CA2324636A1 - 1, 2, 3, 4, - tetrahydro - 1, 3 - dioxo - 4 - acide isoquinolinecarboxylic methyl esters - Google Patents

1, 2, 3, 4, - tetrahydro - 1, 3 - dioxo - 4 - acide isoquinolinecarboxylic methyl esters Download PDF

Info

Publication number: CA2324636A1
Authority: CA; Canada
Prior art keywords: carbon atoms; aryl; formula; lower alkyl; compound
Prior art date: 1990-05-21
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.): Abandoned

Application number

CA002324636A

Other languages

English (en)

Inventor

Michael S. Malamas

Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)

Wyeth LLC

Original Assignee

Individual

Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)

1990-05-21

Filing date

1991-05-08

Publication date

1991-11-22

1990-05-21 Priority claimed from US07/526,362 external-priority patent/US5045544A/en

1991-05-08 Application filed by Individual filed Critical Individual

1991-11-22 Publication of CA2324636A1 publication Critical patent/CA2324636A1/fr

Status Abandoned legal-status Critical Current

Links

CZVOWGZIAVDFJV-UHFFFAOYSA-N COC(=O)C1C(=O)NC(=O)C2=C1C=CC=C2 Chemical class COC(=O)C1C(=O)NC(=O)C2=C1C=CC=C2 CZVOWGZIAVDFJV-UHFFFAOYSA-N 0.000 title 1
150000001875 compounds Chemical class 0.000 claims abstract description 60
125000000217 alkyl group Chemical group 0.000 claims abstract description 38
125000004432 carbon atom Chemical group C* 0.000 claims abstract description 38
125000003118 aryl group Chemical group 0.000 claims abstract description 32
238000000034 method Methods 0.000 claims abstract description 15
229910052739 hydrogen Inorganic materials 0.000 claims abstract description 11
239000001257 hydrogen Substances 0.000 claims abstract description 11
229910052736 halogen Inorganic materials 0.000 claims abstract description 10
125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims abstract description 7
150000002367 halogens Chemical class 0.000 claims abstract description 6
125000003545 alkoxy group Chemical group 0.000 claims abstract description 5
238000004519 manufacturing process Methods 0.000 claims abstract description 5
125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims abstract description 5
125000004435 hydrogen atom Chemical class [H]* 0.000 claims abstract 4
FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 claims description 22
BEPAFCGSDWSTEL-UHFFFAOYSA-N dimethyl malonate Chemical compound COC(=O)CC(=O)OC BEPAFCGSDWSTEL-UHFFFAOYSA-N 0.000 claims description 7
229910021589 Copper(I) bromide Inorganic materials 0.000 claims description 4
230000003197 catalytic effect Effects 0.000 claims description 3
IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 34
ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 30
XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 28
VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 27
ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 26
239000000203 mixture Substances 0.000 description 25
WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 24
RWRDLPDLKQPQOW-UHFFFAOYSA-N tetrahydropyrrole Substances C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 description 23
125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 19
239000007787 solid Substances 0.000 description 15
235000019439 ethyl acetate Nutrition 0.000 description 14
238000006243 chemical reaction Methods 0.000 description 12
238000005160 1H NMR spectroscopy Methods 0.000 description 11
229910052943 magnesium sulfate Inorganic materials 0.000 description 11
230000002411 adverse Effects 0.000 description 10
238000001704 evaporation Methods 0.000 description 10
230000008020 evaporation Effects 0.000 description 10
239000002904 solvent Substances 0.000 description 10
NGNBDVOYPDDBFK-UHFFFAOYSA-N 2-[2,4-di(pentan-2-yl)phenoxy]acetyl chloride Chemical compound CCCC(C)C1=CC=C(OCC(Cl)=O)C(C(C)CCC)=C1 NGNBDVOYPDDBFK-UHFFFAOYSA-N 0.000 description 9
OKKJLVBELUTLKV-UHFFFAOYSA-N methanol Substances OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 9
239000000243 solution Substances 0.000 description 9
-1 4-bromo-2-fluorophenyl Chemical group 0.000 description 8
YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 8
NOESYZHRGYRDHS-UHFFFAOYSA-N insulin Chemical compound N1C(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(NC(=O)CN)C(C)CC)CSSCC(C(NC(CO)C(=O)NC(CC(C)C)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CCC(N)=O)C(=O)NC(CC(C)C)C(=O)NC(CCC(O)=O)C(=O)NC(CC(N)=O)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CSSCC(NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2C=CC(O)=CC=2)NC(=O)C(CC(C)C)NC(=O)C(C)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2NC=NC=2)NC(=O)C(CO)NC(=O)CNC2=O)C(=O)NCC(=O)NC(CCC(O)=O)C(=O)NC(CCCNC(N)=N)C(=O)NCC(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC(O)=CC=3)C(=O)NC(C(C)O)C(=O)N3C(CCC3)C(=O)NC(CCCCN)C(=O)NC(C)C(O)=O)C(=O)NC(CC(N)=O)C(O)=O)=O)NC(=O)C(C(C)CC)NC(=O)C(CO)NC(=O)C(C(C)O)NC(=O)C1CSSCC2NC(=O)C(CC(C)C)NC(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CC(N)=O)NC(=O)C(NC(=O)C(N)CC=1C=CC=CC=1)C(C)C)CC1=CN=CN1 NOESYZHRGYRDHS-UHFFFAOYSA-N 0.000 description 8
229910000104 sodium hydride Inorganic materials 0.000 description 8
RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 7
241000700159 Rattus Species 0.000 description 7
238000003818 flash chromatography Methods 0.000 description 7
239000000725 suspension Substances 0.000 description 7
239000003039 volatile agent Substances 0.000 description 7
DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 6
239000002253 acid Substances 0.000 description 6
239000000284 extract Substances 0.000 description 6
150000002431 hydrogen Chemical class 0.000 description 6
238000005481 NMR spectroscopy Methods 0.000 description 5
229910006124 SOCl2 Inorganic materials 0.000 description 5
235000005911 diet Nutrition 0.000 description 5
230000037213 diet Effects 0.000 description 5
FBPFZTCFMRRESA-GUCUJZIJSA-N galactitol Chemical compound OC[C@H](O)[C@@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-GUCUJZIJSA-N 0.000 description 5
229930182830 galactose Natural products 0.000 description 5
238000000746 purification Methods 0.000 description 5
238000010992 reflux Methods 0.000 description 5
GNFTZDOKVXKIBK-UHFFFAOYSA-N 3-(2-methoxyethoxy)benzohydrazide Chemical compound COCCOC1=CC=CC(C(=O)NN)=C1 GNFTZDOKVXKIBK-UHFFFAOYSA-N 0.000 description 4
LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 4
102000004877 Insulin Human genes 0.000 description 4
108090001061 Insulin Proteins 0.000 description 4
VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 4
YTAHJIFKAKIKAV-XNMGPUDCSA-N [(1R)-3-morpholin-4-yl-1-phenylpropyl] N-[(3S)-2-oxo-5-phenyl-1,3-dihydro-1,4-benzodiazepin-3-yl]carbamate Chemical compound O=C1[C@H](N=C(C2=C(N1)C=CC=C2)C1=CC=CC=C1)NC(O[C@H](CCN1CCOCC1)C1=CC=CC=C1)=O YTAHJIFKAKIKAV-XNMGPUDCSA-N 0.000 description 4
238000009825 accumulation Methods 0.000 description 4
239000004480 active ingredient Substances 0.000 description 4
150000001408 amides Chemical class 0.000 description 4
IOJUPLGTWVMSFF-UHFFFAOYSA-N benzothiazole Chemical compound C1=CC=C2SC=NC2=C1 IOJUPLGTWVMSFF-UHFFFAOYSA-N 0.000 description 4
206010012601 diabetes mellitus Diseases 0.000 description 4
238000002474 experimental method Methods 0.000 description 4
229940125396 insulin Drugs 0.000 description 4
239000003921 oil Substances 0.000 description 4
239000003538 oral antidiabetic agent Substances 0.000 description 4
229940127209 oral hypoglycaemic agent Drugs 0.000 description 4
BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 4
238000003756 stirring Methods 0.000 description 4
JQPCNISBBBPSOS-UHFFFAOYSA-N 2-(1,3-dimethoxy-1,3-dioxopropan-2-yl)benzoic acid Chemical compound COC(=O)C(C(=O)OC)C1=CC=CC=C1C(O)=O JQPCNISBBBPSOS-UHFFFAOYSA-N 0.000 description 3
HPDLIOXFWIOACY-UHFFFAOYSA-N 2-[2-[(4-bromo-2-fluorophenyl)methyl]-4-methoxycarbonyl-1,3-dioxoisoquinolin-4-yl]acetic acid Chemical compound O=C1C2=CC=CC=C2C(C(=O)OC)(CC(O)=O)C(=O)N1CC1=CC=C(Br)C=C1F HPDLIOXFWIOACY-UHFFFAOYSA-N 0.000 description 3
XRXMNWGCKISMOH-UHFFFAOYSA-N 2-bromobenzoic acid Chemical compound OC(=O)C1=CC=CC=C1Br XRXMNWGCKISMOH-UHFFFAOYSA-N 0.000 description 3
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 3
241000124008 Mammalia Species 0.000 description 3
125000002252 acyl group Chemical group 0.000 description 3
239000002775 capsule Substances 0.000 description 3
239000012043 crude product Substances 0.000 description 3
238000002425 crystallisation Methods 0.000 description 3
230000008025 crystallization Effects 0.000 description 3
239000008103 glucose Substances 0.000 description 3
229920005862 polyol Polymers 0.000 description 3
150000003077 polyols Chemical class 0.000 description 3
229910000027 potassium carbonate Inorganic materials 0.000 description 3
238000002360 preparation method Methods 0.000 description 3
BNWCETAHAJSBFG-UHFFFAOYSA-N tert-butyl 2-bromoacetate Chemical compound CC(C)(C)OC(=O)CBr BNWCETAHAJSBFG-UHFFFAOYSA-N 0.000 description 3
YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 3
XFKYKTBPRBZDFG-UHFFFAOYSA-N 2-aminoacetonitrile;hydrochloride Chemical compound Cl.NCC#N XFKYKTBPRBZDFG-UHFFFAOYSA-N 0.000 description 2
IKCLCGXPQILATA-UHFFFAOYSA-N 2-chlorobenzoic acid Chemical compound OC(=O)C1=CC=CC=C1Cl IKCLCGXPQILATA-UHFFFAOYSA-N 0.000 description 2
102000016912 Aldehyde Reductase Human genes 0.000 description 2
108010053754 Aldehyde reductase Proteins 0.000 description 2
241000283690 Bos taurus Species 0.000 description 2
FGUUSXIOTUKUDN-IBGZPJMESA-N C1(=CC=CC=C1)N1C2=C(NC([C@H](C1)NC=1OC(=NN=1)C1=CC=CC=C1)=O)C=CC=C2 Chemical compound C1(=CC=CC=C1)N1C2=C(NC([C@H](C1)NC=1OC(=NN=1)C1=CC=CC=C1)=O)C=CC=C2 FGUUSXIOTUKUDN-IBGZPJMESA-N 0.000 description 2
HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
230000009286 beneficial effect Effects 0.000 description 2
230000037396 body weight Effects 0.000 description 2
229910052799 carbon Inorganic materials 0.000 description 2
239000002552 dosage form Substances 0.000 description 2
239000003937 drug carrier Substances 0.000 description 2
238000000338 in vitro Methods 0.000 description 2
238000001727 in vivo Methods 0.000 description 2
230000002401 inhibitory effect Effects 0.000 description 2
230000005764 inhibitory process Effects 0.000 description 2
150000007529 inorganic bases Chemical class 0.000 description 2
AWJUIBRHMBBTKR-UHFFFAOYSA-N isoquinoline Chemical compound C1=NC=CC2=CC=CC=C21 AWJUIBRHMBBTKR-UHFFFAOYSA-N 0.000 description 2
HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 2
WAAUNVUMROVZIW-UHFFFAOYSA-N methyl 2-(cyanomethyl)-1,3-dioxo-4h-isoquinoline-4-carboxylate Chemical compound C1=CC=C2C(C(=O)OC)C(=O)N(CC#N)C(=O)C2=C1 WAAUNVUMROVZIW-UHFFFAOYSA-N 0.000 description 2
MWKKTHKUEVFYQR-UHFFFAOYSA-N methyl 2-(cyanomethyl)-4-[2-[(2-methylpropan-2-yl)oxy]-2-oxoethyl]-1,3-dioxoisoquinoline-4-carboxylate Chemical compound C1=CC=C2C(C(=O)OC)(CC(=O)OC(C)(C)C)C(=O)N(CC#N)C(=O)C2=C1 MWKKTHKUEVFYQR-UHFFFAOYSA-N 0.000 description 2
DOSZIOVZSICDQS-UHFFFAOYSA-N methyl 2-[(4-bromo-2-fluorophenyl)methyl]-1,3-dioxo-4h-isoquinoline-4-carboxylate Chemical compound O=C1C2=CC=CC=C2C(C(=O)OC)C(=O)N1CC1=CC=C(Br)C=C1F DOSZIOVZSICDQS-UHFFFAOYSA-N 0.000 description 2
150000007524 organic acids Chemical class 0.000 description 2
238000007911 parenteral administration Methods 0.000 description 2
239000000546 pharmaceutical excipient Substances 0.000 description 2
229920006395 saturated elastomer Polymers 0.000 description 2
210000003497 sciatic nerve Anatomy 0.000 description 2
239000000741 silica gel Substances 0.000 description 2
229910002027 silica gel Inorganic materials 0.000 description 2
125000003003 spiro group Chemical group 0.000 description 2
125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 2
YNJBWRMUSHSURL-UHFFFAOYSA-N trichloroacetic acid Chemical compound OC(=O)C(Cl)(Cl)Cl YNJBWRMUSHSURL-UHFFFAOYSA-N 0.000 description 2
HQAJGCKMMKDEKH-UHFFFAOYSA-N 2-(1,3-dimethoxy-1,3-dioxopropan-2-yl)-3-fluorobenzoic acid Chemical compound COC(=O)C(C(=O)OC)C1=C(F)C=CC=C1C(O)=O HQAJGCKMMKDEKH-UHFFFAOYSA-N 0.000 description 1
VRVRGVPWCUEOGV-UHFFFAOYSA-N 2-aminothiophenol Chemical class NC1=CC=CC=C1S VRVRGVPWCUEOGV-UHFFFAOYSA-N 0.000 description 1
GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 1
206010007749 Cataract diabetic Diseases 0.000 description 1
RKWGIWYCVPQPMF-UHFFFAOYSA-N Chloropropamide Chemical compound CCCNC(=O)NS(=O)(=O)C1=CC=C(Cl)C=C1 RKWGIWYCVPQPMF-UHFFFAOYSA-N 0.000 description 1
208000002249 Diabetes Complications Diseases 0.000 description 1
206010012655 Diabetic complications Diseases 0.000 description 1
206010012692 Diabetic uveitis Diseases 0.000 description 1
102000004190 Enzymes Human genes 0.000 description 1
108090000790 Enzymes Proteins 0.000 description 1
241000282414 Homo sapiens Species 0.000 description 1
UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 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
241001465754 Metazoa Species 0.000 description 1
BAVYZALUXZFZLV-UHFFFAOYSA-N Methylamine Chemical class NC BAVYZALUXZFZLV-UHFFFAOYSA-N 0.000 description 1
KJNKBXVITKJVES-UHFFFAOYSA-N O=C1NC(C(C2=CC=CC=C12)CC(=O)O)=O Chemical compound O=C1NC(C(C2=CC=CC=C12)CC(=O)O)=O KJNKBXVITKJVES-UHFFFAOYSA-N 0.000 description 1
241000283973 Oryctolagus cuniculus Species 0.000 description 1
208000017442 Retinal disease Diseases 0.000 description 1
206010038923 Retinopathy Diseases 0.000 description 1
241000283984 Rodentia Species 0.000 description 1
KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 1
229920002472 Starch Polymers 0.000 description 1
JLRGJRBPOGGCBT-UHFFFAOYSA-N Tolbutamide Chemical compound CCCCNC(=O)NS(=O)(=O)C1=CC=C(C)C=C1 JLRGJRBPOGGCBT-UHFFFAOYSA-N 0.000 description 1
FIAGYDIJZOWVAB-UHFFFAOYSA-N [2-sulfanyl-5-(trifluoromethyl)phenyl]azanium;chloride Chemical compound Cl.NC1=CC(C(F)(F)F)=CC=C1S FIAGYDIJZOWVAB-UHFFFAOYSA-N 0.000 description 1
229960001466 acetohexamide Drugs 0.000 description 1
VGZSUPCWNCWDAN-UHFFFAOYSA-N acetohexamide Chemical compound C1=CC(C(=O)C)=CC=C1S(=O)(=O)NC(=O)NC1CCCCC1 VGZSUPCWNCWDAN-UHFFFAOYSA-N 0.000 description 1
239000003288 aldose reductase inhibitor Substances 0.000 description 1
229940090865 aldose reductase inhibitors used in diabetes Drugs 0.000 description 1
150000001412 amines Chemical class 0.000 description 1
125000003710 aryl alkyl group Chemical group 0.000 description 1
150000001721 carbon Chemical group 0.000 description 1
239000000969 carrier Substances 0.000 description 1
239000003153 chemical reaction reagent Substances 0.000 description 1
239000003795 chemical substances by application Substances 0.000 description 1
229960001761 chlorpropamide Drugs 0.000 description 1
238000011210 chromatographic step Methods 0.000 description 1
239000004927 clay Substances 0.000 description 1
239000012059 conventional drug carrier Substances 0.000 description 1
NKNDPYCGAZPOFS-UHFFFAOYSA-M copper(i) bromide Chemical compound Br[Cu] NKNDPYCGAZPOFS-UHFFFAOYSA-M 0.000 description 1
230000002939 deleterious effect Effects 0.000 description 1
201000007025 diabetic cataract Diseases 0.000 description 1
230000003467 diminishing effect Effects 0.000 description 1
239000006185 dispersion Substances 0.000 description 1
230000000694 effects Effects 0.000 description 1
150000002148 esters Chemical class 0.000 description 1
235000019441 ethanol Nutrition 0.000 description 1
125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
239000012467 final product Substances 0.000 description 1
239000006260 foam Substances 0.000 description 1
239000000499 gel Substances 0.000 description 1
239000003701 inert diluent Substances 0.000 description 1
206010023365 keratopathy Diseases 0.000 description 1
208000017169 kidney disease Diseases 0.000 description 1
239000008101 lactose Substances 0.000 description 1
239000010410 layer Substances 0.000 description 1
239000011777 magnesium Substances 0.000 description 1
ZLNQQNXFFQJAID-UHFFFAOYSA-L magnesium carbonate Chemical compound [Mg+2].[O-]C([O-])=O ZLNQQNXFFQJAID-UHFFFAOYSA-L 0.000 description 1
239000001095 magnesium carbonate Substances 0.000 description 1
229910000021 magnesium carbonate Inorganic materials 0.000 description 1
235000019359 magnesium stearate Nutrition 0.000 description 1
239000000463 material Substances 0.000 description 1
YSBUMMCUZXUSQM-UHFFFAOYSA-N methyl 2-(cyanomethyl)-6-fluoro-1,3-dioxo-4h-isoquinoline-4-carboxylate Chemical compound C1=C(F)C=C2C(C(=O)OC)C(=O)N(CC#N)C(=O)C2=C1 YSBUMMCUZXUSQM-UHFFFAOYSA-N 0.000 description 1
FVSCAHMUZCRARN-UHFFFAOYSA-N methyl 2-(cyanomethyl)-6-fluoro-4-[2-[(2-methylpropan-2-yl)oxy]-2-oxoethyl]-1,3-dioxoisoquinoline-4-carboxylate Chemical compound C1=C(F)C=C2C(C(=O)OC)(CC(=O)OC(C)(C)C)C(=O)N(CC#N)C(=O)C2=C1 FVSCAHMUZCRARN-UHFFFAOYSA-N 0.000 description 1
BRSSFJZXYKOLKP-UHFFFAOYSA-N methyl 2-[(4-bromo-2-fluorophenyl)methyl]-4-[2-[(2-methylpropan-2-yl)oxy]-2-oxoethyl]-1,3-dioxoisoquinoline-4-carboxylate Chemical compound O=C1C2=CC=CC=C2C(C(=O)OC)(CC(=O)OC(C)(C)C)C(=O)N1CC1=CC=C(Br)C=C1F BRSSFJZXYKOLKP-UHFFFAOYSA-N 0.000 description 1
VRDRWIRJPFJGHV-UHFFFAOYSA-N methyl 2-[(4-bromo-2-fluorophenyl)methyl]-6-fluoro-1,3-dioxo-4h-isoquinoline-4-carboxylate Chemical compound O=C1C2=CC=C(F)C=C2C(C(=O)OC)C(=O)N1CC1=CC=C(Br)C=C1F VRDRWIRJPFJGHV-UHFFFAOYSA-N 0.000 description 1
LJFNMFQNCSSFJF-UHFFFAOYSA-N methyl 2-[(4-bromo-2-fluorophenyl)methyl]-6-fluoro-4-[2-[(2-methylpropan-2-yl)oxy]-2-oxoethyl]-1,3-dioxoisoquinoline-4-carboxylate Chemical compound O=C1C2=CC=C(F)C=C2C(C(=O)OC)(CC(=O)OC(C)(C)C)C(=O)N1CC1=CC=C(Br)C=C1F LJFNMFQNCSSFJF-UHFFFAOYSA-N 0.000 description 1
VUNCRCXKVHXKLV-UHFFFAOYSA-N methyl 3-methoxy-1-oxoisochromene-4-carboxylate Chemical compound C1=CC=C2C(C(=O)OC)=C(OC)OC(=O)C2=C1 VUNCRCXKVHXKLV-UHFFFAOYSA-N 0.000 description 1
ZQKOHJNKCBIYFQ-UHFFFAOYSA-N methyl 6-fluoro-3-methoxy-1-oxoisochromene-4-carboxylate Chemical compound C1=C(F)C=C2C(C(=O)OC)=C(OC)OC(=O)C2=C1 ZQKOHJNKCBIYFQ-UHFFFAOYSA-N 0.000 description 1
239000002480 mineral oil Substances 0.000 description 1
235000010446 mineral oil Nutrition 0.000 description 1
238000002156 mixing Methods 0.000 description 1
238000012986 modification Methods 0.000 description 1
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201000001119 neuropathy Diseases 0.000 description 1
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ICFJFFQQTFMIBG-UHFFFAOYSA-N phenformin Chemical compound NC(=N)NC(=N)NCCC1=CC=CC=C1 ICFJFFQQTFMIBG-UHFFFAOYSA-N 0.000 description 1
229960003243 phenformin Drugs 0.000 description 1
239000006187 pill Substances 0.000 description 1
230000002265 prevention Effects 0.000 description 1
239000000047 product Substances 0.000 description 1
230000000069 prophylactic effect Effects 0.000 description 1
238000007363 ring formation reaction Methods 0.000 description 1
239000000377 silicon dioxide Substances 0.000 description 1
239000012312 sodium hydride Substances 0.000 description 1
238000012453 sprague-dawley rat model Methods 0.000 description 1
239000008107 starch Substances 0.000 description 1
235000019698 starch Nutrition 0.000 description 1
239000008174 sterile solution Substances 0.000 description 1
239000011550 stock solution Substances 0.000 description 1
125000003107 substituted aryl group Chemical group 0.000 description 1
239000003826 tablet Substances 0.000 description 1
238000012360 testing method Methods 0.000 description 1
238000012956 testing procedure Methods 0.000 description 1
OUDSBRTVNLOZBN-UHFFFAOYSA-N tolazamide Chemical compound C1=CC(C)=CC=C1S(=O)(=O)NC(=O)NN1CCCCCC1 OUDSBRTVNLOZBN-UHFFFAOYSA-N 0.000 description 1
229960002277 tolazamide Drugs 0.000 description 1
229960005371 tolbutamide Drugs 0.000 description 1
238000011200 topical administration Methods 0.000 description 1

Landscapes

Nitrogen Condensed Heterocyclic Rings (AREA)

CA002324636A 1990-05-21 1991-05-08 1, 2, 3, 4, - tetrahydro - 1, 3 - dioxo - 4 - acide isoquinolinecarboxylic methyl esters Abandoned CA2324636A1 (fr)

Applications Claiming Priority (3)

Application Number	Priority Date	Filing Date	Title
US526,362		1990-05-21
US07/526,362 US5045544A (en)	1990-05-21	1990-05-21	N'-alkyl-spiro-isoquinoline-pyrrolidine tetrones and analogs thereof useful as aldose reductase inhibitors
CA002042112A CA2042112C (fr)	1990-05-21	1991-05-08	N'-alkylspiro-isoquinoleinepyrrolidinetetrones et leurs analogues, utiles comme agents inhibiteurs de l'aldose-reductase

Related Parent Applications (1)

Application Number	Title	Priority Date	Filing Date
CA002042112A Division CA2042112C (fr)	1990-05-21	1991-05-08	N'-alkylspiro-isoquinoleinepyrrolidinetetrones et leurs analogues, utiles comme agents inhibiteurs de l'aldose-reductase

Publications (1)

Publication Number	Publication Date
CA2324636A1 true CA2324636A1 (fr)	1991-11-22

Family

ID=25674605

Family Applications (1)

Application Number	Title	Priority Date	Filing Date
CA002324636A Abandoned CA2324636A1 (fr)	1990-05-21	1991-05-08	1, 2, 3, 4, - tetrahydro - 1, 3 - dioxo - 4 - acide isoquinolinecarboxylic methyl esters

Country Status (1)

Country	Link
CA (1)	CA2324636A1 (fr)

1991
- 1991-05-08 CA CA002324636A patent/CA2324636A1/fr not_active Abandoned

Legal Events

Date	Code	Title	Description
2000-11-21	EEER	Examination request
2005-01-31	FZDE	Dead

Publication	Publication Date	Title
US4927831A (en)	1990-05-22	Spiro-isoquinoline-pyrrolidine tetrones and analogs thereof useful as aldose reductase inhibitors
CA2042113C (fr)	2001-08-28	Spiro-isoquinoleinepyrrolidine et leurs analogues, utiles comme agents inhibiteurs de l'aldose-reductase
EP0365324B1 (fr)	1994-05-04	Spiro-isoquinoléine-pyrrolidine-tétrones et leurs analogues utiles comme inhibiteurs de l'aldoseréductase
CA2042112C (fr)	2001-07-24	N'-alkylspiro-isoquinoleinepyrrolidinetetrones et leurs analogues, utiles comme agents inhibiteurs de l'aldose-reductase
EP0555327B1 (fr)	1999-01-13	Analogues d'alcoylidene de 1'-aminospiro-[isoquinoline- 4(1h),3'-pyrrolidine]-1,2',3,5'(2h)-tetrones utiles en tant qu'inhibiteurs de l'aldose reductase in vivo
EP0277791A2 (fr)	1988-08-10	Cinnolines carboxamides et procédé pour leur préparation
US5130425A (en)	1992-07-14	Spiro-lactams and analogs thereof useful as aldose reductase inhibitors
EP0553263B1 (fr)	1998-08-05	1'-aminospiro-[isoquinoline-4(1h),3'-pyrrolidine]- 1,2',3,5'(2h)-tetrones et leurs analogues utiles en tant qu'inhibiteurs de l'aldose reductase in vivo
US5081241A (en)	1992-01-14	Spiro-pyridazines and analogs thereof useful as aldose reductase inhibitors
US4983613A (en)	1991-01-08	Isoquinoline acetic acids and acetyl carbamates useful as aldose reductase inhibitors
AU665796B2 (en)	1996-01-18	1'-amino-2-((benzothiazolyl)methyl)spiro (isoquinoline-4(1H),3'-pyrrolidine)-1,2',3,5'(2H)-tetrones and analogs thereof useful as aldose reductase inhibitors
US5189168A (en)	1993-02-23	1'-amino-2[(benzothiazolyl)methyl]spiro-[isoquinoline-4(1H),3'-pyrrolidine]-1,2'3,5'(2H)-tetrones and analogs thereof useful as aldose reductase inhibitors
US5093496A (en)	1992-03-03	Spiro-isoquinoline-pyrrolidines and analogs thereof useful as aldose reductase inhibitors
IE913604A1 (en)	1992-04-22	1'-aminospiro[isoquinoline-4(1h),3'-pyrrolidine]-1,2',3,5'¹(2h)-tetrones and analogs thereof useful as aldose reductase¹inhibitors
US5189167A (en)	1993-02-23	Alkylidene analogs of 1'-amino-2-[(benzothiazolyl)-methyl]spiro [isoquinoline-4(1H),3'-pyrrolidine]-1,2',3,5'(2H)-tetrones useful as aldose reductase inhibitors
HK1010368A (en)	1999-06-17	N-alkyl-spiro-isoquinoline-pyrrolidine tetrones and analogs thereof useful as aldose reductase inhibitors
HK1009601B (en)	2000-05-12	1'-aminospiro[isoquinoline-4(1h),3'-pyrrolidine]-1,2',3,5'(2h)-tetrones and analogs thereof useful as aldose reductase inhibitors in vivo
GB2252321A (en)	1992-08-05	Isoquinoline intermediates preparation
HK1011356B (en)	2000-05-12	Alkylidene analogs of 1'-aminospiro[isoquinoline-4(1h), 3'-pyrrolidine]-1,2',3,5'(2h)-tetrones useful as aldose reductase inhibitors in vivo