EP0358684A1 - Anti-tumoral targetting agents, preparation thereof and applications - Google Patents
Anti-tumoral targetting agents, preparation thereof and applicationsInfo
- Publication number
- EP0358684A1 EP0358684A1 EP19880904232 EP88904232A EP0358684A1 EP 0358684 A1 EP0358684 A1 EP 0358684A1 EP 19880904232 EP19880904232 EP 19880904232 EP 88904232 A EP88904232 A EP 88904232A EP 0358684 A1 EP0358684 A1 EP 0358684A1
- Authority
- EP
- European Patent Office
- Prior art keywords
- ppm
- nitro
- imidazole
- compound
- chloroethyl
- 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.)
- Ceased
Links
- 238000002360 preparation method Methods 0.000 title description 5
- 230000000259 anti-tumor effect Effects 0.000 title description 2
- 150000001875 compounds Chemical class 0.000 claims abstract description 126
- 230000001472 cytotoxic effect Effects 0.000 claims abstract description 14
- 231100000433 cytotoxic Toxicity 0.000 claims abstract description 13
- 230000003034 chemosensitisation Effects 0.000 claims abstract description 8
- 230000008878 coupling Effects 0.000 claims abstract description 5
- 238000010168 coupling process Methods 0.000 claims abstract description 5
- 238000005859 coupling reaction Methods 0.000 claims abstract description 5
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 3
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 claims description 152
- 125000001340 2-chloroethyl group Chemical group [H]C([H])(Cl)C([H])([H])* 0.000 claims description 34
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 21
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 21
- -1 benzymidazolyl Chemical group 0.000 claims description 16
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 12
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 9
- 150000002148 esters Chemical class 0.000 claims description 8
- 229910052757 nitrogen Inorganic materials 0.000 claims description 8
- HAWPXGHAZFHHAD-UHFFFAOYSA-N mechlorethamine Chemical class ClCCN(C)CCCl HAWPXGHAZFHHAD-UHFFFAOYSA-N 0.000 claims description 6
- 229960004961 mechlorethamine Drugs 0.000 claims description 6
- OSTGTTZJOCZWJG-UHFFFAOYSA-N nitrosourea Chemical compound NC(=O)N=NO OSTGTTZJOCZWJG-UHFFFAOYSA-N 0.000 claims description 6
- 125000005842 heteroatom Chemical group 0.000 claims description 5
- 238000000034 method Methods 0.000 claims description 5
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 claims description 4
- 230000002152 alkylating effect Effects 0.000 claims description 4
- 125000000623 heterocyclic group Chemical group 0.000 claims description 4
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 4
- 239000012312 sodium hydride Substances 0.000 claims description 4
- 229910000104 sodium hydride Inorganic materials 0.000 claims description 4
- 125000003118 aryl group Chemical group 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
- 239000007795 chemical reaction product Substances 0.000 claims description 2
- 125000002883 imidazolyl group Chemical group 0.000 claims description 2
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 2
- 125000003831 tetrazolyl group Chemical group 0.000 claims description 2
- 125000001425 triazolyl group Chemical group 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 claims 2
- WJSDAFAYDXCQLE-UHFFFAOYSA-N (2,4,5-trichlorophenyl) n-(2-chloroethyl)-n-nitrosocarbamate Chemical group ClCCN(N=O)C(=O)OC1=CC(Cl)=C(Cl)C=C1Cl WJSDAFAYDXCQLE-UHFFFAOYSA-N 0.000 claims 1
- 239000002547 new drug Substances 0.000 claims 1
- 239000003814 drug Substances 0.000 abstract description 7
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 108
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 79
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 74
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 72
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 45
- 230000015572 biosynthetic process Effects 0.000 description 39
- 239000000460 chlorine Substances 0.000 description 39
- 238000003786 synthesis reaction Methods 0.000 description 39
- 239000000377 silicon dioxide Substances 0.000 description 37
- 239000003480 eluent Substances 0.000 description 35
- 238000004458 analytical method Methods 0.000 description 29
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 28
- 210000004027 cell Anatomy 0.000 description 21
- YZEUHQHUFTYLPH-UHFFFAOYSA-N 2-nitroimidazole Chemical compound [O-][N+](=O)C1=NC=CN1 YZEUHQHUFTYLPH-UHFFFAOYSA-N 0.000 description 17
- 206010021143 Hypoxia Diseases 0.000 description 16
- 230000001146 hypoxic effect Effects 0.000 description 16
- 238000010586 diagram Methods 0.000 description 11
- VYDWQPKRHOGLPA-UHFFFAOYSA-N 5-nitroimidazole Chemical compound [O-][N+](=O)C1=CN=CN1 VYDWQPKRHOGLPA-UHFFFAOYSA-N 0.000 description 10
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 9
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 8
- 125000001951 carbamoylamino group Chemical group C(N)(=O)N* 0.000 description 8
- 239000000203 mixture Substances 0.000 description 8
- 239000000047 product Substances 0.000 description 8
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- 238000009833 condensation Methods 0.000 description 6
- 230000005494 condensation Effects 0.000 description 6
- 238000001914 filtration Methods 0.000 description 6
- 239000011541 reaction mixture Substances 0.000 description 6
- 239000000725 suspension Substances 0.000 description 6
- 239000004593 Epoxy Substances 0.000 description 5
- 150000001412 amines Chemical class 0.000 description 5
- 238000004587 chromatography analysis Methods 0.000 description 5
- 239000000706 filtrate Substances 0.000 description 5
- 150000002460 imidazoles Chemical class 0.000 description 5
- 238000010992 reflux Methods 0.000 description 5
- 125000000022 2-aminoethyl group Chemical group [H]C([*])([H])C([H])([H])N([H])[H] 0.000 description 4
- 125000000954 2-hydroxyethyl group Chemical group [H]C([*])([H])C([H])([H])O[H] 0.000 description 4
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 4
- 206010028980 Neoplasm Diseases 0.000 description 4
- 238000006243 chemical reaction Methods 0.000 description 4
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 4
- XKJCHHZQLQNZHY-UHFFFAOYSA-N phthalimide Chemical compound C1=CC=C2C(=O)NC(=O)C2=C1 XKJCHHZQLQNZHY-UHFFFAOYSA-N 0.000 description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 4
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 4
- 238000001953 recrystallisation Methods 0.000 description 4
- 150000003839 salts Chemical class 0.000 description 4
- 239000000741 silica gel Substances 0.000 description 4
- 229910002027 silica gel Inorganic materials 0.000 description 4
- SZUVGFMDDVSKSI-WIFOCOSTSA-N (1s,2s,3s,5r)-1-(carboxymethyl)-3,5-bis[(4-phenoxyphenyl)methyl-propylcarbamoyl]cyclopentane-1,2-dicarboxylic acid Chemical compound O=C([C@@H]1[C@@H]([C@](CC(O)=O)([C@H](C(=O)N(CCC)CC=2C=CC(OC=3C=CC=CC=3)=CC=2)C1)C(O)=O)C(O)=O)N(CCC)CC(C=C1)=CC=C1OC1=CC=CC=C1 SZUVGFMDDVSKSI-WIFOCOSTSA-N 0.000 description 3
- DAJARBUJEJVGDQ-UHFFFAOYSA-N (4-nitrophenyl) n-(2-chloroethyl)-n-nitrosocarbamate Chemical compound [O-][N+](=O)C1=CC=C(OC(=O)N(CCCl)N=O)C=C1 DAJARBUJEJVGDQ-UHFFFAOYSA-N 0.000 description 3
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 description 3
- DUILGEYLVHGSEE-UHFFFAOYSA-N 2-(oxiran-2-ylmethyl)isoindole-1,3-dione Chemical compound O=C1C2=CC=CC=C2C(=O)N1CC1CO1 DUILGEYLVHGSEE-UHFFFAOYSA-N 0.000 description 3
- FFYTTYVSDVWNMY-UHFFFAOYSA-N 2-Methyl-5-nitroimidazole Chemical compound CC1=NC=C([N+]([O-])=O)N1 FFYTTYVSDVWNMY-UHFFFAOYSA-N 0.000 description 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
- OAKJQQAXSVQMHS-UHFFFAOYSA-N Hydrazine Chemical compound NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 0.000 description 3
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- 230000009471 action Effects 0.000 description 3
- 229940045719 antineoplastic alkylating agent nitrosoureas Drugs 0.000 description 3
- 238000009835 boiling Methods 0.000 description 3
- 229910052801 chlorine Inorganic materials 0.000 description 3
- 229940126543 compound 14 Drugs 0.000 description 3
- 238000002425 crystallisation Methods 0.000 description 3
- 230000008025 crystallization Effects 0.000 description 3
- 230000003013 cytotoxicity Effects 0.000 description 3
- 231100000135 cytotoxicity Toxicity 0.000 description 3
- 229940079593 drug Drugs 0.000 description 3
- UKYAPGRNQNGWQK-UHFFFAOYSA-N phenyl n-(2-chloroethyl)-n-nitrosocarbamate Chemical compound ClCCN(N=O)C(=O)OC1=CC=CC=C1 UKYAPGRNQNGWQK-UHFFFAOYSA-N 0.000 description 3
- XAEFZNCEHLXOMS-UHFFFAOYSA-M potassium benzoate Chemical compound [K+].[O-]C(=O)C1=CC=CC=C1 XAEFZNCEHLXOMS-UHFFFAOYSA-M 0.000 description 3
- NLKNQRATVPKPDG-UHFFFAOYSA-M potassium iodide Chemical compound [K+].[I-] NLKNQRATVPKPDG-UHFFFAOYSA-M 0.000 description 3
- 230000001988 toxicity Effects 0.000 description 3
- 231100000419 toxicity Toxicity 0.000 description 3
- 210000004881 tumor cell Anatomy 0.000 description 3
- 239000008096 xylene Substances 0.000 description 3
- IBYHHJPAARCAIE-UHFFFAOYSA-N 1-bromo-2-chloroethane Chemical compound ClCCBr IBYHHJPAARCAIE-UHFFFAOYSA-N 0.000 description 2
- IAOGWYABFHUNKI-UHFFFAOYSA-N 1h-imidazole;dihydrochloride Chemical compound Cl.[Cl-].C1=C[NH+]=CN1 IAOGWYABFHUNKI-UHFFFAOYSA-N 0.000 description 2
- 150000004959 2-nitroimidazoles Chemical class 0.000 description 2
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 2
- JOCIMPQRWDNKIC-UHFFFAOYSA-N C1=CN(C(=N1)CCCl)[N+](=O)[O-] Chemical class C1=CN(C(=N1)CCCl)[N+](=O)[O-] JOCIMPQRWDNKIC-UHFFFAOYSA-N 0.000 description 2
- BRLQWZUYTZBJKN-UHFFFAOYSA-N Epichlorohydrin Chemical compound ClCC1CO1 BRLQWZUYTZBJKN-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
- 229910021529 ammonia Inorganic materials 0.000 description 2
- KGNDCEVUMONOKF-UGPLYTSKSA-N benzyl n-[(2r)-1-[(2s,4r)-2-[[(2s)-6-amino-1-(1,3-benzoxazol-2-yl)-1,1-dihydroxyhexan-2-yl]carbamoyl]-4-[(4-methylphenyl)methoxy]pyrrolidin-1-yl]-1-oxo-4-phenylbutan-2-yl]carbamate Chemical compound C1=CC(C)=CC=C1CO[C@H]1CN(C(=O)[C@@H](CCC=2C=CC=CC=2)NC(=O)OCC=2C=CC=CC=2)[C@H](C(=O)N[C@@H](CCCCN)C(O)(O)C=2OC3=CC=CC=C3N=2)C1 KGNDCEVUMONOKF-UGPLYTSKSA-N 0.000 description 2
- 230000004071 biological effect Effects 0.000 description 2
- 229940125773 compound 10 Drugs 0.000 description 2
- 229940125833 compound 23 Drugs 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- 238000010511 deprotection reaction Methods 0.000 description 2
- 238000001704 evaporation Methods 0.000 description 2
- 230000008020 evaporation Effects 0.000 description 2
- 235000019253 formic acid Nutrition 0.000 description 2
- 239000000543 intermediate Substances 0.000 description 2
- 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 2
- 150000002828 nitro derivatives Chemical class 0.000 description 2
- 150000004957 nitroimidazoles Chemical class 0.000 description 2
- 230000000247 oncostatic effect Effects 0.000 description 2
- 150000002924 oxiranes Chemical class 0.000 description 2
- 125000005543 phthalimide group Chemical class 0.000 description 2
- 229910000027 potassium carbonate Inorganic materials 0.000 description 2
- 239000011734 sodium Substances 0.000 description 2
- 229910052708 sodium Inorganic materials 0.000 description 2
- 159000000000 sodium salts Chemical class 0.000 description 2
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 description 2
- AOSZTAHDEDLTLQ-AZKQZHLXSA-N (1S,2S,4R,8S,9S,11S,12R,13S,19S)-6-[(3-chlorophenyl)methyl]-12,19-difluoro-11-hydroxy-8-(2-hydroxyacetyl)-9,13-dimethyl-6-azapentacyclo[10.8.0.02,9.04,8.013,18]icosa-14,17-dien-16-one Chemical compound C([C@@H]1C[C@H]2[C@H]3[C@]([C@]4(C=CC(=O)C=C4[C@@H](F)C3)C)(F)[C@@H](O)C[C@@]2([C@@]1(C1)C(=O)CO)C)N1CC1=CC=CC(Cl)=C1 AOSZTAHDEDLTLQ-AZKQZHLXSA-N 0.000 description 1
- ABJSOROVZZKJGI-OCYUSGCXSA-N (1r,2r,4r)-2-(4-bromophenyl)-n-[(4-chlorophenyl)-(2-fluoropyridin-4-yl)methyl]-4-morpholin-4-ylcyclohexane-1-carboxamide Chemical compound C1=NC(F)=CC(C(NC(=O)[C@H]2[C@@H](C[C@@H](CC2)N2CCOCC2)C=2C=CC(Br)=CC=2)C=2C=CC(Cl)=CC=2)=C1 ABJSOROVZZKJGI-OCYUSGCXSA-N 0.000 description 1
- QFLWZFQWSBQYPS-AWRAUJHKSA-N (3S)-3-[[(2S)-2-[[(2S)-2-[5-[(3aS,6aR)-2-oxo-1,3,3a,4,6,6a-hexahydrothieno[3,4-d]imidazol-4-yl]pentanoylamino]-3-methylbutanoyl]amino]-3-(4-hydroxyphenyl)propanoyl]amino]-4-[1-bis(4-chlorophenoxy)phosphorylbutylamino]-4-oxobutanoic acid Chemical compound CCCC(NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)[C@@H](NC(=O)CCCCC1SC[C@@H]2NC(=O)N[C@H]12)C(C)C)P(=O)(Oc1ccc(Cl)cc1)Oc1ccc(Cl)cc1 QFLWZFQWSBQYPS-AWRAUJHKSA-N 0.000 description 1
- IWZSHWBGHQBIML-ZGGLMWTQSA-N (3S,8S,10R,13S,14S,17S)-17-isoquinolin-7-yl-N,N,10,13-tetramethyl-2,3,4,7,8,9,11,12,14,15,16,17-dodecahydro-1H-cyclopenta[a]phenanthren-3-amine Chemical compound CN(C)[C@H]1CC[C@]2(C)C3CC[C@@]4(C)[C@@H](CC[C@@H]4c4ccc5ccncc5c4)[C@@H]3CC=C2C1 IWZSHWBGHQBIML-ZGGLMWTQSA-N 0.000 description 1
- UDQTXCHQKHIQMH-KYGLGHNPSA-N (3ar,5s,6s,7r,7ar)-5-(difluoromethyl)-2-(ethylamino)-5,6,7,7a-tetrahydro-3ah-pyrano[3,2-d][1,3]thiazole-6,7-diol Chemical compound S1C(NCC)=N[C@H]2[C@@H]1O[C@H](C(F)F)[C@@H](O)[C@@H]2O UDQTXCHQKHIQMH-KYGLGHNPSA-N 0.000 description 1
- NVKGVBZZSJFQLM-UHFFFAOYSA-N 1-(2-chloroethyl)-1-nitrosourea Chemical compound NC(=O)N(N=O)CCCl NVKGVBZZSJFQLM-UHFFFAOYSA-N 0.000 description 1
- UNILWMWFPHPYOR-KXEYIPSPSA-M 1-[6-[2-[3-[3-[3-[2-[2-[3-[[2-[2-[[(2r)-1-[[2-[[(2r)-1-[3-[2-[2-[3-[[2-(2-amino-2-oxoethoxy)acetyl]amino]propoxy]ethoxy]ethoxy]propylamino]-3-hydroxy-1-oxopropan-2-yl]amino]-2-oxoethyl]amino]-3-[(2r)-2,3-di(hexadecanoyloxy)propyl]sulfanyl-1-oxopropan-2-yl Chemical compound O=C1C(SCCC(=O)NCCCOCCOCCOCCCNC(=O)COCC(=O)N[C@@H](CSC[C@@H](COC(=O)CCCCCCCCCCCCCCC)OC(=O)CCCCCCCCCCCCCCC)C(=O)NCC(=O)N[C@H](CO)C(=O)NCCCOCCOCCOCCCNC(=O)COCC(N)=O)CC(=O)N1CCNC(=O)CCCCCN\1C2=CC=C(S([O-])(=O)=O)C=C2CC/1=C/C=C/C=C/C1=[N+](CC)C2=CC=C(S([O-])(=O)=O)C=C2C1 UNILWMWFPHPYOR-KXEYIPSPSA-M 0.000 description 1
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- IWDUDCDZGOLTTJ-UHFFFAOYSA-N 1h-imidazole;silver Chemical compound [Ag].C1=CNC=N1 IWDUDCDZGOLTTJ-UHFFFAOYSA-N 0.000 description 1
- KGLPWQKSKUVKMJ-UHFFFAOYSA-N 2,3-dihydrophthalazine-1,4-dione Chemical compound C1=CC=C2C(=O)NNC(=O)C2=C1 KGLPWQKSKUVKMJ-UHFFFAOYSA-N 0.000 description 1
- FQMZXMVHHKXGTM-UHFFFAOYSA-N 2-(1-adamantyl)-n-[2-[2-(2-hydroxyethylamino)ethylamino]quinolin-5-yl]acetamide Chemical compound C1C(C2)CC(C3)CC2CC13CC(=O)NC1=CC=CC2=NC(NCCNCCO)=CC=C21 FQMZXMVHHKXGTM-UHFFFAOYSA-N 0.000 description 1
- CHZXTOCAICMPQR-UHFFFAOYSA-N 2-(2-bromoethyl)isoindole-1,3-dione Chemical compound C1=CC=C2C(=O)N(CCBr)C(=O)C2=C1 CHZXTOCAICMPQR-UHFFFAOYSA-N 0.000 description 1
- HOCPDSKONPQIQM-UHFFFAOYSA-N 4-(2-bromoethyl)isoindole-1,3-dione Chemical compound BrCCC1=CC=CC2=C1C(=O)NC2=O HOCPDSKONPQIQM-UHFFFAOYSA-N 0.000 description 1
- LLUAYKBVIKUBSD-UHFFFAOYSA-N 5-nitro-1H-imidazole dihydrochloride Chemical compound Cl.Cl.[O-][N+](=O)c1cnc[nH]1 LLUAYKBVIKUBSD-UHFFFAOYSA-N 0.000 description 1
- FUHUQBSNHRFQFQ-UHFFFAOYSA-N 5-nitro-1H-imidazole hydrochloride Chemical compound Cl.[O-][N+](=O)C1=CN=CN1 FUHUQBSNHRFQFQ-UHFFFAOYSA-N 0.000 description 1
- 150000004958 5-nitroimidazoles Chemical class 0.000 description 1
- NOWKCMXCCJGMRR-UHFFFAOYSA-N Aziridine Chemical compound C1CN1 NOWKCMXCCJGMRR-UHFFFAOYSA-N 0.000 description 1
- BQXUPNKLZNSUMC-YUQWMIPFSA-N CCN(CCCCCOCC(=O)N[C@H](C(=O)N1C[C@H](O)C[C@H]1C(=O)N[C@@H](C)c1ccc(cc1)-c1scnc1C)C(C)(C)C)CCOc1ccc(cc1)C(=O)c1c(sc2cc(O)ccc12)-c1ccc(O)cc1 Chemical compound CCN(CCCCCOCC(=O)N[C@H](C(=O)N1C[C@H](O)C[C@H]1C(=O)N[C@@H](C)c1ccc(cc1)-c1scnc1C)C(C)(C)C)CCOc1ccc(cc1)C(=O)c1c(sc2cc(O)ccc12)-c1ccc(O)cc1 BQXUPNKLZNSUMC-YUQWMIPFSA-N 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- 229940126657 Compound 17 Drugs 0.000 description 1
- OPFTUNCRGUEPRZ-QLFBSQMISA-N Cyclohexane Natural products CC(=C)[C@@H]1CC[C@@](C)(C=C)[C@H](C(C)=C)C1 OPFTUNCRGUEPRZ-QLFBSQMISA-N 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- 102000016397 Methyltransferase Human genes 0.000 description 1
- 108060004795 Methyltransferase Proteins 0.000 description 1
- JILGJCGLYLCARC-UHFFFAOYSA-N NCCC=1N(C=CN=1)[N+](=O)[O-] Chemical compound NCCC=1N(C=CN=1)[N+](=O)[O-] JILGJCGLYLCARC-UHFFFAOYSA-N 0.000 description 1
- MXRLMQDRNFNSKK-UHFFFAOYSA-N [N+](=O)([O-])C=1NC=C(N=1)C=1C2C(C(=O)NC2=O)(C=CC=1)CC Chemical compound [N+](=O)([O-])C=1NC=C(N=1)C=1C2C(C(=O)NC2=O)(C=CC=1)CC MXRLMQDRNFNSKK-UHFFFAOYSA-N 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 239000002246 antineoplastic agent Substances 0.000 description 1
- 210000004204 blood vessel Anatomy 0.000 description 1
- 201000011510 cancer Diseases 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 239000006114 chemosensitizer Substances 0.000 description 1
- 238000002512 chemotherapy Methods 0.000 description 1
- 229940125810 compound 20 Drugs 0.000 description 1
- 229940126208 compound 22 Drugs 0.000 description 1
- 229940126214 compound 3 Drugs 0.000 description 1
- 229940125936 compound 42 Drugs 0.000 description 1
- 229940125898 compound 5 Drugs 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- ZBCBWPMODOFKDW-UHFFFAOYSA-N diethanolamine Chemical compound OCCNCCO ZBCBWPMODOFKDW-UHFFFAOYSA-N 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 239000003937 drug carrier Substances 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 229940083124 ganglion-blocking antiadrenergic secondary and tertiary amines Drugs 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 239000008246 gaseous mixture Substances 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
- 238000006698 hydrazinolysis reaction Methods 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 125000002768 hydroxyalkyl group Chemical group 0.000 description 1
- 239000005457 ice water Substances 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 229940079865 intestinal antiinfectives imidazole derivative Drugs 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 231100001231 less toxic Toxicity 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 201000001441 melanoma Diseases 0.000 description 1
- 230000002503 metabolic effect Effects 0.000 description 1
- OBBCSXFCDPPXOL-UHFFFAOYSA-N misonidazole Chemical compound COCC(O)CN1C=CN=C1[N+]([O-])=O OBBCSXFCDPPXOL-UHFFFAOYSA-N 0.000 description 1
- 229950010514 misonidazole Drugs 0.000 description 1
- VQSRKMNBWMHJKY-YTEVENLXSA-N n-[3-[(4ar,7as)-2-amino-6-(5-fluoropyrimidin-2-yl)-4,4a,5,7-tetrahydropyrrolo[3,4-d][1,3]thiazin-7a-yl]-4-fluorophenyl]-5-methoxypyrazine-2-carboxamide Chemical compound C1=NC(OC)=CN=C1C(=O)NC1=CC=C(F)C([C@@]23[C@@H](CN(C2)C=2N=CC(F)=CN=2)CSC(N)=N3)=C1 VQSRKMNBWMHJKY-YTEVENLXSA-N 0.000 description 1
- 150000002829 nitrogen Chemical class 0.000 description 1
- 239000012074 organic phase Substances 0.000 description 1
- 238000010647 peptide synthesis reaction Methods 0.000 description 1
- 150000003141 primary amines Chemical class 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 239000012429 reaction media Substances 0.000 description 1
- 230000008261 resistance mechanism Effects 0.000 description 1
- 150000003335 secondary amines Chemical class 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- ADZWSOLPGZMUMY-UHFFFAOYSA-M silver bromide Chemical compound [Ag]Br ADZWSOLPGZMUMY-UHFFFAOYSA-M 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
- 239000007921 spray Substances 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 238000004781 supercooling Methods 0.000 description 1
- 230000004083 survival effect Effects 0.000 description 1
- 230000008685 targeting Effects 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- FIQMHBFVRAXMOP-UHFFFAOYSA-N triphenylphosphane oxide Chemical compound C=1C=CC=CC=1P(C=1C=CC=CC=1)(=O)C1=CC=CC=C1 FIQMHBFVRAXMOP-UHFFFAOYSA-N 0.000 description 1
- 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 1
- 239000003039 volatile agent Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
- C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
- C07D233/66—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D233/91—Nitro radicals
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
- C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
- C07D233/66—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D233/91—Nitro radicals
- C07D233/92—Nitro radicals attached in position 4 or 5
- C07D233/94—Nitro radicals attached in position 4 or 5 with hydrocarbon radicals, substituted by oxygen or sulfur atoms, attached to other ring members
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
- C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
- C07D233/66—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D233/91—Nitro radicals
- C07D233/92—Nitro radicals attached in position 4 or 5
- C07D233/95—Nitro radicals attached in position 4 or 5 with hydrocarbon radicals, substituted by nitrogen atoms, attached to other ring members
Definitions
- Anti-tumor targeting agents their preparation and applications
- the present invention relates to new compounds which result from the coupling of a molecule having a chemosensitizing structure and a molecule having a cytotoxic structure, their preparation process, as well as their application as medicaments.
- a molecule having a chemosensitizing structure and a molecule having a cytotoxic structure
- their preparation process as well as their application as medicaments.
- Another problem is that caused by solid tumors; the hypoxic cells present in these tumors show therapeutic resistance to most anti-cancer agents.
- the resistance mechanism of these cells is quite complex and involves kinetic, metabolic and physical factors.
- these cells are known to be placed at a distance from blood vessels, which prevents certain drugs from diffusing to the desired location.
- Radiosensitizers have already been proposed having an affinity for hypoxic cells, teksquele Misonidazole.
- the present invention aims to overcome the drawbacks listed above by providing new compounds which result from the coupling of a molecule having a chemosensitizing structure and a molecule having a cytotoxic structure. These compounds will make it possible to chemosensitize hypoxic tumor cells and to specifically deliver to them a cytotoxic entity interacting on their DNA.
- the molecule having a cytotoxic structure is, more preferably, derived from an alkylating cytotoxic molecule. It can be a molecule derived from a nitrosourea or a nitrogen mustard.
- the molecule having a chemosensitizing structure will, preferably, be derived from a molecule with an aromatic cycle, or pseudo-aromatio
- the compounds of the present invention correspond to farmule I in which X is a residue of a benzene ring or of a heterocycle comprising nitrogen as the heteroatom of formula XH in which H represents hydrogen, X being substituted by at least one group -NO 2 , R 1 is H, or SH and R 2 is a group derived from nitrosourea or nitrogen mustard.
- X is chosen from the following radicals: benzyl, triazolyl, benzymidazolyl, imidazolyl, tetrazolyl.
- R 2 is -NH-CO-N (NO) -CH 2 -CH 2 -Cl provided that R 1 is a hydrogen atom, or R 2 is CH 2 -NH- CO-N (NO) -CH 2 -CH 2 Cl, provided that R 1 is OH or SH.
- Particularly preferred compounds are the following: [[(2-chloro-ethyl) -3 3-nitroso-ureido] -3-2-hydroxypropyl] -1 4-nitro imidazole, [[(2-chloro-ethyl) -3 nitroso-3 ureido] -3 hydroxy-2 propyl] -1 nitro-5 imidazole,
- R 2 is NH-CH 2 -CH 2 - Cl or N (CH 2 -CH 2 -Cl) 2 or NH-C 6 H 4 -N (CH 2 CH 2 Cl) 2 provided that R 1 is a hydrogen atom or R 2 is CH 2 -NH- CH 2 -CH 2 -Cl or CH 2 -N (CH 2 CH 2 Cl) 2 or CH 2 -NH-C 6 H 4 -N (CH 2 CH 2 Cl) 2 provided that R 1 is OH or SH.
- Particularly preferred compounds are the following:
- the present invention also relates to a process for the preparation of compounds of formula I.
- R 2 is a nitrosourea
- R 2 -NH-CO-N (CO) -N (NO) -CH 2 -CH 2 -Cl or
- R NO 2
- R 3 CH 2 CH 2 Cl
- XH H is linked to the heteroatom when X represents a heterocycle comprising nitrogen as the heteroatom.
- -R 6 , -R 7 chosen from in particular H, CH 2 -CH 2 OH and
- the invention therefore provides molecules aiming to chemosensitize hypoxic tumor cells and to specifically deliver to them a cytotoxic entity which inter-reacts with their DNA.
- the compounds of the present invention are useful as medicaments.
- the present invention therefore therefore also relates to the application of the compounds as medicaments as well as pharmaceutical compositions comprising, in addition to a pharmaceutically acceptable carrier, an active principle comprising at least one compound as described above.
- an active principle comprising at least one compound as described above.
- - Figure 1 represents, for certain compounds of the present invention, the evolution of the number of surviving cells of a Mer- line as a function of the quantity administered ( ⁇ moles)
- - Figure 2 represents, for certain compounds of the present invention, the evolution of the number of surviving cells of a Mer + line as a function of the quantity administered (in ⁇ moles).
- nitrosoureas of the A and B series were synthesized by coupling between the amine and an active ester comprising the N- (2-chloroethyl) N-nitrosocarbamate unit according to the " active esters "used in peptide synthesis (Diagram 1)).
- the alkanolamines were synthesized by treatment of (epoxyalkyl) -1 nitro-2 imidazoles with a number of secondary and primary amines. By this method of synthesis secondary and tertiary amines are obtained.
- the primary alkanolamines are prepared by the reaction of ammonia with the epoxides.
- 1 '(2-aminoethyl) -1 2-nitro imidazole can be obtained by the action of aziridine on 2-nitro imidazole.
- Nitroimidazoles (hydroxyaminoalkyl) -1 are obtained via nitro-imidazole intermediates N- (hydroxyalkyl) phthalimides.
- R H 19 28 (71%)
- R nltro-4 20 29 (89%)
- R nitro-3 21 30 (67%)
- R nitro-2 23 37 (81%)
- the oil bath is brought to 100 ° C for 10 minutes.
- the solution is then brought to room temperature; 12 ml (155 mmol) of 1,2-dichloroethane are then added.
- the duration of the addition is 1 hour.
- reaction mixture is then evaporated under vacuum; the oily residue is thrown into a mixture of 200 ml of ice water. Neutralized with ammonia and extracted 5 times with 50 ml of toluene then 3 times with 30 ml of dichloromethane.
- This compound was prepared in a manner analogous to Example 3 of compound 14 with a yield of 60%.
- This compound was prepared in a manner analogous to Example 12 from compound No. 7 with a yield of 69%.
- This compound was prepared in a manner analogous to Example 12 from the non-MS compound with a yield of 70%.
- This compound was prepared in a manner analogous to Example 20 from compound No. 16 with a yield of 72%.
- This compound was prepared in a manner analogous to Example 20 from compound No. 17 with a yield of 56%.
- This compound was prepared in a manner analogous to Example 20 from compound 20 with a yield of 69%.
- This compound was prepared in a manner analogous to Example 20 from compound No. 21 with a yield of 67%.
- This compound was prepared in a manner analogous to Example 28 from commercial nitro-4 (5) imidazole. The yield obtained is 71%.
- R H, Nitro-4, Nitro-5, Nitro-2.
- the difference between these two types of cells is the presence or absence of a separating enzyme, 0-6 methyltransferase.
- BME Eagle base medium
- the cells used in an aerobic environment are suspended in 10 ml of Eagle base medium (BME) at a concentration of 1 to 2.10 per milliliter, and placed in a type I treatment flask as described by Whilliams and Rauth.
- BME Eagle base medium
- the cells are added to the vials containing the BME only after the medium has remained in a gaseous mixture 97% N 2 /3% CO 2 for 3 hours.
- the cells are incubated for 10 minutes at a concentration of 2 ⁇ 10 7 cells / ml in a Hamilton syringe
- the relative aerobic and hypoxic toxicity of the various compounds was calculated using the DEF factor defined as the ratio of the amounts required to reduce the surviving cells to 0.01, respectively, under aerobic and hypoxic conditions.
- Figures 1 and 2 illustrate the results obtained and give the percentage of surviving cells as a function of the dose of compound administered (in ⁇ mol).
- N2 represents the hypoxic medium while O2 represents the aerobic medium.
- Figure 1 expresses more precisely the results obtained with Mer- cells while Figure 2 expresses the results obtained with Mer + cells.
- the compounds tested are cytotoxic with respect to Mer- cells (Hela-MR), both under aerobic and hypoxic conditions, except for the non-nitrated imidazole derivatives I-273 (no24) and 1-283 (no. 28).
- the Mer + cells (Hela - 53) are, as should be expected, more resistant to the products tested. All the compounds of the A series are less toxic than those of the B series.
- the compounds I-278 and I-282 (31 and 27) once again exhibit increased cytotoxicity under conditions hypoxic (DEF close to 1.3).
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
La présente invention concerne un composé caractérisé en ce qu'il résulte du couplage d'une molécule ayant une structure chimiosensibilisante et d'une molécule ayant une structure cytotoxique. Elle concerne également son application à titre de médicament et les compositions pharmaceutiques le contenant.The present invention relates to a compound characterized in that it results from the coupling of a molecule having a chemosensitizing structure and a molecule having a cytotoxic structure. It also relates to its application as a medicament and to the pharmaceutical compositions containing it.
Description
Agents de ciblage anti-tumoraux, leur préparation et applications Anti-tumor targeting agents, their preparation and applications
la présente invention concerne de nouveaux composés qui résu tent du couplage d'une molécule ayant une structure chimiosensibilisante et d'une molécule ayant une structure cytotoxique, leur procédé de prépa ration, ainsi que leur application à titre de médicaments. Dans le domaine de la chimiothérapie du cancer se pose souvent le problème de la spécificité des substances utilisées. Un autre problème est celui occasionné par les tumeurs solides ; les cellules hypoxiques, présentes dans ces tumeurs font preuve d'une résistance thérapeutique à la plupart des agents anti-cancéreux. Le mécanisme de résistance de ces cellules est assez complexe et fait intervenir des facteurs cinétiques, métaboliques et physiques. De plus, ces cellules sait placées à distance des vaisseaux sanguins, ce qui empêche certaines drogues de diffuser jusqu'à l'endroit désiré.the present invention relates to new compounds which result from the coupling of a molecule having a chemosensitizing structure and a molecule having a cytotoxic structure, their preparation process, as well as their application as medicaments. In the field of cancer chemotherapy, there is often the problem of the specificity of the substances used. Another problem is that caused by solid tumors; the hypoxic cells present in these tumors show therapeutic resistance to most anti-cancer agents. The resistance mechanism of these cells is quite complex and involves kinetic, metabolic and physical factors. In addition, these cells are known to be placed at a distance from blood vessels, which prevents certain drugs from diffusing to the desired location.
On a déjà proposé des agents radiosensibilisants présentant une affinité vis-à-vis des cellules hypoxiques,teksquele Misonidazole.Radiosensitizers have already been proposed having an affinity for hypoxic cells, teksquele Misonidazole.
La présente invention vise à pallier les inconvénients énumérés plus haut en fournissant de nouveaux composés qui résultent du couplage d'une molécule ayant une structure chimiosensibilisante et d'une molécule ayant une structure cytotoxique. Ces composés permettront de chimiosensibiliser les cellules tumorales hypoxiques et de leur délivrer spécifiquement une entité cytotoxique inter-agissant sur leur ADN. la molécule ayant une structure cytotoxique est, plus préférentiellement, dérivée d'une molécule cytotoxique alkylante. Il peut s'agir d'une molécule dérivée d'une nitroso-urée ou d'une moutarde à l'azote. la molécule ayant une structure chimiosensibilisante sera, de façon préférée, dérivée d'une molécule à cycle aromatique,ou pseudo-aromatioThe present invention aims to overcome the drawbacks listed above by providing new compounds which result from the coupling of a molecule having a chemosensitizing structure and a molecule having a cytotoxic structure. These compounds will make it possible to chemosensitize hypoxic tumor cells and to specifically deliver to them a cytotoxic entity interacting on their DNA. the molecule having a cytotoxic structure is, more preferably, derived from an alkylating cytotoxic molecule. It can be a molecule derived from a nitrosourea or a nitrogen mustard. the molecule having a chemosensitizing structure will, preferably, be derived from a molecule with an aromatic cycle, or pseudo-aromatio
Selon une caractéristique particulière, les composés de la présente invention répondent à la farmule I
dans laquelle X est un reste d'un cycle benzénique ou d'un hétérocycle comportant l'azote comme hétéroatome de formule XH dans laquelle H représente l'hydrogène, X étant substitué par au moins un groupe -NO2, R1 est H, ou SH et R2 est un groupe dérivé d'une nitroso-urée ou d'une moutarde à l'azote.
Selon une autre caractéristique, X est choisi parmi les radicaux suivants : benzyle, triazolyle, benzymidazolyle, imidazolyle, tétrazolyle.According to a particular characteristic, the compounds of the present invention correspond to farmule I in which X is a residue of a benzene ring or of a heterocycle comprising nitrogen as the heteroatom of formula XH in which H represents hydrogen, X being substituted by at least one group -NO 2 , R 1 is H, or SH and R 2 is a group derived from nitrosourea or nitrogen mustard. According to another characteristic, X is chosen from the following radicals: benzyl, triazolyl, benzymidazolyl, imidazolyl, tetrazolyl.
Lorsque X représente un hétérocycle comportant l'azote comme hétéroatome, X est relié àWhen X represents a heterocycle comprising nitrogen as a heteroatom, X is linked to
par cet azote.
by this nitrogen.
Selon une autre caractéristique de l'invention, R2 est -NH-CO-N (NO) -CH2-CH2-Cl à condition que R1 soit un atome d'hydrogène, ou R2 est CH2-NH-CO-N (NO) -CH2-CH2Cl, à condition que R1 soit OH ou SH.According to another characteristic of the invention, R 2 is -NH-CO-N (NO) -CH 2 -CH 2 -Cl provided that R 1 is a hydrogen atom, or R 2 is CH 2 -NH- CO-N (NO) -CH 2 -CH 2 Cl, provided that R 1 is OH or SH.
Des composés particulièrement préférés sont les suivants : [[(chloro-2 éthyl) -3 nitroso-3 uréido ]-3 hydroxy-2 propyl ] -1 nitro-4 imidazole, [ [ (chloro-2 éthyl) -3 nitroso-3 uréido]-3 hydroxy-2 propyl] -1 nitro-5 imidazole,Particularly preferred compounds are the following: [[(2-chloro-ethyl) -3 3-nitroso-ureido] -3-2-hydroxypropyl] -1 4-nitro imidazole, [[(2-chloro-ethyl) -3 nitroso-3 ureido] -3 hydroxy-2 propyl] -1 nitro-5 imidazole,
[ [ (chloro-2 éthyl) -3 nitroso-3 uréido]-3 hydroxy-2 propyl ] -1 nitro-2 imidazole[[(2-chloro-ethyl) -3 nitroso-3 ureido] -3 hydroxy-2 propyl] -1 nitro-2 imidazole
[ [ (chloro-2 éthyl) -3 nitroso-3 uréido]-2 éthyl]-1 nitro -4 imidazole [ [ (chloro-2 éthyl) -3 nitroso-3 uréido ]-2 éthyl ]-1 nitro -5 imidazole,[[(2-chloro-ethyl) -3 nitroso-3 ureido] -2 ethyl] -1 nitro -4 imidazole [[(2-chloro-ethyl) -3 nitroso-3 ureido] -2 ethyl] -1 nitro -5 imidazole ,
[ [ (chloro-2 éthyl) -3 nitroso-3 uréido ]-2 éthyl ]-1 nitro -2 imidazole, Selon une autre caractéristique de l'invention dans la formule I, R2 est NH-CH2-CH2-Cl ou N(CH2-CH2-Cl)2 ou NH-C6H4-N(CH2CH2Cl)2 à condition que R1 soit un atome d'hydrogène ou R2 est CH2-NH-CH2-CH2-Cl ou CH2-N(CH2CH2Cl)2 ou CH2-NH-C6H4-N(CH2CH2Cl)2 à condition que R1 soit OH ou SH.
Des composés particulièrement préférés sont les suivants :[[(2-chloro-ethyl) -3 nitroso-3 ureido] -2 ethyl] -1 nitro -2 imidazole, According to another characteristic of the invention in formula I, R 2 is NH-CH 2 -CH 2 - Cl or N (CH 2 -CH 2 -Cl) 2 or NH-C 6 H 4 -N (CH 2 CH 2 Cl) 2 provided that R 1 is a hydrogen atom or R 2 is CH 2 -NH- CH 2 -CH 2 -Cl or CH 2 -N (CH 2 CH 2 Cl) 2 or CH 2 -NH-C 6 H 4 -N (CH 2 CH 2 Cl) 2 provided that R 1 is OH or SH. Particularly preferred compounds are the following:
[[bis(chloro-2 éthyl)-1 amino]-3 hydroxy-2 propyl]-1 nitro- 2 imidazole, [[bis (chloro-2 éthyl)-1 amino]-3 hydroxy-2 propyl]-1 nitro- 4 imidazole,[[bis (2-chloroethyl) -1 amino] -3 2-hydroxypropyl] -1 nitro- 2 imidazole, [[bis (2-chloroethyl) -1 amino] -3 hydroxy-2 propyl] -1 nitro - 4 imidazole,
[[bis (chloro-2 éthyl)-1 amino]-3 hydroxy-2 propyl]-1 nitro- 5 imidazole,[[bis (2-chloroethyl) -1 amino] -3 hydroxy-2 propyl] -1 nitro-imidazole,
[[bis(chloro-2 éthyl -1 amino]-2 éthyl]-1 nitro-2 imidazole [[bis (chloro-2 éthyl)-1 amino]-2 éthyl]-1 nitro-4 imidazole [[bis (chloro-2 éthyl)-1 amino]-2 éthyl]-1 nitro-5 imidazole.[[bis (2-chloro-ethyl -1 amino] -2 ethyl] -1 2-nitro imidazole [[bis (2-chloro-ethyl) -1 amino] -2 ethyl] -1 4-nitro imidazole [[bis (chloro -2 ethyl) -1 amino] -2 ethyl] -1 nitro-5 imidazole.
La présente invention concerne également un procédé de préparation des composés de formule I. Pour les composés de formule I pour lesquels R2 est une nitrosourée, en particulier R2 = -NH-CO-N(CO)-N(NO)-CH2-CH2-Cl ouThe present invention also relates to a process for the preparation of compounds of formula I. For the compounds of formula I for which R 2 is a nitrosourea, in particular R 2 = -NH-CO-N (CO) -N (NO) -CH 2 -CH 2 -Cl or
-CH2-NH-CO-N(NO)-CH2-CH2-Cl, on fait réagir un composé de formule (II) suivante où X et R1 sont tels que définis plus
haut et où n=o quand R1 =H et
n=1 quand R1 = OH ou SH,
avec un ester comportant le groupement N-(chioro-2 éthyl) N-nitroso carbamate, dans le DMF. Un ester particulièrement préféré est le trichloro-2,4,5 phényl N-(CHLORO-2 éthyl) N-nitrosocarbamate. (J. Martinez, J. Oiry, J.L. Imbach et F. Winternitz, J. Med. Chem., 1982, 25 , 178).-CH 2 -NH-CO-N (NO) -CH 2 -CH 2 -Cl, a compound of formula (II) is reacted below where X and R 1 are as defined more high and where n = o when R 1 = H and n = 1 when R 1 = OH or SH, with an ester comprising the N- (2-chloroethyl) N-nitroso carbamate group, in DMF. A particularly preferred ester is 2,4,5,5-trichloro phenyl N- (2-CHLORO-ethyl) N-nitrosocarbamate. (J. Martinez, J. Oiry, JL Imbach and F. Winternitz, J. Med. Chem., 1982, 25, 178).
Pour les composés de formule I pour lesquels R2 est une moutarde à l'azote en particulier R2=NH-CH2-CH2-Cl, N-(CH2-CH2-Cl)2, ou NH-C6H4-N (CH2-CH2-Cl)2 et R1 = H.
On fait réagir XH par exempleFor the compounds of formula I for which R 2 is nitrogen mustard in particular R 2 = NH-CH 2 -CH 2 -Cl, N- (CH 2 -CH 2 -Cl) 2 , or NH-C 6 H 4 -N (CH 2 -CH 2 -Cl) 2 and R 1 = H. We react XH for example
(R = NO2)
avec l'hydrure de sodium, puis on fait réagir le produit de la réaction avec dans le DMF pour
obtenir avec
R3, R4, et R5 choisis notamment parmi H-CH-2CH-2Cl et C6H-4N (CH2CH2Cl)2et plus particulièrement(R = NO 2 ) with sodium hydride, then react the reaction product with in DMF to get with R 3 , R 4 , and R 5 chosen in particular from H-CH- 2 CH- 2 Cl and C 6 H- 4 N (CH 2 CH 2 Cl) 2 and more particularly
- R 3=R4=R5=-CH2-CH2-Cl ou- R 3 = R 4 = R 5 = -CH 2 -CH 2 -Cl or
- R3=R4=CH2CH2Cl et R5=H ou- R 3 = R 4 = CH 2 CH 2 Cl and R 5 = H or
- R3=CH2CH2Cl R4=-C6H4N(CH2CH2Cl)2 et R5=H. Dans la formule XH, H est lié à l'hétéroatome lorsque X représente un hétérocycle comportant l'azote comme hétéroatome.- R 3 = CH 2 CH 2 Cl R 4 = -C 6 H 4 N (CH 2 CH 2 Cl) 2 and R 5 = H. In the formula XH, H is linked to the heteroatom when X represents a heterocycle comprising nitrogen as the heteroatom.
Pour les composés de formule I pour lesquels R2=CH2-NH-CH2-CH2-Cl, CH-2N (CH2CH2Cl)2 ou CH2-NH-C6H4-N(CH2CH2Cl)2 et R1 =OH ou SH, on peut faire réagir XH par exemple où R=NO2
For the compounds of formula I for which R 2 = CH 2 -NH-CH 2 -CH 2 -Cl, CH- 2 N (CH 2 CH 2 Cl) 2 or CH 2 -NH-C 6 H 4 -N (CH 2 CH 2 Cl) 2 and R 1 = OH or SH, we can react XH for example where R = NO 2
avec on obtient (a) que l'on
fait réagir avec pour donner
with we get (a) that we react with to give
avec -R6,-R7 choisi parmi notamment H, CH2-CH2OH et with -R 6 , -R 7 chosen from in particular H, CH 2 -CH 2 OH and
C6H4-N(CH2CH2OH)2 et plus particulièrement avec -R6=H et R7=-CH2-CH2OH (b1) -R6=H et R7=-C6H4-N(CH2CH2OH)2 (b2) ou -R6=R7=-CH2-CH2OH (b3).C 6 H 4 -N (CH 2 CH 2 OH) 2 and more particularly with -R 6 = H and R 7 = -CH 2 -CH 2 OH (b 1 ) -R 6 = H and R 7 = -C 6 H 4 -N (CH 2 CH 2 OH) 2 (b 2 ) or -R 6 = R 7 = -CH 2 -CH 2 OH (b 3 ).
Le produit (b) est mis en réaction avec Ф3P dans CCI4 pour donner avec R'6 et R'7 choisis notamment
parmi H(CH2CH2Cl) et-C6H-4N (CH2CH2Cl)2 et plus particulièrement avec respectivement -R6'=H et R7'=-CH2-CH2-Cl (c1)The product (b) is reacted with Ф 3 P in CCI 4 to give with R ' 6 and R' 7 chosen in particular among H (CH 2 CH 2 Cl) and-C 6 H- 4 N (CH 2 CH 2 Cl) 2 and more particularly with -R 6 '= H and R 7 ' = -CH 2 -CH 2 -Cl ( c 1 )
-R6'=H et R7'=-C6H4-N(CH2CH2Cl)2 (c2) ou-R 6 '= H and R 7 ' = -C 6 H 4 -N (CH 2 CH 2 Cl) 2 (c 2 ) or
-R6'=R7'=-CH2CH2Cl (c3). L'idée d'associer dans une structure mixte, chimiosensibilisant et entité alkylante, conduit à des drogues cytotoxiques présentant une affinité pour les tumeurs solides.-R 6 '= R 7 ' = -CH 2 CH 2 Cl (c 3 ). The idea of associating in a mixed structure, chemosensitizer and alkylating entity, leads to cytotoxic drugs having an affinity for solid tumors.
L'invention propose donc des molécules visant à chimiosensibiliser les cellules tumorales hypoxiques et à leur délivrer spécifiquement une entité cytotoxique inter-réagissarit avec leur ADN.The invention therefore provides molecules aiming to chemosensitize hypoxic tumor cells and to specifically deliver to them a cytotoxic entity which inter-reacts with their DNA.
Compte tenu de leur activité cytotoxique, en général, et de leur affinité pour les cellules hypoxiques en particulier, les composés de la présente invention sont utiles en tant que médicaments. La présente invention concerne donc également l'application des composés à titre de médicaments ainsi que des compositions pharmaceutiques comportant, outre un support pharmaceutiquement acceptable, un principe actif comprenant au moins un composé tel que décrit ci-dessus.
On décrira ci-après, à titre de simple exemple non limitatif, la préparation de quelques composés de formule générale I, et on montrera leur activité biologique in vivo. Cette description sera faite en référence à des dessins annexés dans lesquels :In view of their cytotoxic activity, in general, and their affinity for hypoxic cells in particular, the compounds of the present invention are useful as medicaments. The present invention therefore therefore also relates to the application of the compounds as medicaments as well as pharmaceutical compositions comprising, in addition to a pharmaceutically acceptable carrier, an active principle comprising at least one compound as described above. The preparation of a few compounds of general formula I will be described below, by way of a simple non-limiting example, and their biological activity will be shown in vivo. This description will be made with reference to appended drawings in which:
- la figure 1 représente, pour certains composés de la présente invention, l'évolution du nombre de cellules survivantes d'une lignée Mer- en fonction de la quantité administrée (μmoles), - la figure 2 représente, pour certains composés de la présente invention, l'évolution du nombre de cellules survivantes d'une lignée Mer + en fonction de la quantité administrée (en μmoles).- Figure 1 represents, for certain compounds of the present invention, the evolution of the number of surviving cells of a Mer- line as a function of the quantity administered (μmoles), - Figure 2 represents, for certain compounds of the present invention, the evolution of the number of surviving cells of a Mer + line as a function of the quantity administered (in μmoles).
EXEMPLES 1 à 27EXAMPLES 1 to 27
- Dans les exemples 1 à 27 suivants, on a effectué la synthèse des nitrosourées des séries A et B par couplage entre l'aminé et un ester actif comportant le motif N-(chloro-2 éthyl)N-nitrosocarbamate selon la méthode aux "esters actifs" utilisée en synthèse peptidique (Schéma 1)).- In Examples 1 to 27 below, the nitrosoureas of the A and B series were synthesized by coupling between the amine and an active ester comprising the N- (2-chloroethyl) N-nitrosocarbamate unit according to the " active esters "used in peptide synthesis (Diagram 1)).
Il était donc nécessaire d'obtenir les aminés correspondantes dans les séries imidazole, nitro-4, nitro-5 et nitro-2 imidazole. It was therefore necessary to obtain the corresponding amines in the imidazole, nitro-4, nitro-5 and nitro-2 imidazole series.
Les alkanolamines ont été synthétisées par traitement des (époxyalkyl)-1 nitro-2 imidazoles avec un certain nombre d'aminés secondaires et primaires. Par cette méthode de synthèse les aminés secondaires et tertiaires sont obtenues. Les alkanolamines primaires sont préparées par réaction de l'ammoniac avec les époxydes. D'autres part, 1'(amino-2 éthyl)-1 nitro-2 imidazole peut être obtenu par action de l'aziridine sur le nitro-2 imidazole.The alkanolamines were synthesized by treatment of (epoxyalkyl) -1 nitro-2 imidazoles with a number of secondary and primary amines. By this method of synthesis secondary and tertiary amines are obtained. The primary alkanolamines are prepared by the reaction of ammonia with the epoxides. On the other hand, 1 '(2-aminoethyl) -1 2-nitro imidazole can be obtained by the action of aziridine on 2-nitro imidazole.
On obtient des (hydroxyaminoalkyl)-1 nitroimidazoles via des intermédiaires nitro-imidazoles N-(hydroxyalkyl) phtalimides.Nitroimidazoles (hydroxyaminoalkyl) -1 are obtained via nitro-imidazole intermediates N- (hydroxyalkyl) phthalimides.
Dans la série (amino-2 éthyl)-1 nitroimidazole (série B), on a préparé les intermédiaires phtalimides par condensation des (chloro-2 éthyl)-1 nitroimidazoles avec le sel de potassium du phtalimide (Schéma 2).In the series (2-amino-ethyl) -1 nitroimidazole (series B), the phthalimide intermediates were prepared by condensation of (2-chloro-ethyl) -1 nitroimidazoles with the potassium salt of the phthalimide (Diagram 2).
Nitro-4 1 3 (45 %) 6 (59 %)Nitro-4 1 3 (45%) 6 (59%)
Nitro-5 1 4 (13 %) 7 (50 %)Nitro-5 1 4 (13%) 7 (50%)
Nitro-2 2 5 (68 %) 8 (58 %)Nitro-2 2 5 (68%) 8 (58%)
- Schéma 2 -
Le composé 8 a été synthétisé par la même voie. Les (chloro-2 éthyl)-1 nitroimidazoles sont obtenus par condensation du sel de sodium du nitro-imidazole correspondant et du dichloro-1,2 éthane. Les dérivés chlorés 3 et 4 ont été synthétisés, mais non séparés par action de SOCl2 sur le mélange des (hydroxy-2 éthyl)-1 nitro-4 et nitro-5 imidazole (9). Alors que la condensation du sel de sodium du nitro-2 imidazole et du bromo-1 chloro-2 éthane conduit à 5 avec 60 % de rendement (8). Le (nitro-2 imidazolyl)-1 éthyl phtalimide 10 a été obtenu avec 57 % de rendement par condensation du sel d'argent de l'imidazole et du bromo-2 éthyl phtalimide dans le xylène (Schéma 3).- Diagram 2 - Compound 8 was synthesized by the same route. The (2-chloroethyl) -1 nitroimidazoles are obtained by condensation of the sodium salt of the corresponding nitroimidazole and of 1,2-dichloroethane. The chlorinated derivatives 3 and 4 were synthesized, but not separated by the action of SOCl 2 on the mixture of (2-hydroxyethyl) -1 nitro-4 and 5-nitro imidazole (9). Whereas the condensation of the sodium salt of 2-nitro-imidazole and of 1-bromo-2-chloroethane leads to 5 with 60% yield (8). (2-Nitro-imidazolyl) -1 ethyl phthalimide 10 was obtained with 57% yield by condensation of the silver salt of imidazole and 2-bromo ethyl phthalimide in xylene (Scheme 3).
L'ouverture du N(époxy-2,3 propyl)phtalimide par les imidazoles a conduit en une seule étape aux composés désirés (Schéma 4).The opening of N (2,3-epoxy propyl) phthalimide by imidazoles led in one step to the desired compounds (Scheme 4).
R = H 11 (33 %)R = H 11 (33%)
R = nitro-4 12 (72 %)R = nitro-4 12 (72%)
R = nitro-5 13 (67 %)R = nitro-5 13 (67%)
- Schéma 4 -
Pour accéder à la série nitro-5 imidazole, il est nécessaire de préparer tout d'abord le (chloro-3 hydroxy-2 propyl)-1 nitro-5 imidazole, par condensation du nitro-4 (5) imidazole et de l'épichlorhydrine en milieu acide par la méthode décrite pour le (chloro-3 hydroxy-2 propyl)-1 méthyl-2 nitro-5 imidazole (11) (Schéma 5).- Diagram 4 - To access the 5-nitro imidazole series, it is necessary to first prepare the (3-chloro-2-hydroxy-propyl) -1 5-nitro imidazole, by condensation of the 4-nitro (5) imidazole and epichlorohydrin in an acid medium by the method described for (3-chloro-2-hydroxy-propyl) -1 2-methyl-5-nitroimidazole (11) (Diagram 5).
- Schéma 5-- Diagram 5-
14 est ensuite condensé avec le sel de potassium du phtalimide pour conduire à 15 avec 60 % de rendement.14 is then condensed with the potassium salt of the phthalimide to yield 15 with 60% yield.
La déprotection des phtalimides 6, 7, 10, 11, 12, 15 est. réalisée en milieu HCl(6N) et conduit aux dichlorhydrates d'aminés (Schéma 6).The deprotection of phthalimides 6, 7, 10, 11, 12, 15 is. carried out in HCl medium (6N) and leads to the amine dihydrochlorides (Diagram 6).
R = nitro-4 6 16 ( 68 %)R = nitro-4 6 16 (68%)
R = nitro-5 7 17 ( 69 %)R = nitro-5 7 17 (69%)
R = H 10 18 ( 69 %)
R = H 10 18 (69%)
R = H 11 19 (67 %)R = H 11 19 (67%)
R = nitre-412 20 ( 73 %)R = nitre-412 20 (73%)
R = nitro-515 21 (71 %)R = nitro-515 21 (71%)
- Schéma 6 -- Diagram 6 -
Dans le cas des nitro-2 imidazoles, la déprotection par HC1 6N a conduit à la substitution du groupement NO2 en 2 par le chlore. On a alors effectué celle-ci par l'hydrazine (12) suivi d'un traitement en milieu HC1 pour isoler l'aminé sous forme de monochlorhydrate (Schéma 7).In the case of 2-nitro imidazoles, deprotection with HCl 6N has led to the substitution of the NO 2 group in 2 with chlorine. This was then carried out with hydrazine (12) followed by treatment in an HCl medium to isolate the amine in the form of the monohydrochloride (Diagram 7).
SYNTHESE DES NITROSOUREES DANS LES SERIES A ET BSYNTHESIS OF NITROSOURES IN SERIES A AND B
La condensation des aminés précédemment obtenues avec un ester actif comportant le motif N-(chloro-2 éthyl) N-nitrosocarbamate dans le DMF a conduit avec de bons rendements aux nitrosourées attendues (Schéma 8).The condensation of the amines previously obtained with an active ester comprising the N- (2-chloroethyl) N-nitrosocarbamate motif in DMF led with good yields to the expected nitrosoureas (Diagram 8).
On a utilisé principalement le p-nitrophényl N-(chloro-2 éthyl) N-nitrosocarbamate (1) et le trichloro- 2,4,5 phényl N-(chloro-2 éthyl) N-nitrosocarbamate (13)
comme esters actifs.We mainly used p-nitrophenyl N- (2-chloro-ethyl) N-nitrosocarbamate (1) and trichloro- 2,4,5 phenyl N- (2-chloro-ethyl) N-nitrosocarbamate (13) as active esters.
- Schéma 8- Diagram 8
R = H 18 24 (38 %) R = nitro-4 16 25 (72 %) R = nitro-5 17R = H 18 24 (38%) R = nitro-4 16 25 (72%) R = nitro-5 17
26 (98 %) R = nitro-2 2226 (98%) R = 2-nitro 22
27 (63 %)27 (63%)
R = H 19 28 (71 %) R = nltro-4 20 29 (89 %) R = nitro-3 21 30 (67 %) R = nitro-2 23 37 (81 %)R = H 19 28 (71%) R = nltro-4 20 29 (89%) R = nitro-3 21 30 (67%) R = nitro-2 23 37 (81%)
EXEMPLE 1 : Synthèse du (chloro-2 éthyl) -1 nitro-4 imidazole (com posé nº 3) et du (chloro-2 éthyl) - 1 nitro-5 imidazole (composé nº 4 ) EXAMPLE 1 Synthesis of (2-chloro-ethyl) -1 nitro-4 imidazole (com posed nº 3) and of (2-chloro ethyl) - 1 nitro-5 imidazole (compound nº 4)
407 mg (17,7 mmoles) de sodium sont ajoutés par petites portions dans 10 ml de méthanol anhydre. Lorsque la totalité du sodium a réagi, on ajoute 40 ml de DMF anhydre. Le méthanol est distillé ; la solution obtenue est refroidie à 20°C afin d'additionner 7 ml (88,8 mmoles) de dichloro-1,2 éthane. Le mélange réactionnel est porté à 80-85°C pendant 3 heures. On évapore la solution après avoir filtré les sels. Les deux isomères synthétisés sont séparés par chromatographie sur colonne de silice : (éluant : éther/cyclohexane, v/v 8/2).407 mg (17.7 mmol) of sodium are added in small portions in 10 ml of anhydrous methanol. When all of the sodium has reacted, 40 ml of anhydrous DMF are added. Methanol is distilled; the solution obtained is cooled to 20 ° C in order to add 7 ml (88.8 mmol) of 1,2-dichloroethane. The reaction mixture is brought to 80-85 ° C for 3 hours. The solution is evaporated after filtering off the salts. The two isomers synthesized are separated by chromatography on a silica column: (eluent: ether / cyclohexane, v / v 8/2).
On isole ainsi le (chloro-2 éthyl)-1 nitro-4 imidazole (composé n° 3) (1,4 g ; 45 %) et le (chloro-2 éthyl)-1 nitro-5 imidazole (composé n° 4) (0,4 g ; 13 %). Composé nº 3 : F = 117,5-118°C (MeOH/éther). Rf (silice) =Is thus isolated (2-chloro-ethyl) -1 nitro-4 imidazole (compound n ° 3) (1.4 g; 45%) and (2-chloro ethyl) -1 nitro-5 imidazole (compound n ° 4 ) (0.4 g; 13%). Compound # 3: M = 117.5-118 ° C (MeOH / ether). R f (silica) =
0,41 (éluant : éther).0.41 (eluent: ether).
UV (EtOH 95º) λmax = 284 nm, log ε = 3, 64. RMN (DMSO d6) δ , 8,48 ppm (d,1H,1 Hz), 7,92 ppm (d,1H,1 Hz), 4,47 ppm (m, 2H), 4,03 ppm (m, 2H). Analyse : Calc. C : 34,20 H : 3,40 N : 23,93 Trouvé C : 34,27 H : 3,40 N : 23 ,92 Composé nº 4 : F = 136-136,5ºC (CH2,Cl2/éther). Rf (silice) = 0,1 (éluant : éther),UV (EtOH 95º) λ max = 284 nm, log ε = 3.64. NMR (DMSO d 6 ) δ, 8.48 ppm (d, 1H, 1 Hz), 7.92 ppm (d, 1H, 1 Hz ), 4.47 ppm (m, 2H), 4.03 ppm (m, 2H). Analysis: Calc. C: 34.20 H: 3.40 N: 23.93 Found C: 34.27 H: 3.40 N: 23.92 Compound No. 4: F = 136-136.5ºC (CH 2 , Cl 2 / ether ). R f (silica) = 0.1 (eluent: ether),
UV (EtOH 95º) λmax = 291 nm, log e = 3,68. RMN (CDCl3) δ, 8,01 ppm (s,1H), 7,67 ppm (s, 1H), 4,68 ppm (t,2H,6 Hz), 3,86 ppm (t, 2H, 6 Hz).
EXEMPLE 2 : Synthèsedu (chloro-2éthyl)-1 nitro-2 imidazole (composé nº 5)UV (EtOH 95º) λ max = 291 nm, log e = 3.68. NMR (CDCl 3 ) δ, 8.01 ppm (s, 1H), 7.67 ppm (s, 1H), 4.68 ppm (t, 2H, 6 Hz), 3.86 ppm (t, 2H, 6 Hz). EXAMPLE 2 Synthesis of (chloro-2ethyl) -1 nitro-2 imidazole (compound nº 5)
A une suspension agitée de nitro-2 imidazole 3,5 g (31 mmoles) dans 50 ml de DMF, 1,24 g (31 mmoles) d'hvdrure de sodium sont ajoutés par petites portions.To a stirred suspension of 2-nitro imidazole 3.5 g (31 mmol) in 50 ml of DMF, 1.24 g (31 mmol) of sodium hydride are added in small portions.
Lorsque l'addition est terminée, on porte le bain d'huile à 100°C pendant 10 minutes. La solution est ensuite ramenée à température ambiante ; on ajoute alors 12 ml (155 mmoles) de dichloro-1,2 éthane.When the addition is complete, the oil bath is brought to 100 ° C for 10 minutes. The solution is then brought to room temperature; 12 ml (155 mmol) of 1,2-dichloroethane are then added.
Le mélange réactionnel est porté à 80-85°C pendant 3 heures. La solution est ensuite évaporée sous vide et le résidu est chromatographié sur colonne de silice. 3,7 g (68 %) de (chloro-2 éthyl)-1 nitro-2 imidazole sont obtenus sous forme d'aiguilles jaunes après recristallisation dans un mélange CH2Cl2/éther.The reaction mixture is brought to 80-85 ° C for 3 hours. The solution is then evaporated under vacuum and the residue is chromatographed on a silica column. 3.7 g (68%) of (2-chloro-ethyl) -1 2-nitro-imidazole are obtained in the form of yellow needles after recrystallization from a CH 2 Cl 2 / ether mixture.
F - 84,5-85°C (CH2Cl2 / éther). Rf (silice) = 0,5 (éluant : éther)F - 84.5-85 ° C (CH 2 Cl 2 / ether). R f (silica) = 0.5 (eluent: ether)
UV (EtOH 95°)λ max = 312 nm, log ε= 3,77. RMN (CDCl3) δ, 720 ppm (s, 2H), 4,73 ppm (t, 2H, 6Hz), 3,91 ppm (t, 2H, 6Hz) Analyse : Calc. C : 34,20 H : 3,40 N : 23,93 Trouvé C : 34,16 H : 3,58 N : 23,94UV (EtOH 95 °) λ max = 312 nm, log ε = 3.77. NMR (CDCl 3 ) δ, 720 ppm (s, 2H), 4.73 ppm (t, 2H, 6Hz), 3.91 ppm (t, 2H, 6Hz) Analysis: Calc. C: 34.20 H: 3.40 N: 23.93 Found C: 34.16 H: 3.58 N: 23.94
EXEMPLE 3 : Synthèsedu (N-phatlimido-2 éthyl)-1 nitro-4 imidazole (composé nº 6)EXAMPLE 3 Synthesis of (N-phatlimido-2 ethyl) -1 nitro-4 imidazole (compound nº 6)
Une suspension de 3 g (17 mmoles de (chloro-2 éthyl) -1 nitrό-4 imidazole (composénº3), 3,5 g (18,9 mmoles) de sel de potassium du phtalimide, 0,5 g (3 mmoles) d'iodure de potassium dans 70 ml de DMF est chauffée à 120°C pendant 8 heures. Le mélange est ensuite filtré sur célite pour éliminer les sels. Le filtrat est évaporé sous vide, coévaporé une fois avec du méthanol. L'huile obtenue est reprise par du méthanol bouillant. 2,38 g (59 %) sont obtenus
par cristallisation.A suspension of 3 g (17 mmol of (2-chloroethyl) -1 nitrό-4 imidazole (compound 3), 3.5 g (18.9 mmol) of potassium salt of phthalimide, 0.5 g (3 mmol) potassium iodide in 70 ml of DMF is heated at 120 ° C. for 8 hours, the mixture is then filtered through Celite to remove the salts, the filtrate is evaporated under vacuum and coevaporated once with methanol. is taken up in boiling methanol 2.38 g (59%) are obtained by crystallization.
F = 235-236ºC (MeOH) . Rf (silice) = 0,6 (éluant : AcOEt). UV (EtOH 95°) λmax = 289 log ε = 3,86. RMN (DMSO d6) δ, 8,48 ppm (d, 1H, 1 Hz), 7,85 ppm (s, 5H), 4,33 ppm (m, 2H), 4,03 ppm (m, 2H).F = 235-236ºC (MeOH). R f (silica) = 0.6 (eluent: AcOEt). UV (EtOH 95 °) λ max = 289 log ε = 3.86. NMR (DMSO d 6 ) δ, 8.48 ppm (d, 1H, 1 Hz), 7.85 ppm (s, 5H), 4.33 ppm (m, 2H), 4.03 ppm (m, 2H) .
Analyse : Calc. C : 54,55 H : 3,52 N : 19,57 Trouvé C : 54,44 H : 3,54 N : 19,30Analysis: Calc. C: 54.55 H: 3.52 N: 19.57 Found C: 54.44 H: 3.54 N: 19.30
EXEMPLE 4 : Synthàse du (N-phtalimido-2 éthyl)-1 nitro-5 imidazole (composé nº 7)EXAMPLE 4 Synthesis of (N-phthalimido-2 ethyl) -1 nitro-5 imidazole (compound no. 7)
Ce composé a été préparé d'une manière analogue à l'exemple 3 à partir du composé nº 4 avec un rendement de 50 %. F = 195-196°C (MeOH). Rf (silice) = 0,5 (éluant / AcOEt). UV (EtOH 95°) λmax = 295 nm, log e = 3,88This compound was prepared in a manner analogous to Example 3 from compound No. 4 with a yield of 50%. Mp 195-196 ° C (MeOH). R f (silica) = 0.5 (eluent / AcOEt). UV (EtOH 95 °) λ max = 295 nm, log e = 3.88
Analyse Calc. C : 54,55 H : 3,52 N : 19,57Calc analysis. C: 54.55 H: 3.52 N: 19.57
Trouvé C : 54,27 H : 3,52 N : 19,48Found C: 54.27 H: 3.52 N: 19.48
EXEMPLE 5 ; Synthèse du (N-phtalimido-2 éthyl)-1 nitro-2imidazole (composénº 8)EXAMPLE 5; Synthesis of (N-phthalimido-2 ethyl) -1 nitro-2imidazole (component 8)
Ce composé a été préparé d'une manière analogue à l'exemple 3 à partir du composé 5. La purification a été effectuée par chromatographie sur colonne de silice. Le rendement obtenu est de 58 %. F = 210-212°C (litt. (8) 210°C, MeOH). Rf (silice) = 0,3 (éluant.: éther)
UV (EtOH 95°) λmax = 312,5 nm, log ε = 3,82. RMN (CDCl3) δ, 7,70 ppm (s, 4H), 7,00 ppm (s,1H), 6,85 ppm (s,1H), 4,7 ppm (m,2H), 4,2 ppm (m,2H).This compound was prepared in a manner analogous to Example 3 from compound 5. The purification was carried out by chromatography on a silica column. The yield obtained is 58%. M = 210-212 ° C (litt. (8) 210 ° C, MeOH). R f (silica) = 0.3 (eluent: ether) UV (EtOH 95 °) λ max = 312.5 nm, log ε = 3.82. NMR (CDCl 3 ) δ, 7.70 ppm (s, 4H), 7.00 ppm (s, 1H), 6.85 ppm (s, 1H), 4.7 ppm (m, 2H), 4.2 ppm (m, 2H).
EXEMPLE 6 : Synthèse du (N-phtalimido-2 éthyl)-1 imidazole (composénº 10)EXAMPLE 6 Synthesis of (N-phthalimido-2 ethyl) -1 imidazole (compound 10)
6,5 g (25,6 mmoles) de N(bromo-2 éthyl) phtalimide et 0,344 g (25,6 mmoles) de sel d'argent de l'imidazole en suspension dans 50 ml de xylène sont chauffés au reflux pendant 16 heures. Le bromure d'argent est éliminé par filtration de la solution à chaud. Le filtrat est ensuite concentré à mivolume. 3,5 g (57 %) sont ainsi obtenus par cristallisation. F = 154-156°C (litt. (14) 157°C, xylène). Rf (silice) = 0,6 (éluant : CH2Cl2). UV (EtOH 95º)λ max = 292 nm, log ε = 3,23. RMN (CDCl3) δ, 7,76 ppm (s, 4H), 7,40 ppm (d, 1H, 7,00 ppm (m, 1H), 6,93 ppm (m, 1H) , 4,16 ppm (m, 4H).6.5 g (25.6 mmol) of N (2-bromo-ethyl) phthalimide and 0.344 g (25.6 mmol) of imidazole silver salt suspended in 50 ml of xylene are heated at reflux for 16 hours. The silver bromide is removed by filtration from the hot solution. The filtrate is then concentrated to mivolume. 3.5 g (57%) are thus obtained by crystallization. Mp 154-156 ° C (litt. (14) 157 ° C, xylene). R f (silica) = 0.6 (eluent: CH 2 Cl 2 ). UV (EtOH 95º) λ max = 292 nm, log ε = 3.23. NMR (CDCl 3 ) δ, 7.76 ppm (s, 4H), 7.40 ppm (d, 1H, 7.00 ppm (m, 1H), 6.93 ppm (m, 1H), 4.16 ppm (m, 4H).
EXEMPLE 7 : Synthèse du (N-phtalimido-3 hydroxy-2 propyl)-1 imidazole (composénº 11)EXAMPLE 7 Synthesis of (N-phthalimido-3-hydroxy-2-propyl) -1 imidazole (compound 11)
Une suspension de 7,6 g (111,6 mmoles) d' imidazole, 25 g (123 mmoles) d'époxy-2,3 propyl phtalimide et de 1 g (7, 3 mmoles) de carbonate de potassium dans 500 ml d'éthanol est chauffée à reflux pendant 17 heures. L'alcool est évaporé sous vide et le résidu est déposé sur colonne de silice (éluant, CH2Cl2/MeOH, v/v, 98/2). Après chromatographie, on isole 10 g (33 %) de produit. Recristallisation dans l'éthanol 95°. F : 201-202°C (EtOH 95°). Rf (silice) = 0,45 (éluant : CH2-Cl2, MeOH, v/v 95/5). UV (EtOH 95º) λmax = 292 nm, log ε= 3,23. RMN (DMSO d6) d, 7,85 ppm (s, 4H), 7,62 ppm (s, 1H), 7,17 ppm (s, 1H), 6,85 ppm (s,1H), 5,42 ppm (m,1H), 4 ppm (m,3H), 3,50 ppm (m, 2H).
Analyse : Calc. C : 53,17 H : 3,82 N : 17,72A suspension of 7.6 g (111.6 mmol) of imidazole, 25 g (123 mmol) of 2,3-epoxy propyl phthalimide and 1 g (7,3 mmol) of potassium carbonate in 500 ml of ethanol is heated at reflux for 17 hours. The alcohol is evaporated in vacuo and the residue is deposited on a silica column (eluent, CH 2 Cl 2 / MeOH, v / v, 98/2). After chromatography, 10 g (33%) of product are isolated. Recrystallization from 95 ° ethanol. Mp: 201-202 ° C (EtOH 95 °). R f (silica) = 0.45 (eluent: CH 2 -Cl 2 , MeOH, v / v 95/5). UV (EtOH 95º) λ max = 292 nm, log ε = 3.23. NMR (DMSO d 6 ) d, 7.85 ppm (s, 4H), 7.62 ppm (s, 1H), 7.17 ppm (s, 1H), 6.85 ppm (s, 1H), 5, 42 ppm (m, 1H), 4 ppm (m, 3H), 3.50 ppm (m, 2H). Analysis: Calc. C: 53.17 H: 3.82 N: 17.72
Trouvé C : 52,91 H : 3,81 N : 17,89Found C: 52.91 H: 3.81 N: 17.89
EXEMPLE 9 :EXAMPLE 9:
Synthèse Du (N-phtalimido-3 hydroxy-2 propyl)-1 nitro-2 imidazole (composé nº 13)Synthesis of (N-phthalimido-3 hydroxy-2 propyl) -1 nitro-2 imidazole (compound 13)
A une suspension de 1,6 g (14,15 mmoles de nitro-2 imidazole dans 120 ml d'éthanol absolu, on ajoute 2,88 g (14,17 mmoles) de N(époxy-2,3 propyl) phtalimide. Le mélange est chauffé à reflux de l'alcool pendant 3 heures. Un premier jet de produit est obtenu par refroidissement et cristallisation de la solution.To a suspension of 1.6 g (14.15 mmol of 2-nitroimidazole in 120 ml of absolute ethanol, 2.88 g (14.17 mmol) of N (2,3-epoxypropyl) phthalimide are added. The mixture is heated at reflux of the alcohol for 3 hours and a first jet of product is obtained by cooling and crystallizing the solution.
Un deuxième jet nécessite une concentration à mivolume ; au total 3 g (67 %) de produit sont ainsi obtenus. F = 207°C (litt. (8) 212°C, MeOH). Rf (silice) = 0,6 (éluant : CH2Cl2, MeOH, v/v, 9/1. UV (EtOH 95º) λ max = 312 nm, log ε= 3,68. RMN (DMSO d6) δ, 7,88 ppm (s,4H), 7,61 ppmA second spray requires a mivolume concentration; in total 3 g (67%) of product are thus obtained. M = 207 ° C (litt. (8) 212 ° C, MeOH). R f (silica) = 0.6 (eluent: CH 2 Cl 2 , MeOH, v / v, 9/1. UV (EtOH 95º) λ max = 312 nm, log ε = 3.68. NMR (DMSO d 6 ) δ, 7.88 ppm (s, 4H), 7.61 ppm
(s, 1H), 7,16 ppm (s,1H), 5,51 ppm (d,1H,5 Hz), 4,35 ppm(s, 1H), 7.16 ppm (s, 1H), 5.51 ppm (d, 1H, 5 Hz), 4.35 ppm
(m, 3H),3,68 ppm (m,2H).(m, 3H), 3.68 ppm (m, 2H).
EXEMPLE 10 : Synthèse du (chloro-3hydroxy-2 propyl)-1 nitro5 imidazole (composénº 14)EXAMPLE 10 Synthesis of (3-chloro-2-hydroxypropyl) -1 nitro5 imidazole (compound 14)
Ce composé a été synthétisé suivant le protocole expérimental décrit par Max Hofter et Emmanuel Grunberg (J.Med. Chem 1974, 9,1019) pour le (chloro-3 hydroκy-2 propyl)-1-méthyl-2, nitro-5 imidazole. 6 g (53 mmoles) de nitro-4 (5) imidazole sont agités à température ambiante dans 150 ml d'acide formique. Lorsque la dissolution est totale, la température est maintenue à 5ºC. On observe la recristallisation du nitro-4 (5) imidazole et 50 ml supplémentaires d'acide formique sont nécessaires pour le dissoudre.This compound was synthesized according to the experimental protocol described by Max Hofter and Emmanuel Grunberg (J. Med. Chem 1974, 9.1019) for (3-chloro-hydroκy-2 propyl) -1-methyl-2, 5-nitro imidazole . 6 g (53 mmol) of nitro-4 (5) imidazole are stirred at room temperature in 150 ml of formic acid. When the dissolution is complete, the temperature is maintained at 5ºC. The recrystallization of nitro-4 (5) imidazole is observed and an additional 50 ml of formic acid are necessary to dissolve it.
On ajoute alors, par l'intermédiaire d'une ampoule
à brome 25 ml (320 mmoles) de chloro-1 époxy-2,3 propane, lentement de façon à ne pas dépasser 5°C.We then add, via a bulb 25 ml (320 mmol) bromine-2,3-chloro-epoxy-propane, slowly so as not to exceed 5 ° C.
La durée de l'addition est de 1 heure.The duration of the addition is 1 hour.
On maintient l'agitation 3 heures et on abandonne le mélange 72 heures à 5-10ºC.Stirring is continued for 3 hours and the mixture is left for 72 hours at 5-10 ° C.
Le mélange réactionnel est alors évaporé sous vide ; le résidu huileux est jeté dans un mélange de 200 ml d'eau glacée. On neutralise par de l'ammoniaque et on extrait 5 fois avec 50 ml de toluène puis 3 fois avec 30 ml de dichlorométhane.The reaction mixture is then evaporated under vacuum; the oily residue is thrown into a mixture of 200 ml of ice water. Neutralized with ammonia and extracted 5 times with 50 ml of toluene then 3 times with 30 ml of dichloromethane.
Les phases organiques sont rassemblées et évaporées à sec ; le résidu est chromatographie sur colonne de silice (éluant : CH2Cl2) pour donner 4,15 g de produit (38 %).The organic phases are combined and evaporated to dryness; the residue is chromatographed on a silica column (eluent: CH 2 Cl 2 ) to give 4.15 g of product (38%).
P = 85-86 : (éther). Rf (silice) = 0,5 (éluant : CH2Cl2,P = 85-86: (ether). R f (silica) = 0.5 (eluent: CH 2 Cl 2 ,
MeOH, v/v, 9/1). UVλmax(EtOH 95º) = 295 nm, log ε= 3,85. RMN (DMSO d6), δ, 830 ppm (d, 1H, 1 Hz), 7,77 ppmMeOH, v / v, 9/1). UVλ max (EtOH 95º) = 295 nm, log ε = 3.85. NMR (DMSO d 6 ), δ, 830 ppm (d, 1H, 1 Hz), 7.77 ppm
(d, 1H, 1 Hz), 5,75 ppm (d, 1H, 6 Hz), 4,15 ppm (m, 3H), 3,60 ppm (d,2H,5 Hz).(d, 1H, 1 Hz), 5.75 ppm (d, 1H, 6 Hz), 4.15 ppm (m, 3H), 3.60 ppm (d, 2H, 5 Hz).
Analyse Calc. C : 35,10 H : 3,85 N : 20,42Calc analysis. C: 35.10 H: 3.85 N: 20.42
Trouvé C : 35,05 H : 3,92 N : 20,44Found C: 35.05 H: 3.92 N: 20.44
EXEMPLE 11 :EXAMPLE 11:
Synthèse du (N-phtalimido-3 hydroxy-2 propyl) -1 nitro-5 imidazole (composénº 15)Synthesis of (N-phthalimido-3 hydroxy-2 propyl) -1 nitro-5 imidazole (component 15)
Ce composé a été préparé d'une manière analogue à l'exemple 3 du composé 14 avec un rendement de 60 %.This compound was prepared in a manner analogous to Example 3 of compound 14 with a yield of 60%.
F : 154-155ºC (MeOH), Rf (silice) = 0,42 (éluant : CH2Cl2/F: 154-155ºC (MeOH), R f (silica) = 0.42 (eluent: C H2 Cl 2 /
MeOH, v/v, 9/1). UV (EtOH 95°) λmax = 296 nm, log ε = 3,89. RMN (DMSO d6), δ, 8,03 ppm (m, 2H), 7,85 ppm (s,4H), 4,25 ppm (m, 3H), 5 ppm (m, 1H), 3,66 pom (d, 2H, 5Hz).
Analyse : Calc. C : 53,17 H : 3,82 N : 17,72 Trouvé C : 52,99 H : 3,98 N : 17,67MeOH, v / v, 9/1). UV (EtOH 95 °) λ max = 296 nm, log ε = 3.89. NMR (DMSO d 6 ), δ, 8.03 ppm (m, 2H), 7.85 ppm (s, 4H), 4.25 ppm (m, 3H), 5 ppm (m, 1H), 3.66 pom (d, 2H, 5Hz). Analysis: Calc. C: 53.17 H: 3.82 N: 17.72 Found C: 52.99 H: 3.98 N: 17.67
EXEMPLE 12 : Synthèse du dichlorhydrate de l'(amino-2 éthyl)-1-nitro-4 imidazole (composé nº 16)EXAMPLE 12 Synthesis of (2-aminoethyl) -1-nitro-4-imidazole dihydrochloride (compound No. 16)
2,4 g (8,4 mmoles) de (N-phtalimido-2 éthyl)-1 nitro-4 imidazole (composé n° 6) sont dissous dans 70 ml d'acide chlorhydrique 6N ; la solution est portée à 90-95°C pendant 15 heures. Après avoir refroidi la solution, le phtalhydrazide est éliminé par filtration. Le filtrat est évaporé sous vide, coévaporé 2 fois avec 20 ml d'alcool.2.4 g (8.4 mmol) of (N-phthalimido-2 ethyl) -1 nitro-4 imidazole (compound No. 6) are dissolved in 70 ml of 6N hydrochloric acid; the solution is brought to 90-95 ° C for 15 hours. After cooling the solution, the phthalhydrazide is removed by filtration. The filtrate is evaporated in vacuo, coevaporated 2 times with 20 ml of alcohol.
Le résidu est recristallisé dans un mélange MeOH/éther pour donner 1,3 g (68 %)de composé .The residue is recrystallized from a MeOH / ether mixture to give 1.3 g (68%) of compound.
F = 235ºC (MeOH/éther). UV (EtOH 95º) λmax = 282 nm, log ε= 3,86. RMN (DMSO d6) δ, 8,55 ppm (d, 1H,1 Hz), 8,40 ppmF = 235ºC (MeOH / ether). UV (EtOH 95º) λ max = 282 nm, log ε = 3.86. NMR (DMSO d 6 ) δ, 8.55 ppm (d, 1H, 1 Hz), 8.40 ppm
(m,3H), 7,95 ppm (d, 1H,1 Hz), 4,25 ppm (t,2H,5 Hz), 3,35 ppm (m, 2H).(m, 3H), 7.95 ppm (d, 1H, 1 Hz), 4.25 ppm (t, 2H, 5 Hz), 3.35 ppm (m, 2H).
Analyse : Calc. C : 26,21 H : 4,40 N : 24,46 Trouvé C : 26,40 H : 4,56 N : 24,54Analysis: Calc. C: 26.21 H: 4.40 N: 24.46 Found C: 26.40 H: 4.56 N: 24.54
EXEMPLE 13 : Synthèse du dichlorhydrate de l (amino-2 éthyl)-1 nitro-5 imidazole (composénº 17)EXAMPLE 13 Synthesis of 2-aminoethyl dihydrochloride -1 5-nitroimidazole (compound 17)
Ce composé a été préparé d'une manière analogue à l'exemple 12 à partir du composé n°7avec un rendement de 69 %.This compound was prepared in a manner analogous to Example 12 from compound No. 7 with a yield of 69%.
F = 204°C (MeOH/éther). UV (EtOH 95°)λ max = 296 nm, logε= 3,83. RMN (DMSO d6) δ , 8,60 ppm (m,3H), 8,51 ppm (d,1H,1 Hz), 8,28 ppm (d, 1H,1 Hz), 4,75 ppm (t, 2H,5 Hz), 3,30 ppm (m, 2H).
Analyse : Calc. C : 26,21 H : 4,40 N : 24,46 Trouvé C : 25,98 H : 4,10 N : 24,55Mp 204 ° C (MeOH / ether). UV (EtOH 95 °) λ max = 296 nm, logε = 3.83. NMR (DMSO d 6 ) δ, 8.60 ppm (m, 3H), 8.51 ppm (d, 1H, 1 Hz), 8.28 ppm (d, 1H, 1 Hz), 4.75 ppm (t , 2H, 5 Hz), 3.30 ppm (m, 2H). Analysis: Calc. C: 26.21 H: 4.40 N: 24.46 Found C: 25.98 H: 4.10 N: 24.55
EXEMPLE 14 : Synthèse du dichlorhydrate de l'(amino-2 éthyl-1)-1 imidazole (composé nº 18)EXAMPLE 14 Synthesis of (2-amino-ethyl-1) -1 imidazole dihydrochloride (compound No. 18)
Ce composé a été préparé d'une manière analogue à l'exemple 12 à partir du composé 10 avec un rendement deThis compound was prepared in a manner analogous to Example 12 from compound 10 with a yield of
69 %.69%.
F = 214-216°C (MeOH/éther) RMN (DMSO d6) δ, 9,26 ppm (m,1H), 7,86 ppm (m, 1H), 7,68 ppm (m, 1H), 4,5a ppm (t, 2H),M = 214-216 ° C (MeOH / ether) NMR (DMSO d 6 ) δ, 9.26 ppm (m, 1H), 7.86 ppm (m, 1H), 7.68 ppm (m, 1H), 4.5a ppm (t, 2H),
3,36 ppm (m, 2H).3.36 ppm (m, 2H).
Analyse : Calc. C : 32,61 H : 6,02 N : 22,82Analysis: Calc. C: 32.61 H: 6.02 N: 22.82
Trouvé C : 32,68 H : 6,15 N : 22,69Found C: 32.68 H: 6.15 N: 22.69
EXEMPLE 15 : Synthèse du dichlorhydrate de l' (amino-3-hydroxy-2 propyl)-1 imidazole (composé nº 19)EXAMPLE 15 Synthesis of (amino-3-hydroxy-2-propyl) -1 imidazole dihydrochloride (compound No. 19)
Ce composé a été préparé d'une manière analogue à l'exemple 12 à partir du composé n° 11 avec un rendement de 76 %. F = 176-177ºC (MeOH/éther. RMN (DMSO d6) δ, 9,18 ppm (m,1H), 7,78 ppm (m,1H), 7,70 ppm (m, 1H), 8,4 ppm (m,3H), 4,2 ppm (m,3H), 2,86 ppm (m,2H).This compound was prepared in a manner analogous to Example 12 from compound No. 11 with a yield of 76%. F = 176-177ºC (MeOH / ether. NMR (DMSO d 6 ) δ, 9.18 ppm (m, 1H), 7.78 ppm (m, 1H), 7.70 ppm (m, 1H), 8, 4 ppm (m, 3H), 4.2 ppm (m, 3H), 2.86 ppm (m, 2H).
Analyse : Calc. C : 33,66 H : 6,12 N : 19,63 Trouvé C : 33,42 H : 6,03 N : 19,48Analysis: Calc. C: 33.66 H: 6.12 N: 19.63 Found C: 33.42 H: 6.03 N: 19.48
EXEMPLE 16 : Synthèse du dichlorhydrate de l'[amino-3 hydroxy-2 propyl]-1 nitro-4 imidazole (composé nº 20)EXAMPLE 16 Synthesis of [3-amino-2-hydroxypropyl] -1 hydrochloride-4-nitroimidazole hydrochloride (compound No. 20)
Ce composé a été préparé d'une manière analogue à l'exemple 12 à partir du composé n°12 avec un rendement de 73 %This compound was prepared in a manner analogous to Example 12 from compound No. 12 with a yield of 73%
F = 151-153°C (MeOH/éther). UV (EtOH 95º) λmax = 285 nm,
log ε=3,85. RMN (DMSO d6)δ 8,40 ppm (s, 1H), 8,25 ppmMp 151-153 ° C (MeOH / ether). UV (EtOH 95º) λ max = 285 nm, log ε = 3.85. NMR (DMSO d 6 ) δ 8.40 ppm (s, 1H), 8.25 ppm
(m, 3H), 7,92 ppm (s,1H), 6, O ppm (m, 1H), 4,2 ppm (m,3H),(m, 3H), 7.92 ppm (s, 1H), 6.0 O ppm (m, 1H), 4.2 ppm (m, 3H),
2,8 ppm (m,2H).2.8 ppm (m, 2H).
Analyse : Calc. C : 27,81 H : 4,67 N : 21,62 Trouvé C : 28,05 H : 4,81 N : 21,52Analysis: Calc. C: 27.81 H: 4.67 N: 21.62 Found C: 28.05 H: 4.81 N: 21.52
EXEMPLE 17 :EXAMPLE 17:
Synthèse du dichlorhydrate de l' (amino-3 hydroxy-2 propyl)-1 nitro-5 imidazole (composé nº 21)Synthesis of (3-amino-2-hydroxy-propyl) -1 hydrochloride-5-nitro-imidazole (compound no. 21)
Ce composé a été préparé d'une manière analogueà l'exemple 12 à partir du composé n'MSavec un rendement de 70 %.This compound was prepared in a manner analogous to Example 12 from the non-MS compound with a yield of 70%.
F = 190°C (MeOH /éther). UV (EtOH 95º) λ max = 295 nm, log ε= 3,82. RMN (DMSO d6) δ, 8,25 ppm (m, 5H), 4,40 ppm (m,4H), 2,80 ppm (m,2H). Analyse : Calc. C : 27,81 H : 4,67 N : 21,62Mp 190 ° C (MeOH / ether). UV (EtOH 95º) λ max = 295 nm, log ε = 3.82. NMR (DMSO d 6 ) δ, 8.25 ppm (m, 5H), 4.40 ppm (m, 4H), 2.80 ppm (m, 2H). Analysis: Calc. C: 27.81 H: 4.67 N: 21.62
Trouvé C : 27,52 H : 4,39 N : 21,41Found C: 27.52 H: 4.39 N: 21.41
EXEMPLE 18 : Synthèse du chlorhydrate de l' (amino-2 éthyl-1) 1 nitro-2 imidazole (composé nº 22) Ce composé a été préparé à partir du composé n° 8 par hydrazinolyse suivant le protocole décrit par I. Ahmed, IJ Stratford et T.C. Jenkins avec un rendement de 68 %. F = 171°C (MeOH/éther). UV (EtOH 95°) λmax = 313, nm, log ε= 3,79. RMN (DMSO d6) δ, 8,40 ppm (m, 3H), 7,81 ppm (s, 1H), 7,18 ppm (s, 1H), 4,71 ppm (t,2H,5Hz), 3,30 ppm (m,2H).EXAMPLE 18 Synthesis of 2-amino-ethyl-1 hydrochloride 1 2-nitroimidazole (compound no. 22) This compound was prepared from compound no. 8 by hydrazinolysis according to the protocol described by I. Ahmed, IJ Stratford and TC Jenkins with 68% yield. Mp 171 ° C (MeOH / ether). UV (EtOH 95 °) λ max = 313, nm, log ε = 3.79. NMR (DMSO d 6 ) δ, 8.40 ppm (m, 3H), 7.81 ppm (s, 1H), 7.18 ppm (s, 1H), 4.71 ppm (t, 2H, 5Hz), 3.30 ppm (m, 2H).
Analyse : Calc. C : 31,18 H : 4,71 N : 29,09 Trouvé C : 30,96 H : 4,76 N : 28,97 EXEMPLE 19 : Synthèse du chlorhydrate de l' (amino-3 hydroxy-2 propyl)- 1 nitro-2 imidazole (composé nº 23).
Ce composé a été préparé d'une manière analogue à l'exemple 18 à partir du composé nº13 avec un rendement de 81 %Analysis: Calc. C: 31.18 H: 4.71 N: 29.09 Found C: 30.96 H: 4.76 N: 28.97 EXAMPLE 19: Synthesis of (3-amino-2-hydroxy-propyl) hydrochloride - 1 nitro-2 imidazole (compound 23). This compound was prepared in a manner analogous to Example 18 from compound No. 13 with a yield of 81%
F = 207°C (litt. (8) : 212°C MeOH / éther). UV (EtOH 95°) λmax = 313 nm, log ε= 3,79. RMN (DMSO d6) δ , 8,20 ppm (m,3h), 7,70 ppm (s, 1H), 7,20 ppm (s,1H), 4,25 ppm (m,3H), 2,80 ppm (m,2H).M = 207 ° C (litt. (8): 212 ° C MeOH / ether). UV (EtOH 95 °) λ max = 313 nm, log ε = 3.79. NMR (DMSO d 6 ) δ, 8.20 ppm (m, 3h), 7.70 ppm (s, 1H), 7.20 ppm (s, 1H), 4.25 ppm (m, 3H), 2, 80 ppm (m, 2H).
EXEMPLE 20 :EXAMPLE 20:
Synthèse du [[(chloro-2 éthyl)-3 nitroso-3 uréido]- 2 éthyl]- 1 imidazole (compos1 n º 24)Synthesis of [[(2-chloro-ethyl) -3 nitroso-3 ureido] - 2 ethyl] - 1 imidazole (compos1 n º 24)
106 g (8,7 mmoles) de dichlorhydrate (amino-2 éthyl)-1 imidazole (composé n° 18) sont dissous dans 150 ml de méthanol bouillant ; on ajoute alors 488 mg (8,7 mmoles) de KOH en solution dans 50 ml de méthanol. On laisse revenir à température ambiante ; le volume est ramené à 30 ml par évaporation sous vide et les sels sont éliminés par filtration.106 g (8.7 mmol) of dihydrochloride (2-aminoethyl) -1 imidazole (compound No. 18) are dissolved in 150 ml of boiling methanol; 488 mg (8.7 mmol) of KOH in solution in 50 ml of methanol are then added. Allow to return to room temperature; the volume is reduced to 30 ml by evaporation under vacuum and the salts are removed by filtration.
Le filtrat est évaporé sous vide ; le résidu est repris dans 5 ml de DMF et amené à 0ºC, puis additionné en 2 fois, à une solution de 3,17 g (9,57 mmoles) de trichloro- 2,4,5 phényl N-(chloro-2 éthyl)N-nitrosocarbamate dansThe filtrate is evaporated under vacuum; the residue is taken up in 5 ml of DMF and brought to 0ºC, then added in 2 batches, to a solution of 3.17 g (9.57 mmol) of 2,4,4-trichlorophenylphenyl N- (2-chloro-ethyl ) N-nitrosocarbamate in
10 ml de DMF à 0°C.10 ml of DMF at 0 ° C.
L'évolution de la réaction est suivie par CCM et est complète en 3 heures. Le DMF est évaporé sous vide (30-35ºC).The progress of the reaction is followed by TLC and is complete in 3 hours. The DMF is evaporated under vacuum (30-35ºC).
Le résidu est chromatographie sur colonne de silice pour donner 1,24 g (58 %) de produit cristallisé. F = 91°C (acétone/éther). Rf (silice) = 0,25 (éluant : acétone RMN (CD3-CD-CD3) δ, 8,40 ppm (m,1H), 7,54 ppm (s,1H), 7,11 ppm (s,1H), 6,89 ppm (s,1H), 4,25 ppm (m,4H), 3,65 ppm (m,4H).The residue is chromatographed on a silica column to give 1.24 g (58%) of crystallized product. Mp 91 ° C (acetone / ether). R f (silica) = 0.25 (eluent: NMR acetone (CD 3 -CD-CD 3 ) δ, 8.40 ppm (m, 1H), 7.54 ppm (s, 1H), 7.11 ppm ( s, 1H), 6.89 ppm (s, 1H), 4.25 ppm (m, 4H), 3.65 ppm (m, 4H).
Analyse : Calc. C : 39,11 H : 4,92 N : 28,50 Trouvé C : 38,98 H : 4,97 N : 28,39
EXEMPLE 21 :Analysis: Calc. C: 39.11 H: 4.92 N: 28.50 Found C: 38.98 H: 4.97 N: 28.39 EXAMPLE 21:
Synthèse du [[(chloro-2 éthyl)-3 nitroso-3 uréido [-2 éthyl ]-1 nitro 4 imidazole (composé nº 25)Synthesis of [[(2-chloroethyl) -3 nitroso-3 ureido [-2 ethyl] -1 nitro 4 imidazole (compound # 25)
Ce composé a été préparé d'une manière analogue à l'exemple 20 à partir du composé n° 16 avec un rendement de 72 %.This compound was prepared in a manner analogous to Example 20 from compound No. 16 with a yield of 72%.
F = 135-135,5°C (acétone/éther). Rf (silice) = 0,57 (éluant : acétone, éther, v/v, 1/1). UV (EtOH 95º) max = 283 nm, logMp 135-135.5 ° C (acetone / ether). R f (silica) = 0.57 (eluent: acetone, ether, v / v, 1/1). UV (EtOH 95º) max = 283 nm, log
= 3,67. RMN (200 MHz) CD3-CO-CD3 δ, 8,4 ppm (m,1H), 8,25 ppm (d,1H,1 Hz), 7,75 ppm (d,1H,1 Hz), 4,50 ppm (t, 2H,5 Hz), 4,15 ppm (t,2H,5 Hz) 3,95 ppm (t,2H,5 Hz), 3,60 ppm (t,2H,5 Hz).= 3.67. NMR (200 MHz) CD 3 -CO-CD 3 δ, 8.4 ppm (m, 1H), 8.25 ppm (d, 1H, 1 Hz), 7.75 ppm (d, 1H, 1 Hz), 4.50 ppm (t, 2H, 5 Hz), 4.15 ppm (t, 2H, 5 Hz) 3.95 ppm (t, 2H, 5 Hz), 3.60 ppm (t, 2H, 5 Hz) .
Analyse : Calc. C : 33,05 H : 3,81 N : 28,91 Trouvé C : 33,03 H : 3,60 N : 28,69Analysis: Calc. C: 33.05 H: 3.81 N: 28.91 Found C: 33.03 H: 3.60 N: 28.69
EXEMPLE 22 : Synthèse du [[(chloro-2 éthyl)-3 nitroso-3 uréido ]-2 éthyl]- 1 nitro-5 imidazole (composé nº 26)EXAMPLE 22 Synthesis of [[(2-chloro-ethyl) -3-3-nitroso-ureido] -2-ethyl] - 1 5-nitro-imidazole (compound No. 26)
Ce composé a été préparé d'une manière analogue à l'exemple 20 à partir du composé nº17 avec un rendement de 56 %.This compound was prepared in a manner analogous to Example 20 from compound No. 17 with a yield of 56%.
F - 107-108ºC (acétone/éther). Rf (silice) = 0,46 (éluant : acétone, éther, v/v, 3/7). UV (EtOH 95º)λ max = 294 nm, log ε= 3,74. RMN (CD3-CO-CD3) δ ,8,20 ppm (m,1H), 7,90 ppm (s,1H), 7,78 ppm (s, 1H), 4,71 ppm (m,2H), 3,98 ppm (m,4H), 3,50 ppm (m,2H).F - 107-108ºC (acetone / ether). R f (silica) = 0.46 (eluent: acetone, ether, v / v, 3/7). UV (EtOH 95º) λ max = 294 nm, log ε = 3.74. NMR (CD 3 -CO-CD 3 ) δ, 8.20 ppm (m, 1H), 7.90 ppm (s, 1H), 7.78 ppm (s, 1H), 4.71 ppm (m, 2H ), 3.98 ppm (m, 4H), 3.50 ppm (m, 2H).
EXEMPLE 23 : Synthèse du [[(chloro-2 éthyl)-3 nitroso-3 uréido ]-2 éthyl ] -1 nitro-2 imidazole (composé nº 27)EXAMPLE 23 Synthesis of [[(2-chloro-ethyl) -3-3-nitroso-ureido] -2-ethyl] -1 2-nitro-imidazole (compound No. 27)
Ce composé a été préparé d'une manière analogue à l'exemple 20 à partir du composé 22 avec un rendement de 65 %.
F = 108°C (acétone/éther). Rf (silice) = 0,37 (éluant : CH2Cl2 / éther, v/v 7/3). UV (EtOH 95º) λmax = 313 nm, log ε= 3,42. RMN (CD3-CO-CD3) δ, 8,27 ppm (m,1H), 7,43 ppm (s, 1H), 7,05 ppm (s,1H), 4,77 ppm (m,2H), 4,00 ppm (m, 4H), 3,53 ppm (t, 2H,5 Hz).This compound was prepared in a manner analogous to Example 20 from compound 22 with a yield of 65%. Mp 108 ° C (acetone / ether). R f (silica) = 0.37 (eluent: CH 2 Cl 2 / ether, v / v 7/3). UV (EtOH 95º) λ max = 313 nm, log ε = 3.42. NMR (CD 3 -CO-CD 3 ) δ, 8.27 ppm (m, 1H), 7.43 ppm (s, 1H), 7.05 ppm (s, 1H), 4.77 ppm (m, 2H ), 4.00 ppm (m, 4H), 3.53 ppm (t, 2H, 5 Hz).
Analyse : Calc. C : 33 ,03 H : 3,81 N : 28,91 Trouvé C : 32,86 H : 3,90 N : 27,72Analysis: Calc. C: 33.03 H: 3.81 N: 28.91 Found C: 32.86 H: 3.90 N: 27.72
EXEMPLE 24 : Synthèse du [[(chloro-2 éthyl)-3 nitroso-3 uréido] -3 hydroxy-2 propyl]-1 imidazole (composé nº 28)EXAMPLE 24 Synthesis of [[(2-chloro-ethyl) -3-3-nitroso-ureido] -3-hydroxy-2-propyl] -1 imidazole (compound No. 28)
Ce composé a été préparé d 'une manière analogue à l'exemple 20 à partir du composé 19 avec un rendement deThis compound was prepared in a manner analogous to Example 20 from compound 19 with a yield of
71 %.71%.
F = 103°C (acétone/éther). Rf (silice) = 0,3 (éluant : CH2Cl2, MeOH, v/v, 9/2). RMN (CDCl3) δ, 7,70 ppm (m,1H), 7,38 ppmMp 103 ° C (acetone / ether). R f (silica) = 0.3 (eluent: CH 2 Cl 2 , MeOH, v / v, 9/2). NMR (CDCl 3 ) δ, 7.70 ppm (m, 1H), 7.38 ppm
(s,1H), 6,93 ppm (s,1H), 6,80 ppm (s,1H), 5,76 ppm (s,1H),(s, 1H), 6.93 ppm (s, 1H), 6.80 ppm (s, 1H), 5.76 ppm (s, 1H),
4,00 ppm (m,5H), 3,40 ppm (m,4H).4.00 ppm (m, 5H), 3.40 ppm (m, 4H).
EXEMPLE 25 :EXAMPLE 25:
Synthèse du [ [ (chloro-2 éthyl) -3 nitroso-3 uréido]-3 hydrox 2 propyl ]-1 nitro-4 imidazo le (composé nº 29) .Synthesis of [[(2-chloroethyl) -3 nitroso-3 ureido] -3 hydrox 2 propyl] -1 nitro-4 imidazo le (compound no. 29).
Ce composé a été préparé d'une manière analogue à l'exemple 20 à partir du composénº20 avec un rendement de 69 %.This compound was prepared in a manner analogous to Example 20 from compound 20 with a yield of 69%.
F = 126 , 5ºC (acétone/éther) . Rf (silice) = 0,5 (éluant : acétone, éther, v:v, 1/1). UV (EtOH 95º)λmax = 282 nm, log ε = 3,67. RMN (CD3-CO-CD3) δ 8,20 ppm (d, (1H,1 Hz),F = 126.5 ° C (acetone / ether). R f (silica) = 0.5 (eluent: acetone, ether, v: v, 1/1). UV (EtOH 95º) λ max = 282 nm, log ε = 3.67. NMR (CD 3 -CO-CD 3 ) δ 8.20 ppm (d, (1H, 1 Hz),
7,85 ppm (d, 1H, 1 Hz), 8,15 ppm (m,(1H), 4,95 ppm (d, 1H,7.85 ppm (d, 1H, 1 Hz), 8.15 ppm (m, (1H), 4.95 ppm (d, 1H,
8 Hz), 4,20 ppm (m, 5H), 3,60 ppm (m, 4H)8 Hz), 4.20 ppm (m, 5H), 3.60 ppm (m, 4H)
Analyse : Calc. C : 33,70 H : 4,08 N : 26,20 Trouvé C : 33,98 H : 4,20 N : 26,05
EXEMPLE 26 : Synthèse du éthyl)-3 nitroso-3 uréido]-3 hydroxy-2propyl]-1 nitro-5 imidoazole (composé nº 30)Analysis: Calc. C: 33.70 H: 4.08 N: 26.20 Found C: 33.98 H: 4.20 N: 26.05 EXAMPLE 26 Synthesis of ethyl) -3 nitroso-3 ureido] -3 hydroxy-2propyl] -1 nitro-5 imidoazole (compound No. 30)
Ce composé a été préparé d'une manière analogue à l'exemple 20 à partir du composé n°21avec un rendement de 67 %.This compound was prepared in a manner analogous to Example 20 from compound No. 21 with a yield of 67%.
F = 91ºC (acétone/éther). Rf (silice) = 0,55 (éluant : acétone, éther, v/v, 3/7).UV (EtOH 95e)λ max = 294 nm, log ε = 3,86. RMN (CD3-CO-CD3) δ, 8,20 ppm (m,1H), 7,90 ppm (m,2H), 4,5 ppm (m,6H), 3,60 ppm (m,4H). Analyse : Calc. C : 33,70 H : 4,08 N : 26,20F = 91ºC (acetone / ether). Rf (silica) = 0.55 (eluent: acetone, ether, v / v, 3/7) .UV (EtOH 95e) λ max = 294 nm, log ε = 3.86. NMR (CD 3 -CO-CD 3 ) δ, 8.20 ppm (m, 1H), 7.90 ppm (m, 2H), 4.5 ppm (m, 6H), 3.60 ppm (m, 4H) ). Analysis: Calc. C: 33.70 H: 4.08 N: 26.20
Trouvé C : 33,48 H : 4,09 N : 25,93Found C: 33.48 H: 4.09 N: 25.93
EXEMPLE 27 Synthèse du [[(chloro-2 éthyl)-3 nitroso-3 uréido ]-3 hydroxy-2 propyl ]-1 nitro-2 imidazole (composé nº 31)EXAMPLE 27 Synthesis of [[(2-chloro-ethyl) -3 3-nitroso-ureido] -3 2-hydroxypropyl] -1 2-nitro imidazole (compound No. 31)
Ce composé a été préparé d'une manière analogue à l'exemple 20 à partir du composénº23avec 81 % de rendement.This compound was prepared in a manner analogous to example 20 from compound 23 with 81% yield.
F : 141ºC (acétone/éther), Rf (silice) = 0,4 (éluant : éther/ acétone v/v, 9/1). UV (EtOH 95º)λ max = 313 nm, log ε = 3,80.F: 141ºC (acetone / ether), R f (silica) = 0.4 (eluent: ether / acetone v / v, 9/1). UV (EtOH 95º) λ max = 313 nm, log ε = 3.80.
RMN (DMSO d6) δ, 8,08 ppm (m,1H), 7,53 ppm (s,1H), 7,08 ppmNMR (DMSO d 6 ) δ, 8.08 ppm (m, 1H), 7.53 ppm (s, 1H), 7.08 ppm
(s,1H), 4,7-4,0 ppm (m,6H), 3,60 ppm (m,4H). Analyse : Calc. C : 33,70 H : 4,08 N : 26,20(s, 1H), 4.7-4.0 ppm (m, 6H), 3.60 ppm (m, 4H). Analysis: Calc. C: 33.70 H: 4.08 N: 26.20
Trouvé C : 33,91 H : 4,24 N : 25,99
Found C: 33.91 H: 4.24 N: 25.99
EXEMPLES 28 à 38EXAMPLES 28 to 38
- Dans les exemples 28 à 38 on a suivi les schémas réactionnels suivants :- In Examples 28 to 38, the following reaction schemes were followed:
R = NO2-2 NO2-4 NO2-5 a n° 32 n° 33 n° 34 b n° 35 n° 36 n° 37 c n° 38 n° 39 n° 40 d n° 41 n° 42 n° 43
EXEMPLE 28 : Synthèse de l'(époxy 2,3 propyl)-1 nitro-2 imidazole (composénº 32)R = NO 2 -2 NO 2 -4 NO 2 -5 year ° 32 n ° 33 n ° 34 bn ° 35 n ° 36 n ° 37 cn ° 38 n ° 39 n ° 40 dn 41 n ° 42 n ° 43 EXAMPLE 28 Synthesis of (epoxy 2,3 propyl) -1 nitro-2 imidazole (compound 32)
Une suspension de 1,13 g (10 mmoles) de nitro-2 imidazole, 8 ml (102 mmoles) d'épichlorhydrine et de 0,1 g (0,7 mmole) de carbonate de potassium dans 50 ml de méthanol est agitée à température ambiante pendant trois jours. Le milieu réactionnel est filtré afin d'éliminer les sels ; le filtrat est évaporé sous vide, puis chromatographie sur colonne de gel de silice. 1,41 gA suspension of 1.13 g (10 mmol) of 2-nitro imidazole, 8 ml (102 mmol) of epichlorohydrin and 0.1 g (0.7 mmol) of potassium carbonate in 50 ml of methanol is stirred at room temperature for three days. The reaction medium is filtered in order to remove the salts; the filtrate is evaporated under vacuum, then chromatography on a column of silica gel. 1.41 g
(69 %) d'époxyde 32 sont obtenus après recristallisation dans un mélange HcOEt, cyclohexane.(69%) of epoxide 32 are obtained after recrystallization from an HcOEt, cyclohexane mixture.
F = 52-53°C (AcOEt/cyclohexane). Rf (silice) = 0,59 (éluant: MeOH/CH2Cl2, V/V, 1/9). RMN (DMSOd6) δ, 7,55 ppm (s,1H), 7,15 ppm (s,1H), 4,65 ppmMp 52-53 ° C (AcOEt / cyclohexane). R f (silica) = 0.59 (eluent: MeOH / CH 2 Cl 2 , V / V, 1/9). NMR (DMSOd 6 ) δ, 7.55 ppm (s, 1H), 7.15 ppm (s, 1H), 4.65 ppm
(dd, 1H, 4Hz, 14Hz), 4,30 ppm (dd, 1H, 8Hz, 14Hz), 4,00 ppm(dd, 1H, 4Hz, 14Hz), 4.30 ppm (dd, 1H, 8Hz, 14Hz), 4.00 ppm
(m, 1H), 3,60 ppm (m, 2H).(m, 1H), 3.60 ppm (m, 2H).
EXEMPLE 29 : Synthèse de l'(époxy 2,3 propyl) -1 nitro-4 imidazole (composé nº 33)EXAMPLE 29 Synthesis of (epoxy 2,3 propyl) -1 nitro-4 imidazole (compound no. 33)
Ce composé a été préparé d'une manière analogue à l'exemple 28 à partir du nitro-4(5) imidazole commercial. Le rendement obtenu est de 71 %.This compound was prepared in a manner analogous to Example 28 from commercial nitro-4 (5) imidazole. The yield obtained is 71%.
F = 82-83°C (AcOEt/cyclohexane) Rf (silice) = 0,64 (éluant : CH2Cl2/MeOH, V/V, 9/1)F = 82-83 ° C (AcOEt / cyclohexane) R f (silica) = 0.64 (eluent: CH 2 Cl 2 / MeOH, V / V, 9/1)
RMN (CDCl3) δ, 8,03 ppm (d, 1H, 1Hz), 7,61 ppm (d, 1H, 1Hz), 4,63 ppm (dd, 1H, 3Hz, 15Hz), 4,03 ppm (dd, 1H, 7Hz, 15Hz), 3,47 ppm (m, 1H) 2,87 ppm (m, 2H).
EXEMPLE 30 Synthèse de l'(epoxy 2,3 propyl)-1 nitro-5 imidazole ( composé n º 34 )NMR (CDCl 3 ) δ, 8.03 ppm (d, 1H, 1Hz), 7.61 ppm (d, 1H, 1Hz), 4.63 ppm (dd, 1H, 3Hz, 15Hz), 4.03 ppm ( dd, 1H, 7Hz, 15Hz), 3.47 ppm (m, 1H) 2.87 ppm (m, 2H). EXAMPLE 30 Synthesis of (epoxy 2,3 propyl) -1 nitro-5 imidazole (compound no. 34)
3 g de (chloro-3 hydroxy-2 propyl)-1 nitro-5 imidazole (composé 14) sont agités avec 20 ml de solution de NaOH 2,5N. Après quelques instants de nouveaux cristaux apparaissent ; 1,92 g (78 %) d'époxyde 34 sont obtenus après filtration.3 g of (3-chloro-2-hydroxypropyl) -1 5-nitro imidazole (compound 14) are stirred with 20 ml of 2.5N NaOH solution. After a few moments new crystals appear; 1.92 g (78%) of epoxy 34 are obtained after filtration.
F = 100,5-101 °C (AcOEt/cyclohexane) Rf(silice) = 0,62 (éluant : CH2Cl2/MeOH, V/V, 9/1)F = 100.5-101 ° C (AcOEt / cyclohexane) R f (silica) = 0.62 (eluent: CH 2 Cl 2 / MeOH, V / V, 9/1)
RMN (CDCl3) δ, 8,03 ppm (s, 1H), 7,60 ppm (o,1H), 4,95 ppm (dd, 1H, 3Hz, 15Hz), 4,15 ppm (dd, 1H, 6Hz, 15Hz), 3,35 ppm (m, 1H), 2,70 ppm (m,2H).NMR (CDCl 3 ) δ, 8.03 ppm (s, 1H), 7.60 ppm (o, 1H), 4.95 ppm (dd, 1H, 3Hz, 15Hz), 4.15 ppm (dd, 1H, 6Hz, 15Hz), 3.35 ppm (m, 1H), 2.70 ppm (m, 2H).
EXEMPLE 31 Synthèse du [[bis (hydroxy-2 éthyl) amino]-3 hydroxy-2 propyl] -1 nitro-2 imidazole (composé nº 35 )EXAMPLE 31 Synthesis of [[bis (2-hydroxyethyl) amino] -3 2-hydroxypropyl] -1 2-nitro imidazole (compound No. 35)
2,1 g (12,4 mmoles) d' (époxy 2,3 propyl)-1 nitro-2 imidazole (composé n° 32) et 1,95 g (18,6 mmoles) de diéthanolamine sont mis en solution dans 100 ml de méthanol ; après 16 heures de reflux, le mélange réactionnel est évaporé sous vide. Le résidu est repris par 50 ml d'AcOEt bouillant et abandonné à température ambiante ; 2,7 g (80 %) de composé 35 sont isolés après cristallisation.2.1 g (12.4 mmol) of (epoxy 2,3 propyl) -1 2-nitro-imidazole (compound No. 32) and 1.95 g (18.6 mmol) of diethanolamine are dissolved in 100 ml of methanol; after 16 hours of reflux, the reaction mixture is evaporated under vacuum. The residue is taken up in 50 ml of boiling AcOEt and left at room temperature; 2.7 g (80%) of compound 35 are isolated after crystallization.
F = 103-103,5°C (AcOEt) Rf(silice) = 0,21 (éluant CH2Cl2/MeOH, V/V, 9/1) UV(EtOH 95°) λmax= 311 nm log ε = 3,91 RMN (DMSOd6) δ, 7,55 ppm (d, 1H, 1Hz), 7,11 ppm (d, 1H, 1Hz), 4,50 ppm (m, 6H), 3,40 ppm (t, 4H, 6Hz), 2,60 ppm (m, 6Hz).
Analyse Calc. C: 43,79 H: 6,61 N: 20,42 Trouvé C: 43,99 H: 6,81 N: 20,64F = 103-103.5 ° C (AcOEt) R f (silica) = 0.21 (eluent CH 2 Cl 2 / MeOH, V / V, 9/1) UV (EtOH 95 °) λ max = 311 nm log ε = 3.91 NMR (DMSOd 6 ) δ, 7.55 ppm (d, 1H, 1Hz), 7.11 ppm (d, 1H, 1Hz), 4.50 ppm (m, 6H), 3.40 ppm (t, 4H, 6Hz), 2.60 ppm (m, 6Hz). Calc analysis. C: 43.79 H: 6.61 N: 20.42 Found C: 43.99 H: 6.81 N: 20.64
EXEMPLE 32 Synthèse du[[bis(hydroxy-2 éthyl)amino]-3 hydroxy-2 propyl ]-1 nitro-4 imidazole (composé nº 36)EXAMPLE 32 Synthesis of [[bis (2-hydroxyethyl) amino] -3 hydroxy-2 propyl] -1 nitro-4 imidazole (compound No. 36)
Ce composé a été préparé d'une manière analogue à l'exemple 31 à partir du composé n° 33. Le rendement obtenu est de 81 %.This compound was prepared in a manner analogous to Example 31 from compound No. 33. The yield obtained is 81%.
F = 97-98°C (AcOEt) Rf(silice) = 0,14 (éluant : CH2Cl2/MeOH, V/V, 9/1) UV(EtOH 95º) λmax = 286 nm log ε = 3,89 RMN (DMSOd6) δ, 8,30 ppm (d, 1H, 1Hz), 7,78 ppm (d, 1H, 1Hz), 4,00 ppm (m, 6H), 3,43 ppm (m, 4H), 2,56 ppm (m, 6H).F = 97-98 ° C (AcOEt) R f (silica) = 0.14 (eluent: CH 2 Cl 2 / MeOH, V / V, 9/1) UV (EtOH 95º) λ max = 286 nm log ε = 3.89 NMR (DMSOd 6 ) δ, 8.30 ppm (d, 1H, 1Hz), 7.78 ppm (d, 1H, 1Hz), 4.00 ppm (m, 6H), 3.43 ppm (m , 4H), 2.56 ppm (m, 6H).
Analyse : Calc. C: 43,79 H: 6,61 N: 20,42 Trouvé C: 44,04 H: 6,68 N: 20,54Analysis: Calc. C: 43.79 H: 6.61 N: 20.42 Found C: 44.04 H: 6.68 N: 20.54
EXEMPLE 33 Synthèse du[[bis(hydroxy-2 éthyl)amino]-3hydroxy-2propyl] -1nitro-5_imidazole (composé nº 37)EXAMPLE 33 Synthesis of [[bis (2-hydroxyethyl) amino] -3-hydroxy-2propyl] -1nitro-5_imidazole (compound No. 37)
Ce composé a été préparé d'une manière analogue à l'exemple 31 à partir du composé n° 34. Le rendement obtenu est de 71 %.This compound was prepared in a manner analogous to Example 31 from compound No. 34. The yield obtained is 71%.
F = 69-71 °C (AcOEt/cyc lohexane) Rf (silice) = 0,22 (éluant: CH2Cl2/MeOH, V/V, 9/1) UV(EtOH 95°) λmax = 294 nm log ε = 3,89 RMN (DMSOd6) δ, 8,06 ppm (s, 1H), 8,00 (s, 1H), 4,30 ppm (m, 6H) 3,40 ppm (m, 4H), 2,50 ppmF = 69-71 ° C (AcOEt / cyc lohexane) R f (silica) = 0.22 (eluent: CH 2 Cl 2 / MeOH, V / V, 9/1) UV (EtOH 95 °) λ max = 294 nm log ε = 3.89 NMR (DMSOd 6 ) δ, 8.06 ppm (s, 1H), 8.00 (s, 1H), 4.30 ppm (m, 6H) 3.40 ppm (m, 4H ), 2.50 ppm
(t, 6H, 6Hz).(t, 6H, 6Hz).
Analyse : Calc. C: 43,79 H: 6,61 N: 20,42Analysis: Calc. C: 43.79 H: 6.61 N: 20.42
Trouvé C: 44,01 H: 6,68 N: 20,58
EXEMPLE 34 Synthèse du[[bis(chloro-2 éthyl)-1 amino]-3 hydroxy- 2 propyl]-1 nitro-2 imidazole (composé nº 38)Found C: 44.01 H: 6.68 N: 20.58 EXAMPLE 34 Synthesis of [[bis (2-chloroethyl) -1 amino] -3 2-hydroxypropyl] -1 2-nitro imidazole (compound no. 38)
A une solution de 2,74 g (10 mmoles) de composé n° 35 dans 150 ml de CH3CN anhydre sont ajoutés 2 ml (20,6 mmoles) de tétrachlorure de carbone anhydre et 5,42 g (20,6 mmoles) de triphénylphophine. Le mélange réactionnel est chauffé à reflux pendant 2 heures. Après évaporation sous vide des volatiles, le résidu est chromatographié sur colonne de gel de silice afin d'éliminer l'oxyde de triphénylphosphine formé au cours de la réaction ; 1,56 g de composé n° 38 sont obtenus cristallisés.To a solution of 2.74 g (10 mmol) of compound No. 35 in 150 ml of anhydrous CH 3 CN are added 2 ml (20.6 mmol) of anhydrous carbon tetrachloride and 5.42 g (20.6 mmol ) of triphenylphophine. The reaction mixture is heated at reflux for 2 hours. After evaporation of the volatiles in vacuo, the residue is chromatographed on a column of silica gel in order to remove the triphenylphosphine oxide formed during the reaction; 1.56 g of compound No. 38 are obtained crystallized.
F = 118° dec (CH2Cl2/Ether) Rf (silice) = 0,33F = 118 ° dec (CH 2 Cl 2 / Ether) R f (silica) = 0.33
(éluant : Ether) UV(EtOH 95°) λmax = 312 nm log ε = 3,80 RMN (DMSOd6) δ, 7,54 ppm (s, 1H), 7,15 ppm (s, 1H), 5,03 ppm (d, 1H, 5Hz), 4,42 ppm (m, 2H), 3,66 ppm (t, 4H, 7Hz), 2,90 ppm (t, 4H, 7Hz) 2,65 ppm (d, 2H, 6Hz), 3,85 ppm (m, 1H).(eluent: Ether) UV (EtOH 95 °) λ max = 312 nm log ε = 3.80 NMR (DMSOd 6 ) δ, 7.54 ppm (s, 1H), 7.15 ppm (s, 1H), 5 , 03 ppm (d, 1H, 5Hz), 4.42 ppm (m, 2H), 3.66 ppm (t, 4H, 7Hz), 2.90 ppm (t, 4H, 7Hz) 2.65 ppm (d , 2H, 6Hz), 3.85 ppm (m, 1H).
Analyse : Calc. C: 38,59 H: 5,18 N: 18,00 Trouvé C: 38,42 H: 5,36 N: 17,78Analysis: Calc. C: 38.59 H: 5.18 N: 18.00 Found C: 38.42 H: 5.36 N: 17.78
EXEMPLE 35 Synthèse du[[bis(chloro-2 éthyl)amino]-3 hydroxy-2 propyl] -1 nitro-4 imidazole (composé n° 39)EXAMPLE 35 Synthesis of [[bis (2-chloroethyl) amino] -3 2-hydroxy-propyl] -1 4-nitro imidazole (compound No. 39)
Ce composé a été préparé d'une manière analogue à l'exemple 34 à partir du composé n° 36. Le rendement obtenu est de 55 %. F = 105-106ºC Rf (silice) = 0,36 (éluant: Ether/MeOH, V/V,This compound was prepared in a manner analogous to Example 34 from compound No. 36. The yield obtained is 55%. F = 105-106ºC R f (silica) = 0.36 (eluent: Ether / MeOH, V / V,
97/3) UV(EtOH 95°) λmax = 285 nm log ε = 3,87
RMN (CD3COCD3) δ, 8,16 ppm (d, 1H, 1Hz), 7,70 ppm97/3) UV (EtOH 95 °) λ max = 285 nm log ε = 3.87 NMR (CD 3 COCD 3 ) δ, 8.16 ppm (d, 1H, 1Hz), 7.70 ppm
(d, 1H, 1Hz), 4,23 ppm (m, 4H), 3,66 ppm (m, 4H), 290 ppm(d, 1H, 1Hz), 4.23 ppm (m, 4H), 3.66 ppm (m, 4H), 290 ppm
(m, 6H).(m, 6H).
Analyse : Calc. C: 38,59 H: 5,18 N: 18,00 Trouvé C: 38,56 H: 5,32 N: 17,80Analysis: Calc. C: 38.59 H: 5.18 N: 18.00 Found C: 38.56 H: 5.32 N: 17.80
EXEMPLE 36 Synthèse du[[bis(chloro-2 éthyl)amino]-3 hydroxy-2 propyl]-1 nitro-5 imidazole (composé_nº 40)EXAMPLE 36 Synthesis of [[bis (2-chloroethyl) amino] -3 2-hydroxypropyl] -1 5-nitro imidazole (compound_nº 40)
Ce composé a été préparé d'une manière analogue à l'exemple 34 à partir du composé n° 37. Le rendement obtenu est de 68 %.This compound was prepared in a manner analogous to Example 34 from compound No. 37. The yield obtained is 68%.
F = 68°C Rf(silice) = 0,15 (éluant : CHCl3/Ether, V/V, 8/2) UV(EtOH 95°) λ max = 295. nm log ε = 3,92 RMN(CDCl3) δ, 7,95 ppm (s, 1H), 7,76 ppm (s, 1H), 4,50 ppm (m, 5H) 3,60 ppm (t, 4H, 6Hz), 2,97 ppm (m,6H).F = 68 ° CR f (silica) = 0.15 (eluent: CHCl 3 / Ether, V / V, 8/2) UV (EtOH 95 °) λ max = 295. nm log ε = 3.92 NMR (CDCl 3 ) δ, 7.95 ppm (s, 1H), 7.76 ppm (s, 1H), 4.50 ppm (m, 5H) 3.60 ppm (t, 4H, 6Hz), 2.97 ppm ( m, 6H).
Analyse: Calc. C: 38,59 H: 5,18 N: 18,00 Trouvé C: 38,56 H: 5,29 N: 17,79Analysis: Calc. C: 38.59 H: 5.18 N: 18.00 Found C: 38.56 H: 5.29 N: 17.79
EXEMPLE 37 Synthèse du[[bis(chloro-2 éthyl)amino]-2 éthyl]-1 nitro -2 imidazole (composé nº 41)EXAMPLE 37 Synthesis of [[bis (2-chloroethyl) amino] -2 ethyl] -1 nitro -2 imidazole (compound No. 41)
A une solution agitée contenant 0,12 g (1,1 mmole) de nitro-2 imidazole dans 30 ml de DMF anhydre, on ajoute 0,05 g (1,2 mmole) d'hydrure de sodium (suspension 60 %/ huile). Lorsque le dégagement gazeux est terminé, on introduit la tri(chloro-2 éthyl) aminé déplacée par NaOH deTo a stirred solution containing 0.12 g (1.1 mmol) of 2-nitroimidazole in 30 ml of anhydrous DMF, 0.05 g (1.2 mmol) of sodium hydride (60% suspension / oil) is added ). When the evolution of gas is complete, the tri (2-chloroethyl) amino displaced by NaOH is introduced.
0,53 g (2,2 mmoles) de son chrlorhydrate. Le mélange réactionnel est porté à 100°C pendant 16 heures. Après filtration, le DMF est évaporé sous vide. Le résidu est chroma
tographié sur colonne de gel de silice avec l'éluant : CH2Cl2 ; 0,16 g de composé n° 41 sont obtenus (54 %).0.53 g (2.2 mmol) of its hydrochloride. The reaction mixture is brought to 100 ° C for 16 hours. After filtration, the DMF is evaporated under vacuum. The residue is chroma tographed on a silica gel column with the eluent: CH 2 Cl 2 ; 0.16 g of compound No. 41 is obtained (54%).
F = 62-62,5°C Rf (silice) = 0,33 (éluant : CH2Cl2) UV(EtOH 95°) λmax = 310,6 nm log ε = 3,81 RMN (CDCl3) δ, 7,27 ppm (s, 1H), 7,13 ppm (s, 1H),F = 62-62.5 ° CR f (silica) = 0.33 (eluent: CH 2 Cl 2 ) UV (EtOH 95 °) λ max = 310.6 nm log ε = 3.81 NMR (CDCl 3 ) δ , 7.27 ppm (s, 1H), 7.13 ppm (s, 1H),
4,47 ppm (1, 2H, 6Hz), 3,40 ppm (t, 4H, 6Hz), 2,95 ppm (m, 6H).4.47 ppm (1, 2H, 6Hz), 3.40 ppm (t, 4H, 6Hz), 2.95 ppm (m, 6H).
Analyse : Calc. C: 38,42 H: 5,02 N: 19,93 Trouvé C: 38,72 H: 5,12 N: 19,86Analysis: Calc. C: 38.42 H: 5.02 N: 19.93 Found C: 38.72 H: 5.12 N: 19.86
EXEMPLE 38 Synthèse du[[bis(chloro-2 éthyl)amino]-2 éthyl]-1 nitro -4 imidazole (composé nº 42) et du[[bis(chloro-2 éthyl) amino]-2éthyl]-1 nitro-5 imidazole (composé nº 43)EXAMPLE 38 Synthesis of [[bis (2-chloroethyl) amino] -2 ethyl] -1 nitro -4 imidazole (compound 42) and [[bis (2-chloroethyl) amino] -2ethyl] -1 nitro- 5 imidazole (compound 43)
Les composés n° 42 et n° 43 ont été préparé d'une manière analogue à l'exemple 37 à partir du nitro-4 (5) imidazole. La séparation des deux isomères 42 et 43 est effectuée par chromatographie sur colonne de gel de silice. Le composé n° 42 est obtenu avec 42 % de rendement et le composé n° 43 avec 18 %.Compounds 42 and 43 were prepared in a manner analogous to Example 37 from nitro-4 (5) imidazole. The separation of the two isomers 42 and 43 is carried out by chromatography on a column of silica gel. Compound No. 42 is obtained with 42% yield and Compound No. 43 with 18%.
Composé nº 42Compound # 42
F = 58-59ºC Rf (silice) = 0,23 (éluant : CH2Cl2)F = 58-59ºC R f (silica) = 0.23 (eluent: CH 2 Cl 2 )
UV(EtOH 95º) λmax = 286 nm log ε = 3,91UV (EtOH 95º) λ max = 286 nm log ε = 3.91
RMN (DMSOd6) δ, 8,41 ppm (d, 1H, 1Hz), 7,83 ppm (d, 1H,NMR (DMSOd 6 ) δ, 8.41 ppm (d, 1H, 1Hz), 7.83 ppm (d, 1H,
1Hz) 4,10 ppm (t, 2H, 6Hz), 3,53 ppm (t, 4H, 6Hz), 2,90 ppm (m, 6H).1Hz) 4.10 ppm (t, 2H, 6Hz), 3.53 ppm (t, 4H, 6Hz), 2.90 ppm (m, 6H).
Analyse : Calc. C: 38,42 H: 5,02 N: 19,93 Trouvé C: 38,12 H: 5,04 N: 19,94
Composé n° 43Analysis: Calc. C: 38.42 H: 5.02 N: 19.93 Found C: 38.12 H: 5.04 N: 19.94 Compound # 43
F = 20-25°C (surfusion) Rf(silice) = 0,34 (éluant : CH2Cl2) UV(EtOH 95°) λmax = 294,5 nm log ε = 3,92 RMN (DMSOd6) δ, 8,30 ppm (d, 1H, 1Hz), 7,81 ppm (d, 1H, 1Hz) 4,25 ppm (t, 2H, 6Hz), 3,65 ppm (t, 4H, 6Hz), 2,95 ppm (m, 6H).F = 20-25 ° C (supercooling) R f (silica) = 0.34 (eluent: CH 2 Cl 2 ) UV (EtOH 95 °) λ max = 294.5 nm log ε = 3.92 NMR (DMSOd 6 ) δ, 8.30 ppm (d, 1H, 1Hz), 7.81 ppm (d, 1H, 1Hz) 4.25 ppm (t, 2H, 6Hz), 3.65 ppm (t, 4H, 6Hz), 2.95 ppm (m, 6H).
Analyse : Calc. C: 38,42 H: 5,02 N: 19,93Analysis: Calc. C: 38.42 H: 5.02 N: 19.93
Trouvé C: 38,49 H: 4,95 N: 19,89Found C: 38.49 H: 4.95 N: 19.89
EXEMPLE 39 : Déterminatign de l'activité biologigueinvivoEXAMPLE 39: Determination of biological activity
1) Activité oncostatique sur la L 12101) Oncostatic activity on the L 1210
Plusieurs composés ont été testés. Le tableau I ci-après illustre les résultats obtenus.Several compounds have been tested. Table I below illustrates the results obtained.
(1) Les numéros se réfèrent aux composés des exemples précédents.(1) The numbers refer to the compounds of the preceding examples.
(2) Les composés de type A répondent à la structure suivante(2) Type A compounds have the following structure
avec R = H, nitro-2, nitro-4, ou nitro-5, alors que les composés de type B ont la structure suivante with R = H, nitro-2, nitro-4, or nitro-5, while type B compounds have the following structure
avec R = H, Nitro-4, Nitro-5, Nitro-2.with R = H, Nitro-4, Nitro-5, Nitro-2.
Les résultats ci-dessus montrent que les composés n° 29 (I 272), nº31 (I 278) et n°30(I 281) sont les plus perfor mants avec une survie de 100 %. Il s'agit de trois composés de type A.The above results show that compounds n ° 29 (I 272), nº31 (I 278) and n ° 30 (I 281) are the most efficient with a survival of 100%. These are three type A compounds.
Il faut noter que l'ensemble de ces dérivés nitrés est relativement peu toxique puisque l'on observe une DL50 comprise entre 60 et 150 mg/kg. 2) Activité oncostatique sur le melanome B16. Le tableau II ci-dessous illustre les résultats obtenus avec les produits testés.
It should be noted that all of these nitro derivatives are relatively little toxic since an LD 50 of between 60 and 150 mg / kg is observed. 2) Oncostatic activity on melanoma B16. Table II below illustrates the results obtained with the products tested.
Ce tableau montre que tous les composés nitrés sont actifs avec un index maximum de 200 pour le composé n° 25This table shows that all the nitro compounds are active with a maximum index of 200 for compound n ° 25
(I 273).(I 273).
3) Cytotoxicité sur des cellules Mer+ (Hela-S3) et Mer- (Hela-MR) dans des conditions aerobiques et hypoxiques.3) Cytotoxicity on Mer + (Hela-S3) and Mer- (Hela-MR) cells under aerobic and hypoxic conditions.
La différence entre ces deux types de cellules consiste en la présence ou l'absence d'une enzyme de séparation, la 0-6 méthyltransférase. a) Conditions opératoires Les cellules utilisées dans un environnement aérobique sont mises en suspension dans 10 ml de milieu de base de Eagle (BME) à une concentration de 1 à 2.10 par millilitre, et placées dans un flacon de traitement de type I comme décrit par Whilliams et Rauth. Pour des mesures dans des conditions hypoxiques, les cellules sont ajoutées dans les flacons contenant le BME seulement après que le milieu ait séjourné dans un mélange gazeux 97 % N2 /3 % CO2 pendant 3 heures. Avant d'être injectées dans les récipients de traitement, les cellules sont incubées pendant 10 minutes à une concentration de 2 x 107 cellules/ml dans une seringue HamiltonThe difference between these two types of cells is the presence or absence of a separating enzyme, 0-6 methyltransferase. a) Operating conditions The cells used in an aerobic environment are suspended in 10 ml of Eagle base medium (BME) at a concentration of 1 to 2.10 per milliliter, and placed in a type I treatment flask as described by Whilliams and Rauth. For measurements under hypoxic conditions, the cells are added to the vials containing the BME only after the medium has remained in a gaseous mixture 97% N 2 /3% CO 2 for 3 hours. Before being injected into the treatment vessels, the cells are incubated for 10 minutes at a concentration of 2 × 10 7 cells / ml in a Hamilton syringe
b) Essaisb) Tests
La toxicité relative aérobique et hypoxique des dif férents composés a été calculée en utilisant le facteur DEF défini comme étant le rapport des quantités requises pour réduire les cellules survivantes à 0,01,respectivement, dans des conditions aérobiques et hypoxiques.The relative aerobic and hypoxic toxicity of the various compounds was calculated using the DEF factor defined as the ratio of the amounts required to reduce the surviving cells to 0.01, respectively, under aerobic and hypoxic conditions.
Un facteur DEF supérieur à 1 indique une toxicite préférentielle dans des conditions hypoxiques.
c) RésultatsA DEF factor greater than 1 indicates preferential toxicity under hypoxic conditions. c) Results
Les composés utilisés sont les mêmes que dans les exemples 39-1) et 2).The compounds used are the same as in Examples 39-1) and 2).
Les figures 1 et 2 illustrent les résultats obtenus et donnent le pourcentage de cellules survivantes en fonction de la dose de composé administrée (en μmole).Figures 1 and 2 illustrate the results obtained and give the percentage of surviving cells as a function of the dose of compound administered (in μmol).
Le symbole N2 représente le milieu hypoxique alors que O2 représente le milieu aérobique.The symbol N2 represents the hypoxic medium while O2 represents the aerobic medium.
La figure 1 exprime plus précisément les résultats obtenus avec des cellules Mer- alors que la figure 2 exprime les résultats obtenus avec des cellules Mer +.Figure 1 expresses more precisely the results obtained with Mer- cells while Figure 2 expresses the results obtained with Mer + cells.
En référence à la figure 1, les composés testés sont cytotoxiques vis à vis des cellules Mer- (Hela-MR), aussi bien sous des conditions aérobiques que hypoxiques, exception faite des dérivés de l'imidazole non nitrés I-273 (nº24) et 1-283 (nº28). On note une cytotoxicité accrue sous des conditions hypoxiques pour les dérivés du nitro-2 imidazole 1-278 (nº 31) et 1-282 (nº 27) puisque leur facteur DEF est voisin de 2,4. En référence à la figure 2, les cellules Mer+ (Hela - 53) sont, comme l'on doit s'y attendre, plus résistantes aux produits testés. Tous les composés de la série A sont moins toxiques que ceux de la série B. Vis à vis des cellules Mer+, les composés I-278 et I-282 (31 et 27) présentent encore une fois, une cytotoxicité accrue sous des conditions hypoxiques (DEF voisin de 1,3).With reference to FIG. 1, the compounds tested are cytotoxic with respect to Mer- cells (Hela-MR), both under aerobic and hypoxic conditions, except for the non-nitrated imidazole derivatives I-273 (nº24) and 1-283 (no. 28). There is an increased cytotoxicity under hypoxic conditions for the 2-nitro-imidazole derivatives 1-278 (nº 31) and 1-282 (nº 27) since their DEF factor is close to 2.4. Referring to Figure 2, the Mer + cells (Hela - 53) are, as should be expected, more resistant to the products tested. All the compounds of the A series are less toxic than those of the B series. With respect to the Mer + cells, the compounds I-278 and I-282 (31 and 27) once again exhibit increased cytotoxicity under conditions hypoxic (DEF close to 1.3).
En ce qui concerne les nitrosourées, les résultats concernant leur action sur les cellules Mer+ et Mer- ont été publiés (Aérobic and Hypoxic Toxicity of a New Class of Mixed - Function Drugs Associating Nitro Imidazoles and Chloroéthylnitrosourea in Nitrosourea-sensitive (Mer-) and résistance (Mer+) Human Tumor Cells.
R.T. MULCAHY, A. CARMINATI , J. BARASCUT et J.L. IMBACH Cancer Research 1988 48 798).With regard to nitrosoureas, the results concerning their action on Mer + and Mer- cells have been published (Aérobic and Hypoxic Toxicity of a New Class of Mixed - Function Drugs Associating Nitro Imidazoles and Chloroéthylnitrosourea in Nitrosourea-sensitive (Mer-) and resistance (Mer +) Human Tumor Cells. RT MULCAHY, A. CARMINATI, J. BARASCUT and JL IMBACH Cancer Research 1988 48 798).
Ces résultats montrent pour les microsourées de la série Nitro-2 une chimiosensibilisation en milieu hypoxique. Si on compare les Séries A et B, on remarque dans tous les cas une activité plus importante pour les composés de la Série B.
These results show for the Nitro-2 micro-sources a chemosensitization in hypoxic medium. If we compare Series A and B, we notice in all cases a higher activity for the compounds of Series B.
Claims
1. Composé caractérisé en ce qu'il résulte du couplage d'une molécule ayant une structure chimiosensibilisante et d'une molécule ayant une structure cytotoxique.1. Compound characterized in that it results from the coupling of a molecule having a chemosensitizing structure and a molecule having a cytotoxic structure.
2. Composé selon la revendication 1, caractérisé en ce que la molécule ayant une structure cytotoxique est dérivée d'une molécule cytotoxique alkylante.2. Compound according to claim 1, characterized in that the molecule having a cytotoxic structure is derived from an alkylating cytotoxic molecule.
3 . Composé selon l ' une des revendications 1 et 2, caractérisé en ce que la molécule ayant une structure chimio sensibilisante est dérivée d'une molécule à cycle aromatique ou pseudo-aromatique.3. Compound according to one of claims 1 and 2, characterized in that the molecule having a chemosensitizing structure is derived from a molecule with an aromatic or pseudo-aromatic ring.
4. Composé selon l'une des revendications 2 et 3, caractérisé en ce que la molécule cytotoxique alkylante dérive d'une nitroso-urée ou d'une moutarde à l'azote.4. Compound according to one of claims 2 and 3, characterized in that the alkylating cytotoxic molecule derives from a nitrosourea or a nitrogen mustard.
5. Composé selon l'une des revendications 1 à 4, caractérisé en ce qu'il répond à la formule (I).5. Compound according to one of claims 1 to 4, characterized in that it corresponds to formula (I).
dans laquelle X est le reste d'un cycle benzénique ou un hétérocycle comportant l'azote comme hétéroatome de formule XH, substitué par au moins un groupe -NO2, R1 est H, OH ou SH, et R2 est un groupe dérivé d'une nitroso-urée ou d'une moutarde à l'azote.in which X is the remainder of a benzene ring or a heterocycle comprising nitrogen as heteroatom of formula a nitrosourea or a nitrogen mustard.
6. Composé selon 1a revendication 5, caractérisé en ce que X est choisi parmi les radicaux suivants : benzyle, triazolyle, benzymidazolyle, imidazolyle, tétrazolyle. 6. Compound according to claim 5, characterized in that X is chosen from the following radicals: benzyl, triazolyl, benzymidazolyl, imidazolyl, tetrazolyl.
7. Composé selon l'une des revendications 5 et 6, caractérisée en ce que R2 est -NH-CO-N (NO) -CH2-CH2-Cl à condition que R1 soit un atome d'hydrogène,
ou R2 est -CH2-NH-CO-N(NO)-CH2-CH2Cl à condition que R1 soit OH ou SH.7. Compound according to one of claims 5 and 6, characterized in that R 2 is -NH-CO-N (NO) -CH 2 -CH 2 -Cl provided that R 1 is a hydrogen atom, or R 2 is -CH 2 -NH-CO-N(NO)-CH 2 -CH 2 Cl provided that R 1 is OH or SH.
8. Composé selon l'une des revendications 5 à 7, caractérisé en ce qu'il est choisi dans le groupe constitué par : [[(chloro-2 éthyl)-3 nitroso-3 uréido ]-3 hydroxy-2 propyl ]8. Compound according to one of claims 5 to 7, characterized in that it is chosen from the group consisting of: [[(2-chloroethyl)-3-nitroso-ureido]-3-hydroxy-2-propyl]
-1 nitro-4 imidazole,-1 nitro-4 imidazole,
[[(chloro-2 éthyl)-3 nitroso-3 uréido]-3 hydroxy-2 propyl ][[(2-chloroethyl)-3-nitroso-ureido]-3-hydroxy-2-propyl]
-1 nitro-5 imidazole, [ [(chloro-2 éthyl)-3 nitroso-3 uréido]-3 hydroxy-2 propyl ]-1-5-nitroimidazole, [[(2-chloroethyl)-3-nitroso-3-ureido]-3-hydroxy-2-propyl]
-1 nitro-2 imidazole-1 nitro-2 imidazole
[ [(chloro-2 éthyl)-3 nitroso-3 uréido]-2 éthyl ]-1 nitro[[(2-chloroethyl)-3-nitroso-3-ureido]-2 ethyl]-1 nitro
-4 imidazole [[(chloro-2 éthyl)-3 nitroso-3 uréido ]-2 éthyl ]-1 nitro-4 imidazole [[(2-chloroethyl)-3-nitroso-3-ureido]-2 ethyl]-1 nitro
-5 imidazole, [[(chloro-2 éthyl) o-3 uréi -3 nitros do ] -2 ethyl ]-1 nitro-5 imidazole, [[(2-chloroethyl) o-3 urei -3 nitros do] -2 ethyl]-1 nitro
-2 imidazole.-2 imidazole.
9. Composé selon l'une des revendications 5 et 6, caractérisé en ce que R2 est NH-CH2-CH2-Cl, N(CH2-CH2-Cl)2 ou9. Compound according to one of claims 5 and 6, characterized in that R 2 is NH-CH 2 -CH 2 -Cl, N(CH 2 -CH 2 -Cl) 2 or
NH-C6H4-N(CH2CH2Cl)2 à condition que R1 soit H, ou R2 est CH2-NH-CH2CH2Cl, CH2-N(CH2-CH2Cl)2 ou CH2-NH-C6H4-N(CH2CH2Cl)2 à condition que R1 soit OH ou SH.NH-C 6 H 4 -N(CH 2 CH 2 Cl) 2 provided that R 1 is H, or R 2 is CH 2 -NH-CH 2 CH 2 Cl, CH 2 -N(CH 2 -CH 2 Cl ) 2 or CH 2 -NH-C 6 H 4 -N(CH 2 CH 2 Cl) 2 provided that R 1 is OH or SH.
10. Composé selon la revendication 9, caractérisé en ce qu'il est choisi parmi10. Compound according to claim 9, characterized in that it is chosen from
[[bis(chloro-2 éthyl)-1 amino]-3 hydroxy-2 propyl]-1 nitro- 2 imidazole,[[bis(2-chloroethyl)-1 amino]-3 2-hydroxypropyl]-1 nitro-2 imidazole,
[[bis(chloro-2 éthyl)-1 amino]-3 hydroxy-2 propyl]-1 nitro- 4 imidazole, [[bis(chloro-2 éthyl)-1 amino]-3 hydroxy-2 propyl]-1 nitro- 5 imidazole,
[[bis(chloro-2 éthyl -1 amino]-2 éthyl]-1 nitro-2 imidazole [[bis (chloro-2 éthyl) -1 amino]-2 éthyl]-1 nitro-4 imidazole [[bis(chloro-2 éthyl) -1 amino]-2 éthyl]-1 nitro-5 imidazole.[[bis(2-chloroethyl)-1 amino]-3 2-hydroxypropyl]-1 nitro-4 imidazole, [[bis(2-chloroethyl)-1 amino]-3 hydroxy-2-propyl]-1 nitro - 5 imidazole, [[bis(2-chloroethyl -1 amino]-2 ethyl]-1-2-nitro imidazole [[bis (2-chloro-ethyl) -1 amino]-2 ethyl]-1-4-nitro imidazole [[bis(chloro -2 ethyl) -1 amino]-2 ethyl]-1 nitro-5 imidazole.
11. Procédé de préparation d'un composé conforme à la formule (I) des revendications 5 à 8, caractérisé en ce que l'on fait réagir un composé de formule quand R1 = H et
quand R1 = OH ou SH
où X est tel que défini précédemment, avec un ester comportant le groupement N-(CHLORO-2 éthyl) N-nitroso carbamate, dans le DMF.11. Process for preparing a compound conforming to formula (I) of claims 5 to 8, characterized in that a compound of formula is reacted when R 1 = H and when R 1 = OH or SH where X is as defined previously, with an ester comprising the N-(2-CHLOROethyl) N-nitroso carbamate group, in DMF.
12. Procédé selon la revendication 11, caractérisé en ce que ledit ester est le trichloro-2,4,5 phényl N-(chloro-2 éthyl)N-nitrosocarbamate. 12. Method according to claim 11, characterized in that said ester is 2,4,5-trichlorophenyl N-(2-chloroethyl)N-nitrosocarbamate.
13. Procédé de préparation d'un composé de formule I où R1 est une moutarde à l'azote selon l'une des revendications 5, 6 et 9, 10, caractérisé en ce que - lorsque R1-H on fait réagir XH avec l'hydrure de sodium, le produit de la réaction étant mis à réagir avec13. Process for preparing a compound of formula I where R 1 is a nitrogen mustard according to one of claims 5, 6 and 9, 10, characterized in that - when R 1 -H, XH is reacted with sodium hydride, the reaction product being reacted with
dans le DMF
pour donner
avec R3, R4, R5 choisi notamment parmi H, CH2CH2Cl, -C6H4-N(CH2CH2Cl)2
- lorsque R1 = OH ou SHin the DMF to give with R 3 , R 4 , R 5 chosen in particular from H, CH 2 CH 2 Cl, -C 6 H 4 -N(CH 2 CH 2 Cl) 2 - when R 1 = OH or SH
1. on fait réagir XH avec
pour donner
1. we make XH react with to give
2. on fait réagir (a) avec pour
donner (b)
avec R6 et R7 choisis notamment parmi H, CH2CH2OH, -C6H4-N(CH2CH2OH)2 2. we react (a) with for give (b) with R 6 and R 7 chosen in particular from H, CH 2 CH 2 OH, -C 6 H 4 -N(CH 2 CH 2 OH) 2
3.(b)est mis en réaction avec Φ3P dans C Cl4 pour donner3.(b)is reacted with Φ 3 P in C Cl 4 to give
où R6' et R7' sont choisis notamment parmi H, CH2CH2Cl, -C6H4-N (CH2CH2Cl)2 where R 6 'and R 7 ' are chosen in particular from H, CH 2 CH 2 Cl, -C 6 H 4 -N (CH 2 CH 2 Cl) 2
14. Procédé selon la revendication 13, caractérisé en ce que R2, R4, R5, R6' et R7' sont d'une part tels que lorsque R1 = H . R3=R4=R5=CH2-CH2-Cl ou14. Method according to claim 13, characterized in that R 2 , R 4 , R 5 , R 6 'and R 7 ' are on the one hand such that when R 1 = H. R 3 =R 4 =R 5 =CH 2 -CH 2 -Cl or
. R3=R4=CH2CH2Cl et R5=H ou. R 3 =R 4 =CH 2 CH 2 Cl and R 5 =H or
. R3=CH2CH2Cl, R4=-C6H4-N(CH2CH2Cl)2 et R5=H et d'autre part, lorsque R1 = OH ou SH . R6' = H et R7' = CH2CH2Cl ou . R6' = H et R7' = C6H4-N(CH2CH2Cl)2 ou. R 3 =CH 2 CH 2 Cl, R 4 =-C 6 H 4 -N(CH 2 CH 2 Cl)2 and R 5 =H and on the other hand, when R 1 = OH or SH. R 6 ' = H and R 7 ' = CH 2 CH 2 Cl or . R 6 ' = H and R 7 ' = C 6 H 4 -N(CH 2 CH 2 Cl) 2 or
· R6' = R7' = CH2CH2Cl.
· R 6 ' = R 7 ' = CH 2 CH 2 Cl.
15. A titre de médicaments nouveaux, un composé conforme à l'une des revendications 1 à 10.15. As new drugs, a compound according to one of claims 1 to 10.
16. Compositions pharmaceutiques, caractérisées en ce qu'elles contiennent, outre un support pharmaceutiquement acceptable, un principe actif comprenant au moins un composé conforme à l'une des revendications 1 à 10.
16. Pharmaceutical compositions, characterized in that they contain, in addition to a pharmaceutically acceptable support, an active principle comprising at least one compound conforming to one of claims 1 to 10.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| FR8706241A FR2614890B1 (en) | 1987-05-04 | 1987-05-04 | COMPOUND RESULTING FROM THE COUPLING OF A CHEMOSENSITIZING STRUCTURE MOLECULE AND A CYTOTOXIC STRUCTURE MOLECULE, PREPARATION METHOD, MEDICAMENT APPLICATION AND PHARMACEUTICAL COMPOSITIONS CONTAINING THE SAME |
| FR8706241 | 1987-05-04 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| EP0358684A1 true EP0358684A1 (en) | 1990-03-21 |
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| EP19880904232 Ceased EP0358684A1 (en) | 1987-05-04 | 1988-05-03 | Anti-tumoral targetting agents, preparation thereof and applications |
Country Status (3)
| Country | Link |
|---|---|
| EP (1) | EP0358684A1 (en) |
| FR (1) | FR2614890B1 (en) |
| WO (1) | WO1988008840A1 (en) |
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| EP0700376A4 (en) * | 1993-05-25 | 1996-05-22 | Auckland Uniservices Ltd | Nitrobenzyl mustard quaternary salts and their use as hypoxia-selective cytotoxic agents |
| CN1270062A (en) * | 1999-04-08 | 2000-10-18 | 广州山河药业股份有限公司 | Glycobiazole metal salt as synergist for radiotherapy or chemicotherapy and its preparing process and application |
| US9056136B2 (en) * | 2006-10-06 | 2015-06-16 | Natural Pharmacia International, Inc. | Weakly basic 2-nitroimidazoles for the non-invasive detection of tissue hypoxia |
| KR20230161929A (en) * | 2021-03-30 | 2023-11-28 | 나믹스 가부시끼가이샤 | Curing catalyst, resin composition, encapsulant, adhesive and cured material |
| JPWO2022210190A1 (en) * | 2021-03-30 | 2022-10-06 |
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| JPS58188892A (en) * | 1982-04-26 | 1983-11-04 | Tetsuo Suami | Novel nitrosourea |
| FR2540491A1 (en) * | 1983-02-08 | 1984-08-10 | Centre Nat Rech Scient | NOVEL NITROSOUREES, PROCESS FOR THE PREPARATION THEREOF AND THERAPEUTIC APPLICATION THEREOF |
-
1987
- 1987-05-04 FR FR8706241A patent/FR2614890B1/en not_active Expired
-
1988
- 1988-05-03 WO PCT/FR1988/000213 patent/WO1988008840A1/en not_active Application Discontinuation
- 1988-05-03 EP EP19880904232 patent/EP0358684A1/en not_active Ceased
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| Title |
|---|
| See references of WO8808840A1 * |
Also Published As
| Publication number | Publication date |
|---|---|
| FR2614890B1 (en) | 1989-08-11 |
| FR2614890A1 (en) | 1988-11-10 |
| WO1988008840A1 (en) | 1988-11-17 |
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