CA1095028A - Anthracyclines - Google Patents
AnthracyclinesInfo
- Publication number
- CA1095028A CA1095028A CA348,323A CA348323A CA1095028A CA 1095028 A CA1095028 A CA 1095028A CA 348323 A CA348323 A CA 348323A CA 1095028 A CA1095028 A CA 1095028A
- Authority
- CA
- Canada
- Prior art keywords
- daunorubicin
- desacetyl
- trifluoroacetyl
- keto
- chloroform
- 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.)
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
ABSTRACT OF THE DISCLOSURE
This invention discloses a process for producing 9-desacetyl-9-keto-N-trifluoroacetyl-daunorubicin and the compound itself. The process comprises oxidizing N-trifluoro-acetyl-13-dihydrodaunorubicin in t-butyl alcohol in the presence of two equivalents of sodium periodate. These compounds are unexpectedly stable intermediates useful in the production of new daunorubicin derivatives which are used in treating certain mammalian tumours.
This invention discloses a process for producing 9-desacetyl-9-keto-N-trifluoroacetyl-daunorubicin and the compound itself. The process comprises oxidizing N-trifluoro-acetyl-13-dihydrodaunorubicin in t-butyl alcohol in the presence of two equivalents of sodium periodate. These compounds are unexpectedly stable intermediates useful in the production of new daunorubicin derivatives which are used in treating certain mammalian tumours.
Description
~0~50~8 1 This is a divisional application o~ Canadian patent application serial number 282,526 filed on July 12, 1977.
The invention relates to novel intermediate compounds useful in the production of anthracyclines which are glycosides and which are useful in the treatment of tumours in man.
The new compound is 9-desacetyl-9-keto-N-trifluoro-acetyl-daunorubicin and is prepared by oxidizing N-trifluoro-acetyl-13-dihydrodaunorubicin in t-butyl alcohol in the presence of two equivalents of sodium periodate at room temperature for two hours.
These compounds are useful in the preparation of daunorubicin derivatives of the general formula I:
O OH
C
~ ' ~O HO
NHR
where X is C~ or C~ or~ C = O
~H H
and R is -COCF3 or H.
These compounds are prepared by hydrogenating the compound of this invention with an alkali metal borohydride, the amino group of the sugar residue is protected, and the derivative so protected is oxidized at the 9-position with a periodate. In the scheme below, daunorubicin (A) is con-verted into 9-desacetyl-9-keto-N-trifluoroacetyl daunorubicin D.
~v4 ~
10~5028 "
CH3 H ~ NaBH4 ~, CH3 1 OH
A N H2 ¦ ~
1) (CF3C0)20 0 ~ 2) MeOH
OOH R
~ NaI04 ~ HOHCH3 CH3 H ! CH30 OH o ~ HO ~ C
\ ~
O OH Q OH
H ~ H
~ ~OH and ~,J `H
HO ~ HO
NHR HR
E: R = COCF3 F: R = COCF3 G: R = H - 2 - H: R = H
'1.0~ 8 1 In the scheme above, the carbonyl group at the l3-position of daunorubicin A was reduced to the corresponding alcohol with sodium borohydride. The reaction was carried out in water at room temperature to give B, isolated as hydrochloride, in about 80% yield. The resulting diol B was protected at the amino group of the sugar residue. The N-trifluoroacetyl group affords the desired protection and can be removed in mild conditions not affecting the remaining portion of the anthracycline molecule. The N-trifluoroacetylation was performed by treatment with trifluoroacetic anhydride, followed by hydrolysis of 0-trifluoroacetyl groups with methanol giving a protected derivative C in 74~ yield. The oxidation of C
was carried out in _-butyl alcohol in the presence of two equivalents of sodium periodate at room temperature for two hours. The protected daunorubicin D which is insoluble in the reaction mixture, was obtained in about 50~ yield. The compound D by treatment with sodium borohydride-cyanide (NaBH3CN) in acid conditions was converted into an epimeric mixture of E and F in an approximate ratio 8:l. The separation Of these compounds by chromatography on a column of silicic acid, followed by mild alkaline treatment to remove the N-trifluoroacetyl protective group, gave 9-desacetyl-daunorubicin G and 9-desacetyl-9-epi-daunorubicin H, isolated as hydro-chlorides.
The new compounds G and H display antimitotic activity and are useful therapeutic agents for the treatment of tumour diseases in humans.
This invention is illustrated by the following Examples, although each Example does not cover the whole of the process of the invention.
~09tio28 N-trifluoroacetyl-13- ~ ubicin C (~AR 4) __ A solution of 3.0 g of daunorubicin hydrochloride in 30Q ml of water was adjusted to pH 9.5 with aqueous 0.1 N sodium hydroxide and treated with 0.3 g of sodium borohydride at room temperature for seven minutes. The reaction mixture was poured into 750 ml of aqueous 0.25 N hydrochloric acid with vigorous stirring to eliminate the excess reducing agent. The solution was adjusted to pH 8.6 and extrac-ted with chloroform until the extracts were no longer coloured. The organic phase dried over anhydrous sodium sulphate, and evaporated under vacuum down to 5~ ml volume. The remaining red solution, adjusted to pH 3.5 (Congo Red) with anhydrous methanolic hydrogen chloride, was mixed with excess diethyl ether to give
The invention relates to novel intermediate compounds useful in the production of anthracyclines which are glycosides and which are useful in the treatment of tumours in man.
The new compound is 9-desacetyl-9-keto-N-trifluoro-acetyl-daunorubicin and is prepared by oxidizing N-trifluoro-acetyl-13-dihydrodaunorubicin in t-butyl alcohol in the presence of two equivalents of sodium periodate at room temperature for two hours.
These compounds are useful in the preparation of daunorubicin derivatives of the general formula I:
O OH
C
~ ' ~O HO
NHR
where X is C~ or C~ or~ C = O
~H H
and R is -COCF3 or H.
These compounds are prepared by hydrogenating the compound of this invention with an alkali metal borohydride, the amino group of the sugar residue is protected, and the derivative so protected is oxidized at the 9-position with a periodate. In the scheme below, daunorubicin (A) is con-verted into 9-desacetyl-9-keto-N-trifluoroacetyl daunorubicin D.
~v4 ~
10~5028 "
CH3 H ~ NaBH4 ~, CH3 1 OH
A N H2 ¦ ~
1) (CF3C0)20 0 ~ 2) MeOH
OOH R
~ NaI04 ~ HOHCH3 CH3 H ! CH30 OH o ~ HO ~ C
\ ~
O OH Q OH
H ~ H
~ ~OH and ~,J `H
HO ~ HO
NHR HR
E: R = COCF3 F: R = COCF3 G: R = H - 2 - H: R = H
'1.0~ 8 1 In the scheme above, the carbonyl group at the l3-position of daunorubicin A was reduced to the corresponding alcohol with sodium borohydride. The reaction was carried out in water at room temperature to give B, isolated as hydrochloride, in about 80% yield. The resulting diol B was protected at the amino group of the sugar residue. The N-trifluoroacetyl group affords the desired protection and can be removed in mild conditions not affecting the remaining portion of the anthracycline molecule. The N-trifluoroacetylation was performed by treatment with trifluoroacetic anhydride, followed by hydrolysis of 0-trifluoroacetyl groups with methanol giving a protected derivative C in 74~ yield. The oxidation of C
was carried out in _-butyl alcohol in the presence of two equivalents of sodium periodate at room temperature for two hours. The protected daunorubicin D which is insoluble in the reaction mixture, was obtained in about 50~ yield. The compound D by treatment with sodium borohydride-cyanide (NaBH3CN) in acid conditions was converted into an epimeric mixture of E and F in an approximate ratio 8:l. The separation Of these compounds by chromatography on a column of silicic acid, followed by mild alkaline treatment to remove the N-trifluoroacetyl protective group, gave 9-desacetyl-daunorubicin G and 9-desacetyl-9-epi-daunorubicin H, isolated as hydro-chlorides.
The new compounds G and H display antimitotic activity and are useful therapeutic agents for the treatment of tumour diseases in humans.
This invention is illustrated by the following Examples, although each Example does not cover the whole of the process of the invention.
~09tio28 N-trifluoroacetyl-13- ~ ubicin C (~AR 4) __ A solution of 3.0 g of daunorubicin hydrochloride in 30Q ml of water was adjusted to pH 9.5 with aqueous 0.1 N sodium hydroxide and treated with 0.3 g of sodium borohydride at room temperature for seven minutes. The reaction mixture was poured into 750 ml of aqueous 0.25 N hydrochloric acid with vigorous stirring to eliminate the excess reducing agent. The solution was adjusted to pH 8.6 and extrac-ted with chloroform until the extracts were no longer coloured. The organic phase dried over anhydrous sodium sulphate, and evaporated under vacuum down to 5~ ml volume. The remaining red solution, adjusted to pH 3.5 (Congo Red) with anhydrous methanolic hydrogen chloride, was mixed with excess diethyl ether to give
2.8 g of pure 13-dihydrodaunorubicin B, as hydrochloride.
A suspension of 2.8 g of B in 300 ml of chloro~orm was treated with 20 ml of trifluoroacetic anhydride at 0 for 1 hour. The reaction mixture was evaporated to dryness under vacuum. The residue was dissolved in 200 ml of methanol and neutralized with an aqueous saturated solution of sodium bicarbonate. After 30' at room temperature, the solvent was eliminated under vacuum and the aqueous solution was extracted with chloroform until the extrac~s were no longer coloured.
The organic phase was washed with water and dried over anhydrous sodium sulphate, was evaporated down to 30 ml volume, and mixed with excess petroleum ether to give 2.3 g of pure N-trifluoroacetyl-13-dihydrodaunorubicin C: m.p. 164-166C (dec.);
TLC (Thin Layer Chromatography) on Merck Kieselgel 60 F254 using a chloroform-acetone solvent system (2:1 v/v): Rf 0.25.
10~0~8 1 EXAMPI.E 2 9-Desacetyl-9-keto-N-trifluoroacetxldaunorubicin D (MAR 18) .
A solution of 2.4 g of C in 120 ml of t-butyl alcohol was treated with 1.6 g of sodium periodate dissolved in 120 ml of water. The reaction mixture was stirred at room t'emperature for two hours. The precipitated compound D was filtered off, washed with water and dried under vacuum. 1.4 g of pure D were obtained: m.p. 200C (dec.); T~C on Merck Kieselgel 60 F254 using a chloroform-acetone solven-t system (2:1 v/v):
Rf 0.57.
Elementary analysis: calcd. ~ for C27H24F3NOlo: H 4.18; C 55.95 found % : H 4.26; C 55.65 _ 9-Desacetyl-daunorubicin G (MAR 29) and 9-desacetyl-9-epi-daunorubicin H (MAR 30) A solution of 1.7 g of D in 250 ml of dioxan and 50 ml of water was adjusted to pH 3 with aqueous 1 N hydrochloric acid and treated with 1 g of sodium borohydride cyanide (NaBH3CN) at room temperature for 24 hours, the acid condition being maintained by addition of 1 N hydrochloric acid. The reaction mixture was mixed with water (300 ml) and extracted with chloroform (5 x 200 ml). The organic phase, washed with water and dried over anhydrous sodium sulphate, was evaPorated to dryness under vacuum. The residue ~1 g~, containing E and F, was chromatographed on a column of silica gel using chloroform with increasing amounts of acetone as eluting agent, to give 0.85 g of pure E, m.p. 204 -206 (dec.); TLC
on Merck Kieselgel 60 F254 using a chloroform~acetone solvent system (2:1 v/v): Rf 0.44 and 0.1 g of pure F, m.p. 180-182C
lO~SO~B
1 (dec.); Rf : 0.3 in the same conditions as for E. In order to hydrolyze the N-trifluoroacetyl group E and F were treated as follows: 50 ml o~ 0.1 N sodium hydroxide were added, after 30' at 0C the pH was adjusted to 8.4 with 0.1 N hydrochloric acid and the solution was repeatedly extracted with chloroform.
The combined extracts were driea over anhydrous sodium sulphate and evaporated under vacuum down to 20 ml volume. The solution, on the addition of the stoichiometric amount of methanolic hydrogen chloride and diethyl ether, gave a red precipitate which was collected, washed with diethyl ether and dried under vacuum. The compound G had m.p. 166 - 167C (dec.); [~]D5 =
+ 282 (c=0.15 in methanol); TLC on Kieselgel plates F254 ~Merck) with a chloroform acetone solvent system (13:6:1 v/v):
Rf 0.55.
Elementary Analysis:
Calcd. % for C25H27NOgHCl : H 5.42; C 57.52; N 2.68 found : H 5.45; C 57.16; N 2.42 Compound H had m.p. 176C (dec.), Rf 0.4 in the same conditions as for compound G.
Activity of doxorubicin [NSC 123127], 9-desacetyl-daunorubicin (G~ ~NSC 268708] and 9-desacetyl-9-epi-daunorubicin (H) [NSC 268709] on P 388 lymphocytic leukemia in C.D.F. male mice (tumour inoculum 106 cells intraperitoneally (ip)~.
Treatment ip on days 1 to 9 10~;02~
1Compoun~_ Dose m~/kg T/C
Doxorubicill 4 83 0.5 142 0.25 152 12~5 228 6.25 180
A suspension of 2.8 g of B in 300 ml of chloro~orm was treated with 20 ml of trifluoroacetic anhydride at 0 for 1 hour. The reaction mixture was evaporated to dryness under vacuum. The residue was dissolved in 200 ml of methanol and neutralized with an aqueous saturated solution of sodium bicarbonate. After 30' at room temperature, the solvent was eliminated under vacuum and the aqueous solution was extracted with chloroform until the extrac~s were no longer coloured.
The organic phase was washed with water and dried over anhydrous sodium sulphate, was evaporated down to 30 ml volume, and mixed with excess petroleum ether to give 2.3 g of pure N-trifluoroacetyl-13-dihydrodaunorubicin C: m.p. 164-166C (dec.);
TLC (Thin Layer Chromatography) on Merck Kieselgel 60 F254 using a chloroform-acetone solvent system (2:1 v/v): Rf 0.25.
10~0~8 1 EXAMPI.E 2 9-Desacetyl-9-keto-N-trifluoroacetxldaunorubicin D (MAR 18) .
A solution of 2.4 g of C in 120 ml of t-butyl alcohol was treated with 1.6 g of sodium periodate dissolved in 120 ml of water. The reaction mixture was stirred at room t'emperature for two hours. The precipitated compound D was filtered off, washed with water and dried under vacuum. 1.4 g of pure D were obtained: m.p. 200C (dec.); T~C on Merck Kieselgel 60 F254 using a chloroform-acetone solven-t system (2:1 v/v):
Rf 0.57.
Elementary analysis: calcd. ~ for C27H24F3NOlo: H 4.18; C 55.95 found % : H 4.26; C 55.65 _ 9-Desacetyl-daunorubicin G (MAR 29) and 9-desacetyl-9-epi-daunorubicin H (MAR 30) A solution of 1.7 g of D in 250 ml of dioxan and 50 ml of water was adjusted to pH 3 with aqueous 1 N hydrochloric acid and treated with 1 g of sodium borohydride cyanide (NaBH3CN) at room temperature for 24 hours, the acid condition being maintained by addition of 1 N hydrochloric acid. The reaction mixture was mixed with water (300 ml) and extracted with chloroform (5 x 200 ml). The organic phase, washed with water and dried over anhydrous sodium sulphate, was evaPorated to dryness under vacuum. The residue ~1 g~, containing E and F, was chromatographed on a column of silica gel using chloroform with increasing amounts of acetone as eluting agent, to give 0.85 g of pure E, m.p. 204 -206 (dec.); TLC
on Merck Kieselgel 60 F254 using a chloroform~acetone solvent system (2:1 v/v): Rf 0.44 and 0.1 g of pure F, m.p. 180-182C
lO~SO~B
1 (dec.); Rf : 0.3 in the same conditions as for E. In order to hydrolyze the N-trifluoroacetyl group E and F were treated as follows: 50 ml o~ 0.1 N sodium hydroxide were added, after 30' at 0C the pH was adjusted to 8.4 with 0.1 N hydrochloric acid and the solution was repeatedly extracted with chloroform.
The combined extracts were driea over anhydrous sodium sulphate and evaporated under vacuum down to 20 ml volume. The solution, on the addition of the stoichiometric amount of methanolic hydrogen chloride and diethyl ether, gave a red precipitate which was collected, washed with diethyl ether and dried under vacuum. The compound G had m.p. 166 - 167C (dec.); [~]D5 =
+ 282 (c=0.15 in methanol); TLC on Kieselgel plates F254 ~Merck) with a chloroform acetone solvent system (13:6:1 v/v):
Rf 0.55.
Elementary Analysis:
Calcd. % for C25H27NOgHCl : H 5.42; C 57.52; N 2.68 found : H 5.45; C 57.16; N 2.42 Compound H had m.p. 176C (dec.), Rf 0.4 in the same conditions as for compound G.
Activity of doxorubicin [NSC 123127], 9-desacetyl-daunorubicin (G~ ~NSC 268708] and 9-desacetyl-9-epi-daunorubicin (H) [NSC 268709] on P 388 lymphocytic leukemia in C.D.F. male mice (tumour inoculum 106 cells intraperitoneally (ip)~.
Treatment ip on days 1 to 9 10~;02~
1Compoun~_ Dose m~/kg T/C
Doxorubicill 4 83 0.5 142 0.25 152 12~5 228 6.25 180
3.13 174 1.56 155 12.5 66 6.25 171 3.13 157 1~ 1.56 142 a Experiment number 4108 - Data obtained under auspices of NCI. Screener : A.D. LITTLE INC.
b Median survival time expressed as percent of untreated controls.
Activity of doxorubicin [NSC 123127] and 9-desacetyl-daunorubicin (G) [NSC 268708] on P 388 lymphocytic leukemia in CDFl male mice (tumour inoculum 10 cells, ip). Treatment ip on days 5, 9, 13 a, 20Compound Dose mg/kgT/C b Doxorubicin 16 120
b Median survival time expressed as percent of untreated controls.
Activity of doxorubicin [NSC 123127] and 9-desacetyl-daunorubicin (G) [NSC 268708] on P 388 lymphocytic leukemia in CDFl male mice (tumour inoculum 10 cells, ip). Treatment ip on days 5, 9, 13 a, 20Compound Dose mg/kgT/C b Doxorubicin 16 120
4 136 37.5 135 lS.8 145 9.4 133 4.7 109 a Experiment number 4832. Data obtained under auspices of NCI. Screener : A.D. LITTLE INC.
b Median survival time expressed as percent of untreated controls~
~0950;~8 1 Although the disclosure describes and illustrates a pxeferred embodiment of the invention, it is to be under-stood that the invention is not restricted to -this particular embodiment.
b Median survival time expressed as percent of untreated controls~
~0950;~8 1 Although the disclosure describes and illustrates a pxeferred embodiment of the invention, it is to be under-stood that the invention is not restricted to -this particular embodiment.
Claims (2)
1. A process for preparing 9-desacetyl-9-keto-N-tri-fluoroacetyl-daunorubicin which comprises oxidizing N-tri-fluoroacetyl-13-dihydrodaunorubicin in t-butyl alcohol in the presence of two equivalents of sodium periodate at room temperature for two hours.
2. 9-Desacetyl-9-keto-N-trifluoroacetyl-daunorubicin whenever prepared by a process as claimed in claim 1 or an obvious chemical equivalent thereof.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CA348,323A CA1095028A (en) | 1976-07-13 | 1980-03-24 | Anthracyclines |
Applications Claiming Priority (4)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB28986/76A GB1524468A (en) | 1976-07-13 | 1976-07-13 | Anthracylines |
| GB28986/76 | 1976-07-13 | ||
| CA282,526A CA1091225A (en) | 1976-07-13 | 1977-07-12 | Anthracyclines |
| CA348,323A CA1095028A (en) | 1976-07-13 | 1980-03-24 | Anthracyclines |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1095028A true CA1095028A (en) | 1981-02-03 |
Family
ID=27165176
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA348,323A Expired CA1095028A (en) | 1976-07-13 | 1980-03-24 | Anthracyclines |
Country Status (1)
| Country | Link |
|---|---|
| CA (1) | CA1095028A (en) |
-
1980
- 1980-03-24 CA CA348,323A patent/CA1095028A/en not_active Expired
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| MKEX | Expiry |