NO123574B - - Google Patents
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- NO123574B NO123574B NO4114/68A NO411468A NO123574B NO 123574 B NO123574 B NO 123574B NO 4114/68 A NO4114/68 A NO 4114/68A NO 411468 A NO411468 A NO 411468A NO 123574 B NO123574 B NO 123574B
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- 150000003839 salts Chemical class 0.000 claims description 14
- 150000001875 compounds Chemical class 0.000 claims description 10
- 125000001935 tetracenyl group Chemical class C1(=CC=CC2=CC3=CC4=CC=CC=C4C=C3C=C12)* 0.000 claims description 8
- 150000003242 quaternary ammonium salts Chemical class 0.000 claims description 5
- -1 thiocarbamoyl group Chemical group 0.000 claims description 5
- 125000004432 carbon atom Chemical group C* 0.000 claims description 4
- 238000000034 method Methods 0.000 claims description 4
- 125000004430 oxygen atom Chemical group O* 0.000 claims description 4
- 125000002252 acyl group Chemical group 0.000 claims description 2
- 125000000217 alkyl group Chemical group 0.000 claims description 2
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 claims description 2
- 125000003739 carbamimidoyl group Chemical group C(N)(=N)* 0.000 claims description 2
- 238000002360 preparation method Methods 0.000 claims description 2
- 125000001453 quaternary ammonium group Chemical group 0.000 claims description 2
- 125000000542 sulfonic acid group Chemical group 0.000 claims description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 24
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 15
- 235000019441 ethanol Nutrition 0.000 description 11
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 10
- 239000000203 mixture Substances 0.000 description 7
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 6
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 6
- 239000000706 filtrate Substances 0.000 description 5
- 238000001914 filtration Methods 0.000 description 5
- 238000002211 ultraviolet spectrum Methods 0.000 description 5
- NAALWFYYHHJEFQ-ZASNTINBSA-N (2s,5r,6r)-6-[[(2r)-2-[[6-[4-[bis(2-hydroxyethyl)sulfamoyl]phenyl]-2-oxo-1h-pyridine-3-carbonyl]amino]-2-(4-hydroxyphenyl)acetyl]amino]-3,3-dimethyl-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylic acid Chemical compound N([C@@H](C(=O)N[C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)C=1C=CC(O)=CC=1)C(=O)C(C(N1)=O)=CC=C1C1=CC=C(S(=O)(=O)N(CCO)CCO)C=C1 NAALWFYYHHJEFQ-ZASNTINBSA-N 0.000 description 4
- 229960000975 daunorubicin Drugs 0.000 description 4
- 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 4
- 229960003109 daunorubicin hydrochloride Drugs 0.000 description 4
- 239000002198 insoluble material Substances 0.000 description 4
- 238000003756 stirring Methods 0.000 description 4
- 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 3
- 239000003960 organic solvent Substances 0.000 description 3
- 239000002244 precipitate Substances 0.000 description 3
- 208000007093 Leukemia L1210 Diseases 0.000 description 2
- 241000699670 Mus sp. Species 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
- 150000007513 acids Chemical class 0.000 description 2
- 230000003115 biocidal effect Effects 0.000 description 2
- 239000012141 concentrate Substances 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- 238000010438 heat treatment Methods 0.000 description 2
- BRWIZMBXBAOCCF-UHFFFAOYSA-N hydrazinecarbothioamide Chemical compound NNC(N)=S BRWIZMBXBAOCCF-UHFFFAOYSA-N 0.000 description 2
- 238000007912 intraperitoneal administration Methods 0.000 description 2
- 239000008176 lyophilized powder Substances 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 229910052751 metal Inorganic materials 0.000 description 2
- 239000002184 metal Substances 0.000 description 2
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 2
- 159000000000 sodium salts Chemical class 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- 239000007858 starting material Substances 0.000 description 2
- 150000003467 sulfuric acid derivatives Chemical class 0.000 description 2
- 230000001225 therapeutic effect Effects 0.000 description 2
- YSULOORXQBDPCU-UHFFFAOYSA-N 2-(trimethylazaniumyl)ethanehydrazonate;hydrochloride Chemical compound [Cl-].C[N+](C)(C)CC(=O)NN YSULOORXQBDPCU-UHFFFAOYSA-N 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- XBDQKXXYIPTUBI-UHFFFAOYSA-N Propionic acid Chemical class CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 1
- ZFXYFBGIUFBOJW-UHFFFAOYSA-N Theophylline Natural products O=C1N(C)C(=O)N(C)C2=C1NC=N2 ZFXYFBGIUFBOJW-UHFFFAOYSA-N 0.000 description 1
- 150000001242 acetic acid derivatives Chemical class 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- HAMNKKUPIHEESI-UHFFFAOYSA-N aminoguanidine Chemical compound NNC(N)=N HAMNKKUPIHEESI-UHFFFAOYSA-N 0.000 description 1
- 230000001093 anti-cancer Effects 0.000 description 1
- 230000000259 anti-tumor effect Effects 0.000 description 1
- SRSXLGNVWSONIS-UHFFFAOYSA-N benzenesulfonic acid Chemical class OS(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-N 0.000 description 1
- WARCRYXKINZHGQ-UHFFFAOYSA-N benzohydrazide Chemical compound NNC(=O)C1=CC=CC=C1 WARCRYXKINZHGQ-UHFFFAOYSA-N 0.000 description 1
- 150000001558 benzoic acid derivatives Chemical class 0.000 description 1
- 238000010908 decantation Methods 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- CCIVGXIOQKPBKL-UHFFFAOYSA-M ethanesulfonate Chemical compound CCS([O-])(=O)=O CCIVGXIOQKPBKL-UHFFFAOYSA-M 0.000 description 1
- 150000002170 ethers Chemical class 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- VZCYOOQTPOCHFL-OWOJBTEDSA-L fumarate(2-) Chemical class [O-]C(=O)\C=C\C([O-])=O VZCYOOQTPOCHFL-OWOJBTEDSA-L 0.000 description 1
- 150000003840 hydrochlorides Chemical class 0.000 description 1
- 150000002485 inorganic esters Chemical class 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 150000002576 ketones Chemical class 0.000 description 1
- 231100000053 low toxicity Toxicity 0.000 description 1
- 150000002688 maleic acid derivatives Chemical class 0.000 description 1
- 125000000325 methylidene group Chemical group [H]C([H])=* 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 150000002823 nitrates Chemical class 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 150000002895 organic esters Chemical class 0.000 description 1
- 235000021317 phosphate Nutrition 0.000 description 1
- 150000003013 phosphoric acid derivatives Chemical class 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 239000012429 reaction media Substances 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 150000003873 salicylate salts Chemical class 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 150000003890 succinate salts Chemical class 0.000 description 1
- 150000003892 tartrate salts Chemical class 0.000 description 1
- 229960000278 theophylline Drugs 0.000 description 1
- 238000002560 therapeutic 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
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Engineering & Computer Science (AREA)
- Health & Medical Sciences (AREA)
- Biochemistry (AREA)
- Biotechnology (AREA)
- General Health & Medical Sciences (AREA)
- Genetics & Genomics (AREA)
- Molecular Biology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Description
Analogifremgangsmåte for fremstilling av nye, terapeutisk virksomme naftacenderivater. Analogy method for the production of new, therapeutically active naphthacene derivatives.
Oppfinnelsen vedrører analogifreargangsmåte for fremstilling av nye, terapeutisk virksomme naftacenderivater med den generelle formel The invention relates to an analogue process for the production of new, therapeutically active naphthacene derivatives with the general formula
hvor både R-^ og R2 betegner et oksygenatom eller der en av R1 og R2 betegner et oksygenatom og den andre betegner en gruppe N-NH-R-j, og der R-j betegner en alkanoylgruppe inneholdende 1-3 karbonatomer (eventuelt substituert med en sulfonsyregruppe eller en kvaternær ammoniumgruppe), en tiokarbamoylgruppe (eventuelt substituert med en alkylgruppe inneholdende 1-4 karbonatomer), en amidinogruppe eller en benzoylgruppe, samt også salter herav innbefattende kvaternære ammoniumsalter, idet fremgangsmåten er karakterisert ved at en forbindelse med den generelle formel hvor R-j har den ovenfor angitte betydning, omsettes med et naftacenderivat med formel: where both R-^ and R 2 denote an oxygen atom or where one of R 1 and R 2 denotes an oxygen atom and the other denotes a group N-NH-R-j, and where R-j denotes an alkanoyl group containing 1-3 carbon atoms (optionally substituted with a sulfonic acid group or a quaternary ammonium group), a thiocarbamoyl group (optionally substituted with an alkyl group containing 1-4 carbon atoms), an amidino group or a benzoyl group, as well as salts thereof including quaternary ammonium salts, the method being characterized in that a compound of the general formula where R-j has the meaning given above, is reacted with a naphthacene derivative with the formula:
hvoretter den dannede forbindelse eventuelt omdannes til et salt. after which the compound formed is optionally converted into a salt.
Man arbeider fortrinnsvis i et inert organisk oppløs-ningsmiddel som en alkohol (etanol) eller dimetylformamid under svak oppvarmning av reaksjonsmediet. One preferably works in an inert organic solvent such as an alcohol (ethanol) or dimethylformamide while gently heating the reaction medium.
Det som utgangsmateriale anvendte naftacenderivat med formel III er det antibiotikum som betegnes med 13.057 R.P. og som har fått navnet daunorubicin. Dets fremstilling og dets fysikalsk-kjemiske egenskaper er omtalt i det norske patent nr. 118.145 (eksempel 6 og 7)- I tidligere publikasjoner er det blitt kalt "rubidomycin". Det er angitt i patentet at 13.057 R.P. er i besittelse av en meget utpreget anticancer-aktivitet. Det var imidlertid ikke kjent før 18. oktober 1967 at dette antibiotkum tilsvarer formel III. The naphthacene derivative of formula III used as starting material is the antibiotic designated by 13,057 R.P. and which has been named daunorubicin. Its preparation and its physico-chemical properties are discussed in the Norwegian patent no. 118,145 (examples 6 and 7) - In previous publications it has been called "rubidomycin". It is stated in the patent that 13,057 R.P. is in possession of a very distinct anticancer activity. However, it was not known until 18 October 1967 that this antibiotic pool corresponds to formula III.
De i henhold til oppfinnelsen fremstilte nye forbindelser kan hvis ønsket omdannes til addisjonssalter med syrer eller med nitrogenholdige baser, til metallsalter eller til kvaternære ammoniumsalter. The new compounds produced according to the invention can, if desired, be converted into addition salts with acids or with nitrogen-containing bases, into metal salts or into quaternary ammonium salts.
Saltene kan fåes ved omsetning av de nye forbindelser med syrer eller baser i et egnet oppløsningsmiddél. Som organiske opp-løsningsmidler anvender man eksempelvis alkoholer, etere, ketoner eller klorerte oppløsningsmidler. Det dannede•salt felles ut etter en eventuell konsentrasjon av dets oppløsning og fraskilles ved filtrering eller dekantéring. The salts can be obtained by reacting the new compounds with acids or bases in a suitable solvent. For example, alcohols, ethers, ketones or chlorinated solvents are used as organic solvents. The formed•salt precipitates after a possible concentration of its solution and is separated by filtration or decantation.
De kvaternære ammoniumsaltene kan fåes ved omsetning av The quaternary ammonium salts can be obtained by reacting
de nye forbindelser med estere, eventuelt i et organisk oppløsnings-middel, ved vanlige temperaturer eller hurtigere ved svak oppvarmning. the new compounds with esters, possibly in an organic solvent, at normal temperatures or more rapidly with gentle heating.
De nye naftacenderivater med den generelle formel I The new naphthacene derivatives of the general formula I
samt deres salter har interessante antitumorale egenskaper for-bundet med en lav toksisitet. as well as their salts have interesting antitumoral properties associated with a low toxicity.
De viste seg spesielt aktive på mus mot leukemi L 1210 (intra-peritoneal administrering). Forsøkene er utført på mus som var 1 måned gamle og veide 18-20 gram og som på intraperitoneal måte ble podet med 10^ celler av leukemi L 1210 og ble behandlet med doser mellom 0,5 og 5 mg/kg i.p. They proved particularly active in mice against leukemia L 1210 (intra-peritoneal administration). The experiments were carried out on mice which were 1 month old and weighed 18-20 grams and which were inoculated intraperitoneally with 10^ cells of leukemia L 1210 and were treated with doses between 0.5 and 5 mg/kg i.p.
For terapeutisk bruk anvender man de nye naftacenderivater av formel (I) enten i fri tilstand eller i form av farmasøytisk godtagbare salter, dvs. ikke toksiske ved anvendelsesdosene. For therapeutic use, the new naphthacene derivatives of formula (I) are used either in the free state or in the form of pharmaceutically acceptable salts, i.e. non-toxic at the application doses.
Som eksempel på farmasøytisk godtagbare salter kan nevnes salter av uorganiske syrer (som hydroklorider, sulfater, nitrater, fosfater) eller av organiske syrer (som acetater, propionater, succinater, benzoater, fumarater, maleater, tartrater, teofyllin-acetater, salicylater, fenolftalinater, metylenbis-g-oksy-naftoater), metallsalter (som natriumsalter) eller salter med nitrogenholdige baser. Examples of pharmaceutically acceptable salts include salts of inorganic acids (such as hydrochlorides, sulphates, nitrates, phosphates) or of organic acids (such as acetates, propionates, succinates, benzoates, fumarates, maleates, tartrates, theophylline acetates, salicylates, phenolphthalinates, methylene bis-g-oxy-naphthoates), metal salts (such as sodium salts) or salts with nitrogenous bases.
Som eksempel på farmasøytisk godtagbare kvaternære ammoniumsalter kan nevnes derivat av uorganiske eller organiske estere som klor-, brom- eller jodmetylater, -etylater, -allylater eller benzylater eller sulfater, benzensulfonater eller substitu-. sjonsderivater av disse forbindelser. Examples of pharmaceutically acceptable quaternary ammonium salts include derivatives of inorganic or organic esters such as chloro-, bromo- or iodomethylates, -ethylates, -allylates or benzylates or sulfates, benzenesulfonates or substitutes. sion derivatives of these compounds.
Innen humanterapien kan mengdene av den aktive forbindelse av formel (I) i medikamenter varieres avhengig av den tilstrebede terapeutiske effekt. Ved'intravenøs administrering er den anvendte dose vanligvis mellom 2 og10 mg/kg pr. døgn for en voksen. Within human therapy, the amounts of the active compound of formula (I) in medicaments can be varied depending on the intended therapeutic effect. For intravenous administration, the dose used is usually between 2 and 10 mg/kg per day for an adult.
Oppfinnelsen skal forklares nærmere ved hjelp av noen eksempler. The invention will be explained in more detail with the help of some examples.
Eksempel 1. Example 1.
Man oppløser 0,5 g hydrokiorid av daunorubicin i en blanding av 20 ml dimetylformamid.og 10 ml vann. Man tilsetter 0,42 g natrium-2-aminokarbamoyl-etansulfonat. Man omrører i 24 timer ved værelsetemperatur og konsentrerer til tørrhet under redusert.trykk (25 mm Hg). Man oppløser det dannede residuum med 100 ml vann. Man eliminerer ved filtrering en liten mengde uoppløselig materiale og lyofiliserer deretter filtratet. Man får således 0,875 g av natrium-saltet av 4-metoksy-5-(eller 12-)okso-6,9,ll-trihydroksy-7-(0-2,3,6-trideoksy-3-amino-l-L-lyksoheksosyl)-9-/<->l-(3-sulfo-propionylhydrazono)-etyl7-12(eller 5)-(3~sulfo-propionylhydrazono)-5,7 58,9,10,12-heksa-hydronaftacen med et utbytte på 95$• 0.5 g of daunorubicin hydrochloride is dissolved in a mixture of 20 ml of dimethylformamide and 10 ml of water. 0.42 g of sodium 2-aminocarbamoyl ethanesulfonate is added. The mixture is stirred for 24 hours at room temperature and concentrated to dryness under reduced pressure (25 mm Hg). The residue formed is dissolved with 100 ml of water. A small amount of insoluble material is eliminated by filtration and the filtrate is then lyophilized. 0.875 g of the sodium salt of 4-methoxy-5-(or 12-)oxo-6,9,11-trihydroxy-7-(0-2,3,6-trideoxy-3-amino-1-L- lyxohexosyl)-9-/<->l-(3-sulfo-propionylhydrazono)-ethyl7-12(or 5)-(3~sulfo-propionylhydrazono)-5,7 58,9,10,12-hexa-hydronaphthacene with a dividend of $95•
S % : 7,47 (teoretisk 7,36) N % : 7,7 (teoretisk: 8,03). S % : 7.47 (theoretical 7.36) N % : 7.7 (theoretical: 8.03).
HV-spektrum: Xmax = 233 my; e = 29.200 HV spectrum: Xmax = 233 my; e = 29,200
Xmax = 252 my; e = 20.920 Xmax = 252 my; e = 20,920
Xmax = 288 my; e'= 6.100 Xmax = 288 my; e'= 6,100
Eksempel 2. Example 2.
Man oppløser 0,6 g hydrokiorid av daunorubicin med 65 ml etylalkohol inneholdende 2,5$ eddiksyre og tilsetter 0,369 g Girards reagens T. Man oppvarmer i 4 timer under omrøring ved 40°C. Man konsentrerer til tørrhet under nedsatt trykk (20 mm Hg) og oppløser det dannede residuum med 50 ml vann. Man eliminerer en liten mengde uopp-løselig materiale ved filtrering og lyofiliserer hele filtratet. 0.6 g of the hydrochloride of daunorubicin is dissolved with 65 ml of ethyl alcohol containing 2.5% acetic acid and 0.369 g of Girard's reagent T is added. The mixture is heated for 4 hours with stirring at 40°C. Concentrate to dryness under reduced pressure (20 mm Hg) and dissolve the residue formed with 50 ml of water. A small amount of insoluble material is eliminated by filtration and the entire filtrate is lyophilized.
Man får således 0,855 g hydrokiorid av dikloridet av 4-metoksy-5 (eller 12-)-okso-6,9/^trihydroksy-7-(0-2,3,6-trideoksy-3-amino-l-L-lykso-heksosyl)-9-/<->(1-trimetylammonioacetylhydrazono)-etyl7-12(eller 5)-(trimetylammonioacetylhydraizono)-5,7,8,9,10,12-heksahydro-naftacen. Thus, 0.855 g of the hydrochloride of the dichloride of 4-methoxy-5 (or 12-)-oxo-6,9β-trihydroxy-7-(0-2,3,6-trideoxy-3-amino-1-L-lyxo- hexosyl)-9-/<->(1-trimethylammonioacetylhydrazono)-ethyl7-12(or 5)-(trimethylammonioacetylhydraizono)-5,7,8,9,10,12-hexahydro-naphthacene.
Cl % : 12,07 (teoretisk: 12,32). Cl%: 12.07 (theoretical: 12.32).
UV-spektrum: Xmax = 233 my; e = 38.200 UV spectrum: Xmax = 233 my; e = 38,200
Xmax = 252 my; e = 27.500 Xmax = 252 my; e = 27,500
Xmax = 290 my; e = 7-720. Xmax = 290 my; e = 7-720.
Eksempel 3. Example 3.
Man oppløser 0,5 g hydrokiorid av daunorubicin med 80 ml etylalkohol inneholdende 2,5# eddiksyre. Man tilsetter 0,084 g tiosemikarbazid, oppvarmer i 4 timer under omrøring i 40°C. Man om-rører deretter i 42 timer ved værelsetemperatur og konsentrerer til tørrhet under nedsatt trykk (25 mm Hg) og oppløser det tørre residuum med 80 ml vann. Man frafiltrerer en liten mengde uoppløselig materiale og lyofiliserer deretter filtratet. Man får således 0,483 g hydrokiorid av 4-metoksy-5,12-diokso-6,9,H-trih<y>droks<y->7-(0-2,3,5- • trideoksy-3-amino-L-lyksoheksosyl)-9-/—(l-t iosemikarbazono)-etyl7- 0.5 g of daunorubicin hydrochloride is dissolved in 80 ml of ethyl alcohol containing 2.5% acetic acid. 0.084 g of thiosemicarbazide is added, heated for 4 hours with stirring at 40°C. The mixture is then stirred for 42 hours at room temperature and concentrated to dryness under reduced pressure (25 mm Hg) and the dry residue is dissolved with 80 ml of water. A small amount of insoluble material is filtered off and the filtrate is then lyophilized. 0.483 g of the hydrochloride of 4-methoxy-5,12-dioxo-6,9,H-trihydroxy-7-(0-2,3,5- • trideoxy-3-amino- L-lyxohexosyl)-9-/—(l-thiosemicarbazono)-ethyl7-
5,7,8,9,10,12-heksahyd.ro-naftac en. 5,7,8,9,10,12-hexahydr.ro-naphthac en.
N % : 8,85 (teoretisk: 8,79) S #:.5,0 (teoretisk: 5,03). N % : 8.85 (theoretical: 8.79) S #:.5.0 (theoretical: 5.03).
UV-spektrum: Xmax = 232 my; e = 32.250 UV spectrum: Xmax = 232 my; e = 32,250
Xmax = 257 my; e = 32.225. Xmax = 257 my; e = 32,225.
Eksempel 4. Example 4.
Man oppløser 0,6 g hydrokiorid av daunorubicin i 30 ml etylalkohol inneholdende 2, 5% eddiksyre. Man fremstiller separat en oppløsning av 0,151 g amminoguanidin i 1,09 ml l-n saltsyre. Man blander disse to oppløsninger og oppvarmer i 4 timer til 50°C. Man lar deretter blandingen stå i 42 timer ved værelsetemperatur og konsentrerer deretter til tørrhet under nedsatt trykk (25. mm Hg). Man oppløser med 60 ml vann, filtrerer en liten mengde uoppløselig materiale og lyofiliserer filtratet. Man får således 0,64 g dihydro-klorid av 4-metoksy-5,12-diokso-6,9,ll-trihydroksy-7-(0-2,3,6-tri-deoksy-3-amino-l-L-lyksoheksosyl)-9-/~1-(amidinohydrazono)-etyl/- 5,7,8,9,10,12-heksahydro-naftacen. 0.6 g of daunorubicin hydrochloride is dissolved in 30 ml of ethyl alcohol containing 2.5% acetic acid. A solution of 0.151 g of aminoguanidine in 1.09 ml of 1-n hydrochloric acid is prepared separately. These two solutions are mixed and heated for 4 hours to 50°C. The mixture is then allowed to stand for 42 hours at room temperature and then concentrated to dryness under reduced pressure (25 mm Hg). Dissolve with 60 ml of water, filter a small amount of insoluble material and lyophilize the filtrate. 0.64 g of dihydrochloride of 4-methoxy-5,12-dioxo-6,9,11-trihydroxy-7-(0-2,3,6-tri-deoxy-3-amino-1-L- lyxohexosyl)-9-[1-(amidinohydrazono)-ethyl]-5,7,8,9,10,12-hexahydro-naphthacene.
N % : 10,72 (teoretisk: 10,66). N % : 10.72 (theoretical: 10.66).
UV-spektrum: Xmax = 233 my; e = 45-500 UV spectrum: Xmax = 233 my; e = 45-500
Xmax = 253 my; e = 27.800 Xmax = 253 my; e = 27,800
Xmax = 291 my; e = 8.515 Xmax = 291 my; e = 8.515
Eksempel 5. Example 5.
Man oppløser 0,4 g hydrokiorid av daunorubicin i 60 ml 0.4 g of daunorubicin hydrochloride is dissolved in 60 ml
etylalkohol inneholdende 2,5$ eddiksyre og tilsetter deretter 0,135 g tiosemikarbazid. Man oppvarmer den dannede blanding i 12 timer under omrøring ved 45°C. Man konsentrerer til tørrhet under redusert trykk og oppløser residuet med 50 ml vann. Den dannede oppløsning lyofili-seres. Man får således 0,476 g hydrokiorid av 4-metoksy-5_(eller 12)-okso-6,9,ll-trihydroksy-7-(0-2-, 3, e-trideoksy-S-amino-l-L-lykso-heksosyl)-9-/~l- (tiosemikarbazono)-etyl7-12(eller 5)-(tiosemi-karbazono)^,7,8,9,10,12-heksahydro-naftacen i et utbytte på 89$. ethyl alcohol containing 2.5% acetic acid and then adds 0.135 g of thiosemicarbazide. The resulting mixture is heated for 12 hours with stirring at 45°C. Concentrate to dryness under reduced pressure and dissolve the residue with 50 ml of water. The resulting solution is lyophilized. 0.476 g of the hydrochloride of 4-methoxy-5_(or 12)-oxo-6,9,11-trihydroxy-7-(0-2-,3,e-trideoxy-S-amino-1-L-lyxo-hexosyl) is thus obtained )-9-/~1-(thiosemicarbazono)-ethyl7-12(or 5)-(thiosemicarbazono)^,7,8,9,10,12-hexahydro-naphthacene in a yield of 89$.
Cl % : 4,97 (teoretisk: 4,99) S % : 8,90 (teoretisk: 9,02). Cl % : 4.97 (theoretical: 4.99) S % : 8.90 (theoretical: 9.02).
UV-spektrum: Xmax = 233 my; £ = 42.000 UV spectrum: Xmax = 233 my; £ = 42,000
Xmax = 257 my; e = 31.800. Xmax = 257 my; e = 31,800.
Eksempel 6. Example 6.
Til en oppløsning av 16 g hydrokiorid av daunorubicin i 1,6 1 av en blanding av etanol og eddiksyre i volumforhold 97,5 : 2,5 setter man 4,18 g benzoylhydrazid. Man oppvarmer under tilbakeløp og omrøring i 20 timer. Etter avkjøling adskilles den dannede utfelling ved filtrering, vaskes med etanol og tørkes under nedsatt trykk 4.18 g of benzoyl hydrazide is added to a solution of 16 g of the hydrochloride of daunorubicin in 1.6 1 of a mixture of ethanol and acetic acid in a volume ratio of 97.5:2.5. It is heated under reflux and stirring for 20 hours. After cooling, the formed precipitate is separated by filtration, washed with ethanol and dried under reduced pressure
(0,3 mm Hg) ved 20°C. (0.3 mm Hg) at 20°C.
Filtratet konsentreres til tørrhet under nedsatt trykk The filtrate is concentrated to dryness under reduced pressure
(30 mm Hg) ved 50°C. Det dannede residuum oppløses i varm etanol. (30 mm Hg) at 50°C. The residue formed is dissolved in hot ethanol.
Etter avkjøling atfkjliles den dannede utfelling ved filtrering, vaskes After cooling, the formed precipitate is cooled by filtration, washed
med etanol og tørkes under nedsatt trykk (0,3 mm Hg) ved 20°C. with ethanol and dried under reduced pressure (0.3 mm Hg) at 20°C.
De to således dannede produkter forenes, idet man får The two products formed in this way are combined to give
18,7 g hydrokiorid av 4-metoksy-5,12-diokso-6,9,ll-trihydroksy-7-(0-2,3,6-tridesoksy-3-amino-l-L-lyksoheksosyl)-9-(l-benzoyl-hydrazonoetyl)-5,7,8,9,10,12-heksahydronaftacen i form av et rødt pulver. 18.7 g of the hydrochloride of 4-methoxy-5,12-dioxo-6,9,11-trihydroxy-7-(0-2,3,6-tridesoxy-3-amino-1-L-lyxohexosyl)-9-(1 -benzoyl-hydrazonoethyl)-5,7,8,9,10,12-hexahydronaphthacene in the form of a red powder.
N % = 6,4 (teoretisk = 6,l6), Cl % 4,7 (teoretisk = 5,19) N % = 6.4 (theoretical = 6.16), Cl % 4.7 (theoretical = 5.19)
C % = 60,0 (teoretisk = 59,86), H % = 5,4 (teoretisk = 5,20). C % = 60.0 (theoretical = 59.86), H % = 5.4 (theoretical = 5.20).
Ved å arbeide på samme måte og idet det gåes ut fra By working in the same way and assuming that
egnede utgangsmaterialer fremstilles også følgende forbindelser: suitable starting materials also produce the following compounds:
Hydrokiorid av 4-metoksy-5,12-diokso-6,9,H-trihydroksy-7-(0-2,3,6-tridesoksy-3-amino-l-L-(lyksoheksosyl)-9-/<->l-(4-metyltio-semikarbazono)etyl7-5,7,8,9,10,12-heksahydronaftacen i form av et rødt, lyofilisert pulver. 4-Methoxy-5,12-dioxo-6,9,H-trihydroxy-7-(0-2,3,6-tridesoxy-3-amino-1-L-(lyxohexosyl)-9-/<->1) hydrochloride -(4-methylthio-semicarbazono)ethyl7-5,7,8,9,10,12-hexahydronaphthacene in the form of a red, lyophilized powder.
N % 8,45 (teoretisk 8,60), S % = 4,89 (teoretisk 4,91). N % 8.45 (theoretical 8.60), S % = 4.89 (theoretical 4.91).
Hydrokloridet av 4-metoksy-5,12-diokso-6,9,ll-trihydroksy-7-(0-.2,3,6-tridesoksy-3-amino-l-L-lyksoheksosyl )-9-/-l-(4-isobutyl-tiosemikarbazono)etyl7-5,7,8,9,10,12-heksahydronaftacen i form av et rødt, lyofilisert pulver: The hydrochloride of 4-methoxy-5,12-dioxo-6,9,11-trihydroxy-7-(0-.2,3,6-tridesoxy-3-amino-1-L-lyxohexosyl )-9-/-1-( 4-isobutyl-thiosemicarbazono)ethyl7-5,7,8,9,10,12-hexahydronaphthacene in the form of a red, lyophilized powder:
N % = 12,53 (teoretisk 11,92), S % = 7,79 (teoretisk 7,79). N % = 12.53 (theoretical 11.92), S % = 7.79 (theoretical 7.79).
UV-spektrum: Xmax = 232 nm; e = '41.510 UV spectrum: Xmax = 232 nm; e = '41,510
Xmax = 255 nm; e = 33.680. X max = 255 nm; e = 33,680.
Claims (1)
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| FR124943 | 1967-10-18 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| NO123574B true NO123574B (en) | 1971-12-13 |
Family
ID=8640288
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| NO4114/68A NO123574B (en) | 1967-10-18 | 1968-10-17 |
Country Status (16)
| Country | Link |
|---|---|
| AT (1) | AT282823B (en) |
| BE (1) | BE722460A (en) |
| BR (1) | BR6803181D0 (en) |
| CH (1) | CH492697A (en) |
| DE (1) | DE1803892A1 (en) |
| DK (1) | DK128113B (en) |
| ES (1) | ES359293A1 (en) |
| FI (1) | FI49984C (en) |
| FR (2) | FR1578722A (en) |
| GB (1) | GB1212459A (en) |
| IE (1) | IE32420B1 (en) |
| IL (1) | IL30899A (en) |
| NL (1) | NL147151B (en) |
| NO (1) | NO123574B (en) |
| SE (1) | SE340449B (en) |
| YU (1) | YU33665B (en) |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| FR2007500A6 (en) * | 1968-04-24 | 1970-01-09 | Farmaceutici Italia |
-
1967
- 1967-10-18 FR FR124943A patent/FR1578722A/fr not_active Expired
-
1968
- 1968-01-15 FR FR136038A patent/FR7123M/fr not_active Expired
- 1968-09-19 FI FI682648A patent/FI49984C/en active
- 1968-10-11 NL NL686814582A patent/NL147151B/en unknown
- 1968-10-16 BR BR203181/68A patent/BR6803181D0/en unknown
- 1968-10-17 GB GB49280/68A patent/GB1212459A/en not_active Expired
- 1968-10-17 DK DK501468AA patent/DK128113B/en unknown
- 1968-10-17 BE BE722460D patent/BE722460A/xx unknown
- 1968-10-17 IE IE1233/68A patent/IE32420B1/en unknown
- 1968-10-17 NO NO4114/68A patent/NO123574B/no unknown
- 1968-10-17 SE SE14021/68A patent/SE340449B/xx unknown
- 1968-10-17 CH CH1554168A patent/CH492697A/en not_active IP Right Cessation
- 1968-10-18 DE DE19681803892 patent/DE1803892A1/en active Pending
- 1968-10-18 AT AT1019468A patent/AT282823B/en not_active IP Right Cessation
- 1968-10-18 YU YU2436/68A patent/YU33665B/en unknown
- 1968-10-18 IL IL30899A patent/IL30899A/en unknown
- 1968-10-18 ES ES359293A patent/ES359293A1/en not_active Expired
Also Published As
| Publication number | Publication date |
|---|---|
| FR7123M (en) | 1969-07-21 |
| IE32420L (en) | 1969-04-18 |
| ES359293A1 (en) | 1970-06-01 |
| NL147151B (en) | 1975-09-15 |
| BE722460A (en) | 1969-04-17 |
| IL30899A (en) | 1972-11-28 |
| DK128113B (en) | 1974-03-04 |
| FI49984C (en) | 1975-11-10 |
| FR1578722A (en) | 1969-08-22 |
| NL6814582A (en) | 1969-04-22 |
| DE1803892A1 (en) | 1969-05-29 |
| BR6803181D0 (en) | 1973-02-22 |
| IL30899A0 (en) | 1968-12-26 |
| SE340449B (en) | 1971-11-22 |
| IE32420B1 (en) | 1973-07-25 |
| YU33665B (en) | 1977-12-31 |
| AT282823B (en) | 1970-07-10 |
| CH492697A (en) | 1970-06-30 |
| FI49984B (en) | 1975-07-31 |
| GB1212459A (en) | 1970-11-18 |
| YU243668A (en) | 1977-06-30 |
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