MXPA01000446A - Bispiperidines as antithrombotic agents - Google Patents
Bispiperidines as antithrombotic agentsInfo
- Publication number
- MXPA01000446A MXPA01000446A MXPA/A/2001/000446A MXPA01000446A MXPA01000446A MX PA01000446 A MXPA01000446 A MX PA01000446A MX PA01000446 A MXPA01000446 A MX PA01000446A MX PA01000446 A MXPA01000446 A MX PA01000446A
- Authority
- MX
- Mexico
- Prior art keywords
- amino
- groups
- piperidyl
- ethyl
- butanoyl
- Prior art date
Links
- 239000003146 anticoagulant agent Substances 0.000 title abstract description 5
- 229960004676 ANTITHROMBOTIC AGENTS Drugs 0.000 title abstract description 3
- 150000001875 compounds Chemical class 0.000 claims abstract description 252
- 210000001772 Blood Platelets Anatomy 0.000 claims abstract description 23
- 229940012952 Fibrinogen Drugs 0.000 claims abstract description 9
- 102000008946 Fibrinogen Human genes 0.000 claims abstract description 9
- 108010049003 Fibrinogen Proteins 0.000 claims abstract description 9
- 229940019698 Fibrinogen containing hemostatics Drugs 0.000 claims abstract description 9
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 368
- -1 benzodioxanyl Chemical group 0.000 claims description 312
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 109
- 239000002253 acid Substances 0.000 claims description 101
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 claims description 98
- 125000004063 butyryl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 70
- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 claims description 42
- 125000000217 alkyl group Chemical group 0.000 claims description 30
- 125000003118 aryl group Chemical group 0.000 claims description 21
- 229910052739 hydrogen Inorganic materials 0.000 claims description 20
- 239000001257 hydrogen Substances 0.000 claims description 19
- 229910052736 halogen Inorganic materials 0.000 claims description 18
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 18
- 125000002047 benzodioxolyl group Chemical group O1OC(C2=C1C=CC=C2)* 0.000 claims description 16
- 150000002367 halogens Chemical class 0.000 claims description 16
- 230000002401 inhibitory effect Effects 0.000 claims description 15
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 15
- 239000000203 mixture Substances 0.000 claims description 14
- 238000007792 addition Methods 0.000 claims description 13
- 125000001072 heteroaryl group Chemical group 0.000 claims description 13
- 150000003839 salts Chemical class 0.000 claims description 13
- 239000011780 sodium chloride Substances 0.000 claims description 13
- 125000003545 alkoxy group Chemical group 0.000 claims description 12
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 12
- 208000010110 Spontaneous Platelet Aggregation Diseases 0.000 claims description 11
- 150000002431 hydrogen Chemical class 0.000 claims description 11
- 238000000034 method Methods 0.000 claims description 11
- 210000004369 Blood Anatomy 0.000 claims description 10
- 239000008280 blood Substances 0.000 claims description 10
- 238000002360 preparation method Methods 0.000 claims description 10
- 125000004076 pyridyl group Chemical group 0.000 claims description 10
- 125000001544 thienyl group Chemical group 0.000 claims description 10
- 125000004196 benzothienyl group Chemical group S1C(=CC2=C1C=CC=C2)* 0.000 claims description 9
- 125000002541 furyl group Chemical group 0.000 claims description 9
- 125000004414 alkyl thio group Chemical group 0.000 claims description 8
- 150000001412 amines Chemical class 0.000 claims description 8
- 125000005418 aryl aryl group Chemical group 0.000 claims description 8
- 125000002950 monocyclic group Chemical group 0.000 claims description 8
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 8
- 230000001681 protective Effects 0.000 claims description 8
- 150000007513 acids Chemical class 0.000 claims description 7
- 125000004618 benzofuryl group Chemical group O1C(=CC2=C1C=CC=C2)* 0.000 claims description 7
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 7
- UFHFLCQGNIYNRP-UHFFFAOYSA-N hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 7
- 125000001624 naphthyl group Chemical group 0.000 claims description 7
- 125000005936 piperidyl group Chemical group 0.000 claims description 7
- 239000001294 propane Substances 0.000 claims description 7
- 125000005493 quinolyl group Chemical group 0.000 claims description 7
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 5
- 125000005843 halogen group Chemical group 0.000 claims description 5
- 125000003170 phenylsulfonyl group Chemical group C1(=CC=CC=C1)S(=O)(=O)* 0.000 claims description 5
- 125000003367 polycyclic group Chemical group 0.000 claims description 5
- 125000006239 protecting group Chemical group 0.000 claims description 5
- 230000001732 thrombotic Effects 0.000 claims description 5
- 125000006527 (C1-C5) alkyl group Chemical group 0.000 claims description 4
- 125000006650 (C2-C4) alkynyl group Chemical group 0.000 claims description 4
- 241000124008 Mammalia Species 0.000 claims description 4
- 125000005037 alkyl phenyl group Chemical group 0.000 claims description 4
- 125000004390 alkyl sulfonyl group Chemical group 0.000 claims description 4
- 125000002619 bicyclic group Chemical group 0.000 claims description 4
- 125000005805 dimethoxy phenyl group Chemical group 0.000 claims description 4
- 125000004435 hydrogen atoms Chemical group [H]* 0.000 claims description 4
- 125000001041 indolyl group Chemical group 0.000 claims description 4
- 125000000842 isoxazolyl group Chemical group 0.000 claims description 4
- 125000004817 pentamethylene group Chemical group [H]C([H])([*:2])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[*:1] 0.000 claims description 4
- 125000003373 pyrazinyl group Chemical group 0.000 claims description 4
- 125000000383 tetramethylene group Chemical group [H]C([H])([*:1])C([H])([H])C([H])([H])C([H])([H])[*:2] 0.000 claims description 4
- 125000004769 (C1-C4) alkylsulfonyl group Chemical group 0.000 claims description 3
- 125000006656 (C2-C4) alkenyl group Chemical group 0.000 claims description 3
- 208000007536 Thrombosis Diseases 0.000 claims description 3
- 125000003277 amino group Chemical group 0.000 claims description 3
- 125000000000 cycloalkoxy group Chemical group 0.000 claims description 3
- 125000001325 propanoyl group Chemical group O=C([*])C([H])([H])C([H])([H])[H] 0.000 claims description 3
- 210000004940 Nucleus Anatomy 0.000 claims description 2
- 230000002785 anti-thrombosis Effects 0.000 claims description 2
- 125000000928 benzodioxinyl group Chemical group O1C(=COC2=C1C=CC=C2)* 0.000 claims description 2
- 125000001164 benzothiazolyl group Chemical group S1C(=NC2=C1C=CC=C2)* 0.000 claims description 2
- 239000004305 biphenyl Substances 0.000 claims description 2
- 125000006267 biphenyl group Chemical group 0.000 claims description 2
- 229910052760 oxygen Inorganic materials 0.000 claims description 2
- 230000003405 preventing Effects 0.000 claims description 2
- 125000003226 pyrazolyl group Chemical group 0.000 claims description 2
- 229910052717 sulfur Inorganic materials 0.000 claims description 2
- 125000000335 thiazolyl group Chemical group 0.000 claims description 2
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims 1
- LSNNMFCWUKXFEE-UHFFFAOYSA-N sulfonic acid Chemical compound OS(O)=O LSNNMFCWUKXFEE-UHFFFAOYSA-N 0.000 claims 1
- 125000002088 tosyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1C([H])([H])[H])S(*)(=O)=O 0.000 claims 1
- 238000002560 therapeutic procedure Methods 0.000 abstract 1
- 239000000463 material Substances 0.000 description 153
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 description 105
- LILRHDIKLODNQJ-UHFFFAOYSA-N C(C)(C)(C)OC(=O)C1NC=CC=C1 Chemical compound C(C)(C)(C)OC(=O)C1NC=CC=C1 LILRHDIKLODNQJ-UHFFFAOYSA-N 0.000 description 100
- 239000007858 starting material Substances 0.000 description 98
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N DMSO-d6 Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 80
- 101700067048 CDC13 Proteins 0.000 description 64
- 230000000977 initiatory Effects 0.000 description 60
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 58
- RQCNHUCCQJMSRG-UHFFFAOYSA-N tert-butyl piperidine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CCCCC1 RQCNHUCCQJMSRG-UHFFFAOYSA-N 0.000 description 57
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 42
- 238000005160 1H NMR spectroscopy Methods 0.000 description 37
- VEXZGXHMUGYJMC-UHFFFAOYSA-N HCl Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 35
- XEKOWRVHYACXOJ-UHFFFAOYSA-N acetic acid ethyl ester Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 27
- 239000000243 solution Substances 0.000 description 23
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 22
- OKKJLVBELUTLKV-MZCSYVLQSA-N cd3od Chemical compound [2H]OC([2H])([2H])[2H] OKKJLVBELUTLKV-MZCSYVLQSA-N 0.000 description 20
- YMWUJEATGCHHMB-UHFFFAOYSA-N methylene dichloride Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 20
- QTBSBXVTEAMEQO-UHFFFAOYSA-N acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 18
- 230000015572 biosynthetic process Effects 0.000 description 14
- 239000007787 solid Substances 0.000 description 14
- VEXZGXHMUGYJMC-UHFFFAOYSA-M chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 13
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 12
- OKKJLVBELUTLKV-UHFFFAOYSA-N methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 12
- PMZURENOXWZQFD-UHFFFAOYSA-L na2so4 Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 12
- 238000003756 stirring Methods 0.000 description 12
- 238000003786 synthesis reaction Methods 0.000 description 12
- 230000002194 synthesizing Effects 0.000 description 12
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 11
- 229910052938 sodium sulfate Inorganic materials 0.000 description 11
- 235000011152 sodium sulphate Nutrition 0.000 description 11
- KNLKRAUJQBLECR-UHFFFAOYSA-N tert-butyl pyridine-2-carboxylate Chemical compound CC(C)(C)OC(=O)C1=CC=CC=N1 KNLKRAUJQBLECR-UHFFFAOYSA-N 0.000 description 11
- 210000004623 Platelet-Rich Plasma Anatomy 0.000 description 8
- RTZKZFJDLAIYFH-UHFFFAOYSA-N diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 8
- 125000003754 ethoxycarbonyl group Chemical group C(=O)(OCC)* 0.000 description 8
- SJRJJKPEHAURKC-UHFFFAOYSA-N n-methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 description 8
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 8
- WYURNTSHIVDZCO-UHFFFAOYSA-N tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 8
- DTQVDTLACAAQTR-UHFFFAOYSA-M Trifluoroacetate Chemical compound [O-]C(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-M 0.000 description 7
- 239000012043 crude product Substances 0.000 description 7
- 239000012074 organic phase Substances 0.000 description 7
- FERIUCNNQQJTOY-UHFFFAOYSA-N Butanoic acid Chemical compound CCCC(O)=O FERIUCNNQQJTOY-UHFFFAOYSA-N 0.000 description 6
- 241000700198 Cavia Species 0.000 description 6
- 150000001413 amino acids Chemical class 0.000 description 6
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 6
- 239000000047 product Substances 0.000 description 6
- 125000004207 3-methoxyphenyl group Chemical group [H]C1=C([H])C(*)=C([H])C(OC([H])([H])[H])=C1[H] 0.000 description 5
- 238000004220 aggregation Methods 0.000 description 5
- 230000002776 aggregation Effects 0.000 description 5
- 238000003818 flash chromatography Methods 0.000 description 5
- 239000003999 initiator Substances 0.000 description 5
- YOETUEMZNOLGDB-UHFFFAOYSA-N 2-methylpropyl carbonochloridate Chemical compound CC(C)COC(Cl)=O YOETUEMZNOLGDB-UHFFFAOYSA-N 0.000 description 4
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 4
- 230000001154 acute Effects 0.000 description 4
- 125000001584 benzyloxycarbonyl group Chemical group C(=O)(OCC1=CC=CC=C1)* 0.000 description 4
- 238000006243 chemical reaction Methods 0.000 description 4
- 239000000284 extract Substances 0.000 description 4
- KDLHZDBZIXYQEI-UHFFFAOYSA-N palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 4
- 239000002904 solvent Substances 0.000 description 4
- 239000000725 suspension Substances 0.000 description 4
- DKGAVHZHDRPRBM-UHFFFAOYSA-N t-BuOH Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 description 4
- 125000000175 2-thienyl group Chemical group S1C([*])=C([H])C([H])=C1[H] 0.000 description 3
- 125000004172 4-methoxyphenyl group Chemical group [H]C1=C([H])C(OC([H])([H])[H])=C([H])C([H])=C1* 0.000 description 3
- BZZMNNZVMKQFED-UHFFFAOYSA-N 4-piperidin-4-yl-2-(2-piperidin-4-ylethyl)butanoic acid;dihydrochloride Chemical compound Cl.Cl.C1CNCCC1CCC(C(=O)O)CCC1CCNCC1 BZZMNNZVMKQFED-UHFFFAOYSA-N 0.000 description 3
- 206010002388 Angina unstable Diseases 0.000 description 3
- CSKNSYBAZOQPLR-UHFFFAOYSA-N Benzenesulfonyl chloride Chemical compound ClS(=O)(=O)C1=CC=CC=C1 CSKNSYBAZOQPLR-UHFFFAOYSA-N 0.000 description 3
- 238000005361 D2 NMR spectroscopy Methods 0.000 description 3
- AQEFLFZSWDEAIP-UHFFFAOYSA-N Di-tert-butyl ether Chemical compound CC(C)(C)OC(C)(C)C AQEFLFZSWDEAIP-UHFFFAOYSA-N 0.000 description 3
- 208000010125 Myocardial Infarction Diseases 0.000 description 3
- 210000002381 Plasma Anatomy 0.000 description 3
- 208000007814 Unstable Angina Diseases 0.000 description 3
- CSCPPACGZOOCGX-UHFFFAOYSA-N acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 3
- 125000000499 benzofuranyl group Chemical group O1C(=CC2=C1C=CC=C2)* 0.000 description 3
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 description 3
- 229910052799 carbon Inorganic materials 0.000 description 3
- HEDRZPFGACZZDS-MICDWDOJSA-N deuterated chloroform Substances [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 238000001802 infusion Methods 0.000 description 3
- 201000004332 intermediate coronary syndrome Diseases 0.000 description 3
- 238000001990 intravenous administration Methods 0.000 description 3
- 238000002844 melting Methods 0.000 description 3
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 3
- 239000008194 pharmaceutical composition Substances 0.000 description 3
- DNUTZBZXLPWRJG-UHFFFAOYSA-M piperidine-1-carboxylate Chemical compound [O-]C(=O)N1CCCCC1 DNUTZBZXLPWRJG-UHFFFAOYSA-M 0.000 description 3
- 239000000843 powder Substances 0.000 description 3
- XBDQKXXYIPTUBI-UHFFFAOYSA-M propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- 238000001356 surgical procedure Methods 0.000 description 3
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 2
- GCHPUFAZSONQIV-UHFFFAOYSA-M 2-amino-2-methylbutanoate Chemical compound CCC(C)(N)C([O-])=O GCHPUFAZSONQIV-UHFFFAOYSA-M 0.000 description 2
- 125000003762 3,4-dimethoxyphenyl group Chemical group [H]C1=C([H])C(OC([H])([H])[H])=C(OC([H])([H])[H])C([H])=C1* 0.000 description 2
- ABGXADJDTPFFSZ-UHFFFAOYSA-N 4-Benzylpiperidine Chemical compound C=1C=CC=CC=1CC1CCNCC1 ABGXADJDTPFFSZ-UHFFFAOYSA-N 0.000 description 2
- 125000001255 4-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1F 0.000 description 2
- 206010003178 Arterial thrombosis Diseases 0.000 description 2
- 230000036912 Bioavailability Effects 0.000 description 2
- 102000008186 Collagen Human genes 0.000 description 2
- 108010035532 Collagen Proteins 0.000 description 2
- FKRCODPIKNYEAC-UHFFFAOYSA-N Ethyl propionate Chemical compound CCOC(=O)CC FKRCODPIKNYEAC-UHFFFAOYSA-N 0.000 description 2
- 241001465754 Metazoa Species 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- HRXKRNGNAMMEHJ-UHFFFAOYSA-K Trisodium citrate Chemical compound [Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O HRXKRNGNAMMEHJ-UHFFFAOYSA-K 0.000 description 2
- 125000000738 acetamido group Chemical group [H]C([H])([H])C(=O)N([H])[*] 0.000 description 2
- 230000004913 activation Effects 0.000 description 2
- 125000003342 alkenyl group Chemical group 0.000 description 2
- 238000002399 angioplasty Methods 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- HDYQLGLEPPGPEV-UHFFFAOYSA-N benzyl 2,2,2-trifluoroacetate Chemical compound FC(F)(F)C(=O)OCC1=CC=CC=C1 HDYQLGLEPPGPEV-UHFFFAOYSA-N 0.000 description 2
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 2
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- IJDNQMDRQITEOD-UHFFFAOYSA-N butane Chemical compound CCCC IJDNQMDRQITEOD-UHFFFAOYSA-N 0.000 description 2
- 239000001273 butane Substances 0.000 description 2
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- 125000001301 ethoxy group Chemical group [H]C([H])([H])C([H])([H])O* 0.000 description 2
- RJCGNNHKSNIUAT-UHFFFAOYSA-N ethyl 3-aminopropanoate;hydron;chloride Chemical compound Cl.CCOC(=O)CCN RJCGNNHKSNIUAT-UHFFFAOYSA-N 0.000 description 2
- 125000000031 ethylamino group Chemical group [H]C([H])([H])C([H])([H])N([H])[*] 0.000 description 2
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- 229910052500 inorganic mineral Inorganic materials 0.000 description 2
- 238000003780 insertion Methods 0.000 description 2
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- KFZMGEQAYNKOFK-UHFFFAOYSA-N iso-propanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 2
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 2
- GLXDVVHUTZTUQK-UHFFFAOYSA-M lithium;hydroxide;hydrate Chemical compound [Li+].O.[OH-] GLXDVVHUTZTUQK-UHFFFAOYSA-M 0.000 description 2
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
- 239000011707 mineral Substances 0.000 description 2
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- 239000011778 trisodium citrate Substances 0.000 description 2
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 description 1
- 125000006729 (C2-C5) alkenyl group Chemical group 0.000 description 1
- TVCVZPPTRJJNOP-UHFFFAOYSA-M 1,2-dihydropyridine-2-carboxylate Chemical compound [O-]C(=O)C1NC=CC=C1 TVCVZPPTRJJNOP-UHFFFAOYSA-M 0.000 description 1
- ICUBASIDCXDQAW-UHFFFAOYSA-N 1,3-benzodioxole-5-sulfonyl chloride Chemical compound ClS(=O)(=O)C1=CC=C2OCOC2=C1 ICUBASIDCXDQAW-UHFFFAOYSA-N 0.000 description 1
- WORJRXHJTUTINR-UHFFFAOYSA-N 1,4-dioxane;hydron;chloride Chemical compound Cl.C1COCCO1 WORJRXHJTUTINR-UHFFFAOYSA-N 0.000 description 1
- RWCKBBSBRTUUHR-UHFFFAOYSA-N 1-benzofuran-2-sulfonyl chloride Chemical compound C1=CC=C2OC(S(=O)(=O)Cl)=CC2=C1 RWCKBBSBRTUUHR-UHFFFAOYSA-N 0.000 description 1
- FKIIVBOPAHICHQ-UHFFFAOYSA-N 1-benzothiophene-2-sulfonyl chloride Chemical compound C1=CC=C2SC(S(=O)(=O)Cl)=CC2=C1 FKIIVBOPAHICHQ-UHFFFAOYSA-N 0.000 description 1
- YZNQITSGDRCUKE-UHFFFAOYSA-N 1-chloropropane Chemical group [CH2]CCCl YZNQITSGDRCUKE-UHFFFAOYSA-N 0.000 description 1
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- SWLIXMXSCZYVTQ-UHFFFAOYSA-N 2,3-dihydro-1H-indene-5-sulfonyl chloride Chemical compound ClS(=O)(=O)C1=CC=C2CCCC2=C1 SWLIXMXSCZYVTQ-UHFFFAOYSA-N 0.000 description 1
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Abstract
The invention concerns compounds of formula (I) wherein:R1, R2, R3, Z1, Z2 are as defined in Claim 1. Said compounds inhibit the fixing of fibrinogen on Gp IIb/IIIa platelet receptors and areuseful in therapy as antithrombotic agents.
Description
BISPIPERIDINAS AS ANTITROMBOTIC AGENTS
Field of the Invention
The present invention relates to novel compounds which are inhibitors of fibrinogen binding to platelet Gp Ilb / IIIa receptors, and which can be used therapeutically as antithrombotic agents.
Background of the Invention
In the course of pathological processes which lead to the formation of a thrombus
(clot), and after its expression, the platelet aggregation represents a key stage, since it is the source of the seriousness of the phenomenon. Specifically, from the initiation of the thrombus, in particular in the arterial blood circulation, the intervention of severe interdependent biochemical reactions induces the aggregation of an increased number of platelets via the conversion of soluble fibrinogen into REF filaments. DO NOT. 126293 of insoluble fibrin which increase the size of the platelet mass, first to the current site of the arterial vascular lesion, and then incrementally in the lumen of the vessel. 5 In this platelet aggregation mechanism, the activation of the Gp Ilb / IIa receptors is the source of the amplification of platelet aggregation. Fibrinogen, which can be linked via its two dimers to these receptors, amplifies the
The binding link of the platelets also induces the formation of a mass of platelets that form a thrombus at the site of the rupture of the atheromatous plaque. This mechanism of platelet aggregation is particularly active in all thromboses
arterials, if they appear in the course of interventional cardiology practices (transluminal percutaneous angioplasty, insertion of "stents"), heart surgery (aor-coronary deviation, valvular surgery), in the course of acute conditions of the
heart (myocardial infarction, unstable angina, acute coronary syndromes, etc.) or in the course of certain cerebral ischemias, or finally in the course of myocardial ischemias which can complicate the follow-up of an anti-thrombotic treatment.
The reduction or prevention of the activation of platelets in contact with a ruptured atherosclerotic plaque, represents thus a new and effective therapeutic scope to the treatment of thrombosis, in particular of arterial thrombosis, and in addition, an efficient means to prevent coronary syndromes acute symptoms including unstable angina and myocardial infarction. Compounds that inhibit the binding of fibrinogen to its receptors are described in EP-A-0 478 362 and J. Med. Chem., 1995, 38, 3332.
Description of the invention
The present invention is directed to provide new competitive inhibitors of fibrinogen binding to Gp Ilb / IIa receptors. An object of the present invention are the compounds of the general formula (I):
* • "* - '• - >« * S
Formula I
wherein: i) either Ri is selected from: Ct.-C4 alkyl groups, C3-C? 2 mono- or bicyclic cycloalkyl / C2-C4 alkenyl groups or C2-C4 alkynyl, these groups are optionally substituted with groups selected from halogens and the hydroxyl group; - C6 mono-, bi- or tricyclic aryl groups
- heteroaryl groups selected from pyridyl, thienyl, furanyl, quinolyl, benzodioxanyl, benzodioxolyl, benzothienyl, benzofuranyl and pyrazinyl groups; alkyl pheni lo groups (C 1 -C) and alkylnaphthyl (C 1 -C 4) optionally substituted on the aryl nuclei, the aryl and heteroaryl groups are possibly substituted with one or more groups independently selected from halogens, C 1 -C 4 alkyl , trifluoromethyl, C 1 -C 4 alkylthio, C 1 -C 4 alkylsulfonyl, C 1 -C 4 alkyloxy, nitro and -COOR groups, -CH 2 COOR or -0-CH 2 -COOR, R is a C 1 -C 6 alkyl group of the formula : 10
Wherein R 4 and R 4 are selected from C 1 -C 6 alkyl and mono- or polycyclic C 3 -C 1 cycloalkyl groups, these groups are optionally substituted with groups selected from halogens and from the hydroxyl group, R ' it is also
Possibly hydrogen, or alternatively R4 and R '4 together form a tetramethylene or pentamethylene group, the latter two groups themselves possibly being substituted, in particular with a C6-C1 aryl or a (C1-C) alkyloyl residue ( C6-C? 4); 25 - the groups of the formula
-Mfc »^ lt« g ^ Hj ^^
wherein m = 1 to 4 and R5 is selected from phenyl, methoxyphenyl, indolyl, benzodioxolyl, benzodioxanyl, benzothienyl and benzofuryl groups, and R2 is hydrogen, ii) or Ri is hydrogen and R2 is selected from the Formula groups:
-NH-CO-Re,
R & is selected from C: -C4 alkoxy, C-C-cycloalkoxy, benzyloxy, methoxyphenyl, dimethoxyphenyl, benzodioxolyl and benzodioxanyl groups, and the groups of formula -NH-SO.-R-, R is selected from: groups C1-C5 alkyl optionally substituted with one or more groups selected from halogens, hydroxyl groups and the trifluoromethyl group;
- • - t - ^ ft, "..., ^", ^ ,, _ ,.; j, ^ C2-C5 alkenyl groups; C3-C1 cycloalkyl groups: mono- or bicyclic; aryl groups Cs-C 14 mono, bi 'or tricyclic heteroaryl groups selected from pyridyl, furyl, thienyl, quinolyl, benzodioxanyl, benzodioxolyl, isoxazolyl, benzodioxinyl, benzothienyl, thiazolyl, pyrazolyl,
Benzofuryl and benzothiazolyl groups; alkyl (C1-C4) alkyl and alkylnaphthyl (Cl-C4) groups; and the groups of the formula
wherein n = 1, 2 or 3 and B is selected from -CH-, O or S and -NH-, the aryl or heteroaryl groups are optionally substituted with one or more groups independently selected from halogens, alkyl C? ~ C4, C3-C7 cycloalkyl,
trifluoromethyl, C1-C4 alkylthio, C1-C4 alkyloxy,
- «------- 1 - Í - I-1- * -----------------« ti-k-í-M Ua-á.- MMdHÉ-tH alkylsulfonyl C: -C 4 / nitro, di (C 4 alkyl) amino and groups -COOR, -CH 2 -COOR or -0-CH 2 COOR, R is an alkyl group, phenyl and naphthyl groups and heteroaryl groups selected from from thienyl, furyl and pyridyl groups, iii) R3 is selected from a hydrogen atom, a C? -C alkyl group and an alkylphenyl group (C? -C4); iv) A is selected from groups -NH-CHR10-,
-. 10 -NH-CHR? O-CH2- and
with p = 1 or 2, - Ri ,, is selected from hydrogen, a C: -C alkyl group. and a C6-C ?4 aryl group, v) and Zi and Z2 are hydrogen or a protecting group of
amine, and the addition salts thereof with pharmaceutically acceptable acids. A specific group of the compounds of the formula (I) are represented by the compounds of the
formula (la):
Formulate the
wherein: i) either Ri is selected from: - C1-C4 alkyl groups, C3-C13 mono- or bicyclic cycloalkyl, C-C4 alkenyl or C2-C4 alkynyl, these groups are optionally substituted with selected groups from halogens and the hydroxyl group; C 1 -C 14 aryl groups mono-, bi- or tricyclic, - heteroaryl groups selected from pyridinyl, thienyl, furanyl, quinolyl, benzodioxanyl, benzodioxolyl, benzothienyl, benzofuranyl and pyrazinyl groups; - alkyl pheni lo groups (C? -C4) and alkylnaphthyl (C? -C4) optionally substituted on the aryl nucleus, aryl and heteroaryl groups
'-? "-" A ^ * * - * - **** •' are substituted with one or more groups independently selected from halogens, d-C_ alkyl, trifluoromethyl, C 1 -C 4 alkylthio, alkylsulfonyl d-C 4 C, -C4 alkyloxy, nitro and groups -COOR, -CH ^ COOR or -0-CH: -COOR, R is a C -C4 alkyl group, the groups of the formula:
wherein R4 and R '4 are selected from C1-Ce alkyl and C3-C12 mono- or polycyclic cycloalkyl groups, these groups are optionally substituted with groups selected from halogens and the hydroxyl group, R' 4 possibly also is hydrogen, or alternatively R4 and R '4 together form a tetramethylene or pentamethylene group, at least these two groups themselves are possibly substituted, in particular with a C6-Ci4 aryl residue or (C1-C4) aryl (C5-C) alkyl ?4); The groups of the formula:
wherein = 1 to 4 and R5 is selected from phenyl, methoxyphenyl, indolyl, benzodioxolyl, benzodioxanyl, benzothienyl and benzofuranyl groups, and R2 is hydrogen, ii) or Rx is hydrogen and R2 is selected from the groups of the formula:
-NH-CO-Re,
R0 is selected from alkoxy groups
C? -C4, C3-C7 cycloalkoxy, benzyloxy, methoxyphenyl, dimethoxy phenyl, benzodioxolyl and benzodioxanyl, and the groups of the formula:
R7 is selected from: C1-C5 alkyl groups optionally substituted with one or more groups selected from halogen groups, hydroxyl and the trifluoromethyl group;
-cyclo-cycloalkyl groups Cs_Ci mono- or bicyclic; C6-C? 4 mono-, bi- or tricyclic aryl groups; - heteroaryl groups selected from pyridyl, thienyl, quinolyl, benzodioxanyl, benzodioxolyl and isoxazolyl groups; alkylphenyl groups (C? -C4) and alkylnaphthyl (C? -C4); 10 and the groups of the formula:
fifteen
wherein n = 1, 2 or 3; the aryl or heteroaryl groups are optionally substituted with one or more groups independently selected from halogens, alkyl dd, trifluoromethyl, C 1 -C 4 alkylthio, C 1 -C 4 alkyloxy, C 1 -C 4 alkylsulfonyl, nitro, di (C 1 - alkyl) C4) amino and groups -COOR, -CH2-COOR or -0-CH: COOR, R is a C1-C4 alkyl group, iii) R3 is selected from an
hydrogen, a C1-C4 alkyl group and an alkylphenyl group (C? -C), iv) and Zi and Z: are hydrogen or a protective amino group, and the addition salts thereof with pharmaceutically acceptable acids. A preferred group of compounds are represented by the compounds in which Rx = H and R; is a group of formula -NH-SO4-R7. The most preferred compounds are the first of this type in which R7 is a group selected from naphthyl, substituted naphthyl, biphenyl, and fentanyl groups. As examples of aryl groups, the mention may be made to phenyl, α-naphthyl, β-nephthyl, fluorenyl and biphenyl groups. The C1-C5 alkyl groups can be linear or branched. Examples which may be mentioned are methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl and pentyl groups. Cycloalkyl groups can be, for example, cyclopentyl or cyclohexyl groups. Polycyclic cycloalkyl groups can be, for example, adamantyl, norbornyl and camphoryl groups.
-. > - »..- ^ 1r? -nlfL? __? _ -k --------- t-i-ák-ui ^? The alkynyl groups can be, for example, ethynyl, propargyl and butynyl groups. The alkenyl groups can be, for example, vinyl, pentenyl and allyl groups. The alkoxy d-d groups can similarly be linear or branched. Examples which may be mentioned are methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy and tert-butoxy groups. The halogens can be selected from fluorine, chlorine, bromine and iodine. The amino protecting groups which may be mentioned are ethoxycarbonyl, benzyloxycarbonyl, p-nitrobenzyloxycarbonyl and t-butoxycarbonyl groups. The "addition salts with pharmaceutically acceptable acids" indicates the salts which give the biological properties of free bases without having an undesirable effect. These salts may be, in particular, formed with mineral acids, such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid or phosphoric acid; acidic metal salts such as disodium orthophosphate and monopotassium sulfate and organic acids. The compounds of the formula (I) can be
? üi.iín'r? p.?im 'fint? i -1 T ¡' •, »rftn,? lft - ^ r ..hm ,,, - •. ^. . ^ ^. ^. ,,.,? ^ ¿.i. * .. ^^ ..
prepared by: ai) reacting an acid of formula
Formula XX
wherein Rs and R9 are protecting groups, with an amine of formula 15
Formula. III or a- reacting an acid of formula
¡¡¡¡¡¡¡¡¡¡¡¡¡¡¡¡¡¡¡¡¡¡¡¡¡¡¡¡¡^^^^^^^^. Í ^ - ^ ..
Formula TV
wherein R8 and Rg are protective groups, with an amine of formula
Formula V
to give the compounds of formula (Ib)
* - »- - -» - »** - > "* Formula Ib
b) optionally, one group R: is converted into another group R2, c) and, optionally, the protecting groups are removed. The compounds of formula (II) can be prepared according to the following reaction scheme (when RK and RQ = Boc):
"'-1" SCHEME 1
Formula II
Addition salts are conventionally obtained by reaction of the compounds of formula (I) with a pharmaceutically acceptable acid in a suitable solvent. Conversely, the bases can be obtained from addition salts, by treatment with a strong base. The examples which follow illustrate the preparation of the compounds of formula 10 (I).
A- Preparation of the acid of formula IV
Synthesis of 4- [1 - (tert-butoxycarbonyl) -4-15-piperidinyl] -2- (2- [1- (tert-butoxycarbonyl) -4-piperidinyl] ethyl] butanoic acid (compound 3)
To the Synthesis of 4- (4-pyridinyl-2- [2- (4-pyridinyl) ethyl] buoic acid dihydrochloride Sodium (3.5 g, 0.15 mol) was added to a solution of 4-vinylpyridine (165 g, 1.49 g. mol) and diethyl malonate (120 g, 0.75 mol) in 400 ml of ethanol.The mixture was refluxed for 18 hours.The majority of the ethanol was completely evaporated and
the residue was taken up in ether (approximately 300 ml) and then washed with brine. The solvent was completely evaporated to give an oil, which was refluxed in 400 ml of 12 N hydrochloric acid for 12 hours. The resulting mixture was evaporated to dryness to give a reddish-brown oil which was recovered in approximately 1 l of isopropanol and allowed to stand at room temperature. The resulting solution was filtered, rinsed with isopropanol and acetone and dried under vacuum to give 190 g of a beige solid. Yield = 74% Melting point = 172 ° C: H-NMR (400MHz, CD3OD): d 2.1 (m, 4H), 2.5 (m, 1H), 3.0 (t, 4H), 8.0 (d, 4H), 8.7 (d, 4H).
A-2 Synthesis of 4- (4-piperidinyl) -2- [2- (4-piperidinyl) ethyl] butanoic acid dihydrochloride (compound 2)
A mixture of 4- (4-pyridinyl-2- [2- (-pyridinyl) eti 1] butanoic acid dihydrochloride (118 g,
0. 344 mol) in 1.5 1 acetic acid was hydrogenated in the presence of 10% palladium in mineral coal
(10 g) under 100 psi at 60 ° C for 24 hours. The mixture
-t J. -l, r ..,? * l », .." «,, -. ,,. «« _. ... * .....,,, ~ - .. ...........,. *._ .... TO -,-.... . .. ......... .. ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ filtered and evaporated to give an oil, which was suspended in each to give a suspension. This suspension was filtered, rinsed with ether and dried to give 126 g of a beige solid. Yield = 104% (acetic acid content) Melting point = 180 ° C: H-NMR (400MHz, CD3OD): d 1.35 (m, 8H), 1.6 (m, 6H), 2.0 (bd, 4H), 2.3 (m, 1H), 3.0 (bt, 4H), 3.4 (bd, 4H). 10 A- 3 Synthesis of 4- [1- (tert-butoxycarbonyl) -4-piperidinyl] -2- (2 - [1- (tert-butoxycarbonyl) -4-piperidinyl] eti.] Butanoic acid (compound 3)
Di-tere-butyl dicarbonate (90 g, 0.413 mol) was added, at room temperature, to a solution of 4- (4-piperidinyl) -2 - [2- (- piperidinyl) ethyl] butanoic acid dihydrochloride ( 71.5 g, 0.203 mol) in 300 ml (1.2 mol) of 4M NaOH and 300 ml of tert-butanol. The agitation is continued for 4 hours. The organic phase was separated and then washed with IN HCl and water, dried over sodium sulfate and evaporated to give the crude product. Cyclohexane was added and the mixture allowed to crystallize at about 0 ° C. The crude product is completely filtered with
, i »« ". a, H« s & a > . AJ .. ^^ f ^^ ggg ^^ cyclohexane and dried under vacuum to give 71 g as a white solid. Yield = 73% Melting point = 162 ° C XH-NMR (400MHz, CDCl 3): d 1.05 (m, 4H), 1.25 (m, 4H),
1. 35 (m, 3H), 1.45 (s, 19H), 1.6 (bd, 6H), 2.25 (m,
1H), 2.88 (bt, 4H), 4.05 (bs, 4H).
B - Preparation of the compounds of formula II
Bl Synthesis 2- [(4- [1- tert -butoxycarbonyl) -4- piperidinyl] -2- (2- [1- (tert-butoxycarbonyl) -4- piperidinyl] ethyl} butanoyl) amino] acetic acid (compound 4)
2, 4,6-Tri-fluoro-1,3,3-triazine (3.6 g, 26.7 mmol) was added at room temperature to a solution of 4- [1- (tert-butoxycarbonyl) -4-piperidini 1 ] -2- . { 2- [1- (tert-butoxycarbonyl) -4-piperidinyl] ethyl} butanoic (18.6 g, 38.6 mmol) in 150 ml of dichloromethane and pyridine (3.1 g, 39.2 mmol). After stirring for 3 hours, water was added. The organic phase was washed with water, dried over sodium sulfate and then filtered. The filtered was used directly in the next stage.
The solution was added to a mixture of methyl glycinate hydrochloride (4.9 g, 39 mmol) and diisopropylethylamine (11 g, 85.3 mmol) in 50 mL of dichloromethane. The stirring is continued at room temperature for one hour and then 1 N hydrochloric acid is added. The organic phase is washed with water, dried over sodium sulfate and evaporated to give an oil, which is directly hydrolyzed. A solution of the product obtained above in 150 ml of tetrahydrofuran, 30 ml of water and monohydrate lithium hydroxide (4.2 g, 100 ml) was stirred at room temperature for 30 minutes. The organic solvent was completely evaporated and the residue was taken up in water, acidified to pH 2 and extracted with ethyl acetate. The extracts were washed, dried over sodium sulfate and evaporated to give 18.2 g of a white solid. Performance = 88% (for the three stages). : H-NMR (400MHz, CDC13): d 0.95-1.65 (m, 36H), 2.04 (m, 1H), 2.65 (bt, 4H), 4.0 (bd, 6H), 6.39 (bs, 1H). The synthesis B-l was used for the preparation of the following compounds:
^^^ B-2 3- [(4- [1- (tert-Butoxycarbonyl) -4-piperidinyl] -2- {2- [1- (tert-butoxycarbonyl) -4-piperidinyl] ethyl} acid. butanoi 1) amino) propanoic 5 (compound 5)
Starter material: Ethyl 3-aminopropanoate hydrochloride Yield = 86% 10 B-3 3- [(4- [1- (tert-butoxycarbonyl) -4-piperidinyl] -2-. {2- 2- [1- ( tert-butoxycarbonyl) -4- piperidinyl] ethyl} utanoyl) amino] -3-methylpropanoic acid (compound 6)
Starter material: ethyl 3-aminobutanoate Yield = 49% ^ -NMR (400MHz, CDC13): d 1.03 (m, 4H), 1.15 (m, 4H), 1.25 (d, 3H), 1.35 (m, 2H) , 1.45 (s, 20H), 1.63 (bd, 6H), 1.95 (m, 1H), 2.55 (dd, 2H), 2.65 (bt, 4H), 4.0
(bs, 4H), 4.35 (m, 1H), 6.25 (d, 1H).
B-4 3- [(4- [1- (tert-Butoxycarbonyl) -4-piperidinyl] -2-. {2- [1- (tert-butoxycarbonyl) -4-piperidinyl] ethyl} butanoyl) acid amino] - 3-25 phenylpropanoic (compound 7)
Starter material: ethyl 3-amino-3-phenylpropanoate hydrochloride Yield = 68% XH-NMR (400MHz, CDC13): d 0.9-1.35 (m, LOH), 1.45 (s, 20H), 1.58 (m, 6H) , 2.00 (m, 1H), 2.60 (bq, 4H), 2.90 (dq, 2H), 4.0 (bd, 4H), 5.45 (q, 1H), 6.78 (d, 1H), 7.25 (m, 5H).
B-5 Acid (3R) -1- (4- [1- (tert-butoxycarbonyl) -4- piperidini 1] -2-. {2- 2- [1- (tert-butoxycarbonyl) -4-piperidini 1] ethyl .}. butanoyl) hexahydr0-3-pyridinecarboxylic (compound 8)
Starter material: L-tartrate (R) -nitpecotate ethyl Yield = 66%
C - Preparation of the compounds of formula Ib
C-1 Preparation of the compounds of formula Ib (R x H, R 2 = H)
1) 4-. { 3-. { [1- (1, 3-benzodioxol-5-yl) -3-ethoxy-3-oxopropyl] amino} -2-oxoethyl) amino] carbonyl} -5- [1- (tert-butoxycarbonyl) -4-piperidinyl] pentyl} tetrahydro-l- (2H) -pyridinecarboxylate (compound 9)
Isobutyl chloroformate (1.5 g, 11 mmol) was added, at room temperature, to a solution of 4- [1- (tert-butoxycarbonyl) -4-piperidinyl] -2-. { 2- [1- (tert-butoxycarbonyl) -4-piperidinyl] ethyl} butanoyl) amino] acetic (compound 4)
(5.4 g, 10 mmol) in 50 ml of ethyl acetate and N-methylmorpholine (2.2 g, 22 mmol). After stirring for 10 minutes, ethyl 3-amino-3- (1,3-benzodioxol-5-yl) propionate hydrochloride (2.8 g, 10 mmol) was added. Stirring is continued at 50 ° C for 2 hours and then 2N hydrochloric acid was added. The organic phase was washed with water, dried over sodium sulfate, evaporated and purified by flash chromatography (dichloromethane / methanol 20/1 ) to give 6.7 g of a white solid. Yield = 88% 2H-NMR (400MHz, CDCl 3): d 0.9-1.7 (m, 39H), 2.05 (m, 1H), 2.6 (bs, 4H), 2.8 (dq, 2H), 4.0 (m, 8H) , 5.3 (q,
»Ni." ^, ^, ",,". * »,«, ,, - r¿. _ ,, ... ,, .., .._..... .. ^ ,, jμ., ^. *, - ^ ... . * ...., _., .. J. ^^ ", ...»,. £. ^ _ ^ ^ 1H), 6.55 (t, 1H), 6.75 (m, 3H), 7.55 (d, 1H).
The method described above was used to prepare the following compounds: 5 2) 4- (5- [1- (tert-butoxycarbonyl) -4-piperidinyl] -3-. {[[(2- {[3-ethoxy] -l- (4-isopropylphenyl) -3-oxopropyl] amino.} -2-oxoethyl) amino] carbonyl} pentyl) tetrahydro-l (2H) -10-tert-butyl pyridinecarboxylate (compound 10)
Starter material: ethyl 3-amino-3- (4-isopropyl-phenyl) propionate hydrochloride Yield = 82% XH-NMR (400MHz, CDC13): d 0.9-1.7 (m, 45H), 2.05 (m, 1H) , 2.6 (bs, 4H) 2.8 (m, 3H), 4.0 (m, 8H), 5.4 (q, 1H), 6.5 (t, 1H), 7.15 (d, 2H), 7.2 (d, 2H), 7.45 (d, 1H).
3) 4- (5- [1- (tert-butoxycarbonyl) -4-piperidinyl] -3-. {[[(2- {[[3-ethoxy-1- (4-methoxy phenyl) -3- oxopropyl] amino.} -2-oxoethyl) amino] carbonyl} pentyl) tetrahydro-1 (2H) -pyridinecarboxylic acid tert-butyl ester (compound 11)
MY * 4 1 * 1tHí ~ * - < * > - * l MffH- HUrt-tra-i--, -f < - - - --.-.-.-. ~ ^. ~. - ..,. .. ^ & ^ ..,.? ^. y, ^ Initiating material: ethyl 3-amino-3- (4-methoxyphenyl) -propionate hydrochloride Yield = 59% XH-NMR (400MHz, CDC13): d 0.9-1.7 (m, 39H), 2.05 (m, 1H), 2.6 (bs, 4H), 2.8 (dq, 2H), 3.75 (s, 3H), 4.0 (m, 8H), 5.38 (q, 1H), 6.55 (t, 1H) ), 6.85 (d, 2H), 7.2 (d, 2H), 7.45 (d, 1H).
4) 4- (5- [1- (tert-butoxycarbonyl) -4-piperidinyl] -3-. {[[(2- {[[3-ethoxy-1- (3,4-dimethoxyphenyl) -3} - oxopropyl] amino.} -2- oxoethyl) amino] carbonyl} pentyl) tetrahydro-1 (2H) -pyridinecarboxylic acid tert -butyl ester (compound 12) Starting material: 3-amino-3-hydrochloride (3, 4 ethyl dimethoxyphenyl) propionate yield = 82%
4- [5- [1- (tert-butoxycarbonyl) -4-piperidinyl] -3- ( { [2- ( { 3-ethoxy-l- [3- (2-ethoxy-2-oxoethyl) ) phenyl] -3-oxopropyl.} amino) -2-oxoethyl] amino.} carbonyl) pentyl] tetrahydro-1 (2H) -pyridinecarboxylate (compound 13)
jj ^^. "ü * - * '* - ^^^ ¡¡¡¡¡¡¡¡¡¡¡¡¡¡¡¡¡¡¡¡¡¡¡¡¡¡¡¡¡¡¡¡¡¡¡¡¡Initiating material: hydrochloride 3-amino-3- (3- (2-ethoxy-2-oxoethoxy) ethyl phenyl) propion Yield = 61%: H-NMR (400MHz, CDC13): d 0.9-1.7 (m, 42H), 2.05 (m, 1H), 2.6 (bs, 4H), 2.8 (dq, 2H) , 4.0 (m, 8H), 4.28 (q, 2H), 4.6 (s, 2H), 5.4 (q, 1H), 6.5 (t, 1H), 6.8 (dd, 1H), 6.9 (m, 2H), 7.2 (d, 1H), 7.45 (d, 1H).
6) 4- (5- [1- (tert-butoxycarbonyl) -4-piperidinyl] -3-. {[[(2 - ([3-ethoxy-1- (3-methoxyphenyl) -1-3- oxopropyl] amino.} -2-oxoethyl) amino] carbonyl. pentyl) tetrahydro-l (2H) -pipdmcarboxylate (compound 14)
Starter material: ethyl 3-amino-3- (3-methoxy-pheny1) propionate hydrochloride Yield = 78% "H-NMR (400MHz, CDC13): d 0.9-1-7 (m, 39H), 2.05 (m, 1H), 2.6 (bs, 4H), 2.83 (dq, 2H), 3.8 (s, 3H), 4.0
(m, 8H), 5.4 (q, 1H), 6.5 (t, 1H), 6.8 (dd, 1H), 6.85
(m, 2H), 7.2 (t, 1H), 7.45 (d, 1H).
t ^ & 7) 4-. { 3-. { [1- (2, 3-dihydro-1,4-benzodioxin-6-yl) -3-ethoxy-3-oxopropyl] amino} -2- oxoethyl) amino] carbonyl} -5- [1- (tert-butoxycarbonyl) -4-piperidyl] pentyl} Tetrahydro-1 (2H) -pyridinecarboxylate tert-butyl ester (compound 15)
Starter material: ethyl 3-amino-3- (2, 3-dihydro-1,4-benzodioxin-6-yl) propionate hydrochloride Yield = 83% XH-NMR (400MHz, CDCl 3): d 0.9-1.7 (m, 39H), 2.05 (m, 1H), 2.65 (bs, 4H), 2.8 (dq, 2H), 4.0 (m, 8H), 4.25 (s, 4H), 5.3 (m, 1H), 6.55 (t, 1H) ), 6.79 (s, 1H), 6.81 (d, 2H) 7.5 (d, 1H).
8) 4- (5- [1- (tere-butoxycarbonyl) -4-piperidinyl] -3-. {[[(2- {[[3-ethoxy-1- (3-pyridinyl) -3-oxopropyl]] amino.} -2-oxoethyl) amino] carbonyl, pent? l) tetrahydro-l (2H) -pyridinecarboxylic acid tert-butyl ester (compound 16)
Initiating material: ethyl 3-amino-3- (3-pyridyl-1) -propionate hydrochloride Yield = 69%
9) 4- (5- [1- (tert-butoxycarbonyl) -4-piperidinyl] -3-. {[[(2- {[[3-ethoxy-3-oxopropyl] amino} -2-oxoethyl ) amino] carbonyl) tetrahydro-1 (2H) -5-pyridinecarboxylic acid tert-butyl ester (compound 17)
Starter material: ethyl 3-aminopropionate hydrochloride Yield = 69% 10: H-NMR (400MHz, CDC13): d 1.05 (m, 4H), 1.2 (m, 4H), 1.25 (t, 3H), 1.3 (m, 2H), 1.4 (s, 20H), 1.6 (m, 6H), 2.05 (m , 1H), 2.5 (t, 2H), 2.6 (bt, 4H), 3.5 (q, 2H), 3.9 (d, 2H), 4.0 (bs, 4H), 4.15 (q, 2H), 6.4 (bt, 1H), 6.65 (bt, 1H). 15 10) 4- (5- [1- (tert-butoxycarbonyl) -4-piperidinyl] -3-. {[[(2- {[[3-ethoxy-l-methyl-3-oxopropyl] amino]} -2- oxoethyl) amino] carbonyl.} Penti 1) tetrahydro-1 (2H) -pyridinecarboxylic acid tert-butyl ester (compound 18) Starting material: ethyl 3-aminobutanoate hydrochloride Yield = 70% ^ - MR (400MHz , CDC13): d 1.0 (m, 4H), 1.1-1.35 (, 25 13H), 1.4 (s, 19H), 1.55 (m, 6H), 2.05 (m, 1H), 2.5
"ifífflÉfif ^ - - '^^ -" "' • *" * "* > '' • **" "»: »«. »« *. ...... f ^ .... > ", .... * ..., ..., ...,.",, ^. ^ .J .. ».; ^. Al ..? AÍ, ...?, A ~ (m, 2H ), 2.6 (bt, 4H), 3.85 (m, 2H), 4.0 (bs, 4H), 4.1 (q, 2H), 4.3 (m, 1H), 6.4 (t, 1H), 6.75 (d, 1H) .
11) 4- (5- [1- (tert-butoxycarbonyl) -4-pLperidinyl] -3- 5. {[[(2- {[[3-ethoxy-3-oxo-l-phenethylpropyl] amino]} -2-oxoethyl) amino] carbonyl} pentyl) tetrahydro-1 (2H) -pyridinecarboxylate tert -butyl ester (compound 19)
Starter material: ethyl 3-amino-5-10 phenylpentanoate hydrochloride Yield = 27% XH-NMR (400MHz, CDC13): d 1.0 (m, 4H), 1.1-1.3 (m, 10H), 1.4 (s, 19H) 1.55 (m, 6H); 1.85 (m, 2H), 2.0 (m, 1H), 2.5 (d, 2H), 2.6 (m, 6H), 3.85 (d, 2H), 4.0
) bs, 4H), 4.1 (q, 2H), 4.25 (m, 1H), 6.25 (t, 1H), 6.6 (d, 1H), 7.1 (m, 3H), 7.2 (t, 2H).
12) Synthesis of 4-. { 3- ( { [2- ( { 1- [(1- adamantyl amino) carbonyl] - (SS) -3-benzyloxy-3-oxo-propyl] -α-ene) -2-oxo-ethyl] -inolcarbonyl ) -5- [1- (tert-butoxycarbonyl) -4-piperidinyl] pentyl} tetrahydro-l (2H) -piper idincarboxy tert-butyl alcohol (compound 20)
Isobutyl chloroformate (1.7 g,
"* * '* - -'- - • -' ^ g ^ É-iínn?," M ^ j ^ j_MtatM »í = fa 12.4 mmol), at room temperature, to a solution of 2- [(4 - [1- (tert-butoxycarbonyl) -4-piperidinyl] -2- {2- [1-tert-butoxycarbonyl) -4-piperidinyl] ethyl} butanoyl) amino] acetic acid (compound 4) 5 (6.9 g, 11 mmol) in 150 ml of ethyl acetate and N-methylmorpholine (5 g, 49.5 mmol) A white solution is obtained.After stirring for 10 minutes, a solution of trifluoroacetate (3S) -3-amino is added. - 4- (1-adamantylamino) -4-oxobutanoate benzyl (6.9
g, 11.2 mmol) in 20 ml of ethyl acetate. Stirring is continued at room temperature for 18 hours. 2N hydrochloric acid is added. The organic phase is washed with water, dried over sodium sulphate and evaporated to give the crude product,
Which is purified by flash chromatography (dichloromethane / methanol 20/1) to give 6.6 g of a beige-colored solid. Performance = 68% The method described above is used to
Prepare the following compounds:
13) 4-. { 3- ( { [2- ( { L - ([2- (lH-indol-4-yl) ethyl] amino] carbonyl] - (SS) -3-benzyloxy-3-oxopropyl} amino ) -2-oxoethyl] amino.} Carbonyl) -5- [1- (tert-butoxycarbonyl) -4,5-piperidinyl] pentyl} tetrahydro-l (2H) -pyridinecarboxylic acid tert -butyl ester (compound 21)
Starter material: trifluoroacetate (3S) -3-amino-4- [2- (1H-indol-4-yl) ethylamino] -4-oxobuty anolate of 10-benzyl Yield = 49% XH-NMR (400MHz, CDC13): d 1.05 (m, 4H), 1.25 (m, 6H), 1.45 (s, 20H), 1.6 (m, 6H), 2.05 (m, 1H), 2.65 (m, 5H), 2.95 (m, 3H), 3.55 (m, 2H), 3.78 (dq, 2H), 4.05 15 (bs, 4H), 4.8 (m, 1H), 5.05 (s, 2H), 6.3 (t, 1H), 6.8 (t, 1H), 7.0 (d, 1H), 7.1 (t, 1H), 7.2 (m, 2H), 7.35 (m, 6H), 7.6 (d, 1H), 8.2 (s, 1H).
14) 4-. { 3- ( { [2- ( { L- [ { (4-methoxyphenethyl) amino} carbonyl] -20 (SS) -3-benzyloxy-3-oxo-propyl} -amino) -2 oxoet il] amino Jcarbonyl) -5- [1- (tert-butoxycarbonyl) -4-piperidyl] pentyl} tetrahydro-1 (2H) -pyridinecarboxylate tert -butyl ester (compound 22) 25
- .. ¿«« tüwfejato ». . - * t.-a. * ». . ".to"". . ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ Initiating material: trifluoroacetate (3S) -3-amino-4-f (4-methoxyphenethyl) amino] -4 -oxobutanoato benzyl Yield = 59% 2H-NMR (400MHz, CDC13): d 1.05 (m, 4H), 1.25 (m, 6H), 1.45 (s, 20H), 1.6 (m, 6H), 2.05 (m, 1H), 2.65 (m, 7H), 3.05 (dd, 1H), 3.4 (m, 2H), 3.75 (s, 3H), 3.85 (d, 2H), 4.05 (bs, 4H), 4.78 (m, 1H) ), 5.1 (s, 2H), 6.4 (t, 1H), 6.8 (m, 3H), 7.1 (d, 2H), 7.2 (d, 1H), 7.4 (m, 5H). 10 15) 4-. { 3- ( { [2- ( { L- [ { (3-phenylpropyl) amino} carbonyl] - (SS) -3-benzyloxy-3-oxopropyl} amino) -2- oxoethyl] amino.} carbonyl) -5- [1- (tert-butoxycarbonyl) -4-piperidinyl] -pentyl} tetrahydro-15 1 (2H) -pyridinecarboxylate tert -butyl ester (compound 23)
Starter matrix: trifluoroacetate (3S) -3-amino-4- [(3-phenylpropyl) amino] -4-oxobutanoate benzyl 20 Yield = 79%
16) 4-. { 3- ( { [2- ( { L- [ { (L, 3-benzodioxol-5-ylmethyl) amino} carbonyl] - (SS) -3-benzyl? Xi-3-oxopropyl .}. amino) -2-oxoethyl] mino} carbonyl) -5- [1- (tert-butoxycarbonyl) -4,5-piperidinyl] pentyl} tetrahydro-l (2H) -pyridinecarboxylate tert -butyl ester (compound 24)
Starter material: trifluoroacetate (3S) -3-amino-4- [(1, 3-benzodioxol-5-yl-yl-yl) amino] -4-oxobutyl-benzoic anolate Yield = 54%
17) 4-. { 3- ( { [2- ( { L- [ { (3- methoxy phenethyl) amino.}. Cerbonyl] - (SS) -3-benzyloxy-15-oxopropyl} amino) - 2-oxoethyl] amino.} Carbonyl) -5- [1- (tert-butoxycarbonyl) -4-piperidinyl] pentyl} tetrahydro-l (2H) -pyridinecarboxylate tert -butyl ester (compound 25)
Starter material: trifluoroacetate (3S) -3-amino-4- [(3-methoxy-phenethi-1) amino] -4-oxobutanoate of benzyl Yield = 65% XH-NMR (400MHz, CDC13): d 0.95-1.25 (m , 7H), 1.25-1.5 (m, 23H), 1.6 (m, 6H), 2.05 (m, 1H), 2.65 (m, 4H),
2.75 (t, 2H), 3.05 (dd, 1H), 3.45 (q, 2H), 3.8 (s,
3H), 3.85 (d, 2H), 4.05 (bs, 4H), 4.78 (m, 1H), 5.1 (s, 2H), 6.48 (t, 1H), 6.75 (m, 3H), 6.9 (t, 1H) ), 7.4 (m, 6H).
4-. { 3- ( { [2- ( { 1- [ { (2-Hydroxy-1, 1-dimethyl-ethyl) amino} carbonyl] - (SS) -3-benzyloxy-3-oxopropyl} amino) -2-oxoethyl] amino.} carbonyl) -5- [1- (tert-butoxycarbonyl) -4-piperidyl] pentyl} tetrahydro-l (2H) -10 pyridinecarboxylic acid tert-butyl ester (compound 26)
Starter material: trifluoroacetate (35) -3-amino-4- [(2-hydroxy-1, 1-dimethyl-yl-yl) amino] -4-oxobutanoate benzyl = yield = 34% XH-NMR (400MHz, CDC13) : d 1.05 (m, 5H), 1.15-1.35 (m, 12H), 1.45 (s, 20H), 1.65 (m, 7H), 2.1 (m, 1H), 2.62 (m, 6H), 3.08 (dd, 1H), 3.5 (q, 2H), 3.8 (dd, 2H), 4.0 (bs, 4H), 4.8 (m, 1H), 5.1 (s, 2H), 6.8 (s, 1H), 20 6.9 (t, 1H), 7.8 (m, 6H).
Uá-tfi-i-M-l-M-ak- -d - ?? UÉ --- U ^ ¿? J É ^ ßmií 19) 4-. { 3- ( { [2- ( { L- [ { (L-isopropyl-2-methylpropyl) amino} carbonyl] - (SS) -3-benzyloxy-3-oxopropyl} amino ) -2-oxoethyl] amino.} Carbonyl) -5- [1- (tert-butoxycarbonyl) -4,5-piperidyl] pentyl} tetrahydro-l (2H) -pyridinecarboxylate tert -butyl ester (compound 27)
Starter material: trifluoroacetate (3S) -3-amino-4- [(l-isopropyl-2-methylpropyl) amino] -4-oxobutanoate
benzyl Performance = 59%: H-NMR (400MHz, CDC13): d 0.9 (m, 9H), 1.0-1.35 (m, 11H), 1.4 (s, 20H), 1.6 (bs, 6H), 1.79 (m , 2H), 2.05 (m, 1H), 2.65 (m, 6H), 3.1 (dd, 1H), 3.55 (m, 1H),
3.9 (d, 2H), 4.05 (bs, 5H), 4.82 (m, 1H), 5.15 (dd, 2H), 6.3 (t, 1H), 6.45 (d, 1H), 7.3 (m, 6H).
) 4-. { 3- ( { [2- ( { (LS) -3- (benzyloxy? -3-oxo-l- [(4-benzylpiperidine) carbonyl] -propyl.} Amino) -2- 20 oxoethyl] in.) carbonyl) -5- [1- (tert-butoxycarbonyl) -4-piperidyl] pentyl} - tetrahydro-1 (2H) -pyridinecarboxylate tert -butyl ester (compound 28)
Starter material: benzyl trifluoroacetate (3S) -3-amino-4-oxo-4- (4-benzylpiperidin) butanoate Yield = 55%
C-2 Preparation of the compounds of formula Ib (Rx = H, R2? H)
1) Synthesis of 4- [(IOS) -3-. { 2- [1- (tert-butoxycarbonyl) -4-piperidinyl] ethyl} -10- (ethoxycarbonyl) -4,7-, 12-trioxo-14-phenyl-1, 13-oxa-5,8,1-triazatetradec-1-yl] tetrahydro-1 (2R) -pyridinecarboxylic acid tert-butyl ester (compound 29)
Isobutyl chloroformate (13 g,
95. 2 mmol), at room temperature, to a solution of 2- [(4- [1- (tert-butoxycarbonyl) -4-piperidinyl] -2-. {2- 2- (tert-butoxycarbonyl) -4 -piperidini 1] ethyl Jbutanol) amino] acetic acid (compound 4) (46 g, 85.2 mmol) in 550 ml of ethyl acetate and N-methylmorpholine (19 g, 188 mmol), and a suspension is obtained. After stirring for 20 minutes, hydrochloride (2S) -3-amino-2- is added. { [(benzyloxy) carbonyl] amino} ethyl propanoate (26.3 g, 86.9 mmol). Agitation is continued for 18 hours
i tí * »». «.« «- -.« M *. . . »». «- > , -.:t, ... wtil .A.Ái.8 ». . - .. ¡^ t ...,.,, «. - a l .j. The reaction medium is then washed with water, with 1 N hydrochloric acid and with water and then dried over sodium sulfate and evaporated to give the crude product, which is purified by flash chromatography (dichloromethane / methanol 20/1) to give 61 g of a white solid. Yield = 91% XH-NMR (400MHz, CDC13): d 1.0 (m, 4H), 1.15 (m, 4H),
1.25 (m, 5H), 1.4 (s, 20H), 1.65 (m, 6H), 2.0 (m, 1H), 2.62 (bt, 4H), 3.62 (bs, 2H), 3.85 (m, 2H), 4.05 (bs, 4H), 4.2 (bt, 2H), 4.4 (m, 1H), 5.08 (s, 2H), 5.95 (d, 1H), 6.4 (bs, 1H), 6.9 (bs, 1H), 7.4 (bs, 5H). The method described above is used to prepare the following compounds:
4- [5- [1- (tert-butoxycarbonyl) -4-piperidinyl] -3- ( { [2- ( { 2- [(cyclohexylsulfonyl) amino] -3-methoxy-3-oxopropyl} amino) -2-oxoethyl] amino} carbonyl) pentyl] tetrahydro-1 (2H) -pyridinecarboxylate tert -butyl ester (compound 30)
Starter material: methyl 3-amino-2- [(cyclohexylsulfonyl) amino] propanoate Yield = 81% XH-NMR (400MHz, CDC13): d 1.05 (m, 4H), 1.1-1.5 (m, 31H), 1.6 (m, 6H), 1.7 (bd, 1H), 1.85 (bd, 2H), 2.05 (m, 1H), 2.2 (bt, 2H), 2.60 (bt, 4H), 2.85 (m, 1H), 3.55 ( m, 1H), 3.7 (m, 1H), 3.80 (s, 3H), 3.95 (m, 2H), 4.05 (bs, 4H), 4.2 (m, 1H), 5.7 (d, 1H), 6.55 (t , 1H), 6.95 (t, 1H). 10 4- [5- [1- (tert-butoxycarbonyl) -4 -piperidinyl] -3- ( { [2- ( { 2- [(isopropylsulfonyl) amino] -3-ethoxy-3-oxopropyl} amino) -2-oxoethyl] amino} carbonyl) pentyl] tetrahydro-1 (2H) -15 pyridinecarboxylate tert-butyl (compound 31)
Starter material: trifluoroacetate 3-amino-2- [(isopropylsulphon 1) ammo] ethyl propanoate Yield = 60% 20 ^ -NMR (400MHz, CDC13): d 1.05 (m, 4H), 1.2 (m, 4H) , 1.3 (t, 3H), 1.35 (dd, 6H), 1.45 (s, 21H), 1.6 (m, 6H), 2.05 (m, 1H), 2.65 (bt, 4H), 3.15 (m, 1H), 3.55 (m, 1H), 3.75 (m, 1H), 3.95 (t, 2H), 4.05 (bs, 4H), 4.20 (m, 1H), 4.25 (q, 2H), 5.6 (d, 1H), 6.45 (t,
1H), 6.85 (t, 1H).
4-. { 3- ( { [2- ( {2 - [(1, 3-benzothiazol-2-ylsulfonyl) amino] -3-ethoxy-3-oxopropyl}. Amino) -2-oxoethyl] amino} carbonyl) -5- [1- (tert-butoxycarbonyl) -4-piperidinyl] pentyl} Tetrahydro-1 (2H) -pyridinecarboxylate tert -butyl ester (compound 32)
Starter material: ethyl 3-amino-2- [(1, 3-benzothiazol-2-ylsulfonyl) amino] propanoate hydrochloride Yield = 43% XH-NMR (400MHz, CDC13): d 1.05 (m, 4H), 1.15 ( t, 3H), 1.20 (m, 4H), 1.3 (m, 2H), 1.45 (s, 20H), 1.60 (m, 6H), 2.10 (m, 1H), 2.65 (bt, 4H), 3.70 (m , 1H), 3.80 (m, 1H), 3.95 (d, 2H), 4.05 (m, 6H), 4.55 (dd, 1H), 6.50 (t, 1H), 6.85 (bs, 1H), 7.10 (t, 1H), 7.55 (m, 2H), 7.95 (dd, 1H), 8.10 (dd, 1H).
4- [(HS) -3-. { 2- [1- (tert-butoxycarbonyl) -4-piperidinyl] ethyl} -11- (ethoxycarbonyl) -4,8,8-trioxo-15-phenyl-14 oxa-5, 9, 12-triazapentadec-l-yl] tetrahydro-l (2H) -p? Ridincarboxy lato tert-butyl (compound 33)
Initiating material: compound 5 and hydrochloride (2S) -3-amino-2-. { [(benzyloxy) carbonyl] am not} ethyl propanoate Yield = 65% 5 1H-NMR (400MHz, CDC13): d 1.0 (m, 4H), 1.15 (m, 4H), 1.25 (t, 5H), 1.4 (s, 20H), 1.55 (m, 6H), 1.9 (m, 1H), 2.3 (bt, 2H), 2.60 (bq, 4H), 3.4 (m, 2H), 3.6 (t, 2H), 4.0 (bs, 4H), 4.2 (q, 2H) ), 4.4 (m, 1H), 5.05 (s, 2H), 5.95 (d, 1H), 6.4 (t, 1H), 6.55 (t, 1H), 7.3 10 (s, 5H).
6) 4- [5- [1- (tert-butoxycarbonyl) -4-piperidinyl] -3- ( { [3- ( { 3-ethoxy-2- [(2-naphthylsulfonyl) amino] -3 - oxopropyl.}. amino) -1-met il-3-oxopropyl] amino.} carbonyl) pentyl] tetrahydro-1 (2H) -pyridinecarboxylate tert -butyl ester (compound 34)
Starter materials: the compuetos 6 and hydrochloride (2S) -3-amino-2- [(naphthylsul fonyl) amino] propanoate of
Ethyl Yield = 75% XH-NMR (400MHz, CDC13): d 0.9 (t, 3H), 1.05 (m, 3H), 1.20 (m, 8H), 1.30 (m, 2H), 1.45 (s, 20H) , 1.60 (m, 6H), 1.95 (m, 1H), 2.40 (dq, 2H), 2.65 (bt, 4H), 3.50
(m, 1H), 3.65 (m, 1H), 3.85 (m, 2H), 4.05 (m, 5H),
.Yntt mm? ? & to, -*? < ! M, «^^».,. , ».... ,,. . - ^ .... . ^ ..i,., ... ...,. ÜÉMUafal ^^ 4.30 (m, 1H), 6.05 (d, 1H), 6.65 (m, 2H), 7.65 (m, 2H), 7.80 (d, 1H), 7.90 (d, 1H), 8.00 (d, 2H) ), 8.40 (s, 1H).
7) 4- [5- [1-tert-butoxycarbonyl) -4-piperidini 1] -3- ( { [3- ( { 3-ethoxy-2- [(2-naphthylsulfonyl) amino] -3 - oxopropyl.}. amino) -3-oxo-phenylpropyl] amino.} carbonyl) pentyl] tetrahydro-1 (2H) -pyridinecarboxylate tert -butyl ester (compound 35).
Starter materials: compound 7 and hydrochloride (2S) -3-amino-2- [(2-naphthylsul fonyl) ami] ethyl propanoate Yield = 77% ^ -NMR (400MHz, CDC13): d 0.95 (t, 3H ), 1.00 (m, 4H), 1.10 (m, 4H), 1.30 (m, 2H), 1.45 (s, 20H), 1.60 (m, 6H), 2.05 (m, 1H), 2.65 (bd, 4H) , 2.70 (m, 2H), 3.40 (m, 1H), 3.60 (m, 1H), 3.80 (m, 2H), 4.00 (m, 6H), 5.40 (m, 1H), 5.85 (d, 1H), 6.40 (m, 1H), 7.25 (m, 5H), 7.65 (m, 2H), 7.76 (m, 1H), 7.90 (d, 1H), 7.95 (m, 2H), 8.40 (d, 1H).
4- [5- [1- (tert-butoxiac rbonyl) -4-piperidinyl] -3-. { [(3R) -3- [( { 3-ethoxy-2- [(2-naphthi-sulphonyl) amino] -3-oxopropyl] -amino) carbonyl] tetrahydro-1 (2H) -pyridinyl] carbonyl } entyl) tert-butyl tetrahydro-1 (2H) -pyridinecarboxylate (compound 36)
Starter materials: compound 8 and ethyl (2S) -3-amino-2- [(2-naphthylsul fonyl) amino] propanoate hydrochloride (10) Yield = 67%
Synthesis of hydrochloride 4 -. { 3- . { [(2- {[(2S) -2-amino-3-ethoxy-3-oxopropyl] amino} -2-oxoethyl) amino] carbonyl} -5- [1- (tert-15-butoxycarbonyl) -4-piperidinyl] pentyl} tetrahydro-1 (2H) -pyridmethylcarboxylate tert -butyl (compound 37)
A mixture of 4- [(1 OS) -3-. { 2- [1- (tert-20-butyclocarbonyl) -4-piperidyl] ethyl) -10- (ethoxycarbonyl) -4,4,7-trioxo-14-phenyl-13-oxa-5,8,11-triazatetradec -l-yl] tetrahydro-l (2H) -pyridinecarboxylic acid tert-butyl ester (compound 29) (60 g, 76.1 mmol), 10% palladium in mineral carbon (5 g) in 400 ml of ethanol and 77 was hydrogenated 77 ml of 1 N hydrochloric ethanol
room temperature under about 25 psi for 30 minutes. The resulting mixture was filtered and evaporated to give 52 g of a beige solid. Yield = 99% XH-NMR (400MHz, CDC13): d 1.0 (m, 4H), 1.18 (m, 4H), 1.27 (t, 5H), 1.42 (s, 20H), 1.58 (m, 6H), 2.0 (m, 1H), 2.6 (bt, 4H), 3.35 (m, 1H), 3.55 (m, 1H), 3.68 (m, 1H), 3.9 (d, 2H), 4.02 (bs, 4H), 4.18 ( q, 2H), 6.38 (bt, 1H), 6.72 (bt, 1H).
The method described above is used to prepare the following compounds:
) Synthesis of. { 3- . { [(3- {[(2S) -2-amino-3-ethoxy-3-oxopropyl] amino} -3-oxopropyl) amino] carbonyl} -5- [1- (tert-butoxycarbonyl) -4-piperidinyl] pentyl} tetrahydro-l (2H) -pyridinecarboxylate tert -butyl ester (compound 38)
Initiating material: compound 33 Yield = 97%
* '"" -'- 11) Synthesis of 4- [5- [1- (tert-butoxycarbonyl) -4-piperidinyl] -3- ( { [2- ( { (2S) -3-ethoxy - 3 -oxo-2- [(phenylsulfonyl) amino] propyl.] Amino) -2-oxoethyl] amino.} Carbonyl) pentyl] tetrahydro-1 (2H) -pyridinecarboxylate tert -butyl ester (compound 39)
It was dissolved 4-. { 3-. { [(2-. {[[(2S) -2-amino-3-ethoxy-3-oxopropyl] amin.} -2-oxoethyl) amino] carbonyl} -5- [1- (tert-butoxycarbonyl) -4-piperidyl] pentyl} tetrahydro-1 (2H) -pyridinecarboxylate tert -butyl ester (compound 37) (3.31 g, 4.8 mmol) in 50 ml dichloromethane containing triethylamine (1.04 g, 5 mmol) and then benzensulfonyl chloride (0.9 g, 5 mmol) is added at about 5 ° C. After 2 hours at room temperature, water was added. The organic phase was washed with 1 N HCl and then with water, dried over sodium sulfate and then evaporated to give the crude product, which was purified by flash chromatography (dichloromethane / methanol 15/1) to give 2.8 g of a white solid. Yield = 74% XH-NMR (400MHz, CDC1): d 1.05 (m, 7H), 1.25 (m, 6H), 1.45 (s, 20H), 1.6 (m, 6H), 2.08 (, 1H), 2.6 ( bs, 4H), 3.5 (m, 1H), 3.67 (m, 1H), 4.0 (m, 9H), 6.28 (t, 1H), 6.62 (t, 1H), 7.1 (t, 1H), 7.5 (m , 3H), 7.82 (d,
m t ^^? ^^ ^ ^^^ ^^ í? ^ ^ i ^^ ^ ^^^ ^^^ táí ^^^^^^^^^^^ 2H). The method described above is used to prepare the following compounds:
12) 4- [5- [1- (tert-butoxycarbonyl) -4-piperidinyl] -3- ( { [2- ( { (2S) -3-ethoxy-3-oxo-2- [( 1,3-benzodioxol-5-ylc-rbonyl) amino] propyl.} Amino) -2-oxoethyl] amino.} Carbonyl) pentyl] tetrahydro-l (2H) -pyridinecarboxylate tert-butyl ester (compound 40) 10 Initiating material : piperonyl chloride acid yield = 74%
13) 4- [5- [1- (tert-butoxycarbonyl) -4-piperidyl] -3-15 ([[2- ( { (2S) -3-ethoxy-3-oxo-2 - [(2 - naphthylsulfonyl) amino] propyl.} amino) -2-oxoethyl] amino.}. cerbonyl) pentyl] tetra idro-l (2H) -pyridinecarboxylic acid tert -butyl ester (compound 41)
Starter material: 2-naft ilsufoni chloride yield = 74% XH-NMR (400MHz, CDC13): d 0.95 (t, 3H), 1.05 (m, 4H), 1.2 (m, 4H), 1.35 (m, 2H ), 1.45 (s, 20H), 1.6 (m, 6H), 2.1 (m, 1H), 2.63 (bt, 4H), 3.55 (m, 1H), 3.7
(m, lH), 3.9 (q, 2H), 4.0 (m, 7H), 6.3 (bs, 1H), 6.55
(t, 1H), 7.05 (t, 1H), 7.65 (m, 2H), 7.8 (d, 1H), 7.9 (d, 1H), 7.95 (d, 2H), 8.4 (s, 1H).
14) 4- [5- [1- (tert-butoxycarbonyl) -4-piperidyl] -3- 5 ( { [2- ( { (2S) -3-ethoxy-3-oxo-2- [ (4-propylphenylsul fonyl) amino] propyl.} Amy no) -2-oxoethyl] amino.} Carbonyl) pentyl] tetrahydro-l (2H) -pyridinecarboxylate tert -butyl ester (compound 42)
Starter material: 4-propylphenylsulfonyl chloride Yield = 78% XH-NMR (400MHz, CDC13): d 0.95 (t, 3H), 1.05-1.4 (, 15H), 1.5 (s, 18H), 1.65 (m, 8H) ), 2.15 (m, 1H), 2.65 (bt, 6H), 3.45 (m, 1H), 3.8 (m, 1H), 4.0 (m, 9H), 6.0 15 (d, 1H), 6.55 (t, 1H) ), 6.9 (t, 1H), 7.35 (d, 2H), 7.75 (d, 2H).
) 4- [5- [1- (tert-butoxycarbonyl) -4-piperidyl] -3-20 ( { [2- ( { (2S) -3-ethoxy-3-oxo- 2- [ ((1,1 '-bifeni 1) -4-ylsulfonyl) amino] propyl} amino) -2-oxoethyl] amino.} Carbonyl) pentyl] terahydro-l (2H) -pyridinecarboxylate tert -butyl ester (compound 43) )
ÉtMai &ai-it-tti'jfH T pr mt. «? .nt. »- *, ... ¥ > «..», ". . * -..... ^ JUE *. , .. .. .., ... ... .. ........ ^ ..- J .. ».. ^» a ... ..- * ". . ^. ...,. ".," ... s _. . ... ^. , ^ ^ mYjn ^ j Starter material: 4-bi phenylsulphyl chloride yield = 81% XH-NMR (400MHz, CDC13): d 1.05 (, 7H), 1.15 (m, 4H), 1.35 (m, 2H), 1.4 (s, 20H), 1.55 (m, 6H), 2.05 (m, 1H), 2.6 (bt, 4H), 3.5 (m, 1H), 3.65 (m, 1H), 3.85-4.1 (m, 9H), 6.25 (bs, 1H), 6.6 (bt, 1H), 7.05 (bt, 1H), 7.4 (m, 3H), 7.55 (d, 2H), 7.65 (d, 2H), 7.85 (d, 2H).
16) 4- [5- [1- (tert-butoxycarbonyl) -4-piperidyl] -3- ( { [2- ( { (2S) -3-ethoxy -3-OXO-2- [( 1- naphthylsulfonyl) amino] propyl.} Amino) -2-oxoethyl] amino.} Carbonyl) pentyl] tetrahydro-1 (2H) -pyridinecarboxylate tert -butyl ester (compound 44)
Initiator material: 1-naft ilsul fonyl chloride Yield = 92% XH-NMR (400MHz, CDCI3): d 0.9 (t, 3H), 1.05 (, 4H), 1.2 (m, 4H), 1.3 (m, 2H), 1.45 (s, 20H), 1.6 (m, 6H), 2.05 (m, 1H), 2.6 (bt, 4H), 3.45 (m, 1H), 3.6 (, 1H), 3.75 (m, 2H), 3.8 ( m, 2H), 4.0 (, 5H), 6.3 (d, 1H), 6.4 (bt, 1H), 6.75 (bt, 1H), 7.5 (t, 1H), 7.6 (t, 1H), 7.7 (t, 1H), 7.9 (d, 1H), 8.05 (d, 1H), 8.2
: d, I H: 65 (d, 1H)
17) 4- [5- [1- (tert-butoxycarbonyl) -4-piperidyl] -3- 5 ( { [2- ( { (2S) -3-ethoxy-3-oxo-2- [ (4- (methylsulfoni 1) phenylsulfonyl) amino] propyl.}. Amino) -2-oxoethyl] amino} carbonyl) pentyl] tetrahydro-l (2H) -pyridinecarboxylate tert -butyl ester (Compound 45)
Starter material: 4- (methylsulfonyl) phenylsulfonyl chloride Yield = 80%: H-NMR (400MHz, CDC13): d 1.0 (m, 4H), 1.1 (t, 3H), 1.2 (m, 4H), 1.3 ( m, 2H), 1.4 (m, 20H), 1.6 (m, 6H), 15 2.05 (m, 1H), 2.65 (bt, 4H), 3.1 (s, 3H), 3.55 (m, 1H), 3.65 ( , 1H), 3.9 (d, 2H), 4.0 (m, 7H), 6.6 (bt, 2H), 7.05 (bt, 1H), 8.05 (dd, 4H).
18) 4- [5- [1- (tert-butoxycarbonyl) -4-piperidyl] -3-20 ( { [2- ( { (2S) -3-ethoxy-3-oxo-2- [ (2-thienylsul fonyl) amino] propyl.} Amino) -2-oxoethyl] amino.} Carbonyl) pentyl] tetrahydro-l (2H) -pyridinecarboxylate tert -butyl ester (compound 46)
Starter material: 2-thienylsulfonyl chloride Yield = 78%: H-NMR (400MHz, CDC13): d 1.0 (m, 4H), 1.15 (m, 7H), 1.3 (m, 2H), 1.4 (s, 20H), 1.6 (m, 6H), 2.05 (m, 1H), 5 2.6 (bt, 4H), 3.55 (m, 1H), 3.7 (m, 1H), 3.9 (dq, 2H), 4.05 (m, 7H), 6.25 (bs, 1H), 6.55 (bt, 1H), 6.95 (bt, 1H), 7.05 (dd, 1H), 7.55 (dd, 2H).
19) 4-. { 5- [1- (tert-butoxycarbonyl) -4-piperidyl] -3-10 [(. {2 - [((2S) -2-. {[[(4-chlorophenyl) sulfonyl] amino}. -3- ethoxy-3-oxopropyl) amino] -2-oxoethyl.} Amino) carbonyl] pentyl} tetrahydro-l (2H) - tert-butyl pyridinecarboxylate (compound 47)
Starter material: 4-chlorophenylsul fonyl chloride Yield = 63% XH-NMR (400MHz, CDC13): d 1.05 (m, 4H), 1.15 (t, 3H), 1.2 (m, 4H), 1.3 (m, 2H) , 1.4 (s, 20H), 1.6 (m, 6H), 2.05 (m, 1H), 2.6 (bt, 4H), 3.45 (m, 1H), 3.7 (m,
1H), 4.0 (m, 9H), 6.1 (bd, 1H), 6.45 (bt, 1H), 6.95 (bt, 1H), 7.45 (d, 2H), 7.75 (d, 2H).
) 4-. { 5- [1- (tert-butoxycarbonyl) -4 -piperidyl] -3- [(. {2- 2- [((2S) -2- { [(4-fluorophenyl) sulphonyl] amino}. 3-25 ethoxy-3-oxoprop? 1) amino] -2-
x ^^ & ~ ~ * t í. *. > > , ..t oxoethyl} amino) carbonyl] pentyl} tetrahydro-l (2H) pyridinecarboxylate tert-butyl ester (compound 4Í
Starter material: 4-fluorofen i lululum fonilo Performance = 82% XH-NMR (400MHz, CDC13): d 1.05 (m, 4H), 1.15 (t, 3H), 1.2 (, 4H), 1.3 (m, 2H ), 1.45 (s, 20H), 1.6 (m, 6H), 2.1 (m, 1H), 2.65 (bt, 4H), 3.5 (m, 1H), 3.7 (m, 1H),
4.1 (m, 9H), 6.2 (bs, 1H), 6.55 (bt, 1H), 7.0 (bt, 1H), 7.2 (t, 2H), 7.85 (dd, 2H).
21) 4- [5- [1- (tert-butoxycarbonyl) -4-piperidyl] -3- ( { [2- ( { (2S) -3-ethoxy-3-oxo- 2- [( 6-methoxy-2- (naphthylsulfonyl) amino) propyl) amino) -2-oxoethyl] amino} carbon] l) pentyl] tetrahydro-l (2H) -pyridinecarboxylic acid tert-butyl ester (compound 49)
Starter material: 6-methoxy-2-naphthylsulfonyl chloride Yield = 71%: H-NMR (400MHz, CDC13): d 0.95 (t, 3H), 1.0 (m, 4H), 1.15 (m, 4H), 1.25 ( m, 2H), 1.45 (s, 20H), 1.6 (m, 6H), 2.05 (m, 1H), 2.6 (bt, 4H), 3.45 (m, 1H), 3.7
(m, 1H), 3.75 (q, 2H), 3.9 (s, 3H), 4.0 (m, 8H), 6.05
(bd, 1H), 6.45 (bt, 1H), 6.75 (bt, 1H), 7.1 (d, 1H), 7.2 (d, 1H), 7.75 (, 3H), 8.25 (s, 1H).
22) 4- [5- [1- (tert-butoxycarbonyl) -4-piper? Dil] -3- ( { [2- ( { (2S) -3-ethoxy-3-oxo-2- [(mesitylsulfonyl) amino] propyl.} amino) -2-oxoethyl] amino.} carbonyl) pentyl] tetrahydro-1 (2H) -pyridinecarboxylic acid tert-butyl ester (compound 50)
Initiating material: metal chloride ion yield = 67%: H-NMR (400MHz, CDC13): d 1.0 (m, 4H), 1.10 (t, 3H), 1.20 (m, 4H), 1.35 (m, 2H ), 1.45 (s, 20H), 1.65 (m, 6H), 2.05 (m, 1H), 2.25 (s, 3H), 2.65 (s, 6H), 2.67
(m, 4H), 3.50 (m, 1H), 3.65 (m, 1H), 3.85-4.15 (m, 9H), 5.90 (d, 1H), 6.40 (bt, 1H), 6.70 (bt, 1H), 6.90
(s, 2H).
23) 4- [5- [1- (tert-butoxycarbonyl) -4-piperidyl] -3- ( { [2- ( { (2S) -3-ethoxy-3-OXO-2- [( butylsulfonyl) amino] propyl.} amino) -2-oxoethyl] amino.} carbon] l) pentyl] tetrahydro-1 (2H) -pyridinecarboxylate tert -butyl ester (compound 51)
> > ** »" ^, ^, ". I.i .. ^. ^ Á ^. »" ». ^ > . .... »-. ^ Km. j .s M? IÉ & YÍ ..- Starter material: n-butyl ilsul fonilo chloride Yield = 66% XH-NMR (400MHz, CDC13): d 0.9 (t, 3H), 1.0 (m, 4H), 1.15 (m, 4H), 1.25-1.4 (s, 27H), 1.6 (m, 6H), 1.75
(m, 2H), 2.05 (m, 1H), 2.65 (bt, 4H), 3.0 (t, 2H), 3.5 (m, 1H), 3.75 (m, 1H), 3.9 (t, 2H), 4.05 (bs, 4H), 4.2 (m, 3H), 5.85 (d, 1H), 6.55 (bt, 1H), 7.0 (bt, 1H).
24) 4- [5- [1- (tert-butoxycarbonyl) -4 -piperidi 1] -3- ( { [2- ( { (2S) -3-ethoxy -3-OXO-2- [(4-methyl-phenylsul-fonyl) -amino] -propyl] -amino) -2-oxo-ethyl] -amino} -carbonyl) -pentyl] -tetrahydro-1 (2H) -pyridinecarboxylic acid-tert-butyl ester (compound 52) 15 Initiating material: chloride 4 -met i 1 phenyl sul fonilo Yield = 68% XH-NMR (400MHz, CDC13): d 1.0 (m, 4H), 1.15 (t, 3H), 1.2 (m, 4H), 1.35 (m, 2H), 1.45 (s, 20H), 1.6 (m, 20 6H), 2.1 (m, 1H), 2.4 (s, 3H), 2.65 (b, 4H), 3.45 (m, 1H), 3.75 (m, 1H), 3.85 -4.15 (m, 9H), 5.95 (bd, 1H), 6.5 (bt, 1H), 6.85 (bt, 1H), 7.25 (d, 2H), 7.7 (d, 2H).
) 4- [5- [1- (tert-butoxycarbonyl) -4-piperidyl] -3- ( { [2- ( { (2S) -3-ethoxy-3-oxo-2- [( 3-methylphenylsul fonyl) amino] propyl.} Amino) -2-oxoethyl] to nino} car onyl) pentyl] tetrahydro-l (2H) -5-pyridinecarboxylic acid tert-butyl ester (compound 53)
Starter material: 3-methylphenyl sulfonyl chloride Yield = 86% XH-NMR (400MHz, CDCl 3): d 1.0 (m, 4H), 1.05 (t, 3H), 10 1.1 (m, 4H), 1.3 (m, 2H ), 1.4 (s, 20H), 1.6 (m, 6H), 2.1 (m, 1H), 2.4 (s, 3H), 2.65 (bt, 4H), 3.4 (m, 1H), 3.75 (m, 1H) , 3.85-4.1 (m, 9H), 5.9 (bs, 1H), 6.45 (bt, 1H), 6.8 (bt, 1H), 7.4 (d, 2H), 7.6 (m, 2H).
26) 4- [(IOS) -3- (2- [1- (tert-butoxycarbonyl) -4-piperidyl] ethyl) -10- (ethoxycarbonyl) -4,7,12,12- tetraoxo-13-phenyl -12? D-thia-5, 8, 11-triazatridec-l-yl] tetrahydro-l (2H) -pyridinecarboxylic acid tert-butyl ester (compound 54) 20 Initiating material: 4-benzyl sulphide chloride yield = 49% XH-NMR (400MHz, CDCl 3): d 1.0 (m, 4H), 1.2 (m, 4H), 1.25 (m, 5H), 1.45 (s, 20H), 1.6 (m, 6H), 2.05 (m, 25 1H), 2.6 (bt, 4H), 3.5 (, 2H), 3.9 (m, 2H), 4.0 (bs,
- * - t - * - «A, .A.- > A • - - "-'1 * - - * S J-« ~ 4H), 4.2 (q, 2H), 4.3 (q, 2H), 5.75 (bd, 1H), 6.4 (bt, 1H) , 6.75 (bt, 1H), 7.55 (m, 5H).
27) 4 - [(10S, 13E) -3-. { 2- [1- (tert-butoxycarbonyl) -4-piperidinyl] ethyl} -10- (ethoxycarbonyl) -4, 7, 12, 12- tetraoxo-14-phenyl-12,6-thia-5,8,1-triaza-13-tetradecen-1-yl] tetrahydro-1 (2H) - 10 tert-butyl pyridinecarboxylate (compound 55)
Initiating material: trans-β-est-irenesulfonyl chloride Yield = 57% XH-NMR (400MHz, CDC13): d 1.0 (m, 4H), 1.1-1.2 (m, 15 7H), 1.3 (m, 2H), 1.45 ( m, 20H), 1.6 (m, 6H), 2.05 (m, 1H), 2.6 (bt, 4H), 3.5 (m, 1H), 3.8 (m, 1H), 3.85-4.15 (m, 9H), 5.95 (bs, 1H), 6.5 (bt, 1H), 6.75 (d, 1H), 6.95 (bt, 1H), 7.35-7.5 (m, 6H).
28) 4- [(IOS) -3-. { 2- [1- (tert-butoxycarbonyl) -4-piperidyl] ethyl} -10- (ethoxycarbonyl) -4, 7, 12, 12- tetraoxo-14-phene 1-12? 6-thia-5, 8, 11-triazatetradec-1-yl] tetrahydro-1 (2H) -pyridinecarboxylate tert- butyl (compound 56) 25
Initiating material: the product of compound hydrogenification 55 Yield = 96% XH-NMR (400MHz, CDC13): d 1.0 (m, 4H), 1.15 (m, 4H), 1.25 (, 5H), 1.4 (s, 20H), 1.55 (m, 6H), 2.05 (m, 1H), 2.6 (bt, 4H), 3.0-3.3 (m, 3H), 3.55 (m, 1H), 3.75 (m, 1H), 3.9 (d , 2H), 4.05 (bs, 5H), 4.25 (d, 2H), 6.0 (bs, 1H), 6.55 (bt, 1H), 7.0 (bt, 1H), 7.1-7.5 (m, 5H). 10 29) 4- [5- [1- (tert-butoxycarbonyl) -4-piperidinyl] -3-. { [(2- {[[2S] -3-ethoxy-3-OXO-2- ({[[3- (trifluoromethyl) phenyl] sulfonyl} amino) propyl] amino} -2-oxoethyl amino] carbonyl} pentyl) tetrahydro-15 1 (2H) -pyridinecarboxylate tert -butyl ester (compound 57)
Starter material: 3- trifluoromethylphenylsphonyl chloride 20 Yield = 77% 2H-NMR (400MHz, CDC13): d 1.0 (m, 7H), 1.15 (m, 4H), 1.25 (m, 2H), 1.4 (s, 20H), 1.55 (m, 6H), 2.05 (m, 1H), 2.55 (bt, 4H), 3.5 (m, 1H), 3.65 (m, 1H), 3.85-4.05 (m, 9H), 6.4 (bs, 1H) , 6.55 (bt, 1H), 7.0
(bt, 1H), 7.6 (t, 1H), 7.75 (d, 1H), 7.95 (d, 1H),
8, 05 (s, 1H).
) 4- [5- [1- (tert-butoxycarbonyl) -4-piperidyl] -3-. { [(2- {[[2S] -3-ethoxy-2- ({[[5-nitrophenyl] sulfonyl} ammo) -3-oxopropyl] amino} -2-oxoethyl) amino] carbonyl} pentyl) tetrahydro-1 (2H) -pyridinecarboxylic acid tert-butyl ester (compound 58)
Initiating material: 3-nitr and phenylsulphonic chloride 10 Yield = 55%: H-NMR (400MHz, CDC13): d 1.0 (m, 4H), 1.15 (t, 3H), 1.2 (m, 4H), 1.35 ( m, 2H), 1.45 (s, 20H), 1.6 (m, 6H), 2.1 (m, 1H), 2.65 (bt, 4H), 3.65 (m, 2H), 3.9-4.2 (m, 9H), 6.65 (bt, 1H), 7.15 (t, 1H), 7.7 (t,
1H), 8.2 (d, 1H), 8.4 (d, 1H), 8.7 (s, LH).
31) 4- [5- [1- (tert-butoxycarbonyl) -4-piperidyl] -3-. { [(2- {[[2S] -3-ethoxy -2- ({[[3-methoxyphenyl] sulfonyl} amino} -3-oxopropyl] amino} -2- 20 oxoethyl) amino] carbonyl} pentyl) tetrah idro-l (2H) - tert-butyl pyridinecarboxylate (compound 59)
Starter material: 4-methoxy-phenyl sulfonyl chloride Yield = 55% 25 XH-NMR (400MHz, CDC13): d 1.0 (m, 4H), 1.15 (t, 3H),
1. 2 (m, 4H), 1.35 (m, 2H), 1.45 (s, 20H), 1.65 (m, 6H), 2.05 (m, 1H), 2.65 (bt, 4H), 3.45 (m, 1H), 3.75 (, 1H), 3.85 (s, 3H), 3.9-4.1 (m, 9H), 5.9 (bs, 1H), 6.5 (bt, 1H), 6.85 (bt, 1H), 6.95 (d, 2H), 7.75 (d, 2H).
32) 4- [5- [1- (tert-butoxycarbonyl) -4-piperidyl] -3- ([. {2- ( { (2S) -3-ethoxy-3 -oxo- 2- [( 8-quinolysulfonyl) amino] propyl.} Amino) -2- 10 oxoethyl] amino.} Carbonyl) pentyl] tetrahydro-l (2H) -pyridinecarboxylate tert -butyl ester (compound 60)
Starter material: 8-quinolinesulfonyl chloride Yield = 55% XH-NMR (400MHz, CDC13): d 0.9 (t, 3H), 1.05 (m, 4H), 1.2 (, 4H), 1.3 (m, 2H), 1.45 (m, 20H), 1.6 (m, 6H), 2.05 (m, 1H), 2.65 (bt, 4H), 3.5 (m, 1H), 3.65-4.2 (m, 10H), 6.35 (bt, 1H), 6.65 (bt, 1H), 7.2 20 (bs, 1H), 7.55 (q, 1H), 7.65 (t, 1H), 8.05 (d, 1H), 8.25 (d, 1H), 8.35 (d, 1H), 9.05 (d, 1H).
--r «- f? > t &ttUS ** á t, fr-t i.-t. ^? H,?, ".... ^ ....... .. ^,. ^, _ ,, ..., , ^ ^,. ^. ^. ^ - AÍÍÍ ^ ....., .. ^^ Í. .,. . "^ J * i, .a * -«? ¿£ 33) 4-. { 5- [1- (tert-butoxycarbonyl) -4-piperidyl] -3- [(. {2- 2- [((2S) -2-. {[[(3,5-dimethyl-4-isoxazolyl) sulphonyl] ] amino.}. 3-ethoxy-3-oxopropyl) amino] -2-5-oxoethyl.} amino) carbonyl] pentyl} tetrahydro-l (2H) -pyridinecarboxylate tert -butyl ester (compound 61)
Starter material: 3,5-dimethyl-4-isoxazolylsulfonyl chloride 10 Yield = 81% XH-NMR (400MHz, CDC13): d 1.05 (m, 4H), 1.2 (m, 7H), 1.3 (m, 2H), 1.45 (m, 20H), 1.65 (m, 6H), 2.05 (m, 1H), 2.4 (s, 3H), 2.6 (s, 3H), 2.65 (bt, 4H), 3.5 (m, 1H), 3.7 (m, 1H), 3.85-4.1 (m, 9H), 6.4 (bs, 1H), 15 6.55 (bt, 1H), 7.0 (bt, 1H).
34) 4-. { 5- [l- (tert-butoxycarbonyl) -4-piperidyl] -3- [(. {2- 2- [((2S) -2- { ([5- (dimethylamino) -1- naphthyl] sulphyl ) amino.}. 3 - ethoxy-3-oxopropyl) amino] -2-oxoethyl.} amino) carbonyl] pentyl} tetrahydro-l (2H) -pyridinecarboxylate tert -butyl ester (compound 62)
Starter material: 5-dimethylamino- l-2-nephthallylsulfonyl chloride
i m, it mjtimMiv-, «? k. H n. t «" ^ "" • > • »» - «• - fr», --- * .- * - * -, - ... --- .. .- * .-. *. * ...., .. ».. .... ^ ^ ... .i. . . . i Afaa. ...
Yield = 73% XH-NMR (400MHz, CDC13): d 0.9 (t, 3H), 1.15 (m, 4H),
1. 3 (m, 2H), 1.45 (m, 20H), 1.6 (m, 6H), 2.05 (m,
1H), 2.6 (bt, 4H), 2.85 (s, 6H), 3.45 (m, 1H), 3.6
(m, 1H), 3.8 (m, 4H), 3.9-4.1 (m, 5H), 6.15 (bs, 1H), 6.35 (bt, 1H), 6.6 (bt, 1H), 7.2 (d, 1H), 7.5 (t,
1H), 7.6 (t, 1H), 8.2 (d, 1H), 8.25 (d, 1H), 8.55 (d, 1H).
) 4-. { 3- [(2- { [(2S) -2- ( { [2- (acetylamino) -4-methyl-l, 3-thiazol-5-yl] sulfonyl.} Amino) -3- ethoxy-3-oxopropyl] amino.} -2-oxoethyl) amino] carbonyl} -5- [1- (tert-butoxycarbonyl) -4-piperidyl] pentyl} tetrahydro-l (2H) -pyridinecarboxylate tert -butyl ester (compound 63)
Initiating material: 2- (acetylamino) -4-methyl-1, 3-thiazol-5-ylsulfonyl chloride yield = 64% XH-NMR (400MHz, CDC13): d 1.05 (m, 4H), 1.15- 1.4 (m, 9H), 1.45 (s, 20H), 1.6 (bd, 6H), 2.1 (m, 1H), 2.3 (s, 3H), 2.45 (s, 3H), 2.65 (bt, 4H), 3.55 (m, 1H), 3.7 (, 1H), 3.9-4.2 (, 9H), 6.85 (bt, 1H), 7.2 (bt, 1H).
i-l-J.-: i || »-. * - Í-tea-t-b * i * M-Hl -.- M -» - 1 uní Mimf ia -tjgmüigaai 36) 4-. { 5- [1- (tert-butoxycarbonyl) -4-piperidyl] -3- [(. {2- [((2S) -2-. {(([3-chloropropyl] -sulfonyl) amino]} - 3-ethoxy-3-oxopropyl) amino] -2-oxoethyl.} Amino) carbonyl] pentyl} tetrahydro-l (2H) -pyridinecarboxylate tert -butyl ester (compound 64)
Starter material: 3-chloropropylsulfonyl chloride
Yield = 68% XH-NMR (400MHz, CDC13): d 1.05 (m, 4H), 1.2 (m, 4H), 1.35 (m, 5H), 1.45 (s, 20H), 1.6 (m, 6H), 2.05 (m,
1H), 2.3 (m, 2H), 2.65 (bt, 4H), 3.2 (t, 2H), 3.6 (m,
1H), 3.65 (t, 2H), 3.75 (m, 1H), 3.95 (d, 2H), 4.05
(bs, 4H), 4.25 (q, 3H), 6.1 (bd, 1H), 6.6 (bt, 1H),
7. 1 (bt, 1H).
37) 4-. { 5- [1- (tert-butoxycarbonyl) -4-piperidyl] -3- [(. {2- 2- [((2S) -2-. {(([4-methoxy-1-naphthyl] sulfonyl) amino} - 3-ethoxy-3-oxopropyl) amino] -2-oxoethyl.} Amino) carbonyl] pentyl} tetrahydro-l (2H) -pyridinecarboxylate tert -butyl ester (compound 65)
Starter material: 4-methoxy-l-naphthylsulfonyl chloride Yield = 71%: H-NMR (400MHz, CDC13): d 0.9 (t, 3H), 1.05 (m, 4H),
1. 15 (m, 4H), 1.35 (m, 2H), 1.45 (s, 20H), 1.6 (,
6H). 2.05 (m, 1H), 2.65 (bt, 4H), 3.45 (m, 1H), 3.6
(m, 1H), 3.75-4.05 (m, 9H), 4.1 (s, 3H), 6.2 (d, 1H),
6. 35 (bt, 1H), 6.65 (bt, 1H), 6.8 (d, 1H), 7.6 (t,
1H), 7.7 (t, 1H), 8.15 (d, 1H), 8.35 (d, 1H), 8.6 (d, 1H).
38) 4-. { 5- [1- (tert-butoxycarbonyl) -4-piperidyl] -3- [(. {2- 2- [((2S) -2-. {(([6,7-dimethoxy-2-naphthyl] sulphyl) ) amino.}. 3-ethoxy-3-oxopropyl) amino] -2-oxoethyl.} amino) carbonyl] pentyl} tetra idro-l (2H) - tert-butyl pyridinecarboxylate (compound 66)
Initiating material: 6,7-dimethoxy-2-naphthylsulfonyl chloride Yield = 63% XH-NMR (400MHz, CDCl 3): d 1.0 (t, 3H), 1.05 (m, 4H), 1.2 (m, 4H), 1.35 ( m, 2H), 1.45 (s, 20H), 1.6 (m, 6H), 2.1 (m, 1H), 2.65 (bt, 4H), 3.45 (m, 1H), 3.75 (m, 1H), 3.8-4.1 (m, 15H), 6.0 (d, 1H), 6.5 (bt, 1H), 6.9 (bt, 1H), 7.15 (s, 1H), 7.2 (s, 1H), 7.3 (s, 1H), 7.7 ( d, 1H), 7.8 (d, 1H), 8.25 (s, 1H).
39) 4-. { 5- [l- (tert-butoxycarbonyl) -4-piperidyl] -3-. { [(2- {[[2S) -2- ( { [2,4-dimethyl-1,3-thiazol-5-yl] sulfonyl-amino) -3-ethoxy-3-oxopropyl] amino}. -2- oxoe) amino) carbonyl} penile } tetrahydro-l (2H) -pyridinecarboxylate tert -butyl ester (compound 67)
Starter material: 2,4-dimethyl-1,3-thiazol-5-ylsulfonyl chloride Yield = 54%
^ -NMR (400MHz, CDCl3): d 1.05 (m, 4H), 1.2 (m, 7H), 1.35 (m, 2H), 1.45 (s, 20H), 1.6 (m, 6H), 2.1 (m, 1H ), 2.6 (s, 3H), 2.7 (m, 7H), 3.55 (m, r 1H), 3.7 (m, 1H), 3.85-4.15 (m, 9H), 6.35 (d, 1H), 6.5 (bt) , 1H), 6.95 (bt, 1H).
40) 4-. { 5- [1- (tert-butoxycarbonyl) -4-piperidyl] -3- ( { [2- ( { (2S) -2- ( { [3, 5-dimethyl-lH-pyrazole- 4-yl] sulfonyl, amino) -3-ethoxy-3-oxopropyl] amino} -2-oxoethyl) amino] carbonyl, pentyl, tetrahydro-l (2H) -pyridinecarboxylate tert -butyl ester ( compound 68)
Initiating material: 3,5-dimethyl-lH-p? Razol-4-ylsulfonyl chloride yield = 50% XH-NMR (400MHz, CDC13): d 1.05 (m, 4H), 1.2 (, 7H), 5 1.3 ( m, 2H), 1.45 (s, 20H), 1.65 (m, 6H), 2.1 (m, 1H), 2.4 (s, 6H), 2.65 (bt, 4H), 3.5 (m, 1H), 3.7 (m , 1H), 3. (bs, 2H), 4.05 (m, 6H), 6.4 (bd, 1H), 6.75 (bt, 1H), 7.15 (bs, 1H), 11.8 (bs, 1H).
41) 4-. { 5- [1- (tert-butoxycarbonyl) -4-p-peridyl] -3- ( { [2- ( { 2S) -3-etox? -3-oxo-2- [(3-pyridinol fonyl) amino] propyl.} amino) -2-oxoethyl] amino} carbonyl) pentyl] tetrahydro-l (2H) -trial-butyl pyridinecarboxylate (compound 69) 15 Initiating material: 3-pyridylsul fonyl chloride Yield = 61%: H-NMR (400MHz, CDCl 3): d 1.05 (m, 4H), 1.15 (t, 3H), 1.2 (m, 4H), 1.35 (m, 2H), 1.45 (m, 20H), 1.65 (m, 20 6H), 2.1 (m, 1H), 2.75 (bt, 4H), 3.6 (m, 1H), 3.7 (m, 1H), 3.9-4.15 (m, 9H), 6.65 (bt, 1H), 6.7 (d, 1H), 7.15 (bt, 1H), 7.45 (q, 1H) , 8.15 (dd, 1H), 8.8 (d, 1H), 9.05 (s, 1H).
42) 4-. { 3-. { [(2- {[(2S) -2- ( { 1, 3-benzodioxo1-5-ylsulfonyl} amino) -3-ethoxy-3-oxopropyl] amino} -2-oxoethyl) amino] carbonyl} -5- [1- (tert-butoxycarbonyl) -4-piperidyl] pentyl} tetrahydro-5-1 (2H) -pyridinecarboxylate tert-butyl ether (compound 70)
Starter material: 1,3-benzodioxol-5-ylsulfonyl chloride 10 Yield = 61% ^ -NMR (400MHz, CDC13): d 1.05 (m, 4H), 1.2 (m, 7H), 1.3 (m, 2H), 1.45 (s, 20H), 1.65 (m, 6H), 2.1 (m, 1H), 2.65 (bt, 4H), 3.5 (m, 1H), 3.7 (m, 1H), 3.85-4.1 (m, 9H), 6.05 (d, 1H), (s, 2H), 6.55 (bt, 15 1H), 6.85 (d, 1H), 6.9 (bt, 1H), 7.25 (d, 1H), 7.4 (d, 1H).
43) 4-. { 5- [1- (tert-butoxycarbonyl) -4-piperidyl] -3-. { [(2- {[[(2S) -2- ({{{{{{{{{{{{{{{{{{{{{{{{{{{{{{{2}}}} -amino-3-oxo-3-oxo-propyl} ] amino.} -2-oxoethyl) amino] carbonyl} pent? l} tetrahydro-1 (2H) -pyridinecarboxylate tert -butyl ester (compound 71)
Initiating material: 2,3-dihydro-1,4-benzodioxin-6-ylsul fonyl chloride yield = 61%
Hirmunltof rdHMrnW.fflft ^ - - i, .., -..... ,,, ...., ._. ".. ui .. ^,., I. ^ ...... ^ A . ^ J. . ... . ,, _ ....... ^ i * .fc »-« * ^ -NMR (400MHz, CDC13): d 1.05 (m, 4H), 1.2 (m, 7H), 1.35 (m, 2H), 1.45 (s, 20H), 1.65 (m, 6H), 2.1 (m, lH), 2.65 (bt, 4H), 3.45 (m, 1H), 3.75 (m, 1H), 3.9-4.1 (rn, 9H) , 4.3 (dd, 4H>, 5.95 (bs, 1H), 6.5 (bt, 1H), 6.85 < d, 1H), 6.95 (d, 1H), 7.3 (dd, 1H >, 7.35 (d, 1 HOUR) .
44) 4-. { 3-. { [(2- {[[(2S) -2- (. {L-benzothiophen-2-ylsulphyl} amino) -3-ethoxy-3-oxopropyl] amino} -2-oxoethyl) amino carbonyl} -5- [l- (tert-butoxycarbonyl) -4-piperidyl] pentyl Jtetrahydro-1 (2H) -pyridinecarboxylate tert -butyl ester (compound 72)
Starter material: 1-benzothiophen-2-ylsulfonyl chloride Yield = 74% ^ - MR (400MHz, CDC13): d 0.95 (t, 3H), 1.05 (m, 4H), 1.2 (m, 4H), 1.3 (m, 2H), 1.45 (s, 20H), 1.6 (m, 6H), 2.1 (m, 1H), 2.65 (bt, 4H), 3.5 (, 1H), 3.7 (m, 1H), 3.85 (m, 4H) , 4.05 (m, 5H), 6.45 (bt, 2H), 6.9 (bt, 1H), 7.5 (m, 2H), 7.9 (d, 1H), 8.2 (d, 1H), 8.25 (s, 1H).
45) 4-. { 5- [1- (tert-butoxycarbonyl) -4-piperidyl] -3-. { [(2- {[[(2S) -2- ({[2, 5-dimethyl-3-furyl] sulfonyl} amino} -3-ethoxy-3-oxopropyl] amino}. -oxoethyl) amino] carbonyl} penile } tetrahydro-1 (2H) -5-pyridinecarboxylate tert -butyl ester (compound 73)
Starter material: chloro 2,5-dimethyl-3-furyl sulfonyl Yield = 78% 10 XH-NMR (400MHz, CDC13): d 1.05 (m, 4H), 1.2 (m, 7H), 1.3 (m, 2H), 1.45 (s, 20H), 1.6 (m, 6H), 2.1 (m, 1H), 2.25 (s, 3H), 2.5 (s, 3H), 2.65 (bt, 4H), 3.45 (m, 1H), 3.75 (m, 1H), 3.85-4.15 (m, 9H), 5.9 (bs, 1H). 6.1 (s, 1H), 6.45 (bt, 1H), 6.85 (bt, 1H). 15 46) 4-. { 5- [1- (tert-butoxycarbonyl) -4-piperidyl] -3-. { [(2- {[[(2S) -2- ( { [4-cyclohexylphenyl] sulfonyl} amino) -3-ethoxy-3-oxopropyl] amino.} -2- 20 oxoethyl) amino carbonyl} penile } tetrahydro-l (2H) -pyridinecarboxylate tert -butyl ester (compound 74)
Starter material: 4-cyclohexylphenylsulfonyl chloride 25 Yield = 64%
> -r * H? f ** l # * < •, • < -; W •: ^. = ^ -.- '»*. .. .. . »> r. .., ...,,,. ,,, ^,, j j ^ fc;
1H-NMR (400MHz, CDC13): d 1.1 (m, 7H), 1.15-1.5 (m, 30H), 1.6 (ni, 6H), 1.8 (, 6H), 2.1 (, 1H), 2.65 (m, 5H) ), 3.45 (m, 1H), 3.75 (m, 1H), 3.85-4.15 (m, 9H), 5.9 (bs, 1H), 6.45 (bt, 1H), 6.85 (bt, 1H), 7.35 (d, 2H). 7.75 (d, 2H).
47) 4- [5- [1- (tert-butoxycarbonyl) -4-p? Per? Dil] -3-. { [(2- {[[2S] -3-ethoxy-2- ( { [4-fluoro-1-naphthyl] sulphonyl} amino) -3-oxopropyl] amino}. 2- oxoethyl) amino] carbonyl} pentyl) tetrahydro-l (2H) -pyridinecarboxylate tert -butyl ester (compound 75)
Starter material: 4-fluoro-l 'naphthylsulfonyl chloride
- MR (400MHz, CDCI3): d 0.9 (t, 3H), 1.05 (m, 4H), 1.2 (m, 4H), 1.35 (, 2H), 1.45 (s, 20H), 1.6 (, 6H), 2.1 (, 1H), 2.65 (bt, 4H), 3.5 (m, 1H), 3.65 (m, 1H), 3.8 (q, 2H), 3.85 (bd, 2H), 4.05 (m, 5H), 6.3. { bs, 1H), 6.45 (bt, 1H), 6.8 (bt, 1H), 7.2 (t, 1H), 7.7 (t, 1H), 7.75 (t, 1H), 8.23 (t, 1H), 8.65 (d , 1 HOUR) .
4- [5- [1- (tert-butoxycarbonyl) -4-piperidyl] -3-. { f (2- { [(2S) -3-ethoxy-2- ( { [4-chloro-l-naphthyl] sulfonyl}. amino) -3-oxopropyl] amino.} -2-oxoethyl amino] carbonyl} pentyl) tetrahydro-1 (2H) -
MW.- tert-butyl pyridinecarboxylate (compound 76)
Starter material: 4-chloro-l-naphthi sulfonyl chloride yield = 63%
1 H-NMR (400MHz, CDC13): 6 0.9 (t, 3H), 1.1 (m, 4H), 1.2 (m, 4H). 1.35 (m, 2H), 1.45 (s, 20H), 1.6 (m, 6H), 2.1 (m, 1H), 2.65 (bt, 4H), 3.5 (rn, 1H), 3.6 (m, 1H), 3.8 (q, 2H), 3.85 (bd, 2H), 3.95-4.15 (m, 5H), 6.4 (bt,
2H), 6.8 (bt, 1H), 7.65 (d, 1H), 7.75 (m, 2H), 8.4 (d,
1H), 8.7 (d, 1H).
49) 4-. { 5- [1- (tert-butoxycarbonyl) -4-piperidyl] -3-. { [(2- {[[(2S) -2- ( { [2, 3-dihydro-1-benzo furan-5-yl] sulphonyl} amino] -3-ethoxy-3-oxopropyl] amino.} -2-oxoethyl) amino] carbonyl} penile } tetrahydro-l (2H) -pyridinecarboxamide tert -butyl (compound 77)
Starter material: 2,3-dihydro-1-benzofuran-5-ylsul fonyl chloride Yield = 74% ^ -NMR (400MHz, CDCl 3): d 1.05 (m, 4H), 1.2 (ra, 7H) 1.35 (m, 2H ), 1.45 (s, 20H), 1.6 (m, 6H), 2.1 (m, 1H)
2. 65 (bt, 4H), 3.25 (t, 2H), 3.45 (m, lH), 3.75 (, 1H), 3.85-4.1 (m, 9H), 4.65 (t, 2H), 5.8 (d, 1H), 6.45 (bt, 1H), 6.8 (d, 2H), 7.6 (d, 1H), 7.65 (a.1H).
50) 4- [5- [1- (tert-butoxycarbonyl) -4-piperidyl] -3- ( { [2- ( { (2S) -3-ethoxy-3-oxo-2-. { [4- (2-thienyl) phenylsulfonyl] amino] propyl, amino) -2- 5-oxoethyl] -no-carbonyl) pentyl] tetrahydro-1 (2H) -pyridinecarboxylate tert -butyl ester (compound 78) )
Starter material: 4- (2-thienyl) -phenylsulfonyl chloride 10 Yield = 78%
^ -NMR (400MHz, CDC13): d 1.1 (m, 7H), 1.2 (m, 4H), 1.35 (m, 2H), 1.45 (s, 20H), 1.6 (m, 6H), 2.1 (m, lH ), 2.65 (bq, 4H), 3.5 (m, 1H), 3.75 (m, 1H), 3.9-4.1 (, 9H), 6.1 (d, 1H), 6.5 (bt, 1H), 6.9 (bt, 1H) ), 7.1 (t, 1H), 7.4 (dd, 2H), 7.7 (d, 2H), 7.85 (d, 2H &.51) 4- [5- [l- (tert-butoxycarbonyl) - 4-piperidyl] -3- ( { [2- ( { (2S) -3-ethoxy-3-oxo-2 - { [2- (2-thienyl) phenylsulfonyl] amino} propyl .}. amino) -2-oxoethyl] amino.} carbonyl) pentyl] tetrahydro-1 (2H) -20 pyridinecarboxylic acid tert-butyl ester (compound 79)
Initiator Material: 2-thienyl chloride) -phenylsulfonyl Yield = 63% 25
XH-NMR (400MHz, CDC13): d 1.05 (m, 4H), 1.2 (m, 7H), 1.3 (m, 2H), 1.45 (s, 20H), 1.65 (m, 6H), 2.05 (m, lH ), 2.65 (bt. 4H), 3.5 (m, 2H), 3.8-4.1 (m, 9H), 5.3 (d, 1H), 6.25 (bt, 1H), 6.4. { bt, 1H), 7.15 (t, 1H), 7.5 (m, 4H), 7.6 (t, 1H), 8.1 (d, 1H).
52) 4- [5- [1- (tert-butoxycarbonyl) -4-piperidyl] -3- ( { [2- ( { (2S) -3-ethoxy-3-oxo-2 -. { [4- (2- (furyl) 1-phenylsulfonyl] amino} propyl} amino) -2-oxoethyl] amino} carbonyl) pentyl] tetrahydro-1 (2H) -pyridinecarboxylic acid tert-butyl ester (compound 80) )
Starter material: 4- (2-furyl) phenylsulfonyl chloride 15 Yield = 62%
^ -NM (400MHz, CDC13): d 1.1 (m, 7H), 1.2 (m, 4H), 1.35 (m, 2H), 1.45 (s, 20H), 1.65 (m, 6H), 2.1 < m, 1H), 2.65 (bt, 4H), 3.5 (m, 1H), 3.75 (m, 1H), 3.85-4.1 (m, 9H), 20 6.05. { bs, 1H), 6.5 (bt, 1H), 6.55 < d, 1H > , 7.5 (s, 1H), 7.75 (d, 2H), 7.8 (d, 2H).
53) 4-. { 3-. { [(2- {[[(2S) -2- ({1-benzofuran-2-ylsulphonyl} amino} -3-ethoxy-3-oxopropyl] amino} -2- 25 oxoethyl) amino carbonyl} -5- [l- (terc-
".- trAMmti * l¡l? U * A. **. *,. > ., ... ^, «.« - .. ............... ............., ... .. , .....-.to........"_. ., ..., Á,, ^. . «.. l. ^ ... j ALa» ^ as. ^ ..
butoxycrbonyl) -4-piperidyl] pentyl Jtetrahydro-1 (2H) -pyridinecarboxylate tert -butyl ester (compound 81)
Starter material: 1-benzofuran-2-ylsulfonyl chloride Yield = 52% ^ -NMR. { 400MHz, CDC13): d 1.1 (m, 7H), 1.2 (m, 4H), 1.3 (m, 2H), 1.45 (s, 20H), 1.6 (m, 6H), 2.1 (m, 1H), 2.65 ( bt, 4H), 3.65 (m, 1H), 3.75 (rn, 1H), 3.9-4.15. { m, 8H), 4.25 (ip, 1H), 6.45 (bt, lH), 6.9 (bt, 1H), 7.35 (m, 2H), 7.48 (t, 1H), 7.65 (d, 1H), 7.7 (d , 1 HOUR) .
54) 4- [5- [1- (tert-butoxycarbonyl) -4-piperidyl] -3- ( { [2- ( { (2S) -3-ethoxy -3-OXO-2- [( 2- naphthylmethyl sulfonyl) amino] propyl.} Amino) -2-oxoethyl] amino.} Carbonyl) pentyl] tetrahydro-1 (2H) -pyridinecarboxylic acid tert-butyl ester (compound 82)
Starter material: 2-naphthylmethanesulfonyl chloride yield = 61%
^ Í-NMR (400MHz, CDCI3): d 1.05 (a, 4H), 1.1 (t, 3H), 1.2 (m, 4H), 1.3. { m, 2H), 1.45 (s, 20H), 1.6 (ra, 6H), 2.05 (m, 1H), 2.65 (bt, 4H), 3.4 (m, 1H), 3.5 (m, 1H), 3.75-4.1 (m, 9H), 4.4. { q, 2H), 5.7 (bs, lH), 6.4 (bt, 1H), 6.7. { bt, 1H), 7.5 (m, 3H), 7.8 (m, 4H).
ii i, n, -,. «-. ^ - .. ¡-m" "^,, -" ,,. .... ...,. < .., ^ .... ^. ^ ¿.... «^. ..., ..... ..., i. i ^ tu-lfa ...
55) 4-. { 5- [1- (tert-butoxycarbonyl) -4-piperidyl] -3-. { [(2- {[[2S) -2- ({[2, 3-dihydro-lH-inden-5-yl] sulfonyl} amino} -3-ethoxy-3-oxopropyl] amino} -2-oxoethyl) amino] carbonyl} penile } tetrahydro-1 (2H) - tert-butyl pyridinecarboxylate (compound 83)
Starter material: 5-indanesulfonyl chloride Yield = 62% 10 ^ - MR (400MHz, CDCl3): d 1.05 (, 4H), 1.1 (t, 3H), 1.2. { m, 4H), 1.35 (m, 2H), 1.45 (s, 20H), 1.6 (m, 6H), 2.05. { m, 1H), 2.1 (t, 2H), 2.65 (bt, 4H), 2.95 (t, 4H), 3.45 (m, 1H), 3.75 (m, lH), 3.85-4.1 (m, 9H), 5.85 (d, 1H), 6.45. { bt, 1H), 6.8 (bt, 1H), 7.3 (d, 1H), 7.6 (d, 1H), 7.65 (s, 1H). fifteen
56) 4- [5- [l- (tert-butoxy-trbonyl) -4-piperidyl] -3- ( { [2- ( { (2S) -3-ethoxy -3-OXO-2-. { [(5-phenyl-2-thienyl) sulfonyl] amino] propyl, amino) -2-20-oxoethyl] amino} carbonyl) pentyl] tetrahydro-1 (2H) -pyridinecarboxylate tert-butyl ester (compound 84)
Starter material: 5-phenyl-2-thiophenesulfonyl chloride Yield = 60% 25
lH-N (400MHz, CDC13): d 1.05 (m, 4H), 1.15 (t, 3H), 1.2 (m, 4H), 1.35 (m, 2H), 1.45 (s, 20H), 1.6 (m, 6H) ), 2.05 (m, 1H), 2.65 (bt, 4H), 3.55 (m, 1H), 3.8 (ra, 1H), 3.9-4.15 (m, 9H), 6.4 (bt, 1H), 6.8 (bt, 1H), 7.25 (d, 1H), 7.4 (m, 3H), 7.55 (ra, 3H).
57) 4- [5- [1- (tert-butoxycarbonyl) -4-piperidyl] -3- ( { [2- ( { (2S) -3-ethoxy -3-OXO-2- [( 5,6,7,8-terahydro-2-naphtenyl sulphonyl) amino] propyl} amino) -2- 10 oxoethyl] amino.} Carbonyl) pentyl] tetrahydro-1 (2H) -pyridinecarboxylate tert -butyl ester ( compound 85)
Starter material: 5, 6, 7, 8-tetrahydro-2-naphthalenesulfonyl chloride 15 Yield = 12%
XH-NMR (400MHz, CDCl 3): d 1.05 (m, 4H), 1.1 (t, 3H), 1.2 (m, 4H), 1.3 (m, 2H), 1.45 (s, 20H), 1.6 (ra, 6H) ). 1.8 20 (bs, 4H), 2.1 (m, 1H), 2.65 (bt, 4H), 2.8 (bs, 4H), 3.45 (ra, 1H), 3.75 (ra, 1H), 3.85-4.15 (ra, 9H ). 5.9 (bs, 1H), 6.5 (bt, 1H), 6.85 (bt, 1H), 7.2 (d, 1H), 7.49 (d, 1H), 7.65. { s, 1H).
58) 4 - [(10S, 13E) -3-. { 2- [1- (tert-butoxycarbonyl) -4-piperidyl] ethyl} -10- (ethoxycarbonyl) -, 7, 12, 12-teraoxo-12? 6-thia-5, 8, 11-tpaza-13-heptadecen-l-yl] tetrahydro-1 (2H) -pyridinecarboxylate tere-5-butyl (compound 86)
Initiating material: chloride (E) -1-pentenylsulfonyl Yield = 21%
Hí-NMR (400MHz, CDC13): d 0.9 (t, 3H), 1.05 (m, 4H), 1.2 10 (m, 4H), 1.27 (t, 3H), 1.30 (m, 2H), 1.45 (s, 20H), 1.6 (m, 6H), 2.05 (m, 1H), 2.2 (q, 2H), 2.65 (bt, 4H), 3.45 (m, 1H), 3.75 (m, 1H), 3.85-4.10. { ra, 7H), 4.2 (q, 2H), 5.65 (d, 1H), 6.15 (d, lH), 6.45 (bt, 1H), 6.75 (dt, 1H), 6.8 (bt, 1H).
59) 4- [5- [1- (tert-butoxycarbonyl) -4-piperidyl] -3- ( { [3- ( { (3S) -3-ethoxy-2- [(2-naphthylsulfonyl ) artiino] -3-oxopropyl.} amino) -3-oxopropyl] amino.} carbonyl) pentyl] tetrahydro-1 (2H) -pyridinecarboxylic acid tert-butyl ester (compound 87) 20 Starter materials: compound 38 and chloride 2 - Naphthylsulfonyl Yield = 76%
XH-NMR (400MHz, CDC13): d 0.95 (t, 3H), 1.05 < m, 4H), 1.2. { m, 4H), 1.30 (ra, 2H), 1.45 (s, 20H), 1.6 (m, 6H), 2.0 (m, 1H), 2.4 (m, 2H), 2.65 (bq, 4H), 3.45 (m , 1H), 3.55 (m, 2H), 3.7 (m, 1H), 3.85 (q, 2H), 4.0 (bs, 4H), 4.1 (bs, 1H), 6.0. { bd, lH), 6.75 (ra, 2H), 7.65 (m, 2H), 7.8 (d, 1H), 7.9 (d, 1H), 7.95 (d, 2H), 8.4. { s, 1H).
60) 4- [5- [1- (tert-butoxycarbonyl) -4-piperidyl] -3- ( { [3- ( { (3S) -3-ethoxy -3-oxo-2- [( phenylsulfonyl) amino] propyl.}. amino) -3-oxopropyl] ammo.} carbonyl) pentyl] tetrahydro-1 (2H) -pyridinecarboxylate tert -butyl ester (compound 88)
Starter materials: compound 38 and benzensulfonyl chloride yield = 76%
Hi-NMR (400MHz, CDC13): d 1.05 (m, 4H), 1.1 (t, 3H), 1.2 (ra, 4H), 1.30 (ra, 2H), 1.45 (s, 20H), 1.6 (m, 6H) ). 2.0 (ra, 1H), 2.4 (t, 2H), 2.65. { bt, 4H), 3.4 (m, 1H), 3.55 (m, 2H), 3.7 (m, 1H), 4.0 (q, 2H), 4.05 (bs, 4H), 5.9 (d, 1H), 6.5 (m , 2H), 7.5 (t, 2H), 7.6 < d, 1H), 7.85 (, 1H).
i. .. ...... you? .... * .. & *, * »..... • - ** - '"- ^ - d-tUÍ-WMM -.- il-dl-Í-HMldl-ri-áH-- ... ..".? Á..Í i? Sa? T? ÜIÉ 61) 4 - [(10S) -3- { 2- [l- (tert-butoxycarbonyl) -piperidyl] ethyl.}. -13- (7,7-dimethyl-2-oxo-bicyclo [2.2.1] hept-1-yl) -10- (ethoxycarbonyl) -4,7,12, 12-tetraoxo-12,6-thia-5,8,1-triazatridec-1-yl] tetrahydro-l (2H) -pyridinecarboxylate tert - Butyl (compound 89)
According to the procedure described by compound 29, starting with hydrochloride (2S) -3- 10 amino-2- ( { [(7, 7-dimeti 1-2 -oxobi cycle [2.2.1] hept-1- il) methyl] sulfonyl.}. amino) propanoate and compound 4. Yield = 78%
XH-NMR (400MHz, CDCl3): d 0.90. { s, 3H), 1.00 (s, 3H), 1.05 (m, 4H), 1.20 (m, 4H), 1.30 (t, 5H), 1.45 (s, 20H), 1.55 (m, 6H), 1.95 (t , 3H), 2.05 (m, 2H), 2.15. { t, 1H), 2.20 (m, 1H), 2.40 (m, 1H), 2.65 (bt, 4H), 3.00 (d, 1H), 3.50 (m, 2H), 3.80. { m, 1H), 3.95. { dq, 2H), 4.05 (bs, 4H), 4.20 (q, 2H), 4.30 (m.1H), 6.4020 (t, 1H), 6.50. { d, 1H), 6.70 (t, 1H).
62) (2R) -3- (. {2- 2- [(4- [1- (tert-butoxycarbonyl) -4-piperidyl] -2- {2- (1- (tert-butoxycarbonyl) -4} - piperidyl] ethyl} butanoyl) amino] acetyl} amino) -2- 25 [(2-naphthylsulfonyl) amino] propanoic (compound 90)
Isobutylchloroformate (3.3 g, 24.2 mmol) was added, at room temperature, to a solution of 2- [(4- [1- (tert-butoxycarbonyl) -4,5-piperidyl] -2-. 1- (tert-butoxycarbonyl) -4-piperidyl] ethyl} butanoyl) amino] acetic (compound 4)
(10.8 g, 20 mmol) in 200 ml of THF and N-methylmorpholine
(5 g, 49.5 mmol). You get a suspension. After stirring for 20 minutes, a mixture is added
(2R) -3-amino-2- [(2-naphthylsulfonyl) amino] propane (8 g, 25 mmol) and water (80 ml), at 0 ° C. Stirring is continued at 0-5 ° C for 30 minutes and then at room temperature for 18 hours. The THF completely evaporated and the solution
The aqueous was acidified to pH 2 with 1 N hydrochloric acid. The mixture was extracted with ether. The extracts were washed with water, dried over sodium sulfate and evaporated to give the crude product, which was purified by intact chromatography.
(dichloromethane / methanol / acetic acid 10 / 0.5 / 0.5) to give 8.3 g of a beige solid. Yield = 51% XH-NMR (400MHz, CDC13): d 1.0 (m, 4H), 1.15 (m, 4H), 1.25 (m, 2H), 1.4 (s, 20H), 1.55 (bd, 6H), 2.1 (m,
1H), 2.6 (bq, 4H), 3.6 (m, 1H), 3.75 (, 1H), 3.8-4.1
m Tlfuart 1 r. »- _» - •,. ,, .- -t "i" < . ,, .. ^ -.-mi - ^ -. ^ > -.-. ^ .. ^ * .... _........ i, ...... ....._.... T | "| t¡, tJ M (m, 7H), 6.6 (d, 1H), 6.95 (bt, 1H), 7.25 (bt, 1H), 7.6 (m, 2H), 7.85 (t, 2H), 7.95 (t, 2H), 8.45 (s, 1H).
D - Preparation of the compounds of formula Ib according to the route a2: Reaction of an acid of formula IV with an amine of formula V
63) 4- [5- [1- (tert-butoxycarbonyl) -4-piperidyl] -3- ( { [2- ( { 3-ethoxy-2- [(2-naphthisul-fonyl) amino] - 3-oxopropyl.}. Amino) -2-oxo-l-phenylethyl] amino.} Carbonyl) pentyl] tetrahydro-1 (2H) -pyridinecarboxylate tert -butyl ester (compound 91)
Ethyl 3- [(2-amino-2-phenylethanoyl) amino] -2 - [(2-naphthylsulfonyl) ammo] propanoate (1.7 g, 3 mmol) and diisopropylethylamine (0.8 g, 6.2 mmol) were added at room temperature environment, to a solution of 4- [1- (tert-butoxycarbonyl) -4-piperidyl] -2- fluoride. { 2- [1- (tert-butoxycarbonyl) -4-piper? Dil] et? L} butanoyl (synthesis ref B-1) (1.55 g, 3 mmol) in 50 ml of dichloromethane. After stirring for 3 hours, water was added. The organic phase was washed with water,
.. ^. , .. ..,,. " . , ... «... S ..-. .. ... * .- ^ ", .... , ....., > . «,» ... ^ .- t. "L. It & '; x & dried over sodium sulfate and evaporated to give the crude product, which was purified by flash chromatography (dichloromethane / methanol 20/1) to give 1.2 g of a white solid. 5 Yield = 44% XH-NMR (400MHz, CDC13): d 0.95 (m, 3H), 1.00 (m, 4H), 1.20 (m, 4H), 1.40 (m, 2H), 1.47 (s, 20H), 1.60 (m, 6H), 2.05 (m, 1H), 2.60 (bd, 4H), 3.50 (, 1H), 3.58 (m, 1H), 3.65 (m, 1H), 3.80 (m, 2H), 3.99 ( m, 4H), 10 5.45 (m, 1H), 5.75 (dd, 1H), 6.40 (dt, 1H), 6.85 (dd, 1H), 7.35 (m, 5H), 7.52 (m, 2H), 7.75 ( d, 1H), 7.95 (m, 3H), 8.37 (d, 1H). This method was used to prepare the following compounds: 15 64) 4- [5- [1- (tert-butoxycarbonyl) -4-piperidyl] -3- ( { [2- (. {3-ethoxy-2 - [(2-naphthylsulfonyl) amino] -3-oxopropyl.] Amino) -l-methyl-2-oxoethyl] amino.} Carbonyl) pentyl] tetrahydro-1 (2H) -20 pyridinecarboxylate tert-butyl ester (compound 92) )
Starter material: ethyl 3 - [(2-aminopropanoyl) amino] -2- [(2-naphthylsulfonyl) amino] propanoate hydrochloride 25 Yield = 71%
r.- Aj < - »&.? & amp; . Í? * .t; , 4 ^ ft¡t. fc ....... ..,. ,TO. -, -. ^ .. «C ^ -Mi - XH-NMR (400MHz, CDC13): d 0.95 (t, 3H), 1.05 (m, 4H),
1. 20 (m, 4H), 1.30) d, 5H), 1.45 (s, 20H), 1.60 (m,
6H), 2.00 (m, 1H), 2.65 (bs, 4H), 3.50 (m, 1H), 3.70
(m, 1H), 3.88 (m, 2H), 4.08 (m, 4H), 4.50 (m, 1H),
6. 10 (bd, 1H), 6.30 (d, 1H), 6.90 (t, 1H), 7.65 (m,
2H), 7.80 (d, 1H), 7.90 (d, 1H), 8.00 (d, 2H), 8.40 (s, 1H).
Example 1: 3- (1,3-Benzodioxol-5-y1) -3- dihydrochloride. { [2- (. {4- (4-piperidyl) -2- [2- (4-piperidyl) ethyl] butanoyl}. Amino) acetyl] amino} ethyl propanoate (CRL42725)
The 4- was dissolved. { 3- . { [1- (1, 3-benzodioxol-5-yl) -3-ethoxy-3-oxopropyl] amine} -2-oxoethyl) ammo] carbonyl} -5- [1- (tert-butoxycarbonyl) -4-piperidyl] pentyl} terahydro-l (2H) -pyridinecarboxylic acid tert -butyl ester (compound 9) (3.3 g, 4.35 mmol) in 5 ml of dioxane and then 10 ml of a 4 N solution of hydrochloric acid-dioxane was added. The mixture was kept stirred at room temperature for 20 minutes and the dioxane is then separated by settling. Ether was added and separated again
^ ¿^^^? ^^ l ^^^^ i ^^! by settling, and the resulting material is then evaporated to dryness. A white powder was obtained, which was dissolved in about 150 ml of water and then filtered and the filtrate was dried by freezing to give 2.4 g of a white solid. Yield = 87% MS (ES): m / z 559 (M + H) + XH-NMR (400MHz, CDC13): d 1.1 (m, 7H), 1.25 (m, 6H), 1.45 (m, 4H), 1.75 (m, 4H), 2.15 (m, 1H), 2.75 (m, 10 6H), 3.2 (m, 4H), 3.62 (m, 2H), 4.0 (q, 2H), 5.12 (q, 1H), 6.0 (s, 2H), 6.8 (dd, 2H), 6.95 (s, 1H), 8.1 (t, 1H), 8.45 (d, 1H), 8.8 (bs, 2H), 9.1 (bs, 2H). The method described in Example 1 was used to prepare the following compounds: EXAMPLE 2 3- [3- (2-Ethoxy-2-oxoethyoxy) phenyl] -3- dihydrochloride. { [2- (. {4- {4-piperidyl) -2- [2- (4-piperidyl) ethyl] butanoyl} amino) acetyl] amino-ethylpropanoate (CRL42640) Starting material: Compound 13 Yield = 92% XH-NMR (400MHz, CD ^ OD): d 1.3 (t, 3H), 1.45 (m, 13H), 1.7 (m, 4H), 1.95 (m, 4H), 2.35 (m, 1H), 3.0 (m, 6H), 25 3.4 (m, 4H), 3.75 (s, 2H), 3.95 (s, 2H), 4.18 (q,
-Ttm-ifrito- "1" 1 * "5 - *** ^ | ^^ •" "*" * - »- -. **** - * - *."? ÁJlfe- ^ fe, .. ... ,, 2H), 4.35 (q, 2H), 4.8 (s, 2H), 5.42 (t, 1H), 6.92 (d, 1H), 7.05 (m, 2H), 7.35 (t, 1H).
Example 3 5 Dihydrochloride 3- [3- (3-methoxy phenyl)] -3-. { [2- (. {4- (4- piperidyl) -2- [2- (4-piperidyl) ethyl] butanoyl} amino) acetyl] amino} ethyl propanoate (CRL42661) Starting material: compound 14 10 Yield = 93% XH-NMR (400MHz, CD3OD): d 1.3 (t, 3H), 1.5 (m, 17H),
2. 0 (m, 4H), 2.33 (m, 1H), 3.0 (m, 6H), 3.4 (m, 4H),
3. 9 (s, 3H), 3.98 (s, 2H), 4.2 (m, 2H), 5.42 (t, 1H),
6. 95 (m, 2H), 7.05 (bs, 2H), 7.32 (t, 1H). EXAMPLE 4: Dihydrochloride (2S) -2- [(2-naphthyl sulphonyl) amino] -3-. { [2- (. {4- {4-piperidyl) -2- [2- (4-piperidyl) ethyl] butanoyl} amino) acetyl) amino-ethylpropanoate (CRL42968) Starting material: compound 41 = 100% [a] D -16.5 (C = 0.97, H20) MS (ES): m / z 644 (m + H) "25 XH-NMR (400MHz, DMSO-d6): d 0.85 (t, 3H) , 1.1 (m,
-O? More? ^^ 4H), 1.25 (m, 6H), 1.45 (m, 4H), 1.7 (bd, 4H), 2.15 (m, 1H), 2.75 (bq, 4H), 3.2 (m , 5H), 3.3 (m, 1H), 3.6 (m, 4H), 3.95 (m, 1H), 7.7 (m, 2H), 7.8 (d, 1H), 8.0-8.2 (m, 5H), 8.4 ( s, 1H), 8.55 (d, 1H), 8.85 (bd, 2H), 9.1 (bd, 2H).
Example 5: 3- (1,3-Benzodioxol-5-i 1) -3- acid dihydrochloride. { [2- (. {4- (4-piperidyl) -2- [2- (4-piperdyl) ethyl] butanoyl}. Amino) acetyl] ami or} -propanoic (CRL42630)
1 g (23.8 mmol) of lithium monohydrate hydroxide was added to a solution of 4. { 3- . { [1- (1, 3-benzodioxol-5-yl) -3-ethoxy-3-oxopropyl] amino} -2-oxoethyl) amino] carbonyl} -5- [1- (tert-butoxycarbonyl) -4-piperidyl] pentyl} tetrahydro-l (2H) -pyridinecarboxylic acid tert -butyl ester (compound 9) (7.6 g, 10 mmol) in 80 ml of tetrahydrofuran and 20 ml of water. After 4 hours at room temperature, the organic solvent was completely evaporated. Water was added and the mixture was acidified to pH 2 and then extracted with ethyl acetate. The extracts were washed with water and dried over sodium sulfate. The filtrate was evaporated to give 6.3 g of acid.
.. ~ .. *? ... IJ: ... * L. The acid thus obtained is dissolved in 10 ml of ethyl acetate and then 50 ml of a solution of hydrochloric acid-ethyl acetate is added. ethyl 3 N. Stirring is continued for 30 minutes at room temperature The mixture is separated by settling in. After addition of water (approximately 200 ml) followed by freeze drying, 4.7 g of a white solid is obtained. MS (ES): m / z 531 (M + H) + ^ -NMR (400MHz, CD3OD): d 1.5 (m, 12H), 1.95 (m, 4H), 2.25 (m, 1H), 2.75 (bs) , 2H), 2.9 (m, 4H), 3.3 (m, 4H), 3.85 (s, 2H), 5.29 (bs, 1H), 5.95 (s, 2H), 6.8 (d, 2H), 6.85 (m, 3H) .The method described in Example 5 was used to prepare the following compounds:
Example 6 3- [4-isopropyl] -3- acid dihydrochloride. { [2- (. {4- (4- 20 piperidyl) -2- [2- (4-piperidyl) ethoxy] butanoyl} - amino) acetyl] amino} propanóico (CRL42548) Material initiator: compound 10 Performance = 98%
MS-C1: m / z 529 (M + H) * ^ -NMR (400MHz, CD3OD): 6 1.5 (m, 16H), 1.65 (m, 4H), 1.95 (m, 5H), 2.35 (m, 1H ), 3.0 (m, 6H), 3.4 (m, 4H), 3.95 (m, 2H), 5.4 (t, 1H), 7.25 (d, 2H), 7.38 (d, 2H).
Example 7: 3- (4-methoxy phenyl) -3- acid dihydrochloride. { [2- (. {4- (-piperidyl) -2- [2- (4-piperidyl) ethyl] butanoyl} amino) acetyl] amino Jpropanoic
(CRL42549) Starter material: Compound 11 Yield = 98% MS-C1: m / z 517 (M + H) * XH-NMR (400MHz, CD3OD): d 1.5. { m, 14H), 1.95 (m, 4H), 2.16 (ra, 1H), 2.9 (dq, 2H), 3.0 (ra, 4H), 3.4 (m, 4H), 15 3.85 (s, 3H), 3.95 ( s, 2H), 5.35 (t, 1H), 6.92 (d, 2H), 7.35 (d, 2H).
Example 8: 3- (3,4-dimethoxyphenyl) -3- acid dihydrochloride. { [2- 20 (. {4- (4-piperidyl) -2- [2- (4-piperidyl) ethoxy] butanoyl}. Amino) -acetyl] amino} propan? co (CRL42590) Starter material: compound 12 Yield = 80% 25
MS-C1: / z: 547 (M + H) * 1 H-NMR (400MHz, CD3OD): d 1.15-1.65 (m, 14H), 1.8 (m, 4H), 2.25 (ra, 1H), 2.85 (m , 6H), 3.3 (bs, 4H), 3.78 (s, 3H), 3.8 (s, 3H), 3.85. { m, 2H), 5.25 (t, 1H), 6.85 (d, 2H), 6.95 (d, 1H).
Example 9: 3- [(3-carboxymethoxy) phenyl] -3- dihydrochloride. { [2- (. {4- (4-piperidyl) -2- [2- (4-piperidyl) ethyl] butanoyl}. Amino) acetyl] amino} -propanoic (CRL42639) Starter material: compound 13 Yield = 79% H-NMR (400MHz, CD3OD): d 1.2-1.65 (m, 14H), 1.85 (ra, H), 2.25 (m, 1H), 2.7- 3.0 (m, 6H), 3.3 (bs, 4H), 3.78
(d, 2H), 4.68 (s, 2H), 5.3 (t, 1H), 6.82 (d, 1H), 6.95 (m.2H), 7.25 (t, 1H).
Example 10: 3- (3-methoxyphenyl) -3- acid dihydrochloride. { [2- (. {4- (4-piperidyl) -2- [2- (4-piperidyl) ethyl] butanoyl}. Amino) acetyl] amino} propanic
(CRL42660) Starter material: compound 14 Yield = 81%
- - > • - '- MS (ES): m / 2 517 (M + H) * XH-NMR (400MHz, CD3OD): d 1.4. { m, 8H), 1.55 (m, 2H), 1.68 (m, 4H), 1.95 (bs, 4H), 2.3 (m, 1H), 2.9 (dd, 2H), 3.0 (m, 4H), 3.4 (m , 4H), 3.86. { s, 3H), 3.95 (s, 2H>, 5.4 (m, 1H), 6.9 (, 1H), 7.0 (m, 2H), 7.3 (t, 1H).
Example 11: 3- (2,3-dihydro-l, 4-benzodioxin-6-yl) -3- acid dihydrochloride. { [2- (. {4- (4-piperidyl) -2- [2- (4- (piperidyl) ethyl] butanoyl} amino) acetyl] amino} propanic (CRL42718 Initiating material: compound 15 Performance = 84%
MS. { ES): m / z 545 (M + H) + 15 XH-NMR (400MHz, DMSO-d «+ D20): d 1.1 (m, 4H), 1.25 (m, 6H), 1.4 (m, 4H), 1.7 (m, 4H), 2.15 (m, 1H), 2.6 (t, 2H), 2.75 (m, 4H), 3.15 (bd, 4H), 3.7 (s, 2H), 4.05 (s, 4H), 5.05 (m, 1H), 6.72. { s, 1H), 6.78 (d, 2H).
Example 12: 3- (3-pyridyl) -3- trichlorohydrate. { [2- (. {4- (4- piperidyl) -2- [2- (4-piperidyl) ethyl] butanoyl} amino) acetyl] amino} propanic (CRL42722) 25 Initiating material: compound 16
Yield = 95% MS (ES): m / z 488 (M + H) + XH-NMR (400MHz, DMSO-d6): d 1.1 (, 4H), 1.25 (m, 6H), 1.4 (m, 4H) , 1.65 (m, 4H), 2.15 (m, 1H), 2.85 (m, 4H), 2.9 (bd, 2H), 3.15 (m, 4H), 3.7 (m, 2H), 5.25 (m, 1H), 8.1 (bs, 1H), 8.25 (bs, 2H), 8.65 (d, 1H), 8.85 (bs, 1H), 8.95 (m, 4H), 9.2 (bs, 2H).
E xemployment 13: Acid 3-hydrochloride. { [2- (. {4- (4-piperid? L) -2- [2- (4-piperidyl) ethyl] butanoyl}. Amino) acetyl] amino} propanic (CRL43040) Starter material: compound 17 Yield = 100% 15 MS (ES): / z 411 (M + H) * aH-NMR (400MHz, DMSO-d6): d 1.15 (m, 4H), 1.3 ( m, 6H), 1.45 (m, 4H), 1.75 (bd, 4H), 2.15 (m, 1H), 2.35 (t, 2H), 2.75 (bq, 4H), 3.15 (bd, 4H), 3.25 (q , 2H), 3.65 (d, 2H), 7.9 (t, 1H), 8.15 (t, 1H), 8.85. { bq, 2H), 9.15 (bd, 2H). 20 Example 14: 3- Acid hydrochloride. { [2- (. {4- (4-piperidyl) -2- [2- (4-piperidyl) ethyl] butanoyl} ammo) acetyl] amino} butanóico 25 (CRL43041)
,. **. --- ^ - »» .. ».. ^ .. ^. - ^ ... Í.?.: Í. ± 3t? Atía ^.
Starter material: compound 18 Yield = 100% MS (ES): m / z 425 (M + H) * lH-NMR (400MHz, DMSO-d6): d 1.1 (d, 3H), 1.15 (, 4H), 1.3 (, 6H), 1.4 (m, 4H), 1.7. { bd, 4H), 2.15 (m, 1H), 2.25. { q, 1H), 2.45. { q, 1H), 2.75 (bq, 4H), 3.15 (bdr 4H), 3.6 (m, 2H), 4.05 (m, 1H), 7.85 (d, 1H), 8.1 (t, 1H), 8.8 (bq, 2H), 9.1 (bd, 2H).
Example 15: 5-phenyl-3- acid dihydrochloride. { [2- (. {4- (4- piperidyl) -2- [2- (4-pyridyl) ethyl] b-tanoyl} amino) acetyl] ami or} pentanoic (CRL43042) Starter material: compound 19 yield = 100%
MS (ES): / z 515. { M + H) + XH NMR (400MHz, DMSO-d6): d 1.15 (m, 4H), 1.25 (m, 6H), 1.45 (m, 4H), 1.75 (m, 6H), 2.2 (m, 1H) , 2.4 (m, 2H), 2.5 (m, 1H), 2.65 (m, 1H), 2.75 (bq, 4H), 3.15 (bd, 4H), 3.7 (bq, 2H), 4.05 (, 1H), 7.2 . { m, 3H), 7.25 (t, 2H), 7.95 (d, 1H), 8.2 (t, 1H), 8.8 (bs, 2H), 9.15 (bd, 2H).
Example 16: (3S) -4- (1-adamantylamino) -4-oxo-3- acid dihydrochloride. { [2- ( { 4- (4-piperidyl) -2- [2- (4-
piperidyl) ethyl] butanoyl} amino) acetyl] amino Jbutanoic (CRL42592) Starter material: compound 20 Yield = 94% 5 MS (ES): m / z 588 (M + H) * AH-NMR (400MHz, CD3OD): 8 1.25 (m, 10H ), 1.5 (ra, 4?), 1.6 (s, 6H), 1.82. { bd, 4H), 1.9 (bs, 9H), 2.2 (m, 1H), 2.6 (m, 2H), 2.86 (bt, 4H), 3.25 (bd, 4H), 3.7 (d, 2H), 4.5 (t , 1 HOUR) .
Example 17: (3S) -4- acid dihydrochloride. { [2- (1H-indol-4-yl) ethyl] amino} -4-OXO-3-. { [2- (. {4- (4-piperidi 1) -2- [2- (4-piperidyl) ethyl] butanoyl}. Amino) acetyl] amino} butanoic 15 (CRL42678) Starter material: compound 21 Yield = 100% MS (ES): m / z 597 (M + H) * ^ -N (400MHz, DMSO-d6): 8 1.15 (m, 4H), 1.3 (m, 6H) 1.45 (m, 4H), 1.75. { m, 4H), 2.2 (m, 1H), 2.55 (m, 2H) 20 2.75 (, 6H), 3.15 (m, 4H), 3.35 (, 2H), 3.75 (bs, 2H) 4.6 (m, 1H) , 6.98 (t, 1H), 7.08 (t, 1H), 7.16 (s, 1H) 7.35 (m, 1H), 7.55 (d, 1H), 8.1 (d, 1H), 8.2. { bs, 2H) 8.9 (bs, 2H), 9.2. { bs, 2H), 10.9 (bs, 1H).
??? * £ *. *. > .- ".. - • '• *,« * •• & Example 18: (3S) -4 - [(4-methoxyphenyl) ethylamino] -4-oxo-3-dihydrochloride. { [2- (. {4- {4-piperidyl) -2- [2- (4-piperidyl) ethyl] butanoyl} amino) acetyl] amino Jbutanoic (CRL42694) Starting material: compound 22 Yield = 97% 1 H-NMR (400MHz, DMSO-d 6): 5 1.15 (m, 4H), 1.25 (ra, 6H), 1.45 (m, 4H), 1.8. { bd, 4H), 2.15 (m, 1H), 2.5 (ra, 2H), 2.65 (t, 2H), 2.75. { bd, 4H), 3.15 (bd, 6H), 3.7 (s, 5H), 4.55 (m, 1H), 6.85 (d, 2H), 7.15 (d, 2H), 8.1 (d, 1H), 8.15 (m , 2H), 8.95 (bd, 2H), 9.2. { bd, 2H).
Example 19: (3S) -4- (3-phenylepropylamino) acid dihydrochloride
4-oxo-3-. { [2- (. {4- (4-piperidyl) -2- [2- (4-piperidyl) ethyl] butanoyl}. Amino) acetyl] amino} butanoic
(CRL42719) Starter material: compound 23 Yield = 100%
MS. { ES): m / z 572 (M + H) * ^ -NMR. { 400MHz, DMSO-de): d 1.15 (m, 4H), 1.3 (m, 6H), 1.4 (ra, 4H), 1.7 (ra, 6H), 2.15 (m, 1H), 2.55 (ra, 4H), 2.75 (bd, 4H), 3.05 (m, 2H), 3.2 (bd, 4H), 3.7. { d, 2H), 4.55 (m, 1H), 7.2 (m, 5H), 8.15 (m, 3H), 8.9 (bs, 2H), 9.15. { bs, 2H).
Example 20: (3S) -4- [(1,3-Benzodioxol-5-ylmethyl) amino] -4-oxo-3-dichlorohydroate. { [2- (. {4- (4-piperidyl) -2- [2- (4-piperidyl) ethoxy] butanoyl} amino) cetyl] amino} butano ico (CRL42720) Starter material: compound 24 15 Yield = 90% MS. { ES): m / z 588 (M + H) * ^ -NMR (400MHz, DMSO-d6): d 1.15 (m, 4H), 1.3 (m, 6H) 1.4 (m, 4H), 1.7 (m, 4H ), 2.15 (m, lH), 2.55 (bs, 2H) 2.75 (bd, 4H), 3.15 (d, 4H), 3.7 (d, 2H), 4.15 (d, 2H) 4.6 (m, 1H), 5.95 (s, 2H), 6.7 (d, 1H), 6.8. { s, 1H)
6.81 (d, 1H), 8.2 (m, 2H), 8.55 (t, 1H), 8.9. { bs, 2H) 9.15 (bs, 2H).
Example 21: (3S) -4 - [(3-methoxyphenyl) amino] -4-oxo-3-dihydrochloride. { [2- (. {4- (4-piperidyl) -2- [2- (4- (5-piperidyl) ethyl] butanoyl} amino) acetyl] amino} butanoic (CRL42721) Starter material: compound 25 Yield = 100% XH-NMR (400MHz, DMSO-d6): d 1.15 (m, 4H), 1.3 (m, 6H)
1.4 (m, 4H), 1.7 (m, 4H), 2.15 (? T ?, 1H), 2.5 (m, 4H) 2.7 (m, 6H), 3.15 (m, 6H), 3.7 (s, 5H) , 4.55 (m, 1H) 6.75 (s, 3H), 7.15 (t, 1H), 8.1 (d, 1H), 8.2 (bs, 2H) 8.9 (bs, 2H), 9.15 (bs, 2H).
Example 22: (3S) -4- [(2-Hydroxy-1, 1-dimethylethyl) amino] -4-oxo-3-acid dihydrochloride. { [2- (. {4- (4-piperidyl) -2- [2- (4-piperidyl) ethyl] butanoyl}. Amino) acetyl] amino} butanóico 20 (CRL42726) Material initiator: the compound 26 Performance = 100%
MS (ES): m / z 526 (M + H) * ^ - NMR (400MHz, DMSO-d6): d 1.1 (m, 7H), 1.25 (m, 7H) 1.4 < m, 4H), 1.7 (m, 4H), 2.15 (m, 1H) 2.5 (m, 2H) 2.6 (m, 1H), 2.7 (bd, 4H), 3.1 (bd, 4H) 3.3 (q, 1H) 3-7. { bs, 2H), 4.05 (m, 1H), 4.45 (m, 1H) 4.65 (m, 1H) 8.05-8.5 (m, 3H), 8.9 (bs, 2H), 9.15 (bs, 2H)
Example 23: (3S) -4- [(1-isopropyl-1) -2-methylpropyl) amino] -4-oxo-3-dihydrochloride. { [2- (. {4- (4-piperidyl) -2- [2- (4-piperidyl) ethyl] butanoyl}. Amino) acetyl] amino} butanoic (CRL42727) Starter material: compound 27 15 Yield = 89% MS (ES): m / z 552 (M + H) * XH-NMR (400MHz, DMSO-d6): d 0.8 (m, 9H), 1.15 (m, 11H) 1.25 (m, 4H), 1.85 (m, 6H), 2.15 (m, 1H), 2.6 (m, 1H) 2.75 (ra, 4H), 3.15. { m, 4H), 3.4 (m, 4H), 3.7 (m, 2H) 4.55 (m, 1H), 7.3 (d, 1H), 8.3 (m, 2H), 8.95 (bs, 2H) 20 9.2 (bs? 2H).
Example 24: (2S) -2- acid dihydrochloride. { [(benzyloxy) carbonyl] amino} -3- . { [2- (. {4- (4-piperidyl) -2- [2- (4- (5-piperidyl) ethyl] butanoyl} amino) acetyl] amino} propanic (CRL42717)
Initiating material: compound 29 Yield = 97% 10 [allo -8 (C = 2.2, H20) MS. { ES): m / z 560 (M + H) * XH-NMR (400MHz, DMS0-d6): d 1.15 (m, 4H), 1.3 (ra, 6H), 1.45 (m, 4H), .1.75 (m , 4H), 2.15 (ra, lH), 2.8. { bd, 4H), 3.2 (bd, 4H), 3.3 (m, 1H), 3.5 (ra, 1H), 3.7 (ra, 2H), 4.1 (q, 1H), 5.05 (s, 2H), 7.35 (m , 4H), 7.55 (d, 1H),
.08.05 (1H), 8.15 (s, 1H), 8.9 (bs, 2H), 9.2 (bs, 2H).
Example 25: 2- [(1, 3-benzodioxol-5- 20 i learbonyl) amino] -3- acid dihydrochloride. { [2- (. {4- (4-piperidyl) -2- [2- (4-piperidyl) ethyl] butanoyl} amino) acetyl] amino-propanoic (CRL42731)
Initiating material: compound 40 Performance = 100%
MS. { ES): m / z 574 (M + H) * ^ -N R (400MHz, DMSO-ds): 8 1.15. { m, 4H), 1.25 (m, 6H), 1.45 (m, 4H), 1.75 (m, 4H), 2.2 (m, lH), 2.75 (m, 4H), 3.2 (bd, 4H), 3.48 (m , 1H), 3.65 (m, 3H), 4.45 (m, 1H), 6.1 (s, 1H), 7.0 (d, 1H), 7.5 (s, lH), 7.55 (d, 1H), 8.25 (bd, 2H), 8.65 (d, 1H), 8.95 (bs, 2H), 9.2 (bs, 2H).
Example 26: 2- [(phenylsulfonyl) amino] -3- acid dihydrochloride. { [2- (. {4- (4-piperidyl) -2- [2- (4-piperidyl) ethyl} butanoyl} amino) acetyl] amine} propanic (CRL42724) 15 Initiating material: compound 39 Yield = 95% MS-C1: / z 566 (M) * ^ -NR (400MHz, DMSO-d5) -: d 1.15 (ra, 4H), 1.25 (m, 6H) 1.45 (m, 4H), 1.75 (m, 4H), 2.2 (ra, 1H), 2.75 (m, 4H)
3.15 (bd, 4H), 3.25 (ra, 1H). 3.5 (m, 2H), 3.8 (p \, 1H) 7.6. { m, 3H), 7.8 (m, 2H), 8.05 (bd, 2H), 8.25 (d, 1H) 9.0 (bd, 2H), 9.25 (bd, 2H).
Example 27: (2S) -2 - [(2-naphthylsul-fonyl) amino] -3- acid dihydrochloride. { [2- (. {4- (4-piperidi 1) -2- [2- (4-piperidyl) ethyl] butanoyl}. Amino) acetyl] amino} propanic (CRL42796)
Starter material: compound 41 Yield = 91% [a] D -10.1 (C = 0.86, H20) MS (ES): m / z 616 (M + H) + 1 H-NMR (400MHz, DMSO-d6): d 1.1 (m, 4H), 1.25 (m.6H) 1.45 (m, 4H), 1.7 (m, 4H), 2.15 (ra, 1H), 2.75. { bd, 4H) 3.2 (bd, 5H), 3.4 (m, 1H), 3.55 (dq, 2H), 3.95 (q, 1H) 7.7 (ra, 2H), 7.8 (d, 1H), 8.0 (m, 3H) ), 8-.15. { dd, 2H) 8.35 (d, 1H), 8.4 (s, 1H), 8.7 (bs, 2H), 8.95 (bd, 2H)
Example 28: 2- Hydrochloride. { [(4-propylphenyl) sulfonyl] amino} -3-. { [2- (. {4- (4-piperidyl) -2- [2- (4-piperidyl) ethyl] butanoyl}. Amino) acetyl] amino} propanic (CRL42811) Starter material: compound 42 Yield = 94%
..? M ». ^ H ^ > A ^. *. . , M. tt,. MS (ES): m / z 608 (M + H) * 1 H-NMR (400MHz, DMSO-ds): d 0.85. { t, 3H), 1.15 (m, 4H) 1.25 (m, 6H), 1.35 (m, 4H), 1.6 (q, 2H) 1.7 (m, 4H) 2.1 (m, 1H), 2.65 (t, 2H) , 2.75 (m, 4H), 3.15 (m, 4H) 3.25 (m, 1H), 3.5 (m, 2H), 3.8 (m, 1H), 7.35 (d, 2H) 7.65 (d, 2H), 8.0 ( t, 1H), 8.05 (ra, 1H), 8.1 (d, 1H) 8.8 (bd, 2H), 9.05 (bd, 2H).
Example 29: (3S) -4-Oxo-4- (4-benzylpiperidin) -3- (3,9) -hydrochloride. { [2- (. {4- (4-piperidi 1) -2- [2- (4-piperidyl) ethyl Jbutanoyl] amino) acetyl] amino} -Butanic (CRL42591)
Initiating material: compound 28 15 Yield = 89%
MS (ES): / z 612 (M + H) + ^ -NMR (400MHz, CD30D): d 1.3-1.6 (m, 12H), 1.9 (m, 6H), 2.26 (m, 1H), 2.55 (m , 4H), 2.92 (m, 6H), 3.45 (m, 6H), 3.85 (bd, 2H), 4 (bt, 1H), 4.4 (bd, 1H), 5.2 (bs, 1H), 20 7.15 (m , 3H), 7.25 (t, 2H).
r ?? l'¡«» tÉl? f-i'- i ?? í-mfMi?] 1 i? t li f-üti 1 - lililí i- TI a ni f i n ir I mil * t fürn I wlii - - - * - * ----- - > - - * - - .--- »- -.--. - l? JUUA ^? Example 30: 2- [([1, 1-biphenyl) -4-ylsulphyl) amino] -3- acid dihydrochloride. { [2- (. {4- (4-piperid? I) -2- [2- (4-piperidyl) ethyl] butanoyl} amino) acetyl] amino Jpropanoic 5 (CRL42913)
Initiating material: compound 43 Yield = 96% MS (ES): m / z 642 (M + H) * 10 ^ -NR (400MHz, DMSO-d6): d 1.15 (rn, 4H), 1.30 (m, 6H ), 1.45 (m, 4H), 1.75 (bd, 4H), 2.15 (ra, 1H), 2.75 (bq, 4H), 3.20 (bd, 5H), 3.40. { m, 1H), 3.60 (dq, 2H), 3.9 (m, 1H), 7.45 (t, 1H), 7.5 (t, 2H), 7.75 (d, 2H), 7.85 (s, 4H), 8.05 (bs , 2H), 8.3 (d, 1H), 8.9 (bq, 2H), 9.15 (bd, 2H). fifteen
Example 31: 2- [(1-naphthylsulfonyl) amino] 3- acid dihydrochloride. { [2- (. {4- (4-piperidyl) -2- [2- (4- (piperidyl) ethyl] butanoyl} amino) acetyl] amino} propanic (CRL42914)
Initiating material: Compound 44 Yield = 96% 25
aM¡ ^^^^^ aKMaII-aM ---- t ---- «- * - k - ta ------ M ------- ^^ MS (S): m / z 616 (M + H) * ^ - MR (400MHz, DMSO-d6): d 1.05 (m, 4H), 1.2 (m, 6H), 1.4 (m, 4H), 1.7 < bd, 4H), 2.1 (m, 1H), 2.75 (bq, 4H), 3.15 (bd, 5H), 3.3 (ra, 1H), 3.45 (dq ", 2H), 3.85 (q, 1H), 7.65 < m, 3H), 7.95 (m, 2H), 8.05 (d, 1H), 8.1 (d, 1H), 8.2 (d, 1H), 8.5 (d, 1H), 8.65 (d, 1H), 8.75 ( bs, 2H), 9.0 (bd, 2H).
Example 32: 2- ( { [4- (Methylsulfonyl) phenyl] sulfonyl} amino] -3- dihydrochloride. { [2- (. {4- (4- piperidyl) -2- [2- (4-piperidyl) ethyl] butanoyl} amino) acetyl] amino} propanic (CRL42969)
Starter material: compound 45 Yield = 91% MS (ES): m / z 644. { M + H) + XH-MR (400MHz, DMSO-d6): d 1.1 (m, 4H), 1.25 (ra, 6H), 1.4 (m, 4H), 1.7 (bd, 4H), 2.1 (m, 1H ), 2.7 (bq, 4H), 3.15. { bd, 5H), 3.25 (s, 3H), 3.35 (m, 1H), 3.55 (dq, 20 2H), 3.9 (m, 1H), 7.95-8.1 (m, 6H), 8.55 (d, 1H), 8.8 (bq, 2H), 9.05 (bd, 2H).
^. ^ A? ? K * A Í. Í. . i.%? * »M. # *,. **. . . . . ....., ".," ..... .. i. -. I Extract 33: 2- [(2-thienylsul foni 1) amino] -3- acid dihydrochloride. { [2- (. {4- (4-piperidyl) -2- [2- (4-piperidyl) ethyl] butanoyl}. Amino) acetyl] amino} propanic (CRL42985)
Initiating material: 46 Yield = 97%
MS (ES): / z 572 (M + H) + hi-NMR (400MHz, DMSO-d6): 5 1.05 (m, 4H), 1.25 (m, 6H),
1. 4 (m, 4H), 1.7. { bd, H), 2.15 (m, 1H), 2.7 (bq, 4H),
3. 15 (bd, 5H), 3.35 (? T ?, 1?), 3.55 (dq, 2H), 3.85 (q, 1H), 7.15 (dd, 1H), 7.5 (t, 1H), 7.9 (t, lH ), 8.0 (t,
1H), 8.05 (t, 1H), 8.4 (d, 1H), 8.8 (bq, 2H), 9.1 (bd, 2H) "
Example 34: 2 - acid dihydrochloride. { [(4-chlorophenyl) sulfonyl] amino} -3-. { [2- (. {4- (4-piperidyl) -2- [2- (4-piperidyl) ethyl] butanoyl} amino) acetyl] amino Jpropanoic (CRL42986)
Initiating material: compound 47 yield = 92%
*, ^ - ^ »- ^^^ * _. * ^ ^ -» "~» j * j ú * Ü MS (ES): / z 600. { M + H) * ^ -N R (400MHz, DMSO-d6): d 1.1 (m, 4H), 1.25. { m, 6H) 1.4 (m, 4H), 1.7 (bd, 4H), 2.1 (m, 1H), 2.7 (bq, 4H) 3.15 (bd, 5H), 3.3 (m, lH), 3.55 (dq, 2H) ), 3.8 (q, 1H) 7.6 < d, 2H), 7.75 (d, 2H), 8.05 (m, 2H), 8.35. { d, 1H) 8.85 (bq, 2H), 9.1. { bd, 2H).
Example 35: 2- Hydrochloride. { [(4- fluorophenyl) sulfonyl] amino} -3- . { [2- (. {4- (4-piperidyl) -2- [2- (4-piperidyl) ethyl] butanoyl}. Amino) acetyl] amino} propanoic 15 (CRL42999)
Initiating material: compound 48 Yield = 97% MS. { ES): m / z 584 (M + H) + 20 H-NMR (400MHz, DMSO-d6): d 1.15 (m, 4H), 1.3 (m, 6H) 1.45 (m, 4H), 1.75 (bd, 4H), 2.15 (ra, 1H), 2.75. { bq 4H), 3.2 (bd, 5H), 3.35 (ra, 1H), 3.6 (dq, 2H), 3.85 (ra 1H), 7.4 (t, 2H), 7.85 (dd, 2H), 8.05 (m, 2H) ), 8.30 (d 1H), 8.8. { bq, 2H), 9.1 (bd, 2H).
Example 36: (2S) -2- acid dihydrochloride. { [(6-methoxy-2-naphthyl) sulfonyl] amino} -3- . { [2- (. {4- (4-piperidl) -2- [2- (4-piperidyl) ethyl] butanoyl}. Amino) acetyl] amino} propanic
(CRL43000)
Initiating material: compound 49 yield = 90%
[a] D-10 (C = 1, H20) MS (ES): m / z 646 (M + H) + ^ -NR (400MHz, DMSO-d6): d 1.1 (m, 4H), 1.25 (m , 6H), 1.4 (m, 4H), 1.7 (bd, 4H), 2.15 (ra, 1H), 2.75 (bq, 4H), 3.2 (bd, 5H), 3.35 (m, 1H), 3.6 (dq, 2H), 3.85 (m, 1H), 3.9 (s, 3H), 7.3 (d, 1H), 7.45 (s, lH), 7.75 (d, lH), 8.0 (d, 1H), 8.05 (m, 3H) ), 8.25 (d, 1H), 8.3 (s, 1H), 8.8. { bq, 2H), 9.1. { bd, 2H).
Example 37: 2- [(mesitylsulfonyl) amino] -3- acid dihydrochloride. { [2- (. {4- (4-piperidyl) -2- [2- (4-piperidyl) ethyl] butanoyl}. Amino) acetyl] amino} propanic (CRL43031) Starter material: compound 50 Yield = 98%
I'm going to ... * _ ..
MS (ES): m / z 608. { M + H) * ^ - R (400MHz, DMSO-de): 8 1.15 (m, 4H), 1.3 (m, 6H), 1.4 (m, 4H), 1.7 (bd, 4H), 2.15 (m, lH ), 2.25 (s, 3H), 2.55 (s, 6H), 2.75 (bq, 4H), 3.2 (bd, 5H), 3.35 (m, 1H), 3.55 (dq, 2H), 3.8 (q, 1H) , 7.0 (s, 2H), 8.0 (ra, 3H), -8.85 (bq, 2H), 9.15 (bd, 2H).
Example 38: (2S) -2- [(Butylsulphonyl) amino] -3- acid dihydrochloride. { [2- (. {4- (4-piperidyl) -2- [2- (4-piperidyl) ethyl] butanoyl}. Amino) acetyl] amino} propan ico (CRL43032)
Starter material: compound 51 Yield = 90% [a] D -10.5 (C = 1, H20) MS (ES): m / z 546. { M + H) * XH-NMR (400MHz, DMSO-d6): 5 0.9 (t, 3H), 1.15 (m, 4H), 1.25-1.5 (m, 12H), 1.6-1.75. { m, 6H), 2.15 (m, lH), 2.75. { bq, 4H), 3.0 (m, 2H), 3.15 (bd, 4H), 3.25 (m, 1H),
3. 45 (m, 1H), 3.7 (dq, 2H), 3.95 (ra, 1H), 7.6 (d, 1H), 8.05 (t, 1H), 8.15 (t, 1H), 8.85 (bq, 2H), 9.1 . { bd, 2H).
..- _, A. ^ .., .., ...,., _. . ... .. - ".... ^. J ... ..., .. ^ ..-. X -. ^^ - ^. ^^ .. - .... ^ .. ... .... and .... ± ... ^ .M *. ... -. «..« -a - ^ - ^ - faS »Example 39: 2- Hydrochloride. { [(4- methylphenyl) sulphonyl] amino} -3-. { [2- (. {4- (4-piperidyl) -2- [2- (4-piperidyl) ethyl] butanoyl} amino) acetyl] a-Jpropanoic (CRL43033)
Initiating material: compound 52 yield = 87%
MS (ES): m / z 580 (M + H) * H-NMR (400MHz, DMS0-d6): d 1.15 (ra, 4H), 1.3 (ra, 6H), 1.45 (m, 4H), 1.75. { bd, 4H), 2.15 (ra, 1H), 2.4 (s, 3H), 2.75. { bq, 4H), 3.15 (bd, 5H), 3.35 (m, lH), 3.55 (dq, 2H), 3.8 (q, 1H), 7.35 (d, 2H), 7.7 (d, 2H), 8.0 (t , 1H), 8.05 (t, 1H), 8.1 (d, 1H), 8.8 (bq, 2H), 9.1 (bd, 2H).
Example 40: 2- Hydrochloride. { [(3-methylphenyl) sulfonyl] amino} -3-. { [2- (. {4- (4-piperidyl) -2- [2- (4- piperidyl) ethyl] butanoyl} amino) acetyl] amino Jpropanoic (CRL43043)
Initiating material: compound 53 Yield = 99%
MS (ES): m / z 580 (M + H) +: H-NMR (400MHz, DMSO-d €): d 1.1 (m, 4H), 1.25 (m, 6H), 1.4 (m, 4H), 1.7 (bd, 4H), 2.1 (m, lH), 2.35 (s, 3H), 2.7 (bq, 4H), 3.15 (bd, 5H), 3.3 (m, 1H), 3.5 (dq, 2H), 3.8 (m, 1H), 7.4 (m, 2H), 7.55 (m, 2H), 8.0 (m, 2H), 8.15 (d, 1H), 8.8 (bq, 2H), 9.1 (bd, 2H).
Example 41: 2- [(Benzylsul-fonyl) amino] -3- acid dihydrochloride. { [2- (. {4- {4-piperidyl) -2- [2- (4-piperidyl) ethyl] butanoyl} amino) acetyl] amino Jpropanoic (CRL43055) 15 Initiating material: Compound 54 Yield = 99 %
MS (ES): / z 580 (M + H) * XH-NMR (400MHz, DMSO-d6): d 1.15 (m, 4H), 1.3 (m, 6H),
1.45 (m, 4H), 1.75 (bd, 4H), 2.15 (m, 1H), 2.75 (bq, 4H), 3.15 (bd, 4H), 3.35 (ra, 1H), 3.45 (m, 1H), 3.7 (d, 2H), 3.95. { m, 1H), 4.35 (s, 2H), 7.35 (m, 5H), 7.6 (d, 1H), 8.1 (t, 1H), 8.15 (t, 1H), 8.85 (bq, 2H), 9.1 (bd) , 2H).
Example 42: 2- (. {(E) -2- phenylethenyl] sulfonyl} amino) -3- acid dihydrochloride. { [2- (. {4- (4-piperidyl) -2- [2- (4-piperidyl) -2- [2- (4-piperidyl) ethyl] butanoyl} amino) acetyl] amino} propanic (CRL43057)
Starter material: compound 55 Yield = 100% 10 MS (ES): m / z 592 (M + H) * aH-NMR (400MHz, DMS0-ds): d 1.15 (ra, 4H), 1.3 (m, 6H ), 1.45 (m, 4H), 1.75 (bd, 4H), 2.15 (m, 1H), 2.75 (bq, 4H), 3.15 (bd, 4H), 3.3 (ra, 1H), 3.45 (m, 1H) , 3.65 (ra, 2H), 3.9 (m, 1H), 7.15 (d, 1H), 7.35 (d, lH), 7.45 (ra, 3H), 7.7 (m, 2H), 7.9 (d, 1H), 8.1 (m, 2H), 8.9. { bq, 15 2H), 9.15 (bd, 2H).
Example 43: 2- [(2-phenethylsulfonyl) amino] -20 3- acid dihydrochloride. { [2- (. {4- (4-piperidi 1) -2- [2- (4-piperidyl) ethyl] butane] l.}. Amino) acetyl] ammolpro anoic (CRL43056)
Starter material: compound 56 Yield = 96% MS (ES): m / z 594 (M + H) * aH-NMR. { 400MHz, DMS0-d6): d 1.15 (m, 4H), 1.3 (m, 6H), 1.45. { m, 4H), 1.7 (bd, 4H), 2.15 (m, lH), 2.75 (bq, 4H), 2.95 (m, lH), 3.1 (m, 1H), 3.15 (bd, 5H), 3.3 (m , 2H), 3.5 (m, 1H), 3.7 (m, 2H), 4.05 (m, 1H), 7.3 (m, 5H), 7.8 (d, 1H), 8.1 (m, 2H), 8.9 (bq, 2H), 9.15 (bd, 2H).
Example 44: 2- ( { [3- (trifluoromethyl) phenyl] sulfonyl} amino] -3- dihydrochloride. { [2- (. {4- (4- piperidyl) -2- [2- (4- (piperidyl) ethyl] butanoyl} amino) acetyl] amino} propanic (CRL43058)
Initiating material: compound 7 Yield = 93% 20 MS (ES): / z 634 (M + H) * XH-NMR. { 400MHz, DMSO): d 1.15 (m, 4H), 1..3 (m, 6H), 1.4 (m, 4H), 1.75 (bd, 4H), 2.15 (ra, 1H), 2.75 (bq, 4H) , 3.2 (bd, 5H), 3.4 (m, 1H), 3.6 (dq, 2H), 3.95 (m, 1H), 7.85 (t, 1H), 8.0 (d, 1H), 8.05 (m, 4H), 8.6 (t, 1H), 8.85 (bq, 2H), 9.1 (bd, 2H). 25
, ... a - »». ^? -a «-. - .-. ^ ",. . * t t . *. , », .-. * + ,, .n.,.,. ..-,., *. . »» Í i, < *? fi ~ ume ..
Example 45: 2- Hydrochloride. { [(3- nitrophenyl) sulfonyl] amino} -3-. { [2- (. {4- (4-piperidyl) -2- [2- (4-piperidyl) ethyl] butanoyl}. Amino) acetyl] amino} propanic (CRL43059)
Starter material: compound 5 Yield = 90% 1C MS (ES): / z 611 (M + H) * H-NMR (400MHz, DMSO-d6): d 1.15 (m, 4H), 1.3 (ra, 6H ), 1.45 (m, 4H), 1.75 (bd, 4H), 2.15 (m, 1H), 2.75 (bq, 4H), 3.2. { bd, 5H), 3.35. { m, 1H), 3.6 (dq, 2H), 3.9 (m, 1H), 7.9 (t, 1H), 8.1 (m, 2H), 8.2 (d, 1H), 8.45 (dd, 1H), 8.55 (s) , 1H), 8.75 (d, 1H), 8.85 (bq, 2H), 9.1 15 (bd, 2H).
Example 46: 2- Acid hydrochloride. { [(4- 20-methoxyphenyl) sulfonyl] amino} -3-. { [2- ( { 4-piperidyl) -2- [2- (4-piperidyl) ethyl] butanoyl} amino) acetyl] ammo} propanic (CRL43060)
^ ¿^^^^^^^^ • - ^^ +? ,, *. < , ~ > . .. »-.,, ..-., .... ..,. "....., > ....,"...-...,._.. ..TO... . .... " < I.ii-ia-a-.j.
Initiating material: compound 59 Yield = 95% MS (ES): m / z 596 (M + H) *: H-NMR (400MHz, DMSO-d6): d 1.15. { m, 4H), 1.3 (rn, 6H),
1. 45 (m, 4H), 1.75 (bd, 4H), 2.15 (m, 1H), 2.75. { bq,
4H), 3.2. { bd, 5H), 3.35. { m, 1H), 3.6 (dq, 2H), 3.8 (m, 1H), 3.85 (S, 3H), 7.1 (d, 2H), 7.7 (d, 2H), 8.05 (m, 3H), 8.85 (bq , 2H), 9.1 (bd, 2H).
Example 47: 2 - [(8-Quinolinylsulfonyl) amino] -3- trichlorohydrate. { [2- (. {4- (4-piperidyl) -2- [2- (4-piperidyl) ethyl] butanoyl}. Amino) acetyl] amino} propanic (CRL43061)
Starter material: compound 60 Yield = 100% MS (ES): m / z 617 (M + H) * XH-MR (400MHz, DMSO): 6 1.15 (m, 4H), 1.25 (rn, 6H), 1.45 . { m, 4H), 1.75. { bd, 4H), 2.15 (m, "1H), 2.75 (bq, 4H), 3.2 (bd, 4H), 3.35 (m, 2H), 3.55 (dq, 2H), 4.25 (m, 1H), 7.75 ( m, 3H), 8.0 (t, 1H), 8.1 (t, 1H), 8.3 (m, 2H), 8.6 (d, 1H), 8.9 { bd, 2H), 9.1 (m, 1H), 9 , (bd, 2H).
. ,? S .. £ ü? ^. . *, ... J - ^.,. .. . . .. JML .. ^. ^ ... ^. ^. ^,. ".... ^. * > "-a" * iil Example 48: 2- {[[(3,5-dimethyl-4-isoxazolyl) sulfonyl] amino acid} -hydrochloride.} -3- { [2- (. {4- (4-piperidyl) -2- [2- (4-piperidyl) ethyl] butanoyl} amino) acetyl] amino Jpropanoic (CRL43068)
Initiating material: compound 61 yield = 85%
MS (ES): m / z 585 (M + H) * ^ -NMR (400MHz, DMS0-d6): d 1.15 (m, 4H), 1.3 (ra, 6H), 1.45. { m, 4H), 1.75. { bd, 4H), 2.15 (m, 1H), 2.35 (s, 3H), 2.6. { s, 3H), 2.75 (bq, 4H), 3.2. { bd, 5H), 3.4 (m, 1H), 3.6 (dq, 2H), 3.85 (m, 1H), 8.1 (t, '2H), 8.6 (d, 1H), 8.9 (bq, 2H), 9.15 ( bd, 2H).
Example 49: 2- ( { [5- (dimethylamino) -1-naphthyl) sulfonyl acid trichlorohydrate} amino) -3-. { [2- (. {4- (4-piperidyl) -2- [2- (4-pipridyl) ethyl] butanoyl}. Amino) acetyl] amino} propanic (CRL43069)
Initiating material: compound 62 yield = 100%
MS. { ES): / z 659 (M + H) + XH-NMR (400MHz, DMSO-d6): d 1.1 (ra, AH), 1.3 (m, 6H), 1.45 (ra, 4H), 1.7 (bd, 4H ), 2.15 (m, 1H), 2.75 (bq, 4H), 3.2 (bs, 11H), 3.35 (m, 2H), 3.5 (q, 1H), 3.9 (q, 1H), 7.75 (q, 2H) , 7.9 (bs, 1H), 7.95 < t, lH), 8.05 (t, 1H), 8.7 (dd, 2H), 8.9 (bq, 2H), 9.15 (bd, 2H).
Example 50: 2- ( { [2- (Acetylamino) -4-methyl-l, 3-thiazol-5-yl] sulphonyl} -3- acid dihydrochloride. { [2 - (. {4- (4- piperidyl) -2- [2- (4-piperidyl) ethyl] butanoyl} amino) acetyl] amino Jpropanoic 15 (CRL43070)
Initiating material: compound 63 yield = 100%
MS (ES): m / z 644 (M + H) * 20? H-NMR (400MHZ, DMSO-d6): d 1.15 (m, 4H), 1.3 (ra, 6H), 1.45. { m, 4H), 1.75 (bd, 4H), 2.15. { m, 1H), 2.2 (s, 3H), 2.45 (s, 3H), 2.8 (bq, 4H), 3.2 (bd, 5H), 3.4 (m, 1H), 3.6 (dq, 2H), 3.9 (m , 1H), 8.1 (m, 2H), 8.45 (d, 1H), 8.85 (bq, 2H), 9.1 (bd, 2H).
? m * .r -tf? lBWlr "n 'H -' # 4 fuf r- • • - - - ->.?: ^, iL >.
Example 51: 2- Acid hydrochloride. { [(3-chloropropyl) sulfonyl] amino} -3- . { [2- ((4- (4-piperidyl) -2- [2- (4-piperidyl) ethyl] butanoyl} amino) acetyl] amino} propane (CRL43078) Starting material: compound 64 Yield = 100 %
MS (ES): m / z 566 (M + H) * 10 XH-NMR (400MHz, DMS0-d6): d 1.15 (ra, 4H), 1.25. { m, 6H), 1.45 (m, 4H), 1.75 (bd, 4H), 2.15 (ra, 3H), 2.75 (bq, 4H), 3.15 (m, 7H), 3.45 (m, 1H), 3.65 (m , 2H), 3.75 (t, 2H), 3.95 (m, 1H), 7.75 (d, 1H), 8.1 (m, 2H), 8.8 (bq, 2H), 9.1 (bd, 2H).
Example 52: 2- Acid hydrochloride. { [(4-methoxy-1-naphthyl) sulfonyl] amino} -3- . { [2- (. {4- (4-piperidyl) -2- [2- (4- (piperidyl) ethyl] butanoyl} amino) acetyl] amino} prpranóico (CRL43079) Material initiator: the compound 65 Performance = 95%
.15 (ra, 4H), 1.3 (m, 6H), 1.45 (m, 4H), 1.7 | (bd, 4H), 2.1 (m, 1H). 2.75 (bq, 4H), 3.15 (bd, 5H), 3.3 (m, 1H), 3.45 (dq, 2H), 3.8 (ra, 1H), 4.05 (s, 3H), 7.1 | (d, 2H), 7.60 (t, 1H), 7.7 (t, 1H), 7.9. { t, 1H), 8.0! (t, 1H), 8.1 (d, 2H), 8.3 (d, 1H), 8.35 (d, 1H), 8.6 i (d, 1H), 8.85 (bs, 2H) "9.1 (bs, 2H)
Example 53: 2- Acid dihydrochloride. { [(6,7-dimethoxy-2-naphthyl) sulfonyl] amaino} -3- . { [2- (. {4- (4-piperidyl) -2- [2- (4-piperidyl) ethyl] butanoyl} amino] acetyl] amino.} Propanoic
(CRL43080)
Initiating material: the compound 66 yield = 86%
MS (ES): m / z 616 (M + H) * 20 Hi-NMR (400MHz, DMSO-d6): d 1.15 (ra, 4H), 1.3 (m, 6H), 1.45 (m, 4H), 1.75 (bd, 4H), 2.15 (m, 1H), 2.75 (bq, 4H), 3.15 (bd, 5H), 3.35 (m, 1H), 3.55. { dq, 2H), 3.85 (ra, 1H), 3.9 (s, 3H), 3.92 (s, 3H), 7.45 (s, 1H), 7.55 (s, 1H), 7.65. { d, 1H), 7.9 (d, 1H), 8.05. { bs, 2H), 8.20 (d, 1H), 8.25 (s, ¡1H), 8.85 (bq, 2H), 9.1 (bd, 2H). 25
.. ~. * r *. * já. ¿aiMftn.
Example 54: 2- [[(2,4-dimethyl-l, 3-thiazol-5-yl) sulfonyl lamino dihydrochloride} -3- . { [2- ( { 4- (4-piperidyl) -2- [2- (4-! Piperidyl) ethyl] bu [tanoyl.}. Amino) acetyl] amino Jpropanoic (CRL43120) ¡
Initiating material: compound 67 Yield = 94%
^ - R (400MHz, DMSO-d6): d 1.15 (m, 4H), 1.3 (m, 6H),
1.45 (m, 4H), 1.7SJ (bd, 4H), 2.15 (ra, 1H), 2.5 (s, 3H), 2.65 (s, 3H), 2.75 (bq, 4H), 3.2. { bd, 5H), 3.4 (m, lH), 3.6 (dq, 2H), 3.9 ^ (q, 1H), 8.1 (ra, 2H), 8.7 (d, lH) 8.9 (bq, 2H), 9.15 (bd) , 2H).
Example 55: (2 -. {[[(3,5-Dimethyl-1H-pyrazol-4-yl) sulfonyl] amino acid dichlorohydrate] -3- { [2- (. {4 - (4-piperidi1) -2- [2- (4-piperidyl) ethyl] butanoyl} amino) acetyl] amino Jpropanoic
; CRL43121
Initiating material: compound 68 yield = 98
MS (ES): m / z 584 (M + H) * 1 H-NMR. { 400MHz, DMS0-d6): d 1.15 (m, 4H), 1.25 (m, 6H), 1.4 (m, 4H), 1.7 (bd, 4H), 2.15. { m, 1H), 2.3 (s, 6H), 2.75 (bq, 4H), 3.15 (bd, 5H), 3.3 (m, 1H), 3.6 (dq, 2H), 3.75 (m, 1H), 7.8 (d , 1H), 8.0 (bt, 1H), 8.1. { bt, 1H), 8.8 (bq, 2H), 9.15 (bd, 2H).
Example 56: 2- [(3-pyridinesulfonyl) 3- {[[2- (. {4- {4-piperidyl) -2- [2- (4-piperidyl) ethyl] butanoyl} trichlorohydrate. amino) acetyl] amino.}. propanic (CRL43122)
Initiating material: compound 69 yield = 69%
MS (ES): m / z 567. { M + H) * XH-NMR. { 400MHz, DMSO): d 1.1 (m, 4H), 1.3 (m, 6H), 1.45 (m, 4H), 1.7 (bd, 4H), 2.15 (m, 1H), 2.75 (bd, 4H), 3.15 ( bd, 5H), 3.45 (m, lH), 3.55 (dq.2H). 3.95 (q, 1H), 7.75 (t, 1H), 8.15 (bd, 2H), 8.35 (d, 1H), 8.75 (d, 1H), 8.9 (bd, 1H), 8.95 (bd, 2H), 9.0 (s, 1H), 9.2 (bd, 2H).
Example 57: 2- [(1,3-Benxodioxol-5-yl sulphonyl) amino acid dihydrochloride} -3- . { [2- (. {4- (4-piperidyl) -2- [2- (4-piperidyl) ethyl] butanoyl} amino) acetyl] amino Jpropanoic (CRL43123)
Initiating material: compound 70 yield = 91%
MS (ES): / z 610 (M + H) * ^ -NM (400MHz, DMSO-dg): d 1.1 (m, 4H), 1.25 (m, 6H),
1. 4 (m, 4H), 1.7 (bd, 4H), 2.15 (m, 1H), 2.75. { bq, 4H), 3.15 (bd, 5H), 3.3 (m, 1H), 3.6 (dq, 2H), 3.75 (m, 1H), 6.1 (d, 2H), 7.0 < d, 1H), 7.2 (s, 1H), 7.25 (d, 1H),
8. 05 (m, 3H), 8.75 (bd, 2H), 9.05 (bd, 2H).
Example 58: 2- [(2,3-Dihydro-l, 4-benzodioxin-6-ylsulfonyl) amino] -3- acid dihydrochloride. { [2- ( { 4- (4-piperidyl) -2- [2- (4-piperidyl) ethyl] butanoyl} amino) acetyl] araino Jpropanoic acid
(CRL43124)
Initiating material: compound 71 yield = 91%
^^ ¡^ ^ j ^^ ¡^ MS (ES): m / z 624 (M + H) + ^ -NMR (400MHz, DMSO-de): d 1.1 (m, 4H), 1.3 (m, 6H ), 1.4 (m, 4H), 1.7 (bd, 4H), 2.15 (m, 1H), 2.75 (bq, 4H), 3.15 (bd, 5H), 3.3 (m, 1H), 3.6 (dq, 2H) , 3.75 (q, 1H), 4.3 (dd, 2H), 6.95 (d, 1H), 7.2 (d, 1H), 7.22 (s, lH), 8.05 (m, 3H), 8.85 (bq, 2H), 9.1 (bd, 2H).
Example 59: 2- [(1-Benzothiophen-2-yl-su1-fonyl) amino] -3- dihydrochloride. { [2- (. {4- (4-piperidyl) -2- [2- (4-piperidyl) ethyl] butanoyl}. Amino) acetyl] amino} propanic (CRL43125)
Initiating material: the compound 72 15 Performance = 99%
Yield = 99% MS (ES): m / z 622 (M + H) + 1 H-NMR (400MHz, DMSO-d 6): d 1.1 (m, 4H), 1.25 (m, 6H). 1.4 (m, 4H), 1.7. { bd, 4H), 2.15 (m, 1H), 2.75 (bq, 4H). 3.15 (bd, 5H), 3.3 (m, 1H), 3.45 (dq, 2H), 3.9 (q, lH),
7.5 (m, 2H), 8.0 (m, 2H), 8.1 (d, 1H), 8.2 (d, 1H). 8.45 (1H), 8.55 (d, 1H), 8.9 (bq, 2H), 9.15 (bd,
^ A ^^ A - ^ - Sj -...- Example 60: 2- Acid hydrochloride. { [(2,5-dimethyl-3-furyl) sulfonyl] amino} -3- . { [2- (. {4- (4-piperidi1) -2- [2- (4-piperidyl) ethyl] butanoyl}. Amino) acetyl] amino} propanic
Performance = 91%
MS (ES): / z 624 (M + H) + 1-NMR (400MHz, DMSO-d 6): d 1.1 (m, 4H), 1.3 (m, 6H), 1.4 (m, 4H), 1.7 (bd) , 4H), 2.15 (m, 1H), 2.75 (bq, 4H), 3.15 (bd, 5H), 3.3 (m, 1H), 3.6 (dq, 2H), 3.75 (q, 1H), 4.3 (dd, 2H), 6.95 (d, 1H), 7.2 (d, 1H), 7.22 (s, lH), 8.05 (m, 3H), 8.85 (bq, 2H), 9.1 (bd, 2H).
Example 61: 2- Acid hydrochloride. { [(4-cyclohexylphenyl) sulfonyl] amino) -3-. { [2- (. {4- (4-piperidyl) -2- [2- (4-piperidyl) ethyl] butanoyl}. Amino) acetyl] amino} propanic (CRL43132)
Initiating material: the compound 74 Yield = 94%
. ".-_ I ^ -_-_ ^ ¿i¿i ^ ___ ^ - 1 > jtlil¡_ ß * ™ "É ^ n * tí * 3 ^ jggSg ^^^^^ MS (ES): / z 648 (M + H) * * H-NMR (400MHz, DMSO-d6): d 1- 0-1.5 (m, 20H), 1.75 (m, 8H), 2.15 (m, 1H), 2.6 (bt, 1H), 2.75 (bq, 4H), 3.2 (bd, 5H), 3.35 (ra, 1H) , 3.5 (dq, 2H), 3.85 (q, 1H), 7.15 (d, 2H), 7.7 (d, 2H), 7.98 (t, 1H), 8.04 (t, 1H), 8.1 (d, 1H), 8.8 { Bq, 2H), 9.05 (bd.2H).
Example 62: 2- acid dihydrochloride. { [(4-fluoro-1-10 naphthyl) sulfonyl] ammo} -3-. { [2- ( { 4- (4-p? Per? D? L) -2- [2-
4- Jipepdil) et? L] butane? L} ammo) acetyl] a? no} propanó? cc; CRL43133) _
Starter material: compound 75 Yield = 90% MS (ES): m / z 634 (M + H) * H-NMR (400MHz, DMSO-d6): d 1.1 (ra, 4H), 1.25 (m, 6H ) 1.4 (m, 4H), 1.7. { bd, 4H), 2.1 (m, 1H), 2.75 (bq, 4H) 3.15. { bd, 5H), 3.3 (ra, 1H), 3.5 (dq, 2H), 3.85 (q, 1H) 20 7.5 (t, 1H), 7.8 (m, 2H), 8.0 (m, 2H), 8.15 (m , 2H) 8.65 (d, 1H), 8.7 (d, 1H), 8.8 (bq, 2H), 9.05 (bd, 2H).
* m ~ ** »¿+. i -. . » .. ... ...,. . ». * Example 63: 2- Acid hydrochloride. { [(4-chloro-1-naphthyl) sulfonyl] amino} -3- . { [2- (. {4- {4-piperidyl) -2- [2- (4- (5-piperidyl) ethyl] butanoyl} amino) acetyl] amino Jpropanoic (CRL43134) Starting material: compound 76 Yield = 91 %
MS (ES): m / z 650 (M + H) * 10 ^ -NMR (400MHz, DMSO-d $): 6 1.1 (m, 4H), 1.25 (m, 6H), 1.4 (m, 4H), 1.7. { bd, 4H), 2.15 (m, 1H), 2.75 (bq, 4H), 3.15 (bd, 5H), 3.35 (m, 1H), 3.5 (dq, 2H), 3.85 (q, 1H), 7.85 (m , 3H), 8.0 (m, 2H), 8.1 (t, 1H), 8.75 (m, 4H), 9.0 (bd, 2H).
Example 64: 2- [(2,3-Dihydro-l-benzofuran-5-i1-sulphonyl) amino] -3- dihydrochloride. { [2- (. {4- {4-piperidyl) -2- [2- (4-piperidyl) ethyl] butanoyl} amino) acetyl] amino Jpropanoic (CRL43142) Starting material: compound 77 Yield = 94 %
MS (ES): m / z 608 (M + H) + 1 H-NMR (400MHz, DMSO-dg): d 1.1 (m, 4H), 1.25 (m, 6H), 1.4 (m, 4H), 1.7 ( bd, 4H), 2.15 (m, 1H), 2.75 (bq, 4H), 3.2 (m, 7H), 3.3 (ra, 1H), 3.6 (dq, 2H), 3.75 (q, 1H), 4.65 (t , 2H), 6.9 (d, 1H), 7.52 (d, 1H), 7.6 (s, lH), 8.0 (d, 1H), 8.05. { t, 1H), 8.10 (t, 1H), 8.85 (bq, 2H), 9.1 (bd, 2H).
Example 65: 2- Hydrochloride. { [(4- (2-thienyl) phenyl] sulfonyl] amino] -3-. { [2- (. {4- (4-piperidyl) -2- [2- (4-piperidyl) ethyl] butanoyl}. Amino) acetyl] amino} propanic (CRL43143)
Initiating material: compound 78 yield = 66%
MS (ES): m / z 648 (M + H) * ^? - NMR (400MHz, DMSO-d6): d 1.1 (m, 4H), 1.25 (m, 6H) 1.35 (m, 4H), 1.7 ( bd, 4H), 2.15 (ra, 1H), 2.75 (bq 4H), 3.1 (bd, 5H), 3.3 (m, 1H), 3.55 (dq, 2H), 3.85 (ra, 1H), 7.2 (bs, 1H), 7.65. { bs, 2H), 7.75. { dd, 4H), 8.05 (ra, 2H), 8.30 (d, 1H), 8.85 (bq, 2H), 9.1 (bd, 2H).
Example 66: 2- acid dihydrochloride. { [(2- (2-thienyl) phenyl] sulfonyl] amino) 3-. { [2- (. {4- (4-piperidyl) -2- [2- (4- (5-piperidyl) ethyl] butanoyl} amino) acetyl] amino} propanic (CRL43144)
Starter material: the compound 79 Yield = 97% 10 MS (ES): m / z 648 (M + H) + XH-NMR (400MHz, DMSO-dg): d 1.1 (m, 4H), 1.25 (ra, 6H ), 1.4 (m, 4H), 1.7 (bd, 4H), 2.1 (ra, 1H) ", 2.75 (bq, 4H), 3.15 (bd, 4H), 3.3 (m, 1H), 3.35 (m, 1H) ), 3.65 (dq, 2H), 3.8 (q, 1H), 7.1 (t, 1H), 7.35 (d, 1H), 7.5 (d, 2H), 7.6 (m, 3H), 7.85 (d, 1H) , 8.0 (d, lH), 8.1 (m,
2H), 8.8 (bq, 2H), 9.1 (bd, 2H).
Example 67: 20 2- Acid dihydrochloride. { [(4- (2-furyl) phenyl] sulfonyl.] Amino) -3-. { [2- (. {4- (4-piperidyl) -2- [2- (4-piperidyl) ethyl] butanoyl}. Amino) acetyl] amino} propanic (CRL43146) 25
«-JMmiffiilliitlri- '' t I a.i ul. intuit ,,, «& , *,« r -. »,, .., ..» ...., ^ ,,, .... A ...... ¥,, "," " ",,, ... ^ ^ _ _ ^. . t. ? Initiating material: compound 80 yield = 84%
MS (ES): m / z 632. { M + H) *: H-NMR (400MHz, DMSO-d6): d 1.1 (ra, 4H), 1.25 (m, 6H), 1.45 (m, 4H), 1.75 (bd, 4H), 2.15 (ra, 1H), 2.75 (bq, 4H), 3.2 (bd, 5H), 3.35 (ra, 1H), 3.6. { dq, 2H), 3.85 (q, 1H), 6.7 (d, 1H), 7.2 (d, 1H), 7.8 (d, 2H), 7.85 (m, 3H), 8.1 (m, 2H), 8.25 (d , 1H), 8.85. { bq, 2H), 9.1 (bd, 2H).
Example 68: 2- [(1-Benzofuran-2-ylsulfonyl) amino] -3- acid dihydrochloride. { [2- (. {4- (4-piperidyl) -2- [2- (4-piperidyl) ethyl] butanoyl}. Amino) acetyl] amino} propanic
(CRL43147) Starter material: compound 81 Yield = 94%
^ -NR (400MHz, DMSO-d6): d 1.1 (m, 4H), 1.2 (m, 6H), 1.4 (m, 4H), 1.75 (bd, 4H), 2.15 (m, 1H), 2.75 ( bq, 4H), 3.15. { bd, 5H), 3.5 (ra, 1H), 3.55 (dq, 2H), 4.05 (m, 1H), 7.4 (t, 1H), 7.5 (m, 2H), 7.7 (d, 1H), 7.75 (d , 1H), 8.05 (bs, 2H), 8.8 (bd, 3H), 9.1. { bd, 2H). 25
Example 69: 2- Acid hydrochloride. { [(2-naphthylmethyl) sulfonyl] amino} -3- . { [2 - (. {4- (4-piperidyl) -2- [2- (4-piperidyl) ethyl] butanoyl}. Amino) acetyl] amino} propanic (CRL43158)
Initiating material: the compound 82 Yield = 88%
XH-NMR (400MHz, DMSO-d6): d 1.2 (m, 7H), 1.45 (m, 4H),
1. 7 (m, 4H), 2.15. { ra, 1H), 2.75 (bq, 4H), 3.1 (bd, 4H),
3. 4 (m, 2H), 3.7 (d, 2H), 4.05 (q, 1H), 4.5 (s, 2H),
7. 55 (d, 2H), 7.65 (d, 1H), 7.95 (m, 4H), 8.05 (t, 1H> 8.1 (t, 1H), 8.6 (bq, 2H), 8.85 (bd, 2H).
Example 70: 2- [(2,3-Dihydro-lH-inden-5-ylsul-fonyl) amino acid dihydrochloride} -3- . { [2- (. {4- (4-piperidyl) -2- [2- (4-piperidyl) ethyl] utanoyl} - a) n) acetyl] amino} propanic (CRL43159)
Initiating material: compound 83 yield = 94%
• ""? - * 'and' - '' »* • ** < -XH-NMR (400MHz, DMSO-d6): d 1.15 (ra, 4H), 1.25 (ra, 6H), 1.4 (m, 4H), 1.7 (bd, 4HJ, 2.05 (m, 2H), 2.15 (m , 1H), 2.75 (bq, 4H), 2.9 (t, 4H), 3.15 (bd, 5H), 3.35 (m, 1H), 3.5 (dq, 2H), 3.8 (q, 1H), 7.4 (d, 1H), 7.55 { D, 1H), 7-6 (s, 1H), 8.0 (m, 4H), 8.75 (bq, 2H), 9.0 (bd, 2H).
Example 71: 2- Acid hydrochloride. { [(5-phenyl-2-thiyl)) sulfonyl] amino} -3-. { [2- ( { 4- (4-piperidyl) -2- [2-
(4-piperidyl) ethyl] utanoyl} amino) acetyl] amino Jpropanoic (CRL43160)
Initiating material: the compound 84 Yield = 97%
MS (ES): m / z 648. { M + H) * H-NMR (400MHz, DMSO-dg): d 1.1 (m, 4H), 1.25 (ra, 6H),
1. 4 (m, 4H), 1.7. { bd, 4H), 2.15 (m, 1H), 2.75 (bq, 4H), 3.15 (bd, 5H), 3.4 (m, 1H), 3.6 (dq, 2H), 3.95 (q, 1H),
7. 4 (m, 3H), 7.55 (s, 2H), 7.75 (d, 2H), 8.05 (bs, 2H), 8.55 (d, 1H), 8.85. { bq, 2H), 9.1 (bd, 2H).
. - - í -.- .. "., .. .... -,». & A. ti. «fa.,. ^ fc - - -,.. ^» a »? i? a < Example 72: 2 - [(5, 6, 7, 8-tetrahydro-2-naphthalenylsulfonyl) amino] -3- { [2- (. {4- (4-piperidyl) -2-dihydrochloride] - [2- (4-piperidyl) ethyl] butanoyl} amino) acetyl] amino.} Propane (CRL43161
Initiating material: the compound 85 Yield = 97% 10 MS (ES): / z 620 (M + H) * XH-MR (400MHz, DMSO-dd): d 1.1 (m, 4H), 1.25 (m, 6H) , 1.45 (m, 4H), 1.75 (bs, 8H), 2.15 (ra, lH), 2.75 (bs, 8H), 3.2 (bd, 5H), 3.35 (m, 1H), 3.55 (dq, 2H), 3.8 (q, 1H), 7.2 (d, 1H), 7.45. { d, 2H), 8.0 (m, 3H), 8.75 (bq, 2H), 9.0 (bd, 2H). fifteen
Example 73: 2- Acid hydrochloride. { [(E) -l- pentenylsulfonyl] amino} -3-. { [2- (. {4- (4-piperidyl) -2- [2- (4-piperidyl) ethyl] butanoyl}. Amino) acetyl] amino} propanic (CRL43176) Starter material: the compound 86 Yield = 93% 25
mM á Á. 1 Vl1 'IÍ M' rr 'r' ff '' '' "~ ', -' ** ^ MS (ES): m / z 558 (M + H) * lH-NMR (400MHz, DMSO-d6): d 0.9 (t, 3H), 1.15 (ra, 4H),
1. 25 { m, 6H), 1.45 (m, 6H), 1.75 (bd, 4H), 2.15 (q,
3H), 2.75 (bq, 4H), 3.2 (bd, 5H), 3.4-3.75 (ra, 4H), 6.3
(d, 1H), 6.5. { dt, 1H), 7.65 (d, 1H), 8.0 (t, 1H), 8.1 (t, 1H), 8.75 (bq, 2H), 9.0 (bd, 2H).
Example 74: 2- [(Cyclohexylsulfonyl) amino acid dihydrochloride} -3- . { [2- (. {4- (4-p? Perid? L) -2- [2- (4-piperidyl) ethyl] butanoyl}. Amino) acetyl] amino} propanic (CRL43190)
Initiating material: compound 30 yield = 93%
MS (ES): m / z 572 (M + H) *: H-NMR (400MHz, DMSO-dg): 5 1.05-1.40 (m, 15H), 1.45 (m, 4H), 1.60 (bd, 1H) , 1.75 (m, 6H), 2.0-2.25 (ra, 3H), 2.75 (bq, 4H), 2.85 (rn, 1H), 3.15 (bd ', 4H), 3.25 (m, 1H), 3.45 (m, 1H), 3.70 (m, 2H), 3.95 (m, 1H), 7.5 (d, 1H), 8.10. { m, 2H), 8.85 (bd, 2H), 9.1 (bd, 2H).
------- ril-üh-ta. Figure imgb0001 Example 75: 2- [(isopropylsul-fonyl) amino] -3- acid dihydrochloride. { [2- (. {4- (4-piperidyl) -2- [2- (4-piperidyl) ethyl] butanoyl}. Amino) acetyl] amino} propanic (CRL43191)
Initiating material: compound 31 yield = 97%
MS (ES): m / z 532 (M + H) * Hl-NMR (400MHz, DMSO-d6): d 1.1-1.35 (m, 16H), 1.45 (m, 4H), 1-75 (bd, 4H ), 2.15. { m, 1H), 2.75 (bq, 4H), 3.1 (m, 1H), '3.2 (bd, 4H), 3.3 (ra, 1H), 3.45 (ra, 1H), 3.70 (m, 2H), 3.95 ( m, 1H), 7.5 (d, 1H), 8.05 (t, 1H), 8.10 (t, 1H), 8.8. { bq, 2H), 9.05 (bd, 2H).
Example 76: 2- [(1,3-Benzothiazol-2-ylsul-fonyl) amino] -3- acid dihydrochloride. { [2- (. {4- (4-piperidyl) -2- [2- (4-piperidyl) ethyl] butanoyl}. Amino) acetyl] amino} propanic (CRL43194)
Initiating material: compound 32 yield = 98%
lg i j ^ MS (ES): m / z 623 (M + H) *
HIFI-NMR (400MHz, DMSO-dg): d 1.15 (ra, 4H), 1.30 < m, 6H > , 1.45 (m, 4H), 1.70 (m, 4H), 2.15 (m, lH), 2.75 (bd, 4H), 3.15 (bd, 4H), 3.25 (m, 1H), 3.60 (m, 3H), 4.20 (q, 1H), 7.70 (m, 2H), 8.05. { bd, 2H), 8.20 (d, 1H), 8.30 (d, 1H), 8.90 (bd, 2H), 9.20 (bd, 2H), 9.25 (d, 1H).
Example 77: (2S) -2- acid dihydrochloride. { [(benzyloxy) carbonyl] amino} -3- . { [3- (. {4- (4-piperidyl) -2- [2- (4-piperidyl) ethyl] butanoyl}. Amino) -propanoyl] amino} propanic (CRL43022) 15 Starter material: compound 33 Yield = 88%
MS (ES): m / z 574 (M + H) * aH-NMR (400MHz, DMSO-dg): d 1.10 (m, 4H), 1.25 (m, 6H), 20 1.45 (m, 4H), 1.75 (bd, 4H), 2.05 (m, 1H), 2.25 (t 2H), 2.75 (bq, 4H), 3.15 (bd. 6H), 3.3 (m, 1H), 3.45 (m, 1H), 4.1. { m, 1H), 5.05 (s, 2H), 7.35 (s, 5H), 7.55 (d, 1H). 7.95 (t, 1H), 8.15 (t, lH), 8.95 (bq, 2H), 9.15. { bs, 2H).
_ ^ ¡^ Gg¡ ^^ - * • - * ••• ** • - ** ¡sS * am Example 78: 2- [(2-naphthylsulfonyl) amino] -3- acid dihydrochloride. { [3- (. {4- (4-piperidyl) -2- [2- (4-piperidyl) ethyl] -butanoyl} amino) propanoyl] amino} propanic (CRL43021)
Initiating material: the compound 87 yield = 84%
MS (ES): m / z 630 (M + H) *: H-NMR (400MHz, DMSO-d6): d 1.05 (m, 4H), 1.25 (m, 6H), 1.40 (m, 4H), 1.75 . { bd, 4H), 2.05. { m, 3H), 2.75 (bq, 4H), 3.15 (m, 7H), 3.3 (m, 1H), 3.95 (q, 1H), 7.7 (m, 2H), 7.8 (d, 1H), 7.9 (t , lH), 8.05 (d, 1H), 8.1 (m, 3H), 8.3 (d, 1H), 8.4 (s, 1H), 9.0 (bd, 2H), 9.25 (bd, 2H).
Example 79: 2- [(phenylsulfonyl) amino] -3- acid dihydrochloride. { [3- (. {4- (4-piperidyl) -2- [2- (4-piperidi 1) ethyl] -b-tainoi-1.} -amino) -propanoyl] -amino} propanic (CRL43145) Starter material: Compound 88 Yield = 86%
"" • ••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••• (400MHz, DMSO-d6): d 1.05 (m, 4H), 1.25 (m.6H), 1.40 (m, 4H), 1.70 { Bd, 4H), 2.05 (ra, 1H), 2.1 (q, 2H), 2.75 (bq, 4H), 3.15 (m, 1H), 3/30 (m, 1H), 3.85 (q, 1H), 7.55 (ra, 3H), 7.8 (d, 1H), 7.9 (t , 1H), 8.1 (t, 1H), 8.25 (d, 1H), 8.9 (bd, 2H), 9.10 (bd, 2H).
Example 80: 2- [(2-naphthylsulfonyl) amino '3- acid dihydrochloride. { [3- (. {4- (4-piperidyl) -2- [2- (4-piper id 1) ethyl] -butanoyl} amino) butanoyl] amino} propanic (CRL43195)
Initiating material: compound 34 Performance = 100%
MS (ES): m / z 644 (M + H) * XH-NMR (400MHz, DMSO-dg): d 0.9 (d, 3H), 1.05. { m, 4H), 1.25 (m, 6H), 1.40 (m, 4H), 1-70 (m, 4H), 1.95. { ra, 1H), 2.00 (m, 1H), 2.15. { dd, 1H), 2.75 (bq, 4H), 3.05 (m, 1H), 3.20 (bd, 4H), 3.35 (ra, 1H), 3.95 (m, 2H), 7.70 (m, 3H), 7.8 (d , 1H), 8.05 (ra, 2H), 8.10 (dd, 2H), 8.30 (d, 1H), 8.35 (s, 1H), 8.75 (bt, 2H), 9-0 (bd, 2H).
* * '- * "-,., -, i 8 ..., - W Example 81: 2- [(2-naphthylsulf onyl) amino] 3- {3-phenyl-3-dihydrochloride} - ( { 4- (4-piperidyl) -2- [2- (4-piperidyl) -ethyl] butanoyl} - a) nono) butanoyl] amino.} Propane (CRL43196)
Initiating material: compound 35 yield = 87%
MS (ES): m / z 706 (M + H) * ^ -NMR (400MHz, DMSO-dg): 5 1.00 (m, 4HI, 1.25 (m, 6H), 1.40 (m, 4H), 1.65 (dd) , 4H), 2.10 (m, 1H), 2.40 (ra, 1H), 2.75 (bd, 4H), 3.00 (m, 1H), 3.10 (bs, 4H), 3.25 (m, 1H), 3.75 (m, 1H), 3.98 (q.1H), 7.25 (m, 5H), 7.65 (m, 2H), 7.80 (m, 1H), 8.00 (t, 1H), 8.10 (m, 3H), 8.30 (t, 1H) ), 8.45 (d, 1H), 8.48 (ra, 1H), 8.75 (bt, 2H), 9.05 { Bt, 2H).
Example 82: 2- [(2-naphthylsulf onyl) amino acid dihydrochloride; 3- . { [((3R) -l- { 4- (4-piperidyl) -2- [2- (-piperidyl) ethyl] butanoyl}. Hexahydro-3-pyridyl) carbonyl] amino} ico propane (CRL43197) Starter material: compound 36 Yield = 93%
MS (ES): / z 670 (M + H) * aH-NMR (400MHz, DMSO-dg): -d 1.05 (ra, 4H), 1.25-1.60 (m, 14H), 1-73 (bt, 4H ), 2.00 (m, 1H), 2.45 (m, 1H), 2.75. { ra, 6H), 3.10 (ra, 5H), 3.35 (m, 1H), 3.90 (m, 2H), 4.30 (dd, 1H), 7.70 (m, 2H), 7.80 (m, 1H), 8.00 (m , 1H), 8.10 (m, 3H), 8.40 (m, 2H), 8.85-9.25 (m, 4H).
Example 83: 2- [(2-naphthylsulfonyl) amino] - dihydrochloride
3-. { [2-phenyl-2- (. {4- (4-piperidyl) -2- [2- (-piperidi-1) -ethyl] -butanoyl} - amino) ethanoyl] amino} propanic (CRL43210) Starter material: compound 91 Yield = 94% 15 XH-NMR (400MHz, DMSO-d6): d 0.95 (m, 1H), 1.0-1.5 (m, 13H), 1.60 (bd, 2H), 1.70 (bd, 2H), 2.35 (m, 1H), 2.70 (ra, 4H), 3.15 (m, 5H), 3.25 (ra, lH), 3.95 (m, lH), 5.50 (t, 1H), 7.25 (m, 5H), 7.65 (ra, 2H), 7.80 (d, lH), 8.01 (d, 1H), 8.10 (m, 1H), 8.15 (d, 1H), 8.30 (q, 1H), 8.40 ( s, 1H), 8.50 (t, 2H), 8.75. { bs, 2H), 9.00 (bs, 2H). twenty
Example 84: 2- [(2-Naphthylsulfonyl) amino] -3- acid dihydrochloride. { [2- (. {4- (4-piperidyl) -2- [2- (4-piperidi 1) ethyl] -butanoyllamino) propanoyl] amino} propanic (CRL43214) Starter material: compound 92 Yield = 98%
hi-NMR (400MHz, DMSO-dg): d 1.00 (d, 3H), 1.08 (ra, 4H), 1.27 (m, 6H), 1.42 (m, 4H), 1.70 (bd, 4H), 2.12 (ra , 1H), 2.73 (bd, 4H), 3.00 (m, 1H), 3.20 (bs, 4H), 3.48 (m, 1H), 3.89 (q, 1H), 4.18 (t, 1H), 7.65 (m, 2H), 7.82. { d, 1H), 7.95 (d, 1H), 8.06 (d, 2H), 8.15 (q, 2H), 8.35 (d, 1H), 8.40 (s, 1H), 8.85 (m, 2H), 9.10. { bs, 2H).
Example 85: 2- ( { [(7,7-d? Methyl-2-oxo-bicyclo [2.2.1] ept-1-yl) ethyl] sulfonyl}. Amino] -3- acid dichloride. [2- (. {4- (4-piperidyl) -2- [2- (4-piperidyl) ethyl] butanoyl} amino) acetyl] amino.} Propane
(CRL43215) Starter material = compound 89 Yield = 90%
.i & , -. ^ AtJaba- ^ - MR (400MHz, DMSO-d6): d 0.80 (s, 3H), 1.05 (s, 3H), 1.15 (ra, 4H), 1.30 (m, 6H), 1.45 (ra, 6H), 1.75 (bd, 4H), 1.90 (m, 2H), 2.05 (t, 1H), 2.15 (ni, 1H), 2.35 (m, 2H), 2.75 (bq, 4H), 3.05 (d, 1H) ), 3.20 (bd, 4H), 3.30 (rtt, 1H), 3.35 (d, 1H), 3.50 (m, 1H), 3.70 (dq, 2H), 4.00 (m, 1H), 7.65 (d, 1H) , 8.10 (m, 2H), 8.85 (bs, 2H), 9.10 (bs, 2H).
Example 86: 10 (2R) -2 - [(2-naphthylsulfonyl) amino] -3- acid dihydrochloride. { [2- (. {4- (4-piperidyl) -2- [2- (4-piperidyl) ethyl] butanoyl}. Amino) acetyl] amino} propanic (CRL42956) 15 (2R) -3- (. {2- 2- [(4- [1- (tert-butoxycarbonyl) -4-piperidyl] -2-. {2- 2- [1- ( tert-butoxycarbonyl) -4-piperidyl] ethyl} butanoyl) amino] acetyl} amino) -2- [(2-naphthylsulfonyl) amino] propane (compound 90) (8 g, 9.8 mmol) in 30 ml of ethyl acetate and 150 ml of 3 N hydrochloric acid-acetate were added at room temperature. Stirring was continued for 40 minutes and then ethyl acetate was added. A white powder was obtained by drying under vacuum. Then it was added
^? ^^^ S & s ^. ^ .... "_. *,. ,. «Ai-tai-i-fc 500 ml of water, 5.92 g of a white solid was obtained by freeze drying. Performance = 98%
[a] D + 9.5 (C = 0.15, H20) 5 MS (ES): m / z 616. { M + H) + XH-NMR. { 400MHz, DMSO-d6): d 1.1 (m, 4H), 1.25 (m, 6H), 1.45 (m, 4H), 1.7 (m, 4H), 2.15 (ra, 1H), 2.75 (bd, 4H), 3.2 '(bd, 5H), 3.4 (m, 1H), 3.55. { dq, 2H), 3.95 (q, 1H), 7.7 (m, 2H), 7.8 (d, 1H), 8.0 (ra, 3H), 8.15 (dd, 2H), 8.35 (d, 1H), 8.4 (s) , 1H), 8.7 (bs, 2H), 8.95 (bd, 2H >
A study of the inhibitory activity of the compounds of formula I on platelet aggregation was carried out i n vi t ro, that is, by contact
direct from the solutions of variable concentrations of the compounds with platelets recently separated from a sample of whole blood, taken under standardized conditions, from laboratory animals (guinea pigs) and from
healthy human subjects, who have not received any substance or drugs that could interfere with blood coagulation. Platelet aggregation activity was also studied ex vi ve / vi tro, that is, after the administration of
the substances claimed with the guinea pigs for
»*« R. ». ^ ¡«. ^. .,. to-t. 4 ^ ".", ",,. ,. ,. . ,. ... »..». * .t &t * ^. ^ measure the intensity and duration of the antiaggregation action induced by the fraction of the test product absorbed and circulating in the blood.
1. Archaeological studies in vi tro
1. 1 Platelet studies of guinea pigs
Blood was taken by intracardiac puncture of male Dunkin-Hartley guinea pigs (weighing about 330 g), at a rate of 4.5 ml per 0.5 ml of trisodium citrate (concentration of the aqueous solution: 1.55%) to prevent all traces or traces of clots Platelet rich plasma (PRP) is obtained by centrifugation of the whole blood tubes for 15 minutes at 150 g. The PRPs are collected as "bags". The platelets contained in these bags are counted using an automatic Coulter ZM hematology device: if necessary, dilution is carried out so that the platelet concentration in the plasma is between 200,000 and 400,000 platelets / mm3. Simultaneously, other samples of these bags serve to prepare the platelet poor plasma (PPP) by centrifugation at 1500 g for 15 minutes. The kinetic study of platelet aggregation is carried out by the addition of a collagen solution (1 μg / ml) to a volume of PRP, using an Aggregometer Chrono-log Corporation (490-D: or 560 VS) which uses an optical detection of the appearance of the thrombus. The determination of 50% inhibitory concentration (IC5o) is carried out by the addition of a given volume of solvent (reference control) and increased concentrations: 1.5 x 0"8 M, 7 x 10" 8 M, 1.5 x 10"7 M, 3 x 10 ~ 7 M, 7 x 10" 7 M, 1.5 x 10 ~ 6 and 7 x 10"5 M, of the compounds for samples of the 15 bags of PRP. Aggregation is carried out after 3 minutes of contact at 37 ° C with shaking.
1. 2 Study on human platelets 20 Venous blood was taken from a group of healthy human subjects of the same age, by puncture in a vein of the elbow part and collected in a glass tube containing a solution of sodium citrate 0.129 M (1 volume of 25 citrate solution per 9 volumes of blood). Each
L *., T # taCt > 1A,, l - •. .., f, -. "*«,,. - "," - .. .. *. «., .. ,, .. ... ^« ... t. .... ". ^"? L ... L ± .. 3 ~ &S3t06 tube is then centrifuged a first time at 20 ° C and 100 g for 15 minutes to obtain the platelet rich plasma (PRP); After removing this PRP, the tube is again centrifuged at 2000 g for 15 minutes at this time, remove the platelet poor plasma (PPP). For each identified sample of PRP, the platelets are counted using a Coulter ZM counter. Each sample is then used to study the variation in inhibition of platelet aggregation caused by the addition of a solution of collagen glucose Chromo-pair Reagent from Coultronics (used at a concentration of 5 μg / ml) as a function of the addition of increased concentrations of each compound in a range that covers the range of 10"? M - 10" 5 M, (example concentrations: 10 ~ b M, 5 x 10"'M, 3 x 10 ~ M, 10 ~ 7 M, x 10"b M, 6 x 10" b M, 4 x 10"b M, 2 10" d M, 10"M, 5 x 10" 5 M, 10"5 M). In advance, an aqueous solution of 10 ~ 3 M was prepared for each compound. A control test proposed to verify the possible effect of the solvents (reference value) on the aggregation of platelets, is introduced in each series of measurements, and is measured
J? * ** »± aee ~ Jít¡? LMmm .M. ~ ... .. ^. - * ._... ...,. , tJ- ^ JM "* •" * - "" • --- "" * - "---" * - ^ • * "** - jMtM after 3 minutes of contact at 37 ° C with agitation. Of the percentages of inhibition of platelet aggregation measured for each 5 concentration of each compound, 50% inhibitory concentration (IC50) is calculated.
2. Ex vivo / vi tro pharmacological study in guinea pig 10 The evaluation of the anti-platelet aggregation activity of the compounds was carried out in the same guinea-pigs as those mentioned above (Dunkin-Hartley strains). The administration of each product in a dose range of 150 mg / kg up to 10
mg / kg and each vehicle (5 ml / kg) was carried out via the gastric route (g.r.) lh, 2h, 4a, 6h, 8h or 12 h, before taking blood from stable guinea pigs. The distribution of the treatments of the animals is random. 20 The blood is taken and then treated under the same conditions as those described above for the vi vi studies. The results of the inhibition of the aggregation of platelets obtained for each
test concentration, makes it possible to calculate the
IC50 concentration of each test product and the emetics of the inhibitory effect and its duration of action. The results are collated in the following table:
~. «", .._... ^ ¿*, t. ~ 3 '*? *. . .-- > - .Ui,. i ^ i ^ -á-te ^ 10
fifteen
twenty
* tJ¡A ákA4tí *** - * - aNít ¡10 15 20
An object of the present invention are furthermore also pharmaceutical compositions comprising an effective amount of a compound of formula (I) or a salt thereof with pharmaceutically acceptable acids. An object of the invention is, more particularly, compounds for the inhibition of blood platelet aggregation, comprising an effective amount of one of these compounds. An object of the invention is also - a process for inhibiting the binding of fibrinogen to blood platelets in a mammal, comprising the administration to this mammal, of an effective amount of one of these compounds, a process for treating a thrombus in a patient, comprising the administration to this patient, of an effective amount of one of these compounds, - a process for preventing the thrombotic risk in a patient, comprising the administration to this patient, of an effective amount of one of these compounds. The compounds of formula (I) can be used, in particular, in the following fields:
& X ^^ jj ^ d ^ í ^ ¡^ i) Acute prevention of arterial thrombotic risk in the course of heart surgery (coronary deviation) or interventional cardiology (percutaneous transluminal angioplasty, endartectomy, insertion of
a "stent"): - in these situations, the compounds are added to the recognized preventive treatment of arterial thrombotic risk; oral administration of acetylsalisilic acid starting before the
intervention (150 to 500 mg / d orally) and then continue as follows; intravenous infusion of the beginning of unfractionated heparin during the intervention and after continuity for 48 to 96 hours. The administration of the compound of formula I
can be carried out either orally (0.5 to 1.5 mg / kg) at the same time as the administration of aspirin, or by intravenous infusion (0.25 to 1 mg / kg / 24 h) combined or not combined with a bolus. After the 48th hour, if the treatment was administered intravenously, it will be delayed by oral administration (0.25 to 10 mg / kg in two doses taken or ingested with an interval of 12 hours) to facilitate hospitalization care and then treatment ambulatory. 5 (ü) Secondary risk prophylaxis
****** - - -.: ** --.-, -.- ^ ...... ^ .. - »- ... . . *****. . .. «. ** .. - * *« * «* -..., -. . ..; ft, f * »< Arterial thrombotic tfrm in patients subjected to episodes of unstable angina or myocardial infarction: in these situations, the high bioavailability of the claimed compounds, is to say, the possibility of rapidly obtaining circulating concentrations that are effective since they are capable of inhibiting the binding of fibrinogen to platelets makes it possible to use orally claimed medicinal products during the period in which patients exhibit this risk of arterial thrombosis. In these situations, these compounds can be administered advantageously in a proportion of 1 to 3 oral doses per day, by virtue of their great bioavailability and their long duration of action, the dose is chosen in the range of 0.5-10 mg / kg . The pharmaceutical compositions which comprise one of the active ingredients described in the present application, incorporate the active substance either in the base form or in the form of a pharmaceutically acceptable salt, or alternatively, in the form of a prodrug comprising an ester function, this function is then released in vivo after oral administration. These pharmaceutical compositions incorporate the
?, iái ti mi * • ~ "or * - ** - * - - * - &- - - - - - -" * - ~ --'- manufacturing adjuvants and vehicles that are known to those experts in the technique. The latter are selected from the range of pharmaceutical tools recognized by the Pharmacopoeias. The 5 examples which can be mentioned for the preparation of pharmaceutical forms proposed for oral route are: starch, magnesium stearate, talc, gelatin, agar, pectin, lactose, polyethylene glycols, etc. The pharmaceutical forms which can be used, will be selected from the following possibilities: cleavable or non-cleavable tablets, gel capsules, dragees, granules, powders. In accordance with the characteristics of the pathology to be treated and the morphology of each patient, the oral daily dose will be between 0.02 and 50 mg / kg / day taking 1 to 3 evenly spaced doses to maintain an effective level of occupation of the recipients of platelets GpIIb / IIa. Via the intravenous route, the pharmaceutical forms proposed for the acute phase of treatment, designed in this way to allow individual dose adaptation based on the inhibition of platelet aggregation, are more efficient as for a function of immediate evolution of the 25 consecutive operation. In this context, lyophilisate and
fr # fttedr? rpH • - * r - r fif - • - - «- • - TG '~ X * - ^ - - - - ** - • * -. ^^ s solution ready to be used for infusion, makes possible modify the dosage individually within the dosage range of 0.01 mg / kg / day- 20 mg / kg / day.
It is noted that in relation to this date, the best method known by the applicant to carry out the aforementioned invention, is the
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. fifteen
twenty
^^^^^ ¡^ & ^^ ^^ ¡j¡ ^^^^^^ i
Claims (13)
1. Formula compounds Formula 1 characterized in that: i) either R i is selected from: - C 1 -C 4 alkyl groups, C 3 -Ci 2 mono- or bicyclic cycloalkyl, C 2 -C 4 alkenyl or C 2 -C 4 alkynyl, these groups are optionally substituted with selected groups from halogens and the hydroxyl group; C6-C4-aryl groups 4 mono-, bi- or tricyclic, heteroaryl groups selected from pyridyl, thienyl, furyl, quinolyl, benzodioxanyl, benzodioxolyl, benzothienyl, benzofuryl and pyrazinyl groups; - alkyl phenyl groups (C1-C4) and alkylnaphthyl (Ci- ^ * ^ áy ^^^^^^^^^ & £ ^^^ ....... i ... ... .. »fc ^« ^ »ft ^. ^. -------- M-. C4) optionally substituted and the aryl nuclei, the aryl and heteroaryl groups are possibly substituted with one or more groups independently selected from halogens, C? ~C alkyl, trifluoromethyl, alkylthio Cl-C4, alkylsulfonyl C1-C4, alkyloxy C1-C4, nitro and groups -COOR, -CH2COOR or -O-CH -COOR, R is a C: -C4 alkyl group, the groups of formula -NR4R '4 in which R and R '. are selected from alkyl groups CI ~ CP and C3-C cycloalkyl? mono- or polycyclic, these groups are optionally substituted with groups selected from halogens and the hydroxyl group, R '4 possibly also is hydrogen, or alternatively R4 and R' 4 together form a tetramethylene or pentamethylene group, these last two groups possibly they themselves are substituted, in particular with an aryl residue C6-C? 4 or with the quil (C? -C4) aryl (C6-C? 4); the formula groups A .. * i kill yourself wherein m = 1 to 4 and R5 is selected from 5 groups phenyl, methoxyphenyl, indolyl, benzodioxolyl, benzodioxanyl, benzothienyl and benzofuryl, and R2 is hydrogen, ii) or Ri is hydrogen and R2 is selected from The groups of formula: -NH-CO-R6, R 6 is selected from C 1 -C 4 alkoxy groups C 3 -C 6 cycloalkoxy, benzyloxy, methoxyphenyl, dimethoxyphenyl, benzodioxolyl and benzodioxanyl, and the group (s) of the formula: -NH-SO2-R-, R7 is selected from: - C1-C5 alkyl groups optionally substituted with one or more groups selected from halogen groups, hydroxyl and the trifluoromethyl group; 25 - C2-C5 alkenyl groups; • - ,.? I¡W-fh ", - M >; < * rlt.? ffltii ^ .-. ".,, ^ -Jtd - ^, 1.,. ^. ^ ... i.- ^,. ^ ^, .... -., .......,., j ... ^ > ^. , &......... JJ.,. «... t, a« -., - > . - C3-C12 cycloalkyl groups mono or bicyclic; - C6-C? 4 aryl groups mono, bi or tricyclic; - heteroaryl groups selected from pyridyl, furyl, thienyl, quinolyl, benzodioxanyl, benzodioxolyl, isoxazolyl, benzodioxinyl, benzothyl, thiazolyl, pyrazolyl, benzofuryl and benzothiazolyl groups; - alkylphenyl groups (C? -C4) and alkylnaphthyl (Ci- C4); 10 - and the groups of formula: Where n = 1, 2 or 3 and B is selected from -CH 2 -, O or S and -NH-, the aryl or heteroaryl groups are optionally substituted with one or more selected groups 20 independently from halogens, C 1 -C 4 alkyl, C 3 -C 6 cycloalkyl, trifluoromethyl, C 1 -C 4 alkylthio, C 1 -C 4 alkyloxy C 1 -C 4 alkylsulfonyl, nitro, di (alkyl) (C 1 -C 4) amino and groups -COOR, -CH2-COOR or -0- CH2COOR, R is a C? -C4 alkyl group, phenyl groups and Naphthyl and heteroaryl groups selected from ^^^ É fete & ^^ & de of thienyl, furyl and pyridyl groups, iii) R3 is selected from a hydrogen atom, a C? -C4 alkyl group and an alkyl (C1-C4) alkyl group; iv) A is selected from groups -NH-CHR? 0-, -NH-CHR10-CH2- and with p = 1 or 2, Rio is selected from hydrogen, a C? -C4 alkyl group and a C6-Ci4 aryl group, v) and Zi and Z2 are hydrogen or a protective amine group, and the addition of salts of the same with pharmaceutically acceptable acids.
2. Compounds in accordance with claim 1, of formula . ^ j ^ * ^^^ *? S '? * ~? & * ** k > . *. Formula Ja characterized in that i) either R i is selected from: C 1 -C 4 alkyl groups, m 3 or C 3 -C 12 bicyclic cycloalkyl, C 2 -C 4 alkenyl or C 2 -C 4 alkynyl, these groups are optionally substituted with groups selected from of halogens and the hydroxyl group; 15 - Ce-C 4 monoaryl, bi or tricyclic aryl groups, heteroaryl groups selected from pyridyl, thienyl, furyl, quinilyl, benzodioxanyl, benzodioxolyl, benzothienyl, benzofuryl and pyrazinyl groups; 20 - alkyl phenyl groups (C1-C) and alkylnaphthyl (C? ~ Cj) optionally substituted on the aryl nucleus, the aryl and heteroaryl groups are possibly substituted with one or more groups selected independently from 25 halogens, C? -C4 alkyl, trifluoromethyl, alkylthio C1-C4, C? -C4 alkylsulfonyl, d-C4 alkyloxy, nitro and -COOR, -CH2COOR or -O-CH2-COOR groups, R is a C? -C alkyl group, - the groups of formula: -NR4 or wherein R 4 and R 4 are selected from C 1 -C 8 alkyl and C 3 -C 12 cycloalkyl mono, or polycyclic groups, these groups are optionally substituted with groups selected from halogens and the hydroxyl group, R 4 possibly it is also hydrogen, or alternatively R4 and R '4 together form a tetramethylene or pentamethylene group, these last two groups possibly themselves being substituted, in particular with an aryl residue Cd-C? 4 or alkyl (C? -4) aryl ( C6-C14); The groups of formula: where m = 1 4 and R5 are selected from ... > 'TO . i - «* a-». phenyl, methoxyphenyl, indolyl, benzodioxolyl, benzodioxanyl, benzothienyl and benzofuryl groups, and R 2 is hydrogen, ii) or Ri is hydrogen and R2 is selected from the groups of formula: -NH-C0-R6, R6 is selected from C?-C4 alkyloxy, C3-C7 cycloalkyloxy, benzyloxy, methoxyphenyl, dimethoxyphenyl, benzodioxolyl and benzodioxanyl groups, and the groups of the formula: R-7 is selected from: C 1 -C 5 alkyl groups optionally substituted with one or more groups selected from halogen groups, hydroxyl and the trifluoromethyl group; - C3-C12 cycloalkyl groups mono or bicyclic; - C6-Ci4 aryl groups mono, bi or tricyclic; - heteroaryl groups selected from pyridyl, thienyl, quinolyl, benzodioxanyl, benzodioxolyl and isoxazolyl groups; alkylphenyl groups (C 1 -C 4 and alkylnaphthyl (Cr C 4), and the groups of the formula: wherein n = 1, 2 or 3; the aryl or heteroaryl groups are optionally substituted with one or more groups independently selected from halogens, C 1 -C 4 alkyl, trifluoromethyl, C 1 -C 4 alkylthio, C 1 -C 4 alkyloxy, C 1 -C 4 alkylsulfonyl, nitro, di (alkyl) (C 1) -C4) amino and groups -COOR, -CH2-COOR or -0-CH COOR, R is a C1-C4 alkyl group, iii) R3 is selected from a hydrogen atom, a C? -C4 alkyl group and a alkyl group phenyl (C1-C4, iv) and Zi and Z2 are hydrogen or a protective amino group, and the addition of salts thereof with pharmaceutically acceptable acids.
3. Compounds according to claim 1, characterized in that Ri = H and R2 is a group of formula -NH-SO2-R-7.
4. Compounds according to claim 3, characterized in that R7 is selected from naphthyl, substituted naphthyl, phenylthienyl and biphenyl groups.
5. Compounds according to claim 1, characterized in that they are: (2S) -2 - [(2-naphthylsul-fonyl) amino] -3-. { [2- (. {-4- (4-piperidyl) -2- [2- (4-piperidyl) ethyl] butanoyl] -. - rimo) acetyl] amino propanoate ethyl; 3- (1,3-benzodioxol-5-yl) -3- acid. { [2- (. {4- (4-piperidyl) -2- [2- (4-piperidyl) ethyl] -butanoyl} amino) acetyl] amino Jpropanoic; 2- [(phenylsulfonyl) amino] -3- acid. { [2- (. {4- (4-piperidyl) -2- [2- (4-piperidyl) ethyl] butanoyl}. Amino) acetyl] amino} -propanóico; (2S) -2- [(2-naphthylsulfonyl) amino] -3- acid. { [2- (. {4- (4-piperidyl) -2- [2- (4-piperidyl) ethyl] -butanoyl} amino) acetyl] amino} propanic; ^ ttm át? itß á? iUm ^^ a ^ ^^ ^^ ??? ^^ Mt ^? ^^ i 2- [([1-1'-Biphenyl] -4-ylsulfonyl) amino] -3- acid. { [2- (. {4- (4-piperidyl) -2- [2- (4-piperidyl) ethyl] butanoyl}. Amino) -acetyl] amino} propanic; 5 2- [(1-naphthylsulfonyl) -amino] -3- acid. { [2 - (. {4- (4-piperidyl) -2- [2- (-piper id 1) -ethyl] butanoyl}. Amino) acetyl] amino} probed ico; 2 - [(2-thienylsulfonyl) amino] -3- acid. { [2- (. {4- (4-piperidyl) -2- [2- (4- (piperidyl) ethyl] butanoyl} amino) acetyl] amino} - propanoic; (2S) -2- acid. { [(6-methoxy-2-naphthyl) sulfonyl] amino} -3- . { [2- (. {4- (4-piperidi 1) -2- [2- (4-piperidyl) ethyl] butanoyl}. Amino) acetyl] amino} - 15 propanic; 2- [(methylsulfoni lamino] -3-. {[[2- (. {4- (4-piperidyl) -2- [2- (4-piperidyl) ethyl] butanoyl} -amino) acetyl acid ] amino.} propanic acid, 2- {[[(4-methyl-phenyl) sulfonyl] amino} -3- 20 { [2- (. {4- (4-piperidyl) -2} - [2- (4-piper id 1) ethyl] -butanoyl} amino) acetyl] amino} propane; 2- ( { [3- (trifluoromethyl) phenyl] sulfonyl} amino} 3 - { [2- ( { 4- (4- piperidyl) -2- [2- (4-piperidyl) ethyl] -25-butanoyl} amino) acetyl] amino} propane; «« Ksitft-itirdBg-bi .. * jt »». «_ ... YES;;,. *, _. . . ,,, ". .. ..... i .. .._. 2- acid. { [(3-nitriphenyl) sulfonyl] amino} -3-. { [2- (. {4- (4-piperidyl) -2- [2- (4-piperidyl) ethyl] -butanoyl} amino) acetyl] amino} propanic; 2- acid. { [(3,5-dimethyl-4-isoxazolyl) sulfonyl] amino} -3-. { [2- (. {4- (4-piperidyl) -2- [2- (4-piperidyl) ethyl] butanoyl} - amino) acetyl] amino} propanic; 2- ( { [5- (dimethylamino) -1-naphthyl) sulphonic acid} amino) -3-. { [2- (. {4- (4-piperidl) -2- [2- (4-piperidyl) ethyl] butanoyl} - amino) acetyl] amino} propanic; 2- acid. { [(6,7-dimethoxy-2-naphthyl) sulfonyl] amino) -3-. { [2- (. {4- (4-pip ridi 1) -2- [2- (4-piper? Dil) ethyl] butanoyl}. Amino) -acetyl] amino} propanic; 2- [(3-pyridylsulfonyl) -amino] -3- acid. { [2- (. {4- (4-piperidyl) -2- [2- (4-piperid? L) -ethyl] butanoyl}. Amino) acetyl] amino} propanic; 2- [(1,3-benzodioxol-5-yl sulphyl) amino] -3- acid. { [2- (. {4- (4-Piperidyl) -2- [2- (4-piperidyl) ethyl] butanoyl] - .ammo) acetyl] amino} propanic; ^^^^ 2- [(2,3-Dihydro-l, 4-benzodioxin-6-ylsul-fonyl) amino] -3- acid. { [2- (. {4- (4-piperidyl) -2- [2- (4-piperidyl) ethyl] butanoyl] -amino) acetyl] amino} propanic 2- [(1-Benzothiophen-2-yl sulphonyl) amino] -3- acid. { [2- (. {4- (4-piperidyl) -2- [2- (4-piper id 1) ethyl] -butanoyl}. Amino) acetyl] amino} propanoic; 2- acid. { [(, 5-dimethyl-3-furyl) sulphonyl] amino} -3- . { [2- ([4- (4-piperidyl) -2- [2- (4-piperidyl) ethyl] butanoyl] -amino) acetyl] amino} propanic; 2- acid. { [(4-fluoro-1-naphthyl) sulfonyl] amino} -3- . { [2- (. {4- (4-pip-ridi-1) -2- [2- (4-piperidyl) -ethyl] -butanoyl} - a-ino) -acetyl] -amino} propane ico; 2- acid. { [(4-chloro-1-naphthyl) sulphonyl] amino} -3-. { [2- (. {4- (4-piperidyl) -2- [2- (4-piperidyl) ethyl] butanoyl}. Amino) -acetyl] amino} propanic; 2- [(1-benzofuran-2-ylsulfonyl) amino] 3- acid. { [2- ([4- (4-piperidyl) -2- [2- (4-piperidyl) ethyl] -butanoyl}. Amino) acetyl] amino} propanic; -I-B-Í-Í-M-Í-Í-M-1 2- [(2, 3-dihydro-H-inden-5-yl s-fonyl) amino] -3- acid. { [2- (. {4- (4-piperidi) -2- [2- (4-piperidyl) ethyl] butanoyl}. Amino) acetyl] -amino} propanic; 2- acid. { [(5-phenyl-2-thiyl)) sulfonyl] amino} -3- . { [2- (. {4- (4-Piperidyl) -2- [2- (4-piperidyl) ethyl] butanoyl} - amino) acetyl] amino} propanic; 2- [(5, 6, 7, 8-tetrahydro-2-naphthalenesulfonyl) amino] -3- acid. { [2- (. {4- (4-piperidyl) -2- [2- (4-piperidyl) ethyljbutanoyl}. Amino) -acetyl] amino} propanic; 2- [(2-naphthylsulfonyl) -amino] -3- acid. { [3- (. {4- (4-piperidyl) -2- [2- (4-piper id 1) -ethyl] butanoyl} amino) propanoyl] amino} propanic; (2R) -2- [(2-naphthylsulfonyl) amino] -3- acid. { [2- (. {4- (4-piperidyl) -2- [2- (4-piperidyl) ethyl] butanoyl}. Amino) -acetyl] amino} propanic and the addition of salts thereof with pharmaceutically acceptable patients.
6. Process for the preparation of compounds of formula (I) characterized by ai) reacting an acid of formula: j ^ jfi ^ h Formula XX characterized in that Rs and Rg are protective groups, with an amine of formula 15 formula TJX or a2) reacting an acid of formula 25 formula IV wherein Re and R9 are protective groups, with an amine of formula Formula V to give compounds of formula (Ib! Fozmulm Ib b) optionally, converting one group R2 into another group R2, c) and, optionally, removing the protecting groups.
7. Anti-thrombotics composition, characterized in that it comprises an effective amount of a compound as defined in claim 1.
8. Process for inhibiting the binding of fibrinogen to platelets in the blood of a mammal, characterized in that it comprises the administration to this mammal of an effective amount of a compound according to claim 1.
9. Process for inhibiting the platelet aggregation of blood of a patient, characterized in that it comprises the administration to this patient of an effective amount of a compound according to claim 1.
10. Process for the treatment for thrombosis in a patient, characterized in that it comprises the administration to this patient of an effective amount of a compound according to claim 1. ^ j ^^^^^ and ^^^^ r ~~ ** "'- * > * - - - • * -» - »• -i • * *** • * - &
11. Process for preventing thrombotic risk in a patient, characterized in that it comprises the administration to this patient of an effective amount of a compound according to claim 1.
12. Formula compounds Formula JJ characterized in that Re and Rq are protective groups and A has the meaning given in claim 1.
13. Formula compounds 25 Formula IV characterized in that Re and R9 are protective groups 10 fifteen twenty 25 t ^? mt¡? -á-rii-i-fii-il-i--. M-MU __? - t-i.
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| FR98/09166 | 1998-07-17 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| MXPA01000446A true MXPA01000446A (en) | 2002-07-25 |
Family
ID=
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