IL92054A - Spiro-isoquinoline-pyrrolidine tetra and their analogues, their preparations and pharmaceutical preparations containing them - Google Patents

Spiro-isoquinoline-pyrrolidine tetra and their analogues, their preparations and pharmaceutical preparations containing them

Info

Publication number: IL92054A
Authority: IL; Israel
Prior art keywords: pharmaceutically acceptable; pyrrolidine; tetrone; bromo; formula
Prior art date: 1988-10-20

Application number

IL9205489A

Other languages

English (en)

Hebrew (he)

Other versions

IL92054A0 (en

Inventor

Michael Sotirios Malamas

Original Assignee

American Home Prod

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.)

1988-10-20

Filing date

1989-10-19

Publication date

1994-07-31

1989-10-19 Application filed by American Home Prod filed Critical American Home Prod

1990-07-12 Publication of IL92054A0 publication Critical patent/IL92054A0/xx

1994-07-31 Publication of IL92054A publication Critical patent/IL92054A/en

Links

RWRDLPDLKQPQOW-UHFFFAOYSA-N tetrahydropyrrole Substances C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 title claims description 66
239000008194 pharmaceutical composition Substances 0.000 title claims description 4
238000002360 preparation method Methods 0.000 title description 20
150000001875 compounds Chemical class 0.000 claims description 133
125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 72
-1 4-bromo-2-fluoro-phenyl Chemical group 0.000 claims description 71
125000000217 alkyl group Chemical group 0.000 claims description 41
150000003839 salts Chemical class 0.000 claims description 41
125000004432 carbon atom Chemical group C* 0.000 claims description 36
125000003003 spiro group Chemical group 0.000 claims description 34
238000000034 method Methods 0.000 claims description 33
239000002904 solvent Substances 0.000 claims description 25
230000008569 process Effects 0.000 claims description 23
229910052736 halogen Inorganic materials 0.000 claims description 18
239000001257 hydrogen Substances 0.000 claims description 17
229910052739 hydrogen Inorganic materials 0.000 claims description 17
125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 15
150000002367 halogens Chemical class 0.000 claims description 13
125000003118 aryl group Chemical group 0.000 claims description 12
125000004189 3,4-dichlorophenyl group Chemical group [H]C1=C([H])C(Cl)=C(Cl)C([H])=C1* 0.000 claims description 10
206010012601 diabetes mellitus Diseases 0.000 claims description 9
150000002431 hydrogen Chemical class 0.000 claims description 9
UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 8
QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 8
YNESATAKKCNGOF-UHFFFAOYSA-N lithium bis(trimethylsilyl)amide Chemical compound [Li+].C[Si](C)(C)[N-][Si](C)(C)C YNESATAKKCNGOF-UHFFFAOYSA-N 0.000 claims description 8
229910052760 oxygen Inorganic materials 0.000 claims description 8
239000001301 oxygen Substances 0.000 claims description 8
241000124008 Mammalia Species 0.000 claims description 6
125000003545 alkoxy group Chemical group 0.000 claims description 6
150000007529 inorganic bases Chemical class 0.000 claims description 6
NVQOFWZLYDVFMU-UHFFFAOYSA-N azane;oxolane Chemical compound N.C1CCOC1 NVQOFWZLYDVFMU-UHFFFAOYSA-N 0.000 claims description 5
BNWCETAHAJSBFG-UHFFFAOYSA-N tert-butyl 2-bromoacetate Chemical compound CC(C)(C)OC(=O)CBr BNWCETAHAJSBFG-UHFFFAOYSA-N 0.000 claims description 5
125000002813 thiocarbonyl group Chemical group *C(*)=S 0.000 claims description 5
208000002177 Cataract Diseases 0.000 claims description 4
208000017442 Retinal disease Diseases 0.000 claims description 4
206010038923 Retinopathy Diseases 0.000 claims description 4
125000002947 alkylene group Chemical group 0.000 claims description 4
125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 4
239000003795 chemical substances by application Substances 0.000 claims description 4
208000017169 kidney disease Diseases 0.000 claims description 4
238000004519 manufacturing process Methods 0.000 claims description 4
201000001119 neuropathy Diseases 0.000 claims description 4
230000007823 neuropathy Effects 0.000 claims description 4
IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 4
150000007524 organic acids Chemical class 0.000 claims description 4
208000033808 peripheral neuropathy Diseases 0.000 claims description 4
NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 3
239000003937 drug carrier Substances 0.000 claims description 3
229910052757 nitrogen Inorganic materials 0.000 claims description 3
229910052717 sulfur Inorganic materials 0.000 claims description 3
239000011593 sulfur Substances 0.000 claims description 3
239000007822 coupling agent Substances 0.000 claims description 2
QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 claims description 2
125000003107 substituted aryl group Chemical group 0.000 claims description 2
125000005843 halogen group Chemical group 0.000 claims 2
239000003814 drug Substances 0.000 claims 1
230000003301 hydrolyzing effect Effects 0.000 claims 1
IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 113
WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical class C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 56
XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 51
239000000203 mixture Substances 0.000 description 34
VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 30
238000006243 chemical reaction Methods 0.000 description 27
239000000243 solution Substances 0.000 description 27
239000002253 acid Substances 0.000 description 26
235000019439 ethyl acetate Nutrition 0.000 description 25
239000007787 solid Substances 0.000 description 25
RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 22
OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 22
229910001868 water Inorganic materials 0.000 description 22
XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 19
ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 18
125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 15
230000002411 adverse Effects 0.000 description 14
238000001704 evaporation Methods 0.000 description 12
230000008020 evaporation Effects 0.000 description 12
238000003818 flash chromatography Methods 0.000 description 12
FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 12
YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 11
VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 10
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 10
ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 9
DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 9
150000001412 amines Chemical class 0.000 description 9
239000012043 crude product Substances 0.000 description 8
150000002148 esters Chemical class 0.000 description 8
BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 8
LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 7
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 7
241000700159 Rattus Species 0.000 description 7
239000002585 base Substances 0.000 description 7
125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 7
125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 7
239000008103 glucose Substances 0.000 description 7
238000000338 in vitro Methods 0.000 description 7
239000003921 oil Substances 0.000 description 7
238000003756 stirring Methods 0.000 description 7
YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 7
239000003039 volatile agent Substances 0.000 description 7
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 6
CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 6
QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 6
BAVYZALUXZFZLV-UHFFFAOYSA-N Methylamine Chemical compound NC BAVYZALUXZFZLV-UHFFFAOYSA-N 0.000 description 6
NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 6
238000009825 accumulation Methods 0.000 description 6
239000000284 extract Substances 0.000 description 6
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 6
229930182830 galactose Natural products 0.000 description 6
150000004702 methyl esters Chemical class 0.000 description 6
125000001570 methylene group Chemical group [H]C([H])([*:1])[*:2] 0.000 description 6
235000011007 phosphoric acid Nutrition 0.000 description 6
238000000746 purification Methods 0.000 description 6
239000000741 silica gel Substances 0.000 description 6
229910002027 silica gel Inorganic materials 0.000 description 6
239000000725 suspension Substances 0.000 description 6
AKHSBAVQPIRVAG-UHFFFAOYSA-N 4h-isochromene-1,3-dione Chemical compound C1=CC=C2C(=O)OC(=O)CC2=C1 AKHSBAVQPIRVAG-UHFFFAOYSA-N 0.000 description 5
UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 5
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 5
102000004877 Insulin Human genes 0.000 description 5
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125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 5
239000003538 oral antidiabetic agent Substances 0.000 description 5
229940127209 oral hypoglycaemic agent Drugs 0.000 description 5
239000000600 sorbitol Substances 0.000 description 5
102000016912 Aldehyde Reductase Human genes 0.000 description 4
108010053754 Aldehyde reductase Proteins 0.000 description 4
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 4
208000002249 Diabetes Complications Diseases 0.000 description 4
206010012655 Diabetic complications Diseases 0.000 description 4
239000004480 active ingredient Substances 0.000 description 4
125000003710 aryl alkyl group Chemical group 0.000 description 4
BEPAFCGSDWSTEL-UHFFFAOYSA-N dimethyl malonate Chemical compound COC(=O)CC(=O)OC BEPAFCGSDWSTEL-UHFFFAOYSA-N 0.000 description 4
238000002474 experimental method Methods 0.000 description 4
238000004128 high performance liquid chromatography Methods 0.000 description 4
230000005764 inhibitory process Effects 0.000 description 4
229910052943 magnesium sulfate Inorganic materials 0.000 description 4
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229910000104 sodium hydride Inorganic materials 0.000 description 4
XRXMNWGCKISMOH-UHFFFAOYSA-N 2-bromobenzoic acid Chemical compound OC(=O)C1=CC=CC=C1Br XRXMNWGCKISMOH-UHFFFAOYSA-N 0.000 description 3
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GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Chemical compound 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 3
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SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 description 3
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OAYLNYINCPYISS-UHFFFAOYSA-N ethyl acetate;hexane Chemical compound CCCCCC.CCOC(C)=O OAYLNYINCPYISS-UHFFFAOYSA-N 0.000 description 3
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229910000069 nitrogen hydride Inorganic materials 0.000 description 3
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210000003497 sciatic nerve Anatomy 0.000 description 3
125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 description 3
KIUPCUCGVCGPPA-UHFFFAOYSA-N (5-methyl-2-propan-2-ylcyclohexyl) carbonochloridate Chemical compound CC(C)C1CCC(C)CC1OC(Cl)=O KIUPCUCGVCGPPA-UHFFFAOYSA-N 0.000 description 2
ASOKPJOREAFHNY-UHFFFAOYSA-N 1-Hydroxybenzotriazole Chemical compound C1=CC=C2N(O)N=NC2=C1 ASOKPJOREAFHNY-UHFFFAOYSA-N 0.000 description 2
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 2
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HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 description 2
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ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 2
229910021589 Copper(I) bromide Inorganic materials 0.000 description 2
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ROMWRJNZSHFGEK-UHFFFAOYSA-N methyl 2-(2-methoxy-2-oxoethyl)benzoate Chemical compound COC(=O)CC1=CC=CC=C1C(=O)OC ROMWRJNZSHFGEK-UHFFFAOYSA-N 0.000 description 2
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238000004809 thin layer chromatography Methods 0.000 description 2
YNJBWRMUSHSURL-UHFFFAOYSA-N trichloroacetic acid Chemical compound OC(=O)C(Cl)(Cl)Cl YNJBWRMUSHSURL-UHFFFAOYSA-N 0.000 description 2
GETQZCLCWQTVFV-UHFFFAOYSA-N trimethylamine Chemical compound CN(C)C GETQZCLCWQTVFV-UHFFFAOYSA-N 0.000 description 2
IXHNFOOSLAWRBQ-UHFFFAOYSA-N (3,4-dichlorophenyl)methanamine Chemical compound NCC1=CC=C(Cl)C(Cl)=C1 IXHNFOOSLAWRBQ-UHFFFAOYSA-N 0.000 description 1
RLTFBWCBGIZCDQ-UHFFFAOYSA-N (4-bromo-2-fluorophenyl)methanamine Chemical compound NCC1=CC=C(Br)C=C1F RLTFBWCBGIZCDQ-UHFFFAOYSA-N 0.000 description 1
RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
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
HCQVOEBHAJXJSJ-UHFFFAOYSA-N 2-(4-methylmorpholin-4-ium-4-yl)ethanol Chemical compound OCC[N+]1(C)CCOCC1 HCQVOEBHAJXJSJ-UHFFFAOYSA-N 0.000 description 1
125000000979 2-amino-2-oxoethyl group Chemical group [H]C([*])([H])C(=O)N([H])[H] 0.000 description 1
YEDUAINPPJYDJZ-UHFFFAOYSA-N 2-hydroxybenzothiazole Chemical compound C1=CC=C2SC(O)=NC2=C1 YEDUAINPPJYDJZ-UHFFFAOYSA-N 0.000 description 1
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QGNQEODJYRGEJX-UHFFFAOYSA-N 4h-isoquinoline-1,3-dione Chemical compound C1=CC=C2C(=O)NC(=O)CC2=C1 QGNQEODJYRGEJX-UHFFFAOYSA-N 0.000 description 1
229940118148 Aldose reductase inhibitor Drugs 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
QGZKDVFQNNGYKY-UHFFFAOYSA-O Ammonium Chemical compound [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 description 1
VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 1
229910014033 C-OH Inorganic materials 0.000 description 1
OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
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229910014570 C—OH Inorganic materials 0.000 description 1
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PQBAWAQIRZIWIV-UHFFFAOYSA-N N-methylpyridinium Chemical compound C[N+]1=CC=CC=C1 PQBAWAQIRZIWIV-UHFFFAOYSA-N 0.000 description 1
241000283973 Oryctolagus cuniculus Species 0.000 description 1
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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
GSEJCLTVZPLZKY-UHFFFAOYSA-N Triethanolamine Chemical compound OCCN(CCO)CCO GSEJCLTVZPLZKY-UHFFFAOYSA-N 0.000 description 1
238000002441 X-ray diffraction Methods 0.000 description 1
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 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
150000007513 acids Chemical class 0.000 description 1
229910052783 alkali metal Inorganic materials 0.000 description 1
150000001340 alkali metals Chemical class 0.000 description 1
229910052784 alkaline earth metal Inorganic materials 0.000 description 1
150000001342 alkaline earth metals Chemical class 0.000 description 1
125000005263 alkylenediamine group Chemical group 0.000 description 1
239000000908 ammonium hydroxide Substances 0.000 description 1
150000003863 ammonium salts Chemical class 0.000 description 1
239000000872 buffer Substances 0.000 description 1
244000309464 bull Species 0.000 description 1
239000011575 calcium Substances 0.000 description 1
229910052791 calcium Inorganic materials 0.000 description 1
125000001589 carboacyl group Chemical group 0.000 description 1
150000001721 carbon Chemical group 0.000 description 1
150000004649 carbonic acid derivatives Chemical class 0.000 description 1
239000000969 carrier Substances 0.000 description 1
230000003197 catalytic effect Effects 0.000 description 1
230000008859 change Effects 0.000 description 1
BJDCWCLMFKKGEE-CMDXXVQNSA-N chembl252518 Chemical compound C([C@@](OO1)(C)O2)C[C@H]3[C@H](C)CC[C@@H]4[C@@]31[C@@H]2O[C@H](O)[C@@H]4C BJDCWCLMFKKGEE-CMDXXVQNSA-N 0.000 description 1
239000003153 chemical reaction reagent Substances 0.000 description 1
125000001309 chloro group Chemical group Cl* 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
210000000695 crystalline len Anatomy 0.000 description 1
125000004122 cyclic group Chemical group 0.000 description 1
230000002939 deleterious effect Effects 0.000 description 1
230000001627 detrimental effect Effects 0.000 description 1
201000007025 diabetic cataract Diseases 0.000 description 1
HPNMFZURTQLUMO-UHFFFAOYSA-N diethylamine Chemical compound CCNCC HPNMFZURTQLUMO-UHFFFAOYSA-N 0.000 description 1
239000003085 diluting agent Substances 0.000 description 1
230000003467 diminishing effect Effects 0.000 description 1
239000006185 dispersion Substances 0.000 description 1
238000010828 elution Methods 0.000 description 1
125000003754 ethoxycarbonyl group Chemical group C(=O)(OCC)* 0.000 description 1
239000011521 glass Substances 0.000 description 1
MNQZXJOMYWMBOU-UHFFFAOYSA-N glyceraldehyde Chemical compound OCC(O)C=O MNQZXJOMYWMBOU-UHFFFAOYSA-N 0.000 description 1
XLYOFNOQVPJJNP-UHFFFAOYSA-M hydroxide Chemical compound [OH-] XLYOFNOQVPJJNP-UHFFFAOYSA-M 0.000 description 1
150000004679 hydroxides Chemical class 0.000 description 1
125000004356 hydroxy functional group Chemical group O* 0.000 description 1
NPZTUJOABDZTLV-UHFFFAOYSA-N hydroxybenzotriazole Substances O=C1C=CC=C2NNN=C12 NPZTUJOABDZTLV-UHFFFAOYSA-N 0.000 description 1
238000001727 in vivo Methods 0.000 description 1
239000003701 inert diluent Substances 0.000 description 1
206010023365 keratopathy Diseases 0.000 description 1
210000003734 kidney Anatomy 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
229910052749 magnesium Inorganic materials 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
NNCAWEWCFVZOGF-UHFFFAOYSA-N mepiquat Chemical class C[N+]1(C)CCCCC1 NNCAWEWCFVZOGF-UHFFFAOYSA-N 0.000 description 1
208000030159 metabolic disease Diseases 0.000 description 1
MYWUZJCMWCOHBA-VIFPVBQESA-N methamphetamine Chemical compound CN[C@@H](C)CC1=CC=CC=C1 MYWUZJCMWCOHBA-VIFPVBQESA-N 0.000 description 1
PWYBXPPFFBXAOJ-UHFFFAOYSA-N methyl 4-chloro-2-(2-methoxy-2-oxoethyl)benzoate Chemical compound COC(=O)CC1=CC(Cl)=CC=C1C(=O)OC PWYBXPPFFBXAOJ-UHFFFAOYSA-N 0.000 description 1
239000002480 mineral oil Substances 0.000 description 1
235000010446 mineral oil Nutrition 0.000 description 1
230000004048 modification Effects 0.000 description 1
238000012986 modification Methods 0.000 description 1
238000012544 monitoring process Methods 0.000 description 1
125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
238000006386 neutralization reaction Methods 0.000 description 1
239000002997 ophthalmic solution Substances 0.000 description 1
239000012044 organic layer Substances 0.000 description 1
239000003960 organic solvent Substances 0.000 description 1
KVNYFPKFSJIPBJ-UHFFFAOYSA-N ortho-diethylbenzene Natural products CCC1=CC=CC=C1CC KVNYFPKFSJIPBJ-UHFFFAOYSA-N 0.000 description 1
230000037361 pathway Effects 0.000 description 1
210000000578 peripheral nerve Anatomy 0.000 description 1
239000003208 petroleum Substances 0.000 description 1
239000008024 pharmaceutical diluent Substances 0.000 description 1
239000000825 pharmaceutical preparation Substances 0.000 description 1
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
125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
VLCMRTMCMQJSKM-UHFFFAOYSA-N phenyl-[4-phenyl-8-(trifluoromethyl)quinolin-3-yl]methanone Chemical compound C=1C=CC=CC=1C(=O)C1=CN=C2C(C(F)(F)F)=CC=CC2=C1C1=CC=CC=C1 VLCMRTMCMQJSKM-UHFFFAOYSA-N 0.000 description 1
239000006187 pill Substances 0.000 description 1
239000011591 potassium Substances 0.000 description 1
229910052700 potassium Inorganic materials 0.000 description 1
239000002244 precipitate Substances 0.000 description 1
238000002953 preparative HPLC Methods 0.000 description 1
230000002265 prevention Effects 0.000 description 1
239000000047 product Substances 0.000 description 1
230000002035 prolonged effect Effects 0.000 description 1
230000000069 prophylactic effect Effects 0.000 description 1
UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
230000005855 radiation Effects 0.000 description 1
150000003254 radicals Chemical class 0.000 description 1
239000011541 reaction mixture Substances 0.000 description 1
230000009467 reduction Effects 0.000 description 1
229910052708 sodium Inorganic materials 0.000 description 1
229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
235000017557 sodium bicarbonate Nutrition 0.000 description 1
229910000029 sodium carbonate Inorganic materials 0.000 description 1
239000012312 sodium hydride Substances 0.000 description 1
159000000000 sodium salts Chemical class 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
239000003826 tablet Substances 0.000 description 1
WMOVHXAZOJBABW-UHFFFAOYSA-N tert-butyl acetate Chemical compound CC(=O)OC(C)(C)C WMOVHXAZOJBABW-UHFFFAOYSA-N 0.000 description 1
238000012360 testing method Methods 0.000 description 1
238000012956 testing procedure Methods 0.000 description 1
125000003698 tetramethyl group Chemical group [H]C([H])([H])* 0.000 description 1
230000001225 therapeutic effect Effects 0.000 description 1
238000002560 therapeutic procedure Methods 0.000 description 1
229960002277 tolazamide Drugs 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
229960005371 tolbutamide Drugs 0.000 description 1
238000011200 topical administration Methods 0.000 description 1
230000009466 transformation Effects 0.000 description 1
238000000844 transformation Methods 0.000 description 1
125000005270 trialkylamine group Chemical group 0.000 description 1
208000019553 vascular disease Diseases 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
- C07D471/10—Spiro-condensed systems
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P13/00—Drugs for disorders of the urinary system
- A61P13/02—Drugs for disorders of the urinary system of urine or of the urinary tract, e.g. urine acidifiers
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P15/00—Drugs for genital or sexual disorders; Contraceptives
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P27/00—Drugs for disorders of the senses
- A61P27/02—Ophthalmic agents
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
- 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
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

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Health & Medical Sciences (AREA)
Organic Chemistry (AREA)
Chemical & Material Sciences (AREA)
Engineering & Computer Science (AREA)
Life Sciences & Earth Sciences (AREA)
Bioinformatics & Cheminformatics (AREA)
Public Health (AREA)
Animal Behavior & Ethology (AREA)
Veterinary Medicine (AREA)
Chemical Kinetics & Catalysis (AREA)
General Chemical & Material Sciences (AREA)
Medicinal Chemistry (AREA)
Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
General Health & Medical Sciences (AREA)
Pharmacology & Pharmacy (AREA)
Diabetes (AREA)
Endocrinology (AREA)
Obesity (AREA)
Hematology (AREA)
Emergency Medicine (AREA)
Biomedical Technology (AREA)
Neurology (AREA)
Neurosurgery (AREA)
Ophthalmology & Optometry (AREA)
Urology & Nephrology (AREA)
Reproductive Health (AREA)
Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Nitrogen Condensed Heterocyclic Rings (AREA)
Other In-Based Heterocyclic Compounds (AREA)
Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)

IL9205489A 1988-10-20 1989-10-19 Spiro-isoquinoline-pyrrolidine tetra and their analogues, their preparations and pharmaceutical preparations containing them IL92054A (en)

Applications Claiming Priority (2)

Application Number	Priority Date	Filing Date	Title
US26043488A	1988-10-20	1988-10-20
US07/357,563 US4927831A (en)	1988-10-20	1989-05-26	Spiro-isoquinoline-pyrrolidine tetrones and analogs thereof useful as aldose reductase inhibitors

Publications (2)

Publication Number	Publication Date
IL92054A0 IL92054A0 (en)	1990-07-12
IL92054A true IL92054A (en)	1994-07-31

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ID=26947989

Family Applications (1)

Application Number	Title	Priority Date	Filing Date
IL9205489A IL92054A (en)	1988-10-20	1989-10-19	Spiro-isoquinoline-pyrrolidine tetra and their analogues, their preparations and pharmaceutical preparations containing them

Country Status (9)

Country	Link
US (1)	US4927831A (da)
JP (1)	JP2888559B2 (da)
KR (1)	KR0143998B1 (da)
CA (1)	CA1337351C (da)
DK (1)	DK170702B1 (da)
HU (1)	HU206211B (da)
IL (1)	IL92054A (da)
PH (1)	PH27278A (da)
PT (1)	PT92025B (da)

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US5428066A (en) *	1989-03-08	1995-06-27	Larner; Joseph	Method of reducing elevated blood sugar in humans
US5037831A (en) *	1990-05-21	1991-08-06	American Home Products Corporation	Spiro-isoquinoline-pyrrolidines and analogs thereof useful as aldose reductase inhibitors
US5093496A (en) *	1990-05-21	1992-03-03	American Home Products Corporation	Spiro-isoquinoline-pyrrolidines and analogs thereof useful as aldose reductase inhibitors
US5045544A (en) *	1990-05-21	1991-09-03	American Home Products Corporation	N'-alkyl-spiro-isoquinoline-pyrrolidine tetrones and analogs thereof useful as aldose reductase inhibitors
US5068332A (en) *	1990-10-12	1991-11-26	American Home Products Corporation	Alkylidene analogs of 1'-aminospiro[isoquinoline-4(1H),3'-pyrrolidine]-1,2',3,5'(2H)-tetrones useful as aldose reductase inhibitors
US5081241A (en) *	1990-10-11	1992-01-14	American Home Products Corporation	Spiro-pyridazines and analogs thereof useful as aldose reductase inhibitors
US5102886A (en) *	1990-10-12	1992-04-07	American Home Products Corporation	1'-aminospiro[isoquinoline-4(1H),3'-pyrrolidine]-1,2',3,5'(2H)-tetrones and analogs thereof useful as aldose reductase inhibitors
US5130425A (en) *	1990-10-12	1992-07-14	American Home Products Corporation	Spiro-lactams and analogs thereof useful as aldose reductase inhibitors
US5169948A (en) *	1991-05-22	1992-12-08	American Home Products Corporation	Process and intermediates for the preparation of spiro[isoquinoline-4(1H),3-pyrrolidine]1,2,3,5 (2H)-tetrones which are useful as aldose reductase inhibitors
US5106978A (en) *	1991-05-22	1992-04-21	American Home Products Corporation	Process and intermediates for the preparation of spiro(isoquinoline-4(1H), 3'-pyrrolidine)-1,2', 3,5'(2H)-tetrones which are useful as aldose reductase inhibitors
US6384013B1 (en)	1992-03-19	2002-05-07	Eli Lilly And Company	Cyclic peptide antifungal agents and process for preparation thereof
US6743777B1 (en) *	1992-03-19	2004-06-01	Eli Lilly And Company	Cyclic peptide antifungal agents and process for preparation thereof
US5221686A (en) *	1992-08-04	1993-06-22	American Home Products Corporation	Spiro[1,2-benzisothiazole-3(2H),5'-oxazolidine]-2',4'-dione 1,1-dioxides as antihyperglycemic agents
CZ299018B6 (cs) *	1997-10-20	2008-04-02	Dainippon Sumitomo Pharma Co., Ltd.	Rychlerozpustný farmaceutický prípravek
KR20020003864A (ko) *	1999-03-03	2002-01-15	피터 지. 스트링거	에키노칸딘/탄수화물 착물
ATE294571T1 (de) *	1999-03-03	2005-05-15	Lilly Co Eli	Echinocandin pharmazeutische zusammensetzungen
US6991800B2 (en) *	2002-06-13	2006-01-31	Vicuron Pharmaceuticals Inc.	Antifungal parenteral products
US6777048B2 (en)	2002-12-18	2004-08-17	Eastman Chemical Company	Polyester compositions containing silicon carbide
ES2385219T3 (es) *	2003-09-12	2012-07-19	Merck Serono Sa	Derivados de sulfonamida para el tratamiento de diabetes
HRP20070527T3 (en) *	2003-09-12	2007-12-31	Laboratoires Serono Sa	Benzothiazole derivatives for the treatment of diabetes
AU2005231980B2 (en) *	2004-04-07	2011-09-08	Merck Serono Sa	1,1'-(1,2-ethynediyl)bis-benzene derivatives as PTP 1-B inhibitors
MX2007000976A (es) *	2004-08-12	2007-04-10	Wyeth Corp	Tratamiento combinado para diabetes, obesidad y enfermedades cardiovasculares utilizando inhibidores del factor 8 de crecimiento y diferenciacion.

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JPS5241587U (da) *	1975-09-18	1977-03-24
JPS5241586U (da) *	1975-09-18	1977-03-24
FR2525603A1 (fr) *	1982-04-27	1983-10-28	Adir	Benzoazacycloalkyl-spiro-imidazolinines, leur preparation et leur application en therapeutique
FR2544317B2 (fr) *	1983-04-12	1985-07-05	Adir	Benzoazacycloalkyl-spiro-imidazolidines et les compositions pharmaceutiques les contenant

1989
- 1989-05-26 US US07/357,563 patent/US4927831A/en not_active Expired - Lifetime
- 1989-09-27 CA CA000613705A patent/CA1337351C/en not_active Expired - Fee Related
- 1989-10-17 HU HU895335A patent/HU206211B/hu not_active IP Right Cessation
- 1989-10-17 JP JP1271423A patent/JP2888559B2/ja not_active Expired - Fee Related
- 1989-10-17 PH PH39372A patent/PH27278A/en unknown
- 1989-10-18 PT PT92025A patent/PT92025B/pt not_active IP Right Cessation
- 1989-10-19 KR KR1019890015023A patent/KR0143998B1/ko not_active Expired - Fee Related
- 1989-10-19 IL IL9205489A patent/IL92054A/en not_active IP Right Cessation
- 1989-10-19 DK DK519189A patent/DK170702B1/da active IP Right Grant

Also Published As

Publication number	Publication date
PH27278A (en)	1993-05-04
DK170702B1 (da)	1995-12-11
HUT52775A (en)	1990-08-28
HU895335D0 (en)	1990-01-28
PT92025A (pt)	1990-04-30
DK519189A (da)	1990-04-21
JPH02164880A (ja)	1990-06-25
CA1337351C (en)	1995-10-17
DK519189D0 (da)	1989-10-19
JP2888559B2 (ja)	1999-05-10
KR0143998B1 (ko)	1998-07-15
PT92025B (pt)	1995-07-18
US4927831A (en)	1990-05-22
HU206211B (en)	1992-09-28
IL92054A0 (en)	1990-07-12
KR900006334A (ko)	1990-05-07

Legal Events

Date	Code	Title
2000-06-01	KB	Patent renewed
2002-09-12	HCA	Change of name of proprietor(s) after amalgamation
2003-12-10	KB	Patent renewed
2008-08-10	MM9K	Patent not in force due to non-payment of renewal fees

Publication	Publication Date	Title
US4927831A (en)	1990-05-22	Spiro-isoquinoline-pyrrolidine tetrones and analogs thereof useful as aldose reductase inhibitors
EP0365324B1 (en)	1994-05-04	Spiro-isoquinoline-pyrrolidine tetrones and analogs thereof useful as aldose reductase inhibitors
US5037831A (en)	1991-08-06	Spiro-isoquinoline-pyrrolidines and analogs thereof useful as aldose reductase inhibitors
HK1004067B (en)	1998-11-13	Spiro-isoquinoline-pyrrolidines and analogs thereof useful as aldose reductase inhibitors
CA2093793C (en)	2001-08-21	Alkylidene analogs of 1'-aminospiro¬isoquinoline-4(1h),-3'-pyrrolidine\|1,2',3,5'(2h)-tetrones useful as aldose reductase inhibitors
US5045544A (en)	1991-09-03	N'-alkyl-spiro-isoquinoline-pyrrolidine tetrones and analogs thereof useful as aldose reductase inhibitors
CA2093794C (en)	2002-01-22	1'-aminospiro¬isoquinoline-4(1h),3-pyrrolidine\|-1,2',3,5'-(2h)-tetrones and analogs thereof useful as aldose reductase inhibitors
US5130425A (en)	1992-07-14	Spiro-lactams and analogs thereof useful as aldose reductase inhibitors
US5482968A (en)	1996-01-09	Naphthalenylmethyl cycloalkenone acetic acids 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
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
US5093496A (en)	1992-03-03	Spiro-isoquinoline-pyrrolidines and analogs thereof useful as aldose reductase inhibitors
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
GB2252321A (en)	1992-08-05	Isoquinoline intermediates preparation
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
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
CA2324636A1 (en)	1991-11-22	1, 2, 3, 4 - tetrahydro - 1, 3 - dioxo - 4 - isoquinolinecarboxylic acid methyl esters
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