EP0837864A1 - Nouveaux acides quinoxaline- et quinoxalinylalkane-phosphoniques - Google Patents
Nouveaux acides quinoxaline- et quinoxalinylalkane-phosphoniquesInfo
- Publication number
- EP0837864A1 EP0837864A1 EP96924829A EP96924829A EP0837864A1 EP 0837864 A1 EP0837864 A1 EP 0837864A1 EP 96924829 A EP96924829 A EP 96924829A EP 96924829 A EP96924829 A EP 96924829A EP 0837864 A1 EP0837864 A1 EP 0837864A1
- Authority
- EP
- European Patent Office
- Prior art keywords
- acid
- quinoxalin
- tetrahydro
- dioxo
- free
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Withdrawn
Links
- 150000003839 salts Chemical class 0.000 claims abstract description 52
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 42
- 239000001257 hydrogen Substances 0.000 claims abstract description 42
- 229910052736 halogen Inorganic materials 0.000 claims abstract description 23
- 150000002367 halogens Chemical class 0.000 claims abstract description 23
- 125000001476 phosphono group Chemical group [H]OP(*)(=O)O[H] 0.000 claims abstract description 23
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims abstract description 22
- 125000003396 thiol group Chemical class [H]S* 0.000 claims abstract description 19
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims abstract description 18
- 150000002431 hydrogen Chemical class 0.000 claims abstract description 17
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims abstract description 17
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims abstract description 13
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims abstract description 11
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims abstract description 9
- 125000004397 aminosulfonyl group Chemical group NS(=O)(=O)* 0.000 claims abstract description 8
- 125000004093 cyano group Chemical group *C#N 0.000 claims abstract description 6
- 230000000903 blocking effect Effects 0.000 claims abstract description 3
- 230000001575 pathological effect Effects 0.000 claims abstract description 3
- -1 nitro, carboxy Chemical group 0.000 claims description 104
- 150000001875 compounds Chemical class 0.000 claims description 95
- 239000002253 acid Substances 0.000 claims description 32
- 125000000217 alkyl group Chemical group 0.000 claims description 25
- 239000000203 mixture Substances 0.000 claims description 21
- 238000000034 method Methods 0.000 claims description 20
- 125000003545 alkoxy group Chemical group 0.000 claims description 16
- 230000008569 process Effects 0.000 claims description 16
- 125000005115 alkyl carbamoyl group Chemical group 0.000 claims description 14
- 125000004453 alkoxycarbonyl group Chemical group 0.000 claims description 12
- 238000002360 preparation method Methods 0.000 claims description 11
- 239000008194 pharmaceutical composition Substances 0.000 claims description 10
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 9
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 9
- 125000003342 alkenyl group Chemical group 0.000 claims description 7
- 125000003282 alkyl amino group Chemical group 0.000 claims description 7
- 125000004390 alkyl sulfonyl group Chemical group 0.000 claims description 7
- 125000004414 alkyl thio group Chemical group 0.000 claims description 7
- 125000001118 alkylidene group Chemical group 0.000 claims description 7
- 125000004644 alkyl sulfinyl group Chemical group 0.000 claims description 6
- 125000002947 alkylene group Chemical group 0.000 claims description 6
- 125000000304 alkynyl group Chemical group 0.000 claims description 6
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims description 6
- UOZUJQGSHJMDSB-UHFFFAOYSA-N (2,3-dioxo-1,4-dihydroquinoxalin-5-yl)methylphosphonic acid Chemical compound N1C(=O)C(=O)NC2=C1C=CC=C2CP(O)(=O)O UOZUJQGSHJMDSB-UHFFFAOYSA-N 0.000 claims description 5
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- QIKGBPGSUJXLBC-UHFFFAOYSA-N 4-(2,3-dioxo-1,4-dihydroquinoxalin-5-yl)but-3-enylphosphonic acid Chemical compound N1C(=O)C(=O)NC2=C1C=CC=C2C=CCCP(O)(=O)O QIKGBPGSUJXLBC-UHFFFAOYSA-N 0.000 claims description 4
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- 125000003754 ethoxycarbonyl group Chemical group C(=O)(OCC)* 0.000 claims description 4
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- 125000001160 methoxycarbonyl group Chemical group [H]C([H])([H])OC(*)=O 0.000 claims description 4
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- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 3
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- QLNKZDJMXWACGQ-UHFFFAOYSA-N (7-bromo-3-methoxy-2-oxo-3,4-dihydro-1h-quinoxalin-5-yl)methylphosphonic acid Chemical compound C1=C(Br)C=C2NC(=O)C(OC)NC2=C1CP(O)(O)=O QLNKZDJMXWACGQ-UHFFFAOYSA-N 0.000 claims description 2
- QUOCHZXXHRECAQ-UHFFFAOYSA-N (7-bromo-6-nitro-2,3-dioxo-1,4-dihydroquinoxalin-5-yl)methylphosphonic acid Chemical compound N1C(=O)C(=O)NC2=C1C=C(Br)C([N+]([O-])=O)=C2CP(O)(=O)O QUOCHZXXHRECAQ-UHFFFAOYSA-N 0.000 claims description 2
- GZDJSOJULKHOIW-UHFFFAOYSA-N 1-(2,3-dioxo-1,4-dihydroquinoxalin-5-yl)ethylphosphonic acid Chemical compound N1C(=O)C(=O)NC2=C1C=CC=C2C(C)P(O)(O)=O GZDJSOJULKHOIW-UHFFFAOYSA-N 0.000 claims description 2
- BABPOUFHWOCNNS-UHFFFAOYSA-N 2-(2,3-dioxo-1,4-dihydroquinoxalin-5-yl)ethenylphosphonic acid Chemical compound N1C(=O)C(=O)NC2=C1C=CC=C2C=CP(O)(=O)O BABPOUFHWOCNNS-UHFFFAOYSA-N 0.000 claims description 2
- OCFXRQBTOUGKRB-UHFFFAOYSA-N 2-(2,3-dioxo-1,4-dihydroquinoxalin-5-yl)ethylphosphonic acid Chemical compound N1C(=O)C(=O)NC2=C1C=CC=C2CCP(O)(=O)O OCFXRQBTOUGKRB-UHFFFAOYSA-N 0.000 claims description 2
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- RMDXKUMEYLOUJB-UHFFFAOYSA-N 3-(2,3-dioxo-1,4-dihydroquinoxalin-5-yl)prop-2-enylphosphonic acid Chemical compound N1C(=O)C(=O)NC2=C1C=CC=C2C=CCP(O)(=O)O RMDXKUMEYLOUJB-UHFFFAOYSA-N 0.000 claims description 2
- HCVMXBCSVAQMSV-UHFFFAOYSA-N 3-(2,3-dioxo-1,4-dihydroquinoxalin-5-yl)prop-2-ynylphosphonic acid Chemical compound N1C(=O)C(=O)NC2=C1C=CC=C2C#CCP(O)(=O)O HCVMXBCSVAQMSV-UHFFFAOYSA-N 0.000 claims description 2
- IRMAUQFNMCPNKR-UHFFFAOYSA-N 3-(2,3-dioxo-1,4-dihydroquinoxalin-5-yl)propylphosphonic acid Chemical compound N1C(=O)C(=O)NC2=C1C=CC=C2CCCP(O)(=O)O IRMAUQFNMCPNKR-UHFFFAOYSA-N 0.000 claims description 2
- UWZRCGOFRIWUQT-UHFFFAOYSA-N 3-(7-bromo-2,3-dioxo-1,4-dihydroquinoxalin-5-yl)propylphosphonic acid Chemical compound N1C(=O)C(=O)NC2=C1C=C(Br)C=C2CCCP(O)(=O)O UWZRCGOFRIWUQT-UHFFFAOYSA-N 0.000 claims description 2
- DIWCSSZWIWIHJC-UHFFFAOYSA-N 4-(2,3-dioxo-1,4-dihydroquinoxalin-5-yl)but-1-enylphosphonic acid Chemical compound N1C(=O)C(=O)NC2=C1C=CC=C2CCC=CP(O)(=O)O DIWCSSZWIWIHJC-UHFFFAOYSA-N 0.000 claims description 2
- WTGPQJYRMFTPLH-UHFFFAOYSA-N 4-(2,3-dioxo-1,4-dihydroquinoxalin-5-yl)butylphosphonic acid Chemical compound N1C(=O)C(=O)NC2=C1C=CC=C2CCCCP(O)(=O)O WTGPQJYRMFTPLH-UHFFFAOYSA-N 0.000 claims description 2
- UCOYQIJKIGUGSB-UHFFFAOYSA-N 4-(7-chloro-2,3-dioxo-1,4-dihydroquinoxalin-5-yl)but-1-enylphosphonic acid Chemical compound N1C(=O)C(=O)NC2=C1C=C(Cl)C=C2CCC=CP(O)(=O)O UCOYQIJKIGUGSB-UHFFFAOYSA-N 0.000 claims description 2
- MQGNUGIYISGXJZ-UHFFFAOYSA-N 4-(7-chloro-2,3-dioxo-1,4-dihydroquinoxalin-5-yl)but-3-enylphosphonic acid Chemical compound N1C(=O)C(=O)NC2=C1C=C(Cl)C=C2C=CCCP(O)(=O)O MQGNUGIYISGXJZ-UHFFFAOYSA-N 0.000 claims description 2
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- PZKZUTUIEQATQD-UHFFFAOYSA-N 3-(7-bromo-2,3-dioxo-1,4-dihydroquinoxalin-5-yl)prop-2-enylphosphonic acid Chemical compound N1C(=O)C(=O)NC2=C1C=C(Br)C=C2C=CCP(O)(=O)O PZKZUTUIEQATQD-UHFFFAOYSA-N 0.000 claims 1
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- QMGVPVSNSZLJIA-UHFFFAOYSA-N Nux Vomica Natural products C1C2C3C4N(C=5C6=CC=CC=5)C(=O)CC3OCC=C2CN2C1C46CC2 QMGVPVSNSZLJIA-UHFFFAOYSA-N 0.000 description 1
- 240000007594 Oryza sativa Species 0.000 description 1
- 235000007164 Oryza sativa Nutrition 0.000 description 1
- 241000282320 Panthera leo Species 0.000 description 1
- 239000005662 Paraffin oil Substances 0.000 description 1
- 241000183024 Populus tremula Species 0.000 description 1
- AAWZDTNXLSGCEK-ZHQZDSKASA-N Quinic acid Natural products O[C@H]1CC(O)(C(O)=O)C[C@H](O)C1O AAWZDTNXLSGCEK-ZHQZDSKASA-N 0.000 description 1
- BLRPTPMANUNPDV-UHFFFAOYSA-N Silane Chemical compound [SiH4] BLRPTPMANUNPDV-UHFFFAOYSA-N 0.000 description 1
- 229930006000 Sucrose Natural products 0.000 description 1
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 1
- 229920001615 Tragacanth Polymers 0.000 description 1
- GSEJCLTVZPLZKY-UHFFFAOYSA-N Triethanolamine Chemical compound OCCN(CCO)CCO GSEJCLTVZPLZKY-UHFFFAOYSA-N 0.000 description 1
- 235000021307 Triticum Nutrition 0.000 description 1
- 244000098338 Triticum aestivum Species 0.000 description 1
- 240000008042 Zea mays Species 0.000 description 1
- 235000005824 Zea mays ssp. parviglumis Nutrition 0.000 description 1
- 235000002017 Zea mays subsp mays Nutrition 0.000 description 1
- SMEGJBVQLJJKKX-HOTMZDKISA-N [(2R,3S,4S,5R,6R)-5-acetyloxy-3,4,6-trihydroxyoxan-2-yl]methyl acetate Chemical compound CC(=O)OC[C@@H]1[C@H]([C@@H]([C@H]([C@@H](O1)O)OC(=O)C)O)O SMEGJBVQLJJKKX-HOTMZDKISA-N 0.000 description 1
- 235000010489 acacia gum Nutrition 0.000 description 1
- 239000000205 acacia gum Substances 0.000 description 1
- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 description 1
- 229940081735 acetylcellulose Drugs 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 230000006978 adaptation Effects 0.000 description 1
- 239000008272 agar Substances 0.000 description 1
- 235000010419 agar Nutrition 0.000 description 1
- 230000001476 alcoholic effect Effects 0.000 description 1
- 150000001299 aldehydes Chemical class 0.000 description 1
- 235000010443 alginic acid Nutrition 0.000 description 1
- 239000000783 alginic acid Substances 0.000 description 1
- 229920000615 alginic acid Polymers 0.000 description 1
- 229960001126 alginic acid Drugs 0.000 description 1
- 150000004781 alginic acids Chemical class 0.000 description 1
- 150000008044 alkali metal hydroxides Chemical class 0.000 description 1
- 150000001340 alkali metals Chemical class 0.000 description 1
- 150000001447 alkali salts Chemical class 0.000 description 1
- 229910052784 alkaline earth metal Inorganic materials 0.000 description 1
- 229930013930 alkaloid Natural products 0.000 description 1
- 150000003797 alkaloid derivatives Chemical class 0.000 description 1
- 125000005907 alkyl ester group Chemical group 0.000 description 1
- 150000001350 alkyl halides Chemical class 0.000 description 1
- 150000001351 alkyl iodides Chemical class 0.000 description 1
- 125000005103 alkyl silyl group Chemical group 0.000 description 1
- 239000002168 alkylating agent Substances 0.000 description 1
- 229940100198 alkylating agent Drugs 0.000 description 1
- BHELZAPQIKSEDF-UHFFFAOYSA-N allyl bromide Chemical compound BrCC=C BHELZAPQIKSEDF-UHFFFAOYSA-N 0.000 description 1
- 125000005336 allyloxy group Chemical group 0.000 description 1
- BJEPYKJPYRNKOW-UHFFFAOYSA-N alpha-hydroxysuccinic acid Natural products OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 description 1
- VSCWAEJMTAWNJL-UHFFFAOYSA-K aluminium trichloride Chemical compound Cl[Al](Cl)Cl VSCWAEJMTAWNJL-UHFFFAOYSA-K 0.000 description 1
- 229910021529 ammonia Inorganic materials 0.000 description 1
- 235000011114 ammonium hydroxide Nutrition 0.000 description 1
- 150000003863 ammonium salts Chemical class 0.000 description 1
- 229940025084 amphetamine Drugs 0.000 description 1
- 239000003708 ampul Substances 0.000 description 1
- 230000003042 antagnostic effect Effects 0.000 description 1
- 230000002082 anti-convulsion Effects 0.000 description 1
- 230000001663 anti-spastic effect Effects 0.000 description 1
- 229910052788 barium Inorganic materials 0.000 description 1
- DSAJWYNOEDNPEQ-UHFFFAOYSA-N barium atom Chemical compound [Ba] DSAJWYNOEDNPEQ-UHFFFAOYSA-N 0.000 description 1
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 1
- 125000001584 benzyloxycarbonyl group Chemical group C(=O)(OCC1=CC=CC=C1)* 0.000 description 1
- IYYIVELXUANFED-UHFFFAOYSA-N bromo(trimethyl)silane Chemical compound C[Si](C)(C)Br IYYIVELXUANFED-UHFFFAOYSA-N 0.000 description 1
- RRKTZKIUPZVBMF-IBTVXLQLSA-N brucine Chemical compound O([C@@H]1[C@H]([C@H]2C3)[C@@H]4N(C(C1)=O)C=1C=C(C(=CC=11)OC)OC)CC=C2CN2[C@@H]3[C@]41CC2 RRKTZKIUPZVBMF-IBTVXLQLSA-N 0.000 description 1
- RRKTZKIUPZVBMF-UHFFFAOYSA-N brucine Natural products C1=2C=C(OC)C(OC)=CC=2N(C(C2)=O)C3C(C4C5)C2OCC=C4CN2C5C31CC2 RRKTZKIUPZVBMF-UHFFFAOYSA-N 0.000 description 1
- 125000004106 butoxy group Chemical group [*]OC([H])([H])C([H])([H])C(C([H])([H])[H])([H])[H] 0.000 description 1
- 125000006309 butyl amino group Chemical group 0.000 description 1
- 239000011575 calcium Substances 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
- FUFJGUQYACFECW-UHFFFAOYSA-L calcium hydrogenphosphate Chemical compound [Ca+2].OP([O-])([O-])=O FUFJGUQYACFECW-UHFFFAOYSA-L 0.000 description 1
- 235000011010 calcium phosphates Nutrition 0.000 description 1
- CJZGTCYPCWQAJB-UHFFFAOYSA-L calcium stearate Chemical compound [Ca+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O CJZGTCYPCWQAJB-UHFFFAOYSA-L 0.000 description 1
- 235000013539 calcium stearate Nutrition 0.000 description 1
- 239000008116 calcium stearate Substances 0.000 description 1
- 125000001589 carboacyl group Chemical group 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 125000004432 carbon atom Chemical group C* 0.000 description 1
- 239000001768 carboxy methyl cellulose Substances 0.000 description 1
- 150000001735 carboxylic acids Chemical class 0.000 description 1
- 125000002057 carboxymethyl group Chemical group [H]OC(=O)C([H])([H])[*] 0.000 description 1
- 238000009903 catalytic hydrogenation reaction Methods 0.000 description 1
- 229920002301 cellulose acetate Polymers 0.000 description 1
- 239000000460 chlorine Substances 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 229960001701 chloroform Drugs 0.000 description 1
- KMPWYEUPVWOPIM-UHFFFAOYSA-N cinchonidine Natural products C1=CC=C2C(C(C3N4CCC(C(C4)C=C)C3)O)=CC=NC2=C1 KMPWYEUPVWOPIM-UHFFFAOYSA-N 0.000 description 1
- KMPWYEUPVWOPIM-LSOMNZGLSA-N cinchonine Chemical compound C1=CC=C2C([C@@H]([C@H]3N4CC[C@H]([C@H](C4)C=C)C3)O)=CC=NC2=C1 KMPWYEUPVWOPIM-LSOMNZGLSA-N 0.000 description 1
- LOUPRKONTZGTKE-UHFFFAOYSA-N cinchonine Natural products C1C(C(C2)C=C)CCN2C1C(O)C1=CC=NC2=CC=C(OC)C=C21 LOUPRKONTZGTKE-UHFFFAOYSA-N 0.000 description 1
- 239000011248 coating agent Substances 0.000 description 1
- 239000000470 constituent Substances 0.000 description 1
- LSXDOTMGLUJQCM-UHFFFAOYSA-M copper(i) iodide Chemical compound I[Cu] LSXDOTMGLUJQCM-UHFFFAOYSA-M 0.000 description 1
- 235000005822 corn Nutrition 0.000 description 1
- KWGRBVOPPLSCSI-UHFFFAOYSA-N d-ephedrine Natural products CNC(C)C(O)C1=CC=CC=C1 KWGRBVOPPLSCSI-UHFFFAOYSA-N 0.000 description 1
- 125000004915 dibutylamino group Chemical group C(CCC)N(CCCC)* 0.000 description 1
- 235000019700 dicalcium phosphate Nutrition 0.000 description 1
- 125000003963 dichloro group Chemical group Cl* 0.000 description 1
- YNHIGQDRGKUECZ-UHFFFAOYSA-N dichloropalladium;triphenylphosphanium Chemical compound Cl[Pd]Cl.C1=CC=CC=C1[PH+](C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1[PH+](C=1C=CC=CC=1)C1=CC=CC=C1 YNHIGQDRGKUECZ-UHFFFAOYSA-N 0.000 description 1
- 235000014113 dietary fatty acids Nutrition 0.000 description 1
- 235000013681 dietary sucrose Nutrition 0.000 description 1
- ZBCBWPMODOFKDW-UHFFFAOYSA-N diethanolamine Chemical compound OCCNCCO ZBCBWPMODOFKDW-UHFFFAOYSA-N 0.000 description 1
- WYACBZDAHNBPPB-UHFFFAOYSA-N diethyl oxalate Chemical compound CCOC(=O)C(=O)OCC WYACBZDAHNBPPB-UHFFFAOYSA-N 0.000 description 1
- HPNMFZURTQLUMO-UHFFFAOYSA-N diethylamine Chemical compound CCNCC HPNMFZURTQLUMO-UHFFFAOYSA-N 0.000 description 1
- 238000006073 displacement reaction Methods 0.000 description 1
- 239000012153 distilled water Substances 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 239000003937 drug carrier Substances 0.000 description 1
- 239000000975 dye Substances 0.000 description 1
- 239000002702 enteric coating Substances 0.000 description 1
- 238000009505 enteric coating Methods 0.000 description 1
- 229960002179 ephedrine Drugs 0.000 description 1
- 125000005678 ethenylene group Chemical group [H]C([*:1])=C([H])[*:2] 0.000 description 1
- 239000012259 ether extract Substances 0.000 description 1
- DQYBDCGIPTYXML-UHFFFAOYSA-N ethoxyethane;hydrate Chemical compound O.CCOCC DQYBDCGIPTYXML-UHFFFAOYSA-N 0.000 description 1
- LVGKNOAMLMIIKO-QXMHVHEDSA-N ethyl oleate Chemical compound CCCCCCCC\C=C/CCCCCCCC(=O)OCC LVGKNOAMLMIIKO-QXMHVHEDSA-N 0.000 description 1
- 229940093471 ethyl oleate Drugs 0.000 description 1
- 125000000219 ethylidene group Chemical group [H]C(=[*])C([H])([H])[H] 0.000 description 1
- 239000000284 extract Substances 0.000 description 1
- 239000000194 fatty acid Substances 0.000 description 1
- 229930195729 fatty acid Natural products 0.000 description 1
- 239000007941 film coated tablet Substances 0.000 description 1
- 239000012065 filter cake Substances 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 125000002485 formyl group Chemical group [H]C(*)=O 0.000 description 1
- 238000001640 fractional crystallisation Methods 0.000 description 1
- 239000003365 glass fiber Substances 0.000 description 1
- 239000004220 glutamic acid Substances 0.000 description 1
- 150000002366 halogen compounds Chemical class 0.000 description 1
- 230000026030 halogenation Effects 0.000 description 1
- 238000005658 halogenation reaction Methods 0.000 description 1
- 125000004970 halomethyl group Chemical group 0.000 description 1
- 125000003187 heptyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000005446 heptyloxy group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])O* 0.000 description 1
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000005935 hexyloxycarbonyl group Chemical group 0.000 description 1
- 150000004677 hydrates Chemical class 0.000 description 1
- 229940031704 hydroxypropyl methylcellulose phthalate Drugs 0.000 description 1
- 229920003132 hydroxypropyl methylcellulose phthalate Polymers 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 229910017053 inorganic salt Inorganic materials 0.000 description 1
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 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
- 238000002955 isolation Methods 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 125000005928 isopropyloxycarbonyl group Chemical group [H]C([H])([H])C([H])(OC(*)=O)C([H])([H])[H] 0.000 description 1
- 229940116298 l- malic acid Drugs 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 229910052749 magnesium Inorganic materials 0.000 description 1
- 159000000003 magnesium salts Chemical class 0.000 description 1
- 235000011090 malic acid Nutrition 0.000 description 1
- MBKDYNNUVRNNRF-UHFFFAOYSA-N medronic acid Chemical compound OP(O)(=O)CP(O)(O)=O MBKDYNNUVRNNRF-UHFFFAOYSA-N 0.000 description 1
- 150000002739 metals Chemical class 0.000 description 1
- 125000005394 methallyl group Chemical group 0.000 description 1
- OJURWUUOVGOHJZ-UHFFFAOYSA-N methyl 2-[(2-acetyloxyphenyl)methyl-[2-[(2-acetyloxyphenyl)methyl-(2-methoxy-2-oxoethyl)amino]ethyl]amino]acetate Chemical compound C=1C=CC=C(OC(C)=O)C=1CN(CC(=O)OC)CCN(CC(=O)OC)CC1=CC=CC=C1OC(C)=O OJURWUUOVGOHJZ-UHFFFAOYSA-N 0.000 description 1
- 229920000609 methyl cellulose Polymers 0.000 description 1
- 239000001923 methylcellulose Substances 0.000 description 1
- 229960002900 methylcellulose Drugs 0.000 description 1
- 235000010981 methylcellulose Nutrition 0.000 description 1
- 125000004170 methylsulfonyl group Chemical group [H]C([H])([H])S(*)(=O)=O 0.000 description 1
- 244000005700 microbiome Species 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 239000003703 n methyl dextro aspartic acid receptor blocking agent Substances 0.000 description 1
- 238000006396 nitration reaction Methods 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 239000003791 organic solvent mixture Substances 0.000 description 1
- 125000004043 oxo group Chemical group O=* 0.000 description 1
- 229910052763 palladium Inorganic materials 0.000 description 1
- 230000036961 partial effect Effects 0.000 description 1
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 1
- 125000001148 pentyloxycarbonyl group Chemical group 0.000 description 1
- UYWQUFXKFGHYNT-UHFFFAOYSA-N phenylmethyl ester of formic acid Natural products O=COCC1=CC=CC=C1 UYWQUFXKFGHYNT-UHFFFAOYSA-N 0.000 description 1
- XNGIFLGASWRNHJ-UHFFFAOYSA-L phthalate(2-) Chemical compound [O-]C(=O)C1=CC=CC=C1C([O-])=O XNGIFLGASWRNHJ-UHFFFAOYSA-L 0.000 description 1
- 239000000049 pigment Substances 0.000 description 1
- 239000004014 plasticizer Substances 0.000 description 1
- 159000000001 potassium salts Chemical class 0.000 description 1
- 229940116317 potato starch Drugs 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 230000002335 preservative effect Effects 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 125000000177 propargylthio group Chemical group [H]C#CC([H])([H])S* 0.000 description 1
- 125000004742 propyloxycarbonyl group Chemical group 0.000 description 1
- NSETWVJZUWGCKE-UHFFFAOYSA-N propylphosphonic acid Chemical compound CCCP(O)(O)=O NSETWVJZUWGCKE-UHFFFAOYSA-N 0.000 description 1
- 125000006239 protecting group Chemical class 0.000 description 1
- 230000001681 protective effect Effects 0.000 description 1
- 239000003586 protic polar solvent Substances 0.000 description 1
- 125000001453 quaternary ammonium group Chemical group 0.000 description 1
- SEPKUNXLGWMPHL-UHFFFAOYSA-N quinoxaline-2,3-dione Chemical compound C1=CC=CC2=NC(=O)C(=O)N=C21 SEPKUNXLGWMPHL-UHFFFAOYSA-N 0.000 description 1
- 239000002287 radioligand Substances 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 235000009566 rice Nutrition 0.000 description 1
- 229940100486 rice starch Drugs 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 239000008159 sesame oil Substances 0.000 description 1
- 235000011803 sesame oil Nutrition 0.000 description 1
- 229910000077 silane Inorganic materials 0.000 description 1
- RMAQACBXLXPBSY-UHFFFAOYSA-N silicic acid Chemical compound O[Si](O)(O)O RMAQACBXLXPBSY-UHFFFAOYSA-N 0.000 description 1
- 125000003808 silyl group Chemical group [H][Si]([H])([H])[*] 0.000 description 1
- 235000010413 sodium alginate Nutrition 0.000 description 1
- 239000000661 sodium alginate Substances 0.000 description 1
- 229940005550 sodium alginate Drugs 0.000 description 1
- WRIKHQLVHPKCJU-UHFFFAOYSA-N sodium bis(trimethylsilyl)amide Chemical compound C[Si](C)(C)N([Na])[Si](C)(C)C WRIKHQLVHPKCJU-UHFFFAOYSA-N 0.000 description 1
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 description 1
- 229920001027 sodium carboxymethylcellulose Polymers 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- GGCZERPQGJTIQP-UHFFFAOYSA-N sodium;9,10-dioxoanthracene-2-sulfonic acid Chemical compound [Na+].C1=CC=C2C(=O)C3=CC(S(=O)(=O)O)=CC=C3C(=O)C2=C1 GGCZERPQGJTIQP-UHFFFAOYSA-N 0.000 description 1
- 239000007901 soft capsule Substances 0.000 description 1
- 238000003797 solvolysis reaction Methods 0.000 description 1
- 241000894007 species Species 0.000 description 1
- 230000007480 spreading Effects 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- 229960004793 sucrose Drugs 0.000 description 1
- 150000008163 sugars Chemical class 0.000 description 1
- 150000003460 sulfonic acids Chemical class 0.000 description 1
- 239000004408 titanium dioxide Substances 0.000 description 1
- 235000010487 tragacanth Nutrition 0.000 description 1
- 239000000196 tragacanth Substances 0.000 description 1
- 229940116362 tragacanth Drugs 0.000 description 1
- 229940078499 tricalcium phosphate Drugs 0.000 description 1
- 235000019731 tricalcium phosphate Nutrition 0.000 description 1
- 229910000391 tricalcium phosphate Inorganic materials 0.000 description 1
- 125000000026 trimethylsilyl group Chemical group [H]C([H])([H])[Si]([*])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 1
- 229960004418 trolamine Drugs 0.000 description 1
- 239000003981 vehicle Substances 0.000 description 1
- 229940100445 wheat starch Drugs 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/645—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having two nitrogen atoms as the only ring hetero atoms
- C07F9/6509—Six-membered rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/645—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having two nitrogen atoms as the only ring hetero atoms
- C07F9/6509—Six-membered rings
- C07F9/650952—Six-membered rings having the nitrogen atoms in the positions 1 and 4
- C07F9/650994—Six-membered rings having the nitrogen atoms in the positions 1 and 4 condensed with carbocyclic rings or carbocyclic ring systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/08—Antiepileptics; Anticonvulsants
-
- 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
- A61P9/10—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
- C07D241/00—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
- C07D241/36—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings condensed with carbocyclic rings or ring systems
- C07D241/38—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings condensed with carbocyclic rings or ring systems with only hydrogen or carbon atoms directly attached to the ring nitrogen atoms
- C07D241/40—Benzopyrazines
- C07D241/44—Benzopyrazines with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the hetero ring
Definitions
- the invention relates to novel quinoxaiine- and quinoxalinylalkane-phosphonic acids of formula I
- R . is free or partially esterified phosphono
- R 2 and R 3 are each independently of the other hydrogen or an aliphatic radical
- the radicals R 4 , R 5 and R 6 are each independently of the others hydrogen, an aliphatic hydrocarbon radical, free or etherified hydroxy, free or etherified mercapto or oxidised free or etherified mercapto, unsubstituted or aliphatically substituted amino, nitro, free or esterified or amidated carboxy, cyano, free or amidated sulfamoyl, halogen or trifluoromethyl, and
- X is a divalent aliphatic radical, and to the tautomers and/or salts thereof, to pharmaceutical compositions comprising the novel compounds and to the use thereof as active ingredients of medicaments.
- Free or esterified carboxy is, for example, carboxy, lower alkoxycarbonyl, or phenyl-lower alkoxycarbonyl that is unsubstituted or substituted by lower alkyl, lower alkoxy, hydroxy, halogen and/or by trifluoromethyl.
- Free or partially esterified phosphono is, for example, lower alkylphosphono.
- Aliphatic radicals R . and/or R 2 are, for example, lower alkyl, lower alkenyl or lower alkynyl radicals; groups R . O and R 2 O are, for example, hydroxy or lower alkoxy, but may also be lower alkenyloxy or lower alkynyloxy.
- Aliphatic hydrocarbon radicals are, for example, lower alkyl or lower alkenyl radicals, but may also be lower alkynyl radicals.
- Free or etherified mercapto or oxidised free or etherified mercapto is, for example, mercapto, lower alkylthio, lower alkanesulfinyl or lower alkanesulfonyl, but may also be lower alkenylthio, lower alkynylthio, lower alkenesulfinyl, lower alkenesulfonyl, lower alkynesulfinyl or lower alkynesulfonyl.
- Unsubstituted or aliphatically substituted amino is, for example, amino or N-mono- or N,N- di-lower alkylamino.
- Free or esterified or amidated carboxy is, for example, carboxy, lower alkoxycarbonyl; phenyl-lower alkoxycarbonyl that is unsubstituted or substituted by lower alkyl, lower alkoxy, hydroxy, halogen and/or by trifluoromethyl; carbamoyl, N-mono- or N,N-di-lower alkyl- carbamoyl, or N-phenylcarbamoyl or N-phenyl-N-lower alkyl-carbamoyl each of which is unsubstituted or substituted in the phenyl moiety by lower alkyl, lower alkoxy, hydroxy, halogen and/or by trifluoromethyl.
- Free or amidated sulfamoyl is, for example, sulfamoyl or N-mono- or N,N-di-lower alkyl- sulfamoyl.
- Halogen is, for example, halogen having an atomic number of up to and including 35, such as fluorine, chlorine or bromine.
- Divalent aliphatic radicals are, for example, lower alkylidene, lower alkylene, lower alkenylene or lower alkynylene radicals.
- lower radicals and compounds are to be understood as being, for example, radicals and compounds having up to and including 7, preferably up to and including 4, carbon atoms.
- Di-lower alkylamino is, for example, di-C ⁇ -C 4 alkylamino, such as dimethylamino, diethyl- amino, dipropylamino, diisopropylamino or dibutylamino.
- Di-lower alkylcarbamoyl is, for example, di-C.-C alkylcarbamoyl, such as dimethylcarbamoyl, diethylcarbamoyl, dipropylcarbamoyl, diisopropylcarbamoyl or dibutylcarbamoyl.
- Di-lower alkylsulfamoyl is, for example, di-C ⁇ -C 4 alkylsulfamoyl, such as dimethylsulfamoyl, diethylsulfamoyl, dipropylsulfamoyl, diisopropylsulfamoyl or dibutylsulfamoyl.
- Lower alkoxycarbonyl is, for example, C.-C 7 alkoxycarbonyl, preferably C ⁇ -C alkoxycarbonyl, such as methoxycarbonyl, ethoxycarbonyl, propyloxycarbonyl, isopropyloxycarbonyl or butyloxycarbonyl, but may also be isobutyloxycarbonyi, secondary butyloxycarbonyl, tertiary butyloxycarbonyl or a pentyloxycarbonyl, hexyloxycarbonyl or heptyloxycarbonyl group.
- C.-C 7 alkoxycarbonyl preferably C ⁇ -C alkoxycarbonyl, such as methoxycarbonyl, ethoxycarbonyl, propyloxycarbonyl, isopropyloxycarbonyl or butyloxycarbonyl, but may also be isobutyloxycarbonyi, secondary butyloxycarbonyl, tertiary butyloxycarbonyl or
- Lower alkanesulfinyl is, for example, C.-C 7 alkanesulfinyl, preferably C ⁇ -C alkanesulfinyl, such as methanesulfinyl, ethanesulfinyl, propanesulfinyl or butanesulfinyl, but may also be a pentanesulfinyl, hexanesulfinyl or heptanesulfinyl group.
- Lower alkanesulfonyl is, for example, C.-C 7 alkanesulfonyl, preferably C.-C 4 alkanesulfonyl, such as methanesulfonyl, ethanesulfonyl, propanesulfonyl or butanesulfonyl, but may also be a pentanesulfonyl, hexanesulfonyl or heptanesulfonyl group.
- Lower alkenesulfinyl is, for example, C 3 -C 4 alkenesulfinyl, such as prop-2-enesulfinyl or but- 2-enesulfinyl.
- Lower alkenesulfonyl is, for example, C 3 -C alkenesulfonyl, such as prop-2-enesulfonyl or but-2-enesulfonyl.
- Lower alkenyl is, for example, C 3 -C 4 alkenyl, such as allyl or methallyl.
- Lower alkenylene may be straight-chained or branched and may be bonded in any desired position and is, for example, straight-chained or branched C 2 -C 7 alkenylene, especially C 2 -C alkylene, such as vinylene, 1 ,3-prop-2-enylene or 1 ,4-but-2-enylene.
- Lower alkenyloxy is, for example, C 3 -C alkenyloxy, such as allyloxy or methallyloxy.
- Lower alkynyl is, for example, C 3 -C 4 alkynyl, such as propargyl.
- Lower alkynyloxy is, for example, C 3 -C alkynyloxy, such as propargyloxy.
- Lower alkynylthio is, for example, C 3 -C 4 alkynylthio, such as propargylthio.
- Lower alkoxy is, for example, C.-C 7 alkoxy, preferably C .-C 4 alkoxy, such as methoxy, ethoxy, propyloxy, isopropyloxy or butyloxy, but may also be isobutyloxy, secondary butyloxy, tertiary butyloxy or a pentyloxy, hexyloxy or heptyloxy group.
- Lower alkyl is, for example, d-C 7 alkyl, preferably C.-C 4 alkyl, such as especially methyl or, secondly, ethyl, propyi, isopropyl or butyl, but may also be isobutyl, secondary butyl, tertiary butyl or a C 5 -C 7 alkyl group, such as a pentyl, hexyl or heptyl group.
- Lower alkylamino is, for example, C .-C 7 alkylamino, C .-C 4 alkylamino, such as especially methylamino, ethylamino, propylamino, isopropylamino or butylamino, but may also be isobutylamino, secondary butylamino, tertiary butylamino or a C 5 -C 7 alkylamino group, such as a pentylamino, hexylamino or heptylamino group.
- Lower alkylcarbamoyl is, for example, C .-C alkylcarbamoyl, preferably C ⁇ -C 4 alkylcarbamoyl, such as methylcarbamoyl, ethylcarbamoyl, propylcarbamoyl, isopropylcarbamoyl, butyl- carbamoyl, but may also be isobutylcarbamoyl, secondary butylcarbamoyl, tertiary butyl- carbamoyl or a C 5 -C 7 alkylcarbamoyl group, such as a pentylcarbamoyl, hexylcarbamoyl or heptylcarbamoyl group.
- C .-C alkylcarbamoyl preferably C ⁇ -C 4 alkylcarbamoyl, such as methylcarbamoyl, ethylcarb
- Lower alkylidene may be straight-chained or branched and is, for example, straight-chained or branched C.-C alkylidene, such methylene, ethylidene, 1 ,1- or 2,2-propylidene or 1 ,1- or 2,2-butylidene.
- Lower alkylene is, for example, straight-chained C,-C alkylene, for example of the formula -(CH 2 )n- (la) wherein n is, for example, 2, 3 or 4.
- Lower alkynylene is, for example, straight-chained C 2 -C 4 alkynylene, for example of the formula -C ⁇ -C-(CH 2 )... 2 - (lc) wherein n is, for example, 2, 3 or 4.
- Lower alkylphosphono is, for example, C ,-C 7 alkylphosphono, such as methylphosphono, ethylphosphono, propylphosphono, isopropylphosphono or butylphosphono, but may also be isobutylphosphono, secondary butylphosphono, tertiary butylphosphono or a C 5 -C 7 alkyl- phosphono group, such as a pentylphosphono, hexylphosphono or heptylphosphono group.
- Lower alkylthio is, for example, C .-C 7 alkylthio, preferably C .-C alkylthio, such as methylthio, ethanylthio, propylthio or butylthio, but may also be a pentylthio, hexylthio or heptylthio group.
- N-Phenyl-N-lower alkyl-carbamoyl is, for example, N-phenyl-C .-C 4 alkyl-carbamoyl, such as N-methyl-N-phenyl-carbamoyl, N-ethyl-N-phenyl-carbamoyl, N-phenyl-N-propyl-carbamoyl or N-butyl-N-phenyl-carbamoyl.
- Phenyl-lower alkoxycarbonyl is, for example, unsubstituted or C ,-C alkyl-, C.-C 4 alkoxy-, hydroxy-, halo- and/or trifluoromethyl-substituted phenyl-C . -C 4 alkoxycarbonyl, such as benzyloxycarbonyl or ⁇ -phenylethoxycarbonyl.
- Tautomers come into consideration especially in the case of compounds of formula I wherein one or both radicals R. and R 2 are hydrogen. Tautomers of such compounds of formula I are best described by the structural formula I', I" or I'"
- Compounds of formula I may form salts with bases or, when at least one of the radicals R , R 5 and R_ is unsubstituted or aliphatically substituted amino, may form internal salts.
- Salts of compounds of formula I with bases are, for example, salts thereof with pharma ⁇ ceutically acceptable bases, such as non-toxic metal salts derived from metals of groups la, lb, Ha and lib, for example alkali metal salts, especially sodium or potassium salts, alkaline earth metal salts, especially calcium or magnesium salts, and also ammonium salts with ammonia or organic amines or quaternary ammonium bases, such as optionally C-hydroxyl- ated aliphatic amines, especially mono-, di- or tri-lower alkylamines, for example methyl-, ethyl- or diethyl-amine, mono-, di- or tri-(hydroxy-lower alkyl)amines, such as ethanol-, diethanol- or triethanol-amine, tris(hydroxymethyl)methylamine or 2-hydroxy-tert-butylamine, or N-(hydroxy-lower alkyl)-N,N-di-lower alkylamines or N-(pol
- total salts and, depending on the number of acid groups, partial salts, that is to say salts with 1, 2 or 3, preferably 2, equivalents of base per mole of acid of formula I, or salts with 1 , 2 or 3 equivalents, preferably 1 equivalent, of acid per mole of base of formula I.
- the compounds of formula I have valuable pharmacological properties. In particular, they have a pronounced and selective antagonistic action with respect to N-methyl-D-aspartic- acid-sensitive (NMDA-sensitive) excitatory amino acid receptors of warm-blooded animals. That can be demonstrated in vitro, for example, in the experimental procedure according to Sills ., Fagg G., Pozza M., Angst Ch., Brundish D., Hurt S., Wilusz E., Williams M.: [ 3 H]CGP 39653: a new N-methyl-D-aspartate antagonist radioligand with low nanomolar affinity in rat brain. Eur. J. Pharmacol. 192. pages 19-24 (1991 ).
- IC 50 concentration required for 50 % displacement
- the compounds of formula I and the pharmaceutically acceptable salts thereof are excellently suitable for the treatment of pathological conditions that are responsive to blocking of NMDA-sensitive receptors, for example ischaemic disorders, such as cerebral ischaemia, and ischaemic disorders of the eyes, vascular and muscular spasms, such as migraine or local or general spasticity, and especially convulsions, such as epilepsy.
- ischaemic disorders such as cerebral ischaemia, and ischaemic disorders of the eyes
- vascular and muscular spasms such as migraine or local or general spasticity
- convulsions such as epilepsy.
- the anticonvulsive properties of the compounds according to the invention can be deter ⁇ mined, for example, in the mouse with reference to their pronounced protective action with respect to convulsions induced by electric shock or audiogenically, it being possible to use, for example, the established electric shock mouse model or the experimental procedure according to Chapman et al., Arzneistoff-Forsch. 34. 1261 (1984).
- the compounds according to the invention have an ED50 of approximately from 1 to 10 mg/kg i.p..
- the antispastic properties on which the suitability of the compounds provided according to the invention for the treatment of migraine is based can be demonstrated, for example, in the rat with reference to their depression-inhibiting action in accordance with the experimental procedure of R. Marannes et al., Brain Res. 457. 226 (1988).
- the compounds provided according to the invention lower the threshold of "spreading depression", and reduce its duration, in a dosage range of approximately from 3 to 30 mg/kg i.p..
- the invention relates especially to compounds of formula I wherein R. is lower alkylphosphono,
- R 2 and R 3 are each independently of the other hydrogen, lower alkyl, lower alkenyl or lower alkynyl, such as propargyl
- the radicals R , R 5 and R 6 are each independently of the others hydrogen, lower alkyl, lowe alkenyl, lower alkynyl, hydroxy, lower alkoxy, lower alkenyloxy, lower alkynyloxy, mercapto, lower alkylthio, lower alkanesulfinyl, lower alkanesulfonyl, lower alkenylthio, lower alkynyl- thio, lower alkenesulfinyl, lower alkanesulfonyl, amino, lower alkylamino, di-lower alkylamino, nitro, carboxy, lower alkoxycarbonyl; unsubstituted or lower alkyl-, lower alkoxy- hydroxy-, halo- and/or trifluoromethyl-substituted phenyl-low
- R 1 is phosphono
- R 2 and R 3 are each independently of the other hydrogen or C ,-C 4 alkyl, such as methyl or ethyl
- the radicals R 4 , R 5 and R 6 are each independently of the others hydrogen, C ,-C alkyl, such as methyl or ethyl, C ⁇ -C 4 alkoxy, such as methoxy or ethoxy, C ⁇ -C 4 alkylthio, such as methyl- thio, amino, nitro, carboxy, C 1 -C 4 alkoxycarbonyl, such as methoxy- or ethoxy-carbonyl, carbamoyl, C ⁇ -C 4 alkylcarbamoyl, such as methylcarbamoyl, di-C ⁇ -C 4 alkyicarbamoyl, such as dimethylcarbamoyl, halogen or trifluoromethyl, and
- C ⁇ -C 4 alkylidene such as methylene, ethylidene, 1,1- or 2,2-propylidene or 1,1- or 2,2- butylidene
- C ⁇ -C 4 alkylene for example of the formula - ⁇ CH 2 )n- (
- the invention relates especially to compounds of formula I wherein
- R. is phosphono
- R 2 is hydrogen or C.-C 4 alkyl, such as methyl or ethyl,
- R 3 is hydrogen
- the radicals R 4 , R 5 and R 6 are each independently of the others hydrogen, C.-C 4 alkyl, such as methyl or ethyl, nitro, halogen or trifluoromethyl, and
- X is C .-C 4 alkylidene, such as methylene or ethylidene, or a group of the formula
- the invention relates specifically to the compounds of formula I mentioned in the Examples and to the salts thereof, especially the pharmaceutically acceptable salts thereof.
- the process for the preparation of the compounds according to the invention comprises removing the phosphono-protecting group, and, if desired, the group(s) R B and/or R c , from a compound of formula II wherein R A is a protected phosphono group, R B is a group R 2 or a hydroxy-protecting group, Re is a group R 3 or a hydroxy-protecting group, and R 4 , R 5 and R 6 are as defined, and if desired converting the resulting compound into a different compound of formula I, separating a mixture of isomers obtainable according to the process into its components and isolating the particular preferred isomer and/or converting a free compound obtainable according to the process into a salt or converting a salt obtainable according to the process into the corresponding free compound.
- Suitable as phosphono-protecting groups and hydroxy-protecting groups are customary phosphono- and hydroxy-protecting groups known in the prior art.
- Protected phosphono groups R A are especially in ester form, for example in the form of esterified phosphono, such as di-lower alkylphosphono or unsubstituted or lower alkyl-, lower alkoxy-, halo- and/or nitro-substituted diphenyl- or dibenzyl-phosphono groups.
- Suitable as protected hydroxy groups R B and R c are, in addition to groups R .
- silyl groups such as tri- lower alkylsilyl, for example trimethylsilyl, also unsubstituted or lower alkyl-, lower alkoxy-, halo- and/or nitro-substituted phenyl or benzyl groups.
- the mentioned protecting groups are removed in customary manner, for example by solvolysis or hydrogenolysis.
- Acid hydrolysing agents are, for example, mineral acids, such as hydrohalic acid or sulfuric acid, if necessary in admixture with a protic solvent, such as acetic acid.
- Such agents are, for example, from appoximately 30 % to approximately 35 % solutions of hydrobromic acid in acetic acid, mixtures of concentrated, for example approximately 35 %, hydrochloric acid in acetic acid or mixtures of equal parts of concentrated, for example approximately 35 %, hydrochloric acid or concentrated sulfuric acid, water and acetic acid.
- the reaction is advantageously carried out at elevated tempera ⁇ ture, for example in a temperature range of from approximately 80°C to approximately 120°C, for example at boiling temperature.
- esterified phosphono such as di-lower alkylphosphono
- R A is esterified phosphono
- R B is a group R 2 other than hydrogen
- R c is a group R 3 other than hydrogen
- reaction with the silyl compound is advantageously carried out in a halogenated hydrocarbon, such as dichloro- methane, and the further reaction with the alcohol is advantageously carried out in the presence of water.
- the nitro group is reduced to amino in customary manner, for example by hydrogenation in the presence of a hydrogenation catalyst, such as Raney nickel; the resulting compound of formula IV is reacted in customary manner with oxalic acid or a reactive derivative thereof, such as an oxalic acid diester, for example with diethyl oxalate; in the resulting quinoxaline-2,3-dione of formula V
- the oxo groups are converted in customary manner, for example by treatment with phosphorus oxychloride and/or phosphorus pentachloride and subsequent reaction with an alcohol of the formula R 2 -OH (Via) or R 3 -OH (Vlb), into groups of the formula -OR 2 or -OR 3 ; in the resulting compound of formula VII
- the group -X-H is halogenated in customary manner, for example using N- bromosuccinimide, in the ⁇ -position relative to the benzo ring and, in order to prepare a compound of formula II wherein R A is esterified phosphono, such as di-lower alkylphosphono, the resulting compound of formula VIII wherein Hal is halogen, for example bromine, is reacted with a phosphonous acid triester, such as a tri-lower alkyl phosphite, such as trimethyl or triethyl phosphite.
- a phosphonous acid triester such as a tri-lower alkyl phosphite, such as trimethyl or triethyl phosphite.
- R A an agent that introduces the group R A , such as a phosphonous acid triester, for example a tri-lower alkyl phosphite, such as trimethyl or triethyl phosphite. That process is especially suitable for the preparation of compounds of formula II wherein R A is an esterified phosphono group, such as di-lower alkylphosphono, and n is 3 or 4.
- Resulting intermediates wherein X has at least one hydrogen atom in the ⁇ -position relative to the benzo ring, i.e. is 1 ,1 -lower alkylidene, for example methylene, are converted in customary manner, for example by treatment with an alkali metal disilazide, for example sodium tetramethyl disilazide, and then with an alkylating agent, such as a lower alkyl iodide of the formula R-l, into the corresponding compounds of the formula wherein X is a lower alkylidene radical, for example of the formula >X-R or -X(R)-R, that is bonded via a chain member.
- an alkali metal disilazide for example sodium tetramethyl disilazide
- an alkylating agent such as a lower alkyl iodide of the formula R-l
- a compound of formula I wherein R is partially esterified phosphono can be hydrolysed in customary manner to form the corresponding compound of the formula wherein R. is phosphono.
- a compound of formula I wherein R 2 and/or R 3 is an aliphatic radical can be solvolysed in customary manner to form the corresponding compound of formula I wherein R 2 and/or R 3 is hydrogen, or the corresponding tautomer of formula I"', for example as described above for the removal of hydroxy-protecting groups R B and R c .
- a compound of formula I wherein R 2 and/or R 3 is hydrogen, or a tautomer thereof of formula I', I" and/or I' can be converted by the introduction of an aliphatic radical in customary manner, for example by treatment with a strong halogenating agent, such as phosphorus oxychloride and/or phosphorus pentachloride, and then with an aliphatic alcohol, into the corresponding compound of formula I wherein R 2 and/or R 3 is an aliphatic radical, or into the corresponding tautomer of formula I', I" or I'".
- a strong halogenating agent such as phosphorus oxychloride and/or phosphorus pentachloride
- a resulting compound of fonmula I wherein at least one of the radicals R , R 5 and R 6 is etherified mercapto, for example lower alkylthio can be oxidised in customary manner to the corresponding compound of formula I wherein R , R 5 and/or R 6 is oxidised esterified mercapto, for example lower alkanesulfinyl or lower alkanesulfonyl.
- the hydrogen atom can be replaced by a radical R 4 , R 5 or R 6 that is other than hydrogen.
- halogenation, nitration or the introduction of lower alkanoyl can be carried out in customary manner, the latter, for example, by reaction with a reactive lower alkanoic acid derivative, such as a lower alkanoic acid chloride, in the presence of aluminium trichloride, preferably in a halogenated hydrocarbon, if necessary at boiling temperature.
- nitro can be converted into amino in customary manner, for example by reduction, and halogen can be removed in customary manner, for example by hydrogenolysis.
- Resulting salts can be converted into the free compounds in a manner known perse, for example by treatment with a base, such as an alkali metal hydroxide, a metal carbonate or metal hydrogen carbonate, or another salt-forming base mentioned at the beginning, or with an acid, such as a mineral acid, for example with hydrochloric acid, or another salt-forming acid mentioned at the beginning.
- a base such as an alkali metal hydroxide, a metal carbonate or metal hydrogen carbonate, or another salt-forming base mentioned at the beginning
- an acid such as a mineral acid, for example with hydrochloric acid, or another salt-forming acid mentioned at the beginning.
- Resulting salts can be converted into different salts in a manner known perse; acid addition salts, for example, by treatment with a suitable metal salt, such as a sodium, barium or silver salt, of a different acid in a suitable solvent in which an inorganic salt being formed is insoluble and is therefore eliminated from the reaction equilibrium, and basic salts by freeing of the free acid and conversion into a salt again.
- a suitable metal salt such as a sodium, barium or silver salt
- the compounds of formula I, including their salts may also be obtained in the form of hydrates or may include the solvent used for crystallisation.
- any reference to the free compounds and their salts is to be understood as including also the corresponding salts and free compounds, respectively, as appropriate and expedient.
- Resulting diastereoisomeric mixtures and mixtures of racemates can be separated into the pure diastereoisomers or racemates in known manner on the basis of the physico-chemical differences between the constituents, for example by chromatography and/or fractional crystallisation.
- Resulting racemates can also be resolved into the optical antipodes in accordance with known methods, for example by recrystallisation from an optically active solvent, with the aid of microorganisms or by reaction of the resulting diastereoisomeric mixture or racemate with an optically active auxiliary compound, for example depending on the acidic, basic or functionally modifiable groups present in compounds of formula I, with an optically active acid, base or an optically active alcohol, to form mixtures of diastereoisomeric salts or functional derivatives, such as esters, and separation thereof into the diastereoisomers from which the desired enantiomer can be freed in the appropriate customary manner.
- an optically active auxiliary compound for example depending on the acidic, basic or functionally modifiable groups present in compounds of formula I, with an optically active acid, base or an optically active alcohol, to form mixtures of diastereoisomeric salts or functional derivatives, such as esters, and separation thereof into the diastereoisomers from which
- acids and alcohols suitable for that purpose are, for example, optically active alkaloid bases, such as strychnine, cinchonine or brucine, or D- or L-(1-phenyl)ethylamine, 3- pipecoline, ephedrine, amphetamine and similar synthetically obtainable bases, optically active carboxylic or sulfonic acids, such as quinic acid or D- or L-tartaric acid, D- or L-di-o- toluyltartaric acid, D- or L-malic acid, D- or L-mandelic acid or D- or L-camphorsulfonic acid, and optically active alcohols, such as bomeol or D- or L-(1-phenyl)ethanol.
- optically active alkaloid bases such as strychnine, cinchonine or brucine, or D- or L-(1-phenyl)ethylamine, 3- pipecoline, ephedrine, amphetamine and similar
- the invention relates also to those forms of the process according to which a compound obtainable as intermediate at any stage of the process is used as starting material and the remaining steps are carried out or a starting material is used in the form of a salt or, espe ⁇ cially, is formed under the reaction conditions.
- the invention relates also to the novel starting materials which have been developed specifically for the preparation of the compounds according to the invention, for example compounds of fonmula XVII
- radicals R 4 , R 5 and R 6 are each independently of the others hydrogen, an aliphatic hydrocarbon radical, free or etherified hydroxy, free or etherified mercapto or oxidised free or etherified mercapto, unsubstituted or aliphatically substituted amino, nitro, free or esterified or amidated carboxy, cyano, free or amidated sulfamoyl, halogen or trifluoromethyl,
- R B is a group R 2 or a hydroxy-protecting group, such as lower alkoxy or phenyl-lower alkoxy
- R c is a group R 3 or a hydroxy-protecting group, such as lower alkoxy or phenyl-lower alkoxy
- R D is a group of the formula
- R E is free or reactive esterified hydroxy, such as hydroxy, halogen, lower alkane- sulfonyloxy, or unsubstituted or lower alkyl-, halo- and/or nitro-substituted benzenesulfonyl- oxy or naphthalenesulfonyloxy, and n is 2, 3 or 4, especially to the group of starting materials leading to the compounds of formula I described at the beginning as being preferred, to the processes for the preparation thereof and to the use thereof as intermediates.
- the invention relates also to pharmaceutical compositions comprising the compounds according to the invention or pharmaceutically acceptable salts thereof as active ingre ⁇ washers, and to processes for the preparation thereof.
- compositions according to the invention which comprise the compounds according to the invention or pharmaceutically acceptable salts thereof, are for enteral, such as oral and also rectal, and parenteral administration to (a) warm-blooded animal(s), the compositions comprising the pharmacological active ingredient alone or together with a pharmaceutically acceptable carrier.
- enteral such as oral and also rectal
- parenteral administration to (a) warm-blooded animal(s), the compositions comprising the pharmacological active ingredient alone or together with a pharmaceutically acceptable carrier.
- the daily dose of the active ingredient depends upon age and individual condition and upon the mode of administration.
- novel pharmaceutical compositions comprise, for example, from approximately 10 % to approximately 80 %, preferably from approximately 20 % to approximately 60 %, active ingredient.
- Pharmaceutical compositions according to the invention for enteral or parenteral administration are, for example, those in unit dose forms, such as dragees, tablets, capsules or suppositories, and also ampoules. They are prepared in a manner known per se, for example by means of conventional mixing, granulating, confectioning, dissolving or lyophilising processes.
- compositions for oral administration can be obtained by combining the active ingredient with solid carriers, optionally granulating a resulting mixture, and processing the mixture or granules, if desired or necessary, after the addition of suitable excipients, to form tablets or dragee cores.
- Suitable carriers are especially fillers, such as sugars, for example lactose, saccharose, mannitol or sorbitol, cellulose preparations and/or calcium phosphates, for example tri- calcium phosphate or calcium hydrogen phosphate, and also binders, such as starch pastes using, for example, corn, wheat, rice or potato starch, gelatin, tragacanth, methylcellulose and/or polyvinylpyrrolidone, if desired disintegrators, such as the above-mentioned starches, and also carboxymethyl starch, cross-linked polyvinylpyrrolidone, agar, alginic acid or a salt thereof, such as sodium alginate.
- fillers such as sugars, for example lactose, saccharose, mannitol or sorbitol
- cellulose preparations and/or calcium phosphates for example tri- calcium phosphate or calcium hydrogen phosphate
- binders such as starch pastes using, for example, corn
- Excipients are especially flow agents, flow- conditioners and lubricants, for example silicic acid, talc, stearic acid or salts thereof, such as magnesium or calcium stearate, and/or polyethylene glycol.
- Dragee cores are provided with suitable, optionally enteric, coatings, there being used inter alia concentrated sugar solutions which may contain gum arabic, talc, polyvinylpyrrolidone, polyethylene glycol and/or titanium dioxide, or coating solutions in suitable organic solvents or solvent mixtures or, for the preparation of enteric coatings, solutions of suitable cellulose preparations, such as acetylcellulose phthalate or hydroxypropylmethylcellulose phthalate. Dyes or pigments may be added to the tablets or dragee coatings, for example for identification purposes or to indicate different doses of active ingredient.
- compositions are hard gelatin capsules and also soft, sealed capsules consisting of gelatin and a plasticiser, such as glycerol or sorbitol.
- the hard gelatin capsules may comprise the active ingredient in the form of granules, for example in admixture with fillers, such as lactose, binders, such as starches, and/or glidants, such as talc or magnesium stearate, and if desired stabilisers.
- fillers such as lactose
- binders such as starches
- glidants such as talc or magnesium stearate
- the active ingredient is preferably dissolved or suspended in suitable liquids, such as fatty oils, paraffin oil or liquid polyethylene glycols, it likewise being possible to add stabilisers.
- Suitable rectally administrable pharmaceutical compositions are, for example, suppositories that consist of a combination of the active ingredient with a suppository base material.
- Suitable suppository base materials are, for example, natural or synthetic triglycerides, paraffin hydrocarbons, polyethylene glycols or higher alkanols. It is also possible to use gelatin rectal capsules which comprise a combination of the active ingredient with a base material.
- Suitable base materials are, for example, liquid triglycerides, polyethylene glycols or paraffin hydrocarbons.
- aqueous solutions of an active ingredient in water-soluble form for example in the form of a water-soluble salt
- suspensions of the active ingredient such as corresponding oily injection suspensions
- suitable lipophilic solvents or vehicles such as fatty oils, for example sesame oil, or synthetic fatty acid esters, for example ethyl oleate or triglycerides, or aqueous injection suspensions which comprise viscosity-increasing substances, for example sodium carboxymethylcellulose, sorbitol and/or dextran, and optionally also stabilisers.
- the dose of the active ingredient depends upon the species of warm-blooded animal, age and individual condition and also upon the mode of administration. In a normal case the approximate daily dose for oral administration to a patient weighing about 75 kg is estimated to be from approximately 10 mg to approximately 500 mg.
- the following Examples serve to illustrate the invention; temperatures are given in degrees Celsius, pressures in mbar.
- Example 1 7-Bromo-2.3-dioxo-1.2.3,4-tetrahydro-quinoxalin-5-ylmethanephosphonic acid 0.68 g (1.62 mmol) of 7-bromo-2,3-dimethoxy-quinoxalin-5-ylmethanephosphonic acid diethyl ester are heated for 15 minutes at 130° in 20 ml of a 33 % solution of hydrobromic acid in acetic acid. The reaction mixture is allowed to cool to room temperature, 80 ml of diethyl ether are added and stirring is carried out for 30 minutes. The crystalline precipitate is filtered off, washed with diethyl ether and dried, yielding the title compound; m.p.
- the starting material can be prepared, for example, as follows:
- the filtrate and the washing solutions are combined and concentrated by evaporation under reduced pressure.
- the evaporation residue is taken up in 1000 ml of 2N hydrochloric acid, 31.15 g (346 mmol) of oxalic acid are added and heating under reflux is carried out overnight.
- the reaction mixture is then allowed to cool to room temperature, poured into 1000 ml of ice-water, filtered with suction, washed with water and dried.
- the resulting solid is made into a slurry in a small amount of acetone, stirred for 30 minutes, filtered with suction again, washed first with acetone and then with diethyl ether and dried, yielding the title compound in the form of a brownish solid, m.p.
- reaction mixture is slowly heated further to 200° until no further phosphorus oxychloride is separated off, then allowed to cool and poured into 2000 ml of water.
- the precipitate that has separated out is filtered off with suction, washed with water and dried and then taken up in 2000 ml of dichloromethane and filtered.
- the filter residue is washed with dichloromethane and the combined filtrates are dried over magnesium sulfate, concen ⁇ trated by evaporation and dried, yielding 25 g of 7-bromo-2,3-dichloro-5-methyl-quinoxaline in the form of a brownish solid which is made into a slurry in 300 ml of methanol.
- Example 2 2.3-Dioxo-1.2.3.4-tetrahydro-quinoxalin-5-ylmethanephosphonic acid 4.21 g (10.8 mmol) of 7-bromo-2,3-dimethoxy-quinoxalin-5-ylmethanephosphonic acid dimethyl ester and 1.2 g of triethylamine are dissolved in 100 ml of methanol, 0.4 g of palladium on carbon is added and the reaction mixture is stirred under a hydrogen atmosphere until 258 ml of hydrogen have been taken up. The catalyst is filtered off, and washing with methanol and concentration to dryness by evaporation are carried out.
- the starting material can be prepared, for example, as follows:
- aqueous phases are extracted by shaking with dichloromethane and all the organic phases are combined, dried over magnesium sulfate and concentrated by evaporation. 21.0 g of a solid are obtained. 15.7 g thereof are dissolved in 200 ml of trimethyl phosphite and heated at reflux overnight.
- Example 4 1-.7-Bromo-2.3-dioxo-1.2.3.4-tetrahydro-quinoxalin-5-v ⁇ ethanephosphonic acid 5.23 ml of a 1 molar solution of sodium hexamethyl disilazide in tetrahydrofuran are added dropwise at -20° to a solution of 1.86 g (4.76 mmol) of 7-bromo-2,3-dimethoxy-quinoxalin-5- ylmethanephosphonic acid dimethyl ester in 20 ml of tetrahydrofuran.
- Example 6 7-Bromo-2.3-dioxo-1.2.3.4-tetrahydro-quinoxalin-5-ylacetic acid
- Tetrabutylammonium cyanide is added to 2.35 g (6.5 mmol) of 7-bromo-2,3-dimethoxy-5- bromomethyl-quinoxaline in 40 ml of water and 40 ml of dichloromethane and the reaction mixture is stirred overnight.
- the organic phase is separated off and washed with water.
- the aqueous phase is back-extracted with dichloromethane.
- the organic phases are combined, dried over magnesium sulfate and concentrated by evaporation.
- the evaporation residue is purified by chromatography on silica gel with hexane/ethyl acetate (first 20:1 , then 15:1 , finally 10:1) and taken up in 10 ml of tetrahydrofuran. 5 ml of 2N hydrochloric acid are added and heating at reflux is carried out overnight. The reaction mixture is allowed to cool to room temperature, poured into 50 ml of water, filtered with suction, washed with water and dried. The filtration residue is made into a slurry in 3 ml of water; 3 ml of acetic acid and 3 ml of concentrated sulfuric acid are added and heating at reflux is carried out for 5 hours.
- the starting material can be prepared, for example, as follows: a) 5-lodo-2.3.7-trichloro-quinoxaline
- Example 10 2-(7-Bromo-2,3-dioxo-1 ⁇ .S -tetrahydro-quinoxalin- ⁇ -vOethenephosphonic acid
- the starting material can be prepared, for example, as follows:
- Example 13 In a manner analogous to that described in Examples 1 to 12, the following compounds can also be prepared:
- Example 14 Tablets, each comprising 50 mg of 2,3-dioxo-1 ,2,3,4-tetrahydro-quinoxalin-5- ylmethanephosphonic acid or a salt, for example the sodium salt, thereof can be prepared as follows:
- composition (10 000 tablets) active ingredient 500.0 g lactose 500.0 g potato starch gelatin 8.0 g talc 60.0 g magnesium stearate 10.0 g silicon dioxide (highly dispersed) 20.0 g ethanol q.s.
- the active ingredient is mixed with the lactose and 292 g of the potato starch, and the mixture is moistened with an ethanolic solution of the gelatin and granulated through a sieve. After drying, the remainder of the potato starch, the magnesium stearate, the talc and the silicon dioxide are mixed in and the mixture is compressed to form tablets each weighing 145.0 mg and comprising 50 mg of active ingredient; if desired, the tablets may be provided with dividing notches for finer adaptation of the dose.
- Example 15 A sterile-filtered aqueous gelatin solution with 20 % cyclodextrins as solubiliser, comprising 3 mg each of 2,3-dioxo-1 ,2,3,4-tetrahydro-quinoxalin-5- ylmethanephosphonic acid or a salt, for example the sodium salt, thereof as active ingredient, is mixed with a sterile gelatin solution containing phenol as preservative, with heating and under aseptic conditions, in such a manner that 1.0 ml of solution has the following composition:
- Example 16 For the preparation of a sterile dry substance for injection comprising 5 mg each of 2,3-dioxo-1 ,2,3,4-tetrahydro-quinoxalin-5-ylmethanephosphonic acid or a salt, for example the sodium salt, thereof, 5 mg of one of the compounds of formula I mentioned in the preceding Examples, as active ingredient, are dissolved in 1 ml of an aqueous solution with 20 mg of mannitol and 20 % cyclodextrins as solubiliser. The solution is sterile-filtered and, under aseptic conditions, introduced into a 2 ml ampoule, deep-frozen and lyophilised.
- the lyophilisate is dissolved in 1 ml of distilled water or 1 ml of physiological sodium chloride solution.
- the solution is administered intramuscularly or intravenously.
- the formulation can also be introduced into double-chamber disposable syringes.
- Example 17 10000 film-coated tablets, each comprising 100 mg of 2,3-dioxo-1 , 2,3,4- tetrahydro-quinoxalin-5-ylmethanephosphonic acid or a salt, for example the sodium salt, thereof, can be prepared as follows:
- active ingredient 1000 g com starch 680 g colloidal silica 200 g magnesium stearate 20 g stearic acid 50 g sodium carboxy methyl starch 250 g water q. s.
- a mixture of one of the compounds of formula I mentioned in the preceding Examples, as active ingredient, 50 g of corn starch and the colloidal silica is made into a moist mass with a starch paste prepared from 250 g of corn starch and 2.2 kg of demineralised water.
- the moist mass is forced through a sieve of 3 mm mesh size and dried in a fluidised bed drier at 45° for 30 minutes.
- the dry granules are pressed through a sieve of 1 mm mesh size, mixed with a previously sieved mixture (1 mm sieve) of 330 g of com starch, the magnesium stearate, the stearic acid and the sodium carboxymethyl starch and compressed to form slightly domed tablets.
- Example 18 In a manner analogous to that described in Examples 14 to 17 it is also possible to prepare pharmaceutical compositions comprising a different compound according to any one of Examples 1 to 13.
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Abstract
Cette invention concerne les acides quinoxaline- et quinoxalinylalkane-phosphoniques représentés par la formule (I), dans laquelle R1 est carboxy libre ou estérifié ou phosphono libre ou partiellement estérifié, R2 et R3 sont chacun, indépendamment l'un de l'autre, l'hydrogène ou un radical aliphatique, les radicaux R4, R5 et R6 sont chacun, indépendamment les uns des autres, l'hydrogène, un radical hydrocarbure aliphatique, hydroxy libre ou étherifié, mercapto libre ou étherifié ou mercapto oxydé libre ou étherifié, amino non substitué ou substitué par un radical aliphatique, nitro, carboxy libre ou estérifié ou amidé, cyano, sulfamoyle libre ou amidé, halogène ou trifluorométhyle et X est un radical aliphatique divalent. L'invention concerne également les tautomères de ces acides et/ou leurs sels qui sont dotés de propriétés antagonistes vis-à-vis de l'acide N-méthyl-D-aspartique (NMDA) et qui peuvent servir au traitement d'états pathologiques qui répondent à un blocage des récepteurs sensibles au NMDA.
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CH2009/95 | 1995-07-10 | ||
CH200995 | 1995-07-10 | ||
PCT/EP1996/002866 WO1997003079A1 (fr) | 1995-07-10 | 1996-07-01 | Nouveaux acides quinoxaline- et quinoxalinylalkane-phosphoniques |
Publications (1)
Publication Number | Publication Date |
---|---|
EP0837864A1 true EP0837864A1 (fr) | 1998-04-29 |
Family
ID=4223780
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
EP96924829A Withdrawn EP0837864A1 (fr) | 1995-07-10 | 1996-07-01 | Nouveaux acides quinoxaline- et quinoxalinylalkane-phosphoniques |
Country Status (15)
Country | Link |
---|---|
EP (1) | EP0837864A1 (fr) |
JP (1) | JPH11508902A (fr) |
KR (1) | KR19990028839A (fr) |
AU (1) | AU6516296A (fr) |
BR (1) | BR9609644A (fr) |
CA (1) | CA2224718A1 (fr) |
CZ (1) | CZ5398A3 (fr) |
HU (1) | HUP9901345A3 (fr) |
IL (1) | IL122872A0 (fr) |
NO (1) | NO980095L (fr) |
PL (1) | PL324340A1 (fr) |
SK (1) | SK2798A3 (fr) |
TR (1) | TR199800022T1 (fr) |
WO (1) | WO1997003079A1 (fr) |
ZA (1) | ZA965800B (fr) |
Families Citing this family (3)
Publication number | Priority date | Publication date | Assignee | Title |
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CZ141399A3 (cs) * | 1996-10-24 | 1999-07-14 | Novartis Ag | Substituované aminoalkanfosfonové kyseliny, způsob jejich přípravy a farmaceutické prostředky, které je obsahují |
US6841684B2 (en) | 1997-12-04 | 2005-01-11 | Allergan, Inc. | Imidiazoles having reduced side effects |
US6329369B1 (en) | 1997-12-04 | 2001-12-11 | Allergan Sales, Inc. | Methods of treating pain and other conditions |
Family Cites Families (2)
Publication number | Priority date | Publication date | Assignee | Title |
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US5118675A (en) * | 1991-02-15 | 1992-06-02 | American Home Products Corporation | Quinoxaline phosphono-amino acids |
IL109397A0 (en) * | 1993-04-28 | 1994-07-31 | Schering Ag | Quinoxalinedione derivatives, processes for the preparation thereof and pharmaceutical compositions containing the same |
-
1996
- 1996-07-01 EP EP96924829A patent/EP0837864A1/fr not_active Withdrawn
- 1996-07-01 CA CA002224718A patent/CA2224718A1/fr not_active Abandoned
- 1996-07-01 AU AU65162/96A patent/AU6516296A/en not_active Abandoned
- 1996-07-01 WO PCT/EP1996/002866 patent/WO1997003079A1/fr not_active Application Discontinuation
- 1996-07-01 BR BR9609644A patent/BR9609644A/pt not_active Application Discontinuation
- 1996-07-01 SK SK27-98A patent/SK2798A3/sk unknown
- 1996-07-01 CZ CZ9853A patent/CZ5398A3/cs unknown
- 1996-07-01 PL PL96324340A patent/PL324340A1/xx unknown
- 1996-07-01 KR KR1019980700140A patent/KR19990028839A/ko not_active Application Discontinuation
- 1996-07-01 TR TR1998/00022T patent/TR199800022T1/xx unknown
- 1996-07-01 HU HU9901345A patent/HUP9901345A3/hu unknown
- 1996-07-01 IL IL12287296A patent/IL122872A0/xx unknown
- 1996-07-01 JP JP9505465A patent/JPH11508902A/ja active Pending
- 1996-07-09 ZA ZA965800A patent/ZA965800B/xx unknown
-
1998
- 1998-01-09 NO NO980095A patent/NO980095L/no unknown
Non-Patent Citations (1)
Title |
---|
See references of WO9703079A1 * |
Also Published As
Publication number | Publication date |
---|---|
HUP9901345A3 (en) | 2000-01-28 |
PL324340A1 (en) | 1998-05-25 |
CZ5398A3 (cs) | 1998-06-17 |
WO1997003079A1 (fr) | 1997-01-30 |
MX9800332A (es) | 1998-07-31 |
ZA965800B (en) | 1997-01-10 |
BR9609644A (pt) | 1999-05-11 |
KR19990028839A (ko) | 1999-04-15 |
JPH11508902A (ja) | 1999-08-03 |
AU6516296A (en) | 1997-02-10 |
TR199800022T1 (xx) | 1998-05-21 |
NO980095D0 (no) | 1998-01-09 |
HUP9901345A2 (hu) | 1999-08-30 |
NO980095L (no) | 1998-03-05 |
IL122872A0 (en) | 1998-08-16 |
SK2798A3 (en) | 1998-07-08 |
CA2224718A1 (fr) | 1997-01-30 |
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