NO874850L - Fremgangsmaate for fremstilling av benzotiadiazinforbindelser og farmasoeytisk akseptable salter derav. - Google Patents
Fremgangsmaate for fremstilling av benzotiadiazinforbindelser og farmasoeytisk akseptable salter derav.Info
- Publication number
- NO874850L NO874850L NO874850A NO874850A NO874850L NO 874850 L NO874850 L NO 874850L NO 874850 A NO874850 A NO 874850A NO 874850 A NO874850 A NO 874850A NO 874850 L NO874850 L NO 874850L
- Authority
- NO
- Norway
- Prior art keywords
- alkyl
- nmr
- nujol
- dioxide
- methyl
- Prior art date
Links
- 150000001875 compounds Chemical class 0.000 title claims description 83
- 150000003839 salts Chemical class 0.000 title claims description 61
- 238000000034 method Methods 0.000 title claims description 41
- 238000002360 preparation method Methods 0.000 title description 6
- 125000000217 alkyl group Chemical group 0.000 claims description 106
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 92
- -1 amino, carboxy Chemical group 0.000 claims description 72
- 238000006243 chemical reaction Methods 0.000 claims description 71
- 125000003545 alkoxy group Chemical group 0.000 claims description 45
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 27
- 229910052736 halogen Inorganic materials 0.000 claims description 26
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 25
- 150000002367 halogens Chemical class 0.000 claims description 22
- 125000003282 alkyl amino group Chemical group 0.000 claims description 21
- 125000000623 heterocyclic group Chemical group 0.000 claims description 18
- 229910052739 hydrogen Inorganic materials 0.000 claims description 18
- 239000001257 hydrogen Substances 0.000 claims description 18
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 15
- 125000005843 halogen group Chemical group 0.000 claims description 13
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 11
- 125000006239 protecting group Chemical group 0.000 claims description 10
- 125000002252 acyl group Chemical group 0.000 claims description 9
- 125000003118 aryl group Chemical group 0.000 claims description 9
- 238000003379 elimination reaction Methods 0.000 claims description 8
- 125000004414 alkyl thio group Chemical group 0.000 claims description 7
- 125000004104 aryloxy group Chemical group 0.000 claims description 7
- 238000004519 manufacturing process Methods 0.000 claims description 7
- 125000004430 oxygen atom Chemical group O* 0.000 claims description 7
- DAHOOCQZIXPFHL-SNVBAGLBSA-N (2r)-2-[[2-(4-chlorophenyl)-4-methyl-1,1,3-trioxo-1$l^{6},2,4-benzothiadiazin-6-yl]oxy]propanoic acid Chemical compound C=1C(O[C@H](C)C(O)=O)=CC=C(S2(=O)=O)C=1N(C)C(=O)N2C1=CC=C(Cl)C=C1 DAHOOCQZIXPFHL-SNVBAGLBSA-N 0.000 claims description 6
- 125000003277 amino group Chemical group 0.000 claims description 6
- 125000001424 substituent group Chemical group 0.000 claims description 6
- 125000004442 acylamino group Chemical group 0.000 claims description 5
- 125000002947 alkylene group Chemical group 0.000 claims description 5
- 230000008030 elimination Effects 0.000 claims description 5
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 4
- 238000005804 alkylation reaction Methods 0.000 claims description 3
- 238000005886 esterification reaction Methods 0.000 claims description 3
- 125000002883 imidazolyl group Chemical group 0.000 claims description 3
- 229910052757 nitrogen Inorganic materials 0.000 claims description 3
- 150000002431 hydrogen Chemical class 0.000 claims 3
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 107
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 95
- 239000000203 mixture Substances 0.000 description 54
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 48
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 46
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 42
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 36
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 33
- 239000002904 solvent Substances 0.000 description 28
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 27
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 26
- 239000000243 solution Substances 0.000 description 26
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 25
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 24
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 21
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 21
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 18
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 15
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 15
- 101150041968 CDC13 gene Proteins 0.000 description 15
- 239000002253 acid Chemical group 0.000 description 15
- 239000002585 base Substances 0.000 description 14
- 238000001914 filtration Methods 0.000 description 14
- 238000000354 decomposition reaction Methods 0.000 description 13
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 12
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 12
- 238000001816 cooling Methods 0.000 description 12
- 238000006460 hydrolysis reaction Methods 0.000 description 12
- 239000013078 crystal Substances 0.000 description 11
- 230000007062 hydrolysis Effects 0.000 description 11
- 230000002829 reductive effect Effects 0.000 description 11
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 11
- HTSGKJQDMSTCGS-UHFFFAOYSA-N 1,4-bis(4-chlorophenyl)-2-(4-methylphenyl)sulfonylbutane-1,4-dione Chemical compound C1=CC(C)=CC=C1S(=O)(=O)C(C(=O)C=1C=CC(Cl)=CC=1)CC(=O)C1=CC=C(Cl)C=C1 HTSGKJQDMSTCGS-UHFFFAOYSA-N 0.000 description 10
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 10
- 238000010438 heat treatment Methods 0.000 description 10
- 239000003054 catalyst Substances 0.000 description 9
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical compound [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 description 9
- 229910000027 potassium carbonate Inorganic materials 0.000 description 9
- 235000011181 potassium carbonates Nutrition 0.000 description 9
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 8
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 description 8
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 8
- 239000005457 ice water Substances 0.000 description 8
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 8
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 8
- IOLCXVTUBQKXJR-UHFFFAOYSA-M potassium bromide Chemical compound [K+].[Br-] IOLCXVTUBQKXJR-UHFFFAOYSA-M 0.000 description 8
- 238000006722 reduction reaction Methods 0.000 description 8
- 239000007787 solid Substances 0.000 description 8
- 239000000725 suspension Substances 0.000 description 8
- 150000007529 inorganic bases Chemical class 0.000 description 7
- 125000002911 monocyclic heterocycle group Chemical group 0.000 description 7
- 239000012074 organic phase Substances 0.000 description 7
- 239000003960 organic solvent Substances 0.000 description 7
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 6
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 6
- 230000002411 adverse Effects 0.000 description 6
- 239000003638 chemical reducing agent Substances 0.000 description 6
- 239000001963 growth medium Substances 0.000 description 6
- 150000007530 organic bases Chemical class 0.000 description 6
- CXWXQJXEFPUFDZ-UHFFFAOYSA-N tetralin Chemical compound C1=CC=C2CCCCC2=C1 CXWXQJXEFPUFDZ-UHFFFAOYSA-N 0.000 description 6
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 6
- UJURMMNUSWYNNQ-UHFFFAOYSA-N 2-(4-chlorophenyl)-6-hydroxy-4-methyl-1,1-dioxo-1$l^{6},2,4-benzothiadiazin-3-one Chemical compound O=S1(=O)C2=CC=C(O)C=C2N(C)C(=O)N1C1=CC=C(Cl)C=C1 UJURMMNUSWYNNQ-UHFFFAOYSA-N 0.000 description 5
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 5
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 description 5
- PXHVJJICTQNCMI-UHFFFAOYSA-N Nickel Chemical compound [Ni] PXHVJJICTQNCMI-UHFFFAOYSA-N 0.000 description 5
- 235000011054 acetic acid Nutrition 0.000 description 5
- 239000012267 brine Substances 0.000 description 5
- 239000011575 calcium Substances 0.000 description 5
- 229910052791 calcium Inorganic materials 0.000 description 5
- 239000003795 chemical substances by application Substances 0.000 description 5
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 5
- 229920006395 saturated elastomer Polymers 0.000 description 5
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 5
- DAHOOCQZIXPFHL-UHFFFAOYSA-N 2-[[2-(4-chlorophenyl)-4-methyl-1,1,3-trioxo-1$l^{6},2,4-benzothiadiazin-6-yl]oxy]propanoic acid Chemical compound C=1C(OC(C)C(O)=O)=CC=C(S2(=O)=O)C=1N(C)C(=O)N2C1=CC=C(Cl)C=C1 DAHOOCQZIXPFHL-UHFFFAOYSA-N 0.000 description 4
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 4
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 4
- OAKJQQAXSVQMHS-UHFFFAOYSA-N Hydrazine Chemical compound NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 0.000 description 4
- 229910052783 alkali metal Inorganic materials 0.000 description 4
- 125000004453 alkoxycarbonyl group Chemical group 0.000 description 4
- ILAHWRKJUDSMFH-UHFFFAOYSA-N boron tribromide Chemical compound BrB(Br)Br ILAHWRKJUDSMFH-UHFFFAOYSA-N 0.000 description 4
- 229940125890 compound Ia Drugs 0.000 description 4
- 229910052802 copper Inorganic materials 0.000 description 4
- 239000010949 copper Substances 0.000 description 4
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 4
- 125000001301 ethoxy group Chemical group [H]C([H])([H])C([H])([H])O* 0.000 description 4
- 125000003754 ethoxycarbonyl group Chemical group C(=O)(OCC)* 0.000 description 4
- 235000019253 formic acid Nutrition 0.000 description 4
- 230000002140 halogenating effect Effects 0.000 description 4
- 239000002244 precipitate Substances 0.000 description 4
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 4
- 235000017557 sodium bicarbonate Nutrition 0.000 description 4
- 239000007858 starting material Substances 0.000 description 4
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 description 4
- CROPERLEGVRULM-LLVKDONJSA-N (2r)-2-[(2-cyclohexyl-4-methyl-1,1,3-trioxo-1$l^{6},2,4-benzothiadiazin-6-yl)oxy]propanoic acid Chemical compound C=1C(O[C@H](C)C(O)=O)=CC=C(S2(=O)=O)C=1N(C)C(=O)N2C1CCCCC1 CROPERLEGVRULM-LLVKDONJSA-N 0.000 description 3
- ALBBOGOWSQJHTN-LLVKDONJSA-N (2r)-2-[(4-methyl-1,1,3-trioxo-2-phenyl-1$l^{6},2,4-benzothiadiazin-6-yl)oxy]propanoic acid Chemical compound C=1C(O[C@H](C)C(O)=O)=CC=C(S2(=O)=O)C=1N(C)C(=O)N2C1=CC=CC=C1 ALBBOGOWSQJHTN-LLVKDONJSA-N 0.000 description 3
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- WZNXINPPSAVBCY-UHFFFAOYSA-N cyclohexylmethyl 4-[6-(cyclohexylmethoxy)-4-methyl-1,1,3-trioxo-1$l^{6},2,4-benzothiadiazin-2-yl]benzoate Chemical compound O=S1(=O)C2=CC=C(OCC3CCCCC3)C=C2N(C)C(=O)N1C(C=C1)=CC=C1C(=O)OCC1CCCCC1 WZNXINPPSAVBCY-UHFFFAOYSA-N 0.000 description 2
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- QWEABDLHBNFNID-CYBMUJFWSA-N ethyl (2r)-2-[(4-methyl-1,1,3-trioxo-2-phenyl-1$l^{6},2,4-benzothiadiazin-6-yl)oxy]propanoate Chemical compound C=1C(O[C@H](C)C(=O)OCC)=CC=C(S2(=O)=O)C=1N(C)C(=O)N2C1=CC=CC=C1 QWEABDLHBNFNID-CYBMUJFWSA-N 0.000 description 2
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- PPJQUJPHGVDTBG-GFCCVEGCSA-N ethyl (2r)-2-[[2-(2-chlorophenyl)-4-methyl-1,1,3-trioxo-1$l^{6},2,4-benzothiadiazin-6-yl]oxy]propanoate Chemical compound C=1C(O[C@H](C)C(=O)OCC)=CC=C(S2(=O)=O)C=1N(C)C(=O)N2C1=CC=CC=C1Cl PPJQUJPHGVDTBG-GFCCVEGCSA-N 0.000 description 2
- XRPKQZGGKDQZNI-LLVKDONJSA-N ethyl (2r)-2-[[2-(3,4-dichlorophenyl)-4-methyl-1,1,3-trioxo-1$l^{6},2,4-benzothiadiazin-6-yl]oxy]propanoate Chemical compound C=1C(O[C@H](C)C(=O)OCC)=CC=C(S2(=O)=O)C=1N(C)C(=O)N2C1=CC=C(Cl)C(Cl)=C1 XRPKQZGGKDQZNI-LLVKDONJSA-N 0.000 description 2
- KCPNSTDWENRZDQ-GFCCVEGCSA-N ethyl (2r)-2-[[2-(3-chlorophenyl)-4-methyl-1,1,3-trioxo-1$l^{6},2,4-benzothiadiazin-6-yl]oxy]propanoate Chemical compound C=1C(O[C@H](C)C(=O)OCC)=CC=C(S2(=O)=O)C=1N(C)C(=O)N2C1=CC=CC(Cl)=C1 KCPNSTDWENRZDQ-GFCCVEGCSA-N 0.000 description 2
- FUVXVVZIHVYMIL-GFCCVEGCSA-N ethyl (2r)-2-[[2-(4-chlorophenyl)-4-methyl-1,1,3-trioxo-1$l^{6},2,4-benzothiadiazin-6-yl]oxy]propanoate Chemical compound C=1C(O[C@H](C)C(=O)OCC)=CC=C(S2(=O)=O)C=1N(C)C(=O)N2C1=CC=C(Cl)C=C1 FUVXVVZIHVYMIL-GFCCVEGCSA-N 0.000 description 2
- YMHIFWVXNBRULR-GFCCVEGCSA-N ethyl (2r)-2-[[2-(4-fluorophenyl)-4-methyl-1,1,3-trioxo-1$l^{6},2,4-benzothiadiazin-6-yl]oxy]propanoate Chemical compound C=1C(O[C@H](C)C(=O)OCC)=CC=C(S2(=O)=O)C=1N(C)C(=O)N2C1=CC=C(F)C=C1 YMHIFWVXNBRULR-GFCCVEGCSA-N 0.000 description 2
- FWWCKIMVGYQSEL-CQSZACIVSA-N ethyl (2r)-2-[[2-[4-(dimethylamino)phenyl]-4-methyl-1,1,3-trioxo-1$l^{6},2,4-benzothiadiazin-6-yl]oxy]propanoate Chemical compound C=1C(O[C@H](C)C(=O)OCC)=CC=C(S2(=O)=O)C=1N(C)C(=O)N2C1=CC=C(N(C)C)C=C1 FWWCKIMVGYQSEL-CQSZACIVSA-N 0.000 description 2
- CZZBBKQCBQKOPK-QGZVFWFLSA-N ethyl (2r)-2-[[4-methyl-1,1,3-trioxo-2-(4-phenoxyphenyl)-1$l^{6},2,4-benzothiadiazin-6-yl]oxy]propanoate Chemical compound C=1C(O[C@H](C)C(=O)OCC)=CC=C(S2(=O)=O)C=1N(C)C(=O)N2C(C=C1)=CC=C1OC1=CC=CC=C1 CZZBBKQCBQKOPK-QGZVFWFLSA-N 0.000 description 2
- NUEJIADGGHGIDC-OAHLLOKOSA-N ethyl (2r)-2-[[4-methyl-1,1,3-trioxo-2-(4-propan-2-ylphenyl)-1$l^{6},2,4-benzothiadiazin-6-yl]oxy]propanoate Chemical compound C=1C(O[C@H](C)C(=O)OCC)=CC=C(S2(=O)=O)C=1N(C)C(=O)N2C1=CC=C(C(C)C)C=C1 NUEJIADGGHGIDC-OAHLLOKOSA-N 0.000 description 2
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- 125000002757 morpholinyl group Chemical group 0.000 description 1
- RNUGYAMXCLOXGV-UHFFFAOYSA-N n-(2-chlorophenyl)-4-methoxy-2-nitrobenzenesulfonamide Chemical compound [O-][N+](=O)C1=CC(OC)=CC=C1S(=O)(=O)NC1=CC=CC=C1Cl RNUGYAMXCLOXGV-UHFFFAOYSA-N 0.000 description 1
- QGUCPGVDXVGCNF-UHFFFAOYSA-N n-(3,4-dichlorophenyl)-4-methoxy-2-nitrobenzenesulfonamide Chemical compound [O-][N+](=O)C1=CC(OC)=CC=C1S(=O)(=O)NC1=CC=C(Cl)C(Cl)=C1 QGUCPGVDXVGCNF-UHFFFAOYSA-N 0.000 description 1
- UAKBINKARMLJCW-UHFFFAOYSA-N n-(3-chlorophenyl)-4-methoxy-2-nitrobenzenesulfonamide Chemical compound [O-][N+](=O)C1=CC(OC)=CC=C1S(=O)(=O)NC1=CC=CC(Cl)=C1 UAKBINKARMLJCW-UHFFFAOYSA-N 0.000 description 1
- KBSSANLETBADQA-UHFFFAOYSA-N n-(4-chlorophenyl)-2-nitro-4-(trifluoromethyl)benzenesulfonamide Chemical compound [O-][N+](=O)C1=CC(C(F)(F)F)=CC=C1S(=O)(=O)NC1=CC=C(Cl)C=C1 KBSSANLETBADQA-UHFFFAOYSA-N 0.000 description 1
- RTXJXTAEAXCKRI-UHFFFAOYSA-N n-(4-chlorophenyl)-2-nitro-4-propan-2-yloxybenzenesulfonamide Chemical compound [O-][N+](=O)C1=CC(OC(C)C)=CC=C1S(=O)(=O)NC1=CC=C(Cl)C=C1 RTXJXTAEAXCKRI-UHFFFAOYSA-N 0.000 description 1
- MNHIVKRGHVGPIJ-UHFFFAOYSA-N n-(4-chlorophenyl)-2-nitrobenzenesulfonamide Chemical compound [O-][N+](=O)C1=CC=CC=C1S(=O)(=O)NC1=CC=C(Cl)C=C1 MNHIVKRGHVGPIJ-UHFFFAOYSA-N 0.000 description 1
- SQTODWBROMJWLV-UHFFFAOYSA-N n-(4-chlorophenyl)-4-methyl-2-nitrobenzenesulfonamide Chemical compound [O-][N+](=O)C1=CC(C)=CC=C1S(=O)(=O)NC1=CC=C(Cl)C=C1 SQTODWBROMJWLV-UHFFFAOYSA-N 0.000 description 1
- AJQBJLKAQYXBJI-UHFFFAOYSA-N n-(4-fluorophenyl)-4-methoxy-2-nitrobenzenesulfonamide Chemical compound [O-][N+](=O)C1=CC(OC)=CC=C1S(=O)(=O)NC1=CC=C(F)C=C1 AJQBJLKAQYXBJI-UHFFFAOYSA-N 0.000 description 1
- HHUDOHSHCQWBCD-UHFFFAOYSA-N n-[(4-chlorophenyl)methyl]-4-methoxy-2-nitrobenzenesulfonamide Chemical compound [O-][N+](=O)C1=CC(OC)=CC=C1S(=O)(=O)NCC1=CC=C(Cl)C=C1 HHUDOHSHCQWBCD-UHFFFAOYSA-N 0.000 description 1
- XUEZCVAFJIUWBY-UHFFFAOYSA-N n-[2-(4-chlorophenyl)-1,1,3-trioxo-4h-1$l^{6},2,4-benzothiadiazin-6-yl]acetamide Chemical compound C=1C(NC(=O)C)=CC=C(S2(=O)=O)C=1NC(=O)N2C1=CC=C(Cl)C=C1 XUEZCVAFJIUWBY-UHFFFAOYSA-N 0.000 description 1
- DXZKIPATWVKBRQ-UHFFFAOYSA-N n-[3-amino-4-[(4-chlorophenyl)sulfamoyl]phenyl]acetamide Chemical compound NC1=CC(NC(=O)C)=CC=C1S(=O)(=O)NC1=CC=C(Cl)C=C1 DXZKIPATWVKBRQ-UHFFFAOYSA-N 0.000 description 1
- WEOQHXKWINAXSQ-UHFFFAOYSA-N n-[4-(dimethylamino)phenyl]-4-methoxy-2-nitrobenzenesulfonamide Chemical compound [O-][N+](=O)C1=CC(OC)=CC=C1S(=O)(=O)NC1=CC=C(N(C)C)C=C1 WEOQHXKWINAXSQ-UHFFFAOYSA-N 0.000 description 1
- DINRKJYGQJEFSH-UHFFFAOYSA-N n-cyclohexyl-4-methoxy-2-nitrobenzenesulfonamide Chemical compound [O-][N+](=O)C1=CC(OC)=CC=C1S(=O)(=O)NC1CCCCC1 DINRKJYGQJEFSH-UHFFFAOYSA-N 0.000 description 1
- LWFWUJCJKPUZLV-UHFFFAOYSA-N n-trimethylsilylacetamide Chemical compound CC(=O)N[Si](C)(C)C LWFWUJCJKPUZLV-UHFFFAOYSA-N 0.000 description 1
- 125000001038 naphthoyl group Chemical group C1(=CC=CC2=CC=CC=C12)C(=O)* 0.000 description 1
- 125000001624 naphthyl group Chemical group 0.000 description 1
- 229910000480 nickel oxide Inorganic materials 0.000 description 1
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 1
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 1
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 1
- KPADFPAILITQBG-UHFFFAOYSA-N non-4-ene Chemical compound CCCCC=CCCC KPADFPAILITQBG-UHFFFAOYSA-N 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- 239000004533 oil dispersion Substances 0.000 description 1
- 125000001181 organosilyl group Chemical group [SiH3]* 0.000 description 1
- AHLPHDHHMVZTML-BYPYZUCNSA-N ornithyl group Chemical class N[C@@H](CCCN)C(=O)O AHLPHDHHMVZTML-BYPYZUCNSA-N 0.000 description 1
- 125000001715 oxadiazolyl group Chemical group 0.000 description 1
- 125000003431 oxalo group Chemical group 0.000 description 1
- 125000002971 oxazolyl group Chemical group 0.000 description 1
- HBEQXAKJSGXAIQ-UHFFFAOYSA-N oxopalladium Chemical compound [Pd]=O HBEQXAKJSGXAIQ-UHFFFAOYSA-N 0.000 description 1
- MUMZUERVLWJKNR-UHFFFAOYSA-N oxoplatinum Chemical compound [Pt]=O MUMZUERVLWJKNR-UHFFFAOYSA-N 0.000 description 1
- 229910003445 palladium oxide Inorganic materials 0.000 description 1
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 1
- 125000001148 pentyloxycarbonyl group Chemical group 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- 229910052698 phosphorus Inorganic materials 0.000 description 1
- 239000011574 phosphorus Substances 0.000 description 1
- 125000005544 phthalimido group Chemical group 0.000 description 1
- 125000000612 phthaloyl group Chemical group C(C=1C(C(=O)*)=CC=CC1)(=O)* 0.000 description 1
- 229910003446 platinum oxide Inorganic materials 0.000 description 1
- 125000003367 polycyclic group Chemical group 0.000 description 1
- XAEFZNCEHLXOMS-UHFFFAOYSA-M potassium benzoate Chemical compound [K+].[O-]C(=O)C1=CC=CC=C1 XAEFZNCEHLXOMS-UHFFFAOYSA-M 0.000 description 1
- 235000015497 potassium bicarbonate Nutrition 0.000 description 1
- 229910000028 potassium bicarbonate Inorganic materials 0.000 description 1
- 239000011736 potassium bicarbonate Substances 0.000 description 1
- 239000011698 potassium fluoride Substances 0.000 description 1
- 235000003270 potassium fluoride Nutrition 0.000 description 1
- NTTOTNSKUYCDAV-UHFFFAOYSA-N potassium hydride Chemical compound [KH] NTTOTNSKUYCDAV-UHFFFAOYSA-N 0.000 description 1
- 229910000105 potassium hydride Inorganic materials 0.000 description 1
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 description 1
- 229940086066 potassium hydrogencarbonate Drugs 0.000 description 1
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 1
- 238000012746 preparative thin layer chromatography Methods 0.000 description 1
- ILFAMWTZLTUIFI-UHFFFAOYSA-N propan-2-yl 4-(4-methyl-1,1,3-trioxo-6-propan-2-yloxy-1$l^{6},2,4-benzothiadiazin-2-yl)butanoate Chemical compound CC(C)OC1=CC=C2S(=O)(=O)N(CCCC(=O)OC(C)C)C(=O)N(C)C2=C1 ILFAMWTZLTUIFI-UHFFFAOYSA-N 0.000 description 1
- 125000001501 propionyl group Chemical group O=C([*])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000004309 pyranyl group Chemical group O1C(C=CC=C1)* 0.000 description 1
- 125000003373 pyrazinyl group Chemical group 0.000 description 1
- 125000003226 pyrazolyl group Chemical group 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 125000004076 pyridyl group Chemical group 0.000 description 1
- 125000000714 pyrimidinyl group Chemical group 0.000 description 1
- 125000000719 pyrrolidinyl group Chemical group 0.000 description 1
- 125000001422 pyrrolinyl group Chemical group 0.000 description 1
- 125000000168 pyrrolyl group Chemical group 0.000 description 1
- 125000001453 quaternary ammonium group Chemical group 0.000 description 1
- 125000005493 quinolyl group Chemical group 0.000 description 1
- 238000006894 reductive elimination reaction Methods 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 238000010898 silica gel chromatography Methods 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- BEOOHQFXGBMRKU-UHFFFAOYSA-N sodium cyanoborohydride Chemical compound [Na+].[B-]C#N BEOOHQFXGBMRKU-UHFFFAOYSA-N 0.000 description 1
- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 229910052717 sulfur Inorganic materials 0.000 description 1
- 239000011593 sulfur Chemical group 0.000 description 1
- YBBRCQOCSYXUOC-UHFFFAOYSA-N sulfuryl dichloride Chemical compound ClS(Cl)(=O)=O YBBRCQOCSYXUOC-UHFFFAOYSA-N 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 229940095064 tartrate Drugs 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 125000005934 tert-pentyloxycarbonyl group Chemical group 0.000 description 1
- 238000010998 test method Methods 0.000 description 1
- 125000003831 tetrazolyl group Chemical group 0.000 description 1
- 125000001113 thiadiazolyl group Chemical group 0.000 description 1
- 125000001984 thiazolidinyl group Chemical group 0.000 description 1
- 125000000335 thiazolyl group Chemical group 0.000 description 1
- 229910052718 tin Inorganic materials 0.000 description 1
- 239000011135 tin Substances 0.000 description 1
- 125000003944 tolyl group Chemical group 0.000 description 1
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 1
- 125000005270 trialkylamine group Chemical group 0.000 description 1
- 125000001425 triazolyl group Chemical group 0.000 description 1
- FAQYAMRNWDIXMY-UHFFFAOYSA-N trichloroborane Chemical compound ClB(Cl)Cl FAQYAMRNWDIXMY-UHFFFAOYSA-N 0.000 description 1
- 125000003866 trichloromethyl group Chemical group ClC(Cl)(Cl)* 0.000 description 1
- IMNIMPAHZVJRPE-UHFFFAOYSA-N triethylenediamine Chemical compound C1CN2CCN1CC2 IMNIMPAHZVJRPE-UHFFFAOYSA-N 0.000 description 1
- RXJKFRMDXUJTEX-UHFFFAOYSA-N triethylphosphine Chemical compound CCP(CC)CC RXJKFRMDXUJTEX-UHFFFAOYSA-N 0.000 description 1
- 125000004044 trifluoroacetyl group Chemical group FC(C(=O)*)(F)F 0.000 description 1
- 125000004205 trifluoroethyl group Chemical group [H]C([H])(*)C(F)(F)F 0.000 description 1
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 1
- ZNEOHLHCKGUAEB-UHFFFAOYSA-N trimethylphenylammonium Chemical compound C[N+](C)(C)C1=CC=CC=C1 ZNEOHLHCKGUAEB-UHFFFAOYSA-N 0.000 description 1
- MDDPTCUZZASZIQ-UHFFFAOYSA-N tris[(2-methylpropan-2-yl)oxy]alumane Chemical compound [Al+3].CC(C)(C)[O-].CC(C)(C)[O-].CC(C)(C)[O-] MDDPTCUZZASZIQ-UHFFFAOYSA-N 0.000 description 1
- 125000003774 valeryl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
- 125000005023 xylyl group Chemical group 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/72—Nitrogen atoms
- C07D213/76—Nitrogen atoms to which a second hetero atom is attached
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
- A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
- A61P19/10—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease for osteoporosis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
-
- 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
-
- 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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
- C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
- C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
- C07D239/69—Benzenesulfonamido-pyrimidines
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D285/00—Heterocyclic compounds containing rings having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by groups C07D275/00 - C07D283/00
- C07D285/15—Six-membered rings
- C07D285/16—Thiadiazines; Hydrogenated thiadiazines
- C07D285/18—1,2,4-Thiadiazines; Hydrogenated 1,2,4-thiadiazines
- C07D285/20—1,2,4-Thiadiazines; Hydrogenated 1,2,4-thiadiazines condensed with carbocyclic rings or ring systems
- C07D285/22—1,2,4-Thiadiazines; Hydrogenated 1,2,4-thiadiazines condensed with carbocyclic rings or ring systems condensed with one six-membered ring
- C07D285/24—1,2,4-Thiadiazines; Hydrogenated 1,2,4-thiadiazines condensed with carbocyclic rings or ring systems condensed with one six-membered ring with oxygen atoms directly attached to the ring sulfur atom
-
- 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
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Veterinary Medicine (AREA)
- Pharmacology & Pharmacy (AREA)
- Public Health (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Rheumatology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Physical Education & Sports Medicine (AREA)
- Engineering & Computer Science (AREA)
- Orthopedic Medicine & Surgery (AREA)
- Hematology (AREA)
- Pain & Pain Management (AREA)
- Obesity (AREA)
- Diabetes (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
- Nitrogen- Or Sulfur-Containing Heterocyclic Ring Compounds With Rings Of Six Or More Members (AREA)
- Other In-Based Heterocyclic Compounds (AREA)
- Heterocyclic Compounds Containing Sulfur Atoms (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Quinoline Compounds (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
- Indole Compounds (AREA)
- Pyridine Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
Description
Den foreliggende oppfinnelse angår fremstilling av hittil
ukjente benzotiadiazinforbindelser og farmasøytisk akseptable salter derav, som f.eks. har inhiberende virkning på knokkel-resorpsj on.
Forbindelsene kan anvendes i et farmasøytisk preparat for behandling av bensykdommer som erkarakterisert vedabnorm knokkelmetabolisme, så som osteoporose, Pagets knokkelsykdom, osteolyse, malign hypercalcemi og reumatisk artritt, hos mennesker og dyr.
Benzotiadiazinforbindelsene ifølge den foreliggende oppfinnelse
er hittil ukjente og kan vises ved følgende generelle formel I
hvor R<1>er fenyl som kan være substituert med halogen, lavere alkyl, lavere alkoksy, halogen(lavere)alkyl, lavere alkylamino, lavere alkyltio, aryloksy, karboksy, forestret karboksy, karboksy(lavere)alkyl eller forestret karboksy(lavere)alkyl; cyklo(lavere)alkyl;
lavere alkyl som kan være substituert med karboksy eller forestret karboksy; eller en heterocyklisk gruppe som kan være substituert med lavere alkyl;
A er lavere alkylen,
n er et helt tall på 0 eller 1,
R<2>er hydrogen eller lavere alkyl,
R<3>er hydrogen; hydroksy; halogen; halogen(lavere)alkyl;
lavere alkyl; lavere alkylamino; acylamino; acyl-(lavere)alkylamino; lavere alkoksy som kan være substituert med aryl, beskyttet amino, en heterocyklisk gruppe, amino, karboksy, forestret karboksy eller cyklo(lavere)alkyl som kan være substituert med amino(lavere)alkyl eller beskyttet amino(lavere)alkyl;
eller cyklo(lavere)alkyloksy som kan være substituert med karboksy eller forestret karboksy;
R<4>er hydrogen eller halogen, og
R<5>er hydrogen eller halogen,
med det forbehold at
R<1>er fenyl substituert med lavere alkoksy, lavere alkylamino, lavere alkyltio, aryloksy, karboksy, forestret karboksy, karboksy(lavere)alkyl eller forestret karboksy(lavere)alkyl; lavere alkyl
substituert med karboksy eller forestret karboksy;
eller en heterocyklisk gruppe substituert med lavere alkyl,
nårR<3>er hydrogen eller halogen.
Den omhandlede forbindelse I kan fremstilles ved følgende fremgangsmåter.
Fremgangsmåtevariant 1
hvorR<1>,R<2>,R<3>,R<4>,R<5>, A og n hver er som definert ovenfor,
R^ er fenyl substituert med forestret karboksy(lavere)-alkyl eller forestret karboksy; eller forestret karboksy(lavere)alkyl;
Rjljer fenyl substituert med karboksy (lavere) alkyl eller
karboksy; eller karboksy(lavere)alkyl;
R|[ er lavere alkyl,
R=| er lavere alkoksy som kan være substituert med aryl,
cyklo(lavere)alkyl, karboksy eller forestret karboksy;
eller cyklo(lavere)alkyloksy som kan være substituert med karboksy eller forestret karboksy;
r£ er lavere alkyl som kan være substituert med aryl,
beskyttet amino, en heterocyklisk gruppe, karboksy, forestret karboksy eller cyklo(lavere)alkyl som kan
være substituert med beskyttet amino(lavere)alkyl;
eller cyklo(lavere)alkyl som kan være substituert med karboksy eller forestret karboksy;
R<3>, er forestret karboksy (lavere) alkoksy som kan være substituert med cyklo(lavere)alkyl; eller forestret karboksycyklo(lavere)alkyloksy;
er karboksy(lavere)alkoksy som kan være substituert med cyklo(lavere)alkyl; eller karboksycyklo(lavere)-alkyloksy;
Rg er acyl(lavere)alkylamino eller lavere alkoksy substituert med beskyttet amino eller cyklo(lavere)-alkyl substituert med beskyttet amino(lavere)alkyl,
er lavere alkylamino eller lavere alkoksy substituert med amino eller cyklo(lavere)alkyl substituert med amino(lavere)alkyl,
R^ er hydrogen,
r£ er halogen,
r£ er hydrogen,
R<6>ogR<7>hver er halogen, lavere alkoksy eller imidazolyl,R<8>ogR<9>hver er lavere alkyl, og
X er en avspaltbar enhet.
Blant utgangsforbindelsene ved ovenstående fremgangsmåter er forbindelsen II hittil ukjent og kan fremstilles ved de i det følgende viste fremgangsmåter.
hvorR<1>,R<3>,R<4>,R<5>, A og n hver er som definert ovenfor.
I ovenstående og etterfølgende beskrivelse er hensiktsmessige eksempler og illustrasjoner av de forskjellige definisjoner som er omfattet av den foreliggende oppfinnelse, forklart nærmere som følger: Uttrykket "lavere" skal betegne 1 til 6 karbonatomer, medmindre annet er angitt.
Antallet av substituenter på fenyl forR<1>kan være 1 til 3, fortrinnsvis 1 eller 2.
Hensiktsmessige eksempler på lavere alkyl kan være rettkjedet eller forgrenet alkyl så som metyl, etyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, heksyl eller lignende. Hensiktsmessige eksempler på en "lavere alkyl"-del i uttrykkene "halogen(lavere)alkyl", "lavere alkylamino", "lavere alkyltio", "amino(lavere)alkyl", "beskyttet amino(lavere)alkyl", "acyl-(lavere)alkylamino", "karboksy(lavere)alkyl" og "forestret karboksy(lavere)alkyl" kan være de samme som eksemplifisert ovenfor.
Hensiktsmessige eksempler på "halogen(lavere)alkyl" kan omfatte "monohalogen(lavere)alkyl" [f.eks. klormetyl, brommetyl, fluormetyl, etc], "dihalogen (lavere) alkyl" [f. eks. diklormetyl, dibrommetyl, difluormetyl, etc.] og "trihalogen(lavere)alkyl"
[f.eks. triklormetyl, tribrommetyl, trifluormetyl, trifluoretyl, etc] og lignende.
Hensiktsmessige eksempler på "lavere alkylamino" kan omfatte "mono(lavere)alkylamino" [f.eks. metylamino, etylamino, isopropylamino, heksylamino, etc] og "di(lavere)alkylamino"
[f.eks. dimetylamino, dietylamino, dipropylamino, metyletylamino, etc.] og lignende.
Hensiktsmessige eksempler på lavere alkylen kan være rettkjedet eller forgrenet lavere alkylen så som metylen, etylen, tri-metylen, tetrametylen, pentametylen, heksametylen, propylen, metyletylen, etyletylen, propyletylen, isopropyletylen, metylpentametylen eller lignende.
Hensiktsmessige eksempler på "halogen" kan omfatte klor, brom, jod og fluor.
Hensiktsmessige eksempler på "lavere alkoksy" og en "lavere alkoksy"-del i uttrykkene "karboksy(lavere)alkoksy" og "forestret karboksy(lavere)alkoksy" kan omfatte metoksy, etoksy, propoksy, isopropoksy, butoksy, isobutoksy, tert-butoksy, pentyloksy, heksyloksy og lignende.
Hensiktsmessige eksempler på "aryl" kan omfatte fenyl, tolyl, xylyl, kumenyl, naftyl og lignende.
Hensiktsmessige eksempler på "aryloksy" kan omfatte fenoksy, tolyloksy, naftyloksy og lignende.
Hensiktsmessige eksempler på "cyklo(lavere)alkyl" kan omfatte cyklopropyl, cyklobutyl, cyklopentyl, cykloheksyl og lignende.
Hensiktsmessige eksempler på en "cyklo(lavere)alkyl"-del i uttrykkene "cyklo(lavere)alkyloksy", "karboksycyklo(lavere)-alkyloksy" og "forestret karboksycyklo(lavere)alkyloksy" kan være de samme som eksemplifisert ovenfor.
Hensiktsmessige eksempler på en "acyl"-del i uttrykkene "acylamino" og "acyl(lavere)alkylamino" kan omfatte lavere alkanoyl [f.eks. formyl, acetyl, propionyl, valeryl, pivaloyl, etc], lavere alkoksykarbonyl [f.eks. metoksykarbonyl, etoksykarbonyl, propoksykarbonyl, isopropoksykarbonyl, butoksykarbonyl, tert-butoksykarbonyl, pentyloksykarbonyl, heksyl-oksykarbonyl, etc], lavere alkansulfonyl [f.eks. metansulfonyl, etansulfonyl, propansulfonyl, butansulfonyl, pentansulfonyl, heksansulf onyl, etc], aroyl [f.eks. benzoyl, naf toyl, etc], som kan være substituert med halogen som eksemplifisert ovenfor, arylkarbamoyl [f.eks. fenylkarbamoyl, tolylkarbamoyl, etc] som kan være substituert med halogen som nevnt ovenfor, og lignende.
En hensiktsmessig "avspaltbar enhet" kan omfatte hydroksy og syrerest, og hensiktsmessige eksempler på "syrerest" kan være halogen (f.eks. klor, brom, jod eller fluor), sulfonyloksy (f.eks. metansulfonyloksy, benzensulfonyloksy, toluensulfonyl-oksy, etc) eller lignende, idet et foretrukket eksempel kan være halogen.
En hensiktsmessig "beskyttet amino" og "beskyttet amino"-del i uttrykket "beskyttet amino(lavere)alkyl" kan omfatte acylamino, hvor eksempler på "acyl"-delen kan være de samme som nevnt ovenfor, ftalimido, fosfonoamino, ar(lavere)alkylamino så som benzylamino, fenetylamino, tritylamino; og lignende.
En hensiktsmessig "forestret karboksy" og "forestret karboksy"-del i uttrykkene "forestret karboksy(lavere)alkyl", "forestret karboksy(lavere)alkoksy" og "forestret karboksycyklo(lavere)-alkyloksy" kan omfatte lavere alkoksykarbonyl (f.eks. metoksykarbonyl, etoksykarbonyl, propoksykarbonyl, isopropoksykarbonyl, butoksykarbonyl, tert-butoksykarbonyl, etc), mono- (eller di-eller tri)fenyl(lavere)alkoksykarbonyl som kan ha en nitrogruppe (f.eks. benzyloksykarbonyl, 4-nitrobenzyloksykarbonyl, fenetyl-oksykarbonyl, benzhydryloksykarbonyl, trityloksykarbonyl, etc.) og lignende, idet et mer foretrukket eksempel kan være Cq__4-alkoksykarbonyl, og det mest foretrukne eksempel kan være etoksykarbonyl.
En hensiktsmessig "heterocyklisk gruppe" kan være en gruppe inneholdende minst ett heteroatom valgt blant nitrogen-, svovel- og oksygenatomer og kan omfatte en mettet eller umettet, monocyklisk eller polycyklisk heterocyklisk gruppe, og en heterocyklisk gruppe kan fortrinnsvis være en N-holdig heterocyklisk gruppe så som en umettet 3-6-leddet heteromonocyklisk gruppe inneholdende 1-4 nitrogenatomer, f.eks. pyrrolyl, pyrrolinyl, imidazolyl, pyrazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazolyl (f.eks. 4H-1,2,4-triazolyl, 1H-1,2,3-triazolyl, 2H-1,2,3-triazolyl, etc), tetrazolyl (f.eks. 1H-tetrazolyl, 2H-tetrazolyl, etc), etc;
en mettet 3-6-leddet heteromonocyklisk gruppe inneholdende 1-4 nitrogenatomer (f.eks. pyrrolidinyl, imidazolidinyl, piperidino, piperazinyl, etc); en umettet kondensert heterocyklisk gruppe inneholdende 1-5 nitrogenatomer, f.eks. indolyl, isoindolyl, indolizinyl, benzimidazolyl, kinolyl, isokinolyl, indazolyl, benzotriazolyl, tetrazolopyridazinyl (f.eks. tetrazolo-[l,5-b]pyridazinyl, etc), etc;
en umettet 3-6-leddet heteromonocyklisk gruppe inneholdende et oksygenatom, f.eks. pyranyl, furyl, etc;
en umettet 3-6-leddet heteromonocyklisk gruppe inneholdende 1-2 oksygenatomer og 1-3 nitrogenatomer, f.eks. oksazolyl, isoksazolyl, oksadiazolyl (f.eks. 1,2,4-oksadiazolyl, 1,3,4-oksadiazolyl, 1,2,5-oksadiazolyl, etc), etc;
en mettet 3-6-leddet heteromonocyklisk gruppe inneholdende 1-2 oksygenatomer og 1-3 nitrogenatomer (f.eks. morfolinyl, etc);
en umettet kondensert heterocyklisk gruppe inneholdende 1-2 oksygenatomer og 1-3 nitrogenatomer (f.eks. benzoksazolyl, benzoksadiazolyl, etc);
en umettet 3-6-leddet heteromonocyklisk gruppe inneholdende 1-2 svovelatomer og 1-3 nitrogenatomer, f.eks. tiazolyl, tiadiazolyl (f.eks. 1,2,4-tiadiazolyl, 1,3,4-tiadiazolyl, 1,2,5-tiadiazolyl, etc.), etc.;
en mettet 3-6-leddet heteromonocyklisk gruppe inneholdende 1-2 svovelatomer og 1-3 nitrogenatomer (f.eks. tiazolidinyl, etc);
en umettet kondensert heterocyklisk gruppe inneholdende 1-2 svovelatomer og 1-3 nitrogenatomer (f.eks. benzotiazolyl, benzotiadiazolyl, etc.) og lignende. Den "heterocykliske gruppe" kan ha 1-4 substituenter så som lavere alkyl som eksemplifisert ovenfor.
Hensiktsmessige farmasøytisk akseptable salter av den omhandlede forbindelse I er konvensjonelle ikke-toksiske salter og omfatter et organisk syresalt [f.eks. formiat, acetat, trifluor-acetat, maleat, tartrat, metansulfonat, benzensulfonat, toluensulfonat, etc], et uorganisk syresalt [f.eks. hydroklorid, hydrobromid, sulfat, fosfat, etc], et salt med en aminosyre [f.eks. argininsalt, ornitinsalt, etc], et salt med en base så som alkalimetallsalt [f.eks. natriumsalt, kaliumsalt, etc], et jordalkalimetallsalt [f.eks. kalsiumsalt, magnesiumsalt, etc] eller lignende, og lignende.
I denne forbindelse skal det bemerkes at forbindelsene Ia-Ip er omfattet innenfor rammene av forbindelsen I, og med hensyn til hensiktsmessige salter av disse forbindelser Ia-Ip henvises det følgelig til de salter som er eksemplifisert ovenfor for den omhandlede forbindelse I.
Det skal også bemerkes at både den omhandlede forbindelse I og utgangsforbindelsen II omfatter én eller flere stereoisomerer på grunn av det asymmetriske karbonatom i molekylet, og alle slike isomerer av forbindelsen I og II er omfattet av den foreliggende oppfinnelse.
Fremgangsmåter for fremstilling av den omhandlede forbindelse I eller salter derav er forklart i detaljer i det følgende:
Fremqanqsmåtevariant 1
Den omhandlede forbindelse Ia eller et salt derav kan fremstilles ved omsetning av forbindelsen II eller et reaktivt derivat derav ved aminogruppen eller et salt derav med forbindelsen III.
Hensiktsmessige reaktive derivater ved aminogruppen av forbindelsen II omfatter konvensjonelle derivater som anvendes ved amidering, f.eks. Schiffs basetype-imino eller dens tautomere isomer av enamin-type, som er dannet ved omsetning av forbindelsen II med en karbonylforbindelse, et silylderivat dannet ved omsetning av forbindelsen II med en silylforbindelse så som trimetylsilylacetamid, bis(trimetylsilyl)acetamid eller lignende, et derivat dannet ved omsetning av forbindelsen II
med fosfortriklorid eller fosgen og lignende.
Denne reaksjon utføres vanligvis i et konvensjonelt oppløsnings-middel så som tetrahydrofuran, dioksan, metylenklorid, kloroform, benzen, dimetylformamid, dimetylsulfoksyd eller et hvilket som helst annet organisk oppløsningsmiddel som ikke påvirker reaksjonen ugunstig.
Reaksjonstemperaturen er ikke kritisk, og reaksjonen kan utføres under betingelser fra avkjøling til oppvarmning.
Fremqanqsmåtevariant 2
Forbindelsen Ib eller et salt derav kan fremstilles ved å underkaste forbindelsen Ia eller et salt derav en reaksjon for innføring av en substituent på nitrogenatomet.
Denne innføringsreaksjon kan utføres ved omsetning av forbindelsen Ia eller et salt derav med en forbindelse med formelen Rg-X, hvor R|| og X hver er som definert ovenfor.
Innføringsreaksjonen kan også utføres ved omsetning av forbindelsen Ia eller et salt derav med di(lavere)alkylsulfat [f.eks. dimetylsulfat, dietylsulfat, etc], diazo(lavere)alkan [f.eks. diazometan, diazoetan, etc] og lignende.
Reaksjonen under anvendelse av di(lavere)alkylsulfat eller en forbindelse med formelen r|-X utføres vanligvis i et oppløsnings-middel så som vann, aceton, etanol, eter, N,N-dimetylformamid eller et hvilket som helst annet oppløsningsmiddel som ikke påvirker reaksjonen ugunstig. Den foreliggende reaksjon utføres fortrinnsvis i nærvær av en base så som en uorganisk base eller en organisk base.
En hensiktsmessig organisk eller uorganisk base kan være alkalimetallhydrid [f.eks. natriumhydrid, kaliumhydrid, etc], jordalkalimetallhydrid [f.eks. kalsiumhydrid, magnesiumhydrid, etc], alkalimetallhydroksyd [f.eks. natriumhydroksyd, kalium-hydroksyd, etc], alkalimetallkarbonat [f.eks. natriumkarbonat, kaliumkarbonat, etc], alkalimetallhydrogenkarbonat [f.eks. natriumhydrogenkarbonat, kaliumhydrogenkarbonat, etc], alkalimetallfluorid [f.eks. kaliumfluorid, cesiumfluorid,
etc], alkalimetallalkoksyd [f.eks. natriummetoksyd, natrium-etoksyd, kalium-tert-butoksyd, etc], trialkylamin [f.eks. trimetylamin, trietylamin, etc], pikolin, 1,5-diazabicyklo-
[4,3,0]non-5-en, 1,4-diazabicyklo[2,2,2]oktan, 1,5-diaza-bicyklo[5,4,0]undecen-5 eller lignende.
Reaksjonstemperaturen er ikke kritisk, og reaksjonen utføres vanligvis under betingelser fra avkjøling til oppvarmning.
Reaksjonen under anvendelse av diazoalkan utføres vanligvis i et oppløsningsmiddel så som eter, tetrahydrofuran eller lignende. Reaksjonstemperaturen er ikke kritisk, og reaksjonen utføres vanligvis under avkjøling eller ved omgivelsestemperatur.
Fremgangsmåtevariant 3
Den omhandlede forbindelse Id eller et salt derav kan fremstilles ved å underkaste forbindelsen Ic eller et salt derav en reaksjon for eliminering av en substituent på oksygenatomet.
Reaksjonen utføres fortrinnsvis i nærvær av en Lewis-syre, f.eks. borhalogenid (f.eks. bortriklorid, bortribromid, etc), hydrohalogensyre (f.eks. bromhydrogensyre, jodhydrogensyre,
etc.) og lignende.
Reaksjonen utføres vanligvis uten oppløsningsmiddel eller i et oppløsningsmiddel som ikke påvirker reaksjonen ugunstig, så som kloroform, metylenklorid, karbontetraklorid eller lignende.
Reaksjonstemperaturen er ikke kritisk, og reaksjonen utføres vanligvis under betingelser fra avkjøling til oppvarmning.
Fremganqsmåtevariant 4
Den omhandlede forbindelse If eller et salt derav kan fremstilles ved omsetning av forbindelsen le eller et salt derav med forbindelsen IV.
Omsetningen utføres fortrinnsvis i nærvær av en base så som en uorganisk base eller en organisk base som beskrevet under fremgangsmåtevariant 2.
Denne reaksjon utføres vanligvis i et konvensjonelt oppløsnings-middel så som vann, metanol, etanol, propanol, tetralin, tetrahydrofuran, dioksan, kloroform, toluen, N,N-dimetylformamid, dimetylsulfoksyd eller et hvilket som helst annet organisk oppløsningsmiddel som ikke påvirker reaksjonen ugunstig.
Reaksjonstemperaturen er ikke kritisk, og reaksjonen utføres vanligvis under avkjøling, ved omgivelsestemperatur eller under oppvarmning.
Fremgangsmåtevariant 5
Den omhandlede forbindelse Ih eller et salt derav kan fremstilles ved å underkaste forbindelsen lg eller et salt derav en deforestringsreaksjon.
Deforestringsreaksjonen kan utføres ved konvensjonell hydrolyse, reduksjon og lignende.
Hydrolysereaksjonen kan utføres i nærvær av en base eller en syre, og en hensiktsmessig base kan være en uorganisk base som beskrevet under fremgangsmåtevariant 2. En hensiktsmessig syre kan være en organisk syre (f.eks. maursyre, eddiksyre, propionsyre, trifluoreddiksyre, benzensulfonsyre, p-toluensulfonsyre, etc.) og en uorganisk syre (f.eks. saltsyre, bromhydrogensyre, svovelsyre, fosforsyre, etc).
Denne reaksjon utføres vanligvis i et konvensjonelt oppløsnings-middel som ikke påvirker reaksjonen ugunstig, så som vann, aceton, diklormetan, metanol, etanol, propanol, pyridin, N--dimetylf ormamid , tetrahydrof uran, etc, eller en blanding derav, og i tilfelle av at den base eller syre som skal anvendes ved denne reaksjon, er flytende, kan den også anvendes som oppløsningsmiddel.
Reaksjonstemperaturen er ikke kritisk, og reaksjonen utføres vanligvis under betingelser fra avkjøling til oppvarmning. Hvis
R<1>ved denne reaksjon er fenyl substituert med forestret karboksy eller forestret karboksy(lavere)alkyl; eller forestret karboksy(lavere)alkyl, kan det under reaksjonen omdannes til henholdsvis fenyl substituert med karboksy eller karboksy-(lavere)alkyl; og karboksy(lavere)alkyl. Dette tilfelle er også omfattet av denne reaksjon.
Fremgangsmåtevariant 6
Den omhandlede forbindelse Ij eller et salt derav kan fremstilles ved å underkaste forbindelsen li eller et salt derav en deforestringsreaksj on.
Denne reaksjon kan utføres på i det vesentlige samme måte som fremgangsmåtevariant 5, og derfor svarer reaksjonsmåte [f.eks. hydrolyse, reduksjon, etc] og reaksjonsbetingelser [f.eks. reduksjonsmiddel, base, syre, oppløsningsmiddel, reaksjons-temperatur, etc] ved denne reaksjon til dem som er beskrevet under fremgangsmåtevariant 5. Hvis R<3>ved denne reaksjon er lavere alkoksy substituert med forestret karboksy eller cyklo(lavere)alkyloksy substituert med forestret karboksy, kan det under reaksjonen omdannes til henholdsvis lavere alkoksy substituert med karboksy og cyklo(lavere)alkyloksy substituert med karboksy. Dette tilfelle er også omfattet av denne reaksjon.
Fremgangsmåtevariant 7
Den omhandlede forbindelse II eller et salt derav kan fremstilles ved å halogenere forbindelsen Ik eller et salt derav.
Hensiktsmessige halogeneringsmidler for denne reaksjon kan omfatte konvensjonelle halogeneringsmidler, f.eks. halogen [f.eks. klor, brom, jod, etc], sulfurylhalogenid [f.eks. sulfurylklorid, sulfurylbromid, etc], N-halogensuccinimid [f.eks. N-klorsuccinimid, N-bromsuccinimid, etc], pyridinium-hydrohalogenid-perhalogenid [f.eks. pyridiniumhydrobromid-perbromid, pyridiniumhydroklorid-perklorid, etc], kvaternær ammoniumperhalogenid [f.eks. fenyltrimetylammonium-perbromid, etc], uj-trihalogenacetofenon [f-eks. <-u-tribromacetofenon, etc], kobber(II)- eller kaliumbromid, selenium-oksyklorid eller lignende. Disse halogeneringsmidler kan velges avhengig av arten av den utgangsforbindelse Ik som skal anvendes.
Denne reaksjon utføres vanligvis i et konvensjonelt oppløsnings-middel så som kloroform, metylenklorid, karbontetraklorid, eddiksyre, en blanding av hydrogenhalogenid [f.eks. hydrogen-bromid, hydrogenklorid, etc] og eddiksyre, vann, dimetylformamid eller lignende.
Reaksjonstemperaturen er ikke kritisk, og reaksjonen utføres vanligvis under avkjøling, ved romtemperatur eller under svak eller kraftig oppvarmning.
Fremganqsmåtevariant 8
Forbindelsen In eller et salt derav kan fremstilles ved å underkaste forbindelsen Im eller et salt derav en alkyleringsreaksjon.
Det alkyleringsmiddel som skal anvendes ved denne alkyleringsreaksjon, kan omfatte di(lavere)alkylsulfat [f.eks. dimetylsulfat, dietylsulfat, etc], diazo(lavere)alkan [f.eks. diazometan, diazoetan, etc], lavere alkylhalogenid [f.eks. metyljodid, etyljodid, etc], lavere alkylsulfonat [f.eks. metyl-p-toluensulfonat, etc] og lignende.
Reaksjonen under anvendelse av di(lavere)alkylsulfat, lavere alkylhalogenid eller lavere alkylsulfonat utføres vanligvis i et oppløsningsmiddel så som vann, aceton, etanol, eter, tetrahydrofuran, dimetylformamid eller et hvilket som helst annet oppløsningsmiddel som ikke påvirker reaksjonen ugunstig.
Omsetningen utføres fortrinnsvis i nærvær av en base så som en uorganisk base eller en organisk base som nevnt under fremgangsmåtevariant 2. Reaksjonstemperaturen er ikke kritisk, og reaksjonen utføres vanligvis under betingelser fra avkjøling til oppvarmning omkring oppløsningsmidlets kokepunkt.
Reaksjonen under anvendelse av diazoalkan utføres vanligvis i et oppløsningsmiddel så som eter, tetrahydrofuran eller lignende. Reaksjonstemperaturen er ikke kritisk, og reaksjonen utføres vanligvis under avkjøling eller ved omgivelsestemperatur. Forbindelsen In eller et salt derav kan også fremstilles ved omsetning av forbindelsen Im eller et salt derav med alkanaldehyd i nærvær av et reduksjonsmiddel. Et hensiktsmessig alkanaldehyd kan omfatte formaldehyd, acetaldehyd, propionaldehyd og lignende. Hensiktsmessige reduksjonsmidler kan være de samme som nevnt under fremgangsmåtevariant B. Denne reaksjon utføres vanligvis i et konvensjonelt oppløsningsmiddel så som vann, metanol, etanol, propanol, tetralin, tetrahydrofuran, acetonitril, dioksan, kloroform, toluen, dimetylformamid, dimetylsulfoksyd eller et hvilket som helst annet organisk oppløs-ningsmiddel som ikke påvirker reaksjonen ugunstig.
Reaksjonstemperaturen er ikke kritisk, og reaksjonen utføres vanligvis ved omgivelsestemperatur eller under avkjøling eller oppvarmning.
Fremganqsmåtevariant 9
Den omhandlede forbindelse lp eller et salt derav derav kan fremstilles ved å underkaste forbindelsen Io eller et salt derav en reaksjon for eliminering av aminobeskyttelsesgruppen.
Denne elimineringsreaksjon utføres ved en konvensjonell metode så som hydrolyse; reduksjon; en metode, hvorved forbindelsen Io, hvor beskyttelsesgruppen er acyl, omsettes med et imino-halogeneringsmiddel og derefter med et iminoforetringsmiddel, hvorefter den resulterende forbindelse om nødvendig underkastes hydrolyse; eller lignende. Hydrolysen kan omfatte en metode under anvendelse av en syre eller base eller hydrazin og lignende. Disse metoder kan velges avhengig av arten av de beskyttelsesgrupper som skal elimineres.
Blant disse metoder er hydrolyse under anvendelse av en syre én av de almindelige og foretrukne metoder for eliminering av beskyttelsesgruppen så som substituert eller usubstituert alkoksykarbonyl (f.eks. tert-pentyloksykarbonyl, tert-butoksykarbonyl, etc), alkanoyl (f.eks. formyl, acetyl, etc), cykloalkoksykarbonyl, substituert eller usubstituert aralkoksykarbonyl (f.eks. benzyloksykarbonyl, substituert benzyloksykarbonyl, etc), ar (lavere) alkyl (f.eks. benzyl, trityl, etc.) eller lignende.
En hensiktsmessig syre kan omfatte en organisk eller en uorganisk syre, f.eks. maursyre, trifluoreddiksyre, benzensulfonsyre, p-toluensulfonsyre, saltsyre og lignende, og en foretrukket syre er f.eks. maursyre, trifluoreddiksyre, saltsyre, etc. Den syre som er hensiktsmessig for reaksjonen, kan velges avhengig av arten av den beskyttelsesgruppe som skal elimineres. Når elimineringsreaksjonen utføres med en syre, kan den utføres i nærvær eller fravær av et oppløsnings-middel. Et hensiktsmessig oppløsningsmiddel kan omfatte et konvensjonelt organisk oppløsningsmiddel (f.eks. metanol, etanol, tetrahydrofuran, etc), vann eller en blanding derav. Når det benyttes trifluoreddiksyre, kan elimineringsreaksjonen fortrinnsvis utføres i nærvær av anisol.
Hydrolyse under anvendelse av hydrazin anvendes vanligvis for eliminering av en beskyttelsesgruppe, f.eks. succinyl eller ftaloyl.
Hydrolysen med en base anvendes fortrinnsvis for eliminering av en acylgruppe, f.eks. halogenalkanoyl (f.eks. dikloracetyl, trifluoracetyl, etc), etc. En hensiktsmessig base kan f.eks. omfatte en uorganisk base og en organisk base som eksemplifisert ovenfor under fremgangsmåtevariant 2. Hydrolysen under anvendelse av en base utføres ofte i vann, et konvensjonelt organisk oppløsningsmiddel eller en blanding derav.
Av beskyttelsesgruppene kan acylgruppen generelt elimineres ved hydrolyse som nevnt ovenfor eller ved en annen konvensjonell hydrolyse. Hvis acylgruppen er halogensubstituert alkoksykarbonyl eller 8-kinolyloksykarbonyl, elimineres disse ved behandling med et tungmetall så som kobber, sink eller lignende.
Den reduktive eliminering anvendes generelt for eliminering av beskyttelsesgruppen, f.eks. halogenalkoksykarbonyl (f.eks. trikloretoksykarbonyl, etc), substituert eller usubstituert aralkoksykarbonyl (f.eks. benzyloksykarbonyl, substituert benzyloksykarbonyl etc), 2-pyridylmetoksykarbonyl, etc. En hensiktsmessig reduksjon kan f.eks. omfatte reduksjon med et alkalimetallborhydrid (f.eks. natriumborhydrid, etc.) og lignende.
Reaksjonstemperaturen er ikke kritisk og kan hensiktsmessig velges avhengig av arten av beskyttelsesgruppen på aminogruppen og elimineringsmetoden som nevnt ovenfor, og den foreliggende reaksjon utføres fortrinnsvis under skånsomme betingelser så
som under avkjøling, ved omgivelsestemperatur eller lett forhøyet temperatur.
Fremgangsmåtene for fremstilling av utgangsforbindelsen II
eller et salt derav er beskrevet nærmere i det følgende.
Fremganqsmåtevariant A
Forbindelsen VII eller et salt derav kan fremstilles ved omsetning av forbindelsen V eller et reaktivt derivat derav ved sulfogruppen eller et salt derav med forbindelsen VI eller et reaktivt derivat derav ved aminogruppen eller et salt derav.
Hensiktsmessige eksempler på det reaktive derivat ved sulfogruppen kan omfatte konvensjonelle derivater så som syrehalogenid (f.eks. syreklorid, syrebromid, etc), syreanhydrid, aktivert ester eller amid og lignende.
Hensiktsmessige eksempler på det reaktive derivat ved aminogruppen kan være de samme som nevnt ovenfor under fremgangsmåtevariant 1.
Reaksjonen kan fortrinnsvis utføres i nærvær av en organisk eller uorganisk base som beskrevet under fremgangsmåtevariant 2.
Reaksjonen utføres vanligvis i et oppløsningsmiddel. Et hensiktsmessig oppløsningsmiddel som kan anvendes, kan være vann, alkohol [f.eks. metanol, etanol, propanol, etc], acetonitril eller et hvilket som helst annet konvensjonelt organisk oppløsningsmiddel så som dietyleter, dioksan, tetrahydrofuran, etc. eller en blanding derav. Dessuten kan de ovenfor nevnte flytende baser også anvendes som oppløsningsmiddel.
Reaksjonen utføres fortrinnsvis under betingelser fra avkjøling til oppvarmning.
Fremgangsmåtevariant B
Forbindelsen II eller et salt derav kan fremstilles ved å redusere forbindelsen VII eller et salt derav.
Reaksjonen kan omfatte kjemisk reduksjon og katalytisk reduksjon som utføres på konvensjonell måte.
Hensiktsmessige reduksjonsmidler som kan anvendes ved kjemisk reduksjon, er et metall [f.eks. tinn, sink, jern, etc], en kombinasjon av et slikt metall og/eller metalllisk forbindelse [f.eks. kromklorid, kromacetat, etc] og en organisk eller uorganisk syre [f.eks. maursyre, eddiksyre, propionsyre, trifluoreddiksyre, p-toluensulfonsyre, saltsyre, bromhydrogensyre, etc], en kombinasjon av et slikt metall og/eller en metalllisk forbindelse og en base [f.eks. ammoniakk, ammoniumklorid, natriumhydroksyd, etc], en metallhydridforbindelse så som en aluminumhydridforbindelse [f.eks. litiumaluminumhydrid, natriumaluminumhydrid, aluminiumhydrid, litiumtrimetoksy-aluminiumhydrid, litiumtri-tert-butoksyaluminiumhydrid, etc], en borhydridforbindelse [f.eks. natriumborhydrid, litiumbor-hydrid, natriumcyanoborohydrid, tetrametylammoniumborhydrid, boran, diboran, etc], en fosforforbindelse [f.eks. fosfortriklorid, fosfortribromid, trifenylfosfin, trietylfosfin, etc] og lignende.
Hensiktsmessige katalysatorer for anvendelse ved katalytisk reduksjon er konvensjonelle katalysatorer så som platina-katalysatorer [f.eks. platinaplate, platinasvamp, platinasort, kolloidalt platina, platinaoksyd, platinatråd, etc], palladium-katalysatorer [f.eks. palladiumsvamp, palladiumsort, palladium-oksyd, palladium-på-karbon, kolloidalt palladium, palladium-på-bariumsulfat, palladium-på-bariumkarbonat, etc], nikkelkata-lysatorer [f.eks. redusert nikkel, nikkeloksyd, Raney-nikkel, etc], koboltkatalysatorer [f.eks. redusert kobolt, Raney-kobolt, etc], jernkatalysatorer [f.eks. redusert jern, Raney-jern, etc], kobberkatalysatorer [f.eks. redusert kobber, Raney-kobber, Ullman-kobber, etc] eller lignende.
Reduksjonen utføres vanligvis i et oppløsningsmiddel. Et hensiktsmessig oppløsningsmiddel som kan anvendes, kan være vann, alkohol [f.eks. metanol, etanol, propanol, etc], acetonitril eller et hvilket som helst annet konvensjonelt organisk oppløsningsmiddel så som dietyleter, dioksan, tetrahydrofuran, etc. eller en blanding derav.
Reaksjonen utføres fortrinnsvis under svak til kraftig oppvarmning.
De forbindelser som således er oppnådd ved fremgangsmåtevariantene 1-9 og fremgangsmåtevariantene A og B, kan omdannes til ovennevnte farmasøytisk akseptable salter derav på konvensjonell måte.
Den omhandlede forbindelse I og farmasøytisk akseptable salter derav har f.eks. sterk inhiberende virkning på knokkelresorpsjon og er nyttige for terapeutisk behandling av knokkelsykdommer som erkarakterisert vedabnorm knokkelmetabolisme, så som osteoporose, Pagets knokkelsygdom, osteolyse, malign hypercalcemi og reumatisk artritt.
Til terapeutiske formål kan forbindelsene I og farmasøytisk akseptable salter derav ifølge den foreliggende oppfinnelse anvendes i form av et farmasøytisk preparat som inneholder én av disse forbindelser som aktiv bestanddel i blanding med en farmasøytisk akseptabel bærer så som et organisk eller uorganisk fast eller flytende hjelpestoff, som er egnet til oral, parenteral eller ekstern administrering. De farmasøytiske preparater kan være kapsler, tabletter, dragéer, granuler, en oppløsning, suspensjon, emulsjon eller lignende. Om ønsket kan det i disse preparater være inkorporert hjelpestoffer, stabili-satorer, fuktemidler, emulgatorer, buffere og andre almindelig anvendte additiver.
Mens dosen av forbindelsene I varierer avhengig av pasientens alder og tilstand, kan en gjennomsnittlig enkeltdose på ca. 0,1 mg, 1 mg, 10 mg, 50 mg, 100 mg, 250 mg, 500 mg og 1000 mg av forbindelsen I være virksom for behandling av de omtalte knokkelsykdommer. Generelt kan det daglig administreres mengder på mellom 0,1 mg/kg kropsvekt og ca. 1000 mg/kg kropsvekt.
For å belyse anvendeligheten av den omhandlede forbindelse I er farmakologiske testdata for noen representative forbindelser for forbindelsene med formelen I vist i det følgende.
Testmetode
Neonatale calvaria ble dissekert aseptisk fra 1-2 dager gamle rotter (Wistar), vasket i Dulbeccos modifiserte Eagles medium og delt langs sagittalsuturen. Calvaria-halvdelene ble samlet og fordelt vilkårlig i de forskjellige grupper. Calvaria-halvdelene ble dyrket separat som frittflytende knokler i multibrøndeskåle inneholdende 2 ml av Dubeccos modifiserte Eagles medium med 10% varme-inaktivert (56°C i 1 time) føtalt kalveserum. Behandling med hPTH(l-34) (1 x 10~<8>M) og testforbindelse (1 x 10"<5>M) ble påbegynt på tidspunkt null. Alle inkubasjoner ble utført ved 37°C under en atmosfære av 95% luft og 5% C02i 6 dager. Knokkelresorpsjon ble bestemt ved å måle akkumuleringen av kalsium i mediet efter 6 dager. Konsentrasjonen av totalt kalsium i dyrkningsmediet ble målt ved OCPC-metoden med et spektrofotometer (Hitachi modell U-3200, Tokyo, Japan).
Som samraenligningsdata ble lignende tester utført under anvendelse av et dyrkningsmedium med hPTH (1 x 10~<8>M) alene og dyrkningsmedium uten både hPTH og testforbindelse.
Testresultatene vises som prosentvis inhibering beregnet ved hjelp av følgende formel:
CD: konsentrasjonen av totalt kalsium i dyrkningsmediet
behandlet med både hPTH og testforbindelse
C0: konsentrasjonen av totalt kalsium i kontrolldyrknings-mediet uten både hPTH og testforbindelse
Cp: konsentrasjonen av totalt kalsium i dyrkningsmediet behandlet med hPTH alene
Testforbindelser:
(a) 2-(4-Klorfenyl)-6-isopropoksy-4-metyl-2H-l,2,4-benzotiadia-zin-3(4H)-on-1,1-dioksyd (eksempel 4 og eksempel 6-(22)) (b) 2-(4-Klorfenyl)-4-metyl-6-(2-metylpropoksy)-2H-1,2,4-benzo-tiadiazin-3(4H)-on-1,1-dioksyd (eksempel 6-(24) og
eksempel 10)
(c) 2-(4-Klorfenyl)-4-metyl-6-cykloheksylmetoksy-2H-l,2,4-ben-zotiadiazin-3(4H)-on-1,1-dioksyd (eksempel 6-(25) og
eksempel 11)
(d) 2-(4-Trifluormetylfenyl)-4-metyl-6-isopropoksy-2H-l,2,4-benzotiadiazin-3(4H)-on-1,1-dioksyd (eksempel 6-(23) og eksempel 9) (e) 2-(4-Klorfenyl)-6-(1-karboksyetoksy)-4-metyl-2H-l,2,4-ben-zotiadiazin-3(4H)-on-1,1-dioksyd (R,S-blanding) (eksempel
6-(29), eksempel 14, eksempel 15-(5))
(f) (IR)-(+)-2-(4-Klorfenyl)-6-(1-karboksyetoksy)-4-metyl-2H-1,2,4-benzotiadiazin-3(4H)-on-1,1-dioksyd (eksempel 6-(44), eksempel 15-(12), eksempel 16-(5))
Testresultater:
Oppfinnelsen belyses nærmere ved følgende fremstillinger og eksempler.
FREMSTILLING 1
Til en blanding av 4-kloranilin (14,51 g) og 4-metoksy-2-nitro-benzensulfonylklorid (28,54 g) ble dråpevis satt vandig natriumhydroksydoppløsning (0,7 N, 162 ml) i løpet av 3 0 minutter ved 70°C. Efter tilsetningen ble blandingen omrørt i 3 0 minutter ved den samme temperatur. Den avkjølte blanding ble fortynnet med vandig IN saltsyre. Den fraskilte olje ble ekstrahert med etylacetat. Ekstrakten ble tørret over magnesium-sulfat og konsentrert under redusert trykk. Det gule faste stoff ble triturert med n-heksan og oppsamlet ved filtrering, hvorved man fikk 4-metoksy-2-nitro-N-(4-klorfenyl)benzensulfonamid
(37,23 g).
smp.: 56-60°C
IR (CHC13) : 1600, 1540, 1490, 1170 cm<-1>
NMR (CDCI3, 6) : 3,92 (3H, s), 6,90-7,80 (7H, m), 7,70
(1H, d, J=9Hz)
FREMSTILLING 2
Til en blanding av 4-metoksy-2-nitro-N-(4-klorfenyl)benzen-sulfonamid (37,2 g) og ammoniumklorid (75,4 g) i en blanding av metanol (400 ml) og vann (400 ml) ble satt jern (76,4 g) i små porsjoner i løpet av halvannen time ved 100°C. Reaksjonsblandingen ble tilbakeløpskjølt i 8 timer, og den varme blanding ble filtrert. Filterkaken ble vasket med varm metanol. De samlede filtrater ble inndampet under redusert trykk, og residuet ble ekstrahert tre ganger med etylacetat. Ekstraktene ble vasket med vann, tørret og konsentrert, hvorved man fikk et råprodukt, som ble renset ved silikagelkolonne-kromatografi (eluering med metylenklorid), hvorved man fikk 2-amino-4-metoksy-N-(4-klorfenyl)benzensulfonamid (25,77 g).
smp.: 94-96°C
IR (Nujol) : 3400, 3300, 1600, 1580, 1500 cm"<1>
NMR (CDCI3, S) : 3,76 (3H, s), 4,90 (2H, bred s), 6,20-6,30 (2H, m), 6,90-7,50 (6H, m)
FREMSTILLING 3
På lignende måte som beskrevet i fremstilling 1 ble oppnådd følgende forbindelser: (1) 4-Metoksy-2-nitro-N-(p-tolyl)benzensulfonamid smp.: 100-101°C
IR (Nujol) : 3320, 1600, 1540, 1390, 1240, 1150 cm"<1>NMR (CDCI3, S) : 2,28 (3H, s), 3,90 (3H, s), 6,90-7,40
(6H, m), 7,70 (1H, d, J=9Hz)
(2) 4-Metoksy-2-nitro-N-(fenyl)benzensulfonamid smp.: 126-128 °C
IR (Nujol) : 3400, 3300, 1600, 1540, 1460, 1170 cm<-1>
NMR (CDC13, S) : 3,90 (3H, s), 6,96 (1H, dd, J=2Hz og 9Hz), 7,10-7,40 (5H, m) , 7,72 (1H, d, J=9Hz)
(3) 4-Metoksy-2-nitro-N-(4-trifluormetylfenyl)benzensulfonamid smp.: 108-110°C
IR (Nujol) : 1600, 1540, 1460, 1330, 1170, 1120 cm"<1>NMR (CDC13, 6) : 3,90 (3H, s), 7,02 (1H, dd, J=2Hz og 9Hz), 7,20-7,70 (5H, m), 7,83 (1H, d, J=9Hz)
(4) 4-Metoksy-2-nitro-N-(3,4-diklorfenyl)benzensulfonamid smp.: 146-150°C
IR (Nujol) : 3300, 1610, 1550, 1470, 1380 cm"<1>
NMR (CDCI3, S) : 3,90 (3H, s), 6,90-7,40 (5H, m), 7,30
(1H, d, J=9Hz)
(5) 4-Metoksy-2-nitro-N-(4-fluorfenyl)benzensulfonamid smp.: 98-100°C
IR (Nujol) : 3350, 1600, 1530, 1380, 1240, 1170 cm"<1>NMR (DMS0-d6, 6) : 3,85 (3H, s), 7,00-7,20 (4H, m), 7,30
(1H, dd, J=2Hz og 9Hz), 7,55 (1H, d, J=2Hz), 7,82 (1H, d, J=9Hz), 10,5 (1H, bred s)
(6) 4-Isopropoksy-2-nitro-N-(4-metoksyfenyl)benzensulfonamid IR (CHCI3) : 1600, 1540, 1510, 1390, 1240, 1160 cm"<1>NMR (CDCI3, S) : 1,37 (6H, d, J=6Hz), 3,77 (3H, s), 4,62
(1H, m), 6,78 (1H, d, J=9Hz), 6,90 (1H, dd, J=2Hz og 9Hz), 7,00-7,30 (4H, m), 7,62 (1H, d, J=9Hz)
(7) 2-Nitro-N-(4-klorfenyl)benzensulfonamid smp.: 120-123°C
IR (Nujol) : 3300, 1600, 1550, 1490, 1460, 1340, 1170,
1160 cm"<1>
NMR (CDCI3, S) : 7,00-7,40 (4H, m), 7,50-7,95 (4H, m)
(8) 4-Klor-2-nitro-N-(4-klorfenyl)benzensulfonamid smp.: 116-118°C
IR (Nujol) : 1540, 1490, 1460, 1360, 1240, 1180,
1170cm"1
NMR (CDCI3, S) : 7,10-7,33 (4H, m), 7,55 (1H, dd, J=2Hzog 9Hz), 7,75 (1H, d, J=9Hz), 7,83 (1H, d, J=2Hz)
(9) 4-Metoksy-2-nitro-N-(2-klorfenyl)benzensulfonamid smp.: 94-95°C
IR (Nujol) : 3350, 3300, 1600, 1540, 1480, 1460,
1180 cm"1
NMR (CDCI3, S) : 3,90 (3H, s), 6,90-7,40 (5H, m), 7,60-7,90 (2H, m)
(10) 4-Metoksy-2-nitro-N-(3-klorfenyl)benzensulfonamid smp.: 137-138°C
IR (Nujol) : 3300, 1610, 1590, 1550, 1330, 1170 cm"<1>NMR (CDCI3, 6) : 3,82 (3H, s), 7,00 (1H, dd, J=2Hz og 9Hz), 7,10-7,40 (5H, m), 7,89 (1H, d, J=9Hz)
(11) 4-Isopropoksy-2-nitro-N-(4-klorfenyl)benzensulfonamid IR (CHCI3) : 1600, 1540, 1490, 1390, 1170 cm"<1>
NMR (CDCI3, S) : 1,36 (6H, d, J=6Hz), 4,62 (1H, m), 6,92
(1H, dd, J=2Hz og 9Hz), 7,0-7,5 (6H, m), 7,69 (1H, d, J=9Hz)
(12) 4-Metoksy-2-nitro-N-(4-klorbenzyl)benzensulfonamid smp.: 110,5-111,5°C
IR (Nujol) : 3320, 1610, 1530, 1165 cm"<1>
NMR (CDCI3, S) : 3,93 (3H, s), 4,25 (2H, s), 5,65 (1H,
bred s), 7,05 (1H, dd, J=2,5 og 8,8Hz), 7,18 og 7,2 0 (4H, ABq, J=8,8Hz), 7,30 (1H, d, J=2,5Hz), 7,88 (1H, d, J=8,8Hz)
(13) 4-Metoksy-2-nitro-N-cykloheksylbenzensulfonamid smp.: 91-93 °C
IR (Nujol) : 3320, 1605, 1540, 1330, 1155, 1050 cm"<1>NMR (CDCI3, 6) : 1,05-1,4 (5H, m), 1,45-1,9 (5H, m), 3,27
(1H, bred), 3,94 (3H, s), 5,13 (1H, d, J=7,3Hz), 7,16 (1H, dd, J=2,5 og 8,8Hz), 7,43 (1H, d, J=2,5Hz), 8,03
(1H, d, J=8,8Hz)
(14) 4-Isopropoksy-2-nitro-N-(2-pyridyl)benzensulfonamid smp.: 123-125°C
IR (Nujol) : 1635, 1620, 1605, 1240, 1150 cm"<1>
NMR (DMS0-d6, <S) : 1,25 (6H, d, J=5,5Hz), 4,65-4,85 (1H,
m), 6,8-6,9 (1H, m), 7,10-7,17 (1H, m), 7,26 (1H, dd, J=2Hz og 9Hz), 7,40 (1H, d, J=2Hz), 7,75-7,87 (1H,
m), 7,9-7,98 (2H, m).
(15) 4-Metoksy-2-nitro-N-(pentyl)benzensulfonamid smp.: 48-50°C
IR (Nujol) : 3300, 1600, 1560, 1350, 1340, 1160cm<_1>
NMR (DMS0-d6, S) : 0,85 (3H, t, J=7Hz), 1,10-1,60 (6H,
m), 3,05 (2H, q, J=7Hz), 3,94 (3H, s), 5,13 (1H, bred s), 7,15 (1H, dd, J=3Hz og 9Hz), 7,35 (1H, d, J=3Hz), 8,04 (1H, d, J=9Hz)
(16) 4-Acetylamino-2-nitro-N-(4-klorfenyl)benzensulfonamid smp.: 207-209 °C
IR (Nujol) : 3370, 3230, 1695, 1590, 1250, 1170,
1155cm"1
NMR (DMSO-d6, 6) : 2,15 (3H, s), 7,15 og 7,35 (4H, ABq,
J=9,0Hz), 7,72-7,85 (1H, m), 7,85-8,0 (1H, m), 8,17 (1H, s), 10,7 (1H, s), 10,75 (1H, s)
(17) 4-Metoksy-2-nitro-N-(4-metoksykarbonylfenyl)benzensulfonamid smp.: 170°C (spaltning)
IR (Nujol) : 3250, 1690, 1605, 1545, 1295 cm"<1>
NMR (DMS0-d6, S) : 3,79 (3H, s), 3,87 (3H, s), 7,25 og 7,90 (4H, ABq, J=8,5Hz), 7,33 (1H, dd, J=2Hz og 9Hz), 7,60 (1H, d, J=2,0Hz), 7,96 (1H, d, J=9Hz), 11,11
(1H, s)
(18) 4-Cykloheksylmetoksy-2-nitro-N-(2-pyridyl)benzensulfonamid smp.: 164°C (spaltning)
IR (Nujol) : 3140, 1640, 1610, 1560, 1155 cm"<1>
NMR (DMS0-d6, S) : 0,9-1,4 (5H, m), 1,5-1,9 (6H, m), 3,89
(2H, d, J=6Hz), 6,8-6,9 (1H, m), 7,1-7,2 (1H, m),
7,26 (1H, dd, J=2,4Hz og 8,8Hz), 7,43 (1H, d,
J=2,4Hz), 7,75-7,90 (1H, m), 7,9-8,0 (1H, m), 7,95
(1H, d, J=8,8Hz).
(19) 4-Metoksy-2-nitro-N-(4-metoksykarbonylmetylfenyl)benzensul-fonamid
smp.: 93-94 °C
IR (Nujol) : 3330, 1715, 1545, 1160 cm"<1>
NMR (DMS0-d6, S) : 3,33 (2H, s), 3,58 (3H, s), 3,86 (3H,
s), 7,05 og 7,15 (4H, ABq, J=8,3Hz), 7,32 (1H, dd, J=2,0 og 8,8Hz), 7,56 (1H, d, J=2,0Hz), 7,56 (1H, d, J=8,8Hz), 10,52 (1H, s)
(20) 4-Metoksy-2-nitro-N-(3-etoksykarbonylpropyl)benzensulfonamid smp.: 55-56°C
IR (Nujol) : 3350, 1720, 1610, 1550, 1470, 1380, 1280,
1170cm"1
NMR (CDC13, 6) : 1,25 (3H, t, J=7Hz), 1,86 (2H, m), 2,39
(2H, t, J=7Hz), 3,12 (2H, q, J=7Hz), 4,12 (2H, q, J=7Hz), 3,94 (3H, s), 5,33 (1H, bred s), 7,15 (1H,
dd, J=2Hz og 9Hz), 7,33 (1H, d, J=2Hz), 8,03 (1H, d, J=9Hz)
(21) 4-Metyl-2-nitro-N-(4-klorfenyl)benzensulfonamid smp.: 112-114'C
IR (Nujol) : 3350, 1600, 1550, 1490, 1430, 1380, 1360,
1340, 1170 cm"<1>
NMR (CDCI3, 6) : 2,48 (3H, s), 7,14 (2H, d, J=8Hz), 7,24
(2H, d, J=8Hz), 7,38 (1H, d, J=8Hz), 7,67 (1H, s), 7,70 (1H, d, J=8Hz)
(22) 4-Isopropoksy-2-nitro-N-[2-(4,6-dimetylpyridyl)]-benzensulfonamid
smp.: 175-180°C
IR (Nujol) : 1620, 1540, 1390, 1300, 1230, 1150 cm"<1>
NMR (DMS0-d6, S) : 1,30 (6H, d, J=6Hz), 2,20 (3H, s),
2,30 (3H, s), 4,80 (1H, m), 6,50 (1H, s), 6,82 (1H,
s), 7,22 (1H, dd, J=2Hz og 9Hz), 7,42 (1H, d, J=2Hz), 7,92 (1H, d, J=9Hz)
(23) 4-Trifluormetyl-2-nitro-N-(4-klorfenyl)benzensulfonamid smp.: 88-90°C
IR (Nujol) : 3300, 1550, 1490, 1400, 1320, 1160, 1140,
1080cm"<1>
NMR (CDC13, S) : 7,14 (2H, d, J=9Hz), 7,26 (2H, d,
J=9Hz), 7,86 (1H, d, J=9Hz), 7,98 (1H, d, J=9Hz),
8,11 (1H, s).
(24) 4-Isopropoksy-2-nitro-N-(2-pyrimidinyl)benzensulfonamid smp.: 218-220°C
IR (Nujol) : 1610, 1580, 1440, 1380, 1350, 1240,
1110 cm-1
NMR (DMS0-d6, S) : 1,30 (6H, d, J=6Hz), 4,80 (1H, m),
7,05 (1H, t, J=4Hz), 7,30 (1H, dd, J=2Hz og 9Hz),
7,48 (1H, d, J=2Hz), 8,10 (1H, d, J=9Hz), 8,50 (2H,
d, J=4Hz)
(25) 4-Metoksy-2-nitro-N-(4-fenoksyfenyl)benzensulfonamid smp.: 130-132°C
IR (Nujol) : 3330, 1600, 1540, 1240, 1170 cm"<1>
NMR (CDCI3, S) : 3,90 (3H, s), 6,85-7,40 (11H, m), 7,70
(1H, d, J=9Hz)
(26) 4-Metoksy-2-nitro-N-(4-isopropylfenyl)benzensulfonamid smp.: 108-109 °C
IR (Nujol) : 3300, 1605, 1545, 1165 cm"<1>
NMR (CDCI3, <5) : 1,20 (6H, d, J=7Hz), 2,85 (1H, m) , 3,90
(3H, s), 6,97 (1H, dd, J=2Hz og 9Hz), 7,05-7,15 (4H, m), 7,32 (1H, d, J=2Hz), 7,72 (1H, d, J=9Hz).
(27) 4-Metoksy-2-nitro-N-[(3-klor-4-metyl)fenyl]benzensulfonamid smp.: 138-139 °C
IR (Nujol) : 3300, 1600, 1545, 1170 cm"<1>
NMR (CDCI3, 6) : 2,38 (3H, s), 3,90 (3H, s), 7,00 (1H,
dd, J=2Hz og 9Hz), 7,05-7,15 (2H, m), 7,22 (1H, d, J=2Hz), 7,33 (1H, d, J=2Hz), 7,75 (1H, d, J=9Hz).
(28) 4-Metoksy-2-nitro-N-(4-metyltiofenyl)benzensulfonamid smp.: 120-121°C
IR (Nujol) : 3250, 3100, 1600, 1550, 1490, 1245,
1170 cm"<1>
NMR (CDC13, <S) : 2,44 (3H, s) , 3,90 (3H, s) , 6,97 (1H,
dd, J=2Hz og 9Hz), 7,12 (4H, s), 7,31 (1H, d, J=2Hz), 7,70 (1H, d, J=9Hz)
(29) 4-Metoksy-2-nitro-N-(4-dimetylaminofenyl)benzensulfonamid smp.: 127-128°C
IR (Nujol) : 3350, 3340, 1600, 1540, 1520, 1350, 1280,
1230, 1160 cm"<1>
NMR (DMS0-d6, <S) : 2,82 (6H, s) , 3,86 (3H, s) , 6,60 (2H,
d, J=9Hz), 6,91 (2H, d, J=9Hz), 7,28 (1H, dd, J=2Hz og 9Hz), 7,53 (1H, d, J=2Hz), 7,73 (1H, d, J=9Hz).
FREMSTILLING 4
På lignende måte som beskrevet i fremstilling 2 ble oppnådd følgende forbindelser:
(1) 2-Amino-4-metoksy-N-(P-tolyl)benzensulfonamid
IR (CHCI3) : 3500, 3400, 1610, 1570, 1450, 1150 cm"<1>NMR (CDCI3, <S) : 2,23 (3H, s) , 3,75 (3H, s) , 4,90 (2H,
bred s), 6,18-6,25 (2H, m), 6,85-7,10 (4H, m), 7,40
(1H, d, J=9Hz)
(2) 2-Amino-4-metoksy-N-(fenyl)benzensulfonamid smp.: 112-114°C
IR (Nujol) : 3500, 3400, 3200, 1630, 1610, 1500,
1470cm"<1>
NMR (CDCI3, 5) : 3,75 (3H, s), 4,90 (2H, bred s), 6,10-6,30 (2H, m), 7,00-7,30 (5H, m), 7,40 (1H, d, J=9Hz)
(3) 2-Amino-4-metoksy-N-(4-trifluormetylfenyl)benzensulfonamid smp.: 92-94 °C
IR (Nujol) : 3400, 3300, 1620, 1600, 1460, 1330,
1130 cm"<1>
NMR (CDC13, S) : 3,60 (3H, s), 6,00 (2H, bred s), 6,18
(1H, dd, J=2Hz og 9Hz), 6,22 (1H, d, J=2Hz), 7,22 (2H, d, J=7Hz), 7,52 (1H, d, J=9Hz), 7,60 (2H, d, J=7Hz), 10,7 (1H, bred s)
(4) 2-Amino-4-metoksy-N-(3,4-diklorfenyl)benzensulfonamid smp.: 135-138 °C
IR (Nujol) : 3400, 3300, 1600, 1470, 1380 cm"<1>
NMR (CDCI3, 6) : 3,77 (3H, s), 4,85 (2H, bred s), 6,19
(1H, d, J=2Hz), 6,27 (1H, dd, J=2Hz, og 9Hz), 6,80
(1H, bred s)
(5) 2-Amino-4-metoksy-N-(4-fluorfenyl)benzensulfonamid smp.: 94-97 °C
IR (CHCI3) : 3500, 3400, 3200, 1630, 1600, 1460, 1310,
1220cm"1
NMR (DMS0-d6, 6) : 3,65 (3H, s), 5,95 (2H, bred s), 6,13
(1H, dd, J=2Hz og 9Hz), 6,22 (1H, d, J=2Hz), 7,35
(1H, d, J=9Hz)
(6) 2-Amino-4-isopropoksy-N-(4-metoksyfenyl)benzensulfonamid IR (CHCI3) : 3500, 3350, 1720, 1600, 1510, 1240 cm"<1>NMR (CDCI3, <S) : 1,30 (6H, d, J=6Hz), 3,75 (3H, s) , 4,50
(1H, m), 4,80 (2H, bred s), 6,12-6,20 (2H, m), 6,72 (2H, d, J=7Hz), 6,95 (2H, d, J=7Hz), 7,80 (1H, d,
J=9Hz)
(7) 2-Amino-N-(4-klorfenyl)benzensulfonamid smp.: 100-105 °C
IR (Nujol) : 1620, 1490, 1460, 1450, 1320, 1150,
1140cm"<1>
NMR (CDCI3, <S) : 4,85 (2H, bred s) , 6,60-6,80 (2H, m) ,
6,90-7,40 (5H, m), 7,50 (1H, d, J=9Hz)
(8) 2-Amino-4-klor-N-(4-klorfenyl)benzensulfonamid
smp.: 114-115°C
IR (Nujol) : 1610, 1590, 1480, 1440, 1310, 1160,
1140 cm"<1>
NMR (CDC13, S) : 4,95 (2H, bred s), 6,63 (1H, dd, J=2Hzog 9Hz), 6,72 (1H, d, J=2Hz), 6,90-7,30 (4H, m), 7,38
(1H, d, J=9Hz)
(9) 2-Amino-4-metoksy-N-(2-klorfenyl)benzensulfonamid smp.: 137-138°C
IR (Nujol) : 3700, 3500, 3300, 1640, 1600, 1570, 1380,
1320, 1220, 1140 cm"<1>
NMR (CDCI3, 6) : 3,75 (3H, s), 4,99 (2H, bred s), 6,12
(1H, d, J=2Hz), 6,22 (1H, dd, J=2Hz og 9Hz), 6,90-7,70 (5H, m)
(10) 2-Amino-4-metoksy-N-(3-klorfenyl)benzensulfonamid smp.: 138-140°C
IR (Nujol) : 3450, 3350, 3250, 1640, 1600, 1460, 1380,
1160, 1140 cm"<1>
NMR (CDCI3, <S) : 3,75 (3H, s) , 4,90 (2H, bred s) , 6,20
(1H, d, J=2Hz), 6,25 (1H, dd, J=2Hz og 9Hz), 6,75 (1H, bred s), 6,90-7,30 (3H, m), 7,45 (1H, d, J=9Hz) (11) 2-Amino-4-isopropoksy-N-(4-klorfenyl)benzensulfonamid IR (CHCI3) : 3400, 3300, 3100, 1650, 1600, 1490,
1320cm"1
NMR (CDCI3, 6) : 1,30 (6H, d, J=6Hz), 1,50 (1H, m), 4,85
(2H, bred s) , 6,10-6,25 (2H, m) , 6,90-7,25 (4H, m) , 7,90 (1H, d, J=9Hz)
(12) 2-Amino-4-metoksy-N-(4-klorbenzyl)benzensulfonamid smp.: 121-122°C
IR (Nujol) : 3470, 3370, 3250, 1620, 1600, 1565,
1265 cm"1
NMR (CDCI3, 6) : 3,81 (3H, s), 4,00 (2H, d, J=6,0Hz),
4,85 (2H, s), 4,96 (1H, t, J=6,0Hz), 6,21 (1H, d, J=2,4Hz), 6,34 (1H, dd, J=2,4 og 8,8Hz), 7,13 og 7,23 (4H, ABq, J=8,5Hz), 7,61 (1H, d, J=8,8Hz)
(13) 2-Amino-4-metoksy-N-cykloheksylbenzensulfonamid smp.: 95-98 °C
IR (Nujol) : 3450, 3360, 3280, 1650, 1600, 1575, 1300,
1130, 1065 cm"<1>
NMR (CDC13, S) : 1,0-1,4 (5H, m), 1,4-1,8 (5H, m), 2,95-3,15 (1H, m), 3,81 (3H, s), 4,58 (1H, d, J=7,5Hz), 4,84 (2H, s), 6,22 (1H, d, J=2,3Hz), 6,35 (1H, dd, J=2,3 og 8,8Hz), 7,64 (1H, d, J=8,8Hz)
(14) 2-Amino-4-isopropoksy-N-(2-pyridyl)benzensulfonamid smp.: 176-177 °C
IR (Nujol) : 3460, 3370, 1630, 1610, 1260 cm"<1>
NMR (DMS0-d6, <S) : 1,23 (6H, d, J=6Hz) , 4,4-4,6 (1H, m) ,
6,0 (2H, bred s), 6,15 (1H, dd, J=2Hz og 9Hz), 6,22 (1H, d, J=2Hz), 6,85-6,95 (1H, m), 7,0-7,10 (1H, m), 7,52 (1H, d, J=9Hz), 7,6-7,75 (1H, m), 8,03-8,1 (1H,
m)
(15) 2-Amino-4-metoksy-N-(pentyl)benzensulfonamid
IR (Nujol) : 3500, 3350, 1620, 1320, 1300, 1160,
1140cm"1
NMR (DMS0-d6, 6) : 0,85 (3H, t, J=7Hz), 1,05-1,60 (6H,
m), 2,85 (2H, q, J=7Hz), 3,80 (3H, s), 4,60 (1H, t, J=7Hz), 4,90 (2H, bred s), 6,25 (1H, d, J=3Hz), 6,85 (1H, dd, J=3Hz og 9Hz), 7,62 (1H, d, J=9Hz)
(16) 2-Amino-4-metoksy-N-(4-metoksykarbonylfenyl)benzensulfonamid smp.: 195°C (spaltning)
IR (Nujol) : 3460, 3370, 3230, 1690, 1610, 1300 cm"<1>
NMR (DMS0-d6, S) : 3,65 (3H, s), 3,75 (3H, s), 6,03 (2H,
bred s), 6,15-6,30 (2H, m), 7,14 og 7,80 (4H, ABq, J=9,5Hz), 7,50 (1H, d, J=9,5Hz), 10,68 (1H, bred s)
(17) 2-Amino-4-cykloheksylmetoksy-N-(2-pyridyl)benzensulfonamid smp.: 213-214°C
IR (Nujol) : 3460, 3360, 1630, 1620, 1130 cm"<1>
NMR (DMS0-d6, <S) : 0,85-1,4 (5H, m) , 1,55-1,85 (6H, m) ,
3,70 (2H, d, J=6Hz), 6,0 (2H, bred s), 6,16 (1H, dd,
J=2,3Hz og 8,8Hz), 6,23 (1H, d, J=2,3Hz), 6,83-6,95 (1H, m), 7,0-7,08 (2H, m), 7,53 (1H, d, J=8,8Hz), 7,6-7,72 (1H, m), 8,0-8,1 (1H, m)
(18) 2-Amino-4-metoksy-N-(4-metoksykarbonylmetylfenyl)benzen-sulf onamid
smp.: 111-113°C
IR (Nujol) : 3450, 3360, 3270, 1720, 1595, 1135 cm"<1>
NMR (DMS0-d6, 5) : 3,54 (2H, s), 3,57 (3H, s), 3,67 (3H,
s), 5,99 (2H, s, NH2), 6,1-6,2 (1H, m), 6,22-6,27
(1H, m), 6,96 og 7,10 (4H, ABq, J=8,2Hz), 7,42 (1H,
d, J=8,8Hz), 10,1 (1H, bred s)
(19) 2-Amino-4-metoksy-N-(3-etoksykarbonylpropyl)benzensulfonamid smp.: 53-54 °C
IR (Nujol) : 3500, 3400, 3300, 1710, 1630, 1610, 1570,
1470, 1380, 1310, 1270, 1220, 1160 cm"<1>
NMR (CDC13, S) : 1,24 (3H, t, J=7Hz), 1,76 (2H, m), 2,33
(2H, t, J=7Hz), 2,91 (2H, q, J=7Hz), 3,80 (3H, s), 4,10 (2H, q, J=7Hz), 4,85 (1H, bred s), 6,23 (1H, d, J=2Hz), 6,35 (1H, dd, J=2Hz og 9Hz), 7,61 (1H, d, J=9Hz)
(20) 2-Amino-4-metyl-N-(4-klorfenyl)benzensulfonamid smp.: 96-98°C
IR (Nujol) : 3400, 3300, 3100, 1610, 1500, 1330, 1230,
1140 cm"1
NMR (CDCI3, S) : 2,25 (3H, s), 4,77 (2H, bred s), 6,50
(1H, d, J=8Hz), 6,54 (1H, s), 7,00 (2H, d, J=8Hz)
(21) 2-Amino-4-isopropoksy-N-[2-(4,6-dimetylpyridyl)]benzen-sulfonamid
smp.: 180-182 °C
IR (Nujol) : 3450, 3350, 3250, 1620, 1600, 1400, 1250,
1130 cm-1
NMR (DMS0-d6, 6) : 1,22 (6H, d, J=6Hz), 2,15 (3H, s),
2,22 (3H, s), 4,50 (1H, m), 5,85 (2H, bred s), 6,12
(1H, d, J=9Hz), 6,22 (1H, s), 6,50 (1H, s), 6,70 (1H, s), 7,50 (1H, d, J=9Hz)
(22) 2-Amino-4-trifluormetyl-N-(4-klorfenyl)benzensulfonamid smp.: 100-102 °C
IR (Nujol) : 3420, 3350, 1630, 1500, 1340, 1190, 1140,
1090 cm-1
NMR (CDC13, S) : 5,00 (2H, bred s), 6,70-7,40 (6H, m),
7,70 (1H, d, J=9Hz)
(23) 2-Amino-4-isopropoksy-N-(2-pyrimidinyl)benzensulfonamid smp.: 204-206°C
IR (Nujol) : 3400, 3300, 1610, 1580, 1500, 1450, 1380,
1320, 1130 cm-<1>
NMR (DMS0-d6, S) : 1,25 (6H, d, J=6Hz), 1,45 (1H, m),
6,00 (2H, bred s), 6,15 (1H, d, J=9Hz), 7,00 (1H, t, J=4Hz), 7,60 (1H, d, J=9Hz), 8,50 (2H, d, J=4Hz),
11,4 (1H, bred s)
(24) 2-Amino-4-metoksy-N-(4-fenoksyfenyl)benzensulfonamid smp.: 100-101°C
IR (Nujol) : 3460, 3360, 3270, 1600, 1310, 1245,
1135cm"1
NMR (CDCI3, S) : 3,50 (2H, bred), 3,77 (3H, s), 6,25
(1H, d, J=2Hz), 6,26 (1H, dd, J=2Hz og 9Hz), 6,73
(1H, bred s), 6,80-7,45 (10H, m)
(25) 2-Amino-4-metoksy-N-(4-isopropylfenyl)benzensulfonamid smp.: 98-99°C
IR (Nujol) : 3460, 3360, 3260, 1605, 1575, 1305,
1215 cm"<1>
NMR (CDCI3, 6) : 1,18 (6H, d, J=7Hz), 2,82 (1H, m), 3,45
(2H, bred), 3,76 (3H, s), 6,23 (1H, dd, J=2Hz og 9Hz), 6,25 (1H, d, J=2Hz), 6,72 (1H, bred s), 6,95 og 7,05 (4H, ABq, J=9Hz), 7,40 (1H, d, J=9Hz)
(26) 2-Amino-4-metoksy-N-[(3-klor-4-metyl)fenyl]benzensulfonamid smp.: 138-139°C
IR (Nujol) : 3420, 3350, 3250, 1600, 1315, 1140 cm"<1>
NMR (CDC13, 6) : 2,27 (3H, s), 3,45 (2H, bred), 6,24 (1H,
d, J=2Hz), 6,27 (1H, dd, J=2Hz og 9Hz), 6,80 (1H,
bred s), 6,85 (1H, dd, J=2Hz og 9Hz), 7,05 (1H, d, J=9Hz), 7,08 (1H, d, J=2Hz), 7,43 (1H, d, J=9Hz)
(27) 2-Amino-4-metoksy-N-(4-metyltiofenyl)benzensulfonamid smp.: 91-92 °C
IR (Nujol) : 3450, 3375, 3250, 1625, 1600, 1570, 1490,
1215, 1160, 1140 cm"<1>
NMR (CDCI3, 6) : 2,51 (3H, s), 3,86 (3H, s), 6,50 (1H, d,
J=2Hz), 6,82 (1H, dd, J=2Hzog 9Hz), 7,36 (4H, s), 7,79 (1H, d, J=9Hz), 8,51 (1H, s)
(28) 2-Amino-4-metoksy-N-(4-dimetylaminofenyl)benzensulfonamid smp.: 119-121°C
IR (Nujol) : 3450, 3440, 3350, 3250, 1600, 1520, 1210,
1160, 1140 cm"<1>
NMR (DMSO-d6, S) : 2,79 (6H, s) , 3,68 (3H, s) , 6,10 (1H,
dd, J=2Hz og 9Hz), 6,24 (1H, d, J=2Hz), 6,55 (2H, d, J=9Hz), 6,85 (2H, d, J=9Hz), 7,26 (1H, d, J=9Hz),
9,42 (1H, s)
FREMSTILLING 5
Til en oppløsning av 4-acetylamino-2-nitro-N-(4-klorfenyl)benzen-sulfonamid (4,85 g) i etylacetat (485 ml) ble satt 10% palladium på karbon, og blandingen ble hydrogenert ved romtemperatur under atmosfæretrykk i syv timer. Katalysatoren ble fjernet ved filtrering, og oppløsningsmidlet ble inndampet under redusert trykk. Residuet ble triturert med diisopropyleter og oppsamlet ved filtrering, hvorved man fikk 4-acetylamino-2-amino-N-(4-klorfenyl)benzensulfonamid som et farveløst pulver (4,76 g).
smp.: 127°C (spaltning)
IR (Nujol) : 3340, 1665, 1600, 1310, 1135 cm"<1>
NMR (DMS0-d6, 6) : 2,01 (3H, s), 5,87 (2H, bred), 6,67- 6,75 (1H, m) , 7,0-7,56 (6H, m) , 9,95 (1H, bred), 10,4
(1H, bred)
EKSEMPEL 1
En blanding av 2-amino-4-metoksy-N-(4-klorfenyl)benzensulfonamid (24,37 g) og 1,1'-karbonyldiimidazol (18,93 g) i tørt dioksan (500 ml) ble tilbakeløpskjølt natten over og derefter konsentrert til tørrhet. Residuet ble vasket med metanol og oppsamlet ved filtrering, hvorved man fikk 2-(4-klorfenyl)-6-metoksy-2H-1,2,4-benzotiadiazin-3(4H)-on-1,1-dioksyd (23,9 g).
smp.: 229-230°C
IR (Nujol) : 1700, 1610, 1600, 1480, 1360, 1300 cm"<1>
NMR (DMS0-d6, 6) : 3,38 (1H, bred s), 3,85 (3H, s),
6,30-7,00 (2H, m), 7,40-7,70 (4H, m), 7,85 (1H, d, J=9Hz)
EKSEMPEL 2
Til en oppløsning av 2-(4-klorfenyl)-6-metoksy-2H-l,2,4-benzo-tiadiazin-3(4H)-on-1,1-dioksyd (23,50 g) i tørt N,N-dimetylformamid (150 ml) ble satt natriumhydrid (60% oljedispersjon) i én porsjon ved 0°C. Suspensjonen ble omrørt i én time ved omgivelsestemperatur, og derefter ble metyljodid (5,18 ml) tilsatt ved den samme temperatur. Reaksjonsblandingen ble omrørt i halvannen time ved omgivelsestemperatur og derefter hellet i isvann. Det fraskilte faste stoff ble filtrert, tørret og omkrystallisert fra etanol, hvorved man fikk 2-(4-klorfenyl)-6-metoksy-4-metyl-2H-l,2,4-benzotiadiazin-3(4H)-on-1,1-dioksyd (21,07 g) som nåleformede hvite krystaller,
smp.: 167-168"C
IR (Nujol) : 1710, 1600, 1330, 1180, 1130 cm"<1>
NMR (DMS0-d6, <S) : 3,42 (3H, s) , 3,95 (3H, s) , 6,95-7,10
(2H, m), 7,38-7,65 (2H, m), 8,90 (1H, d, J=9Hz)
EKSEMPEL 3
Til en oppløsning av 2-(4-klorfenyl)-6-metoksy-4-metyl-2H-1,2,4-benzotiadiazin-3(4H)-on-1,1-dioksyd (21,0 g) i metylenklorid (200 ml) ble satt bortribromid (IN oppløsning i metylenklorid, 89,2 ml) ved omgivelsestemperatur. Blandingen ble omrørt i 8 timer ved den samme temperatur og derefter hellet i isvann. Det fraskilte faste stoff ble oppsamlet ved filtrering, tørret og omkrystallisert fra etanol, hvorved man fikk 2-(4-klorfenyl)-6-hydroksy-4-metyl-2H-l,2,4-benzotiadiazin-3(4H)-on-1,1-dioksyd (18,86 g).
smp.: >250°C
IR (Nujol) : 3300, 1660,,1650,1610 cm"<1>
NMR (DMS0-d6, S) : 3,45 (3H, s), 6,80 (1H, d, J=9Hz),
7,90 (1H, s), 7,35-7,65 (4H, m), 7,70 (1H, d, J=9Hz)
EKSEMPEL 4
En suspensjon av 2-(4-klorfenyl)-6-hydroksy-4-metyl-2H-l,2,4-benzotiadiazin-3(4H)-on-1,1-dioksyd (15,33 g), kaliumkarbonat (7,50 g) og 2-jodpropan (5,43 ml) i N,N-dimetylformamid (150 ml) ble omrørt i 2 timer ved 60°C. Blandingen ble hellet i isvann. Det fraskilte faste stoff ble oppsamlet ved filtrering, tørret og omkrystallisert fra etanol, hvorved man fikk 2-(4-klorfenyl)-6-isopropoksy-4-metyl-2H-l,2,4-benzotiadiazin-3(4H)-on-1,1-dioksyd (13,54 g) som en hvit krystall,
smp.: 157-159°C
IR (Nujol) : 1700, 1605, 1460, 1330, 1320, 1300 cm"<1>
NMR (DMS0-d6, 6) : 1,32 (3H, s), 1,35 (3H, s), 3,50 (3H,
s), 4,89 (1H, m), 7,00 (1H, d, J=9Hz), 7,02 (1H, s), 7,35-7,60 (4H, m), 7,85 (1H, d, J=9Hz)
EKSEMPEL 5
På lignende måte som beskrevet i eksempel 1 ble oppnådd følgende forbindelser: (1) 6-Metoksy-2-(p-tolyl)-2H-1,2,4-benzotiadiazin-3(4H)-on-1,1-dioksyd
smp. : 228-23C<T>C
IR (Nujol) : 1710, 1700, 1630, 1610, 1480, 1400, 1340,
1200, 1120 cm"<1>
NMR (DMS0-d6, S) : 2,38 (3H, s), 3,88 (3H, s), 6,70-7,10
(2H, m), 7,20-7,50 (4H, m), 7,85 (1H, d, J=9Hz), 11,45 (1H, bred s)
(2) 6-Metoksy-2-fenyl-2H-l,2,4-benzotiadiazin-3(4H)-on-1,1-dioksyd
smp.: 2 03-2 35 ° C
IR (Nujol) : 3500, 1700, 1690, 1610, 1590, 1460,
1370 cm"<1>
NMR (DMS0-d6, <S) : 3,85 (3H, s) , 6,80 (1H, s) , 6,95 (1H,
d, J=9Hz), 7,30-7,70 (5H, m), 7,82 (1H, d, J=9Hz), 11,5 (1H, bred s)
(3) 6-Metoksy-2-(4-trifluormetylfenyl)-2H-1,2,4-benzotiadiazin-3(4H)-on-1,1-dioksyd
smp.: 202-204 °C
IR (Nujol) : 1700, 1610, 1590, 1460, 1380, 1320,
1180 cm"<1>
NMR (DMS0-d6, S) : 3,85 (3H, s), 6,50 (1H, d, J=2Hz),
6,85 (1H, dd, J=2Hzog 9Hz), 7,62 (2H, d, J=7Hz), 7,72 (2H, d, J=7Hz), 7,80 (1H, d, J=9Hz)
(4) 2-(3,4-Diklorfenyl)-6-metoksy-2H-l,2,4-benzotiadiazin-3(4H)-on-1,1-dioksyd
smp. : 239-24CC
IR (Nujol) : 1720, 1600, 1470, 1360, 1190 cm
NMR (DMSO-d6, 6) : 3,45 (3H, s), 6,70-7,00 (2H, m), 7,45
(1H, d, J=8Hz), 7,70-7,95 (3H, m), 11,50 (1H, bred s)
(5) 2-(4-Fluorfenyl)-6-metoksy-2H-l,2,4-benzotiadiazin-3(4H)-on-1,1-dioksyd
smp.: 224-225°C
IR (Nujol) : 3250, 3150, 1690, 1600, 1360, 1290, 1180,
1170, 1150 cm"<1>
NMR (DMS0-d6, S) : 3,85 (3H, s), 6,80 (1H, s), 6,92 (1H,
d, J=10Hz), 7,30-7,60 (4H, m), 7,85 (1H, d, J=10Hz)
(6) 6-Isopropoksy-2-(4-metoksyfenyl)-2H-1,2,4-benzotiadiazin-3(4H)on-1,1-dioksyd
smp.: 208-210°C
IR (Nujol) : 3200, 1700, 1620, 1590, 1460 cm"<1>
NMR (DMS0-d6, S) : 1,32 (6H, d, J=6Hz), 3,82 (3H, s),
4,69 (1H, m), 6,76 (1H, d, J=2Hz), 6,90 (1H, dd, J=2Hz og 9Hz), 7,05 (2H, d, J=7Hz), 7,30 (2H, d, J=7Hz), 7,80 (1H, d, J=9Hz), 11,4 (1H, bred s)
(7) 6-Klor-2-(4-klorfenyl)-2H-1,2,4-benzotiadiazin-3(4H)-on-1,1-dioksyd
smp.: 235-237 °C
IR (Nujol) : 1720, 1710, 1600, 1580, 1460, 1310, 1170,
1160, 1100 cm"<1>
NMR (DMS0-d6, <5): 7,20-7,75 (6H, m) , 7,98 (1H, d, J=9Hz),
11,8 (1H, bred s)
(8) 2-(2-Klorfenyl)-6-metoksy-2H-l,2,4-benzotiadiazin-3(4H)-on-1,1-dioksyd
smp.: 234-235°C
IR (Nujol) : 3400, 1720, 1620, 1600, 1590, 1460, 1320,
1290, 1140 cm"<1>
NMR (DMS0-d6, S) : 3,87 (3H, s), 6,87 (1H, s), 9,24 (1H,
dd, J=2Hz og 9Hz), 7,50-7,72 (4H, m), 7,84 (1H, d, J=9Hz), 11,6 (1H, bred s)
(9) 2-(3-Klorfenyl)-6-metoksy-2H-l,2,4-benzotiadiazin-3(4H)-on-1,1-dioksyd
smp.: 204-205°C
IR (Nujol) : 1700, 1590, 1470, 1370, 1350, 1200, 1170,
1140 cm"<1>
NMR (DMS0-d6, 6) : 3,90 (3H, s), 6,80 (1H, d, J=2Hz),
6,92 (1H, dd, J=2Hz og 9Hz), 7,30-7,75 (3H, m), 7,85
(1H, d, J=9Hz)
(10) 2-(4-Klorfenyl)-6-isopropoksy-2H-l,2,4-benzotiadiazin-3(4H)-on-1,1-dioksyd
smp. : 132-133 °C
IR (Nujol) : 1700, 1460, 1370, 1340 cm"<1>
NMR (DMS0-d6, <5) : 1,32 (6H, d, J=6Hz), 4,70 (1H, m) ,
6,78 (1H, d, J=2Hz), 6,90 (1H, dd, J=2Hz og 9Hz), 7,42 (2H, d, J=7Hz), 7,60 (2H, d, J=7Hz), 7,90 (1H,
d, J=9Hz)
(11) 2-(4-Klorbenzyl)-6-metoksy-2H-l,2,4-benzotiadiazin-3(4H)-on-1,1-dioksyd
smp.: 199-200°C
IR (Nujol)' : 3200, 3060, 1695, 1610, 1590, 1335,
1320 cm"<1>
NMR (DMS0-d6, 6) : 3,84 (3H, s), 4,95 (2H, s), 6,77 (1H,
d, J=2,0Hz), 6,90 (1H, dd, J=2,0 og 9,0Hz), 7,35 og 7,40 (4H, ABq, J=8,7Hz), 7,80 (1H, d, J=9,0Hz), 11,37
(1H, bred)
(12) 2-Cykloheksyl-6-metoksy-2H-l,2,4-benzotiadiazin-3(4H)-on-1,1-dioksyd
smp.: 190-191°C
IR (Nujol) : 3200, 3070, 1690, 1600, 1185, 1170 cm"<1>
NMR (DMS0-d6, S) : 1,0-1,5 (3H, m), 1,5-1,95 (5H, m),
2,1-2,4 (2H, m), 3,82 (3H, s), 4,2-4,45 (1H, m), 6,73 (1H, s), 6,85 (1H, dd, J=2,2og 8,8Hz), 7,72 (1H, d, J=8,8Hz), 11,17 (1H, bred)
(13) 6-1sopropoksy-2-(2-pyridyl)-2H-1,2,4-benzotiadiazin-3(4H)-on-1,1-dioksyd
smp.: 183-184°C
IR (Nujol) : 3450, 1745, 1615, 1340 cm"<1>
NMR (DMS0-d6, 6) : 1,32 (6H, d, J=6Hz) , 4,6-4,8 (1H, m) ,
6,81 (1H, d, J=2,2Hz), 6,90 (1H, J=2,2Hz og 8,8Hz), 7,45-7,6 (2H, m), 7,76 (1H, d, J=8,8Hz), 7,95-8,06 (1H, m), 8,55-8,65 (1H, m), 11,48 (1H, bred s)
(14) 6-Metoksy-2-pentyl-2H-l,2,4-benzotiadiazin-3(4H)-on-1,1-dioksyd
smp.: 100-104°C
IR (Nujol) : 1690, 1610, 1600, 1470, 1350, 1330 cm"<1>NMR (DMS0-d6,, S) : 0,85 (3H, t, J=6Hz), 1,15-1,40 (4H,
m), 1,50-1,70 (2H, m), 3,73 (3H, t, J=7Hz), 3,83 (3H, s), 6,73 (1H, d, J=2Hz), 6,87 (1H, dd, J=2Hz og 9Hz), 7,76 (1H, d, J=9Hz)
(15) 6-Acetylamino-2-(4-klorfenyl)-2H-1,2,4-benzotiadiazin-3(4H)-on-1,1-dioksyd
smp.: >250°C
IR (Nujol) : 3360, 1725, 1600, 1325 cm"<1>
NMR (DMS0-d6, <5) : 2,11 (3H, s) , 7,4-7,5 (3H, m) , 7,55-7,67 (2H, m), 7,80-7,90 (2H, m), 10,51 (1H, s), 11,60
(1H, s)
(16) 6-Metoksy-2-(4-metoksykarbonylfenyl)-2H-1,2,4-benzotiadiazin-3(4H)-on-1,1-dioksyd
smp.: 2 31-233 °C
IR (Nujol) : 3260, 1720, 1695, 1600, 1335, 1320 cm"<1>NMR (DMS0-d6, S) : 3,88 (3H, s), 3,91 (3H, s), 6,84 (1H,
d, J=2Hz), 6,95 (1H, dd, J=2Hzog 9Hz), 7,60 og 8,10 (4H, ABq, J=8,5Hz), 7,85 (1H, d, J=9Hz) , 11,58 (1H, bred s)
(17) 6-Cykloheksylmetoksy-2-(2-pyridyl)-2H-1,2,4-benzotiadiazin-3(4H)-on-1,1-dioksyd
smp.: 206-208°C
IR (Nujol) : 3150, 1745, 1610, 1595, 1340, 1325, 1310,
1180cm"<1>
NMR (DMS0-d6, S) : 0,9-1,4 (5H, m), 1,55-1,9 (6H, m),
3,99 (2H, d, J=6Hz), 6,82 (1H, d, J=2,lHz), 6,92 (1H, dd, J=2,lHz og 8,8Hz) 7,45-7,6 (2H, m) , 7,77 (1H, d, J=8,8Hz), 7,95-8,08 (1H, m) , 8,55-8,65 (1H, m) , 11,49
(1H, bred s)
(18) 2-(4-Metoksykarbonylmetylfenyl)-6-metoksy-2H-l,2,4-benzo-tiadiazin-3(4H)-on-1,1-dioksyd
smp.: 214-215°C
IR (Nujol) : 3200, 1720, 1700, 1340 cm"<1>
NMR (DMS0-d6, 6) : 3,65 (3H, s), 3,79 (2H, s), 3,86 (3H,
s), 6,80-6,85 (1H, m), 6,43 (1H, dd, J=2,0 og 9,0Hz), 7,35 og 7,45 (4H, ABq, J=8,3Hz), 7,85 (1H, d, J=9,0Hz), 11,5 (1H, bred)
(19) 2-(3-Etoksykarbonylpropyl)-6-metoksy-2H-l,2,4-benzotia-diazin-3(4H)-on-1,1-dioksyd
smp.: 118-120°C
IR (Nujol) : 3250, 1730, 1700, 1450, 1380, 1320 cm"<1>NMR (DMS0-d6, <5) : 1,15 (3H, t, J=7Hz), 1,88 (2H, m) ,
2,34 (2H, t, J=7Hz), 3,35 (1H, bred s), 3,60-3,80 (2H, m), 6,88 (1H, dd, J=2Hz og 9Hz), 7,77 (1H, d, J=9Hz)
(20) 2-(4-Klorfenyl)-6-metyl-2H-l,2,4-benzotiadiazin-3(4H)-on-1,1-dioksyd
smp.: 245-248 °C
IR (Nujol) : 1690, 1610, 1590, 1490, 1350, 1190, 1150,
1090cm"1
NMR (DMS0-d6, S) : 2,41 (3H, s), 3,35 (1H, bred s), 7,13
(1H, s), 7,18 (1H, d, J=8Hz), 7,46 (2H, d, J=8Hz), 7,60 (2H, d, J=8Hz), 7,79 (1H, d, J=8Hz)
(21) 2-[2-(4,6-Dimetylpyridyl)]-6-isopropoksy-2H-l,2,4-benzo-tiadiazin-3(4H)-on-1,1-dioksyd
smp.: 188-190°C
IR (Nujol) : 3600, 1740, 1600, 1330, 1180 cm"<1>
NMR (DMS0-d6, S) : 1,33 (6H, d, J=8Hz), 2,35 (3H, s),
2,45 (3H, s), 4,72 (1H, m) , 6,80 (1H, d, J=2Hz), 6,90 (1H, dd, J=2Hz og 9Hz), 7,10 (1H, s), 7,25 (1H, s), 7,75 (1H, d, J=9Hz)
(22) 2-(4-Klorfenyl)-6-trifluormetyl-2H-l,2,4-benzotiadiazin-3(4H)-on-1,1-dioksyd
smp.: 234-235°C
IR (Nujol) : 1720, 1600, 1490, 1360, 1340, 1190, 1140,
1090cm"<1>
NMR (DMS0-d6, S) : 7,40-7,80 (6H, m), 8,17 (1H, d,
J=9Hz)
(23) 6-Isopropoksy-2-(2-pyrimidinyl)-2H-1,2,4-benzotiadiazin-3(4H)-on-1,1-dioksyd
smp.: 168-170°C
IR (Nujol) : 3600, 1740, 1600, 1570, 1350, 1320,
1180 cm"<1>
NMR (DMS0-d6, S) : 1,30 (6H, d, J=6Hz), 4,72 (1H, m),
6,80 (1H, d, J=2Hz), 6,92 (1H, dd, J=2Hz og 9Hz), 7,70 (1H, t, J=4Hz), 7,80 (1H, d, J=9Hz), 9,00 (2H, d, J=4Hz), 11,65 (1H, bred s)
(24) 6-Metoksy-2-(4-fenoksyfenyl)-2H-1,2,4-benzotiadiazin-3(4H)-on-1,1-dioksyd
smp. : 247-248 °C
IR (Nujol) : 3210, 3110, 3060, 1700, 1595, 1340,
1245 cm"<1>
NMR (DMS0-d6, <S) : 3,86 (3H, s) , 6,81 (1H, d, J=2Hz),
6,92 (1H, dd, J=2Hzog 9Hz), 7,00-7,55 (9H, m), 7,82 (1H, d, J=9Hz), 11,47 (1H, bred)
(25) 2-(4-Isopropylfenyl)-6-metoksy-2H-l,2,4-benzotiadiazin-3(4H)-on-1,1-dioksyd
smp.: 213-214°C
IR (Nujol) : 3200, 2960, 1695, 1610, 1590, 1195 cm"<1>
NMR (DMSO-d6, 5) : 1,25 (6H, d, J=7Hz), 3,00 (1H, m) ,
3,86 (3H, s), 6,81 (1H, d, J=2Hz), 6,92 (1H, dd,
J=2Hz og 9Hz), 7,30 og 7,40 (4H, ABq, J=8,5Hz), 7,81 (1H, d, J=9Hz), 11,45 (1H, bred)
(26) 2-[(3-Klor-4-metyl)fenyl]-6-metoksy-2H-l,2,4-benzotiadiazin-3(4H)-on-1,1-dioksyd
smp. : 222-223 °C
IR (Nujol) : 3220, 1710, 1600, 1180 cm"<1>
NMR (DMS0-d6, <S) : 2,40 (3H, s) , 3,87 (3H, s) , 6,80 (1H,
d, J=2Hz), 7,32 (1H, dd, J=2Hz og 8,5Hz), 7,5 (1H, d, J=2Hz), 7,52 (1H, d, J=8,5Hz), 7,83 (1H, d, J=9Hz), 9,93 (1H, dd, J=2Hz og 9Hz), 11,5 (1H, bred s)
(27) 6-Metoksy-2-(4-metyltiofenyl)-2H-1,2,4-benzotiadiazin-3(4H)-on-1,1-dioksyd
smp.: 218-219 °C
IR (Nujol) : 1685, 1590, 1210, 1190, 1180 cm"<1>
NMR (DMS0-d6, <S) : 2,51 (3H, s) , 3,86 (3H, s) , 6,81 (1H,
d, J=2Hz), 6,92 (1H, dd, J=2Hz og 9Hz), 7,31 (2H, d, J=8Hz), 7,39 (2H, d, J=8Hz), 7,82 (1H, d, J=9Hz)
(28) 2-(4-Dimetylaminofenyl)-6-metoksy-2H-l,2,4-benzotiadiaz in-3(4H)-on-1,1-dioksyd
smp.: >250 °C
IR (Nujol) : 1680, 1600, 1520, 1350, 1210, 1170 cm"<1>
NMR (DMS0-d6, 6) : 2,96 (6H, s), 3,85 (3H, s), 6,76 (2H,
d, J=9Hz), 7,13 (2H, d, J=9Hz), 6,79 (1H, d, J=2Hz), 6,90 (1H, dd, J=2Hz og 9Hz), 7,79 (1H, d, J=9Hz)
EKSEMPEL 6
På lignende måte som beskrevet i eksempel 2 ble oppnådd følgende forbindelser: (1) 6-Metoksy-4-metyl-2-(P-tolyl)-2H-1,2,4-benzotiadiazin-3(4H)-on-1,1-dioksyd
smp.: 170-173°C
IR (Nujol) : 1690, 1460, 1440, 1330, 1310, 1180,
1130 cm"<1>
NMR (DMSO-d6,6) : 3,50 (3H, s), 3,95 (3H, s), 6,95-7,10
(2H, m), 7,20-7,40 (4H, m), 7,95 (1H, d, J=9Hz)
(2) 6-Metoksy-4-metyl-2-fenyl-2H-l,2,4-benzotiadiazin-3(4H)-on-1,1-dioksyd
smp.: 203-206°C
IR (Nujol) : 1710, 1700, 1600, 1450, 1330, 1300, 1220,
1180cm"1
NMR (DMS0-d6, S) : 3,50 (3H, s), 3,95 (3H, s), 7,00 (1H,
d, J=9Hz), 7,05 (1H, s), 7,35-7,65 (5H, m), 7,88 (1H, d, J=9Hz)
(3) 6-Metoksy-4-metyl-2-(4-trifluormetylfenyl)-2H-1,2,4-benzo-tiadiazin-3(4H)-on-1,1-dioksyd
smp.: 165-168 °C
IR (Nujol) : 1700, 1610, 1580, 1460, 1340, 1170,
1140cm"1
NMR (DMS0-d6, <5) : 3,52 (3H, s) , 3,95 (3H, s) , 7,02 (1H,
dd, J=2Hz og 9Hz), 7,10 (1H, d, J=2Hz), 7,65 (2H, d, J=7Hz), 7,92 (1H, d, J=9Hz), 7,98 (2H, d, J=7Hz)
(4) 2-(3,4-Diklorfenyl)-6-metoksy-4-metyl-2H-l,2,4-benzotiadia-zin-3(4H)-on-1,1-dioksyd
smp.: 150-151°C
IR (Nujol) : 1710,,1600, 1470, 1340, 1320 cm"<1>
NMR (DMS0-d6, 6) : 3,50 (3H, s), 3,95 (3H, s), 7,02 (1H,
d, J=9Hz), 7,06 (1H, s), 7,45 (1H, d, J=8Hz), 7,70-8,00 (3H, m)
(5) 2-(4-Fluorfenyl)-6-metoksy-4-metyl-2H-l,2,4-benzotiadiazin-3(4H)-on-1,1-dioksyd
smp.: 203-204 °C
IR (Nujol) : 1700, 1590, 1440 cm"<1>
NMR (DMS0-d6, <S) : 3,52 (3H, s) , 3,95 (3H, s) , 7,02 (1H, d, J=9Hz), 7,10 (1H, s), 7,30-7,60 (4H, m), 7,90 (1H, d, J=9Hz)
(6) 6-Isopropoksy-2-(4-metoksyfenyl)-4-metyl-2H-l,2,4-benzotia-diazin-3(4H)-on-1,1-dioksyd
smp.: 182-183°C
IR (Nujol) : 1690, 1600, 1460, 1370, 1340 cm"<1>
NMR (DMS0-d6, S) : 1,34 (6H, d, J=6Hz), 3,50 (3H, s),
3,82 (3H, s), 4,89 (1H, m), 7,00-7,08 (4H, m), 7,25-7,32 (2H, m), 7,84 (1H, d, J=9Hz)
(7) 2-(4-Klorfenyl)-4-metyl-2H-l,2,4-benzotiadiazin-3(4H)-on-1,1-dioksyd
smp.: 178-180°C
IR (Nujol) : 1690, 1600, 1500, 1470, 1450, 1350, 1270,
1180, 1140 cm"<1>
NMR (DMS0-d6, 6) : 3,53 (3H, s), 7,40-8,00 (8H, m)
(8) 6-Klor-2-(4-klorfenyl)-4-metyl-2H-l,2,4-benzotiadiazin-3(4H)-on-1,1-dioksyd
smp.: 154-157°C
IR (Nujol) : 1700, 1590, 1560, 1460, 1340, 1310,
1180 cm"<1>
NMR (DMS0-d6, 6) : 3,51 (3H, s), 7,43 (2H, d, J=8Hz),
7,52 (1H, dd, J=lHz og 8Hz), 7,57 (2H, d, J=8Hz), 7,78 (1H, d, J=lHz), 8,00 (1H, d, J=8Hz)
(9) 2-(2-Klorfenyl)-6-metoksy-4-metyl-2H-1,2,4benzotiadiazin-3(4H)-on-1,1-dioksyd
smp.: 155-156°C
IR (Nujol) : 1710, 1600, 1460, 1330, 1300, 1180,
1140 cm"<1>
NMR (DMS0-d6, 6) : 3,54 (3H, s), 3,95 (3H, s), 7,03 (1H,
dd, J=2Hz og 9Hz), 7,11 (1H, d, J=2Hz), 7,50-7,70
(4H, m), 7,90 (1H, d, J=9Hz)
(10) 2-(3-Klorfenyl)-6-metoksy-4-metyl-2H-l,2,4-benzotiadiazin-3(4H)-on-1,l-dioksyd smp.: 153-154°C
IR (Nujol) : 1710, 1600, 1590, 1460, 1340, 1320, 1180,
1130, 1060, 1030 cm"<1>
NMR (DMS0-d6, S) : 3,51 (3H, s), 3,94 (3H, s), 7,02 (1H,
dd, J=2Hz og 9Hz), 7,07 (1H, d, J=2Hz), 7,34-7,65 (4H, m), 7,90 (1H, d, J=9Hz)
(11) 6-Isopropoksy-4-metyl-2-(P-tolyl)-2H-1,2,4-benzotiadiazin-3(4H)-on-1,1-dioksyd
smp.: 163-165°C
IR (Nujol) : 1690, 1600, 1580, 1340, 1320, 1130,
1110cm"1
NMR (DMS0-d6, S) : 1,33 (3H, s), 1,36 (3H, s), 2,38 (3H,
s), 3,49 (3H, s), 4,90 (1H, m), 6,90-7,10 (2H, m), 7,20-7,34 (4H, m), 7,84 (1H, d, J=8Hz)
(12) 6-Isopropoksy-4-metyl-2-fenyl-2H-l,2,4-benzotiadiazin-3(4H)-on-1,1-dioksyd
smp.: 134-135°C
IR (Nujol) : 1690, 1600, 1580, 1450, 1340, 1190 cm"<1>NMR (CDC13, 6) : 1,42 (6H, d, J=6Hz), 3,55 (3H, s), 4,70
(1H, m), 6,70-7,90 (2H, m), 7,35-7,60 (5H, m), 7,82
(1H, d, J=9Hz)
(13) 2-(3,4-Diklorfenyl)-6-isopropoksy-4-metyl-2H-1,2,4-benzo-tiadiazin-3(4H)-on-1,1-dioksyd
smp.: 109-110 0 C
IR (Nujol) : 1710, 1570, 1460, 1350, 1320 cm"<1>
NMR (DMS0-d6, 6) : 1,34 (6H, d, J=5Hz), 3,49 (3H, s),
4,90 (1H, m), 7,01 (1H, d, J=8Hz), 7,03 (1H, s), 7,45 (1H, d, J=9Hz), 7,74-7,89 (3H, m)
(14) 2-(4-Fluorfenyl)-6-isopropoksy-4-metyl-2H-l,2,4-benzotia-diazin-3(4H)-on-1,1-dioksyd
smp.: 139-140°C
IR (Nujol) : 1700, 1600, 1570, 1460, 1380, 1330,
1210cm"1
NMR (DMSO-d6, S) : 1,33 (6H, d, J=6Hz), 3,50 (3H, s),
4,90 (1H, m), 6,98-7,02 (2H, m) , 7,30-7,48 (4H, m), 7,85 (1H, d, J=9Hz)
(15) 2-(4-Klorfenyl)-6-etoksy-4-metyl-2H-l,2,4-benzotiadiazin-3(4H)-on-1,1-dioksyd
smp.: 150-151°C
IR (Nujol) : 1680, 1600, 1580, 1460, 1350, 1320, 1220,
1190, 1130 cm"<1>
NMR (DMS0-d6, 6) : 1,39 (3H, t, J=7Hz), 3,50 (3H, s),
4,23 (2H, q, J=7Hz), 7,00 (1H, dd, J=2Hz og 9Hz), 7,05 (1H, d, J=2Hz), 7,40-7,63 (4H, m), 7,87 (1H, d, J=9Hz)
(16) 6-Benzyloksy-2-(4-klorfenyl)-4-metyl-2H-l,2,4-benzotia-diazin-3(4H)-on-1,1-dioksyd
smp.: 174-175°C
IR (Nujol) : 1690, 1600, 1590, 1460, 1320, 1310,
1180 cm"<1>
NMR (DMS0-d6, S) : 3,34 (3H, s), 5,32 (2H, s), 7,07 (1H,
dd, J=2Hz, 2Hz), 7,20 (1H, d, J=2Hz), 7,30-7,63 (9H, m) , 7,90 (1H, d, J=9Hz)
(17) 2-(4-Klorfenyl)-6-cyklopropylmetoksy-4-metyl-2H-l,2,4-benzotiadiazin-3(4H)-on-1,1-dioksyd
smp.: 145-146°C
IR (Nujol) : 1690, 1600, 1580, 1540, 1330 cm'<1>
NMR (DMS0-d6, 6) : 0,30-0,45 (4H, m), 1,30 (1H, m), 3,45
(3H, s), 4,01 (2H, d, J=7Hz), 6,90-7,10 (2H, m), 7,35-7,70 (4H, m), 7,85 (1H, d, J=9Hz)
(18) 2-(2-Klorfenyl)-6-isopropoksy-4-metyl-2H-l,2,4-benzotiadia-zin-3(4H)-on-1,1-dioksyd
smp.: 150-152°C
IR (Nujol) : 1700, 1600, 1580, 1450, 1360, 1320,
1200 cm"1
NMR (DMS0-d6, <5) : 1,34 (6H, d, J=6Hz), 3,52 (3H, s) , 4,90 (1H, m) , 6,95-7,10 (2H, m) , 7,50-7,70 (4H, m), 7,86 (1H, d, J=9Hz)
(19) 2-(3-Klorfenyl)-6-isopropoksy-4-metyl-2H-l,2,4-benzotiadia-zin-3(4H)-on-1,1-dioksyd
smp.: 126-127°C
IR (Nujol) : 1700, 1600, 1590, 1380, 1330, 1310,
1180cm"<1>
NMR (DMS0-d6, S) : 1,34 (6H, d, J=6Hz), 3,49 (3H, s),
4,90 (1H, m), 6,98-7,03 (2H, m), 7,37-7,65 (4H, m), 7,86 (1H, d, J=9Hz)
(20) 2-(4-Klorfenyl)-4-metyl-6-propoksy-2H-l,2,4-benzotiadiazin-3(4H)-on-1,1-dioksyd
smp.: 142-143°C
IR (Nujol) : 1700, 1690, 1610, 1580, 1340, 1320 cm"<1>
NMR (DMS0-d6, S) : 1,02 (3H, t, J=7Hz), 1,80 (2H, q,
J=7Hz), 3,50 (3H, s), 4,10 (2H, t, J=7Hz), 6,95-7,10 (2H, m), 7,40-7,70 (4H, m), 7,90 (1H, d, J=9Hz)
(21) 6-Butoksy-2-(4-klorfenyl)-4-metyl-2H-l,2,4-benzotiadiazin-3(4H)-on-1,1-dioksyd
smp.: 102-103°C
IR (Nujol) : 1700, 1600, 1340, 1320, 1180, 1130 cm"<1>
NMR (DMS0-d6, 6) : 0,96 (3H, t, J=7Hz), 1,35-1,90 (4H,
m), 3,50 (3H, s), 4,18 (2H, t, J=7Hz), 6,95-7,10 (2H, m), 7,35-7,70 (4H, m), 8,90 (1H, d, J=9Hz)
(22) 2-(4-Klorfenyl)-6-isopropoksy-4-metyl-2H-1,2,4-benzotiadia-zin-3(4H)-on-1,1-dioksyd
smp.: 157-159°C
IR (Nujol) : 1700, 1605, 1460, 1330, 1320, 1300 cm"<1>
NMR (DMS0-d6, 6) : 1,32 (3H, s), 1,35 (3H, s), 3,50 (3H,
s), 4,89 (1H, m), 7,00 (1H, d, J=9Hz), 7,02 (1H, s), 7,35-7,60 (4H, m), 7,85 (1H, d, J=9Hz)
(23) 2-(4-Trifluormetylfenyl)-4-metyl-6-isopropoksy-2H-l,2,4-benzotiadiazin-3(4H)-on-1,1-dioksyd smp.: 158-160°C
IR (Nujol) : 1690, 1600, 1460, 1370, 1320, 1130 cm"<1>
NMR (DMS0-d6, <S) : 1,34 (6H, d, J=6Hz), 3,50 (3H, s) ,
4,90 (1H, m), 7,00-7,10 (2H, m), 7,64 (2H, d, J=7Hz), 7,80-8,00 (3H, m)
(24) 2-(4-Klorfenyl)-4-metyl-6-(2-metylpropoksy)-2H-1,2,4-benzotiadiazin-3(4H)-on-1,1-dioksyd
smp.: 108-110" C
IR (Nujol) : 1690, 1600, 1580, 1460, 1340, 1320,
1190 cm"<1>
NMR (DMS0-d6, <S) : 1,02 (6H, d, J=7Hz), 2,08 (1H, m) ,
3,51 (3H, s), 3,95 (2H, d, J=8Hz), 6,99-7,06 (2H, m), 7,39-7,63 (4H, m), 7,87 (1H, d, J=9Hz)
(25) 2-(4-Klorfenyl)-4-metyl-6-cykloheksylmetoksy-2H-l,2,4-benzotiadiazin-3(4H)-on-1,1-dioksyd
smp.: 127-129°C
IR (Nujol) : 1690, 1600, 1590, 1460, 1320, 1310, 1180,
1130 cm"<1>
NMR (DMS0-d6, 6) : 1,04-1,40 (5H, m), 1,50-1,90 (6H, m),
3,50 (3H, s), 3,98 (2H, d, J=6Hz), 6,98-7,05 (2H, m), 7,38-7,63 (4H, m), 7,86 (1H, d, J=9Hz)
(26) 2-(4-Klorbenzyl)-6-metoksy-4-metyl-2H-l,2,4-benzotiadiazin-3(4H)-on-1,1-dioksyd
smp.: 132-133 °C
IR (Nujol) : 1675, 1600, 1350, 1330, 1195 cm"<1>
NMR (DMS0-d6, 6) : 3,47 (3H, s), 3,92 (3H, s), 4,96 (2H,
s), 6,98 (1H, d, J=9,0Hz), 7,00 (1H, s), 7,35 og 7,40 (4H, ABq, J=8,7Hz), 7,87 (1H, d, J=9,0Hz)
(27) 2-(4-Klorfenyl)-6-karboksymetoksy-4-metyl-2H-l,2,4-benzo-tiadiazin-3(4H)-on-1,1-dioksyd
smp. : 228-230 °C
IR (Nujol) : 1730, 1690, 1600, 1460, 1340, 1320 cm"<1>
NMR (DMS0-d6, <5) : 3,34 (1H, bred s) , 3,50 (3H, s) , 4,95
(2H, s), 6,99 (1H, dd, J=9Hz og 2Hz), 7,11 (1H, d, J=2Hz), 7,35-7,65 (4H, m), 7,89 (1H, d, J=9Hz)
(28) 2-(4-Klorfenyl)-6-[1-(etoksykarbonyl)etoksy]-4-metyl-2H-1,2,4-benzotiadiazin-3(4H)-on-1,1-dioksyd (R,S-blanding) smp.: 111-112°C
IR (Nujol) : 1750, 1690, 1605, 1340, 1210, 1140 cm"<1>NMR (CDC13,.$) : 1,29 (3H, t, J=7,lHz), 1,69 (3H, d,
J=6,7Hz), 3,52 (3H, s), 4,26 (2H, q, J=7,lHz), 4,88 (1H, q, J=6,7Hz), 6,73 (1H, dd, J=8,7Hz og 2,0Hz), 6,84 (1H, d, J=2,0Hz), 7,35 og 7,46 (4H, ABq, J=8,6Hz), 7,83 (1H, d, J=8,7Hz)
(29) 2-(4-Klorfenyl)-6-(1-karboksyetoksy)-4-metyl-2H-l,2,4-benzotiadiazin-3(4H)-on-1,1-dioksyd (R,S-blanding)
smp.: 179,5-180,5°C
IR (Nujol) : 3250, 1760, 1665, 1600, 1350 cm"<1>
NMR (CDC13, S) : 1,74 (3H, d, J=6,7Hz), 3,52 (3H, s),
4,94 (1H, q, J=6,7Hz), 5,54 (1H, bred s), 6,76 (1H, dd, J=l,9Hz og 8,7Hz), 7,40 (4H, ABq, J=8,6Hz), 7,85
(1H, d, J=8,7Hz)
(30) 2-(4-Klorfenyl)-6-(1-etoksykarbonyl-l-metyletoksy)-4-metyl-2H-l,2,4-benzotiadiazin-3(4H)-on-1,1-dioksyd smp.: 184-185°C
IR (Nujol) : 1720, 1700, 1580, 1370, 1340 cm"<1>
NMR (CDCI3, 6) : 1,30 (3H, t, J=7Hz), 1,73 (6H, s), 3,53
(3H, s), 4,28 (2H, q, J=7Hz), 6,68 (1H, dd, J=9Hz og 2Hz), 6,80 (1H, d, J=2Hz), 7,37 (2H, d, J=9Hz), 7,50 (2H, d, J=9Hz), 7,81 (1H, d, J=9Hz)
(31) 2-(4-Klorfenyl)-6-(3-etoksykarbonylpropoksy)-4-metyl-2H-1,2,4-benzotiadiazin-3(4H)-on-1,1-dioksyd smp.: 90-92 °C
IR (Nujol) : 1730, 1700, 1600, 1580, 1470, 1330,
1320 cm"<1>
NMR (CDCI3, <5) : 1,28 (3H, t, J=7Hz), 2,17 (2H, m) , 2,54
(2H, t, J=7Hz), 3,54 (3H, s), 4,15 (2H, t, J=7Hz),
4,17 (2H, q, J=7Hz), 6,70-6,90 (2H, m) , 7,30-7,55 (4H, m), 7,84 (1H, d, J=9Hz)
(32) 2-(4-Klorfenyl)-6-(1-etoksykarbonylpropoksy)-4-metyl-2H-1,2,4-benzotiadiazin-3(4H)-on-1,1-dioksyd smp.: 105-108°C
IR (Nujol) : 1750, 1690, 1600, 1580, 1210 cm"<1>
NMR (CDC13, S) : 1,11 (3H, t, J=7Hz), 1,29 (3H, t,
J=7Hz), 2,06 (2H, m), 3,50 (3H, s), 4,26 (2H, q, J=7Hz), 4,69 (1H, t, J=6Hz), 6,74 (1H, dd, J=9Hz og 6Hz), 6,84 (1H, d, J=2Hz), 7,30-7,50 (4H, m), 7,83
(1H, d, J=9Hz)
(33) 2-(4-Klorfenyl)-6-(1-etoksykarbonylcyklobutyloksy)-4-metyl-2H-l,2,4-benzotiadiazin-3(4H)-on-1,1-dioksyd smp.: 140-142oC
IR (Nujol) : 1730, 1690, 1610, 1590, 1360 cm"<1>
NMR (CDCI3, 6) : 1,69 (3H, t, J=7Hz), 1,85-2,90 (6H, m),
3,46 (3H, s), 4,20 (2H, q, J=7Hz), 6,57 (1H, dd, J=9Hz og 2Hz), 6,92 (1H, d, J=2Hz), 7,41 (2H, d, J=8Hz), 7,60 (2H, d, J=8Hz), 7,87 (1H, d, J=9Hz)
(34) 2-(4-Klorfenyl)-6-(1-karboksy-l-metyletoksy)-4-metyl-2H-1,2,4-benzotiadiazin-3(4H)-on-1,1-dioksyd smp.: 208-210°C
IR (Nujol) : 3250, 1750, 1670, 1600, 1350, 1330 cm"<1>NMR (CDCI3, S) : 1,75 (6H, s), 3,51 (3H, s), 6,74 (1H,
dd, J=9Hz og 2Hz), 6,83 (1H, d, J=2Hz), 7,34 (2H, d, J=9Hz), 7,46 (2H, d, J=9Hz), 7,82 (1H, d, J=9Hz)
(35) 2-(4-Klorfenyl)-6-(3-karboksypropoksy)-4-metyl-2H-l,2,4-benzotiadiazin-3(4H)-on-1,1-dioksyd
smp.: 170-171°C
IR (Nujol) : 1700, 1600, 1580, 1330, 1310 cm"<1>
NMR (CDCI3, S) : 2,19 (2H, m), 2,62 (2H, t, J=7Hz), 3,54
(3H, s), 4,17 (2H, t, J=6Hz), 6,70-6,90 (2H, m), 7,35 (2H, d, J=9Hz), 7,47 (2H, d, J=9Hz), 7,84 (1H, d, J=9HZ)
(3 6) 2-(4-Klorfenyl)-6-(1-karboksypropoksy)-4-metyl-2H-l,2, 4-benzotiadiazin-3(4H)-on-1,1-dioksyd
smp.: 179-181°C
IR (Nujol): 3250, 1760, 1680, 1600, 1590, 1380, 1200 cm"<1>NMR (CDC13, 6) : 1,15 (3H, t, J=7Hz), 2,11 (2H, m), 3,53
(3H, s), 4,78 (1H, t, J=6Hz), 6,76 (1H, dd, J=9Hz og 2Hz), 6,86 (1H, d, J=2Hz), 7,30-7,50 (4H, m), 7,85
(1H, d, J=9Hz)
(37) 2-(4-Klorfenyl)-6-(1-karboksycyklobutyloksy)-4-metyl-2H-1,2,4-benzotiadiazin-3(4H)-on-1,1-dioksyd
smp.: 148-151°C
IR (Nujol) : 1700, 1600, 1380, 1320, 1180 cm"<1>
NMR (CDCI3, S) : 2,00-2,30 (2H, m), 2,50-2,75 (2H, m),
2,78-2,95 (2H, m), 3,51 (3H, s), 6,53 (1H, dd, J=9Hz og 2Hz), 6,73 (1H, d, J=2Hz), 7,34 (2H, d, J=9Hz), 7,46 (2H, d, J=9Hz), 7,80 (1H, d, J=9Hz)
(38) 4-Isopropyl-2-(4-Klorfenyl)-6-metoksy-2H-l,2,4-benzotiadia-zin-3(4H)-on-1,1-dioksyd
smp.: 166-168 °C
IR (Nujol) : 1690, 1600, 1570, 1460, 1340, 1300 cm"<1>NMR (DMS0-d6, <5) : 1,54 (6H, d, J=6Hz), 3,94 (3H, s) ,
4,61 (1H, m), 6,90-7,10 (2H, m), 7,30-7,70 (4H, m), 7,85 (1H, d, J=9Hz)
(39) 2-(4-Klorfenyl)-6-isopropoksy-4-isopropyl-2H-l,2,4-benzo-tiadiazin-3(4H)-on-1,1-dioksyd
smp.: 158-160°C
IR (Nujol) : 1690, 1590, 1490, 1460, 1340, 1300 cm"<1>NMR (DMS0-d6, S) : 1,34 (6H, d, J=6Hz), 1,52 (6H, d,
J=6Hz), 4,58 (1H, m), 4,88 (1H, m), 6,90-7,05 (2H,
m), 7,30-7,65 (4H, m), 7,82 (1H, d, J=9Hz)
(40) 2-(4-Klorfenyl)-4-etyl-6-metoksy-2H-l,2,4-benzotiadiazin-3(4H)-on-1,1-dioksyd
smp.: 106-107 °C
IR (Nujol) : 1690, 1600, 1570, 1490, 1460, 1350,
1310 cm"<1>
NMR (DMS0-d6, 6) : 1,28 (3H, t, J=7Hz), 3,95 (3H, s),
4,14 (2H, q, J=7Hz), 7,03 (1H, d, J=9Hz), 7,09 (1H, s), 7,42 (2H, d, J=9Hz), 7,60 (2H, d, J=9Hz), 7,90
(1H, d, J=9Hz)
(41) 2-(4-Klorfenyl)-4-etyl-6-isopropoksy-2H-l,2,4-benzotia-diazin-3(4H)-on-1,1-dioksyd
smp.: 167-168 °C
IR (Nujol) : 1700, 1600, 1580, 1460, 1340, 1310 cm"<1>NMR (DMS0-d6, S) : 1,26 (3H, t, J=7Hz), 1,34 (6H, d,
J=6Hz), 4,13 (2H, q, J=7Hz), 7,05-7,09 (2H, m), 7,42 (2H, d, J=9Hz), 7,60 (2H, d, J=9Hz), 7,87 (2H, d, J=9Hz)
(42) (IR)-(+)-2-(4-Klorfenyl)-6-[l-(etoksykarbonyl)etoksy]-4-metyl-2H-l,2,4-benzotiadiazin-3(4H)-on-1,1-dioksyd smp.: 86-88 °C
[a]D+24,0° (C=1,0, EtOH)
IR (Nujol) : 1740, 1690, 1680, 1600, 1590, 1500, 1210,
1185 cm-1 .
NMR (CDC13, S) : 1,30 (3H, t, J=7Hz), 1,69 (3H, d,
J=7Hz), 3,53 (3H, s), 4,26 (2H, q, J=7Hz), 4,87 (1H, q, J=7Hz), 6,74 (1H, dd, J=2Hz og 9Hz), 6,83 (1H, d, J=9Hz), 7,35 (2H, d, J=9Hz), 7,46 (2H, d, J=9Hz), 7,83 (1H, d, J=9Hz)
(43) (IS)-(-)-2-(4-Klorfenyl)-6-[1-(etoksykarbonyl)etoksy]-4-metyl-2H-1,2,4-benzotiadiazin-3(4H)-on-1,1-dioksyd smp.: 96-98 °C
[a]D-24,7° (C=1,0, EtOH)
IR (Nujol) : 1730, 1690, 1680, 1600, 1590, 1340,
1190 cm"<1>
NMR (CDCI3, <S) : 1,29 (3H, t, J=7Hz), 1,69 (3H, d,
J=7Hz), 3,52 (3H, s), 4,26 (2H, q, J=7Hz), 4,88 (1H, q, J=7Hz), 6,74 (1H, d, J=9Hz), 6,83 (1H, s), 7,35
(2H, d, J=9Hz), 7,46 (2H, d, J=9Hz), 7,83 (1H, d, J=9Hz)
(44) (IR)-(+)-2-(4-Klorfenyl)-6-(1-karboksyetoksy)-4-metyl-2H-1,2,4-benzotiadiazin-3(4H)-on-1,1-dioksyd
smp.: 75-85°C
[a]D+16,4° (C=1,0, EtOH)
IR (Nujol) : 3200, 1740, 1700, 1690, 1660, 1600, 1580,
1380, 1130 cm"<1>
NMR (CDC13, S) : 1,77 (3H, d, J=7Hz), 3,55 (3H, s), 4,98
(1H, q, J=7Hz), 6,79 (1H, dd, J=2Hz og 9Hz), 6,88
(1H, d, J=2Hz), 7,37 (2H, d, J=9Hz), 7,49 (2H, d, J=9Hz), 7,88 (1H, d, J=9Hz)
(45) (IS)-(-)-2-(4-Klorfenyl)-6-(1-karboksyetoksy)-4-metyl-2H-1,2,4-benzotiadiazin-3(4H)-on-1,1-dioksyd
smp.: 85-95°C
[a]D-17,0° (C=1,0, EtOH)
IR (Nujol) : 3200, 1740, 1700, 1665, 1600, 1580, 1200,
1130 cm"1
NMR (CDCI3, S) : 1,75 (3H, d, J=7Hz), 3,52 (3H, s), 4,95
(1H, q, J=7Hz), 6,50 (1H, bred s), 6,75 (1H, dd,
J=2Hz og 9Hz), 6,88 (1H, d, J=2Hz), 7,32 (2H, d, J=9Hz), 7,45 (2H, d, J=9Hz), 7,85 (1H, d, J=9Hz)
(46) 2-Cykloheksyl-6-metoksy-4-metyl-2H-l,2,4-benzotiadiazin-3(4H)-on-1,1-dioksyd
smp.: 124,5-126°C
IR (Nujol) : 1690, 1595, 1325, 1310, 1300, 1175 cm"<1>
NMR (DMS0-d6, S) : 1,0-1,5 (3H, m), 1,55-1,9 (5H, m),
2,05-2,35 (2H, m), 3,45 (3H, s), 3,90 (3H, s), 4,15-4,4 (1H, m), 6,95 (1H, d, J=8,3Hz), 6,97 (1H, s),
7,78 (1H, d, J=8,3HZ)
(47) 6-Isopropoksy-4-metyl-2-(2-pyridyl)-2H-1,2,4-benzotiadiazin-3(4H)-on-1,1-dioksyd
smp.: 173-174 °C
IR (Nujol) : 1700, 1600, 1590, 1340, 1215 cm"<1>
NMR (CDC13, S) : 1,40 (6H, d, J=6Hz), 3,53 (3H, s), 4,6-4,8 (1H, m), 6,73-6,85 (2H, m), 7,35-7,55 (2H, m), 7,82 (1H, d, J=8,7Hz), 7,8-7,95 (1H, m), 8,6-8,68
(1H, m)
(48) 6-Metoksy-4-metyl-2-pentyl-2H-l,2,4-benzotiadiazin-3(4H)-on-1,1-dioksyd
smp.: 85-88 °C
IR (Nujol) : 1690, 1600, 1450, 1330, 1310, 1180 cm"<1>NMR (DMS0-d6, S) : 0,84 (3H, t, J=6Hz), 1,10-1,40 (4H,
m) , 1,50-1,75 (2H, m) , 3,47 (3H, s) , 3,75 (2H, t, J=7Hz), 3,91 (3H, s), 6,90-7,05 (2H, m), 7,82 (1H, d, J=9Hz)
(49) 2-(4-Klorfenyl)-4-metyl-6-(N-metylacetylamino)-2H-1,2,4-benzotiadiazin-3(4H)-on-1,1-dioksyd
smp.: 168-172°C
IR (Nujol) : 1690, 1655, 1590, 1340 cm"<1>
NMR (CDCI3, S) : 2,09 (3H, s), 3,38 (3H, s), 3,57 (3H,
s), 7,10-7,55 (6H, m), 7,95-8,05 (1H, m)
(50) 6-Metoksy-2-(4-metoksykarbonylfenyl)-4-metyl-2H-l,2,4-benzotiadiazin-3(4H)-on-1,1-dioksyd
smp.: 153-156°C
IR (Nujol) : 1725, 1690, 1590, 1320, 1280 cm"<1>
NMR (DMS0-d6, 6) : 3,52 (3H, s), 3,89 (3H, s), 3,95 (3H,
s), 6,97-7,13 (2H, m), 7,55 og 8,10 (4H, ABq, J=8,3Hz), 7,90 (1H, d, J=8,8Hz)
(51) 6-Cykloheksylmetoksy-4-metyl-2-(2-pyridyl)-2H-1,2,4-benzo-tiadiazin-3(4H)-on-1,1-dioksyd
smp.: 161,5-162,5°C
IR (Nujol) : 1700, 1600, 1310 cm'<1>
NMR (CDCI3, S) : 0,95-1,45 (5H, m), 1,65-2,0 (6H, m),
3,54 (3H, s), 3,86 (2H, d, J=6Hz), 6,73-6,85 (2H, m), 7,35-7,55 (2H, m), 7,82 (1H, d, J=8,5Hz), 7,81-7,95 (1H, m), 8,6-8,67 (1H, m)
(52) 2-(4-Metoksykarbonylmetylfenyl)-6-metoksy-4-metyl-2H-1,2,4-benzotiadiazin-3(4H)-on-1,1-dioksyd smp.: 173-176°C
IR (Nujol) : 1735, 1690, 1600, 1335, 1320 cm"<1>
NMR (DMS0-d6, <5) : 3,52 (3H, s) , 3,65 (3H, s) , 3,79 (2H,
s), 3,95 (3H, s), 6,96-7,10 (2H, m), 7,33 og 7,43 (4H, ABq, J=8,3Hz), 7,88 (1H, d, J=8,7Hz)
(53) 2-(3-Etoksykarbonylpropyl)-6-metoksy-4-metyl-2H-l,2,4-benzotiadiazin-3(4H)-on-1,1-dioksyd
smp.: 63-65 ° C
IR (Nujol) : 1740, 1690, 1600, 1480, 1380, 1360, 1340,
1320, 1180 cm"<1>
NMR (CDC13, 6) : 1,23 (3H, t, J=7Hz), 2,06 (2H, m), 2,37
(2H, t, J=7Hz), 3,49 (3H, s), 3,90 (3H, s), 3,96 (2H, t, J=7Hz), 4,09 (2H, q, J=7Hz), 6,69 (1H, d, J=2Hz), 6,80 (1H, dd, J=2Hz og 9Hz), 7,79 (1H, d, J=9Hz)
(54) 2-(4-Klorfenyl)-4,6-dimetyl-2H-l,2,4-benzotiadiazin-3(4H)-on-1,1-dioksyd
smp.: 164-166 °C
IR (Nujol) : 1700, 1600, 1490, 1350, 1330, 1280, 1180,
1090cm"1
NMR (DMSO-d6, 6) : 2,50 (3H, s), 3,51 (3H, s), 7,28 (1H,
d, J=8Hz), 7,41 (2H, d, J=9Hz), 7,50 (1H, s), 7,60 (2H, d, J=9Hz), 7,84 (1H, d, J=8Hz)
(55) 2-[2-(4,6-Dimetylpyridyl)]-6-isopropoksy-4-metyl-2H-l,2,4-benzotiadiazin-3(4H)-on-1,1-dioksyd
smp.: 202-203 °C
IR (Nujol) : 1700, 1600, 1580, 1350, 1320, 1180 cm"<1>NMR (DMS0-d6, 6) : 1,37 (6H, d, J=6Hz), 2,34 (3H, s),
2,48 (3H, s), 3,49 (3H, s), 4,89 (1H, m), 7,01 (1H, d, J=9Hz), 7,04 (1H, s), 7,13 (1H, s), 7,24 (1H, s), 7,80 (1H, d, J=9Hz)
(56) 2-(4-Klorfenyl)-4-metyl-6-trifluormetyl-2H-1,2,4-benzotia-diazin-3(4H)-on-1,1-dioksyd
smp.: 148-150°C
IR (Nujol) : 1700, 1380, 1360, 1270, 1190, 1140,
1080 cm"<1>
NMR (DMS0-d6, 6) : 3,60 (3H, s), 7,45 (2H, d, J=9Hz),
7,62 (2H, d, J=9Hz), 7,81 (1H, d, J=8Hz), 7,96 (1H, s), 8,21 (1H, d, J=8Hz)
(57) 6-Isopropoksy-4-metyl-2-(2-pyrimidinyl)-2H-1,2,4-benzotia-diazin-3(4H)-on-1,1-dioksyd
smp.: 176-178°C
IR (Nujol) : 1700, 1600, 1400, 1380, 1350, 1330, 1280,
1230cm"<1>
NMR (DMS0-d6, 6) : 1,33 (6H, d, J=6Hz), 3,53 (3H, s),
4,90 (1H, m), 7,00 (1H, dd, J=2Hz og 9Hz), 7,10 (1H, d, J=7Hz), 7,67 (1H, t, J=4Hz), 7,84 (1H, t, J=9Hz), 8,97 (2H, d, J=4Hz)
(58) 6-Metoksy-4-metyl-2-(4-fenoksyfenyl)-2H-1,2,4-benzotia-diazin-3(4H)-on-1,1-dioksyd
smp.: 184-186 °C
IR (Nujol) : 1690, 1590, 1330, 1180 cm"<1>
NMR (DMS0-d6, S) : 3,52 (3H, s), 3,94 (3H, s), 6,95-7,55
(11H, m), 7,89 (1H, d, J=9Hz)
(59) 2-(4-Isopropylfenyl)-6-metoksy-4-metyl-2H-l,2,4-benzotia-diazin-3(4H)-on-1,1-dioksyd
smp.: 158-159°C
IR (Nujol) : 1700, 1595, 1330, 1310, 1125 cm"<1>
NMR (DMS0-d6, S) : 1,24 (6H, d, J=7Hz), 2,98 (1H, m),
3,51 (3H, s), 3,94 (3H, s), 7,01 (1H, dd, J=2Hz og 9Hz), 7,06 (1H, d, J=2Hz), 7,27 og 7,39 (4H, ABq, J=8Hz), 7,87 (1H, d, J=9Hz)
(60) 2-[(3-Klor-4-metyl)fenyl]-6-metoksy-4-metyl-2H-l,2,4-benzotiadiazin-3(4H)-on-1,1-dioksyd
smp.: 208-211°C
IR (Nujol) : 1695, 1595, 1315, 1180 cm<-1>
NMR (DMSO-d6, S) : 2,40 (3H, s), 3,51 (3H, s), 3,94 (3H,
s), 7,02 (1H, dd, J=2Hz og 9Hz), 7,07 (1H, d, J=2Hz), 7,39 (1H, dd, J=2Hz og 8Hz), 7,46 (1H, d, J=2Hz),
7,52 (1H, d, J=8Hz), 7,89 (1H, d, J=9Hz)
(61) 6-Metoksy-4-metyl-2-(4-metyltiofenyl)-2H-1,2,4-benzotiadia-zin-3(4H)-on-1,1-dioksyd
smp.: 154-155°C
IR (Nujol) : 1690, 1610, 1580, 1490, 1310, 1185,
1135 cm-<1>
NMR (CDC13, S) : 2,51 (3H, s), 3,54 (3H, s), 3,93 (3H,
s), 6,76 (1H, d, J=2Hz), 6,83 (1H, dd, J=2Hz og 9Hz), 7,32 (4H, s), 7,85 (1H, d, J=9Hz)
(62) 2-(4-Dimetylaminofenyl)-6-metoksy-4-metyl-2H-1,2,4-benzo-tiadiazin-3(4H)-on-1,1-dioksyd
smp.: 244-245°C
IR (Nujol) : 1690, 1600, 1520, 1330, 1310, 1180,
1130 cm-1
NMR (DMS0-d6, 6) : 2,96 (6H, s), 3,50 (3H, s), 3,94 (3H,
s), 6,75 (2H, d, J=9Hz), 7,10 (2H, d, J=9Hz), 7,02
(1H, dd, J=2Hz og 9Hz), 7,02 (1H, d, J=2Hz), 7,85
(1H, d, J=9Hz)
(63) 2-(4-Klorbenzyl)-6-isopropoksy-4-metyl-2H-1,2,4-benzotia-diazin-3(4H)-on-1,1-dioksyd
IR (rent) : 2980, 1680, 1600, 1580, 1330, 1180, 1110 cm"<1>NMR (CDCI3, S) : 1,38 (6H, d, J=6,0Hz), 3,45 (3H, s),
4,55-4,75 (1H, m), 5,00 (2H, s), 6,65 (1H, d, J=l,9Hz), 6,77 (1H, dd, J=l,9 og 8,8Hz), 7,27 og 7,40 (4H, ABq, J=8,4Hz), 7,80 (1H, d, J=8,8Hz)
(64) 2-Cykloheksyl-6-isopropoksy-4-metyl-2H-l,2,4-benzotiadiazin-3(4H)-on-1,1-dioksyd
smp.: 111-112°C
IR (Nujol) : 1685, 1605, 1330, 1180, 1110 cm<-1>
NMR (DMSO-d6, 6) : 1,0-1,45 (3H, m) , 1,31 (6H, d,
J=6,0Hz), 1,5-1,9 (5H, m) , 2,05-2,35 (2H, m), 3,43 (3H, s), 4,25-4,4 (1H, m), 4,84 (1H, m) , 6,91 (1H, s), 6,78 (1H, d, J=9,0Hz), 7,75 (1H, d, J=9,0Hz)
(65) 6-Isopropoksy-4-metyl-2-pentyl-2H-l,2,4-benzotiadiazin-3(4H)-on-1,1-dioksyd
smp.: 44-46 "C
IR (Nujol) : 1690, 1600, 1580, 1460, 1340, 1320,
1190 cm"<1>
NMR (DMS0-d6, 6) : 0,84 (3H, t, J=6Hz), 1,05-1,40 (4H,
m), 1,31 (6H, d, J=6Hz), 1,50-1,75 (2H, m), 3,44 (3H, s), 3,74 (2H, t, J=7Hz), 4,85 (1H, m), 6,90-7,05 (2H, m), 7,78 (1H, d, J=9Hz)
(66) 6-Isopropoksy-2-(4-isopropoksykarbonylfenyl)-4-metyl-2H-1,2,4-benzotiadiazin-3(4H)-on-1,1-dioksyd smp.: 128-129°C
IR (Nujol) : 1720, 1710, 1610, 1340, 1280 cm"<1>
NMR (CDC13, 6) : 1,38 (6H, d, J=6,8Hz), 1,43 (6H, d,
J=6,5Hz), 3,54 (3H, s), 4,63-4,8 (1H, m), 5,2-5,35 (1H, m), 6,76 (1H, d, J=2Hz), 6,82 (1H, dd, J=2Hz og 8,7Hz), 7,50 og 8,15 (4H, ABq, J=8,4Hz), 7,83 (1H, d, J=8,7Hz)
(67) 2-(4-Isopropoksykarbonylmetylfenyl)-6-isopropoksy-4-metyl-2H-1,2,4-benzotiadiazin-3(4H)-on-1,1-dioksyd smp.: 117-120°C
IR (Nujol) : 1730, 1690, 1595, 1335, 1325 cm"<1>
NMR (CDCI3, 6) : 1,24 (6H, d, J=6,0Hz), 1,41 (6H, d,
J=6,0Hz), 3,52 (3H, s), 3,63 (2H, s), 4,6-4,8 (1H, m), 4,9-5,1 (1H, m), 6,7-6,85 (2H, m), 7,3-7,5 (4H, m), 7,75-7,80 (1H, m)
(68) 4-Isopropoksy-2-(3-isopropoksykarbonylpropyl)-4-metyl-2H-1,2,4-benzotiadiazin-3(4H)-on-1,1-dioksyd
IR (CHCI3) : 1720, 1700, 1600, 1580, 1340, 1270,
1120cm"<1>
NMR (CDCI3, S) : 1,12 (6H, d, J=6Hz), 1,3 0 (6H, d,
J=6Hz), 1,99 (2H, m), 2,28 (2H, t, J=7Hz), 3,41 (3H, s), 3,90 (2H, t, J=7Hz), 4,60 (1H, m) , 4,92 (1H, m) , 6,60 (1H, d, J=2Hz), 6,70 (1H, dd, J=2Hz og 9Hz), 7,70 (1H, d, J=9Hz)
(69) 2-(4-Klorfenyl)-5,7-diklor-6-isopropoksy-4-metyl-2H-l,2,4-benzotiadiazin-3(4H)-on-1,1-dioksyd
smp.: 185-188 °C
IR (Nujol) : 1710, 1470, 1380, 1360, 1190 cm"<1>
NMR (DMS0-d6, <S) : 1,38 (6H, d, J=6Hz), 3,33 (3H, s) ,
4,75 (1H, m), 7,44 (2H, d, J=9Hz), 7,61 (2H, d, J=9Hz), 8,14 (1H, s)
(70) (IR)-(+)-6-[1-(Etoksykarbonyl)etoksy]-4-metyl-2-fenyl-2H-1,2,4-benzotiadiazin-3(4H)-on-1,1-dioksyd
smp.: 137,5-139°C
IR (Nujol) : 1740, 1700, 1605, 1340, 1210, 1140 cm"<1>NMR (CDCI3, S) : 1,30 (3H, t, J=7Hz), 1,69 (3H, d,
J=7Hz), 3,53 (3H, s), 4,26 (2H, q, J=7Hz), 4,88 (1H, q, J=7Hz), 6,73 (1H, dd, J=2Hz og 9Hz), 6,84 (1H, d, J=2Hz), 7,35-7,55 (5H, m), 7,84 (1H, d, J=9Hz)
(71) (IR)-(+)-6-[1-(Etoksykarbonyl)etoksy]-4-methvl-2-(4-fenoksyfenyl)-2H-1,2,4-benzotiadiazin-3(4H)-on-1,1-dioksyd smp.: 128-130 °C
IR (Nujol) : 1740, 1685, 1610, 1330, 1195, 1130 cm"<1>NMR (CDCI3, 6) : 1,29 (3H, t, J=7Hz), 1,69 (3H, d,
J=7Hz), 3,53 (3H, s), 4,26 (2H, q, J=7Hz), 4,88 (1H, q, J=7Hz), 6,75 (1H, dd, J=2Hz og 9Hz), 6,83 (1H, d, J=2Hz), 7,0-7,45 (9H, m), 7,85 (1H, d, J=9Hz)
(72) (IR)-(+)-6-[1-(Etoksykarbonyl)etoksy]-2-(4-isopropylfenyl)-4-metyl-2H-l,2,4-benzotiadiazin-3(4H)-on-1,1-dioksyd smp.: 154-155°C
IR (Nujol) : 1740, 1695, 1600, 1340, 1310, 1200,
1130 cm"1
NMR (CDCI3, <S) : 1,27 (6H, d, J=7Hz) , 1,29 (3H, t,
J=7Hz), 1,69 (3H, d, J=7Hz), 2,95 (1H, m), 3,52 (3H, s), 4,26 (2H, q, J=7Hs), 4,88 (1H, q, J=7Hz), 6,73 (1H, dd, J=2Hz og 9Hz), 6,83 (1H, d, J=2Hz), 7,32 (4H, s), 7,83 (1H, d, J=9Hz)
(73) (IR)-(+)-2-[(3-Klor-4-metyl)fenyl]-6-[1(etoksykarbonyl)-etoksy]-4-metyl-2H-l,2,4-benzotiadiazin-3(4H)-on-1,1-dioksyd smp.: 149-150°C
IR (Nujol) : 1740, 1685, 1600, 1335 cm"<1>
NMR (DMS0-d6, <5) : 1,21 (3H, t, J=7Hz), 1,58 (3H, d,
J=7Hz), 2,40 (3H, s), 3,48 (3H, s), 4,18 (2H, q, J=7Hz), 5,33 (1H, q, J=7Hz), 6,95 (1H, dd, J=2Hz og 9Hz), 7,08 (1H, d, J=2Hz), 7,30 (1H, dd, J=2Hz og 8Hz), 7,47 (1H, d, J=2Hz), 7,51 (1H, d, J=8Hz), 7,87
(1H, d, J=9Hz)
(74) (IR)-(+)-2-Cykloheksyl-6-[l-(etoksykarbonyl)etoksy]-4-metyl-2H-1,2,4-benzotiadiazin-3(4H)-on-1,1-dioksyd smp.: 139-141°C
IR (Nujol) : 1740, 1690, 1600, 1580, 1340, 1300, 1200,
1170 cm"<1>
NMR (CDCI3, 6) : 1,28 (3H, t, J=6Hz), 1,16-1,45 (3H, m),
1,66 (3H, d, J=6Hz), 1,80-1,92 (5H, m), 2,22-2,42 (2H, m), 3,44 (3H, s), 4,23 (2H, q, J=6Hz), 4,29-4,49 (1H, m), 4,83 (1H, q, J=6Hz), 6,65 (1H, dd, J=2Hz og 8Hz), 6,71 (1H, d, J=2Hz), 7,74 (1H, d, J=6Hz)
(75) (IR)-(+)-6-[1-(Etoksykarbonyl)etoksy]-4-mety1-2-(4-metyl-fenyl)-2H-1,2,4-benzotiadiazin-3(4H)-on-1,1-dioksyd smp.: 134-135°C
IR (Nujol) : 1740, 1680, 1600, 1580, 1340, 1320, 1200,
1130 cm"<1>
NMR (CDCI3, <S) : 1,30 (3H, t, J=6Hz), 1,69 (3H, d,
J=6HZ), 2,40 (3H, s), 3,52 (3H, s), 4,25 (2H, q, J=6Hz), 4,88 (1H, q, J=6Hz), 6,70 (1H, dd, J=2Hz og 8Hz), 6,82 (1H, d, J=2Hz), 7,28 (4H, s), 7,83 (1H, d, J=8Hz)
(76) (IR)-(+)-6-[l-(Etoksykarbonyl)etoksy]-4-metyl-2-(2-pyridyl)-2H-1,2,4-benzotiadiazin-3(4H)-on-1,1-dioksyd smp.: 153-154°C
IR (Nujol) : 1740, 1690, 1605, 1580, 1460, 1330, 1205,
1115cm"1
NMR (CDC13, S) : 1,29 (3H, t, J=7Hz), 1,69 (3H, d,
J=7Hz), 3,52 (3H, s), 4,25 (2H, q, J=7Hz), 4,86 (1H,
q, J=7Hz), 6,72 (1H, dd, J=2Hz og 8Hz), 6,84 (1H, d, J=2Hz), 7,38-7,51 (2H, m), 7,82 (1H, d, J=8Hz), 7,90 (1H, dd, J=2Hz og 8Hz), 8,62-8,66 (1H, m)
(77) (IR)-(+)-2-(3,4-Diklorfenyl)-6-[1-(etoksykarbonyl)etoksy]-4-metyl-2H-l,2,4-benzotiadiazin-3(4H)-on-1,1-dioksyd smp.: 108-110°C
IR (Nujol) : 1720, 1685, 1600, 1190, 1135 cm"<1>
NMR (CDCI3, 6) : 1,30 (3H, t, J=8Hz), 1,69 (3H, d,
J=7Hz), 3,53 (3H, s), 4,29 (2H, q, J=8Hz), 4,87 (1H,
q, J=7Hz), 6,74 (1H, dd, J=2Hz og 9Hz), 6,83 (1H, d, J=2Hz), 7,28 (1H, dd, J=2Hz og 9Hz), 7,53 (1H, d, J=2Hz), 7,55 (1H, d, J=9Hz), 7,83 (1H, d, J=9Hz)
(78) (IR)-(+)-2-(3-Klorfenyl)-6-[1-(etoksykarbonyl)etoksy]-4-metyl-2H-l,2,4-benzotiadiazin-3(4H)-on-1,1-dioksyd smp.: 135-137 °C
IR (Nujol) : 1740, 1700, 1600, 1580, 1340, 1210 cm"<1>
NMR (CDCI3, <S) : 1,30 (3H, t, J=7Hz), 1,70 (3H, d,
J=7HZ) , 3,46 (3H, s) , 4,27 (2H, q, J=7Hz), 4,86 (1H,
q, J=7Hz), 6,81-7,37 (6H, m), 7,85 (1H, d, J=9Hz) (79) (IR)-(+)-2-(2-Klorfenyl)-6-[1-(etoksykarbonyl)etoksy]-4-metyl-2H-l,2,4-benzotiadiazin-3(4H)-on-1,1-dioksyd IR (CHCI3) : 1745, 1700, 1605, 1580, 1350, 1320,
1140cm"<1>
NMR (CDC13,<S): 1,30 (3H, t, J=7Hz), 1,69 (3H, d, J=7Hz),
3,54 (3H, s), 4,27 (2H, q, J=7Hz), 4,88 (1H, q, J=7Hz), 6,70-7,72 (6H, m), 7,82 (1H, d, J=9Hz)
(80) (IR)-(+)-6-[1-(Etoksykarbonyl)etoksy]-2-(4-fluorfenyl)-4-metyl-2H-l,2,4-benzotiadiazin-3(4H)-on-1,1-dioksyd smp.: 100-102 °C
IR (Nujol): 1740, 1680, 1605, 1370, 1340 cm"<1>
NMR (CDC13, S) : 1,30 (3H, t, J=7Hz), 1,69 (3H, d,
J=7Hz), 3,52 (3H, s), 4,26 (2H, q, J=7Hz), 4,88 (1H, q, J=7Hz), 6,71-7,43 (6H, m), 7,83 (1H, d, J=9Hz)
(81) (IR)-(+)-6-[l-(Etoksykarbonyl)etoksy]-4-metyl-2-(4-metyl-tiofenyl)-2H-1,2,4-benzotiadiazin-3(4H)-on-1,1-dioksyd smp.: 156-157 °C
IR (Nujol) : 1720, 1605, 1600, 1580, 1205, 1180,
1130cm"<1>
NMR (CDCI3, 6) : 1,29 (3H, t, J=7Hz), 1,69 (3H, d,
J=7Hz), 2,50 (3H, s), 3,52 (3H, s), 4,25 (2H, q, J=7Hz), 4,87 (1H, q, J=7Hz), 6,72 (1H, dd, J=2Hz og 9Hz), 6,82 (1H, d, J=2Hz), 7,32 (4H, s), 7,83 (1H, d, J=9Hz)
(82) (IR)-(+)-2-(4-Dimetylaminofenyl)-6-[1-(etoksykarbonyl)-etoksy]-4-metyl-2H-l,2,4-benzotiadiazin-3(4H)-on-1,1-dioksyd smp.: 190-192 *C
IR (Nujol) : 1715, 1680, 1600, 1195, 1130 cm"<1>
NMR (CDCI3, <5) : 1,29 (3H, t, J=7Hz), 1,67 (3H, d,
J=7Hz), 3,00 (6H, s), 3,51 (3H, s), 4,25 (2H, q, J=7Hz), 4,87 (1H, q, J=7Hz), 6,69-6,81 (4H, m), 7,24 (2H, d, J=8Hz), 7,84 (1H, d, J=8Hz)
(83) (IR)-(+)-6-(1-Karboksyetoksy)-4-metyl-2-fenyl-2H-l,2,4-benzotiadiazin-3(4H)-on-1,1-dioksyd
smp.: 184-185,5°C
IR (Nujol) : 3200, 1750, 1660, 1610, 1320, 1180 cm"<1>NMR (CDCI3, 6) : 1,74 (3H, d, J=7Hz), 3,53 (3H, s), 3,55-4,1 (1H, bred), 4,95 (1H, q, J=7Hz), 6,76 (1H, dd, J=2Hz og 9Hz), 6,85 (1H, d, J=2Hz), 7,35-7,55 (5H, m), 7,86 (1H, d, J=9Hz)
(84) (IR)-(+)-6-(l-Karboksyetoksy)-4-metyl-2-(4-fenoksyfenyl)-2H-1,2,4-benzotiadiazin-3(4H)-on-1,1-dioksyd smp.: 106°C (spaltning)
IR (Nujol) : 3600-2400, 1740, 1695, 1665, 1600, 1585,
1345, 1215 cm"<1>
NMR (CDC13, 6) : 1,74 (3H, d, J=7Hz), 3,53 (3H, s), 3,63
(1H, bred), 4,95 (1H, q, J=7Hz), 6,76 (1H, dd, J=2Hz og 9Hz), 6,85 (1H, d, J=2Hz), 7,0-7,45 (9H, m), 7,86
(1H, d, J=9Hz)
(85) (IR)-(+)-6-(1-Karboksyetoksy)-2-(4-isopropylfenyl)-4-metyl-2H-l,2,4-benzotiadiazin-3(4H)-on-1,1-dioksyd smp.: 74°C (spaltning)
IR (Nujol) : 3600-2400, 1730, 1695, 1600, 1340,
1315 cm"<1>
NMR (CDCI3, 6) : 1,27 (6H, d, J=7Hz), 1,74 (3H, d,
J=7Hz), 2,76 (1H, m), 3,43 (1H, bred), 3,52 (3H, s), 4,95 (1H, q, J=7Hz), 6,76 (1H, dd, J=2Hz og 9Hz), 6,85 (1H, d, J=2Hz), 7,32 (4H, s), 7,85 (1H, d, J=9Hz)
(86) (IR)-(+)-6-(1-Karboksyetoksy)-2-[(3-klor-4-metyl)-fenyl]-4-metyl-2H-l,2,4-benzotiadiazin-3(4H)-on-1,1-dioksyd smp.: 184-186°C
IR (Nujol) : 3600-2500, 1720, 1700, 1595, 1330 cm"<1>NMR (CDCI3, <5) : 1,75 (3H, d, J=7Hz), 2,42 (3H, s) , 3,25
(1H, bred), 3,53 (3H, s), 4,94 (1H, q, J=7Hz), 6,77 (1H, dd, J=2Hz og 9Hz), 6,85 (1H, d, J=2Hz), 7,23 (1H, dd, J=2Hz og 8Hz), 7,34 (1H, d, J=8Hz), 7,41 (1H, d, J=2Hz), 7,85 (1H, d, J=9Hz)
(87) (IR)-(+)-6-(1-Karboksyetoksy)-4-metyl-2-(4-trifluormetyl-fenyl)-2H-1,2,4-benzotiadiazin-3(4H)-on-1,1-dioksyd smp.: 162-163 °C
IR (CHCI3) : 3600-3300, 1720, 1690, 1600, 1340, 1320,
1130 cm"1
NMR (CDCI3, <S) : 1,75 (3H, d, J=6Hz), 3,54 (3H, s) ,
4,90-5,01 (1H, q, J=6Hz), 6,77 (1H, dd, J=2Hz og
8Hz), 6,87 (1H, d, J=2Hz), 7,54 (2H, d, J=8Hz), 7,74 (2H, d, J=8Hz), 7,86 (1H, d, J=8Hz)
(88) (IR)-(+)-6-(1-Karboksyetoksy)-2-cykloheksyl-4-metyl-2H-1,2,4-benzotiadiazin-3(4H)-on-1,1-dioksyd
smp.: 76-77 °C
IR (CHC13) : 3600-2400, 1720, 1680, 1600, 1330, 1310,
1170 cm-1
NMR (CDCI3, S) : 1,20-1,45 (3H, m), 1,70 (3H, d, J=6Hz),
1,82-1,88 (5H, m), 2,20-2,38 (2H, m), 3,44 (3H, s), 4,35-4,47 (1H, m), 4,76 (1H, s), 4,89 (1H, q, J=6Hz), 6,67-6,74 (2H, m), 7,75 (1H, d, J=8Hz)
(89) (IR)-(+)-6-(1-Karboksyetoksy)-4-metyl-2-(4-metylfenyl)-2H-1,2,4-benzotiadiazin-3(4H)-on-1,1-dioksyd
smp.: 182-183 °C
IR (CHCI3) : 1700, 1600, 1320, 1130 cm"<1>
NMR (CDCI3, 6) : 1,74 (3H, d, J=6Hz), 2,40 (3H, s), 3,17
(1H, bred s), 3,52 (3H, s), 4,89-5,00 (1H, q, J=6Hz), 6,75 (1H, dd, J=2Hz og 8Hz), 6,84 (1H, d, J=2Hz), 7,29 (4H, s), 7,85 (1H, d, J=8Hz)
(90) (IR)-(+)-6-(1-Karboksyetoksy)-4-metyl-2-(2-pyridyl)-2H-1,2,4-benzotiadiazin-3(4H)-on-1,1-dioksyd
smp.: 142-143°C
IR (Nujol) : 3700-2300, 1700, 1600, 1350, 1320, 1275,
1210, 1190 cm"<1>
NMR (CDCI3, S) : 1,56 (3H, d, J=7Hz), 3,47 (3H, s), 5,17
(1H, q, J=7Hz), 6,92 (1H, dd, J=2Hz og 9Hz), 7,08 (1H, d, J=2Hz), 7,45-7,60 (2H, m), 7,84 (1H, d, J=9Hz), 8,00 (1H, m), 8,56-8,59 (1H, m)
(91) (IR)-(+)-6-(1-Karboksyetoksy)-2-(3,4-diklorfenyl)-4-metyl-2H-1,2,4-benzotiadiazin-3(4H)-on-1,1-dioksyd smp.: 105-106°C
IR (Nujol) : 3250-2400, 1735, 1690, 1600, 1585, 1300,
1290, 1175cm"<1>
NMR (DMSO-d6, S) : 1,57 (3H, d, J=7Hz), 3,48 (3H, s),
5,20 (1H, q, J=7Hz), 6,93 (1H, dd, J=2Hz og 9Hz), 7,08 (1H, d, J=2Hz), 7,46 (1H, dd, J=2Hz og 9Hz), 7,76-7,93 (3H, m),
(92) (IR)-(+)-6-(1-Karboksyetoksy)-2-(3-klorfenyl)-4-metyl-2H-1,2,4-benzotiadiazin-3(4H)-on-1,1-dioksyd
smp.: 174-176°C
IR (Nujol) : 1725, 1700, 1610, 1580, 1330, 1310,
1180 cm-<1>
NMR (CDC13, <S) : 1,74 (3H, d, J=7Hz) , 2,72 (1H, bred s) ,
3,53 (3H, s), 4,95 (1H, q, J=7Hz), 6,74-7,51 (6H, m), 7,86 (1H, d, J=9Hz)
(93) (IR)-(+)-6-(1-Karboksyetoksy)-2-(2-klorfenyl)-4-metyl-2H-1,2,4-benzotiadiazin-3(4H)-on-1,1-dioksyd
smp.: 110-112°C
IR (Nujol): 1740, 1700, 1600, 1580, 1375, 1190 cm"<1>NMR (CDCI3, <S) : 1,75 (3H, d, J=7Hz), 3,55 (3H, s) , 4,95
(1H, q, J=7Hz), 6,74-7,67 (6H, m), 7,85 (1H, d, J=9Hz)
(94) (IR)- ( + )-6-(1-Karboksyetoksy)-2-(4-fluorfenyl)-4-metyl-2H-1,2,4-benzotiadiaz in-3(4H)-on-1,1-dioksyd
smp.: 130-132 °C
IR (Nujol): 1740, 1700, 1600, 1500, 1380, 1210 cm"<1>NMR (CDCI3, 5) : 1,74 (3H, d, J=7Hz), 3,52 (3H, s), 4,94
(1H, q, J=7Hz) , 5,80 (1H, bred s) , 6,74-7,43 (6H, m) , 7,85 (1H, d, J=9Hz)
(95) (IR)-(+)-6-(1-Karboksyetoksy)-4-metyl-2-(4-metyltiofenyl)-2H-1,2,4-benzotiadiazin-3(4H)-on-1,1-dioksyd smp. : 143-144 0 C
IR (Nujol): 3350-2300, 1730, 1660, 1600, 1580, 1190,
1090cm"1
NMR (CDCI3, <S) : 1,74 (3H, d, J=7Hz) , 2,50 (3H, s) , 3,53
(3H, s), 4,95 (1H, q, J=7Hz), 6,76 (1H, dd, J=2Hz og
9Hz), 6,85 (1H, d, J=2Hz), 7,32 (4H, s), 7,85 (1H, d, J=9Hz)
(96) (IR)-(+)-6-(1-Karboksyetoksy)-2-(4-dimetylaminofenyl)-4-metyl-2H-l,2,4-benzotiadiazin-3(4H)-on-1,1-dioksyd smp.: 190°C (spaltning)
IR (KBr): 3400, 2750-2200, 1690, 1590, 1450, 1320, 1180,
1125 cm"<1>
NMR (DMSO-d6, S) : 1,57 (3H, d, J=7Hz), 2,97 (6H, s),
3,47 (3H, s), 5,22 (1H, q, J=7Hz), 6,85 (2H, d, J=9Hz), 7,15 (2H, d, J=9Hz), 6,92 (1H, dd, J=2Hz og 9Hz), 7,05 (1H, d, J=2Hz), 7,85 (1H, d, J=9Hz)
(97) 6-[1-(Karboksy)cykloheksylmetoksy]-2-(4-klorfenyl)-4-metyl-2H-l,2,4-benzotiadiazin-3(4H)-on-1,1-dioksyd smp.: 145-150°C
IR (Nujol) : 3300, 1700, 1600, 1580, 1370, 1310, 1190,
1130cm"1
NMR (CDC13, 6) : 1,10-2,10 (11H, m), 3,40 (3H, s), 4,40
(1H, bred s), 6,60 (1H, d, J=9Hz), 6,85 (1H, s), 7,25 (2H, d, J=9Hz), 7,42 (2H, d, J=9Hz), 7,70 (1H, d, J=9Hz)
(98) (IR)-(+)-6-[1-(Etoksykarbonyl)etoksy]-4-mety1-2-(4— trifluormetylfenyl)-2H-1,2,4-benzotiadiazin-3(4H)-on-1,1-dioksyd
smp.: 124-125°C
IR (Nujol) : 1720, 1685, 1595, 1330, 1130, 1060 cm"<1>NMR (CDCI3, <S) : 1,30 (3H, t, J=6Hz), 1,70 (3H, d,
J=6Hz), 3,54 (3H, s), 4,26 (2H, q, J=6Hz), 4,88 (1H, q, J=6Hz), 6,75 (1H, dd, J=2Hz og 8Hz), 6,85 (1H, d, J=2Hz), 7,55 (2H, d, J=8Hz), 7,75 (2H, d, J=8Hz),
7,84 (1H, d, J=8Hz)
(99) 6-Cykloheksylmetoksy-2-(4-cykloheksylmetoksykarbonylfenyl)-4-metyl-2H-l,2,4-benzotiadiazin-3(4H)-on-1,1-dioksyd smp.: 119-121°C
IR (Nujol) : 1720, 1690, 1600, 1320 cm"<1>
NMR (DMSO-d6, S) : 0,95-1,40 (10H, m), 1,55-1,95 (12H,
m) , 3,52 (3H, s), 4,00 (2H, d, J=5,8Hz), 4,15 (2H, d, J=5,8Hz), 6,97-7,10 (2H, m), 7,55 og 8,10 (4H, ABq, J=8,3Hz), 7,87 (1H, d, J=8,7Hz)
(100) 2-(4-Klorfenyl)-4-metyl-6-(2-ftalimidoetoksy)-2H-1,2,4-benzotiadiazin-3(4H)-on-1,1-dioksyd
smp.: 175-180°C
IR (Nujol) : 1770, 1710, 1605, 1585 cm"<1>
NMR (DMSO-d6, 6) : 3,50 (3H, s), 4,0-4,1 (2H, m), 4,4-4,5
(2H, m), 6,95-7,05 (2H, m), 7,35-7,45 (2H, m), 7,55-7,56 (3H, m), 7,8-8,0 (4H, m)
(101) 6-[trans-4-(tert-Butoksykarbonylaminometyl)cykloheksyl-metoksy] -2-(4-klorfenyl)-4-metyl-2H-l,2,4-benzotiadiazin-3(4H)-on-1,1-dioksyd
smp.: 133-136°C
IR (Nujol) : 3400, 1690, 1600, 1590, 1520, 1450, 1360,
1340, 1180 cm"<1>
NMR (DMS0-d6, 8) : 0,75-1,20 (4H, m), 1,40 (9H, s),
1,40-2,00 (6H, m), 2,73 (2H, t, J=6Hz), 3,50 (3H, s), 3,98 (2H, d, J=7Hz), 7,00 (1H, d, J=9Hz), 7,08 (1H, s), 7,40 (2H, d, J=9Hz), 7,60 (2H, d, J=9Hz), 7,88
(1H, d, J=9Hz)
(102) 2-(4-Klorfenyl)-6-[1-(etoksykarbonyl)cykloheksylmetoksy]-4-metyl-2H-l,2,4-benzotiadiazin-3(4H)-on-1,1-dioksyd smp.: 128-131°C
IR (Nujol) : 1730, 1690, 1600, 1590, 1380, 1180 cm"<1>NMR (CDC13, S) : 1,30 (3H, t, J=8Hz), 1,10-2,10 (11H, m), 3,52 (3H, s), 4,25 (2H, q, J=8Hz), 4,50 (1H, d, J=5Hz), 6,75 (1H, dd, J=2Hz og 9Hz), 6,82 (1H, d, J=2Hz), 7,35 (2H, d, J=9Hz), 7,45 (2H, d, J=9Hz), 7,85 (1H, d, J=9Hz)
(103) 2-(4-Klorfenyl)-4-metyl-6-[2-(tetrahydro-2H-pyranyl)-metoksy]-2H-1,2,4-benzotiadiazin-3(4H)-on-1,1-dioksyd smp.: >2 50°C
IR (Nujol) : 1700, 1600, 1580, 1490, 1340, 1320,
1190 cm"<1>
NMR (DMS0-d6, 6) : 1,20-1,90 (6H, ra), 3,40-3,90 (3H, m) ,
3,50 (3H, s), 4,10 (2H, d, J=6Hz), 7,00 (1H, dd, J=2Hz og 9Hz), 7,10 (1H, d, J=2Hz), 7,40 (2H, d, J=9Hz), 7,60 (2H, d, J=9Hz), 7,86 (1H, d, J=9Hz)
(104) 2-(4-Karboksymetylfenyl)-6-isopropoksy-4-metyl-2H-l,2,4-benzotiadiazin-3(4H)-on-1,1-dioksyd
smp.: 232-233 °C
IR (Nujol) : 3600-2500, 1700, 1685, 1600 cm"<1>
NMR (DMS0-d6, S) : 1,34 (6H, d, J=6,0Hz), 3,49 (3H, s),
3.66 (2H, s), 4,8-5,0 (1H, m), 6,95-7,01 (2H, m), 7,30 og 7,40 (4H, ABq, J=8,0Hz), 7,84 (1H, d, J=9,0Hz)
(105) 2-(4-Karboksyfenyl)-6-isopropoksy-4-metyl-2H-l,2,4-benzotiadiazin-3(4H)-on-1,1-dioksyd
smp.: 247,5-248,5°C
IR (Nujol) : 3200-2400, 1690, 1605 cm"<1>
NMR (DMS0-d6, <5) : 1,34 (6H, d, J=6,0Hz), 3,50 (3H, s) ,
4,80-5,0 (1H, m), 6,95-7,07 (2H, m), 7,51 og 8,09 (4H, ABq, J=8,3Hz), 7,86 (1H, d, J=8,4Hz), 13,3 (1H, bred s)
(10 6) 2-(3-Karboksypropyl)-6-isopropoksy-4-metyl-2H-l,2,4-benzotiadiazin-3(4H)-on-1,1-dioksyd
smp.: 150-152 °C
IR (Nujol) : 1710, 1690, 1600, 1580, 1470, 1380,
1100 cm"1
NMR (CDC13, 6) : 1,38 (6H, d, J=6Hz), 2,05 (2H, m), 2,43
(2H, t, J=7Hz), 3,46 (3H, s), 3,98 (2H, t, J=7Hz), 4.67 (1H, m), 6,67 (1H, d, J=2Hz), 6,76 (1H, dd, J=2Hz og 9Hz), 7,76 (1H, d, J=9Hz)
(107) 2-(4-Karboksyfenyl)-6-cykloheksylmetoksy-4-metyl-2H-1,2,4-benzotiadiazin-3(4H)-on-1,1-dioksyd smp.: 240,5-241°C
IR (Nujol) : 3300-2400, 1690, 1600, 1330 cm<-1>
NMR (DMS0-d6, S) : 1,40-1,95 (5H, m), 1,55-1,95 (6H, ra),
3,52 (3H, s), 4,00 (1H, d, J=5,8Hz), 6,95-7,10 (2H, m), 7,50 og 8,05 (4H, ABq, J=8,3Hz), 7,86 (1H, d, J=8,7Hz), 13,3 (1H, bred s)
(108) Hydrokloridsalt av 6-[trans-4-(aminometyl)cykloheksyl-metoksy] -2-(4-klorfenyl)-4-metyl-2H-l,2,4-benzotiadiazin-3(4H)-on-1,1-dioksyd
smp.: >250°C
IR (Nujol) : 3400, 1700, 1610, 1600, 1380, 1330, 1310,
1280, 1130 cm"<1>
NMR (DMS0-d6, S) : 0,90-1,20 (4H, m), 1,40-2,10 (6H, m),
2,70 (2H, m), 3,50 (3H, s), 4,02 (2H, d, J=7Hz), 7,03 (1H, dd, J=2Hz og 9Hz), 7,10 (1H, d, J=2Hz), 7,40 (2H, d, J=9Hz), 7,60 (2H, d, J=9Hz), 7,90 (1H, d, J=9Hz), 8,00 (1H, bred s)
(109) 7-Klor-6-isopropoksy-4-metyl-2-(2-pyridyl)-2H-1,2,4-benzotiadiazin-3(4H)-on-1,1-dioksyd
smp.: 193-194 °C
IR (Nujol) : 1685, 1590, 1345 cm"<1>
NMR (CDC13, 6) : 1,46 (6H, d, J=6Hz), 3,55 (3H, s), 4,6-4,85 (1H, m), 6,75 (1H, s), 7,35-7,55 (2H, m), 7,90 (1H, s), 7,85-7,95 (1H, m), 8,6-8,7 (1H, m)
(110) 7-Brom-6-isopropoksy-4-metyl-2-(2-pyridyl)-2H-1,2,4-benzotiadiazin-3(4H)-on-1,1-dioksyd
smp.: 194,5-195,5°C
IR (Nujol) : 1690, 1590, 1345 cm"<1>
NMR (CDCI3, 6) : 1,47 (6H, d, J=6Hz), 3,55 (3H, s), 4,6-4,85 (1H, ra), 6,71 (1H, s), 7,35-7,55 (2H, m), 7,85-7,95 (1H, m), 8,04 (1H, s), 8,60-8,70 (1H, m)
(111) 2-(4-Klorfenyl)-5,7-diklor-6-hydroksy-4-metyl-2H-l,2,4-benzotiadiazin-3(4H)-on-1,1-dioksyd
smp.: 197-198°C
IR (Nujol) : 1720, 1700, 1500, 1360, 1180 cm"<1>
NMR (DMSO-d6, S) : 3,55 (3H, s), 7,42 (2H, d, J=9Hz),
7,60 (2H, d, J=9Hz), 8,00 (1H, s)
EKSEMPEL 7
På lignende måte som beskrevet i eksempel 3 ble oppnådd
følgende forbindelser:
(1) 6-Hydroksy-4-metyl-2-(P-tolyl)-2H-1,2,4-benzotiadiazin-3(4H)-on-1,1-dioksyd
smp.: 163-165°C
IR (Nujol) : 3400, 1670, 1610, 1590, 1480, 1340, 1320,
1220, 1190, 1140 cm<-1>
NMR (DMS0-d6, S) : 2,35 (3H, s), 3,40 (3H, s), 6,80 (1H,
d, J=9Hz), 6,90 (1H, s), 7,10-7,40 (4H, m), 7,75 (1H, d, J=9Hz)
(2) 6-Hydroksy-4-metyl-2-fenyl-2H-l,2,4-benzotiadiazin-3(4H)-on-1,1-dioksyd
smp.: 235-237 °C
IR (Nujol) : 1680, 1610, 1590, 1470, 1330, 1210,
1190 cm<-1>
NMR (DMS0-d6, 6) : 3,45 (3H, s), 6,80 (1H, d, J=9Hz),
6,90 (1H, s), 7,30-7,60 (5H, m), 7,78 (1H, d, J=9H)
(3) 6-Hydroksy-4-metyl-2-(4-trifluormetylfenyl)-2H-1,2,4-benzo-tiadiazin-3(4H)-on-1,1-dioksyd
smp.: 230-233 °C
IR (Nujol) : 3300, 1660, 1610, 1590, 1460, 1350, 1320,
1190, 1110 cm"<1>
NMR (DMS0-d6, S) : 3,42 (3H, s), 6,80 (2H, d, J=9Hz),
6,90 (1H, s), 7,60 (2H, d, J=7Hz), 7,77 (1H, d, J=9Hz), 7,92 (2H, d, J=7Hz)
(4) 2-(3,4-Diklorfenyl)-6-hydroksy-4-metyl-2H-l,2,4-benzotiadia-zin-3(4H)-on-1,1-dioksyd
smp.: >250°C
IR (Nujol) : 3350, 1660, 1610, 1590, 1460, 1350,
1340 cm"1
NMR (DMS0-d6, <5) : 3,45 (3H, s) , 6,82 (1H, d, J=8Hz),
6,86 (1H, s), 7,45 (1H, dd, J=2Hz og 9Hz), 7,65-7,90 (3H, m) , 11,0 (1H, s)
(5) 2-(4-Fluorfenyl)-6-hydroksy-4-metyl-2H-l,2,4-benzotiadiazin-3(4H)-on-1,1-dioksyd
smp.: 228-230°C
IR (Nujol) : 3400, 1650, 1610, 1580, 1460, 1350,
1210cm"1
NMR (DMS0-d6, 5) : 3,40 (3H, s), 6,80 (1H, d, J=9Hz),
6,85 (1H, s), 7,30-7,60 (4H, m), 7,75 (1H, d, J=9Hz), 11,0 (1H, bred s)
(6) 2-(2-Klorfenyl)-6-hydroksy-4-metyl-2H-l,2,4-benzotiadiazin-3(4H)-on-1,1-dioksyd
smp.: 195-196 °C
IR (Nujol) : 3400, 1670, 1620, 1590, 1470, 1460,
1330cm"<1>
NMR (DMSO-d6, 6) : 3,48 (3H, s), 6,83 (1H, d, J=9Hz),
6,93 (1H, s), 7,40-7,75 (4H, m), 7,77 (1H, d, J=9Hz), 11,0 (1H, bred s)
(7) 2-(3-Klorfenyl)-6-hydroksy-4-metyl-2H-1,2,4-benzotiadiazin-3(4H)-on-1,1-dioksyd
smp.: 242-243 °C
IR (Nujol) : 3500, 1680, 1660, 1610, 1590, 1460, 1370,
1320 cm"1
NMR (DMS0-d6, 6) : 3,45 (3H, s), 6,83 (1H, dd, J=2Hz og 9Hz), 6,89 (1H, d, J=2Hz), 7,30-7,65 (4H, m), 7,77
(1H, d, J=9Hz)
(8) 2-(4-Klorfenyl)-6-hydroksy-4-isopropyl-2H-l,2,4-benzotia-diazin-3(4H)-on-1,1-dioksyd
smp.: 212-213 °C
IR (Nujol) : 3350, 1660, 1610, 1460, 1350, 1320 cm"<1>
NMR (DMSO-d6, 6) : 1,52 (6H, d, J=6Hz), 4,52 (1H, m),
6,81 (1H, d, J=9Hz), 6,96 (1H, s), 7,25-7,70 (4H, m), 7,72 (1H, d, J=9Hz)
(9) 2-(4-Klorfenyl)-4-etyl-6-hydroksy-2H-l,2,4-benzotiadiazin-3(4H)-on-1,1-dioksyd
smp.: 253-255 °C
IR (Nujol) : 3300, 1640, 1610, 1580, 1460, 1350,
1330cm"<1>
NMR (DMS0-d6, 6) : 1,28 (3H, t, J=7Hz), 4,05 (2H, q,
J=7Hz), 6,82 (1H, dd, J=2Hzog 9Hz), 6,90 (1H, d, J=2Hz), 7,42 (2H, d, J=9Hz), 7,60 (2H, d, J=9Hz),
7,78 (1H, d, J=9Hz)
(10) 2-(4-Klorbenzyl)-6-hydroksy-4-metyl-2H-1,2,4-benzotiadiazin-3(4H)-on-1,1-dioksyd
smp.: 130-132 °C
IR (Nujol) : 3250, 1645, 1610, 1580, 1335, 1180 cm"<1>
NMR (DMS0-d6, S) : 3,41 (3H, s), 4,94 (2H, s), 6,80 (1H,
d, J=9,0Hz), 6,82 (1H, s), 7,35 og 7,39 (4H, ABq, J=8,6Hz), 7,75 (1H, d, J=9,0Hz), 10,93 (1H, bred s)
(11) 2-Cykloheksyl-6-hydroksy-4-metyl-2H-l,2,4-benzotiadiazin-3(4H)-on-1,1-dioksyd
smp.: 189-190°C
IR (Nujol) : 3300, 1665, 1610, 1585, 1320, 1200,
1180cm"<1>
NMR (DMS0-d6, S) : 1,0-1,5 (3H, m) , 1,5-1,9 (5H, m) ,
2,05-2,35 (2H, m), 3,38 (3H, s), 4,2-4,4 (1H, m),
6,76 (1H, d, J=8,2Hz), 6,78 (1H, s), 7,66 (1H, d, J=8,2Hz), 10,84 (1H, bred s)
(12) 6-Hydroksy-4-metyl-2-pentyl-2H-l,2,4-benzotiadiazin-3(4H)-on-1,1-dioksyd
smp.: 108-110°C
IR (Nujol) : 3300, 1640, 1600, 1580, 1460, 1340,
1180cm"1
NMR (DMSO-d6, S) : 0,84 (3H, t, J=6Hz), 1,10-1,40 (4H,
m), 1,50-1,70 (2H, m), 3,40 (3H, s), 3,74 (2H, t, J=7Hz), 6,70-6,90 (2H, m), 7,70 (1H, d, J=9Hz), 10,9
(1H, bred s)
(13) 2-(4-Karboksyfenyl)-6-hydroksy-4-metyl-2H-l,2,4-benzo-tiadiazin-3(4H)-on-1,1-dioksyd
smp.: >250°C
IR (Nujol) : 3600-2500, 3350, 1705, 1610 cm"<1>
NMR (DMS0-d6, S) : 3,46 (3H, s), 6,80-6,95 (2H, m), 7,50
og 8,05 (4H, ABq, J=8,4Hz), 7,80 (1H, d, J=8,7Hz), 10,99 (1H, s)
(14) 2-(4-Karboksymetylfenyl)-6-hydroksy-4-metyl-2H-l,2,4-benzotiadiazin-3(4H)-on-1,1-dioksyd
smp.: >250°C
IR (Nujol) : 3210, 1715, 1665, 1620, 1585, 1340 cm"<1>NMR (DMS0-d6, S) : 3,45 (3H, s), 3,66 (2H, s), 6,75-6,90
(2H, m), 7,30 og 7,40 (4H, ABq, J=8,3Hz), 7,75 (1H, d, J=8,6Hz), 10,96 (1H, s)
(15) 2-(3-Karboksypropyl)-6-hydroksy-4-metyl-2H-l,2,4-benzotiadiazin-3(4H)-on-1,1-dioksyd
smp.: 145-148°C
IR (Nujol) : 3300, 1690, 1600, 1590, 1470, 1380, 1340,
1120cm"1
NMR (DMS0-d6, S) : 1,80 (2H, m), 2,24 (2H, t, J=7Hz),
3,40 (3H, s), 3,80 (2H, t, J=7Hz), 6,78 (1H, d, J=9Hz), 6,80 (1H, s), 7,71 (1H, d, J=9Hz), 10,8 (1H, bred s)
(16) 6-Hydroksy-4-metyl-2-(4-fenoksyfenyl)-2H-1,2,4-benzotiadiazin-3(4H)-on-1,1-dioksyd
smp.: 239-240°C
IR (Nujol) : 3260, 1645, 1610, 1585, 1345, 1210 cm"<1>NMR (CDC13, S) : 3,51 (3H, s), 6,75-6,85 (2H, m), 7,0-7,45 (9H, m), 1, 61- 1, IQ (1H, m)
(17) 6-Hydroksy-2-(4-isopropylfenyl)-4-metyl-2H-l,2,4-benzotia-diazin-3(4H)-on-1,1-dioksyd
smp.: >250°C
IR (Nujol) : 3410, 3370, 1670, 1610, 1585, 1325 cm"<1>
NMR (CDC13, S) : 1,23 (6H, d, J=7Hz), 2,93 (1H, m), 3,31
(1H, bred s), 3,47 (3H, s) , 6,70 (1H, d, J=2Hz), 6,72
(1H, dd, J=2Hz og 9Hz), 7,28 (4H, s), 7,70 (1H, d, J=9Hz)
(18) 2-[(3-Klor-4-metyl)fenyl]-6-hydroksy-4-metyl-2H-l,2,4-benzotiadiazin-3(4H)-on-1,1-dioksyd
smp.: >250°C
IR (Nujol) : 3400, 1670, 1610, 1590, 1325 cm"<1>
NMR (DMS0-d6, <5) : 2,39 (3H, s) , 3,45 (3H, s) , 6,82 (1H,
dd, J=2Hz og 9Hz), 6,88 (1H, d, J=2Hz), 7,28 (1H, dd, J=2Hz og 8Hz), 7,44 (1H, d, J=2Hz), 7,51 (1H, d, J=8Hz), 7,76 (1H, d, J=9Hz)
(19) 6-Hydroksy-4-metyl-2-(4-metyltiofenyl)-2H-1,2,4-benzotia-diazin-3(4H)-on-1,1-dioksyd
smp.: 248-249 °C
IR (Nujol) : 3250, 1670, 1610, 1580, 1330, 1180 cm"<1>NMR (DMS0-d6, S) : 2,52 (3H, s), 3,45 (3H, s), 6,81 (1H,
dd, J=2Hz og 9Hz), 6,87 (1H, d, J=2Hz), 7,27 (2H, d, J=9Hz), 7,37 (2H, d, J=9Hz), 7,86 (1H, d, J=9Hz)
(20) 2-(4-Dimetylaminofenyl)-6-hydroksy-4-metyl-2H-l,2,4-benzo-tiadiazin-3(4H)-on-1,1-dioksyd
smp.: 190-191°C
IR (Nujol) : 3350, 1660, 1600, 1580, 1520, 1480, 1320,
1180, 1140 cm"<1>
NMR (DMS0-d6, <S) : 2,95 (6H, s) , 3,44 (3H, s) , 6,73-6,85
(4H, m), 7,10 (2H, d, J=9Hz), 7,73 (1H, d, J=8Hz), 10,90 (1H, s)
EKSEMPEL 8
På lignende måte som beskrevet i eksempel 4 ble det oppnådd følgende forbindelser.
(1) 6-Isopropoksy-4-metyl-2-(P-tolyl)-2H-1,2,4-benzotiadiazin-3(4H)-on-1,1-dioksyd
smp.: 163-165°C
IR (Nujol) : 1690, 1600, 1580, 1340, 1320, 1130,
1110 cm"<1>
NMR (DMS0-d6, S) : 1,33 (3H, s), 1,36 (3H, s), 2,38 (3H,
s), 3,49 (3H, s), 4,90 (1H, m), 6,90-7,10 (2H, m), 7,20-7,34 (4H, m), 7,84 (1H, d, J=8Hz)
(2) 6-Isopropoksy-4-metyl-2-fenyl-2H-l,2,4-benzotiadiazin-3(4H)-on-1,1-dioksyd
smp.: 134-135°C
IR (Nujol) : 1690, 1600, 1580, 1450, 1340, 1190 cm"<1>NMR (CDC13, <S) : 1,42 (6H, d, J=6Hz), 3,55 (3H, s) , 4,70
(1H, m), 6,70-7,90 (2H, m), 7,35-7,60 (5H, m), 7,82
(1H, d, J=9Hz)
(3) 2-(3,4-Diklorfenyl)-6-isopropoksy-4-metyl-2H-l,2,4-benzo-tiadiazin-3(4H)-on-1,1-dioksyd
smp.: 109-110°C
IR (Nujol) : 1710, 1570, 1460, 1350, 1320 cm"<1>
NMR (DMS0-d6, S) : 1,34 (6H, d, J=5Hz), 3,49 (3H, s),
4,90 (1H, m), 7,01 (1H, d, J=8Hz), 7,03 (1H, s), 7,45 (1H, d, J=9Hz), 7,74-7,89 (3H, m)
(4) 2-(4-Fluorfenyl)-6-isopropoksy-4-metyl-2H-l,2,4-benzotia-diazin-3(4H)-on-1,1-dioksyd
smp.: 139-140°C
IR (Nujol) : 1700, 1600, 1570, 1460, 1380, 1330,
1210cm"1
NMR (DMS0-d6, 6) : 1,33 (6H, d, J=6Hz), 3,50 (3H, s),
4,90 (1H, m) , 6,98-7,02 (2H, m) , 7,30-7,48 (4H, m) , 7,85 (1H, d, J=9Hz)
(5) 2-(4-Klorfenyl)-6-etoksy-4-metyl-2H-l,2,4-benzotiadiazin-3(4H)-on-1,1-dioksyd
smp.: 150-151°C
IR (Nujol) : 1680, 1600, 1580, 1460, 1350, 1320, 1220,
1190, 1130 cm"<1>
NMR (DMS0-d6, S) : 1,39 (3H, t, J=7Hz), 3,50 (3H, s) ,
4,23 (2H, q, J=7Hz), 7,00 (1H, dd, J=2Hz og 9Hz), 7,05 (1H, d, J=2Hz), 7,40-7,63 (4H, m), 7,87 (1H, d, J=9Hz)
(6) 6-Benzyloksy-2-(4-klorfenyl)-4-metyl-2H-l,2,4-benzotia-diazin-3(4H)-on-1,1-dioksyd
smp.: 174-175°C
IR (Nujol) : 1690, 1600, 1590, 1460, 1320, 1310,
1180cm"<1>
NMR (DMS0-d6, 6) : 3,34 (3H, s), 5,32 (2H, s), 7,07 (1H,
dd, J=9Hz og 2Hz), 7,20 (1H, d, J=2Hz), 7,30-7,63 (9H, m), 7,90 (1H, d, J=9Hz)
(7) 2-(4-Klorfenyl)-6-cyklopropylmetoksy-4-metyl-2H-l,2,4-ben-zotiadiazin-3(4H)-on-1,1-dioksyd
smp.: 145-146°C
IR (Nujol) : 1690, 1600, 1580, 1540, 1330 cm"<1>
NMR (DMS0-d6, 6) : 0,30-0,45 (4H, m), 1,30 (1H, m), 3,45
(3H, s), 4,01 (2H, d, J=7Hz), 6,90-7,10 (2H, m), 7,35-7,70 (4H, m), 7,85 (1H, d, J=9Hz)
(8) 2-(2-Klorfenyl)-6-isopropoksy-4-metyl-2H-1,2,4-benzotia-diazin-3(4H)-on-1,1-dioksyd
smp.: 150-152 °C
IR (Nujol) : 1700, 1600, 1580, 1450, 1360, 1320,
1200 cm"<1>
NMR (DMS0-d6, 6) : 1,34 (6H, d, J=6Hz), 3,52 (3H, s),
4,90 (1H, m), 6,95-7,10 (2H, m), 7,50-7,70 (4H, m), 7,86 (1H, d, J=9Hz)
(9) 2-(3-Klorfenyl)-6-isopropoksy-4-metyl-2H-l,2,4-benzotia-diazin-3(4H)-on-1,1-dioksyd
smp.: 126-127 °C
IR (Nujol) : 1700, 1600, 1590, 1380, 1330, 1310,
1180 cm<-1>
NMR (DMS0-d6, S) : 1,34 (6H, d, J=6Hz), 3,49 (3H, s),
4,90 (1H, m), 6,98-7,03 (2H, m), 7,37-7,65 (4H, m), 7,86 (1H, d, J=9Hz)
(10) 2-(4-Klorfenyl)-4-metyl-6-propoksy-2H-l,2,4-benzotiadiazin-3(4H)-on-1,1-dioksyd
smp.: 142-143 °C
IR (Nujol) : 1700, 1690, 1610, 1580, 1340, 1320 cm<-1>NMR (DMS0-d6, <5) : 1,02 (3H, t, J=7Hz), 1,80 (2H, q,
J=7Hz), 3,50 (3H, s), 4,10 (2H, t, J=7Hz), 6,95-7,10 (2H, m), 7,40-7,70 (4H, m), 7,90 (1H, d, J=9Hz)
(11) 6-Butoksy-2-(4-klorfenyl)-4-metyl-2H-l,2,4-benzotiadiazin-3(4H)-on-1,1-dioksyd
smp.: 102-103 °C
IR (Nujol) : 1700, 1600, 1340, 1320, 1180, 1130 cm"<1>NMR (DMS0-d6, S) : 0,96 (3H, t, J=7Hz), 1,35-1,90 (4H,
m), 3,50 (3H, s), 4,18 (2H, t, J=7Hz), 6,95-7,10 (2H, m), 7,35-7,70 (4H, m), 8,90 (1H, d, J=9Hz)
(12) 6-Metoksy-4-metyl-2-(P-tolyl)-2H-1,2,4-benzotiadiazin-3(4H)-on-1,1-dioksyd
smp.: 170-173°C.
IR (Nujol) : 1690, 1460, 1440, 1330, 1310, 1180,
1130 cm"<1>
NMR (DMS0-d6, 6) : 3,50 (3H, s), 3,95 (3H, s), 6,95-7,10
(2H, m), 7,20-7,40 (4H, m), 7,95 (1H, d, J=9Hz)
(13) 6-Metoksy-4-metyl-2-fenyl-2H-l,2,4-benzotiadiazin-3(4H)-on-1,1-dioksyd
smp.: 203-206°C
IR (Nujol) : 1710, 1700, 1600, 1450, 1330, 1300, 1220,
1180cm"1
NMR (DMSO-d6, <S) : 3,50 (3H, s) , 3,95 (3H, s) , 7,00 (1H,
d, J=9Hz), 7,05 (1H, s), 7,25-7,65 (5H, m), 7,88 (1H, d, J=9Hz)
(14) 6-Metoksy-4-metyl-2-(4-trifluormetylfenyl)-2H-1,2,4-benzo-tiadiazin-3(4H)-on-1,1-dioksyd
smp.: 165-168 °C
IR (Nujol) : 1700, 1610, 1580, 1460, 1340, 1170,
1140cm-<1>
NMR (DMS0-d6, 6) : 3,52 (3H, s), 3,95 (3H, s), 7,02 (1H,
dd, J=2Hz og 9Hz), 7,10 (1H, d, J=2Hz), 7,65 (2H, d, J=7Hz), 7,92 (1H, d, J=9Hz), 7,98 (2H, d, J=7Hz)
(15) 2-(3,4-Diklorfenyl)-6-metoksy-4-metyl-2H-l,2,4-benzotiadia-zin-3(4H)-on-1,1-dioksyd
smp.: 150-151°C
IR (Nujol) : 1710, 1600, 1470, 1340, 1320 cm"<1>
NMR (DMS0-d6, 6) : 3,50 (3H, s), 3,95 (3H, s), 7,02 (1H,
d, J=9Hz), 7,06 (1H, s), 7,45 (1H, d, J=8Hz), 7,70-8,00 (3H, m)
(16) 2-(4-Fluorfenyl)-6-metoksy-4-metyl-2H-l,2,4-benzotiadiazin-3(4H)-on-1,1-dioksyd
smp. : 203-204 °C
IR (Nujol) : 1700, 1590, 1440 cm"<1>
NMR (DMS0-d6, 6) : 3,52 (3H, s), 3,95 (3H, s), 7,02 (1H,
d, J=9Hz), 7,10 (1H, s), 7,30-7,60 (4H, m), 7,90 (1H, d, J=9Hz)
(17) 6-Isopropoksy-2-(4-metoksyfenyl)-4-metyl-2H-l,2,4-benzo-tiadiazin-3(4H)-on-1,1-dioksyd
smp.: 182-183 °C
IR (Nujol) : 1690, 1600, 1460, 1370, 1340 cm"<1>
NMR (DMS0-d6, 6) : 1,34 (6H, d, J=6Hz), 3,50 (3H, s),
3,82 (3H, s), 4,89 (1H, m), 7,00-7,08 (4H, m), 7,25-7,32 (2H, m), 7,84 (1H, d, J=9Hz)
(18) 2-(2-Klorfenyl)-6-metoksy-4-metyl-2H-l,2,4-benzotiadiazin-3(4H)-on-1,1-dioksyd
smp.: 155-156°C
IR (Nujol) : 1710, 1600, 1460, 1330, 1300, 1180,
1140 cm-<1>
NMR (DMS0-d6, S) : 3,54 (3H, s), 3,95 (3H, s), 7,03 (1H,
dd, J=2Hz og 9Hz), 7,11 (1H, d, J=2Hz), 7,50-7,70
(4H, m), 7,90 (1H, d, J=9Hz)
(19) 2-(3-Klorfenyl)-6-metoksy-4-metyl-2H-l,2,4-benzotiadiazin-3(4H)-on-1,1-dioksyd
smp.: 153-154°C
IR (Nujol) : 1710, 1600, 1590, 1460, 1340, 1320, 1180,
1130, 1060, 1030 cm"<1>
NMR (DMS0-d6, S) : 3,51 (3H, s), 3,94 (3H, s), 7,02 (1H,
dd, J=2Hz og 9Hz), 7,07 (1H, d, J=2Hz), 7,34-7,65
(4H, m), 7,90 (1H, d, J=9Hz)
(20) 2-(4-Klorfenyl)-6-metoksy-4-metyl-2H-1,2,4-benzotiadiazin-3(4H)-on-1,1-dioksyd
smp.: 167-168 °C
IR (Nujol) : 1710, 1600, 1330, 1180, 1130 cm"<1>
NMR (DMS0-d6, S) : 3,42 (3H, s), 3,95 (3H, s), 6,95-7,10
(2H, m), 7,38-7,65 (2H, m), 8,90 (1H, d, J=9Hz)
(21) 2-(4-Klorbenzyl)-6-isopropoksy-4-metyl-2H-l,2,4-benzotia-diazin-3(4H)-on-1,1-dioksyd
IR (rent) : 2980, 1680, 1600, 1580, 1330, 1180, 1110 cm"<1>NMR (CDC13, 5) : 1,38 (6H, d, J=6,0Hz), 3,45 (3H, s) ,
4,55-4,75 (1H, m), 5,00 (2H, s), 6,65 (1H, d, J=l,9Hz), 6,77 (1H, dd, J=l,9 og 8,8Hz), 7,27 og 7,40 (4H, ABq, J=8,4Hz), 7,80 (1H, d, J=8,8Hz)
(22) 4-Isopropyl-2-(4-Klorfenyl)-6-metoksy-2H-l,2,4-benzotiadia-zin-3(4H)-on-1,1-dioksyd
smp.: 166-168 °C
IR (Nujol) : 1690, 1600, 1570, 1460, 1340, 1300 cm"<1>
NMR (DMSO-d6, 6) : 1,54 (6H, d, J=6Hz), 3,94 (3H, s),
4,61 (1H, m), 6,90-7,10 (2H, m), 7,30-7,70 (4H, m) , 7,85 (1H, d, J=9Hz)
(23) 2-(4-Klorfenyl)-6-isopropoksy-4-isopropyl-2H-l,2,4-benzo-tiadiazin-3(4H)-on-1,1-dioksyd
smp.: 158-160°C
IR (Nujol) : 1690, 1590, 1490, 1460, 1340, 1300 cm"<1>
NMR (DMS0-d6, S) : 1,34 (6H, d, J=6Hz), 1,52 (6H, d,
J=6Hz), 4,58 (1H, m), 4,88 (1H, m), 6,90-7,05 (2H,
m), 7,30-7,65 (4H, m), 7,82 (1H, d, J=9Hz)
(24) 2-(4-Klorfenyl)-4-etyl-6-metoksy-2H-l,2,4-benzotiadiazin-3(4H)-on-1,1-dioksyd
smp.: 106-107°C
IR (Nujol) : 1690, 1600, 1570, 1490, 1460, 1350,
1310cm'<1>
NMR (DMS0-d6, S) : 1,28 (3H, t, J=7Hz), 3,95 (3H, s),
4,14 (2H, q, J=7Hz), 7,03 (1H, d, J=9Hz), 7,09 (1H,
s), 7,42 (2H, d, J=9Hz), 7,60 (2H, d, J=9Hz), 7,90
(1H, d, J=9Hz)
(25) 2-(4-Klorfenyl)-4-etyl-6-isopropoksy-2H-l,2,4-benzotia-diazin-3(4H)-on-1,1-dioksyd
smp.: 167-168°C
IR (Nujol) : 1700, 1600, 1580, 1460, 1340, 1310 cm"<1>
NMR (DMS0-d6, <5) : 1,26 (3H, t, J=7Hz), 1,34 (6H, d,
J=6Hz), 4,13 (2H, q, J=7Hz), 7,05-7,09 (2H, m), 7,42 (2H, d, J=9Hz), 7,60 (2H, d, J=9Hz), 7,87 (2H, d, J=9Hz)
(26) 2-Cykloheksyl-6-isopropoksy-4-metyl-2H-l,2,4-benzotiadiazin-3(4H)-on-1,1-dioksyd
smp.: 111-112°C
IR (Nujol) : 1685, 1605, 1330, 1180, 1110 cm"<1>
NMR (DMS0-d6, 6) : 1,0-1,45 (3H, m), 1,31 (6H, d,
J=6,0Hz), 1,5-1,9 (5H, m), 2,05-2,35 (2H, m), 3,43
(3H, s), 4,25-4,4 (1H, m), 4,84 (1H, m) , 6,91 (1H, s), 6,78 (1H, d, J=9,0Hz), 7,75 (1H, d, J=9,0Hz)
(27) 6-Isopropoksy-4-metyl-2-pentyl-2H-l,2,4-benzotiadiazin-3(4H)-on-1,1-dioksyd
smp.: 44-46°C
IR (Nujol) : 1690, 1600, 1580, 1460, 1340, 1320,
1190 cm"1
NMR (DMS0-d6, <S) : 0,84 (3H, t, J=6Hz), 1,05-1,40 (4H,
m), 1,31 (6H, d, J=6Hz), 1,50-1,75 (2H, m), 3,44 (3H, s), 3,74 (2H, t, J=7Hz), 4,85 (1H, m), 6,90-7,05 (2H, m), 7,78 (1H, d, J=9Hz)
(28) 6-Isopropoksy-2-(4-isopropoksykarbonylfenyl)-4-metyl-2H-1,2,4-benzotiadiazin-3(4H)-on-1,1-dioksyd smp.: 128-129°C
IR (Nujol) : 1720, 1710, 1610, 1340, 1280 cm"<1>
NMR (CDC13, S) : 1,38 (6H, d, J=6,8Hz), 1,43 (6H, d,
J=6,5Hz), 3,54 (3H, s), 4,63-4,8 (1H, m), 5,2-5,35 (1H, m), 6,76 (1H, d, J=2Hz), 6,82 (1H, dd, J=2Hz og 8,7Hz), 7,50 og 8,15 (4H, ABq, J=8,4Hz), 7,83 (1H, d, J=8,7Hz)
(29) 2-(4-lsopropoksykarbonylmetylfenyl)-6-isopropoksy-4-metyl-2H-1,2,4-benzotiadiazin-3(4H)-on-1,1-dioksyd smp.: 117-120°C
IR (Nujol) : 1730, 1690, 1595, 1335, 1325 cm"<1>
NMR (CDCI3, 6) : 1,24 (6H, d, J=6,0Hz), 1,41 (6H, d,
J=6,0Hz), 3,52 (3H, s), 3,63 (2H, s), 4,6-4,8 (1H, m), 4,9-5,1 (1H, m), 6,7-6,85 (2H, m), 7,3-7,5 (4H, m) , 7,75-7,80 (1H, m)
(30) 6-Isopropoksy-2-(3-isopropoksykarbonylpropyl)-4-metyl-2H-1,2,4-benzotiadiazin-3(4H)-on-1,1-dioksyd
IR (CHCI3) : 1720, 1700, 1600, 1580, 1340, 1270,
1120 cm"<1>
NMR (CDCI3, S) : 1,12 (6H, d, J=6Hz), 1,30 (6H, d,
J=6HZ), 1,99 (2H, m), 2,28 (2H, t, J=7Hz), 3,41 (3H, s), 3,90 (2H, t, J=7Hz), 4,60 (1H, m), 4,92 (1H, m), 6,60 (1H, d, J=2Hz), 6,70 (1H, dd, J=2Hz og 9Hz),
7,70 (1H, d, J=9Hz)
(31) 2-(4-Klorfenyl)-5,7-diklor-6-isopropoksy-4-metyl-2H-l,2,4-benzotiadiazin-3(4H)-on-1,1-dioksyd
smp.: 185-188 °C
IR (Nujol) : 1710, 1470, 1380, 1360, 1190 cm"<1>
NMR (DMS0-d6, 6) : 1,38 (6H, d, J=6Hz), 3,33 (3H, s),
4,75 (1H, m), 7,44 (2H, d, J=9Hz), 7,61 (2H, d, J=9HZ), 8,14 (1H, s)
(32) 2-(4-Klorbenzyl)-6-metoksy-4-metyl-2H-l,2,4-benzotiadiazin-3(4H)-on-1,1-dioksyd
smp. : 132-133 °C
IR (Nujol) : 1675, 1600, 1350, 1330, 1195 cm"<1>
NMR (DMS0-d6, <S) : 3,47 (3H, s) , 3,92 (3H, s) , 4,96 (2H,
s), 6,98 (1H, d, J=9,0Hz), 7,00 (1H, s), 7,35 og 7,40 (4H, ABq, J=8,7Hz), 7,87 (1H, d, J=9,0Hz)
(33) 2-Cykloheksyl-6-metoksy-4-metyl-2H-l,2,4-benzotiadiazin-3(4H)-on-1,1-dioksyd
smp.: 124,5-126°C
IR (Nujol) : 1690, 1595, 1325, 1310, 1300, 1175 cm"<1>
NMR (DMS0-d6, S) : 1,0-1,5 (3H, m) , 1,55-1,9 (5H, m) ,
2,05-2,35 (2H, m), 3,45 (3H, s), 3,90 (3H, s), 4,15-4,4 (1H, m), 6,95 (1H, d, J=8,3Hz), 6,97 (1H, s),
7,78 (1H, d, J=8,3Hz)
(34) 6-Isopropoksy-4-metyl-2-(2-pyridyl)-2H-1,2,4-benzotiadiazin-3(4H)-on-1,1-dioksyd
smp.: 173-174°C
IR (Nujol) : 1700, 1600, 1590, 1340, 1215 cm"<1>
NMR (CDC13, S) : 1,40 (6H, d, J=6Hz), 3,53 (3H, s), 4,6-4,8 (1H, m), 6,73-6,85 (2H, m), 7,35-7,55 (2H, m),
7,82 (1H, d, J=8,7Hz), 7,8-7,95 (1H, m), 8,6-8,68
(1H, m)
(35) 6-Metoksy-4-metyl-2-pentyl-2H-l,2,4-benzotiadiazin-3(4H)-on-1,1-dioksyd
smp.: 85-88 °C
IR (Nujol) : 1690, 1600, 1450, 1330, 1310, 1180 cm"<1>NMR (DMS0-d6, 6) : 0,84 (3H, t, J=6Hz), 1,10-1,40 (4H,
m), 1,50-1,75 (2H, m), 3,47 (3H, s), 3,75 (2H, t, J=7Hz), 3,91 (3H, s), 6,90-7,05 (2H, m), 7,82 (1H, d, J=9Hz)
(36) 6-Metoksy-2-(4-metoksykarbonylfenyl)-4-metyl-2H-l,2,4-benzotiadiazin-3(4H)-on-1,1-dioksyd
smp.: 153-156°C
IR (Nujol) : 1725, 1690, 1590, 1320, 1280 cm"<1>
NMR (DMS0-d6, S) : 3,52 (3H, s), 3,89 (3H, s), 3,95 (3H,
s), 6,97-7,13 (2H, m), 7,55 og 8,10 (4H, ABq, J=8,3Hz), 7,90 (1H, d, J=8,8Hz)
(37) 6-Cykloheksylmetoksy-4-metyl-2-(2-pyridyl)-2H-1,2,4-benzotiadiazin-3(4H)-on-1,1-dioksyd
smp.: 161,5-162,5°C
IR (Nujol) : 1700, 1600, 1310 cm"<1>
NMR (CDC13, <5) : 0, 95-1,45 (5H, m) , 1,65-2,0 (6H, m) ,
3,54 (3H, s), 3,86 (2H, d, J=6Hz), 6,73-6,85 (2H, m), 7,35-7,55 (2H, m), 7,82 (1H, d, J=8,5Hz), 7,81-7,95 (1H, m), 8,6-8,67 (1H, m)
(38) 2-(4-Metoksykarbonylmetylfenyl)-6-metoksy-4-metyl-2H-1,2,4-benzotiadiazin-3(4H)-on-1,1-dioksyd smp.: 173-176°C
IR (Nujol) : 1735, 1690, 1600, 1335, 1320 cm"<1>
NMR (DMS0-d6, <S) : 3,52 (3H, s) , 3,65 (3H, s) , 3,79 (2H,
s), 3,95 (3H, s), 6,96-7,10 (2H, m), 7,33 og 7,43 (4H, ABq, J=8,3Hz), 7,88 (1H, d, J=8,7Hz)
(39) 2-(3-Etoksykarbonylpropyl)-6-metoksy-4-metyl-2H-l,2,4-benzotiadiazin-3(4H)-on-1,1-dioksyd
smp.: 6 3-6 5 0C
IR (Nujol) : 1740, 1690, 1600, 1480, 1380, 1360, 1340,
1320, 1180 cm"<1>
NMR (CDC13, S) : 1,23 (3H, t, J=7Hz), 2,06 (2H, m) , 2,37
(2H, t, J=7Hz), 3,49 (3H, s), 3,90 (3H, s), 3,96 (2H, t, J=7Hz), 4,09 (2H, q, J=7Hz), 6,69 (1H, d, J=2Hz), 6,80 (1H, dd, J=2Hz og 9Hz), 7,79 (1H, d, J=9Hz)
(40) 2-[2-(4,6-Dimetylpyridyl)]-6-isopropoksy-4-metyl-2H-l,2,4-benzotiadiazin-3(4H)-on-1,1-dioksyd
smp.: 202-203 °C
IR (Nujol) : 1700, 1600, 1580, 1350, 1320, 1180 cm"<1>
NMR (DMS0-d6, S) : 1,37 (6H, d, J=6Hz), 2,34 (3H, s),
2,48 (3H, s), 3,49 (3H, s), 4,89 (1H, m), 7,01 (1H,
d, J=9Hz), 7,04 (1H, s), 7,13 (1H, s), 7,25 (1H, s), 7,80 (1H, d, J=9Hz)
(41) 6-Isopropoksy-4-metyl-2-(2-pyrimidinyl)-2H-1,2,4-benzotiadiazin-3(4H)-on-1,1-dioksyd
smp.: 176-178 °C
IR (Nujol) : 1700, 1600, 1400, 1380, 1350, 1330, 1280,
1230cm"<1>
NMR (DMS0-d6, <S) : 1,33 (6H, d, J=6Hz), 3,53 (3H, s) ,
4,90 (1H, m), 7,00 (1H, dd, J=2Hz og 9Hz), 7,10 (1H,
d, J=2Hz), 7,67 (1H, t, J=4Hz), 7,84 (1H, t, J=9Hz), 8,97 (2H, d, J=4Hz)
(42) 6-Metoksy-4-metyl-2-(4-fenoksyfenyl)-2H-1,2,4-benzotiadiazin-3(4H)-on-1,1-dioksyd
smp.: 184-186°C
IR (Nujol) : 1690, 1590, 1330, 1180 cm"<1>
NMR (DMS0-d6, 6) : 3,52 (3H, s), 3,94 (3H, s), 6,95-7,55
(11H, m), 7,89 (1H, d, J=9Hz)
(43) 2-(4-Isopropylfenyl)-6-metoksy-4-metyl-2H-l,2,4-benzotiadia-zin-3(4H)-on-1,1-dioksyd
smp.: 158-159 °C
IR (Nujol) : 1700, 1595, 1330, 1310, 1125 cm"<1>
NMR (DMSO-d6, S) : 1,24 (6H, d, J=7Hz), 2,98 (1H, m) ,
3.51 (3H, s), 3,94 (3H, s), 7,01 (1H, dd, J=2Hz og 9Hz), 7,06 (1H, d, J=2Hz), 7,27 og 7,39 (4H, ABq, J=8Hz), 7,87 (1H, d, J=9Hz)
(44) 2-[(3-Klor-4-metyl)fenyl]-6-metoksy-4-metyl-2H-l,2,4-benzotiadiazin-3(4H)-on-1,1-dioksyd
smp.: 208-211°C
IR (Nujol) : 1695, 1595, 1315, 1180 cm<-1>
NMR (DMS0-d6, S) : 2,40 (3H, s), 3,51 (3H, s), 3,94 (3H,
s), 7,02 (1H, dd, J=2Hz og 9Hz), 7,07 (1H, d, J=2Hz), 7,39 (1H, dd, J=2Hzog 8Hz), 7,46 (1H, d, J=2Hz),
7.52 (1H, d, J=8Hz), 7,89 (1H, d, J=9Hz)
(45) 6-Metoksy-4-metyl-2-(4-metyltiofenyl)-2H-1,2,4-benzotiadia-zin-3(4H)-on-1,1-dioksyd
smp.: 154-155°C
IR (Nujol) : 1690, 1610, 1580, 1490, 1310, 1185,
1135cm"1
NMR (CDC13, <5) : 2,51 (3H, s) , 3,54 (3H, s) , 3,93 (3H,
s), 6,76 (1H, d, J=2Hz), 6,83 (1H, dd, J=2Hz og 9Hz), 7,32 (4H, s), 7,85 (1H, d, J=9Hz)
(4 6) 2-(4-Dimetylaminofenyl)-6-metoksy-4-metyl-2H-l,2,4-benzotia-diazin-3(4H)-on-1,1-dioksyd
smp.: 244-245°C
IR (Nujol) : 1690, 1600, 1520, 1330, 1310, 1180,
1130 cm"<1>
NMR (DMS0-d6, 5) : 2,96 (6H, s), 3,50 (3H, s), 3,94 (3H,
s), 6,75 (2H, d, J=9Hz), 7,10 (2H, d, J=9Hz), 7,02
(1H, dd, J=2Hz og 9Hz), 7,02 (1H, d, J=2Hz), 7,85
(1H, d, J=9Hz)
(47) 2-(4-Karboksymetylfenyl)-6-isopropoksy-4-metyl-2H-l,2,4-benzotiadiazin-3(4H)-on-1,1-dioksyd
smp. : 232-233 °C
IR (Nujol) : 3600-2500, 1700, 1685, 1600 cm"<1>
NMR (DMSO-d6, S) : 1,34 (6H, d, J=6,0Hz), 3,49 (3H, s),
3.66 (2H, s), 4,8-5,0 (1H, m), 6,95-7,01 (2H, m), 7,30 og 7,40 (4H, ABq, J=8,0Hz), 7,84 (1H, d, J=9,0Hz)
(48) 2-(4-Karboksyfenyl)-6-isopropoksy-4-metyl-2H-l,2,4-benzotiadiazin-3(4H)-on-1,1-dioksyd
smp.: 247,5-248,5°C
IR (Nujol) : 3200-2400, 1690, 1605 cm<-1>
NMR (DMS0-d6, S) : 1,34 (6H, d, J=6,0Hz), 3,50 (3H, s),
4,80-5,0 (1H, m), 6,95-7,07 (2H, m), 7,51 og 8,09 (4H, ABq, J=8,3Hz), 7,86 (1H, d, J=8,4Hz), 13,3 (1H, bred s)
(49) 2-(3-Karboksypropyl)-6-isopropoksy-4-metyl-2H-l,2,4-benzotiadiazin-3(4H)-on-1,1-dioksyd
smp.: 150-152°C
IR (Nujol) : 1710, 1690, 1600, 1580, 1470, 1380,
1100 cm"<1>
NMR (CDC13, S) : 1,38 (6H, d, J=6Hz), 2,05 (2H, m), 2,43
(2H, t, J=7Hz), 3,46 (3H, s), 3,98 (2H, t, J=7Hz), 4.67 (1H, m), 6,67 (1H, d, J=2Hz), 6,76 (1H, dd, J=2Hz og 9Hz), 7,76 (1H, d, J=9Hz)
(50) 2-(4-Karboksyfenyl)-6-cykloheksylmetoksy-4-metyl-2H-l,2,4-benzotiadiazin-3(4H)-on-1,1-dioksyd
smp.: 240,5-241°C
IR (Nujol) : 3300-2400, 1690, 1600, 1330 cm"<1>
NMR (DMS0-d6, <S) : 1,40-1,95 (5H, m) , 1,55-1,95 (6H, m) ,
3,52 (3H, s), 4,00 (1H, d, J=5,8Hz), 6,95-7,10 (2H, m), 7,50 og 8,05 (4H, ABq, J=8,3Hz), 7,86 (1H, d, J=8,7Hz), 13,3 (1H, bred s)
(51) 7-Klor-6-isopropoksy-4-metyl-2-(2-pyridyl)-2H-1,2,4-benzotiadiazin-3(4H)-on-1,1-dioksyd (115 mg) som farveløse nåleformede krystaller
smp.: 193-194°C
IR (Nujol) : 1685, 1590, 1345 cm<-1>
NMR (CDCI3, S) : 1,46 (6H, d, J=6Hz), 3,55 (3H, s), 4,6-4,85 (1H, m), 6,75 (1H, s), 7,35-7,55 (2H, m), 7,90 (1H, s), 7,85-7,95 (1H, m), 8,6-8,7 (1H, m)
EKSEMPEL 9
En suspensjon av 6-hydroksy-4-metyl-2-(4-trifluormetylfenyl)-2H-1,2,4-benzotiadiazin-3(4H)-on-1,1-dioksyd (124 mg), kaliumkarbonat (55 mg) og 2-jodpropan (68 mg) i N,N-dimetylformamid
(1 ml) ble omrørt i 2 timer ved 60°C. Blandingen ble hellet i isvann. Det fraskilte faste stoff ble oppsamlet ved filtrering, tørret og omkrystallisert fra etanol, hvorved man fikk2-(4-trifluormetylfenyl)-4-metyl-6-isopropoksy-2H-l,2,4-benzotiadiazin-3(4H)-on-1,1-dioksyd (78 mg),
smp.: 158-160°C
IR (Nujol) : 1690, 1600, 1460, 1370, 1320, 1130 cm"<1>
NMR (DMS0-d6, 6) : 1,34 (6H, d, J=6Hz), 3,50 (3H, s),
4,90 (1H, m), 7,00-7,10 (2H, m), 7,64 (2H, d, J=7Hz), 7,80-8,00 (3H, m)
EKSEMPEL 10
En suspensjon av 2-(4-klorfenyl)-6-hydroksy-4-metyl-2H-l,2,4-benzotiadiazin-3(4H)-on-1,1-dioksyd (250 mg), kaliumkarbonat (122 mg) og 1-jodisobutan (163 mg) i N,N-dimetylformamid (1 ml) ble omrørt i 2 timer ved 60°C. Blandingen ble hellet i isvann. Det fraskilte faste stoff ble oppsamlet ved filtrering, tørret og omkrystallisert fra etanol, hvorved man fikk 2-(4-klorfenyl)-4-metyl-6-(2-metylpropoksy)-2H-1,2,4-benzotiadiazin-3(4H)-on-1,1-dioksyd (169 mg),
smp.: 108-110°C
IR (Nujol) : 1690, 1600, 1580, 1460, 1340, 1320,
1190 cm"<1>
NMR (DMSO-d6, S) : 1,02 (6H, d, J=7Hz), 2,08 (1H, m),
3,51 (3H, s), 3,95 (2H, d, J=8Hz), 6,99-7,06 (2H, m), 7,39-7,63 (4H, m), 7,87 (1H, d, J=9Hz)
EKSEMPEL 11
En suspensjon av 2-(4-klorfenyl)-6-hydroksy-4-metyl-2H-l,2,4-benzotiadiazin-3(4H)-on-1,1-dioksyd (250 mg), kaliumkarbonat (12 2 mg) og brommetylcykloheksan (159 mg) i N,N-dimetylformamid (1 ml) ble omrørt i 2 timer ved 60°C. Blandingen ble hellet i isvann. Det fraskilte faste stoff ble oppsamlet ved filtrering, tørret og omkrystallisert fra etanol, hvorved man fikk 2-(4-klorfenyl)-4-metyl-6-cykloheksylmetoksy-2H-l,2,4-benzotiadiazin-3(4H)-on-1,1-dioksyd (230 mg),
smp.: 127-129°C
IR (Nujol) : 1690, 1600, 1590, 1460, 1320, 1310, 1180,
1130 cm"1
NMR (DMS0-d6, 6) : 1,04-1,40 (5H, m), 1,50-1,90 (6H, m),
3,50 (3H, s), 3,98 (2H, d, J=6Hz), 6,98-7,05 (2H, m), 7,38-7,63 (4H, m), 7,86 (1H, d, J=9Hz)
EKSEMPEL 12
En blanding av 2-(4-klorfenyl)-6-hydroksy-4-metyl-2H-l,2,4-ben-zotiadiazin-3(4H)-on-1,1-dioksyd (500 mg), etylbromacetat
(0,2 ml) og kaliumkarbonat (245 mg) i N,N-dimetylformamid (1 ml) ble omrørt ved 80°C i 3 timer. Blandingen ble avkjølt og hellet i isvann. Det fraskilte faste stoff ble filtrert og oppløst i en blanding av etanol (15 ml) og tetrahydrofuran
(15 ml). Til oppløsningen inneholdende 2-(4-klorfenyl)-6-etoksykarbonylmetoksy-4-metyl-2H-l,2,4-benzotiadiazin-3(4H)-on-1,1-dioksyd ble satt på én gang vandig IN natriumhydroksydoppløs-ning (2,2 ml) ved omgivelsestemperatur. Oppløsningen ble omrørt i én time ved omgivelsestemperatur og konsentrert i vakuum. Residuet ble ekstrahert med metylenklorid. Den organiske fase ble vasket med saltoppløsning, tørret og inndampet, hvorved man fikk et råprodukt som ble omkrystallisert fra metanol, hvorved man fikk 2-(4-klorfenyl)-6-karboksymetoksy-4-metyl-2H-l,2,4-benzotiadiazin-3(4H)-on-1,1-dioksyd (213 mg).
smp.: 228-230°C
IR (Nujol) : 1730, 1690, 1600, 1460, 1340, 1320 cm"<1>NMR (DMS0-d6, 6) : 3,34 (1H, bred s), 3,50 (3H, s), 4,95
(2H, s), 6,99 (1H, dd, J=9Hz og 2Hz), 7,11 (1H, d, J=2Hz), 7,35-7,65 (4H, m), 7,89 (1H, d, J=9Hz)
EKSEMPEL 13
En blanding av 2-(4-klorfenyl)-6-hydroksy-4-metyl-2H-l,2,4-ben-zotiadiazin-3(4H)-on-1,1-dioksyd (678 mg), etyl 2-brompropionat (362 mg) og kaliumkarbonat (207mg) i tørtN,N-dimetylformamid (2 ml) ble omrørt natten over ved omgivelsestemperatur. Blandingen ble hellet i vann og ekstrahert to ganger med etylacetat. De organiske faser ble vasket med vann, tørret og inndampet under redusert trykk. Residuet ble krystallisert fra n-heksan, hvorved man fikk 2-(4-klorfenyl)-6-[1-(etoksykarbonyl)-etoksy]-4-metyl-2H-l,2,4-benzotiadiazin-3(4H)-on-1,1-dioksyd (816 mg) (R,S-blanding).
smp.: 111-112°C
IR (Nujol) : 1750, 1690, 1605, 1340, 1210, 1140 cm"<1>NMR (CDC13, S) : 1,29 (3H, t, J=7,lHz), 1,69 (3H, d,
J=6,7Hz), 3,52 (3H, s), 4,26 (2H, q, J=7,lHz), 4,88 (1H, q, J=6,7Hz), 6,73 (1H, dd, J=8,7Hz og 2,0Hz), 6,84 (1H, d, J=2,0Hz), 7,35 og 7,46 (4H, ABq, J=8,6Hz), 7,83 (1H, d, J=8,7Hz)
EKSEMPEL 14
Til en suspensjon av 2-(4-klorfenyl)-6-[1-(etoksykarbonyl)-etoksy]-4-metyl-2H-l,2,4-benzotiadiazin-3(4H)-on-1,1-dioksyd (400 mg) i en blanding av etanol (5 ml) og vann (5 ml) ble satt på én gang vandig IN natriumhydroksydoppløsning (1,1 ml). Blandingen ble tilbakeløpskjølt i en halv time og konsentrert i vakuum. Residuet ble oppløst i vann og vasket med etyleter. Den vandige fase ble gjort sur med saltsyre. Den fraskilte olje ble ekstrahert med etylacetat. Den organiske fase ble vasket med saltoppløsning, tørret og inndampet til tørrhet. Residuet ble krystallisert fra en blanding av n-heksan og etylacetat, hvorved man fikk 2-(4-klorfenyl)-6-(1-karboksyetoksy)-4-metyl-2H-1,2,4-benzotiadiazin-3(4H)-on-1,1-dioksyd (240 mg) (R,S-blanding).
smp.: 179,5-180,5°C
IR (Nujol) : 3250, 1760, 1665, 1600, 1350 cm<-1>
NMR (CDC13, <S) : 1,74 (3H, d, J=6,7Hz), 3,52 (3H, s) ,
4,94 (1H, q, J=6,7Hz), 5,54 (1H, bred s), 6,76 (1H, dd, J=l,9Hz og 8,7Hz), 7,40 (4H, ABq, J=8,6Hz), 7,85
(1H, d, J=8,7Hz)
EKSEMPEL 15
På lignende måte som beskrevet i eksempel 13 ble oppnådd følgende forbindelser.
(1) 2-(4-Klorfenyl)-6-(1-etoksykarbonyl-l-metyletoksy)-4-metyl-2H-1,2,4-benzotiadiazin-3(4H)-on-1,1-dioksyd smp.: 184-185°C
IR (Nujol) : 1720, 1700, 1580, 1370, 1340 cm"<1>
NMR (CDCI3, 6) : 1,30 (3H, t, J=7Hz), 1,73 (6H, s), 3,53
(3H, s), 4,28 (2H, q, J=7Hz), 6,68 (1H, dd, J=9Hz og 2Hz), 6,80 (1H, d, J=2Hz), 7,37 (2H, d, J=9Hz), 7,50 (2H, d, J=9Hz), 7,81 (1H, d, J=9Hz)
(2) 2-(4-Klorfenyl)-6-(3-etoksykarbonylpropoksy)-4-metyl-2H-1,2,4-benzotiadiazin-3(4H)-on-1,1 dioksyd
smp.: 90-92 °C
IR (Nujol) : 1730, 1700, 1600, 1580, 1470, 1330,
1320 cm-1
NMR (CDCI3, S) : 1,28 (3H, t, J=7Hz), 2,17 (2H, m), 2,54
(2H, t, J=7Hz), 3,54 (3H, s), 4,15 (2H, t, J=7Hz), 4,17 (2H, q, J=7Hz), 6,70-6,90 (2H, m), 7,30-7,55
(4H, m), 7,84 (1H, d, J=9Hz)
(3) 2-(4-Klorfenyl)-6-(1-etoksykarbonylpropoksy)-4-metyl-2H-1,2,4-benzotiadiazin-3(4H)-on-1,1-dioksyd
smp.: 105-108°C
IR (Nujol) : 1750, 1690, 1600, 1580, 1210 cm<-1>
NMR (CDC13, 6) : 1,11 (3H, t, J=7Hz), 1,29 (3H, t,
J=7Hz), 2,06 (2H, m), 3,50 (3H, s), 4,26 (2H, q, J=7Hz), 4,69 (1H, t, J=6Hz), 6,74 (1H, dd, J=9Hz og 6Hz), 6,84 (1H, d, J=2Hz), 7,30-7,50 (4H, m), 7,83
(1H, d, J=9Hz)
(4) 2-(4-Klorfenyl)-6-(1-etoksykarbonylcyklobutyloksy)-4-metyl-2H-1,2,4-benzotiadiazin-3(4H)-on-1,1-dioksyd smp.: 140-142°C
IR (Nujol) : 1730, 1690, 1610, 1590, 1360 cm"<1>
NMR (CDCI3, 6) : 1,69 (3H, t, J=7Hz), 1,85-2,90 (6H, m) ,
3,46 (3H, s), 4,20 (2H, q, J=7Hz), 6,57 (1H, dd, J=9Hz og 2Hz), 6,92 (1H, d, J=2Hz), 7,41 (2H, d, J=8Hz), 7,60 (2H, d, J=8Hz), 7,87 (1H, d, J=9Hz)
(5) 2-(4-Klorfenyl)-6-(1-karboksyetoksy)-4-metyl-2H-l,2,4-benzotiadiazin-3(4H)-on-1,1-dioksyd (R,S-blanding)
smp.: 179,5-180,5°C
IR (Nujol) : 3250, 1760, 1665, 1600, 1350 cm"<1>
NMR (CDCI3, 5) : 1,74 (3H, d, J=6,7Hz), 3,52 (3H, s),
4,94 (1H, q, J=6,7Hz), 5,54 (1H, bred s), 6,76 (1H, dd, J=l,9Hz og 8,7Hz), 7,40 (4H, ABq, J=8,6Hz), 7,85
(1H, d, J=8,7Hz)
(6) 2-(4-Klorfenyl)-6-(1-karboksy-l-metyletoksy)-4-metyl-2H-1,2,4-benzotiadiazin-3(4H)-on-1,1 dioksyd
smp.: 208-210°C
IR (Nujol) : 3250, 1750, 1670, 1600, 1350, 1330 cm"<1>
NMR (CDCI3, 6) : 1,75 (6H, s), 3,51 (3H, s), 6,74 (1H,
dd, J=9Hzog 2Hz), 6,83 (1H, d, J=2Hz), 7,34 (2H, d, J=9Hz), 7,46 (2H, d, J=9Hz), 7,82 (1H, d, J=9Hz)
(7) 2-(4-Klorfenyl)-6-(3-karboksypropoksy)-4-metyl-2H-l,2,4-benzotiadiazin-3(4H)-on-1,1-dioksyd smp.: 170-171°C
IR (Nujol) : 1700, 1600, 1580, 1330, 1310 cm"<1>
NMR (CDC13, S) : 2,19 (2H, m), 2,62 (2H, t, J=7Hz), 3,54
(3H, s), 4,17 (2H, t, J=6Hz), 6,70-6,90 (2H, m), 7,35 (2H, d, J=9Hz), 7,47 (2H, d, J=9Hz), 7,84 (1H, d, J=9Hz)
(8) 2-(4-Klorfenyl)-6-(1-karboksypropoksy)-4-metyl-2H-l,2,4-benzotiadiazin-3(4H)-on-1,1-dioksyd
smp.: 179-181°C
IR (Nujol) : 3250, 1760, 1680, 1600, 1590, 1380,
1200cm"1
NMR (CDCI3, 6) : 1,15 (3H, t, J=7Hz), 2,11 (2H, m), 3,53
(3H, s), 4,78 (1H, t, J=6Hz), 6,76 (1H, dd, J=9Hzog 2Hz), 6,86 (1H, d, J=2Hz), 7,30-7,50 (4H, m), 7,85
(1H, d, J=9Hz)
(9) 2-(4-Klorfenyl)-6-(1-karboksycyklobutyloksy)-4-metyl-2H-1,2,4-benzotiadiazin-3(4H)-on-1,1-dioksyd
smp.: 148-151°C
IR (Nujol) : 1700, 1600, 1380, 1320, 1180 cm"<1>
NMR (CDCI3, S) : 2,00-2,30 (2H, m), 2,50-2,75 (2H, m),
2,78-2,95 (2H, m), 3,51 (3H, s), 6,53 (1H, dd, J=9Hz og 2Hz), 6,73 (1H, d, J=2Hz), 7,34 (2H, d, J=9Hz), 7,46 (2H, d, J=9Hz), 7,80 (1H, d, J=9Hz)
(10) (IR)-(+)-2-(4-Klorfenyl)-6-[1-(etoksykarbonyl)etoksy]-4-metyl-2H-1,2,4-benzotiadiazin-3(4H)-on-1,1-dioksyd smp.: 86-88 °C
[a]D+24,0° (C=1,0, EtOH)
IR (Nujol) : 1740, 1690, 1680, 1600, 1590, 1500, 1210,
1185 cm"<1>
NMR (CDCI3, S) : 1,30 (3H, t, J=7Hz), 1,69 (3H, d,
J=7Hz), 3,53 (3H, s), 4,26 (2H, q, J=7Hz), 4,87 (1H, q, J=7Hz), 6,74 (1H, dd, J=2Hz og 9Hz), 6,83 (1H, d, J=9Hz), 7,35 (2H, d, J=9Hz), 7,46 (2H, d, J=9Hz), 7,83 (1H, d, J=9Hz)
(11) (IS)-(-)-2-(4-Klorfenyl)-6-[1-(etoksykarbonyl)etoksy]-4-metyl-2H-l,2,4-benzotiadiazin-3(4H)-on-1,1-dioksyd smp.: 96-98 °C
[a]D-24,7<0>(C=l,0, EtOH)
IR (Nujol) : 1730, 1690, 1680, 1600, 1590, 1340,
1190cm"<1>
NMR (CDC13, S) : 1,29 (3H, t, J=7Hz), 1,69 (3H,, d,
J=7Hz), 3,52 (3H, s), 4,26 (2H, q, J=7Hz), 4,88 (1H, q, J=7Hz), 6,74 (1H, d, J=9Hz), 6,83 (1H, s), 7,35 (2H, d, J=9Hz), 7,46 (2H, d, J=9Hz), 7,83 (1H, d, J=9Hz)
(12) (IR)-(+)-2-(4-Klorfenyl)-6-(1-karboksyetoksy)-4-metyl-2H-1,2,4-benzotiadiazin-3(4H)-on-1,1-dioksyd smp.: 75-85 °C
[a]D+16,4° (C=1,0, EtOH)
IR (Nujol) : 3200, 1740, 1700, 1690, 1660, 1600, 1580,
1380, 1130cm-<1>
NMR (CDCI3, 6) : 1,77 (3H, d, J=7Hz), 3,55 (3H, s), 4,98
(1H, q, J=7Hz), 6,79 (1H, dd, J=2Hz og 9Hz), 6,88 (1H, d, J=2Hz), 7,37 (2H, d, J=9Hz), 7,49 (2H, d, J=9Hz), 7,88 (1H, d, J=9Hz)
(13) (IS)-(-)-2-(4-Klorfenyl)-6-(1-karboksyetoksy)-4-metyl-2H-1,2,4-benzotiadiazin-3(4H)-on-1,1-dioksyd smp.: 85-95°C
[a]D-17,0° (C=1,0, EtOH)
IR (Nujol) : 3200, 1740, 1700, 1665, 1600, 1580, 1200,
1130 cm"<1>
NMR (CDCI3, <S) : 1,75 (3H, d, J=7Hz), 3,52 (3H, s) , 4,95
(1H, q, J=7Hz), 6,50 (1H, bred s), 6,75 (1H, dd, J=2Hz og 9Hz), 6,88 (1H, d, J=2Hz), 7,32 (2H, d, J=9Hz), 7,45 (2H, d, J=9Hz), 7,85 (1H, d, J=9Hz)
(14) (IR)-(+)-6-[1-(Etoksykarbonyl)etoksy]-4-mety1-2-fenyl-2H-1,2,4-benzotiadiazin-3(4H)-on-1,1-dioksyd smp.: 137,5-139°C
IR (Nujol) : 1740, 1700, 1605, 1340, 1210, 1140 cm<-1>
NMR (CDCI3, <S) : 1,30 (3H, t, J=7Hz) , 1,69 (3H, d,
J=7Hz), 3,53 (3H, s), 4,26 (2H, q, J=7Hz), 4,88 (1H, q, J=7Hz), 6,73 (1H, dd, J=2Hz og 9Hz), 6,84 (1H, d, J=2Hz), 7,35-7,55 (5H, m), 7,84 (1H, d, J=9Hz)
(15) (IR)-(+)-6-[l-(Etoksykarbonyl)etoksy]-4-metyl-2-(4-fenoksyfenyl)-2H-1,2,4-benzotiadiazin-3(4H)-on-1,1-dioksyd smp.: 128-130°C
IR (Nujol) : 1740, 1685, 1610, 1330, 1195, 1130 cm"<1>NMR (CDCI3, S) : 1,29 (3H, t, J=7Hz), 1,69 (3H, d,
J=7Hz), 3,53 (3H, s), 4,26 (2H, q, J=7Hz), 4,88 (1H, q, J=7Hz), 6,75 (1H, dd, J=2Hz og 9Hz), 6,83 (1H, d, J=2Hz), 7,0-7,45 (9H, m), 7,85 (1H, d, J=9Hz)
(16) (IR)-(+)-6-[l-(Etoksykarbonyl)etoksy]-2-(4-isopropylfenyl)-4-metyl-2H-l,2,4-benzotiadiazin-3(4H)-on-1,1-dioksyd smp.: 154-155°C
IR (Nujol) : 1740, 1695, 1600, 1340, 1310, 1200,
1130cm"1
NMR (CDCI3, 6) : 1,27 (6H, d, J=7Hz), 1,29 (3H, t,
J=7Hz), 1,69 (3H, d, J=7Hz), 2,95 (1H, m), 3,52 (3H, s), 4,26 (2H, q, J=7Hz), 4,88 (1H, q, J=7Hz), 6,73 (1H, dd, J=2Hz og 9Hz), 6,83 (1H, d, J=2Hz), 7,32
(4H, s), 7,83 (1H, d, J=9Hz)
(17) (IR)-(+)-2-[(3-Klor-4-metyl)fenyl]-6-[1-(etoksykarbonyl) etoksy]-4-metyl-2H-l,2,4-benzotiadiazin-3(4H)-on-1,1-dioksyd
smp.: 149-150 °C
IR (Nujol) : 1740, 1685, 1600, 1335 cm<-1>
NMR (DMSO-d6, 6) : 1,21 (3H, t, J=7Hz), 1,58 (3H, d,
J=7Hz), 2,40 (3H, s), 3,48 (3H, s), 4,18 (2H, q, J=7Hz), 5,33 (1H, q, J=7Hz), 6,95 (1H, dd, J=2Hz og 9Hz), 7,08 (1H, d, J=2Hz), 7,30 (1H, dd, J=2Hz og 8Hz), 7,47 (1H, d, J=2Hz), 7,51 (1H, d, J=8Hz), 7,87
(1H, d, J=9Hz)
(18) (IR)-(+)-2-Cykloheksyl-6-[l-(etoksykarbonyl)etoksy]-4-metyl-2H-l,2,4-benzotiadiazin-3(4H)-on-1,1-dioksyd smp.: 139-141°C
IR (Nujol) : 1740, 1690, 1600, 1580, 1340, 1300, 1200,
1170ci"1
NMR (CDC13, S) : 1,28 (3H, t, J=6Hz), 1,16-1,45 (3H, m),
1,66 (3H, d, J=6Hz), 1,80-1,92 (5H, m), 2,22-2,42
(2H, m), 3,44 (3H, s), 4,23 (2H, q, J=6Hz), 4,29-4,49 (1H, m), 4,83 (1H, q, J=6Hz), 6,65 (1H, dd, J=2Hz og 8Hz), 6,71 (1H, d, J=2Hz), 7,74 (1H, d, J=6Hz)
(19) (IR)-(+)-6-[1-(Etoksykarbonyl)etoksy]-4-metyl-2-(4-metyl-fenyl)-2H-1,2,4-benzotiadiazin-3(4H)-on-1,1-dioksyd smp.: 134-135°C
IR (Nujol) : 1740, 1680, 1600, 1580, 1340, 1320, 1200,
1130 cm-<1>
NMR (CDCI3, 6) : 1,30 (3H, t, J=6Hz), 1,69 (3H, d,
J=6Hz), 2,40 (3H, s), 3,52 (3H, s), 4,25 (2H, q, J=6Hz), 4,88 (1H, q, J=6Hz), 6,70 (1H, dd, J=2Hz og 8Hz), 6,82 (1H, d, J=2Hz), 7,28 (4H, s), 7,83 (1H, d, J=8Hz)
(20) (IR)-(+)-6-[1-(Etoksykarbonyl)etoksy]-4-metyl-2-(2-pyridyl)-2H-1,2,4-benzotiadiazin-3(4H)-on-1,1-dioksyd smp.: 153-154°C
IR (Nujol) : 1740, 1690, 1605, 1580, 1460, 1330, 1205,
1115 cm"<1>
NMR (CDCI3, <S) : 1,29 (3H, t, J=7Hz), 1,69 (3H, d,
J=7Hz), 3,53 (3H, s), 4,25 (2H, q, J=7Hz), 4,86 (1H,
q, J=7Hz), 6,72 (1H, dd, J=2Hz og 8Hz), 6,84 (1H, d, J=2Hz), 7,38-7,51 (2H, m), 7,82 (1H, d, J=8Hz), 7,90 (1H, dd, J=2Hzog 8Hz), 8,62-8,66 (1H, m)
(21) (IR)-(+)-2-(3,4-Diklorfenyl)-6-[1-(etoksykarbonyl)etoksy]-4-metyl-2H-l,2,4-benzotiadiazin-3(4H)-on-1,1-dioksyd smp.: 108-110°C
IR (Nujol) : 1720, 1685, 1600, 1190, 1135 cm<-1>
NMR (CDCI3, 6) : 1,30 (3H, t, J=8Hz), 1,69 (3H, d,
J=7Hz), 3,53 (3H, s), 4,29 (2H, q, J=8Hz), 4,87 (1H, q, J=7Hz), 6,74 (1H, dd, J=2Hz og 9Hz), 6,83 (1H, d, J=2Hz), 7,28 (1H, dd, J=2Hz og 9Hz), 7,53 (1H, d, J=2Hz), 7,55 (1H, d, J=9Hz), 7,83 (1H, d, J=9Hz)
(22) (IR)-(+)-2-(3-Klorfenyl)-6-[1-(etoksykarbonyl)etoksy]-4-metyl-2H-l,2,4-benzotiadiazin-3(4H)-on-1,1-dioksyd smp.: 135-137°C
IR (Nujol) : 1740, 1700, 1600, 1580, 1340, 1210 cm"<1>NMR (CDCI3, <S) : 1,30 (3H, t, J=7Hz), 1,70 (3H, d,
J=7Hz), 3,46 (3H, s), 4,27 (2H, q, J=7Hz), 4,86 (1H, q, J=7Hz), 6,81-7,37 (6H, m), 7,85 (1H, d, J=9Hz) (23) (IR)-( + )-2-(2-Klorfenyl)-6-[1-(etoksykarbonyl)etoksy]-4-metyl-2H-1,2,4-benzotiadiazin-3(4H)-on-1,1-dioksyd IR (CHCI3) : 1745, 1700, 1605, 1580, 1350, 1320,
1140 cm"<1>
NMR (CDCI3, 6) : 1,30 (3H, t, J=7Hz), 1,69 (3H, d,
J=7Hz), 3,54 (3H, s), 4,27 (2H, q, J=7Hz), 4,88 (1H, q, J=7Hz), 6,70-7,72 (6H, m), 7,82 (1H, d, J=9Hz)
(24) (IR)-(+)-6-[1-(Etoksykarbonyl)etoksy]-2-(4-fluorfenyl)-4-metyl-2H-l,2,4-benzotiadiazin-3(4H)-on-1,1-dioksyd smp.: 100-102 °C
IR (Nujol) : 1740, 1680, 1605, 1370, 1340 cm"<1>
NMR (CDCI3, 6) : 1,30 (3H, t, J=7Hz), 1,69 (3H, d,
J=7Hz), 3,52 (3H, s), 4,26 (2H, q, J=7Hz), 4,88 (1H, q, J=7Hz), 6,71-7,43 (6H, m), 7,83 (1H, d, J=9Hz)
(25) (IR)-( + )-6-[1-(Etoksykarbonyl)etoksy]-4-metyl-2-(4-metyl-tiofenyl)-2H-1,2,4-benzotiadiazin-3(4H)-on-1,1-dioksyd smp.: 156-157°C
IR (Nujol) : 1720, 1605, 1600, 1580, 1205, 1180
1130 cm-1
NMR (CDCI3, <5) : 1,29 (3H, t, J=7Hz), 1,69 (3H, d,
J=7Hz), 2,50 (3H, s), 3,52 (3H, s), 4,25 (2H, q, J=7Hz), 4,87 (1H, q, J=7Hz), 6,72 (1H, dd, J=2Hz og 9Hz), 6,82 (1H, d, J=2Hz), 7,32 (4H, s), 7,83 (1H, d, J=9Hz)
(26) (IR)-(+)-2-(4-Dimetylaminofenyl)-6-[1-(etoksykarbonyl)-etoksy]-4-metyl-2H-l,2,4-benzotiadiazin-3(4H)-on-1,1-dioksyd smp.: 190-192 °C
IR (Nujol) : 1715, 1680, 1600, 1195, 1130 cm<-1>
NMR (CDC13, 6) : 1,29 (3H, t, J=7Hz), 1,67 (3H, d,
J=7Hz), 3,00 (6H, s), 3,51 (3H, s), 4,25 (2H, q, J=7Hz), 4,87 (1H, q, J=7Hz), 6,69-6,81 (4H, m), 7,24 (2H, d, J=8Hz), 7,84 (1H, d, J=8Hz)
(27) (IR)-(+)-6-(1-Karboksyetoksy)-4-metyl-2-fenyl-2H-l,2,4-benzotiadiazin-3(4H)-on-1,1-dioksyd
smp.: 184-185,5°C
IR (Nujol) : 3200, 1750, 1660, 1610, 1320, 1180 cm<-1>NMR (CDCI3, <5) : 1,74 (3H, d, J=7Hz), 3,53 (3H, s) , 3,55-4,1 (1H, br), 4,95 (1H, q, J=7Hz), 6,76 (1H, dd, J=2Hz og 9Hz), 6,85 (1H, d, J=2Hz), 7,35-7,55 (5H, m), 7,86 (1H, d, J=9Hz)
(28) (IR)-(+)-6-(1-Karboksyetoksy)-4-metyl-2-(4-fenoksyfenyl)-2H-1,2,4-benzotiadiazin-3(4H)-on-1,1-dioksyd smp.: 106°C (spaltning)
IR (Nujol) : 3600-2400, 1740, 1695, 1665, 1600, 1585,
1345, 1215 cm"<1>
NMR (CDCI3, <S) : 1,74 (3H, d, J=7Hz), 3,53 (3H, s) , 3,63
(1H, br), 4,95 (1H, q, J=7Hz), 6,76 (1H, dd, J=2Hz og 9Hz), 6,85 (1H, d, J=2Hz), 7,0-7,45 (9H, m), 7,86
(1H, d, J=9Hz)
(29) (IR)-(+)-6-(1-Karboksyetoksy)-2-(4-isopropylfenyl)-4-metyl-2H-l,2,4-benzotiadiazin-3(4H)-on-1,1-dioksyd smp.: 74°C (spaltning)
IR (Nujol) : 3600-2400, 1730, 1695, 1600, 1340,
1315cm"1
NMR (CDCI3, 6) : 1,27 (6H, d, J=7Hz), 1,74 (3H, d,
J=7Hz), 2,76 (1H, m), 3,43 (1H, br), 3,52 (3H, s), 4,95 (1H, q, J=7Hz), 6,76 (1H, dd, J=2Hz og 9Hz), 6,85 (1H, d, J=2Hz), 7,32 (4H, s), 7,85 (1H, d, J=9Hz)
(30) (IR)-(+)-6-(1-Karboksyetoksy)-2-[(3-klor-4-metyl)-fenyl]-4-metyl-2H-l,2,4-benzotiadiazin-3(4H)-on-1,1-dioksyd smp.: 184-186°C
IR (Nujol) : 3600-2500, 1720, 1700, 1595, 1330 cm"<1>NMR (CDC13, S) : 1,75 (3H, d, J=7Hz), 2,42 (3H, s), 3,25
(1H, br), 3,53 (3H, s), 4,94 (1H, q, J=7Hz), 6,77 (1H, dd, J=2Hz og 9Hz), 6,85 (1H, d, J=2Hz), 7,23 (1H, dd, J=2Hz og 8Hz), 7,34 (1H, d, J=8Hz), 7,41 (1H, d, J=2Hz), 7,85 (1H, d, J=9Hz)
(31) (IR)-(+)-6-(1-Karboksyetoksy)-4-metyl-2-(4trifluormetyl-fenyl)-2H-1,2,4-benzotiadiazin-3(4H)-on-1,1-dioksyd smp.: 162-163 0 C
IR (CHCI3) : 3600-3300, 1720, 1690, 1600, 1340, 1320,
1130 cm"<1>
NMR (CDCI3, S) : 1,75 (3H, d, J=6Hz), 3,54 (3H, s),
4,90-5,01 (1H, q, J=6Hz), 6,77 (1H, dd, J=2Hz og 8Hz), 6,87 (1H, d, J=2Hz), 7,54 (2H, d, J=8Hz), 7,74 (2H, d, J=8Hz), 7,86 (1H, d, J=8Hz)
(32) (IR)-(+)-6-(1-Karboksyetoksy)-2-cykloheksyl-4-metyl-2H-1,2,4-benzotiadiazin-3(4H)-on-1,1-dioksyd
smp.: 16- 11" C
IR (CHCI3) : 3600-2400, 1720, 1680, 1600, 1330, 1310,
1170 cm"<1>
NMR (CDCI3, S) : 1,20-1,45 (3H, m), 1,70 (3H, d, J=6Hz),
1,82-1,88 (5H, m), 2,20-2,38 (2H, m), 3,44 (3H, s), 4,35-4,47 (1H, m), 4,76 (1H, s), 4,89 (1H, q, J=6Hz), 6,67-6,74 (2H, m), 7,75 (1H, d, J=8Hz)
(33) (IR)-(+)-6-(1-Karboksyetoksy)-4-metyl-2-(4-metylfenyl)-2H-1,2,4-benzotiadiazin-3(4H)-on-1,1-dioksyd
smp.: 182-183 °C
IR (CHCI3) : 1700, 1600, 1320, 1130 cm"<1>
NMR (CDCI3, 6) : 1,74 (3H, d, J=6Hz), 2,40 (3H, s), 3,17
(1H, bred s), 3,52 (3H, s), 4,89-5,00 (1H, q, J=6Hz), 6,75 (1H, dd, J=2Hz og 8Hz), 6,84 (1H, d, J=2Hz), 7,29 (4H, s), 7,85 (1H, d, J=8Hz)
(34) (IR)-(+)-6-(1-Karboksyetoksy)-4-metyl-2-(2-pyridyl)-2H-1,2,4-benzotiadiazin-3(4H)-on-1,1-dioksyd smp.: 142-143°C
IR (Nujol) : 3700-2300, 1700, 1600, 1350, 1320, 1275,
1210, 1190 cm"<1>
NMR (CDCI3, S) : 1,56 (3H, d, J=7Hz), 3,47 (3H, s), 5,17
(1H, q, J=7Hz), 6,92 (1H, dd, J=2Hz og 9Hz), 7,08 (1H, d, J=2Hz), 7,45-7,60 (2H, m), 7,84 (1H, d, J=9Hz), 8,00 (1H, m), 8,56-8,59 (1H, m)
(35) (IR)-(+)-6-(1-Karboksyetoksy)-2-(3,4-diklorfenyl)-4-metyl-2H-1,2,4-benzotiadiazin-3(4H)-on-1,1-dioksyd smp.: 105-106°C
IR (Nujol) : 3250-2400, 1735, 1690, 1600, 1585, 1300,
1290, 1175 cm"<1>
NMR (DMS0-d6, <S) : 1,57 (3H, d, J=7Hz), 3,48 (3H, s) ,
5,20 (1H, q, J=7Hz), 6,93 (1H, dd, J=2Hz og 9Hz), 7,08 (1H, d, J=2Hz), 7,46 (1H, dd, J=2Hz og 9Hz), 7,76-7,93 (3H, m)
(36) (IR)-(+)-6-(1-Karboksyetoksy)-2-(3-klorfenyl)-4-metyl-2H-1,2,4-benzotiadiazin-3(4H)-on-1,1-dioksyd
smp.: 174-176°C
IR (Nujol) : 1725, 1700, 1610, 1580, 1330, 1310,
1180 cm"<1>
NMR (CDCI3, S) : 1,74 (3H, d, J=7Hz), 2,72 (1H, bred s),
3,53 (3H, s), 4,95 (1H, q, J=7Hz), 6,74-7,51 (6H, m), 7,86 (1H, d, J=9Hz)
(37) (IR)-(+)-6-(1-Karboksyetoksy)-2-(2-klorfenyl)-4-metyl-2H-1,2,4-benzotiadiazin-3(4H)-on-1,1-dioksyd
smp.: 110-112°C
IR (Nujol) : 1740, 1700, 1600, 1580, 1375, 1190 cm"<1>
NMR (CDC13,5) : 1,75 (3H, d, J=7Hz), 3,55 (3H, s), 4,95
(1H, q, J=7Hz), 6,74-7,67 (6H, m), 7,85 (1H, d, J=9Hz)
(38) (IR)-(+)-6-(1-Karboksyetoksy)-2-(4-fluorfenyl)-4-metyl-2H-1,2,4-benzotiadiazin-3(4H)-on-1,1-dioksyd smp.: 130-132°C
IR (Nujol) : 1740, 1700, 1600, 1500, 1380, 1210 cm"<1>NMR (CDC13, S) : 1,74 (3H, d, J=7Hz), 3,52 (3H, s), 4,94
(1H, q, J=7Hz) , 5,80 (1H, bred s) , 6,747,43 (6H, m) , 7,85 (1H, d, J=9Hz)
(39) (IR)-(+)-6-(1-Karboksyetoksy)-4-metyl-2-(4-metyltiofenyl)-2H-1,2,4-benzotiadiazin-3(4H)-on-1,1-dioksyd smp.: 143-144 0 C
IR (Nujol) : 3350-2300, 1730, 1660, 1600, 1580, 1190,
1090cm"<1>
NMR (CDCI3, 6) : 1,74 (3H, d, J=7Hz), 2,50 (3H, s), 3,53
(3H, s), 4,95 (1H, q, J=7Hz), 6,76 (1H, dd, J=2Hz og 9Hz), 6,85 (1H, d, J=2Hz), 7,32 (4H, s), 7,85 (1H, d, J=9Hz)
(40) (IR)-(+)-6-(1-Karboksyetoksy)-2-(4-dimetylaminofenyl)-4-metyl-2H-l,2,4-benzotiadiazin-3(4H)-on-1,1-dioksyd smp.: 190°C (spaltning)
IR (KBr) : 3400, 2750-2200, 1690, 1590, 1450, 1320,
1180, 1125 cm"<1>
NMR (DMS0-d6, 6) : 1,57 (3H, d, J=7Hz), 2,97 (6H, s),
3,47 (3H, s), 5,22 (1H, q, J=7Hz), 6,85 (2H, d, J=9Hz), 7,15 (2H, d, J=9Hz), 6,92 (1H, dd, J=2Hz og 9Hz), 7,05 (1H, d, J=2Hz), 7,85 (1H, d, J=9Hz)
(41) 6-[1-(Karboksy)cykloheksylmetoksy]-2-(4-klorfenyl)-4-metyl-2H-l,2,4-benzotiadiazin-3(4H)-on-1,1-dioksyd smp.: 145-150°C
IR (Nujol) : 3300, 1700, 1600, 1580, 1370, 1310, 1190,
1130 cm"1
NMR (CDC13, 5): 1,10-2,10 (UH, m) , 3,40 (3H, s) , 4,40
(1H, bred s), 6,60 (1H, d, J=9Hz), 6,85 (1H, s), 7,25 (2H, d, J=9Hz), 7,43 (2H, d, J=9Hz), 7,70 (1H, d, J=9Hz)
EKSEMPEL 16
På lignende måte som beskrevet i eksempel 14 ble oppnådd følgende forbindelser.
(1) 2-(4-Klorfenyl)-6-(1-karboksy-l-metyletoksy)-4-metyl-2H-1,2,4-benzotiadiazin-3(4H)-on-1,1-dioksyd smp.: 208-210°C
IR (Nujol) : 3250, 1750, 1670, 1600, 1350, 1330 cm"<1>NMR (CDC13, S) : 1,75 (6H, s), 3,51 (3H, s), 6,74 (1H,
dd, J=9Hz og 2Hz), 6,83 (1H, d, J=2Hz), 7,34 (2H, d, J=9Hz), 7,46 (2H, d, J=9Hz), 7,82 (1H, d, J=9Hz)
(2) 2-(4-Klorfenyl)-6-(3-karboksypropoksy)-4-metyl-2H-l,2,4-benzotiadiazin-3(4H)-on-1,1-dioksyd
smp.: 170-171°C
IR (Nujol) : 1700, 1600, 1580, 1330, 1310 cm'<1>
NMR (CDCI3, 6) : 2,19 (2H,m), 2,62 (2H, t, J=7Hz), 3,54
(3H, s), 4,17 (2H, t, J=6Hz), 6,70-6,90 (2H, m), 7,35 (2H, d, J=9Hz), 7,47 (2H, d, J=9Hz), 7,84 (1H, d, J=9Hz)
(3) 2-(4-Klorfenyl)-6-(1-karboksypropoksy)-4-metyl-2H-l,2,4-benzotiadiazin-3(4H)-on-1,1-dioksyd
smp.: 179-181°C
IR (Nujol) : 3250, 1760, 1680, 1600, 1590, 1380,
1200cm"1
NMR (CDCI3, S) : 1,15 (3H, t, J=7Hz), 2,11 (2H, m), 3,53
(3H, s), 4,78 (1H, t, J=6Hz), 6,76 (1H, dd, J=9Hz og 2Hz), 6,86 (1H, d, J=2Hz), 7,30-7,50 (4H, m), 7,85
(1H, d, J=9Hz)
(4) 2-(4-Klorfenyl)-6-(1-karboksycyklobutyloksy)-4-metyl-2H-1,2,4-benzotiadiazin-3(4H)-on-1,1-dioksyd smp.: 148-151°C
IR (Nujol) : 1700, 1600, 1380, 1320, 1180 cm"<1>
NMR (CDC13, 6) : 2,00-2,30 (2H, m), 2,50-2,75 (2H, m),
2,78-2,95 (2H, m), 3,51 (3H, s), 6,53 (1H, dd, J=9Hz og 2Hz), 6,73 (1H, d, J=2Hz), 7,34 (2H, d, J=9Hz), 7,46 (2H, d, J=9Hz), 7,80 (1H, d, J=9Hz)
(5) (IR)-(+)-2-(4-Klorfenyl)-6-(1-karboksyetoksy)-4-metyl-2H-1,2,4-benzotiadiazin-3(4H)-on-1,1-dioksyd smp.: 75-85°C
[a]D+16,4° (C=1,0, EtOH)
IR (Nujol) : 3200, 1740, 1700, 1690, 1660, 1600, 1580,
1380, 1130 cm"<1>
NMR (CDCI3, <5) : 1,77 (3H, d, J=7Hz), 3,55 (3H, s) , 4,98
(1H, q, J=7Hz), 6,79 (1H, dd, J=2Hz og 9Hz), 6,88 (1H, d, J=2Hz), 7,37 (2H, d, J=9Hz), 7,49 (2H, d, J=9Hz), 7,88 (1H, d, J=9Hz)
(6) (IS)-(-)-2-(4-Klorfenyl)-6-(1-karboksyetoksy)-4-metyl-2H-1,2,4-benzotiadiazin-3(4H)-on-1,1-dioksyd smp.: 85-95 °C
[a]D-17,0° (C=1,0, EtOH)
IR (Nujol) : 3200, 1740, 1700, 1665, 1600, 1580, 1200,
1130cm"<1>
NMR (CDCI3, 6) : 1,75 (3H, d, J=7Hz), 3,52 (3H, s), 4,95
(1H, q, J=7Hz), 6,50 (1H, bred s), 6,75 (1H, dd, J=2Hz og 9Hz), 6,88 (1H, d, J=2Hz), 7,32 (2H, d, J=9Hz), 7,45 (2H, d, J=9Hz), 7,85 (1H, d, J=9Hz)
(7) (IR)-(+)-6-(1-Karboksyetoksy)-4-metyl-2-fenyl-2H-l,2,4-benzotiadiazin-3(4H)-on-1,1-dioksyd
smp.: 184-185,5°C
IR (Nujol) : 3200, 1750, 1660, 1610, 1320, 1180 cm"<1>NMR (CDCI3, S) : 1,74 (3H, d, J=7Hz), 3,53 (3H, s),
3,55-4,1 (1H, br), 4,95 (1H, q, J=7Hz), 6,76 (1H, dd,
J=2Hz og 9Hz), 6,85 (1H, d, J=2Hz), 7,35-7,55 (5H,
m), 7,86 (1H, d, J=9Hz)
(8) (IR)-(+)-6-(1-Karboksyetoksy)-4-metyl-2-(4-fenoksyfenyl)-2H-1,2,4-benzotiadiazin-3(4H)-on-1,1-dioksyd smp.: 106°C (spaltning)
IR (Nujol) : 3600-2400, 1740, 1695, 1665, 1600, 1585,
1345, 1215 cm"<1>
NMR (CDC13, 6) : 1,74 (3H, d, J=7Hz), 3,53 (3H, s), 3,63
(1H, br), 4,95 (1H, q, J=7Hz), 6,76 (1H, dd, J=2Hz og 9Hz), 6,85 (1H, d, J=2Hz), 7,0-7,45 (9H, m), 7,86
(1H, d, J=9Hz)
(9) (IR)-(+)-6-(1-Karboksyetoksy)-2-(4-isopropylfenyl)-4-metyl-2H-1,2,4-benzotiadiazin-3(4H)-on-1,1-dioksyd smp.: 74°C (spaltning)
IR (Nujol) : 3600-2400, 1730, 1695, 1600, 1340,
1315 cm"1
NMR (CDCI3, S) : 1,27 (6H, d, J=7Hz), 1,74 (3H, d,
J=7Hz), 2,76 (1H, m), 3,43 (1H, br), 3,52 (3H, s), 4,95 (1H, q, J=7Hz), 6,76 (1H, dd, J=2Hz og 9Hz), 6,85 (1H, d, J=2Hz), 7,32 (4H, s), 7,85 (1H, d, J=9Hz)
(10) (IR)-(+)-6-(1-Karboksyetoksy)-2-[(3-klor-4-metyl)fenyl]-4-metyl-2H-l,2,4-benzotiadiazin-3(4H)-on-1,1-dioksyd smp.: 184-186°C
IR (Nujol) : 3600-2500, 1720, 1700, 1595, 1330 cm"<1>
NMR (CDCI3, S) : 1,75 (3H, d, J=7Hz), 2,42 (3H, s), 3,25
(1H, br), 3,53 (3H, s), 4,94 (1H, q, J=7Hz), 6,77
(1H, dd, J=2Hz og 9Hz), 6,85 (1H, d, J=2Hz), 7,23
(1H, dd, J=2Hz og 8Hz), 7,34 (1H, d, J=8Hz), 7,41
(1H, d, J=2Hz), 7,85 (1H, d, J=9Hz)
(11) (IR)-(+)-6-(1-Karboksyetoksy)-4-metyl-2-(4-trifluormetyl-fenyl)-2H-1,2,4-benzotiadiazin-3(4H)-on-1,1-dioksyd smp.: 162-163 °C
IR (CHCI3) : 3600-3300, 1720, 1690, 1600, 1340, 1320,
1130 cm-<1>
NMR (CDCI3, 6) : 1,75 (3H, d, J=6Hz), 3,54 (3H, s),
4,90-5,01 (1H, q, J=6Hz), 6,77 (1H, dd, J=2Hz og 8Hz), 6,87 (1H, d, J=2Hz), 7,54 (2H, d, J=8Hz), 7,74 (2H, d, J=8Hz), 7,86 (1H, d, J=8Hz)
(12) (IR)-(+)-6-(1-Karboksyetoksy)-2-cykloheksyl-4-metyl-2H-1,2,4-benzotiadiazin-3(4H)-on-1,1-dioksyd
smp.: 76-77"C
IR (CHCI3) : 3600-2400, 1720, 1680, 1600, 1330, 1310,
1170 cm-<1>
NMR (CDCI3, 6) : 1,20-1,45 (3H, m), 1,70 (3H, d, J=6Hz),
1,82-1,88 (5H, m), 2,20-2,38 (2H, m), 3,44 (3H, s), 4,35-4,47 (1H, m), 4,76 (1H, s), 4,89 (1H, q, J=6Hz), 6,67-6,74 (2H, m), 7,75 (1H, d, J=8Hz)
(13) (IR)-(+)-6-(1-Karboksyetoksy)-4-metyl-2-(4-metylfenyl)-2H-1,2,4-benzotiadiazin-3(4H)-on-1,1-dioksyd
smp.: 182-183 °C
IR (CHCI3) : 1700, 1600, 1320, 1130 cm<-1>
NMR (CDCI3, 6) : 1,74 (3H, d, J=6Hz), 2,40 (3H, s), 3,17
(1H, bred s), 3,52 (3H, s), 4,89-5,00 (1H, q, J=6Hz), 6,75 (1H, dd, J=2Hz og 8Hz), 6,84 (1H, d, J=2Hz), 7,29 (4H, s), 7,85 (1H, d, J=8Hz)
(14) (IR)-(+)-6-(1-Karboksyetoksy)-4-metyl-2-(2-pyridyl)-2H-1,2,4-benzotiadiazin-3(4H)-on-1,1-dioksyd
smp. : 142-143 °C
IR (Nujol) : 3700-2300, 1700, 1600, 1350, 1320, 1275,
1210, 1190 cm"<1>
NMR (CDCI3, S) : 1,56 (3H, d, J=7Hz), 3,47 (3H, s), 5,17
(1H, q, J=7Hz), 6,92 (1H, dd, J=2Hz og 9Hz), 7,08 (1H, d, J=2Hz), 7,45-7,60 (2H, m), 7,84 (1H, d, J=9Hz), 8,00 (1H, m), 8,56-8,59 (1H, m)
(15) (IR)-(+)-6-(1-Karboksyetoksy)-2-(3,4-diklorfenyl)-4-metyl-2H-1,2,4-benzotiadiazin-3(4H)-on-1,1-dioksyd smp.: 105-106°C
IR (Nujol) : 3250-2400, 1735, 1690, 1600, 1585, 1300,
1290, 1175 cm"<1>
NMR (DMS0-d6, 6) : 1,57 (3H, d, J=7Hz), 3,48 (3H, s),
5,20 (1H, q, J=7Hz), 6,93 (1H, dd, J=2Hz og 9Hz), 7,08 (1H, d, J=2Hz), 7,46 (1H, dd, J=2Hz og 9Hz), 7,76-7,93 (3H, m)
(16) (IR)-(+)-6-(1-Karboksyetoksy)-2-(3-klorfenyl)-4-metyl-2H-1,2,4-benzotiadiazin-3(4H)-on-1,1-dioksyd
smp.: 174-176°C
IR (Nujol) : 1725, 1700, 1610, 1580, 1330, 1310,
1180 cm"<1>
NMR (CDC13, <S) : 1,74 (3H, d, J=7Hz), 2,72 (1H, bred s) ,
3,53 (3H, s), 4,95 (1H, q, J=7Hz), 6,74-7,51 (6H, m), 7,86 (1H, d, J=9Hz)
(17) (IR)-(+)-6-(1-Karboksyetoksy)-2-(2-klorfenyl)-4-metyl-2H-1,2,4-benzotiadiazin-3(4H)-on-1,1-dioksyd
smp.: 110-112°C
IR (Nujol) : 1740, 1700, 1600, 1580, 1375, 1190 cm"<1>NMR (CDCI3, 6) : 1,75 (3H, d, J=7Hz), 3,55 (3H, s), 4,95
(1H, q, J=7Hz), 6,74-7,67 (6H, m), 7,85 (1H, d, J=9Hz)
(18) (IR)-(+)-6-(1-Karboksyetoksy)-2-(4-fluorfenyl)-4-metyl-2H-1,2,4-benzotiadiazin-3(4H)-on-1,1-dioksyd
smp.: 130-132 °C
IR (Nujol) : 1740, 1700, 1600, 1500, 1380, 1210 cm"<1>NMR (CDCI3, 6) : 1,74 (3H, d, J=7Hz), 3,52 (3H, s), 4,94
(1H, q, J=7Hz) , 5,80 (1H, bred s) , 6,74-7,43 (6H, m) , 7,85 (1H, d, J=9Hz)
(19) (IR)-(+)-6-(1-Karboksyetoksy)-4-metyl-2-(4-metyltiofenyl)-2H-1,2,4-benzotiadiazin-3(4H)-on-1,1-dioksyd smp.: 143-144 °C
IR (Nujol) : 3350-2300, 1730, 1660, 1600, 1580, 1190,
1090 cm-1
NMR (CDCI3, <5) : 1,74 (3H, d, J=7Hz), 2,50 (3H, s), 3,53
(3H, s), 4,95 (1H, q, J=7Hz), 6,76 (1H, dd, J=2Hz og 9Hz), 6,85 (1H, d, J=2Hz), 7,32 (4H, s), 7,85 (1H, d, J=9Hz)
(20) (IR)-(+)-6-(1-Karboksyetoksy)-2-(4-dimetylaminofenyl)-4-metyl-2H-l,2,4-benzotiadiazin-3(4H)-on-1,1-dioksyd smp.: 190°C (spaltning)
IR (KBr) : 3400, 2750-2200, 1690, 1590, 1450, 1320,
1180, 1125 cm"<1>
NMR (DMS0-d6, S) : 1,57 (3H, d, J=7Hz), 2,97 (6H, s),
3,47 (3H, s), 5,22 (1H, q, J=7Hz), 6,85 (2H, d, J=9Hz), 7,15 (2H, d, J=9Hz), 6,92 (1H, dd, J=2Hz og 9Hz), 7,05 (1H, d, J=2Hz), 7,85 (1H, d, J=9Hz)
(21) 6-[1-(Karboksy)cykloheksylmetoksy]-2-(4-klorfenyl)-4-metyl-2H-l,2,4-benzotiadiazin-3(4H)-on-1,1-dioksyd smp.: 145-150°C
IR (Nujol) : 3300, 1700, 1600, 1580, 1370, 1310, 1190,
1130cm"<1>
NMR (CDCI3, S) : 1,10-2,10 (UH, m) , 3,40 (3H, s) , 4,40
(1H, bred s), 6,60 (1H, d, J=9Hz), 6,85 (1H, s), 7,25 (2H, d, J=9Hz), 7,42 (2H, d, J=9Hz), 7,70 (1H, d, J=9Hz)
EKSEMPEL 17
Til en oppløsning av (IR)-(+)-2-(4-klorfenyl)-6-(1-karboksy-etoksy) -4-metyl-2H-l,2,4-benzotiadiazin-3(4H)-on-1,1-dioksyd (250 mg) i acetonitril (5 ml) ble satt på én gang en oppløsning av natriumhydrogenkarbonat (51 mg) i vann (1 ml) ved omgivelsestemperatur. Blandingen ble konsentrert i vakuum. Residuet ble omkrystallisert fra en blanding av etanol og acetonitril, hvorved man fikk natriumsaltet av (IR)-(+)-2-(4-klorfenyl)-6-(1-karboksyetoksy)-4-metyl-2H-l,2,4-benzotia-diazin-3(4H)-on-1,1-dioksyd (205 mg) som krystaller,
smp.: 225-230°C
[a]D+8,34° (C=1,0, EtOH)
IR (Nujol) : 3300, 1710, 1600, 1580, 1380, 1210, 1190,
1130 cm"<1>
NMR (DMS0-d6, S) : 1,43 (3H, d, J=7Hz), 3,45 (3H, s),
4.48 (1H, q, J=7Hz), 6,80 (1H, dd, J=2Hz og 9Hz), 6,95 (1H, d, J=2Hz), 7,42 (2H, d, J=9Hz), 7,59 (2H, d, J=9Hz), 7,77 (1H, d, J=9Hz)
EKSEMPEL 18
På lignende måte som beskrevet i eksempel 17 ble oppnådd føl-gende forbindelse.
Natriumsalt av (IS)-(-)-2-(4-klorfenyl)-6-(1-karboksyetoksy)-4-metyl-2H-l,2,4-benzotiadiazin-3(4H)-on-1,1-dioksyd
smp.: 210-215 °C
[a]D-8,53° (C=0,1, EtOH)
IR (Nujol) : 3550, 3400, 1710, 1600, 1380, 1220, 1180,
1120 cm"<1>
NMR (DMS0-d6, 6) : 1,44 (3H, d, J=7Hz), 3,45 (3H, s),
4.49 (1H, q, J=7Hz), 6,81 (1H, dd, J=2Hz og 9Hz), 7,39 (1H, d, J=2Hz), 7,42 (2H, d, J=9Hz), 7,59 (2H, d, J=9Hz), 7,77 (1H, d, J=9Hz)
EKSEMPEL 19
En blanding av 2-(4-karboksyfenyl)-6-hydroksy-4-metyl-2H-l,2,4-benzotiadiazin-3(4H)-on-1,1-dioksyd (0,13 g), kaliumkarbonat (0,103 g) og brommetylcykloheksan (0,14 g) i tørt N,N-dimetylformamid (1,3 ml) ble omrørt ved 80°C i 16 timer. Den avkjølte blanding ble hellet i fortynnet saltsyre. Den fraskilte olje ble ekstrahert med dietyleter. Den organiske fase ble vasket med vann, vandig natriumhydrogenkarbonatoppløsning og salt-oppløsning. Det tørrede oppløsningsmiddel ble konsentrert i vakuum, hvorved man fikk 6-cykloheksylmetoksy-2-(4-cykloheksyl- metoksykarbonylfenyl)-4-metyl-2H-l,2,4-benzotiadiazin-3(4H)-on-1,1-dioksyd (0,13 g) som farveløse krystaller,
smp.: 119-121°C
IR (Nujol) : 1720, 1690, 1600, 1320 cm"<1>
NMR (DMS0-d6, <S) : 0,95-1,40 (10H, m) , 1,55-1,95 (12H,
m), 3,52 (3H, s), 4,00 (2H, d, J=5,8Hz), 4,15 (2H, d, J=5,8Hz), 6,97-7,10 (2H, m), 7,55 og 8,10 (4H, ABq, J=8,3Hz), 7,87 (1H, d, J=8,7Hz)
EKSEMPEL 2 0
På lignende måte som beskrevet i eksempel 19 ble oppnådd følgende forbindelser.
(1) 2-(4-Klorfenyl)-4-metyl-6-(2-ftalimidoetoksy)-2H-1,2,4-benzotiadiazin-3(4H)-on-1,1-dioksyd
smp.: 175-180°C
IR (Nujol) : 1770, 1710, 1605, 1585 cm"<1>
NMR (DMS0-d6, S) : 3,50 (3H, s), 4,0-4,1 (2H, m), 4,4-4,5
(2H, m), 6,95-7,05 (2H, m), 7,35-7,45 (2H, m), 7,55-7,56 (3H, m), 7,8-8,0 (4H, m)
(2) 6-[trans-4-(tert-Butoksykarbonylaminometyl)cykloheksyl-metoksy] -2- (4-klorfenyl) -4-metyl-2H-l,2,4-benzotiadiazin-3(4H)-on-1,1-dioksyd
smp.: 133-136 °C
IR (Nujol) : 3400, 1690, 1600, 1590, 1520, 1450, 1360,
1340, 1180 cm"<1>
NMR (DMS0-d6, 6): 0,75-1,20 (4H, m), 1,40 (9H, s), 1,40-2,00 (6H, m), 2,73 (2H, t, J=6Hz), 3,50 (3H, s), 3,98 (2H, d, J=7Hz), 7,00 (1H, d, J=9Hz), 7,08 (1H, s), 7,40 (2H, d, J=9Hz), 7,60 (2H, d, J=9Hz), 7,88 (1H,
d, J=9Hz)
(3) 2-(4-Klorfenyl)-6-[1-(etoksykarbonyl)cykloheksylmetoksy]-4-metyl-2H-l,2,4-benzotiadiazin-3(4H)-on-1,1-dioksyd smp.: 128-131°C
IR (Nujol): 1730, 1690, 1600, 1590, 1380, 1180 cm"<1>NMR (CDC13, 6) : 1,30 (3H, t, J=8Hz), 1,10-2,10 (11H, m) ,
3,52 (3H, s), 4,25 (2H, q, J=8Hz), 4,50 (1H, d, J=5Hz), 6,75 (1H, dd, J=2Hz og 9Hz), 6,82 (1H, d, J=2Hz), 7,35 (2H, d, J=9Hz), 7,45 (2H, d, J=9Hz), 7,85 (1H, d, J=9Hz)
(4) 2-(4-Klorfenyl)-4-metyl-6-[2-(tetrahydro-2H— pyranyl)metoksy]-2H-1,2,4-benzotiadiazin-3(4H)-on-1,1-dioksyd
smp.: >250°C
IR (Nujol) : 1700, 1600, 1580, 1490, 1340, 1320,
1190 cm"1
NMR (DMS0-d6, 6) : 1,20-1,90 (6H, m), 3,40-3,90 (3H, m),
3,50 (3H, s), 4,10 (2H, d, J=6Hz), 7,00 (1H, dd, J=2Hz og 9Hz), 7,10 (1H, d, J=2Hz), 7,40 (2H, d, J=9Hz), 7,60 (2H, d, J=9Hz), 7,86 (1H, d, J=9Hz)
EKSEMPEL 21
En oppløsning av 2-(4-isopropoksykarbonylmetylfenyl)-6-isopropoksy-4-metyl-2H-1,2,4-benzotiadiazin-3(4H)-on-1,1-dioksyd (95 mg) i en blanding av 1,4-dioksan (6 ml), vann (2 ml) og konsentrert saltsyre (1 ml) ble tilbakeløpskjølt i to timer. Efter konsentrering av blandingen i vakuum ble residuet ekstrahert to ganger med etylacetat. De samlede organiske faser ble vasket med vann og saltoppløsning og tørret over MgS04. Efter avdampning av oppløsningsmidlet under redusert trykk ble det krystallinske residuum omkrystallisert fra etanol, hvorved man fikk 2-(4-karboksymetylfenyl)-6-isopropoksy-4-metyl-2H-1,2,4-benzotiadiazin-3(4H)-on-1,1-dioksyd (61 mg) som blekgule krystaller.
smp.: 232-233 °C
IR (Nujol) : 3600-2500, 1700, 1685, 1600 cm"<1>
NMR (DMS0-d6, S) : 1,34 (6H, d, J=6,0Hz), 3,49 (3H, s),
3,66 (2H, s), 4,8-5,0 (1H, m), 6,95-7,01 (2H, m),
7,30 og 7,40 (4H, ABq, J=8,0Hz), 7,84 (1H, d, J=9,0Hz)
EKSEMPEL 2 2
På lignende måte som beskrevet i eksempel 21 ble oppnådd følgende forbindelser.
(1) 2-(4-Karboksyfenyl)-6-isopropoksy-4-metyl-2H-l,2,4-benzo-tiadiazin-3(4H)-on-1,1-dioksyd
smp.: 247,5-248,5°C
IR (Nujol) : 3200-2400, 1690, 1605 cm"<1>
NMR (DMSO-d6, 6) : 1,34 (6H, d, J=6,0Hz), 3,50 (3H, s),
4,80-5,0 (1H, m), 6,95-7,07 (2H, m), 7,51 og 8,09 (4H, ABq, J=8,3Hz), 7,86 (1H, d, J=8,4Hz), 13,3 (1H, bred s)
(2) 2-(3-Karboksypropyl)-6-isopropoksy-4-metyl-2H-l,2,4-benzo-tiadiazin-3 (4H)-on-1,1-dioksyd
smp.: 150-152°C
IR (Nujol) : 1710, 1690, 1600, 1580, 1470, 1380,
1100 cm"<1>
NMR (CDC13, 6) : 1,38 (6H, d, J=6Hz), 2,05 (2H, m), 2,43
(2H, t, J=7Hz), 3,46 (3H, s), 3,98 (2H, t, J=7Hz), 4,67 (1H, m), 6,67 (1H, d, J=2Hz), 6,76 (1H, dd, J=2Hz og 9Hz), 7,76 (1H, d, J=9Hz)
EKSEMPEL 2 3
En oppløsning av 6-cykloheksylmetoksy-2-(4-cykloheksyl-metoksykarbonylfenyl)-4-metyl-2H-l,2,4-benzotiadiazin-3(4H)-on-1,1-dioksyd (0,12 g) i en blanding av konsentrert saltsyre (1 ml), vann (2 ml) og 1,4-dioksan (8 ml) ble tilbakeløpskjølt natten over. Blandingen ble konsentrert i vakuum. Residuet ble behandlet med en blanding av etylacetat og vandig IN natrium-hydroksydoppløsning. Bunnfallene ble oppsamlet ved filtrering, vasket med etylacetat og derefter oppløst i en blanding av etylacetat og vandig IN saltsyre. Den organiske fase ble vasket med vann, tørret og inndampet under redusert trykk. Residuet ble omkrystallisert fra etanol, hvorved man fikk 2-(4-karboksy-fenyl)-6-cykloheksylmetoksy-4-metyl-2H-l,2,4-benzotiadiazin-3(4H)-on-1,1-dioksyd som farveløse krystaller,
smp.: 240,5-241°C
IR (Nujol) : 3300-2400, 1690, 1600, 1330 cm"<1>
NMR (DMSO-d6, S) : 1,40-1,95 (5H, m), 1,55-1,95 (6H, m),
3,52 (3H, s), 4,00 (1H, d, J=5,8Hz), 6,95-7,10 (2H, m), 7,50 og 8,05 (4H, ABq, J=8,3Hz), 7,86 (1H, d, J=8,7Hz), 13,3 (1H, bred s)
EKSEMPEL 2 4
Til en oppløsning av 2-(4-klorfenyl)-4-metyl-6-(N-metylacetyl-amino)-2H-1,2,4-benzotiadiazin-3(4H)-on-1,1-dioksyd (0,14 g) i etanol (2,8 ml) ble satt konsentrert saltsyre (2,8 ml). Blandingen ble tilbakeløpskjølt i én time og nøytralisert med vandig mettet NaHC03-oppløsning. De resulterende krystaller ble oppsamlet ved filtrering, hvorved man fikk 2-(4-klorfenyl)-4-metyl-6-(N-metylamino)-2H-1,2,4-benzotiadiazin-3(4H)-on-1,1-dioksyd (0,105 g) som et farveløst pulver,
smp.: 207-209 °C
IR (Nujol) : 3400, 1690, 1600, 1320 cm"<1>
NMR (CDC13, <S) : 2,95 (3H, s) , 3,51 (3H, s) , 4,5 (1H,
br), 6,28 (1H, bred s), 6,4-6,5 (1H, m), 7,3-7,5 (4H, m), 7,62-7,7 (1H, m)
EKSEMPEL 25
På lignende måte som beskrevet i eksempel 24 ble oppnådd følgende forbindelse.
Hydrokloridsalt av 6-[trans-4-(aminometyl)cykloheksylmetoksy]- 2-(4-klorfenyl)-4-metyl-2H-l,2,4-benzotiadiazin-3(4H)-on-1,1-dioksyd
smp.: >250 °C
IR (Nujol) : 3400, 1700, 1610, 1600, 1380, 1330, 1310,
1280, 1130 cm"<1>
NMR (DMS0-d6, <S) : 0,90-1,20 (4H, m), 1,40-2,10 (6H, m),
2,70 (2H, m), 3,50 (3H, s), 4,02 (2H, d, J=7Hz), 7,03 (1H, dd, J=2Hz og 9Hz), 7,10 (1H, d, J=2Hz), 7,40
(2H, d, J=9Hz), 7,60 (2H, d, J=9Hz), 7,90 (1H, d, J=9Hz), 8,00 (1H, bred s)
EKSEMPEL 2 6
Til en oppløsning av 2-(4-klorfenyl)-4-metyl-6-(2-ftalimidoetoksy)-2H-1,2,4-benzotiadiazin-3(4H)-on-1,1-dioksyd (0,153 g) i metanol (1,5 ml) ble satt hydrazinmonohydrat (30 mg). Efter tilbakeløpskjøling av blandingen i én time ble reaksjonsblandingen behandlet med konsentrert HCl og ytter-ligere tilbakeløpskjølt i 30 minutter. Bunnfallet ble fjernet ved filtrering, og filtratet ble vasket to ganger med eter. Den vandige fase ble behandlet med vandig IN NaOH-oppløsning og ekstrahert med etylacetat. Ekstrakten ble vasket med saltoppløs-ning og tørret over MgS04. Efter avdampning av oppløsnings-midlet under redusert trykk ble residuet triturert med IPE. De farveløse krystaller ble oppsamlet ved filtrering og omkrystallisert fra etanol, hvorved man fikk 6-(2-aminoetoksy)-2-(4-klorfenyl)-4-metyl-2H-l,2,4-benzotiadiazin-3(4H)-on-1,1-dioksyd (30 mg) som farveløse prismer,
smp.: 175-176°C
IR (Nujol) : 3370, 3310, 1705, 1685, 1600, 1195 cm"<1>NMR (CDC13, <S) : 1,66 (2H, bred s) , 3,19 (2H, bred s) ,
3,54 (3H, s), 4,12 (2H, t, J=5,0Hz), 6,77-7,90 (2H, m), 7,35 og 7,46 (4H, ABq, J=8,5Hz), 7,85 (1H, d, J=8,5Hz)
EKSEMPEL 2 7
Til en oppløsning av 6-isopropoksy-4-metyl-2-(2-pyridyl)-2H-1,2,4-benzotiadiazin-3(4H)-on-1,1-dioksyd (0,174 g) i kloroform (5 ml) ble boblet klorgass i noen få minutter ved 5°C. Blandingen ble vasket med vandig natriumhydrogenkarbonatoppløsning, tørret og konsentrert i vakuum. Residuet ble krystallisert fra etanol, hvorved man fikk 7-klor-6-isopropoksy-4-metyl-2-(2-pyridyl)-2H-1,2,4-benzotiadiazin-3(4H)-on-1,1-dioksyd (115 mg) som farveløse nåleformede krystaller,
smp.: 193-194°C
IR (Nujol) : 1685, 1590, 1345 cm"<1>
NMR (CDC13, 6) : 1,46 (6H, d, J=6Hz), 3,55 (3H, s), 4,6-4,85 (1H, m), 6,75 (1H, s), 7,35-7,55 (2H, m), 7,90 (1H, s), 7,85-7,95 (1H, m), 8,6-8,7 (1H, m)
EKSEMPEL 2 8
På lignende måte som beskrevet i eksempel 27 ble oppnådd følgende forbindelse.
7-Brom-6-isopropoksy-4-metyl-2-(2-pyridyl)-2H-1,2,4-benzotia-diazin-3(4H)-on-1,1-dioksyd
smp.: 194,5-195,5°C
IR (Nujol) : 1690, 1590, 1345 cm"<1>
NMR (CDCI3, <5) : 1,47 (6H, d, J=6Hz), 3,55 (3H, s), 4,6-4,85 (1H, m), 6,71 (1H, s), 7,35-7,55 (2H, m), 7,85-7,95 (1H, m), 8,04 (1H, s), 8,60-8,70 (1H, m)
EKSEMPEL 2 9
Til en suspensjon av 2-(4-klorfenyl)-6-hydroksy-4-metyl-2H-1,2,4-benzotiadiazin-3(4H)-on-1,1-dioksyd (700 mg) i eddiksyre (70 ml) ble boblet klorgass, hvorved man fikk en farveløs opp-løsning ved omgivelsestemperatur. Blandingen ble hellet i isvann. Bunnfallene ble oppsamlet ved filtrering og omkrystal lisert fra etanol, hvorved man fikk 2-(4-klorfenyl)-5,7-diklor-6-hydroksy-4-metyl-2H-l,2,4-benzotiadiazin-3(4H)-on-1,1-dioksyd (350 mg) som krystaller,
smp.: 197-198 °C
IR (Nujol) : 1720, 1700, 1500, 1360, 1180 cm<-1>
NMR (DMSO-d6, 6) : 3,55 (3H, s), 7,42 (2H, d, J=9Hz),
7,60 (2H, d, J=9Hz), 8,00 (1H, s)
EKSEMPEL 3 0
Til en oppløsning av 2-(4-klorfenyl)-4-metyl-6-(N-metylamino)-2H-1,2,4-benzotiadiazin-3(4H)-on-1,1-dioksyd (55 mg) i tørt THF (2 ml) ble satt en 1,5M oppløsning av n-butyllitium i n-heksan (0,16 ml) ved -78°C. Blandingen ble omrørt ved 0°C i 30 minutter og tilsatt metyljodid (0,05 ml) ved den samme temperatur. Efter omrøring av blandingen ved 0°C i 3 0 minutter ble vann tilsatt. Blandingen ble ekstrahert to ganger med etylacetat, og de samlede organiske faser ble vasket med vann og saltopp-løsning og tørret over MgS04. Efter avdampning av oppløsnings-midlet under redusert trykk ble residuet renset ved preparativ tynnskiktskromatografi (eluert med en blanding av benzen og aceton (9:1)), hvorved man fikk 2-(4-klorfenyl)-6-(N,N-dimetylamino)-4-metyl-2H-l,2,4-benzotiadiazin-3(4H)-on-1,1-dioksyd (8 mg) som et farveløst pulver,
smp.: 205-206°C
IR (Nujol) : 1690, 1605 cm-<1>
NMR (CDC13, 6) : 3,12 (6H, s), 3,54 (3H, s), 6,32 (1H,
d, J=2,0Hz), 6,56 (1H, dd, J=2,0 og 9,0Hz), 7,35 og 7,45 (4H, ABq, J=8,8Hz), 7,70 (1H, d, J=9,0Hz)
EKSEMPEL 31
En blanding av 6-hydroksy-4-metyl-2-(4-trifluormetylfenyl)-2H-1,2,4-benzotiadiazin-3(4H)-on-1,1-dioksyd (1,56 g), (S)-(-)-etyl-2-[[(4-metylfenyl)sulfonyl]oksy]propionat (1,37 g) og kaliumkarbonat (578 mg) i N,N-dimetylformamid (15,6 ml) ble omrørt ved 60-65"C i én time. Den avkjølte blanding ble fra-filtrert, og filtratet ble hellet i en blanding av is og IN saltsyre. Bunnfallene ble oppsamlet og oppløst i metylenklorid. Oppløsningen ble tørret og konsentrert i vakuum. Residuet ble krystallisert fra diisopropyleter, hvorved man fikk (lR)-(+)-6-[1-(etoksykarbonyl)etoksy]-4-metyl-2-(4-trifluormetylfenyl)-2H-1,2,4-benzotiadiazin-3(4H)-on-1,1-dioksyd (1,58 g).
smp.: 124-125°C
IR (Nujol) : 1720, 1685, 1595, 1330, 1130, 1060 cm"<1>NMR (CDC13, 6) : 1,30 (3H, t, J=6Hz), 1,70 (3H, d,
J=6Hz), 3,54 (3H, s), 4,26 (2H, q, J=6Hz), 4,88 (1H, q, J=6Hz), 6,75 (1H, dd, J=2Hz og 8Hz), 6,85 (1H, d, J=2Hz), 7,55 (2H, d, J=8Hz), 7,75 (2H, d, J=8Hz), 7,84 (1H, d, J=8Hz)
Claims (6)
1. Fremgangsmåte for fremstilling av en forbindelse med den generelle formel I
hvor R <1> er fenyl som kan være substituert med halogen, lavere
alkyl, lavere alkoksy, halogen(lavere)alkyl, lavere alkylamino, lavere alkyltio, aryloksy, karboksy, forestret karboksy, karboksy(lavere)alkyl eller forestret karboksy(lavere)alkyl; cyklo(lavere)alkyl; lavere alkyl som kan være substituert med karboksy eller forestret karboksy; eller en heterocyklisk
gruppe som kan være substituert med lavere alkyl;
A er lavere alkylen,
n er et helt tall på 0 eller 1,
R <2> er hydrogen eller lavere alkyl,
R <3> er hydrogen; hydroksy; halogen; halogen(lavere)alkyl;
lavere alkyl; lavere alkylamino; acylamino; acyl-(lavere)alkylamino; lavere alkoksy som kan være substituert med aryl, beskyttet amino, en heterocyklisk gruppe, amino, karboksy, forestret karboksy eller cyklo(lavere)alkyl som kan være substituert med amino(lavere)alkyl eller beskyttet amino(lavere)alkyl; eller cyklo(lavere)alkyloksy som kan være substituert med karboksy eller forestret karboksy;
R<4> er hydrogen eller halogen, og
R<5> er hydrogen eller halogen,
med det forbehold at
R <1> er fenyl substituert med lavere alkoksy, lavere
alkylamino, lavere alkyltio, aryloksy, karboksy, forestret karboksy, karboksy(lavere)alkyl eller forestret karboksy(lavere)alkyl; lavere alkyl substi tuert med karboksy eller forestret karboksy; eller en heterocyklisk gruppe substituert med lavere alkyl,
nårR<3> er hydrogen eller halogen,
eller salter derav,
karakterisert ved at
(1) en forbindelse med den generelle formel II
eller et reaktivt derivat derav ved aminogruppen eller et salt derav omsettes med en forbindelse med den generelle formel III
for å danne en forbindelse med den generelle formel Ia
eller et salt derav, hvor R <1> , R <3> ,R<4> , R^, A og n hver er som definert ovenfor, og R <6> og R <7> hver er halogen, lavere alkoksy eller imidazolyl, eller
(2) en forbindelse med den generelle formel Ia eller et salt derav underkastes en reaksjon for innføring av en substituent på nitrogenatomet, hvilket gir en forbindelse med den generelle formel Ib
eller et salt derav, hvorR<1> ,R<3> ,R<4> ,R<5> , A og n hver er som definert ovenfor, og r| er lavere alkyl, eller
(3) en forbindelse med den generelle formel Ic
eller et salt derav underkastes en reaksjon for eliminering av
en substituent på oksygenatomet, hvilket gir en forbindelse med den generelle formel Id
eller et salt derav, hvorR<1> ,R<2> ,R<4> ,R<5> , A og n hver er som definert ovenfor, og
R=[ er lavere alkoksy som kan være substituert med aryl, cyklo(lavere)alkyl, karboksy eller forestret karboksy; eller cyklo(lavere)alkyloksy som kan være substituert med karboksy eller forestret karboksy, eller
(4) en forbindelse med den generelle formel le
eller et salt derav omsettes med en forbindelse med den generelle formel IV
for å danne en forbindelse med den generelle formel If
eller et salt derav, hvorR<1> , r|,R<4> ,R<5> , A og n hver er som definert ovenfor,
R^ er lavere alkyl som kan være substituert med aryl, beskyttet amino, en heterocyklisk gruppe, karboksy, forestret karboksy eller cyklo(lavere)alkyl som kan være substituert med beskyttet amino(lavere)alkyl; eller cyklo(lavere)alkyl som kan være substituert med karboksy eller forestret karboksy, og
X er en avspaltbar enhet, eller
(5) en forbindelse med den generelle formel lg eller et salt derav underkastes en deforestringsreaksjon, hvilket gir en forbindelse med den generelle formel Ih
eller et salt derav, hvorR<1> ,R<2> ,R<4> ,R<5> , A og n hver er som definert ovenfor,
Rq er forestret karboksy(lavere)alkoksy som kan være substi
tuert med cyklo(lavere)alkyl; eller forestret karboksy-cyklo (lavere) alkyloksy , og
R3} er karboksy (lavere) alkoksy som kan være substituert med
cyklo(lavere)alkyl; eller karboksycyklo(lavere)alkyloksy, eller
(6) en forbindelse med den generelle formel li
eller et salt derav underkastes en deforestringsreaksjon, hvilket gir en forbindelse med den generelle formel Ij
eller et salt derav, hvorR<2> ,R<3> ,R<4> ,R<5> , A og n hver er som definert ovenfor,
Ra er fenyl substituert med forestret karboksy(lavere)alkyl
eller forestret karboksy; eller forestret karboksy(lavere)-alkyl, og
R^ er fenyl substituert med karboksy(lavere)alkyl eller karboksy; eller karboksy(lavere)alkyl, eller
(7) en forbindelse med den generelle formel Ik
eller et salt derav halogeneres, hvilket gir en forbindelse med den generelle formel II
eller et salt derav, hvorR<1> ,R<2> ,R<3> ,R<5> , A og n hver er som definert ovenfor,
R^ er hydrogen,
R<4>) er halogen, og
r| er hydrogen, eller
(8) en forbindelse med den generelle formel Im
eller et salt derav underkastes en alkyleringsreaksjon, hvilket gir en forbindelse med den generelle formel In
eller et salt derav, hvorR 1,R<2> ,R<4> ,R<5> , A og n hver er som definert ovenfor, og R <8> ogR<9> hver er lavere alkyl, eller
(9) en forbindelse med den generelle formel Io
eller et salt derav underkastes en reaksjon for eliminering av aminobeskyttelsesgruppen, hvilket gir en forbindelse med den generelle formel lp
eller et salt derav, hvorR 1,R<2> ,R<4> ,R<5> , A og n hver er som definert ovenfor,
Rg er acyl(lavere)alkylamino eller lavere alkoksy substituert
med beskyttet amino eller cyklo(lavere)alkyl substituert med beskyttet amino(lavere)alkyl, og
R3; er lavere alkylamino eller lavere alkoksy substituert med
amino eller cyklo(lavere)alkyl substituert med amino-(lavere)alkyl.
2. Fremgangsmåte ifølge krav 1,
karakterisert ved at
R<4> ogR ^ begge er hydrogen, og
n er 0.
3. Fremgangsmåte ifølge krav 2,
karakterisert ved at
R <1> er fenyl som kan være substituert med halogen, lavere
alkyl, lavere alkoksy, halogen(lavere)alkyl, lavere alkylamino, lavere alkyltio, aryloksy, karboksy, forestret karboksy, karboksy(lavere)alkyl eller forestret karboksy(lavere)alkyl,
R<2> er lavere alkyl, og
R <3> er lavere alkoksy som kan være substituert med aryl,
beskyttet amino, en heterocyklisk gruppe, amino, karboksy, forestret karboksy eller cyklo(lavere)alkyl som kan være substituert med amino(lavere)alkyl eller beskyttet amino(lavere)alkyl.
4. Fremgangsmåte ifølge krav 3
karakterisert ved at
R<1> er fenyl substituert med halogen, og
R <3> er lavere alkoksy substituert med karboksy.
5. Fremgangsmåte ifølge krav 4,
karakterisert ved at den fremstillte forbindelse er (IR)-(+)-2-(4-klorfenyl)-6-(1-karboksyetoksy)-4-metyl-2H-1,2,4-benzotiadiazin-3(4H)-on-1,1-dioksyd eller et salt derav.
6. Forbindelse med den generelle formel II
hvor R <1> er fenyl som kan være substituert med halogen, lavere
alkyl, lavere alkoksy, halogen(lavere)alkyl, lavere alkylamino, lavere alkyltio, aryloksy, forestret karboksy eller forestret karboksy(lavere)alkyl; cyklo(lavere)alkyl; lavere alkyl som kan være substituert med forestret karboksy; eller en heterocyklisk gruppe som kan være substituert med lavere alkyl,
R <3> er hydrogen; hydroksy; halogen; halogen(lavere)alkyl;
lavere alkyl; acylamino; lavere alkoksy som kan være substituert med aryl, cyklo(lavere)alkyl, karboksy eller forestret karboksy; eller cyklo(lavere)alkyloksy som kan være substituert med karboksy eller forestret karboksy;
R<4> er hydrogen eller halogen,
R<5> er hydrogen eller halogen,
A er lavere alkylen, og
n er et helt tall på 0 eller 1,
og salter derav.
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
GB868627857A GB8627857D0 (en) | 1986-11-21 | 1986-11-21 | Benzothiadiazine compounds |
GB878714598A GB8714598D0 (en) | 1987-06-22 | 1987-06-22 | Benzothiadiazine compounds |
GB878720659A GB8720659D0 (en) | 1987-09-02 | 1987-09-02 | Benzothiadiazine compounds |
Publications (2)
Publication Number | Publication Date |
---|---|
NO874850D0 NO874850D0 (no) | 1987-11-20 |
NO874850L true NO874850L (no) | 1988-05-24 |
Family
ID=27263212
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
NO874850A NO874850L (no) | 1986-11-21 | 1987-11-20 | Fremgangsmaate for fremstilling av benzotiadiazinforbindelser og farmasoeytisk akseptable salter derav. |
Country Status (9)
Country | Link |
---|---|
US (1) | US4889851A (no) |
EP (1) | EP0268990A3 (no) |
JP (1) | JP2564860B2 (no) |
KR (1) | KR880006219A (no) |
CN (1) | CN87107990A (no) |
AU (1) | AU603842B2 (no) |
DK (1) | DK597387A (no) |
FI (1) | FI875086A (no) |
NO (1) | NO874850L (no) |
Families Citing this family (13)
Publication number | Priority date | Publication date | Assignee | Title |
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NZ223237A (en) * | 1987-01-22 | 1991-03-26 | Shiseido Co Ltd | Hair growth promoting agent and compositions |
WO1994017075A1 (en) * | 1993-01-20 | 1994-08-04 | A. Menarini Industrie Farmaceutiche Riunite S.R.L. | Diazepin derivatives and antiviral compositions |
FR2710062B1 (fr) * | 1993-09-17 | 1995-12-01 | Rhone Poulenc Rorer Sa | Dérivés d'acide 3,4-dihydro-2H-1,2,4-benzothiadiazine 1,1-dioxyde-3-carboxylique, leur préparation et les médicaments les contenant. |
US6008208A (en) | 1995-10-23 | 1999-12-28 | Osteoscreen, Inc. | Compositions and methods for treating bone deficit conditions |
AU706262B2 (en) * | 1995-10-23 | 1999-06-10 | Osteoscreen, Inc. | Compositions and methods for treating bone deficit conditions |
EP0973513A4 (en) * | 1996-10-23 | 2003-03-19 | Zymogenetics Inc | COMPOSITIONS AND METHODS FOR TREATING CONDITIONS ASSOCIATED WITH BONE DEFICIT |
CA2271116A1 (en) * | 1996-11-13 | 1998-05-22 | Gregory J. Wells | Benzothiazo and related heterocyclic group-containing cysteine and serine protease inhibitors |
US5952328A (en) * | 1997-11-12 | 1999-09-14 | Cephalon, Inc. | Benzothiazo and related heterocyclic group-containing cysteine and serine protease inhibitors |
JP2002543163A (ja) | 1999-04-30 | 2002-12-17 | スリル バイオメディカル コーポレイション | 癌および前立腺疾患のための治療としての結合体 |
ES2238383T3 (es) * | 2000-12-16 | 2005-09-01 | Aventis Pharma Deutschland Gmbh | Uso de heparina de bajo peso molecular para el tratamiento de la osteoartrosis. |
EP1436246A1 (en) * | 2001-10-16 | 2004-07-14 | SLIL Biomedical Corporation | Oligoamine compounds and derivatives thereof for cancer therapy |
KR100787130B1 (ko) * | 2006-03-23 | 2007-12-21 | 한국화학연구원 | 신규의 치환된 1,1-다이옥소-벤조[1,2,4]티아디아진-3-온, 이의 제조방법 및 이를 포함하는 약학적 조성물 |
UA100120C2 (en) * | 2007-04-03 | 2012-11-26 | Анадис Фармасьютикалз, Инк. | 5,6-dihydro-1h-pyridin-2-one compounds |
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US3296070A (en) * | 1967-01-03 | Method for the treatment of hypertension | ||
DE1067028B (no) * | 1959-10-15 | |||
US3287362A (en) * | 1966-11-22 | Substituted j-oxo-j,x-dihydro-l,z,x-benzo- thiadiazine i,i-dioxides and a method for their preparation | ||
US3267096A (en) * | 1965-02-24 | 1966-08-16 | Miles Lab | Derivatives of 2h, 4h-benzothiadiazine 1, 1-dioxide |
FR5571M (no) * | 1965-12-23 | 1967-11-27 | ||
US3892738A (en) * | 1972-03-20 | 1975-07-01 | Merck & Co Inc | 7-Thiasubstituted-1,2,4-benzothiadiazine-1,1-dioxides and their salts |
GB8524663D0 (en) * | 1985-10-07 | 1985-11-13 | Fujisawa Pharmaceutical Co | Quinazoline derivatives |
-
1987
- 1987-11-05 US US07/116,913 patent/US4889851A/en not_active Expired - Fee Related
- 1987-11-13 DK DK597387A patent/DK597387A/da not_active Application Discontinuation
- 1987-11-18 FI FI875086A patent/FI875086A/fi not_active IP Right Cessation
- 1987-11-18 EP EP87117019A patent/EP0268990A3/en not_active Withdrawn
- 1987-11-20 NO NO874850A patent/NO874850L/no unknown
- 1987-11-20 AU AU81465/87A patent/AU603842B2/en not_active Expired - Fee Related
- 1987-11-20 KR KR1019870013086A patent/KR880006219A/ko not_active Application Discontinuation
- 1987-11-20 CN CN198787107990A patent/CN87107990A/zh active Pending
- 1987-11-20 JP JP62294588A patent/JP2564860B2/ja not_active Expired - Lifetime
Also Published As
Publication number | Publication date |
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DK597387A (da) | 1988-05-22 |
DK597387D0 (da) | 1987-11-13 |
EP0268990A3 (en) | 1988-08-10 |
KR880006219A (ko) | 1988-07-22 |
CN87107990A (zh) | 1988-06-01 |
FI875086A (fi) | 1988-05-22 |
FI875086A0 (fi) | 1987-11-18 |
JPS63183572A (ja) | 1988-07-28 |
EP0268990A2 (en) | 1988-06-01 |
NO874850D0 (no) | 1987-11-20 |
US4889851A (en) | 1989-12-26 |
AU8146587A (en) | 1988-05-26 |
AU603842B2 (en) | 1990-11-29 |
JP2564860B2 (ja) | 1996-12-18 |
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