MXPA98010201A - Derivatives in n- (4-carbamimido-fenil) -fenilglicinam - Google Patents
Derivatives in n- (4-carbamimido-fenil) -fenilglicinamInfo
- Publication number
- MXPA98010201A MXPA98010201A MXPA/A/1998/010201A MX9810201A MXPA98010201A MX PA98010201 A MXPA98010201 A MX PA98010201A MX 9810201 A MX9810201 A MX 9810201A MX PA98010201 A MXPA98010201 A MX PA98010201A
- Authority
- MX
- Mexico
- Prior art keywords
- benzyloxy
- methoxyphenyl
- phenylamino
- alkyl
- acetamide
- Prior art date
Links
- 239000011780 sodium chloride Substances 0.000 claims abstract description 16
- 150000003839 salts Chemical class 0.000 claims abstract description 15
- 239000012453 solvate Substances 0.000 claims abstract description 8
- 239000003814 drug Substances 0.000 claims abstract description 7
- 108010000499 Thromboplastin Proteins 0.000 claims abstract description 5
- 102000002262 Thromboplastin Human genes 0.000 claims abstract description 5
- 230000002401 inhibitory effect Effects 0.000 claims abstract description 5
- 206010003210 Arteriosclerosis Diseases 0.000 claims abstract description 4
- 206010061216 Infarction Diseases 0.000 claims abstract description 4
- 206010061218 Inflammation Diseases 0.000 claims abstract description 4
- 208000007536 Thrombosis Diseases 0.000 claims abstract description 4
- 239000002246 antineoplastic agent Substances 0.000 claims abstract description 4
- 230000015572 biosynthetic process Effects 0.000 claims abstract description 4
- 230000000747 cardiac effect Effects 0.000 claims abstract description 4
- 238000005755 formation reaction Methods 0.000 claims abstract description 4
- 230000004054 inflammatory process Effects 0.000 claims abstract description 4
- 230000002265 prevention Effects 0.000 claims abstract description 4
- NKCXQMYPWXSLIZ-PSRDDEIFSA-N (2S)-2-[[(2S)-1-[(2S)-5-amino-2-[[2-[[(2S)-6-amino-2-[[2-[[(2S)-2-[[(2S)-4-amino-2-[[(2S)-2-[[(2S,3R)-2-[[(2S)-2-[[(2S,3R)-2-amino-3-hydroxybutanoyl]amino]-3-(1H-indol-3-yl)propanoyl]amino]-3-hydroxybutanoyl]amino]propanoyl]amino]-4-oxobutanoyl]amino]-3-m Chemical compound O=C([C@H](CCC(N)=O)NC(=O)CNC(=O)[C@H](CCCCN)NC(=O)CNC(=O)[C@@H](NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](C)NC(=O)[C@@H](NC(=O)[C@H](CC=1C2=CC=CC=C2NC=1)NC(=O)[C@@H](N)[C@@H](C)O)[C@@H](C)O)C(C)C)N1CCC[C@H]1C(=O)N[C@@H](CO)C(O)=O NKCXQMYPWXSLIZ-PSRDDEIFSA-N 0.000 claims abstract description 3
- 108010039209 Blood Coagulation Factors Proteins 0.000 claims abstract description 3
- 102000015081 Blood Coagulation Factors Human genes 0.000 claims abstract description 3
- 108090000190 Thrombin Proteins 0.000 claims abstract description 3
- 239000003114 blood coagulation factor Substances 0.000 claims abstract description 3
- 150000004677 hydrates Chemical class 0.000 claims abstract description 3
- 239000003112 inhibitor Substances 0.000 claims abstract description 3
- 229960004072 thrombin Drugs 0.000 claims abstract description 3
- -1 pyrrolidino, piperidino Chemical group 0.000 claims description 517
- 239000002253 acid Substances 0.000 claims description 89
- 150000001875 compounds Chemical class 0.000 claims description 69
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 59
- 125000000738 acetamido group Chemical group [H]C([H])([H])C(=O)N([H])[*] 0.000 claims description 52
- QTBSBXVTEAMEQO-UHFFFAOYSA-N acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 48
- DLFVBJFMPXGRIB-UHFFFAOYSA-N acetamide Chemical compound CC(N)=O DLFVBJFMPXGRIB-UHFFFAOYSA-N 0.000 claims description 40
- 239000001257 hydrogen Substances 0.000 claims description 31
- 229910052739 hydrogen Inorganic materials 0.000 claims description 31
- 150000002825 nitriles Chemical class 0.000 claims description 28
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 27
- 125000003545 alkoxy group Chemical group 0.000 claims description 26
- 125000000217 alkyl group Chemical group 0.000 claims description 26
- 125000003118 aryl group Chemical group 0.000 claims description 21
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 21
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 20
- 125000004435 hydrogen atoms Chemical group [H]* 0.000 claims description 16
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 15
- 238000002360 preparation method Methods 0.000 claims description 12
- 125000002102 aryl alkyloxo group Chemical group 0.000 claims description 11
- UFHFLCQGNIYNRP-UHFFFAOYSA-N hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 9
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 9
- 125000004104 aryloxy group Chemical group 0.000 claims description 8
- 239000004480 active ingredient Substances 0.000 claims description 6
- 229910052736 halogen Inorganic materials 0.000 claims description 6
- 150000002367 halogens Chemical class 0.000 claims description 6
- 238000000034 method Methods 0.000 claims description 6
- 229910052757 nitrogen Inorganic materials 0.000 claims description 6
- WPANETAWYGDRLL-UHFFFAOYSA-N 4-aminobenzenecarboximidamide Chemical compound NC(=N)C1=CC=C(N)C=C1 WPANETAWYGDRLL-UHFFFAOYSA-N 0.000 claims description 5
- 125000000051 benzyloxy group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])O* 0.000 claims description 5
- XFXPMWWXUTWYJX-UHFFFAOYSA-N cyanide Chemical compound N#[C-] XFXPMWWXUTWYJX-UHFFFAOYSA-N 0.000 claims description 5
- 125000004663 dialkyl amino group Chemical group 0.000 claims description 5
- 125000005114 heteroarylalkoxy group Chemical group 0.000 claims description 5
- 239000000825 pharmaceutical preparation Substances 0.000 claims description 5
- 125000005530 alkylenedioxy group Chemical group 0.000 claims description 4
- 125000003435 aroyl group Chemical group 0.000 claims description 4
- 125000001301 ethoxy group Chemical group [H]C([H])([H])C([H])([H])O* 0.000 claims description 4
- 125000001072 heteroaryl group Chemical group 0.000 claims description 4
- 125000003710 aryl alkyl group Chemical group 0.000 claims description 3
- 125000005418 aryl aryl group Chemical group 0.000 claims description 3
- 125000001316 cycloalkyl alkyl group Chemical group 0.000 claims description 3
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 3
- 125000004446 heteroarylalkyl group Chemical group 0.000 claims description 3
- 150000002829 nitrogen Chemical group 0.000 claims description 3
- 125000003739 carbamimidoyl group Chemical group C(N)(=N)* 0.000 claims description 2
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 2
- 125000004367 cycloalkylaryl group Chemical group 0.000 claims description 2
- BEBCJVAWIBVWNZ-UHFFFAOYSA-N glycinamide Chemical class NCC(N)=O BEBCJVAWIBVWNZ-UHFFFAOYSA-N 0.000 claims description 2
- 125000006239 protecting group Chemical group 0.000 claims description 2
- 150000002431 hydrogen Chemical group 0.000 claims 6
- WGEGXJPYFSZDMU-IZLXSDGUSA-N (2S)-2-[[(2R)-2-(4-carbamimidoylanilino)-2-(3-methoxy-4-phenylmethoxyphenyl)acetyl]amino]-2-phenylacetic acid Chemical compound COC1=CC([C@@H](NC=2C=CC(=CC=2)C(N)=N)C(=O)N[C@H](C(O)=O)C=2C=CC=CC=2)=CC=C1OCC1=CC=CC=C1 WGEGXJPYFSZDMU-IZLXSDGUSA-N 0.000 claims 1
- GOKMXGJLEDPKOL-MPQUPPDSSA-N (2S)-2-[[(2R)-2-(4-carbamimidoylanilino)-2-[5-methoxy-2-[(2-phenylacetyl)amino]-4-phenylmethoxyphenyl]acetyl]amino]-2-phenylacetic acid Chemical compound N([C@H](C=1C=C(C(=CC=1NC(=O)CC=1C=CC=CC=1)OCC=1C=CC=CC=1)OC)C(=O)N[C@H](C(O)=O)C=1C=CC=CC=1)C1=CC=C(C(N)=N)C=C1 GOKMXGJLEDPKOL-MPQUPPDSSA-N 0.000 claims 1
- IXHWKNNMARHCLQ-SZAHLOSFSA-N (2S)-2-[[(2R)-2-[2-(benzenesulfonamido)-5-methoxy-4-phenylmethoxyphenyl]-2-(4-carbamimidoylanilino)acetyl]amino]-2-phenylacetic acid Chemical compound N([C@H](C=1C=C(C(=CC=1NS(=O)(=O)C=1C=CC=CC=1)OCC=1C=CC=CC=1)OC)C(=O)N[C@H](C(O)=O)C=1C=CC=CC=1)C1=CC=C(C(N)=N)C=C1 IXHWKNNMARHCLQ-SZAHLOSFSA-N 0.000 claims 1
- IXHWKNNMARHCLQ-HEVIKAOCSA-N (2S)-2-[[(2S)-2-[2-(benzenesulfonamido)-5-methoxy-4-phenylmethoxyphenyl]-2-(4-carbamimidoylanilino)acetyl]amino]-2-phenylacetic acid Chemical compound N([C@@H](C=1C=C(C(=CC=1NS(=O)(=O)C=1C=CC=CC=1)OCC=1C=CC=CC=1)OC)C(=O)N[C@H](C(O)=O)C=1C=CC=CC=1)C1=CC=C(C(N)=N)C=C1 IXHWKNNMARHCLQ-HEVIKAOCSA-N 0.000 claims 1
- BMDYWWBOVIRAFQ-UHFFFAOYSA-N 2-[[2-(4-carbamimidoylanilino)-2-(3-methoxy-4-phenylmethoxyphenyl)acetyl]amino]-2,2-diphenylacetic acid Chemical compound COC1=CC(C(NC=2C=CC(=CC=2)C(N)=N)C(=O)NC(C(O)=O)(C=2C=CC=CC=2)C=2C=CC=CC=2)=CC=C1OCC1=CC=CC=C1 BMDYWWBOVIRAFQ-UHFFFAOYSA-N 0.000 claims 1
- 125000002485 formyl group Chemical class [H]C(*)=O 0.000 claims 1
- GXBRYTMUEZNYJT-UHFFFAOYSA-N 2-anilinoacetamide Chemical class NC(=O)CNC1=CC=CC=C1 GXBRYTMUEZNYJT-UHFFFAOYSA-N 0.000 abstract 1
- 201000001320 atherosclerosis Diseases 0.000 abstract 1
- 229940079593 drugs Drugs 0.000 abstract 1
- 239000007787 solid Substances 0.000 description 99
- XEKOWRVHYACXOJ-UHFFFAOYSA-N acetic acid ethyl ester Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 96
- 239000000203 mixture Substances 0.000 description 78
- 239000000243 solution Substances 0.000 description 78
- WYURNTSHIVDZCO-UHFFFAOYSA-N tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 76
- ZMANZCXQSJIPKH-UHFFFAOYSA-N triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 66
- 239000000047 product Substances 0.000 description 59
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 58
- RIWNFZUWWRVGEU-UHFFFAOYSA-N isocyanomethylbenzene Chemical compound [C-]#[N+]CC1=CC=CC=C1 RIWNFZUWWRVGEU-UHFFFAOYSA-N 0.000 description 56
- OKKJLVBELUTLKV-UHFFFAOYSA-N methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 56
- 125000002490 anilino group Chemical group [H]N(*)C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 52
- CSCPPACGZOOCGX-UHFFFAOYSA-N acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 51
- 229910001868 water Inorganic materials 0.000 description 49
- 235000019439 ethyl acetate Nutrition 0.000 description 45
- VEXZGXHMUGYJMC-UHFFFAOYSA-N HCl Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 44
- 239000011734 sodium Substances 0.000 description 41
- QTBSBXVTEAMEQO-UHFFFAOYSA-M acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 35
- YBAZINRZQSAIAY-UHFFFAOYSA-N 4-aminobenzonitrile Chemical compound NC1=CC=C(C#N)C=C1 YBAZINRZQSAIAY-UHFFFAOYSA-N 0.000 description 33
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 32
- 230000000875 corresponding Effects 0.000 description 26
- YMWUJEATGCHHMB-UHFFFAOYSA-N methylene dichloride Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 26
- GHEHNICLPWTXJC-UHFFFAOYSA-N p-Aminobenzamidine dihydrochloride Chemical compound [Cl-].[Cl-].NC(=[NH2+])C1=CC=C([NH3+])C=C1 GHEHNICLPWTXJC-UHFFFAOYSA-N 0.000 description 26
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 24
- 239000002904 solvent Substances 0.000 description 24
- 239000000741 silica gel Substances 0.000 description 23
- 229910002027 silica gel Inorganic materials 0.000 description 23
- 238000004587 chromatography analysis Methods 0.000 description 21
- 239000011541 reaction mixture Substances 0.000 description 21
- 239000000463 material Substances 0.000 description 20
- XBDQKXXYIPTUBI-UHFFFAOYSA-N propionic acid Chemical compound CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 19
- 239000000706 filtrate Substances 0.000 description 18
- 239000012074 organic phase Substances 0.000 description 18
- 150000001299 aldehydes Chemical class 0.000 description 17
- 238000006243 chemical reaction Methods 0.000 description 17
- 239000008259 solid foam Substances 0.000 description 17
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 16
- 239000003054 catalyst Substances 0.000 description 16
- 125000000325 methylidene group Chemical group [H]C([H])=* 0.000 description 16
- WPYMKLBDIGXBTP-UHFFFAOYSA-N Benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 15
- KZMGYPLQYOPHEL-UHFFFAOYSA-N ethoxyethane;trifluoroborane Chemical compound FB(F)F.CCOCC KZMGYPLQYOPHEL-UHFFFAOYSA-N 0.000 description 15
- 238000000926 separation method Methods 0.000 description 15
- KDLHZDBZIXYQEI-UHFFFAOYSA-N palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 14
- YXFVVABEGXRONW-UHFFFAOYSA-N toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 14
- DTQVDTLACAAQTR-UHFFFAOYSA-N trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 14
- 229910004373 HOAc Inorganic materials 0.000 description 12
- WTDHULULXKLSOZ-UHFFFAOYSA-N Hydroxylamine hydrochloride Chemical compound Cl.ON WTDHULULXKLSOZ-UHFFFAOYSA-N 0.000 description 12
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 12
- RTZKZFJDLAIYFH-UHFFFAOYSA-N diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 12
- 238000001914 filtration Methods 0.000 description 12
- VLKZOEOYAKHREP-UHFFFAOYSA-N hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 12
- 239000003279 phenylacetic acid Substances 0.000 description 12
- FAPWRFPIFSIZLT-UHFFFAOYSA-M sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 12
- 229960000583 Acetic Acid Drugs 0.000 description 11
- 239000000543 intermediate Substances 0.000 description 11
- KFZMGEQAYNKOFK-UHFFFAOYSA-N iso-propanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 11
- WMFOQBRAJBCJND-UHFFFAOYSA-M lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 11
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 10
- 239000000725 suspension Substances 0.000 description 10
- JLGCLUWZAYARGI-UHFFFAOYSA-N 2-(2-amino-5-methoxy-4-phenylmethoxyphenyl)-N-benzyl-2-(4-cyanoanilino)acetamide Chemical compound NC=1C=C(OCC=2C=CC=CC=2)C(OC)=CC=1C(C(=O)NCC=1C=CC=CC=1)NC1=CC=C(C#N)C=C1 JLGCLUWZAYARGI-UHFFFAOYSA-N 0.000 description 9
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-dimethylformamide Substances CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 9
- 125000000896 monocarboxylic acid group Chemical group 0.000 description 9
- 238000010898 silica gel chromatography Methods 0.000 description 9
- JSHLOPGSDZTEGQ-UHFFFAOYSA-N 3-methoxy-4-phenylmethoxybenzaldehyde Chemical compound COC1=CC(C=O)=CC=C1OCC1=CC=CC=C1 JSHLOPGSDZTEGQ-UHFFFAOYSA-N 0.000 description 8
- SHXXMRORPCUINS-UHFFFAOYSA-N N-[2-[2-(benzylamino)-1-(4-carbamimidoylanilino)-2-oxoethyl]-4-methoxy-5-phenylmethoxyphenyl]benzamide Chemical compound C=1C=CC=CC=1C(=O)NC=1C=C(OCC=2C=CC=CC=2)C(OC)=CC=1C(C(=O)NCC=1C=CC=CC=1)NC1=CC=C(C(N)=N)C=C1 SHXXMRORPCUINS-UHFFFAOYSA-N 0.000 description 8
- MQCKJEXXPCMUMU-UHFFFAOYSA-N N-[amino-[4-[5-[4-[amino(nitroso)methylidene]cyclohexa-2,5-dien-1-ylidene]furan-2-ylidene]cyclohexa-2,5-dien-1-ylidene]methyl]hydroxylamine Chemical compound C1=CC(=C(NO)N)C=CC1=C(C=C1)OC1=C1C=CC(=C(N)N=O)C=C1 MQCKJEXXPCMUMU-UHFFFAOYSA-N 0.000 description 8
- 239000012300 argon atmosphere Substances 0.000 description 8
- HEDRZPFGACZZDS-UHFFFAOYSA-N chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 8
- PXHVJJICTQNCMI-UHFFFAOYSA-N nickel Substances [Ni] PXHVJJICTQNCMI-UHFFFAOYSA-N 0.000 description 8
- 229910052763 palladium Inorganic materials 0.000 description 8
- NFHFRUOZVGFOOS-UHFFFAOYSA-N palladium;triphenylphosphane Chemical compound [Pd].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 NFHFRUOZVGFOOS-UHFFFAOYSA-N 0.000 description 8
- SJSYJHLLBBSLIH-SDNWHVSQSA-N (E)-3-(2-methoxyphenyl)-2-phenylprop-2-enoic acid Chemical compound COC1=CC=CC=C1\C=C(\C(O)=O)C1=CC=CC=C1 SJSYJHLLBBSLIH-SDNWHVSQSA-N 0.000 description 7
- 239000005711 Benzoic acid Substances 0.000 description 7
- WLJVXDMOQOGPHL-UHFFFAOYSA-N Phenylacetic acid Natural products OC(=O)CC1=CC=CC=C1 WLJVXDMOQOGPHL-UHFFFAOYSA-N 0.000 description 7
- 239000012043 crude product Substances 0.000 description 7
- UKJLNMAFNRKWGR-UHFFFAOYSA-N cyclohexatrienamine Chemical group NC1=CC=C=C[CH]1 UKJLNMAFNRKWGR-UHFFFAOYSA-N 0.000 description 7
- 229960003424 phenylacetic acid Drugs 0.000 description 7
- 150000003254 radicals Chemical class 0.000 description 7
- 238000010992 reflux Methods 0.000 description 7
- FAMRKDQNMBBFBR-BQYQJAHWSA-N Diethyl azodicarboxylate Chemical compound CCOC(=O)\N=N\C(=O)OCC FAMRKDQNMBBFBR-BQYQJAHWSA-N 0.000 description 6
- 235000010233 benzoic acid Nutrition 0.000 description 6
- OKTJSMMVPCPJKN-UHFFFAOYSA-N carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 6
- 239000008079 hexane Substances 0.000 description 6
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 6
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 6
- 239000003921 oil Substances 0.000 description 6
- 235000019198 oils Nutrition 0.000 description 6
- 239000012071 phase Substances 0.000 description 6
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Substances [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 description 6
- 235000019260 propionic acid Nutrition 0.000 description 6
- WQDUMFSSJAZKTM-UHFFFAOYSA-N sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 6
- 239000011877 solvent mixture Substances 0.000 description 6
- 239000007868 Raney catalyst Substances 0.000 description 5
- 229910000564 Raney nickel Inorganic materials 0.000 description 5
- 150000001412 amines Chemical class 0.000 description 5
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 5
- UIIMBOGNXHQVGW-UHFFFAOYSA-M buffer Substances [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 5
- KXDHJXZQYSOELW-UHFFFAOYSA-M carbamate Chemical compound NC([O-])=O KXDHJXZQYSOELW-UHFFFAOYSA-M 0.000 description 5
- 229910052697 platinum Inorganic materials 0.000 description 5
- 239000000843 powder Substances 0.000 description 5
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 4
- VMZCDNSFRSVYKQ-UHFFFAOYSA-N 2-phenylacetyl chloride Chemical compound ClC(=O)CC1=CC=CC=C1 VMZCDNSFRSVYKQ-UHFFFAOYSA-N 0.000 description 4
- PASDCCFISLVPSO-UHFFFAOYSA-N Benzoyl chloride Chemical compound ClC(=O)C1=CC=CC=C1 PASDCCFISLVPSO-UHFFFAOYSA-N 0.000 description 4
- FERIUCNNQQJTOY-UHFFFAOYSA-N Butanoic acid Chemical compound CCCC(O)=O FERIUCNNQQJTOY-UHFFFAOYSA-N 0.000 description 4
- QPJVMBTYPHYUOC-UHFFFAOYSA-N Methyl benzoate Chemical compound COC(=O)C1=CC=CC=C1 QPJVMBTYPHYUOC-UHFFFAOYSA-N 0.000 description 4
- JOXIMZWYDAKGHI-UHFFFAOYSA-N P-Toluenesulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 4
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 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
- 125000003277 amino group Chemical group 0.000 description 4
- QGZKDVFQNNGYKY-UHFFFAOYSA-N ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 4
- 229960004106 citric acid Drugs 0.000 description 4
- 238000001816 cooling Methods 0.000 description 4
- 239000006260 foam Substances 0.000 description 4
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 4
- CSNNHWWHGAXBCP-UHFFFAOYSA-L magnesium sulphate Substances [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 4
- 235000019341 magnesium sulphate Nutrition 0.000 description 4
- 150000002828 nitro derivatives Chemical class 0.000 description 4
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 4
- 229920005862 polyol Polymers 0.000 description 4
- 150000003077 polyols Chemical class 0.000 description 4
- 239000002244 precipitate Substances 0.000 description 4
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- 125000005843 halogen group Chemical group 0.000 description 1
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Abstract
The novel N- (4-carbimidophenyl-amino) phenyl-glycinamide derivatives of the formula wherein E, G1, G2, Q, R and X1 to X4 are each as defined in the description, and hydrates or solvates and their physiologically acceptable salts can be used as inhibitors of the formation of coagulation factors Xa, IXa and thrombin induced by factor VIIA and by tissue factor, specifically as drugs for the treatment and / or prevention of thrombosis, stroke, cardiac infarction , inflammation and atherosclerosis or as antitumor agents
Description
- DERIVATIVES OF N- (4-CARBAMIMID0-PHENYL) - FENILGLIC INAMIDA
The invention relates to novel N- (4-carbamimidophenyl glycinamide derivatives, in particular to those of the formula
wherein E is hydrogen or OH, Q is hydrogen or alkyl, R is aryl, cycloalkyl or alkyl which is substituted by R1, R2 and R3, R1 is hydrogen, COOH, COO-alkyl or aryl, R2 is hydrogen, aryl, cycloalkyl or heteroaryl,
Ref. 029037 - - R is hydrogen, aryl or (in a different position than
the position with respect to the nitrogen atom to which the optionally protected alkyl group R) OH, alkoxy or amino is attached, N (Q, R) is COOH- or COO-alkyl-substituted, pyrrolidino, piperidino or 1, 2, 3 , 4-tetrahydroisoquinolin-3-yl,
three of the radicals X1 to X4 independently of one another are a group C (Ra), C (Rb) or C (RC) and the fourth
radical is a group C (Rd) or N, Ra a Rd independently of one another are H, OH, N02, dialkylamino, halogen, alkyl, alkoxy, aryloxy, aralkyloxy, heteroarylalkyloxy, heterocyclalkyloxy, COOH, COO-alkyl, NH-S02 - alkyl, NHS02-aryl, NHCO-alkyl, NHCO-aryl, NHCOO-alkyl, NHCO-alkyl-NH2, NHCO-alkyl-NH-G, aralkyl-CONH, alkyl-0-alkyl-C? NH, aryl-O - alkyl-CONH, alkyl-COOH, alkyl-COO-alkyl, O-alkyl-COOH or O-alkyl-COO-alkyl, or two adjacent groups Ra a Rd together are alkylenedioxy,
where no more than tees of radicals Ra to Rd must have the same meaning and X1 should not be CCOOH or CCOO-? alkyl, 'G is an amino protecting group and
one of the radicals G1 and G2 is hydrogen and the other radical is hydrogen, alkyl, OH, alkoxy, aroyl, alkanoyl-OCH2, aroyl-OCH2 or a group COO-Rs or OCO-Rg,
R8 is optionally alkyl, halogen-, OH-, alkoxy-,
COOH- or COO-alkyl-substituted, and hydrates or solvates and their physiologically acceptable salts. In addition, the invention relates to processes for the preparation of the above compounds, to pharmaceutical preparations comprising these compounds, and to the use of these compounds in the preparation of pharmaceutical compositions. Examples of physiologically acceptable salts of these compounds of formula I are salts with physiologically tolerable mineral acids, such as hydrochloric acid, sulfuric acid, sulfurous acid or phosphoric acid; or with organic acids, such as methanesulfonic acid, p-toluenesulfonic acid, acetic acid, trifluoroacetic acid, citric acid, fumaric acid, maleic acid, tartaric acid, succinic acid or salicylic acid. The compounds of the formula I can be solvated, in particular hydrated. The hydration can be carried out during the preparation process or slowly as a consequence of the hygroscopic properties of an initially anhydrous compound of the formula I.
The compounds of the formula I contain at least one asymmetric carbon atom and can therefore be present as a mixture of enantiomers or as optically pure compounds. In the context of the present invention "alkyl", by itself or in combination, such as in COO-alkyl, alkoxy, dialkylamino, aralkyloxy, heteroarylalkyloxy, heterocyclylalkyloxy, NHS02-alkyl, NHCO-alkyl, aralkyl-CONH, alkyl-O -alkyl-CONH, alkyl-COOH, CCOO-alkyl, alkanoyl and: imides denotes a straight or branched chain group containing up to 6 carbon atoms, preferably up to 4. Examples include methyl, ethyl and butyl. The "aryl", by itself or in combination, such as in aryloxy, aralkyl, NHS02-aryl, NHCO-aryl, aralkyl-CONH, aryl-O-alkyl-CONH, aroyl and the like, denotes groups such as phenyl or naphthyl which may be substituted, for example, by halogen, such as bromine, fluorine or chlorine; alkoxy, such as methoxy, ethoxy or propoxy, alkylenedioxy, such as methylenedioxyl; hydroxyl, nitro, amino, amidino, sulfamoyl, phenyl, phenoxy, COOH or COO-alkyl, such as COOCH3 or COOC2H5. Examples of aryl groups include phenyl and amidinophenyl, of araZ-ruyl groups: benzyl, phenethyl, naphthylmethyl, mono- or dimethoxybenzyl, aminobenzyl or nitrobenzyl, of aryloxy groups: phenoxy or methoxycarbonyl-phenoxy, of aralkylxyl groups: benzyloxy, nitrobenzyloxy, bromobenzyloxy, dichlorobenzyloxy, ethoxybenzyloxy, phenoxybenzyloxy, phenetoxy or diphenyl methoxy. The "cycloalkylalkyl" denotes saturated groups having 3 to 7 carbon atoms that are linked via an alkyl group. An example of these is cyclopropylmethyl. He
"heteroarylalkyl", per se or in "heteroarylalkoxy", denotes a 5- to 10-membered aromatic group which is linked via an alkyl and alkoxy group, respectively, and which is constituted by one or two rings and contains one or more atoms of nitrogen. Examples of these are imidazolylethyl and indolylethyl and pyridinylmethoxy, indolylmethoxy, quinolylmethoxy or isoquinolylmethoxy, respectively. He
"heterocyclylalcoxy" denotes a non-aromatic saturated or unsaturated group of 5 to 10 members that is linked via an alkoxy group and comprises one or two rings and contains one or more N, O and / or S heteroatoms. Examples of these are morpholyl ethoxy, thiomorpholinylethoxy and tetrahydroquinolylmethoxy. Examples of these groups COO-alkyl, NHS02-alkyl and NHS02-aryl are COOCH3, NHS02CH3 and HS? 2C6Hs, respectively. An example of an alkylenedioxyl group is methylenedioxyl. Preferred compounds of the formula I are those in which R1 is aryl, in particular phenyl or amidinophenyl; aralkyl, in particular benzyl, phenethyl, naphthylmethyl, mono- or dimethoxybenzyl, aminobenzyl or nitrobenzyl; benzhydryl; cycloalkylalkyl, in particular cyclopropylmethyl; or heteroarylalkyl, in particular imidazolylethyl or indolylethyl. Preferred compounds of the formula I are further those wherein Q is hydrogen or methyl, and / or wherein R is aryl, such as phenyl, amidinophenyl or carboxyphenyl, or wherein R is alkyl which is substituted by R1, R2 and R3 and wherein R1 is a COOH or COO-alkyl group, R2 is aryl or H, and R3 is aryl, H, amino or protected amino, or wherein R is H, R is aryl or heteroaryl and R3 is H > or OH. Preferred alkyl groups R 1 -, R 2 - and R 3 - substituted are methyl, ethyl, propyl and isopropyl. Preferred aryl groups R, R 1, R 2 or R 3 are phenyl groups which are substituted by COOH or COO-alkyl, such as COOCH 3 or COOC 2 H 5; N02, NH2, S02NH2 or by one or two OH or alkoxy groups, such as OCH3 or OC2H5. Preferred R or R2 cycloalkyl groups are optionally COOH- or COO-alkyl-substituted cyclopentyl groups. Preferred heteroaryl R2 groups are imidazolyl, indolyl and pyridinyl. Preferred COO-alkyl groups R1 are COOCH3 and COCC2H5. A preferred R3 protected amino group is NH-Boc (t-butoxycarbonylamino). Preferred compounds of the formula I are also those in which one of the radicals G1 or G2 is an OH or COO-alkyl group, such as COOCH3 or COOC2H5. Preferred compounds of formula I are also those in which X 1 is a group C (Ra) in which R a is H, OH, N 0 2, halogen, in particular fluorine; alkoxy, in particular ethoxy; NHS02-alkyl or NHS02 ~ aryl, in particular methanesulfonylamino or phenylsulfonylamino and / or wherein X2 is a group C (Rb) wherein Rb is H, OH, NO2, alkyl, in particular methyl; alkoxy, in particular methoxy, ethoxy or butoxy; aryloxy, in particular phenoxy; aralkyloxy, in particular benzyloxy, and / or wherein X3 is a group C (Rc) wherein Rc is H, OH, NO2, dialkylamino, in particular dimethylamino; halogen, in particular bromine; alkyl, in particular methyl; alkoxy, in particular methoxy, ethoxy or propoxy;
aryloxy, in particular methoxycarbonyl phenoxy; aralkyloxy, in particular benzyloxy, nitrobenzyloxy, bromobenzyloxy, dichlorobenzyloxy, methoxybenzyloxy, phenoxybenzyloxy, phenetoxy or diphenyl methoxy; heteroarylalkyloxy, in particular pyridinylmethoxy, indolylmethoxy, quinolylmethoxy or isoquinylmethoxy; or heterocyclylalkyl, in particular, morpholinyl ethoxy, thiomorpholinyl ethoxy or tetrahydroquinolinyl methoxy, or wherein Rb and R together form an alkylenedioxy group, in particular the methylenedioxyl group, and / or wherein X is a group C (R) wherein Rd is H, N02, alkoxy, in particular methoxy; or aralkoxy, in particular benzyloxy. Preferred compounds of the formula I are further those wherein X 1 to X independently of one another are a group C (Ra) to C (Rd) - wherein Ra a Rd are NHCO-alkyl, such as NH-acetyl, NHCO- aryl, such as NH-benzoyl, NHCOO-alkyl, such as NHCOOCH3, NHCO-alkyl- (optionally protected amino), such as NHCOCH2NH2, NHCOCH2CH2NH2 and NHCOCH2NH-Boc; aralkyl-CONH, such as benzyl-COONH, alkyl-O-alkyl-CONH, such as CH3OCH2CONH, alkyl-COOH, such as CH2CH2COOH, O-alkyl-COOH, such as 0 (CH2) io 3COOH and OCH (CH3) COOH , aryloxy, such as OC6H4COOH and aralkyloxy, such as OCH2C6H4COOH, wherein a COO-alkyl group, such as COO (CH3 or C2H5) may be present instead of a COOH group. Preferred compounds of the formula I are also those in which one of the radicals X1 to X4 is a nitrogen atom and the other three independently of one another are a group C (Ra), C (Rb) or C (RC), in particular wherein one group of Ra, Rb and Rc denotes H and the other two denote lower alkoxy, such as methoxy or ethoxy. Preferred compounds of the formula I are also those in which one of the groups G1 and G2 is hydrogen and the other group is aroyl, in particular optionally halogen-substituted benzoyl, such as fluorobenzoyl, alkyl-COOCH2-benzoyl or phenyl-C00CH2- benzoyl, or is haloalkyl-OCO, such as trichloroethyl-OCO. Particular preference is given to the compounds wherein E, G, G2 and Q are each hydrogen, and / or wherein R is alkyl R1-, R2- and R3-substituted, in particular methyl or ethyl, in particular where R1 is aryl, specifically phenyl, or COOH, R2 is hydrogen or aryl, specifically phenyl, and R is hydrogen, and / or wherein X1 to X4 are a group C (R ') to C (Rd) in particular - a group wherein Ra is H, aralkyloxy, specifically carboxybenzyloxy; NHS02-aryl, specifically phenylsulfonylamino; aralkyl-CONH, specifically phenylacetylamino, or 0-alkyl-COOH, specifically carboxymethoxy, R is H or alkoxy, specifically methoxy or ethoxy, Rc is H, alkoxy, specifically methoxy or aralkyloxy, specifically benzyloxy, and
Rd is H or alkoxy, specifically methoxy. Examples of these compounds are: (R, S) -N-benzyl-2- (4-benzyloxy-3-ethoxyphenyl) -2- (4-carbamimidoyl-phenylamino) acetamide, 2- (2-phenylsulfonylamino-4-benzyloxy) -5-methoxyphenyl) -N-benzyl-2- (4-carbamimidoylphenylamino) acetamide and furthermore acid (RS) - [2- (4-benzyloxy-3-methoxyphenyl) -2- (4-carbamimidoyl-phenylamino) acetylamino] diphenylacetic , acid (RS) - and (SR) -3- [(RS) -2- (4-benzyloxy-3-methoxyphenyl) -2- (4-carbamimidoylphenylamino) acetylamino] -3-phenylepropionic acid (S) - [ (R) -2- (4-benzyloxy-3-methoxyphenyl) -2- (4-carbamimidoyl-phenylamino) acetylamino] phenylacetic acid (S) - [(S) -2- (4-carbamimidoylphenylamino) -2- ( 3,5-dimethoxyphenyl) acetylamino] phenylacetic acid (RS) -3- [2- [benzylcarbamoyl- (4-carbamimidoylphenylamino) methyl] -4,5-dimethoxyphenoxymethyl] benzoic acid (RS) - [2- [benzylcarbamoyl- (4-carbamimidoylphenylamino) -methyl] -4,5-dimethoxyphenoxy] acetic acid (S) - [(R) -2- (2-phenylsulfonylamino-4-benzyloxy-5-methoxyphenyl) -2- (4-carbam imidoylphenylamino) acetylamino] -phenylacetic acid (S) - [(S) -2- (2-phenylsulfonylamino-4-benzyloxy-5-ethoxyphenyl) -2- (4-carbamimidoylphenylamino) acetylamino] -phenylacetic acid (S) - [(R) -2- (4-benzyloxy-5-methoxy-2-phenylacetylaminophenyl) -2- 1-carbamimidoylphenylamino) acetylamino] -phenylacetic acid (S) - [(S) -2- (4-benzyloxy) -5-methoxy-2-phenylacetylaminophenyl) -2- (4-carbamimidoylphenylamino) acetylamino] -phenylacetic acid. Other examples of compounds of the formula I are the following compounds: (S) -2- [(R) -2- (4-benzyloxy-3-methoxyphenyl) -2- (4-carbamimidoylphenylamino) acetylamino] propionic acid, acid (S) -2- [(S) -2- (4-benzyloxy-3-methoxyphenyl) -2- (4-carbamimidoylphenylamino) acetylamino] propionic acid (S) -2- [(R) -2- (4 -benzyloxy-3-methoxyphenyl) -2- (4-carbamimidoylphenylamino) acetylamino] -3-phenylpropionic acid, (S) -2- [(S) -2- (4-benzyloxy-3-methoxyphenyl) -2- (4 -carbamimidoylphenylamino) acetylamino] -3-phenylpropionic acid (S) -2- [(R) -2- (4-benzyloxy-3-methoxyphenyl) -2- (4-carbamimidoylphenylamino) acetylamino] -3- (4-hydroxyphenyl) ) -propionic, (S) -2- [(S) -2- (4-benzyloxy-3-methoxyphenyl) -2- (4-carbamimidoylphenylamino) acetylamino] -3- (4-hydroxyphenyl) -propionic acid, acid ( S) -l- [(R) - and [(S) - (4-benzyloxy-3-methoxyphenyl) - (4-carbamimidoylphenylamino) acetyl] pyrrolidine-2-carboxylic acid,
(RS) -2- [2- (4-benzyloxy-3-methoxyphenyl) -2- (4-carbamimidoyl-phenylamino) acetylamino] -2-methylpropionic acid (S) - [[(R) - (4-benzyloxy -3-methoxyphenyl) - (4-carbamimidoylphenylamino) acetyl] ethylamino] phenylacetic, (S) - [[(S) - (4-benzyloxy-3-methoxyphenyl) - (4-carbamimidoyl-phenylamino) acetyl] methylamino] phenylacetic, acid (RS) - and (SR) -1- [(RS) - (4-benzyloxy-3-methoxyphenyl) -> 4-carbamimidoyl-anilamino) acetyl] pyrrolidine-3-carboxylic acid, (RS) - or (SR) -2- [(RS) - (4-benzyloxy-3-methoxyphenyl) - (4-carbamimidoylphenylamino) acetyl] -1,2,3,4-tetrahydro-isoquinoline-3-carboxylic acid (RS) -1- [ 2- (4-benzyloxy-3-methoxyphenyl) -2- (4-carbamimidoylphenylamino) acetylamino] cyclopentanecarboxylic acid, (S) -2- [(R) -2- (4-benzyloxy-3-methoxyphenyl) -2 - (4-carbamimidoylphenylamino) acetylamino] -4-tert-butoxycarbonylaminobutyric acid (S) -2- [(S) -2- (4-benzyloxy-3-methoxyphenyl) -2- (4-carbamimidoylphenylamino) acetylamino] -4-tert-butoxycarbonyl-inobutyric acid (S) -2- [(R) -2- (4-benzyloxy-3-methoxyphenyl) -2- (4-carbamimidoylphenylamino) acetylamino] -3-tert-butoxycarbonylaminopropionic acid, (S) -2- [(S) -2- (4-benzyloxy-3-methoxyphenyl) -2- (4-carba imidoylphenylamino) acetylamino] -3-tert-butoxycarbonylaminopropionic acid (RS) -2- [2- (4-benzyloxy-3-methoxyphenyl) -2- ( 4-carbamimidoylphenylamino) acetylamino] benzoic acid (RS) -3- [2- (4-benzyloxy-3-methoxyphenyl) -2- (4-carbamimidoylphenylamino) acetylamino] benzoic acid (RS) -4- [2- ( 4-benzyloxy-3-methoxyphenyl) -2- (4-carbamyiaidoylphenylamino) acetylamino] benzoic acid (E) - and / or (Z) - (S) -2- [(R) - and - [(S) - 2- (4-benzyloxy-3-methoxyphenyl) -2- [4- (N-hydroxycarbamimidoyl) phenylamino] -acetylamino] -propionic, acid (E) - and / or (Z) - (S) -2- [(R) -2- (4-benzyloxy-3-methoxyphenyl) -2- [4- (N-hydroxycarbamimidoyl) phenylamino] -acetylamino ] -3-phenylpropionic acid (E) - and / or (Z) - (S) -2- [(S) -2- (4-benzyloxy-3-methoxyphenyl) -2- [4- (N-hydroxycarbamimidoyl) ) phenylamino] -acetylamino] -3-phenylpropionic acid (E) - and / or (Z) - (S) -2- [(R) - and - [(S) -2- (4-benzyloxy-3- methoxyphenyl) -2- [4- (N-hydroxycarbamimidoyl) phenylamino] -acetylamino] -3- (4-hydroxyphenylpropionic acid, (E) - and / or (Z) - (S) -1- [(R) - and - [(S) - (4-benzyloxy-3-methoxyphenyl) - [4- (N-hydroxycarbamimidoyl) phenylamino] -acetyl] pyrrolidine-2-carboxylic acid, (E) - and / or (Z) - (RS) ) -2- [2- (4-benzyloxy-3-methoxyphenyl) -2- [4- (N-hydroxycarbamimidoyl) phenylamino] acetylamino] -2-methylpropionic acid, .icido (E) - and / or (Z) - ( S) [[(R) - and - [[(S) - (4-benzyloxy-3-methoxyphenyl) - [4- (N-hydroxycarbamimidoyl) phenylamino] -acetyl] methylamino] phenylacetic acid (E) - y / or (Z) - (RS) - and - (SR) -1- [(RS) - (4-benzyloxy-3-methoxyphenyl) - [4- (N-hydroxycarbamimidoyl) phenylamino] -acetyl] pyrrolidine-3-carboxylic acid (E) - and / or (Z) - (RS) - and - (SR) -2- [(RS) - (4-benzyloxy-) 3-methoxyphenyl) - [4- (N-hydroxycarbamimidoyl) phenylamino] -acetyl] -1,2,4,4-tetrahydroisoquinoline-3-carboxylic acid (E) - and / or (Z) - (RS) -1 - [2- (4-benzyloxy-3-methoxy-phenyl) -2- [4- (N-hydroxycarbamimidoyl) phenylamino] -acetylamino] -cyclopentanecarboxylic acid (E) - and / or (Z) - (RS) - [2- (4-benzyloxy-3-methoxyphenyl) -2- [4- (N-hydroxycarbamimidoyl) phenylamino] acetylamino] -diphenylacetic acid (S) -2 - [(R) - and - [(S) -2 - (4- benzyloxy-3-methoxy-spheryl) -2- [4 - [(E) - and / or - [(Z) -N-hydroxycarbamimidoyl] phenylamino] -acetylamino] 4-tert-butoxycarbonylaminobutyric acid (S) ) -2 - [(R) - and - [(S) -2- (4-benzyloxy-3-methoxyphenyl) -2- [4 - [(E) - and / or - [(Z) -N-hydroxycarbamimidoyl) ] phenylamino] -acetylamino] 3-tert-butoxycarbonylamino] ropionic acid (E) - and / or (Z) - (RS) -3- [2- (4-benzyloxy-3-methoxy-phenyl) -2- [ 4- (N-hydroxycarbamimidoyl) phenylamino] -acetyl mino] -3-terbutoxycarbonylaminopropionic acid (E) - and / or (Z) - (RS) -4- [2- (4-benzyloxy-3-methoxy-phenyl) -2- [4- (N-hydroxycarbamimidoyl) phenylamino] -acetylamino] -benzoic acid, (E) - and / or (Z) - (RS) - and - (SR) -3- [(RS) -2- (4-benzyloxy-3-methoxyphenyl) -2 - (4- (N-hydroxycarbamimidoyl) phenylamino] -acetylamino] -3-phenylpropionic acid (S) -4-amino-2- [(R) - and - L (S) -2- (4-benzyloxy-3) -methoxyphenyl) -2- [4- (N-hydroxycarbamimidoylphenylamino) -acetylamino] -butyric acid, (S) -3-amino-2- [) R) - and - [(S) -2- (4-benzyloxy- 3-methoxyphenyl) -2- (4-carbamimidoylphenylamino) acetylamino] -propionic acid (E) - and / or (Z) - (S) [(R) - or - [(S) -2- (4-benzyloxy -3-methoxyphenyl) -2- [4- (N-hydroxycarbamimidoyl) phenylamino] -acetylamino-phenylacetic acid, (S) [(S) -2- (4-benzyloxy-3-methoxyphenyl) -2- (4-carbamimidoylphenylamino) ) acetylamino] phenylacetic acid (R) [(R) -2- [4-benzyloxy-3-methoxyphenyl] -2- (4-carbamimidoylphenylamino) acetylamino] -phenylacetic acid, -acid (R) [(S) - 2- (4-benzyloxy-3-methoxyphenyl) -2- (4-carbamimidoylphenylamino) acetylamino] phenylacetic, "" * - and / or (Z) - (S) -3- (4-aminophenyl) -2- [( R) - and - [(S) -2- (4-benzyloxy-3-methoxyphenyl) -2- [4- (N-hydroxycarbamimidoyl) -phenylamino] acetylamino] ethyl propionate, (S) -3- (4- aminophenyl) -2- [(R) - and - [(S) -2- (4-benzyloxy-3-methoxyphenyl) -2- (4-carbamimidoylphenylamino) acetylamino] -propionate ethyl, acid (S) -3- (4-aminophenyl) -2- [(R) -2- (4-benzyloxy-3-methoxyphenyl) -2- (4-carbamimidoylphenylamino) acetylamino] -propionic acid (S) -3- (4-aminophenyl) - 2- [(S) -2- (4-Be-Iloxy-3-methoxyphenyl) -2- (4-carbamimidoylphenylamino) acetylamino] • propionic acid (S) - [(R) -2- (4-carbamimidoylphenylamino) -2- (3,5-dimethoxyphenyl) acetylamino] phenylacetic acid, (RS) -2- (4-benzyloxy-3-methoxyphenyl) -2- (-4-carbamidoyl-phenylamino) -N- [2- (3, 4 -hydroxyphenyl) ethyl] acetamide,
(RS) -N-benzyl-2- (4-benzyloxy-3-methoxyphenyl) -2- (4-carbamimidoylphenylamino) -N-methylacetamide, (RS) -2- (4-benzyloxy-3-methoxyphenyl) -2- (4-carbamimidoyl-phenylamino) -N- [2- (4-sulfamoylphenyl) -ethyl] acetamide,
(RS) -2- (4-benzyloxy-3-methoxyphenyl) -2- (4-carbamimidoyl-phenylamino) -N- (2-pyridin-2-ylethyl) acetamide, (RS) -N- [2- (4 -aminophenyl) ethyl] -2- (4-benzyloxy-3-methoxyphenyl) -2- (4-carbamimidoylphenylamino) acetamide,
(R) -2- (4-benzyloxy-3-methoxyphenyl) -2- (4-carbamimidoyl-phenyla ino) -N- [(R) -2-hydroxy-l-phenylethyl] acetamide,
(S) -2- (4-benzyloxy-3-methoxyphenyl) -2- (4-carbamimidoyl-phenylamino) -N- [(R) -2-hydroxy-l-phenylethyl] acetamide,
(R) -2- (4-benzyloxy-3-methoxyphenyl) -2- (4-carbamimidoyl-phenylamino) -N- [(S) -2-hydroxy-l-phenylethyl] acetamide,
(S) -2- (4-benzyloxy-3-methoxyphenyl) -2- (4-carbamimidoyl-phenylamino) -N- [(S) -2-hydroxy-1-phenylethyl] acetamide, (R) -2- ( 4-benzyloxy-3-methoxyphenyl) -2- (4-carbamimidoyl-phenylamino) -N- [(R) -1-phenylethyl] acetamide, (S) -2- (4-benzyloxy-3-methoxyphenyl) -2- (4-carbamimidoyl-phenylamino) -N- [(R) -1-phenylethyl] acetamide, (R) -2- (4-benzyloxy-3-methoxyphenyl) -2- (4-carbamimidoyl-phenylamino) -N- [ (S) -2-hydroxy-l-phenylethyl] acetamide,
(S) -2- (4-benzyloxy-3-methoxyphenyl) -2- (4-carbamimidoyl-phenylamino) -N- [(S) -1-phenylethyl] acetamide, (E) - and / or (Z) - (RS) -N-benzyl-2- (4-benzyloxy-3-methoxyphenyl) -2- [4- (N-hydroxycarbamimidoyl) phenylamino] -N-methylacetamide, (E) - and / or (Z) - (RS ) -2- (4-benzyloxy-3-methoxyphenyl) -2- [4- (N-hydroxycarbamimidoyl) phenylamino] -N- [2- (4-sulfamoylphenyl) -ethyl] acetamide, (E) - and / or ( Z) - (RS) -2- (4-benzyloxy-3-methoxyphenyl) -2- [4- (N-hydroxycarbamimidoyl) phenylamino] -N- [2-pyridin-2-ylethyl] -acetamide, (E) - and / or (Z) - (RS) -2- (4-benzyloxy-3-methoxyphenyl) -2- [4- (N-hydroxycarbamimidoyl) phenylamino] -N- [2- (4-nitrophenyl) -ethyl] acetamide , (E) - and / or (Z) - (R) -2- (4-benzyloxy-3-methoxyphenyl) -2- [4- (N-hydroxycarbamimidoyl) phenylamino] -N- [(R) - (2 -hydroxy-l-phenylethyl] acetamide, (E) - and / or (Z) - (S) -2- (4-benzyloxy-3-methoxyphenyl) -2- [4- (N-hydroxycarbamimidoyl) phenylamino] -N - [(R) - (2-hydroxy-l-phenylethyl] acetamide, (E) - and / or (Z) - (R) -2- (4-benzyloxy-3-methoxyphenyl) -2- [4- ( N-hydroxycarb ami idoyl) phenylamino] -N- [(S) -2-hydroxy-l-phenylethyl] acetamide, (E) - and / or _, - (S) -2- (4-benzyloxy-3-methoxyphenyl) -2 - [4- (N-hydroxycarbamimidoyl) phenylamino] -N- [(S) -2-hydroxy-l-eylethyl] acetamide, (E) - and / or (Z) - (R) -2- (4-benzyloxy) -3-methoxyphenyl) -2- [4- (N-hydroxycarbamimidoyl) phenylamino] -N- [(R) -1-phenylethyl] -acetamide, (E) - and / or (Z) - (S) -2- (4-benzyloxy-3-methoxyphenyl) -2- [4- (N-hydroxycarbamimidoyl) phenylamino] -N- [(R) -1-phenylethyl] -acetamide, (E) - and / or (Z) - (R ) -2- (4-benzyloxy-3-methoxyphenyl) -2- [4- (N-hydroxycarbamimidoyl) phenylamino] -N- [(S) -1-phenylethyl] -acetamide, (E) - and / or (Z ) - (S) -2- (4-benzyloxy-3-methoxyphenyl) -2- [4- (N-hydroxycarbamimidoyl) phenylamino] -N- [(S) -1-phenylethyl] -acetamide, (RS) acetate -N- [2- [benzylcarbamoyl- (4-carbamimidoyl-phenylamino) methyl] -5-benzyloxy-4-methoxyphenyl] benzamide, (RS) - [2- [benzylcarbamoyl- (4-carbamimidoyl-phenylamino) methyl] acetate] Methyl-5-benzyloxy-4-methoxyphenyl] carbamate, (RS) -2- (2-acetylamino) no-4-benzyloxy-5-methoxyphenyl) -N-benzyl-2- (4-carbamimidoylphenylamino) acetamide, (RS) -N-benzyl-2- (4-benzyloxy-5-methoxy-2-phenylacetylamino-phenii) - 2- (4-carbamimidoylphenylamino) acetamide, (RS) -N-benzyl-2- (4-carbamimidoylphenylamino) -2- (4,5-dimethoxy-2-phenylacetylaminophenyl) acetamide, RS) - [2- [benzylcarbamoyl- (4-carbamimidoylphenylamino) - et l] -4,5-dimethoxyphenyl] methyl carbamate, (RS) - [2- [benzylcarbamoyl- (4-carbamimidoylphenylamino) -methyl] -4,5-dimethoxyphenyl] benzamide, (RS, ) - [2- [benzylcarbamoyl- (4-carbamimidoylphenylamino) -methyl] -4-methoxyphenyl] benzamide, (RS) -2- (2-benzenesulfonylamino-5-methoxyphenyl) -N-benzyl-2- (4-carbamimidoylphenylamino) acetamide, (RS) -N- (2- [benzylcarbamoyl- [4- (N-hydroxycarbamimidoyl) -phenylamino] methyl] -5-benzyloxy-4-methoxyphenyl) benzamide, (RS- (2- [benzylcarbamoyl- [4- (N-hydroxycarbamimidoyl) phenyl-amino] methyl] -5-benzyloxy-4-methoxyphenyl) carbamate methyl, (E) - and / or (Z) - (RS ) -2- (2-Acetylamino-4-benzyloxy-5-methoxyphenyl) -N-benzyl-2- [4- (N-hydroxycarbamimidoyl) -phenylamino] acetamide, (E) - and / or (Z) - (RS ) -N-benzyl-2- (4-benzyloxy-5-methoxy-2-phenylacetylaminophenyl) -2- [4- (N-hydroxycarbamimidoyl) -phenylamino] acetamide, (E) - and / or (Z) - (RS ) -N-benzyl-2- (4,5-dimethoxy-2-phenylacetylaminophenyl) -2- [4- (N-hydroxycarbamido-4-1) phenylamino] -acetamide, (E) - and / or (Z ) - (RS) - [2-Ebencilcarbamoyl [4- (N-hydroxycarbamimidoyl) phenylamino] methyl] -4,5-dimethoxyphenyl] -carbamic acid methyl ester, (E) - and / or (Z) - (RS) -N - [2-Ebencylcarbamoyl- [4- (N-hydroxycarbamimidoyl) phenylamino] methyl] -4,5-dimethoxyphenyl] -benzamide, (E) - and / or (Z) - (RS) -N- [2- [benzylcarbamoyl] - [4- (N-hydroxycarbamimidoyl) phenylamino] methyl] -4-methoxyphenyl] benzamide, (E) - and / or (Z) - (RS) -2- (2-phenylsulfonylamino-5-methoxyphenyl) -N-benzyl -2- [4- (N-hydroxycarbon bamimidoyl) phenylamino] -acetamide, (RS) -N-benzyl-2- [4-benzyloxy-5-methoxy-2- (2-methoxyacetylamine) phenyl] -2- [4- (N-hydroxycarbamimidoyl) -phenylamino ] -acetamide.
(RS) -N-benzyl-2- [4-benzyloxy-5-methoxy-2- (2-methoxyacetyl-amino) phenyl] -2- (4-carbamimidoylphenylamino) acetamide,
(RS) - [(2- (benzylcarbamoyl- [4- (N-hydroxycarbamimidoyl) -phenylamino] methyl] -5-benzyloxy-4-methoxyphenylcarbamoyl) -methyl] carbamic acid tert-butyl ester, (RS) -2- [2 - (2-aminoacetylamino) -4-benzyloxy-5-methoxyphenyl] -N-benzyl-2- (4-carbamimidoylphenylamino) -acetamide, (RS) -4- [2- [benzylcarbamoyl- (4-carbamimidoyl-phenylamino)] -methyl] -4,5-dimethoxyphenoxymethyl] benzoic acid (RS) -4- [2- [i. : ncylcarbamoyl- (4-carbamimidoyl-phenylamino) -methyl] -4,5-dimethoxyphenoxy] butyric acid (RS) - [2- [benzylcarbamoyl- (4-carbamimidoyl-phenylamino) -methyl] -4-methoxyphenoxy] acetic acid, acid (RS) - [2-rbenzylcarbamoyl- (4-carbamimidoyl-phenylamino) -methyl] -4,6-dimethylphenoxy] acetic acid (E) - and / or (Z) - (RS) -3- [2- [benzylcarbamoyl- [4- (N-hydroxy-carbamimidoyl) phenylamino] methyl] -4,5-dimethoxyphenoxymethyl] -benzoic acid (E) - and / or (Z) - (RS) -3- [2- [benzylcarbamoyl] - [4- (N-hydroxycarbamimidoyl) phenylamino] ethyl] -4,5-dimethoxy-phenoxy] acetic acid (E) - and / or (Z) - (RS) -4- [2- [benzylcarbamoyl- [4] - (N-hydroxycarbamimidoyl) phenylamino] methyl] -4,5-dimethoxy-phenoxymethyl] -benzoic acid (E) - and / or (Z) - (RS) -4- [2-E-benzylcarbamoyl- [4- (N -hydroxycarbamimidoyl) phenylamino] methyl] -4,5-dimethoxy-phenoxy] butyric acid (E) - and / or (Z) - (RS) - [2- [benzylcarbamoyl- [4- (N-hydroxycarbamimidoyl) phenylamino] methyl] -4-methoxyphenoxy] -acetic acid (E) - and / or (Z) - (RS) - [2- [benzyl] arbamoyl- [4- (N-hydroxycarbamimidoyl) phenylaminolmethyl] -4,6-dimethyl-phenoxy] acetic acid (E) - and / or (Z) - (R) -2- [2- [(R) -benzylcarbamoyl- [4- (N-hydroxycarbamimidoyl) phenylamino] ethyl] -4,5-dimethoxyphenoxy] propionic acid (E) - and / or (Z) - (R) -2- [2- [(S) - benzylcarbamoyl- [4- (N-hydroxycarb imidoyl) phenylamino] ethyl] -4,5-dimethoxy-phenoxy] propionic, acid R) -2- [2- [(R-benzylcarbamoyl- (4-carbamimidoyl-phenylamino) -methyl] ] -4,5-Dimethoxyphenoxy] propionic acid (R) -2- [2- [(S-benzylcarbamoyl- (4-carbamimidoyl-phenylamino) -methyl] -4,5-dimethoxyphenoxy] propionic acid (E) - and / or (Z) - (S) -2- [2- [(R) -benzylcarbamoyl- [4- (N-hydroxycarbamimidoyl) phenylamino] methyl] -4,5-dimethoxy-phenoxy] propionic acid (E) - and / or (Z) - (S) -2- [2- [(S) -benzylcarbamoyl- [4- (N-hydroxycarbamimidoyl) phenylamino] methyl-4,5-dimethoxy-phenoxy] propionic acid (S) -2- [2- [(R) -benzylcarbamoyl- (4-carbamimidoyl-phenylamino) -methyl] -4,5-dimethoxyphenoxy] propionic, acid or (S) -2- [2- [(S) -benzylcarbar ^ oil- (4-carbamimidoyl-phenylamino) -methyl] -4,5-dimethoxyphenoxy] propionic acid (RS) -3- [4- [benzyl] ^ arbamoi-l- (4-carbamimidoyl-phenylamino) -methyl] -2-methoxyphenoxy] benzoic acid (RS) -2- [4- [benzylcarbamoyl- (4-carbamimidoyl-phenylamino) -methyl] -2-methoxyphenoxy] benzoic, acid (RS) -4- [4- [benzylcarbamoyl- (4-carbamimidoyl-phenylamino) -methyl] -2-methoxyphenoxy] benzoic acid (RS) -3- [4- [benzylcarbamoyl- [4- (N -hydroxycarbamimidoyl) phenylamino] methyl] -2-methoxyphenoxy) benzoic acid (RS) -4- (4- [benzylcarbamoyl- [4- (N-hydroxycarbamimidoyl) phenylamino] methyl] -2-methoxyphenoxy) benzoic acid, (RS) - 5- [Benzylcarbamoyl- [4- (N-hydroxycarbamimidoyl) -phenylamino] -methyl] -2, 3-dimethoxybenzoate methyl, (RS) -5- [benzylcarbamoyl- (4-carbamimidoylphenylamino) -methyl] -2, 3- methyl dimethoxybenzoate, (RS) -5- [benzylcarbamoyl- (4-carbamimidoyl-phenylamino) methyl] -2,3-dimethoxybenzoic acid, (RS) -2- (4- [benzylcarbamoyl- [4- (N-hydroxycarb amimidoyl) -phenylamino] methyl] -2-methoxyphenoxy) benzoic acid (E) - and / or (Z) - (RS) -3- [2- [benzylcarbamoyl- [4- (N-hydroxycarbamimidoyl) phenylamino] methyl] -4,5-dimethoxy-phenyl] propionic acid (RS) -3- [2- [benzylcarbamoyl- (4-carbamimidoyl-phenylamino) -methyl] -4,5-diemtoxyphenyl] ropionic acid, (E) - and / or (Z) - (RS) -2- (S-acetylaminopheniD-N-benzyl ^ - ^ - 'N-hydroxycarbamimidoyl) phenylamino] acetamide, (RS) -2- (3-acetylaminophenyl) -N-benzyl-2- ( 4-carbamimidoyl-phenylamino) acetamide, (RS) -N-benzyl-2- (4-carbamimidoylphenylamino) -2- (3-nitrophenyl) -acetamide, (RS) -N-benzyl-2- (4-carbamimidoylphenylamino) -2- (2,6-dimethoxypyridin-4-yl) acetamide, (RS) -N-benzyl-2- (4-carbamimidoylphenylamino) -2- (4,6-dimethoxypyridin-2-yl) acetamide, (RS) -N-benzyl-2- (4-benzyloxy-3,5-dimethylphenyl) -2- (4-carbamimidoylphenylamino) acetamide, hydrochloride (RS) - N-benzyl-2- (3-benzyloxy-5-propoxyphenyl) -2- (4-carbamimidoylphenylamino) acetamide, hydrochloride of (RS) -N-benzyl-2- (3,5-bisbenzyloxyphenyl) -2- (4- carbamimidoylphenylamino) acetamide, (RS) -N-benzyl-2- (4-carbamimidoylphenylamino) -2- (2,6-diethoxypyridin-4-yl) acetamide, (RS) -N-benzyl-2- (4-benzyloxy) 3-ethoxyphenyl) -2- [3-hydroxy-4- (N-hydroxycarbamimidoyl) phenylamino] acetamide, (RS) -N-benzyl-2- (4-benzyloxy-3-ethoxyphenyl) -2- (4-carbamimidoi1- 3-hydroxy phenylamino) acetamide, (S) acid [(R) - and - [(S) -2- (2-phenylsulfonylamino-4-benzyloxy? -5-methoxyphenyl) -2- [4- [(E) - and / or - [(Z) -N-hydroxycarba imidoyl) phenylamino] acetylamino] phenylacetic acid (S) [(R) - and - [(S) -2- (4-benzyloxy-5 -methoxy-2-phenyl) -acetyl inophenyl) -2- [4- [(E) - and / or - [(Z) -N-hydroxycarbamimidoyl) -phenylamino] acetylamino] -phenylacetic acid acetate (S) - [(R) -2- (2-acetylamino-4-benzyloxy-5-methoxyphenyl) -2- (4-carbamimidoylphenylamino) acetylamino] -phenylacetic acid (S) - [(S) -2- (2-acetylamino- 4-benzyloxy-5-methoxyphenyl) -2- (4-carbamimidoylphenylamino) -acetylamino] -phenylacetic acid, (RS) -N- [amino- (4- [[benzylcarbamoyl- (4-benzyloxy-3-ethoxyphenyl) methyl] amino] ] phenyl) methylene] -4-fluoro-benzamide, (RS) -2- [[amino- (4- [[benzylcarbamo - (4-benzyloxy-3-ethoxyphenyl) -methyl] amino] phenyl) methylene] carbamoyl] benzyl benzoate, 2,2, 2-trichloroethyl (RS) - [amino- (4- [[benzylcarbamoyl- (4-benzyl-oxy-3-ethoxyphenyl) methyl] amino] phenyl] -methylene] -carbamate, (RS) - [Methyl- (4- [[benzylcarbamoyl- (4-benzyloxy-3-ethoxyphenyl) ethyl] amino] phenyl) methylene] carbamate. The compounds of the formula I, according to the invention, can be prepared by a) reacting an aldehyde of the formula
with an isonitrile of the formula RLNC and a 4-aminobenzamidine of the formula
b) converting the cyano group CN contained in an appropriate nitrile of the following formula
in an amidino group C (N-G1) NH-G2, c) functionally derivatizing, if desired, a reactive group contained in a compound I, and d) converting, if desired, a compound of formula I in a physiologically salt acceptable or converting a salt of u-compound I into the free acid or base. The reaction of a substituted benzaldehyde of the formula II, an isonitrile of the formula RNC and a 4-aminobenzamidine of the formula III is advantageously carried out in a solvent, such as methanol, isopropane, ethanol, dioxane, tetrahydrofuran, or in a solvent mixture, such as tetrahydrofuran and water or isopropanol and water, advantageously using an inorganic acid, such as hydrochloric acid, sulfuric acid or boron trifluoride etherate, or an organic acid, such as toluensulfanic acid, or an acidic ion exchanger , such as Amberlyst KIO as catalyst, at a temperature between 0 ° C and 100 ° c, giving compounds of the formula I. The reaction of a substituted aldehyde of the formula II, of an isonitrile of the formula R! NC and 4- aminobenzonitrile under similar reaction conditions leads to compounds of formula IV wherein Q is hydrogen. The compounds of formula IV are also obtained a) by reaction of an aldehyde of formula II, benzyl isonitrile and an optionally 2-hydroxylated 4-aminobenzonitrile in anhydrous methanol and boron trifluoride etherate, b) subsequent treatment with water, c) hydrolysis of the compound resulting from the formula
for example advantageously in THF using lithium hydroxide, and then d) c version of the resulting acid of the formula - -
in a corresponding nitrile of the formula IV by reaction with an amine of the formula HN (R, Q) in a solvent, such as DMF or dichloromethane, with the addition of a coupling reagent, such as benzotriazole hexafluorophosphate-1-xyloxytris (di ethylamino) phosphonium (BOP) in the presence of a carbodiimide, such as di-propylcarbodiimide or dicyclohexylcarbodiimide, and, if appropriate, a tertiary amine, such as diisopropylamine. Compounds of formula IV can also be obtained by converting a compound IV to one of groups X2, X3 and X4 is C-0-allyl or C-O-benzyl in the corresponding phenol, followed, if desired, by alkylation. The allyl group is preferably separated in a protic solvent, such as tetrahydrofuran (THF), using a palladium (O) catalyst, such as tetrakis (triphenylphosphine) palladium in THF, in the presence of a reducing agent, such as sodium borohydride. . The benzyl group is preferably separated by catalytic iodination (Pd / C) in a solvent, for example ethanol and dioxane. The resulting phenol can then be alkylated, if desired, in a solvent, such as THF, using triphenylphosphine and diethyl azodicarboxylate as the catalyst, and in an appropriate alcohol. The alkylation can be carried out Tibien using an appropriate alkyl bromide in acetone or DMF in the presence of K2CO3. Reactive groups that are present in the compounds of the formulas I and IV a. "I can be functionally depilated eg as: A group C-N02 X1, X2, X3 or X4 can be reduced by hydrogenation: catalytic nation (Pd) , Pt or Ni) in a solvent, for example ethyl acetate and ethanol, to give the group C-NH2 A group C-NH2 X1, X2, X3 or X4 can be admixed, for example, in THF in the presence of diisopropylethylane using an acyl chloride, such as benzoyl chloride, to give the C-NH-acyl group It is possible to use the corresponding acid instead of the acyl chloride In this case the procedure is as described above for the reaction of an amine HN (R, Q) with an acid of the formula VI A group C-Br X1, X2, X3 or X4 can be converted into a C-alkyl group or a group X1, X2, X3 or X4 which is linked via alkyl, in a first stage, for example, a bromide IV is converted to dimethylacetamide using a terminally unsaturated compound, such as CH2 = CH-alkyl-C00H, triethylamine, Pd acetate and tri-o-tolyl phosphine in the corresponding compound IV wherein X1, X2, X3 or X4 denotes CCH = CH-alkyl-COOH. The resulting unsaturated acid IV is hydrogenated, for example, in ethanol and THF using hydrochloric acid and Pd / C to give the corresponding acid IV wherein X1, X2, X3 or X4 is CCH2CH2-aikyl-COOH. A COO-alkyl group present in a R group can be hydrolyzed in THF using LiOH to give COOH. To convert CN into a group C (N-G ') NH-G2 wherein one of the groups G1 and G2 is H and the other is OH, the nitrile starting material of the formula IV is dissolved in a solvent such as DMF, ethanol or methanol and is added to a reaction solution comprising a base, such as diisopropylethylamine or triethylamine, sodium hydride, sodium methoxide or sodium hydroxide and hydroxylamine or a hydroxylamine salt with an inorganic acid, such as hydroxylamine hydrochloride, advantageously at a temperature of up to 80 ° C. To convert CN to C (NH) NH2, the nitrile starting material can be degassed in a solvent, such as ethanol or methanol, or a solvent mixture, such as chloroform and methanol or chloroform and ethanol, using a dry stream of hydrogen, advantageously, at a temperature below 10 ° C. The reaction solution is mixed with a solvent, such as diethyl ether, and the intermediate which is precipitated in this way is filtered off. The intermediate can
• then dissolved in water, neutralized with a base such as sodium carbonate or sodium hydroxide and extracted from the aqueous phase using a solvent, such as dichloromethane, chloroform or ethyl acetate. The resulting material is treated in a solvent such as methanol or ethanol with gaseous ammonia or an ammonium salt, such as ammonium chloride, advantageously at a temperature of up to 80 ° C. Alternatively, the intermediate is filtered off and treated immediately with gaseous ammonia or an ammonium salt in methanol or ethanol. To convert CN to C (NH) NH2, it is also possible to hydrogenate the amidoximes of formula I which are obtained after conversion of CN into a group C (N-Gl) NH-G2, wherein one of the groups G1 and G2 is H and the other is OH, in a solvent, such as ethanol, methanol, dioxane, THF or glacial acetic acid, or in a solvent mixture, such as ethanol and glacial acetic acid, using hydrogen and a catalyst, such as palladium, platinum or nickel. A nitro group Ra, R, Rc or Rd which is contained in a compound of formula I is reduced to an amino group. If the hydrogenation is carried out using palladium, a benzyloxy group Ra, R, Rc or Rd which is contained in an amidoxime of the formula I is converted to the hydroxyl group. By reacting a compound of the formula I, wherein G1 and G2 are hydrogen, in a solvent such as dichloromethane, dioxane or DMF, or a solvent mixture such as dichloromethane and water or ethyl acetate and water in the presence of an organic base such as pyridine or triethylamine, or an inorganic base such as sodium hydroxide, sodium carbonate or potassium bicarbonate, with a chloroformate of the formula C1C (0) 0-A or a 2,4-dinitrophenyl-formate of the formula [2, 4 (N0 ) 2C6H3] OC (O) OA provides the corresponding compound wherein G1 or G2 is the group C (0) 0-A and A denotes alkyl. Reacting a compound I wherein G and G are hydrogen with an acetyl chloride such as an aroyl chloride provides the corresponding compound I wherein one of the groups G and G2 is hydrogen and the other group is acyl. Analogously it is possible to convert a compound I where G1 and G2 are hydrogen with a p-nitrophenyl carbonate of the formula p- N03COHOCO-R [illegible] in the corresponding compound I wherein one of the groups G1 and G2 denotes COO- R [illegible].
To carry out the reaction, the acyl chloride or the p-nitrophenyl carbonate in THF and DMF is first mixed with
N, N-diisopropylethylamine and then with the unsubstituted amidine of the formula I. A protected amino group which is contained in a R group can be converted to the free amino group. Thus, a compound I containing a Boc-protected amino group can be converted to methylene chloride with trifluoroacetic acid in the free amine I. In addition, some of the examples that follow contain details with respect to the preparation of certain starting and intermediate materials. The compounds of formulas IV, V and VI are new and therefore also form part of the object of the present invention. The compounds of the formulas II and III are known or can be prepared analogously to the known compounds. Thus, the optionally 2-substituted 4-aminobenzamidines III are obtained from the corresponding 4-aminobenzonitriles via the 4-nitrobenzonitriles.
The compounds of the formula I and their solvates and salts inhibit the formation of coagulation factors
Xa, IXa and thrombin induced by factor VIIA and tissue factor. The compounds in question consequently influence both the aggregation of platelets that is induced by these factors and the coagulation of plasma blood. They therefore inhibit the formation of thrombi and can be used to control or prevent diseases, such as thrombosis, stroke, cardiac infarction, inflammation and arteriosclerosis. In addition, these compounds have an effect on tumor cells and prevent metastasis. They can also be used, therefore, as antitumor agents. The inhibition of the amidolitic activity of the Vlla factor / tissue factor complex by the compounds according to the invention was demonstrated with the aid of a chromogenic peptide substrate, as described below. The measurements were carried out on microtitre plates at room temperature. For this purpose, per well of the plate, 100 μl of a solution of 26 nM tissue factor, 9 nM of soluble factor Vlla and 8 mM of calcium chloride were added to 25 μl of a solution of the inhibitor in a buffer [pH 7.5, 100 mM, comprising 0.14 M NaCl, N (2-hydroxyethyl) piperazine-N'- (2-ethanesulfonic acid) (HEPES), 0.5 mg / l of fatty acid-free BSA (bovine serum albumin) and 0.05% of NaN3].
After a 15-minute incubation time, the reaction was initiated by the addition of 50 μl chromogenic substrate Chromozym-tPA (3.5 mM, MeS ?2-D-Phe-Gly-Arg-paranitroanilide), and substrate hydrolysis was followed spectrophotometrically on a kinetic microtiter plate reader for 10 minutes.
Using the trace of the inhibition curves, the Ki values were determined according to the method described in Biochem. J. 55, 1953, 170-171. The results are shown in the following Table (Ki in microM):
As indicated at the beginning, medicaments comprising a compound of the formula I, a solvate or a respective sai also form part of the object of the present invention, and also also a process for the preparation of these medicaments characterized in that one or more of these compounds, solvates or salts and, if desired, other therapeutically useful substances are prepared as pharmaceutical formulations. These medicaments can be administered orally, for example in the form of sugar-coated tablets, hard and soft gelatin capsules, solutions, emulsions or suspensions, or rectally, for example in the form of suppositories, or as a spray. However, the administration can also be carried out parenterally, for example in the form of solutions for injection. For the preparation of tablets, film tablets, sugar-coated tablets and hard gelatin capsules, the active ingredient can be mixed with inorganic or organically inert excipients. The excipients which are suitable for tablets, film tablets, sugar-coated tablets and hard gelatine capsules are, for example, lactose, corn starch or its derivatives, talc, stearic acid or its salts. Excipients that are suitable for soft gelatine capsules are, for example, vegetable oils, waxes, fats, semi-solid and liquid polyols; however, depending on the properties of the active ingredient certain gelatin capsules bla. . They may not require any excipient. The excipients which are suitable for the preparation of solutions and syrups are, for example, water, polyols, sucrose, invert sugar and glucose; for use in solutions for injection are suitable, for example, water, alcohols, polyols, glycerol and vegetable oils; and for use in suppositories natural and hardened oils, waxes, fats, semi-liquid or liquid polyols are suitable. In addition, the pharmaceutical preparations may also contain preservatives, solubilizers, stabilizers, wetting agents, emulsifiers, sweeteners, colorants, flavors, salts to modify the osmotic pressure, buffers, coatings or antioxidants. The dose of the active ingredient for the control and / or prevention of the aforementioned diseases can vary within wide limits and must, of course, be adapted to the individual circumstances in each individual case. In general, for oral or parenteral administration, for example intravenous or subcutaneous, a dose of from about 0.1 to 20 mg / kg, preferably from about 0.6 to 4 mg / kg, per day for adults, but considering appropriate the upper limit just exposed may be exceeded or the dose may be lowered.
- - Example 1
At room temperature, 1 mmol of 4-aminobenzamidine dihydrochloride (208 mg), 1 mmol of triethylamine (101 mg), 1 mmol of benzyl isonitrile (117 mg) and 1 mmol of 4-benzyloxy-3-methoxybenzaldehyde (260 mg) are stirred. in a solvent mixture of 1.2 ml of isopropanol and 0.8 ml of water for 5 days. The mixture is then combined with 0.5 ml of 25% strength hydrochloric acid and stirred at room temperature for 1 hour, and the precipitated crystals are filtered off and washed with 5 ml of water. This provides 218 mg (41%) of (R, S) -N-benzyl-2- (4-benzyloxy-3-methoxyphenyl) -2 (4-carbamimidoylphenylamino) -acetamide hydrochloride in the form of colorless crystals. ISP-MS: 495.5 ([M + H] ~, 100).
Example 2
The following compounds are prepared with the method of Example 1: 2a) 4-aminobenzamidine dihydrochloride, triethylamine, benzyl isonitrile and 3,4-dimethoxybenzaldehyde give hydrochloride, S) -N-benzyl-2- (4-carbamimidoyl-phenylamino) -2- (3, 4-dimethoxyphenyl) acetamide in the form of colorless crystals ISP-MS: 455 ([M + H] ~ 100) 2.b) 4-aminobenzamidine dihydrochloride, triethylamine, benzyl isonitrile and piperonylbenzaldehyde give hydrochloride of (R, S) -2-benzo [1,3] dioxo-5-yl-N-benzyl-2- (4-carbamimidoylphenylamino) acetamide in. form of colorless crystals. ISP-MS: 439 ([M + H] ", 100) 2.c) 4-aminobenzamidine dihydrochloride, triethylamine, benzyl isonitrile and 2-hydroxy-4-methoxybenzaldehyde give (R, S) -N-benzyl hydrochloride 2- (4-carbamimidoyl-phenylamino-2- (2-hydroxy-4-methoxy-phenyl) acetamide in the form of colorless crystals ISP-MS: 405 ([M + H] -, 100) 2.d) dihydrochloride of 4-aminobenzamidine, triethylamine, benzyl isonitrile and 4-hydroxy-3-methoxy-5-nitrobenzaldehyde give (R, S) -N-benzyl-2- (4-carbamimidoylphenylamino-2- (4-hydroxy-3-methoxy) hydrochloride -5-nitrophenyl) acetamide in the form of colorless crystals ISP-MS: 450 ([M + H] ", 100) 2.e) 4-aminobenzamidine dihydrochloride, triethylamine, benzyl isonitrile and 4-hydroxy-3, 5- dimethoxybenzaldehyde give (R, S) -N-benzyl-2- (4-carbamimidoylphenylamino-2- (4-carbamimidoylphenylamino) -2- (4-hydroxy-3,5-dimethoxy-phenyl) acetamide hydrochloride in the form of colorless crystals ISP-MS: 435 ([M + H] +, 100) 2.f) 4-aminobenzamidine dihydrochloride, - -trietylamine, benzyl isonitrile and 4-formylbenzoate or of methyl give methyl (R, S) -4- [benzylcarbamoyl- (4-carbamimidoyl-phenylamino) methyl] enozoate hydrochloride in the form of colorless crystals. ISP-MS: 417 ([M + H] +, 100). 2.g) 4-aminobenzamidine dihydrochloride, triethylamine, benzyl isonitrile and 2,3,4-trimethoxybenzaldehyde give (R, S) -N-benzyl-2- (4-carbamimidoylphenylamino-2- (2, 3, 4) hydrochloride trimethoxyphenyl) -acetamide in the form of colorless crystals ISP-MS: 449 [M + H] ~, 100) 2.h) 4-aminobenzamidine dihydrochloride, triethylamine, benzyl isonitrile and 3,4-dimethylbenzaldehyde give hydrochloride (R, S) ) -N-benzyl-2- (4-carbamimidoyl-phenylamino-2- (3,4-dimethylphenyl) acetamide in the form of colorless crystals ISP-MS: 387 ([M + H] ", 100). ) 4-aminobenzamidine dihydrochloride, triethylamine, benzyl isonitrile and 4-methoxy-3-methyl-benzaldehyde give (R, S) -N-benzyl-2- (4-carbamimidoylphenylamino-2- (4-methoxy-3-methylphenyl) acetamide hydrochloride in the form of colorless crystals ISP-MS: 403 ([M + H] ", 100) 2.j) 4-aminobenzamidine dihydrochloride, triethylamine, benzyl isonitrile and 4,5-dimethoxy-2-nitrobenzaldehyde give hydrochloride (R) , S) -N-benzyl-2- (4-carbamimidoylphenylamino-2- (4,5-dimethoxy-2-nitr ofenyl) - - -acetamide in the form of colorless crystals. ISP-MS: 464
([M + H] ~, 100). 2.k) 4-aminobenzamidine dihydrochloride, triethylamine, benzyl isonitrile and 2,3-dimethoxybenzaldehyde give (R, S) -N-benzyl-2- (4-carbamimidoyl-phenylamino-2- (3,4-dimethoxyphenyl) hydrochloride) acetamide in the form of colorless crystals ISP-MS: 419 ([M + H] "" 100) 2.1) 4-aminobenzamidine dihydrochloride, triethylamine, benzyl isonitrile and 2,4-trimethoxy-benzaldehyde give hydrochloride (R) , S) -N-benzyl-2- (4-carbamimidoylphenylamino-2- (2,4, 5-trimethoxyphenyl) acetamide in the form of colorless crystals ISP-MS: 449 ([M + H] ",
2. m) 4-aminobenzamidine dihydrochloride, triethylamine, ~ benzyl isonitrile and 3-hydroxy-4-dimethoxybenzaldehyde give (R, S) -N-benzyl-2- (4-carbamimidoylphenylamino-2- (3-hydroxyphenyl) acetamide hydrochloride in the form of colorless crystals ISP-MS: 405 ([M + H] ", 100) 2.n) 4-aminobenzamidine dihydrochloride, triethylamine, benzyl isonitrile and 2,4-dimethoxybenzaldehyde give N-benzyl-2 hydrochloride (4-carbamimidoylphenylamino-2- (2,4-dimethoxy-phenyl) acetamide in the form of colorless crystals ISP-MS: 419 ([M + H], 100) 2. o) 4-aminobenzamidine dihydrochloride, triethylamine, benzyl isonitrile and 2-fluoro-4,5-dimethoxybenzaldehyde give (R, S) -N-benzyl-2- (4-carbamimidoylphenylamino) -2 (2-fluoro-4,5-dimethoxy-phenyl) acetamide hydrochloride in the form of colorless crystals ISP-MS: 437 ([M + H] ", 100). 2.p) 4-aminobenzamidine dihydrochloride, triethylamine, cyclopropylmethyl-isonitrile and 3,4,5-trimethoxybenzaldehyde give (R, S) -2-N- (4-carbamimidoylphenylamino-N-cyclopropylmethyl-2- (3,4, 5-trimethoxyphenyl) acetamide in the form of colorless crystals.
ISP-MS: 413 ([M + H] ", 100) 2.q) 4-aminobenzamidine dihydrochloride, triethylamine, 3,4-dimethoxybenzylisonitrile and 3,4,5-trimethoxybenzaldehyde give hydrochloride (R, S) - 2- (4-carbamimidoylphenylamino) -N- (3,4-dimethoxybenzyl) -2- (3, 4, 5-trimethoxyphenyl) acetamide in the form of colorless crystals.
ISP-MS: 509 ([M + H] ", 100) 2.r) 4-aminobenzamidine dihydrochloride, triethylamine, benzylisonitrile and methyl 2- (formyl-2-methoxyphenoxy) benzoate give hydrochloride (R, S) - 2- {4- [benzylcarbamoyl- (4-carbamimidoylphenylamino) methyl] -2-methoxyphenoxy] methyl benzoate in the form of colorless crystals ISP-MS: 539.4 ([M + H] +, 100). 2.s) 4-aminobenza-midin dihydrochloride, triethylamine, 2-phenylethylisonitrile and 4-dimethylamino-3-nitrobenzaldehyde give (R, S) -N- (2-phenylethyl) -2- (4-carbamimidoyl-phenyl) hydrochloride -amino) -2- (4-dimethyl-amino-3-nitrophenyl) acetamide in the form of colorless crystals ISP-MS: 461.7 ([M + H] ", 100). 2.t) 4-aminobenzamidine dihydrochloride, triethylamine, benzyl isonitrile and 3,5-dimethoxy-4-methylbenzaldehyde give (R, S) -N-benzyl-2- (4-carbamimidoylphenylamino-2- (3, 5) hydrochloride dimethoxy-4-methylphenyl) -acetamide in the form of colorless crystals ISP-MS: 433 ([M + H] ", 100) 2.u) 4-aminobenzamidine dihydrochloride, triethylamine, benzyl isonitrile and 3-phenoxybenzaldehyde give hydrochloride (R, S) -N-benzyl-2- (3-phenoxyphenyl) -2- (4-carbamimidoylphenylamino) acetamide in the form of colorless crystals ISP-MS: 451.6 [M + H] ", 100). 2.v) 4-aminebenzam dihydrochloride: ina, triethylamine, benzyl isonitrile and 3,5-bis-benzyloxy-benzaldehyde give (R, S) -N-benzyl-2- (3,5-bis-benzyloxyphenyl) hydrochloride - 2- (4-carbamimidoylphenylamino) acetamide in the form of colorless crystals. ISP-MS: 571 ([M + H] ", 100) 2.) 4-aminobenzamidine dihydrochloride, triethylamine, benzyl isonitrile and 3-benzyl-4-hydroxybenzaldehyde give (R, S) -N-benzyl-2 hydrochloride - (3-benzyloxy-4-hydroxyphenyl) -2- (4-carbamimidoylphenylamino) acetamide in the form of colorless crystals ISP-MS:
481 ([M + H] \ 100). 2.x) 4-aminobenzamidine dihydrochloride, triethylamine, benzyl isonitrile and 4-bromo-3,5-dimethoxy-benzaldehyde give (R, S) -N-benzyl-2- (4-bromo-3,5-dimethoxy) hydrochloride phenyl) -2- (4-carbamimidoylphenylamino) -acetamide in the form of colorless crystals. ISP-MS: 498
([M + H] ", 100) 2. y) 4-aminobenzamidine dihydrochloride, triethylamine, benzyl isonitrile and 3,5-dimethoxy-4-nitrobenzaldehyde give (R, S) -N-benzyl-2- hydrochloride ( 4-carbamimidoylphenylamino-2- (3,5-dimethoxy-4-nitrophenyl) -acetamide in the form of colorless crystals ISP-MS: 464
([M + H] ', 100).
Example 3
mmol of 4-aminobenzamidine dihydrochloride (2.8 g), 10 mmol of triethylamine (1.01 g), 0.5 ml of water, 10 mmol of 4-benzyloxy-3-methoxybenzaldehyde (2.6 g) and 10 mmol of benzyl isonitrile (1.2 ml) they are initially charged in 40 ml of methanol, and then 3.8 ml of boron trifluoride etherate (30 mmol) is added dropwise with ice bath cooling and for a period of 2 hours. The mixture is stirred at room temperature for an additional hour, then the solvent is removed under reduced pressure and the crude product is chromatographed on a RP-18 column using water / methanol as the mobile phase.
Alternatively, the crude product is mixed with ice cooling with 5 ml of hydrochloric acid at a concentration of 25%, 10 ml of dichloromethane and 10 ml of water are added and the precipitated crystals are filtered off with suction after 5 hours. This provides 1.6 g (30%) of hydrochloride
(R, S) -N-benzyl-2- (4-benzyloxy-3-methoxyphenyl) -2- (4-carbamimidoylphenylamino) acetamide in the form of colorless crystals. ISP: 495.5 ([M + H] ", 100). Chromatography of the crude product on a RP-18 column using a mobile phase from methanol / water with 0.1% trifluoroacetic acid gives 0.8 g (15%) of trifluoroacetate
(R, S) -N-benzyl-2- (4-benzyloxy-3-methoxyphenyl) -2- (4-carbamimidoylphenylamino) acetamide in the form of colorless crystals. ISP-MS: 495.2 ([M + H] +, 100).
Example 4
mmol of 4-aminobenzonitrile (1.2 g), 0.5 ml of water, 10 mmol of 4-benzyloxy-3-methoxybenzaldehyde (2.6 g) in 40 ml of methanol are charged initially and stirred at room temperature for one hour, and then 10 mmol of benzyl isonitrile (1.2 ml) is added dropwise and, with ice-bath cooling and stirring, 3.8 ml of boron trifluoride etherate is added over a period of 2 hours. The mixture is stirred at room temperature for a further hour, then the solvent is removed under reduced pressure and the crude product is filtered on a silica gel column using hexane / ethyl acetate 1/1 as the mobile phase.
The main fraction is concentrated and the resulting crude (R, S) -N-benzyl-2- (4-benzyloxy-3-methoxyphenyl) -2- (4-cyano-phenylamino) acetamide is dissolved in a 20 ml solvent mixture. of chloroform and 4 ml of methanol and, with stirring and at a temperature lower than 5 ° C, is gassed with dry hydrogen chloride for 20 minutes. The mixture is then allowed to react at 5 ° C for 24 hours, then 20 ml of diethyl ether are added and the precipitated crystals are filtered off with suction and washed with diethyl ether and the residue is taken up in methanol, which is saturated with ammonia. The ammonia solution is boiled under reflux for 2 hours and then the solvent is removed using a water pump vacuum. Then, 5 ml of an IN solution of hydrochloric acid is added to the residue and the solvent is separated again using a water pump vacuum. The resulting crude product is chromatographed on a RP-18 column using water / methanol as the mobile phase.
This gives 228 mg (43%) of (R, S) -N-benzyl-2- (4-benzyloxy-3-methoxyphenyl) -2- (4-carbamimidoyl-phenylamino) acetamide hydrochloride in the form of colorless crystals. ISP-MS: 495.5 ([M + H] ", 100).
Example 5
With the method of Example 4 the following compounds are prepared: 5.a) 4-aminobenzonitrile, benzyl isonitrile and 3,4,5-trimethoxybenzaldehyde give (R, S) -N-benzyl-2- (4-carbamimidoylphenylamino) hydrochloride - 2- (3, 4, 5-trimethoxyphenyl) -acetamide in the form of colorless crystals. ISP-MS: 449.2 ([M + H] ', 100). 5.b) 4-aminobenzonitrile, -benzylisonitrile and 3,5-dimethoxybenzaldehyde give (R, S) -N-benzyl-2- (4-carbamimidoylphenylamino) -2- (3,5-dimethoxyphenyl) -acetamide hydrochloride in the form of colorless crystals. ISP-MS: 419 ([M + H] ", 100) 5.c) 4-aminobenzonitrile, benzhydrylisonitrile and 3,4-dimethoxybenzaldehyde give (R, S) -N-bezhidpl-2- (4-carbamimidoylphenylamino) hydrochloride ) -2- (3,4-trimethoxy-phenyl) acetamide in the form of colorless crystals ISP-MS: 495 ([M + H] ", 100).
. d) 4-Aminobenzonitrile, benzylisonitrile and 3,4-diethoxybenzaldehyde give (R, S) -N-benzyl-2- (4-carbamimidoylphenylamino) -2- (3,4-diethoxyphenyl) acetamide hydrochloride in the form of colorless crystals. ISP-MS: 447.2 ([M + H] ", 100) 5.e) 4-aminobenzonitrile, benzhydrylisonitrile and 4-benzyloxy-3-methoxybenzaldehyde give (R, S) -N-bezhydril-2- (4) hydrochloride -benzyloxy-3-methoxyphenyl) -2- (4-carbamimidoylphenylamino) acetamide in the form of colorless crystals ISP-MS: 571.4 ([M + H] ", 100). 5.f) 4-aminobenzonitrile, benzhydryl isonitrile and 4-benzyloxy-3-ethoxybenzaldehyde give (R, S) -N-bezhydril-2- (4-benzyloxy-3-ethoxyphenyl) -2- (4-carbamimidoylphenylamino) acetamide hydrochloride in the form of colorless crystals. ISP-MS: 585.4 ([M + H] ", 100) 5.g) 4-aminobenzonitrile, benzylisonitrile and 4-benzyloxy-3-ethoxybenzaldehyde give (R, S) -N-benzyl-2- (4) hydrochloride -benzyloxy-3-ethoxyphenyl) -2- (4-carbamimidoyl-phenylamino) acetamide in the form of colorless crystals ISP-MS: 509.4 ([M + H] ", 100). 5.h) 4-aminobenzonitrile, 4-methoxybenzylisonitrile and 4-benzyloxy-3-methoxybenzaldehyde give (R, S) -N-2- (4-benzyloxy-3-methoxyphenyl) -2- (4-carbamimidoyl-phenylamino) hydrochloride ) -N- (4-methoxybenzyl) acetamide in the form of colorless crystals. ISP-MS: 525.2 ([M + H] +, 100).
. i) 4-aminobenzonitrile, naphthyl-1-yl-methylisonitrile and 4-benzyloxy-3-methoxybenzaldehyde give hydrochloride of (R, S) -N-becyloxy-3-methoxyphenyl) -2- (4-carbamimidoylphenylamino) -N-naphthalen-1-yl-methylacetamide in the form of colorless crystals. ISP-MS: 545.3 ([M + H] ", 100) 5.j) 4-aminobenzonitrile, benzyl isonitrile and 3-butoxy-5-methoxybenzaldehyde give (R, S) -N-benzyl-2- (3) hydrochloride -butoxy-5-methoxyphenyl) -2- (4-carbamimidoylphenylamino) acetamide in the form of colorless crystals ISP-MS: 461.3 ([M + H] ", 100). 5.k) 4-aminobenzonitrile, benzylisonitrile and 3-benzyloxy-5-ethoxybenzaldehyde give (R, S) -N-benzyl-2- (3-benzyloxy-5-ethoxyphenyl) -2- (4-carbamimidoyl-phenylamino) hydrochloride ) acetamide in the form of colorless crystals. ISP-MS: 509.4 ([M + H] ", 100) 5.1) 4-aminobenzonitrile, benzyl isonitrile and 3-benzyloxy-5-methoxybenzaldehyde give (R, S) -N-benzyl-2- (3-benzyloxy) hydrochloride -5-methoxyphenyl) -2- (4-carbamimidoyl-phenylamino) acetamide in the form of colorless crystals ISP-MS: 495.3 ([M + H] +, 100).
Example 6
Under an argon atmosphere, NaOMe solution was prepared freshly from 130 mg (5.6 mmol) of sodium - and 10 ml of MeOH, and the solution was combined with 474 mg
(6.8 mmol) of hydroxylamine hydrochloride. The suspension was stirred at room temperature for 30 minutes. 286 mg (0.6 mmol) of (R, S) -N-benzyl-2- (4-cyano-phenylamino) -2- [3-methoxy-4- (3-methoxybenzyloxy) phenyl] -acetamide (Example 18) was added and heated the mixture react under reflux overnight. The solvent was then distilled off under reduced pressure. The residue was taken up in water and extracted with EtOAc. The organic phase was washed with saturated NaCl solution, dried over MgSO4, filtered and concentrated under reduced pressure. The residue was taken up in 10 ml of ethanol, 1 ml of THF and 1 ml of HOAc and combined with a Raney nickel spatula tip. The reaction mixture was hydrogenated for 5 hours. The catalyst was filtered off. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography (EtOAc / acetone / H20 / HOAc 6: 2: 1: 1). This gave 191 mg (53%) of (R, S) -N-benzyl-2- (4-carbamimidoyl-phenylamino) -2- [3-methoxy-4- (3-methoxybenzyloxy) phenyl] -acetamide acetate in form of colorless crystals. ISP-MS: 525.2 ([M + H]).
Example 7
With the method of Example 6 the following compounds were obtained: 7.a) (R, S) -N-benzyl-2- (4-cyano-phenylamino) -2- [3-methoxy-4 (pyridin-4-ylmethoxy) phenyl acetamide (Example 19.a) gave N-benzyl-2- (4-carbamimidoyl-phenylamino) -2- [3-methoxy-4- (pyridin-4-ylmethoxy) phenyl] -acetamide acetate with a yield of 18%. 'Colorless solid. ISP-MS: 496.2 ([M + H]). 7.b) (R, S) -N-benzyl-2- (4-cyanophenylamino) -2- [3-methoxy-4 (pyridin-4- (2-morpholin-4-ylethoxy) phenyl] acecamide (Example 19 b) gave (R, S) -N-benzyl-2- (4-carbamimidoylphenylamino) -2- [3-methoxy-4- (2-morpholin-4-ylethoxy) phenyl] acetamide acetate with a yield of 15%. % Colorless solid ISP-MS: 518.3 ([M + H]) 7. c) (R, S) -N-benzyl-2- (4-cyano-phenylamino) -2- [3-methoxy-4- ( pyridin-4- (2-thiomorpholin-4-ylethoxy) phenyl] -acetamide (Example 19. C) gave (R, S) -N-benzyl-2- (4-carbamimidoylphenylamino) -2- [3-methoxy] acetate -4- (2-morpholin-4-ylethoxy) phenyl] acetamide with a yield of 22% Yellow-green solid ISP-MS: 534.3 ([M + H]). 7.d) (R, S) - N-benzyl-2- (4-cyanophenylamino) -2- [3-methoxy-4- (pyridin-4- (3-phenoxybenzyloxy) phenyl] acetamide (Example 19. d) gave (R, S) -N acetate -benzyl-2- (4-carbamimidoylphenylamino) -2- [3-methoxy-4- (3-phenoxy-benzyloxy) phenyl] acetamide with a yield of 28%.
Colorless solid. ISP-MS: 587.4 ([M + H]). 7.e) (R, S) -N-benzyl-2- (4-cyanophenylamins) -2- [4- (1H-indol-5-ylmethoxy) -3-methoxyphenyl] acetamide (Example 19.e) gave acetate of (R, S) -N-benzyl-2- (4-carbamimidoyl-phenylamino) -2- [4- (lH-indol-5-ylmethoxy) -3-methoxyphenyl] -acetamide in 23% yield. Colorless solid.
ISP-MS: 534.3 ([M + H]). 7.f) (R, S) -N-benzyl-2- (4-cyano-phenylamino) -2- [3-methoxy-4 (quinolin-7-ylmethoxy) phenyl] acetamide (Example 19. f) gave ( R, S) -N-benzyl-2- (4-carbamimidoyl-phenylamino) -2- [3-methoxy-4 (1,2,3,4-tetrahydroquinolin-7-ylmethoxy) phenyl] acetamide with a yield of 13 %. Colorless solid. ISP-MS: 550.2 ([M + H]). 7.g) (R, S) -N-benzyl-2- (4-cyano-phenylamino) -2- [3-methoxy-4- (quinolin-7-ylmethoxy) phenyl] acetamide (Example 19. f) gave (R, S) -N-benzyl-2- (4-carbamimidoyl-phenylamino) -2- [3-methoxy-4 (quinolin-7-ylmethoxy) phenyl] -acetamide with a yield of 16%. Slightly pink solid. ISP-MS: 546.3 ([M + H]). 7.h) (R, S) -N-benzyl-2- (4-cyano-phenylamino) -2- (3-methoxy-4-phenethyloxyphenyl) acetamide (Example 19. g) gave (R, S) -N acetate -benzyl-2- (4-carbamimidoylphenylamino) -2- (3-methoxy-4-phenethyloxyphenyl) acetamide with a yield of 21%. Colorless solid. ISP-MS: 509.4
([M + H]). 7. i) (R, S) -N-benzyl-2- (4- (diphenyl-4-ylmethoxy) -3-methoxyphenyl] -2- (4-cyano-phenylamino) -acetamide (Example 19. h) gave da acetate ( R, S) -N-benzyl-2- [4- (diphenyl-4-ylmethoxy-3-methoxyphenyl] -2- (4-carbamimidoylphenylamino) -acetamide with a yield of 58% .Colourless solid.
ISP-MS: 571.3 ([M + H]). 7. j) (R, S) -N-benzyl-2- (4-cyano-phenylamino) -2- [4- (2,6-dichlorobenzyloxy) -3-methoxyphenyl] acetamide (Example 19. i) gave ( R, S) -N-benzyl-2- (4-carbamimidoylphenylamino) -2- [4- (2,6-dichlorobenzyloxy) -3-methoxyphenyl] acetamide with a yield of 58%. Colorless solid. ISP-MS: 563.3 ([M + H]). 7.k) (R / S) -N-benzyl-2- (4-cyano-phenylamino) -2- [4- (3,5-dichlorobenzyloxy) -3-methoxyphenyl] acetamide (Example
19. j) gave (R, S) -N-benzyl-2- (4-carbamimidoylphenylamino) -2- [4- (3,5-dichlorobenzyloxy) -3-methoxyphenyl] acetamide acetate in 47% yield. Colorless solid. ISP-MS: 563.3 ([M + H]). 7.1) (R, S) -N-benzyl-2- (4- (3-bromobenzyloxy) -3-methoxyphenyl] -2- (4-cyano-phenylamino) -acetamide (Example 19.k) gave (R, S) acetate -N-Benzyl-2- (4- (3-bromobenzyloxy) -3-methoxyphenyl] -2- (4-carbamimidoylphenylamino) acetamide with a yield of 35% Colorless solid ISP-MS: 573 ([M + H]). 7.m) (R, S) -N-benzyl-2- (4-cyano-phenylamino) -2- [3-methoxy-4- (pyridin-4- (pyridin-2-ylmethoxy) phenyl] acetamide
(Example 19.1) gave (R, S) -N-benzyl-2- (4-carbamimidoylphenylamino) -2- [3-methoxy-4- (pyridin-2-ylmethoxy) phenyl] acetamide acetate with a yield of 34% .
Colorless solid. ISP-MS: 496.3 ([M + H]). 7.n) (R, S) -N-benzyl-2- (4-cyano-phenylamino) -2- [4- (isoquinolin-6-ylmethoxy) -3-methoxyphenyl] acetamide (Example 19.m) gave acetate ( R, S) -N-benzyl-2- (4-carbamimidoyl-phenylamino) -2- [4- (isoquinolin-6-ylmethoxyphenyl] acetamide with a yield of 11% Colorless solid ISP-MS: 546.3 ([M + H]). 7.0) (R, S) -2- (4-benzyloxy-3-methoxyphenyl) -2- (4-cyano-phenylamino) -N- (3,4-dimethoxybenzyl) acetamide (Example 24.a) (R, S) -2- (4-benzyloxy-3-methoxyphenyl) -2- (4-carbamimidoylphenylamino) -N- [3,4-dimethoxybenzyl] -acetamide acetate in 5% yield. Colorless solid. ISP-MS: 555.3 ([M + H]). 7.p) (R / S) -2- (4-benzyloxy-3-methoxyphenyl) -2- (4-cyano-phenylamino) -N-phenethylacetamide (Example 23) gave (R, S) -2- (4) acetate. -benzyloxy-3-methoxyphenyl) -2- (4-carbamimidoylphenylamino) -N-phenethylacetamide with a yield of 30%. Colorless solid. ISP-MS: 555.3 ([M + H]).
7. q) (R, S) -2- (4-benzyloxy-3-methoxyphenyl) -2- (4-cyano-phenylamino) -N- (4-nitrobenzyl) acetamide (Example
24. b) gave (R, S) -N- (4-aminobenzyl) -2- (4-benzyloxy-3-methoxyphenyl) -2- (4-carbamimidoylphenylamino) -acetamide acetate in 5% yield. Colorless solid.
ISP-MS: 510.4 ([M + H]). 7. r) (R, S) -2- (4-benzyloxy-3-methoxyphenyl) -N- (4-cyanophenyl) -2- (4-cyanophenylamino) acetamide (Example 24. d) gave acetate (R, S) -2- (4-benzyloxy-3-methoxyphenyl-) - N - (4-carbamimidoylphenyl) -2- (4-carbamimidoylphenylamino) -acetamide with a yield of 30%. Colorless solid. ISP-MS: 523.3 ([M + H]). 7.s) (R, S) -2- (4-benzyloxy-3-methoxyphenyl) -N- (4-cyanophenyl) -2- (4-cyano-phenylamino) -N-phenylacetamide (Example 24. c) gave acetate of (R, S) -2- (4-benzyloxy-3-methoxyphenyl) -2- (4-carbamimidoylphenyl) -N-phenylacetamide with a yield of 30%. Colorless solid. ISP-MS: 481.4 ([M + H]). 7.t. ) (R, S) -2- (4-benzyloxy-3-methoxyphenyl) -2- (4-cyanophenyl) -2- (4-cyano-phenylamino) -N- [2- (3H-imidazol-4-yl) ethyl) ] acetamide (Example 24. e) gave (R, S) -2- (4-benzyloxy-3-methoxyphenyl) -2- (4-carbamimidoylphenylamino) -N- [2- (3H-imidazol-4-y) acetate. ) ethyl] acetamide with a yield of 9%. Colorless solid. ISP-MS: 482.4 ([M + H]).
- 7.u) (R, S) -2- (4-benzyloxy-3-methoxyphenyl) -2- (4-cyano-phenylamino) -N- [2- (lH-indol-3-yl) ethyl] acetamide (Example
24. f) gave (R, S) -2- (4-benzyloxy-3-methoxyphenyl) -2- (4-carbamimidoylphenylamino) -N- [2- (lH-indol-3-yl) ethyl] -acetamide acetate with a yield of 68%. Colorless solid.
ISP-MS: 553.3 ([M + Na]), 548.3 (M + NH4]), 531.3 ([M + H]).
Example 8
440 mg of N-benzyl-2- (4-benzyloxy-2-phenylsulphonyl-amino-5-methoxyphenyl) -2- [4- (N-hydroxycarbamimidoyl) phenylamino] acetamide (0.66 mmol) (Example 14) were dissolved in 10 ml. ml of MeOH, mixed with a drop of AcOH and mixed with 200 mg of 5% Pt / C. The reaction mixture was hydrogenated overnight. The catalyst was filtered off. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography (EtOAc / acetone / H20 / HOAc). This gave 263 mg of 2- (2-phenylsulfonylamino-4-benzyloxy-5-methoxyphenyl) -N-benzyl-2- (4-carbamimidoylphenylamino) -acetamide acetate as a colorless solid. ISP-MS: 650 (M + H).
Example 9
With the method of Example 8, N-benzyl-2- (4-benzyloxy-2-methanesulfonylamino-5-methoxyphenyl) -2- [4- (N-hydroxycarbamimidoyl) phenylamino] acetamide (Example 15) gave, after purification with HPLC on a RP-18 column using a mobile phase of CH3CN / water with 0.1% trifluoroacetic acid, N-benzyl-2- (4-benzyloxy-2-methanesulfonylamino-5-methoxyphenyl) -2- (4-carbamimidoylphenylamino) trifluoroacetate ) acetamide in the form of a colorless solid. ISP-MS: 588 (M + H).
Example 10
350 mg of N-benzyl-2- (4-benzyloxy-2-phenylsulfonylamino-5-methoxyphenyl) -2- [4- (N-hydroxycarbamimidoyl) phenylamino] acetamide (0.53 mmol) (Example 14) was dissolved in 3 ml of AcOH was mixed with 100 ml of Ac20 and hydrogenated in the presence of 150 mg of 5% Pd / C overnight. The catalyst was filtered off. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography (EtOAc / acetone / H20 / HOAc). This gave 188 mg (64%) of 2- (2-phenylsulfonylamino-4-hydroxy-5-methoxyphenyl) -N-benzyl-2- (4-carbamimidoylphenylamino) -acetamide acetate as a colorless solid. ISP-MS: 560
(M + H).
Example 11
With the method of Example 10, N-benzyl-2- (4-benzyloxy-2-methanesulfonylamino-5-methoxyphenyl) -2- [4- (N-hydroxycarbamimidoyl) phenylaminclacetamide (Example 15) gave, after purification by HPLC over a column RP-18 a mobile phase of CH3CN / water with 0.1% trifluoroacetic acid, trifluoroacetate of N-benzyl-2- (4-carbamimidoylphenylamino) -2- (4-hydroxy-2-methanesulfonyl-amino-5-methoxyphenyl) acetamide in the form of a colorless solid. ISP-MS: 498 (M + H).
Example 12
Under an argon atmosphere a fresh solution of NaOMe prepared from 115 mg (5 mmol) of sodium and 15 ml of MeOH was prepared, and this solution was mixed with 420 mg (6 mmol) of hydroxylamine hydrochloride. The suspension was stirred at room temperature for 30 minutes. 261 mg (0.5 mmol) of (R, S) -N-benzyl-2- (4-cyano-phenylamino) -2- [3-methoxy-4- (4-nitrobenzyloxy) phenyl] -acetamide was added (Example 19. n ) and then the mixture was heated-0 -react under reflux overnight. The solvent was then distilled off under reduced pressure. The residue was taken up in water and extracted with EtOAc. The organic phase was washed with saturated NaCl solution, dried over MgSO, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography (EtOAc). This gave 166 mg (60%) of (R, S) -N-benzyl-2- [4- (N-hydroxycarbamimidoyl) -phenylamino] -2- [3-methoxy-4- (4-nitrobenzyloxy) phenyl] - acetamide in the form of a colorless solid foam. ISP-MS: 556.3 [M + H].
Example 13
With the method of Example 12, 13.a) (R, S) -N-benzyl-2- (4-cyanophenylamino) -2- [3-methoxy-4- (pyridin-4-ylmethoxy) phenyl] acetamide (Example 19.a) gave (R, S) -N-benzyl-2- [4- (N-hydroxycarbamimidoyl) -phenylamino] -2- [3-methoxy-4- (pyridin-4-ylmethoxy) phenyl] -acetamide with a yield of 35%. Colorless solid foam. ISP-MS: 512.4 ([M + H]). 13.b) (R, S) -N-benzyl-2- (4-cyano-phenylamino) -2- [3-methoxy-4- (2-morpholin-4-ylethoxy) phenyl] acetamide (Example 19.b) (R, S) -N-benzyl-2- [4- (N-hydroxycarbamimidoyl) -phenylamino] -2- [3-methoxy-4- (2-morpholin-4-ylethoxy) phenyl] - - - acetamide with a 28% yield. Colorless solid foam. ISP-MS: 534.4 ([M + H]). 13.c) (R, S) -N-benzyl-2- (4-cyano-phenylamino) -2- [3-methoxy-4- (pyridin-4- (3-phenoxybenzyloxy) phenyl] acetamide (Example 19. d) dio (R, S) -N-benzyl-2- [4- (N-hydroxycarbamimidoyl) phenylamino] -2- [3-methoxy-4- (4-phenoxy-benzyloxy) phenyl] acetamide with a yield of 40%. Solid grayish slightly foam ISP-MS: 603.2 [M + H]). 13. d) (R, S) -2- (4-benzyloxy-3-methoxyphenyl) -2- (4-cyanophenylamino) -N- (4-nitrobenzyl) acetamide (Example 24.b) dio (R, S) -2- (4-benzyloxy-3-methoxyphenyl) -2- [4- (N-hydroxycarbamimidoyl) phenylamino] -N- (4-nitrobenzyl) -acetamide in 98% yield. Yellow oil ISP-MS: 545.2 ([M + Na]), 540.3 ([M + NH4]), 523.3 ([M + H]). 13.e) (R, S) -2- (4-benzyloxy-3-methoxyphenyl) -2- (4-cyano-phenylamino) -N- [2- (3H-imidazol-4-yl) ethyl] acetamide (Example 24) e) gave (R, S) -2- (4-benzyloxy-3-methoxyphenyl) -2- [4- (N-hydroxycarbamimidoyl) -phenylamino] -N- [2- (3H-imidazol-4-yl) ethyl] -acetamide with a yield of 85%. A grayish-green solid foam. ISP-MS: 515.3 ([M + H]).
13. f) (R, S) -2- (4-benzyloxy) -3-methoxyphenyl) -2- (4-cyano-phenylamino) -N- [2- (lH-indol-3-yl) ethyl] acetamide (Example 24. f) gave (R, S) -2- (4-benzyloxy-3-methoxyphenyl) -2- [4- (N-hydroxycarbamimidoyl) phenylamino] -N- [lH-indol-3-yl) -ethyl] acetamide with a yield of 85%. A grayish-green solid foam. ISP-MS: 545.2 ([M + Na]), 564.4 ([M + NH4]), 564.4 ([M + H]). 13. g) (R, S) -N-benzyl-2- (4-cyano-phenylamino) -2- (3, 4, 5-trimethoxyphenyl) acetamide (Example 17.a) gave (R, S) -N-benzyl -2- [4- (N-hydroxycarbamimidoyl) phenylamino] -2- (3, 4, 5-trimethoxyphenyl) acetamide as a colorless solid. ISP-MS: 465.6 ([M + H] +, 100) 13.h) (R, S) -N-benzyl-2- (3,5-dimethoxyphenyl) -2- (4-cyano-phenylamino) -acetamide (Example 17) .b) gave (R, S) -N-benzyl-2- (3,5-dimethoxyphenyl) -2- [4- (N-hydroxycarbamimidoyl) phenylaminolacetamide as a colorless solid. ISP-MS: 435.5 ([M + H] *, 100). 13. i) (R, S) -N-benzyl-2- (4-benzyloxy-3-methoxyphenyl) -2- (4-cyano-phenylamino) -acetamide (Example 17. c) dio (R, S) -N-benzyl -2- [4-benzyloxy-3-methoxyphenyl) -2- [4- (N-hydroxy-carbamimidoyl) phenylamino] acetamide as a colorless solid. ISP-MS: 511.6 ([M + H] ", 100) 13. j) (R, S) -N-benzyl-2- (4-benzyloxy-3-ethoxy-phenyl) -2- (4-cyano-phenylamino) acetamide (Example 17. d) gave (R, S) -N-benzyl-2 (4-benzyloxy-3-ethoxyphenyl) -2- [4- (N-hydroxycarbamimidoyl) phenylamino] acetamide, in the form of a solid, colorless ISP-MS: 525.5 ([M + H] ", 100).
Example 14
Initially charged in 5 ml of EtOH 995 mg of 2- (2-phenylsulfonylamino-4-benzyl-oxy-5-methoxyphenyl) -N-benzyl-2- (4-cyanophenylamino) acetamide (1.57 mmol) (Example 28), 547 mg of hydroxylamine hydrochloride (7.87 mmol) and 2.2 ml of triethylamine (15.7 mmol). The reaction mixture was heated under reflux for 5 hours. The solvent was then distilled off under reduced pressure. The residue was taken up in water and extracted with EtOAc. The organic phase was washed with saturated NaCl solution, dried over MgSO 4, filtered and concentrated under reduced pressure. This gave 885 mg (85%) of 2- (2-phenylisulfonylamino-4-benzyloxy-5-methoxyphenyl) -N-benzyl-2- [4- (N-hydroxycarbamimidoyl) phenylamino] acetamide as an oily yellow solid. ISP-MS: 666 (M + H).
Example 15
With the method of Example 14 N-benzyl-2- (4-benzyloxy-2-methanesulfonylamino-5-methoxyphenyl) -2- (4-cyano-phenylamino) acetamide (Example 29) gave N-benzyl-2- (4- benzyloxy-2-methanesulfonylamino-5-methoxyphenyl) -2- [4- (N-hydroxycarbamimidoyl) phenylamino] acetamide, in the form of a yellow oil with a yield of 95%. ISP-MS: 604 (M + H).
Example 16 10 g of 4-benzyloxy-5-methoxy-2-nitrobenzaldehyde (34.8 mmol) and 4.11 g of 4-aminobenzonitrile (34.8 mmol) were dissolved in 140 ml of methanol and stirred at room temperature for one hour. The mixture was then combined with 4.25 ml of benzyl isonitrile (34.8 mol). Subsequently, 12.9 ml of boron trifluoride etherate was added to this mixture, dropwise and with cooling by an ice bath, over a period of half an hour. After 30 minutes the ice bath was removed. The reaction mixture was stirred at room temperature for another day. The solvent was then distilled off under reduced pressure. The residue was taken up in EtOAc and washed with water. The organic phase was dried over MgSO, filtered and concentrated under reduced pressure. The crude product was purified by silica gel chromatography using acetone / toluene (3/97). This gave 8.9 g (48%) of N-benzyl-2- (4-benzyloxy-5-methoxy-2-nitrophenyl) -2- (4-cyano-phenylamino) -acetamide as an oily orange solid. ISP-MS: 523 (M + H).
Example 17
With the method of example 16: 17.a) 4-aminobenzonitrile, 3,4-trimethoxy-benzaldehyde and benzyl isonitrile gave (R, S) -N-benzyl-2- (4-cyanogonylamino-2- (3, 4 , 5-trimethoxyphenyl) acetamide in the form of colorless crystals .IH NMR (DMSO-D6): 8.80 (t; NH; lH), 5.02 (d; CH; ÍH), 4.28 (d; CH2; 2H), 3.75 (s); CH3; 6H), 2.61 (s; CH3; 3H), 17.b) 4-aminobenzonitrile, 3,5-dimethoxybenzaldehyde and benzyl isonitrile gave (R, S) -N-benzyl-2- (3,5-dimethoxy). phenyl-2- (4-cyano-phenylamino) acetamide in the form of colorless crystals. H NMR (DMSO-D6): 8.82 (t; NH; lH), 5.15 (d; CH; ÍH), 4.28 (d; CH2; 2H), 3.72 (s; CH3; 6H). 17. c) 4-aminobenzonitrile; 4-benzyloxy-3-methoxybenzaldehyde and oencyl isonitrile gave (R, S) -N-benzyl-2- (4-benzyloxy-3-methoxyphenyl) -2- (4-cyano-phenylamino) -acetamide in the form of colorless crystals. H NMR (DMSO-D6): 8.80 (t; NH; lH), 5.07 (d; CH; 2H * >, 4.99 (d; CH; 2H), 4.28 (s; CH2; 2H), 3.73 (s; CH 3; 3H) 17. d) 4-aminobenzonitrile, 4-benzyloxy-3-ethoxy-benzaldehyde and benzylisonitrile dio (R, S) -N-benzyl-2- (4-benzyloxy-3-ethoxyphenyl) -2- ( 4-cyano-phenylamino) -acetamide in the form of colorless crystals. HH NMR (DMSO-Dβ): 8.75 (t; NH; lH), 5.10 (s; CH2; 2H), 4.95 (d; CH; 1H), 4.28 (d;
CH2; 2H), 4.05 (q; CH2; 2H), 1.32 (t; CH3; 3H).
Example 18
Under an argon atmosphere a solution of 290 mg
(0.75 mmol) of (R, S) -N-benzyl-2- (4-cyano-phenylamino) -2- (4-hydroxy-3-methoxyphenyl) acetamide (Example 20), 110 ml (0.9 mmol) of 3- alcohol methoxybenzyl and 236 mg (0.9 mmol) of triphenylphosphine in 15 ml of THF were combined with 140 ml
(0.9 mmol) of diethyl azodicarboxylate, and the mixture was stirred at room temperature overnight. The solution was concentrated to react under reduced pressure.
The residue was purified by silica gel chromatography (CH2C12 / EtOAc 9: 1). This gave 326 mg (86%) of
(R, 5) -N-benzyl-2- (4-cyano-phenylamino) -2- [3-methoxy-4- (3-methoxy-benzyloxy) -phenyl] -acetamide as a colorless solid. ISP-MS: 530.2 ([M + Na]), 525.2 ([M + NH4]), 508.4
([M + H]), 390.2.
Example 19
With the method of Example 18, (R, S) -N-benzyl-2- (4-cyano-phenylamino) -2- (4-hydroxy-3-methoxyphenyl) acetamide 19.a) and 4-hydroxymethylpyridine dioxide (R, S ) -N-benzyl-2- (4-cyanophenylamino-2- [3-methoxy-4- (pyridin-4-ylmethoxy) -phenyl] -acetamide with a yield of 72% ISP-MS: 479.3
[M + H] 19. b) and N- (2-hydroxyethyl) morpholine gave (R, S) -N-benzyl-2- (4-cyanophenylamino-2- [3-methoxy-4- (2-morpholinyl-ethoxy) phenyl] acetamide with a yield of 66% Colorless resin ISP-MS: 501.3 [M + H] 19. c) and N- (2-hydroxyethyl) thiomorpholine (LA
Burrows, E.E. Reid, Journal of American Chemical Society (1934) 5_6, 1720) gave (R, S) -N-benzyl-2- (4-cyanophenylamino) -2- [3-methoxy-4- (2-thiomorpholin-4-ylethoxy ) -phenyl] acetamide with a yield of 84%. Colorless solid foam. ISP-MS: 517.3 [M + H]. 19. d) and 3-phenoxybenzylalcohol dio (R, S) -N-benzyl-2-; 4-cyanophenylamino) -2- [3-methoxy-4- (3-phenoxybenzyloxy) -phenyl] acetamide with a yield of 44%. %. Colorless solid foam. ISN-MS: 628.3 ([M + AcOH-H]), 568.3
[M-H] 19. e) and 5-hydroxymethylindol (M. Somei, Y. Saida, N. Koura, Chem. Pharm. Bull. (1986) 34, 4116)
(R, S) -N-benzyl-2- (4-cyano-phenylamino) -2- [4- (lH-indol-5-yl-ethoxy) -3-methoxyphenyl] acetamide with a yield of
67%. Light yellow solid foam. ISP-MS: 539.3
([M + Na]), 534.3 ([M + NH4]), 517.2 (M + H]), 399.3. 19. f) and 7-hydroxymethylquinoline (C. Kaslsw, W.R.
Clark, Journal of Organic Chemistry (1953) 1_8, 55)
(R, S) -N-benzyl-2- (4-cyano-phenylamino) -2- [3-methoxy-4- (quinolin-7-ylmethoxy) phenyl] acetamide in 100% yield. Colorless solid. ISP-MS: 529.2 [M + H]. 19. g) and 2-phenylethyl alcohol dio (R, S) -N-benzyl- 2- (4-cyanophenylamino) -2- [3-methoxy-4-phenethyloxyphenyl) -acetamide in 90% yield. Light green resin.
ISP-MS: 492.2 [M + H]. 19.h) and 4-hydroxymethyldiphenyl gave (R, S) -N-benzyl-2- [4- (diphenyl-4-ylmethoxy) -3-methoxyphenyl] -2- (4-cyanophenyl-amino) acetamide with a yield of 25%. Colorless solid. ISN-MS: 612.3 ([M + AcOH-H]), 552.2 [M-H]. 19. i) and 2,6-dichlorobenzyl alcohol dioxide (R, S) -N-benzyl-2- (4-cyano-phenylamino) -2- [4- (2,6-dichlorobenzylc.:i) -3-methoxyphenyl] acetamide with a 70% yield.
Colorless crystals "SN-MS: 604.1 ([M + AcOH-H]), 544.1
[M-H] 19. j) and 3,5-dichlorobenzyl alcohol gave (R, S) -N-benzyl-2- (4-cyano-phenylamino) -2- [4- (3,5-dichlorobenzyloxy) -3-methoxyphenyl] acetamide with a 74% yield.
Colorless crystals ISN-MS: 604.1 ([M + AcOH-H]), 544.1
[M-H] 19. k) and 3-bromobenzyl alcohol gave (R, S) -N-benzyl-2- (4- (3-bromobenzyloxy) -3-methoxyphenyl] -2- (4-cyano-phenylamino) acetamide with a yield of 51%
Colorless crystals ISN-MS: 614.2 ([M + AcOH-H]), 556.0
[M-H] 19.1) and 2-hydroxymethylpyridine gave (R, S) -N-benzyl-2- (4-cyano-phenylamino) -2- [3-methoxy-4- (pyridin-2-yl-methoxy) phenyl] acetamide with a yield of 89% Colorless resin ISN-MS: 479.3 [M + H]. 19.) and 6-hydroxymethylisoquinoline (PE 385 662) gave (R, S) -N-benzyl-2- (4-cyano-phenylamino) -2- [4- (i. Oquinolin-6-ylmethoxy) -3-methoxyphenyl] acetamide with a yield of 100 *. Colorless solid. ISN-MS: 529.3 [M + H]. 19. n) and 4-nitrobenzyl alcohol gave (R, S) -N-benzyl-2- (-cyanophenylamino) -2- [3-methoxy-4- (4-nitro-benzyloxy) phenyl] acetamide with a yield of 71%. Light yellow solid foam. ISN-MS: 581.2 ([M + AcOH-H]), 521.2 [M + H].
Example 20
460 mg (0.4 mmol) of tetrakis (triphenylphosphine) palladium were added to a solution of 8.5 g (20 mmol) of (R, S) -2- (4-allyloxy-3-methoxyphenyl) -N-benzyl-2- (4-cyano-phenylamino) -acetamide (Example 21) in 250 ml of THF. The solution was stirred at room temperature for 10 minutes and then mixed with 1.13 g (30 mmol) of NaBH 4. The mixture was stirred at room temperature for 2 hours and then concentrated under reduced pressure. The residue was taken up in CH2Cl2 / EtOAc 9: 1 and stirred in the presence of activated carbon for 30 minutes. The suspension was filtered through Dicalite. The filtrate was concentrated under reduced pressure and the residue was recrystallized from EtOAc / hexane. This gave 6.81 g (88%) of (R, S) -N-benzyl-2- (4-cyanophenylamino) -2- (4-hydroxy-3-methoxy-phenyl) acetamide as colorless crystals. ISN-MS:
386. 1 ([M-H]), 268.3.
Example 21
A solution of 17.8 g (35 mmol) of (R, S) -2- (4-allyloxy-3-methoxyphenyl) -N-benzyl-2- (4-cyano-phenylamino) -acetamidate (Example 22) in 35 ml of DMSO it was stirred at room temperature overnight. The solvent was evaporated off under high vacuum. The residue was purified by silica gel chromatography (CH2C12 / EtOAc 19: 1). This gave 10.6 g (71%) of (R, -) -2- (4-allyloxy-3-methoxyphenyl) -N-benzyl-2- (4-cyanophenyl-amino) -acetamide as a colorless solid. ISN-MS: 486.1 ([M + AcOH-H]), 426.1 [M-H].
Example 22
Under an argon atmosphere, a solution of 17.72 g (150 mmol) of 4-aminobenzonitrile and 28.8 g of 4-allyloxy-3-methoxybenzaldehyde was stirred at room temperature for 1 hour (A.A. Yesterday, PA Craw, Can. J. Chem. (1991) _69, 1909). 18.3 ml (150 mmol) of benzyl isonitrile was added. Subsequently, 56 ml (450 mmol) of boron trifluoride ethyl etherate was slowly added dropwise at 0 ° C. After a short period of time crystals were formed, which were separated by filtration under an argon atmosphere and dried under high vacuum. This gave 74.1 g (87%) of (R, S) -2- (4-allyloxy-3-methoxyphenyl) -N-benzyl-2- (4-cyanophenylamino) acetimidate as a light yellow solid. ISP-MS: 442.3 [M + H].
Example 23
Under an argon atmosphere, 144 mg (0.75 mmol) of N- (3-dimethylaminopropyl) -N'-ethylcarbodiimide hydrochloride was added to a solution of 194 mg (0.5 mmol) of acid (R, S) - (4-benzyloxy) -3-methoxyphenyl) - (4-cyano-phenylamino) acetic acid (Example 25), 75 ml (0.6 mmol) of phenethylamine, 115 mg (0.75 mmol) of 1-hydroxybenzotriazole and 128 ml (0.75 mmol) of N, N-diisopropylethylamine in 2.5 ml of THF. The reaction mixture was stirred at room temperature for 5 hours and then concentrated under reduced pressure. The residue was collected in EtOAc and washed with saturated KHCO3 solution with citric acid solution at 2% concentration, with H20 and then saturated NaCl solution. The organic phase was dried over MgSO4, filtered and concentrated under reduced pressure.
The crude product was purified by silica gel chromatography (cyclohexane / EtOAc 2: 1). This gave 210 mg
(86%) of (R, S) -2- (4-benzyloxy-3-methoxyphenyl) -2- (4-cyano-phenylamino) -N-phenethylacetamide as a colorless solid foam. ISP-MS: 492.3 ([M + Na]), 509.4 ([M-NH]), 523.3 ([M + H]).
Example 24
With the method of Example 23, (R, S) - (4-benzyloxy-3-methoxyphenyl) - (4-cyano-phenylamino) -acetic acid 24 a) and veratrylamine gave (R, S) -2- (4-benzyloxy-3) methoxyphenyl) -2- (4-cyano-phenylamino) -N- (3,4-dimethoxy-benzyl) acetamide; on a yield of 80%. Light yellow solid foam. ISP-MS: 560.4 ([M + Na]), 555.3 ([M + NH4]), 538.4 [M + H]). 24 b) and 4-nitrobenzylamine hydrochloride dio- (R, S) -2- (4-benzyloxy-3-methoxyphenyl) -2- (4-cyano-phenylamino) -N- (4-nitrobenzyl) acetamide with a yield of 43%. %.
Colorless solid. ISP-MS: 545.2 ([M + Na]), 540.3 ([M + NH4]),
523. 2 ([M + H]). 24 c) and aniline gave (R, S) -2- (4-benzyloxy-3-ethoxyphenyl) -2- (4-cyano-phenylamino) -N-phenylacetamide with a yield of 52%. Colorless solid. ISP-MS: 486.2
([M + Na]), 464.2 ([M + H]). 24 d) and 4-aminobenzonitrile gave (R, 3) -2- (4-benzyloxy-3-methoxyphenyl) -N- (4-cyanophenyl) -2- (4-cyano-phenylamino) acetamide with a yield of 10% . Colorless solid. ISN-MS: 547.2 ([M + AcOH-H]), 487.2 ([M-H]). 24 e) and histamine dihydrochloride gave (R, S) -2- (4-benzyloxy-3-methoxyphenyl) -2- (4-cyano-phenylamino) -N- [2- (3H-imidazol-4-yl; ethyl] Acetamide with a yield of 74%.
Colorless solid foam. ISP -...: 482.4 ([M + H]). 24 f) and tryptamine gave (R, S) -2- (4-benzyloxy-3-methoxyphenyl) -2- (4-cyano-phenylamino) -N- [2- (lH-indol-3-yl) -ethyl] -acetamide with a yield of 92%. Orange solid foam. ISP-MS: 553.3 ([M + Na]), 548.3 ([M + NH4]), 531.3
([M + H]).
Example 25
A solution of 1.17 g (2.9 mol) of (R, S) - (4-benzyloxy-3-methoxyphenyl) - (4-cyano-phenylamino) acetate in 6 ml of THF was cooled to 0 ° C and mixed with 14.5 ml (14.5 ml). mmol) of LiOH IN solution. The mixture was stirred at 0 ° C for 30 minutes and at room temperature for 2 hours. The THF was distilled off under reduced pressure. The remaining solution was adjusted to pH 3 using IN HCl. A colorless precipitate formed which was filtered off and washed with water. The solid was recrystallized from EtOH / H20. This gave 788 mg (70%) of acid
(R, S) - (4-benzyloxy-3-methoxyphenyl) - (4-cyano-phenylamino) -acetic acid in the form of a colorless solid. ISN-MS: 387.1
([M-H]).
Example 26
Under an argon atmosphere, a solution of 970 mg A mmol) of 4-benzyloxy-3-methoxybenzaldehyde and 473 mg (4 mmol) of 4-aminobenzsnitrile in 16 ml of MeOH were stirred at room temperature for 1 hour. A light yellow precipitate formed. The suspension was mixed with 488 ml (4 mmol) of benzyl isonitrile and cooled to 0 ° C. Then 1.52 ml (12 mmol) of boron trifluoride ethyl etherate was added slowly to gels. After 2 hours the mixture was allowed to warm to room temperature and concentrated under reduced pressure. The residue was taken up in MeOH. The solution was slowly mixed with water until crystallization. The mixture was allowed to stand
4 ° C during the night. The solid was filtered off and dried under high vacuum. The residue was recrystallized from cyclohexane / EtOAc. This gave 1.17 g (73%) of (R, S) - (4-benzyloxy-3-methoxyphenyl) - (4-cyano-phenylamino) -ethyl acetate as a colorless solid. ISP-MS: 425
([M + Na]), 420.2 ([M + NH4]).
Example 27
2.0 g of N-benzyl-2- (4-benzyloxy-5-methoxy-2-nitrophenyl) -2- (4-cyano-phenylamino) -acetamide (3.8 mmol) (Example 16) were dissolved in 50 ml of EtOAc and 50 ml of EtOH, mixed with 1.2 g of 5% Pt / C and hydrogenated for 3 hours. The catalyst was filtered off. The filtrate was concentrated under reduced pressure. This gave 1.42 g (76%) of 2- (2-amino-4-benzyloxy-5-methoxyphenyl) -N-benzyl-2- (4-cyano-phenylamino) -acetamide as an oily yellow solid. ISP-MS: 493 (M + H).
Example 28
1.7 g of 2- (2-amino-4-benzyloxy-5-methoxyphenyl) -N-benzyl-2- (4-cyano-phenylamino) -acetamide (3.4 mmol) (Example 27) were dissolved in 60 ml of CH2C12 and 20 ml of DMF and mixed with 0.7 ml of Hünig base. At 0 ° C, 0.7 ml of phenylsulfonyl chloride (3.8 mmol) was added dropwise. The reaction mixture was stirred at room temperature for 4 hours and then diluted with 100 ml of CH 2 Cl 2 and washed with 5% NaHCO 3 solution. The organic phase was washed with saturated NaCl solution, dried over MgSO 4, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography using acetone / toluene (10/90). This gave 995 mg (46%) of 2- (2-phenylsulfonylamino-4-benzyloxy-5-methoxyphenyl) -N-benzyl-2- (4-cyanophenylamine, -acetamide as an orange-orange solid.) ISN-MS: 631 (MH).
Example 29
With the method of Example 28 2- (2-amino-4-benzyloxy-5-methoxyphenyl) -N-benzyl-2- (4-cyano-phenylamino) -acetamide (Example 27) and methanesulfonyl chloride gave N-benzyl-2- (4-benzyloxy-2-methanesulfonylamino-5-methoxy-phenyl) -2- (4-cyano-phenylamino) -acetamide in the form of an orange solid with a yield of 36%. ISN-MS: 569 (M-H).
- Example 30
Under an argon atmosphere at 0 ° C, 0.2 mmole of (R, S) -N-benzyl-2- (4-benzyloxy-3-methoxyphenyl) -2- (4-carbamimidoylphenylamino) acetamide trifluoroacetate (Example 3) (120 mg) in 1.3 ml of tetrahydrofuran was mixed with 0.335 mmole of O '-methyl O- (4-nitrophenyl) carbonate (66 mg). Then, the reaction mixture was allowed to warm to room temperature overnight, the solvent was removed under reduced pressure and the residue was extracted with ethyl acetate and water. The combined organic phases were dried with sodium sulfate. The mixture was filtered and the solvent was removed, and the residue was then suspended in diethyl ether and filtered off. 88 mg (82%) of [methyl- (4- {[[benzylcarbamoyl- (4-benzyloxy-3-methoxyphenyl) methyl] amino} phenyl) methylenemalcarbamate was obtained as a colorless solid. ISP-MS: 553.3 ([M + H] ", 100).
Example 31
By the method of Example 30, the following compounds were prepared: 31 a) Hydrochloride of (R, S) -N-benzyl-2- (4-carbamimidoylphenylamino) -1- (3,4-dimethoxyphenyl) acetamide
(Example 2) gives [methyl- (4- {[[benzylcarbamoyl- (3,4-dimethoxyphenyl) methyl] amino} phenyl) methylene] carbamate in the form of a colorless solid. ISP-MS: 477.5 ([M + H] ", 100). 31 b) (R, S) -N-benzyl-2- (4-carbamimidoylphenylamino) -2- (3,5-dimethoxyphenyl) acetamide hydrochloride.
(Example 5b) gives the [amino- (4- {[methyl benzylcarbamoyl- (3,5-dimethoxyphenyl) methyl] -amino} phenyl) methylene] carbamate as a colorless solid. ISP-MS: 477.5 ([M + H] ", 100) 31 c) Hydrochloride of (R, S) -N-benzyl-2- (4-carbamimidoylphenylamino) -2- (3, 4, 5-trimethoxyphenyl) - acetamide (example 5a) gives [amino- (4. {[[benzylcarbamoyl- (3,4,5-trimethoxyphenyl) methyl] amino] phenyl) methylene] -carbamic acid methyl ester as a colorless solid. -MS: 501.6 ([M + H] ", 100) A compound of formula I, a hydrate, a solvate or a salt thereof, can be used as an active ingredient for the preparation of pharmaceutical preparations, similar to those following.
Example 32
A degassed solution of 369 mg of the material prepared according to example 36.3 in 5 ml of EtOH,
ml of THF, 2 ml of H20 and 1 ml of HOAc, mixed with a Raney nickel spatula tip and hydrogenated for 5 hours. The catalyst was removed by filtration.
The filtrate was concentrated. The residue was purified by chromatography on silica gel (EtOAc / acetone / H2? / HOAc
6: 2: 1: 1). The two epimers were obtained: 1. (S) -2- [(R) -2- (4-benzyloxy-3-methoxyphenyl) -2- (4-carbamimidoylphenylamino) acetylamino] -propionic acid acetate (1: 1) and 2. (S) -2- [(S) -2- (4-benzyloxy-3-methoxyphenyl) -2- (4-carbamimidoylphenylamino) acetylamino] -propionic acid acetate (1: 1), both in the form of freeze-dried, colorless, ISP-MS: 477.3 [M + H].
Example 33
By the method of example 32,
33. a The mixture of the epimeros of example 37.a.1 gave: 1. Acetate of (S) -2- [(R) -2- (4-benzyloxy-3-methoxyphenyl) -2- (4-carbamimidoylphenylamino) acetylamino] -3-phenylpropionic acid (1: 1), and the mixture of the epimeros of example 37.a gave - - 2. (S) -2- [(S) -2- (4-benzyloxy-3) acid acetate -methoxyphenyl) -2- (4-carbamimidoylphenylamino) acetylamino] -3-phenylpropionic acid (1: 1), ISP-MS: 553.3 [M + H],
33. b the product of example 37.b gave, after the chromatographic separation, the two epimers: 1. (S) -2- [(R) -2- (4-benzyloxy-3-ethoxyphenyl) -2- acid acetate. (4-carbamimidoylphenylamino) acetylamino] -3- (4-hydroxyphenyl) propionic acid (1: 2), and 2. Acid acetate (S) -2- [(S) -2- (4-benzyloxy-3-methoxyphenyl) -2- (4-carbamimidoylphenylamino) acetylamino] -3- (4-hydroxyphenyl) propionic acid (1: 1), ISP-MS: 569.3 [M + H],
33 c The product of the example 37. c gave a mixture of (S) -1- [(R) - and - [(S) - (4-benzyloxy-3-methoxyphenyl) - (4-carbamimi doilphenylamino) acetyl] pyrrolidine-2-acetate. carboxyl, ISP-MS: 503. 3 [M + H],
33 d The product of example 37. d gave (RS) -2- [2- (4-benzyloxy-3-methoxyphenyl) -2- (4-carbamimidoylphenylamino) acetylamino] -2-methylpropionic acid acetate (1: 0.5), ISP-MS: 491.5 [M + H], 513.5 [M + Na], 33. e The product of Example 37. gave, after chromatographic separation, the two epimers: 1. (S) -acetate [[(R) - (4-benzyloxy-3-methoxyphenyl) - (4-carbamimidoylphenylamino) acetyl] methylamino] phenylacetic (1: 2), and 2. (S) - [[(S) - (4-benzyloxy-3-methoxyphenyl) - (4-carbamimidoylphenylamino) acetyl] methyl-a-ino] phenylacetic (1: 1), ISP-MS: 553.3 [M + H], 575.1 [M + Na],
33. f The product of example 37. f gave the mixture of acid (RS) - and (SR) -l- [(RS) - (4-benzyloxy-3-methoxyphenyl) - (4-carbamimidoylphenylamino) acetyl) pyrrolidine-3- carboxyl, ISP-MS: 503.3 [M + H],
33. g The product of example 37. g gave, after the chromatographic separation, the two diastereomeric racemates of (RS) - or (SR) -2- [(RS) - (4-benzyloxy-3-methoxyphenyl) - acetate. (4-carbamimidoylphenylamino) acetyl] -1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid (1: 1), ISP-MS: 563.3 [M + H], 587.2 [M + Na], -
33. h The product of Example 37. h gave (RS) -1- [2- (4-benzyloxy-3-methoxyphenyl) -2- (4-carbamimidoylphenylamino) acetylamino] cyclopentanecarboxylic acid acetate (1: 2), ISP-MS: 517.2 [M + H], 539.3 [M + Na],
33. 1 The product of example 37. i gave (RS) - [2- (4-benzyloxy-3-methoxyphenyl) -2- (4-carbamimidoylphenylamino) acetylamino] diphenylacetic acid acetate (1: 1), ISP-MS: 615.3 [M + H],
33. j The product of example 37. gave, after the chromatographic separation, the two epimers: 1. (S) -2- [(R) -2- (4-benzyloxy-3-methoxyphenyl) -2- acid acetate. (4-carbamimidoylphenylamino) acetylamino] -4-tert-butoxycarbonyl-aminobutyric acid (1: 3), and 2. (S) -2, - [(S) -2- (4-benzyloxy-3-methoxyphenyl) -2-acetate. - (4-carbamimidoylphenylamino) acetylamino] -4-tert-butoxycarbonyl-aminobutyric acid (1: 3), ISP-MS: 606.1
[M + H], 628.2 [M + H], - 33. k The product of Example 37. k gave, after chromatographic separation, the two epimers: 1. (S) -2- [( R) -2- (4-benzyloxy-3-methoxyphenyl) -2- (4-carbamimidoylphenylamino) acetylamino] -3-tert-butoxycarbonylaminopropionic acid (1: 1), and 2. (S) -2- [( S) -2- (4-benzyloxy-3-methoxyphenyl) -2- (4-carbamimidoylphenylamino) acetylamino] -3-tert-butoxycarbonylaminopropionic acid (1: 1), ISP-MS: 592.2 [M + H].
Example 34
By the method of example 32,
34. a The product of example 38.a gave (RS) -2- [2- (4-benzyloxy-3-methoxyphenyl) -2- (4-carbamimidoylphenylamino) acetylamino] benzoic acid acetate (1: 1), ISP- MS: 525.1 [M + H],
34. b The product of example 38.b gave the acid acetate - (RS) -3- [2- (4-benzyloxy-3-methoxyphenyl) -2- (4-carbamimidoylphenylamino) acetylamino] benzoic acid (1: 1), ISP - - - S: 525.1 [M + H],
34. c The product of Example 38. c gave (RS) -4- [2- (4-benzyloxy-3-methoxyphenyl) -2- (4-carbamimidoylphenylamino) acetylamino] benzoic acid acetate (1: 1), ISP- MS: 525.1 [M + H].
Example 35
By the method of Example 32, the product of Example 39 gave a mixture of acid (RS) - and (SR) -3- [(RS) -2- (4-benzyloxy-3-methoxyphenyl) -2- (4- carbamimidoylphenyl-amino) acetylamino] -3-phenylpropionic acid.
Example 36
36. 1 335 mg of methyl L-alaninate hydrochloride, 1.03 ml of diisopropylethylamine and 1.06 g of (benzotriazol-1-yloxy) tris- (dimethylamino) phosphonium hexafluorophosphate were added to a solution of 777 mg of the material prepared in the example 25 in 10 ml of DMF. The reaction solution was stirred at RT for 2 hours and then concentrated to high vacuum. The residue was dissolved in ethyl acetate and then washed with 10% solution of KHC03 with citric acid at room temperature.
%, water and saturated NaCl solution. The organic phase was dried with MgSO4 and concentrated under reduced pressure. The residue was purified by chromatography on silica gel. 823 mg (87%) of a 1: 1 mixture of (S) -2 - [(R) - and [(S) -2 (4-benzyloxy-3-methoxyphenyl) -2- (4-cyano-phenylamino) were obtained acetylamino] methyl propionate, in the form of a colorless solid foam. ISP-MS: 474.3 [M + H],
496. 1 [M + Na], 512.2 [M + K].
36. 2 8.4 ml of a 1N LiOH solution was added to a 0 ° C cooled solution of 792 mg of the talking material. It was prepared according to example 36.1 in 10 ml of THF. The mixture was stirred at 0 ° C for 3.0 minutes and at RT for 2 hours. The THF was distilled off under reduced pressure. The remaining aqueous solution was acidified using IN HCl, and a colorless precipitate formed. This was separated by filtration and dried at high vacuum. 712 mg (91%) of a 1: 1 mixture of (S) -2- [(R) - and - [(S) -2- (4-benzyloxy-3-methoxyphenyl) -2- (4 -cyanophenylamino) acetylamino] propionic acid in the form of a colorless solid. ISN-MS: 458.3 [M-H].
36.3 4.1 ml of triethylamine and then 683 mg of the material prepared according to example 36.2 were added to a suspension of 1.04 g of hydroxylamine hydrochloride in 25 ml of EtOH. The reaction mixture was heated to reflux overnight and then concentrated under reduced pressure. The residue was purified by chromatography on silica gel (EtOAc / acetone / H2? / HOAc 6: 2: 1: 1). 625 mg (86%) of a 1: 1 mixture of (E) - and / or (Z) - (S) -2- [(R) - - [(S) -2- (4-benzyloxy -3-methoxyphenyl) -2- [4- (N-hydroxycarbamimidoyl) phenylamino] acetylamino] propionic in the form of a pale pink lyophilisate. ISP-MS: 493.3 [M + H], 515.3 [M + Na].
Example 37
By the method of example 36, the material prepared in example 25,
37. and methyl L-phenylalaninate hydrochloride gave a 1: 1 mixture of (S) -2 - [(R) - and - [(S) -2- (4-benzyloxy-3-methoxyphenyl) -2- ( Methyl 4-cyano-phenylamino) acetylamino] -3-phenylpropionate, which gave a 1: 1 - (1) -2- [(R) - and - [(S) -2- (4- benzyloxy-3-methoxyphenyl) -2- (4-cyano-phenylamino) -acetylamino] -3-phenylpropionic acid, from which, after the chromatographic separation, the two products were obtained: 1. Acid (E) - and / or (Z) - (S) -2- [(R) -2- (4-benzyloxy-3-methoxyphenyl) -2- [4- (N-hydroxycarbamimidoyl) phenylamino] -acetylamino] -3-phenylpropionic acid, and 2. Acid (E) - and / or (Z) - (S) -2- [(S) -2- (4-benzyloxy-3-methoxyphenyl) -2- [4- (N-hydroxycarbamimidoyl) phenylamino] -acetylamino] -3-phenylpropionic ,
37. by ethyl L-tyrosinate hydrochloride gave a 1: 1 mixture of (S) -2 - [(R) - and - [(S) -2- (4-benzyloxy-3-methoxyphenyl) -2- (4 ethyl-cyanophenylamino) acetylamino] -3- (4-hydroxyphenyl) propionate, which in turn gave a 1: 1 mixture of (S) -2 - [(R) - and - [(S) -2- (4-benzyloxy-3-methoxyphenyl) -2- (4-cyano-phenylamino) -acetylamino] -3- (4-hydroxyphenyl) propionic acid, which in turn gave a 1: 1 mixture of (E) - and / or (Z) acid ) - (S) -? - [(R) - and - [(S) -2- (4-benzyloxy-3-methoxyphenyl) -2- [4- (N-hydroxy-carbamimidoyl) -phenylamino) acetylamino] - 3- (4-hydroxyphenyl) propionic,
37. cy methyl L-prolineate, gave a 1: 1 mixture of (S) -l- [(R) - and - [(S) - (4-benzyloxy-3-methoxyphenyl) - (4-cyano-phenylamino) -acetyl] -pyrrolidine -2-methyl carboxylate, which in turn gave a mixture of (S) -l- [(R) - and [(S) - (4-benzyloxy-3-methoxyphenyl) - (4-cyanophenyl-amino) acid acetyl] pyrrolidine-2-carboxylic acid, which in turn gave a 1: 1 mixture of acid (E) and / or (Z) - (S) -1- [(R) - and - [(S) - i '.-benzyloxy-S-methoxyphenyl) - [4- (N-hydroxycarbamimidoyl) -phenylamino] acetyl] pyrrolidine-2-carboxylic acid,
37. d and methyl 2-aminoisobutyrate hydrochloride, gave methyl (RS) -2- [2- (4-benzyloxy-3-methoxyphenyl) -2- (4-cyano-phenylamino) acetylamino] -2-methylpropionate, which at its it gave the acid (RS) -2- [2- (4-benzyloxy-3-methoxyphenyl) -2- (4-cyano-phenylamino) -acetylamino] -2-methyl-propionic acid, which in turn gave the acid (E) - and / or (Z) - (RS) -2- [2- (4-benzyloxy-3-methoxyphenyl) -2- [4-N-hydroxy-carbamimidoyl) phenylamino] acetylamino] -2-methylpropionic,
37. e and ethyl N-methyl-1-phenylglycinate hydrochloride gave a 1: 1 mixture of (S) - [[(R) - and - [[(S) - (4-benzyloxy-3-methoxyphenyl) - ( Ethyl 4-cyanophenylamino) acetyl] -methylamino] phenyl ethyl acetate, which in turn gave a 1: 1 mixture of (S) - [[(R) - and [[(S) - (4- benzyloxy-3-methoxyphenyl) - (4-cyano-phenylamino) -acetyl] -methylamino] -phenylacetic acid, which in turn gave a mixture of acid (E) -y / o (Z) - (S) - [[(R) - and - [[(S) - (4-benzyloxy-3-methoxyphenyl) - [4- (N-hydroxycarbamimidoyl) phenylamino] acetyl] methylamino] -phenylacetic,
37. f and ethyl beta-D, L-proline hydrochloride, gave a mixture of (RS) - and - (SR) -1- [(RS) - (4-benzyloxy-3-methoxyphenyl) - (4-cyano-phenylamino) acetyl] pyrrolidin-3-carboxylic acid ethyl ester, which in turn gave a mixture of acid (RS) - and (SR) -l- [(RS) - (4-benzyloxy-3-methoxyphenyl) - (4-cyano-phenylamino ) acetyl] pyrrolidine-3-carboxylic acid, which in turn gave a mixture of (E) - and / or (Z) - (RS) - and - (SR) -1- [(RS) - (4-benzyloxy -3-methoxyphenyl) - [4- (N-hydroxycarbamimidoyl) phenylamino] acetyl] pyrrolidine-3-carboxylic acid,
37. g and ethyl 1, 2, 3, 4-tetrahydro-3-isoquinoline-carboxylate hydrochloride gave a mixture of (RS) - and (SR) 2- [(RS) - (4-benzyloxy-3-methoxyphenyl) - [4-cyano-phenylamino) -acetyl] -1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid ethyl ester, which in turn gave a mixture of acid (RS) - and (SR) -2- [(RS) - (4-benzyloxy-3-methoxyphenyl) - [4-cyano-phenylamino) -acetyl] -1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid, which in turn gave a mixture of acid (E) -y / or (Z) - (RS) - and - (SR) -2- [(RS) - (4-benzyloxy-3-methoxyphenyl) - [4- (N-hydroxycarbamimidoyl) phenylamino] -acetyl] -1, 2, 3,4-tetrahydroisoquinoline-3-carboxylic acid,
37. hy and ethyl 1-amino-1-cyclopentanecarboxylate hydrochloride, gave (RS) -1- [2- (4-benzyloxy-3-methoxyphenyl) -2- (4-cyano-phenylamino) -acetyl-amino] -cyclopentanecarboxylate ethyl, which in turn gave the acid (RS) -1- [2- (4-benzyloxy-3-methoxyphenyl) -2- (4-cyano-phenylamino) -acetylamino] -cyclopentanecarboxylic acid, which in turn gave the acid (E ) - and / or (Z) - (RS) -1- [2- (4-benzyloxy-3-methoxyphenyl) -2- [4- (N-hydroxycarbamimidoyl) -phenylamino) acetylamino] cyclopentanecarboxylic,
37. and methyl a, a-diphenylglycinate hydrochloride, gave methyl (RS) - [2- (4-benzyloxy-3-methoxyphenyl) -2- (4-cyano-phenylamino) acetylamino] diphenylacetate, which in turn gave (RS) - [2- (4-benzyloxy-3-methoxyphenyl) -2- (4-cyano-phenylamino) -acetylamino] -diphenyl-acetic acid, which in turn gave the acid (E) - and / or (Z) - (RS) - [2- (4-benzyloxy-3-methoxyphenyl) -2- [4- (N-hydroxy-carbamimidoyl) phenylamino) acetylamino] diphenylacetic acid, 37. j and N -? - Boc-1- hydrochloride a, methyl-diaminobutyrate gave a 1: 1 mixture of (S) -2 - [(R) - and - [(S) -2- (4-benzyloxy-3-methoxyphenyl) -2- (4- cyanophenylamino) acetylamino] -4-tert-butoxycarbonylaminobutyrate methyl, which in turn gave a 1: 1 mixture of (S) -2 - [(R) - and - [(S) -2- (4-benzyloxy -3-methoxyphenyl) -2- (4-cyano-phenylamino) -acetylamino] -4-tert-butoxycarbonylamino-butyric acid, which in turn gave a 1.1 mixture of (S) -2 - [(R) - and [(S) -2- (4-benzyloxy-3-methoxy-phenyl) -2- [4- [(E) - and / or - [(Z) -N-hydroxycarbamimidoi l] phenylamino] acetylamino] -4-tert-butoxycarbonylaminobutyric,
37. k and N-ß-Boc-La hydrochloride, methyl ß-diaminopropionate, gave a 1: 1 mixture of (S) -2 - '[(R) - and - [(S) -2- (4-benzyloxy Methyl-3-methoxyphenyl) -2- (4-cyano-phenylamino) -acetylamino] -3-tert-butoxycarbonylamino-propionate, which in turn gave a 1: 1 mixture of (S) -2 - [(R)) - and - [(S) -2- (4-benzyloxy-3-methoxyphenyl) -2- (4-cyano-phenylamino) -acetylamino] -3-tert-butoxycarbonylamino-propionic acid, which in turn gave a 1: 1 mixture of acid
(S) -2 - [(R) - and - [(S) -2- (4-benzyloxy-3-methoxyphenyl) -2- [4- [(E) - and / or - [(Z) -N -hydroxy-carbamimidoyl] phenylamino] -acetylamino] -3-tert-butoxy-carbonylaminopropionic acid.
Example 38
By the method of example 36, the material prepared in example 25,
38. and the ethyl 2-aminobenzoate, gave ethyl (RS) -2- [2- (4-benzyloxy-3-methoxyphenyl) -2- (4-cyano-phenylamino) acetylamino] benzoate, which in turn gave the acid (RS) -2- [2- (4-benzyloxy-3-methoxyphenyl) -2- (4-cyano-phenylamino) -acetylamino] benzoic acid, which in turn gave the acid (E) - and / or (Z) - ( RS) -2- [2- (4-benzyloxy-3-methoxyphenyl) -2- [4- (N-hydroxycarbamimidoyl) phenylamino] acetylamino] -benzoic acid,
38. by ethyl 3-aminobenzoate, gave ethyl (RS) -3- [2- (4-benzyloxy-3-methoxyphenyl) -2- (4-cyano-phenylamino) acetylamino] benzoate, which in turn gave the acid (RS) -3- [2- (4-benzyloxy-3-methoxyphenyl) -2- (4-cyanophenyl-amino) acetylamino] benzoic acid, which in turn gave the acid (E) and / or (Z) - (RS) -3- [2- (4-benzyloxy-3-methoxyphenyl) -2- [4- (N-hydroxycarbamimidoyl) phenylamino] acetylamino] benzoic, - -38. C and ethyl 4-aminobenzoate, gave the ( RS) -4- [2- (4-benzyloxy-3-methoxyphenyl) -2- (4-cyano-phenylamino) -acetylamino] -benzoic acid ethyl ester, which in turn gave the acid (RS) -4- [2- (4 -benzyloxy-3-methoxyphenyl) -2- (4-cyano-phenylamino) -acetylamino] benzoic acid, which in turn gave the acid (E) and / or (Z) - (RS) -4- [2- (4-benzyloxy -3-methoxyphenyl) -2- [4- (-hydroxycarbamimidoyl) phenylamino] acetylamino] benzoic acid.
Example 39
By the method of example 36, the material prepared in Example 25 and the methyl D, L-3-amino-3-phenylpropionate hydrochloride, gave the diastereomer mixtures of the corresponding nitrile esters, which in turn gave the corresponding acid nitrile, and finally a mixture of (E) - and / or (Z) - (RS) - and - (SR) -3- [(RS) -2- (4-benzyloxy-3-methoxyphenyl) - 2- [4- (N-hydroxycarbamimidoyl) phenylamino] acetylamino] -3-phenyl-propionic acid.
Example 40
40. a A suspension of 107 mg of the epimer mixture obtained according to example 33. in 3 ml of CH 2 Cl 2 was mixed with 0.5 ml of trifluoroacetic acid and stirred at RT for 1 hour. The reaction mixture was concentrated.
The residue was purified by chromatography on silica gel (EtOAc / acetone / H20 / HOAC 6: 2: 2: 4). They were obtained
79 mg (85%) of a mixture of (S) -4-amino-2- [(R) - and - [(S) -2- (4-benzyloxy-3-methoxyphenyl) -2- ( 4-carbamimidoylphenylamino) acetylamino] -butyric acid (1: 1), in the form of a beige lyophilisate.
40. b By the method of example 40.a, the mixture of epimers obtained according to Example 33. k gave a 1: 1 mixture of acetate, (S) -3-amino-2- [(R) - and - [(S) -2- (4-benzyloxy-3-methoxyphenyl) -2- (4-carbamimidoyl-phenylamino) acetylamino] -propionic (1: 1), with a yield of 44% in the form of a color freeze-dried beige
Example 41
41. a By the method of Example 32 and the acid (E) and / or (Z) - (S) - [(R) - or - [(S) -2- (4-benzyloxy-3-methoxyphenyl) 2- [ 4- (N-hydroxycarbamimidoyl) phenylamino] acetylamino] - - phenylacetic the following compounds were obtained: a) Acid (S) - [(R) -2- (4-benzyloxy-3-methoxyphenyl) -2- (4-) carbamimidoylphenylamino) acetylamino] phenylacetic, and b) (S) - [(S) -2- (4-benzyloxy-3-methoxyphenyl-2- (4-carbamimidoylphenylamino) acetylamino] phenylacetic acid.
41. b The amidoxime used in 41.a was prepared by the method of Example 37 from the material obtained according to Example 25 and methyl (S) -phenylglycinate by the corresponding nitrile esters and the corresponding nitrile acids, prepared from them.
Example 42
42. a By the method of example 41, but using methyl (R) -phenylglycinate hydrochloride, instead of methyl (S) -phenylglycinate hydrochloride, the two epimers were obtained: 1. Acid (R) - [( R) -2- (4-benzyloxy-3-methoxyphenyl) -2- (4-carbamimidoylphenylamino) acetylamino] phenylacetic, and 2. Acid (R) - [(S) -2- (4-benzyloxy-3-methoxyphenyl) -2-25 (4-carbamimidoylphenylamino) acetylamino] phenylacetic acid.
42. b By the method of Example 41, but using ethyl p-amino-1-phenylalaninate dihydrochloride, instead of (S) -phenylglycinate hydrochloride, a 1: 1 mixture of (S) -3- (4 -aminophenyl) -2- [(R) - and (S) -2- (4-benzyloxy-3-methoxyphenyl) -2- (4-cyano-phenylamino) -acetylamino] -ethyl propionate, which in turn gave 1 A 1: 1 mixture of (E) - and / or (Z) - (S) -3- (4-aminophenyl) -2- [(R) - and - [(S) -2- (4-benzyloxy) -3-methoxy-phenyl) -2- [4- (N-hydroxycarbamimidoyl) phenylamino] -acetylamino] propionate ethyl, which in turn gave 2. A 1: 1 mixture of (S) -3- acetate (4-aminophenii) -2 [(R) - and - [(S) -2- (4-benzyloxy-3-methoxyphenyl) -2- (4-carbamimidoylphenylamino) acetylamino] propionate ethyl (1: 1), which finally gave, after the chromatographic separation, 3. (S) -3- (4-aminophenyl) -2- [(R) -2- (4-benzyloxy-3-methoxyphenyl) -2- (4 -carbamimidoylphenylamino) acetylamino] propionic acid (1: 3) and 4. (S) -3- (4-aminophene) acetate nil) -2- [(S) -2- (4-benzyloxy-3-methoxyphenyl) -2- (4-carbamimidoylphenylamino) -acetylamino] propionic (1: 3), ISP-MS: 568.3 [M + H], 590.3 [M + Na].
- 7 - Example 43
43. 1 By the method of Example 26, 3,5-dimethoxybenzoic aldehyde, 4-aminobenzonitrile and benzyl isonitrile gave methyl (RS) - (4-cyanophenylamino) - (3,5-dimethoxyphenyl) acetate.
43. 2 By the method of Example 25, the product prepared according to 43.1 gave the acid (RS) - (4-cyanophenylamino) - (3,5-dimethoxyphenyl) acetic acid.
43. 3 By the method of example 41, the acid prepared according to 43.2 and the methyl (S) -phenylglycinate hydrochloride gave, after the chromatographic separation of the mixture of epimers, the two products: a) Acetate of the acid (S) - [(R) -2- (4-carbamimidoylphenylamino) -2- (3, 5-dimethoxyphenyl) acetylamino] phenylacetic (1: 1.6), and b) (S) - [(S) -2- (4- carbamimidoyl-phenylamino) -2- (3,5-dimethoxyphenyl) acetylamino] phenylacetic (1: 1.75), ISP-MS: 463.2 [M + H].
- - Example 44
By the method of Example 26, 3,4-diethoxybenzoic aldehyde, 4-aminobenzonitrile and benzyl isonitrile gave (RS) - (4-cyano-phenylamino) - (3,4-diethoxyphenyl) acetic acid.
Example 45
A degassed solution of 147 mg of the product of example 47. b in 5 ml of EtOH, 5 ml of THF, 2 ml of H20 and 1 ml of HOAc, was mixed with a Raney nickel spatula tip and hydrogenated for 5 hours . The catalyst was removed by filtration. The filtrate was concentrated. The residue was purified by chromatography on silica gel (EtOAc / acetone / H20 / HOAc 6: 2: 1: 1). 80 mg (56%) of (RS) -2- (4-benzyloxy-3-methoxyphenyl) -2- (4-carbamimidoylphenylamino) - (N- [2- (3,4-dihydroxyphenyl) ethyl] acetate was obtained] acetamide (1: 1) in the form of a colorless lyophilisate ISP-MS: 541.2 [M + H].
Example 46
Using the method of example 45 - -
46. a The product of example 48.a gave (RS) -N-benzyl-2- (4-benzyloxy-3-methoxyphenyl) -2- (4-carbamimidoylphenylamino) -N-methylacetamide, ISP-MS: 509.5 [ M + H],
46. b The product of example 48. b gave (RS) -2- (4-benzyloxy-3-methoxyphenyl) -2- (4-carbamimidoylphenylamino) -N- [2- (4-sulfamoylphenyl) ethyl] acetamide, ISP- MS: 588.4 [M + H],
46. c The product of Example 48. c gave the acetate of (RS) -2- (4-benzyloxy-3-methoxyphenyl) -2- (4-carbamimidoyl-phenylamino) -N- (2-pyridin-2-ylethyl) acetamide, (1: 1) ISP-MS: 510.3 [M + H],
46. d The product of Example 48. gave the acetate of (RS) -N- [2- (4-aminophenyl) ethyl] -2- (4-benzyloxy-3-methoxy-phenyl) -2 (4-carbamimi. oilphenylamino) acetamide, (1: 1) ISP-MS: 523.4 [M + H],
46. e 1. The diastereomer of example 48. gave the corresponding acetate of (R) -2- (4-benzyloxy-3-methoxyphenyl) -2- (4-carbamimidoylphenylamino) -N- [(R) -2-hydroxy -1-phenylethyl] acetamide (1: 1), and 2. The diastereomer of example 48. e.2 gave the corresponding acetate of (S) -2- (4-benzyloxy-3-methoxyphenyl -2- (4- carbamimidoylphenylamino) -N- [(R) -2-hydroxy-1-renylethyl] acetamide (1: 1), ISP-MS: 525.2 [M + H],
46. f 1. The diastereomer of example 48.fl gave the corresponding acetate of (R) -2- (4-benzyloxy-3-methoxyphenyl) -2- (4-carbamimidoylphenylamino) -N- [(S) -2-hydrox ? -1-phenylethyl] acetamide (1: 1), and 2. The diastereomer of example 48. f.2 gave the corresponding acetate of (S) -2- (4-benzyloxy-3-methoxyphenyl) -2- ( 4-carbamimidoylphenylamino) -N- [(S) -2-hydroxy-1-phenylethyl] acetamide (1: 1), ISP-MS: 525.4 [M + H],
46. g 1. The diastereomer of example 48. g gave the corresponding acetate of (R) -2- (4-benzyloxy-3-methoxyphenyl) -2- (4-carbamimidoylphenylamino) -N- [(R) -1-phenylethyl ] acetamide (1: 1), and 2. The diastereomer of Example 48. g.2 gave the corresponding acetate of (S) -2- (4-benzyloxy-3-methoxyphenyl) -2- (4-carbamimidoylphenylamino) ) -N- [(R) -1-phenylethyl] acetamide (1: 1), ISP-MS: 509.4 [M + H],
46. h 1. The diastereomer of example 48.hl gave the corresponding acetate of (R) -2- (4-benzyloxy-3-methoxyphenyl) -2- (4-carbamimidoylphenylamino) -N- [(S) -1-phenylethyl ] acetamide (1: 1), and 3. The diastereomer of Example 48. h.2 gave the corresponding acetate of (S) -2- (4-benzyloxy-3-methoxyphenyl) -2- (4-carbamimidoylphenylamino) - N- [(S) -1-phenylethyl] acetamide (1: 1), ISP-MS: 509.4 [M + H].
Example 47
47. a By the method of Example 36.1, 388 mg of product from Example 25 and 184 mg of 3-hydroxytryramine gave 323 mg (62%) of (RS) -2- (4-benzyloxy-3-methoxyphenyl) -2- ( 4-cyano-phenylamino) -N- [2- (3, 4-dihydroxy-phenyl) -ethyl] -acetamide, in the form of a colorless solid foam. ISN-MS: 522.1 [M-H].
17. b By the method of example 36.3, 258 mg of the product obtained according to example 47.a gave
222 mg (81%) of (RS) -2- (4-benzyloxy-3-methoxyphenyl) -2- (4-cyano-phenylamino) -N- [2- (3, 4-dihydroxyphenyl) ethyl] -acetamide in the form of a colorless powder. ISP-MS: 557.2 [M + H].
Example 48
By the method of the procedure described in examples 36.1 and 36.3, the following compounds were prepared: From the product of example 25,
48. a and N-benzylmethylamine, through the intermediate (RS) -N-benzyl-2- (4-benzyloxy-3-methoxyphenyl) -2- (4-cyano-phenylamino) -N-methylacetamide, the (E) - and / or (Z) - (RS) -N-benzyl-2- (4-benzyloxy-3-methoxyphenyl) -2- [4- (N-hydroxycarbamimidoyl) phenylamino] -N-methyl] acetamide,
48. by 4- (2-aminoethyl) benzenesulfonamide, via the intermediate (RS) -2- (4-benzyloxy-3-methoxyphenyl) -2- (4-cyano-phenylamino) -N- [2- (4-sulfamoylphenyl) et_ _] -acetamide, (E) - and / or (Z) - (RS) -2- (4-benzyloxy-3-methoxyphenyl) -2- [4- (N-hydroxycarbamimidoyl) phenylamino] -N- [2 - (4-sulfamoylphenyl) ethyl] acetamide,
48. cy 2- (2-aminoethyl) pyridine, by the intermediate (RS) -2- -benzyloxy-3-methoxyphenyl) -2- (4-cyano-phenylamino) -N- (2-pyridin-2-ylethyl) acetamide, (E) -and / or (Z) - (RS) -2- (4-benzyloxy-3-methoxyphenyl) -2- [4- (N-hydroxycarbamimidoyl) phenylamino] -N- (2-pyridine-2- ileyl) -acetamide,
48. d and 4-nitrophenethylamine, by the intermediate (RS) -2- (4-benzyloxy-3-methoxyphenyl) -2- (4-cyano-phenylamino) -N- [2- (4-nitrophenyl) ethyl] acetamide, the ( E) - and / or (Z) (RS) -2- (4-benzyloxy-3-methoxyphenyl) -2- [4- (N-hydroxycarbamimidoyl) phenylamino] -N- [2- (4-nitrophenyl) -ethyl ] acetamide,
48. e and (R) -phenylglycinol, after chromatographic separation, the two diastereomers (R) -2- (4-benzyloxy-3-methoxyphenyl) -2- (4-cyano-phenylamino) -N- [(R) -2-hydroxy) 1-phenylethyl] acetamide, and (S) -2- (4-benzyloxy-3-methoxyphenyl) -2- (4-cyano-phenylamino) -N- [(R) -2-hydroxy-1-phenylethyl] -acetamide;
1. The first diastereomer gave the (E) - and / or (Z)
(R) -2- (4-benzyloxy-3-methoxyphenyl) -2- [4- (N-hydroxycarbamimidoyl) phenylamino) -N- [(R) -2-hydroxy-l-phenylethyl] acetamide, and 2. The second diastereomer gave the (E) - and / or (Z) (S) -2- (4-benzyloxy-3-methoxyphenyl) -2- [4- (N-hydroxycarbamimidoyl) phenylamino] -N- [(R) - 2-hydroxy-l-phenylethyl] acetamide,
48. f and (S) -phenirglicinol, after chromatographic separation, the two diastereomers (R) -2- (4-benzyloxy-3-methoxyphenyl) -2- (4-cyano-phenylamino) -N- [(S) -2- hydroxy-1-phenylethyl] acetamide, and (S) -2- (4-benzyloxy-3-methoxyphenyl) -2- (4-cyano-phenylamino) -N- [(S) -2-hydroxy-1-phenylethyl] acetamide; 1. The first diastereomer gave (E) - and / or (Z) - (R) -2- (4-benzyloxy-3-methoxyphenyl) -2- [4- (N-hydroxycarbamimidoyl) phenylamino) -N- [ (S) -2-hydroxy-l-phenylethyl] acetamide, and 2. The second diastereomer gave (E) - and / or (Z) - (S) -2- (4-benzyloxy-3-methoxyphenyl) -2 - [4- (N-hydroxycarbamimidoyl) phenylamino] -N- [(S) -2-hydroxy-l-phenylethyl] acetamide, 48. g and (R) -1-phenylethylamine, after chromatographic separation, the two diastereomers 1. (E) - and / or (Z) - (R) -2- (4-benzyloxy-3-methoxyphenyl) -2- [4- (N-hydroxycarbamimidoyl) phenylamino) -N- [(R) -1 phenylethyl] acetamide, and 2. (E) - and / or (Z) - (S) -2- (4-benzyloxy-3-methoxyphenyl) -2- [4- (N-hydroxycarbamimidoyl) phenylamino] -N- [(R) -1-phenylethyl] acetamide, 48. h and (S) -1-phenylethylamine, after chromatographic separation, the two diastereomers (R) -2- (4-benzyloxy-3-methoxyphenyl) -2- (4-cyano-phenylamino) -N- ['(S) -1-phenylethyl] acetamide, and (S) -2- (4-benzyloxy-3-methoxyphenyl) -2- (4-cyano-phenylamino) -N- [(S ) -1-f enylethyl] acetamide; 1. The first diastereomer gave (E) - and / or (Z) - (R) -2- (4-benzyloxy-3-methoxyphenyl) -2- [4- (N-hydroxycarbamimidoyl) phenylamino) -N- [ (S) -1-phenylethyl] acetamide, 2. The second diastereomer gave (E) - and / or (Z) - (S) -2- (4-benzyloxy-3-methoxyphenyl) -2- [4- ( N-hydroxycarbamimidoyl) phenylamino] -N- [(S) -1-phenylethyl] acetamide.
Example 49
By the method of Example 45 49.a the product of Example 50.2 gave the acetate of (RS) -N- [2- [benzylcarbamoyl- (4-carbamimidoylphenylamino) -methyl] -5-benzyloxy-4-methoxyphenyl] benzamide (1) : 1.5) in the form of a colorless solid,
49. b the product of Example 51.a gave methyl (RS) - [2- [benzylcarbamoyl- (4-carbamimidoylphenylamino) -methyl] -5-benzyloxy-4-methoxyphenyl] carbamate acetate (1: 1.3) in the form of a colorless solid,
49. c the product of example 51. b gave (RS) 2- (2-acetylamino-4-benzyloxy-5-methoxyphenyl) -N-benzyl-2- (4-carbamimidoylphenylamino) acetamide (1: 1) acetate in the form of a colorless solid,
49. d the product of example 51. c gave the acetate of (RS) N-benzyl-2- (4-benzyloxy-5-methoxy-2-phenylacetylamino-phenyl) -2- (4-carbamimidoylphenylamino) acetamide (1: 1) in the form of a brown solid debb, 49. e the product of example 52.3 gave the acetate of (RS) -N-benzyl-2- (4-carbamimidoylphenylamino) -2- (4,5-dimethoxy-2- acetylaminophenyl) acetamide (1: 1) as a colorless solid,
49. f the product of Example 53.a gave methyl (RS) - [2- [benzylcarbamoyl- (4-carbamimidoylphenylamino) -methyl] -4,5-dimethoxyphenyl carbamate acetate (1: 1) as a solid Weak brown color,
49. g the product of example 53.b gave the acetate of (-3) -N- [2- [benzylcarbamoyl- (4-carbamimidoylphenylamino) -methyl] -4,5-dimethoxyphenyl] benzamide (1: 1) in the form of a colorless solid, ISP-MS: 588.3 [M + H],
49. h the product of example 54.3 gave (RS) -N- [2-benzylcarbamoyl- (4-carbamimidoylphenylamino) -methyl] -4-methoxyphenyl] benzamide (1: 1) acetate as a colorless lyophilisate, ISP-MS : 508.3 [M + H], 49. i the product of Example 55 gave (RS) -2 (2-benzenesulfonylamino-5-methoxyphenyl] -N-benzyl-2- (4-carbamimidoylphenylamino) acetamide acetate (1: 1 ^ in the form of a colorless lyophilisate, ISP-MS: 544.1 [M + H].
Example 50
50. 1 0.26 ml of diisopropylethylamine and 0.08 ml of benzoyl chloride were added to a solution of 300 mg of the nitrile obtained according to example 27 in 10 ml of THF. The reaction solution was stirred at RT for 3 hours. The THF was then removed by distillation under reduced pressure. The residue was dissolved in CH2C12 and washed with saturated NaCl solution. The organic phase was dried with Na 2 SO 4, filtered and concentrated under reduced pressure. The residue was crystallized with cyclohexane / toluene / acetone. 288 mg (79%) of (RS) -N- [2- [benzylcarbamoyl- (4-cyanophenylamino) methyl] -5-benzyloxy-4-methoxyphenyl were obtained} benzamide, in the form of a weak brown chloro solid.
50. 2 By the method of example 36.3, 280 mg of the material prepared above gave 254 mg (861) of
(RS) -N- (2- {benzylcarbamoyl- [4- (N-hydroxycarbamimidoyl) -phenylamino] methyl} -5-benzyloxy-4-methoxyphenyl) benzamide, in the form of a weak brown solid.
Example 51
Using the method of Example 50.1, the product of Example 27 and,
51. to methyl chloroformate, (RS) - (2- {benzylcarbamoyl- [4- (N-hydroxycarbamimidoyl) phenylamino] -methyl} -5-benzyloxy-4-methoxyphenyl) carbamate was obtained,
51. b the acetyl chloride gave the (E) and / or (Z) - (RS) -2- (2-acetylamino-4-benzyloxy-5-methoxyphenyl) -N-benzyl-2- [4- (N-hydroxycarbamimidoyl ) phenylamino] acetamide,
51. c the phenylacetyl chloride gave the (E) and / or (Z) - (RS) -N-oenzyl-2- (4-benzyloxy-5-methoxy-2-phenylacetylamino-phenyl) -2- [4- (N -hydroxycarbamimidoyl) phenylamino] acetamide.
Example 52
52. 1 By the method of example 16 and starting from the 6-nitroverácidal aldehyde, 4-aminobenzonitrile and benzyl isonitrile, (RS) -N-benzyl-2- (4-cyanophenylamino) -2- [4,5-dimethoxy-2 was obtained -nitrophenyl) acetamide with a yield of 10% in the form of yellow crystals.
52. 2 By the method of Example 27, the nitro compound prepared in 52.1 gave the (RS) -2- (2-amino-4,5-dimethoxyphenyl) -N-benzyl-2- (4-cyano-phenylamino) -acetamide with a yield of 25% Crystals of slightly gray color.
52. 3 By the method of Example 50, the aniline compound prepared above and the phenylacetyl chloride gave the (E) - and / or (Z) - (RS) -N-benzyl-2- (4,5-di. - ethoxy-2-phenylacetylamino-phenyl) -2- [4- (N-hydroxycarbamimidoyl) -phenylamino] acetamide.
Example 53
By the method of Example 50, the aniline compound prepared in 52.2 and:
53. to methyl claroformate, gave (E) - and / or (Z) - (RS) - [2- [benzylcarbamoyl- [4- (N-hydroxycarbamimidoyl) -phenylamino] methyl] -4,5-dimethoxyphenyl] carbamate of methyl,
53. b the benzoyl chloride gave the (E) - and / or (Z) - (RS) -N- [2- [benzylcarbamoyl- [4- (N-hydroxycarbamimidoyl) phenylamino] ethyl] -4,5-dimethoxyphenyl] benzamide .
Example 54
54. 1 By the method of example 16 and starting from the 6-nitroverácidal aldehyde, 4-aminobenzonitrile and benzyl isonitrile, the (RS) -N-benzyl-2- (i-cyanophenylamino) -2- (5-methoxy-2-nitrophenyl) was obtained ) acetamide with a yield of 24%. Crystals of yellow color.
- - 54.2 By the method of example 27, the nitro compound prepared above gave the (RS) -N-benzyl-2- (4-cyano-phenylamino) -2- (2-amino-5-methoxyphenyl) acetamide with a yield of 79%. %. ISP-MS: 387.1 [M + H], 409.2 [M + Na].
54. 3 By the method of Example 50, the nitrile obtained in Example 54.2 and the benzoyl chloride gave the (E) - and / or (Z) - (RS) -N- [2- [benzylcarbamoyl- [4- ( N-hydroxycarbamimidoyl) phenylamino] methyl] -4-methoxyphenyl] -benzamide.
Example 55
By the method of Example 50, the nitrile obtained in Example 54.2 and the phenylsulfonyl chloride gave the (E) - and / or (Z) - (RS) -2- (2-benzenesulfonylamino-5-methoxyphenyl) -N -benzyl-2- [4- (N-hydroxycarbamimidoyl) phenylamino] acetamide.
Example 56 56.1 By the method of example 36.1, the material obtained according to example 27 and the methoxyacetic acid gave the (RS) -N-benzyl-2- [4-benzyloxy-5-methoxy-2- (2- methoxyacetylamino) -phenyl] -2- (4-cyanophenyl-amino) acetamide with a yield of 66%. Solid.
56. 2 By the method of Example 36.3, the nitrile prepared in Example 56.1 was reacted with a yield of 81% obtaining (RS) -N-benzyl-2- [4-benzyloxy-5-methoxy-2- (2- methoxyacetylamino) phenyl] -2- [4- (N-hydroxycarbamimidoyl) phenylamino] acetamide. Solid of weak brown color.
56. 3 By the method of Example 45, the amidoxime obtained in Example 56.2, was reduced to hydrochloride of
(RS) -N-benzyl-2- [4-benzyloxy-5-methoxy-2- (2-methoxyacetyl-amino) phenyl] -2- (4-carbamimidoylphenylamino) acetamide (1: 2).
Example 57
57. 1 By the method of Example 36.1, the product of Example 27 and N-Boc-glycine gave the (RS) - (. {2- [benzylcarbamoyl- (4-cyanophenylamino) methyl] -5-benzyloxy-4- methoxyphenylcarbamoyl.] tere-butyl methylcarbamate with a 65% yield.
57. The product obtained above was reacted by the method of Example 36.3 to give the (RS) - [(2- {benzylcarbamoyl- [4- (hydroxycarbamimidoyl) phenylamino] -methyl] -5-benzyloxy-4 -methoxyphenylcarba oil) methyl] carbamate terebutil with a yield of 65%. Solid of weak brown color.
-7.3 A solution of 170 mg of the amidoxime obtained according to Example 57.2 in 10 ml of EtOH was mixed with a Raney nickel spatula tip and a few drops of acetic acid. The mixture was then hydrogenated for 2 hours and then filtered off the catalyst. The filtrate was concentrated. The residue was purified by chromatography with silica gel (EtOAc / acetone / H20 / HOAc 6: 2: 1: 1). The product fractions were concentrated. The residue was dissolved in CH2C12, mixed with 5 ml of trifluoroacetic acid and stirred at 0 ° C for 3 hours. Then, the mixture was concentrated under reduced pressure. The residue was crystallized with Et20. 107 mg (76%) of (RS) -2- [2- (2-aminoacetylamino) -4-benzyloxy-5-methoxy-phenyl] -N-benzyl-2- (4-carbamimidoyl-phenylamino) trifluoroacetate were obtained acetamide
(1: 2) in the form of a weak brown solid.
Example 58
By the method of example 45:
58. to the product obtained in Example 59.5 gave (RS) -3- [2- [benzylcarbamoyl- (4-carbamimidoylphenylamino) methyl] -4,5-dimethoxyphenoxymethyl] -benzoic acid acetate (1: 1), ISP-MS : 569.3 [M + H],
58. b the product obtained in example 60.a gave (RS) - [2- [benzylcarbamoyl- (4-carbamimidoylphenylamino) methyl] -4,5-dimethoxyphenoxy] acetic acid acetate (1: 1),
-i 8. c the product obtained in example 60.b gave (RS) -4- [2- [benzylcarbamoyl- (4-carbamimidoylphenylamino) methyl] -4,5-dimethoxyphenoxymethyl] -benzoic acid acetate (1: 1), ISP-MS: 569. 3 [M + H],
58 d the product obtained in example 60. c gave (RS) -4- [2- [benzylcarbamoyl- (4-carbamimidoylphenylamino) methyl] -4,5-dimethoxyphenoxymethyl] butyric acid (1: 1),
58. e the product obtained in Example 61 gave the acid (RS) - [2- [benzylcarbamoyl- (4-carbamimidoylphenylamino) -methyl] -4-methoxyphenoxy] acetic acid, ISP-MS: M + H [463.2],
58. f the product obtained in Example 62 gave (RS) - [2- [benzylcarbamoyl- (4-carbamimidoylphenylamino) methyl] -4,6-dimethylphenoxy] acetic acid acetate (1: 0.5), ISP-MS: 461.3 [ M + H], 483.4 [M + Na]
Example 59
59. 1.18 g of 4-aminobenzonitrile and 1.22 ml of benzyl isonitrile were added to a solution of 2.78 mg of 2-benzyloxy-4,5-dimethoxybenzaldehyde in 36 ml of THF and 4 ml of H20. The mixture was stirred at RT for 5 minutes and then mixed with 2.85 g of p-toluenesulfonic acid. The reaction solution was stirred at RT for 24 hours and then concentrated at reduced pressure. The residue was dissolved in CH2C12 and then washed with saturated NaHCO3 solution and saturated NaCl solution. The organic phase was dried with Na 2 SO 4, filtered off and concentrated under reduced pressure. The residue was purified by chromatography on silica gel (toluene / acetone 9: 1) 2.13 g (42%) of (RS) -N-benzyl-2- (2-benzyloxy-4,5-dimethoxyphenyl) -2- were obtained. (4-cyano-phenylamino) acetamide, in the form of a weak yellow solid.
59. 2 A solution of 1.4 g of the material obtained in 59.1 in 140 ml of EtOH was mixed with 420 mg of 10% Pd / C and hydrogenated for 5 hours, during which a colorless precipitate formed. This was redissolved by the addition of 75 ml of dioxane. Then, the catalyst was removed by filtration. The filtrate was concentrated under reduced pressure. The residue was crystallized with EtOH. 907 mg (79%) of (RS) -N-benzyl-2- (4-cyano-phenylamino) -2- (2-hydroxy-4,5-dimethoxyphenyl) -acetamide were obtained as colorless crystals.
59. 3 A solution of 418 mg of the material obtained in 59.2 in 30 ml of acetone was mixed with 415 mg of K2C03 and 252 mg of methyl 3-bromomethylbenzoate. The reaction mixture was refluxed for 3 hours and then filtered. The filtrate was concentrated. The residue was dissolved in CH2C12 and washed with H2O. The organic phase was dried with Na 2 SO 4, filtered and concentrated under reduced pressure. The residue was purified by chromatography on silica gel (EtOAc / hexane 2: 3). 365 mg (65%) of methyl (RS) -3- [2- [benzylcarbamoyl- (4-cyanophenylamino) -methyl] -4,5-dimethoxyphenoxymethyl] benzoate was obtained as a colorless solid.
59. 4 By the method of example 36.2, the material obtained in 59.3 gave the acid (RS) -3- [2- [benzylcarbamoyl- (4-cyano-phenylamino) -methyl] -4,5-dimethoxyphenoxymethyl] -benzoic acid in a quantitative yield. Colorless solid.
59. 5 By the method of example 36.3, the material obtained in accordance with 59.4 gave the acid (E) and / or (Z) - (RS) -3- [2- [benzylcarbamoyl- [4- (N-hydroxycarbamimidoyl) phenylamino] methyl] -4,5-dimethoxyphenoxymethyl] benzoic acid, with a yield of 70%. Colorless solid.
Example 60
By the methods of examples 59.3-59.5, the material obtained according to example 59.2 and
60. to ethyl bromoacetate, gave by means of nitriles (RS) - [2- [benzylcarbamoyl- (4-cyanophenylamino) methyl] -4,5-dimethoxyphenoxy] ethyl acetate and acid (RS) - [2- [benzylcarbamoyl] - (4-cyanophenylamino) methyl] -4,5-dimethoxyphenoxy] acetic acid, (E) - and / or (Z) - (RS) - [2- [benzylcarbamoyl- [4- (N-hydroxycarbamimidoyl) phenylamino] -methyl] -4,5-di-methoxyphenoxy] acetic,
60. b methyl 4-bromoethylbenzoate, gave via nitriles- (RS) -4- [2- [benzylcarbamoyl- (4-cyano-phenylamino) methyl] -4,5-dimethoxyphenoxymethyl] -benzoic acid methyl ester and (RS) -4- [2- [benzylcarbamoyl- (4-cyanophenylamino) methyl] -4,5-dimethoxyphenoxymethyl] benzoic acid (E) and / or (Z) - (RS) -4- [2- [benzylcarbamoyl- [ 4- (N-hydroxycarbamimidoyl) phenylamino] methyl] -4,5-dimethoxy-phenoxymethyl] benzoic acid,
60. c ethyl 4-bromobutyrate, gave by means of nitriles (RS) -4- [2- [benzylcarbamoyl- (4-cyanophenyl-amino) ethyl] -4,5-dimethoxyphenoxy] butyrate of ethyl and acid (RS) -4- [2- [benzyl-carbamoyl- (4-cyanophenyl-amino) methyl] -4,5-dimethoxyphenoxy] butyric acid (E) - and / or (Z) - (RS) -4- [2 - [benzylcarbamoyl- [4- (N-hydroxycarbamimidoyl) -phenylamino] methyl] -4,5-dimethoxyphenoxy] -butyric,
Example 61
By the method of Example 60, the (RS) -N-benzyl-2- (4-cyano-phenylamino) -2- (2-hydroxy-5-methoxyphenyl) -acetamide and the ethyl bromoacetate, gave via nitriles ( RS) - [2- [benzylcarbamoyl- (4-cyanophenylamino) methyl] -4-methoxyphenoxy] ethyl acetate and (RS) - [2- [benzylcarbamoyl- (4-cyanophenylamino) methyl] -4-methoxyphenoxy] acetic acid, (E) - and / or (Z) - (RS) - [2- [benzylcarbamoyl- [4- (N-hydroxycarbamimidoyl) phenylamino] -methyl] -4-methoxyphenoxy] acetic acid. The starting material was prepared as follows: 61.1 A solution of 30 g of 2-hydroxy-5-methoxy-benzaldehyde in 200 ml of acetone was mixed with 51.2 ml of allyl bromide and 81.75 g of K2C03 and heated to reflux for 2 hours. Next, the reaction mixture was filtered. The filtrate was concentrated under reduced pressure. The residue is dissolved. in CH2Cl2 and washed with H20. The organic phases were dried with Na 2 SO, filtered and concentrated under reduced pressure. The residue was distilled at high vacuum. 24.5 g (65%) of 2-allyloxy-5-methoxybenzaldehyde were obtained in the form of a weak green oil.
61. 2 By the method of example 59.1, the aldehyde obtained above, 4-aminobenzonitrile and benzyl isonitrile gave (RS) - [2- (2-allyloxy-5-methoxy-phenyl) -N-benzyl-2- (4 -cyanophenylamino) acetamide, with a yield of 35%. ISP-MS: 428.3 [M + H], 450.1 [M + Na].
61. 3 A solution of 4.6 g of the nitrile obtained above in 140 ml of THF was mixed with 249 mg of tetrakis (triphenylphosphine) palladium (0). The mixture was stirred at RT for 10 minutes, and then 626 mg of NaBH was added little by little. The mixture was stirred at RT for 2 hours and then concentrated under reduced pressure. The residue was dissolved in EtOAc and washed with H20. The organic phase was dried with Na 2 SO, filtered and concentrated under reduced pressure. The residue was dissolved in CH2Cl2 / EtOAc 9: 1 and decolorized with activated charcoal. The product was then crystallized with Et2? / CH2Cl2. 3.22 g (77%) of (RS) -N-benzyl-2- (4-cyano-phenylamino) -2- (2-hydroxy-5-methoxyphenyl) acetamide were obtained in the form of a weak brown crystalline solid. ISN-MS: '386.1 [M-H].
Example 62
By the method of Example 60, the (RS) -N-benzyl-2- (4-cyano-phenylamino) -2- (2-hydroxy-3,5-d-methyl-phenyl) -acetamide, and the bromoacetate of ethyl, the (RS) - [2- [benzylcarbamoyl- (4-cyanophenylamino) methyl] -4,6-dimethylphenoxy] ethyl acetate was obtained, with which in turn (E) - and / or (Z) - (RS) - [2- [Benzylcarbamoyl-4- (N-hydroxycarbamimidoyl) phenylamino] methyl] -4,6-dimethyl-phenoxy] acetic acid. The starting material was prepared by the method of Example 16 from 3,5-dimethyl-2-hydroxybenzaldehyde (G. Casiraghi et al., J. Chem. Soc.
(1980), 1862), 4-aminobenzonitrile and benzyl isonitrile.
Example 63 63.1 A solution of 1.04 g of the nitrile obtained in Example 59.2, 0.35 ml of (S) -methyl methyl ester and 785 mg of triphenylphosphine in 75 ml of THF was mixed with 0.475 ml of diethyl azodicarboxylate and stirred at RT. During 4 hours. The THF was then removed by distillation under reduced pressure. The residue was dissolved in EtOAc and washed with saturated NaCl solution. The organic phase was dried with MgSO, filtered and concentrated under reduced pressure. The residue was purified by chromatography on silica gel (CH2Cl2 / EtOAc 9: 1). There were obtained 1145 g (88%) of a 1: 1 mixture of (R) -2 [2- [(R) - and - [(S) -benzylcarbamoyl- (4-cyanophenylamino) methyl] -4,5-dimethoxy -phenoxy] ethyl propionate in the form of a yellow foam. ISP-MS: 518.2 [M + H], 540.3 [M + Na].
63. 2 By the method of example 36.2, the ester prepared above, after chromatographic separation on silica gel, gave the two diastereomers acid (R) -2 [2- [(R) -benzylcarbamoyl- (4-cyano-phenylamino) -methyl] -4, 5-dimethoxyphenoxy] propionic, and acid) -2- [2- - - [(S) -benzylcarbamoyl- (4-cyano-phenylamino) methyl] -4,5-di-ethoxyphenoxy] propionic, with a yield of 49% , both as a pale yellow resin. ISP-MS:
490. 3 [M + H], 512.3 [M + Na].
63. 3 By the method of Example 36.3, the first of the diastereomers obtained above gave a) the acid (E) - and / or (Z) - (R) -2- [2- [(R) -benzylcarbamoyl) - [4- (N-hydroxy-carbamimidoyl) phenylamino) methyl] -4,5-dimethoxyphenoxy] -propionic acid, and the second of the diastereomers obtained above gave the a) acid (E) - and / or (Z) - (R) -2- [2- [(S) -benzylcarbamoyl- [4- (N-hydroxycarbamimidoyl) phenylamino] methyl] -4,5-dimethoxyphenoxy] propionic acid, both in the form of a colorless powder. ISP-MS: 523.2 [M + H], 545.2 [M + Na], 567.2 [M + 2Na].
63. 4 By the method of Example 33, the respective diastereomeric amidoximes of Example 63.3 gave the amidines: a) (R) -2- [2- [(R) -benzylcarbamoyl- (4-carbamimidoylphenylamino) methyl] -4 acid acetate, 5-dimethoxy-phenoxy] propionic and c) (R) -2- [2- [(S) -benzylcarbamoyl- (4-carbamimidoylphenylamino) methyl] -4,5-dimethoxy-phenoxy] propionic acid acetate (1: 1) , ISP-MS: 507.4 [M + H].
Example 64
64. 1 By the method of Examples 63.1-63.3, the material obtained in Example 59.2 and the (R) -ethyl ethyl ester, gave, by means of the mixture of epimers of the corresponding nitrile ester, the two nitrile diastereomeric acids, the which in turn gave the corresponding epimers a) acid (E) - and / or (Z) - (S) -2- [2- [(R) -benzyl-carbamoyl- [4- (N-hydroxycarbamimidoyl) phenylamino] methyl] -4,4-dimethoxyphenoxy] propionic, and b) (E) - and / or (Z) - (S) -2- [2- [(S) -benzylcarbamoyl- [4- (N-hydroxycarbamimidoyl) phenylamino] ] -methyl] -4,5-dimethoxyphenoxy] propionic, both in the form of colorless lyophilisates.
64. 2 By the method of Example 33, the amidoximes obtained above, gave the corresponding amidines a) (S) -2- [2- [(R) -benzylcarbamoyl- (4-carbamidoyl) phenylamino) methyl] -4 acid, 5-dimethoxyphenoxy] -propionic, and b) (S) -2- [2- [(S) -benzylcarbamoyl- (4-carbamimidoyl) -phenylamino) methyl] -4,5-dimethoxyphenoxy] -propionic acid, both in the form of colorless lyophilisates, ISP-MS: 507.4 [M + H], 529.2 [M + Na].
Example 65
By the method of example 45,
65. to the product of Example 66.4 gave the acid (RS) -3- [4- [benzylcarbamoyl- (4-carbamimidoylphenylamino) methyl] -2-methoxyphenoxy} benzoic, with a 44% yield. Colorless solid, ISP-MS: 525.2 [M + H], 65.b The product of example 67.a gave the acid (RS) -2- [4- [benzylcarbamoyl- (4-carbamimidoylphenylamino) methyl] -2-methoxyphen } benzoic, ISP-MS: 525.2 [M + H], 65. c The product of Example 67.b gave the acid (RS) -4-. { 4 [benzylcarbamoyl- (4-carbamimidoylphenylamino) ethyl] -2-methoxyphenoxy} benzoic Solid of weak brown color. ISP-MS: 525.2 [M + H].
Example 66
66. 1 A solution of 3 g of vanillin, 11 g of ethyl 3-iodobenzoate and 2.9 g of CU20 in 5 ml of dimethylacetamide was heated at 165 ° C for 24 hours. The mixture was allowed to cool to RT and filtered. The filtrate was concentrated to high vacuum. The residue was purified by chromatography on silica gel (EtOAc / hexane 3: 7). 1.93 g (32%) of ethyl 3- (4-formyl-2-methoxyphenoxy) benzoate were obtained in the form of a weak brown oil.
66. 2 By the method of example 59.1, the aldehyde obtained above gave the (RS) -3-. { 4- [benzylcarbamoyl- (4-cyanophenylamino) methyl] -2-methoxyphenoxy} ethyl benzoate, with a yield of 58%. Colorless solid.
66. 3 By the method of example 36.2, the nitrile ester obtained above gave the acid (RS) -3-. { 4- [benzylcarbamoyl- (4-cyanophenylamino) methyl] -2-methoxy-phenoxy} benzoic, with a 51% yield. Colorless solid. ISN-MS: 506.2 [M-H].
66. 4 By the method of example 36.3, the acid nitrile obtained above gave the acid (RS) -3- (4- [benzylcarbamoyl- [4- (N-hydroxycarbamimidoyl) phenylamino] -methyl] -2-methoxyphenoxy) benzoic acid , with a 94% yield. Colorless solid. ISP-MS: 541.2 L? + H], 563.3 [M + Na].
Example 67
Using the method of example 66
67. and using methyl 2-iodobenzoate in place of methyl 3-iodobenzoate, (RS) -2- (4-. {benzylcarbamoyl- [4- (N-hydroxycarbamimidoyl) phenyl-amino] methyl was obtained. .2-methoxyphenoxy) benzoic, passing through the corresponding intermediates 4- (2-carbomethoxy) -phenoxy-3-methoxybenzaldehyde, (RS) -2- [4- [benzylcarbamoyl- (4-cyano-phenylamino) methyl] -2- methoxyphenoxy] methyl benzoate, and (RS) -2- acid. { 4- [benzylcarbamoyl- (4-cyanophenylamino) methyl] -2-methoxyphenoxy} -benzoic acid, - - 67.b and using methyl 4-iodobenzoate in place of ethyl 3-iodobenzoate, (RS) -4- acid was obtained. { 4- . { benzylcarbamoyl- [4- (N-hydroxycarbamimidoyl) phenyl-amino] methyl} -2-methoxyphenoxy J benzoic, passing through the corresponding intermediate products 4- (4-formyl-2-methoxyphenoxy) methyl benzoate, (RS) -4-. { 4- [benzylcarbamoyl- (4-cyanophenylamino) methyl] -2-methoxy-phenoxy methylbenzoate, and (RS) -4- acid. { 4- [benzylcarbamoyl- (4-cyanophenylamino) methyl] -2-methoxyphenoxy} benzoic
Example 68
By the method of Examples 66.2-66.4, methyl 5-formyl-2,3-dimethoxybenzoate (FY Wu, DL Brink, J. Agrie. Food Chem. (1977), 25, 692) gave, passing through the product intermediate (RS) -5- [benzylcarbamoyl- (4-cyanophenyl-amino) methyl] -2,4-dimethoxybenzoate methyl, a) (RS) -5-. { benzylcarbamoyl- [4- (N-hydroxycarbamimidoyl) -phenylamino] methyl} Methyl -2-, 3-dimethoxybenzoate, and b) (RS) -5- [benzylcarbamoyl- (4-carbamimidoyl-phenylamino) methyl] -2, 3-dimethoxybenzoate methyl, and c) acid (RS) -5- [benzylcarbamoyl- (4-carbamimidoyl-phenylamino) methyl] -2,3-dimethoxybenzoic acid. Solid of weak brown color.
Example 69
69. 1 By the method of example 59.1, 6-bromoveratric aldehyde, 4-aminobenzonitrile and benzyl isonitrile gave (RS) -N-benzyl-2- (2-bromo-4,5-dimethoxyphenyl) -2- (4-cyano-phenylamino) acetamide, with a yield of 476.
Colorless solid.
69. 2 A solution of 2.4 g of the nitrile obtained in example 69.1 in 10 ml of dimethylacetamide was mixed with 0.41 ml of cronic acid, 1.51 ml of triethylamine, 22 mg of palladium acetate and 122 mg of tri-o-tolylphosphine and heated at 120 ° C for 2 hours. The reaction mixture was diluted with water, the pH adjusted to 1 using 1N HCl, then extracted with EtOAc. The organic phase was concentrated under reduced pressure. The residue was dissolved in MeOH and filtered. The filtrate was concentrated under reduced pressure. The residue was stirred in Et20. The solid was separated by filtration and dried at high vacuum. 1.71 g (73%) of the (E) - (RS) -3- [2- [benzylcarbamoyl- (4-cyano-phenylamino) ethyl] -4,5-dimethoxy-phenyl] -acrylic acid was obtained in the form of a beige.
69. 3 A solution of 236 mg of the nitrile obtained above in 2 ml of EtOH and 3 ml of THF was mixed with 5 ml of IN HCl and 106 mg of 10% Pd / C and hydrogenated for 2 hours. The reaction mixture was filtered. The filtrate was extracted with EtOAC. The organic phase was dried with MgSO 4, and concentrated under reduced pressure. The residue was purified by chromatography on silica gel. 44 mg (18%) of the acid (RS) -3- [2- [benzylcarbamoyl- (4-c-anophenylamino) methyl] -4,5-dimethoxyphenyl] propionic acid was obtained in the form of a pale yellow solid.
69. 4 By the method of example 36.3, the nitrile obtained in Example 69.3 gave the acid (E) - and / or (Z) - (RS) -3- [2- [benzylcarbamoyl- [4- (N-hydroxycarbamimidoyl) - phenylamino] methyl] -4,5-dimethoxyphenyl] propionic, with a yield of 26%. Freeze-dried beige.
69. The reduction by the method of Example 45 of the amidoxime obtained above, gave the acid (RS) -3- [2- [benzylcarbamoyl- (4-carbamimidoylphenylamino) methyl] -4,4-dimethoxyphenyl] propionic acid, with a yield of 63%.
Freeze-dried white
Example 70
70. 1 By the method of Example 16, 3-nitro-benzaldehyde, 4-aminobenzonitrile and benzyl isonitrile, gave (RS) -N-benzyl-2- (4-cyano-phenylamino) -2- (3-nitrophenyl) acetamide with a yield of 11%. Light yellow crystalline solid. ISP-MS: 387.2 [M + H], 409.3 [M + Na].
70. 2 A solution of 1.4 g of the nitro compound obtained above in 80 ml of THF was mixed with 1 * "mg of 10% Pd / C and hydrogenated for 6 hours.The catalyst was removed by filtration and the filtrate was concentrated by evaporation. reduced pressure The residue was purified by chromatography on silica gel (CH2Cl2 / MeOH 19: 1) 1.15 g (89%) of (RS) -2- [3-aminophenyl) -N-benzyl-2- (4 -cyanophenylamino) acetamide, in the form of a yellow foam ISP-MS: 357.2 [M + H], 379.3 [M + Na].
70. 3 By the method of Example 50.1, the amine obtained above was reacted with acetyl chloride to give (RS) -2- [3-acetylaminophenyl) -N-benzyl-2- (4-cyano-phenylamino) -acetamide, with a performance of
99% ISP-MS: 399.4 [M + H], 421.3 [M + Na], 437.3 [M + K].
70. 4 By the method of example 36.3 and starting from the nitrile above, (E) and / or (Z) - (RS) -2- (3-acetylaminophenyl) -N-benzyl-2- [4- ( N-hydroxycarbamimidoyl) -phenylammo] acetamide, with a quantitative yield. Colorless solid.
70. Using the method of Example 45, the amidoxime obtained according to Example 70.4 was reduced to (RS) -2- (3-acetylaminophenyl) -N-benzyl-2- (4-carbamimidoylphenylamino) acetamide acetate (1). : 1), with a yield of 65%. Colorless powder
Example 71
At 5-100 ° C, dry HCl gas was introduced into a solution of 386 mg of the nitrile of example 70.1 in 20 ml of MeOH and 10 ml of CHC13, for 2 hours. The reaction solution was then concentrated under reduced pressure. The residue was dissolved in 30 ml of MeOH saturated with NH3. The solution was allowed to stand at RT overnight and then heated at 40 ° C for 4 hours and finally concentrated under reduced pressure. The residue was purified by chromatography on silica gel. 160 mg (35%) of (RS) -N-benzyl-2- (4-carbamimidoylphenylamino) -2- (3-nitrophenyl) acetamide (1: 1) acetate was obtained as a yellow solid. ISP-MS: 404.4 [M + H].
Example 72
A solution of 201 mg of 2,6-dimethoxyisonicotinic aldehyde (I. ": ompis et al., Eur. J. Med. Chem. - Chim. Ther. (1977), 12, 531) and 575 mg of 4-diethuenesulfonate. Amine benzamidine in 4.8 ml of THF / H20 9: 1 was mixed with 0.15 ml of benzyl isonitrile.The reaction mixture was stirred at RT for 6 hours and then concentrated under reduced pressure, the residue was suspended in diethyl ether. it was filtered off and recrystallized from EtOH / water, 2.02 g (28%) of (RS) -N-benzyl-2- (4-carbamimidoyl-phenylamino) -2- (2,6-dimethoxypyridin-4-) were obtained. il) acetamide in the form of a colorless crystalline solid.
Example 73 c
By the method of example 72,
73. 4,6-dimethoxypicolino aldehyde (I. Kompis et al., Eur. J. Med. Chem. - Chim. Ther. (1977), 12, 531), 4-amidinobenzamidine ditoluenesulfonate, and benzyl isonitrile, the (RS) -N-benzyl-2- (4-carbamimidoylphenylamino) -2- (4,6-dimethoxypyridin-2-yl) -acetamide was obtained in 41% yield as a colorless crystalline solid.
73. b of the 4-benzyloxy-3,5-dimethoxybenzoic aldehyde, 4-amidinobenzamidine ditoluenesulfonate, and benzyl isonitrile, the (RS) -N-benzyl-2- (4-benzyloxy-3,5-dimethylphenyl) - 2- (4-carbamimidoylphenylamino) acetamide, with a yield of 23%, in the form of a colorless crystalline solid.
Example 74
By the method of example 1,
74. The aldehyde 3-benzyloxy-5-propoxybenzoic acid, the 4-aminobenzamidine dihydrochloride, and the benzyl isonitrile gave the (RS) -N-benzyl-2- (3-benzyloxy-5-propoxyphenyl) -2- hydrochloride ( 4-carbamimidoyl-phenylamino) acetamide.
74. b of aldehyde 3, 5-bis (benzyloxy) benzoic acid, 4-aminobenzamidine dihydrochloride, and benzyl isonitrile, (RS) -N-benzyl-2- (3,5-bis-benzyl-oxyphenyl) hydrochloride was obtained -2- (4-carbamimidoylphenylamino) -acetamide.
Example 75
75. a By the method of Example 59.1, 2,6-diethoxypyridine-4-carbaldehyde (I. Kompis et al., Eur. J. Med. Chem. Chim. Ther. (1977), 12, 531), 4-aminobenzonitrile and benzyl isonitrile, (RS) -N-benzyl-2- (4-cyano-phenylamino) -2- (2,6-diethoxypyridin-4-yl) acetamide was obtained.
75. b By the method of Example 71, the product of Example 75.a gave (RS) -N-benzyl-2- (4-carbamimido-phenylamino) -2- (2,6-diethoxypyridin-4-yl) -acetamide hydrochloride. .
Example 76
76. 1 A solution of 5 g of 2-hydroxy-4-nitrobenzonitrile (W. Borsche, Ann. Chem. (1912) 390, 1) in 80.5 i? ml of isopropane, was mixed with 1 g of 10% Pd / C and hydrogenated for 1.5 hours. Next, the catalyst was removed by filtering the mixture, and the filtrate was concentrated. 3.3 g (80%) of 4-amino-2-hydroxybenzonitrile were obtained. 20 76.2 By the method of Example 59.1, the nitrile of example 76.1, 4-benzyloxy-3-ethoxybenzoic acid aldehyde and benzyl isonitrile gave (RS) -N-benzyl-2- (4-benzyloxy-3-ethoxyphenyl) -2- (4-cyano-3-hydroxyphenylamino) acetamide.
76. 3 Using the method of Example 13, the material obtained above gave the (RS) -N-benzyl-2- (4-benzyloxy-3-ethoxyphenyl) -2- [3-hydroxy-4- (N-hydroxycarbamimidoyl) ) -phenylamino] acetamide.
76. 4 Reduction of the amidoxime of Example 76.3 by the method of Example 45 gave the (RS) -N-benzyl-2- (4-benzyloxy-3-ethoxyphenyl) -2- (4-carbamimidoyl-3-hydroxy-phenylamino) acetamide.
Example 77
77. A solution of 14.35 g of the 4-benzyloxy-5-methoxy-2-nitrobenzoic aldehyde in 175 ml of MeOH was mixed with 5.9 g of 4-aminobenzonitrile and stirred at RT for 1 hr. A suspension was obtained which was mixed with 6.1 ml of benzyl isonitrile, and then cooled to 0 ° C. Then, 19 ml of boron trifluoride ethyl etherate was added dropwise over a period of 15 minutes. The mixture was allowed to warm to RT and was stirred for another 1.5 hours, obtaining a solution. This was concentrated under reduced pressure. The residue was dissolved in 330 ml of MeOH and 3.6 ml of H20. The reaction mixture was stirred at RT overnight, whereupon a solid crystallized. This was separated by filtration, washed with
MeOH / H20 8: 2 and Et20 and dried under high vacuum. 16.3 g (61%) of (RS) - (4-benzyloxy-5-methoxy-2-nitrophenyl) - (4-cyano-phenylamino) -ethyl acetate were obtained in the form of a pale yellow crystalline solid.
77. 2 A solution of 4.47 g of the nitrile obtained above in 100 ml of THF was mixed with 1.79 g of 5% Pt / C and hydrogenated for 1 day. The catalyst was then removed by filtration and the solution was concentrated under reduced pressure. The residue was purified by chromatography on silica gel (toluene / EtOAc 2: 1). 2.24 g (50%) of (RS) -2-amino-4-benzyloxy-5-methoxyphenyl) - (4-cyano-phenylamino) -ethyl acetate were obtained as a weak orange solid. ISP-MS: 440.3 [M + Na].
77. 3 A solution of 1.79 g of the material obtained in example 77.2 in 60 ml of CH2C12 was mixed with 4 ml of DMF and 2.21 ml of diisopropylethylamine and cooled to 0 ° C. Then, 1.21 ml of phenylsulfonyl chloride in 10 ml of CH2C12 was added dropwise over a period of 20 minutes. The mixture was then allowed to warm to RT over a period of 3 hours. The reaction solution was concentrated under reduced pressure. The residue was purified by chromatography on silica gel
(toluene / EtOAc 4: 1). 635 mg (21%) of (RS) - [4-benzyloxy-2- [bisphenylsulphonylamino) -5-methoxyphenyl] - (4-cyano-phenylamino) -ethyl acetate was obtained as a weak brown solid. ISP-MS: 698.2 [M + H], 720.2 [M + Na].
77. 4 By the method of Example 25, 795 mg of the nitrile obtained in Example 77.3 gave the acid (RS) -4-benzyloxy-2- [bisphenylsulfonylamino) -5-methoxyphenyl] - (4-cyano-phenylamino) -acetic acid. This was reacted by the method of example 36.1, but using methyl (S) -phenylglycinate instead of methyl L-alaninate hydrochloride., to give a 1: 1 mixture of (S) - [(R) - and - [(S) -2- [4-benzyloxy-2- (bisphenylsulfonylamino) -5-methoxyphenyl] -2- (4-) acetate cyanophenylamino) acetylamino] -phenyl. The latter, in turn, was dissolved in 20 ml of THF and mixed with 11 ml of IN solution of LiOH. The reaction mixture was heated at 60 ° C for 6 hours and at 40 ° C overnight. The THF is then removed by-1-distillation under reduced pressure. The aqueous solution of the residue was diluted with 2% citric acid and extracted with EtOAc. The organic phase was washed with saturated NaCl solution, dried with MgSO4, filtered off and concentrated under reduced pressure. The residue was dissolved in 25 ml of EtOH and mixed with 3.07 ml of triethylamine and 794 mg of hydroxylamine hydrochloride. The reaction solution was heated to reflux overnight and then concentrated under reduced pressure. The residue was purified twice by chromatography on silica gel (EtOAc / acetone / H20 / HOAc 6: 2: 1: 1). They were obtained
256 mg (29%) of a 1: 1 mixture of (S) - [(R) and - [(S) -2- (2-phenylsulfonylamino-4-benzyloxy-5-methoxyphenyl) -2- [4- [(E) - and / or - [(Z) -N-hydroxy-carbamimidoyl) phenylamino] -acetylamino] phenylacetic, e: form of a light brown lyophilizate. ISP-MS: 710: 1 [M + H], 732.2 [M + Na].
77. A solution of 190 mg of the amidoxime obtained above in 8 ml of EtOH, and 1 ml of HOAc were mixed with a Raney nickel spatula tip and hydrogenated overnight. The catalyst was removed by filtration and the filtrate was concentrated under reduced pressure. The residue was purified by chromatography on silica gel. The two epimers were obtained a) (S) - [(R) -2- (2-phenylsulphonyl-amino-4-benzyloxy-5-methoxyphenyl) -2- [4-carbamimidoylphenyl-a-ino] acetylamino] phenylacetic acid acetate (1: 1), and b) (S) - [(S) -2- (2-phenylsulfonyl-amino-4-benzyloxy-5-methoxyphenyl) -2- [4-carbamimidoylphenylamino) acetylamino] phenylacetic acid acetate (1) : 1), both in the form of colorless lyophilisates. ISP-MS: 694.2 [M + H].
Example 78
78. 1 5.9 g of 4-aminobenzonitrile were added to a solution of 14.3 g of the aldehyde 4-benzyloxy-5-methoxy-2-nitrobenzoic acid, in 350 ml of aulic alcohol. The formed yellow suspension was stirred at RT for 1.5 hours. Then, 6.1 ml of benzyl isonitrile was added and the reaction mixture was cooled to 0 ° C. 19 ml of boron trifluoride etherate were added dropwise. The suspension was allowed to warm to RT. Then the solid was stopped by filtration, washed with diethyl ether and suspended in 200 ml of allylic alcohol and 18 ml of water. The reaction mixture was stirred at RT overnight and then concentrated under reduced pressure. The residue was purified by chromatography on silica gel (toluene / acetone 9: 1). The product was recrystallized with THF / hexane. There were obtained 7.35 g (45%) of (RS) - (4-benzyloxy-5-methoxy-3-nitrophenyl) - (4-cyanophenylamino) allyl acetate, in the form of light yellow crystals. ISN-MS: 472.1 [M-H].
78. 2 g of dimedone (5, 5-dimethyl-l, 3-cyclohexanedione) and 1.8 g of tetrakis (triphenyl-phosphine) palladium were added to a 7.1 g solution of the nitrile obtained according to Example 78.1, 75 ml of THF. The reaction mixture was stirred at RT for 30 minutes and then mixed with activated charcoal, stirred at RT for a further 30 minutes and then filtered. The filtrate was concentrated under reduced pressure. The residue was purified twice by chromatography on silica gel (first with CH2Cl2 / MeOH 19: 1, then EtOAc). This gave 2.25 g (35%) of (RS) - (4-benzyloxy-5-methoxy-2-nitrophenyl) - (4-cyano-phenylamino) acetic acid, in the form of a yellow solid. ISP-MS: 434.3 [M + H].
78. 3 Using the method of example 36.1, using 1.67 g of the nitrile obtained according to Example 78.2 and (S) -phenylglycinate methyl instead of the hydrochloride of
Methyl lalaninate, 1.03 g (46%) of a 1: 1 mixture of (S) - [(R) - and - [(S) -2- (4-benzyloxy-5-methoxy-2-nitrophenyl) were obtained) -2- (4-cyano-phenylamino) acetylamino] phenyl-methyl acetate, in the form of a solid, reddish-brown foam. ISP-MS: 581.1 [M + H], 603.0 [M + Na].
78. 4 By the method of example 27, 636 mg of the nitro compound of Example 78.3 gave 235 mg (40%) of a 1: 1 mixture of (S) - [(R) - and - [(S) -2- (2- amino-4-benzyloxy-5-methoxyphenyl) -2- (4-cyano-phenylamino) -acetylamino] -phenyl-methyl acetate, in the form of a colorless crystalline solid. ISN-MS: 549.1 [M + H].
78. 5 By the method of Example 50.1, 100 mg of the aminonitrile above and the phenylacetyl chloride gave 118 mg (98%) of a 1: 1 mixture of (S) - [(R) - and - (S) - Methyl 2- (4-benzyloxy-5-methoxy-2-phenylacetylaminophenyl) -2- (4-cyanophenyl-amino) acetylamino] phenylacetate, in the form of a colorless solid foam. ISN-MS: 667.2 [M-H].
78. 6 By the method of example 36.2, 108 mg of the nitrile obtained in Example 78.5 gave 104 mg (98%) of a 1: 1 mixture of (S) - [(R) - and - [(S) -2- (4-benzyloxy-5-methoxy-2-phenylacetylaminophenyl) -2- (4-cyano-phenylamino) acetylamino] phenylacetic, in the form of a solid foam of a slightly yellow color. ISP-MS:
655. 1 [M + H].
78. 7 By the method of Example 36.3, 180 mg of the above nitrile gave 133 mg (70%) of a 1: 1 mixture of (S) - [(R) - and - [(S) -2- (4 -benzyloxy-5-methoxy-2-phenylacetylaminophenyl) -2- (4- [(E) - and / or - [(Z) -N-hydroxycarbamimidoyl] phenylamino] acetylamino] phenylacetic acid, in the form of a colorless powder. MS: 688.2 [M + H], 710.1 [M + Na].
78. The mixture of epimeros of example 78.7 gave, by the method of example 33 and after the chromatographic separation of the product on silica gel, the two epimers, a) acetate of (S) - [(R) -2- (2- benzenesulfonylamino-4-benzyloxy-5-methoxyphenyl) -2- (4-carbamimidoylphenylamino) acetylamino] phenylacetic (1: 1), and b) (S) - [(S) -2- (2-benzenesulfonylamino-4) -acetate benzyloxy-5-methoxyphenyl) -2- (4-carbamimidoylphenylamino) acetylamino] phenylacetic (1: 1), both in the form of a colorless powder. ISP-MS: 672.3 [M + H].
Example 79
By the methods of Examples 78.5-78.8, but using acetic anhydride instead of phenylacetyl chloride, the product of Example 78.4 gave, after chromatographic separation, the two epimeric acid (S) - [(R) -2 - (2-Acetylamino-4-benzyloxy-5-methoxyphenyl) -2- (4-cyano-phenylamino) -acetylamino] -phenylacetic acid and (S) - [(S) -2- (2-acetylamino-4-benzyloxy-5-methoxyphenyl) ) -2- (4-cyanophenylamino) acetylamino] phenylacetic. Via the respective amidoximes, these compounds were reacted to give the two epimers a) (S) - [(R) -2- (2-acetylamino-4-benzyloxy-5-methoxyphenyl) -2- acetate. (4-carbamimidoylphenylamino) -acetylamino] phenylacetic acid, and b) (S) - [(S) -2- (2-acetylamino-4-benzyloxy-5-methoxyphenyl) -2- (4-carbamimidoylphenylamino) -acetylamino] acetate] phenylacetic ISP-MS: 596.2 [M + H].
Example 80
A solution of 0.024 ml of 4-fluorobenzoyl chloride in 1.0 ml of THF and 0.5 ml of DMF was mixed with 0.038 ml of N, N-diisopropylethylamine and stirred at RT for 5 minutes. Next, 100 mg of the product of example 5.g. The reaction mixture was stirred at RT overnight. Another 0.024 ml of 4-fluorobenzoyl chloride and 0.1 ml of N, N-diisopropylethylamine were added, and the mixture was stirred at RT for 3 hours. The reaction mixture was concentrated under reduced pressure. The residue was treated with saturated NaHCO 3 solution and extracted with EtOAc. The organic phase was dried with MgSO 4, filtered and concentrated under reduced pressure. The residue was purified by chromatography on silica gel (hexane / EtOAc 2: 1). The product was crystallized with Et20 20 mg was obtained
(170%) of (RS) -N- [amino- (4. {[[Benzylcarbamoyl- (4-benzyloxy-3-ethoxyphenyl) methyl] amino] phenyl) methylene] -4-fluorobenzamide, in the form of a crystalline solid. ISP-MS: 631.2 [M + H].
Example 81
By the method of Example 80, the product of Example 5.g and 2-benzyloxymethylbenzoyl chloride gave the (RS) -2- benzoate. { [amino- (4. {[[benzylcarbamoyl- (4-benzyloxy-3-ethoxyphenyl) methyl] amino] phenyl) -methylene] carbamoyl} benzyl, with a 21% yield. Crystal yellow solid. ISP-MS: 747.4 [M + H].
EXAMPLE 82 By the method of Example 80, the product of Example 5.g and p-nitrophenyl 2,2-trichloroethyl carbonate gave the (RS) - [amino- (4- {[benzylcarbamoyl- ( 2, 2-trichloroethyl-benzyloxy-3-ethoxyphenyl) -methyl] amino.}. phenyl) methylene] -carbamate, in a yield of 60%. Crystal solid. ISP-MS: 683.1 [M + H].
EXAMPLE 83 By the method of Example 80, the product from example 5.g and methyl 4-nitrophenylcarbonate, gave the (RS) - [amino- (4- {[[benzylcarbamoyl- (4-benzyloxy-3-ethoxy- phenyl) ethyl] amino.} phenyl) methylene] carbamate, with a 91% yield in the form of a solid. ISP-MS: 567.3 [M + H]. A compound of formula I, a hydrate, a solvate or a salt thereof, can be used as an active ingredient for the preparation of pharmaceutical preparations similar to those which follow.
Example A Example B
It is noted that in relation to this date, the best method known to the applicant to carry out the aforementioned invention, is that which is clear from the present description of the invention. Having described the invention as above, the content of the following is claimed as property.
Claims (10)
1. - The N- (carbamidophenyl) glycinamide derivatives of the formula characterized in that E is hydrogen or OH, C is hydrogen or alkyl, R is aryl, cycloalkyl or alkyl which is substituted by R1, R2 and R3, R1 is hydrogen, COOH, COO-alkyl or aryl, R2 is hydrogen, aryl, cycloalkyl or heteroaryl, R3 is hydrogen, aryl or (at a position different from the position a to the nitrogen atom to which the optionally protected alkyl group R) OH, alkoxy or amino is attached, N (Q, R) is COOH- or COO-alkyl-substituted, pyrrolidino, piperidino or 1,2,3,4-tetrahydroisoquinolin-3-yl, three of the radicals X to X4 independently of one another are a group C (Ra), C (Rb) or C ( RC) and the fourth radical is a group C (R) or N, Ra a Rd independently of one another are H, OH, N02, dialkylamino, halogen, alkyl, alkoxy, aryloxy, aralkyloxy, heteroaryalkyloxy, heterocyclalkyloxy, COOH, COO -alkyl, NH-S02-alkyl, NHS02-aryl, NHCO-alkyl, NHCO-aryl, NHCOO-alkyl, NHCO-alkyl-NH2, NHCO-alkyl-NH-G, aralkyl-CONH, alkyl lo-O-alkyl-CONH, aryl-O-alkyl-CONH, alkyl-COOH, alkyl-COO-alkyl, 0-alkyl-COOH or 0-alkyl-COO-alkyl, or two adjacent groups Ra a Rd together are alkylenedioxy , where no more than three of the radicals Ra to R must have the same meaning and X1? or should be CCOOH or CCOO-alkyl, G is an amino protecting group and one of the radicals G1 and G2 is hydrogen and the other radical is hydrogen, alkyl, OH, alkoxy, aroyl, alkanoyl-OCH2, aroyl-OCH2 or a group COO-Rg or OCO-Rs, Rg is optionally alkyl halogen-, OH-, alkoxy-, COOH- or COO-alkyl-substituted, and hydrates or solvates and their physiologically acceptable salts.
2. - The compounds, according to claim 1, characterized in that G2 and Q are hydrogen, R is alkyl, aryl, aralkyl, benzhydryl, cycloalkylalkyl or heteroarylalkyl, G1 is hydrogen, OH or COO-alkyl, X1 to X4 are a C group (Ra) a C (Rd) and Ra a Rd independently of one another are H, OH, N02, dialkylamino, halogen, alkyl, alkoxy, aryloxy, aralkyloxy, heteroarylalkyloxy, heterocyclyl-alkyloxy, COO-alkyl, NHS02, alkyl or NHS02 -aril, where no more than three of the radicals Ra to Rd must have the same meaning and X1 must not be COO-alkyl.
3. - The compounds, according to claim 1 or 2, characterized in that E, G1, and Q are hydrogen.
4. - The compounds according to claim 1 or 3, characterized in that R is alkyl, in particular methyl or ethyl, which is substituted by R1, R2 and R, in particular where R1 is aryl, specifically phenyl, or COOH, R2 is hydrogen or aryl, specifically phenyl, and R3 is hydrogen.
5. - The compounds according to claim 1, 3 or 4, wherein X1 to X4 are a group C (Ra) to C (R), in particular a group wherein Ra is H, aralkyloxy, specifically carboxybenzyloxy; NHS02-aryl, specifically phenylsulfonylamino; aralkyl-CONH, specifically phenylacetylamino, or O-alkyl-COOH, specifically carboxymethoxy, R is H or alkoxy, specifically methoxy or ethoxy, Rc is H, alkoxy, specifically methoxy; or aralkyloxy, specifically benzyloxy, and R is H or alkoxy, specifically methoxy.
6. - The compounds according to any of claims 1 to 5, that is: (R, S) -N-benzyl-2- (4-benzyloxy-3-ethoxyphenyl) -2- (4-carbamimido-1-phenylametamide, 2- ( 2-phenylsulfonylamino-4-benzyloxy-5-methoxyphenyl) -N-benzyl-2- (4-carbamimidoylphenylamine ---: o) acetamide. - - 1 .
The compounds according to any of claims 1 to 3-5, that is: (R, S) -N-benzyl-2- (4-benzyloxy-3-ethoxyphenyl) -2- (4-carbamimidoyl-phenylamino) ) acetamide, 2- (2-phenylsulfonylamino-4-benzyloxy-5-methoxyphenyl) -N-benzyl-2- (4-carbam-midoylphenylamino) acetamide and furthermore acid (RS) - [2- (4-benzyloxy-3- methoxyphenyl) -2- (4-carbamimidoylphenylamino) acetylamino] diphenylacetic acid (RS) - and (SR) -3- [(RS) -2- (4-benzyloxy-3-methoxyphenyl) -2- (4-carbamimidoylphenylamino) acetylamino] -3-phenylpropionic, (S) - [(R) -2- (4-Benzyloxy-3-methoxyphenyl) -2- (4-carbamimidoyl-phenylamino) acetylamino] phenylacetic acid, (S) - [(S) -2- (4) acid -carbamimidoylphenylamino) -2- (3,5-dimethoxyphenyl) acetylamino] phenylacetic acid (RS) -3- [2- [benzylcarbamoyl- (4-carbamimidoyl-phenyl-amino) ethyl] -4,5-dimethoxyphenoxymethyl] benzoic acid, (RS) - [2-Ibencylcarbamoyl- (4-carbainimidoyl-phenylamino) -methyl] -4,5-dimethoxyphenoxy] acetic acid, (S) - [(R) -2- (2-phenylsulfonylamino-4-benzyloxy- 5-methoxyphenyl) -2- (4-carbamimidoylphenylamino) acetylamino] phenylacetic acid (S) - [(S) -2- (2-phenylsulfonylamino-4-benzyloxy-5-methoxyphenyl) -2- (4-carbamimidoylphenylamino ) acetylamino] -phenylacetic acid (S) - [(R) -2- (4-benzyloxy-5-methoxy-2-phenylacetylaminophenyl) -2- (4-carbamimidoylphenylamino) acetylamino] phenylacetic acid, (S) - [( S) -2- (4-benzyloxy-5-methoxy-2-phenylacetylaminophenyl) -2- (4-carbamimidoylphenylamino) acetylamino] phenylacetic.
8. - The compounds of the formula .56 - wherein E, Q, R and X1 to X4 are each as defined in claim 1.
9. - The pharmaceutical preparations comprising a compound according to any of claims 1-7 as an active ingredient. -
10. Process for the preparation of the compounds of the formula I according to claim 1, characterized in that a) an aldehyde of the formula is reacted with an isonitrile of the formula R'NC and a 4-aminobenzamidine of the formula b) the cyano group LN that is contained in an appropriate nitrile of the formula it becomes an amidino group C (NG) NH-G, c) a reactive group contained in a compound I, if desired, is functionally derivatized and d) a compound of formula I is converted, if desired, into a salt physiologically acceptable, or a salt of a compound I is converted to the free acid or base.
11. - The compounds according to any of claims 1-7 for use as medicaments, in particular as inhibitors of the formation of coagulation factors Xa, IXa and thrombin induced by the factor VIIA and by the tissue factor, specifically as medications for the treatment and / or prevention of thrombosis, stroke, cardiac infarction, inflammation and arteriosclerosis, or as antitumor agents.
13. The use of a compound, according to any of claims 1-5, for the preparation of medicaments for the treatment and / or prevention of thrombosis, stroke, cardiac infarction, inflammation and arteriosclerosis or for the preparation of antitumor agents.
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CH97121285.7 | 1997-12-04 | ||
CH971212857 | 1997-12-04 |
Publications (1)
Publication Number | Publication Date |
---|---|
MXPA98010201A true MXPA98010201A (en) | 2000-08-01 |
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