WO2003010147A1 - Acidic quinolone derivatives - Google Patents
Acidic quinolone derivatives Download PDFInfo
- Publication number
- WO2003010147A1 WO2003010147A1 PCT/EP2002/006881 EP0206881W WO03010147A1 WO 2003010147 A1 WO2003010147 A1 WO 2003010147A1 EP 0206881 W EP0206881 W EP 0206881W WO 03010147 A1 WO03010147 A1 WO 03010147A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- alkoxy
- optionally substituted
- alkyl
- aryl
- halogen
- Prior art date
Links
- 230000002378 acidificating effect Effects 0.000 title description 4
- 150000007660 quinolones Chemical class 0.000 title description 2
- 150000001875 compounds Chemical class 0.000 claims abstract description 25
- 206010012601 diabetes mellitus Diseases 0.000 claims abstract description 8
- -1 amino, hydroxyl Chemical group 0.000 claims description 53
- 125000003545 alkoxy group Chemical group 0.000 claims description 51
- 125000000217 alkyl group Chemical group 0.000 claims description 45
- 125000003118 aryl group Chemical group 0.000 claims description 32
- 229910052736 halogen Inorganic materials 0.000 claims description 28
- 229910052739 hydrogen Inorganic materials 0.000 claims description 27
- 150000002367 halogens Chemical class 0.000 claims description 24
- 125000006552 (C3-C8) cycloalkyl group Chemical group 0.000 claims description 18
- 229910052717 sulfur Chemical class 0.000 claims description 17
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical class N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 14
- 125000003282 alkyl amino group Chemical group 0.000 claims description 12
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 12
- 125000002057 carboxymethyl group Chemical group [H]OC(=O)C([H])([H])[*] 0.000 claims description 12
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 12
- 125000000446 sulfanediyl group Chemical group *S* 0.000 claims description 12
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 12
- 150000002148 esters Chemical class 0.000 claims description 11
- 125000005842 heteroatom Chemical group 0.000 claims description 11
- 229910052760 oxygen Inorganic materials 0.000 claims description 11
- 125000004104 aryloxy group Chemical group 0.000 claims description 10
- 125000000592 heterocycloalkyl group Chemical group 0.000 claims description 10
- 229910052757 nitrogen Inorganic materials 0.000 claims description 9
- 239000002904 solvent Substances 0.000 claims description 9
- 125000005843 halogen group Chemical group 0.000 claims description 8
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 8
- 125000004432 carbon atom Chemical group C* 0.000 claims description 7
- 125000006715 (C1-C5) alkylthio group Chemical group 0.000 claims description 6
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 6
- 125000004414 alkyl thio group Chemical group 0.000 claims description 6
- 150000001408 amides Chemical class 0.000 claims description 6
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 6
- 238000009833 condensation Methods 0.000 claims description 6
- 230000005494 condensation Effects 0.000 claims description 6
- 238000010438 heat treatment Methods 0.000 claims description 6
- 125000004437 phosphorous atom Chemical group 0.000 claims description 6
- 229910052698 phosphorus Inorganic materials 0.000 claims description 6
- 239000011593 sulfur Substances 0.000 claims description 6
- 102000016912 Aldehyde Reductase Human genes 0.000 claims description 5
- 108010053754 Aldehyde reductase Proteins 0.000 claims description 5
- 125000005915 C6-C14 aryl group Chemical group 0.000 claims description 5
- 150000004982 aromatic amines Chemical class 0.000 claims description 5
- 125000000623 heterocyclic group Chemical group 0.000 claims description 5
- 239000000203 mixture Substances 0.000 claims description 5
- 239000008194 pharmaceutical composition Substances 0.000 claims description 5
- 150000003839 salts Chemical class 0.000 claims description 5
- 150000001345 alkine derivatives Chemical class 0.000 claims description 4
- 125000002947 alkylene group Chemical group 0.000 claims description 4
- 125000003277 amino group Chemical group 0.000 claims description 4
- LTMHNWPUDSTBKD-UHFFFAOYSA-N diethyl 2-(ethoxymethylidene)propanedioate Chemical compound CCOC=C(C(=O)OCC)C(=O)OCC LTMHNWPUDSTBKD-UHFFFAOYSA-N 0.000 claims description 4
- 125000001072 heteroaryl group Chemical group 0.000 claims description 4
- 125000005241 heteroarylamino group Chemical group 0.000 claims description 4
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 4
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 4
- 150000003254 radicals Chemical class 0.000 claims description 4
- 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 claims description 3
- 238000009835 boiling Methods 0.000 claims description 3
- 229910052799 carbon Chemical group 0.000 claims description 3
- 239000003795 chemical substances by application Substances 0.000 claims description 3
- HZVOZRGWRWCICA-UHFFFAOYSA-N methanediyl Chemical class [CH2] HZVOZRGWRWCICA-UHFFFAOYSA-N 0.000 claims description 3
- 125000005914 C6-C14 aryloxy group Chemical group 0.000 claims description 2
- MYMOFIZGZYHOMD-UHFFFAOYSA-N Dioxygen Chemical class O=O MYMOFIZGZYHOMD-UHFFFAOYSA-N 0.000 claims description 2
- 238000007126 N-alkylation reaction Methods 0.000 claims description 2
- 206010038923 Retinopathy Diseases 0.000 claims description 2
- 125000002877 alkyl aryl group Chemical group 0.000 claims description 2
- 150000001412 amines Chemical class 0.000 claims description 2
- 125000003710 aryl alkyl group Chemical group 0.000 claims description 2
- 239000001257 hydrogen Substances 0.000 claims description 2
- 208000017169 kidney disease Diseases 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 claims description 2
- 125000001570 methylene group Chemical group [H]C([H])([*:1])[*:2] 0.000 claims description 2
- 201000001119 neuropathy Diseases 0.000 claims description 2
- 230000007823 neuropathy Effects 0.000 claims description 2
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 claims description 2
- 239000001301 oxygen Chemical class 0.000 claims description 2
- 125000003386 piperidinyl group Chemical group 0.000 claims description 2
- 238000002360 preparation method Methods 0.000 claims description 2
- 238000007127 saponification reaction Methods 0.000 claims description 2
- 125000004434 sulfur atom Chemical class 0.000 claims description 2
- 208000019553 vascular disease Diseases 0.000 claims description 2
- 208000017442 Retinal disease Diseases 0.000 claims 1
- 230000002401 inhibitory effect Effects 0.000 claims 1
- 208000033808 peripheral neuropathy Diseases 0.000 claims 1
- 230000002265 prevention Effects 0.000 abstract description 2
- 239000007787 solid Substances 0.000 description 19
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 14
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 14
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 12
- 238000005160 1H NMR spectroscopy Methods 0.000 description 10
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 10
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 9
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 9
- 239000000243 solution Substances 0.000 description 9
- 239000000725 suspension Substances 0.000 description 8
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 7
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 6
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 6
- 239000008103 glucose Substances 0.000 description 6
- 238000000034 method Methods 0.000 description 6
- 238000010992 reflux Methods 0.000 description 6
- 229910000027 potassium carbonate Inorganic materials 0.000 description 5
- 239000000047 product Substances 0.000 description 5
- 239000011541 reaction mixture Substances 0.000 description 5
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 4
- USIUVYZYUHIAEV-UHFFFAOYSA-N diphenyl ether Chemical compound C=1C=CC=CC=1OC1=CC=CC=C1 USIUVYZYUHIAEV-UHFFFAOYSA-N 0.000 description 4
- VNGGYIBIGOOVNP-UHFFFAOYSA-N ethyl 6-methoxy-4-oxo-1h-quinoline-3-carboxylate Chemical compound C1=C(OC)C=C2C(=O)C(C(=O)OCC)=CNC2=C1 VNGGYIBIGOOVNP-UHFFFAOYSA-N 0.000 description 4
- 239000002244 precipitate Substances 0.000 description 4
- MHCVCKDNQYMGEX-UHFFFAOYSA-N 1,1'-biphenyl;phenoxybenzene Chemical compound C1=CC=CC=C1C1=CC=CC=C1.C=1C=CC=CC=1OC1=CC=CC=C1 MHCVCKDNQYMGEX-UHFFFAOYSA-N 0.000 description 3
- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 description 3
- FBPFZTCFMRRESA-JGWLITMVSA-N D-glucitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-JGWLITMVSA-N 0.000 description 3
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 description 3
- XJLXINKUBYWONI-DQQFMEOOSA-N [[(2r,3r,4r,5r)-5-(6-aminopurin-9-yl)-3-hydroxy-4-phosphonooxyoxolan-2-yl]methoxy-hydroxyphosphoryl] [(2s,3r,4s,5s)-5-(3-carbamoylpyridin-1-ium-1-yl)-3,4-dihydroxyoxolan-2-yl]methyl phosphate Chemical compound NC(=O)C1=CC=C[N+]([C@@H]2[C@H]([C@@H](O)[C@H](COP([O-])(=O)OP(O)(=O)OC[C@@H]3[C@H]([C@@H](OP(O)(O)=O)[C@@H](O3)N3C4=NC=NC(N)=C4N=C3)O)O2)O)=C1 XJLXINKUBYWONI-DQQFMEOOSA-N 0.000 description 3
- 239000003288 aldose reductase inhibitor Substances 0.000 description 3
- 229940090865 aldose reductase inhibitors used in diabetes Drugs 0.000 description 3
- 239000002775 capsule Substances 0.000 description 3
- 238000001816 cooling Methods 0.000 description 3
- 229910052500 inorganic mineral Inorganic materials 0.000 description 3
- 238000002844 melting Methods 0.000 description 3
- 230000008018 melting Effects 0.000 description 3
- 239000011707 mineral Substances 0.000 description 3
- NLKNQRATVPKPDG-UHFFFAOYSA-M potassium iodide Chemical compound [K+].[I-] NLKNQRATVPKPDG-UHFFFAOYSA-M 0.000 description 3
- 239000000600 sorbitol Substances 0.000 description 3
- 208000002249 Diabetes Complications Diseases 0.000 description 2
- 102000004190 Enzymes Human genes 0.000 description 2
- 108090000790 Enzymes Proteins 0.000 description 2
- 102000005548 Hexokinase Human genes 0.000 description 2
- 108700040460 Hexokinases Proteins 0.000 description 2
- MNQZXJOMYWMBOU-GSVOUGTGSA-N L-(-)-glyceraldehyde Chemical compound OC[C@H](O)C=O MNQZXJOMYWMBOU-GSVOUGTGSA-N 0.000 description 2
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 description 2
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- CIUQDSCDWFSTQR-UHFFFAOYSA-N [C]1=CC=CC=C1 Chemical compound [C]1=CC=CC=C1 CIUQDSCDWFSTQR-UHFFFAOYSA-N 0.000 description 2
- HXXFSFRBOHSIMQ-VFUOTHLCSA-N alpha-D-glucose 1-phosphate Chemical compound OC[C@H]1O[C@H](OP(O)(O)=O)[C@H](O)[C@@H](O)[C@@H]1O HXXFSFRBOHSIMQ-VFUOTHLCSA-N 0.000 description 2
- 150000005840 aryl radicals Chemical class 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- 229950010772 glucose-1-phosphate Drugs 0.000 description 2
- 230000007935 neutral effect Effects 0.000 description 2
- 229930027945 nicotinamide-adenine dinucleotide Natural products 0.000 description 2
- 239000000546 pharmaceutical excipient Substances 0.000 description 2
- 239000000843 powder Substances 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 2
- FBZWYFBNIGSUPS-UHFFFAOYSA-N (2-chlorophenyl) ethaneperoxoate Chemical compound CC(=O)OOC1=CC=CC=C1Cl FBZWYFBNIGSUPS-UHFFFAOYSA-N 0.000 description 1
- CCIIYDHSIAQXGR-UHFFFAOYSA-N 1-(carboxymethyl)-8-methoxy-4-oxoquinoline-3-carboxylic acid;5-(carboxymethyl)-8-oxo-[1,3]dioxolo[4,5-g]quinoline-7-carboxylic acid Chemical compound OC(=O)CN1C=C(C(O)=O)C(=O)C2=C1C(OC)=CC=C2.C1=C2N(CC(=O)O)C=C(C(O)=O)C(=O)C2=CC2=C1OCO2 CCIIYDHSIAQXGR-UHFFFAOYSA-N 0.000 description 1
- PFZOGZCKIUASPV-UHFFFAOYSA-N 1-[2-(3-chloroanilino)-2-oxoethyl]-7-methoxy-4-oxoquinoline-3-carboxylic acid Chemical compound C=1C(OC)=CC=C(C(C(C(O)=O)=C2)=O)C=1N2CC(=O)NC1=CC=CC(Cl)=C1 PFZOGZCKIUASPV-UHFFFAOYSA-N 0.000 description 1
- DZJPPNKDTDTWSY-UHFFFAOYSA-N 1-[2-(4-chloroanilino)-2-oxoethyl]-6-methoxy-4-oxoquinoline-3-carboxylic acid Chemical compound C1=C(C(O)=O)C(=O)C2=CC(OC)=CC=C2N1CC(=O)NC1=CC=C(Cl)C=C1 DZJPPNKDTDTWSY-UHFFFAOYSA-N 0.000 description 1
- FOHVQSHWVNMKAW-UHFFFAOYSA-N 1-[2-(4-chloroanilino)-2-oxoethyl]-7-methoxy-4-oxoquinoline-3-carboxylic acid Chemical compound C=1C(OC)=CC=C(C(C(C(O)=O)=C2)=O)C=1N2CC(=O)NC1=CC=C(Cl)C=C1 FOHVQSHWVNMKAW-UHFFFAOYSA-N 0.000 description 1
- HZNQSWJZTWOTKM-UHFFFAOYSA-N 2,3,4-trimethoxybenzoic acid Chemical compound COC1=CC=C(C(O)=O)C(OC)=C1OC HZNQSWJZTWOTKM-UHFFFAOYSA-N 0.000 description 1
- IKQCSJBQLWJEPU-UHFFFAOYSA-N 2,5-dihydroxybenzenesulfonic acid Chemical compound OC1=CC=C(O)C(S(O)(=O)=O)=C1 IKQCSJBQLWJEPU-UHFFFAOYSA-N 0.000 description 1
- KNVBYGNINQITJC-UHFFFAOYSA-N 2-chloro-n-(3-chlorophenyl)acetamide Chemical compound ClCC(=O)NC1=CC=CC(Cl)=C1 KNVBYGNINQITJC-UHFFFAOYSA-N 0.000 description 1
- CITIOELQTFSEGI-UHFFFAOYSA-N 2-chloro-n-(4-methylphenyl)acetamide Chemical compound CC1=CC=C(NC(=O)CCl)C=C1 CITIOELQTFSEGI-UHFFFAOYSA-N 0.000 description 1
- 125000004493 2-methylbut-1-yl group Chemical group CC(C*)CC 0.000 description 1
- 125000005916 2-methylpentyl group Chemical group 0.000 description 1
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 description 1
- 229940086681 4-aminobenzoate Drugs 0.000 description 1
- ALYNCZNDIQEVRV-UHFFFAOYSA-N 4-aminobenzoic acid Chemical compound NC1=CC=C(C(O)=O)C=C1 ALYNCZNDIQEVRV-UHFFFAOYSA-N 0.000 description 1
- SQDAZGGFXASXDW-UHFFFAOYSA-N 5-bromo-2-(trifluoromethoxy)pyridine Chemical compound FC(F)(F)OC1=CC=C(Br)C=N1 SQDAZGGFXASXDW-UHFFFAOYSA-N 0.000 description 1
- ODHCTXKNWHHXJC-VKHMYHEASA-M 5-oxo-L-prolinate Chemical compound [O-]C(=O)[C@@H]1CCC(=O)N1 ODHCTXKNWHHXJC-VKHMYHEASA-M 0.000 description 1
- FHVDTGUDJYJELY-UHFFFAOYSA-N 6-{[2-carboxy-4,5-dihydroxy-6-(phosphanyloxy)oxan-3-yl]oxy}-4,5-dihydroxy-3-phosphanyloxane-2-carboxylic acid Chemical compound O1C(C(O)=O)C(P)C(O)C(O)C1OC1C(C(O)=O)OC(OP)C(O)C1O FHVDTGUDJYJELY-UHFFFAOYSA-N 0.000 description 1
- OCUDOEALGWMNKQ-UHFFFAOYSA-N 7-methoxy-1-[2-(4-methylanilino)-2-oxoethyl]-4-oxoquinoline-3-carboxylic acid Chemical compound C=1C(OC)=CC=C(C(C(C(O)=O)=C2)=O)C=1N2CC(=O)NC1=CC=C(C)C=C1 OCUDOEALGWMNKQ-UHFFFAOYSA-N 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical group [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- 208000002177 Cataract Diseases 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- 229920001287 Chondroitin sulfate Polymers 0.000 description 1
- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 description 1
- AEMOLEFTQBMNLQ-AQKNRBDQSA-N D-glucopyranuronic acid Chemical compound OC1O[C@H](C(O)=O)[C@@H](O)[C@H](O)[C@H]1O AEMOLEFTQBMNLQ-AQKNRBDQSA-N 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
- 206010012655 Diabetic complications Diseases 0.000 description 1
- SNRUBQQJIBEYMU-UHFFFAOYSA-N Dodecane Natural products CCCCCCCCCCCC SNRUBQQJIBEYMU-UHFFFAOYSA-N 0.000 description 1
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 1
- BDAGIHXWWSANSR-UHFFFAOYSA-M Formate Chemical compound [O-]C=O BDAGIHXWWSANSR-UHFFFAOYSA-M 0.000 description 1
- 229930091371 Fructose Natural products 0.000 description 1
- RFSUNEUAIZKAJO-ARQDHWQXSA-N Fructose Chemical compound OC[C@H]1O[C@](O)(CO)[C@@H](O)[C@@H]1O RFSUNEUAIZKAJO-ARQDHWQXSA-N 0.000 description 1
- 239000005715 Fructose Substances 0.000 description 1
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 1
- AEMRFAOFKBGASW-UHFFFAOYSA-M Glycolate Chemical compound OCC([O-])=O AEMRFAOFKBGASW-UHFFFAOYSA-M 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- WRYCSMQKUKOKBP-UHFFFAOYSA-N Imidazolidine Chemical compound C1CNCN1 WRYCSMQKUKOKBP-UHFFFAOYSA-N 0.000 description 1
- 108010009384 L-Iditol 2-Dehydrogenase Proteins 0.000 description 1
- CKLJMWTZIZZHCS-REOHCLBHSA-N L-aspartic acid Chemical compound OC(=O)[C@@H](N)CC(O)=O CKLJMWTZIZZHCS-REOHCLBHSA-N 0.000 description 1
- WHUUTDBJXJRKMK-VKHMYHEASA-N L-glutamic acid Chemical compound OC(=O)[C@@H](N)CCC(O)=O WHUUTDBJXJRKMK-VKHMYHEASA-N 0.000 description 1
- JVTAAEKCZFNVCJ-UHFFFAOYSA-M Lactate Chemical compound CC(O)C([O-])=O JVTAAEKCZFNVCJ-UHFFFAOYSA-M 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
- 238000005684 Liebig rearrangement reaction Methods 0.000 description 1
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 1
- 229920000168 Microcrystalline cellulose Polymers 0.000 description 1
- 229920000881 Modified starch Polymers 0.000 description 1
- QIAFMBKCNZACKA-UHFFFAOYSA-N N-benzoylglycine Chemical compound OC(=O)CNC(=O)C1=CC=CC=C1 QIAFMBKCNZACKA-UHFFFAOYSA-N 0.000 description 1
- 238000005481 NMR spectroscopy Methods 0.000 description 1
- 229910002651 NO3 Inorganic materials 0.000 description 1
- NHNBFGGVMKEFGY-UHFFFAOYSA-N Nitrate Chemical compound [O-][N+]([O-])=O NHNBFGGVMKEFGY-UHFFFAOYSA-N 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- 239000002202 Polyethylene glycol Substances 0.000 description 1
- LCTONWCANYUPML-UHFFFAOYSA-M Pyruvate Chemical compound CC(=O)C([O-])=O LCTONWCANYUPML-UHFFFAOYSA-M 0.000 description 1
- 241000700159 Rattus Species 0.000 description 1
- 102100026974 Sorbitol dehydrogenase Human genes 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 1
- LSNNMFCWUKXFEE-UHFFFAOYSA-N Sulfurous acid Chemical compound OS(O)=O LSNNMFCWUKXFEE-UHFFFAOYSA-N 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-N acetic acid Substances CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- JIMXXGFJRDUSRO-UHFFFAOYSA-N adamantane-1-carboxylic acid Chemical compound C1C(C2)CC3CC2CC1(C(=O)O)C3 JIMXXGFJRDUSRO-UHFFFAOYSA-N 0.000 description 1
- 229940072056 alginate Drugs 0.000 description 1
- 235000010443 alginic acid Nutrition 0.000 description 1
- 229920000615 alginic acid Polymers 0.000 description 1
- 229910052783 alkali metal Inorganic materials 0.000 description 1
- 229910052784 alkaline earth metal Inorganic materials 0.000 description 1
- 230000029936 alkylation Effects 0.000 description 1
- 238000005804 alkylation reaction Methods 0.000 description 1
- HSFWRNGVRCDJHI-UHFFFAOYSA-N alpha-acetylene Natural products C#C HSFWRNGVRCDJHI-UHFFFAOYSA-N 0.000 description 1
- BFNBIHQBYMNNAN-UHFFFAOYSA-N ammonium sulfate Chemical compound N.N.OS(O)(=O)=O BFNBIHQBYMNNAN-UHFFFAOYSA-N 0.000 description 1
- 229910052921 ammonium sulfate Inorganic materials 0.000 description 1
- 235000011130 ammonium sulphate Nutrition 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 229940009098 aspartate Drugs 0.000 description 1
- 238000010533 azeotropic distillation Methods 0.000 description 1
- 239000002585 base Substances 0.000 description 1
- 229940077388 benzenesulfonate Drugs 0.000 description 1
- SRSXLGNVWSONIS-UHFFFAOYSA-M benzenesulfonate Chemical compound [O-]S(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-M 0.000 description 1
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 1
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 210000004369 blood Anatomy 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
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 230000015556 catabolic process Effects 0.000 description 1
- 239000001913 cellulose Substances 0.000 description 1
- 235000010980 cellulose Nutrition 0.000 description 1
- 229920002678 cellulose Polymers 0.000 description 1
- 238000005119 centrifugation Methods 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- 239000000460 chlorine Substances 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 229940099352 cholate Drugs 0.000 description 1
- BHQCQFFYRZLCQQ-OELDTZBJSA-N cholic acid Chemical compound C([C@H]1C[C@H]2O)[C@H](O)CC[C@]1(C)[C@@H]1[C@@H]2[C@@H]2CC[C@H]([C@@H](CCC(O)=O)C)[C@@]2(C)[C@@H](O)C1 BHQCQFFYRZLCQQ-OELDTZBJSA-N 0.000 description 1
- 229940059329 chondroitin sulfate Drugs 0.000 description 1
- 229940110456 cocoa butter Drugs 0.000 description 1
- 235000019868 cocoa butter Nutrition 0.000 description 1
- 125000000753 cycloalkyl group Chemical group 0.000 description 1
- NZNMSOFKMUBTKW-UHFFFAOYSA-M cyclohexanecarboxylate Chemical compound [O-]C(=O)C1CCCCC1 NZNMSOFKMUBTKW-UHFFFAOYSA-M 0.000 description 1
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 1
- GHVNFZFCNZKVNT-UHFFFAOYSA-N decanoic acid Chemical compound CCCCCCCCCC(O)=O GHVNFZFCNZKVNT-UHFFFAOYSA-N 0.000 description 1
- 125000002704 decyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 230000007850 degeneration Effects 0.000 description 1
- 238000006731 degradation reaction Methods 0.000 description 1
- JBQNXIFJGSBDQB-UHFFFAOYSA-N diethyl 2-[(4-methoxyanilino)methylidene]propanedioate Chemical compound CCOC(=O)C(C(=O)OCC)=CNC1=CC=C(OC)C=C1 JBQNXIFJGSBDQB-UHFFFAOYSA-N 0.000 description 1
- 229940075933 dithionate Drugs 0.000 description 1
- 125000003438 dodecyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 239000008298 dragée Substances 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 229950005627 embonate Drugs 0.000 description 1
- 230000002255 enzymatic effect Effects 0.000 description 1
- 125000005677 ethinylene group Chemical group [*:2]C#C[*:1] 0.000 description 1
- VVPWQEMJPDNOPC-UHFFFAOYSA-N ethyl 1-(2-ethoxy-2-oxoethyl)-6-methoxy-4h-quinoline-3-carboxylate Chemical compound COC1=CC=C2N(CC(=O)OCC)C=C(C(=O)OCC)CC2=C1 VVPWQEMJPDNOPC-UHFFFAOYSA-N 0.000 description 1
- RZBAOZWBEYECOZ-UHFFFAOYSA-N ethyl 1-[2-(tert-butylamino)-2-oxoethyl]-6-methoxy-4-oxoquinoline-3-carboxylate Chemical compound CC(C)(C)NC(CN1C=C(C(C2=CC(=CC=C12)OC)=O)C(=O)OCC)=O RZBAOZWBEYECOZ-UHFFFAOYSA-N 0.000 description 1
- XBNKFQBIFGZOBI-UHFFFAOYSA-N ethyl 1-[2-(tert-butylamino)-2-oxoethyl]-6-methoxy-4h-quinoline-3-carboxylate Chemical compound C1=C(OC)C=C2CC(C(=O)OCC)=CN(CC(=O)NC(C)(C)C)C2=C1 XBNKFQBIFGZOBI-UHFFFAOYSA-N 0.000 description 1
- BQDGHKVVQXLKPG-UHFFFAOYSA-N ethyl 6-methoxy-1-[2-(4-methylanilino)-2-oxoethyl]-4-oxoquinoline-3-carboxylate Chemical compound C12=CC=C(OC)C=C2C(=O)C(C(=O)OCC)=CN1CC(=O)NC1=CC=C(C)C=C1 BQDGHKVVQXLKPG-UHFFFAOYSA-N 0.000 description 1
- PQJJJMRNHATNKG-UHFFFAOYSA-N ethyl bromoacetate Chemical compound CCOC(=O)CBr PQJJJMRNHATNKG-UHFFFAOYSA-N 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- 125000002541 furyl group Chemical group 0.000 description 1
- 150000002303 glucose derivatives Chemical class 0.000 description 1
- 229940097042 glucuronate Drugs 0.000 description 1
- 229930195712 glutamate Natural products 0.000 description 1
- 230000034659 glycolysis Effects 0.000 description 1
- IPCSVZSSVZVIGE-UHFFFAOYSA-N hexadecanoic acid Chemical compound CCCCCCCCCCCCCCCC(O)=O IPCSVZSSVZVIGE-UHFFFAOYSA-N 0.000 description 1
- FUZZWVXGSFPDMH-UHFFFAOYSA-N hexanoic acid Chemical compound CCCCCC(O)=O FUZZWVXGSFPDMH-UHFFFAOYSA-N 0.000 description 1
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000002883 imidazolyl group Chemical group 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 125000001041 indolyl group Chemical group 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 125000000904 isoindolyl group Chemical group C=1(NC=C2C=CC=CC12)* 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 239000000644 isotonic solution Substances 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- AGBQKNBQESQNJD-UHFFFAOYSA-N lipoic acid Chemical compound OC(=O)CCCCC1CCSS1 AGBQKNBQESQNJD-UHFFFAOYSA-N 0.000 description 1
- GVALZJMUIHGIMD-UHFFFAOYSA-H magnesium phosphate Chemical compound [Mg+2].[Mg+2].[Mg+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O GVALZJMUIHGIMD-UHFFFAOYSA-H 0.000 description 1
- 239000004137 magnesium phosphate Substances 0.000 description 1
- 229960002261 magnesium phosphate Drugs 0.000 description 1
- 229910000157 magnesium phosphate Inorganic materials 0.000 description 1
- 235000010994 magnesium phosphates 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
- 230000002503 metabolic effect Effects 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 235000019813 microcrystalline cellulose Nutrition 0.000 description 1
- 239000008108 microcrystalline cellulose Substances 0.000 description 1
- 229940016286 microcrystalline cellulose Drugs 0.000 description 1
- 235000019426 modified starch Nutrition 0.000 description 1
- NQVPSGXLCXZSTB-UHFFFAOYSA-N n-tert-butyl-2-chloroacetamide Chemical compound CC(C)(C)NC(=O)CCl NQVPSGXLCXZSTB-UHFFFAOYSA-N 0.000 description 1
- MHWLWQUZZRMNGJ-UHFFFAOYSA-N nalidixic acid Chemical compound C1=C(C)N=C2N(CC)C=C(C(O)=O)C(=O)C2=C1 MHWLWQUZZRMNGJ-UHFFFAOYSA-N 0.000 description 1
- 229960000210 nalidixic acid Drugs 0.000 description 1
- PSZYNBSKGUBXEH-UHFFFAOYSA-M naphthalene-1-sulfonate Chemical compound C1=CC=C2C(S(=O)(=O)[O-])=CC=CC2=C1 PSZYNBSKGUBXEH-UHFFFAOYSA-M 0.000 description 1
- 239000012299 nitrogen atmosphere Substances 0.000 description 1
- 125000001400 nonyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 1
- QIQXTHQIDYTFRH-UHFFFAOYSA-M octadecanoate Chemical compound CCCCCCCCCCCCCCCCCC([O-])=O QIQXTHQIDYTFRH-UHFFFAOYSA-M 0.000 description 1
- WWZKQHOCKIZLMA-UHFFFAOYSA-M octanoate Chemical compound CCCCCCCC([O-])=O WWZKQHOCKIZLMA-UHFFFAOYSA-M 0.000 description 1
- 125000002347 octyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 230000003204 osmotic effect Effects 0.000 description 1
- BHAAPTBBJKJZER-UHFFFAOYSA-N p-anisidine Chemical compound COC1=CC=C(N)C=C1 BHAAPTBBJKJZER-UHFFFAOYSA-N 0.000 description 1
- 125000000913 palmityl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 239000008188 pellet Substances 0.000 description 1
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 1
- 229940021222 peritoneal dialysis isotonic solution Drugs 0.000 description 1
- 239000003208 petroleum Substances 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- 239000008363 phosphate buffer Substances 0.000 description 1
- 239000002504 physiological saline solution Substances 0.000 description 1
- 239000006187 pill Substances 0.000 description 1
- 125000004193 piperazinyl group Chemical group 0.000 description 1
- 239000002798 polar solvent Substances 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 229920005862 polyol Polymers 0.000 description 1
- 150000003077 polyols Chemical class 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- USPWKWBDZOARPV-UHFFFAOYSA-N pyrazolidine Chemical compound C1CNNC1 USPWKWBDZOARPV-UHFFFAOYSA-N 0.000 description 1
- 125000004076 pyridyl group Chemical group 0.000 description 1
- 125000000714 pyrimidinyl group Chemical group 0.000 description 1
- 229940071139 pyrrolidone carboxylate Drugs 0.000 description 1
- LISFMEBWQUVKPJ-UHFFFAOYSA-N quinolin-2-ol Chemical class C1=CC=C2NC(=O)C=CC2=C1 LISFMEBWQUVKPJ-UHFFFAOYSA-N 0.000 description 1
- 125000002943 quinolinyl group Chemical group N1=C(C=CC2=CC=CC=C12)* 0.000 description 1
- 125000005493 quinolyl group Chemical group 0.000 description 1
- 239000012429 reaction media Substances 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 239000000377 silicon dioxide Substances 0.000 description 1
- RYYKJJJTJZKILX-UHFFFAOYSA-M sodium octadecanoate Chemical class [Na+].CCCCCCCCCCCCCCCCCC([O-])=O RYYKJJJTJZKILX-UHFFFAOYSA-M 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 description 1
- 239000007940 sugar coated tablet Substances 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 229940095064 tartrate Drugs 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
- 230000001225 therapeutic effect Effects 0.000 description 1
- 229940068511 thioctate Drugs 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-M toluene-4-sulfonate Chemical compound CC1=CC=C(S([O-])(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-M 0.000 description 1
- 229920002554 vinyl polymer Polymers 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
-
- 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
- A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
- A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
- A61P7/12—Antidiuretics, e.g. drugs for diabetes insipidus
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
- C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
- C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D215/48—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
- C07D215/54—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen attached in position 3
- C07D215/56—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen attached in position 3 with oxygen atoms in position 4
Definitions
- the present invention relates to acidic quinolone derivatives that are useful in the treatment or prevention of diabetic complications.
- Diabetes is characterised by a high concentration of glucose in the blood.
- This glucose is normally metabolised by the enzyme hexokinase during the first step of glycolysis, resulting in degradation to pyruvate.
- the polyol route which successively involves two enzymes: aldose reductase, which converts the glucose to sorbitol, and sorbitol dehydrogenase, which converts the sorbitol to fructose.
- aldose reductase which converts the glucose to sorbitol
- sorbitol dehydrogenase which converts the sorbitol to fructose.
- the excess glucose accelerates the formation of sorbitol, which tends to accumulate. This results in serious metabolic disturbances such as, for example, an increase in osmotic pressure, which is liable to result in tissue degeneration.
- Aldose reductase inhibitors are thus useful for treating or preventing some of the complications induced by diabetes.
- the compounds of the invention are of the general formula (I) below:
- X represents, independently of each other, an optionally substituted methylene radical or a nitrogen, oxygen or sulfur atom
- R1 represents a group chosen from: radical of the formula OR2, Amine optionally substituted by one or more of the following groups: (C1-C5) alkyl, (C 3 -C 8 ) cycloalkyl, (C- ⁇ -C 5 ) alkoxy, aryl, alkylaryl or aralkyl, these groups possibly being interrupted with one or more hetero atoms and/or possibly being substituted, especially with one or more halogen atoms, the nitrogen of the amine group also possibly forming part of a heterocycloalkyl, R2, which may be identical or different, represents a group chosen from: hydrogen,
- C-i-C 2 o alkyl optionally substituted by one or more of the following groups: halogen, (C1-C5) alkyl, (C 3 -C 8 ) cycloalkyl, (C1-C 5 ) alkoxy, substituted or unsubstituted amino, optionally substituted carbonyl, ester, amide, a sulfur or phosphorus atom,
- heterocycloalkyl bearing one or more hetero atoms chosen from N, O and S and optionally substituted by (C 1 -C 5 ) alkyl or (C1-C 5 ) alkoxy, - (C 6 -Ci 4 )aryl(C ⁇ -C 2 o)alkyl optionally substituted by amino, hydroxyl, thio, halogen, (C 1 -C5) alkyl, (C 1 -C5) alkoxy, (C1-C5) alkylthio, (C Cs) alkylamino, (C 6 -C ⁇ ) aryl, (C 6 -C ⁇ 4 ) aryloxy, (C 6 -Ci4)aryl(C ⁇ -C 5 )alkoxy, cyano, trifluoro- methyl, carboxyl, carboxymethyl or carboxyethyl,
- C ⁇ -C ) aryl optionally substituted by amino, hydroxyl, thio, halogen, (C C 5 ) alkyl, (C1-C5) alkoxy, (C C 5 ) alkylthio, (C1-C 5 ) alkylamino, (C 6 -C ⁇ 4 ) aryl, (C ⁇ -Cu) aryloxy, (C 6 -C ⁇ 4 )aryl(C ⁇ -C 5 )alkoxy, cyano, trifluoromethyl, carboxyl, carboxymethyl or carboxyethyl,
- heteroaryl bearing one or more hetero atoms chosen from N, O and S and optionally substituted by amino, hydroxyl, thio, halogen, (C1-C5) alkyl, (C1-C 5 ) alkoxy, (C1-C5) alkylthio, (C1-C5) alkylamino, (C 6 -C ⁇ 4 ) aryl,
- A represents a single bond or a (C C ⁇ ) alkyl group optionally substituted by one or more of the following groups: halogen, (C 3 -C 8 ) cycloalkyl, (C1-C5) alkoxy, substituted or unsubstituted amino, optionally substituted carbonyl, ester, amide, a sulfur or phosphorus atom,
- R1 , R2 and A are as defined above, and R3 and R4, which may be identical or different, represent groups chosen from: a hydrogen atom,
- C1-C2 0 alkyl optionally substituted by one or more of the following groups: halogen, (C1-C5) alkyl, (C 3 -C 8 ) cycloalkyl, (C 1 -C 5 ) alkoxy, substituted or unsubstituted amino, optionally substituted carbonyl, ester, amide, a sulfur or phosphorus atom,
- C 1 -C 20 alkoxy optionally substituted by one or more of the following groups: halogen, (C1-C5) alkyl, (C 3 -C 8 ) cycloalkyl, (CrC 5 ) alkoxy, substituted or unsubstituted amino,
- aryl optionally substituted by amino, hydroxyl, thio, halogen, (C1-C5) alkyl, (C1-C5) alkoxy, (C ⁇ -C 5 ) alkylthio, (C r C 5 ) alkylamino, (C 6 -C 14 ) aryl, (C6-C1 4 ) aryloxy, (C 6 -C 1 )aryl(C ⁇ -C 5 )alkoxy, cyano, trifluoromethyl, carboxyl, carboxymethyl or carboxyethyl,
- heteroaryl bearing one or more hetero atoms chosen from N, O and S and optionally substituted by amino, hydroxyl, thio, halogen, (C1-C 5 ) alkyl, (C1-C5) alkoxy, (C- ⁇ -C 5 ) alkylthio, (C C 5 ) alkylamino, (C 6 -C ⁇ 4 ) aryl, aryloxy (C ⁇ -C-u), (C 6 -Ci 4 )aryl(C ⁇ -C 5 )alkoxy, cyano, trifluoromethyl, carboxyl, carboxymethyl or carboxyethyl,
- R3 and R4 may also together form a heterocycle adjacent to the phenyl ring.
- the alkyl radicals contain from 1 to 20 carbon atoms and preferably from 1 to 5 carbon atoms. When they are linear, mention may be made especially of the methyl, ethyl, propyl, butyl, pentyl, hexyl, octyl, nonyl, decyl, dodecyl, hexadecyl and octadecyl radicals.
- alkyl radicals When they are branched or substituted by one or more alkyl radicals, mention may be made especially of the isopropyl, tert-butyl, 2-ethylhexyl, 2- methylbutyl, 2-methylpentyl, 1 -methylpentyl and 3-methylheptyl radicals.
- alkoxy radicals according to the present invention are radicals of the formula -O-alkyl, the alkyl being as defined above.
- halogen atoms mention is made more particularly of the fluorine, chlorine, bromine and iodine atoms.
- the alkylene radicals contain one or more ethylenic unsaturations.
- alkylene radicals that may be mentioned especially are the allyl and vinyl radicals.
- the alkyne radicals contain one or more acetylenic unsaturations.
- alkyne radicals that may especially be mentioned is acetylene.
- the (C 3 -C 8 ) cycloalkyl radical is a cyclic hydrocarbon-based radical such as, especially, cyclopropyl, cyclopentyl or cyclohexyl.
- the aryl radical corresponds more particularly to an aromatic ring of 6 carbon atoms, such as the phenyl radical, optionally fused with one or two other aromatic rings containing 6 carbon atoms, such as the naphthyl radical.
- aryl radicals that may thus especially be mentioned is the phenyl radical, more particularly substituted by at least one halogen atom.
- (C 6 -Ci 4 )aryl(C ⁇ -C 2 o)alkyl radicals that may be mentioned especially are the benzyl and phenethyl radicals.
- the heteroaryl radical corresponds more particularly to a 5- or 6-atom aromatic heterocycle containing one or two hetero atoms chosen from N, S and O, optionally fused with one or two aromatic rings containing six carbon atoms or 5- or 6-atom heteroaromatic rings.
- heteroaryl radicals that may be mentioned are the furyl, pyridyl, quinolinyl, indolyl, isoindolyl, quinolyl, imidazolyl, pyrimidinyl and carbazolyl radicals.
- heterocycles that may especially be mentioned are the piperi- dine, morpholine, pyrrolidine, imidazolidine, pyrazolidine and piperazine rings.
- R3 and R4 together form a heterocycle adjacent to the phenyl ring, they can especially represent the ring -O-(CH2)n-O-, n being an integer ranging from 1 to 4.
- the said heterocycloalkyl is more particularly a piperidine ring.
- A is an optionally substituted methylene group. More particularly, A represents an unsubstituted methylene radical.
- R4 is a hydrogen atom and R3 represents an alkoxy radical.
- the invention also relates to the tautomeric forms, to the enantiomers, diastereoisomers and epimers and to the organic or mineral salts of the compounds of the general formula (I).
- the compounds of the invention of the formula (I) as defined above containing a sufficiently acidic function or a sufficiently basic function, or both, may include the pharmaceutically acceptable corresponding salts of an organic or mineral acid or of an organic or mineral base.
- salts such as the hydrochloride, acetate, benzoate, citrate, fumarate, embonate, chlorophenoxyacetate, glycolate, palm- oate, aspartate, methanesulfonate, maleate, para-chlorophenoxyisobutyrate, formate, lactate, succinate, sulfate, tartrate, cyclohexanecarboxylate, hexanoate, octanoate, decanoate, hexadecanoate, octadecanoate, benzenesulfonate, trimethoxybenzoate, para-toluenesulfonate, adamantanecarboxylate, glycoxylate, glutamate, pyrrolidonecarboxylate, naphthalenesulfonate, glucose-1 -phosphate, nitrate, sulfite, dithionate, phosphate, dobesil
- the compounds of the formula (I) may especially be chosen from:
- the compounds of the general formula (I) may be prepared according to the method of Gould-Jacobs (J. Amer. Chem. Soc, 61 , 2890, 1939) proposed in 1962 for the synthesis of nalidixic acid (Scheme 1).
- the present invention thus also relates to a process for preparing compounds of the formula (I), comprising the following steps: a) condensation of an arylamine or of a heteroarylamine, which is optionally substituted, with diethyl ethoxymethylenemalonate, the arylamine or heteroarylamine being of the formula (1) below:
- X represents a nitrogen or carbon atom and R represents R3 or R4 as defined above
- Scheme 1 is as follows:
- Step a) is the condensation of an optionally substituted arylamine or hetarylamine (1) with diethyl ethoxymethylenemalonate according to Claisen (Liebigs Anna!. Chem, 297, 1 , 1897).
- Step b) is the thermal cyclisation of the malonic derivative (2) obtained. It is carried out by heating in a solvent with a high boiling point, preferably at 250°C in diphenyl ether or Dowtherm.
- the tautomeric form (4) of the cyclised product (3) is then conventionally N-alkylated: step (c).
- This condensation which is well known in under the name Hoffman alkylation, may be carried out in the usual solvents, preferably anhydrous dimethylformamide or toluene, in the presence of an alkaline agent such as potassium carbonate.
- the ester (5) obtained is con- ventionally saponified to (6).
- the compounds of the present invention have activity as aldose reductase inhibitors.
- Aldose reductase is partially purified from the lenses of male rats (Wistar, 200-
- the extract is prepared by centrifugation and precipitation with ammonium sulfate according to W.H.J. WARD et al. (1990, Biochem. Pharmacol. 39, 2, 337-346).
- the enzyme is preincubated at 37°C with or without the test products and
- NADPH (0.125 mM) in a phosphate buffer for 10 minutes.
- the reaction is started by addition of L-glyceraldehyde (5 mM) used as substrate.
- the enzymatic activity is measured using a spectrophotometer at 340 nm. The values measured are indicated in the table below:
- the compounds of the formula (I) may thus be used as medicaments as aldose reductase inhibitors, and especially in the treatment of diabetes complications, these complications possibly being cataracts, retinopathies, neuropathies, nephropathies or certain vascular diseases.
- the present invention thus also relates to pharmaceutical compositions comprising, as active principle, a compound according to the invention.
- compositions according to the invention may be presented in forms intended for parenteral, oral, rectal, permucous or percutaneous administration.
- excipients that are suitable for such administrations are cellulose derivatives, microcrystalline cellulose derivatives, alkaline-earth metal carbonates, magnesium phosphate, starches, modified starches and lactose for the solid forms.
- the preferred excipients for rectal use are cocoa butter or polyethylene glycol stearates.
- the vehicles that are most suitable for parenteral use are water, aqueous solutions, physiological saline and isotonic solutions.
- the dosage may vary within a wide range (0.5 mg to 1000 mg) depending on the therapeutic indication and the route of administration, and also the age and weight of the individual.
- the present invention thus also relates to the use of compounds of the general formula (I) for the preparation of pharmaceutical compositions intended for treating or preventing a complication induced by diabetes.
- the examples that follow illustrate the invention without, however, limiting it.
- the starting materials used are known products or products prepared according to known procedures.
- Example 1 3-carboxy-6-methoxy-4-oxo-1.4-dihvdro ⁇ uinoline-1 -acetic acid
- the white precipitate formed is filtered off, washed with demineralised water until the filtrate is neutral, and then dried under vacuum. 7.5 g of white solid are obtained.
- the solid is filtered off by suction, washed with 10 ml of N,N-dimethylformamide, slurried in demineralised water until the filtrate is neutral, and dried under reduced pressure.
- a suspension containing 5 g (0.02 M) of ethyl 6-methoxy-4-oxo-1 ,4-dihydro- quinoline-3-carboxylate, 4.2 g (0.03 M) of potassium carbonate and 5.1 g (0.025 M) of N-(3-chlorophenyl)chloroacetamide in 50 ml of N,N-dimethylform- amide is heated at 50°C for 5 hours.
- the reaction mixture is cooled to room temperature and then poured into 450 ml of cold demineralised water.
- the precipitate obtained is filtered off by suction and washed thoroughly with demineralised water.
- the solid that sublimes on drying is used wet in the following step. 15.4 g of wet solid are obtained.
- NMR NMR : The NMR spectra were acquired using a Br ⁇ ker Advanced DPX 200 MHz spectrometer. Melting points: The melting points (m.p.) were measured on a block of K ⁇ fler Leica VMHB type.
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Diabetes (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- Hematology (AREA)
- Emergency Medicine (AREA)
- Endocrinology (AREA)
- Obesity (AREA)
- Cardiology (AREA)
- Heart & Thoracic Surgery (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
Description
Claims
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
FR01/09771 | 2001-07-20 | ||
FR0109771A FR2827600A1 (en) | 2001-07-20 | 2001-07-20 | New quinolone acid derivatives with aldose reductase inhibiting activity, useful for prevention and treatment of diabetes-related disorders |
Publications (1)
Publication Number | Publication Date |
---|---|
WO2003010147A1 true WO2003010147A1 (en) | 2003-02-06 |
Family
ID=8865780
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/EP2002/006881 WO2003010147A1 (en) | 2001-07-20 | 2002-06-21 | Acidic quinolone derivatives |
Country Status (2)
Country | Link |
---|---|
FR (1) | FR2827600A1 (en) |
WO (1) | WO2003010147A1 (en) |
Cited By (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2005073230A1 (en) * | 2004-01-31 | 2005-08-11 | Sanofi-Aventis Deutschland Gmbh | Heterocyclically substituted 7-amino-4-quinolone-3-carboxylic acid derivatives, method for the production thereof and their use as medicaments |
US7498341B2 (en) | 2004-01-31 | 2009-03-03 | Sanofi Aventis Deutschland Gmbh | Heterocyclically substituted 7-amino-4-quinolone-3-carboxylic acid derivatives, process for their preparation and their use as medicaments |
US7635704B2 (en) | 2004-05-20 | 2009-12-22 | Japan Tobacco Inc. | Stable crystal of 4-oxoquinoline compound |
Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US3287458A (en) * | 1963-12-12 | 1966-11-22 | Warner Lambert Pharmaceutical | 1, 4-dihydro-1-lower alkyl-6, 7-methylene-dioxy-4-oxo-3-quinoline-carboxylic acid |
EP0614664A1 (en) * | 1993-03-09 | 1994-09-14 | Takeda Chemical Industries, Ltd. | Quinolonecarboxylic acid derivatives, their preparation and their use as cell adhesion inhibitors |
US5594005A (en) * | 1992-04-06 | 1997-01-14 | Pharmacia Ab | Use of quinoline-3-carboxamide compounds for treatment of diabetes |
-
2001
- 2001-07-20 FR FR0109771A patent/FR2827600A1/en not_active Withdrawn
-
2002
- 2002-06-21 WO PCT/EP2002/006881 patent/WO2003010147A1/en not_active Application Discontinuation
Patent Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US3287458A (en) * | 1963-12-12 | 1966-11-22 | Warner Lambert Pharmaceutical | 1, 4-dihydro-1-lower alkyl-6, 7-methylene-dioxy-4-oxo-3-quinoline-carboxylic acid |
US5594005A (en) * | 1992-04-06 | 1997-01-14 | Pharmacia Ab | Use of quinoline-3-carboxamide compounds for treatment of diabetes |
EP0614664A1 (en) * | 1993-03-09 | 1994-09-14 | Takeda Chemical Industries, Ltd. | Quinolonecarboxylic acid derivatives, their preparation and their use as cell adhesion inhibitors |
Non-Patent Citations (1)
Title |
---|
TETSUO OKADA ET AL: "Synthesis and antibacterial activities of novel oxazine and thiazine ring-fused tricyclic quinolonecarboxylic acids", JOURNAL OF HETEROCYCLIC CHEMISTRY., vol. 28, no. 4, 1991, HETEROCORPORATION. PROVO., US, pages 1067 - 1074, XP002194320, ISSN: 0022-152X * |
Cited By (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2005073230A1 (en) * | 2004-01-31 | 2005-08-11 | Sanofi-Aventis Deutschland Gmbh | Heterocyclically substituted 7-amino-4-quinolone-3-carboxylic acid derivatives, method for the production thereof and their use as medicaments |
US7498341B2 (en) | 2004-01-31 | 2009-03-03 | Sanofi Aventis Deutschland Gmbh | Heterocyclically substituted 7-amino-4-quinolone-3-carboxylic acid derivatives, process for their preparation and their use as medicaments |
US7635704B2 (en) | 2004-05-20 | 2009-12-22 | Japan Tobacco Inc. | Stable crystal of 4-oxoquinoline compound |
US8981103B2 (en) | 2004-05-20 | 2015-03-17 | Japan Tobacco Inc. | Stable crystal of 4-oxoquinoline compound |
Also Published As
Publication number | Publication date |
---|---|
FR2827600A1 (en) | 2003-01-24 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
CA1333802C (en) | Substituted 4-(quinolin-2-yl-methoxy)phenyl-acetic acid derivatives | |
IL105806A (en) | Aminoquinoline derivatives and pharmaceutical compositions containing the same | |
JP4188839B2 (en) | Pyrimidotriazines as phosphatase inhibitors | |
JPH0219112B2 (en) | ||
KR20180043329A (en) | [4- (1,3,3-trimethyl-2-oxo-3,4-dihydro-1H-quinoxalin-7-yl) phenoxy] ethyloxy compound or its salt | |
WO2004101570A1 (en) | Sulfur-containing naphthoylimide derivatives | |
JPH0774204B2 (en) | Compound | |
WO2003024937A1 (en) | Benzimidazolylalkoxyaryl alkanoic acid derivatives and their use as antihyperglycemics | |
EP0546102B1 (en) | Tropolone derivatives and pharmaceutical composition thereof for preventing and treating ischemic diseases | |
HU208960B (en) | Process for producing disubstituted (quinolin-2-yl-methoxy)-phenylacetic acid derivatives | |
JPH04234389A (en) | Naphthyridine derivative and antiulcer agent containing the derivative as active component | |
JPH0764819B2 (en) | Phenylquinoline derivative, its production method and pharmaceutical composition | |
EP0093521B1 (en) | Quinoline derivatives | |
AU617489B2 (en) | Pyridazinone derivatives | |
SE433215B (en) | PROCEDURE FOR PREPARING 2-PIPERAZINYL-PYRIDO- / 2,3-D / PYRIMIDINE DERIVATIVES | |
JP2993316B2 (en) | Aryl or heteroaromatic group-substituted aminoquinolone derivatives and therapeutic agents for AIDS | |
WO2003010147A1 (en) | Acidic quinolone derivatives | |
US5266578A (en) | Heterocyclically substituted quinolylmethoxy-phenylacetamides | |
HU194227B (en) | Process for preparing 4-alkoxy-pyrido (2,3-d) pyrimidinederivatives and pharmaceuticals containing the same | |
EP0773214A1 (en) | Trifluoromethylquinolinecarboxylic acid derivative | |
EP0405442A1 (en) | 4,5-Dihydro-6H-imidazo[4,5,1-ij]quinolin-6-one-6-oxime-O-sulfonic acid derivatives | |
JP2930539B2 (en) | Trifluoromethylquinoline carboxylic acid derivative | |
US4677108A (en) | 4-oxo-pyrido[2,3-d]pyrimidinone derivatives | |
MXPA05002734A (en) | Acyl derivatives of 5- (2-(4 -(1, 2 benzisothiazole -3- yl)-1- piperazinyl) ethyl)- 6-chloro -1, 3-dihydro -2h -indol-2 -one having neuroleptic activity. | |
HUT72075A (en) | Improved process for the preparation of substituted indolone derivatives |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
AK | Designated states |
Kind code of ref document: A1 Designated state(s): AE AG AL AM AT AU AZ BA BB BG BR BY BZ CA CH CN CO CR CU CZ DE DK DM DZ EC EE ES FI GB GD GE GH GM HR HU ID IL IN IS JP KE KG KP KR KZ LC LK LR LS LT LU LV MA MD MG MK MN MW MX MZ NO NZ OM PH PL PT RO RU SD SE SG SI SK SL TJ TM TN TR TT TZ UA UG US UZ VN YU ZA ZM ZW Kind code of ref document: A1 Designated state(s): AE AG AL AM AT AU AZ BA BB BG BY BZ CA CH CN CO CR CU CZ DE DM DZ EC EE ES FI GB GD GE GH HR HU ID IL IN IS JP KE KG KP KR LC LK LR LS LT LU LV MA MD MG MN MW MX MZ NO NZ OM PH PL PT RU SD SE SG SI SK SL TJ TM TN TR TZ UA UG US UZ VN YU ZA ZM |
|
AL | Designated countries for regional patents |
Kind code of ref document: A1 Designated state(s): GH GM KE LS MW MZ SD SL SZ UG ZM ZW AM AZ BY KG KZ RU TJ TM AT BE CH CY DE DK FI FR GB GR IE IT LU MC NL PT SE TR BF BJ CF CG CI CM GA GN GQ ML MR NE SN TD TG Kind code of ref document: A1 Designated state(s): GH GM KE LS MW MZ SD SL SZ TZ UG ZM ZW AM AZ BY KG KZ MD RU TJ TM AT BE CH CY DE DK ES FI FR GB GR IE IT LU MC NL PT SE TR BF BJ CF CG CI CM GA GN GQ GW ML MR NE SN TD TG |
|
121 | Ep: the epo has been informed by wipo that ep was designated in this application | ||
DFPE | Request for preliminary examination filed prior to expiration of 19th month from priority date (pct application filed before 20040101) | ||
REG | Reference to national code |
Ref country code: DE Ref legal event code: 8642 |
|
122 | Ep: pct application non-entry in european phase | ||
NENP | Non-entry into the national phase |
Ref country code: JP |
|
WWW | Wipo information: withdrawn in national office |
Country of ref document: JP |