CN1209123A - 新的巴比妥酸类衍生物,其制备方法以及含有该类化合物的药物制剂 - Google Patents
新的巴比妥酸类衍生物,其制备方法以及含有该类化合物的药物制剂 Download PDFInfo
- Publication number
- CN1209123A CN1209123A CN96180027A CN96180027A CN1209123A CN 1209123 A CN1209123 A CN 1209123A CN 96180027 A CN96180027 A CN 96180027A CN 96180027 A CN96180027 A CN 96180027A CN 1209123 A CN1209123 A CN 1209123A
- Authority
- CN
- China
- Prior art keywords
- phenyl
- group
- alkyl
- barbituric acid
- 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.)
- Granted
Links
- 238000000034 method Methods 0.000 title claims description 36
- 150000007656 barbituric acids Chemical class 0.000 title description 4
- 230000008569 process Effects 0.000 title description 2
- 239000008177 pharmaceutical agent Substances 0.000 title 1
- 150000001875 compounds Chemical class 0.000 claims abstract description 66
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 36
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims abstract description 23
- 229910052760 oxygen Inorganic materials 0.000 claims abstract description 23
- 239000001301 oxygen Substances 0.000 claims abstract description 21
- 125000002252 acyl group Chemical group 0.000 claims abstract description 20
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 18
- 125000005842 heteroatom Chemical group 0.000 claims abstract description 17
- 239000001257 hydrogen Substances 0.000 claims abstract description 17
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims abstract description 12
- 125000004390 alkyl sulfonyl group Chemical group 0.000 claims abstract description 12
- 239000005864 Sulphur Substances 0.000 claims abstract description 11
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims abstract description 10
- 125000004453 alkoxycarbonyl group Chemical group 0.000 claims abstract description 10
- 125000004457 alkyl amino carbonyl group Chemical group 0.000 claims abstract description 8
- 125000004682 aminothiocarbonyl group Chemical group NC(=S)* 0.000 claims abstract description 8
- 125000004433 nitrogen atom Chemical group N* 0.000 claims abstract description 8
- 125000003342 alkenyl group Chemical group 0.000 claims abstract description 5
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims abstract description 5
- 125000004648 C2-C8 alkenyl group Chemical group 0.000 claims abstract description 3
- 125000004432 carbon atom Chemical group C* 0.000 claims abstract description 3
- -1 aminocarboxyl Chemical group 0.000 claims description 140
- 238000002360 preparation method Methods 0.000 claims description 64
- 125000004193 piperazinyl group Chemical group 0.000 claims description 40
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 38
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 38
- 238000006243 chemical reaction Methods 0.000 claims description 32
- 150000003839 salts Chemical class 0.000 claims description 22
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 19
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 19
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 18
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 claims description 17
- 125000005936 piperidyl group Chemical group 0.000 claims description 17
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 17
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 16
- 229910052794 bromium Inorganic materials 0.000 claims description 16
- 125000003545 alkoxy group Chemical group 0.000 claims description 15
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 14
- 125000003118 aryl group Chemical group 0.000 claims description 13
- 229910052736 halogen Inorganic materials 0.000 claims description 12
- 150000002367 halogens Chemical class 0.000 claims description 12
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 12
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 12
- 150000003053 piperidines Chemical class 0.000 claims description 12
- 229910052757 nitrogen Inorganic materials 0.000 claims description 11
- 125000003282 alkyl amino group Chemical group 0.000 claims description 10
- 125000003368 amide group Chemical group 0.000 claims description 9
- 125000004391 aryl sulfonyl group Chemical group 0.000 claims description 8
- 229910052799 carbon Inorganic materials 0.000 claims description 8
- 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 claims description 7
- 125000002347 octyl 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])[H] 0.000 claims description 7
- 125000004001 thioalkyl group Chemical group 0.000 claims description 7
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 6
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 6
- 239000000460 chlorine Substances 0.000 claims description 6
- 229910052801 chlorine Inorganic materials 0.000 claims description 6
- 125000005956 isoquinolyl group Chemical group 0.000 claims description 6
- XYFCBTPGUUZFHI-UHFFFAOYSA-N Phosphine Natural products P XYFCBTPGUUZFHI-UHFFFAOYSA-N 0.000 claims description 5
- 150000001721 carbon Chemical group 0.000 claims description 5
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 5
- 150000002431 hydrogen Chemical class 0.000 claims description 5
- 125000001624 naphthyl group Chemical group 0.000 claims description 5
- 125000004076 pyridyl group Chemical group 0.000 claims description 5
- 229920006395 saturated elastomer Polymers 0.000 claims description 5
- 125000004414 alkyl thio group Chemical group 0.000 claims description 4
- 125000005161 aryl oxy carbonyl group Chemical group 0.000 claims description 4
- 125000001072 heteroaryl group Chemical group 0.000 claims description 4
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 4
- 125000002883 imidazolyl group Chemical group 0.000 claims description 4
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical compound II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 claims description 4
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 claims description 4
- 229910000073 phosphorus hydride Inorganic materials 0.000 claims description 4
- 239000000651 prodrug Substances 0.000 claims description 4
- 229940002612 prodrug Drugs 0.000 claims description 4
- 125000002943 quinolinyl group Chemical group N1=C(C=CC2=CC=CC=C12)* 0.000 claims description 4
- 125000005493 quinolyl group Chemical group 0.000 claims description 4
- 125000005110 aryl thio group Chemical group 0.000 claims description 3
- 125000004104 aryloxy group Chemical group 0.000 claims description 3
- 239000003814 drug Substances 0.000 claims description 3
- 230000000694 effects Effects 0.000 claims description 3
- 239000000203 mixture Substances 0.000 claims description 3
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 3
- 230000003287 optical effect Effects 0.000 claims description 3
- 125000001476 phosphono group Chemical group [H]OP(*)(=O)O[H] 0.000 claims description 3
- 125000003373 pyrazinyl group Chemical group 0.000 claims description 3
- 125000006656 (C2-C4) alkenyl group Chemical group 0.000 claims description 2
- 102000002274 Matrix Metalloproteinases Human genes 0.000 claims description 2
- 108010000684 Matrix Metalloproteinases Proteins 0.000 claims description 2
- PCKPVGOLPKLUHR-UHFFFAOYSA-N OH-Indolxyl Natural products C1=CC=C2C(O)=CNC2=C1 PCKPVGOLPKLUHR-UHFFFAOYSA-N 0.000 claims description 2
- KDCGOANMDULRCW-UHFFFAOYSA-N Purine Natural products N1=CNC2=NC=NC2=C1 KDCGOANMDULRCW-UHFFFAOYSA-N 0.000 claims description 2
- 125000004644 alkyl sulfinyl group Chemical group 0.000 claims description 2
- 125000004656 alkyl sulfonylamino group Chemical group 0.000 claims description 2
- 125000005466 alkylenyl group Chemical group 0.000 claims description 2
- 125000004618 benzofuryl group Chemical group O1C(=CC2=C1C=CC=C2)* 0.000 claims description 2
- 125000001164 benzothiazolyl group Chemical group S1C(=NC2=C1C=CC=C2)* 0.000 claims description 2
- 125000004196 benzothienyl group Chemical group S1C(=CC2=C1C=CC=C2)* 0.000 claims description 2
- 125000004541 benzoxazolyl group Chemical group O1C(=NC2=C1C=CC=C2)* 0.000 claims description 2
- 239000012876 carrier material Substances 0.000 claims description 2
- 125000004122 cyclic group Chemical group 0.000 claims description 2
- 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 2
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 2
- NNBZCPXTIHJBJL-UHFFFAOYSA-N decalin Chemical compound C1CCCC2CCCCC21 NNBZCPXTIHJBJL-UHFFFAOYSA-N 0.000 claims description 2
- 125000002541 furyl group Chemical group 0.000 claims description 2
- 125000002768 hydroxyalkyl group Chemical group 0.000 claims description 2
- 125000003453 indazolyl group Chemical group N1N=C(C2=C1C=CC=C2)* 0.000 claims description 2
- JYGFTBXVXVMTGB-UHFFFAOYSA-N indolin-2-one Chemical compound C1=CC=C2NC(=O)CC2=C1 JYGFTBXVXVMTGB-UHFFFAOYSA-N 0.000 claims description 2
- 125000001786 isothiazolyl group Chemical group 0.000 claims description 2
- 125000000842 isoxazolyl group Chemical group 0.000 claims description 2
- CYEBJEDOHLIWNP-UHFFFAOYSA-N methanethioamide Chemical compound NC=S CYEBJEDOHLIWNP-UHFFFAOYSA-N 0.000 claims description 2
- 125000002757 morpholinyl group Chemical group 0.000 claims description 2
- 150000002825 nitriles Chemical class 0.000 claims description 2
- 125000002971 oxazolyl group Chemical group 0.000 claims description 2
- 125000002098 pyridazinyl group Chemical group 0.000 claims description 2
- 125000000714 pyrimidinyl group Chemical group 0.000 claims description 2
- 238000007363 ring formation reaction Methods 0.000 claims description 2
- 125000000335 thiazolyl group Chemical group 0.000 claims description 2
- 125000001544 thienyl group Chemical group 0.000 claims description 2
- 125000004568 thiomorpholinyl group Chemical group 0.000 claims description 2
- 125000001399 1,2,3-triazolyl group Chemical group N1N=NC(=C1)* 0.000 claims 1
- 230000002401 inhibitory effect Effects 0.000 claims 1
- 230000001131 transforming effect Effects 0.000 claims 1
- 125000003837 (C1-C20) alkyl group Chemical group 0.000 abstract 1
- 125000004209 (C1-C8) alkyl group Chemical group 0.000 abstract 1
- 125000004670 alkyl amino thio carbonyl group Chemical group 0.000 abstract 1
- 125000004435 hydrogen atom Chemical class [H]* 0.000 abstract 1
- 125000005740 oxycarbonyl group Chemical group [*:1]OC([*:2])=O 0.000 abstract 1
- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 abstract 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 128
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 87
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 87
- HNYOPLTXPVRDBG-UHFFFAOYSA-N barbituric acid Chemical compound O=C1CC(=O)NC(=O)N1 HNYOPLTXPVRDBG-UHFFFAOYSA-N 0.000 description 76
- 239000000243 solution Substances 0.000 description 67
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 62
- 239000000047 product Substances 0.000 description 60
- 239000007787 solid Substances 0.000 description 59
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 56
- 235000019439 ethyl acetate Nutrition 0.000 description 46
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Chemical compound NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 description 42
- 239000011259 mixed solution Substances 0.000 description 29
- 229960004756 ethanol Drugs 0.000 description 27
- 238000003756 stirring Methods 0.000 description 26
- 239000011541 reaction mixture Substances 0.000 description 25
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 24
- KXDAEFPNCMNJSK-UHFFFAOYSA-N benzene carboxamide Natural products NC(=O)C1=CC=CC=C1 KXDAEFPNCMNJSK-UHFFFAOYSA-N 0.000 description 23
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 22
- 239000012074 organic phase Substances 0.000 description 22
- 125000003386 piperidinyl group Chemical group 0.000 description 22
- 229910052938 sodium sulfate Inorganic materials 0.000 description 22
- 235000011152 sodium sulphate Nutrition 0.000 description 22
- 239000002585 base Substances 0.000 description 21
- 239000004202 carbamide Substances 0.000 description 21
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 20
- 238000005160 1H NMR spectroscopy Methods 0.000 description 19
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 19
- 235000002639 sodium chloride Nutrition 0.000 description 19
- 238000001291 vacuum drying Methods 0.000 description 19
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 18
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 18
- 239000002253 acid Substances 0.000 description 17
- 239000000725 suspension Substances 0.000 description 17
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 16
- 238000001914 filtration Methods 0.000 description 16
- 238000010898 silica gel chromatography Methods 0.000 description 16
- 239000011734 sodium Substances 0.000 description 16
- 229910052708 sodium Inorganic materials 0.000 description 16
- WFCSWCVEJLETKA-UHFFFAOYSA-N 2-piperazin-1-ylethanol Chemical compound OCCN1CCNCC1 WFCSWCVEJLETKA-UHFFFAOYSA-N 0.000 description 15
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 15
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 15
- 239000002904 solvent Substances 0.000 description 15
- 238000010025 steaming Methods 0.000 description 14
- 238000003810 ethyl acetate extraction Methods 0.000 description 13
- 238000005406 washing Methods 0.000 description 13
- DLFVBJFMPXGRIB-UHFFFAOYSA-N Acetamide Chemical compound CC(N)=O DLFVBJFMPXGRIB-UHFFFAOYSA-N 0.000 description 12
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 12
- 150000001408 amides Chemical class 0.000 description 12
- 238000002425 crystallisation Methods 0.000 description 12
- 230000008025 crystallization Effects 0.000 description 12
- 239000003480 eluent Substances 0.000 description 12
- 125000000954 2-hydroxyethyl group Chemical group [H]C([*])([H])C([H])([H])O[H] 0.000 description 11
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 11
- 239000007864 aqueous solution Substances 0.000 description 11
- 238000000605 extraction Methods 0.000 description 11
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 11
- LTMRRSWNXVJMBA-UHFFFAOYSA-L 2,2-diethylpropanedioate Chemical compound CCC(CC)(C([O-])=O)C([O-])=O LTMRRSWNXVJMBA-UHFFFAOYSA-L 0.000 description 10
- 239000007788 liquid Substances 0.000 description 10
- 238000001953 recrystallisation Methods 0.000 description 10
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 9
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 9
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 9
- YCNCUDVLKBSVDY-UHFFFAOYSA-N [O].C(CCC)[SiH2]N(C)C Chemical group [O].C(CCC)[SiH2]N(C)C YCNCUDVLKBSVDY-UHFFFAOYSA-N 0.000 description 9
- 239000003112 inhibitor Substances 0.000 description 9
- 238000001556 precipitation Methods 0.000 description 9
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 8
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 8
- 150000001412 amines Chemical class 0.000 description 8
- 229910000042 hydrogen bromide Inorganic materials 0.000 description 8
- 238000010992 reflux Methods 0.000 description 8
- UMGDCJDMYOKAJW-UHFFFAOYSA-N thiourea Chemical compound NC(N)=S UMGDCJDMYOKAJW-UHFFFAOYSA-N 0.000 description 8
- LDSQQXKSEFZAPE-UHFFFAOYSA-N 2-piperidin-4-ylethanol Chemical class OCCC1CCNCC1 LDSQQXKSEFZAPE-UHFFFAOYSA-N 0.000 description 7
- 102000004190 Enzymes Human genes 0.000 description 7
- 108090000790 Enzymes Proteins 0.000 description 7
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 7
- 239000007900 aqueous suspension Substances 0.000 description 7
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid group Chemical group C(C1=CC=CC=C1)(=O)O WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 7
- 229940088598 enzyme Drugs 0.000 description 7
- 238000011010 flushing procedure Methods 0.000 description 7
- 239000000758 substrate Substances 0.000 description 7
- HRPVXLWXLXDGHG-UHFFFAOYSA-N Acrylamide Chemical compound NC(=O)C=C HRPVXLWXLXDGHG-UHFFFAOYSA-N 0.000 description 6
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 6
- ZRALSGWEFCBTJO-UHFFFAOYSA-N Guanidine Chemical compound NC(N)=N ZRALSGWEFCBTJO-UHFFFAOYSA-N 0.000 description 6
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 description 6
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 6
- 238000001816 cooling Methods 0.000 description 6
- 238000013016 damping Methods 0.000 description 6
- 239000000706 filtrate Substances 0.000 description 6
- 239000012530 fluid Substances 0.000 description 6
- 239000003921 oil Substances 0.000 description 6
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 6
- OIFBSDVPJOWBCH-UHFFFAOYSA-N Diethyl carbonate Chemical compound CCOC(=O)OCC OIFBSDVPJOWBCH-UHFFFAOYSA-N 0.000 description 5
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 5
- 150000002460 imidazoles Chemical class 0.000 description 5
- 125000001424 substituent group Chemical group 0.000 description 5
- KZNICNPSHKQLFF-UHFFFAOYSA-N succinimide Chemical group O=C1CCC(=O)N1 KZNICNPSHKQLFF-UHFFFAOYSA-N 0.000 description 5
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 5
- IVPPDIXCKHOMLU-UHFFFAOYSA-N 1-o-ethyl 3-o-phenyl propanedioate Chemical compound CCOC(=O)CC(=O)OC1=CC=CC=C1 IVPPDIXCKHOMLU-UHFFFAOYSA-N 0.000 description 4
- CNPURSDMOWDNOQ-UHFFFAOYSA-N 4-methoxy-7h-pyrrolo[2,3-d]pyrimidin-2-amine Chemical compound COC1=NC(N)=NC2=C1C=CN2 CNPURSDMOWDNOQ-UHFFFAOYSA-N 0.000 description 4
- 125000004172 4-methoxyphenyl group Chemical group [H]C1=C([H])C(OC([H])([H])[H])=C([H])C([H])=C1* 0.000 description 4
- UZOFELREXGAFOI-UHFFFAOYSA-N 4-methylpiperidine Chemical compound CC1CCNCC1 UZOFELREXGAFOI-UHFFFAOYSA-N 0.000 description 4
- 108060005980 Collagenase Proteins 0.000 description 4
- 102000029816 Collagenase Human genes 0.000 description 4
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 4
- BXDZOYLPNAIDOC-UHFFFAOYSA-N N-[5-[(5-tert-butyl-1,3-oxazol-2-yl)methylsulfanyl]-1,3-thiazol-2-yl]-1-[2-[2-[2-[2-[2-[[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-4-yl]amino]ethoxy]ethoxy]ethoxy]ethylamino]-2-oxoethyl]piperidine-4-carboxamide Chemical compound CC(C)(C)c1cnc(CSc2cnc(NC(=O)C3CCN(CC(=O)NCCOCCOCCOCCNc4cccc5C(=O)N(C6CCC(=O)NC6=O)C(=O)c45)CC3)s2)o1 BXDZOYLPNAIDOC-UHFFFAOYSA-N 0.000 description 4
- PCLIMKBDDGJMGD-UHFFFAOYSA-N N-bromosuccinimide Chemical compound BrN1C(=O)CCC1=O PCLIMKBDDGJMGD-UHFFFAOYSA-N 0.000 description 4
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 4
- 229960000583 acetic acid Drugs 0.000 description 4
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 description 4
- 125000001246 bromo group Chemical class Br* 0.000 description 4
- SOKKGFZWZZLHEK-UHFFFAOYSA-N butoxy(dimethyl)silane Chemical group CCCCO[SiH](C)C SOKKGFZWZZLHEK-UHFFFAOYSA-N 0.000 description 4
- 230000003197 catalytic effect Effects 0.000 description 4
- 229960002424 collagenase Drugs 0.000 description 4
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 4
- 125000000636 p-nitrophenyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)[N+]([O-])=O 0.000 description 4
- 239000002244 precipitate Substances 0.000 description 4
- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 description 4
- 239000012312 sodium hydride Substances 0.000 description 4
- 229910000104 sodium hydride Inorganic materials 0.000 description 4
- 239000012265 solid product Substances 0.000 description 4
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 description 3
- GWRSATNRNFYMDI-UHFFFAOYSA-N 4-[(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-8h-pyrimido[4,5-b][1,4]diazepin-2-yl)amino]-2-fluoro-5-methoxy-n-(1-methylpiperidin-4-yl)benzamide Chemical compound FC=1C=C(NC=2N=C3N(C4CCCC4)CC(F)(F)C(=O)N(C)C3=CN=2)C(OC)=CC=1C(=O)NC1CCN(C)CC1 GWRSATNRNFYMDI-UHFFFAOYSA-N 0.000 description 3
- BQMHSAAXSOJYOV-UHFFFAOYSA-N 5-bromo-1,3-diazinane-2,4,6-trione Chemical compound BrC1C(=O)NC(=O)NC1=O BQMHSAAXSOJYOV-UHFFFAOYSA-N 0.000 description 3
- CRVVMZCBPNDWJE-UHFFFAOYSA-N 5-bromo-5-phenyl-1,3-diazinane-2,4,6-trione Chemical compound C=1C=CC=CC=1C1(Br)C(=O)NC(=O)NC1=O CRVVMZCBPNDWJE-UHFFFAOYSA-N 0.000 description 3
- 102000034473 Adamalysin Human genes 0.000 description 3
- 108030001653 Adamalysin Proteins 0.000 description 3
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- OMPJBNCRMGITSC-UHFFFAOYSA-N Benzoylperoxide Chemical compound C=1C=CC=CC=1C(=O)OOC(=O)C1=CC=CC=C1 OMPJBNCRMGITSC-UHFFFAOYSA-N 0.000 description 3
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 3
- 108010037362 Extracellular Matrix Proteins Proteins 0.000 description 3
- 102000010834 Extracellular Matrix Proteins Human genes 0.000 description 3
- CHJJGSNFBQVOTG-UHFFFAOYSA-N N-methyl-guanidine Natural products CNC(N)=N CHJJGSNFBQVOTG-UHFFFAOYSA-N 0.000 description 3
- YGYAWVDWMABLBF-UHFFFAOYSA-N Phosgene Chemical compound ClC(Cl)=O YGYAWVDWMABLBF-UHFFFAOYSA-N 0.000 description 3
- 239000003513 alkali Substances 0.000 description 3
- 235000019400 benzoyl peroxide Nutrition 0.000 description 3
- 238000009835 boiling Methods 0.000 description 3
- 230000031709 bromination Effects 0.000 description 3
- 238000005893 bromination reaction Methods 0.000 description 3
- HHSARRMUXPDGJD-UHFFFAOYSA-N butyl(dimethyl)silicon Chemical group CCCC[Si](C)C HHSARRMUXPDGJD-UHFFFAOYSA-N 0.000 description 3
- 150000003857 carboxamides Chemical class 0.000 description 3
- 239000012141 concentrate Substances 0.000 description 3
- 235000008504 concentrate Nutrition 0.000 description 3
- 238000010586 diagram Methods 0.000 description 3
- 229960001760 dimethyl sulfoxide Drugs 0.000 description 3
- SWSQBOPZIKWTGO-UHFFFAOYSA-N dimethylaminoamidine Natural products CN(C)C(N)=N SWSQBOPZIKWTGO-UHFFFAOYSA-N 0.000 description 3
- 238000001035 drying Methods 0.000 description 3
- 150000002148 esters Chemical class 0.000 description 3
- 238000002474 experimental method Methods 0.000 description 3
- 210000002744 extracellular matrix Anatomy 0.000 description 3
- 239000012442 inert solvent Substances 0.000 description 3
- 238000002347 injection Methods 0.000 description 3
- 239000007924 injection Substances 0.000 description 3
- 125000001972 isopentyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 description 3
- 229940121386 matrix metalloproteinase inhibitor Drugs 0.000 description 3
- 239000003771 matrix metalloproteinase inhibitor Substances 0.000 description 3
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 3
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 3
- 125000003854 p-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Cl 0.000 description 3
- 229920000642 polymer Polymers 0.000 description 3
- 108090000765 processed proteins & peptides Proteins 0.000 description 3
- QLNJFJADRCOGBJ-UHFFFAOYSA-N propionamide Chemical compound CCC(N)=O QLNJFJADRCOGBJ-UHFFFAOYSA-N 0.000 description 3
- 229940080818 propionamide Drugs 0.000 description 3
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 3
- 125000004528 pyrimidin-5-yl group Chemical group N1=CN=CC(=C1)* 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- KWGRBVOPPLSCSI-WPRPVWTQSA-N (-)-ephedrine Chemical compound CN[C@@H](C)[C@H](O)C1=CC=CC=C1 KWGRBVOPPLSCSI-WPRPVWTQSA-N 0.000 description 2
- WHODZHGGQVLWBA-UHFFFAOYSA-N (4-phenoxyphenyl) acetate Chemical compound C1=CC(OC(=O)C)=CC=C1OC1=CC=CC=C1 WHODZHGGQVLWBA-UHFFFAOYSA-N 0.000 description 2
- UWYZHKAOTLEWKK-UHFFFAOYSA-N 1,2,3,4-tetrahydroisoquinoline Chemical compound C1=CC=C2CNCCC2=C1 UWYZHKAOTLEWKK-UHFFFAOYSA-N 0.000 description 2
- LBUJPTNKIBCYBY-UHFFFAOYSA-N 1,2,3,4-tetrahydroquinoline Chemical compound C1=CC=C2CCCNC2=C1 LBUJPTNKIBCYBY-UHFFFAOYSA-N 0.000 description 2
- VOYADQIFGGIKAT-UHFFFAOYSA-N 1,3-dibutyl-4-hydroxy-2,6-dioxopyrimidine-5-carboximidamide Chemical compound CCCCn1c(O)c(C(N)=N)c(=O)n(CCCC)c1=O VOYADQIFGGIKAT-UHFFFAOYSA-N 0.000 description 2
- FCYSNQACNGYXEW-UHFFFAOYSA-N 1-(4-bromobutyl)-4-methylbenzene Chemical compound CC1=CC=C(CCCCBr)C=C1 FCYSNQACNGYXEW-UHFFFAOYSA-N 0.000 description 2
- LNETULKMXZVUST-UHFFFAOYSA-N 1-naphthoic acid Chemical compound C1=CC=C2C(C(=O)O)=CC=CC2=C1 LNETULKMXZVUST-UHFFFAOYSA-N 0.000 description 2
- 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 2
- 125000004105 2-pyridyl group Chemical group N1=C([*])C([H])=C([H])C([H])=C1[H] 0.000 description 2
- RVBUGGBMJDPOST-UHFFFAOYSA-N 2-thiobarbituric acid Chemical compound O=C1CC(=O)NC(=S)N1 RVBUGGBMJDPOST-UHFFFAOYSA-N 0.000 description 2
- 125000006275 3-bromophenyl group Chemical group [H]C1=C([H])C(Br)=C([H])C(*)=C1[H] 0.000 description 2
- 125000003349 3-pyridyl group Chemical group N1=C([H])C([*])=C([H])C([H])=C1[H] 0.000 description 2
- XQXPVVBIMDBYFF-UHFFFAOYSA-N 4-hydroxyphenylacetic acid Chemical compound OC(=O)CC1=CC=C(O)C=C1 XQXPVVBIMDBYFF-UHFFFAOYSA-N 0.000 description 2
- CUWNONFTCUPXFJ-UHFFFAOYSA-N 5-(4-hydroxyphenyl)-1,3-diazinane-2,4,6-trione Chemical compound C1=CC(O)=CC=C1C1C(=O)NC(=O)NC1=O CUWNONFTCUPXFJ-UHFFFAOYSA-N 0.000 description 2
- NNRYJLARUIVRRO-UHFFFAOYSA-N 5-(4-phenoxyphenyl)-1,3-diazinane-2,4,6-trione Chemical compound O=C1NC(=O)NC(=O)C1C(C=C1)=CC=C1OC1=CC=CC=C1 NNRYJLARUIVRRO-UHFFFAOYSA-N 0.000 description 2
- MENIJRPFVLNJIH-UHFFFAOYSA-N 5-benzyl-1,3-diazinane-2,4,6-trione Chemical compound O=C1NC(=O)NC(=O)C1CC1=CC=CC=C1 MENIJRPFVLNJIH-UHFFFAOYSA-N 0.000 description 2
- DAWNOTOEYBYDHF-UHFFFAOYSA-N 5-benzyl-5-bromo-1,3-diazinane-2,4,6-trione Chemical compound C=1C=CC=CC=1CC1(Br)C(=O)NC(=O)NC1=O DAWNOTOEYBYDHF-UHFFFAOYSA-N 0.000 description 2
- CMWDWOZYVQQAMI-UHFFFAOYSA-N 5-benzylidene-1,3-diazinane-2,4,6-trione Chemical compound O=C1NC(=O)NC(=O)C1=CC1=CC=CC=C1 CMWDWOZYVQQAMI-UHFFFAOYSA-N 0.000 description 2
- PZADWOLLCHSQIG-UHFFFAOYSA-N 5-bromo-5-(4-phenoxyphenyl)-1,3-diazinane-2,4,6-trione Chemical compound C=1C=C(OC=2C=CC=CC=2)C=CC=1C1(Br)C(=O)NC(=O)NC1=O PZADWOLLCHSQIG-UHFFFAOYSA-N 0.000 description 2
- XRMYRFXTJBWVCU-UHFFFAOYSA-N 5-bromo-5-decyl-1,3-diazinane-2,4,6-trione Chemical compound CCCCCCCCCCC1(Br)C(=O)NC(=O)NC1=O XRMYRFXTJBWVCU-UHFFFAOYSA-N 0.000 description 2
- ZCTHLEWNBFASPY-UHFFFAOYSA-N 5-bromo-5-naphthalen-1-yl-1,3-diazinane-2,4,6-trione Chemical compound C=1C=CC2=CC=CC=C2C=1C1(Br)C(=O)NC(=O)NC1=O ZCTHLEWNBFASPY-UHFFFAOYSA-N 0.000 description 2
- NUEVOKYGRAPXGJ-UHFFFAOYSA-N 5-decyl-1,3-diazinane-2,4,6-trione Chemical compound CCCCCCCCCCC1C(=O)NC(=O)NC1=O NUEVOKYGRAPXGJ-UHFFFAOYSA-N 0.000 description 2
- NHBSGFRCWHEXLZ-UHFFFAOYSA-N 5-naphthalen-1-yl-1,3-diazinane-2,4,6-trione Chemical compound O=C1NC(=O)NC(=O)C1C1=CC=CC2=CC=CC=C12 NHBSGFRCWHEXLZ-UHFFFAOYSA-N 0.000 description 2
- BWENXQFVCQHWHP-UHFFFAOYSA-N 5-phenyl-1,3-diazinan-2-one Chemical compound C1NC(=O)NCC1C1=CC=CC=C1 BWENXQFVCQHWHP-UHFFFAOYSA-N 0.000 description 2
- ALEJRRYANZMPQU-UHFFFAOYSA-N 5-phenyl-5-piperidin-1-yl-1,3-diazinane-2,4,6-trione Chemical compound O=C1NC(=O)NC(=O)C1(C=1C=CC=CC=1)N1CCCCC1 ALEJRRYANZMPQU-UHFFFAOYSA-N 0.000 description 2
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 2
- KHBQMWCZKVMBLN-UHFFFAOYSA-N Benzenesulfonamide Chemical compound NS(=O)(=O)C1=CC=CC=C1 KHBQMWCZKVMBLN-UHFFFAOYSA-N 0.000 description 2
- LSNNMFCWUKXFEE-UHFFFAOYSA-M Bisulfite Chemical compound OS([O-])=O LSNNMFCWUKXFEE-UHFFFAOYSA-M 0.000 description 2
- UTIIZUDNLKTEHQ-UHFFFAOYSA-N C1=CC(=CC=C1CN)C2(C(=O)NC(=O)NC2=O)Br Chemical compound C1=CC(=CC=C1CN)C2(C(=O)NC(=O)NC2=O)Br UTIIZUDNLKTEHQ-UHFFFAOYSA-N 0.000 description 2
- KLXHLECZNUTGDO-UHFFFAOYSA-N C1=CC(=CC=C1CN)C2C(=O)NC(=O)NC2=O Chemical compound C1=CC(=CC=C1CN)C2C(=O)NC(=O)NC2=O KLXHLECZNUTGDO-UHFFFAOYSA-N 0.000 description 2
- IZWQNECMVDNMBA-UHFFFAOYSA-N CCCCCl(C)(C)[SiH3] Chemical group CCCCCl(C)(C)[SiH3] IZWQNECMVDNMBA-UHFFFAOYSA-N 0.000 description 2
- 102000008186 Collagen Human genes 0.000 description 2
- 108010035532 Collagen Proteins 0.000 description 2
- KCXVZYZYPLLWCC-UHFFFAOYSA-N EDTA Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 description 2
- DULCUDSUACXJJC-UHFFFAOYSA-N Ethyl phenylacetate Chemical compound CCOC(=O)CC1=CC=CC=C1 DULCUDSUACXJJC-UHFFFAOYSA-N 0.000 description 2
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 2
- ZHNUHDYFZUAESO-UHFFFAOYSA-N Formamide Chemical compound NC=O ZHNUHDYFZUAESO-UHFFFAOYSA-N 0.000 description 2
- 108010026132 Gelatinases Proteins 0.000 description 2
- 102000013382 Gelatinases Human genes 0.000 description 2
- 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 2
- 206010029379 Neutrophilia Diseases 0.000 description 2
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 2
- 102000035195 Peptidases Human genes 0.000 description 2
- 108091005804 Peptidases Proteins 0.000 description 2
- 229920003171 Poly (ethylene oxide) Polymers 0.000 description 2
- KYQCOXFCLRTKLS-UHFFFAOYSA-N Pyrazine Chemical compound C1=CN=CC=N1 KYQCOXFCLRTKLS-UHFFFAOYSA-N 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical class [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 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
- QIVBCDIJIAJPQS-UHFFFAOYSA-N Tryptophan Natural products C1=CC=C2C(CC(N)C(O)=O)=CNC2=C1 QIVBCDIJIAJPQS-UHFFFAOYSA-N 0.000 description 2
- 239000006035 Tryptophane Substances 0.000 description 2
- 239000000654 additive Substances 0.000 description 2
- 230000003113 alkalizing effect Effects 0.000 description 2
- 125000002877 alkyl aryl group Chemical group 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- ILAHWRKJUDSMFH-UHFFFAOYSA-N boron tribromide Chemical compound BrB(Br)Br ILAHWRKJUDSMFH-UHFFFAOYSA-N 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- 239000012230 colorless oil Substances 0.000 description 2
- 230000006837 decompression Effects 0.000 description 2
- 230000000593 degrading effect Effects 0.000 description 2
- 229960000935 dehydrated alcohol Drugs 0.000 description 2
- PZNMRIQALHUBSJ-UHFFFAOYSA-N ethyl 2-naphthalen-2-ylacetate Chemical compound C1=CC=CC2=CC(CC(=O)OCC)=CC=C21 PZNMRIQALHUBSJ-UHFFFAOYSA-N 0.000 description 2
- 125000000031 ethylamino group Chemical group [H]C([H])([H])C([H])([H])N([H])[*] 0.000 description 2
- 238000001704 evaporation Methods 0.000 description 2
- 230000008020 evaporation Effects 0.000 description 2
- PJJJBBJSCAKJQF-UHFFFAOYSA-N guanidinium chloride Chemical compound [Cl-].NC(N)=[NH2+] PJJJBBJSCAKJQF-UHFFFAOYSA-N 0.000 description 2
- BPMFZUMJYQTVII-UHFFFAOYSA-N guanidinoacetic acid Chemical compound NC(=N)NCC(O)=O BPMFZUMJYQTVII-UHFFFAOYSA-N 0.000 description 2
- 238000010438 heat treatment Methods 0.000 description 2
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 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
- 239000000463 material Substances 0.000 description 2
- VNWKTOKETHGBQD-UHFFFAOYSA-N methane Natural products C VNWKTOKETHGBQD-UHFFFAOYSA-N 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 238000006386 neutralization reaction Methods 0.000 description 2
- 229910017604 nitric acid Inorganic materials 0.000 description 2
- CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 description 2
- 239000003208 petroleum Substances 0.000 description 2
- 239000000825 pharmaceutical preparation Substances 0.000 description 2
- UHZYTMXLRWXGPK-UHFFFAOYSA-N phosphorus pentachloride Chemical compound ClP(Cl)(Cl)(Cl)Cl UHZYTMXLRWXGPK-UHFFFAOYSA-N 0.000 description 2
- 125000004194 piperazin-1-yl group Chemical group [H]N1C([H])([H])C([H])([H])N(*)C([H])([H])C1([H])[H] 0.000 description 2
- HDOWRFHMPULYOA-UHFFFAOYSA-N piperidin-4-ol Chemical compound OC1CCNCC1 HDOWRFHMPULYOA-UHFFFAOYSA-N 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Substances [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- 235000015320 potassium carbonate Nutrition 0.000 description 2
- 102000004196 processed proteins & peptides Human genes 0.000 description 2
- RZWZRACFZGVKFM-UHFFFAOYSA-N propanoyl chloride Chemical compound CCC(Cl)=O RZWZRACFZGVKFM-UHFFFAOYSA-N 0.000 description 2
- 235000019260 propionic acid Nutrition 0.000 description 2
- 125000001501 propionyl group Chemical group O=C([*])C([H])([H])C([H])([H])[H] 0.000 description 2
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 2
- LOUPRKONTZGTKE-LHHVKLHASA-N quinidine Chemical compound C([C@H]([C@H](C1)C=C)C2)C[N@@]1[C@H]2[C@@H](O)C1=CC=NC2=CC=C(OC)C=C21 LOUPRKONTZGTKE-LHHVKLHASA-N 0.000 description 2
- 238000000926 separation method Methods 0.000 description 2
- APSBXTVYXVQYAB-UHFFFAOYSA-M sodium docusate Chemical compound [Na+].CCCCC(CC)COC(=O)CC(S([O-])(=O)=O)C(=O)OCC(CC)CCCC APSBXTVYXVQYAB-UHFFFAOYSA-M 0.000 description 2
- 241000894007 species Species 0.000 description 2
- 108091007196 stromelysin Proteins 0.000 description 2
- 229960002317 succinimide Drugs 0.000 description 2
- 229910052717 sulfur Inorganic materials 0.000 description 2
- YBBRCQOCSYXUOC-UHFFFAOYSA-N sulfuryl dichloride Chemical compound ClS(Cl)(=O)=O YBBRCQOCSYXUOC-UHFFFAOYSA-N 0.000 description 2
- 230000002194 synthesizing effect Effects 0.000 description 2
- 239000003826 tablet Substances 0.000 description 2
- DZLFLBLQUQXARW-UHFFFAOYSA-N tetrabutylammonium Chemical compound CCCC[N+](CCCC)(CCCC)CCCC DZLFLBLQUQXARW-UHFFFAOYSA-N 0.000 description 2
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 description 2
- 125000002813 thiocarbonyl group Chemical group *C(*)=S 0.000 description 2
- 125000003396 thiol group Chemical class [H]S* 0.000 description 2
- 210000001519 tissue Anatomy 0.000 description 2
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 2
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 2
- 229960004799 tryptophan Drugs 0.000 description 2
- RQEUFEKYXDPUSK-ZETCQYMHSA-N (1S)-1-phenylethanamine Chemical compound C[C@H](N)C1=CC=CC=C1 RQEUFEKYXDPUSK-ZETCQYMHSA-N 0.000 description 1
- LNAZSHAWQACDHT-XIYTZBAFSA-N (2r,3r,4s,5r,6s)-4,5-dimethoxy-2-(methoxymethyl)-3-[(2s,3r,4s,5r,6r)-3,4,5-trimethoxy-6-(methoxymethyl)oxan-2-yl]oxy-6-[(2r,3r,4s,5r,6r)-4,5,6-trimethoxy-2-(methoxymethyl)oxan-3-yl]oxyoxane Chemical compound CO[C@@H]1[C@@H](OC)[C@H](OC)[C@@H](COC)O[C@H]1O[C@H]1[C@H](OC)[C@@H](OC)[C@H](O[C@H]2[C@@H]([C@@H](OC)[C@H](OC)O[C@@H]2COC)OC)O[C@@H]1COC LNAZSHAWQACDHT-XIYTZBAFSA-N 0.000 description 1
- YMMPZCZOLKBHAP-IHPCNDPISA-N (2s)-2-[[(2s)-1-[2-[[2-[[(2s)-1-[2-(phenylmethoxycarbonylamino)acetyl]pyrrolidine-2-carbonyl]amino]acetyl]amino]acetyl]pyrrolidine-2-carbonyl]amino]propanoic acid Chemical compound OC(=O)[C@H](C)NC(=O)[C@@H]1CCCN1C(=O)CNC(=O)CNC(=O)[C@H]1N(C(=O)CNC(=O)OCC=2C=CC=CC=2)CCC1 YMMPZCZOLKBHAP-IHPCNDPISA-N 0.000 description 1
- YZGSLLPFIVQGHO-UHFFFAOYSA-N 1,2,3,4-tetrahydrobenzo[g]isoquinoline Chemical compound C1=CC=C2C=C(CNCC3)C3=CC2=C1 YZGSLLPFIVQGHO-UHFFFAOYSA-N 0.000 description 1
- UOFGSWVZMUXXIY-UHFFFAOYSA-N 1,5-Diphenyl-3-thiocarbazone Chemical compound C=1C=CC=CC=1N=NC(=S)NNC1=CC=CC=C1 UOFGSWVZMUXXIY-UHFFFAOYSA-N 0.000 description 1
- OGFAWKRXZLGJSK-UHFFFAOYSA-N 1-(2,4-dihydroxyphenyl)-2-(4-nitrophenyl)ethanone Chemical compound OC1=CC(O)=CC=C1C(=O)CC1=CC=C([N+]([O-])=O)C=C1 OGFAWKRXZLGJSK-UHFFFAOYSA-N 0.000 description 1
- SFLNVAVCCYTHCQ-UHFFFAOYSA-N 1-(3,4-dimethylphenyl)piperazine Chemical compound C1=C(C)C(C)=CC=C1N1CCNCC1 SFLNVAVCCYTHCQ-UHFFFAOYSA-N 0.000 description 1
- VWOJSRICSKDKAW-UHFFFAOYSA-N 1-(4-nitrophenyl)piperazine Chemical compound C1=CC([N+](=O)[O-])=CC=C1N1CCNCC1 VWOJSRICSKDKAW-UHFFFAOYSA-N 0.000 description 1
- DJNIFZYQFLFGDT-UHFFFAOYSA-N 1-(4-phenoxyphenyl)ethanone Chemical compound C1=CC(C(=O)C)=CC=C1OC1=CC=CC=C1 DJNIFZYQFLFGDT-UHFFFAOYSA-N 0.000 description 1
- MPPPKRYCTPRNTB-UHFFFAOYSA-N 1-bromobutane Chemical compound CCCCBr MPPPKRYCTPRNTB-UHFFFAOYSA-N 0.000 description 1
- MYMSJFSOOQERIO-UHFFFAOYSA-N 1-bromodecane Chemical compound CCCCCCCCCCBr MYMSJFSOOQERIO-UHFFFAOYSA-N 0.000 description 1
- VMKOFRJSULQZRM-UHFFFAOYSA-N 1-bromooctane Chemical compound CCCCCCCCBr VMKOFRJSULQZRM-UHFFFAOYSA-N 0.000 description 1
- SBPIDKODQVLBGV-UHFFFAOYSA-N 1h-imidazole;pyridine Chemical class C1=CNC=N1.C1=CC=NC=C1 SBPIDKODQVLBGV-UHFFFAOYSA-N 0.000 description 1
- ROGHUJUFCRFUSO-UHFFFAOYSA-N 1h-indole-4-carboxylic acid Chemical compound OC(=O)C1=CC=CC2=C1C=CN2 ROGHUJUFCRFUSO-UHFFFAOYSA-N 0.000 description 1
- 125000004201 2,4-dichlorophenyl group Chemical group [H]C1=C([H])C(*)=C(Cl)C([H])=C1Cl 0.000 description 1
- UFBJCMHMOXMLKC-UHFFFAOYSA-N 2,4-dinitrophenol Chemical compound OC1=CC=C([N+]([O-])=O)C=C1[N+]([O-])=O UFBJCMHMOXMLKC-UHFFFAOYSA-N 0.000 description 1
- 125000004174 2-benzimidazolyl group Chemical group [H]N1C(*)=NC2=C([H])C([H])=C([H])C([H])=C12 0.000 description 1
- NEAQRZUHTPSBBM-UHFFFAOYSA-N 2-hydroxy-3,3-dimethyl-7-nitro-4h-isoquinolin-1-one Chemical compound C1=C([N+]([O-])=O)C=C2C(=O)N(O)C(C)(C)CC2=C1 NEAQRZUHTPSBBM-UHFFFAOYSA-N 0.000 description 1
- 125000004200 2-methoxyethyl group Chemical group [H]C([H])([H])OC([H])([H])C([H])([H])* 0.000 description 1
- 125000004204 2-methoxyphenyl group Chemical group [H]C1=C([H])C(*)=C(OC([H])([H])[H])C([H])=C1[H] 0.000 description 1
- HWCCVMGTQFWJSS-UHFFFAOYSA-N 2-methyl-2,3-dihydro-1-benzofuran-7-carboxylic acid Chemical compound C1=CC(C(O)=O)=C2OC(C)CC2=C1 HWCCVMGTQFWJSS-UHFFFAOYSA-N 0.000 description 1
- 125000001622 2-naphthyl group Chemical group [H]C1=C([H])C([H])=C2C([H])=C(*)C([H])=C([H])C2=C1[H] 0.000 description 1
- VIBOGIYPPWLDTI-UHFFFAOYSA-N 2-naphthylacetic acid Chemical compound C1=CC=CC2=CC(CC(=O)O)=CC=C21 VIBOGIYPPWLDTI-UHFFFAOYSA-N 0.000 description 1
- 125000001494 2-propynyl group Chemical group [H]C#CC([H])([H])* 0.000 description 1
- 125000005809 3,4,5-trimethoxyphenyl group Chemical group [H]C1=C(OC([H])([H])[H])C(OC([H])([H])[H])=C(OC([H])([H])[H])C([H])=C1* 0.000 description 1
- 125000004189 3,4-dichlorophenyl group Chemical group [H]C1=C([H])C(Cl)=C(Cl)C([H])=C1* 0.000 description 1
- 125000003762 3,4-dimethoxyphenyl group Chemical group [H]C1=C([H])C(OC([H])([H])[H])=C(OC([H])([H])[H])C([H])=C1* 0.000 description 1
- QJCBOVATTIAKOV-UHFFFAOYSA-N 3-(4-phenylmethoxyphenyl)benzoic acid Chemical compound OC(=O)C1=CC=CC(C=2C=CC(OCC=3C=CC=CC=3)=CC=2)=C1 QJCBOVATTIAKOV-UHFFFAOYSA-N 0.000 description 1
- 125000004179 3-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C(Cl)=C1[H] 0.000 description 1
- FVMDYYGIDFPZAX-UHFFFAOYSA-N 3-hydroxyphenylacetic acid Chemical compound OC(=O)CC1=CC=CC(O)=C1 FVMDYYGIDFPZAX-UHFFFAOYSA-N 0.000 description 1
- 125000004207 3-methoxyphenyl group Chemical group [H]C1=C([H])C(*)=C([H])C(OC([H])([H])[H])=C1[H] 0.000 description 1
- LLJRXVHJOJRCSM-UHFFFAOYSA-N 3-pyridin-4-yl-1H-indole Chemical group C=1NC2=CC=CC=C2C=1C1=CC=NC=C1 LLJRXVHJOJRCSM-UHFFFAOYSA-N 0.000 description 1
- 125000006283 4-chlorobenzyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1Cl)C([H])([H])* 0.000 description 1
- 125000001255 4-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1F 0.000 description 1
- 125000000590 4-methylphenyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)C([H])([H])[H] 0.000 description 1
- 125000000339 4-pyridyl group Chemical group N1=C([H])C([H])=C([*])C([H])=C1[H] 0.000 description 1
- OUWVMWLMLIGPKC-UHFFFAOYSA-N 5-[1-(2-hydroxyethyl)piperazin-2-yl]-5-(3-hydroxyphenyl)-1,3-diazinane-2,4,6-trione Chemical compound OCCN1CCNCC1C1(C=2C=C(O)C=CC=2)C(=O)NC(=O)NC1=O OUWVMWLMLIGPKC-UHFFFAOYSA-N 0.000 description 1
- BDLZYJWTWWHOIX-UHFFFAOYSA-N 5-[1-(2-hydroxyethyl)piperazin-2-yl]-5-(4-hydroxyphenyl)-1,3-diazinane-2,4,6-trione Chemical compound OCCN1CCNCC1C1(C=2C=CC(O)=CC=2)C(=O)NC(=O)NC1=O BDLZYJWTWWHOIX-UHFFFAOYSA-N 0.000 description 1
- XGRWNESWBOCCOL-UHFFFAOYSA-N 5-[1-(2-hydroxyethyl)piperazin-2-yl]-5-(4-phenoxyphenyl)-1,3-diazinane-2,4,6-trione Chemical compound OCCN1CCNCC1C1(C=2C=CC(OC=3C=CC=CC=3)=CC=2)C(=O)NC(=O)NC1=O XGRWNESWBOCCOL-UHFFFAOYSA-N 0.000 description 1
- PSQZLWHRJMYZHD-UHFFFAOYSA-N 5-amino-1,3-diazinane-2,4,6-trione Chemical compound NC1C(=O)NC(=O)NC1=O PSQZLWHRJMYZHD-UHFFFAOYSA-N 0.000 description 1
- QQQDEXUUABJCHD-UHFFFAOYSA-N 5-benzyl-5-[1-(2-hydroxyethyl)piperazin-2-yl]-1,3-diazinane-2,4,6-trione Chemical compound OCCN1CCNCC1C1(CC=2C=CC=CC=2)C(=O)NC(=O)NC1=O QQQDEXUUABJCHD-UHFFFAOYSA-N 0.000 description 1
- KBYREIKVHAUQAR-UHFFFAOYSA-N 5-decyl-5-[1-(2-hydroxyethyl)piperazin-2-yl]-1,3-diazinane-2,4,6-trione Chemical compound C1NCCN(CCO)C1C1(CCCCCCCCCC)C(=O)NC(=O)NC1=O KBYREIKVHAUQAR-UHFFFAOYSA-N 0.000 description 1
- HTEHILLCBQWTLP-UHFFFAOYSA-N 5-phenyl-1,3-diazinane-2,4,6-trione Chemical compound O=C1NC(=O)NC(=O)C1C1=CC=CC=C1 HTEHILLCBQWTLP-UHFFFAOYSA-N 0.000 description 1
- NTZOGKMMPWSJOX-UHFFFAOYSA-N 5-phenyl-5-(4-phenylpiperazin-1-yl)-4H-pyrimidine Chemical compound C1CN(CCN1C2=CC=CC=C2)C3(CN=CN=C3)C4=CC=CC=C4 NTZOGKMMPWSJOX-UHFFFAOYSA-N 0.000 description 1
- DZWKAUBCFARYSC-UHFFFAOYSA-N 5-phenyl-5-(4-phenylpiperidin-1-yl)-4H-pyrimidine Chemical compound C1CN(CCC1C2=CC=CC=C2)C3(CN=CN=C3)C4=CC=CC=C4 DZWKAUBCFARYSC-UHFFFAOYSA-N 0.000 description 1
- ZLBGPEIOIHSYEU-UHFFFAOYSA-N 5-phenyl-5-[4-(2-phenylethyl)piperazin-1-yl]-1,3-diazinane-2,4,6-trione Chemical compound O=C1NC(=O)NC(=O)C1(C=1C=CC=CC=1)N1CCN(CCC=2C=CC=CC=2)CC1 ZLBGPEIOIHSYEU-UHFFFAOYSA-N 0.000 description 1
- BYHDDXPKOZIZRV-UHFFFAOYSA-N 5-phenylpentanoic acid Chemical compound OC(=O)CCCCC1=CC=CC=C1 BYHDDXPKOZIZRV-UHFFFAOYSA-N 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- CBEFMGJHEKAMNI-UHFFFAOYSA-N 9-oxofluorene-1-carboxylic acid Chemical compound C12=CC=CC=C2C(=O)C2=C1C=CC=C2C(=O)O CBEFMGJHEKAMNI-UHFFFAOYSA-N 0.000 description 1
- HTPXFGUCAUTOEL-UHFFFAOYSA-N 9h-fluorene-1-carboxylic acid Chemical compound C1C2=CC=CC=C2C2=C1C(C(=O)O)=CC=C2 HTPXFGUCAUTOEL-UHFFFAOYSA-N 0.000 description 1
- 229920001817 Agar Polymers 0.000 description 1
- 102100033312 Alpha-2-macroglobulin Human genes 0.000 description 1
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 1
- LKMWSZGRRBBDDD-UHFFFAOYSA-N C1(=CC=CC2=CC=CC=C12)C1(C(NC(NC1=O)=O)=O)C1N(CCNC1)CCO Chemical compound C1(=CC=CC2=CC=CC=C12)C1(C(NC(NC1=O)=O)=O)C1N(CCNC1)CCO LKMWSZGRRBBDDD-UHFFFAOYSA-N 0.000 description 1
- GXXSPMNXJOQQJW-UHFFFAOYSA-N C1CN(C(CN1)C2(C(=O)NC(=O)NC2=O)C3=CC=C(C=C3)CN)CCO Chemical compound C1CN(C(CN1)C2(C(=O)NC(=O)NC2=O)C3=CC=C(C=C3)CN)CCO GXXSPMNXJOQQJW-UHFFFAOYSA-N 0.000 description 1
- 101100386719 Caenorhabditis elegans dcs-1 gene Proteins 0.000 description 1
- QGJOPFRUJISHPQ-UHFFFAOYSA-N Carbon disulfide Chemical compound S=C=S QGJOPFRUJISHPQ-UHFFFAOYSA-N 0.000 description 1
- 241001212149 Cathetus Species 0.000 description 1
- 241000723346 Cinnamomum camphora Species 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
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
- 239000004278 EU approved seasoning Substances 0.000 description 1
- 241000196324 Embryophyta Species 0.000 description 1
- 108010010803 Gelatin Proteins 0.000 description 1
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 1
- COLNVLDHVKWLRT-QMMMGPOBSA-N L-phenylalanine Chemical compound OC(=O)[C@@H](N)CC1=CC=CC=C1 COLNVLDHVKWLRT-QMMMGPOBSA-N 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-L L-tartrate(2-) Chemical compound [O-]C(=O)[C@H](O)[C@@H](O)C([O-])=O FEWJPZIEWOKRBE-JCYAYHJZSA-L 0.000 description 1
- 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 1
- OFOBLEOULBTSOW-UHFFFAOYSA-L Malonate Chemical compound [O-]C(=O)CC([O-])=O OFOBLEOULBTSOW-UHFFFAOYSA-L 0.000 description 1
- 229930195725 Mannitol Natural products 0.000 description 1
- 102000000380 Matrix Metalloproteinase 1 Human genes 0.000 description 1
- 108010016113 Matrix Metalloproteinase 1 Proteins 0.000 description 1
- 102000000422 Matrix Metalloproteinase 3 Human genes 0.000 description 1
- 102000005741 Metalloproteases Human genes 0.000 description 1
- 108010006035 Metalloproteases Proteins 0.000 description 1
- 206010027476 Metastases Diseases 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical class CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 1
- PHSPJQZRQAJPPF-UHFFFAOYSA-N N-alpha-Methylhistamine Chemical compound CNCCC1=CN=CN1 PHSPJQZRQAJPPF-UHFFFAOYSA-N 0.000 description 1
- 102100030411 Neutrophil collagenase Human genes 0.000 description 1
- 101710118230 Neutrophil collagenase Proteins 0.000 description 1
- PCNDJXKNXGMECE-UHFFFAOYSA-N Phenazine Natural products C1=CC=CC2=NC3=CC=CC=C3N=C21 PCNDJXKNXGMECE-UHFFFAOYSA-N 0.000 description 1
- 108010015078 Pregnancy-Associated alpha 2-Macroglobulins Proteins 0.000 description 1
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- 235000021355 Stearic acid Nutrition 0.000 description 1
- FZWLAAWBMGSTSO-UHFFFAOYSA-N Thiazole Chemical compound C1=CSC=N1 FZWLAAWBMGSTSO-UHFFFAOYSA-N 0.000 description 1
- ZMZDMBWJUHKJPS-UHFFFAOYSA-M Thiocyanate anion Chemical compound [S-]C#N ZMZDMBWJUHKJPS-UHFFFAOYSA-M 0.000 description 1
- RTAQQCXQSZGOHL-UHFFFAOYSA-N Titanium Chemical compound [Ti] RTAQQCXQSZGOHL-UHFFFAOYSA-N 0.000 description 1
- DUQIJXRFTVEJSR-UHFFFAOYSA-N [Cl].C(CCC)[SiH2]N(C)C Chemical group [Cl].C(CCC)[SiH2]N(C)C DUQIJXRFTVEJSR-UHFFFAOYSA-N 0.000 description 1
- DPDMMXDBJGCCQC-UHFFFAOYSA-N [Na].[Cl] Chemical compound [Na].[Cl] DPDMMXDBJGCCQC-UHFFFAOYSA-N 0.000 description 1
- WETWJCDKMRHUPV-UHFFFAOYSA-N acetyl chloride Chemical compound CC(Cl)=O WETWJCDKMRHUPV-UHFFFAOYSA-N 0.000 description 1
- 239000012346 acetyl chloride Substances 0.000 description 1
- 238000005903 acid hydrolysis reaction Methods 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 230000000996 additive effect Effects 0.000 description 1
- 239000008272 agar Substances 0.000 description 1
- 235000010419 agar Nutrition 0.000 description 1
- 238000013019 agitation Methods 0.000 description 1
- 230000001476 alcoholic effect Effects 0.000 description 1
- 150000001447 alkali salts Chemical class 0.000 description 1
- 150000001350 alkyl halides Chemical class 0.000 description 1
- QUMXDOLUJCHOAY-UHFFFAOYSA-N alpha-methylbenzyl acetate Natural products CC(=O)OC(C)C1=CC=CC=C1 QUMXDOLUJCHOAY-UHFFFAOYSA-N 0.000 description 1
- 125000000539 amino acid group Chemical group 0.000 description 1
- 235000011114 ammonium hydroxide Nutrition 0.000 description 1
- 150000003863 ammonium salts Chemical class 0.000 description 1
- BFNBIHQBYMNNAN-UHFFFAOYSA-N ammonium sulfate Chemical compound N.N.OS(O)(=O)=O BFNBIHQBYMNNAN-UHFFFAOYSA-N 0.000 description 1
- 229910052921 ammonium sulfate Inorganic materials 0.000 description 1
- 235000011130 ammonium sulphate Nutrition 0.000 description 1
- 239000003708 ampul Substances 0.000 description 1
- 229910052786 argon Inorganic materials 0.000 description 1
- 125000003710 aryl alkyl group Chemical group 0.000 description 1
- 238000003556 assay Methods 0.000 description 1
- 125000002648 azanetriyl group Chemical group *N(*)* 0.000 description 1
- 150000001540 azides Chemical class 0.000 description 1
- 229960002319 barbital Drugs 0.000 description 1
- FTOAOBMCPZCFFF-UHFFFAOYSA-N barbitone sodium Natural products CCC1(CC)C(=O)NC(=O)NC1=O FTOAOBMCPZCFFF-UHFFFAOYSA-N 0.000 description 1
- 230000004888 barrier function Effects 0.000 description 1
- MDHYEMXUFSJLGV-UHFFFAOYSA-N beta-phenethyl acetate Natural products CC(=O)OCCC1=CC=CC=C1 MDHYEMXUFSJLGV-UHFFFAOYSA-N 0.000 description 1
- SIPUZPBQZHNSDW-UHFFFAOYSA-N bis(2-methylpropyl)aluminum Chemical compound CC(C)C[Al]CC(C)C SIPUZPBQZHNSDW-UHFFFAOYSA-N 0.000 description 1
- 125000006367 bivalent amino carbonyl group Chemical group [H]N([*:1])C([*:2])=O 0.000 description 1
- 210000000988 bone and bone Anatomy 0.000 description 1
- 239000000872 buffer Substances 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 210000004899 c-terminal region Anatomy 0.000 description 1
- 239000011575 calcium Substances 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
- 239000001506 calcium phosphate Substances 0.000 description 1
- 229910000389 calcium phosphate Inorganic materials 0.000 description 1
- 235000011010 calcium phosphates Nutrition 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 1
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 1
- 150000001733 carboxylic acid esters Chemical class 0.000 description 1
- HOPSCVCBEOCPJZ-UHFFFAOYSA-N carboxymethyl(trimethyl)azanium;chloride Chemical compound [Cl-].C[N+](C)(C)CC(O)=O HOPSCVCBEOCPJZ-UHFFFAOYSA-N 0.000 description 1
- 230000015556 catabolic process Effects 0.000 description 1
- 238000006555 catalytic reaction Methods 0.000 description 1
- 210000004027 cell Anatomy 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- BFPSDSIWYFKGBC-UHFFFAOYSA-N chlorotrianisene Chemical group C1=CC(OC)=CC=C1C(Cl)=C(C=1C=CC(OC)=CC=1)C1=CC=C(OC)C=C1 BFPSDSIWYFKGBC-UHFFFAOYSA-N 0.000 description 1
- LOUPRKONTZGTKE-UHFFFAOYSA-N cinchonine Natural products C1C(C(C2)C=C)CCN2C1C(O)C1=CC=NC2=CC=C(OC)C=C21 LOUPRKONTZGTKE-UHFFFAOYSA-N 0.000 description 1
- 239000007979 citrate buffer Substances 0.000 description 1
- 238000003776 cleavage reaction Methods 0.000 description 1
- 239000011248 coating agent Substances 0.000 description 1
- 238000000576 coating method Methods 0.000 description 1
- 239000000470 constituent Substances 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- KWGRBVOPPLSCSI-UHFFFAOYSA-N d-ephedrine Natural products CNC(C)C(O)C1=CC=CC=C1 KWGRBVOPPLSCSI-UHFFFAOYSA-N 0.000 description 1
- 238000000354 decomposition reaction Methods 0.000 description 1
- 238000006731 degradation reaction Methods 0.000 description 1
- 238000000151 deposition Methods 0.000 description 1
- 230000000994 depressogenic effect Effects 0.000 description 1
- 125000004663 dialkyl amino group Chemical group 0.000 description 1
- 235000014113 dietary fatty acids Nutrition 0.000 description 1
- VQAZCUCWHIIFGE-UHFFFAOYSA-N diethyl 2-ethylpropanedioate Chemical compound CCOC(=O)C(CC)C(=O)OCC VQAZCUCWHIIFGE-UHFFFAOYSA-N 0.000 description 1
- 125000006371 dihalo methyl group Chemical group 0.000 description 1
- 238000010790 dilution Methods 0.000 description 1
- 239000012895 dilution Substances 0.000 description 1
- HPYNZHMRTTWQTB-UHFFFAOYSA-N dimethylpyridine Natural products CC1=CC=CN=C1C HPYNZHMRTTWQTB-UHFFFAOYSA-N 0.000 description 1
- FPAFDBFIGPHWGO-UHFFFAOYSA-N dioxosilane;oxomagnesium;hydrate Chemical compound O.[Mg]=O.[Mg]=O.[Mg]=O.O=[Si]=O.O=[Si]=O.O=[Si]=O.O=[Si]=O FPAFDBFIGPHWGO-UHFFFAOYSA-N 0.000 description 1
- HCUYBXPSSCRKRF-UHFFFAOYSA-N diphosgene Chemical compound ClC(=O)OC(Cl)(Cl)Cl HCUYBXPSSCRKRF-UHFFFAOYSA-N 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 238000010828 elution Methods 0.000 description 1
- 229960002179 ephedrine Drugs 0.000 description 1
- 230000032050 esterification Effects 0.000 description 1
- 238000005886 esterification reaction Methods 0.000 description 1
- 150000002170 ethers Chemical class 0.000 description 1
- 125000001301 ethoxy group Chemical group [H]C([H])([H])C([H])([H])O* 0.000 description 1
- HCPOCMMGKBZWSJ-UHFFFAOYSA-N ethyl 3-hydrazinyl-3-oxopropanoate Chemical compound CCOC(=O)CC(=O)NN HCPOCMMGKBZWSJ-UHFFFAOYSA-N 0.000 description 1
- MHYCRLGKOZWVEF-UHFFFAOYSA-N ethyl acetate;hydrate Chemical compound O.CCOC(C)=O MHYCRLGKOZWVEF-UHFFFAOYSA-N 0.000 description 1
- 230000003203 everyday effect Effects 0.000 description 1
- 230000005284 excitation Effects 0.000 description 1
- 239000000194 fatty acid Substances 0.000 description 1
- 229930195729 fatty acid Natural products 0.000 description 1
- 150000004665 fatty acids Chemical class 0.000 description 1
- 230000002349 favourable effect Effects 0.000 description 1
- 239000000835 fiber Substances 0.000 description 1
- ZONYXWQDUYMKFB-UHFFFAOYSA-N flavanone Chemical compound O1C2=CC=CC=C2C(=O)CC1C1=CC=CC=C1 ZONYXWQDUYMKFB-UHFFFAOYSA-N 0.000 description 1
- 238000002189 fluorescence spectrum Methods 0.000 description 1
- 239000007850 fluorescent dye Substances 0.000 description 1
- 235000011194 food seasoning agent Nutrition 0.000 description 1
- 239000012634 fragment Substances 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 239000008273 gelatin Substances 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 235000011852 gelatine desserts Nutrition 0.000 description 1
- 239000012362 glacial acetic acid Substances 0.000 description 1
- 239000003292 glue Substances 0.000 description 1
- 150000004820 halides Chemical class 0.000 description 1
- 230000003862 health status Effects 0.000 description 1
- 125000003187 heptyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 239000012943 hotmelt Substances 0.000 description 1
- ZMZDMBWJUHKJPS-UHFFFAOYSA-N hydrogen thiocyanate Natural products SC#N ZMZDMBWJUHKJPS-UHFFFAOYSA-N 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 230000003301 hydrolyzing effect Effects 0.000 description 1
- SXWRTZOXMUOJER-UHFFFAOYSA-N hydron;piperidin-4-one;chloride;hydrate Chemical compound O.Cl.O=C1CCNCC1 SXWRTZOXMUOJER-UHFFFAOYSA-N 0.000 description 1
- WGCNASOHLSPBMP-UHFFFAOYSA-N hydroxyacetaldehyde Natural products OCC=O WGCNASOHLSPBMP-UHFFFAOYSA-N 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- IENZCGNHSIMFJE-UHFFFAOYSA-N indole-5-carboxylic acid Chemical compound OC(=O)C1=CC=C2NC=CC2=C1 IENZCGNHSIMFJE-UHFFFAOYSA-N 0.000 description 1
- 125000001041 indolyl group Chemical group 0.000 description 1
- 208000027866 inflammatory disease Diseases 0.000 description 1
- 230000000977 initiatory effect Effects 0.000 description 1
- 150000007529 inorganic bases Chemical class 0.000 description 1
- 229910052500 inorganic mineral Inorganic materials 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- VFQXVTODMYMSMJ-UHFFFAOYSA-N isonicotinamide Chemical compound NC(=O)C1=CC=NC=C1 VFQXVTODMYMSMJ-UHFFFAOYSA-N 0.000 description 1
- 125000002183 isoquinolinyl group Chemical group C1(=NC=CC2=CC=CC=C12)* 0.000 description 1
- 150000002576 ketones Chemical class 0.000 description 1
- 239000004310 lactic acid Substances 0.000 description 1
- 235000014655 lactic acid Nutrition 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 238000012417 linear regression Methods 0.000 description 1
- 239000011777 magnesium Substances 0.000 description 1
- 229910052749 magnesium Inorganic materials 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- IWYDHOAUDWTVEP-UHFFFAOYSA-N mandelic acid Chemical compound OC(=O)C(O)C1=CC=CC=C1 IWYDHOAUDWTVEP-UHFFFAOYSA-N 0.000 description 1
- 229960002510 mandelic acid Drugs 0.000 description 1
- 239000000594 mannitol Substances 0.000 description 1
- 235000010355 mannitol Nutrition 0.000 description 1
- 238000004949 mass spectrometry Methods 0.000 description 1
- 239000011159 matrix material Substances 0.000 description 1
- UZKWTJUDCOPSNM-UHFFFAOYSA-N methoxybenzene Substances CCCCOC=C UZKWTJUDCOPSNM-UHFFFAOYSA-N 0.000 description 1
- 229920000609 methyl cellulose Polymers 0.000 description 1
- 125000000250 methylamino group Chemical group [H]N(*)C([H])([H])[H] 0.000 description 1
- 239000001923 methylcellulose Substances 0.000 description 1
- 235000010755 mineral Nutrition 0.000 description 1
- 239000011707 mineral Substances 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 125000002950 monocyclic group Chemical group 0.000 description 1
- 230000002969 morbid Effects 0.000 description 1
- 201000006417 multiple sclerosis Diseases 0.000 description 1
- CJJZCWJJAZMVCJ-UHFFFAOYSA-N n-benzyl-2,5-dimethylaniline Chemical compound CC1=CC=C(C)C(NCC=2C=CC=CC=2)=C1 CJJZCWJJAZMVCJ-UHFFFAOYSA-N 0.000 description 1
- LSCYTCMNCWMCQE-UHFFFAOYSA-N n-methylpyridin-4-amine Chemical compound CNC1=CC=NC=C1 LSCYTCMNCWMCQE-UHFFFAOYSA-N 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 1
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 1
- 125000002801 octanoyl group Chemical group C(CCCCCCC)(=O)* 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- 201000008482 osteoarthritis Diseases 0.000 description 1
- 125000004043 oxo group Chemical group O=* 0.000 description 1
- CFHIDWOYWUOIHU-UHFFFAOYSA-N oxomethyl Chemical compound O=[CH] CFHIDWOYWUOIHU-UHFFFAOYSA-N 0.000 description 1
- 230000020477 pH reduction Effects 0.000 description 1
- 235000001954 papillon Nutrition 0.000 description 1
- 244000229285 papillon Species 0.000 description 1
- 125000002958 pentadecyl 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])C([H])([H])[H] 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- COLNVLDHVKWLRT-UHFFFAOYSA-N phenylalanine Natural products OC(=O)C(N)CC1=CC=CC=C1 COLNVLDHVKWLRT-UHFFFAOYSA-N 0.000 description 1
- 125000003170 phenylsulfonyl group Chemical group C1(=CC=CC=C1)S(=O)(=O)* 0.000 description 1
- 125000004482 piperidin-4-yl group Chemical group N1CCC(CC1)* 0.000 description 1
- GKKCIDNWFBPDBW-UHFFFAOYSA-M potassium cyanate Chemical compound [K]OC#N GKKCIDNWFBPDBW-UHFFFAOYSA-M 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 229960001404 quinidine Drugs 0.000 description 1
- 150000003254 radicals Chemical class 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 230000036632 reaction speed Effects 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 230000004044 response Effects 0.000 description 1
- 201000003068 rheumatic fever Diseases 0.000 description 1
- 230000007017 scission Effects 0.000 description 1
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- FZHAPNGMFPVSLP-UHFFFAOYSA-N silanamine Chemical compound [SiH3]N FZHAPNGMFPVSLP-UHFFFAOYSA-N 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- RMAQACBXLXPBSY-UHFFFAOYSA-N silicic acid Chemical compound O[Si](O)(O)O RMAQACBXLXPBSY-UHFFFAOYSA-N 0.000 description 1
- 235000012239 silicon dioxide Nutrition 0.000 description 1
- 238000006884 silylation reaction Methods 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 229910000033 sodium borohydride Inorganic materials 0.000 description 1
- 239000012279 sodium borohydride Substances 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- BEOOHQFXGBMRKU-UHFFFAOYSA-N sodium cyanoborohydride Chemical compound [Na+].[B-]C#N BEOOHQFXGBMRKU-UHFFFAOYSA-N 0.000 description 1
- JXAZAUKOWVKTLO-UHFFFAOYSA-L sodium pyrosulfate Chemical class [Na+].[Na+].[O-]S(=O)(=O)OS([O-])(=O)=O JXAZAUKOWVKTLO-UHFFFAOYSA-L 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 229940095064 tartrate Drugs 0.000 description 1
- MHSKRLJMQQNJNC-UHFFFAOYSA-N terephthalamide Chemical compound NC(=O)C1=CC=C(C(N)=O)C=C1 MHSKRLJMQQNJNC-UHFFFAOYSA-N 0.000 description 1
- 150000003512 tertiary amines Chemical class 0.000 description 1
- 238000001149 thermolysis Methods 0.000 description 1
- 229930192474 thiophene Natural products 0.000 description 1
- WHLUQAYNVOGZST-UHFFFAOYSA-N tifenamil Chemical group C=1C=CC=CC=1C(C(=O)SCCN(CC)CC)C1=CC=CC=C1 WHLUQAYNVOGZST-UHFFFAOYSA-N 0.000 description 1
- 229910052719 titanium Inorganic materials 0.000 description 1
- 239000010936 titanium Substances 0.000 description 1
- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 description 1
- 125000004953 trihalomethyl group Chemical group 0.000 description 1
- 125000000430 tryptophan group Chemical group [H]N([H])C(C(=O)O*)C([H])([H])C1=C([H])N([H])C2=C([H])C([H])=C([H])C([H])=C12 0.000 description 1
- 125000002948 undecyl 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])[H] 0.000 description 1
- 238000003809 water extraction Methods 0.000 description 1
- 230000004572 zinc-binding Effects 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/513—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim having oxo groups directly attached to the heterocyclic ring, e.g. cytosine
- A61K31/515—Barbituric acids; Derivatives thereof, e.g. sodium pentobarbital
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
- A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
- A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P27/00—Drugs for disorders of the senses
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P27/00—Drugs for disorders of the senses
- A61P27/02—Ophthalmic agents
-
- 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
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
- A61P35/04—Antineoplastic agents specific for metastasis
-
- 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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
- C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
- C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
- C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
- C07D239/60—Three or more oxygen or sulfur atoms
- C07D239/62—Barbituric acids
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
- C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
- C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
- C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
- C07D239/60—Three or more oxygen or sulfur atoms
- C07D239/66—Thiobarbituric acids
Landscapes
- Chemical & Material Sciences (AREA)
- Health & Medical Sciences (AREA)
- Organic Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Medicinal Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Physical Education & Sports Medicine (AREA)
- Rheumatology (AREA)
- Orthopedic Medicine & Surgery (AREA)
- Oncology (AREA)
- Ophthalmology & Optometry (AREA)
- Communicable Diseases (AREA)
- Pain & Pain Management (AREA)
- Immunology (AREA)
- Epidemiology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
Abstract
式Ⅰ化合物,其药学上可接受的盐,其前体药物以及光学活性形式,其制备方法,以及含有具有基质金属蛋白酶抑制作用的该类化合物的药用制剂:其中X、Y和Z相互独立为氧、硫或NH;R1代表W-V:W是一个共价键-或是一直链或支链任选一次或多次取代的C1-C8烷基或C2-C8链烯基,V是一个任选取代的含有一个或几个杂原子的单环或双环,或W-V是可由杂原子间断的C1-C20的烷基,其中一个或多个碳原子是任选取代的;R2和R3代表氢或其中一个代表低级烷基或低级酰基;R4和R5相互独立代表A-D,其中A代表-烷基、链烯基、酰基、烷基磺酰基、磺酰基、烷基氨基羰基、氨基羰基、烷氧基羰基、氧化羰基、烷基氨基硫代羰基、氨基硫代羰基,以上基团可一次或多次任选取代;D代表氢、单环或双环,所述单环或双环任选一次或多次由杂原子间断,以及所述单环或双环可由一次或多次取代,或R4和R5以及与它们相邻的N原子形成一个环。
Description
在正常组织在存在着一个合成与降解之间的平衡。细胞外基质被属于至少三组的基质金属蛋白酶的蛋白来降解。它们是胶原酶、明胶酶和stromelysins。正常情况下存在着这些降解酶的专一抑制剂如α2巨球蛋白和MMP(=金属蛋白酶的组织抑制剂(MMP)),所以不会发生细胞外基质的过度降解。与蛋白酶相关的一组酶为adamalysins。adamalysins中著名的成员为TACE(TNF-α-转化酶)。
已经鉴定了至少11个不同但却高度同源的MMP种属,包括间质纤维细胞胶原酶(MMP-1,HFC)、嗜中性胶原酶(MMP-8,HNC)、两个明胶酶、stromelysin(如HSL-1)和HPUMP(最近综述,见Birkedal-Hansen,H.,Moore,W.G.I.,Bodden,M.K.,Windsor,L.J.,Birkedal-Hansen;B.,DeCarlo,A.,Engler,J.A.,Critical Rev,Oral Biol.Med.(1993)4,197-250)。这些蛋白酶共有一些结构上及功能上的特征但它们底物专一性上有某些不同。只有HNC和HFC能够在一单键上降解类型I、II和III的天然三螺旋状(triple-helica])胶原蛋白,同时生成原来链长度的3/4和1/4片段。这就降低了胶原蛋白的熔点,使其容易被其它基质降解酶接近进一步的进攻。
然而失控的该基质的过度的降解是许多病态的特征,例如在风湿性关节炎、骨关节炎、多种硬化病、在肿瘤转移、角膜溃疡、炎症疾病及发病的形成以及骨和牙齿的疾病的临床图片中。
可以认为这些临床图片中的发病机理能够通过基质金属蛋白酶抑制剂的给与受到有利的影响。同时大量的化合物在文献(见Nigel RABeeley等的Curr.Opin.ther,Patents 4(1),7(1994))报道或在专利文献中所述,它们主要是带有异羟肟酸残基、作为锌键合基团的硫羟或膦基的肽(见Glycomed的WO-A-9209563,Hoffmann-LaRoche的EP-A-497192,British Biotechnology的WO-A-9005719,Celltech的EP-A-489577,Beecham的EP-A-320118,Seatle的US-A-4595700等)。
部分此类化合物作为基质金属蛋白酶抑制剂具有很高的活性,但是只有很低的口服利用度。
已经发现本权利要求的新的巴比妥酸类衍生物作为基质金属蛋白酶抑制剂是非常有效的,并且具有很好的口服利用度。
因此本发明涉及通式I的物质,其药学上可接受的盐或其前药,以及这些化合物生产药物制剂的用途:其中X、Y和Z相互独立为氧、硫或NH,R1代表基团W-VW是一个共价键或是一直链或支链任选一次或多次取代的C1-C8烷基或C2-C8链烯基,V是一个任选取代的含有一个或几个杂原子的单环或双环,或W-V是可由杂原子间断的C1-C20烷基,其中一个或多个碳原子是可选取代的,R2和R3代表氢或其中一个代表低级烷基或低级酰基,R4和R5相互独立代表A-D,其中A代表-烷基、链烯基、酰基、烷基磺酰基、磺酰基、烷基氨基羰基、氨基羰基、烷氧基羰基、氧代羰基、烷基氨基硫代羰基、氨基硫代羰基,以上基团可一次或多次任选取代,D代表氢、单或双环,所述单环或双环任选一次或多次由杂原子间断,以及单环或双环由一次或多次取代,或R4和R5以及与其键合的N原子一起代表一个可由另一个N原子任选间断的环,该环可缩合为一单环或双环;该环可由下列基团一次或多次独立任选取代:羟基、烷氧基、氨基、烷基氨基、二烷基氨基、腈基或E-G,其中E代表-、可选取代的烷基、链烯基、酰基、烷基磺酰基、磺酰基、烷基氨基羰基、氨基羰基、烷氧基羰基、氧代羰基、烷基氨基硫代羰基、氨基硫代羰基;G代表氢、单或双环,所述单环或双环可选一次或多次由杂原子间断,以及所述单环或双环由一次或多次取代。
在R1、R4和R5中提到的单环被认为是饱和的或不饱和的带有3-8个,优选5-7个碳原子的任选由如氮、氧或硫杂原子一或多次间断的环系,具体地是环戊基、环己基、环庚基、吗啉基、硫代吗啉基、哌啶基、哌嗪基、四氢呋喃基、四氢吡喃基、苯基、吡啶基、嘧啶基、哒嗪基、吡嗪基、呋喃基、硫代苯基、咪唑基、噻唑基、噁唑基、异噻唑基、异噁唑基、1,2,3-***基或1,2,4-***基。首先认为低级烷基、烷氧基和卤素为取代基。
在R1、R4和R5中提到的双环被认为是缩和的双环或单环1-L-单环2类型的双环,其中L表示为共价键C1-C4烷基、C2-C4链烯基、氧或-C(O)-基团。
双环优选为萘基、四氢萘基、十氢化萘基(dekalinyl)、喹啉基、异喹啉基、四氢喹啉基、四氢异喹啉基、吲哚基、苯并咪唑基、吲唑基、羟吲哚基、苯并呋喃基、苯并硫代苯基、苯并噻唑基、苯并噁唑基、嘌呤基、联苯基或(4-苯氧基)苯基,特别是萘基、联苯基、喹啉基、异喹啉基、四氢喹啉基、吲哚基或苯并咪唑基。
在R1、R4和R5中提到的基团可一次或多次由下列基团任选取代:卤素、羟基、硫代、烷基、羟烷基、烷氧基、烷硫基、烷基亚磺酰基、烷基磺酰基、氨基、烷基氨基、二烷基氨基、硝基、羧基、甲酰胺、烷氧基羰基、氨基或氨基羰基,以上基团可由低级烷基、腈、氧代、硫代甲酰胺、烷氧基硫代羰基、烷基巯基羰基(alkmercaptocarbonyl)、膦酰基、烷基膦酰基、二烷基膦酰基、烷基磺酰氨基、芳氨基、芳基、杂芳基、芳氧基、芳硫基、芳基亚磺酰基、芳磺酰基或酰基一次或多次任选取代。
在此情况下优选卤素、羟基、氧代、硫代、烷氧基、烷硫基、氨基、氨基羰基、羧基和酰基基团。
低级烷基指C1-C6烷基,优选甲基、乙基、丙基、异丙基或叔丁基。
在上述基团R2和R3中的低级酰基指-C(O)-C1-C6烷基或C(O)H,优选乙酰基。
在R1、R4和R5中的烷基可一次或几次由杂原子(O、S、NH)任选间断。
在R4和R5中的烷基同上或与烷氧基、烷硫基、芳磺酰基、烷基磺酰基、烷基氨基羰基、芳基氨基羰基、烷基氨基、烷氧基羰基、芳氧基羰基、烷基氨基硫代羰基、芳基氨基硫代羰基、芳基氨基硫代羰基结合的一直链、支链、饱和的或不饱和的带有1-11个碳原子优选1-8个碳原子的基团,例如甲基、乙基、丙基、戊基、辛基、烯丙基、炔丙基、2,4-戊二烯基、异丙基、仲丁基、3-甲基丁基、2-羟己基,更优选甲基、丙基、异丙基、戊基、辛基、烯丙基、3-甲基丁基、2-羟基己基炔丙基。
也与芳氧基、芳硫基、芳磺酰基、芳氨基羰基、芳氧基羰基、芳氨基硫代羰基结合的芳基被认为是苯基或萘基,它任选尤其由卤素、低级烷基或烷氧基取代。
R1中的C1-C20烷基为直链或支链的饱和基团,例如,甲基、乙基、丙基、丁基、戊基、辛基、癸基、十一烷基、异丁基、3-甲基丁基或7-甲基辛基。首先认为羟基或氨基为取代基。烷基链可由氧、氮或硫一次或几次间断。优选的杂原子间断为氧(醚键)或-C(O)NH-(酰胺键)。最优选的间断杂原子基团为-(CH2CH2O)n-(CH2)mH,n=2或3,m=1或2。
R1的W优选甲基、乙基、丁基或己基;V优选由低级烷基、羟基、烷氧基酰胺基(alkoxyamid)、磺酰胺基或卤素优选取代的苯基、吡啶基、咪唑基。最优选的R1基团为C6-C12的烷基或-(CH2)nC6H4-(CH2)mH基团,其中m和n相等或小于8,基团(CH2)-可由氧、硫或NH任选间断,苯环的1或2个碳原子由N-杂原子取代。烷基、芳基、杂芳基可由小的极性取代基任选取代。
最优选的R1基团是含有2或3个氧杂原子如2-(2-(2-甲氧基乙氧基)-乙氧基)乙基,2-(2-乙氧基乙氧基)乙基的正辛基、正癸基、联苯基或辛基或癸基类型基团或为含有1或2个氮杂原子的联苯基类型基团。桥键单环任选邻位取代,联苯基或联苯基类型基团的末端单环可任选由小的极性取代基如NH2、-NO2、-SO2NH2、-SO2CH3、乙酰基、羟基、甲氧基、乙氧基或腈基基团邻位或对位取代。更优选末端单环的对位取代。
认为卤素是氯、溴、碘并优选氯。
R4和R5中的杂芳基团优选为吡啶、吡嗪、哌嗪、咪唑、噻唑、噻吩或吲哚环,更优选吡啶咪唑和噻吩环。
R4和R5基团中的酰基是带有1-10个碳原子,优选6-8个碳原子的基团,例如己酰基或辛酰基基团。烷基基团可由如S、O、NH、SO2、酰氨基或羰基的杂原子或杂原子基团一次或多次间断。这些基团可由氨基、烷基、芳基、芳烷基、烷基氨基、二烷基氨基、烷氧基基团或芳族化合物取代。它们是氨基酸基团时优选苯丙氨酸和色氨酸基团。
如果R4和R5及与其键连的氮原子形成一个环,它们是5-7元环,优选6元环。优选哌啶、哌嗪、四氢喹啉和四氢异喹啉、双环(9.4.0)十五烷基及1,2,3,4-四氢苯并(g)异喹啉环。
如果通式I化合物含有1个或几个不对称碳原子,那么通式I的光学活性化合物也在本发明内。
X、Y、Z相互独立优选为氧,R2和R3互独立地优选为氢。更优选的组合为X、Y和Z相互相等为氧而R2与R3相等都为氢。
也优选R4和R5不都代表氢。
与单环或双环中杂原子有关的术语“几个”优选1,2或3,更优选1或2,最优选的杂原子为氮。
与取代基或取代有关的术语“几个”优选1至5,更优选1,2或3,最优选1或2。
与烷基或酰基有关的术语“杂原子”优选氧、或NH,更优选氧。
R1、R4和R5中单环或双环的取代基为卤素、硝基、羟基、烷氧基、氨基、烷基氨基、二烷基氨基、卤代甲基、二卤代甲基、三卤代甲基、膦酰基、烷基膦酰基、二烷基膦酰基、SO2NH2、SO2NH(烷基)、SO2N(烷基)2、SO2(烷基)、乙酰基、甲酰基、腈基(nitril)、-COOH、COO烷基、OC(O)烷基、-NHC(O)O烷基、OC(O)O-芳基、-NHC(S)NH2、-NHC(S)NH烷基、NHCO)-芳基。
R4和R5与氮原子共同形成的环结构优选哌嗪或哌啶,二者都优选在4位取代。哌啶的4位可由羟基、氨基、烷基氨基、烷基氨基、二烷基氨基或烷氧基任选第二次取代。哌啶的4位也可与4位上的取代基形成双键。
哌啶或哌嗪的4位取代基优选6元芳族单环,更优选在芳族单环的对位上由小的极性取代基如羟基、低级烷氧基、氨基、低级烷基氨基、低级二烷基氨基、硝基、次氮基、SO2NH2、SO2NH低级烷基、SO2低级烷基取代。6元芳单环优选通过共价键或低级烷基间隔基与4位键合。
当R4为氢低级烷基低级烷基芳基时,则R5优选为优选由单环或低级烷基芳基取代的酰基衍生物;或-CHR50-CHR51-NR52-R53,其中R50和R51相互独立代表氢、低级烷基低级烷氧基。R52代表氢或低级烷基,R53代表一次或几次任选取代且优选通过共价键或低级烷基间隔基与氮原子键合的6元芳单环。
在通式I中最优选的结合为:X等于Y等于Z等于氧R2等于R3等于氢R1为正辛基、正癸基、联苯基或辛基或含有2或3个氧杂原子如2-(2-(2-甲氧基乙氧基)-乙氧基)乙基,2-(2-(2-乙氧基乙氧基)乙基的癸基类型基团,或含有1或2个氮杂原子的联苯基类型基团;其中桥键单环任选邻位取代,联苯基或联苯基类型基团的末端单环任选由小的极性取代基如NH2、-NO2、-SO2NH2、SO2CH3、乙酰基、羟基、甲氧基、乙氧基或腈基基团邻位或更优选对位取代。R4和R5与其键连的氮原子共同形成哌嗪或哌啶,二者都在4位上由优选在对位上由小的极性基团取代的苯基、吡啶基或吡嗪基(pyrazidyl)羟基、低级烷氧基、腈基或由低级烷基单或双取代的氨基取代。
通式I化合物可优选用以下熟知的方法来合成及可选转化为药学上可接受的盐:(a)使通式II化合物其中X、Y、Z、R1、R2和R3定义同上,T代表如卤素或OSO2R6的离去基团,卤素指氯、溴或碘,R6代表芳基或甲基,与通式III化合物反应并任选转化为其药学上可接受的盐:其中R4和R5定义同上,或b)使通式IV化合物其中R1、R4和R5定义同上,Y和Z相互独立代表氧、硫或NH基,R7等于甲基、乙基或苯基,与通式V化合物反应并任选转化为其药学上可接受的盐:其中R2、R3和X定义同上或当R4和/或R5代表酰基、烷基磺酰基、芳磺酰基、烷基氨基羰基、芳基氨基羰基、烷氧基羰基、芳氧基羰基、烷基氨基硫代羰基或芳氨基硫代羰基基团的情况下(c)使通式VI的化合物其中X、Y、Z、R1、R2和R3定义同上,与通式VII或VIII化合物反应:
R8-D-Hal(VII)R8N=C=A(VIII)其中R8代表任选取代的烷基或芳基基团,D=C(O),O-C(O),SO2或共价键。Hal=氯、溴或碘,A代表氧或硫。
通式II化合物在文献中有报道。例如5位上溴化的2,4,6-嘧啶三酮通过使适当的溴代丙二酸二烷基酯与脲反应来合成(如Acta Chim.Acad.Sci.Hung.107(2),139(1981))。通式II对应的溴化或氯化的化合物通过5位上R1取代的2,4,6-嘧啶三酮与溴(类似于J.pr.Chemie 136,329(1933)或J.Chem.Soc.1931,1870)或与磺酰氯(J.Chem,Soc.1938,1622)反应而制备。同样的方法可以合成对应在5位上卤化的通式II的2-亚氨基-4,6-嘧啶二酮,类似于Collect.Czech.Comm.48(1),299(1933)。5位上由R1取代的2-硫代-4,6-嘧啶二酮与溴在冰醋酸(类似于Am.Chem.J.34,186)中反应制得对应在5位上溴化的通式II化合物。
通式III胺市场上买得到或在文献中常有报道。
根据熟知的方法使通式IV化合物与脲(见J.Med.Chem.10,1078(1967)或Helvetica Chim.Acta 34,459(1959)或Pharmacie 38(1),65(1983)),硫脲(见Indian.J.Chem.24(10),1094(1985)或J.Het.Chem,18(3),635(1981))或通式V的胍(见如Collect.Czech.Chem.Comm.45(12),3583(1980))反应。
反应通常在如甲醇、乙醇或丁醇的醇中,在适当的醇钠存在下,在40-100℃温度范围内,若为胍时反应温度达到200℃以上(加压)的条件下进行。若为硫脲情况下反应一般在乙酰氯(也作为溶剂)存在下进行。
通式IV化合物文献中有报道或根据文献中已知的方法制备。例如它们可能通过对应的双内酰亚胺醚的弱酸水解来合成(见J.ChemSoc.Chem.Comm.5,400(1990))。合成的其它方法见例如Farmaco Ed.Sci,31(7),478(1976)或Aust.J.Chem.,23(6),1229(1970)中所述。
脲、硫脲及通式V胍市场上可买得到。
通式VI化合物可很容易由使适当的取代的乙酰胺基丙二酸酯根据方法b)反应及随后的乙酰基的水解断裂而合成(见Can.J.Chem.42(3),605(1964))。
通式VII羧酰氯是熟知的或可根据通用的方法从对应的羧酸来合成。反应通常与亚硫酰氯或三溴化磷或五溴化磷或五氯化磷在如二氯甲烷、***、二噁烷或四氢呋喃的惰性溶剂中,在0℃-50℃优选20℃-40℃温度下进行。
通式VII的氯甲酸酯是文献中熟知的或可根据已知通用的方法由对应的醇与光气或双光气反应而得到。反应在如***、二氯甲烷、二噁烷、四氢呋喃或甲苯的惰性溶剂中,在-20℃~20℃温度范围内进行。当光气反应时,反应在碱,通常为叔胺如三乙胺或吡啶存在下进行。
通式VII的磺酰氯是熟知的或可根据所述的类似的方法由对应的磺酸与五氯化磷或亚硫酰氯反应而合成。反应通常在如二甲基甲酰胺的惰性溶剂或也可无溶剂下,在20℃-180℃,优选50℃-100℃范围内进行。
通式VIII的异氰酸酯是熟知的或可通过文献中已知的方法合成。例如将通式R8-Hal的适当的卤代烷与氰酸钾反应,类似于Synthesis1978,760。另外的方法有使通式R8-CONH2的酰胺与草酰氯反应,通式R8-CON3的酰基叠氮的热分解,或通式R8-NH2的胺与光气反应(类似于Ann,Chem.562,110)。
通式VIII的异硫代氰酸酯是文献中熟知的或可通过类似于已知的方法来合成。通式R8-NH2的胺优选在碱性条件下与二硫化碳反应,类似于Chem.Ber.74,1375。
通式VII的羧酰卤、磺酰卤或氯甲酸酯与通式VI的胺反应通常在如二氯甲烷、二甲基甲酰胺或吡啶的溶剂中,在加入辅助碱如三乙胺或4-甲胺基吡啶下,在-10℃~50℃温度范围,优选室温下进行。
通式I化合物可含有1个或几个手性中心,可以以外消旋体或光学活性形式存在。外消旋体可根据熟知的方法分离成对映体。能从重结晶中分离出的非对映异构体的盐优选通过外消旋混合物与光学活性的酸如D-或L-酒石酸、扁桃酸、苹果酸、乳酸或樟酸磺酸或与光学活性的胺如D-或L-α-苯基乙胺、麻黄碱、奎尼丁或辛可尼定反应而制得。
主要用作药学上可接受的盐为碱性盐,碱土金属盐如Ca或Mg盐、铵盐、乙酸盐或盐酸盐,它们是根据常用的方法如用无机或有机碱或无机酸如氢氧化钠、氢氧化钾、氨水、如三乙胺的C1-C4-烷基胺或盐酸研磨(tritrating)化合物而制备。这些盐通常通过从水/丙酮中再沉淀来纯化。
根据本发明的式I的新化合物及其盐可以液体或固体的形式肠道内或胃肠外给药。在这方面所有常用的给药形式都考虑在内如片剂、胶囊、包衣片、糖浆剂、溶液剂、混悬剂等。注射剂的介质优选为含有通常用作注射液中添加剂如稳定剂、增溶剂及缓冲剂的水。
这些添加剂有如酒石酸盐和柠檬酸盐缓冲液,乙醇、配位剂(如乙二胺四乙酸及其非毒性盐)用来调节粘度的高分子聚合物(如液体的聚环氧乙烷)。用于注射液的载体物质必须是无菌的且优选分放于安瓿中。固体载体物质为如淀粉、乳糖、甘露糖醇、甲基纤维素。滑石粉、高度分散的硅酸、高分子脂肪酸(如硬脂酸)、明胶、琼脂、磷酸钙、硬脂酸镁、动植物脂肪、固体高分子聚合物(例如聚乙二醇);适当的口服应用的制剂可任选含有调味剂及甜味剂。
给药剂量依各种因素而定如给药方式、物种、年龄及/或个人体健康状况。每日的给药剂量约为10~1000mg/人,优选100-500mg/人,可单剂量或分剂量多次给药。
本发明化合物的前药为在体内转化成药理活性化合物的化合物。最普通的前药为羧酸酯。
在本发明的意义范围内除在实施例中提到的化合物以及在权利要求书中提到通过化合所有意义的取代基而衍生的化合物,以下给出的巴比妥酸衍生物是优选的。1.5-(N-苄基-N-辛基)-5-苯基巴比妥酸2.5-(N-苄基-N-苯乙基)-5-苯基巴比妥酸3.5-(N-苄基-N-[2-(4-吡啶基)乙基])-5-苯基巴比妥酸4.5-(N-苄基-N-[2-(3-吡啶基)乙基])-5-苯基巴比妥酸5.5-(N-苄基-N-[2-(2-吡啶基)乙基])-5-苯基巴比妥酸6.5-(N-苄基-N-[2-(2-硫代苯基)乙基])-5-苯基巴比妥酸7.5-[N-(3-甲基丁基)-N-(3-苯基丙基)]-5-苯基巴比妥酸8.5-(N-苄基-N-[3-(4-吡啶基)丙基])-5-苯基巴比妥酸9.5-(N-苄基-N-[2-(2-咪唑基)乙基])-5-苯基巴比妥酸10.5-(N-苄基-N-[2-(1-咪唑基)乙基])-5-苯基巴比妥酸11.5-(N-丁基-N-苯基丙氨酰基)-5-苯基巴比妥酸12.5-(N-丁基-N-色氨酰基)-5-苯基巴比妥酸13.5-(N-苄基-N-环己基)-5-苯基巴比妥酸14.5-(N-苄基-N-(2-吡啶基)]-5-苯基巴比妥酸15.5-[N-丁基-N-(4-哌啶基)]-5-苯基巴比妥酸16.5-[N-苄基-N-(2-咪唑基)]-5-苯基巴比妥酸17.5-(N-辛基-N苯基)-5-苯基巴比妥酸18.5-[N-(2-萘基)-N-丙基]-5-苯基巴比妥酸19.5-[N-(4-四氢喹啉基)-N-丙基]-5-苯基巴比妥酸20.5-[N-苄基-N-(2-硫代苯基)]-5-苯基巴比妥酸21.5-[N-(3-甲基丁基)-N-[3-(4-吡啶基)丙基)]-5-苯基巴比妥酸22.5-[N-(7-甲基辛基)-N-[3-(2-吡啶基)丙基)]-5-苯基巴比妥酸23.5-(N-(2-羟基己基)-N-[3-(3-吡啶基)丙基])-5-苯基巴比妥酸24.5-(N-苄基-N-己酰基)-5-苯基巴比妥酸25.5-(N-苄基-N-辛酰基)-5-苯基巴比妥酸26.5-(N-苄基-N-辛磺酰基)-5-苯基巴比妥酸27.5-[N-丁基-N-(2-萘磺酰基)]-5-苯基巴比妥酸28.5-[N-己氧基羰基-N-丙基)-5-苯基巴比妥酸29.5-[N-(4-甲氧基-苯磺酰基)-N-己基]-5-苯基巴比妥酸30.5-[N-(4-丁氧基苯磺酰基)]-N-己基]-5-苯基巴比妥酸31.5-[N-苄基-N-(2-苯乙基)]-5-(4-吡啶基)巴比妥酸32.5-[N-苄基-N-(2-苯乙基)]-5-(2-吡啶基)巴比妥酸33.5-(N,N-二戊基)-5-(4-哌啶基)巴比妥酸34.5-(N,N-二辛基)-5-(2-硫代苯基)巴比妥酸35.5-(N-苄基-N-[2-(2-吡啶基)乙基]-5-(3-咪唑基)巴比妥酸36.5-[1-(4-羟基)哌啶基]-5-(4-吡啶基)巴比妥酸37.5-[1-(4-羟基)哌啶基]-5-(3-吡啶基)巴比妥酸38.5-[1-(4-羟基)哌啶基]-5-(2-吡啶基)巴比妥酸39.5-[1-(4-羟基)哌啶基]-5-(4-哌啶基)巴比妥酸40.5-[1-(4-羟基)哌啶基]-5-(2-硫代苯基)巴比妥酸41.5-[1-(4-羟基)哌啶基]-5-(4-咪唑基)巴比妥酸42.5-苄基-5-[1-(4-羟基)哌啶基]巴比妥酸43.5-[1-(4-羟基)哌啶基]-5-(2-苯乙基)巴比妥酸44.5-[1-(4-羟基)哌啶基]-5-(1-萘基)巴比妥酸45.5-[1-(4-羟基)哌啶基]-5-(2-萘基)巴比妥酸46.5-(2-喹啉基)-5-[1-(4-羟基)哌啶基]巴比妥酸47.5-[1-(4-羟基)哌啶基]-5-(1-异喹啉基)巴比妥酸48.5-[1-(4-羟基)哌啶基]-5-(2-四氢喹啉基)巴比妥酸49.5-(2-吲哚基)-5-[1-(4-羟基)哌啶基]巴比妥酸50.5-(2-苯并咪唑基)-5-[1-(4-羟基)哌啶基]巴比妥酸51.5-(1-[4-(2-羟基乙基)哌啶基])-5-辛基巴比妥酸52.5-癸基-5-(1-[4-(2-羟基乙基)哌嗪基])巴比妥酸53.5-(1-[4-(2-羟基乙基)哌嗪基])-5-十一烷基巴比妥酸54.5-(1-[4-(2-羟基乙基)哌嗪基])-5-(7-甲基辛基)巴比妥酸55.5-(1-[4-(2-羟基乙基)哌嗪基])-5-(8-羟基辛基)巴比妥酸56.5-(8-氨基辛基)-5-(1-[4-(2-羟基乙基)哌嗪基])巴比妥酸57.5-(1-[4-(2-羟基乙基)哌嗪基])-5-(2-苯乙基)巴比妥酸58.5-(1-[4-(2-羟基乙基)哌嗪基])-5-(4-苯丁基)巴比妥酸59.5-(1-[4-(2-羟基乙基)哌嗪基])-5-(6-苯己基)巴比妥酸60.5-(1-[4-(2-羟基乙基)哌嗪基])-5-(6-(4-甲基苯基)己基]巴比妥酸61.5-(1-[4-(2-羟基乙基)哌嗪基])-5-(2-吡啶基甲基)巴比妥酸62.5-(1-[4-(2-羟基乙基)哌嗪基])-5-(4-咪唑基甲基)巴比妥酸63.5-(1-[4-(2-羟基乙基)哌嗪基])-5-(1-咪唑基甲基)巴比妥酸64.5-苯基-5-(1-(4-丙基)哌嗪基]巴比妥酸65.5-苯基-5-(1-四氢喹啉基)巴比妥酸66.5-苯基-5-(1-四氢异喹啉基)巴比妥酸67.5-苯基-5-[2-(1,2,3,4-四氢苯并(g)异喹啉基]巴比妥酸68.5-[2-(2-氮杂双环[9.4.0]十五烷基)]-5-苯基巴比妥酸69.5-[2-(2,11-二氮杂-12-氧代-双环[9.4.0]十五烷基)]-5-苯基巴比妥酸70.5-(1-[4-(1-氧代丙基)]哌啶基)-5-苯基巴比妥酸71.5-[1-(3-氧代-4-丙基)]哌啶基-5-苯基巴比妥酸72.5-苯基-5-[1-(4-丙基)哌嗪基]巴比妥酸73.5-[1-(3,5-二羟基-4-丙基)哌啶基]-5-苯基巴比妥酸74.5-(4-氯苯基)-5-[1-(4-羟基)]哌啶基]巴比妥酸75.5-(4-氯苄基)-5-[1-(4-羟基)]哌啶基]巴比妥酸76.5-[1-(4-羟基)哌啶基]-5-(4-甲氧基苄基)巴比妥酸77.3-甲基-5-[1-(4-羟基)哌啶基]-5-苯基巴比妥酸78.1-异丙基-5-[1-(4-羟基)哌啶基]-5-苯基巴比妥酸79.3-乙酰基-5-[1-(4-羟基)哌啶基]-5-苯基巴比妥酸80.5-[1-(4-甲氧基)哌啶基]-5-苯基-2-硫代巴比妥酸81.2-亚氨基-5-[1-(4-甲氧基)哌啶基]-5-苯基巴比妥酸82.5-[1-(4-甲氧基)哌啶基]-5-苯基-2,4,6-三亚氨基巴比妥酸83.4,6-二亚氨基-5-[1-(4-甲氧基)哌啶基]-5-苯基巴比妥酸84.5-[1-(4-甲氧基)哌啶基]-5-苯基-2,4,6-三硫代巴比妥酸85.5-(6-氨基己基)-5-[N-(2-羟乙基)哌嗪基]巴比妥酸86.5-(6-甲酰氨基己基)-5-[N-(2-羟乙基)哌嗪基]巴比妥酸87.5-(6-乙酰氨基己基)-5-[N-(2-羟乙基)哌嗪基]巴比妥酸88.5-[7-(乙氧基羰基)庚基]-5-[N-(2-羟乙基)哌嗪基]巴比妥酸89.5-(8-羟辛基)-5-[N-(2-羟乙基)哌嗪基]巴比妥酸90.5-(7-羧基庚基)-5-[N-(2-羟乙基)哌嗪基]巴比妥酸91.5-[7-(氨基羰基)庚基]-5-[N-(2-羟乙基)哌嗪基]巴比妥酸92.5-[3-((氨基羰基甲基)氨基羰基)丙基]-5-[N-(2-羟乙基)哌嗪基]巴比妥酸93.5-[6-(甲基氨基)己基]-5-[N-(4-硝基苯基)哌嗪基]巴比妥酸94.5-[4-(正丙氧基)丁基]-5-[N-(4-硝基苯基)哌嗪基]巴比妥酸95.5-[2-(2-(2-甲氧基乙氧基)乙氧基)乙基]-5-[N-(4-硝基苯基)哌嗪基]巴比妥酸96.5-[2-(2-(乙氧基)乙氧基)乙基]-5-[N-(4-硝基苯基)哌嗪基]巴比妥酸97.5-癸基-5-[N-(4-硝基苯基)哌嗪基]巴比妥酸98.5-辛基-5-[N-(4-羟基磺酰基)苯基)哌嗪基]巴比妥酸99.5-辛基-5-[N-(4-氨基磺酰基)苯基)哌嗪基]巴比妥酸100.5-辛基-5-[N-(4-氰基苯基)哌嗪基]巴比妥酸101.5-辛基-5-[N-(4-羧基苯基)哌嗪基]巴比妥酸102.5-辛基-5-[N-(4-丁氧基羰基)苯基)哌嗪基]巴比妥酸103.5-辛基-5-[N-(4-(脒基)苯基)哌嗪基]巴比妥酸104.5-辛基-5-[N-(4-(氨基硫代羰基)苯基)哌嗪基]巴比妥酸105.5-辛基-5-[N-(4-(甲磺酰基)苯基)哌嗪基]巴比妥酸106.5-辛基-5-[N-(4-氨基羰基)苯基)哌嗪基]巴比妥酸107.5-辛基-5-[N-(4-(甲基羰基)苯基)哌嗪基]巴比妥酸108.5-辛基-5-[N-(4-(二甲基膦酰基)苯基)哌嗪基]巴比妥酸109.5-辛基-5-[N-(4-(氨基)苯基)哌嗪基]巴比妥酸110.5-辛基-5-[N-(4-(乙酰氨基)苯基)哌嗪基]巴比妥酸111.5-辛基-5-[N-(4-(三氟乙酰胺基)苯基)哌嗪基]巴比妥酸112.5-辛基-5-[N-(4-(甲基磺酰胺基)苯基)哌嗪基]巴比妥酸113.5-辛基-5-[N-(5-硝基吡啶-2-基)哌嗪基]巴比妥酸114.5-辛基-5-[N-(N-氧代吡啶-4-基)哌嗪基]巴比妥酸115.5-辛基-5-[N-(4-(5-***基)苯基)哌嗪基]巴比妥酸116.5-辛基-5-[(N-苄酰基-N-苄基)氨基]巴比妥酸117.5-[4-(苯基)苯基]-5-[(N-苄酰基-N-苄基)氨基]巴比妥酸118.5-(4-[4-硝基苯基)哌嗪基])-5-辛基巴比妥酸119.N-苄基-3-(4-硝基苯基)-N-(2,4,6-三氧代-5-苯基-六氢嘧啶-5-基)丙烯酰胺120.5-[4-(苯基)苯基]-5-[(N-苄酰基-N-苄基)氨基]巴比妥酸121.N-苄基-2-(3-溴苯基)-N-(2,4,6-三氧代-5-苯基-六氢嘧啶-5-基)乙酰胺实施例15-(1-[4-(2-羟乙基)哌嗪基])-5-苯基巴比妥酸
将5-溴-5-苯基巴比妥酸(Acta Chim.Acad.Sci.Hung.107 139-45(1981))(7mmol)和N-(2-羟乙基)哌嗪(8mmol)混溶在40ml无水乙醇中。回流3小时后真空浓缩。残留物经硅胶层析(乙酸乙酯/甲醇3∶1)纯化。经异丙醇重结晶得到无色结晶。收率56%;Fp.238-40℃(分解)。实施例25-(1-[4-(4-甲基苯基)甲基]哌嗪基]-5-苯基巴比妥酸
将5-溴-5-苯基巴比妥酸(7mmol)和N-(甲基-p-甲苯基)哌嗪(8mmol)混溶在40ml无水乙醇中。回流2小时后真空浓缩。残留物用***研磨,吸去***,再用20ml***冲洗、干燥。粗品经硅胶层析(丙酮)纯化。得到无色结晶。收率72%;Fp.247-48℃。实施例35-(1-[4-(4-(4-甲基苯基))丁基]哌嗪基]-5-苯基巴比妥酸4-(对甲苯基)丁基溴
本化合物按文献类似的方法制备。Synth.Commus.22(20)2945-8(1992)。收率91%,无色油状物。苯基-(4-(对甲苯基)丁基)丙二酸二乙酯
将溶解在5ml无水四氢呋喃中的苯基丙二酸二乙酯(8.8mmol)滴加到20ml无水四氢呋喃和氢化钠(9.7mmol)中。15分钟后加入溶于10ml无水四氢呋喃的4-对甲苯基丁基溴(8.8mmol)。加热回流3天。真空浓缩溶剂。将残留物溶解在50ml乙酸乙酯中,用2×50ml水提取。有机相用硫酸镁干燥、过滤、蒸发浓缩。经硅胶层析(庚烷/乙酸乙酯9∶1)纯化。收率55%,无色油状物。5-1-[4-(4-(4-甲基苯基))丁基]哌嗪基)-5-苯基巴比妥酸
将脲(4.6mmol)和苯基-(4-(对甲苯基)丁基丙二酸二乙酯(3.1mmol)加入到乙醇钠(6.2mmol)的无水乙醇溶液中。加热回流12小时,真空浓缩,残留物溶解在15ml水中。用6N盐酸调节混合液的pH值至1-2,用2×30ml乙酸乙酯提取。有机相用硫酸镁干燥、过滤、蒸发浓缩。残留物经硅胶层析(庚烷/乙酸乙酯3∶1)纯化。收率46%,无色结晶;Fp.163-5℃。实施例45-(1-[4-(2-羟基乙基)哌啶基])-5-苯基巴比妥酸
将14.6g(50mmol)苯基丙二酸二乙酯及其后10g(166mmol)脲慢慢加入到搅拌的1.3g钠的40ml甲醇溶液中。加热微沸2小时。在此过程中有沉淀生成。冷却至10-15℃,然后慢慢混入12.9g(100mmol)4-(2-羟乙基)哌啶,13.8g(100mmol)碳酸钾和2.87ml(112.3mmol)溴。将混合液在10-15℃搅拌2小时,然后慢慢加热至沸腾,在回流下沸腾1小时。冷却,将反应液倒入240ml 1N硝酸中,溶液用甲苯洗涤1次,用饱和的乙酸钠溶液中和。生成脂膏状物质沉淀,将其溶于热的乙醇中。此热熔液用活性碳处理,加入热水混合直至混浊开始。冷却后吸滤得结晶。收率:7.3g=44%;Fp.222-223℃。实施例55-苯基-5-(1-哌啶基)巴比妥酸
用哌啶代替4-(2-羟乙基)哌啶根据实施例4类似的方法得到5-苯基-5-(1-哌啶基)巴比妥酸,收率92%;Fp.244-246℃。实施例65-[1-(4-羟基)哌啶基]-5-苯基巴比妥酸
用4-羟基哌啶代替4-(2-羟乙基)哌啶根据实施例4类似的方法得到5-[1-(4-羟基)哌啶基]-5-苯基巴比妥酸,收率39%;Fp:241-242℃(从乙醇中)。实施例75-[1-(4,4-二甲基)哌啶基]-5-苯基巴比妥酸
用4,4-二甲基哌啶代替4-(2-羟乙基)哌啶根据实施例4类似的方法得到5-[1-(4,4-二甲基)哌啶基]-5-苯基巴比妥酸,收率69%;Fp:238-240℃(从乙醇/水中)。实施例85-[1-(4-甲基)哌啶基]-5-苯基巴比妥酸
用4-甲基哌啶代替4-(2-羟乙基)哌啶根据实施例4类似的方法得到5-[1-(4-甲基)哌啶基]-5-苯基巴比妥酸,收率87%;Fp:208-209℃(从甲醇/水中)。实施例95-[1-(4-甲氧基)哌啶基]-5-苯基巴比妥酸
用4-甲氧基哌啶代替4-(2-羟乙基)哌啶根据实施例4类似的方法得到5-[1-(4-甲氧基)哌啶基]-5-苯基巴比妥酸,收率67%;Fp:184-185℃(从乙醇/水中)。实施例105-乙基-5-[1-(4-甲基)哌啶基]巴比妥酸
将14.1g(75mmol)乙基丙二酸二乙酯和15g(264mmol)脲先后慢慢加入到搅拌的1.95g钠的60ml甲醇中。沸腾2小时后产生沉淀。冷却至10-15℃,慢慢顺序混入15g(15mmol)4-甲基哌啶、21g(150mmol)碳酸钾和4.3ml(168mmol)溴。在同一温度下将混合液搅拌2小时,慢慢加热至沸,加热回流1小时。冷却后将反应液倒入360ml 1N硝酸中,溶液用甲苯洗涤1次,再混合过量的饱和乙酸钠溶液。将析出的沉淀从乙醇中加入活性炭重结晶。收率:4.4g=23%;Fp:194-195℃。实施例115-乙基-5-[1-(4-甲氧基)哌啶基]巴比妥酸
用4-甲氧基哌啶代替4-甲基哌啶,用实施例10类似的方法得到5-乙基-5-[1-(4-甲氧基)哌啶基]巴比妥酸,收率15%;Fp.:201-202℃(从乙醇中)。实施例125-乙基-5-(1-(4-羟基)哌啶基]巴比妥酸
用4-羟基哌啶代替4-甲氧基哌啶,用实施例10类似的方法得到5-乙基-5-(1-(4-羟基)哌啶基]巴比妥酸,收率5%;Fp.:110-112℃(从乙醇中)。实施例135-乙基-5-[1-(4-(2-羟乙基)哌啶基)]巴比妥酸
用4-(2-羟乙基)哌啶代替4-甲基哌啶,用实施例10类似的方法得到5-乙基-5-[1-(4-(2-羟乙基)哌啶基)]巴比妥酸,收率17%;Fp:238-240℃(从甲醇中)。实施例145-(4-甲氧基苯基)-5-[N-(2-羟乙基)哌嗪基]巴比妥酸a)4-甲氧基苯基乙酸乙酯的制备
将4-甲氧基苯基乙酸(2g)和对甲苯磺酸(230mg)的30ml乙醇溶液回流2小时。减压蒸除溶剂,将残留物混溶在饱和的碳酸氢钠水溶液中,用乙酸乙酯提取2次。收集有机提取液,用水洗涤,用硫酸钠干燥,减压蒸除溶剂后得产物2.14g。b)4-甲氧基苯基丙二酸乙酯的制备
将4-甲氧基苯基乙酸乙酯(27.8g)和钠(3.68g)的90ml碳酸二乙酯混合液回流3小时,减压蒸除溶剂,残留物用水稀释,用乙酸中和。水相用***提取两次。收集有机提取液,用1N氢氧化钠洗涤2次,用水洗1次,再将有机相用硫酸钠干燥,浓缩至干。得到产物34.2g。c)5-(4-甲氧基苯基)巴比妥酸的制备
向660mg钠的50ml乙醇溶液中加入3.86g4-甲氧基苯基丙二酸乙酯和1.28g脲。将所述反应混合液回流3小时。析出白色固体,过滤收集,将其再溶于15ml水中。加入6N盐酸酸化溶液至pH=1-2。过滤,用水在滤器上冲洗得白色固体。50℃下减压干燥数小时,得到产物2.28g。d)5-溴-5-(4-甲氧基苯基)巴比妥酸的制备
向冰浴冷却至0-5℃的5-(4-甲氧基苯基)巴比妥酸(222mg)的3ml水混悬液中滴加136μl的48%的氢溴酸和56μl的溴。在温度低于10℃1小时后,过滤收集固体,用水在滤器上冲洗固体。在50℃减压干燥数小时,得产物283mg。e)标题化合物的制备
将5-溴-5-(4-甲氧基苯基)巴比妥酸(11.5g)和N-(2-羟乙基)哌嗪(15.755g)的260ml甲醇溶液回流约2小时,过滤收集固体,将固体溶于100ml甲醇中加热回流1小时。再次过滤得固体,80℃下真空干燥得含8-9%甲醇的9g产物。将固体溶于40ml 1N盐酸中,用3.42g碳酸氢钠碱化溶液,再于0-5℃冷却4小时。过滤得产物,在80℃下真空干燥数小时得到纯品8.55g,m.p.247-248℃。1H-NMR in d6-DMSO:2.36 ppm(m,6H);2.55 ppm(m,4H);3.44 ppm(q,2H);3.74ppm(s,3H);4.33 ppm(t.1H);6.95 ppm(d,2H);7.3 ppm(d,2H);11.54 ppm(br s,2H).实施例155-[3-(4-甲氧基苯基)丙基]-5-[4-(2-羟乙基)哌嗪基]巴比妥酸a)3-(4-甲氧基苯基)丙酰氯的制备
在3-(4-甲氧基苯基)丙酸(10g)的150ml甲苯的混悬液中加入8ml亚硫酰氯,将混合液加热至65℃4小时。减压蒸除溶剂,再将残留物溶解在甲苯中,然后浓缩至干。此步骤重复2次。得到11g产物,为黄色油状物。b)5-[3-(4-甲氧基苯基)丙酰基]巴比妥酸的制备
在巴比妥酸(6.4g)的48ml吡啶混悬液中滴加11g 3-(4-甲氧基苯基)丙酰氯,室温下搅拌所述混合液18小时。然后将反应混合液倾入到冰水中,用6N盐酸酸化pH=1。固体沉淀,过滤,再将其混溶于甲醇中。将此混悬液搅拌15分钟,过滤得固体产物12.2g,m.p.248-250℃。c)5-[3-(4-甲氧基苯基)丙基]巴比妥酸的制备
在5-[3-(4-甲氧基苯基)丙酰基]巴比妥酸(10g)的100ml乙酸液中分部分加入4.5g氰硼氢化钠,将混合液加热至60℃。1小时后将所述反应混合液冷却至室温,再倒入冰水中。30分钟后过滤得固体,50℃下真空干燥得产物8.74g,m.p.195-197℃。d)5-溴-5-[3-(4-甲氧基苯基)丙基]巴比妥酸的制备
将5-[3-(4-甲氧基苯基)丙基]巴比妥酸(2.5g)、N-溴代琥珀酰亚胺(2g)和过氧化二苯甲酰(催化量)的110ml的四氯化碳溶液回流约1小时,然后过滤得固体。将固体再溶解在乙酸乙酯中,通过硅胶饼过滤以除去琥珀酰亚胺残留物。将有机相浓缩至干,残留物用***/四氯化碳混合液结晶。过滤分离浅黄色固体,在60℃下真空干燥得产物2.8g,m.p.113-114℃。e)标题化合物的制备
将5-溴-5-[3-(4-甲氧基苯基)丙基]巴比妥酸(710mg)和N-(2-羟乙基)哌嗪(281mg)的25ml乙醇溶液加热回流4小时。减压蒸除溶剂,将残留物在1N盐酸和乙酸乙酯中分配。水相碱化至pH=6-7,再用乙酸乙酯提取。将有机相浓缩至干,残留物用乙酸乙酯结晶得产物30mg。1H-NMR in d6-DMSO:1.32 ppm(m,2H);1.86 ppm(m,2H);2.33 ppm(m,6H);2.45ppm(m,2H);2.53 ppm(m,4H);3.43 ppm(q,2H);3.7 ppm(s,3H);4.35 ppm(t,1H);6.8 ppm(d,2H);7.04 ppm(d,2H);11.53 ppm(br s,2H).实施例165-苯基-5-[4-(2-羟基亚乙基)哌啶基]巴比妥酸a)4-(乙氧基羰基亚甲基)哌啶的制备
在冷却至0℃,保持通氮气下在氢化钠(2.6g)的30ml四氢呋喃混悬液中滴加溶于10ml四氢呋喃中的13ml膦酰基乙酸三乙酯。然后将温度升至室温,继续搅拌30分钟。再将混合液冷却至0℃,滴加通过分部加入2.6g氢化钠至4-哌啶酮单水合物盐酸盐(10g)的THF溶液中得到的溶液,过滤除去生成的氯化钠。加料完毕后将温度升至室温,继续搅拌20小时。然后减压除溶剂,将残留物再溶于乙酸乙酯中,用1N盐酸洗涤。水相用乙酸乙酯和氯仿提取,然后加入20%氢氧化钠碱化至pH=9-10,再用氯仿提取。然后使水相成盐,用氯仿提取三次。合并的提取液用硫酸钠干燥,蒸发得黄色油状产物7.1g。b)4-(羟基亚乙基)哌啶的制备
在15ml DIBAL(1.5M的甲苯溶液)在20ml甲苯中的溶液中滴加溶于数毫升甲苯中的0.976g 4-(乙氧基羰基亚甲基)哌啶。将反应混合物室温下搅拌2小时,然后冷却至0-5℃,滴加甲醇直至看到气体生成。将反应混合液浓缩至小体积,再加入***,生成白色固体,过滤除去。将有机相浓缩至干,加入***再溶解,再过滤。将澄清溶液浓缩至干得产物500mg。c)标题化合物的制备
将5-溴-5-苯基巴比妥酸(2.45g),4-(羟基亚乙基)哌啶(1.053g)和三乙胺(1.15ml)的50ml乙醇混合液回流2小时。减压蒸除溶剂,残留物经硅胶层析(40g;洗脱剂:乙酸乙酯/石油醚8∶2)纯化得产物450mg。1H-NMR in d6-DMSO:2.13 ppm(m,4H);2.55 ppm(m,4H);3.89 ppm(d,2H];4.46ppm(br s,1H);5.24 ppm(t,1H);7.42 ppm(m,5H);11.6 ppm(br s,2H).
亦得到作为副产物的5-苯基-5-[4-(2-羟乙基)-1,2-5,6-四氢吡啶基]比妥酸50mg。1H-NMR in d6-DMSO:1.96 ppm(m,2H);2.09 ppm(t,2H);2.64 ppm(t,2H);3.00ppm(m,2H);3.47 ppm(q,2H);4.43 ppm(t,1H);5.3 ppm(m,1H);7.4 ppm(s,5H);11.63 ppm(br s,2H).实施例175-苯基-5-[N-(2-羟乙基)哌嗪基]-2-硫代巴比妥酸a)2-溴-2-苯基丙二酸二乙酯的制备
在保持0℃通氮气下,在2-苯基丙二酸二乙酯(15ml)的200ml四氢呋喃溶液中加入3.475g氢化钠,在0℃下将所述混合液搅拌30分钟然后升至室温。再冷却至0℃,向反应混合液中加入14.3g N-溴琥珀酰亚胺。约15分钟后滤除生成的白色固体,将滤液浓缩至干,将残留物再溶于氯仿中,用硫酸钠干燥。减压蒸除溶剂得产物15.66g。b)2-苯基-2-[4-(2-羟乙基)哌嗪基]丙二酸二乙酯的制备
将2-溴-2-苯基丙二酸二乙酯(16.8g)的150ml二甲基亚砜溶液加热至90-100℃,然后加入N-(2-羟乙基)哌嗪(27.9g),再将反应液加热4小时。将反应液倒入水中,用乙酸乙酯提取三次。收集的有机提取液用1N盐酸冲洗。水相用1N氢氧化钠碱化pH=8-9,用乙酸乙酯提取2次。收集有机提取液,用饱和的氯化钠水溶液洗涤,用硫酸钠干燥。减压去除溶剂,残留物用***/石油醚1∶1结晶,得产物6.5g,m.p.63-64℃。c)标题化合物的制备
在钠(27mg)的3ml乙醇溶液中加入218mg 2-苯基-2[4-(2-羟乙基)哌嗪基]丙二酸二乙酯和288mg硫脲,再将所述混合液回流约13小时。将所述反应混合液冷却至室温,加入140μl乙酸,然后减压蒸除溶剂。再将残留物溶解在乙酸乙酯/甲醇9∶1混合液中。滤除生成的固体,滤液浓缩至干,经硅胶层析(洗脱剂:从乙酸乙酯至乙酸乙酯/甲醇9∶1)纯化,经乙酸乙酯结晶得到产物30mg,m.p.>250℃。1H-NMR in d6-DMSO:2.4 ppm(m,6H);2.59 ppm(m,4H);3.46 ppm(q,2H);4.4ppm(t,1H);7.4 ppm(m,5H);12.5 ppm(br s,2H).实施例185-苯基-5-[N-(2-羟乙基)哌嗪基]-2-偶氮巴比妥酸在钠(70mg)的5ml乙醇溶液中加入218mg 2-苯基-2-[4-(2-羟乙基)哌嗪基]丙二酸二乙酯(实施例4-步骤b)和172mg盐酸胍,将所述混合液回流8小时。再加入57mg的盐酸胍,将混合液再回流6小时。温度升至室温,加入乙酸至中和,滤除生成的固体。将滤液浓缩至干,再加乙醇溶解残留物,加入乙酸乙酯生成固体。在-4℃下1小时过滤得白色固体,用甲醇(2ml)重结晶,在90℃下真空干燥4小时得产物78mg,m.p>250℃。1H-NMR in d6-DMSO:2.33 ppm(m,6H);2.54 ppm(m,4H);3.41 ppm(t,2H);4.33ppm(br s,1H);7.00 ppm(br s,1H);7.33 ppm(m,5H);7.5 ppm(br s,1H);11.4 ppm(br s,1H).实施例195-苄基-5-[N-(2-羟乙基)哌嗪基]巴比妥酸a)5-亚苄基巴比妥酸的制备
将5g巴比妥酸的50ml水混悬液加热至完全溶解,然后加入4.3ml苯甲醛(benzaldheide)。将混合液回流1小时,过滤分离出的固体,用水冲洗数次,在100℃下真空干燥得产物8.17g,m.p.>258℃。b)5-苄基巴比妥酸的制备
在5-亚苄基巴比妥酸(4g)的200ml甲醇混悬液中分部分加入1.4g硼氢化钠。加完10分钟后,加入100ml水,用1N盐酸酸化所述混合液至pH=2。蒸除溶剂,水相用乙酸乙酯提取。合并的提取液用硫酸钠干燥,浓缩至干得结晶状产物3.6g,m.p.207-209℃。c)5-溴-5-苄基巴比妥酸的制备
在冷却至0-5℃的5-苄基巴比妥酸(1.7g)的15ml水混悬液中加入1ml 48%的氢溴酸,然后滴加0.437ml溴至所述反应混合液中。在低于10℃下搅拌1小时后,过滤分离生成的固体,用水冲洗得产物2.17g,m.p.164-166℃。d)标题化合物的制备。
将5-溴-5-苄基巴比妥酸(2.15g)和N-(2-羟乙基)哌嗪的50ml乙醇溶液回流4小时,然后冷至室温加入4ml三乙胺。蒸除溶剂,将白色残留物溶于乙酸乙酯/甲醇3∶1混合液中。生成桔黄色结晶,过滤收集。从乙醇中重结晶得产物0.62g,m.p.243-246℃。1H-NMR in d6-DMSO:2.43 ppm(t,2H);2.58 ppm(m,4H);3.03 ppm(m,4H);3.34ppm(s,2H);3.49 ppm(q,2H);4.5 ppm(t,1H);7.13 ppm(m,5H);8.8 ppm(br s,2H).实施例205-[N-(2-羟乙基)哌嗪基]-5-(4-羟基苯基)巴比妥酸a)5-(4-羟基苯基)巴比妥酸的制备
在保持-5/-10℃通氮气下,在5-(4-甲氧基苯基)巴比妥酸(222mg)的5ml二氯甲烷混悬液中滴加溶于2ml二氯甲烷中的三溴化硼(473μl)溶液。在-5℃下继续搅拌2小时,然后将温度升至室温继续搅拌20小时。再用冰浴将反应液冷却至0℃,滴加5%的氢氧化钠碱化至pH=9-10。分离水相,用硅藻土塞过滤,冰浴冷却,用37%的盐酸酸化至pH=1。1小时后过滤分离白色固体,在60℃下真空干燥得到所述产物215mg。b)5-[4-(叔丁基二甲基硅烷氧基)苯基)巴比妥酸
在5-(4-羟基苯基)巴比妥酸(1.9g)和叔丁基二甲硅烷氯(4.68g)的20ml无水二甲基甲酰胺溶液中加入4.4g咪唑,将所述混合液加热至55℃5小时。然后降至室温,将所述反应混合物倒入1N盐酸中,用乙酸乙酯提取2次。合并的有机提取液用水冲洗,用硫酸钠干燥。浓缩溶液得白色固体,在0℃下保持过夜,然后过滤得产物2.185g。c)5-溴-5-[(4-叔丁基二甲基硅烷氧基)苯基]巴比妥酸的制备
在5-[4-(叔丁基二甲基硅烷氧基)苯基]巴比妥酸(330mg)和过氧化二苯甲酰(催化剂量)的10ml四氯化碳混悬液中加入210mg N-溴琥珀酰亚胺。将所述混合液在室温下搅拌1小时。然后蒸除溶剂,残留物经硅胶层析(洗脱剂:石油醚/乙酸乙酯8∶2)纯化得产物260mg。d)5-[N-(2-羟乙基)哌嗪基]-5-[((4-叔丁基二甲基硅烷基氧基)苯基]巴比妥酸的制备
将5-溴-5-[(4-叔丁基二甲硅烷氧基)苯基]巴比妥酸(260mg)和N-(2-羟乙基)哌嗪(98mg)的5ml乙醇溶液回流1小时,然后降至室温,加入0.3ml三乙胺。蒸除溶剂,残留物经硅胶层析(25g;洗脱剂:乙酸乙酯/甲醇3∶1)纯化,用乙酸乙酯结晶后,得产物170mg,m.p.220-221℃。
e)标题化合物的制备
将5-[N-(2-羟乙基)哌嗪基]-5-[(4-叔丁基二甲基硅烷基氧)苯基]巴比妥酸(148mg),氟化四丁基铵(1.1M于THF中;0.6ml)和乙酸(290μl)的10ml四氢呋喃混合液在0℃下搅拌2小时30分钟,然后蒸除溶剂,残留物经硅胶层析(12g;洗脱剂:乙酸乙酯/甲醇3∶1)纯化,经乙酸乙酯结晶后再经乙酸乙酯/甲醇重结晶后得产物40mg,m.p.>25℃。1H-NMR in d6-DMSO:2.37 ppm(m,6H);2.55 ppm(m,4H);3.45 ppm(q,2H),4.35ppm(t,1H);6.76 ppm(d,2H);7.17 ppm(d,2H);9.72 ppm(s,1H);11.47 ppm(br s,2H).实施例215-[N-(2-羟乙基)哌嗪基]-5-(3-羟基苯基)巴比妥酸
a)3-羟基苯基乙酸乙酯的制备
将3-羟基苯基乙酸(5.4g)和对甲苯磺酸(650mg)的80ml乙醇混悬液回流4小时,然后蒸除溶剂,残留物溶解在乙酸乙酯中,用饱和的碳酸氢钠水溶液洗涤2次,有机相用硫酸钠干燥,蒸除溶剂得黄色油状产物6.08g。
b)3-(叔丁基二甲硅烷氧基)苯基乙酸乙酯的制备
在3-羟基苯基乙酸乙酯(6g)和叔丁二甲硅烷氯(6g)的80ml无水二甲基甲酰胺溶液中加入5.66g咪唑,将混合液在室温下搅拌1小时30分钟。然后将反应混合液倒入水中,用乙酸乙酯提取2次。合并的有机萃取液用硫酸钠干燥,浓缩至干得到黄色油状产物10g。
c)3-(叔丁基二甲硅烷氧基)苯基丙二酸二乙酯的制备
在3-(叔丁基二甲硅烷基氧基)苯基乙酸乙酯(10g)的25ml碳酸二乙酯溶液中分部分加入0.86g钠,将混合液回流2小时。蒸除溶剂,残留物倒入水中(90ml)。用乙酸调节pH=6,混合液用***提取。有机相用硫酸钠干燥,浓缩至干得到桔黄色油状物10g,经硅胶层析(洗脱剂:石油醚/乙酸乙酯95∶5)纯化得到产物2.45g。
d)5-[3-(叔丁基二甲硅烷氧基)苯基]巴比妥酸的制备
在3-(叔丁基二甲基硅烷基氧基)苯基丙二酸二乙酯(1.5g)的15ml乙醇溶液中加入0.445g乙醇钠和0.295g脲,将混合液回流3小时。将所述反应混合液冷至室温,过滤收集的固体。将固体再溶于水中,用6N盐酸调节pH=1-2,过滤生成沉淀的固体。浓缩滤液除去乙醇,然后碱化溶液,用乙酸乙酯提取。将有机相浓缩至干得250mg残留物,与前面过滤收集的沉淀(350mg)合并。如此所得残留物中含有产物及去硅烷基化衍生物的混合物。
将该残留物(550mg)溶解于5ml无水二甲基甲酰胺中,顺序加入790mg叔丁基二甲硅烷基氯和745mg的咪唑。将反应液加热至55℃5小时。再加入75mg咪唑和79mg叔丁基二甲硅烷基氯,继续加热1小时。将反应混合液倒入1N盐酸中,用乙酸乙酯提取3次。合并有机提取液用水洗涤,用硫酸钠干燥。浓缩溶液,生成白色固体沉淀。过滤得产物710mg。
e)5-[3-(叔丁基二甲硅烷氧基)苯基]-5-溴代巴比妥酸的制备
将5-[3-(叔丁基二甲硅烷氧基)苯基]-5-溴代巴比妥酸(680mg)、N-溴代琥珀酰亚胺(432mg)和过氧化二苯甲酰(催化剂量)的10ml四氯化碳混合液室温下搅拌1小时。蒸除溶液,残留物经硅胶层析(洗脱剂:乙酸乙酯/己烷7∶3)纯化得产物550mg,m.p.170-172℃。
f)5-[N-(2-羟乙基)哌嗪基]-5-[3-(叔丁基二甲硅烷氧基)苯基]巴比妥酸的制备
将5-[3-(叔丁基二甲硅烷氧基)苯基]-5-溴代巴比妥酸(444mg)和N-(2-羟乙基)哌嗪(420mg)的10ml甲醇溶液室温下搅拌5小时,然后蒸除溶剂,残留物经硅胶层析(13g;洗脱剂:乙酸乙酯/甲醇3∶1)纯化,得产物70mg。
g)标题化合物的制备
在保持0℃通氮气下,在5-[N-(2-羟乙基)哌嗪基]-5-[3-(叔丁基二甲硅烷氧基)苯基]巴比妥酸(170mg)的12ml四氢呋喃溶液中加入333μl乙酸和0.69ml氟化四丁基铵。将混合液搅拌3小时,蒸除溶剂,残留物经硅胶层析(15g;洗脱剂:乙酸乙酯/甲醇4∶1)纯化,经甲醇重结晶后得产物35mg,m.p.219-221℃。1H-NMR in d6-DMSO:2.37 ppm(m,6H);2.59 ppm(m,4H);3.45 ppm(q,2H);4.35ppm(t,1H);6.74 ppm(m,2H);6.92 ppm(t,1H);7.18 ppm(t,1H);9.62 ppm(s,1H);11.54 ppm(br s,2H).实施例225-[N-(2-羟乙基)哌嗪基]-5-(4-甲基苯基)巴比妥酸
a)5-(4-甲基苯基)巴比妥酸的制备
在钠(184mg)的12ml乙醇溶液中加入0.95ml 2-(4-甲基苯基)丙二酸二乙酯和360mg脲,然后将混合液回流3小时。过滤生成的白色固体,将其溶解在40ml水中。加6N盐酸酸化pH=1-2。过滤收集生成的白色固体,用15ml水冲洗,真空干燥。得产物619mg,m.p.271℃。
b)5-溴-5-(4-甲基苯基)巴比妥酸的制备
在保持10℃搅拌下向5-(4-甲基苯基)巴比妥酸(218mg)的2ml水的混悬液中加入136μl48%的氢溴酸,然后滴加56μl的溴,继续搅拌3小时。过滤收集生成的沉淀,用水洗涤,然后真空干燥得产物270mg,m.p.210-213℃。
c)标题化合物的制备
将5-溴-5-(4-甲基苯基)巴比妥酸(3.1g)和N-(2-羟乙基)哌嗪(1.53g)的60ml乙醇溶液回流3小时。蒸除溶剂,将残留物溶解在1N盐酸中,用乙酸乙酯洗涤2次。水相用1N氢氧化钠碱化,用乙酸乙酯提取。将有机提取物浓缩至干,残留物经硅胶层析(100g;洗脱剂:乙酸乙酯/甲醇3∶1)纯化,蒸除溶剂后得到产物的氢溴酸盐1.97g。
将该盐的乙酸乙酯(200ml)混悬液用50ml饱和碳酸氢钠水溶液处理,再用乙酸乙酯提取水相得到游离碱。经浓缩至干从合并的有机提取物中得到产物1.18g。1H-NMR in d6-DMSO:2.3 ppm(s,3H);2.35 ppm(m,6H);2.57 ppm(m,4H);3.45ppm(q,2H);4.35 ppm(t,1H);7.19 ppm(d,2H);7.28 ppm(d,2H);11.55 ppm(br s,2H).实施例235-辛基-5-[N-(2-羟乙基)哌嗪基]巴比妥酸
a)2-辛基丙二酸二乙酯的制备
在2.63g钠的100ml乙醇溶液中滴加19.1ml丙二酸二乙醇的10ml乙醇溶液。在混合液中顺序加入溶于10ml乙醇中的20.4ml的1-溴辛烷溶液,然后将混合液回流6小时。将反应混合液浓缩至小体积,残留物在饱和碳酸氢钠水溶液(200ml)和乙酸乙酯(200ml)间分配。有机相用75ml水和75ml饱和的氯化钠溶液洗涤,用硫酸钠干燥,浓缩至干,得一油状产物3.18g。1H-NMR in CDCl3:0.80-0.95 ppm(m,3H);1.15-1.40 ppm(m,18H),1.88 ppm(q,2H);3.33 ppm(t,1H);4.19 ppm(q,4H).
b)5-辛基巴比妥酸的制备
在钠(5.32g)的400ml无水乙醇溶液中加入2-辛基丙二酸二乙酯(31.5g)的50ml乙醇溶液,再加入10.27g脲,然后将混合液回流2小时30分钟。将混合液迅速冷至室温,过滤收集生成的固体,用***洗涤。然后将固体溶于200ml水中,用6N盐酸酸化至pH=1.5-2。分离出固体。混合液中加入200ml乙酯乙酯,将其搅拌2小时,然后加800ml热乙酸乙酯。分离有机相,水相用200ml乙酸乙酯洗涤。合并有机相用250ml饱和氯化钠水溶液洗涤,用硫酸钠干燥,浓缩至干,得产物21.03g。1H-NMR in d6-DMSO:0.77-0.80 ppm(m,3H);1.23 ppm(s,12H);1.80-1.95 ppm(m,2H);3.52 ppm(t,1H);11.15 ppm(s,2H).
c)5-溴-5-辛基巴比妥酸的制备
在冷却至0-5℃的5-辛基巴比妥酸(20g)的120ml水混悬液中加入12ml 48%的氢溴酸,再滴加4.72ml溴。搅拌2小时后过滤收集生成的白色固体,用水洗涤,再在200ml***和100ml水中分配。水相再用50ml***提取。合并的有机相用75ml饱和的氯化钠水溶液洗涤,用硫酸钠干燥,浓缩至干,得白色固体产物25.8g。1H-NMR in d6-DMSO:0.78-0.90 ppm(m,3H);1.10-1.38 ppm(m,12H);2.20-2.34ppm(m,2H);11.80 ppm(s,2H).
d)标题化合物的制备
在温度5-10℃通氮气下,在5-溴-5-辛基巴比妥酸(23.52g)的70ml二甲亚砜溶液中滴加N-(2-羟乙基)哌嗪(36.2ml),然后将混合液在室温下搅拌2小时30分钟。将反应混合液倒入搅拌冰浴冷却下的水(1L)中。过滤收集生成的白色固体,用水冲洗,在40℃下40℃真空干燥,用乙醇(140ml)结晶,得到白色固体状产物10.91g,m.p.183-184℃。1H-NMR in d6-DMSO:0.75-0.88 ppm(m,3H);0.90-1.10 ppm(m,2H);1.12-1.30 ppm(m,10H);1.75-1.90 ppm(m,2H);2.23-2.40 ppm(m,6H);2.45-2.60 ppm(m,4H);3.45ppm(br t,2H);4.35 ppm(br s,1H);11.55 ppm(s,2H).
实施例24
5-萘基-5-[N-(2-羟乙基)哌嗪基]巴比妥酸
a)2-萘基乙酸乙酯的制备
在2-萘基乙酸(5g)的50ml乙醇溶液中加入0.5g对甲苯磺酸,然后将反应混合液回流约4小时。蒸除溶剂,将残留物溶于***中,用饱和的碳酸氢钠水溶液洗涤2次,用盐水洗一次,然后将合并的有机相用硫酸钠干燥,浓缩至干。得到为黄色油状的产物5.64g。
b)2-萘基丙二酸二乙酯的制备
在室温搅拌下向2-萘基乙酸乙酯的23.3ml的碳酸二乙酯溶液中分部分加入0.232g钠。将反应混合液回流2小时30分钟,然后浓缩以除去未反应的碳酸二乙酯,再加入20ml冷水。然后用乙酸酸化混合液直至呈弱酸性,再用***提取3次。将合并的有机提取液用硫酸钠干燥,蒸除溶剂,用***(19ml)重结晶后得白色固体产物1.015g。
c)5-萘基巴比妥酸的制备
在钠(0.32g)的30ml无水乙醇溶液中加入2-萘基丙二酸二乙酯(2g),再加入脲(0.63g)。将混合液回流2小时,然后过滤收集生成的固体,再将固体溶解在7ml水中,用6N盐酸酸化pH=1。搅拌30分钟后过滤生成的白色固体沉淀,用水洗。在40℃真空下干燥过夜,得产物0.96g。
d)5-溴-5-萘基巴比妥酸的制备
在冷却至0℃搅拌下的5-萘基巴比妥酸(0.2g)的1.5ml 95%乙醇混悬液中滴加48%的氢溴酸(0.5ml),再滴加4.4μl溴。室温下搅拌4小时后,过滤固体,用水冲洗,在40℃下真空干燥过夜得产物0.25g。
e)标题化合物的制备
在5-溴-5-萘基巴比妥酸(0.24g)的3.5ml乙醇混悬液中加入N-(2-羟乙基)哌嗪(0.112g)的1.5ml乙醇溶液。然后将反应混合液回流5小时,然后冷至室温,滤除生成的固体。滤液中加入100μl三乙胺,然后蒸除溶剂得0.364g固体,用甲醇(4.5ml)和乙酸乙酯(10ml)的混合液重结晶。得到的固体(70mg)在搅拌下用乙酸乙酯/水混合液洗涤2小时,在40℃下真空干燥8小时得产品60mg。1H-NMR in d6-DMSO:2.3-2.5 ppm(m,6H);2.6 ppm(m,4H);3.45 ppm(m,2H);4.35ppm(t,1H);7.4-8.1 ppm(m,7H);11.65 ppm(s,2H).
实施例25
5-(4’-联苯基)-5-[N-(2-羟乙基)哌嗪基]巴比妥酸
a)(4’-联苯基)乙酸乙酯的制备
在(4’-联苯基)乙酸(6.4g)的60ml乙醇混悬液中加入1.1g对甲苯磺酸,然后将反应混合液回流4小时30分钟。蒸除溶剂,将残留物溶解在***中,有机相用饱和的碳酸氢钠水溶液洗涤3次,用盐水洗一次。然后用硫酸钠干燥有机相,蒸除溶剂得黄色油状产物7.1g。
b)(4’-联苯基)丙二酸二乙酯的制备
在保持通氮气的(4’-联苯基)乙酸乙酯(7.1g)的60ml碳酸二乙酯溶液中分部分加入钠(0.734g),然后加热至120℃3小时。蒸除溶剂,将残留物溶解在65ml冷水中,再用乙酸酸化至pH=5-6。用***提取水相3次,将合并的有机相用硫酸钠干燥,浓缩至干。残留物经硅胶层析(洗脱剂:石油醚/***9.4∶0.6)纯化得产物7.05g,m.p.51-53℃。
c)5-(4’-联苯基)巴比妥酸的制备
在钠(0.322g)的40ml无水乙醇溶液中加入(4’-联苯基)丙二酸二乙酯(2.2g),再加入脲(0.63g)。将反应混合液回流3小时30分钟,然后冷至室温,过滤得固体。将得到的固体再溶解于40ml热水中,用6N盐酸酸化水相pH=1。将分离出的固体搅拌15分钟,然后过滤,在60℃下真空干燥,得产物1.1g,m.p.>240℃。
d)5-溴-5-(4’-联苯基)巴比妥酸的制备
在冷却至0℃搅拌下向5-(4’-联苯基)巴比妥酸(0.28g)的1.4ml水混悬液中滴加0.14ml 48%的氢溴酸并连续加入55.5μl溴。然后将温度升至室温,继续搅拌1小时,过滤收集悬浮的固体,在60℃下真空干燥2小时得产物0.336g,m.p.203-205℃。
e)标题化合物的制备
在5-溴-5-(4’-联苯基)巴比妥酸(0.323g)的4.4ml乙醇混悬液中加入0.14gN-(2-羟乙基)哌嗪,将反应混合液回流2小时。滤除悬浮的固体,用125μl三乙胺处理得到的澄清溶液再蒸除溶剂。残留物再溶解在2ml乙醇中,有固体结晶形成,搅拌30分钟,然后过滤。所得物质从乙醇中重结晶得纯品100mg,m.p.225-226℃。1H-NMR in d6-DMSO:2.3-2.5 ppm(m,6H);2.65 ppm(m,4H);3.45 ppm(m,2H);4.4ppm(s,1H);7.3-7.8 ppm(m,9H);11.6 ppm(s,2H).
实施例26
5-(4’-联苯基)-5-[N-(4-硝基苯基)哌嗪基]巴比妥酸
在5-溴-5-(4’-联苯基)巴比妥酸(0.359g;实施例25,步骤d)的9ml甲醇溶液中加入N-(4-硝基苯基)哌嗪(0.622g),将混合液回流约2小时。蒸除溶剂,残留物分配在水和乙酸乙酯中。分离有机相,用盐水洗涤,用硫酸钠干燥。减压蒸除溶剂得到残留物0.74g,经硅胶层析(洗脱剂:二氯甲烷/丙酮9∶1)纯化得产物400mg.m.p.181℃。1H-NMR in d6-DMSO:2.8 ppm(m,4H);3.5 ppm(m,4H);7.00 ppm(d,2H);7.3-7.85ppm(m,9H);8.05 ppm(d,2H);11.7 ppm(s,2H).实施例275-(4’-苯氧基苯基)-5-[N-(2-羟乙基)哌嗪基]巴比妥酸
a)N-[(4’-苯氧基苄基)硫代羰基]吗啉的制备
将(4’-苯氧基苯基)甲基酮(19.1g),吗啉(20ml)和硫(4.32g)混合液回流24小时,然后用***提取。将有机相浓缩至干,残留物经石油醚/乙酸乙酯混合液8∶2(600ml)重结晶后得产物12.2g,m.p.75-77℃。
b)(4’-苯氧基苯基)乙酸的制备
将N-[(4’-苯氧基苄基)硫代羰基]吗啉(1.725g)的87ml 10%的氢氧化钾混悬液回流8小时30分钟,然后将反应液降至室温,用1N盐酸酸化。有白色固体生成,搅拌30分钟,过滤。固体用水洗涤,真空干燥得产物1.095g,m.p.70-72℃。
c)(4’-苯氧基苯基)乙酸乙酯的制备
在(4’-苯氧基苯基)乙酸(0.456g)的4ml乙醇混悬液中加入对甲苯磺酸(0.076g),将产生的混合液回流2小时。蒸除溶剂,将残留物溶于***中,有机相用饱和的碳酸氢钠水溶液洗涤,再用盐水洗。有机相用硫酸钠干燥,浓缩至干得棕色油状产物0.458g。
d)5-(4’-苯氧基苯基)巴比妥酸的制备
在乙醇钠(0.27g)的3ml无水乙醇溶液中加入0.657g(4’-苯氧基苯基)乙酸乙酯的5ml乙醇溶液,然后加入脲(0.18g)。将反应混合液回流2小时30分钟,然后将其冷却至室温,过滤悬浮的固体。将固体再溶解在8ml水中,用1N盐酸酸化。过滤收集生成的固体得产物0.165g,m.p.>240℃。
e)5-溴-5-(4’-苯氧基苯基)巴比妥酸的制备
在冷至0℃搅拌下向5-(4’-苯氧基苯基)巴比妥酸(48mg)的0.23ml水混悬液中加入23μl48%的氢溴酸,再加入9μl溴。室温下2小时后再加入9μl溴,继续搅拌2小时。然后过滤悬浮的固体,用水洗,在60℃下真空干燥后得产品57mg,m.p.125-127℃。
f)标题化合物的制备
在5-溴-5-(4’-苯氧基苯基)巴比妥酸(50mg)的0.2ml甲醇溶液中滴加N-(2-羟乙基)哌嗪(52mg)的0.6ml甲醇溶液,将混合液搅拌2小时。过滤收集白色沉淀,60℃下真空干燥过夜得产品42.6mg,m.p.>240℃。1H-NMR in d6-DMSO:2.2-2.45 ppm(m,6H);2.55 ppm(m,4H);3.45 ppm(m,2H);4.4 ppm(t,1H);6.9-7.7 ppm(m,9H);11.6 ppm(s,2H).实施例285-癸基-5-[N-(2-羟乙基)哌嗪基]巴比妥酸
a)癸基丙二酸二乙酯的制备
在钠(0.46g)的10无水乙醇溶液中加入3.35ml丙二酸二乙酯的3ml乙醇溶液,再加入溴癸烷(4.15ml)的3ml乙醇溶液。将反应混合液回流4小时,滤除沉淀,将滤液浓缩至干。将残留物再溶解在饱和的硫酸氢钠水溶液中,用乙酸乙酯提取。有机提取液用硫酸钠干燥,蒸除溶剂。残留物用于下面连续反应。
b)5-癸基巴比妥酸的制备
在步骤a)的癸基丙二酸二乙酯的40ml乙醇溶液中加入2.72g乙醇钠,再加入1.8g脲。将反应混合物回流2小时,然后过滤沉淀,将沉淀再溶解于40ml水中。产生的水溶液用6N盐酸酸化。过滤分离出固体,40℃下真空干燥过夜得产物2.152g,m.p.>190℃。
c)5-溴-5-癸基巴比妥酸的制备
在5-癸基巴比妥酸(0.537g)的2.9ml水混悬液中室温搅拌下加入0.29ml48%的氢溴酸。将混合液冷却至0℃,滴加0.113ml溴。将反应混合液在室温下搅拌1小时30分钟,然后过滤白色沉淀,用水冲洗。将固体分配于水和***之间,分离有机相,用盐水冲洗,最后用硫酸钠干燥。减压蒸除溶剂得产物0.62g。
d)标题化合物的制备
在保持0℃搅拌向5-溴-5-癸基巴比妥酸(0.619g)的二甲亚砜(1.3ml)溶液中滴加0.93g N-(2-羟乙基)哌嗪的0.7ml二甲亚砜溶液,然后将反应混合液室温下搅拌1小时。然后将混合液冷却至0℃,加入30ml水。搅拌1小时后,然后过滤生成的固体,在50℃下真空干燥得产物0.309g,m.p.181-182℃。1H-NMR in d6-DMSO:0.85 ppm(t,3H);0.9-1.1 ppm(m,2H);1.15-1.4 ppm(m,14H);1.8-1.9 ppm(m,2H);2.2-2.45 ppm(m,6H);2.55 ppm(m,4H);3.45 ppm(m,2H);4.35 ppm(t,1H);11.55 ppm(s,2H).实施例295-十六烷基-5-[N-(2-羟乙基)哌嗪]巴比妥酸按照实施例28化合物类似的方法制备该标题化合物。实施例5-二十烷氧基-5-[N-(2-羟乙基)哌嗪]巴比妥酸依照如实施例28化合物类似的方法制备该标题化合物。实施例315-(4-丁氧基苯基)-5-[4-(2-羟基苯基)哌嗪基]巴比妥酸m.p.184-185°H-N.M.R.in d6-DMSO:0.91 ppm(t,3H);1.4 ppm(m,2H);1.67 ppm(m,2H);2.36ppm(m,6H);2.55 ppm(m,4H);3.44 ppm(q,2H);3.95 ppm(t,2H);4.37 ppm(t,1H);6.95 ppm(d,2H);7.28 ppm(d,2H);11.5 ppm(br.s,2H).
按实施例14所述的方法制备本化合物。不同之处为起始原料4-丁氧基苯基乙酸乙酯可根据已知的操作法先通过使4-羟基苯基乙酸与乙醇的酯化反应(见实施例14-a),再根据已知的方法通过4-羟基苯基乙酸乙酯与溴丁烷的烷基化反应而制备。
实施例32
下成合成的化合物的方法在说明书及以前的实施例的例子中说明过。它们由质谱定性。
名称 分子量 质谱指数01 N-(2,4,6-三氧代-5-苯基-六氢-嘧啶-5-基)苯甲酰胺 323.3 32302 3-(3,4-二甲氧基苯基)-N-(2,4,6-三氧代-5-苯基-六氢 409.4 409嘧啶-5-基)丙烯酰胺03 3-(3,4,5-三甲氧基苯基)-N-(2,4,6-三氧代-5-苯基-六 439.4 439氢嘧啶-5-基)丙烯酰胺04 3-苯基-N-(2,4,6-三氧代-5-苯基六氢嘧啶-5-基)丙酰 351.4 351胺05 5-苯基戊酸(2,4,6-三氧代-5-苯基六氢嘧啶-5-基)酰 379.4 379胺06 2-(4-硝基苯基)-N-(2,4,6-三氧代-5-苯基六氢嘧啶- 382.3 3825-基)乙酰胺07 3-苯磺酰基-N-(2,4,6-三氧代-5-苯基六氢嘧啶-5-基) 415.4 415丙酰胺08 2-(4-溴甲基-苯基)-N-(2,4,6-三氧代-5-苯基六氢嘧 430.3 429啶-5-基)乙酰胺09 2-萘-2-基-N-(2,4,6-三氧代-5-苯基六氢嘧啶-5-基) 387.4 387乙酰胺10 2-(3-氯苯基)-N-(2,4,6-三氧代-5-苯基六氢嘧啶-5- 371.8 371基)乙酰胺11 3-(2-甲氧基苯基)-N-(2,4,6-三氧代-5-苯基六氢嘧啶 381.4 381-5-基)丙酰胺12 3-(4-甲氧基苯基)-N-(2,4,6-三氧代-5-苯基六氢嘧啶 381.4 381-5-基)丙酰胺13 2-(3-溴苯基)-N-(2,4,6-三氧代-5-苯基六氢嘧啶-5- 416.2 415基)乙酰胺14 3-苯基-N-(2,4,6-三氧代-5-苯基六氢嘧啶-5-基)丙烯 349.3 349酰胺15 4-溴-N-(2,4,6-三氧代-5-苯基六氢嘧啶-5-基)苯甲酰 402.2 401胺16 3-甲基-N-(2,4,6-三氧代-5-苯基六氢嘧啶-5-基)苯甲 337.3 337酰胺17 4-甲基硫烷基(sulfanyl)-N-(2,4,6-三氧代-5-苯基六 369.4 369氢嘧啶-5-基)苯甲酰胺18 3-氯-N-(2,4,6-三氧代-5-苯基六氢嘧啶-5-基)苯甲酰 357.8 357胺19 4-氯-N-(2,4,6-三氧代-5-苯基六氢嘧啶-5-基)苯甲酰 357.8 357胺20 3,4-二甲基-N-(2,4,6-三氧代-5-苯基六氢嘧啶-5-基) 351.4 351苯甲酰胺21 3,5-二甲基-N-(2,4,6-三氧代-5-苯基六氢嘧啶-5-基) 351.4 351苯甲酰胺22 4-乙氧基-N-(2,4,6-三氧代-5-苯基六氢嘧啶-5-基)苯 367.4 367甲酰胺23 4-氰基-N-(2,4,6-三氧代-5-苯基六氢嘧啶-5-基)苯甲 348.3 348酰胺24 3-甲氧基-N-(2,4,6-三氧代-5-苯基六氢嘧啶-5-基)苯 353.3 353甲酰胺25 4-甲氧基-N-(2,4,6-三氧代-5-苯基六氢嘧啶-5-基)苯 353.3 353甲酰胺26 2-甲基-N-(2,4,6-三氧代-5-苯基六氢嘧啶-5-基)苯甲 337.3 337酰胺27 2,4-二氟-N-(2,4,6-三氧代-5-苯基六氢嘧啶-5-基)苯 359.3 359甲酰胺28 N-(2,4,6-三氧代-5-苯基六氢嘧啶-5-基)异烟酰胺 324.3 32429 萘-1-羧酸(2,4,6-三氧代-5-苯基六氢嘧啶-5-基)酰胺 373.4 37330 1-(4-氟苯基)-3-(2,4,6-三氧代-5-苯基六氢嘧啶-5- 356.3 356基)脲31 3-(4-甲氧基苯基)-N-(2,4,6-三氧代-5-苯基六氢嘧啶 379.4 379-5-基)丙烯酰胺32 1-(3-三氟甲基苯基)-3-(2,4,6-三氧代-5-苯基六氢嘧 406.3 406啶-5-基)脲33 3-(4-氯苯基)-N-(2,4,6-三氧代-5-苯基六氢嘧啶-5- 383.8 383基)丙烯酰胺34 1-(2,4-二氯苯基)-3-(2,4,6-三氧代-5-苯基六氢嘧啶- 407.2 4065-基)脲35 1-(3,4-二氯苯基)-3-(2,4,6-三氧代-5-苯基六氢嘧啶- 407.2 4065-基)脲36 1-(氯苯基)-3-(2,4,6-三氧代-5-苯基六氢嘧啶-5-基) 372.7 372脲37 1-(4-甲氧基苯基)-3-(2,4,6-三氧代-5-苯基六氢嘧啶 368.4 368-5-基)脲38 1-苯基-3-(2,4,6-三氧代-5-苯基六氢嘧啶-5-基)脲 338.3 33839 萘-2-羧酸(2,4,6-三氧代-5-苯基六氢嘧啶-5-基)酰胺 373.4 37340 1H-吲哚-5-羧酸(2,4,6-三氧代-5-苯基六氢嘧啶-5- 362.3 362基)酰胺41 N-(2,4,6-三氧代-5-苯基六氢嘧啶-5-基)对苯二酰胺 366.3 36642 4-氨磺酰基-N-(2,4,6-三氧代-5-苯基六氢嘧啶-5-基) 402.4 402苯甲酰胺43 4-甲基-N-(2,4,6-三氧代-5-苯基六氢嘧啶-5-基)苯甲 337.3 337酰胺44 4-乙基-N-(2,4,6-三氧代-5-苯基六氢嘧啶-5-基)苯甲 351.4 351酰胺45 4-甲基-N-(2,4,6-三氧代-5-苯基六氢嘧啶-5-基)苯磺 373.4 373酰胺46 4-溴-N-(2,4,6-三氧代-5-苯基六氢嘧啶-5-基)苯磺酰 438.3 437胺47 2-三氟甲基-N-(2,4,6-三氧代-5-苯基六氢嘧啶-5-基) 427.4 427苯磺酰胺48 5-苯基-5-(4-苯基哌啶-1-基)嘧啶-2,4,6-三酮 363.4 36349 2,3-二甲氧基-N-(2,4,6-三氧代-5-苯基六氢嘧啶-5- 383.4 383基)苯甲酰胺50 2,3-二甲基-N-(2,4,6-三氧代-5-苯基六氢嘧啶-5-基) 351.4 351苯甲酰胺51 4-羟基-N-(2,4,6-三氧代-5-苯基六氢嘧啶-5-基)苯甲 339.3 411酰胺 甲硅烷基52 3,4-二甲氧基-N-(2,4,6-三氧代-5-苯基六氢嘧啶-5- 383.4 383基)苯甲酰胺53 3-二甲胺基-N-(2,4,6-三氧代-5-苯基六氢嘧啶-5-基) 366.4 366苯甲酰胺54 3-叔丁基-N-(2,4,6-三氧代-5-苯基六氢嘧啶-5-基)苯 379.4 379甲酰胺55 3,4-二甲氧基-2-硝基-N-(2,4,6-三氧代-5-苯基六氢 428.4 428+嘧啶-5-基)苯甲酰胺 FAB56 4-丁氧基-3-甲氧基-N-(2,4,6-三氧代-5-苯基六氢嘧 425.4 425+啶-5-基)苯甲酰胺 FAB57 2-甲基-2,3-二氢苯并呋喃-7-羧酸(2,4,6-三氧代-5- 379.4 379+苯基六氢嘧啶-5-基)酰胺 FAB58 1H-吲哚-4-羧酸(2,4,6-三氧代-5-苯基六氢嘧啶-5- 362.3 362基)酰胺59 4-甲基-3-氨磺酰基-N-(2,4,6-三氧代-5-苯基六氢嘧 416.4 416啶-5-基)苯甲酰胺60 乙酸6-甲基-2-硝基-3-(2,4,6-三氧代-5-苯基六氢嘧 440.4 440+啶-5-基氨酰基)苯酯 FAB61 碳酸乙酯2-甲氧基-4-(2,4,6-三氧代-5-苯基六氢嘧 441.4 441+啶-5-基氨基甲酰基)苯基酯 FAB62 2-溴-3-硝基-N-(2,4,6-三氧代-5-苯基六氢嘧啶-5- 447.2 446基)苯甲酰胺63 “4-氯-3-氨磺酰基-N-(2,4,6-三氧代-5-苯基六氢嘧 436.8 436啶-5-基)苯甲酰胺”65 3-叔丁基-2-羟基-N-(2,4,6-三氧代-5-苯基六氢嘧啶- 395.4 3955-基)苯甲酰胺66 4’-苄氧基-联苯基-3-羧酸(2,4,6-三氧代-5-苯基六氢 505.5 505+嘧啶-5-基)苯甲酰胺 FAB67 3-氰基-N-(2,4,6-三氧代-5-苯基六氢嘧啶-5-基)苯甲 348.3 348酰胺68 3-溴-N-(2,4,6-三氧代-5-苯基六氢嘧啶-5-基)苯甲酰 402.2 401胺69 3-苯氧基-N-(2,4,6-三氧代-5-苯基六氢嘧啶-5-基)苯 415.4 415+甲酰胺 FAB70 3-苄酰基-N-(2,4,6-三氧代-5-苯基六氢嘧啶-5-基)苯 427.4 427甲酰胺71 3-三氟甲基-N-(2,4,6-三氧代-5-苯基六氢嘧啶-5-基) 391.3 391苯甲酰胺72 N-(2,4,6-三氧代-5-苯基六氢嘧啶-5-基)邻氨甲酰苯 381.3 381甲酸甲酯73 9H-芴-1-羧酸(2,4,6-三氧代-5-苯基六氢嘧啶-5-基) 411.4 411酰胺74 9-氧代-9H-芴-1-羧酸(2,4,6-三氧代-5-苯基六氢嘧 425.4 425啶-5-基)酰胺75 5-苯基-5-(4-苯基哌嗪-1-基)嘧啶-2,4,6-三酮 364.4 36476 5-苯基-5-[4-(2-三氟甲基苯基)哌嗪-1-基]嘧啶- 432.4 4322,4,6-三酮77 4-[4-(4-硝基苯基)哌嗪-1-基]-5-苯基嘧啶-2,4,6-三 409.4 409酮78 5-(4-苯乙基-哌嗪-1-基)-5-苯基嘧啶-2,4,6-三酮 392.5 39279 5-[4-(3-甲氧基苯基)哌嗪-1-基]-5-苯基嘧啶-2,4,6- 394.4 394三酮80 3-乙酰氨基-N-(2,4,6-三氧代-5-苯基六氢嘧啶-5-基) 380.4 380苯甲酰胺81 乙酸3-(2,4,6-三氧代-5-苯基六氢嘧啶-5-基氨基甲 381.3 381酰基)苯甲酰胺82 3-乙氧基-N-(2,4,6-三氧代-5-苯基六氢嘧啶-5-基)苯 367.4 367甲酰胺83 5-苯基-5-(4-吡啶-4-基-哌嗪-1-基)嘧啶-2,4,6-三酮 365.4 36584 5-苯基-5-[4-(3-三氟甲基苯基)哌嗪-1-基]嘧啶- 432.4 4322,4,6-三酮85 5-[4-(4-甲氧基-苯基)-哌嗪-1-基]-5-苯基嘧啶-2,4,6- 394.4 394三酮86 5-[4-二苯甲基-哌嗪-1-基)-5-苯基-嘧啶-2,4,6-三酮 454.5 454+
FAB87 5-苯基-5-[4-(3-苯基烯丙基)哌嗪-1-基]-嘧啶-2,4,6- 404.5 404+三酮 FAB88 5-苯基-5-(2-吡咯烷基-1-基乙氨基)嘧啶-2,4,6-三酮 316.4 31689 5-[2-(3H-咪唑-4-基)乙氨基]-5-苯基嘧啶-2,4,6-三酮 313.3 313+
FAB
实施例33
为了测定如HNC的MMPs的抑制作用,用具有不同浓度的抑制剂来培育催化的区域结构(分离及纯化见例如Schniener,S.,Kleine,T,Gote,T.,Hillemann,A.,Knauper,V.,Tschesche,H.,Biochem.Biophys,Res,Commun.(1993)191,319-326)。接着按类似于Grams F等,FEBS335(1993)76-80的方法测定在标准底物的转化中的初反应速率。
结果通过以速率的倒数对抑制剂的浓度作图来评价。根据Dixon,M.,Biochem,J.(1953)55,170-202中的图解方法,抑制常数(Ki)为横坐标的负数部分(negative section)。
合成的胶原酶底物是在羧基末端与DNP(二硝基苯酚)成对的七肽,所述DNP基团通过立体障碍抑制了相邻的七肽的色氨酸的荧光。在包括DNP基团的三肽断裂后,色氨酸的荧光增加。因此底物的蛋白水解作用的断裂可通过荧光值来测定。
a)方法一
本实验在25℃下在新鲜制备用双硫腙处理除去微量重金属的50mM Tris缓冲液(pH 8.0)中进行。加入4mM CaCl2,用氩饱和缓冲液。Adamalysin II诸备液通过从硫酸铵混悬液中离心蛋白质,再溶于所述测定缓冲液中来制备。胶原酶储备液用所述测定缓冲液来稀释。酶浓度通过UV测定法测定(ε280=2.8×104M-1.cm-1,ε288=2.2×104M- 1.cm-1),储备液体保存于冷处。溶液以1∶100比例稀释得到最后16nM的测定浓度。具有52μM的Km的荧光底物DNP-Proleu-Gly-LeuTrp-Ala-D-Arg-NH2使用浓度为21.4μm;在测定Ki时也用12.8μM的浓度。底物的荧光在配有恒温吸收池架的分光荧光计(Perkin Elmer,Model650-40)上,在激发波长和发射波长分别为λ=320nm和420nm下进行测定。加入酶后立即监测底物水解10分钟。所有实验至少进行三次。抑制剂的Ki值通过图示Vo/Vi/Vs[抑制剂的浓度]中直线的交叉点来计算,而IC50值通过用简单耐用的加权(simple robust weighting)非线性回归方法由图示Vi/Vo[抑制剂的浓度]来计算。
b)方法二
实验缓冲液
50mM Tris/HCl pH 7.6(Tri=三-(羟甲基)-氨基甲烷(methan))
100mM NaCl/10mM CaCl 12/5%MeOH(若必要时)
酶:8mM人的嗜中性胶原酶的催化区域结构(Met 80-Gly 242)
底物:10μM DNP-Pro-Leu-Gly-Leu-Trp-Ala-D-Arg-NH2
总测定体积:1ml
制备在测定缓冲液(250℃)中的酶和抑制剂的溶液。反应通过向溶液中加入底物直接开始。产生荧光的底物的断裂后发生激发和发射波长分别为280和350nm的荧光光谱。IC50以抑制剂的浓度来计算,有必要将反应的速度降低至未有抑制剂时反应速度的一半。
表1为测定的IC50值。
化合物 | IC-50[nM] |
实施例32.74 | 890 |
优选编号20 | 150 |
实施例25 | 140 |
实施例23 | 110 |
实施例20 | 860 |
实施例32.77 | 160 |
优选编号118 | 60 |
实施例28 | 320 |
实施例26 | 15 |
Claims (10)
1.式化合物、其药学上可接受的盐、光学活性形式或前体药物:其中X、Y和Z相互独立为氧、硫或NH,R1代表基团W-VW是一个共价键或是一直链或支链任选一次或多次取代的C1-C8烷基或C2-C8链烯基,V是一个任选取代的含有一个或几个杂原子的单环或双环,或W-V是可由杂原子间断的C1-C20烷基,其中一个或多个碳原子是任选取代的,R2和R3代表氢或其中一个代表低级烷基或低级酰基,R4和R5相互独立代表A-D,其中A代表-烷基、链烯基、酰基、烷基磺酰基、磺酰基、烷基氨基羰基、氨基羰基、烷氧基羰基、氧代羰基、烷基氨基硫代羰基、氨基硫代羰基,以上基团可一次或多次任选取代,D代表氢、单或双环,所述单环或双环任选一次或多次由杂原子间断,以及单环或双环由一次或多次取代,或R4和R5与它们所连接的氮原子一起代表一个可由另一个N原子任选间断的环;该环可缩合为一单环或双环;该环可任选由以下基团一次或多次独立取代:羟基、烷氧基、氨基、烷基氨基、二烷基氨基、腈基或或被E-G取代其中E代表共价键-任选取代的烷基、链烯基、酰基、烷基磺酰基磺酰基、烷基氨基羰基、氨基羰基、烷氧基羰基、氧代羰基、烷基氨基硫代羰基、氨基硫代羰基;G代表氢、单或双环,所述单环或双环任选一次或多次由杂原子间断,以及所述单环或双环由一次或多次取代,在R1、R4和R5中提到的单环是饱和的或不饱和的带有3-8个碳原子的任选由杂原子如氮、氧或硫一或多次间断的环系,在R1、R4和R5中提到的双环是缩和的双环或单环1-L-单环2类型的双环,其中L共价键-C1-C4烷基、C2-C4链烯基、氧或-C(O)-基团,在R1、R4和R5中提到的基团可一次或多次由下列基团任选取代:卤素、羟基、硫代、烷基、羟基烷基、烷氧基、烷硫基、烷基亚磺酰基、烷基磺酰基、氨基、烷基氨基、二烷基氨基、硝基、羧基、甲酰胺基、烷氧基羰基、氨基或氨基羰基,以上基团可由低级烷基、腈、氧代、硫代甲酰胺基、烷氧基硫代羰基、烷基巯基羰基、膦酰基、烷基膦酰基、二烷基膦酰基、烷基磺酰氨基、芳氨基、芳基、杂芳基、芳氧基、芳硫基、芳基亚磺酰基、芳磺酰基或酰基一次或二次任选取代。
2.根据权利要求1的式化合物,其中单环代表环戊基、环己基、环庚基、吗啉基、硫代吗啉基、哌啶基、哌嗪基、四氢呋喃基、四氢吡喃基、苯基、吡啶基、嘧啶基、哒嗪基、吡嗪基、呋喃基、硫代苯基、咪唑基、噻唑基、噁唑基、异噻唑基、异噁唑基、1,2,3-***基或1,2,4-***基。
3.根据权利要求1或2中任一项的化合物,其中双环指萘基、四氢萘基、十氢化萘基、喹啉基、异喹啉基、四氢喹啉基、四氢异喹啉基、吲哚基、苯并咪唑基、吲唑基、羟吲哚基、苯并呋喃基、苯并硫代苯基、苯并噻唑基、苯并噁唑基、嘌呤基、联苯基或(4-苯氧基)苯基,特别是萘基、联苯基、喹啉基、异喹啉基、四氢喹啉基、吲哚基或苯并咪唑基。
4.根据权利要求1-3中任一项的化合物,其中R1的W代表甲基、乙基、丁基或己基;V代表苯基、吡啶基、咪唑基或W-V指正辛基、正癸基、联苯基或有2或3个氧原子的辛基或癸基类型基团,或有1或2个氮杂原子的联苯基类型基团。
5.根据权利要求1-4中任一项的化合物,其中X、Y和Z都是氧,R2和R3都是氢。
6.根据权利要求1-5中任一项的化合物,其中N、R4和R5形成均在4位取代的哌嗪或哌啶。
7.根据权利要求1的式化合物的制备方法及其将该化合物任选转化成为药学上可接受的盐或其光学活性形式:其中熟知的方法为(a)使通式II化合物其中X、Y、Z、R1、R2和R3定义同上,T代表如卤素或OSO2R6的离去基团,卤素指氯、溴或碘,R6代表芳基或甲基,与通式III化合物反应并任选转化为其药学上可接受的盐:其中R4和R5定义同上,或b)使通式IV化合物其中R1、R4和R5定义同上,Y和Z相互独立代表氧、硫或NH基,R7等于甲基、乙基或苯基,与通式V化合物反应并任选转化为其药学上可接受的盐:其中R2、R3和X定义同上或当R4和/或R5代表酰基、烷基磺酰基、芳基磺酰基、烷基氨基羰基、芳基氨基羰基、烷氧基羰基、芳氧基羰基、烷基氨基硫代羰基或芳氨基硫代羰基基团的情况下(c)使通式VI的化合物其中X、Y、Z、R1、R2和R3定义同上,与通式VII或VIII化合物反应:
R8-D-Hal(VII)R8N=C=A(VIII)其中R8代表任选取代的烷基或芳基基团,D=C(O),O-C(O),SO2或共价键,Hal=氯、溴或碘,A代表氧或硫。
8.含有至少1个根据权利要求1-6中任一项的式I化合物以及常用载体物质及赋形剂的药用组合物。
9.根据权利要求1-6中任一项的式I化合物用于生产具有基质金属蛋白酶抑制作用的药物的用途。
10.根据权利要求1-6中任一项的式I化合物用于生产具有抑制adamysins作用的药物的用途。
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
DE19548624A DE19548624A1 (de) | 1995-12-23 | 1995-12-23 | Neue Barbitursäure-Derivate, Verfahren zu deren Herstellung und diese Verbindungen enthaltende Arzneimittel |
DE19548624.2 | 1995-12-23 |
Publications (2)
Publication Number | Publication Date |
---|---|
CN1209123A true CN1209123A (zh) | 1999-02-24 |
CN1318406C CN1318406C (zh) | 2007-05-30 |
Family
ID=7781338
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CNB961800275A Expired - Fee Related CN1318406C (zh) | 1995-12-23 | 1996-12-20 | 新的巴比妥酸类衍生物,其制备方法以及含有该类化合物的药物制剂 |
Country Status (22)
Country | Link |
---|---|
US (2) | US6110924A (zh) |
EP (1) | EP0869947B1 (zh) |
JP (1) | JP4198752B2 (zh) |
KR (1) | KR100440035B1 (zh) |
CN (1) | CN1318406C (zh) |
AT (1) | ATE226575T1 (zh) |
BR (1) | BR9612232A (zh) |
CZ (1) | CZ292503B6 (zh) |
DE (2) | DE19548624A1 (zh) |
DK (1) | DK0869947T3 (zh) |
ES (1) | ES2184903T3 (zh) |
HU (1) | HUP9901065A3 (zh) |
IL (1) | IL125048A (zh) |
MX (1) | MX9805063A (zh) |
NO (1) | NO311572B1 (zh) |
NZ (1) | NZ325802A (zh) |
PL (1) | PL190217B1 (zh) |
PT (1) | PT869947E (zh) |
RU (1) | RU2177475C2 (zh) |
TW (1) | TW518324B (zh) |
WO (1) | WO1997023465A1 (zh) |
ZA (1) | ZA9610765B (zh) |
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN1950110B (zh) * | 2004-04-01 | 2012-11-21 | 列日大学 | 嘧啶-2,4,6-三酮的药物组合物 |
CN109804249A (zh) * | 2017-06-14 | 2019-05-24 | 清滔制药株式会社 | 用于测定人体体液氧化应激的方法 |
Families Citing this family (20)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
ATE302200T1 (de) | 1997-06-21 | 2005-09-15 | Roche Diagnostics Gmbh | Barbitursaure derivaten mit antimetastatischer und antitumorischer wirkung |
DE19726427A1 (de) | 1997-06-23 | 1998-12-24 | Boehringer Mannheim Gmbh | Pyrimidin-2,4,6-trion-Derivate, Verfahren zu deren Herstellung und diese Verbindungen enthaltende Arzneimittel |
US6350786B1 (en) | 1998-09-22 | 2002-02-26 | Hoffmann-La Roche Inc. | Stable complexes of poorly soluble compounds in ionic polymers |
US6265578B1 (en) * | 1999-02-12 | 2001-07-24 | Hoffmann-La Roche Inc. | Pyrimidine-2,4,6-triones |
PE20010659A1 (es) | 1999-10-01 | 2001-06-20 | Hoffmann La Roche | Derivados de las pirimidin-2,4,6-trionas como inhibidores de metaloproteasas |
AU2002210800A1 (en) | 2000-10-26 | 2002-05-06 | Pfizer Products Inc. | Pyrimidine-2,4,6-trione metalloproteinase inhibitors |
US6716845B2 (en) * | 2001-03-30 | 2004-04-06 | Hoffmann-La Roche Inc. | Barbituric acid derivatives |
WO2002089824A1 (en) * | 2001-05-03 | 2002-11-14 | F. Hoffmann-La Roche Ag | Combination of a gelatinase inhibitor and an anti-tumor agent, and uses thereof |
CA2446356C (en) | 2001-05-09 | 2012-07-10 | The Regents Of The University Of Michigan | Use of compositions for treating rosacea |
AU2002346729A1 (en) * | 2001-12-20 | 2003-07-09 | Bristol-Myers Squibb Company | Barbituric acid derivatives as inhibitors of tnf-$g(a) converting enzyme (tace) and/or matrix metalloproteinases |
NI200300045A (es) * | 2002-04-26 | 2005-07-08 | Pfizer Prod Inc | Inhibidores de triariloxiariloxipirimidin-2,4,6-triona de metaloproteinasa. |
US20040225077A1 (en) | 2002-12-30 | 2004-11-11 | Angiotech International Ag | Drug delivery from rapid gelling polymer composition |
WO2004084903A1 (en) * | 2003-03-27 | 2004-10-07 | F. Hoffmann-La Roche Ag | Use of a trioxopyrimidine for the treatment and prevention of ocular pathologic angiogenesis |
WO2004084902A1 (en) * | 2003-03-28 | 2004-10-07 | F. Hoffmann-La Roche Ag | Use of a trioxopyrimidine for the treatment of chronic wounds |
WO2004110457A1 (en) * | 2003-06-06 | 2004-12-23 | F. Hoffmann-La Roche Ag | Matrix metalloproteinases inhibitors for the stimulation and protection of bone marrow stem cells |
EP1737464B1 (en) * | 2004-04-01 | 2008-07-23 | F. Hoffmann-La Roche AG | Use of a trioxopyrimidine for the treatment and prevention of bronchial inflammatory diseases |
EP1632489A1 (en) * | 2004-08-24 | 2006-03-08 | University of Liege | 5-(1,1'-Biphenyl)-4-yl-5-(4-(4-aminoacylphenyl)-piperazin)-1-yl-pyrimidine-2,4,6-trione derivatives, as inhibitors of zinc metallondopeptidases, their preparation and use. |
CN102234249B (zh) * | 2010-04-23 | 2013-08-28 | 首都医科大学 | N-(六氢嘧啶-1,3-二基)-二-l-氨基酸甲酯及其制备方法和应用 |
AU2011261375B2 (en) | 2010-06-04 | 2016-09-22 | Albany Molecular Research, Inc. | Glycine transporter-1 inhibitors, methods of making them, and uses thereof |
KR102432016B1 (ko) | 2020-07-31 | 2022-08-16 | 부산대학교 산학협력단 | 신경염증질환 예방 또는 치료용 조성물 |
Family Cites Families (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US2078323A (en) * | 1937-04-27 | C-amino-substituted barbituric | ||
US2084136A (en) * | 1933-06-03 | 1937-06-15 | Heyden Chem Fab | Barbituric acid containing in the 5-position a pyridine group and method of preparing the same |
DE763145C (de) * | 1942-05-29 | 1954-05-03 | Chem Fab Von Heyden A G | Verfahren zur Herstellung von 5-AEthyl-5-piperidinobarbitursaeure |
US3930006A (en) * | 1963-04-30 | 1975-12-30 | Aspro Nicholas Ltd | Antiparkinsonism compositions and method |
DE1246743B (de) * | 1965-01-12 | 1967-08-10 | Dresden Arzneimittel | Verfahren zur Herstellung von 5-Phenyl-5-piperidinobarbitursaeuren |
DE19726427A1 (de) * | 1997-06-23 | 1998-12-24 | Boehringer Mannheim Gmbh | Pyrimidin-2,4,6-trion-Derivate, Verfahren zu deren Herstellung und diese Verbindungen enthaltende Arzneimittel |
-
1995
- 1995-12-23 DE DE19548624A patent/DE19548624A1/de not_active Withdrawn
-
1996
- 1996-12-20 BR BR9612232A patent/BR9612232A/pt not_active IP Right Cessation
- 1996-12-20 ZA ZA9610765A patent/ZA9610765B/xx unknown
- 1996-12-20 JP JP52331897A patent/JP4198752B2/ja not_active Expired - Fee Related
- 1996-12-20 PL PL96327466A patent/PL190217B1/pl not_active IP Right Cessation
- 1996-12-20 HU HU9901065A patent/HUP9901065A3/hu unknown
- 1996-12-20 CZ CZ19981968A patent/CZ292503B6/cs not_active IP Right Cessation
- 1996-12-20 CN CNB961800275A patent/CN1318406C/zh not_active Expired - Fee Related
- 1996-12-20 KR KR10-1998-0704855A patent/KR100440035B1/ko not_active IP Right Cessation
- 1996-12-20 PT PT96944612T patent/PT869947E/pt unknown
- 1996-12-20 DK DK96944612T patent/DK0869947T3/da active
- 1996-12-20 EP EP96944612A patent/EP0869947B1/en not_active Expired - Lifetime
- 1996-12-20 AT AT96944612T patent/ATE226575T1/de not_active IP Right Cessation
- 1996-12-20 US US09/091,352 patent/US6110924A/en not_active Expired - Fee Related
- 1996-12-20 WO PCT/EP1996/005766 patent/WO1997023465A1/en active IP Right Grant
- 1996-12-20 ES ES96944612T patent/ES2184903T3/es not_active Expired - Lifetime
- 1996-12-20 IL IL12504896A patent/IL125048A/en not_active IP Right Cessation
- 1996-12-20 NZ NZ325802A patent/NZ325802A/xx unknown
- 1996-12-20 RU RU98113916/04A patent/RU2177475C2/ru not_active IP Right Cessation
- 1996-12-20 DE DE69624500T patent/DE69624500T2/de not_active Expired - Fee Related
-
1997
- 1997-01-28 TW TW086101091A patent/TW518324B/zh not_active IP Right Cessation
-
1998
- 1998-06-22 MX MX9805063A patent/MX9805063A/es not_active IP Right Cessation
- 1998-06-22 NO NO19982901A patent/NO311572B1/no unknown
-
2000
- 2000-06-16 US US09/594,700 patent/US6472396B1/en not_active Expired - Fee Related
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN1950110B (zh) * | 2004-04-01 | 2012-11-21 | 列日大学 | 嘧啶-2,4,6-三酮的药物组合物 |
CN109804249A (zh) * | 2017-06-14 | 2019-05-24 | 清滔制药株式会社 | 用于测定人体体液氧化应激的方法 |
Also Published As
Similar Documents
Publication | Publication Date | Title |
---|---|---|
CN1209123A (zh) | 新的巴比妥酸类衍生物,其制备方法以及含有该类化合物的药物制剂 | |
CN1295227C (zh) | 具有抗转移和抗肿瘤活性的巴比土酸衍生物 | |
CN1304377C (zh) | 金属蛋白酶抑制剂 | |
CN1143855C (zh) | 作为抗凝剂的邻氨基苯甲酰胺衍生物 | |
CN1324347A (zh) | 作为金属蛋白酶抑制剂(mmp)的芳基哌嗪和它们的用途 | |
CN1418199A (zh) | 作为ldl-pla2抑制剂的嘧啶-4-酮衍生物 | |
CN1283183A (zh) | 具有mmp和tnf抑制活性的异羟肟酸和羧酸衍生物 | |
CN1137886C (zh) | 新的2,3-二氧-1,2,3,4-四氢-喹喔啉基衍生物 | |
CN1358175A (zh) | 嘧啶酮化合物 | |
CN1265647A (zh) | 无环金属蛋白酶抑制剂 | |
CN1260781A (zh) | 具有综合的5ht1a、5ht1b和5ht1d受体拮抗剂活性的吲哚衍生物 | |
CN1235597A (zh) | 抑制因子Xa的杂环衍生物 | |
CN1296481A (zh) | (4-芳基磺酰氨基)-四氢吡喃-4-羧酸羟基酰胺 | |
CN1190424C (zh) | 含喹啉的α-酮酰胺半胱氨酸和丝氨酸蛋白酶抑制剂 | |
CN1230177A (zh) | 作为基质金属蛋白酶抑制剂的β-磺酰基异羟肟酸 | |
CN1239949A (zh) | 新的杂环取代的苯甲酰胺及其控制疾病的用途 | |
CN1278247A (zh) | 作为基质金属蛋白酶抑制剂的β-磺酰基异羟肟酸的α-羟基、-氨基和卤代衍生物 | |
CN1048239C (zh) | 萘衍生物 | |
CN1349498A (zh) | 含有链烯基和炔基的金属蛋白酶抑制剂 | |
CN1764648A (zh) | 作为组蛋白脱乙酰酶(hdac)抑制剂的异羟肟酸衍生物 | |
CN1418197A (zh) | 作为金属蛋白酶抑制剂的哌啶和哌嗪取代的n-羟基甲酰胺 | |
CN1157382C (zh) | 新型嘧啶-2,4,6-三酮衍生物,它们的生产方法和含有这些化合物的药剂 | |
CN1849306A (zh) | 基质金属蛋白酶抑制剂 | |
CN1443164A (zh) | 作为金属蛋白酶抑制剂的吡咯烷衍生物 | |
CN1378538A (zh) | 二氮芳辛-二酮衍生物及其作为类胰蛋白酶抑制剂的应用 |
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: 20070530 Termination date: 20100120 |