ITMI942220A1 - "BENZOSSAZINONIC AND BENZOTHIAZINONIC DERIVATIVES AND THEIR THERAPEUTIC USE" - Google Patents
"BENZOSSAZINONIC AND BENZOTHIAZINONIC DERIVATIVES AND THEIR THERAPEUTIC USE" Download PDFInfo
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- ITMI942220A1 ITMI942220A1 IT002220A ITMI942220A ITMI942220A1 IT MI942220 A1 ITMI942220 A1 IT MI942220A1 IT 002220 A IT002220 A IT 002220A IT MI942220 A ITMI942220 A IT MI942220A IT MI942220 A1 ITMI942220 A1 IT MI942220A1
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- 230000001225 therapeutic effect Effects 0.000 title description 3
- 150000001875 compounds Chemical class 0.000 claims description 55
- -1 optionally branched Chemical group 0.000 claims description 27
- 229910052739 hydrogen Inorganic materials 0.000 claims description 9
- 239000001257 hydrogen Substances 0.000 claims description 9
- 239000002253 acid Substances 0.000 claims description 7
- 239000004480 active ingredient Substances 0.000 claims description 5
- 230000003257 anti-anginal effect Effects 0.000 claims description 5
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 5
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 4
- 150000007513 acids Chemical class 0.000 claims description 4
- 150000002825 nitriles Chemical class 0.000 claims description 3
- 239000008194 pharmaceutical composition Substances 0.000 claims description 3
- 238000002360 preparation method Methods 0.000 claims description 3
- 150000003839 salts Chemical class 0.000 claims description 3
- MYMOFIZGZYHOMD-UHFFFAOYSA-N Dioxygen Chemical compound O=O MYMOFIZGZYHOMD-UHFFFAOYSA-N 0.000 claims description 2
- IYABWNGZIDDRAK-UHFFFAOYSA-N allene Chemical group C=C=C IYABWNGZIDDRAK-UHFFFAOYSA-N 0.000 claims description 2
- 125000004956 cyclohexylene group Chemical group 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
- 229910052760 oxygen Inorganic materials 0.000 claims description 2
- 239000001301 oxygen Substances 0.000 claims description 2
- 229910052717 sulfur Inorganic materials 0.000 claims description 2
- 125000004434 sulfur atom Chemical group 0.000 claims description 2
- 239000013543 active substance Substances 0.000 claims 1
- PXQLVRUNWNTZOS-UHFFFAOYSA-N sulfanyl Chemical class [SH] PXQLVRUNWNTZOS-UHFFFAOYSA-N 0.000 claims 1
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 24
- 238000000034 method Methods 0.000 description 18
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 16
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 12
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 10
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 10
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 9
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 9
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 9
- 238000005160 1H NMR spectroscopy Methods 0.000 description 8
- 238000006243 chemical reaction Methods 0.000 description 8
- 230000015572 biosynthetic process Effects 0.000 description 7
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- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- 239000000203 mixture Substances 0.000 description 6
- 239000012074 organic phase Substances 0.000 description 6
- 125000003396 thiol group Chemical group [H]S* 0.000 description 6
- 125000004191 (C1-C6) alkoxy group Chemical group 0.000 description 5
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 description 5
- 125000004423 acyloxy group Chemical group 0.000 description 5
- 239000011541 reaction mixture Substances 0.000 description 5
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 5
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 4
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 4
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 4
- 238000001704 evaporation Methods 0.000 description 4
- 230000008020 evaporation Effects 0.000 description 4
- 239000003960 organic solvent Substances 0.000 description 4
- KDLHZDBZIXYQEI-UHFFFAOYSA-N palladium Substances [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 4
- 238000010992 reflux Methods 0.000 description 4
- 239000002904 solvent Substances 0.000 description 4
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 4
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 3
- 241001465754 Metazoa Species 0.000 description 3
- 238000005481 NMR spectroscopy Methods 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
- 125000002252 acyl group Chemical group 0.000 description 3
- 239000003153 chemical reaction reagent Substances 0.000 description 3
- 238000009833 condensation Methods 0.000 description 3
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- 238000001816 cooling Methods 0.000 description 3
- 150000002431 hydrogen Chemical group 0.000 description 3
- 150000007530 organic bases Chemical class 0.000 description 3
- 229910052938 sodium sulfate Inorganic materials 0.000 description 3
- 235000011152 sodium sulphate Nutrition 0.000 description 3
- HZAXFHJVJLSVMW-UHFFFAOYSA-N 2-Aminoethan-1-ol Chemical compound NCCO HZAXFHJVJLSVMW-UHFFFAOYSA-N 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- AVXURJPOCDRRFD-UHFFFAOYSA-N Hydroxylamine Chemical compound ON AVXURJPOCDRRFD-UHFFFAOYSA-N 0.000 description 2
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 2
- 229930040373 Paraformaldehyde Natural products 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- 241000700159 Rattus Species 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
- 230000001476 alcoholic effect Effects 0.000 description 2
- 150000001350 alkyl halides Chemical class 0.000 description 2
- 150000008064 anhydrides Chemical class 0.000 description 2
- 229910052799 carbon Inorganic materials 0.000 description 2
- 230000005792 cardiovascular activity Effects 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- MVPPADPHJFYWMZ-UHFFFAOYSA-N chlorobenzene Chemical compound ClC1=CC=CC=C1 MVPPADPHJFYWMZ-UHFFFAOYSA-N 0.000 description 2
- 239000012954 diazonium Substances 0.000 description 2
- 230000002526 effect on cardiovascular system Effects 0.000 description 2
- 150000002148 esters Chemical class 0.000 description 2
- 125000002485 formyl group Chemical group [H]C(*)=O 0.000 description 2
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 2
- 230000007062 hydrolysis Effects 0.000 description 2
- 238000006460 hydrolysis reaction Methods 0.000 description 2
- 229910052500 inorganic mineral Inorganic materials 0.000 description 2
- 239000000543 intermediate Substances 0.000 description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 2
- 239000011707 mineral Substances 0.000 description 2
- 235000010755 mineral Nutrition 0.000 description 2
- 208000031225 myocardial ischemia Diseases 0.000 description 2
- LQNUZADURLCDLV-UHFFFAOYSA-N nitrobenzene Chemical compound [O-][N+](=O)C1=CC=CC=C1 LQNUZADURLCDLV-UHFFFAOYSA-N 0.000 description 2
- 229910052757 nitrogen Inorganic materials 0.000 description 2
- 229920002866 paraformaldehyde Polymers 0.000 description 2
- 239000002243 precursor Substances 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- 125000001424 substituent group Chemical group 0.000 description 2
- 238000002560 therapeutic procedure Methods 0.000 description 2
- UMGDCJDMYOKAJW-UHFFFAOYSA-N thiourea Chemical compound NC(N)=S UMGDCJDMYOKAJW-UHFFFAOYSA-N 0.000 description 2
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 2
- 238000011282 treatment Methods 0.000 description 2
- ODIGIKRIUKFKHP-UHFFFAOYSA-N (n-propan-2-yloxycarbonylanilino) acetate Chemical compound CC(C)OC(=O)N(OC(C)=O)C1=CC=CC=C1 ODIGIKRIUKFKHP-UHFFFAOYSA-N 0.000 description 1
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-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
- CWYKVHKSRMEAKA-UHFFFAOYSA-N 1-hydroxysulfanyl-4-methylbenzene Chemical compound CC1=CC=C(SO)C=C1 CWYKVHKSRMEAKA-UHFFFAOYSA-N 0.000 description 1
- SNACYIAVJXIXOC-UHFFFAOYSA-N 2-(7-methyl-4-oxo-2h-1,3-benzoxazin-3-yl)ethyl acetate Chemical compound CC1=CC=C2C(=O)N(CCOC(=O)C)COC2=C1 SNACYIAVJXIXOC-UHFFFAOYSA-N 0.000 description 1
- YBFKALVNQKUNHX-UHFFFAOYSA-N 2-[4-oxo-7-(trifluoromethyl)-2h-1,3-benzoxazin-3-yl]ethyl acetate Chemical compound FC(F)(F)C1=CC=C2C(=O)N(CCOC(=O)C)COC2=C1 YBFKALVNQKUNHX-UHFFFAOYSA-N 0.000 description 1
- 125000004080 3-carboxypropanoyl group Chemical group O=C([*])C([H])([H])C([H])([H])C(O[H])=O 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
- 206010003225 Arteriospasm coronary Diseases 0.000 description 1
- 229940127291 Calcium channel antagonist Drugs 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 1
- BDAGIHXWWSANSR-UHFFFAOYSA-M Formate Chemical compound [O-]C=O BDAGIHXWWSANSR-UHFFFAOYSA-M 0.000 description 1
- 206010022998 Irritability Diseases 0.000 description 1
- 241000699670 Mus sp. Species 0.000 description 1
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 1
- PHSPJQZRQAJPPF-UHFFFAOYSA-N N-alpha-Methylhistamine Chemical compound CNCCC1=CN=CN1 PHSPJQZRQAJPPF-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
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 description 1
- 241000220304 Prunus dulcis Species 0.000 description 1
- SKZKKFZAGNVIMN-UHFFFAOYSA-N Salicilamide Chemical compound NC(=O)C1=CC=CC=C1O SKZKKFZAGNVIMN-UHFFFAOYSA-N 0.000 description 1
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 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
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Natural products NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 description 1
- 238000006959 Williamson synthesis reaction Methods 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
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- 230000002378 acidificating effect Effects 0.000 description 1
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- 125000004442 acylamino group Chemical group 0.000 description 1
- 125000001931 aliphatic group Chemical group 0.000 description 1
- 150000008044 alkali metal hydroxides Chemical class 0.000 description 1
- 125000003545 alkoxy group Chemical group 0.000 description 1
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- 125000000217 alkyl group Chemical group 0.000 description 1
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- 125000003277 amino group Chemical group 0.000 description 1
- 230000000202 analgesic effect Effects 0.000 description 1
- 238000010171 animal model Methods 0.000 description 1
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- 230000002253 anti-ischaemic effect Effects 0.000 description 1
- 229940124345 antianginal agent Drugs 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
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- 230000000059 bradycardiac effect Effects 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
- 125000004063 butyryl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 239000000480 calcium channel blocker Substances 0.000 description 1
- 125000004432 carbon atom Chemical group C* 0.000 description 1
- PFKFTWBEEFSNDU-UHFFFAOYSA-N carbonyldiimidazole Chemical compound C1=CN=CN1C(=O)N1C=CN=C1 PFKFTWBEEFSNDU-UHFFFAOYSA-N 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
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- 239000000460 chlorine Substances 0.000 description 1
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- 150000001989 diazonium salts Chemical class 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
- XXUJMEYKYHETBZ-UHFFFAOYSA-N ethyl 4-nitrophenyl ethylphosphonate Chemical group CCOP(=O)(CC)OC1=CC=C([N+]([O-])=O)C=C1 XXUJMEYKYHETBZ-UHFFFAOYSA-N 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 230000002349 favourable effect Effects 0.000 description 1
- 238000003818 flash chromatography Methods 0.000 description 1
- 125000002795 guanidino group Chemical group C(N)(=N)N* 0.000 description 1
- 150000004820 halides Chemical class 0.000 description 1
- 229910052736 halogen Inorganic materials 0.000 description 1
- 125000005843 halogen group Chemical group 0.000 description 1
- 230000002140 halogenating effect Effects 0.000 description 1
- 238000005658 halogenation reaction Methods 0.000 description 1
- 150000002367 halogens Chemical class 0.000 description 1
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- 150000002430 hydrocarbons Chemical class 0.000 description 1
- 125000004356 hydroxy functional group Chemical group O* 0.000 description 1
- JBFYUZGYRGXSFL-UHFFFAOYSA-N imidazolide Chemical compound C1=C[N-]C=N1 JBFYUZGYRGXSFL-UHFFFAOYSA-N 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 238000010348 incorporation Methods 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 238000007918 intramuscular administration Methods 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 125000001972 isopentyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([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
- 231100000053 low toxicity Toxicity 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 125000005905 mesyloxy group Chemical group 0.000 description 1
- 229940098779 methanesulfonic acid Drugs 0.000 description 1
- XJKWVPNWHOCFBR-UHFFFAOYSA-N methyl 5-formyl-2-hydroxybenzoate Chemical compound COC(=O)C1=CC(C=O)=CC=C1O XJKWVPNWHOCFBR-UHFFFAOYSA-N 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
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- 125000001280 n-hexyl group Chemical group C(CCCCC)* 0.000 description 1
- KVBGVZZKJNLNJU-UHFFFAOYSA-N naphthalene-2-sulfonic acid Chemical class C1=CC=CC2=CC(S(=O)(=O)O)=CC=C21 KVBGVZZKJNLNJU-UHFFFAOYSA-N 0.000 description 1
- 125000004433 nitrogen atom Chemical group N* 0.000 description 1
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- 125000003431 oxalo group Chemical group 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
- 229910052698 phosphorus Inorganic materials 0.000 description 1
- 239000011574 phosphorus Substances 0.000 description 1
- UHZYTMXLRWXGPK-UHFFFAOYSA-N phosphorus pentachloride Chemical compound ClP(Cl)(Cl)(Cl)Cl UHZYTMXLRWXGPK-UHFFFAOYSA-N 0.000 description 1
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 description 1
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical compound [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 description 1
- 238000011321 prophylaxis Methods 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000006239 protecting group Chemical group 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 238000007363 ring formation reaction Methods 0.000 description 1
- 229960000581 salicylamide Drugs 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
- 239000007787 solid Substances 0.000 description 1
- 238000012453 sprague-dawley rat model Methods 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 238000006467 substitution reaction Methods 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
- 239000000725 suspension Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 150000003512 tertiary amines Chemical class 0.000 description 1
- 125000005424 tosyloxy group Chemical group S(=O)(=O)(C1=CC=C(C)C=C1)O* 0.000 description 1
- 230000009466 transformation Effects 0.000 description 1
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen- Or Sulfur-Containing Heterocyclic Ring Compounds With Rings Of Six Or More Members (AREA)
Description
Descrizione dell'invenzione industriale avente per titolo: «DERIVATI BENZOSSAZINONICI E BENZOTI AZINONICI E LORO USO TERAPEUTICO" Description of the industrial invention having as title: "BENZOXY-ZINONE DERIVATIVES AND AZINONE BENZOTES AND THEIR THERAPEUTIC USE"
La presente invenzione si riferisce derivati di 2,3-diidro-4H-l,3-benzossazin- e -benzotiazin-4-oni, e al loro uso in canpo cardiovascolare. The present invention relates to derivatives of 2,3-dihydro-4H-1,3-benzoxazin- and -benzothiazin-4-oni, and to their use in the cardiovascular field.
2,3-Diidro-4H-l,3-benzossazin-4-cni non sostituiti sull'azoto sono stati descritti da B.W. Horrom et al., J. Qrg. Chem., 72, 721 (1950) come dotati di attività analgesica. Altri 2,3-diidro-4H-l,3-benzossazin-4-oni sono stati descritti da R.B. Gammil, J. Qrg. Chem., 46, 3340 (1981). 2,3-Dihydro-4H-1,3-benzoxazin-4-cni not substituted on nitrogen have been described by B.W. Horrom et al., J. Qrg. Chem., 72, 721 (1950) as endowed with analgesic activity. Other 2,3-dihydro-4H-1,3-benzoxazin-4-oni have been described by R.B. Gammil, J. Qrg. Chem., 46, 3340 (1981).
Derivati dello stesso eteraciclo, ma con l'atomo di azoto sostituito, sano stati descritti da J. Finkelstein et al., J. Med. Chem., 11, 1038 (1968) come ccnposti che sembrano possedere attività antiinfianmatoria. Analoghi derivati recanti un gruppo armino sulla posizione 6, anch'essi dotati di attività antiinfiairmatoria, sono stati riportati da F. Fontanini et al., Rivendicazione. Farmacol. Ter., 4(1), 119 (1973) (Chem. Abs. 73745η,Voi. 79, pag. 40, 1073). Derivatives of the same heteracycle, but with the nitrogen atom substituted, have been described by J. Finkelstein et al., J. Med. Chem., 11, 1038 (1968) as compounds which appear to possess anti-inflammatory activity. Derivative analogues bearing an armine group on position 6, also endowed with anti-infrairmatory activity, have been reported by F. Fontanini et al., Claim. Pharmacol. Ter., 4 (1), 119 (1973) (Chem. Abs. 73745η, Vol. 79, p. 40, 1073).
La pubblicazione della domanda di brevetto EP-A-0490183 (a nome della richiedente) si riferisce a derivati di 2,3-diidro-4H-l,3-benzossazin- e -benzotiazin-4-cni recanti nella struttura un gruppo nitroossi: questi conposti sono dotati di buona attività cardiovascolare, in particolare antianginosa. The publication of patent application EP-A-0490183 (in the name of the applicant) refers to derivatives of 2,3-dihydro-4H-1, 3-benzoxazin- and -benzothiazin-4-cni bearing in the structure a nitroxy group: these compounds are endowed with good cardiovascular activity, in particular antianginal.
La pubblicazione della domanda di brevetto EP-A-0 359 627 descrive derivati benzossazin-4-cnici utili come intermedi per la sintesi di composti bradicardizzanti, antiischemici e calcio-antagonisti. The publication of the patent application EP-A-0 359 627 describes benzoxazine-4-cnic derivatives useful as intermediates for the synthesis of bradycardic, anti-ischemic and calcium antagonist compounds.
La presente invenzione si riferisce a composti di formula generale The present invention relates to compounds of general formula
dove X rappresenta un atomo di ossigeno o di zolfo; where X represents an oxygen or sulfur atom;
Y rappresenta metilene, etilene, facoltativamente rami-ficato, oppure ciclopentilene, cicloesilene o cicloeptilene facoltativamente sostituiti da Y represents methylene, ethylene, optionally branched, or cyclopentylene, cyclohexylene or cycloepylene optionally replaced by
A rappresenta idrossi; mercapto; A represents hydroxy; mercapto;
guanidino, mono- o di-(C1-C6)alchil-guanidino, carbamoilossi, mono- o di-(C1-C6)alchil-carbamoilossi, formilossi, (C2--C6) acilossi, arrmino, mono- o di-(C1-C6)alchil-ammino, (C1-C6)alcossi-carbonilossi, forn iiammino , (C2-C6)acilammino facoltativamente N-sostituito da un gruppo (C1-C6)alchile, N-ureido facoltativamente N-sostituito da uno, due o tre gruppi (C1-C6)alchile, aminometilimino, N'-mono- o N' ,N'-di-(C1-C6 achilamminometilimino , nitro, nitrile, mercapto facoltativamente sostituito da (C1-C6)alchile; e guanidino, mono- or di- (C1-C6) alkyl-guanidino, carbamoyloxy, mono- or di- (C1-C6) alkyl-carbamoyloxy, formyloxy, (C2 - C6) acyloxy, arrmine, mono- or di- ( C1-C6) alkyl-amino, (C1-C6) alkoxy-carbonyloxy, hylamine, (C2-C6) acylamino optionally N-substituted by a group (C1-C6) alkyl, N-ureido optionally N-substituted by one, two or three groups (C1-C6) alkyl, aminomethylimino, N'-mono- or N ', N'-di- (C1-C6 akylaminomethylimino, nitro, nitrile, mercapto optionally substituted by (C1-C6) alkyl; and
R2 rappresenta idrogeno, idrossi(C1-C6)alchile, trifluorcmetile, formile, (C2-C6)acile, (C1-C6)alcossi, (C1-C6)alchile, alogeno e idro ssilammiro; a patto che R2 rappresenta idrogeno solo quando rappresenta formile, (C2-C6)acile o idrossilanmino o idrossi(C1-C6)alchile; R2 represents hydrogen, hydroxy (C1-C6) alkyl, trifluorcmethyl, formyl, (C2-C6) acyl, (C1-C6) alkoxy, (C1-C6) alkyl, halogen and hydroxylamine; provided that R2 represents hydrogen only when it represents formyl, (C2-C6) acyl or hydroxylamine or hydroxy (C1-C6) alkyl;
e loro sali con acidi e basi farmaceuticamente accettabili. and their salts with pharmaceutically acceptable acids and bases.
Un altro oggetto dell'invenzione riguarda l'uso dei composti di formula (I) come principi attivi per la fabbricazione di un medicamento utile in campo cardiovascolare. Another object of the invention relates to the use of the compounds of formula (I) as active ingredients for the manufacture of a medicament useful in the cardiovascular field.
Come inteso di seguito, i gruppi alchile si identificano essenzialmente con metile, etile, propile, i-propile, butile, 2-metilprcpile, npentile, 3-metilbutile, i-pentile, n-esile e simili, mentre i gruppi alcossi vengono preferibilmente scelti tra metossi, etossi, propossi, ipropossi, butossi, 2-metilbutossi, t-butossi. Per gruppo (C3-C6)-alchilene, lineare o ramificato, si intende, ad esenpio, 2-metiletilene, 1,3-propilene, 1,4-butilene, 2-etiletilene, 3-metilpropilene, 1,5-pentilene, 2-etilpropilene, 2-metilbutilene, 1,6-esilene, 1-etil-l~metilpropilene, 3-metilpentilene e simili. Per grippi si intendono, ad esenpio, acetile, propicnile, butirrile, ossalile, malcnile, succinile. As understood below, the alkyl groups are essentially identified with methyl, ethyl, propyl, i-propyl, butyl, 2-methylprcpyl, npentyl, 3-methylbutyl, i-pentyl, n-hexyl and the like, while the alkoxy groups are preferably selected from methoxy, ethoxy, propoxy, hypropoxy, butoxy, 2-methylbutoxy, t-butoxy. By group (C3-C6) -alkylene, linear or branched, we mean, for example, 2-methylethylene, 1,3-propylene, 1,4-butylene, 2-ethyl ethylene, 3-methylpropylene, 1,5-pentylene, 2-ethylpropylene, 2-methylbutylene, 1,6-hexylene, 1-ethyl-1 ~ methylpropylene, 3-methylpentylene and the like. By grippi we mean, for example, acetyl, propychnyl, butyryl, oxalyl, malcnyl, succinyl.
I carposti della presente invenzione vengono preparati secondo processi noti all'esperto del ramo. Così, ad esenpio, i composti di formula (I) dove X, Y, R, e R2 sono come sopra definiti, A è idroesi, possono venire ottenuti secondo una delle procedure descritte nella pubblicazione di domanda di brevetto EP-A-0 490 183 e EP-A-0566 018 mediante condensazione di una salicilantnide o tiosalicilanmide di formula (II) The compounds of the present invention are prepared according to processes known to those skilled in the art. Thus, for example, the compounds of formula (I) where X, Y, R, and R2 are as defined above, A is hydroesis, can be obtained according to one of the procedures described in the patent application publication EP-A-0 490 183 and EP-A-0566 018 by condensation of a salicylantnide or thiosalicylanmide of formula (II)
in cui R è come sopra definito, o un suo derivato, o un suo precursore. where R is as defined above, or a derivative thereof, or a precursor thereof.
La condensazione avviene generalmente in un ambiente acido, ad esempio in un sistema costituito da un acido minerale forte e un acido alifatico da 2 a 6 atomi di carbonio, col che quando R^ è idrogeno, si ottengono composti di formula (I) in cui A è oppure per azione di setacci molecolari in presenza di acidi solfonici quali, ad esenpio, acido p-toluensolfonico, acido metansolfonico, Condensation generally occurs in an acidic environment, for example in a system consisting of a strong mineral acid and an aliphatic acid of 2 to 6 carbon atoms, with which when R ^ is hydrogen, compounds of formula (I) are obtained in which A is or by the action of molecular sieves in the presence of sulphonic acids such as, for example, p-toluenesulfonic acid, methanesulfonic acid,
β-naftalensolfonici, gli acidi fosforici, i loro esteri e analoghi, oppure, ancora, semplicemente in presenza di uno o più degli acidi sopramenzicnati. La condensazione è effettuata in presenza di un solvente organico, preferibilmente un solvente organico inerte quale, ad esempio, acetato di etile, acetonitrile, benzene, toluene, nitrobenzene o clorobenzene, idrocarburi alitatici alogenati cane cloruro di metilene, cloroformio, 1,2-dicloroetano o 1,1,2-tricloroetilene, cicloesano, tetraidrofurano, tetraidropirano, dimetilformanmide, dimetilacetammide. La temperatura della reazione può variare entro limiti abbastanza ampi senza pregiudicare il decorso della stessa. L'intervallo preferito di temperatura è oonpreso fra circa -10°C e la temperatura di riflusso della miscela di reazione, che è completa in un periodo di tempo che varia da circa 2 a circa 30 ore. β-naphthalenesulfonic acids, phosphoric acids, their esters and analogues, or, again, simply in the presence of one or more of the above mentioned acids. The condensation is carried out in the presence of an organic solvent, preferably an inert organic solvent such as, for example, ethyl acetate, acetonitrile, benzene, toluene, nitrobenzene or chlorobenzene, halogenated halitatic hydrocarbons such as methylene chloride, chloroform, 1,2-dichloroethane or 1,1,2-trichlorethylene, cyclohexane, tetrahydrofuran, tetrahydropyran, dimethylformanmide, dimethylacetamide. The temperature of the reaction can vary within fairly wide limits without compromising its course. The preferred temperature range is from about -10 ° C to the reflux temperature of the reaction mixture, which is complete over a period of time ranging from about 2 to about 30 hours.
Le quantità molari dei reagenti di formula (II) e (III) non sono critiche per il buon andamento della ciclizzazione, potendosi usare tali reagenti nei più ampi reciproci rapporti stechiometrici. Quando si vogliono ottenere composti di formula (I) in cui R è idrogeno oppure metile, vengono preferibilmente inpiegati dei precursori del composto di formula (III), quali la paraformaldeide e la paraldeide. The molar quantities of the reagents of formula (II) and (III) are not critical for the good progress of the cyclization, since such reagents can be used in the widest reciprocal stoichiometric ratios. When it is desired to obtain compounds of formula (I) in which R is hydrogen or methyl, precursors of the compound of formula (III), such as paraformaldehyde and paraldehyde, are preferably used.
I composti di formula (I) dove X, Y, R, 1 e R2 sono come sopra de-finiti, ed A è idrossi, che si possono anche ottenere per idrolisi dei corrispondenti (C2-C6)acilossi derivati, possono venire utilizzati cane materiale di partenza per la sintesi di altri composti di formula (I). The compounds of formula (I) where X, Y, R, 1 and R2 are defined as above, and A is hydroxy, which can also be obtained by hydrolysis of the corresponding (C2-C6) acyloxy derivatives, can be used as starting material for the synthesis of other compounds of formula (I).
Ad esempio, per ottenere composti di formula (I) dove X, Y, R, R1 e R2 sono cane sopra definiti, e A è mesilossi, (C2-C6)alchilsolfonilossi, tosilossi, fenil-solfcnilossi facoltativamente sostituito da For example, to obtain compounds of formula (I) where X, Y, R, R1 and R2 are defined above, and A is mesyloxy, (C2-C6) alkylsulfonyloxy, tosyloxy, phenyl-sulfonyloxy optionally replaced by
dove R3 è un gruppo oppure formilossi o si tratta un conposto di formula (I) in cui A è idrossi con l'opportuno acido organico o inorganico attivato in forma di estere, anidride, alogenuro o imidazolide, usato in eccesso, preferibilmente in presenza di una base organica quale piridina. Adatti solventi per tale sintesi seno, ad esempio, cloroformio o cloruro di metilene, mentre la temperatura di reazione varia da circa -10"C a circa 40<e>C, ed i tempi sono di circa 1-20 ore. where R3 is a group or formyloxy or it is a compound of formula (I) in which A is hydroxy with the suitable organic or inorganic acid activated in the form of ester, anhydride, halide or imidazolide, used in excess, preferably in the presence of an organic base such as pyridine. Suitable solvents for such synthesis are, for example, chloroform or methylene chloride, while the reaction temperature ranges from about -10 ° C to about 40 ° C, and the times are about 1-20 hours.
In particolare, nel caso di il composto di formula (I) dove A è idrossi, viene preferibilmente fatto re agire con, rispettivamente, cloruro di tionile o carbonildiimidazolo, operando a basse temperature, pre feribilmente sotto i 0°C, e a fine reazione viene aggiunta un'opportuna quantità dell'alcol desiderato. Risulta chiaro che nella sintesi sopra illustrata, come pure in altre , laddove l'esperto del ramo lo ritenga opportuno, altri sostituenti reattivi alla sintesi in questione eventualmente pre senti potranno venire protetti opportunamente (cfr. T.W Greene e P.J3.M WUts - "Protective groups in organic synthesis", 2° ed., J. Wiley & Son, 1991). In particular, in the case of the compound of formula (I) where A is hydroxy, it is preferably made to act with, respectively, thionyl chloride or carbonyldiimidazole, operating at low temperatures, preferably below 0 ° C, and at the end of the reaction it is added an appropriate amount of the desired alcohol. It is clear that in the synthesis illustrated above, as well as in others, where the expert in the art deems it appropriate, other substituents reactive to the synthesis in question possibly present may be suitably protected (see T.W Greene and P.J3.M WUts - "Protective groups in organic synthesis", 2nd ed., J. Wiley & Son, 1991).
Ancora, i composti di formula (I) in cui A è idrossi possono dare luogo a conposti di formula (I) in cui A è mercapto o Furthermore, the compounds of formula (I) in which A is hydroxy can give rise to compounds of formula (I) in which A is mercapto or
capto, attraverso un intermedio dì formula IV I capture, through an intermediate of formula IV
dove X, Y,R, R1 e R2 sono come sopra definiti, e Alo è un atomo di alogeno, preferibilmente cloro, ottenuto per trattamento del gruppo OH con agenti alogenanti quali, ad esempio,cloruro di tionile,cloruro di solforile, tricloruro di fosforo, pentacloruro di fosforo, ossitricloruro di fosforo, tribromuro di fosforo, bromuro di solforile e analoghi. Detta reazione di alogenazione decorre in un solvente organico, preferibilmente un solvente organico inerte scelto ancora fra quelli sopra impiegati nella reazione di formazione del conposto di formula (I) sopra illustrata, ad una temperatura variante fra circa la tenperatura ambiente e la tenperatura di riflusso della miscela di reazione. Il conposto di formula (IV) vien convertito in un composto di formula (I) in cui A è mercapto,per reazione con tiourea in soluzione alcolica, alla temperatura di riflusso della miscela di reazione per circa 5-12 ore, e successiva idrolisi con basi organiche forti, quale un idrossido di metallo alcalino,alla tenperatura di riflusso per circa 2-10 ore. where X, Y, R, R1 and R2 are as defined above, and Alo is a halogen atom, preferably chlorine, obtained by treating the OH group with halogenating agents such as, for example, thionyl chloride, sulfuryl chloride, phosphorus, phosphorus pentachloride, phosphorus oxytrichloride, phosphorus tribromide, sulfuryl bromide and analogues. Said halogenation reaction proceeds in an organic solvent, preferably an inert organic solvent still selected from those used above in the reaction of formation of the compound of formula (I) illustrated above, at a temperature varying between about the ambient temperature and the reflux temperature of the reaction mixture. The compound of formula (IV) is converted into a compound of formula (I) in which A is mercapto, by reaction with thiourea in alcoholic solution, at the reflux temperature of the reaction mixture for about 5-12 hours, and subsequent hydrolysis with strong organic bases, such as an alkali metal hydroxide, at reflux temperature for about 2-10 hours.
Il composto di formula (I) in cui A è mercapto può venire convertito nel conposto di formula (I) in cui A è per trattamento oon l'opportuno alogenuro alchilico in presenza di una base organica quale diazabicicloundecene, secondo quanto insegnato in Palai, parte 2°,pag. 721-735. The compound of formula (I) in which A is mercapto can be converted into the compound of formula (I) in which A is by treatment with the appropriate alkyl halide in the presence of an organic base such as diazabicicloundecene, according to what is taught in Palai, part 2 °, p. 721-735.
I composti di formula (I) deve A è idrossi, danno inoltre i composti di formula (I) dove A è (C1-C6)alcossi, secondo la cosiddetta sintesi di Williamson effettuata con l'opportuno alogenuro alchilioo. The compounds of formula (I) must A is hydroxy, furthermore they give the compounds of formula (I) where A is (C1-C6) alkoxy, according to the so-called Williamson synthesis carried out with the suitable alkyl halide.
Inoltre i composti di formula (I) possono venire convertiti in altri composti di formula (I) mediante adatte procedure di modificazione dei sostituenti R1 e R2 , procedure del tutto familiari all'esperto del ramo.Così, ad esempio, è possibile formilare o acilare un gruppo ariminico facoltativamente N-sostituito con un gruppo (C1-C6)alchile facendolo reagire con un adatto alogenuro C 2-C6)acilico o una anidride sirrmetrica o mista. La trasformazione di detto gruppo armonico nel gruppo ureido può avvenire impiegando un adatto alogenuro carbamoilico. Ancora,quando si desiderano composti di formula (I) in cui X, Y, R ed R2 sono come sopra definiti, A è (C1-C6)alcossi o (C2-C6)acilossi, e è il gruppo nitro, si fa reagire un composto di formula (Ι') Furthermore, the compounds of formula (I) can be converted into other compounds of formula (I) by means of suitable procedures for modifying the substituents R1 and R2, procedures completely familiar to those skilled in the art. Thus, for example, it is possible to formylate or acylate an optionally N-substituted ariminic group with a (C1-C6) alkyl group by reacting it with a suitable C 2-C6) acyl halide or a syrmetric or mixed anhydride. The transformation of said harmonic group into the ureid group can take place using a suitable carbamoyl halide. Again, when compounds of formula (I) are desired in which X, Y, R and R2 are as defined above, A is (C1-C6) alkoxy or (C2-C6) acyloxy, and is the nitro group, is reacted a compound of formula (Ι ')
dove R, Y e X sono come sopra definiti,A è (C1-C6)alcossi o (C2-C6)acilossi, e R ha gli stessi significati di R2 sopra ad eccezione di idrogeno, con acido nitrico fumante ad una temperatura oenpresa tra circa -20°C e circa 0°C, e per un tenpo che varia tra circa 10 minuti e circa 2 ore. Questo conposto può essere a sua volta sottoposto ad idrogenazione catalitica del gruppo nitro,ad una tenperatura di 10-40°C, in un solvente alcolico,per un tenpo che varia tra circa 30 minuti e circa 10 ore, usando uno dei comuni catalizzatori quali, ade esenpio, palladio o spugna di platino. A seconda del tenpo della reazione e della pressione di idrogeno applicata e della tenperatura, si potranno così ottenere conposti in cui A è idrossi e R1 è idrossilannu.no eppure un gruppo airminico primario. where R, Y and X are as defined above, A is (C1-C6) alkoxy or (C2-C6) acyloxy, and R has the same meanings as R2 above except for hydrogen, with fuming nitric acid at a temperature between about -20 ° C and about 0 ° C, and for a time that varies between about 10 minutes and about 2 hours. This compound can in turn be subjected to catalytic hydrogenation of the nitro group, at a temperature of 10-40 ° C, in an alcoholic solvent, for a period ranging from about 30 minutes to about 10 hours, using one of the common catalysts such as , eg, palladium or platinum sponge. According to the reaction time and the applied hydrogen pressure and the temperature, it will thus be possible to obtain compounds in which A is hydroxy and R1 is hydroxylannuated and yet a primary airminic group.
Un modo per introdurre sulle posizioni da 5 a 8 gruppi idrossi, nitro, nitrile e mercapto consiste nel sottoporre un composto di formula (I) deve A è idrossi, (C1-C6)alcossi o (C2-C6)acile e R1 è un gruppo animino, ad una reazione di diazotazione con un nitrato alcalino in presenza di un acido minerale quale acido cloridrico, nitrico, e solforico, secondo modalità ben note all'esperto del ramo. Il sale di diazonio così formato viene sottoposto ad una reazione di sostituzione in presenza di un sale rameoso, tramite la quale il catione diazonio viene sostituito dal gruppo desiderato. One way to introduce hydroxy, nitro, nitrile and mercapto groups on the 5 to 8 positions is to subject a compound of formula (I) where A is hydroxy, (C1-C6) alkoxy or (C2-C6) acyl and R1 is a amino group, to a diazotation reaction with an alkaline nitrate in the presence of a mineral acid such as hydrochloric, nitric, and sulfuric acid, according to methods well known to the skilled in the art. The diazonium salt thus formed is subjected to a substitution reaction in the presence of a cuprous salt, by which the diazonium cation is replaced by the desired group.
La conversione di un gruppo o R2 in un altro gruppo R1 o R2 avente i significati conpresi dalla formula (I), può comunque avvenire secondo procedure convenzionali familiari al tecnico dell'arte; queste procedure rieadeno negli soopi dell'invenzione, così come le ovvie modifiche ai metodi di preparazione dei composti dell'invenzione appena illustrate. Ad esenpio, un gruppo idrossi può essere convertito in un gruppo acilossi per reazione con il corrispondente cloruro acilice, facoltativanente in pre senza di un'amnina terziaria, ad una temperatura attorno a 0°C. The conversion of a group or R2 into another group R1 or R2 having the meanings understood by formula (I), can in any case take place according to conventional procedures familiar to those skilled in the art; these procedures fall within the scope of the invention, as well as the obvious modifications to the methods of preparation of the compounds of the invention just illustrated. For example, a hydroxy group can be converted into an acyloxy group by reaction with the corresponding acyl chloride, optional in the presence of a tertiary amine, at a temperature around 0 ° C.
Di seguito vengono fom iti esenpi di preparazione di composti rappresentativi dell'invenzione. Examples of preparation of representative compounds of the invention are given below.
I composti di formula (II) e, in generale, i reagenti utilizzati per la sintesi dei ccnposti dell'invenzione, sono ccnposti ccmnercialmente disponibili e/o noti in letteratura (cfr. EP-A-0490183 e EP-A-0 566 018) oppure possono venire sintetizzati da composti cannereialmente disponibili e/o noti in letteratura attraverso metodi conosciuti dall'esperto del ramo. The compounds of formula (II) and, in general, the reagents used for the synthesis of the compounds of the invention, are commercially available and / or known compounds in the literature (see EP-A-0490183 and EP-A-0 566 018 ) or they can be synthesized from cannereially available and / or known compounds in the literature by methods known to the skilled in the art.
ESEMPIO 1 EXAMPLE 1
3-(2'-Acetossietil )-2,3-diidro-6-nitro-7-trifluorcmetil-4H— 1,3-benzossazin-4-one 3- (2'-Acetoxyethyl) -2,3-dihydro-6-nitro-7-trifluorcmethyl-4H— 1,3-benzoxazin-4-one
3 mi (0,07 moli) di acido nitrico fumante al 100% furono gocciolati alla temperatura di -50"C in 3 g (0,013 moli) di N-(2'-acetossietil)-2.3-diidro-7-trifluorometil-4H-l,3-benzossazin-4-one. Al termine dell'aggiunta, la miscela di reazione fu posta sotto agitazione a 0e per 24 ore, e quindi venne versata in ghiaccio e successivamente estratta con cloroformio. La fase organica venne lavata con acqua, idrossido di sodio 0,1 N e nuovamente con acqua,quindi fu anidrificata su solfato di sodio e concentrata a secco. Si ottennero 1,9 g del prodotto del titolo. 3 ml (0.07 mol) of 100% fuming nitric acid was dropped at -50 "C into 3 g (0.013 mol) of N- (2'-acetoxyethyl) -2.3-dihydro-7-trifluoromethyl-4H -1, 3-benzoxazin-4-one. At the end of the addition, the reaction mixture was stirred at 0e for 24 hours, and then poured into ice and subsequently extracted with chloroform. The organic phase was washed with water , 0.1 N sodium hydroxide and again with water, then it was dried over sodium sulfate and concentrated to dryness 1.9 g of the title product were obtained.
1H-NMR (200 MHz,DMSO) 1H-NMR (200 MHz, DMSO)
8,50 (IH, s); 7,82 (IH, s); 5,64 (2H, s); 4,19 (2H, t); 3,75 (2H, t); 2,05 (3H, s). 8.50 (1H, s); 7.82 (1H, s); 5.64 (2H, s); 4.19 (2H, t); 3.75 (2H, t); 2.05 (3H, s).
ESEMPIO 2 EXAMPLE 2
2.3-Piidro-3-(2'-idrossietil)-6-nitro-7-trifluoronietil-4H-l,3-benzossazin-4-cne 2.3-Piidro-3- (2'-hydroxyethyl) -6-nitro-7-trifluoronethyl-4H-1,3-benzoxazin-4-cne
Ad una soluzione di 1,9 g (0,005 moli) del carposto dell'Esempio 1, in 35 mi di metanolo, furono aggiunti 0,3 g (0,003 moli) di carbonato di sodio, e la miscela risultante venne lasciata a terrperatura ambiente per 12 ore. Il residuo grezzo ottenuto dopo evaporazione del solvente fu ripreso con cloruro di metilene, e la risultante fase organica venne lavata con acqua ed essiccata su solfato di sodio. Dopo evaporazione del cloruro di metilene, si ottennero 1,4 g del prodotto del titolo. To a solution of 1.9 g (0.005 moles) of the compound of Example 1, in 35 ml of methanol, 0.3 g (0.003 moles) of sodium carbonate was added, and the resulting mixture was left at room temperature for 12 hours. The crude residue obtained after evaporation of the solvent was taken up with methylene chloride, and the resulting organic phase was washed with water and dried over sodium sulfate. After evaporation of the methylene chloride, 1.4 g of the title product were obtained.
1H-NMR (200 MHz, DMSO) 1H-NMR (200 MHz, DMSO)
8,49 (IH, s); 7,80 (IH, s); 5,61 (2H, s); 4,91 (IH, t); 3,60 (4H, s). ESEMPIO 3 8.49 (1H, s); 7.80 (1H, s); 5.61 (2H, s); 4.91 (1H, t); 3.60 (4H, s). EXAMPLE 3
3-(2 1-Acetossietil)-6-ammino-2,3-diidro-7-trifluororoetil-4H-1,3-benzossazin-4-one 3- (2 1-Acetoxyethyl) -6-amino-2,3-dihydro-7-trifluororoethyl-4H-1,3-benzoxazin-4-one
Una soluzione di 5 g (0,014 moli) del corposto dell'Esempio 1 in 150 mi di metanolo/tetraidrofurano 1:1 (v/v) fu idrogenata a temperatura ambiente e pressione di 2 atm in presenza di 500 mg di Pd/C. Terminato il consumo di idrogeno, la soluzione fu filtrata e portata a secco. Si ottennero 2,7 g del prodotto del titolo. A solution of 5 g (0.014 moles) of the compound of Example 1 in 150 ml of methanol / tetrahydrofuran 1: 1 (v / v) was hydrogenated at room temperature and pressure of 2 atm in the presence of 500 mg of Pd / C. When the hydrogen consumption was over, the solution was filtered and dried. 2.7 g of the title product were obtained.
1H-NMR (200 MHz, DMSO) 1H-NMR (200 MHz, DMSO)
7,38 (IH, s); 7,07 (IH, s); 5,26 (2H, s); 4,20 (2H, t); 3,70 (2H, t); 2,02 (3H, s). 7.38 (1H, s); 7.07 (1H, s); 5.26 (2H, s); 4.20 (2H, t); 3.70 (2H, t); 2.02 (3H, s).
ESEMPIO 4 EXAMPLE 4
6-Ammino -2,3-diidro-3-(2'-idrossietil)-7-trifluoranetil-4H-1,3-benzossazin-4-one 6-Amino -2,3-dihydro-3- (2'-hydroxyethyl) -7-trifluoranethyl-4H-1,3-benzoxazin-4-one
Seguendo la procedura dell'Esempio 2 e partendo da 1 g (0,003 moli) del composto dell'Esempio 3, si ottennero 0,7 g del prodotto del titolo. 1⁄2 -NMR (200 MHz, DM90) Following the procedure of Example 2 and starting from 1 g (0.003 moles) of the compound of Example 3, 0.7 g of the title product were obtained. 1⁄2 -NMR (200 MHz, DM90)
7,37 (1H, s); 7,07 (11, s); 5,26 (2H, s); 4,90 (IH, t); 3,60 (4H, m). 7.37 (1H, s); 7.07 (11, s); 5.26 (2H, s); 4.90 (1H, t); 3.60 (4H, m).
ESEMPIO 5 EXAMPLE 5
3- (2 '-Acetossietil )-2,3-diidro-6-idrossilammino -7-trifluorametil-4H-1 ,3-benzossazin-4-one 3- (2 '-Acetoxyethyl) -2,3-dihydro-6-hydroxylamino -7-trifluoramethyl-4H-1,3-benzoxazin-4-one
Una soluzione di 5 g (0,014 moli) del composto dell'Esempio 1 in 70 mi di tetraidrofurano e 30 mi di etanolo fu idrogenata a pressione e temperatura ambiente in presenza di 500 mg di Pd/C. Esaurito il consumo di idrogeno, la soluzione fu filtrata ed evaporata a secco. Si ottennero 2,4 g del prodotto del titolo. A solution of 5 g (0.014 moles) of the compound of Example 1 in 70 ml of tetrahydrofuran and 30 ml of ethanol was hydrogenated at room temperature and pressure in the presence of 500 mg of Pd / C. When the hydrogen consumption was exhausted, the solution was filtered and evaporated to dryness. 2.4 g of the title product were obtained.
1H-NMR (200 MHz, DMSO) 1H-NMR (200 MHz, DMSO)
8,75 (1H, s); 8,34 (IH, s); 7,80 (IH, s); 7,22 (1H, s); 5,29 (2H, s); 4,21 (2H, t); 3,72 (2H, t); 2,00 (3H, s). 8.75 (1H, s); 8.34 (1H, s); 7.80 (1H, s); 7.22 (1H, s); 5.29 (2H, s); 4.21 (2H, t); 3.72 (2H, t); 2.00 (3H, s).
ESEMPIO 6 EXAMPLE 6
2 ,3-Diidro-3- (21-idrossietil )-6-idrossilammino -7-trifluoro-metil-4H-1 ,3-benzossazin-4-cne 2,3-Dihydro-3- (21-hydroxyethyl) -6-hydroxylamino -7-trifluoro-methyl-4H-1,3-benzoxazine-4-cne
Seguendo la procedura dell'Esempio 2 e partendo da 2 g (0,006 moli) del composto dell'Esenpio 5, si ottennero 1,3 g del prodotto del titolo. Following the procedure of Example 2 and starting from 2 g (0.006 moles) of the compound of Example 5, 1.3 g of the title product were obtained.
1H-NMR (200 MHz, DMS0) 1H-NMR (200 MHz, DMS0)
8,74 (IH, s); 8,33 (IH, s); 7,81 (IH, s); 7,21 (IH, s); 5,28 (2H, s); 4,90 (IH, t); 3,55 (4H, s). 8.74 (1H, s); 8.33 (1H, s); 7.81 (1H, s); 7.21 (1H, s); 5.28 (2H, s); 4.90 (1H, t); 3.55 (4H, s).
ESEMPIO 7 EXAMPLE 7
3- (2'-Acetossietil)-2 ,3-diidro-7-metil-6-nitro-4H-l ,3-benzossazin-4-one Seguendo la procedura dell'Esenpio 1 e partendo da 2 g (0,008 moli) di 3-(2'-acetossietil)-2,3-diidro-7-metil-4H-1,3-benzossazin-4-one, si ottennero 1,5 g del prodotto del titolo. 3- (2'-Acetoxyethyl) -2, 3-dihydro-7-methyl-6-nitro-4H-1, 3-benzoxazin-4-one Following the procedure of Example 1 and starting from 2 g (0.008 mol) of 3- (2'-acetoxyethyl) -2,3-dihydro-7-methyl-4H-1,3-benzoxazin-4-one, 1.5 g of the title product were obtained.
1H-NMR (200 MHz, DMSO) 1H-NMR (200 MHz, DMSO)
8,40 (IH, s); 7,28 (IH, s); 5,50 (2H, s); 4,20 (2H, t); 3,70 (2H, t); 2,60 (3H, s); 2,00 (3H, s). 8.40 (1H, s); 7.28 (1H, s); 5.50 (2H, s); 4.20 (2H, t); 3.70 (2H, t); 2.60 (3H, s); 2.00 (3H, s).
ESEMPIO 8 EXAMPLE 8
2,3-Diidro-3-(2'-idrossietil)-7-metil-6-nitro-4H-1,3-benzossazin-4-one Seguendo la procedura dell'Esempio 2 e partendo da 1,5 g (0,005 moli) del composto dell’Esenpio 7, si ottennero 0,9 g del prodotto del titolo. 2,3-Dihydro-3- (2'-hydroxyethyl) -7-methyl-6-nitro-4H-1,3-benzoxazin-4-one Following the procedure of Example 2 and starting from 1.5 g (0.005 moles) of the compound of Example 7, 0.9 g of the title product were obtained.
1H-NMR (200 MHz, DMSO) 1H-NMR (200 MHz, DMSO)
8,39 (IH, s); 7,29 (IH, s); 5,48 (2H, s); 4,90 (IH, t); 3,62 (4H, s>. 8.39 (1H, s); 7.29 (1H, s); 5.48 (2H, s); 4.90 (1H, t); 3.62 (4H, s>.
ESH4PIO 9 ESH4PIO 9
6-3⁄4nnino-2,3-diidro>3-(2'-idrossietil)-7-metil-4H-l,3-benzossazin—4-cne Seguendo la procedura dell'Esenpio 3 e partendo da 4 g (0,013 moli) del composto dell'Esenpio 8, si ottennero 2,6 g del prodotto del titolo, p.f.: 160-163°C (etere etilico) 6-3⁄4nnino-2,3-dihydro> 3- (2'-hydroxyethyl) -7-methyl-4H-1,3-benzoxazin-4-cne Following the procedure of Example 3 and starting from 4 g (0.013 moles) of the compound of Example 8, 2.6 g of the title product were obtained, m.p .: 160-163 ° C (ethyl ether)
1⁄2-NMR (200 MHz, DMSO) 1⁄2-NMR (200 MHz, DMSO)
7.10 (IH, s); 6,70 (IH, s); 5,19 (2H, s); 4,85 (IH, t); 3,55 (4H, m); 2.10 (3H, s). 7.10 (1H, s); 6.70 (1H, s); 5.19 (2H, s); 4.85 (1H, t); 3.55 (4H, m); 2.10 (3H, s).
ESEMPIO 10 EXAMPLE 10
6-Acetanmino-2,3-diidro-3-(2'-idrossietil)-7-metil-4H~l,3-benzossazin-4-one 6-Acetanmino-2,3-dihydro-3- (2'-hydroxyethyl) -7-methyl-4H ~ 1,3-benzoxazin-4-one
A 50 mi di cloroformio a 0eC furono aggiunti 3 g (0,013 moli) del composto dell'Esenpio 9 e 1,4 g (0,014 moli) di trietilanmina. Nella sospensione così ottenuta furono gocciolati 2,3 g (0,003 moli) di cloruro di acetile. La soluzione risultante fu lasciata sotto agitazione per 1 ora a 0"C, e successivamente per 18 ore sotto agitazione a temperatura ambiente. Al termine la soluzione fu lavata prima con acqua, poi con bicarbonato di sodio al 5eyi, e nuovamente con acqua, poi concentrata a secco. Il solido ottenuto fu trattato con idrossido di sodio IN, concentrato a piccolo volume e ripreso con cloroformio. La fase organica fu separata, lavata con acqua, anidrif icata e concentrata a secco, ottenendo, dopo cristallizzazione, 1,1 g del prodotto del titolo. 3 g (0.013 moles) of the compound of Example 9 and 1.4 g (0.014 moles) of triethylanine were added to 50 ml of chloroform at 0eC. 2.3 g (0.003 moles) of acetyl chloride were dropped into the suspension thus obtained. The resulting solution was left under stirring for 1 hour at 0 "C, and subsequently for 18 hours under stirring at room temperature. At the end the solution was washed first with water, then with 5eyi sodium bicarbonate, and again with water, then The solid obtained was treated with 1N sodium hydroxide, concentrated to a small volume and taken up with chloroform. The organic phase was separated, washed with water, anhydrified and concentrated to dryness, obtaining, after crystallization, 1.1 g of the title product.
ESEMPIO 11 EXAMPLE 11
A) 9 g (0,05 moli) di 5-formil-salicilato di metile in 3,9 mi di 2-amminoetanolo vennero scaldati a 170°C per 3 ore. Dopo raffreddamento a temperatura ambiente la miscela di reazione fu ripresa con acetato di etile, lavata con acido cloridrico al 5% ed essiccata su solfato di sodio. Si ottennero 4 g di 5-fomill-N-(2·-idrossietil)salicilammide,che fu usata come tale nella fase successiva. B) 3 g (0,0014 moli) del composto ottenuto in A) e 0,2 g (0,0013 moli) di acido p-toluensolfcnico furono sciolti in 70 mi di benzene,e 1,5 g di paraformaldeide furono aggiunti alla soluzione cosi ottenuta. La miscela venne scaldata a 90°C per 3 ore,distillando via l'acqua formatasi, e dopo raffreddamento atemperatura ambiente, lavata con acqua. La fase organica venne recuperata, e dopo evaporazione del solvente, si ottenne un residuo che fu disciolto in 150 mi di tetraidrofurano e 14 mi di HC1 -1N La miscela fu posta a riflusso per 8 ore e, dopo raffre ddamento a temperatura ambiente, estratta ccn acetato di etile. Dopo anidrificazione ed evaporazione sotto vuoto della fase organica, si ottennero 1,3 g del prodotto del titolo. 1 H-NMR (200 MHz, DM90) A) 9 g (0.05 moles) of methyl 5-formyl-salicylate in 3.9 ml of 2-aminoethanol were heated at 170 ° C for 3 hours. After cooling to room temperature the reaction mixture was taken up with ethyl acetate, washed with 5% hydrochloric acid and dried over sodium sulphate. 4 g of 5-fomyl-N- (2 · -hydroxyethyl) salicylamide were obtained, which was used as such in the next step. B) 3 g (0.0014 moles) of the compound obtained in A) and 0.2 g (0.0013 moles) of p-toluenesulfenic acid were dissolved in 70 ml of benzene, and 1.5 g of paraformaldehyde were added to the solution thus obtained. The mixture was heated to 90 ° C for 3 hours, distilling away the water formed, and after cooling to room temperature, washed with water. The organic phase was recovered, and after evaporation of the solvent, a residue was obtained which was dissolved in 150 ml of tetrahydrofuran and 14 ml of HCl -1N The mixture was refluxed for 8 hours and, after cooling to room temperature, extracted with ethyl acetate. After drying and evaporation of the organic phase under vacuum, 1.3 g of the title product were obtained. 1 H-NMR (200 MHz, DM90)
10,00 (IH, s); 8,40 (IH, s); 8,06 (IH, dd); 7,30 (IH, d); 5,50 (2H, s); 4,92 (IH, t); 4,59 (4H, s). 10.00 (1H, s); 8.40 (1H, s); 8.06 (1H, dd); 7.30 (1H, d); 5.50 (2H, s); 4.92 (1H, t); 4.59 (4H, s).
ES9PIO 12 EXAMPLE 12
6-Ac etarimino-2 ,3-diidro-3- (2 '-acetossietil )-7-trifluorometil-4H-l ,3-benzossa2Ìn-4-one 6-Acetarimino-2,3-dihydro-3- (2 '-acetoxyethyl) -7-trifluoromethyl-4H-1,3-benzoxy2n-4-one
Seguendo la procedura dell 'Esempio 10, e partendo da 2 g (0,0006 moli) del composto dell 'Esempio 3, si ottennero 1,2 g di un gre zzo che venne sciolto in una miscela composta da 25 mi di tetraidrofurano e 12 mi di idrossido di sodio IN. La miscela venne lasciata a sè a tenperatura ambiente per 3 ore, quindi estratta ccn cloroformio, e la fase organica venne anidrificata ed evaporata. Il gre zzo così ottenuto venne purificato per flash-crcmatografia (eluente: cloroformio /acetone 8:2), fornendo 300 mg del prodotto del titolo, Following the procedure of Example 10, and starting from 2 g (0.0006 moles) of the compound of Example 3, 1.2 g of a crude were obtained which was dissolved in a mixture composed of 25 ml of tetrahydrofuran and 12 ml of sodium hydroxide IN. The mixture was left alone at room temperature for 3 hours, then extracted with chloroform, and the organic phase was dried and evaporated. The crude thus obtained was purified by flash-chromatography (eluent: chloroform / acetone 8: 2), giving 300 mg of the title product,
p.f.: 161-162®C (cloroformio /acetone) m.p .: 161-162®C (chloroform / acetone)
1H -NMR (200 MHz, DMSO) 1H -NMR (200 MHz, DMSO)
9,61 (IH, s); 7,80 (IH, s); 7,44 (IH, s); 5,44 (2H, s); 4,91 (IH, t); 3,58 (4H, m); 2,06 (3H, s). 9.61 (1H, s); 7.80 (1H, s); 7.44 (1H, s); 5.44 (2H, s); 4.91 (1H, t); 3.58 (4H, m); 2.06 (3H, s).
Come affermato sopra, i carposti dell'invenzione possiedono attività cardiovascolare . In particolare , essi hanno mostrato una notevole attività antianginosa nell'animale da laboratorio. As stated above, the compounds of the invention possess cardiovascular activity. In particular, they showed considerable antianginal activity in the laboratory animal.
Pertanto, è compreso ne 11'ambito della presente invenzione l'uso dei composti di formula I come principi attivi nella terapia antianginosa. Therefore, the use of the compounds of formula I as active ingredients in antianginal therapy is included within the scope of the present invention.
L'attività antianginosa in vivo è stata determinata su ratti anestetizzati di ceppo Sprague Dawley (peso medio - 350-400 g.), operando secondo la metodica di M. Leitold et al., Arzneim. Forsch. 36, 1454, 1986. Il test viene condotto somministrando per via endovenosa all'animale 1 U.I./kg, pari a 3 mg/kg, di Arg-vasopressina la quale induce uno spasmo coronarico riproducibile ed evidenziabile elettrocardiograficamente con un aumento dell'onda T. Gli animali venivano poi trattati endovena con quattro dosi crescenti di composti rappresentativi dell'invenzione allo scopo di misurarne la ED50, cioè la dose in grado di dare il 50% di inibizione sulla crescita dell'onda T. I composti dell'invenzione testati hanno mostrato valori di ED50 conpresi tra circa 1 e circa 300 μg/Kg. The antianginal activity in vivo was determined on anesthetized rats of the Sprague Dawley strain (average weight - 350-400 g.), Operating according to the method of M. Leitold et al., Arzneim. Forsch. 36, 1454, 1986. The test is conducted by administering intravenously to the animal 1 I.U./kg, equal to 3 mg / kg, of Arg-vasopressin which induces a reproducible and electrocardiographically detectable coronary spasm with an increase in the T wave. The animals were then treated intravenously with four increasing doses of compounds representative of the invention in order to measure their ED50, that is the dose capable of giving 50% inhibition on the growth of the T wave. The compounds of the invention tested have ED50 values included between about 1 and about 300 μg / Kg.
Le favorevoli proprietà biologiche sopra riportate, sono inoltre accompagnate da una bassa tossicità: i valori di LD,50# determinati secondo il metodo di Lichtfield e Wilcoxcn, J. Pharm. Expt. Iher. 96, 99, 1949, sono infatti superiori a 500 mg/kg i.p. nel topo e 800 mg/kg p.o. nel ratto. The above mentioned favorable biological properties are also accompanied by a low toxicity: the LD values, 50 # determined according to the method of Lichtfield and Wilcoxcn, J. Pharm. Expt. Iher. 96, 99, 1949, are in fact higher than 500 mg / kg i.p. in mice and 800 mg / kg p.o. in the rat.
Oggetto della presente invenzione è altresì l'uso dei nuovi ccrposti come agenti antianginosi e agenti utili nel trattamento delle cardiopatie ischemiche, con attinenza agli atti e agli aspetti industrialmente applicabili di detto uso, inclusa la loro incorporazione in oorrposizioni farmaceutiche. Esempi di tali conposizioni farmaceutiche sono le compre sse, i confetti, gli sciroppi e le fiale, queste ultime adatte sia per la somministrazione orale che per quella intramuscolare o endovenosa. Esse contengono il principio attivo da solo o in unione con i comuni veicoli ed eccipienti farmaceuticamente accettabili. The object of the present invention is also the use of the new compounds as antianginal agents and agents useful in the treatment of ischemic heart disease, with relevance to the industrially applicable acts and aspects of said use, including their incorporation in pharmaceutical compositions. Examples of such pharmaceutical compositions are packets, sugared almonds, syrups and vials, the latter suitable for both oral and intramuscular or intravenous administration. They contain the active ingredient alone or in conjunction with the common pharmaceutically acceptable carriers and excipients.
Le composizioni oggetto dell'invenzione sono preparate con tecniche note all'esperto del settore, come ad esempio descritto in "Remington's Pharmaceutical Sciences Handbook", Mack Pub. Ine. USA. The compositions object of the invention are prepared with techniques known to those skilled in the art, as described for example in "Remington's Pharmaceutical Sciences Handbook", Mack Pub. Ine. USA.
I dosaggi di principio attivo usati per coniattere gli attacchi anginosi e per curare le cardiopatie ischemiche possono variare entro ampi limiti a seconda della natura del ccnposto inpiegato e sono scelti in modo da assicurare al paziente la più efficace copertura terapeutica nell'arco delle 24 ore. Ad esempio, si possono utilizzare dosi unitarie da circa 0,01 a 1 mg da somministrarsi da 1 a 4 volte al giorno, a seconda delle necessità del paziente (profilassi, terapia o attacco acuto). The dosages of the active ingredient used to treat anginal attacks and to treat ischemic heart disease can vary within wide limits depending on the nature of the used component and are chosen in such a way as to ensure the patient the most effective therapeutic coverage within 24 hours. For example, unit doses of about 0.01 to 1 mg can be used to be administered 1 to 4 times a day, depending on the patient's needs (prophylaxis, therapy or acute attack).
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