MXPA01003006A - Novel n-(iminomethyl)amine derivatives, their preparation, their use as medicines and compositions containing them - Google Patents
Novel n-(iminomethyl)amine derivatives, their preparation, their use as medicines and compositions containing themInfo
- Publication number
- MXPA01003006A MXPA01003006A MXPA/A/2001/003006A MXPA01003006A MXPA01003006A MX PA01003006 A MXPA01003006 A MX PA01003006A MX PA01003006 A MXPA01003006 A MX PA01003006A MX PA01003006 A MXPA01003006 A MX PA01003006A
- Authority
- MX
- Mexico
- Prior art keywords
- amino
- radical
- phenyl
- carbon atoms
- linear
- Prior art date
Links
- 239000003814 drug Substances 0.000 title claims abstract description 12
- 229940079593 drugs Drugs 0.000 title abstract 2
- 239000000203 mixture Substances 0.000 title description 26
- 238000002360 preparation method Methods 0.000 title description 19
- -1 oxodiphenylamine Chemical compound 0.000 claims abstract description 232
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims abstract description 107
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims abstract description 102
- 125000000175 2-thienyl group Chemical group S1C([*])=C([H])C([H])=C1[H] 0.000 claims abstract description 57
- 150000001875 compounds Chemical class 0.000 claims abstract description 52
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims abstract description 42
- 125000001841 imino group Chemical group [H]N=* 0.000 claims abstract description 40
- 125000000325 methylidene group Chemical group [H]C([H])=* 0.000 claims abstract description 19
- DNSISZSEWVHGLH-UHFFFAOYSA-N Butyramide Chemical compound CCCC(N)=O DNSISZSEWVHGLH-UHFFFAOYSA-N 0.000 claims abstract description 8
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 6
- 125000004432 carbon atoms Chemical group C* 0.000 claims description 103
- 125000004435 hydrogen atoms Chemical group [H]* 0.000 claims description 102
- 150000003254 radicals Chemical class 0.000 claims description 71
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 70
- 125000000217 alkyl group Chemical group 0.000 claims description 61
- 150000003839 salts Chemical class 0.000 claims description 51
- 239000011780 sodium chloride Substances 0.000 claims description 51
- YTPLMLYBLZKORZ-UHFFFAOYSA-N thiophene Chemical compound C=1C=CSC=1 YTPLMLYBLZKORZ-UHFFFAOYSA-N 0.000 claims description 30
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 24
- 229910052736 halogen Inorganic materials 0.000 claims description 17
- 150000002367 halogens Chemical class 0.000 claims description 17
- GLUUGHFHXGJENI-UHFFFAOYSA-N piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 claims description 16
- 229910052739 hydrogen Inorganic materials 0.000 claims description 14
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 13
- 230000002401 inhibitory effect Effects 0.000 claims description 12
- 229910052760 oxygen Inorganic materials 0.000 claims description 12
- 239000001257 hydrogen Substances 0.000 claims description 10
- JUJWROOIHBZHMG-UHFFFAOYSA-N pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 10
- 229910052717 sulfur Inorganic materials 0.000 claims description 10
- 102000008299 Nitric Oxide Synthase Human genes 0.000 claims description 9
- 108010021487 Nitric Oxide Synthase Proteins 0.000 claims description 9
- 125000003545 alkoxy group Chemical group 0.000 claims description 9
- 230000003859 lipid peroxidation Effects 0.000 claims description 9
- 229910052757 nitrogen Inorganic materials 0.000 claims description 9
- BCIIMDOZSUCSEN-UHFFFAOYSA-N piperidin-4-amine Chemical compound NC1CCNCC1 BCIIMDOZSUCSEN-UHFFFAOYSA-N 0.000 claims description 9
- FQUYSHZXSKYCSY-UHFFFAOYSA-N 1,4-diazepane Chemical group C1CNCCNC1 FQUYSHZXSKYCSY-UHFFFAOYSA-N 0.000 claims description 8
- JEVCWSUVFOYBFI-UHFFFAOYSA-N Cyano radical Chemical compound N#[C] JEVCWSUVFOYBFI-UHFFFAOYSA-N 0.000 claims description 8
- 230000000694 effects Effects 0.000 claims description 8
- 125000004193 piperazinyl group Chemical group 0.000 claims description 8
- 125000000094 2-phenylethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])C([H])([H])* 0.000 claims description 7
- WCYWZMWISLQXQU-UHFFFAOYSA-N Methyl radical Chemical compound [CH3] WCYWZMWISLQXQU-UHFFFAOYSA-N 0.000 claims description 6
- 125000003342 alkenyl group Chemical group 0.000 claims description 6
- 125000004429 atoms Chemical group 0.000 claims description 6
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 6
- KXDHJXZQYSOELW-UHFFFAOYSA-M carbamate Chemical compound NC([O-])=O KXDHJXZQYSOELW-UHFFFAOYSA-M 0.000 claims description 6
- 239000004202 carbamide Substances 0.000 claims description 6
- YLQBMQCUIZJEEH-UHFFFAOYSA-N furane Chemical compound C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 6
- KAESVJOAVNADME-UHFFFAOYSA-N pyrrole Chemical compound C=1C=CNC=1 KAESVJOAVNADME-UHFFFAOYSA-N 0.000 claims description 6
- FERIUCNNQQJTOY-UHFFFAOYSA-M butyrate Chemical compound CCCC([O-])=O FERIUCNNQQJTOY-UHFFFAOYSA-M 0.000 claims description 5
- 238000004519 manufacturing process Methods 0.000 claims description 5
- 125000001820 oxy group Chemical group [*:1]O[*:2] 0.000 claims description 5
- NSMWYRLQHIXVAP-UHFFFAOYSA-N 2,5-dimethylpiperazine Chemical compound CC1CNC(C)CN1 NSMWYRLQHIXVAP-UHFFFAOYSA-N 0.000 claims description 4
- JOMNTHCQHJPVAZ-UHFFFAOYSA-N 2-methylpiperazine Chemical compound CC1CNCCN1 JOMNTHCQHJPVAZ-UHFFFAOYSA-N 0.000 claims description 4
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 4
- 125000005842 heteroatoms Chemical group 0.000 claims description 4
- 230000001681 protective Effects 0.000 claims description 4
- 125000001424 substituent group Chemical group 0.000 claims description 4
- REAJAFMJZGTZPE-UHFFFAOYSA-N N(C1=CC=CC=C1)C=1C=C(OCCCCC2=CC=C(C=C2)C2=C(SC=C2)C(N)=N)C=CC=1 Chemical compound N(C1=CC=CC=C1)C=1C=C(OCCCCC2=CC=C(C=C2)C2=C(SC=C2)C(N)=N)C=CC=1 REAJAFMJZGTZPE-UHFFFAOYSA-N 0.000 claims description 3
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 3
- 125000000623 heterocyclic group Chemical group 0.000 claims description 3
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 3
- 125000001054 5 membered carbocyclic group Chemical group 0.000 claims description 2
- 125000004008 6 membered carbocyclic group Chemical group 0.000 claims description 2
- 241001024304 Mino Species 0.000 claims description 2
- CFJPVMMDEBOCSE-UHFFFAOYSA-N S1C(=CC=C1)C(=N)NC1=C(C=CC=C1)CCCCNC1=CC=C(C=C1)NC1=CC=CC=C1 Chemical compound S1C(=CC=C1)C(=N)NC1=C(C=CC=C1)CCCCNC1=CC=C(C=C1)NC1=CC=CC=C1 CFJPVMMDEBOCSE-UHFFFAOYSA-N 0.000 claims description 2
- KXDAEFPNCMNJSK-UHFFFAOYSA-N benzamide Chemical compound NC(=O)C1=CC=CC=C1 KXDAEFPNCMNJSK-UHFFFAOYSA-N 0.000 claims description 2
- 239000004480 active ingredient Substances 0.000 claims 1
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 claims 1
- 125000004433 nitrogen atoms Chemical group N* 0.000 claims 1
- 125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 claims 1
- FZWLAAWBMGSTSO-UHFFFAOYSA-N thiazole Chemical compound C1=CSC=N1 FZWLAAWBMGSTSO-UHFFFAOYSA-N 0.000 claims 1
- UJOBWOGCFQCDNV-UHFFFAOYSA-N Carbazole Chemical compound C1=CC=C2C3=CC=CC=C3NC2=C1 UJOBWOGCFQCDNV-UHFFFAOYSA-N 0.000 abstract description 4
- PCNDJXKNXGMECE-UHFFFAOYSA-N Phenazine Chemical compound C1=CC=CC2=NC3=CC=CC=C3N=C21 PCNDJXKNXGMECE-UHFFFAOYSA-N 0.000 abstract description 2
- TZMSYXZUNZXBOL-UHFFFAOYSA-N Phenoxazine Chemical compound C1=CC=C2NC3=CC=CC=C3OC2=C1 TZMSYXZUNZXBOL-UHFFFAOYSA-N 0.000 abstract description 2
- HKOOXMFOFWEVGF-UHFFFAOYSA-N Phenylhydrazine Chemical compound NNC1=CC=CC=C1 HKOOXMFOFWEVGF-UHFFFAOYSA-N 0.000 abstract 1
- 210000002356 Skeleton Anatomy 0.000 abstract 1
- PNKUSGQVOMIXLU-UHFFFAOYSA-N methanoic acid amidine Chemical class NC=N PNKUSGQVOMIXLU-UHFFFAOYSA-N 0.000 abstract 1
- 239000000543 intermediate Substances 0.000 description 94
- XEKOWRVHYACXOJ-UHFFFAOYSA-N acetic acid ethyl ester Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 80
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 69
- YMWUJEATGCHHMB-UHFFFAOYSA-N methylene dichloride Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 66
- 238000010586 diagram Methods 0.000 description 65
- 238000002844 melting Methods 0.000 description 64
- 239000000243 solution Substances 0.000 description 58
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 55
- 239000007787 solid Substances 0.000 description 54
- 239000000047 product Substances 0.000 description 43
- 230000015572 biosynthetic process Effects 0.000 description 42
- WYURNTSHIVDZCO-UHFFFAOYSA-N tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 42
- 230000002194 synthesizing Effects 0.000 description 41
- 239000011541 reaction mixture Substances 0.000 description 37
- 238000003786 synthesis reaction Methods 0.000 description 37
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 34
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 33
- 150000001412 amines Chemical class 0.000 description 30
- HEMHJVSKTPXQMS-UHFFFAOYSA-M sodium hydroxide Inorganic materials [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 30
- 239000000843 powder Substances 0.000 description 28
- KFZMGEQAYNKOFK-UHFFFAOYSA-N iso-propanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 25
- 239000003480 eluent Substances 0.000 description 21
- 239000002904 solvent Substances 0.000 description 21
- VEXZGXHMUGYJMC-UHFFFAOYSA-N HCl Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 19
- 239000012074 organic phase Substances 0.000 description 19
- 238000003756 stirring Methods 0.000 description 19
- CSNNHWWHGAXBCP-UHFFFAOYSA-L mgso4 Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 18
- RTZKZFJDLAIYFH-UHFFFAOYSA-N diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 17
- KDLHZDBZIXYQEI-UHFFFAOYSA-N palladium Substances [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 17
- 238000007792 addition Methods 0.000 description 16
- 150000001409 amidines Chemical class 0.000 description 16
- 230000001603 reducing Effects 0.000 description 16
- 238000009833 condensation Methods 0.000 description 15
- 230000005494 condensation Effects 0.000 description 15
- 238000001704 evaporation Methods 0.000 description 14
- OKKJLVBELUTLKV-UHFFFAOYSA-N methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 14
- 239000002585 base Substances 0.000 description 13
- 238000001914 filtration Methods 0.000 description 13
- 229910052731 fluorine Inorganic materials 0.000 description 13
- 238000001035 drying Methods 0.000 description 12
- 239000000377 silicon dioxide Substances 0.000 description 12
- ZMANZCXQSJIPKH-UHFFFAOYSA-N triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 11
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Natural products NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 description 10
- 239000002253 acid Substances 0.000 description 10
- 238000006243 chemical reaction Methods 0.000 description 10
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 10
- 239000002244 precipitate Substances 0.000 description 10
- 150000001408 amides Chemical class 0.000 description 9
- 125000002490 anilino group Chemical group [H]N(*)C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 9
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 9
- 235000019341 magnesium sulphate Nutrition 0.000 description 9
- 239000000741 silica gel Substances 0.000 description 9
- 229910002027 silica gel Inorganic materials 0.000 description 9
- XBGNOMBPRQVJSR-UHFFFAOYSA-N 2-(4-nitrophenyl)butanoic acid Chemical compound CCC(C(O)=O)C1=CC=C([N+]([O-])=O)C=C1 XBGNOMBPRQVJSR-UHFFFAOYSA-N 0.000 description 8
- XKRFYHLGVUSROY-UHFFFAOYSA-N argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 8
- 239000012458 free base Substances 0.000 description 8
- OAKJQQAXSVQMHS-UHFFFAOYSA-N hydrazine Chemical compound NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 0.000 description 8
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 description 8
- IMNFDUFMRHMDMM-UHFFFAOYSA-N n-heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 8
- 238000010992 reflux Methods 0.000 description 8
- 150000007513 acids Chemical class 0.000 description 7
- 239000012300 argon atmosphere Substances 0.000 description 7
- 150000003857 carboxamides Chemical class 0.000 description 7
- 229910000027 potassium carbonate Inorganic materials 0.000 description 7
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Carbodicyclohexylimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 description 6
- ODKSFYDXXFIFQN-BYPYZUCNSA-N L-arginine Chemical compound OC(=O)[C@@H](N)CCCN=C(N)N ODKSFYDXXFIFQN-BYPYZUCNSA-N 0.000 description 6
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 6
- CSCPPACGZOOCGX-UHFFFAOYSA-N acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 6
- 150000001735 carboxylic acids Chemical class 0.000 description 6
- 239000003153 chemical reaction reagent Substances 0.000 description 6
- 238000010511 deprotection reaction Methods 0.000 description 6
- 239000000706 filtrate Substances 0.000 description 6
- 239000003921 oil Substances 0.000 description 6
- ATGUVEKSASEFFO-UHFFFAOYSA-N p-aminodiphenylamine Chemical compound C1=CC(N)=CC=C1NC1=CC=CC=C1 ATGUVEKSASEFFO-UHFFFAOYSA-N 0.000 description 6
- BZKBCQXYZZXSCO-UHFFFAOYSA-N sodium hydride Inorganic materials [H-].[Na+] BZKBCQXYZZXSCO-UHFFFAOYSA-N 0.000 description 6
- DTQVDTLACAAQTR-UHFFFAOYSA-N trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 6
- VWOJSRICSKDKAW-UHFFFAOYSA-N 1-(4-Nitrophenyl)piperazine Chemical compound C1=CC([N+](=O)[O-])=CC=C1N1CCNCC1 VWOJSRICSKDKAW-UHFFFAOYSA-N 0.000 description 5
- BXIQHVVAHDCWFM-UHFFFAOYSA-N 2-(4-aminophenyl)-N-(4-anilinophenyl)acetamide Chemical compound C1=CC(N)=CC=C1CC(=O)NC(C=C1)=CC=C1NC1=CC=CC=C1 BXIQHVVAHDCWFM-UHFFFAOYSA-N 0.000 description 5
- IOXOZOPLBFXYLM-UHFFFAOYSA-N 2-(4-nitrophenyl)ethanamine Chemical compound NCCC1=CC=C([N+]([O-])=O)C=C1 IOXOZOPLBFXYLM-UHFFFAOYSA-N 0.000 description 5
- PFKFTWBEEFSNDU-UHFFFAOYSA-N Carbonyldiimidazole Chemical compound C1=CN=CN1C(=O)N1C=CN=C1 PFKFTWBEEFSNDU-UHFFFAOYSA-N 0.000 description 5
- 229940118019 Malondialdehyde Drugs 0.000 description 5
- QVCHUOXTWNURMO-UHFFFAOYSA-N N-(4-anilinophenyl)-2-(4-nitrophenyl)acetamide Chemical compound C1=CC([N+](=O)[O-])=CC=C1CC(=O)NC(C=C1)=CC=C1NC1=CC=CC=C1 QVCHUOXTWNURMO-UHFFFAOYSA-N 0.000 description 5
- 150000001298 alcohols Chemical class 0.000 description 5
- 239000007864 aqueous solution Substances 0.000 description 5
- 125000006367 bivalent amino carbonyl group Chemical group [H]N([*:1])C([*:2])=O 0.000 description 5
- 235000013877 carbamide Nutrition 0.000 description 5
- 201000010099 disease Diseases 0.000 description 5
- 238000010438 heat treatment Methods 0.000 description 5
- MVFGXYPEQHIKIX-UHFFFAOYSA-M heptane;acetate Chemical compound CC([O-])=O.CCCCCCC MVFGXYPEQHIKIX-UHFFFAOYSA-M 0.000 description 5
- 239000012442 inert solvent Substances 0.000 description 5
- 239000003112 inhibitor Substances 0.000 description 5
- WSMYVTOQOOLQHP-UHFFFAOYSA-N malondialdehyde Chemical compound O=CCC=O WSMYVTOQOOLQHP-UHFFFAOYSA-N 0.000 description 5
- 238000000034 method Methods 0.000 description 5
- PMZURENOXWZQFD-UHFFFAOYSA-L na2so4 Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 5
- 235000019198 oils Nutrition 0.000 description 5
- 230000002829 reduced Effects 0.000 description 5
- 239000011734 sodium Substances 0.000 description 5
- 239000000126 substance Substances 0.000 description 5
- NPZTUJOABDZTLV-UHFFFAOYSA-N 1,2-dihydrobenzotriazol-4-one Chemical compound O=C1C=CC=C2NNN=C12 NPZTUJOABDZTLV-UHFFFAOYSA-N 0.000 description 4
- UIIMBOGNXHQVGW-UHFFFAOYSA-M NaHCO3 Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 4
- 241000700159 Rattus Species 0.000 description 4
- 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 4
- UCPYLLCMEDAXFR-UHFFFAOYSA-N Triphosgene Chemical compound ClC(Cl)(Cl)OC(=O)OC(Cl)(Cl)Cl UCPYLLCMEDAXFR-UHFFFAOYSA-N 0.000 description 4
- DLFVBJFMPXGRIB-UHFFFAOYSA-N acetamide Chemical compound CC(N)=O DLFVBJFMPXGRIB-UHFFFAOYSA-N 0.000 description 4
- 150000001299 aldehydes Chemical class 0.000 description 4
- 125000004414 alkyl thio group Chemical group 0.000 description 4
- 229910052786 argon Inorganic materials 0.000 description 4
- 125000003118 aryl group Chemical group 0.000 description 4
- 239000000460 chlorine Substances 0.000 description 4
- KCXVZYZYPLLWCC-UHFFFAOYSA-N edta Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 description 4
- 150000002170 ethers Chemical class 0.000 description 4
- 150000004820 halides Chemical class 0.000 description 4
- UFHFLCQGNIYNRP-UHFFFAOYSA-N hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 4
- WMFOQBRAJBCJND-UHFFFAOYSA-M lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 4
- 238000005192 partition Methods 0.000 description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 4
- 229910052938 sodium sulfate Inorganic materials 0.000 description 4
- 235000011152 sodium sulphate Nutrition 0.000 description 4
- LSNNMFCWUKXFEE-UHFFFAOYSA-N sulfonic acid Chemical compound OS(O)=O LSNNMFCWUKXFEE-UHFFFAOYSA-N 0.000 description 4
- YBADLXQNJCMBKR-UHFFFAOYSA-N (4-nitrophenyl)acetic acid Chemical compound OC(=O)CC1=CC=C([N+]([O-])=O)C=C1 YBADLXQNJCMBKR-UHFFFAOYSA-N 0.000 description 3
- VYOKOQDVBBWPKO-UHFFFAOYSA-N 1-nitro-9H-carbazole Chemical class N1C2=CC=CC=C2C2=C1C([N+](=O)[O-])=CC=C2 VYOKOQDVBBWPKO-UHFFFAOYSA-N 0.000 description 3
- 238000005160 1H NMR spectroscopy Methods 0.000 description 3
- 101700067048 CDC13 Proteins 0.000 description 3
- 210000003710 Cerebral Cortex Anatomy 0.000 description 3
- ADFXKUOMJKEIND-UHFFFAOYSA-N Dicyclohexylurea Chemical compound C1CCCCC1NC(=O)NC1CCCCC1 ADFXKUOMJKEIND-UHFFFAOYSA-N 0.000 description 3
- JKMHFZQWWAIEOD-UHFFFAOYSA-N HEPES Chemical compound OCC[NH+]1CCN(CCS([O-])(=O)=O)CC1 JKMHFZQWWAIEOD-UHFFFAOYSA-N 0.000 description 3
- 239000007995 HEPES buffer Substances 0.000 description 3
- 235000014852 L-arginine Nutrition 0.000 description 3
- QARBMVPHQWIHKH-UHFFFAOYSA-N Methanesulfonyl chloride Chemical compound CS(Cl)(=O)=O QARBMVPHQWIHKH-UHFFFAOYSA-N 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-N acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- 125000003277 amino group Chemical group 0.000 description 3
- 230000000875 corresponding Effects 0.000 description 3
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 description 3
- 239000006260 foam Substances 0.000 description 3
- PEDCQBHIVMGVHV-UHFFFAOYSA-N glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 3
- VLKZOEOYAKHREP-UHFFFAOYSA-N hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 3
- 239000007788 liquid Substances 0.000 description 3
- 239000012299 nitrogen atmosphere Substances 0.000 description 3
- 229910052763 palladium Inorganic materials 0.000 description 3
- 238000010647 peptide synthesis reaction Methods 0.000 description 3
- 150000002990 phenothiazines Chemical class 0.000 description 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- OZAIFHULBGXAKX-UHFFFAOYSA-N precursor Substances N#CC(C)(C)N=NC(C)(C)C#N OZAIFHULBGXAKX-UHFFFAOYSA-N 0.000 description 3
- 150000003141 primary amines Chemical class 0.000 description 3
- 125000006239 protecting group Chemical group 0.000 description 3
- 239000012047 saturated solution Substances 0.000 description 3
- PXIPVTKHYLBLMZ-UHFFFAOYSA-N sodium azide Chemical compound [Na+].[N-]=[N+]=[N-] PXIPVTKHYLBLMZ-UHFFFAOYSA-N 0.000 description 3
- 241000894007 species Species 0.000 description 3
- 229910001220 stainless steel Inorganic materials 0.000 description 3
- 239000010935 stainless steel Substances 0.000 description 3
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Abstract
The invention concerns novel N-(iminomethyl)amine derivatives comprising in their skeleton the aminophenylamine, oxodiphenylamine, carbazole, phenazine, phenoxazine or oxodiphenyl motif, their use as medicines and pharmaceutical compositions containing them. The invention concerns in particular the following compounds:-4-{[2-thienyl (imino) methyl]amino}-N- [2-(phenylamino) phenyl]- benzenebutanamide;-4-{[2- thienyl (imino) methyl]amino}- N-[4-(phenylamino) phenyl]- benzenebutanamide;-N'-[4- (10H- phenothiazin - 2-yloxy) phenyl]- 2-thiophenecarboximidamide;-4-(4-{[amino (2-thienyl) methylidene]amino}phenyl) -N-(10H- phenothiazin- 3-ylH) butanamide;-3-[(3-{[amino (2-thienyl) methylidene]amino}-benzyl) amino]-N- (4-anilinophenyl) propanamide;-N'-(4-{2- [(10H-phenothiazin- 3-ylmethyl) amino]ethyl}phenyl- 2-thiophene carboximidamide.
Description
New derivatives of N- (iminomethyl) amines, their preparation, their use as medicaments and pharmaceutical compositions containing them
Description of the Invention A subject of the present invention are the novel N- (iminomethyl) amines derivatives which contain the unit aminodiphenylamine, oxodiphenylamine, carbazole, phenazine, phenothiazine, phenoxazine or oxodiphenyl in their backbone. These derivatives have an inhibitory activity on NO synthase enzymes that produce NO nitrogen monoxide and / or an activity that traps species that react with oxygen (ROS). The invention relates to derivatives corresponding to the general formula (I) defined below, their methods of preparation, the pharmaceutical preparations containing them and their use for therapeutic purposes, in particular their use as inhibitors of NO-synthase and selective traps. or non-selective for species that react with oxygen. Given the potential role of NO and ROS in physiology, the new described derivatives corresponding to the general formula (I) could produce beneficial or favorable effects in the treatment of
Ref: 128163 pathologies where these chemical species are involved. In particular: • Proliferative and inflammatory diseases such as for example atherosclerosis, pulmonary hypertension, respiratory distress, glomerulonephritis, portal hypertension, psoriasis, osteoarthritis and rheumatoid arthritis, fibrosis, angiogenesis, amyloidosis, inflammations of the gastro-intestinal system (ulcerative or non-ulcerative colitis) , Crohn's disease), diarrhea. • Diseases that affect the pulmonary system and respiratory tract (asthma, sinusitis, rhinitis). Cardio-vascular and cerebral-vascular diseases, which include, for example, migraine, arterial hypertension, septic shock, ischemia or hemorrhage, cardiac or cerebral infarcts, ischemia and thrombosis. • Central or peripheral nervous system disorders such as, for example, neurodegenerative diseases, where in particular cerebral infarcts, sub-arachnoid hemorrhage, aging, senile dementias including Alzheimer's disease, Huntington's disease, Parkinson's disease, Creutzfeld Jacob's disease can be mentioned. and petrel diseases, amyotrophic lateral sclerosis; ocular neuropathies such as glaucoma but also pain, brain and bone marrow traumas, addiction to opiates, alcohol and addictive substances, cognitive diseases, encephalopathies, encephalopathies of viral or toxic origin. • Skeletal muscle and neuromuscular joint diseases (myopathy, miosis) as well as skin diseases. • Waterfalls. • Organ transplants. • Autoimmune and viral diseases such as lupus, AIDS, parasitic and viral infections, diabetes and its complications, multiple sclerosis. • Cancer. • Neurological diseases associated with poisoning (poisoning with cadmium, inhalation of n-hexane, pesticides, herbicides), associated with treatments (radiotherapy) or diseases of genetic origin (Wilson's disease). • All pathologies characterized by an excessive production of NO and / or ROS dysfunction. In all these pathologies, there is experimental evidence demonstrating the involvement of NO or ROS (J. Med. Chem. (1995) 38, 4343-4362; FreeJ.ac.ic. Bi. Med. (1996) 20, 675- 705; Th e Neurosci en ti st (1997) 3, 327-333). In addition, in previous patents, the inventors have already described NO Sintase inhibitors and their use (US Patent 5,081,148; 5,360,925) and more recently the combination of these inhibitors with products having antioxidant or antiradical properties (PCT Patent Application WO / 09653). Other derivatives of amidines or, more recently, derivatives of aminopyridines have also been described in Requests not yet published. These derivatives of amidines or aminopyridines have the characteristic of being both inhibitors of NO Synthase and inhibitors of ROS. A subject of the present invention are the new amidine derivatives, their preparation and their use in therapeutics. The compounds of the invention correspond to the general formula (I):
a >
wherein F represents a bond or a phenylene radical which may include, in addition to the two chains already represented in the general formula (I), up to two chosen substituents of a hydrogen atom, a halogen, an OH group, and a radical linear or branched alkyl or alkoxy having from 1 to 6 carbon atoms; A represents a
radical wherein R.sup.lf R.sup.2, R.sup.3, R.sup.4, R.sup.5 represent, independently, a hydrogen atom, a halogen, the OH group, a linear or branched alkyl or alkoxy radical having from 1 to 6 carbon atoms, or a cyano radical , nitro or NR6R7, R6 and R7 independently represent a hydrogen atom, the OH group, a linear or branched alkyl or alkoxy radical having 1 to 6 carbon atoms, or also a group -COR8, R8 represents an atom of hydrogen, the OH group, a linear or branched alkyl or alkoxy radical having 1 to 6 carbon atoms, or NR9R10, R9 and R10 independently represent a hydrogen atom, the OH group or a linear or branched alkyl radical having 1 to 6 carbon atoms, Rn represents a hydrogen atom, the OH group, a linear or branched alkyl or alkoxy radical having 1 to 6 carbon atoms, or a radical -COR12, and R12 represents an atom of hydrogen, the OH group, a linear or branched alkyl radical you have of
1 to 6 carbon atoms, or a
radical wherein R 1 t R 2, R 3, R 4, R 5 represent, independently, a hydrogen atom, a halogen, the OH group, a linear or branched alkyl or alkoxy radical having from 1 to 6 carbon atoms, or a radical cyano, nitro or NR6R7, R6 and R7 independently represent a hydrogen atom, the OH group, a linear or branched alkyl or alkoxy radical having from 1 to 6 carbon atoms, or also a group -COR8, R8 represents a hydrogen atom, the OH group, a linear or branched alkyl or alkoxy radical having 1 to 6 carbon atoms, or NR9R10, Rg and R10 independently represent a hydrogen atom, the OH group or a linear alkyl radical
0 branched having 1 to 6 carbon atoms, B represents -CH-N02, a linear or branched alkyl radical having from 1 to 6 carbon atoms, carbocyclic aryl or heterocyclic with 5 or 6 members containing from 1 to 4 selected heteroatoms of O, S, N and in particular the thiophene, furan, pyrrole or thiazole radicals, the aryl radical is optionally substituted by one or more groups selected from linear or branched alkyl, alkenyl or alkoxy radicals having
1 to 6 carbon atoms, or B represents a radical NR13R14, in which R13 and R14 represent, independently, a hydrogen atom
Or a linear or branched alkyl radical having
1 to 6 carbon atoms or a cyano or nitro radical, or Ri3 and Ri4 form with the nitrogen atom a non-aromatic heterocycle with five to six members, the elements of the chain are chosen from a group consisting of -CH2-, - NH-, -O- or -S-; W does not exist or represents a bond, or O, S or NR15, in which R15 represents a hydrogen atom or a linear or branched alkyl radical having from 1 to 6 carbon atoms;
X represents a bond or a radical (CH2) k-NR16-, -0-, -S-, -CO-, -NR16-C0-, -C0-NR16-, -0-C0-, -C0-0- , -NR16-C0-0-, -NR16-CO-NR17-, k represents 0 or 1; Y represents a bond or radical selected from the radicals - (CH2) m-, - (CH2) m-0- (CH2) n-, - (CH2) mS- (CH2) n-, - (CH2) m- NR18- (CH2) n-, - (CH2) m-NR18-CO- (CH2) n-, - (CH2) m -CO-NR18- (CH2) n-, - (CH2) mQ- (CH2) n - Q represents radicals piperazine, homopiperazine, 2-methylpiperazine, 2,5-dimethyl-piperazine, 4-oxypiperidine or 4-aminopiperidine, myn are integers from 0 to 6; Ri6f Ri and R? S independently represent a hydrogen atom or a linear or branched alkyl radical having from 1 to 6 carbon atoms; or are salts of the products mentioned previously. By linear or branched alkyl having from 1 to 6 carbon atoms, the methyl radicals are indicated in particularethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl and tert-butyl, pentyl, neopentyl, isopentyl, hexyl, isohexyl. By linear or branched alkoxy having from 1 to 6 carbon atoms, the alkyl radical of which the meaning indicated above is indicated is indicated. Finally, fluorine, chlorine, bromine or iodine atoms are indicated by halogen. Preferably, the compounds according to the invention are the compounds of general formula (I) such that: A represents a
radical in which R.sup.lf R.sup.2, R.sup.3, R.sup.4, R.sup.5 represent, independently, a hydrogen atom, the OH group or a linear or branched alkyl or alkoxy radical having from 1 to 6 carbon atoms, Ru represents a hydrogen atom or a linear or branched alkyl radical having from 1 to 6 carbon atoms, or a
radical wherein R 1 R2, R 3, R 4, R 5 represent, independently, a hydrogen atom, the OH group or a linear or branched alkyl or alkoxy radical having from 1 to 6 carbon atoms; B represents a 5- or 6-membered carbocyclic or heterocyclic aryl radical containing from 1 to 4 heteroatoms selected from 0, S, N and in particular the thiophene, furan, pyrrole or thiazole radicals, the aryl radical is optionally substituted by one or more selected groups of linear or branched alkyl, alkenyl or alkoxy radicals having from 1 to 6 carbon atoms; W does not exist or represents a bond, S or NR15, in which R15 represents a hydrogen atom or a linear or branched alkyl radical having from 1 to 6 carbon atoms; X represents a bond or a radical (CH2) k-NR16-, -O-, -S-, -CO-, -NR16-C0-, -C0-NR16-, -0-C0-, -C0-0- , -NR16-C0-0-, -NR16-CO-NR17- k represents 0 or 1; Y represents a bond or radical selected from the radicals - (CH2) m-, - (CH2) m-0- (CH2) n-, - (CH2) mS- (CH2) n-, - (CH2) m- NR18- (CH2) n-, - (CH2) m-NR18-CO- (CH2) n-, - (CH2) m-CO-NR18- (CH2) n-, - (CH2) ffi-Q- (CH2 ) n-, Q represents piperazine, homopiperazine, 2-methylpiperazine, 2,5-dimethoxypiper azine, 4-oxypiperidine or 4-aminopiperidine, myn are integers from 0 to 6; or are salts of the products mentioned previously. More preferably, the compounds according to the invention are compounds of the general formula (I) such that: A represents a
radical in which R.sup.lf R.sup.2, R.sup.3, R.sup.4 and R.sup.5 represent, independently, a hydrogen atom, the OH group or a linear or branched alkyl or alkoxy radical having from 1 to 6 carbon atoms, R:? represents a hydrogen atom or a methyl radical, or an R, R u. X °? I radical in which Rl R2, R3, R4, R5 represent, independently, a hydrogen atom, the OH group
Or a linear or branched alkyl or alkoxy radical having from 1 to 6 carbon atoms; B represents one of the phenyl, thiophene, furan, pyrrole or thiazole radicals optionally substituted by one or more groups chosen from linear or branched alkyl, alkenyl or alkoxy radicals having
1 to 6 carbon atoms; W does not exist or represents a bond, S or NR1S, in which R15 represents a hydrogen atom or a linear or branched alkyl radical having from 1 to 6 carbon atoms; X represents a bond or radical (CH2) k-NR16-, -O-, -S-, -CO-, -NR16-C0-, -CO-NR16-, -O-CO-, -CO-0- , -NR16-CO-0-, -NR16-CO-NR17-, k represents 0 or 1; Y represents a bond or radical selected from the radicals - (CH2) m-, - (CH2) m-0- (CH2) n-, - (CH2) mS- (CH2) n-, - (CH2) ffi- NR18- (CH2) n-, - (CH2) m-NR18-CO- (CH2) n-, - (CH2) m-C0-NR18- (CH2) n-, - (CH2) ffi-Q- (CH2) ) n-, Q represents piperazine, homopiperazine, 2-methyl-piperazine, 2,5-dimethylopiperazine, 4-oxypiperidine or 4-aminopiperidine, m and n are integers from 0 to 6;
or are salts of the products mentioned previously. Even more preferably, the compounds according to the invention are compounds of general formula (I) such that: A represents a
radical wherein R 1 R2, R 3, R 4, R 5 represent, independently, a hydrogen atom or a methyl radical, Ru represents a hydrogen atom or a methyl radical; B represents the thiophene radical; W does not exist, represents a simple link or S; X represents a bond or represents a radical - (CH2) K-NR16-, -O-, -S-, -CO-, -NR16-CO-, -CO-NR16-, -0-C0-, -CO- 0-, -NR16-C0-0-, -NR16-CO-NR17-; k represents 0 or 1; Y represents a bond or radical selected from the radicals - (CH2) m-, - (CH2) ffi-0- (CH2) n-, - (CH2) mS- (CH2) n, - (CH2) m-NR18 - (CH2) n-, - (CH2) ffi-NR18-CO- (CH2) n-, - (CH2) n-CO-NR18- (CH2) n-, - (CH2) mQ- (CH2) n- , Q represents piperazine, m and n are integers between 0 and 6; R16, R17 and R18 represent a hydrogen atom; or are salts of the products mentioned previously. Particularly preferred are the following compounds described in the examples: -N- [4 (f-enylamino) phenyl] -2-thiofcarboxy-idamide;
-4-. { [2-thienyl (imino) methyl] amino} -N- [4 - (f -arylamino) phenyl] -be ncenacet amide; -. { 4-. { [2-thienyl (imino) methyl] amino} phenoxy } -N- [4- (f-enylamino) phenyl] -acetamide; -4-. { [2-thienyl (imino) methyl] amino} -N- [2- (f-enylamino) phenyl] -benzenebutanamide; -4- . { [2-thienyl (imino) methyl] amino} -N- [4 - (f-phenylamino) phenyl] -benzenebutanamide; -4-. { [2-thienyl (imino) methyl] amino} -N- [4- (4-methoxy-phenylamino) phenyl] -benzenebutanamide; -2-. { 4-. { [2-thienyl (imino) methyl] amino} f} ethyl [4- (phenylamino) phenyl] -carbamate; -N- { 2-. { 4-. { [2-thienyl (imino) methyl] amino} phenyl } ethyl} - '- [4- (f-enylamino) phenyl] -urea; -4-. { 4-. { [2-thienyl (imino) methyl] amino} phenyl } -N- [4- (f-enylamino) phenyl] -1-piperazine-acetylamide; -l- { [(4-f-enylamino) f -arylamino] carbonyl} -4- . { 4- . { [2-t-enyl (imino) methyl] amino} f} -piperazine; -4-. { [2-thienyl (imino) methyl] amino} -N- [4 - (f-enylamino) phenyl] -benzenebutanamine; -3-. { [2-thienyl (imino) methyl] amino} -N- [4- (phenylamino) phenyl] -benzenepropanamine; -4- (4- { [Amino (2-thienyl) methylidene] amino.}. Phenyl) -N- [2- (4-toluidino) phenyl] butanamide; -4-anilinophenyl-4- (4- { [Amino (2-thienyl) ethylidene] amino.} - phenyl) butanoate; -4- (4- { [Amino (2-thienyl) methylidene] amino.}. Phenyl) -N- [2- (4-toluidino) phenyl] butanamide; -N'-. { 4- [4- (3-anilinophenoxy) butyl] phenyl} -2-thiophenecarboximidamide; - '- (9H-carbazol-3-yl) -2-thiophenecarboximidamide; -4- (4- { [Amino (2-thienyl) methylidene] amino} phenyl) -N- (9 I-carbazol-3-yl) butanamide; -N '- [4- (10'i-phenothiazin-2-yloxy) phenyl] -2-thiophenecarboximidamide; -N'-. { 4- (10-methyl-10 tf-phenothiazin-2-yl) oxy] phenyl} -2-thiophenecarboximidamide; -4- (4- { [Amino (2-thienyl) methylidene] mino} phenyl) -N- (lOi? - phethiazin-3-yl) butanamide; -N '- (4- { 4- [2- (10ff-phenothiazin-2-yloxy) ethyl] -l-piperazinyl}. Phenyl) -2-thiophenecarboximidamide; -4- (4- { [Amino (2-thienyl) methylidene] amino.}. Phenyl) -N- [4- (4-toluidino) phenyl] butanamide; -3-anilinophenyl 4- (4- { [Amino (2-thienyl) methylidene] amino.} - phenyl) butanoate; -2- (4- { [Amino (2-thienyl) methylidene] amino} phenyl) -N- [2- (9-carbazol-4-yloxy) ethyl] acetamide; -N- (4- { [Amino (2-thienyl) methylidene] amino.}. Phenyl) -2-anilinobenzamide; -N- (4- { [Amino (2-thienyl) methylidene] amino.}. Phenethyl) -2- (2,3-dimethylamino) benzamide; -N '-. { 4- [4- (2-anilinob.enzoyl) -1-piperazinyl] phenyl} -2 -thiophenecarboximidamide; -N '- (4- { 4- [2- (2, 3-dimethylanilino) benzoyl] -l-piperazinyl} phenyl) -2-thiophenecarboximidamide; -4- (4- { [Amino (2-thienyl) methylidene] amino} phenyl) -N-t 4-phenoxyphenyl) butanamide; -N- (4- { [Amino (2-thienyl) methylidene] amino.}. Phenethyl) -4- (4-hydroxyphenoxy) benzamide; -N- [2- (9JÍ-carbazol-4-yloxy) ethyl] -2-thiophenecarboximidamide; -N- [3- (9H-carbazol-4-yloxy) propyl] -2-thiophenecarboximidamide; -N- { 4- [4- (1 OH-phenothiazin-2-yloxy) butyl] phenyl] -2-thiophenecarboximidamide;
-3- [(3- { [Amino (2-thienyl) methylidene] amino.}. -benzyl) amino] -N- (4-anilinylphenyl) propanamide; -N '- (4 - {2 - [(10H-f-enothiazin-3-ylmethyl) amino] ethyl} phenyl) -2 -thiofloboximidamide; -N- (4- { [Amino (2-thienyl) methylidene] amino.}. Phenethyl) -2-methoxy-IOH-f enotiaz i n-1 -carboxamide; -N '- [4- (2-. {[[(2-methoxy-1 OH-f-enotiazin-1-yl) methyl] amino} ethyl) phenyl] -2-thiofcarboximidamide; N '-. { 4- [(10 H -phenothiazin-2-yloxy) methyl] phenyl} -2-thiof, carboboximidamide; or its salts. Among the exemplified compounds, the following compounds are particularly preferred: { 4-. { (2-thienyl (imino) methyl] amino} phenoxy] -N- [4- (f-enylamino) phenyl] -acetamide; -4-. {(2-thienyl (imino (methyl) amino} - N- [2 - (f-enylamino) phenyl] -benzenebutanamide; -4- { [2-thienyl (imino) methyl] amino.} - N - [4 - (f -arylamino) phenyl] -benzenebutanamide; -2- {4.4 { (2-thienyl (imino) methyl] amino.}. Phenyl.}. -ethyl [4- (f-enylamino) phenyl] -carbamate; -4-. {4- {(2-thienyl (imino) methyl] amino} phenyl.} - N - [4- (f-enylamino) phenyl] -1-piperazine-acetylamide; -3-. {(2-thienyl (imino) methyl] amino.}. - N- [4 - (f -ylamino) phenyl] -benzenepropanamide;
-4-. { 4-. { [amino (2-thienyl (methylidene) amino.} f-enyl-N- [2- (4-toluidino) phenyl] butanamide; -N'-. {4- [4- (3-anilinophenoxy) butyl] phenyl .} -2-thiofcarboximomidamide; -4- (4- { [Amino (2-thienyl) methylidene] amino.}. Phenyl) -N- (9H-carbazol-3-yl) butanamide; -N ' - [4- (10 H -phenothiazin-2-yloxy) phenyl] -2-thiofcarboximidamide; -4- (4- { [Amino (2-thienyl) methylidene] amino.} Phenyl) -N- (10H -phenothiazin-3-yl) butanamide; -N '- (4-. {4- [2- (lOH-f-enothiazin-2-yloxy] ethyl] -1-piperazinyl}. phenyl) -2 -thiofloboximidamide; -4- (4- { [Amino (2-thienyl) methylidene] amino.}. Phenyl) -N- (4-f enoxyphenyl) butanamide; -3- [(3- { [Amino ( 2-thienyl) methylidene] amino.}. - benzyl) amino] -N- (4-anilino-phenyl) -propanamide; - N '- (4-. {2- 2- [(10H-phenothiazin-3-yl-methyl) amino) ] ethyl.} phenyl) -2-thiofcarboximidamide; -N- (4- { [amino (2-thienyl) met i 1 iden] amino.}. phenethyl) -2-methoxy-1 OH- f enotiaz in-1 -carboxamide; or its salts. The following compounds are more particularly preferred: -4-. { [2-thienyl (imino) methyl] amino} -N- [2- (f eni lamino) phenyl] -benzenebutanamide;
-4-. { [2-thienyl (imino) methyl] amino} -N- [4- (phenylamino) phenyl] -benzenebutanamide; _ N '- [4- (10 H -phenothiazin-2-yloxy) phenyl] -2-thiophenecarboximidamide; -4- (4- { [Amino (2-thieni1) methylidene] amino} phenyl) -N- (10H-phenothiazin-3-yl) butanamide; -3- [(3- { [Amino (2-thienyl) methylidene] amino.}. -benzyl) amino] -N- (4-anilinophenyl) propanamide; -N '- (4- {2 - [(10H-phenothiazin-3-ylmethyl) amino] ethyl} phenyl) -2-thiophenecarboximidamide; or its salts. In a general manner, compounds of general formula (I) in which X represents a bond or one of the radicals -O-, CH2-NR16-, -NR16-CO- or -NR16-CO-0- and Y represents one of the radicals - (CH2) m- or - (CH2) m-NR18- (CH2) n- which will be preferred. In certain cases, the compounds according to the present invention may contain asymmetric carbon atoms. As a result, the compounds according to the present invention have two possible enantiomeric forms, i.e. "R" and "S" configurations. The present invention includes the two enantiomeric forms and all combinations of these forms, which include the racemic mixtures "RS". In an effort to simplify the matter, when the specific configuration in the structural formula is not indicated, it should be understood that the two enantiomeric forms and their mixtures are represented. The invention also relates, as new industrial products, to the synthesis of intermediates of general formula (IS), useful for the preparation of products of general formula (I) defined above,
A-X-Y-f-T (IS) general formula (IS) in which A represents a
radical wherein R 1 R2, R 3, R 4, R 5 represent, independently, a hydrogen atom, a halogen, the OH group, a linear or branched alkyl or alkoxy radical having from 1 to 6 carbon atoms, or a cyano radical , nitro or NR6R7, R6 and R7 independently represent a hydrogen atom, the OH group, a linear or branched alkyl-1 alkyl or alkoxy having from 1 to 6 carbon atoms, or also a group -COR8, R8 represents , a hydrogen atom, the OH group, a linear or branched alkyl or alkoxy radical having 1 to 6 carbon atoms, or NR9R10, R9 and R10 independently represent a hydrogen atom, the OH group or an alkyl radical linear
0 branched having 1 to 6 carbon atoms, RX1 represents a hydrogen atom, the OH group, a linear or branched alkyl or alkoxy radical having 1 to 6 carbon atoms, or a radical -COR12, and R12 represents a hydrogen atom, the OH group, a linear or branched alkyl radical having
1 to 6 carbon atoms, or a
radical in which R? R2, R3, R4, R5 represent, independently, a hydrogen atom, a halogen, the OH group, a linear or branched alkyl or alkoxy radical having 1 to 6 carbon atoms, or a cyano, nitro or NR6R7 radical , R6 and R7 represent, independently, a hydrogen atom, the OH group, a linear or branched alkyl or alkoxy radical having from 1 to 6 carbon atoms, or also a group -COR8, R8 represents a hydrogen atom, the OH group, a linear or branched alkyl or alkoxy radical which has from 1 to 6 carbon atoms, or NR9R10, R9 and R10 represent, independently, a hydrogen atom, the OH group or a linear or branched alkyl radical having from 1 to 6 carbon atoms, W does not exist, or represents a bond, or O, S or NR15, in which R15 represents a hydrogen atom or a linear or branched alkyl radical having from 1 to 6 carbon atoms; X represents a bond or a radical (CH2) k-NR16-, -0-, -S-, -CO-, -NR16-C0-, -CO-NR16-, -0-C0-, -C0-0- , -NR16-C0-0- or -NR16-CO-NR17-, k represents 0 or 1; Y represents a bond or radical selected from the radicals - (CH2) m-, - (CH2) m-0- (CH2) n-, - (CH2) mS- (CH2) n-, - (CH2) m- NR18- (CH2) n-, - (CH2) m-NR18-CO- (CH2) n-, - (CH2) ffi-C0-NR18- (CH2) n-, - (CH2) ra-Q- (CH2) ) n-, Q represents piperazine, homopiperazine, 2-me t-ylpiperazine, 2, 5 -dime ti lpiper azine, 4-oxypiperidine or 4-aminopiperidine, m * and n are integers from 0 to 6; F represents a bond or a phenylene radical which could comprise, in addition to the two chains already represented in the general formula (I), up to two chosen substituents of a hydrogen atom, a halogen, an OH group, and an alkyl or alkoxy radical linear or branched having 1 to 6 carbon atoms; T represents N02 or NH2; Ri6 Ri7 and Ri8 represent, independently, a hydrogen atom or a linear or branched alkyl radical having from 1 to 6 carbon atoms. The invention also relates, as new industrial products, to the synthesis of intermediates of general formula (IS '), useful for the preparation of general formula (I) in which X represents the radical
-NR16-CO- and Y represents the radical - (CH2) m-NR18- (CH2) n-,
< IS ') general formula (IS') in which A represents a
radical wherein R1 f R2, R3, R4 and R5 represent, independently, a hydrogen atom, a halogen, the OH group, a linear or branched alkyl or alkoxy radical having from 1 to 6 carbon atoms, or a radical cyano, nitro or NR6R7, R6 and R7 independently represent a hydrogen atom, the OH group, a linear or branched alkyl or alkoxy radical having from 1 to 6 carbon atoms, or also a group -C0R8, R8 represents a hydrogen atom, the OH group, a linear or branched alkyl or alkoxy radical having from 1 to 6 carbon atoms, or NR9R10, R9 and R10 independently represent a hydrogen atom, the OH group, a linear alkyl radical or branched having 1 to 6 carbon atoms, R1X represents a hydrogen atom, the OH group, a linear or branched alkyl or alkoxy radical having 1 to 6 carbon atoms, or else a radical -COR12, and R12 represents a hydrogen atom, the OH group, a linear alkyl radical or branched that has 1 to 6 carbon atoms, or a
radical wherein R 1 R2, R 3, R 4, R 5 represent, independently, a hydrogen atom, a halogen, the OH group, a linear or branched alkyl or alkoxy radical having from 1 to 6 carbon atoms, or a cyano radical , nitro or NR6R7, R6 and R7 independently represent a hydrogen atom, the OH group, a linear or branched alkyl or alkoxy radical having 1 to 6 carbon atoms, or also a group -COR8, R8 represents an atom of hydrogen, the OH group, a linear or branched alkyl or alkoxy radical having 1 to 6 carbon atoms, or NR9R10, R9 and R10 independently represent a hydrogen atom, the OH group or a linear or branched alkyl radical having 1 to 6 carbon atoms, W does not exist or represents a bond, or 0, S or NR15, in which R15 represents a hydrogen atom or a linear or branched alkyl radical having from 1 to 6 carbon atoms; p represents a hydrogen atom or a protective group of the carbamate type; R? ß- Ri7 and R? ß represent, independently, a hydrogen atom or a linear or branched alkyl radical having from 1 to 6 carbon atoms; and m represents an integer from 0 to 6. A subject of the present invention is also, as medicaments, the compounds of general formula (I) described above or their pharmaceutically acceptable salts. It also relates to pharmaceutical compositions containing these compounds or their pharmaceutically acceptable salts, and the use of these compounds or their pharmaceutically acceptable salts to produce medicaments intended to inhibit neuronal NO synthase or inducible NO synthase, to inhibit lipid peroxidation or provide the double function of inhibiting NO synthase and inhibiting lipid peroxidation. By a pharmaceutically acceptable salt, in particular, salts by addition of inorganic acids such as hydrochloride, hydrobromide, hydroiodide, sulfate, phosphate, bisphosphate and nitrate, or organic acids, such as acetate, maleate, fumarate, tartrate, succinate, citrate, lactate, are indicated. , methanesulfonate, p-toluenesulfonate, pamoate, oxalate and stearate. Salts formed from bases such as sodium or potassium hydroxide also fall within the scope of the present invention, when they can be used. For other examples of pharmaceutically acceptable salts, reference can be made to "Pharmaceutical salts", J. Pharm. Sci. 66: 1 (1977). The pharmaceutical composition can be made in the form of a solid, for example powders, granules, tablets, capsules, liposomes or suppositories. Suitable solid supports can be for example calcium phosphate, magnesium stearate, talc, sugars, lactose, dextrin, starch, gelatin, methyl cellulose, sodium carboxymethyl cellulose, polyvinyl pyrrolidone and wax. Pharmaceutical compositions containing a compound of the invention can also be presented in the form of a liquid, for example, solutions, emulsions, suspensions or syrups. Suitable liquid supports can be, for example, water, organic solvents such as glycerol or the glycols, as well as their mixtures, in varying proportions, in water. A medicament according to the invention can be administered by topical, oral or parenteral route, by intramuscular injection, etc. The contemplated administration dose of a medicament according to the invention is comprised between 0.1 mg and 10 g according to the type of active compound used. According to the invention, the compounds of general formula (I) can be prepared by the process described below.
Preparation of the compounds of general formula (I): The compounds of general formula (I) can be prepared from intermediates of general formula (II) according to Diagram 1, where A, B, X, Y and F are as they defined before and Gp is a carbamate type protecting group such as for example the t-butoxycarbonyl group.
(H) A-X-Y-F-NH-
Diagram 1
The aniline derivatives of the general formula (II) can be condensed with the compounds of the general formula (III), in which L represents a partition group (for example an alkoxy, alkylthio, aralkylthio radical, sulfonic acid, halide, aryl alcohol or tosyl), to produce the final compounds of general formula (I) of the substituted amidine type (cf Diagram 1). For example, for B = thiophene, the derivatives of general formula (II) can be condensed with S-methylthiophen thiocarboxamide hydroiodide, prepared according to a literature method (Ann Chim. (1962), 7, 303-337). . The condensation can be carried out by heating in an alcohol (for example in methanol or isopropanol), optionally in the presence of DMF and / or pyridine at a temperature preferably comprised between 20 and 100 ° C for a duration generally comprised between a few hours and all. the night. In the case where B is an amine, the final compounds of general formula (I) are guanidines. These can be prepared, for example, by the condensation of amines of general formula (II) with the derivatives of general formula (IV) or (IV). Reagents of the general formula (IV) in which L represents, for example, a pyrazole ring, are condensed with the amines of the general formula (II) according to the conditions described in the literature (J. "Org. Ch em. (1992) 57, 2497-2502), similarly for reagents of general formula (IV) in which L represents, for example, a pyrazole ring and Gp the tBuOCO group (Tetrahedron Let t. (1993) 34 ( 21), 3389-3392) or when L represents the group -N-S02-CF3 and Gp the tBuOCO group (J. Org. Chem. (1998) 63, 3804-3805) During the final stage of the synthesis, the Deprotection of the guanidine function is carried out in the presence of a strong acid such as for example trifluoroacetic acid, therefore the invention also relates to a process for the preparation of a product of general formula (I) as previously defined, characterized in that the intermediate of general formula (II)
A-X-Y- -NH2 (ID
wherein A, B, X, Y and F are as defined above, are reacted with the intermediate of general formula (III)
(III)
wherein B is as defined above and L represents a partition group, for example an alkoxy, alkylthio, aralkylthio, sulphonic acid, halide, aryl or tosyl alcohol radical. Furthermore, the invention relates to a process for the preparation of a product of general formula (I) in which B is an amine, characterized in that the intermediate of general formula (II)
A-X-Y-F-NH, '(II) in which A, B, X, Y and F are as defined above, is reacted, a) either with the intermediate of general formula (IV)
H, N ^ NH (IV)
wherein L represents a partition group, for example an alkoxy, alkylthio, aralkylthio radical, sulfonic acid, halide, aryl or tosyl alcohol, b) or with the intermediate of general formula (VI ')
(IV)
wherein L represents a partition group, for example an alkoxy, alkylthio, aralkylthio radical, sulfonic acid, halide, aryl or tosyl alcohol, and Gp a carbamate type protecting group, for example the T-butoxycarbonyl group, this reaction is follows, in the case where the reaction with the compound of general formula (IV) is selected, by hydrolysis in the presence of a strong acid, for example trifluoroacetic acid.
When -XYF- represents a direct bond: The intermediates of general formula (II) in the particular case when -XYF- represents a direct bond are comparable to the compounds of general formula (X), A-NH2, described in the chapter " Synthesis of intermediaries ". In this case, these amines A-NH2 can be directly condensed with the derivatives of general formula (III) or (IV) which were described in the previous chapter.
Preparation of the compounds of general formula (II): The non-commercial intermediates of general formula (II) are obtained either from the separation of a protecting group, or from the reduction of a nitride or nitro type precursor, or it is illustrated later in the synthesis diagrams.
Deprotection of the amino group: Intermediates of general formula (II), in which A, X, Y and F are as defined above, can be prepared from intermediates of general formula (V), Diagram 2, which are compounds comprising a protected amine (N = Gp ') in the form of, for example, phthalimide or 2,5-dimethylpyrrole. In the case of phthalimides, these are deprotected in a standard way using hydrazine hydrated in ethanol reflux and in the case of pyrroles, the deprotection is carried out by heating in the presence of hydroxylamine hydrochloride, to finally produce the primary amines of the general formula (II).
A_x _? _ F_N = Gp. A-X-Y-F-NH, (V) (")
Diagram 2
Reduction of azido type precursors: Synthetic intermediates of general formula (VI), Diagram 3, in which A, X, Y and F are as defined above, are azide derivatives that are converted into a primary amine of formula (II), for example, using hydrogen in the presence of Pd / C in an appropriate solvent such as ethanol.
H A- X-Y-F-N, A-X-Y-F-NH, (VI) (II)
Diagram 3 Reduction of nitro type precursors: The reduction of nitro function of intermediates of general formula (VII), Diagram 4, in which A, X, Y and F are as defined above, is carried out in general by means of catalytic hydrogenation, in ethanol, in the presence of Pd / C, except in the case of molecules sensitive to these conditions where the nitro group is selectively reduced, for example, by heating the product in an appropriate solvent such as ethyl acetate with a little ethanol in the presence of SnCl2 (J. Het erocycl ic Ch em. (1987), 24, 927-930; Tetrahedron Letters (1984), 25 (8), 839-842), also using SnCl2 in the presence of Zn (Syn thesi s (1996), (9), 1076-1078), or using NaBH4-BiCl3 (Synth, Com. (1995) 25 (23), 3799-3803) in a solvent such as ethanol, or in such case using Ni Raney with hydrated hydrazine (Mona t sheft e für Chemi e, (1995), 126, 725-732; Pharmazie (1993) 48 (11), 817-820) added in the case, for example or, of nitrocarbazoles.
A_x _? _ F-N0, A-X-Y-F-NH, (VII) (")
Diagram 4 Preparation of the compounds of general formula (V):
The intermediates of general formula (V), Diagram 5, contain a protected amine in the phthalimide form, where X = -O-, Y = - (CH2) m- with A, R1, R2, R3, R4, R5, W, m and F, as defined above, can be prepared from hydroxylated aromatic rings of general formula (VIII). In the particular case of hydroxycarbazoles, the compounds of general formula (VIII) are prepared according to an experimental protocol of the literature (J. Ch em. Soc. (1955), 3475-3477; J. Med. Chem. (1964 ) 7, 158-161) and in which the hydroxyphenothiazine protocol is described in J. Med. Chem. (1992) 35, 716. Compounds of general formula (VIII) are condensed with commercial haloalkyl phthalimides in the presence of a base, for example NaH, in a solvent such as DMF, to produce intermediates of general formula (V).
Diagram 5 Preparation of the compounds of general formula (VI):
Intermediates of general formula (VI), Diagram 6, wherein A, X, Y, Rlf R2, R3, R4, R5, w, m and F are as defined above, are azido derivatives. They are prepared in two stages from intermediates of general formula (VIII) (Diagram 5). The OH radical of the compounds of general formula (VIII) can be alkylated by means of dihalogenated derivatives of the dibromoalkane type, in the presence of a base, for example NaH or NaOH, to produce the compounds of general formula (IX) which are then substituted using sodium azide in DMF to produce intermediates of general formula (VI).
(VIII) (IX)
Diagram 6
Preparation of the compounds of general formula (VII):
The synthesis of the compounds of general formula (VII), which carry a terminal nitro group, in which A, X, Y and F are as described above, is illustrated in the following synthesis diagrams.
Synthesis of the carboxamides of the general formula (VII):
The carboxamides of the general formula (VII), Diagram 7, in which X represents -NR16-CO- and A, Y, F and R16 are as defined above, are prepared by condensation of the commercial amines of general formula (X) with the commercial acids of the general formula (XI). Carboxamide bonds are formed under standard conditions of peptide synthesis (M. Bodanszky and Bodanszky, The Practice of Peptide Synthesis, 145 (Springer-Verlag, 1984)) in THF, dichloromethane or DMF in the presence of a coupling reagent such such as dicyclohexylcarbodiimide (DCC), 1,1'-carbonyldiimidazole (CDl) (J. Med. Chem. (1992), 35 (23), 4464-4472) or l- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (EDC or SCI) (John Jones, The chemical syn thesi s of peptides, 54 (Clarendon Press, Oxford, 1991)). The synthesis of the non-commercial amines of general formula (X) and the synthesis of the non-commercial carboxylic acids of general formula (XI) are described in the chapter Preparing Intermediaries.
f.16, RI6, -N + HO -Y-F-NO, ** A-N-C-Y-F-NO, H O (X) (XI) (VII)
Diagram 7
The carboxamides of the general formula (VII),
Diagram 8, where X represents -CO-NR16- and A, Y, Q,
F and R16 are as defined above, are prepared by condensation of commercial acids of general formula (XII) with commercial amines of general formula (XIII) or amines of general formula (XIV) under standard conditions for the synthesis of peptides previously described. The synthesis of the non-commercial acids of the general formula (XII) and amines of the general formula (XIV) are described in the chapter
Preparation of Intermediaries.
(XIV) H- -Q- F- NO, (VII) Diagram 8 The carboxamides of general formula (VII), Diagram 9, in which X represents -O-, Y represents - (CH2) m-NR18-CO- (CH2) n- with A, R18, m, n and F as defined above, are prepared by condensation of standard peptide of the acids of general formula (XI) (Diagram 7) with the amines of general formula (II), synthesis of which has been described in Diagrams 2 and 3.
A-Cr- (CH.) - NH + H02C- Y- F-NO, A-O- (CH, -) m- N-C | | -Y-F-NO, O (ll) (XI) (Vil)
Di agrama 9
Synthesis of the amines of the general formula (VII): The amines of the general formula (VII) in which X = -NR16- and Y = - (CH2) m- with A, R16, m and F as defined above, are prepared , Diagram 10, from the carboxamides of the general formula (VII). The reduction of the carboxamide function is carried out in the presence of an excess (5 eq.) Of diborane in THF, heating the mixture to reflux of the solvent to produce the amines of the general formula (VII).
R I '»A-N-C-Y-F-NO, A-N-C-Y-F-NO, H H (VII) (VII)
Diagram 10
Synthesis of the carbamates of the general formula (VII): The carbamate derivatives of the general formula (VII) in which X = -NR16-C0-0- and Y = - (CH2) m- with A, R16, and F as were defined above, are prepared, Diagram 11, by condensation of an amine of general formula (X) (Diagram 7) with a commercial alcohol of general formula (XV) in the presence of triphosgene and a base such as for example N, N- dimethylaniline in an inert solvent such as, for example, dichloromethane, according to a protocol described in Tetrah edron Let t. (1993) 34 (44), 7129-7132.
Trifosgen A-NH, + H -Y-F-NO, ** (X) (XV) (VII)
Diagram 11 Synthesis of the ureas of general formula (VII): The ureas of general formula (VII) in which X = -NR16-CO-NR17- and Y = - (CH2) m- or XY = -NR16-CO- (in the case of a heterocycle with nitrogen) with A, R17, m, Q and F as defined above, are prepared, Diagram 12, from the primary amines of general formula (X) (Diagram 7) and the amines of the general formula -NR16-CO- (XIII) or (XIV) (Diagram 8) in the presence of triphosgene and a tertiary amine, such as, for example, diisopropylethylamine, in a neutral solvent such as dichloromethane (J. Org. . (1994), 59 (7), 1937-1938).
A-NH + (X) (XIII) (VII)
Trifosgen H A-NH + H-Q-F-NO, > • A-N-C-Q-F-NO,
(X) (XIV) (VII)
Di agrama 12
Synthesis of the esters of the general formula (VII): The carboxylic esters of the general formula (VII) in which X = -0-CO- or -C0-0- and Y = - (CH2) m with A, m and F as defined above, they are prepared in a single step from alcohols of general formula (VIII) (Diagram 5) and carboxylic acids of general formula (XI) (Diagram 7) or acids of general formula (XII) (Diagram 8) ) and alcohols of general formula (XV) (Diagram 11) in the presence of a coupling agent such as, for example, carbonyldiimidazole or dicyclohexylcarbodiimide, in an appropriate solvent such as, for example, dichloromethane.
A-OH + HO, C-Y-F-N0, -O-C-Y-F-NO, II or (VIII) (XI) (VII)
A-C0, H + HO-Y-F-NO, A-C-O-Y-F-NO, O (XII) (XV) (VM)
Diagram 13
Synthesis of the ethers of the general formula (VII): The ethers of the general formula (VII) in which X = -O- and Y = Y = - (CH2) B with A, m and F as defined above, Diagram 14, they are prepared in a single step by condensation of the aromatic alcohols of the general formula (VIII) (Diagram 5) and the alcohols of the general formula (XV) (Diagram 11) under the standard conditions of Mitsunobu (Syn thesi s (1981), 1 ) in the presence of, for example, diethylazocarboxylate and tribultylphosphine, in a solvent such as, for example, THF.
DEADPBu A-OH + HO-Y-F-NO, - J A-o -? - c ^ N02 (viii) (xv) (VII)
Diagram 14
When X = -O-, Y is a bond and F = phenylene, with A and n as defined above, the ethers of general formula (VII), Diagram 15, can also be prepared in a single step by condensation of the aromatic alcohols of general formula (VIII) (Diagram 5) with the halogenated derivatives of the general formula (XVI), in which Hal represents a halogen atom, in the presence of a base such as, for example, K2C03, in a polar solvent such as, for example, THF or DMF, at a reaction temperature comprised between 20 and 140 ° C.
(VIII) (XVI) (Vil)
Diagram 15
When X = -O- and Y = - (CH2) mQ- (CH2) n- with A, F, Q and m as defined above, the ethers of general formula (VII), Diagram 16, can also be prepared by condensation of the aromatic alcohols of the general formula (VIII) (Diagram 5) with the halogenated derivatives of the general formula (XVII), in which Hal represents a halogen atom, in the presence of a base such as, for example, K2C03, in a solvent inert such as, for example, CH2C12, at a temperature between 40 ° C and the reflux temperature of the reaction mixture. The synthesis of the compounds of general formula (XVII) is described in the chapter on Preparation of Intermediaries.
Hal- (CH -Q- F- NO, * m 2
(XVI I)
Diagram 16
Synthesis of amines of general formula (VII) reducing amination: The amines of general formula (VII), wherein X = -NR16-CO- and Y = - (CH2) m-NR18- (CH2) n- with A, F, R16, R18, m and n as defined above, are prepared, Diagram 17, by condensation of an aldehyde of general formula (XIX) with an amine of general formula (XVIII) in reducing medium. The reaction is carried out in an alcoholic solvent such as, for example, methanol in the presence or sprayed on a 4A molecular sieve, activated in advance, and a reducing agent such as, for example, NaBH 4 or NaBH 3 CN. The synthesis of the non-commercial amines of the general formula (XVIII) is described in the chapter on Preparation of Intermediaries.
F-NO, (XVIII) (XIX) (VII)
Diagram 17
In an analogous manner, the amines of the general formula (VII), in which X = -CH2-NR16-, with A, Y, F and R16 as defined above, are prepared, Diagram 18, by condensation of the aldehydes of general formula (XX) with the amines of the general formula (XIII) (Diagram 8) in reducing medium under the conditions previously described. The preparation of the non-commercial aldehydes of general formula (XX) is described in the chapter Preparing Intermediaries.
_P v? Net ? A - + HN - Y - F - NO, A - C - N - Y - F - NO, H H H (XX) (XII I) (VII)
Diagram 18 Modification of radical A in compounds of general formula (VII.: Intermediates of general formula (VII), in which A, X, Y, F, Rl R2, R3, R4 and Rs are as described above, can be subjected to chemical modifications at the level of radical A, Diagram 19, in particular at the level of the nitrogen atom that can be alkylated using a Ru-Hal reagent, as defined above, and in particular using methyl iodide in the presence of such a base as, for example, NaH, in an inert solvent such as for example THF.
Diagram 19
Preparation of the different intermediates of synthesis Synthesis of intermediaries (X): The intermediates of general formula (X) in which A is a diphenylamine (does not exist), are accessible using the methods described in the literature (Syn th esi s (1990 ) 430; Indi an J. Ch em. (1981) 20B, 611-613; J. Med. Chem. (1975) 18 (4), 386-391) which operate by reducing a nitrodiphenylamine intermediate. The reduction of the nitro function is carried out in the standard manner, by hydrogenation in the presence of a catalytic amount of Pd / C to have access to the aminodiphenylamines of the general formula (X). When A is a carbazole derivative (W then represents a direct bond), the preparation methods for the aminocarbazoles of general formula (X) operate by the synthesis of a nitrocarbazole intermediate. These methods are described in Pharmazi e (1993) 48 (11), 817-820; Syn th. Commun. (1994) 24 (1), 1-10; J. Org. Chem. (1980) 45, 1493-1496; J. Org. Chem. (1964) 29 (8), 2474-2476; Org Prep. Procedure In t. (1981) 13 (6), 419-421 or J. Org. Chem. (1936) 28, 884. The reduction of the nitro function of the nitrocarbazole intermediates is carried out, in this case, preferably using hydrazine hydrated in the presence of Raney Nickel. Intermediates of general formula (X) in which A is a phenothiazine derivative (represents a sulfur atom), are accessible by methods of the literature, which operate by the synthesis of a nitrophenothiazine derivative. In particular 3-nitrophenothiazine is described in J. Org. Chem. (1972) 37, 2691. The reduction of the nitro function to access the aminophenothiazines of the general formula (X) is carried out in a standard manner, by hydrogenation in the presence of a catalytic amount of Pd / C in such a solvent. as ethanol.
Synthesis of intermediates (XI): The synthesis of non-commercial acids of general formula (XI), is described in diagrams 7.1 and 7.2. In the particular case where Y = - (CH2) m-Q- (CH2) n- and
F is a phenylene radical, with Q, m and n as defined above, the carboxylic acids of general formula (XI), Diagram 7.1, are prepared, in two steps, from a heterocyclic amine of the general formula
(XIV) (Diagram 8), for example 4-nitrophenylpiperazine, and a haloester of general formula (XI.1) such as for example ethyl bromoacetate. The condensation is carried out at 20 ° C in the presence of a base such as, for example, triethylamine in an inert solvent such as, for example, dichloromethane to produce intermediates of the general formula (XI.2). Saponification by means of LiOH at 20 ° C produces the carboxylic acids of general formula (XI). In the cases where Y = - (CH2) m-0- (CH2) n- and F is a phenylene radical, with m and n as defined above, the synthesis of the carboxylic acids of general formula (XI), Diagram 7.1, operates by condensing the halogenated derivatives of the general formula (XI.1) or the alcohols of the general formula (XI.3) in the presence of a base such as, for example, triethylamine or potassium carbonate, under reflux of a polar solvent such as, for example, THF or DMF. The deprotection of the ester function of the intermediate of general formula (XI.4) is then carried out in a standard manner in the presence of a base or a strong acid, in the case of ter-butyl esters. H-Q-F-NO,
Diagram 7 The carboxylic acids of the general formula (XI) in which Y = - (CH2) m- and F represent a substituted phenylene group, with m as defined above, are prepared in 3 steps from the commercial alcohols of the general formula (XI.3), Diagram 7.2. The activation of the alcohol is carried out in a standard manner using methan sulfonyl chloride (MsCl) in the presence of a base, such as triethylamine, in an inert solvent, such as dichloromethane, to produce intermediates of the general formula (XI.4) . The mesylate is then displaced by sodium cyanide in DMF to produce intermediates of the general formula (XI.5). The nitrile function is then hydrolysed by heating in a mixture of ethanol and concentrated HCl to produce the acids of general formula (XI).
(XI.3) (XI.4) (XI.5) Diagram 7. 2 Synthesis of intermediates (XII): The synthesis of the carboxylic acid derivatives of the phenothiazines of the general formula (XII) is described in the literature (J. Med. Chem. (1992) 35 (4), 716-724).
Synthesis of intermediates (XIV): The non-commercial amines of general formula (XIV) previously defined, in which Q represents h omop iperazine, 2-me ti 1 piperazine, 2,5-dimethylpiperazine, 4-aminopiperidine, are synthesized in three stages of the corresponding commercial diamines. The diamines are selectively mono-protected in the carbamate form (Syn th esi s (1984), (12), 1032-1033, Syn th. Commun. (1990), 20, (16), 2559-2564) before react by nucleophilic substitution with a halogenonitrobenzene, in particular 4-fluoronitrobenzene. The amines, which have been previously protected, are released in the last stage, according to the methods described in the literature (T. Greene and PGM Wuts, Prot ective Groups in Organic Syn thesis, Second Edition (Wiley Interscience 1991)) , to produce intermediates of general formula (XIV).
Synthesis of intermediates (XVII): The halogenated derivatives of general formula (XVII) previously defined, Diagram 16.1, are accessible in two stages from the amines of general formula (XIII) or (XIV) (Diagram 8) and the halogenated derivatives commercial of general formula (XVII.1). The condensation to produce intermediates of general formula (XVII.2) or (XVII.3) is carried out in a standard manner in the presence of a base such as, for example, K2C03 in a suitable inert solvent such as, for example, dichloromethane. The alcohol function is then activated in the form of a halogenated derivative using, for example, carbon tetrabromide in the presence of triphenylphosphine to produce intermediates of general formula (XVII).
(XVII)
(XVII) (XIV) H-O-F-NO, (XVII.3)
Diagram 16.1 Synthesis of intermediates (XVIII): The amines of general formula (XVIII) previously defined, Diagram 17.1, in which A, R16, R18 and m are as defined above, are prepared by condensation of the amines of the general formula (X ) (Diagram 7) with the protected amino acids (Gp: protective group) of the general formula (XVIII.1), under the standard conditions of peptide synthesis (see chapter on "carboxamide synthesis"). The deprotection of the amine of the compounds of the general formula (XVIII.2) is then carried out in a standard manner according to the conditions described in the literature (TW Greene et PGM Wuts, Prot ect i ve Groups in Organi c Syn thesi s, Second edition (iley-Interscience, 1991)).
A- (X) (XVIII.1) (XVIII.2)
Deprotection t (XVIII)
Say agrama 17. 1 Synthesis of intermediates (XX): The synthesis of the aldehydes of phenothiazines of general formula (XX) previously defined is described in the literature (J. Chem. Soc. (1951), 1834; Bul l. Soc. Chim. . (1969), 1769).
Unless defined differently, all chemical and scientific terms used herein have the same meaning as usually understood by an ordinary specialist in the field to which the invention pertains. Similarly, all publications, patent applications, patents and other references mentioned herein are incorporated by reference.
The following examples are presented to illustrate the above procedures and should not be considered in the form of restricting the scope of the invention.
EXAMPLES: Example 1: N- [4- (phenylamino) phenyl] -2-thiophene-carboximidamide hydroiodide: 1_ 0.92 g (5 mmol) of 4-aminodiphenylamine and 2.85 g (10 mmol) of S-methyl-2-hydroiodide thiophene thiocarboximide in 15 ml of isopropanol are mixed together in a 50 ml flask under an argon atmosphere. The reaction mixture is heated at 70 ° C for 48 hours. The solvent is partially evaporated in vacuo and the solid obtained is filtered and washed several times successively with isopropanol and ether. A yellow powder with a yield of 98% is obtained. Melting point: 216.3-216.8 ° C. H-NMR (400 MHz, DMSO d6, d): 6.90 (m, 1H, arom.); 7.10-7.30 (m, 8H, arom.); 7.40 (m, 1H, thiophene); 8.10-8.20 (m, 2H, thiophene); 8.50 (s, 1H, NH); 8.75 (s, 1H, NH +); 9.70 (s, 1H, NH +); 11.15 (s, 1H, NH? • IR: vc = N (amidine): 1590 was "1.
Example 2: Hydrochloride 4-. { [2-thienyl (imino) methyl] amino} -N- [4- (phenylamino) phenyl] -bencenace amide: 2 2.1) 4-Nitro-N- [4- (phenylamino) phenyl] -benzenacetamide:
1. 84 g (10 mmol) of 4-aminodiphenylamine, 1.81 g (10 mmol) of 4-nitrophenylacetic acid and 1.48 g (11 mmol) of hydroxybenzotriazole in 40 ml of THF are dissolved successively in a 100 ml flask. Then 2.27 g (11 mmol) of 1,3-dicyclohexylcarbodiimide (DCC) are added and the reaction mixture is stirred for 15 hours. A precipitate of dicyclohexylurea (DCU) is formed which is filtered and rinsed with 100 ml of ethyl acetate. The filtrate is then washed successively with 50 ml of a saturated solution of Na 2 CO 3, 50 ml of water, 50 ml of a molar solution of HCl and finally 2 x 50 ml of water with salt. The organic phase is dried with magnesium sulfate, filtered and concentrated in vacuo. The residue is purified rapidly on a column of silica gel (eluent: heptane / ethyl acetate 1/1). The purest fractions are collected and evaporated in vacuo to produce a brown powder. The product is used in the next stage. NMR E (100 MHz, CDCl 3, d): 1.61 (broad s, 1H,
NH); 3.82 (s, 2H, CH2); 5.70 (s broad, 1H, NH); 6.85-7.50 (, 10H, arom., NH-CO); 7.90 (AB, 4H, Ph-N02).
2. 2) 4-Amino-N- [4- (phenylamino) phenyl] -benzenacetamide:
A solution of intermediate 2.1 (0.54 g, 1.54 mmol) in 40 ml of a mixture of ethyl acetate / ethanol (1/1), as well as 0.1 g of 10% Pd / C are introduced in a stainless steel autoclave fitted with a magnetic stirrer. The reaction mixture is stirred at a hydrogen pressure (1.5 bar) for 1 hour 30 minutes at a temperature of 20 ° C. The Pd / C is then removed by filtration and the filtrate is concentrated in vacuo. The residue of the evaporation is purified on a silica gel column (eluent: heptane / ethyl acetate: 4/6), the pure fractions are collected and concentrated in vacuo. A white powder with a yield of 90% is obtained. Melting point: 162-163 ° C. NMR? H (100 MHz, CDCl3, d): 1.61 (broad s, 1H, NH); 3.61 (s, 2H, CH2); 3.70 (broad s, 2H, NH2); 5.62 (s broad 1H, NH-CO); 6.68-7.40 (m, 13H, arom.).
2. 3) Hydrochloride of 4-. { [2-thienyl (imino) methyl] amino} -N- [4- (phenylamino) phenyl] -benzenacetamide: 2_ 0.44 g (1.39 mmol) of intermediate 2.2 and 0.47 g (1.67 mmol) of S-methyl-2-thiophene thiocarboximide hydroiodide are dissolved in 15 ml of isopropanol in a 50 ml flask. The reaction mixture is stirred for 20 hours at a temperature of 60 ° C. After evaporation of the solvent in vacuo, the residue is taken up in 100 ml of a mixture of 1 N sodium hydroxide and ethyl acetate (1/1). After decanting, the organic phase is washed with 50 ml of water followed by 50 ml of water with salt. The organic solution is dried with magnesium sulfate, filtered, concentrated in vacuo and the residue is purified on a column of silica gel (eluent: ethyl acetate). The pure fractions are collected and concentrated in vacuo. A white powder with a yield of 25% is obtained. The compound is then dissolved in methanol and salts are formed by adding a solution of 1N HCl in ethyl ether (1 ml). After stirring for one hour at 20 ° C, the reaction mixture is concentrated in vacuo to yield a pale yellow powder. Melting point: the product becomes a foam. H-NMR (400 MHz, DMSO d6, d): 3.71 (s, 2H, CH2);
4. 60 (broad s, 1H, NH); 6.75 (m, 1H, thiophene); 7.00 (m, 4H, arom.); 7.19 (m, 2H, arom); 7.40 (m, 3H, arom.); 7.55 (m, 4H, arom.); 8.14 (m, 2H, thiophene); 8.95 (broad s, 1H, NH +); 9.86 (broad s, 1H, NH +); 10.41 (s, 1H, NH-CO); 11.60 (broad s, 1H, NH +). IR: vc = 0 (amide): 1649 c "1; vc = N (amidine): 1597 cm
Example 3: Yodhidrate of. { 4-. { [2-thienyl (imino) methyl] amino} phenoxy } -N- [4- (phenylamino) phenyl] -acetamide: 3_ 3.1) tert-butyl 4-nitrophenoxyacetate: 3 g (21.6 mmol) of para-nitrophenol are introduced,
8. 94 g (64.8 mmol) of potassium carbonate and 8.42 g (43.2 mmol) of tert-butyl bromoacetate under a nitrogen atmosphere in a 250 ml flask containing 100 ml of THF. The reaction mixture is stirred at reflux for 2 hours. The solid is filtered and the filtrate is concentrated under reduced pressure. The residue is taken up in 50 ml of ethyl acetate and washed successively with 50 ml of water and 50 ml of water with salt. The organic phase is dried with sodium sulfate, filtered and evaporated in vacuo. After purification of the pure fractions on a column of silica gel (eluent: ethyl acetate / heptane 1: 8) and concentration in vacuo, a white powder is obtained in 50% yield. Melting point: 81-83 ° C. NMR * H (100 MHz, CDCl 3, d): 1.50 (s, 9H, 3 x CH 3); 4.60 (s, 2H, CH2); 7.57 (AB, 4H, Ph-N02).
3. 2) 4-nitrophenoxyacetic acid: 2.58 g (10.2 mmol) of intermediate 3.1 is dissolved in 45 mmol of dichloromethane in a 100 ml flask under a nitrogen atmosphere. The mixture is cooled down to 0 ° C and 7.85 ml (102 mmol) of trifluoroacetic acid is added dropwise. The reaction mixture is stirred for 3 and a half hour at room temperature. Then the solution is concentrated under reduced pressure. The residue of the evaporation is taken up in 30 ml of ethyl acetate and washed with 20 ml of water, the organic phase is dried with sodium sulphate, filtered and evaporated in vacuo. 89% The product obtained is sufficiently pure to be used directly in the next stage Melting point: 190-192 ° C. * H NMR (100 MHz, CDC13, d): 2.00 (broad s, 1H, COOH); (s, 2H, CH2), 7.60 (B, 4H, Ph-N02).
3. 3) (4-nitrophenoxy) -N- [(4-phenylamino) phenyl] acetamide:
1.65 g (8.98 mmol) of 4-aminodiphenylamine, 1.77 g (8.98 mmol) of intermediate 3.2 and 1.27 g (9.42 mmol) of hydroxybenzotriazole are dissolved in 40 ml of THF in a 100 ml flask under a nitrogen atmosphere. When all is dissolved, 1.94 g (9.42 mmol) of 1,3-dicyclohexylcarbodiimide is added and the reaction medium is allowed to stir for 15 hours. The formed dicyclohexylurea precipitate is filtered and rinsed with ethyl acetate. The filtrate is evaporated in vacuo and the residue of the evaporation is taken up in ethyl acetate, then a precipitate is formed which is filtered and rinsed using the same solvent. A greenish solid is obtained with a yield of 65%. The product is pure enough to be used directly in the next stage. Melting point: 192-195 ° C. NMR * H (100 MHz, CDCl3, d): 4.75 (s, 2H, CH2-0); 5.70 (s broad, 1H, NH); 7.10 (m, 9H, arom.); 7.85 (AB, 4H, Ph-N02); 8.05 (broad s, 1H, NH-CO).
3. 4) (4-aminophenoxy) -N- [(4-phenylamino) phenyl] acetamide:
1 g (2.75 mmol) of intermediate 3.3 dissolved in 200 ml of a solvent mixture (ethanol / dichloromethane / THF 1: 1: 1) and 0.1 g of Palladium in 10% carbon are introduced in a 300 ml autoclave. The mixture is placed at a hydrogen pressure of 1.5 bar and stirred at room temperature for 15 minutes. The catalyst is filtered and the solvents are concentrated under reduced pressure to yield a pink beige solid with a 71% yield. Melting point: 146-148 ° C.
NMR * H (100 MHz, CDCl 3, d): 3.50 (broad s, 2H, NH 2); 4.50 (s, 2H, CH2-0); 5.70 (s broad, 1H, NH); 6.70 (m, 4H, arom.); 7.10 (m, 4H, arom.); 7.25 (m, 5H, arom.); 8.20 (broad s, 1H, NH-CO).
3. 5) Hydroxide of [4-. { [imino (2-thienyl) methyl] amino} phenoxy] -N- [(4-phenylamino) phenyl] acetamide: 3_ A mixture of 0.3 g (0.9 mmol) of intermediate 3.4 in the presence of 0.25 g (0.9 mmol) of S-methyl-2-thiophene thiocarboximide hydroiodide in solution in 20 ml of isopropanol is heated to 50 ° C, for 15 hours. The reaction mixture is filtered and the solid obtained is rinsed with ethyl ether. A yellow powder is obtained with a yield of 78%. Melting point: 163-166 ° C. NMR? (400 MHz, DMSO d6, d): 4.75 (s, 2H, CH20); 6.77 (m, 1H, thiophene); 7.04 (m, 4H, arom.); 7.19 (m, 4H, arom.); 7.40 (m, 3H, arom.); 7.50 (m, 2H, arom.); 8.12 (m, 2H, thiophene); 8.81 (broad s, 1H, NH +); 9.70 (broad s, 1H, NH +); 10.01 (s, 1H, CO-NH); 11.20 (broad s, 1H, NH +). IR: vc = 0 (amide): 1647 cm "1; vc = N (amidine): 1598 cm" 1.
Example 4: 4-. { [2-thienyl (imino) me il] amino} -N- [2- (phenylamino) phenyl] -benzenebutanamide: 4_ The experimental protocol used is the same as that described for Example 2. The product is obtained in the form of the free base (white solid). Melting point: 164-167 ° C. 1 H NMR (400 MHz, DMSO d 6, d): 1.86 (m, 2 H, CH 2);
2. 35 (, 2H, CH2); 2.55 (, 2H, CH2); 6.37 (broad s, 2H, NH2); 6.76 (m, 3H, arom.); 6.87 (m, 2H, arom.); 6.96 (m, 1H, thiophene); 7.10 (m, 3H, thiophene); 7.18 (m, 2H, arom.); 7.25 (m, 1H, arom.); 7.33 (s, 1H, NH); 7.52 (, 1H, thiophene); 7.73 (m, 1H, thiophene); 9.36 (s, 1H, NHCO). IR: vc_0 (amide): 1627 cm "1; vc = N (amidine): 1591 cm" 1.
Example 5: 4- Hydrochloride. { [2-thienyl (imino) methyl] amino} -N- [4- (phenylamino) phenyl] -benzenebutanamide: 5_ The experimental protocol used is the same as that described for Example 2. The hydrochloride is obtained in the form of a pink salmon powder. Melting point: 167-170 ° C.
NMR: H (400 MHz, DMSO d6, d): 1.90 (m, 2H, CH2); 2.35 (m, 2H, CH2); 2.70 (m, 2H, CH2); 6.70 (m, 1H, thiophene); 7.00 (m, 4H, arom.); 7.20 (m, 2H, arom.); 7.40 (m, 5H, arom.); 7.50 (m, 2H, arom.); 8.20 (m, 2H, thiophene); 8.90 (s, 1H, NH +); 9.85 (s, 1H, NH +); 9-90 (s, 1H, NHCO); 11.55 (s, 1H, NH +) - IR: vc = 0 (amide): 1654 cm "1; vc = N (amidine): 1597 cm" 1.
Example 6: 4- Hydrochloride. { [2-thienyl (imino) methyl] amino} -N- [4- (4-methoxyphenylamino) phenyl] -benzenebutanamide: 6_ The experimental protocol used is the same as that described for intermediate 2.3, the intermediate
6. 2 which replaces 4-amino-N- [4- (phenylamino) phenyl] -benzenacetamide. A beige powder with a yield of 65% is obtained. Melting point: 200-202 ° C. NMR: H (400 MHz, DMSO d6, d): 1.91 (m, 2H, CH2); 2.33 (m, 2H, CH2); 2.67 (m, 2H, CH2); 3.69 (s, 3H, 0-NH3); 4.71 (broad s, 1H, NH); 6.81-7.00 (m, 6H, arom.); 7.37-7.45 (m, 7H, arom.); 8.20 (m, 2H, thiophene); 8.90 (broad s, 1H, NH +); 9.87 (broad s, 1H, NH +); 9.92 (s, 1H, NH-CO); 11.67 (broad s, 1H, NH +).
IR: vc = 0 (amide): 1664 cm "1; vc = N (amidine): 1603 cm" 1.
Example 7: 2- Hydrochloride. { 4-. { [2-thienyl (imino) me il] amino} phenyl } -e il: [4- (phenylamino) phenyl] -carbamate: 1_ 7.1) 2- (4-nitrophenyl) -ethyl [4- (phenylamino) phenyl] -carbamate: 1.18 g (3.9 mmol) of triphosgene are dissolved in 15 ml. ml of dichloromethane in a 250 ml flask under argon. Using a motorized syringe, a solution of 2 g (12 mmol) of 4-nitrophenylethanol and 1.7 ml (13 mmol) of N, N-dimethylaniline in 40 ml of dichloromethane is added over 1 hour. The reaction mixture is stirred for a few minutes at 20 ° C adding before adding in a solution of 2.2 g (12 mmol) of 4-aminodiphenylamine and 1.7 ml (13 mmol) of, -dimethylaniline in 40 ml of dichloromethane. After stirring for one hour at 20 ° C, the contents of the flask are poured into 100 ml of water. The mixture is diluted with 100 ml of dichloromethane and stirred. The organic phase is decanted, dried with magnesium sulfate, filtered and evaporated in vacuo. The solid obtained is taken up in ethyl ether, triturated and filtered. After drying, a greenish powder is obtained with a yield of 22%. Melting point: 146.4-148 ° C. NMR: H (400 MHz, CDCl 3, d): 3.10 (m, 2H, CH 2); 4.40 (m, 2H, CH2); 5.65 (s, 1H, NH); 6.50 (s, 1H, NH); 6.80-7.60 (m, 11H, arom.); 8.20 (m, 2H, arom.).
7. 2) 2- (4-aminophenyl) -ethyl [4-phenylamino) phenyl] -carbamate: The experimental protocol used is the same as that described for intermediate 2.2, intermediate 7.1 replaces 4-nitro-N- [4- (phenylamino) phenyl] -benzenacetamide. A white solid is obtained with a yield of 48%. Melting point: 140-140.5 ° C. NMR, H (400 MHz, DMSO d6, d): 2.75 (m, 2H, CH2);
4. 15 (m, 2H, CH2); 5.20 (s, 2H, NH2); 6.50 (m, 2H, arom.); 6.70 (m, 1H, arom.); 7.00 (m, 6H, arom.); 7.15
(m, 2H, arom.); 7.30 (m, 2H, arom.); 8.00 (s, 1H, NH);
9. 40 (s, 1H, NH).
7. 3) 2- Hydrochloride. { 4- . { [2-thienyl (imino) methyl] amino} phenyl -e-l [4- (phenylamino) phenyl] -carbamate: 7_ The experimental protocol used is the same as that described for intermediate 2.3, intermediate 7.2 replaces 4-amino-N- [4- (phenylamino) phenyl] -benzenacetamide. A white solid is obtained with a yield of 34%. Melting point: 153-159 ° C. NMR: H (400 MHz, DMSO d6, d): 3.00 (m, 2H, CH2);
4. 30 (m, 2H, CH2); 6.60-7.70 (m, 14H, arom.); 8.20 (m, 2H, thiophene); 8.90 (s, 1H, NH +); 9.50 (s, 1H, NH-CO); 9.90 (s, 1H, NH +); 11.70 (s, 1H, NH +). IR: vc = 0 (carbamate): 1719 cm "1; vc = N (amidine): 1598 cm
Example 8: N- Hydrochloride. { 2- . { 4- . { [2-thienyl (imino) methyl] amino} phenyl } ethyl} -N '- [4- (phenylamino) phenyl] -urea: 8 8.1) N- [2- (4-nitrophenyl) -ethyl] -N' - [4-phenylamino) phenyl] -urea: 0.5 g is dissolved ( 1.7 mmol) of triphosgene in 8 ml of dichloromethane in a 100 ml flask under argon. Using a motorized syringe, a solution of 0.92 g (5 mmol) of 4-aminodiphenylamine and 1.44 ml (8.2 mmol) of diisopropylethylamine in 15 ml of dichloromethane is added over one hour. 5 minutes after the addition was finished, 1.01 g (5 mmol) of 4-nitrophenethylamine hydrochloride followed by a solution of 1.44 ml (8.2 mmol) of diisopropylethylamine in 10 ml of dichloromethane are added in a single portion. After stirring for two hours at 20 ° C, the reaction mixture is diluted with 50 ml of dichloromethane and 20 ml of water. The organic phase is decanted and re-treated with 20 ml of water. After drying with MgSO 4, the organic solution is partially concentrated in vacuo. The formed precipitate is collected by filtration and rinsed with dichloromethane. A yellow solid is obtained with a yield of 40%. Melting point: 204-205 ° C. NMR: H (100 MHz, DMSO d6, d): 2.96 (m, 2H, CH2); 3.50 (m, 2H, CH.-NH); 5.78 (m, 1H, HN-CH,); 6.45 (broad s, 1H, Ph-NH-CO); 6.72-7.49 (m, 11H, arom.); 7.81 (broad s, 1H, NH); 8.15 (m, 2H, arom.).
8. 2) N- [2- (4- (aminophenyl) ethyl] -N'-4- (phenylamino) phenyl] urea: A solution of intermediate 8.1 (0.68 g, 1.81 mmol) in 40 ml of a THF / ethanol mixture ( 3/1) as well as
0. 1 g of 10% Pd / C is introduced in a stainless steel autoclave equipped with a magnetic stirrer. The reaction mixture is stirred under hydrogen pressure
(1.5 bar) for 1 hour at a temperature of 20 ° C. The Pd / C is then removed by filtration and the filtrate is concentrated in vacuo. The solid obtained is washed successively with ethyl acetate and dichloromethane. A beige powder is obtained with a yield of 61%.
Melting point > 260 ° C. X H NMR (100 MHz, DMSO d 6, d): 2.70 (m, 2 H, CH 2);
3. 40 (m, 2H, CH2-NH); 5.18 (broad s, 2H, NH2); 6.07 (m,
1H, HN-CH2); 6.60-7.45 (m, 13H, arom.); 8.00 (s broad,
1H, NH); 8.41 (broad s, 1H, Ph-NH-CO).
8. 3) N- Hydrochloride. { 2-. { 4-. { [2-thienyl (imino) methyl] amino} phenyl } ethyl} -N '- [4- (phenylamino) phenyl] -urea: 8_ 0.38 g (1.10 mmol) of intermediate 8.2 and 0.34 g (1.21 mmol) of S-methyl-2-thiophene thiocarboximide hydroiodide are dissolved in 20 ml of isopropanol. in a 50 ml flask. The reaction mixture is stirred for 20 hours at a temperature of 60 ° C. After evaporation of the solvent in vacuo, the residue is taken up in 50 ml of a 1/1 mixture of a saturated solution of Na 2 CO 3 and ethyl acetate. The reaction medium is stirred vigorously and after a moment a precipitate appears. This is collected, filtered and rinsed successively with ethyl acetate and water. After drying, the precipitate is purified on a column of silica gel (eluent THF). The pure fractions are collected and concentrated in vacuo. The solid obtained (300 mg) is dissolved in 80 ml of THF, to which is added 2 ml of a 1 N HCl solution in ethyl ether. The precipitates formed from hydrochloride are filtered and rinsed with THF followed by ethyl ether to produce a light gray powder. Melting point: the product becomes a foam. H-NMR (400 MHz, DMSO d6, d): 2.80 (m, 2H, CH2); 3.37 (m, 2H, CH2); 4.46 (broad s, 1H, NH); 6.40 (broad s, 1H, NH-CH2); 6.70 (m, 1H, thiophene); 6.94 (m, 4H, arom.); 7.15 (m, 2H, arom.); 7.28 (m, 2H, arom.); 7.40 (m, 5H, arom.); 8.17 (m, 2H, thiophene); 8.78 (broad s, 1H, Ph-NH-CO); 8.93 (broad s, 1H, NH +); 9-84 (s broad, 1H, H?, * 11.52 (broad s, 1H, NH +) - IR: vc = 0 (urea): 1654 cm "1; vc_N (amidine): 1598 cm" 1.
Example 9: 4- Hydrochloride. { 4- . { [2-thienyl (imino) methyl] amino} phenyl } -N- [4- (phenylamino) phenyl] -1-piperazine acetamide: 9. 9.1) ethyl acetate 4- (nitrophenyl) -1-piperazine 3 g (14.5 mmol) of l- (4-nitrophenylpiperazine) are dissolved and 1.8 ml (15.9 mmol) of bromoethyl acetate in 60 ml of dichloromethane in a 100 ml flask. After the addition of 2.42 ml (17.4 mmol) of triethylamine, the reaction mixture is stirred, at 20 ° C, for one hour. The solution is then poured into 100 ml of water and extracted with 100 ml of dichloromethane. After decanting, the organic phase is dried with magnesium sulfate, filtered and concentrated in vacuo. The solid obtained is taken up in ethyl ether, triturated and filtered. A yellow powder is obtained with a yield of 89%. Melting point: 122.1-122.5 ° C. NMR: H (400 MHz, CDCl 3, d): 1.3 (t, 3 H, CH 3, J = 7 Hz); 2.75 (m, 4H, piperazine); 3.30 (s, 2H, CO-CH2); 3.50 (m, 4H, piperazine); 4.20 (q, 2H, CH2-CH3, J = 7 Hz); 7.45 (AB, 4H, Ph-N02).
9. 2) 4- (Nitrophenyl) -1-piperazine acetic acid: 32.4 ml of a 1 M aqueous LiOH solution are added dropwise at 20 ° C in a flask containing a solution of 3.8 g (13 mmol) of intermediate 9.1 in solution in 80 ml of THF. After stirring for one hour, the reaction mixture is acidified to pH = 5 with a 2N hydrochloric acid solution. The precipitate obtained is filtered and rinsed with a minimum amount of THF and water. The product is used as it is in the next stage. X H NMR (100 MHz, D 20, d): 3.30 (m, 4H, piperazine); 3.60 (m, 6H, piperazine + CO-CH2); 7.45 (AB, 4H, Ph-N02).
9. 3) 4- (-nitrophenyl) -N- [4- (phenylamino) phenyl] -1-piperazine acetamide: The protocol used is the same as that described for intermediary 2.1, intermediate 9.2 replaces 4-nitrophenylacetic acid. A yellow solid is obtained with a yield of 84%. Melting point:
212-213 ° C. X H NMR (400 MHz, CDCl 3, d): 2.80 (m, 4H, piperazine); 3.25 (s, 2H, CO-CH2); 3.50 (m, 4H, piperazine); 5.70 (s, 1H, NH); 6.90 (m, 3H, arom.); 7.10 (m, 4H, arom.); 7.30 (m, 2H, arom.); 7.85 (AB, 4H, Ph-N02); 8.90 (s, 1H, NHCO).
9. 4) 4- (4-Aminophenyl) -N- [4- (phenylamino) phenyl] -1-piperazine acetamide: The protocol used is the same as that described for intermediate 2.2, intermediate 9.3 replaces 4-nitro-N - [4- (phenylamino) phenyl] -benzenacetamide. A brown oil with a yield of 71% is obtained. X H NMR (400 MHz, CDCl 3, d): 2.80 (m, 4H, piperazine); 3.15 (m, 4H, piperazine); 3.20 (s, 2H, CO-CH2); 5.70 (s, 1H, NH); 6.70 (m, 2H, arom.); 6.90 (m, 3H, arom.); 7.10 (m, 4H, arom.); 7.30 (m, 2H, arom.); 7.50 (m, 2H, arom.); 9.10 (s, 1H, NHCO).
9. 5) Hydrochloride of 4-. { 4- . { [2-thienyl (imino) methyl] amino} phenyl } -N- [4- (phenylamino) phenyl] -1-piperazine acetamide: 9. The protocol used is the same as that described for intermediate 2.3, intermediate 9.4 replaces 4-amino-N- [4- (phenylamino) phenyl] -benzenacetamide. A yellow solid is obtained with a yield of 30%.
Melting point: 230-240 ° C. NMR 'H (400 MHz, DMSO d6, d): 3.10-3.50 (m, 4H, piperazine); 3.65 (m, 2H, piperazine); 3.90 (m, 2H, piperazine); 4.30 (s, 2H, CO-CH2); 6.80 (m, 1H, thiophene); 6.90-7.40 (m, 11H, arom.); 7.50 (m, 2H, arom.); 8.15 (m, 2H, thiophene); 8.75 (s, 1H, NH +); 9.80 (s, 1H, NH?; 10.9 (m, 2H, NHCO + NH? 11.40 (s, 1H, NH +). IR: vc = 0 (amide): 1680 cm "1; vc = N (amidine): 1512 cm "1.
Example 10: 1- hydrochloride. { [(-phenylamino) phenylamino] carbonyl} -4-. { 4-. { [2-thienyl (imino) methyl] amino} phenyl } -piperazine: 1.0 The protocol used is the same as that described for Example 8. The product forms salts under conditions that are identical to compound 2. except that THF replaces methanol. A yellow powder is obtained. Melting point: 239-240 ° C. X H NMR (400 MHz, DMSO d 6, d): 3.30 (broad s, 4H, piperazine); 3.70 (broad s, 4H, piperazine); 5.80 (broad s, 1H, NH); 6.73 (m, 1H, thiophene); 6.98 (m, 4H, arom.); 7.17 (m, 2H, arom.); 7.28-7.37 (m, 7H, arom.); 8.16 (m, 2H, thiophene); 8.65 (broad s, 1H, Ph-NH-CO); 8.80 (broad s, 1H, NH +); 9.80 (broad s, 1H, NH +); 11.52 (broad s, 1H, NH +). IR: vc = 0 (urea): 1654 cm "1; vc = N (amidine): 1597 cm" 1.
Example 11: 4- hydrochloride. { [2-thienyl (imino) methyl] amino} -N- [4- (phenylamino) phenyl] -benzenebutanamine: 1_1
11. 1) 4-Nitro-N- [4- (phenylamino) phenyl] -benzenebutanamine: 1.12 g (3 mmol) of 4-nitro-N- [4- (phenylamino) phenyl] -benzenebutanamide (obtained under the same conditions are dissolved. than intermediate 2.1) in 50 ml of anhydrous THF in a 250 ml three-necked flask in an argon atmosphere. The solution is cooled using an ice bath, before the dropwise addition of 15 ml (15 mmol) of a diborane / THF solution. The reaction mixture is refluxed for 5 hours. After returning the temperature to 20 ° C, 25 ml of a solution of HCl (6 N) is added slowly dropwise and the mixture is refluxed for 2 hours. The solution is then cooled using an ice bath before the addition of a 20% sodium hydroxide solution until a basic pH is reached. The product is extracted using ethyl ether (2 x 50 ml), the organic solution is washed with water with salt (2 x 50 ml) and dried with magnesium sulfate. After filtration and concentration in vacuo, the residue is purified on a column of silica gel (eluent: heptane / AcOEt 1/1). The pure fractions are collected and evaporated under vacuum to produce a brown oil with a yield of 28%. NMR: H (400 MHz, DMSO d6, d): 1.55 (m, 2H, CH2); 1.71 (m, 2H, CH2); 2.75 (m, 2H, CH2-Arom); 2.98 (m, 2H, HN-CH2); 5.29 (m, 1H, NH); 6.51-7.51 (m, 12H, Arom. + NH); 8.15 (m, 2H, Ph-N02).
11. 2) 4-Amino-N- [4- (phenylamino) phenyl] -benzenebutamine: The experimental protocol used is the same as that described for intermediate 2.2, intermediate 11.1 replaces 4-nitro-N- [4- (phenylamino ) phenyl] -benzenacetamide. A brown oil with a yield of 36% is obtained. NMR? (400 MHz, DMSO d6, d): 1.55 (m, 4H, 2 x CH2); 2.44 (m, 2H, CH2); 2.97 (m, 2H, CH2); 4.81 (s, 2H, NH2); 5.27 (m, 1H, NH); 6.47-7.10 (m, 13H, arom.); 7.49 (s, 1H, NH).
11. 3) Hydrochloride of 4-. { [2-thienyl (imino) me il] amino} - N- [4- (phenylamino) phenyl] -benzenebutanamine: 1_1 0.10 g (0.3 mmol) of intermediate 11.2 and 0.11 g (0.37 mmol) of S-methyl-2-thiophene thiocarboximide hydroiodide are dissolved in 5 ml of isopropanol with 0.05 ml (0.6 mmol) of pyridine added to it, in a 50 ml flask. The reaction mixture is stirred for 20 hours at a temperature of 23 ° C. After evaporation of the solvent in vacuo, the residue is taken up in 25 ml of a mixture (1/1) of a saturated solution of NaHCO 3 and dichloromethane. After decanting, the organic phase is washed with 2 x 25 ml of water with salt. The organic solution is dried with magnesium sulfate, filtered, concentrated in vacuo and the residue is purified on a column of silica gel (eluent: dichloromethane + 5% ethanol). The pure fractions are collected and concentrated in vacuo. A pink powder is obtained which forms salts by adding a solution of 1 N HCl in ethyl ether (1 ml) to the solution of the base in acetone. After stirring for 1 hour at 20 ° C, the reaction mixture is filtered and the powder washed successively with 20 ml of acetone and 20 ml of ethyl ether. Melting point: 165-166 ° C. H NMR (400 MHz, DMSO d6, d): 1.71 (m, 4H, 2 x CH2); 2.66 (, 2H, CH2); 3.20 (m, 2H, CH2); 6.85-7.41 (m, 14H, arom.); 8.16 (m, 2H, thiophene); 8.53 (broad s, 1H, NH); 8.87 (broad s, 1H, NH +); 9.83 (broad s, 1H, NH +); 11.19 (broad s, 2H, 2 x NH +); 11.56 (broad s, 1H, NH +). IR: vc = N (amidine): 1595 cm "1.
Example 12: 3- Hydrochloride. { [2-thienyl (imino) methyl] amino} -N- [4- (phenylamino) phenyl] -benzenepropanamide: 12. 12.1) 3-nitrophenylethanol mesylate: A solution of 4.63 ml (59.8 mmol) of methanesulfonyl chloride diluted with 20 ml of dichloromethane is added dropwise to a solution of 10 g (59.8 mmol) of 3-nitrophenylethanol and 8.31 ml (59.8 mmol) of triethylamine in 120 ml of dichloromethane, cooled with an ice bath. Stirring is maintained for 1 hour at 0 ° C and for 2 hours at 20 ° C. The reaction mixture is then concentrated in vacuo and the residue taken up in 125 ml of ethyl acetate and 100 ml of water. After stirring and decanting, the organic phase is washed successively with 100 ml of water and 100 ml of water with salt. The organic solution is dried with magnesium sulfate, filtered and concentrated in vacuo. The evaporation residue is purified on a silica column (eluent: heptane / ethyl acetate 6/4) and the pure fractions are collected and evaporated to yield a yellow oil with a yield of 71%. X H NMR (100 MHz, CDCl 3, d): 3.00 (s, 3 H, CH 3); 3.20 (t, 2H, CH2, J = 5.8 Hz); 4.50 (t, 2H, CH2); 7.60 (m, 2H, arom.); 8.20 (m, 2H, arom.).
12. 2) 3-Nitrobenzene-propanenitrile: 0.49 g (10 mmol) of NaCN are introduced in one portion into a 100 ml flask, under an argon atmosphere, containing a solution of 1.22 g (5 mmol) of intermediate 12.1 in 20 ml. ml of DMF dried. The reaction mixture is heated at 60 ° C for 3 hours and, after allowing the temperature to return to 20 ° C, it is poured into 100 ml of water. The solution is extracted with 5 x 50 ml of ethyl acetate, the organic phases are collected and washed successively with 100 ml of water and 100 ml of water with salt. After drying with magnesium sulfate, the organic solution is concentrated in vacuo and the residue is purified on a silica column (eluent: heptane / ethyl acetate: 7/3). The pure fractions are collected and concentrated in vacuo to yield a light yellow powder with a yield of 78%. Melting point: 86-88 ° C. NMR JH (100 MHz, CDCl 3, d): 2.70 (t, 2H, CH 2, J = 5.8 Hz); 3.10 (t, 2H, CH2); 7.60 (m, 2H, arom.); 8.20 (m, 2H, arom.).
12. 3) 3-nitrobenzene propanoic acid: A solution of 2.33 g (19.2 mmol) of intermediate 12.2 in 100 ml of an aqueous solution of 10% HCl and 100 ml of ethanol is refluxed for 72 hours. After allowing the temperature to return to 20 ° C, the reaction mixture is concentrated to dryness in vacuo. The residue is taken up in 100 ml of ethyl acetate and washed with 3 x 100 ml of water and 50 ml of water with salt. After drying with sodium sulfate, the organic solution is filtered and concentrated in vacuo. The residue from the evaporation is purified on a silica column (eluent: heptane / ethyl acetate 95/5 to 80/20). A bright yellow powder is obtained with a yield of 21%. Melting point: 107-109 ° C. X H NMR (100 MHz, CDCl 3, d): 2.70 (m, 2 H, CH 2); 3.10 (, 2H, CH2); 5.40 (broad s, 1H); 7.50 (m, 2H, arom.); 8.10 (m, 2H arom.).
12. 4) 3-Nitro-N- [4- (phenylamino) phenyl] -benzenepropanamide: The experimental protocol used is the same as that described for intermediary 2.1, the intermediate
12. 3 replaces 4-nitrophenylacetic acid. A brown powder with a yield of 70% is obtained. Melting point 130-132 ° C. X H NMR (CDC13, 100 MHz, d): 2.70 (t, 2H, CH2, J = 5.8 Hz); 3.20 (t, 2H, CH2); 5.70 (s broad, 1H, NH); 6.90-7.60 (m, 13H, arom.).
12. 5) 3-amino-N- [4- (phenylamino) phenyl] -benzenepropane ida: The experimental protocol used is the same as that described for intermediate 2.2, intermediate 12.4 replaces 4-nitro-N- [4- ( phenylamino) phenyl] -benzenacetamide. A white powder with a yield of 64% is obtained. Melting point: 164-166 ° C. X H NMR (CDC13, 100 MHz, d): 2.80 (m, 2H, CH2); 3.50 (m, 2H, CH2); 5.10 (broad s, 2H, NH2); 6.50 (m, 3H, arom.); 6.80-7.45 (m, 8H, arom.); 7.60 (m, 2H, arom.); 8.15 (broad s, 1H, NH); 9.88 (s, 1H, NH-CO).
12. 6) 3- Hydrochloride. { [2-thienyl (imino) methyl] amino) -N- [4-phenylamino) phenyl] -benzenepropanamide: 1_2 The experimental protocol used is the same as that described for intermediate 2.3, intermediate 12.5 replaces 4-amino-N - [4- (phenylamino) phenyl] -benzenacetamide. After the salt formation, a light beige powder is obtained with a yield of 78%. Melting point 228-230 ° C. NMR? E (400 MHz, DMSO d6, d): 2.70 (m, 2H, CH2);
2. 96 (m, 2H, CH2); 5.20 (broad s, 1H, NH); 6.74 (m, 1H, thiophene); 7.00 (m, 4H, arom.); 7.19 (m, 2H, arom.); 7.29 (m, 1H, arom.); 7.39 (m, 3H, arom.); 7.47 (m, 3H, arom.); 8.18 (m, 2H, thiophene); 8.96 (broad s, 1H, NH +); 9.90 (broad s, 1H, NH +); 10.07 (s, 1H, NH-CO); 11.60 (broad s, 1H, NH +). IR: vc = 0 (amide): 1649cm_1; vc = N (amidine): 1596 cm "1.
Example 13: 4- (4- { [Amino (2-thienyl) methylidene] amino.}. Phenyl) -N- [2- (4-toluidino) phenyl] butanamide: 13_ 13.1) N '- (4- methyl phenyl) -1,2-benzenediamine: The reduction of the nitro function of N- (4-methylphenyl) -2-nitroaniline (Syn thesi s (1990) 430 is carried out in the presence of Pd / C in ethanol, in the conditions previously described for the intermediate 2.2 A violet product is obtained in a semi-oil, semi-crystal form with a 90% yield.
13. 2) 4- (4- { [Amino (2-thienyl) methylidene] amino.}. Phenyl) -N- [2- (4-toluidino) phenyl] butanamide: The experimental protocol used is the same as that described for Example 2, which starts from 4-nitrophenylbutyric acid and from intermediate 13.1. The product is isolated in the form of a free base. White solid. Melting point: 66-68 ° C.
Example 14: 4-anilinophenyl-4- (4- {[amino (2-thienyl) methylidene] amino} - phenyl) bu anoa or: 1.4 14.1) 4-anilinophenyl 4- (4-nitrophenyl) butanoate: 0.98 g (6.02 mmol) of 1, 1'-carbonyldiimidazole is added slowly at 20 ° C to a solution of 1.25 g (5.96 mmol) of 4-nitrophenylbutyric acid in 25 ml of CH2Cl2. The reaction mixture is stirred for 30 minutes before the addition of 1 g (5.42 mmol) of 4-hydroxy diphenylamine. After stirring for 3 hours, the reaction is stopped by the addition of 3 ml of MeOH and the solvent is evaporated in vacuo. The residue from the evaporation is purified on a column of silica gel (eluent: Heptane / AcOEt: 100/0 to 80/20). A yellow solid is obtained with a yield of 89%.
14. 2) 4-anil-inophenyl 4- (4 - { [Amino (2-t-ene-1) -methylidene] -amino} -phenyl) -butanoate: The experimental protocol used is the same as that described for intermediaries 2.2 and 2.3 , that starting from the intermediary 14.1. The product is isolated in the form of a free base. Pale yellow solid. Melting point: 147-148 ° C.
Example 15: 4- (4- { [Amino (2-thienyl) methylidene] amino.}. Phenyl) -N- [2- (4-toluidino) phenyl] butanamide: 1_5 15.1) N-. { 4- [4- (4-nitrophenyl) butoxy] phenyl} -N-phenylamine: 20 g (10.88 mmol) of 4-hydroxy-phenylamine, 2.0 ml (12 mmol) of 4- (4-nitrophenyl) -1-butanol and 1.66 ml (12 mmol) of tributylphosphine are successively introduced into a flask containing 10 ml of CH2C12. 1.90 ml (12 mmol) of diethylazodicarboxylate is added dropwise and everything is stirred at 20 ° C for 16 hours. The solvent is evaporated in vacuo and the residue is purified on a silica column (eluent: heptane / AcOEt: 100/0 to 80/20). The expected product is obtained in the form of a dark red oil with a yield of 35%.
. 2) N '-. { 4- [4- (4-anilinophenoxy) butyl] phenyl} -2- iofencarboximidamide: The experimental protocol used is the same as that described for intermediaries 2.2 and 2.3, starting from intermediary 14.1. The product is isolated in the form of a free base. White solid. Melting point: 120-121 ° C.
Example 16: N '-. { 4- [4- (3-anilinophenoxy) butyl] phenyl} -2-thiophenecarboximidamide: Ij6 The experimental protocol used is the same as that described for Example 15, starting from 3-hydroxy-diphenylamine. The product is isolated in the form of a free base. White solid. Melting point: 73-74 ° C.
Example 17: N '- (9ff-carbazol-3-yl) -2-thiophenecarboximidamide: 17_ The experimental protocol used is the same as that described for Example 1, starting from 3-aminocarbazole (Pharmazie (1993) 48 (11), 817-820). The product is isolated in the form of a free base. Solid light beige. Melting point: 243-244 ° C.
Example 18: 4- (4. {[[Amino (2-thienyl) methylidene] amino] phenyl) -N- (9J-carbazol-3-yl) butanamide hydrochloride: The experimental protocol used is the same as that described for Example 2, starting from 3-aminocarbazole (Pharmazi e (1993) 48 (11), 817-820) and 4-nitrophenylbutyric acid. Solid light beige. Melting point > 250 ° C. MS: MH +: 452.2.
Example 19: N '- [4- (lOH-phenothiazin-2-yloxy) phenyl] -2-thiophenecarboximidamide hydroiodide: .19. 19.1) 2- (4-ni-rhenoxy-1OH-phenothiazine: 1.1 g (5.11 mmol) of 2-hydroxy-1-OH-phenothiazine (J. Med. Chem. (1992) 35, 716), 1.34 g (9.71 mmol) of K2C03 and 0.94 g (6.64 mmol) of 4-fluoro-1-nitrobenzene are mixed in 25 ml of anhydrous DMF in a flask under argon, the reaction mixture is heated at 70 ° C for 18 hours. After evaporation and decantation, the organic phase is washed with 50 ml of water with salt, the organic solution is dried with MgSO 4, filtered and concentrated in vacuo, the residue is crystallized with diisopropyl ether, after drying, a yellow solid is obtained with a yield of 83% Melting point: 210-211 ° C.
19. 2) N '- [4- (lOH-phenothiazin-2-yloxy) phenyl] -2-thiophenecarboximidamide hydroiodide: The experimental protocol used is the same as that described for intermediaries 2.2 and 2.3, starting from intermediate 19.1 . The expected final product precipitates directly from the reaction mixture, is isolated by filtration and washed using iPrOH. Solid yellow. Melting point: 175-180 ° C.
Example 20: N '- Hydrochloride. { 4- (10-methyl-10fl-phenothiazin-2-yl) oxy] phenyl} -2-thiophenecarboximidamide: 2 < ) 20.1) 10-methyl-lOH-phenothiazin-2-yl-4-nitrophenylether:
0. 014 g (0.58 mmol) of NaH (60%) are added to a flask under an argon atmosphere, containing a solution of 0.1 g (0.29 mmol) of intermediate 19.1 in 10 ml of anhydrous DMF. Agitation is maintained, at 20 ° C, for 16 hours. 0.04 ml (0.58 mmol) of Mel are then added to the reaction mixture, with stirring at 20 ° C. At the end of the reaction, everything is poured into 50 ml of ice-cold water and the product is extracted using 50 ml of AcOEt. The organic phase is decanted, washed with 50 ml of water with salt, dried with MgSO 4, filtered and concentrated in vacuo. The residue is purified on a silica column (eluent: heptane / AcOEt: 80/20). An orange oil with a yield of 50% is obtained.
. 2) N '- Hydrochloride. { 4- (10-methyl-10H-phenothiazin-2-yl) oxy] phenyl} -2-thiophenecarboximidamide: The experimental protocol used is the same as that described for intermediaries 2.2 and 2.3, starting from intermediary 20.1. a white solid is obtained. Melting point: 256-257 ° C.
Example 21: 4- (4. {[Amino (2-thienyl) methylidene] amino] phenyl) -N- (10 H -phenothiazin-3-yl) butanamide hydrochloride: 2 1 21.1) 3-amino-10H -f enotiazine: The reduction of the nitro function of -nitro-10H-phenothiazine (J. Org. Chem. (1972) 37, 2691) is carried out in the presence of Pd / C in a mixture of EtOH / THF at the conditions described for the intermediary 2.2. A gray solid is obtained with a yield of 97%. Melting point: 150-156 ° C.
21. 2) 4- (4. {[[Amino (2-thienyl) methylidene] amino] phenyl) -N- (lOff-phenothiazin-3-yl) butanamide hydrochloride: The experimental protocol used is the same as the described for Example 2, starting from 4-nitrophenylbutyric acid and intermediate 21.1. Light green solid. Melting point: 170-176 ° C.
Example 22: -N '- (-. {4- [2- (10H-phenothiazin-2-yloxy) ethyl] -l-piperazinyl} phenyl) -2-thiophenecarboximidamide dihydrochloride: 2_2 22.1) 2- [ 4- (4-nitrophenyl) -l-piperazinyl] -1-ethanol: 7.5 g (60 mmol) of 2-bromoethanol are added, under an argon atmosphere, to a mixture of 10.35 g (50 mmol) of 1- (4 -nitrophenyl) piperazine, 7.6 g (55 mmol) of K2C03 and 9 mL (65 mmol) of Et3N in 200 mL of CH2Cl2. Everything is heated at 45 ° C for 18 hours. The reaction mixture is finally diluted with 50 ml of water, stirred and decanted. The organic phase is washed with 50 ml of water with salt, dried with MgSO 4, filtered and concentrated in vacuo. The residue is crystallized with diisopropyl ether. A yellow solid is obtained with a yield of 89%. Melting point: 98-99 ° C.
22. 2) 1- (2-bromoethyl) -4- (4-nitrophenyl) piperazine: 8.6 g (26 mmol) of CBr4 is added to a solution of 5 g (20 mmol) of intermediate 22.1 in 75 ml of CH2Cl2. Everything is cooled using an ice bath before the addition, in portions, of 6.3 g (24 mmol) of triphenylphosphine. Stirring is maintained for 2 hours at 20 ° C. After the addition of 50 ml of water, stirring and decanting, the organic phase is washed with 50 ml of water with salt, dried with MgSO 4, filtered and concentrated in vacuo. The residue of the evaporation is purified on a silica column (eluent: CH2Cl2 / EtOH: 95/5) and finally crystallized with ethyl ether. An orange yellow solid is obtained with a yield of 40%. Melting point: 134-135 ° C.
22. 3) 2-. { 2- [4- (4-Nitrophenyl) -l-piperazinyl] ethoxy} -10H-phenothiazine: The experimental protocol used is the same as that described for intermediary 19.1, starting from broker 22.2. A yellow solid is obtained with a yield of 43%. Melting point: 224-225 ° C.
22. 4) -N '- (4. {4- [2- (lOtf-phenothiazin-2-yloxy) yl] -1-piperazinyl} -phi] -2-phenylphenoxyamide-dihydrochloride: The protocol used experimental is the same as that described for intermediaries 2.2 and 2.3, starting from broker 22.3. Solid light beige. Melting point: 198-200 ° C.
Example 23: 4- (4. {[Amino (2-thienyl) methylidene] amino] phenyl) -N- [4- (4-toluidino) phenyl] butanamide hydrochloride: 23. 23.1) N '- (4-methylphenyl) -1,4-benzenediamine: The reduction of the nitro function of N- (4-methylphenyl) -4-nitroaniline (Indi an J. Chem. (1981) 20B, 611-613) is carried out in the presence of Pd / C in ethanol, at the conditions described for the intermediary 2.2. A gray solid is obtained with a yield of 85%.
23. 2) 4- (4. {[[Amino (2-thienyl) methylidene] amino] phenyl) -N- [4- (4-toluidino) phenyl] butanamide hydrochloride: The experimental protocol used is the same as that described for Example 2, starting from intermediate 22.3 and 4-nitrophenylbutyric acid. Solid yellow. Melting point: 142-145 ° C.
Example 24: 3-anilinophenyl 4- (4- { [Amino (2-thienyl) methylidene] amino.}. - phenyl) butanoate: 2_4 The experimental protocol used is the same as that described for Example 14, starting from from 3-hydroxy diphenylamine and 4-nitrophenylbutyric acid. White solid. Melting point: 110-112 ° C.
Example 25: 2- (4. {[Amino (2-thienyl) methylidene] amino] phenyl) -N- [2- (9H-carbazol-4-yloxy) ethyl] acetamide hydrochloride: 25. 25.1 ) 3- (2-bromoethoxy) -9H-carbazole: A mixture of 1.83 g (10 mmol) of 4-hydroxycarbazole
(J. Chem. Soc. (1955), 3475-3477; J Med. Ch. (1964) 7, 158-161), 1.08 ml (12.5 mmol) of 1,2-dibromomethane and 2.6 ml (10.5 mmol). ) of an aqueous solution of 4 M NaOH in 2 ml of water is heated at reflux for 5 hours. After the temperature returns to 20 ° C, the product is extracted using 2 times 30 ml of CH2Cl2. The organic solutions collected are then washed successively with 20 ml of water and 20 ml of water with salt. After drying with MgSO 4, filtration and concentration in vacuo, the residue is purified on a silica column (eluent: heptane / AcOEt). A beige powder with a yield of 32% is obtained. Melting point: 135-136 ° C.
. 2) 3- (2-azidoethoxy) -9H-carbazole: A mixture of 0.9 g (3.1 mmol) of intermediate 25.1 and 0.20 g (3.1 mmol) of NaN3 in 10 ml of DMF is heated at 70 ° C for 1 hour. Everything is then poured into 30 ml of a mixture of water and ice. After the addition of 50 ml of AcOEt and stirring, the organic phase is decanted and washed successively with 20 ml of water and 20 ml of water with salt. The organic solution is then dried with Na 2 SO 4, filtered and concentrated in vacuo. After drying, a beige powder is obtained (quantitative yield) which is used as it is in the next step.
. 3) 2- (9H-carbazol-3-yloxy) ethylamine: A solution of intermediate 25.2 in 50 ml of EtOH, as well as 0.3 g of Pd / C (10%) are introduced in a stainless steel autoclave equipped with an agitator magnetic. The reaction mixture is stirred for 2 hours at 1.5 bar of H2 at a temperature of 25 ° C. The Pd / C is then removed by filtration, and the filtrate is concentrated in vacuo to dryness. The residue is taken up in ethyl ether and the crystals formed are filtered and rinsed abundantly with ethyl ether. After drying, a white powder with a yield of 82% is obtained. Melting point: 145-146 ° C.
. 4) 2 - (4 - { [Amino (2-thienyl) methylidene] amino] phenyl) - N - [2- (9H-carbazol-4-yloxy) ethyl] acetamide hydrochloride: The experimental protocol used is the same as that described for Example 2, starting from intermediate 25.3 and 4-nitrophenylbutyric acid. Solid light beige. Melting point: 233-234 ° C.
Example 26: N- (4. {[[Amino (2-thienyl) methylidene] amino] phenyl) -2-anilinobenzamide hydrochloride: The experimental protocol used is the same as that described for Example 2, starting from from N-phenylanthranilic acid and 4-nitrofenetilamy. Pale yellow solid. Melting point: 163-165 ° C.
Example 27: N- (4. {[[Amino (2-thienyl) methylidene] amino} phenethyl) -2- (2,3-dimethylanilino) benzamide hydrochloride: 27. The experimental protocol used is the same as the one described for Example 2, starting from mefenamic acid and 4-nitrophenethylamine. Pale yellow solid. Melting point: 168-170 ° C.
Example 2_8: N'- dihydrochloride. { 4- [4- (2-anilinobenzoyl) -1-piperazinyl] phenyl} - 2-thiophenecarboximidamide: 2_8 The experimental protocol used is the same as that described for Example 2, starting from N-phenylanthranilic acid and 4-nitrophenylpiperazine. Pale yellow solid. Melting point: 168-170 ° C.
Example 29: N '- (4-. {4- [2- (2,3-dimethylanilino) benzoyl] -l-piperazinyl} phenyl) -2-thiophenecarboximidamide dihydrochloride: 29_ The experimental protocol used is the same than that described for Example 2, starting from mefenamic acid and 4-nitrophenylpiperazine. Pale yellow solid. Melting point: 166-168 ° C.
Example 30: 4- (4. {[[Amino (2-thienyl) methylidene] amino] phenyl) -N- [4-phenoxyphenyl] butanamide hydrochloride: 30.
The experimental protocol used is the same as that described for Example 14, starting from 4-nitrophenylbutyric acid and 4-phenoxyphenol. Pale yellow solid. Melting point: 119-123 ° C.
Example 31: N- (4. {[[Amino (2-thienyl) methylidene] amino} phenethyl) -4- (4-hydroxyphenoxy) benzamide hydrochloride: The experimental protocol used is the same as that described for Example 2, starting from 4- (4-hydroxyphenoxy) benzoic acid and 4-nitrophenethylamine pale yellow solid, melting point: 155-157 ° C.
Example 32: N- [2- (9ff-carbazol-4-yloxy) ethyl] -2-thiophenecarboximidamide: 32. The experimental protocol used is the same as that described for intermediate 2.3, starting from intermediate 25.3. The expected product is isolated in the form of a free base. White solid. Melting point: 180-181 ° C.
Example 33: N- [3- (9H-carbazol-4-yloxy) propyl] -2-thiophenecarboximidamide: 33. 33.1) 2- [3- (9H-carbazol-4-yloxy) propyl] -lff-isoindol-1 , 3 (2H) dione: 1 g (5.46 mmol) of 4-hydroxycarbazole (J. Ch em. Soc. (1955), 3475-3477; J Med. Chem. (1964) 7, 158-161) is added to a suspension, under argon, of 0.23 g (5.73 mmol) of NaH (60%) in 20 ml of anhydrous DMF. After stirring for 30 minutes at 20 ° C, 1.46 g (5.46 mmol) of 3-bromopropylphthalimide in solution in 10 ml of anhydrous DMF is added dropwise to the reaction mixture. Everything is heated at 80 ° C for 16 hours. After the temperature returns to 20 ° C, 5 ml of water are added and the mixture is concentrated in vacuo. The residue is taken up in 300 ml of CH2C12 and the organic solution is washed successively with 50 ml of 1 M NaOH, 100 ml of water and 100 ml of water with salt. After drying with MgSO 4, filtration and concentration in vacuo, an oily residue is obtained which crystallizes slowly. The crystals are washed using ethyl ether. A beige solid is obtained with a yield of 40%.
Melting point: 171-172 ° C.
33. 2) 3- (9H-carbazol-4-yloxy) propylamine: A solution of 0.13 ml (3.24 mmol) of hydrated hydrazine in 5 ml of ethanol is added dropwise to a solution of 0.8 g (2.16 mmol) of intermediate 33.1 in 30 ml of ethanol, heat to reflux. The reaction mixture is stirred and heated to reflux for 4 hours. After the temperature returns to 20 ° C, the product is separated between 100 ml of AcOEt and 50 ml of 1 M NaOH. After decanting, the organic phase is washed successively with 50 ml of water and 50 ml of water with salt . The organic solution is dried with Na 2 SO 4, filtered and concentrated in vacuo. A beige powder is obtained with a yield of 41%. Melting point: 146-147 ° C.
33. 3) N- [3- (9H-carbazol-4-yloxy) propyl] -2-thiophenecarboximidamide: The experimental protocol used is the same as that described for intermediate 2.3, starting from intermediate 33.2. The expected product is isolated in the form of a free base. Pale beige solid.
Melting point: 189-190 ° C.
Example 34: N- Yodhydrate. { 4- [4- (lOff-phenothiazin-2-yloxy) butyl] phenyl] -2-thiophenecarboximidamide: 34. The experimental protocol used is the same as that described for Example 15, starting from 4- (4-nitrophenyl) ) -1-butanol and 2-hydroxy-10H-phenothiazine (J. Med. Chem. (1992) 35, 716). The expected product precipitates directly from the reaction mixture, is isolated by filtration and washed using iPrOH. Solid yellow. Melting point: 262-270 ° C.
Example 35: 3- [(3. {[Amino (2-thienyl) methylidene] amino]} -benzyl) amino] -N- (4-anilinophenyl) propanamide trichlorohydrate: 3J5. 35.1) tert-butyl-3- (4-anilinoanilino) -3-oxopropyl carbamate: The experimental protocol used is the same as that described for intermediate 2.1, starting from Boc-β-Alanine and 4-aminodiphenylamine. After rapid filtration on a silica column (eluent: Heptane / AcOEt: 1/1), the expected product is obtained with a quantitative yield.
. 2) 3-amino-N- (4-anilinophenyl) propanamide: 15 g (42.2 mmol) of intermediate 35.1 are dissolved in 300 ml of AcOEt and 120 ml of an aqueous solution of 6 N HCl are added. Stir vigorously, at 20 ° C, for 1 hour. After decanting, the aqueous phase is recovered and made basic (pH> 11) by the addition of an aqueous solution of 2 M NaOH. The product is then extracted using 2 times 50 ml of CH 2 Cl 2 and the organic phase is washed with 50 ml of water with salt. After drying with MgSO 4, filtration and concentration in vacuo, the residue is purified on a silica column (eluent: CH 2 Cl 2 / EtOH / NH 4 OH (20%): 20/5 / 0.5). A violet powder with a yield of 73% is obtained. Melting point: 108-110 ° C.
. 3) N- (4-anilinophenyl) -3- [(3-nitrobenzyl) amino] ropanamide: 1.40 g (5.5 mmol) of the intermediate 35.2, 0.92 g (6 mmol) of 3-nitrobenzaldehyde and 3 g of pulverized in or sieve 4A molecular weight that has been activated in advance is added successively, under an inert atmosphere, in a flask containing 100 ml of anhydrous MeOH. The reaction mixture is stirred vigorously for 15 hours before the addition, in portions, of 0.24 g (6 mmol) of NaBH 4. Stirring is maintained for another 4 hours before the addition of 10 ml of water. After one hour, the sieve is filtered and the reaction mixture is extracted twice with 100 ml of CH2C12. The organic phase is washed successively with 50 ml of water and 50 ml of water with salt, dried over sodium sulfate, filtered and concentrated in vacuo. The residue is purified on a silica column (eluent: CH2Cl2 / EtOH: 20/1). An orange oil with a yield of 94% is obtained.
. 4) 3 - [(3-aminobenzyl) amino] -N- (4-anilinophenyl) propanamide: The reduction of the nitro function of intermediate 35.3 is carried out in the presence of Pd / C in ethanol, under the conditions described for intermediary 2.2. After filtering the Pd / C and concentration in vacuo, the product is used directly in the next step.
. 5) 3 - [(3 -. {[[Amino (2-thienyl (methylidene] amino]} -benzyl) amino] -N- (4 -anilin phenyl) propanamide trichlorohydrate: 0.50 g (1.40 mmol) of the intermediate 35.4 and 0.50 g
(1.75 mmol) of S-methyl-2-thiophene thiocarboximide hydroiodide are dissolved in 15 ml of isopropanol and 15 ml of DMF in a 50 ml flask, in the presence of 0.11 ml (1.40 mmol) of pyridine. The reaction mixture is stirred for 20 hours at 23 ° C. After evaporation of the solvent in vacuo, the residue is taken up in 100 ml of a mixture of 1 N NaOH and ethyl acetate (1/1). After decanting, the organic phase is washed with 50 ml of water followed by 50 ml of water with salt. The organic solution is dried with magnesium sulfate, filtered, concentrated in vacuo and the residue is purified on a column of silica gel (eluent: CH2Cl2 / EtOH / NH4OH (20%): 20/5 / 0.5). The pure fractions are collected and concentrated in vacuo. The compound is then dissolved in methanol and salts are formed by the addition of a solution of 1 N HCl in ethyl ether (10 ml). After stirring for one hour at 20 ° C, the reaction mixture is concentrated in vacuo to yield a pale yellow powder. Melting point: 184-186 ° C.
Example 36: N '- (4- { 2- [(10 H -phenothiazin-3-ylmethyl) amino] ethyl] phenyl) -2-thiophenecarboximidamide: 36. The experimental protocol used is the same as that described for intermediates 35.3, 35.4 and 35.5, starting from lOH-phenothiazine-3-carbaldehyde (J. Chem. Soc. (1951), 1834; Bul l. Soc. Chim. Fr. (1969), 1769) and 4- Nitrophenethylamine. Beige foam. MS:
MH +: 457.1.
Example 37: N- (4. {[[Amino (2-thienyl) methylidene] amino} phenethyl) -2-methoxy-1OH-phenothiaz-1-carboxamide hydrochloride: 3_7_ The experimental protocol used is the same than that described for Example 2, starting from 2-methoxy-10H-phenothiazine-1-carboxylic acid (J. Med. Ch em. (1992) 35 (4), 716-724) and 4-nitrophenethylamine. Pale yellow solid. Melting point > 200 ° C (decomposition).
Example 38: N '- [4- (2-. {[[(2-methoxy-lOH-phenothiazin-1-yl) methyl] amino} ethyl) phenyl] -2-thiophenecarboximidamide: 38. 38.1) 2- methoxy-1OH-phenothiazine-1-carbaldehyde: 4.6 g (20 mmol) of 2-methoxy-1 OH-phenothiazine are dissolved in an argon atmosphere in a three-necked flask containing 140 ml of anhydrous ethyl ether. 20 ml (50 mmol) of a solution of nBuLi (2.5 M) in hexane is then added dropwise at 20 ° C. The reaction mixture is stirred for 3 hours at 20 ° C before the dropwise addition of 6.2 ml (80 mmol) of anhydrous DMF. Stirring is maintained for a further 15 hours at 20 ° C. All is then poured into 150 ml of ice water and the product is extracted twice using 200 ml of ethyl acetate. The organic solution is washed with 100 ml of water with salt, dried with MgSO 4, filtered and concentrated in vacuo. The evaporation residue is taken up in diisopropyl ether, filtered and dried to yield a red solid with a yield of 30%. Melting point: 155-160 ° C.
38. 2) N '- [4- (2-. {[[(2-methoxy-10H-phenothiazin-1-yl) -yl] amino]} ethyl) phenyl] -2-thiophenecarboximidamide: The experimental protocol used is the same as that described for Example 36, starting from intermediate 38.1 and 4-nitrophenethylamine. Solid gray. MS: MH +: 487.2.
Example 39: N'-. { 4- [(lOH-phenothiazin-2-yloxy) methyl] phenyl} -2-thiophenecarboximidamide: 3_9 39.1) 2- [(4-nitrobenzyl) oxy] -lOH-phenothiazine: 1.08 g (5 mmol) of 2-hydroxy-10H-phenothiazine (J. Med. Ch., (1992) 35, 716) is dissolved in an argon atmosphere in 20 ml of anhydrous THF in a flask. The solution is then cooled to 0 ° C and 0.22 g (5.5 mmol) of NaH (60%) is added in portions. After stirring for 15 minutes, 1.2 g (5.5 mmol) of 4-nitrobenzyl bromide is added in portions and the reaction mixture is stirred for 15 hours at 20 ° C before it is poured into 50 ml of water cooled with ice. The product is extracted twice with 25 ml of CH2C12 and the organic solution is washed successively with 25 ml of water and 25 ml of water with salt. After drying with MgSO 4, filtration and concentration in vacuo, the residue of the evaporation is purified on a silica column (eluent: CH 2 Cl 2 / EtOH: 99/1 to 98/2). After concentration of the purest fractions, a brown solid is obtained, which is recrystallized using isopropyl acetate. A brown solid is finally obtained with a yield of 37%.
39. 2) 4- [(lOH-phenothiazin-2-yloxy) methyl] aniline: 1.02 g (4.52 mmol) of SnCl2.2H20 and 0.29 g (4.52 mmol) of Zn are successively added to a solution of 0.65 g (1.86 mmol) of intermediate 39.1 in a mixture of 9.3 ml of acetic acid and 1.2 ml of HCl (12 N). Everything is stirred for 18 hours at 20 ° C. The reaction mixture is then made basic by the addition of an aqueous solution of 30% NaOH. The product is then extracted twice using 50 ml of CH2Cl2. The organic solution is washed with 50 ml of water with salt, dried with MgSO 4, filtered and concentrated in vacuo. The residue is purified on a silica column (eluent: Heptane / AcOEt: 1/1). A pale yellow solid is obtained with a yield of 20%. Melting point: > 175 ° C (decomposition).
39. 3) N'-. { 4- [(10 H -phenothiazin-2-yloxy) methyl] phenyl} -2-thiophenecarboximidamide: The experimental protocol developed is the same as that described for intermediate 2.3, starting from intermediary 39.2. Solid pink salmon. Melting point: 105-116 ° C.
Pharmacological study of the products of the invention
Study of the effects on neuronal constitutive NO synthase of a rat cerebellum The inhibitory activity of the products of the invention is determined by measuring their effects on the conversion by the NO synthase of [3 H] L-arginine to [3 H] L-citrulline, according to the modified method of Bredt and Snyder (Proc. Na ti. Acad. Sci. USA, (1990) 87: 682-685). The cerebellum of Sprague-Dawley rats (300 g -Charles River) are rapidly removed, dissected at 4 ° C and homogenized in a volume of extraction buffer (50 mM HEPES, 1 mM EDTA, pH 7.4, pepstatin A 10 mg / ml, leupeptin 10 mg / ml). The homogenates are centrifuged at 21000 g for 15 min at 4 ° C. Dosing is carried out in glass test tubes in which 100 μl of incubation buffer containing 100 mM HEPES (pH 7.4), 2 mM EDTA, 2.5 mM CaCl 2, 2 mM dithiothreitol, 2 is distributed. mM of reduced NADPH and 10 μg / ml of calmodulin. 25 μl of a solution containing 100 nM of [3 H] L-arginine (Specific activity: 56.4 Ci / mmol, Amersham) and 40 μM of non-radioactive L-arginine is added. The reaction is started by adding 50 μl of homogenate, the final volume is 200 μl (the remaining 25 μl is either water or the product tested). After 15 min, the reaction is stopped with 2 ml of stop buffer (20 mM HEPES, pH 5.5, 2 mM EDTA). After passing the samples through a 1 ml column of DOWEX resin, the radioactivity is quantified by means of a liquid scintillation spectrometer. The compounds of Examples 3 to 5, 7, 9 to 12, 15, 16, 18, 19, 21, 22, 26, 27, 30, 31 and 35 to 37 described above show an IC 50 of less than 3.5 μM.
Study of lipid peroxidation effects of the cerebral cortex of a rat The inhibitory activity of the products of the invention is determined by measuring their effects on the degree of lipid peroxidation, determined by the concentration of malondialdehyde (MDA). MDA produced by peroxidation of unsaturated fatty acids is a good indication of lipid peroxidation (H Esterbauer and KH Cheeseman, Meth., In zymol. (1990) 186: 407-421). Male Sprague Da lawns weighing 200 to 250 g (Charles River) were sacrificed by decapitation. The cerebral cortex is removed, then homogenized using a Thomas manual homogenizer in a 20 mM Tris-HCl buffer, pH = 7.4. The homogenate was centrifuged twice at 50000 g for 10 minutes at 4 ° C. The package is stored at -80 ° C. On the day of the experiment, the pack is placed in suspension at a concentration of g / 15 ml and centrifuged at 515 g for 10 minutes at 4 ° C. The supernatant is used immediately to determine lipid peroxidation. The rat cerebral cortex homogenate (500 μl) is incubated at 37 ° C for 15 minutes in the presence of the compounds to be tested or solvent (10 μl). The lipid peroxidation reaction is initiated by adding 50 μl FeCl 2 at 1 mM, EDTA at 1 mM and ascorbic acid at 4 mM. After incubation for 30 minutes at 37 ° C, the reaction is stopped by adding 50 μl of a solution of di-t-butyl toluene hydroxylated (BHT, 0.2%). The MDA is quantified using a colorimetric test, reacting a chromogenic reagent (R), N-methyl-2-phenylindole (650 μl) with 200 μl of the homogenate for 1 hour at 45 ° C. The condensation of an MDA molecule with two molecules of the R reagent produces a stable chromophore, the maximum absorption wavelength of this is equal to 586 nm. (Caldwell et al., Buropean J. Ph., Arma., (1995) 285, 203-206). The compounds of Examples 1 9, 12 to 19, 21 to 23, 30 and 35 to 37 described above show an IC 50 lower than 30 μM.
It is noted that in relation to this date, the best method known by the applicant to carry out the aforementioned invention, is the conventional one for the manufacture of the objects to which it relates.
Claims (14)
1. Product of general formula (I) (I) wherein F represents a bond or a phenylene radical which may include, in addition to the two chains already represented in the general formula (I), up to two chosen substituents of a hydrogen atom, a halogen, an OH group, and a radical linear or branched alkyl or alkoxy having from 1 to 6 carbon atoms; A represents a radical in which R? R2, R3, R4, R5 represent, independently, a hydrogen atom, a halogen, the OH group, a linear or branched alkyl or alkoxy radical having from 1 to 6 carbon atoms, or a cyano, nitro or NR6R7 radical, R6 and R7 represent, independently, a hydrogen atom, the OH group, a linear or branched alkyl or alkoxy radical having from 1 to 6 carbon atoms, or also a group -COR8, R8 represents a hydrogen atom, the group OH, a linear or branched alkyl or alkoxy radical having from 1 to 6 carbon atoms, or NR 9 R 10, R 9 and R 10 represent, independently, a hydrogen atom, the OH group or a linear or branched alkyl radical having from 1 to 6 carbon atoms, Rn represents a hydrogen atom, the OH group, a linear or branched alkyl or alkoxy radical having from 1 to 6 carbon atoms, or a radical -COR12, and R12 represents a hydrogen atom, the group OH, a linear or branched alkyl radical having from 1 to 6 carbon atoms, or a radical wherein R1 R2, R3, R4, Rs represent, independently, a hydrogen atom, a halogen, the OH group, a linear or branched alkyl or alkoxy radical having from 1 to 6 carbon atoms, or a cyano radical , nitro or NR6R7, R6 and R7 independently represent a hydrogen atom, the OH group, a linear or branched alkyl or alkoxy radical having 1 to 6 carbon atoms, or also a group -COR8, R8 represents an atom of hydrogen, the OH group, a linear or branched alkyl or alkoxy radical having 1 to 6 carbon atoms, or NR9R10, R9 and R10 independently represent a hydrogen atom, the OH group or a linear or branched alkyl radical having 1 to 6 carbon atoms, B represents -CH-N02, a linear or branched alkyl radical having from 1 to 6 carbon atoms, carbocyclic aryl or heterocyclic with 5 or 6 members containing from 1 to 4 heteroatoms chosen of O, S, N and in particular the thiophene radicals , furan, pyrrole or thiazole, the aryl radical is optionally substituted by one or more groups chosen from linear or branched alkyl, alkenyl or alkoxy radicals having from 1 to 6 carbon atoms, or B represents a radical NR13R14, wherein R13 and Rx represent, independently, a hydrogen atom Or a linear or branched alkyl radical having 1 to 6 carbon atoms or a cyano or nitro radical, or Ri3 and Ri4 form with the nitrogen atom a non-aromatic heterocycle with five to six members, the elements of the chain are chosen from a group consisting of -CH2-, - NH-, -O- or -S-; W does not exist or represents a bond, or O, S or NR15, in which R15 represents a hydrogen atom or a linear or branched alkyl radical having from 1 to 6 carbon atoms; X represents a bond or a radical (CH2) k-NR16-, -0-, -S-, -CO-, -NR16-C0-, -C0-NR16-, -0-C0-, -C0-0- , -NR16-C0-0-, -NR16-CO-NR17-, k represents 0 or 1; Y represents a bond or radical selected from the radicals - (CH2) m-, - (CH2) m-0- (CH2) n-, - (CH2) mS- (CH2) n-, - (CH2) m- NR18- (CH2) n-, - (CH2) m-NR18-CO- (CH2) n-, - (CH2) a-C0-NR18- (CH2) n-, - (CH2) mQ- (CH2) n -, Q represents piperazine radicals, homopiperazine,
2 - . 2-methylpiperazine, 2,5-dimethylpiperazine, 4-oxypiperidine or 4-aminopiperidine, m and n are integers from 0 to 6; Ri6 Ri7 and R? ß represent, independently, a hydrogen atom or a linear or branched alkyl radical having from 1 to 6 carbon atoms; or a salt of the product. 2. Product according to claim 1, characterized in that: A represents a radical wherein R 1 R 2, R 3, R 4, R 5 represent, independently, a hydrogen atom, the OH group or a linear or branched alkyl or alkoxy radical having from 1 to 6 carbon atoms, R n represents a hydrogen atom or a linear or branched alkyl radical having from 1 to 6 carbon atoms, or a radical wherein R 1 t R 2, R 3, R 4, R 5 represent, independently, a hydrogen atom, the OH group or a linear or branched alkyl or alkoxy radical having from 1 to 6 carbon atoms; B represents a 5- or 6-membered carbocyclic or heterocyclic aryl radical containing from 1 to 4 heteroatoms selected from O, S, N and in particular the thiophene, furan, pyrrole or thiazole radicals, the aryl radical is optionally substituted by one or more selected groups of linear or branched alkyl, alkenyl or alkoxy radicals having from 1 to 6 carbon atoms; W does not exist or represents a bond, S or NR15, in which R15 represents a hydrogen atom or a linear or branched alkyl radical having from 1 to 6 carbon atoms; X represents a bond or a radical (CH2) k-NR16-, -0-, -S-, -CO-, -NR16-C0-, -C0-NR16-, -0-C0-, -C0-0- , -NR16-C0-0-, -NR16-CO-NR17- k represents 0 or 1; Y represents a bond or radical selected from the radicals - (CH2) m-, - (CH2) m-0- (CH2) n-, - (CH2) mS- (CH2) n-, - (CH2) m- NR18- (CH2) n-, - (CH2) m-NR18-CO- (CH2) n-, - (CH2) m-C0-NR18- (CH2) n-, - (CH2) ffi-Q- (CH2) ) n-, Q represents piperazine, homopiperazine, 2-meth i piperazine, 2, 5-dime ti lp iperaz ina, 4-oxypiperidine or 4-aminopiperidine, myn are integers from 0 to 6.
3. Product according to claim 1 or 2, characterized in that: A represents a wherein R.sub.1 R.sub.2, R.sub.3, R.sub.4 and R.sub.5 represent, independently, a hydrogen atom, the OH group or a linear or branched alkyl or alkoxy radical having from 1 to 6 carbon atoms, Ru represents a hydrogen atom or a methyl radical, or a radical in which R? r R2, R3, R4, R5 represent, independently, a hydrogen atom, the OH group Or a linear or branched alkyl or alkoxy radical having from 1 to 6 carbon atoms; B represents one of the phenyl, thiophene, furan, pyrrole or thiazole radicals optionally substituted by one or more groups chosen from linear or branched alkyl, alkenyl or alkoxy radicals having 1 to 6 carbon atoms; W does not exist or represents a bond, S or NR15, in which R15 represents a hydrogen atom or a linear or branched alkyl radical having from 1 to 6 carbon atoms; X represents a bond or a radical (CH2) k-NR16-, -o-, -S-, -CO-, -NR16-CO-, -CO-NR16-, -O-CO-, -CO-O- , -NR16-CO-0-, -NR16-CO-NR17-, k represents 0 or 1; Y represents a bond or radical selected from the radicals - (CH2) m-, - (CH2) m-0- (CH2) n-, - (CH2) mS- (CH2) n-, - (CH2) m- NR18- (CH2) n-, - (CH2) m-NR18-CO- (CH2) n-, - (CH2) m-CO-NR18- (CH2) n-, - (CH2) mQ- (CH2) n -, Q represents piperazine, homopiperazine, 2-me ilpiper azine, 2, 5 -dimet i lpiper azine, 4-oxypiperidine or 4-aminopiperidine, m and n are integers from 0 to 6.
4. Product according to one of claims 1 to 3, characterized in that: A represents a radical in which R.sup.lf R.sup.2, R.sup.3, R.sup.4, R.sup.5 represent, independently, a hydrogen atom or a methyl radical, R.sup.n represents a hydrogen atom or a methyl radical; B represents the thiophene radical; W does not exist, represents a simple link or S; X represents a bond or represents a radical - (CH2) K-NR16-, -O-, -S-, -CO-, -NR16-CO-, -CO-NR16-, -O-CO-, -CO- O-, -NR16-CO-0-, -NR16-CO-NR17-; k represents 0 or 1; Y represents a bond or radical selected from the radicals - (CH2) m-, - (CH2) m-0- (CH2) n-, - (CH2) mS- (CH2) n, - (CH2) m-NR18 - (CH2) n-, - (CH2) ffi-NR18-CO- (CH2) n-, - (CH2) m-CO-NR18- (CH2) n-, - (CH2) mQ- (CH2) n- , Q represents piperazine, m and n are integers between 0 and 6; R? ß Ri7 and R? ß represent a hydrogen atom. Product according to one of claims 1 to 4, characterized in that it is one of the following compounds: -N- [4 (f-enylamino) phenyl] -2 -thiofcarboximidamide; -4- . { [2-thienyl (imino) methyl] amino} -N- [4 - (f-enylamino) phenyl] -benzenacetamide; -. { 4-. { [2-thienyl (imino) methyl] amino} phenoxy } -N- [4- (f-enylamino) phenyl] -acetamide; -4- . { [2-thienyl (imino) methyl] amino} -N- [2 - (f-enylamino) phenyl] -benzenebutanamide; -4- . { [2-thienyl (imino) me t i 1] amino} -N- [4 - (f-phenylamino) phenyl] -benzenebutanamide; -4-. { [2-thienyl (imino) methyl] amino} -N- [4- (4-me t-oxy-f-phenylamino) phenyl] -benzenebutanamide; -2-. { 4-. { [2-thienyl (imino) methyl] amino} phenyl } ethyl [4- (f-enylamino) phenyl] -carbamate; -N- { 2-. { 4-. { [2-thienyl (imino) methyl] mino} f} ethyl} -N '- [4- (f-enylamino) phenyl] -urea; -4-. { 4-. { [2-thienyl (imino) methyl] amino} phenyl } -N- [4- (f-enylamino) phenyl] -1-piperazineacetamide; -l- { [(4-f-enylamino) f -arylamino] carbonyl} -4- . { 4- . { [2-thienyl (imino) methyl] amino} f} -piperazine; -4- . { [2-thienyl (imino) methyl] amino} -N- [4- (phenylamino) phenyl] -benzenebutanamine; -3-. { [2-thienyl (imino) methyl] amino} -N- [4- (phenylamino) phenyl] -benzenepropanamine; -4- (4- { [Amino (2-thienyl) methylidene] amino.}. Phenyl) -N- [2- (4-toluidino) phenyl] butanamide; -4-anilinophenyl-4- (4- { [Amino (2-thienyl) methylidene] amino.} - phenyl) butanoate; -4- (4- { [Amino (2-thieni1) methylidene] amino.}. Phenyl) -N- [2- (4-toluidino) phenyl] butanamide; -N'-. { 4- [4- (3-anilinophenoxy) butyl] phenyl} -2-thiophenecarboximidamide; -N '- (9H-carbazol-3-yl) -2-thiophenecarboximidamide; -4- (4- { [Amino (2-thienyl) methylidene] amino} phenyl) -N- (9H-carbazol-3-yl) butanamide; -N '- [4- (10H-phenothiazin-2-yloxy) phenyl] -2-thiophenecarboximidamide; -N'-. { 4- (1O-methyl-1OH-phenothiazin-2-yl) oxy] phenyl} -2-thiophenecarboximidamide; -4- (4- { [Amino (2-thienyl) methylidene] amino} phenyl) -N- (lOH-phenothiazin-3-yl) butanamide; -N '- (4-. {4- [2- (10H-phenothiazin-2-yloxy) ethyl] -l-piperazinyl} phenyl) -2-thiophenecarboximidamide; -4- (4- { [Amino (2-thienyl) methylidene] amino.}. Phenyl) -N- [4- (4-toluidino) phenyl] butanamide; -3-anilinophenyl 4- (4- { [Amino (2-thienyl) methylidene] amino.} - phenyl) butanoate; -2- (4- { [Amino (2-thienyl) methylidene] amino.}. Phenyl) -N- [2- (9H-carbazol-4-yloxy) ethyl] acetamide; -N- (4- { [Amino (2-thienyl) methylidene] amino.}. Phenyl) -2-anilinobenzamide; -N- (4- { [Amino (2-thienyl) methylidene] amino.}. Phenethyl) -2- (2,3-dimethylamino) benzamide; -N '-. { 4- [4- (2-anilinobenzoyl) -l-piperazinyl] fenyl} -2-toflocarboximidamide; -N '- (4- { 4- [2- (2,3-dimethylanilino) benzoyl] -l-piperazinyl}. Phenyl) -2 -thiofcarboximidamide; -4- (4- { [Amino (2-thienyl) methylidene] amino} phenyl) -N- [4-phenoxyphenyl) butanamide; -N- (4- { [Amino (2-thienyl) methylidene] amino.}. Phenethyl) -4- (4-hydroxy-enoxy) -benzamide; -N- [2 - (9H-c arbaz or l-4-i l ox i) et i l] -2-toflocarboximidamide; -N- [3- (9H-carbazol-4-yloxy) propyl] -2 -thiofcarboximidamide; _N- { 4- [4- (1 OH-phenothiazin-2-yloxy) butyl] phenyl] -2-thiofcarboximidamide; -3- [(3- { [Amino (2-thienyl) methylidene] amino.}. -benzyl) amino] -N- (4-anilinophenyl) propanamide; -N '- (4- {2 - [(10H-f-enothiazin-3-ylmethyl) amino] ethyl} phenyl) -2 -thiofcarboximidamide;
-N- (4- { [Amino (2-thienyl) methylidene] amino.}. Phenethyl) -2-methoxy-lOH-f enotiazin-1 -carboxamide; -N '- [4- (2- { [(2-methoxy-1 OH-f-enotiazin-1-yl) ethyl] ami no.} Ethyl) phenyl] -2-thiofcarboximomidamide; N'-. { 4- [(lOH-f enothiazin-2-yloxy) methyl] phenyl} -2-thiof, carboboximidamide; or one of its salts. 6. Product according to claim 5, characterized in that it is one of the following compounds:. { 4-. { (2-thienyl (imino) methyl] amino.}. Phenoxy.} - N - [4- (f-enylamino) phenyl] -acetamide; -4-. {(2-thienyl (imino) me ti 1] amino .}.-N- [2 - (f -ylamino) phenyl] -benzenebutanamide; -4- { [2-thienyl (imino) methyl] amino.}. -N- [4- (f-enylamino) phenyl] - benzene-butanamide; -2- {4.4 { (2-thienyl (imino) methyl] amino.}. phenyl.}. -ethyl [4- (f-enylamino) phenyl] -carbamate; -4-. 4- {(2-thienyl (imino) methyl] amino} phenyl} - N- [4- (f-enylamino) phenyl] -1-pipe-i-acetylamide; -3-. {(2-thienyl (imino) methyl] amino.}. -N- [4 - (f-enylamino) phenyl] -benzenepropanamide; -4- { 4- { [Amino (2-thienyl (methylidene)] amino.}. phenyl-N- [2- (4-toluidino) phenyl] butanamide; -N'-. {4- [4- (3-anilinophenoxy) butyl] phenyl] -2-thiophenecarboximidamide; - (4- { [Amino (2-thienyl) methylidene] amino.}. Phenyl) -N- (9H-carbazol-3-yl) butanamide; -N '- [4- (10H-phenothiazine-2 - iloxy) phenyl] -2-thiophenecarboximidamide; -4- (4-. { [amino (2-thienyl) methylidene] amino} phenyl) -N- (lOH-phenothiazin-3-yl) butanamide; -N '- (4- { 4- [2- (lOH-phenothiazin-2-yloxy] ethyl] -1-piperazinyl}. Phenyl) -2-thiophenecarboximidamide; -4- (4- { [ amino (2-thienyl) methylidene] amino.}. phenyl) -N- (4-phenoxyphenyl) butanamide; -3- [(3 { [amino (2-thienyl) methylidene] amino.}. -benzyl) amino] -N- (4-anilinophenyl) propanamide; -N '- (4- {2- [(10 H -phenothiazin-3-ylmethyl) amino] ethyl} phenyl) -2-thiophenecarboximidamide; (4- {[amino (2-thienyl) methylidene] amino} phenethyl) -2-methoxy-lOH-phenothiazine-1-carboxamide; or one of its salts 7. Product according to claim 6, characterized in that it is one of the following compounds: -4- { [2-thienyl (imino) methyl] amino.}. -N- [2- (phenylamino) phenyl] -benzenebutanamide; -4- { [2 -thienyl (imino) methyl] amino.}. -N- [4- (phenylamino) phenyl] -benzenebutanamide;
-N '- [4- (10H-phenothiazin-2-yloxy) phenyl] -2-thiofcarboximomidamide; -4- (4- { [Amino (2-thienyl) methylidene] amino} phenyl) -N- (lOH-f-enothiazin-3-yl) butanamide; -3- [(3- { [Amino (2-thienyl) methylidene] amino.}. -benzyl) amino] -N- (4-anilinylphenyl) propanamide; -N '- (4- {2 - [(10H-phenothiazin-3-ylmethyl) amino] ethyl} phenyl) -2 -thiofcarboximidamide; or one of its salts. 8. As new industrial products, the compounds of general formula (IS)
A-X-Y-f-T (IS) characterized because A represents a radical wherein R.sup.lf R.sup.2, R.sup.3, R.sup.4, R.sup.5 represent, independently, a hydrogen atom, a halogen, the OH group, a linear or branched alkyl or alkoxy radical having from 1 to 6 carbon atoms, or a cyano radical , nitro or NR6R7, R6 and R7 independently represent a hydrogen atom, the OH group, a linear or branched alkyl or alkoxy radical having 1 to 6 carbon atoms, or also a group -COR8, R8 represents, hydrogen atom, the OH group, a linear or branched alkyl or alkoxy radical having 1 to 6 carbon atoms, or NR9R10, R9 and R10 independently represent a hydrogen atom, the OH group or a linear alkyl radical 0 branched having 1 to 6 carbon atoms, Ru represents a hydrogen atom, the OH group, a linear or branched alkyl or alkoxy radical having from 1 to 6 carbon atoms, or a radical -COR12, and R12 represents a hydrogen atom, the OH group, a linear or branched alkyl radical having 1 to 6 carbon atoms, or a radical wherein R 1 R2, R 3, R 4, R 5 represent, independently, a hydrogen atom, a halogen, the OH group, a linear or branched alkyl or alkoxy radical having from 1 to 6 carbon atoms, or a cyano radical , nitro or NR6R7, R6 and R7 represent, independently, a hydrogen atom, the OH group, a linear or branched alkyl or alkoxy radical having from 1 to 6 carbon atoms, or also a group -COR8, R8 represents a hydrogen atom, the OH group, a radical linear or branched alkyl or alkoxy having from 1 to 6 carbon atoms, or NR9R10, R9 and R10 represent, independently, a hydrogen atom, the OH group or a linear or branched alkyl radical having from 1 to 6 carbon atoms , W does not exist, or represents a bond, or O, S or NR15, in which R15 represents a hydrogen atom or a linear or branched alkyl radical having from 1 to 6 carbon atoms; X represents a bond or radical (CH2) k-NR16-,
-O-, -S-, -CO-, -NR16-CO-, -CO-NR16-, -O-CO-, -CO-O-, -NR16-CO-0- OR -NR16-CO-NR17 -, k represents 0 or 1; Y represents a bond or radical selected from the radicals - (CH2) m-, - (CH2) m-0- (CH2) n-, - (CH2) mS- (CH2) n-, - (CH2) m- NR18- (CH2) n-, - (CH2) m-NR18-CO- (CH2) n-, - (CH2) m-CO-NR18- (CH2) n-, - (CH2) ffi-Q- (CH2 ) n-, Q represents piperazine, homopiperazine, 2-me thiolpiper azine, 2,5-dimethylpiperazine, 4-oxypiperidine or 4-aminopiperidine, myn are integers from 0 to 6; F represents a bond or a phenylene radical which could comprise, in addition to the two chains already represented in the general formula (I), up to two chosen substituents of a hydrogen atom, a halogen, an OH group, and an alkyl or alkoxy radical linear or branched having 1 to 6 carbon atoms; T represents N02 or NH2; R16, R17 and R18 represent, independently, a hydrogen atom or a linear or branched alkyl radical having from 1 to 6 carbon atoms. 9. As new industrial products, the compounds of general formula (IS ')
(IS ') characterized because A represents a radical wherein R 1 R2, R 3, R 4 and R 5 represent, independently, a hydrogen atom, a halogen, the OH group, a linear or branched alkyl or alkoxy radical having from 1 to 6 carbon atoms, or a cyano radical , nitro or NR6R7, R6 and R7 independently represent a hydrogen atom, the OH group, a linear or branched alkyl or alkoxy radical having 1 to 6 carbon atoms, or also a group -C0R8, R8 represents an atom of hydrogen, the OH group, a linear or branched alkyl or alkoxy radical having 1 to 6 carbon atoms, or NR9R10, R9 and R10 independently represent a hydrogen atom, the OH group, a linear or branched alkyl radical which has 1 to 6 carbon atoms, Rl? represents a hydrogen atom, the OH group, a linear or branched alkyl or alkoxy radical having from 1 to 6 carbon atoms, or else a radical -COR12, and R12 represents a hydrogen atom, the OH group, an alkyl radical linear or branched having 1 to 6 carbon atoms, or a radical wherein R 1 R2, R 3, R 4, R 5 represent, independently, a hydrogen atom, a halogen, the OH group, a linear or branched alkyl or alkoxy radical having from 1 to 6 carbon atoms, or a cyano radical , nitro or NR6R7, R6 and R7 independently represent a hydrogen atom, the OH group, a linear or branched alkyl or alkoxy radical having 1 to 6 carbon atoms, or also a group -COR8, R8 represents an atom of hydrogen, the OH group, a linear or branched alkyl or alkoxy radical having 1 to 6 carbon atoms, or NR9R10, R9 and R10 independently represent a hydrogen atom, the OH group or a linear or branched alkyl radical having 1 to 6 carbon atoms, W does not exist or represents a bond, or O, S or NR15, in which R15 represents a hydrogen atom or a linear or branched alkyl radical having from 1 to 6 carbon atoms; p represents a hydrogen atom or a protective group of the carbamate type; R? ß Ri7 and R? S represent, independently, a hydrogen atom or a linear or branched alkyl radical having from 1 to 6 carbon atoms; and m represents an integer from 0 to 6.
10. As a medicament, a product of general formula (I) according to one of claims 1 to 7, or a pharmaceutically acceptable salt of the product.
11. Pharmaceutical composition, characterized in that it contains as an active ingredient at least one product according to one of claims 1 to 7, or a pharmaceutically acceptable salt of the product.
12. Use of a product of general formula (I) according to any of claims 1 to 7, or a pharmaceutically acceptable salt of the product, for the production of a medicament intended to inhibit NO synthase.
13. Use of a product of general formula (I) according to any of claims 1 to 7, or a pharmaceutically acceptable salt of the product, for the production of a medicament intended to inhibit lipid peroxidation.
14. Use of a product of general formula (I) according to any of claims 1 to 7, or a pharmaceutically acceptable salt of the product, for the production of a medicament having both a NO synthase inhibitory activity and a inhibition activity of lipid peroxidation.
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| FR98/11867 | 1998-09-23 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| MXPA01003006A true MXPA01003006A (en) | 2001-12-13 |
Family
ID=
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