IL99064A - 3-[1-azabicyloalkano[1,2-a] indolyl]-4- (1h-indol-3-yl)-1h-pyrrole-2,5- dione derivatives their preparation and pharmaceutical compositions containing them and certain novel intermediates therefor - Google Patents

3-[1-azabicyloalkano[1,2-a] indolyl]-4- (1h-indol-3-yl)-1h-pyrrole-2,5- dione derivatives their preparation and pharmaceutical compositions containing them and certain novel intermediates therefor

Info

Publication number: IL99064A
Authority: IL; Israel
Prior art keywords: solution; methyl; stands; alkyl; bond
Prior art date: 1990-08-07

Application number

IL9906491A

Other languages

English (en)

Hebrew (he)

Other versions

IL99064A0 (en

Original Assignee

Hoffmann La Roche

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.)

1990-08-07

Filing date

1991-08-02

Publication date

1995-08-31

1990-08-07 Priority claimed from GB909017269A external-priority patent/GB9017269D0/en

1991-05-08 Priority claimed from GB919109959A external-priority patent/GB9109959D0/en

1991-08-02 Application filed by Hoffmann La Roche filed Critical Hoffmann La Roche

1992-07-15 Publication of IL99064A0 publication Critical patent/IL99064A0/xx

1995-08-31 Publication of IL99064A publication Critical patent/IL99064A/en

Links

239000000825 pharmaceutical preparation Substances 0.000 title description 6
239000000543 intermediate Substances 0.000 title description 3
238000002360 preparation method Methods 0.000 title description 3
125000001041 indolyl group Chemical group 0.000 title description 2
150000001875 compounds Chemical class 0.000 claims abstract description 62
239000001257 hydrogen Substances 0.000 claims abstract description 44
229910052739 hydrogen Inorganic materials 0.000 claims abstract description 44
150000003839 salts Chemical class 0.000 claims abstract description 30
125000000217 alkyl group Chemical group 0.000 claims abstract description 29
125000003710 aryl alkyl group Chemical group 0.000 claims abstract description 15
-1 nitro, amino Chemical group 0.000 claims abstract description 14
150000007513 acids Chemical class 0.000 claims abstract description 13
239000002253 acid Substances 0.000 claims abstract description 12
UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims abstract description 11
229910052736 halogen Inorganic materials 0.000 claims abstract description 9
150000002367 halogens Chemical class 0.000 claims abstract description 9
208000030507 AIDS Diseases 0.000 claims abstract description 8
208000002249 Diabetes Complications Diseases 0.000 claims abstract description 8
206010012655 Diabetic complications Diseases 0.000 claims abstract description 8
125000003545 alkoxy group Chemical group 0.000 claims abstract description 8
208000006673 asthma Diseases 0.000 claims abstract description 8
150000007514 bases Chemical class 0.000 claims abstract description 8
125000001589 carboacyl group Chemical group 0.000 claims abstract description 8
230000003779 hair growth Effects 0.000 claims abstract description 8
125000001188 haloalkyl group Chemical group 0.000 claims abstract description 7
230000001900 immune effect Effects 0.000 claims abstract description 7
230000000638 stimulation Effects 0.000 claims abstract description 7
230000000771 oncological effect Effects 0.000 claims abstract description 6
208000024172 Cardiovascular disease Diseases 0.000 claims abstract description 5
125000005239 aroylamino group Chemical group 0.000 claims abstract description 5
230000002757 inflammatory effect Effects 0.000 claims abstract description 5
125000005236 alkanoylamino group Chemical group 0.000 claims abstract description 4
125000004390 alkyl sulfonyl group Chemical group 0.000 claims abstract description 4
125000004414 alkyl thio group Chemical group 0.000 claims abstract description 4
OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 186
FFUAGWLWBBFQJT-UHFFFAOYSA-N hexamethyldisilazane Chemical compound C[Si](C)(C)N[Si](C)(C)C FFUAGWLWBBFQJT-UHFFFAOYSA-N 0.000 claims description 23
125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 20
238000000034 method Methods 0.000 claims description 17
QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 claims description 15
125000004453 alkoxycarbonyl group Chemical group 0.000 claims description 11
125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 11
239000003814 drug Substances 0.000 claims description 10
238000004519 manufacturing process Methods 0.000 claims description 10
239000013543 active substance Substances 0.000 claims description 6
239000007795 chemical reaction product Substances 0.000 claims description 6
125000005161 aryl oxy carbonyl 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
229910021529 ammonia Inorganic materials 0.000 claims description 3
125000003435 aroyl group Chemical group 0.000 claims description 3
125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 claims description 3
239000012876 carrier material Substances 0.000 claims description 3
230000002526 effect on cardiovascular system Effects 0.000 claims description 3
125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 3
125000001424 substituent group Chemical group 0.000 claims description 3
125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 2
239000000126 substance Substances 0.000 claims description 2
230000003110 anti-inflammatory effect Effects 0.000 claims 2
229940000033 dermatological agent Drugs 0.000 claims 1
125000003884 phenylalkyl group Chemical group 0.000 claims 1
150000002431 hydrogen Chemical class 0.000 abstract description 14
IAODRFIZLKITMK-UHFFFAOYSA-N furan-2,3-dione Chemical class O=C1OC=CC1=O IAODRFIZLKITMK-UHFFFAOYSA-N 0.000 abstract description 11
230000002265 prevention Effects 0.000 abstract description 8
XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 225
YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 219
239000000243 solution Substances 0.000 description 169
SIKJAQJRHWYJAI-UHFFFAOYSA-N Indole Chemical compound C1=CC=C2NC=CC2=C1 SIKJAQJRHWYJAI-UHFFFAOYSA-N 0.000 description 86
ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 82
239000000203 mixture Substances 0.000 description 80
RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 78
238000002844 melting Methods 0.000 description 74
230000008018 melting Effects 0.000 description 74
VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 73
XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 69
239000000047 product Substances 0.000 description 65
ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 63
239000002904 solvent Substances 0.000 description 48
LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 45
WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 41
VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 38
QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 37
VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 35
238000010828 elution Methods 0.000 description 35
239000000741 silica gel Substances 0.000 description 35
229910002027 silica gel Inorganic materials 0.000 description 35
238000004587 chromatography analysis Methods 0.000 description 31
239000000284 extract Substances 0.000 description 30
PZOUSPYUWWUPPK-UHFFFAOYSA-N indole Natural products CC1=CC=CC2=C1C=CN2 PZOUSPYUWWUPPK-UHFFFAOYSA-N 0.000 description 30
RKJUIXBNRJVNHR-UHFFFAOYSA-N indolenine Natural products C1=CC=C2CC=NC2=C1 RKJUIXBNRJVNHR-UHFFFAOYSA-N 0.000 description 30
FPYJFEHAWHCUMM-UHFFFAOYSA-N maleic anhydride Chemical compound O=C1OC(=O)C=C1 FPYJFEHAWHCUMM-UHFFFAOYSA-N 0.000 description 30
230000002829 reductive effect Effects 0.000 description 30
239000012299 nitrogen atmosphere Substances 0.000 description 27
238000010992 reflux Methods 0.000 description 26
FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 24
HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 24
UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 23
239000000725 suspension Substances 0.000 description 23
238000001704 evaporation Methods 0.000 description 22
230000008020 evaporation Effects 0.000 description 22
239000007787 solid Substances 0.000 description 21
229940086542 triethylamine Drugs 0.000 description 21
CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 description 20
YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 20
239000012047 saturated solution Substances 0.000 description 17
239000007858 starting material Substances 0.000 description 17
IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 16
229910000041 hydrogen chloride Inorganic materials 0.000 description 16
239000002244 precipitate Substances 0.000 description 16
YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 15
239000000706 filtrate Substances 0.000 description 14
CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 12
WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 description 12
DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 12
239000011780 sodium chloride Substances 0.000 description 12
125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 11
239000012074 organic phase Substances 0.000 description 11
KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 10
238000002425 crystallisation Methods 0.000 description 10
230000008025 crystallization Effects 0.000 description 10
WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 9
238000000354 decomposition reaction Methods 0.000 description 9
239000003921 oil Substances 0.000 description 9
235000019198 oils Nutrition 0.000 description 9
VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 8
DTQVDTLACAAQTR-UHFFFAOYSA-M Trifluoroacetate Chemical compound [O-]C(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-M 0.000 description 8
125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 8
229910000030 sodium bicarbonate Inorganic materials 0.000 description 8
235000017557 sodium bicarbonate Nutrition 0.000 description 8
DYHSDKLCOJIUFX-UHFFFAOYSA-N tert-butoxycarbonyl anhydride Chemical compound CC(C)(C)OC(=O)OC(=O)OC(C)(C)C DYHSDKLCOJIUFX-UHFFFAOYSA-N 0.000 description 8
IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 7
BDAGIHXWWSANSR-UHFFFAOYSA-M Formate Chemical compound [O-]C=O BDAGIHXWWSANSR-UHFFFAOYSA-M 0.000 description 7
239000002775 capsule Substances 0.000 description 7
239000000969 carrier Substances 0.000 description 7
239000003054 catalyst Substances 0.000 description 7
238000006243 chemical reaction Methods 0.000 description 7
RWRDLPDLKQPQOW-UHFFFAOYSA-N tetrahydropyrrole Substances C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 description 7
WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 6
KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 6
239000007868 Raney catalyst Substances 0.000 description 6
NPXOKRUENSOPAO-UHFFFAOYSA-N Raney nickel Chemical compound [Al].[Ni] NPXOKRUENSOPAO-UHFFFAOYSA-N 0.000 description 6
229910000564 Raney nickel Inorganic materials 0.000 description 6
238000003776 cleavage reaction Methods 0.000 description 6
230000007017 scission Effects 0.000 description 6
238000003756 stirring Methods 0.000 description 6
NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical class [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 5
KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 5
VZTDIZULWFCMLS-UHFFFAOYSA-N ammonium formate Chemical compound [NH4+].[O-]C=O VZTDIZULWFCMLS-UHFFFAOYSA-N 0.000 description 5
239000012280 lithium aluminium hydride Substances 0.000 description 5
239000003960 organic solvent Substances 0.000 description 5
239000012312 sodium hydride Substances 0.000 description 5
229910000104 sodium hydride Inorganic materials 0.000 description 5
QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 4
HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 4
239000001828 Gelatine Substances 0.000 description 4
JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 4
229920000159 gelatin Polymers 0.000 description 4
235000019322 gelatine Nutrition 0.000 description 4
239000002480 mineral oil Substances 0.000 description 4
235000010446 mineral oil Nutrition 0.000 description 4
239000003208 petroleum Substances 0.000 description 4
229920005862 polyol Polymers 0.000 description 4
150000003077 polyols Chemical class 0.000 description 4
229920006395 saturated elastomer Polymers 0.000 description 4
HZAXFHJVJLSVMW-UHFFFAOYSA-N 2-Aminoethan-1-ol Chemical compound NCCO HZAXFHJVJLSVMW-UHFFFAOYSA-N 0.000 description 3
ATRRKUHOCOJYRX-UHFFFAOYSA-N Ammonium bicarbonate Chemical compound [NH4+].OC([O-])=O ATRRKUHOCOJYRX-UHFFFAOYSA-N 0.000 description 3
UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
229920002261 Corn starch Polymers 0.000 description 3
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 3
235000019759 Maize starch Nutrition 0.000 description 3
239000001099 ammonium carbonate Substances 0.000 description 3
235000012501 ammonium carbonate Nutrition 0.000 description 3
125000004432 carbon atom Chemical group C* 0.000 description 3
238000001816 cooling Methods 0.000 description 3
UAOMVDZJSHZZME-UHFFFAOYSA-N diisopropylamine Chemical compound CC(C)NC(C)C UAOMVDZJSHZZME-UHFFFAOYSA-N 0.000 description 3
239000004615 ingredient Substances 0.000 description 3
239000008101 lactose Substances 0.000 description 3
239000012044 organic layer Substances 0.000 description 3
239000011541 reaction mixture Substances 0.000 description 3
239000012279 sodium borohydride Substances 0.000 description 3
229910000033 sodium borohydride Inorganic materials 0.000 description 3
239000000454 talc Substances 0.000 description 3
229910052623 talc Inorganic materials 0.000 description 3
238000005406 washing Methods 0.000 description 3
RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 2
IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
FPQTVZNFABWSMU-UHFFFAOYSA-N Cl.O=C1OC=CC1=O Chemical compound Cl.O=C1OC=CC1=O FPQTVZNFABWSMU-UHFFFAOYSA-N 0.000 description 2
XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 description 2
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 2
PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 2
WTDHULULXKLSOZ-UHFFFAOYSA-N Hydroxylamine hydrochloride Chemical compound Cl.ON WTDHULULXKLSOZ-UHFFFAOYSA-N 0.000 description 2
BAPJBEWLBFYGME-UHFFFAOYSA-N Methyl acrylate Chemical compound COC(=O)C=C BAPJBEWLBFYGME-UHFFFAOYSA-N 0.000 description 2
JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 2
MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 2
RKOTXQYWCBGZLP-UHFFFAOYSA-N N-[(2,4-difluorophenyl)methyl]-2-ethyl-9-hydroxy-3-methoxy-1,8-dioxospiro[3H-pyrido[1,2-a]pyrazine-4,3'-oxolane]-7-carboxamide Chemical compound CCN1C(OC)C2(CCOC2)N2C=C(C(=O)NCC3=C(F)C=C(F)C=C3)C(=O)C(O)=C2C1=O RKOTXQYWCBGZLP-UHFFFAOYSA-N 0.000 description 2
GMNVCNOFNRXPJF-UHFFFAOYSA-N OC=O.N1=CC=CC2=C(NC=C3)C3=CC=C21 Chemical compound OC=O.N1=CC=CC2=C(NC=C3)C3=CC=C21 GMNVCNOFNRXPJF-UHFFFAOYSA-N 0.000 description 2
PXIPVTKHYLBLMZ-UHFFFAOYSA-N Sodium azide Chemical compound [Na+].[N-]=[N+]=[N-] PXIPVTKHYLBLMZ-UHFFFAOYSA-N 0.000 description 2
150000001338 aliphatic hydrocarbons Chemical class 0.000 description 2
230000029936 alkylation Effects 0.000 description 2
238000005804 alkylation reaction Methods 0.000 description 2
235000019270 ammonium chloride Nutrition 0.000 description 2
HUMNYLRZRPPJDN-UHFFFAOYSA-N benzaldehyde Chemical compound O=CC1=CC=CC=C1 HUMNYLRZRPPJDN-UHFFFAOYSA-N 0.000 description 2
WGQKYBSKWIADBV-UHFFFAOYSA-N benzylamine Chemical compound NCC1=CC=CC=C1 WGQKYBSKWIADBV-UHFFFAOYSA-N 0.000 description 2
UORVGPXVDQYIDP-UHFFFAOYSA-N borane Chemical compound B UORVGPXVDQYIDP-UHFFFAOYSA-N 0.000 description 2
125000004744 butyloxycarbonyl group Chemical group 0.000 description 2
MVPPADPHJFYWMZ-UHFFFAOYSA-N chlorobenzene Chemical compound ClC1=CC=CC=C1 MVPPADPHJFYWMZ-UHFFFAOYSA-N 0.000 description 2
238000006264 debenzylation reaction Methods 0.000 description 2
125000004177 diethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 2
239000006185 dispersion Substances 0.000 description 2
239000008298 dragée Substances 0.000 description 2
PQJJJMRNHATNKG-UHFFFAOYSA-N ethyl bromoacetate Chemical compound CCOC(=O)CBr PQJJJMRNHATNKG-UHFFFAOYSA-N 0.000 description 2
239000003925 fat Substances 0.000 description 2
239000008103 glucose Substances 0.000 description 2
238000002347 injection Methods 0.000 description 2
239000007924 injection Substances 0.000 description 2
239000012948 isocyanate Substances 0.000 description 2
150000002513 isocyanates Chemical class 0.000 description 2
239000007788 liquid Substances 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
BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 2
UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 2
239000000829 suppository Substances 0.000 description 2
LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 description 2
VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 description 2
238000001665 trituration Methods 0.000 description 2
235000015112 vegetable and seed oil Nutrition 0.000 description 2
239000008158 vegetable oil Substances 0.000 description 2
239000001993 wax Substances 0.000 description 2
KBSBQLOHOJDZCR-UHFFFAOYSA-N (1-benzyl-5-oxopyrrolidin-3-yl) 4-methylbenzenesulfonate Chemical compound C1=CC(C)=CC=C1S(=O)(=O)OC1CC(=O)N(CC=2C=CC=CC=2)C1 KBSBQLOHOJDZCR-UHFFFAOYSA-N 0.000 description 1
MRQAYFYTWNIVFN-UHFFFAOYSA-N (5-methylpyridin-3-yl)methanol Chemical compound CC1=CN=CC(CO)=C1 MRQAYFYTWNIVFN-UHFFFAOYSA-N 0.000 description 1
KYVBNYUBXIEUFW-UHFFFAOYSA-N 1,1,3,3-tetramethylguanidine Chemical compound CN(C)C(=N)N(C)C KYVBNYUBXIEUFW-UHFFFAOYSA-N 0.000 description 1
125000001088 1-naphthoyl group Chemical group C1(=CC=CC2=CC=CC=C12)C(=O)* 0.000 description 1
QOPBEBWGSGFROG-UHFFFAOYSA-N 2-(1h-indol-2-yl)acetic acid Chemical compound C1=CC=C2NC(CC(=O)O)=CC2=C1 QOPBEBWGSGFROG-UHFFFAOYSA-N 0.000 description 1
VZSRBBMJRBPUNF-UHFFFAOYSA-N 2-(2,3-dihydro-1H-inden-2-ylamino)-N-[3-oxo-3-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)propyl]pyrimidine-5-carboxamide Chemical compound C1C(CC2=CC=CC=C12)NC1=NC=C(C=N1)C(=O)NCCC(N1CC2=C(CC1)NN=N2)=O VZSRBBMJRBPUNF-UHFFFAOYSA-N 0.000 description 1
125000003541 2-chlorobenzoyl group Chemical group ClC1=C(C(=O)*)C=CC=C1 0.000 description 1
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Classifications

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- 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
- C07D471/12—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 three hetero rings
- C07D471/20—Spiro-condensed systems
- 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
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- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
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- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
- 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
- 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
- C07D471/12—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 three hetero rings
- C07D471/14—Ortho-condensed systems

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Endocrinology (AREA)
Heart & Thoracic Surgery (AREA)
Obesity (AREA)
Oncology (AREA)
Communicable Diseases (AREA)
Urology & Nephrology (AREA)
AIDS & HIV (AREA)
Tropical Medicine & Parasitology (AREA)
Molecular Biology (AREA)
Rheumatology (AREA)
Pain & Pain Management (AREA)
Vascular Medicine (AREA)
Pulmonology (AREA)
Dermatology (AREA)
Epidemiology (AREA)
Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Nitrogen Condensed Heterocyclic Rings (AREA)
Pyrrole Compounds (AREA)
Pyridine Compounds (AREA)
Plural Heterocyclic Compounds (AREA)

IL9906491A 1990-08-07 1991-08-02 3-[1-azabicyloalkano[1,2-a] indolyl]-4- (1h-indol-3-yl)-1h-pyrrole-2,5- dione derivatives their preparation and pharmaceutical compositions containing them and certain novel intermediates therefor IL99064A (en)

Applications Claiming Priority (2)

Application Number	Priority Date	Filing Date	Title
GB909017269A GB9017269D0 (en)	1990-08-07	1990-08-07	Substituted pyrroles
GB919109959A GB9109959D0 (en)	1991-05-08	1991-05-08	Substituted pyrroles

Publications (2)

Publication Number	Publication Date
IL99064A0 IL99064A0 (en)	1992-07-15
IL99064A true IL99064A (en)	1995-08-31

Family

ID=26297468

Family Applications (1)

Application Number	Title	Priority Date	Filing Date
IL9906491A IL99064A (en)	1990-08-07	1991-08-02	3-[1-azabicyloalkano[1,2-a] indolyl]-4- (1h-indol-3-yl)-1h-pyrrole-2,5- dione derivatives their preparation and pharmaceutical compositions containing them and certain novel intermediates therefor

Country Status (26)

Country	Link
EP (1)	EP0470490B1 (hu)
JP (1)	JPH0780880B2 (hu)
KR (1)	KR100233964B1 (hu)
AT (1)	ATE179710T1 (hu)
AU (1)	AU649699B2 (hu)
CA (1)	CA2046801C (hu)
CZ (1)	CZ280359B6 (hu)
DE (1)	DE69131190T2 (hu)
DK (1)	DK0470490T3 (hu)
DZ (1)	DZ1521A1 (hu)
ES (1)	ES2132076T3 (hu)
FI (1)	FI95909C (hu)
GR (1)	GR3030677T3 (hu)
HU (1)	HU210547B (hu)
IE (1)	IE912787A1 (hu)
IL (1)	IL99064A (hu)
IS (1)	IS1682B (hu)
MC (1)	MC2279A1 (hu)
MY (1)	MY106400A (hu)
NO (1)	NO179143C (hu)
NZ (1)	NZ239216A (hu)
PT (1)	PT98583B (hu)
RO (1)	RO112724B1 (hu)
RU (1)	RU2075474C1 (hu)
SK (1)	SK279566B6 (hu)
UA (1)	UA27100A1 (hu)

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GB9123396D0 (en) *	1991-11-04	1991-12-18	Hoffmann La Roche	A process for the manufacture of substituted maleimides
EP0630241A1 (en) *	1992-03-20	1994-12-28	The Wellcome Foundation Limited	Indole derivatives with antiviral activity
AU678435B2 (en) *	1993-05-10	1997-05-29	F. Hoffmann-La Roche Ag	Substituted pyrroles
US5721230A (en) *	1993-05-10	1998-02-24	Hoffmann-La Roche Inc.	Substituted pyrroles
US5405864A (en) *	1993-10-15	1995-04-11	Syntex (U.S.A.) Inc.	Chemotherapeutic maleimides
US5723456A (en) *	1993-12-07	1998-03-03	Eli Lilly & Company	Therapeutic treatment for cardiovascular diseases
HUT69164A (en) *	1993-12-07	1995-08-28	Lilly Co Eli	Improved process for producing bis-indolyl-maleimide derivatives
US5843935A (en) *	1993-12-07	1998-12-01	Eli Lilly And Company	Protein kinase C inhibitors
ES2162843T3 (es) *	1993-12-07	2002-01-16	Lilly Co Eli	Inhibidores de la proteina quinasa c.
US5541347A (en) *	1993-12-07	1996-07-30	Eli Lilly And Company	Synthesis of bisindolylmaleimides
US5624949A (en) *	1993-12-07	1997-04-29	Eli Lilly And Company	Protein kinase C inhibitors
US6025897A (en)	1993-12-21	2000-02-15	3M Innovative Properties Co.	Display with reflective polarizer and randomizing cavity
US6804058B1 (en)	1993-12-21	2004-10-12	3M Innovative Properties Company	Electroluminescent light source and display incorporating same
DK0817627T3 (da) *	1993-12-23	2005-06-06	Lilly Co Eli	Inhibitorer af proteinkinase C
US5491242A (en) *	1994-06-22	1996-02-13	Eli Lilly And Company	Protein kinase C inhibitors
US5481003A (en) *	1994-06-22	1996-01-02	Eli Lilly And Company	Protein kinase C inhibitors
US5554608A (en) *	1994-09-28	1996-09-10	Ahluwalia; Gurpreet S.	Inhibition of hair growth
CA2268399C (en) *	1996-10-31	2008-08-19	Harbor Branch Oceanographic Institution, Inc.	Anti-neurogenic inflammatory compounds and compositions and methods of use thereof
ATE277010T1 (de)	1998-07-08	2004-10-15	Harbor Branch Oceanographic	Bis-indolederivate und ihre verwendung als entzündungshemmende mittel
GB9828640D0 (en) *	1998-12-23	1999-02-17	Smithkline Beecham Plc	Novel method and compounds
FR2796274B1 (fr) *	1999-07-16	2001-09-21	Oreal	Utilisation de l'acide 4,6-dimethoxy-indole 2-carboxylique ou de ses derives pour stimuler ou induire la pousse des cheveux et/ou stopper leur chute
TW201041580A (en)	2001-09-27	2010-12-01	Alcon Inc	Inhibitors of glycogen synthase kinase-3 (GSK-3) for treating glaucoma
CA2393720C (en)	2002-07-12	2010-09-14	Eli Lilly And Company	Crystalline 2,5-dione-3-(1-methyl-1h-indol-3-yl)-4-[1-(pyridin-2-ylmethyl)piperidin-4-yl]-1h-indol-3-yl]-1h-pyrrole mono-hydrochloride
TWI324604B (en) *	2003-06-18	2010-05-11	Novartis Ag	New use of staurosporine derivatives
CA2533861A1 (en)	2003-08-08	2005-02-17	Novartis Ag	Combinations comprising staurosporines
EP1734952A1 (en) *	2004-04-08	2006-12-27	Novartis AG	Protein kinase c inhibitors for the treatment of autoimmune diseases and of transplant rejection
FR2870538B1 (fr) *	2004-05-19	2006-07-14	Servier Lab	Nouveaux derives de pyrrolidines et de thiazolidines, leur procede de preparation et les compositions pharmaceutiques qui les contiennent
US20170209488A1 (en)	2014-07-17	2017-07-27	Inserm (Institut National De La Sante Et De La Recherche Medicale)	Methods for treating neuromuscular junction-related diseases
WO2016207366A1 (en)	2015-06-26	2016-12-29	INSERM (Institut National de la Santé et de la Recherche Médicale)	Methods and pharmaceutical compositions for the treatment of viral infections

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* Cited by examiner, † Cited by third party
Publication number	Priority date	Publication date	Assignee	Title
CZ280738B6 (cs) *	1988-02-10	1996-04-17	F. Hoffmann - La Roche And Co., Aktiengesellschaft	Substituované pyrroly, jejich použití pro výrobu léčiv a léčiva na jejich bázi
MC2096A1 (fr) *	1989-02-23	1991-02-15	Hoffmann La Roche	Pyrroles substitues
IL94274A0 (en) *	1989-05-05	1991-03-10	Goedecke Ag	Maleinimide derivatives,process for the preparation thereof and pharmaceutical compositions containing the same

1991
- 1991-07-11 CA CA002046801A patent/CA2046801C/en not_active Expired - Fee Related
- 1991-07-17 RO RO148021A patent/RO112724B1/ro unknown
- 1991-07-30 AT AT91112829T patent/ATE179710T1/de not_active IP Right Cessation
- 1991-07-30 ES ES91112829T patent/ES2132076T3/es not_active Expired - Lifetime
- 1991-07-30 EP EP91112829A patent/EP0470490B1/en not_active Expired - Lifetime
- 1991-07-30 MC MC912209A patent/MC2279A1/xx unknown
- 1991-07-30 DE DE69131190T patent/DE69131190T2/de not_active Expired - Fee Related
- 1991-07-30 DK DK91112829T patent/DK0470490T3/da active
- 1991-08-01 NZ NZ239216A patent/NZ239216A/en unknown
- 1991-08-02 HU HU912589A patent/HU210547B/hu not_active IP Right Cessation
- 1991-08-02 IS IS3741A patent/IS1682B/is unknown
- 1991-08-02 IL IL9906491A patent/IL99064A/en unknown
- 1991-08-06 NO NO913051A patent/NO179143C/no not_active IP Right Cessation
- 1991-08-06 CZ CS912435A patent/CZ280359B6/cs not_active IP Right Cessation
- 1991-08-06 KR KR1019910013605A patent/KR100233964B1/ko not_active Expired - Fee Related
- 1991-08-06 RU SU915001208A patent/RU2075474C1/ru active
- 1991-08-06 SK SK2435-91A patent/SK279566B6/sk unknown
- 1991-08-06 IE IE278791A patent/IE912787A1/en not_active IP Right Cessation
- 1991-08-06 DZ DZ910109A patent/DZ1521A1/fr active
- 1991-08-06 JP JP3219401A patent/JPH0780880B2/ja not_active Expired - Fee Related
- 1991-08-06 MY MYPI91001423A patent/MY106400A/en unknown
- 1991-08-06 PT PT98583A patent/PT98583B/pt not_active IP Right Cessation
- 1991-08-07 FI FI913754A patent/FI95909C/fi not_active IP Right Cessation
- 1991-08-07 UA UA5001208A patent/UA27100A1/uk unknown
- 1991-08-07 AU AU81672/91A patent/AU649699B2/en not_active Ceased
1999
- 1999-07-02 GR GR990401759T patent/GR3030677T3/el unknown

Also Published As

Publication number	Publication date
NZ239216A (en)	1994-05-26
HU912589D0 (en)	1992-01-28
JPH0780880B2 (ja)	1995-08-30
CA2046801A1 (en)	1992-02-08
ATE179710T1 (de)	1999-05-15
NO913051D0 (no)	1991-08-06
DE69131190D1 (de)	1999-06-10
PT98583A (pt)	1992-06-30
MC2279A1 (fr)	1993-06-23
AU649699B2 (en)	1994-06-02
IS3741A7 (is)	1992-02-08
JPH04230686A (ja)	1992-08-19
SK279566B6 (sk)	1999-01-11
PT98583B (pt)	1999-03-31
FI95909B (fi)	1995-12-29
CA2046801C (en)	2002-02-26
RO112724B1 (ro)	1997-12-30
EP0470490B1 (en)	1999-05-06
EP0470490A1 (en)	1992-02-12
FI913754A0 (fi)	1991-08-07
FI913754L (fi)	1992-02-08
NO179143B (no)	1996-05-06
DK0470490T3 (da)	1999-11-01
UA27100A1 (uk)	2000-02-28
KR100233964B1 (ko)	1999-12-15
AU8167291A (en)	1992-02-13
KR920004380A (ko)	1992-03-27
DE69131190T2 (de)	1999-11-04
IS1682B (is)	1998-02-24
ES2132076T3 (es)	1999-08-16
NO179143C (no)	1996-08-14
CS243591A3 (en)	1992-02-19
FI95909C (fi)	1996-04-10
RU2075474C1 (ru)	1997-03-20
HU210547B (en)	1995-05-29
IL99064A0 (en)	1992-07-15
MY106400A (en)	1995-05-30
GR3030677T3 (en)	1999-11-30
DZ1521A1 (fr)	2004-09-13
HUT61542A (en)	1993-01-28
IE912787A1 (en)	1992-02-12
NO913051L (no)	1992-02-10
CZ280359B6 (cs)	1995-12-13

Publication	Publication Date	Title
EP0470490B1 (en)	1999-05-06	Substituted pyrroles
US5292747A (en)	1994-03-08	Substituted pyrroles
AU633051B2 (en)	1993-01-21	Substituted pyrroles
AU2006232375A1 (en)	2006-10-12	1-substituted pyrazolo (3,4-c) ring compounds as modulators of cytokine biosynthesis for the treatment of viral infections and neoplastic diseases
US4997831A (en)	1991-03-05	Lactam derivatives
LV11690B (en)	1997-06-20	Tetracyclic derivatives, process of preparation and use
AU678435B2 (en)	1997-05-29	Substituted pyrroles
JPH11171774A (ja)	1999-06-29	血球増多剤
US5407940A (en)	1995-04-18	New ellipticine compounds
US4515949A (en)	1985-05-07	[2-(1H-indol-1-yl)ethyl]-2-piperazine and pyrido[1,2-a]indol-9-one as intermediates for pyrazino(2,3-3,4)pyrido(1,2-a) indoles which are useful for treating hypertension in mammals
CA2011107A1 (en)	1991-08-31	Lactam derivatives
HU185651B (en)	1985-03-28	Process for preparing new condensed pyrazine derivatives
EP0115920A2 (en)	1984-08-15	Pyrazino(2',3'-3,4)pyrido(1,2-a) indole derivatives
HU207318B (en)	1993-03-29	Process for producing lactame derivatives and pharmaceutical compositions containing them
EP0301426A1 (en)	1989-02-01	Spiro[(piperidine-, pyrrolidine- or hexahydroazepine substituted)pyrrolo[2,1-c][1,4]benzoxazepines], a process for their preparation, intermediates thereof, and their use as medicaments
IE900723A1 (en)	1991-08-28	Lactam derivatives

Legal Events

Date	Code	Title	Description
1998-01-04	KB	Patent renewed