CN1192035C - 白介素-1β转化酶抑制剂 - Google Patents
白介素-1β转化酶抑制剂 Download PDFInfo
- Publication number
- CN1192035C CN1192035C CNB951943812A CN95194381A CN1192035C CN 1192035 C CN1192035 C CN 1192035C CN B951943812 A CNB951943812 A CN B951943812A CN 95194381 A CN95194381 A CN 95194381A CN 1192035 C CN1192035 C CN 1192035C
- Authority
- CN
- China
- Prior art keywords
- group
- linear
- phenyl
- branched alkyl
- compound
- 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.)
- Expired - Fee Related
Links
- 102000000589 Interleukin-1 Human genes 0.000 title claims abstract description 36
- 108010002352 Interleukin-1 Proteins 0.000 title claims abstract description 36
- 239000003112 inhibitor Substances 0.000 title abstract description 52
- 102000004190 Enzymes Human genes 0.000 title description 11
- 108090000790 Enzymes Proteins 0.000 title description 11
- 150000001875 compounds Chemical class 0.000 claims abstract description 421
- 238000000034 method Methods 0.000 claims abstract description 101
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 24
- 230000001404 mediated effect Effects 0.000 claims abstract description 23
- 201000010099 disease Diseases 0.000 claims abstract description 22
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 17
- 230000002401 inhibitory effect Effects 0.000 claims abstract description 15
- 208000023275 Autoimmune disease Diseases 0.000 claims abstract description 8
- 230000004770 neurodegeneration Effects 0.000 claims abstract description 7
- 208000015122 neurodegenerative disease Diseases 0.000 claims abstract description 7
- 208000027866 inflammatory disease Diseases 0.000 claims abstract description 5
- -1 phenyl Chemical group 0.000 claims description 269
- 125000000217 alkyl group Chemical group 0.000 claims description 133
- 125000004429 atom Chemical group 0.000 claims description 62
- 229910052757 nitrogen Inorganic materials 0.000 claims description 58
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 57
- 229920006395 saturated elastomer Polymers 0.000 claims description 46
- 229910052799 carbon Inorganic materials 0.000 claims description 45
- 229910052760 oxygen Inorganic materials 0.000 claims description 39
- 229910052739 hydrogen Inorganic materials 0.000 claims description 38
- 229910052717 sulfur Inorganic materials 0.000 claims description 37
- 239000001257 hydrogen Substances 0.000 claims description 34
- 230000002209 hydrophobic effect Effects 0.000 claims description 32
- 125000004432 carbon atom Chemical group C* 0.000 claims description 28
- 238000002360 preparation method Methods 0.000 claims description 28
- 150000003839 salts Chemical class 0.000 claims description 23
- 125000003118 aryl group Chemical group 0.000 claims description 21
- 125000001309 chloro group Chemical group Cl* 0.000 claims description 20
- 239000000126 substance Substances 0.000 claims description 15
- 125000001424 substituent group Chemical group 0.000 claims description 13
- 101000828805 Cowpox virus (strain Brighton Red) Serine proteinase inhibitor 2 Proteins 0.000 claims description 12
- 238000011282 treatment Methods 0.000 claims description 12
- 239000003814 drug Substances 0.000 claims description 11
- 229910052731 fluorine Inorganic materials 0.000 claims description 11
- 238000006467 substitution reaction Methods 0.000 claims description 11
- 125000000539 amino acid group Chemical group 0.000 claims description 8
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 7
- 125000004203 4-hydroxyphenyl group Chemical group [H]OC1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 6
- 238000004519 manufacturing process Methods 0.000 claims description 6
- 230000002265 prevention Effects 0.000 claims description 6
- 125000001541 3-thienyl group Chemical group S1C([H])=C([*])C([H])=C1[H] 0.000 claims description 5
- 125000001255 4-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1F 0.000 claims description 5
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 claims description 5
- 239000003937 drug carrier Substances 0.000 claims description 5
- 238000011156 evaluation Methods 0.000 claims description 5
- 125000001072 heteroaryl group Chemical group 0.000 claims description 5
- 230000002757 inflammatory effect Effects 0.000 claims description 5
- 125000003545 alkoxy group Chemical group 0.000 claims description 4
- 239000003054 catalyst Substances 0.000 claims description 4
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 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
- 125000001622 2-naphthyl group Chemical group [H]C1=C([H])C([H])=C2C([H])=C(*)C([H])=C([H])C2=C1[H] 0.000 claims description 3
- 230000009881 electrostatic interaction Effects 0.000 claims description 3
- 238000005259 measurement Methods 0.000 claims description 3
- 238000012216 screening Methods 0.000 claims description 3
- 208000035473 Communicable disease Diseases 0.000 claims description 2
- 230000029663 wound healing Effects 0.000 claims description 2
- 125000004430 oxygen atom Chemical group O* 0.000 claims 6
- 125000005493 quinolyl group Chemical group 0.000 claims 4
- 125000001637 1-naphthyl group Chemical group [H]C1=C([H])C([H])=C2C(*)=C([H])C([H])=C([H])C2=C1[H] 0.000 claims 2
- 125000004189 3,4-dichlorophenyl group Chemical group [H]C1=C([H])C(Cl)=C(Cl)C([H])=C1* 0.000 claims 2
- SMWDFEZZVXVKRB-UHFFFAOYSA-N Quinoline Chemical compound N1=CC=CC2=CC=CC=C21 SMWDFEZZVXVKRB-UHFFFAOYSA-N 0.000 claims 2
- 239000007795 chemical reaction product Substances 0.000 claims 2
- CBOIHMRHGLHBPB-UHFFFAOYSA-N hydroxymethyl Chemical compound O[CH2] CBOIHMRHGLHBPB-UHFFFAOYSA-N 0.000 claims 2
- UGUHFDPGDQDVGX-UHFFFAOYSA-N 1,2,3-thiadiazole Chemical compound C1=CSN=N1 UGUHFDPGDQDVGX-UHFFFAOYSA-N 0.000 claims 1
- IMLSAISZLJGWPP-UHFFFAOYSA-N 1,3-dithiolane Chemical group C1CSCS1 IMLSAISZLJGWPP-UHFFFAOYSA-N 0.000 claims 1
- IANQTJSKSUMEQM-UHFFFAOYSA-N 1-benzofuran Chemical group C1=CC=C2OC=CC2=C1 IANQTJSKSUMEQM-UHFFFAOYSA-N 0.000 claims 1
- ZYHQGITXIJDDKC-UHFFFAOYSA-N 2-[2-(2-aminophenyl)ethyl]aniline Chemical group NC1=CC=CC=C1CCC1=CC=CC=C1N ZYHQGITXIJDDKC-UHFFFAOYSA-N 0.000 claims 1
- 125000004198 2-fluorophenyl group Chemical group [H]C1=C([H])C(F)=C(*)C([H])=C1[H] 0.000 claims 1
- 125000000175 2-thienyl group Chemical group S1C([*])=C([H])C([H])=C1[H] 0.000 claims 1
- 125000004180 3-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C(F)=C1[H] 0.000 claims 1
- 125000003349 3-pyridyl group Chemical group N1=C([H])C([*])=C([H])C([H])=C1[H] 0.000 claims 1
- YCKRFDGAMUMZLT-UHFFFAOYSA-N Fluorine atom Chemical compound [F] YCKRFDGAMUMZLT-UHFFFAOYSA-N 0.000 claims 1
- DBTDEFJAFBUGPP-UHFFFAOYSA-N Methanethial Chemical compound S=C DBTDEFJAFBUGPP-UHFFFAOYSA-N 0.000 claims 1
- 125000003277 amino group Chemical group 0.000 claims 1
- 125000000319 biphenyl-4-yl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1C1=C([H])C([H])=C([*])C([H])=C1[H] 0.000 claims 1
- AOJDZKCUAATBGE-UHFFFAOYSA-N bromomethane Chemical compound Br[CH2] AOJDZKCUAATBGE-UHFFFAOYSA-N 0.000 claims 1
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims 1
- 125000000068 chlorophenyl group Chemical group 0.000 claims 1
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims 1
- 125000003963 dichloro group Chemical group Cl* 0.000 claims 1
- 239000011737 fluorine Substances 0.000 claims 1
- VUWZPRWSIVNGKG-UHFFFAOYSA-N fluoromethane Chemical compound F[CH2] VUWZPRWSIVNGKG-UHFFFAOYSA-N 0.000 claims 1
- 208000015181 infectious disease Diseases 0.000 claims 1
- UFWIBTONFRDIAS-UHFFFAOYSA-N naphthalene-acid Natural products C1=CC=CC2=CC=CC=C21 UFWIBTONFRDIAS-UHFFFAOYSA-N 0.000 claims 1
- 150000002790 naphthalenes Chemical class 0.000 claims 1
- 125000006574 non-aromatic ring group Chemical group 0.000 claims 1
- 125000003854 p-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Cl 0.000 claims 1
- 125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 claims 1
- 230000001737 promoting effect Effects 0.000 claims 1
- 238000011321 prophylaxis Methods 0.000 claims 1
- 238000007142 ring opening reaction Methods 0.000 claims 1
- 239000000203 mixture Substances 0.000 abstract description 175
- 230000000694 effects Effects 0.000 abstract description 10
- 239000003795 chemical substances by application Substances 0.000 abstract description 8
- 108090000426 Caspase-1 Proteins 0.000 abstract description 6
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 273
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 268
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 230
- 238000005160 1H NMR spectroscopy Methods 0.000 description 223
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 208
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 166
- OKKJLVBELUTLKV-MZCSYVLQSA-N Deuterated methanol Chemical compound [2H]OC([2H])([2H])[2H] OKKJLVBELUTLKV-MZCSYVLQSA-N 0.000 description 150
- 239000007787 solid Substances 0.000 description 149
- 235000019439 ethyl acetate Nutrition 0.000 description 90
- 239000000243 solution Substances 0.000 description 78
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 77
- 229910001868 water Inorganic materials 0.000 description 65
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 61
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 56
- 238000000921 elemental analysis Methods 0.000 description 56
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 54
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 50
- 238000006243 chemical reaction Methods 0.000 description 47
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 44
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 44
- 239000003921 oil Substances 0.000 description 44
- 235000019198 oils Nutrition 0.000 description 44
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 42
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 41
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 40
- 238000003818 flash chromatography Methods 0.000 description 38
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 37
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 34
- 239000012267 brine Substances 0.000 description 31
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 31
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 30
- 235000002639 sodium chloride Nutrition 0.000 description 28
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 27
- 239000012074 organic phase Substances 0.000 description 26
- 125000000623 heterocyclic group Chemical group 0.000 description 25
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 25
- 235000017557 sodium bicarbonate Nutrition 0.000 description 22
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 21
- 238000000746 purification Methods 0.000 description 20
- 239000000758 substrate Substances 0.000 description 20
- 239000000047 product Substances 0.000 description 19
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 18
- 239000000284 extract Substances 0.000 description 18
- FPQQSJJWHUJYPU-UHFFFAOYSA-N 3-(dimethylamino)propyliminomethylidene-ethylazanium;chloride Chemical compound Cl.CCN=C=NCCCN(C)C FPQQSJJWHUJYPU-UHFFFAOYSA-N 0.000 description 16
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 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 16
- 239000002253 acid Substances 0.000 description 16
- 238000003556 assay Methods 0.000 description 16
- 210000004027 cell Anatomy 0.000 description 16
- NPZTUJOABDZTLV-UHFFFAOYSA-N hydroxybenzotriazole Substances O=C1C=CC=C2NNN=C12 NPZTUJOABDZTLV-UHFFFAOYSA-N 0.000 description 16
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 15
- 235000008206 alpha-amino acids Nutrition 0.000 description 15
- 229940024606 amino acid Drugs 0.000 description 15
- 235000001014 amino acid Nutrition 0.000 description 15
- 150000002148 esters Chemical class 0.000 description 15
- KDLHZDBZIXYQEI-UHFFFAOYSA-N palladium Substances [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 15
- 239000002904 solvent Substances 0.000 description 15
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 15
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 14
- 102000003777 Interleukin-1 beta Human genes 0.000 description 14
- 108090000193 Interleukin-1 beta Proteins 0.000 description 14
- 125000003275 alpha amino acid group Chemical group 0.000 description 14
- 239000011521 glass Substances 0.000 description 14
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 13
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 13
- 229960003767 alanine Drugs 0.000 description 13
- 239000013078 crystal Substances 0.000 description 13
- 125000000753 cycloalkyl group Chemical group 0.000 description 13
- COLNVLDHVKWLRT-UHFFFAOYSA-N phenylalanine Natural products OC(=O)C(N)CC1=CC=CC=C1 COLNVLDHVKWLRT-UHFFFAOYSA-N 0.000 description 13
- 229960005190 phenylalanine Drugs 0.000 description 13
- 108090000623 proteins and genes Proteins 0.000 description 13
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 13
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 12
- ONIBWKKTOPOVIA-BYPYZUCNSA-N L-Proline Chemical compound OC(=O)[C@@H]1CCCN1 ONIBWKKTOPOVIA-BYPYZUCNSA-N 0.000 description 12
- QNAYBMKLOCPYGJ-REOHCLBHSA-N L-alanine Chemical compound C[C@H](N)C(O)=O QNAYBMKLOCPYGJ-REOHCLBHSA-N 0.000 description 12
- ZDXPYRJPNDTMRX-VKHMYHEASA-N L-glutamine Chemical compound OC(=O)[C@@H](N)CCC(N)=O ZDXPYRJPNDTMRX-VKHMYHEASA-N 0.000 description 12
- ONIBWKKTOPOVIA-UHFFFAOYSA-N Proline Natural products OC(=O)C1CCCN1 ONIBWKKTOPOVIA-UHFFFAOYSA-N 0.000 description 12
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 12
- KZSNJWFQEVHDMF-UHFFFAOYSA-N Valine Chemical compound CC(C)C(N)C(O)=O KZSNJWFQEVHDMF-UHFFFAOYSA-N 0.000 description 12
- 235000004279 alanine Nutrition 0.000 description 12
- 239000012043 crude product Substances 0.000 description 12
- 229960002429 proline Drugs 0.000 description 12
- 235000013930 proline Nutrition 0.000 description 12
- 235000018102 proteins Nutrition 0.000 description 12
- 102000004169 proteins and genes Human genes 0.000 description 12
- 239000000725 suspension Substances 0.000 description 12
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 11
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 11
- KDXKERNSBIXSRK-YFKPBYRVSA-N L-lysine Chemical compound NCCCC[C@H](N)C(O)=O KDXKERNSBIXSRK-YFKPBYRVSA-N 0.000 description 11
- OUYCCCASQSFEME-QMMMGPOBSA-N L-tyrosine Chemical compound OC(=O)[C@@H](N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-QMMMGPOBSA-N 0.000 description 11
- KDXKERNSBIXSRK-UHFFFAOYSA-N Lysine Natural products NCCCCC(N)C(O)=O KDXKERNSBIXSRK-UHFFFAOYSA-N 0.000 description 11
- 239000000460 chlorine Substances 0.000 description 11
- 239000012230 colorless oil Substances 0.000 description 11
- 238000000354 decomposition reaction Methods 0.000 description 11
- 238000001035 drying Methods 0.000 description 11
- 229960002743 glutamine Drugs 0.000 description 11
- 150000003254 radicals Chemical class 0.000 description 11
- PMZURENOXWZQFD-UHFFFAOYSA-L sodium sulphate Substances [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 11
- 229960004295 valine Drugs 0.000 description 11
- 239000004474 valine Substances 0.000 description 11
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 10
- 125000000094 2-phenylethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])C([H])([H])* 0.000 description 10
- 239000004472 Lysine Substances 0.000 description 10
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 10
- 239000002585 base Substances 0.000 description 10
- ZDXPYRJPNDTMRX-UHFFFAOYSA-N glutamine Natural products OC(=O)C(N)CCC(N)=O ZDXPYRJPNDTMRX-UHFFFAOYSA-N 0.000 description 10
- 235000004554 glutamine Nutrition 0.000 description 10
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 10
- 210000003819 peripheral blood mononuclear cell Anatomy 0.000 description 10
- 108090000765 processed proteins & peptides Proteins 0.000 description 10
- 238000003756 stirring Methods 0.000 description 10
- 229960004441 tyrosine Drugs 0.000 description 10
- OUYCCCASQSFEME-UHFFFAOYSA-N tyrosine Natural products OC(=O)C(N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-UHFFFAOYSA-N 0.000 description 10
- ASOKPJOREAFHNY-UHFFFAOYSA-N 1-Hydroxybenzotriazole Chemical compound C1=CC=C2N(O)N=NC2=C1 ASOKPJOREAFHNY-UHFFFAOYSA-N 0.000 description 9
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 9
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 9
- 125000004122 cyclic group Chemical group 0.000 description 9
- FVIZARNDLVOMSU-UHFFFAOYSA-N ginsenoside K Natural products C1CC(C2(CCC3C(C)(C)C(O)CCC3(C)C2CC2O)C)(C)C2C1C(C)(CCC=C(C)C)OC1OC(CO)C(O)C(O)C1O FVIZARNDLVOMSU-UHFFFAOYSA-N 0.000 description 9
- UTPAQHZDTCJMIN-UHFFFAOYSA-N methyl 3-benzamido-4-oxo-7,8-dihydro-6h-pyrrolo[1,2-a]pyrimidine-6-carboxylate Chemical compound O=C1N2C(C(=O)OC)CCC2=NC=C1NC(=O)C1=CC=CC=C1 UTPAQHZDTCJMIN-UHFFFAOYSA-N 0.000 description 9
- WBHQBSYUUJJSRZ-UHFFFAOYSA-M sodium bisulfate Chemical compound [Na+].OS([O-])(=O)=O WBHQBSYUUJJSRZ-UHFFFAOYSA-M 0.000 description 9
- 238000010189 synthetic method Methods 0.000 description 9
- HOSWPDPVFBCLSY-UHFFFAOYSA-N 2-azaniumyl-4-oxobutanoate Chemical compound OC(=O)C(N)CC=O HOSWPDPVFBCLSY-UHFFFAOYSA-N 0.000 description 8
- JMTMSDXUXJISAY-UHFFFAOYSA-N 2H-benzotriazol-4-ol Chemical compound OC1=CC=CC2=C1N=NN2 JMTMSDXUXJISAY-UHFFFAOYSA-N 0.000 description 8
- AGPKZVBTJJNPAG-WHFBIAKZSA-N L-isoleucine Chemical compound CC[C@H](C)[C@H](N)C(O)=O AGPKZVBTJJNPAG-WHFBIAKZSA-N 0.000 description 8
- 238000005481 NMR spectroscopy Methods 0.000 description 8
- 150000001371 alpha-amino acids Chemical class 0.000 description 8
- 150000001408 amides Chemical class 0.000 description 8
- 238000004587 chromatography analysis Methods 0.000 description 8
- 239000006260 foam Substances 0.000 description 8
- 239000011541 reaction mixture Substances 0.000 description 8
- 230000002829 reductive effect Effects 0.000 description 8
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 7
- FFEARJCKVFRZRR-BYPYZUCNSA-N L-methionine Chemical compound CSCC[C@H](N)C(O)=O FFEARJCKVFRZRR-BYPYZUCNSA-N 0.000 description 7
- COLNVLDHVKWLRT-QMMMGPOBSA-N L-phenylalanine Chemical compound OC(=O)[C@@H](N)CC1=CC=CC=C1 COLNVLDHVKWLRT-QMMMGPOBSA-N 0.000 description 7
- KZSNJWFQEVHDMF-BYPYZUCNSA-N L-valine Chemical compound CC(C)[C@H](N)C(O)=O KZSNJWFQEVHDMF-BYPYZUCNSA-N 0.000 description 7
- ROHFNLRQFUQHCH-UHFFFAOYSA-N Leucine Natural products CC(C)CC(N)C(O)=O ROHFNLRQFUQHCH-UHFFFAOYSA-N 0.000 description 7
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 7
- 239000002671 adjuvant Substances 0.000 description 7
- 150000001370 alpha-amino acid derivatives Chemical class 0.000 description 7
- 239000000872 buffer Substances 0.000 description 7
- 238000009510 drug design Methods 0.000 description 7
- 238000010828 elution Methods 0.000 description 7
- 230000005764 inhibitory process Effects 0.000 description 7
- AGPKZVBTJJNPAG-UHFFFAOYSA-N isoleucine Natural products CCC(C)C(N)C(O)=O AGPKZVBTJJNPAG-UHFFFAOYSA-N 0.000 description 7
- 229960000310 isoleucine Drugs 0.000 description 7
- 229960003136 leucine Drugs 0.000 description 7
- 239000002609 medium Substances 0.000 description 7
- 229930182817 methionine Natural products 0.000 description 7
- 229960004452 methionine Drugs 0.000 description 7
- 239000000843 powder Substances 0.000 description 7
- 230000008569 process Effects 0.000 description 7
- 239000000741 silica gel Substances 0.000 description 7
- 229910002027 silica gel Inorganic materials 0.000 description 7
- 239000006228 supernatant Substances 0.000 description 7
- DBGVGMSCBYYSLD-UHFFFAOYSA-N tributylstannane Chemical compound CCCC[SnH](CCCC)CCCC DBGVGMSCBYYSLD-UHFFFAOYSA-N 0.000 description 7
- LMDZBCPBFSXMTL-UHFFFAOYSA-N 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide Chemical compound CCN=C=NCCCN(C)C LMDZBCPBFSXMTL-UHFFFAOYSA-N 0.000 description 6
- 125000006201 3-phenylpropyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 6
- WVDDGKGOMKODPV-UHFFFAOYSA-N Benzyl alcohol Chemical compound OCC1=CC=CC=C1 WVDDGKGOMKODPV-UHFFFAOYSA-N 0.000 description 6
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 description 6
- HNDVDQJCIGZPNO-YFKPBYRVSA-N L-histidine Chemical compound OC(=O)[C@@H](N)CC1=CN=CN1 HNDVDQJCIGZPNO-YFKPBYRVSA-N 0.000 description 6
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 6
- OFBQJSOFQDEBGM-UHFFFAOYSA-N Pentane Chemical compound CCCCC OFBQJSOFQDEBGM-UHFFFAOYSA-N 0.000 description 6
- 230000001464 adherent effect Effects 0.000 description 6
- 125000001584 benzyloxycarbonyl group Chemical group C(=O)(OCC1=CC=CC=C1)* 0.000 description 6
- YNHIGQDRGKUECZ-UHFFFAOYSA-L bis(triphenylphosphine)palladium(ii) dichloride Chemical compound [Cl-].[Cl-].[Pd+2].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 YNHIGQDRGKUECZ-UHFFFAOYSA-L 0.000 description 6
- 238000004440 column chromatography Methods 0.000 description 6
- 238000004992 fast atom bombardment mass spectroscopy Methods 0.000 description 6
- 229910052736 halogen Inorganic materials 0.000 description 6
- 150000002367 halogens Chemical group 0.000 description 6
- HNDVDQJCIGZPNO-UHFFFAOYSA-N histidine Natural products OC(=O)C(N)CC1=CN=CN1 HNDVDQJCIGZPNO-UHFFFAOYSA-N 0.000 description 6
- 229960002885 histidine Drugs 0.000 description 6
- 235000014304 histidine Nutrition 0.000 description 6
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 6
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 6
- 210000001616 monocyte Anatomy 0.000 description 6
- UYWQUFXKFGHYNT-UHFFFAOYSA-N phenylmethyl ester of formic acid Natural products O=COCC1=CC=CC=C1 UYWQUFXKFGHYNT-UHFFFAOYSA-N 0.000 description 6
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 6
- 238000010992 reflux Methods 0.000 description 6
- 125000006413 ring segment Chemical group 0.000 description 6
- 229910000342 sodium bisulfate Inorganic materials 0.000 description 6
- 239000011780 sodium chloride Substances 0.000 description 6
- HMDPRCXQHIWBED-INIZCTEOSA-N 2-[(3s)-4-oxo-3-(3-phenylpropanoylamino)-2,3-dihydro-1h-1,5-benzodiazepin-5-yl]acetic acid Chemical compound N([C@H]1CNC2=CC=CC=C2N(C1=O)CC(=O)O)C(=O)CCC1=CC=CC=C1 HMDPRCXQHIWBED-INIZCTEOSA-N 0.000 description 5
- NQKMZDSIVVCDMV-UHFFFAOYSA-N 2-[6-benzyl-2-oxo-3-(3-phenylpropanoylamino)pyridin-1-yl]acetic acid Chemical compound C=1C=C(NC(=O)CCC=2C=CC=CC=2)C(=O)N(CC(=O)O)C=1CC1=CC=CC=C1 NQKMZDSIVVCDMV-UHFFFAOYSA-N 0.000 description 5
- WTOFYLAWDLQMBZ-UHFFFAOYSA-N 2-azaniumyl-3-thiophen-2-ylpropanoate Chemical compound OC(=O)C(N)CC1=CC=CS1 WTOFYLAWDLQMBZ-UHFFFAOYSA-N 0.000 description 5
- YEDUAINPPJYDJZ-UHFFFAOYSA-N 2-hydroxybenzothiazole Chemical compound C1=CC=C2SC(O)=NC2=C1 YEDUAINPPJYDJZ-UHFFFAOYSA-N 0.000 description 5
- MFEILWXBDBCWKF-UHFFFAOYSA-N 3-phenylpropanoyl chloride Chemical compound ClC(=O)CCC1=CC=CC=C1 MFEILWXBDBCWKF-UHFFFAOYSA-N 0.000 description 5
- UNHMNTPOMNHDRX-UHFFFAOYSA-N 6,10-dioxo-n-(5-oxo-2-phenylmethoxyoxolan-3-yl)-7-(3-phenylpropanoylamino)-2,3,4,7,8,9-hexahydro-1h-pyridazino[1,2-a]diazepine-4-carboxamide Chemical compound C1CC(=O)N2CCCC(C(=O)NC3C(OC(=O)C3)OCC=3C=CC=CC=3)N2C(=O)C1NC(=O)CCC1=CC=CC=C1 UNHMNTPOMNHDRX-UHFFFAOYSA-N 0.000 description 5
- 206010061218 Inflammation Diseases 0.000 description 5
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 description 5
- 125000005605 benzo group Chemical group 0.000 description 5
- 230000008878 coupling Effects 0.000 description 5
- 238000010168 coupling process Methods 0.000 description 5
- 238000005859 coupling reaction Methods 0.000 description 5
- 238000010790 dilution Methods 0.000 description 5
- 239000012895 dilution Substances 0.000 description 5
- 229940079593 drug Drugs 0.000 description 5
- 238000002474 experimental method Methods 0.000 description 5
- 230000004054 inflammatory process Effects 0.000 description 5
- 230000003993 interaction Effects 0.000 description 5
- RUZLIIJDZBWWSA-INIZCTEOSA-N methyl 2-[[(1s)-1-(7-methyl-2-morpholin-4-yl-4-oxopyrido[1,2-a]pyrimidin-9-yl)ethyl]amino]benzoate Chemical group COC(=O)C1=CC=CC=C1N[C@@H](C)C1=CC(C)=CN2C(=O)C=C(N3CCOCC3)N=C12 RUZLIIJDZBWWSA-INIZCTEOSA-N 0.000 description 5
- KXKVLQRXCPHEJC-UHFFFAOYSA-N methyl acetate Chemical compound COC(C)=O KXKVLQRXCPHEJC-UHFFFAOYSA-N 0.000 description 5
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 5
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 5
- 239000012071 phase Substances 0.000 description 5
- 239000002243 precursor Substances 0.000 description 5
- 125000006239 protecting group Chemical group 0.000 description 5
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 5
- 239000007858 starting material Substances 0.000 description 5
- 238000003786 synthesis reaction Methods 0.000 description 5
- 238000012360 testing method Methods 0.000 description 5
- MTCFGRXMJLQNBG-REOHCLBHSA-N (2S)-2-Amino-3-hydroxypropansäure Chemical compound OC[C@H](N)C(O)=O MTCFGRXMJLQNBG-REOHCLBHSA-N 0.000 description 4
- CQBAMMGSJDPVDB-KBPBESRZSA-N (2s)-2-[[(2s)-2-acetamido-3-(4-hydroxyphenyl)propanoyl]amino]-3-methylbutanoic acid Chemical compound CC(C)[C@@H](C(O)=O)NC(=O)[C@@H](NC(C)=O)CC1=CC=C(O)C=C1 CQBAMMGSJDPVDB-KBPBESRZSA-N 0.000 description 4
- SDENZUKEGLEZAE-LURJTMIESA-N (2s)-2-amino-4-(7-methoxy-1,3-benzoxazol-2-yl)-4-oxobutanoic acid Chemical compound COC1=CC=CC2=C1OC(C(=O)C[C@H](N)C(O)=O)=N2 SDENZUKEGLEZAE-LURJTMIESA-N 0.000 description 4
- WVBZQFVGCYEOSG-HOTGVXAUSA-N (4s,7s)-6-oxo-7-(3-phenylpropanoylamino)-1,2,3,4,7,8,9,10-octahydropyridazino[1,2-a]diazepine-4-carboxylic acid Chemical compound N([C@H]1CCCN2CCC[C@H](N2C1=O)C(=O)O)C(=O)CCC1=CC=CC=C1 WVBZQFVGCYEOSG-HOTGVXAUSA-N 0.000 description 4
- KYWMCFOWDYFYLV-UHFFFAOYSA-N 1h-imidazole-2-carboxylic acid Chemical compound OC(=O)C1=NC=CN1 KYWMCFOWDYFYLV-UHFFFAOYSA-N 0.000 description 4
- AIJIZYHCPGYPLP-UHFFFAOYSA-N 2-(2-phenylethyl)-1h-imidazole-5-carboxylic acid Chemical compound OC(=O)C1=CNC(CCC=2C=CC=CC=2)=N1 AIJIZYHCPGYPLP-UHFFFAOYSA-N 0.000 description 4
- ZBSCFAWMXYYNNB-UHFFFAOYSA-N 5-benzyl-1h-pyrrole-2-carboxylic acid Chemical compound N1C(C(=O)O)=CC=C1CC1=CC=CC=C1 ZBSCFAWMXYYNNB-UHFFFAOYSA-N 0.000 description 4
- QNCZYKAFILNYTR-UHFFFAOYSA-N 7-methoxy-1,3-benzoxazole Chemical compound COC1=CC=CC2=C1OC=N2 QNCZYKAFILNYTR-UHFFFAOYSA-N 0.000 description 4
- CKLJMWTZIZZHCS-REOHCLBHSA-N L-aspartic acid Chemical compound OC(=O)[C@@H](N)CC(O)=O CKLJMWTZIZZHCS-REOHCLBHSA-N 0.000 description 4
- ROHFNLRQFUQHCH-YFKPBYRVSA-N L-leucine Chemical compound CC(C)C[C@H](N)C(O)=O ROHFNLRQFUQHCH-YFKPBYRVSA-N 0.000 description 4
- AYFVYJQAPQTCCC-GBXIJSLDSA-N L-threonine Chemical compound C[C@@H](O)[C@H](N)C(O)=O AYFVYJQAPQTCCC-GBXIJSLDSA-N 0.000 description 4
- SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 description 4
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 description 4
- 150000001299 aldehydes Chemical class 0.000 description 4
- 239000008346 aqueous phase Substances 0.000 description 4
- 239000007864 aqueous solution Substances 0.000 description 4
- 230000015572 biosynthetic process Effects 0.000 description 4
- 210000004369 blood Anatomy 0.000 description 4
- 239000008280 blood Substances 0.000 description 4
- 229910052801 chlorine Inorganic materials 0.000 description 4
- 238000013375 chromatographic separation Methods 0.000 description 4
- 238000004590 computer program Methods 0.000 description 4
- 239000003085 diluting agent Substances 0.000 description 4
- 238000001952 enzyme assay Methods 0.000 description 4
- MDKXBBPLEGPIRI-UHFFFAOYSA-N ethoxyethane;methanol Chemical compound OC.CCOCC MDKXBBPLEGPIRI-UHFFFAOYSA-N 0.000 description 4
- 239000000706 filtrate Substances 0.000 description 4
- 150000002373 hemiacetals Chemical class 0.000 description 4
- 238000004128 high performance liquid chromatography Methods 0.000 description 4
- 238000011534 incubation Methods 0.000 description 4
- 238000002955 isolation Methods 0.000 description 4
- NVOHQSLXALMXBY-UHFFFAOYSA-M lithium;3-benzamido-4-oxo-7,8-dihydro-6h-pyrrolo[1,2-a]pyrimidine-6-carboxylate Chemical compound [Li+].O=C1N2C(C(=O)[O-])CCC2=NC=C1NC(=O)C1=CC=CC=C1 NVOHQSLXALMXBY-UHFFFAOYSA-M 0.000 description 4
- GLXDVVHUTZTUQK-UHFFFAOYSA-M lithium;hydroxide;hydrate Chemical compound [Li+].O.[OH-] GLXDVVHUTZTUQK-UHFFFAOYSA-M 0.000 description 4
- 238000002156 mixing Methods 0.000 description 4
- 238000012986 modification Methods 0.000 description 4
- 230000004048 modification Effects 0.000 description 4
- 238000000302 molecular modelling Methods 0.000 description 4
- 125000002950 monocyclic group Chemical group 0.000 description 4
- 239000000546 pharmaceutical excipient Substances 0.000 description 4
- NROKBHXJSPEDAR-UHFFFAOYSA-M potassium fluoride Chemical compound [F-].[K+] NROKBHXJSPEDAR-UHFFFAOYSA-M 0.000 description 4
- 102000004196 processed proteins & peptides Human genes 0.000 description 4
- 230000000069 prophylactic effect Effects 0.000 description 4
- 230000002441 reversible effect Effects 0.000 description 4
- 150000007659 semicarbazones Chemical class 0.000 description 4
- 239000011734 sodium Substances 0.000 description 4
- AKHNMLFCWUSKQB-UHFFFAOYSA-L sodium thiosulfate Chemical class [Na+].[Na+].[O-]S([O-])(=O)=S AKHNMLFCWUSKQB-UHFFFAOYSA-L 0.000 description 4
- 239000011593 sulfur Chemical group 0.000 description 4
- BAAFYYXCCOAVAR-ROUUACIJSA-N tert-butyl (4s,7s)-6,10-dioxo-7-(3-phenylpropanoylamino)-2,3,4,7,8,9-hexahydro-1h-pyridazino[1,2-a]diazepine-4-carboxylate Chemical compound N([C@@H]1C(=O)N2N(C(CC1)=O)CCC[C@H]2C(=O)OC(C)(C)C)C(=O)CCC1=CC=CC=C1 BAAFYYXCCOAVAR-ROUUACIJSA-N 0.000 description 4
- XXNWJEHOEFHCDX-OALUTQOASA-N tert-butyl (4s,7s)-6-oxo-7-(3-phenylpropanoylamino)-1,2,3,4,7,8,9,10-octahydropyridazino[1,2-a]diazepine-4-carboxylate Chemical compound N([C@H]1CCCN2CCC[C@H](N2C1=O)C(=O)OC(C)(C)C)C(=O)CCC1=CC=CC=C1 XXNWJEHOEFHCDX-OALUTQOASA-N 0.000 description 4
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 4
- 150000003679 valine derivatives Chemical class 0.000 description 4
- NBKZFOUZMJSOJI-KYJUHHDHSA-N (3s)-4-(7-methoxy-1,3-benzoxazol-2-yl)-4-oxo-3-[[2-[(3s)-4-oxo-1-(3-phenylpropanoyl)-3-(3-phenylpropanoylamino)-2,3-dihydro-1,5-benzodiazepin-5-yl]acetyl]amino]butanoic acid Chemical compound N([C@H]1CN(C2=CC=CC=C2N(C1=O)CC(=O)N[C@@H](CC(O)=O)C(=O)C1=NC=2C=CC=C(C=2O1)OC)C(=O)CCC=1C=CC=CC=1)C(=O)CCC1=CC=CC=C1 NBKZFOUZMJSOJI-KYJUHHDHSA-N 0.000 description 3
- SGNQHEHEPYPJOY-HKUYNNGSSA-N (3s)-4-oxo-3-[[2-[(3s)-4-oxo-3-(3-phenylpropanoylamino)-2,3-dihydro-1h-1,5-benzodiazepin-5-yl]acetyl]amino]butanoic acid Chemical compound N([C@H]1CNC2=CC=CC=C2N(C1=O)CC(=O)N[C@@H](CC(=O)O)C=O)C(=O)CCC1=CC=CC=C1 SGNQHEHEPYPJOY-HKUYNNGSSA-N 0.000 description 3
- KHFAVJAWUGOZPA-GJZGRUSLSA-N (4s,7s)-6,10-dioxo-7-(3-phenylpropanoylamino)-2,3,4,7,8,9-hexahydro-1h-pyridazino[1,2-a]diazepine-4-carboxylic acid Chemical compound N([C@@H]1C(=O)N2N(C(CC1)=O)CCC[C@H]2C(=O)O)C(=O)CCC1=CC=CC=C1 KHFAVJAWUGOZPA-GJZGRUSLSA-N 0.000 description 3
- MRUDNSFOFOQZDA-UHFFFAOYSA-N 2,6-dichlorobenzoic acid Chemical compound OC(=O)C1=C(Cl)C=CC=C1Cl MRUDNSFOFOQZDA-UHFFFAOYSA-N 0.000 description 3
- IAZCHZAQEQNYRN-QFIPXVFZSA-N 2-[(3s)-1-benzyl-4-oxo-3-(3-phenylpropanoylamino)-2,3-dihydro-1,5-benzodiazepin-5-yl]acetic acid Chemical compound O=C([C@@H](NC(=O)CCC=1C=CC=CC=1)C1)N(CC(=O)O)C2=CC=CC=C2N1CC1=CC=CC=C1 IAZCHZAQEQNYRN-QFIPXVFZSA-N 0.000 description 3
- 125000004172 4-methoxyphenyl group Chemical group [H]C1=C([H])C(OC([H])([H])[H])=C([H])C([H])=C1* 0.000 description 3
- ACAFOQAUOWZNDG-UHFFFAOYSA-N 5-(3-phenylpropyl)-1h-imidazole-2-carboxylic acid Chemical compound N1C(C(=O)O)=NC(CCCC=2C=CC=CC=2)=C1 ACAFOQAUOWZNDG-UHFFFAOYSA-N 0.000 description 3
- LPMZYBQRZXTZMF-UHFFFAOYSA-N 5-[3-(4-hydroxyphenyl)propyl]-1h-imidazole-2-carboxylic acid Chemical compound N1C(C(=O)O)=NC(CCCC=2C=CC(O)=CC=2)=C1 LPMZYBQRZXTZMF-UHFFFAOYSA-N 0.000 description 3
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 3
- SFJBCYYWKUUZSH-UHFFFAOYSA-N C(C1=CC=CC=C1)C1=CC=C(C(N1CC(=O)NC(C(=O)O)CC(CSCC1=C(C=CC=C1)Cl)=O)=O)NC(CCC1=CC=CC=C1)=O Chemical compound C(C1=CC=CC=C1)C1=CC=C(C(N1CC(=O)NC(C(=O)O)CC(CSCC1=C(C=CC=C1)Cl)=O)=O)NC(CCC1=CC=CC=C1)=O SFJBCYYWKUUZSH-UHFFFAOYSA-N 0.000 description 3
- WHUUTDBJXJRKMK-UHFFFAOYSA-N Glutamic acid Natural products OC(=O)C(N)CCC(O)=O WHUUTDBJXJRKMK-UHFFFAOYSA-N 0.000 description 3
- 239000004471 Glycine Substances 0.000 description 3
- DCXYFEDJOCDNAF-REOHCLBHSA-N L-asparagine Chemical compound OC(=O)[C@@H](N)CC(N)=O DCXYFEDJOCDNAF-REOHCLBHSA-N 0.000 description 3
- WHUUTDBJXJRKMK-VKHMYHEASA-N L-glutamic acid Chemical compound OC(=O)[C@@H](N)CCC(O)=O WHUUTDBJXJRKMK-VKHMYHEASA-N 0.000 description 3
- 125000000174 L-prolyl group Chemical group [H]N1C([H])([H])C([H])([H])C([H])([H])[C@@]1([H])C(*)=O 0.000 description 3
- QIVBCDIJIAJPQS-VIFPVBQESA-N L-tryptophane Chemical compound C1=CC=C2C(C[C@H](N)C(O)=O)=CNC2=C1 QIVBCDIJIAJPQS-VIFPVBQESA-N 0.000 description 3
- 241000124008 Mammalia Species 0.000 description 3
- RJUFJBKOKNCXHH-UHFFFAOYSA-N Methyl propionate Chemical compound CCC(=O)OC RJUFJBKOKNCXHH-UHFFFAOYSA-N 0.000 description 3
- 239000004677 Nylon Substances 0.000 description 3
- 108091005804 Peptidases Proteins 0.000 description 3
- 102000035195 Peptidases Human genes 0.000 description 3
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 3
- 239000004365 Protease Substances 0.000 description 3
- MTCFGRXMJLQNBG-UHFFFAOYSA-N Serine Natural products OCC(N)C(O)=O MTCFGRXMJLQNBG-UHFFFAOYSA-N 0.000 description 3
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 3
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical group [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 3
- AYFVYJQAPQTCCC-UHFFFAOYSA-N Threonine Natural products CC(O)C(N)C(O)=O AYFVYJQAPQTCCC-UHFFFAOYSA-N 0.000 description 3
- 239000004473 Threonine Substances 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- QIVBCDIJIAJPQS-UHFFFAOYSA-N Tryptophan Natural products C1=CC=C2C(CC(N)C(O)=O)=CNC2=C1 QIVBCDIJIAJPQS-UHFFFAOYSA-N 0.000 description 3
- DHKHKXVYLBGOIT-UHFFFAOYSA-N acetaldehyde Diethyl Acetal Natural products CCOC(C)OCC DHKHKXVYLBGOIT-UHFFFAOYSA-N 0.000 description 3
- 150000001241 acetals Chemical class 0.000 description 3
- 125000000738 acetamido group Chemical group [H]C([H])([H])C(=O)N([H])[*] 0.000 description 3
- 150000007513 acids Chemical class 0.000 description 3
- 239000004480 active ingredient Substances 0.000 description 3
- 150000001413 amino acids Chemical class 0.000 description 3
- 229960005261 aspartic acid Drugs 0.000 description 3
- 235000003704 aspartic acid Nutrition 0.000 description 3
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 3
- 230000001363 autoimmune Effects 0.000 description 3
- 125000004196 benzothienyl group Chemical group S1C(=CC2=C1C=CC=C2)* 0.000 description 3
- WIYOQYFVHUUHSF-UHFFFAOYSA-N benzyl n-(6-butyl-2-oxo-1h-pyridin-3-yl)carbamate Chemical compound O=C1NC(CCCC)=CC=C1NC(=O)OCC1=CC=CC=C1 WIYOQYFVHUUHSF-UHFFFAOYSA-N 0.000 description 3
- OQFSQFPPLPISGP-UHFFFAOYSA-N beta-carboxyaspartic acid Natural products OC(=O)C(N)C(C(O)=O)C(O)=O OQFSQFPPLPISGP-UHFFFAOYSA-N 0.000 description 3
- 150000007942 carboxylates Chemical group 0.000 description 3
- 239000000969 carrier Substances 0.000 description 3
- 238000000423 cell based assay Methods 0.000 description 3
- 238000004113 cell culture Methods 0.000 description 3
- 239000003153 chemical reaction reagent Substances 0.000 description 3
- 239000006071 cream Substances 0.000 description 3
- 238000013461 design Methods 0.000 description 3
- 239000002270 dispersing agent Substances 0.000 description 3
- 238000005516 engineering process Methods 0.000 description 3
- 238000001704 evaporation Methods 0.000 description 3
- 230000008020 evaporation Effects 0.000 description 3
- 229960002449 glycine Drugs 0.000 description 3
- 125000005842 heteroatom Chemical group 0.000 description 3
- 230000007062 hydrolysis Effects 0.000 description 3
- 238000006460 hydrolysis reaction Methods 0.000 description 3
- 125000001041 indolyl group Chemical group 0.000 description 3
- 229910052740 iodine Inorganic materials 0.000 description 3
- 150000002576 ketones Chemical group 0.000 description 3
- 239000007788 liquid Substances 0.000 description 3
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 3
- 239000000463 material Substances 0.000 description 3
- 238000000691 measurement method Methods 0.000 description 3
- CBFYMAMJVFNERO-UHFFFAOYSA-N methyl 2-(2-phenylethyl)-4,5-dihydro-1h-imidazole-5-carboxylate Chemical compound COC(=O)C1CNC(CCC=2C=CC=CC=2)=N1 CBFYMAMJVFNERO-UHFFFAOYSA-N 0.000 description 3
- 150000004702 methyl esters Chemical class 0.000 description 3
- 125000001624 naphthyl group Chemical group 0.000 description 3
- 231100000252 nontoxic Toxicity 0.000 description 3
- 230000003000 nontoxic effect Effects 0.000 description 3
- 229920001778 nylon Polymers 0.000 description 3
- 125000004287 oxazol-2-yl group Chemical group [H]C1=C([H])N=C(*)O1 0.000 description 3
- 239000001301 oxygen Substances 0.000 description 3
- 229910052763 palladium Inorganic materials 0.000 description 3
- 229910052698 phosphorus Inorganic materials 0.000 description 3
- 125000003367 polycyclic group Chemical group 0.000 description 3
- 229920001223 polyethylene glycol Polymers 0.000 description 3
- 125000001500 prolyl group Chemical group [H]N1C([H])(C(=O)[*])C([H])([H])C([H])([H])C1([H])[H] 0.000 description 3
- ZEZKRQQOECKKCQ-UHFFFAOYSA-N prop-2-enyl n-(5-oxo-2-phenylmethoxyoxolan-3-yl)carbamate Chemical compound C=CCOC(=O)NC1CC(=O)OC1OCC1=CC=CC=C1 ZEZKRQQOECKKCQ-UHFFFAOYSA-N 0.000 description 3
- 125000004076 pyridyl group Chemical group 0.000 description 3
- WRHZVMBBRYBTKZ-UHFFFAOYSA-N pyrrole-2-carboxylic acid Chemical compound OC(=O)C1=CC=CN1 WRHZVMBBRYBTKZ-UHFFFAOYSA-N 0.000 description 3
- 238000001953 recrystallisation Methods 0.000 description 3
- 229960001153 serine Drugs 0.000 description 3
- 239000012312 sodium hydride Substances 0.000 description 3
- 229910000104 sodium hydride Inorganic materials 0.000 description 3
- 239000012265 solid product Substances 0.000 description 3
- YLUCNSSIRTYRLV-VMPREFPWSA-N tert-butyl (2S)-2-[[2-[(3S)-4-oxo-1-(3-phenylpropanoyl)-3-(3-phenylpropanoylamino)-2,3-dihydro-1,5-benzodiazepin-5-yl]acetyl]amino]butanoate Chemical compound C(C)(C)(C)OC([C@H](CC)NC(CN1C2=C(N(C[C@@H](C1=O)NC(CCC1=CC=CC=C1)=O)C(CCC1=CC=CC=C1)=O)C=CC=C2)=O)=O YLUCNSSIRTYRLV-VMPREFPWSA-N 0.000 description 3
- KBDOSCSBNLAADN-LURJTMIESA-N tert-butyl (3s)-3-amino-n-carbamoyl-4-oxobutanehydrazonate Chemical compound O=C[C@@H](N)CC(OC(C)(C)C)=NNC(N)=O KBDOSCSBNLAADN-LURJTMIESA-N 0.000 description 3
- LDFIJUNNUAUOQM-UHFFFAOYSA-N tert-butyl 2-[2-phenylethyl-(5-propyl-1h-imidazole-2-carbonyl)amino]acetate Chemical compound N1C(CCC)=CN=C1C(=O)N(CC(=O)OC(C)(C)C)CCC1=CC=CC=C1 LDFIJUNNUAUOQM-UHFFFAOYSA-N 0.000 description 3
- KBDOSCSBNLAADN-UHFFFAOYSA-N tert-butyl 3-amino-n-carbamoyl-4-oxobutanehydrazonate Chemical compound O=CC(N)CC(OC(C)(C)C)=NNC(N)=O KBDOSCSBNLAADN-UHFFFAOYSA-N 0.000 description 3
- 230000001225 therapeutic effect Effects 0.000 description 3
- 229960002898 threonine Drugs 0.000 description 3
- 238000011200 topical administration Methods 0.000 description 3
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 3
- 229960004799 tryptophan Drugs 0.000 description 3
- PUPZLCDOIYMWBV-UHFFFAOYSA-N (+/-)-1,3-Butanediol Chemical compound CC(O)CCO PUPZLCDOIYMWBV-UHFFFAOYSA-N 0.000 description 2
- JOFSPZZNFWOLMO-UIOOFZCWSA-N (2S)-2-[[2-[(3S)-4-oxo-1-(3-phenylpropanoyl)-3-(3-phenylpropanoylamino)-2,3-dihydro-1,5-benzodiazepin-5-yl]acetyl]amino]butanoic acid Chemical compound O=C1[C@H](CN(C2=C(N1CC(=O)N[C@H](C(=O)O)CC)C=CC=C2)C(CCC1=CC=CC=C1)=O)NC(CCC1=CC=CC=C1)=O JOFSPZZNFWOLMO-UIOOFZCWSA-N 0.000 description 2
- BVAUMRCGVHUWOZ-ZETCQYMHSA-N (2s)-2-(cyclohexylazaniumyl)propanoate Chemical compound OC(=O)[C@H](C)NC1CCCCC1 BVAUMRCGVHUWOZ-ZETCQYMHSA-N 0.000 description 2
- WAMWSIDTKSNDCU-ZETCQYMHSA-N (2s)-2-azaniumyl-2-cyclohexylacetate Chemical compound OC(=O)[C@@H](N)C1CCCCC1 WAMWSIDTKSNDCU-ZETCQYMHSA-N 0.000 description 2
- UDQTXCHQKHIQMH-KYGLGHNPSA-N (3ar,5s,6s,7r,7ar)-5-(difluoromethyl)-2-(ethylamino)-5,6,7,7a-tetrahydro-3ah-pyrano[3,2-d][1,3]thiazole-6,7-diol Chemical compound S1C(NCC)=N[C@H]2[C@@H]1O[C@H](C(F)F)[C@@H](O)[C@@H]2O UDQTXCHQKHIQMH-KYGLGHNPSA-N 0.000 description 2
- WCUUZLQLUXTSIP-UAHUIJJESA-N (3s)-2-[(2s)-2-[[(2s)-2-[[(2s)-2-acetamido-3-(4-hydroxyphenyl)propanoyl]amino]-3-methylbutanoyl]amino]propanoyl]-3-amino-5-[(2-chlorophenyl)methoxy]-4-oxopentanoic acid Chemical compound C([C@@H](C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](C)C(=O)C([C@H](N)C(=O)COCC=1C(=CC=CC=1)Cl)C(O)=O)NC(C)=O)C1=CC=C(O)C=C1 WCUUZLQLUXTSIP-UAHUIJJESA-N 0.000 description 2
- WHHZPNLFYAFDEL-DHLKQENFSA-N (3s)-2-oxo-3-[[2-[(3s)-4-oxo-1-(3-phenylpropanoyl)-3-(3-phenylpropanoylamino)-2,3-dihydro-1,5-benzodiazepin-5-yl]acetyl]amino]butanoic acid Chemical compound N([C@H]1CN(C2=CC=CC=C2N(C1=O)CC(=O)N[C@@H](C)C(=O)C(O)=O)C(=O)CCC=1C=CC=CC=1)C(=O)CCC1=CC=CC=C1 WHHZPNLFYAFDEL-DHLKQENFSA-N 0.000 description 2
- GEHKKICLKZCABT-QMMMGPOBSA-N (3s)-3-[[2-(7-methyl-4-oxo-5h-pyrrolo[3,2-d]pyrimidin-3-yl)acetyl]amino]-4-oxobutanoic acid Chemical compound N1=CN(CC(=O)N[C@@H](CC(O)=O)C=O)C(=O)C2=C1C(C)=CN2 GEHKKICLKZCABT-QMMMGPOBSA-N 0.000 description 2
- PNYWGEMIRGPRTK-QHCPKHFHSA-N (3s)-3-[[2-[6-benzyl-2-oxo-3-(3-phenylpropanoylamino)pyridin-1-yl]acetyl]amino]-5-hydroxy-4-oxopentanoic acid Chemical compound C=1C=C(NC(=O)CCC=2C=CC=CC=2)C(=O)N(CC(=O)N[C@@H](CC(O)=O)C(=O)CO)C=1CC1=CC=CC=C1 PNYWGEMIRGPRTK-QHCPKHFHSA-N 0.000 description 2
- VUDZSIYXZUYWSC-DBRKOABJSA-N (4r)-1-[(2r,4r,5r)-3,3-difluoro-4-hydroxy-5-(hydroxymethyl)oxolan-2-yl]-4-hydroxy-1,3-diazinan-2-one Chemical compound FC1(F)[C@H](O)[C@@H](CO)O[C@H]1N1C(=O)N[C@H](O)CC1 VUDZSIYXZUYWSC-DBRKOABJSA-N 0.000 description 2
- BCMCBBGGLRIHSE-UHFFFAOYSA-N 1,3-benzoxazole Chemical compound C1=CC=C2OC=NC2=C1 BCMCBBGGLRIHSE-UHFFFAOYSA-N 0.000 description 2
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 2
- JQAOHGMPAAWWQO-UHFFFAOYSA-N 1-[(2-methylpropan-2-yl)oxycarbonyl]piperidine-2-carboxylic acid Chemical compound CC(C)(C)OC(=O)N1CCCCC1C(O)=O JQAOHGMPAAWWQO-UHFFFAOYSA-N 0.000 description 2
- OTDKILWMUJUUSV-KZUDCZAMSA-N 1-o-tert-butyl 2-o-methyl (2s)-4-phenoxypyrrolidine-1,2-dicarboxylate Chemical compound C1N(C(=O)OC(C)(C)C)[C@H](C(=O)OC)CC1OC1=CC=CC=C1 OTDKILWMUJUUSV-KZUDCZAMSA-N 0.000 description 2
- FUOOLUPWFVMBKG-UHFFFAOYSA-N 2-Aminoisobutyric acid Chemical compound CC(C)(N)C(O)=O FUOOLUPWFVMBKG-UHFFFAOYSA-N 0.000 description 2
- LKRPALYSBTXFIS-UHFFFAOYSA-N 2-[2-[4-(trifluoromethyl)phenyl]ethyl]-1h-imidazole-5-carboxylic acid Chemical compound OC(=O)C1=CNC(CCC=2C=CC(=CC=2)C(F)(F)F)=N1 LKRPALYSBTXFIS-UHFFFAOYSA-N 0.000 description 2
- HAAPULCZLZPIHS-UHFFFAOYSA-N 2-[2-oxo-6-(2-phenylethyl)-3-(3-phenylpropanoylamino)pyridin-1-yl]acetic acid Chemical compound C=1C=C(NC(=O)CCC=2C=CC=CC=2)C(=O)N(CC(=O)O)C=1CCC1=CC=CC=C1 HAAPULCZLZPIHS-UHFFFAOYSA-N 0.000 description 2
- ITDAPJUMTLJIKO-UHFFFAOYSA-N 2-[2-oxo-6-phenyl-3-(3-phenylpropanoylamino)pyridin-1-yl]acetic acid Chemical compound O=C1N(CC(=O)O)C(C=2C=CC=CC=2)=CC=C1NC(=O)CCC1=CC=CC=C1 ITDAPJUMTLJIKO-UHFFFAOYSA-N 0.000 description 2
- UIECPXJOSDZPIR-UHFFFAOYSA-N 2-[6-benzyl-2-oxo-3-(2-phenylethoxycarbonylamino)pyridin-1-yl]acetic acid Chemical compound C=1C=C(NC(=O)OCCC=2C=CC=CC=2)C(=O)N(CC(=O)O)C=1CC1=CC=CC=C1 UIECPXJOSDZPIR-UHFFFAOYSA-N 0.000 description 2
- RXCUZRDOBSTIOK-UHFFFAOYSA-N 2-[6-benzyl-2-oxo-3-(2-phenylethylsulfonylamino)pyridin-1-yl]acetic acid Chemical compound C=1C=C(NS(=O)(=O)CCC=2C=CC=CC=2)C(=O)N(CC(=O)O)C=1CC1=CC=CC=C1 RXCUZRDOBSTIOK-UHFFFAOYSA-N 0.000 description 2
- YMWIOYUKKSFCJX-UHFFFAOYSA-N 2-[6-butyl-2-oxo-3-(3-phenylpropanoylamino)pyridin-1-yl]acetic acid Chemical compound O=C1N(CC(O)=O)C(CCCC)=CC=C1NC(=O)CCC1=CC=CC=C1 YMWIOYUKKSFCJX-UHFFFAOYSA-N 0.000 description 2
- KKOZPXNBPLBGQH-UHFFFAOYSA-N 2-[6-methyl-2-oxo-3-(3-phenylpropanoylamino)pyridin-1-yl]acetic acid Chemical compound O=C1N(CC(O)=O)C(C)=CC=C1NC(=O)CCC1=CC=CC=C1 KKOZPXNBPLBGQH-UHFFFAOYSA-N 0.000 description 2
- RTPIPGUAJMIOCH-UHFFFAOYSA-N 2-acetamido-4-oxobutanoic acid Chemical compound CC(=O)NC(C(O)=O)CC=O RTPIPGUAJMIOCH-UHFFFAOYSA-N 0.000 description 2
- UNSHMXUHOHBLIQ-UHFFFAOYSA-N 3-[4-chloro-3-(2-methylphenoxy)naphthalen-1-yl]-6-(trifluoromethyl)-1H-pyrimidine-2,4-dione Chemical compound ClC1=C(C=C(C2=CC=CC=C12)N1C(NC(=CC1=O)C(F)(F)F)=O)OC1=C(C=CC=C1)C UNSHMXUHOHBLIQ-UHFFFAOYSA-N 0.000 description 2
- SEDBGMKMDQWSLO-UHFFFAOYSA-N 3-[[2-[6-benzyl-2-oxo-3-(3-phenylpropanoylamino)pyridin-1-yl]acetyl]amino]-5-(2,6-dichlorobenzoyl)oxy-4-oxopentanoic acid Chemical compound ClC=1C=CC=C(Cl)C=1C(=O)OCC(=O)C(CC(=O)O)NC(=O)CN(C(C(NC(=O)CCC=1C=CC=CC=1)=CC=1)=O)C=1CC1=CC=CC=C1 SEDBGMKMDQWSLO-UHFFFAOYSA-N 0.000 description 2
- OLOOZURDNBYFLO-UHFFFAOYSA-N 3-[[2-[6-benzyl-2-oxo-3-(3-phenylpropanoylamino)pyridin-1-yl]acetyl]amino]-5-[(2-chlorophenyl)methoxy]-4-oxopentanoic acid Chemical compound C=1C=CC=C(Cl)C=1COCC(=O)C(CC(=O)O)NC(=O)CN(C(C(NC(=O)CCC=1C=CC=CC=1)=CC=1)=O)C=1CC1=CC=CC=C1 OLOOZURDNBYFLO-UHFFFAOYSA-N 0.000 description 2
- VCKPUUFAIGNJHC-UHFFFAOYSA-N 3-hydroxykynurenine Chemical compound OC(=O)C(N)CC(=O)C1=CC=CC(O)=C1N VCKPUUFAIGNJHC-UHFFFAOYSA-N 0.000 description 2
- XMIIGOLPHOKFCH-UHFFFAOYSA-N 3-phenylpropionic acid Chemical compound OC(=O)CCC1=CC=CC=C1 XMIIGOLPHOKFCH-UHFFFAOYSA-N 0.000 description 2
- QCQCHGYLTSGIGX-GHXANHINSA-N 4-[[(3ar,5ar,5br,7ar,9s,11ar,11br,13as)-5a,5b,8,8,11a-pentamethyl-3a-[(5-methylpyridine-3-carbonyl)amino]-2-oxo-1-propan-2-yl-4,5,6,7,7a,9,10,11,11b,12,13,13a-dodecahydro-3h-cyclopenta[a]chrysen-9-yl]oxy]-2,2-dimethyl-4-oxobutanoic acid Chemical compound N([C@@]12CC[C@@]3(C)[C@]4(C)CC[C@H]5C(C)(C)[C@@H](OC(=O)CC(C)(C)C(O)=O)CC[C@]5(C)[C@H]4CC[C@@H]3C1=C(C(C2)=O)C(C)C)C(=O)C1=CN=CC(C)=C1 QCQCHGYLTSGIGX-GHXANHINSA-N 0.000 description 2
- VHCOEXCZDAHYMW-UHFFFAOYSA-N 4-methoxy-1,3-benzoxazole Chemical compound COC1=CC=CC2=C1N=CO2 VHCOEXCZDAHYMW-UHFFFAOYSA-N 0.000 description 2
- LVJRNUSDANLSGK-UHFFFAOYSA-N 5-(2,6-dichlorobenzoyl)oxy-4-oxo-3-[[2-[2-oxo-3-(phenylmethoxycarbonylamino)pyridin-1-yl]acetyl]amino]pentanoic acid Chemical compound ClC=1C=CC=C(Cl)C=1C(=O)OCC(=O)C(CC(=O)O)NC(=O)CN(C1=O)C=CC=C1NC(=O)OCC1=CC=CC=C1 LVJRNUSDANLSGK-UHFFFAOYSA-N 0.000 description 2
- AFQWQMNKBKVLNA-UHFFFAOYSA-N 5-(2-phenylethyl)-1h-imidazole-2-carboxylic acid Chemical compound N1C(C(=O)O)=NC(CCC=2C=CC=CC=2)=C1 AFQWQMNKBKVLNA-UHFFFAOYSA-N 0.000 description 2
- AQHFZMRRVOSLSQ-UHFFFAOYSA-N 5-[(2-chlorophenyl)methylsulfanyl]-2-(diazepine-1-carbonylamino)-4-oxopentanoic acid Chemical compound C1=CC=CC=NN1C(=O)NC(C(=O)O)CC(=O)CSCC1=CC=CC=C1Cl AQHFZMRRVOSLSQ-UHFFFAOYSA-N 0.000 description 2
- VLWZYTKIXLVUIK-UHFFFAOYSA-N 5-[3-(4-methoxyphenyl)propyl]-1h-imidazole-2-carboxylic acid Chemical compound C1=CC(OC)=CC=C1CCCC1=CNC(C(O)=O)=N1 VLWZYTKIXLVUIK-UHFFFAOYSA-N 0.000 description 2
- IYVQVGPNDPCPNP-UHFFFAOYSA-N 5-benzyl-1h-imidazole-2-carboxylic acid Chemical compound N1C(C(=O)O)=NC(CC=2C=CC=CC=2)=C1 IYVQVGPNDPCPNP-UHFFFAOYSA-N 0.000 description 2
- 125000003627 8 membered carbocyclic group Chemical group 0.000 description 2
- 208000024827 Alzheimer disease Diseases 0.000 description 2
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 2
- DCXYFEDJOCDNAF-UHFFFAOYSA-N Asparagine Natural products OC(=O)C(N)CC(N)=O DCXYFEDJOCDNAF-UHFFFAOYSA-N 0.000 description 2
- KCBAMQOKOLXLOX-BSZYMOERSA-N CC1=C(SC=N1)C2=CC=C(C=C2)[C@H](C)NC(=O)[C@@H]3C[C@H](CN3C(=O)[C@H](C(C)(C)C)NC(=O)CCCCCCCCCCNCCCONC(=O)C4=C(C(=C(C=C4)F)F)NC5=C(C=C(C=C5)I)F)O Chemical compound CC1=C(SC=N1)C2=CC=C(C=C2)[C@H](C)NC(=O)[C@@H]3C[C@H](CN3C(=O)[C@H](C(C)(C)C)NC(=O)CCCCCCCCCCNCCCONC(=O)C4=C(C(=C(C=C4)F)F)NC5=C(C=C(C=C5)I)F)O KCBAMQOKOLXLOX-BSZYMOERSA-N 0.000 description 2
- VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 description 2
- 229920002261 Corn starch Polymers 0.000 description 2
- 102000004127 Cytokines Human genes 0.000 description 2
- 108090000695 Cytokines Proteins 0.000 description 2
- 238000002965 ELISA Methods 0.000 description 2
- 238000012286 ELISA Assay Methods 0.000 description 2
- 102000010911 Enzyme Precursors Human genes 0.000 description 2
- 108010062466 Enzyme Precursors Proteins 0.000 description 2
- XPDWGBQVDMORPB-UHFFFAOYSA-N Fluoroform Chemical compound FC(F)F XPDWGBQVDMORPB-UHFFFAOYSA-N 0.000 description 2
- HCUARRIEZVDMPT-UHFFFAOYSA-N Indole-2-carboxylic acid Chemical compound C1=CC=C2NC(C(=O)O)=CC2=C1 HCUARRIEZVDMPT-UHFFFAOYSA-N 0.000 description 2
- 102000006992 Interferon-alpha Human genes 0.000 description 2
- 108010047761 Interferon-alpha Proteins 0.000 description 2
- XUJNEKJLAYXESH-REOHCLBHSA-N L-Cysteine Chemical compound SC[C@H](N)C(O)=O XUJNEKJLAYXESH-REOHCLBHSA-N 0.000 description 2
- AGPKZVBTJJNPAG-UHNVWZDZSA-N L-allo-Isoleucine Chemical compound CC[C@@H](C)[C@H](N)C(O)=O AGPKZVBTJJNPAG-UHNVWZDZSA-N 0.000 description 2
- LRQKBLKVPFOOQJ-YFKPBYRVSA-N L-norleucine Chemical compound CCCC[C@H]([NH3+])C([O-])=O LRQKBLKVPFOOQJ-YFKPBYRVSA-N 0.000 description 2
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 2
- CBENFWSGALASAD-UHFFFAOYSA-N Ozone Chemical compound [O-][O+]=O CBENFWSGALASAD-UHFFFAOYSA-N 0.000 description 2
- 208000018737 Parkinson disease Diseases 0.000 description 2
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 2
- 239000002202 Polyethylene glycol Substances 0.000 description 2
- ASNFTDCKZKHJSW-REOHCLBHSA-N Quisqualic acid Chemical compound OC(=O)[C@@H](N)CN1OC(=O)NC1=O ASNFTDCKZKHJSW-REOHCLBHSA-N 0.000 description 2
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- YTPLMLYBLZKORZ-UHFFFAOYSA-N Thiophene Chemical compound C=1C=CSC=1 YTPLMLYBLZKORZ-UHFFFAOYSA-N 0.000 description 2
- 239000007983 Tris buffer Substances 0.000 description 2
- 230000004913 activation Effects 0.000 description 2
- 230000001154 acute effect Effects 0.000 description 2
- 239000000956 alloy Substances 0.000 description 2
- 229910045601 alloy Inorganic materials 0.000 description 2
- 150000001412 amines Chemical class 0.000 description 2
- 229940121363 anti-inflammatory agent Drugs 0.000 description 2
- 239000002260 anti-inflammatory agent Substances 0.000 description 2
- 230000006907 apoptotic process Effects 0.000 description 2
- 239000007900 aqueous suspension Substances 0.000 description 2
- 229960001230 asparagine Drugs 0.000 description 2
- 235000009582 asparagine Nutrition 0.000 description 2
- XRWSZZJLZRKHHD-WVWIJVSJSA-N asunaprevir Chemical compound O=C([C@@H]1C[C@H](CN1C(=O)[C@@H](NC(=O)OC(C)(C)C)C(C)(C)C)OC1=NC=C(C2=CC=C(Cl)C=C21)OC)N[C@]1(C(=O)NS(=O)(=O)C2CC2)C[C@H]1C=C XRWSZZJLZRKHHD-WVWIJVSJSA-N 0.000 description 2
- UHOVQNZJYSORNB-MZWXYZOWSA-N benzene-d6 Chemical compound [2H]C1=C([2H])C([2H])=C([2H])C([2H])=C1[2H] UHOVQNZJYSORNB-MZWXYZOWSA-N 0.000 description 2
- 125000000499 benzofuranyl group Chemical group O1C(=CC2=C1C=CC=C2)* 0.000 description 2
- 125000001164 benzothiazolyl group Chemical group S1C(=NC2=C1C=CC=C2)* 0.000 description 2
- 125000004541 benzoxazolyl group Chemical group O1C(=NC2=C1C=CC=C2)* 0.000 description 2
- 235000019445 benzyl alcohol Nutrition 0.000 description 2
- MAJFINHRLBJIQL-UHFFFAOYSA-N benzyl n-(2-oxo-1h-pyridin-3-yl)carbamate Chemical compound OC1=NC=CC=C1NC(=O)OCC1=CC=CC=C1 MAJFINHRLBJIQL-UHFFFAOYSA-N 0.000 description 2
- MFIOHZLWLKAYOM-UHFFFAOYSA-N benzyl n-(6-benzyl-2-oxo-1h-pyridin-3-yl)carbamate Chemical compound C=1C=CC=CC=1COC(=O)NC(C(N1)=O)=CC=C1CC1=CC=CC=C1 MFIOHZLWLKAYOM-UHFFFAOYSA-N 0.000 description 2
- ILAHWRKJUDSMFH-UHFFFAOYSA-N boron tribromide Chemical compound BrB(Br)Br ILAHWRKJUDSMFH-UHFFFAOYSA-N 0.000 description 2
- 239000002775 capsule Substances 0.000 description 2
- 239000006285 cell suspension Substances 0.000 description 2
- 238000005119 centrifugation Methods 0.000 description 2
- 230000001684 chronic effect Effects 0.000 description 2
- 238000003776 cleavage reaction Methods 0.000 description 2
- 239000000084 colloidal system Substances 0.000 description 2
- 239000002299 complementary DNA Substances 0.000 description 2
- 229940125833 compound 23 Drugs 0.000 description 2
- 229940125961 compound 24 Drugs 0.000 description 2
- 229940125936 compound 42 Drugs 0.000 description 2
- 238000007796 conventional method Methods 0.000 description 2
- 239000008120 corn starch Substances 0.000 description 2
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 2
- XUJNEKJLAYXESH-UHFFFAOYSA-N cysteine Natural products SCC(N)C(O)=O XUJNEKJLAYXESH-UHFFFAOYSA-N 0.000 description 2
- 229960002433 cysteine Drugs 0.000 description 2
- 235000018417 cysteine Nutrition 0.000 description 2
- 239000002852 cysteine proteinase inhibitor Substances 0.000 description 2
- 238000010511 deprotection reaction Methods 0.000 description 2
- NKLCNNUWBJBICK-UHFFFAOYSA-N dess–martin periodinane Chemical compound C1=CC=C2I(OC(=O)C)(OC(C)=O)(OC(C)=O)OC(=O)C2=C1 NKLCNNUWBJBICK-UHFFFAOYSA-N 0.000 description 2
- 235000014113 dietary fatty acids Nutrition 0.000 description 2
- 125000004177 diethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 2
- ZUOUZKKEUPVFJK-UHFFFAOYSA-N diphenyl Chemical compound C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 description 2
- 208000035475 disorder Diseases 0.000 description 2
- 239000003480 eluent Substances 0.000 description 2
- VFRSADQPWYCXDG-LEUCUCNGSA-N ethyl (2s,5s)-5-methylpyrrolidine-2-carboxylate;2,2,2-trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F.CCOC(=O)[C@@H]1CC[C@H](C)N1 VFRSADQPWYCXDG-LEUCUCNGSA-N 0.000 description 2
- 125000004494 ethyl ester group Chemical group 0.000 description 2
- 235000019197 fats Nutrition 0.000 description 2
- 229930195729 fatty acid Natural products 0.000 description 2
- 239000000194 fatty acid Substances 0.000 description 2
- 150000004665 fatty acids Chemical class 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 125000000524 functional group Chemical group 0.000 description 2
- 229960002989 glutamic acid Drugs 0.000 description 2
- 235000013922 glutamic acid Nutrition 0.000 description 2
- 239000004220 glutamic acid Substances 0.000 description 2
- 238000010438 heat treatment Methods 0.000 description 2
- XLYOFNOQVPJJNP-ZSJDYOACSA-N heavy water Substances [2H]O[2H] XLYOFNOQVPJJNP-ZSJDYOACSA-N 0.000 description 2
- 239000008241 heterogeneous mixture Substances 0.000 description 2
- 239000002955 immunomodulating agent Substances 0.000 description 2
- 229940121354 immunomodulator Drugs 0.000 description 2
- 238000002347 injection Methods 0.000 description 2
- 239000007924 injection Substances 0.000 description 2
- 125000000468 ketone group Chemical group 0.000 description 2
- YGPSJZOEDVAXAB-UHFFFAOYSA-N kynurenine Chemical compound OC(=O)C(N)CC(=O)C1=CC=CC=C1N YGPSJZOEDVAXAB-UHFFFAOYSA-N 0.000 description 2
- 239000008101 lactose Substances 0.000 description 2
- 239000003446 ligand Substances 0.000 description 2
- 229910001623 magnesium bromide Inorganic materials 0.000 description 2
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
- 235000019341 magnesium sulphate Nutrition 0.000 description 2
- NUJOXMJBOLGQSY-UHFFFAOYSA-N manganese dioxide Chemical compound O=[Mn]=O NUJOXMJBOLGQSY-UHFFFAOYSA-N 0.000 description 2
- 230000007246 mechanism Effects 0.000 description 2
- 239000012528 membrane Substances 0.000 description 2
- 230000004060 metabolic process Effects 0.000 description 2
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 2
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 2
- DOCGRDFKRQBQFF-KRWDZBQOSA-N methyl (8s)-7-[5-(3-phenylpropyl)-1h-imidazole-2-carbonyl]-1,4-dithia-7-azaspiro[4.4]nonane-8-carboxylate Chemical compound C([C@H](N(C1)C(=O)C=2NC(CCCC=3C=CC=CC=3)=CN=2)C(=O)OC)C21SCCS2 DOCGRDFKRQBQFF-KRWDZBQOSA-N 0.000 description 2
- BUKTZGUYDUVLJM-UHFFFAOYSA-N methyl 2-(2-phenylethyl)-1h-imidazole-5-carboxylate Chemical compound COC(=O)C1=CNC(CCC=2C=CC=CC=2)=N1 BUKTZGUYDUVLJM-UHFFFAOYSA-N 0.000 description 2
- FZFYRORDBZQQOQ-UHFFFAOYSA-N methyl 2-(3-amino-2-oxo-6-phenylpyridin-1-yl)acetate Chemical compound C1=C(N)C(=O)N(CC(=O)OC)C(C=2C=CC=CC=2)=C1 FZFYRORDBZQQOQ-UHFFFAOYSA-N 0.000 description 2
- NYMNBORMCDHVDS-UHFFFAOYSA-N methyl 2-(3-amino-6-benzyl-2-oxopyridin-1-yl)acetate Chemical compound C1=C(N)C(=O)N(CC(=O)OC)C(CC=2C=CC=CC=2)=C1 NYMNBORMCDHVDS-UHFFFAOYSA-N 0.000 description 2
- FRUAXPAGXVSIPH-UHFFFAOYSA-N methyl 2-(3-amino-6-butyl-2-oxopyridin-1-yl)acetate Chemical compound CCCCC1=CC=C(N)C(=O)N1CC(=O)OC FRUAXPAGXVSIPH-UHFFFAOYSA-N 0.000 description 2
- MUULMTAXURPNJY-UHFFFAOYSA-N methyl 2-(3-amino-6-methyl-2-oxopyridin-1-yl)acetate Chemical compound COC(=O)CN1C(C)=CC=C(N)C1=O MUULMTAXURPNJY-UHFFFAOYSA-N 0.000 description 2
- NKICBUPPCJNSGF-QHCPKHFHSA-N methyl 2-[(3s)-1-benzyl-4-oxo-3-(3-phenylpropanoylamino)-2,3-dihydro-1,5-benzodiazepin-5-yl]acetate Chemical compound O=C([C@@H](NC(=O)CCC=1C=CC=CC=1)C1)N(CC(=O)OC)C2=CC=CC=C2N1CC1=CC=CC=C1 NKICBUPPCJNSGF-QHCPKHFHSA-N 0.000 description 2
- NCRLHLOMZXXTNT-QRPNPIFTSA-N methyl 2-[(3s)-3-amino-4-oxo-2,3-dihydro-1h-1,5-benzodiazepin-5-yl]acetate;hydrochloride Chemical compound Cl.N1C[C@H](N)C(=O)N(CC(=O)OC)C2=CC=CC=C21 NCRLHLOMZXXTNT-QRPNPIFTSA-N 0.000 description 2
- CNPAYLQABWDLFR-KRWDZBQOSA-N methyl 2-[(3s)-4-oxo-3-(3-phenylpropanoylamino)-2,3-dihydro-1h-1,5-benzodiazepin-5-yl]acetate Chemical compound N([C@H]1CNC2=CC=CC=C2N(C1=O)CC(=O)OC)C(=O)CCC1=CC=CC=C1 CNPAYLQABWDLFR-KRWDZBQOSA-N 0.000 description 2
- GOHUSRJTCWFWKS-UHFFFAOYSA-N methyl 2-[2-[4-(trifluoromethyl)phenyl]ethyl]-1h-imidazole-5-carboxylate Chemical compound COC(=O)C1=CNC(CCC=2C=CC(=CC=2)C(F)(F)F)=N1 GOHUSRJTCWFWKS-UHFFFAOYSA-N 0.000 description 2
- JYMDGTTWDLVRRR-UHFFFAOYSA-N methyl 2-[2-oxo-6-(2-phenylethyl)-3-(3-phenylpropanoylamino)pyridin-1-yl]acetate Chemical compound C=1C=C(NC(=O)CCC=2C=CC=CC=2)C(=O)N(CC(=O)OC)C=1CCC1=CC=CC=C1 JYMDGTTWDLVRRR-UHFFFAOYSA-N 0.000 description 2
- PJPRISZTOCCYOI-UHFFFAOYSA-N methyl 2-[2-oxo-6-(2-phenylethyl)-3-(phenylmethoxycarbonylamino)pyridin-1-yl]acetate Chemical compound C=1C=C(NC(=O)OCC=2C=CC=CC=2)C(=O)N(CC(=O)OC)C=1CCC1=CC=CC=C1 PJPRISZTOCCYOI-UHFFFAOYSA-N 0.000 description 2
- GFRATVPUOADIGG-UHFFFAOYSA-N methyl 2-[2-oxo-6-phenyl-3-(3-phenylpropanoylamino)pyridin-1-yl]acetate Chemical compound O=C1N(CC(=O)OC)C(C=2C=CC=CC=2)=CC=C1NC(=O)CCC1=CC=CC=C1 GFRATVPUOADIGG-UHFFFAOYSA-N 0.000 description 2
- SHBGUYJGAFRQIY-UHFFFAOYSA-N methyl 2-[3-[(2-methylpropan-2-yl)oxycarbonylamino]-4-oxo-2,3-dihydro-1h-1,5-benzodiazepin-5-yl]acetate Chemical compound N1CC(NC(=O)OC(C)(C)C)C(=O)N(CC(=O)OC)C2=CC=CC=C21 SHBGUYJGAFRQIY-UHFFFAOYSA-N 0.000 description 2
- WPKJNYIEWNXJNV-UHFFFAOYSA-N methyl 2-[3-amino-2-oxo-6-(2-phenylethyl)pyridin-1-yl]acetate Chemical compound C1=C(N)C(=O)N(CC(=O)OC)C(CCC=2C=CC=CC=2)=C1 WPKJNYIEWNXJNV-UHFFFAOYSA-N 0.000 description 2
- OFJWWQWZZXNPCZ-UHFFFAOYSA-N methyl 2-[6-benzyl-2-oxo-3-(2-phenylethylsulfonylamino)pyridin-1-yl]acetate Chemical compound C=1C=C(NS(=O)(=O)CCC=2C=CC=CC=2)C(=O)N(CC(=O)OC)C=1CC1=CC=CC=C1 OFJWWQWZZXNPCZ-UHFFFAOYSA-N 0.000 description 2
- VDBRAGIDQBSPPX-UHFFFAOYSA-N methyl 2-[6-benzyl-2-oxo-3-(3-phenylpropanoylamino)pyridin-1-yl]acetate Chemical compound C=1C=C(NC(=O)CCC=2C=CC=CC=2)C(=O)N(CC(=O)OC)C=1CC1=CC=CC=C1 VDBRAGIDQBSPPX-UHFFFAOYSA-N 0.000 description 2
- HUFAJAIYCHOMJW-UHFFFAOYSA-N methyl 2-[6-benzyl-2-oxo-3-(phenylmethoxycarbonylamino)pyridin-1-yl]acetate Chemical compound C=1C=C(NC(=O)OCC=2C=CC=CC=2)C(=O)N(CC(=O)OC)C=1CC1=CC=CC=C1 HUFAJAIYCHOMJW-UHFFFAOYSA-N 0.000 description 2
- VZEFAUURPCDATM-UHFFFAOYSA-N methyl 2-[6-butyl-2-oxo-3-(3-phenylpropanoylamino)pyridin-1-yl]acetate Chemical compound O=C1N(CC(=O)OC)C(CCCC)=CC=C1NC(=O)CCC1=CC=CC=C1 VZEFAUURPCDATM-UHFFFAOYSA-N 0.000 description 2
- SNXPAHFYZKDJKU-UHFFFAOYSA-N methyl 2-[6-butyl-2-oxo-3-(phenylmethoxycarbonylamino)pyridin-1-yl]acetate Chemical compound O=C1N(CC(=O)OC)C(CCCC)=CC=C1NC(=O)OCC1=CC=CC=C1 SNXPAHFYZKDJKU-UHFFFAOYSA-N 0.000 description 2
- YEXYDANBRXWNLJ-UHFFFAOYSA-N methyl 2-[6-methyl-2-oxo-3-(3-phenylpropanoylamino)pyridin-1-yl]acetate Chemical compound O=C1N(CC(=O)OC)C(C)=CC=C1NC(=O)CCC1=CC=CC=C1 YEXYDANBRXWNLJ-UHFFFAOYSA-N 0.000 description 2
- BXYMKZIMURGQHR-UHFFFAOYSA-N methyl 2-[6-methyl-2-oxo-3-(phenylmethoxycarbonylamino)pyridin-1-yl]acetate Chemical compound O=C1N(CC(=O)OC)C(C)=CC=C1NC(=O)OCC1=CC=CC=C1 BXYMKZIMURGQHR-UHFFFAOYSA-N 0.000 description 2
- NXUMAWBKMWPSOQ-UHFFFAOYSA-N methyl 2-[6-phenyl-3-(phenylmethoxycarbonylamino)-2H-pyridin-1-yl]acetate Chemical compound C=1C=C(C=2C=CC=CC=2)N(CC(=O)OC)CC=1NC(=O)OCC1=CC=CC=C1 NXUMAWBKMWPSOQ-UHFFFAOYSA-N 0.000 description 2
- YDCHPLOFQATIDS-UHFFFAOYSA-N methyl 2-bromoacetate Chemical compound COC(=O)CBr YDCHPLOFQATIDS-UHFFFAOYSA-N 0.000 description 2
- KQSSATDQUYCRGS-UHFFFAOYSA-N methyl glycinate Chemical compound COC(=O)CN KQSSATDQUYCRGS-UHFFFAOYSA-N 0.000 description 2
- 229940017219 methyl propionate Drugs 0.000 description 2
- 239000002480 mineral oil Substances 0.000 description 2
- 235000010446 mineral oil Nutrition 0.000 description 2
- 238000000324 molecular mechanic Methods 0.000 description 2
- YGBMCLDVRUGXOV-UHFFFAOYSA-N n-[6-[6-chloro-5-[(4-fluorophenyl)sulfonylamino]pyridin-3-yl]-1,3-benzothiazol-2-yl]acetamide Chemical compound C1=C2SC(NC(=O)C)=NC2=CC=C1C(C=1)=CN=C(Cl)C=1NS(=O)(=O)C1=CC=C(F)C=C1 YGBMCLDVRUGXOV-UHFFFAOYSA-N 0.000 description 2
- IOMMMLWIABWRKL-WUTDNEBXSA-N nazartinib Chemical compound C1N(C(=O)/C=C/CN(C)C)CCCC[C@H]1N1C2=C(Cl)C=CC=C2N=C1NC(=O)C1=CC=NC(C)=C1 IOMMMLWIABWRKL-WUTDNEBXSA-N 0.000 description 2
- 125000004433 nitrogen atom Chemical group N* 0.000 description 2
- 230000036963 noncompetitive effect Effects 0.000 description 2
- 239000000346 nonvolatile oil Substances 0.000 description 2
- 239000004533 oil dispersion Substances 0.000 description 2
- 229940094443 oxytocics prostaglandins Drugs 0.000 description 2
- 239000008188 pellet Substances 0.000 description 2
- 229920001184 polypeptide Polymers 0.000 description 2
- 239000013641 positive control Substances 0.000 description 2
- 235000003270 potassium fluoride Nutrition 0.000 description 2
- 239000011698 potassium fluoride Substances 0.000 description 2
- 239000002244 precipitate Substances 0.000 description 2
- 239000000651 prodrug Substances 0.000 description 2
- 229940002612 prodrug Drugs 0.000 description 2
- 150000003180 prostaglandins Chemical class 0.000 description 2
- 235000019419 proteases Nutrition 0.000 description 2
- 125000000714 pyrimidinyl group Chemical group 0.000 description 2
- 238000005956 quaternization reaction Methods 0.000 description 2
- 230000007017 scission Effects 0.000 description 2
- NDVLTYZPCACLMA-UHFFFAOYSA-N silver oxide Chemical compound [O-2].[Ag+].[Ag+] NDVLTYZPCACLMA-UHFFFAOYSA-N 0.000 description 2
- 159000000000 sodium salts Chemical class 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-N sodium;hydron;carbonate Chemical class [Na+].OC(O)=O UIIMBOGNXHQVGW-UHFFFAOYSA-N 0.000 description 2
- 239000000375 suspending agent Substances 0.000 description 2
- 230000009897 systematic effect Effects 0.000 description 2
- 239000003826 tablet Substances 0.000 description 2
- NMVHVMBSLRZJGD-JTJYXVOQSA-N tert-butyl (3s)-4-(1,3-benzoxazol-2-yl)-3-[[(2s)-2-[[(2s)-3-methyl-2-(phenylmethoxycarbonylamino)butanoyl]amino]propanoyl]amino]-4-oxobutanoate Chemical compound N([C@@H](C(C)C)C(=O)N[C@@H](C)C(=O)N[C@@H](CC(=O)OC(C)(C)C)C(=O)C=1OC2=CC=CC=C2N=1)C(=O)OCC1=CC=CC=C1 NMVHVMBSLRZJGD-JTJYXVOQSA-N 0.000 description 2
- JERRQZSXDFGTPN-UHFFFAOYSA-N tert-butyl 3-amino-4-(1,3-benzoxazol-2-yl)-4-hydroxybutanoate Chemical compound C1=CC=C2OC(C(O)C(N)CC(=O)OC(C)(C)C)=NC2=C1 JERRQZSXDFGTPN-UHFFFAOYSA-N 0.000 description 2
- QJLHQQMNUTXHPL-UHFFFAOYSA-N tert-butyl 4-(1,3-benzoxazol-2-yl)-4-hydroxy-3-(phenylmethoxycarbonylamino)butanoate Chemical compound N=1C2=CC=CC=C2OC=1C(O)C(CC(=O)OC(C)(C)C)NC(=O)OCC1=CC=CC=C1 QJLHQQMNUTXHPL-UHFFFAOYSA-N 0.000 description 2
- MLVSXQYPIHABKW-IXLFUCOQSA-N tert-butyl 4-(1,3-benzoxazol-2-yl)-4-hydroxy-3-[[(2s)-2-[[(2s)-3-methyl-2-(phenylmethoxycarbonylamino)butanoyl]amino]propanoyl]amino]butanoate Chemical compound N([C@@H](C(C)C)C(=O)N[C@@H](C)C(=O)NC(CC(=O)OC(C)(C)C)C(O)C=1OC2=CC=CC=C2N=1)C(=O)OCC1=CC=CC=C1 MLVSXQYPIHABKW-IXLFUCOQSA-N 0.000 description 2
- WYRQJCWZHMEHOX-UHFFFAOYSA-N tert-butyl diazepine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1C=CC=CC=N1 WYRQJCWZHMEHOX-UHFFFAOYSA-N 0.000 description 2
- SCSLUABEVMLYEA-UHFFFAOYSA-N tert-butyl pentanoate Chemical compound CCCCC(=O)OC(C)(C)C SCSLUABEVMLYEA-UHFFFAOYSA-N 0.000 description 2
- 125000003507 tetrahydrothiofenyl group Chemical group 0.000 description 2
- GKASDNZWUGIAMG-UHFFFAOYSA-N triethyl orthoformate Chemical compound CCOC(OCC)OCC GKASDNZWUGIAMG-UHFFFAOYSA-N 0.000 description 2
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 2
- 239000003981 vehicle Substances 0.000 description 2
- HMJIYCCIJYRONP-UHFFFAOYSA-N (+-)-Isradipine Chemical compound COC(=O)C1=C(C)NC(C)=C(C(=O)OC(C)C)C1C1=CC=CC2=NON=C12 HMJIYCCIJYRONP-UHFFFAOYSA-N 0.000 description 1
- 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 1
- ABJSOROVZZKJGI-OCYUSGCXSA-N (1r,2r,4r)-2-(4-bromophenyl)-n-[(4-chlorophenyl)-(2-fluoropyridin-4-yl)methyl]-4-morpholin-4-ylcyclohexane-1-carboxamide Chemical compound C1=NC(F)=CC(C(NC(=O)[C@H]2[C@@H](C[C@@H](CC2)N2CCOCC2)C=2C=CC(Br)=CC=2)C=2C=CC(Cl)=CC=2)=C1 ABJSOROVZZKJGI-OCYUSGCXSA-N 0.000 description 1
- WWFIIZLHSNBNTC-UHFFFAOYSA-N (2-chlorophenyl)methanethiol Chemical compound SCC1=CC=CC=C1Cl WWFIIZLHSNBNTC-UHFFFAOYSA-N 0.000 description 1
- IZQODKKJJRLEGA-VIFPVBQESA-N (2r)-2-(2-pyridin-4-ylethylamino)-3-sulfanylpropanoic acid Chemical compound OC(=O)[C@H](CS)NCCC1=CC=NC=C1 IZQODKKJJRLEGA-VIFPVBQESA-N 0.000 description 1
- DGIGGVANZFKXLS-KZUDCZAMSA-N (2s)-1-[(2-methylpropan-2-yl)oxycarbonyl]-4-phenylmethoxypyrrolidine-2-carboxylic acid Chemical compound C1[C@@H](C(O)=O)N(C(=O)OC(C)(C)C)CC1OCC1=CC=CC=C1 DGIGGVANZFKXLS-KZUDCZAMSA-N 0.000 description 1
- QKKUARGGBZPAFA-NSBVFQKPSA-N (2s)-1-[(2s)-2-[[(2s)-2-acetamido-3-(4-hydroxyphenyl)propanoyl]amino]-3-methylbutanoyl]-4-phenoxypyrrolidine-2-carboxylic acid Chemical compound C([C@@H](C(=O)N[C@@H](C(C)C)C(=O)N1[C@@H](CC(C1)OC=1C=CC=CC=1)C(O)=O)NC(C)=O)C1=CC=C(O)C=C1 QKKUARGGBZPAFA-NSBVFQKPSA-N 0.000 description 1
- MSJVZYZBQGBEQX-BYPYZUCNSA-N (2s)-2-(ethenylamino)propanoic acid Chemical compound OC(=O)[C@H](C)NC=C MSJVZYZBQGBEQX-BYPYZUCNSA-N 0.000 description 1
- HKZCDMUOAAWVBO-YFKPBYRVSA-N (2s)-2-(furan-3-ylamino)propanoic acid Chemical compound OC(=O)[C@H](C)NC=1C=COC=1 HKZCDMUOAAWVBO-YFKPBYRVSA-N 0.000 description 1
- WTKYBFQVZPCGAO-LURJTMIESA-N (2s)-2-(pyridin-3-ylamino)propanoic acid Chemical compound OC(=O)[C@H](C)NC1=CC=CN=C1 WTKYBFQVZPCGAO-LURJTMIESA-N 0.000 description 1
- SAAQPSNNIOGFSQ-LURJTMIESA-N (2s)-2-(pyridin-4-ylamino)propanoic acid Chemical compound OC(=O)[C@H](C)NC1=CC=NC=C1 SAAQPSNNIOGFSQ-LURJTMIESA-N 0.000 description 1
- MRTPISKDZDHEQI-YFKPBYRVSA-N (2s)-2-(tert-butylamino)propanoic acid Chemical compound OC(=O)[C@H](C)NC(C)(C)C MRTPISKDZDHEQI-YFKPBYRVSA-N 0.000 description 1
- TVYGDHGAJIURNC-REOHCLBHSA-N (2s)-2-(trifluoromethylamino)propanoic acid Chemical compound OC(=O)[C@H](C)NC(F)(F)F TVYGDHGAJIURNC-REOHCLBHSA-N 0.000 description 1
- YKEQILJFMVLPPY-JTQLQIEISA-N (2s)-2-[(2-methylpropan-2-yl)oxycarbonylamino]-3-(2-nitroanilino)propanoic acid Chemical compound CC(C)(C)OC(=O)N[C@H](C(O)=O)CNC1=CC=CC=C1[N+]([O-])=O YKEQILJFMVLPPY-JTQLQIEISA-N 0.000 description 1
- ZAVSPTOJKOFMTA-SFHVURJKSA-N (2s)-2-[(2-methylpropan-2-yl)oxycarbonylamino]-3-(4-phenylmethoxyphenyl)propanoic acid Chemical compound C1=CC(C[C@H](NC(=O)OC(C)(C)C)C(O)=O)=CC=C1OCC1=CC=CC=C1 ZAVSPTOJKOFMTA-SFHVURJKSA-N 0.000 description 1
- QVHJQCGUWFKTSE-YFKPBYRVSA-N (2s)-2-[(2-methylpropan-2-yl)oxycarbonylamino]propanoic acid Chemical compound OC(=O)[C@H](C)NC(=O)OC(C)(C)C QVHJQCGUWFKTSE-YFKPBYRVSA-N 0.000 description 1
- WGYHAEUCHXNWLQ-UVBJJODRSA-N (2s)-2-[[(2s)-2-[[(2s)-2-acetamido-3-(4-hydroxyphenyl)propanoyl]amino]-3-methylbutanoyl]amino]propanoic acid Chemical compound OC(=O)[C@H](C)NC(=O)[C@H](C(C)C)NC(=O)[C@@H](NC(C)=O)CC1=CC=C(O)C=C1 WGYHAEUCHXNWLQ-UVBJJODRSA-N 0.000 description 1
- VCXXRMRBSJAWIA-KRWDZBQOSA-N (2s)-2-acetamido-3-(4-phenylmethoxyphenyl)propanoic acid Chemical compound C1=CC(C[C@H](NC(=O)C)C(O)=O)=CC=C1OCC1=CC=CC=C1 VCXXRMRBSJAWIA-KRWDZBQOSA-N 0.000 description 1
- NPDBDJFLKKQMCM-SCSAIBSYSA-N (2s)-2-amino-3,3-dimethylbutanoic acid Chemical compound CC(C)(C)[C@H](N)C(O)=O NPDBDJFLKKQMCM-SCSAIBSYSA-N 0.000 description 1
- FVNKWWBXNSNIAR-BYPYZUCNSA-N (2s)-2-amino-3-(2-sulfanylidene-1,3-dihydroimidazol-4-yl)propanoic acid Chemical compound OC(=O)[C@@H](N)CC1=CNC(=S)N1 FVNKWWBXNSNIAR-BYPYZUCNSA-N 0.000 description 1
- POGSZHUEECCEAP-ZETCQYMHSA-N (2s)-2-amino-3-(3-amino-4-hydroxyphenyl)propanoic acid Chemical compound OC(=O)[C@@H](N)CC1=CC=C(O)C(N)=C1 POGSZHUEECCEAP-ZETCQYMHSA-N 0.000 description 1
- NSEFEMVEUDJWIH-LURJTMIESA-N (2s)-2-amino-3-(4-hydroxy-3-phosphonophenyl)propanoic acid Chemical compound OC(=O)[C@@H](N)CC1=CC=C(O)C(P(O)(O)=O)=C1 NSEFEMVEUDJWIH-LURJTMIESA-N 0.000 description 1
- VXGXODOSTOUUBH-LURJTMIESA-N (2s)-2-amino-3-(4-hydroxy-3-sulfophenyl)propanoic acid Chemical compound OC(=O)[C@@H](N)CC1=CC=C(O)C(S(O)(=O)=O)=C1 VXGXODOSTOUUBH-LURJTMIESA-N 0.000 description 1
- NXANGIZFHQQBCC-VIFPVBQESA-N (2s)-2-amino-3-(6-hydroxy-1h-indol-3-yl)propanoic acid Chemical compound OC1=CC=C2C(C[C@H](N)C(O)=O)=CNC2=C1 NXANGIZFHQQBCC-VIFPVBQESA-N 0.000 description 1
- RXZQHZDTHUUJQJ-LURJTMIESA-N (2s)-2-amino-3-(furan-2-yl)propanoic acid Chemical compound OC(=O)[C@@H](N)CC1=CC=CO1 RXZQHZDTHUUJQJ-LURJTMIESA-N 0.000 description 1
- BURBNIPKSRJAIQ-QMMMGPOBSA-N (2s)-2-amino-3-[3-(trifluoromethyl)phenyl]propanoic acid Chemical compound OC(=O)[C@@H](N)CC1=CC=CC(C(F)(F)F)=C1 BURBNIPKSRJAIQ-QMMMGPOBSA-N 0.000 description 1
- CRFFPDBJLGAGQL-QMMMGPOBSA-N (2s)-2-amino-3-[4-(trifluoromethyl)phenyl]propanoic acid Chemical compound OC(=O)[C@@H](N)CC1=CC=C(C(F)(F)F)C=C1 CRFFPDBJLGAGQL-QMMMGPOBSA-N 0.000 description 1
- PXFXXRSFSGRBRT-BYPYZUCNSA-N (2s)-2-azaniumyl-3-(1,3-thiazol-2-yl)propanoate Chemical compound OC(=O)[C@@H](N)CC1=NC=CS1 PXFXXRSFSGRBRT-BYPYZUCNSA-N 0.000 description 1
- VWTFNYVAFGYEKI-QMMMGPOBSA-N (2s)-2-azaniumyl-3-(3,4-dimethoxyphenyl)propanoate Chemical compound COC1=CC=C(C[C@H](N)C(O)=O)C=C1OC VWTFNYVAFGYEKI-QMMMGPOBSA-N 0.000 description 1
- OIXLLKLZKCBCPS-RZVRUWJTSA-N (2s)-2-azanyl-5-[bis(azanyl)methylideneamino]pentanoic acid Chemical compound OC(=O)[C@@H](N)CCCNC(N)=N.OC(=O)[C@@H](N)CCCNC(N)=N OIXLLKLZKCBCPS-RZVRUWJTSA-N 0.000 description 1
- LOVUSASSMLUWRR-REOHCLBHSA-N (2s)-2-hydrazinylpropanoic acid Chemical compound NN[C@@H](C)C(O)=O LOVUSASSMLUWRR-REOHCLBHSA-N 0.000 description 1
- VJSHIAIYIGMNRN-NSHDSACASA-N (2s)-3-(2-aminoanilino)-2-[(2-methylpropan-2-yl)oxycarbonylamino]propanoic acid Chemical compound CC(C)(C)OC(=O)N[C@H](C(O)=O)CNC1=CC=CC=C1N VJSHIAIYIGMNRN-NSHDSACASA-N 0.000 description 1
- ITYVCUQVLKIGEY-LWMBPPNESA-N (2s,3s)-2-azaniumyl-4,4,4-trifluoro-3-hydroxybutanoate Chemical compound [O-]C(=O)[C@@H]([NH3+])[C@H](O)C(F)(F)F ITYVCUQVLKIGEY-LWMBPPNESA-N 0.000 description 1
- BENKAPCDIOILGV-RQJHMYQMSA-N (2s,4r)-4-hydroxy-1-[(2-methylpropan-2-yl)oxycarbonyl]pyrrolidine-2-carboxylic acid Chemical compound CC(C)(C)OC(=O)N1C[C@H](O)C[C@H]1C(O)=O BENKAPCDIOILGV-RQJHMYQMSA-N 0.000 description 1
- PGIINKQYXGSXKY-BQBZGAKWSA-N (2s,4s)-4-hydroxy-1-[(2-methylpropan-2-yl)oxy]pyrrolidine-2-carboxylic acid Chemical compound CC(C)(C)ON1C[C@@H](O)C[C@H]1C(O)=O PGIINKQYXGSXKY-BQBZGAKWSA-N 0.000 description 1
- SJDGKHUHLHQUQW-JCNMPKRYSA-N (3r)-5-[(2,6-dichlorophenyl)methoxy]-3-[[(2s)-2-[[(2s)-3-methyl-2-(phenylmethoxycarbonylamino)butanoyl]amino]propanoyl]amino]-4-oxopentanoic acid Chemical compound N([C@@H](C(C)C)C(=O)N[C@@H](C)C(=O)N[C@H](CC(O)=O)C(=O)COCC=1C(=CC=CC=1Cl)Cl)C(=O)OCC1=CC=CC=C1 SJDGKHUHLHQUQW-JCNMPKRYSA-N 0.000 description 1
- OOKAZRDERJMRCJ-KOUAFAAESA-N (3r)-7-[(1s,2s,4ar,6s,8s)-2,6-dimethyl-8-[(2s)-2-methylbutanoyl]oxy-1,2,4a,5,6,7,8,8a-octahydronaphthalen-1-yl]-3-hydroxy-5-oxoheptanoic acid Chemical compound C1=C[C@H](C)[C@H](CCC(=O)C[C@@H](O)CC(O)=O)C2[C@@H](OC(=O)[C@@H](C)CC)C[C@@H](C)C[C@@H]21 OOKAZRDERJMRCJ-KOUAFAAESA-N 0.000 description 1
- HUWSZNZAROKDRZ-RRLWZMAJSA-N (3r,4r)-3-azaniumyl-5-[[(2s,3r)-1-[(2s)-2,3-dicarboxypyrrolidin-1-yl]-3-methyl-1-oxopentan-2-yl]amino]-5-oxo-4-sulfanylpentane-1-sulfonate Chemical compound OS(=O)(=O)CC[C@@H](N)[C@@H](S)C(=O)N[C@@H]([C@H](C)CC)C(=O)N1CCC(C(O)=O)[C@H]1C(O)=O HUWSZNZAROKDRZ-RRLWZMAJSA-N 0.000 description 1
- HFPVZPNLMJDJFB-LBPRGKRZSA-N (3s)-2-[(2-methylpropan-2-yl)oxycarbonyl]-3,4-dihydro-1h-isoquinoline-3-carboxylic acid Chemical compound C1=CC=C2C[C@@H](C(O)=O)N(C(=O)OC(C)(C)C)CC2=C1 HFPVZPNLMJDJFB-LBPRGKRZSA-N 0.000 description 1
- JESQBVJUABQVEZ-BPXKWBHBSA-N (3s)-4-(1,3-benzoxazol-2-yl)-3-[[(2s)-2-[[(2s)-3-methyl-2-(phenylmethoxycarbonylamino)butanoyl]amino]propanoyl]amino]-4-oxobutanoic acid Chemical compound N([C@@H](C(C)C)C(=O)N[C@@H](C)C(=O)N[C@@H](CC(O)=O)C(=O)C=1OC2=CC=CC=C2N=1)C(=O)OCC1=CC=CC=C1 JESQBVJUABQVEZ-BPXKWBHBSA-N 0.000 description 1
- SJHPCNCNNSSLPL-NTMALXAHSA-N (4z)-4-(ethoxymethylidene)-2-phenyl-1,3-oxazol-5-one Chemical compound O1C(=O)C(=C/OCC)/N=C1C1=CC=CC=C1 SJHPCNCNNSSLPL-NTMALXAHSA-N 0.000 description 1
- WRIDQFICGBMAFQ-UHFFFAOYSA-N (E)-8-Octadecenoic acid Natural products CCCCCCCCCC=CCCCCCCC(O)=O WRIDQFICGBMAFQ-UHFFFAOYSA-N 0.000 description 1
- DNXZGSAWQFFROP-UHFFFAOYSA-N (tert-butylamino)urea Chemical compound CC(C)(C)NNC(N)=O DNXZGSAWQFFROP-UHFFFAOYSA-N 0.000 description 1
- UKAUYVFTDYCKQA-UHFFFAOYSA-N -2-Amino-4-hydroxybutanoic acid Natural products OC(=O)C(N)CCO UKAUYVFTDYCKQA-UHFFFAOYSA-N 0.000 description 1
- NYPYHUZRZVSYKL-UHFFFAOYSA-N -3,5-Diiodotyrosine Natural products OC(=O)C(N)CC1=CC(I)=C(O)C(I)=C1 NYPYHUZRZVSYKL-UHFFFAOYSA-N 0.000 description 1
- MGQPBXGHGXFKJW-UHFFFAOYSA-N 1,3-benzoxazol-4-ol Chemical compound OC1=CC=CC2=C1N=CO2 MGQPBXGHGXFKJW-UHFFFAOYSA-N 0.000 description 1
- YXUHAYXVTIKGTJ-UHFFFAOYSA-N 1,3-dichloro-2-(iodomethyl)benzene Chemical compound ClC1=CC=CC(Cl)=C1CI YXUHAYXVTIKGTJ-UHFFFAOYSA-N 0.000 description 1
- WOXWUZCRWJWTRT-UHFFFAOYSA-N 1-amino-1-cyclohexanecarboxylic acid Chemical compound OC(=O)C1(N)CCCCC1 WOXWUZCRWJWTRT-UHFFFAOYSA-N 0.000 description 1
- IINRZEIPFQHEAP-UHFFFAOYSA-N 1-aminocycloheptane-1-carboxylic acid Chemical compound OC(=O)C1(N)CCCCCC1 IINRZEIPFQHEAP-UHFFFAOYSA-N 0.000 description 1
- VUQPJRPDRDVQMN-UHFFFAOYSA-N 1-chlorooctadecane Chemical class CCCCCCCCCCCCCCCCCCCl VUQPJRPDRDVQMN-UHFFFAOYSA-N 0.000 description 1
- PWKNBLFSJAVFAB-UHFFFAOYSA-N 1-fluoro-2-nitrobenzene Chemical compound [O-][N+](=O)C1=CC=CC=C1F PWKNBLFSJAVFAB-UHFFFAOYSA-N 0.000 description 1
- ZMIIQXLXWATXIB-UHFFFAOYSA-N 1-n',6-n'-bis(4-methoxybenzoyl)hexanedihydrazide Chemical compound C1=CC(OC)=CC=C1C(=O)NNC(=O)CCCCC(=O)NNC(=O)C1=CC=C(OC)C=C1 ZMIIQXLXWATXIB-UHFFFAOYSA-N 0.000 description 1
- IIZPXYDJLKNOIY-JXPKJXOSSA-N 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphocholine Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCC\C=C/C\C=C/C\C=C/C\C=C/CCCCC IIZPXYDJLKNOIY-JXPKJXOSSA-N 0.000 description 1
- 238000004293 19F NMR spectroscopy Methods 0.000 description 1
- NKWCGTOZTHZDHB-UHFFFAOYSA-N 1h-imidazol-1-ium-4-carboxylate Chemical compound OC(=O)C1=CNC=N1 NKWCGTOZTHZDHB-UHFFFAOYSA-N 0.000 description 1
- CHHHXKFHOYLYRE-UHFFFAOYSA-M 2,4-Hexadienoic acid, potassium salt (1:1), (2E,4E)- Chemical compound [K+].CC=CC=CC([O-])=O CHHHXKFHOYLYRE-UHFFFAOYSA-M 0.000 description 1
- OMGHIGVFLOPEHJ-UHFFFAOYSA-N 2,5-dihydro-1h-pyrrol-1-ium-2-carboxylate Chemical compound OC(=O)C1NCC=C1 OMGHIGVFLOPEHJ-UHFFFAOYSA-N 0.000 description 1
- QEBYEVQKHRUYPE-UHFFFAOYSA-N 2-(2-chlorophenyl)-5-[(1-methylpyrazol-3-yl)methyl]-4-[[methyl(pyridin-3-ylmethyl)amino]methyl]-1h-pyrazolo[4,3-c]pyridine-3,6-dione Chemical compound C1=CN(C)N=C1CN1C(=O)C=C2NN(C=3C(=CC=CC=3)Cl)C(=O)C2=C1CN(C)CC1=CC=CN=C1 QEBYEVQKHRUYPE-UHFFFAOYSA-N 0.000 description 1
- CQNXKTPKFVKCHG-UHFFFAOYSA-N 2-(7-methyl-4-oxo-5h-pyrrolo[3,2-d]pyrimidin-3-yl)-n-(5-oxo-2-phenylmethoxyoxolan-3-yl)acetamide Chemical compound CC1=CNC(C2=O)=C1N=CN2CC(=O)NC1CC(=O)OC1OCC1=CC=CC=C1 CQNXKTPKFVKCHG-UHFFFAOYSA-N 0.000 description 1
- FNEJUNUMJKDLDH-UHFFFAOYSA-N 2-(7-methyl-4-oxo-5h-pyrrolo[3,2-d]pyrimidin-3-yl)acetic acid Chemical compound N1=CN(CC(O)=O)C(=O)C2=C1C(C)=CN2 FNEJUNUMJKDLDH-UHFFFAOYSA-N 0.000 description 1
- YKEQILJFMVLPPY-UHFFFAOYSA-N 2-[(2-methylpropan-2-yl)oxycarbonylamino]-3-(2-nitroanilino)propanoic acid Chemical compound CC(C)(C)OC(=O)NC(C(O)=O)CNC1=CC=CC=C1[N+]([O-])=O YKEQILJFMVLPPY-UHFFFAOYSA-N 0.000 description 1
- QTFKZUCIRARIAE-UHFFFAOYSA-N 2-[2-oxo-3-(3-phenylpropanoylamino)pyridin-1-yl]acetic acid Chemical compound O=C1N(CC(=O)O)C=CC=C1NC(=O)CCC1=CC=CC=C1 QTFKZUCIRARIAE-UHFFFAOYSA-N 0.000 description 1
- JKMHFZQWWAIEOD-UHFFFAOYSA-N 2-[4-(2-hydroxyethyl)piperazin-1-yl]ethanesulfonic acid Chemical compound OCC[NH+]1CCN(CCS([O-])(=O)=O)CC1 JKMHFZQWWAIEOD-UHFFFAOYSA-N 0.000 description 1
- FMKGJQHNYMWDFJ-CVEARBPZSA-N 2-[[4-(2,2-difluoropropoxy)pyrimidin-5-yl]methylamino]-4-[[(1R,4S)-4-hydroxy-3,3-dimethylcyclohexyl]amino]pyrimidine-5-carbonitrile Chemical compound FC(COC1=NC=NC=C1CNC1=NC=C(C(=N1)N[C@H]1CC([C@H](CC1)O)(C)C)C#N)(C)F FMKGJQHNYMWDFJ-CVEARBPZSA-N 0.000 description 1
- JTEOUQBVCOJKKT-UHFFFAOYSA-N 2-amino-2-methyl-5-oxopentanoic acid Chemical compound NC(C(=O)O)(CCC=O)C JTEOUQBVCOJKKT-UHFFFAOYSA-N 0.000 description 1
- YSUIQYOGTINQIN-UZFYAQMZSA-N 2-amino-9-[(1S,6R,8R,9S,10R,15R,17R,18R)-8-(6-aminopurin-9-yl)-9,18-difluoro-3,12-dihydroxy-3,12-bis(sulfanylidene)-2,4,7,11,13,16-hexaoxa-3lambda5,12lambda5-diphosphatricyclo[13.2.1.06,10]octadecan-17-yl]-1H-purin-6-one Chemical compound NC1=NC2=C(N=CN2[C@@H]2O[C@@H]3COP(S)(=O)O[C@@H]4[C@@H](COP(S)(=O)O[C@@H]2[C@@H]3F)O[C@H]([C@H]4F)N2C=NC3=C2N=CN=C3N)C(=O)N1 YSUIQYOGTINQIN-UZFYAQMZSA-N 0.000 description 1
- TVTJUIAKQFIXCE-HUKYDQBMSA-N 2-amino-9-[(2R,3S,4S,5R)-4-fluoro-3-hydroxy-5-(hydroxymethyl)oxolan-2-yl]-7-prop-2-ynyl-1H-purine-6,8-dione Chemical compound NC=1NC(C=2N(C(N(C=2N=1)[C@@H]1O[C@@H]([C@H]([C@H]1O)F)CO)=O)CC#C)=O TVTJUIAKQFIXCE-HUKYDQBMSA-N 0.000 description 1
- UBXUDSPYIGPGGP-UHFFFAOYSA-N 2-azaniumyl-2-phenylbutanoate Chemical compound CCC(N)(C(O)=O)C1=CC=CC=C1 UBXUDSPYIGPGGP-UHFFFAOYSA-N 0.000 description 1
- OFYAYGJCPXRNBL-UHFFFAOYSA-N 2-azaniumyl-3-naphthalen-1-ylpropanoate Chemical compound C1=CC=C2C(CC(N)C(O)=O)=CC=CC2=C1 OFYAYGJCPXRNBL-UHFFFAOYSA-N 0.000 description 1
- YVOOPGWEIRIUOX-UHFFFAOYSA-N 2-azanyl-3-sulfanyl-propanoic acid Chemical compound SCC(N)C(O)=O.SCC(N)C(O)=O YVOOPGWEIRIUOX-UHFFFAOYSA-N 0.000 description 1
- KXIYCFCVBMFSEH-UHFFFAOYSA-N 2-benzyl-1h-imidazole-5-carboxylic acid Chemical compound OC(=O)C1=CNC(CC=2C=CC=CC=2)=N1 KXIYCFCVBMFSEH-UHFFFAOYSA-N 0.000 description 1
- WRXFJKBQZVRPHI-UHFFFAOYSA-N 2-methoxy-6-nitrophenol Chemical compound COC1=CC=CC([N+]([O-])=O)=C1O WRXFJKBQZVRPHI-UHFFFAOYSA-N 0.000 description 1
- LEACJMVNYZDSKR-UHFFFAOYSA-N 2-octyldodecan-1-ol Chemical compound CCCCCCCCCCC(CO)CCCCCCCC LEACJMVNYZDSKR-UHFFFAOYSA-N 0.000 description 1
- LKFNLHZZPHHFEC-UHFFFAOYSA-N 2-phenylethanesulfonyl chloride Chemical compound ClS(=O)(=O)CCC1=CC=CC=C1 LKFNLHZZPHHFEC-UHFFFAOYSA-N 0.000 description 1
- WMPPDTMATNBGJN-UHFFFAOYSA-N 2-phenylethylbromide Chemical class BrCCC1=CC=CC=C1 WMPPDTMATNBGJN-UHFFFAOYSA-N 0.000 description 1
- 125000005975 2-phenylethyloxy group Chemical group 0.000 description 1
- LQJBNNIYVWPHFW-UHFFFAOYSA-N 20:1omega9c fatty acid Natural products CCCCCCCCCCC=CCCCCCCCC(O)=O LQJBNNIYVWPHFW-UHFFFAOYSA-N 0.000 description 1
- NYPYHUZRZVSYKL-ZETCQYMHSA-N 3,5-diiodo-L-tyrosine Chemical compound OC(=O)[C@@H](N)CC1=CC(I)=C(O)C(I)=C1 NYPYHUZRZVSYKL-ZETCQYMHSA-N 0.000 description 1
- VJSHIAIYIGMNRN-UHFFFAOYSA-N 3-(2-aminoanilino)-2-[(2-methylpropan-2-yl)oxycarbonylamino]propanoic acid Chemical compound CC(C)(C)OC(=O)NC(C(O)=O)CNC1=CC=CC=C1N VJSHIAIYIGMNRN-UHFFFAOYSA-N 0.000 description 1
- AZXBADPWXOWMKQ-UHFFFAOYSA-N 3-Carboxy-tyrosin Natural products OC(=O)C(N)CC1=CC=C(O)C(C(O)=O)=C1 AZXBADPWXOWMKQ-UHFFFAOYSA-N 0.000 description 1
- PFDUUKDQEHURQC-UHFFFAOYSA-N 3-Methoxytyrosine Chemical compound COC1=CC(CC(N)C(O)=O)=CC=C1O PFDUUKDQEHURQC-UHFFFAOYSA-N 0.000 description 1
- QBWKPGNFQQJGFY-QLFBSQMISA-N 3-[(1r)-1-[(2r,6s)-2,6-dimethylmorpholin-4-yl]ethyl]-n-[6-methyl-3-(1h-pyrazol-4-yl)imidazo[1,2-a]pyrazin-8-yl]-1,2-thiazol-5-amine Chemical compound N1([C@H](C)C2=NSC(NC=3C4=NC=C(N4C=C(C)N=3)C3=CNN=C3)=C2)C[C@H](C)O[C@H](C)C1 QBWKPGNFQQJGFY-QLFBSQMISA-N 0.000 description 1
- JUIJCASWWPFGDU-NTCVPXNASA-N 3-[[(2s)-1-[(2s)-2-[[(2s)-2-acetamido-3-(4-hydroxyphenyl)propanoyl]amino]-3-methylbutanoyl]-4-phenoxypyrrolidine-2-carbonyl]amino]-4-oxobutanoic acid Chemical compound C([C@@H](C(=O)N[C@@H](C(C)C)C(=O)N1[C@@H](CC(C1)OC=1C=CC=CC=1)C(=O)NC(CC(O)=O)C=O)NC(C)=O)C1=CC=C(O)C=C1 JUIJCASWWPFGDU-NTCVPXNASA-N 0.000 description 1
- KRJLRVZLNABMAT-UHFFFAOYSA-N 3-azaniumyl-2-[(2-methylpropan-2-yl)oxycarbonylamino]propanoate Chemical compound CC(C)(C)OC(=O)NC(CN)C(O)=O KRJLRVZLNABMAT-UHFFFAOYSA-N 0.000 description 1
- BXRLWGXPSRYJDZ-UHFFFAOYSA-N 3-cyanoalanine Chemical compound OC(=O)C(N)CC#N BXRLWGXPSRYJDZ-UHFFFAOYSA-N 0.000 description 1
- FBTSQILOGYXGMD-LURJTMIESA-N 3-nitro-L-tyrosine Chemical compound OC(=O)[C@@H](N)CC1=CC=C(O)C([N+]([O-])=O)=C1 FBTSQILOGYXGMD-LURJTMIESA-N 0.000 description 1
- YPXMNQUCQFBNRH-UHFFFAOYSA-N 4,5-dihydro-1h-imidazole-5-carboxylic acid Chemical compound OC(=O)C1CNC=N1 YPXMNQUCQFBNRH-UHFFFAOYSA-N 0.000 description 1
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 1
- MPMKMQHJHDHPBE-RUZDIDTESA-N 4-[[(2r)-1-(1-benzothiophene-3-carbonyl)-2-methylazetidine-2-carbonyl]-[(3-chlorophenyl)methyl]amino]butanoic acid Chemical compound O=C([C@@]1(N(CC1)C(=O)C=1C2=CC=CC=C2SC=1)C)N(CCCC(O)=O)CC1=CC=CC(Cl)=C1 MPMKMQHJHDHPBE-RUZDIDTESA-N 0.000 description 1
- CMUHFUGDYMFHEI-QMMMGPOBSA-N 4-amino-L-phenylalanine Chemical compound OC(=O)[C@@H](N)CC1=CC=C(N)C=C1 CMUHFUGDYMFHEI-QMMMGPOBSA-N 0.000 description 1
- 125000004199 4-trifluoromethylphenyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)C(F)(F)F 0.000 description 1
- BDQNHDQAKZXKTP-UHFFFAOYSA-N 5-(2,6-dichlorophenyl)-1,3-oxazole Chemical compound ClC1=CC=CC(Cl)=C1C1=CN=CO1 BDQNHDQAKZXKTP-UHFFFAOYSA-N 0.000 description 1
- YNGIGGINWYSNLW-UHFFFAOYSA-N 5-(iminomethylideneamino)-n,n-dimethylpentan-1-amine;hydrochloride Chemical compound Cl.CN(C)CCCCCN=C=N YNGIGGINWYSNLW-UHFFFAOYSA-N 0.000 description 1
- AZXBADPWXOWMKQ-ZETCQYMHSA-N 5-[(2s)-2-amino-2-carboxyethyl]-2-hydroxybenzoic acid Chemical compound OC(=O)[C@@H](N)CC1=CC=C(O)C(C(O)=O)=C1 AZXBADPWXOWMKQ-ZETCQYMHSA-N 0.000 description 1
- VKLKXFOZNHEBSW-UHFFFAOYSA-N 5-[[3-[(4-morpholin-4-ylbenzoyl)amino]phenyl]methoxy]pyridine-3-carboxamide Chemical compound O1CCN(CC1)C1=CC=C(C(=O)NC=2C=C(COC=3C=NC=C(C(=O)N)C=3)C=CC=2)C=C1 VKLKXFOZNHEBSW-UHFFFAOYSA-N 0.000 description 1
- LDCYZAJDBXYCGN-VIFPVBQESA-N 5-hydroxy-L-tryptophan Chemical compound C1=C(O)C=C2C(C[C@H](N)C(O)=O)=CNC2=C1 LDCYZAJDBXYCGN-VIFPVBQESA-N 0.000 description 1
- 229940000681 5-hydroxytryptophan Drugs 0.000 description 1
- RSIWALKZYXPAGW-NSHDSACASA-N 6-(3-fluorophenyl)-3-methyl-7-[(1s)-1-(7h-purin-6-ylamino)ethyl]-[1,3]thiazolo[3,2-a]pyrimidin-5-one Chemical compound C=1([C@@H](NC=2C=3N=CNC=3N=CN=2)C)N=C2SC=C(C)N2C(=O)C=1C1=CC=CC(F)=C1 RSIWALKZYXPAGW-NSHDSACASA-N 0.000 description 1
- QSHLMQDRPXXYEE-UHFFFAOYSA-N 6-Hydroxytryptophan Natural products C1=CC(O)=C2C(CC(N)C(O)=O)=CNC2=C1 QSHLMQDRPXXYEE-UHFFFAOYSA-N 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 description 1
- QSBYPNXLFMSGKH-UHFFFAOYSA-N 9-Heptadecensaeure Natural products CCCCCCCC=CCCCCCCCC(O)=O QSBYPNXLFMSGKH-UHFFFAOYSA-N 0.000 description 1
- 239000005541 ACE inhibitor Substances 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- 206010001052 Acute respiratory distress syndrome Diseases 0.000 description 1
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 1
- 239000004475 Arginine Substances 0.000 description 1
- 206010055128 Autoimmune neutropenia Diseases 0.000 description 1
- 208000023328 Basedow disease Diseases 0.000 description 1
- 102000004506 Blood Proteins Human genes 0.000 description 1
- 108010017384 Blood Proteins Proteins 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- COVZYZSDYWQREU-UHFFFAOYSA-N Busulfan Chemical compound CS(=O)(=O)OCCCCOS(C)(=O)=O COVZYZSDYWQREU-UHFFFAOYSA-N 0.000 description 1
- SXEDIRSYRALQMZ-UHFFFAOYSA-N C1(=CC=CC=C1)CCC#N.C1(=CC=CC=C1)CCC#N Chemical compound C1(=CC=CC=C1)CCC#N.C1(=CC=CC=C1)CCC#N SXEDIRSYRALQMZ-UHFFFAOYSA-N 0.000 description 1
- 206010008909 Chronic Hepatitis Diseases 0.000 description 1
- 102000029816 Collagenase Human genes 0.000 description 1
- 108060005980 Collagenase Proteins 0.000 description 1
- 108010005843 Cysteine Proteases Proteins 0.000 description 1
- 102000005927 Cysteine Proteases Human genes 0.000 description 1
- LJCWONGJFPCTTL-SSDOTTSWSA-N D-4-hydroxyphenylglycine Chemical compound [O-]C(=O)[C@H]([NH3+])C1=CC=C(O)C=C1 LJCWONGJFPCTTL-SSDOTTSWSA-N 0.000 description 1
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 1
- RBNPOMFGQQGHHO-UWTATZPHSA-M D-glycerate Chemical compound OC[C@@H](O)C([O-])=O RBNPOMFGQQGHHO-UWTATZPHSA-M 0.000 description 1
- NXANGIZFHQQBCC-UHFFFAOYSA-N DL-6-Hydroxy-tryptophan Natural products OC1=CC=C2C(CC(N)C(O)=O)=CNC2=C1 NXANGIZFHQQBCC-UHFFFAOYSA-N 0.000 description 1
- ASNFTDCKZKHJSW-UHFFFAOYSA-N DL-Quisqualic acid Natural products OC(=O)C(N)CN1OC(=O)NC1=O ASNFTDCKZKHJSW-UHFFFAOYSA-N 0.000 description 1
- 239000004150 EU approved colour Substances 0.000 description 1
- 229940122858 Elastase inhibitor Drugs 0.000 description 1
- 241000792859 Enema Species 0.000 description 1
- 230000005526 G1 to G0 transition Effects 0.000 description 1
- 108010017213 Granulocyte-Macrophage Colony-Stimulating Factor Proteins 0.000 description 1
- 102100039620 Granulocyte-macrophage colony-stimulating factor Human genes 0.000 description 1
- 208000015023 Graves' disease Diseases 0.000 description 1
- ZRALSGWEFCBTJO-UHFFFAOYSA-N Guanidine Chemical group NC(N)=N ZRALSGWEFCBTJO-UHFFFAOYSA-N 0.000 description 1
- 239000007995 HEPES buffer Substances 0.000 description 1
- 208000035186 Hemolytic Autoimmune Anemia Diseases 0.000 description 1
- 206010019755 Hepatitis chronic active Diseases 0.000 description 1
- 101000715398 Homo sapiens Caspase-1 Proteins 0.000 description 1
- 102000008100 Human Serum Albumin Human genes 0.000 description 1
- 108091006905 Human Serum Albumin Proteins 0.000 description 1
- LCWXJXMHJVIJFK-UHFFFAOYSA-N Hydroxylysine Natural products NCC(O)CC(N)CC(O)=O LCWXJXMHJVIJFK-UHFFFAOYSA-N 0.000 description 1
- PMMYEEVYMWASQN-DMTCNVIQSA-N Hydroxyproline Chemical compound O[C@H]1CN[C@H](C(O)=O)C1 PMMYEEVYMWASQN-DMTCNVIQSA-N 0.000 description 1
- 235000000177 Indigofera tinctoria Nutrition 0.000 description 1
- 102100020881 Interleukin-1 alpha Human genes 0.000 description 1
- 108010082786 Interleukin-1alpha Proteins 0.000 description 1
- 108010002350 Interleukin-2 Proteins 0.000 description 1
- 102000015696 Interleukins Human genes 0.000 description 1
- 108010063738 Interleukins Proteins 0.000 description 1
- 229930194542 Keto Natural products 0.000 description 1
- SNDPXSYFESPGGJ-BYPYZUCNSA-N L-2-aminopentanoic acid Chemical compound CCC[C@H](N)C(O)=O SNDPXSYFESPGGJ-BYPYZUCNSA-N 0.000 description 1
- QUOGESRFPZDMMT-UHFFFAOYSA-N L-Homoarginine Natural products OC(=O)C(N)CCCCNC(N)=N QUOGESRFPZDMMT-UHFFFAOYSA-N 0.000 description 1
- LOOZZTFGSTZNRX-VIFPVBQESA-N L-Homotyrosine Chemical compound OC(=O)[C@@H](N)CCC1=CC=C(O)C=C1 LOOZZTFGSTZNRX-VIFPVBQESA-N 0.000 description 1
- AHLPHDHHMVZTML-BYPYZUCNSA-N L-Ornithine Chemical compound NCCC[C@H](N)C(O)=O AHLPHDHHMVZTML-BYPYZUCNSA-N 0.000 description 1
- ZGUNAGUHMKGQNY-ZETCQYMHSA-N L-alpha-phenylglycine zwitterion Chemical compound OC(=O)[C@@H](N)C1=CC=CC=C1 ZGUNAGUHMKGQNY-ZETCQYMHSA-N 0.000 description 1
- ODKSFYDXXFIFQN-BYPYZUCNSA-P L-argininium(2+) Chemical compound NC(=[NH2+])NCCC[C@H]([NH3+])C(O)=O ODKSFYDXXFIFQN-BYPYZUCNSA-P 0.000 description 1
- RHGKLRLOHDJJDR-BYPYZUCNSA-N L-citrulline Chemical compound NC(=O)NCCC[C@H]([NH3+])C([O-])=O RHGKLRLOHDJJDR-BYPYZUCNSA-N 0.000 description 1
- 229930182816 L-glutamine Natural products 0.000 description 1
- QUOGESRFPZDMMT-YFKPBYRVSA-N L-homoarginine Chemical compound OC(=O)[C@@H](N)CCCCNC(N)=N QUOGESRFPZDMMT-YFKPBYRVSA-N 0.000 description 1
- FFFHZYDWPBMWHY-VKHMYHEASA-N L-homocysteine Chemical class OC(=O)[C@@H](N)CCS FFFHZYDWPBMWHY-VKHMYHEASA-N 0.000 description 1
- JTTHKOPSMAVJFE-VIFPVBQESA-N L-homophenylalanine Chemical compound OC(=O)[C@@H](N)CCC1=CC=CC=C1 JTTHKOPSMAVJFE-VIFPVBQESA-N 0.000 description 1
- UKAUYVFTDYCKQA-VKHMYHEASA-N L-homoserine Chemical compound OC(=O)[C@@H](N)CCO UKAUYVFTDYCKQA-VKHMYHEASA-N 0.000 description 1
- UCUNFLYVYCGDHP-BYPYZUCNSA-N L-methionine sulfone Chemical compound CS(=O)(=O)CC[C@H](N)C(O)=O UCUNFLYVYCGDHP-BYPYZUCNSA-N 0.000 description 1
- SNDPXSYFESPGGJ-UHFFFAOYSA-N L-norVal-OH Natural products CCCC(N)C(O)=O SNDPXSYFESPGGJ-UHFFFAOYSA-N 0.000 description 1
- DGYHPLMPMRKMPD-UHFFFAOYSA-N L-propargyl glycine Natural products OC(=O)C(N)CC#C DGYHPLMPMRKMPD-UHFFFAOYSA-N 0.000 description 1
- DZLNHFMRPBPULJ-VKHMYHEASA-N L-thioproline Chemical compound OC(=O)[C@@H]1CSCN1 DZLNHFMRPBPULJ-VKHMYHEASA-N 0.000 description 1
- KKCIOUWDFWQUBT-AWEZNQCLSA-N L-thyronine Chemical compound C1=CC(C[C@H](N)C(O)=O)=CC=C1OC1=CC=C(O)C=C1 KKCIOUWDFWQUBT-AWEZNQCLSA-N 0.000 description 1
- 239000000867 Lipoxygenase Inhibitor Substances 0.000 description 1
- 229930195725 Mannitol Natural products 0.000 description 1
- YFGBQHOOROIVKG-FKBYEOEOSA-N Met-enkephalin Chemical compound C([C@@H](C(=O)N[C@@H](CCSC)C(O)=O)NC(=O)CNC(=O)CNC(=O)[C@@H](N)CC=1C=CC(O)=CC=1)C1=CC=CC=C1 YFGBQHOOROIVKG-FKBYEOEOSA-N 0.000 description 1
- 108010042237 Methionine Enkephalin Proteins 0.000 description 1
- 101000715411 Mus musculus Caspase-1 Proteins 0.000 description 1
- 125000003047 N-acetyl group Chemical group 0.000 description 1
- RHGKLRLOHDJJDR-UHFFFAOYSA-N Ndelta-carbamoyl-DL-ornithine Natural products OC(=O)C(N)CCCNC(N)=O RHGKLRLOHDJJDR-UHFFFAOYSA-N 0.000 description 1
- 206010028980 Neoplasm Diseases 0.000 description 1
- CIQHWLTYGMYQQR-QMMMGPOBSA-N O(4')-sulfo-L-tyrosine Chemical compound OC(=O)[C@@H](N)CC1=CC=C(OS(O)(=O)=O)C=C1 CIQHWLTYGMYQQR-QMMMGPOBSA-N 0.000 description 1
- 239000005642 Oleic acid Substances 0.000 description 1
- ZQPPMHVWECSIRJ-UHFFFAOYSA-N Oleic acid Natural products CCCCCCCCC=CCCCCCCCC(O)=O ZQPPMHVWECSIRJ-UHFFFAOYSA-N 0.000 description 1
- AHLPHDHHMVZTML-UHFFFAOYSA-N Orn-delta-NH2 Natural products NCCCC(N)C(O)=O AHLPHDHHMVZTML-UHFFFAOYSA-N 0.000 description 1
- UTJLXEIPEHZYQJ-UHFFFAOYSA-N Ornithine Natural products OC(=O)C(C)CCCN UTJLXEIPEHZYQJ-UHFFFAOYSA-N 0.000 description 1
- ZCQWOFVYLHDMMC-UHFFFAOYSA-N Oxazole Chemical compound C1=COC=N1 ZCQWOFVYLHDMMC-UHFFFAOYSA-N 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- 229910002666 PdCl2 Inorganic materials 0.000 description 1
- 229930182555 Penicillin Natural products 0.000 description 1
- JGSARLDLIJGVTE-MBNYWOFBSA-N Penicillin G Chemical compound N([C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)C(=O)CC1=CC=CC=C1 JGSARLDLIJGVTE-MBNYWOFBSA-N 0.000 description 1
- 102000015439 Phospholipases Human genes 0.000 description 1
- 108010064785 Phospholipases Proteins 0.000 description 1
- 208000013544 Platelet disease Diseases 0.000 description 1
- 229920001214 Polysorbate 60 Polymers 0.000 description 1
- 102000007327 Protamines Human genes 0.000 description 1
- 108010007568 Protamines Proteins 0.000 description 1
- 239000012979 RPMI medium Substances 0.000 description 1
- 101000983552 Rattus norvegicus Caspase-1 Proteins 0.000 description 1
- 208000013616 Respiratory Distress Syndrome Diseases 0.000 description 1
- 206010039710 Scleroderma Diseases 0.000 description 1
- 208000034189 Sclerosis Diseases 0.000 description 1
- 206010053879 Sepsis syndrome Diseases 0.000 description 1
- 206010040070 Septic Shock Diseases 0.000 description 1
- XUIMIQQOPSSXEZ-UHFFFAOYSA-N Silicon Chemical compound [Si] XUIMIQQOPSSXEZ-UHFFFAOYSA-N 0.000 description 1
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 description 1
- HVUMOYIDDBPOLL-XWVZOOPGSA-N Sorbitan monostearate Chemical compound CCCCCCCCCCCCCCCCCC(=O)OC[C@@H](O)[C@H]1OC[C@H](O)[C@H]1O HVUMOYIDDBPOLL-XWVZOOPGSA-N 0.000 description 1
- 229910000831 Steel Inorganic materials 0.000 description 1
- 206010051379 Systemic Inflammatory Response Syndrome Diseases 0.000 description 1
- FZWLAAWBMGSTSO-UHFFFAOYSA-N Thiazole Chemical compound C1=CSC=N1 FZWLAAWBMGSTSO-UHFFFAOYSA-N 0.000 description 1
- 206010043781 Thyroiditis chronic Diseases 0.000 description 1
- DTQVDTLACAAQTR-UHFFFAOYSA-M Trifluoroacetate Chemical compound [O-]C(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-M 0.000 description 1
- 108060008682 Tumor Necrosis Factor Proteins 0.000 description 1
- 102000000852 Tumor Necrosis Factor-alpha Human genes 0.000 description 1
- 206010067584 Type 1 diabetes mellitus Diseases 0.000 description 1
- LJOOWESTVASNOG-UFJKPHDISA-N [(1s,3r,4ar,7s,8s,8as)-3-hydroxy-8-[2-[(4r)-4-hydroxy-6-oxooxan-2-yl]ethyl]-7-methyl-1,2,3,4,4a,7,8,8a-octahydronaphthalen-1-yl] (2s)-2-methylbutanoate Chemical compound C([C@H]1[C@@H](C)C=C[C@H]2C[C@@H](O)C[C@@H]([C@H]12)OC(=O)[C@@H](C)CC)CC1C[C@@H](O)CC(=O)O1 LJOOWESTVASNOG-UFJKPHDISA-N 0.000 description 1
- 229940124532 absorption promoter Drugs 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 description 1
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 1
- 125000005073 adamantyl group Chemical group C12(CC3CC(CC(C1)C3)C2)* 0.000 description 1
- 208000011341 adult acute respiratory distress syndrome Diseases 0.000 description 1
- 201000000028 adult respiratory distress syndrome Diseases 0.000 description 1
- 238000001042 affinity chromatography Methods 0.000 description 1
- 239000000556 agonist Substances 0.000 description 1
- 125000003295 alanine group Chemical group N[C@@H](C)C(=O)* 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 125000003172 aldehyde group Chemical group 0.000 description 1
- QBYJBZPUGVGKQQ-SJJAEHHWSA-N aldrin Chemical compound C1[C@H]2C=C[C@@H]1[C@H]1[C@@](C3(Cl)Cl)(Cl)C(Cl)=C(Cl)[C@@]3(Cl)[C@H]12 QBYJBZPUGVGKQQ-SJJAEHHWSA-N 0.000 description 1
- 150000001335 aliphatic alkanes Chemical class 0.000 description 1
- 229910052783 alkali metal Inorganic materials 0.000 description 1
- 229910052784 alkaline earth metal Inorganic materials 0.000 description 1
- 150000001336 alkenes Chemical class 0.000 description 1
- 150000001345 alkine derivatives Chemical class 0.000 description 1
- 150000001350 alkyl halides Chemical class 0.000 description 1
- BHELZAPQIKSEDF-UHFFFAOYSA-N allyl bromide Chemical compound BrCC=C BHELZAPQIKSEDF-UHFFFAOYSA-N 0.000 description 1
- QWCKQJZIFLGMSD-UHFFFAOYSA-N alpha-aminobutyric acid Chemical compound CCC(N)C(O)=O QWCKQJZIFLGMSD-UHFFFAOYSA-N 0.000 description 1
- CEGOLXSVJUTHNZ-UHFFFAOYSA-K aluminium tristearate Chemical compound [Al+3].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O CEGOLXSVJUTHNZ-UHFFFAOYSA-K 0.000 description 1
- 229940024548 aluminum oxide Drugs 0.000 description 1
- 229940063655 aluminum stearate Drugs 0.000 description 1
- 239000000908 ammonium hydroxide Substances 0.000 description 1
- 150000003863 ammonium salts Chemical class 0.000 description 1
- 206010002026 amyotrophic lateral sclerosis Diseases 0.000 description 1
- 239000005557 antagonist Substances 0.000 description 1
- 239000003242 anti bacterial agent Substances 0.000 description 1
- 229940088710 antibiotic agent Drugs 0.000 description 1
- ODKSFYDXXFIFQN-UHFFFAOYSA-N arginine Natural products OC(=O)C(N)CCCNC(N)=N ODKSFYDXXFIFQN-UHFFFAOYSA-N 0.000 description 1
- 125000000637 arginyl group Chemical group N[C@@H](CCCNC(N)=N)C(=O)* 0.000 description 1
- 229910052786 argon Inorganic materials 0.000 description 1
- 206010003246 arthritis Diseases 0.000 description 1
- 239000012298 atmosphere Substances 0.000 description 1
- 201000005000 autoimmune gastritis Diseases 0.000 description 1
- 201000000448 autoimmune hemolytic anemia Diseases 0.000 description 1
- ZSIQJIWKELUFRJ-UHFFFAOYSA-N azepane Chemical compound C1CCCNCC1 ZSIQJIWKELUFRJ-UHFFFAOYSA-N 0.000 description 1
- 125000002785 azepinyl group Chemical group 0.000 description 1
- 210000003651 basophil Anatomy 0.000 description 1
- 230000003796 beauty Effects 0.000 description 1
- 235000013871 bee wax Nutrition 0.000 description 1
- 239000012166 beeswax Substances 0.000 description 1
- 230000008901 benefit Effects 0.000 description 1
- 150000008107 benzenesulfonic acids Chemical class 0.000 description 1
- 125000003785 benzimidazolyl group Chemical group N1=C(NC2=C1C=CC=C2)* 0.000 description 1
- 125000002047 benzodioxolyl group Chemical group O1OC(C2=C1C=CC=C2)* 0.000 description 1
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid group Chemical group C(C1=CC=CC=C1)(=O)O WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 1
- AGEZXYOZHKGVCM-UHFFFAOYSA-N benzyl bromide Chemical compound BrCC1=CC=CC=C1 AGEZXYOZHKGVCM-UHFFFAOYSA-N 0.000 description 1
- 230000003851 biochemical process Effects 0.000 description 1
- 239000004305 biphenyl Substances 0.000 description 1
- 235000010290 biphenyl Nutrition 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- 229910052794 bromium Inorganic materials 0.000 description 1
- 150000001649 bromium compounds Chemical class 0.000 description 1
- 230000005587 bubbling Effects 0.000 description 1
- 244000309464 bull Species 0.000 description 1
- 235000019437 butane-1,3-diol Nutrition 0.000 description 1
- FAOSYNUKPVJLNZ-UHFFFAOYSA-N butylstannane Chemical compound CCCC[SnH3] FAOSYNUKPVJLNZ-UHFFFAOYSA-N 0.000 description 1
- 210000004900 c-terminal fragment Anatomy 0.000 description 1
- 229910000019 calcium carbonate Inorganic materials 0.000 description 1
- 229910002091 carbon monoxide Inorganic materials 0.000 description 1
- 239000001768 carboxy methyl cellulose Substances 0.000 description 1
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 1
- 125000002843 carboxylic acid group Chemical group 0.000 description 1
- 239000004359 castor oil Substances 0.000 description 1
- 235000019438 castor oil Nutrition 0.000 description 1
- 239000006143 cell culture medium Substances 0.000 description 1
- 210000000170 cell membrane Anatomy 0.000 description 1
- 210000003850 cellular structure Anatomy 0.000 description 1
- 239000001913 cellulose Substances 0.000 description 1
- 229920002678 cellulose Polymers 0.000 description 1
- 235000010980 cellulose Nutrition 0.000 description 1
- 210000003169 central nervous system Anatomy 0.000 description 1
- 229940081733 cetearyl alcohol Drugs 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 239000003610 charcoal Substances 0.000 description 1
- 210000001612 chondrocyte Anatomy 0.000 description 1
- 238000011097 chromatography purification Methods 0.000 description 1
- 235000013477 citrulline Nutrition 0.000 description 1
- 229960002173 citrulline Drugs 0.000 description 1
- 229940110456 cocoa butter Drugs 0.000 description 1
- 235000019868 cocoa butter Nutrition 0.000 description 1
- 239000008119 colloidal silica Substances 0.000 description 1
- 238000004891 communication Methods 0.000 description 1
- 230000002860 competitive effect Effects 0.000 description 1
- 229940125846 compound 25 Drugs 0.000 description 1
- 229940125851 compound 27 Drugs 0.000 description 1
- 229940127204 compound 29 Drugs 0.000 description 1
- 229940126214 compound 3 Drugs 0.000 description 1
- 229940127113 compound 57 Drugs 0.000 description 1
- 238000005094 computer simulation Methods 0.000 description 1
- 239000012228 culture supernatant Substances 0.000 description 1
- 150000001924 cycloalkanes Chemical class 0.000 description 1
- 150000001925 cycloalkenes Chemical class 0.000 description 1
- 150000001944 cysteine derivatives Chemical class 0.000 description 1
- 230000016396 cytokine production Effects 0.000 description 1
- 230000001086 cytosolic effect Effects 0.000 description 1
- 125000002704 decyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- YSMODUONRAFBET-UHFFFAOYSA-N delta-DL-hydroxylysine Natural products NCC(O)CCC(N)C(O)=O YSMODUONRAFBET-UHFFFAOYSA-N 0.000 description 1
- 238000001212 derivatisation Methods 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 150000008050 dialkyl sulfates Chemical class 0.000 description 1
- QRKPPWPLSQRGSU-UHFFFAOYSA-N diazepine-1-carboxylic acid Chemical compound OC(=O)N1C=CC=CC=N1 QRKPPWPLSQRGSU-UHFFFAOYSA-N 0.000 description 1
- ZJULYDCRWUEPTK-UHFFFAOYSA-N dichloromethyl Chemical compound Cl[CH]Cl ZJULYDCRWUEPTK-UHFFFAOYSA-N 0.000 description 1
- YNHIGQDRGKUECZ-UHFFFAOYSA-N dichloropalladium;triphenylphosphanium Chemical compound Cl[Pd]Cl.C1=CC=CC=C1[PH+](C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1[PH+](C=1C=CC=CC=1)C1=CC=CC=C1 YNHIGQDRGKUECZ-UHFFFAOYSA-N 0.000 description 1
- 229940116901 diethyldithiocarbamate Drugs 0.000 description 1
- LMBWSYZSUOEYSN-UHFFFAOYSA-N diethyldithiocarbamic acid Chemical compound CCN(CC)C(S)=S LMBWSYZSUOEYSN-UHFFFAOYSA-N 0.000 description 1
- 230000004069 differentiation Effects 0.000 description 1
- UAOMVDZJSHZZME-UHFFFAOYSA-N diisopropylamine Chemical compound CC(C)NC(C)C UAOMVDZJSHZZME-UHFFFAOYSA-N 0.000 description 1
- GXGAKHNRMVGRPK-UHFFFAOYSA-N dimagnesium;dioxido-bis[[oxido(oxo)silyl]oxy]silane Chemical compound [Mg+2].[Mg+2].[O-][Si](=O)O[Si]([O-])([O-])O[Si]([O-])=O GXGAKHNRMVGRPK-UHFFFAOYSA-N 0.000 description 1
- 125000000118 dimethyl group Chemical group [H]C([H])([H])* 0.000 description 1
- GAFRWLVTHPVQGK-UHFFFAOYSA-N dipentyl sulfate Chemical class CCCCCOS(=O)(=O)OCCCCC GAFRWLVTHPVQGK-UHFFFAOYSA-N 0.000 description 1
- ZPWVASYFFYYZEW-UHFFFAOYSA-L dipotassium hydrogen phosphate Chemical compound [K+].[K+].OP([O-])([O-])=O ZPWVASYFFYYZEW-UHFFFAOYSA-L 0.000 description 1
- 229910000396 dipotassium phosphate Inorganic materials 0.000 description 1
- 235000019797 dipotassium phosphate Nutrition 0.000 description 1
- BNIILDVGGAEEIG-UHFFFAOYSA-L disodium hydrogen phosphate Chemical compound [Na+].[Na+].OP([O-])([O-])=O BNIILDVGGAEEIG-UHFFFAOYSA-L 0.000 description 1
- PMMYEEVYMWASQN-UHFFFAOYSA-N dl-hydroxyproline Natural products OC1C[NH2+]C(C([O-])=O)C1 PMMYEEVYMWASQN-UHFFFAOYSA-N 0.000 description 1
- 125000003438 dodecyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 238000007876 drug discovery Methods 0.000 description 1
- 239000003602 elastase inhibitor Substances 0.000 description 1
- 239000003792 electrolyte Substances 0.000 description 1
- 239000003995 emulsifying agent Substances 0.000 description 1
- 230000001804 emulsifying effect Effects 0.000 description 1
- 239000008387 emulsifying waxe Substances 0.000 description 1
- 239000007920 enema Substances 0.000 description 1
- 229940095399 enema Drugs 0.000 description 1
- 238000007824 enzymatic assay Methods 0.000 description 1
- 239000002532 enzyme inhibitor Substances 0.000 description 1
- 229940125532 enzyme inhibitor Drugs 0.000 description 1
- 210000003979 eosinophil Anatomy 0.000 description 1
- YSMODUONRAFBET-UHNVWZDZSA-N erythro-5-hydroxy-L-lysine Chemical compound NC[C@H](O)CC[C@H](N)C(O)=O YSMODUONRAFBET-UHNVWZDZSA-N 0.000 description 1
- BEFDCLMNVWHSGT-UHFFFAOYSA-N ethenylcyclopentane Chemical compound C=CC1CCCC1 BEFDCLMNVWHSGT-UHFFFAOYSA-N 0.000 description 1
- SRCZQMGIVIYBBJ-UHFFFAOYSA-N ethoxyethane;ethyl acetate Chemical compound CCOCC.CCOC(C)=O SRCZQMGIVIYBBJ-UHFFFAOYSA-N 0.000 description 1
- FJRFJRJUYZVNFL-UHFFFAOYSA-N ethyl 3-benzamido-4-oxo-7,8-dihydro-6h-pyrrolo[1,2-a]pyrimidine-6-carboxylate Chemical compound O=C1N2C(C(=O)OCC)CCC2=NC=C1NC(=O)C1=CC=CC=C1 FJRFJRJUYZVNFL-UHFFFAOYSA-N 0.000 description 1
- ULVSKULWTASVGS-UHFFFAOYSA-N ethyl 5-benzyl-1h-pyrrole-2-carboxylate Chemical compound N1C(C(=O)OCC)=CC=C1CC1=CC=CC=C1 ULVSKULWTASVGS-UHFFFAOYSA-N 0.000 description 1
- OAYLNYINCPYISS-UHFFFAOYSA-N ethyl acetate;hexane Chemical compound CCCCCC.CCOC(C)=O OAYLNYINCPYISS-UHFFFAOYSA-N 0.000 description 1
- 230000005284 excitation Effects 0.000 description 1
- 230000029142 excretion Effects 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 210000002950 fibroblast Anatomy 0.000 description 1
- 239000000796 flavoring agent Substances 0.000 description 1
- 238000002795 fluorescence method Methods 0.000 description 1
- 239000007850 fluorescent dye Substances 0.000 description 1
- 238000007478 fluorogenic assay Methods 0.000 description 1
- 235000019253 formic acid Nutrition 0.000 description 1
- 239000012634 fragment Substances 0.000 description 1
- 125000002541 furyl group Chemical group 0.000 description 1
- UHBYWPGGCSDKFX-VKHMYHEASA-N gamma-carboxy-L-glutamic acid Chemical compound OC(=O)[C@@H](N)CC(C(O)=O)C(O)=O UHBYWPGGCSDKFX-VKHMYHEASA-N 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 210000001035 gastrointestinal tract Anatomy 0.000 description 1
- 125000000291 glutamic acid group Chemical group N[C@@H](CCC(O)=O)C(=O)* 0.000 description 1
- 125000005456 glyceride group Chemical group 0.000 description 1
- ZEMPKEQAKRGZGQ-XOQCFJPHSA-N glycerol triricinoleate Natural products CCCCCC[C@@H](O)CC=CCCCCCCCC(=O)OC[C@@H](COC(=O)CCCCCCCC=CC[C@@H](O)CCCCCC)OC(=O)CCCCCCCC=CC[C@H](O)CCCCCC ZEMPKEQAKRGZGQ-XOQCFJPHSA-N 0.000 description 1
- 150000004820 halides Chemical class 0.000 description 1
- 150000002391 heterocyclic compounds Chemical class 0.000 description 1
- 239000000833 heterodimer Substances 0.000 description 1
- UBHWBODXJBSFLH-UHFFFAOYSA-N hexadecan-1-ol;octadecan-1-ol Chemical compound CCCCCCCCCCCCCCCCO.CCCCCCCCCCCCCCCCCCO UBHWBODXJBSFLH-UHFFFAOYSA-N 0.000 description 1
- 125000005597 hydrazone group Chemical group 0.000 description 1
- 229930195733 hydrocarbon Natural products 0.000 description 1
- 150000002430 hydrocarbons Chemical class 0.000 description 1
- 238000005984 hydrogenation reaction Methods 0.000 description 1
- 238000007327 hydrogenolysis reaction Methods 0.000 description 1
- 230000003301 hydrolyzing effect Effects 0.000 description 1
- DCPMPXBYPZGNDC-UHFFFAOYSA-N hydron;methanediimine;chloride Chemical compound Cl.N=C=N DCPMPXBYPZGNDC-UHFFFAOYSA-N 0.000 description 1
- QJHBJHUKURJDLG-UHFFFAOYSA-N hydroxy-L-lysine Natural products NCCCCC(NO)C(O)=O QJHBJHUKURJDLG-UHFFFAOYSA-N 0.000 description 1
- 229960002591 hydroxyproline Drugs 0.000 description 1
- 125000002632 imidazolidinyl group Chemical group 0.000 description 1
- 125000002636 imidazolinyl group Chemical group 0.000 description 1
- 125000002883 imidazolyl group Chemical group 0.000 description 1
- 230000004957 immunoregulator effect Effects 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 229940097275 indigo Drugs 0.000 description 1
- COHYTHOBJLSHDF-UHFFFAOYSA-N indigo powder Natural products N1C2=CC=CC=C2C(=O)C1=C1C(=O)C2=CC=CC=C2N1 COHYTHOBJLSHDF-UHFFFAOYSA-N 0.000 description 1
- 125000003387 indolinyl group Chemical group N1(CCC2=CC=CC=C12)* 0.000 description 1
- 230000028709 inflammatory response Effects 0.000 description 1
- 238000001802 infusion Methods 0.000 description 1
- 230000000977 initiatory effect Effects 0.000 description 1
- 229940102223 injectable solution Drugs 0.000 description 1
- 229940102213 injectable suspension Drugs 0.000 description 1
- 229940047122 interleukins Drugs 0.000 description 1
- 238000007917 intracranial administration Methods 0.000 description 1
- 238000007918 intramuscular administration Methods 0.000 description 1
- 238000007919 intrasynovial administration Methods 0.000 description 1
- 238000007913 intrathecal administration Methods 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 150000004694 iodide salts Chemical class 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 1
- 150000002500 ions Chemical class 0.000 description 1
- QXJSBBXBKPUZAA-UHFFFAOYSA-N isooleic acid Natural products CCCCCCCC=CCCCCCCCCC(O)=O QXJSBBXBKPUZAA-UHFFFAOYSA-N 0.000 description 1
- 125000002183 isoquinolinyl group Chemical group C1(=NC=CC2=CC=CC=C12)* 0.000 description 1
- 125000000842 isoxazolyl group Chemical group 0.000 description 1
- 238000011031 large-scale manufacturing process Methods 0.000 description 1
- 239000000787 lecithin Substances 0.000 description 1
- 235000010445 lecithin Nutrition 0.000 description 1
- 229940067606 lecithin Drugs 0.000 description 1
- 125000005647 linker group Chemical group 0.000 description 1
- YNESATAKKCNGOF-UHFFFAOYSA-N lithium bis(trimethylsilyl)amide Chemical compound [Li+].C[Si](C)(C)[N-][Si](C)(C)C YNESATAKKCNGOF-UHFFFAOYSA-N 0.000 description 1
- BYTMFVAPIBULRS-UHFFFAOYSA-M lithium pyrimidine-4-carboxylate Chemical compound N1=CN=CC=C1C(=O)[O-].[Li+] BYTMFVAPIBULRS-UHFFFAOYSA-M 0.000 description 1
- 239000006210 lotion Substances 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 210000004324 lymphatic system Anatomy 0.000 description 1
- 210000004698 lymphocyte Anatomy 0.000 description 1
- 229920002521 macromolecule Polymers 0.000 description 1
- 159000000003 magnesium salts Chemical class 0.000 description 1
- 239000000391 magnesium silicate Substances 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- 229910000386 magnesium trisilicate Inorganic materials 0.000 description 1
- 229940099273 magnesium trisilicate Drugs 0.000 description 1
- 235000019793 magnesium trisilicate Nutrition 0.000 description 1
- JGZKUKYUQJUUNE-UHFFFAOYSA-L magnesium;ethoxyethane;dibromide Chemical compound [Mg+2].[Br-].[Br-].CCOCC JGZKUKYUQJUUNE-UHFFFAOYSA-L 0.000 description 1
- 239000000594 mannitol Substances 0.000 description 1
- 235000010355 mannitol Nutrition 0.000 description 1
- 239000003771 matrix metalloproteinase inhibitor Substances 0.000 description 1
- 229940121386 matrix metalloproteinase inhibitor Drugs 0.000 description 1
- 239000000155 melt Substances 0.000 description 1
- 230000002503 metabolic effect Effects 0.000 description 1
- 239000002207 metabolite Substances 0.000 description 1
- LVWZTYCIRDMTEY-UHFFFAOYSA-N metamizole Chemical compound O=C1C(N(CS(O)(=O)=O)C)=C(C)N(C)N1C1=CC=CC=C1 LVWZTYCIRDMTEY-UHFFFAOYSA-N 0.000 description 1
- FBBDOOHMGLLEGJ-UHFFFAOYSA-N methane;hydrochloride Chemical compound C.Cl FBBDOOHMGLLEGJ-UHFFFAOYSA-N 0.000 description 1
- UXRWDKQRYTZQQK-ZDZYZNPZSA-N methyl (2s)-1-[(2s)-2-[[(2s)-2-acetamido-3-(4-hydroxyphenyl)propanoyl]amino]-3-methylbutanoyl]-4-phenoxypyrrolidine-2-carboxylate Chemical compound C([C@@H](C(=O)N[C@H](C(=O)N1CC(C[C@H]1C(=O)OC)OC=1C=CC=CC=1)C(C)C)NC(C)=O)C1=CC=C(O)C=C1 UXRWDKQRYTZQQK-ZDZYZNPZSA-N 0.000 description 1
- DRULTGGYJWUCKF-GQNCZFCYSA-N methyl (2s)-4-phenoxypyrrolidine-2-carboxylate;hydrochloride Chemical compound Cl.C1N[C@H](C(=O)OC)CC1OC1=CC=CC=C1 DRULTGGYJWUCKF-GQNCZFCYSA-N 0.000 description 1
- GHCJABAEWJYBRI-RGMNGODLSA-N methyl (8s)-1,4-dithia-7-azaspiro[4.4]nonane-8-carboxylate;hydrobromide Chemical compound Br.C1N[C@H](C(=O)OC)CC21SCCS2 GHCJABAEWJYBRI-RGMNGODLSA-N 0.000 description 1
- WLXXVJOVQCQAMX-UHFFFAOYSA-N methyl 2,3-diaminopropanoate Chemical compound COC(=O)C(N)CN WLXXVJOVQCQAMX-UHFFFAOYSA-N 0.000 description 1
- AVTCVMQZWVXNJF-UHFFFAOYSA-N methyl 2-(3-amino-2-oxopyridin-1-yl)acetate Chemical compound COC(=O)CN1C=CC=C(N)C1=O AVTCVMQZWVXNJF-UHFFFAOYSA-N 0.000 description 1
- MDFCFFBDEZWXNZ-UHFFFAOYSA-N methyl 2-[2-oxo-3-(3-phenylpropanoylamino)pyridin-1-yl]acetate Chemical compound O=C1N(CC(=O)OC)C=CC=C1NC(=O)CCC1=CC=CC=C1 MDFCFFBDEZWXNZ-UHFFFAOYSA-N 0.000 description 1
- XDFHZKRRQSJJNL-UHFFFAOYSA-N methyl 2-[2-oxo-3-(phenylmethoxycarbonylamino)pyridin-1-yl]acetate Chemical compound O=C1N(CC(=O)OC)C=CC=C1NC(=O)OCC1=CC=CC=C1 XDFHZKRRQSJJNL-UHFFFAOYSA-N 0.000 description 1
- QAKAXFZPXFDSEI-UHFFFAOYSA-N methyl 2-[6-benzyl-2-oxo-3-(2-phenylethoxycarbonylamino)pyridin-1-yl]acetate Chemical compound C=1C=C(NC(=O)OCCC=2C=CC=CC=2)C(=O)N(CC(=O)OC)C=1CC1=CC=CC=C1 QAKAXFZPXFDSEI-UHFFFAOYSA-N 0.000 description 1
- ACIGHHFEFXFXIX-UHFFFAOYSA-N methyl 2-[6-benzyl-2-oxo-3-(4-phenylbutanoylamino)pyridin-1-yl]acetate Chemical compound C=1C=C(NC(=O)CCCC=2C=CC=CC=2)C(=O)N(CC(=O)OC)C=1CC1=CC=CC=C1 ACIGHHFEFXFXIX-UHFFFAOYSA-N 0.000 description 1
- 125000001570 methylene group Chemical group [H]C([H])([*:1])[*:2] 0.000 description 1
- 229940042472 mineral oil Drugs 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 238000003032 molecular docking Methods 0.000 description 1
- 238000000329 molecular dynamics simulation Methods 0.000 description 1
- 239000002808 molecular sieve Substances 0.000 description 1
- 125000002757 morpholinyl group Chemical group 0.000 description 1
- 201000006417 multiple sclerosis Diseases 0.000 description 1
- 206010028417 myasthenia gravis Diseases 0.000 description 1
- 125000001421 myristyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- DYGBNAYFDZEYBA-UHFFFAOYSA-N n-(cyclopropylmethyl)-2-[4-(4-methoxybenzoyl)piperidin-1-yl]-n-[(4-oxo-1,5,7,8-tetrahydropyrano[4,3-d]pyrimidin-2-yl)methyl]acetamide Chemical compound C1=CC(OC)=CC=C1C(=O)C1CCN(CC(=O)N(CC2CC2)CC=2NC(=O)C=3COCCC=3N=2)CC1 DYGBNAYFDZEYBA-UHFFFAOYSA-N 0.000 description 1
- UPSFMJHZUCSEHU-JYGUBCOQSA-N n-[(2s,3r,4r,5s,6r)-2-[(2r,3s,4r,5r,6s)-5-acetamido-4-hydroxy-2-(hydroxymethyl)-6-(4-methyl-2-oxochromen-7-yl)oxyoxan-3-yl]oxy-4,5-dihydroxy-6-(hydroxymethyl)oxan-3-yl]acetamide Chemical compound CC(=O)N[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@H]1O[C@H]1[C@H](O)[C@@H](NC(C)=O)[C@H](OC=2C=C3OC(=O)C=C(C)C3=CC=2)O[C@@H]1CO UPSFMJHZUCSEHU-JYGUBCOQSA-N 0.000 description 1
- CJPMSUUANYLPET-UHFFFAOYSA-N n-[3-[[5-cyclopropyl-2-(4-morpholin-4-ylanilino)pyrimidin-4-yl]amino]propyl]cyclobutanecarboxamide Chemical compound C1CCC1C(=O)NCCCNC(C(=CN=1)C2CC2)=NC=1NC(C=C1)=CC=C1N1CCOCC1 CJPMSUUANYLPET-UHFFFAOYSA-N 0.000 description 1
- DQCKKXVULJGBQN-XFWGSAIBSA-N naltrexone Chemical compound N1([C@@H]2CC3=CC=C(C=4O[C@@H]5[C@](C3=4)([C@]2(CCC5=O)O)CC1)O)CC1CC1 DQCKKXVULJGBQN-XFWGSAIBSA-N 0.000 description 1
- 229960003086 naltrexone Drugs 0.000 description 1
- 229940097496 nasal spray Drugs 0.000 description 1
- 239000007922 nasal spray Substances 0.000 description 1
- 230000001272 neurogenic effect Effects 0.000 description 1
- 210000000440 neutrophil Anatomy 0.000 description 1
- 231100000344 non-irritating Toxicity 0.000 description 1
- 125000002868 norbornyl group Chemical group C12(CCC(CC1)C2)* 0.000 description 1
- 150000007523 nucleic acids Chemical group 0.000 description 1
- 239000002674 ointment Substances 0.000 description 1
- ZQPPMHVWECSIRJ-KTKRTIGZSA-N oleic acid Chemical compound CCCCCCCC\C=C/CCCCCCCC(O)=O ZQPPMHVWECSIRJ-KTKRTIGZSA-N 0.000 description 1
- 239000004006 olive oil Substances 0.000 description 1
- 235000008390 olive oil Nutrition 0.000 description 1
- 229940006093 opthalmologic coloring agent diagnostic Drugs 0.000 description 1
- 239000006186 oral dosage form Substances 0.000 description 1
- 210000000056 organ Anatomy 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 229960003104 ornithine Drugs 0.000 description 1
- 150000002923 oximes Chemical class 0.000 description 1
- LDCYZAJDBXYCGN-UHFFFAOYSA-N oxitriptan Natural products C1=C(O)C=C2C(CC(N)C(O)=O)=CNC2=C1 LDCYZAJDBXYCGN-UHFFFAOYSA-N 0.000 description 1
- TWNQGVIAIRXVLR-UHFFFAOYSA-N oxo(oxoalumanyloxy)alumane Chemical compound O=[Al]O[Al]=O TWNQGVIAIRXVLR-UHFFFAOYSA-N 0.000 description 1
- 125000005476 oxopyrrolidinyl group Chemical group 0.000 description 1
- 230000020477 pH reduction Effects 0.000 description 1
- NXJCBFBQEVOTOW-UHFFFAOYSA-L palladium(2+);dihydroxide Chemical compound O[Pd]O NXJCBFBQEVOTOW-UHFFFAOYSA-L 0.000 description 1
- 239000012188 paraffin wax Substances 0.000 description 1
- 230000036961 partial effect Effects 0.000 description 1
- 230000008506 pathogenesis Effects 0.000 description 1
- 229940049954 penicillin Drugs 0.000 description 1
- 238000005897 peptide coupling reaction Methods 0.000 description 1
- 238000010647 peptide synthesis reaction Methods 0.000 description 1
- 230000035699 permeability Effects 0.000 description 1
- 235000019271 petrolatum Nutrition 0.000 description 1
- 239000003208 petroleum Substances 0.000 description 1
- FAQJJMHZNSSFSM-UHFFFAOYSA-N phenylglyoxylic acid Chemical compound OC(=O)C(=O)C1=CC=CC=C1 FAQJJMHZNSSFSM-UHFFFAOYSA-N 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 235000021317 phosphate Nutrition 0.000 description 1
- 150000003013 phosphoric acid derivatives Chemical class 0.000 description 1
- 230000001766 physiological effect Effects 0.000 description 1
- HXEACLLIILLPRG-UHFFFAOYSA-N pipecolic acid Chemical compound OC(=O)C1CCCCN1 HXEACLLIILLPRG-UHFFFAOYSA-N 0.000 description 1
- 125000003386 piperidinyl group Chemical group 0.000 description 1
- 229920000058 polyacrylate Polymers 0.000 description 1
- 229920000642 polymer Polymers 0.000 description 1
- 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 description 1
- 239000001818 polyoxyethylene sorbitan monostearate Substances 0.000 description 1
- 235000010989 polyoxyethylene sorbitan monostearate Nutrition 0.000 description 1
- 229920002503 polyoxyethylene-polyoxypropylene Polymers 0.000 description 1
- 229940113124 polysorbate 60 Drugs 0.000 description 1
- 229920000053 polysorbate 80 Polymers 0.000 description 1
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 1
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 1
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 1
- 235000015497 potassium bicarbonate Nutrition 0.000 description 1
- 229910000028 potassium bicarbonate Inorganic materials 0.000 description 1
- 239000011736 potassium bicarbonate Substances 0.000 description 1
- CHKVPAROMQMJNQ-UHFFFAOYSA-M potassium bisulfate Chemical compound [K+].OS([O-])(=O)=O CHKVPAROMQMJNQ-UHFFFAOYSA-M 0.000 description 1
- 229910000343 potassium bisulfate Inorganic materials 0.000 description 1
- NNFCIKHAZHQZJG-UHFFFAOYSA-N potassium cyanide Chemical compound [K+].N#[C-] NNFCIKHAZHQZJG-UHFFFAOYSA-N 0.000 description 1
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 description 1
- 239000004302 potassium sorbate Substances 0.000 description 1
- 235000010241 potassium sorbate Nutrition 0.000 description 1
- 229940069338 potassium sorbate Drugs 0.000 description 1
- 230000003389 potentiating effect Effects 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 238000012545 processing Methods 0.000 description 1
- 230000000770 proinflammatory effect Effects 0.000 description 1
- 230000035755 proliferation Effects 0.000 description 1
- 229950008679 protamine sulfate Drugs 0.000 description 1
- 230000012846 protein folding Effects 0.000 description 1
- 230000017854 proteolysis Effects 0.000 description 1
- 125000000561 purinyl group Chemical group N1=C(N=C2N=CNC2=C1)* 0.000 description 1
- 125000003373 pyrazinyl group Chemical group 0.000 description 1
- 125000003226 pyrazolyl group Chemical group 0.000 description 1
- UBQKCCHYAOITMY-UHFFFAOYSA-N pyridin-2-ol Chemical class OC1=CC=CC=N1 UBQKCCHYAOITMY-UHFFFAOYSA-N 0.000 description 1
- DOYOPBSXEIZLRE-UHFFFAOYSA-N pyrrole-3-carboxylic acid Natural products OC(=O)C=1C=CNC=1 DOYOPBSXEIZLRE-UHFFFAOYSA-N 0.000 description 1
- 125000000719 pyrrolidinyl group Chemical group 0.000 description 1
- 125000000168 pyrrolyl group Chemical group 0.000 description 1
- 230000005610 quantum mechanics Effects 0.000 description 1
- 125000002943 quinolinyl group Chemical group N1=C(C=CC2=CC=CC=C12)* 0.000 description 1
- 125000001567 quinoxalinyl group Chemical group N1=C(C=NC2=CC=CC=C12)* 0.000 description 1
- 229940100618 rectal suppository Drugs 0.000 description 1
- 239000006215 rectal suppository Substances 0.000 description 1
- 210000000664 rectum Anatomy 0.000 description 1
- 230000025915 regulation of apoptotic process Effects 0.000 description 1
- 230000020129 regulation of cell death Effects 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 239000011347 resin Substances 0.000 description 1
- 229920005989 resin Polymers 0.000 description 1
- 230000004044 response Effects 0.000 description 1
- 238000012552 review Methods 0.000 description 1
- 238000005070 sampling Methods 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 230000036303 septic shock Effects 0.000 description 1
- 210000002966 serum Anatomy 0.000 description 1
- 229910052710 silicon Inorganic materials 0.000 description 1
- 239000010703 silicon Substances 0.000 description 1
- 229910001923 silver oxide Inorganic materials 0.000 description 1
- 238000002922 simulated annealing Methods 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000001632 sodium acetate Substances 0.000 description 1
- 235000017281 sodium acetate Nutrition 0.000 description 1
- URGAHOPLAPQHLN-UHFFFAOYSA-N sodium aluminosilicate Chemical compound [Na+].[Al+3].[O-][Si]([O-])=O.[O-][Si]([O-])=O URGAHOPLAPQHLN-UHFFFAOYSA-N 0.000 description 1
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 description 1
- 229920001027 sodium carboxymethylcellulose Polymers 0.000 description 1
- BEOOHQFXGBMRKU-UHFFFAOYSA-N sodium cyanoborohydride Chemical compound [Na+].[B-]C#N BEOOHQFXGBMRKU-UHFFFAOYSA-N 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
- 230000003381 solubilizing effect Effects 0.000 description 1
- 239000004334 sorbic acid Substances 0.000 description 1
- 235000010199 sorbic acid Nutrition 0.000 description 1
- 229940075582 sorbic acid Drugs 0.000 description 1
- 239000001587 sorbitan monostearate Substances 0.000 description 1
- 235000011076 sorbitan monostearate Nutrition 0.000 description 1
- 229940035048 sorbitan monostearate Drugs 0.000 description 1
- 230000003595 spectral effect Effects 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 239000007921 spray Substances 0.000 description 1
- 230000000087 stabilizing effect Effects 0.000 description 1
- 239000010959 steel Substances 0.000 description 1
- 239000012258 stirred mixture Substances 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 210000001179 synovial fluid Anatomy 0.000 description 1
- 238000001308 synthesis method Methods 0.000 description 1
- 201000000596 systemic lupus erythematosus Diseases 0.000 description 1
- 230000008685 targeting Effects 0.000 description 1
- QDASFECSQYSVMK-UHFFFAOYSA-N tert-butyl 2-(2-phenylethylamino)acetate Chemical compound CC(C)(C)OC(=O)CNCCC1=CC=CC=C1 QDASFECSQYSVMK-UHFFFAOYSA-N 0.000 description 1
- WBTVBIDDRLMHQP-UHFFFAOYSA-N tert-butyl 3-amino-4-oxobutanoate Chemical compound CC(C)(C)OC(=O)CC(N)C=O WBTVBIDDRLMHQP-UHFFFAOYSA-N 0.000 description 1
- NETWMZIHMUWUMS-UHFFFAOYSA-N tert-butyl n-(4-oxo-1,2,3,5-tetrahydro-1,5-benzodiazepin-3-yl)carbamate Chemical compound N1C(=O)C(NC(=O)OC(C)(C)C)CNC2=CC=CC=C21 NETWMZIHMUWUMS-UHFFFAOYSA-N 0.000 description 1
- MHXBHWLGRWOABW-UHFFFAOYSA-N tetradecyl octadecanoate Chemical compound CCCCCCCCCCCCCCCCCC(=O)OCCCCCCCCCCCCCC MHXBHWLGRWOABW-UHFFFAOYSA-N 0.000 description 1
- 125000003718 tetrahydrofuranyl group Chemical group 0.000 description 1
- 125000003039 tetrahydroisoquinolinyl group Chemical group C1(NCCC2=CC=CC=C12)* 0.000 description 1
- 125000001412 tetrahydropyranyl group Chemical group 0.000 description 1
- 125000000147 tetrahydroquinolinyl group Chemical group N1(CCCC2=CC=CC=C12)* 0.000 description 1
- 125000003831 tetrazolyl group Chemical group 0.000 description 1
- 229940124597 therapeutic agent Drugs 0.000 description 1
- 125000001113 thiadiazolyl group Chemical group 0.000 description 1
- 125000001984 thiazolidinyl group Chemical group 0.000 description 1
- 125000000335 thiazolyl group Chemical group 0.000 description 1
- 150000003568 thioethers Chemical class 0.000 description 1
- 125000004568 thiomorpholinyl group Chemical group 0.000 description 1
- WCNFFKHKJLERFM-UHFFFAOYSA-N thiomorpholinyl sulfone group Chemical group N1(CCSCC1)S(=O)(=O)N1CCSCC1 WCNFFKHKJLERFM-UHFFFAOYSA-N 0.000 description 1
- 229930192474 thiophene Natural products 0.000 description 1
- 210000001519 tissue Anatomy 0.000 description 1
- 238000004448 titration Methods 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- FGMPLJWBKKVCDB-UHFFFAOYSA-N trans-L-hydroxy-proline Natural products ON1CCCC1C(O)=O FGMPLJWBKKVCDB-UHFFFAOYSA-N 0.000 description 1
- 125000001425 triazolyl group Chemical group 0.000 description 1
- 238000001665 trituration Methods 0.000 description 1
- 208000035408 type 1 diabetes mellitus 1 Diseases 0.000 description 1
- 108010087967 type I signal peptidase Proteins 0.000 description 1
- 229960005486 vaccine Drugs 0.000 description 1
- 235000013311 vegetables Nutrition 0.000 description 1
- 210000004127 vitreous body Anatomy 0.000 description 1
- 238000001262 western blot Methods 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
- 239000003871 white petrolatum Substances 0.000 description 1
- 210000002268 wool Anatomy 0.000 description 1
- 150000003751 zinc Chemical class 0.000 description 1
- JPZXHKDZASGCLU-LBPRGKRZSA-N β-(2-naphthyl)-alanine Chemical compound C1=CC=CC2=CC(C[C@H](N)C(O)=O)=CC=C21 JPZXHKDZASGCLU-LBPRGKRZSA-N 0.000 description 1
- 125000004933 β-carbolinyl group Chemical group C1(=NC=CC=2C3=CC=CC=C3NC12)* 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
- C07K5/02—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing at least one abnormal peptide link
- C07K5/0202—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing at least one abnormal peptide link containing the structure -NH-X-X-C(=0)-, X being an optionally substituted carbon atom or a heteroatom, e.g. beta-amino acids
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
-
- 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
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Medicinal Chemistry (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Genetics & Genomics (AREA)
- Crystallography & Structural Chemistry (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Molecular Biology (AREA)
- Biophysics (AREA)
- Biochemistry (AREA)
- Immunology (AREA)
- Neurosurgery (AREA)
- Neurology (AREA)
- Pain & Pain Management (AREA)
- Biomedical Technology (AREA)
- Rheumatology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Paper (AREA)
- Plural Heterocyclic Compounds (AREA)
- Enzymes And Modification Thereof (AREA)
- Peptides Or Proteins (AREA)
Abstract
本发明涉及一类新型化合物即白介素-1β转化酶的抑制剂。本发明ICE抑制剂用其特定的结构和物理化学特性来表征。本发明还涉及含有这些化合物的药物组合物。本发明化合物和药物组合物特别适合于抑制ICE活性,因而,它们被用作抗白介素-1介导的疾病是非常有利的,这些疾病包括炎症,自身免疫疾病和神经变性疾病。本发明还涉及使用本发明化合物和组合物抑制ICE活性的方法和治疗白介素-1介导的疾病的方法。
Description
本发明技术领域
本发明涉及一类新的化合物即白介素-1β转化酶的抑制剂(“ICE”)。本发明ICE抑制剂以其特殊结构和物理化学特性来表征。本发明还涉及含有这些化合物的药物组合物。本发明化合物和药物组合物特别适于抑制ICE活性,因而,它们被用作抗白介素-1(“IL-1”)介导的疾病是非常有利的,这些疾病包括炎症,自身免疫疾病和神经变性疾病。本发明还涉及用本发明化合物和组合物抑制ICE活性的方法和治疗白介素-1介导的疾病的方法。
发明背景
白介素-1(“IL-1”)是主要的原炎性和免疫调节蛋白,其刺激成纤维细胞的分化和增生,通过滑液细胞和软骨细胞,嗜碱细胞和嗜曙红细胞的脱粒作用和中性白细胞的活化作用产生前列腺素,胶原酶和磷脂酶。Oppenheim,J.H.,等人,
Immunology Today,7,pp.45-56(1986)。因此,它与慢性和急性炎症和自身免疫疾病的发病机理有关。IL-1主要由作为炎症反应一部分的外周血单核细胞产生,并以两种完全不同的激动剂形式——IL-1α和IL-1β——存在。Mosely,B.S.,等人,
Proc.Nat. Acad.Sci.,84,pp.4572-4576(1987);Lonnemann,G.,等人,
Eur.J. Immunol.,19,pp.1531-1536(1989)。
IL-1β被合成为无生物活性前体pIL-1β。pIL-1β缺乏常规前导序列,而且不经过信号肽酶加工。March,C.J.,Nature,315,pp.641-647(1985)。相反,pIL-1β在Asp-116和Ala-117之间被白介素-1β转化酶裂解,产生人类血清和滑液中发现的生物活性C-末端片段。Sleath,P.R.,等人,
J.Biol.Chem.,265,pp.14526-14528(1992);A.D.Howard等人,
J.Immunol.,147,pp.2964-2969(1991)。ICE加工对成熟IL-1β过程细胞膜的传输也是必要的。
ICE是主要集中在单核细胞中的半胱氨酸蛋白酶,它将前体IL-1β转化为成熟形式。Black,R.A.等人,
FEBS Lett.,247,pp.386-390(1989);Kostura,M.J.等人,
Proc.Natl.Acad.Sci.USA,86,pp.5227-5231(1991)。ICE或其同系物似乎也与细胞死亡或细胞编程性死亡的调节有关。Yuan,J.等人,
Cell,75,pp.641-652(1993);Miura,M.等人,
Cell,75,pp.653-660(1993);Nett-Fiordalisi,M.A.等人,
J.Cell Biochem.,17B,pp.117(1993)。特别地,ICE或ICE同系物被认为与神经生成(neurogenerative)疾病如阿尔茨海默病和帕金森病中的细胞编程性死亡的调节有关。Marx,J.and M.Baringa,
Science,259,pp.760-762(1993);Gagliardini,V.等人,
Science,263,pp.826-828(1994)。
ICE以前被作为两个亚基p20和p10(分子量分别为20kDa和10kDa)组成的异源双体而被描述过。这些亚基是经过p30形式,通过自动催化的活化机理,从45kDa酶原(p45)衍生而成的。Thornberry,N.A.等人,Nature,356,pp.768-774(1992)。该ICE酶原已经被分成几个功能域:前域(prodomain)(p14),p22/20亚基,多肽接头和p10亚基。
Thornberry 等人,
supra;Casano等人,
Genomics,20,pp.474-481(1994)。
全长p45已经由其cDNA和氨基酸序列表征。PCT专利申请WO91/15577和WO 94/00154。p20和p10 cDNA和氨基酸序列也是已知的。Thornberry等人,
supra。小鼠和大鼠的ICE也已经被测序和克隆。它们具有与人ICE高同源性的氨基酸和核酸序列。Miller,D.K.等人,
Ann. N.Y.Acad.Sci.,696,pp.133-148(1993);Molineaux,S.M.等人,
Proc.Nat. Acad.Sci.,90,pp.1809-1813(1993)。然而,对ICE一级结构的认识程度还不足以对ICE三级结构作出预测。它确实不能让人理解ICE及其底物pIL-1β或其它底物或抑制剂的结构,构象和化学相互作用。
ICE抑制剂代表用来控制炎症或细胞编程性死亡或二者的一类化合物。ICE的肽和肽基抑制剂已有描述。PCT专利申请WO 91/15577;WO93/05071;WO 93/09135;WO 93/14777和WO 93/16710;欧洲专利申请0 547 699。但是,由于它们肽的本质,这样的抑制剂也有典型的不良药物性质,例如,口服吸收差,稳定性差和代谢快。Plattner,J.J.and D.W.Norbeck,in
Drug Discovery Technologies,C.R.Clerk and W.H.Moos,Eds.(Ellis Horwood,Chichester,England,1990),pp.92-126。这些已经阻碍了它们发展成有效药物。
因此,需要能有效抑制ICE作用的化合物,以用作预防和治疗慢性和急性IL-1介导的疾病的药剂,所说疾病包括各种癌症,及炎症,自身免疫或神经变性疾病。
发明概述
本发明提供一类新的化合物及其药物上可接受的衍生物,它们被用作ICE抑制剂。这些化合物可以单独使用,或与其它治疗剂或预防剂如抗菌素,免疫调节剂和其它消炎剂一起使用,用于治疗或预防IL-1介导的疾病。根据优选实例,本发明化合物能够结合到ICE的活性部位,而且能抑制此酶的活性。
本发明的主要目的是提供一类新的ICE抑制剂。这些新型ICE抑制剂由下列结构和物理化学性质表征:
a)第一和第二氢键合部分,每个所说的部分都能够与ICE不同的主链原子形成氢键,所说主链原子选自Arg-341的羰基氧,Arg-341的酰胺-NH-基团,Ser-339的羰基氧和Ser-339的酰胺-NH-基团;
b)第一和第二中等疏水部分,当该抑制剂被结合时,所说部分能够与ICE分开的结合袋缔合,所说结合袋选自P2结合袋,P3结合袋,P4结合袋和P’结合袋;及
c)包含一或多个负电性原子的负电性部分,所说原子与这部分中的相同原子或相邻原子相连,所说部分能够与ICE的P1结合袋中的残基形成一或多个氢键或盐桥。
本发明另一个目的是提供识别,设计或预测ICE抑制剂的方法,该方法包括下列步骤:
a)选择有确定化学结构的候选化合物,该化合物含有至少两个氢结合部分,至少两个中等疏水部分和一个含有一或多个负电性原子的负电性部分,所说负电性原子可连到该负电性部分中的相同原子或相邻原子上;
b)测定所说化合物与ICE活性部位结合的低能构象;
c)评价所说化合物以所说构象与ICE的Arg-341和Ser-339非碳主链原子形成至少两个氢键的能力;
d)评价所说化合物以所说构象与ICE的至少两个结合袋缔合的能力,所说结合袋选自P2结合袋,P3结合袋,P4结合袋和P’结合袋;
e)评价所说构型中所说化合物与ICE的P1结合袋相互作用的能力;
f)根据以上述步骤进行的测定和评价结果确定接受或放弃所说候选化合物作为ICE抑制剂。
本发明进一步的目的是提供由下列结构式代表的一类新型ICE抑制剂:
和
缩写和定义
缩写
符号
试剂或片段
Ala 丙氨酸
Arg 精氨酸
Asn 天冬酰胺
Asp 天冬氨酸
Cys 半胱氨酸
Gln 谷氨酰胺
Glu 谷氨酸
Gly 甘氨酸
His 组氨酸
Ile 异亮氨酸
Leu 亮氨酸
Lys 赖氨酸
Met 甲硫氨酸
Phe 苯丙氨酸
Pro 脯氨酸
Ser 丝氨酸
Thr 苏氨酸
Trp 色氨酸
Tyr 酪氨酸
Val 缬氨酸
定义
此处使用下列术语:
术语“活性部位”指ICE中的任一或所有下列部位:底物结合部位,抑制剂结合的部位和底物裂解发生的部位。活性部位由至少下列氨基酸残基表征:
173,176,177,178,179,180,236,237,238,239,244,248,283,284,285,290,338,339,340,341,342,343,344,345,348,352,381,383,使用按照
Thornberry等人,
supra的序列和编号。
术语“P结合袋”,“S亚部位(subsite)”,“S袋”等指结合亚部位或ICE分子上的底物结合部位的几部分。根据底物的氨基酸残基相对于裂开键,即被蛋白酶打断的键的位置给残基命名。对于向底物N-末端延伸的残基命名为P1,P2等,对于向底物C-末端延伸的残基命名为P1’,P2’等。依此类推,与底物的P或P’残基对应的抑制剂部分被记为P1,P1’等。ICE分子的结合亚部位被命名为S1,S1’等,或者可被命名为“P1结合袋”,“P1’结合袋”等,这些亚部位接收标有P1,P1’等的残基。[I.Schecher and A.Berger,“On the Size of the Active Site in Proteases”,Biochem.Biophys.Res.Commun.,vol.27,pp.157-162(1967)。]
术语ICE活性部位的“P2结合袋”或“S2亚部位”是等同的并被定义为被氨基酸残基Pro-290,Val-338或Trp-340包围的空间。
术语ICE活性部位的“P3结合袋”或“S3亚部位”是等同的并被定义为被氨基酸残基Pro-177,Arg-178,Thr-180,Arg-341或Pro-343包围的空间。
术语ICE活性部位的“P4结合袋”或“S4亚部位”是等同的并被定义为被氨基酸残基His-342,Met-345,Val-348,Arg-352,Asp-381,Arg-383或Trp-340包围的空间。
术语ICE活性部位的“P1结合袋”或“S1亚部位”是等同的并被定义为被氨基酸残基Arg-179,His-237,Gln-283,或Arg-341包围的空间。
术语ICE活性部位的“P’结合袋”或“S’亚部位”是等同的并被定义为被氨基酸残基Phe-173,Ile-176,His-237,Gly-238,Ile-239,Cys-244或His-248包围的空间。
术语“疏水的”指几乎不溶于水但溶于脂肪的部分。疏水部分包括(但不限于)烃,如烷烃,烯烃,炔烃,环烷烃,环烯烃,环炔烃,及芳香化合物,如芳基,某些饱和和不饱和杂环及基本上类似于疏水性天然和非天然α-氨基酸侧链的部分,所说氨基酸包括缬氨酸,亮氨酸,异亮氨酸,甲硫氨酸,苯丙氨酸,α-氨基异丁酸,别异亮氨酸,酪氨酸,和色氨酸。
术语“中等疏水的”指其中一或两个碳原子已经被极性较强的原子如氧和氮置换的疏水部分。
术语“杂环”或“杂环的”指稳定的单或多环化合物,它可选择性地含有一或两个双键或可以选择性地含有一或两个芳香环。每个杂环由碳原子和1-4个分别选自氮,氧和硫的杂原子组成。这里所用的术语“氮杂原子”和“硫杂原子”包括氮或硫的任何氧化形式和碱性氮的季铵化形式。上面定义的杂环包括,例如,嘧啶基,四氢喹啉基,四氢异喹啉基,嘌呤基,嘧啶基,二氢吲哚基,苯并咪唑基,咪唑基,咪唑啉基,咪唑烷基,喹啉基,异喹啉基,吲哚基,吡啶基,吡咯基,吡咯烷基,吡唑基,吡嗪基,喹喔啉基,哌啶基,吗啉基,硫代吗啉基,呋喃基,三唑基,噻唑基,β-咔啉基,四唑基,噻唑烷基,苯并呋喃基(benzofuranoyl),硫代吗啉基砜,苯并口恶唑基,氧代哌啶基,氧代吡咯烷基,氧代氮杂_基,氮杂_基,异噁唑基,四氢吡喃基,四氢呋喃基,噻二唑基,苯并间二氧杂环戊烯基,苯并噻吩基,四氢苯硫基和四氢噻吩砜基。其它杂环在下列文献中有所描述:A.R.Katritzky and C.W.Rees,eds.,
Comprehensive Heterocyclic Chemistry:The Structure,Reactions,Synthesis and Use of Heterocyclic Compounds,Vol.1-8,Pergamon Press,NY(1984)。
术语“环烷基”指含有3-15个碳原子并可选择性地含有一或两个双键的单-或多环基团,例如,环己基,金刚烷基和降冰片基。
术语“芳基”指含有6,10,12或14个碳原子的单-或多环基团,其中至少一个环是芳香环,例如,苯基,萘基和联苯基。
术语“杂芳基”指含有1-15个碳原子和1-4个杂原子的单-或多环基团,其中每个杂原子都独立地选自硫,氮和氧,该基团还含有1-3个五或六元环,其中至少一个是芳香环。
术语“阿尔法-氨基酸”(α-氨基酸)指天然存在的氨基酸和在制备天然存在肽的合成类似物时肽化学领域中常用的其它“非蛋白质”α-氨基酸,包括D和L形式。天然存在氨基酸有甘氨酸,丙氨酸,缬氨酸,亮氨酸,异亮氨酸,丝氨酸,甲硫氨酸,苏氨酸,苯丙氨酸,酪氨酸,色氨酸,半胱氨酸,脯氨酸,组氨酸,天冬氨酸,天冬酰胺,谷氨酸,谷氨酰胺,γ-羧基谷氨酸,精氨酸,鸟氨酸和赖氨酸。“非蛋白质”α-氨基酸的实例包括羟基赖氨酸,高丝氨酸,高酪氨酸,高苯丙氨酸,瓜氨酸,犬尿氨酸,4-氨基-苯丙氨酸,3-(2-萘基)-丙氨酸,3-(1-萘基)-丙氨酸,甲硫氨酸砜,叔丁基-丙氨酸,叔丁基甘氨酸,4-羟基苯基甘氨酸,氨基丙氨酸,苯基甘氨酸,乙烯基丙氨酸,炔丙基-甘氨酸,1,2,4-三唑并-3-丙氨酸,4,4,4-三氟-苏氨酸,甲状腺原氨酸,6-羟基色氨酸,5-羟基色氨酸,3-羟基犬尿氨酸,3-氨基酪氨酸,三氟甲基-丙氨酸,2-噻吩基丙氨酸,(2-(4-吡啶基)乙基)-半胱氨酸,3,4-二甲氧基-苯丙氨酸,3-(2-噻唑基)-丙氨酸,鹅膏蕈氨酸,1-氨基-1-环庚烷羧酸,1-氨基-1-环己烷羧酸,使君子氨酸,3-三氟甲基苯丙氨酸,4-三氟甲基苯丙氨酸,环己基丙氨酸,环己基甘氨酸,硫代组氨酸,3-甲氧基酪氨酸,弹性蛋白酶抑制剂,降亮氨酸,降缬氨酸,别异亮氨酸,高精氨酸,硫代脯氨酸,脱氢脯氨酸,羟基脯氨酸,异哌啶甲酸,高脯氨酸,环己基甘氨酸,α-氨基-正丁酸,环己基丙氨酸,氨基苯基丁酸,在苯基部分的邻位,间位或对位被一或两个下列基团取代的苯丙氨酸:(C1-C4)烷基,(C1-C4)烷氧基,卤素或硝基或被亚甲基二氧基取代的苯丙氨酸;β-2-和3-噻吩基-丙氨酸,β-2-和3-呋喃基丙氨酸,β-2-,3-和4-吡啶丙氨酸,β-(苯并噻吩基-2-和3-基)丙氨酸,β-(1-和2-萘基)丙氨酸,丝氨酸、苏氨酸或酪氨酸的O-烷基化衍生物,S-烷基化半胱氨酸,S-烷基化高半胱氨酸,酪氨酸的O-硫酸酯、O-磷酸酯和O-羧酸酯,3-磺基-酪氨酸,3-羧基-酪氨酸,3-磷酸-酪氨酸,酪氨酸的4-甲磺酸酯,酪氨酸的4-甲膦酸酯,3,5-二碘酪氨酸,3-硝基-酪氨酸,ε-烷基赖氨酸和δ-烷基鸟氨酸。这些α-氨基酸中任何一个都可以在α位被甲基取代,在α-氨基侧链上的任一个芳香残基上被卤素取代,或被适当保护基取代。所说保护基公开于“有机合成中的保护基”,T.W.Greene and P.G.M.Wuts,J.Wiley & Sons,NY,NY,1991。
术语“α-氨基酸侧链残基”指连到α-氨基酸的α-碳原子上的化学部分。
术语“-CO2H的生物等排置换”指可以在生物活性分子中取代羧酸基的基团。这些基团的实例公开于Christopher A.Lipinski,“Bioisosteres inDrug Design”
Annual Reports In Medical Chemstry,21,pp.286-88(1986)和C.W.Thornber,“Isosterism and Molecular Modification in DrugDesign”
Chemical Society Reviews,pp.563-580(1979)。
术语“缔合”指抑制剂或其部分与ICE分子或其部分之间的接近状态,这种接近是依靠静电或范德瓦尔斯(van der Waals)相互作用。
术语“氢键”指当适当供体原子X(带有一个质子H)#和适当受体原子Y间隔2.5-3.5_(埃)且其中X-H---Y的夹角大于90度时发生的有利相互作用。适当供体和受体原子是医药化学中完全理解的(G.C.Pimentel and A.L.McClellan,
The Hydrogen Bond,Freeman,SanFrancisco,1960;R.Taylor and O.Kennard,“Hydrogen Bond Geometryin Organic Crystals”,
Accounts of Chemical Research,17,pp.320-326(1984))。
术语“盐桥”指当正电荷部分(P)和负电荷部分(N)的质量中心相距2-6埃(_)时P与N之间的非共价键引力相互作用。在计算质量中心时,包括可含有形式电荷的原子和与这些原子紧密相邻的原子。例如,盐桥可以在精氨酸残基的正电荷鈲盐侧链与谷氨酸残基的负电荷羧酸盐侧链之间形成。盐桥在医药化学中极易理解(L.Stryer,
Biochemistry,Freeman,Fan Francisco,(1975);K.A.Dill,“Dominant Forces in ProteinFolding”,
Biochemistry,29 No.31,pp.7133-7155,(1990))。
术语“质量中心”指代表构成物体质量权重平均位置的三维空间中的点。
术语“主链”和“骨架”指含有重复单位-CO-CH-NH-的多肽中的部分。
术语“骨架”指构成本发明ICE抑制剂基础的结构单元。各种基团和功能团将被附加于骨架上。因此,表示本发明骨架具有打开的化合价。本发明ICE抑制剂的各种骨架包括下列部分:
或
在这些骨架中,NH和CO或SO2部分代表第一和第二氢键键合部分,这些部分每个都能与ICE主链原子形成氢键,所说主链原子选自Arg-341的羰基氧,Arg-341的酰胺-NH-,Ser-339的羰基氧和Ser-339的酰胺-NH-。
术语“取代”指化合物中的氢原子被取代基置换。本发明中那些形成一部分氢键键合部分的氢原子不在被取代之列,所说氢键键合部分能够与ICE的Arg-341的羰基氧或ICE的Ser-339的羰基氧形成氢键。这些例外的氢原子包括含有α连接到Z或-CO-基团上的-NH-基团的氢原子,并被表示为-NH-而不是X基团或下列结构中的一些其它的形式:(a)到(t),(v)到(y)及(I)到(VIID)。
术语“直链”指共价结合的成员即原子紧密相连成无分支的串,这些原子形成环的一部分。直链和它构成其中一部分的环可以被取代,但这些取代基并不是直链的一部分。
术语“Ki”指在抑制目标酶如ICE活性时化合物有效性的数值计量单位。较低的Ki值代表较高的有效性。Ki值是通过将实验测得的速度数据代入标准酶动力方程(见I.H.Segel,
Enzyme Kinetics,Wiley-Interscience,1975)而得到的。
术语“最小化”指分子或分子复合物的原子几何形状的系统改变使得原子几何形状的任何进一步的微扰都会引起,如用分子力学力场测得的该系统全部能量的增加。最小化和分子力学力场在计算化学中是极易理解的(U.Burkert and N.L.Allinger,Melocular mechanics,ACS Monograph 177,American Chemical Society,Washington,D.C.1982,pp.59-78)。
用于本说明书的术语“应变能”指化合物的自由构象能和该化合物与ICE结合时的结合构象能的差。应变能可通过下述步骤测定:当其具有与ICE结合所需的构象时,评估该分子的能量。然后最小化和重新评估该能量——这是自由构象能。可能的抑制剂与ICE结合的应变能是自由构象能与结合构象能之差。在优选实例中,本发明抑制剂的应变能小于约10kcal/mol。
用于本说明书的术语“患者”指任何哺乳动物,特别指人。
术语“有效药量”指有效治疗或改善患者IL-1介导的疾病的药量。术语“有效预防量”指有效预防或基本减轻患者IL-1介导的疾病的药量。
术语“药物上可接受的载体或辅剂”指与本发明化合物一起可以用于患者的无毒载体或辅剂,它不破坏化合物的药物活性。
术语“药物上可接受的衍生物”指本发明化合物或任何其它化合物的药物上可接受的盐,酯,或这些酯的盐,所说的其它化合物,当给药于患者时,能够提供(直接或间接)本发明化合物或抗ICE活性代谢物或其残基。
本发明化合物药物上可接受的盐,例如,包括从药物上可接受的无机和有机酸和碱衍生的那些盐。适宜的酸的实例包括盐酸,氢溴酸,硫酸,硝酸,高氯酸,富马酸,马来酸,磷酸,乙醇酸,乳酸,水杨酸,琥珀酸,甲苯-对磺酸,酒石酸,乙酸,柠檬酸,甲磺酸,甲酸,苯甲酸,丙二酸,萘-2-磺酸和苯磺酸。其它酸如草酸虽然不在药物上可接受的酸之列,但也可以用于作为获得本发明化合物及其药物上可接受的酸加成盐的中间体盐的制备。从适当碱衍生的盐包括碱金属盐(如钠盐),碱土金属盐(如镁盐),铵盐和N-(C1-4烷基)4 +盐。
本发明还预计了这里公开的化合物的任何含碱性氮基团的“季铵化作用”。碱性氮可用本领域普通技术人员已知的任何试剂季铵化,例如,用低级烷基卤,如甲基、乙基、丙基和丁基氮、溴和碘;二烷基硫酸酯,包括二甲基、二乙基、二丁基和二戊基硫酸酯;长链卤化物如癸基、月桂基、肉豆蔻基和硬脂基氯化物、溴化物和碘化物;及芳烷基卤化物,包括苄基和苯乙基溴化物。水溶性或油溶性或可分散性产物可以通过此季铵化反应得到。
本发明ICE抑制剂可以含有一或多个“不对称”碳原子,因此作为外消旋体和外消旋混合物,单个对映体,非对映体混合物和单个非对映体存在。这些化合物的所有异构体形式都包括在本发明之内。每个可产生立体构型的(stereogenic)碳可以是R或S构型之一。虽然本说明书举例的具体化合物和骨架可以用特定的立体化学构型表示,但具有在任何所给手性中心相反的立体化学或其混合物的化合物和骨架也被预计到。
本发明ICE抑制剂可以包含环形结构,该结构可以选择性地在碳、氮或其它原子位置被多种取代基取代。这种环形结构可以被单或多取代。优选地,该环形结构含有0-3个取代基。当多取代时,每个取代基可以分别精选于其它取代基,条件是结合这些取代基能形成稳定的化合物。
取代基和由本发明预计的各种可能取代基的结合仅指形成稳定化合物的那些取代基。这里所用术语“稳定的”指具有足够的稳定性以便用本领域已知方法制备和给哺乳动物施药的化合物。具体地,这类化合物在40℃或更低温度,在不存在潮湿或其它化学反应条件下,至少稳定一星期。
发明详述
为使这里所述的本发明能够被更充分地理解,我们进行以下更详细的描述。
已经发现,具有以下各种新特性的化合物是极为有效的ICE抑制剂:
a)第一和第二氢键键合部分,每个所说的部分都能够与ICE不同的主链原子形成氢键,所说主链原子选自Arg-341的羰基氧,Arg-341的酰胺-NH-,Ser-339的羰基氧和Ser-339的酰胺-NH-;
b)第一和第二中等疏水部分,当该抑制剂被结合时,所说部分能够与ICE分开的结合袋缔合,所说结合袋选自P2结合袋,P3结合袋,P4结合袋和P’结合袋;及
c)包含一或多个负电性原子的负电性部分,所说原子与这部分中的相同原子或相邻原子相连,所说部分能够与ICE的P1结合袋中的残基形成一或多个氢键或盐桥。
优选地,与ICE P2结合袋缔合的任何中等疏水部分都是以下列方式进行:
a)P2结合袋中中等疏水部分的质量中心与ICE的Arg-341的羰基氧之间的距离约为7.1_-12.5_(埃);
b)P2结合袋中中等疏水部分的质量中心与ICE的Arg-341的酰胺氮之间的距离约为6.0_-12_;
c)P2结合袋中中等疏水部分的质量中心与ICE的Ser-339的羰基氧之间的距离约为3.7_-9.5_。
优选地,与ICE P3结合袋缔合的任何中等疏水部分都是以下列方式进行:
a)P3结合袋中中等疏水部分的质量中心与ICE的Arg-341的羰基氧之间的距离约为3.9_-9.5_;
b)P3结合袋中中等疏水部分的质量中心与ICE的Arg-341的酰胺氮之间的距离约为5.4_-11_;
c)P3结合袋中中等疏水部分的质量中心与ICE的Ser-339的羰基氧之间的距离约为7.0_-13_。
优选地,与ICE P4结合袋缔合的任何中等疏水部分都是以下列方式进行:
a)P4结合袋中中等疏水部分的质量中心与ICE的Arg-341的羰基氧之间的距离约为4.5_-7.5_;
b)P4结合袋中中等疏水部分的质量中心与ICE的Arg-341的酰胺氮之间的距离约为5.5_-8.5_;
c)P4结合袋中中等疏水部分的质量中心与ICE的Ser-339的羰基氧之间的距离约为8_-11_。
优选地,与ICE P’结合袋缔合的任何中等疏水部分都是以下列方式进行:
a)P’结合袋中中等疏水部分的质量中心与ICE的Arg-341的羰基氧之间的距离约为11A-16A;
b)P’结合袋中中等疏水部分的质量中心与ICE的Arg-341的酰胺氮之间的距离约为10A-15A;
c)P’结合袋中中等疏水部分的质量中心与ICE的Ser-339的羰基氧之间的距离约为8A-12A。
更优选地,所有上述缔合条件适用于本发明化合物。
本领域普通技术人员将认识到有大量设计本发明抑制剂的方法。这些相同的方法可用来筛选作为ICE抑制剂的候选化合物。该设计或选择可从选取各种填充结合袋的部分开始。
有很多方法选取填充各结合袋的部分,包括直接观察活性部位的物理模型或计算机模型和所选部分的模型手动停靠剂各结合袋中。可以使用本领域中熟知的和可得到的制作模型的软件,包括QUANTA〔分子模拟公司,伯灵顿,马萨诸塞州,1992〕,SYBYL〔分子模型化软件,Tripos联合公司,圣路易斯,密苏里州,1992〕,AMBER〔S.J.Weiner,P.A.Kollman,D.A.Case,U.C.Singh,C.Ghio.G.Alagona,和P.Weiner,
美 国化学杂志,106卷,pp.765-784(1984)〕,或CHARMM〔B.R.Brooks,R.E.Bruccoleri,B.D.Olafson,D.J.States,S Swaminathan,和M.Karplus,
组合物化学杂志4卷,pp.187-217(1983)〕。该制作模型步骤之后可用标准分子力学力场如CHARMM和AMBER进行能量最小化。另外,有许多更具体化的计算机程序有助于选择本发明结合部分的过程,它们包括:
1.GRID(Goodford,P.J.一种确定具生物重要性大分子上基因有利性结合位点的计算机程序。
医药化学杂志,28,pp.849-857(1985))。GRID可购自牛津大学(英国牛津)。
2.MCSS(Miranker,A.;Karplus,M.结合位点功能图:一种多拷贝同时研究方法;蛋白质:结构、功能和遗传,11,pp.29-34(1991)).MCSS可购自分子模拟公司(马萨诸塞州伯灵顿)。
3.AUTODOCK(Goodsell,D.S.;Olsen,A.J.通过模拟退火将底物自动对接在蛋白质上;蛋白质:结构、功能和遗传,8,pp.195-202(1990)).AUTODOCK可购自Scripps研究所(加利福尼亚州La Jolla)。
4.DOCK(Kuntz,I.D.;Blaney,J.M.;Oatley,S.J.;Langridge,R.;Ferrin,T.E.大分子配体相互作用的几何学方法;分子生物学杂志,161,pp.269-288(1982))。DOCK可购自加利福尼亚大学(加利福尼亚州旧金山)。
一旦适宜的结合部分被选中,它们可以被组装成单一的抑制剂。这种组装过程可以通过将各部分与中心骨架相连来完成。例如,该组装过程可以通过直接观察,然后建立手动模型,再使用软件如Quanta或Sybyl来实现。许多其它程序也可用于帮助选择连接各部分的方法,包括:
1.CAVEAT(Bartlett,P.A.;Shea,G.T.;Telfer,S.J.;Waterman,S.CAVEAT:促进生物活性分子结构衍生性设计的程序,见:“化学和生物学问题中的分子识别”,专版,皇家化学学会,78,pp.182-196(1989))。GAVEAT可购自加利福尼亚大学(加利福尼亚州,伯克利)。
2.3D数据库系统,如MACCS-3D(MDL信息系统,加利福尼亚州,圣莱安德罗)。该领域最近已由Martin做过评述(Martin,Y.C.药物设计中的3D数据库检索,医药化学杂志,35,pp.2145-2154(1992))。
3.HOOK(可购自分子模拟公司,马萨诸塞州,伯灵顿)
除了上述帮助建立抑制剂化合物模型的计算机程序外,本发明抑制剂可用空活性部位或选择性地包括已知抑制剂的某些部分从头构建。这些方法是本领域已知的。例如,它们包括:
1.LUDI(Bohm,H.J.计算机程序LUDI:一种用于酶抑制剂重新设计的新方法,组合物辅助分子设计杂志,6,61-78(1992))。LUDI可购自生物系统技术公司(加利福尼亚州圣迭戈)。
2.LEGEBND(Nishibata,Y.,Itai,A.,四面体,47,8985(1991))。LEGEND可购自分子模拟公司,马萨诸塞州伯灵顿。
3.LeapFrog(可购自Tripos联合公司,圣路易斯,马萨诸塞州)。
常用于药物模型设计的许多技术都可以使用(例如,参见Cohen,N.C.;Blaney,J.M.;Humblet,C.;Gund,P.;Barry,D.C.,“Molecular ModelingSoftware and Methods for Medicinal Chemistry”,
J.Med.Chem.,33,pp.883-894(1990))。在化学文献中还有许多技术的实例可用于具体药物设计项目。例如,参见Navia,M.A.and Murcko,M.A.,“The Use of StructuralInformation in Drug Design”,
Current Opinions in Structural Biology,2,pp.202-210(1992)。这些具体应用的一些实例包括:
Baldwin,J.J.et al.,″Thienothiopyran-2-sulfonamides:
Novel Topically Active Carbonic Anhydrase Inhibitors
for the Treatment of Glaucoma″,
J.Med.Chem.,32,pp.
2510-2513(1989);Appelt,K.et al.,″Design of Enzyme
Inhibitors Using Iterative Protein Crystallographic
Analysis″,
J.Med.Chem.,34,pp.1925-1934(1991);and
Ealick,S.E.et al.,″Application of Crystallographic
and Modeling Methods in the Design of Purine Nucleotide
Phosphorylase Inhibitors″
Proc.Nat.Acad.Sci.USA,
88,pp.11540-11544(1991).
使用本发明新的结合步骤,本领域技术人员可以大大避免浪费时间和昂贵的实验以确定具体化合物的酶抑制活性。该方法也可用于ICE抑制剂和抗IL-1介导的疾病的治疗剂和预防剂的合理设计。因此,本发明涉及这类抑制剂。
可将多种常用技术用于进行上述各种评价以及在筛选ICE抑制活性的候选化合物时所需的评价。总之,这些技术包括确定所给部分的位置和结合程度,结合的抑制剂所占的空间,所给化合物的结合用变形能以及静电相互作用能。用于上述评价的常规技术的实例包括:量子力学,分子力学,分子动力学,蒙托卡罗采样,系统搜寻和距离几何方法(G.R.Marshall,
Ann. Rev.Pharmacol.Toxical.,27,pp.193(1987))。具体计算机软件也已开发用来实施这些方法。被设计用于此目的的程序的实例包括:Gaussion 92,E.2版(M.J.Frisch,Gaussion,Inc.,Pittsburgh,PA_1993);
AMBER,4.0版(P.A.Kollman,加利福尼亚大学旧金山分校,_1993);QUANTA/CHARMM(分子模拟公司_1992);和InsightII/Discover(生物系统技术公司,圣迭戈,CA_1992)。这些程序,例如,可以在Silicon Graphics Indigo 2工作站或IBM RISC/6000工作站550型上运行。其它硬件系统和软件包应是本领域技术人员已知的并具有明显的实用性。
根据本发明,不同类型的活性ICE抑制剂可以类似方式与ICE活性部位的各种结合袋相互作用。这些重要基团的空间排列经常被称作药效团。药效团的概念已在文献(D.Mayer,C.B.Naylor,I.Motoc,和G.R.Marshall,组合物辅助分子设计杂志,1卷,pp.3-16(1987);A.Hopfinger和B.J.Burke,见“分子相似性的概念与应用”,M.A.Johnson和G.M.Maggiora,编著,Wiley(1990))中有详尽的描述。
本发明不同类型的ICE抑制剂也可以采用不同的骨架或核心结构,但所有这些核心将允许必要的部分被置于活性部位,使得可以得到结合所必需的特定相互作用。这些化合物最好根据它们和药效团相配的能力,即其与ICE活性部位的形状和性质有关的结构一致性来定义。
本发明一个实施方案的ICE抑制剂含有第一和第二氢键键合部分,第一和第二中等疏水部分,及含有或与下列骨架之一共价结合的负电性部分:
和
本发明另一实施方案(A)的ICE抑制剂是具有式α的那些化合物:
其中:
X1是CH或N;
g是0或1;
每个J分别选自-H,-OH和-F,条件是当第一和第二J结合到C上且所说第一J是-OH时,所说第二J是-H;
m是0,1,或2;
T是-Ar3,-OH,-CF3,-CO-CO2H,-CO2H或对-CO2H的任何生物等排置换;
R1选自下列结构式,其中任何环都可以选择性地在任何碳上被Q1,在任何氮上被R5,或在任何原子上被=O,-OH,-CO2H或卤素单或多取代,其中任何饱和的环可以选择性地在一或两个键上不饱和:
R20选自下列基团:
和
其中每个环C分别选自苯并,吡啶并,噻吩并,吡咯并,呋喃并,噻唑并,异噻唑并,噁唑并,异噁唑并,嘧啶并,咪唑并,环戊基和环己基;
R3是
-CN,
-CH=CH-R9,
-CH=N-O-R9,
-(CH2)1-3-T1-R9,
-CJ2-R9,
-CO-R13,或
每个R4分别选自下列基团:
-H,
-Ar1,
-R9,
-T1-R9,和
-(CH2)1,2,3-T2-R9,
每个T1分别选自下列基团:
-CH=CH-,
-O-,
-S-,
-SO-,
-SO2-,
-NR10-,
-NR10-CO-,
-CO-,
-O-CO-,
-CO-O-,
-CO-NR10-,
-O-CO-NR10-,
-NR10-CO-O-,
-NR10-CO-NR10-,
-SO2-NR10-,
-NR10-SO2-,和
-NR10-SO2-NR10-,
每个R5分别选自下列基团:
-H,
-Ar1,
-CO-Ar1,
-SO2-Ar1,
-R9,
-CO-R9,
-CO-O-R9,
-SO2-R9,
R6和R7一起形成饱和的4-8员碳环或含有-O-,-S-或-NH-的杂环,或
R7是-H和R6是
-H
-Ar1,
-R9,或
-(CH2)1,2,3-T1-R9;
每个R9是选择性地被-OH,-F,或=O单或多取代和选择性地被一或两个Ar1基团取代的直链或支链C1-6烷基;
每个R10分别选自-H或直链或支链C1-6烷基;
每个R13分别选自-Ar2和-R4;
每个Ar1是分别选自下列一组的环基:含有6,10,12,或14个碳原子且有1-3个环的芳基,含有3-15个碳原子且有1-3个环的环烷基,所说环烷基选择性地被苯并稠合,和含有5-15个环原子并有1-3个环的杂环基,所说杂环基至少含有一个选自-O-,-S-,-SO-,-SO2-,=N-,和-NH-的杂原子,所说杂环基选择性地含有一或多个双键,所说杂环基选择性地含有一或多个芳香环,并且所说环基选择性地被=O,-OH,全氟C1-3烷基,或-Q1单或多取代;
每个Ar2分别选自下列基团,其中任何环可以选择性地被-Q1取代:
和
Ar3是选自苯环,5-员杂芳香环和6-员杂芳香环的环基,所说杂芳香环含有1-3个选自-O-,-S-,-SO-,-SO2-,=N-和-NH-的杂原子,所说环基选择性地被=O,-OH,卤素,全氟C1-3烷基,或-CO2H单或多取代;
每个Q1分别选自:
-Ar1
-R9,
-T1-R9, 和
-(CH2)1,2,3-T1-R9,
条件是当-Ar1被含有一或多个其它-Ar1基团的Q1基团取代时,所说其它-Ar1基团不被Q1取代;
每个X分别选自=N-和=CH-;
每个X2分别选自-O-,-CH2-,-NH-,-S-,-SO-和-SO2-;
每个X3分别选自-CH2-,-S-,-SO-和-SO2-;
每个X4分别选自-CH2-和-NH-;
X6是CH或N,条件是当X6是在标有(o)的R1基上的N,并且,X5是CH,X2是CH2时,标有(o)的R1基的环必须被Q1取代或苯并稠合;
每个Y分别选自-O-和-S-;
每个Z分别为CO或SO2;
每个a分别为0或1;
每个c分别为1或2;
每个d分别为0,1或2;及
每个e分别为0,1,2或3。
本发明另一实施方案(B)的ICE抑制剂是具有式
α的那些化合物:
其中:
X1是-CH;
g是0或1;
每个J分别选自-H,-OH和-F,条件是当第一和第二J结合到C上且所说第一J是-OH时,所说第二J是-H;
m是0,1,或2;
T是-OH,-CO-CO2H,-CO2H或对-CO2H的任何生物等排置换;
R1选自下列结构式,其中任何环都可以选择性地在任何碳上被Q1,在任何氮上被R5,或在任何原子上被=O,-OH,-CO2H或卤素取代,其中任何饱和的环可以选择性地在一或两个键上不饱和;其中R1(e)和R1(y)选择性地被苯并稠合;
R20选自下列基团:
和
其中每个环C分别选自苯并,吡啶并,噻吩并,吡咯并,呋喃并,噻唑并,异噻唑并,噁唑并,异噁唑并,嘧啶并,咪唑并,环戊基和环己基;
R3是
-CN,
-CH=CH-R9,
-CH=N-O-R9,
-(CH2)1-3-T1-R9,
-CJ2-R9,
-CO-R13,or
每个R4分别选自下列基团:
-H,
-Ar1,
-R9,
-T1-R9,及
-(CH2)1,2,3-T1-R9,
每个T1分别选自下列基团:
-CH=CH-,
-O-,
-S-,
-SO-,
-SO2-,
-NR10-,
-NR10-CO-,
-CO-,
-O-CO-,
-CO-O-,
-CO-NR10-,
-O-CO-NR10-,
-NR10-CO-O-,
-NR10-CO-NR10-,
-SO2-NR10-,
-NR10-SO2-,和
-NR10-SO2-NR10-,
每个R5分别选自下列基团:
-H,
-Ar1,
-CO-Ar1,
-SO2-Ar1,
-CO-NH2,
-SO2-NH2,
-R9,
-CO-R9,
-CO-O-R9,
-SO2-R9,
和
R6和R7一起形成饱和的4-8员碳环或含有-O-,-S-或-NH-的杂环,或
R7是-H和R6是
-H,
-Ar1,
-R9,
-(CH2)1,2,3-T1-R9,
或α-氨基酸侧链残基;
每个R9是选择性地被-OH,-F,或=O单或多取代和选择性地被一或两个Ar1基团取代的直链或支链C1-6烷基;
每个R10分别选自-H或直链或支链C1-6烷基;
每个R13分别选自-Ar2,-R4和
每个Ar1是分别选自下列一组的环基:含有6,10,12,或14个碳原子且有1-3个环的芳基,含有3-15个碳原子且有1-3个环的环烷基,所说环烷基选择性地被苯并稠合,和含有5-15个环原子并有1-3个环的杂环基,所说杂环基至少含有一个选自-O-,-S-,-SO-,-SO2-,=N-,和-NH-的杂原子,所说杂环基选择性地含有一或多个双键,所说杂环基选择性地含有一或多个芳香环,而所说环基选择性地被-NH2,-CO2H,-Cl,-F,-Br,-I,-NO2,-CN,=O,-OH,全氟C1-3烷基,
或-Q1单或多取代;
每个Ar2分别选自下列基团,其中任何环可以选择性地被-Q1和-Q2单或多取代:
每个Q1分别选自:
-Ar1
-O-Ar1
-R9,
及
-T1-R9,
-(CH2)1,2,3-T1-R9;
每个Q2分别选自-OH,-NH2,-CO2H,-Cl,-F,-Br,-I,-NO2,-CN,-CF3和
条件是当-Ar1被含有一或多个其它-Ar1基团的Q1基团取代时,所说其它-Ar1基团不被Q1取代;
每个X分别选自=N-和=CH-:
每个X2分别选自-O-,-CH2-,-NH-,-S-,-SO-和-SO2-;
每个X3分别选自-CH2-,-S-,-SO-和-SO2-;
每个X4分别选自-CH2-和-NH-;
X6是CH或N,条件是当X6是在标有(o)的R1基上的N,并且,X5是CH,X2是CH2时,标有(o)的R1基的环必须被Q1取代或苯并稠合;
每个Y分别选自-O-和-S-和-NH;
每个Z分别为CO或SO2;
每个a分别为0或1;
每个c分别为1或2;
每个d分别为0,1或2;及
每个e分别为0,1,2或3,
条件是,当
R1是(f),
R6是α-氨基酸侧链残基,及
R7是-H时,
(aa1)和(aa2)必须被Q1取代;
此外,条件是,当
R1是(o),
g是0,
J是-H,
m是1,
R6是α-氨基酸侧链残基,
R7是-H,
X2是-CH2-,
X5是-CH-,
X6是
及
或-CO-R13,当R13是 -CH2-O-CO-Ar1,
-CH2-S-CO-Af1,
-CH2-O-Ar1,
-CH2-S-Ar1,或
-R4
其中-R4是-H,
时,R1(o)基的环必须被Q1取代或苯并稠合;及
此外,条件是,当
R1是(w),
g是0,
J是-H,
m是1,
T是-CO2H或-CO-NH-OH,
X2是O,
R5是苄氧羰基,及
环C是苯并时,
R3不能是-CO-R13,其中
R13是-CH2-O-Ar1,而
Ar1是1-苯基-3-氯或3-三氟甲基-吡唑-5-基;
或其中
R13是-CH2-O-CO-Ar1,而
Ar1是2,6-二氯苯基。
实施方案A和B中R1基团中(a)的优选形式是:
R1基团中(b)的优选形式是:
R1基团中(c)的优选形式是:
条件是,当
R1是(c1),
g是0,
J是-H,
m是1,
T是-CO2H,
X是N,
R5是苄氧羰基,及
R6是-H时,
R3不能是-CO-R13,其中
R13是-CH2-O-Ar1,而
Ar1是氯取代的1-苯基-3-三氟甲基-吡唑-5-基,
或其中
R13是-CH2-O-CO-Ar1,而
Ar1是2,6-二氯苯基,
而且骨架环的2-位被对-氟-苯基取代;
R1基团中(d)的优选形式是:
R1基团中(e)的优选形式是:
其选择性地被苯并稠合
条件是,当
R1是(e4),
g是0,
J是-H,
m是1,
T是-CO2H,
R5是苄氧羰基,及
c是1时,
R3不能是-CO-R13,其中
R13是-CH2-O-Ar1,而
Ar1是1-苯基-3-三氟甲基-吡唑-5-基,其中苯基选择性地被氯原子取代;
或其中
R13是-CH2-O-CO-Ar1,而
Ar1是2,6-二氯苯基,
而且骨架环的2-位被对-氟-苯基取代;及
还一个条件是,当
R1是(e7),
g是0,
J是-H,
m是1,
T是-CO2H或-CO-NH-OH,
R5是氨基酸侧链残基上N原子的保护基,及
每个c是1时,
R3不能是-CO-R13,其中
R13是
-CH2-O-CO-Ar1,
-CH2-S-CO-Ar1,
-CH2-O-Ar1,
-CH2-S-Ar1.
R1基团中(g)的优选形式是:
和
R1基团中(h)的优选形式是:
R1基团中(i)的优选形式是:
R1基团中(j)的优选形式是:
和
R1基团中(k)的优选形式是:
R1基团中(l)的优选形式是:
R1基团中(m)的优选形式是:
R1基团中(n)的优选形式是:
和
R1基团中(O)的优选形式是:
实施方案B中R1基团中(o)的优选形式是:
其中X2是-O-,-S-,-SO2-或-NH-。
对于实施方案A和B,R1基团中(p)的优选形式是:
R1基团中(q)的优选形式是:
和
R1基团中(r)的优选形式是:
R1基团中(s)的优选形式是:
R1基团中(t)的优选形式是:
R1基团中(v)的优选形式是:
和
实施方案B中R1基团中(w)的优选形式是:
其中X2是-O-,-S-,-SO2-或-NH-。
本发明实施方案A和B的优选化合物是采用式α的那些化合物,其中:
X1是CH;
g是0;
J是-H;
m是0或1及T是-Ar3,-CO-CO2H,-CO2H或对-CO2H的任何生物等排置换,或
m是1或2及T是-OH,-CF3或-CO2H;
更优选地,m是1及T是-CO2H;
R1是
R20是
R20 is
或
其中环C是苯并;
R3是-CO-R13或
最优选的R3是下列1),2)或3)之一:1)-CO-Ar2,2)-CO-R9,其中R9是被两个Ar1基团取代的C3-6烷基或一个被Ar1基团本身取代的Ar1基团;-C1-2烷基-Ar1,-Cl,-CH3或-CF3,或3)-(CH2)1,2-T1-R9,其中T1是-O-或-S-,而R9是被两个Ar1基团取代的C1-2烷基或一个被Ar1基团本身取代的Ar1基团;-C1-2-Ar1,-Cl,-CH3或-CF3;
R4是-H或-R9;
T1是
-O-,
-S-,
-CO-,
-O-CO-,或
-SO2-;
当R1是(a),(b),(k)或(m)时,R5优选为-Ar1或C1-4-Ar1;
当R1是(c),(e),(f),(o)或(r)时,R5优选为-SO2-Ar1,-SO2-R9或-CO-C1-4-Ar1;
R7是-H,R6是C1-4-Ar1;
R10是-H或直链或支链C1-3烷基;
R13是-Ar2;
Ar1是苯基,萘基,吡啶基,苯并噻唑基,噻吩基,苯并噻吩基,苯并噁唑基,2-2,3-二氢化茚基或吲哚基;
Ar2优选被-Ar1或-C1-4-Ar1取代;
Ar3是苯基,噻吩,噻唑,吡啶或噁唑;及
Q1是-R9或-(CH2)1,2-T1-(CH2)1-3-Ar1,其中T1是-O-或-S-。
就这个部分继续申请而言,我们优选本发明实施方案B采用式α的化合物,其中:
X1是-CH;
g是0;
J是-H;
m是0或1及T是-CO-CO2H或对-CO2H的任何生物等排置换;或
m是1及T是-CO2H;
R1选自下列结构式,其中任何环都可以选择性地在任何碳上被Q1,在任何氮上被R5,或在任何原子上被=O,-OH,-CO2H或卤素单或多取代,而且其中(e)选择性地被苯并稠合:
或
R20是
其中c是1;
环C是选择性地被-C1-3烷基,-O-C1-3烷基,-Cl,-F或-CF3取代的苯并;
R3是
-CO-R13,或
更优选地R3是下列1),2)或3)之一:1)-CO-Ar2;2)-CO-R9,其中R9是被Ar1取代的C1-5烷基;或3)-CH2-T1-R9,其中T1是-O-或-S-,而R9是被一个Ar1基团取代的C1-2烷基;
R4是-H或-R9;
T1是
-O-,
-S-,
-CO-,
-O-CO-,或
-SO2-;
当R1是(a)或(b)时,R5优选为-H;及
当R1是(c),(e),(f),(o),(r),(w),(x)或(y)时,R5优选为
-CO-Ar1
-SO2-Ar1,
-CO-NH2,
-CO-NH-Ar1
-CO-R9,
-CO-O-R9,
-SO2-R9,或
-CO-NH-R9,
R7是-H,R6是
-H,
-R9或
-Ar1;
R9是选择性地被=O和选择性地被-Ar1取代的直链或支链C1-6烷基;
R10是-H或直链或支链C1-3烷基;
R13是
-H,
-R9,
-Ar2,或
-CH2-T1-R9,
更优选其中-Ar2是(hh),这里,(hh)选择性地被下列基团单或多取代:-C1-6烷基,-O-C1-6烷基,-NH-C1-6烷基,-N-(C1-6烷基)2,-S-C1-6烷基,-Cl,-F,-CF3或
Ar1是被-O-C1-3烷基,-NH-C1-3烷基,-N-(C1-3烷基)2,-Cl,-F,-CF3,-C1-3烷基,或
单或多取代的苯基,萘基,吡啶基,苯并噻唑基,噻吩基,苯并噻吩基,苯并恶唑基,2-2,3-二氢化茚基或吲哚基;
优选其中Ar2是:
或
每个X分别选自=N-和=CH-;
每个X2分别选自-O-,-CH2-,-NH-,-S-,-SO-和-SO2-;
X6是
和
及
Z是C=O;
条件是,当
R1是(f),
R6是α-氨基酸侧链残基,及
R7是-H时,
则(aa1)和(aa2)必须被Q1取代;
此外,条件是,当
R1是(o),
g是0,
J是-H,
m是1,
R6是α-氨基酸侧链残基,
R7是-H,
X2是-CH2-,
X5是-CH-,
R3是
或
-CO-R13,
其中R13是
-CH2-O-CO-Ar1,
-CH2-S-CO-Ar1,
-CH2-O-Ar1,
-CH2-S-Ar1,或
-R4
其中-R4是-H,
时,R1(o)环必须被Q1取代或苯并稠合;及
此外,条件是,当
R1是(w),
g是0,
J是-H,
m是1,
T是-CO2H,
X2是O,
R5是苄氧羰基,及
环C是苯并时,
R3不能是-CO-R13,其中
R13是-CH2-O-Ar1,而
Ar1是1-苯基-3-三氟甲基-吡唑-5-基,其中苯基选择性地被氯原子取代;
或其中
R13是-CH2-O-CO-Ar1,其中Ar1是2,6-二氯苯基。
R13的优选形式是-CH2-O-R9,其中R9是选择性地被=O和选择性地被Ar1取代的直链或支链C1-6烷基;
R13另一种优选形式是-CH2-S-R9,其中R9是选择性地被Ar1取代的直链或支链C1-6烷基;
R13另一种优选形式是-CH2-O-R9,其中R9是选择性地被Ar1取代的直链或支链C1-6烷基;
R13另一种优选形式是-H。
R1基团中(a)的更优选形式是选择性地被Q1取代的
其中:
R5是-H;
R7是-H;及
Z是C=O;
R1基团中(b)的更优选形式是选择性地被Q1取代的
其中:
R5是-H;
R7是-H;及
Z是C=O;
R1基团中(c)的更优选形式是:
和
条件是,当
R1是(c1),
g是0,
J是-H,
m是1,
T是-CO2H,
X是N,
R5是苄氧羰基,及
R6是-H时,
R3不能是-CO-R13,其中
R13是-CH2-O-Ar1,而
Ar1是1-苯基-3-三氟甲基-吡唑-5-基,其中苯基选择性地被氯原子取代;
或其中
R13是-CH2-O-CO-Ar1,其中Ar1是2,6-二氯苯基,
而其中骨架环的2-位被对-氟-苯基取代;
R1基团中(e)的更优选形式是:
其中c是2;及
和
其选择性地被苯并稠合
其中c是1或2;
条件是,当
R1是(e4),
g是0,
J是-H,
m是1,
T是-CO2H,
R5是苄氧羰基,及
c是1时,
R3不能是-CO-R13,其中
R13是-CH2-O-Ar1,而
Ar1是1-苯基-3-三氟甲基-吡唑-5-基,其中苯基选择性地被氯原子取代;
或其中
R13是-CH2-O-CO-Ar1,而
Ar1是2,6-二氯苯基,
而其中骨架环的2-位被对-氟-苯基取代;及
还一个条件是,当
R1是(e7),
g是0,
J是-H,
m是1,
T是-CO2H或-CO-NH-OH,或对-CO2H的生物等排置换;
R5是氨基酸侧链残基上N原子的保护基,及
每个c是1时,
R3不能是-CO-R13,其中
R13是
-CH2-O-CO-Ar1,
-CH2-S-CO-Ar1,
-CH2-O-Ar1,或
-CH2-S-Ar1.
R1基团中(f)的更优选形式是:
R1基团中(g)的更优选形式是:
其中
R20是选择性地被Q1单或多取代的(aa1),及
Z是C=O;
R1基团中(h)的更优选形式是:
其中
R20是选择性地被Q1单或多取代的(aa1),及
Z是C=O;
R1基团中(o)的更优选形式是:
其中d是1或2;及
R1基团中(r)的更优选形式是选择性地被Q1取代的
和
R1基团中(w)的更优选形式是选择性地被R5或在X2(X2是-N-)上被Q1取代的
其中X2是
-NH-,
-S-,
或
-O-,
-SO2-;
环C是被-C1-3烷基,-O-C1-3烷基,-Cl,-F或-CF3取代的苯并。
当R1是
时,本发明优选化合物包括但不限于:
实施方案B优选化合物具有式α,其中R1是
该实施方案的优选化合物包括但不限于:
和
其中R1是:
本发明优选化合物包括但不限于:
和
本发明实施方案B优选化合物具有式
α,其中R1是
及
c是2;
m是1;
T是-CO2H;及
R3是-CO-R13。
该实施方案优选化合物包括但不限于:
其中R1是
本发明优选化合物包括但不限于:
和
其中R1是
本发明优选化合物包括但不限于:
和
其中R1是
本发明优选化合物包括但不限于:
本发明实施方案B的优选化合物采用式
α,其中:
R1是
X2是-NH-;
m是1;
T是-CO2H;
R3是-CO-R13。
该实施方案的优选化合物包括但不限于:
和
其中R1是选择性地被Q1取代的
或
本发明实施方案B的优选化合物包括但不限于:
和
其中R1是
本发明优选化合物包括但不限于:
本发明另一个实施方案(C)的ICE抑制剂由式
σ代表,
其中的环选择性地被一或多个R基团取代,优选0,1或2个;及其中:
R1是R5-(A)p-;
R5选自下列基团:
-H,
-Ar1,
-CO-Ar1,
-SO2-Ar1,
-R9,
-CO-R9,
-CO-O-R9,
-SO2-R9,
每个A分别选自任何α-氨基酸;
p是0,1,2,3,或4;
Y是
Y is:
-O-,
-S-或
-NH;
R是
-H,
-O-C1-6烷基,
-NH(C1-6烷基),
-N(C1-6烷基)2,
-S-C1-6烷基,
-C1-6烷基,或
-Q2;
每个R9是选择性地被-OH,-F或=O单或多取代和选择性地被一或两个Ar1基团取代的直链或支链C1-6烷基;
每个R10分别选自-H或直链或支链C1-6烷基;
每个T1分别选自下列基团:
-CH=CH-,
-O-,
-S-,
-SO-,
-SO2-,
-NR10-,
-NR10-CO-,
-CO-,
-O-CO-,
-CO-O-,
-CO-NR10-,
-O-CO-NR10-,
-NR10-CO-O-,
-NR10-CO-NR10-,
-SO2-NR10-,
-NR10-SO2-,和
-NR10-SO2-NR10-,
每个Ar1是分别选自下列基团的环基:含有6,10,12或14个碳原子并有1-3个环的芳基;含有3-15个碳原子并有1-3个环的环烷基,所说环烷基选择性地被苯并稠合;及含有5-15个环原子并有1-3个环的杂环基,所说杂环基含有至少一个选自-O-,-S-,-SO-,-SO2-,=N-和-NH-的杂原子基团,所说杂环基选择性地含有一或多个双键,所说杂环基选择性地由一或多个芳香环组成,及所说环基选择性地被-NH2-,-CO2H,-Cl,-F,-Br-,-I,-NO2,-CN,=O,-OH,-全氟C1-3烷基,
或-Q1单或多取代;
每个Q1分别选自
-Ar1
-R9,
-T1-R9,和
-(CH2)1,2,3-T1-R9;
每个Q2分别选自-OH,-NH2-,-CO2H,-Cl,-F,-Br-,-I,-NO2,-CN,-CF3和
条件是当-Ar1被由其它一或多个-Ar1基团组成的Q1取代时,所说其它-Ar1基团不被Q1取代。
本发明实施方案C的优选化合物包括但不限于:
本发明实施方案C的优选化合物还有其中每个A选自下列α-氨基酸的化合物:
丙氨酸,
组氨酸,
赖氨酸,
苯丙氨酸,
脯氨酸,
酪氨酸,
缬氨酸,
亮氨酸,
异亮氨酸,
谷氨酰胺,
甲硫氨酸,
高脯氨酸,
3-(2-噻吩基)丙氨酸,及
3-(3-噻吩基)丙氨酸。
本发明另一个实施方案(D)的ICE抑制剂由式π代表:
其中:
R1是R5-(A)p-;
每个T1分别选自下列基团:
-CH=CH-,
-O-,
-S-,
-SO-,
-SO2-,
-NR10-,
-NR10-CO-,
-CO-,
-O-CO-,
-CO-O-,
-CO-NR10-,
-O-CO-NR10-,
-NR10-CO-O-,
-NR10-CO-NR10-,
-SO2-NR10-,
-NR10-SO2-,和
-NR10-SO2-NR10-;
R5选自下列基团:
-H,
-Ar1,
-CO-Ar1,
-SO2-Ar1,
-R9,
-CO-R9,
-CO-O-R9,
-SO2-R9,
和
每个A分别选自任何α-氨基酸;
p是0,1,2,3或4;
每个R9是选择性地被-OH或-F单或多取代和选择性地被一个Ar1基团取代的直链或支链C1-6烷基;
每个R10分别选自-H或直链或支链C1-6烷基;
Ar1是分别选自下列基团的环基:含有6,10,12或14个碳原子并有1-3个环的芳基;含有3-15个碳原子并有1-3个环的环烷基,所说环烷基选择性地被苯并稠合;及含有5-15个环原子并有1-3个环的杂环基,所说杂环基含有至少一个选自-O-,-S-,-SO-,-SO2-,=N-和-NH-的杂原子基团,所说杂环基选择性地含有一或多个双键,所说杂环基选择性地由一或多个芳香环组成,及所说环基选择性地被-NH2-,-CO2H,-Cl,-F,-Br-,-I,-NO2,-CN,=O,-OH,-全氟C1-3烷基,或
-R9或-T1-R9单或多取代。
本发明实施方案D的优选化合物是其中R9为被Ar1(Ar1是苯基)取代的直链或支链C1-4烷基的那些化合物。
本发明实施方案D的优选化合物包括但不限于:
和
本发明实施方案D的优选化合物还有其中每个A选自下列α-氨基酸的化合物:
丙氨酸,
组氨酸,
赖氨酸,
苯丙氨酸,
脯氨酸,
酪氨酸,
缬氨酸,
亮氨酸,
异亮氨酸,
谷氨酰胺,
甲硫氨酸,
高脯氨酸,
3-(2-噻吩基)丙氨酸,及
3-(3-噻吩基)丙氨酸。
本发明另一个实施方案(E)的ICE抑制剂由式
v代表:
其中:
m是0,1或2;
T是-CO2H或对-CO2H的任何生物等排置换,
R3是
-CN,
-COR13,或
R5选自下列基团:
-H,
-Ar1,
-CO-Ar1,
-SO2-Ar1,
-R9,
-CO-R9,
-CO-O-R9,
-SO2-R9,
和
每个A分别选自任何α-氨基酸;
p是2或3;
每个R9是选择性地被-OH,-F或=O单或多取代和选择性地被一个Ar1基团取代的直链或支链C1-6烷基;
每个T1分别选自下列基团:
-CH=CH-,
-O-,
-S-,
-SO-,
-SO2-,
-NR10-,
-NR10-CO-,
-CO-,
-O-CO-,
-CO-O-,
-CO-NR10-,
-O-CO-NR10-,
-NR10-CO-O-,
-NR10-CO-NR10-,
-SO2-NR10-,
-NR10-SO2-,和
-NR10-SO2-NR10-;
每个R10分别选自-H或直链或支链C1-6烷基;
每个R13分别选自H,R9,Ar2和CH2T1R9;
每个Ar1是分别选自下列基团的环基:含有6,10,12或14个碳原子并有1-3个环的芳基;含有3-15个碳原子并有1-3个环的环烷基,所说环烷基选择性地被苯并稠合;及含有5-15个环原子并有1-3个环的杂环基,所说杂环基含有至少一个选自-O-,-S-,-SO-,-SO2-,=N-和-NH-的杂原子基团,所说杂环基选择性地含有一或多个双键,所说杂环基选择性地由一或多个芳香环组成,及所说环基选择性地被-NH2-,-CO2H,-Cl,-F,-Br-,-I,-NO2,-CN,=O,-OH,-全氟C1-3烷基,
或-Q1单或多取代;及
每个Ar2分别选自下列基团,其中任何环都可以选择性地被-Q1和-Q2单或多取代:
X为N或CH;
Y为O或S;
每个Q1分别选自
-Ar1
-O-Ar1
-R9,
-T1-R9,和
-(CH2)1,2,3-T1-R9;
每个Q2分别选自-OH,-NH2-,-CO2H,-Cl,-F,-Br-,-I,-NO2,-CN,-CF3和
条件是当-Ar1被由一或多个其它-Ar1基团组成的Q1取代时,所说其它-Ar1基团不被Q1取代。
本发明实施方案E的优选化合物包括但不限于:
本发明实施方案E的优选化合物还有其中每个A选自下列α-氨基酸的化合物:
丙氨酸,
组氨酸,
赖氨酸,
苯丙氨酸,
脯氨酸,
酪氨酸,
缬氨酸,
亮氨酸,
异亮氨酸,
谷氨酰胺,
甲硫氨酸,
高脯氨酸,
3-(2-噻吩基)丙氨酸,及
3-(3-噻吩基)丙氨酸。
本发明另一个实施方案(F)的ICE抑制剂由式
δ代表:
其中:
R1是R5-(A)p-;
R5选自下列基团:
-H,
-Ar1,
-CO-Ar1,
-SO2-Ar1,
-R9,
-CO-R9,
-CO-O-R9,
-SO2-R9,
和
每个A分别选自任何α-氨基酸;
p是0,1,2,3或4;
每个R9是选择性地被-OH,-F或=O单或多取代和选择性地被一个Ar1基团取代的直链或支链C1-6烷基;
每个R10分别选自-H或直链或支链C1-6烷基;
每个T1分别选自下列基团:
-CH=CH-,
-O-,
-S-,
-SO-,
每个Ar1是分别选自下列基团的环基:含有6,10,12或14个碳原子并有1-3个环的芳基;含有3-15个碳原子并有1-3个环的环烷基,所说环烷基选择性地被苯并稠合;及含有5-15个环原子并有1-3个环的杂环基,所说杂环基含有至少一个选自-O-,-S-,-SO-,-SO2-,=N-和-NH-的杂原子基团,所说杂环基选择性地含有一或多个双键,所说杂环基选择性地由一或多个芳香环组成,及所说环基选择性地被-NH2-,-CO2H,-Cl,-F,-Br-,-I,-NO2,-CN,=O,-OH,-全氟C1-3烷基,
或-Q1单或多取代;及
每个Ar2分别选自下列基团,其中任何环都可以选择性地被-Q1和-Q2单或多取代:
每个Q1分别选自
-Ar1
-O-Ar1
-R9,
-T1-R9,和
-(CH2)1,2,3-T1-R9;
每个Q2分别选自-OH,-NH2-,-CO2H,-Cl,-F,-Br-,-I,-NO2,-CN,-CF3和
条件是当-Ar1被由一或多个其它-Ar1基团组成的Q1取代时,所说其它-Ar1基团不被Q1取代;
每个X分别选自=N-和=CH-;及
每个Y分别选自-O-,-S-和-NH。
本发明实施方案F的优选化合物包括但不限于:
本发明实施方案F的优选化合物还有其中每个A选自下列α-氨基酸的化合物:
丙氨酸,
组氨酸,
赖氨酸,
苯丙氨酸,
脯氨酸,
酪氨酸,
缬氨酸,
亮氨酸,
异亮氨酸,
谷氨酰胺,
甲硫氨酸,
高脯氨酸,
3-(2-噻吩基)丙氨酸,及
3-(3-噻吩基)丙氨酸。
本发明化合物的分子量优选小于或等于约700道尔顿,更优选约400-600道尔顿。这些优选的化合物可以通过口服被患者血液吸收。口服的有效性使这些化合物成为口服给药治疗和预防IL-1介导的疾病的极好药剂。
本发明ICE抑制剂可用常规技术合成。便利地,这些化合物可从容易得到的起始原料很方便地合成。
本发明化合物属于已知的最容易合成的ICE抑制剂。以前描述的ICE抑制剂经常包含4个或多个手性中心和大量肽键。与之相比本发明化合物的合成比较容易,这使本发明化合物大规模生产具有明显优势。
应该理解,本发明化合物可以根据情况以各种平衡形式存在,这取决于溶剂的选择,pH及其它本领域普通技术人员已知的情况。这些化合物的所有这些形式都明显地包括在本发明范围内。特别地,许多本发明化合物,特别是在R3中含有醛或酮基和在T中含有羧酸的化合物可以半-缩酮(或半-缩醛)或水合物形式存在,如下图所示:
根据溶剂的选取和其它本领域技术人员已知的情况,本发明化合物还可以为酸基缩酮,酸基缩醛,缩酮或缩醛形式:
另外,还应该理解,本发明化合物的平衡形式可以包括互变异构形式。这些化合物的所有这些形式都明显地包括在本发明范围内。
应该理解,本发明化合物可以用适当的功能团加以修改以提高生物选择性。所说修饰是本领域已知的,而且包括以下几方面的改善:增加向所给生物系统(例如,血液,淋巴系统,中枢神经系统)的生物渗透性,增加口服有效性,增加溶解性以利于注射给药,改变新陈代谢及改变排泄率。另外,这些化合物可以被转变成前体药物形式,由于代谢作用或其它生物化学过程对前体药物的作用使得在患者体内产生所需的化合物。前体药物形式的一些实例包括含有酮或醛基的化合物的缩酮,缩醛,肟和腙形式,特别是它们产生于本发明化合物的R3基上。
本发明化合物是ICE极好的配位体。因此,这些化合物能够瞄准和抑制IL-1介导的疾病,如IL-1β前体到成熟IL-1β的转变,因而该蛋白质在炎症,自身免疫疾病及神经变性疾病中的最终活性。例如,本发明化合物通过抑制ICE来抑制前体IL-1β到成熟IL-1β的转化。因为ICE主要用来产生成熟IL-1,所以,通过抑制成熟IL-1的产生,这种酶的抑制可有效地阻断IL-1介导的生理作用和症状如炎症的引发。因此,通过抑制IL-1β前体活性使本发明化合物可有效地作为IL-1抑制剂。
本发明化合物还可以常规方式用于治疗IL-1介导的疾病。这些治疗方法,使用剂量和要求可由本领域普通技术人员从可利用的方法和技术中选取。例如,本发明化合物可与药物上可接受的辅剂结合,以药物上可接受的方式和可有效减轻疾病严重程度的用量给患有IL-1介导的疾病的患者用药。
或者,本发明化合物可以用于组合物和方法中以治疗或在一段较长的时间内预防IL-1介导的疾病。这些化合物既可以在这种组合物中单独使用,也可以与本发明其它化合物以符合ICE抑制剂在药物组合物中通常的使用方式一起使用。例如,本发明化合物可与通常用于疫苗的药物上可接受的辅剂结合并以有效预防的剂量给药以使个体在一段较长的时间内免受IL-1介导的疾病的侵扰。
本发明化合物还可以与其它ICE抑制剂共同给药以增加治疗或预防各种IL-1介导的疾病的效果。
另外,本发明化合物既可以与常规消炎药结合使用,又可以与基质金属蛋白酶抑制剂,脂氧合酶抑制剂和非IL-1β的细胞因子拮抗剂一起使用。
本发明化合物还可以与免疫调节剂(例如,溴匹利胺,抗人类α干扰素抗体,IL-2,GM-CSF,甲硫氨酸脑啡肽,干扰素α,二硫代氨基甲酸二乙酯,肿瘤坏死因子,环丙甲羟二羟吗啡酮和rEPO)或与前列腺素结合使用,以防止或战胜IL-1介导的病症如炎症。
当本发明化合物与其它治疗剂结合使用时,它们可以被相继地或同时地用于患者。或者,本发明治疗或预防组合物可以由本发明ICE抑制剂与另一种治疗或预防剂结合而成。
本发明药物组合物由本发明任一化合物及其药物上可接受的盐与任何药物上可接受的载体,辅剂或赋形剂组成。可用于本发明药物组合物的药物上可接受的载体,辅剂和赋形剂包括但不限于:离子交换剂,氧化铝,硬脂酸铝,卵磷脂,血清蛋白如人血清蛋白,缓冲物质如磷酸盐,甘氨酸,山梨酸,山梨酸钾,饱和植物脂肪酸的部分甘油酸酯混合物,水,盐或电解质如硫酸鱼精蛋白,磷酸氢二钠,磷酸氢钾,氯化钠,锌盐,胶态硅石,三硅酸镁,聚乙烯基吡咯烷酮,以纤维素为基础的物质,聚乙二醇,羧甲基纤维素钠,聚丙烯酸酯,石蜡,聚乙烯-聚氧丙烯-嵌段聚合物,聚乙二醇和羊毛脂。
本发明药物组合物可以通过口服,肠道外,喷吸入剂,表面,直肠,鼻子,脸颊,阴道或通过植入的贮器给药。我们优选口服给药。本发明药物组合物可以含有所有常规无毒的药物上可接受的载体,辅剂或赋形剂。这里所用术语“肠道外”包括皮下,皮内,静脉内,肌肉内,关节内,滑膜内,胸骨内,鞘内,损害部位内和颅内注射或输液技术。
药物组合物可以灭菌可注射制剂形式,例如,无菌注射水或油悬浮液形式存在。该悬浮液可以根据本领域已知的技术用适当分散剂或润湿剂(例如,Tween 80)和悬浮剂来配制。无菌可注射制剂也可以是在无毒肠道外可接受的稀释剂或溶剂中的无菌注射溶液或悬浮液如1,3-丁二醇的溶液。可用的和可接受的赋形剂和溶剂有甘露糖醇,水,林格(Ringer)溶液和等渗氯化钠溶液。另外,无菌的固定油通常也用作溶剂或悬浮介质。为此目的,任何无刺激的固定油都可以使用,如合成的单酸甘油酯或甘油二酯。脂肪酸如油酸及其甘油酯衍生物可以用于注射液的制备,如天然的药物上可接受的油如橄榄油或蓖麻油,特别是它们的聚氧乙烯化形式。这些油溶液或悬浮液也可以含有长链醇稀释剂或分散剂如在Pharmacopeia Helvetica
Ph. Helv中描述那些或类似的醇。
本发明组合物可以任何可接受的口服剂量形式进行口服给药,包括但不限于胶囊剂,片剂及水悬浮液和溶液。对于口服用片剂,通常要使用载体,该载体包括乳糖和玉米淀粉。一般还要加入润滑剂如硬脂酸镁。对于以胶囊剂形式进行口服给药来说,可用的稀释剂包括乳糖和干玉米淀粉。当用水悬浮液口服给药时,活性成份要与乳化剂和悬浮剂混合使用。如果需要,可以加入甜味剂和/或调味剂和/或着色剂。
本发明组合物也可以栓剂形式用于直肠给药。这些组合物可以通过将本发明化合物与适当的无刺激性赋形剂混合而成,该赋形剂在室温是固体,而在直肠温度下则为液体,因此它在直肠内熔化并释放出活性成份。这些材料包括但不限于可可油,蜂蜡和聚乙二醇。
当需要治疗的部位或器官通过表面给药更易吸收时本发明药物组合物的表面给药是特别有用的。对于皮肤表面的应用,药物组合物应该用含有悬浮或溶解于载体中的活性成份的适当油膏配制。用于本发明化合物表面给药的载体包括但不限于矿物油,液体石油,白凡士林(white petroleum),丙二醇,聚氧乙烯聚氧丙烯化合物,乳化蜡和水。另外,药物组合物可以用含有悬浮或溶解于载体中的活性化合物的适当洗液或乳膏配制。适当的载体包括但不限于矿物油,脱水山梨糖醇一硬脂酸酯,多乙氧基醚-60,鲸蜡酯蜡,cetearyl醇,2-辛基十二烷醇,苄醇和水。本发明药物组合物也可以通过直肠栓剂或适当灌肠剂表面施用到下部肠道。本发明还包括表面透皮贴剂。
本发明药物组合物可通过鼻喷雾器或吸入器给药。这些组合物可根据药物制剂领域熟知的技术来制备,而且可以制成盐水溶液,采用苄醇或其它适当防腐剂,吸收促进剂以提高生物利用率,氟碳,和/或其它本领域已知的加溶剂或分散剂。
可用本发明化合物治疗或预防的IL-1介导的疾病包括但不限于炎症,自身免疫疾病和神经变性疾病。
可以治疗或预防的炎症包括,例如,败血性休克,败血症和成年呼吸窘迫综合征。靶自身免疫疾病包括,例如,类风温病,关节炎,系统性红斑狼疮,硬皮病,慢性甲状腺炎,格雷夫斯病,自身免疫性胃炎,依赖胰岛素的糖尿病,自身免疫性溶血性贫血症,自身免疫性中性白细胞减少症,血小板病,慢性活性肝炎,重症肌无力和多发性硬化。靶神经变性疾病包括,例如,肌萎缩侧索硬化,阿尔茨海默病,帕金森病和原发性脊髓侧索硬化。本发明ICE抑制剂还可以用于促进伤口愈合。本发明化合物还可以用于治疗感染性疾病。
虽然本发明重点在这里公开预防和治疗IL-1介导的疾病的化合物的应用方面,但本发明化合物也可以用作其它半胱氨酸蛋白酶抑制剂。
本发明化合物还可以用作有效结合ICE或其它半胱氨酸蛋白酶的商品试剂。作为商品试剂本发明化合物及其衍生物可以用来抑制靶肽的蛋白水解,或可以被衍生以结合到稳定树脂上作为亲合色谱应用的固定相(tethered substrate)。这些或其它表征商品半胱氨酸蛋白酶抑制剂的应用对于本领域普通技术人员是显而易见的。
为使本发明能够被更全面地理解,我们给出下列实施例。这些实施例的目的只是为了说明本发明而非以任何方式限制本发明范围。
实施例1
下列实施例用以说明本发明中药物设计方法:
步骤1)选择ICE的两个氢键键合部分,在此为Arg-341的主链
C=O和N-H。
步骤2)选择骨架,在此为吡啶酮衍生物,并确定骨架的氢键键合部分能够与步骤1所选氢键键合部分形成满足要求的氢键。该确定过程是运用分子力学技术使ICE活性部位周围的骨架段缩到最小来实现的。
步骤3)选择疏水袋,在此为S2作为下一个目标,疏水部分是苯。在S2袋中使苯基缩到最小以保证能够得到基本疏水的重叠。
步骤4)选择另一种疏水袋,在此为S4作为下一个目标,疏水部分是苯。在S4袋中使苯基缩到最小以保证能够得到基本疏水的重叠。
步骤5)用负电性部分——由天冬氨酸提供的羧酸盐侧链,其中C末端已被还原成醛——填充S1极性袋。最小化以保证羧酸盐侧链保持与S1极性袋良好的静电相互作用。
步骤6)将骨架与来自步骤3,4和5的部分连接,优选使用符合合理化学结构的最少的键。最小化ICE活性部分中整个组合分子。
步骤7)估算当其具有与ICE结合所必需的构象时的分子能量。然后最小化并重新估算该能量,即自由构象能。可能的抑制剂与ICE结合的应变能是自由构象能和结合构象能之差。该应变能应该小于约10kcal/mol。在此情况下,对于10.1kcal/mol的应变能,结合构象能为-1.6kcal/mol,自由构象能为-11.7kcal/mol。
步骤8)采用上述步骤设计的抑制剂已经制成,并显示出Ki为150nM。
实施例2
我们用下面所述三种方法得到本发明几种化合物的抑制常数(Ki)和IC50值。
1.
用紫外-可见底物进行酶测定
用琥珀酰-Tyr-Val-Ala-Asp-对硝基苯胺底物进行此测定。类似底物的合成L.A.Reiter曾有描述(Int.J.Peptide Protein Res.
43,87-96(1994))。该测定混合物含有:
65μl缓冲液(10mM Tris,1mM DTT,0.1%CHAPS@pH8.1)
10μl ICE(50nM最终浓度以得到约1mOD/分钟速率)
5μl DMSO/抑制剂混合物
20μl 400μM底物(最终浓度80μM)
100μl总的反应体积
可见的ICE测定在96孔微量滴定板中进行。按顺序将缓冲液,ICE和DMSO(如果存在抑制剂的话)加到每个孔中。在所有成份存在于所有孔中时起将这些成份在室温下温育15分钟,再将该微量滴定板读数器置于37℃下温育。温育15分钟后将底物直接加到各孔中,并在37℃通过跟踪405-603nm发色团(pNA)的释放来监视反应20分钟。进行数据的线性拟合,并以mOD/分钟计算速率。DMSO是实验期间仅存的抑制剂,其它实验中用缓冲液使体积达到100μl。
2.
用荧光底物进行酶测定
基本上根据Thornberry等人所述(Nature
356:768-774(1992)),并用该文献中的底物17进行该项测定。该底物是:乙酰基-Tyr-Val-Ala-Asp-氨基-4-甲基香豆素(AMC)。混合下列成份:
65μl缓冲液(10mM Tris,1mM DTT,0.1%CHAPS @pH8.1)
10μl ICE(2-10nM最终浓度)
5μl DMSO/抑制剂溶液
20μl 150μM底物(最终浓度30μM)
100μl总的反应体积
该测定在96孔微量滴定板中进行。将缓冲液和ICE加到各孔中。在有温度控制的孔板中在37℃下温育这些成份15分钟。温育15分钟后,将底物直接加到各孔中使反应开始。并在37℃通过用激发波长为380nm及发射波长为460nm跟踪AMC荧光团的释放来监视反应30分钟。对每个孔的数据进行线性拟合,并且以每秒荧光单位确定速率。
对于酶抑制常数(Ki)或抑制方式(竞争性,无竞争性或非竞争性)的确定,各种抑制剂浓度下进行酶测定时确定的速率数据被计算机拟合成标准酶动力方程(参见I.H.Segel,
Enzym Kinetics,Wiley-Interscience,1975)。
3.
细胞测定
用人外周血液单核细胞(PBMC)或富集的贴壁单核细胞的混合群体进行IL-1β测定
用ICE处理前-IL-1β的过程可以用各种细胞源在细胞培养物中进行。从健康供血者得到的人PBMC提供了人淋巴细胞亚型和单核细胞的混合群体,它们对多种生理刺激物作出反应而产生白介素和细胞因子。从PBMC得到的贴壁单核细胞提供了用于选择性研究活化细胞产生的细胞因子的正常单核细胞富集源。
实验方法:
制备一系列在DMSO或乙醇中初步稀释的试验化合物,然后在RPMI-10%FBS介质(含有2mM L-谷氨酰胺,10mM HEPES,50U和50μg/ml pen/strep)中稀释,分别生成4倍于最终试验浓度的药物,含有0.4%DMSO或0.4%乙醇。对于所有药物稀释液DMSO的最终浓度是0.1%。浓度滴定——用于将在ICE抑制测定中所确定的试验化合物的表观Ki分类——通常被用于化合物的初级筛选。
我们一般试验5-6种化合物稀释液,并已对细胞成份进行了一式两份的测定,并且对每种细胞培养物上清液进行了完全一样的ELISA测定。PBMC分离和IL-1测定:
从1品脱人血分离出的淡黄色外被细胞(生成40-45ml最终体积的血浆加细胞)用介质稀释到80ml,然后每个LeukoPREP分离管(BectonDickinson)中装入10ml此细胞悬浮液。以1500-1800×g离心15分钟后,吸出血浆/介质层,用巴斯德吸液管收集单核细胞层,并转移到15ml圆锥形离心管(Corning)中。加入介质使体积达到15ml,通过翻转轻轻地混合细胞,然后以300×g离心15分钟。重新将PBMC沉淀悬浮于少量介质中,数细胞个数,并调节至6×106细胞/ml。
为了进行细胞测定,将1.0ml细胞悬浮液,0.5ml试验化合物稀释液和0.5ml LPS溶液(Sigma #L-3012;在完全RPMI介质中制备的20ng/ml溶液;最终LPS浓度为5ng/ml)加到24孔平底组织培养平板(Corning)的每个孔中。添加0.5ml试验化合物和LPS一般足以混合每个孔中的内容物。每个实验中采用3个对照混合物,与单独的LPS,溶剂赋形剂对照物,和/或额外的介质使最终培养液体积达到2.0ml。在5%CO2存在下,细胞培养液在37℃培养16-18小时。
培养结束时收获细胞,并将其转移到15ml圆锥形离心管中。以200×g离心10分钟后收获上清液,并转移到1.5ml Eppendorf管中。可以注意到,通过蛋白质印迹或用前-IL-1β特异性抗血清进行ELISA,该细胞沉淀可以用于前-IL-1β和/或成熟IL-1β在细胞溶质提取物中的含量的生物化学估算。
贴壁单核细胞的分离:
如上所述分离和制备PBMC。首先在各孔中加入介质(1.0ml),然后加入0.5ml PBMC悬浮液。培养1小时后轻轻摇动平板,并从每个孔中吸出非贴壁细胞。用1.0ml介质温和地洗涤各孔三次,最后再悬浮在1.0ml介质中。贴壁细胞的富集使每个孔通常能产生2.5-3.0×105个细胞。试验化合物和LPS的添加,细胞培养条件和上清液处理方法如上所述。
ELISA:
我们已经使用了Quantikine试剂盒(R&D Systems)来测定成熟IL-1β。测定是根据厂家的指导进行的。观察到在PBMC和贴壁单核细胞阳性对照物中成熟IL-1β的含量约为1-3ng/ml。对得自LPS-阳性对照的1∶5,1∶10和1∶20上清液稀释液进行ELISA测定以在试验对象中选择最佳的上清液稀释液。
本发明化合物的抑制能力可以用IC50值表示,它是与阳性对照相比在上清液中检测到50%成熟IL-1β时的抑制剂浓度。
下列Ki和IC50值是用所示的测定方法对化合物A-N测定的结果。化合物A-N的结构遵循下表。
化合物
用所示的测定方法得到的Ki(μM)
紫外-可见法
荧光法
细胞
Ki(μM) Ki(μM) IC50(μM)
A 5.5 25.0
B 8.6 20.0
C 10 >30
D 4.7
E 3.2
E 0.15 2-4
G 4.8
H 0.023 0.0047 6-11
I 0.0072 0.0052 2.6
J 0.012 0.0039 5-7
K 0.010 0.002 2-11
L 0.014
M 0.15
N 0.95
化合物A-N的结构如下:
实施例3
实施例2的化合物合成如下:
H.
N-(N-乙酰基-酪氨酰基-缬氨酰基-2-哌啶酸基)-3-氨基 -4-氧代丁酸
步骤A
N-(N-叔丁氧羰基-2-哌啶酸基)-4-氨基-5-苄氧 基-2-氧代四氢呋喃
用类似于Chapman所述方法(Bioorg.&Med.Chem.Lett.1992,2,613-618),将N-叔丁氧羰基-2-哌啶酸(460mg,2.0mmol)与N-烯丙氧羰基-4-氨基-5-苄氧基-2-氧代四氢呋喃(530mg,1.82mmol)反应,得到654mg标题化合物。
1H NMR(500MHz,CDCl3(作为旋转异构体存在))δ
7.35(m,5H),6.88(br.s,1H),4.9-4.45(m,4H),3.95
(br.m,2H),3.06(m,1H),2.9(m,1H),2.7(br.m,
1H),2.45(m,1H),2.2(m,1H),1.7-1.5(m,3H),1.45
(s,9H).
步骤B
N-2-哌啶酸基-4-氨基-5-苄氧基-2-氧代四氢呋喃
将N-(N-叔丁氧羰基-2-哌啶酸基)-4-氨基-5-苄氧基-2-氧代四氢呋喃(654mg)溶解于15ml二氯甲烷的25%三氟乙酸中,并在室温搅拌。将混合物浓缩得到胶状剩余物。该剩余物被溶解于二氯甲烷,并用10%碳酸氢钠洗涤。有机相用无水硫酸镁干燥,过滤,浓缩,得到422mg标题化合物为米色固体。
1H NMR(500MHz,CDCl3)δ7.38(m,5H),7.15(d,
1H),5.55(d,1H),4.95-4.8(m,1H),4.78(m,1H),4.65
(d,1H),4.45(m,1H),3.2(m,0.5H),3.05(m,0.5H),
2.95(m,0.5H),2.85(m,0.5H),2.65(m,1H),2.55-
2.38(m,1H),1.95(m,1H),1.8(m,1H),1.6(m,2H),
1.38(m,2H).
步骤C
N-(N-乙酰基-酪氨酰基-缬氨酰基-2-哌啶酸基)-4 -氨基-5-苄氧基-2-氧代四氢呋喃
将N-乙酰基-酪氨酰基-缬氨酸(464mg,1.44mmol)和N-2-哌啶酸基-4-氨基-5-苄氧基-2-氧代四氢呋喃(412mg,1.3mmol)溶解于5ml二甲基甲酰胺和5ml二氯甲烷,并冷却至0℃。在冷却的溶液中加入1-羟基苯并三唑(HOBT;210mg,1.56mmol),然后加入1-(3-二甲基氨基丙基)-3-乙基碳化二亚胺盐酸盐(EDC;326mg,1.7mmol)。搅拌18小时后,混合物用乙酸乙酯稀释,并依次用水,10%硫酸氢钠,10%碳酸氢钠和水洗涤。浓缩有机相,得到粗固体产物。用快速色谱(SiO2)纯化,94∶6∶1二氯甲烷∶异丙醇∶吡啶洗脱,得到370mg标题化合物。
1H NMR(500MHz,CD3OD(
以非对映体及旋转异构体形式存在))δ7.35(m,5H),
7.05(m,2H),6.68(m,2H),5.65&5.25(m,1H),4.9-
3.95(m,8H),3.4-2.6(m,4H),2.5-2.1(m,1H),1.98
(s,1H),1.9(s,1H),1.85(s,1H),1.8-1.6(m,2H),
1.55-1.3(m,4H),0.95-0.85(m,6H).
步骤D
N-(N-乙酰基-酪氨酰基-缬氨酰基-2-哌啶酸基)-3 -氨基-4-氧代丁酸
向100mg N-(N-乙酰基-酪氨酰基-缬氨酰基-2-哌啶酸基)-4-氨基-5-苄氧基-2-氧代四氢呋喃的10ml甲醇溶液中加入60mgPd(OH)2/碳,并通过气球将混合物放到氢气中。用硅藻土过滤混合物,浓缩得到白色固体。将该粗固体产物溶解于2ml甲醇,并用乙醚研制,得到26mg标题化合物。
1H NMR(500MHz,CD3OD(以非对映体及旋转异构体形式存在
))δ7.1(m,2H),6.7(m,2H),5.2
(br.m,1H),4.8-3.6(m,6H),3.2-2.5(m,4H),2.5-2.1
(m,1H),1.95(three s,3H),1.9-1.3(m,6H),1.1-0.7
(m,6H).
下列化合物用类似于H的制备方法制备:
J.
N-[N-乙酰基-酪氨酰基-缬氨酰基-(4-羟基脯氨酰基)]-3 -氨基-4-氧代丁酸
用N-叔丁氧羰基-4-苄氧基脯氨酸代替N-叔丁氧羰基-2-吡啶酸。
L.
N-[2-(N-乙酰基-酪氨酰基-缬氨酰基)-(S)-1,2,3, 4-四氢异喹啉-3-羰基]-3-氨基-4-氧代丁酸
用(S)-N-叔丁氧羰基-1,2,3,4-四氢异喹啉-3-羧酸代替N-叔丁氧羰基-2-哌啶酸。
I.
N-[N-乙酰基-酪氨酰基-缬氨酰基-(4-苯氧基脯氨酰基)]-3 -氨基-4-氧代丁酸
步骤A
N-叔丁氧羰基-4-苯氧基脯氨酸甲酯
用30分钟将氮杂二羧酸二乙酯(1.4ml,9mmol)滴加到N-叔丁氧基-顺-4-羟基脯氨酸(2.0g,8.15mmol),苯酚(0.77g,8.15mmol)和三苯膦(2.14g,8.15mmol)的20ml四氢呋喃冷溶液(0℃)中。反应物在室温搅拌16小时,然后浓缩得到粘性剩余物。用快速色谱(SiO2)纯化该粗剩余物,用3∶7乙酸乙酯∶己烷洗脱,得到1.89g标题化合物。
1H NMR(500MHz,CDCl3)δ7.3(m,2H),6.95(m,
1H),6.85(d,2H),4.9(m br.,1H),4.55-4.15(m,2H),
3.88-3.65(m,1H),3.70(s,3H),2.58(m,1H),2.22(m,
1H),1.4(3xs,9H).
步骤B
4-苯氧基脯氨酸甲酯盐酸盐
向N-叔丁氧羰基-4-苯氧基脯氨酸甲酯(0.6g)的20ml乙酸乙酯冷溶液(冰浴)鼓入无水氯化氢直到饱和。将混合物暖至室温并搅拌3小时,然后浓缩得到480mg标题化合物。
1H NMR(500MHz,CDCl3)δ7.22(m,2H),6.95(m 1
H),6.83(m,2H),5.1(br.,1H),4.6(br.m,1H),4.06
(br.m,1H),3.75(s,3H),3.55(br.m,1H),2.58(m,
2H).
步骤C
N-乙酰基-酪氨酰基-缬氨酰基-(4-苯氧基)脯氨酸甲酯
将N-乙酰基-酪氨酰基-缬氨酸(0.524g,1.63mmol)和4-苯氧基脯氨酸甲酯(0.381g,1.48mmol)溶解于4ml二甲基甲酰胺和4ml二氯甲烷,并冷却至0℃。在该冷溶液中加入二异丙基乙胺(258μl,1.86mmol),HOBT(0.24g,1.78mmol)和EDC(0.37g,1.92mmol),并将反应物搅拌18小时。混合物用400ml乙酸乙酯稀释,并依次用水,10%硫酸氢钠,10%碳酸氢钠和水洗涤。浓缩有机相,得到粗剩余物。用快速色谱(SiO2)纯化,94∶6∶1二氯甲烷∶异丙醇∶吡啶洗脱,得到360mg标题化合物。
1H NMR(500MHz,CDCl3(以旋转异构体形式存在))δ
7.3(m,2H),7.05(m,1H),6.95(d,2H),6.9-6.2(4x
d,4H),5.05(br.s,1H),4.7-3.94(m,5H),2.93(m,
1H),2.82(m,1H),2.65(m,1H),2.2(m,1H),2.05(m,
1H),1.95(s,3H),1.86,(m,1H),0.98(d,3H),0.88
(d,3H).
步骤D
N-乙酰基-酪氨酰基-缬氨酰基-(4-苯氧基)脯氨酸
将氢氧化锂(57mg,1.37mmol)加到N-乙酰基-酪氨酰基-缬氨酰基-(4-苯氧基)脯氨酸甲酯(360mg,0.685mmol)的8ml四氢呋喃/水中,并在室温搅拌1小时。混合物用10%盐酸酸化,产生白色沉淀,收集后得到175mg标题化合物。
1H NMR(500MHz,DMSO-d6)δ9.2(br.s,1H),
8.05-7.95(m,2H),7.3(m,1H),7.0-6.9(m,4H),6.65
(d,2H),4.42(m,1H),4.35(m,1H),4.05-3.95(m,2H),
3.3(br.s,2H),2.75(m,1H),2.55-2.3 8(m,2H),2.2
(m,1H),2.0(m,1H),1.7(s,3H),0.95(d,3H),0.85
(d,3H).
步骤E
N-[N-乙酰基-酪氨酰基-缬氨酰基-(4-苯氧基)脯氨酰 基]-4-氨基-5-苄氧基-2-氧代四氢呋喃
用化合物H步骤A所述方法,将N-乙酰基-酪氨酰基-缬氨酰基-(4-苯氧基)腩氨酸与N-烯丙氧羰基-4-氨基-5-苄氧基四氢呋喃反应,制备标题化合物。
1H NMR(500MHz,CDCl3(
以1∶1非对映体和半缩醛混合物形式存在))δ7.8-6.3(m,
17H),5.6(d,1H),5.1-4.15(m,5H),4.15-3.75(m,2H),
2.95-2.15(m,5H),2.15-1.95(m,1H),1.9-1.85(2xs,
3H),1.1-0.75(m,6H).
步骤F
N-[N-乙酰基-酪氨酰基-缬氨酰基-(4-苯氧基)脯氨酰 基]-3-氨基-4-氧代丁酸
用化合物H步骤D所述氢解方法制备标题化合物。
1H NMR(500MHz,CD3OD(
以1∶1非对映体和半缩醛混合物形式存在))δ7.25(m,
2H),7.10-6.85(m,5H),6.65(d,2H),5.1(br.m,1H),
4.65-4.05(m,5H),4.0-3.40(m,2H),2.95-2.35(m,5H),
2.25(m,1H),2.05(m,1H),1.85(s,3H),1.0(d,3H),
0.95(d,3H).
K
N-[N-乙酰基-酪氨酰基-缬氨酰基-(4-苄氧基)脯氨酰基]-3 -氨基-4-氧代丁酸
步骤A
N-(N-烯丙氧羰基-4-苄氧基脯氨酰基)-3-氨基-4 -氧代丁酸叔丁酯缩氨基脲
在上述(化合物H步骤C)相似的肽偶合条件下将N-烯丙氧羰基-4-苄氧基脯氨酸与3-氨基-4-氧代丁酸叔丁酯缩氨基脲(T.L.Graybill et al.,Abstracts of papers,206th National meeting of theAmerican Chemical Society,Abstract MEDI-235,Chicago,IL.(1993))反应,制备标题化合物。
1H NMR(500MHz,CDCl3)δ9.05(br.s,1H),7.85
(br.m,1H),7.4-7.2(m,5H),7.15(br.s,1H),6.55
(br.s,1H),5.9(m,1H),5.1-4.9(br.m,2H),4.65-4.4
(m,4H),4.2(br.m,1H),3.75-3.5(m,2H),2.75-2.55
(m,2H),2.5(br.m,1H),2.25(br.m,1H)1.4(s,9H).
步骤B
N-[N-乙酰基-酪氨酰基-缬氨酰基-(4-苄氧基脯氨酰 基)]-3-氨基-4-氧代丁酸叔丁酯缩氨基脲
在化合物H步骤A所述反应条件下将N-乙酰基-酪氨酰基-缬氨酸与N-(N-烯丙氧羰基-4-苄氧基脯氨酰基)-3-氨基-4-氧代丁酸叔丁酯缩氨基脲反应,制备标题化合物。
1H NMR(50OMHz,CD3OD)δ7.35-7.2(m,6H),7.0
(d,2H),6.65(d,2H),4.85(m,1H),4.6-4.45(m,4H),
4.3(br.m,1H),4.15(m,1H),3.7(m,1H),2.95(m,
IH),2.75-2.6(m,3H),2.35(m,1H),2.1(m,1H),1.9
(s,3H),1.4(s,9H),0.95(d,3H),0.90(s,3H).
步骤C
N-[N-乙酰基-酪氨酰基-缬氨酰基-(4-苄氧基脯氨酰 基)]-3-氨基-4-氧代丁酸
将N-[N-乙酰基-酪氨酰基-缬氨酰基-(4-苄氧基脯氨酰基)]-3-氨基-4-氧代丁酸叔丁酯缩氨基脲(270mg)溶解于10ml 25%三氟乙酸的二氯甲烷,并在室温搅拌3小时。浓缩混合物得到固体剩余物。将该剩余物溶解于10ml甲醇∶乙酸∶37%甲醛(3∶1∶1)的混合物中,并在室温搅拌1小时。浓缩混合物,用快速色谱(SiO2)纯化所得剩余物,用二氯甲烷/甲醇/甲酸(100∶5∶0.5)洗脱,得到37mg标题化合物。
H NMR(500MHz,CD3OD(
以1∶1非对映体和半缩醛的混合物形式存在))δ7.4-7.25
(m,5H),7.0(d,2H),6.65(d,2H),4.65-4.05(m,7H),
3.75-3.4(m,2H),3.05-2.3(m,5H),2.2-1.95(m,2H),
1.90(s,3H),1.0(d,3H),0.95(d,3H).
实施例4
我们按实施例2所述用紫外-可见底物和细胞测定法进行酶测定,得到了本发明某些化合物的抑制常数(Ki)和IC50值。下面为用所示的测定方法确定的化合物7a,7b,20a-d,21c-f,22e,25,28,33a-c,36a,36b,39,43,47a,47b,54a-1,63,69a,69b,84a和84b的Ki和IC50值。附带指出相应的用字母分类标明的化合物名称。这些化合物的结构示于实施例2和5。
测定方法
紫外-可见
细胞
化合物
Ki(μM) IC50(μM)
7a 35
7b 1.2
20a(=
E) 3.2
20b 0.85 16.4
20c(=
N) 0.95
20d 0.1 6.2
21c 0.64
21d 0.24 4.8
21e 0.22 2.9
21f 0.17 2.9
22e 0.19
25 6.2
28 12.0
33a(=
A) 5.5 25.0
33b(=
C) 10.0 >30.0
33c(=
B) 8.6 20.0
36a(=
D) 4.7
36b 0.8 17.0
39 2.5
43 20.0
47a 0.019 2.1
47b 0.027 1.8
54a(=
F) 0.15 2.7
54b(=
M) 0.15 9.1
54c 1.2 >19.0
54d 1.0
54e 3.5
54f 0.9
54g(=
G) 4.8 >20.0
54h 0.97
54i 0.054 2.4
54j 0.28
54k 0.085
54l 0.215 7.0
63(=
O) 0.85 4.1
69a(=
R) 0.011 0.735
69b(=
S) 0.050 0.745
84a(=
V) 0.100 3.3
84b(=
W) 0.019 0.50
实施例5
实施例4化合物合成如下:
3-苯甲酰氨基-4-氧代-4,6,7,8-四氢-吡咯并[1,2-a]嘧啶-6-羧酸甲酯(3)
将(4S)-2-氨基-1-吡咯-5-羧酸乙酯盐酸盐(1,0.44g,2.38mmol;用类似于下列文献中所述的甲酯制备方法制备:Lee andLown,
J.Org.Chem.,52,5717-21(1987));4-乙氧基亚甲基-2-苯基-噁唑啉-5-酮(2,0.50g,2.31mmol)和甲醇钠(0.12g,2.22mmol)的乙醇(10ml)混合物回流2小时。使反应物冷却至室温并真空浓缩。将剩余物悬浮于水中,加1N硫酸至pH1。将该水混合物用二氯甲烷萃取,分离有机相并真空浓缩,生成0.6g橙色固体。色谱分离(快速,SiO2,60%乙酸乙酯/己烷到100%乙酸乙酯的逐步增加梯度,然后用10%甲醇/二氯甲烷洗脱),得到0.5g橙色固体。将该固体与氰化钾(0.03g,0.5mmol)的混合物在甲醇(10ml)中回流过夜。真空浓缩冷却的反应物,得到黄色固体。色谱分离(快速,SiO2,40%乙酸乙酯/己烷到100%乙酸乙酯梯度洗脱),得到0.22g(31.6%)标题化合物:
1H NMR(d6-DMSO)δ2.25
(m,1H),2.65(m,1H),3.15(m,2H),3.75(s,3H),5.15
(dd,1H),7.5(t,2H),7.6(t,1H),7.95(d,2H),8.6
(s,1H),9.5(s,1H).
(3S)-[(3-苯甲酰氨基-4-氧代-4,6,7,8-四氢-吡咯并[1,2-a]嘧啶-6-羰基)-氨基]-4-氧代丁酸叔丁酯缩氨基脲(5a和5b)
将3-苯甲酰氨基-4-氧代-4,6,7,8-四氢-吡咯并[1,2-a]嘧啶-6-羧酸乙酯(3,0.22g,0.70mmol)和氢氧化锂水合物(0.032g,0.76mmol)的甲醇(5ml)和四氢呋喃(5ml)混合物在室温搅拌18小时。浓缩反应物,得到3-苯甲酰氨基-4-氧代-4,6,7,8-四氢-吡咯并[1,2-a]嘧啶-6-羧酸锂盐(4)为白色固体。该固体无需进一步纯化便可用于下面的反应。
将(3S)-氨基-4-氧代-丁酸叔丁酯缩氨基脲(0.163g,0.71mmol;Graybill et al.,
Int.J.Protein Res.,44,pp.173-82(1994))和3-苯甲酰氨基-4-氧代-4,6,7,8-四氢-吡咯并[1,2-a]嘧啶-6-羧酸锂盐(4)在二甲基甲酰胺(5ml)和二氯甲烷(5ml)中的0℃混合物用羟基苯并三唑(0.104g,0.77mmol)和1-(3-二甲氨基丙基)-3-乙基碳化二亚胺氯化氢(0.148g,0.37mmol)处理。使反应物冷却至室温并搅拌18小时。将反应物倒入水(50ml)中,用乙酸乙酯(2×50ml)萃取。合并的有机相依次用1M硫酸氢钠水溶液,碳酸氢钠稀水溶液(50ml)和饱和氯化钠水溶液洗涤。真空浓缩有机相,得到0.43g黄色固体。色谱分离(快速,SiO2,氢氧化铵/甲醇/二氯甲烷1∶1∶99到1∶10∶90梯度洗脱),得到0.11g(30.9%)较高Rf的非对映体(5a):
1H NMR(CD3OD)δ1.45(s,9H),2.29-2.35(m,1H),2.6-
2.7(m,2H),2.8(dd,1H),3.1-3.15(m,1H),3.2-3.3
(m,1H),4.9-4.95(m,1H),5.2(dd,1H),7.25(d,1H),
7.5-7.55(m,2H),7.55-7.6(m,1H),7.95(d,2H),8.9
(s,1H)和0.11g(30.9%)较低Rf的非对映体(5b):
1H NMR(CD3OD)δ1.45(s,9H),2.3-2.4(m,1H),
2.6-2.7(m,1H),2.7-2.8(m,2H),3.1-3.15(m,1H),
3.2-3.3(m,1H),4.85-4.95(m,1H),5.15(dd,1H),7.25
(d,1H),7.55(t,2H),7.6(t,1H),7.95(d,2H),8.9
(s,1H).
然后将非对映体(5a)与非对映体(5b)分开。
(3S)-[(3-苯甲酰氨基-4-氧代-4,6,7,8-四氢-吡咯并[1,2-a]嘧啶-6-羰基)-氨基]-4-氧代丁酸(7a)
将(3S)-[(3-苯甲酰氨基-4-氧代-4,6,7,8-四氢-吡咯并[1,2-a]嘧啶-6-羰基)-氨基]-4-氧代丁酸叔丁酯缩氨基脲(5a,0.11g,0.22mmol)的二氯甲烷(7.5ml)和三氟乙酸(2.5ml)的悬浮液搅拌5小时。真空浓缩反应物,剩余物溶解于二氯甲烷,真空浓缩,悬浮于甲苯,真空浓缩,得到0.07g(3S)-[(3-苯甲酰氨基-4-氧代-4,6,7,8-四氢-吡咯并[1,2-a]嘧啶-6-羰基)-氨基]-4-氧代丁酸缩氨基脲(6a)为白色固体。将固体悬浮于37%甲醛水溶液/乙酸/甲醇(1∶1∶5)的混合物中并在室温搅拌18小时。真空浓缩反应物,剩余物悬浮于乙腈,再真空浓缩,得到0.1g白色固体。色谱分离(HPLC,反相C18,1%到75%乙腈/水(用0.1%三氟乙酸缓冲)梯度洗脱),得到0.05g(60%)7a为白色固体。RT=7.9分钟(HPLC,C18反相,1至100%乙腈/水(0.1%三氟乙酸缓冲剂);20分钟梯度洗脱);
1H NMR(CD3OD(以1∶1半酸基乙缩醛异头物的混合物形式存在))
δ2.25-2.4(m,1H),
2.45-2.8(m,4H),3.05-3.15(m,1H),4.25-4.35(m,1H),
4.55-4.6(m,1H),5.1-5.2(m,1H),7.45-7.65(m,3H),
7.9-8.0(m,2H),8.9(s,1H).
(3S)-[(3-苯甲酰氨基-4-氧代-4,6,7,8-四氢-吡咯并[1,2-a]嘧啶-6-羰基)-氨基]-4-氧代丁酸(7b)
制备方法同非对映体(7a)的制备,得到0.03g(35%)7b为白色固体。RT=8.1分钟(HPLC,C18反相,1至100%乙腈/水(0.1%三氟乙酸缓冲剂);20分钟梯度洗脱);
1H NMR(d6-DMSO(以1∶1半酸基乙缩醛异头物的混合物形式存在))
δ2.1-2.2(m,1H),2.4(d,1H),
2.7-2.8(m,1H),3.0-3.2(m,3H),5.0(dd,1H),5.1-5.2
(m,1H),5.5(s,1H),5.7-5.8(m,1H),7.55(t,2H),
7.67(t,1H),7.95(d,2H),8.55(s,1H),9.0-9.15(m,
1H),9.4-9.5(m,1H).
a R=H
b R=PhCH2
c R=Ph(CH2)2
d R=Ph(CH2)3
e R=4MeO-Ph(CH2)3
f R=4HO-Ph(CH2)3
咪唑-2-羧酸(13)用文献所述方法的改进方法制备:
(Yamanaka et al.,
Chem.Pharm.Bull.,31,pp.4549-53(1983));Suzuki et
al.,
J.Org.Chem.,38,pp.3571-75(1973));and Oliver
et al.(
J.Org.Chem.,38,pp.1437-38(1973)).
咪唑-2-羧酸(13a)根据Curtis and Brown,J.Org.Chem.,45,pp.4038-40(1980)所述制备。
4-苄基咪唑-2-羧酸(13b)被分离出来,为乳白色固体。
mp.153-155℃;IR(KBr)3026-
2624,1630,1515,1498,1438,1405;1H NMR(d6-DMSO)δ
7.31(5H,m),7.14(1H,s),3.95(2H,s).
4-(2-苯基乙基)咪唑-2-羧酸(13c)被分离出来,为淡黄色固体:
mp.151-153℃;IR
(KBr)3054-2617,1637,1497,1376;1H NMR(d6-DMSO)δ
7.27(5H,m),7.11(1H,s),2.92(4H,s).
4-(3-苯基丙基)咪唑-2-羧酸(13d)被分离出来,为淡黄色固体:
mp.148-150℃;IR
(KBr)3020-2615,1636,1509,1498,1383;1H NMR(d6-
DMSO)δ7.35-7.22(5H,m),7.01(1H,s),2.62(4H,m),
1.94(2H,m).
4-[3-(4-甲氧基苯基)丙基]咪唑-2-羧酸(13e)被分离出来,为白色晶状固体:
mp.155-156℃(分解);IR(KBr)3300-2300,1633,
1513,1376,1244;1H NMR(d6-DMSO)δ9.50-7.50(2H,bs),
7.15(1H,s),7.11(2H,d,J=8.5),6.84(2H,d,J=8.5),
3.71(3H,s),2.60-2.50(4H,m),1.86(2H,m).
元素分析C14H16N2O3:
计算值:C,64.60;H,6.20;N,10.76,
实测值:C,64.45;H,6.21;N,10.70。
4-[3-(4-羟基苯基)丙基]咪唑-2-羧酸(13f)
将13e的乙酯(1.15g,4.0mmol)的无水二氯甲烷(50ml)溶液在0℃用三溴化硼(16ml,1.0M的CH2Cl2溶液,16.0mmol)处理。在0℃15分钟后将混合物暖至25℃,并搅拌16小时。反应混合物在冰浴中冷却,并滴加水(20ml)淬灭反应。所得的混合物在25℃短暂搅拌之后过滤。小心地添加固体NaHCO3来中和滤液,得到标题化合物13f(700mg,71%)为白色固体。m.p.186-187℃(分解)(从MeOH重结晶)。
IR(KBr)3500-2400,2935,
1640,1516,1396,1232;1H NMR(d6-DMSO)δ9.83(3H,bs),
7.16(1H,s),6.98(2H,d,J=8.2),6.66(2H,d,J=8.2),
2.60-2.40(4H,m),1.84(2H,m).
元素分析C13H14N2O3:
计算值:C,63.40;H,5.73;N,11.38,
实测值:C,62.96;H,5.70;N,11.27。
(2R,S,3S)N2-叔丁氧羰基-N-(四氢-2-苄氧基-5-氧代-3-呋喃基)-L-丙氨酰胺(14)
将三-正丁基氢化锡(4.0ml,14.9mmol)滴加到(2R,S,3S)3-(N-烯丙氧羰基)-氨基-2-苄氧基-5-氧代四氢呋喃(2.91g,10mmol;Chapman,Biorg.Med.Chem.Lett.,2,pp.613-18(1992)),N-叔丁氧羰基-L-丙氨酸(2.08g,11mmol)和双(三苯膦)氯化钯(II)(150mg)的二氯甲烷(75ml)溶液中直到溶液的颜色变成深橙色。加入羟基苯并三唑(2.70g,20mmol),并将混合物冷却到0℃。加入1-(3-二甲氨基-丙基)-3-乙基碳化二亚胺盐酸盐(2.30g,12mmol),然后用4小时将混合物缓慢升至室温。混合物用乙酸乙酯(250ml)稀释,依次用1N盐酸(3×150ml),饱和碳酸氢钠水溶液(3×150ml)和盐水(2×150ml)洗涤,干燥(MgSO4),过滤并浓缩。粗产物用柱色谱纯化(50-70%乙酸乙酯/己烷),得到3.17g(84%)非对映体的混合物。重结晶(乙酸乙酯/己烷)后得到无色晶体: mp.132-145℃;
IR(KBr)3357,3345,1781,1688,1661,1535,1517,
1165;1H NMR(d6-DMSO)δ8.49(d,J=6.8),8.23(d,J=
7.4),7.40(5H,m),7.01(1H,m),5.68(d,J=5.0),
4.75(m),4.31(m),3.97(1H,m),2.82(m),3.11(m),
2.82(m),2.59(m),2.45(m),1.40(9H,s),1.20(d,J
=7.2),1.16(d,J=7.2).
元素分析C19H26N2O6:
计算值:C,60.31;H,6.92;N,7.40,
实测值:C,60.30;H,6.91;N,7.38。
(2R,S,3S)叔丁氧羰基-N-(四氢-2-苄氧基-5-氧代-3-呋喃基)-L-脯氨酰胺(15)
用14所述方法制备,得到1.64g(81%)无色玻璃体。
IR(KBr)3317,2978,1797,
1697,1670,1546,1400,1366,1164,1121;1H NMR(CDCl3)
δ7.68(1H,brm),7.35(5H,m);5.53(d,J=5.2),5.43
(s),4.93-4.61(m),4.44(m),4.25(brm),3.39(2H,
brm),3.10-2.81(1H,m),2.44(1H,m),2.32(brm),1.88
(brm),1.67(brm),1.42(9H,s).
(2R,S,3S)N-(N-叔丁氧羰基-(4(R)-苯氧基-L-脯氨酰基)-3-氨基-2-苄氧基-5-氧WA四氢呋喃(16)
用14所述方法制备,得到530mg(84%)无色非晶状固体:
1H NMR
(CDCl3)δ7.65(1H,m),7.4-7.2(7H,m),6.95(1H,m),
6.85(1H,m),5.55(1H,d),4.95(1H,d),4.8-4.7(1H,
brm),4.65(1H,d),4.55-4.45(1H,brm),4.4-4.3(0.5H,
brm),3.95-3.85(0.5H,brm),3.75-3.58(2H,m),2.95-
2.8(1H,m),2.7-2.55(1H,m),2.54-2.4(1H,m),2.35-
2.2(1H,m),1.4(9H,s).
(2R,S,3S)N2-[4-(3-苯基丙基)咪唑-2-羰基]-N-(四氢-2-苄氧基-5-氧代-3-呋喃基)-L-丙氨酰胺(17d)
在0℃将三氟乙酸(7ml)加到(2R,S,3S)N2-叔丁氧羰基-N-(四氢-2-苄氧基-5-氧代-3-呋喃基)-L-脯氨酰胺(14)(1.00g,2.64mmol)的二氯甲烷(7ml)溶液中。在0℃搅拌混合物75分钟。浓缩混合物,剩余物用乙醚处理,然后真空除去乙醚。重复这个过程两次,得到浅黄色玻璃体。将该固体溶解于DMF(20ml)。加入二异丙基乙胺(1.38ml,7.92mmol),然后向溶液中加入4-(3-苯基丙基)咪唑-2-羧酸(13d)(0.67g,290mmol),1-(3-二甲氨基丙基)-3-乙基碳化二亚胺盐酸盐(0.56g,2.90mmol)和羟基苯并三唑(0.71g,5.28mmol)。将混合物在室温搅拌20小时,然后倒入盐水中。用乙酸乙酯(3×50ml)萃取混合物。合并的有机萃取液用饱和碳酸氢钠水溶液(2×100ml)洗涤之后用盐水(2×100ml)洗涤,干燥(MgSO4),过滤并浓缩。剩余物用柱色谱纯化(乙酸乙酯),得到0.99g(76%)标题化合物17d为非对映体的混合物:
IR(KBr)3293,
3064,2937,1793,1650,1530,1451,1446,1119;1H NMR
(CDCl3)δ7.96(brm),7.62(brd),7.36-7.10(10H,m),
6.88(s),6.86(s),5.53(d,J=5.2),5.48(s),4.87-
4.52(4H,m),3.11-2.38(2H,m),2.65(4H,m),1.99
(2H,m),1.47(d,J=6.9),1.46(d,J=7.0).
用类似方法制备下列化合物。
(2R,S,3S)N2-(咪唑-2-羰基)-N-(四氢-2-苄氧基-5-氧代-3-呋喃基)-L-丙氨酰胺(17a)
分离出的标题化合物(74%)为浅黄色固体:
IR(KBr)3289,3056,2937,1793,1664,1642;1528;1453,1440,1124;1H NMR(d6-DMSO)δ13.13(1H,brs),8.67(d,J=7.0),8.48(d,J=7.8),8.2 9(d,J=6.8),8.25(d,J=7.6),7.4 0-7.34(6H,m),7.11(1H,s),5.69(d,J=5.0),5.49(d,J=0.8),4.85-4.31(4H,m),3.19-2.42(2H,m),1.38(d,J=7.4),1.34(d,J=7.4).
(2R,S,3S)N2-(4-苄基咪唑-2-羰基)-N-(四氢-2-苄氧基-5-氧代-3-呋喃基)-L-丙氨酰胺(17b)
分离出的标题化合物(75%)为浅黄色玻璃体:
IR
(KBr)3294,3031,2937,1792,1650,1530,1453,1444,
1119;1H NMR(CDCl3)δ7.99(brm),7.75(brd),7.36-7.11
(10H,m),6.81(1H,s),5.51,5.45(d,s,J=5.3),4.85-
4.47(4H,m),3.95(2H,s),3.04-2.72(1H,m),2.48-
2.35(1H,m),1.44(d,J=6.9),1.43(d,J=7.1).
(2R,S,3S)N2-[4-(2-苯乙基)咪唑-2-羰基]-N-(四氢-2-苄氧基-5-氧代-3-呋喃基)-L-丙氨酰胺(17c)
分离出的标题化合物(79%)为浅黄色玻璃体:
IR
(KBr)3292,3029,2936,1793,1650,1530,1453,1444,
1119;1H NMR(CDCl3)δ8.06(brm),7.70(brs),7.39-7.15
(10H,m),6.82(s),6.81(s),5.53(d,J=5.2),5.48
(s),4.87-4.53(4H,m),2.95(4H,m),3.11-2.37(2H,
m),1.48(d,J=5.6),1.45(d,J=6.7).
(2R,S,3S)1-[4-(2-苯乙基)咪唑-2-羰基]-N-(四氢-2-苄氧基-5-氧代-3-呋喃基)-L-脯氨酰胺(18c)
分离出的标题化合物(79%)为浅黄色玻璃体:
IR
(CH2Cl2)3422,2959,1795,1685,1611,1497,1116;
1H NMR(d6-DMSO)δ12.78-12.59(1H,m),8.61-8.34(1H,
m),7.39-7.22(10H,m),6.99-6.61(1H,m),5.71-5.26
(1H,m),4.85-4.02(4H,m),3.63(1H,m),3.18-1.74
(11H,m).
(2R,S,3S)1-[4-(3-苯丙基)咪唑-2-羰基]-N-(四氢-2-苄氧基-5-氧代-3-呋喃基)-L-脯氨酰胺(18d)
分离出的标题化合物(87%)为无色玻璃体:
IR(CH2Cl2)3422,3214,2945,1794,1685,1604,
1496,1117;1H NMR(d6-DMSO)δ12.71(1H,brm),8.61-
8.34(1H,m),7.45-7.18(10H,m),7.05-6.64(1H,m),
5.70-5.28(1H,m),4.85-4.02(4H,m),3.62(1H,m)
3.18-1.71(13H,m).
(2R,S,3S)1-{4-[3-(4-甲氧基苯基)丙基]咪唑-2-羰基}-N-(四氢-2-苄氧基-5-氧代-3-呋喃基)-L-脯氨酰胺(18e)
分离出的标题化合物(72%)为白色玻璃状固体:
mp.62-65℃;IR(KBr)3213,2937,1793,
1680,1606,1606,1512,1245;1H NMR(d6-DMSO)δ12.71,
12.67,12.58(1H,3xbs),8.60-8.30(1H,m),7.40-7.20
(5H,m),7.15-6.55(5H,m),5.66-5.20(1H,m),4.81-
4.59(2H,m),4.55-4.05(2H,m),3.71(3H,s),3.65-
3.45(1H,m),3.15-1.50(13H,m).FABSMS m/e 547(M+,
100%),439,412,340,312,243,177,154.
(2R,S,3S)1-{4-[3-(4-羟基苯基)丙基]咪唑-2-羰基}-N-(四氢-2-苄氧基-5-氧代-3-呋喃基)-L-脯氨酰胺(18f)
分离出的标题化合物(70%)为浅黄色玻璃状固体:
mp.86-90℃;IR(KBr)3298,1790,
1669,1606,1515,1242;1H NMR(d6-DMSO)δ12.66,12.56
(1H,2xbs),9.14(1H,s),8.57-8.30(1H,m),7.36-
7.30(5H,m),7.02-6.83(3H,m),6.70-6.57(2H,m),
5.65-5.28(1H,m),4.80-4.49(2H,m),4.50-4.05(2H,
m),3.65-3.45(1H,m),3.15-1.55(13H,m).FABMS m/e
533(M+,100%),425,298,229,176,154.
1-{5-[3-(4-甲氧基苯基)丙基]-1H-咪唑-2-羰基}-4(R)-苯氧基吡咯烷-2(S)-羰基-(四氢-2(R,S)-苄氧基-5-氧代-3(S)-基)酰胺(19e)
分离出的标题化合物(77%)为透明无色非晶状固体。
1H NMR(CDCl3)δ9.95-9.75(1H,m),7.95(1H,
brs),7.40-7.2(7H,m),7.2-6.78(7H,m),5.65-5.6(1H,
m),5.55-5.45(1H,m),5.3-5.2(1H,m),5.15-5.0(1H,
m),4.95-4.75(1H,m),4.7-4.6(1H,m),4.5-4.4(1H,
m),4.35-4.4.25(1H,m),3.8(3H,s),3.05-1.75(10H,
m).
(3S)3-{N-[4-(3-苯基丙基)咪唑-2-羰基]-L-丙氨酰基}氨基-4-氧代-丁酸(20d)
将(2R,S,3S)N2-[4-(3-苯基丙基)咪唑-2-羰基]-N-(四氢-2-苄氧基-5-氧代-3-呋喃基)-L-丙氨酰胺(0.93g,1.90mmol)和10%钯/活性炭(0.93g)的甲醇(100ml)混合物在氢气下搅拌5小时。过滤所得混合物并浓缩,得到无色玻璃体。从甲醇-乙醚重结晶,得到401mg(53%)标题化合物20d为无色固体:
mp.94-96℃;[α]D 27+16.4°(c 0.5,
MeOH);IR(KBr)3300,3287,1786,1732,1659,1651,
1532,1451;1H NMR(CD3OD)δ7.19(5H,m),6.91(1H,s),
4.60-4.46(2H,m),4.27(1H,m),2.63(4H,m),2.75-
2.40(2H,m),1.96(2H,m),1.44(3H,d,J=7.0).
用类似方法制备下列化合物。
(3S)3-[N-(咪唑-2-羰基)-L-丙氨酰基]氨基-4-氧代丁酸(20a;E)
分离出的标题化合物(83%)为透明无色固体:
mp.115℃;[α]D 25+4.4°(c 0.5,MeOH);
IR(KBr)3303,1782,1658,1650,1563,1521,1454;1H
NMR(CD3OD)δ7.18(2H,s),4.55(2H,m),4.27(1H,m),
2.56(2H,m),1.45(d,J=7.1),1.44(d,J=7.0).
(3S)3-[N-(4-苄基咪唑-2-羰基)-L-丙氨酰基]氨基-4-氧代丁酸(20b)
分离出的标题化合物(56%)为无色固体:
mp.113-115℃;[α]D 29+18.2°
(c 0.5 MeOH).IR(KBr)3301,3288,1783,1727,1650,
1531,1452;1H NMR(CD3OD)δ7.25(5H,m),6.90(1H,s),
4.59-4.45(2H,m),4.26(1H,m),3.95(2H,s),2.74-
2.39(2H,m),1.42(3H,d,J=7.0).
元素分析C18H20N4O5:
计算值:C,56.69;H,5.55;N,14.69,
实测值:C,57.06;H,5.54;N,14.41。
(3S)3-{N-[4-(2-苯基乙基)咪唑-2-羰基]-L-丙氨酰基}氨基-4-氧代丁酸(20c;N)
分离出的标题化合物(53%)为无色固体:
mp.102-104℃;
[α]D 27+13.7°(c 0.5,MeOH);IR(KBr)3299,3289,1785,
1732,1650,1531,1452;1H NMR(CD3OD)δ7.20(5H,m),
6.82(1H,s),4.60-4.46(2H,m),4.29(1H,m),2.92
(4H,s),2.76-2.41(2H,m),1.44(3H,2xd,J=7.1).
元素分析C19H22N4O5·H2O:
计算值:C,56.43;H,5.98;N,13.85,
实测值:C,56.65;H,5.84;N,13.91。
(3S)3-{N-[4-(2-苯基乙基)咪唑-2-羰基]-L-脯氨酰基}氨基-4-氧代丁酸(21c)
分离出的标题化合物(85%)为无色玻璃体:m.p.101-103℃(甲醇-乙醚);
[α]D 27-63.8°(c 0.25,MeOH);IR(KBr)
3275,1784,1728,1664,1606,1498,1429;1H NMR(CD3OD)
δ7.24(5H,m),6.83(s),6.79(s),4.58-4.14(3H,m),
3.69(1H,m),2.93(4H,brs),2.75-1.99(6H,m).
元素分析C21H24N4O5·H2O:
计算值:C,58.60;H,6.09;N,13.02,
实测值:C,58.34;H,5.96;N,12.67。
(3S)3-{N-[4-(3-苯基丙基)咪唑-2-羰基]-L-脯氨酰基}氨基-4-氧代丁酸(21d)
分离出的标题化合物(81%)为无色玻璃体:m.p.91-94℃(甲醇-乙醚);
[α]D 25-68°(c 0.25,MeOH);IR
(KBr)3277,2939,1784,1727,1662,1606,1498,1429;
1H NMR(CD3OD)δ7.29-7.16(5H,m),6.92(s),6.86(s),
4.58-4.16(3H,m),3.71(1H,m),2.75-1.92(13H,m).
元素分析C22H26N4O5·H2O:
计算值:C,59.45;H,6.35;N,12.60,
实测值:C,59.75;H,6.21;N,12.41。
(3S)3-{N-[4-[3-(4-甲氧基苯基)丙基]咪唑-2-羰基]-L-脯氨酰基}氨基-4-氧代丁酸(21e)
分离出的标题化合物(65%)为白色玻璃状固体:
mp.101-
105℃;[α]D 23-60.6(c 0.05,MeOH);IR(KBr)3231,1784,
1726,1611,1512,1245;1H NMR(CD3OD)δ7.09(2H,d,
J=8.6),6.92,6.85(1H,2xs),6.81.(2H,d,J=8.6),
5.45-5.30(1H,m),4.64-4.46(1H,m),4.28-4.10(2H,
m),3.75(3H,s),3.74-3.66(1H,m),2.67-1.84(13H,
m).
元素分析C23H28N4O6·H2O:
计算值:C,58.22;H,6.37;N,11.81,
实测值:C,58.39;H,6.34;N,11.45。FABMS m/e
457(M+),405,312,243,215,176,154(100%).
(3S)3-{N-[4-[3-(4-羟基苯基)丙基]咪唑-2-羰基]-L-脯氨酰基}氨基-4-氧代丁酸(21f)
分离出的标题化合物(43%)为白色玻璃状固体:
mp.114-
118℃;[α]D 25-55.7°(c 0.05,MeOH);IR(KBr)3288,
2935,1780,1715,1662,1610,1515,1441;1H NMR(CD3OD)
δ6.99(2H,d,J=8.5),6.91,6.85(1H,2xs),6.68
(2H,d,J=8.5),5.45-5.30(1H,m),4.60-4.47(1H,m),
4.30-4.10(2H,m),3.80-3.55(1H,m),2.70-1.80(13H,
m).
元素分析C22H26N4O6·H2O:
计算值:C,57.38;H,6.13;N,12.17,
实测值:C,57.68;H,6.25;N,11.66。
FABMS m/e 443(M+),298,229,154(100%).
3(S)-[(1-{5-[3-(4-甲氧基苯基)丙基]-1H-咪唑-2-羰基}-4(R)-苯氧基吡咯烷-2(S)-羰基)氨基]-4-氧代丁酸(22e)
分离出的标题化合物(43%)为米色固体:
1H NMR(CD3OD)δ7.35-7.2
(3H,m),7.15-7.0(2H,m),6.98-6.85(3H,m),6.83-6.77
(2H,d),5.4-5.1(1H,m),4.65-4.5(1H,m),4.35-4.2
(2H,m),4.15-3.90(1H,m),3.78(3H,s),3.62-3.48(1H,
m),2.78-2.25(8H,m),2.02-1.9(2H,m).
{苯乙基-[5-(3-丙基)-1H-咪唑-2-羰基]氨基}-乙酸叔丁酯(23)
将0℃的4-(3-苯丙基)-咪唑-3-羧酸(13d)(150mg,0.65mmol)和N-(2-苯乙基)甘氨酸叔丁酯(140mg,0.59mmol)的5ml无水二甲基甲酰胺溶液用二异丙基乙胺(150μl,0.89mmol),羟基苯并三唑(160mg,1.18mmol)和1-(3-二甲氨基丙基)-3-乙基碳化二亚胺盐酸盐(136mg,0.71mmol)处理。搅拌36小时后将反应物倒入饱和氯化钠水溶液,用乙酸乙酯(3×50ml)萃取。合并的有机萃取液用饱和碳酸氢钠水溶液(2×)和饱和氯化钠水溶液(1×)洗涤两次,干燥(Na2SO4),过滤,并真空浓缩,得到棕色油。色谱分离(快速,SiO2,30%乙酸乙酯/己烷),得到160mg(61%)标题化合物23为白色固体: 1H NMR
(CDCl3)δ7.38-7.14(10H,m),6.85-6.8(1H,m),4.84-
4.76(1H,d),4.5-4.42(1H,m),4.07-4.0(1H,d),3.78-
3.72(1H,m),3.12-2.94(2H,2xm),2.75-2.55(4H,m),
2.1-1.95(2H,m),1.5-1.45(9H,3xs).
(3S)-(2-{苯乙基-[5-(3-苯丙基)-1H-咪唑-2-羰基]氨基}乙酰氨基)-4-氧代丁酸叔丁酯缩氨基脲(24)
将酯(23)(160mg,0.357mmol)用25%三氟乙酸/二氯甲烷(7ml)处理4小时。真空浓缩反应物,得到180mg酸。按化合物5a和5b的制备方法将该酸(180mg,0.357mmol)与(3S)-3-氨基-4-氧代丁酸叔丁酯缩氨基脲(161mg,0.357mmol)偶合,得到86mg(33%)标题化合物24(一种非对映体)为白色固体:1H NMR(CDCl3)δ10.9-10.3(1H,2d),10.08-
9.78(1H,2d),9.25-9.15(1H,m),8.35-8.10(1H,2m),
7.9-7.85(1H,2s),7.40-7.05(10H,m),6.9-6.75
(1H,m),6.3-5.8(1H,br s),5.2-4.65(2H,m),4.35-3.5
(3H,m),3.25-3.0(2H,m),2.9-2.45(6H,m),2.05-1.8
(2H,m),1.4(9H,s).
(3S)-(2-{苯乙基-[5-(3-苯丙基)-1H-咪唑-2-羰基]氨基}乙酰氨基)-4-氧代丁酸三氟乙酸盐(25)
用制备化合物7a时所述方法制备,得到32mg(82%)标题化合物25为白色固体:
1H NMR(CD3OD)δ7.05-7.35(m,11H),4.65
(m,1H),4.4(m,1H),4.3(s,2H),3.6-4.0(m,2H),
2.5-2.95(m,8H),2.05(m,2H).
7-[5-(3-苯丙基)-1H-咪唑-2-羰基]-1,4-二噻-7-氮杂螺[4.4]壬烷-8(S)-羧酸甲酯(26)
用化合物23的制备方法将4-(3-苯丙基)咪唑-2-羧酸(13d)与1,4-二噻-7-氮杂螺[4.4]壬烷-8(S)-羧酸甲酯氢溴化物(Smith et al.,J.Med.Chem.,31,pp.875-85(1988))偶合,得到140mg(65%)标题化合物26为黄色胶体:
1H NMR(CDCl3)δ7.34-
7.15(5H,m),6.98-6.8(1H,3s),5.7-5.65(0.5H,m),
5.2-5.1(1H,m),4.82-4.75(0.5H,m),4.4-4.35(1H,m),
4.05(1H,d),3.75-3.7(3H,2s),3.4-3.3(4H,m),2.95-
2.45(8H,m),2.05-1.95(2H,m).
(3S)-({7-[5-(3-苯丙基)-1H-咪唑-2-羰基]-1,4-二噻-7-氮杂螺[4.4]壬烷-8(S)-羰基}-氨基)-4-氧代丁酸叔丁酯缩氨基脲(27)
用化合物4的制备方法将酯26转化成它的酸,接着采用化合物24的制备方法将其与(3S)-3-氨基-4-氧代丁酸叔丁酯缩氨基脲偶合,得到70mg(33%)标题化合物27为棕色固体。
1H NMR(CD3OD)δ7.28-7.10
(5H,m),6.90(1H,br s),4.94(1H,m),3.96-3.86
(2H,q),3.35-3.25(4H,d),3.0(2H,s),2.73-2.59(6H,
m),2.0-1.92(2H,m),1.44(9H,s).
(3S)-({7-[5-(3-苯丙基)-1H-咪唑-2-羰基]-1,4-二噻-7-氮杂螺[4.4]壬烷-8(S)-羰基}-氨基)-4-氧代丁酸(28)
用化合物7a的制备方法制备,得到17mg(26%)标题化合物28为浅棕色固体:
1H NMR(CD3OD)δ7.4(s,1H),7.1-7.25(m,5H),
4.9(m,1H),4.6(m,1H),4.3(m,1H),3.95(s,2H),
3.25-3.4(m,4H),3.0(d,2H),2.6-2.8(m,5H),2.45
(m,1H),2.05(m,22H).
a R=Ph(CH2)2
b R=4CF3-Ph(CH2)2
c R=PhCH2
4,5-二氢咪唑-4-羧酸酯(29)
用Jones et al.,Tetrahedron Lett.,29,pp.3853-56(1988)所述方法的改进方法制备标题化合物29。
(4R,S)2-(2-苯乙基)-4,5-二氢咪唑-4-羧酸甲酯(29a)
在0℃向氢化肉桂腈(hydrocinnamonitrile)(3.28ml,25mmol)的甲醇(125ml)溶液鼓入干燥氯化氢气体45分钟。除去溶剂后得到亚氨酸盐,将其与2,3-二氨基丙酸甲酯(25mmol)(Jones et al.,
supra)一起溶解于甲醇(125ml)。将混合物保持在室温2.5小时,然后浓缩成黄色油。粗产物用柱色谱纯化(10-20%甲醇/二氯甲烷),得到3.52g(61%)无色玻璃体:
1H NMR(CDCl3)δ7.30-7.15(5H,m),
4.63(1H,t,J=9.7),3.96(2H,d,J=9.7),3.72(3H,s),
3.10(4H,m),13C NMR(CDCl3)δ171.3,168.8,138.3,
128.4,128.2,126.6,57.3,53.0,47.7,31.7,27.9.
(4R,S)2-[2-(4-三氟甲基苯基)乙基]-4,5-二氢咪唑-4-羧酸甲酯(29b)
用29a所述方法制备,得到6.80g(78%)无色固体:
mp.136-141℃;1H NMR(CDCl3)δ7.45
(4H,s),4.71(1H,dd,J=8.6,10.8),4.02(2H,m),3.73
(3H,s),3.19(4H,m).
咪唑-4-羧酸酯(30)
采用Martin et al.,
J.Org.Chem.,33,pp.3758-61(1968)所述方法的改进方法制备。
2-(2-苯乙基)咪唑-4-羧酸甲酯(30a)
将(4R,S)2-(2-苯乙基)-4,5-二氢咪唑-4-羧酸甲酯(29a)(3.40g,14.64mmol),氯仿(75ml)和氧化锰(IV)(13.0g,150mmol)的混合物加热回流2小时,然后趁热过滤。所得固体用氯仿和甲醇洗涤。浓缩合并的滤液,得到黄棕色固体。经柱色谱(2-5%甲醇/二氯甲烷)纯化后得到1.46g(43%)浅黄色固体: mp.151-
155℃;IR(KBr)3028,2946,1720,1533,1433,1348,
1195,1166;1H NMR(CDCl3)δ7.62(1H,s),7.26-7.02(5H,
m),3.82(3H,s),3.03(4H,brs),13C NMR(CDCl3)δ
162.9,150.2,140.3,128.5,128.2,126.3,51.5,34.5,
30.4.
元素分析C13H14N2O2:
计算值:C,67.81;H,6.13;N,12.16,
实测值:C,67.70;H,6.15;N,12.16。
2-[2-(4-三氟甲基苯基)乙基]咪唑-4-羧酸甲酯(30b)
用30a所述方法制备,然后从乙酸乙酯中重结晶,得到1.88g(33%)乳白色晶体:
mp.225-26℃;IR
(KBr)3239,2951,1715,1532,1331,1158,1105,1068;
1H NMR(CDCl3)δ7.61(1H,s),7.54(2H,d,J=8.1),
7.26(2H,d,J=8.1),3.89(3H,s),3.10(4H,m).
元素分析C14H13F3N2O2:
计算值:C,56.38;H,4.39;N,9.39;F,19.11,
实测值:C,56.23;H,4.44;N,9.33;F,19.08。
2-(2-苯乙基)咪唑-4-羧酸(31a)
将2-(2-苯乙基)咪唑-4-羧酸甲酯(30a)(1.38g,6mmol),甲醇(30ml)和1M氢氧化钠水溶液(30ml)的混合物加热回流16小时。减压除去甲醇,所得水溶液用4M盐酸中和,命名浅黄色固体析出。收集沉淀,用水洗涤并干燥,得到1.18g(91%)浅黄色固体:
mp.117-120℃;IR(KBr)
3375,3131,2616,2472,1638,1592,1551,1421,1388,
1360;1H NMR(d6-DMSO)δ7.59(1H,s),7.26(5H,m),2.99
(4H,m).
元素分析C12H12N2O2·1/4H2O:
计算值:C,65.29;H,5.71;N,12.69,
实测值:C,65.00;H,5.64;N,12.58。
2-[2-(4-三氟甲基苯基)乙基]咪唑-4-羧酸(31b)
用31a所述方法制备,得到1.09g(76%)浅黄色固体:
mp.126-130℃;IR(KBr)3339,2640-2467,1638,1589,1545,1383,1323;1H NMR(d6-DMSO)δ7.69(2H,d,J=8.0),7.59(1H,s),7.47(2H,d,J=8.0),3.06(4H,m).
(2R,S,3S)N2-[2-(2-苯乙基)咪唑-4-羰基]-N-(四氢-2-苄氧基-5-氧代-3-呋喃基)-L-丙氨酰胺(32a)
向冷却到0℃的(2R,S,3S)N2-叔丁氧羰基-N-(四氢-2-苄氧基-5-氧代-3-呋喃基)-L-丙氨酰胺(14)(1.59g,4.20mmol;Chapman,
Biorg.Med.Chem.Lett.,2,pp.6131-18(1992))的二氯甲烷(15ml)溶液中加入三氟乙酸(15ml)。将混合物在0℃搅拌1小时,然后浓缩。剩余物用乙醚处理,然后真空除去乙醚。重复上述过程两次,得到浅黄色玻璃体。将此固体溶解于DMF(20ml),并在所得溶液中加入二异丙基乙胺(2.19ml,12.6mmol),2-(2-苯乙基)咪唑-4-羧酸(31a)(1.0g,4.62mmol),1-(3-二甲氨基丙基)-3-乙基碳化二亚胺盐酸盐(0.89g,4.62mmol)和羟基苯并三唑(1.14g,8.40mmol)。将反应混合物在室温搅拌20小时,然后倒入盐水中。混合物用乙酸乙酯(3×50ml)萃取,合并的有机萃取液用饱和碳酸氢钠水溶液(3×100ml)洗涤,然后用盐水(3×100ml)洗涤,干燥(MgSO4)并浓缩。剩余物用柱色谱纯化(2-10%异丙醇的二氯甲烷,然后用0-6%异丙醇的乙酸乙酯洗脱),得到1.10g(55%)标题化合物32a为非对映体的混合物:
IR(KBr)3278,3065,1790,1641,
1577,1545,1499,1454,1120;1H NMR(CDCl3)δ10.26(1H,
s),8.14(1H,s),7.66(d,J=7.0),7.56(d,J=7.0),
7.43(1H,s),7.31-7.11(10H,m),5.49(d,J=5.6),5.48
(s),4.83-4.41(4H,m),3.04-2.41(2H,m),2.99(4H,
s),1.45(d,J=7.0),1.44(d,J=7.0).
(2R,S,3S)N2-{2-[2-(4-三氟甲基苯基)乙基]咪唑-4-羰基}-N-(四氢-2-苄氧基-5-氧代-3-呋喃基)-L-丙氨酰胺(32b)
用32a所述方法制备,得到1.08g(62%)浅黄色玻璃体:
IR(KBr)3376,3284,3070,2938,
1791,1642,1578,1546,1327,1165,1122,1068;
1H NMR(CDCl3)δ7.95(0.5H,m),7.55-7.25(11.5H,m),
5.53(s),5.49(d,J=5.3),4.88-4.48(4H,m),3.11-2.96
(4H,m),2.91(1H,m),2.51(1H,m),1.47(3H,d,
J=7.1).
(2R,S,3S)N2-(2-苄基咪唑-4-羰基)-N-(四氢-2-苄氧基-5-氧代-3-呋喃基)-L-丙氨酰胺(32c)
用32a所述方法由2-苄基咪唑-4-羧酸(Ger.Offen.DE 3427136)制备,得到1.13g(83%)黄色玻璃体:
IR(CH2Cl2)3433,3062,2990,1803,1693,1584,1504,
1429,1285,1258;1H NMR(CDCl3)δ9.50(s),9.37(s),
7.86(0.5H,d,J=6.1),7.56-7.21(10.5H,m),7.48(1H,
s),5.51(d,J=5.2),5.48(s),4.87-4.41(4H,m),4.08
(s),4.07(s),3.03-2.39(2H,m),1.46(3H,d,J=7.0).
(3S)3-{N-[2-(2-苯乙基)咪唑-4-羰基]-L-丙氨酰基}氨基-4-氧代丁酸(33a;A)
将(2R,S,3S)N2-[2-(2-苯乙基)咪唑-4-羰基]-N-(四氢-2-苄氧基-5-氧代-3-呋喃基)-L-丙氨酰胺(32a)(1.0g,2.10mmol)和10%钯/活性炭(1.0g)的甲醇(50ml)混合物在氮气下搅拌4.5小时。过滤所得混合物并浓缩,得到无色玻璃体。将其从甲醇-乙醚中重结晶,得到510mg(63%)无色固体:
mp.127℃;IR(KBr)3360,3279,2981,1781,
1732,1646,1577,1547;1H NMR(CD3OD)δ7.54(1H,s),
7.29-7.12(5H,m),4.60-4.47(2H,m),4.28(1H,m),
3.01(4H,s),2.76-2.39(2H,m),1.43(3H,2xd,
J=7.0,J=7.0),13C NMR(CD3OD)δ176.2,176.0,174.7,
174.6,164.4,164.3,150.5,141.9,134.8,129.5,12 9.3,
127.3,122.3,98.8,98.4,52.3,52.0,50.3,35.6,31.2,
18.8,18.7.
元素分析C19H22N4O5·H2O:
计算值:C,56.43;H,5.98;N,13.85,
实测值:C,56.78;H,5.70;N,13.77。
(3S)3-{N-[2-(2-[4-三氟甲基苯基]乙基)咪唑-4-羰基]-L-丙氨酰基}-氨基-4-氧代丁酸(33b;C)
用33a所述方法制备,得到612mg(73%)无色固体:
120-124℃;[α]D 23+14.3°(c 0.5,MeOH);IR(KBr)3287,
2985,2937,1782,1732,1646,1579,1547,1327;1H NMR
(CD3OD)δ7.56(2H,d,J=8.0),7.54(1H,s),7.36(2H,
d,J=8.0),4.60-4.48(2H,m),4.28(1H,m),3.08(4H,
m),2.75-2.41(2H,m),1.43(3H,d,J=7.0).
元素分析C20H21F3N4O5·1/2H2O:
计算值:C,51.84;H,4.78;N,12.09;F,12.30,
实测值:C,51.83;H,4.72;N,12.14;F,12.36。
(3S)3-[N-(2-苄基咪唑-4-羰基)-L-丙氨酰基}氨基-4-氧代丁酸(33c;B)
用33a所述方法制备,得到426mg(64%)无色固体:
[α]D 23+13.4°(c
0.407,MeOH).IR(KBr)3260,3150,2980,1779,1727,
1649,1573,1547;1H NMR(CD3OD)δ7.58(1H,s),7.34-
7.22(5H,m),4.59-4.47(2H,m),4.28(1H,m),4.07
(2H,s),2.74-2.41(2H,m),1.42(3H,d,J=6.7);13C NMR
(CD3OD)δ175.6,175.5,175.0,164.6,164.5,150.1,
138.7,135.3,130.0,129.9,128.2,122.9,98.9,98.5,
52.5,52.2,35.5,35.1,35.0,19.0,18.9.
元素分析C18H20N4O5·H2O:
计算值:C,55.37;H,5.68;N,14.35,
实测值:C,55.83;H,5.75;N,13.96。
MS(FAB,m/z):373((M-),
228,185,91.
(a)R=H
(b)R=CH2Ph
5-苄基吡咯-2-羧酸(34b)
将5-苄基吡咯-2-羧酸乙酯(0.7g,3.05mmol;Elder et al.,
Synthetic Communication,19,pp.763-767,(1989)),乙醇(20ml)和1M氢氧化钠(9.2ml,9.2mmol)的混合物搅拌并加热回流3小时。除去大部分乙醇,剩余的液体加水稀释。用乙醚洗涤,用冰冷却,并用浓盐酸酸化。用乙醚萃取混合物,合并的萃取液用盐水洗涤,干燥(Na2SO4)并浓缩,得到0.567g(92%)乳白色固体:
mp.130-134℃;1H NMR(CDCl3)δ
8.87(1H,brs),7.37-6.95(5H,m),6.97(1H,m),6.07
(1H,m),4.00(2H,s).
(2R,S,3S)N2-(吡咯-2-羰基)-N-(四氢-2-苄氧基-5-氧代-3-呋喃基)-L-丙氨酰胺(35a)
在0℃用三氟乙酸(8ml)处理(2R,S,3S)N2-叔丁氧羰基-N-(四氢-2-苄氧基-5-氧代-3-呋喃基)-L-丙氨酰胺(14)(756mg,2.0mmol)的无水二氯甲烷(8ml)溶液1小时,然后蒸发至干。在剩余物中加入干醚,并将混合物浓缩得到粘性油。将该油溶解于无水DMF(10ml),加入吡咯-2-羧酸(34a)(244mg,2.2mmol),并将溶液在冰浴中冷却。加入N,N-二异丙胺(0.78g,6.0mmol),1-羟基苯并三唑(0.54g,4.0mmol)和乙基二甲氨基丙基碳化二亚胺盐酸盐(0.42g,2.2mmol),将所得混合物在25℃搅拌17小时,然后加入饱和氯化钠水溶液(30ml)。混合物用乙酸乙酯(3×20ml)萃取,合并的有机萃取液用5%碳酸氢钠水溶液(3×10ml)和盐水(10ml)洗涤,干燥(MgSO4)并浓缩。快速色谱纯化(25%己烷-乙酸乙酯),得到557mg(75%)1∶1非对映体的混合物为白色玻璃状固体:
mp.85-90℃;IR(KBr)3288,
1789,1665,1629,1557 and 1122;1H NMR(d6-DMSO)δ11.46
(1H,bs),8.55(0.5H,d,J=7.0),8.30(0.5H,d,J=7.6),
8.06(0.5H,d,J=7.0),8.04(0.5H,d,J=7.6),7.36-7.30
(5H,m),6.88-6.85(2H,m),6.10-6.07(1H,m),5.63
(0.5H,d,J=5.0),5.42(0.5H,s),4.72(2H,q,J=12.2),
4.74-4.25(2H,m),3.14-2.35(2H,m),1.29,1.25(3H,2
xd,J=7.2).
(2R,S,3S)N2-(5-苄基吡咯-2-羰基)-N-(四氢-2-苄氧基-5-氧代-3-呋喃基)-L-丙氨酰胺(35b)
用化合物35a所述方法,从5-苄基吡咯-2-羧酸(34b)制备标题化合物(65%)。给出单个非对映体的数据。 1H NMR
(d6-DMSO)δ11.37(1H,brs,),8.27(1H,d,J=7.4),7.93
(1H,d,J=7.6),7.33-7.16(10H,m),6.76(1H,m),5.82
(1H,m),5.62(1H,d,J=5.2),4.76(1H,d,J=12.0),
4.65(1H,m),4.62(1H,d,J=12.2),4.47(1H,m),3.88
(2H,s),2.77(1H,dd,J=9.0,18.0),2.5(dd),1.23(3H,
d,J=7.0).
(3S)3-[N-(吡咯-2-羰基)-L-丙氨酰胺]氨基-4-氧代丁酸(36a;D)
将化合物35a(612mg,1.65mmol),甲醇(40ml)和10%钯/炭(500mg)的混合物在氢气中剧烈搅拌4小时。用0.2μM尼龙膜过滤混合物,然后浓缩。剩余物用快速色谱纯化(5-10%甲醇的二氯甲烷),从乙酸乙酯-乙醚混合物中沉淀后得到化合物36a的半水合物(223mg,48%)为白色固体,产物中含有痕量溶剂。
mp.96-100℃;IR(KBr)3381,
1774,1729(EtOAc),1632,1558,1523,1123;
1H NMR(CD3OD)δ6.94-6.85(2H,m),6.17(1H,dd,J=3.8
and 2.6),4.58(0.5H,d,J=3.94),4.56(0.5H,d,
J=4.24),4.51(1H,q,J=7.16),4.35-4.20(1H,m),2.74-
2.40(2H,m),1.42 and 1.41(3H,2xd,J=7.13).
(3S)3-[N-(5-苄基吡咯-2-羰基)-L-丙氨酰胺]氨基-4-氧代丁酸(36b)
用化合物36a所述方法,从化合物35b制备标题化合物(41%),得到乳白色固体。 mp.109-112℃;[α]D 25
+6.3°(c 0.3,甲醇);IR(KBr)3368,1724,1630,
1530,1453,1414,1233,1049;1H NMR(d4甲醇)δ
7.25-7.11(5H,m),6.76(1H,d,J=3.5),5.84(1H,d,
J=3.5),4.51(1H,m),4.43(1H,q,J=7.1),4.23(1H,
m),2.5(2H,m),1.35(3H,d,J=7.0).
元素分析C19H21N3O5·1.75H2O:
计算值:C,56.64;H,6.13;N,10.43,
实测值:C,56.34;H,5.72;N,10.00。
(2R,S,3S)1-(吲哚-2-羰基)-N-(四氢-2-苄氧基-5-氧代-3-呋喃基)-L-脯氨酰胺(38)
在0℃将三氟乙酸(4ml)加到(2R,S,3S)1-叔丁氧羰基-N-(四氢-2-苄氧基-5-氧代-3-呋喃基)-L-脯氨酰胺(15)(0.607g,1.5mmol)的二氯甲烷(4ml)溶液中。将混合物在0℃搅拌75分钟。浓缩混合物,剩余物用乙醚处理,然后真空除去乙醚。这个过程重复两次,得到黄色油。将该油溶解于DMF(12ml),然后在所得溶液中先加入二异丙基乙胺(0.78ml,4.5mmol),再加入吲哚-2-羧酸(266mg,1.65mmol),1-(3-二甲氨基丙基)-3-乙基碳化二亚胺盐酸盐(316mg,1.65mmol)和羟基苯并三唑(405mg,3mmol)。混合物在室温搅拌20小时,然后倒入盐水中。用乙酸乙酯(3×30ml)萃取混合物,合并的有机萃取液用饱和碳酸氢钠水溶液(2×60ml)和盐水(2×60ml)洗涤,干燥(MgSO4),过滤并浓缩。剩余物用柱色谱纯化(乙酸乙酯),得到518mg(77%)非对映体的混合物:
IR(KBr)3314,1780,1677,
1609,1524,1435,1406,1344;1H NMR(d6-DMSO),δ11.58
(1H,m),8.81-8.41(1H,m),7.71-6.67(10H,m),5.70
(d,J=5.2),5.48(s),4.89-4.29(4H,m),3.99-3.74(2H,
m),3.20-2.44(2H,m),2.39-1.77(4H,m).
(3S)3-[1-(吲哚-2-羰基)-L-脯氨酰胺]氨基-4-氧代丁酸(39)
将(2R,S,3S)1-(吲哚-2-羰基)-N-(四氢-2-苄氧基-5-氧代-3-呋喃基)-L-脯氨酰胺(38)(478mg,1.07mmol),10%钯/炭(475mg)和甲醇(150ml)的混合物在氢气中搅拌6小时。过滤所得混合物并浓缩,得到无色玻璃体。从甲醇和乙醚混合物重结晶,得到202mg(53%)无色固体:
mp.135-138℃;[α]D 24-44°(c
0.25,CH3OH);IR(KBr)3287,2977,2879,1781,1725,
1716,1667,1662,1600,1529,1441,1346;1H NMR(CD3OD)
δ7.65(1H,d,J=8.0),7.44(1H,d,J=8.4),7.22(1H,
m),7.09-6.84(2H,m),4.62(2H,m),4.29(1H,m),
4.15-3.73(2H,m),2.74-1.72(6H,m).
2-(3,5-二氢-7-甲基-4-氧代-4H-吡咯[3,2-d]嘧啶-3-基)乙酸甲酯(40)
将刚刚制好的甘氨酸甲酯(1.25g,14mmol)加到搅拌的3-[N-(二甲氨基)亚甲基]氨基-4-甲基吡咯-2-羧酸乙酯(1.56g,7.0mmol;Lim et al.,J.Org.Chem.,44,pp.3826-29(1979))的无水甲醇溶液中。将所得混合物保持在70℃,在70℃加热18小时和42小时后,分两批加入甘氨酸甲酯(1.25g,14.0mmol)。最后一次添加之后24小时,将混合物冷却并过滤。浓缩滤液,剩余物用快速色谱纯化(2-5%甲醇/氯仿),得到0.54g(35%)白色晶状固体(从乙酸乙酯重结晶)。
mp.233-235℃
IR(KBr)3135,2958,1745,1675,1254;
1H NMR(d6-DMSO)δ11.90(1H,s),8.07(1H,s),7.23
(1H,s),4.83(2H,s),3.69(3H,s),2.16(3H,s).
元素分析C10H11N3O3·0.1H2O:
计算值:C,53.85;H,5.07;N,18.84,
实测值:C,53.85;H,4.96;N,18.81。
MS(70eVE.I.)m/e 222,221(M+,100%),189,162,133,
105.
2-(3,5-二氢-7-甲基-4-氧代-4H-吡咯[3,2-d]嘧啶-3-基)乙酸,钠盐(41)
将化合物40(354mg,1.6mmol)在甲醇(15ml)中的悬浮液用0.5N氢氧化钠(4.8ml)处理,所得混合物在25℃搅拌1小时。过滤反应混合物,得到41的半水合物(354mg,97%)为白色晶状固体(从甲醇重结晶)。
mp.
>340℃ IR(KBr)3461,
3143,1676,1666,1605,1415;1H NMR(d6 DMSO)δ11.63
(1H,s),7.83(1H,s),7.11(1H,d,J=2.0),4.24(2H,
s),2.14(3H,s).
元素分析C9H8N3O3Na·0.5H2O:
计算值:C,45.39;H,3.81;N,17.64,
实测值:C,45.57;H,4.05;N,17.39。
(2R,S,3S)2-(3,5-二氢-7-甲基-4-氧代-4H-吡咯[3,2-d]嘧啶-3-基)-N-(四氢-2-苄氧基-5-氧代-3-呋喃基)乙酰胺(42)
将钠盐41(344mg,1.5mmol)的无水DMF(15ml)悬浮液用乙基二甲氨基丙基碳化二亚胺盐酸盐(373mg,1.95mmol)和1-羟基苯并三唑(405mg,3.0mmol)处理。将混合物保持在25℃1小时,然后加入(2R,S,3S)N-烯丙氧羰基-3-氨基-2-苄氧基-5-氧代四氢呋喃(437mg,1.5mmol;Chapman,
Biorg.Med.Chem.Lett.,2,pp.613-18(1992))和(Ph3P)2PdCl2,接着滴加正丁基氢化锡(0.6ml,2.25mmol)。所得混合物在25℃搅拌1小时,然后加水(20ml)。用乙酸乙酯(3×15ml)萃取混合物,合并的有机萃取液用水(5ml)洗涤,干燥(MgSO4)并浓缩,得到非对映体的混合物。蒸发水相,剩余物用快速色谱纯化(5%甲醇/氯仿),得到总量为182mg的化合物42(31%): m.p.240-244℃;
IR(KBr)3274,1772,1691,1664,1562;1H NMR(d6-DMSO)
δ11.81(1H,s),8.85(0.6H,d,J=6.6),8.72(0.4H,d,
J=7.4),7.98 (0.6H,s),7.95(0.4H,s),7.40-7.30(5H,
m),7.20(1H,d,J=2.2),5.61(0.4H,d,J=5.0),5.46
(s),4.85-4.60(m),4.28(m),3.20-2.35(2H,m),2.16
(3H,s).
(3S)-3-[2-(3,5-二氢-7-甲基-4-氧代-4H-吡咯[3,2-d]嘧啶-3-基)-1-氧代-乙氨基]-4-氧代丁酸(43)
将化合物42(131mg,0.33mmol)的甲醇(50ml)和10%钯/炭(100mg)的混合物在氢气中剧烈搅拌2小时。再加入额外量的催化剂(100mg),并将混合物再氢化2小时。用0.2μM尼龙膜过滤混合物,然后浓缩。剩余物从甲醇/乙醚重结晶,得到79mg(78%)标题化合物43为吸湿性白色固体。m.p.222-226℃(分解)。 [α]D 32
+0.5(c 0.02,MeOH);IR(KBr)3282,1680,1558,1425
1275;1H NMR(CD3OD)δ8.03(1H,s),7.18(1H,d,
J=0.7),4.79-4.74(2H,m),4.63-4.59(1H,2xd,
J=3.6),4.36-4.25(1H,m),2.78-2.39(2H,m),2.24(3H,
d,J=0.7).
元素分析C13H14N4O5·1.4H2O:
计算值:C,47.10;H,5.12;N,16.90,
实测值:C,47.00;H,4.79;N,16.59。
FABMS m/e 307,306(M+),244,207,190,152,115(100%).
(a)X=O
(b)X=H2
(1S,9S)6,10-二氧代-八氢-9-(3-苯基丙酰氨基)-6H-哒嗪并[1,2-a][1,2]二氮杂_-1-羧酸叔丁酯(44a)
在0℃向(1S,9S)9-氨基-6,10-二氧代-八氢-6H-哒嗪并[1,2-a][1,2]二氮杂草-1-羧酸叔丁酯(690mg,2.32mmol;GB 21 28984)的二噁烷(16ml)和水(4ml)溶液中加入固体碳酸氢钠(292mg,3.48mmol),接着滴加3-苯基丙酰氯(470mg,2.78mmol)。将混合物在室温再搅拌2小时,然后再加入碳酸氢钠(200mg,2.38mmol)和3-苯基丙酰氯(100mg,0.6mmol)。混合物在室温搅拌2小时后用乙酸乙酯(50ml)稀释,饱和碳酸氢钠(2×25ml)洗涤,干燥(MgSO4)并浓缩。剩余物用快速色谱纯化(0-50%乙酸乙酯/氯仿),最后通过用乙醚研制使之结晶,得到860mg(86%)白色固体:
mp.137-138℃;
[α]D 23-95.1°(c 0.549,CH2Cl2);IR(KBr)3327,1736,
1677,1664,1536,1422,1156;1H NMR(CDCl3)δ 7.24(5H,
m),6.50(1H,d,J=7.5),5.24(1H,m),4.90(1H,m),
4.60(1H,m),3.44(1H,m),2.93(2H,m),2.84(1H,m),
2.64(1H,m),2.54(2H,m),2.26(2H,m),1.70(4H,m),
1.70(9H,s).MS(FAB,m/z):430(M++1),374,242,
105,91.
(1S,9S)八氢-10-氧代-9-(3-苯基丙酰氨基)-6H-哒嗪并[1,2-a][1,2]二氮杂_-1-羧酸叔丁酯(44b)
用44a所述方法由(1S,9S) 9-氨基-八氢-10-氧代-6H-哒嗪并[1,2-a][1,2]二氮杂_-1-羧酸叔丁酯(Attwood et al.,
J.Chem.Soc. Perkin 1,pp.1011-19(1986))制备,得到810mg(81%)无色油。
[α]D 23-33.5°(c 0.545,CH2Cl2);IR(film)3334,2935,
1737,1728,1659,1642;1H NMR(CDCl3)δ7.24(5H,m),
6.75(1H,d,J=6.7),5.27(1H,m),4.92(1H,m),3.39
(1H,m),3.03(4H,m),2.55(3H,m),2.33(1H,m),2.17
(1H,m),1.80(5H,m),1.47(9H,s),1.39(1H,m).
MS(FAB,m/z):416(M++1),360,211,143,97.
(1S,9S)6,10-二氧代-八氢-9-(3-苯基丙酰氨基)-6H-哒嗪并[1,2-a][1,2]二氮杂_-1-羧酸(45a)
在0℃向(1S,9S)6,10-二氧代-八氢-9-(3-苯基丙酰氨基)-6H-哒嗪并[1,2-a][1,2]二氮杂_-1-羧酸叔丁酯(44a)(800mg,1.863mmol)的无水二氯甲烷(5ml)溶液中加入三氟乙酸(5ml)。将溶液在室温搅拌3小时后浓缩。剩余物中加入干醚(10ml),然后再真空除去。将这一过程重复3次,得到结晶固体。将该固体用乙醚研制并过滤,得到590mg(85%)白色晶状固体:
mp.196-197.5℃;[α]D 23-129.5°
(c 0.2,CH3OH);IR(KBr)3237,1729,1688,1660,1633,
1574,1432,1285,1205;1H NMR(CD3OD)δ8.28(1H,d,
J=7.4),7.22(5H,m),5.32(1H,dd,J=5.9,2.9),4.75
(1H,m),4.51(1H,m),3.50(1H,m),3.01(1H,m),2.91
(2H,m),2.55(2H,m),2.29(3H,m),1.95(2H,m),1.71
(2H,m).
元素分析C19H23N3O5:
计算值:C,61.12;H,6.21;N,11.25,
实测值:C,60.80;H,6.28;N,10.97。
MS(FAB,
m/z)374(M++1),242,105,91.
(1S,9S)八氢-10-氧代-9-(3-苯基丙酰氨基)-6H-哒嗪并[1,2-a][1,2]二氮杂_-1-羧酸(45b)
用化合物45a所述方法,由(1S,9S)八氢-10-氧代-9-(3-苯基丙酰氨基)-6H-哒嗪并[1,2-a][1,2]二氮杂_-1-羧酸叔丁酯(44b)制备,得到657mg(96%)标题化合物45b为结晶固体:
mp.198-202℃;[α]D 23-86.2°(c
0.5,CH3OH);IR(KBr)3294,2939,1729,1645,1620,
1574,1453,1214;1H NMR(CD3OD)δ7.92(1H,d,J=7.9),
7.20(5H,m),5.29(1H,m),4.90(1H,m),3.47(1H,m),
3.08(2H,m),2.90(2H,m),2.55(3H,m),2.36(1H,m),
1.81(5H,m),1.43(2H,m).MS(FAB,m/z)360(M++1),
211,143,91.
[3S,2R,S,(1S,9S)]N-(2-苄氧基-5-氧代四氢呋喃-3-基)-6,10-二氧代-八氢-9-(3-苯基丙酰氨基)-6H-哒嗪并[1,2-a][1,2]二氮杂_-1-甲酰胺(46a)
室温下向(1S,9S)6,10-二氧代-八氢-9-(3-苯基丙酰氨基)-6H-哒嗪并[1,2-a][1,2]二氮杂_-1-羧酸(45a)(662mg,1.773mmol)的无水二氯甲烷(9ml)和无水二甲基甲酰胺(3ml)溶液中加入双(三苯膦)氯化钯(30mg)和(3S,2R,S)-3-烯丙氧羰基氨基-2-苄氧基-5-氧代四氢呋喃(568mg,1.95mmol;Chapman,Biorg.Med.Chem.Lett.,2,pp.613-18(1992)),接着滴加三-正丁基氢化锡(1.19g,4.09mmol)。将1-羟基-苯并三唑(479mg,3.546mmol)加到混合物中,并将混合物冷却至0℃,之后,再加入1-(3-二甲氨基丙基)-3-乙基碳化二亚胺盐酸盐(408mg,2.128mmol)。将混合物在室温搅拌3.25小时,然后用乙酸乙酯(50ml)稀释,用稀盐酸(20ml)洗涤两次,饱和碳酸氢钠(20ml)洗涤两次,盐水洗涤一次,然后干燥(MgSO4)并浓缩。得到的油用快速色谱纯化(0-100%乙酸乙酯/氯仿),得到810mg(81%)标题化合物46a为异头物的混合物。
mp.92-94℃;IR(KBr)3311,1791,
1659,1651,1536;1H NMR(CDCl3)δ7.49,6.56(1H,2d,
J=6.7,7.8),7.29(10H,m),6.37,6.18(1H,2d,
J=7.7,7.6),5.56,5.34(1H,d,s,J=5.2),5.08-4.47
(6H),3.18-2.80(5H),2.62-2.28(5H),2.04-1.53(5H).
MS(FAB,m/z),563(M++1),328,149,91.
[3S,2R,S,(1S,9S)]N-(2-苄氧基-5-氧代四氢呋喃-3-基)-八氢-10-氧砼-9-(3-苯基丙酰氨基)-6H-哒嗪并[1,2-a][1,2]二氮杂_-1-甲酰胺(46b)
用46a所述方法从化合物45b制备,得到790mg(96%)玻璃体。
m.p.58-60℃;IR(KBr)3316,2940,
1793,1678,1641,1523,1453,1120;1H NMR(CDCl3)δ
7.28(10H,m),6.52,6.42(1H,2d,J=7.2,7.1),5.53,
5.44(1H,d,s,J=5.2),5.35(1H,m),4.6-4.9,4.34
(4H,m),3.1-2.8(6H,m),2.6-2.1(7H),1.95-1.05(5H).
MS(FAB,m/z),549(M++1),400,310,279,91.
[3S,(1S,9S)]3-(6,10-二氧代-八氢-9-(3-苯基丙酰氨基)-6H-哒嗪并[1,2-a][1,2]二氮杂_-1-甲酰胺)-4-氧代丁酸(47a)
将[3S,2R,S,(1S,9S)]N-(2-苄氧基-5-氧代四氢呋喃-3-基)-6,10-二氧代-八氢-9-(3-苯基丙酰氨基)-6H-哒嗪并[1,2-a][1,2]二氮杂_-1-甲酰胺(46a)(205mg,0.364mmol),10%钯/炭(200mg)和甲醇(20ml)的混合物在氢气下搅拌5小时。过滤混合物并浓缩,得到154mg(90%)玻璃体。
mp.116-118℃;[α]D 23-140°(c
0.1,CH3OH);IR(KBr)3323(br),1783,1731,1658,1539,
1455,1425;1H NMR(CD3OD)δ7.21(5H,m),5.17(1H,
m),4.73(1H,m),4.50(2H,m),4.23(1H,m),3.38(1H,
m),3.06(1H,m),2.91(2H,m),2.73-2.18(6H,m)and
2.01-1.59(5H,m).
元素分析C23H27N4O7·H2O:
计算值:C,56.32;H,6.16;N,11.42,
实测值:C,56.29;H,6.11;N,11.25。
MS(FAB,m/z)473(M++1),176,149,105,91.
[3S,(1S,9S)]3-(八氢-10-氧代-9-(3-苯基丙酰氨基)-6H-哒嗪并[1,2-a][1,2]二氮杂_-1-甲酰胺)-4-氧代丁酸(47b)
用47a所述方法由46b制备,剩余物经快速色谱纯化(0-10%甲醇/氯仿),得到65mg(52%)玻璃体。
m.p.87-90℃;[α]D 23-167.0°(c 0.1,甲醇);IR(KBr)
3329,2936,1786,1727,1637;1H NMR(CD3OD)δ7.23
(5H,m),5.29(1H,m),4.83(1H,m),4.59(1H,d,
J=3.6),4.29(1H,m),3.3-3.0(3H,m),2.91(2H,m),
2.70-2.34(5H,m),2.19(2H,m),1.75(4H,m),1.36
(2
H,m).
元素分析C23H30N4O6·0.5H2O:
计算值:C,59.09;H,6.68;N,11.98,
实测值:C,58.97;H,6.68;N,11.73。
MS(FAB,m/z)459(M++1),310,149,105,91.
R1 R2 R3
(a) PhCH2 H (S)Me
(b) PhCH2 CH2Ph H
(c) PhCH2 (CH2)2Ph H
(d) PhCH2 nBu H
(e) PhCH2 Me H
(f) PhCH2 Ph H
(g) PhCH2 H H
(h) PhCH2 CH2Ph (S)-Me
(i) Ph(CH2)2 CH2Ph H
吡啶酮48采用Damewood et al.,J.Med.Chem.,37,pp.3303-12(1994)所述方法制备。化合物48d是新的。
3-苄氧羰基氨基-6-丁基-吡啶-2-酮(48d)
分离后得到乳白色固体。
mp.158-160℃;IR(KBr)
3382,2953,2930,2866,1729,1643,1524,1468,1202,
1044;1H NMR(d6-DMSO)δ8.26(1H,s),7.72(1H,d),
7.39(5H,m),6.00(1H,d),5.14(2H,s),2.41(2H,t),
1.52(2H,m),1.24(2H,m),0.87(3H,t).
元素分析C17H20N2O3:
计算值:C,67.98;H,6.71;N,9.33,
实测值:C,67.69;H,6.68;N,9.20。
MS CI M+=300(m))28%.
(2S)2-[苄氧羰基氨基-1,2-二氢-2-氧代-1-吡啶基]丙酸甲酯(49a)
室温下将氢化钠(0.35g,11.64mmol;80%的油分散液)加到搅拌的3-(苄氧羰基氨基)吡啶-2-酮(48a)(2.58g,10.58mmol)和四氢呋喃(100ml)的混合物中。搅拌混合物10分钟,室温下用10分钟将所得溶液加到2(R)2((三氟甲烷)磺酰氧基)丙酸甲酯(2.5g,10.58mmol;Feenstra etal.,Tetrahedron Lett.,28,pp.1215-18(1987))的四氢呋喃(5ml)溶液中。混合物在室温搅拌80分钟后倒入乙酸乙酯。混合物用1M HCl洗涤两次,用碳酸氢钠水溶液洗涤两次,然后用盐水洗涤一次。干燥(MgSO4)并浓缩,剩余物用快速色谱纯化(30%乙酸乙酯/己烷),得到2.945g(84%)无色固体:
mp.96-7°;[α]D 20-
71.36(c 2.5,CHCl2);IR(KBr)3370,1764,1729,1648,
1602,1564,1523,1515,1503,1449,1359,1203,1064;
1H NMR(CDCl3)δ8.04(1H,d,J=7.2),7.86(1H,s),7.36
(5H,m),6.98(1H,dd,J=7.1,J=1.7),6.30(1H,t,
J=7.2),5.46(1H,q,J=7.4),5.20(2H,s),3.74(3H,
s),1.66(3H,d,J=7.4).
元素分析C17H18N2O5:
计算值:C,61.81;H,5.49;N,8.48,
实测值:C,61.49;H,5.51;N,8.41。
MS(FAB,m/z)331(M++1),299,223,196,163,91.
[6-苄基-3-苄氧羰基氨基-1,2-二氢-2-氧代-1-吡啶基]乙酸甲酯(49b)
室温下将氢化钠(0.65g,26.2mmol;80%的油分散液)加到搅拌的6-苄基-3-(苄氧羰基氨基)吡啶-2-酮(48b)(7.3g,2.18mmol)和四氢呋喃(150ml)的混合物中。混合物搅拌10分钟后用溴乙酸甲酯(2.5ml,26.2mmol)处理,并保持3小时。将所得混合物倒入冰和1M HCl的混合物中。将过滤所得固体溶解于二氯甲烷。干燥(MgSO4)所得溶液,用活性炭脱色并浓缩。剩余物用色谱纯化(2-5%乙酸乙酯/二氯甲烷),得到7.2g(81%)无色晶体。 mp.117-9°;IR(KBr)3375,1753,
1730,1651,1605,1513,1384,1223,1185,1071;1H NMR
(CDCl3)δ8.02(1H,d,J=7.5),7.78(1H,s),7.31(8H,
m),7.10(2H,m),6.15(1H,d,J=7.5),5.20(2H,s),
4.70(2H,s),3.88(2H,s),3.66(3H,s).
用类似方法制备下列化合物:
[3-苄氧羰基氨基-1,2-二氢-2-氧代-6-苯乙基-1-吡啶基]乙酸甲酯(49c)
产率:97% m.p.
102-4℃.IR(KBr)3245,3232,1741,1725,1648,1600,
1526,1216;1H NMR(d6-DMSO)δ8.45(1H,s),7.76(1H,
d,J=7.6),7.35(10H,m),6.15(1H,d,J=7.6),5.15
(2H,s),4.85(2H,s),3.68(3H,s),2.86(4H,s).
[3-苄氧羰基氨基-6-丁基-1,2-二氢-2-氧代-1-吡啶基]乙酸甲酯(49d)
产率:90%。 mp.111-
112℃;IR(KBr)3393,1738,1731,1645,1598,1517,
1225,1208;1H NMR(d6-DMSO)δ8.39(1H,s),7.78(1H,
d,J=7.7),7.35(5H,m),6.17(1H,d,J=7.7),5.15
(2H,s),4.80(2H,s),3.67(3H,s),1.38(6H,m),0.89
(3H,t).
[3-苄氧羰基氨基-1,2-二氢-6-甲基-2-氧代-1-吡啶基]乙酸甲酯(49e)
产率:84%,为无色固体。
mp.115-6℃;IR(KBr)3246,1740,
1725,1649,1598,1573,1535,1417,1365,1259,1219,
1193,1090,1068,1006;1H NMR(d6-DMSO)δ8.40(1H,s),
7.75(1H,d,J=7.6),7.38(5H,m),6.20(1H,d,J=
7.6),5.15(2H,s),4.85(2H,s),3.6 8(3H,s),2.26
(3H,s).
[3-苄氧羰基氨基-1,2-二氢-6-苯基-1-吡啶基]乙酸甲酯(49f)
产率:67%,为无色油。
IR(KBr)3266,1739,1727,1646,1606,1566,
1517,1490,1365,1213,1163,1075;1H NMR(CDCl3)δ
8.15(1H,d),7.85(1H,s),7.39(10H,m),6.22(1H,
d),5.22(2H,s),4.57(2H,s),3.74(3H,s).
[3-苄氧羰基氨基-1,2-二氢-2-氧代-1-吡啶基]乙酸甲酯(49g)
产率:80%,为无色晶状固体。
m.p.110-111℃.IR(KBr)3385,
1745,1726,1650,1601,1512,1502,1378,1369,1358,
1215,1195,1162,1067;1H NMR(CDCl3)δ8.06(1H,d),
7.84(1H,s),7.36(5H,m),6.88(1H,dd),6.27(1H,
t),5.20(2H,s),4.68(2H,s),3.78 (3H,s).
元素分析C16H16N2O5:
计算值:C,60.75;H,5.10;N,8.85,
实测值:C,60.65;H,5.15;N,8.85。
MS FAB(+)M+=317(M+1).
2(S)2-甲基-[6-苄基-(3-苄氧羰基氨基)-1,2-二氢-2-氧代-1-吡啶基]乙酸甲酯(49h)
用化合物49a的制备方法制备,得到一种油(58%)。
[α]D 25-25.0°(c 1,
CH2Cl2);IR(KBr)3381,1736,1650,1604,1513,1218,
1190,1068;1H NMR(CDCl3)δ7.97(1H,d),7.78(1H,s),
7.4-7.14(10H,m),6.17(1H,d),5.19(2H,s),4.64
(1H,q),3.98(2H,s),3.62(3H,s),1.31(3H,d).
[6-苄基-1,2-二氢-2-氧代-3-(2-苯基乙氧基)-羰基氨基-1-吡啶基]乙酸甲酯(49i)
分离得到无色固体(88%)。mp.130-133℃;IR(KBr)
3363,1746,1732,1651,1604,1515,1368,1231,1212,
1185;1H NMR(CDCl3)δ8.00(1H,d,J=7.0),7.68(1H,
s),7.36-7.10(10H,m),6.15(1H,d,J=7.6),4.7(2H,
s),4.38(2H,t,J=7.0),3.88(2H,s),3.67(3H,s),
2.98(2H,t,J=7).
2(S)2-[3-氨基-1,2-二氢-2-氧代-1-吡啶基]丙酸甲酯(50a)
将2(S)2-[3-苄氧羰基氨基-1,2-二氢-2-氧代-1-吡啶基]丙酸甲酯49a(2.75g,8.33mmol),甲醇(100ml)和10%钯/炭(300mg)的混合物在氢气中搅拌30分钟。过滤混合物并浓缩,得到1.63g(100%)无色固体。
1H NMR(d6-DMSO)δ8.35
(1H,brs),7.46(1H,d),7.22(1H,d),6.29(1H,t),
5.22(1H,q),3.63(3H,s),1.55(3H,d).
用类似方法制备下列化合物:
[3-氨基-6-苄基-1,2-二氢-2-氧代-1-吡啶基]乙酸甲酯(50b)
产率:100%,为灰色固体:
mp.
134-6℃;IR(KBr)3418,3312,1723,1658,1596,1548,
1435,1290,1245,1011;1H NMR(d6-DMSO)δ7.25(5H,m),
6.45(1H,d,J=7.4),5.92(1H,d,J=7.4),5.00(2H,
s),4.63(2H,s),3.88(2H,s),3.51(3H,s).
[3-氨基-1,2-二氢-2-氧代-6-苯乙基-1-吡啶基]乙酸甲酯(50c)
产率:99%,为粘性油: IR
(KBr)3456,341,2953,1745,1649,1600,1548,1219;
1H NMR(CDCl3)δ7.25(5H,m),6.51(1H,d,J=7.4),
5.92(1H,d,J=7.4),4.79(2H,s),3.77(3H,s),2.80
(4H,m).
[3-氨基-6-丁基-1,2-二氢-2-氧代-1-吡啶基]乙酸甲酯(50d)
产率:97%,为棕色固体: mp.75-
7℃;IR(KBr)3437,3342,2955,1745,1655,1609,
1550,1432,1301,1222,1200;1H NMR(CDCl3)δ6.53(1H,
d,J=6.8),5.93(1H,d,J=6.8),4.81(2H,s),3.77
(3H,s),2.44(2H,t),1.45(4H,m),0.93(3H,t).
[3-氨基-1,2-二氢-6-甲基-2-氧代-1-吡啶基]乙酸甲酯(50e)
分离出无色晶状固体(100%):mp.87-9℃;IR(KBr)
3442,3326,1735,1647,1600,1549,1434,1407,1383,
1366,1225,1209;1H NMR(d6-DMSO)δ6.40(1H,d,
J=7.3),5.93(1H,d,J=7.3),4.86(2H,s),4.79
(2H,s),3.67(3H,s),2.15(3H,s).
[3-氨基-1,2-二氢-2-氧代-6-苯基-1-吡啶基]乙酸甲酯(50f)
分离出灰色固体(86%):
mp.207-9℃;IR(KBr)3473,3345,1750,1644,
1600,1536,1443,1366,13 09,1212,1184,1156;1H NMR
(d6-DMSO)δ7.30(5H,m),6.54(1H,d),6.03(1H,d),
5.25(2H,s),4.49(2H,s),3.61(3H,s).
[3-氨基-1,2-二氢-2-氧代-1-吡啶基]乙酸甲酯(50g)
制得的无色油可直接用于下步。
2(S)2-甲基-[3-氨基-6-苄基-1,2-二氢-2-氧代-1-吡啶基]乙酸甲酯(50h)
分离出无色油(69%)。
IR(胶片)3354,1743,1646,1600,1548,
1494,1455,1309,1268,1227,113;1H NMR(C6D6)δ7.29-
6.76(5H,m),5.86(1H,d,J=7.2),5.51(1H,d,J=
7.2),4.43(1H,q,J=6.7),3.69(2H,s),3.41(2H,
s),3.36(3H,s),1.43(3H,d,J=6.7).
R1 R2 R3
(a) Ph(CH2)2CO H (S)Me
(b) Ph(CH2)2CO CH2Ph H
(c) Ph(CH2)2CO (CH2)2Ph H
(d) Ph(CH2)2CO nBu H
(e) Ph(CH2)2CO Me H
(f) Ph(CH2)2CO Ph H
(g) Ph(CH2)2CO H H
(h) Ph(CH2)2CO CH2Ph (S)-Me or
(R,S)-Me
(i) AcTyr CH2Ph H
(j) Ph(CH2)2SO2CH2Ph H
(k) Ph(CH2)2OCO CH2Ph H
(l) Ph(CH2)3CO CH2Ph H
2(S)2-[1,2-二氢-2-氧代-3-(3-苯基丙酰基)氨基-1-吡啶基]丙酸甲酯(51a)
将3-苯基丙酰氯(1.5g,9mmol)滴加到搅拌的2S 2-[3-氨基-1,2-二氢-2-氧代-1-吡啶基]丙酸甲酯(50a)(1.63g,8.33mmol),二噁烷(60ml),水(15ml)和碳酸氢钠(1.54g,16.7mmol)的混合物中。将混合物保持1小时,然后用乙酸乙酯萃取。萃取液用碳酸氢钠水溶液洗涤,干燥(MgSO4)并浓缩。所得红色油用快速色谱纯化,得到2.54g(93%)油。
[α]D 20-68℃(1,CH2Cl2);IR(CH2Cl2)3369,1747,1690,
1650,1602,1512,1267,1260,1217;1H NMR(CDCl3)δ
8.41(1H,dd),8.36(1H,s),7.24(5H,m),7.02(1H,
dd),6.32(1H,t),5.44(1H,q),3.75(3H,s),3.03
(2H,t),2.70(2H,t),1.66(3H,d).FAB M+=329(M+
1),197,165,131,110,91.
用类似方法制备下列化合物:
[6-苄基-1,2-二氢-2-氧工-3-(3-苯基丙酰基)氨基-1-吡啶基]乙酸甲酯(51b)
分离得到结晶(93%): mp.95-7℃;IR(KBr)3265,
1747,1686,1642,1590,1563,1511,1454,1401,1220,
1183,1133;1H NMR(CDCl3)δ8.39(1H,d,J=7.7),8.27
(1H,s),7.21(10H,m),6.17(1H,d,J=7.7),4.70
(2H,s),3.89(2H,s),3.67(3H,s),3.02(2H,m),2.70
(2H,m).
[1,2-二氢-2-氧代-6-苯乙基-3-(3-苯基丙酰基)氨基-1-吡啶基]乙酸甲酯(51c)
分离得到无色结晶(81%): mp.105-8℃;IR
(KBr)3378,1746,1680,1646,1597,1517,1221;1H NMR
(CDCl3)δ8.34(1H,d,J=7.7),8.25(1H,s),7.23
(10H,m),6.11(1H,d,J=7.7),4.77(2H,s),3.78
(3H,s),2.88(8H,m).
[6-丁基-1,2-二氢-2-氧代-3-(3-苯基丙酰基)氨基-1-吡啶基]乙酸甲酯(51d)
分离得到无色结晶(88%): mp.84-5℃;IR
(KBr)3345,2958,2930,1756,1693,1650,1602,1510,
1227,1180,1137;1H NMR(CDCl3)δ8.34(1H,d,J=
7.7),8.22(1H,s),7.26(5H,m),6.12(1H,d,J=
7.7),4.80(2H,s),3.79(3H,s),3.03(2H,t),2.68
(2H,t),2.50(2H,t),1.46(4H,m),0.95(3H,t).
[1,2-二氢-6-甲基-2-氧代-3-(3-苯基丙酰基)氨基-1-吡啶基]乙酸甲酯(51e)
分离得到浅黄色油(100%): IR(胶片)3264,
1745,1691,1644,1587,1566,1518,1495,1400,1215,
1183,1136;1H NMR(CDCl3)δ8.33(1H,d,J=7.6),7.26
(5H,m),6.13(1H,d,J=7.6),4.83(2H,s),3.79(3H,
s),3.03(2H,m),2.69(2H,m),2.28(3H,s).
[1,2-二氢-2-氧代-6-苯基-3-(3-苯基丙酰基)氨基-1-吡啶基]乙酸甲酯(51f)
分离得到浅黄色油(99%): IR(胶片)3365,
3299,1751,1689,1643,1600,1563,1519,1493,1419,
1370,1224;1H NMR(CDCl3)δ8.46(1H,d,J=7.7),8.32
(1H,s),7.32(10H,m),6.24(2H,d,J=7.7),4.57
(2H,s),3.73(3H,s),3.06(2H,m),2.72(2H,m).
[1,2-二氢-2-氧代-3-(3-苯基丙酰基)氨基-1-吡啶基]乙酸甲酯(51g)
分离得到一种油(81%):
IR(胶片)3330,1753,1689,1650,1600,1560,1517,
1374,1225,1208;1H NMR(CDCl3)δ8.43(1H,dd,J=
7.4,1.7),8.33(1H,s),7.28(5H,m),6.92(1H,dd,J
=6.9,1.7),6.29(1H,t),4.67(2H,s),3.79(3H,s),
3.04(2H,m),2.70(2H,m).MS FAB(+)M+=315(M+
1).
2(S)2-甲基-[6-苄基-1,2-二氢-2-氧代-3-(3-苯基丙酰基)氨基-1-吡啶基]乙酸甲酯(51h)
分离得到无色油(93%): [α]D 30-19°(c 1,
CH2Cl2);IR(胶片)3354,3313,3028,2950,1745,1687,
1645,1600,1567,1514,1454,1225;1H NMR(CDCl3)δ
8.35(1H,d,J=7.5),8.26(1H,s),7.27(10H,m),
6.20(1H,d,J=7.5),4.65(1H,q,J=6.8),3.99(2H,
s),3.71(3H,s),3.03(2H,m),2.68(2H,m),1.31(3H,
d,J=6.8).
[3-(N-乙酰基-O-苄基-L-酪氨酸)氨基-6-苄基-1,2-二氢-2-氧代-吡啶基]乙酸甲酯(51i)
将[3-氨基-6-苄基-1,2-二氢-2-氧代-1-吡啶基]乙酸甲酯(100mg,0.367mmol),BOC-Tyr(Bn)-OH(136mg,0.367mmol),二甲基甲酰胺(1ml),二异丙基乙胺(0.25ml,1.468mmol)和2-(1H-苯并三唑-1-基)-1,1,3,3-四甲基脲鎓六氟磷酸盐(118mg,0.367mmol)的混合物在室温搅拌过夜。混合物用乙酸乙酯稀释,用1M盐酸洗涤两次,用碳酸氢钠水溶液洗涤两次,用盐水洗涤一次,然后干燥(MgSO4)并浓缩。剩余物用快速色谱纯化(10%乙酸乙酯/二氯甲烷),得到162mg(70%)无色油。将该油(160mg,0.255mmol)溶解于二氯甲烷(1ml),并在0℃用三氟乙酸(1ml)处理。用40分钟将所得溶液的温度升至室温,然后在30℃蒸发至干。将剩余物溶解于二氯甲烷,并再次蒸发至干。这个过程重复三次。将剩余物溶解于吡啶(0.5ml),并在0℃用乙酐(0.03ml,0.3mmol)处理。将所得混合物升至室温后保持3.5小时。之后,用乙酸乙酯稀释,用1M盐酸洗涤两次,用碳酸氢钠水溶液洗涤两次,干燥(MgSO4)并浓缩,得到128g(86%)无色油。
IR(胶片)3290,1751,1649,1602,1568,1513,1455,
1438,1375,1224,1179;1H NMR(CDCl3)δ8.78(1H,s),
8.33(1H,d,J=7.6),7.33(8H,m),7.11(4H,m),6.86
(2H,d,J=8.5),6.47(1H,d,J=7.6),6.12(1H,d,J
=7.6),4.99(2H,s),4.85(1H,m),4.69(2H,s),3.87
(2H,s),3.62(3H,s),3.08(2H,m),1.96(3H,s).
[6-苄基-1,2-二氢-2-氧代-3-(2-苯乙烷磺酰基)氨基-1-吡啶基]乙酸甲酯(51j)
将2-苯乙烷磺酰氯(Zhong et al.,
J.Am.Chem.Soc.,113,pp.2259-63(1991))加到搅拌的[3-氨基-6-苄基-2-氧代-1,2-二氢-1-吡啶基]乙酸甲酯(49b)(1.0g,3.67mmol),二氯甲烷(15ml)和三乙胺(1.0ml,7.34mmol)的混合物中。经过一夜后将混合物倒入乙酸乙酯。所得混合物用碳酸氢钠水溶液洗涤两次,用1M盐酸洗涤三次,最后用盐水洗涤一次,干燥(MgSO4)并浓缩。所得浅棕色固体用快速色谱纯化(10%乙酸乙酯/二氯甲烷),得到1.25g(77%)浅黄色固体。
m.p.92-4℃;IR(KBr)3181,1737,1646,1595,
1565,1454,1241,1220,1150;1H NMR(CDCl3)δ7.53(1H,
d,J=7.5),7.29(10H,m),6.10(1H,d,J=7.5),4.75
(2H,s),3.89(2H,s),3.67(3H,s),3.34(2H,m),3.14
(2H,m).
[6-苄基-1,2-二氢-2-氧代-3-(4-苯基丁酰基)氨基-1-吡啶基]乙酸甲酯(51l)
分离得到无色结晶(74%)。
mp.93-95℃;IR(KBr)3285,1747,
1683,1642,1591,1563,1512,1455,1220,1181;1H NMR
(CDCl3)δ8.39(1H,d,J=7.6),8.24(1H,s),7.2(10H,
m),6.18(1H,d,J=7.6),4.7(2H,s),3.90(2H,s),
3.67(3H,s),2.69(2H,t),2.40(2H,t),2.04(2H,m).
2(S)2-[1,2-二氢-2-氧代-3-(3-苯基丙酰基)氨基-1-吡啶基]丙酸(52a)
在0℃将1M氢氧化钠(15ml,15mmol)加到搅拌的2(S)2-[1,2-二氢-2-氧代-3-(3-苯基丙酰基)氨基-1-吡啶基]丙酸甲酯(51a)(2.39g,7.3mmol)的甲醇(30ml)溶液中。将混合物保持在此温度2小时,之后用1M盐酸(15.1ml)酸化。用乙酸乙酯萃取,萃取液用盐水洗涤,干燥(MgSO4)并浓缩,得到1.98g(87%)无色固体。
[α]D 20-75°(1,CH2Cl2);IR(KBr)3301,1724,
1693,1637,1563,1523,1453,1233,1216,765 ;1H NMR
(CDCl3)δ8.47(2H,m),7.20(5H,m),7.03(1H,d),6.36
(1H,t),5.35(1H,q),3.01(2H,m),2.70(2H,m),1.69
(3H,m).
用类似方法制备下列化合物:
[6-苄基-1,2-二氢-2-氧代-3-(3-苯基丙酰基)氨基-1-吡啶基]乙酸(52b)
分离得到淡琥珀色油(100%)。
IR(膜)3291,1738,1686,1644,
1591,1554,1519,1496,1454,14 03,1215,1182;1H NMR
(CDCl3)δ8.44(1H,d,J=7.8),8.4(1H,s),7.21(10H,
m),6.19(1H,d,J=7.8),4.71(2H,s),3.90(2H,s),
2.99(2H,m),2.71(2H,m).
[1,2-二氢-2-氧代-6-苯乙基-3-(3-苯基丙酰基)氨基-1-吡啶基]乙酸(52c)
分离得到米色固体(94%)。
mp.214-6℃;IR(KBr)3289,1740,
1680,1640;1H NMR(d6-DMSO)δ9.24(1H,s),8.14(1H,
d,J=7.7),7.22(10H,m),6.11(1H,d,J=7.8),4.78
(2H,s),2.81(8H,m).
[6-丁基-1,2-二氢-2-氧代-3-(3-苯基丙酰基)氨基-1-吡啶基]乙酸(52d)
分离得到淡棕色固体(99%)。
mp.132-4℃;IR(KBr)3286,1739,
1676,1641,1584,1555,1535,1455,1414,1249,1227,
1204;1H NMR(CDCl3)δ8.42(1H,d,J=7.8),8.37(1H,
s),7.24(5H,m),6.19(1H,d,J=7.8),4.82(2H,s),
3.55(1H,s),3.00(2H,t),2.67(2H,t),2.53(2H,t),
1.41(4H,m),0.94(3H,t).
[1,2-二氢-6-甲基-2-氧代-3-(3-苯基丙酰基)氨基-1-吡啶基]乙酸(52e)
分离得到固体(100%)。
mp.159-61℃;IR(KBr)3335,1731,1686,1642,
1536,1516,1430,1420,1401,1222,1195;1H NMR(d6-
DMSO)δ9.21(1H,s),8.13(1H,d,J=7.6),7.20(5H,
m),6.15(1H,d,J=7.6),4.77(2H,s),2.87(2H,m),
2.70(2H,m),2.25(3H,s).
[1,2-二氢-2-氧代-6-苯基-3-(3-苯基丙酰基)氨基-1-吡啶基]乙酸(52f)
分离得到淡黄色泡沫(100%)。
IR(KBr)3271,1747,1683,1634,
1580,1536,1490,1406,1392,1365,1235,1219;1H NMR
(CDCl3)δ8.52(1H,d,J=7.7),7.31(10H,m),6.48
(2H,s),6.30(1H,d,J7.7),4.60(2H,s),3.03(2H,
m),2.71(2H,m).
[1,2-二氢-2-氧代-3-(3-苯基丙酰基)氨基-1-吡啶基]乙酸(52g)
分离得到无色固体(94%)。
mp.195-7℃;IR(KBr)3324,1724,
1693,1644,1569,1555,1512,1427,1370,1240;1H NMR
(d6-DMSO)δ9.31(1H,s),8.23(1H,d,J=6.8),7.36
(1H,dd,J=6.8,1.71),7.25(5H,m),6.25(1H,t),
4.66(2H,s),2.84(4H,m).
2(R,S)2-[6-苄基-1,2-二氢-2-氧代-3-(3-苯基丙酰基)氨基-1-吡啶基]丙酸(52h)
在40℃将化合物51h置于四氢呋喃水溶液中水解5小时,得到黄色油(95%)。
IR(膜)3330,1734,1686,1643,1600,
1587,1553,1524,1498,1208;1H NMR(d6-DMSO)δ9.29
(1H,s),8.18(1H,d,J=7.6),7.21(10H,m),6.22
(1H,d,J=7.6),4.82(1H,q,J=6.6),4.08(2H,m),
2.76(4H,m),1.05(3H,d,J=6.6).
[3-(乙酰基-Tyr(Bn))氨基-6-苄基-1,2-二氢-2-氧代-1-吡啶基]乙酸(52i)
分离得到泡沫(93%)。
IR(KBr)3302,1731,1646,1603,1562,1512,
1454,1428,1379,1231,1178;1H NMR(CDCl3)δ9.48(1H,
s),8.36(1H,d,J=7.6),7.30(8H,m),7.10(2H,m),
6.85(2H,d,J=8.3),6.91(2H,d,J=8.3),6.71(1H,
d,J7.6),4.95(1H,m),4.90(2H,s),4.68(2H,s),
3.92(2H,s),3.17-2.83(2H,m),1.92(3H,s).
[6-苄基-1,2-二氢-2-氧代-3-(2-苯乙烷磺酰基)氨基-1-吡啶基]乙酸(52j)
分离得到无色固体(100%)。
mp.
165-7℃;IR(KBr)3174,1760,1646,1593,1567,1497,
1453,1424,1326,1225,1140,1127;1H NMR(d6-DMSO)δ
13.09(1H,s),9.08(1H,s),7.30(11H,m),6.02(1H,
d),4.68(2H,s),4.99(2H,s),3.29(2H,m),3.03(2H,
m).
[6-苄基-1,2-二氢-2-氧代-3-(2-苯基乙氧基)羰基氨基-1-吡啶基]乙酸(52k)
在60℃将化合物49i水解1小时,制备标题化合物(70%)。
IR(CH2Cl2)1797,1689,1649,1601,1512,734;1H NMR
(CDCl3)δ8.39(1H,s),8.03(1H,d),7.81(1H,s),
7.33-7.07(10H,m),6.13(1H,d,J=7.8),4.72(2H,
s),4.33(2H,t,J=7.0),3.86(2H,s),2.93(2H,t,J
=7.0).
[6-苄基-1,2-二氢-2-氧wa-3-(4-苯基丁酰基)氨基-1-吡啶基]乙酸(52l)
分离得到白色泡沫(100%)。
m.p.159-161℃;IR(KBr)3373-3310,1787,
1726,1691,1649,1599,1567,1517,1367,1215;1H NMR
(CDCl3)δ8.43(1H,d,J=7.7),8.25(1H,s),7.37-7.09
(10H,m),6.21(1H,d,J=7.7),4.73(2H,s),4.15
(3H,s),3.91(2H,s),2.67(2H,t),2.39(2H,t),2.02
(2H,m).
2(S),N-3(S)2-[1,2-二氢-2-氧代-3-(3-苯基丙酰基)氨基-1-吡啶基]-N-(2-苄氧基-5-氧代四氢呋喃-3-基)丙酰胺(53a)
将三-正丁基氢化锡(1.7ml,6.3mmol)滴加到搅拌的2(S)-2-[1,2-二氢-2-氧代-3-(3-苯基丙酰基)氨基-1-吡啶基]丙酸(52a)(1.1g,3.49mmol),3(S),2(R,S)3-烯丙氧羰基氨基-2-苄氧基-5-氧代四氢呋喃(1.02g,3.49mmol;Chapman,
Biorg.Med.Chem.Lett.,2,pp.613-18(1992)),双(三苯膦)氯化钯(II)(55mg),二氯甲烷(35ml)和二甲基甲酰胺(1ml)的混合物中。将所得混合物搅拌5分钟,加入1-羟基苯并三唑(946mg,7mmol)。将混合物冷却至0℃,然后加入1-(3-二甲氨基丙基)-2-乙基碳化二亚胺盐酸盐(740mg,3.84mmol)。混合物放在室温过夜,然后将其倒入乙酸乙酯。混合物用1M盐酸洗涤两次,用碳酸氢钠水溶液洗涤两次,用盐水洗涤一次,干燥(MgSO4)和浓缩。剩余物用戊烷研制,剩下的固体用快速色谱纯化(40-60%乙酸乙酯/己烷),得到1.28g(73%)无色固体。
IR(KBr)1796,1692,
1647,1595,1557,1512,1119;1H NMR(d6-DMSO)δ9.28,
9.26(1H,2xs),8.77,8.69(1H,2xd),8.24,8.20
(1H,2xdd),7.20(11H,m),6.31,6.26(1H,2xt),
5.65(0.5H,d),5.46(0.5H,d),5.41,5.28(1H,2xq),
4.7(2.5H,m),4.24(0.5H,t),3.24(2H,m),2.80(4H,
m),1.51,1.46(3H,2xd).
用类似方法制备下列化合物:
N(3(S))2-[6-苄基-1,2-二氢-2-氧代-3-(3-苯基丙酰基)氨基-1-吡啶基]-N-(2-苄氧基-5-氧代四氢呋喃-3-基)乙酰胺(53b)
制得标题化合物为泡沫(86%)。
IR(KBr)3345,3297,1807,1791,
1688,1679,1650,1602,1554,1525,1497,1453,1372,
1257,1119;1H NMR(d6-DMSO)δ9.25(0.5H,s),9.23
(0.5H,s),8.75(0.5H,d,J=6.5),8.67(0.5H,d,J=
7.4),8.18(1H,2d),7.21(15H,m),6.07(1H,2d),5.65
(0.5H,d,J=5.0),5.38(0.5H,s),4.83-4.45(4.5H,
m),4.19(0.5H,m),3.94,3.83(2H,m),3.10-2.31(6H,
m).
N(3(S))2-[1,2-二氢-2-氧代-6-苯乙基-3-(3-苯基丙酰基)氨基-1-吡啶基]-N-(2-苄氧基-5-氧代四氢呋喃-4-基)乙酰胺(53c)
制得标题化合物为异头物的混合物(74%)。
1H NMR(d6-DMSO)δ9.71
(1H,d),9.41(0.5H,d),9.25(0.5H,d),8.64(1H,d,J=7.7),7.75(15H,m),6.61(1H,2d),6.11(0.5H,d),
5.93(0.5H,s),5.17(5H,m),4.77(0.5H,m),3.68-2.94
(2H,m),3.32(8H,m).
N(3(S))2-[6-丁基-1,2-二氢-2-氧代-3-(3-苯基丙酰基)氨基-1-吡啶基]-N-(2-苄氧基-5-氧代四氢呋喃-3-基)乙酰胺(53d)
制得标题化合物为异头物的混合物(74%)。
IR(KBr)3300,1791,
1689,1645,1597,1566,1546,1514,1454,1417,1378;
1H NMR(CDCl3)δ8.38(1H,d,J=7.7),8.13(1H,s),
7.30(10H,m),6.18(1H,t),5.47(0.5H,d,J=5.2),
5.43(0.5H,s),4.75(4.5H,m),4.38(0.5H,m),3.08-
2.35(8H,m),1.43(4H,m),0.95(3H,t).
N(3(S))2-[1,2-二氢-6-甲基-2-氧代-3-(3-苯基丙酰基)氨基-1-吡啶基]-N-(2-苄氧基-5-氧代四氢呋喃-3-基)乙酰胺(53e)
制得标题化合物为异头物的混合物(67%)。
IR(KBr)3282,1774,
1667,1651,1596,1561,1556,1498,1265,1254,1236,
1199,1143;1H NMR(d6-DMSO)δ9.17 and 9.15(1H,2x
s),8.89(0.5H,d,J=6.5),8.73(0.5H,d,J=7.4),
7.25(10H,m),6.13(1H,t),5.64(0.5H,d,J=5.0),
5.45(0.5H,s),4.89-4.61(4.5H,m),4.26(0.5H,m),
3.17-2.36(6H,m),2.23 and 2.15(3H,2s).
N(3(S))2-[1,2-二氢-2-氧代-6-苯基-3-(3-苯基丙酰基)氨基-1-吡啶基]-N-(2-苄氧基-5-氧代四氢呋喃-3-基)乙酰胺(53f)
制得标题化合物为异头物的混合物(73%)。
IR(KBr)3296,1792,
1691,1643,1595,1561,1514,1489,1453,1420,1373,
1230,1118;1H NMR(d6-DMSO)δ9.40,9.36(1H,2s),8.70
(0.5H,d,J=7.6),8.52(0.5H,d,J=7.5),8.29(1H,
dd),7.25(15H,m),6.20(1H,d,J=7.6),5.61(0.5H,
d,J=5.0),5.28(0.5H,s),4.78-4.20(5H,m),3.12-
2.24(6H,m).
N(3(S))2-[1,2-二氢-2-氧代-3-(3-苯基丙酰基)氨基-1-吡啶基]-N-(2-苄氧基-5-氧代四氢呋喃-3-基)乙酰胺(53c)
制得标题化合物为异头物的混合物(70%)。
IR(KBr)3336,3290,1791,1691,1646,1595,
1582,1556,1518,1454,1376,1351,1150,1122;1H NMR
(d6-DMSO)δ9.26(1H,2s),8.86(0.5H,d,J=6.4),8.67
(0.5H,d,J=7.5),8.23(1H,m),7.40-7.13(11H,m),
6.24(1H,2t,J=7.2),5.61(0.5H,d,J=5.0),5.44
(0.5H,s),4.83-4.59(2.5H,m),4.25(0.5H,m),3.15-
2.34(2H,m),2.91-2.70(4H,m).
元素分析C27H27N3O6·H2O:
计算值:C,63.90;H,5.76;N,8.28,
实测值:C,63.70;H,5.68;N,8.22。
MS FAB M+=490(M+1).
2(R,S)N(3(S))2-[6-苄基-1,2-二氢-2-氧代-3-(3-苯基丙酰基)氨基-1-吡啶基]-N-(2-苄氧基-5-氧代四氢呋喃-3-基)丙酰胺(53h)
制得标题化合物为非对映体的混合物(89%)。给出单个非对映体的数据。
IR(膜)3356,1788,
1677,1645,1602,1517,1455,1377,1203,1167,1120;
1H NMR(CDCl3)δ8.34(1H,d,J=7.6),8.19(1H,s),
7.38-7.13(10H,m),6.26(1H,d,J=7.6),5.58(1H,
t),5.31,5.24(1H,2xs),4.62(2H,2q),4.60(1H,
m),4.27(1H,m),2.98,2.68(4H,2m),3.0-2.0(2H,m),
1.42(3H,d).
N(3(S))2-[6-苄基-1,2-二氢-2-氧代-3-(N-乙酰基-O-苄基酪氨酰基)氨基-1-吡啶基]-N-(2-苄氧基-5-氧代四氢呋喃-3-基)乙酰胺(53i)
制得标题化合物为异头物的混合物(76%)。
IR(KBr)1794,1698,
1651,1612,1514,1454,1374,1247,1177,1126;1H NMR
(d6-DMSO)δ9.34,9.31(2x 0.5H,2s),8.71(1H,2d),
8.38(1H,m),8.17(1H,d),7.48-6.88(19H,m),6.08
(1H,2d),5.65(0.5H,d,J=5.0),5.40(0.5H,s),5.04
(2H,s),4.68(5.5H,m),4.15(0.5H,m),3.95,3.84
(2H,s+abq),3.20-2.40(4H,m),1.78(3H,s).
N(3(S))2-[6-苄基-1,2-二氢-2-氧代-3-(2-苯乙烷磺酰基)氨基-1-吡啶基]-N-(2-苄氧基-5-氧代四氢呋喃-4-基)乙酰胺(53j)
制得标题化合物为异头物的混合物(78%)。
IR(KBr)3344,1792,
1691,1647,1599,1566,1454,1365,1150,1121,973;
1H NMR(d6-DMSO)δ9.02,8.99(1H,2s),8.80(0.5H,d,J
=6.4),8.70(0.5H,d,J=7.4),7.26(15H,m),6.00
(1H,dd),5.63(0.5H,d,J=5.0),5.39(0.5H,s),4.68
(4.5H,m),4.18(0.5H,m),3.90(2H,m),3.30-2.30(6H,
m).
N(3(S))2-[6-苄基-1,2-二氢-2-氧代-3-(2-苯基乙氧基)羰基氨基-1-吡啶基]-N-(2-苄氧基-5-氧代四氢呋喃-3-基)乙酰胺(53k)
制得标题化合物为异头物的混合物(78%)。
IR(KBr)3386,1794,
1726,1650,1603,1518,1366,1214,699;1H NMR(CDCl3)
δ8.03(1H,bd),7.63,7.61(1H,2xs),7.34-7.04
(15H,m),6.21,6.18(1H,2d),5.44(0.5H,d,J=5.4),
5.37(0.5H,s),4.85,4.83(1H,2d,J=11.6,11.5),
4.61-4.48,4.32(4H,2m),4.4(2H,t),4.08,4.03(2H,
2bs),3.07-2.78(3H,m),2.47-2.30(1H,m).
N(3(S))2-[6-苄基-1,2-二氢-2-氧代-3-(4-苯基丁酰基)氨基-1-吡啶基]-N-(2-苄氧基-5-氧代四氢呋喃-3-基)乙酰胺(53l)
制备得到无色油(86%)。 IR(CH2Cl2)1797,1689,1649,
1601,1512,734;1H NMR(CDCl3)δ8.42,8.40(1H,2d,J
=7.6),7.35-7.07(15H,m),6.21,6.19(1H,2d,J=
7.6),5.44(0.5H,d),5.37(0.5H,s),4.84,4.81(1H,
2d,J=11.7,11.4),4.73-4.48,4.34(4H,2m),4.05
(2H,m),3.05-2.63,2.46-2.30(6H,2m),2.01(2H,m).
R1 R2 R3
(a) Ph(CH2)2CO H (S)Me
(b) Ph(CH2)2CO CH2Ph H
(c) Ph(CH2)2CO (CH2)2Ph H
(d) Ph(CH2)2CO nBu H
(e) Ph(CH2)2CO Me H
(f) Ph(CH2)2CO Ph H
(g) Ph(CH2)2CO H H
(h) Ph(CH2)2CO CH2Ph (R,S)-Me
(i) AcTyr CH2Ph H
(j) Ph(CH2)2SO2 CH2Ph H
(k) Ph(CH2)2OCO CH2Ph H
(l) Ph(CH2)3CO CH2Ph H
3(S),N(2(S))3-(2-(1,2-二氢-2-氧代-3-(3-苯基丙酰基)氨基-1-吡啶基)-丙酰氨基)-4-氧代丁酸(54a;F)
将2(S),N(3(S))2-[1,2-二氢-2-氧代-3-(3-苯基丙酰基)氨基-1-吡啶基]-N-(2-苄氧基-5-氧代四氢呋喃-3-基)丙酰胺(53a)(1.28g,2.5mmol),甲醇(140ml),乙酸乙酯(60ml)和10%钯/炭(1.4g)的混合物在氢气中搅拌。2.5小时之后加入催化剂(300mg),继续氢化1小时。用CeliteTM过滤混合物,然后通过0.2μM尼龙过滤器重新过滤,并浓缩。剩余的油用甲醇和乙醚的混合物研制,得到916mg(87%)无色结晶。
mp.198-200℃;[
α]D 28-120°(0.1,
CH3OH);IR(KBr)3330,1794,1688,1644,1583,1556,
1515,1427;1H NMR(CD3OD)δ8.28(1H,d),7.35(1H,d),
7.20(5H,m),6.36(1H,t),5.49(1H,q),4.59(1H,t),
4.25(1H,m),2.98,2.74(2x2H,2xm),2.59(2H,m),
1.57(3H,d).
元素分析C21H23N3O6·0.75H2O:
计算值:C,59.08;H,5.78;N,9.84,
实测值:C,59.24;H,5.96;N,9.84。
FAB M+=414(M+1),297,165,91.
用类似方法制备下列化合物:
3(S)3-(6-苄基-1,2-二氢-2-氧代-3-(3-苯基丙酰基)氨基
-1-吡啶基)乙酰氨基-4-氧代丁酸(54b;M)分离得到无色结晶(59%):m.p.115℃(分解)。
IR(KBr)
3440,3297,1718,1646,1598,1565,1526,1496,1260;
1H NMR(CD3OD)8.25(1H,d,J=7.7),7.25(10H,m),6.15
(1H,2d,each J=7.7),4.73(2H,2q),4.59(1H,m),4.30
(1H,m),3.95(2H,s),2.98(2H,m),2.75(2H,m),2.8-
2.42(2H,m).
元素分析C27H27N3O6·0.7H2O:
计算值:C,64.58;H,5.70;N,8.37,
实测值:C,64.51;H,5.63;N,8.38。
MS FAB+M+=490(M+1).
3(S)3-(1,2-二氢-2-氧代-6-苯乙基-3-(3-苯基丙酰基)氨基-1-吡啶基)乙酰氨基-4-氧代丁酸(54c)
分离得到白色固体(46%): IR
(KBr)3375,1694,1643,1586,1561,1515,1377,1254,
1188,1070;1H NMR(CD3OD)8.18(1H,d,J=7.8),7.22
(10H,m),6.15(1H,d,J=7.8),4.75(2H,s),4.58(1H,
m),4.30(1H,m),3.01-2.28(10H,m);MS FAB+M+=504
(M+1).
3(S)3-(6-丁基-1,2-二氢-2-氧代-3-(3-苯基丙酰基)氨基-1-吡啶基)乙酰氨基-4-氧代丁酸(54d)
分离得到无色结晶(90%)。
m.p.120-5℃;IR(KBr)3315,1784,1679,
1644,1589,1561,1556,1520,1415,1379,1186;1H NMR
(CD3OD)8.22(1H,d,J=7.8),7.24(5H,m),6.22(1H,d,
J=7.8),4.80(2H,m),4.60(1H,s),4.28(1H,m),2.98
(2H,m),2.72(2H,m),2.58(4H,m),1.48(4H,m),0.97
(3H,t,J=7.1).
元素分析C24H29N3O6·0.5H2O:
计算值:C,62.06;H,6.51;N,9.05,
实测值:C,62.08;H,6.43;N,9.01。
MS FAB+M+=456(M+1).
3(S)3-(1,2-二氢-6-甲基-2-氧代-3-(3-苯基丙酰基)氨基-1-吡啶基)乙酰氨基-4-氧代丁酸(54e)
分离得到无色固体(85%)。
mp.129-138℃;IR(KBr)327,3294,
1710,1695,1682,1554,1525,1379,1272,1240;1H NMR
(CD3OD)δ8.19(1H,d,J=7.6),7.19(5H,m),6.21(1H,
d,J=7.6),4.80(2H,m),4.59(1H,m),4.30(1H,m),
2.98(2H,m),2.72(2H,m),2.80-2.40(2H,m),2.30
(3H,s).
元素分析C21H22N3O6·H2O:
计算值:C,58.46;H,5.84;N,9.74,
实测值:C,58.82;H,6.05;N,9.42。
3(S)3-(1,2-二氢-2-氧代-6-苯基-3-(3-苯基丙酰基)氨基-1-吡啶基)乙酰氨基-4-氧代丁酸(54f)
分离得到乳白色固体(73%):。m.p.140℃(分解)。
[α]D 24=-8.5°(c 0.1,MeOH).IR(KBr)3302,
1796,1726,1679,1643,1590,1560,1516,1490,1449,
1420,1398,1376,1231;1H NMR(CD3OD)δ8.36(1H,d),
7.49-7.14(10H,m),6.27(1H,dd),4.54(3H,m),4.30
(1H,m),3.0,2.73(2x2H,2xm),2.7-2.29(2H,m).
3(S)3-(1,2-二氢-2-氧代-3-(3-苯基丙酰基)氨基-1-吡啶基)乙酰氨基-4-氧代丁酸(54g;G)
分离得到泡沫(73%):m.p.140-5℃(分解)。 IR
(KBr)3352,3314,1719,1700,1668,1649,1600,1559,
1514,1379,1261;1H NMR(CD3OD)δ8.32(1H,d,J=7.5),
7.19(6H,m),6.34(1H,t),5.1-4.6(3H,m),4.32(1H,
m),2.7(6H,m).
元素分析C20H21N3O6·0.6H2O:
计算值:C,58.50;H,5.45;N,10.24,
实测值:C,58.43;H,5.35;N,9.85。
MS FAB+M+=400(M+1).
3(S),N(2(R,S))3-(2-(6-苄基-1,2-二氢-2-氧代-3-(3-苯基丙酰基)氨基-1-吡啶基)丙酰氨基-4-氧代丁酸(54h)
制得无色泡沫(69%)。
m.p.120℃;[α]D 20-16.0°(c,0.11,
CH2Cl2).IR(KBr)3315,1783,1727,1666,1644,1599,
1564,1517,1454,1379;1H NMR(CD3OD)δ8.23(1H,m),
7.27(10H,m),6.28(1H,m),4.84(1H,m),4.53(1H,
m),4.22(1H,m),4.10(2H,m),2.96(2H,m),2.72(2H,
m),2.39(2H,m),1.21(3H,m).
元素分析C28H29N3O6·1.25H2O:
计算值:C,63.93;H,6.03;N,7.99,
实测值:C,63.98;H,5.85;N,7.86。
MS FAB(+)M+=504(M+1).
3(S)3-(3-(2-乙酰基-L-酪氨酰基)氨基-6-苄基-1,2-二氢-2-氧代-1-吡啶基)乙酰氨基-4-氧代丁酸(54i)
分离得到无色晶体(79%):m.p.193-6℃(分解)。
IR(KBr)3284,1644,1599,1565,
1519,1455,1429,1407,1375,1267,1251;1H NMR(d6-
DMSO/CDCl3)δ8.16(1H,d,J=7.7),7.26(5H,m),7.03
(2H,d,J=8.4),6.61(2H,d,J=8.4),6.03(1H,d,
J=7.7),4.58(3H,m),4.44(1H,m),4.13(1H,m),3.84
(2H,s),3.07-2.30(4H,m).
元素分析C29H30N4O8·2H2O:
计算值:C,58.19;H,5.72;N,9.36,
实测值:C,58.11;H,5.63;N,9.29。
MS FAB+M+=563(M+1).
3(S)3-(6-苄基-1,2-二氢-2-氧代-3-(2-苯乙烷磺酰基)氨基-1-吡啶基)乙酰氨基-4-氧代丁酸(54j)
分离得到无色固体(85%)。
mp.102-5℃;[α]D 23-9.9°(c 0.1,MeOH);IR(KBr)3452,
3328,3155,1719,1679,1645,1594,1567,1453,1425,
1357,1307,1225,1148,1132;1H NMR(CD3OD)δ7.52(1H,
d,J=7.6),7.33(10H,m),6.12(1H,d,J=7.6),4.73
(2H,m),4.58(1H,d,J=3.7),4.34(1H,m),3.97(2H,
s),3.29(2H,m),3.08(2H,m),2.75-2.37(2H,m).
元素分析C26H27N3O7S·1.7H2O:
计算值:C,56.14;H,5.51;N,7.55,
实测值:C,56.20;H,5.49;N,7.29。
MS FAB+M+=526(M+1).
3(S)3-(6-苄基-1,2-二氢-2-氧代-3-(2-苯基乙氧基)羰基氨基-1-吡啶基)乙酰氨基-4-氧代丁酸(54k)
分离得到乳白色固体(54%)。
mp.84-86℃;IR(KBr)3373-3310,1787,
1726,1691,1649,1599,1567,1517,1367,1215;1H NMR
(CD3OD)δ7.93(1H,bd,J=7.4),7.37-7.18(10H,m),6.15
(1H,d,J=7.4),4.77(1H,d,J=3.7),4.67 and 4.58(2H,
2m),4.35(2H,t,J=6.9),4.35(1H,m),3.94(2H,s),
2.98(2H,t,J=6.9),2.76-2.39(2H,m).
3(S)3-(6-苄基-1,2-二氢-2-氧代-3-(4-苯基丁酰基)氨基-1-吡啶基)乙酰氨基-4-氧代丁酸(541)
分离得到白色固体(50%)。
IR(KBr)3369-3302,1678,1645,
1594,1565,1517,1379,1258;1H NMR(d1-甲醇)δ
8.25(1H,d,J=7.6),7.37-7.18(10H,m),6.15(1H,d,
J=7.4),4.74(2H,m),4.60(1H,m),4.30(1H,m),3.97
(2H,s),2.76-2.37(2H,m),2.67(2H,t),2.45(2H,t)
1.98(2H,m).
元素分析C28H29N3O6·1.5H2O:
计算值:C,63.39;H,6.08;N,7.92,
实测值:C,63.69;H,5.74;N,7.83。
N-2-(3-苄氧羰基氨基-1,2-二氢-2-氧代-1-吡啶基)乙酰基-3-氨基-5-(2,6-二氯-苯甲酸基)-4-氧代-戊酸叔丁酯(56a)
将乙酸(55a)(WO 93 21213)的THF(2ml)溶液在室温搅拌,并用1-羟基苯并三唑(60mg,0.448mmol)和二甲氨基丙基-3-乙基碳化二亚胺盐酸盐(47mg,0.246mmol)处理。5分钟后加水(2滴)并继续搅拌20分钟。加入双(三苯膦)氯化钯(II)(6mg),接着加入3-(烯丙氧羰基氨基)-4-氧代-5-(2,6-二氯苯甲酸基)戊酸叔丁酯(WO 93 16710)(103mg,0.224mmol)的THF(1ml)溶液。在室温用1小时滴加三丁基氢化锡(0.09ml,0.336mmol)。将混合物进一步搅拌3小时,然后倒入乙酸乙酯中。依次用1M HCl,NaHCO3水溶液和盐水洗涤,干燥(MgSO4)并真空浓缩。剩余物用戊烷研制。弃去上清液,余下的固体用快速色谱纯化(50%乙酸乙酯/己烷),得到92mg(63%)标题化合物为无色油。
[α]D 26-29.6°(c 1.1,CH2Cl2);IR
(膜)3377,3365,3332,3312,1733,1691,1650,1599,
1515,1366,1261,1153,1068,747;1H NMR(CDCl3)δ8.09
(1H,d,J=6.8),7.84(1H,s),7.58(1H,d,J=8.3),
7.33(8H,m),7.02(1H,dd,J=6.9,1.7),6.33(1H,t,
J=7.2),5.20(2H,s),5.12(2H,m),4.89(1H,dt),
4.65(2H,m),2.80(2H,m),1.38(9H,s).
N-2-(6-苄基-1,2-二氢-2-氧代-3-(3-苯基丙酰基)氨基-1-吡啶基)乙酰基-3-氨基-5-(2,6-二氯-苯甲酸基)-4-氧代-戊酸叔丁酯(56b)
用56a所述方法制备,得到标题化合物为无色油(66%)。
IR(膜)
3364,3313,1738,1688,1648,1600,1566,1514,1433,
1369,1254,1152;1H NMR(CDCl3)δ8.40(1H,d,J7.6),
8.30(1H,s),7.28(13H,m),6.20(1H,d,J=7.6),
5.12(2H,q),4.86(1H,m),4.65(2H,q),4.06(2H,s),
3.07-2.61(6H,m),1.39(9H,s).
N-2-(3-苄氧羰基氨基-1,2-二氢-2-氧代-1-吡啶基)乙酰基-3-氨基-5-(2,6-二氯-苯甲酸基)-4-氧代-戊酸(57a;O)
将酯(56a)(210mg,0.356mmol)的二氯甲烷(0.5ml)溶液冷却到0℃,并用三氟乙酸(0.5ml)处理。搅拌并用30分钟缓慢升至20℃。将该溶液减压蒸发至干,再溶解于二氯甲烷,并浓缩(×3)。剩余物用乙酸乙酯研制,用乙醚稀释,得到162mg(85%)标题化合物为无色固体。m.p.165-8℃(分解)。
[α]D 23-38.8°(c 0.1,CH3OH);IR(KBr)
3332,3275,1723,1658,1649,1597,1581,1562,1526,
1432,1385,1258,1218,1206;1H NMR(d6-DMSO)δ8.96
(1H,d,J=7.3),8.34(1H,s),7.85(1H,dd,J=7.3),
7.58(3H,m),7.35(5H,m),6.29(1H,t,J=7.3),5.26
(2H,m),5.15(2H,s),4.69(3H,m),2.75(2H,m).
元素分析C27H23N3O9Cl2:
计算值:C,53.66;H,3.84;N,6.95,
实测值:C,53.66;H,3.90;N,6.81。M.S.(+FAB);604
(M++1),285,241,195,173,149,91.
N-2-(6-苄基-1,2-二氢-2-氧代-3-(3-苯基丙酰基)氨基-1-吡啶基)乙酰基-3-氨基-5-(2,6-二氯-苯甲酸基)-4-氧代-戊酸(57b;P)
用57a所述方法制备,得到标题化合物(78%)为无色晶体:m.p.116-120℃(分解)。
[α]D 26-41.1°(c 0.1,CH3OH);IR
(KBr)3299,1739,1715,1689,1666,1645,1598,1563,
1518,1432,1209,1151;1H NMR(d6-DMSO)δ9.24(1H,s),
8.88(1H,d,J=7.6),8.18(1H,d,J=7.7),7.60(3H,
m),7.26(10H,m),6.06(1H,d,J=7.7),5.23(2H,
ABq),4.69(3H,m),3.93(2H,s),2.78(6H,m).
元素分析C35H31N3O8Cl2·H2O:
计算值:C,59.16;H,4.68;N,5.91,
实测值:C,59.38;H,4.53;N,5.84。
M.S.(+FAB);
694,(Cl=35,37),(M++1);692(Cl=35,35),(M++1).
(3S,4R,S)N-(苄氧羰基)-3-氨基-4-(2-苯并噁唑基)-4-羟基-丁酸叔丁酯(59)
在-78℃的氮气下向搅拌的苯并噁唑(250.2mg,2.1mmol)的无水THF(10.5ml)溶液中滴加2.3M正丁基锂的己烷(0.96ml,2.2mmol)。在-78℃搅拌20分钟后加入MgBr2OEt2固体(594.0mg,2.3mmol)。将所得非均匀混合物升温至-45℃,并搅拌15分钟。然后将反应混合物重新冷却到-78℃,并滴加醛58(644.6mg,2.1mmol;Graybill et al.,
Int.J.Peptide Protein Res.,44,pp.173-182(1993))的THF(10.5ml)溶液。将反应物在-78℃搅拌30分钟,升温至0℃1小时,然后在室温搅拌16小时。用5%碳酸氢钠(2.0ml)淬灭反应,真空除去THF。所得水性剩余物用二氯甲烷萃取4次。合并的萃取液用盐水洗涤,干燥(MgSO4),过滤并真空浓缩,得到880.0mg粗产物。快速色谱纯化(45∶55乙酸乙酯/己烷)后得到567.2mg(63%)标题化合物为一种油,是在C-4的非对映体混合物。
IR(膜)3324,
2976,1726,1517,1455,1368,1243,1159,1048,747;
1H NMR(CDCl3)δ7.71-7.64(1H,m),7.52-7.48(1H,m),
7.37-7.20(7H,m),5.91(1H,brd,J=9.0),5.79(1H,
d,J=9.0),5.41-4.78(4H,m),4.75-4.54(1H,m),
2.91-2.51(2H,m),1.42(9H,s),1.37(9H,s).
(3S,4R,S)3-氨基-4-(2-苯并噁唑基)-4-羟基丁酸叔丁酯(60)
将酯59(189.0mg,0.44mmol)的乙醇(5.0ml)溶液用10%钯/炭(20.5mg)处理,并在氢气下搅拌21小时。混合物经Celite_过滤,蒸发溶剂,得到125.0mg(98%)粗胺60为一种油。该油无需进一步纯化即可使用。
1H NMR(CDCl3)
δ7.73-7.64(1H,m),7.51-7.42(1H,m),7.35-7.22(2H,
m),6.48(3H,brs),5.58(1H,d,J=3.0),5.27(1H,d,
J=6.5),4.23-4.05(1H,m),2.92-2.63(2H,m),1.36
(9H,s),1.33(9H,s).
(3S,4R,S)N-(N-苄氧羰基-(S)-缬氨酰基-(S)-丙氨酰基)-3-氨基-4-(2-苯并噁唑基)-4-羟基丁酸叔丁酯(61)
将胺60(261.4mg,0.89mmol),Z-Val-Ala-OH(286.9mg,0.89mmol)(用标准肽合成方法制备)和羟基苯并三唑(120.3mg,0.89mmol)的DMF(3.0ml)溶液在0℃用1-乙基-3-[3-(二甲氨基)丙基]碳化二亚胺盐酸盐(179.2mg,0.93mmol)处理。将反应物暖至室温并搅拌16小时。反应物用乙酸乙酯稀释,用1M硫酸氢钠洗涤两次,用饱和碳酸氢钠洗涤两次,用水和盐水各洗涤一次。干燥(MgSO4)有机相,过滤并减压浓缩,得到494.8mg粗产物。用快速色谱纯化(95∶5二氯甲烷/甲醇),得到480.9mg(91%)标题化合物为黄色固体。
mp.81-83℃;IR(KBr)
3312,2974,1723,1709,1529,1455,1368,1243,1156,
747;1H NMR(CDCl3)δ7.79(0.5H,d,J=8.0),7.73-7.20
(9.5H,m),6.15(1H,t,J=8.5),5.74(0.5H,brd,J=
5.5),5.45(1H,brd,J=7.5),5.28-5.20(0.5H,m),
4.82-4.11(3.5H,m),4.78-4.55(1H,m),4.40-4.22(1H,
m),2.95-2.51(2H,m),2.12-1.95(1H,m),1.45-1.32
(12H,m),1.11-0.81(6H,m),13C NMR(CDCl3)δ173.14,
172.94,171.82,171.03,170.78,165.98,165.45,157.29,
157.17,151.23,151.10,140.92,140.82,136.83,136.79,
128.91,128.52,125.75,124.97,120.60,120.40,111.38,
81.82,81.68,70.27,68.97,67.44,60.43,50.74,50.55,
49.18,49.07,36.87,36.57,32.37,28.51,19.88,19.80,
18.53.
元素分析C31H40N4O8·H2O:
计算值:C,60.57;H,6.89;N,9.11,
实测值:C,60.84;H,6.64;N,9.09。
M.S.(+FAB);597(M++1);541,91.
(3S)N-(N-苄氧羰基-(S)-缬氨酰基-(S)-丙氨酰基)-3-氨基-4-(2-苯并噁唑基)-4-氧代丁酸叔丁酯(62)
将醇61(100.3mg,0.17mmol)溶解于二氯甲烷(2.0ml),然后加入Dess-Martin试剂(142.6mg,0.34mmol;Ireland et al.,
J.Org.Chem.,58,pp.2899(1993);Dess et al.,
J.Org.Chem.,48,pp.4155-4156(1983))。将所得混合物搅拌22分钟,然后在饱和硫代硫酸钠∶饱和碳酸氢钠(1∶1,10ml)和乙酸乙酯(10ml)之间分配。所得有机相依次用饱和硫代硫酸钠∶饱和碳酸氢钠(1∶1),饱和碳酸氢钠和盐水洗涤。干燥(MgSO4)有机相,过滤并真空浓缩,得到111.3mg粗产物。用快速色谱纯化(95∶5二氯甲烷/甲醇),得到97.3mg(96%)标题化合物为油。
[α]D 23-11.74°(c 0.95,CH2Cl2);IR(CH2Cl2)3419,2974,
1721,1677,1501,1369,1221,1156;1H NMR(CDCl3)δ
7.89-7.84(1H,m),7.73-7.22(10H,m),5.98(1H,d,J=
9.0),5.72(1H,m),5.10(2H,q,J=12.5),4.73(2H,
m),4.20(1H,dd,J=7.0,8.5),3.30(1H,dd,J=5.0,
16.5),3.03(1H,dd,J=5.5,16.5),2.18-1.97(1H,m),
1.39(3H,d,J=7.0),1.34(9H,s),0.93(3H,d,J=
6.0),0.90(3H,d,J=6.0),13C NMR(CDCl3)δ186.46,
172.73,171.90,170.13,157.17,156.28,151.16,140.99,
136.99,129.39,129.08,128.66,128.59,126.49,123.06,
112.55,82.73,67.60,60.84,53.75,49.41,38.58,
32.05,28.52,19.85,19.32,18.51.M.S.(+FAB);595
(M++1);539,91.
(3S)N-(N-苄氧羰基-(S)-缬氨酰基-(S)-丙氨酰基)-3-氨基-4-(2-苯并噁唑基)-4-氧代丁酸酯(63;O)
在干燥氮气中将酯62(95.0mg,0.16mmol)在1∶1二氯甲烷和三氟乙酸(10.0ml)的混合物中的溶液搅拌1小时。然后真空浓缩溶液,溶解于乙醚并再次浓缩。这个过程被重复6次,得到的粗产物为乳白色固体。快速色谱纯化(95∶5二氯甲烷/甲醇)后得到60.0mg(69%)标题化合物为白色固体。产物以CD3OD中的三种异构体的混合物形式存在,即酮形式(一种异构体,c 44%)及其酸基缩酮形式(C-4位的两种异构体,c.56%)。
m.p.156-159℃[α]D 26
-45.6°(c 0.13,甲醇);IR(KBr)3440,2967,1713,
1703,1638,1531,1427;1H NMR(CD3OD)δ7.93-7.24(9H,
m),5.59(1H,brt),5.16-5.00(2H,m),5.0-4.78(1H,
m),4.50-4.22(1H,m),3.95-3.81(1H,m),3.11(2H,d,
J=6.5),3.05-2.92(1H,m),2.70-2.39(1H,m),2.08-
1.89(1H,m),1.19-0.78(9H,m).
C27H30N4O8.0.5H2O:C,59.22;C,59.48,H,5.36,N,10.17.
元素分析C27H30N4O8·0.5H2O:
计算值:C,59.22;H,5.71;N,10.23,
实测值:C,59.48;H,5.36;N,10.17。
(a)R1=OCH3,R2=H
(b)R1=H,R2=OCH3
7-甲氧基苯并噁唑(65a)
将2-硝基-6-甲氧基苯酚(2.62g,15.5mmol;EP 333176)和10%钯/炭(130mg)的乙醇(50.0ml)的混合物在氢气下搅拌75分钟。用Celite_过滤混合物,然后立即用对甲苯磺酸(32.0mg)和原甲酸三乙酯(6.45ml,38.8mmol)处理,然后在氮气中加热回流。20小时后加入对甲苯磺酸(30.0mg)和原甲酸三乙酯(6.45ml,38.8mmol)。总共加热44小时后使反应物冷却,并真空浓缩。所得剩余物用快速色谱纯化(25∶75乙酸乙酯/己烷),得到1.97g(85%)标题化合物为黄色固体。
m.p.28-31℃;IR(膜)1629,1497,1434,1285,1097;
1H NMR(CDCl3)δ8.09(1H,s),7.40(1H,d,J=8.0),
7.28(1H,t,J=8.0),6.89(1H,d,J=8.0),4.02(3H,
s);13C NMR(CDCl3)δ152.84,145.82,142.50,139.99,
125.75,113.42,108.80,56.97.
元素分析C8H7N1O2·0.1H2O:
计算值:C,63.65;H,4.81;N,9.29,
实测值:C,63.43;H,4.88;N,9.05。
M.S.(+FAB);150(M++1).
4-甲氧基苯并噁唑(65b)
向4-羟基苯并噁唑(2.00g,14.8mmol;Musser et al.,
J.Med.Chem.,30,pp.62-67(1987))的丙酮(80.0ml)悬浮液中加入干燥的K2CO3(2.25g,16.3mmol),接着加入碘甲烷(1.38ml,22.2mmol)。将反应物在氮气中加热回流4.5小时,过滤并真空浓缩,得到粗产物。将粗产物用快速色谱纯化(25∶75乙酸乙酯/己烷),得到2.0g(91%)标题化合物为白色结晶固体。
m.p.72-
74℃;IR(KBr)3089,1619,1610,1503,1496,1322,
1275,1090,1071,780,741;1H NMR(CDCl3)δ8.02(1H,
s),7.32(1H,t,J=8.0),7.18(1H,d,J=8.0),6.81
(1H,d,J=8.0),4.04(3H,s).
元素分析C8H7NO2:
计算值:C,64.42;H,4.73;N,9.39,
实测值:C,64.40;H,4.84;N,9.31。
m/z(EI)149(M++1,100%).
(3S,4R,S)N-(烯丙氧羰基)-3-氨基-4-羟基-(2-(7-甲氧基苯并噁唑基))丁酸叔丁酯(66a)
在-78℃的氮气下向搅拌的7-甲氧基苯并噁唑65a(548.6mg,3.68mmol)的无水THF(18.5ml)溶液中滴加1.56M正丁基锂的己烷(2.47ml,3.86mmol),生成黄色溶液。在-78℃搅拌20分钟后加入无水MgBr2OEt2固体(1.045g,4.05mmol)。将所得非均匀混合物升温至-45℃,并搅拌15分钟,然后将反应混合物重新冷却到-78℃,并滴加(S)-Alloc-Asp(t-Bu)H1b(946.4mg,3.68mmol)的THF(18.5ml)溶液。反应物在-78℃搅拌30分钟,暖至0℃,并搅拌1小时。再将所得非均匀反应物暖至室温,并搅拌16小时。用5%碳酸氢钠(3.5ml)淬灭反应,真空除去THF。所得水性剩余物用二氯甲烷萃取(×6)。合并的萃取液用盐水洗涤,干燥(MgSO4),过滤并真空浓缩,得到1.8g粗产物。用快速色谱纯化(40∶60乙酸乙酯/己烷),得到1.21g(81%)标题化合物为油,是在C-4位的非对映体混合物。
IR(CH2Cl2)3425,2983,1725,
1504,1290,1157,1101;1H NMR(CDCl3)δ7.35-7.19(2H,
m),6.89-6.81(1H,m),6.00-5.57(2H,m),5.32-5.05
(3H,m),4.68-4.35(3H,m),4.01(3H,s),2.86-2.59
(2H,m),1.45(9H,s),1.41(9H,s);13C NMR(CDCl3)δ
171.18,171.09,165.80,165.30,156.71,156.60,145.65,
142.76,142.71,140.82,140.72,133.23,125.81,125.72,
118.41,118.21,113.07,112.87,108.95,82.16,70.28,
69.98,66.52,66.39,57.03,52.57,52.29,37.83,36.86,
28.65.
元素分析C20H26N2O7·0.6H2O:
计算值:C,57.57;H,6.57;N,6.72,
实测值:C,57.49;H,6.34;N,6.60。
M.S.(+FAB);407(M++1);351,307,154.
(3S,4R,S)N-(烯丙氧羰基)-3-氨基-4-羟基-4-(2-(4-甲氧基苯并噁唑基))丁酸叔丁酯(66b)
根据66a所述方法制备,得到1.29g(26%,基于回收的起始原料为68%)标题化合物为油,并且是在C-4位的非对映体混合物。
IR(CH2Cl2)
3400,1725,1625,1505,1369,1354,1281,1263,1226,
1158,1092,1048;1H NMR(CDCl3)δ7.34-7.24(1H,m),
7.16(1H,d,J=8.2),6.79(1H,d,J=7.9),6.00-5.50
(2H,m),5.30-5.05(3H,m),4.70-4.35(4H,m),4.02
(3H,s),2.90-2.45(2H,m),1.45-1.41(9H,2xs).
元素分析C20H26N2O7·0.4H2O:
计算值:C,58.07;H,6.53;N,6.77,
实测值:C,58.09;H,6.41;N,6.63。
M.S.(+FAB);407(M++1,88%);351(100).
(3S,4R,S)N-(N-乙酰基-(S)-(O-叔丁基-酪氨酰基)-(S)-缬氨酰基-(S)-丙氨酰基)-3-氨基-4-羟基-4-(2-(7-甲氧基苯并噁唑基))丁酸叔丁酯(67a)
向搅拌的苯并噁唑66a(481.9mg,1.19mmol)和Ac-Tyr(tBu)-Val-Ala-OH(586.3mg,1.30mmol)的二氯甲烷(3.5ml)和DMF(3.5ml)溶液中加入双(三苯膦)氯化钯(II)(18.0mg),接着滴加三丁基氢化锡(0.80ml,2.96mmol)。加入羟基苯并三唑(320.4mg,2.37mmol),并将混合物冷却到0℃。加入1-乙基-3-[3-(二甲氨基)丙基]碳化二亚胺盐酸盐(278.2mg,1.42mmol),并将混合物升至室温搅拌16.5小时。反应物用乙酸乙酯稀释,用1M硫酸氢钠洗涤两次,用饱和碳酸氢钠洗涤两次,用水和盐水各洗涤一次。干燥(MgSO4)有机相,过滤并真空浓缩,得到2.0g粗产物。用快速色谱纯化(95∶5二氯甲烷/甲醇),得到844.0mg(94%)标题化合物为白色固体。 m.p.205℃;IR(KBr)
3399,3304,2977,1729,1643,1506,1367,1290,1161;
1H NMR(d6-DMSO)δ8.24-7.78(4H,m),7.43-7.32(2H,m),
7.23(2H,d,J=8.5),7.16-7.07(1H,m),6.93(2H,d,
J=8.5),6.52,6.40(1H,2xd,J=5.5,J=5.0),
5.03,4.78-4.49,4.45-4.16(5H,brt,2xm),4.05,4.04
(3H,2xs),3.08-2.35(14H,m),2.11-1.89(1H,m),
1.83(3H,s),1.49-1.32,1.15,1.0-0.81(27H,s,2xm,
J=7.0);13C NMR(d6-DMSO)δ175.55,175.18,173.88,
173.75,173.05,169.23,157.28,148.55,146.16,143.21,
136.63,133.55,128.87,127.17,115.78,111.92,84.02,
81.50,71.40,61.15,60.05,57.79,53.39,51.62,43.76,
40.52,34.58,32.52,31.60,26.35,23.11,22.71,21.76.
元素分析C39H55N5O10·0.5H2O:
计算值:C,61.40;H,7.40;N,9.18,
实测值:C,61.43;H,7.31;N,9.07。
M.S.(+FAB);754(M++1);698,338,267.
(3S,4R,S)N-(N-乙酰基-(S)-(O-叔丁基-酪氨酰基)-(S)-缬氨酰基-(S)-丙氨酰基)-3-氨基-4-羟基-4-(2-(4-甲氧基苯并噁唑基))丁酸叔丁酯(67b)
根据67a所述方法制备,得到1.05g(94%)标题化合物为纯白色粉末。
m.p.210-213℃(分解);IR(KBr)3284,
2977,1736,1691,1632,1536,1505,1452,1392,1367,
1258,1236,1161,1091;1H NMR(d6-DMSO)δ8.20-7.75
(4H,m),7.40-7.10(4H,m),7.00-6.80(3H,m),6.45,
6.34(1H,2xd,J=5.3,J=5.0),5.00-4.10(5H,m),
4.00,3.99(3H,2xs),3.00-2.25(4H,m),1.95(1H,
m),1.78(3H,s),1.39-0.80(27H,m).
元素分析C39H55N5O10·0.5H2O:
计算值:C,61.40;H,7.40;N,9.18,
实测值:C,61.58;H,7.38;N,8.91。
M.S.(+FAB);754(M++1,30%);72(100).
(3S)N-(N-乙酰基-(S)-(O-叔丁基-酪氨酰基)-(S)-缬氨酰基-(S)-丙氨酰基)-3-氨基-4-(2-(7-甲氧基苯并噁唑基))-4-氧代丁酸叔丁酯(68a)
将Dess-Martin试剂(1.082g,2.55mmol;Ireland et al.,
J.Org.Chem.,58,pp.2899(1993);Dess et al.,
J.Org.Chem.,48,pp.4155-4156(1983))加到搅拌的醇67a(641.0mg,0.85mmol)的二氯甲烷(46.0ml)悬浮液中。将所得混合物搅拌1小时后在饱和硫代硫酸钠∶饱和碳酸氢钠(1∶1,86.0ml)和乙酸乙酯(86.0ml)之间分配。有机相依次用饱和硫代硫酸钠∶饱和碳酸氢钠(1∶1),饱和碳酸氢钠和盐水洗涤。干燥(MgSO4)有机相,过滤并真空浓缩,得到660.0mg粗产物。用快速色谱纯化(94∶6二氯甲烷/甲醇),得到636.0mg(100%)标题化合物为白色固体。
m.p.209℃;[α]D 24-21.8°(c 0.16,甲醇);IR
(KBr)3395,3294,2977,1722,1641,1535,1505,1161;
1H NMR(CDCl3)δ8.43-8.16(1H,m),7.97-7.62(2H,m),
7.49-7.14(3H,m),7.08-6.95(3H,m),6.89-6.73(2H,
m),5.81-5.68(1H,m),5.16-4.86(2H,m),4.53(1H,
brt),4.03(3H,s),3.16-2.84(4H,m),2.11-1.84(4H,
m),1.46-1.14(21H,m),0.92-0.78(6H,m);13C NMR
(CDCl3)δ186.28,173.39,171.90,171.19,171.03,
169.89,156.43,154.75,146.32,142.88,140.98,132.31,
130.54,126.98,124.73,114.95,111.42,82.44,78.71,
58.92,57.20,54.91,53.47,48.77,39.43,38.15,32.79,
29.44,28.60,23.55,20.27,19.70,19.34.M.S.
(+FAB);752(M++1);696,336,265.
(3S)N-(N-乙酰基-(S)-(O-叔丁基-酪氨酰基)-(S)-缬氨酰基-(S)-丙氨酰基)-3-氨基-4-(2-(4-甲氧基苯并噁唑基))-4-氧代丁酸叔丁酯(68b)
根据68a所述方法制备,得到420mg(55%)标题化合物为白色固体。
m.p.211-213℃(分解);[α]D 24
-23.9°(c 0.82,甲醇);IR(KBr)3277,3075,1723,
1690,1632,1530,1506,1392,1366,1269,1234,1160,
1094;1H NMR(CDCl3)δ8.15(1H,brs),7.7(2H,brs),
7.46(1H,t,J=8.3),7.24(2H,d,J=8.3),7.10(1H,
brs),7.03(2H,d,J=8.3),6.83(3H,m),5.74(1H,q,
J=6.9),5.00(2H,m),4.51(1H,t,J=7.0),4.07
(3H,s),3.20-2.95(4H,m),2.00(4H,m),1.42(3H,d,
J=6.8),1.35(9H,s),1.23(9H,8),0.86(6H,d,J=
6.7).M.S.(+FAB);752(M++1,7%);72(100).
(3S)N-(N-乙酰基-(S)-酪氨酰基-(S)-缬氨酰基-(S)-丙氨酰基)-3-氨基-4-(2-(7-甲氧基苯并恶唑基))-4-氧代丁酸叔丁酯(69a;R)
将在1∶1二氯甲烷和三氟乙酸混合物(65.0ml)中的酯68a(600.0mg,0.80mmol)溶液在干燥氮气下搅拌1小时,然后真空浓缩溶液。溶解于乙醚后再浓缩。如此重复6次,得到粗产物为乳白色固体。用快速色谱纯化(95∶5到80∶20二氯甲烷/甲醇梯度洗脱),得到420.8mg(83%)标题化合物为吸湿性白色固体。该产物以CD3OD中三种异构体的混合物形式存在,即酮形式(一种异构体,c 50%)及其酸基缩酮形式(C-4位的两种异构体,c.50%)。m.p.:在150℃以上分解。
[α]D 24-33.2°(c 0.17,甲醇);IR(KBr)
3300,1715,1658,1650,1531,1517,1204;1H NMR(CD3OD)
δ7.46-7.19(2H,m),7.16-6.91(3H,m),6.70-6.59(2H,
m),5.62-5.49(1H,m),5.00-4.72(1H,模糊不可见m),
4.69-4.51(1H,m),4.49-4.08(2H,m),4.05-3.89(3H,
m),3.16-2.47(4H,m),2.05-1.78(4H,m),1.41-1.11,
1.05-0.70(9H,2xm).
元素分析C31H37N5O10·3H2O:
计算值:C,53.67;H,6.25;N,10.10,
实测值:C,53.76;H,5.56;N,10.28。
(3S)N-(N-乙酰基-(S)-酪氨酰基-(S)-缬氨酰基-(S)-丙氨酰基)-3-氨基-4-(2-(4-甲氧基苯并噁唑基))-4-氧代丁酸叔丁酯(69b;S)
根据酸69a所述方法制备,得到252mg(96%)吸湿性标题化合物。该产物以CD3OD中三种异构体的混合物形式存在,即酮形式及其酸基缩酮形式(C-4位的两种异构体)。该产物还以d-6DMSO中的单一异构体形式存在。
m.p.200-203℃(分解);[α]D 24
-38.0°(c 0.23,甲醇);IR(KBr)3289,2968,1718,
1713,1658,1634,1548,1517,1506,1461,1453,1393,
1369,1268,1228,1174,1092;1H NMR(d6-DMSO)δ9.20
(1H,brs),8.71(1H,d,J=6.2),8.10(2H,m),7.83
(1H,d,J=8.7),7.61(1H,t,J=8.2),7.46(1H,d,J
=8.2),7.08 (3H,m),6.65(2H,d,J=8.3),5.50(1H,
q,J=6.5),4.50(1H,m),4.37(1H,m),4.20(1H,m),
4.05(3H,s),3.09-2.77(4H,m),1.94(1H,m),1.79
(3H,s),1.23(3H,d,J=7.0),0.82(6H,m).
元素分析C31H37N5O10·1.5H2O:
计算值:C,55.85;H,6.05;N,10.51,
实测值:C,55.21;H,5.69;N,10.13。
M.S.(+FAB);640(M++1,22%);107(100).
(3S)N-(烯丙氧羰基)-3-氨基-4-氧代-5-(1,2-二氧代-2-苯基乙氧基)-戊酸叔丁酯(80)
将氟化钾(792mg,13.6mmol)和苯甲酰甲酸(1.02g,6.82mmol)加到搅拌的(3S)N-(烯丙氧羰基)-3-氨基-5-溴-4-氧代-戊酸叔丁酯(2.17g,6.20mmol;WO 93 16710)的二甲基甲酰胺(30ml)溶液中。将混合物搅拌140分钟,用水(50ml)淬灭,用乙酸乙酯(2×50ml)萃取。合并的有机萃取液用水(4×50ml),然后用盐水(50ml)洗涤,干燥(MgSO4)并浓缩,得到一种油。经快速色谱纯化(20-45%乙酸乙酯的己烷),得到2.44g(94%)标题化合物为无色油。
[α]D 20-35.0°(c
1.41,CH2Cl2);IR(膜)3359,2981,2938,1752,1740,
1726,1712,1512,1369,1285,1177,1053,991,939,
688;1H NMR(CDCl3)δ8.15(2H,m),7.66(1H,m),7.53
(2H,m),5.90(2H,m),5.33(2H,m),5.31(1H,d,J=
16.9),5.18(1H,d,J=16.9),4.63(3H,m),3.03(1H,
dd,J=17.3,4.6),2.74(1H,dd,J=17.3,4.9),1.44
(9H,s).MS(C.I.)420(M++120%);364(100).
(3S)N-(烯丙氧羰基)-3-氨基-5-羟基-4-氧代-戊酸叔丁酯(81)
将酯80(2.40g,5.71mmol),四氢呋喃(200ml)和1M含水碳酸氢钾(200ml)的混合物在室温剧烈搅拌18小时。分离各相,水相用乙酸乙酯(100ml)萃取。合并的有机萃取液用盐水(100ml)洗涤,干燥(MgSO4)并浓缩。剩余物用快速色谱纯化(10-60%乙酸乙酯的己烷),得到1.48g(90%)淡黄色油。
[α]D 20-5.9°(c 1.06,CH2Cl2);IR(膜)
3345,2981,2936,1739,1725,1712,1692,1515,1368,
1259,1158,1051;1H NMR(CDCl3)δ5.92(2H,m),5.30
(2H,m),4.36-4.69(5H,m),3.05(1H,dd,J=17.4,
4.3),2.93(1H,t),2.70(1H,dd,J=17.4,4.9),1.43
(9H,s).
元素分析C18H21N1O6·0.25H2O:
计算值:C,53.51;H,7.43;N,4.80,
实测值:C,53.61;H,7.18;N,4.71。
MS(C.I.)280(M++1,87%);232(100).
(3S)N-(烯丙氧羰基)-3-氨基-5-(2,6-二氯苯基-甲氧基)-4-氧代-戊酸叔丁酯(82)
将搅拌的醇81(1.44g,5.01mmol),2,6-二氯苄基碘化物(4.31g,15.0mmol;Abraham et al.,
J.Chem.Soc.,pp.1605-1607(1936)),氧化银(2.32g,10.0mmol)和二氯甲烷(25ml)的混合物加热回流45小时。使混合物冷却至室温,用水(50ml)稀释后用乙酸乙酯萃取(50ml,25ml)。有机相用水(50ml)洗涤,然后用盐水(50ml)洗涤,干燥(MgSO4)并浓缩。剩余物用快速色谱纯化(10-100%乙酸乙酯的己烷),得到1.65g(74%)无色油。
[α]D 20+8.8°(c 1.13,CH2Cl2);IR(膜)3339,2980,
2935,1724,1712,1503,1438,1368,1246,1156,1106,
770;1H NMR(CDCl3)δ7.33(2H,m),7.22(1H,ddd),5.92
(2H,m),5.28(2H,m),4.87(2H,m),4.67(1H,m),4.58
(2H,br d),4.56(1H,d,J=16.9),4.31(1H,d,J=
16.9),3.04(1H,dd,J=16.7,4.5),2.77(1H,dd,J=
16.7,4.9),1.40(9H,s).
元素分析C20H25Cl2N1O6·0.25H2O:
计算值:C,53.28;H,5.70;N,3.11,
实测值:C,53.15;H,5.52;N,2.98。
M.S.(C.I.);446(M+,27%);390(100).
(3S)N-[N-苯基甲氧羰基缬氨酰基-丙氨酰基]-3-氨基-5-(2,6-二氯苯基甲氧基)-4-氧代-戊酸叔丁酯(83a)
将1-(3-二甲氨基-丙基)-3-乙基碳化二亚胺盐酸盐(379g,1.98mmol)和1-羟基苯并三唑(486mg,3.60mmol)加到搅拌的N-苯基-甲氧羰基缬氨酰基-丙氨酰基(637mg,1.98mmol)的四氢呋喃(40ml)和水(1ml)的溶液中。搅拌混合物15分钟,然后加入酯82(802mg,1.80mmol)和双(三苯膦)氯化钯(II)(约5mg)。用20分钟时间滴加三丁基氢化锡(785mg,7251,2.70mmol),并将所得溶液搅拌3.75小时,然后用1M盐酸(50ml)淬灭。混合物用乙酸乙酯萃取两次。合并的有机萃取液用1M盐酸洗涤,用碳酸氢钠水溶液洗涤两次,用水和盐水各洗涤一次,干燥(MgSO4)并浓缩。剩余物用快速色谱纯化(10-30%乙酸乙酯/二氯甲烷),得到941mg(79%)淡黄色固体。
m.p.148-52℃;IR(KBr)3287,3070,1730,1691,
1641,1536,1369,1289,1247,1156;1H NMR(CDCl3)δ
7.33(8H,m),7.23(1H,dd),6.61(1H,br,d),5.42
(1H,br,d),5.11(2H,s),4.85(3H,m),4.50(1H,m),
4.40(1H,d,J=16.9),4.26(1H,d,J=16.9),4.02
(1H,m),2.99(1H,dd,J=16.8,4.7),2.73(1H,dd,J
=16.8,5.0),2.09(1H,m),1.37(12H,m),0.96(3H,d,
J=6.9),0.91(3H,d,J=6.8).
元素分析C32H41Cl2N3O8·0.25H2O:
计算值:C,57.25;H,6.23;Cl,10.57;N,6.26,
实测值:C,57.18;H,6.23;Cl,10.58;N,5.95。
M.S.(+FAB);667(M+1,1%);666(3),159(25),91
(100).
(3R,S)N-[(N-乙酰基-O-叔丁基酪氨酰基)-缬氨酰基-丙氨酰基]-3-氨基-5-(2,6-二氯苯基甲氧基)-4-氧代-戊酸叔丁酯(83b)
根据83a所述方法制备,得到554mg(64%)无色固体。
m.p.184-6℃;IR(KBr)
3282,3075,1736,1690,1633,1536,1508,1366,1236,
1161;1H NMR(d6-DMSO)δ8.49(1H,d),8.14(1H,d),
8.08(1H,d),7.84(1H,d),7.43(3H,m),7.14(2H,d),
6.83(2H,d),4.71(2H,s),4.51(2H,m),4.36(2H,
dd),4.17(2H,m),2.93(1H,m),2.73(1H,m),1.94
(1H,m),1.74(3H,s),1.37(9H,s),1.23(12H,m),
0.83(6H,m).M.S.(+FAB);793(M+1,4%);737(5),
681(1),178(40),159(45),136(100),107(40).M.S.
(-FAB);792(20),791(40),447(100).
(R,S)N-[N-(苯基甲氧基)羰基-缬氨酰基-丙氨酰基]-3-氨基-5-(2,6-二氯苯基甲氧基)-4-氧代-戊酸(84a;V)
将三氟乙酸(5ml)加到搅拌的酯83a(918mg,1.38mmol)的二氯甲烷(20ml)溶液中。将混合物搅拌2.5小时,然后蒸发至干。剩余物用乙醚(25ml)处理,然后蒸发至干。所得产物用乙醚(10ml)研制,然后干燥,得到730mg(87%)浅棕色粉末。
m.p.156-
60℃;IR(KBr)3282,2965,1702,1694,1642,1536,
1438,1246,1230;1H NMR(d6-DMSO)δ8.48(1H,d),8.09
(1H,d),7.47(9H,m),5.02(2H,s),4.70(2H,s),4.49
(1H,m),4.37(2H,dd),4.27(1H,m),3.88(1H,m),
2.75(1H,dd),2.54(1H,dd),1.96(1H,m),1.19(3H,
s),0.84(6H,m).
元素分析C28H33Cl2N3O8·0.5H2O:
计算值:C,54.27;H,5.53;Cl,11.45;N,6.78,
实测值:C,54.49;H,5.39;Cl,11.33;N,6.73。
M.S.(+FAB);610(M+1,10%);91(100).
(R,S)N-[N-(乙酰基)酪氨酰基-缬氨酰基-丙氨酰基]-3-氨基-5-(2,6-二氯苯基甲氧基)-4-氧代-戊酸(84b;W)
用84a所述方法制备,得到无色粉末(95%)。
m.p.165-8℃:IR(KBr)3295,
2968,1733,1642,1517,1438,1231,1105;1H NMR(d6-
DMSO)9.2(1H,br,s),8.48(1H,br,d),8.14(1H,
br,d),8.02(1H,br,d),7.81(1H,br,d),7.45(3H,
m),7.02(2H,d),6.62(2H,d),4.70(2H,s),4.12-4.53
(3H,m),3.60(3H,m),2.51-2.92(4H,m),1.96 (1H,m)
1.75(3H,s),1.21(3H,d),0.83(6H,m).
元素分析C31H38Cl2N4O9·H2O:
计算值:C,53.22;H,5.76;Cl,10.14;N,8.09,
实测值:C,53.33;H,5.54;Cl,10.02;N,7.85。
M.S.(+FAB);682(M+ 2,30%);681(67),158(100).
(-FAB);680(45),679(100).
实施例6
我们用实施例2所述的紫外-可见底物,荧光底物和细胞测定进行酶的测定,得到本发明一些化合物的抑制常数(Ki)和IC50值。用所示的测定方法测定了下列化合物的Ki和IC50值:
22e,54b,54j,54k,57b,85,86,87,88,89,
90,91,92,98,102a-c,106a-c,108a-c,114a,114b,
115,121,125a,125b,126,127,128,129,130,131,
132a,132b,133,135a,135b,136,137,138,139,140,
141,142,144,145,146,147,148,149,150,151,152,
153,154,155,156,157,158,159,160,161,162,和
163
其中,化合物22e,54b,54j,54k和57b的结构示于实施例5,其它化合物的结构示于实施例7。
测定
化合物
紫外-可见
细胞
Ki(μM) IC50(μM)
22e 0.19 >20
54b 20
54j 10
54k 6.6
57b 2.2
85 0.0035 9.8
86 0.175 4.0
87 7.2 35.0
88 0.9
89 0.018
90 0.42 6.2
91 0.26 >25
92 3.8
98 0.535 4.0
102a 4.0
102b 0.29 1.75
102c 0.68
106a 2.3 30.0
106b 0.2 2.9
106c 3.8 >30.0
108a 17.5
108b 0.4 25.0
108c 0.43
114a 0.12 3.8
114b 3.7
115 0.345 6.0
121 4.3
125a 0.39 >30.0
125b 0.060 0.30
126 0.45 1.5
127 0.39 8.0
128 0.04 7.5
129 0.59 25.0
130 1.20
131 12.0 30.0
132a 5.0 >30.0
132b 12.5
133 50.0 >30.0
135a 0.090 0.90
135b 0.32 0.95
136 1.0
137 0.04 0.25
138 0.375
139 0.350 2.0
140 0.87 >30.0
141 0.670
142 1.75
144 0.32 >20.0
145 0.34 8.5
146 0.16 3.8
147 0.26 8.5
148 6.3 30.0
149 14.0 >30.0
150 10.0 30.0
151 13.0 30.0
152 8.8
153 0.24
154 0.042 2.4
155 0.023
156 0.001 2.7
157 0.26
158 1.1
159 0.0017 8.0
160 0.145 2.25
161 0.011
162 0.0025
163 0.0028 1.2
实施例7
化合物 126,127,128,129,135a,135b,137
144,145,14 6,147,148,149,150,151,152,153,154,
155,156,157,159,160,162,and 163
是用类似于化合物69a的合成方法合成的。
化合物158是用类似于化合物K的合成方法合成的。
化合物130是用类似于化合物56b的合成方法合成的。
化合物131,136,138和142是用类似于化合物57b的合成方法合成的。
化合物132a,132b,139,140和141是用类似于化合物47a的合成方法合成的。化合物140的起始原料是按下列文献所述得到:Robl,et al.,J.Am.Chem.Soc.,116,pp.2348-2355(1994)。化合物141的起始原料是按下列文献所述得到:Wyvratt,et al.,
Pept.Struct:Funct.Proc.(8th Am.Pept. Symp.),(1983)或USP 4415496。
和
化合物133是用类似于化合物47b的合成方法合成的。
化合物161是用类似于化合物125a的合成方法合成的。
化合物22e,54b,54j,54k和57b是根据实施例5所述合成的。
化合物 85,86,87,88,89,90,91,92,98,
102a,102b,102c,106a,106b,106c,108a,108b,108c,
114a,114b,115,121,125a,和125b
的合成方法如下:
N-(N-乙酰基-酪氨酰基-缬氨酰基-(4(R)-烯丙酰氧基脯氨酰基))-3-(S)-氨基-4-氧代丁酸(85)
步骤A N-叔丁氧羰基-4(R)-烯丙氧基脯氨酸
将N-叔丁氧羰基-4(R)-羟基脯氨酸(9.25g,40mmol)加到60%氢化钠(3.36g,84mmol)的无水四氢呋喃(100ml)溶液中,在室温搅拌2小时。在混合物中加入烯丙基溴(6.9ml,80mmol),并回流6小时。添加冰块淬灭反应,然后加水,混合物用己烷洗涤。水相用10%硫酸氢钠酸化,用乙酸乙酯萃取(2×150ml)。合并的萃取液用无水硫酸钠干燥,过滤和蒸发,得到5g标题产物,无需进一步纯化。
1H NMR(CDCl3;以旋转异构体形式存在)δ5.92-5.82(1H,
m),5.3-5.14(2H,m)4.5-4.31(1H,m),4.16-4.05(1H,
m),4.04-3.9(1H,m),3.79-3.5(3H,m),2.43-2.2
(1.5H,m),2.15-2.10(0.5H,m),1.45(4.5H,s),1.35
(4.5H,s).
步骤B 4(R)-烯丙氧基脯氨酸甲酯盐酸盐
将N-叔丁氧羰基-4(R)-烯丙氧基脯氨酸(5g,18.4mmol)在50ml饱和甲醇氯化氢中回流6小时。真空蒸发混合物,得到3.78g黄色胶体为标题化合物。 1H NMR
(CDCl3)δ5.83-5.72(1H,m),5.24-5.14(1H,d),5.13-
5.08(1H,d),4.55-4.3(3H,m),4.25-4.15(1H,m),
3.9(1.5H,s),3.78(1.5H,s),3.7-3.28(3H,m),
2.45-2.32(1H,m),2.2-2.05(1H,m).
步骤C N-乙酰基-酪氨酰基-缬氨酰基-(4(R)-烯丙氧基脯氨酸)甲酯
将4(R)-烯丙氧基脯氨酸甲酯盐酸盐(1.05g,4.75mmol)和N-乙酰基-Tyr-Val-OH(1.68g,5.21mmol)溶解在10ml二氯甲烷和二甲基甲酰胺的1∶1混合物中,并冷却至0℃。将二异丙基乙胺(1ml,5.93mmol)加到冷却的混合物中,然后加入N-羟基苯并三唑(0.769g,5.69mmol)和1-(3-二甲氨基丙基)-3-乙基碳化二亚胺盐酸盐(1.18g,6.2mmol)。搅拌2小时后将混合物升至室温,并搅拌16小时。将反应物倒入150ml乙酸乙酯,用水,10%硫酸氢钠和10%碳酸氢钠各50ml洗涤。有机相用硫酸钠干燥,过滤并蒸发,得到浅黄色固体。将其用快速色谱纯化(二氯甲烷/甲醇/吡啶100∶3∶0.5),得到780mg标题化合物。
1H NMR(CD3OD)δ7.02-
6.96(2H,d),6.67-6.63(2H,d),5.95-5.85(1H,m),
5.34-5.27(1H,d),5.16-5.13(1H,d),4.53-4.38(3H,
m),4.28-4.22(1H,m),4.12-3.97(3H,m),3.82-3.73
(1H,m),3.72(3H,s),3.04-2.88(2H,m),2.85-2.72
(2H,m),2.45-2.34(1H,m),2.08-1.95(2H,m),1.92
(3H,s),1.00-0.92(6H,2xd).
步骤D N-(N-乙酰基-酪氨酰基-缬氨酰基-(4(R)-烯丙氧基脯氨酰基))-3(S)-氨基-4-氧代丁酸叔丁酯缩氨基脲
将N-乙酰基-酪氨酰基-缬氨酰基-(4-烯丙氧基脯氨酸)甲酯(770mg,1.57mmol)溶解于20ml四氢呋喃和4ml甲醇。在混合物中加入氢氧化锂(145mg,3.46mmol),并在室温搅拌。2小时后加入1ml 10%盐酸,并真空蒸发混合物,得到固体剩余物。将其在5ml水和50ml乙酸乙酯之间分配。分离有机相并真空蒸发,得到430mg酸,它可直接用于下一步。
N-乙酰基-酪氨酰基-缬氨酰基-4-烯丙氧基脯氨酸(420mg,0.88mmol)和3-氨基-4-氧代丁酸叔丁酯缩氨基脲(184mg,0.8mol;Graybill et al.,
Int.J.Protein Res.,44,pp.173-82(1994)),得到100mg(20%)标题化合物为白色非晶状固体。
1H NMR(CD3OD)δ7.24-7.2(1H,m),
7.04-6.97(2H,d),6.73-6.65(2H,d),5.98-5.86(1H,
m),5.35-5.24(1H,d),5.17-5.12(1H,m),4.12-3.98
(2H,m),3.72-3.67(1H,m),2.98-2.92(3H,m),2.38-
2.32(1H,m),2.1-2.02(2H,m),1.92(3H,s),0.98-
0.89(6H,2xd).
步骤E N-(N-乙酰基-酪氨酰基-缬氨酰基-(4(R)-烯丙氧基脯氨酰基))-3(S)-氨基-4-氧代丁酸(85)
用实施例3化合物K步骤C所述方法对N-(N-乙酰基-酪氨酰基-缬氨酰基-(4(R)-烯丙氧基脯氨酰基))-3(S)-氨基-4-氧代丁酸叔丁酯缩氨基脲(100mg)进行脱保护,得到44.2mg(53%)标题化合物。
1H
NMR(CD3OD)δ7.04-6.97(2H,d),6.72-6.65(2H,d),
5.97-5.86(1H,m),5.32-5.25(1H,d),5.17-5.12(1H,
d),4.62-4.40(3H,m),4.30-4.13(2H,m),4.12-3.96
(3H,m),3.75-3.68(1H,m),2.99-2.92(1H,m),2.78-
2.70(1H,m),2.70-2.48(2H,m),2.35-2.30(1H,m),
2.17-1.95(2H,m),1.92(3H,s),0.98-0.88(6H,2x
d).
用类似于实施例5中化合物69a的合成方法制备化合物86和87。
N-乙酰基-(S)-缬氨酰基-(4(S)-苯氧基)脯氨酰基-3(S)-氨基-4-(7-甲氧基苯并噁唑-2-基)-4-氧代丁酸(86)
将N-乙酰基-(S)-缬氨酰基-(S)-(4(S)-苯氧基)脯氨酸转化成化合物86,为白色粉末。
1H NMR(DMSO-d6)δ8.75(d,1H),7.6-7.2(m,
4H),7.0-6.8(m,4H),5.5(m,1H),5.05(s,1H),4.5(t,
1H),4.29(t,1H),4.0(s,3H),4.0-3.8(m,2H),3.0-
2.8(dd,2H),2.3(m,1H),2.09(m,1H),1.95-1.8(m,
2H),1.78(s,3H),1-0.7(dd,6H).
N-乙酰基(4(R)-苯氧基)脯氨酰基-3(S)-氨基-4-(7-甲氧基苯并恶唑-2-基)-4-氧代丁酸(87)
将N-乙酰基-(S)-(4(S)-苯氧基)脯氨酸转化成化合物87,为白色粉末。 1H NMR(DMSO-d6)δ9.1(d,1H),
8.76(d,1H),7.6-7.2(m,4H),7.0-6.9(m,4H),5.55(m,
1H),5.45(m,1H),5.0(m,2H),4.56(t,1H),4.40(t,
1H),4.0(s,3H),3.9(dd,1H),3.76(d,1H),3.64(d,
1H),3.1-2.9(m,1H),2.8(m,1H),2.50(m,1H),2.3-
2.2(m,1H),2.09(m,1H),1.95和1.75(2xs,3H,
旋转异构体)
N-2-(6-苄基-1,2-二氢-2-氧代-3-(3-苯基丙酰基)氨基-1-吡啶基)乙酰基-3(S)-氨基-5-羟基-4-氧代戊酸(88)
按照83a所述的合成方法,从52b和81制备N-2-(6-苄基-1,2-二氢-2-氧代-3-(3-苯基丙酰基)氨基-1-吡啶基)乙酰基-3(S)-氨基-5-羟基-4-氧代戊酸叔丁酯,为白色固体(45%)。
1H NMR(CDCl3)δ
8.40(d,1H),8.20(s,1H),7.4-7.1(m,11H),6.18(s,
1H),4.72(m,1H),4.65-4.5(q,2H),4.4-4.2(dd,2H),
4.0(s,2H),3.04(t,2H),2.9(dd,1H),2.76(t,2H),
2.55(dd,1H),1.39(s,9H).
将所得产物用实施例5化合物84a所述方法转化成88,得到标题化合物(42%)为白色固体。 1H NMR(CDCl3)
δ8.5(d,1H),8.1(d,1H),8.0(m,1H),7.4-7.1(m,
11H),6.3(d,1H),4.9-4.8(m,2H),4.6-4.4(m,2H),
4.3(dd,1H),4.1(s,2H),3.3(t,1H),3.05(t,2H),
2.8-2.6(m,3H)
用类似于实施例5中化合物84a的制备方法制备化合物89和90。
N-乙酰基-(S)-酪氨酰基-(S)-缬氨酰基-(S)-丙氨酰基-3(S)-氨基-5-(2-氯苄氧基)-4-氧代戊酸(89)
由Ac-Tyr-Val-Ala-OH和(3S)N-(烯丙氧羰基)-3-氨基-5-(2-氯苯基甲氧基)-4-氧代-戊酸叔丁酯(用类似制备化合物82的方法制备的)制备,得到白色固体。 1H NMR(DMSO-
d6)δ9.15(s,1H),8.5(d,1H),7.98(d,1H),7.75(d,
1H),7.55-7.3(m,4H),7.0(d,1H),6.6(d,2H),4.6-
4.3(m,6H),4.3-4.1(m,2H),2.9(d,1H),2.76(dd,1H),
2.7-2.5(m,2H),1.95(m,1H),1.75(s,3H),1.2(d,3H),
0.9-0.7(dd,6H)
N-2-(6-苄基-1,2-二氢-2-氧代-3-(3-苯基丙酰基)氨基-1-吡啶基)乙酰基-3-氨基-5-(2-氯苄氧基)-4-氧代戊酸(90)
由化合物52b和(3S)N-(烯丙氧羰基)-3-氨基-5-(2-氯苯基甲氧基)-4-氧代-戊酸叔丁酯(用类似制备化合物82的方法制备的)制备,得到白色固体。 1H NMR(DMSO-d6)
δ9.2(s,1H),8.75(d,1H),7.7-7.1(m,14H),6.4(d,
1H),4.65(d,6H),4.56(s,1H),4.6-4.35(dd,1H),
3.9(s,2H),2.9-2.6(m,6H)
N-2-(6-苄基-1,2-二氢-2-氧代-3-(3-苯基丙酰基)氨基-1-吡啶基)乙酰基-3(S)-氨基-5-(5(2,6-二氯苯基)噻唑-2-基)-4-氧代戊酸(91)
用化合物69a所述制备方法,由化合物52b和3-(烯丙氧羰基)-氨基-4-[(2,6-二氯-苯基)噻唑-2-基]-4-羟基-丁酸叔丁酯(99)制备标题化合物,得到乳白色粉末。
1H NMR(DMSO-d6)δ9.32(s,
1H),9.05(d,1H),8.27(a,1H),8.18 (d,1H),7.7(d,
1H),7.6(t,1H),7.4-7.1(m 11H),6.1(d,1H),5.64(m,
1H),4.8-4.6(dd,2H),3.85(s,2H),3.02(m,1H),2.9-
2.7(m,4H).
3-(S)-(2-(3-[3-(S)-(4-羟基-苯基)丙酰氨基]-2-氧代-吖庚因(azepan)-1-基)乙酰氨基)-4-氧代丁酸(92)
用类似于化合物54a所述合成方法,由2-(3-[3-(S)-(4-羟基-苯基)丙酰氨基]-2-氧代-吖庚因-1-基)乙酸和N-烯丙氧羰基-4-氨基-5-苄氧基-2-氧代四氢呋喃(Chapman,
Biorg.Med.Chem. Lett.,2,pp.613-18(1992))制备标题化合物,得到白色固体。
1H NMR(DMSO-d6)δ9.10-9.20(s,1H),
8.40(s,1H),7.88(d,1H),7.0(d,2H),6.64(d,2H),
4.60(t,1H),4.10(q,2H),3.9-4.2(m,2H),3.6(m,1H),
3.18(d,2H),2.70(t,2H),2.40(m,2H),1.85-1.40(m,
8H).
4-乙氧基亚甲基-2-苯乙烯基-4H-噁唑基-5-酮(94)
根据下列文献所述制备:Cornforth,
The Chemistry of Penicillin.Clarkw,Johnson,Robinson,(eds.)Princeton University Press,pp.804(1949)。
4-氧代-3-(3-苯基-丙烯酰氨基)-4,6,7,8-四氢-吡咯并[1,2-a]嘧啶-(6S)-羧酸乙酯(95)
用实施例5中化合物3的制备方法由化合物94制备,得到4.5g(30%)标题化合物。 1H NMR(CD3OD)δ1.3(t,3H),2.35
(m,1H),2.65(m,1H),3.1(m,1H),3.15(m,1H),
4.25(q,2H),5.15(dd,1H),6.95(d,1H),7.4(m,
3H),7.6(m,2H),7.65(d,1H),8.95(s,1H).
4-氧代-3-(3-苯基-丙烯酰氨基)-4,6,7,8-四氢-吡咯并[1,2-a]嘧啶-(6S)-羧酸(96)
将4-氧代-3-(3-苯基-丙烯酰氨基)-4,6,7,8-四氢-吡咯并[1,2-a]嘧啶-(6S)-羧酸乙酯(95;3.1g,8.8mmol)和1N氢氧化锂水溶液(8.8ml,8.8mmol)的甲醇(10ml)混合物在室温搅拌18小时。反应物用水稀释,用乙酸乙酯(1×20ml)洗涤。水相用浓盐酸酸化。过滤收集的固体用水洗涤,并放于50℃真空炉中干燥18小时,得到2.2g(75%)标题化合物为褐色固体。
1H
NMR(CD3OD)δ2.4(m 1H),2.7(m,1H),3.1(m,1H),
3.2(m,1H),5.15(dd,1H),7.0(d,1H),7.4(m,3H),
7.6(m,2H),7.65(d,1H),8.95(s,1H)
4-氧代-3-(3-苯基-丙烯酰氨基)-4,6,7,8-四氢-吡咯并[1,2-a]嘧啶-(6S)-羧酸(2-苄氧基-5-氧代-四氢呋喃-(3S)-基)酰胺(97)
用实施例3化合物H步骤A所述方法由化合物96制备,得到0.52g(75%)标题化合物为非对映体的混合物。
1H NMR(CDCl3)δ2.3-2.7(m,3H),2.9(dd,1H),3.05(m,
1H),3.3(m,1H),4.4-4.8(m,2H),4.9(2xd,1H),
5.05(m,1H),5.55(2xs,1H),6.6(2xd,1H),7.4(m,
6H),7.55(m,4H),7.65(2xd,1H),8.0(m,2H),9.2(s
x2,1H).
4-氧代-(3S)-{[4-氧代-3-(3-苯基-丙酰氨基)-4,6,7,8-四氢-吡咯并[1,2-a]嘧啶-(6S)-羰基]-氨基}-丁酸(98)
用实施例3化合物H步骤D所述方法制备,得到0.13g(45%)标题化合物。
1H
NMR(CD3OD)δ2.35(m,1H),2.45-2.75(m,3H),2.8(t,
2H),3.0(t,2H),3.1(m,1H),3.25(m,1H),4.3(m,1H),
6.65(dd,1H),5.15(m,1H),7.15(m,1H),7.3(m,4H),
8.8(a,1H).
3(S)-(烯丙氧羰基)-氨基-4-[(2,6-二氯苯基)-噁唑-2-基]-4(R,S)-羟基-丁酸叔丁酯(99)
将5-(2,6-二氯苯基)噁唑(2.71g,12.7mmol;用类似于Tet.Lett.23,p2369(1972)所述方法制备的)的四氢呋喃(65ml)溶液在氮气下冷却到-78℃。向该溶液中加入正丁基锂(1.5M的己烷溶液,8.5ml,13.3mmol),并在-78℃搅拌30分钟。加入溴化镁醚合物(3.6g,13.9mmol),并用15分钟使溶液升温至-45℃。再将反应物冷却至-78℃,并滴加醛58(3.26g,12.7mmol;Graybill et al.,
Int.J.Protein Res.,44,pp.173-182(1993))的四氢呋喃(65ml)。将反应物搅拌25分钟,然后升至-40℃,再搅拌3小时,然后在室温搅拌1小时。用5%NaHCO3(12ml)淬灭反应,并将反应物搅拌3小时。真空除去四氢呋喃,所得剩余物用二氯甲烷萃取。有机相用饱和氯化钠溶液洗涤,硫酸镁干燥,过滤并浓缩,得到6.14g标题化合物。纯化后得到4.79g(80%)化合物99。
1H NMR(CDCl3)δ1.45(s,9H),2.7-2.5(m,2H),
2.8(dd,1H),4.2,4.4(2xd,1H),4.7-4.5(m,3H),
5.35-5.1(m,2H),5.6,5.7(2xd,1H),6.0-5.8(m,1H),
7.2(d,1H),7.3(m,1H),7.4(m,2H).
4-氧代-3-(3-苯基-丙酰氨基)-4,6,7,8-四氢-吡咯并[1,2-a]嘧啶-(6S)-羧酸(100)
将4-氧代-3-(3-苯基-丙烯酰氨基)-4,6,7,8-四氢-吡咯并[1,2-a]嘧啶-(6S)-羧酸(96;2.1g,6.5mmol)和20%氢氧化钯/炭(0.5g)的甲醇(50ml)混合物在氢气下搅拌4小时。过滤所得混合物并浓缩,得到2.1g(100%)标题化合物为白色固体。
1H NMR(CD3OD)δ2.35(m,1H),2.65(m,1H),
2.75(t,2H),3.0(t,2H),3.1(m,1H),3.15(m,1H),
5.1(dd,1H),7.15(m,1H),7.25(m,4H),8.75(s,1H)
2,6-二氯-苯甲酸4-叔丁氧羰基-2-氧代-(3S)-{[4-氧代-3-(3-苯基-丙酰氨基)-4,6,7,8-四氢-吡咯并[1,2-a]嘧啶-(6S)-羰基]-氨基}丁酯(101a)
用实施例5化合物56a所用方法制备,得到0.16g(20%)标题化合物。
1H NMR(CD3OD)δ1.45(s,
9H),2.3(m,1H),2.6(m,1H),2.7(m,3H),2.95(m,3H),
4.8(m,1H),5.1(m,1H),5.2(q,2H),7.1(m,1H),
7.2(m,4H),7.4(m,3H),8.75(s,1H).
4-(7-甲氧基-苯并噁唑-2-基)-4-氧代-(3S)-{[4-氧代-3-(3-苯基-1-丙酰氨基)-4,6,7,8-四氢-吡咯并[1,2-a]嘧啶-(6S)-羰基]-氨基}丁酸叔丁酯(101b)
用实施例5化合物67a的方法,由化合物100和66a制备4-羟基-4-(7-甲氧基-苯并噁唑-2-基)-(3S)-{[4-氧代-3-(3-苯基-丙酰氨基)-4,6,7,8-四氢-吡咯并[1,2-a]嘧啶-(6S)-羰基]-氨基}丁酸叔丁酯,得到0.95g(定量的)产物为非对映体的混合物。
1H NMR(CD3OD)δ1.45(2xs,9H),2.2(2
xm,1H),2.35-3.0(m,9H),4.0(m,3H),4.75 (m,1H),
4.85(m,1H),5.05(2xdd,1H),7.1(2xdd,1H),7.15-
7.3(m,4H),7.5(2xt,1H),7.8(2xd,1H),8.55(2x
dd,1H),8.7(2xs,1H).
用实施例5化合物68a的方法将所得产物转化成101b,得到0.36g(50%)标题化合物。 1H NMR(CD3OD)δ
1.4(s,9H),2.35(m,1H),2.55(m,1H),2.75(t,2H),
2.95(t,2H),3.00(m,1H),3.1(dd,2H),3.15(m,1H),
5.15(dd,1H),5.65(t,1H),7.1(m,2H),7.2(m,4H),
7.4(m,2H),8.7(s,1H)
4-[5-(2,6-二氯-苯基)-噁唑-2-基]-4-氧代-(3S)-{[4-氧代-3-(3-苯基-丙酰氨基)-4,6,7,8-四氢-吡咯并[1,2-a]嘧啶-(6S)-羰基]-氨基}-丁酸叔丁酯(101c)
用实施例5化合物67a所述方法,由化合物100和99制备4-[5-(2,6-二氯-苯基)-噁唑-2-基]-4-羟基-(3S)-{[4-氧代-3-(3-苯基-丙酰氨基)-4,6,7,8-四氢-吡咯并[1,2-a]嘧啶-(6S)-羰基]-氨基}-丁酸叔丁酯,得到0.09g(60%)产物为非对映体的混合物。
1H NMR(CD3OD)δ1.45(2xs,9H),
2.2(m,1H),2.5(m,2H),2.7(2xdd,1H),2.75(t,2H),
2.9-3.1(m,4H),4.7(m,1H),5.1(m,2H),7.1(m,1H),
7.1-7.25(m,4H),7.4(t,1H),7.5(t,1H),8.55(d,1H),
8.75(s,1H).
用实施例5化合物68a所述方法将所得产物转化成101c,得到0.04g(45%)标题化合物。 1H NMR(CD3OD)δ
1.4(s,9H),2.3(m,1H),2.6(m,1H),2.75(t,2H),
2.95(t,2H),2.9-3.2(m,4H),5.2(dd,1H),5.55(t,
1H),7.1(m,1H),7.25(m,4H),7.55(m,3H),8.75(s,
1H).
2,6-二氯-苯甲酸4-羧基-2-氧代-(3S)-{[4-氧代-3-(3-苯基-丙酰氨基)-4,6,7,8-四氢-吡咯并[1,2-a]嘧啶-(6S)-羰基]-氨基}-丁酸叔丁酯(102a)
用实施例5化合物57a的方法由化合物101a制备,得到0.12g(80%)标题化合物。 1H NMR(CD3OD)δ2.35(m,1H),
2.65(m,1H),2.75(m,2H),2.85(dd,1H),2.95(m,2H),
3.0(dd,1H),3.15(m,1H),3.25(m,1H),4.55(dd,1H),
5.15 (m,1H),5.25(q,2H),7.15(m,1H),7.25(m,4H),
7.45(m,1H),8.8(s,1H).
4-(7-甲氧基-苯并噁唑-2-基)-4-氧代-(3S)-{[4-氧代-3-(3-苯基-丙酰氨基)-4,6,7,8-四氢-吡咯并[1,2-a]嘧啶-(6S)-羰基]-氨基}-丁酸(102b)
用实施例5化合物69a所述方法由化合物101b制备,得到0.12g(35%)标题化合物。 1
H NMR(DMSO-d6)δ2.1(m,1H),2.55(m,1H),2.7-
3.1(m,8H),4.05(s,3H),5.1(dd,1H),5.55(t,1H),7.2(m,
1H),7.25(m,5H),7.5(t,1H),7.55(d,1H),8.7(s,1H),
9.2(d,1H),9.4(s,1H),12.7(br,1H).
4-[5-(2,6-二氯-苯基)-噁唑-2-基]-4-氧代-(3S)-{[4-氧代-3-(3-苯基-丙酰氨基)-4,6,7,8-四氢吡咯并[1,2-a]嘧啶-(6S)-羰基]-氨基}-丁酸(102c)
用实施例5化合物69a所述方法由化合物101c制备,得到0.01g(40%)标题化合物。
1H NMR(CD3OD)δ2.35(m,
1H),2.6(m,1H),2.75(t,2H),2.95(t,2H),3.05(m,
1H),3.15(m,3H),5.15(dd,1H),5.55(t,1H),7.15(m,
1H),7.2(m,4H),7.55(m,3H),8.8(s,1H)
(3-叔丁氧羰基氨基-2-氧代-2,3,4,5-四氢苯并[b][1,4]二氮杂_-1-基)-乙酸甲酯(103)
步骤A 2(S)-叔丁氧羰基氨基-3-(2-硝基苯基-氨基)-丙酸
将2-叔丁氧羰基氨基-3-氨基丙酸(10g,49mmol),2-氟硝基苯(5.7ml,54mmol)和碳酸氢钠(8.25g,98mmol)溶解于130ml二甲基甲酰胺,并在80℃加热18小时。真空蒸发反应物,得到粘稠的橙色剩余物。将其溶解于300ml水,并用乙醚萃取(3×150ml)。用10%硫酸氢钠将该水溶液酸化至pH5,然后用乙酸乙酯萃取(3×250ml)。合并的萃取液用无水硫酸钠干燥,过滤并蒸发,得到12.64g(83%)标题化合物为橙色非晶状固体。
1H NMR(CD3OD)
δ8.15-8.10(1H,d),7.54-7.48(1H,t),7.13-7.08(1H,
d),6.73-6.65(1H,t),4.45-4.35(1H,m),3.9-3.8
(1H,dd),3.65-3.55(1H,dd),1.45(9H,s).
步骤B 2(S)-叔丁氧羰基氨基-3-(2-氨基苯基-氨基)-丙酸
将2-叔丁氧羰基氨基-3-(2-硝基苯基-氨基)-丙酸(12.65g,40.5mmol)和0.5g 10%Pd/C的100ml甲醇混合物在1大气压氢气下搅拌4小时。用Celite 545过滤溶液,真空蒸发滤液,得到11.95g大量标题化合物为深棕色固体,无需纯化即可使用。 1H NMR
(CD3OD)δ6.75-6.70(3H,m),6.65-6.58(1H,m),4.35-
4.31H,m),3.6-3.38(2H,m),1.45(9H,s).
步骤C 3(S)-叔丁氧羰基氨基-1,3,4,5-四氢苯并[b][1,4]二氮杂_-2-酮
将1-(3-二甲氨基丙基)-3-乙基碳化二亚胺盐酸盐(8.54g,44.5mmol)加到冷却的(0℃)2-叔丁氧羰基氨基-3-(2-氨基苯基-氨基)-丙酸(11.95g,40.5mmol)的100ml二甲基甲酰胺溶液中,并搅拌18小时。将反应物倒入700ml乙酸乙酯,并用100ml水洗涤4次。有机相用无水硫酸钠干燥,过滤并蒸发,得到棕色固体。经快速色谱纯化(3∶7乙酸乙酯/己烷)得到8g(71%)标题化合物。
1H NMR(CDCl3)δ7.78(1H,
s),7.02-6.95(1H,m),6.88-6.82(1H,m),6.82-6.78
(1H,m),6.75-6.70(1H,m),5.8-5.7(1H,d),4.55-4.45
(1H,m),3.95(1H,s),3.9-3.82(1H,m),3.48-3.40
(1H,m),1.45(9H,s).
步骤D (3(S)-叔丁氧羰基氨基-2-氧代-2,3,4,5-四氢苯并[b][1,4]二氮杂_-1-基)乙酸甲酯(103)
将1.0M双(三甲基甲硅烷基)氨基化锂(3.4ml,3.4mmol)的THF溶液滴加到-78℃3-叔丁氧羰基氨基-1,3,4,5-四氢苯并[b][1,4]二氮杂_-2-酮(0.94g,3.38mmol)的20ml无水四氢呋喃溶液中,并搅拌30分钟。在反应混合物中滴加溴乙酸甲酯(0.44ml,4mmol),然后升至室温。反应物用100ml乙酸乙酯稀释,用0.3N硫酸氢钾(50ml),水(2×50ml)和盐水洗涤。用无水硫酸钠干燥合并的有机相,过滤并蒸发,得到一种胶。将其用快速色谱纯化(3∶7 EtOAc/Hex),得到0.98g(83%)标题化合物为白色固体。
1H NMR(CDCl3)δ
7.15-7.07(2H,m),6.98-6.94(1H,m),6.88-6.84(1H,
d),5.62-5.55(1H,d),4.71-4.65(1H,d),4.65-4.6
(1H,m),4.33-4.27(1H,d),3.96-3.90(1H,m),3.78
(3H,s),3.44-3.37(1H,m),1.4(9H,s).
a R=H
b R=COCH2CH2Ph
c R=CH2Ph
(2-氧代-3(S)-(3-苯基丙酰氨基)-2,3,4,5-四氢苯并[b][1,4]二氮杂_-1-基)乙酸甲酯(104a)
将无水氯化氢鼓入(3(S)-叔丁氧羰基氨基-2-氧代-2,3,4,5-四氢苯并[b][1,4]二氮杂_-1-基)乙酸甲酯(103,1g,2.86mmol)的25ml乙酸乙酯溶液2分钟,然后在室温搅拌1小时。蒸发反应物,得到2-氧代-3(S)-氨基-2,3,4,5-四氢苯并[b][1,4]二氮杂卓-1-基乙酸甲酯盐酸盐为白色固体。将该盐酸盐和氢化肉桂酸(0.47g,3.15mmol)一起溶解于20ml二甲基甲酰胺,并冷却到0℃。在所得溶液中加入二异丙基乙胺(1ml,5.72mmol),然后加入N-羟基苯并三唑和1-(3-二甲氨基丙基)-3-乙基碳化二亚胺。室温搅拌18小时后混合物用150ml乙酸乙酯稀释,先后用10%硫酸氢钠,10%碳酸氢钠和盐水洗涤。有机相用无水硫酸钠干燥,过滤并蒸发,得到粗固体产物。将其用快速色谱纯化(7∶3乙酸乙酯/二氯甲烷),得到600mg(55%)标题化合物为白色固体。
1H NMR(CDCl3)δ7.3-6.85(9H,m),6.55-6.0(1H,
d),4.88-4.82(1H,m),4.72-4.65(1H,d),4.28-4.22
(1H,m),3.95-3.9(1H,m),3.78(3H,s),3.65(1H,br.
s),3.28-3.2(1H,m),2.95-2.84(2H,m),2.55-2.4(2H,
m).
(3(S)-(3-苯基丙酰氨基)-2-氧代-2,3,4,5-四氢苯并[b][1,4]二氮杂_-1-基)乙酸(105a)
将(3(S)-(3-苯基丙酰氨基)-2-氧代-2,3,4,5-四氢苯并[b][1,4]二氮杂_-1-基)乙酸甲酯(104a)溶解于90%甲醇。在反应物中加入氢氧化锂水合物,然后在室温搅拌4小时。真空蒸发反应物,得到白色固体。将其溶解于20ml水中并酸化至pH5。用乙酸乙酯萃取,得到304mg(88%)标题化合物为白色固体。
1H NMR(CDCl3)δ7.5-6.9(11H,m),4.92-4.8
(1H,m),4.7-4.58(1H,d),4.38-4.25(1H,d),3.88-
3.78(1H,m),3.45-3.25(1H,m),3.05-2.85(2H,m),
2.55-2.45(2H,m).
4-氧代-3(S)-{2-[2-氧代-3(S)-(3-苯基丙酰氨基)-2,3,4,5-四氢苯并[b][1,4]二氮杂_-1-基]乙酰氨基}丁酸(106a)
用实施例3化合物H步骤A所述方法,从化合物105a制备N-[1-(2-苄氧基-5-氧代四氢呋喃-3-基氨基甲酰基-甲基)-2-氧代-2,3,4,5-四氢-1H-苯并[b][1,4]二氮杂_-1-基]-3-苯基丙酰胺,得到390mg(93%)产物为非对映体。
1H NMR
(CD3OD)δ7.58-7.22(14H,m),5.78-5.73(0.5H,d),
5.64(0.5H,s),5.0-4.72(4H,m),4.54-4.42(2H,m),
3.82-3.76(0.5H,m),3.68-3.62(0.5H,m),3.28-3.21
(0.5H,m),3.19-3.12(0.5H,m),3.07-2.98(2H,m),
2.78-2.48(4H,m).
用实施例3化合物H步骤D所述方法,将所得产物转化成化合物106a,得到标题化合物(17%)为白色固体。
1H
NMR(CD3OD)δ7.54-6.98(9H,m),5.58-5.44(1H,m),
4.8-4.2(4H,m),3.96-3.3(2H,m),3.30-3.05(1H,m),
2.98-2.25(5H,m).
[2-氧wa-5-(3-苯基丙酰基)-3(S)-(3-苯基丙酰氨基)-2,3,4,5-四氢苯并[b][1,4]二氮杂_-1-基)乙酸甲酯(104b)
将无水氯化氢鼓入(3(S)-叔丁氧羰基氨基-2-氧代-2,3,4,5-四氢苯并[b][1,4]二氮杂_-1-基)乙酸甲酯(103,1g,2.86mmol)的25ml乙酸乙酯溶液2分钟,然后在室温搅拌1小时。蒸发反应物,得到2-氧代-3(S)-氨基-2,3,4,5-四氢苯并[b][1,4]二氮杂_-1-基乙酸甲酯盐酸盐为白色固体。将该盐酸盐悬浮于20ml二氯甲烷,并冷却到0℃。在所得悬浮液中加入三乙胺(1.6ml,11.5mmol),然后滴加二氢肉桂酰基氯(0.9ml,6mmol)。将混合物升至室温并搅拌18小时,然后用25ml二氯甲烷稀释,用50ml水洗涤两次,用50ml盐水洗涤一次。有机相用无水硫酸钠干燥,过滤并蒸发,得到粘稠的黄色油。将其用快速色谱纯化(1∶1乙酸乙酯/二氯甲烷),得到1.35g(92%)标题化合物为白色固体。
1H NMR(CDCl3)δ7.45-
7.02(14H,m),6.37-6.32(1H,d),4.78-4.72(1H,m),
4.52-4.3(3H,m),3.82-3.77(1H,m),3.74(3H,s),
3.03-2.87(4H,m),2.58-2.45(2H,m),2.45-2.35(1H,
m),2.25-2.16(1H,m).
[2-氧代-5-(3-苯基丙酰基)-3-(3(S)-苯基丙酰氨基)-2,3,4,5-四氢苯并[b][1,4]二氮杂_-1-基)乙酸(105b)
用化合物105a的制备方法水解[2-氧代-5-(3-苯基丙酰基)-3-(3-苯基丙酰氨基)-2,3,4,5-四氢苯并[b][1,4]二氮杂_-1-基)乙酸甲酯(104b,680mg,1.32mmol),得到645mg(98%)标题化合物为白色固体。
1H NMR
(CDCl3)δ7.58(1H,br.s),7.5-7.42(1H,m),7.35-
6.95(14H,m),4.95-4.88(1H,m),4.64-4.55(1H,d),
4.54-4.45(1H,t),4.15-4.05(1H,d),3.75(1H,m),
3.05-2.75(4H,m),2.58-2.45(2H,m),2.45-2.28(1H,
m),2.25-2.14(1H,m).
2-氧代-3(S)-{2-[2-氧代-5-(3-苯基丙酰基)-3(S)-(3-苯基丙酰氨基)-2,3,4,5-四氢苯并[b][1,4]二氮杂_-1-基]乙酰氨基}丁酸(106b)
用实施例3化合物K步骤A的制备方法偶合[2-氧代-5-(3-苯基丙酰基)-3-(3-苯基丙酰氨基)-2,3,4,5-四氢苯并[b][1,4]二氮杂_-1-基)乙酸和3-氨基-4-氧代丁酸叔丁酯缩氨基脲,得到350mg(85%)白色固体。
1H NMR(CDCl3)δ9.05(1H,br.s),7.58-7.55
(1H,d),7.5-7.35(1H,m),7.35-6.95(14H,m),6.75-
6.72(1H,d),6.25(1H,br.s),5.25(1H,br.s),
4.95-4.88(1H,m),4.8-4.72(1H,m),4.55-4.4(2H,
m),3.92-3.88(1H,d),3.73-3.68(1H,m),2.95-2.8
(4H,m),2.8-2.72(1H,m),2.62-2.55(1H,m),2.55-
2.45(2H,m),2.4-2.32(1H,m),2.2-2.12(1H,m),1.45
(9H,s).
用实施例3化合物K步骤C的制备方法将4-氧代-3-{2-[2-氧代-5-(3-苯基丙酰基)-3-(3-苯基丙酰氨基)-2,3,4,5-四氢苯并[b][1,4]二氮杂_-1-基]乙酰氨基}丁酸叔丁酯缩氨基脲去保护,得到118mg(47%)标题化合物为白色固体。
1H NMR(CD3OD)δ7.48-6.95(14H,m),
4.65-4.15(6H,m),3.5-3.4(1H,m),2.85-2.72(4H,m),
2.65-2.5(1H,m),2.5-2.34(3H,m),2.34-2.15(2H,m).
[5-苄基-2-氧代-3(S)-(3-苯基丙酰氨基)-2,3,4,5-四氢苯并[b][1,4]二氮杂_-1-基]乙酸甲酯(104c)
将[2-氧代-3-(3-苯基丙酰氨基)-2,3,4,5-四氢苯并[b][1,4]二氮杂_-1-基]乙酸甲酯(104a;500mg,1.31mmol),碳酸钙(155mg,1.58mmol)和苄基溴(170μl,1.44mmol)溶于10ml二甲基甲酰胺中,并在80℃加热8小时。混合物用150ml乙酸乙酯稀释,用50ml水洗涤4次。有机相用无水硫酸钠干燥,过滤并蒸发,得到粘稠的黄色油。将其用快速色谱纯化(8∶2二氯甲烷/乙酸乙酯),得到460mg(75%)标题化合物为白色固体。 1H NMR(CDCl3)δ7.34-7.05
(14H,m),6.32-6.28(1H,d),4.84-4.76(1H,d),4.76-
4.70(1H,m),4.43-4.37(1H,d),4.26-4.18(1H,d),
4.06-4.00(1H,d),3.79(3H,s),3.45-3.37(1H,m),
3.02-2.95(1H,m),2.90-2.82(2H,m),2.5-2.34(2H,
m).
[5-苄基-2-氧代-3(S)-(3-苯基丙酰氨基)-2,3,4,5-四氢苯并[b][1,4]二氮杂_-1-基]乙酸(105c)
用化合物105a所述方法对酯102c进行水解,得到450mg(98%)标题化合物为白色固体。
1H NMR(CD3OD)δ7.5-7.05(14H,m),6.4(1H,
br.s),4.85-4.55(2H,m),4.5-4.21(2H,m),4.12-3.92
(1H,d),3.45-3.3(1H,m),3.1-2.8(3H,m),2.55-2.28
(3H,m).
3(S)-{2-[5-苄基-2-氧代-3-(3(S)-苯基丙酰氨基)-2,3,4,5-四氢苯并[b][1,4]二氮杂_-1-基]乙酰氨基}-4-氧代丁酸(106c)
用实施例3化合物K步骤A所述方法将[5-苄基-2-氧代-3(S)-(3-苯基丙酰氨基)-2,3,4,5-四氢苯并[b][1,4]二氮杂_-1-基]乙酸和3(S)-氨基-4-氧代丁酸叔丁酯缩氨基脲偶合,得到260mg(85%)白色固体。
1H NMR(CD3OD)δ7.35-7.0(15H,m),4.94-4.88(1H,
m),4.68-4.58(1H,d),4.57-4.52(1H,m),4.41-4.34
(1H,d),4.3-4.23(1H,d),4.1-4.04(1H,d),3.18-3.11
(1H,m),3.09-2.98(1H,m),2.78-2.72(2H,t),2.65-
2.57(1H,m),2.42-2.33(3H,m).
用实施例3化合物K步骤C所述方法将3(S)-{2-[5-苄基-2-氧代-3(S)-(3-苯基丙酰氨基)-2,3,4,5-四氢苯并[b][1,4]二氮杂_-1-基]乙酰氨基}-4-氧代丁酸叔丁酯缩氨基脲去保护,得到168mg(81%)标题化合物为白色固体。 1H NMR(CD3OD)δ
7.37-7.0(14H,m),4.75-4.62(1H,m),4.6-4.45(2H,
m),4.4-4.21(2H,m),4.15-3.95(2H,m),3.15-3.0(2H,
m),2.82-2.67(2H,m),2.65-2.52(1H,m),2.5-2.32
(3H.m).
2,6-二氯苯甲酸4-叔丁氧羰基-2-氧代-3(S)-{2-[2-氧代-5-(3-苯基丙酰基)-3(S)-(3-苯基丙酰氨基)-2,3,4,5-四氢苯并[b][1,4]二氮杂_-1-基]乙酰氨基}丁酯(107a)
用化合物56a所述方法将化合物105b与3-(烯丙氧羰基氨基)-4-氧代-5-(2,6-二氯苯甲酸基)戊酸叔丁酯(WO 93 16710)偶合制备所得的缩氨基脲,得到256mg(58%)标题化合物为白色固体。
1H NMR(CDCl3)δ7.45-
7.04(17H,m),6.45-6.34(2H,m),5.28-5.21(1H,m),
5.1-5.0(1H,m),4.95-4.90(1H,m),4.75-4.70(1H,m),
4.55-4.44(1H,m),4.32-4.22(1H,dd),3.99-3.85(1H,
dd),3.85-3.76(1H,m),3.06-2.83(5H,m),2.83-2.74
(1H,m),2.6-2.44(2H,m),2.43-2.33(1H,m),2.24-
2.15(1H,m),1.45(9H,s).
2,6-二氯苯甲酸4-羧基-2-氧砼-3(S)-{2-[2-氧代-5-(3-苯基丙酰基)-3(S)-(3-苯基丙酰氨基)-2,3,4,5-四氢苯并[b][1,4]二氮杂_-1-基]乙酰氨基}丁酯(108a)
用化合物57a所述方法由化合物107a制备,得到156mg(68%)标题化合物为白色固体。 1H NMR
(CD3OD)δ7.5-6.9(17H,m),5.16-5.02(1H,dd),4.88-
4.71(2H,m),4.62-4.44(2H,m),4.42-4.28(2H,m),
4.27-4.18(1H,m),3.47-3.41(1H,m),2.90-2.60(5H,
m),2.46-2.4(2H,m),2.39-2.18(2H,m).
4-(7-甲氧基苯并噁唑-2-基)-4-氧代-3(S)-{2-[2-氧代-5-(3-苯基丙酰基)-3(S)-(3-苯基丙酰氨基)-2,3,4,5-四氢苯并[b][1,4]二氮杂_-1-基]乙酰氨基}丁酸叔丁酯(107b)
用实施例5化合物67所述方法,由化合物105b和66a制备4(R,S)-羟基-4-(7-甲氧基苯并噁唑-2-基)-3(S)-{2-[2-氧代-5-(3-苯基丙酰基)-3(S)-(3-苯基丙酰氨基)-2,3,4,5-四氢苯并[b][1,4]二氮杂_-1-基]乙酰氨基}丁酸叔丁酯,得到56%白色固体。
1H NMR(CDCl3)δ7.72-6.78
(19H,m),6.37-6.28(1H,m),5.17-5.08(0.5H,m),
4.92-4.82(0.5H,m),4.81-4.6(1H,m),4.6-4.35
((3H,m),4.05-3.9(1H,m),3.95(3H,s),3.82-3.7(1H,
m),2.96-2.05(10H,m),1.45(4.5H,s),1.38(4.5H,
s).
用实施例5化合物68a所述方法,将所得产物转化成107b,得到标题化合物(56%)为白色固体。 1H NMR
(CD3OD)δ7.62-6.8(17H,m),5.64-5.58(0.5H,t),5.52-
5.46(0.5H,t),4.62-4.47(2H,m),4.40-4.32(1H,m),
3.9(1.5H,s),3.88(1.5H,s),3.43-3.37(1H,m),
3.0-2.92(1H,m),2.90-2.62(6H,m),2.5-2.4(2H,m),
2.28-2.15(2H,m),1.32(4.5H,s),1.25(4.5H,s).
4-(7-甲氧基苯并噁唑-2-基)-4-氧代-3(S)-{2-[2-氧代-5-(3-苯基丙酰基)-3(S)-(3-苯基丙酰氨基)-2,3,4,5-四氢苯并[b][1,4]二氮杂_-1-基]乙酰氨基}丁酸(108b)
用实施例5化合物69a所述方法制备,得到标题化合物(50%)为白色固体。
1H NMR
(CD3OD)δ7.41-6.88(17H,m),5.6-5.55(0.5H,t),5.48-
5.43(0.5H,t),4.64-4.45(2H,m),4.45-4.30(1H,m),
3.93(1.5H,s),3.90(1.5H,s),3.47-3.34(1H,m),
3.10-2.85(2H,m),2.84-2.63(5H,m),2.6-2.4(2H,m),
2.3-2.1(2H,m).
4-[5-(2,6-二氯苯基)噁唑-2-基]-4-氧代-3(S)-{2-[2-氧代-5-(3-苯基丙酰基)-3(S)-(3-苯基丙酰氨基)-2,3,4,5-四氢苯并[b][1,4]二氮杂_-1-基]乙酰氨基}丁酸叔丁酯(107c)
用类似于实施例5化合物67a所述方法,由化合物106c和99制备4-[5-(2,6-二氯苯基)噁唑-2-基]-4(R,S)-羟基-3(S)-{2-[2-氧代-5-(3-苯基丙酰基)-3(S)-(3-苯基丙酰氨基)-2,3,4,5-四氢苯并[b][1,4]二氮杂_-1-基]乙酰氨基}丁酸叔丁酯,得到72%白色固体。
1H NMR
(CDCl3)δ7.71-7.64(1H,m),7.58-7.42(2H,m),7.42-
6.92(15H,m),6.5-6.37(2H,m),5.15-5.04(1H,m),
4.88-4.68(2H,m),4.57-4.37(2H,m),4.28-4.13(1H,
m),3.87-3.64(2H,m),3.04-2.80(4H,m),2.76-2.68
(1H,m),2.67-2.42(3H,m),2.41-2.31(1H,m),2.22-
2.12(1H,m),1.45(9H,s).
用类似于实施例5化合物68a所述方法,将所得产物转化成107c,以定量产率得到标题化合物为白色固体。
1H NMR(CDCl3)δ7.47-6.98
(18H,m),6.52-6.42(1H,d),5.6-5.52(1H,m),4.78-
4.71(1H,m),4.52-4.40(2H,m),4.03-3.94(0.67H,m),
3.94-3.85(0.33H,m),3.85-3.75(1H,m),3.45-3.33
(1H,m),3.08-2.98(1H,m),2.97-2.84(4H,m),2.55-
2.43(2H,m),2.43-2.32(1H,m),2.23-2.13(1H,m),
1.35(9H,s).
4-[5-(2,6-二氯苯基)噁唑-2-基]-4-氧代-3(S)-{2-[2-氧代-5-(3-苯基丙酰基)-3(S)-(3-苯基丙酰氨基)-2,3,4,5-四氢苯并[b][1,4]二氮杂_-1-基]乙酰氨基}丁酸(108c)
用类似于实施例5化合物69a所述方法,由化合物107c制备,得到72%标题化合物为白色固体。
1H NMR(CD3OD)δ7.58-7.0(18H,m),5.62-5.53
(0.67H,m),5.52-5.47(0.33H,m),4.68(3H,m),3.54-
3.42(1H,m),3.1-2.92(2H,m),2.88-2.68(5H,m),
2.63-2.45(2H,m)2.40-2.22(2H,m).
3(S)-{2(R,S)-[4-苄基-7-氧代-6(S)-(N-苄氧羰基氨基)-[1,4]二氮杂_-1-基]丙酰氨基}-4-氧代丁酸三氟乙酸盐(114a)
步骤A
向2-N-苄氧羰基-3-N-苄基-(S)-2,3-二氨基丙酸叔丁酯(110;0.85g,2.2mmol),3-(N-叔丁氧羰基)氨基-2-甲基-5-氧代-戊酸甲酯(109a;0.65g,2.7mmol),乙酸(0.1ml,1.8mmol),乙酸钠(0.36g,2mmol)和4A(埃)分子筛(1g)的甲醇(45ml)溶液中加入氰基硼氢化钠(0.33g,5.3mmol)。将混合物在25℃搅拌过夜,然后用Celite过滤,并减压浓缩。将剩余物溶解于1N NaOH,并用乙酸乙酯萃取(3×40ml)。干燥(MgSO4)有机相,过滤并蒸发,得到一种油。色谱(硅胶,4∶1己烷∶乙酸乙酯作为洗脱剂)纯化,得到0.92g(68%)111a为油。
步骤B
将上述原料溶解于冷却到0℃的二氯甲烷(3ml),然后用25%三氟乙酸的二氯甲烷(20ml)溶液处理,并允许升温至25℃,搅拌直到用TLC(4∶1己烷∶乙酸乙酯)判断反应已完全。减压除去溶剂,真空干燥剩余物,然后将剩余物溶解于二氯甲烷(40ml),并用4-甲基吗啉(1ml,9mmol),HOBT(0.2g,1.5mmol)和EDC(0.61g,3.2mmol)处理。将混合物在25℃搅拌过夜,然后用二氯甲烷稀释,用水洗涤。干燥(MgSO4)有机相,过滤并蒸发,得到一种油。色谱(硅胶,3∶2己烷∶乙酸乙酯)纯化,得到0.49g(74%)112a为粘稠的油。
步骤C
将2(R,S)-[4-苄基-7-氧代-6(S)-(N-苄氧羰基氨基)-[1,4]二氮杂卓-1-基]-丙酸甲酯(112a;0.15g,0.32mmol)溶解于甲醇,并用1M LiOH(0.32ml)处理,在25℃搅拌5.5小时后蒸发至干。剩余物与乙醇(2×10ml),乙腈(2×10ml),苯(2×10ml)共沸,然后真空干燥。用类似于实施例3化合物K(步骤A,B和C)的制备方法将所得剩余物转化成114a,然后用反相(C18柱)HPLC纯化,用0.1%TFA∶水/0.1%TFA∶乙腈洗脱,得到17mg(10%)粘稠油。
1H NMR(500MHz,CD3OD)δ
1.15(m,3H),2.30-2.70(m,6H),2.72-2.95(bm,6
H),3.30-3.80(m,4H),4.10(m,1),4.40(m,4
H),4.95(m,1H)6.95-7.10(bs,5H),和7.12-7.20
ppm(bs,5H).
3(S)-{2-[4-苄基-7-氧代-6(S)-(N-苄氧羰基氨基)-[1,4]二氮杂_-1-基]乙酰氨基}-4-氧代-丁酸三氟乙酸盐(114b)
用类似于化合物114a的合成方法从109b制备,得到85mg粘稠油。
1H NMR(500MHz,CD3OD)δ1.20
(d,J=.7Hz,3H),2.28(m,2H),2.60(m,2H),
3.18(bs,6H),3.35-3.45(m,2H),3.60-3.95(m,2
H),4.15(m,1H),4.32(m,1H),4.42(m,1H),5.00
(bm,2H),7.20(bs,5H),and 7.40ppm(bs,5H);19F
NMR(470MHz,CD3OD)δ-10.72ppm(s,3F).
4-氧代-3(S)-{2(R,S)-[7-氧代-4-(3-苯基丙酰基)-6(S)-(3-苯基丙酰氨基)-[1,4]二氮杂_-1-基]丙酰氨基}-丁酸(115)
步骤D
将2(R,S)-[4-苄基-7-氧代-6(S)-(N-苄氧羰基氨基)-[1,4]二氮杂_-1-基]丙酸甲酯(112b;0.22g,0.49mmol)和20%Pd(OH)2/炭(50mg)的乙醇悬浮液在氢气下搅拌7小时。减压蒸发溶剂,剩余物溶解于二氯甲烷(20ml),然后用三乙胺(1ml)和二氢肉桂酰氯(170mg,1mmol)处理。所得混合物被搅拌过夜后用乙酸乙酯稀释,用1N NaOH洗涤。干燥(MgSO4)有机相,过滤并蒸发,得到一种油。色谱(硅胶,4∶1己烷∶乙酸乙酯)纯化,得到0.175g(75%)113为油。
步骤C
将0.15g化合物113(0.32mmol)溶解于甲醇,用1M LiOH(0.32ml)处理,在40℃搅拌过夜后蒸发至干。剩余物与乙醇(2×10ml),乙腈(2×10ml),苯(2×10ml)共沸,然后真空干燥。用类似于实施例3化合物K(步骤A,B和C)的制备方法将所得剩余物转化成115。
3-{2-[2,4-二苄基-3,7-二氧代-6-(N-苄氧羰基氨基)-[1,4]二氮杂_-1-基]丙酰氨基}-4-氧代-丁酸(121)
步骤E
将2-N-苄酯基-3-N-苄基-(S)-2,3-二氨基丙酸叔丁酯(110;1.77g,4.6mmol),N-烯丙基-N-叔丁氧羰基-(S)-苯基丙氨酸(116;1.04g,4.8mmol),HOBT(0.74g,5.5mmol)和EDC (1.33g,6.9mmol)的二氯甲烷(50ml)溶液在25℃搅拌16小时,然后用二氯甲烷(100ml)稀释,用水洗涤。干燥(MgSO4)有机相,过滤并蒸发,得到一种油。色谱(硅胶,85∶15己烷∶乙酸乙酯)纯化,得到1.34g(43%)117为无色粘稠油。
步骤F
将1.34g化合物117溶解于二氯甲烷(3ml),然后用50%三氟乙酸的二氯甲烷(20ml)溶液处理。1.5小时后减压除去溶剂。剩余物经真空干燥后被溶解于二氯甲烷(50ml),并与4-甲基吗啉(0.2ml,2mmol),HOBT(0.27g,2mmol)和EDC(0.8g,4mmol)混合。将混合物在25℃搅拌过夜,然后用二氯甲烷稀释,用水洗涤。干燥(MgSO4)有机相,过滤并蒸发,得到一种油。色谱(硅胶,7∶3己烷∶乙酸乙酯)纯化,得到0.8g(80%)118为粘稠油。
步骤G
将0.8g化合物118溶解于甲醇(40ml),然后冷却至-78℃,用臭氧饱和直到溶液呈蓝色。通入氩气清除过量臭氧,然后加入二甲基亚砜(5ml)。将混合物升温至25℃,并搅拌3小时。除去溶剂,然后色谱(硅胶,1∶1己烷∶乙酸乙酯)纯化,得到0.74g(74%)119为白色固体。
步骤H
将0.2g(0.4mmol)化合物119溶解于丙酮(25ml),并冷却至0℃,然后滴加Jones试剂的溶液处理直到持续呈橙色。混合物中加入2-丙醇(5ml),用Celite过滤所得溶液,用丙酮洗涤。除去溶剂,得到绿白色固体,真空干燥后得到化合物120。用类似于实施例3化合物K(步骤A,B和C)所述方法将所得剩余物(120)转化成化合物121。色谱纯化(SiO2,洗脱剂为95∶4.5∶0.5二氯甲烷∶甲醇∶乙酸),得到85mg(53%)奶油色固体,根据下列谱数据它被认定为3-{2-[2,4-二苄基-3,7-二氧代-6-(N-苄氧羰基氨基)-[1,4]二氮杂卓-1-基]丙酰氨基}-4-氧代-丁酸(121)。
1H NMR(500MHz,CD3OD)
δ2.38(m,1H),2.45(m,1H),3.21(bs,2H),3.32-
3.39(bm,6H),3.85(m,1H),4.05(m,1H),4.21
(bm,1H),4.31(bs,1H),4.45(dm,J=11Hz,1H),
4.95(bs,4H),7.20(bs,5H),和7.33-7.45 ppm
(m,5H);19F NMR(470MHz,CD3OD)d-10.62ppm(s,3
F).
(3S)N-(烯丙氧羰基)-3-氨基-5-(2-氯苯基甲硫基)-4-氧代-戊酸叔丁酯(123)
先后将氟化钾(273mg,4.70mmol)和2-氯苯基甲基硫醇(373mg,2.35mmol)加到搅拌的(3S)N-(烯丙氧羰基)-3-氨基-5-溴-4-氧代-戊酸叔丁酯(122;749mg,2.14mmol;WO 93 16710)的二甲基甲酰胺(20ml)溶液中。将混合物搅拌3.5小时后用水(50ml)淬灭,用乙酸乙酯萃取(2×50ml)。合并的萃取液用水(4×50ml)和盐水(50ml)洗涤,干燥(MgSO4)并浓缩,得到一种油。将其用快速色谱纯化(10-35%乙酸乙酯/己烷),得到832mg(91%)无色固体。
mp.45-6
℃;[α]D 20-19.0°(c 1.0,CH2Cl2);IR(膜)3340,
2980,2935,1725,1712,1511,1503,1474,1446,1421,
1393,1368,1281,1244,1157,1052,1040,995,764,
739;1H NMR(CDCl3)δ7.36(2H,m),7.21(2H,m),
5.91(2H,m),5.27(2H,m),4.76(1H,m),4.59(2H,
d),3.78(2H,s),3.36(2H,m),2.91(1H,dd),2.74
(1H,dd),1.43(9H,s).
元素分析C20H26ClNO5S:
计算值:C,56.13;H,6.12;N,3.27;S,7.49,
实测值:C,56.08;H,6.11;N,3.26;S,7.54。
MS(C.I.)430/28(M++1,3%),374/2(100).
(3S)3-(2-(6-苄基-1,2-二氢-2-氧代-3-(3-苯基丙酰氨基)-1-吡啶基)乙酰氨基-5-(2-氯苯基甲硫基)-4-氧代-戊酸叔丁酯(124a)
将6-苄基-1,2-二氢-2-氧代-3-(3-苯基丙酰氨基)吡啶基乙酸(52b;300mg,0.76mmol)的THF(7ml)与1-羟基苯并三唑(205mg,1.52mmol)和1-(3-二甲氨基丙基-3-乙基碳化二亚胺盐酸盐)一起搅拌,3分钟后滴加水(12滴)。将混合物搅拌10分钟,然后用(3S)N-(烯丙氧羰基)-3-氨基-5-(2-氯苯基甲硫基)-4-氧代-戊酸叔丁酯(123;325mg,0.76mmol),双(三苯膦)氯化钯(II)(20mg)和三丁基氢化锡(0.6ml,2.28mmol)处理。将混合物在室温搅拌5小时,然后倒入乙酸乙酯中,并用1M HCl水溶液(×2),碳酸氢钠水溶液和盐水洗涤。干燥(MgSO4)并浓缩,剩余物用戊烷研制,并弃去上清液。色谱纯化(硅胶,50%乙酸乙酯/己烷),得到439mg(81%)无色泡沫。
[α]D 21-18.3°(c 0.5,CH2Cl2);IR(KBr)
3356,3311,1722,1689,1646,1599,1567,1513,1367,
1154;1H NMR(CDCl3)δ8.39(1H,d),8.23(1H,s),
7.24(14H,m),6.16(1H,d),4.95(1H,m),4.63(2H,
m),4.02(2H,s),3.74(2H,s),3.27(2H,s),2.85
(6H,m),1.40(9H,s).
元素分析C39H42ClN3O6S:
计算值:C,65.39;H,5.91;N,5.87,
实测值:C,65.51;H,5.99;N,5.77。
[3S(1S,9S)]-3-(6,10-二氧代-1,2,3,4,7,8,9,10-八氢)-9-(3-苯基丙酰氨基)-6H-哒嗪[1,2-a][1,2]二氮杂_-1-甲酰氨基-5-(2-氯苯基甲硫基)-4-氧代戊酸叔丁酯(124b)
用类似于化合物124a的制备方法,从硫醚123和3S(1S,9S)-3-(6,10-二氧代-1,2,3,4,7,8,9,10-八氢)-9-(3-苯基丙酰氨基)-6H-哒嗪并[1,2-a][1,2]二氮杂_-1-羧酸(45a)制备,得到452mg(50%)无色泡沫。
mp 55-7℃;[α]D 22-
94.0°(c 0.12,CH2Cl2);IR(KBr)3288,2934,1741,
1722,1686,1666,1644,1523,1433,1260,1225,1146,
757;1H NMR(CDCl3)δ7.35(3H,m),7.20(7H,m),6.46
(1H,d),5.21(1H,m),4.97(2H,m),4.56(1H,m),
3.75(2H,s),3.25(3H,m),2.93(5H,m),2.71(1H,
dd),2.55(2H,m),2.30(1H,m),1.92(3H,m),1.66
(2H,m),1.42(9H,s).
元素分析C35H43ClN4O7S·0.25H2O:
计算值:C,59.73;H,6.23;Cl,5.04;N,7.96;S,4.56,
实测值:C,59.73;H,6.19;Cl,5.10;N,7.79;S,4.58。
MS(-FAB)697(M-1,100).
(3S)3-(2-(6-苄基-1,2-二氢-2-氧代-3-(3-苯基丙酰氨基)-1-吡啶基)乙酰氨基-5-(2-氯苯基甲硫基)-4-氧代-戊酸(125a)
将3-(2-(6-苄基-1,2-二氢-2-氧代-3-(3-苯基丙酰氨基)-1-吡啶基)乙酰氨基-5-(2-氯苯基甲硫基)-4-氧代-戊酸叔丁酯(124a;400mg,0.56mmol)的二氯甲烷(3ml)在0℃用三氟乙酸(3ml)处理,并在0℃搅拌1小时,然后在室温搅拌0.5小时。浓缩溶液,然后重新溶解于二氯甲烷,再浓缩。如此重复三次。剩余物在乙醚中搅拌1小时,过滤,得到无色固体(364mg,99%)。
mp.165-7℃;[α]D 22-27.7°(c 0.2,CH2Cl2);IR(KBr)
3289,1712,1682,1657,1645,1593,1562,1527,1497,
1416,1203,1182;1H NMR(CDCl3)d 8.47(1H,d),8.21
(1H,s),7.70(1H,d),7.22(14H,m),6.24(1H,d),
5.03(1H,m),4.65(2H,m),4.06(2H,s),3.69(2H,
m),3.23(2H,m),2.88(6H,m).
[3S(1S,9S)]-3-(6,10-二氧代-1,2,3,4,7,8,9,10-八氢)-9-(3-苯基丙酰氨基)-6H-哒嗪[1,2-a][1,2]二氮杂_-1-甲酰氨基-5-(2-氯苯基甲硫基)-4-氧代戊酸(125b)
用类似于化合物125a的制备方法,从叔丁酯124b制备,得到362mg(93%)无色粉末。 mp 76-80℃;[α]D 21
-134°(c 0.10,MeOH);IR(KBr)3309,2935,1725,
1658,1528,1445,1417,1277,1219,1175;1H NMR(D6-
DMSO)δ8.80(1H,d),8.19(1H,d),7.31(9H,m),
5.09(1H,m),4.74(1H,m),4.63(1H,m),4.35(1H,
m),3.76(2H,m),3.28(3H,m),2.80(5H,m),2.52
(4H,m),2.16(2H,m),1.90(3H,m).
元素分析C31H35Cl2N4O7S·0.25H2O:
计算值:C,57.49;H,5.53;N,8.65;S,4.95,
实测值:C,57.35;H,5.43;N,8.45;S,4.88。
MS(-FAB)641(M-1,100).
以上实施例中的数据表明本发明化合物显示出对IL-1β转化酶的抑制活性。
就本发明化合物而言,它们能在体外抑制ICE,因此,可以给哺乳动物口服,它们可用于治疗IL-1介导的疾病,具有明显的临床实用性。这些试验预示着本发明化合物有在体内抑制ICE的能力。
尽管我们描述了本发明的大量具体实例,但很明显,我们的基本结构可以改变以提供利用本发明产物和方法的其它具体实例。因此,应该认识到本发明的范围由所附的权利要求书限定,而不是由所列举的具体实施例限定。
Claims (40)
1.下式代表的化合物:
其中:
R1选自下列结构式:
(a1)
(a2)
(g2)
其中:
m为1,
R为H或C1-6直链或支链烷基,
R20为任选被苯氧基或1,3-二硫戊环取代的
Q1为H或被苯基取代的C1-6直链或支链烷基,其中的苯基任选地被-OH,-OC1-6直链或支链烷基或-CF3取代,
R3是
R3为-C(O)H,-C(=N-N(H)-C(O)-NH2)H,-C(O)CH2OC(O)Ar1,其中Ar1为2,6-二氯苯基,或
R5为H或被苯基取代的C1-6直链或支链烷基,并且
R6为H或C1-6直链或支链烷基;
或R1为
其中
m为1
R为H或C1-6直链或支链烷基;
X为CH,
R3为
-C(O)H,
-C(O)CH2OH,
-C(O)CH2CH3,
-C(O)CH2OC(O)Ar1,其中Ar1为2,6-二氯苯基,
-C(O)CH2OCH2Ar1,其中Ar1为2-氯苯基,
-C(O)CH2SCH2Ar1,其中Ar1为2-氯苯基,
或
R5为-COR9,-CO-O-R9,-SO2-R9或AcTyr,其中R9为被苯基取代的C1-6直链或支链烷基,
R6为H或C1-6直链或支链烷基,并且
Q1为H,苯基或任选被苯基取代的C1-6直链或支链烷基;
或R1为
(d2)
其中m为1,R为H,Q1为C1-6直链或支链烷基,并且R3为-C(O)H;
或R1为
其中:
m为1,
R为H或C1-6直链或支链烷基,
R5为
H,
-C(O)R9,其中R9为任选被苯基取代的C1-6直链或支链烷基,
4-吡啶基酰氧基,
-C(O)C(O)N(H)-Ar1,其中Ar1为4-氯苯基,
-C(O)C(O)-Ar1,其中Ar1为苯基或2,6-(R9O)2-苯基,其中R9为C1-6直链或支链烷基,或
-C(O)OR9,其中R9为被苯基取代的C1-6直链或支链烷基,
-C(O)NR9R10,其中R9为C1-6直链或支链烷基,并且R10为H,或
-SO2-R9,其中R9为C1-6直链或支链烷基,
-SO2-Ar1,其中Ar1为苯基,
-SO2-N(R9)(R10),其中R9和R10各自为C1-6直链或支链烷基,或
-COAr1,其中Ar1为
苯基,
4-R9C(O)-氨基-3-氯苯基,其中R9为C1-6直链或支链烷基,
1-异喹啉基,
2,6-二氯苯基,
3-氯-4-(R9C(O)N(H))苯基,其中R9为C1-6直链或支链烷基,
2-喹啉基,
3-喹啉基,
4-喹啉基,
6-喹啉基,
8-喹啉基,
4-烷氧基-2-喹啉基,其中烷氧基为C1-6直链或支链烷氧基,
2-R9C(O)-氨基苯基,其中R9为C1-6直链或支链烷基,
3-(R9)2N-苯基,其中R9为C1-6直链或支链烷基,
4-(R9)2N-苯基,其中R9为C1-6直链或支链烷基,
4-R9C(O)N(H)苯基,其中R9为C1-6直链或支链烷基,并且其中烷基任选地被苯基取代,
3-R9C(O)N(H)苯基,其中R9为C1-6直链或支链烷基,
4-R9C(O)N(R9)苯基,其中每个R9为C1-6直链或支链烷基,
4-R9N(H)C(O)N(H)苯基,其中R9为C1-6直链或支链烷基,
4-R9OC(O)N(H)苯基,其中R9为C1-6直链或支链烷基,
3,4-(R9C(O)N(H))2苯基,其中每个R9为C1-6直链或支链烷基,
4-R9S(O)2-氨基苯基,其中R9为C1-6直链或支链烷基,
4-RS(O)2-苯基,其中R9为C1-6直链或支链烷基,
4-氨基磺酰基苯基,
2-R9-苯基,其中R9为C1-6直链或支链烷基,
2-R9-3-羟基苯基,其中R9为C1-6直链或支链烷基,
3,5-(R9)2-4-羟基苯基,其中R9为C1-6直链或支链烷基,
2-R9O-苯基,其中R9为C1-6直链或支链烷基,
3-R9O-苯基,其中R9为C1-6直链或支链烷基,
4-R9O-苯基,其中R9为C1-6直链或支链烷基,并且其中烷基可以任选地被苯基取代,
2-氯苯基,
3-氯苯基,
4-氯苯基,
3,4-二氯苯基,
3,5-二氯苯基,
3,5-二氯-4-羟基苯基,
3,5-二氯-4-R9O-苯基,其中R9为C1-6直链或支链烷基,
2-R9-3-氯苯基,其中R9为C1-6直链或支链烷基,
2-R9-5-氯苯基,其中R9为C1-6直链或支链烷基,
3-氯-4-R9O-苯基,其中R9为C1-6直链或支链烷基,
3-氯-4-羟基苯基,
3-氯-4-氨基苯基,
3,5-二氯-4-氨基苯基,
2-氟苯基,
3-氟苯基,
4-氟苯基,
3,4-二氟苯基,
3-氯-4-氟苯基,
3-氟-4-R9O-苯基,其中R9为C1-6直链或支链烷基,
4-羟基苯基,
4-(4-羟基苯甲酰氧基)苯基,
4-苯甲酰氧基苯基,
4-羟基-3-甲基-N-吗啉基苯基,
4-羟基烷基苯基,其中的烷基为C1-6直链或支链烷基,
4-R9C(O)苯基,其中的R9为C1-6直链或支链烷基,
4-苯甲酰基氨基苯基,
4-氨基苯基,
4-苯氧基苯基,
肉桂酰基,
1-萘基,
2-萘基,
4-联苯基,
1-羟基-2-萘基,
6-羟基-2-萘基,
2-氨基-3-萘基,
4-(R10)2N-1-萘基,其中R10为H或C1-6直链或支链烷基,
2-R9-4,5-亚甲基二氧基苯基,其中R9为C1-6直链或支链烷基,
3,4-亚甲基二氧基苯基,
2-噻吩基,
3-噻吩基,
2-噻吩并噻吩基,
2-苯并噻吩基,
2-苯并呋喃基,
3-吡啶基,
环丙基,
环己基,
3,4,5-(R9O)3-苯基,其中R9为C1-6直链或支链烷基,
1,3-二烷基-5-吡唑基,其中每个烷基为C1-6直链或支链烷基,
1,4-二烷基-5-噻唑基,其中每个烷基为C1-6直链或支链烷基,
4-烷基-2-三氟甲基苯基-5-噻唑,其中每个烷基为C1-6直链或支链烷基,
5-烷基-3-异噻唑,其中每个烷基为C1-6直链或支链烷基,
6-苯并三唑基,
2-吲哚基,
1-烷基-2-吲哚基,其中每个烷基为C1-6直链或支链烷基,
2-咪唑基,
6-苯并咪唑基,或
5-(1,2,3-噻二唑),并且
R3为
-C(O)H,
-C(O)CH2SCH2Ar1,其中Ar1为2-氯苯基,
-C(O)CH2OCH2Ar1,其中Ar1为2-氯苯基,
-C(O)CH2OC(O)Ar1,其中Ar1为
2,6-二氯苯基,
1-萘基,
4-(3-苯基-5-甲基异噁唑基),
2-苯氧基苯基,
3-苯氧基苯基,
3-甲基-2-噻吩基,或
2,6-(R9)2苯基,其中R9为C1-6直链或支链烷基,
-C(O)CH2F,
-C(O)CH2Br,
-CN,
-C(=N-O-(CH2)nAr1)H,其中n为1-6,并且Ar1为苯基或2,6-二氯苯基,
-C(=N-O-R9)H,其中R9为C1-6直链或支链烷基,
-C(=N-N(H)C(O)NH2)H,
-(C(O)CH2S(CH3)CH2Ar1)+BF4 -,其中Ar1为2-氯苯基,
其中
m为1,
R为H,
e为O,
Y为H2,
Q1为H,
R5为
-COR9,其中R9为被苯基取代的C1-6直链或支链烷基,
COAr1,其中Ar1为苯基,并且
R3为-C(O)H;或
其中:
m为1,
R为H,
e为O,
Y为O,
Q1为R9,其中R9为被苯基取代的C1-6直链或支链烷基,或
R5为-COAr1,其中Ar1为苯基,并且
R3为-C(O)H,或
m为2,
R为H或C1-6直链或支链烷基,
e为O,
Y为O,
Q为H,
R5为-COAr1,其中Ar1为苯基,并且
R3为-C(O)或-C(=N-N(H)C(O)NH2)H;
其中,
m为1,
R为H或C1-6直链或支链烷基,
R3为-C(O)H,并且
R5为
-C(O)R9,其中R9为C1-6直链或支链烷基,其中的烷基任选为不饱和的,并且其中的烷基任选被以下基团取代:
苯基,
4-氯苯基,
3,4-亚甲基二氧基苯基,
3,4-二氯苯基,
环己基,和
2,4,6-(R9)3-苯基,其中R9为C1-6直链或支链烷基,
-SO2-Ar1,其中Ar1为2-萘基,
-C(O)NHAr1,其中Ar1为苯基,2-R9O-苯基或3-R9O-苯基,其中R9为C1-6直链或支链烷基,
-C(O)Ar1,其中Ar1为
苯基,
2,3-亚甲基二氧基苯基,
4-R9C(O)N(H)苯基,其中的R9为C1-6直链或支链烷基,
4-R9C(O)-苯基,其中的R9为C1-6直链或支链烷基,
2-苯并噻吩基,
4-羟基苯基,
2-吲哚基,
4-R9O-3,5-R9-苯基,其中每个R9为C1-6直链或支链烷基,或
4-R9O-3,5-二氯苯基,其中每个R9为C1-6直链或支链烷基,
-C(O)C(O)Ar1,其中Ar1为:
苯基,
噻吩基,
3-吲哚基,
3,4-亚甲基二氧基苯基,
4-R9O-苯基,其中R9为C1-6直链或支链烷基,
2-R9O-苯基,其中R9为C1-6直链或支链烷基,
2,6-(R9O)2-苯基,其中R9为C1-6直链或支链烷基,
2,4,6-(R9)3-苯基,其中R9为C1-6直链或支链烷基,或
3,4,5-(R9O)3-苯基,其中每个R9为C1-6直链或支链烷基,
-C(O)C(O)N(H)Ar1,其中Ar1为4-氯苯基;
或R1为
(e4)
或
其中
m为1,
R5为-C(O)R9,其中R9为C1-6直链或支链烷基,其中的烷基被苯基取代,并且
R3为-C(O)H;
或R1为
(f4)
或
其中:
m为1,
R为H或C1-6直链或支链烷基,
R5为-COR9,其中R9为C1-6直链或支链烷基,
每个R9独立地为任选被4-羟基苯基取代的C1-6直链或支链烷基,
Q1为-O-苯基,或-OR9,其中R9为C1-6直链或支链烷基,所述烷基被苯基取代或为不饱和的,并且
R3为:
-C(O)H,
-C(=N-N(H)-C(O)-NH2)H,
-C(O)CH2SCH2Ar1,其中Ar1为2-氯苯基,
或
或R1为
(h2)
其中:
m为1,R为H,R3为-C(O)H,并且
R20为
或R1为
或
其中:
m为1,
R为H,
R3为-C(O)H,
Q1为被苯基取代的C1-6直链或支链烷基,
每个R5独立地为
-C(O)R9,其中R9为被苯基或4-羟基苯基取代的C1-6直链或支链烷基,或
-C(O)OR9,其中R9为被苯基取代的C1-6直链或支链烷基,并且
R6为H或C1-6直链或支链烷基;
或R1为
其中:
m为1,
R为H或C1-6直链或支链烷基,
R3为
-C(O)H,
-C(=N-N(H)-C(O)-NH2)H,
-C(O)CH2OC(O)Ar1,其中Ar1为2,6-二氯苯基
或
和
R5为
-C(O)Ar1,其中Ar1为苯基,或
-C(O)R9,其中R9为被苯基取代的C1-6直链或支链烷基;
或R1为
(w1)
其中:
m为1,
R为H或C1-6直链或支链烷基,
R3为
-C(O)H,
-C(O)CH2OH,
-C(O)CH2CH3,
-C(O)CH2OC(O)Ar1,其中Ar1为2,6-二氯苯基,
-C(=N-O-CH2Ar1)H,其中Ar1为2,6-二氯苯基,
R5为-C(O)R9,其中R9为任选被苯基取代的C1-6直链或支链烷基,
并且
R7为
-H,
-R9,其中R9为被苯基取代的C1-6直链或支链烷基,
-C(O)R9,其中R9为任选被苯基取代的C1-6直链或支链烷基。
3.根据权利要求1的化合物,其中R1是
(c)
5.根据权利要求1的化合物,其中R1是
(e6)
6.根据权利要求1的化合物,其中R1是
(e2)
12.权利要求1的化合物,其中R1是
(w1)
15.根据权利要求4的化合物,其为:
43
21.权利要求9的化合物,其选自:
39
32.权利要求1的化合物,其选自:
226e
227e
429
217c
217e
282
284
404
405
407
411
413
418
423
432
434
436
437
441
444
445
447
448
449
450
452
453
454
455
456
458
459
464
469
470
474
480
481s
482s
486
487
491
493
495
497
499
214k
605a
605b
605d
605g
605i
605o
605p
605s
609a
609b
620
621
628
630
632
633
634
3050
3053
3054
3056
3057
3059
3061
3062
3065
3066
3067
3070
3072
3073
3074
3077
3080
3085
3086
3093
3095
3096
3097
3098
3100
3101
3104
3106
3107
3109
3110
3112
3113
3116
3117
3119
3120
3121
3123
3124
3125
3130
3132
3133
3134
3136
3138
3142
3143
3144
3145
3147
3148
3154
3157
3158
3161
3162
*非对映体
4055
4006a
4006c
4017a
4019b
2201
913
916
656
669
689a
915
918
684
689b
691a
917
920
696-1
699
和
5026
33.包含权利要求1-32任一项所述化合物的药物组合物及药学上可接受的载体的药物组合物。
34.权利要求1-32任一项所述的化合物用于制备治疗或预防下列疾病的药物的用途:IL-1介导的疾病,自身免疫病,炎症和神经变性疾病。
35.权利要求1-32任一项所述的化合物用于制备抑制ICE介导的功能的药物的用途。
36.权利要求1-32任一项所述的化合物用于制备促进伤口愈合的药物的用途。
37.权利要求1-32任一项所述的化合物用于制备治疗或预防感染性疾病的药物的用途。
38.一种筛选ICE抑制剂的方法,它包括以下步骤:
a)选择有确定化学结构的候选化合物,该化合物含有至少两个氢键键合部分,至少两个中等疏水部分和一个含有一或多个负电性原子的负电性部分,所说的一个或多个负电性原子可连到该负电性部分中的单一原子或相邻原子上;
其中包含至少两个氢键合的部分的化学结构选自以下基团:
其中每一个X独立地为C或N;
每一个Z为CO-或SO2;
W1独立地为含有1-3个共价键合的成员的直链,独立地选自由C,N,S和O组成的组,在所述成员之间的共价键独立地为饱和或不饱和的,并且所述链含有通过键r与两个不同的X原子共价键合的两个端点;
W2独立地为含有3-5个共价键合的成员的直链,独立地选自由C,N,S和O组成的组,在所述成员之间的共价键独立地为饱和或不饱和的,并且所述链含有通过键r与两个不同的X原子共价键合的两个端点;
每一个r的键独立地为单或双键;
W14独立地为含有1-3个共价键合的成员的直链,独立地选自由C,N,S和O组成的组,在所述成员之间的共价键独立地为饱和或不饱和的,并且所述链含有通过键r与两个不同的C原子共价键合的两个端点;
W1a独立地为含有1-3个共价键合的成员的直链,独立地选自由C,N,S和O组成的组,在所述成员之间的共价键独立地为饱和或不饱和的,并且所述链含有通过键r与两个不同的X原子共价键合的两个端点;
W2a独立地为含有3-4个共价键合的成员的直链,独立地选自由C,N,S和O组成的组,并且所述键包含与两个不同原子共价键合的两个端点以形成芳基或杂芳环;
每一个X1独立地为C,N或O;
W14a独立地为含有1-3个共价键合的成员的直链,独立地选自由C,N,S和O组成的组,在所述成员之间的共价键为饱和或不饱和的,并且所述键包含与两个不同X1原子共价键合的两个端点以形成非芳环;
W3独立地为含有2-4个共价键合的成员的直链,独立地选自由C,N,S和O组成的组,在所述成员之间的共价键独立地为饱和或不饱和的,并且所述链含有通过键r与两个不同的X原子共价键合的两个端点;
W15独立地为含有1-2个共价键合的成员的直链,独立地选自由C,N,S和O组成的组,在所述成员之间的共价键独立地为饱和或不饱和的,并且所述链含有与两个不同的X原子共价键合的两个端点;
W16独立地为含有1-2个共价键合的成员的直链,独立地选自由C,N,S和O组成的组,在所述成员之间的共价键独立地为饱和或不饱和的,并且所述链含有通过键r与两个不同的C原子共价键合的两个端点;
W4独立地为含有2-4个共价键合的成员的直链,独立地选自由C,N,S和O组成的组,在所述成员之间的共价键独立地为饱和或不饱和的,并且所述链含有与两个不同的原子共价键合的两个端点;
每个W5独立地为含有1-2个共价键合的成员的直链,独立地选自由C,N,S和O组成的组,在所述成员之间的共价键独立地为饱和或不饱和的,并且所述链含有通过键r与两个不同的原子共价键合的两个端点;
W6独立地为含有3-5个共价键合的成员的直链,独立地选自由C,N,S和O组成的组,在所述成员之间的共价键独立地为饱和或不饱和的,并且所述链含有通过键r与两个不同的X原子共价键合的两个端点;
W17独立地为含有1-3个共价键合的成员的直链,独立地选自由C,N,S和O组成的组,在所述成员之间的共价键独立地为饱和或不饱和的,并且所述链含有通过键r与两个不同的C原子共价键合的两个端点;
W7独立地为含有3-5个共价键合的成员的直链,独立地选自由C,N,S和O组成的组,在所述成员之间的共价键独立地为饱和或不饱和的,并且所述链含有通过键r与两个不同的X原子共价键合的两个端点;
W8独立地为含有1-3个共价键合的成员的直链,独立地选自由C,N,S和O组成的组,在所述成员之间的共价键独立地为饱和或不饱和的,并且所述链含有通过键r与两个不同的X原子共价键合的两个端点;
W18独立地为含有1-3个共价键合的成员的直链,独立地选自由C,N,S和O组成的组,在所述成员之间的共价键独立地为饱和或不饱和的,并且所述链含有通过键r与两个不同的C原子共价键合的两个端点;
W8a独立地为含有1-3个共价键合的成员的直链,独立地选自由C,N,S和O组成的组,在所述成员之间的共价键独立地为饱和或不饱和的,并且所述链含有与两个不同的C原子共价键合的两个端点;
W19独立地为含有1-3个共价键合的成员的直链,独立地选自由C,N,S和O组成的组,在所述成员之间的共价键独立地为饱和或不饱和的,并且所述链含有通过键r与两个不同的C原子共价键合的两个端点;
W7a独立地为含有3个共价键合的成员的直链,独立地选自由C,N,S和O组成的组,并且所述键包含与两个不同的C原子共价键合的两个端点以形成芳基或杂芳环;
W9独立地为含有1-3个共价键合的成员的直链,独立地选自由C,N,S和O组成的组,在所述成员之间的共价键独立地为饱和或不饱和的,并且所述链含有通过键r与两个不同的X原子共价键合的两个端点;
W10独立地为含有1-3个共价键合的成员的直链,独立地选自由C,N,S和O组成的组,在所述成员之间的共价键独立地为饱和或不饱和的,并且所述链含有通过键r与两个不同的X原子共价键合的两个端点;
W9a独立地为含有1-3个共价键合的成员的直链,独立地选自由C,N,S和O组成的组,在所述成员之间的共价键独立地为饱和或不饱和的,并且所述链含有与两个不同的C原子共价键合的两个端点;
W10a独立地为含有1-3个共价键合的成员的直链,独立地选自由C,N,S和O组成的组,在所述成员之间的共价键独立地为饱和或不饱和的,并且所述链含有与两个不同的X原子共价键合的两个端点;
W11独立地为含有3-5个共价键合的成员的直链,独立地选自由C,N,S和O组成的组,在所述成员之间的共价键独立地为饱和或不饱和的,并且所述链含有与两个不同的原子共价键合的两个端点以形成被苯并稠合或吡啶并稠合的环;
W12独立地为含有4-6个共价键合的成员的直链,独立地选自由C,N,S和O组成的组,在所述成员之间的共价键独立地为饱和或不饱和的,并且所述链含有通过键r与指定的X原子共价键合的两个端点;
每一个Xb独立地为C或N;
W12a独立地为含有4-6个共价键合的成员的直链,独立地选自由C,N,S和O组成的组,在所述成员之间的共价键独立地为饱和或不饱和的,并且所述链含有通过键r与指定的Xb共价键合的两个端点;
W20独立地为含有1-3个共价键合的成员的直链,独立地选自由C,N,S和O组成的组,在所述成员之间的共价键独立地为饱和或不饱和的,并且所述链含有通过键r与两个不同的C原子共价键合的两个端点;
W21独立地为含有1-2个共价键合的成员的直链,独立地选自由C,N,S和O组成的组,在所述成员之间的共价键独立地为饱和或不饱和的,并且所述键包含与两个不同的C原子共价键合的两个端点以形成芳基;
W13独立地为含有3-5个共价键合的成员的直链,独立地选自由C,N,S和O组成的组,在所述成员之间的共价键独立地为饱和或不饱和的,并且所述链含有与两个不同的原子共价键合的两个端点;
W22独立地为含有1-3个共价键合的成员的直链,独立地选自由C,N,S和O组成的组,在所述成员之间的共价键独立地为饱和或不饱和的,并且所述链含有与两个不同的原子共价键合的两个端点;
W23独立地为含有1-3个共价键合的成员的直链,独立地选自由C,N,S和O组成的组,在所述成员之间的共价键独立地为饱和或不饱和的,并且所述链含有与两个不同的原子共价键合的两个端点;
W22a独立地为含有1-3个共价键合的成员的直链,独立地选自由C,N,S和O组成的组,在所述成员之间的共价键独立地为饱和或不饱和的,并且所述链含有通过键r与两个不同的原子共价键合的两个端点;
b)确定所说化合物与ICE活性部位结合的低能构象;
c)评价所说化合物以所说构象与ICE的非碳主链原子Arg-341和Ser-339形成至少两个氢键的能力;
d)评价所说化合物以所说构象与ICE的至少两个结合袋缔合的能力,所说结合袋选自P2结合袋,P3结合袋,P4结合袋和P’结合袋;
e)评价所说化合物以所说构象与ICE的P1结合袋相互作用的能力;及
f)根据上述步骤进行的测定和评价结果确定接受或放弃所说候选化合物作为ICE抑制剂。
39.权利要求38的方法,另外在步骤e)和f)之后还包含以下两个步骤:
g)评价所说化合物与ICE结合的变形能;及
h)评价ICE与具有所说的与ICE结合的构象的所说化合物之间全部静电相互作用的总和。
40.根据权利要求38或39的方法筛选的ICE抑制剂。
Applications Claiming Priority (6)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US08/261,452 US5756466A (en) | 1994-06-17 | 1994-06-17 | Inhibitors of interleukin-1β converting enzyme |
US08/261,452 | 1994-06-17 | ||
US08/405,581 US5656627A (en) | 1994-06-17 | 1995-03-17 | Inhibitors of interleukin-1β converting enzyme |
US08/405,581 | 1995-03-17 | ||
US08/440,898 | 1995-05-25 | ||
US08/440,898 US5847135A (en) | 1994-06-17 | 1995-05-25 | Inhibitors of interleukin-1β converting enzyme |
Publications (2)
Publication Number | Publication Date |
---|---|
CN1159196A CN1159196A (zh) | 1997-09-10 |
CN1192035C true CN1192035C (zh) | 2005-03-09 |
Family
ID=27401408
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CNB951943812A Expired - Fee Related CN1192035C (zh) | 1994-06-17 | 1995-06-16 | 白介素-1β转化酶抑制剂 |
Country Status (22)
Country | Link |
---|---|
US (2) | US5716929A (zh) |
EP (1) | EP0784628A1 (zh) |
JP (1) | JP4190029B2 (zh) |
CN (1) | CN1192035C (zh) |
AP (1) | AP797A (zh) |
AU (1) | AU709114B2 (zh) |
BG (1) | BG63634B1 (zh) |
BR (1) | BR9508051A (zh) |
CA (1) | CA2192089C (zh) |
CZ (1) | CZ298625B6 (zh) |
FI (1) | FI965036A (zh) |
GE (1) | GEP20012446B (zh) |
HU (1) | HUT76622A (zh) |
IL (1) | IL114015A0 (zh) |
IS (1) | IS4399A (zh) |
MA (1) | MA24511A1 (zh) |
MX (1) | MX9606546A (zh) |
NZ (1) | NZ289560A (zh) |
PL (1) | PL185693B1 (zh) |
SK (1) | SK287422B6 (zh) |
TW (1) | TW509698B (zh) |
WO (1) | WO1995035308A1 (zh) |
Families Citing this family (138)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5874424A (en) * | 1995-12-20 | 1999-02-23 | Vertex Pharmaceuticals Incorporated | Inhibitors of interleukin-1β converting enzyme |
US6204261B1 (en) * | 1995-12-20 | 2001-03-20 | Vertex Pharmaceuticals Incorporated | Inhibitors of interleukin-1β Converting enzyme inhibitors |
US5846981A (en) * | 1993-05-28 | 1998-12-08 | Gpi Nil Holdings Inc. | Inhibitors of rotamase enzyme activity |
US5798355A (en) * | 1995-06-07 | 1998-08-25 | Gpi Nil Holdings, Inc. | Inhibitors of rotamase enzyme activity |
US6420522B1 (en) * | 1995-06-05 | 2002-07-16 | Vertex Pharmaceuticals Incorporated | Inhibitors of interleukin-1β converting enzyme |
US6699869B1 (en) | 1995-03-24 | 2004-03-02 | Myriad Genetics Inc. | β-sheet mimetics and use thereof as inhibitors of biologically active peptides or proteins |
US6245764B1 (en) | 1995-03-24 | 2001-06-12 | Molecumetics Ltd. | β-sheet mimetics and use thereof as inhibitors of biologically active peptides or proteins |
US6020331A (en) | 1995-03-24 | 2000-02-01 | Molecumetics, Ltd. | β-sheet mimetics and use thereof as protease inhibitors |
CA2215211A1 (en) * | 1995-03-31 | 1996-10-03 | Takeda Chemical Industries, Ltd. | Cysteine protease inhibitor |
US5859031A (en) * | 1995-06-07 | 1999-01-12 | Gpi Nil Holdings, Inc. | Small molecule inhibitors of rotamase enzyme activity |
US5696135A (en) | 1995-06-07 | 1997-12-09 | Gpi Nil Holdings, Inc. | Inhibitors of rotamase enzyme activity effective at stimulating neuronal growth |
US5744451A (en) * | 1995-09-12 | 1998-04-28 | Warner-Lambert Company | N-substituted glutamic acid derivatives with interleukin-1 β converting enzyme inhibitory activity |
US5801197A (en) * | 1995-10-31 | 1998-09-01 | Gpi Nil Holdings, Inc. | Rotamase enzyme activity inhibitors |
US5843904A (en) * | 1995-12-20 | 1998-12-01 | Vertex Pharmaceuticals, Inc. | Inhibitors of interleukin-1βconverting enzyme |
US5834457A (en) * | 1996-01-26 | 1998-11-10 | The Regents Of The University Of California | Method of modulating radical formation by mutant cuznsod enzymes |
ES2262184T3 (es) * | 1996-08-05 | 2006-11-16 | Myriad Genetics, Inc. | Utilizacion de mimeticos de hojas beta como inhibidores de proteasa y de kinasa o como inhibidores de factores de transcripcion. |
US6117896A (en) | 1997-02-10 | 2000-09-12 | Molecumetics Ltd. | Methods for regulating transcription factors |
EP1661566A3 (en) * | 1996-08-05 | 2008-04-16 | Myriad Genetics, Inc. | Use of beta-sheet mimetics as protease and kinase inhibitors and as inhibitors of transcription factors |
US5869519A (en) * | 1996-12-16 | 1999-02-09 | Idun Pharmaceuticals, Inc. | C-terminal modified (n-substituted)-2-indolyl dipeptides as inhibitors of the ICE/ced-3 family of cysteine proteases |
US5801187A (en) | 1996-09-25 | 1998-09-01 | Gpi-Nil Holdings, Inc. | Heterocyclic esters and amides |
US6218424B1 (en) | 1996-09-25 | 2001-04-17 | Gpi Nil Holdings, Inc. | Heterocyclic ketone and thioester compounds and uses |
US5786378A (en) * | 1996-09-25 | 1998-07-28 | Gpi Nil Holdings, Inc. | Heterocyclic thioesters |
US6194435B1 (en) | 1996-10-11 | 2001-02-27 | Cor Therapeutics, Inc. | Lactams as selective factor Xa inhibitors |
US6316415B1 (en) | 1996-10-11 | 2001-11-13 | Basf Aktiengesellschaft | Sulfonamide interleukin-1β converting enzyme inhibitors |
AU742746B2 (en) * | 1996-10-11 | 2002-01-10 | Abbott Gmbh & Co. Kg | Sulfonamide substituted aspartic acid interleukin-1beta converting enzyme inhibitors |
US6063794A (en) | 1996-10-11 | 2000-05-16 | Cor Therapeutics Inc. | Selective factor Xa inhibitors |
US5919790A (en) * | 1996-10-11 | 1999-07-06 | Warner-Lambert Company | Hydroxamate inhibitors of interleukin-1β converting enzyme |
US6262047B1 (en) | 1996-10-11 | 2001-07-17 | Cor Therapeutics, Inc. | Selective factor Xa inhibitors |
US6369080B2 (en) | 1996-10-11 | 2002-04-09 | Cor Therapeutics, Inc. | Selective factor Xa inhibitors |
CA2268391A1 (en) * | 1996-10-18 | 1998-04-30 | Vertex Pharmaceuticals Incorporated | Inhibitors of serine proteases, particularly hepatitis c virus ns3 protease |
SI0932617T1 (en) * | 1996-10-18 | 2002-06-30 | Vertex Pharmaceuticals Incorporated | Inhibitors of serine proteases, particularly hepatitis c virus ns3 protease |
EP0940400A4 (en) * | 1996-10-25 | 2002-10-02 | Mitsubishi Pharma Corp | NOVEL HETEROCYCLIC AMIDE COMPOUNDS AND THEIR USE FOR MEDICINAL PURPOSES |
WO1998024805A1 (en) * | 1996-12-06 | 1998-06-11 | Vertex Pharmaceuticals Incorporated | INHIBITORS OF INTERLEUKIN-1β CONVERTING ENZYME |
DE69736984T2 (de) | 1996-12-06 | 2007-09-13 | Vertex Pharmaceuticals Inc., Cambridge | Inhibitoren des interleukin-1-beta konvertierenden enzyms |
EP1466921A1 (en) * | 1996-12-06 | 2004-10-13 | Vertex Pharmaceuticals Incorporated | Inhibitors of interleukin-1 beta converting enzyme |
US6184244B1 (en) | 1996-12-16 | 2001-02-06 | Idun Pharmaceuticals, Inc. | C-terminal modified (N-substituted)-2-indolyl dipeptides as inhibitors of the ICE/ced-3 family of cysteine proteases |
US5877197A (en) * | 1996-12-16 | 1999-03-02 | Karanewsky; Donald S. | C-terminal modified (N-substituted)-2-indolyl dipeptides as inhibitors of the ICE/ced-3 family of cysteine proteases |
US5846979A (en) | 1997-02-28 | 1998-12-08 | Gpi Nil Holdings, Inc. | N-oxides of heterocyclic esters, amides, thioesters, and ketones |
US6054487A (en) * | 1997-03-18 | 2000-04-25 | Basf Aktiengesellschaft | Methods and compositions for modulating responsiveness to corticosteroids |
WO1998046626A1 (en) | 1997-04-14 | 1998-10-22 | Cor Therapeutics, Inc. | SELECTIVE FACTOR Xa INHIBITORS |
JP2001521524A (ja) * | 1997-04-14 | 2001-11-06 | シーオーアール セラピューティクス インコーポレイテッド | 選択的Xa因子阻害剤 |
CA2285659A1 (en) | 1997-04-14 | 1998-10-22 | Cor Therapeutics, Inc. | Selective factor xa inhibitors |
HUP9700816A3 (en) * | 1997-04-28 | 1999-06-28 | Gyogyszerkutato Intezet | 3(r)-3-amino-4-carboxy-butiraldehyde derivatives inhibiting release of interleukin-1-beta |
FR2766188B1 (fr) * | 1997-07-15 | 2000-02-11 | Hoechst Marion Roussel Inc | Nouveau procede de preparation de derives amines d'alkyloxy furanone, composes issus de ce procede et utilisation de ces composes |
US6228854B1 (en) | 1997-08-11 | 2001-05-08 | Cor Therapeutics, Inc. | Selective factor Xa inhibitors |
US6218382B1 (en) | 1997-08-11 | 2001-04-17 | Cor Therapeutics, Inc | Selective factor Xa inhibitors |
US6333321B1 (en) | 1997-08-11 | 2001-12-25 | Cor Therapeutics, Inc. | Selective factor Xa inhibitors |
US6645939B1 (en) | 1997-11-24 | 2003-11-11 | Merck & Co., Inc. | Substituted β-alanine derivatives as cell adhesion inhibitors |
ES2221227T3 (es) * | 1997-11-24 | 2004-12-16 | MERCK & CO., INC. | Derivados sustituidos de beta-alanina como inhibidores de la adhesion celular. |
JP4524039B2 (ja) * | 1997-12-18 | 2010-08-11 | ベーリンガー インゲルハイム ファーマシューティカルズ インコーポレイテッド | Srcファミリーsh2ドメインインヒビターとしてのピリドン |
WO1999046248A1 (en) | 1998-03-09 | 1999-09-16 | Vertex Pharmaceuticals Incorporated | 1,2-diazepane derivatives as interleukin-1beta converting enzyme inhibitors |
AP2000001919A0 (en) | 1998-03-19 | 2000-09-30 | Vertex Pharma | Inhibitors of caspases. |
GB9809664D0 (en) * | 1998-05-06 | 1998-07-01 | Hoffmann La Roche | a-Ketoamide derivatives |
US6384056B1 (en) | 1998-08-14 | 2002-05-07 | Gpi Nil Holdings, Inc. | Heterocyclic thioesters or ketones for vision and memory disorders |
US6376517B1 (en) | 1998-08-14 | 2002-04-23 | Gpi Nil Holdings, Inc. | Pipecolic acid derivatives for vision and memory disorders |
US6395758B1 (en) | 1998-08-14 | 2002-05-28 | Gpi Nil Holdings, Inc. | Small molecule carbamates or ureas for vision and memory disorders |
US6506788B1 (en) | 1998-08-14 | 2003-01-14 | Gpi Nil Holdings, Inc. | N-linked urea or carbamate of heterocyclic thioesters for vision and memory disorders |
US6333340B1 (en) | 1998-08-14 | 2001-12-25 | Gpi Nil Holdings, Inc. | Small molecule sulfonamides for vision and memory disorders |
US6335348B1 (en) | 1998-08-14 | 2002-01-01 | Gpi Nil Holdings, Inc. | Nitrogen-containing linear and azepinyl/ compositions and uses for vision and memory disorders |
US6399648B1 (en) | 1998-08-14 | 2002-06-04 | Gpi Nil Holdings, Inc. | N-oxides of heterocyclic ester, amide, thioester, or ketone for vision and memory disorders |
US6339101B1 (en) | 1998-08-14 | 2002-01-15 | Gpi Nil Holdings, Inc. | N-linked sulfonamides of N-heterocyclic carboxylic acids or isosteres for vision and memory disorders |
US6218423B1 (en) | 1998-08-14 | 2001-04-17 | Gpi Nil Holdings, Inc. | Pyrrolidine derivatives for vision and memory disorders |
US7338976B1 (en) | 1998-08-14 | 2008-03-04 | Gpi Nil Holdings, Inc. | Heterocyclic esters or amides for vision and memory disorders |
US6337340B1 (en) | 1998-08-14 | 2002-01-08 | Gpi Nil Holdings, Inc. | Carboxylic acids and isosteres of heterocyclic ring compounds having multiple heteroatoms for vision and memory disorders |
US6177565B1 (en) * | 1998-08-19 | 2001-01-23 | Vertex Pharmaceuticals Inc. | Process for synthesizing piperazic acid |
US6559304B1 (en) | 1998-08-19 | 2003-05-06 | Vertex Pharmaceuticals Incorporated | Method for synthesizing caspase inhibitors |
US6201118B1 (en) | 1998-08-19 | 2001-03-13 | Vertex Pharmaceuticals Inc. | Process for forming an N-acylated, N,N-containing bicyclic ring from piperazic acid or an ester thereof especially useful as an intermediate in the manufacture of a caspase inhibitor |
US6462072B1 (en) | 1998-09-21 | 2002-10-08 | Gpi Nil Holdings, Inc. | Cyclic ester or amide derivatives |
JP2003524603A (ja) * | 1998-10-06 | 2003-08-19 | スミスクライン・ビーチャム・コーポレイション | カスパーゼおよびアポトーシス |
JP2002531464A (ja) | 1998-12-02 | 2002-09-24 | メルク フロスト カナダ アンド カンパニー | カスパーゼ−3阻害薬としてのγ−ケト酸テトラペプチド類 |
WO2000051998A1 (en) | 1999-03-02 | 2000-09-08 | Boehringer Ingelheim Pharmaceuticals, Inc. | Compounds useful as reversible inhibitors of cathepsin s |
TW200404789A (en) * | 1999-03-15 | 2004-04-01 | Axys Pharm Inc | Novel compounds and compositions as protease inhibitors |
US6724942B1 (en) | 1999-05-24 | 2004-04-20 | Fuji Photo Film Co., Ltd. | Image processing method and system |
EP1202976B1 (en) * | 1999-07-19 | 2006-11-02 | Merck Frosst Canada Ltd. | Pyrazinones, compositions containing such compounds |
US6420364B1 (en) | 1999-09-13 | 2002-07-16 | Boehringer Ingelheim Pharmaceuticals, Inc. | Compound useful as reversible inhibitors of cysteine proteases |
US6417189B1 (en) | 1999-11-12 | 2002-07-09 | Gpi Nil Holdings, Inc. | AZA compounds, pharmaceutical compositions and methods of use |
US7253169B2 (en) | 1999-11-12 | 2007-08-07 | Gliamed, Inc. | Aza compounds, pharmaceutical compositions and methods of use |
US6358928B1 (en) | 1999-11-22 | 2002-03-19 | Enzyme Systems Products | Peptidyl sulfonyl imidazolides as selective inhibitors of serine proteases |
EP1289966A1 (en) | 2000-04-11 | 2003-03-12 | Bristol-Myers Squibb Pharma Company | SUBSTITUTED LACTAMS AS INHIBITORS OF A$g(b) PROTEIN PRODUCTION |
EP1282435A2 (en) * | 2000-05-12 | 2003-02-12 | Immunex Corporation | Interleukin-1 inhibitors in the treatment of diseases |
PE20011350A1 (es) | 2000-05-19 | 2002-01-15 | Vertex Pharma | PROFARMACO DE UN INHIBIDOR DE ENZIMA CONVERTIDORA DE INTERLEUCINA-1ß (ICE) |
CN1386118A (zh) | 2000-06-01 | 2002-12-18 | 布里斯托尔-迈尔斯斯奎布药品公司 | 作为Aβ蛋白产生抑制剂的被环状琥珀酸酯取代的内酰胺类化合物 |
EP1289993B9 (en) | 2000-06-07 | 2008-08-20 | Vertex Pharmaceuticals Incorporated | Caspase inhibitors and uses thereof |
SV2003000617A (es) * | 2000-08-31 | 2003-01-13 | Lilly Co Eli | Inhibidores de la proteasa peptidomimetica ref. x-14912m |
NZ526420A (en) * | 2000-11-21 | 2005-08-26 | Vertex Pharma | Imidazole and benzimidazole caspase inhibitors and uses thereof |
AU2002230763A1 (en) * | 2000-12-13 | 2008-01-03 | Bristol-Myers Squibb Pharma Company | Inhibitors of hepatitis c virus ns3 protease |
US6653295B2 (en) | 2000-12-13 | 2003-11-25 | Bristol-Myers Squibb Company | Inhibitors of hepatitis C virus NS3 protease |
AUPR215700A0 (en) * | 2000-12-19 | 2001-01-25 | Fujisawa Pharmaceutical Co., Ltd. | Carboxylic acid compound having cyclopropane ring |
US20050192228A1 (en) * | 2001-02-05 | 2005-09-01 | Jean Rapin | Tripeptide derivatives for the treatment of neurodegenerative diseases |
DE10105038B4 (de) * | 2001-02-05 | 2005-07-07 | Neurotell Ag | Tripeptid-Derivate für die Behandlung von postläsionalen Krankheiten des Nervensystems |
DE10105041A1 (de) * | 2001-02-05 | 2002-08-14 | Tell Pharm Ag Hergiswil | Tripeptide und Tripeptid-Derivate für die Behandlung neurodegenerativer Krankheiten |
DE10105040A1 (de) * | 2001-02-05 | 2002-08-14 | Tell Pharm Ag Hergiswil | Tripeptid-Derivate für die Behandlung von postläsionalen Krankheiten des Nervensystems |
DE10105039A1 (de) * | 2001-02-05 | 2002-08-08 | Tell Pharm Ag Hergiswil | Tripeptid-Derivate für die Behandlung neurodegenerativer Krankheiten |
EP1395560A1 (en) * | 2001-05-23 | 2004-03-10 | Ucb, S.A. | 2-oxo-piperidinyl- and 2-oxo-azepanyl alkanoic acid derivativ es for the treatment of epilepsy and other neurological disorders |
GB0129260D0 (en) * | 2001-12-06 | 2002-01-23 | Eisai London Res Lab Ltd | Pharmaceutical compositions and their uses |
JP2005170790A (ja) * | 2002-01-09 | 2005-06-30 | Ajinomoto Co Inc | N−アルキルスルフォニル置換アミド誘導体 |
AU2003211052A1 (en) * | 2002-02-11 | 2003-09-04 | Vertex Pharmaceuticals Incorporated | Phospholipids as caspase inhibitor prodrugs |
CA2476113A1 (en) | 2002-02-14 | 2003-08-21 | Myriad Genetics, Inc. | Beta-sheet mimetics and composition and methods relating thereto |
KR100852649B1 (ko) * | 2002-04-22 | 2008-08-18 | 유니버시티 오브 메릴랜드, 볼티모어 카운티 | 캡시드 단백질의 항바이러스 억제 |
US7001899B2 (en) * | 2002-06-10 | 2006-02-21 | The Procter & Gamble Company | Interleukin converting enzyme inhibitors |
US7138395B2 (en) * | 2002-06-10 | 2006-11-21 | The Procter & Gamble Company | Interleukin-1β converting enzyme inhibitors |
EP1523483A4 (en) | 2002-06-26 | 2006-03-08 | Bristol Myers Squibb Co | AMINO-BICYCLIC PYRAZINONE AND PYRIDINONE FOR INHIBITING THE COOKING OF SERIN PROTEASE |
WO2004002406A2 (en) * | 2002-06-26 | 2004-01-08 | Bristol-Myers Squibb Company | Bicyclic pyrimidinones as coagulation cascade inhibitors |
CN100503572C (zh) | 2002-06-28 | 2009-06-24 | 沃泰克斯药物股份有限公司 | 天冬氨酸特异性半胱氨酸蛋白酶抑制剂及其用途 |
US7612091B2 (en) * | 2002-12-20 | 2009-11-03 | Vertex Pharmaceuticals Incorporated | Caspase inhibitors and uses thereof |
PE20050159A1 (es) * | 2003-05-27 | 2005-04-19 | Vertex Pharma | Derivados de acido 3-[2-(3-amino-2-oxo-2h-piridin-1-il)-acetilamino]-4-oxo-pentanoico como inhibidores de caspasa |
MY148123A (en) | 2003-09-05 | 2013-02-28 | Vertex Pharma | Inhibitors of serine proteases, particularly hcv ns3-ns4a protease |
CA2820541A1 (en) * | 2004-02-27 | 2005-09-15 | Vertex Pharmaceuticals Incorporated | Caspase inhibitors and uses thereof |
US7652153B2 (en) * | 2004-02-27 | 2010-01-26 | Vertex Pharmaceuticals Incorporated | Caspase inhibitors and uses thereof |
AU2011226946B2 (en) * | 2004-02-27 | 2012-05-03 | Vertex Pharmaceuticals Incoporated | Caspase Inhibitors and Uses Thereof |
SG150546A1 (en) * | 2004-03-12 | 2009-03-30 | Vertex Pharma | Processes and intermediates |
NZ588448A (en) | 2004-05-15 | 2012-01-12 | Vertex Pharma | Treating seizures using interleukin-1beta converting enzyme (ICE) inhibitors |
GB0411056D0 (en) | 2004-05-18 | 2004-06-23 | Novartis Ag | Organic compounds |
CA2567080A1 (en) | 2004-05-27 | 2005-12-15 | Vertex Pharmaceuticals Incorporated | Ice inhibitors for the treatment of autoinflammatory diseases |
CN101098855B (zh) * | 2004-11-24 | 2012-06-06 | 沃泰克斯药物股份有限公司 | 3-[2-(3-酰氨基-2-氧代-2h-吡啶-1-基)-乙酰氨基]-4-氧代-戊酸衍生物及其作为天冬氨酸特异性半胱氨酸蛋白酶抑制剂的用途 |
WO2006126730A1 (ja) * | 2005-05-26 | 2006-11-30 | Ajinomoto Co., Inc. | 二環式ピリミジン化合物及びその製造方法 |
CN101268084A (zh) | 2005-07-28 | 2008-09-17 | 沃泰克斯药物股份有限公司 | 天冬氨酸特异性半胱氨酸蛋白酶抑制剂前体药物 |
MX2008001528A (es) * | 2005-08-02 | 2008-04-04 | Vertex Pharma | Inhibidores de serina proteasas. |
US7964624B1 (en) * | 2005-08-26 | 2011-06-21 | Vertex Pharmaceuticals Incorporated | Inhibitors of serine proteases |
AR055395A1 (es) * | 2005-08-26 | 2007-08-22 | Vertex Pharma | Compuestos inhibidores de la actividad de la serina proteasa ns3-ns4a del virus de la hepatitis c |
EP1991229A2 (en) | 2006-02-27 | 2008-11-19 | Vertex Pharmaceuticals Incorporated | Co-crystals and pharmaceutical compositions comprising the same |
BRPI0709567A2 (pt) * | 2006-03-16 | 2011-07-12 | Vertex Pharma | inibidores deuterados de protease de hepatite c |
AU2008219704A1 (en) * | 2007-02-27 | 2008-09-04 | Vertex Pharmaceuticals Incorporated | Inhibitors of serine proteases |
EP2463285A1 (en) * | 2007-02-27 | 2012-06-13 | Vertex Pharmaceuticals Inc. | Co-crystals and pharmaceutical compositions comprising the same |
MX2010002407A (es) * | 2007-08-30 | 2010-03-26 | Vertex Pharma | Cocristales y composiciones farmaceuticas que los comprenden. |
TW200920355A (en) * | 2007-09-06 | 2009-05-16 | Lexicon Pharmaceuticals Inc | Compositions and methods for treating immunological and inflammatory diseases and disorders |
ES2700613T3 (es) * | 2008-07-16 | 2019-02-18 | Bitop Ag | Síntesis de amidinas cíclicas |
EP2635907A4 (en) | 2010-11-05 | 2014-04-16 | Univ Brandeis | ALPHA-SYNUCLEINE CLIVED ICE AS A BIOLOGICAL MARKER |
HU1000676D0 (en) | 2010-12-17 | 2011-02-28 | Pharmahungary 2000 Kft | Inhibitors of matrix metalloproteinase, pharmaceutical compositions thereof and use of them for preventing and treating diseases where the activation of mmp is involved |
US9956260B1 (en) | 2011-07-22 | 2018-05-01 | The J. David Gladstone Institutes | Treatment of HIV-1 infection and AIDS |
ES2779748T3 (es) * | 2012-08-23 | 2020-08-19 | Janssen Biopharma Inc | Compuestos para el tratamiento de infecciones víricas por paramixovirus |
TWI770525B (zh) | 2014-12-30 | 2022-07-11 | 美商瓦洛健康公司 | 作為泛素特異性蛋白酶7抑制劑之吡咯并及吡唑并嘧啶 |
MA41291A (fr) | 2014-12-30 | 2017-11-07 | Forma Therapeutics Inc | Dérivés de la pyrrolotriazinone et de l'imidazotriazinone en tant qu'inhibiteurs de la protéase spécifique de l'ubiquitine n° 7 (usp7) pour le traitement d'un cancer |
JP2018504432A (ja) | 2015-02-05 | 2018-02-15 | フォーマ セラピューティクス,インコーポレイテッド | ユビキチン特異的プロテアーゼ7阻害物質としてのイソチアゾロピリミジノン、ピラゾロピリミジノン及びピロロピリミジノン |
JP2018504430A (ja) | 2015-02-05 | 2018-02-15 | フォーマ セラピューティクス,インコーポレイテッド | ユビキチン特異的プロテアーゼ7阻害物質としてのキナゾリノン及びアザキナゾリノン |
US9932351B2 (en) | 2015-02-05 | 2018-04-03 | Forma Therapeutics, Inc. | Thienopyrimidinones as ubiquitin-specific protease 7 inhibitors |
KR20230038457A (ko) | 2020-06-10 | 2023-03-20 | 알리고스 테라퓨틱스 인코포레이티드 | 코로나바이러스, 피코르나바이러스 및 노로바이러스 감염을 치료하기 위한 항바이러스 화합물 |
IL309732A (en) | 2021-07-09 | 2024-02-01 | Aligos Therapeutics Inc | Antiviral compounds |
Family Cites Families (50)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4276298A (en) * | 1978-03-24 | 1981-06-30 | Merck & Co., Inc. | 2-Aryl-1,2-benzisothiazolinone-1,1-dioxides and their use as selective protease inhibitors |
US4369183A (en) * | 1979-09-06 | 1983-01-18 | Merck & Co., Inc. | 2-Pyridyl-1,2-benzisothiazolinone-1,1-dioxides and their use as selective protease inhibitors |
US4584397A (en) * | 1983-05-09 | 1986-04-22 | G. D. Searle & Co. | Protease inhibitors |
US4499295A (en) * | 1983-05-09 | 1985-02-12 | G. D. Searle & Co. | Protease inhibitors |
US4551279A (en) * | 1984-01-09 | 1985-11-05 | G. D. Searle & Co. | Protease inhibitors |
US5055451A (en) * | 1986-12-22 | 1991-10-08 | Syntex Inc. | Aryloxy and arylacyloxy methyl ketones as thiol protease inhibitors |
US5158936A (en) * | 1986-12-22 | 1992-10-27 | Syntex (U.S.A.) Inc. | Aryloxy and arylacyloxy methyl ketones as thiol protease inhibitors |
NZ223148A (en) * | 1987-01-16 | 1989-10-27 | Merrell Dow Pharma | Peptide derivatives having peptidase inhibition activity |
US5081228A (en) * | 1988-02-25 | 1992-01-14 | Immunex Corporation | Interleukin-1 receptors |
WO1989004838A1 (en) * | 1987-11-25 | 1989-06-01 | Immunex Corporation | Interleukin-1 receptors |
US4968607A (en) * | 1987-11-25 | 1990-11-06 | Immunex Corporation | Interleukin-1 receptors |
US5008245A (en) * | 1988-10-27 | 1991-04-16 | University Of Kentucky Research Foundation | Novel peptidyl carbamate inhibitors of the enzyme elastase |
CA2021660A1 (en) * | 1989-07-26 | 1991-01-27 | Philippe Bey | Peptidase inhibitors |
NZ235155A (en) * | 1989-09-11 | 1993-04-28 | Merrell Dow Pharma | Peptidase substrates in which the carboxy terminal group has been replaced by a tricarbonyl radical |
US5416013A (en) * | 1990-04-04 | 1995-05-16 | Sterling Winthrop Inc. | Interleukin 1β protease and interleukin 1β protease inhibitors |
WO1991015577A1 (en) * | 1990-04-04 | 1991-10-17 | Black, Roy, A. | INTERLEUKIN 1'beta' PROTEASE |
IL99527A (en) * | 1990-09-28 | 1997-08-14 | Lilly Co Eli | Tripeptide antithrombotic agents |
EP0504938A3 (en) * | 1991-03-22 | 1993-04-14 | Suntory Limited | Prophylactic and therapeutic agent for bone diseases comprising di- or tripeptide derivative as active ingredient |
EP0519748B1 (en) * | 1991-06-21 | 1998-09-02 | Merck & Co. Inc. | Peptidyl derivatives as inhibitors of interleukin-1B converting enzyme |
JP3190431B2 (ja) * | 1991-07-01 | 2001-07-23 | 三菱化学株式会社 | ケトン誘導体 |
EP0533226A3 (en) * | 1991-08-16 | 1993-08-18 | Merck & Co. Inc. | Novel chromophore containing compounds |
US5278061A (en) * | 1991-08-16 | 1994-01-11 | Merck & Co., Inc. | Affinity chromatography matrix useful in purifying interleukin-1β converting enzyme |
US6348570B1 (en) * | 1991-08-16 | 2002-02-19 | Merck & Co., Inc. | Chromophore containing compounds and their use in determining interleukin-1β convertase activity |
EP0533350B1 (en) * | 1991-08-16 | 1999-05-26 | Merck & Co. Inc. | DNA encoding precursor interleukin 1B converting enzyme |
DK0600880T3 (da) * | 1991-08-30 | 2004-04-13 | Vertex Pharma | Interleukin 1-beta-protease og interleukin 1-beta-proteasehæmmere |
GB9123326D0 (en) * | 1991-11-04 | 1991-12-18 | Sandoz Ltd | Improvements in or relating to organic compounds |
EP0547699A1 (en) * | 1991-12-19 | 1993-06-23 | Merck & Co. Inc. | Peptidyl derivatives as inhibitors of interleukin-1B converting enzyme |
AU3479593A (en) * | 1992-01-31 | 1993-09-01 | Merck & Co., Inc. | Peptidyl derivatives as inhibitors of interleukin-1beta converting enzyme |
EP0627926B1 (en) * | 1992-02-21 | 1998-08-05 | Merck & Co., Inc. (a New Jersey corp.) | PEPTIDYL DERIVATIVES AS INHIBITORS OF INTERLEUKIN-1$g(b) CONVERTING ENZYME |
WO1993025683A1 (en) * | 1992-06-12 | 1993-12-23 | Massachusetts Institute Of Technology | A gene which prevents programmed cell death |
JPH08500482A (ja) * | 1992-06-12 | 1996-01-23 | マサチューセッツ インスティテュート オブ テクノロジー | Ced−3及び関連蛋白質のインヒビター |
WO1993025685A1 (en) * | 1992-06-12 | 1993-12-23 | Massachusetts Institute Of Technology | Cloning and characterization of the cell death genes ced-3 and ced-4 |
JPH08500242A (ja) * | 1992-06-24 | 1996-01-16 | メルク エンド カンパニー インコーポレーテッド | インターロイキン1β前駆体の転換酵素をコードするDNA |
WO1994003480A1 (en) * | 1992-07-31 | 1994-02-17 | Pfizer Inc. | Peptidyl 4-amino-2,2-difluoro-3-oxo-1,6-hexanedioic acid derivatives as antiinflammatory agents |
US5374623A (en) * | 1992-08-20 | 1994-12-20 | Prototek, Inc. | Cysteine protease inhibitors effective for in vivo use |
CA2109646C (en) * | 1992-11-24 | 2000-03-07 | Gaston O. Daumy | Para-nitroanilide peptides |
EP0618223A3 (en) * | 1993-03-08 | 1996-06-12 | Sandoz Ltd | Peptides, the release of Interleukin 1-Bêta, useful as anti-inflammatory agents. |
TW494094B (en) * | 1993-04-29 | 2002-07-11 | Vertex Pharma | Peptide analogs as irreversible interleukin-1β protease inhibitors and pharmaceutical compositions comprising the same |
US5462939A (en) * | 1993-05-07 | 1995-10-31 | Sterling Winthrop Inc. | Peptidic ketones as interleukin-1β-converting enzyme inhibitors |
US5411985A (en) * | 1993-05-17 | 1995-05-02 | Merck & Co., Inc. | Gamma-pyrone-3-acetic acid as an inhibitor or interleukin-1 β inventory enzyme |
JPH0789951A (ja) * | 1993-06-03 | 1995-04-04 | Sterling Winthrop Inc | インターロイキン−1β転換酵素阻害剤 |
ES2122145T3 (es) * | 1993-06-04 | 1998-12-16 | Vertex Pharma | Fosfiniloximetil-cetonas peptidicas como inhibidores de la enzima convertida de la interleuquina-1 beta. |
DE69408598T2 (de) * | 1993-06-08 | 1998-09-17 | Vertex Pharmaceuticals Inc Cam | Pyridazine als Interleukin-1-beta Verwandlungsenzym Inhibitoren |
WO1995000160A1 (en) * | 1993-06-24 | 1995-01-05 | The General Hospital Corporation | Programmed cell death genes and proteins |
AU7714594A (en) * | 1993-08-13 | 1995-03-14 | Merck & Co., Inc. | Substituted ketone derivatives as inhibitors of interleukin-1beta converting enzyme |
US5486623A (en) * | 1993-12-08 | 1996-01-23 | Prototek, Inc. | Cysteine protease inhibitors containing heterocyclic leaving groups |
CN1118458C (zh) * | 1994-03-31 | 2003-08-20 | 弗特克斯药品有限公司 | 作为白细胞介素抑制剂的嘧啶基衍生物 |
US5552400A (en) * | 1994-06-08 | 1996-09-03 | Sterling Winthrop Inc. | Fused-bicyclic lactams as interleukin-1β converting enzyme inhibitors |
US5565430A (en) * | 1994-08-02 | 1996-10-15 | Sterling Winthrop Inc. | Azaaspartic acid analogs as interleukin-1β converting enzyme inhibitors |
US5498616A (en) * | 1994-11-04 | 1996-03-12 | Cephalon, Inc. | Cysteine protease and serine protease inhibitors |
-
1995
- 1995-06-05 US US08/464,964 patent/US5716929A/en not_active Expired - Lifetime
- 1995-06-06 IL IL11401595A patent/IL114015A0/xx not_active IP Right Cessation
- 1995-06-09 TW TW084105903A patent/TW509698B/zh not_active IP Right Cessation
- 1995-06-16 BR BR9508051A patent/BR9508051A/pt not_active Application Discontinuation
- 1995-06-16 PL PL95318220A patent/PL185693B1/pl not_active IP Right Cessation
- 1995-06-16 NZ NZ289560A patent/NZ289560A/en not_active IP Right Cessation
- 1995-06-16 MX MX9606546A patent/MX9606546A/es not_active IP Right Cessation
- 1995-06-16 AU AU29446/95A patent/AU709114B2/en not_active Ceased
- 1995-06-16 CN CNB951943812A patent/CN1192035C/zh not_active Expired - Fee Related
- 1995-06-16 EP EP95925257A patent/EP0784628A1/en not_active Withdrawn
- 1995-06-16 MA MA23932A patent/MA24511A1/fr unknown
- 1995-06-16 WO PCT/US1995/007617 patent/WO1995035308A1/en active IP Right Grant
- 1995-06-16 CZ CZ0369896A patent/CZ298625B6/cs not_active IP Right Cessation
- 1995-06-16 CA CA002192089A patent/CA2192089C/en not_active Expired - Fee Related
- 1995-06-16 GE GEAP19953528A patent/GEP20012446B/en unknown
- 1995-06-16 JP JP50247896A patent/JP4190029B2/ja not_active Expired - Lifetime
- 1995-06-16 SK SK1609-96A patent/SK287422B6/sk not_active IP Right Cessation
- 1995-06-16 HU HU9603475A patent/HUT76622A/hu not_active Application Discontinuation
- 1995-06-16 AP APAP/P/1997/000960A patent/AP797A/en active
-
1996
- 1996-12-16 FI FI965036A patent/FI965036A/fi not_active Application Discontinuation
- 1996-12-17 IS IS4399A patent/IS4399A/is unknown
-
1997
- 1997-01-14 BG BG101130A patent/BG63634B1/bg unknown
- 1997-03-28 US US08/828,941 patent/US5973111A/en not_active Expired - Lifetime
Also Published As
Publication number | Publication date |
---|---|
US5973111A (en) | 1999-10-26 |
JPH10504285A (ja) | 1998-04-28 |
PL318220A1 (en) | 1997-05-26 |
NZ289560A (en) | 1999-09-29 |
CN1159196A (zh) | 1997-09-10 |
CZ369896A3 (en) | 1997-06-11 |
IL114015A0 (en) | 1995-10-31 |
AP797A (en) | 2000-01-07 |
BG101130A (en) | 1997-08-29 |
TW509698B (en) | 2002-11-11 |
EP0784628A1 (en) | 1997-07-23 |
IS4399A (is) | 1996-12-17 |
GEP20012446B (en) | 2001-05-25 |
AU709114B2 (en) | 1999-08-19 |
US5716929A (en) | 1998-02-10 |
CZ298625B6 (cs) | 2007-11-28 |
PL185693B1 (pl) | 2003-07-31 |
MX9606546A (es) | 1997-03-29 |
HUT76622A (en) | 1997-10-28 |
BG63634B1 (bg) | 2002-07-31 |
FI965036A (fi) | 1997-02-14 |
BR9508051A (pt) | 1997-10-21 |
JP4190029B2 (ja) | 2008-12-03 |
AP9700960A0 (en) | 1997-04-30 |
SK287422B6 (sk) | 2010-09-07 |
FI965036A0 (fi) | 1996-12-16 |
WO1995035308A1 (en) | 1995-12-28 |
AU2944695A (en) | 1996-01-15 |
MA24511A1 (fr) | 1998-12-31 |
CA2192089A1 (en) | 1995-12-28 |
CA2192089C (en) | 2010-01-12 |
SK160996A3 (en) | 1997-09-10 |
HU9603475D0 (en) | 1997-02-28 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
CN1192035C (zh) | 白介素-1β转化酶抑制剂 | |
CN1195778C (zh) | 细胞粘附抑制剂 | |
KR100478323B1 (ko) | 인터류킨-1베타 전환 효소 억제제 | |
CN1225471C (zh) | 具有生长激素释放特性的化合物 | |
US7772366B2 (en) | Inhibitors of interleukin-1β converting enzyme | |
CN1253441C (zh) | 蛋白酶抑制剂 | |
CN1146575C (zh) | 用于治疗与凝血酶有关的疾病的肽基杂环化合物 | |
CN1041950A (zh) | 新型肽酶抑制剂 | |
CN101076516A (zh) | 作为丙型肝炎病毒ns3丝氨酸蛋白酶抑制剂的硫化合物 | |
CN1238779A (zh) | 抑制β-淀粉样肽释放和/或其合成的方法和化合物 | |
CN1950393A (zh) | 丙型肝炎病毒ns3蛋白酶的抑制剂 | |
CN1229412A (zh) | 白细胞介素-1β转化酶抑制剂 | |
CN1894274A (zh) | 丙肝病毒ns3丝氨酸蛋白酶的大环抑制剂 | |
CN1084849A (zh) | 双重作用抑制剂 | |
CN1946718A (zh) | 用作丙型肝炎病毒ns3丝氨酸蛋白酶抑制剂的具有环p4′s的新型酮酰胺 | |
CN1946691A (zh) | 作为丙型肝炎病毒ns3丝氨酸蛋白酶抑制剂的化合物 | |
CN1313855A (zh) | α4β1介导的细胞粘着抑制剂 | |
CN1500781A (zh) | 白介素-1β转化酶的抑制剂 | |
CN1313863A (zh) | 尿激酶和血管形成的抑制剂 | |
CN1353701A (zh) | 用作类胰蛋白酶抑制剂的肽基杂环酮类化合物 | |
CN101029080A (zh) | 用于对iap抑制卡斯蛋白酶进行去阻遏的方法及组合物 | |
CN1058019C (zh) | 环状氨基酸衍生物 | |
CN1491942A (zh) | N-[n-n-(4-(哌啶-4-基)丁酰基)-n-乙基甘氨酰基]化合物的不吸湿的稳定结晶形式 | |
CN1047084A (zh) | 具有酶抑制作用的二肽衍生物 | |
CN1289341A (zh) | 凝血酶抑制剂 |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
C06 | Publication | ||
PB01 | Publication | ||
C10 | Entry into substantive examination | ||
SE01 | Entry into force of request for substantive examination | ||
C14 | Grant of patent or utility model | ||
GR01 | Patent grant | ||
C17 | Cessation of patent right | ||
CF01 | Termination of patent right due to non-payment of annual fee |
Granted publication date: 20050309 Termination date: 20130616 |