CN1314895A - 取代的哌嗪酮及其治疗应用 - Google Patents
取代的哌嗪酮及其治疗应用 Download PDFInfo
- Publication number
- CN1314895A CN1314895A CN99808732A CN99808732A CN1314895A CN 1314895 A CN1314895 A CN 1314895A CN 99808732 A CN99808732 A CN 99808732A CN 99808732 A CN99808732 A CN 99808732A CN 1314895 A CN1314895 A CN 1314895A
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- CN
- China
- Prior art keywords
- amino
- compound
- phenyl
- group
- ethanoyl
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
- 230000001225 therapeutic effect Effects 0.000 title claims 2
- IWELDVXSEVIIGI-UHFFFAOYSA-N piperazin-2-one Chemical class O=C1CNCCN1 IWELDVXSEVIIGI-UHFFFAOYSA-N 0.000 title 1
- 150000001875 compounds Chemical class 0.000 claims abstract description 63
- 239000003146 anticoagulant agent Substances 0.000 claims abstract description 10
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 182
- 229910052760 oxygen Inorganic materials 0.000 claims description 96
- 239000001301 oxygen Substances 0.000 claims description 96
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 claims description 83
- -1 benzyloxy, methoxyphenyl Chemical group 0.000 claims description 65
- FKRCODPIKNYEAC-UHFFFAOYSA-N propionic acid ethyl ester Natural products CCOC(=O)CC FKRCODPIKNYEAC-UHFFFAOYSA-N 0.000 claims description 59
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 52
- 125000003739 carbamimidoyl group Chemical group C(N)(=N)* 0.000 claims description 29
- 238000000034 method Methods 0.000 claims description 27
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 24
- XBDQKXXYIPTUBI-UHFFFAOYSA-N Propionic acid Substances CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 claims description 23
- 239000000203 mixture Substances 0.000 claims description 19
- 210000001772 blood platelet Anatomy 0.000 claims description 18
- 150000003839 salts Chemical class 0.000 claims description 15
- 208000007536 Thrombosis Diseases 0.000 claims description 14
- 208000010110 spontaneous platelet aggregation Diseases 0.000 claims description 13
- 239000002253 acid Substances 0.000 claims description 12
- 238000011282 treatment Methods 0.000 claims description 10
- 229910052739 hydrogen Inorganic materials 0.000 claims description 8
- 239000001257 hydrogen Substances 0.000 claims description 8
- 238000002360 preparation method Methods 0.000 claims description 8
- KHLXTMZRKBVYST-UHFFFAOYSA-N 2-(benzenesulfonamido)propanoic acid Chemical compound OC(=O)C(C)NS(=O)(=O)C1=CC=CC=C1 KHLXTMZRKBVYST-UHFFFAOYSA-N 0.000 claims description 6
- 239000000654 additive Substances 0.000 claims description 6
- 230000000996 additive effect Effects 0.000 claims description 6
- 125000001072 heteroaryl group Chemical group 0.000 claims description 6
- 150000002431 hydrogen Chemical class 0.000 claims description 6
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 claims description 5
- 229910052736 halogen Inorganic materials 0.000 claims description 5
- 238000001727 in vivo Methods 0.000 claims description 5
- 150000001412 amines Chemical class 0.000 claims description 4
- BNBQRQQYDMDJAH-UHFFFAOYSA-N benzodioxan Chemical compound C1=CC=C2OCCOC2=C1 BNBQRQQYDMDJAH-UHFFFAOYSA-N 0.000 claims description 4
- 125000002047 benzodioxolyl group Chemical group O1OC(C2=C1C=CC=C2)* 0.000 claims description 4
- 230000015572 biosynthetic process Effects 0.000 claims description 4
- 150000002367 halogens Chemical class 0.000 claims description 4
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 4
- 125000002757 morpholinyl group Chemical group 0.000 claims description 4
- 125000004076 pyridyl group Chemical group 0.000 claims description 4
- 125000001544 thienyl group Chemical group 0.000 claims description 4
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 4
- 230000000903 blocking effect Effects 0.000 claims description 3
- 238000006243 chemical reaction Methods 0.000 claims description 3
- 239000003814 drug Substances 0.000 claims description 3
- 125000003754 ethoxycarbonyl group Chemical group C(=O)(OCC)* 0.000 claims description 3
- 125000005936 piperidyl group Chemical group 0.000 claims description 3
- 241000124008 Mammalia Species 0.000 claims description 2
- RAHZWNYVWXNFOC-UHFFFAOYSA-N Sulphur dioxide Chemical group O=S=O RAHZWNYVWXNFOC-UHFFFAOYSA-N 0.000 claims description 2
- 230000002785 anti-thrombosis Effects 0.000 claims description 2
- 125000005418 aryl aryl group Chemical group 0.000 claims description 2
- 125000005805 dimethoxy phenyl group Chemical group 0.000 claims description 2
- 125000002541 furyl group Chemical group 0.000 claims description 2
- 125000000842 isoxazolyl group Chemical group 0.000 claims description 2
- 125000001624 naphthyl group Chemical group 0.000 claims description 2
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 2
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 2
- 125000004043 oxo group Chemical group O=* 0.000 claims description 2
- 239000002243 precursor Substances 0.000 claims description 2
- 125000005493 quinolyl group Chemical group 0.000 claims description 2
- 125000005843 halogen group Chemical group 0.000 claims 1
- 125000003944 tolyl group Chemical group 0.000 claims 1
- 229960004676 antithrombotic agent Drugs 0.000 abstract 1
- 239000002994 raw material Substances 0.000 description 59
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 53
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 33
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 29
- 125000004390 alkyl sulfonyl group Chemical group 0.000 description 27
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 24
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 21
- 239000007787 solid Substances 0.000 description 19
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 18
- 239000000725 suspension Substances 0.000 description 17
- 239000000047 product Substances 0.000 description 16
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 14
- 239000011734 sodium Substances 0.000 description 13
- 238000003756 stirring Methods 0.000 description 13
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 12
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 12
- 239000002585 base Substances 0.000 description 12
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 12
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 11
- 210000004369 blood Anatomy 0.000 description 11
- 239000008280 blood Substances 0.000 description 11
- YJJCBPAEWVURMJ-UHFFFAOYSA-N ethyl propanoate;hydrochloride Chemical compound Cl.CCOC(=O)CC YJJCBPAEWVURMJ-UHFFFAOYSA-N 0.000 description 11
- 235000019260 propionic acid Nutrition 0.000 description 11
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 10
- 239000000243 solution Substances 0.000 description 10
- SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 description 9
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 9
- JFDZBHWFFUWGJE-UHFFFAOYSA-N benzonitrile Chemical compound N#CC1=CC=CC=C1 JFDZBHWFFUWGJE-UHFFFAOYSA-N 0.000 description 9
- 210000004623 platelet-rich plasma Anatomy 0.000 description 9
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 8
- 229940017219 methyl propionate Drugs 0.000 description 8
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 8
- 229910052938 sodium sulfate Inorganic materials 0.000 description 8
- 235000011152 sodium sulphate Nutrition 0.000 description 8
- CFHAYNINGQHXOI-UHFFFAOYSA-N acetic acid ethyl propanoate Chemical compound CC(O)=O.CCOC(=O)CC CFHAYNINGQHXOI-UHFFFAOYSA-N 0.000 description 7
- FMSYDXGRGZMLRB-UHFFFAOYSA-N methyl propanoate;2,2,2-trifluoroacetic acid Chemical compound CCC(=O)OC.OC(=O)C(F)(F)F FMSYDXGRGZMLRB-UHFFFAOYSA-N 0.000 description 7
- 230000008569 process Effects 0.000 description 7
- 238000010992 reflux Methods 0.000 description 7
- 239000002904 solvent Substances 0.000 description 7
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 6
- RJUFJBKOKNCXHH-UHFFFAOYSA-N Methyl propionate Chemical compound CCC(=O)OC RJUFJBKOKNCXHH-UHFFFAOYSA-N 0.000 description 6
- 230000000694 effects Effects 0.000 description 6
- 238000011160 research Methods 0.000 description 6
- 238000012360 testing method Methods 0.000 description 6
- 238000001291 vacuum drying Methods 0.000 description 6
- 239000003513 alkali Substances 0.000 description 5
- 229940127219 anticoagulant drug Drugs 0.000 description 5
- 238000004108 freeze drying Methods 0.000 description 5
- YOETUEMZNOLGDB-UHFFFAOYSA-N 2-methylpropyl carbonochloridate Chemical compound CC(C)COC(Cl)=O YOETUEMZNOLGDB-UHFFFAOYSA-N 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 4
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 4
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 4
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 4
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 4
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 4
- 239000007864 aqueous solution Substances 0.000 description 4
- 210000001367 artery Anatomy 0.000 description 4
- PQJJJMRNHATNKG-UHFFFAOYSA-N ethyl bromoacetate Chemical compound CCOC(=O)CBr PQJJJMRNHATNKG-UHFFFAOYSA-N 0.000 description 4
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 4
- 238000001704 evaporation Methods 0.000 description 4
- 238000001914 filtration Methods 0.000 description 4
- 238000007327 hydrogenolysis reaction Methods 0.000 description 4
- 239000012074 organic phase Substances 0.000 description 4
- 125000003170 phenylsulfonyl group Chemical group C1(=CC=CC=C1)S(=O)(=O)* 0.000 description 4
- DYWOPZYICSJYMT-UHFFFAOYSA-N propanoic acid;2,2,2-trifluoroacetic acid Chemical compound CCC(O)=O.OC(=O)C(F)(F)F DYWOPZYICSJYMT-UHFFFAOYSA-N 0.000 description 4
- 208000032843 Hemorrhage Diseases 0.000 description 3
- WTDHULULXKLSOZ-UHFFFAOYSA-N Hydroxylamine hydrochloride Chemical compound Cl.ON WTDHULULXKLSOZ-UHFFFAOYSA-N 0.000 description 3
- 239000000370 acceptor Substances 0.000 description 3
- 238000013019 agitation Methods 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 229940125904 compound 1 Drugs 0.000 description 3
- 229940125782 compound 2 Drugs 0.000 description 3
- 238000003810 ethyl acetate extraction Methods 0.000 description 3
- 239000000706 filtrate Substances 0.000 description 3
- 229910052731 fluorine Inorganic materials 0.000 description 3
- 230000002401 inhibitory effect Effects 0.000 description 3
- 230000005764 inhibitory process Effects 0.000 description 3
- 229910052500 inorganic mineral Inorganic materials 0.000 description 3
- 239000011707 mineral Substances 0.000 description 3
- 235000010755 mineral Nutrition 0.000 description 3
- 208000010125 myocardial infarction Diseases 0.000 description 3
- 239000008194 pharmaceutical composition Substances 0.000 description 3
- 210000002381 plasma Anatomy 0.000 description 3
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Substances [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 3
- 235000015320 potassium carbonate Nutrition 0.000 description 3
- 238000010898 silica gel chromatography Methods 0.000 description 3
- FVAUCKIRQBBSSJ-UHFFFAOYSA-M sodium iodide Chemical compound [Na+].[I-] FVAUCKIRQBBSSJ-UHFFFAOYSA-M 0.000 description 3
- 210000003462 vein Anatomy 0.000 description 3
- 238000005406 washing Methods 0.000 description 3
- UAOUIVVJBYDFKD-XKCDOFEDSA-N (1R,9R,10S,11R,12R,15S,18S,21R)-10,11,21-trihydroxy-8,8-dimethyl-14-methylidene-4-(prop-2-enylamino)-20-oxa-5-thia-3-azahexacyclo[9.7.2.112,15.01,9.02,6.012,18]henicosa-2(6),3-dien-13-one Chemical compound C([C@@H]1[C@@H](O)[C@@]23C(C1=C)=O)C[C@H]2[C@]12C(N=C(NCC=C)S4)=C4CC(C)(C)[C@H]1[C@H](O)[C@]3(O)OC2 UAOUIVVJBYDFKD-XKCDOFEDSA-N 0.000 description 2
- AOSZTAHDEDLTLQ-AZKQZHLXSA-N (1S,2S,4R,8S,9S,11S,12R,13S,19S)-6-[(3-chlorophenyl)methyl]-12,19-difluoro-11-hydroxy-8-(2-hydroxyacetyl)-9,13-dimethyl-6-azapentacyclo[10.8.0.02,9.04,8.013,18]icosa-14,17-dien-16-one Chemical compound C([C@@H]1C[C@H]2[C@H]3[C@]([C@]4(C=CC(=O)C=C4[C@@H](F)C3)C)(F)[C@@H](O)C[C@@]2([C@@]1(C1)C(=O)CO)C)N1CC1=CC=CC(Cl)=C1 AOSZTAHDEDLTLQ-AZKQZHLXSA-N 0.000 description 2
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- GHYOCDFICYLMRF-UTIIJYGPSA-N (2S,3R)-N-[(2S)-3-(cyclopenten-1-yl)-1-[(2R)-2-methyloxiran-2-yl]-1-oxopropan-2-yl]-3-hydroxy-3-(4-methoxyphenyl)-2-[[(2S)-2-[(2-morpholin-4-ylacetyl)amino]propanoyl]amino]propanamide Chemical compound C1(=CCCC1)C[C@@H](C(=O)[C@@]1(OC1)C)NC([C@H]([C@@H](C1=CC=C(C=C1)OC)O)NC([C@H](C)NC(CN1CCOCC1)=O)=O)=O GHYOCDFICYLMRF-UTIIJYGPSA-N 0.000 description 2
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- IWZSHWBGHQBIML-ZGGLMWTQSA-N (3S,8S,10R,13S,14S,17S)-17-isoquinolin-7-yl-N,N,10,13-tetramethyl-2,3,4,7,8,9,11,12,14,15,16,17-dodecahydro-1H-cyclopenta[a]phenanthren-3-amine Chemical compound CN(C)[C@H]1CC[C@]2(C)C3CC[C@@]4(C)[C@@H](CC[C@@H]4c4ccc5ccncc5c4)[C@@H]3CC=C2C1 IWZSHWBGHQBIML-ZGGLMWTQSA-N 0.000 description 2
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- UYWQUFXKFGHYNT-UHFFFAOYSA-N phenylmethyl ester of formic acid Natural products O=COCC1=CC=CC=C1 UYWQUFXKFGHYNT-UHFFFAOYSA-N 0.000 description 1
- 150000003053 piperidines Chemical class 0.000 description 1
- CHKVPAROMQMJNQ-UHFFFAOYSA-M potassium bisulfate Chemical compound [K+].OS([O-])(=O)=O CHKVPAROMQMJNQ-UHFFFAOYSA-M 0.000 description 1
- 238000012545 processing Methods 0.000 description 1
- 239000000651 prodrug Substances 0.000 description 1
- 229940002612 prodrug Drugs 0.000 description 1
- 238000011321 prophylaxis Methods 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- LVTJOONKWUXEFR-FZRMHRINSA-N protoneodioscin Natural products O(C[C@@H](CC[C@]1(O)[C@H](C)[C@@H]2[C@]3(C)[C@H]([C@H]4[C@@H]([C@]5(C)C(=CC4)C[C@@H](O[C@@H]4[C@H](O[C@H]6[C@@H](O)[C@@H](O)[C@@H](O)[C@H](C)O6)[C@@H](O)[C@H](O[C@H]6[C@@H](O)[C@@H](O)[C@@H](O)[C@H](C)O6)[C@H](CO)O4)CC5)CC3)C[C@@H]2O1)C)[C@H]1[C@H](O)[C@H](O)[C@H](O)[C@@H](CO)O1 LVTJOONKWUXEFR-FZRMHRINSA-N 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 230000000452 restraining effect Effects 0.000 description 1
- 230000000630 rising effect Effects 0.000 description 1
- NLJMYIDDQXHKNR-UHFFFAOYSA-K sodium citrate Chemical compound O.O.[Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O NLJMYIDDQXHKNR-UHFFFAOYSA-K 0.000 description 1
- 235000009518 sodium iodide Nutrition 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 238000010025 steaming Methods 0.000 description 1
- 210000002784 stomach Anatomy 0.000 description 1
- 238000001356 surgical procedure Methods 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 235000012222 talc Nutrition 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 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 1
- 229940038773 trisodium citrate Drugs 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D241/00—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
- C07D241/02—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings
- C07D241/06—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having one or two double bonds between ring members or between ring members and non-ring members
- C07D241/08—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having one or two double bonds between ring members or between ring members and non-ring members with oxygen atoms directly attached to ring carbon atoms
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
- A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Abstract
本发明涉及式(Ⅰ)的化合物,其中:R1、R2、R3、R4和R5如权利要求1所定义。所述化合物用作抗血栓形成的治疗剂。
Description
本发明涉及新的作为血纤维蛋白原与GpⅡb/Ⅲa血小板受体结合的抑制剂并且可以作为抗凝血剂用于治疗的化合物。
在导致血栓(血凝块)形成及增长的病理学过程中,血小板聚集代表一个关键步骤,其原因在于它是这一现象加剧的根源。特别地,从开始形成血栓,尤其在动脉血液循环中,一些相互依赖的生物化学反应的作用导致可溶性血纤维蛋白原转化成不溶性血纤维蛋白丝,这种血纤维蛋白丝增加了血小板团块的体积,从而使愈来愈多的血小板首先在动脉血管损害的所在部位、然后逐渐发展到管腔中聚集。
在血小板聚集的机制中,GpⅡb/Ⅲa受体活化是血小板聚集增长的根源。血纤维蛋白原,可以通过其两个二聚物结合到这些受体上,扩大血小板之间的这种结合,从而导致形成血小板团块,在动脉粥样化斑块破裂的位置形成血栓。
无论血小板聚集出现在进行介入心脏病学(经腔经皮血管成形术;插入移植片固定模)、心脏手术(主动脉冠状动脉搭桥术;瓣膜手术)实践中,在急性心脏病(心肌梗塞,不稳定的心绞痛、急性冠脉综合征,等)过程中或某些脑局部出血过程中,或在会使随后的抗血栓形成的治疗复杂化的心肌局部出血过程中的哪个阶段,这种血小板聚集机制在所有动脉血栓中都特别活跃。
降低或抑止血小板与破裂的动脉粥样硬化斑块接触的活性,代表一种独特的和有效的治疗血栓-尤其是动脉血栓-的方法,和一种有效的预防包括不稳定心绞痛和心肌梗塞在内的急性冠脉综合征的方法。
本发明的目的在于提供可以用作抗血栓形成药品的新的竞争性地抑制血纤维蛋白原结合到GpⅡb/Ⅲa受体上的抑制剂。
本发明的目的还在于提供可以口服的因而能得到延长的作用时间并可以避免出血危险的化合物。
R6选自C1-C4烷氧基,C3-C7环烷氧基,苄氧基,甲氧苯基,二甲氧苯基,苯并间二氧杂环戊烯基和苯并二噁烷基,
和基团-NH-SO2-R7
R7选自
-任选地被一或多个选自卤素、羟基和三氟甲基的基团取代的C1-C5烷基;
-单-或二环C3-C12环烷基;
-单-,二-或三环C6-C14芳基;
-选自吡啶基、噻吩基、喹啉基、苯并二噁烷基、苯并间二氧杂环戊烯基和异噁唑基的杂芳基;
-苯基(C1-C4)烷基和萘基(C1-C4)烷基;-下式的基团:
其中n=1,2或3;
R7芳基或杂芳基任选地被一或多个独立地选自卤素、C1-C4烷基、三氟甲基、C1-C4烷硫基、C1-C4烷氧基、C1-C4烷基磺酰基、硝基、二(C1-C4烷基)氨基、苯基、萘基的基团取代,杂芳基选自噻吩基、呋喃基和吡啶基,还可以选自-COOR、-CH2-COOR或-O-CH2COOR,R是C1-C4烷基,.R4和R5独立地选自氢、C1-C5烷基,或共同与氮原子形成选自哌啶基或吗啉基的基团,.桥氧基处在哌嗪的2或3位,及与药学上可接受的酸形成的加成盐。
脒基的保护基团可以是乙氧羰基,苄氧基羰基,p-硝基苄氧基羰基和叔丁氧基羰基。
芳基的例子可以是苯基、α-萘基、β-萘基、芴基和联苯基。
C1-C5烷基可以是直链或支链。例如甲基、乙基、丙基、异丙基、丁基、异丁基、叔丁基和戊基。
C1-C4烷氧基类似地是直链或支链。例如甲氧基、乙氧基、丙氧基、异丙氧基、丁氧基和异丁氧基。
卤素可以选自F、Cl、Br和I。
“与药学上可接受的酸形成的加成盐”表示具有自由碱基的生物学性质,而没有不良作用的盐。这些盐尤其可以是与无机酸如盐酸、氢溴酸、硫酸、硝酸或磷酸形成的盐;酸性金属盐如正磷酸二钠和硫酸氢钾以及与有机酸形成的盐。
式Ⅰ的化合物可以通过以下方法制备:
式(Ⅱ)的酸可以与式(Ⅲ)的胺在有偶合剂(DCC/HOBT,BOP或氯甲酸异丁酯)存在下在极性溶剂如DMF、THF或乙酸乙酯中反应,反应温度为15℃-50℃。
当Z是N≡C-基团时,基团Z可以通过在适宜的碱(K2CO3、Et3N或C2H5ONa)存在下在醇溶剂中在腈基处加成胲转化成偕胺肟。在钯炭存在下,在乙酸酐和乙酸的混合物中,由所得化合物的氢解得到其中R2是氢的式(Ⅰ)化合物。
当Z是N≡C-基团时,也可以通过在盐酸存在下在乙酸乙酯中加入乙醇将Z基团转化成亚氨酸盐。然后可以通过在乙醇/乙酸乙酯的介质中与相应的胺反应,将得到的亚氨酸盐转化成其中R2是氢、-NR4R5是哌啶基或吗啉基的式(Ⅰ)化合物。
流程1
在质子惰性溶剂中,4-氟苄腈与过量乙二胺反应,产生4-(2-氨基乙基)苄腈,然后在有无机碱或叔胺存在下在极性溶剂如乙醇或乙腈中,用溴乙酸乙酯将其单烷基化。用氯乙酰氯将其酰化,随后环化并水解,得到酸(1)。
流程2
用溴乙酸乙酯对4-(2-氨基乙基)苄腈二烷基化;在叔胺、无机碱或其混合物存在下进行环化;水解后,得到酸(2)。
通常通过将式Ⅰ化合物与药学可接受的酸在适宜的溶剂中反应得到加成盐。相反地,通过用强碱处理可从加成盐得到碱。
以下实施例说明式Ⅰ化合物的制备。
A-式Ⅱ化合物的制备
A-1:合成2-[4-(4-氰基苯基)-2-氧哌嗪基]乙酸(化合物1)
a)4-(2-氨基乙基氨基)苄腈(化合物1a)
将4-氟苄腈(167g,1.38mol)、乙二胺(330g,5.5mol)和碳酸钾(300g,2.17mol)在21甲苯中形成的混悬液加热回流6小时。冷却到室温后,将混合物过滤,用甲苯清洗,蒸发滤液得到黄色的油,将其在甲苯中结晶。将产品过滤,用甲苯清洗,在50℃真空干燥,得到200g淡黄色固体。
产率=90%。
熔点=85℃
1H-RMN(400MHz,CDCl3):δ1,2(bs,2H),2,9(t,2H),3,12(q,2H),4,7(bs,
1H),6,5(d,2H),7,3(d,2H)。
b)2-{2-(氯乙酰基)-2-(4-氰基苯胺基)乙氨基}乙酸乙酯(化合物1b)
将溴乙酸乙酯(84g,0.5mol)加入4-(2-氨基乙氨基)苄腈(80.5g,0.5mol)和二异丙基乙胺[DIEA](65g,0.5mol)在800ml乙腈中形成的混悬液中。室温下持续搅拌18小时。蒸除大部分乙腈,将残余物溶于二氯甲烷。水洗,并用硫酸钠干燥;使粗产品通过硅胶短柱[洗脱液:二氯甲烷,然后是20/1二氯甲烷/甲醇]得到油状物。
将以上得到的产品溶于1L四氢呋喃。加入二异丙基乙胺(51g,0.4mol),在约5℃缓慢添加氯乙酰氯(45g,0.4mol)。在室温搅拌18小时后,加入1L乙酸乙酯,用水洗涤3次,用硫酸钠干燥并蒸发溶剂。得到一种固体,将其与二氯甲烷/乙醚(1/3)混合物搅拌。将混悬液过滤,用二氯甲烷/乙醚(1/3)清洗,并真空干燥,得到100g晶状淡棕色固体。
产率=62%
1H-RMN(400MHz,CDCl3):δ1,2(q,6H),3,3(m,4H),3,65(m,4H),3,8(s,
2H),3,9(d,4H),4,1(s,4H),4,15(q,4H),4,9(t,1H),5,3(t,1H),6,5(dd,
4H),7,3(dd,4H)。
c)2-[4-(4-氰基苯基)-2-氧哌嗪基]乙酸乙酯(化合物1c)
将由2-{2-(氯乙酰基)-2-(4-氰基苯胺基)乙基氨基}乙酸乙酯(152g,0.47mol)、二异丙基乙胺(73g,0.57mol)和碘化钠(85g,0.57mol)在1.2L乙腈中形成的混悬液加热回流2小时。蒸除溶剂,将残余物溶于二氯甲烷并用水洗,用硫酸钠干燥并蒸发溶剂,得到棕色油状物,其在环己烷/乙酸乙酯混合物中结晶,得到125g棕色晶状固体。
产率=93%
熔点=108℃
1H-RMN(400MHz,CDCl3):δ1,3(t,3H),3,65(m,4H),4,05(s,2H),4,2(m,
4H),6,8(d,2H),7,5(d,2H)。
d)2-[4-(4-氰基苯基)-2-氧哌嗪基]乙酸(化合物1d)
将2-[4-(4-氰基苯基)-2-氧哌嗪基]乙酸乙酯(20.7g,72mmol)溶于80ml甲醇、80ml四氢呋喃和100ml水,然后在搅拌下加入氢氧化锂一水合物(4g,98mmol)。持续搅拌20分钟,然后在真空下除去有机溶剂。在得到的混悬液中加入约100ml水,酸化。过滤并且水洗,在50℃真空干燥,得到18.5g淡棕色粉末。
产率=100%
熔点=215℃(分解)
1H-RMN(200MHz,DMSO-d6):δ3,5(t,2H),3,65(t,2H),4,0(s,2H),4,1(s,
2H),7,0(d,2H),7,6(d,2H)。A-2:合成2-[4-(4-氰基苯基)-3-氧哌嗪基]乙酸(化合物2)a)2-[2-(4-氰基苯氨基)乙基(2-乙氧基-2-氧乙基)氨基]乙酸乙酯
(化合物2a)
将4-(2-氨基乙氨基)苄腈(化合物1a)(32g,0.2mol),碳酸钾(55g,0.4mol)和溴乙酸乙酯(67g,0.4mol)在400ml乙腈中形成的混悬液加热回流18小时。过滤并将粗产品通过短硅胶柱(洗脱剂:二氯甲烷),得到58g棕色油。
产率=87%
1H-RMN(200MHz,CDCl3):δ1,3(t,3H),3,05(t,2H),3,4(s,2H),3,55(s,
2H),3,8(t,2H),4,2(q,2H),7,45(d,2H),7,6(d,2H)。
MS-Cl:m/z287(M+H)+b)2-[4-(4-氰基苯基)-3-氧哌嗪基]乙酸(化合物2b)
2-[2-(4-氰基苯氨基)乙基(2-乙氧基-2-氧乙基)氨基]乙酸乙酯(58g,0.174mol)、二异丙基乙胺(4g,0.03mol)和碳酸钾(24g,0.174mol)在400ml乙腈中形成的混悬液加热回流2天。将混合物过滤并用二氯甲烷清洗。蒸发滤液得到棕色固体,将它溶于150ml甲醇和50ml水,然后加入氢氧化锂一水合物(8.4g,0.2mol)。在室温搅拌30分钟,真空除去-半甲醇,得到一混悬液。加入约100ml水并在5℃将混合物酸化。将产物过滤,用水清洗,在50℃真空干燥得到27.2g淡棕色粉末。
产率=55%
熔点=120℃
1H-RMN(200MHz,DMSO-d6):δ2,95(t,2H),3,3(s,2H),3,4(s,2H),3,7(t,
2H),7,65(d,2H),7,85(d,2H)。
B-制备式Ⅳ的中间体产品B-1:合成(2S)-3-{2-[(4-(4-氰基苯基)-2-氧哌嗪基)乙酰基]氨基}-2-[(苯磺酰基)氨基]丙酸乙酯(化合物3)
在约5℃向2-[4-(4-氰基苯基)-2-氧哌嗪基]乙酸(1)(2.02g,7.8mmol)和N-甲基吗啉(1.6g,15.8mmol)在50ml四氢呋喃中形成的混悬液中加入氯甲酸异丁酯(1.1g,8mmol)。在5℃20分钟后,加入(2S)-3-氨基-2-(苯磺酰基氨基)丙酸乙酯盐酸盐(2.39g,7.8mmol)。持续搅拌18小时得到稠混悬液。加入100ml乙酸乙酯,过滤,水洗,然后用乙酸乙酯和乙醚清洗,干燥,得到2.8g白色固体。
产率=70%
1H-RMN(400MHz,DMSO-d6):δ1,0(t,3H),3,2(m,1H),3,4(m,3H),3,45
(t,2H),3,8(q,2H),3,95(m,5H),7,0(d,2H),7,55(m,5H),7,75(d,2H),8,15
(t,1H),8,4(bd,1H)。用上述方法合成以下化合物:B-2:(2S)-3-{2-[(4-(4-氰基苯基)-2-氧哌嗪基)乙酰基]氨基}-2-[(3-吡啶基磺酰基)氨基]丙酸乙酯(化合物4)
原料:(2S)-3-氨基-2-[(3-吡啶基磺酰基)氨基]丙酸乙酯二盐酸盐
产率=74%
1H-RMN(400MHz,DMSO-d6):δ1,0(t,3H),3,2(m,1H),3,45(m,3H),3,7
(t,2H),3,8(q,2H),4,0(m,5H),7,0(d,2H),7,6(m,3H),8,1(dd,1H),8,15
(t,1H),8,70(bs,1H),8,8(d,1H),8,9(d,1H)。B-3:(2S)-3-{2-[(4-(4-氰基苯基)-2-氧哌嗪基)乙酰基]氨基}-2-[(8-喹啉基磺酰基)氨基]丙酸乙酯(化合物5)
原料:(2S)-3-氨基-2-[(8-喹啉基磺酰基)氨基]丙酸乙酯二盐酸盐
产率=70%
1H-RMN(400MHz,DMSO-d6):δ0,8(t,3H),3,4(m,4H),3,65(m,4H),4,0
(m,4H),4,5(bs,1H),7,0(d,2H),7,6(d,2H),7,75(m,2H),7,85(bs,1H),
8,15(t,1H),8,3(dd,2H),8,6(d,1H),9,05(dd,1H)。B-4:(2S)-3-{2-[(4-(4-氰基苯基)-2-氧哌嗪基)乙酰基]氨基}-2-[(苄磺酰基)氨基]丙酸乙酯(化合物6)
原料:(2S)-3-氨基-2-[(苄磺酰基)氨基]丙酸乙酯盐酸盐
产率=68%
1H-RMN(400MHz,DMSO-d6):δ1,2(t,3H),3,4(m,4H),3,65(m,2H),3,95
(s,2H),4,05(s,2H),4,08(m,1H),4,1(q,2H),4,35(t,2H),6,95(d,2H),
7,35(m,5H),7,6(d,2H),7,7(d,1H),8,1(t,1H)。B-5:(2S)-3-{2-[(4-(4-氰基苯基)-2-氧哌嗪基)乙酰基]氨基}-2-[(苯乙基磺酰基)氨基]丙酸乙酯(化合物7)
原料:(2S)-3-氨基-2-[(苯乙基磺酰基)氨基]丙酸乙酯盐酸盐
产率=63%
1H-RMN(400MHz,DMSO-d6):δ1,2(t,3H),3,4(m,4H),3,65(m,2H),3,95
(s,2H),4,05(s,2H),4,08(m,1H),4,1(q,2H),4,35(t,2H),6,95(d,2H),
7,35(m,5H),7,6(d,2H),7,7(d,1H),8,1(t,1H)。B-6:乙基(2S)-3-{2-[(4-(4-氰基苯基)-2-氧哌嗪基)乙酰基]氨基}-2-{[(4-甲氧基苯基)磺酰基]氨基}丙酸乙酯(化合物8)
原料:(2S)-3-氨基-2-{[(4-甲氧基苯基)磺酰基]氨基}丙酸乙酯盐酸盐
产率=70%
1H-RMN(400MHz,DMSO-d6):δ1,05(t,3H),3,15(m,1H), 3,35(m,2H),
3,45(m,2H),3,65(m,2H),3,8~3,95(m,9H),6,9(d,2H),7,05(d,2H),7,55
(d,2H),7,65(d,2H),8,1(t,1H),8,15(bs,1H)。B-7:(2S)-3-{2-[(4-(4-氰基苯基)-2-氧哌嗪基)乙酰基]氨基}-2-{[(4-甲氧基苯基)磺酰基]氨基}丙酸乙酯(化合物9)
原料:(2S)-3-氨基-2-[(4-甲苯磺酰基)氨基]丙酸乙酯盐酸盐
产率=55%
1H-RMN(400MHz,DMSO-d6):δ1,0(t,3H),3,15(m,1H),3,4(m,1H),3,45
(m,2H),3,65(m,2H),3,8(q,2H),3,95(m,5H),6,95(d,2H),7,6(d,2H),
7,65(d,2H),7,75(d,2H),8,15(t 1H),8,5(bs,1H)。B-8:(2S)-3-{2-[(4-(4-氰基苯基)-2-氧哌嗪基)乙酰基]氨基}-2-{[(4-氯苯基)磺酰基]氨基}丙酸乙酯(化合物10)
原料:(2S)-3-氨基-2-{[(4-氯苯基)磺酰基]氨基}丙酸乙酯盐酸盐
产率=56%
1H-RMN(400MHz,DMSO-d6):δ1,0(t,3H),3,15(m,1H),3,4(m,1H),3,45
(m,2H),3,65(m,2H),3,8(q,2H),3,95(m,5H),6,95(d,2H),7,6(d,2H),
7,65(d,2H),7,75(d,2H),8,15(t1H),8,5(bs,1H)。B-9:(2S)-3-{2-[(4-(4-氰基苯基)-2-氧哌嗪基)乙酰基]氨基}-2-[(2-萘基磺酰基)氨基}丙酸乙酯(化合物11)
原料:(2S)-3-氨基-2-[(2-萘基磺酰基)氨基]丙酸乙酯盐酸盐
产率=54%
1H-RMN(400MHz,DMSO-d6):δ0,8(t,3H),3,15(m,1H),3,35(m,3H),3,6
(m,4H),3,95(m,5H),6,95(d,2H),7,55(d,2H),7,7(m,2H),7,8(d,1H),
8,05(d,1H),8,15(m,3H),8,45(s,1H),8,55(d,1H)。B-10:(2S)-3-{2-[(4-(4-氰基苯基)-2-氧哌嗪基)乙酰基]氨基}-2-{[(苄氧基)羰基]-氨基}丙酸乙酯(化合物12)
原料:(2S)-3-氨基-2-{[(苄氧基)羰基]氨基}丙酸乙酯盐酸盐
产率=49%
1H-RMN(400MHz,CDCl3):δ1,28(t,3H),3,6(m,6H),3,95(s,2H),4,05(s,
2H),4,18(m,2H),4,4(m,1H),5,08(s,2H),6,05(bd,1H),6,75(d,2H),7,06
(bs,1H),7,3(m,5H),7,48(d,2H)。B-11:(2S)-3-{2-[(4-(4-氰基苯基)-2-氧哌嗪基)乙酰基]氨基}-2-{(异丁氧基羰基)氨基}丙酸乙酯(化合物13)
原料:(2S)-3-氨基-2-{(异丁氧羰基)氨基}丙酸乙酯盐酸盐
产率=51%
1H-RMN(400MHz,CDCl3):δ0,8(d,6H),1,25(t,3H),1,8(m,1H),3,5~3,75
(m,8H),3,95(s,2H),4,02(s,2H),4,1(m,2H),4,3(m,1H),5,75(d,1H),
6,75(d,2H),7,0(bs,1H),7,45(d,2H)。B-12:(2S)-3-{2-[(4-(4-氰基苯基)-2-氧哌嗪基)乙酰基]氨基}-2-{[丁氧基羰基]氨基}丙酸乙酯(化合物14)
原料:(2S)-3-氨基-2-{(丁氧基羰基)氨基}丙酸乙酯盐酸盐
产率=59%
1H-RMN(400MHz,CDCl3):δ0,9(t,3H),1,25(t,3H),1,35(m,2H),1,55(m,
2H),3,6(m,6H),4,0(m,6H),4,2(m,2H),4,4(m,1H),5,75(d,1H),6,75(d,
2H),7,05(bt,1H),7,5(d,2H)。B-13:(2S)-3-{2-[(4-(4-氰基苯基)-2-氧哌嗪基)乙酰基]氨基}-2-[(丁基磺酰基)氨基]丙酸乙酯(化合物15)
原料:(2S)-3-氨基-2-[(丁基磺酰基)氨基}丙酸乙酯三氟乙酸盐
产率=27%
1H-RMN(400MHz,CDCl3):δ0,9(t,3H),1,25(t,3H),1,4(m,2H),1,7(m,
2H),2,95(t,2H),3,4(m,1H),3,6(s,4H),3,7(m,1H),3,95~4,2(m,7H),5,9
(d,1H),6,95(d,2H),7,1(t,1H),7,45(d,2H)。B-14:合成(2S)-3-{2-[(4-(4-氰基苯基)-2-氧哌嗪基)乙酰基]氨基}-2-{[(1,1’-联苯基)-4-基磺酰基]氨基}丙酸甲酯(化合物16)
在2-[4-(4-氰基苯基)-2-氧哌嗪基]乙酸(化合物1)(0.29g,1.12mmol)在7ml DMF中形成的溶液中依次加入溴三吡咯烷磷鎓六氟磷酸盐(PyBroP)(1.04g,2.23mmol),DIEA(0.78ml,4.46mmol)和(2S)-3-氨基-2-[(1,1’-联苯基)-4-基磺酰基氨基]丙酸甲酯三氟乙酸盐(0.5g,1.15mmol)。连续搅拌5小时。加入乙酸乙酯,用5%柠檬酸然后用水洗涤有机相,用硫酸钠干燥。通过硅胶色谱提纯(9/1二氯甲烷/甲醇),得到0.58g白色固体。
产率=90%
MS-ES:m/z574(M+H)+
1H-RMN(270MHz,CDCl3):δ3,15(m,1H),3,50(m,4H),3,55(m,4H),4,05
(m,5H),6,45(d,1H),6,75(d,2H),7,55(m,8H),7,65(d,2H),7,85(d,2H)。
用此方法合成以下化合物:B-15:(2S)-3-{2-[(4-(4-氰基苯基)-2-氧哌嗪基)乙酰基]氨基}-2-[(3-三氟甲基苯磺酰基)氨基]丙酸甲酯(化合物17)原料:(2S)-3-氨基-2-[(3-三氟甲基苯磺酰基)氨基]丙酸甲酯三氟乙酸盐
产率=83%
MS-ES:m/z568(M+H)+
1H-RMN(270MHz,CDCl3):δ3,50(s,5H),3,65(s,4H),4,05(m,4H),4,20
(m,1H),6,65(d,1H),6,75(d,2H),7,25(m,1H),7,50(d,2H),7,60(m,1H),
7,80(m,1H),8,00(m,1H),8,10(m,1H)。B-16:(2S)-3-{2-[(4-(4-氰基苯基)-2-氧哌嗪基)乙酰基]氨基}-2-[(2-噻吩磺酰基)氨基]丙酸甲酯(化合物18)原料:(2S)-3-氨基-2-[(2-噻吩磺酰基)氨基]丙酸甲酯三氟乙酸盐
产率=36%
1H-RMN(270MHz,CDCl3):δ3,50(s,5H),3,65(m,2H),3,75(m,2H),4,00
(s,3H),4,05(s,2H),7,00(d,2H),7,20(m,1H),7,55(m,3H),7,90(d,1H)。
MS-ES:m/z528(M+Na)+B-17:(2S)-3-(2-[(4-(4-氰基苯基)-2-氧哌嗪基)乙酰基]氨基}-2-{[(3,5-二甲基-4-异噁唑基)磺酰基]氨基}丙酸甲酯(化合物19)原料:(2S)-3-氨基-2-{[(3,5-二甲基-4-异噁唑基)磺酰基]氨基]丙酸甲酯三氟乙酸盐
产率=62%
MS-ES-:m/z 517(M-H)-B-18:(2S)-3-{2-[(4-(4-氰基苯基)-2-氧哌嗪基)乙酰基]氨基}-2-[(4-氟苯磺酰基)氨基]丙酸甲酯(化合物20)
原料:(2S)-3-氨基-2-[(4-氟苯磺酰基)氨基]丙酸甲酯三氟乙酸盐
产率=46%B-19:(2S)-3-{2-[(4-(4-氰基苯基)-2-氧哌嗪基)乙酰基]氨基}-2-{[(1,3-苯并间二氧杂环戊烯-5-基-磺酰基)氨基]丙酸甲酯(化合物22)
原料:(2S)-3-氨基-2-{[(1,3-苯并间二氧杂环戊烯-5-基-磺酰基)氨基]丙酸甲酯三氟乙酸盐
产率=37%
MS-ES:m/z 544(M+H)+B-20:(2S)-3-{2-[(4-(4-氰基苯基)-2-氧哌嗪基)乙酰基]氨基}-2-[(异丙基磺酰基)氨基]丙酸甲酯(化合物23)
原料:(2S)-3-氨基-2-{[(异丙基磺酰基)氨基]丙酸甲酯三氟乙酸盐
产率=30%
MS-ES:m/z 466(M+H)+B-21:合成(2S)-3-{2-[(4-(4-氰基苯基)-3-氧哌嗪基)乙酰基]氨基]-2-{[(苯磺酰基)氨基]丙酸乙酯(化合物24)
在约5℃向2-[4-(4-氰基苯基)-3-氧哌嗪基]乙酸(化合物2)(2.59g,10mmol)和N-甲基吗啉(2.2g,21.8mmol)在50ml四氢呋喃中的悬浮液中加入氯甲酸异丁酯(1.47g,10.8mmol),随后将混合物在室温搅拌20分钟;加入2-(S)-3-氨基-2-(苯磺酰基氨基)丙酸乙酯盐酸盐(10.2mmol)。持续搅拌18小时。加入100ml乙酸乙酯和水,沉降分离有机相,用水洗,用硫酸钠干燥。用快速色谱法将粗产品纯化(15/1二氯甲烷/甲醇)得到2.5g白色固体。
产率=48%
1H-RMN(400MHz,CDCl3):δ1,0(t,3H),2,85(m,1H),2,95(m,1H),3,1(s,
2H),3,3(m,1H),3,35(s,2H),3,7(m,3H),3,85(q,2H),3,9(bs,1H),5,7
(bs,1H),7,35(m,4H),7,4(m,1H),7,55(d,2H),7,7(d,2H)。B-22:合成(2S)-3-{2-[(4-(4-氰基苯基)-2-氧哌嗪基)乙酰基]氨基}-2-[(苯磺酰基)氨基]丙酸(化合物25)
在5℃向2-[4-(4-氰基苯基)-2-氧哌嗪基]乙酸(化合物1)(5.18g,20mmol)和N-甲基吗啉(2.5g,25mmol)在100ml四氢呋喃中的混悬液中加入氯甲酸异丁酯(2.9g,21.2mmol);搅拌20分钟后,加入(2S)-3-氨基-2-(苯磺酰基氨基)丙酸(5g,20.5mmol)和二异丙基乙胺(2.8g,21.7mmol)在30ml水中的混合物和50mlTHF。持续搅拌2小时。蒸除有机溶剂,加入水,将混合物酸化得到混悬液,将其用乙酸乙酯提取。用水洗涤提取物,并用硫酸钠干燥。经过快速色谱法纯化(10/1/0.5二氯甲烷/甲醇/AcOH),得到4.6g产物。
产率=47%
1H-RMN(400MHz,DMSO-d6):δ3,2(m,1H),3,35(m,1H),3,45(t,2H),
3,65(t,2H),3,95(m,4H),7,0(d,2H),7,2(dt,2H),7,6(m,5H),7,8(d,2H),
8,15(t,1H),8,2(d,1H)。
按以上工艺合成以下化合物:B-23:(2S)-3-{2-[(4-(4-氰基苯基)-2-氧哌嗪基)乙酰基]氨基}-2-[(4-甲苯磺酰基)氨基]丙酸(化合物26)
原料:(2S)-3-氨基-2-[(4-甲苯磺酰基)氨基]丙酸
产率=55%
1H-RMN(400MHz,DMSO-d6):δ2,35(s,3H),3,2(m,1H),3,35(m,1H),
3,45(t,2H),3,65(t,2H),3,85~4,05(m,4H),7,0(d,2H),7,35(d,2H),7,5(d,
2H),7,8(d,2H),8,15(t,1H),8,2(d,1H)。B-24:合成(2S)-3-{2-[(4-(4-氰基苯基)-2-氧哌嗪基)乙酰基]氨基}-2-{[(1,1’-联苯基)-4-基磺酰基]氨基}丙酸(化合物27)
将(2S)-3-{2-[(4-(4-氰基苯基)-2-氧哌嗪基)乙酰基]氨基}-2-{[(1,1’-联苯基)-4-基磺酰基]氨基}丙酸甲酯(化合物16)(0.6g,1.04mmol)在10ml THF中的溶液和1.2ml 1N LiOH的水溶液在室温搅拌过夜。加入乙酸乙酯,然后用1N盐酸将混合物酸化到pH2。分层后分离有机相,用乙酸乙酯提取水相,合并有机相,用水洗,用硫酸钠干燥;蒸发溶剂,将残余物用硅胶色谱提纯[洗脱剂:10/1/0.5二氯甲烷/甲醇/AcOH],得到0.44g白色固体。
产率=76%
MS-ES:m/z562(M+H)+
1H-RMN(270MHz,CDCl3):δ3,50(m,1H),3,65(m,2H),3,75(m,2H),4,15
(s,6H),7,00(d,1H),7,20(m,1H),7,60(m,4H),7,80(m,1H),7,95(d,2H),
8,00(d,2H)。
用以上方法合成以下化合物:B-25:(2S)-3-{2-[(4-(4-氰基苯基)-2-氧哌嗪基)乙酰基]氨基}-2-[3-三氟甲基苯磺酰基)氨基]丙酸(化合物28)
原料:化合物17
产率=73%
MS-ES-:m/z 552(M-H)-B-26:(2S)-3-{2-[(4-(4-氰基苯基)-2-氧哌嗪基)乙酰基]氨基}-2-[(2-噻吩磺酰基)氨基]丙酸(化合物29)
原料:化合物18
产率=88%
MS-ES-:m/z490(M-H)-
1H-RMN(270MHz,CDCl3):δ3,50(m,1H),3,65(m,3H),3,75(m,3H),4,15
(s,2H),4,20(s,2H),7,00(d,2H),7,15(m,1H),7,55(d,2H),7,65(m,1H),
7,85(m,1H)。B-27:(2S)-3-{2-[(4-(4-氰基苯基)-2-氧哌嗪基)乙酰基]氨基}-2-{[(3,5-二甲基-4-异噁唑基)磺酰基]氨基}丙酸(化合物30)
原料:化合物19
产率=75%
MS-ES:m/z504(M)+B-28:(2S)-3-{2-[(4-(4-氰基苯基)-2-氧哌嗪基)乙酰基]氨基}-2-[(4-氟苯磺酰基)氨基]丙酸(化合物31)
原料:化合物20
产率=59%
MS-ES:m/z 502(M-H)-B-29:(2S)-3-{2-[(4-(4-氰基苯基)-2-氧哌嗪基)乙酰基]氨基}-2-[(1,3-苯并间二氧杂环戊烯-5-基磺酰基)氨基]丙酸(化合物33)
原料:化合物22
产率=82%
MS-ES:m/z 530(M+H)+B-30:(2S)-3-{2-[(4-(4-氰基苯基)-2-氧哌嗪基)乙酰基]氨基}-2-[(异丙基磺酰基)氨基]丙酸(化合物34)
原料:化合物23
产率=66%
1H-RMN(400MHz,DMSO-d6):δ1,24(d,6H),3,20(m,1H),3,25(m,2H),
3,50(m,2H),3,70(m,2H),4,00(s,4H),6,40(bs,1H),7,00(d,2H),7,60(d,
2H),8,05(bs,1H)。
实施例1:合成(2S)-3-{[2-(4-{4-[氨基(羟基亚氨基)甲基]苯基}-2-氧哌嗪基)乙酰基]氨基}-2-[(苯磺酰基)氨基]丙酸乙酯(CRL42800)
将在100ml乙醇中含有(2S)-3-{2-[(4-(4-氰基苯基)-2-氧哌嗪基)乙酰基]氨基}-2-[(苯磺酰基)-氨基]丙酸乙酯(化合物3)(2.3g,4.48mmol)、三乙胺(1g,9.9mmol)和盐酸羟胺(0.68g,9.78mmol)的混悬液加热回流20小时。过滤沉淀物,用乙醇清洗,真空干燥,得到1.9g白色固体。
产率=78%
MS-ES:m/z 569(M+Na)+.
1H-RMN(400MHz,DMSO-d6):δ1,0(t,3H),3,1(m,1H),3,35(m,3H),3,5
(bs,2H),3,75(q,2H),3,8~4,0(m,5H),5,65(s,2H),6,85(d,2H), 7,55(m,
5H),7,75(d,2H),8,1(t,1H),8,35(bd,1H),9,35(bs,1H)。
用实施例1所述方法合成以下化合物:
实施例2:
(2S)-3-{[2-(4-{4-[氨基(羟基亚氨基)甲基]苯基}-2-氧哌嗪基)乙酰基]氨基}-2-[(3-吡啶基磺酰基)氨基]丙酸乙酯(CRL42814)
原料:化合物4
产率=75%
MS-ES:m/z570(M+Na)+
1H-RMN(400MHz,DMSO-d6):δ1,0(t,3H),3,2(m,1H),3,4(m,3H),3,5
(m,2H),3,8(q,2H),3,85(s,2H),3,95(q,2H),4,05(dd,1H),5,65(s,2H),
6,9(d,2H),7,55(d,2H),7,6(dd,1H),8,1(dd,2H),8,7(bs,1H),8,85(d,
1H),8,9(d,1H),9,35(bs,1H)。
实施例3:
(2S)-3-{[2-(4-{4-[氨基(羟基亚氨基)甲基]苯基}-2-氧哌嗪基)乙酰基]氨基}-2-[(8-喹啉基磺酰基)氨基]丙酸乙酯(CRL42813)
原料:化合物5
产率=73%
1H-RMN(400MHz,DMSO-d6):δ0,85(t,3H),3,35(m,4H),3,55(m,4H),
3,85(s,2H),3,95(dd,2H),4,5(dd,1H),5,7(s,2H),6,9(d,2H),7,55(d,
2H),7,75(m,2H),7,9(bd,1H),8,15(t,1H),8,3(m,2H),8,55(d,1H),9,05
(d,1H),9,4(s,1H)。
实施例4:
(2S)-3-{[2-(4-{4-[氨基(羟基亚氨基)甲基]苯基}-2-氧哌嗪基)乙酰基]氨基}-2-[(苄基磺酰基)氨基]丙酸乙酯(CRL42830)
原料:化合物6
产率=64%
MS-ES:m/z583(M+Na)+
1H-RMN(400MHz,DMSO-d6):δ1,2(t,3H),3,3~3,55(m,7H),3,85(s,2H),
4,0(s,2H),4,1(q,2H),4,4(s,2H),5,65(s,2H),6,9(d,2H),7,35(m,5H),
7,55(d,2H),7,75(d,1H),8,05(t,1H),9,4(s,1H)。
实施例5:
(2S)-3-{[2-(4-{4-[氨基(羟基亚氨基)甲基]苯基}-2-氧哌嗪基)乙酰基]氨基}-2-[(苯乙基磺酰基)氨基]丙酸乙酯(CRL42832)
原料:化合物7
产率=82%
MS-ES:m/z597(M+Na)+
1H-RMN(400MHz,DMSO-d6):δ1,25(t,3H),3,0(m,2H),3,25~3,6(m,
9H),3,85(s,2H),4,05(q,2H),4,2(m,2H),5,7(s,2H),6,9(d,2H),7,3(m,
5H),7,6(d,2H),7,9(d,1H),8,15(t,1H),9,4(s,1H)。
实施例6:
(2S)-3-{[2-(4-{4-[氨基(羟基亚氨基)甲基]苯基}-2-氧哌嗪基)乙酰基]氨基}-2-{[(4-甲氧基苯基)磺酰基]氨基}丙酸乙酯(CRL42834)
原料:化合物8
产率=87%
MS-ES:m/z577(M+H)+
1H-RMN(400MHz,DMSO-d6):δ1,05(t,3H),3,2(m,1H),3,4(m,3H),3,55
(m,2H),3,8~4,5(m,10H),5,65(s,2H),6,95(d,2H),7,1(d,2H),7,55(d,
2H),7,7(d,2H),8,1(t,1H),8,2(d,1H),9,4(s,1H)。
实施例7:
(2S)-3-{[2-(4-{4-[氨基(羟基亚氨基)甲基]苯基}-2-氧哌嗪基)乙酰基]氨基}-2-{[4-甲苯磺酰基]氨基}丙酸乙酯(CRL42874)
原料:化合物9
产率=83%
MS-ES:m/z583(M+Na)+
1H-RMN(400MHz,DMSO-d6):δ1,0(t,3H),2,35(s,3H),3,1(m,1H),3,3
(m,4H),3,4(m,2H),3,7(m,3H),3,9(m,3H),5,6(s,2H),6,85(d,2H),7,4
(d,2H),7,5(d,2H),7,6(d,2H),8,05(t,1H),8,25(bd,1H),9,4(s,1H)。
实施例8:
(2S)-3-{[2-(4-{4-[氨基(羟基亚氨基)甲基]苯基}-2-氧哌嗪基)乙酰基]氨基}-2-{[(4-氯苯基)磺酰基]氨基}丙酸乙酯(CRL42876)
原料:化合物10
产率=67%
MS-ES:m/z603(M+Na)+
1H-RMN(400MHz,DMSO-d6):δ1,05(t,3H),3,2(m,1H),3,35(m,4H),3,5
(m,2H),3,9(m,6H),5,7(s,2H),6,9(d,2H),7,6(d,2H),7,7(d,2H),7,75(d,
2H),8,15(t,1H),8,55(bs,1H),9,35(bs,1H)。
实施例9:
(2S)-3-{[2-(4-{4-[氨基(羟基亚氨基)甲基]苯基}-2-氧哌嗪基)乙酰基]氨基}-2-[(2-萘基磺酰基)氨基]丙酸乙酯(CRL42878)
原料:化合物11
产率=73%
MS-ES:m/z619(M+Na)+
1H-RMN(400MHz,DMSO-d6):δ0,85(t,3H),2,85(m,1H),3,35(m,4H),
3,5(t,2H),3,6(m,2H),3,9(m,4H),5,65(s,2H),6,85(d,2H),7,55(d,2H),
7,65(m,2H),7,7(d,1H),8,05(d,1H),8,1(dd,3H),8,35(s,1H),8,5(bd
1H),9,35(s,1H)。
实施例10:
(2S)-3-{[2-(4-{4-[氨基(羟基亚氨基)甲基]苯基}-2-氧哌嗪基)乙酰基]氨基}-2-{[(苄氧基)羰基]氨基}丙酸乙酯(CRL42771)
原料:化合物12
产率=49%
MS-ES:m/z563(M+Na)+
1H-RMN(400MHz,DMSO-d6):δ1,1(t,3H),3,35(m,6H),3,78(s,2H),3,9
(s,2H),4,0(q,2H),4,1(bq,1H),4,98(s,2H),5,6(s,2H),6,8(d,2H),7,3
(m,5H),7,48(d,2H),7,58(d,1H),8,0(bs,1H),9,3(s,1H)。
实施例11:
(2S)-3-{[2-(4-{4-[氨基(羟基亚氨基)甲基]苯基}-2-氧哌嗪基)乙酰基]氨基}-2-[(异丁氧基羰基)氨基]丙酸乙酯(CRL42893)
原料:化合物13
产率=63%
MS-ES:m/z529(M+Na)+
1H-RMN(400MHz,DMSO-d6):δ0,87(d,6H),1,2(t,3H),1,8(m,1H),
3,25~3,55(m,6H),3,75(q,2H),3,85(s,2H),4,0(s,2H),4,1(q,2H),4,15
(m,1H),5,7(s,2H),6,9(d,2H),7,48(d,1H),7,55(d,2H),8,1(t,1H),9,35
(s,1H)。
实施例12:
(2S)-3-{[2-(4-{4-[氨基(羟基亚氨基)甲基]苯基}-2-氧哌嗪基)乙酰基]氨基}-2-[(丁氧基羰基)氨基]丙酸乙酯(CRL42895)
原料:化合物14
产率=60%
MS-ES:m/z529(M+Na)+
1H-RMN(400MHz,DMSO-d6):δ0,95(t,3H),1,25(t,3H),1,35(m,2H),
1,55(m,2H),3,3~3,6(m,6H),3,9(s,2H),4,0(t,2H),4,05(s,2H),4,1(q,
2H),4,2(m,1H),5,75(s,2H),6,95(d,2H),7,55(d,1H),7,6(d,2H),8,15(t,1H),9,4(s,1H)。
实施例13:
(2S)-3-{[2-(4-{4-[氨基(羟基亚氨基)甲基]苯基}-2-氧哌嗪基)乙酰基]氨基}-2-[(丁基磺酰基)氨基]丙酸乙酯(CRL42905)
原料:化合物15
产率=66%
MS-ES:m/z549(M+Na)+
1H-RMN(400MHz,DMSO-d6):δ0,9(t,3H),1,2(t,3H),1,35(m,2H),1,65
(m,2H),3,0(m,2H),3,3(m,1H),3,45(m,3H),3,55(m,2H),3,85(s,2H),
4,0(s,2H),4,1(m,3H),5,7(s,2H),6,9(d,2H),7,55(d,2H),7,75(d,1H),
8,1(t,1H),9,4(s,1H)。
实施例14:
(2S)-3-{[2-(4-{4-[氨基(羟基亚氨基)甲基]苯基}-3-氧哌嗪基)乙酰基]氨基}-2-[(苯磺酰基)氨基]丙酸乙酯(CRL42836)
原料:化合物24
产率=73%
MS-ES:m/z547(M+H)+
1H-RMN(400MHz,DMSO-d6):δ1,0(t,3H),2,8(t,2H),3,0(dd,2H),3,2
(m,2H),3,4(s,2H),3,45(m,1H),3,7(bt,2H),3,75(q,2H),5,8(s,2H),7,3
(d,2H),7,55(m,3H),7,7(d,2H),7,75(d,2H),8,05(t,1H),8,4(bd,1H),
9,65(s,1H)。
实施例15:
合成(2S)-3-{[2-(4-{4-[氨基(羟基亚氨基)甲基]苯基}-2-氧哌嗪基)乙酰基]氨基}-2-[(苯磺酰基)氨基]丙酸
将在150ml乙醇中含有(2S)-3-{2-[(4-(4-氰基苯基)-2-氧哌嗪基)乙酰基]氨基}-2-[(苯磺酰基)氨基]丙酸(化合物25)(4.43g,9.13mmol)、三乙胺(2.3g,22.7mmol)和盐酸羟胺(1.58g,22.7mmol)的混悬液加热回流16小时。过滤沉淀物,用乙醇清洗,真空干燥,得到4.05g淡棕色固体。
产率=86%
1H-RMN(400MHz,DMSO-d6):δ3,15(m,1H),3,35~4,05(m,10H),5,8(s,
2H),6,9(d,2H),7,6(m,4H),7,8(d,2H),8,1(m,2H),9,5(bs,1H)。
用同样方法合成下述产物:
实施例16:(2S)-3-{[2-(4-{4-[氨基(羟基亚氨基)甲基]苯基}-2-氧哌嗪基)乙酰基]氨基}-2-{[4-甲苯磺酰基)氨基]丙酸
原料:化合物26
产率=55%
1H-RMN(400MHz,DMSO-d6):δ2,35(s,3H),3,15(m,3H),3,45~3,9(m,
8H),5,85(s,2H),6,95(d,2H),7,35(d,2H),7,5(d,2H),7,65(d,2H),8,0
(bs,1H),8,05(t,1H),9,5(bs,1H)。
实施例17:合成(2S)-3-{[2-(4-{4-[氨基(亚氨基)甲基]苯基}-2-氧哌嗪基)乙酰基]氨基}-2-[(苯磺酰基)氨基]丙酸乙酯乙酸盐(CRL42817)
将(2S)-3-{[2-(4-{4-[氨基(羟基亚氨基)甲基]苯基}-2-氧哌嗪基)乙酰基]氨基}-2-[(苯磺酰基)氨基]丙酸乙酯(实施例1)(1.5g,2.75mmol)溶解在50ml乙酸中。加入600mg乙酸酐(5.6mmol)和0.76g 10%钯/炭。在50 psi压力在室温进行氢解3小时。过滤催化剂,将溶液蒸发至干。将所得固体溶解于150ml水,用活性炭处理。将溶液过滤。将滤液冻干,得到1.3g白色固体。
产率=80%
MS-ES:m/z531(M+H)+
1H-RMN(400MHz,DMSO-d6):δ1,0(t,3H),1,85(bs,3H),3,2(m,1H),
3,35(m,1H),3,45(bs,2H),3,75(bs,2H),3,85(q,2H),3,95(t,3H),4,05(s,
2H),7,05(d,2H),7,6(t,2H),7,65(q,1H),7,8(d,4H),8,3(t,1H)。
用实施例17所述方法合成以下化合物:
实施例18:(2S)-3-{[2-(4-{4-[氨基(亚氨基)甲基]苯基}-2-氧哌嗪基)乙酰基]氨基}-2-[(3-吡啶基磺酰基)氨基]丙酸乙酯二乙酸盐(CRL42815)
原料:化合物2
产率=74%
MS-ES:m/z532(M+H)+
1H-RMN(400MHz,DMSO-d6):δ0,95 (t,3H),1,75(bs,6H),3,2(m,1H),
3,4(m,1H),3,45(m,3H),3,62(bs,2H),3,8(q,2H),4,0(m,4H),7,0(d,2H),
7,6(dd,1H),7,7(d,2H),8,1(d,1H),8,25(t,1H),8,8(d,1H),8,9(d,1H)。
实施例19:(2S)-3-{[2-(4-{4-[氨基(亚氨基)甲基]苯基}-2-氧哌嗪基)乙酰基]氨基}-2-[(1,2,3,4-四氢-8-喹啉基磺酰基)氨基]丙酸乙酯乙酸盐(CRL42812)
原料:实施例3
产率=77%
MS-ES:m/z586(M+H)+
1H-RMN(400MHz,DMSO-d6):δ1,05(t,3H),1,8(m,5H),2,7(t,2H),3,2
(m,1H),3,4(m,3H),3,45(bs,2H),3,65(bs,2H),3,8(m,3H),3,95(m,4H),
5,95(s,1H),6,45(t,1H),7,0(m,3H),7,3(d,1H),7,7(d,2H),8,3(t,1H)。
实施例20:(2S)-3-{[2-(4-{4-[氨基(亚氨基)甲基]苯基}-2-氧哌嗪基)乙酰基]氨基}-2-[(苄基磺酰基)氨基]丙酸乙酯乙酸盐(CRL42829)
原料:实施例4
产率=83%
MS-ES:m/z545(M+H)+
1H-RMN(400MHz,DMSO-d6):δ1,2(t,3H),1,8(s,3H),3,35(m,2H),3,45
(bs,2H),3,65(bs,2H),4,1(m,7H),4,4(m,2H),7,05(d,2H),7,35(m,5H),
7,75(d,2H),8,3(bs,1H),8,7(bs,1H),10,9(bs,1H)。
实施例21:(2S)-3-{[2-(4-{4-[氨基(亚氨基)甲基]苯基}-2-氧哌嗪基)乙酰基]氨基}-2-[(苯乙基磺酰基)氨基]丙酸乙酯乙酸盐(CRL42831)
原料:实施例5
产率=85%
MS-ES:m/z559(M+H)+
1H-RMN(400MHz,DMSO-d6):δ1,2(t,3H),1,85(bs,3H),3,0(m,2H),3,3
(m,3H),3,45(m,3H),3,7(bs,2H),4,05(m,7H),7,05(d,2H),7,25(m,1H),
7,3(m,4H),7,8(d,2H),8,45(bs,1H),8,7(bs,1H),10,9(bs,1H)。
实施例22:(2S)-3-{[2-(4-{4-[氨基(亚氨基)甲基]苯基}-2-氧哌嗪基)乙酰基]氨基}-2-{[(4-甲氧基苯基)磺酰基]氨基}丙酸乙酯乙酸盐(CRL42833)
原料:实施例6
产率=82%
MS-ES:m/z561(M+H)+
1H-RMN(400MHz,DMSO-d6):δ1,0(t,3H),1,75(s,3H),3,2(m,1H),3,35
(m,1H),3,4(m,3H),3,7(m,2H),3,8~4,0(m,9H),7,05(dd,2H),7,7(dd,
4H),8,3(bs,1H)。
实施例23:(2S)-3-{[2-(4-{4-[氨基(亚氨基)甲基]苯基}-2-氧哌嗪基)乙酰基]氨基}-2-{[4-甲苯磺酰基)氨基]丙酸乙酯乙酸盐(CRL42875)
原料:实施例7
产率=63%
MS-ES:m/z545(M+H)+
1H-RMN(400MHz,DMSO-d6):δ1,0(t,3H),1,75(bs,3H),2,4(s,3H),3,2
(m,1H),3,35(m,1H),3,4(bs,3H),3,7(bs,2H),3,85(dd,2H),3,9(q,2H),
4,0(s,2H),6,95(d,2H),7,4(d,2H),7,65(d,2H),7,8(d,2H),8,35(bs,1H)。
实施例24:(2S)-3-{[2-(4-{4-[氨基(亚氨基)甲基]苯基}-2-氧哌嗪基)乙酰基]氨基}-2-{[(4-氯苯基)磺酰基]氨基}丙酸乙酯乙酸盐(CRL42877)
原料:实施例8
产率=81%
MS-ES:m/z565(M+H)+
1H-RMN(400MHz,DMSO-d6):δ1,0(t,3H),1,8(bs,3H),3,15(m,1H),3,3
(m,1H),3,4(bs,2H),3,65(bs,2H),3,8(m,2H),4,0(m,5H),7,05(d,2H),
7,7(d,2H),7,8(dd,2H),8,3(m,1H),8,8(bs,1H),9,8(bs,1H)。
实施例25:(2S)-3-{[2-(4-{4-[氨基(亚氨基)甲基]苯基}-2-氧哌嗪基)乙酰基]氨基}-2-[(2-萘基磺酰基)氨基]丙酸乙酯乙酸盐(CRL42879)
原料:实施例9
产率=82%
MS-ES:m/z581(M+H)+
1H-RMN(400MHz,DMSO-d6):δ0,85(t,3H),1,8(bs,3H),3,2(m,1H),
3,35(m,3H),3,65(m,4H),3,9(m,5H),7,0(d,2H),7,7(m,5H),8,0(d,1H),
8,15(dd,2H),8,3(t,1H),8,4(bs,1H),8,7(bs,1H)。
实施例26:(2S)-3-{[2-(4-{4-[氨基(亚氨基)甲基]苯基}-2-氧哌嗪基)乙酰基]氨基}-2-[(异丁氧基羰基)氨基]丙酸乙酯乙酸盐(CRL42894)
原料:实施例11
产率=76%
MS-ES:m/z491(M+H)+
1H-RMN(400MHz,DMSO-d6):δ0,9(d,6H),1,2(t,3H),1,8(bs,3H),1,95
(m,1H),3,25~3,5(m,5H),3,7(m,4H),3,9~4,15(m,6H),7,0(d,2H),7,55
(bs,1H),7,75(d,2H),8,2(bs,1H)。
实施例27:(2S)-3-{[2-(4-{4-[氨基(亚氨基)甲基]苯基}-2-氧哌嗪基)乙酰基]氨基}-2-[(丁氧基羰基)氨基]丙酸乙酯乙酸盐(CRL42896)
原料:实施例12
产率=75%
MS-ES:m/z491(M+H)+
1H-RMN(400MHz,DMSO-d6):δ0,85(t,3H),1,2(t,3H),1,35(m,2H),1,5
(m,2H),1,75(bs,3H),3,35(m,2H),3,5(bs,4H),3,7(bs,2H),3,9(t,2H),
4,1(m,5H),7,0(d,2H),7,25(bd,1H),7,75(d,2H),8,2(bs,1H)。实施例28:乙基(2S)-3-{[2-(4-{4-[氨基(亚氨基)甲基]苯基}-2-氧哌嗪子基)乙酰基]氨基}-2-[(丁基磺酰基)氨基]丙酸乙酯乙酸盐(CRL42906)
原料:实施例13
产率=82%
MS-ES:m/z511(M+H)+
1H-RMN(400MHz,DMSO-d6):δ0,9(t,3H),1,2(t,3H),1,35(m,2H),1,65
(m,2H),1,75(bs,3H),2,95(m,2H),3,3(m,1H),3,45(m,3H),3,7(bs,2H),
4,1(m,6H),7,05(d,2H),7,75(d,2H),8,3(bs,1H)。
实施例29:(2S)-3-{[2-(4-{4-[氨基(亚氨基)甲基]苯基}-3-氧哌嗪基)乙酰基]氨基}-2-[(苯磺酰基)氨基]丙酸乙酯乙酸盐(CRL42835)
原料:实施例14
产率=93%
MS-ES:m/z531(M+H)+
1H-RMN(400MHz,DMSO-d6):δ1,0(t,3H),1,75(bs,3H),2,75(bs,2H),
2,9(dd,2H),3,2(m,1H),3,35(s,2H),3,45(m,1H),3,7(m,4H),3,9(t,1H),
7,55(m,5H),7,75(d,2H),7,85(d,2H),8,2(t,1H),9,2(bs,1H)。
实施例30:合成(2S)-3-{[2-(4-{4-[氨基(亚氨基)甲基]苯基}-2-氧哌嗪基)乙酰基]氨基}-2-[(苯磺酰基)氨基]丙酸盐酸盐(CRL42872)
在(2S)-3-{[2-(4-{4-[氨基(羟基亚氨基)甲基]苯基}-2-氧哌嗪基)乙酰基]氨基}-2-[(苯磺酰基)氨基]丙酸(实施例15)(3.1g,6mmol)溶解在150ml乙酸中,并加入1.6g乙酸酐(15.7mmol)和1.5g10%钯炭。在50 psi压力在室温进行氢解4小时。过滤,蒸发至干,加入200ml水和10ml 4NHCl。用活性炭处理混合物,冻干,得到1g淡黄色固体。
产率=31%
MS-ES:m/z503(M+H)+
1H-RMN(400MHz,DMSO-d6):δ3,2(m,1H),3,4(m,1H),3,45(bs,2H),
3,7(bs,2H),3,95(m,5H),7,05(d,2H),7,65(m,3H),7,85(dd,4H),8,3(m,
2H),8,95(bs,2H),9,2(bs,2H)。
用上述方法合成以下产物:
实施例31(2S)-3-{[2-(4-{4-[氨基(亚氨基)甲基]苯基}-2-氧哌嗪基)乙酰基]氨基}-2-{[4-甲苯磺酰基]氨基}丙酸盐酸盐(CRL42873)
原料:实施例16
产率=46%
MS-ES:m/z517(M+H)+
1H-RMN(400MHz,DMSO-d6):δ2,2(s,3H),3,05(bs,1H),3,2(m,1H),3,3
(m,1H),3,35(bs,2H),3,7(bs,2H),3,9(m,4H),7,05(d,2H),7,35(d,2H),
7,7(d,2H),7,85(d,2H),8,2(d,1H),8,3(bs,1H),9,0(bs,2H),9,2(bs,2H)。
实施例32合成(2S)-3-{[2-(4-{4-[氨基(亚氨基)甲基]苯基}-2-氧哌嗪基)乙酰基]氨基}-2-{[(1,1’-联苯基)-4-基磺酰基]氨基}丙酸三氟乙酸盐(CRL43203)
将在20ml乙醇中含有(2S)-3-{2-[(4-(4-氰基苯基)-2-氧哌嗪基)乙酰基]氨基}-2-{[(1,1’-联苯基)-4-基磺酰基]氨基}丙酸(化合物27)(0.65g,1.15mmol)、三乙胺(0.43ml,2.9mmol)和盐酸羟胺(0.2g,2.9mmol)的混悬液加热回流18小时。过滤,用乙醇清洗,减压干燥,得到0.42g白色固体。
将以上得到的偕胺肟(0.42g,0.71mmol)溶解在30ml乙酸中,加入0.175ml乙酸酐(1.9mmol)和0.19g 10%钯炭。在50psi压力室温下进行氢解4小时。过滤催化剂,蒸发至干,得到淡棕色固体。用HPLC纯化(水/乙腈/0.2%TFA),然后冻干,得到8mg产品。
MS-ES:m/z579(M+H)+
用实施例32所述方法合成以下化合物:
实施例33(2S)-3-{[2-(4-{4-[氨基(亚氨基)甲基]苯基}-2-氧哌嗪基)乙酰基]氨基}-2-{[(4-氟苯基)磺酰基)氨基]丙酸三氟乙酸盐(CRL43204)
原料:化合物31
MS-ES:m/z521(M+H)+
1H-RMN(400MHz,DMSO-d6):δ3,30(m,1H),3,50(m,1H),3,55(bs,2H),
3,80(bs,2H),4,0~4,15(m,5H),7,10(d,2H),7,50(t,2H),7,90(m,4H),8,2
(bs,1H),8,4(d,1H),9,0(bs,2H),9,1(bs,2H)。
实施例34(2S)-3-{[2-(4-{4-[氨基(亚氨基)甲基]苯基}-2-氧哌嗪基)乙酰基]氨基}-2-{[(3-三氟甲基苯基)磺酰基]氨基}丙酸三氟乙酸盐(CRL43205)
原料:化合物28
MS-ES:m/z571(M+H)+
1H-RMN(400MHz,DMSO-d6):δ3,20(m,1H),3,45(m,3H),3,70(bs,2H),
4,0~4,15(m,5H),7,05(d,2H),7,80(d,2H),7,90(d,1H),8,10(bs,3H),8,15
(t,H),8,50(d,1H),8,65(bs,2H),8,95(bs,2H)。
实施例35(2S)-3-{[2-(4-{4-[氨基(亚氨基)甲基]苯基}-2-氧哌嗪基)乙酰基]氨基}-2-{[(3,5-二甲基-4-异噁唑基)磺酰基]氨基}丙酸三氟乙酸盐(CRL43206)
原料:化合物30
MS-ES:m/z522(M+H)+
1H-RMN(400MHz,DMSO-d6):δ2,45(s,3H),2,60(s,3H),3,30(m,1H),
3,50(m,3H),3,75(bs,2H),4,0~4,15(m,5H),7,10(d,2H),7,95(d,2H),
7,90(d,1H),8,30(t,1H),8,60(d,1H),8,90(bs,2H),9,05(bs,2H)。
实施例36:(2S)-3-{[2-(4-{4-[氨基(亚氨基)甲基]苯基}-2-氧哌嗪基)乙酰基]氨基}-2-[(2-噻吩磺酰基)氨基]丙酸三氟乙酸盐(CRL43207)
原料:化合物29
MS-ES:m/z509(M+H)+
实施例37:(2S)-3-{[2-(4-{4-[氨基(亚氨基)甲基]苯基)-2-氧哌嗪基)乙酰基]氨基}-2-[(1,3-苯并间二氧杂环戊烯-5-基磺酰基)氨基]丙酸三氟乙酸盐(CRL43208)
原料:化合物33
MS-ES:m/z547(M+H)+
实施例38:(2S)-3-{[2-(4-{4-[氨基(亚氨基)甲基]苯基}-2-氧哌嗪基)乙酰基]氨基}-2-[(异丙基磺酰基)氨基]丙酸三氟乙酸盐(CRL43209)
原料:化合物34
MS-ES:m/z469(M+H)+
实施例39
(2S)-3-{[2-(4-{4-[氨基(乙氧基羰基)亚氨基]甲基]苯基}-2-氧哌嗪基)乙酰基]氨基}-2-{[苯磺酰基]氨基]丙酸乙酯(CRL42959)
通过加入2N盐酸溶液然后冻干将(2S)-3-{[2-(4-{4-[氨基(亚氨基)甲基]苯基}-2-氧哌嗪基)乙酰基]氨基}-2-[(苯磺酰基)氨基]丙酸乙酯(实施例17)转化成盐酸盐。
在5℃向所得盐酸盐(2.83g,5mmol)在50ml DMF中的溶液中相继加入三乙胺(1.25g,12.4mmol)和氯甲酸乙酯(0.65g,6mmol)。在室温持续搅拌18小时。加水,用乙酸乙酯提取,用硫酸钠干燥。经过硅胶色谱提纯(10/1乙酸乙酯/甲醇)后,得到1.2g黄色固体。
产率=40% MS-ES:m/z 625(M+Na)+
1H-RMN(400MHz,CDCl3):δ1,05(t,3H),1,35(t,3H),3,3(m,1H),3,5~3,7
(m,5H),3,9(q,3H),3,95~4,4(m,6H),6,7(d,2H),7,25(t,1H),7,45(t,2H),
7.5(m,1H),7,8(d,2H),7,85(s,2H)。
实施例40
(2S)-3-{[2-(4-{4-[亚氨基(吗啉代)甲基]苯基}-2-氧哌嗪基)乙酰基]氨基}-2-{[4-甲苯磺酰基]氨基]丙酸乙酯(CRL43100)
在5℃向(2S)-3-{2-[(4-(4-氰基苯基)-2-氧哌嗪基)乙酰基]氨基}-2-{[(4-甲基苯基)磺酰基]氨基}丙酸乙酯(化合物9)(2.45g,4.6mmol)在3ml乙醇中的混合物中加入40ml4N乙酸乙酯盐酸盐溶液。在室温持续搅拌40小时。蒸发至干,得到淡棕色固体。
将吗啉(1.6g,18mmol)加入上述得到的亚氨酸盐(1.4g,2.3mmol)在5ml乙醇和40ml乙酸乙酯中形成的混悬液中。室温搅拌24小时后,将粗产品过滤,并在乙酸乙酯和乙醇的混合物中重结晶,得到0.86g白色固体。
产率=58%
MS-ES:m/z615(M+H)+
1H-RMN(400MHz,DMSO-d6):δ1,05(t,3H),2,4(s,3H),3,2(m,1H),3,3
(m,1H),3,45(m,2H),3,6~3,7(m,10H),3,8(q,2H),3,9(m,2H),4,0(m,
3H),7,1(d,2H),7,35(d,2H),7,5(d,2H),7,65(d,2H),8,35(t,1H),8,4(bs,
1H),9,4(bs,2H)。
用实施例40的方法合成以下化合物:
实施例41
(2S)-3-{[2-(4-{4-[亚氨基(哌啶子基)甲基]苯基}-2-氧哌嗪基)乙酰基]氨基}-2-{[4-甲苯磺酰基]氨基]丙酸乙酯(CRL43117)
原料:化合物9和哌啶
产率=27%
MS-ES:m/z613(M+H)+
1H-RMN(400MHz,DMSO-d6):δ1,05(t,3H),1,55(m,2H),1,65(m,4H),
2,35(s,3H),3,2(m,1H),3,3(m,1H),3,4(m,4H),3,65(m,4H),3,8(q,2H),
3,9(m,2H),4,0(m,2H),7,05(d,2H),7,35(d,2H),7,45(d,2H),7,65(d,
2H),8,25(t,1H),8,35(bs,1H),9,05(bs,1H),9,15(bs,1H)。
在体外研究式Ⅰ化合物对血小板聚集的抑制活性,即在标准条件下,通过将各种浓度化合物的溶液与从全血样品中分离出的新鲜血小板直接接触,全血样品取自未接受任何会干扰血液凝固的物质或药物的实验室动物(豚鼠)和健康人受试者。也从体内/体外进行了抗血小板凝固活性的研究,即在给豚鼠施用本申请要求保护的物质后,测定被吸收并进入血液循环的试验产品的抗凝聚作用的强度和持续时间。
1.体外药理学研究
1.1对豚鼠的血小板进行研究
通过心内穿刺从雄性Dunkin-Hartley豚鼠(体重约330g)取得血液,以每0.5ml柠檬酸三钠(水溶液的浓度:1.55%)对4.5ml血液的比率以免发生任何凝结。通过在150g将全血的试管离心15分钟得到富血小板血浆(PRP)。
收集PRP在池中。用Coulter ZM血液研究自动装置对这些池中所含的血小板计数:如果需要,进行稀释以使血浆中血小板的浓度在200 000和400 000血小板/mm3之间。同时,通过在1500g离心15分钟用这些池中其他样品制备贫血小板血浆(PPP)。
通过向1体积PRP中加入胶原溶液(1μg/ml)进行血小板聚集的动力学研究,使用Chrono-log公司的聚集计数器(490-D1或560VS),其使用血栓形成光学检测器。
通过向PRP池中的样品中加入一定体积溶剂(对照参比)和增加的浓度:1.5×10-8M、7×10-8M、1.5×10-7M、3×10-7M、7×10-7M、1.5×10-6M和7×10-5M的化合物测定50%抑制浓度(IC50)。在搅拌条件下在37℃经过3分钟的接触后测定聚集抑制作用。
1.2对人血小板的研究
通过穿刺肘弯静脉,从10个同年龄健康男士受试者组取得静脉血,将其收集在含有0.129M柠檬酸钠水溶液的玻璃试管中(每1体积柠檬酸盐溶液对应9体积血液)。首先在20℃和100g离心15分钟以得到富血小板血浆(PRP);移出此PRP后,将此试管在2000g再次离心15分钟,以便取得贫血小板血浆(PPP)。
对于每个确定的PRP样品,用Coulter ZM计数器对血小板计数。然后采用每个样品以下列方式研究对血小板聚集的抑制作用的变化:随着在10-8M~10-5M范围内被加入化合物的浓度升高(化合物的浓度例如为10-8M,5×10-7M,3×10-7M,10-7M,8×10-6M,6×10-6M,4×10-6M,2×10-6M,10-6M,5×10-5M,10-5M),加入来自Coultronics的Chromo-par Reagent胶原葡萄糖溶液(在5μg/ml浓度使用)引发血小板聚集。预先制备每个化合物的10-3M水溶液。用一对照实验检验在每个测定系列中溶剂对血小板聚集可能产生的作用(参比值),在搅拌下,在37℃接触3分钟后测定血小板聚集。
从测定的每个化合物的各个浓度的血小板聚集抑制百分率,计算50%抑制浓度(IC50)。
2.对豚鼠进行的体内/体外药理学研究
用与上述同样的豚鼠(Dunkin-Hartley种系)评价化合物的抗血小板聚集活性。在禁食一天的豚鼠取血前1h,2h,4h,6h,8h或12h,通过胃的途径(g.r.)以150mg/kg-10mg/kg剂量范围内给药各种产品和各种赋形剂(5ml/kg)。对动物进行随机治疗。
在与上述进行体外研究的同样条件下取血并处理血液。
从每个实验浓度测得的抑制血小板聚集的结果,能够计算每个试验产品的IC50浓度、抑制作用的动力学及其作用的持续时间。
结果收集于下表:
实施例 | 化合物CRL | 体外的IC50(M) | g.r.抑制百分率%豚鼠体内实验 | ||||
豚鼠 | 人 | d=150mg/kg | d=150mg/kg | ||||
1h | 2h | 1h | 2h | ||||
1 | 42800 | - | - | -79 | -76 | - | - |
17 | 42817 | 1.1×10-1 | 1.0×10-5 | -71 | -59 | -37 | -39 |
18 | 42815 | 9.1×10-7 | 3.2×10-5 | -51 | - | - | - |
19 | 42812 | 2.5×10-7 | 8.2×10-6 | -59 | - | -19 | - |
24 | 42877 | 3.2×10-7 | 9.3×10-6 | - | - | -21 | - |
29 | 42835 | 1.8×10-6 | 5.3×10-6 | -59 | -46 | - | - |
30 | 42872 | 9.4×10-8 | 1.2×10-7 | - | - | -68 | -64 |
31 | 42873 | 3.1×10-7 | 3.4×10-7 | - | - | -49 | - |
23 | 42875 | 4.2×10-7 | 1.8×10-5 | - | - | -4 | - |
25 | 42879 | 2.0×10-7 | 9.5×10-5 | -59 | -46 | -6 | - |
26 | 42894 | 4.0×10-7 | 5.7×10-6 | - | - | -12 | - |
40 | 43100 | 1.0×10-6 | - | - | - | -60 | -35 |
41 | 43117 | 1.6×10-6 | - | - | - | -12 | - |
39 | 42959 | - | - | - | - | -58 | - |
-:不能得到的数据
因此本发明还涉及含有有效量式(Ⅰ)化合物或它与药学可接受的酸形成的盐的药物组合物。
本发明尤其涉及用于抑制血小板聚集的含有有效量这些化合物的组合物。
本发明还涉及:
-用于抑制哺乳动物体内血纤维蛋白原结合到血小板上的方法,其中包括向哺乳动物给药有效量一种此类化合物,
-用于治疗患者体内血栓的方法,其中包括向患者给药有效量一种此类化合物,
-防止患者体内血栓形成可能性的方法,其中包括向患者给药有效量一种此类化合物,
尤其可以在以下领域使用式(Ⅰ)化合物:
ⅰ)在心脏手术(冠脉搭桥)或介入心脏病学(经腔经皮血管成形术,动脉内膜切除术,插入移植片固定模)过程中快速抑制动脉形成血栓的危险:在这些情况下,将这些化合物加入到已知的动脉形成血栓的危险的预防治疗中;在介入之前开始口服乙酰水杨酸(150-500mg/天口服),然后连续给药;在介入过程中静脉内输入非分馏的(non-fractionate)肝素,然后持续48-96小时。可以在给药阿司匹林时口服式Ⅰ化合物(0.5-1.5mg/kg),或在与或不与快速浓注结合的条件下进行静脉输入(0.25-1mg/kg/24小时)。48小时后,如果治疗是静脉给药,将代之以口服给药(0.25-10mg/kg,分成两次间隔12小时给药)以便于医院护理,然后进行非卧床治疗。
ⅱ)第二,对于显示出不稳定心绞痛或心肌梗塞发作的患者体内动脉血栓危险的预防:在这些情况下,本申请要求保护的化合物呈现出优良的生物利用率,即迅速地获得有效的循环浓度的可能性,其原因在于在病人出现动脉血栓的期间口服使用本申请要求保护的药品能够抑制血纤维蛋白原与血小板结合。在这些情况下,可以按每天1-3次口服的频率有益地给药这些化合物,由于其高的生物利用率和长的作用持续时间,其剂量选择在0.5-10mg/kg范围内。
含有一种本申请所述的活性成分的药物组合物含有呈碱或药用盐或含有一种或多种在口服给药后在体内被释出的酯官能团的前药形式的活性物质。这些药物组合物结合本领域技术人员已知的制备辅剂或载体。后者选自药典确定的制药辅剂。用于制备口服药剂的辅剂的例子有:淀粉、硬脂酸镁、滑石、明胶、琼脂、乳糖、果胶、聚乙二醇等。可以使用的剂型选自以下可能的剂型:分层或不分层的片剂、胶囊、锭剂、颗粒剂、粉剂。根据所治疗的病理学特点和每个病人的形态,日口服剂量为0.02-50mg/kg/日,有规律地间隔1~3次以保证占领血小板GpⅡb/Ⅲa受体的有效水平。通过静脉内途径,设计用于急性期治疗的药物剂型以便根据后续治疗的即时安排为了最有效地抑制血小板聚集采用独立的剂量。在此情况下,冷冻干燥产品和即用输入液能够在0.01mg/kg/天-20mg/kg/天范围内独立地变更剂量。
Claims (11)
R1选自氢、C1-C4烷基和苯基(C1-C4烷基);
R2选自氢、羟基和脒基的保护基团;
R3选自基团-NH-CO-R6,
R6选自C1-C4烷氧基,C3-C7环烷氧基,苄氧基,甲氧苯基,二甲氧苯基,苯并间二氧杂环戊烯基和苯并二噁烷基,
和基团-NH-SO2-R7
R7选自
-任选地被一或多个选自卤素、羟基和三氟甲基的基团取代的C1-C5烷基;
-单-或二环C3-C12环烷基;
-单-、二-或三环C6-C14芳基;
-选自吡啶基、噻吩基、喹啉基、苯并二噁烷基、苯并间二氧杂环戊烯基和异噁唑基的杂芳基;
-苯基(C1-C4)烷基和萘基(C1-C4)烷基;
其中n=1,2或3;
R7芳基或杂芳基任选地被一或多个独立地选自卤素、C1-C4烷基、三氟甲基、C1-C4烷硫基、C1-C4烷氧基、C1-C4烷基磺酰基、硝基、二(C1-C4烷基)氨基、苯基、萘基的基团取代,杂芳基选自噻吩基、呋喃基和吡啶基,还可以选自基团-COOR、-CH4-COOR或-O-CH2COOR,R是C1-C4烷基;
R4和R5独立地选自氢、C1-C5烷基,或共同与氮原子形成选自哌啶基或吗啉基的基团;
桥氧基处在哌嗪的2或3位,及与药学上可接受的酸形成的加成盐。
2.根据权利要求1的化合物,其中R3是基团-NH-SO2-R7。
3.根据权利要求2的化合物,其中R7选自苯基和甲苯基。
4.根据权利要求3的化合物,其特征在于其选自:(2S)-3-{[2-(4-{4-[氨基(亚氨基)甲基]苯基}-2-氧哌嗪基)乙酰基]氨基}-2-[(苯磺酰基)氨基]丙酸乙酯;(2S)-3-{[2-(4-{4-[氨基(亚氨基)甲基]苯基}-2-氧哌嗪基)乙酰基]氨基}-2-[(苯磺酰基)氨基]丙酸;(2S)-3-{[2-(4-{4-[氨基(乙氧基羰基)亚氨基]甲基]苯基}-2-氧哌嗪基)乙酰基]氨基}-2-[(苯磺酰基)氨基]丙酸;(2S)-3-{[2-(4-{4-[氨基(吗啉基)甲基]苯基}2-氧哌嗪基)乙酰基]氨基}2-{[4-甲苯磺酰基]氨基}丙酸乙酯;(2S)-3-{[2-(4-{4-[氨基(亚氨基)甲基]苯基}2-氧哌嗪基)乙酰基]氨基}-2-{[4-甲苯磺酰基]氨基}-丙酸;及与药学可接受的酸形成的加成盐。
6.具有治疗作用的组合物,其中含有权利要求1-4中任一项的化合物作为活性成分。
7.权利要求1-4中任一项的化合物在制备抗血栓形成的药物中的用途。
8.用于抑制哺乳动物体内血纤维蛋白原连接到血小板上的方法,其中包括向此哺乳动物给药有效量权利要求1的化合物。
9.用于抑制患者体内血小板聚集的方法,其中包括向此患者给药有效量权利要求1的化合物。
10.用于治疗患者体内血栓的方法,其中包括向此患者给药有效量权利要求1的化合物。
11.用于预防患者体内血栓形成危险的方法,其中包括向此患者给药有效量权利要求1的化合物。
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FR98/09169 | 1998-07-17 | ||
FR9809169A FR2781221B1 (fr) | 1998-07-17 | 1998-07-17 | Piperazinones substituees en alpha |
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EP (1) | EP1098889A1 (zh) |
JP (1) | JP2002520402A (zh) |
CN (1) | CN1173957C (zh) |
AU (1) | AU751981B2 (zh) |
BR (1) | BR9912153A (zh) |
CA (1) | CA2337880A1 (zh) |
EA (1) | EA003430B1 (zh) |
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CN104080772A (zh) * | 2011-11-29 | 2014-10-01 | 佩罗斯菲尔股份有限公司 | 抗凝血逆转剂 |
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TWI288745B (en) * | 2000-04-05 | 2007-10-21 | Daiichi Seiyaku Co | Ethylenediamine derivatives |
AR047894A1 (es) | 2004-02-25 | 2006-03-01 | Wyeth Corp | Derivados de tiofeno como inhibidores de la proteina tirosina fosfatasa 1b (ptpasa 1b); metodos para su preparacion, composiciones farmaceuticas que los contienen y su uso en el tratamiento de enfermedades mediadas por ptpasa 1b |
HUE029336T2 (en) * | 2005-09-16 | 2017-02-28 | Daiichi Sankyo Co Ltd | For the preparation of an optically active diamine derivative and process |
CA2756915C (en) * | 2009-03-30 | 2015-06-02 | Dong-A Pharmaceutical Co., Ltd. | Improved method for manufacturing dipeptidyl peptidase-iv inhibitor and intermediate |
GB201412545D0 (en) * | 2014-07-15 | 2014-08-27 | Univ Manchester The And Manchester Metropolitan University | Enzymatic processes and uses |
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1999
- 1999-07-16 EP EP99929498A patent/EP1098889A1/fr not_active Withdrawn
- 1999-07-16 US US09/743,352 patent/US6335337B1/en not_active Expired - Lifetime
- 1999-07-16 NZ NZ509167A patent/NZ509167A/en unknown
- 1999-07-16 JP JP2000560108A patent/JP2002520402A/ja active Pending
- 1999-07-16 CN CNB998087327A patent/CN1173957C/zh not_active Expired - Fee Related
- 1999-07-16 WO PCT/FR1999/001751 patent/WO2000004001A1/fr not_active Application Discontinuation
- 1999-07-16 CA CA002337880A patent/CA2337880A1/en not_active Abandoned
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Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
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CN104080772A (zh) * | 2011-11-29 | 2014-10-01 | 佩罗斯菲尔股份有限公司 | 抗凝血逆转剂 |
CN104080772B (zh) * | 2011-11-29 | 2016-10-05 | 佩罗斯菲尔股份有限公司 | 抗凝血逆转剂 |
Also Published As
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US6335337B1 (en) | 2002-01-01 |
CA2337880A1 (en) | 2000-01-27 |
EA200100152A1 (ru) | 2001-06-25 |
FR2781221A1 (fr) | 2000-01-21 |
EA003430B1 (ru) | 2003-04-24 |
NZ509167A (en) | 2003-08-29 |
WO2000004001A1 (fr) | 2000-01-27 |
EP1098889A1 (fr) | 2001-05-16 |
FR2781221B1 (fr) | 2000-10-13 |
CN1173957C (zh) | 2004-11-03 |
AU4629399A (en) | 2000-02-07 |
BR9912153A (pt) | 2001-04-10 |
AU751981B2 (en) | 2002-09-05 |
JP2002520402A (ja) | 2002-07-09 |
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