IL105158A - Benzoxazinone and benzothiazinone derivatives having cardiovascular activity - Google Patents
Benzoxazinone and benzothiazinone derivatives having cardiovascular activityInfo
- Publication number
- IL105158A IL105158A IL10515893A IL10515893A IL105158A IL 105158 A IL105158 A IL 105158A IL 10515893 A IL10515893 A IL 10515893A IL 10515893 A IL10515893 A IL 10515893A IL 105158 A IL105158 A IL 105158A
- Authority
- IL
- Israel
- Prior art keywords
- mole
- dihydro
- benzoxazin
- alkyl
- compound
- Prior art date
Links
- 230000005792 cardiovascular activity Effects 0.000 title description 4
- MJNPHLBKHKJDEF-UHFFFAOYSA-N 2h-1$l^{4},2-benzothiazine 1-oxide Chemical class C1=CC=C2S(=O)NC=CC2=C1 MJNPHLBKHKJDEF-UHFFFAOYSA-N 0.000 title description 3
- HQQTZCPKNZVLFF-UHFFFAOYSA-N 4h-1,2-benzoxazin-3-one Chemical compound C1=CC=C2ONC(=O)CC2=C1 HQQTZCPKNZVLFF-UHFFFAOYSA-N 0.000 title description 3
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 23
- 239000001257 hydrogen Substances 0.000 claims abstract description 23
- -1 methylenedioxy Chemical group 0.000 claims abstract description 18
- 239000002253 acid Substances 0.000 claims abstract description 9
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims abstract description 8
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims abstract description 6
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims abstract description 6
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims abstract description 6
- 125000002947 alkylene group Chemical group 0.000 claims abstract description 4
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical group [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims abstract description 3
- 150000008043 acidic salts Chemical class 0.000 claims abstract description 3
- 150000001447 alkali salts Chemical class 0.000 claims abstract description 3
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical group [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims abstract description 3
- 229910052736 halogen Inorganic materials 0.000 claims abstract description 3
- 150000002367 halogens Chemical group 0.000 claims abstract description 3
- 229910052760 oxygen Inorganic materials 0.000 claims abstract description 3
- 239000001301 oxygen Substances 0.000 claims abstract description 3
- 150000001875 compounds Chemical class 0.000 claims description 74
- 125000000217 alkyl group Chemical group 0.000 claims description 13
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 9
- 150000002431 hydrogen Chemical class 0.000 claims description 6
- 230000003257 anti-anginal effect Effects 0.000 claims description 5
- 239000008194 pharmaceutical composition Substances 0.000 claims description 3
- 238000002360 preparation method Methods 0.000 claims description 3
- 238000002560 therapeutic procedure Methods 0.000 claims description 3
- 125000000582 cycloheptyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 claims description 2
- 125000004977 cycloheptylene group Chemical group 0.000 claims description 2
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 claims description 2
- 125000004956 cyclohexylene group Chemical group 0.000 claims description 2
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 2
- 125000004979 cyclopentylene group Chemical group 0.000 claims description 2
- 239000003814 drug Substances 0.000 claims description 2
- 239000003937 drug carrier Substances 0.000 claims description 2
- 125000000229 (C1-C4)alkoxy group Chemical group 0.000 claims 1
- 150000001408 amides Chemical class 0.000 abstract description 3
- 125000004191 (C1-C6) alkoxy group Chemical group 0.000 abstract description 2
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 abstract 2
- YBYIZRPBXCCDQW-UHFFFAOYSA-N 2,3-dihydro-1,3-benzoxazin-4-one Chemical class C1=CC=C2C(=O)NCOC2=C1 YBYIZRPBXCCDQW-UHFFFAOYSA-N 0.000 abstract 1
- 125000000753 cycloalkyl group Chemical group 0.000 abstract 1
- 125000002993 cycloalkylene group Chemical group 0.000 abstract 1
- 125000003396 thiol group Chemical class [H]S* 0.000 abstract 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 48
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 45
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 38
- 239000000243 solution Substances 0.000 description 38
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 32
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 30
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 28
- 238000000034 method Methods 0.000 description 25
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 24
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 24
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 20
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 18
- 229910052938 sodium sulfate Inorganic materials 0.000 description 16
- 235000011152 sodium sulphate Nutrition 0.000 description 16
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 15
- 239000012044 organic layer Substances 0.000 description 14
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 14
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 12
- 238000006243 chemical reaction Methods 0.000 description 12
- 239000002904 solvent Substances 0.000 description 12
- SQGYOTSLMSWVJD-UHFFFAOYSA-N silver(1+) nitrate Chemical compound [Ag+].[O-]N(=O)=O SQGYOTSLMSWVJD-UHFFFAOYSA-N 0.000 description 10
- 238000001704 evaporation Methods 0.000 description 9
- 230000008020 evaporation Effects 0.000 description 9
- 239000000047 product Substances 0.000 description 9
- 239000011541 reaction mixture Substances 0.000 description 9
- 238000005481 NMR spectroscopy Methods 0.000 description 8
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 8
- 238000007792 addition Methods 0.000 description 8
- 239000000203 mixture Substances 0.000 description 8
- 125000005843 halogen group Chemical group 0.000 description 7
- 238000010992 reflux Methods 0.000 description 7
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 6
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 6
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 6
- 239000000725 suspension Substances 0.000 description 6
- HZAXFHJVJLSVMW-UHFFFAOYSA-N 2-Aminoethan-1-ol Chemical compound NCCO HZAXFHJVJLSVMW-UHFFFAOYSA-N 0.000 description 5
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 5
- 239000003960 organic solvent Substances 0.000 description 5
- 229910001961 silver nitrate Inorganic materials 0.000 description 5
- 239000007787 solid Substances 0.000 description 5
- 229940086542 triethylamine Drugs 0.000 description 5
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 4
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 4
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 4
- 229930040373 Paraformaldehyde Natural products 0.000 description 4
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 4
- 125000003277 amino group Chemical group 0.000 description 4
- 229960001760 dimethyl sulfoxide Drugs 0.000 description 4
- 239000010410 layer Substances 0.000 description 4
- 229920002866 paraformaldehyde Polymers 0.000 description 4
- 239000002243 precursor Substances 0.000 description 4
- 238000003756 stirring Methods 0.000 description 4
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 3
- 241001465754 Metazoa Species 0.000 description 3
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- 150000007513 acids Chemical class 0.000 description 3
- 239000013543 active substance Substances 0.000 description 3
- 238000009833 condensation Methods 0.000 description 3
- 230000005494 condensation Effects 0.000 description 3
- 238000001816 cooling Methods 0.000 description 3
- 238000001914 filtration Methods 0.000 description 3
- IBIKHMZPHNKTHM-RDTXWAMCSA-N merck compound 25 Chemical compound C1C[C@@H](C(O)=O)[C@H](O)CN1C(C1=C(F)C=CC=C11)=NN1C(=O)C1=C(Cl)C=CC=C1C1CC1 IBIKHMZPHNKTHM-RDTXWAMCSA-N 0.000 description 3
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 3
- 238000012986 modification Methods 0.000 description 3
- 230000004048 modification Effects 0.000 description 3
- 238000006396 nitration reaction Methods 0.000 description 3
- KDLHZDBZIXYQEI-UHFFFAOYSA-N palladium Substances [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 3
- 150000003839 salts Chemical class 0.000 description 3
- 239000011734 sodium Substances 0.000 description 3
- 229910052708 sodium Inorganic materials 0.000 description 3
- 238000012360 testing method Methods 0.000 description 3
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 3
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 2
- XGDPKUKRQHHZTH-UHFFFAOYSA-N Methyl 2,5-dihydroxybenzoate Chemical compound COC(=O)C1=CC(O)=CC=C1O XGDPKUKRQHHZTH-UHFFFAOYSA-N 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 2
- 229960000583 acetic acid Drugs 0.000 description 2
- 125000002252 acyl group Chemical group 0.000 description 2
- 230000001476 alcoholic effect Effects 0.000 description 2
- 239000003513 alkali Substances 0.000 description 2
- 125000003545 alkoxy group Chemical group 0.000 description 2
- 230000003110 anti-inflammatory effect Effects 0.000 description 2
- 210000000709 aorta Anatomy 0.000 description 2
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- MVPPADPHJFYWMZ-UHFFFAOYSA-N chlorobenzene Chemical compound ClC1=CC=CC=C1 MVPPADPHJFYWMZ-UHFFFAOYSA-N 0.000 description 2
- 238000002425 crystallisation Methods 0.000 description 2
- 230000008025 crystallization Effects 0.000 description 2
- 239000012954 diazonium Substances 0.000 description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 2
- WUDNUHPRLBTKOJ-UHFFFAOYSA-N ethyl isocyanate Chemical compound CCN=C=O WUDNUHPRLBTKOJ-UHFFFAOYSA-N 0.000 description 2
- 230000002349 favourable effect Effects 0.000 description 2
- 125000002485 formyl group Chemical class [H]C(*)=O 0.000 description 2
- 125000001475 halogen functional group Chemical group 0.000 description 2
- 125000000623 heterocyclic group Chemical group 0.000 description 2
- 230000005764 inhibitory process Effects 0.000 description 2
- 229910052500 inorganic mineral Inorganic materials 0.000 description 2
- 125000001972 isopentyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 description 2
- OSWPMRLSEDHDFF-UHFFFAOYSA-N methyl salicylate Chemical compound COC(=O)C1=CC=CC=C1O OSWPMRLSEDHDFF-UHFFFAOYSA-N 0.000 description 2
- 239000011707 mineral Substances 0.000 description 2
- LQNUZADURLCDLV-UHFFFAOYSA-N nitrobenzene Chemical compound [O-][N+](=O)C1=CC=CC=C1 LQNUZADURLCDLV-UHFFFAOYSA-N 0.000 description 2
- 239000002244 precipitate Substances 0.000 description 2
- 239000000376 reactant Substances 0.000 description 2
- 238000010898 silica gel chromatography Methods 0.000 description 2
- 239000011780 sodium chloride Substances 0.000 description 2
- 238000006467 substitution reaction Methods 0.000 description 2
- 239000001117 sulphuric acid Substances 0.000 description 2
- 235000011149 sulphuric acid Nutrition 0.000 description 2
- 230000000304 vasodilatating effect Effects 0.000 description 2
- SFLSHLFXELFNJZ-QMMMGPOBSA-N (-)-norepinephrine Chemical compound NC[C@H](O)C1=CC=C(O)C(O)=C1 SFLSHLFXELFNJZ-QMMMGPOBSA-N 0.000 description 1
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 description 1
- HTWMTDKMOSSPMU-UHFFFAOYSA-N 1,2-benzoxazin-4-one Chemical compound C1=CC=C2C(=O)C=NOC2=C1 HTWMTDKMOSSPMU-UHFFFAOYSA-N 0.000 description 1
- OQKYGBNJIBWJQS-UHFFFAOYSA-N 1,3-benzoxazin-4-one Chemical compound C1=CC=C2C(=O)N=COC2=C1 OQKYGBNJIBWJQS-UHFFFAOYSA-N 0.000 description 1
- POVFCWQCRHXYAB-UHFFFAOYSA-N 2-(4-oxo-2h-1,3-benzoxazin-3-yl)ethyl nitrate Chemical compound C1=CC=C2C(=O)N(CCO[N+](=O)[O-])COC2=C1 POVFCWQCRHXYAB-UHFFFAOYSA-N 0.000 description 1
- VWVRASTUFJRTHW-UHFFFAOYSA-N 2-[3-(azetidin-3-yloxy)-4-[2-(2,3-dihydro-1H-inden-2-ylamino)pyrimidin-5-yl]pyrazol-1-yl]-1-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)ethanone Chemical compound O=C(CN1C=C(C(OC2CNC2)=N1)C1=CN=C(NC2CC3=C(C2)C=CC=C3)N=C1)N1CCC2=C(C1)N=NN2 VWVRASTUFJRTHW-UHFFFAOYSA-N 0.000 description 1
- LPZOCVVDSHQFST-UHFFFAOYSA-N 2-[4-[2-(2,3-dihydro-1H-inden-2-ylamino)pyrimidin-5-yl]-3-ethylpyrazol-1-yl]-1-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)ethanone Chemical compound C1C(CC2=CC=CC=C12)NC1=NC=C(C=N1)C=1C(=NN(C=1)CC(=O)N1CC2=C(CC1)NN=N2)CC LPZOCVVDSHQFST-UHFFFAOYSA-N 0.000 description 1
- JQMFQLVAJGZSQS-UHFFFAOYSA-N 2-[4-[2-(2,3-dihydro-1H-inden-2-ylamino)pyrimidin-5-yl]piperazin-1-yl]-N-(2-oxo-3H-1,3-benzoxazol-6-yl)acetamide Chemical compound C1C(CC2=CC=CC=C12)NC1=NC=C(C=N1)N1CCN(CC1)CC(=O)NC1=CC2=C(NC(O2)=O)C=C1 JQMFQLVAJGZSQS-UHFFFAOYSA-N 0.000 description 1
- JVKRKMWZYMKVTQ-UHFFFAOYSA-N 2-[4-[2-(2,3-dihydro-1H-inden-2-ylamino)pyrimidin-5-yl]pyrazol-1-yl]-N-(2-oxo-3H-1,3-benzoxazol-6-yl)acetamide Chemical compound C1C(CC2=CC=CC=C12)NC1=NC=C(C=N1)C=1C=NN(C=1)CC(=O)NC1=CC2=C(NC(O2)=O)C=C1 JVKRKMWZYMKVTQ-UHFFFAOYSA-N 0.000 description 1
- NCPLWPQEVIBZKJ-UHFFFAOYSA-N 2-hydroxy-n-(2-hydroxyethyl)benzamide Chemical compound OCCNC(=O)C1=CC=CC=C1O NCPLWPQEVIBZKJ-UHFFFAOYSA-N 0.000 description 1
- DGMOBVGABMBZSB-UHFFFAOYSA-N 2-methylpropanoyl chloride Chemical compound CC(C)C(Cl)=O DGMOBVGABMBZSB-UHFFFAOYSA-N 0.000 description 1
- YOETUEMZNOLGDB-UHFFFAOYSA-N 2-methylpropyl carbonochloridate Chemical compound CC(C)COC(Cl)=O YOETUEMZNOLGDB-UHFFFAOYSA-N 0.000 description 1
- 125000004839 3-methylpentylene group Chemical group [H]C([H])([H])C([H])(C([H])([H])C([H])([H])[*:1])C([H])([H])C([H])([H])[*:2] 0.000 description 1
- OCKGFTQIICXDQW-ZEQRLZLVSA-N 5-[(1r)-1-hydroxy-2-[4-[(2r)-2-hydroxy-2-(4-methyl-1-oxo-3h-2-benzofuran-5-yl)ethyl]piperazin-1-yl]ethyl]-4-methyl-3h-2-benzofuran-1-one Chemical compound C1=C2C(=O)OCC2=C(C)C([C@@H](O)CN2CCN(CC2)C[C@H](O)C2=CC=C3C(=O)OCC3=C2C)=C1 OCKGFTQIICXDQW-ZEQRLZLVSA-N 0.000 description 1
- FAQBEQPGRQJHAM-UHFFFAOYSA-N 5-cyano-2-(2-hydroxyethoxy)benzamide Chemical compound NC(=O)C1=CC(C#N)=CC=C1OCCO FAQBEQPGRQJHAM-UHFFFAOYSA-N 0.000 description 1
- KUABYBGDWWBXGI-UHFFFAOYSA-N 6-amino-3-(2-hydroxyethyl)-2h-1,3-benzoxazin-4-one Chemical compound O1CN(CCO)C(=O)C2=CC(N)=CC=C21 KUABYBGDWWBXGI-UHFFFAOYSA-N 0.000 description 1
- IBRMSVXKKDPMKA-UHFFFAOYSA-N 7-hydroxy-3-(2-hydroxyethyl)-2h-1,3-benzoxazin-4-one Chemical compound OC1=CC=C2C(=O)N(CCO)COC2=C1 IBRMSVXKKDPMKA-UHFFFAOYSA-N 0.000 description 1
- 206010002383 Angina Pectoris Diseases 0.000 description 1
- 102400000059 Arg-vasopressin Human genes 0.000 description 1
- 101800001144 Arg-vasopressin Proteins 0.000 description 1
- 239000005711 Benzoic acid Substances 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 description 1
- VMQMZMRVKUZKQL-UHFFFAOYSA-N Cu+ Chemical class [Cu+] VMQMZMRVKUZKQL-UHFFFAOYSA-N 0.000 description 1
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 1
- 206010022998 Irritability Diseases 0.000 description 1
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 1
- 229910002651 NO3 Inorganic materials 0.000 description 1
- NHNBFGGVMKEFGY-UHFFFAOYSA-N Nitrate Chemical compound [O-][N+]([O-])=O NHNBFGGVMKEFGY-UHFFFAOYSA-N 0.000 description 1
- 241000283973 Oryctolagus cuniculus Species 0.000 description 1
- SKZKKFZAGNVIMN-UHFFFAOYSA-N Salicilamide Chemical compound NC(=O)C1=CC=CC=C1O SKZKKFZAGNVIMN-UHFFFAOYSA-N 0.000 description 1
- 208000005392 Spasm Diseases 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 1
- DHXVGJBLRPWPCS-UHFFFAOYSA-N Tetrahydropyran Chemical compound C1CCOCC1 DHXVGJBLRPWPCS-UHFFFAOYSA-N 0.000 description 1
- XSTXAVWGXDQKEL-UHFFFAOYSA-N Trichloroethylene Chemical group ClC=C(Cl)Cl XSTXAVWGXDQKEL-UHFFFAOYSA-N 0.000 description 1
- SUQPXPSEIVBYFV-UHFFFAOYSA-N [3-(2-chloroethyl)-4-oxo-2h-1,3-benzoxazin-7-yl] 2-methylpropyl carbonate Chemical compound O=C1N(CCCl)COC2=CC(OC(=O)OCC(C)C)=CC=C21 SUQPXPSEIVBYFV-UHFFFAOYSA-N 0.000 description 1
- WETWJCDKMRHUPV-UHFFFAOYSA-N acetyl chloride Chemical compound CC(Cl)=O WETWJCDKMRHUPV-UHFFFAOYSA-N 0.000 description 1
- 239000012346 acetyl chloride Substances 0.000 description 1
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 1
- 150000001266 acyl halides Chemical class 0.000 description 1
- 150000001338 aliphatic hydrocarbons Chemical class 0.000 description 1
- 150000001412 amines Chemical group 0.000 description 1
- 230000000202 analgesic effect Effects 0.000 description 1
- 150000008064 anhydrides Chemical class 0.000 description 1
- 238000010171 animal model Methods 0.000 description 1
- 230000003288 anthiarrhythmic effect Effects 0.000 description 1
- 239000004004 anti-anginal agent Substances 0.000 description 1
- 229940124345 antianginal agent Drugs 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- KBZOIRJILGZLEJ-LGYYRGKSSA-N argipressin Chemical compound C([C@H]1C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CSSC[C@@H](C(N[C@@H](CC=2C=CC(O)=CC=2)C(=O)N1)=O)N)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CCCN=C(N)N)C(=O)NCC(N)=O)C1=CC=CC=C1 KBZOIRJILGZLEJ-LGYYRGKSSA-N 0.000 description 1
- 206010003119 arrhythmia Diseases 0.000 description 1
- 230000006793 arrhythmia Effects 0.000 description 1
- 239000012298 atmosphere Substances 0.000 description 1
- 235000010233 benzoic acid Nutrition 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- 244000309464 bull Species 0.000 description 1
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 238000001460 carbon-13 nuclear magnetic resonance spectrum Methods 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- HRYZWHHZPQKTII-UHFFFAOYSA-N chloroethane Chemical compound CCCl HRYZWHHZPQKTII-UHFFFAOYSA-N 0.000 description 1
- 230000008602 contraction Effects 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- 150000001989 diazonium salts Chemical class 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 239000008298 dragée Substances 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 239000003480 eluent Substances 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 239000007941 film coated tablet Substances 0.000 description 1
- 238000003818 flash chromatography Methods 0.000 description 1
- 239000012362 glacial acetic acid Substances 0.000 description 1
- 230000002140 halogenating effect Effects 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- BHEPBYXIRTUNPN-UHFFFAOYSA-N hydridophosphorus(.) (triplet) Chemical compound [PH] BHEPBYXIRTUNPN-UHFFFAOYSA-N 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-M hydroxide Chemical compound [OH-] XLYOFNOQVPJJNP-UHFFFAOYSA-M 0.000 description 1
- 230000001077 hypotensive effect Effects 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 238000010348 incorporation Methods 0.000 description 1
- 230000001939 inductive effect Effects 0.000 description 1
- 238000003780 insertion Methods 0.000 description 1
- 230000037431 insertion Effects 0.000 description 1
- 238000007918 intramuscular administration Methods 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 229940098779 methanesulfonic acid Drugs 0.000 description 1
- 239000002808 molecular sieve Substances 0.000 description 1
- JFCUYZTYGJQNCI-UHFFFAOYSA-N n-[3-(2-hydroxyethyl)-4-oxo-2h-1,3-benzoxazin-6-yl]acetamide Chemical compound O1CN(CCO)C(=O)C2=CC(NC(=O)C)=CC=C21 JFCUYZTYGJQNCI-UHFFFAOYSA-N 0.000 description 1
- 125000001280 n-hexyl group Chemical group C(CCCCC)* 0.000 description 1
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 150000002828 nitro derivatives Chemical class 0.000 description 1
- 229960002748 norepinephrine Drugs 0.000 description 1
- SFLSHLFXELFNJZ-UHFFFAOYSA-N norepinephrine Natural products NCC(O)C1=CC=C(O)C(O)=C1 SFLSHLFXELFNJZ-UHFFFAOYSA-N 0.000 description 1
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 1
- 229910052763 palladium Inorganic materials 0.000 description 1
- SQYNKIJPMDEDEG-UHFFFAOYSA-N paraldehyde Chemical compound CC1OC(C)OC(C)O1 SQYNKIJPMDEDEG-UHFFFAOYSA-N 0.000 description 1
- 229960003868 paraldehyde Drugs 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 235000011007 phosphoric acid Nutrition 0.000 description 1
- 150000003016 phosphoric acids Chemical class 0.000 description 1
- UHZYTMXLRWXGPK-UHFFFAOYSA-N phosphorus pentachloride Chemical compound ClP(Cl)(Cl)(Cl)Cl UHZYTMXLRWXGPK-UHFFFAOYSA-N 0.000 description 1
- IPNPIHIZVLFAFP-UHFFFAOYSA-N phosphorus tribromide Chemical compound BrP(Br)Br IPNPIHIZVLFAFP-UHFFFAOYSA-N 0.000 description 1
- FAIAAWCVCHQXDN-UHFFFAOYSA-N phosphorus trichloride Chemical compound ClP(Cl)Cl FAIAAWCVCHQXDN-UHFFFAOYSA-N 0.000 description 1
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical compound [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 description 1
- 150000003141 primary amines Chemical group 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 238000007363 ring formation reaction Methods 0.000 description 1
- 229960000581 salicylamide Drugs 0.000 description 1
- 150000003902 salicylic acid esters Chemical class 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 239000012047 saturated solution Substances 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- URGAHOPLAPQHLN-UHFFFAOYSA-N sodium aluminosilicate Chemical compound [Na+].[Al+3].[O-][Si]([O-])=O.[O-][Si]([O-])=O URGAHOPLAPQHLN-UHFFFAOYSA-N 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 238000012453 sprague-dawley rat model Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 239000007940 sugar coated tablet Substances 0.000 description 1
- NBNBICNWNFQDDD-UHFFFAOYSA-N sulfuryl dibromide Chemical compound BrS(Br)(=O)=O NBNBICNWNFQDDD-UHFFFAOYSA-N 0.000 description 1
- YBBRCQOCSYXUOC-UHFFFAOYSA-N sulfuryl dichloride Chemical compound ClS(Cl)(=O)=O YBBRCQOCSYXUOC-UHFFFAOYSA-N 0.000 description 1
- 229910021653 sulphate ion Inorganic materials 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 230000009466 transformation Effects 0.000 description 1
- 229960002415 trichloroethylene Drugs 0.000 description 1
- UBOXGVDOUJQMTN-UHFFFAOYSA-N trichloroethylene Natural products ClCC(Cl)Cl UBOXGVDOUJQMTN-UHFFFAOYSA-N 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D265/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom and one oxygen atom as the only ring hetero atoms
- C07D265/04—1,3-Oxazines; Hydrogenated 1,3-oxazines
- C07D265/12—1,3-Oxazines; Hydrogenated 1,3-oxazines condensed with carbocyclic rings or ring systems
- C07D265/14—1,3-Oxazines; Hydrogenated 1,3-oxazines condensed with carbocyclic rings or ring systems condensed with one six-membered ring
- C07D265/20—1,3-Oxazines; Hydrogenated 1,3-oxazines condensed with carbocyclic rings or ring systems condensed with one six-membered ring with hetero atoms directly attached in position 4
- C07D265/22—Oxygen atoms
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/08—Vasodilators for multiple indications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D279/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom and one sulfur atom as the only ring hetero atoms
- C07D279/04—1,3-Thiazines; Hydrogenated 1,3-thiazines
- C07D279/08—1,3-Thiazines; Hydrogenated 1,3-thiazines condensed with carbocyclic rings or ring systems
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Life Sciences & Earth Sciences (AREA)
- Veterinary Medicine (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Heart & Thoracic Surgery (AREA)
- Pharmacology & Pharmacy (AREA)
- Cardiology (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Urology & Nephrology (AREA)
- Vascular Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
- Nitrogen- Or Sulfur-Containing Heterocyclic Ring Compounds With Rings Of Six Or More Members (AREA)
- Solid-Sorbent Or Filter-Aiding Compositions (AREA)
- Control Of Transmission Device (AREA)
- Optical Filters (AREA)
- Plural Heterocyclic Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| ITMI920940A IT1254884B (it) | 1992-04-16 | 1992-04-16 | Benzossazinoni e benzotiazinoni ad attivita' cardiovascolare |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| IL105158A true IL105158A (en) | 1996-10-31 |
Family
ID=11362985
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| IL10515893A IL105158A (en) | 1992-04-16 | 1993-03-24 | Benzoxazinone and benzothiazinone derivatives having cardiovascular activity |
Country Status (17)
| Country | Link |
|---|---|
| US (1) | US5480882A (es) |
| EP (1) | EP0566018B1 (es) |
| JP (1) | JP3257716B2 (es) |
| CN (1) | CN1078466A (es) |
| AT (1) | ATE169293T1 (es) |
| AU (1) | AU655540B2 (es) |
| CA (1) | CA2092342A1 (es) |
| DE (1) | DE69320087T2 (es) |
| FI (1) | FI931688A (es) |
| HU (1) | HUT68605A (es) |
| IL (1) | IL105158A (es) |
| IT (1) | IT1254884B (es) |
| MX (1) | MX9302165A (es) |
| NO (1) | NO931225L (es) |
| NZ (1) | NZ247249A (es) |
| TW (1) | TW288013B (es) |
| ZA (1) | ZA932030B (es) |
Families Citing this family (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| IT1264812B1 (it) * | 1993-07-28 | 1996-10-10 | Italfarmaco Spa | Derivati benzossazinonici e benzotiazinonici terapeuticamente attivi |
| WO2001004103A1 (en) * | 1999-07-13 | 2001-01-18 | F. Hoffmann-La Roche Ag | Benzazepinones and quinazolines |
| CA2419838A1 (en) | 2000-08-31 | 2003-02-18 | Takeda Chemical Industries, Ltd. | Heart muscular cell apoptosis inhibitors and remedies/preventives for heart diseases |
| JP5700547B2 (ja) | 2011-05-30 | 2015-04-15 | 国立大学法人京都大学 | バイオチップ形成用感光性樹脂組成物、及びバイオチップ |
| CN102367239B (zh) * | 2011-07-20 | 2015-10-28 | 沈阳药科大学 | 2-芳基-2,3-二氢-4h-1,3-苯并噻嗪-4-酮衍生物及其用途 |
| CN103012188A (zh) * | 2011-09-20 | 2013-04-03 | 北京京卫信康医药科技发展有限公司 | 一种龙胆酸乙醇胺的制备方法 |
| CN102631108A (zh) * | 2012-04-25 | 2012-08-15 | 张家港市立达金属制品有限公司 | 帽子展示架 |
| ITMI20122221A1 (it) * | 2012-12-21 | 2014-06-22 | C4T S C A R L | Nuovi composti del 2,3-diidro-4h-1,3-benzossazin-4-one, metodo per prepararli e forma farmaceutica che li comprende |
Family Cites Families (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3539563A (en) * | 1965-09-27 | 1970-11-10 | Istituto Chemioterapico | Tetracycline: 6-amino-4-oxo-2-(beta-chloroethyl) - 2,3 - dihydrobenzene - 1,3-oxazine double salt dihydrate |
| US3459748A (en) * | 1967-04-28 | 1969-08-05 | Squibb & Sons Inc | Hydroxyalkylene-substituted benzoxazines and benzothiazines |
| FR2636065B1 (fr) * | 1988-09-08 | 1993-05-07 | Fabre Sa Pierre | Nouveaux derives de dihydro-2,3 arylacoylaminoalcoyl-3 4h-benzoxazine-1,3 ones-4, leur preparation et leur application en tant que medicaments utiles en therapeutique |
| IT1244472B (it) * | 1990-12-14 | 1994-07-15 | Italfarmaco Spa | Benzossazinoni e benzotiazinoni ad attivita' cardiovascolare |
-
1992
- 1992-04-16 IT ITMI920940A patent/IT1254884B/it active IP Right Grant
-
1993
- 1993-03-22 ZA ZA932030A patent/ZA932030B/xx unknown
- 1993-03-24 IL IL10515893A patent/IL105158A/en not_active IP Right Cessation
- 1993-03-24 CA CA002092342A patent/CA2092342A1/en not_active Abandoned
- 1993-03-25 NZ NZ247249A patent/NZ247249A/xx unknown
- 1993-03-30 AU AU35617/93A patent/AU655540B2/en not_active Ceased
- 1993-03-31 NO NO93931225A patent/NO931225L/no unknown
- 1993-04-07 DE DE69320087T patent/DE69320087T2/de not_active Expired - Fee Related
- 1993-04-07 EP EP93105752A patent/EP0566018B1/en not_active Expired - Lifetime
- 1993-04-07 AT AT93105752T patent/ATE169293T1/de active
- 1993-04-14 FI FI931688A patent/FI931688A/fi not_active Application Discontinuation
- 1993-04-14 TW TW082102853A patent/TW288013B/zh active
- 1993-04-14 MX MX9302165A patent/MX9302165A/es unknown
- 1993-04-15 JP JP11214993A patent/JP3257716B2/ja not_active Expired - Fee Related
- 1993-04-15 HU HU9301106A patent/HUT68605A/hu unknown
- 1993-04-16 CN CN 93104624 patent/CN1078466A/zh active Pending
-
1994
- 1994-11-23 US US08/347,217 patent/US5480882A/en not_active Expired - Fee Related
Also Published As
| Publication number | Publication date |
|---|---|
| JP3257716B2 (ja) | 2002-02-18 |
| EP0566018B1 (en) | 1998-08-05 |
| FI931688A0 (fi) | 1993-04-14 |
| AU655540B2 (en) | 1994-12-22 |
| EP0566018A3 (en) | 1994-06-01 |
| ITMI920940A0 (it) | 1992-04-16 |
| DE69320087D1 (de) | 1998-09-10 |
| ATE169293T1 (de) | 1998-08-15 |
| HUT68605A (en) | 1995-06-28 |
| DE69320087T2 (de) | 1998-12-10 |
| MX9302165A (es) | 1993-10-01 |
| ZA932030B (en) | 1993-10-19 |
| FI931688A (fi) | 1993-10-17 |
| HU9301106D0 (en) | 1993-07-28 |
| NO931225L (no) | 1993-10-18 |
| NO931225D0 (no) | 1993-03-31 |
| ITMI920940A1 (it) | 1993-10-16 |
| EP0566018A2 (en) | 1993-10-20 |
| AU3561793A (en) | 1993-10-21 |
| TW288013B (es) | 1996-10-11 |
| US5480882A (en) | 1996-01-02 |
| NZ247249A (en) | 1995-01-27 |
| JPH0625194A (ja) | 1994-02-01 |
| CA2092342A1 (en) | 1993-10-17 |
| CN1078466A (zh) | 1993-11-17 |
| IT1254884B (it) | 1995-10-11 |
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| FF | Patent granted | ||
| KB | Patent renewed | ||
| RH | Patent void |