IE60412B1 - New anthracyclines - Google Patents
New anthracyclinesInfo
- Publication number
- IE60412B1 IE60412B1 IE153887A IE153887A IE60412B1 IE 60412 B1 IE60412 B1 IE 60412B1 IE 153887 A IE153887 A IE 153887A IE 153887 A IE153887 A IE 153887A IE 60412 B1 IE60412 B1 IE 60412B1
- Authority
- IE
- Ireland
- Prior art keywords
- epi
- glycoside
- formula
- group
- deoxy
- Prior art date
Links
- 229940045799 anthracyclines and related substance Drugs 0.000 title claims abstract description 11
- 150000002338 glycosides Chemical class 0.000 claims abstract description 30
- 229930182470 glycoside Natural products 0.000 claims abstract description 29
- 150000001875 compounds Chemical class 0.000 claims abstract description 21
- 150000003839 salts Chemical class 0.000 claims abstract description 17
- 239000002253 acid Substances 0.000 claims abstract description 12
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims abstract description 10
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims abstract description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 20
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 18
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 14
- 238000000034 method Methods 0.000 claims description 14
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 11
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 10
- 229960000975 daunorubicin Drugs 0.000 claims description 10
- 239000000203 mixture Substances 0.000 claims description 9
- SMQUZDBALVYZAC-UHFFFAOYSA-N salicylaldehyde Chemical compound OC1=CC=CC=C1C=O SMQUZDBALVYZAC-UHFFFAOYSA-N 0.000 claims description 8
- 229960004679 doxorubicin Drugs 0.000 claims description 7
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 6
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 6
- QAEDZJGFFMLHHQ-UHFFFAOYSA-N trifluoroacetic anhydride Chemical compound FC(F)(F)C(=O)OC(=O)C(F)(F)F QAEDZJGFFMLHHQ-UHFFFAOYSA-N 0.000 claims description 6
- 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 claims description 5
- 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 claims description 5
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 claims description 5
- 229910000041 hydrogen chloride Inorganic materials 0.000 claims description 5
- STQGQHZAVUOBTE-GKPNIHARSA-N (7s,9s)-9-acetyl-7-[(2r,4r,5s,6s)-4-amino-5-hydroxy-6-methyloxan-2-yl]oxy-6,9,11-trihydroxy-4-methoxy-8,10-dihydro-7h-tetracene-5,12-dione 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-GKPNIHARSA-N 0.000 claims description 4
- 238000005903 acid hydrolysis reaction Methods 0.000 claims description 4
- 238000006073 displacement reaction Methods 0.000 claims description 4
- 239000008194 pharmaceutical composition Substances 0.000 claims description 4
- 239000004280 Sodium formate Substances 0.000 claims description 3
- 230000003197 catalytic effect Effects 0.000 claims description 3
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 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
- 125000002827 triflate group Chemical group FC(S(=O)(=O)O*)(F)F 0.000 claims description 3
- 241001465754 Metazoa Species 0.000 claims description 2
- 238000005904 alkaline hydrolysis reaction Methods 0.000 claims description 2
- 150000008064 anhydrides Chemical class 0.000 claims description 2
- 239000002246 antineoplastic agent Substances 0.000 claims description 2
- 230000031709 bromination Effects 0.000 claims description 2
- 238000005893 bromination reaction Methods 0.000 claims description 2
- 239000003085 diluting agent Substances 0.000 claims description 2
- 239000003937 drug carrier Substances 0.000 claims description 2
- 230000003301 hydrolyzing effect Effects 0.000 claims description 2
- 125000006239 protecting group Chemical group 0.000 claims description 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 1
- 230000000259 anti-tumor effect Effects 0.000 abstract description 2
- 239000003795 chemical substances by application Substances 0.000 abstract 1
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 28
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 9
- 208000032839 leukemia Diseases 0.000 description 8
- SDWZXVTWORCAMD-MVGXARHUSA-N 2-[[3-hydroxy-2-methyl-6-[[(1s,3s)-3,5,12-trihydroxy-3-(2-hydroxyacetyl)-10-methoxy-6,11-dioxo-2,4-dihydro-1h-tetracen-1-yl]oxy]oxan-4-yl]amino]acetonitrile 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)C1CC(NCC#N)C(O)C(C)O1 SDWZXVTWORCAMD-MVGXARHUSA-N 0.000 description 7
- 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 6
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 6
- 239000003480 eluent Substances 0.000 description 6
- 239000002904 solvent Substances 0.000 description 6
- 239000011877 solvent mixture Substances 0.000 description 4
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- 238000006243 chemical reaction Methods 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 238000000338 in vitro Methods 0.000 description 3
- 239000012074 organic phase Substances 0.000 description 3
- 229910052938 sodium sulfate Inorganic materials 0.000 description 3
- 235000011152 sodium sulphate Nutrition 0.000 description 3
- 230000004083 survival effect Effects 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 2
- BVKZGUZCCUSVTD-UHFFFAOYSA-M Bicarbonate Chemical compound OC([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-M 0.000 description 2
- 101150041968 CDC13 gene Proteins 0.000 description 2
- 241000699670 Mus sp. Species 0.000 description 2
- 206010028980 Neoplasm Diseases 0.000 description 2
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 2
- 201000010897 colon adenocarcinoma Diseases 0.000 description 2
- 208000029742 colonic neoplasm Diseases 0.000 description 2
- 239000002054 inoculum Substances 0.000 description 2
- VNWKTOKETHGBQD-UHFFFAOYSA-N methane Natural products C VNWKTOKETHGBQD-UHFFFAOYSA-N 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 239000000741 silica gel Substances 0.000 description 2
- 229910002027 silica gel Inorganic materials 0.000 description 2
- 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 description 2
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- 238000011735 C3H mouse Methods 0.000 description 1
- 201000009030 Carcinoma Diseases 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-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
- NIPNSKYNPDTRPC-UHFFFAOYSA-N N-[2-oxo-2-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)ethyl]-2-[[3-(trifluoromethoxy)phenyl]methylamino]pyrimidine-5-carboxamide Chemical compound O=C(CNC(=O)C=1C=NC(=NC=1)NCC1=CC(=CC=C1)OC(F)(F)F)N1CC2=C(CC1)NN=N2 NIPNSKYNPDTRPC-UHFFFAOYSA-N 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 239000008346 aqueous phase Substances 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- 229910052794 bromium Inorganic materials 0.000 description 1
- 210000003679 cervix uteri Anatomy 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 239000012050 conventional carrier Substances 0.000 description 1
- 239000013058 crude material Substances 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- 230000001472 cytotoxic effect Effects 0.000 description 1
- 230000034994 death Effects 0.000 description 1
- 231100000517 death Toxicity 0.000 description 1
- FHHZOYXKOICLGH-UHFFFAOYSA-N dichloromethane;ethanol Chemical compound CCO.ClCCl FHHZOYXKOICLGH-UHFFFAOYSA-N 0.000 description 1
- FDSGHYHRLSWSLQ-UHFFFAOYSA-N dichloromethane;propan-2-one Chemical compound ClCCl.CC(C)=O FDSGHYHRLSWSLQ-UHFFFAOYSA-N 0.000 description 1
- 238000000434 field desorption mass spectrometry Methods 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- -1 toluensulfonic acid monohydrate Chemical class 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
Abstract
Anthracycline glycosides represented by the general formulae (I) and (II): in which R1 represents a hydrogen atom or a hydroxyl group, and their pharmaceutically acceptable addition salts with an acid. Use of these compounds as antitumour agents.
Description
j The invention relates to novel anthracycline glycoside derivatives/ to their preparation and to pharmaceutical compositions containing them™ The present invention provides anthracycline 5 glycosides having the general formulae (II): a: It, = H b: R1 = OH wherein R1 represents a hydrogen atom or hydroxyl group; and pharmaceutically acceptable acid addition salts thereof.
The invention also provides a process for the preparation of a glycoside of formula (II) wherein R.( represents a hydrogen acom? i.e. compound (Ila) , or a hydroxy grcip, i.e™ compound (lib) , or a phar aaceutically acceptable acid addition salt thereof, which process comprises converting 3'-deamino-4'-deoxv-3e-epi~4'- into the corresponding N-trifluoroacetyl derivative; converting the said N-trifluoroacetyl derivative into 4*deoxy-4"-epi-tr ifluoroacetamido-3’-deamino-3 8-hvdroxydaunorubicin; removing the K-trifluoroacetyl group from the 48-deoxy-4’-epi-tri fluoroacetarnido-3’-deamino™3’-hydroxydaunorubicin so as to obtain the glycos ) of formula (XI) wherein Rx is a hydrogen atom; if desired, converting the said glycoside of formula (II) into a pharmaceutically acceptable acid addition salt thereof; if desired, brominating the said glycoside of formula (II) or pharmaceutically acceptable salt thereof and hydrolysing the 14-bromo derivative thus obtained so as to form the glycoside of formula (II) wherein Rx is a hydroxy group; and, if desired, converting the said glycoside formula (II) wherein Rx is a hydroxy group into a pharmaceutically acceptable acid addition salt thereof.
Treatment of the 3’ f, 4'-epimino daunorubicin derivative (la) with trifluoroacetic anhydride gives the corresponding N-trifluoroacetyl derivative (Ve).
Reaction of this compound with a catalytic amount of sulfuric acid in acetone gives 43"deoxy-4’~epitr ifluoroacetamido-3 9-deamino-3hydroxy-daunorublein (VI) which,,, by treatment with aqueous sodium hydroxidet, gives the compound (Ila) . Typically,, the N-trifluoroacetyl group may be removed by mild alkaline hydrolysis» at a temperature of 0°C by means of 0.1N aqueous sodium hydroxide. Glycoside (Ha) can be isolated as its hydrochloride by treatment with hydrogen chloride in methanol.
The 3’-deamino-4’-deoxy-3'-epi-4’-epi-3’ t. 4’-epimino-daunorubicin» i.e. compound (la)f may be prepared by reacting 3’-epi-daunorubicin with salicylaldehvde so as to obtain the corresponding 39-epi-N-salicylidene derivative; converting the 4’-hydroxy group of the said 3'-epx-N-salicylidene derivative into a trifluocomethanesulfonate group; and removing from the 3’-epi-N-salicylidene-4’-O-trixluoromethanesulfonafce thus obtained the salicylidene group by acid hydrolysis so as to cause the 3’-deamino-4’-deoxy-3’-epi-4*-epi-3’» 4’-epimino-daunorubicin to be obtained via displacement of the 4’-O~trifluoromethanesulfonate group.
The compound (la) may therefore be prepared by reaction of the 3'-amino group of 3'-epi-daunorubicin (III) (F. Arcamone, A. Bargiotii, G. Cassinelli: Ger.Patent 2752115 (June 1, 1978)) with salicylaldehyde, in a mixture of water and acetone at room temperature, to obtain the corresponding 3*-epi-N~salicylidene derivative (IVc) which by treatment with trixluoromethanesulfonic anhydride in anhydrous methylene dichloride and in the presence of pyridine gives the corresponding 3’-epi-N-salicylidene4‘-’-•O-trifluoromethansulfonate (XVd). This compound, dissolved in methanol, can then be subjected to acidic hydrolysis of the salicylidene protecting group by means of p-fcoiuensulfonic acid at room temperature to give, via the displacement cf tr ifluoromethanesulfonate leaving group, the desired compound of formula (la).
The compound (lib) can be prepared by bromination of (Ila) followed by treatment of the resultant 14-bromo derivative with aqueous sodium formate at room temperature, according to the procedure described in United Patent Specification No. 3803124. It may be isolated as its hydrochloride in the same manner as glycoside (Ila).
The processes of the invention are summarised in the reaction scheme below.
The present invention also provides a pharmaceutical composition comprising as active ingredient an anthracycline glycoside of the Invention or 1- 5 pharmaceutically acceptable acid addition salt thereof together with a pharmaceutically acceptable carrier or J diluent. A therapeutically effective amount of a compound of formula (II) is combined with an inert carrier.
Conventional carriers may be used and the composition may be formulated in conventional manner.
The compounds of the invention are useful in methods of treatment of the human or animal body by therapy. In particular# the compounds of the invention are useful as antitumor agents JV c — d VI C Rn: OOHC-H.CH= o 4s d R2: OOHCgH^CHRj: OH R3: OSO2CF3 e : COCF3 The following Examples illustrate the invention.
EXAMPLE 1 3 -epi-N-salicylidene-daunorubicin (IVc) n solution of 2 c of 3’-epi-daunoruhicin (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 mins, ethyl acetate was added and the organic phase separated off, washed with water twice, dried over anhydrous sodium sulphate, filtered and evaporated to dryness under vacuum.
The residue was first triturated with hexan*·· ·ο eliminate the traces of salicylaldeyde, then collected an; dried under vacuum at 30°C to give (IVc) in almost quantitative yield. Rf 0.21 on TLC Kieselgel F 254 (Merck) using as eluent the solvent mixture CH^Cl .^-Acetone (8/2 v/v) .
EXAMPLE 2 3’-deamino-4-deoxy-3’-epi-4 9-epi-3·, 4 9-epiminv20 daunorubicin (la) To a solution of 2 g of 33-epi-N-salicylidene daunorubicin (IVc) in 20 ml of anhydrous dichloromethane and 2.ml of dry pyridine kept at -10°C, was added a solution of 0.8 ml of trifluoromethane sulfonic anhydride in 10 ml of dichloromethane. After 1 hour at -10°C, the mixture was diluted with dichloromethane and washed with water, cold 0.1M hydrochloric acid, cold aqueous 5% w/v sci hydrogen carbonate and water. The organic phase, dried over anhydrous sodium sulphate, was filtered off and the solvent removed in vacuo to give (IVd) Rf 0.50 on TC Kieselgel F 254 (Merck) using as eluent the solvent mixture CH2Cl2-Acetone (95/5 v/v).
The crude product was dissolved in 50 ml of methanol and 0.2 g of p~toluensulfonic acid monohydrate was added. The solution was kept at room temperature for 1 hour, then 100 ml of water was added and extracted with little dichloromethane. The aqueous phase was adjusted to pH 8 with 0.1M sodium hydroxyde and dichloromethane added. The organic phase was separated off, washed with water, dried over anhydrous sodium sulphate and the solvent evaporated to a small volume.
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 (la) was washed with water, evaporated in vacuum, picked up with a little dichloromethane and crystallised FD HS 509 [H+J m.p. 135-137°C Rf 0.38 on TLC Kieselgel F 254 (Merck) using as eluent the mixture CH3Cl2-CH30H~CH3eOOH-H2O (30/4/1/0.5 v/v). 1,(200 KHz t CDC13): 8.02 (dd, J«l.l, 7.7Hz, IH, H-l) 7.76 (dd, J=7.7, 7.7Hz, IH, H-2) „ 8 - 7.37 (dd, J=l.le 7.7Hz , IH, H-3) 5.31 (dd, J=3.0, 4.8Hz , IH, H-l’) 5.17 (dd, J=2»0, 3.6Hz , IH, H-7) 4.32 (qd, J=<1, 6.7Hz , IH, H-5’) 4.07 (S, 3H, OCH3-4) 3.17 (dd, J=19.2Hz, 1H , H-lOe) 2.95 (d, J=19.2Hz, IH, H-lOax) 2.46 (ddd, J=2.0, 2.0, 15.0Hz, IH, H-8e) 2.43 (S, 3H, COCH3) 2.30 (ddd, J-1.5, 4.3, 6.4Hz, IH, H-3) 1.9-2 .0 (m, 2H, H-eax, H-2ax, 1.87 (ddd, J~1.5, 3.0, 14.6Hz, IH. H2’e) 1.44 (d, J=6.7Hz, 3H, CH3-59) EXAMPLE 3 ' "deamino-4 -deoxy-? ’ -hydroxv·-» *-epi-4 ’ -aminodaunorubicin (Ila) The title compound was prepared starting fioir. the asir idine la. Ig of la was transformed into the N-trifluoroacetyl derivative Ve by treatment with 1.2 ml of trifluoroacetic anhydride in anhydrous methylene dichloride. After work up the crude material (Rf 0.'/ on TLC, Kieselgel F 254 (Merck) using as eluent the solvent mixture CH^Cl^-Aeetone (4/1 v/v)] was dissolved in 20 ml of acetone and treated with a catalytic amount of sulfuric acid at 10°C.
T.he mixture was diluted with 200 ml of methylene dichloride# washed with water# aqueous 5% w/v so+ hydrogen carbonate and water, The solvent was removed in j vacuum and the residue purified on a column of silica gel using methylene dichloride as the eluting system to afford 0.7 g of pure VI.
Rf 0.21 on TLC# Kieselgel F 254 (Merck) using as eluent the solvent mixture CH2C12-Acetone (4/1 v/v).
The product VI was slowly dissolved in aqueous 0.1N sodium hydroxide, at 0°C in order to perform the hydrolysis of the N-trifluoroacetyl protecting group.
After 1 hour at 0°C, th® solution was adjusted to pH 8.6 with 0.1N hydrochloric acid and extracted with methylene dichloride. The solvent was evaporated off, affording 0.5 g of a residue that was converted by treatment with methanolic hydrogen chloride into the hydrochloride of 4'-deoxy-4'-amino-4'-epi-3'~deamino3e’ -hydroxy-daunorubi cin.
MS FD 527 (K+h m.p.l53°C (dec).
Rf 0.18 on TLC Kieselgel F 254 (Merck) using the solvent system CH,Cl2~CH3OH~CH3CQQH~HZO (30/4/1/0.5 v/v) 1 A'H a - NMR (200 MH?, CDC13) 8.02 (dd, 1^0.9 , 8.5Hz, IH, H-l) 7.77 (dd, , 3.5Hz, IH, H-2) 7.38 (dd, J-0.9 , 8.5Hz, IH, H-3 ) 5.52 (dd, J=<1, 4.0Hz, IH, H-lf ) .28 (dd, J=1.8, 4.0Hz, IH, H-7) 4.07 (S, 3H, OCH3-4) 3.69 (dq, J=6.3, 9-5Hz, IH, H-5’) 3.51 (ddd, J=4.8, 9.5, 11.6Hz, IH, H- 3.22 (dd, Js1.9, 18.9Hz , IH, H-lOe) 2.94 (d, J-18.9Hz, IH, H-iOax) 2.40 (s, 3H, COCH3) 2.2-2 .4 (in, IH, H-8ax) 2.30 (dd, J=9.5, 9.5Hz, IH, H-4 9 ) 2.0-2 .2 (m, 2H, H-8e, H -2 *e) 1.70 ’ (ddd, J = 4.0, 4..6, 13.2Hz, IH, H· 1.31 (d, J=6.3Kz, 3H, CH3-53) EXAMPLE 4 39»deamino-3’"hydroxy-4 ‘-deoxy-A’-ep amino-doxorubicin (lib) 0.5 g of Ila was dissolved in a mixture of methanol and dioxane. The solution was treated„ as described in united Patent Specification No.3,803,124 first with bromine to give the 14-bromo-derivative and then with aqueous sodium formate to give the title com-.'ound.
This was converted into its hydrochloride by treatment with methanolic hydrogen chloride. FD-MS 543 (M+)„ TLC on Kieselgel F 254 (Merck) using the solvent system CHjCl2"CH3OH~CH3COOH~H9O (30/4/1/0.5 v/v) Rf 0.10.
The cytotoxic activity of the new anthracycline glycoside of the invention (Ila) was tested in vitro against HeLa cells P388, P388/DX, LoVo and LoVo/DX.
Time of exposure to the compound: 24 hours/in comparison with daunorubicin.
The results are shown in Table 1.
The compound, when tested in vitro against P-388 ascitic leukemia and Gross leukemia, exhibited good antitumor activity, in comparison with daunorubicin, especially when orally administered.
The results are given in Tables 2 and 3.
Table 1 In vitro activity of 3i-deamino-4,-deoxy-3i=-hydrcxy-4I-epi=4 1-aniino-oaunorubicin (Ila) in comparison with DNR ID (ng/ml) Compound _____________________________ ~ _ . b) c) d) e) f) HeLa P388 P388/DX LoVo LoUo/Dx DNR ,5 730 43 820 I CN «"Ί i I la 24,5 235 230 a) Dose giving 50% reduction of cell number in comparison with untreated controls. b) Human cervix epithelioid carcinoma cells c) P 388 leukemia cells sensitive to Doxorubicin . . d) P 238 leukemia cells resistant' to Doxorubicin e) Human colon adenocarcinoma cells Sensitive to Doxorubicin f) Human colon adenocarcinoma cells resistant to ,κ ubicin Table 2 Effect against P 383 ascitic leukemia Compound dose T/C%C ... . d lox ic deaths DiJR 2.9 155 0/10 Xj « 170 8/10 Ila 1.96 Ί55 0/10 2.9 150 0/10 ' 140 9/10 6.6 100 10/10 ^CxDeriments were performed in CDF. mice, inccnlated '.’ith 10 leukemia cells i.p. b Treatment i.p. on day 1 ePei tumor inoculum.
'Median survival time of treated mice/mecian controls x 100. :ur Evaluated on the basis of autoptic findings. - 14 Table 3 Effect against Gross leukemia Compound dose mg/Kg T/c%c DNR 10 15 165 192 G/20 2/20 Ila 8.2 . 175 0/20 11.5 230 0/10 Toil 240 0/10 22.5 130 0/10 atxpegiments were performed in C3H mice, inocul, 2x10 leukemia cells i.v. b Treatment i.v. on day 1 after tumor inoculum. :ed CMedian survival time of treated tnice/median survival time of controls x 100. d Evaluated on the basis of autoptic findings.
Claims (12)
1. An anthracvcline glycoside having the genetc'. formula (II): OH (II) II a,b where j 5 1 represents a hydrogen atom or a hydroxyl group, 5 and pharmaceutically acceptable acid addition salts thereof.
2. - A compound according to claim 1» which is 3 ’-deamino~4-deoxy-3 *-hydroxy-4’-epi-4'-amino-daunorubicin or its hydrochloride. 10 3. A compound according to claim 1, which is
3. '-deamino-4 ,J -deoxy-3 ’-hydroxy-4 ? -epi-4 ’-amino-doxorubicin or its hydrochloride.
4. Ά process for the preparation of a glycoside of formula (II) as defined an claim 1 or a pharmaceutically 15 acceptable salt thereof, which process comprises converting 3-deamino-4'-deoxy-3’-epi-4'-epi-3’,4’-epimino-daunorubicin into the corresponding N-trifluoroacetyl derivative; converting the said N-trifluoroacetyl derivative into 4 a -deoxv-4“epi-ttrrluoroacetamidor 3 5 -deamino-3’-hydroxy daunorubicin; removing the N-trifluoroacetyl group from the 4 e -deoxy-4 9 -epi- k tr ifluoroacetamido-3 u -dearnino-3’-hydroxy 5. Daunorubicin so as to obtain the glycoside of formula (II) wherein R^ is a hydrogen atom; if desired, converting the said glycoside of formula (II) into a pharmaceutically acceptable acid addition salt thereof; if desired# brominating the said glycoside of formula (II) or 10 pharmaceutically acceptable salt thereof and hydrolysing the l4-bromo derivative thus obtained so as to form the glycoside of formula (II) wherein R^ is a hydroxy group; and# if desired, converting the said glycoside of formula (II) wherein is a hydroxy group into a pharmaceutically 15 acceptable acid addition salt thereof.
5. A process according to claim 4, wherein the 3'-deamino-4-deoxy-3’-epi-4 e -epi«3’#4’-epiminodaunorubicin is reacted with trifluoroacetic anhydride to obtain the corresponding N-trifluoroacetyl derivative 20 which, by treatment with a catalytic amount of sulfuric acid in acetone gives 4’-deoxy-4 9 epi-trifluoroacetamido-3 5 deamino -3’-hydroxy-daunorubicin; removing the N-trifluoroacetyl protecting group therefrom by mild alkaline hydrolysis, at a temperature of 0°C, by means of i. 25 O.lN ageuous sodium hydroxide; optionally, isolating the glycoside of formula (II) wherein is a hydrogen atom as its hydrochloride by treatment with hydrogen chloride in methanol; optionally, converting the said glycoside of formula (II) or hydrochloride thereof to the glycoside of formula (II) wherein is a hydroxy group by bromination followed by treatment of the resultant 14-bromo derivative with aqueous sodium formate at room temperature; and, optionally, isolating the said glycoside of formula (II) wherein is a hydroxy group as its hydrochloride by treatment with a methanolic solution of hydrogen chloride.
6. A process according to claim 4 or 5 wherein the 3 5 -deamino-4’-deoxy-3’-epi-4-epi-3, 4’-epiminodaunorubicin is prepared by reacting 3-epi-daunorubicin uifch salicylaldehyde so as to obtain the corresponding 3 -epi-N-salicylider';· derivative; converting the 4’-hydrcxy group of the said 3’- epi -N-salicylxdene derivative into a trifluoromethanesulfonate group; and removing from the 3’ep i-N-· salicylidene-4'-O-trifIuoromethanesulfonate thus obtained the salicylidene group by acid hydrolysis so as tc cause the 3'-deanino-4’-deoxy -3-epi-4'-epi-3’, 4 3 -epiminodaunorubicin to be obtained via displacement of the 4 s -O-trifluoromethanesulfonate group.
7. A process according to claim 6, wherein 3’-epi-daunorubicin dissolved in a mixture of water and acetone is reacted, at room temperature, with salicylaldehyde to obtain the corresponding 3*-epi~N~salicylidene derivative which is subsequently 18 treated, in anhydrous methyler.: ciculoride and in tr... presence of dry pyridine, with tr if luoromethanesul f or. ic anhydride to give the corresponding N-salicylidene-3'-epi-4’-O-trifluoromethanesulfonate of which the 5 salicylidene, protecting group is subjected to acidic hydrolysis by means of p-toluensulfonic acid, at room temperature with the said trifluorornethanesulfonate being dissolved in methanol, to obtain, via the displacement of the trifluorornethanesulfonate leaving group, the 10 3'-deamino-4’-deoxy-3’-epi-4’-epi-3’, 4’-epiminodaunqrubjcin.
8. » A pharmaceutical composition comprising an antnracycline glycoside of formula (II) as defined in claim 1 or a pharmaceutically acceptable acid addition 15 salt thereof» together with a pharmaceutically acceptable carrier or diluent, ?. An anthracycline glycoside of formula (IX) ss defined in claim 1, or a pharmaceutically acceptable salt thereof, for use in a method of treatment 20 of the human or animal body by therapy10. An anthracycline glycoside or salt thereof according to claim 9 for use an an antitumor agent.
9. 11. A process for the preparation of an anthracycline glycoside of formula (ΪΧ) as defined in claim 25 1 or a pharmaceutically acceptable salt thereof, said process being substantially as hereinbefore described in - 19 Example 3 or Examples 3 and 4 together.
10. 12. An anthracycline glycoside, as defined in J acia addition claim 1 or a pharmaceutically acceptable/salt thereof whenever prepared by a process as claimed in any of claims 4 to 7 or claim 11. as defined in
11. 13« An anthracycline glycoside acid additipn , . claim 1 or a pharmaceutically acceptableysalt thereof substantially as hereinbefore described with reference to Example 3 or Examples 3 and 4 together. as defined in Claim 8»
12. 14«. A pharmaceutical composition/substantially as hereinbefore described by way of Example.
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB868614323A GB8614323D0 (en) | 1986-06-12 | 1986-06-12 | Anthracyclines |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| IE871538L IE871538L (en) | 1987-12-13 |
| IE60412B1 true IE60412B1 (en) | 1994-07-13 |
Family
ID=10599357
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| IE153887A IE60412B1 (en) | 1986-06-12 | 1987-06-10 | New anthracyclines |
Country Status (24)
| Country | Link |
|---|---|
| JP (1) | JP2516769B2 (en) |
| KR (1) | KR950004897B1 (en) |
| AT (1) | AT392793B (en) |
| AU (1) | AU595328B2 (en) |
| BE (1) | BE1000158A4 (en) |
| CA (1) | CA1291122C (en) |
| CH (1) | CH676985A5 (en) |
| DE (1) | DE3719377C2 (en) |
| DK (1) | DK169076B1 (en) |
| ES (1) | ES2006488A6 (en) |
| FI (1) | FI84075C (en) |
| FR (1) | FR2600066B1 (en) |
| GB (2) | GB8614323D0 (en) |
| GR (1) | GR870909B (en) |
| HU (1) | HU196220B (en) |
| IE (1) | IE60412B1 (en) |
| IL (1) | IL82820A0 (en) |
| IT (1) | IT1215552B (en) |
| NL (1) | NL8701349A (en) |
| NZ (1) | NZ220604A (en) |
| PT (1) | PT85056B (en) |
| SE (1) | SE500732C2 (en) |
| SU (1) | SU1590045A3 (en) |
| ZA (1) | ZA874202B (en) |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| DE3842836A1 (en) * | 1988-12-20 | 1990-06-21 | Behringwerke Ag | RHODOMYCINE WITH A MODIFIED CARBOHYDRATE UNIT |
| GB9325417D0 (en) * | 1993-12-13 | 1994-02-16 | Erba Carlo Spa | 3'- aziridino-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 |
| WO2000026223A2 (en) * | 1998-11-02 | 2000-05-11 | Board Of Regents, The University Of Texas System | Methods and compositions for the manufacture of highly potent anthracycline-based antitumor agents |
| GB0114654D0 (en) * | 2001-06-15 | 2001-08-08 | Pharmacia & Upjohn Spa | Anti-tumor compound |
| CN110483871A (en) * | 2019-08-15 | 2019-11-22 | 陈全明 | A kind of HDPE double-wall corrugated pipe of anti-pressure and abrasion-proof |
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| US3803124A (en) * | 1968-04-12 | 1974-04-09 | Farmaceutici It Soc | Process for the preparation of adriamycin and adriamycinone and adriamycin derivatives |
| EP0051280B1 (en) * | 1980-11-01 | 1984-07-11 | FARMITALIA CARLO ERBA S.p.A. | Anthracycline glycosides, process for the preparation thereof, intermediate compounds and their preparation and pharmaceutical compositions |
| GB8508079D0 (en) * | 1985-03-28 | 1985-05-01 | Erba Farmitalia | Antitumor anthracyclines |
-
1986
- 1986-06-12 GB GB868614323A patent/GB8614323D0/en active Pending
-
1987
- 1987-05-19 CH CH1952/87A patent/CH676985A5/it not_active IP Right Cessation
- 1987-06-01 ES ES878701700A patent/ES2006488A6/en not_active Expired
- 1987-06-08 CA CA000539119A patent/CA1291122C/en not_active Expired - Fee Related
- 1987-06-08 NZ NZ220604A patent/NZ220604A/en unknown
- 1987-06-09 FR FR878708005A patent/FR2600066B1/en not_active Expired - Fee Related
- 1987-06-09 IL IL82820A patent/IL82820A0/en not_active IP Right Cessation
- 1987-06-09 PT PT85056A patent/PT85056B/en not_active IP Right Cessation
- 1987-06-09 FI FI872571A patent/FI84075C/en not_active IP Right Cessation
- 1987-06-09 IT IT8720834A patent/IT1215552B/en active
- 1987-06-09 AT AT1449/87A patent/AT392793B/en not_active IP Right Cessation
- 1987-06-09 GB GB8713443A patent/GB2195998B/en not_active Expired - Fee Related
- 1987-06-10 GR GR870909A patent/GR870909B/en unknown
- 1987-06-10 AU AU74108/87A patent/AU595328B2/en not_active Ceased
- 1987-06-10 IE IE153887A patent/IE60412B1/en not_active IP Right Cessation
- 1987-06-10 DE DE3719377A patent/DE3719377C2/en not_active Expired - Fee Related
- 1987-06-10 NL NL8701349A patent/NL8701349A/en not_active Application Discontinuation
- 1987-06-10 HU HU872657A patent/HU196220B/en unknown
- 1987-06-10 BE BE8700645A patent/BE1000158A4/en not_active IP Right Cessation
- 1987-06-10 SE SE8702409A patent/SE500732C2/en unknown
- 1987-06-11 SU SU874202740A patent/SU1590045A3/en active
- 1987-06-11 DK DK298787A patent/DK169076B1/en active
- 1987-06-11 JP JP62146162A patent/JP2516769B2/en not_active Expired - Lifetime
- 1987-06-11 ZA ZA874202A patent/ZA874202B/en unknown
- 1987-06-11 KR KR1019870005911A patent/KR950004897B1/en not_active IP Right Cessation
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