HU226232B1 - Substituted 3,5-diphenyl-1,2,4-triazoles, their production processes, their use as pharmaceutical metal chelators and pharamceutical compositions comprising said compositions - Google Patents
Substituted 3,5-diphenyl-1,2,4-triazoles, their production processes, their use as pharmaceutical metal chelators and pharamceutical compositions comprising said compositions Download PDFInfo
- Publication number
- HU226232B1 HU226232B1 HU9903111A HUP9903111A HU226232B1 HU 226232 B1 HU226232 B1 HU 226232B1 HU 9903111 A HU9903111 A HU 9903111A HU P9903111 A HUP9903111 A HU P9903111A HU 226232 B1 HU226232 B1 HU 226232B1
- Authority
- HU
- Hungary
- Prior art keywords
- alkyl
- hydroxy
- bis
- lower alkyl
- hydroxyphenyl
- Prior art date
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- 229910052751 metal Inorganic materials 0.000 title claims description 9
- 239000002184 metal Substances 0.000 title claims description 9
- 238000004519 manufacturing process Methods 0.000 title claims description 7
- 239000000203 mixture Substances 0.000 title description 90
- KPKQWXGFEKRQQA-UHFFFAOYSA-N 3,5-diphenyl-1h-1,2,4-triazole Chemical class C1=CC=CC=C1C1=NNC(C=2C=CC=CC=2)=N1 KPKQWXGFEKRQQA-UHFFFAOYSA-N 0.000 title description 3
- 239000002738 chelating agent Substances 0.000 title 1
- 125000000217 alkyl group Chemical group 0.000 claims description 211
- -1 carbamoyl - Chemical class 0.000 claims description 91
- 150000001875 compounds Chemical class 0.000 claims description 85
- 150000003839 salts Chemical class 0.000 claims description 73
- 229910052757 nitrogen Inorganic materials 0.000 claims description 60
- 229910052739 hydrogen Inorganic materials 0.000 claims description 55
- 239000001257 hydrogen Substances 0.000 claims description 55
- 125000003545 alkoxy group Chemical group 0.000 claims description 50
- 125000003282 alkyl amino group Chemical group 0.000 claims description 50
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 46
- 150000002431 hydrogen Chemical class 0.000 claims description 42
- 125000005843 halogen group Chemical group 0.000 claims description 28
- 229910052736 halogen Inorganic materials 0.000 claims description 26
- 150000002367 halogens Chemical class 0.000 claims description 26
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 claims description 20
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 18
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 18
- 125000005115 alkyl carbamoyl group Chemical group 0.000 claims description 14
- 125000001072 heteroaryl group Chemical group 0.000 claims description 14
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 13
- 125000004453 alkoxycarbonyl group Chemical group 0.000 claims description 13
- 150000002825 nitriles Chemical class 0.000 claims description 13
- 239000008194 pharmaceutical composition Substances 0.000 claims description 13
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 13
- DLFVBJFMPXGRIB-UHFFFAOYSA-N Acetamide Chemical compound CC(N)=O DLFVBJFMPXGRIB-UHFFFAOYSA-N 0.000 claims description 12
- 125000003118 aryl group Chemical group 0.000 claims description 12
- 125000004475 heteroaralkyl group Chemical group 0.000 claims description 12
- UUEVFMOUBSLVJW-UHFFFAOYSA-N oxo-[[1-[2-[2-[2-[4-(oxoazaniumylmethylidene)pyridin-1-yl]ethoxy]ethoxy]ethyl]pyridin-4-ylidene]methyl]azanium;dibromide Chemical compound [Br-].[Br-].C1=CC(=C[NH+]=O)C=CN1CCOCCOCCN1C=CC(=C[NH+]=O)C=C1 UUEVFMOUBSLVJW-UHFFFAOYSA-N 0.000 claims description 12
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 11
- 125000003107 substituted aryl group Chemical group 0.000 claims description 11
- 229910052742 iron Inorganic materials 0.000 claims description 10
- 241001465754 Metazoa Species 0.000 claims description 9
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 9
- 239000003814 drug Substances 0.000 claims description 9
- 125000001424 substituent group Chemical group 0.000 claims description 9
- 125000003435 aroyl group Chemical group 0.000 claims description 8
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims description 8
- 125000001589 carboacyl group Chemical group 0.000 claims description 8
- 125000004432 carbon atom Chemical group C* 0.000 claims description 8
- 201000010099 disease Diseases 0.000 claims description 8
- 125000005113 hydroxyalkoxy group Chemical group 0.000 claims description 7
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 6
- 230000004962 physiological condition Effects 0.000 claims description 6
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 claims description 5
- 239000003937 drug carrier Substances 0.000 claims description 5
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 5
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 5
- PMDCZENCAXMSOU-UHFFFAOYSA-N N-ethylacetamide Chemical compound CCNC(C)=O PMDCZENCAXMSOU-UHFFFAOYSA-N 0.000 claims description 3
- 150000001450 anions Chemical class 0.000 claims description 3
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 claims description 3
- 238000002360 preparation method Methods 0.000 claims description 3
- 125000002112 pyrrolidino group Chemical group [*]N1C([H])([H])C([H])([H])C([H])([H])C1([H])[H] 0.000 claims description 3
- QNABQSQCXMUBAY-UHFFFAOYSA-N 2-[3,5-bis(5-chloro-2-hydroxyphenyl)-1,2,4-triazol-1-yl]-N-(2-morpholin-4-ylethyl)acetamide Chemical compound OC1=CC=C(Cl)C=C1C1=NN(CC(=O)NCCN2CCOCC2)C(C=2C(=CC=C(Cl)C=2)O)=N1 QNABQSQCXMUBAY-UHFFFAOYSA-N 0.000 claims description 2
- 125000004195 4-methylpiperazin-1-yl group Chemical group [H]C([H])([H])N1C([H])([H])C([H])([H])N(*)C([H])([H])C1([H])[H] 0.000 claims description 2
- KPUSQGVHCQFTLV-UHFFFAOYSA-N 2-[3,5-bis(2-hydroxyphenyl)-1,2,4-triazol-1-yl]-1-(4-methylpiperazin-1-yl)ethanone Chemical compound C1CN(C)CCN1C(=O)CN1C(C=2C(=CC=CC=2)O)=NC(C=2C(=CC=CC=2)O)=N1 KPUSQGVHCQFTLV-UHFFFAOYSA-N 0.000 claims 1
- RIOWRULWAPJMLT-UHFFFAOYSA-N 2-[3,5-bis(2-hydroxyphenyl)-1,2,4-triazol-1-yl]-N-(2,3-dihydroxypropyl)acetamide Chemical compound OCC(O)CNC(=O)CN1N=C(C=2C(=CC=CC=2)O)N=C1C1=CC=CC=C1O RIOWRULWAPJMLT-UHFFFAOYSA-N 0.000 claims 1
- ATLJTHIODMLXBM-UHFFFAOYSA-N 2-[3,5-bis(2-hydroxyphenyl)-1,2,4-triazol-1-yl]-N-(2-methoxyethyl)acetamide Chemical compound COCCNC(=O)CN1N=C(C=2C(=CC=CC=2)O)N=C1C1=CC=CC=C1O ATLJTHIODMLXBM-UHFFFAOYSA-N 0.000 claims 1
- JQJJURQBPNASNY-UHFFFAOYSA-N 2-[3,5-bis(2-hydroxyphenyl)-1,2,4-triazol-1-yl]-N-(2-morpholin-4-ylethyl)acetamide Chemical compound OC1=CC=CC=C1C1=NN(CC(=O)NCCN2CCOCC2)C(C=2C(=CC=CC=2)O)=N1 JQJJURQBPNASNY-UHFFFAOYSA-N 0.000 claims 1
- NGJKKFWOJDDGJI-UHFFFAOYSA-N 2-[3,5-bis(2-hydroxyphenyl)-1,2,4-triazol-1-yl]-N-[2-(2-hydroxyethoxy)ethyl]acetamide Chemical compound OCCOCCNC(=O)CN1N=C(C=2C(=CC=CC=2)O)N=C1C1=CC=CC=C1O NGJKKFWOJDDGJI-UHFFFAOYSA-N 0.000 claims 1
- ZFBNGAMIZWACNE-UHFFFAOYSA-N 2-[3,5-bis(2-hydroxyphenyl)-1,2,4-triazol-1-yl]-N-[2-(dimethylamino)ethyl]-N-methylacetamide Chemical compound CN(C)CCN(C)C(=O)CN1N=C(C=2C(=CC=CC=2)O)N=C1C1=CC=CC=C1O ZFBNGAMIZWACNE-UHFFFAOYSA-N 0.000 claims 1
- VHHPZCJPIQOZAG-UHFFFAOYSA-N 2-[3,5-bis(2-hydroxyphenyl)-1,2,4-triazol-1-yl]-N-methylacetamide Chemical compound CNC(=O)CN1N=C(C=2C(=CC=CC=2)O)N=C1C1=CC=CC=C1O VHHPZCJPIQOZAG-UHFFFAOYSA-N 0.000 claims 1
- WFGVLHPUZNSTQY-UHFFFAOYSA-N 4-chloro-2-[5-(5-chloro-2-hydroxyphenyl)-1-(pyridin-2-ylmethyl)-1,2,4-triazol-3-yl]phenol Chemical compound OC1=CC=C(Cl)C=C1C1=NN(CC=2N=CC=CC=2)C(C=2C(=CC=C(Cl)C=2)O)=N1 WFGVLHPUZNSTQY-UHFFFAOYSA-N 0.000 claims 1
- ADUDKTKINNIAHV-UHFFFAOYSA-N CN(C)C1=CC=C(C=C1)CN2C=NC(=N2)C3=C(C=CC(=C3)Cl)O Chemical compound CN(C)C1=CC=C(C=C1)CN2C=NC(=N2)C3=C(C=CC(=C3)Cl)O ADUDKTKINNIAHV-UHFFFAOYSA-N 0.000 claims 1
- PVCJKHHOXFKFRP-UHFFFAOYSA-N N-acetylethanolamine Chemical compound CC(=O)NCCO PVCJKHHOXFKFRP-UHFFFAOYSA-N 0.000 claims 1
- FLLXZXMPTCCCNO-UHFFFAOYSA-N [4-[3,5-bis(2-hydroxyphenyl)-1,2,4-triazol-1-yl]phenyl]-morpholin-4-ylmethanone Chemical compound OC1=CC=CC=C1C1=NN(C=2C=CC(=CC=2)C(=O)N2CCOCC2)C(C=2C(=CC=CC=2)O)=N1 FLLXZXMPTCCCNO-UHFFFAOYSA-N 0.000 claims 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 165
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 87
- 239000013078 crystal Substances 0.000 description 55
- 238000001035 drying Methods 0.000 description 48
- 239000000047 product Substances 0.000 description 47
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 45
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 38
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 37
- YJKFSPXKSRMHAB-UHFFFAOYSA-N ethyl 2-[3,5-bis(2-hydroxyphenyl)-1,2,4-triazol-1-yl]acetate Chemical compound CCOC(=O)CN1N=C(C=2C(=CC=CC=2)O)N=C1C1=CC=CC=C1O YJKFSPXKSRMHAB-UHFFFAOYSA-N 0.000 description 28
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 24
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 24
- 239000004480 active ingredient Substances 0.000 description 24
- 229910052938 sodium sulfate Inorganic materials 0.000 description 24
- 235000011152 sodium sulphate Nutrition 0.000 description 24
- 239000012044 organic layer Substances 0.000 description 23
- 238000000034 method Methods 0.000 description 19
- IVKNUIVDQMARCO-UHFFFAOYSA-N oxazin-4-one Chemical compound O=C1C=CON=C1 IVKNUIVDQMARCO-UHFFFAOYSA-N 0.000 description 19
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 18
- 239000002253 acid Substances 0.000 description 17
- 239000007858 starting material Substances 0.000 description 16
- 238000006243 chemical reaction Methods 0.000 description 15
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 15
- 150000003973 alkyl amines Chemical class 0.000 description 14
- 239000003826 tablet Substances 0.000 description 12
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Substances [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 11
- 239000002904 solvent Substances 0.000 description 11
- 238000001816 cooling Methods 0.000 description 10
- 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 9
- 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 9
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 9
- 239000008101 lactose Substances 0.000 description 9
- 238000003756 stirring Methods 0.000 description 9
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 8
- 239000002585 base Substances 0.000 description 8
- 230000008569 process Effects 0.000 description 8
- 239000000243 solution Substances 0.000 description 8
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 7
- 239000000543 intermediate Substances 0.000 description 7
- 125000006239 protecting group Chemical group 0.000 description 7
- 238000010992 reflux Methods 0.000 description 7
- 239000000454 talc Substances 0.000 description 7
- 235000012222 talc Nutrition 0.000 description 7
- 229910052623 talc Inorganic materials 0.000 description 7
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 6
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 6
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 description 6
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 6
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 6
- 235000019359 magnesium stearate Nutrition 0.000 description 6
- 239000000725 suspension Substances 0.000 description 6
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 6
- 125000003626 1,2,4-triazol-1-yl group Chemical group [*]N1N=C([H])N=C1[H] 0.000 description 5
- LLEMOWNGBBNAJR-UHFFFAOYSA-N biphenyl-2-ol Chemical compound OC1=CC=CC=C1C1=CC=CC=C1 LLEMOWNGBBNAJR-UHFFFAOYSA-N 0.000 description 5
- 239000008280 blood Substances 0.000 description 5
- 210000004369 blood Anatomy 0.000 description 5
- 239000003153 chemical reaction reagent Substances 0.000 description 5
- 239000003795 chemical substances by application Substances 0.000 description 5
- 125000004494 ethyl ester group Chemical group 0.000 description 5
- 239000007903 gelatin capsule Substances 0.000 description 5
- 239000000546 pharmaceutical excipient Substances 0.000 description 5
- 229920001223 polyethylene glycol Polymers 0.000 description 5
- 239000002244 precipitate Substances 0.000 description 5
- 239000000741 silica gel Substances 0.000 description 5
- 229910002027 silica gel Inorganic materials 0.000 description 5
- 125000000954 2-hydroxyethyl group Chemical group [H]C([*])([H])C([H])([H])O[H] 0.000 description 4
- 229920002261 Corn starch Polymers 0.000 description 4
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 4
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 4
- 241000282412 Homo Species 0.000 description 4
- DBMJMQXJHONAFJ-UHFFFAOYSA-M Sodium laurylsulphate Chemical compound [Na+].CCCCCCCCCCCCOS([O-])(=O)=O DBMJMQXJHONAFJ-UHFFFAOYSA-M 0.000 description 4
- 229920002472 Starch Polymers 0.000 description 4
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 4
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 4
- 125000002723 alicyclic group Chemical group 0.000 description 4
- 150000001335 aliphatic alkanes Chemical class 0.000 description 4
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- 239000008298 dragée Substances 0.000 description 4
- LCDQBBHEQOLPRB-UHFFFAOYSA-N ethyl 2-[3,5-bis(5-chloro-2-hydroxyphenyl)-1,2,4-triazol-1-yl]acetate Chemical compound CCOC(=O)CN1N=C(C=2C(=CC=C(Cl)C=2)O)N=C1C1=CC(Cl)=CC=C1O LCDQBBHEQOLPRB-UHFFFAOYSA-N 0.000 description 4
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- 238000005342 ion exchange Methods 0.000 description 4
- 239000007788 liquid Substances 0.000 description 4
- 239000000463 material Substances 0.000 description 4
- RWIVICVCHVMHMU-UHFFFAOYSA-N n-aminoethylmorpholine Chemical compound NCCN1CCOCC1 RWIVICVCHVMHMU-UHFFFAOYSA-N 0.000 description 4
- 229920001592 potato starch Polymers 0.000 description 4
- 239000000843 powder Substances 0.000 description 4
- 230000001376 precipitating effect Effects 0.000 description 4
- YGSDEFSMJLZEOE-UHFFFAOYSA-N salicylic acid Chemical compound OC(=O)C1=CC=CC=C1O YGSDEFSMJLZEOE-UHFFFAOYSA-N 0.000 description 4
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- 239000011975 tartaric acid Substances 0.000 description 4
- 235000002906 tartaric acid Nutrition 0.000 description 4
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 4
- 238000005160 1H NMR spectroscopy Methods 0.000 description 3
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- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 3
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- 125000004457 alkyl amino carbonyl group Chemical group 0.000 description 3
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- 208000005980 beta thalassemia Diseases 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 3
- CJZGTCYPCWQAJB-UHFFFAOYSA-L calcium stearate Chemical compound [Ca+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O CJZGTCYPCWQAJB-UHFFFAOYSA-L 0.000 description 3
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- 238000002425 crystallisation Methods 0.000 description 3
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- 125000004183 alkoxy alkyl group Chemical group 0.000 description 1
- 229910052782 aluminium Inorganic materials 0.000 description 1
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 150000001408 amides Chemical class 0.000 description 1
- ZWWXDCOPVYATOQ-UHFFFAOYSA-N amino-(4-nitrophenyl)azanium;chloride Chemical compound [Cl-].N[NH2+]C1=CC=C([N+]([O-])=O)C=C1 ZWWXDCOPVYATOQ-UHFFFAOYSA-N 0.000 description 1
- LHIJANUOQQMGNT-UHFFFAOYSA-N aminoethylethanolamine Chemical compound NCCNCCO LHIJANUOQQMGNT-UHFFFAOYSA-N 0.000 description 1
- QXAITBQSYVNQDR-UHFFFAOYSA-N amitraz Chemical compound C=1C=C(C)C=C(C)C=1N=CN(C)C=NC1=CC=C(C)C=C1C QXAITBQSYVNQDR-UHFFFAOYSA-N 0.000 description 1
- 239000002333 angiotensin II receptor antagonist Substances 0.000 description 1
- 229940126317 angiotensin II receptor antagonist Drugs 0.000 description 1
- 238000010171 animal model Methods 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 150000001491 aromatic compounds Chemical class 0.000 description 1
- 125000003710 aryl alkyl group Chemical group 0.000 description 1
- 229910052788 barium Inorganic materials 0.000 description 1
- DSAJWYNOEDNPEQ-UHFFFAOYSA-N barium atom Chemical compound [Ba] DSAJWYNOEDNPEQ-UHFFFAOYSA-N 0.000 description 1
- 150000008107 benzenesulfonic acids Chemical class 0.000 description 1
- JFDZBHWFFUWGJE-UHFFFAOYSA-N benzonitrile Substances N#CC1=CC=CC=C1 JFDZBHWFFUWGJE-UHFFFAOYSA-N 0.000 description 1
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 description 1
- PRBLRLQZOKOQCQ-UHFFFAOYSA-N benzylhydrazine;hydron;chloride Chemical compound Cl.NNCC1=CC=CC=C1 PRBLRLQZOKOQCQ-UHFFFAOYSA-N 0.000 description 1
- MSWZFWKMSRAUBD-UHFFFAOYSA-N beta-D-galactosamine Natural products NC1C(O)OC(CO)C(O)C1O MSWZFWKMSRAUBD-UHFFFAOYSA-N 0.000 description 1
- 125000000319 biphenyl-4-yl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1C1=C([H])C([H])=C([*])C([H])=C1[H] 0.000 description 1
- 230000037396 body weight Effects 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- 229910052794 bromium Inorganic materials 0.000 description 1
- 125000004063 butyryl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- FUFJGUQYACFECW-UHFFFAOYSA-L calcium hydrogenphosphate Chemical compound [Ca+2].OP([O-])([O-])=O FUFJGUQYACFECW-UHFFFAOYSA-L 0.000 description 1
- 235000011010 calcium phosphates Nutrition 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-N carbonic acid Chemical class OC(O)=O BVKZGUZCCUSVTD-UHFFFAOYSA-N 0.000 description 1
- 239000001768 carboxy methyl cellulose Substances 0.000 description 1
- 150000001735 carboxylic acids Chemical class 0.000 description 1
- 125000002057 carboxymethyl group Chemical group [H]OC(=O)C([H])([H])[*] 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 229920002301 cellulose acetate Polymers 0.000 description 1
- 238000005119 centrifugation Methods 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- 239000007910 chewable tablet Substances 0.000 description 1
- 229940068682 chewable tablet Drugs 0.000 description 1
- 239000000470 constituent Substances 0.000 description 1
- 235000005822 corn Nutrition 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- 125000004093 cyano group Chemical group *C#N 0.000 description 1
- 238000000354 decomposition reaction Methods 0.000 description 1
- 230000001419 dependent effect Effects 0.000 description 1
- 230000008021 deposition Effects 0.000 description 1
- 238000000502 dialysis Methods 0.000 description 1
- 235000019700 dicalcium phosphate Nutrition 0.000 description 1
- 150000001991 dicarboxylic acids Chemical class 0.000 description 1
- 235000014113 dietary fatty acids Nutrition 0.000 description 1
- ZBCBWPMODOFKDW-UHFFFAOYSA-N diethanolamine Chemical compound OCCNCCO ZBCBWPMODOFKDW-UHFFFAOYSA-N 0.000 description 1
- 125000004177 diethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- IJKVHSBPTUYDLN-UHFFFAOYSA-N dihydroxy(oxo)silane Chemical compound O[Si](O)=O IJKVHSBPTUYDLN-UHFFFAOYSA-N 0.000 description 1
- 229940043279 diisopropylamine Drugs 0.000 description 1
- 239000003085 diluting agent Substances 0.000 description 1
- 150000002009 diols Chemical class 0.000 description 1
- KPUWHANPEXNPJT-UHFFFAOYSA-N disiloxane Chemical group [SiH3]O[SiH3] KPUWHANPEXNPJT-UHFFFAOYSA-N 0.000 description 1
- 208000035475 disorder Diseases 0.000 description 1
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- 239000007938 effervescent tablet Substances 0.000 description 1
- 230000002124 endocrine Effects 0.000 description 1
- 230000002708 enhancing effect Effects 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
- 125000003754 ethoxycarbonyl group Chemical group C(=O)(OCC)* 0.000 description 1
- NLFBCYMMUAKCPC-KQQUZDAGSA-N ethyl (e)-3-[3-amino-2-cyano-1-[(e)-3-ethoxy-3-oxoprop-1-enyl]sulfanyl-3-oxoprop-1-enyl]sulfanylprop-2-enoate Chemical compound CCOC(=O)\C=C\SC(=C(C#N)C(N)=O)S\C=C\C(=O)OCC NLFBCYMMUAKCPC-KQQUZDAGSA-N 0.000 description 1
- GETVBTMFGVOGRW-UHFFFAOYSA-N ethyl 2-hydrazinylacetate Chemical compound CCOC(=O)CNN GETVBTMFGVOGRW-UHFFFAOYSA-N 0.000 description 1
- DKIRUWOCDZGRHG-UHFFFAOYSA-N ethyl acetate;hydrazine;hydrochloride Chemical compound Cl.NN.CCOC(C)=O DKIRUWOCDZGRHG-UHFFFAOYSA-N 0.000 description 1
- 125000000031 ethylamino group Chemical group [H]C([H])([H])C([H])([H])N([H])[*] 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
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- 238000000605 extraction Methods 0.000 description 1
- 239000000194 fatty acid Substances 0.000 description 1
- 229930195729 fatty acid Natural products 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
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- 239000012467 final product Substances 0.000 description 1
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- 239000001530 fumaric acid Substances 0.000 description 1
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- 238000005227 gel permeation chromatography Methods 0.000 description 1
- 230000009395 genetic defect Effects 0.000 description 1
- 239000011521 glass Substances 0.000 description 1
- 229960002442 glucosamine Drugs 0.000 description 1
- 230000036541 health Effects 0.000 description 1
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- 239000004009 herbicide Substances 0.000 description 1
- 125000005842 heteroatom Chemical group 0.000 description 1
- 125000005343 heterocyclic alkyl group Chemical group 0.000 description 1
- 150000002391 heterocyclic compounds Chemical class 0.000 description 1
- GNOIPBMMFNIUFM-UHFFFAOYSA-N hexamethylphosphoric triamide Chemical compound CN(C)P(=O)(N(C)C)N(C)C GNOIPBMMFNIUFM-UHFFFAOYSA-N 0.000 description 1
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 229940031704 hydroxypropyl methylcellulose phthalate Drugs 0.000 description 1
- 229920003132 hydroxypropyl methylcellulose phthalate Polymers 0.000 description 1
- 125000002883 imidazolyl group Chemical group 0.000 description 1
- 239000004615 ingredient Substances 0.000 description 1
- 229910052500 inorganic mineral Inorganic materials 0.000 description 1
- 229910017053 inorganic salt Inorganic materials 0.000 description 1
- 239000003049 inorganic solvent Substances 0.000 description 1
- 230000002452 interceptive effect Effects 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- 238000004255 ion exchange chromatography Methods 0.000 description 1
- 229940075525 iron chelating agent Drugs 0.000 description 1
- 239000000797 iron chelating agent Substances 0.000 description 1
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- 125000005929 isobutyloxycarbonyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])OC(*)=O 0.000 description 1
- 125000003253 isopropoxy group Chemical group [H]C([H])([H])C([H])(O*)C([H])([H])[H] 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 125000005928 isopropyloxycarbonyl group Chemical group [H]C([H])([H])C([H])(OC(*)=O)C([H])([H])[H] 0.000 description 1
- 150000002576 ketones Chemical class 0.000 description 1
- 229940057995 liquid paraffin Drugs 0.000 description 1
- 210000004185 liver Anatomy 0.000 description 1
- 229910052749 magnesium Inorganic materials 0.000 description 1
- 159000000003 magnesium salts Chemical class 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
- 239000000594 mannitol Substances 0.000 description 1
- 235000010355 mannitol Nutrition 0.000 description 1
- 230000007721 medicinal effect Effects 0.000 description 1
- AFVFQIVMOAPDHO-UHFFFAOYSA-N methanesulfonic acid Substances CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 1
- GBMDVOWEEQVZKZ-UHFFFAOYSA-N methanol;hydrate Chemical compound O.OC GBMDVOWEEQVZKZ-UHFFFAOYSA-N 0.000 description 1
- WSFSSNUMVMOOMR-BJUDXGSMSA-N methanone Chemical compound O=[11CH2] WSFSSNUMVMOOMR-BJUDXGSMSA-N 0.000 description 1
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 1
- NSPJNIDYTSSIIY-UHFFFAOYSA-N methoxy(methoxymethoxy)methane Chemical compound COCOCOC NSPJNIDYTSSIIY-UHFFFAOYSA-N 0.000 description 1
- 125000001160 methoxycarbonyl group Chemical group [H]C([H])([H])OC(*)=O 0.000 description 1
- 229920000609 methyl cellulose Polymers 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 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
- 235000010981 methylcellulose Nutrition 0.000 description 1
- 244000005700 microbiome Species 0.000 description 1
- 239000011707 mineral Substances 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 239000012452 mother liquor Substances 0.000 description 1
- ZCKMKMQBBGLEND-UHFFFAOYSA-N n,n-diethyl-4-(hydrazinylmethyl)aniline;hydrochloride Chemical compound Cl.CCN(CC)C1=CC=C(CNN)C=C1 ZCKMKMQBBGLEND-UHFFFAOYSA-N 0.000 description 1
- SHJZVYGVWZJJQN-UHFFFAOYSA-N n-ethyl-4-methylpiperazin-1-amine Chemical compound CCNN1CCN(C)CC1 SHJZVYGVWZJJQN-UHFFFAOYSA-N 0.000 description 1
- RIWRFSMVIUAEBX-UHFFFAOYSA-N n-methyl-1-phenylmethanamine Chemical compound CNCC1=CC=CC=C1 RIWRFSMVIUAEBX-UHFFFAOYSA-N 0.000 description 1
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000001038 naphthoyl group Chemical group C1(=CC=CC2=CC=CC=C12)C(=O)* 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
- 239000003921 oil Substances 0.000 description 1
- 235000019198 oils Nutrition 0.000 description 1
- 229940049964 oleate Drugs 0.000 description 1
- 239000012074 organic phase Substances 0.000 description 1
- 239000003791 organic solvent mixture Substances 0.000 description 1
- 208000005368 osteomalacia Diseases 0.000 description 1
- 125000002971 oxazolyl group Chemical group 0.000 description 1
- 230000020477 pH reduction Effects 0.000 description 1
- 244000045947 parasite Species 0.000 description 1
- 239000006201 parenteral dosage form Substances 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 239000008180 pharmaceutical surfactant Substances 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- WVDDGKGOMKODPV-ZQBYOMGUSA-N phenyl(114C)methanol Chemical compound O[14CH2]C1=CC=CC=C1 WVDDGKGOMKODPV-ZQBYOMGUSA-N 0.000 description 1
- 125000000286 phenylethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])C([H])([H])* 0.000 description 1
- 238000006303 photolysis reaction Methods 0.000 description 1
- 230000015843 photosynthesis, light reaction Effects 0.000 description 1
- XNGIFLGASWRNHJ-UHFFFAOYSA-L phthalate(2-) Chemical compound [O-]C(=O)C1=CC=CC=C1C([O-])=O XNGIFLGASWRNHJ-UHFFFAOYSA-L 0.000 description 1
- 239000004014 plasticizer Substances 0.000 description 1
- 229920005862 polyol Polymers 0.000 description 1
- 150000003077 polyols Chemical class 0.000 description 1
- 229950008882 polysorbate Drugs 0.000 description 1
- 229920000136 polysorbate Polymers 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 229940116317 potato starch Drugs 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 238000003672 processing method Methods 0.000 description 1
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 1
- 125000001325 propanoyl group Chemical group O=C([*])C([H])([H])C([H])([H])[H] 0.000 description 1
- 239000003586 protic polar solvent Substances 0.000 description 1
- 125000004309 pyranyl group Chemical group O1C(C=CC=C1)* 0.000 description 1
- 125000003373 pyrazinyl group Chemical group 0.000 description 1
- MNRWHUKMYOKCMQ-UHFFFAOYSA-N pyridin-4-ylmethylhydrazine;hydrochloride Chemical compound Cl.NNCC1=CC=NC=C1 MNRWHUKMYOKCMQ-UHFFFAOYSA-N 0.000 description 1
- 125000004076 pyridyl group Chemical group 0.000 description 1
- 125000000714 pyrimidinyl group Chemical group 0.000 description 1
- 125000000168 pyrrolyl group Chemical group 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 238000006722 reduction reaction Methods 0.000 description 1
- 235000009566 rice Nutrition 0.000 description 1
- 229940100486 rice starch Drugs 0.000 description 1
- 238000005730 ring rearrangement reaction Methods 0.000 description 1
- 229920006395 saturated elastomer Polymers 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
- 125000005930 sec-butyloxycarbonyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(OC(*)=O)C([H])([H])[H] 0.000 description 1
- 239000008159 sesame oil Substances 0.000 description 1
- 235000011803 sesame oil Nutrition 0.000 description 1
- 230000009528 severe injury Effects 0.000 description 1
- 208000007056 sickle cell anemia Diseases 0.000 description 1
- 238000007086 side reaction Methods 0.000 description 1
- 235000012239 silicon dioxide Nutrition 0.000 description 1
- 235000010413 sodium alginate Nutrition 0.000 description 1
- 239000000661 sodium alginate Substances 0.000 description 1
- 229940005550 sodium alginate Drugs 0.000 description 1
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 description 1
- 229920001027 sodium carboxymethylcellulose Polymers 0.000 description 1
- 235000002639 sodium chloride Nutrition 0.000 description 1
- 229940057950 sodium laureth sulfate Drugs 0.000 description 1
- SXHLENDCVBIJFO-UHFFFAOYSA-M sodium;2-[2-(2-dodecoxyethoxy)ethoxy]ethyl sulfate Chemical compound [Na+].CCCCCCCCCCCCOCCOCCOCCOS([O-])(=O)=O SXHLENDCVBIJFO-UHFFFAOYSA-M 0.000 description 1
- GGCZERPQGJTIQP-UHFFFAOYSA-N sodium;9,10-dioxoanthracene-2-sulfonic acid Chemical compound [Na+].C1=CC=C2C(=O)C3=CC(S(=O)(=O)O)=CC=C3C(=O)C2=C1 GGCZERPQGJTIQP-UHFFFAOYSA-N 0.000 description 1
- 239000007901 soft capsule Substances 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 150000008163 sugars Chemical class 0.000 description 1
- 150000003460 sulfonic acids Chemical class 0.000 description 1
- 150000003462 sulfoxides Chemical class 0.000 description 1
- 239000002511 suppository base Substances 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 238000009492 tablet coating Methods 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- DKACXUFSLUYRFU-UHFFFAOYSA-N tert-butyl n-aminocarbamate Chemical compound CC(C)(C)OC(=O)NN DKACXUFSLUYRFU-UHFFFAOYSA-N 0.000 description 1
- YBRBMKDOPFTVDT-UHFFFAOYSA-N tert-butylamine Chemical compound CC(C)(C)N YBRBMKDOPFTVDT-UHFFFAOYSA-N 0.000 description 1
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 150000003512 tertiary amines Chemical class 0.000 description 1
- 125000001412 tetrahydropyranyl group Chemical group 0.000 description 1
- 125000003831 tetrazolyl group Chemical group 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 125000004305 thiazinyl group Chemical group S1NC(=CC=C1)* 0.000 description 1
- 125000000335 thiazolyl group Chemical group 0.000 description 1
- 125000001544 thienyl group Chemical group 0.000 description 1
- 239000004408 titanium dioxide Substances 0.000 description 1
- 125000005425 toluyl group Chemical group 0.000 description 1
- 231100000027 toxicology Toxicity 0.000 description 1
- 235000010487 tragacanth Nutrition 0.000 description 1
- 239000000196 tragacanth Substances 0.000 description 1
- 229940116362 tragacanth Drugs 0.000 description 1
- 229910052723 transition metal Inorganic materials 0.000 description 1
- 125000001425 triazolyl group Chemical group 0.000 description 1
- 229940078499 tricalcium phosphate Drugs 0.000 description 1
- 235000019731 tricalcium phosphate Nutrition 0.000 description 1
- 229910000391 tricalcium phosphate Inorganic materials 0.000 description 1
- 229940100445 wheat starch Drugs 0.000 description 1
- 150000003751 zinc Chemical class 0.000 description 1
Classifications
-
- 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
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
- C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
- C07D249/08—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P39/00—General protective or antinoxious agents
- A61P39/04—Chelating agents
-
- 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
- C07D401/06—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 linked by a carbon chain containing only aliphatic carbon atoms
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Public Health (AREA)
- Medicinal Chemistry (AREA)
- Veterinary Medicine (AREA)
- General Health & Medical Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Toxicology (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Diabetes (AREA)
- Hematology (AREA)
- Obesity (AREA)
- Epidemiology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
Description
Összetétel (10 000 tabletta) | |
Hatóanyag | 2000,0 g |
Laktóz | 500,0 g |
Burgonyakeményítő | 352,0 g |
Zselatin | 8,0 g |
Talkum | 60,0 g |
Magnézium-sztearát | 10,0 g |
Szilícium-dioxid (nagy diszperzitású) | 20,0 g |
Etanol | q.s. |
A hatóanyagot összekeverjük a laktózzal és 292 g |
Összetétel (1000 tabletta) | |
Hatóanyag | 400,0 g |
Laktóz | 100,0 g |
Kukoricakeményítő | 70,0 g |
Talkum | 8,5 g |
Kalcium-sztearát | 1,5 g |
Hidroxi-propil-metil-cellulóz | 2,36 g |
Sellakk | 0,64 g |
Víz | q.s. |
Diklór-metán | q.s. |
A hatóanyagot összekeverjük a laktózzal és 40 g |
összetétel (1000 kapszula) | |
Hatóanyag | 500,0 g |
Laktóz | 250,0 g |
Mikrokristályos cellulóz | 30,0 g |
Nátrium-lauril-szulfát | 2,0 g |
Magnézium-sztearát | 8,0 g |
A liofilizált hatóanyagba 0,2 | mm lyukméretű szitán |
Claims (13)
- SZABADALMI IGÉNYPONTOK1. (I) általános képletű vegyületek és sóik - e képletbenR1 és R5 jelentése egyidejűleg vagy egymástól függetlenül hidrogén, halogén, hidroxi-, rövid szénláncú alkil-, halo-(rövid szénláncú)-alkil, rövid szénláncú alkoxi-, halo-(rövid szénláncú)-alkoxi-, karboxil-, karbamoil-, N-(rövid szénláncú)-alkil-karbamoil-, N,N-di(rövid-szénláncú)-alkil-karbamoil- vagy nitrilcsoport,R2 és R4 jelentése egyidejűleg vagy egymástól függetlenül hidrogén, adott esetben helyettesített rövidHU 226 232 Β1 szénláncú alkanoil- vagy aroil-, vagy egy fiziológiás körülmények között eltávolítható csoport,R3 jelentése hidrogén, rövid szénláncü alkil-, hidroxi-(rövld szénláncú)-alkil-, halo(rövid szénláncúj-alkil-, karboxi-(rövid szénláncúj-alkil-, (rövid szénláncúj-alkoxikarbonil-(rövid szénláncú)-alkil-, R6R7-N-C(O)-(rövid szénláncú)-alkil-, adott esetben helyettesített arilvagy aril-(rövid szénláncú)-alkil- vagy adott esetben helyettesített heteroaril- vagy heteroaralkilcsoport,R6 és R7 jelentése egyidejűleg vagy egymástól függetlenül hidrogén, rövid szénláncú alkil-, hidroxi-(rövid szénláncúj-alkil-, alkoxi-(rövid szénláncúj-alkil-, hidroxi-alkoxi-(rövid szénláncúj-alkil-, amino-(rövid szénláncúj-alkil-, N-(rövid szénláncúj-alkil-amino(rövid szénláncúj-alkil-, N,N-di(rövld szénláncú)-alkil-amino-(rövid szénláncúj-alkil-, N-(hidroxi-rövid szénláncú)-alkil-amino-(rövid szénláncúj-alkil-, N,N-di(hidroxi-rövid szénláncú)-alkil-amino-(rövid szénláncúj-alkil- vagy a kapcsolódó nitrogénatommal együtt aza-aliciklusos gyűrűt képez, és a „rövid szénláncú” kifejezés maximálisan 4 szénatomos csoportot jelöl - alkalmazása olyan betegségek kezelésére szolgáló gyógyszerkészítmények előállítására, amelyek fémfelesleget okoznak az emberi vagy állati szervezetben vagy amelyeket ilyen felesleg vált ki.
- 2. Az 1. igénypont szerinti (I) általános képletű vegyületek alkalmazása olyan betegségek kezelésére szolgáló gyógyszerkészítmények előállítására, amelyeket vasfelesleg vált ki vagy amelyek vasfelesleget okoznak az emberi vagy állati szervezetben.
- 3. Gyógyszerkészítmény, amely legalább egy 1. igénypont szerinti (I) általános képletű vegyületet vagy gyógyászatilag elfogadható sóját - e képletbenR1 és R5 jelentése egyidejűleg vagy egymástól függetlenül hidrogén, halogén, hidroxi-, rövid szénláncú alkil-, halo-(rövid szénláncúj-alkil-, rövid szénláncú alkoxi-, halo-(rövid szénláncúj-alkoxi-, karboxil-, karbamoil-, N-(rövid szénláncúj-alkil-karbamoil-, N,N-di(rövid szénláncúj-alkil-karbamoil- vagy nitrilcsoport,R2 és R4 jelentése egyidejűleg vagy egymástól függetlenül hidrogén, adott esetben helyettesített rövid szénláncú alkanoil- vagy aroil-, vagy egy fiziológiás körülmények között eltávolítható csoport,R3 jelentése hidrogén, rövid szénláncú alkil-, hidroxi-(rövid szénláncúj-alkil-, halo-(rövid szénláncúj-alkil-, karboxi-(rövid szénláncúj-alkil-, (rövid szénláncú)-alkoxi-karbonil-(rövid szénláncúj-alkil-, R6Rt-N-C(O)(rövid szénláncúj-alkil-, adott esetben helyettesített aril-, N-(rövid szénláncúj-alkil-amino-, N,N-di(rövid szénláncúj-alkil-amino- vagy pirrolidinocsoporttal helyettesített aril-(rövid szénláncúj-alkil-, adott esetben helyettesített heteroaril- vagy heteroaralkilcsoport,R6 és R7 jelentése egyidejűleg vagy egymástól függetlenül hidrogén, rövid szénláncú alkil-, hidroxi-(rövid szénláncúj-alkil-, alkoxi-(rövid szénláncúj-alkil-, hidroxi-alkoxi-(rövid szénláncúj-alkil-, amino-(rövid szénláncúj-alkil-, N-(rövid szénláncúj-alkil-amino(rövld szénláncúj-alkil-, N,N-di(rövid szénláncú)-alkil-amino-(rövid szénláncúj-alkil-, N-(hidroxi-rövid szénláncú/-alkil-amino-/rövid-szénláncú/-alkil-, N,Ndi-/hidroxi-rövid szénláncú)-alkil-amino-(rövid szénláncúj-alkil-csoport vagy a kapcsolódó nitrogénatommal együtt aza-aliciklusos gyűrűt képez, ahol a „rövid szénláncú” kifejezés maximálisan 4 szénatomos csoportot jelöl és legalább egy gyógyászatilag elfogadható vivőanyagot tartalmaz.
- 4. Gyógyszerkészítmény, amely legalább egy, az 1. igénypont szerinti (I) általános képletű vegyületet vagy gyógyászatilag elfogadható sóját - e képletbenRí és R5 jelentése egyidejűleg vagy egymástól függetlenül hidrogén, halogén, hidroxi-, rövid szénláncú alkil-, halo-(rövid szénláncúj-alkil-, rövid szénláncú alkoxi- vagy halo-(rövid szénláncúj-alkoxi-csoport,R2 és R4 jelentése egyidejűleg vagy egymástól függetlenül hidrogén vagy egy fiziológiás körülmények között eltávolítható csoport,R3 jelentése rövid szénláncú alkil-, hidroxi-(rövid szénláncúj-alkil-, karboxi-(rövid szénláncúj-alkil-, (rövid szénláncú)-alkoxi-karbonil-(rövid szénláncúj-alkil-, R6R7=N-C(O)-(rövid szénláncúj-alkil-, helyettesített aril-, N-(rövid szénláncúj-alkil-amino-, N,N-di(rövid szénláncúj-alkil-amino- vagy pirrolidinocsoporttal helyettesített aril-(rövid szénláncúj-alkil-, adott esetben helyettesített heteroaril- vagy heteroaralkilcsoport,Rg és R7 jelentése egyidejűleg vagy egymástól függetlenül hidrogén, rövid szénláncú alkil-, hidroxi-(rövid szénláncúj-alkil-, alkoxi-(rövid szénláncúj-alkil-, hidroxi-alkoxi-(rövid szénláncúj-alkil-, amino-(rövid szénláncúj-alkil-, N-(rövid szénláncúj-alkil-amino(rövid szénláncúj-alkil-, N,N-di(rövid szénláncú)-alkil-amino-(rövid szénláncúj-alkil-, N-(hidroxi-rövid szénláncú)-alkil-amino-(rövid szénláncúj-alkil-, N,N-di(hidroxi-rövid szénláncú)-alkil-amino-(rövid szénláncúj-alkil- vagy a kapcsolódó nitrogénatommal együtt aza-aliciklusos gyűrűt képez, ahol a „rövid szénláncú” kifejezés maximálisan 4 szénatomos csoportot jelöl és legalább egy gyógyászatilag elfogadható vivőanyagot tartalmaz.
- 5. Az 1. igénypont szerinti (I) általános képletű vegyületek; e képletbenR-, és R5 jelentése egyidejűleg vagy egymástól függetlenül hidrogén, halogén, rövid szénláncú alkil-, halo(rövid szénláncúj-alkil-, rövid szénláncú alkoxi-, halo(rövid szénláncúj-alkoxi-, karboxil-, karbamoil-, N-(rövid szénláncúj-alkil-karbamoil-, N,N-di(rövid szénláncúj-alkil-karbamoil- vagy nltrilcsoport,R2 és R4 jelentése egyidejűleg vagy egymástól függetlenül hidrogén, adott esetben helyettesített rövid szénláncú alkanoil- vagy aroil-, vagy egy fiziológiás körülmények között eltávolítható csoport,R3 jelentése R6R7=N-C(O)-(rövid szénláncúj-alkil-, adott esetben helyettesített aril-, N-(rövid szénláncúj-alkil-amino-, N,N-di(rövid szénláncúj-alkilamino- vagy pin-olidinocsoporttal helyettesített aril(rövid szénláncúj-alkil- vagy adott esetben helyettesített heteroaril- vagy heteroaralkilcsoport,HU 226 232 Β1 azzal a feltétellel, hogyR3 nem jelenthet adott esetben halogénnel, nitro-, nitril-, hidroxi-, rövid szénláncú alkil-, halo-(rövid szénláncú)-alkil-, rövid szénláncú alkoxi- vagy rövid szénláncú alkoxi-karbonil-csoporttal helyettesített fenilcsoportot, haR2 és R4 jelentése hidrogén, ésRí és R5 jelentése hidrogén, halogén, nitril-, rövid szénláncú alkil-, halo-(rövid szénláncú)-alkil- vagy rövid szénláncú alkoxicsoport, és azzal a további feltétellel, hogyR3 nem jelenthet fenilcsoportot, haR2 és R4 jelentése acetilcsoport, ésR3 és R5 jelentése hidrogén,R6 és R7 jelentése egyidejűleg vagy egymástól függetlenül hidrogén, rövid szénláncú alkil-, hidroxi-(rövid szénláncú)-alkil-, alkoxi-(rövid szénláncú)-alkil-, hidroxi-alkoxi-(rövid szénláncú)-alkil-, amino-(rövid szénláncú)-alkil-, N-(rövid szénláncú)-alkil-amino(rövid szénláncú)-alkil-, N,N-di(rövid szénláncú)-alkil-amino-(rövid szénláncú)-alkil-, N-(hidroxi-rövid szénláncú-alkil)-amino-(rövid szénláncú)-alkil-, N,N-di(hidroxi-rövid szénláncú-alkil)-amino-(rövid szénláncúj-alkil-csoport vagy a nitrogénatommal együtt, amelyhez kapcsolódnak, aza-aliciklusos gyűrűt képez -, ahol a „rövid szénláncú kifejezés maximálisan 4 szénatomos csoportot jelöl és sóik.
- 6. Az 5. igénypont szerinti (I) általános képletű vegyületek; e képletbenR3 és R5 jelentése egyidejűleg vagy egymástól függetlenül hidrogén, halogén, rövid szénláncú alkil-, halo-(rövid szénláncú)-alkil-, rövid szénláncú alkoxi- vagy halo-(rövid szénláncú)-alkoxi-csoport,R2 és R4 jelentése egyidejűleg vagy egymástól függetlenül hidrogén vagy egy fiziológiás körülmények között eltávolítható csoport,R3 jelentése R6R7=N-C(O)-(rövid szénláncú)-alkil-, helyettesített aril-, N-(rövid szénláncú)-alkil-amino-, N,N-di(rövid szénláncú)-alkil-amino- vagy pirrolidinocsoporttal helyettesített aril-(rövid szénláncú)-alkil- vagy adott esetben helyettesített heteroaralkilcsoport, azzal a feltétellel, hogyR3 nem jelenthet halogénnel, nitro-, nitril-, hidroxi-, rövid szénláncú alkil-, halo(rövid szénláncú)-alkil-, rövid szénláncú alkoxi- vagy rövid szénláncú alkoxikarbonil-csoporttal helyettesített fenilcsoportot, haR2 és R4 jelentése hidrogén, ésRt és R5 jelentése hidrogén, halogén, rövid szénláncú alkil-, halo(rövid szénláncú)-alkil- vagy rövid szénláncú alkoxicsoport,R6 és R7 jelentése egyidejűleg vagy egymástól függetlenül hidrogén, rövid szénláncú alkil-, hidroxi-(rövid szénláncú)-alkil-, alkoxi-(rövid szénláncú)-alkil-, hidroxi-alkoxi-(rövid szénláncú)-alkil-, amino-(rövid szénláncú)-alkil-, N-(rövid szénláncú)-alkil-amino(rövid szénláncú)-alkil-, N,N-di(rövid szénláncú)-alkil-amino-(rövid szénláncú)-alkil-, N-(hidroxi-rövid szénláncú-alkil)-amino-(rövid szénláncú)-alkil-,N,N-di(hidroxi-rövid szénláncú-alkil)-amino-(rövid szénláncú)-alkil-csoport vagy a nitrogénatommal együtt, amelyhez kapcsolódnak, aza-aliciklusos gyűrűt képez -, ahol a „rövid szénláncú” kifejezés maximálisan 4 szénatomos csoportot jelöl és sóik.
- 7. Az 5. igénypont szerinti (I) általános képletű vegyületek; e képletbenRi és R5 jelentése egyidejűleg vagy egymástól függetlenül hidrogén, halogén vagy rövid szénláncú alkilcsoport,R2 és R4 jelentése hidrogén,R3 jelentése R6R7=N-C(O)-(rövid szénláncú)-alkil-, karboxil- vagy R8R9N-C(O)-csoporttal helyettesített aril-, N-(rövid szénláncú)-alkil-amino-, N,Ndi(rövid szénláncú)-alkil-amino- vagy pirrolidinocsoporttal helyettesített aril-(rövid szénláncú)-alkil- vagy adott esetben helyettesített heteroaralkilcsoport,R6 és R7 jelentése egyidejűleg vagy egymástól függetlenül hidrogén, rövid szénláncú alkil-, hidroxi-(rövid szénláncú)-alkil-, alkoxi-(rövid szénláncú)-alkil-, hidroxi-alkoxi-(rövid szénláncú)-alkil-, amino-(rövid szénláncú)-alkil-, N-(rövid szénláncú)-alkil-amino(rövid szénláncú)-alkil-, N,N-di(rövid szénláncú)-alkil-amino-(rövld szénláncú)-alkil-, N-(hidroxi-rövid szénláncú-alkil)-amino-(rövid szénláncú)-alkil-, N,N-di(hidroxi-rövid szénláncú-alkil)-amino-(rövid szénláncú)-alkil-csoport vagy a nitrogénatommal együtt, amelyhez kapcsolódnak, aza-aliciklusos gyűrűt képez, ésR8 és R9 jelentése egyidejűleg vagy egymástól függetlenül hidrogén vagy rövid szénláncú alkilcsoport vagy a nitrogénatommal együtt, amelyhez kapcsolódik, aza-aliciklusos gyűrűt képez ahol a „rövid szénláncú” kifejezés maximálisan 4 szénatomos csoportot jelöl és gyógyászatilag elfogadható sóik.
- 8. Az 5. igénypont szerinti (I) általános képletű vegyületek közül a következők: {4-/3,5-bisz/2-hidroxi-fenil/-/[1,2,4]-triazol-1il/-fenil}-/4-metil-piperazin-1-il/-metanon, {4-/3,5-bisz/2-hidroxi-fenil/-/[1,2,4]-triazol-1il/-fenil}-/morfolin-4-il/-metanon, 2-/3,5-bisz/2-hidroxi-fenil/-/[1,2,4]-triazol-1ÍI/-1-/morfolin-4-il/-etanon,2-/3,5-bisz/2-hidroxi-fenil/-/[1,2,4]-triazol-1-il/-1(4-metil-piperazin-1-il)-etanon, 2-/3,5-bisz/2-hidroxi-fenil/-/[1,2,4]-triazol-1 -il/-N,Nbisz/2-hidroxi-etil/-acetamid,2-/3,5-bisz/2-hidroxi-fenil/-/[1,2,4]-triazol-1il/-N,N-/dimetil/-acetamid,2-/3,5-bisz/2-hidroxi-fenil/-/[1,2,4]-triazol-1 -il/-N-/2,3dihidroxi-propil/-acetamid,2-/3,5-bisz/2-hidroxi-fenil/-/[1,2,4]-triazol-1il/-N-/2-dimetil-amino-etil/-N-metil-acetamid, 2-/3,5-bisz/2-hidroxi-fenil/-/[1,2,4]-triazol-1il/-N-/2-hidroxi-1-hidroxi-metil-etil/-acetamid,HU 226 232 Β12-/3,5-bisz/2-hidroxi-fe ni l/-/[1,2,4]-triazol-1il/-N-/2-hidroxi-etil/-acetamid,2-/3,5-bisz/2-h i d roxi-f en i I/-/[ 1,2,4j-triazol-1il/-N-/2-hidroxi-etil/-N-metil-acetamid, 2-/3,5-bisz/2-hidroxi-fenil/-/[1,2,4]-triazol-1 il/-N-/2-metoxi-etil/-acetamid,2-/3,5-bisz/2-hid roxi-fe nil/-/[1,2,4]-triazol-1il/-N-/2-morfolin-4-il-etil/-acetamid,2-/3,5-bisz/2-hidroxi-fen i!/-/[ 1,2,4]-triazol-1 il/-N-/2-(2-hidroxi-etoxi)-etil/-acetamid,2-/3,5-bisz/2-hid roxi-fe nil/-/[1,2,4]-triazol-1il/-N-/2-[4-metil-piperazin-1-il]-etil/-acetamid, 2-/3,5-bisz/2-hidroxi-fenil/-/[1,2,4]-triazol-1-il/-N-metilacetamid,2-/3,5-bisz/5-klór-2-hidroxi-fenil/-/[1,2,4]-tri azol -1 il/-N-/2-morfolin-4-il-etil/-acetamid,3.5- bisz/2-hid roxi-f e nil/-1-/4-dietil-aminobenzil/-1 H-/1,2,4/-triazol,3.5- bisz/2-hidroxi-fenil/-1 -/4-pirrolidin-1 - ilbenzil/-1 H-/1,2,4/-triazol,3.5- bisz/2-hidroxi-fenil/-1-/piridin-4-ilmetil/-1 H-/1,2,4/-triazol,3.5- bisz/2-hidroxi-fenil/-1-/piridin-3-ilmetil/-1H-/1,2,4/-triazol,3.5- bisz/5-klór-2-hidroxi-fenil/-1-/4-dimetil-aminobenzil/-1 H-/1,2,4/-triazol,3.5- bisz/5-klór-2-h id roxi-fe ni I/-1 -/piridin-2-ilmetil/-1 H-/1,2,4/-triazol,4-/3,5-bisz/2-hidroxi-5-metil-fenil//-/1,2,4/-triazol-1-ilbenzoesav,4-/3,5-bisz/5-klór-2-hidroxi-fenil//-/1,2,4/-triazol-1-ilbenzoesav,4-/3,5-bisz/5-fluor-2-hidroxi-fenil//-/1,2,4/-triazol-1 il/-benzoesav,N-/2-bisz/2-hidroxi-etil-amino-etil/-2-/3,5-bisz/2-hidroxifenil/-/[1,2,4]-triazol-1 -il/-acetamid,N-benzil-2-/3,5-bisz/2-h id roxi-fe η ÍI/-/1,2,4/-triazol-1 il/-N-metil-acetamid és gyógyászatilag elfogadható sóik.
- 9. Az 5. igénypont szerinti (I) általános képletű vegyületek közül a 4-/3,5-bisz/2-hidroxi-fenil/-/[1,2,4]triazol-1-il/-benzoesav és gyógyászatilag elfogadható sói.
- 10. Gyógyszerkészítmény, amely az 5-7. igénypontok bármelyike szerinti vagy a 9. igénypont szerinti legalább egy vegyületet vagy annak gyógyászatilag elfogadható sóját tartalmazza, legalább egy gyógyászatilag elfogadható vivőanyaggal együtt.
- 11. Az 5-9. igénypontok bármelyike szerinti vegyület alkalmazása gyógyszerkészítmények előállítására.
- 12. Az 5-9. igénypontok bármelyike szerinti vegyület alkalmazása az emberi vagy állati szervezetben fellépő vasfelesleg kezelésére alkalmas gyógyszerkészítmények előállítására.
- 13. Eljárás az 5. igénypont szerinti (I) általános képletű vegyületek és sóik előállítására, azzal jellemezve, hogy (a) egy (II) általános képletű vegyületet, amelyben a helyettesítők jelentése az 5. igénypontban megadott és X-jelentése anion, egy (lll) általános képletű vegyülettel - amelyben R3 jelentése az 5. igénypontban megadott - vagy sójával reagáltatunk, vagy (b) egy (IV) általános képletű vegyületet, amelyben a helyettesítők jelentése az 5. igénypontban megadott, vagy sóját egy (lll) általános képletű vegyülettel amelyben R3 jelentése az 5. igénypontban megadott vagy sójával reagáltatunk, vagy (c) egy (V) általános képletű vegyületet, amelyben a helyettesítők jelentése az 5. igénypontban megadott, egy (lll) általános képletű vegyülettel - amelyben R3 jelentése az 5. igénypontban megadott - vagy sójával reagáltatunk, majd szükség esetén a védőcsoportok eltávolításával ezt a vegyületet az 5. igénypont szerinti (I) általános képletű vegyületté alakítjuk át, és kívánt esetben ezt egy másik, az 5. igénypont szerinti (I) általános képletű vegyületté alakítjuk át, és/vagy kívánt esetben egy kapott sót a szabad vegyületté vagy egy másik sóvá alakítunk át, és/vagy kívánt esetben egy kapott, az 5. igénypont szerinti (I) általános képletű, sóképző tulajdonságokkal rendelkező szabad vegyületből sót képzünk.
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CH159396 | 1996-06-25 | ||
PCT/EP1997/003315 WO1997049395A1 (en) | 1996-06-25 | 1997-06-24 | Substituted 3,5-diphenyl-1,2,4-triazoles and their use as pharmaceutical metal chelators |
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HUP9903111A2 HUP9903111A2 (hu) | 2000-01-28 |
HUP9903111A3 HUP9903111A3 (en) | 2000-06-28 |
HU226232B1 true HU226232B1 (en) | 2008-07-28 |
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US (3) | US6465504B1 (hu) |
EP (1) | EP0914118B1 (hu) |
JP (1) | JP3541042B2 (hu) |
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