GB2159518A - New anthracyclines and process for manufacture - Google Patents
New anthracyclines and process for manufacture Download PDFInfo
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- GB2159518A GB2159518A GB08513606A GB8513606A GB2159518A GB 2159518 A GB2159518 A GB 2159518A GB 08513606 A GB08513606 A GB 08513606A GB 8513606 A GB8513606 A GB 8513606A GB 2159518 A GB2159518 A GB 2159518A
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- United Kingdom
- Prior art keywords
- compound
- amino
- fluoro
- formula
- pharmaceutically acceptable
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- 229940045799 anthracyclines and related substance Drugs 0.000 title claims abstract description 8
- 238000000034 method Methods 0.000 title claims description 14
- 238000004519 manufacturing process Methods 0.000 title description 2
- 150000001875 compounds Chemical class 0.000 claims abstract description 35
- AOJJSUZBOXZQNB-TZSSRYMLSA-N Doxorubicin Chemical class 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 claims abstract description 20
- STQGQHZAVUOBTE-VGBVRHCVSA-N daunorubicin Chemical class 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 abstract description 15
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims abstract description 13
- 239000000203 mixture Substances 0.000 claims abstract description 10
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims abstract description 8
- 229930182470 glycoside Natural products 0.000 claims abstract description 8
- 150000002338 glycosides Chemical class 0.000 claims abstract description 8
- 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 abstract description 8
- STQGQHZAVUOBTE-RPDDNNBZSA-N (7s,9s)-9-acetyl-7-[(2r,4s,5r,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-RPDDNNBZSA-N 0.000 claims abstract description 6
- 125000003277 amino group Chemical group 0.000 claims abstract description 6
- 238000004587 chromatography analysis Methods 0.000 claims abstract description 5
- 238000005903 acid hydrolysis reaction Methods 0.000 claims abstract description 4
- -1 benzophenone Schiff base Chemical class 0.000 claims abstract description 4
- 150000003840 hydrochlorides Chemical class 0.000 claims abstract description 4
- 239000000741 silica gel Substances 0.000 claims abstract description 4
- 229910002027 silica gel Inorganic materials 0.000 claims abstract description 4
- FPGGTKZVZWFYPV-UHFFFAOYSA-M tetrabutylammonium fluoride Chemical compound [F-].CCCC[N+](CCCC)(CCCC)CCCC FPGGTKZVZWFYPV-UHFFFAOYSA-M 0.000 claims abstract description 4
- 239000004280 Sodium formate Substances 0.000 claims abstract description 3
- HLBBKKJFGFRGMU-UHFFFAOYSA-M sodium formate Chemical compound [Na+].[O-]C=O HLBBKKJFGFRGMU-UHFFFAOYSA-M 0.000 claims abstract description 3
- 235000019254 sodium formate Nutrition 0.000 claims abstract description 3
- 230000000259 anti-tumor effect Effects 0.000 claims abstract 2
- 230000007062 hydrolysis Effects 0.000 claims abstract 2
- 238000006460 hydrolysis reaction Methods 0.000 claims abstract 2
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 47
- 229960000975 daunorubicin Drugs 0.000 claims description 20
- 239000002253 acid Substances 0.000 claims description 17
- 150000003839 salts Chemical class 0.000 claims description 17
- 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 14
- 238000002360 preparation method Methods 0.000 claims description 14
- 229960004679 doxorubicin Drugs 0.000 claims description 10
- 125000001153 fluoro group Chemical group F* 0.000 claims description 10
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 8
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 8
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 8
- 229910052757 nitrogen Inorganic materials 0.000 claims description 4
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 4
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 4
- SXZIXHOMFPUIRK-UHFFFAOYSA-N diphenylmethanimine Chemical compound C=1C=CC=CC=1C(=N)C1=CC=CC=C1 SXZIXHOMFPUIRK-UHFFFAOYSA-N 0.000 claims description 3
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 3
- 239000008194 pharmaceutical composition Substances 0.000 claims description 3
- JVBXVOWTABLYPX-UHFFFAOYSA-L sodium dithionite Chemical compound [Na+].[Na+].[O-]S(=O)S([O-])=O JVBXVOWTABLYPX-UHFFFAOYSA-L 0.000 claims description 3
- 206010028980 Neoplasm Diseases 0.000 claims description 2
- 239000004480 active ingredient Substances 0.000 claims description 2
- 239000003937 drug carrier Substances 0.000 claims description 2
- 125000004029 hydroxymethyl group Chemical group [H]OC([H])([H])* 0.000 claims description 2
- 125000006239 protecting group Chemical group 0.000 claims description 2
- 238000002560 therapeutic procedure Methods 0.000 claims description 2
- 238000006073 displacement reaction Methods 0.000 claims 1
- ITMCEJHCFYSIIV-UHFFFAOYSA-M triflate Chemical compound [O-]S(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-M 0.000 claims 1
- 235000000346 sugar Nutrition 0.000 abstract description 5
- 239000002262 Schiff base Substances 0.000 abstract description 2
- 239000002585 base Substances 0.000 abstract description 2
- 239000012965 benzophenone Substances 0.000 abstract description 2
- 239000007858 starting material Substances 0.000 abstract description 2
- 238000000926 separation method Methods 0.000 abstract 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 7
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-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
- 238000006243 chemical reaction Methods 0.000 description 6
- 239000003480 eluent Substances 0.000 description 6
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 5
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 4
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 4
- 239000002904 solvent Substances 0.000 description 4
- 239000011877 solvent mixture Substances 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 150000007513 acids Chemical class 0.000 description 3
- 238000000434 field desorption mass spectrometry Methods 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
- 229910052938 sodium sulfate Inorganic materials 0.000 description 3
- 235000011152 sodium sulphate Nutrition 0.000 description 3
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- 239000002246 antineoplastic agent Substances 0.000 description 2
- FHHZOYXKOICLGH-UHFFFAOYSA-N dichloromethane;ethanol Chemical compound CCO.ClCCl FHHZOYXKOICLGH-UHFFFAOYSA-N 0.000 description 2
- 229910052731 fluorine Inorganic materials 0.000 description 2
- 239000012458 free base Substances 0.000 description 2
- 239000000543 intermediate Substances 0.000 description 2
- 239000011541 reaction mixture Substances 0.000 description 2
- MWROBUNHUAIFQH-YBTHPKLGSA-N (7s,9s)-6,7,9,11-tetrahydroxy-9-(2-hydroxyacetyl)-8,10-dihydro-7h-tetracene-5,12-dione Chemical compound O=C1C2=CC=CC=C2C(=O)C2=C1C(O)=C1[C@@H](O)C[C@@](C(=O)CO)(O)CC1=C2O MWROBUNHUAIFQH-YBTHPKLGSA-N 0.000 description 1
- YOFDHOWPGULAQF-MQJDWESPSA-N (7s,9s)-9-acetyl-6,7,9,11-tetrahydroxy-4-methoxy-8,10-dihydro-7h-tetracene-5,12-dione Chemical compound C1[C@@](O)(C(C)=O)C[C@H](O)C2=C1C(O)=C1C(=O)C(C=CC=C3OC)=C3C(=O)C1=C2O YOFDHOWPGULAQF-MQJDWESPSA-N 0.000 description 1
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- ZUFQFGSMHXKORU-UHFFFAOYSA-N 9-acetyl-6,7,9,11-tetrahydroxy-8,10-dihydro-7h-tetracene-5,12-dione Chemical compound O=C1C2=CC=CC=C2C(=O)C2=C1C(O)=C1C(O)CC(C(=O)C)(O)CC1=C2O ZUFQFGSMHXKORU-UHFFFAOYSA-N 0.000 description 1
- IBZGBXXTIGCACK-CWKPULSASA-N Adriamycinone Chemical compound C1[C@@](O)(C(=O)CO)C[C@H](O)C2=C1C(O)=C1C(=O)C(C=CC=C3OC)=C3C(=O)C1=C2O IBZGBXXTIGCACK-CWKPULSASA-N 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- YOFDHOWPGULAQF-UHFFFAOYSA-N Daunomycin-Aglycone Natural products C1C(O)(C(C)=O)CC(O)C2=C1C(O)=C1C(=O)C(C=CC=C3OC)=C3C(=O)C1=C2O YOFDHOWPGULAQF-UHFFFAOYSA-N 0.000 description 1
- 239000000010 aprotic solvent Substances 0.000 description 1
- 239000008346 aqueous phase Substances 0.000 description 1
- 229940024874 benzophenone Drugs 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
- OSVHLUXLWQLPIY-KBAYOESNSA-N butyl 2-[(6aR,9R,10aR)-1-hydroxy-9-(hydroxymethyl)-6,6-dimethyl-6a,7,8,9,10,10a-hexahydrobenzo[c]chromen-3-yl]-2-methylpropanoate Chemical compound C(CCC)OC(C(C)(C)C1=CC(=C2[C@H]3[C@H](C(OC2=C1)(C)C)CC[C@H](C3)CO)O)=O OSVHLUXLWQLPIY-KBAYOESNSA-N 0.000 description 1
- 201000011510 cancer Diseases 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 125000004432 carbon atom Chemical group C* 0.000 description 1
- 239000012050 conventional carrier Substances 0.000 description 1
- ZKQFHRVKCYFVCN-UHFFFAOYSA-N ethoxyethane;hexane Chemical compound CCOCC.CCCCCC ZKQFHRVKCYFVCN-UHFFFAOYSA-N 0.000 description 1
- 150000004673 fluoride salts Chemical class 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- 229910052500 inorganic mineral Inorganic materials 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 239000011707 mineral Substances 0.000 description 1
- 235000010755 mineral Nutrition 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- XMGMFRIEKMMMSU-UHFFFAOYSA-N phenylmethylbenzene Chemical group C=1C=CC=CC=1[C]C1=CC=CC=C1 XMGMFRIEKMMMSU-UHFFFAOYSA-N 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 239000001488 sodium phosphate Substances 0.000 description 1
- 229910000162 sodium phosphate Inorganic materials 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 150000008163 sugars Chemical class 0.000 description 1
- RYFMWSXOAZQYPI-UHFFFAOYSA-K trisodium phosphate Chemical compound [Na+].[Na+].[Na+].[O-]P([O-])([O-])=O RYFMWSXOAZQYPI-UHFFFAOYSA-K 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
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Engineering & Computer Science (AREA)
- Biochemistry (AREA)
- Biotechnology (AREA)
- General Health & Medical Sciences (AREA)
- Genetics & Genomics (AREA)
- Molecular Biology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Saccharide Compounds (AREA)
Abstract
A new class of antitumoral anthracyclines glycosides of the general formula I and II: <IMAGE> wherein R<1> = H, OCH3 and R<2> is H, OH, is described. The used starting material is 4'-epi-daunorubicin or its 4-demethoxy analogue, which, after protection of the amino group on the sugar moiety as benzophenone Schiff base, are reacted with trifluoromethanesulfonic anhydride to obtain the corresponding 4'-epi-4'-O-trifluoromethanesulfonates from which, after treatment with n-tetrabutyl ammonium fluoride and a subsequent mild acidic hydrolysis of the N-protecting group, the daunorubicin derivatives of formula I and II are obtained as a mixture of free bases. A chromatography on a column of buffered silica gel allows the separation of the compounds I and II which are finally isolated at their hydrochlorides and transformed, in case, into their doxorubicin analogues via their 14-bromo derivatives and subsequent hydrolysis with aqueous sodium formate.
Description
SPECIFICATION
New anthracyclines and process for manufacture
The present invention relates to anthracycline glycoside derivatives, to their preparation and to pharmaceutical compositions containing them as well as to intermediates useful in the preparation of the glycosides.
The present invention provides anthracycline glycosides having the general formula I or II
wherein Rq represents an hydrogen atom or a methoxy group and R2 represents an hydrogen atom or an hydroxy group and pharmaceutically acceptable acid addition salts thereof.
Suitable acid addition salts include salts of the mineral acids such as hydrohalic acids, especially hydrochloric acid as well as salts of organic carboxylic and sulphonic acids especially acetic acid.
The present invention thus provides daunorubicin and doxorubicin analogs bearing a fluorine atom in the sugar moiety; more particularly the C-7 OH of the natural anthracyclinones, daunomycinone and adriamycinone, and the totally synthetic 4-demethoxydaunomycinone and 4-demethoxy-adriamycinone is glycosidically linked to the new sugars 2, 3,4,6-tetradeoxy-3-amino-4-fluoro-L-arabinohexopyranose Ill and 2,3,5,6-tetradeoxy-3-amino-5-fluoro-L-arabinohexo- furanose or 2,3,5,6-tetradeoxy-3-am ino-5-fluoro-D xylohexo- furanose IV. The above mentioned nomenclatures for the sugar IV derive from the uncertainty concerning the absolute configuration of the fluorine bearing carbon atom.
The present invention also provides the intermediates Ill and IV and compounds 2 to 7 shown in the
Reaction Scheme useful for the preparation of compounds of general formulas I and II. The present invention further provides a process for producing a compound of Formula (1) or (II) which process comprises protecting the amino group of a compound of Formula (V)
wherein R1 is as defined in relation to Formulae I and II converting the 4'-hydroxy group into a fluoro substituent, removing the amino protecting group and, if required converting the 14-methyl group into a hydroxy methyl group, and optionally thereafter forming a pharmaceutically acceptable acid addition salt.
The process of the invention are summarized in the following Reaction Scheme:
Reaction Scheme
The starting materials for the preparation of the new anthracyclines 6-9 a,b are: 4'-epidaunorubicin (1a) [see F. Arcamone et al., J. Med Chem. 18, 703 (1975)] and 4-demethoxy-4'!epidaunorubicin (ib) [see A. Di
Marco et al., Cancer Treat. Rep. 62, 375 (1978)].
In order to form the fluoro derivatives, the amino group on the sugar moiety is protected as a benzophenone Schiff base 2a,b, then treatment with trifluoromethane- sulfonic anhydrode in anhydrous methylene dichloride and in the presence of an organic base such as dry pyridine gives the corresponding 4'
epi-4'-O-trifluoromethanesulfonate 3a,b in almost quantitative yield.
Reaction of 3a,b with a fluoride salt in an aprotic solvent gives a mixture of products 4-5a,b.
Mild acidic hydrolysis of the N-diphenylmethylene protecting group yields the new daunorubicin deriv
atives 6-7a,b which are separated by chromatography.
The conversion of 6-7a,b to the corresponding doxo anaiogs 8-9a,b is performed as described in US
Patent 3,803,124 for the conversion of daunorubicin to doxorubicin via the 14-bromo-derivative The gly
cosides 6a (Ra = OCH3), 6b (Ra = H), 7a (R1 = OCH3), 7b (RI = H) and the corresponding doxo derivatives:
8a (R' = OCH3), 8b (R1 = H), 9a (R' = OCH3) and 9b (RI = H) are useful as antitumor agents.
The invention further provides a pharmaceutical composition comprising an anthracyclic glycosides of
the general formula I or II or a pharmaceutically acceptable acid addition salt thereof as active ingredient
together with a pharmaceutically acceptable carrier therefor.
The compositions may be formulated in conventional manner using conventional carriers.
The compounds of formulae (I) and (II) may be administered in therapeutically effective amounts by
conventional routes and in conventional dosage regimes such as those used for daunorubicin and doxo
rubicin.
The compounds of formulae (I) are useful in methods of treatment of the human or animal body by
therapy. In particular the compounds of formulae (I) and (II) are useful as antitumor agents.
The following Examples illustrate the invention.
EXAMPLE 1
Preparation of 4'-epi-N-(diphenylmethylene)-daunorubicin (2a) A solution of 2 g of 4-epidaunorubicin (1a) in 80 ml of dichloromethane was treated with 1 g of benzo
phenone imine at 35"C. After four hours the solvent was removed in vacuum and the residue was first
triturated with hexane to eliminate the traces of benzophenone imine then crystallized from diethyl ether
hexane to give 2a m.p. 190-195 C - FD-MS 691 (M+) Ref 0.35 on TLC Kieselgel F 254 (Merck) using as eluent the solvent mixture dichloromethane/acetone (8/2
v/v).
; EXAMPLE 2 Preparation of 4'-epi-4'-0-trifluoromethanesulfonate-N- (diphenylrnethylene)-daunorubicin (3a) To a solution of 2 g of 4'-epi-N-(diphenylmethylene)-dauno- rubicin (2a) in 40 ml of anhydrous dichlo
romethane and 0.3 ml of dry pyridine kept at -10 C under nitrogen, was added a solution of 0.6 ml of
trifluoromethanesulfonic anhydride in 10 ml of anhydrous dichloromethane. After 30 minutes the reaction
mixture was diluted with dichloromethane and washed with water, cold 0.1 N HCI, cold aqueous 5%
NaHCO3 and water.
The organic phase, dried over anhydrous sodium sulphate, was filtered off and the solvent removed in
vacuum to give 3a. Rf 0.6 on TLC Kieselgel F 254 (Merck) using as eluent the solvent mixture dichlorome
thane/acetone (95/5 v/v).
i PMR (200 M Hz, CDCI3): 1.39 (d, J=6.2 Hz, 3H, CH3), 1.79 (dd, J=5 3, 13.6 Hz, 1H, H2' eq), 2.07-2.2 (m, 1H,
H2' ax), 2.34 (s, 3H, COCH3), 3.86 (ddd, J=5 3, 9.5, 12,0 Hz, 1H, H-3'), 3.96 (dq, J=6 2, 9.5 Hz, 1H, H-5'), 4.07 (s, 3H, OCH3), 4.97 (dd, J=9.5, 9.5 Hz, 1H, H-4'), 5.26 (dd, J=2.4, 3.6 Hz, 1H, H-7), 5.46 (dd, J= < 1, 3.5
Hz, 1H, H-1'), 7 00-7.63 (m, 10H, (Ph)2C=N)
EXAMPLE 3
Preparation of 2', 3',4',6'-tetradeoxy-3'iamino-4'- fluoro-L-arabino-hexopyranosyl-daunorubicin (6a) and 2',3',5',6'-tetradeoxy-3'-amino-5'-fluoro-hexofuranosyl- daunorubicin (7a) To 1.5 g of 4'-epi-4'-O-trifluoromethanesulfonate-N- (diphenylmethylene)-daunorubicin (3a) dissolved in 8 ml of an hydros dichloromethane, was added a solution of anhydrous n-tetra-butylammonium fluoride (2 g) in 8 ml of anhydrous acetonitrile. The reaction mixture was kept at 0 C with stirring under nitrogen for 24 hours, then was poured into 500 ml of ethyl acetate. The organic phase was washed with water, dried over anhydrous sodium sulphate, filtered off and the solvent was removed in vacuum.
The crude mixture, containing 4a and 5a was treated with 0.1 N HCI in methanol for 1 hour at room temperature, then was diluted with water and extracted with dichloromethane in order to eliminate the aglycones.
The separated aqueous phase was adjusted to pH 8 with 0.1 N NaOH and extracted with dichloromethane.
The organic phase was separated, washed with water, dried over anhydrous sodium sulphate and evaporate in vacuum to small volume. The mixture was separated by chromatography on a column of silica gel, buffered at pH 7 with 0.1 M sodium phosphate, using dichloromethane-ethanol as eluent to give the fluoro derivative 6a, isolated as free base (m.p. 215"C, FD-MS 529 (M+)), Rf 0.31 on TLC Kieselgel
F 254 Merck using as eluent the solvent mixture dichloromethane/ethanol (9/1 v/v).
PMR (200 M Hz, CDCI3): 1.34 (dd, 3H, 6.2 Hz), 1.59 (ddd, 1H, J=4.0,13.0,13.0 Hz, H-2'ax), 2 03 (dddd, J= < 1, 5.0, 5.0, 13.0 Hz, 1H, H-2'eq), 2 41 (s, 3H, COCH3), 3.1-3 3 (m, 1H, H-3'), 3.85 (ddd, J=50.0, 9.4, 9.4 Hz, 1H,
H-4'), 3.9-4.1 (m, 1H, H-5'), 4.07 (s, 3H, OCH3), 5.27 (dd, J=2.2, 4 Hz, 1H, H-7), 5.44 (ddd, J= < 1, 3.0, 4.0 Hz,
1H, H-1')
and the fluoro derivative 7a as free base (m p. 210 dec. FD-MS 529 (my), RF 0.20 on TLC Kieselgel F 254
(Merck) using as eluent the solvent mixture dichlomethane/ethanol (9/1 v/v).
PMR (200 M Hz, CDCI3) 1.45 (dd, J=6.4, 24.8 Hz, 3H, CH3CHF), 1.83-1.96 (m, 1H, H-2'), 2.17 (ddb, J=6.0,
13.0 Hz, 1H, H-2'), 2.39 (s, 2H, COCH3), 3.57-3.82 (m, 2H, H-3', H-4'), 4.06 (s, 3H, OCH3), 4.78 (ddq, J=50.0, 6.4, 6.4 Hz, 1H, H-5'), 5.17 (dd, J=2 9, 4.0 Hz, 1H, H-7), 5.68 (bd, J = 5.5 Hz, 1H, H-1').
The free amino base 6a and 7a were transformed into the corresponding hydrochloride by treatment with methanolic HC1.
EXAMPLE 4
Preparation of 2',3',4' 6'-tetradeoxy-3'-amino-4'-fluoro- L-arabinohexopyranosyl-doxorubicin (8a)
A solution of 6a in a mixture of methanol and dioxane as described in US Patent 3,803,124, was treated with bromine to give 14-bromo derivative which by treatment with sodium formate afforded 8a converted by treatment with methanolic HCI into the hydrochloride.
EXAMPLE 5
Preparation of 2,3'5,6'-tetradeoxy-3'-amino-5'-fluoro- hexofuranosyl-doxorubicin (9a) Following the procedure described in Example 4, 7a was converted into its doxorubicin analog isolated as hydrochloride by treatment with methanolic HCI.
EXAMPLE 6
Preparation of 4demethoxy-4'-epi-4tO-trifluoromethane- sulfonate-N-(diphenylrnethylene)-daunorubicin (3b)
The title compound was prepared starting from 4-demethoxy- 4'-epi-daunorubicin (1b) via its N-diphenylmethylene derivative 2b prepared as described in the Example 1.
Treatment of 2b with trifluoromethanesulfonic anhydride in anhydrous dichloromethane and dry pyridine gave, after removal of the solvent, 4-demethoxy-4'-epi-4'-O-trifluoro- methanesulfonate-N-(diphenylmethylene) daunorubicin (3b).
EXAMPLE 7
Preparation of 4-demethoxy-2',3',4' 6'-tetradeoxy-3'-amino- 4'-fluoro-L-arabino-hexopyranosyl daunorubicin (sub) and 4-demethoxy-2 ',3 ', 5', 5'-tetra deoxy-3'-amino-5'-fluornhexo-furanosyi daunorubicin (7b) Compound 3b was transformed in its fluoro derivatives 6b and 7b by treatment with anhydrous n-tetrabutyl- ammonium fluoride in a mixture of an hydros dichloromethane and dry acetonitrile as described in Example 3.
Acidic hydrolysis of the mixture gave, after chromatography on a column of silica gel buffered at pH 7 using dichloromethane-ethanol as eluent, the pure 4-demethoxy-2',3',4',6'-tetradeoxy-3'-amino-4'-fluoro-L- arabino-hexopyranosyl daunorubicin (6b) and 4-demethoxy-2',3',5',6'-tetradeoxy-3'-amino-5'-fluoro-hexo- furanosyl daunorubicin (7b).
Both compounds were transformed into the hydrochloride derivative by treatment with methanolic HCI.
EXAMPLE 8
Preparation of 4-dernethoxy-2 ',3 ',4', 6'-tetradeoxy-3'- -amino-4'ifluoro-L-arabino-hexopyranosyl doxorubicin t8b) The title compound was prepared from 6b according to the procedure described in US Patent 3,803,124 and converted into the hydrochloride by treatment with methanolic HCI.
EXAMPLE 9
Preparation of 4-dernethoxy-2 ',3',5', 6'-tetradeoxy-3 '-amino- -5'-fluoro-hexofuranosyl doxorubicin (9b) The title compound was prepared from 7b according to the procedure described in US Patent 3,803,124 and converted into the hydrochloride by treatment with methanolic HCI.
Claims (21)
1. An antitumoral anthracycline glycoside having the general formula 1 or II:
wherein RI represents an hydrogen atom or a methoxy group and R2 represents an hydrogen atom or an hydroxy group or a pharmaceutically acceptable acid addition salt thereof.
2. A compound according to claim 1, which is 2',3',4',6'- tetradeoxy-3'-amino-4'-fluoro-L-arabino-hexo- pyranosyl- daunorubicin or a pharmaceutically acceptable acid addition salt thereof.
3. A compound according to claim 1, which is 4-demethoxy- 2',3',4',6'-tetradeoxy-3'-amino-4'4luoro-L- hexopiranosyl daunorubicin or a pharmaceutically acceptable acid addition salt thereof.
4. A compound according to claim 1, which is 2',3',4',6'- tetradeoxy-3'-amino-4',fluoro-L-arabino-hexopyranosyl- doxorubicin or a pharmaceutically acceptable acid addition salt thereof.
5. A compound according to claim 1, which is 4-demethoxy- 2',3',4',6'-tetradeoxy-3'-amino-4'fluoro-L- arabino- hexopyranosyl doxorubicin or a pharmaceutically acceptable acid addition salt thereof.
6. A compound according to claim 1, which is 2',3',5',6'- tetradeoxy-3'-amino-5'-fluoro-hexofuranosyl daunorubicin or a pharmaceutically acceptable acid addition salt thereof.
7. A compound according to claim 1, which is 4-demethoxy- 2',3',5',6'-tetradeoxy-3'-amino-5'-fluoro- hexofuranosyl daunorubicin or a pharmaceutically acceptable acid addition salt thereof.
8. A compound according to claim 1, which is 2',3',5',6'-tetradeoxy-3'-amino-5'-fluoro-hexofuranosyl doxorubicin or a pharmaceutically acceptable acid addition salt thereof.
9. A compound according to claim 1, which is 4-demethoxy- 2',3',5',6'-tetradeoxy-3'-amino-5'-fluoro- hexofuranosyl doxorubicin or a pharmaceutically acceptable acid addition salt thereof.
10. A process for producing a compound of Formula (I) or (II) which process comprises protecting the amino group of a compound of formula (V)
wherein R1 is as defined in relation to Formulae I and II, converting the 4'-hydroxy group into a fluoro substituent, removing the amino protecting group and, if required converting the 14-methyl group into a hydroxy methyl group, and optionally thereafter forming a pharmaceutically acceptable acid addition salt.
11. A process for the preparation of a giycosidic compound of the general formula I or II, according to claim 1, wherein R1 is an hydrogen atom or a methoxy group and R2 is an hydrogen atom or an hydrogen atom or an hydrogen group, characterised in that 4'-epi-daunorubicin or its 4-demethoxy analogue, dissolved in dichloromethane, are reacted with benzophenone imine, at a temperature of 35"C, to obtain their corresponding 4'-epi-N-(diphenylmethylene) derivatives which are subsequently treated, in anhydrous dichloromethane and in the presence of dry pyridine, at a temperature of -10"C under nitrogen, with trifluoromethane sulfonic anhydride to give the corresponding 4'-epi-N-(diphenylmethylene)-4'-Otrifluoromethanesulfonate which, in an hydros dichloro- methane, at a temperature of 0 and under nitrogen, are reacted, for a time of 24h, with anhydrous n-tetrabutyl-ammonium fluoride to obtain, via the subsequent displacement of the trifluoromethanesulfonate leaving group, a mixture of the N-protected derivatives of formula I and II (RI=H, OCH3; R2=H), subjecting said mixture to a mild acidic hydrolysis, separating the so obtained free glycosidic bases by chromatography on a column of buffered silica gel and isolating them as their respective hydrochlorides which, if desired, are eventually converted via their 14-bromo derivatives and subsequent hydrolysis with sodium formate into their doxorubicin analogues of formula I and II (RI=H, OCH3; R2=OH) which are as well isolated as their corresponding hydrochlo
rides.
12. A pharmaceutical composition comprising as active ingredient an anthracycline glycoside as claimed in any one of claims 1 to 5 or which has been prepared by a process as claimed in any one of claims 10 to together with a pharmaceutically acceptable carrier therefor.
13. A compound of formula (I) or (II) as defined in claim 1 for use in the treatment of the human or animal body by therapy.
14. A compound or salt thereof according to claim 12 for use in treating a tumor.
15. A process for producing a compound as defined in claim 1 and substantially as hereinbefore described with reference to the Examples.
16. A compound useful as an intermediate for producing a compound as claimed in claim 1 and hav
ing the formula V
wherein R3 is selected from
wherein R4 is amino or a protected amino group and R5 is a fluoro, hydroxy or trifluoromethyl sulphonyloxy group.
17. A compound as claimed in claim 16 wherein R4 is amine.
18. A compound as claimed in claim 16 wherein R4 is a diphenylmethylenimino group.
19. A compound as claimed in any one of claims 16 to 18 wherein R5 is fluoro.
20. A compound useful as an intermediate for producing a compound of formula (I) as defined in claim 1 and having the formula (III).
21. A compound useful as an intermediate for producing a compound of formula (II) as defined in claim 1 and having the formula (IV)
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB08513606A GB2159518A (en) | 1984-06-08 | 1985-05-30 | New anthracyclines and process for manufacture |
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB848414619A GB8414619D0 (en) | 1984-06-08 | 1984-06-08 | Anthracyclines |
| GB08513606A GB2159518A (en) | 1984-06-08 | 1985-05-30 | New anthracyclines and process for manufacture |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| GB8513606D0 GB8513606D0 (en) | 1985-07-03 |
| GB2159518A true GB2159518A (en) | 1985-12-04 |
Family
ID=26287838
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| GB08513606A Pending GB2159518A (en) | 1984-06-08 | 1985-05-30 | New anthracyclines and process for manufacture |
Country Status (1)
| Country | Link |
|---|---|
| GB (1) | GB2159518A (en) |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB2144744A (en) * | 1983-08-11 | 1985-03-13 | Erba Farmitalia | 4'-halo-anthracycline glycosides |
-
1985
- 1985-05-30 GB GB08513606A patent/GB2159518A/en active Pending
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB2144744A (en) * | 1983-08-11 | 1985-03-13 | Erba Farmitalia | 4'-halo-anthracycline glycosides |
Also Published As
| Publication number | Publication date |
|---|---|
| GB8513606D0 (en) | 1985-07-03 |
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