NO311572B1 - Nye barbitursyrederivater, farmasöytiske midler inneholdende slike forbindelser, samt anvendelse av slike forbindelser tilfremstilling av et farmasöytisk middel - Google Patents
Nye barbitursyrederivater, farmasöytiske midler inneholdende slike forbindelser, samt anvendelse av slike forbindelser tilfremstilling av et farmasöytisk middel Download PDFInfo
- Publication number
- NO311572B1 NO311572B1 NO19982901A NO982901A NO311572B1 NO 311572 B1 NO311572 B1 NO 311572B1 NO 19982901 A NO19982901 A NO 19982901A NO 982901 A NO982901 A NO 982901A NO 311572 B1 NO311572 B1 NO 311572B1
- Authority
- NO
- Norway
- Prior art keywords
- ppm
- acid
- alkyl
- phenyl
- denotes
- Prior art date
Links
- 150000001875 compounds Chemical class 0.000 title claims abstract description 57
- 239000008177 pharmaceutical agent Substances 0.000 title claims description 5
- 238000002360 preparation method Methods 0.000 title abstract description 52
- 150000007656 barbituric acids Chemical class 0.000 title description 3
- 150000003839 salts Chemical class 0.000 claims abstract description 18
- 239000011159 matrix material Substances 0.000 claims abstract description 7
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims abstract description 5
- 239000001257 hydrogen Substances 0.000 claims abstract description 5
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 5
- 239000001301 oxygen Substances 0.000 claims abstract description 5
- 229910052760 oxygen Inorganic materials 0.000 claims abstract description 5
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims abstract description 4
- 125000004433 nitrogen atom Chemical group N* 0.000 claims abstract description 4
- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 claims abstract description 4
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims abstract description 3
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims abstract description 3
- 230000002401 inhibitory effect Effects 0.000 claims abstract 3
- HNYOPLTXPVRDBG-UHFFFAOYSA-N barbituric acid Chemical compound O=C1CC(=O)NC(=O)N1 HNYOPLTXPVRDBG-UHFFFAOYSA-N 0.000 claims description 23
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 23
- -1 hydroxy, thio Chemical group 0.000 claims description 21
- 238000004519 manufacturing process Methods 0.000 claims description 15
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 claims description 10
- 239000004305 biphenyl Substances 0.000 claims description 10
- 125000004193 piperazinyl group Chemical group 0.000 claims description 9
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 8
- 229910052736 halogen Inorganic materials 0.000 claims description 7
- 150000002367 halogens Chemical class 0.000 claims description 7
- 229910052757 nitrogen Inorganic materials 0.000 claims description 7
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 6
- 125000004076 pyridyl group Chemical group 0.000 claims description 6
- 102000034473 Adamalysin Human genes 0.000 claims description 4
- 108030001653 Adamalysin Proteins 0.000 claims description 4
- 102000005741 Metalloproteases Human genes 0.000 claims description 4
- 108010006035 Metalloproteases Proteins 0.000 claims description 4
- 125000004397 aminosulfonyl group Chemical group NS(=O)(=O)* 0.000 claims description 4
- 125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 claims description 4
- 125000002098 pyridazinyl group Chemical group 0.000 claims description 4
- 125000001424 substituent group Chemical group 0.000 claims description 4
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 3
- 125000002883 imidazolyl group Chemical group 0.000 claims description 3
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 3
- 125000006590 (C2-C6) alkenylene group Chemical group 0.000 claims description 2
- 229910006074 SO2NH2 Inorganic materials 0.000 claims description 2
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 claims description 2
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 2
- 125000005518 carboxamido group Chemical group 0.000 claims description 2
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 2
- 125000003983 fluorenyl group Chemical group C1(=CC=CC=2C3=CC=CC=C3CC12)* 0.000 claims description 2
- 125000001041 indolyl group Chemical group 0.000 claims description 2
- 125000001624 naphthyl group Chemical group 0.000 claims description 2
- 150000002825 nitriles Chemical class 0.000 claims description 2
- 125000004043 oxo group Chemical group O=* 0.000 claims description 2
- 239000000825 pharmaceutical preparation Substances 0.000 claims description 2
- 125000000719 pyrrolidinyl group Chemical group 0.000 claims description 2
- 125000004454 (C1-C6) alkoxycarbonyl group Chemical group 0.000 claims 1
- JCXJVPUVTGWSNB-UHFFFAOYSA-N Nitrogen dioxide Chemical compound O=[N]=O JCXJVPUVTGWSNB-UHFFFAOYSA-N 0.000 claims 1
- 239000000126 substance Substances 0.000 claims 1
- 238000000034 method Methods 0.000 abstract description 20
- 125000002619 bicyclic group Chemical group 0.000 abstract description 6
- 125000002950 monocyclic group Chemical group 0.000 abstract description 6
- 125000005842 heteroatom Chemical group 0.000 abstract description 5
- 108091005804 Peptidases Proteins 0.000 abstract description 4
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 abstract description 4
- 239000004365 Protease Substances 0.000 abstract description 3
- 125000002252 acyl group Chemical group 0.000 abstract description 3
- 239000000651 prodrug Substances 0.000 abstract description 3
- 229940002612 prodrug Drugs 0.000 abstract description 3
- 229910052717 sulfur Inorganic materials 0.000 abstract description 3
- 239000011593 sulfur Substances 0.000 abstract description 3
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 abstract description 2
- 125000004453 alkoxycarbonyl group Chemical group 0.000 abstract description 2
- 125000004457 alkyl amino carbonyl group Chemical group 0.000 abstract description 2
- 125000004670 alkyl amino thio carbonyl group Chemical group 0.000 abstract description 2
- 125000004390 alkyl sulfonyl group Chemical group 0.000 abstract description 2
- 125000004432 carbon atom Chemical group C* 0.000 abstract description 2
- 125000000217 alkyl group Chemical group 0.000 abstract 2
- 125000000008 (C1-C10) alkyl group Chemical group 0.000 abstract 1
- 125000006727 (C1-C6) alkenyl group Chemical group 0.000 abstract 1
- 102100037486 Reverse transcriptase/ribonuclease H Human genes 0.000 abstract 1
- 125000003342 alkenyl group Chemical group 0.000 abstract 1
- 239000003814 drug Substances 0.000 abstract 1
- 239000002184 metal Substances 0.000 abstract 1
- 125000005740 oxycarbonyl group Chemical group [*:1]OC([*:2])=O 0.000 abstract 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 153
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 138
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 87
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 78
- 239000000047 product Substances 0.000 description 65
- 239000000243 solution Substances 0.000 description 65
- 239000000203 mixture Substances 0.000 description 61
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 59
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 43
- 239000002904 solvent Substances 0.000 description 40
- 239000011343 solid material Substances 0.000 description 37
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 29
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Chemical compound NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 description 29
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 28
- 239000011541 reaction mixture Substances 0.000 description 27
- 238000003756 stirring Methods 0.000 description 27
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N DMSO Substances CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 26
- 239000002253 acid Substances 0.000 description 26
- 238000002844 melting Methods 0.000 description 26
- 230000008018 melting Effects 0.000 description 26
- 239000000725 suspension Substances 0.000 description 26
- 239000007787 solid Substances 0.000 description 25
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 24
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 24
- 238000006243 chemical reaction Methods 0.000 description 24
- 238000001914 filtration Methods 0.000 description 24
- 229910052938 sodium sulfate Inorganic materials 0.000 description 22
- 235000011152 sodium sulphate Nutrition 0.000 description 22
- 238000005160 1H NMR spectroscopy Methods 0.000 description 20
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 20
- 239000012074 organic phase Substances 0.000 description 20
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 18
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 18
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 17
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 16
- 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 16
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 16
- 229910052794 bromium Inorganic materials 0.000 description 16
- 239000011734 sodium Substances 0.000 description 16
- 229910052708 sodium Inorganic materials 0.000 description 16
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 15
- 239000000284 extract Substances 0.000 description 15
- 235000013877 carbamide Nutrition 0.000 description 14
- 239000008346 aqueous phase Substances 0.000 description 13
- 239000004202 carbamide Substances 0.000 description 13
- 229920006395 saturated elastomer Polymers 0.000 description 13
- WFCSWCVEJLETKA-UHFFFAOYSA-N 2-piperazin-1-ylethanol Chemical compound OCCN1CCNCC1 WFCSWCVEJLETKA-UHFFFAOYSA-N 0.000 description 12
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 12
- 239000007864 aqueous solution Substances 0.000 description 12
- 239000003480 eluent Substances 0.000 description 12
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 12
- 239000002244 precipitate Substances 0.000 description 12
- 238000010898 silica gel chromatography Methods 0.000 description 12
- 239000003112 inhibitor Substances 0.000 description 11
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 description 10
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 10
- 229960000583 acetic acid Drugs 0.000 description 10
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 9
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 8
- PCLIMKBDDGJMGD-UHFFFAOYSA-N N-bromosuccinimide Chemical compound BrN1C(=O)CCC1=O PCLIMKBDDGJMGD-UHFFFAOYSA-N 0.000 description 8
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 8
- 229910000042 hydrogen bromide Inorganic materials 0.000 description 8
- 239000003921 oil Substances 0.000 description 8
- 235000019198 oils Nutrition 0.000 description 8
- 238000010992 reflux Methods 0.000 description 8
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 description 8
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 8
- LDSQQXKSEFZAPE-UHFFFAOYSA-N 2-piperidin-4-ylethanol Chemical compound OCCC1CCNCC1 LDSQQXKSEFZAPE-UHFFFAOYSA-N 0.000 description 7
- 238000002425 crystallisation Methods 0.000 description 7
- 230000008025 crystallization Effects 0.000 description 7
- 239000000758 substrate Substances 0.000 description 7
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 6
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 6
- 239000000706 filtrate Substances 0.000 description 6
- 239000012299 nitrogen atmosphere Substances 0.000 description 6
- 239000003208 petroleum Substances 0.000 description 6
- 239000011780 sodium chloride Substances 0.000 description 6
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 6
- UMGDCJDMYOKAJW-UHFFFAOYSA-N thiourea Chemical compound NC(N)=S UMGDCJDMYOKAJW-UHFFFAOYSA-N 0.000 description 6
- OIFBSDVPJOWBCH-UHFFFAOYSA-N Diethyl carbonate Chemical compound CCOC(=O)OCC OIFBSDVPJOWBCH-UHFFFAOYSA-N 0.000 description 5
- 102000004190 Enzymes Human genes 0.000 description 5
- 108090000790 Enzymes Proteins 0.000 description 5
- 150000001412 amines Chemical class 0.000 description 5
- 238000004458 analytical method Methods 0.000 description 5
- 238000009835 boiling Methods 0.000 description 5
- 239000000872 buffer Substances 0.000 description 5
- 230000003197 catalytic effect Effects 0.000 description 5
- 238000001816 cooling Methods 0.000 description 5
- 229940088598 enzyme Drugs 0.000 description 5
- 238000001704 evaporation Methods 0.000 description 5
- 125000003386 piperidinyl group Chemical group 0.000 description 5
- 239000000741 silica gel Substances 0.000 description 5
- 229910002027 silica gel Inorganic materials 0.000 description 5
- 235000017557 sodium bicarbonate Nutrition 0.000 description 5
- 229910000030 sodium bicarbonate Inorganic materials 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
- 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 4
- UZOFELREXGAFOI-UHFFFAOYSA-N 4-methylpiperidine Chemical compound CC1CCNCC1 UZOFELREXGAFOI-UHFFFAOYSA-N 0.000 description 4
- 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 4
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 4
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 4
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 description 4
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 4
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 4
- 239000000460 chlorine Substances 0.000 description 4
- 229910052801 chlorine Inorganic materials 0.000 description 4
- 238000004587 chromatography analysis Methods 0.000 description 4
- 239000013078 crystal Substances 0.000 description 4
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 4
- 230000008020 evaporation Effects 0.000 description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 4
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 4
- 238000001953 recrystallisation Methods 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
- BCNZYOJHNLTNEZ-UHFFFAOYSA-N tert-butyldimethylsilyl chloride Chemical compound CC(C)(C)[Si](C)(C)Cl BCNZYOJHNLTNEZ-UHFFFAOYSA-N 0.000 description 4
- FPGGTKZVZWFYPV-UHFFFAOYSA-M tetrabutylammonium fluoride Chemical compound [F-].CCCC[N+](CCCC)(CCCC)CCCC FPGGTKZVZWFYPV-UHFFFAOYSA-M 0.000 description 4
- ZEYSHALLPAKUHG-UHFFFAOYSA-N 4-methoxypiperidine Chemical compound COC1CCNCC1 ZEYSHALLPAKUHG-UHFFFAOYSA-N 0.000 description 3
- WMXVOGBSFLNIGL-UHFFFAOYSA-N 5-(4-methoxyphenyl)-1,3-diazinane-2,4,6-trione Chemical compound C1=CC(OC)=CC=C1C1C(=O)NC(=O)NC1=O WMXVOGBSFLNIGL-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
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-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
- QGJOPFRUJISHPQ-UHFFFAOYSA-N Carbon disulfide Chemical compound S=C=S QGJOPFRUJISHPQ-UHFFFAOYSA-N 0.000 description 3
- 102000035195 Peptidases Human genes 0.000 description 3
- YGYAWVDWMABLBF-UHFFFAOYSA-N Phosgene Chemical compound ClC(Cl)=O YGYAWVDWMABLBF-UHFFFAOYSA-N 0.000 description 3
- 239000007983 Tris buffer Substances 0.000 description 3
- 235000019400 benzoyl peroxide Nutrition 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 3
- 229910052799 carbon Inorganic materials 0.000 description 3
- 230000015556 catabolic process Effects 0.000 description 3
- 238000003776 cleavage reaction Methods 0.000 description 3
- FGYDHYCFHBSNPE-UHFFFAOYSA-N diethyl phenylmalonate Chemical compound CCOC(=O)C(C(=O)OCC)C1=CC=CC=C1 FGYDHYCFHBSNPE-UHFFFAOYSA-N 0.000 description 3
- 238000001035 drying Methods 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
- 229910052740 iodine Inorganic materials 0.000 description 3
- 239000011630 iodine Substances 0.000 description 3
- 239000007788 liquid Substances 0.000 description 3
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 3
- 230000007017 scission Effects 0.000 description 3
- 239000011550 stock solution 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
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 2
- LTMRRSWNXVJMBA-UHFFFAOYSA-L 2,2-diethylpropanedioate Chemical compound CCC(CC)(C([O-])=O)C([O-])=O LTMRRSWNXVJMBA-UHFFFAOYSA-L 0.000 description 2
- VARVNFDGRLLTCI-UHFFFAOYSA-N 2-(4-phenoxyphenyl)acetic acid Chemical compound C1=CC(CC(=O)O)=CC=C1OC1=CC=CC=C1 VARVNFDGRLLTCI-UHFFFAOYSA-N 0.000 description 2
- MHIAOGTWZISBLM-UHFFFAOYSA-N 3-(3-bromophenyl)benzoic acid Chemical compound OC(=O)C1=CC=CC(C=2C=C(Br)C=CC=2)=C1 MHIAOGTWZISBLM-UHFFFAOYSA-N 0.000 description 2
- VBIDRIWAYGDGDV-UHFFFAOYSA-N 3-ethoxy-2-(4-methoxyphenyl)-3-oxopropanoic acid Chemical compound CCOC(=O)C(C(O)=O)C1=CC=C(OC)C=C1 VBIDRIWAYGDGDV-UHFFFAOYSA-N 0.000 description 2
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 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
- NRPFNQUDKRYCNX-UHFFFAOYSA-N 4-methoxyphenylacetic acid Chemical compound COC1=CC=C(CC(O)=O)C=C1 NRPFNQUDKRYCNX-UHFFFAOYSA-N 0.000 description 2
- IHHIJOXCOGNCCB-UHFFFAOYSA-N 5-(4-methylphenyl)-1,3-diazinane-2,4,6-trione Chemical compound C1=CC(C)=CC=C1C1C(=O)NC(=O)NC1=O IHHIJOXCOGNCCB-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
- BECTZXKJFHQQTK-UHFFFAOYSA-N 5-bromo-5-(4-methoxyphenyl)-1,3-diazinane-2,4,6-trione Chemical compound C1=CC(OC)=CC=C1C1(Br)C(=O)NC(=O)NC1=O BECTZXKJFHQQTK-UHFFFAOYSA-N 0.000 description 2
- AOTXVECLDRAFLA-UHFFFAOYSA-N 5-bromo-5-(4-methylphenyl)-1,3-diazinane-2,4,6-trione Chemical compound C1=CC(C)=CC=C1C1(Br)C(=O)NC(=O)NC1=O AOTXVECLDRAFLA-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
- ITKMNTURBJKPEO-UHFFFAOYSA-N 5-bromo-5-octyl-1,3-diazinane-2,4,6-trione Chemical compound CCCCCCCCC1(Br)C(=O)NC(=O)NC1=O ITKMNTURBJKPEO-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
- GLNANLFCPOATHP-UHFFFAOYSA-N 5-octyl-1,3-diazinane-2,4,6-trione Chemical compound CCCCCCCCC1C(=O)NC(=O)NC1=O GLNANLFCPOATHP-UHFFFAOYSA-N 0.000 description 2
- LDMNAUFAKBNKJB-UHFFFAOYSA-N 5-piperidin-1-yl-1,3-diazinane-2,4,6-trione Chemical compound N1(CCCCC1)C1C(NC(NC1=O)=O)=O LDMNAUFAKBNKJB-UHFFFAOYSA-N 0.000 description 2
- 102000043279 ADAM17 Human genes 0.000 description 2
- 108091007505 ADAM17 Proteins 0.000 description 2
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 2
- UXVMQQNJUSDDNG-UHFFFAOYSA-L Calcium chloride Chemical compound [Cl-].[Cl-].[Ca+2] UXVMQQNJUSDDNG-UHFFFAOYSA-L 0.000 description 2
- 102000008186 Collagen Human genes 0.000 description 2
- 108010035532 Collagen Proteins 0.000 description 2
- 102000029816 Collagenase Human genes 0.000 description 2
- 108060005980 Collagenase Proteins 0.000 description 2
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 2
- 108010037362 Extracellular Matrix Proteins Proteins 0.000 description 2
- 102000010834 Extracellular Matrix Proteins Human genes 0.000 description 2
- NPPJLSILDPVHCM-UHFFFAOYSA-N Felbinac ethyl Chemical compound C1=CC(CC(=O)OCC)=CC=C1C1=CC=CC=C1 NPPJLSILDPVHCM-UHFFFAOYSA-N 0.000 description 2
- 102000013382 Gelatinases Human genes 0.000 description 2
- 108010026132 Gelatinases Proteins 0.000 description 2
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 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
- 108010016113 Matrix Metalloproteinase 1 Proteins 0.000 description 2
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 2
- 102000056189 Neutrophil collagenases Human genes 0.000 description 2
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 2
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical class [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 description 2
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 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
- IPBVNPXQWQGGJP-UHFFFAOYSA-N acetic acid phenyl ester Natural products CC(=O)OC1=CC=CC=C1 IPBVNPXQWQGGJP-UHFFFAOYSA-N 0.000 description 2
- 239000000654 additive Substances 0.000 description 2
- 125000003118 aryl group Chemical group 0.000 description 2
- 239000002585 base Substances 0.000 description 2
- HUMNYLRZRPPJDN-UHFFFAOYSA-N benzaldehyde Chemical compound O=CC1=CC=CC=C1 HUMNYLRZRPPJDN-UHFFFAOYSA-N 0.000 description 2
- ILAHWRKJUDSMFH-UHFFFAOYSA-N boron tribromide Chemical compound BrB(Br)Br ILAHWRKJUDSMFH-UHFFFAOYSA-N 0.000 description 2
- 239000012267 brine Substances 0.000 description 2
- 239000001110 calcium chloride Substances 0.000 description 2
- 235000011148 calcium chloride Nutrition 0.000 description 2
- 229910001628 calcium chloride Inorganic materials 0.000 description 2
- 239000000969 carrier Substances 0.000 description 2
- AOGYCOYQMAVAFD-UHFFFAOYSA-N chlorocarbonic acid Chemical class OC(Cl)=O AOGYCOYQMAVAFD-UHFFFAOYSA-N 0.000 description 2
- 229920001436 collagen Polymers 0.000 description 2
- 239000012230 colorless oil Substances 0.000 description 2
- KGYSAKFWKDJHPV-UHFFFAOYSA-N diethyl 2-(4-phenylphenyl)propanedioate Chemical compound C1=CC(C(C(=O)OCC)C(=O)OCC)=CC=C1C1=CC=CC=C1 KGYSAKFWKDJHPV-UHFFFAOYSA-N 0.000 description 2
- ICEVZECYOWNLDP-UHFFFAOYSA-N diethyl 2-[4-(2-hydroxyethyl)piperazin-1-yl]-2-phenylpropanedioate Chemical compound C=1C=CC=CC=1C(C(=O)OCC)(C(=O)OCC)N1CCN(CCO)CC1 ICEVZECYOWNLDP-UHFFFAOYSA-N 0.000 description 2
- JCPHYJQUUKKFKV-UHFFFAOYSA-N diethyl 2-[4-(4-methylphenyl)butyl]-2-phenylpropanedioate Chemical compound C=1C=CC=CC=1C(C(=O)OCC)(C(=O)OCC)CCCCC1=CC=C(C)C=C1 JCPHYJQUUKKFKV-UHFFFAOYSA-N 0.000 description 2
- LJXVFUNQCQOJJV-UHFFFAOYSA-N diethyl 2-bromo-2-phenylpropanedioate Chemical compound CCOC(=O)C(Br)(C(=O)OCC)C1=CC=CC=C1 LJXVFUNQCQOJJV-UHFFFAOYSA-N 0.000 description 2
- PAMYCOKKVLYDHI-UHFFFAOYSA-N diethyl 2-decylpropanedioate Chemical compound CCCCCCCCCCC(C(=O)OCC)C(=O)OCC PAMYCOKKVLYDHI-UHFFFAOYSA-N 0.000 description 2
- YZYBVYGISZANLI-UHFFFAOYSA-N diethyl 2-octylpropanedioate Chemical compound CCCCCCCCC(C(=O)OCC)C(=O)OCC YZYBVYGISZANLI-UHFFFAOYSA-N 0.000 description 2
- 125000004177 diethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 2
- ZUOUZKKEUPVFJK-UHFFFAOYSA-N diphenyl Chemical compound C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 description 2
- NSQBADKMIYCCSC-UHFFFAOYSA-N ethyl 2-(3-hydroxyphenyl)acetate Chemical compound CCOC(=O)CC1=CC=CC(O)=C1 NSQBADKMIYCCSC-UHFFFAOYSA-N 0.000 description 2
- DOCCDOCIYYDLGJ-UHFFFAOYSA-N ethyl 2-(4-methoxyphenyl)acetate Chemical compound CCOC(=O)CC1=CC=C(OC)C=C1 DOCCDOCIYYDLGJ-UHFFFAOYSA-N 0.000 description 2
- CPYLMUNOJSVCRZ-UHFFFAOYSA-N ethyl 2-(4-phenoxyphenyl)acetate Chemical compound C1=CC(CC(=O)OCC)=CC=C1OC1=CC=CC=C1 CPYLMUNOJSVCRZ-UHFFFAOYSA-N 0.000 description 2
- VAYPMPDBKBYGSQ-UHFFFAOYSA-N ethyl 2-piperidin-4-ylideneacetate Chemical compound CCOC(=O)C=C1CCNCC1 VAYPMPDBKBYGSQ-UHFFFAOYSA-N 0.000 description 2
- 230000005284 excitation Effects 0.000 description 2
- 210000002744 extracellular matrix Anatomy 0.000 description 2
- 239000007850 fluorescent dye Substances 0.000 description 2
- 229960000789 guanidine hydrochloride Drugs 0.000 description 2
- PJJJBBJSCAKJQF-UHFFFAOYSA-N guanidinium chloride Chemical compound [Cl-].NC(N)=[NH2+] PJJJBBJSCAKJQF-UHFFFAOYSA-N 0.000 description 2
- 230000005764 inhibitory process Effects 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
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 2
- 235000019341 magnesium sulphate Nutrition 0.000 description 2
- 239000003475 metalloproteinase inhibitor Substances 0.000 description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 2
- UPSFMJHZUCSEHU-JYGUBCOQSA-N n-[(2s,3r,4r,5s,6r)-2-[(2r,3s,4r,5r,6s)-5-acetamido-4-hydroxy-2-(hydroxymethyl)-6-(4-methyl-2-oxochromen-7-yl)oxyoxan-3-yl]oxy-4,5-dihydroxy-6-(hydroxymethyl)oxan-3-yl]acetamide Chemical compound CC(=O)N[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@H]1O[C@H]1[C@H](O)[C@@H](NC(C)=O)[C@H](OC=2C=C3OC(=O)C=C(C)C3=CC=2)O[C@@H]1CO UPSFMJHZUCSEHU-JYGUBCOQSA-N 0.000 description 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
- 229940049953 phenylacetate Drugs 0.000 description 2
- WLJVXDMOQOGPHL-UHFFFAOYSA-N phenylacetic acid Chemical compound OC(=O)CC1=CC=CC=C1 WLJVXDMOQOGPHL-UHFFFAOYSA-N 0.000 description 2
- UHZYTMXLRWXGPK-UHFFFAOYSA-N phosphorus pentachloride Chemical compound ClP(Cl)(Cl)(Cl)Cl UHZYTMXLRWXGPK-UHFFFAOYSA-N 0.000 description 2
- HDOWRFHMPULYOA-UHFFFAOYSA-N piperidin-4-ol Chemical compound OC1CCNCC1 HDOWRFHMPULYOA-UHFFFAOYSA-N 0.000 description 2
- 229910000027 potassium carbonate Inorganic materials 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
- WWYDYZMNFQIYPT-UHFFFAOYSA-N ru78191 Chemical compound OC(=O)C(C(O)=O)C1=CC=CC=C1 WWYDYZMNFQIYPT-UHFFFAOYSA-N 0.000 description 2
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 2
- 241000894007 species Species 0.000 description 2
- 108091007196 stromelysin Proteins 0.000 description 2
- 238000006467 substitution reaction Methods 0.000 description 2
- KZNICNPSHKQLFF-UHFFFAOYSA-N succinimide Chemical compound O=C1CCC(=O)N1 KZNICNPSHKQLFF-UHFFFAOYSA-N 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- 210000001519 tissue Anatomy 0.000 description 2
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 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
- QBYIENPQHBMVBV-HFEGYEGKSA-N (2R)-2-hydroxy-2-phenylacetic acid Chemical compound O[C@@H](C(O)=O)c1ccccc1.O[C@@H](C(O)=O)c1ccccc1 QBYIENPQHBMVBV-HFEGYEGKSA-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
- 125000003161 (C1-C6) alkylene group Chemical group 0.000 description 1
- MIOPJNTWMNEORI-GMSGAONNSA-N (S)-camphorsulfonic acid Chemical compound C1C[C@@]2(CS(O)(=O)=O)C(=O)C[C@@H]1C2(C)C MIOPJNTWMNEORI-GMSGAONNSA-N 0.000 description 1
- BWYRVFHMSIFKNF-UHFFFAOYSA-N 1,2,6-thiadiazinane-3,5-dione Chemical class O=C1CC(=O)NSN1 BWYRVFHMSIFKNF-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
- BWKWNLMXXRCEPL-UHFFFAOYSA-N 1-(2-hydroxyethyl)piperazin-2-one Chemical compound OCCN1CCNCC1=O BWKWNLMXXRCEPL-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
- FCYSNQACNGYXEW-UHFFFAOYSA-N 1-(4-bromobutyl)-4-methylbenzene Chemical compound CC1=CC=C(CCCCBr)C=C1 FCYSNQACNGYXEW-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
- BTYNVOQLMBUUMS-UHFFFAOYSA-N 2-amino-1h-pyrimidine-4,6-dione Chemical class NC1=NC(=O)CC(=O)N1 BTYNVOQLMBUUMS-UHFFFAOYSA-N 0.000 description 1
- VBZOUUJVGADJBK-UHFFFAOYSA-N 2-bromopropanedioic acid Chemical compound OC(=O)C(Br)C(O)=O VBZOUUJVGADJBK-UHFFFAOYSA-N 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
- VIBOGIYPPWLDTI-UHFFFAOYSA-N 2-naphthylacetic acid Chemical compound C1=CC=CC2=CC(CC(=O)O)=CC=C21 VIBOGIYPPWLDTI-UHFFFAOYSA-N 0.000 description 1
- SMGCRQWNSNABKJ-UHFFFAOYSA-N 2-piperidin-4-ylideneethanol Chemical compound OCC=C1CCNCC1 SMGCRQWNSNABKJ-UHFFFAOYSA-N 0.000 description 1
- GNPISAHACGIXLZ-UHFFFAOYSA-N 3-(4-methylphenoxy)propanoic acid Chemical compound CC1=CC=C(OCCC(O)=O)C=C1 GNPISAHACGIXLZ-UHFFFAOYSA-N 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
- IECMOFZIMWVOAS-UHFFFAOYSA-N 4,4-dimethylpiperidine Chemical compound CC1(C)CCNCC1 IECMOFZIMWVOAS-UHFFFAOYSA-N 0.000 description 1
- 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 1
- LYFJLLBHFUCGCJ-UHFFFAOYSA-N 5-[3-(4-methoxyphenyl)propanoyl]-1,3-diazinane-2,4,6-trione Chemical compound C1=CC(OC)=CC=C1CCC(=O)C1C(=O)NC(=O)NC1=O LYFJLLBHFUCGCJ-UHFFFAOYSA-N 0.000 description 1
- XHQIJBZETZKGLB-UHFFFAOYSA-N 5-[3-(4-methoxyphenyl)propyl]-1,3-diazinane-2,4,6-trione Chemical compound C1=CC(OC)=CC=C1CCCC1C(=O)NC(=O)NC1=O XHQIJBZETZKGLB-UHFFFAOYSA-N 0.000 description 1
- CURAXXCMZKLFLS-UHFFFAOYSA-N 5-bromo-5-[3-(4-methoxyphenyl)propyl]-1,3-diazinane-2,4,6-trione Chemical compound C1=CC(OC)=CC=C1CCCC1(Br)C(=O)NC(=O)NC1=O CURAXXCMZKLFLS-UHFFFAOYSA-N 0.000 description 1
- GPZOPZZUNUCLCG-UHFFFAOYSA-N 5-bromo-5-[3-[tert-butyl(dimethyl)silyl]oxyphenyl]-1,3-diazinane-2,4,6-trione Chemical compound CC(C)(C)[Si](C)(C)OC1=CC=CC(C2(Br)C(NC(=O)NC2=O)=O)=C1 GPZOPZZUNUCLCG-UHFFFAOYSA-N 0.000 description 1
- SIECVDZGBFOCBB-UHFFFAOYSA-N 5-piperazin-1-yl-1,3-diazinane-2,4,6-trione Chemical compound O=C1NC(=O)C(N2CCNCC2)C(=O)N1 SIECVDZGBFOCBB-UHFFFAOYSA-N 0.000 description 1
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 description 1
- 229920001817 Agar Polymers 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
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 1
- 101100386719 Caenorhabditis elegans dcs-1 gene Proteins 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
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 1
- 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 1
- 108010010803 Gelatin Proteins 0.000 description 1
- 241000206672 Gelidium Species 0.000 description 1
- 101000990908 Homo sapiens Neutrophil collagenase Proteins 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
- 229930195725 Mannitol Natural products 0.000 description 1
- 102000000380 Matrix Metalloproteinase 1 Human genes 0.000 description 1
- 206010027476 Metastases Diseases 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- PHSPJQZRQAJPPF-UHFFFAOYSA-N N-alpha-Methylhistamine Chemical compound CNCCC1=CN=CN1 PHSPJQZRQAJPPF-UHFFFAOYSA-N 0.000 description 1
- 206010028980 Neoplasm Diseases 0.000 description 1
- 102100030411 Neutrophil collagenase Human genes 0.000 description 1
- 101710118230 Neutrophil collagenase Proteins 0.000 description 1
- 108030001564 Neutrophil collagenases Proteins 0.000 description 1
- 235000019502 Orange oil Nutrition 0.000 description 1
- 241000276498 Pollachius virens Species 0.000 description 1
- 229920003171 Poly (ethylene oxide) Polymers 0.000 description 1
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 1
- IWYDHOAUDWTVEP-UHFFFAOYSA-N R-2-phenyl-2-hydroxyacetic acid Natural products OC(=O)C(O)C1=CC=CC=C1 IWYDHOAUDWTVEP-UHFFFAOYSA-N 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- 235000021355 Stearic acid Nutrition 0.000 description 1
- 239000005864 Sulphur Substances 0.000 description 1
- 206010064996 Ulcerative keratitis Diseases 0.000 description 1
- 150000001242 acetic acid derivatives Chemical class 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
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 1
- 238000005903 acid hydrolysis reaction Methods 0.000 description 1
- 235000010419 agar Nutrition 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 150000001447 alkali salts Chemical class 0.000 description 1
- 125000003545 alkoxy group Chemical group 0.000 description 1
- 150000003973 alkyl amines Chemical class 0.000 description 1
- 150000001350 alkyl halides Chemical class 0.000 description 1
- 230000029936 alkylation Effects 0.000 description 1
- 238000005804 alkylation reaction Methods 0.000 description 1
- 150000001408 amides Chemical class 0.000 description 1
- QGZKDVFQNNGYKY-UHFFFAOYSA-N ammonia Natural products N QGZKDVFQNNGYKY-UHFFFAOYSA-N 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
- 239000001166 ammonium sulphate Substances 0.000 description 1
- 235000011130 ammonium sulphate Nutrition 0.000 description 1
- 229910052786 argon Inorganic materials 0.000 description 1
- 125000005100 aryl amino carbonyl group Chemical group 0.000 description 1
- 125000005161 aryl oxy carbonyl group Chemical group 0.000 description 1
- 125000004391 aryl sulfonyl group Chemical group 0.000 description 1
- 238000003556 assay Methods 0.000 description 1
- 239000012131 assay buffer Substances 0.000 description 1
- 150000001540 azides Chemical class 0.000 description 1
- 229940125717 barbiturate Drugs 0.000 description 1
- 230000027455 binding Effects 0.000 description 1
- 235000010290 biphenyl Nutrition 0.000 description 1
- QRZAKQDHEVVFRX-UHFFFAOYSA-N biphenyl-4-ylacetic acid Chemical compound C1=CC(CC(=O)O)=CC=C1C1=CC=CC=C1 QRZAKQDHEVVFRX-UHFFFAOYSA-N 0.000 description 1
- 210000000988 bone and bone Anatomy 0.000 description 1
- 239000006227 byproduct Substances 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
- 150000001733 carboxylic acid esters Chemical class 0.000 description 1
- 150000001735 carboxylic acids Chemical class 0.000 description 1
- 230000001925 catabolic effect Effects 0.000 description 1
- 210000004027 cell Anatomy 0.000 description 1
- KMPWYEUPVWOPIM-KODHJQJWSA-N cinchonidine Chemical compound C1=CC=C2C([C@H]([C@H]3[N@]4CC[C@H]([C@H](C4)C=C)C3)O)=CC=NC2=C1 KMPWYEUPVWOPIM-KODHJQJWSA-N 0.000 description 1
- KMPWYEUPVWOPIM-UHFFFAOYSA-N cinchonidine Natural products C1=CC=C2C(C(C3N4CCC(C(C4)C=C)C3)O)=CC=NC2=C1 KMPWYEUPVWOPIM-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
- 229960002424 collagenase Drugs 0.000 description 1
- 239000008139 complexing agent Substances 0.000 description 1
- 229940125904 compound 1 Drugs 0.000 description 1
- 229940125782 compound 2 Drugs 0.000 description 1
- 239000012043 crude product 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
- 235000014113 dietary fatty acids Nutrition 0.000 description 1
- WGBSHZUHSDGHLV-UHFFFAOYSA-N diethyl 2-(4-methylphenyl)propanedioate Chemical compound CCOC(=O)C(C(=O)OCC)C1=CC=C(C)C=C1 WGBSHZUHSDGHLV-UHFFFAOYSA-N 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
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- BNIILDVGGAEEIG-UHFFFAOYSA-L disodium hydrogen phosphate Chemical compound [Na+].[Na+].OP([O-])([O-])=O BNIILDVGGAEEIG-UHFFFAOYSA-L 0.000 description 1
- 229910000397 disodium phosphate Inorganic materials 0.000 description 1
- 235000019800 disodium phosphate Nutrition 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 230000000694 effects Effects 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
- 150000002148 esters Chemical class 0.000 description 1
- DQYBDCGIPTYXML-UHFFFAOYSA-N ethoxyethane;hydrate Chemical compound O.CCOCC DQYBDCGIPTYXML-UHFFFAOYSA-N 0.000 description 1
- PUIBRHJUTVHVPI-UHFFFAOYSA-N ethyl 2-(4-butoxyphenyl)acetate Chemical compound CCCCOC1=CC=C(CC(=O)OCC)C=C1 PUIBRHJUTVHVPI-UHFFFAOYSA-N 0.000 description 1
- HYUPPKVFCGIMDB-UHFFFAOYSA-N ethyl 2-(4-hydroxyphenyl)acetate Chemical compound CCOC(=O)CC1=CC=C(O)C=C1 HYUPPKVFCGIMDB-UHFFFAOYSA-N 0.000 description 1
- 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 1
- 102000036444 extracellular matrix enzymes Human genes 0.000 description 1
- 108091007167 extracellular matrix enzymes Proteins 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
- 239000000796 flavoring agent Substances 0.000 description 1
- 238000001506 fluorescence spectroscopy Methods 0.000 description 1
- 235000013355 food flavoring agent Nutrition 0.000 description 1
- 235000003599 food sweetener Nutrition 0.000 description 1
- 239000012634 fragment Substances 0.000 description 1
- 239000012458 free base Substances 0.000 description 1
- 239000007789 gas 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
- 150000002357 guanidines Chemical class 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 229910001385 heavy metal Inorganic materials 0.000 description 1
- 125000001072 heteroaryl group Chemical group 0.000 description 1
- 229920006158 high molecular weight polymer Polymers 0.000 description 1
- 150000003840 hydrochlorides Chemical class 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
- 238000001727 in vivo Methods 0.000 description 1
- 208000027866 inflammatory disease Diseases 0.000 description 1
- 150000007529 inorganic bases Chemical class 0.000 description 1
- 230000009545 invasion Effects 0.000 description 1
- 239000012948 isocyanate Substances 0.000 description 1
- 150000002513 isocyanates Chemical class 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- 150000002540 isothiocyanates 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
- 238000011068 loading method 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
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- 239000011976 maleic acid Substances 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
- 239000000463 material Substances 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 229920000609 methyl cellulose Polymers 0.000 description 1
- 239000001923 methylcellulose Substances 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 201000006417 multiple sclerosis Diseases 0.000 description 1
- 238000006386 neutralization reaction Methods 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
- 239000010502 orange oil Substances 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- 201000008482 osteoarthritis Diseases 0.000 description 1
- 125000000636 p-nitrophenyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)[N+]([O-])=O 0.000 description 1
- QNGNSVIICDLXHT-UHFFFAOYSA-N para-ethylbenzaldehyde Natural products CCC1=CC=C(C=O)C=C1 QNGNSVIICDLXHT-UHFFFAOYSA-N 0.000 description 1
- 230000008506 pathogenesis Effects 0.000 description 1
- 230000001575 pathological effect Effects 0.000 description 1
- 230000037361 pathway Effects 0.000 description 1
- XYFCBTPGUUZFHI-UHFFFAOYSA-N phosphine group Chemical group P XYFCBTPGUUZFHI-UHFFFAOYSA-N 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 229920000642 polymer Polymers 0.000 description 1
- GKKCIDNWFBPDBW-UHFFFAOYSA-M potassium cyanate Chemical compound [K]OC#N GKKCIDNWFBPDBW-UHFFFAOYSA-M 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 102000004196 processed proteins & peptides Human genes 0.000 description 1
- 108090000765 processed proteins & peptides Proteins 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 235000019833 protease Nutrition 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 230000006337 proteolytic cleavage Effects 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 229960001404 quinidine Drugs 0.000 description 1
- 238000005057 refrigeration Methods 0.000 description 1
- 206010039073 rheumatoid arthritis Diseases 0.000 description 1
- 125000005624 silicic acid group Chemical class 0.000 description 1
- 235000012239 silicon dioxide Nutrition 0.000 description 1
- WBHQBSYUUJJSRZ-UHFFFAOYSA-M sodium bisulfate Chemical compound [Na+].OS([O-])(=O)=O WBHQBSYUUJJSRZ-UHFFFAOYSA-M 0.000 description 1
- 239000012279 sodium borohydride Substances 0.000 description 1
- 229910000033 sodium borohydride Inorganic materials 0.000 description 1
- BEOOHQFXGBMRKU-UHFFFAOYSA-N sodium cyanoborohydride Chemical compound [Na+].[B-]C#N BEOOHQFXGBMRKU-UHFFFAOYSA-N 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 125000000547 substituted alkyl group Chemical group 0.000 description 1
- 229960002317 succinimide Drugs 0.000 description 1
- 150000003460 sulfonic acids Chemical class 0.000 description 1
- YBBRCQOCSYXUOC-UHFFFAOYSA-N sulfuryl dichloride Chemical compound ClS(Cl)(=O)=O YBBRCQOCSYXUOC-UHFFFAOYSA-N 0.000 description 1
- 239000003765 sweetening agent Substances 0.000 description 1
- 238000001308 synthesis method Methods 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 229940095064 tartrate Drugs 0.000 description 1
- 150000003512 tertiary amines Chemical class 0.000 description 1
- 125000002813 thiocarbonyl group Chemical group *C(*)=S 0.000 description 1
- 150000003573 thiols Chemical class 0.000 description 1
- 150000003585 thioureas Chemical class 0.000 description 1
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 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
- GGUBFICZYGKNTD-UHFFFAOYSA-N triethyl phosphonoacetate Chemical compound CCOC(=O)CP(=O)(OCC)OCC GGUBFICZYGKNTD-UHFFFAOYSA-N 0.000 description 1
- 150000003672 ureas Chemical class 0.000 description 1
- 235000019871 vegetable fat Nutrition 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)
- Animal Behavior & Ethology (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (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)
- Pain & Pain Management (AREA)
- Communicable Diseases (AREA)
- Ophthalmology & Optometry (AREA)
- Immunology (AREA)
- Epidemiology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
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 |
| PCT/EP1996/005766 WO1997023465A1 (en) | 1995-12-23 | 1996-12-20 | New barbituric acid derivatives, processes for their production and pharmaceutical agents containing these compounds |
Publications (3)
| Publication Number | Publication Date |
|---|---|
| NO982901D0 NO982901D0 (no) | 1998-06-22 |
| NO982901L NO982901L (no) | 1998-08-24 |
| NO311572B1 true NO311572B1 (no) | 2001-12-10 |
Family
ID=7781338
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| NO19982901A NO311572B1 (no) | 1995-12-23 | 1998-06-22 | Nye barbitursyrederivater, farmasöytiske midler inneholdende slike forbindelser, samt anvendelse av slike forbindelser tilfremstilling av et farmasöytisk middel |
Country Status (22)
| Country | Link |
|---|---|
| US (2) | US6110924A (ru) |
| EP (1) | EP0869947B1 (ru) |
| JP (1) | JP4198752B2 (ru) |
| KR (1) | KR100440035B1 (ru) |
| CN (1) | CN1318406C (ru) |
| AT (1) | ATE226575T1 (ru) |
| BR (1) | BR9612232A (ru) |
| CZ (1) | CZ292503B6 (ru) |
| DE (2) | DE19548624A1 (ru) |
| DK (1) | DK0869947T3 (ru) |
| ES (1) | ES2184903T3 (ru) |
| HU (1) | HUP9901065A3 (ru) |
| IL (1) | IL125048A (ru) |
| MX (1) | MX9805063A (ru) |
| NO (1) | NO311572B1 (ru) |
| NZ (1) | NZ325802A (ru) |
| PL (1) | PL190217B1 (ru) |
| PT (1) | PT869947E (ru) |
| RU (1) | RU2177475C2 (ru) |
| TW (1) | TW518324B (ru) |
| WO (1) | WO1997023465A1 (ru) |
| ZA (1) | ZA9610765B (ru) |
Families Citing this family (22)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2002504916A (ja) | 1997-06-21 | 2002-02-12 | ロシュ ダイアグノスティクス ゲゼルシャフト ミット ベシュレンクテル ハフツング | 抗転移及び抗腫瘍活性を有するバルビツール酸誘導体 |
| 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 |
| CO5210860A1 (es) * | 1999-10-01 | 2002-10-30 | Hoffmann La Roche | Nuevos derivados de pirimidina-2,4,6-triona |
| JP2004512327A (ja) | 2000-10-26 | 2004-04-22 | ファイザー・プロダクツ・インク | ピリミジン−２，４，６−トリオン・メタロプロテイナーゼ阻害剤 |
| 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 |
| WO2003053940A1 (en) * | 2001-12-20 | 2003-07-03 | 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. |
| WO2004060346A2 (en) | 2002-12-30 | 2004-07-22 | 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 |
| RU2411043C2 (ru) * | 2004-04-01 | 2011-02-10 | Юниверсите Де Льеж | Фармацевтические композиции пиримидин-2,4,6-трионов |
| 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 |
| SG186885A1 (en) | 2010-06-04 | 2013-02-28 | Albany Molecular Res Inc | Glycine transporter-1 inhibitors, methods of making them, and uses thereof |
| KR101822417B1 (ko) * | 2017-06-14 | 2018-01-29 | 주식회사 청도제약 | 인간의 체액에서 산화 스트레스를 측정하기 위한 방법 |
| 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 AT AT96944612T patent/ATE226575T1/de not_active IP Right Cessation
- 1996-12-20 DK DK96944612T patent/DK0869947T3/da active
- 1996-12-20 IL IL12504896A patent/IL125048A/en not_active IP Right Cessation
- 1996-12-20 RU RU98113916/04A patent/RU2177475C2/ru not_active IP Right Cessation
- 1996-12-20 JP JP52331897A patent/JP4198752B2/ja not_active Expired - Fee Related
- 1996-12-20 CN CNB961800275A patent/CN1318406C/zh not_active Expired - Fee Related
- 1996-12-20 PT PT96944612T patent/PT869947E/pt unknown
- 1996-12-20 CZ CZ19981968A patent/CZ292503B6/cs not_active IP Right Cessation
- 1996-12-20 US US09/091,352 patent/US6110924A/en not_active Expired - Fee Related
- 1996-12-20 KR KR10-1998-0704855A patent/KR100440035B1/ko not_active IP Right Cessation
- 1996-12-20 ZA ZA9610765A patent/ZA9610765B/xx unknown
- 1996-12-20 NZ NZ325802A patent/NZ325802A/xx unknown
- 1996-12-20 HU HU9901065A patent/HUP9901065A3/hu unknown
- 1996-12-20 EP EP96944612A patent/EP0869947B1/en not_active Expired - Lifetime
- 1996-12-20 BR BR9612232A patent/BR9612232A/pt not_active IP Right Cessation
- 1996-12-20 DE DE69624500T patent/DE69624500T2/de not_active Expired - Fee Related
- 1996-12-20 ES ES96944612T patent/ES2184903T3/es not_active Expired - Lifetime
- 1996-12-20 WO PCT/EP1996/005766 patent/WO1997023465A1/en active IP Right Grant
- 1996-12-20 PL PL96327466A patent/PL190217B1/pl not_active IP Right Cessation
-
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
Also Published As
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| NO311572B1 (no) | Nye barbitursyrederivater, farmasöytiske midler inneholdende slike forbindelser, samt anvendelse av slike forbindelser tilfremstilling av et farmasöytisk middel | |
| AU746853B2 (en) | Barbituric acid derivatives with antimetastatic and antitumor activity | |
| NO324691B1 (no) | Pyrimidin-4-on derivater, farmasoytisk sammensetning inneholdende en slik forbindelse, samt anvendelse av forbindelsene | |
| MXPA99000981A (es) | Inhibidores de metaloproteasa. | |
| ZA200610698B (en) | Novel hydantoin derivatives for the treatment of obstructive airway diseases | |
| SE449748B (sv) | 2-(4-((4,4-dialkyl-2,6-piperidindion-1-yl)butyl)-1-piperazinyl)pyridiner, deras framstellning och farmaceutiska komposition | |
| NO311615B1 (no) | Nye substituerte [2-(1-piperazinyl)etoksy]metylforbindelser, fremgangsmåte for fremstilling og anvendelse av slike | |
| KR20120084771A (ko) | 브래디키닌 수용체 길항제로서 유용한 2-아릴-프로피온아미드 유도체 및 이를 함유하는 약학적 조성물 | |
| US20100280018A1 (en) | Derivatives Of Hydroxamic Acid As Metalloproteinase Inhibitors | |
| AU2007249443A1 (en) | Isothiazolidines useful in the treatment of ocular hypertensive conditions | |
| NZ516338A (en) | 2-(4-Pyridyl)-5-sulphonyl-benzofuran derivatives useful as metalloprotease inhibitors | |
| US20040171543A1 (en) | Matrix metalloproteinase inhibitors and methods for identification of lead compounds | |
| US6727266B2 (en) | Substituted tryptophan derivatives | |
| CA2240845C (en) | New barbituric acid derivatives, processes for their production and pharmaceutical agents containing these compounds | |
| US20050014817A1 (en) | Fluorothiophene derivatives, process for preparing them and pharmaceutical compositions containing them | |
| AU722513C (en) | New barbituric acid derivatives, processes for their production and pharmaceutical agents containing these compounds | |
| US6716845B2 (en) | Barbituric acid derivatives | |
| CS252828B2 (en) | Method of n,3-disubstituted 2-oxindole-1-carboxamides production | |
| AU2002302470A1 (en) | Pyrimidine-2,4,6-trione derivatives, processes for their production and pharmaceutical agents containing them | |
| JP2002541256A (ja) | 新規エンドセリン転換酵素阻害剤、その製造および使用 |