces amount of impurities, which were removed in the next step.
- c. Preparation of 1H: 1,1-Dioxo-2-(2-trifluoromethyl-phenyl)-1,2-dihydro-1λ6-benzo [d]isothiazol-3-one
- Compound 1G (300 g, 0.876 moles) was slurried in acetic anhydride (350 mL). Methanesulfonic acid (3 drops) was added, and the resulting mixture was heated to reflux for 20 minutes. The resulting solution was allowed to stand without further heating for 30 minutes, then the apparatus was rearranged for distillation, and 190 mL of distillate was removed. The pot residue had begun to precipitate solids even at the boiling point, and 20 mL of the distillate was added back to improve workability of the mixture. The solids were broken up carefully as the mixture cooled, and heptane (˜100 mL) was added, followed by ether (˜50 mL). The product was collected with suction, and washed with several small portions of ether (˜150 mL total). Yield 266 g, 94%.
- d. Preparation of 1B from 1H
- Compound 1H (244 g, 0.745 mol) was added to a solution of sodium methoxide freshly prepared from 19 g (0.83 mol) of sodium and 600 mL methanol in a 3N 3-L round bottom flask equipped with a reflux condenser under nitrogen. The mixture was stirred for 30 minutes without further heating, at which point a greenish-yellow solution had formed. Methyl bromoacetate (83 mL, 137 g, 0.9 moles) was added, and the mixture was stirred without heat for 15 minutes, then heated to reflux for 90 minutes. The mixture was then cooled to 0° C., and the resulting ppt was collected with suction, washed 2×75 mL with ether, then 4×200 mL with water. The product was dried in vacuo (1 mm Hg) 2 hours at 60° C. Yield 228 g, 71%.
- 4-Hydroxy-1,1-dioxo2-(2-trifluoromethyl-phenyl) 1,2-dihydro-1λ6-benzo[e][1,2]-thiazine-3carboxylic acid methyl ester
- In a 250 mL dry RB flask, 4.50 mL of TiCl4 -(40.8 mmol) was dissolved in 100 mL of CH2Cl2 and was cooled to 30° C. A solution of 2-[methoxycarbonyl methyl(2-trifluoromethyl-phenyl)-sulfamoyl]benzoic acid methyl ester (8.0 g, 18.54 mmol) in 50 mL CH2CI2 was added dropwise. The resulting solution was kept at 30° C. for 30 minutes and was then cooled to 78° C. Et3N (7.75 mL, 55.6 mmol) in 50 mL CH2CI2 was slowly syringed in resulting a dark red solution. The reaction mixture was stirred at 78° C. for 4 hours and was then poured into a 1 L flask containing 250 mL of Et2O, 100 mL concentrated HCl, and 100 mL of H2O. The mixture was stirred at room temperature overnight. The layers were separated, and the organic layer was washed with brine and dried over MgSO4. Upon evaporation of the solvent, light yellowish crystals of 4-hydroxy-1,1-dioxo2-(2-trifluoromethyl-phenyl)-1,2-dihydro-1λ6-benzo[e][1,2]thiazine-3-carboxylic acid methyl ester were formed. The product was collected through filtration and dried in oven to provide 2.2 g, 86% yield.
- Analysis calculated for C15H12F3N1O4S1: C, 50.12; H, 3.74; N, 3.25;
- Found: C, 50.04; H, 3.76; N, 3.11.
- 1.1-Dioxo-4-(trifluoro-methanesulfonyloxy)-2-(2-trifluoromethyl-phenyl)-1.2-dihydro-1λ6-benzo[e][1,2]-thiazine-3-carboxylic acid methyl ester
- To dichloromethane (150 mL) was added 4-hydroxy-1,1-dioxo-2-(2-trifluoromethyl-phenyl)-1,2dihydro-1λ6-benzo[e][1,2]thiazine-3-carboxylic acid methyl ester, (13.1 g, 32 mmol). After cooling to 0° C., pyridine (12.8 mL, 158 mmol) was added, followed by trifluoroacetic anhydride (10.7 g, 38 mmol). The mixture was stirred 30 minutes and allowed to warm to 25° C., then was poured into ethyl acetate (200 mL). The mixture was washed with brine, dried over anhydrous magnesium sulfate, filtered, and evaporated to a solid. Recrystallization from ethyl acetate and ethyl ether gave a crystalline solid which was filtered and dried in vacuo giving a solid, 15.5 g, 92% yield.
-
- 4-(3,5-Dimethoxy-phenyl)-2-(2-trifluoromethyl-phenyl)-1,1-dioxo 1,2-dihydro 1λ6-benzof[e][1,2]thiazine-3-carboxylic acid methyl ester
- 1. Preparation of 3,5-dimethoxyphenylboronic acid
- 3,5Dimethoxychlorobenzene (14.0 g, 81 mmol) in 10 mL of THF was added dropwise into a refluxing solution of 2.5 g (100 mmol) of Mg turning in 15 mL of THF with 2 drops of dibromoethane. After the addition, the reaction mixture was refluxed for 48 hours. The Grignard solution was then added into a solution of 40.0 g (380 mmol) of trimethyl borate in 300 mL of THF at 0° C., stirring at room temperature overnight. The reaction solution was diluted with 1N HCl (400 mL) and ethyl acetate (300 mL). The organic layer was separated and was washed with 1N HCl (50 mL), water, brine, dried with MgSO4, concentrated down, and recrystallized in ethyl acetate and ether to give 3.15 g (17.5 mmol, 22% yield) boronic acid.
- 1HNMR (300 MHz, CDCl3): δ6.48 -(s, 1H), 5.14 -(b, 2H), 6.96 -(s, 2H).
- 2. Preparation of 4-(3,5-dimethoxy-phenyl)-2-(2-trifluoromethyl-phenyl) 1.1-dioxo-1,2-dihydro-1λ6-benzo[e][1,2]thiazine-3-carboxylic acid methyl ester (1E)
- To dimethylformamide (18 mL) was added 1,1-dioxo-4-(trifluoro-methanesulfonyloxy)2-(2-trifluoromethyl-phenyl) 1,2-dihydro-1λ6-benzo[e][1,2]thiazine-3-carboxylic acid methyl ester, (1.60 g, 3.0 mmol), palladium tetrakis(triphenyl phosphine) (0.2 g, 0.17 mmol), potassium carbonate (0.7 g, 6.0 mmol), 2-methoxyphenylboronic acid (0.88 g, 6.0 mmol), and toluene (50 mL). The mixture was heated to 100° C. for 30 minutes and was filtered through a pad of Celite. The filtrate and EtOAc washing solution was washed three times with saturated sodium bicarbonate solution, brine, and dried over charcoal and anhydrous magnesium sulfate. The suspension was filtered and stripped to an oil which was resuspended in ethyl acetate and ethyl ether. Insoluble material from this mixture was filtered off, and the filtrate was concentrated in vacuo to an oil. The residue was chromatographed on silica gel eluted with a mixture of ethyl acetate and hexane (25:75). The appropriate fractions were concentrated in vacuo and crystallized from ethyl ether giving a solid 1.29 g, 83% yield.
- Analysis calculated for C25H20F3N1O6S1: C, 57.80;H, 3.88; N, 2.70;
- Found: C, 57.56;H, 3.86; N, 2.66.
- MS: m/e 519 (M+)
- 4-(3,5-Dimethoxyphenyl)2-(2-trifluoromethyl-phenyl)-1,1-dioxo-1,2-dihydro-1λ6-benzo[e][1,2]thiazine-3-carboxylic acid
- The solution of 4-(3,5-dimethoxyphenyl)-2-(2-trifluoromethyl-phenyl) 1,1-dioxo-1,2-dihydro-1λ6-benzo[e][1,2]thiazine-3-carboxylic acid methyl ester (1.29 g, 2.5 mmol) and lithium hydroxide monohydrate (0.3 g 12.5 mmol) in 30 mL of MeOH and 15 mL water was refluxed for 2.5 hours and evaporated to an oil. The residue was dissolved in water, washed with ethyl ether, and the aqueous layer decanted. The aqueous layer was acidified to pH 1 with concentrated HCl and extracted into ethyl ether, washed with brine, dried over anhydrous magnesium sulfate, filtered, and evaporated to a foam. The residue was chromatographed on 50 g silica gel eluted with chloroform, and the appropriate fractions were concentrated in vacuo and evaporated from ethyl ether giving a solid foam, 1.4 g, 66% yield. NMR spectra and elemental analysis were consistent with the structure.
- MS: m/e 505 (M+)
- 2-(2-Chlorophenylsulfamoyl)-benzoic acid methyl ester
- Prepared in the same way as illustrated in Example 1A in 28% yield. The NMR spectra and elemental analysis were consistent with the structure.
- 2-[(2-Chloro-phenyl)-methoxycarbonylmethyl-sulfamoyl]-benzoic acid methyl ester
- Prepared in the same way as illustrated in Example 1B in 84% yield. The NMR spectra and elemental analysis were consistent with the structure.
- 2-(2-Chloro-phenyl)-4-hydroxy-1,1-dioxo-1,2-dihydro-1λ6-benzo[e][1,2]-thiazine-3-carboxylic acid methyl ester
- Prepared in the same way as illustrated in Example 1C in 77% yield. The NMR spectra and elemental analysis were consistent with the structure.
- 2-(2Chloro-phenyl)-1,1-dioxo-4-(trifluoro-methanesulfonyloxy)-1,2-dihydro-1λ6-benzo[e][1,2]-thiazine-3-carboxylic acid methyl ester
- Prepared in the same way as illustrated in Example 1D in 75% yield. The NMR spectra and elemental analysis were consistent with the structure.
- 2-(2Chloro-phenyl)-4-(7-methoxy-benzo-[1,3]-dioxo-5-yl)1,1-dioxo-1,2-dihydro-1λ6-benzo [e][1,2]thiazine-3carboxylic acid methyl ester Prepared in the same way as illustrated in Example 1E in 88% yield. The NMR spectra and elemental analysis were consistent with the structure. MS: m/z 485 (M+)
- 2-(2Chloro-phenyl)4-(3 .5dimethoxyphenyl) 1.1 dioxo 1,2-dihydro 1λ6 benzo[e][1,2thiazine-3carboxylic acid
- Prepared in the same way as illustrated in Example 1 in 99% yield. The NMR spectra and elemental analysis were consistent with the structure.
- MS: m/z 471 (M+)
- 2-(2Bromophenylsulfamoyl)-benzoic acid methyl ester
- Prepared in the same way as illustrated in Example 1A in 81% yield. The NMR spectra and elemental analysis were consistent with the structure.
- 2-[(2-Bromo-phenyl)-methoxncarbonylmethyl-sulfamoyl]-benzoic acid methyl ester
- Prepared in the same way as illustrated in Example 1B in 76% yield. The NMR spectra and elemental analysis were consistent with the structure.
- 2-(2-Bromophenyl)-4hydroxy-1,1-dioxo-1,2-dihydro-1λ6-benzo[e][1,2]thiazine-3carboxylic acid methyl ester
- Prepared in the same way as illustrated in Example 1C in 58% yield. The NMR spectra and elemental analysis were consistent with the structure.
- 2-(2Bromo-phenyl)-1,1-dioxo-4-(trifluoro-methanesulfonyloxy)-1 2dihydro-1λ6-benzo[e][1,2]thiazine-3-carboxylic acid methyl ester
- Prepared in the same way as illustrated in Example 1D in 75% yield. The NMR spectra and elemental analysis were cgonsistent with the structure.
- 2-(2-Bromophenyl)-4-(3,5-dimethoxy-phenyl)-1,1-dioxo-1,2-dihydro-1λ6-benzo[e]1,2]thiazine-3-carboxylic acid methyl ester
- Prepared in the same way as illustrated in Example 1E in 88% yield. The NMR spectra and elemental analysis were consistent with the structure.
- 2-(2-Bromophenyl)-4-(3,5-dimethoxy-phenyl)-1,1-dioxo-1,2-dihydro-1 λ6-benzo[e][1,2]thiazine-3-carboxylic acid
- Prepared in the same way as illustrated in Example 1 in 81% yield. The NMR spectra and elemental analysis were consistent with the structure.
- MS: m/z 471 (M+)
- 2-(2-Chloro-phenyl)-4-(7-methoxy-benzo[1,3]dioxol-5-yl)-1,1-dioxo 1,2-dihydro-1λ6-benzo[e][1,2]-thiazine-3-carboxylic acid methyl ester
- 1. Preparation of (1-bromo-3,4-methylenedioxy-5-methoxybenzene)
- To dimethylformamide (400 mL) was added 1-bromo-3,4-dihydroxy-5-methoxybenzene (40 g, 182 mmol), potassium carbonate (75.7 g, 548 mmol), and dibromomethane (95.2 g, 548 mmol), followed by heating to reflux for 1 hour. The solvent was evaporated in vacuo, and the residue was taken up into ethyl ether, filtered, washed with saturated potassium carbonate solution, brine, 1N citric acid solution, and brine. The organic phase was dried over anhydrous magnesium sulfate and filtered through charcoal. The filtrate was concentrated in vacuo giving a crystalline precipitate which was filtered, washed with hexane, and dried in vacuo to a solid. This material was distilled at 2 mm Hg, 125° C., giving a crystalline solid, 21.7 g, 52% yield. NMR spectra and elemental analysis were consistent with the structure.
- 2. Preparation of (4-Methoxy-1,3-benzodioxol-6-yl boronic acid)
- To tetrahydrofuran (40 mL) was added magnesium turnings (2.33 g, 95.8 mmol), 1 bromo-3,4-methylenedioxy-5-methoxybenzene (21.7 g, 93.9 mmol) and a catalytic amount of iodine. Following vigorous reaction, the metal was consumed, and the solution was added to a solution of trimethylborate (38 mL, 334 mmol) in tetrahydrofuran (100 mL) at 78° C. over 45 minutes. The mixture was stirred at 78° C. for an additional 2 hours, then at 25° C. overnight. To the mixture was added 1N HCl (200 mL) followed by stirring at 25° C. for 3 days. 5 The solvent was removed in vacuo, and the suspension was extracted with ethyl ether. The ether phase was washed with brine, and the product was extracted into 0.5N NaOH. The NaOH solution was washed with ethyl ether and acidified to pH 1 with 2N HCl. The acidified aqueous phase was extracted with ethyl ether, washed with brine, dried over anhydrous magnesium sulfate, filtered, and evaporated to a brown solid, 7.43 g, 40% yield. The material was of sufficient purity to be used in subsequent preparations.
- 3. Example 4E was prepared in the same way as illustrated in Example 1E in
- 85% yield. The NMR spectra and elemental analysis were consistent with the structure.
- 2-(2-Chloro-phenyl)-4-(7-methoxy-benzo[1,3]dioxol-5-yl)-1,1-dioxo-1,2-dihydro-1λ6-benzo[e][1,2]-thiazine-3-carboxylic acid
- Prepared in the same way as illustrated in Example 1 in 67% yield. The NMR spectra and elemental analysis were consistent with the structure.
- 2-(2-Benzyl-phenolsulfamoyl)-benzoic acid methyl ester
- Prepared in the same way as illustrated in Example 1A in 43% yield. The NMR spectra and elemental analysis were consistent with the structure.
- 2-(2-Benzylphenyl)-methoxycarbonylmethyl-sulfamoyl)-benzoic acid methyl ester
- Prepared in the same way as illustrated in Example 1B in 67% yield. The NMR spectra and elemental analysis were consistent with the structure.
- 2-(2-Benzyl-phenyl)-4hydroxy-1,1-dioxo-1,2-dihydro-1λ6-benzo[e][1,2]thiazine-3-carboxylic acid methyl ester
- Prepared in the same way as illustrated in Example 1C in 87% yield. The NMR spectra and elemental analysis were consistent with the structure.
- 2-(2-Benzyl-phenyl)-1,1-dioxo-4-(trifluoro-methanesulfonyloxy)-1,2-dihydro-1λ6-benzo[e][1,2]thiazine-3-carboxylic acid methyl ester
- Prepared in the same way as illustrated in Example 1D in 85% yield. The NMR spectra and elemental analysis were consistent with the structure.
- 2-(2-Benzylphenyl)4-(7-methoxy-benzo[1,3]-dioxol-5-yl)-1,1-dioxo-1,2-dihydro-1λ6-benzo[e][1,2]thiazine-3-carboxylic acid methyl ester
- Prepared in the same way as illustrated in Example 1E in 50% yield. The NMR spectra and elemental analysis were consistent with the structure.
- 2-(2-Benzylphenyl)4-(7-methoxy-benzo[1,3]dioxo-5-yl)-1,1-dioxo-1,2-dihydro-1λ6-benzo[e][1,2]thiazine-3-carboxylic acid
- Prepared in the same way as illustrated in Example 1 in 54% yield. The NMR spectra and elemental analysis were consistent with the structure. Analysis calculated for C30H23N1O7S1 -(H2O)1.75: C, 60.55;H, 4.32; N, 2.35;
- Found: C, 60.76;H, 4.37; N, 2.29.
- 2-(2,6-Dimethyl-phenylsulfamoyl)-benzoic acid methyl ester
- Prepared in the same way as illustrated in Example 1A in 50% yield. The NMR spectra and elemental analysis were consistent with the structure.
- 2-[(2,6-Dimethyl-phenyl)methoxycarbonylmethyl-sulfamoyl]benzoic acid methyl ester
- Prepared in the same way as illustrated in Example 1B in 88% yield. The NMR spectra and elemental analysis were consistent with the structure.
- 2-(2,6-Dimethyl-phenyl)-4hydroxy-1,1-dioxo-1,2-dihydro-1λ6-benzo[e][1.2]thiazine-3-carboxylic acid methyl ester
- Prepared in the same way as illustrated in Example 1C in 87% yield. The NMR spectra and elemental analysis were consistent with the structure.
- 2-(2,6-Dimethyl-phenyl)-1,1-dioxo-4-(trifluoromethanesulfonyloxy)-1,2-dihydro 1λ6-benzo [e][1,2]thiazine-3-carboxylic acid methyl ester Prepared in the same way as illustrated in Example 1D in 94% yield. The NMR spectra and elemental analysis were consistent with the structure.
- 2-(2,6-Dimethyl-phenyl)4-(7-methoxy-benzo [1,3dioxol-5-yl)-1,1 dioxo 1,2-dihydro- 1λ6-benzo[e][1,2]thiazine-3-carboxylic acid methyl ester Prepared in the same way as illustrated in Example 1E in 58% yield. The NMR spectra and elemental analysis were consistent with the structure.
- 2-(2,6-Dimeth Iphenyl)4-(7-methoxy-benzo-[1,3]dioxol-5vl)-1,1 dioxo 1,2dihydro 1λ6-benzo[e][1,2]thiazine-3-carboxylic acid monosodium salt
- To dioxane (15 mL) was added 2-(2,6dimethyl-phenyl)4-(7-methoxy benzo[1,3]dioxol-5-yl)1,1 dioxo 1,2-dihydro1λ6-benzo[e][1,2]thiazine 3-carboxylic acid methyl ester, (0.99 g, 2.01 mmol) and a solution of lithium hydroxide monohydrate (0.42 g, 10 mmol) in 15 mL water. The mixture was heated at 90° C. for 18 hours, filtered, and evaporated to a solid. The residue was dissolved in water and ethyl ether and the aqueous layer decanted. The aqueous layer was acidified to pH 1 with concentrated HCl and extracted into ethyl ether, washed with brine, dried over anhydrous magnesium sulfate, filtered, and evaporated to a white solid, 1.05 g. To methanol (20 mL) was added this solid (0.63 g, 1.32 mmol), followed by 0.985N NaOH (1.34 mL, 0.683 mmol). The mixture was evaporated to a glassy solid, redissolved in 30 mL water, and filtered at 45 μ. The filtrate was lyophilized to a white solid, 0.65 g. NMR spectra was consistent with the structure. Elemental analysis was consistent for the structure as a hydrate, holding an additional 1.75 mol of water.
- Analysis calculated for C25H20N1O7S1Na(H2O)1.75:
- C, 56.10;H, 4.32; N, 2.53; S, 5.91; Na, 4.09;H2O, 5.68. %Found: C, 56.33;H, 4.44; N, 2.62; S, 6.02; Na, 4.31;H20, 5.91.
- 4-(7-Methoxy-benzo[1,3]dioxol-5-yl)-1,1 dioxo-2-(2-trifluoromethyl-phenyl) 1,2-dihydro-1λ6-benzo[e][1,2]thiazine-3-carboxylic acid methyl ester
- Prepared in the same way as illustrated in Example 1E in 75% yield. The NMR spectra and elemental analysis were consistent with the structure.
- 4-(7-Methoxybenzo[1,3]-dioxol-5-yl)-1,1-dioxo-2-(2-trifluoromethyl-phenyl) 1,2-dihydro 1λ6-benzo [e][1,2thiazine-3-carboxylic acid
- Prepared in the same way as illustrated except using dioxane as solvent in Example I E in 66% yield. The NMR spectra and elemental analysis were consistent with the structure. The acid (0.495 g, 0.953 mmol) was dissolved in 10 mL of MeOH and was treated with 0.985N NaOH (0.967 mL, 0.953 mmol). The mixture was evaporated to a glassy solid, redissolved in 50 mL water and filtered at 45 μ. The filtrate was lyophilized to a white solid, 0.502 g. NMR spectra was consistent with the structure. Elemental analysis was consistent for the structure as a hydrate, holding an additional 1.75 mol of water. Analysis calculated for C24H15N1O7S1Na(H2O)1.75:
- %Theory: C, 49.52;H, 3.05; N, 2.30; S, 5.54; Na, 3.93;H2O, 5.30; F, 10.23.
- %Found: C, 50.31;H, 3.25; N, 2.44; S, 5.60; Na, 4.01;H2O, 5.50; F, 9.94.
- Following illustrate the preparation in Scheme 3.
- 2-[Hydroxy(7-methoxy-benzo[1,3]-dioxol-5-yl)methyl]N-o-tolyl-benzenesulfonamide
- To tetrahydrofuran (200 mL) was added N-o-tolyl-benzenesulfonamide (4.95 g, 20 mmol). After cooling to 72° C., a solution of n-butyllithium (1.6 M, 25 mL in hexane) was added, and the mixture was stirred for 3 hours at 72° C. A solution of 3-methoxy-4,5methylenedioxybenzaldehyde (3.60 g, 20 mmol) in tetrahydrofuran (70 mL) was added, and the mixture was stirred and warmed to 0° C. over 1.5 hours. The mixture was poured into 200 mL saturated ammonium chloride solution, and the organic phase was decanted. The solvent was evaporated in vacuo and the residue was suspended in ethyl ether, washed with saturated sodium bicarbonate and brine solutions. The solution was dried over anhydrous magnesium sulfate, filtered, and evaporated to give a syrup which was chromatographed on 500 g silica gel eluted with a mixture of ethyl acetate and hexane (35:65). The appropriate fractions were concentrated in vacuo and crystallized giving a solid, 4.15 g, 48.6% yield, mp 155-158° C. NMR spectra and elemental analysis were consistent with the structure.
- ({2-[Hydroxy(7-methoxy-benzo[1,3]dioxol-5-yl)-methyl]benzenesulfonyl}-o-tolyl-amino)-acetic acid methyl ester
- Sixty percent sodium hydride suspension in oil (0.422 g, 10.55 mmol) was washed with tetrahydrofuran and was added to tetrahydrofuran (175 mL). To this was added 2-[hydroxy(7-methoxy-benzo[1,3]dioxol-5-yl)-methyl]N-otolyl-benzenesulfonamide (4.1 g, 9.59 mmol). After stirring for 30 minutes, methyl bromoacetate (1.09 mL, 11.5 mmol) was added followed by stirring at reflux for 18 hours. The mixture was evaporated to an oil in vacuo, and the residue was resuspended in ethyl ether, washed with 1N citric and brine. The solution was dried over anhydrous magnesium sulfate, filtered, and evaporated to a solid. The material was chromatographed on 300 g silica gel eluted with a mixture of ethyl acetate and hexane (35:65). The appropriate fractions were concentrated in vacuo from ethyl ether giving a solid, 4.29 g, 89.5% yield. NMR spectra and elemental analysis were consistent with the structure.
- {[2-(7-Methoxybenzo[1,3]dioxole-5-carbonyl)-benzene-sulfonyl]-o-tolyl-amino}-acetic acid methyl ester
- To acetone (225 mL) was added ({2-[hydroxy(7-methoxy benzo[1,3]dioxol-5-yl)-methyl]benzenesulfonyl} otolylamino)acetic acid methyl ester (4.17 g, 8.35 mmol), and 8N Jones reagent (4 mL). The mixture was stirred 15 minutes giving a suspended solid. Isopropanol (20 mL) was added followed by stirring for 15 minutes. The mixture was filtered, saturated sodium bicarbonate solution was added, and the solvent was removed in vacuo giving a paste. The paste was resuspended in ethyl acetate and water, filtered, and washed with saturated sodium bicarbonate, brine and dried over anhydrous magnesium sulfate. The solution was filtered and evaporated to a solid which was crystallized from ethyl acetate and ethyl ether giving a white solid, 2.41 g, 59% yield, mp 159-170° C. NMR spectra and elemental analysis were consistent with the structure.
- 4-(7-Methoxybenzo [1,3]-dioxol-5-yl)-1,1-dioxo-2-o-tolyl 1,2-dihydro-1λ6-benzo[e][1,2]thiazine-3-carboxylic acid methyl ester
- To a dry 100mL flask was added {[2-(7-methoxy-benzo[1,3]dioxole-5carbonyl)-benzenesulfonyl]otolylamino}acetic acid methyl ester (2.0 g, 4.2 mmol), dry 4 angstrom molecular sieves (8 g), and Ti(TfO)2Cl2 -(0.56 g, 0.48 mmol). The flask was cooled to 60° C. and dichloromethane (45 mL) was added. A solution of triethylamine (1.35 g, 9.73 mmol) in dichloromenthan (18 mL) was added. The mixture was warmed to 5° C. over 2 hours, followed by refrigeration at 0° C. for 18 hours. The mixture was poured in to 50mL ammonium phosphate buffer solution (pH 7), stirred 20 minutes, and filtered. The organic phase was washed with brine, dried over anhydrous magnesium sulfate, filtered, and evaporated in vacuo to an oil. The oil was chromatographed on 150 g silica gel eluted with a mixture of ethyl acetate and hexane (40:60). The appropriate fractions were evaporated in vacuo, and the residue was evaporated to a foam, 1.02 g, 53%. NMR spectra and elemental analysis were consistent with the structure.
- 4-(7-Methoxy-benzo[1,3]dioxol-5-yl)-1,1-dioxo-2o-tolyl-1,2-dihydro-1,6-benzo[e][1,2]-thiazine-3-carboxylic acid
- To dioxane (10 mL) was added 4-(7-methoxy-benzo[1,3]dioxol-5-yl) 1,1dioxo-2-o-tolyl-1,2-dihydro-1λ6-benzo[e][1,2]thiazine-3-carboxylic acid methyl ester (0.72 g, 1.49 mmol) and a solution of lithium hydroxide monohydrate (0.374 g, 8.9 mmol) in 6 mL water. The mixture was heated at 80° C. for 1.5 hours, filtered, and evaporated to a solid. The residue was dissolved in water and ethyl ether and the aqueous layer decanted. The aqueous layer was acidified to pH 1 with concentrated HCl and extracted into ethyl ether, washed with brine, dried over anhydrous magnesium sulfate, filtered, and evaporated to a solid, 0.70 g. The material was chromatographed on 15 g silica gel eluted with chloroform. The appropriate fractions were combined and evaporated in vacuo from ethyl ether giving a solid, 0.272 g. NMR spectra was consistent with the structure. Elemental analysis was consistent for the structure as a hydrate, holding an additional 0.25 moles of water.
- Analysis calculated for C24H I9N1O7S1(H2O)0.25:
- %Theory: C, 61,11;H, 4.33; N, 2.84; S, 6.74;H2O, 0.43.
- %Found: C, 61,33;H, 4.18; N, 2.198; S, 6.82;H2O, 0.96.
- 2-(2-Bromophenyl)4-(7-methoxy-benzo [1,3dioxol-5yl)-1,1-dioxo-1,2-dihydro-1λ6-benzo[e[[1,21]-thiazine-3-carboxylic acid methyl ester
- This example was prepared according to Scheme la.
- 1. Preparation of (1bromo-3,4-methylenedioxy-5-methoxybenzene)
- To dimethylformamide (400 mL) was added 1bromo-3,4dihydroxy 5-methoxybenzene (40 g, 182 mmol), potassium carbonate (75.7 g, 548 mmol), and dibromomethane (95.2 g, 548 mmol), followed by heating to reflux for 1 hour. The solvent was evaporated in vacuo, and the residue was taken up into ethyl ether, filtered, washed with saturated potassium carbonate solution, brine, 1N citric acid solution, and brine. The organic phase was dried over anhydrous magnesium sulfate and filtered through charcoal. The filtrate was concentrated in vacuo giving a crystalline precipitate which was filtered, washed with hexane, and dried in vacuo to a solid. This material was distilled at 2 mm Hg, 125° C., giving a crystalline solid, 21.7 g, 52% yield. NMR spectra and elemental analysis were consistent with the structure.
- 2. To tetrahydrofuran (30 mL) was added 1-bromo-3,4-methylenedioxy-5-methoxybenzene (1.25 g, 5.41 mmol). After cooling to 72° C., a solution of n-butyllithium (1.6 M in hexane, 3.54 mL) was added. After stirring for 45 minutes, a solution of zinc bromide (1.27 g, 5.69 mmol) in tetrahydrofuran (20 mL) was added, and the mixture was stirred at 72° C. for 45 minutes, followed by warming to 25° C. To this mixture was added 2-(2bromophenyl)-1,1 dioxo 4-(trifluoromethanesulfonyloxy)-1,2-dihydro 16-benzo[e][1,2]thiazine-3carboxylic acid methyl ester and (1.48 g, 2.80 mmol), palladium tetrakis(triphenyl phosphine) (1,30 g, 1.05 mmol). The mixture was heated to reflux for 1 hour and was evaporated in vacuo to a paste. The mixture was resuspended in ethyl acetate, washed with 1N citric acid solution, brine, filtered, and dried over anhydrous magnesium sulfate. The suspension was filtered and stripped to an oil which was partially crystallized from ethyl ether giving a solid. The solid was chromatographed on 50 g silica gel eluted with a mixture of ethyl acetate and hexane (20:80). The appropriate fractions were concentrated in vacuo and crystallized from ethyl ether. These solids were combined with those recovered from the initial crystallization and were in vacuo giving a solid, 0.836 g, 28% yield. NMR spectra and elemental analysis were consistent with the structure.
- 2-(2-Bromo-phenyl)4-(7-methoxy-benzo[1,3]-dioxol-5-yl)-1,1 dioxo 1,2-dihydro-1λ6-benzo[e][1,2]-thiazine-3-carboxylic acid monosodium salt
- To dioxane (20 mL) was added 2-(2bromophenyl)4-(7-methoxy benzo[1,3]dioxol-5-yl)1,1dioxo-1,2-dihydro1λ6-benzo[e][1,2]thiazine-3-carboxylic acid methyl ester, (0.75 g, 1,38 mmol) and a solution of lithium hydroxide monohydrate (0.28 g, 6.74 mmol) in 8 mL water. The mixture was heated at 80° C. for 2 hours and evaporated to an oil. The residue was dissolved in water, washed with ethyl ether, and the aqueous layer decanted. The aqueous layer was acidified to pH 1 with 6N HCl and extracted into ethyl ether, washed with brine, dried over anhydrous magnesium sulfate, filtered, and evaporated to a yellow solid. To methanol (4 mL) was added the solid (0.652 g, followed by 0.985N NaOH (1.22 mL). The mixture was evaporated to a glassy solid, redissolved in 30 mL water, and filtered at 45 microns. The filtrate was lyophilized to a white solid, 0.65 g. NMR spectra was consistent with the structure. Elemental analysis was consistent for the structure as a hydrate, holding an additional 1.25 mol of water.
- Analysis calculated for C23H15N1O7S1Br1(H2O)1.25:
- %Theory: C, 47.78;H, 3.03; N, 2.40; S, 5.23; Na, 4.12;H2O, 3.81; Br, 13.23.
- %Found: C, 48.05;H, 3.07; N, 2.44; S, 5.58; Na, 4.00;H2O, 3.92; Br, 13.90.
- 4-(7Ethylbenzo [1,3]dioxol-5-yl)-1,1 dioxo-2-(2-trifluoro-methyl-phenyl)-1,2-dihydro 1λ6-benzoel][1,2]thiazine-3-carboxylic acid methyl ester
- This example was prepared according to Scheme 1a.
- a. Preparation of 5bromo-2,3-dihydroxybenzaldehyde
- To dichloromethane (400 mL) was added 5bromo-2-hydroxy-3-methoxy-benzaldehyde (prepared perSynthetic Communications, 1991;21-(8,9):1091-5; 94.6 g, 409.4 mmol). To this was added with cooling to 10° C. a solution of boron tribromide (153.9 g, 614 mmol) in dichloromethane (400 mL) over 20 minutes, followed by warming to 25° C. overnight. The mixture was poured into 2 L of ice and extracted with chloroform. The chloroform solution was washed with brine, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated in vacuo and hexane was added giving a crystalline precipitate which was filtered, washed with hexane, and dried in vacuo to a solid, 80.0 g, 90% yield. NMR spectra and elemental analysis were consistent with the structure.
- b. Preparation of 6bromo-benzo[1,3]dioxole-4carbaldehyde Dimethylformamide, 750 mL, was purged with dry nitrogen gas and 5bromo-2,3-dihydroxybenzaldehyde (83 g, 382 mmol) was added. To the solution was added potassium carbonate (158 g, 1,14 mol) followed by diiodomethane (306 g, 1,14 mol). The mixture was warmed to 85° C. for 2.5 hours, and evaporated in vacuo to an oil. The mixture was partitioned between ethyl acetate and water and filtered through celite. The phases were separated, and the organic phase was washed with brine, dried over anhydrous magnesium sulfate, filtered, and evaporated to a small volume causing a solid to precipitate. The solid was filtered, washed with 50:50 hexane/ethyl acetate, and set aside. Three more crops of solid were subsequently isolated in this manner from the filtrate. The solids were combined and dried in vacuo giving a beige solid, 69.45 g, 79.4% yield. NMR spectra and elemental analysis were consistent with the structure.
- c. Preparation of 1-(6-bromo-benzo[1,3]dioxol-4-yl)ethanol
- To 150 mL tetrahydrofuran, was added 6-bromo-benzo[1,3]dioxole 4carbaldehyde (15 g, 65.4 mmol). To the solution was added a solution of methyl magnesium bromide (1.0 M) in din butyl ether (72 mL) followed by exotherm and solid formation. The mixture was stirred at 25° C. for 2.5 hours and evaporated in vacuo to a solid. The mixture was suspended in ethyl acetate washed with 1N citric acid, brine, and dried over anhydrous magnesium sulfate. The mixture was filtered and evaporated to an oil. The oil was induced to crystallize from ethyl acetate and hexane giving a white solid which was filtered and dried in vacuo giving a solid, 10.48 g, 65.4% yield. NMR spectra and elemental analysis were consistent with the structure.
- d. Preparation of 1-(6bromo-4ethylbenzo[1,3]dioxole
- To a 250mL flask was added 1-(6bromo-benzo[1,3]dioxol-4-yl)ethanol (9.3 g, 37.9 mmol) was added. The solid was cooled to 50° C. and trifluoroacetic acid (44 mL, 568 mmol) was added. Followed addition of triethylsilane (60.5 mL, 379 mmol). The mixture was stirred at reflux for 5 hours, and evaporated in vacuo to an oil. The oil was distilled twice, collecting the fraction boiling between 80° C. and 110° C. at 1.5 mm Hg. The oil was chromatographed on 100 g silica gel, eluted with 5:95 ethyl acetate/hexane. Evaporation of the appropriate fractions gave a clear oil, 6.56 g, 75.6% yield. NMR spectra and elemental analysis were consistent with the structure.
- e. Alternate Preparation of 1-(6bromo-4-ethylbenzo[1,3]dioxole-Preparation of 5bromo-2,3-dihydroxyethylbenzene
- A 2 L flask was charged with tetrahydrofuran (600 mL) and one normal aqueous sodium hydroxide (260 mL). To this solution was added 5-bromo-3ethylsalicylaldehyde (58 g, 0.25 mol, prepared by the procedure described by S. A. Weerawarna et al.,J Het. Chem., 1991;28:1400). With good stirring, hydrogen peroxide (400 mL of 3% solution, 0.35 mol) was slowly added. After 30 minutes, tlc (silica plate eluted with hexane:ethyl acetate, 7:3) showed no more starting material. The reaction mixture was brought to a pH of 5.0 by addition of acetic acid. The tetrahydrofuran was removed under vacuum, then the aqueous mixture was extracted twice with 300 mL portions of methyl t-butyl ether. The ether solution was dried over magnesium sulfate, filtered, and concentrated to a dark oil (54.8 g). This material was not further purified, but used directly in the next reaction.
- Preparation of 1-(6bromo-4ethylbenzo[1,3]dioxole
- A 2 L, 3 neck round bottom flask was equipped with an overhead stirrer, heating mantle, condenser, and nitrogen inlet. The flask was flushed with nitrogen and charged with acetonitrile (700 mL), followed by 5bromo-2,3dihydroxyethylbenzene (54.5 g, assumed to be 0.25 mol), then anhydrous cesium carbonate (121 g, 0.37 mol) and bromochloromethane (57 g, 0.44 mol). The mixture was stirred and heated to reflux (74° C.). At that point, sodium iodide (5 g, 0.03 mol) was added, and the mixture was boiled for 90 minutes. The mixture was then cooled and filtered with suction. The filter cake was rinsed with acetonitrile, then the solvent was removed under vacuum. The residue was treated with water (700 mL), and the mixture was extracted twice with 400 mL portions of hexane. The hexane was removed under vacuum, then the residue (36 g) was distilled under high vacuum. The distillate, collected at a head temperature of 84° C. (0.8 mm Hg) weighed 24 g (0.10 mol, 41% for the two steps). The product thus obtained has NMR characteristics consistent with the title compound and is greater than 95% pure by gas chromatography.
- f. Preparation of 10E
- To tetrahydrofuran (30 mL) was added (6bromo-4ethyl-benzo[1,3]dioxole) (1.24 g, 5.41 mmol). After cooling to 78° C., a solution of n-butyllithium (1.6 M in hexane, 3.54 mL) was added. After stirring for 45 minutes, a solution of anhydrous zinc bromide (1.27 g, 5.69 mmol) in tetrahydrofuran (20 mL) was added, and the mixture was stirred at 72° C. for 45 minutes, followed by wanning to 25° C. To this mixture was added 1,1-dioxo 4-(trifluoromethanesulfonyloxy)2-(2-trifluoromethyl-phenyl)-1,2-dihydro 1λ6-benzo[e][1,2]thiazine-3-carboxylic acid methyl ester (1.49 g, 2.80 mmol), and palladium tetrakis(triphenyl phosphine) (1,30 g, 1.05 mmol). The mixture was heated to 70° C. for 2.5 hours and was evaporated in vacuo to an oil. The mixture was resuspended in ethyl acetate, washed with 1N citric acid solution, brine, filtered, and dried over anhydrous magnesium sulfate. The suspension was filtered and stripped to an oil which was partially crystallized from ethyl ether giving a solid. The filtrate was concentrated in vacuo and was chromatographed on 50 g silica gel eluted with a mixture of ethyl acetate and hexane (30:70). The appropriate fractions were concentrated in vacuo and crystallized from ethyl ether. These solids were combined with those recovered from the initial crystallization and were dried in vacuo giving a solid, 0.836 g, 53% yield. NMR spectra and elemental analysis were consistent with the structure.
- 4-(7-Ethylbenzo[1,3]dioxol-5yl)-1,1 dioxo-2-(2-trifluoromethyl-phenyl) 1,2-dihydro1λ6-benzo[e]11.2]thiazine-3-carboxylic acid, sodium salt
- To dioxane (15 mL) was added 4-(7-ethylbenzo[1,3]dioxol-5-yl) 1,1 dioxo-2-(2-trifluoromethyl-phenyl)-1,2-dihydro 1 26-benzo [e][1,2]thiazine 3-carboxylic acid methyl ester, (0.7 g, 1,32 mmol) and a solution of lithium hydroxide monohydrate (0.28 g, 6.58 mmol) in 15 mL water. The mixture was heated at reflux for 2.5 hours and evaporated to a solid. The residue was dissolved in water, filtered, and washed with ethyl ether and the organic layer decanted. The aqueous layer was acidified to pH 1 with 6N HCl and extracted into ethyl ether, washed with brine, dried over anhydrous magnesium sulfate, filtered, and evaporated to a yellow foam, 0.51 g. To methanol (4 mL) was added the solid (0.465 g), followed by 0.985N NaOH (0.91 mL). The mixture was evaporated to a glassy solid, redissolved in 30 mL water, and filtered at 45 μ. The filtrate was lyophilized to a white solid, 0.448 g, 70% yield. NMR spectra was consistent with the structure. Elemental analysis was consistent for the structure as a hydrate, holding an additional 1.5 moles of water.
- Analysis calculated for C25H18N1O6SF3Na(H2O)1.5, MWT 566.46:
- C, 51.82;H, 3.41; N, 2.35; S, 6.13; F, 9.79; Na, 4.06;H2O, 4.53.
- Found: C, 53.00;H, 3.56; N, 2.47; S, 5.66; F, 10.06; Na, 4.05;H2O, 4.77.
- The free acid 10 -(32.1 g, 62 mmol) was dissolved in 100 mL of MeOH. To this was added 62 mL of 1N KOH. After stirring at room temperature for 1 hour, most of the MeOH was removed by rotatory evaporator. EtOH was then added (250 mL), and the solution was stirred for a while at ˜60° C. Then 30 mL of isopropyl alcohol (IPA) was added, and the mixture was cooled to room temperature for 2 hours. The precipitate was collected by filtration and was washed with some portions of cold IPA. The product was dried in vacuum at 45° C. overnight.
- Analysis calculated for C25H17F3N6S1K1(H2O)0.15: C, 53.79;H, 3.12; N, 2.51.
- Found: C, 53.75;H, 2.84; N, 2.41.
- 4-Benzo[1,3]dioxol-5-yl-1,1 dioxo-2-(2-trifluoromethyl-phenyl)-1,2-dihydro-1λ6-benzo[e][1,2]thiazine-3-carboxylic acid methyl ester
- Prepared in the same way as illustrated in Example 1E in 95% yield. The NMR spectra and elemental analysis were consistent with the structure.
- 4-Benzo[1,3]dioxol-5-yl-1,1-dioxo-2-(2-trifluoromethyl-phenyl)-1,2-dihydro-1λ6-benzo[e][1,2]thiazine-3-carboxylic acid
- Prepared in the same way as illustrated in Example 1E in 98% yield. The NMR spectra and elemental analysis were consistent with the structure. MS m/z 489 (M+)
- The following procedures are illustrated in Scheme 2.
- 2-o-Tolylsulfamoyl-benzoic acid methyl ester
- A solution of 22.24 g (85.3 mmol) of 90% methyl-2-(chlorgsulfonyl) benzoate in CH2Cl2 was treated with 7.6 mL (93.8 mmol, 1,1 eq) of pyridine, 10.01 mL (93.8 mmol, 1,1 eq) of amine, and 3.47 g (28.4 mmol, 0.33 eq) of DMAP. The reaction mixture was then stirred overnight at room temperature under N2. The solvent was concentrated to onethird volume, diluted with ethyl acetate, washed with 1N HCl, brine, dried over MgSO4, and evaporated. Crystallization from Hex/EtOAc afforded the product as 19.50 g of orange cubes, 75% yield.
- Analysis calculated for C15H15N1O4: C, 59.00;H, 4.95; N, 4.59.
- Found: C, 59.02;H, 4.69; N, 4.35.
- 2-(6-Methyl-benzo[1,3]dioxol-5-yl)-1,1 dioxo-1,2dihydro-1λ6-benzo[d]isothiazol-3-one
- A solution of 16.15 g (53.0 mmol) of 12A, 4.28 mL (53.0 mmol, 1.0 eq) of pyridine, and 2.15 g (17.6 mmol, 0.33 eq) of DMAP in 150 mL of xylenes was heated to reflux overnight, cooled to room temperature, treated with 1N HCl, and allowed to stir for 2 hours. The ppt solid was collected, washed with 1N HCl, water, and xylenes, then air dried overnight under high house vacuum to give the product as 8.20 g of white solid, 57% yield.
- MS(CI) m/e: 273 (M+)
- 3-[2-(6-Methyl-benzo[1,3]dioxol-5-ylsulfamoyl)phenyl]-3-oxo-propionic acid tert-butyl ester
- KN-(TMS)2, 95%, 16.6 g (78.8 mmol, 3 eq), was dissolved in 175 mL of dry THF and cooled to 78° C. This was treated with 10.6 mL (78.8 mmol, 3 eq) of t-butylacetate and the reaction mixture stirred for 30 minutes at 78° C. To this was added 7.18 g (26.3 mmol) of 12H, in portions over 40 minutes, the reaction mixture stirred for 4 hours at 78° C., then quenched with saturated aqueous NH4Cl and allowed to come slowly to room temperature overnight. The mixture was treated with 1N HCl, stirred for 1 hour, then extracted with EtOAc. The organic portion was washed with water, brine, dried over MgSO4, and evaporated. The oil was purified on a silica gel column eluted with CHCl3 to give the product as an orange oil which solidified upon standing, 70% yield.
- MS(CI) m/e: 334 (M+tBu)
- 2-Bromo3-[2-(2methyl-phenylsulfamoyl)-phenyl]3-oxo-propionic acid tert-butyl ester
- A solution of 5.47 g (14.0 mmol) of 121 in 80 mL of CC14 was treated with 2.50 g (14.0 mmol, 1.0 eq) of NBS and 0.1 g (0.04 mmol) of benzoyl peroxide and the reaction mixture heated to reflux for 5 hours, cooled to room temperature, passed through a plug of silica gel, washed with CCl4, and evaporated. The crude product was obtained as an orange oil after attempts to purify it by column chromatography, 64% crude yield. The NMR is consistent with the structure.
- 2-(6-Methyl-benzo[1 3]dioxol-5yl)-4hydroxy 1,1-dioxo-1,2-dihydro-1λ6-benzo[e][1,2]thiazine-3-carboxylic acid tert-butyl ester A solution of 4.24 g (9.06 mmol) of the crude brominated product in DMF was treated with 3.13 g (22.6 mmol, 2 eq) of K2CO3 and stirred overnight at room temperature. The solution was diluted with 1N HCl, the ppt'd solid collected, washed with water, and dried. The solid was dissolved in ether, dried over MgSO4, filtered, and evaporated. The impure foam was dried overnight under high vacuum, then treated with Hex/EtOAc 2:1 to afford the product as a white solid, 26% yield.
- MS(CI) m/e: 387 (M+)
- 4-Benzo[3]dioxol-5-yl-2-(6methyl-benzo[1,3]dioxol-5-yl) 1,1-dioxo-1,2-dihydro1 benzo[e][1,2]thiazine-3-carboxylic acid tert-butyl ester
- The triflate was prepared according to procedures described in Example 1D. Then, a solution of 1.14 g (4.39 mmol) of the crude triflate in toluene/DMF (10 mL/3 mL) was treated with 0.55 g (3.29 mmol, 1.5 eq) of boronic acid, 0.45 g (3.29 mmol, 1.5 eq) of K2CO3, and 0.25 g (0.2 mmol, 0.1 eq) of Pd(PPh3)4, and the reaction mixture heated to reflux for 2 hours. Cooled to room temperature, diluted with ethyl acetate, extracted with saturated aqueous NaHCO3, and the organic portion washed with brine, dried over MgSO4, and evaporated. The dark oil was purified on a silica gel column eluted with Hex/EtOAc 2:1, then on a silica gel column eluted with CHCl3. -Drying afforded the product as 0.62 g of white foam; 57% yield.
- MS(APCI) m/e: 492 (M+)
- 4-Benzol-1,3]dioxol-5yl-2-(6-methylbenzol1,3dioxol-5yl)1,1 dioxo-1 2dihydro 1λ6-benzorel [1,2]thiazine-3-carboxylic acid
- A solution of 0.49 g (0.1 mmol) of the above mentioned Example 12L in CH2Cl2 was treated with 1 mL of trifluoroacetic acid and the reaction mixture stirred overnight at room temperature. The volume was concentrated, diluted with ether, washed with water (3×), brine, dried over MgSO4, and evaporated. The foam was dried under high vacuum, dissolved in ether, and extracted with 1N NaOH/H20. The aqueous portions were acidified with 1N HCl, extract with ether, washed with brine, dried over MgSO4, and evaporated. The foam was taken up in CHCl3, evaporated, and dried under high vacuum at 72° C. This process afforded the product as a light yellow foam.
- MS(ES) m/e: 435 (M+)
- 2-(2-Ethyl-phenylsulfamoyl)-benzoic acid methyl ester
- Prepared in the same way as illustrated in Example 1A in 49% yield.
- Analysis calculated for C16H17N1O4S1: %C 60.17; %H 5.37; %N 4.39.
- Found: %C 60.12; %H 5.27; %N 4.32.
- MS(ES) m/e: 319 (M+)
- 2-(2-Ethyl-phenyl)methoxycarbonylmethyl-sulfamoyl]-benzoic acid methyl ester
- Prepared in the same way as illustrated in Example I B in 58% yield. Analysis calculated for C19H21N1O6S1:
- %C, 58.30; %H, 5.41; %N, 3.58.
- Found: %C, 58.27; %H, 5.17; %N, 3.51.
- MS(ES) m/e: 391 (M+)
- 2-(2-Ethylphenyl)-4hydroxy-1,1-dioxo-1,2-dihydro-1λ6-benzo[e][1,2]thiazine-3-carboxylic acid methyl ester
- Prepared in the same way as illustrated in Example 1C in 81% yield. The NMR spectra and elemental analysis were consistent with the structure.
- MS(ES) m/e: 359 (M+)
- 2-(2-Ethylphenyl)-1,1-dioxo-4-(trifluoromethanesulfonyloxy)-1,2dihydro-1λ6-benzo[e][1,2]thiazine-3-carboxylic acid methyl ester Prepared in the same way as illustrated in Example 1D in 98% yield. The NMR spectra is consistent with the structure.
- 4-Benzo[1,3]dioxol-5-yl-2-(2ethyl-phenyl)-1,1-dioxo 1,2-dihydro- 1λ6-benzo[e][1,2]thiazine-3-carboxylic acid methyl ester
- Prepared in the same way as illustrated in Example 1E in 81% yield. Analysis calculated for C25H21N19 O6S1:
- %C, 64.78; %H, 4.57; %N, 3.02.
- Found: %C, 64.6; %H, 4.44; %N, 2.87.
- 4-Benzo [1,3]dioxol-5-yl-2-(2ethyl-phenyl)-1,1-dioxo-1,2-dihydro- 1λ6-benzo[e][1,2]thiazine-3-carboxylic acid
- Prepared in the same way as illustrated in Example 1 in 65% yield. Analysis calculated for C24H19N1O6S1:
- %C, 64.13; %H, 4.26; %N, 3.12.
- Found: %C, 63.45; OH, 4.02; %N, 3.02.
- MS(ES) m/e: 404 (M+-COOH)
- 2-(2Propyl-phenylsulfamoyl)-benzoic acid methyl ester
- Prepared in the same way as illustrated in Example 1A in 71% yield. MS(CI) m/e: 333 (M+)
- 2-[(2Propyl-phenyl)-methoxycarbonylmethyl-sulfamoyl]-benzoic acid methyl ester
- Prepared in the same way as illustrated in Example 1B in 91% yield. Analysis calculated for C19H21N1O6S1: %C, 58.30; %H, 5.41; %N, 3.58.
- Found: %C, 58.27; %H, 5.17; %N, 3.51.
- MS(APCI) m/e: 406 (M++1)
- 2-(2Propylphenyl)-4hydroxy 1,1-dioxo 1,2dihydro-1λ6-benzo-[e][1,2]thiazine 3-carboxylic acid methyl ester
- Prepared in the same way as illustrated in Example 1C in 74% yield. The NMR spectra and elemental analysis were consistent with the structure. MS(APCI) m/e: 374 (M++1)
- 4-Benzo[1,3]dioxol-5-yl-2-(2propylphenyl)-1,1-dioxo 1,2-dihydro 1λ6-benzo[e][1,2]thiazine-3-carboxylic acid methyl ester
- The triflate was prepared in the same way as illustrated in Example 1D and the coupling reaction was run in the same way as illustrated in Example 1E with crude 14D in 72% overall yield. The NMR spectra and elemental analysis were consistent with the structure.
- 4-Benzo[1,3]dioxol-5-yl-2-(2-1,2-pyphenyl)-1,1-dioxo 1,2-dihydro-1λ6-benzo[e][1,2]thiazine-3-carboxylic acid
- Prepared in the same way as illustrated in Example 1 in 96% yield. Analysis calculated for C25H21N1O6S1: %C, 64.78; %H, 4.57; %N, 3.02.
- Found: %C, 64.51; %H, 4.81; %N, 2.89.
- 2-(2Isopropylphenylsulfamoyl)-benzoic acid methyl ester
- Prepared in the same way as illustrated in Example 1A in 76% yield. MS(CI) m/e: 333 (M+)
- 2-[(2Isopropyl-phenyl)methoxycarbonylmethyl-sulfamoyl]benzoic acid methyl ester
- Prepared in the same way as illustrated in Example 1B in 77% yield. MS(APCI) m/e: 406 (M++1)
- 2-(2Isopropylphenyl)-4hydroxy-1,1-dioxo-1,2-dihydro 1 λ6-benzo[e][1,2]thiazine-3-carboxylic acid methyl ester
- Prepared in the same way as illustrated in Example 1C in 65% yield. The NMR spectra and elemental analysis were consistent with the structure.
- MS(APCI) m/e: 373 (M+)
- 4-Benzo[-1,3]dioxol-5-yl-2-(2isopropylphenyl)1,1-dioxo-1,2-dihydro 1λ6-benzo[e][1,2]thiazine-3-carboxylic acid methyl ester
- The triflate was prepared in the same way as illustrated in Example 1D and the coupling reaction was run in the same way as illustrated in Example 1E in 63% overall yield.
- MS(APCI) m/e: 477 (M+)
- 4-Benzo[1,3]dioxol-5-yl-2-(2isopropylphenyl)-1,1-dioxo 1,2-dihydro 1λ6-benzo[e][1,2]thiazine-3-carboxylic acid
- Prepared in the same way as illustrated in Example 1 in 99% yield. Analysis calculated for C25H21N1O6S1: %C, 64.78; %H, 4.57; %N, 3.02.
- Found: %C, 64.73; %H, 4.76; %N, 2.77.
- 2-(2-Butyl-phenylsulfamoyl)-benzoic acid methyl ester Prepared in the same way as illustrated in Example 1A in 44% yield. The NMR spectra and elemental analysis were consistent with the structure.
- 2-[(2-Butyl-phenyl)methoxycarbonylmethyl-sulfamoyl]-benzoic acid methyl ester
- Prepared in the same way as illustrated in Example 1B. The crude product was carried to the next step without purification.
- MS(ES) m/e: 419 (M+−1)
- 2-(2-Butylphenyl)-4hydroxy-1,1-dioxo 1,2-dihydro 1 λ6-benzo[e][1,2]thiazine 3-carboxylic acid methyl ester
- Prepared in the same way as illustrated in Example 1C in 55% overall yield.
- Analysis calculated for C20H21N1O5S1:
- %C, 62.00; %H, 5.46; oN, 3.62.
- Found: %C, 61.78; %H, 5.57; %N, 3.48.
- MS(ES) m/e: 386 (M+1)
- 2-(2-Butylphenyl)-1,1-dioxo-4-(trifluoro-methanesulfonyloxy)-1,2dihydro-1λ6-benzo[e][1,2]thiazine-3-carboxylic acid methyl ester
- Prepared in the same way as illustrated in Example 1D in 88% yield. The NMR spectra is consistent with the structure.
- 4-Benzo[1,3]dioxol-5-yl-2-(2butylphenyl)-11-dioxo-1,2-dihydro-1λ6-benzo[e][1,2]thiazine-3-carboxylic acid methyl ester Prepared in the same way as illustrated in Example 1E in 59% yield.
- Analysis calculated for C27H25N1O6S1:
- %C, 65.92; %H, 5.15; %N, 2.84.
- Found: %C, 65.84; %H, 5.32; %N, 2.70.
- MS(ES) m/e:491 (M+)
- 4-Benzo[1,3]dioxol-5-yl-2-(2butylphenyl)-1,1-dioxo-1,2-dihydro- 1λ6-benzo[e][1,2]thiazine-3-carboxylic acid
- Prepared in the same way as illustrated in Example 1 in 26% yield.
- MS(CI) m/e: 459 (M+−OH)
- The following procedures are illustrated in Scheme 2.
- 2-(2-Bromophenylsulfamoyl)-benzoic acid methyl ester
- Prepared in the same way as illustrated in Example 12A in 79% yield. MS(CI) m/e: 369 (M+)
- 2-(2-Bromo-phenyl)-1,1-dioxo-1,2-dihydro-1λ6-benzo[d]isothiazol-3-one
- Prepared in the same way as illustrated in Example 12A in 56% yield. MS(CI) m/e: 338 (M+)
- 3-[2-(2-Bromo-phenylsulfamoyl)phenyl-3-oxo-propionic acid tert-butyl ester
- Prepared in the same way as illustrated in Example 12H in quantitative yield and was carried to the next step without purification.
- 2-Bromo3-[2-(2bromo-phenylsulfamoyl)phenyl]3-oxo-propionic acid tert-butyl ester
- Prepared in the same way as illustrated in Example 12J in quantitative yield and was carried to the next step without purification.
- 2-(2-Bromo-phenyl)-4hydroxy-1,1-dioxo 1,2dihydro 1λ6-benzo[e][1,2]thiazine-3-carboxylic acid tertbutyl ester
- Prepared in the same way as illustrated in Example 12K in 68% yield. MS(CI) m/e: 451 (M+)
- 4-Benzo[e][1,3]dioxol-5yl-2-(2bromophenyl)-1,1-dioxo 1,2-dihydro 1λ6-benzo[e][1,2]thiazine-3-carboxylic acid tert-butyl ester
- The triflate was prepared according to procedures described in Example 1D. The coupling reaction was carried out in the same way as illustrated in Example 12L in 57% yield.
- MS(APCI) m/e: 556 (M+)
- 4-Benzo[1,3]dioxol-5yl-2-(2bromophenyl)-1,1-dioxo-1,2-dihydro- 1λ6-benzo[e][1,2]thiazine-3-carboxylic acid
- Prepared in the same way as illustrated in Example 12 as a yellow foam. Analysis calculated for C22H14Br1N1O6S1: %C, 52.81; %H, 2.82; %N, 2.80.
- Found: %C, 52.69; %H, 2.68; %N, 2.55.
- 2-(2-Chloro-phenylsulfamoyl)-benzoic acid methyl ester
- Prepared in the same way as illustrated in Example 12A in 92% yield. MS(CI) m/e: 325 (M+)
- 2-(2-Chloro-phenyl)-1,1-dioxo 1,2dihydro-1λ6-benzo[d]isothiazol-3one
- Prepared in the same way as illustrated in Example 12H in 52% yield. MS(CI) m/e: 294 (M+)
- 3-[2-(2-Chloro-phenylsulfamoyl)phenol]-3oxo-propionic acid tert-butyl ester
- Prepared in the same way as illustrated in Example 12I in quantitative yield and was carried to the next step without purification. MS(CI) m/e: 354 (M+−t−Bu)
- 2-Bromo-3-[2-(2-chlorophenylsulfamoyl)phenyl]3oxo-propionic acid tert-butyl ester
- Prepared in the same way as illustrated in Example 12J in quantitative yield and was carried to the next step without purification. MS(CI) m/e: 352 (M+−t−Bu−Br)
- 2-(2-Chloro-phenyl)-4hydroxy-1,1-dioxo-1,2dihydro-1λ6-benzo[e][1,2]thiazine-3-carboxylic acid tert-butyl ester
- Prepared in the same way as illustrated in Example 12K in 57% yield. MS(CI) m/e: 407 (M+).
- 4-Benzo[1,3]dioxol-5-yl-2-(2-chlorophenyl)-1,1-dioxo-1,2-dihydro-1λ6 benzo[e][1,2]thiazine-3-carboxylic acid tert-butyl ester
- The triflate was prepared according to procedures described in Example 1D. The coupling reaction was carried out in the same way as illustrated in Example 12L in 68% yield. MS(APCI) m/e: 512 (M+)
- 4-Benzo [1,3]dioxol-5yl-2-(2-chlorophenyl)-1,1-dioxo-1,2-dihydro-1λ6-benzo[e][1,2]thiazine-3-carboxylic acid
- Prepared in the same way as illustrated in Example 12 in 71% yield. MS(ES) m/e: 456 (M+)
- 2-(2Fluoro-phenylsulfamoyl)-benzoic acid methyl ester
- Prepared in the same way as illustrated in Example 1A in 82% yield. MS(CI) m/e: 309 (M+)
- 2-[(2Fluoro-phenyl)methoxycarbonylmethyl-sulfamoyl]-benzoic acid methyl ester
- Prepared in the same way as illustrated in Example 1B in 93% yield. MS(APCI) m/e: 382 (M+)
- 2-(2Fluoro-phenyl)-4hydroxy-1,1-dioxo-1,2-dihydro-1λ6-benzo[e][1,2]thiazine-3-carboxylic acid methyl ester
- Prepared in the same way as illustrated in Example 1C in 33% yield. MS(APCI) m/e: 350 (M+)
- 2-(2Fluoro-phenyl)-1,1-dioxo-4-(trifluoromethanesulfonyloxy)-1,2dihydro-1λ6-benzo[e][1,2]thiazine-3-carboxylic acid methyl ester
- Prepared in the same way as illustrated in Example 1D in 84% yield. The NMR spectra is consistent with the structure.
- 4-Benzo[1,3]dioxol-5-yl-2-(2-fluorophenyl)-1,1-dioxo-1,2-dihydro-1λ6-benzo[e]][1,2-thiazine-3-carboxylic acid methyl ester
- Prepared in the same way as illustrated in Example 1E in 91% yield. MS(CI) m/e: 453 (M+)
- 4-Benzo-[1,3]dioxol-5-yl-2-(2-fluoro henyl)-1,1-dioxo-1,2dihydro-1λ6-benzo[e]rl[2]thiazine-3-carboxylic acid
- Prepared in the same way as illustrated in Example 1 in 23% yield. MS(CI) m/e: 439 (M+)
- 2-(2-Benzyloxy-phenylsulfamoyl)-benzoic acid methyl ester
- Prepared in the same way as illustrated in Example 1A in 95% yield. The NMR spectra and elemental analysis were consistent with the structure.
- 2-[(2-Benzyloxyphenyl)-methoxycarbonylmethyl-sulfamoyl]-benzoic acid methyl ester
- Prepared in the same way as illustrated in Example 1B in 89% yield. The NMR spectra and elemental analysis were consistent with the structure.
- 2-(2-Benzyloxyphenyl)-4hydroxy-1,1-dioxo-1,2-dihydro-1λ6benzo[e][1,2]thiazine-3-carboxylic acid methyl ester
- Prepared in the same way as illustrated in Example 1C in 89% yield. The NMR spectra and elemental analysis were consistent with the structure.
- 2-(2-Benzyloxylphenyl)-1,1-dioxo-4-(trifluoromethanesulfonyloxy)-1,2dihydro-1λ6-benzo[e][1,2]thiazine-3-carboxylic acid methyl ester
- Prepared in the same way as illustrated in Example 1D in 97% yield. The NMR spectra and elemental analysis were consistent with the structure.
- 4-Benzo[1,3]dioxol-5-yl-2-(2-hydroxyphenyl)-1,1-dioxo-1,2dihydro-1λ6-benzo[e][1,2]thiazine-3-carboxylic acid methyl ester
- The coupling reaction was carried out with 20-D and the corresponding boronic acid in the same way as illustrated in Example lE in 80% yield. The product was dissolved in DMF and was treated with 20% Pd/C under 50 atm pressure for 2 days to obtain 20E in 20% yield and recovery of the rest as the starting material. The NMR spectra and elemental analysis were consistent with the structure.
- 4-Benzo-1,3]dioxol-5yl-2-(2-hydroxyphenyl)-1,1-dioxo-1,2dihydro-1λ6-benzo[e][1,2]thiazine-3-carboxylic acid
- Prepared in the same way as illustrated in Example 1 in 99% yield. The NMR spectra and elemental analysis were consistent with the structure. MS: m/z 471 (M+)
- 2-(2,3-Dichlorophenylsulfamoyl)-benzoic acid methyl ester
- Prepared in the same way as illustrated in Example 1A in 80% yield. The NMR spectra is consistent with the structure.
- 2-[(2,3-Dichloro-2phenyl)methoxycarbonylmethyl-sulfamoyl]-benzoic acid methyl ester
- Prepared in the same way as illustrated in Example 1B in 52% yield. The NMR spectra is consistent with the structure.
- 2-(2,3-Dichloro2phenyl)-4hydroxy-1,1-dioxo-1,2dihydro-1λ6-benzo[e][1,2]thiazine-3-carboxylic acid methyl ester
- Prepared in the same way as illustrated in Example 1C in 59% yield. The NMR spectra is consistent with the structure.
- 2-(2,3-Dichlorophenyl)-1,1-dioxo-4-(trifluoromethanesulfonyloxy)-1,2-dihydro 1λ6-benzo[e][1,2]thiazine-3 carboxylic acid methyl ester Prepared in the same way as illustrated in Example 1D in 100% yield. The NMR spectra is consistent with the structure.
- 4-Benzo[1,3]dioxol-5-yl-2-(2,3-dichlorophenyl)-1,1-dioxo-1,2dihydro1λ6-benzo[e][1,2]-thiazine-3-carboxylic acid methyl ester
- Prepared in the same way as illustrated in Example 1E in 65% yield. The NMR spectra is consistent with the structure.
- 4-Benzo-[1,3]dioxol-5-yl-2-(2,3-dichlorophenyl)1,1-dioxo-1,2dihydro1λ6-benzo [e][1,2]thiazine-3-carboxylic acid
- Prepared in the same way as illustrated in Example 1 in 100% yield. MS: m/z 489 (M+)
- 2-(2.4-Dichlorophenylsulfamoyl)-benzoic acid methyl ester Prepared in the same way as illustrated in Example 1A in 55% yield. Analysis calculated for C14H11Cl2N1O4S1: %C, 46.48; %H, 3.08; %N, 3.89.
- Found: %C, 46.65; %H, 2.85; %N, 3.87.
- 2-[(2,4-Dichlorophenyl)methoxycarbonylmethyl-sulfamoyl]-benzoic acid methyl ester
- Prepared in the same way as illustrated in Example 1B in 51% yield. MS(APCI) m/e: 431 (M+)
- 2-(2,4-Dichlorophenyl)-4hydroxy-1,1-dioxo-1,2dihydro-1λ6-benzo[e][1,2 thiazine-3-carboxylic acid methyl ester
- Prepared in the same way as illustrated in Example 1 C in 75% yield. Analysis calculated for C16H17Cl2N1O5S1: %C, 48.02; %H, 2.77; %N, 3.50.
- Found: %C, 47.92; %H, 2.62; %N, 3.43.
- 2-(2,4-Dichlorophenyl)-1,1-dioxo-4-(trifluoromethanesulfonyloxy)-1,2-dihydro 1λ6-benzo [e][1,1,2]thiazine-3-carboxylic acid methyl ester
- Prepared in the same way as illustrated in Example 1D in 83% yield. The NMR spectra is consistent with the structure.
- 4-Benzo-[1,3]-dioxol-5-yl-2-(2,4dichlorophenyl)-1-dioxo-1,2-dihydrol-1λ6-benzo[e][1,2]thiazine-3-carboxylic acid methyl ester
- Prepared in the same way as illustrated in Example 1E in 68% yield.
- Analysis calculated for C23H15C12N1O6S1: %C, 54.99; %H, 2.96; %N, 2.79.
- Found: %C, 54.99; %H, 3.22%N, 2.60.
- MS(CI) m/e: 502 (M+)
- 4-Benzo-1,3]-dioxol-5-yl-2-(2,4dichlorophenyl)-1,1-dioxo-1,2-dihydro-1λ6 benzo[e][1,2]thiazine-3-carboxylic acid
- Prepared in the same way as illustrated in Example 1 in 89% yield. Analysis calculated for C22H13Cl2N1O6S1: %C, 53.89; %H, 2.67; %N, 2.86.
- Found: %C, 53.25; %H, 2.96; %N, 2.68.
- MS: m/z 489 (M+)
- 2-(2-Chloro-4-methoxyphenylsulfamoyl)-benzoic acid methyl ester
- Prepared in the same way as illustrated in Example 1A in 53% yield. MS(CI) m/e: 355 (M+)
- 2-[(2-Chloro-4-methoxyphenol)methoxycarbonylmethyl-sulfamoyl]-benzoic acid methyl ester
- Prepared in the same way as illustrated in Example 1B in 96% yield. MS(CI) m/e: 428 (M+)
- 2-(2-Chloro-4-methoxyphenyl)-4hydroxy-1,1-dioxo-1,2dihydro-1λ6-benzo[e][1,2]thiazine-3-carboxylic acid methyl ester
- Prepared in the same way as illustrated in Example I C in 73% yield. MS(CI) m/e: 395 (M+)
- 2-(2-Chloro-4-methoxyphenyl)-1,1-dioxo-4-(trifluoro-methanesulfonyloxy)-1,2dihydro-1λ6-benzo[e][1,2]thiazine-3-carboxylic acid methyl ester
- Prepared in the same way as illustrated in Example 1D in 99% yield. The NMR spectra is consistent with the structure.
- 4-Benzo[1,3]dioxol-5yl-2-(2-chloro4-methoxyphenyl)-1,1-dioxo-1,2-dihydro-1λ6-benzo [e][1,2]thiazine-3-carboxylic acid methyl ester
- Prepared in the same way as illustrated in Example 1 E in 94% yield. MS(CI) m/e: 499 (M+)
- 4-Benzo[1,3]dioxol-5-yl-2-(2-chloro-4-methoxyphenyl)-1,1-dioxo-1,2-dihydro-1λ6-benzo[e][1,2]thiazine-3-carboxylic acid Prepared in the same way as illustrated in Example 1 in 97% yield. MS(CI): m/z 486 (M+)
- 2-(3Chloro-2methyl-phenylsulfamoyl)-benzoic acid methyl ester
- Prepared in the same way as illustrated in Example 1A in 66% yield. Analysis calculated for C15H14Cl1N1O4S1: %C, 53.02; %H, 4.15; %N, 4.12.
- Found: %C, 52.80; %H, 3.91; %N, 4.07.
- 2-[(3Chloro-2-methyl-phenyl)methoxycarbonylmethyl-sulfamoyl]-benzoic acid methyl ester
- Prepared in the same way as illustrated in Example 1B in 76% yield. Analysis calculated for C18H16Cl1N1O6S1: %C, 52.49; %H, 4.41; %N, 3.40.
- Found: %C, 52.49; %H, 4.41; %N, 3.29.
- 2-(3Chloro-2methyl-phenyl)-4hydroxy-1,1-dioxo-1,2-dihydro-1λ6-benzo[e][l.21thiazine-3-carboxylic acid methyl ester
- Prepared in the same way as illustrated in Example 1C in 86% yield. Analysis calculated for C17H14Cl2N1O5S1: %C, 53.13; %H, 3.72; %N, 3.69.
- Found: %C, 52.85; %H, 3.65; %N, 3.59.
- 2-(3Chloro-2methyl-phenyl)-1,1-dioxo-4-(trifluoro-methanesulfonyloxy)-1,2-dihydro1λ6-benzo[e][1,2thiazine-3-carboxylic acid methyl ester
- Prepared in the same way as illustrated in Example 1D in 91 % yield. The NMR spectra is consistent with the structure.
- 4-Benzo[1,3]dioxol-5-yl-2-(3chloro-2-methyl-phenyl)1,1-dioxo-1,2-dihydro-1λ6-benzo [e][1,2]thiazine-3-carboxylic acid methyl ester
- Prepared in the same way as illustrated in Example 1E in 95% yield.
- MS(CI) m:e: 483 (M+)
- 4-Benzo[1,3]dioxol-5-yl-2-(3chloro-2-methyl-phenyl)-1,1-dioxo-1,1,2-dihydro-1λ6-benzo[e]1,2]thiazine-3-carboxylic acid
- Prepared in the same way as illustrated in Example 1 in 45% yield. Analysis calculated for C23H16Cl1N1O6S1: %C, 59.59; %/H, 4.29; %/N, 2.58.
- Found: %C, 59.69; %H, 4.75; %/N, 2.52.
- MS: m/z 469 (M+)
- 2-(6-Chlorobenzo-[1,3]dioxol-5-ylsulfamoyl)-benzoic acid methyl ester
- Prepared in the same way as illustrated in Example 12F in 84% yield. MS(CI) m/e: 370 (M+)
- 2-(6-Chlorobenzo-[1,3]dioxol-5-yl)1,1dioxo-1,2-dihydro-1λ6-benzo[d]isothiazol-3one
- Prepared in the same way as illustrated in Example 12H in 66% yield. MS(CI) m/e: 338 (M+)
- 3-[2-(6-Chlorobenzo-[1,3dioxol-5-ylsulfamoyl)phenyl]3-oxo-propionic acid tert-butyl ester
- Prepared in the same way as illustrated in Example 12I in 57% yield and was carried to the next step without purification.
- MS(CI) m/e: 453 (M+)
- 2-Bromo-3-[2-(6-chloro-benzo-[1,3]dioxol-5-ylsulfamoyl)-phenyl]-3-oxo-propionic acid tert-butyl ester
- Prepared in the same way as illustrated in Example 12J in 47% yield.
- Prepared in the same way as illustrated in Example 12K in 82% yield.
- MS(CI) m/e: 451 (M+)
- 4-Benzo[1,3]dioxol-5-yl-2-(6-chloro-benzo[1,3]dioxol-5-yl)-1,1-dioxo-1,2dihydro-1λ6-benzo[e][1,2]thiazine-3-carboxylic acid tertbutI ester
- The triflate was prepared according to procedures described in Example 1D. The coupling reaction was carried out in the same way as illustrated in Example 12L in 63% yield.
- MS(APCI) m/e: 556 (M+)
- 4-Benzof1,3]dioxol-5-yl-2-6-Chlorobenzo[1,3]dioxol-5-yl)-1,1-dioxo-1,2-dihydro-1λ6-benzo-[1,2]thiazine-3-carboxylic acid
- Prepared in the same way as illustrated in Example 12 in 71% yield. MS(ES) m/e: 500 (M+)
- 2-(2.6-Dimethyl-phenylsulfamoyl)-benzoic acid methyl ester
- Prepared in the same way as illustrated in Example 1A in 80% yield. Analysis calculated for C16H17N1O4S1: %C, 60.17; %H, 5.37; %N, 4.39.
- Found: %C, 59.91, %H, 5.32, %N, 4.33.
- 2-(2,6-Dimethyl-phenyl)methoxycarbonylmethyl-sulfamoyl]-benzoic acid methyl ester
- Prepared in the same way as illustrated in Example 1B in 85% yield. MS(CI) m/e: 392 (M++1)
- 2-(2,6-Dimethyl-phenyl)-4hydroxy-1,1-dioxo-12dihydro-1λ6-benzo[e][1,2]thiazine-3-carboxylic acid methyl ester
- Prepared in the same way as illustrated in Example 1C in 56% yield. MS(CI) m/e: 360 (M+)
- 4-Benzo [1,3]dioxol-5-yl-2-(2.6dimethyl-phenyl)-1,1-dioxo-1,2dihydro-1λ6-benzo[e][1,2]thiazine-3-carboxylic acid methyl ester
- The triflate was prepared in the same way as illustrated in Example 1D, and the coupling reaction was carried out in the same way as illustrated in Example 1E in 64% overall yield.
- MS(CI) m/e: 463 (M+)
- 4-Benzo[1,3]dioxol-5-yl-2-(2,6dimethyl-phenyl)-1,1-dioxo-1,2dihydro-1λ6-benzo[e][1,2]thiazine-3-carboxylic acid
- Prepared in the same way as illustrated in Example 1 in 100% yield. MS(CI): m/z 448 (M+1)
- 2-(2Pyrrol-1-yl-phenylsulfamoyl)-benzoic acid methyl ester
- Prepared in the same way as illustrated in Example lA in 74% yield. Analysis calculated for CI8HI6N204S1: %C, 60.66; %H, 4.53; %N, 7.86.
- Found: %C, 60.63; %H, 4.40; %N, 7.77.
- MS(CI) m/e: 356 (M+)
- 2-[Methoxycarbonylmethyl-(2-pyrrol-1-yl-phenyl)sulfamoyl]-benzoic acid methyl ester
- Prepared in the same way as illustrated in Example 1B in 70% yield. MS(CI) m/e: 365 (M+)
- 4Hydroxy 1,1-dioxo-2-(2-pyrrol-1-ylphenyl)-1,2dihydro-1λ6-benzo[e][1,2]thiazine-3-carboxylic acid methyl ester
- Prepared in the same way as illustrated in Example 1C in 77% yield. MS(CI) m/e: 496 (M+)
- 1,1-Dioxo2-(2pyrrol 1 -ylphenyl)-4-(trifluoro-methanesulfonyloxy) 1,1,2-dihydro-1λ6-benzo[e][1,2]thiazine-3-carboxylic acid methyl ester
- Prepared in the same way as illustrated in Example 1D in 93% yield. The NMR spectra is consistent with the structure.
- 4-Benzo[1,3]dioxol-5-yl-1,1-dioxo-2-(2pyrrol-1-ylphenyl)-1,2-dihydro-1λ6-benzo[e][1,2]thiazine-3-carboxylic acid methyl ester
- Prepared in the same way as illustrated in Example 1E in 80% yield. MS(CI) m/e: 500 (M+)
- 4-Benzo[1,3]dioxol-5-yl-1,1-dioxo-2-(2-2-pyrrol-1-ylphenyl)-1,2-dihydro-1λ6-benzo[e][12]thiazine-3-carboxylic acid
- Prepared in the same way as illustrated in Example 1 in 60% yield. MS: m/z 486 (M+)
- 2-(3,4-Dimethyl-isoxazol-5-ylsulfamoyl)-benzoic acid methyl ester
- Prepared in the same way as illustrated in Example 1A in 29% yield. The NMR spectra and elemental analysis were consistent with the structure.
- 2-[(3,4-Dimethylisoxazol5-yl)methoxycarbonylmethyl-sulfamoyl]-benzoic acid methyl ester
- Prepared in the same way as illustrated in Example 1B in 46% yield. The NMR spectra and elemental analysis were consistent with the structure.
- 2-(3 4-Dimethylisoxazol-5-yl)-4hydroxy-1,1-dioxo-1,2-dihydro-1λ6-benzo[e][1,2]thiazine-3-carboxylic acid methyl ester
- Prepared in the same way as illustrated in Example 1C in 76% yield. The NMR spectra and elemental analysis were consistent with the structure.
- 2-(3,4-Dimethylisoxazol5-yl)-1,1-dioxo-4-(trifluoro-methanesulfonyloxy)-1,2-dihydro-1λ6-benzo[e][1 .21thiazine-3-carboxylic acid methyl ester
- Prepared in the same way as illustrated in Example 1D in 99% yield. The NMR spectra is consistent with the structure.
- 4-Benzo[e][1,3]dioxol-5-yl-2-(3,4dimethylisoxazol5-yl)-1,1-dioxo-1,2dihydro-1λ6-benzo[e][1,2]thiazine-3-carboxylic acid methyl ester
- Prepared in the same way as illustrated in Example 1E in 41% yield. The NMR spectra is consistent with the structure.
- 4-Benzo [1,3]dioxol-5-yl-2-(3,4dimethylisoxazol5-yl)-1,1-dioxo-1,2-dihydro 1λ6-benzo [e][1,2-thiazine-3-carboxylic acid
- Prepared in the same way as illustrated in Example 1 in 93% yield. Analysis calculated for C21H16N2O7S1(H2O)0.81: %C, 56.46; %H, 4.22; %N, 5.73; %S, 6.55.
- Found: %C, 56.49; %H, 4.22; %N, 5.73; %S, 6.55.
- 4-Benzo[1,3]dioxol-5-yl-2-(2benzylphenyl)-1,1-dioxo-1,2dihydro-1λ6-benzo[e][1,2]thiazine-3-carboxylic acid methyl ester
- Prepared in the same way as illustrated in Example 9E in 52% yield. The NMR spectra and elemental analysis were consistent with the structure.
- 4-Benzo[1,3]dioxol-5-yl-2-(2benzylphenyl)-1,1-dioxo-1,2-dihydro-1λ6-benzo[e][1,2]thiazine-3-carboxylic acid
- Prepared in the same way as illustrated in Example 1 in 79% yield. The NMR spectra and elemental analysis were consistent with the structure. Analysis calculated for C29H21N1O6S1-(H2O)2.5: C, 60.20;H, 4.35; N, 2.30;
- Found: C, 59.87;H, 4.25; N, 2.42.
- 4-(6-Methoxy-benzo[1,3dioxol-5-yl)-1,1-dioxo-2-(2-trifluoro-methyl-phenyl) 1,2dihydro-1λ6-benzo[e][1,2]thiazine-3-carboxylic acid methyl ester
- 5-Methoxy 1,3-benzodioxol-6-ylboronic acid was prepared in the same way as illustrated in Example 4E in 91% yield. The coupling reaction was carried out in the same way as illustrated in Example 1E in 94% yield. MS(CI) m/e: 533 (M+)
- 4-(6-Methoxybenzo[1,3]dioxol-5-yl)-1,1-dioxo-2-(2-trifluoro-methyl-phenyl)-1,2-dihydro-1λ6-benzo[e]r [1,2]thiazine-3-carboxylic acid
- Prepared in the same way as illustrated in Example 1 in 83% yield. MS(CI) m/e: 501 (M+H2O)
- 4-(3,5-Dimethyl-phenyl)2-(2-trifluoro-methyl-phenyl)-1,1-dioxo-1,2dihydro-1λ6-benzo[e][2,2]thiazine-3-carboxylic acid methyl ester The coupling reaction was carried out in the same way as illustrated in Example 1 E in 46% yield. The NMR spectra is consistent with the structure.
- 4-(3,5-Dimethyl-phenyl)-2-(2-trifluoro-methyl-phenyl)-1,1-dioxo-1,2dihydro-1λ6-benzo[e][1,2]thiazine-3-carboxylic acid
- Prepared in the same way as illustrated in Example 1 in 96% yield. The NMR spectra is consistent with the structure.
Claims (40)
1. A process for the preparation of a compound of Formula 1
or a pharmaceutically acceptable salt thereof wherein
R1 is hydrogen, alkyl, or alkoxy;
R2 is hydrogen or alkoxy;
R3 is alkyl or alkoxy;
R2 and R3 may be joined to form a ring
R4 is hydrogen or alkyl;
R5 is hydrogen, alkyl, alkoxy, halogen at the 2 or 3, or 4, or 5 positions or R5 is a 3,4-methylenedioxo; and
R6 is CF3, halogen, alkyl, benzyl, phenyl, hydroxy, or pyrrole comprising:
a) alkylating a compound of formula A
with sodium hydride in DMF followed by reaction with methyl bromoacetate to produce a compound of formula B
b) combining compound B in THF with a solution of TiCl4 in solvent at −78° C. and treating with triethylamine and quenching with an acid to produce a compound of formula C
c) treating compound C with triflic anhydride in a solvent in the presence of pyridine for from 1 to 5 hours to produce a compound of formula
d) coupling the compound D with a boronic acid of formula X
in DMF and toluene in the presence of a palladium catalyst and potassium carbonate under reflux to produce a compound of Formula 1.
2. A process according to wherein in Step b) compound B is treated with TiCl2 -(OTf)2 and triethylamine, and acidic aqueous workup.
claim 1
3. A process for the preparation of a compound of Formula 1
4. A process according to claims 1 and 4 wherein the methyl ester of Formula 1 is sponified with an alkaline solution to form the corresponding acid.
5. A process according to wherein the compound of Formula I produced is:
claim 1
4-(3,5-Dimethoxyphenyl)2-(2-trifluoro-methyl-phenyl)-1,1-dioxo-1,2-dihydro-1 ,6-benzo[e][1,2]thiazine-3-carboxylic acid;
(2-Chloro-phenyl)4-(3,5-dimethoxy-phenyl)-1,1-dioxo-1,2-dihydro-1λ6-benzo[e][1,2]thiazine-3-carboxylic acid;
(2-Bromo-phenyl)4-(3,5-dimethoxy-phenyl)-1,1-dioxo-1,2-dihydro-1λ6-benzo[e][1,2]thiazine-3-carboxylic acid;
(2-Chloro-phenyl)4-(7-methoxy-benzo[1,3]dioxol-5-yl) 1,1-dioxo-1,2-dihydro-1λ6-benzo[e][1,2]thiazine-3-carboxylic acid;
(2-Benzylphenyl)4-(7-methoxy-benzo[1,3]dioxol-5-yl)-1,1-dioxo-1,2-dihydro-1λ6-benzo[e][1,2]thiazine-3-carboxylic acid;
(2,6-Dimethyl-phenyl)4-(7-methoxy-benzo[1,3]dioxol-5-yl)-1,1-dioxo-1,2-dihydro-1λ6-benzo[e][1,2]thiazine-3 carboxylic acid monosodium salt;
(7-Methoxybenzo[1,3]dioxol-5-yl)-1,1-dioxo-2-(2-trifluoro-methyl-phenyl)-1,2-dihydro-1 λ6-benzo[e][1,2]thiazine-3-carboxylic acid;
4-Benzo[1,3]dioxol-5-yl 1,1-dioxo-2-(2-trifluoro-methyl-phenyl)-1,2-dihydro-1λ6-benzo [e][1,2]thiazine-3-carboxylic acid;
4-Benzo[1,3]dioxol-5-yl-2-(2ethyl-phenyl)-1,1-dioxo-1,2-dihydro-1λ6-benzo [e][1,2]thiazine-3-carboxylic acid;
4-Benzo[1,3]dioxol-5-yl-2-(2propylphenyl)-1,1-dioxo-1,2-dihydro-1λ6-benzo[e][1,2]thiazine-3-carboxylic acid;
4-Benzo[1,3]dioxol-5-yl-2-(2isopropylphenyl)-1,1-dioxo-1,2-dihydro-1λ6-benzo[e][1,2]thiazine-3-carboxylic acid;
4-Benzo[1,3]dioxol-5-yl-2-(2butylphenyl)I ,1-dioxo-1,2-dihydro-1λ6-benzo[e][1,2]thiazine-3-carboxylic acid;
4-Benzo[1,3]dioxol-5-yl-2-(2-fluorophenyl)1,1-dioxo-1,2-dihydro1λ6-benzo[e][1,2]thiazine-3-carboxylic acid;
4-Benzo[1,3]dioxol-5-yl-2-(2-hydroxyphenyl)-1,1-dioxo-1,2-dihydro-1λ6-benzo[e][1,2]thiazine-3-carboxylic acid;
4-Benzo[1,3]dioxol-5-yl-2-(2,3-dichlorophenyl)1, 1dioxo-1,2-dihydro-1λ6-benzo[e][1,2]thiazine-3-carboxylic acid;
4-Benzo[1,3]dioxol-5-yl-2-(2,4dichlorophenyl)-1,1-dioxo-1,2-dihydro-1λ6-benzo[e][1,2]thiazine-3-carboxylic acid;
4-Benzo[1,3]dioxol-5-yl-2-(2-chloro-4-methoxyphenyl)-1,1-dioxo-1,2-dihydro-1λ6-benzo[e][1,2]thiazine-3-carboxylic acid;
4-Benzo[1,3]dioxol-5-yl-2-(3chloro-2methyl-phenyl)-1,1-dioxo-1,2-dihydro-1λ6-benzo[e][1,2]thiazine-3-carboxylic acid;
4-Benzo[1,3]dioxol-5-yl-2-(2,6dimethyl-phenyl)1,1-dioxo-1,2-dihydro-1λ6-benzo[e][1,2]thiazine-3-carboxylic acid;
4-Benzo [1,3]dioxol-5-yl 1,1-dioxo-2-(2pyrrol-1-yl-phenyl)-1,2-dihydro-1λ6-benzo[e][1,2]thiazine-3-carboxylic acid;
4-Benzo[1,3 ]dioxol-5-yl-2-(3 ,4dimethylisoxazol5-yl)-1,1-dioxo-1,2-dihydro-1λ6-benzo[e][1,2]thiazine-3-carboxylic acid;
(6-Methoxybenzo[1,3]dioxol-5-yl)-1,1-dioxo-2-(2-trifluoro-methyl-phenyl)-1,2-dihydro-1λ6-benzo[e][1,2]thiazine 3-carboxylic acid; and
(3,5-Dimethyl-phenyl)2-(2-trifluoro-methyl-phenyl)-1,1-dioxo-1,2-dihydro-1λ6-benzo[e][1,2]thiazine-3-carboxylic acid.
6. A process for the preparation of a compound of formula B
comprising
a) reacting a phenyl sulfonyl chloride with 1 equivalent of aniline to produce a sulfonamide of formula F
b) lithiating the product of step a) above at low temperatures and quenching with CO2 to form a compound of formula G
c) treating the product of step b) above with acetic anhydride and a catalytic amount of methanesulfonic acid to produce a compound of formula H
d) treating the product of step c) above with NaOMe followed by methyl bromoacetate to produce a compound B as above.
7. A process according to wherein the compound produced is selected from:
claim 4
2-(2-Bromo-phenyl)4-(7-methoxy-benzo[1,3]dioxol-5-yl)-1,1-dioxo-1,2-dihydro-1 )6-benzo[e][1,2]thiazine-3-carboxylic acid, sodium salt;
(7Ethylbenzo[1,3]dioxol-5-yl)-1,1-dioxo-2-(2-trifluoro-methyl-phenyl)-1,2-dihydro-1λ6-benzo[e][1,2]thiazine-3-carboxylic acid, potassium salt; and
4-Benzo[1,3]dioxol-5-yl-2-(2benzylphenyl)1,1-dioxo-1,2-dihydro-1 )6-benzo[e][1,2]thiazine-3-carboxylic acid.
8. A process for the preparation of a compound of Formula 1 as above which comprises
a) refluxing
with one equivalent of pyridine and DMAP to produce cyclic
intermediate of formula
b) treating the product of Step a) above with potassium hexamethyldisilylazide followed by t-butyl acetate in THF to produce the keto ester of formula I
c) brominating the product from Step b) above to produce an intermediate of formula J
d) cyclizing the product of Step c) above using potassium carbonate in DMF to produce enol of formula K
9. A compound according to wherein the product produced is:
claim 9
(6-Methyl-benzo[1,3]dioxol-5-yl)-4hydroxy-1,1-dioxo-1,2-dihydro-1λ6-benzo[e][1,2]thiazine-3 carboxylic acid tert-butyl ester;
(2-Bromo-phenyl)-4hydroxy-1,1-dioxo-1,2-dihydro-1λ6-benzo[e][1,2]thiazine-3-carboxylic acid tert-butyl ester;
(2-Chloro-phenyl)-4hydroxy-1,1-dioxo-1,2-dihydro-1λ6-benzo[e][1,2]thiazine-3-carboxylic acid tert-butyl ester; and
(6-Chlorobenzo[1,3]dioxol-5-yl)-4hydroxy-1,1-dioxo-1,2-dihydro-1λ6-benzo[e]1,2]thiazine-3 carboxylic acid tert-butyl ester.
10. A process for the preparation of a compound of Formula 1 as above which comprises:
a) reacting 2-methylanaline with benzenesulfonyl chloride to produce a compound of formula F
b) treating the product of step a) above with n-butyl lithium and then with a solution of 3-methoxy-4,5methylenedioxybenzaldehyde to produce a compound of formula M
c) treating the product of step b) above with sodium hydride followed by methyl bromoacetate to produce a compound of formula N
d) oxidizing the product of step c) above to produce the corresponding keto ester of formula O
e) cyclizing the product of step d) above by treating with a base or a Lewis acid in an appropriate solvent to produce the corresponding ester of Formula 1
f) sponifying the esters in alkaline solutions produce the corresponding free acid.
11. A process according to ,1 wherein the compound produced is 4-(7-Methoxybenzo[1,3]dioxol-5-yl)-1,1-dioxo-2-o-tolyl 1,2-dihydro-1λ6-benzo[e][1,2]thiazine-3-carboxylic acid methyl ester.
claim 1
12. A compound named 4-(7Ethylbenzo[1,3]dioxol-5-yl)1,1dioxo-2-(2-trifluoro-methyl-phenyl)-1,2-dihydro-1λ6-benzo[e][1,2]thiazine-3-carboxylic acid methyl ester sodium salt.
13. A compound named 4-(7Ethylbenzo[1,3]dioxol-5-yl)-1,1-dioxo-2-(2-trifluoro-methyl-phenyl)-1,2-dihydro 1λ6-benzo[e][1,2]thiazine-3-carboxylic acid methyl ester potassium salt.
14. A compound named 5bromo-2,3-dihydroxyethylbenzene or a compound named 1-(6bromo-4ethylbenzo[1,3]dioxole.
15. A pharmaceutical composition comprising a therapeutically effective amount of a compound of Formula I in admixture with a pharmaceutically acceptable carrier.
16. A method of inhibiting elevated levels of endothelin comprising administering to a host in need thereof a therapeutically effective amount of a compound of Formula 1 in unit dosage form.
17. A method of treating subarachnoid hemorrhage comprising administering to a host suffering therefrom a therapeutically effective amount of a compound of Formula 1 in unit dosage form.
18. A method of treating essential, renovascular, malignant and pulmonary hypertension comprising administering to a host suffering therefrom a therapeutically effective amount of a compound of Formula 1 in unit dosage form.
19. A method of treating congestive heart failure comprising administering to a host suffering therefrom a therapeutically effective amount of a compound of Formula 1 in unit dosage form.
20. A method of treating cerebral ischemia or cerebral infarction comprising administering to a host suffering therefrom a therapeutically effective amount of a compound of Formula 1 in unit dosage form.
21. A method of treating acute and chronic renal failure comprising administering to a host suffering therefrom a therapeutically effective amount of a compound of Formula 1 in unit dosage form.
22. A method of treating cerebral vasospasm comprising administering to a host suffering therefrom a therapeutically effective amount of a compound of Formula 1 in unit dosage form.
23. A method of treating cirrhosis comprising administering to a host suffering therefrom a therapeutically effective amount of a compound of Formula 1 in unit dosage form.
24. A method of treating septic shock comprising administering to a host suffering therefrom a therapeutically effective amount of a compound of Formula 1 in unit dosage form.
25. A method of treating endotoxic shock comprising administering to a host suffering therefrom a therapeutically effective amount of a compound of Formula 1 in unit dosage form.
26. A method of treating arrhythmias comprising administering to a host suffering therefrom a therapeutically effective amount of a compound of Formula 1 in unit dosage form.
27. A method of treating asthma comprising administering to a host suffering therefrom a therapeutically effective amount of a compound of Formula I in unit dosage form.
28. A method of treating preeclampsia comprising administering to a host suffering therefrom a therapeutically effective amount of a compound of Formula 1 in unit dosage form.
29. A method of treating atherosclerotic disorders comprising administering to a host suffering therefrom a therapeutically effective amount of a compound of Formula 1 in unit dosage form.
30. A method of treating angina comprising administering to a host suffering therefrom a therapeutically effective amount of a compound of Formula 1 in unit dosage form.
31. A method of treating cancer comprising administering to a host suffering therefrom a therapeutically effective amount of a compound of Formula 1 in unit dosage form.
32. A method of treating benign prostatic hyperplasia comprising administering to a host suffering therefrom a therapeutically effective amount of a compound of Formula 1 in unit dosage form.
33. A method of treating ischemic disease comprising administering to a host suffering therefrom a therapeutically effective amount of a compound of Formula 1 in unit dosage form.
34. A method of treating gastric mucosal damage comprising administering to a host suffering therefrom a therapeutically effective amount of a compound of Formula 1 in unit dosage form.
35. A method of treating hemorrhagic shock comprising administering to a host suffering therefrom a therapeutically effective amount of a compound of Formula 1 in unit dosage form.
36. A method of treating ischemic bowel damage comprising administering to a host suffering therefrom a therapeutically effective amount of a compound of Formula 1 in unit dosage form.
37. A method of treating diabetes comprising administering to a host suffering therefrom a therapeutically effective amount of a compound of Formula 1 in unit dosage form.
38. A compound selected from:
(3,5-Dimethoxyphenyl)2-(2-trifluoro-methyl-phenyl)-1,1-dioxo-1,2-dihydro-1λ6-benzo[e][1,2]thiazine-3-carboxylic acid;
(2-Chloro-phenyl)4-(3,5-dimethoxy-phenyl)-1,1-dioxo-1,2-dihydro-1λ6-benzo[e][1,2]thiazine-3-carboxylic acid;
(2-Bromo-phenyl)4-(3,5-dimethoxy-phenyl)1,1-dioxo-1,2-dihydro 1λ6-benzo[e][1,2]thiazine-3-carboxylic acid;
(2-Chloro-phenyl)4-(7-methoxy-benzo[1,3]dioxol-5-yl)-1,1-dioxo-1,2-dihydro-1λ6-benzo[e][1,2]thiazine-3 carboxylic acid;
(2-Benzylphenyl)4-(7-methoxy-benzo[1,3]dioxol-5-yl)-1,1-dioxo-1,2-dihydro-1λ6-benzo[e][1,2]thiazine-3-carboxylic acid;
(2,6-Dimethyl-phenyl)4-(7-methoxy-benzo[1,3]dioxol-5-yl)-1,1-dioxo-1,2-dihydro-1λ6-benzo[e][1,2]thiazine-3-carboxylic acid monosodium salt;
(7-Methoxybenzo[1,3]dioxol-5-yl)-1,1-dioxo-2-(2-trifluoro-methyl-phenyl)-1,2-dihydro-1λ6-benzo[e][1,2]thiazine 3-carboxylic acid;
(2-Bromo-phenyl)4-(7-methoxy-benzo[1,3]dioxol-5-yl)-1,1-dioxo-1,2-dihydro-1 %6-benzo[e][1,2]thiazine-3-carboxylic acid monosodium salt;
4-Benzo[1,3]dioxol-5-yl 1,1-dioxo-2-(2-trifluoro-methyl-phenyl)-1,2-dihydro1 )6-benzo[e][1,2]thiazine-3-carboxylic acid;
4-Benzo[1,3]dioxol-5-yl-2-(2ethyl-phenyl)-1,1-dioxo-1,2-dihydro-1λ6-benzo[e][1,2]thiazine-3-carboxylic acid;
4-Benzo[1,3]dioxol-5-yl-2-(2propylphenyl)1,1dioxo-1,2-dihydro-1λ6-benzo[e][1,2]thiazine-3-carboxylic acid;
4-Benzo[1,3]dioxol-5-yl-2-(2isopropylphenyl)-1,1-dioxo-1,2-dihydro-1λ6-benzo[e][1,2]thiazine-3-carboxylic acid;
4-Benzo[1,3]dioxol-5-yl-2-(2butylphenyl)-1,1-dioxo-1,2-dihydro-1λ6-benzo[e][1,2]thiazine-3-carboxylic acid;
4-Benzo[1,3]dioxol-5-yl-2-(2-fluorophenyl)-1,1-dioxo-1,2-dihydro-1λ6-benzo[e][1,2]thiazine-3-carboxylic acid;
4-Benzo[1,3]dioxol-5-yl-2-(2-hydroxyphenyl)1,1-dioxo-1,2-dihydro-1λ6-benzo[e][1,2]thiazine-3 carboxylic acid;
4-Benzo [1,3]dioxol-5-yl-2-(2,3-dichlorophenyl)-1,1-dioxo-1,2-dihydro-1λ6-benzo[e][1,2]thiazine-3-carboxylic acid;
4-Benzo[1,3]dioxol-5-yl-2-(2,4dichlorophenyl)1,1-dioxo-1,2-dihydro-1λ6-benzo[e][1,2]thiazine-3-carboxylic acid;
4-Benzo[1,3]dioxol-5-yl-2-(2-chloro-4-methoxyphenyl)-1,1-dioxo-1,2-dihydro-1λ6-benzo[e][1,2]thiazine-3-carboxylic acid;
4-Benzo [1,3]dioxol-5-yl-2-(3chloro-2methyl-phenyl)-1,1-dioxo-1,2-dihydro-1λ6-benzo[e][1,2]thiazine-3-carboxylic acid;
4-Benzo[1,3]dioxol-5-yl-2-(2,6dimethyl-phenyl)-1,1-dioxo-1,2-dihydro-1λ6-benzo[e][1,2]thiazine-3-carboxylic acid;
4-Benzo[1,3]dioxol-5-yl 1,1-dioxo-2-(2pyrrol 1-yl-phenyl)-1,2-dihydro-1λ6-benzo[e][1,2]thiazine-3-carboxylic acid;
4-Benzo[1,3]dioxol-5-yl-2-(3 ,4dimethylisoxazol5-yl)-1,1-dioxo-1,2-dihydro-1λ6-benzo[e][1,2]thiazine-3-carboxylic acid;
4-Benzo[1,3]dioxol-5-yl-2-(2benzylphenyl)1,1dioxo-1,2-dihydro-1λ6-benzo[e][1,2]thiazine-3-carboxylic acid;
(6-Methoxybenzo[1,3]dioxol-5-yl)1,1dioxo-2-(2-trifluoro-methyl-phenyl)-1,2-dihydro-1),6-benzo[e][1,2]thiazine-3-carboxylic acid; and
(3,5-Dimethyl-phenyl)2-(2-trifluoro-methyl-phenyl)-1,1-dioxo-1,2-dihydro-1λ6-benzo[e][1,2]thiazine-3-carboxylic acid.
39. A compound selected from:
(2-Bromo-phenyl)4-(7-methoxy-benzo[1,3]dioxol-5-yl)-1,1-dioxo-1,2-dihydro-1λ6-benzo[e][1,2]thiazine-3-carboxylic acid; and
(7-Ethylbenzo[1,3]dioxol-5-yl)1,1-dioxo-2-(2-trifluoro-methyl-phenyl)-1,2-dihydro-1λ6-benzo [e][1,2]thiazine-3-carboxylic acid.
40. A compound selected from:
(6-Methyl-benzo[1,3]dioxol-5-yl)-4hydroxy-1,1dioxo-1,2-dihydro-1λ6-benzo[e][1,2]thiazine-3-carboxylic acid;
(2-Bromo-phenyl)-4hydroxy-1,1-dioxo-1,2-dihydro-1λ6-benzo[e][1,2]thiazine-3 carboxylic acid;
(2-Chloro-phenyl)-4hydroxy-1,1-dioxo-1,2-dihydro-1λ6-benzo[e][1,2]thiazine-3-carboxylic acid; and
(6-Chlorobenzo[1,3]dioxol-5-yl)-4hydroxy-1,1-dioxo-1,2-dihydro-1λ6-benzo[e][1,2]thiazine-3-carboxylic acid.
Priority Applications (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US09/818,394 US6440962B2 (en) | 1997-09-05 | 2001-03-27 | Certain benzothiazine dioxide endothelin antagonists and processes for their preparation |
US10/006,589 US6545150B2 (en) | 1997-09-05 | 2001-12-05 | Certain benzothiazine dioxide endothelin antagonists and processes for their preparation |
US10/161,569 US20030073684A1 (en) | 1997-09-05 | 2002-06-03 | Certain benzothiazine dioxide endothelin antagonists and processes for their preparation |
Applications Claiming Priority (4)
Application Number | Priority Date | Filing Date | Title |
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US5811197P | 1997-09-05 | 1997-09-05 | |
US9232698P | 1998-07-09 | 1998-07-09 | |
US09/445,504 US6265399B1 (en) | 1997-09-05 | 1998-08-13 | Certain benzothiazine dioxide endothelin antagonists and processes for their preparation |
US09/818,394 US6440962B2 (en) | 1997-09-05 | 2001-03-27 | Certain benzothiazine dioxide endothelin antagonists and processes for their preparation |
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US09/445,504 Division US6265399B1 (en) | 1997-09-05 | 1998-08-13 | Certain benzothiazine dioxide endothelin antagonists and processes for their preparation |
PCT/US1998/016856 Division WO1999012916A1 (en) | 1997-09-05 | 1998-08-13 | Certain benzothiazine dioxide endothelin antagonists and processes for their preparation |
Related Child Applications (2)
Application Number | Title | Priority Date | Filing Date |
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US10/006,589 Division US6545150B2 (en) | 1997-09-05 | 2001-12-05 | Certain benzothiazine dioxide endothelin antagonists and processes for their preparation |
US10/161,569 Division US20030073684A1 (en) | 1997-09-05 | 2002-06-03 | Certain benzothiazine dioxide endothelin antagonists and processes for their preparation |
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Publication Number | Publication Date |
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US20010036944A1 true US20010036944A1 (en) | 2001-11-01 |
US6440962B2 US6440962B2 (en) | 2002-08-27 |
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US09/445,504 Expired - Fee Related US6265399B1 (en) | 1997-09-05 | 1998-08-13 | Certain benzothiazine dioxide endothelin antagonists and processes for their preparation |
US09/633,720 Expired - Fee Related US6252070B1 (en) | 1997-09-05 | 2000-08-07 | Certain benzothiazine dioxide endothelin antagonists and processes for their preparation |
US09/818,394 Expired - Fee Related US6440962B2 (en) | 1997-09-05 | 2001-03-27 | Certain benzothiazine dioxide endothelin antagonists and processes for their preparation |
US10/006,589 Expired - Fee Related US6545150B2 (en) | 1997-09-05 | 2001-12-05 | Certain benzothiazine dioxide endothelin antagonists and processes for their preparation |
US10/161,569 Abandoned US20030073684A1 (en) | 1997-09-05 | 2002-06-03 | Certain benzothiazine dioxide endothelin antagonists and processes for their preparation |
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US09/445,504 Expired - Fee Related US6265399B1 (en) | 1997-09-05 | 1998-08-13 | Certain benzothiazine dioxide endothelin antagonists and processes for their preparation |
US09/633,720 Expired - Fee Related US6252070B1 (en) | 1997-09-05 | 2000-08-07 | Certain benzothiazine dioxide endothelin antagonists and processes for their preparation |
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US10/006,589 Expired - Fee Related US6545150B2 (en) | 1997-09-05 | 2001-12-05 | Certain benzothiazine dioxide endothelin antagonists and processes for their preparation |
US10/161,569 Abandoned US20030073684A1 (en) | 1997-09-05 | 2002-06-03 | Certain benzothiazine dioxide endothelin antagonists and processes for their preparation |
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US (5) | US6265399B1 (en) |
EP (1) | EP1009743B1 (en) |
JP (1) | JP2001515893A (en) |
KR (1) | KR20010023686A (en) |
AR (1) | AR017056A1 (en) |
AT (1) | ATE270281T1 (en) |
AU (1) | AU759169B2 (en) |
BR (1) | BR9812431A (en) |
CA (1) | CA2296358A1 (en) |
CO (1) | CO4970725A1 (en) |
DE (1) | DE69824863T2 (en) |
ES (1) | ES2221191T3 (en) |
HU (1) | HUP0003689A3 (en) |
IL (1) | IL134057A0 (en) |
IS (1) | IS5356A (en) |
MY (1) | MY116277A (en) |
NO (1) | NO20001078L (en) |
NZ (1) | NZ502670A (en) |
PE (1) | PE116699A1 (en) |
PL (1) | PL338983A1 (en) |
PT (1) | PT1009743E (en) |
TW (1) | TW508355B (en) |
UY (1) | UY25168A1 (en) |
WO (1) | WO1999012916A1 (en) |
Cited By (1)
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US20090305011A1 (en) * | 2008-06-05 | 2009-12-10 | Evonik Degussa Gmbh | Ink Jet Ink |
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US6265399B1 (en) | 1997-09-05 | 2001-07-24 | Warner-Lambert Company | Certain benzothiazine dioxide endothelin antagonists and processes for their preparation |
US6897237B2 (en) | 2000-04-28 | 2005-05-24 | Shionogi & Co. Ltd. | MMP-12 inhibitors |
WO2001091736A2 (en) * | 2000-05-31 | 2001-12-06 | Warner-Lambert Company | Combinations of an endothelin receptor antagonist and an antiepileptic compound having pain alleviating properties or analgesic |
US20020115661A1 (en) * | 2000-12-07 | 2002-08-22 | Keller Laurence Harvey | Method for treating chronic obstructive pulmonary disease |
EP2428516A1 (en) | 2003-11-19 | 2012-03-14 | Metabasis Therapeutics, Inc. | Novel phosphorus-containing thyromimetics |
FR2874011B1 (en) * | 2004-08-03 | 2007-06-15 | Sanofi Synthelabo | SULFONAMIDE DERIVATIVES, THEIR PREPARATION AND THEIR THERAPEUTIC APPLICATION |
CA2969756A1 (en) * | 2014-12-05 | 2016-06-09 | Aquinnah Pharmaceuticals, Inc. | Sulfonamide derivatives, compositions and methods of use in the treatment of neurodegenerative diseases |
CN108727176B (en) * | 2018-07-26 | 2021-05-18 | 荆楚理工学院 | Method for preparing 5-halogen-2, 3-dihydroxy benzaldehyde |
CN113214299A (en) * | 2021-03-01 | 2021-08-06 | 重庆西南制药二厂有限责任公司 | Gamma-biphenyldicarboxylate intermediate, synthetic method thereof and gamma-biphenyldicarboxylate synthetic method |
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US3960856A (en) * | 1975-06-20 | 1976-06-01 | Warner-Lambert Company | Process for the preparation of 4-hydroxy-3-(5-methyl-3-isoxazolylcarbamoyl)-2-methyl-2H-1,2-benzothiazine 1,1-dioxide |
IN159273B (en) * | 1981-10-05 | 1987-04-25 | Pfizer | |
JPH0495057A (en) * | 1990-08-08 | 1992-03-27 | Taisho Pharmaceut Co Ltd | N-substituted sulfonanilide compound |
US5389620A (en) | 1993-08-18 | 1995-02-14 | Banyu Pharmaceutical Co., Ltd. | Endothelin antagonistic heteroaromatic ring-fused cyclopentene derivatives |
EP0714897B1 (en) * | 1993-08-18 | 2001-02-14 | Banyu Pharmaceutical Co., Ltd. | Fused heteroaromatic cyclopentene derivative having endothelin-antagonist activity |
CN1058492C (en) | 1993-12-24 | 2000-11-15 | 三得利株式会社 | Benzothiazine derivative |
JPH0912562A (en) | 1995-06-22 | 1997-01-14 | Suntory Ltd | Substituted benzothiazine derivative |
US5482960A (en) | 1994-11-14 | 1996-01-09 | Warner-Lambert Company | Nonpeptide endothelin antagonists |
US5599811A (en) * | 1995-02-21 | 1997-02-04 | Warner-Lambert Company | Benzothiazine dioxides as endothelin antagonists |
CA2190708A1 (en) | 1995-12-08 | 1997-06-09 | Johannes Aebi | Aminoalkyl substituted benzo-heterocyclic compounds |
US6265399B1 (en) | 1997-09-05 | 2001-07-24 | Warner-Lambert Company | Certain benzothiazine dioxide endothelin antagonists and processes for their preparation |
-
1998
- 1998-08-13 US US09/445,504 patent/US6265399B1/en not_active Expired - Fee Related
- 1998-08-13 DE DE69824863T patent/DE69824863T2/en not_active Expired - Fee Related
- 1998-08-13 EP EP98942061A patent/EP1009743B1/en not_active Expired - Lifetime
- 1998-08-13 IL IL13405798A patent/IL134057A0/en unknown
- 1998-08-13 AT AT98942061T patent/ATE270281T1/en not_active IP Right Cessation
- 1998-08-13 WO PCT/US1998/016856 patent/WO1999012916A1/en active IP Right Grant
- 1998-08-13 AU AU90196/98A patent/AU759169B2/en not_active Ceased
- 1998-08-13 CA CA002296358A patent/CA2296358A1/en not_active Abandoned
- 1998-08-13 ES ES98942061T patent/ES2221191T3/en not_active Expired - Lifetime
- 1998-08-13 BR BR9812431-5A patent/BR9812431A/en not_active Application Discontinuation
- 1998-08-13 NZ NZ502670A patent/NZ502670A/en unknown
- 1998-08-13 PL PL98338983A patent/PL338983A1/en unknown
- 1998-08-13 JP JP2000510724A patent/JP2001515893A/en not_active Abandoned
- 1998-08-13 PT PT98942061T patent/PT1009743E/en unknown
- 1998-08-13 HU HU0003689A patent/HUP0003689A3/en unknown
- 1998-08-13 KR KR1020007002339A patent/KR20010023686A/en not_active Application Discontinuation
- 1998-09-03 MY MYPI98004024A patent/MY116277A/en unknown
- 1998-09-04 AR ARP980104414A patent/AR017056A1/en unknown
- 1998-09-04 UY UY25168A patent/UY25168A1/en not_active IP Right Cessation
- 1998-09-04 PE PE1998000822A patent/PE116699A1/en not_active Application Discontinuation
- 1998-09-04 CO CO98050781A patent/CO4970725A1/en unknown
- 1998-10-28 TW TW087114760A patent/TW508355B/en not_active IP Right Cessation
-
2000
- 2000-01-21 IS IS5356A patent/IS5356A/en unknown
- 2000-03-02 NO NO20001078A patent/NO20001078L/en unknown
- 2000-08-07 US US09/633,720 patent/US6252070B1/en not_active Expired - Fee Related
-
2001
- 2001-03-27 US US09/818,394 patent/US6440962B2/en not_active Expired - Fee Related
- 2001-12-05 US US10/006,589 patent/US6545150B2/en not_active Expired - Fee Related
-
2002
- 2002-06-03 US US10/161,569 patent/US20030073684A1/en not_active Abandoned
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20090305011A1 (en) * | 2008-06-05 | 2009-12-10 | Evonik Degussa Gmbh | Ink Jet Ink |
Also Published As
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BR9812431A (en) | 2000-09-19 |
IS5356A (en) | 2000-01-21 |
PT1009743E (en) | 2004-09-30 |
US6252070B1 (en) | 2001-06-26 |
PL338983A1 (en) | 2000-12-04 |
US20030073684A1 (en) | 2003-04-17 |
HUP0003689A3 (en) | 2003-05-28 |
US6265399B1 (en) | 2001-07-24 |
NO20001078D0 (en) | 2000-03-02 |
NZ502670A (en) | 2003-01-31 |
AU9019698A (en) | 1999-03-29 |
AR017056A1 (en) | 2001-08-22 |
US20020094980A1 (en) | 2002-07-18 |
CA2296358A1 (en) | 1999-03-18 |
EP1009743B1 (en) | 2004-06-30 |
TW508355B (en) | 2002-11-01 |
ATE270281T1 (en) | 2004-07-15 |
CO4970725A1 (en) | 2000-11-07 |
EP1009743A1 (en) | 2000-06-21 |
PE116699A1 (en) | 1999-12-19 |
IL134057A0 (en) | 2001-04-30 |
DE69824863T2 (en) | 2005-06-30 |
US6440962B2 (en) | 2002-08-27 |
DE69824863D1 (en) | 2004-08-05 |
AU759169B2 (en) | 2003-04-10 |
UY25168A1 (en) | 1999-05-14 |
KR20010023686A (en) | 2001-03-26 |
HUP0003689A2 (en) | 2001-09-28 |
JP2001515893A (en) | 2001-09-25 |
ES2221191T3 (en) | 2004-12-16 |
WO1999012916A1 (en) | 1999-03-18 |
MY116277A (en) | 2003-12-31 |
NO20001078L (en) | 2000-03-02 |
US6545150B2 (en) | 2003-04-08 |
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