CA1250833A - Process for preparing 4'-haloanthracycline glycosides - Google Patents
Process for preparing 4'-haloanthracycline glycosidesInfo
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- CA1250833A CA1250833A CA000460796A CA460796A CA1250833A CA 1250833 A CA1250833 A CA 1250833A CA 000460796 A CA000460796 A CA 000460796A CA 460796 A CA460796 A CA 460796A CA 1250833 A CA1250833 A CA 1250833A
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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
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Abstract
\
ABSTRACT OF THE DISCLOSURE
A process for preparing 4'-halo-anthracycline glycosides having general formula A :
A
in which X=H or OH, R1=H, OH or OCH3, R2=Br, Cl or F
useful as antitumour agents. Those in which X=H may be prepared by an exchange reaction between a 4'-epi-4'-O-trifluoromethanesulphonyl-N-protected-daunorubicin (or a corresponding 4-demethyl or 4-demethoxy derivative) and (C4H9)4NCl, (C4H9)4NBr or C5F. Those in which X=OH are prepared from those in which X=H by bromination and reaction with aqueous sodium formate.
ABSTRACT OF THE DISCLOSURE
A process for preparing 4'-halo-anthracycline glycosides having general formula A :
A
in which X=H or OH, R1=H, OH or OCH3, R2=Br, Cl or F
useful as antitumour agents. Those in which X=H may be prepared by an exchange reaction between a 4'-epi-4'-O-trifluoromethanesulphonyl-N-protected-daunorubicin (or a corresponding 4-demethyl or 4-demethoxy derivative) and (C4H9)4NCl, (C4H9)4NBr or C5F. Those in which X=OH are prepared from those in which X=H by bromination and reaction with aqueous sodium formate.
Description
~2~
1 The inven-tion relates to a process for preparing 4'-halo-anthracycline glycosides useEul as antitumor agents.
More particularly the invention concerns a process for preparing anthracycline glycosides having general formula A
O 0~
/~ ~ COCH2X
Rl O OH O
H3C ~ ~ A
wherein X represen-ts a hydrogen atom or a hydroxy group, Rl represents a hydrogen atom or a hydroxy or a methoxy group and R2 represents a bromine, chlorine or fluorine atom, characterized in that an exchange reaction is carried out between a compound of general formula 2 whexein Rl is as above defined and R3 represents an amino protecting group and a fluorine, chloride or bromide, followed by de-protection of the resultant compound of the general formula3 to give a compound of formula A in which X is a hydrogen atom, such reactions being followed first by a bromina-tion and then by a treatment of the resultant 14-bromo derivative with aqueous sodium forma-te to give still a compound of formula A in which X is a hydroxy group. The process is illustrated by the following scheme :
~$~
O OH
1; ~ ~ OH
H3C ~ O ~
CF3S02~T-- /
O ~ , OH
~3 Rl O OH
3 ~ ~ 3 R2 Nï 3 A(X=H) When R2 represents a bromine or chlorine atom, the exchange reaction is preferably between the compound 2 and tetra (_-butyl) ammonium bromide or chloride respectively, and the amine protecting group R3 is preferably a trifluoroace-tyl group. The deprotection reaction may then be a mild alka-line hydrolysis, for example with 0.1 N a~ueous sodium hydroxide solu-tion. When R2 represents a fluorine atom, the 1 exchange reac-tion is preferably between -the compound 2 and caesium fluoride, and the amine protecting group R3 is preferably a trichloroethox~carbonyl group. The deprotec-tion reaction may then be a hydrogenation, for example with zinc dust and acetic acid. The exchange reaction may be carried out in an organic solvent such as methylene dichloride or ace-tonitrile.
The starting materials 2 are either known com-pounds, for example 4'-epi-4'-O-tri-Eluoromethanesulphonyl-N-trifluoroacetyl-daunorubicin ~2: R1=OCI-13, R3=COCF3: see ~uropean Patent Application No. 8117~18.1), or are readily prepared from known 4'-epi-daunorubicin derivatives by reaction wit~ trifluoromethanesulphonic anhydride.
The compounds according to the invention and their pharmaceutically accep-table acid addition salts are useful as antitumour agents. These novel compounds of formula A
are usea in the same way as the parent compounds (i.e., daunorubicin and doxorubicin) in treating various murine experimental -tumors, e.g~ L1210, P388, P388/04 and the like.
It has been found in preliminary screening tests that these new compounds are in some cases more active than the paren-t compounds. Accordingly the invention further provides a pharmaceutical composition comprising an anthracycline gly-coside according to -the invention or a pharmaceutically acceptable acid addition salt thereof in admixture with a pharmaceutically acceptable diluent cr carrier.
l BIOLOGICAL ACTIVITY TESTS
-The compounds of Examples 1, 2 and 3 have been tested _ vitro in comparison with daunorubicin tDNR) and doxorubicin (DX) against HeLa cells, P388 cells sensitive and resistan-t to DX (P388/DX). Results are reported in Table 1. All the new derivatives appear -to be more cytotoxic than their paren-t compound against HeLa and P388 cells sensitive to DX. This increased cytotoxicity is, however, much more pronounced if we consider the activity of these compounds against P388/DX. Here a 100 to 250 fold increase in cytotoxicity, in respect to the parent drug, can be noticed with these derivatives. In vivo the compounds have been tested against three different experimental leukemias.
The antitumor activity obtained agains-t ascitic P388 leukemia is reported in Table 2. The activity showed by -the compounds of Example 3 is equal to that exerted by DNR, while the other DNR derivative, the compound of Example 1, has an anti-tumor activity definitely superior to that of DNR.
The compound of Example 2 at the maximal tolerated dose (4.15 mg/kg) has about the same ac-tivity as DX. All the new compounds show activity against P388/DX leukemia, as reported in Table 3, while DNR and DX have no efficacy.
The three new compounds have been a]so tested after i.v.
administra-tion against dissemina-ted Gross leukemia, the resul-ts are reported in Table ~. In this system the compound of Example 3 is as active as DNR, while the compound of Example 1 appears more ac-tive than the parent compound.
_ ~ _ ~2~i~D1333 1 The compound of Example 2 shows about the same e-Eficacy as DX. Two of -these compounds have also been tes-ted after oral adminis-tration showing an in-teresting activity while DNR and DX are not active when given orally.
Table 1 Cytotoxic activity of Compounds of Examples 1, 3 and 2.
Compound ID50(ng/ml) HeLa P388P388/DX
_ DNR 12.3 2.8 980 Example 16.8 0.5 Example 35.8 2.4 8.8 DX 12.5 4.251250 Example 2 3 0.2 7 .
+ colony inhibition test after 24 hours exposure to the drugs ++ cytotoxicity evaluated after 48 hours exposure to the drugs Data from several experimen-ts.
1 Table 2 Effect against P388 ascitic leukemia Compound dose T/cc LTsd toxic (mg/kg) ~ deaths DNR 2.9165,155 0/20 0/20 4.4170,135 0/18 0/18 6.6130,115 0/20 12/20 Example 1 2.9 145 0/10 0/10 4.4160 0/10 0/10 6.6195 0/10 0/10 Example 3 2.9 130 0/10 0/10 4.4~.55 0/10 0/10 6~6145 0/10 0/10 D~ . 4.4215 0/10 0/].0 6.6235 0/10 0/10 .
Example 2 2.4 200 0/10 0/10
1 The inven-tion relates to a process for preparing 4'-halo-anthracycline glycosides useEul as antitumor agents.
More particularly the invention concerns a process for preparing anthracycline glycosides having general formula A
O 0~
/~ ~ COCH2X
Rl O OH O
H3C ~ ~ A
wherein X represen-ts a hydrogen atom or a hydroxy group, Rl represents a hydrogen atom or a hydroxy or a methoxy group and R2 represents a bromine, chlorine or fluorine atom, characterized in that an exchange reaction is carried out between a compound of general formula 2 whexein Rl is as above defined and R3 represents an amino protecting group and a fluorine, chloride or bromide, followed by de-protection of the resultant compound of the general formula3 to give a compound of formula A in which X is a hydrogen atom, such reactions being followed first by a bromina-tion and then by a treatment of the resultant 14-bromo derivative with aqueous sodium forma-te to give still a compound of formula A in which X is a hydroxy group. The process is illustrated by the following scheme :
~$~
O OH
1; ~ ~ OH
H3C ~ O ~
CF3S02~T-- /
O ~ , OH
~3 Rl O OH
3 ~ ~ 3 R2 Nï 3 A(X=H) When R2 represents a bromine or chlorine atom, the exchange reaction is preferably between the compound 2 and tetra (_-butyl) ammonium bromide or chloride respectively, and the amine protecting group R3 is preferably a trifluoroace-tyl group. The deprotection reaction may then be a mild alka-line hydrolysis, for example with 0.1 N a~ueous sodium hydroxide solu-tion. When R2 represents a fluorine atom, the 1 exchange reac-tion is preferably between -the compound 2 and caesium fluoride, and the amine protecting group R3 is preferably a trichloroethox~carbonyl group. The deprotec-tion reaction may then be a hydrogenation, for example with zinc dust and acetic acid. The exchange reaction may be carried out in an organic solvent such as methylene dichloride or ace-tonitrile.
The starting materials 2 are either known com-pounds, for example 4'-epi-4'-O-tri-Eluoromethanesulphonyl-N-trifluoroacetyl-daunorubicin ~2: R1=OCI-13, R3=COCF3: see ~uropean Patent Application No. 8117~18.1), or are readily prepared from known 4'-epi-daunorubicin derivatives by reaction wit~ trifluoromethanesulphonic anhydride.
The compounds according to the invention and their pharmaceutically accep-table acid addition salts are useful as antitumour agents. These novel compounds of formula A
are usea in the same way as the parent compounds (i.e., daunorubicin and doxorubicin) in treating various murine experimental -tumors, e.g~ L1210, P388, P388/04 and the like.
It has been found in preliminary screening tests that these new compounds are in some cases more active than the paren-t compounds. Accordingly the invention further provides a pharmaceutical composition comprising an anthracycline gly-coside according to -the invention or a pharmaceutically acceptable acid addition salt thereof in admixture with a pharmaceutically acceptable diluent cr carrier.
l BIOLOGICAL ACTIVITY TESTS
-The compounds of Examples 1, 2 and 3 have been tested _ vitro in comparison with daunorubicin tDNR) and doxorubicin (DX) against HeLa cells, P388 cells sensitive and resistan-t to DX (P388/DX). Results are reported in Table 1. All the new derivatives appear -to be more cytotoxic than their paren-t compound against HeLa and P388 cells sensitive to DX. This increased cytotoxicity is, however, much more pronounced if we consider the activity of these compounds against P388/DX. Here a 100 to 250 fold increase in cytotoxicity, in respect to the parent drug, can be noticed with these derivatives. In vivo the compounds have been tested against three different experimental leukemias.
The antitumor activity obtained agains-t ascitic P388 leukemia is reported in Table 2. The activity showed by -the compounds of Example 3 is equal to that exerted by DNR, while the other DNR derivative, the compound of Example 1, has an anti-tumor activity definitely superior to that of DNR.
The compound of Example 2 at the maximal tolerated dose (4.15 mg/kg) has about the same ac-tivity as DX. All the new compounds show activity against P388/DX leukemia, as reported in Table 3, while DNR and DX have no efficacy.
The three new compounds have been a]so tested after i.v.
administra-tion against dissemina-ted Gross leukemia, the resul-ts are reported in Table ~. In this system the compound of Example 3 is as active as DNR, while the compound of Example 1 appears more ac-tive than the parent compound.
_ ~ _ ~2~i~D1333 1 The compound of Example 2 shows about the same e-Eficacy as DX. Two of -these compounds have also been tes-ted after oral adminis-tration showing an in-teresting activity while DNR and DX are not active when given orally.
Table 1 Cytotoxic activity of Compounds of Examples 1, 3 and 2.
Compound ID50(ng/ml) HeLa P388P388/DX
_ DNR 12.3 2.8 980 Example 16.8 0.5 Example 35.8 2.4 8.8 DX 12.5 4.251250 Example 2 3 0.2 7 .
+ colony inhibition test after 24 hours exposure to the drugs ++ cytotoxicity evaluated after 48 hours exposure to the drugs Data from several experimen-ts.
1 Table 2 Effect against P388 ascitic leukemia Compound dose T/cc LTsd toxic (mg/kg) ~ deaths DNR 2.9165,155 0/20 0/20 4.4170,135 0/18 0/18 6.6130,115 0/20 12/20 Example 1 2.9 145 0/10 0/10 4.4160 0/10 0/10 6.6195 0/10 0/10 Example 3 2.9 130 0/10 0/10 4.4~.55 0/10 0/10 6~6145 0/10 0/10 D~ . 4.4215 0/10 0/].0 6.6235 0/10 0/10 .
Example 2 2.4 200 0/10 0/10
2.88230 0/10 0/10
3.46210 0/10 0/10 ~.15325 4/10 1/10 a Experiments were performed in CDFl mice, inoculated with 106 leukemia cells ip.
b Treatment ip on day 1 after -tumor inoculum.
c Median survival time of treated mice/median survival time of controls x 100.
d Long term survivors ~>60 days).
e Evaluated on the ~asis of au-toptic findings.
1 Table 3 Effect agains-t P388/DX asci-tic leukemia Compound dose T/CC toxic (mg/kg) % deaths DNR 4.4 91 0/10 6.6 ~7 0/10 Example 1 4.4 143 0/10 . 10 1~3 0/10 Example 3 6.6 148 0/10 DX 6.6 108 1/20 117 ~./20 Example 2 2.88 122 0/20 3.46 125 0/20
b Treatment ip on day 1 after -tumor inoculum.
c Median survival time of treated mice/median survival time of controls x 100.
d Long term survivors ~>60 days).
e Evaluated on the ~asis of au-toptic findings.
1 Table 3 Effect agains-t P388/DX asci-tic leukemia Compound dose T/CC toxic (mg/kg) % deaths DNR 4.4 91 0/10 6.6 ~7 0/10 Example 1 4.4 143 0/10 . 10 1~3 0/10 Example 3 6.6 148 0/10 DX 6.6 108 1/20 117 ~./20 Example 2 2.88 122 0/20 3.46 125 0/20
4.15 137 1/20 a Experiments were performed in BDFl mice inocula-ted with 106 cells ip.
b Treatment ip on day 1 after tumor inoculum.
c Median su~vival time of treated mice/median survival time of controls~ x 100.
d Evaluated on -the basis of autoptic findings.
~2~
1Table 4 Effect against Gross leukemia route doseb T/cc toxic Compound of admi- (mg/kg) % deaths nis-tr.
s DNR iv 10 142,138 2/18 183,185 1/18 22.5 217,92 9/18 Example 1 iv 10 217 0/10 22.5 100 9/9 Example 3 iv 6.6 185 0/10 oral 6.6 154 0/10 DX iv 10 183 0/10 16.9 242 0/10 Example 2 iv 4.05 233 0/10
b Treatment ip on day 1 after tumor inoculum.
c Median su~vival time of treated mice/median survival time of controls~ x 100.
d Evaluated on -the basis of autoptic findings.
~2~
1Table 4 Effect against Gross leukemia route doseb T/cc toxic Compound of admi- (mg/kg) % deaths nis-tr.
s DNR iv 10 142,138 2/18 183,185 1/18 22.5 217,92 9/18 Example 1 iv 10 217 0/10 22.5 100 9/9 Example 3 iv 6.6 185 0/10 oral 6.6 154 0/10 DX iv 10 183 0/10 16.9 242 0/10 Example 2 iv 4.05 233 0/10
5.27 258 0/10
6.~5 2~2 3/10 oral 4.05 114 0/10 5.27 157 0/10 a Experiments were performed in C3H mice, inoculated with 2X106 leukemia cells iv.
b Treatment iv or orally on day 1 after tumor inoculum~
c Median survival time of treated mice/median survival time o~ controls, x 100.
d Evaluated on the basis of autoptic findings.
1 The invention is illustrated by -the following Examples.
Ex'ample_ 4'-Deoxy~ bromodaunorubicin (A: X=H, R =OCH , R2=Br) 2 g of tetra (_-butyl) ammonium bromide was added to a solution of 4O0 g of 4'-epi-4~-O-trifluoromethane-sulphonyl-N-trifluoroacetyldaunorubicin (2: Rl=OCII3, R3=
COCF3) in 80 ml of anhydrous methylene dichlorid~. After 1 hour at room temperature the reaction mixture was washed with water and the organic phase evapora-ted in vacuo. The residue was purified on silica gel, using the mixture methylene dichloride:acetone as eluent, to give 3.5 g of 4'-deoxy-4'-bromo-N-trifluoroacetyldaunorubicinr m.p. 130C;
FD,MS 685 (M ~, TLC on Kieselgel plates (Merck F 254) using the solvent system methylene dichloride:acetone (10:1 by volume) Rf 0.5. To a solution of 3 g of 4'-deoxy-4'-bromo-N-trifluoroacetyldaunorubicin in 20 ml of acetone~ 160 ml of 0.1 N aqueous sodium hydroxide solution was added. After 4 hours at 0C, the solution was adjusted to p~l 8.6 with 0.lN hydrochloric acid and extracted with methylene dichloride. The solvent was evaporated off, a-ffording a residue that was converted by treatment with methanolic hydrogen chloride into the hydrochloride (2.2 g, m.p. 180C
with decomposition, TLC on Kieselgel plates (Merck F 254) using the solven-t system methylene dichloride:methanol:
water:acetic acicl (80:20:7:3 by volume) RE 0.32 * Trade Mark _ g _ , :~
~ ., ~3 1 Example 2 4'-Deoxy-4'-bromodoxorubi'cin (A: X=OH, Rl=OCH3, R2=Br) 2 g of 4'-deoxy-4'-bromodaunorubicin, prepared as described in Example 1, was dissolved in a mixture of methanol and dioxan. The solution was treated, as described in United S-tates Patent Speci-fica-tion No. 3803124, first with bromine to give the 14-bromo-deriva-tive and then with aqueous sodium formate to give 4'-deoxy-4'-bromodoxorubicin.
This was converted into its hydrochloride by treatment with methanolic hydroyen chloride. m.p. ~70C (with decomposi-tion), FD--MS 605 (M ), TLC on Rieselgel plates (Me~ck F
254) using the solvent system rnethylene dichloride:methanol:
wa-ter:acetic acid (80:20:7:3 by volume) Rf 0.20.
Example 3 4' Deoxy-4'-chlorodaunorubicin ~A: X=H, Rl=OCH3, R2=Cl) The treatmen-t of 4'-epi-4'-O-trifluoromethane-sulphonyl-N--trifluoroacetyldaunorubicin (2, Rl=OCH3, R3=
COCF3) wi-th tetra(_-butyl) ammonium chloride, following the procedure described in Example 1, afforded 4'-deoxy-4'-chlorodaunorubicin, m.p. 175C with decomposition, FD~MS 545 (M ), TLC on Kieselgel plates (Merck F 254) using the solvent system methylene dichloride:methanol:water:acetic acid (80:20:7:3 by volume) Rf 0.32.
Example 4 4'-Deoxy-4'-chlorodoXorubicin (A: X=OH, Rl=OCH3, R2=Cl) Followiny the procedure described in Example 2, 4'-deoxy-4'-chlorodaunorubicin was converted into 4l-deoxy-4'-3~
1 chlorodoxorubicin, isolated as its hydrochloride; m.p. 180V
(dec.); FC mass spectrum: 561 [M ] TLC on Kieselgel plates (Merck F 254) using solvent sys-tem methylene chloride/
methanol/water/acetic acid (80:20:7:3 v/v). RF 0.2.
E ample 5 4'-Deoxy~~'-fluorodaunorubicin (A: X=H, Rl=OCH3, R2=F) To a stirred solution of 26 g of 4'-epi-N-trichloro-ethoxycarbonyldaunorubicin, described in United States Patent Specification No. 4345068, in 650 ml of anhydrous methylene dichloride and 32 ml of anhydrous pyridi~e, cooled a-t 0C, was added a solution of 11 ml of trifluoromethane-sulphonic anhydride in 1~0 ml of anhydrous methylene di-chloride. The reaction mix-ture was washed with a cooled 5 aqueous solution of sodium bicarbonate, water, a O.lN
14 hydrochloric acid and wa-ter in that order. The organic solution, dried over anhydrous sodium sulphate, was used in the following step without further purification.
A solution of 2 g of ~'-epi-4'-O-trifluoromethane-sulphonyl-N--trichloroethoxycarbonyldaunorubicin in 30 ml of acetonitrile was treated with 0.5 g of caesium fluoride.
After 10 minutes at room temperature the mixture was poured into wa-ter and extracted with methylene dichloride. The organic phase, dried over anhydrous sodium sulphate, was evaporated to dryness under vacuum. The residue, dissolved in 30 ml of ethanol, was treated with ~ ml of acetic acid and 0.2 g of zinc dust at 0C~ After 1 hour, the mixture, filtered on celite, was diluted with water and ex-tracted 1 with methylene dichloride. The crude product, obtained by evapora-ting of the solvent under vacuum, was purified by chroma-tography on a column of silica gel, using methyle~e dichloride as eluent, to give pure 4'-deoxy-4'-fluorodauno-rubicin, isola-ted as its hydrochloride: FD-MS 529 (M ), TLC on Kieselgel plates (Merck F 254) using the solvent system methylene chloride:methanol:water:acetic acid (80:20:7:3 by volume) Rf 0.32.
Example 6 4'-Deoxy-4'-fluorodoxorubicin (A: X=OH, R =OCH ;
. - 1 3 R2=F) Following the procedure described in Example 2, 4'-deoxy-4'-fluorodaunorubicin was converted into 4'-deoxy-4'-fluorodoxorubicin, isolated as its hydrochloride.
b Treatment iv or orally on day 1 after tumor inoculum~
c Median survival time of treated mice/median survival time o~ controls, x 100.
d Evaluated on the basis of autoptic findings.
1 The invention is illustrated by -the following Examples.
Ex'ample_ 4'-Deoxy~ bromodaunorubicin (A: X=H, R =OCH , R2=Br) 2 g of tetra (_-butyl) ammonium bromide was added to a solution of 4O0 g of 4'-epi-4~-O-trifluoromethane-sulphonyl-N-trifluoroacetyldaunorubicin (2: Rl=OCII3, R3=
COCF3) in 80 ml of anhydrous methylene dichlorid~. After 1 hour at room temperature the reaction mixture was washed with water and the organic phase evapora-ted in vacuo. The residue was purified on silica gel, using the mixture methylene dichloride:acetone as eluent, to give 3.5 g of 4'-deoxy-4'-bromo-N-trifluoroacetyldaunorubicinr m.p. 130C;
FD,MS 685 (M ~, TLC on Kieselgel plates (Merck F 254) using the solvent system methylene dichloride:acetone (10:1 by volume) Rf 0.5. To a solution of 3 g of 4'-deoxy-4'-bromo-N-trifluoroacetyldaunorubicin in 20 ml of acetone~ 160 ml of 0.1 N aqueous sodium hydroxide solution was added. After 4 hours at 0C, the solution was adjusted to p~l 8.6 with 0.lN hydrochloric acid and extracted with methylene dichloride. The solvent was evaporated off, a-ffording a residue that was converted by treatment with methanolic hydrogen chloride into the hydrochloride (2.2 g, m.p. 180C
with decomposition, TLC on Kieselgel plates (Merck F 254) using the solven-t system methylene dichloride:methanol:
water:acetic acicl (80:20:7:3 by volume) RE 0.32 * Trade Mark _ g _ , :~
~ ., ~3 1 Example 2 4'-Deoxy-4'-bromodoxorubi'cin (A: X=OH, Rl=OCH3, R2=Br) 2 g of 4'-deoxy-4'-bromodaunorubicin, prepared as described in Example 1, was dissolved in a mixture of methanol and dioxan. The solution was treated, as described in United S-tates Patent Speci-fica-tion No. 3803124, first with bromine to give the 14-bromo-deriva-tive and then with aqueous sodium formate to give 4'-deoxy-4'-bromodoxorubicin.
This was converted into its hydrochloride by treatment with methanolic hydroyen chloride. m.p. ~70C (with decomposi-tion), FD--MS 605 (M ), TLC on Rieselgel plates (Me~ck F
254) using the solvent system rnethylene dichloride:methanol:
wa-ter:acetic acid (80:20:7:3 by volume) Rf 0.20.
Example 3 4' Deoxy-4'-chlorodaunorubicin ~A: X=H, Rl=OCH3, R2=Cl) The treatmen-t of 4'-epi-4'-O-trifluoromethane-sulphonyl-N--trifluoroacetyldaunorubicin (2, Rl=OCH3, R3=
COCF3) wi-th tetra(_-butyl) ammonium chloride, following the procedure described in Example 1, afforded 4'-deoxy-4'-chlorodaunorubicin, m.p. 175C with decomposition, FD~MS 545 (M ), TLC on Kieselgel plates (Merck F 254) using the solvent system methylene dichloride:methanol:water:acetic acid (80:20:7:3 by volume) Rf 0.32.
Example 4 4'-Deoxy-4'-chlorodoXorubicin (A: X=OH, Rl=OCH3, R2=Cl) Followiny the procedure described in Example 2, 4'-deoxy-4'-chlorodaunorubicin was converted into 4l-deoxy-4'-3~
1 chlorodoxorubicin, isolated as its hydrochloride; m.p. 180V
(dec.); FC mass spectrum: 561 [M ] TLC on Kieselgel plates (Merck F 254) using solvent sys-tem methylene chloride/
methanol/water/acetic acid (80:20:7:3 v/v). RF 0.2.
E ample 5 4'-Deoxy~~'-fluorodaunorubicin (A: X=H, Rl=OCH3, R2=F) To a stirred solution of 26 g of 4'-epi-N-trichloro-ethoxycarbonyldaunorubicin, described in United States Patent Specification No. 4345068, in 650 ml of anhydrous methylene dichloride and 32 ml of anhydrous pyridi~e, cooled a-t 0C, was added a solution of 11 ml of trifluoromethane-sulphonic anhydride in 1~0 ml of anhydrous methylene di-chloride. The reaction mix-ture was washed with a cooled 5 aqueous solution of sodium bicarbonate, water, a O.lN
14 hydrochloric acid and wa-ter in that order. The organic solution, dried over anhydrous sodium sulphate, was used in the following step without further purification.
A solution of 2 g of ~'-epi-4'-O-trifluoromethane-sulphonyl-N--trichloroethoxycarbonyldaunorubicin in 30 ml of acetonitrile was treated with 0.5 g of caesium fluoride.
After 10 minutes at room temperature the mixture was poured into wa-ter and extracted with methylene dichloride. The organic phase, dried over anhydrous sodium sulphate, was evaporated to dryness under vacuum. The residue, dissolved in 30 ml of ethanol, was treated with ~ ml of acetic acid and 0.2 g of zinc dust at 0C~ After 1 hour, the mixture, filtered on celite, was diluted with water and ex-tracted 1 with methylene dichloride. The crude product, obtained by evapora-ting of the solvent under vacuum, was purified by chroma-tography on a column of silica gel, using methyle~e dichloride as eluent, to give pure 4'-deoxy-4'-fluorodauno-rubicin, isola-ted as its hydrochloride: FD-MS 529 (M ), TLC on Kieselgel plates (Merck F 254) using the solvent system methylene chloride:methanol:water:acetic acid (80:20:7:3 by volume) Rf 0.32.
Example 6 4'-Deoxy-4'-fluorodoxorubicin (A: X=OH, R =OCH ;
. - 1 3 R2=F) Following the procedure described in Example 2, 4'-deoxy-4'-fluorodaunorubicin was converted into 4'-deoxy-4'-fluorodoxorubicin, isolated as its hydrochloride.
Claims (11)
1. A process for preparing 4'-halo-anthracycline glycosides having the general formula A:
A
wherein X represents a hydrogen atom or a hydroxy group, R1 represents a hydrogen atom or a hydroxy or a methoxy group and R2 represents a bromine, chlorine or fluorine atom, which comprises (a) subjecting a compound of the general formula 2:
wherein R1 is defined hereinbefore, and R3 represents an amino protecting group to an exchange reaction with a fluoride, chloride or a bromide;
(b) deprotecting the resultant compound of the general formula 3:
3 to produce a compound of the general formula A wherein X is a hydrogen atom; and (c) for the production of compounds of the formula A wherein X is a hydroxy group; brominating the resultant compound of step B and subsequently treating the resultant 14-bromo derivative with aqueous formate.
A
wherein X represents a hydrogen atom or a hydroxy group, R1 represents a hydrogen atom or a hydroxy or a methoxy group and R2 represents a bromine, chlorine or fluorine atom, which comprises (a) subjecting a compound of the general formula 2:
wherein R1 is defined hereinbefore, and R3 represents an amino protecting group to an exchange reaction with a fluoride, chloride or a bromide;
(b) deprotecting the resultant compound of the general formula 3:
3 to produce a compound of the general formula A wherein X is a hydrogen atom; and (c) for the production of compounds of the formula A wherein X is a hydroxy group; brominating the resultant compound of step B and subsequently treating the resultant 14-bromo derivative with aqueous formate.
2. A process according to claim 1 in which the fluoride is caesium fluoride.
3. A process according to claim 1 in which the bromide is tetra (n-butyl) ammonium bromide.
4. A process according to claim 1 in which the chloride is tetra (n-butyl) ammonium chloride.
5. A process according to claim 1 in which the amine protecting group is a trichloroethoxy-carbonyl group.
6. A process according to claim 5 in which the deportation reaction is a hydrogenation reaction.
7. A process according to claim 5 or claim 6 in which the deportation is effected with zinc dust and acetic acid.
8. A process according to claim 1 in which the amine protecting group is a trifluoroacetyl group.
9. A process according to claim 8 in which the deportation reaction is a mild alkaline hydrolysis.
10. A process according to claim 8 or claim 9 in which the deportation is effected with 0.1 N aqueous sodium hydroxide solution.
11. A process according to claim 1 in which the exchange reaction is carried out in methylene dichloride or acetonitrile.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB8321676 | 1983-08-11 | ||
| GB838321676A GB8321676D0 (en) | 1983-08-11 | 1983-08-11 | 4'-haloanthrocycline glycosides |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1250833A true CA1250833A (en) | 1989-03-07 |
Family
ID=10547171
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA000460796A Expired CA1250833A (en) | 1983-08-11 | 1984-08-10 | Process for preparing 4'-haloanthracycline glycosides |
Country Status (19)
| Country | Link |
|---|---|
| JP (1) | JPS6058997A (en) |
| AT (1) | AT384226B (en) |
| AU (1) | AU563396B2 (en) |
| BE (1) | BE900336A (en) |
| CA (1) | CA1250833A (en) |
| CH (1) | CH660740A5 (en) |
| CS (1) | CS270411B2 (en) |
| DE (1) | DE3428945A1 (en) |
| DK (1) | DK381884A (en) |
| FI (1) | FI78109C (en) |
| FR (1) | FR2554450B1 (en) |
| GB (2) | GB8321676D0 (en) |
| GR (1) | GR80046B (en) |
| HU (1) | HU194266B (en) |
| IT (1) | IT1209576B (en) |
| NL (1) | NL8402477A (en) |
| SE (1) | SE8404005L (en) |
| SU (1) | SU1579465A3 (en) |
| ZA (1) | ZA846147B (en) |
Families Citing this family (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB2159518A (en) * | 1984-06-08 | 1985-12-04 | Erba Farmitalia | New anthracyclines and process for manufacture |
| GB8414619D0 (en) * | 1984-06-08 | 1984-07-11 | Erba Farmitalia | Anthracyclines |
| DE3500017A1 (en) * | 1985-01-02 | 1986-07-10 | Farmitalia Carlo Erba S.p.A., Mailand/Milano | 4'-Haloanthracycline esters |
| GB2218087B (en) * | 1988-04-22 | 1991-01-30 | Erba Carlo Spa | 4-demethoxy-4'-deoxy-4'iodo anthracycline glycosides |
| AU601857B2 (en) * | 1988-06-30 | 1990-09-20 | Pharmacia & Upjohn S.P.A. | A new antitumor agent obtained by microbial stereoselective reduction of 4'-deoxy-4'-iododoxorubicin |
| MA21995A1 (en) * | 1989-11-13 | 1991-07-01 | Menarini Farma Ind | NOVEL FLUORONAPHTHACENEDIONES, THEIR GLYCOZYL DERIVATIVES AND THEIR MANUFACTURING METHODS. |
| GB9418260D0 (en) * | 1994-09-09 | 1994-10-26 | Erba Carlo Spa | Anthracycline derivatives |
Family Cites Families (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| FR892943A (en) * | 1942-03-06 | 1944-05-24 | Ig Farbenindustrie Ag | Process for purifying gamma-keto-pimelic dilactone |
| US4345070A (en) * | 1980-09-29 | 1982-08-17 | Farmitalia Carlo Erba S.P.A. | Process for the preparation of 4'-deoxy-daunorubicin and 4'-deoxy-doxorubicin |
| US4438105A (en) * | 1982-04-19 | 1984-03-20 | Farmaitalia Carlo Erba S.P.A | 4'-Iododerivatives of anthracycline glycosides |
-
1983
- 1983-08-11 GB GB838321676A patent/GB8321676D0/en active Pending
-
1984
- 1984-08-06 IT IT8422232A patent/IT1209576B/en active
- 1984-08-06 DE DE3428945A patent/DE3428945A1/en not_active Withdrawn
- 1984-08-06 AT AT0253884A patent/AT384226B/en not_active IP Right Cessation
- 1984-08-07 GR GR80046A patent/GR80046B/en unknown
- 1984-08-07 FR FR8412467A patent/FR2554450B1/en not_active Expired
- 1984-08-07 AU AU31685/84A patent/AU563396B2/en not_active Ceased
- 1984-08-07 SU SU843781800A patent/SU1579465A3/en active
- 1984-08-07 SE SE8404005A patent/SE8404005L/en unknown
- 1984-08-08 ZA ZA846147A patent/ZA846147B/en unknown
- 1984-08-08 FI FI843110A patent/FI78109C/en not_active IP Right Cessation
- 1984-08-08 DK DK381884A patent/DK381884A/en not_active Application Discontinuation
- 1984-08-09 GB GB08420237A patent/GB2144744B/en not_active Expired
- 1984-08-09 JP JP59165760A patent/JPS6058997A/en active Pending
- 1984-08-09 CS CS846052A patent/CS270411B2/en unknown
- 1984-08-10 NL NL8402477A patent/NL8402477A/en unknown
- 1984-08-10 HU HU843055A patent/HU194266B/en not_active IP Right Cessation
- 1984-08-10 BE BE0/213475A patent/BE900336A/en not_active IP Right Cessation
- 1984-08-10 CH CH3853/84A patent/CH660740A5/en not_active IP Right Cessation
- 1984-08-10 CA CA000460796A patent/CA1250833A/en not_active Expired
Also Published As
| Publication number | Publication date |
|---|---|
| ATA253884A (en) | 1987-03-15 |
| IT1209576B (en) | 1989-08-30 |
| IT8422232A0 (en) | 1984-08-06 |
| SE8404005L (en) | 1985-02-12 |
| FI843110A (en) | 1985-02-12 |
| AU563396B2 (en) | 1987-07-09 |
| AT384226B (en) | 1987-10-12 |
| CH660740A5 (en) | 1987-06-15 |
| DE3428945A1 (en) | 1985-02-28 |
| FR2554450A1 (en) | 1985-05-10 |
| GB2144744B (en) | 1986-12-03 |
| GB8420237D0 (en) | 1984-09-12 |
| DK381884D0 (en) | 1984-08-08 |
| HU194266B (en) | 1988-01-28 |
| NL8402477A (en) | 1985-03-01 |
| FI843110A0 (en) | 1984-08-08 |
| GR80046B (en) | 1984-12-10 |
| FI78109C (en) | 1989-06-12 |
| GB8321676D0 (en) | 1983-09-14 |
| FR2554450B1 (en) | 1987-01-30 |
| BE900336A (en) | 1985-02-11 |
| ZA846147B (en) | 1985-03-27 |
| AU3168584A (en) | 1985-02-14 |
| HUT35691A (en) | 1985-07-29 |
| CS270411B2 (en) | 1990-06-13 |
| FI78109B (en) | 1989-02-28 |
| SU1579465A3 (en) | 1990-07-15 |
| JPS6058997A (en) | 1985-04-05 |
| GB2144744A (en) | 1985-03-13 |
| DK381884A (en) | 1985-02-12 |
| SE8404005D0 (en) | 1984-08-07 |
| CS605284A2 (en) | 1989-11-14 |
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