CN1097421A - 粘着受体拮抗剂 - Google Patents
粘着受体拮抗剂 Download PDFInfo
- Publication number
- CN1097421A CN1097421A CN94105008A CN94105008A CN1097421A CN 1097421 A CN1097421 A CN 1097421A CN 94105008 A CN94105008 A CN 94105008A CN 94105008 A CN94105008 A CN 94105008A CN 1097421 A CN1097421 A CN 1097421A
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- China
- Prior art keywords
- oxo
- compound
- formula
- acid
- phenyl
- Prior art date
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- Granted
Links
- 102000019997 adhesion receptor Human genes 0.000 title description 2
- 108010013985 adhesion receptor Proteins 0.000 title description 2
- 239000002464 receptor antagonist Substances 0.000 title description 2
- 229940044551 receptor antagonist Drugs 0.000 title description 2
- 150000001875 compounds Chemical class 0.000 claims abstract description 94
- 208000007536 Thrombosis Diseases 0.000 claims abstract description 4
- 206010003210 Arteriosclerosis Diseases 0.000 claims abstract description 3
- 206010008190 Cerebrovascular accident Diseases 0.000 claims abstract description 3
- 208000006011 Stroke Diseases 0.000 claims abstract description 3
- 208000011775 arteriosclerosis disease Diseases 0.000 claims abstract description 3
- 201000010099 disease Diseases 0.000 claims abstract description 3
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 3
- 230000004054 inflammatory process Effects 0.000 claims abstract description 3
- 208000010125 myocardial infarction Diseases 0.000 claims abstract description 3
- 206010061218 Inflammation Diseases 0.000 claims abstract 2
- 206010028980 Neoplasm Diseases 0.000 claims abstract 2
- 208000001132 Osteoporosis Diseases 0.000 claims abstract 2
- -1 hydrogen azepines Chemical class 0.000 claims description 130
- 238000000034 method Methods 0.000 claims description 53
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 45
- 239000002253 acid Substances 0.000 claims description 26
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 18
- 239000000203 mixture Substances 0.000 claims description 17
- 150000003839 salts Chemical class 0.000 claims description 14
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 11
- 229910052799 carbon Inorganic materials 0.000 claims description 10
- 239000003814 drug Substances 0.000 claims description 10
- 229910052739 hydrogen Inorganic materials 0.000 claims description 10
- 229910052760 oxygen Inorganic materials 0.000 claims description 10
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 claims description 9
- 238000007327 hydrogenolysis reaction Methods 0.000 claims description 9
- 229910052740 iodine Inorganic materials 0.000 claims description 9
- 125000002252 acyl group Chemical group 0.000 claims description 8
- 125000004432 carbon atom Chemical group C* 0.000 claims description 8
- 239000003795 chemical substances by application Substances 0.000 claims description 8
- 239000001301 oxygen Substances 0.000 claims description 8
- 238000002360 preparation method Methods 0.000 claims description 8
- 230000035479 physiological effects, processes and functions Effects 0.000 claims description 7
- 230000008859 change Effects 0.000 claims description 6
- 239000001257 hydrogen Substances 0.000 claims description 6
- HONIICLYMWZJFZ-UHFFFAOYSA-N azetidine Chemical compound C1CNC1 HONIICLYMWZJFZ-UHFFFAOYSA-N 0.000 claims description 4
- 150000004649 carbonic acid derivatives Chemical class 0.000 claims description 4
- 239000007788 liquid Substances 0.000 claims description 4
- 238000003797 solvolysis reaction Methods 0.000 claims description 4
- CHJJGSNFBQVOTG-UHFFFAOYSA-N N-methyl-guanidine Natural products CNC(N)=N CHJJGSNFBQVOTG-UHFFFAOYSA-N 0.000 claims description 3
- 125000000217 alkyl group Chemical group 0.000 claims description 3
- ZRALSGWEFCBTJO-UHFFFAOYSA-N anhydrous guanidine Natural products NC(N)=N ZRALSGWEFCBTJO-UHFFFAOYSA-N 0.000 claims description 3
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 3
- 229910052794 bromium Inorganic materials 0.000 claims description 3
- SWSQBOPZIKWTGO-UHFFFAOYSA-N dimethylaminoamidine Natural products CN(C)C(N)=N SWSQBOPZIKWTGO-UHFFFAOYSA-N 0.000 claims description 3
- 229910052717 sulfur Inorganic materials 0.000 claims description 3
- NOWKCMXCCJGMRR-UHFFFAOYSA-N Aziridine Chemical compound C1CN1 NOWKCMXCCJGMRR-UHFFFAOYSA-N 0.000 claims description 2
- 238000009472 formulation Methods 0.000 claims description 2
- 238000000746 purification Methods 0.000 claims 1
- 239000007787 solid Substances 0.000 claims 1
- 150000002148 esters Chemical class 0.000 abstract description 5
- 108010049003 Fibrinogen Proteins 0.000 abstract description 4
- 102000008946 Fibrinogen Human genes 0.000 abstract description 4
- 229940012952 fibrinogen Drugs 0.000 abstract description 4
- 239000002585 base Substances 0.000 description 90
- JFDZBHWFFUWGJE-UHFFFAOYSA-N benzonitrile Substances N#CC1=CC=CC=C1 JFDZBHWFFUWGJE-UHFFFAOYSA-N 0.000 description 80
- 238000006243 chemical reaction Methods 0.000 description 52
- 238000010265 fast atom bombardment Methods 0.000 description 48
- 125000004494 ethyl ester group Chemical group 0.000 description 38
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 35
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 21
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 20
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 19
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 18
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 15
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 14
- FKRCODPIKNYEAC-UHFFFAOYSA-N ethyl propionate Chemical compound CCOC(=O)CC FKRCODPIKNYEAC-UHFFFAOYSA-N 0.000 description 14
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 description 12
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 12
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 12
- KDLHZDBZIXYQEI-UHFFFAOYSA-N palladium Substances [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 11
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 11
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 9
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 9
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 9
- 238000001704 evaporation Methods 0.000 description 9
- 230000008020 evaporation Effects 0.000 description 9
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 9
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 8
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 8
- 239000003513 alkali Substances 0.000 description 8
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 8
- 125000006239 protecting group Chemical group 0.000 description 8
- 239000002904 solvent Substances 0.000 description 8
- 239000003826 tablet Substances 0.000 description 8
- OIFBSDVPJOWBCH-UHFFFAOYSA-N Diethyl carbonate Chemical compound CCOC(=O)OCC OIFBSDVPJOWBCH-UHFFFAOYSA-N 0.000 description 7
- JSSXHAMIXJGYCS-UHFFFAOYSA-N piperazin-4-ium-2-carboxylate Chemical compound OC(=O)C1CNCCN1 JSSXHAMIXJGYCS-UHFFFAOYSA-N 0.000 description 7
- 150000003053 piperidines Chemical class 0.000 description 7
- APSBXTVYXVQYAB-UHFFFAOYSA-M sodium docusate Chemical compound [Na+].CCCCC(CC)COC(=O)CC(S([O-])(=O)=O)C(=O)OCC(CC)CCCC APSBXTVYXVQYAB-UHFFFAOYSA-M 0.000 description 7
- 239000000243 solution Substances 0.000 description 7
- QGLVWTFUWVTDEQ-UHFFFAOYSA-N 2-chloro-3-methoxyphenol Chemical compound COC1=CC=CC(O)=C1Cl QGLVWTFUWVTDEQ-UHFFFAOYSA-N 0.000 description 6
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 6
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 6
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 6
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 6
- 238000000354 decomposition reaction Methods 0.000 description 6
- 238000005984 hydrogenation reaction Methods 0.000 description 6
- 235000019260 propionic acid Nutrition 0.000 description 6
- 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 6
- 239000002775 capsule Substances 0.000 description 5
- QARBMVPHQWIHKH-UHFFFAOYSA-N methanesulfonyl chloride Chemical compound CS(Cl)(=O)=O QARBMVPHQWIHKH-UHFFFAOYSA-N 0.000 description 5
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 5
- 125000001917 2,4-dinitrophenyl group Chemical group [H]C1=C([H])C(=C([H])C(=C1*)[N+]([O-])=O)[N+]([O-])=O 0.000 description 4
- WRJZKSHNBALIGH-UHFFFAOYSA-N 2-piperazin-1-ium-1-ylacetate Chemical compound OC(=O)CN1CCNCC1 WRJZKSHNBALIGH-UHFFFAOYSA-N 0.000 description 4
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 4
- LSNNMFCWUKXFEE-UHFFFAOYSA-M Bisulfite Chemical compound OS([O-])=O LSNNMFCWUKXFEE-UHFFFAOYSA-M 0.000 description 4
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 4
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 4
- 125000003739 carbamimidoyl group Chemical group C(N)(=N)* 0.000 description 4
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- 238000000576 coating method Methods 0.000 description 4
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- 230000032050 esterification Effects 0.000 description 4
- 238000005886 esterification reaction Methods 0.000 description 4
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 4
- 238000006460 hydrolysis reaction Methods 0.000 description 4
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- 239000003999 initiator Substances 0.000 description 4
- 238000002347 injection Methods 0.000 description 4
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- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 4
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 4
- 239000000463 material Substances 0.000 description 4
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 4
- 230000003287 optical effect Effects 0.000 description 4
- VLTRZXGMWDSKGL-UHFFFAOYSA-N perchloric acid Chemical compound OCl(=O)(=O)=O VLTRZXGMWDSKGL-UHFFFAOYSA-N 0.000 description 4
- NLKNQRATVPKPDG-UHFFFAOYSA-M potassium iodide Substances [K+].[I-] NLKNQRATVPKPDG-UHFFFAOYSA-M 0.000 description 4
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 4
- 125000004801 4-cyanophenyl group Chemical group [H]C1=C([H])C(C#N)=C([H])C([H])=C1* 0.000 description 3
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 3
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 3
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- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- 238000010521 absorption reaction Methods 0.000 description 3
- 150000001298 alcohols Chemical class 0.000 description 3
- 150000001408 amides Chemical class 0.000 description 3
- 125000004202 aminomethyl group Chemical group [H]N([H])C([H])([H])* 0.000 description 3
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 description 3
- 230000000903 blocking effect Effects 0.000 description 3
- 150000001732 carboxylic acid derivatives Chemical class 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
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- 125000004435 hydrogen atom Chemical class [H]* 0.000 description 3
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- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 3
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- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 3
- JLPULHDHAOZNQI-ZTIMHPMXSA-N 1-hexadecanoyl-2-(9Z,12Z-octadecadienoyl)-sn-glycero-3-phosphocholine Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCCCCCC\C=C/C\C=C/CCCCC JLPULHDHAOZNQI-ZTIMHPMXSA-N 0.000 description 2
- IZXIZTKNFFYFOF-UHFFFAOYSA-N 2-Oxazolidone Chemical compound O=C1NCCO1 IZXIZTKNFFYFOF-UHFFFAOYSA-N 0.000 description 2
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- ZLHLYESIHSHXGM-UHFFFAOYSA-N 4,6-dimethyl-1h-imidazo[1,2-a]purin-9-one Chemical compound N=1C(C)=CN(C2=O)C=1N(C)C1=C2NC=N1 ZLHLYESIHSHXGM-UHFFFAOYSA-N 0.000 description 2
- ZCLCUDWXYYXPOC-UHFFFAOYSA-N 4-[[3-[4-(aminomethyl)phenyl]-2-oxo-1,3-oxazolidin-5-yl]methyl]piperazine-2-carboxylic acid Chemical compound C1=CC(CN)=CC=C1N1C(=O)OC(CN2CC(NCC2)C(O)=O)C1 ZCLCUDWXYYXPOC-UHFFFAOYSA-N 0.000 description 2
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- RGHNJXZEOKUKBD-SQOUGZDYSA-N D-gluconic acid Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C(O)=O RGHNJXZEOKUKBD-SQOUGZDYSA-N 0.000 description 2
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 2
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- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 2
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- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Substances [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
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- 125000001501 propionyl group Chemical group O=C([*])C([H])([H])C([H])([H])[H] 0.000 description 2
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- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 description 2
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 2
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
- C07D263/02—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings
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Abstract
新颖的式I化合物及其盐类(其中R、X和Y的
定义见专利权利要求1),可以抑制纤维蛋白与纤维
蛋白原受体之间的结合,并且可以用于治疗血栓、中
风、心肌梗塞、炎症、动脉硬化、骨质疏松和肿瘤等疾
病。
Description
本发明涉及新颖的式1化合物及其盐其中:
X是O,S,NH或NA,
Y是未取代的或R2取代的氮丙啶并,氮杂环丁烷并,吡咯烷并,哌啶子基,1-氧杂-8-氮杂螺旋[4.5]癸-8-基,六氢氮杂
并或4-R哌啶子基,R2可被OZ,SZ或N(Z)基团和/或羰基氧所取代,
Z在所有情况下,是H,A,苯基-CkH2k或Ac
R是可被下列基团所取代的苯基:CN,H2N-CH2-、-(A)2N-CH2,H2N-,C(=NH)-,H2N-C(=NH)-NH-,
H2N-C(=NH)-NH-CH2-,HO-NH-C(=NH)或HO-NH-C(=NH)-NH,
R是-CmH2m-COOR3或-CnH2n-O-CpH2p-COOR3,
R是H,A或苄基,
R是H,A,苄基或-CmH2m-COOR3,
A在所有情况下,是具有1-6个碳原子的烷基,
Ac是具有1-11个碳原子的酰基,
K和M在所有情况下,是0,1,2或3,
n是0,1或2,且
p是1,2或3。
类似的化合物参见EP-A1-0 381 033。
本发明的目的是发现具有用性质的新颖化合物,特别是可将这些化合物用于制备药物。
本发明已达到这个目的,即发现了式Ⅰ化合物,该化合物的溶剂化物及其盐类,这些化合物具有有价值的药理学性质且有良好耐受性,特别是它们能抑制纤维蛋白原,fibronectin及von willebrand因子与血小板(糖蛋白Ⅱb/Ⅲa)上的纤维蛋白原受体相结合,以及能抑制这些蛋白质,及进一步的粘着蛋白如vitronectin,胶原蛋白及laminin与存在于各类细胞表面上的,相应的受体相结合。因而,它们必然地影响了细胞-细胞和细胞-基质间的相互作用,特别是它们能防止血小板血栓的发展,并因此可用于活疗血栓、中风、心肌梗塞、炎症和动脉硬化等疾病。另外,对肿瘤细胞有作用,它们能防止肿瘤转移。因而,也可被当做抗肿瘤剂用。
该化合物还适合做防止感染的抗微生物活性物质,例如由细菌、真菌或酵母菌所引发的感染。因此,当在机体内介入外来物,如仿生物质,植入体,导管或起博器时,最好将该化合物同时给予体内,作为伴随性抗微生物活性物质,此时它们起到抗菌剂的作用。
可用EP-A1-0 462 960中所述方法来证实该化合物的特性。可用EP-A1-0 381 033中所述方法来证实对纤维蛋白原与其受体结合的抑制作用,可在体外实验中,用Born的方法(Nature 4832,927-929,1962)来证实其对血小板凝集的抑制作用。
本发明还涉及到制备上述式Ⅰ化合物及其盐类的方法,其特征为:
(a)用溶剂分解或氢解剂处理式Ⅰ化合物的功能衍生物之一,释出式Ⅰ化合物,或者
(b)将式Ⅱ化合物
(其中,E是Cl,Br,I或反应性的酯化OH基团,且R′及X的含义同上所述)与具式Ⅲ的氨基化合物反应
其中
Y的含义同上所述,或者,
(c)将式Ⅳ化合物或其活性衍生物之一
(其中,R′X及Y的含义同上所述)与羧酸的反应活性衍生物进行反应,或者,
(d)为了制备具式Ⅰ的胍化合物(R1=被H2N-C(=NH)-NH所取代的苯基),将相应于式Ⅰ的氨基化合物(其中,含有一个替代R1基的氨基苯基)用脒化剂处理,
和/或,在式Ⅰ化合物中,R1基和/或Y基之中的一个或二个转化为另一个R1和/或Y基,和/或用酸或碱来处理式Ⅰ化合物,使之转化为盐。
式Ⅰ化合物中具有至少一个手性中心,因而可以几种对映体的形式存在。所有这些型式(例如,D和L型)及其混合物(如,DL型)均包括在式Ⅰ中。
在上文及下文中,除非另外说明,基团或符号X,Y,Z,R1至R4A,Ac,K,m,n,p及E的含义,见式Ⅰ或Ⅱ中所述。在式Ⅰ、Ⅱ和/或的分子中存在几外A基团和/或Z基团时,它们既可相同也可彼此不同。
在上式中,基团A有1-6个,最好是1,2,3或4个碳原子,特别可取的是甲基、乙基、丙基、异丙基、丁基、异丁基、仲丁基或叔丁基及其它的如,戍基,1-,2-或3-甲基丁基,1,1-,1,2-或2,2-二甲基丙基,1-乙基丙基,己基或1-,2-,3-或4-甲基戍基。
X较可取的是O,或其它如S,NH或NA,例如N-CH。
Y较可取的是如下基团:3-(R3OOC)-氮杂环丁烷并,3-(R3OOC-CH2-O-)氮杂环丁烷并,2-(R3OOC-)吡咯烷并,3-(R3OOC-)吡咯烷并,2-(R3OOC-)哌啶子基,3-(R3OOC-)哌啶子基,4-(R3OOC-)哌啶子基,2-(R3OOC-CH2)哌啶子基,3-(R3OOC-CH2)哌啶子基,4-(R3OOC-CH2-)哌啶子基,4-(R3OOC-CH2CH2-)哌啶子基,4-羟基-4-(R3OOC)-哌啶子基,4-羟基-4-(R3OOC-CH2-)哌啶子基,4-氨基-4-(R3OOC)-哌啶子基,4-氨基-4-(R3OOC-CH2-)哌啶子基,3-氧代-4-(R3OOC-CH2-)哌啶子基,2-(R3OOC-CH2-O-)哌啶子基,3-(R3OOC-CH2-O-)哌啶子基,4-(R3OOC-CH2-O-)哌啶子基,1-氧杂-2-氧代-8-氮
杂螺旋[4.5]癸-8-基,2-,3-,或4-(R3OOC)-六氢氮杂
并4-(R3OOC-CH2-)哌嗪并,4-(R3OOC-CH2CH2-)哌嗪并,2-(R3OOC)-哌嗪并,3-(R3OOC)-哌嗪并,或4-苄基-3-(ROOC)-哌嗪并。
Z较可取的是H,较可取的A是,如甲基,或乙基,苯基,苄基,乙酰基或苯甲酰基。
R1较可取为苯基,该苯基可在其4-位,或在2或3位上被取代,特别可取的是2-,3-,或(特别是)4-氰基苯基,2-,3-或(特别是)4-氨甲基苯基,2-,3-,或(特别是)4-二甲基氨基苯基,2-,3-,或(特别是)4-脒基苯基,2-,3-,或4-胍基苯基或2-,3-,或4-胍基甲基苯基,2-,3-,或(特别是)4-羟基脒基苯基。
R2较可取的是-COOR3,-CH2COOR3或-O-CH2COOR3。
R3较可取的是H,甲基、乙基、叔丁基或苄基。
R4较可取的是H,甲基、乙基、苄基或CH2COOR3。
Ac较可取的是具有1-6个碳原子的链烷酰基,例如,甲酰基,乙酰基,丙酰基,丁酰基,异丁酰基,戍酰基或己酰基,以及苯甲酰基,甲苯基,1-或2-萘甲酰基或苯乙酰基。
参数K及m较可取的是0或1,参数n较可取的为0,参数P较可取的为1。
这样的式Ⅰ化合物是较可取的,即其中至少在所指的,基团和/或参数中的一个具有所指的较可取含义中的一种。某些类可取的化合物为即些相应于式Ⅰ中的式Ⅰa至Ⅰd化合物,其中:
在Ⅰa中,X是O;
在Ⅰb中,X是O且
R1是氰基苯基;
在Ⅰc中,X是O,且
R1为氨基甲苯基;
在Ⅰd中,X是O,且
R1是脒基苯基。
进一步地,较可取的化合物还有式Ⅰe,以及Ⅰae,Ⅰbe,Oce及Ⅰde,(相应于式Ⅰ,Ⅰa,Ⅰb,Ⅰc及Ⅰd)
然而,条件是,
Y是3-R2-氮杂环丁烷并,2-R2-吡咯烷并,2-R2-哌啶子基,3-R2-哌啶子基,4-R2-哌啶子基,4-R2-哌嗪并或3-R2-4-R4-哌嗪并,
R2是-COOR3,-CH2COOR3或-OCH2COOR3,且
R4是-CH2COOR3,
较少选择的化合物为式Ⅰf及Ⅰg所表示的即些,它们是相应于式Ⅰ的,但其中:
在Ⅰf中,X是O,
Y是3-(R3OOC-CH2-O-)-氮杂环丁烷并,2-(R3OOC-)吡咯烷并,2-,3-,或4-(R3OOC-)-哌啶子基,4-(R3OOC-CH2-)-哌啶子基,3-或4-(R3OOC-CH2-O-)哌嗪并,4-(R3OOC-CH2)-哌嗪并或3-(R3OOC-)-4-R4-哌嗪并,
R1是4-氰基苯基,4-氨甲基苯基,4-脒基苯基,或4-胍基甲基苯基,
R3是H,C1-4-烷基或苄基且
R4是H或苄基,并且
在Ⅰg中,X 是O
Y是4-(R3OOC-)-哌啶子基或4-(R3OOC-CH2O-)-哌啶子基,
R1是4-氰基苯基,4-氨基甲基苯基或4-脒基苯基,且
R3是H,C1-4-烷基或苄基。
另外,也可用本身已知的方法,即文献中所述的方法来制备式Ⅰ化合物及其起始物[例如,在常规著作中,如,Houben-Wegl,Methoden der organischen Chrmie(有机化学方法),Grorg-Thirme Verlag,stuugart;EP-A1-0381033及EP-A1-0462960],特别是在所述反应中已知的,适合的反应条件下进行反应。在本文中,也可采用该方法的各种已知的变更的方法,其不再详细论述。
如果需要的话,也可将反应中生成起始物,不经分离而直接让其在反应混合物进一步反应,从而得到式Ⅰ化合物。
可用溶剂解,特别是水解或用氢解的方法,将式1化合物从其功能基衍生物中游离出来。
较可取的用于溶剂解或氢解的起始物是即些除了相应于式Ⅰ之外,还带有代替了一或多个游离的氨基和/或羟基的保护的氨基和/或羟基的化合物,较可取的化合物带有代替了与氮相连的氢原子的氨基保护基,特别是带有代替了HN基团的R1-N-基团,其中的R1氨基保护基,例如,相应于式Ⅰ,且带有代替3-COOH基团的-COOR2基团,其中R2为羟基保护基。
几种(同样的或不同的)保护的氨基和/或羟基也可存在于起始化合物的分子中。如果保护基相互不同,则在多数情况下可以选择性地将它们除去。
术语“氨基保护基”为已知的,并且是涉及在化学反应中适宜保护(阻断)氨基的基团,且该基团在分子的另一部位上所需进行的化学反应发生后,可以十分容易地被除去。具有这类特性的基团特指,未取代或取代的酰基,芳基(例如,2,4-二硝基苯基(DNP)),芳烷氧甲基(例如,苄氧甲基(BOM))或芳烷基(如,苄基,4-硝基苄基或三苯甲基)。由于氨基保护基是在所需反应之后(或紧接着反应)被除去的,故对其特性及大小的要求不是那么苛刻的,但是通常以1-20,特别是1-8个碳原子较为可取。联系到本文中的方法,术语“酰基”具有很广泛的含义,它包括衍生自脂肪性,芳香性,芳香脂肪性或杂环的羧酸或磺酸的酰基,例如,烷氧羟基,芳氧羰基,尤其是芳烷氧羰基。具此特性的酰基的实例包括链烷酰基,如乙酰基,丙酰基或丁酰基;芳烷酰基,如苯乙酰基;芳烷酰基,如苯甲酰基或甲苯基;芳氧基链烷酰基,如苯氧乙酰基;烷氧羰基,如甲氧羰基,乙氧羰基,2,2,2,-三氯乙氧羰基,异丙氧羰基,叔丁氧羰基(BOC)或2-碘二氧羰基;攻烷氧羰基,如苄羰基(CBZ),4-甲氧苄氧羰基或9-芴基甲氧羰基(FMOC)。这些氨基保护基中较可取的是BOC,DNP,及BOM,还有其它的,如CBZ,苄基及乙酰基。
术语“羟基保护基”是已知的,并且涉及在化学反应中适宜保护羟基的基团,且该基团在分子的另一部位所需进行的化学反应发生后,可十分容易地被除去。具有这类特性的典型基团为上述未取代或取代的芳基、芳烷基或酰基,另外还有烷基。由于羟基保护基在所需反应之后或紧接着反应被除去,故对其特性和大小的要求不那么苛刻。较可取的保护基含有1-20,特别是1-10个碳原子,羟基保护基的实例有:叔丁基、苄基,对硝基苯甲酰基,对甲苯磺酰基及乙酰基,以苄基和乙酰基尤为可取。
可用常规方法制备用以作为起始化合物的具式Ⅰ化合物的功能衍生物,例如,在上述的经典著作及专利申请中所描述的常规方法。如用相应于式Ⅱ及式Ⅲ的化合物至少一种含有取代了H原子的保护基团的该类化合物进行反应。
将式Ⅰ化合物从其功能衍生物中游离出来的方法取决于所用的保护基团,例如用强酸,特别是三氟乙酸或高氯酸,或用其它无机酸,如盐酸和硫酸,强有机羧酸,如三氯乙酸或磺酸,如苯磺酸或对甲苯磺酸。可在反应中加入其它惰性溶剂,但这并不总是必需的。
合适的惰性溶剂为有机类的羧酸,如乙酸;醚类,如四氢呋喃或二噁烷;酰胺类,如二甲基甲酰胺(DMF);卤代烃类,如二氯甲烷;亚砜类化合物,如二甲基亚砜(DMSO);另外还有醇类,如甲醇、乙醇、异丙醇以及水。另外,上述溶剂的混合物也可作溶剂。三氟乙酸在使用时,一般是过量的,不用再加入其它溶剂,高氯酸在使用时以与乙酸混合的形式,其比例是乙酸:70%的记氯酸=9∶1。较有利的裂解反应温度在约0~50°,较好的是在15~30°(室温)。
例如,在15~60°下,用溶于二氯甲烷的40%三氟乙酸或溶于二噁烷中的3~5NHCL可将BOC基团消去,在15~60°下,用溶于DMF中的,约5~20%的二甲胺,二乙胺或哌啶的溶液可将FMOC基团消去。消去DNP基团也可实现,例如在15~30°下,用溶于DMF/水中约3~10%的2-巯基乙醇进行处理。
保护基(例如BOM,CBZ或苄基)可通过氢解反应消去,例如在催化剂存在下(象经典的金属催化剂Pd,较有利的是以C为载体)用氢气进行反应。在此反应步骤中合适的溶剂有醇类,象甲醇或乙醇;酰胺类,如DMF。作为常规,氢解反应在约0~100°下,压力为约1巴~200巴,较好的是20~30°,压力为1~10巴。对CBZ基团的氢解也很令人满意,例如在20~30°下,于5~10%Pd/C存在下,在甲醇中进行。
通过式Ⅱ化合物与式Ⅲ化合物的碱进行反应可以制得式Ⅰ化合物,常用的是熟知的N-烷基化反应。
较好的离去基团为Cl,Br,I,C1-6-烷磺酰氧基,如苯磺酰氧基,对甲苯磺酰氧基或1或2-苯磺酰氧基。
反应最好在有碱存在下进行,例如碱金属或碱土金属的氢氧化物或碳酸盐,如氢氧化钠,氢氧化钾,氢氧化钙,或碳酸钠,碳酸钾,碳酸钙,反应于惰性溶剂中进行,如卤代烃,象二氯甲烷,醚类,如THF或二噁烷,酰胺类,如DMF或二甲基乙酰胺,或腈类,如乙腈,反应温度在-10~200°,较好的是0~120°。如果式Ⅰ中的离去基团E是不同的,建议加入碘,如KI。
作为常规,式Ⅱ的起始化合物是新制备的,例如,通过取代的具式R1-NH2的苯胺与式R5CH2-CHR6-CH2)H(其中R5为E,R6为XR7,R7是保护基团,且R5和R6一起为O)进行反应,给出式R1-NH-CH2-CHR8-CH2OH(其中R8为XR7或OH)化合物,将保护基R7用合适的方法消除,给出式R1-NH-CH2-CH(XH)-CH2OH化合物,后者与碳酸衍生物进行反应,例如碳酸二乙酯,得到3-R-5-羟甲基-2-唑烷酮,将羟甲基转化成CH2E基团,例如可用SOd2SOBr2,甲磺酰氯或对甲苯横酰氯。作为常规,式H-Y(Ⅲ)化合物是已知的,或可用已知化合物并以相似的方法制得。
另外,式1化合物可通过使式Ⅳ化合物(或其活性衍生物)与碳酸活性衍生物反应制得。
特别地,合适的碳酸衍生物有碳酸二烷酯,如碳酸二乙酯,另外还有氯甲酸烷基酯,如氯代甲酸乙酯。较好地,碳酸衍生物(较有利的是过量使用),亦可以作为溶剂或悬浮剂。任何上述给出的溶剂均可使用,前提是它在反应中是惰性的。进一步而言,反应时加碱是可行的,通常是碱金属醇化物,例如叔丁醇钾,反应温度一般在0~150°,较好的是70~120°。
就常规而言,超始化合物Ⅳ是新制备的,其步骤如下:通过对上述式R1-NH-CH2-H(XH)-CH2OH化合物功能化,给出化合物R1-NH-CH2-CH(XH)-CH2-E,后者再与式H-Y(Ⅲ)反应。
为了制备式Ⅰ化合物,(其中R1为胍基苯基团),可用脒基化剂对相应的氨基苯基化合物进行处理,1-脒基-3,5-二甲基吡唑(以其硝酸盐形式被使用)可作为脒基化试剂。反应较有利地是在有碱存在下进行,如三乙胺或乙基二异丙胺,反应溶剂为惰性的或用混合溶剂,例如水/二噁烷,反应温度为0~120°,较好地为60~120°。
进一步讲,将式Ⅰ化合物中的一个或两个R1基团和/或Y转化成其他R和/或Y基团。
特别地,氰基基团可被还原成氨甲基基团,或转化成脒基或羟基脒基,酯化的羟基基团,裂解的酯基,可经过氢解除去的苄基以及可转化成胍基甲基的氨甲基基团。
氰基还原成氨甲基的反应较有利的是通过用催化氢化完成,例如,在有Raney镍存在下,温度为0~100°较好的是10~30°,压力为1~200巴,较好的是常压,于惰性溶剂中,如低级醇,例如甲醇或乙醇,且较有利的是在有NH气存在下进行反应。如果反应在约20°且压力为1巴时进行,存在于起始物中的苄基酯或N-苄酯基团得以保留。如果需要通过氢解裂解这些基团,可使用较经典的金属催化剂,较好的是Pd/C,可向反应体系中加入酸,例如乙酸,也可加水。
为了制备式1的脒基化合物(R1=脒基苯基)可将NH3加到式Ⅰ的腈化物中(R1=氰基苯基)。此加成反应可用以下几种方法来完成。a)用H2S将腈化合物转化成硫代酰胺,后者可用烷基化试剂,例如CH3I转化成相应的S-烷基亚胺基硫代酯,其再与NH3反应,给出脒类化合物,b)用醇类,例如乙醇,在有HCL存在下,将腈化合物转化成相应的亚胺基酯,后者用NH3处理,或c)使腈化合物与双(三甲基甲硅烷基)酰胺锂化合物进行反应,然后水解所得产物。
按照上述方法a)或b),用羟胺代替氨气,从腈化合物可以制备相应的式1N-羟基脒类化合物(R=被HO-NH-C(=NH)取代的苯基)。
对于酯化反应来说,可用过量的式R3-OH(R3=A或苄基)的醇对式1化合物(R3=H)的酸进行处理,较有利的是在有强酸存在下进行,如盐酸或硫酸,温度在0~100°之间,较好的是20~50°。
相反地,通过上述的溶剂分解方法,例如用NaOH或KOH,在水/二噁烷中,于0~40°下,较好的是10~30°,式1化合物的酯(R=A或苄基),可以转化成相应式1化合物的酸(R=H)。
用酸处理式1化合物的碱可以转化成相应的酸加碱盐。这些酸需适合此反应,并能生成生理学上无害的盐类。它们包括无机酸类,如硫酸,硝酸、氢卤酸、象盐酸、氢溴酸、磷酸、象(正)磷酸、氨基磺酸、有机酸类,特别是脂肪酸,脂环酸、芳香脂肪酸,芳香或杂环单元或多元羧酸,磺酸或硫酸,例如甲酸、乙酸、三氟乙酸、丙酸,新戊酸,二乙基乙酸、丙二酸、琥珀酸、庚二酸、富马酸、马来酸、乳酸、酒石酸、苹果酸、柠檬酸、葡萄糖酸、抗坏血酸、烟酸、异烟酸、甲磺酸或乙磺酸,乙烷二磺酸、2-羟基乙磺酸,苯磺酸,对甲苯磺酸、萘单磺酸及萘双磺酸,以及月桂基硫酸。生理学上无害的酸加成盐,例如苦味酸盐,可以用来分离和/或纯化式Ⅰ化合物。
如果需要的话,式Ⅰ化合物的游离碱可通过强碱处理(如用KOH或者Na2CO3或K2CO3)。从它们的盐中释放出来。
通过与相应的碱反应,也可以将式Ⅰ(R3=H)羧酸化合物转变成它们的金属盐或铵盐,例如钠盐、钾盐或钙盐。
式Ⅰ化合物含有一个式多个手性中心,因此可以外消旋体或光学活性形式存在。根据熟知的机械的或化学的方法可将所得的外消旋体拆分成对映体。较好地,外消旋体混合物通过与光学活性拆分试剂反应,可以形成非对映体,合适的拆分试剂有光学活性酸,如D或L型酒石酸,二乙基酒石酸,二苯甲基酒石酸,扁桃酸、苹果酸或乳酸或各种具光学活性的樟脑酸,如β-樟脑磺酸。采用填充有光学活性拆分剂(例如二硝基苯甲基苯基甘氨酸)的柱子进行对映体拆分也是比较有利的;合适的洗脱剂的例子是己烷/异丙醇/乙腈的混合物,其体积比为82∶15∶3。
自然地,按照上述方法,通过使用已具光学活性的起始化合物(如式Ⅱ化合物)可以获得具光学活性的式Ⅰ化合物。
新颖的式Ⅰ化合物以及它们生理学上无害盐类可用于生产药物制剂,即可将它们与至少一种赋形剂或辅助剂混合,如果需要的话,还可与一种或多种其它活性化合物一起做成合适的剂型。所获得的配方可用于制备人用或兽用药物。这些有机或无机化合物可作为载体物质,它们适合肠道(如口腔或直肠)或非肠道给药,或也可以吸入喷雾剂的形式给药,它们不与新颖的化合物反应,例如水,植物油,苄醇,聚乙二醇,三乙酸甘油酯以及其它脂肪酸甘油酯,明胶,大豆卵磷脂,碳水化合物,例如乳糖或淀粉,硬脂酸镁,滑石和纤维素。片剂,包衣片,胶囊,喷雾剂,汁剂或滴剂,特别适用于口服给药;具有抗胃液性质的包衣或胶囊套的涂层药片及胶囊尤被看好。栓剂可经直肠给药。溶液,特别是油状或水溶液,此外还有悬浮液,乳浊液或植入剂可用于非肠道给药。
对于吸入喷雾来说,含有活性成份的喷雾剂可以溶于或悬浮于推进剂气体混合物中使用。较有利的情况是活性成份以微粒形式被使用,同时可以有一种或多种其它生理学上可耐受的溶剂存在,例如,乙醇。吸入溶液可用常规的吸入器给药。此新颖化合物亦可经冷冻干燥,然后使用其生成的冷冻干燥剂,例如用于制备注射用制剂。所给出的配方,可以是无菌的和/或含有辅助剂,如防腐剂,稳定剂和/或加湿剂,乳化剂,可影响渗透压的盐类,缓冲物质以及着色剂和/或香料。如果需要的话,他们可以含有一种或多种其它活性化合物,例如一种或多种维生素。
本发明化合物可用与其它已知的且有市售的药物相同的给药方法给药,特别是EP-A-459256中描述的化合物的给药方法,较好的剂量是在约5mg~1g之间,特别是40~500mg每剂量单位。每日的剂量较好的是在约0.1~20mg/kg之间,特别是1~10mg/kg体重。然而对于每个病人所用的特定剂量取决于很多因素,例如所用化合物的活性,病人的年龄、体重,一般健康状况,性别,饮食,给药时间和途径,排泄速度,所用的药物的组合以及所欲治疗的病情的严重程度等等。口服给药是较可取的。
在上文或下文中,所有温度以℃给出,在下列实例中,“常规操作”意指如果需要,加水,PH可调节在2~8之间(取决于最终产品的组份),可用乙酸乙酯或二氯甲烷提取,分层,有机层经Na2SO4干燥并蒸发,然后用硅胶层析和/或重结晶进行纯化。FAB=(M++1)在质谱中的峰值,它是用“快原子轰击法”测得的。
实例1
在20℃下,将溶于12ml二氯甲烷中的1g1-叔丁氧羰基-4-(3-(4-氰基苯基)-2-氧代-5-恶唑烷基甲基)-哌嗪-2-羧酸乙酯(按照实例3所述的方法,由3-(4-氰苯基)-5-溴甲基-2-恶唑烷酮与1-叔丁氧羰基哌嗪-2-羧酸乙酯反应制得)及12ml三氟乙酸一起在20℃时放置反应1小时,然后蒸发浓缩。得1-(3-(4-氰苯基)-2-氧代-5-恶唑烷基甲基)哌嗪-3-羧酸乙酯,FAB359。
用相类似的方法,从1-叔丁氧羰基-4-(3-(4-氰苯基)-2-氧代-5-恶唑烷基甲基)哌嗪-2-羧酸或其苄酯可以制备1-(3-(4-氰苯基)-2-氧代-5-噁唑烷基甲基)-哌嗪-3-羧酸及其苄酯。
实例2:
在20℃下,且压力为1巴,于0.6g5%Pd/C上,将溶于38ml甲醇,6ml水及6ml乙酸混合物中的1g1-(3-(4-苄基氧羰基氨甲基苯基)-2-氧代-5-恶唑烷基甲基)哌啶-4-氧乙酸叔丁酯(按照实例3中所述方法,由3-(4-苄氧羰基氨甲基苯基)-5-氯甲基-2-恶唑烷酮和哌啶-4-氧乙酸叔丁酯反应制得)进行氢化反应,直至H2吸收停止。过滤反应混合物,蒸发浓缩滤液,得1-(3-(4-氨甲基苯基)-2-氧代-5-唑烷基甲基)哌啶-4-氧乙酸叔丁酯,m,p95~96°,FAB 420。
实例3:
将2.96g3-(4-氰苯基)-5-甲磺酰氧甲基-2-噁唑烷酮(m.p.162~163°;制备方法如下:使4-氨基苯甲腈与2,3-环氧丙醇进行反应,得4-(2,3-二羟基丙氨基)-苯甲腈(油状),再于110℃下使之与碳酸二乙酯/叔丁醇钾进行反应,得3-(4-氰苯基)-5-羟甲基-2-噁唑烷酮(m.p.130~131°)。然后用甲磺酰氯进行酯化],1.69g哌啶-4-羟酸乙酯,70ml乙腈,1.38g碳酸钾及1.65g碘化钾一起煮沸25小时,经常规处理后,得1-(3-(4-氰苯基)-2-氧代-5-恶唑烷基甲基)-哌啶-4-羧酸乙酯(“IA”),FAB 358。
用相类似的方法,可制得下列化合物:
与哌啶-4-羧酸苄酯反应:
得1-(3-(4-氰苯基)-2-氧代-5-噁唑烷基甲基)
哌啶-4-羧酸苄酯,m.p.96°,FAB 420;
与哌啶-4-羧酸叔丁酯反应:
得1-(3-(4-氰苯基)-2-氧代-5-噁唑烷基甲基)哌啶-4-羧酸叔丁酯;
与哌啶-3-羧酸乙酯反应:
得1-(3-(4-氰苯基)-2-氧代-5-噁唑烷基甲基)哌啶-3-羧酸乙酯;
与哌啶-3-羧酸苄酯反应:
得1-(3-(4-氰苯基)-2-氧代-5-噁唑烷基甲基)哌啶-3-羧酸苄酯;FAB 420;
与哌啶-3-羧酸叔丁酯反应:
得1-(3-(4-氰苯基)-2-氧代-5-噁唑烷基甲基)哌啶-3-羧酸叔丁酯;
与哌啶-2-羧酸乙酯反应:
得1-(3-(4-氰苯基)-2氧代-5-噁唑烷基甲基)哌啶-2-羧酸乙酯;
与哌啶-2-羧酸苄酯反应:
得1-(3-(4-氰苯基)-2-氧代-5-噁唑烷基甲基)哌啶-2-羧酸苄酯,FAB 420;
与哌啶-2-羧酸叔丁酯反应:
得1-(3-(4-氰苯基)-2-氧代-5-噁唑烷基甲基)哌啶-2羧酸叔丁酯;
与吡咯烷-2-羧酸乙酯反应:
得1-(3-(4-氰苯基)-2-氧代-5-噁唑烷基甲基)吡咯烷-2-羧酸乙酯;
与吡咯烷-2-羧酸苄酯反应:
得1-(3-(4-氰苯基)-2-氧代-5-噁唑烷基甲基)吡咯烷-2-羧酸苄酯;
与吡咯烷-2-羧酸叔丁酯反应:
得1-(3-(4-氰苯基)-2-氧代-5-噁唑烷基甲基)吡咯烷-2-羧酸叔丁酯;
与哌啶-4-乙酸乙酯反应:
得1-(3-(4-氰苯基)-2-氧代-5-噁唑烷基甲基)哌啶-4-乙酸乙酯;
与哌啶-4-乙酸苄酯反应:
得1-(3-(4-氰苯基)-2-氧代-5-噁唑烷基甲基)哌啶-4-乙酸苄酯;
与哌啶-4-乙酸叔丁酯反应:
得1-(3-(4-氰苯基)-2-氧代-5-噁唑烷基甲基)哌啶-4-乙酸叔丁酯;
与哌啶-4-氧乙酸乙酯反应:
得1-(3-(4-氰苯基)-2-氧代-5-噁唑烷基甲基)哌啶-4-氧乙酸乙酯;
与哌啶-4-氧乙酸苄酯反应:
得1-(3-(4-氰苯基)-2-氧代-5-噁唑烷基甲基)哌啶-4-氧乙酸苄酯;
与哌啶-4-氧乙酸叔丁酯反应:
得1-(3-(4-氰苯基)-2-氧代-5-噁唑烷基甲基)哌啶-4-氧乙酸叔丁酯,m.p,88~89°;FAB 416
与哌啶-3-氧乙酸乙酯反应:
得1-(3-(4-氰苯基)-2-氧代-5-噁唑烷基甲基)哌啶-3-氧乙酸乙酯;
与哌啶-3-氧乙酸苄酯反应:
得1-(3-(4-氰苯基)-2-氧代-5-噁唑烷基甲基)哌啶-3-氧乙酸苄酯;
与哌啶-3-氧乙酸叔丁酯反应:
得1-(3-(4-氰苯基)-2-氧代-5-噁唑烷基甲基)哌啶-3-氧乙酸叔丁酯;
与哌嗉-1-乙酸乙酯反应:
得1-(3-(4-氰苯基)-2-氧代-5-噁唑烷基甲基)哌嗪-4-乙酸乙酯;
与哌嗪-1-乙酸苄酯反应:
得1-(3-(4-氰苯基)-2-氧代-5-噁唑烷基甲基)哌嗪-4-乙酸苄酯;
与哌嗪-1-乙酸叔丁酯反应:
得1-(3-(4-氰苯基)-2-氧代-5-噁唑烷基甲基)哌嗪-4-乙酸叔丁酯;
与氮杂环丁烷-3-氧乙酸乙酯反应:
得1-(3-(4-氰苯基)-2-氧代-5-噁唑烷基甲基)氮杂环丁烷-3氧乙酸乙酯;
与氮杂环丁烷-3-氧乙酸苄酯反应:
得1-(3-(4-氰苯基)-2-氧代-5-噁唑烷基甲基)氮杂环丁烷-3-氧乙酸苄酯;
与氮杂环丁烷-3-氧乙酸叔丁酯反应:
得1-(3-(4-氰苯基)-2-氧代-5-噁唑烷基甲基)氮杂环丁烷-3-氧乙酸叔丁酯;
与1-苄基哌嗪-2-羧酸乙酯反应:
得1-苄基-4-(3-(4-氰苯基)-2-氧代-5-噁唑烷基)哌嗪-2-羧酸乙酯;
与1-苄基哌嗪-2-羧酸苄酯反应:
得1-苄基-4-(3-(4-氰苯基)-2-氧代-5-噁唑烷基)哌嗪-2-羧酸苄酯;
与1-苄基哌嗪-2-羧酸叔丁酯反应:
得1-苄基-4-(3-(4-氰苯基)-2-氧代-5-噁唑烷基)哌嗪-2-羧酸叔丁酯;
下列化合物可用相似方法,通过3-(4-氰苯基)-5S-甲磺酰氧甲基-2-噁唑烷酮(m.p.141~142°;[χ]20 0+75.3°(C=3.9mg/ml甲醇);此产品由4-氨基苯甲腈与2R-2,3-环氧丙醇反应制得4-(2S,3-二羟丙氨基)苯甲腈,后者再与碳酸二乙酯/叔丁醇钾反应,得到3-(4-氰苯基)-5S-羟甲基-2-噁唑烷酮,然后用甲磺酰氯酯化制备而成)。
与哌啶-4-羧酸苄酯反应:
下列化合物可用相似方法制备:
与哌啶-4-羧酸乙酯反应:
得1-(3-(4-氰苯基)-2-氧代-5S-噁唑烷基甲基)哌啶-4-羧酸乙酯;
与哌啶-4-羧酸叔丁酯反应:
得1-(3-(4-氰苯基)-2-氧代-5S-噁唑烷基甲基)哌啶-4-羧酸叔丁酯。
用相似的方法,从3-(4-氰苯基)-5R-甲磺酰氧甲基-2-噁唑烷酮[从2S-2,3-环氧丙醇起始,经4-(2R,3-二羟丙氨基)苯甲腈和3-(4-氰苯基)-5R-羟甲基-2-恶唑烷酮制得]可制得1-(3-(4-氰苯基)-2-氧代-5R-噁唑烷基甲基)哌啶-4-羧酸苄酯和相应的乙酯以及相应的叔丁酯。
实例4:
用与实例3相似的方法,通过3-(4-二甲氨基甲基苯基)-5-溴甲基-2-噁唑烷酮[由4-二甲氨基甲基苯胺与2,3-环氧丙醇反应,得3-(4-二甲氨基甲基苯基氨基)-1,2-丙二醇,后者与碳酸二乙酯/叔丁醇钾反应,给出3-(4-二甲氨基甲基苯基)-5-羟甲基-2-噁唑烷酮,然后再与SOBr2进行反应制得]与哌啶-4-羧酸叔丁酯反应,可制得1-(3-(4-二甲氨基甲基苯基)-2-氧代-5-噁唑烷基甲基)哌啶-4-羧酸叔丁酯,FAB 432。
实例5:
将3.31g1-(3-(4-氰苯基)-2-羟丙基)哌啶-4-羧酸乙酯[由3-(4-氰苯基)-1,2-丙二醇-1-甲磺酸盐与哌啶-4-羧酸乙酯反应制得],15ml碳酸二乙酯,0.1g叔丁醇钾组成的混合物一起在110℃的热浴上搅拌反应2小时,蒸发浓缩,经常规处理后,得“IA”化合物,FAB 358。
实例6:
将0.17ml乙基二异丙胺加到含有210mg1-脒基-3,5-二甲基吡唑硝酸盐于17ml二噁烷和5ml水的混合溶液中,一起搅拌15分钟,然后加入375mg1-(3-(4-氨基苯基)-2-氧代-5-恶唑烷基甲基)哌啶-4-羧酸叔丁酯[通过4-氨基乙酰替苯脒与2,3-环氧丙醇反应,得到4-(2,3-二羟丙氨基)乙酰替苯胺,然后再与碳酸二乙酯反应,得3-(4-乙酰胺基苯基)-5-羟甲基-2-噁唑烷酮,转化成甲磺酸酯后,再与哌啶-4-羧酸叔丁酯反应制得],使混合物沸腾45小时,蒸发浓缩,经常规处理后,得1-(3-(4-胍基苯基)-2-氧代-5-噁唑烷基甲基)哌啶-4-羧酸叔丁酯。
用相似的方法,1-(3-(4-氨甲基苯基)-2-氧代-5-噁唑烷基甲基)哌啶-4-羧酸叔丁酯与1-脒基-3,5-二甲基吡唑硝酸盐反应,可制得1-(3-(4-胍基甲基苯基)-2-氧代-5-噁唑烷基甲基)哌啶-4-羧酸叔丁酯,TAB 432。
实例7:
在20℃,1巴压力下,将1g溶于40ml 10%氨气/甲醇溶液中的“IA”,在0.6gRaneyNi存在下进行氢化,直至H2吸收停止为止。过滤,蒸发浓缩后,得1-(3-(4-氨甲基苯基)-2-氧代-5-噁唑烷基甲基)哌啶-4-羧酸乙酯,FAB 362。
用相似的方法,通过相应腈化合物的氢化,可制得下列1-(3-(4-氨甲基苯基)-2-氧代-5-噁唑烷基甲基)哌啶化合物:
-4-羧酸叔丁酯
-3-羧酸乙酯
-3-羧酸叔丁酯
-2-羧酸乙酯
-2-羧酸叔丁酯
-4-乙酸乙酯
-4-乙酸叔丁酯
-4-氧乙酸乙酯
-4-氧乙酸叔丁酯 m.p.95~96°FAB 420
-3-氧乙酸乙酯
-3-氧乙酸叔丁酯;
下列1-(3-(4-氮甲基苯基)-2-氧代-5-噁唑烷基甲基)吡咯烷化合物是:
-2-羧酸乙酯
-2-羧酸叔丁酯
下列1-(3-(4-氨甲基苯基)-2-氧代-5-噁唑烷基甲基)哌嗪化合物是:
-4-乙酸乙酯
-4-乙酸叔丁酯
下列1-(3-(4-氨甲基苯基)-2-氧代-5-噁唑烷基甲基)氮杂环丁烷化合物是:
-3-氧乙酸乙酯
-3-氧乙酸叔丁酯;
下列1-(3-(4-氨甲基苯基)-2-氧代-5-噁唑烷基甲基)-4-苄基哌嗪化合物是:
-3-羧酸乙酯
-3-羧酸叔丁酯;
下列1-(3-(4-氨甲基苯基)-2-氧代-5S-噁唑烷基甲基)哌啶化合物是:
-4-羧酸乙酯
-4-羧酸叔丁酯;
下列1-(3-(4-氨甲基苯基)-2-氧代-5R-噁唑烷基甲基)哌啶化合物是:
-4-羧酸乙酯
-4-羧酸叔丁酯。
实例8:
在-10℃下,将H2S在45分钟之内通过溶于50ml吡啶及6.6ml三乙胺溶液的3.57g“IA”中,混合物在20℃下搅拌14小时,浓缩,将残渣溶于50ml丙酮中,加入9ml碘甲烷,20℃下搅拌6小时,过滤,残渣用少量丙酮洗涤,然后溶于30ml甲醇中,向其中加入4.6g乙酸铵,混合物于20℃下搅拌30小时,将生成的1-(3-(4-脒基苯基)-2-氧代-5-噁唑烷基甲基)哌啶-4-羧酸乙酯过滤,然后进行硅胶层析(二氯甲烷/甲醇/乙酸70∶30∶2);m.p.200°(分解);FAB 375。
用相似的方法,从相应的腈化物出发,可以制备下列1-(3-(4-脒基苯基)-2-氧代-5-噁唑烷基甲基)哌啶化合物:
-4-羧酸苄酯[m.p.204°(分解);FAB 437;二盐酸盐 m.p182°]
-4-羧酸叔丁酯
-3-羧酸乙酯
-3-羧酸苄酯,乙酸盐,FAB 437
-3-羧酸叔丁酯
-2-羧酸乙酯
-2-羧酸苄酯,FAB 437
-2-羧酸叔丁酯
-4-乙酸乙酯
-4-乙酸苄酯
-4-乙酸叔丁酯
-4-氧乙酸乙酯
-4-氧乙酸苄酯,乙酸盐 m.p.206°
-4-氧乙酸叔丁酯,m.p.187°(分解);FAB 433
-3-氧乙酸乙酯
-3-氧乙酸苄酯
-3-氧乙酸叔丁酯;
下列1-(3-(4-脒基苯基)-2-氧代-5-噁唑烷基甲基)吡咯烷化合物是:
-2-羧酸乙酯
-2-羧酸苄酯
-2-羧酸叔丁酯;
下列1-(3-(4-脒基苯基)-2-氧代-5-噁唑烷基甲基)哌嗪化合物是:
-4-乙酸乙酯
-4-乙酸苄酯,FAB 452
-4-乙酸叔丁酯;
下列1-(3-(4-脒基苯基)-2-氧代-5-噁唑烷基甲基)氮杂环丁烷类化合物是:
-3-氧乙酸乙酯
-3-氧乙酸苄酯
-3-氧乙酸叔丁酯;
下列1-(3-(4-脒基苯基)-2-氧代-5-噁唑烷基甲基)-4-苄基哌嗪化合物是:
-3-羧酸乙酯
-3-羧酸苄酯
-3-羧酸叔丁酯;
下列1-(3-(4-脒基苯基)-2-氧代-5S-噁唑烷基甲基)哌啶化合物是:
-4-羧酸乙酯
-4-羧酸苄酯
-4-羧酸叔丁酯;
下列1-(3-(4-脒基苯基)-2氧代-5R-噁唑烷基甲基)哌啶化合物是:
-4-羧酸乙酯
-4-羧酸苄酯
-4-羧酸叔丁酯。
实例9:
用与实例8相似的方法,从“IA”起始,但以等量的乙酸羟基铵代替乙酸铵,可以制备1-(3-(4-羟基脒基苯基)-2-氧代-5-噁唑烷基甲基)哌啶-4-羧酸乙酯。
实例10:
将1g1-(3-(4-氰苯基)-2-氧代-5-噁唑烷基甲基)哌啶-4-羧酸叔丁酯溶于12ml二氯甲烷中,然后加入12ml三氟乙酸,混合物放置5分钟后,蒸发浓缩,经常规处理,得1-(3-(4-氰基苯基)-2-氧代-5-噁唑烷基甲基)哌啶-4-羧酸,FAB 330。
用相似的方法,从相应的叔丁酯起始,可以制备下列酸:
1-(3-(4-氰苯基)-2-氧代-5-噁唑烷基甲基)哌啶-3-羧酸
1-(3-(4-氰苯基)-2-氧代-5-噁唑烷基甲基)哌啶-2-羧酸
1-(3-(4-氰苯基)-2-氧代-5-噁唑烷基甲基)吡咯烷-2-羧酸
1-(3-(4-氰苯基)-2-氧代-5-噁唑烷基甲基)哌啶-4-乙酸
1-(3-(4-氰苯基)-2-氧代-5-噁唑烷基甲基)哌啶-4-氧乙酸
1-(3-(4-氰苯基)-2-氧代-5-噁唑烷基甲基)哌啶-3-氧乙酸
1-(3-(4-氰苯基)-2-氧代-5-噁唑烷基甲基)哌嗪-4-乙酸
1-(3-(4-氰苯基)-2-氧代-5-噁唑烷基甲基)氮杂环丁烷-3-氧乙酸
1-苄基-4-(3-(4-氰苯基)-2-氧代-5-噁唑烷基甲基)哌嗪-2-羧酸
1-(3-(4-氮苯基)-2-氧代-5-噁唑烷基甲基)哌啶-4-羧酸,m.p.190°(分解);FAB 334
1-(3-(4-氨甲基苯基)-2-氧代-5-噁唑烷基甲基)哌啶-3-羧酸
1-(3-(4-氨甲基苯基)-2-氧代-5-噁唑烷基甲基)哌啶-2-羧酸
1-(3-(4-氨甲基苯基)-2-氧代-5-噁唑烷基甲基)吡咯烷-2-羧酸
1-(3-(4-氨甲基苯基)-2-氧代-5-噁唑烷基甲基)哌啶-4-乙酸
1-(3-(4-氨甲基苯基)-2-氧代-5-噁唑烷基甲基)哌啶-4-氧乙酸,m.p.135°;FAB 364
1-(3-(4-氨甲基苯基)-2-氧代-5-噁唑烷基甲基)哌啶-3-氧乙酸
1-(3-(4-氨甲基苯基)-2-氧代-5-噁唑烷基甲基)哌嗪-4-乙酸
1-(3-(4-氨甲基苯基)-2-氧代-5-噁唑烷基甲基)氮杂环丁烷-3-氧乙酸
1-苄基-4-(3-(4-氨甲基苯基)-2-氧代-5-噁唑烷基甲基)哌嗪-2-羧酸
1-(3-(4-脒基苯基)-2-氧代-5-噁唑烷基甲基)哌啶-4-羧酸[m.p.265(分解;FAB 347;二盐酸盐,m.p.142°]
1-(3-(4-脒基苯基)-2-氧代-5-噁唑烷基甲基)哌啶-3-羧酸
1-(3-(4-脒基苯基)-2-氧代-5-噁唑烷基甲基)哌啶-2-羧酸,m.p.198°,FAB 347
1-(3-(4-脒基苯基)-2-氧代-5-噁唑烷基甲基)吡咯烷-2-羧酸
1-(3-(4-脒基苯基)-2-氧代-5-噁唑烷基甲基)哌啶-4-乙酸,m.p,256°
1-(3-(4-脒基苯基)-2-氧代-5-噁唑烷基甲基)哌啶-4-氧乙酸,油状物,FAB 377
1-(3-(4-脒基苯基)-2-氧代-5-噁唑烷基甲基)哌啶-3-氧乙酸,m.p,167~168°
1-(3-(4-脒基苯基)-2-氧代-5-噁唑烷基甲基)哌嗪-4-乙酸,FAB 362
1-(3-(4-脒基苯基)-2-氧代-5-噁唑烷基甲基)氮杂环丁烷-3-氧乙酸
1-苄基-4-(3-(4-脒基苯基)-2-氧代-5-噁唑烷基甲基)哌啶-2-羧酸
1-(3-(4-脒基苯基)-2-氧代-5-噁唑烷基甲基)哌啶-4-羧酸
1-(3-(4-胍基甲基苯基)-2-氧代-5-噁唑烷基甲基)哌啶-4-羧酸,FAB 376
1-(3-(4-氰苯基)-2-氧代-5S-噁唑烷基甲基)哌啶-4-羧酸
1-(3-(4-氰苯基)-2-氧代-5R-噁唑烷基甲基)哌啶-4-羧酸
1-(3-(4-氨甲基苯基)-2-氧代-5S-噁唑烷基甲基)哌啶-4-羧酸
1-(3-(4-氨甲基苯基)-2-氧代-5R-噁唑烷基甲基)哌啶-4-羧酸
1-(3-(4-脒基甲基苯基)-2-氧代-5S-噁唑烷基甲基)哌啶-4-羧酸
1-(3-(4-脒基甲基苯基)-2-氧代-5R-噁唑烷基甲基)哌啶-4-羧酸
1-(3-(4-二甲氨基甲基苯基)-2-氧代-5-噁唑烷基甲基)哌啶-4-羧酸
实例11
20℃且压力为1巴下,使溶于100ml甲醇,17ml乙酸及17ml水中的1g1-(3-(4-脒基苯基)-2-氧代-5-恶唑烷基甲基)哌啶-4-羧酸苄酯在0.7g5%Pd/C的存在下进行氢化反应,直至氢气吸收停止为止。混合物过滤后,蒸发浓缩,残渣用乙醚处理,得1-(3-(4-脒基苯基)-2-氧代-5-恶唑烷基甲基)哌啶-4-羧酸,m.p 265°;FAB 347;二盐酸盐,m.p 142°
实例12
用与实例11相似的方法,对1-苄基-4-(3-(4-氰苯基)-2-氧代-5-恶唑烷基甲基)哌嗪-2-羧酸(“IA”;或“IB”的苄酯)进行氢化,可以制和1-(3-(4-氨甲基苯基)-2-氧代-5-噁唑烷基甲基)哌嗪-3-羧酸。
用相似的方法,对1-苄基-4-(3-(4-氨甲基苯基)-2-氧代-5-恶唑烷基甲基)哌嗪-2-羧酸(或其苄酯)进行氧代,可以制得相同的物质。
用相似的方法,分别从“IB”化合物的乙酯和叔丁酯起始,可相应地制得1-(3-(4-氨甲基苯基)-2-氧代-5-恶唑烷基甲基)哌嗪-3-羧酸乙酯以及1-(3-(4-氨甲基苯基)-2-氧代-5-噁唑烷基甲基)哌嗪-3-羧酸叔丁酯。
实例13
用与实例3类似的方法,从3-(4-氰苯基)-5-甲磺酰氧甲基-2-噁唑烷酮起始,可制得下列化合物:
与哌啶-3-乙酸苄酯反应:
得1-(3-(4-氰苯基)-2-氧代-5-噁唑烷基甲基)哌啶-3-乙酸苄酯,FAB 434
与3-(1-哌嗪基)丙酸甲酯反应:
得3-(4-(3-(4-氰苯基)-2-氧代-5-噁唑烷基甲基)-1-哌嗪基)丙酸甲酯,FAB 373
与3-(1-哌嗪基)丙酸乙酯反应:
得3-(4-(3-(4-氰苯基)-2-氧代-5-噁唑烷基甲基)-1-哌嗪基)丙酸乙酯,FAB 387
与2-氧代哌嗪-1-乙酸乙酯反应:
得1-(3-4-氰苯基)-2-氧代-5-噁唑烷基甲基)-3-氧代哌嗪-4-乙酸乙酯,FAB 387
与3-(2-氧代-1-哌嗪)丙酸乙酯反应:
得3-(4-(3-(4-氰苯基)-2-氧代-5-噁唑烷基甲基)-2-氧代-1-哌嗪基)丙酸乙酯,FAB 401
与4-羟基哌啶-4-羧酸乙酯反应:
得1-(3-(4-氰苯基)-2-氧代-5-噁唑烷基甲基)-4-羟基哌啶-4-羧酸乙酯,FAB 374
与4-羟基哌啶-4-乙酸乙酯反应:
得1-(3-(4-氰苯基)-2-氧代-5-噁唑烷基甲基)-4-羟基哌啶-4-乙酸乙酯,FAB 388
与1-氧杂-8-氮杂螺旋[4,5]癸-2-酮-(=3-(4-羟基-4-哌啶基)丙酸的内酯)反应:
得8-(3-(4-氰苯基)-2-氧代-5-噁唑烷基甲基)-1-氧杂-8-氮杂螺旋[4,5]癸-2-酮,FAB 356。
用类似的方法,从3-(4-氰苯基)-5R或5S-甲磺酰氧甲基-2-唑烷酮起始,可制备下列化合物:
与哌啶-4-羧酸苄酯反应:
得1-(3-(4-氰苯基)-2-氧代-5R-噁唑烷基甲基)哌啶-4-羧酸苄酯和1-(3-(4-氰苯基)-2-氧代-5S-噁唑烷基甲基)哌-4-羧酸苄酯
与哌嗪-4-乙酸乙酯反应:
得1-(3-(4-氰苯基)-2-氧代-5R-噁唑烷基甲基)哌嗪-4-乙酸乙酯,FAB 373和1-(3-(4-氰苯基)-2-氧代-5S-噁唑烷基甲基)哌嗪-4-乙酸乙酯,FAB 373
与3-(1-哌嗪)丙酸苄酯反应:
得3-(4-(3-(4-氰苯基)-2-氧代-5R-噁唑烷基甲基)-1-哌嗪基)丙酸苄酯,m.p 90°和3-(4-(3-(4-氰苯基)-2-氧代-5S-噁唑烷基甲基)-1-哌嗪基)丙酸苄酯,m.p,90°
实例14
用与实例8类似的方法,从相应的腈化物(参见实例13)起始,可以制备下列化合物:
1-(3-(4-脒基苯基)-2-氧代-5-噁唑烷基甲基)哌啶-3-乙酸苄酯,二乙酸盐,m.p 287~299°
3-(4-(3-(4-伙基苯基)-2-氧代-5-噁唑烷基甲基)-1-哌嗪基)丙酸乙酯,m.p,206°
1-(3-(4-脒基苯基)-2-氧代-5-噁唑烷基甲基)-3-氧代-哌嗪-4-乙酸乙酯,m.p 224°
3-(4-(3-(4-脒基苯基)-2-氧代-5-噁唑烷基甲基)-2-氧代-1-哌嗪基)丙酸乙酯,FAB 418
1-(3-(4-脒基苯基)-2-氧代-5-噁唑烷基甲基)-4-羟基哌啶-4-羧酸乙酯
1-(3-(4-脒基苯基)-2-氧代-5-噁唑烷基甲基)-4-羟基哌啶-4-乙酸乙酯,乙酸盐,m.p 108°
8-(3-(4-脒基苯基)-2-氧代-5-噁唑烷基甲基)1-氧杂-8-氮杂螺旋[4,5]癸-2-酮,FAB 373
1-(3-(4-脒基苯基)-2-氧代-5R-噁唑烷基甲基)哌嗪-4-乙酸乙酯,FAB 390
1-(3-(4-脒基苯基)-2-氧代-5S-噁唑烷基甲基)哌嗪-4-乙酸乙酯,FAB 390。
实例15
按照与实例9相同的方法,从相应的腈化合物起始,可制备下列化合物:
1-(3-(4-羟基脒基苯基)-2-氧代-5-噁唑烷基甲基)-4-羟基哌啶-4-乙酸乙酯,乙酸盐,m.p 178°~180°
3-(4-(3-(4-羟基脒基苯基)-2-氧代-5-噁唑烷基甲基)-1-哌嗪基)丙酸甲酯,m.p 202°
3-(4-(3-(4-羟基脒基苯基)-2-氧代-5R-噁唑烷基甲基)-1-哌嗪基)丙酸苄酯,m.p 159°
3-(4-(3-(4-羟基脒基苯基)-2-氧代-5S-噁唑烷基甲基)-1-哌嗪基)丙酸苄酯,m.p 159°
实例16
将1g3-(4-(3-(4-脒基苯基)-2-氧代-5-噁唑烷基甲基)-1-哌嗪基)丙酸乙酯,0.2g NaOH,8ml二噁烷及2ml水组成的混合物在20℃下搅拌5小时,酸化,经常规处理,得3-(4-(3-(4-脒基苯基)-2-氧代-5-噁唑烷基甲基)-1-哌嗪基)丙酸,m.p269℃
用相似的方法,通过相应的酯水解,可以制备下列化合物:
1-(3-(4-脒基苯基)-2-氧代-5-噁唑烷基甲基)-3-氧代-哌嗪-4-乙酸,单水合物,m.p 261℃
3-(4-(3-(4-脒基苯基)-2-氧代-5-噁唑烷基甲基)-2-氧代-1-哌嗪基)丙酸,FAB 390。
1-(3-(4-脒基苯基)-2-氧代-5-噁唑烷基甲基)-4-羟基哌啶-4-羧酸
1-(3-(4-脒基苯基)-2-氧代-5-噁唑烷基甲基)-4-羟基哌啶-4-乙酸,m.p 230°
1-(3-(4-脒基苯基)-2-氧代-5S-噁唑烷基甲基)-哌嗪-4-乙酸,乙酸盐,FAB 362,[α]20 +24.0°(C=1,DMSO)
实例17
a)将1g1-(3-(4-氰苯基)-2-氧代-5-噁唑烷基甲基)-4-甲磺酰氧哌啶-4-乙酸乙酯[由4-羟基化合物(参见实例13)与甲磺酰氯/吡啶反应制得]溶于10ml2%NH3的乙醇和THF(1∶1)溶液中,在20℃下放置2小时,蒸发浓缩,经常规处理后,得1-(3-(4-氰苯基)-2-氧代-5-噁唑烷基甲基)-4-氨基哌啶-4-乙酸乙酯,FAB 387
b)用与实例8相似的方法,可以得到1-(3-(4-脒基苯基)-2-氧代-5-噁唑烷基甲基)-4-氨基哌啶-4-乙酸乙酯,FAB 404
c)用与实例16相似的方法,通过水解反应可以制得1-(3-(4-脒基苯基)-2-氧代-5-噁唑烷基甲基)-4-氨基哌啶-4-乙酸,FAB 376。
实例18
a)用与寮例17a)相类似的方法,使1-(3-(4-氰苯基)-2-氧代-5-噁唑烷基甲基)-4-甲磺酰氧哌啶-4-羧酸乙酯[由4-羟基化合物(参见实例13)与甲磺酰氯/吡啶反应制得]与NH3进行反应,得1-(3-(4-氯苯基)-2-氧代-5-噁唑烷基甲基)-4-氨基哌啶-4-羧酸乙酯,FAB 373
b)用与实例8相似的方法,得1-(3-(4-脒基苯基)-2-氧代-5-噁唑烷基甲基)-4-氨基哌啶-4-羧酸乙酯,FAB 390
c)用与实例16相似的方法,通过水解反应,得1-(3-(4-脒基苯基)-2-氧代-5-噁唑烷基甲基)-4-氨基哌啶-4-羧酸,GAB 362。
实例19
向1g溶于30ml乙酸中的3-(4-(3-(4-羟基脒基苯基)-2-氧代-5R-或-5S-噁唑烷基甲基)-1-哌嗪基)丙酸苄酯(参见实例15)中加入1ml乙酸酐,然后在20℃压力为1巴下,于0.2g10%Pd/C存在下进行氢化,直到计算量的氢气被吸收。过滤反应混合物,用常规处理后得:
下列实例涉及药物配方:
实例A:药片
将1kg具式1的活性化合物,4kg乳糖,1.2kg玉米淀粉,200g滑石和100g硬脂酸镁组成的混合物用常规方法压片,形成的药片每片含100mg活性化合物。
实例B:包衣片
用实例A相似的方法做成药片后,用常规方法进行包衣,包衣剂由蔗糖、玉米淀粉、滑石、黄蓍胶及着色剂组成。
实例C:胶囊
用常规方法将具式1的500g活性化合物填入硬明胶胶囊中,每个胶囊含500g活性化合物。
实例D:注射液小瓶
将100g式1活性化合物溶于4升双蒸水中,用2N盐酸调PH至6.5,过滤使之无菌,然后装入注射液小瓶。小瓶在无菌条件下进行冷冻干燥,然后密封。每个注射液小瓶含50mg活性化合物。
实例E:栓剂
将50g式1活性化合物与10g大豆卵磷脂及140g可可脂组成的混合物熔化,然后倾入模型中并使之冷却,每个栓剂中含有250mg活性化合物。
Claims (7)
1、式Ⅰ化合物及其盐,
其中
X是O,S,NH,或NA,
Z是H,A,苯基-CkH2k或AC
R′是可被下基团所取代的苯基:CN,H2N-CH2-,(A)2N-CH2-,H2N-C(=NH)-,H2N-C(=NH)-NH-,H2N-C(=NH)-NH-CH2-,HO-NH-C(=NH)或HO-NH-C(=NH)-NH,
R2是-CmH2m-COOR3或-CnH2n-O-CpH2p-COOR3,
R3是H,A或苄基,
R4是H,A苄基或-CmH2m-COOR3,
A在所有情况下是具有1-6个碳原子的烷基,
Ac是具有1-11个碳原子的酰基,
K和m在所有情况下是0,1,2,或3,
n是0,1或2,且
p是1,2或3
2、1-(3-(4-脒基苯基)-2-氧代-5-噁唑烷基甲基)哌啶-4-羧酸。
3、制备权利要求1中具式1化合物及其盐的方法,其特征在于:
(a)用溶剂分解或氢解剂处理式1化合物的功能性衍生物,使其从它们之中的任意一个中释放出来,或
(b)使式Ⅱ化合物
其中
E为CL,Br,I,或活性的酯化OH基团,
且
R′和X的含义同上,
与式Ⅲ氨基化合物进行反应
其中
Y的含义同上,
或
(c)使式Ⅳ化合物或其活性衍生物之一
其中
R′,X和Y的含义同上,
与活性碳酸衍生物进行反应,或
(d)为了制备式1化合物的胍基化合物(R′=被H2N-C(=NH)-NH基团取代的苯基),用脒基化剂对式Ⅰ相应的氨基化合物(其中含有氨基-苯基基团,而不是基团R′)进行处理。
和/或在于将式1化合物中的一个或两个基团R′和/或Y转化成其它R1和/或Y,和/或将式1化合物通过用酸或碱处理转化成它的一种盐。
4、制备药物配方的方法,其特征在于将权利要求1中式1化合物和/或其任意一种生理学上可接受的无害盐与至少一种固体,液体或半液体赋形剂或辅助剂一起转化成为一种合适的剂型。
5、药物配方,其特征在于含有至少一种权利要求1中的式1化合物和/或其生理学上的无害的盐。
6、权利要求1中式1化合物或其生理学上无害的盐,用来制备药物的用途。
7、权利要求1中式1化合物或其生理学上无害的盐在控制血栓、心肌梗塞、中风、骨质疏松、动脉硬化、炎症和/或肿瘤等疾病方面的用途。
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US5086055A (en) * | 1990-12-24 | 1992-02-04 | A. H. Robins Company, Incorporated | Series of 5-[-(4-aryl-1-piperazinyl)alkyl]-2-oxazolidinone derivatives useful in the treatment of allergic conditions |
DE4324393A1 (de) * | 1993-07-21 | 1995-01-26 | Merck Patent Gmbh | 4-Aryloxy- und 4-Arylthiopiperidinderivate |
-
1994
- 1994-04-19 EP EP94106049A patent/EP0623615B1/de not_active Expired - Lifetime
- 1994-04-19 DK DK94106049T patent/DK0623615T3/da active
- 1994-04-19 ES ES94106049T patent/ES2134870T3/es not_active Expired - Lifetime
- 1994-04-19 AT AT94106049T patent/ATE181735T1/de not_active IP Right Cessation
- 1994-04-21 AU AU60643/94A patent/AU675698B2/en not_active Ceased
- 1994-04-26 SK SK484-94A patent/SK281469B6/sk unknown
- 1994-04-27 CZ CZ941019A patent/CZ285761B6/cs not_active IP Right Cessation
- 1994-04-27 CN CN94105008A patent/CN1052231C/zh not_active Expired - Fee Related
- 1994-04-28 PL PL94303242A patent/PL178131B1/pl not_active IP Right Cessation
- 1994-04-28 JP JP09205894A patent/JP3570744B2/ja not_active Expired - Fee Related
- 1994-04-29 US US08/234,691 patent/US5532255A/en not_active Expired - Fee Related
- 1994-04-29 NO NO941592A patent/NO301419B1/no not_active IP Right Cessation
- 1994-04-29 RU RU94015184A patent/RU2145961C1/ru not_active IP Right Cessation
- 1994-04-29 CA CA002122571A patent/CA2122571C/en not_active Expired - Fee Related
- 1994-05-02 HU HU9401274A patent/HU224549B1/hu not_active IP Right Cessation
-
1999
- 1999-09-22 GR GR990402369T patent/GR3031271T3/el unknown
Also Published As
Publication number | Publication date |
---|---|
CA2122571C (en) | 2005-04-12 |
CZ101994A3 (en) | 1994-11-16 |
RU2145961C1 (ru) | 2000-02-27 |
JPH072847A (ja) | 1995-01-06 |
AU675698B2 (en) | 1997-02-13 |
PL178131B1 (pl) | 2000-03-31 |
NO941592D0 (zh) | 1994-04-29 |
HUT70541A (en) | 1995-10-30 |
GR3031271T3 (en) | 1999-12-31 |
EP0623615A1 (de) | 1994-11-09 |
NO301419B1 (no) | 1997-10-27 |
ES2134870T3 (es) | 1999-10-16 |
US5532255A (en) | 1996-07-02 |
CA2122571A1 (en) | 1994-11-02 |
CZ285761B6 (cs) | 1999-11-17 |
SK48494A3 (en) | 1995-02-08 |
DK0623615T3 (da) | 1999-12-13 |
JP3570744B2 (ja) | 2004-09-29 |
ATE181735T1 (de) | 1999-07-15 |
HU9401274D0 (en) | 1994-08-29 |
CN1052231C (zh) | 2000-05-10 |
NO941592L (no) | 1994-11-02 |
AU6064394A (en) | 1994-11-03 |
EP0623615B1 (de) | 1999-06-30 |
SK281469B6 (sk) | 2001-04-09 |
HU224549B1 (hu) | 2005-10-28 |
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