SE500732C2 - New anthracyclic glycoside derivatives, process for their preparation and pharmaceutical compositions thereof - Google Patents
New anthracyclic glycoside derivatives, process for their preparation and pharmaceutical compositions thereofInfo
- Publication number
- SE500732C2 SE500732C2 SE8702409A SE8702409A SE500732C2 SE 500732 C2 SE500732 C2 SE 500732C2 SE 8702409 A SE8702409 A SE 8702409A SE 8702409 A SE8702409 A SE 8702409A SE 500732 C2 SE500732 C2 SE 500732C2
- Authority
- SE
- Sweden
- Prior art keywords
- epi
- prepared
- daunorubicin
- hydrochloride
- deamino
- Prior art date
Links
- 229930182470 glycoside Natural products 0.000 title claims abstract description 11
- 150000002338 glycosides Chemical class 0.000 title claims abstract description 11
- 238000000034 method Methods 0.000 title claims description 11
- 239000008194 pharmaceutical composition Substances 0.000 title claims description 3
- 150000001875 compounds Chemical class 0.000 claims abstract description 15
- 229940045799 anthracyclines and related substance Drugs 0.000 claims abstract description 8
- 239000002253 acid Substances 0.000 claims abstract description 5
- 150000003839 salts Chemical class 0.000 claims abstract description 4
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims abstract 3
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims abstract 3
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 19
- 229960000975 daunorubicin Drugs 0.000 claims description 15
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 12
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 12
- 239000000203 mixture Substances 0.000 claims description 12
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 12
- 239000000243 solution Substances 0.000 claims description 11
- 239000007864 aqueous solution Substances 0.000 claims description 8
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 6
- 238000006243 chemical reaction Methods 0.000 claims description 6
- SMQUZDBALVYZAC-UHFFFAOYSA-N salicylaldehyde Chemical compound OC1=CC=CC=C1C=O SMQUZDBALVYZAC-UHFFFAOYSA-N 0.000 claims description 6
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 4
- 239000004280 Sodium formate Substances 0.000 claims description 3
- 230000003197 catalytic effect Effects 0.000 claims description 3
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 claims description 3
- 229910000041 hydrogen chloride Inorganic materials 0.000 claims description 3
- HLBBKKJFGFRGMU-UHFFFAOYSA-M sodium formate Chemical compound [Na+].[O-]C=O HLBBKKJFGFRGMU-UHFFFAOYSA-M 0.000 claims description 3
- 235000019254 sodium formate Nutrition 0.000 claims description 3
- WJKHJLXJJJATHN-UHFFFAOYSA-N triflic anhydride Chemical compound FC(F)(F)S(=O)(=O)OS(=O)(=O)C(F)(F)F WJKHJLXJJJATHN-UHFFFAOYSA-N 0.000 claims description 3
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 2
- 238000005904 alkaline hydrolysis reaction Methods 0.000 claims description 2
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 2
- 229910052794 bromium Inorganic materials 0.000 claims description 2
- 239000003085 diluting agent Substances 0.000 claims description 2
- 239000003937 drug carrier Substances 0.000 claims description 2
- 230000007062 hydrolysis Effects 0.000 claims description 2
- 238000006460 hydrolysis reaction Methods 0.000 claims description 2
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 2
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 claims 2
- 239000012458 free base Substances 0.000 claims 2
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 claims 2
- 238000005903 acid hydrolysis reaction Methods 0.000 claims 1
- 125000006239 protecting group Chemical group 0.000 claims 1
- 239000002246 antineoplastic agent Substances 0.000 abstract description 2
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 26
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 12
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 12
- AOJJSUZBOXZQNB-TZSSRYMLSA-N Doxorubicin Chemical compound O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(=O)CO)[C@H]1C[C@H](N)[C@H](O)[C@H](C)O1 AOJJSUZBOXZQNB-TZSSRYMLSA-N 0.000 description 8
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 8
- STQGQHZAVUOBTE-UHFFFAOYSA-N 7-Cyan-hept-2t-en-4,6-diinsaeure Natural products C1=2C(O)=C3C(=O)C=4C(OC)=CC=CC=4C(=O)C3=C(O)C=2CC(O)(C(C)=O)CC1OC1CC(N)C(O)C(C)O1 STQGQHZAVUOBTE-UHFFFAOYSA-N 0.000 description 7
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 7
- STQGQHZAVUOBTE-VGBVRHCVSA-N daunorubicin Chemical compound O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(C)=O)[C@H]1C[C@H](N)[C@H](O)[C@H](C)O1 STQGQHZAVUOBTE-VGBVRHCVSA-N 0.000 description 7
- 239000003480 eluent Substances 0.000 description 7
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 6
- 208000032839 leukemia Diseases 0.000 description 6
- 229960004679 doxorubicin Drugs 0.000 description 5
- 239000002904 solvent Substances 0.000 description 5
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 4
- 241000699670 Mus sp. Species 0.000 description 4
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 4
- 229960001701 chloroform Drugs 0.000 description 4
- 239000011877 solvent mixture Substances 0.000 description 4
- 230000004083 survival effect Effects 0.000 description 4
- QAEDZJGFFMLHHQ-UHFFFAOYSA-N trifluoroacetic anhydride Chemical compound FC(F)(F)C(=O)OC(=O)C(F)(F)F QAEDZJGFFMLHHQ-UHFFFAOYSA-N 0.000 description 4
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 3
- 239000008346 aqueous phase Substances 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 239000000284 extract Substances 0.000 description 3
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 3
- 239000012074 organic phase Substances 0.000 description 3
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 2
- 206010028980 Neoplasm Diseases 0.000 description 2
- 238000011888 autopsy Methods 0.000 description 2
- 210000001072 colon Anatomy 0.000 description 2
- 239000012043 crude product Substances 0.000 description 2
- 238000000354 decomposition reaction Methods 0.000 description 2
- FDSGHYHRLSWSLQ-UHFFFAOYSA-N dichloromethane;propan-2-one Chemical compound ClCCl.CC(C)=O FDSGHYHRLSWSLQ-UHFFFAOYSA-N 0.000 description 2
- 238000010828 elution Methods 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- 229910000042 hydrogen bromide Inorganic materials 0.000 description 2
- 238000000338 in vitro Methods 0.000 description 2
- 230000008018 melting Effects 0.000 description 2
- 238000002844 melting Methods 0.000 description 2
- KJIFKLIQANRMOU-UHFFFAOYSA-N oxidanium;4-methylbenzenesulfonate Chemical compound O.CC1=CC=C(S(O)(=O)=O)C=C1 KJIFKLIQANRMOU-UHFFFAOYSA-N 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 238000002271 resection Methods 0.000 description 2
- 239000000741 silica gel Substances 0.000 description 2
- 229910002027 silica gel Inorganic materials 0.000 description 2
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 2
- 235000017557 sodium bicarbonate Nutrition 0.000 description 2
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- IHCCLXNEEPMSIO-UHFFFAOYSA-N 2-[4-[2-(2,3-dihydro-1H-inden-2-ylamino)pyrimidin-5-yl]piperidin-1-yl]-1-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)ethanone Chemical compound C1C(CC2=CC=CC=C12)NC1=NC=C(C=N1)C1CCN(CC1)CC(=O)N1CC2=C(CC1)NN=N2 IHCCLXNEEPMSIO-UHFFFAOYSA-N 0.000 description 1
- NOWKCMXCCJGMRR-UHFFFAOYSA-N Aziridine Chemical compound C1CN1 NOWKCMXCCJGMRR-UHFFFAOYSA-N 0.000 description 1
- 201000009030 Carcinoma Diseases 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 230000000259 anti-tumor effect Effects 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 230000031709 bromination Effects 0.000 description 1
- 238000005893 bromination reaction Methods 0.000 description 1
- 210000003679 cervix uteri Anatomy 0.000 description 1
- 239000002026 chloroform extract Substances 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 229940125890 compound Ia Drugs 0.000 description 1
- 239000012050 conventional carrier Substances 0.000 description 1
- 230000001472 cytotoxic effect Effects 0.000 description 1
- FHHZOYXKOICLGH-UHFFFAOYSA-N dichloromethane;ethanol Chemical compound CCO.ClCCl FHHZOYXKOICLGH-UHFFFAOYSA-N 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 230000008020 evaporation Effects 0.000 description 1
- WBJINCZRORDGAQ-UHFFFAOYSA-N formic acid ethyl ester Natural products CCOC=O WBJINCZRORDGAQ-UHFFFAOYSA-N 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 230000035800 maturation Effects 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 239000003208 petroleum Substances 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 230000029058 respiratory gaseous exchange Effects 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 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 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- GKASDNZWUGIAMG-UHFFFAOYSA-N triethyl orthoformate Chemical compound CCOC(OCC)OCC GKASDNZWUGIAMG-UHFFFAOYSA-N 0.000 description 1
- 238000010626 work up procedure Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H15/00—Compounds containing hydrocarbon or substituted hydrocarbon radicals directly attached to hetero atoms of saccharide radicals
- C07H15/20—Carbocyclic rings
- C07H15/24—Condensed ring systems having three or more rings
- C07H15/252—Naphthacene radicals, e.g. daunomycins, adriamycins
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Biotechnology (AREA)
- Engineering & Computer Science (AREA)
- Molecular Biology (AREA)
- Genetics & Genomics (AREA)
- Biochemistry (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Saccharide Compounds (AREA)
- Preparation Of Compounds By Using Micro-Organisms (AREA)
Abstract
Description
EÛÜ 752 Behandling av 3',4'-epimino-daunorubicinderivatet (Ia) med tri- fluoro-ättiksyraanhydrid ger motsvarande N-trifluoroacetylderivat (VIIi). Re- aktion av denna förening med en katalytisk mängd svavelsyra i aceton ger 4'- deoxi-lP-epi-N-trifluoroacetyl-T-deamino-3'-hydroxi-daunorubicin (VIII) vil- ken genom behandling med en vattenlösning av natriumhydroxid ger förening- en IIa. N-trifluoroacetylgruppen avlägsnas genom mild alkalisk hydrolys vid en temperatur av O°C medelst en 0,1 N vattenlösning av natriumhydroxid. Treatment of the 3 ', 4'-epimino-daunorubicin derivative (Ia) with trifluoroacetic anhydride gives the corresponding N-trifluoroacetyl derivative (VIIi). Reaction of this compound with a catalytic amount of sulfuric acid in acetone gives 4'-deoxy-1P-epi-N-trifluoroacetyl-T-deamino-3'-hydroxy-daunorubicin (VIII) which by treatment with an aqueous solution of sodium hydroxide gives the compound IIa. The N-trifluoroacetyl group is removed by mild alkaline hydrolysis at a temperature of 0 ° C by means of a 0.1 N aqueous solution of sodium hydroxide.
Glykosiden IIa kan isoleras som hydroklorid genom behandling med klorväte i metanol.Glycoside IIa can be isolated as hydrochloride by treatment with hydrogen chloride in methanol.
Föreningen Hb kan framställas genom bromering av IIa följd av behandling av det erhållna lli-bromderivatet med en vattenlösning av na- triumformiat vid rumstemperatur, enligt det i US-patentet 3 803 124 beskrivna förfarandet. Den kan även isoleras som sin hydroklorid på samma sätt som glykosiden IIa.The compound Hb can be prepared by bromination of IIa following treatment of the obtained lli-bromo derivative with an aqueous solution of sodium formate at room temperature, according to the procedure described in U.S. Pat. No. 3,803,124. It can also be isolated as its hydrochloride in the same way as glycoside IIa.
Förfarandet enligt uppfinningen sammanfattas i efterföljande reaktionsschema.The process of the invention is summarized in the following reaction scheme.
Föreliggande uppfinning tillhandahåller även en farmacevtisk komposition innefattande som aktiv beståndsdel en antracyklinglykosid enligt uppfinningen eller ett farmacevtiskt godtagbart syraadditionssalt därav till- sammans med en farmacevtiskt godtagbar bärare eller spädningsmedel. En terapeutiskt verksam mängd av en förening med formeln II kombineras med en inert bärare. Gängse bärare kan användas och kompositionen kanformule- ras på gängse sätt.The present invention also provides a pharmaceutical composition comprising as an active ingredient an anthracycline glycoside of the invention or a pharmaceutically acceptable acid addition salt thereof together with a pharmaceutically acceptable carrier or diluent. A therapeutically effective amount of a compound of formula II is combined with an inert carrier. Conventional carriers can be used and the composition can be formulated in conventional manner.
Föreningarna enligt uppfinningen är användbara vid behandlings- metoder vid terapi inom human- eller veterinärmedicin. I synnerhet är föreningama enligt uppfinningen användbara som antitumörmedel. 500 752 REAKTTONSSCHEMA fi:oou:.: M ....,_u~0mo n; "Iuqzouïoo ha U :o ud fl1o.:oo:o°"~: o ^z>v . fiW=>v OI n ZIOU :U J.. o oo _ :o o ofo _ :o o ofo 35111151 _ f. f. _ ...få OÖOQ IDOQ »IUOU nluou _ :o o :o o Cïozv :_ :i o: fu ~Iz 4| . o :o o omö :of o o OQOQ I 500 732 Följande exempel illustrerar uppfinningen.The compounds of the invention are useful in treatment methods in therapy in human or veterinary medicine. In particular, the compounds of the invention are useful as antitumor agents. 500 752 REACTION SCHEME fi: oou:.: M ...., _ u ~ 0mo n; "Iuqzouïoo ha U: o ud fl1 o.:oo:o°"~: o ^ z> v. fi W => v OI n ZIOU: U J .. o oo _: oo ofo _: oo ofo 35111151 _ ff _ ... få OÖOQ IDOQ »IUOU nluou _: oo: oo Cïozv: _: io: fu ~ Iz 4 | . o: o o omö: of o o OQOQ I 500 732 The following examples illustrate the invention.
EXEMPEL I 3'-epi-N-salicyliden-daunorubicin (IVc) En lösning av 2 g T-epi-daunorubicin (III) i en blandning av 80 ml vatten och 20 ml aceton behandlades vid rumstemperatur med 0,5 ml salicylaldehyd vid' pH 8. Efter 10 minuter tillsattes etylacetat och den organiska fasen separerades, tvättades två gånger med vatten, torkades över vattenfritt natriumsulfat, filtrerades och indunstades till torrhet under vakuum. Återstoden sönderdelades först i hexan för att avlägsna spår av salicylaldehyd och uppsamlades sedan och torkades under vakuum vid 30°C, varvid erhölls IVc i nästan kvantitativt utbyte. Rf 0,21 på TLC Kieselgel F 254 (Merclfi med användning av lösningsmedelsblandningen CHZCI -ace- 2 ton (8/2 v/v) som elueringsmedel.EXAMPLE I 3'-Epi-N-salicylidene-daunorubicin (IVc) A solution of 2 g of T-epi-daunorubicin (III) in a mixture of 80 ml of water and 20 ml of acetone was treated at room temperature with 0.5 ml of salicylaldehyde at pH 8. After 10 minutes, ethyl acetate was added and the organic phase was separated, washed twice with water, dried over anhydrous sodium sulfate, filtered and evaporated to dryness under vacuum. The residue was first decomposed in hexane to remove traces of salicylaldehyde and then collected and dried under vacuum at 30 ° C to give IVc in almost quantitative yield. Rf 0.21 on TLC Kieselgel F 254 (Mercl fi using the solvent mixture CH 2 Cl 2 -acetone (8/2 v / v) as eluent.
EXEMPEL 2 3'-deamino-lP-deoxi-3'-epi-l+'-epi-3','+'-epimino-daunorubicin (Ia) Till en lösning av 2 g 3'-epi-N-salicyliden-daunorubicin (IVc) i ml vattenfri diklorometan och 2 ml torrt pyridin, som hölls vid -l0°C, tillsattes en lösning av 0,8 ml trifluorometansulfonsyraanhydrid i 10 ml triklormetan. Efter I timme vid -10°C späddes blandningen med diklorometan och tvättades med vatten, kall 0,1 M saltsyra, kall 5 96-ig vattenlösning av natriumvätekarbonat och vatten. Den organiska fasen torkad över vattenfritt natriumsulfat, filtrerades av och lösningsmedlet avlägsnades i vakuum, varvid erhölls IVd.EXAMPLE 2 3'-Deamino-1P-deoxy-3'-epi-1 + '- epi-3', '+' - epimino-daunorubicin (Ia) To a solution of 2 g of 3'-epi-N-salicylidene-daunorubicin (IVc) in ml of anhydrous dichloromethane and 2 ml of dry pyridine, kept at -10 ° C, was added a solution of 0.8 ml of trifluoromethanesulfonic anhydride in 10 ml of trichloromethane. After 1 hour at -10 ° C, the mixture was diluted with dichloromethane and washed with water, cold 0.1 M hydrochloric acid, cold 96 g aqueous sodium bicarbonate solution and water. The organic phase was dried over anhydrous sodium sulfate, filtered off and the solvent was removed in vacuo to give IVd.
Rf 0,50 på TLC Kieselgel F 254 (Merckß) med användning av lösningsmedelsblandningen Cl-lzClz-aceton (95/5 v/v) som elueringsmedel.Rf 0.50 on TLC Kieselgel F 254 (Merckß) using the solvent mixture Cl-1zCl2-acetone (95/5 v / v) as eluent.
Råprodukten löstes i 50 ml metanol och försattes med 0,2 g p- toluensulfonsyramonohydrat. Lösningen hölls vid rumstemperatur i l timme, varefter 100 ml vatten tillsattes och man extraherade med något diklorme- tan. Vattenfasen justerades till pH 8 med 0,1 M natriumhydroxid och diklorometan tillsattes. Den organiska fasen frånseparerades, tvättades med vatten, torkades över vattenfritt natriumsulfat och lösningsmedlet indun- stades till liten volym. 500 732 Blandningen renades genom kromatografi på en kolonn av kisel- syragel buífrad vid pH 7 med användning av diklorometan-etanol som elue- ringsmedel. Eluatet innehållande produkten la tvättades med vatten, induns- tades i vakuum, samlades upp i en liten mängd diklorometan och kristallisera- des.The crude product was dissolved in 50 ml of methanol and added with 0.2 g of p-toluenesulfonic acid monohydrate. The solution was kept at room temperature for 1 hour, after which 100 ml of water were added and extracted with some dichloromethane. The aqueous phase was adjusted to pH 8 with 0.1 M sodium hydroxide and dichloromethane was added. The organic phase was separated, washed with water, dried over anhydrous sodium sulfate and the solvent was evaporated to a small volume. 500 732 The mixture was purified by chromatography on a column of silica gel buffered at pH 7 using dichloromethane-ethanol as eluent. The eluate containing the product Ia was washed with water, evaporated in vacuo, collected in a small amount of dichloromethane and crystallized.
FD Ms 509 (m), smäupunkf 135 _ 137°c:.FD Ms 509 (m), m.p. 135 _ 137 ° C:.
Rf 0,38 på TLC Kieselgel F 254 (Merclß med användning av blandningen CH2Cl2-CH3OH-CH3C0Ol-I-I-l2O (30/lL/1/0,5 v/v) som eluerings- medel. 11-1 - NMR (zoo MHz, cDc13), 8.02 (dd, J=1.1, 7.7Hz, m, 5-1) 7.76 (dd,:1=7.7, 7.7Hz, m, 5.2) 7.37 (dd, J=1.1, 711-12, m, 5.3) .31 (dd, :i=3.o, 4.sHz, m, g-v) .17 (dd, J=2.o, 246m, m, 5-7) 4.32 (qd, J=<1, sJHz, m, gå) 4.07 (s, an, ocg3-4) 3.17 (dd, J=19.2Hz, m, g-ioe) 2.95 (d, J=19.zHz, m, g-ioax) 2.46 (ddd, J=2.o, 2.0, 110m, m, 54:e) 2.43 (s, an, cocgg) 2.30 (ddd, J=1.5, 4.3, s.4Hz, m, _1-_1-3') 1.9-2.0 (m, 2H, H-Sax, fl-Tax) 1.87 (ddd, J=1.5, 3.0, 14.611; m, gøe) 1.44 (d, J=6.7Hz, 31-1, cI_-13-5') ExEMPEL 3 3'-deamino-4'-deoxi-3'-hydroxi-W-epi-lifl-amino-daunorubicin (IIa) Den rubricerade föreningen framställdes utgående från aziridin- föreningen Ia. 1 g Ia överfördes till N-trifluoroacetylderivatet VIIi genom behandling med 1,2 ml trifluoroättiksyraanhydrid i vattenfritt diklorometan.Rf 0.38 on TLC Kieselgel F 254 (Merclß using the mixture CH2Cl2-CH3OH-CH3COO1-II-12O (30 / lL / 1 / 0.5 v / v) as eluent. 11-1 - NMR (zoo MHz, cDc13), 8.02 (dd, J = 1.1, 7.7Hz, m, 5-1) 7.76 (dd,: 1 = 7.7, 7.7Hz, m, 5.2) 7.37 (dd, J = 1.1, 711-12, m, 5.3) .31 (dd,: i = 3.o, 4.sHz, m, gv) .17 (dd, J = 2.o, 246m, m, 5-7) 4.32 (qd, J = < 1, sJHz, m, go) 4.07 (s, an, ocg3-4) 3.17 (dd, J = 19.2Hz, m, g-ioe) 2.95 (d, J = 19.zHz, m, g-ioax) 2.46 (ddd, J = 2.o, 2.0, 110m, m, 54: e) 2.43 (s, an, cocgg) 2.30 (ddd, J = 1.5, 4.3, s.4Hz, m, _1-_1-3 ') 1.9-2.0 (m, 2H, H-Sax, fl-Tax) 1.87 (ddd, J = 1.5, 3.0, 14.611; m, bark) 1.44 (d, J = 6.7Hz, 31-1, cI_-13-5 ') EXAMPLE 3 3'-Deamino-4'-deoxy-3'-hydroxy---epi-β-amino-daunorubicin (IIa) The title compound was prepared from the aziridine compound Ia. 1 g of Ia was transferred to the N-trifluoroacetyl derivative VIIi by treatment with 1.2 ml of trifluoroacetic anhydride in anhydrous dichloromethane.
Efter upparbetning löstes râprodukten (Rf 0,7 på TLC, Kieselgel F 2514 (Merckfi) med användning av lösningsmedelsblandningen CHzClz-aceton (4/1 v/v) som elueringsmedel) i 20 ml aceton och behandlades med en katalytisk mängd svavelsyra vid IOOC.After work-up, the crude product (Rf 0.7 on TLC, Kieselgel F 2514 (Merck fi) was dissolved using the solvent mixture CH 2 Cl 2 -acetone (4/1 v / v) as eluent) in 20 ml of acetone and treated with a catalytic amount of sulfuric acid at 100 ° C.
L-.J Cl) \'l LN I\D Blandníngen späddes med 200 ml diklorometan, tvättades med vatten, en 5 %-íg vattenlösning av natriumvätekarbonat och vatten. Lösnings- medlet avlägsnades i vakuum och återstoden renades på en kolonn av kiselsyragel med användning av diklorometan som elueringssystem, varvid erhölls 0,7 g rent IIa.The mixture was diluted with 200 ml of dichloromethane, washed with water, a 5% aqueous solution of sodium hydrogencarbonate and water. The solvent was removed in vacuo and the residue was purified on a column of silica gel using dichloromethane as elution system to give 0.7 g of pure IIa.
Rf 0,21 på TLC, Kieselgel F 254 (MerckR) med användning av lösningsmedelsblandningen Cl-lzClz-aceton (4/1 v/V) som elueringsmedel.Rf 0.21 on TLC, Kieselgel F 254 (MerckR) using the solvent mixture Cl-1zCl 2 -acetone (4/1 v / V) as eluent.
Produkten IIa upplöstes långsamt i en 0,1 N vattenlösning av natriumhydroxid vid 0°C för att genomföra hydrolysen av N-trifluoroacetyl- skyddsgruppen.The product IIa was slowly dissolved in a 0.1 N aqueous solution of sodium hydroxide at 0 ° C to carry out the hydrolysis of the N-trifluoroacetyl protecting group.
Efter 1 timme vid O°C justerades lösningen till pH 8,6 med 0,1 N saltsyra och extraherades med metylendikloríd. Lösningsmedlet indunstades, varvid erhölls 0,5 g av en återstod som överfördes genom behandling med metanolisk saltsyra till hydrokloriden av lP-deoxi-lH-amino-ß'-epi-3'-deamino- 3'-hydroxi-daunorubicin.After 1 hour at 0 ° C, the solution was adjusted to pH 8.6 with 0.1 N hydrochloric acid and extracted with methylene dichloride. The solvent was evaporated, yielding 0.5 g of a residue which was transferred by treatment with methanolic hydrochloric acid to the hydrochloride of 1P-deoxy-1H-amino-β'-epi-3'-deamino-3'-hydroxy-daunorubicin.
Ms Fo 527 (1v1+), smäupunk: 153°c (sönderdeming).Ms Fo 527 (1v1 +), melting point: 153 ° C (decomposition).
Rf 0,18 på 'rLc Kieselgei F 2511 (MerdQ med användning av lösningsmedelssystemet CHzClz-CHBOH-CH COOH-HZO (30/11/1 /0,5 v/v)som elueringsmedel. 3 11-1 _ NMR (zoo MHz, cocig) 8.02 (dd, J=o.9, 8.552, 111, 5-1) 7.77 (dd, 3=8.5, 8.552, 111, 5-2) 7.38 (dd, J=o.9, 8.552, 111, 5-3) .52 (dd, 3=<1, 4.052, 111, 5-10 .28 (dd, J=1.8, 4.052, 111, 5-7) 11.07 (s, 311, oc53-4) 3.69 (dq, :1=e.3, 9.552, 111, 5-51) 3.51 (ddd, J=u.8, 9.5, 11.652, 11-1, 5-30 3.22 (dd, J=1.9, 18.952, 111, 5-1oe) 2.94 (d, :1=18.9Hz, 111, 5-1odx) 2.40 (s, 31-1, coc53) 2.2-2» (rn, 111, n-sax) 2.3 (dd, J=9.5, 9.552, 1H, 5-40 2.o-2.2 (m, 21-1, fl-se, 11-216) 1.70 (ddd, J=4.o, 4.6, 13.252, 111, 5-2'ax) 1.31 (d, :1=s.311z, 311, C535) 500 732 EXEMPEL 4 3'-deamino-3'-hydroxi-4'-deoxi-4'-epi-lP-amino-doxorubicin (IIb) 0,5 g Ila löstes i en blandning av 7,5 ml vattenfri metanol, Zl ml dioxan och 0,53 ml etylortoformat och behandlades med 2,10 ml av en lösning av 0.93 g brom i 10 ml kloroform. Efter 3 timmar vid l0°C hälldes reaktionsblandning i en blandning av 105 ml etyleter och 50 ml petroleum- eter. Den resulterande röda fällningen upplöstes, efter att filtrerats och tvättats med etyleter flera gånger för att helt avlägsna syran, i en blandning av 15 ml aceton och 15 ml 0.25 N vattenlösning av vätebromid. Efter 15 timmar vid rumstemperatur tillsattes 9 ml vatten och lösningen extraherades flera gånger med kloroform för att avlägsna aglyconerna. Sålunda extrahera- des vattenfasen med N-butanol tills dess att extrakten blivit färglösa.Rf 0.18 on 'rLc Kieselgei F 2511 (MerdQ using the solvent system CH 2 Cl 2 -CHBOH-CH COOH-H 2 O (30/11/1 / 0.5 v / v) as eluent. 3 11-1 - NMR (zoo MHz , cocig) 8.02 (dd, J = o.9, 8.552, 111, 5-1) 7.77 (dd, 3 = 8.5, 8.552, 111, 5-2) 7.38 (dd, J = o.9, 8.552, 111 , 5-3) .52 (dd, 3 = <1, 4.052, 111, 5-10 .28 (dd, J = 1.8, 4.052, 111, 5-7) 11.07 (s, 311, oc53-4) 3.69 (dq,: 1 = e.3, 9.552, 111, 5-51) 3.51 (ddd, J = u.8, 9.5, 11.652, 11-1, 5-30 3.22 (dd, J = 1.9, 18.952, 111 , 5-1oe) 2.94 (d,: 1 = 18.9Hz, 111, 5-1odx) 2.40 (s, 31-1, coc53) 2.2-2 »(rn, 111, n-sax) 2.3 (dd, J = 9.5, 9.552, 1H, 5-40 2.o-2.2 (m, 21-1, fl- se, 11-216) 1.70 (ddd, J = 4.o, 4.6, 13.252, 111, 5-2'ax ) 1.31 (d,: 1 = p.311z, 311, C535) 500 732 EXAMPLE 4 3'-deamino-3'-hydroxy-4'-deoxy-4'-epi-1P-amino-doxorubicin (IIb) 0, 5 g of IIa was dissolved in a mixture of 7.5 ml of anhydrous methanol, 1 ml of dioxane and 0.53 ml of ethyl orthoformate and treated with 2.10 ml of a solution of 0.93 g of bromine in 10 ml of chloroform. was poured reaction bl breathing in a mixture of 105 ml of ethyl ether and 50 ml of petroleum ether. The resulting red precipitate, after being filtered and washed with ethyl ether several times to completely remove the acid, was dissolved in a mixture of 15 ml of acetone and 15 ml of 0.25 N aqueous solution of hydrogen bromide. After 15 hours at room temperature, 9 ml of water were added and the solution was extracted several times with chloroform to remove the aglycones. Thus, the aqueous phase was extracted with N-butanol until the extracts became colorless.
Indunstning av de kombinerade organiska lösningsmedelsextrakten (N-butanol) under vacuum till en liten (ca. 9 ml) och fällning med etyleter av 0,45 g av lll-bromderivatet. Denna senare förening löstes i 9 ml 0,25 N vattenlösning av vätebromid och behandlades med 0,75 g natriumformiat i 8 ml vatten.Evaporation of the combined organic solvent extracts (N-butanol) under vacuum to a small (ca. 9 ml) and precipitation with ethyl ether of 0.45 g of the III-bromo derivative. This latter compound was dissolved in 9 ml of 0.25 N aqueous solution of hydrogen bromide and treated with 0.75 g of sodium formate in 8 ml of water.
Reaktionsblandningen hölls i rumstemperatur under omrörning i #8 timmar och därefter tillsattes 1 N saltsyra tills pH nådde 4. Den resulterade blandningen extraherades med en 1:1 blandning av etyleter och etylacetat för att avlägsna vissa lipofila föroreningar. Vattenfasen extraherades efter att ha justerats till pH 7,6 med vattenlösning av NaHC03 flera gånger med kloroform tills extrakten var färglösa.The reaction mixture was kept at room temperature with stirring for # 8 hours and then 1 N hydrochloric acid was added until the pH reached 4. The resulting mixture was extracted with a 1: 1 mixture of ethyl ether and ethyl acetate to remove some lipophilic impurities. The aqueous phase was extracted after adjusting to pH 7.6 with aqueous NaHCO 3 solution several times with chloroform until the extracts were colorless.
De kombinerade kloroformextrakten torkades med NazSOq och indunstades till liten volym (ca. 145 ml) under vacuum. Den resulterande röda lösningen justerades til pH 3,5 med vattenfri metanolisk väteklorid, och till detta sattes överskott av etyleter varvid erhölls 0,30 g av föreningen (IIb).The combined chloroform extracts were dried over Na 2 SO 4 and evaporated to a small volume (ca. 145 ml) under vacuum. The resulting red solution was adjusted to pH 3.5 with anhydrous methanolic hydrogen chloride, and to this was added excess ethyl ether to give 0.30 g of the compound (IIb).
Smältpunkt l80°C (sönderdelning).Melting point 180 ° C (decomposition).
FD-Ms 543 [M+] TLC på Kieselgel F 254 (MerckR) med användning av eluerings- systemet CH2Cl2-CH3Ol-l-CH3COOH-H2O (30:4:1:O5 v/v) Rf=0.l0. 500 732 BIOLOGISK AKTIVITET Den cytotoxiska aktiviteten hos den nya antracyklinglykosiden IIa enligt uppfinningen provades "in vitro" mot HeLa-celler, P 388, P 388/DX, LoVo och LoVo/DX.FD-Ms 543 [M +] TLC on Kieselgel F 254 (MerckR) using the elution system CH2Cl2-CH3O1-1-CH3COOH-H2O (30: 4: 1: O5 v / v) Rf = 0.10. 500 732 BIOLOGICAL ACTIVITY The cytotoxic activity of the novel anthracycline glycoside IIa of the invention was tested "in vitro" against HeLa cells, P 388, P 388 / DX, LoVo and LoVo / DX.
Exponeringstid för föreningen: 24 timmar/i jämförelse med dauno- rubicin.Exposure time for the compound: 24 hours / in comparison with daunorubicin.
Resultaten framgår av tabell 1.The results are shown in Table 1.
När föreningen provades "in vivo" mot P 388 askitisk leukemi och Gross-leukemi uppvisade den god antitumöraktivitet jämfört med daunorubi- cin särskilt vid oral administration.When tested "in vivo" against P 388 ascitic leukemia and Gross leukemia, it showed good antitumor activity compared to daunorubicin, especially when administered orally.
Resultaten framgår av tabellerna 2 och 3. 500 732 TABELL 1 In vitro-aktivitet hos Bßdeamino-lfldeoxi-3'-hydroxi-4'-epi-4'-amino- -daunorubicin (IIa) jämförd med DNR (daunorubicin) ID 50 (ng/ m Da Förening HeLab P 3ss° P ass/Dxd Lovoe Lovo/Dxf DNR 19 10,5 730 #3 820 IIa 11 2l+,5 235 37 230 a) Dos som ger 5096 reduktion av antalet celler jämfört med obehandlad kontrollgrupp. b) Celler av typ "Human cervix epithelioid carcinoma". c) P 388-1eukemiceller som är påverkbara av doxorubicin. d) P 388-leukemiceller som är resistenta mot doxorubicin. e) Celler av typ "Human colon adenocarcioma" som är pàverkbara av doxorubicin. f) Celler av typ "Human colon adenocarcioma" som är resistenta mot doxorubicin.The results are shown in Tables 2 and 3. 500 732 TABLE 1 In vitro activity of Bβdeamino-1 ldeoxy-3'-hydroxy-4'-epi-4'-amino-daunorubicin (IIa) compared to DNR (daunorubicin) ID 50 ( ng / m Da Compound HeLab P 3ss ° P ass / Dxd Lovoe Lovo / Dxf DNR 19 10.5 730 # 3 820 IIa 11 2l +, 5 235 37 230 a) Dose that gives 5096 reduction in the number of cells compared with untreated control group. b) Cells of the type "Human cervix epithelioid carcinoma". c) P 388-1eukemic cells that are susceptible to doxorubicin. d) P 388 leukemia cells resistant to doxorubicin. e) Cells of the type "Human colon adenocarcioma" which are affected by doxorubicin. f) "Human colon adenocarcioma" type cells that are resistant to doxorubicin.
U'l CI) Cl) \~'l i |\_) TABELL 2 Effekt mo: P ass askmsk leukemi' Förening D65” T/c 96° Föfgiffnings- dödsfaud DNR 2,9 155 o/10 4,4 170 8/10 na 1,96 155 o/1o 2,9 150 o/10 4,4 140 9/10 6,6 1oo 1o/1o a) Experimenten utfördes på CDFI-möss, ympade med 106 leukemiceller i.p. b) Behandling i.p. dag 1 efter tumörympning. c) Genomsnittlig överlevnadstid för behandlade möss/genomsnittlig överlevnadstid för kontrollgruppen x 100. d) Utvârderat pâ basis av obduktionsresultat. 11 TABELL 3 Effekt mot Grossleukemia 500 732 Förening Dosb T/ C %C Förgiítnings- mg/Kg dödsfalld DNR 10 165 0/20 192 2/20 IIa 8,2 175 0/20 1 1,5 230 0/10 16,1 240 0/10 2 2,5 130 0/ l 0 a) Försöken utfördes på CBH-möss, ympade med 2 x 106 leukemiceller i.v. b) Behandling i.v. dag 1 efter tumörympning. c) Genomsnittlig överlevnadstid för behandlade möss/genomsnittlig överlevnadstid för kontrollgruppen x 100. d) Utvärderat på basis av obduktionsresultat.U'l CI) Cl) \ ~ 'li | \ _) TABLE 2 Effect mo: P ass askmsk leukemia' Compound D65 ”T / c 96 ° Föfgiffnings- dödsfaud DNR 2,9 155 o / 10 4,4 170 8 / 1.96 155 o / 1o 2.9 150 o / 10 4.4 140 9/10 6.6 1oo 1o / 1o a) The experiments were performed on CDFI mice, inoculated with 106 leukemia cells ip b) Treatment i.p. day 1 after tumor resection. c) Mean survival time of treated mice / mean survival time of the control group x 100. d) Evaluated on the basis of autopsy results. 11 TABLE 3 Effect against Grossleukemia 500 732 Compound Dosb T / C% C Maturation mg / Kg death DNR 10 165 0/20 192 2/20 IIa 8.2 175 0/20 1 1.5 230 0/10 16.1 240 0/10 2 2.5 130 0 / l 0 a) The experiments were performed on CBH mice, inoculated with 2 x 106 leukemia cells iv b) Treatment i.v. day 1 after tumor resection. c) Mean survival time of treated mice / mean survival time of the control group x 100. d) Evaluated on the basis of autopsy results.
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| GB9309663D0 (en) * | 1993-05-11 | 1993-06-23 | Erba Carlo Spa | Biologically active compounds |
| GB9325417D0 (en) * | 1993-12-13 | 1994-02-16 | Erba Carlo Spa | 3'- aziridino-anthracycline derivatives |
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| GB9418260D0 (en) * | 1994-09-09 | 1994-10-26 | Erba Carlo Spa | Anthracycline derivatives |
| IT1275953B1 (en) * | 1995-03-22 | 1997-10-24 | Sicor Spa | PROCEDURE FOR THE PREPARATION OF ANTIBIOTICS OF THE CLASS OF ANTHRACYCLINES |
| GB9808027D0 (en) * | 1998-04-15 | 1998-06-17 | Pharmacia & Upjohn Spa | 13-dihydro-3' aziridino anthracyclines |
| AU2343900A (en) * | 1998-11-02 | 2000-05-22 | Board Of Regents, The University Of Texas System | Methods and compositions for the manufacture of highly potent anthracycline-based antitumor agents |
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