NO159933B - Analogifremgangsmaate ved fremstilling av nye terapeutisk aktive isoquinolinderivater. - Google Patents
Analogifremgangsmaate ved fremstilling av nye terapeutisk aktive isoquinolinderivater. Download PDFInfo
- Publication number
- NO159933B NO159933B NO834019A NO834019A NO159933B NO 159933 B NO159933 B NO 159933B NO 834019 A NO834019 A NO 834019A NO 834019 A NO834019 A NO 834019A NO 159933 B NO159933 B NO 159933B
- Authority
- NO
- Norway
- Prior art keywords
- preparation
- therapeutically active
- new therapeutically
- analogy procedure
- compound
- Prior art date
Links
- 238000000034 method Methods 0.000 title claims description 5
- 238000002360 preparation method Methods 0.000 title description 4
- AWJUIBRHMBBTKR-UHFFFAOYSA-N isoquinoline Chemical class C1=NC=CC2=CC=CC=C21 AWJUIBRHMBBTKR-UHFFFAOYSA-N 0.000 title 1
- 150000001875 compounds Chemical class 0.000 claims abstract description 12
- FRASJONUBLZVQX-UHFFFAOYSA-N 1,4-naphthoquinone Chemical compound C1=CC=C2C(=O)C=CC(=O)C2=C1 FRASJONUBLZVQX-UHFFFAOYSA-N 0.000 claims abstract description 10
- MHRNGQVWZRPUJI-UHFFFAOYSA-N 2-formyl-3,4-dihydro-1h-isoquinoline-3-carboxylic acid Chemical compound C1=CC=C2CN(C=O)C(C(=O)O)CC2=C1 MHRNGQVWZRPUJI-UHFFFAOYSA-N 0.000 claims abstract description 5
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 claims description 15
- 238000010438 heat treatment Methods 0.000 claims description 3
- 150000008064 anhydrides Chemical class 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 claims description 2
- 230000001093 anti-cancer Effects 0.000 abstract description 2
- 239000000725 suspension Substances 0.000 abstract 1
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 6
- 206010028980 Neoplasm Diseases 0.000 description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 6
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 4
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 4
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 3
- 238000002329 infrared spectrum Methods 0.000 description 3
- 239000002904 solvent Substances 0.000 description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 206010073071 hepatocellular carcinoma Diseases 0.000 description 2
- MQUPWTBHHPUUMC-UHFFFAOYSA-N isoindole Chemical compound C1=CC=C[C]2C=NC=C21 MQUPWTBHHPUUMC-UHFFFAOYSA-N 0.000 description 2
- 239000002480 mineral oil Substances 0.000 description 2
- 235000010446 mineral oil Nutrition 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- 239000011541 reaction mixture Substances 0.000 description 2
- 238000001953 recrystallisation Methods 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- 239000004215 Carbon black (E152) Substances 0.000 description 1
- 201000009030 Carcinoma Diseases 0.000 description 1
- 208000028018 Lymphocytic leukaemia Diseases 0.000 description 1
- 241000699666 Mus <mouse, genus> Species 0.000 description 1
- 241000699660 Mus musculus Species 0.000 description 1
- 241000699670 Mus sp. Species 0.000 description 1
- 206010039491 Sarcoma Diseases 0.000 description 1
- -1 acetic anhydride Chemical class 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 201000011510 cancer Diseases 0.000 description 1
- 210000001072 colon Anatomy 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 229930195733 hydrocarbon Natural products 0.000 description 1
- 150000002430 hydrocarbons Chemical class 0.000 description 1
- 238000002513 implantation Methods 0.000 description 1
- 238000011835 investigation Methods 0.000 description 1
- 208000003747 lymphoid leukemia Diseases 0.000 description 1
- 238000011580 nude mouse model Methods 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 239000002002 slurry Substances 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 230000004614 tumor growth Effects 0.000 description 1
- 238000002424 x-ray crystallography Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
Landscapes
- Organic Chemistry (AREA)
- Chemical & Material Sciences (AREA)
- Health & Medical Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Public Health (AREA)
- Medicinal Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Plural Heterocyclic Compounds (AREA)
- Other In-Based Heterocyclic Compounds (AREA)
- Indole Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Saccharide Compounds (AREA)
- Solid-Sorbent Or Filter-Aiding Compositions (AREA)
Description
Foreliggende oppfinnelse vedrører fremstillingen av den nye forbindelse 5,14-dihydrobenz[5,6]-isoindol[2,1-b]isokinolin-8,13-dion med formel I som er i besiddelse av en aktivitet som er anvendelig ved behandlingen av kreft.
Forbindelsen med formel I
fremstilles ved en fremgangsmåte som omfatter omsetning av 2-formyl-3-karboksy-l,2,3,4-tetrahydroisokinolin med 1,4-naftokinon under karboksylaktiverende betingelser.
Således kan fremgangsmåten f.eks. utføres i nærvær av et alkanonsyreanhydrid, slik som eddiksyreanhydrid, eventuelt i nærvær av et oppløsningmiddel, f.eks. et hydrokarbonopp-løsningsmiddel, slik som toluen. Fortrinnsvis utføres fremgangsmåten under oppvarmning til f.eks. 80-120°C.
Forbindelsen som fremstilles ifølge oppfinnelsen foreligger i minst to krystallinske former og fremstillingen av begge former faller innenfor rammen av oppfinnelsen. De to krystallinske former som er blitt isolert er ved pulver-røntgen-krystallografi blitt påvist å være morfologisk distinkte og oppviser forskjellige IR-spektra. Disse to former betegnes i det følgende som form A og form B og kan bl. a. skilles fra hverandre ved form B's betydelig høyere oppløselighet i dimetylformamid.
Omkrystallisasjon av det opprinnelige produkt, som normalt foreligger som form B, hvis reaksjonen utføres i fravær av et ytterligere oppløsningsmiddel f.eks. fra kloroform og metylenklorid, gir forbindelsen som form A. Dessuten kan form A også erholdes fra form B ved oppvarmning som en oppslemning i toluen, fortrinnsvis i nærvær av et podekry-stall av form A.
Forbindelsen med formel I er i besiddelse av antikreftak-tivitet, spesielt mot tumorer slik som sarcomas, carcinomas og hepatomas, og kan således anvendes ved behandling av slike tumorer.
Således, når forbindelsen administreres intraperitonealt eller intravenøst til mus eller med en subkutan svulst som stammer fra en implantering av S180 celler, har etter-følgende undersøkelse vist at svulstvekst er blitt betydelig redusert og i noen tilfeller har total tilbakegang av svulsten inntruffet. Aktiviteter mot hepatoma (D23 Rat Solid Tumor), HT29 Human Colon Xenograft in Nude Mice, og L1210 (Mouse lymphocitic leukaemia, grown ascitally) er også blitt vist.
Oppfinnelsen er ytterligere illustrert ved de følgende eksempler.
EKSEMPEL 1
Fremstilling av 5, 14- dihydrobenz[ 5, 6] isoindol[ 2, 1- b] isokinolin- 8, 13- dion
En blanding av 2-formyl-3-karboksy-l,2,3,4-tetrahydroiso-kinolin (17,50 g) og 1,4-naftokinon (26,95 g) i eddiksyreanhydrid (4 37 ml) ble oppvarmet ved 100°C under omrøring i 30 minutter. Reaksjonsblandingen ble kjølt og det faste stoff samlet opp ved filtrering, vasket med eter og tørket.
Omkrystallisasjon.fra kloroform/metylenklorid ga tittelforbindelsen som form A (11,13 g) , /\maks. (etanol) 245 (£43,700), 265 (t14,100) og 363 nm (£5,200).
Det infrarøde spektrum til tittelforbindelsen som form A som en pasta (mull) i mineralolje oppviste karakteristiske topper ved 1756 (skulder), 1748, 1598, 1572, 1546 og 838 cm
EKSEMPEL 2
Fremstilling av 5, 14- dihydrobenz[ 5, 6] isoindol[ 2, 1- b] isokinolin- 8 , 13- dion
En blanding av 2-formyl-3~karboksy-l,2,3,4-tetrahydroiso-kinolin (20 g) og 1,4 naftokinon (30,8 g) i eddiksyreanhydrid (500 ml) ble oppvarmet ved 100°C under røring:i 30 minutter. Reaksjonsblandingen ble kjølt, det faste stoff samlet opp ved filtrering, vasket med eddiksyreanhydrid (50 g) med eter (2 x 100 ml) og tørket og ga tittelforbindelsen som form B (26 g).
Analyse - funnet C 80,4, H4,3, N4,7
(C20H13N02 bere9net: c Q0>2> H 4,3, N 4,6.%)
Det infrarøde spektrum for tittelforbindelsen som form B som en pasta (mull) i mineralolje oppviste karakteristiske topper ved 1766, 1742, 1594, 1564, 1544 og 1292 cm"<1>.
Claims (1)
- Analogifremgangsmåte ved fremstilling av en terapeutisk aktiv forbindelse med formel samt dens krystallinske A- og B-former,karakterisert ved at 2-formyl-3-karboksy-1,2,3,4-tetrahydroisokinolin omsettes med 1,4-naftokinon i et alkansyreanhydrid, fortrinnsvis eddiksyreanhydrid, under oppvarming fortrinnsvis til 80-120"C, og om ønsket, fremstilles de krystallinske A- og B-former på kjent måte.
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB8231540 | 1982-11-04 |
Publications (3)
| Publication Number | Publication Date |
|---|---|
| NO834019L NO834019L (no) | 1984-05-07 |
| NO159933B true NO159933B (no) | 1988-11-14 |
| NO159933C NO159933C (no) | 1989-02-22 |
Family
ID=10534035
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| NO834019A NO159933C (no) | 1982-11-04 | 1983-11-03 | Analogifremgangsmaate ved fremstilling av nye terapeutisk aktive isoquinolinderivater. |
Country Status (20)
| Country | Link |
|---|---|
| US (1) | US4831039A (no) |
| EP (1) | EP0108620B1 (no) |
| JP (1) | JPS5998084A (no) |
| KR (1) | KR900008697B1 (no) |
| AT (1) | ATE25256T1 (no) |
| AU (1) | AU566898B2 (no) |
| CA (1) | CA1272198A (no) |
| DE (1) | DE3369515D1 (no) |
| DK (1) | DK158666C (no) |
| ES (1) | ES8504796A1 (no) |
| FI (1) | FI74003C (no) |
| GB (1) | GB2129799B (no) |
| GR (1) | GR78749B (no) |
| IE (1) | IE56206B1 (no) |
| IL (1) | IL70124A (no) |
| NO (1) | NO159933C (no) |
| NZ (1) | NZ206141A (no) |
| PH (1) | PH19013A (no) |
| PT (1) | PT77601B (no) |
| ZA (1) | ZA838237B (no) |
Families Citing this family (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DK158666C (da) * | 1982-11-04 | 1990-11-19 | Glaxo Group Ltd | Analogifremgangsmaade til fremstilling af 5,14-dihydrobenz-oe5,6aa-isoindolooe2,1-baa-isoquinolin-8,13-dion |
| DE3576066D1 (de) * | 1984-05-03 | 1990-03-29 | Glaxo Group Ltd | Isochinolinderivate. |
| GB8513460D0 (en) * | 1985-05-29 | 1985-07-03 | Glaxo Group Ltd | Chemical compounds |
| NO872963L (no) * | 1986-07-29 | 1988-02-01 | Glaxo Group Ltd | Isokinolinderivater. |
| DK616087A (da) * | 1986-11-27 | 1988-05-28 | Glaxo Group Ltd | Isoquinolinderivater og farmaceutiske praeparater indeholdende dem |
| GB8800312D0 (en) * | 1988-01-07 | 1988-02-10 | Glaxo Group Ltd | Process |
Family Cites Families (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB1459137A (en) * | 1973-05-30 | 1976-12-22 | Sandoz Ltd | Naphthoquinone derivatives |
| FR2387229A1 (fr) * | 1977-04-13 | 1978-11-10 | Anvar | Dipyrido (4,3-b) (3,4-f) indoles, procede d'obtention, application therapeutique et compositions pharmaceutiques les contenant |
| FR2436786A1 (fr) * | 1978-09-21 | 1980-04-18 | Anvar | Nouveaux derives des pyrido (4,3-b) carbazoles (ellipticines), substitues en position 1 par une chaine polyaminee, leur obtention et leur application a titre de medicaments |
| DK158666C (da) * | 1982-11-04 | 1990-11-19 | Glaxo Group Ltd | Analogifremgangsmaade til fremstilling af 5,14-dihydrobenz-oe5,6aa-isoindolooe2,1-baa-isoquinolin-8,13-dion |
| DE3576066D1 (de) * | 1984-05-03 | 1990-03-29 | Glaxo Group Ltd | Isochinolinderivate. |
-
1983
- 1983-11-01 DK DK499583A patent/DK158666C/da not_active IP Right Cessation
- 1983-11-03 GB GB08329342A patent/GB2129799B/en not_active Expired
- 1983-11-03 CA CA000440383A patent/CA1272198A/en not_active Expired - Fee Related
- 1983-11-03 AT AT83306709T patent/ATE25256T1/de not_active IP Right Cessation
- 1983-11-03 IE IE2575/83A patent/IE56206B1/xx unknown
- 1983-11-03 PT PT77601A patent/PT77601B/pt not_active IP Right Cessation
- 1983-11-03 FI FI834045A patent/FI74003C/fi not_active IP Right Cessation
- 1983-11-03 ES ES526995A patent/ES8504796A1/es not_active Expired
- 1983-11-03 PH PH29787A patent/PH19013A/en unknown
- 1983-11-03 NO NO834019A patent/NO159933C/no unknown
- 1983-11-03 IL IL70124A patent/IL70124A/xx unknown
- 1983-11-03 EP EP83306709A patent/EP0108620B1/en not_active Expired
- 1983-11-03 DE DE8383306709T patent/DE3369515D1/de not_active Expired
- 1983-11-03 NZ NZ206141A patent/NZ206141A/en unknown
- 1983-11-04 JP JP58207303A patent/JPS5998084A/ja active Granted
- 1983-11-04 ZA ZA838237A patent/ZA838237B/xx unknown
- 1983-11-04 KR KR1019830005234A patent/KR900008697B1/ko not_active IP Right Cessation
- 1983-11-04 AU AU20966/83A patent/AU566898B2/en not_active Ceased
- 1983-11-04 GR GR72876A patent/GR78749B/el unknown
-
1987
- 1987-12-07 US US07/129,064 patent/US4831039A/en not_active Expired - Fee Related
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