GB2091243A - Anthracycline glycosides - Google Patents
Anthracycline glycosides Download PDFInfo
- Publication number
- GB2091243A GB2091243A GB8134852A GB8134852A GB2091243A GB 2091243 A GB2091243 A GB 2091243A GB 8134852 A GB8134852 A GB 8134852A GB 8134852 A GB8134852 A GB 8134852A GB 2091243 A GB2091243 A GB 2091243A
- Authority
- GB
- United Kingdom
- Prior art keywords
- epi
- daunorubicin
- deoxy
- trifluoroacetyl
- treatment
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
- 229940045799 anthracyclines and related substance Drugs 0.000 title description 3
- 229930182470 glycoside Natural products 0.000 title description 3
- 150000002338 glycosides Chemical class 0.000 title description 3
- 229960001904 epirubicin Drugs 0.000 claims abstract description 9
- 150000003839 salts Chemical class 0.000 claims abstract description 7
- DPKBAXPHAYBPRL-UHFFFAOYSA-M tetrabutylazanium;iodide Chemical compound [I-].CCCC[N+](CCCC)(CCCC)CCCC DPKBAXPHAYBPRL-UHFFFAOYSA-M 0.000 claims abstract description 6
- DBGVGMSCBYYSLD-UHFFFAOYSA-N tributylstannane Chemical compound CCCC[SnH](CCCC)CCCC DBGVGMSCBYYSLD-UHFFFAOYSA-N 0.000 claims abstract description 5
- 239000012279 sodium borohydride Substances 0.000 claims abstract description 4
- 229910000033 sodium borohydride Inorganic materials 0.000 claims abstract description 4
- 238000005904 alkaline hydrolysis reaction Methods 0.000 claims abstract description 3
- WJKHJLXJJJATHN-UHFFFAOYSA-N triflic anhydride Chemical compound FC(F)(F)S(=O)(=O)OS(=O)(=O)C(F)(F)F WJKHJLXJJJATHN-UHFFFAOYSA-N 0.000 claims abstract description 3
- 238000000034 method Methods 0.000 claims description 9
- 239000000203 mixture Substances 0.000 claims description 7
- 238000002360 preparation method Methods 0.000 claims description 6
- 239000004280 Sodium formate Substances 0.000 claims description 3
- 150000007530 organic bases Chemical class 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
- OZAIFHULBGXAKX-UHFFFAOYSA-N 2-(2-cyanopropan-2-yldiazenyl)-2-methylpropanenitrile Chemical compound N#CC(C)(C)N=NC(C)(C)C#N OZAIFHULBGXAKX-UHFFFAOYSA-N 0.000 claims description 2
- AOJJSUZBOXZQNB-VTZDEGQISA-N 4'-epidoxorubicin 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-VTZDEGQISA-N 0.000 claims description 2
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical group [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 claims description 2
- 239000003085 diluting agent Substances 0.000 claims description 2
- 229910052740 iodine Inorganic materials 0.000 claims description 2
- 239000008194 pharmaceutical composition Substances 0.000 claims description 2
- 238000006243 chemical reaction Methods 0.000 abstract description 7
- 229960000975 daunorubicin Drugs 0.000 abstract description 7
- 230000000259 anti-tumor effect Effects 0.000 abstract description 2
- 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 abstract 1
- 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 abstract 1
- 125000001475 halogen functional group Chemical group 0.000 abstract 1
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 15
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 14
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 12
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 12
- 239000000243 solution Substances 0.000 description 10
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 9
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 8
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-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
- 239000007864 aqueous solution Substances 0.000 description 5
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 5
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 4
- 150000001875 compounds Chemical class 0.000 description 4
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 239000011541 reaction mixture Substances 0.000 description 3
- 239000000741 silica gel Substances 0.000 description 3
- 229910002027 silica gel Inorganic materials 0.000 description 3
- 229910052938 sodium sulfate Inorganic materials 0.000 description 3
- 235000011152 sodium sulphate Nutrition 0.000 description 3
- 239000002904 solvent Substances 0.000 description 3
- -1 trifluoromethylsulphonyloxy group Chemical group 0.000 description 3
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical class [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 2
- 238000006073 displacement reaction Methods 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 239000003208 petroleum Substances 0.000 description 2
- QAEDZJGFFMLHHQ-UHFFFAOYSA-N trifluoroacetic anhydride Chemical compound FC(F)(F)C(=O)OC(=O)C(F)(F)F QAEDZJGFFMLHHQ-UHFFFAOYSA-N 0.000 description 2
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- WTFUTSCZYYCBAY-SXBRIOAWSA-N 6-[(E)-C-[[4-[2-(2,3-dihydro-1H-inden-2-ylamino)pyrimidin-5-yl]piperazin-1-yl]methyl]-N-hydroxycarbonimidoyl]-3H-1,3-benzoxazol-2-one Chemical compound C1C(CC2=CC=CC=C12)NC1=NC=C(C=N1)N1CCN(CC1)C/C(=N/O)/C1=CC2=C(NC(O2)=O)C=C1 WTFUTSCZYYCBAY-SXBRIOAWSA-N 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 description 1
- TUCNEACPLKLKNU-UHFFFAOYSA-N acetyl Chemical compound C[C]=O TUCNEACPLKLKNU-UHFFFAOYSA-N 0.000 description 1
- 230000003213 activating effect Effects 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 150000008064 anhydrides Chemical class 0.000 description 1
- 239000002585 base Substances 0.000 description 1
- 230000031709 bromination Effects 0.000 description 1
- 238000005893 bromination reaction Methods 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
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 238000000354 decomposition reaction Methods 0.000 description 1
- 239000003480 eluent Substances 0.000 description 1
- 239000000284 extract Substances 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 125000005843 halogen group Chemical group 0.000 description 1
- 150000004678 hydrides Chemical class 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 1
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 1
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 239000012299 nitrogen atmosphere Substances 0.000 description 1
- 239000012074 organic phase Substances 0.000 description 1
- 239000008363 phosphate buffer Substances 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- JVBXVOWTABLYPX-UHFFFAOYSA-L sodium dithionite Chemical compound [Na+].[Na+].[O-]S(=O)S([O-])=O JVBXVOWTABLYPX-UHFFFAOYSA-L 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 230000009466 transformation Effects 0.000 description 1
- ITMCEJHCFYSIIV-UHFFFAOYSA-N triflic acid Chemical class OS(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-N 0.000 description 1
- 125000004044 trifluoroacetyl group Chemical group FC(C(=O)*)(F)F 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
-
- 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
There are provided 4'-deoxy-3'- epi-daunorubicin, 4-deoxy-3'-epi- doxorubicin and pharmaceutically acceptable salts thereof of formula <IMAGE> where R is H or OH. These have anti-tumour properties. 4'-Deoxy-3'-epi-daunorubicin is prepared from 3'-epi-4'-keto-N-trifluoracetyl- daunorubicin by reduction of the 4'-keto group with sodium borohydride to the corresponding 4'-hydroxy group, reaction of the resultant intermediate with trifluoro- methanesulphonic anhydride followed by treatment with n-tetrabutylammonium iodide to give a 4'- halo derivative which is reductively dehalogenated by treatment with tributyltin hydride to 4'-deoxy-3'- epi-N-trifluoracetyl-daunorubicin. Mild alkaline hydrolysis removes the N-protecting group to give 4'- deoxy-3'epi-daunorubicin. This may be transformed, via its 14- bromo derivative, to its doxorubicin analogue.
Description
SPECIFICATION
Anthracycline glycosides
The invention relates to anthracycline glycosides having antitumour properties, to processes for their preparation, and to pharamaceutical compositions containing them.
The invention provides 4'-deoxy-3'-epi-daunorubicin, 4'-deoxy-3'-epi-doxorubicin and their pharmaceutically acceptable salts.
4'-Deoxy-3'-epi-daunorubicin and 4'-deoxy-3'-epi-doxorubicin have the following formula
R representing a hydrogen atom and a hydroxy group respectively.
The invention further provides a process for the preparation of 4'-deoxy-3'-epi-daunorubicin, which process comprises reducing 3'-epi-4'-keto-N-trifoluroactyl-daunorubicin (1) with sodium borohydride to obtain a mixture of 3'-epi-N-trifluoroacetyl-daunorubicin (2) and 3',4'-diepi-Ntrifluoroacetyl-daunorubicin (3), replacing the 4'-hydroxy group of either or both thereof by an iodine atom by treatment with triflouromethanesulphonic anhydride in the presence of an organic base followed by treatment with an excess of tetrabutylammonium iodide, reductively dehalogenating the resultant 3'-epi-4'-iodo-N-trifluoroacetyl-daunorubicin (5) and/or 3',4'-diepi4'-iodo-N-trifluoroacetyl-daunorubicin (4) by treatment with tributyltin hydride in the presence of a,cx'-azobis (isobutyronitrile), and removing the N-trifluoroacetyl group from the resultant 4'deoxy-3'-epi-N-trifluoroacetyl-daunorubicin (6) mild alkaline hydrolysis.
The process is illustrated by th following reaction scheme, to which the compound numbers included in the last preceding paragraph refer. In the reaction scheme, D represents the group
Me represents a methyl group and TFA represents a trifluoroacetyl group.
REACTION SCHEME
D 0 o \ NHTFA / (1) NABS D D H Me Me NHTFA .' NHTFA (2) HO 1.(CF3S02)20 12.n.Bu4NI 20 r2.n.BuqNI ID D 0 IMe / Me (4) . n.Bu3SnH I D 0 ≈ mild Me alkali 4 ' -deoxy-3 ' -epi b NHTFA / (6) -daunorubicin In order to introduce a halogen atom at the C-4' position of (2) and (3) via SN2 displacement, the trifluoromethylsulphonyloxy group is employed as leaving group.The trifluoromethylsulphonyl derivative allows the displacement to be carried out in mild conditions so as not to affect the glycosidic linkage. The introduction of the trifluoro-methylsulphonyl group at the C-4' position of (2) and (3) is performed using trifluoromethylsulphonic anhydride. The organic base is suitably pyridine, and the reaction may be carried out at 0 C. The corresponding trifluoromethylsulphonates on treatment with an excess of tetrabutylammonium iodide are promptly converted in high yield to the iododerivatives (4) and (5).
The 4'-deoxy-3'-epi-daunorubicin may be isolated as such or as one of its addition salts after suitable work-up procedures. 4'-deoxy-3'-epi daunorubicin may be converted to 4'-deoxy-3'-epidoxorubicin by bromination and treatment of the resultant 14- bromo derivative with aqueous sodium formate in accordance with the method described in United States Patent Specification
No 3803124, and this conversion is within the scope of the invention.
The invention also provides a pharmaceutical composition comprising 4'-deoxy-3'-epi-daunorubicin, 4'-deoxy-3'epi-doxorubicin or a pharmaceutically acceptable salt of either thereof in admixture with a pharmaceutically acceptable diluent or carrier.
The starting material, 3'-epi-4'-keto-N-trifluoroacetyl-daunorubicin (1), may be prepared from
N-trifluroacetyl-daunorubicin by treatment thereof with activated dimethylsulphoxide in a basic solvent. The activated dimethylsulphoxide is known (see K. Omura 8r D. Swern, Tetrahedron
1978, 34, 1651-1660). Trifluoroacetic anhydride is the preferred activating agent. The reagent is suitably prepared in anhydrous methylene dichloride at from - 50"C to - 70"C. The nature of the basic solvent affects the course of the reaction.For example, a bulky base such as 1,5diazodicyclo (4,3,0)-non-5-ene (DBN) leads to 4'-keto-N-trifluoroacetyl-daunorubicin whereas the use of triethylamine causes partial epimerisation at C-3' and leads to a mixture of 4'-keto-Ntrifluoroacetyl-daunorubicin and 3'-epi-4'-keto-N-trifluoroacetyl-daunorubicin in the approximate ratio 1:1. The 4'-keto-N-trifluoroacetyl-daunorubicin obtained using DBN as the basic solvent can also be epimerised to give an approximately 1:1 mixture of 4'-keto-N-trifluoroacetyldaunorubicin and 3'-epi-4'-keto-N-trifluoroacetyl-daunorubicin by filtration over silica gel buffered to pH 7 with phosphate buffer.
The invention is illustrated by the following Examples.
Example 1
Preparation of 3'-epi-N-tnfluornacetyldaunorubicin (2) and 3' 4 '-diepi-N-trifluoroacetylda unorubicin (3)
A solution of 5 g (8.05 mmol) of 3'-epi-4'-keto-N-trifluoroacetyl-daunorubicin (1) in 500 ml of acetone was treated at room temperature with 0.4 g (10 mmol) of sodium borohydride dissolved in 200 ml of methanol. After five minutes the reduction was complete. The reaction mixture was then neutralized with 0.1 N aqueous hydrochloric acid, evaporated to a small volume (50 ml) under vacuum and diluted with 250 ml of methylene dichloride. The organic solution, washed with water, was dried over anhydrous sodium sulphate and evaporated by dryness.The residue, containing a mixture of (2) and (3) approximately in the ratio 1:1, was chromatographed on a column of silica gel eluting with methylene dichloride:acetone (97:3 by volume) to give 1.8 g of 3',4'-diepi-N-trifluoroacetyl-daunorubicin (3) and 2.4 g of 3'-epi-N-trifluoroacetyl-daunorubicin (2).
Example 2
Preparation of 4 '-deoxy-3 '-epi-4 '-iodo-N-trifluoro-acetyl-da un orubicin (5) and 4'-deoxy-4'-iodo- 3', 4 '-diepi-N-trifluoroacetyl-daunorubicin (4)
To a stirred solution of 5 g of 3'-epi-N-trifluoroacetyl-daunorubicin (2), prepared as described in Example 1, in 100 ml of anhydrous methylene dichloride and 6 ml of anhydrous pryidine, cooled to O"C, was added over a period of 10 minutes a solution of 2.7 ml of trifluoromethanesulphonic an hydride in 20 ml of anhydrous methylene dichloride. Then the organic phase was washed with a cooled 5% aqueous solution of sodium bicarbonate, water, 0.1 N aqueous solution of hydrochloric acid and water in that order. The organic solution, dried over an hydros sodium sulphate, was used in the following step without further purification.To the organic solution was added 10 g of tetra-butylammonium iodide. After 1 hour at 40"C the transformation was complete and the reaction mixture afforded (4) in crude form. This was purified by chromatography on a column of silica gel using methylene dichloride as eluent to give 3.7 9 of the iododerivative (4) (yield 63%).
m.p. 142"C. TLC on Kiesel gel plate F 254 (Merck) using chloroform:acetone (9:1 by volume): Rf 0.42. 5 g of 3',4'-diepi-N-trifluoroacetyl-daunorubicin (3) was converted to iododerivative (5) (4.6 g yield 78.8%) as described for compound (2):
TLC on Kieselgel plate F 254 (Merck) using chloroform:acetone (9:1 by volume): Rf 0.5. m.p.
144-148'C with (decomposition).
Example 3 4 '-Deoxy-3'-epi-N-rnfluornacetyl-daunowbicin (6)
A solution of 0.5 g of iododerivative (4), prepared as described in Example 2, in 20 ml of anhydrous toluene at refluxing temperature was treated under stirring and a nitrogen atmosphere with 0.25 ml of tributyltin hydride and with 0.1 g of a,a'-azobis (isobutyronitrile). After 1 5 minutes the reduction was complete. The reaction mixture was cooled to room temperature and poured into an excess of petroleum ether (40"-60'C). The precipitate was collected by filtration, washed with petroleum ether and dried under vacuum. 0.36 g of 4'-deoxy-3'epi-Ntrifluoroacetyldaunorubicin (6) were obtained (yield 87%).
m.p. 133 . TLC on Kieselgel plate F 254 (Merck) using chloroform:acetone (9:1 by volume):
Rf 0.38. PMR (CDCl3) inter alia: 1.22 8(d, 3H, CH3-C-5'); 1.5-2.5 8(m, 6H, CH2-C-21, CH2-C-4' and CH2-C-8); 2.40 8(s, 3H, CH3CO); 5.17 8(m, H, H-7); 5.48 8(m, H-1', W1 = 5
Hz).
The iododerivative (5) was converted to (6), as described for compound (4).
Example 4 4 '-Deoxy-3'-epi-daunorubicin A solution of 0.710 9 of 4'-deoxy-3'-epi-N- trifluoroacetyl-daunorubicin, prepared as described in Example 3, in 10 ml of acetone was treated with 40 ml of a 0.1 N aqueous solution of sodium hydroxide at O"C for 3 hours. Then to the solution was added 0.1 N aqueous hydrochloric acid to adjust the pH to 4.5 and the aglycones were eliminated by extractions with chloroform. Then the aqueous solution was adjusted to pH 8.6 and repeatedly extracted with chloroform. The combined extracts were dried over anhydrous sodium sulphate, concentrated to a small volume and acidified to pH 4.5 with 0.1 N methanolic hydrogen chloride to allow crystallization of the title compound as its hydrochloride: m.p. 188-189"C, [a]20+ 268' (c = 0.05, methanol).
TLC on Kieselgel plate F 254 (Merck) using chloroform: methanol: Water: acetic acid (80:20:7:3 by volume):Rf 0.85.
Example 5 4'-Deoxy-3'-epi-doxorobicin A solution of 4'-deoxy-3'-epi-daunorubicin, prepared as described in Example 5, in a mixture of methanol and dioxan was treated with bromine to form the 1 4-bromoderivative. Treatment of the 14-bromoderivative with an aqueous solution of sodium formate gave 4'-deoxy-3'-epidoxorubicin which was isolated as its hydrochloride. TLC. on Kieselgel plate F 254 (Merck) using chloroform: methanol: water: acetic acid (80:20:7:3 by volume):Rf = 0.75.
Claims (5)
1. 4'-Deoxy-3'-epi-daunorubicin or a pharmaceutically acceptable salt thereof.
2. 4'-Deoxy-3'-epi-doxorubicin or a pharmaceutically acceptable salt thereof.
3. A process for the preparation of 4'-deoxy-3'-epi-daunorubicin, the process comprising reducing 3'-epi-4'-keto-N-trifluoroacetyl-daunorubicin with sodium borohydride to obtain a mixture of 3'-epi-N-trifluoroacetyl-daunorubicin and 3',4'-diepi-N-trifluoroacetyl-daunorubicin, replacing the 4-hydroxy group of either or both thereof by an iodine atom by treatment with trifluoromethane-sulphonic anhydride in the presence of an organic base followed by treatment with an excess of tetrabutylammonium iodide, reductively dehalogenating the resultant 3'-epi-4'iodo-N-trifluoroacetyl-daunorubicin and/or 3',42-diepi-4'-iodo-N-trifluoroacetyl-daunorubicin by treatment with tributyltin hydride in the presence of a,a'-azobis (isobutyronitrile), and removing the N-trifluoroacetyl group from resultant 4'-deoxy-3'-epi-N-trifluoroacetyl-daunorubicin by mild alkaline hydrolysis.
4. A process for the preparation of 4'-deoxy-3'-epi-doxorubicin, the process comprising preparing 4'-deoxy-3'-epi-daunorubicin according to claim 3, brominating it and treating the resultant 14-bromo derivative with aqueous sodium formate.
5. A pharmaceutical composition comprising 4'-deoxy-3'-epi-daunorubicin, 4'-deoxy-3'epidoxorubicin or a pharmaceutically acceptable salt of either thereof in admixture with a pharmaceutically acceptable diluent or carrier.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB8134852A GB2091243B (en) | 1981-01-21 | 1981-11-19 | Anthracycline glycosides |
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB8101792 | 1981-01-21 | ||
| GB8134852A GB2091243B (en) | 1981-01-21 | 1981-11-19 | Anthracycline glycosides |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| GB2091243A true GB2091243A (en) | 1982-07-28 |
| GB2091243B GB2091243B (en) | 1984-06-20 |
Family
ID=26278171
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| GB8134852A Expired GB2091243B (en) | 1981-01-21 | 1981-11-19 | Anthracycline glycosides |
Country Status (1)
| Country | Link |
|---|---|
| GB (1) | GB2091243B (en) |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| FR2565982A1 (en) * | 1984-06-15 | 1985-12-20 | Hoechst Lab | NOVEL AMINO-3-TRIDESOXY-3,4,6-GLYCALS, THEIR PREPARATION METHODS AND ANTHRACYCLINES OBTAINED USING THESE GLYCALS |
| EP0381989A1 (en) * | 1989-02-07 | 1990-08-16 | FARMITALIA CARLO ERBA S.r.l. | New 4'-epi-4'-amino anthracyclines |
| US5412081A (en) * | 1989-02-07 | 1995-05-02 | Farmitalia Carlo Erba S.R.L. | New 4'-epi-4'-amino anthracyclines |
-
1981
- 1981-11-19 GB GB8134852A patent/GB2091243B/en not_active Expired
Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| FR2565982A1 (en) * | 1984-06-15 | 1985-12-20 | Hoechst Lab | NOVEL AMINO-3-TRIDESOXY-3,4,6-GLYCALS, THEIR PREPARATION METHODS AND ANTHRACYCLINES OBTAINED USING THESE GLYCALS |
| EP0170820A3 (en) * | 1984-06-15 | 1987-07-01 | Laboratoires Hoechst S.A. | 3-amino-3,4,6-trideoxyglycals, processes for their preparation and anthracylines obtained with those glycals |
| EP0272735A3 (en) * | 1984-06-15 | 1989-11-02 | Laboratoires Hoechst S.A. | 3-Amino-3,4,6-trideoxyglycals, method for their preparation and anthracyclines obtained by using these glycals |
| EP0381989A1 (en) * | 1989-02-07 | 1990-08-16 | FARMITALIA CARLO ERBA S.r.l. | New 4'-epi-4'-amino anthracyclines |
| WO1990009392A1 (en) * | 1989-02-07 | 1990-08-23 | Farmitalia Carlo Erba S.R.L. | New 4'-epi-4'-amino anthracyclines |
| US5412081A (en) * | 1989-02-07 | 1995-05-02 | Farmitalia Carlo Erba S.R.L. | New 4'-epi-4'-amino anthracyclines |
Also Published As
| Publication number | Publication date |
|---|---|
| GB2091243B (en) | 1984-06-20 |
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| 732 | Registration of transactions, instruments or events in the register (sect. 32/1977) | ||
| PCNP | Patent ceased through non-payment of renewal fee |