GB2195998A - New anthracyclines - Google Patents
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- GB2195998A GB2195998A GB08713443A GB8713443A GB2195998A GB 2195998 A GB2195998 A GB 2195998A GB 08713443 A GB08713443 A GB 08713443A GB 8713443 A GB8713443 A GB 8713443A GB 2195998 A GB2195998 A GB 2195998A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H15/00—Compounds containing hydrocarbon or substituted hydrocarbon radicals directly attached to hetero atoms of saccharide radicals
- C07H15/20—Carbocyclic rings
- C07H15/24—Condensed ring systems having three or more rings
- C07H15/252—Naphthacene radicals, e.g. daunomycins, adriamycins
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
Description
SPECIFICATION
New anthracyclines
The invention relates to novel 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 formulae (I) and (ill):
wherein R, represents a hydrogen atom or hydroxyl group; and pharmaceutically acceptable acid addition salts thereof.
The invention further provides a process for the preparation of a glycoside of formula (I) wherein R1 represents a hydrogen atom, i.e. compound (la), which process comprises reacting 3'-epi-daunorubicin with salicylaldehyde so as to obtain the corresponding 3'-epi-N-salicylidene derivative; converting the 4'-hydroxy group of the said 3'-epi-N-salicylidene derivative into a trifluoromethanesulfonate group; and removing from the 3' epi-N-salicylidene-4'-0-trifluoromethanesulfonate thus obtained the salicylidene group by acid hydrolysis so as to cause the desired glycoside of formula (I) to be obtained via displacement of-the 4'-0-trifluoromethanesulfonate group.
The compound (la) may therefore be prepared by reaction of the 3'-amino group of 3'-epidaunorubicin (III) [F. Arcamone, A. Bargiotti, G. Cassinellic: 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 trifluoromethanesulfonic anhydride in anhydrous methylene dichloride and in the presence of pyridine gives the corresponding 3'-epi-N-salicylidene-4'-0-trifluoromethansulfonate (IVd). This compoud, dissolved in methanol, can then be subjected to acidic hydrolysis of the salicylidene protecting group by means of p-toluensulfonic acid at room temperature to give, via the displacement of trifluoromethanesulfonate leaving group, the desired compound of formula (lea).
The invention also provides a process for the preparation of a glycoside compound of formula (I) wherein R, represents a hydroxyl group, i.e. compound (Ib), which process comprises reacting 3'-epi-doxorubicin with salicylaldehyde so as to obtain the corresponding 3'-epi-N-salicylidene derivative; protecting the 14-hyroxy group of the said 3'-epi-N-salicylidene derivative with a tert.butyl-diphenyl-silyl group, converting the 4'-hydroxy group of the 3'-epi-N-salicylidene- 14-0- [tert.butyl-dephenyl-silyl]-doxorubicin thus obtained into a trifluoromethanesulfonate group; and removing from the 1 4-O-[tert. butyl-diphenyl-silyl-3'-epi-N-salicylidene-4'-0-trifluoromethanesulfon- ate thus obtained the salicylidene group by acid hydrolysis and the 14-O-[tert.butyl-diphenyl-silyl] group so as to cause the desired glycoside of formula (I) to be obtained via displacement of the 4'-0-trifluoromethanesulfonate group.
The compound (Ib) may therefore be prepared by the conversion of the 3'-amino group of 3'epi-doxorubicin (V) [see F. Arcamone et al. Ger.Patent 2752155] into 3'-epi-N-salicylidene-doxorubicin (Vle) by reaction with salicylaldehyde, protection of the 14-hydroxy group with a tertbutyl-diphenyl-silyl group, obtaining 3'-epi-N-salicylidene- 1 4-O-[tert-butyl-diphenyl-silyl]-doxorubicin (Vlf); conversion of the 4'-hydroxy group into a trifluoromethanesulfonate (Vlg), hydrolysis by means of p-toluensulfonic acid with formation of compound (Ih), and reaction with tetra-n-butylammonium fluoride to remove the 14-0-[tert-butyl-diphenyl-silyl]-protecting group and obtain compound of formula (lb).
Typically 3'-epi-doxorubicin, dissolved in a mixture of water and acetone, is reacted at room temperature with salicyaldehyde to obtain the corresponding 3'-epi-N-salicylidene derivative which is subsequently treated, in anhydrous dimethylformamide, at room temperature, with t-butyldiphenylchlorosilane in the presence of imidazole to give its 3'-epi-N-salicylidene- 1 4-O-[t-butyl- diphenyl-silyl]ether, which dissolved in anhydrous methylene chloride is converted, by treatment with trifluoromethanesulfonic anhydride, in the presence of dry pyridine, into its 3'-epi-N-salicyli dene-4'-0-trifluornmethanesulfonate- I 4-O-[t-butyl-diphenyl-silyl] ether of which the salicylidene protecting group is subjected to acid hyrolysis at room temperature and in a methanolic solution by means of a catalytic amount of p-toluensulfonic acid and from which subsequently the 14-0 [t-butyl-diphenyl-silyl] protecting group is removed by treatment with tetra-n-butyl ammonium fluoride in tetrahydrofuran, at room temperature, to obtain the desired glycoside of formula (I).
The invention also provides a process for the preparation of a glycoside formula (ill) wherein R, represents a hydrogen atom, i.e. compound (Ila), or a hydroxy group, i.e. compound (llb), or a pharmaceutically acceptable acid addition 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'-deoxy-4'-epi-N-trifluoroacetyl3'-deamino-3'-hydroxy daunorubicin; removing the N-trifluoroacetyl group from the 4'-deoxy-4' epi-N-trifluoroacetyl-3'-deamino-3'-hydroxy daunorubicin so as to obtain the glycoside of formula (Il) wherein R1 is a hydrogen atom; if desired, converting the said glycoside of formula (Il) into a pharmaceutically acceptable acid addition salt thereof; if desired, brominating the said glycoside of formula (11) or pharmaceutically acceptable salt thereof and hydrolysing the 14-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 R, is a hydroxy group into a pharmaceutically acceptable acid addition salt thereof.
Treatment of the 3',4'-epimino daunorubicin derivative (la) with trifluoroacetic anhydride gives the corresponding N-trifluoroacetyl derivative (Vlli). Reaction of this compound with a catalytic amount of sulfuric acid in acetone gives 4'-deoxy-4epi-N-trifluoroa cetyl3'-dea m ino-a'-hyd roxy- daunorubicin (VIII) which, by treatment with aqueous sodium hydroxide, 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 0.1 N aqueous sodium hydroxide. Glycoside (Ila) can be isolated as its hydrochloride by treatment with hydrogen chloride in methanol.
The compound (alb) can be prepared by bromination of (ill) 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 summarized in the reaction scheme below.
The present invention also provides a pharmaceutical composition comprising as active ingredient an anthracycline glycoside of the invention or pharmaceutically acceptable acid addition salt thereof together with a pharmaceutically acceptable carrier or diluent. A therapeutically effective amount of a compound of formula (I) 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.
REACTION SCHEME
c R2: oOHC6H4CH= R3: OH d R2: oOHC6H4CH- R3: OSO2CF3 e R1= R3a. OH R2: oOHC6H4CHs f R1: -O-Si(C6N5)2-t-Bu R2: oOHC H4CH= R3: OH g R1 : -O-Si(C6H5)2 -t-Bu R2 : OOHC@H4CH= R3: OSO2CF3 h R1 : -O-Si(C6H5)2 -t-Bu i R4: COCF3
The following Examples illustrate the invention.
EXAMPLE 1 3'-Epi-N-salicylidene-daunorubicin (IVc)
A solution of 2 g of 3'-epi-daunorubicin (111) 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 min.
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 hexane to eliminate the traces of salicylaldehyde, then collected and dried under vacuum at 300C to give (IVc) in almost quantitative yield.
Rf 0.21 on TLC Kieselgel F 254 (Merck) using as eluent the solvent mixture CH2CI2-Acetone (8/2 v/v).
EXAMPLE 2 3'-deamino-4'deoxy-3'-epi-4'-epi-3',4'-epimino-daunorubicin (la)
To a solution of 2 g of 3'-epi-N-salicylidene daunorubicin (1Vc) in 20 ml of anhydrous dichloromethane and 2 ml of dry pyridine kept at - 100C, was added a solution of 0.8 ml of trifluoromethane sulfonic anhydride in 10 ml of dichloromethane. After 1 hour at - 100C, the mixture was diluted with dichloromethane and washed with water, cold 0.1M hydrocloric acid, cold aqueous 5% sodium hyrogen 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 TLC Kieselgel F 254 (Merck) using as eluent the solvent mixture CH2CI2-Acetone (95/5 v/v).
The crude product was dissolved in 50 ml of methanol and added with 0.2 g of p-toluensulfonic acid monohydrate. The solution was kept at room temperature for 1 hr, then was added 100 ml of water 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 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 crystallyzed FD MS 509 [M+] m.p. 135-137"C Rf 0.38 on TLC Kieselgel F 254 (Merck) using as eluent the mixture CH2CI2-CH3OH-CH3COOH-H2O (30/4/1/0.5 v/v).
'H-NMR (200 MHz, CDCI3): 8.02 (dd, J=1.1, 7.7Hz, 1H, H-1) 7.76 (dd, J=7.7, 7.7Hz, 1H, H-2) 7.37 (dd. J=1.1, 7.7Hz, 1H, H-3) 5.31 (dd, J=3.0, 4.8Hz, 1H, H-1') 5.17 (dd, J=2.0, 3.6Hz, 1H, H-7) 4.32 (qd, J= < 1, 6.7Hz, 1H, H-5') 4.07 (s, 3H, OCH3-4) 3.17 (dd, J=19.2Hz, 1H, H-10e) 2.95 (d, J=19.2Hz, 1H, H-10ax) 2.46 (ddd, J=2.0, 2.0, 15.0Hz, 1H, H-8e) 2.43 (s, 3H, COCH3) 2.30 (ddd, J=1.5, 4.3, 6.4Hz, 1H, H-3') 1.9-2.0 (m, 2H, H-8ax, H-2'ax) 1.87 (ddd, J=1.5, 3.0, 14.6Hz, 1H, H2'e) 1.44 (d, J=6.7Hz, 3H, CH3-5')
EXAMPLE 3 3'-epi-N-salicilydene doxorubicin (Vle)
The title compound was prepared from the corresponding 3'-epi-doxorubicin (V) as described in Example 1.
Rf 0.15 on TLC, Kieselgel F 254 (Merck) using as eluent the solvent mixture CH2CI2-Acetone (4/1 v/v).
EXAMPLE 4 3'-epi-N-salicylidene- 1 4-0-[tert-butyl-diphenyl-silyl]-doxorubicin (Vf)
A solution of 1 g of 3'-epi-N-salicylidene doxorubicin (Vle) in 20 ml of anhydrous dimethylformamide was treated with 0.5 ml of tetr-butyl-diphenyl-chlorosilane and 0.3 g of imidazole. The reaction mixture was left standing overnight at room temperature, after which 200 ml of water was added and the solution was extracted with methylene dichloride.
The organic layer was separated off, dried over anhydrous sodium sulphate, filtered and evaporated to dryness under vacuum. The residue was triturated with hexane and collected on a sintered glass, washed with hexane-diethyl ether and dried in vacuum to give the compound (V If)..
Rf 0.25 on TLC, Kieselgel F 254 (Merck) using as eluent the solvent mixture CH2CI2-acetone (4/1 v/v).
EXAMPLE 5 3'-epi-3'-deamino-4'-deoxy-4'-epi-3',4'-epimino doxorubicin (lb)
The title compound was prepared starting from (Vlf) "via" its 3'-epi-4'-0-trifluoromethanesulfonate (Vlg) prepared as described in example 2.
Acidic hydrolysis of Vlg in methanol with a catalytic amount of p-toluensulfonic acid monohydrate, gave, after work up Ih. The crude product was triturated with hexane and collected on a sintered glass, washed with hexane-diethyl ether and dissolved in 100 ml of tetrahydrofurane.
The solution was treated with 0.5 g of tetra-n-butyl-ammonium fluoride. After 2 hours the hydrolysis of the tert-butyl-diphenyl-silyl group was complete. The residue obtained by evaporating off the solvent under vacuum was purified by chromatography on a column of silica gel buffered at pH 7 using dichloromethane-ethanol as eluting system to afford pure Ib. The precipitated was collected on a sintered glass, washed with hexane-diethyl ether and dried in vacuum.
Rf 0.20 on TLC Kieselgel F 254 (Merck) using as eluent the solvent mixture CH2Ci2-CH30H-CH3COOH-H20 (30/4/1/0.5 v/v)
EXAMPLE 6 3'-deamino-4'-deoxy-3'-hydroxy-4'-epi-4'-amino-daunorubicin (Ila)
The title compound was prepared starting from the aziridine 1a. 1 g of la was transformed into the N-trifluoroacetyl derivative Vlli by treatement with 1.2 ml of trifluoroacetic anhydride in anhydrous methylene dichloride. After work up the crude material [Rf 0.7 on TLC, Kieselgel F 254 (Merck) using as eluent the solvent mixture CH2CI2-Acetone (4/1 v/v)] was dissolved in 20 ml of acetone and treated with a catalitic amount of sulforic acid at 10 C.
The mixture was diluted 200 ml of methylene dichloride, washed with water, aqueous 5% sodium hydrogen carbonate and water. The solvent was removed in vacuum and the residue purified on a column of silic gel using methylene dichloride as the eluting system to afford 0.7 g of pure Ia.
Rf 0.21 on TLC, Kieselgel F 254 (Merck) using as eluent the solvent mixture CH2CI2-Acetone (4/1 v/v).
The product ila was slowly dissolved in aqueous 0.1N sodium hydroxyde, at 0 C in order to perform the hydrolysis of the N-trifluoroacetyl protecting group.
After 1 hr at 0 C, the solution was adjusted to pi-el 8.6 with 0.1Nhydrnchlodc acid and extracted with methylene dichloride. The solvent was evaporated off, affording 0.5g of a residue that was converted by treatment with methanolic hydrogen chloride into the hydrochloride of 4' deoxy-4'-amino-4'-epi-3'-deamino-3'-hydroxy-daunorubicin.
MS FD 527 [M+], m.p.153 C (dec).
Rf 0.18 on TLC Kieselgel F 254 (Merck) using the solvent system CH2CI2-CH30H-CH3COOH-H20 (30/4/1/0.5/v/v) 1H-NMR (200 MHz, CDCI3) 8.02 (dd, J=0.9, 8.5Hz, 1H, H-1) 7.77 (dd, J=8.5, 8.5Hz, 1H, H-2) 7.38 (dd, J=0.9, 8.5Hz, 1H, H-3) 5.52 (dd, J= < 1, 4.0Hz, 1H, H-l') 5.28 (dd, J=1.8, 4.0Hz, 1H, H-7) 4.07 (s, 3H, OCH3-4) 3.69 (dq, J=6.3, 9.5Hz, 1H, S5') 3.22 (dd, J=1.9, 18.9Hz, 1H, H-10e) 2.94 (d, J=18.9Hz, 1H, H-lOax) 2.40 (s, 3H, COCH3) 2.2-2.4 (m, 1H, H-8ax) 2.30 (dd, J=9.5, 9.5Hz, 1H, K4') 2.0-2.2 (m, 2H, H-8e, H-2'e) 1.70 (ddd, J=4.0, 4.6, 13.2Hz, 1H, H-2'ax) 1.31 (d, J=6.3Hz, 3H, CH3-5')
EXAMPLE 7 3'-deamino-3'-hydroxy-4'-deoxy-4'-epi-4'-amino-doXorubicin (llb)
0.59 of Ia 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-bromoderivative and then with aqueous sodium formate to give the title compound.
This was converted into its hydrochloride by treatment with methanolic hydrogen chloride. FD
MS 543 [M+], TLC on Kieselgel F254 (Merck) using the solvent system CH2CI2-CH30H-CH3COOH-H20 (30/4/1/0.5 v/v) Rf 0.10
BIOLOGICAL ACTIVITY
The cytotoxic activity of the new anthracycline glycoside of the invention (FCE 24782/X00-0333) was tested "in vitro" against HeLa cells, P388, P388/DX, LoVo and Lo
Vo/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 vivo" against P-388 ascitic leukemia and Gross leukemia, exibited good antitumour activity, in comparison with daunorubicin, especially when orally administered.
The results are given in Tables 2 and 3.
Table 1
In vitro activity of 3'-deamino-4'-deoxy-3'-hydroxy-4'-epi-4'-amino-daunorubicin (FCE 24782/XOO-0333) in comparison with DNR
ID50(ng/ml) a)
Compound ---------------------- ----------b) c) d) e) f)
HeLa P388 P388/DX LoVo LoVo/Dx
DNR 19 10.5 730 43 820
FCE 24782/XOO-0333 11 24.5 235 37 230 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 388 leukemia cells resistant to Doxorubicin e) Human colon adenocarcinona cells sensitive to Doxorubicin f) Human colon adenocarcinoma cells resistant to Doxorubicin Table 2 Effect against P 388 ascitic leukemia a
Compound dose b T/C%c Toxicd deaths
DNR 2.9 155 0/10
4.4 170 8/10
FCE 24782/ 1.96 155 0/10
XOO-0333 2.9 150 0/10
4.4 140 9/10
6.6 100 10/10 aExperiments were performed in CDF1 mice, inoculated with 106 leukemia cells i.p.
bTreatment i.p. on day 1 after tumor inoculum.
@Median survival time of treated mice/median survival timeof controlsx 100.
dEvaluated on the basis of autoptic findings.
Table 3 Effect against Gross leukemia a Compound doseb T/C%c Toxicd
mg/Kg dea@@s DNR 10 165 0/20
15 192 2/20
FCE 24782/ 8.2 175 0/20
X00-0333 11.5 230 0/10
16.1 240 0/10
22.5 130 0/10 aExperiments were performed in C3H mice, inoculated with 2 X 106 leukemia cells i.v.
bTreatment i.v. on day 1 after tumor inoculum.
median survival time of treated mice/median survival time of controls x 100.
dEvaluated on the basis of autoptic findings.
Claims (16)
1. An anthracycline glycoside having the general formula (I) or (ill):
wherein R1 represents a hydrogen atom or a hydroxyl group, and pharmaceutically acceptable acid addition salts thereof.
2. A compound according to claim 1, which is 3'-deamino-4'-deoxy-3'-epi-4'-epi-3',4'-epiminodaunorubicin.
3. A compound according to claim 1, which is 3'-deamino-4'-deoxy-3'-epi-4'-epi-3',4'-epiminodoxorubicin.
4. A compound according to claim 1, which is 3'-deamino-4'-deoxy-3'-hydroxy-4'-epi-4'-amino-daunorubicin or its hydrochloride.
5. A compound according to claim 1, which is 3'-deamino-4'-deoxy-3'-hydroxy-4'-epi-4'-amino-doxorubicin or its hydrochloride.
6. A process for the preparation of a glycoside of formula (I) as defined in claim 1 wherein
R, represents a hydrogen atom, which process comprises reacting 3'-epi-daunorubicin with salicylaldehyde so as to obtain the corresponding 3'-epi-N-salicylidene derivative; converting the 4'-hydroxy group of the said 3'-epi-N-salicylidene derivative into a trifluoromethanesulfonate group; - and removing from the 3'epi-N-salicylidene-4'-0-trifluoromethanesulfonate thus obtained the salicylidene group by acid hydrolysis so as to cause the desired glycolside of formula (I) to be obtained via displacement of the 4'-0-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 treated, in anhydrous methylene dichloride and in the presence of dry pyridine, with trfluoromethanesulfonic anhydride to give the corresponding N-salicylidene-3'-epi-4'-0-trifluoromethanesulfonate of which the salicylidene protecting group is subjected to acidic hydrolysis by means of p-toluensulfonic acid, at room temperature with the said trifluoromethanesulfonate being dissolved in methanol, to obtain, via the displacement of the trifluoromethanesulfonate leaving group, the desired glycoside of formula (l)
8.A process for the preparation of a glycoside of formula (I) as defined in claim 1 wherein
R, represents a hydroxy group, which process comprises reacting 3'-epi-doxorubicin with salicylaldehyde so as to obtain the corresponding 3'-epi-N-salicylidene derivative; protecting the 14hydroxy group of the said 3'-epi-N-salicylidene derivative with a tert.butyl-diphenyl-silyl group, converting the 4-hydroxy group of the 3'-epi-N-salicylidene-14-0-[tert.butyl-diphenyl-silyl]-doXoru- bicin thus obtained into a trifluoromethanesulfonate group; and removing from the 14-0-[tert.bu tyl-diphenyl-silyl]-3'-epi-N-salicylidene-4'-0-trifluoromethanesulfonate thus obtained the salicylidene group by acid hydrolysis and the 14-0-[tert.butyl-diphenyl-silyl] group so as to cause the desired glycoside of formula (I) to be obtained via displacement of the 4'-0-trifluoromethanesulfonate group.
9. A process according to claim 8, wherein 3'-epi-doxorubicin, dissolved in a mixture of water and acetone, is reacted at room temperature with salicylaldehyde to obtain the corresponding 3'-epi-N-salicyldene derivative which is subsequently treated, in anhydrous dimethylformamide, at room temperature. with t-butyl-diphenylchlorosilane in the presence of imidazole to give its 3'-epi-N-salicylidene- 1 4-0-[t-butyl-diphenyl-silyl]ether, which dissolved in anhydrous methylene dichloride is converted, by treatment with trifluoromerthanesulfonic anhydride, in the presence of dry pyridine, into its 3'-epi-N-salicylidene-4'-0-trifluoromethanesulfonate- 1 4-0-[t-butyl- diphenyl-silyl] ether of which the salicylidene protecting group is subjected to acidic hyrolysis at room temperature and in a methanolic solution by means of a catalytic amount of p-toluensulfonic acid and from which subsequently the 1 4-0-[t-butyl-diphenyl-silyl] protecting group is removed by treatment with tetra-n-butyl ammonium fluoride in tetrahydrofuran, at room tempera ture, to obtain the desired glycoside of formula (I).
10. A process for the preparation of a glycoside of formula (II) as defined in claim 1 or a pharmaceutically acceptable salt thereof, which process comprises converting 3'-deamino-4'deoxy-3'-epi-3,4'-epimino-daunorubicin into the corresponding N-trifluoroacetyl derivative; converting the said N-trifluoroacetyl derivative into 4'-deoxy-4'-epi-N-trifluoroacetyl-3'-deamino-3'-hydroxy daunorubicin; removing the N-trifluoroacetyl group from the 4'-deoxy-4'-epi-N-trifluoroacetyl-3'- deamino-3'-hydroxy 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 pharmaceutically acceptable salt thereof and hyrolysing the 14-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 R1 is a hydroxy group into a pharmaceutically acceptable acid addition salt thereof.
11. A process according to claim 10, wherein the 3'-deamino-4'-deoxy-3'-epi-4'-epi-3',4'epimino-daunorubicin is reached with trifluoroacetic anhydride to obtain the corresponding Ntrifluoroacetyl derivative which, by treatment with a catalytic amount of sulfuric acid in acetone gives 4'-deoxy-4'-epi-N-trifluoroacetyl-3'-deamino-3'-hydroxy-daunorubicin; removing the N-trifluoroacetyl protecting group therefrom by mild alkaline hyrolysis, at a temperature of 0 C, by means of 0.1N aqueous sodium hydroxide; optionally, isolation the glycoside of formula (II) wherein R, is a hydrogen atom as its hydrochloide 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 R, 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 (Il) wherein R, is a hydroxy group as its hydrochloride by treatment with a methanolic solution of hydrogen chloride.
12. A pharmaceutical composition comprising an anthracycline glycoside of formula (I) or (II) as defined in claim 1 or a pharmaceutically acceptable acid addition salt thereof, together with a pharmaceutically acceptable carrier or diluent.
13. An anthracycline glycoside of formula (I) or (II) as defined in claim 1, or a pharmaceutically acceptable salt thereof, for use in a method of treatment of the human or animal body by therapy.
14. An anthracycline glycoside or salt thereof according to claim 13 for use an an antitumor agent.
15. A process for the preparation of an anthracycline glycoside of formula (I) as defined in claim 1, said process being substantially as hereinbefore described in Examples 1 and 2 together or Examples 3 to 5 together.
16. A process for the preparation of an anthracycline glycoside of formula (II) as defined in claim 1 or a pharmaceutically acceptable salt thereof, said process being substantially as hereinbefore- described in Example 6 or Example 6 and 7 together.
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB868614323A GB8614323D0 (en) | 1986-06-12 | 1986-06-12 | Anthracyclines |
Publications (3)
| Publication Number | Publication Date |
|---|---|
| GB8713443D0 GB8713443D0 (en) | 1987-07-15 |
| GB2195998A true GB2195998A (en) | 1988-04-20 |
| GB2195998B GB2195998B (en) | 1990-02-14 |
Family
ID=10599357
Family Applications (2)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| GB868614323A Pending GB8614323D0 (en) | 1986-06-12 | 1986-06-12 | Anthracyclines |
| GB8713443A Expired - Fee Related GB2195998B (en) | 1986-06-12 | 1987-06-09 | New anthracyclines |
Family Applications Before (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| GB868614323A Pending GB8614323D0 (en) | 1986-06-12 | 1986-06-12 | 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) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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 |
| WO2002102817A1 (en) * | 2001-06-15 | 2002-12-27 | Pharmacia Italia S.P.A. | Anti-tumour anthracycline glycoside 14-sulfonic acid derivatives |
Families Citing this family (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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 |
| 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 |
Family Cites Families (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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
Non-Patent Citations (1)
| Title |
|---|
| CHEMICAL ABSTRACTS VOL 106 NO 11 16TH MARCH, 1987 NO 84994V * |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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 |
| WO2000026223A3 (en) * | 1998-11-02 | 2000-09-21 | Univ Texas | Methods and compositions for the manufacture of highly potent anthracycline-based antitumor agents |
| WO2002102817A1 (en) * | 2001-06-15 | 2002-12-27 | Pharmacia Italia S.P.A. | Anti-tumour anthracycline glycoside 14-sulfonic acid derivatives |
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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 |
Effective date: 20000609 |