NO173185B - Analogifremgangsmaate for fremstilling av terapeutisk aktive imidazokinoxalinforbindelser - Google Patents
Analogifremgangsmaate for fremstilling av terapeutisk aktive imidazokinoxalinforbindelser Download PDFInfo
- Publication number
- NO173185B NO173185B NO892204A NO892204A NO173185B NO 173185 B NO173185 B NO 173185B NO 892204 A NO892204 A NO 892204A NO 892204 A NO892204 A NO 892204A NO 173185 B NO173185 B NO 173185B
- Authority
- NO
- Norway
- Prior art keywords
- quinoxaline
- cyclopropyl
- dihydro
- oxo
- compound
- Prior art date
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- 150000001875 compounds Chemical class 0.000 title claims description 49
- 238000000034 method Methods 0.000 title claims description 9
- 238000002360 preparation method Methods 0.000 title claims description 8
- 230000001225 therapeutic effect Effects 0.000 title 1
- -1 C1-4- alkoxycarbonyl Chemical group 0.000 claims description 10
- 229910052736 halogen Inorganic materials 0.000 claims description 7
- 150000002367 halogens Chemical group 0.000 claims description 7
- 239000007858 starting material Substances 0.000 claims description 7
- YELMWJNXDALKFE-UHFFFAOYSA-N 3h-imidazo[4,5-f]quinoxaline Chemical class N1=CC=NC2=C(NC=N3)C3=CC=C21 YELMWJNXDALKFE-UHFFFAOYSA-N 0.000 claims description 6
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 4
- 238000004519 manufacturing process Methods 0.000 claims description 4
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 4
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 3
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 3
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 2
- SANOAHQLNAFPBJ-UHFFFAOYSA-N 3-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)-5-[(4-methoxyphenyl)methyl]imidazo[1,5-a]quinoxalin-4-one Chemical compound C1=CC(OC)=CC=C1CN1C(=O)C2=C(C=3N=C(ON=3)C3CC3)N=CN2C2=CC=CC=C21 SANOAHQLNAFPBJ-UHFFFAOYSA-N 0.000 claims description 2
- DXQIOCHVIUTGED-UHFFFAOYSA-N 3-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)-5-methyl-6-(trifluoromethyl)imidazo[1,5-a]quinoxalin-4-one Chemical compound C=12C(=O)N(C)C3=C(C(F)(F)F)C=CC=C3N2C=NC=1C(N=1)=NOC=1C1CC1 DXQIOCHVIUTGED-UHFFFAOYSA-N 0.000 claims description 2
- 125000000882 C2-C6 alkenyl group Chemical group 0.000 claims description 2
- XAKBSHICSHRJCL-UHFFFAOYSA-N [CH2]C(=O)C1=CC=CC=C1 Chemical group [CH2]C(=O)C1=CC=CC=C1 XAKBSHICSHRJCL-UHFFFAOYSA-N 0.000 claims description 2
- 125000000852 azido group Chemical group *N=[N+]=[N-] 0.000 claims description 2
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 2
- 230000015572 biosynthetic process Effects 0.000 claims description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 2
- 125000001064 morpholinomethyl group Chemical group [H]C([H])(*)N1C([H])([H])C([H])([H])OC([H])([H])C1([H])[H] 0.000 claims description 2
- 125000004076 pyridyl group Chemical group 0.000 claims description 2
- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 claims description 2
- ASOUKPMQUOTJSJ-UHFFFAOYSA-N 5-benzyl-3-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)imidazo[1,5-a]quinoxalin-4-one Chemical compound C12=CC=CC=C2N2C=NC(C=3N=C(ON=3)C3CC3)=C2C(=O)N1CC1=CC=CC=C1 ASOUKPMQUOTJSJ-UHFFFAOYSA-N 0.000 claims 1
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 33
- 238000006243 chemical reaction Methods 0.000 description 21
- 239000000243 solution Substances 0.000 description 20
- 238000012360 testing method Methods 0.000 description 19
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 18
- 230000027455 binding Effects 0.000 description 14
- 239000003921 oil Substances 0.000 description 14
- 239000000203 mixture Substances 0.000 description 13
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 13
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 12
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 12
- 230000009870 specific binding Effects 0.000 description 11
- 238000005984 hydrogenation reaction Methods 0.000 description 10
- BGHGVAKKIBOJGS-UHFFFAOYSA-N 5-cyclopropyl-3-(isocyanomethyl)-1,2,4-oxadiazole Chemical compound [C-]#[N+]CC1=NOC(C2CC2)=N1 BGHGVAKKIBOJGS-UHFFFAOYSA-N 0.000 description 9
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 9
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 9
- 102000004300 GABA-A Receptors Human genes 0.000 description 9
- 108090000839 GABA-A Receptors Proteins 0.000 description 9
- 229960002200 flunitrazepam Drugs 0.000 description 9
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 8
- 239000013078 crystal Substances 0.000 description 8
- 238000001953 recrystallisation Methods 0.000 description 8
- 241000699670 Mus sp. Species 0.000 description 7
- 239000002904 solvent Substances 0.000 description 7
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 6
- 230000029936 alkylation Effects 0.000 description 6
- 238000005804 alkylation reaction Methods 0.000 description 6
- 238000001704 evaporation Methods 0.000 description 6
- 230000008020 evaporation Effects 0.000 description 6
- 238000005574 benzylation reaction Methods 0.000 description 5
- 238000000354 decomposition reaction Methods 0.000 description 5
- 238000001914 filtration Methods 0.000 description 5
- 239000000047 product Substances 0.000 description 5
- 238000003756 stirring Methods 0.000 description 5
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 4
- 210000004556 brain Anatomy 0.000 description 4
- 239000003054 catalyst Substances 0.000 description 4
- 238000000338 in vitro Methods 0.000 description 4
- 238000000746 purification Methods 0.000 description 4
- XSCHRSMBECNVNS-UHFFFAOYSA-N quinoxaline Chemical compound N1=CC=NC2=CC=CC=C21 XSCHRSMBECNVNS-UHFFFAOYSA-N 0.000 description 4
- 239000011734 sodium Substances 0.000 description 4
- 239000000126 substance Substances 0.000 description 4
- PPTYJKAXVCCBDU-UHFFFAOYSA-N Rohypnol Chemical compound N=1CC(=O)N(C)C2=CC=C([N+]([O-])=O)C=C2C=1C1=CC=CC=C1F PPTYJKAXVCCBDU-UHFFFAOYSA-N 0.000 description 3
- 125000000217 alkyl group Chemical group 0.000 description 3
- DGBIGWXXNGSACT-UHFFFAOYSA-N clonazepam Chemical compound C12=CC([N+](=O)[O-])=CC=C2NC(=O)CN=C1C1=CC=CC=C1Cl DGBIGWXXNGSACT-UHFFFAOYSA-N 0.000 description 3
- 229960003120 clonazepam Drugs 0.000 description 3
- 238000001816 cooling Methods 0.000 description 3
- IGTAQWQSTWWBIN-UHFFFAOYSA-N ethyl 2-(2-methyl-6-nitroanilino)-2-oxoacetate Chemical compound CCOC(=O)C(=O)NC1=C(C)C=CC=C1[N+]([O-])=O IGTAQWQSTWWBIN-UHFFFAOYSA-N 0.000 description 3
- OWZFULPEVHKEKS-UHFFFAOYSA-N ethyl 2-chloro-2-oxoacetate Chemical compound CCOC(=O)C(Cl)=O OWZFULPEVHKEKS-UHFFFAOYSA-N 0.000 description 3
- 238000002474 experimental method Methods 0.000 description 3
- 239000000706 filtrate Substances 0.000 description 3
- 230000005764 inhibitory process Effects 0.000 description 3
- 239000012528 membrane Substances 0.000 description 3
- 239000012074 organic phase Substances 0.000 description 3
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 3
- 239000002244 precipitate Substances 0.000 description 3
- 238000010992 reflux Methods 0.000 description 3
- 229910000104 sodium hydride Inorganic materials 0.000 description 3
- PWKNBLFSJAVFAB-UHFFFAOYSA-N 1-fluoro-2-nitrobenzene Chemical compound [O-][N+](=O)C1=CC=CC=C1F PWKNBLFSJAVFAB-UHFFFAOYSA-N 0.000 description 2
- OARGFWQSVACNCO-UHFFFAOYSA-N 1-oxidoquinoxalin-1-ium Chemical class C1=CC=C2[N+]([O-])=CC=NC2=C1 OARGFWQSVACNCO-UHFFFAOYSA-N 0.000 description 2
- JLJLETOTDNHVIP-UHFFFAOYSA-N 2-[4-[[3-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)-4-oxoimidazo[1,5-a]quinoxalin-5-yl]methyl]phenyl]isoindole-1,3-dione Chemical compound O=C1C2=CC=CC=C2C(=O)N1C(C=C1)=CC=C1CN(C(C1=2)=O)C3=CC=CC=C3N1C=NC=2C(N=1)=NOC=1C1CC1 JLJLETOTDNHVIP-UHFFFAOYSA-N 0.000 description 2
- SVJNQVIWKIZMRC-UHFFFAOYSA-N 3-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)-5h-imidazo[1,5-a]quinoxalin-4-one Chemical compound C=12C(=O)NC3=CC=CC=C3N2C=NC=1C(N=1)=NOC=1C1CC1 SVJNQVIWKIZMRC-UHFFFAOYSA-N 0.000 description 2
- MSWWEVDXTOMRBH-UHFFFAOYSA-N 4-(2-morpholin-4-ylethyl)-1h-quinoxaline-2,3-dione Chemical compound O=C1C(=O)NC2=CC=CC=C2N1CCN1CCOCC1 MSWWEVDXTOMRBH-UHFFFAOYSA-N 0.000 description 2
- KXHGZQSYWAZQCY-UHFFFAOYSA-N 4-(2-phenylethyl)-1h-quinoxaline-2,3-dione Chemical compound O=C1C(=O)NC2=CC=CC=C2N1CCC1=CC=CC=C1 KXHGZQSYWAZQCY-UHFFFAOYSA-N 0.000 description 2
- MZSCYTKFLASYPJ-UHFFFAOYSA-N 4-(cyclopropylmethyl)-1h-quinoxaline-2,3-dione Chemical compound O=C1C(=O)NC2=CC=CC=C2N1CC1CC1 MZSCYTKFLASYPJ-UHFFFAOYSA-N 0.000 description 2
- ZZQRPPDUPMPUEN-UHFFFAOYSA-N 4-(pyridin-2-ylmethyl)-1h-quinoxaline-2,3-dione Chemical compound O=C1C(=O)NC2=CC=CC=C2N1CC1=CC=CC=N1 ZZQRPPDUPMPUEN-UHFFFAOYSA-N 0.000 description 2
- GAVNQTDPNIIKJC-UHFFFAOYSA-N 4-[(2-chlorophenyl)methyl]-1h-quinoxaline-2,3-dione Chemical compound ClC1=CC=CC=C1CN1C(=O)C(=O)NC2=CC=CC=C21 GAVNQTDPNIIKJC-UHFFFAOYSA-N 0.000 description 2
- WXGHYOYBNYQPOR-UHFFFAOYSA-N 4-[(2-methoxyphenyl)methyl]-1h-quinoxaline-2,3-dione Chemical compound COC1=CC=CC=C1CN1C(=O)C(=O)NC2=CC=CC=C21 WXGHYOYBNYQPOR-UHFFFAOYSA-N 0.000 description 2
- RWKKRTGDEZLHOT-UHFFFAOYSA-N 4-[(4-methoxyphenyl)methyl]-1h-quinoxaline-2,3-dione Chemical compound C1=CC(OC)=CC=C1CN1C(=O)C(=O)NC2=CC=CC=C21 RWKKRTGDEZLHOT-UHFFFAOYSA-N 0.000 description 2
- SIBKUTVOUINYEG-UHFFFAOYSA-N 4-benzyl-1h-quinoxaline-2,3-dione Chemical compound O=C1C(=O)NC2=CC=CC=C2N1CC1=CC=CC=C1 SIBKUTVOUINYEG-UHFFFAOYSA-N 0.000 description 2
- RJOOVGXDNJYMLN-UHFFFAOYSA-N 4-methyl-5-(trifluoromethyl)-1h-quinoxaline-2,3-dione Chemical compound C1=CC=C2NC(=O)C(=O)N(C)C2=C1C(F)(F)F RJOOVGXDNJYMLN-UHFFFAOYSA-N 0.000 description 2
- NQDZYYBPYMUOHM-UHFFFAOYSA-N 5-chloro-4-[(2-chlorophenyl)methyl]-1h-quinoxaline-2,3-dione Chemical compound ClC1=CC=CC=C1CN1C(=O)C(=O)NC2=CC=CC(Cl)=C21 NQDZYYBPYMUOHM-UHFFFAOYSA-N 0.000 description 2
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 2
- 241000283690 Bos taurus Species 0.000 description 2
- OAKJQQAXSVQMHS-UHFFFAOYSA-N Hydrazine Chemical compound NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 0.000 description 2
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 2
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 2
- 239000007836 KH2PO4 Substances 0.000 description 2
- PXHVJJICTQNCMI-UHFFFAOYSA-N Nickel Chemical compound [Ni] PXHVJJICTQNCMI-UHFFFAOYSA-N 0.000 description 2
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 2
- OFBQJSOFQDEBGM-UHFFFAOYSA-N Pentane Chemical compound CCCCC OFBQJSOFQDEBGM-UHFFFAOYSA-N 0.000 description 2
- BHHGXPLMPWCGHP-UHFFFAOYSA-N Phenethylamine Chemical compound NCCC1=CC=CC=C1 BHHGXPLMPWCGHP-UHFFFAOYSA-N 0.000 description 2
- 229910004298 SiO 2 Inorganic materials 0.000 description 2
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 2
- PXIPVTKHYLBLMZ-UHFFFAOYSA-N Sodium azide Chemical compound [Na+].[N-]=[N+]=[N-] PXIPVTKHYLBLMZ-UHFFFAOYSA-N 0.000 description 2
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 2
- 125000003545 alkoxy group Chemical group 0.000 description 2
- 239000002585 base Substances 0.000 description 2
- 229910052681 coesite Inorganic materials 0.000 description 2
- 229910052906 cristobalite Inorganic materials 0.000 description 2
- 239000012043 crude product Substances 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- MYUUELKWXBKDLD-UHFFFAOYSA-N ethyl 2-[2-chloro-n-[(2-chlorophenyl)methyl]-6-nitroanilino]-2-oxoacetate Chemical compound ClC=1C=CC=C([N+]([O-])=O)C=1N(C(=O)C(=O)OCC)CC1=CC=CC=C1Cl MYUUELKWXBKDLD-UHFFFAOYSA-N 0.000 description 2
- IPARZNCOGXJAIW-UHFFFAOYSA-N ethyl 2-[2-nitro-n-(2-phenylethyl)anilino]-2-oxoacetate Chemical compound C=1C=CC=C([N+]([O-])=O)C=1N(C(=O)C(=O)OCC)CCC1=CC=CC=C1 IPARZNCOGXJAIW-UHFFFAOYSA-N 0.000 description 2
- CKXVSXDELNBDJL-UHFFFAOYSA-N ethyl 2-[2-nitro-n-(pyridin-2-ylmethyl)anilino]-2-oxoacetate Chemical compound C=1C=CC=C([N+]([O-])=O)C=1N(C(=O)C(=O)OCC)CC1=CC=CC=N1 CKXVSXDELNBDJL-UHFFFAOYSA-N 0.000 description 2
- SFEGNHXTMWQDDB-UHFFFAOYSA-N ethyl 2-[4-chloro-2-(trifluoromethyl)anilino]-2-oxoacetate Chemical compound CCOC(=O)C(=O)NC1=CC=C(Cl)C=C1C(F)(F)F SFEGNHXTMWQDDB-UHFFFAOYSA-N 0.000 description 2
- QLQPQHXECPDHQO-UHFFFAOYSA-N ethyl 2-[4-chloro-2-nitro-6-(trifluoromethyl)anilino]-2-oxoacetate Chemical compound CCOC(=O)C(=O)NC1=C([N+]([O-])=O)C=C(Cl)C=C1C(F)(F)F QLQPQHXECPDHQO-UHFFFAOYSA-N 0.000 description 2
- UIUPBYZOZKPTQI-UHFFFAOYSA-N ethyl 2-[n-(2-morpholin-4-ylethyl)-2-nitroanilino]-2-oxoacetate Chemical compound C=1C=CC=C([N+]([O-])=O)C=1N(C(=O)C(=O)OCC)CCN1CCOCC1 UIUPBYZOZKPTQI-UHFFFAOYSA-N 0.000 description 2
- KKJAXXJNQOWTRF-UHFFFAOYSA-N ethyl 2-[n-[(2-chlorophenyl)methyl]-2-nitroanilino]-2-oxoacetate Chemical compound C=1C=CC=C([N+]([O-])=O)C=1N(C(=O)C(=O)OCC)CC1=CC=CC=C1Cl KKJAXXJNQOWTRF-UHFFFAOYSA-N 0.000 description 2
- GGNPWPBNIOGCTC-UHFFFAOYSA-N ethyl 2-[n-[(2-methoxyphenyl)methyl]-2-nitroanilino]-2-oxoacetate Chemical compound C=1C=CC=C([N+]([O-])=O)C=1N(C(=O)C(=O)OCC)CC1=CC=CC=C1OC GGNPWPBNIOGCTC-UHFFFAOYSA-N 0.000 description 2
- VNYCTJDKROAOIW-UHFFFAOYSA-N ethyl 2-[n-[(4-methoxyphenyl)methyl]-2-nitroanilino]-2-oxoacetate Chemical compound C=1C=CC=C([N+]([O-])=O)C=1N(C(=O)C(=O)OCC)CC1=CC=C(OC)C=C1 VNYCTJDKROAOIW-UHFFFAOYSA-N 0.000 description 2
- 239000003365 glass fiber Substances 0.000 description 2
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 2
- 229910000402 monopotassium phosphate Inorganic materials 0.000 description 2
- 235000019796 monopotassium phosphate Nutrition 0.000 description 2
- OMCUPXRCMTUDHI-UHFFFAOYSA-N n'-hydroxycyclopropanecarboximidamide Chemical compound ON=C(N)C1CC1 OMCUPXRCMTUDHI-UHFFFAOYSA-N 0.000 description 2
- 230000009871 nonspecific binding Effects 0.000 description 2
- GNSKLFRGEWLPPA-UHFFFAOYSA-M potassium dihydrogen phosphate Chemical compound [K+].OP(O)([O-])=O GNSKLFRGEWLPPA-UHFFFAOYSA-M 0.000 description 2
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- 239000012312 sodium hydride Substances 0.000 description 2
- LPXPTNMVRIOKMN-UHFFFAOYSA-M sodium nitrite Chemical compound [Na+].[O-]N=O LPXPTNMVRIOKMN-UHFFFAOYSA-M 0.000 description 2
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- 125000001424 substituent group Chemical group 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N sulfuric acid Substances OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
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- ILWRPSCZWQJDMK-UHFFFAOYSA-N triethylazanium;chloride Chemical compound Cl.CCN(CC)CC ILWRPSCZWQJDMK-UHFFFAOYSA-N 0.000 description 2
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 2
- UAOUIVVJBYDFKD-XKCDOFEDSA-N (1R,9R,10S,11R,12R,15S,18S,21R)-10,11,21-trihydroxy-8,8-dimethyl-14-methylidene-4-(prop-2-enylamino)-20-oxa-5-thia-3-azahexacyclo[9.7.2.112,15.01,9.02,6.012,18]henicosa-2(6),3-dien-13-one Chemical compound C([C@@H]1[C@@H](O)[C@@]23C(C1=C)=O)C[C@H]2[C@]12C(N=C(NCC=C)S4)=C4CC(C)(C)[C@H]1[C@H](O)[C@]3(O)OC2 UAOUIVVJBYDFKD-XKCDOFEDSA-N 0.000 description 1
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- LJOOWESTVASNOG-UFJKPHDISA-N [(1s,3r,4ar,7s,8s,8as)-3-hydroxy-8-[2-[(4r)-4-hydroxy-6-oxooxan-2-yl]ethyl]-7-methyl-1,2,3,4,4a,7,8,8a-octahydronaphthalen-1-yl] (2s)-2-methylbutanoate Chemical compound C([C@H]1[C@@H](C)C=C[C@H]2C[C@@H](O)C[C@@H]([C@H]12)OC(=O)[C@@H](C)CC)CC1C[C@@H](O)CC(=O)O1 LJOOWESTVASNOG-UFJKPHDISA-N 0.000 description 1
- LNUFLCYMSVYYNW-ZPJMAFJPSA-N [(2r,3r,4s,5r,6r)-2-[(2r,3r,4s,5r,6r)-6-[(2r,3r,4s,5r,6r)-6-[(2r,3r,4s,5r,6r)-6-[[(3s,5s,8r,9s,10s,13r,14s,17r)-10,13-dimethyl-17-[(2r)-6-methylheptan-2-yl]-2,3,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydro-1h-cyclopenta[a]phenanthren-3-yl]oxy]-4,5-disulfo Chemical compound O([C@@H]1[C@@H](COS(O)(=O)=O)O[C@@H]([C@@H]([C@H]1OS(O)(=O)=O)OS(O)(=O)=O)O[C@@H]1[C@@H](COS(O)(=O)=O)O[C@@H]([C@@H]([C@H]1OS(O)(=O)=O)OS(O)(=O)=O)O[C@@H]1[C@@H](COS(O)(=O)=O)O[C@H]([C@@H]([C@H]1OS(O)(=O)=O)OS(O)(=O)=O)O[C@@H]1C[C@@H]2CC[C@H]3[C@@H]4CC[C@@H]([C@]4(CC[C@@H]3[C@@]2(C)CC1)C)[C@H](C)CCCC(C)C)[C@H]1O[C@H](COS(O)(=O)=O)[C@@H](OS(O)(=O)=O)[C@H](OS(O)(=O)=O)[C@H]1OS(O)(=O)=O LNUFLCYMSVYYNW-ZPJMAFJPSA-N 0.000 description 1
- SMNRFWMNPDABKZ-WVALLCKVSA-N [[(2R,3S,4R,5S)-5-(2,6-dioxo-3H-pyridin-3-yl)-3,4-dihydroxyoxolan-2-yl]methoxy-hydroxyphosphoryl] [[[(2R,3S,4S,5R,6R)-4-fluoro-3,5-dihydroxy-6-(hydroxymethyl)oxan-2-yl]oxy-hydroxyphosphoryl]oxy-hydroxyphosphoryl] hydrogen phosphate Chemical compound OC[C@H]1O[C@H](OP(O)(=O)OP(O)(=O)OP(O)(=O)OP(O)(=O)OC[C@H]2O[C@H]([C@H](O)[C@@H]2O)C2C=CC(=O)NC2=O)[C@H](O)[C@@H](F)[C@@H]1O SMNRFWMNPDABKZ-WVALLCKVSA-N 0.000 description 1
- 229910052783 alkali metal Inorganic materials 0.000 description 1
- 150000001340 alkali metals Chemical class 0.000 description 1
- 150000004703 alkoxides Chemical class 0.000 description 1
- 125000004414 alkyl thio group Chemical group 0.000 description 1
- BHELZAPQIKSEDF-UHFFFAOYSA-N allyl bromide Chemical compound BrCC=C BHELZAPQIKSEDF-UHFFFAOYSA-N 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 150000001448 anilines Chemical class 0.000 description 1
- 229940125681 anticonvulsant agent Drugs 0.000 description 1
- 239000001961 anticonvulsive agent Substances 0.000 description 1
- 239000002249 anxiolytic agent Substances 0.000 description 1
- 230000000949 anxiolytic effect Effects 0.000 description 1
- 229940005530 anxiolytics Drugs 0.000 description 1
- 239000000010 aprotic solvent Substances 0.000 description 1
- 125000004659 aryl alkyl thio group Chemical group 0.000 description 1
- XRWSZZJLZRKHHD-WVWIJVSJSA-N asunaprevir Chemical compound O=C([C@@H]1C[C@H](CN1C(=O)[C@@H](NC(=O)OC(C)(C)C)C(C)(C)C)OC1=NC=C(C2=CC=C(Cl)C=C21)OC)N[C@]1(C(=O)NS(=O)(=O)C2CC2)C[C@H]1C=C XRWSZZJLZRKHHD-WVWIJVSJSA-N 0.000 description 1
- 229940049706 benzodiazepine Drugs 0.000 description 1
- 150000001557 benzodiazepines Chemical class 0.000 description 1
- 239000004359 castor oil Substances 0.000 description 1
- 235000019438 castor oil Nutrition 0.000 description 1
- 210000003169 central nervous system Anatomy 0.000 description 1
- 208000015114 central nervous system disease Diseases 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- BULLHNJGPPOUOX-UHFFFAOYSA-N chloroacetone Chemical compound CC(=O)CCl BULLHNJGPPOUOX-UHFFFAOYSA-N 0.000 description 1
- 238000011097 chromatography purification Methods 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 229940125904 compound 1 Drugs 0.000 description 1
- 229940125773 compound 10 Drugs 0.000 description 1
- 229940125782 compound 2 Drugs 0.000 description 1
- 229940125810 compound 20 Drugs 0.000 description 1
- 229940126086 compound 21 Drugs 0.000 description 1
- 229940126208 compound 22 Drugs 0.000 description 1
- 229940125833 compound 23 Drugs 0.000 description 1
- 229940125961 compound 24 Drugs 0.000 description 1
- 229940125846 compound 25 Drugs 0.000 description 1
- 229940125851 compound 27 Drugs 0.000 description 1
- 229940127204 compound 29 Drugs 0.000 description 1
- 229940126214 compound 3 Drugs 0.000 description 1
- 229940125877 compound 31 Drugs 0.000 description 1
- 229940125898 compound 5 Drugs 0.000 description 1
- FDSGHYHRLSWSLQ-UHFFFAOYSA-N dichloromethane;propan-2-one Chemical compound ClCCl.CC(C)=O FDSGHYHRLSWSLQ-UHFFFAOYSA-N 0.000 description 1
- LGTLXDJOAJDFLR-UHFFFAOYSA-N diethyl chlorophosphate Chemical compound CCOP(Cl)(=O)OCC LGTLXDJOAJDFLR-UHFFFAOYSA-N 0.000 description 1
- 238000010790 dilution Methods 0.000 description 1
- 239000012895 dilution Substances 0.000 description 1
- 238000006073 displacement reaction Methods 0.000 description 1
- 231100000673 dose–response relationship Toxicity 0.000 description 1
- 230000001804 emulsifying effect Effects 0.000 description 1
- UKOOFCDBPQTEMN-UHFFFAOYSA-N ethyl 2-(2-amino-n-ethyl-6-methylanilino)-2-oxoacetate Chemical compound CCOC(=O)C(=O)N(CC)C1=C(C)C=CC=C1N UKOOFCDBPQTEMN-UHFFFAOYSA-N 0.000 description 1
- YETCHFCSGMIGCG-UHFFFAOYSA-N ethyl 2-(n,2-dimethyl-6-nitroanilino)-2-oxoacetate Chemical compound CCOC(=O)C(=O)N(C)C1=C(C)C=CC=C1[N+]([O-])=O YETCHFCSGMIGCG-UHFFFAOYSA-N 0.000 description 1
- JBNSDIIYAHXPRP-UHFFFAOYSA-N ethyl 2-(n-benzyl-2-nitroanilino)-2-oxoacetate Chemical compound C=1C=CC=C([N+]([O-])=O)C=1N(C(=O)C(=O)OCC)CC1=CC=CC=C1 JBNSDIIYAHXPRP-UHFFFAOYSA-N 0.000 description 1
- YORWFQDNJTVELY-UHFFFAOYSA-N ethyl 2-(n-ethyl-2-methyl-6-nitroanilino)-2-oxoacetate Chemical compound CCOC(=O)C(=O)N(CC)C1=C(C)C=CC=C1[N+]([O-])=O YORWFQDNJTVELY-UHFFFAOYSA-N 0.000 description 1
- FMXMNHQNNVUGLQ-UHFFFAOYSA-N ethyl 2-[4-chloro-n-methyl-2-nitro-6-(trifluoromethyl)anilino]-2-oxoacetate Chemical compound CCOC(=O)C(=O)N(C)C1=C([N+]([O-])=O)C=C(Cl)C=C1C(F)(F)F FMXMNHQNNVUGLQ-UHFFFAOYSA-N 0.000 description 1
- ZUUGCWCMPFGVQW-UHFFFAOYSA-N ethyl 2-[n-(cyclopropylmethyl)-2-nitroanilino]-2-oxoacetate Chemical compound C=1C=CC=C([N+]([O-])=O)C=1N(C(=O)C(=O)OCC)CC1CC1 ZUUGCWCMPFGVQW-UHFFFAOYSA-N 0.000 description 1
- YDGAUBHNAKCSKF-UHFFFAOYSA-N ethyl 2-anilino-2-oxoacetate Chemical class CCOC(=O)C(=O)NC1=CC=CC=C1 YDGAUBHNAKCSKF-UHFFFAOYSA-N 0.000 description 1
- GFJPZNJPGZBJOO-UHFFFAOYSA-N ethyl 5,6-dimethyl-4-oxoimidazo[1,5-a]quinoxaline-3-carboxylate Chemical compound C1=CC=C2N3C=NC(C(=O)OCC)=C3C(=O)N(C)C2=C1C GFJPZNJPGZBJOO-UHFFFAOYSA-N 0.000 description 1
- VEUUMBGHMNQHGO-UHFFFAOYSA-N ethyl chloroacetate Chemical compound CCOC(=O)CCl VEUUMBGHMNQHGO-UHFFFAOYSA-N 0.000 description 1
- 125000004494 ethyl ester group Chemical group 0.000 description 1
- 239000000284 extract Substances 0.000 description 1
- ZEMPKEQAKRGZGQ-XOQCFJPHSA-N glycerol triricinoleate Natural products CCCCCC[C@@H](O)CC=CCCCCCCCC(=O)OC[C@@H](COC(=O)CCCCCCCC=CC[C@@H](O)CCCCCC)OC(=O)CCCCCCCC=CC[C@H](O)CCCCCC ZEMPKEQAKRGZGQ-XOQCFJPHSA-N 0.000 description 1
- JAXFJECJQZDFJS-XHEPKHHKSA-N gtpl8555 Chemical compound OC(=O)C[C@H](N)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](C(C)C)C(=O)N1CCC[C@@H]1C(=O)N[C@H](B1O[C@@]2(C)[C@H]3C[C@H](C3(C)C)C[C@H]2O1)CCC1=CC=C(F)C=C1 JAXFJECJQZDFJS-XHEPKHHKSA-N 0.000 description 1
- 150000004820 halides Chemical class 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 150000004679 hydroxides Chemical class 0.000 description 1
- 239000005457 ice water Substances 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 238000011534 incubation Methods 0.000 description 1
- HVTICUPFWKNHNG-UHFFFAOYSA-N iodoethane Chemical compound CCI HVTICUPFWKNHNG-UHFFFAOYSA-N 0.000 description 1
- 150000002527 isonitriles Chemical class 0.000 description 1
- ZLVXBBHTMQJRSX-VMGNSXQWSA-N jdtic Chemical compound C1([C@]2(C)CCN(C[C@@H]2C)C[C@H](C(C)C)NC(=O)[C@@H]2NCC3=CC(O)=CC=C3C2)=CC=CC(O)=C1 ZLVXBBHTMQJRSX-VMGNSXQWSA-N 0.000 description 1
- 238000005567 liquid scintillation counting Methods 0.000 description 1
- 125000002816 methylsulfanyl group Chemical group [H]C([H])([H])S[*] 0.000 description 1
- 239000002808 molecular sieve Substances 0.000 description 1
- NSZYSZQFVBHJBA-UHFFFAOYSA-N n-(2-morpholin-4-ylethyl)-2-nitroaniline Chemical compound [O-][N+](=O)C1=CC=CC=C1NCCN1CCOCC1 NSZYSZQFVBHJBA-UHFFFAOYSA-N 0.000 description 1
- DRQPRDPGSQDAMA-UHFFFAOYSA-N n-[(2-chlorophenyl)methyl]-2-nitroaniline Chemical compound [O-][N+](=O)C1=CC=CC=C1NCC1=CC=CC=C1Cl DRQPRDPGSQDAMA-UHFFFAOYSA-N 0.000 description 1
- AYXCJSMKISRCNM-UHFFFAOYSA-N n-[(2-methoxyphenyl)methyl]-2-nitroaniline Chemical compound COC1=CC=CC=C1CNC1=CC=CC=C1[N+]([O-])=O AYXCJSMKISRCNM-UHFFFAOYSA-N 0.000 description 1
- KLPVHDQLXCJUOA-UHFFFAOYSA-N n-[(4-methoxyphenyl)methyl]-2-nitroaniline Chemical compound C1=CC(OC)=CC=C1CNC1=CC=CC=C1[N+]([O-])=O KLPVHDQLXCJUOA-UHFFFAOYSA-N 0.000 description 1
- 229910017604 nitric acid Inorganic materials 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 125000004433 nitrogen atom Chemical group N* 0.000 description 1
- 150000002894 organic compounds Chemical class 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 150000004866 oxadiazoles Chemical class 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- LIGACIXOYTUXAW-UHFFFAOYSA-N phenacyl bromide Chemical compound BrCC(=O)C1=CC=CC=C1 LIGACIXOYTUXAW-UHFFFAOYSA-N 0.000 description 1
- 229940117803 phenethylamine Drugs 0.000 description 1
- 239000002504 physiological saline solution Substances 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- MYEBTINIPPNJGS-UHFFFAOYSA-N potassium;quinoxaline Chemical compound [K].N1=CC=NC2=CC=CC=C21 MYEBTINIPPNJGS-UHFFFAOYSA-N 0.000 description 1
- 210000004129 prosencephalon Anatomy 0.000 description 1
- 239000000376 reactant Substances 0.000 description 1
- 102000005962 receptors Human genes 0.000 description 1
- 108020003175 receptors Proteins 0.000 description 1
- 238000007363 ring formation reaction Methods 0.000 description 1
- 238000003345 scintillation counting Methods 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
- 235000010288 sodium nitrite Nutrition 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 230000003381 solubilizing effect Effects 0.000 description 1
- 238000000527 sonication Methods 0.000 description 1
- 239000012258 stirred mixture Substances 0.000 description 1
- PXQLVRUNWNTZOS-UHFFFAOYSA-N sulfanyl Chemical class [SH] PXQLVRUNWNTZOS-UHFFFAOYSA-N 0.000 description 1
- 238000001308 synthesis method Methods 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 238000010998 test method Methods 0.000 description 1
- 239000012085 test solution Substances 0.000 description 1
- MLGCXEBRWGEOQX-UHFFFAOYSA-N tetradifon Chemical compound C1=CC(Cl)=CC=C1S(=O)(=O)C1=CC(Cl)=C(Cl)C=C1Cl MLGCXEBRWGEOQX-UHFFFAOYSA-N 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- 230000007704 transition Effects 0.000 description 1
- 230000007306 turnover Effects 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed 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
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmacology & Pharmacy (AREA)
- Neurosurgery (AREA)
- Biomedical Technology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Neurology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
Description
Foreliggende oppfinnelse vedrører fremstilling av terapeutisk aktive imidazokinoxalinforbindelser. De nye forbindelsene er nyttige i psykofarmasøytiske anvendelser, f.eks. ved behandlingen av sentralnervesystemlidelser, f.eks. som antikrampemidler eller angstdempende midler.
Det er godt kjent (Squires, R.F. og Braestrup, C. i Nature (London), 266 (1977), s. 732-734) at bestemte steder i sentralnervesystemene til virveldyr har en høy spesifikk aktivitet for binding av 1,4- og 1,5-benzodiazepiner. Disse stedene kalles benzodiazepinreseptorer.
Det er nå funnet at medlemmer av en ny gruppe imidazokinoxalinforbindelser har sterk affinitet for benzodiaze-pinreseptorene, noe som gjør dem anvendbare i psykofarmasøyt-iske preparater.
Følgelig er det et formål ved oppfinnelsen å tilveie-bringe slike nye imidazokinoxalinforbindelser.
Imidazokinoxalinforbindelsene som fremstilles ifølge oppfinnelsen, har den generelle formel I
hvor R<3> er eller
hvor R' er cyklopropyl; R<5> er methyl som eventuelt er substituert med Cj_4-alkyl, C1.4-alkoxycarbonyl, pyridyl, morfolino-methyl, cyklopropyl, C2.6-alkenyl, fenacyl, C^-alkylacyl, C1.4-alkoxymethyl, fthalimidofenyl, benzyl eller fenyl, som alle er usubstituert eller substituert med halogen, C^-alkyl, amino, azido eller C^-alkoxy; og R6 er H, C^-alkyl, halogen eller CF3; forutsatt at R<5> ikke er methyl eller ethyl når R<6> er H, halogen eller C^-alkyl.
De ovenfor nevnte forbindelser fremstilles ifølge oppfinnelsen ved en fremgangsmåte som er kjennetegnet ved at:
a) en forbindelse med formel II
hvor R<5> og R<6> har de ovenfor angitte betydninger, og hvor Y er
en uttredende gruppe, omsettes med en forbindelse med formel
III
hvor R3 har den ovenfor angitte betydning, eller b) et reaktivt derivat av en forbindelse med den generelle formel IV hvor R<5> og R<6> har de ovenfor angitte betydninger, omsettes med en forbindelse med den generelle formel V hvor R' har den ovenfor angitte betydning, hvorved det fås en forbindelse med den generelle formel I hvor R<3> er
hvor R' har den ovenfor angitte betydning.
Den uttredende gruppe Y kan være hvilken som helst egnet uttredende gruppe, og er f.eks. de som er beskrevet i U.S. patentskrifter nr. 4.031.079 eller 4.359.420, f.eks. halogen, alkylthio, som f.eks. methylthio, aralkylthio, N-nitrosoalkylamino, alkoxy, mercapto, -0P(0)(0R)2, hvor R er lavere alkyl, eller -0P(0)(NR'R''), hvor R' og R'' hver er lavere alkyl eller fenyl eller er sammen med nitrogenatomet, som de er bundet til, et heterocyklisk radikal, slik som morfolino, pyrrolidino, piperidino eller methylpiperazino. Omsetningen utføres fortrinnsvis under alkaliske betingelser, dvs. i nærvær av en base, og blant basene er alkalimetall-, f.eks. kalium- eller natrium-, alkoxyder eller hydroxyder foretrukket. Omsetningen utføres fortrinnsvis i nærvær av et organisk oppløsningsmiddel som er ikke-reaktivt med reaktan-tene og produktene fra reaksjonen under reaksjonsbetingel-sene, spesielt et vannfritt oppløsningsmiddel, og fortrinnsvis et vannfritt aprotisk oppløsningsmiddel, slik som dimethylformamid (DMF) e.l. Det anvendte temperaturområde kan være ethvert område som er egnet for at omsetningen skal skje ved en rimelig hastighet og uten unødig forsinkelse eller dekomponering, og et område fra -5-40°C til ca. værelsetemperatur er følgelig vanligvis særlig egnet.
Utgangsmaterialene kan fremstilles fra kommersielt tilgjengelige organiske forbindelser og ved å bruke godt kjente syntesemetoder, som beskrevet i Synthesis, vol. 10, s. 681-682.
De farmasøytiske egenskapene til forbindelsene som fremstilles ifølge oppfinnelsen, kan illustreres ved å bestemme deres evne til å fortrenge radioaktivt merket flunitrazepam fra benzodiazepinreseptorer.
Fortrengningsaktiviteten til forbindelsene fremstilt ifølge oppfinnelsen kan finnes ved å bestemme ED50-verdien. ED50-verdien utgjør den dose (mg/kg) av en testforbindelse som forårsaker at den spesifikke binding av flunitrazepam til benzodiazepinreseptorer i en levende hjerne reduseres til 50 % av kontrollverdien.
En slik in vivo-test utføres på følgende måte: Prinsipp. Tyve minutter etter en dose av <3>H-flunitrazepam (<3>H-FNM) (200 uCi/kg, i.v.) har mengden av spesifikk <3>H-FNM-binding til hjerne-benzodiazepinreseptorer nådd sin mak-simale verdi. Denne spesifikke binding av 3H-FNM kan delvis eller fullstendig forhindres ved samtidig eller forutgående administrering av farmakologisk aktive benzodiazepiner og ved hjelp av noen benzodiazepinlignende midler (Chang og Snyder, Eur. J. Pharmacol. 48, s. 212-218 (1978)).
Testfremganqsmåte. Suspensjoner av teststoffer
(2 mg/ml) ble fremstilt i 5 % Duphasol-X ("Duphar", ricinus-olje/ethylenoxydderivat for emulgering og oppløseliggjøring av olje og andre vannuoppløselige stoffer) ved lydbølgebehandling i 10 min. under anvendelse av et Branson Bl5 ultralydapparat med mikrospiss (innstilling 7). Grupper med tre mus (hunkjønn, NMR, 18-22 g) injiseres med teststoffet ved 100 mg/kg intra-peritonealt. Femten minutter etter administrering av teststoff utfordres musene med 4 uCi <3>H-FNM (70-90 Ci/mol) i 200 ul fysiologisk saltoppløsning intravenøst. Tyve minutter etter <3>H-FNM-administrering avlives musene ved dekapitasjon, for-hjernene fjernes hurtig (innen 30 sek.) og homogeniseres i 12 ml iskald mM KH2P04, pH 7,1, under anvendelse av en Ultra-Turrax homogenisator utstyrt med en N 10-aksel. To aliquoter å
1 ml filtreres øyeblikkelig gjennom Whatman GF/C glassfiberfiltre og vaskes med 2 x 5 ml av den ovenfor nevnte buffer. Radioaktiv!tetsmengdene på filtrene bestemmes ved vanlig scintillasjonstelling. En gruppe ubehandlede mus tjener som kontroll. Én til tre mus injiseres med 25 ug/kg clonazepam i.p. 30 min. før <3>H-FNM for å bestemme mengden av ikke-spesifikk <3>H-FNM-binding, som bør være mellom 8 og 15 % av total-binding. Når doser på 100 mg/kg hemmer mer enn 50 % av spesifikk <3>H-flunitrazepambinding, administreres testforbindelser i doser som er faktorer på 3,16 ganger lavere enn 100 mg/kg. ED50 for en testforbindelse defineres som den dose som hemmer 50 % av spesifikk <3>H-FNM-binding. Spesifikk binding er mengden av binding i kontroller minus mengden av binding i clonazepam-behandlede mus. Resultater. ED50-verdien bestemmes ut fra dose-responskurver. Dersom bare én dose av testforbindelsen administreres, beregnes ED50-verdien på følgende måte, forutsatt at hemmingen av spesifikk binding ligger innenfor området 25-75 %:
hvor CG er spesifikk binding i kontroller og Cx er spesifikk binding i mus behandlet med testforbindelse.
Testresultatene som ble oppnådd ved å teste noen av forbindelsene fremstilt ifølge oppfinnelsen, vil fremgå av den følgende tabell I.
Fra EP patentsøknad nr. 225.013 er det kjent imidazokinoxalinforbindelser med affinitet overfor benzodiazepinre-septoren, hvor substituentene i 5- og/eller 6-stillingene er forskjellige fra substituentene i de tilsvarende stillinger hos forbindelsene fremstilt ifølge foreliggende oppfinnelse. Tabell II nedenunder sammenligner in vitro bindingsaffinitet mellom de nye forbindelsene og de nærmest beslektede, tid-ligere kjente forbindelser fra EP 225.013.
Testen for in vitro bindingsaffinitet er som følger: In vitro inhiberinq av iH- flunitrazepambindinq
Prinsipp: <3>H-flunitrazepam binder spesifikt og med høy affinitet til hjernemembraner hos alle høyere pattedyr. En forbindelses evne til å hemme spesifikt flunitrazepambinding har helt klart sammenheng med dens affinitet for hjernebenzo-diazepinreseptorer (Braestrup, C. og Squires, R.F., Eur. J. Pharmacol., 48, s. 263-270 (1978)).
Frysetørkede bovin-cortexmembraner har vist seg å ha samme bindingskarakteristika som friske rottemembraner (Lund, J., Sean. J. Clin. Lab. Invest., 41, s. 275-280 (1981)).
Test: Frysetørkede bovin-benzodiazepinreseptor-preparater (prep. 38912 eller etterfølgende preparater) opp-slemmes i 40 ml (10 mg/ml) 25 mM KH2P04/ pH 7,1. 25 pl test-preparatoppløsning settes til 0,5 ml reseptorsuspensjons-ekvivalenter, etterfulgt av 25 ul <3>H-flunitrazepamoppløsning (1 nM, sluttkonsentrasjon); og blandingen inkuberes i 60 min i et isbad (in duplo). Etter inkubering filtreres prøvene direkte på Whatman GF/C glassfiberfiltre under sug og vaskes straks med 2 x 10 ml iskald buffer. Mengden av radioaktivitet på filtrene bestemmes ved konvensjonell væskescintillasjons-telling. Ikke-spesifikk binding bestemmes in duplo med clonazepam (100 ng/ml, sluttkonsentrasjon) som testoppløsning. Spesifikk binding er total binding minus ikke-spesifikk binding.
Metode: Testforbindelser oppløses i 10 ml eller 96 % etanol (om nødvendig surgjort med 25 ul i 1 N HC1 og varmet på et dampbad i maksimalt 5 min) ved en konsentrasjon på 0,22 mg/ml. Det foretas tre fortynninger i vann eller 48 % etanol (220 ng/ml, 2,2 ug/ml og 22 ug/ml). Konsentrasjoner på 10, 100 og 1000 ng/ml (sluttkonsentrasjon) settes til dublerende tester. 25-75 % hemming av spesifikk binding skal være oppnådd før IC50 beregnes.
Resultater: Testverdien vil bli gitt som IC50 (konsentrasjon (ng/ml) av testforbindelsen som hemmer spesifikk binding av <3>H-flunitrazepam med 50 %). hvor C0 er spesifikk binding i kontrollforsøk g Cx er spesifikk binding i testforsøk.
Av tabell II fremgår det tydelig at forbindelsene fremstilt ifølge foreliggende oppfinnelse utviser overraskende bedre in vitro affinitet for benzodiazepinreseptorer enn de tilsvarende, kjente forbindelser.
Oppfinnelsen vil bli nærmere beskrevet i de følgende eksempler:
Eksempel 1
a. N- fenethvl- 2- nitroanilin
Til en omrørt oppløsning av 14,1 g (0,1 mol) 1-fluor-2-nitrobenzen og 14 ml (0,1 mol) triethylamin i 150 ml DMF ble det tilsatt 12,1 g (0,1 mol) fenethylamin. Blandingen ble så oppvarmet til 100 °C og omsetningen overvåket ved hjelp av TLC. Etter at reaksjonen var fullført (2 timer), ble oppløs-ningsmidlet fjernet ved avdamping under vakuum. Resten ble fordelt mellom 100 ml 0,5 N vandig HC1 og 100 ml ether. Den organiske fase ble vasket med vann, tørket og inndampet, hvorved man fikk tittel forbindelsen som en gul olje.
På en lignende måte ble de følgende forbindelser fremstilt ved omsetning av 1-fluor-2-nitrobenzen med de passende aminer: N-(2-morfolinoethyl)-2-nitroanilin, sm.p. 42-44 °C. N-(2-klorbenzyl)-2-nitroanilin, sm.p. 106-107 °C. N-(2-methoxybenzyl)-2-nitroanilin, sm.p. 114-115 °C. N-(4-methoxybenzyl)-2-nitroanilin, sm.p. 92-93 °C. N-(2-pyridylmethyl)-2-nitroanilin, sm.p. 87-88 °C.
N-(2-klorbenzyl)-2-klor-6-nitroanilin, sm.p. 69-
71 °C, ble fremstilt fra 2,3-diklornitrobenzen og 2-klorben-zylklorid. Rensing på Si02 (pentan/ether 15:1).
b. N- ethoxalyl- 2- nitro- 6- methvlanilin
Til en omrørt oppløsning av 10 g (65 mmol) 2-nitro-6-methylanilin og 11 ml (80 mmol) triethylamin i 80 ml THF ble det dråpevis tilsatt 9 ml (80 mmol) av en oppløsning av ethoxalylklorid. Etter fullførelse av tilsetningen ble blandingen brakt til tilbakeløpskoking ved hjelp av ekstern opp-varming. Etter 3 timer ble blandingen avkjølt til værelsetemperatur, og det ut felte triethylammoniumklorid ble frafiltrert. Filtratet ble inndampet, hvorved man fikk råpro-duktet som en olje. Rensing (Si02/ether: pent an, 1:1) gav den rene tittelforbindelse som en olje.
På en lignende måte ble de følgende N-ethoxalylani-linene erholdt ved omsetning mellom ethoxalylklorid og de tilsvarende aniliner. N-ethoxalyl-N-(2-methoxybenzyl)-2-nitroanilin, olje. N-ethoxalyl-N-(4-methoxybenzyl)-2-nitroanilin, olje.
N-ethoxalyl-N-(2-pyridylmethyl)-2-nitroanilin, olje.
N-(2-klorbenzyl)-N-ethoxalyl-2-nitroanilin, sm.p. 98-99 °C.
N-ethoxalyl-N-(2-morfolinoethyl)-2-nitroanilin, sm.p. 75-76 °C.
N-benzyl-N-ethoxalyl-2-nitroanilin, sm.p. 170-175 °C.
N-(2-klorbenzyl)-2-klor-N-ethoxalyl-6-nitroanilin, sm.p. 101-102 °C.
N-ethoxalyl-N-fenethyl-2-nitroanilin, olje. N-cyklopropylmethyl-N-ethoxalyl-2-nitroanilin, olje.
c. N- ethoxalyl- N- methyl- 2- nitro- 6- methylanilin
1 g (22 mmol) NaH ble tilsatt i porsjoner til en omrørt oppløsning av 5 g (20 mmol) N-ethoxalyl-2-nitro-6-methylanilin i 50 ml DMF. 2 ml (22 mmol) methyljodid ble deretter tilsatt. Blandingen ble hensatt over natten ved værelsetemperatur, hvoretter oppløsningsmidlet ble fjernet ved fordamping under vakuum. Resten ble fordelt mellom ether og vann. Den organiske fase ble vasket med vann, tørket over Na2S04 og avdampet, hvorved man fikk tittelforbindelsen som en olje.
På en lignende måte ble den følgende forbindelse erholdt ved alkylering av de passende utgangsmaterialer: N-ethoxalyl-N-ethyl-2-nitro-6-methylanilin (olje) ble fremstilt fra N-ethoxalyl-2-nitro-6-methylanilin og ethyl-jodid.
d. N- ethoxalyl- 4- klor- 2- trifluormethylanilin
En blanding av 14,4 ml (0,1 mol) 2-amino-5-klorbenzo-trifluorid og 14,0 ml (0,1 mol) triethylamin ble oppløst i 250 ml tørt tetrahydrofuran, THF. Til denne oppløsning ble det under omrøring tilsatt 50 ml av en oppløsning av ethoxalylklorid i THF. Etter fullførelse av tilsetningen (30 min.) ble blandingen omrørt ved omgivelsestemperatur i 3 timer, hvoretter det utfelte triethylammoniumklorid ble frafiltrert og filtratet inndampet under vakuum. Dette etterlot 24 g av den urene tittelforbindelse som lyse krystaller, sm.p. 55-58 "C.
e. N- ethoxalyl- 4- klor- 6- nitro- 2- trifluormethylanilin
125 ml av en oppløsning av N-ethoxalyl-4-klor-2-trifluormethylanilin i konsentrert svovelsyre ble tilsatt 120 ml av en omrørt blanding av 100 % salpetersyre og 240 ml konsentrert svovelsyre. Temperaturen ble holdt mellom 8 og 10 °C under tilsetningen. Etter at tilsetningen var fullført, ble oppløsningen omrørt i ytterligere 20 min. uten ekstern avkjøling, hvoretter den ble helt over i isvann. Dette gav utfelling av tittelforbindelsen som en olje som utkrystalli-serte som lysegule krystaller etter henstand. Krystallene ble frafiltrert og vasket grundig med vann, sm.p. 100-101 °C.
f. N- ethoxalyl- N- methyl- 4- klor- 6- nitro- 2- trifluormethylanilin
Til en omrørt oppløsning av 11 g (32,3 mmol) N-ethoxalyl-4-klor-6-nitro-2-trifluormethylanilin og 3,0 ml (48 mmol) methyljodid i 50 ml tørt dimethylformamid (DMF) ble det i porsjoner tilsatt i alt 1,7 g (39 mmol) natriumhydrid. Ekstern avkjøling ble brukt for å holde reaksjonstemperaturen under 25 °C. Omrøring ble fortsatt ved værelsetemperatur i 3 timer, hvoretter oppløsningsmidlet ble fjernet ved avdamping under vakuum. Resten ble så fordelt mellom ether og vann. Den organiske fase ble vasket to ganger med vann, tørket over Na2S04 og inndampet. Denne behandlingen etterlot tittelforbindelsen som en olje som ble prosessert uten ytterligere rensing.
g. 3, 4- dihydro- 2- hydroxy- 3- oxo- 4- methyl- 5- trifluormethyl-kinoxalin- 1- oxyd
En oppløsning av 12 g (32 mmol) N-ethoxalyl-N-methyl-4-klor-6-nitro-2-trifluoranilin og 5,6 ml (32 mmol) triethylamin i 150 ml 96 % ethanol ble hydrogenert under standardbetingelser med 1 g 5 % Pd/C som katalysator. Etter fullfør-else av denne reaksjonen ble katalysatoren frafiltrert, og oppløsningsmidlet ble fjernet ved avdamping. Behandling av resten med vann/ethylacetat (150 ml/50 ml) etterlot produktet som hvite krystaller som ble samlet opp ved filtrering, sm.p. 196-198 °C.
På en lignende måte ble de følgende kinoxalin-1-oxyder erholdt: 4-benzyl-3,4-dihydro-2-hydroxy-3-oxo-kinoxalin-l-oxyd, sm.p. 170-175 °C, ved hydrogenering av N-ethoxalyl-N-benzy1~2-nitroani1in.
3,4-dihydro-2-hydroxy-4-(2-morfolinoethyl)-3-oxo-kinoxalin-l-oxyd, sm.p. 170-172 °C, ved hydrogenering av N-ethoxalyl-N-(2-morfolinoethyl)-2-nitroanilin.
3,4-dihydro-2-hydroxy-3-oxo-4-fenethyl-kinoxalin-l-oxyd, sm.p. 200-201 °C, ved hydrogenering av N-ethoxalyl-N-fenethyl-2-nitroanilin.
4- ( 2-klorbenzyl) -3,4-dihydro-2-hydroxy-3-oxo-kinoxalin-l-oxyd, sm.p. 250-260 °C, dekomponering, ved hydrogenering av N-ethoxalyl-N-(2-klorbenzyl)-2-nitroanilin. RaNi brukt som katalysator.
3,4-dihydro-2-hydroxy-4-(4-methoxybenzyl)-3-oxo-kinoxalin-l-oxyd, sm.p. 193-194 °C, ved hydrogenering av N-ethoxalyl-N-(4-methoxybenzyl)-2-nitroanilin.
3,4-dihydro-2-hydroxy-4-(2-pyridylmethyl)-3-oxo-kinoxalin-l-oxyd, sm.p. 220 °C (dekomponering), ved hydrogenering av N-ethoxalyl-N-(2-pyridylmethyl)-2-nitroanilin.
3,4-dihydro-2-hydroxy-4-(2-methoxybenzyl)-3-oxo-kinoxalin-l-oxyd, sm.p. 243-244 °C, ved hydrogenering av N-ethoxalyl-N-(2-methoxybenzyl)-2-nitroanilin.
5- klor-4-(2-klorbenzyl)-3,4-dihydro-2-hydroxy-3-oxo-kinoxalin-l-oxyd, sm.p. 222-223 °C, ved hydrogenering av 2-klor-N-(2-klorbenzyl)-N-ethoxalyl-6-nitroanilin. RaNi brukt som katalysator.
4-cyklopropylmethyl-3,4-dihydro-2-hydroxy-3-oxo-kinoxalin-l-oxyd, sm.p. 205-206 °C.
I noen tilfeller stanset ikke hydrogeneringene ved kinoxalin-l-oxydet, men på amino- eller kinoxalinoxydasjons-stadiet.
h. 4- ethyl- l, 2, 3, 4- tetrahydro- 5- methyl- 2, 3- dioxo- kinoxalin
Hydrogenering av N-ethoxalyl-N-ethyl-6-methyl-2-nitro-nitroanilin under standardbetingelser gav N-ethoxalyl-N-ethyl-2-amino-6-methylanilin som en olje. Ringslutning til tittelforbindelsen ble utført i ethanol/1 N HC1 (50 ml/25 ml) ved tilbakeløpskoking i 10 min. Produktet utfeltes etter avkjøling og ble samlet opp ved filtrering, sm.p. >300 °C.
i. 4- benzyl- l, 2 , 3 , 4- tetrahydro— 2, 3- dioxo- kinoxalin
En oppløsning av 14,6 g (54 mmol) 4-benzyl-l,2,3,4-tetrahydro-2,3-dioxo-kinoxalin-l-oxyd og 21 g (80 mmol) tri-fenylfosfin i 200 ml dimethylformamid ble omrørt ved 110 °C i 24 timer. Oppløsningen ble inndampet under vakuum, hvoretter resten ble omrørt i 100 ml methylenklorid. Denne behandlingen etterlot den urene tittelforbindelse som en krystallinsk utfelling.
Produktet ble renset ved rekrystallisering fra ethanol, sm.p. 273-274 °C.
På lignende måte ble de følgende kinoxaliner frem-stilt fra de tilsvarende 1-oxyder: 1,2,3,4-tetrahydro-2,3-dioxo-4-fenethyl-kinoxalin, sm.p. 105-106 °C.
4- ( 2-klorbenzyl )-l, 2, 3, 4-tetrahydro-2, 3-dioxo-kinoxalin, sm.p. >300 °C.
1,2,3,4-tetrahydro-4-(4-methoxybenzyl)-2,3-dioxo-kinoxalin, sm.p. 246-247 °C.
5- klor-4-( 2-klorbenzyl )-l, 2, 3, 4-tetrahydro-2, 3-dioxo-kinoxalin, sm.p. 234-236 °C.
1,2,3,4-tetrahydro-4-(2-methoxybenzyl)-2,3-dioxo-kinoxalin, sm.p. 271-272 °C.
1,2,3,4-tetrahydro-4-(2-morfolinoethyl)-2,3-dioxo-kinoxalin, sm.p. 233-236 °C.
1,2,3,4-tetrahydro-4-(2-pyridylmethyl)-2,3-dioxo-kinoxalin, sm.p. 295-297 °C.
4-cyklopropylmethyl-l,2,3,4-tetrahydro-2,3-dioxo-kinoxalin, sm.p. 211-213 °C.
i . 5- benzyl- 3-( 5- cyklopropyl- l, 2, 4- oxadiazol- 3- vl)- 4, 5- di-hvdro- 4- oxo- imidazori, 5- alkinoxalin ( forbindelse 1)
Til en isavkjølt, omrørt oppløsning av 1 g (4 mmol) 4-benzyl-l,2,3,4-tetrahydro-2,3-dioxo-kinoxalin i 20 ml tørt DMF ble det tilsatt 0,56 g (5 mmol) kalium-t-butylat. Omrør-ingen ble fortsatt inntil alt kalium-t-butylat var oppløst. I noen forsøk ble det observert et tungt bunnfall av kalium-kinoxalinsaltet.
Til blandingen ble det så tilsatt 0,7 ml (5 mmol) diethylklorfosfat, og omrøringen ble fortsatt ved værelsetemperatur i 30 min., hvoretter en fordannet, *40 °C kald oppløsning av 0,56 g (5 mmol) kalium-t-butylat og 0,8 g (5 mmol) 5-cyklopropyl-3-isocyanomethyl-l, 2,4-oxadiazol i 15 ml tørt DMF ble tilsatt.
Det urene produkt ble utkrystallisert fra den olje-aktige rest ved behandling med en blanding av 25 ml vann og 10 ml ethylacetat. Krystallene ble samlet opp ved filtrering og renset ved kolonnekromatografi (Si02/ethylacetat), sm.p. 250-255 °C.
På en lignende måte ble de følgende forbindelser frem-stilt fra de passende kinoxaliner og isonitriler: 3-( 5-cyklopropyl-1, 2,4-oxadiazol-3-yl )-4, 5-dihydro-5-methyl-4-oxo-6-trifluormethyl-imidazo[1, 5-a]kinoxalin, sm.p. 231- 234 °C, ved omsetning mellom 5-cyklopropyl-3-isocyanomet-hyl-1,2,4-oxadiazol og 1,2,3,4-tetrahydro-4-methyl-2,3-dioxo-5-trifluormethyl-kinoxalin (forbindelse 2).
3- ( 5-cyklopropyl-l, 2, 4-oxadiazol-3-yl) -4, 5-dihydro-4-oxo-5-fenethyl-imidazo[l,5-a]kinoxalin, sm.p. 200-201 °C, ved omsetning mellom 5-cyklopropyl-3-isocyanomethyl-l, 2, 4-oxadiazol og 1, 2,3, 4-tetrahydro-2, 3-dioxo-4-fenethyl-kinoxalin (forbindelse 3).
5- ( 2-klorbenzyl)-3-( 5-cyklopropyl )-l, 2, 4-oxadiazol-3-yl)-4,5-dihydro-4-oxo-imidazo[l,5-a]kinoxalin, sm.p. 243-
244 °C, ved omsetning mellom 5-cyklopropyl-3-isocyanomethyl-1,2,4-oxadiazol og 4-(2-klorbenzyl)-l, 2, 3, 4-tetrahydro-2,3-dioxo-kinoxalin (forbindelse 4).
3-( 5-cyklopropyl-l, 2, 4-oxadiazol-3-yl )-4, 5-dihydro-5-(4-methoxybenzyl)-4-oxo-imidazo[l,5-a]kinoxalin, sm.p. 200-203 °C, ved omsetning mellom 5-cyklopropyl-3-isocyanomethyl-1,2,4-oxadiazol og 1,2,3,4-tetrahydro-4-(4-methoxybenzyl)-2,3-dioxo-kinoxalin (forbindelse 5).
3-(3-cyklopropyl-l, 2,4-oxadiazol-5-yl )-4, 5-dihydro-5-methyl-4-oxo-6-trifluormethyl-imidazo[1,5-a]kinoxalin, sm.p. 232- 233 °C, ved omsetning mellom 3-cyklopropyl-5-isocyanomet-hyl-1,2,4-oxadiazol og 1,2,3,4-tetrahydro-4-methyl-2,3-dioxo-5-trifluormethyl-kinoxalin (forbindelse 6).
6- klor-5-(2-klorbenzyl)-3-( 5-cyklopropyl-l,2,4-oxadiazol-3-yl)-4,5-dihydro-4-oxo-imidazo[l, 5-a]kinoxalin, sm.p. 244-245 °C, ved omsetning mellom 5-cyklopropyl-3-isocyanomet-
hyl-1,2,4-oxadiazol og 5-klor-4-(2-klorbenzyl)-1,2,3,4-tetrahydro-2,3-dioxo-kinoxalin (forbindelse 7).
3-( 5-cyklopropyl-l, 2, 4-oxadiazol-3-yl )-4, 5-dihydro-4-oxo-5-(2-pyridylmethyl)-imidazo[l,5-a]kinoxalin, sm.p. 197-198 °C, ved omsetning mellom 5-cyklopropyl-3-isocyanomethyl-l,2,4-oxadiazol og 1,2,3,4-tetrahydro-4-(2-pyridylmethyl)-2,3-dioxo-kinoxalin (forbindelse 8).
3-(5-cyklopropyl-l,2, 4-oxadiazol-3-yl)-4,5-dihydro-5-(2-methoxybenzyl)-4-oxo-imidazo[l,5-a]kinoxalin, sm.p. 201-203 °C, ved omsetning mellom 5-cyklopropyl-3-isocyanomethyl-1,2,4-oxadiazol og 1,2,3,4-tetrahydro-4-(2-methoxybenzyl)-2,3-dioxo-kinoxalin (forbindelse 9).
3-( 5-cyklopropyl-l, 2, 4-oxadiazol-3-yl )-4, 5-dihydro-5-5-(2-morfolinoethyl)-4-oxo-imidazo[1, 5-a]kinoxalin, sm.p. 187-188 °C, ved omsetning mellom 5-cyklopropyl-3-isocyanomethyl-1,2,4-oxadiazol og 1,2,3,4-tetrahydro-4-(2-morfolinoethyl )-2, 3-dioxo-kinoxalin (forbindelse 10).
3- ( 5-cyklopropyl-l, 2,4-oxadiazol-3-yl)-5-cyklopropyl-methyl-4,5-dihydro-4-oxo-imidazo[l,5-a]kinoxalin, sm.p. 213-215 °C, ved omsetning mellom 4-cyklopropylmethyl-l,2,3,4-tetrahydro-2,3-dioxo-kinoxalin og 5-cyklopropyl-3-isocyano-methyl-1,2,4-oxadiazol (forbindelse 11).
Eksempel 2
3- ( 3- cyklopropyl- 1. 2, 4- oxadiazol- 5- yl)- 4, 5- dihydro- 5,6-di-methyl- 4- oxo- imidazori, 5- alkinoxalin ( forbindelse 17)
En blanding av 450 mg ethyl-4,5-dihydro-5,6-dimethyl-4- oxo-imidazo[1,5-a]kinoxalin-3-carboxylat, 500 mg cyklopropancarboxamidoxim og 5 g knuste molekylsikter 4Å ble tilsatt 70 mg av en oppløsning av natrium i 50 ml tørr ethanol. Den omrørte oppløsning ble kokt under tilbakeløpskjøling i 3 timer, avkjølt og filtrert gjennom en pute av filterhjelpe-middel. Filtratet ble oppkonsentrert til et volum på 10 ml ved inndamping under vakuum, hvorved tittelforbindelsen delvis utfeltes. Tilsetning av 50 ml vann gav en ytterligere utfelling av tittelforbindelsen. Krystallene ble samlet opp ved filtrering og vasket med vann, sm.p. 223-224 °C.
På en lignende måte ble de følgende oxadiazoler frem-stilt ved omsetning mellom cyklopropancarboxamidoxim og de tilsvarende ethylestere. Rensing av forbindelsene ble gjort ved rekrystallisering fra isopropanol.
3-(3-cyklopropyl-l,2,4-oxadiazol-5-yl)-4,5-dihydro-4-oxo-5-fenethyl-imidazo[l,5-a]kinoxalin, sm.p. 235-236 °C (forbindelse 18).
5-(2-klorbenzyl)-3-(3-cyklopropyl-1,2,4-oxadiazol-5-yl)-4,5-dihydro-4-oxo-imidazo[l,5-a]kinoxalin, sm.p. 276-
277 °C (forbindelse 19).
3-(3-cyklopropyl-1,2,4-oxadiazol-5-yl)-4,5-dihydro-5-(4-methoxybenzyl)-4-oxo-imidazo[l,5-a]kinoxalin, sm.p. 260-261 °C (forbindelse 20).
3-(3-cyklopropyl-l,2,4-oxadiazol-5-yl)-5-ethyl-4,5-dihydro-6-methyl-4-oxo-imidazo[l,5-a]kinoxalin, sm.p. 211-212 °C (forbindelse 21).
Eksempel 3
3-( 5- cyklopropvl- l, 2, 4- oxadiazol- 3- yl)- 5- ethoxvcarbonylmethvl-4. 5- dihydro- 4- oxo- imidazofl, 5- alkinoxalin ( forbindelse 22)
Til en omrørt oppløsning av 200 mg 3-(5-cyklopropyl-1,2, 4-oxadiazol-3-yl)-4,5-dihydro-4-oxo-imidazo[l,5-a]kinoxalin i 10 ml DMF ble det tilsatt 50 mg natriumhydrid og etter 10 min. 1 ml ethylmonokloracetat. Blandingen ble omrørt i ytterligere 2 timer, hvoretter oppløsningsmidlet ble fjernet ved inndamping under vakuum. Resten ble fordelt mellom 25 ml vann og 20 ml ether, og det krystallinske produkt ble frafiltrert, sm.p. 245-246 °C.
Med 3-(5-cyklopropyl-l,2,4-oxadiazol-3-yl)-4,5-dihydro-4-oxo-imidazo[l,5-a]kinoxalin og passende halogenider som utgangsmaterialer, og DMF som oppløsningsmiddel, ble de følgende forbindelser fremstilt: 3-(5-cyklopropyl-l,2,4-oxadiazol-3-yl)-4, 5-dihydro-5-(3,3-dimethylallyl)-4-oxo-imidazo[l,5-a]kinoxalin, sm.p. 133-134 °C, ved alkylering med 3,3-dimethylallylbromid (forbindelse 23).
5-allyl-3-(5-cyklopropyl-l,2,4-oxadiazol-3-yl)-4,5-dihydro-4-oxo-imidazo[l,5-a]kinoxalin, sm.p. 188-189 °C, ved alkylering med allylbromid (forbindelse 24).
3-(5-cyklopropyl-l,2,4-oxadiazol-3-yl)-4,5-dihydro-4-oxo-5-fenacyl-imidazo[l,5-a]kinoxalin, sm.p. 258-259 °C, ved alkylering med fenacylbromid (forbindelse 25).
5-acetonyl-3-(5-cyklopropyl-l,2,4-oxadiazol-3-yl)-4, 5-dihydro-4-oxo-imidazo[l,5-a]kinoxalin, sm.p. 280-282 °C, ved alkylering med kloraceton. Rekrystallisering fra methanol (forbindelse 26).
3-(5-cyklopropyl-l,2,4-oxadiazol-3-yl)-5-(2-fluor-benzyl)-4,5-dihydro-4-oxo-imidazo[l,5-a]kinoxalin, sm.p. 229-230 °C, ved benzylering med 2-fluorbenzylklorid. Rekrystallisering fra toluen (forbindelse 27).
3-(5-cyklopropyl-l,2,4-oxadiazol-3-yl)-4,5-dihydro-5-( 2-methylbenzyl)-4-oxo-imidazo[1,5-a]kinoxalin, sm.p. 235-237 °C, ved benzylering med 2-methylbenzylklorid. Rekrystallisering fra methanol (forbindelse 28).
5-(2-brombenzyl)-3-(5-cyklopropyl-l,2,4-oxadiazol-3-yl )-4, 5-dihydro-4-oxo-imidazo[l,5-a]kinoxalin, sm.p. 236-
237 °C, ved benzylering med 2-brombenzylbromid (forbindelse 29).
3-(5-cyklopropyl-l,2,4-oxadiazol-3-yl)-4,5-dihydro-5-(3-methoxybenzyl)-4-oxo-imidazo[l,5-a]kinoxalin, sm.p. 188-190 °C, ved benzylering med m-methoxybenzylklorid. Rekrystallisering fra toluen (forbindelse 30).
3-(5-cyklopropyl-l,2,4-oxadiazol-3-yl)-5-(2-ethoxy-ethyl)-4,5-dihydro-4-oxo-imidazo[l,5-a]kinoxalin, sm.p. 161-162 °C, ved alkylering med 2-bromethylethylether. Rekrystallisering fra ethanol (forbindelse 31).
3-(5-cyklopropyl-l,2,4-oxadiazol-3-yl)-4,5-dihydro-4-oxo-5-(4-fthalimidobenzyl)-imidazo[l,5-a]kinoxalin, sm.p. 195-197 °C, overgang til krystaller med sm.p. 280-282 °C, ved benzylering med 4-(fthalimido)benzylklorid. Rekrystallisering fra diklormethan/aceton, 4:1 (forbindelse 32).
Eksempel 4
5- ( 4- aminobenzyl)- 3-( 5- cyklopropyl- l, 2, 4- oxadiazol- 3- yl)- 4, 5-dihydro- 4- oxo- imidazori, 5- alkinoxalin ( forbindelse 33)
En blanding av 0,46 g (0,87 mmol) 3-(5-cyklopropyl-1,2,4-oxadiazol-3-yl)-4,5-dihydro-4-oxo-5-(4-fthalimidoben-zyl)-imidazo[l,5-a]kinoxalin og 2 ml hydrazin i 25 ml ethanol ble omrørt ved værelsetemperatur i 1,5 time. Bunnfallet ble samlet opp ved filtrering, vasket med ethanol og tørket, hvorved man fikk tittelforbindelsen, sm.p. 246-248 °C.
Eksempel 5
5-( 4- azidobenzyl)- 3-( 5- cyklopropyl- l. 2. 4- oxadiazol- 3- yl)- 4, 5-dihydro- 4- oxo- imidazori, 5- alkinoxalin ( forbindelse 34)
Til en omrørt oppløsning av 0,1 g (0,25 mmol) 5-(4-aminobenzyl)-3-(5-cyklopropyl-l,2,4-oxadiazol-3-yl)-4,5-dihydro-4-oxo-imidazo[l,5-a]kinoxalin i 3 ml trifluoreddiksyre ble det ved 0 °C tilsatt 0,1 g (1,4 mmol) natriumnitritt. Etter 5 min. ble 0,16 g (2,5 mmol) natriumazid tilsatt. Om-røringen ble fortsatt i 1 time. Så ble 20 ml vann tilsatt, og blandingen ble ekstrahert to ganger med 20 ml diklormethan. De kombinerte ekstrakter ble tørket over natriumsulfat og inndampet, hvorved man fikk tittelforbindelsen som et lysegult, fast stoff, sm.p. 183-184 °C (dekomponering). Kromatografisk rensing (Si02/CH2Cl2-aceton 4:1) gav krystaller med sm.p. 194-197 ° C (dekomponering).
Claims (6)
1. Analogifremgangsmåte for fremstilling av terapeutisk aktive imidazokinoxalinforbindelser med formel I
hvor
R<3> er
eller
hvor R' er cyklopropyl; R<5> er methyl som eventuelt er substituert med C1_4-alkyl, C1.4-alkoxycarbonyl, pyridyl, morfolino-methyl, cyklopropyl, C2.6-alkenyl, fenacyl, C^-alkylacyl, Cx_ 4-alkoxymethyl, fthalimidofenyl, benzyl eller fenyl, som alle er usubstituert eller substituert med halogen, C^-alkyl, amino, azido eller C-^-alkoxy; og R6 er H, C^-alkyl, halogen eller CF3;
forutsatt at R<5> ikke er methyl eller ethyl når R<6> er H, halogen eller C1.6-alkyl,
karakterisert ved at a) en forbindelse med formel II
hvor R<5> og R<6> har de ovenfor angitte betydninger, og hvor Y er en uttredende gruppe, omsettes med en forbindelse med formel III
hvor R3 har den ovenfor angitte betydning, eller b) et reaktivt derivat av en forbindelse med den
generelle formel IV
hvor R<5> og R<6> har de ovenfor angitte betydninger, omsettes med en forbindelse med den generelle formel V
hvor R' har den ovenfor angitte betydning, for dannelse av en forbindelse med den generelle formel I hvor R<3> er
hvor R' har den ovenfor angitte betydning.
2. Fremgangsmåte ifølge krav 1 for fremstilling av 5-benzyl-3-(5-cyklopropyl-l,2,4-oxadiazol-3-yl)-4,5-dihydro-4-oxo-imidazo[1,5-a]kinoxalin,
karakterisert ved at det anvendes tilsvarende utgangsforbindelser.
3. Fremgangsmåte ifølge krav 1 for fremstilling av 3-(5-cyklopropyl-1,2,4-oxadiazol-3-yl)-4,5-dihydro-5-methyl-4-oxo-6-trifluormethyl-imidazo[1,5-a]kinoxalin, karakterisert ved at det anvendes tilsvarende utgangsforbindelser.
4. Fremgangsmåte ifølge krav 1 for fremstilling av 5-cyklopropyl-methyl-3-(5-cyklopropyl-l,2,4-oxadiazol-3-yl)-4,5-dihydro-4-oxo-imidazo[1,5-a]kinoxalin, karakterisert ved at det anvendes tilsvarende utgangsforbindelser.
5. Fremgangsmåte ifølge krav 1 for fremstilling av 3-(5-cyklopropyl-1,2,4-oxadiazol-3-yl)-4,5-dihydro-5-(3,3-dimethyl-allyl)-4-oxo-imidazo[l,5-a]kinoxalin, karakterisert ved at det anvendes tilsvarende utgangsforbindelser.
6. Fremgangsmåte ifølge krav 1 for fremstilling av 3-(5-cyklopropyl-1,2,4-oxadiazol-3-yl)-4,5-dihydro-5-(4-methoxy-benzyl )-4-oxo-imidazo[l, 5-a]kinoxalin, karakterisert ved at det anvendes tilsvarende utgangsforbindelser.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DK297188A DK297188D0 (da) | 1988-06-01 | 1988-06-01 | Imidazoquinoxalinforbindelser, deres fremstilling og anvendelse |
| DK625988A DK625988D0 (da) | 1988-11-10 | 1988-11-10 | Imidazoquinoxalinforbindelser, deres fremstilling og anvendelse |
Publications (4)
| Publication Number | Publication Date |
|---|---|
| NO892204D0 NO892204D0 (no) | 1989-05-31 |
| NO892204L NO892204L (no) | 1989-12-04 |
| NO173185B true NO173185B (no) | 1993-08-02 |
| NO173185C NO173185C (no) | 1993-11-10 |
Family
ID=26066829
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| NO892204A NO173185C (no) | 1988-06-01 | 1989-05-31 | Analogifremgangsmaate for fremstilling av terapeutisk aktive imidazokinoxalinforbindelser |
Country Status (12)
| Country | Link |
|---|---|
| US (1) | US5075304A (no) |
| EP (1) | EP0344943A1 (no) |
| JP (1) | JPH0225486A (no) |
| KR (1) | KR900018102A (no) |
| AU (1) | AU627181B2 (no) |
| CA (1) | CA1315786C (no) |
| FI (1) | FI92203C (no) |
| IL (1) | IL90315A0 (no) |
| NO (1) | NO173185C (no) |
| NZ (1) | NZ229346A (no) |
| PH (1) | PH26379A (no) |
| PT (1) | PT90721B (no) |
Families Citing this family (13)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DK155524C (da) * | 1987-03-18 | 1989-09-11 | Ferrosan As | Kondenserede imidazolderivater og farmaceutiske praeparater indeholdende disse |
| DK626288D0 (da) * | 1988-11-10 | 1988-11-10 | Ferrosan As | Kemisk proces til fremstilling af imidazoquinoxaliner og mellemprodukter til brug i processen |
| US5371080A (en) * | 1990-06-22 | 1994-12-06 | Novo Nordisk A/S | Imidazoquinazoline compounds and their use |
| US5276028A (en) * | 1990-06-22 | 1994-01-04 | Nordisk A/S | Imidazoquinoxaline compounds |
| DK151890D0 (da) * | 1990-06-22 | 1990-06-22 | Ferrosan As | Heterocykliske forbindelser deres fremstilling og brug |
| WO1992004350A1 (en) * | 1990-09-04 | 1992-03-19 | The Upjohn Company | Oxygenated quinoxalines |
| WO1992022552A1 (en) * | 1991-06-14 | 1992-12-23 | The Upjohn Company | IMIDAZO[1,5-a]QUINOXALINES |
| US5182386A (en) * | 1991-08-27 | 1993-01-26 | Neurogen Corporation | Certain imidazoquinoxalinones; a new class of gaba brain receptor ligands |
| US5597920A (en) * | 1992-04-30 | 1997-01-28 | Neurogen Corporation | Gabaa receptor subtypes and methods for screening drug compounds using imidazoquinoxalines and pyrrolopyrimidines to bind to gabaa receptor subtypes |
| DE4228095A1 (de) * | 1992-08-24 | 1994-03-03 | Asta Medica Ag | Neue 4,5-Dihydro-4-oxo-pyrrolo[1,2-a]chinoxaline und entsprechende Aza-analoga und Verfahren zu deren Herstellung |
| IL109397A0 (en) * | 1993-04-28 | 1994-07-31 | Schering Ag | Quinoxalinedione derivatives, processes for the preparation thereof and pharmaceutical compositions containing the same |
| US5792766A (en) | 1996-03-13 | 1998-08-11 | Neurogen Corporation | Imidazo 1,5-c! quinazolines; a new class of GABA brain receptor ligands |
| CA3005353A1 (en) | 2015-11-20 | 2017-05-26 | Forma Therapeutics, Inc. | Purinones as ubiquitin-specific protease 1 inhibitors |
Family Cites Families (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4440929A (en) * | 1981-07-16 | 1984-04-03 | Usv Pharmaceutical Corporation | Imidazoquinoxaline compounds |
| DK476885D0 (da) * | 1985-10-17 | 1985-10-17 | Ferrosan As | Heterocycliske forbindelser og fremgangsmaader til fremstilling heraf |
| DK155524C (da) * | 1987-03-18 | 1989-09-11 | Ferrosan As | Kondenserede imidazolderivater og farmaceutiske praeparater indeholdende disse |
| DK160876C (da) * | 1987-12-08 | 1991-10-14 | Novo Nordisk As | Imidazoquinoxalinforbindelser, fremgangsmaade til deres fremstilling, anvendelse af forbindelserne og farmaceutiske praeparater, hvori forbindelserne indgaar |
-
1989
- 1989-05-16 IL IL90315A patent/IL90315A0/xx not_active IP Right Cessation
- 1989-05-17 EP EP89304982A patent/EP0344943A1/en not_active Ceased
- 1989-05-18 US US07/353,793 patent/US5075304A/en not_active Expired - Fee Related
- 1989-05-24 PH PH38687A patent/PH26379A/en unknown
- 1989-05-26 AU AU35174/89A patent/AU627181B2/en not_active Ceased
- 1989-05-30 NZ NZ229346A patent/NZ229346A/xx unknown
- 1989-05-30 CA CA000601114A patent/CA1315786C/en not_active Expired - Fee Related
- 1989-05-31 KR KR1019890007386A patent/KR900018102A/ko not_active Application Discontinuation
- 1989-05-31 NO NO892204A patent/NO173185C/no unknown
- 1989-06-01 FI FI892684A patent/FI92203C/fi not_active IP Right Cessation
- 1989-06-01 PT PT90721A patent/PT90721B/pt not_active IP Right Cessation
- 1989-06-01 JP JP1137578A patent/JPH0225486A/ja active Pending
Also Published As
| Publication number | Publication date |
|---|---|
| NO173185C (no) | 1993-11-10 |
| EP0344943A1 (en) | 1989-12-06 |
| FI92203B (fi) | 1994-06-30 |
| FI892684A (fi) | 1989-12-02 |
| FI92203C (fi) | 1994-10-10 |
| NZ229346A (en) | 1991-11-26 |
| AU627181B2 (en) | 1992-08-20 |
| PT90721A (pt) | 1989-12-29 |
| NO892204L (no) | 1989-12-04 |
| CA1315786C (en) | 1993-04-06 |
| PT90721B (pt) | 1994-11-30 |
| AU3517489A (en) | 1989-12-07 |
| PH26379A (en) | 1992-06-01 |
| IL90315A0 (en) | 1989-12-15 |
| JPH0225486A (ja) | 1990-01-26 |
| NO892204D0 (no) | 1989-05-31 |
| US5075304A (en) | 1991-12-24 |
| KR900018102A (ko) | 1990-12-20 |
| FI892684A0 (fi) | 1989-06-01 |
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