IE52913B1 - Anthracycline glycosides - Google Patents
Anthracycline glycosidesInfo
- Publication number
- IE52913B1 IE52913B1 IE93882A IE93882A IE52913B1 IE 52913 B1 IE52913 B1 IE 52913B1 IE 93882 A IE93882 A IE 93882A IE 93882 A IE93882 A IE 93882A IE 52913 B1 IE52913 B1 IE 52913B1
- Authority
- IE
- Ireland
- Prior art keywords
- deoxy
- iodo
- daunorubicin
- doxorubicin
- preparation
- Prior art date
Links
Description
The Invention relates to enthracycllne glycosides, to processes for their preparation end to pharmaceutical composition· containing them.
The invention provides 4'-deoxy-4'-iodo-daunorubicin and 5 4'-deoxy-4*-iodo-doxorubicin, and pharmaceutically acceptable salts of either thereof. The structural formula for these
I in which R=H for 4'-deoxy-4'-iodo-daunorubicin and R=OH for 4'-deoxy-4'-iodo-doxorubicin. The glycosides according to the invention have been found to be endowed with outstanding antitumoural activity.
The starting material for their preparation is 4'-deoxy-4'20 iodo-N-trifluoroacetyl-daunorubicin, an intermediate compound already described in our Patent Specification 51600. Mild alkaline hydrolysis of said intermediate, suitably with an aqueous solution of 0.1 N sodium hydroxide, provides 4'-deoxy-4'-iodo-daunorubicin. The doxorubicin analogue may be prepared from 4’-deoxy-41-iodo25 daunorubicin by bromination at C-14 followed by treatment with aqueous sodium formate. Details of this conversion method are given in United Stated Patent Specification No. 3803124. These processes for the preparation of compounds of the invention are within the scope of the invention.
-252913
The new anthracycline glycosides of the invention display antitumour activity. Particularly, 41-deoxy-4*-iododoxorubicin displays remarkable activity on experimental tumours in mice.
Accordingly, the invention further provides a pharmaceutical composition comprising a pharmaceutically effective amount of 4'-deoxy - 4'-iodo-daunorubicin or 4'-deoxy - 4'-iododoxorubicin or a pharmaceutically acceptable salt of either thereof in admixture with a pharmaceutically acceptable diluent or carrier.
The invention is illustrated by the following Examples. Example 1
4'-deoxy-4'-iodo-daunorubicin (XOO-O138)
A solution of 2.0 g of 4'-deoxy-4'-iodo-N-trifluoroacetyl-daunorubicin in 10 ml of acetone was treated with 80 ml of a 0.1 N aqueous solution of sodium hydroxide. After hours at 0°C, the solution was adjusted to pH 4.5 with 0.1 N aqueous hydrochloric acid and extracted with chloroform in order to eliminate the aglyeones. The aqueous solution was then adjusted to pH 8.6 and extracted 20 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. Yield 1.5 g; m.p. 157° (with decomposition)j FD-MS: 637 (M+)
TLC on Kieselgel plates F254 (Merck) Using chloroform: methanol:water:acetic acid (80:20:7:3) by volume: Rf =
0.72 Έ.Merck' is a Trade Mark.
53913 ‘ Example 2 ' 4'-deoxy-41-iodo-doxorubicln (XOO-O163)
A solution of 41-deoxy-4'-iodo-daunorubicin in a mixture of methanol and dioxan was treated, in accordance with the method described in United States Patent Specification
No. 3803124, with bromine to form the 14-bromo derivative, which by treatment with an aqueous solution of sodium formate gave 4'-deoxy-4'-iodo-doxorubicin, which was isolated as hydrochloride, m.p. 230°C (with decomposition);
FD-MS: 653 (M+)
TLC on Kieselgel plates ^54 (MercW using chloroform: methanol:water:acetic acid (80:20:7:3'by volume): Rf=0.5.
Biological Activity of compounds X00-0138 and X00-0163
The compounds have been tested in comparison with dauno15 ruhicin (DNR) and doxorubicin (DX) against HeLa cells in vitro. Data reported in Table 1 show that XOO-0138 was less cytotoxic than DNR, while XOO-O163 was more cytotoxic than DX.
The antitumour activity was assessed in vivo in mice bearing P388 ascitic leukemia. Results are reported in
Table 2. Both the new derivatives are active against P388 leukemia. Of particular interest is the result obtained by treatment of the tumoured mice with compound XOO-O163: at the optimal, non-toxic dose of 15 mg/kg,
XO0-O163 cured more than 50% of the mice (6/10), and at the dose of 10 mg/kg cured 3/10 mice and produced a
-4remarkably high increase of life span In comparison with controls (205%). Therefore, the antitumour activity of XOO-O163 is definitely superior to that of DX, which, at the optimal non-toxic dose of 10 mg/kg, cures only occasionally the tumoured mice,
Compound XO0-O138 was also tested against Gross leukemia (treatment on Day 1 after tumour inoculum), Data reported In Table 3 show· that, at the optimal non-toxic dose of
11,8 mg/kg, XOO-0138 showed an antitumour activity superior to that of DNR, and similar to that of DX.
Table 1. Effect on HeLa' cells' cloning efficiency5
Compound Dose (ng/ml) ί1D50 (ng/ml) Daunorubicin 12..5 7 7 6.25 53 3.1 110 XOO-0138 100 0 15 25 5 6.2 109 Doxorubicin 25 0 8 12.5 16 6.2 70 XOO-O163 25 0 5.5 6.2 16 1.5 91 0.39 104
treatment for 24 hours f
-5Table 2. Effect against P 388 ascitic leUkemlaa
Compound „ b Dose (mg/kg) T/CC % LTSfl Toxlce deaths Daunorubicin 2.9 160, 165 0/10,0/10 0/10,0/10 4.4 160, 185 0/10,0/10 1/10,0/10 6.6 175, 135 0/10,0/10 7/10,7/10 X00-0138 4.4 140 0/10 0/10 6.6 155 1/10 0/10 10 185, 75 0/10,0/10 0/10,6/10 15 70 0/10 8/10 22.5 60 0/10 10/10 Doxorubicin 4.4 210 0/10 0/10 6.6 260 0/10 0/10 10 265 1/10 0/10 XOO-O163 6.6 240 0/10 0/10 10 305 3/10 0/10 15- 620 6/10 0/10 22.5 390 3/10 1/10
Experiments were performed in BDF1 or CDF1 mice, inoculated with 10® leukemia cells i.p.
^Treatment i.p. on Day 1 after tumour inoculum
Eedian survival time of treated mice/median survival time of controls x 100
Eong term survivors (>60 days)
Evaluated on the basis of autoptic findings.
2913
-6Table 3. Effect against Gross leukemia*
Compound Doseb (mg/kg) T/C »c LTS • Toxic6 deaths Daunorubicin 15 191 0/8 0/8 22.5 158 0/8 4/8 Doxorubicin 7.7 150 0/10 0/10 10 175 0/10 0/10 13 200 0/10 0/10 16.9 233 0/10 0/10 22 266 0/10 1/10 XQ0-0138 11.8 208 0/10 0/10 15.4 208 0/10 2/10 4'-iodo-dauno- 20 175,117 0/8,0/10 4/8,6/10 rubicin 30 100 0/8 8/8 40 92 0/8 8/8
aC3H mice were injected i.v. with 2xlO6 leukemia cells ^Treatment i.v. on Day 1 after tumour inoculum c'fl'esee Table 2.
Claims (7)
1. 4'-Deoxy-4'-iodo-daunorubicin or a pharmaceutically acceptable salt thereof.
2. 4'-Deoxy-4'-iodo-doxorubicin ox a pharmaceutically 5 acceptable salt thereof.
3. A method for the preparation of
4. '-deoxy-4'-iodo-daunorubicin, the method comprising mild alkaline hydrolysis of 4'-deoxy-4’-iodo-N-trifluoroacetyl-daunoruhicin. 10 4. A method for the preparation of 4'-deoxy-4’-iodo-doxorubicin, the method comprising bromination of 4'-deoxy-4'-iodo-daunorubicin at C-14 followed by treatment with aqueous sodium formate.
5. A method for the preparation of 4'-deoxy-4'-iodo15 -daunorubicin, the method being substantially as described herein with reference to Example 1.
6. A method for the preparation of 4'-deoxy-4'-iodo-doxorubicin, the method being substantially as described herein with reference to Example 2. 20
7. A pharmaceutical composition comprising a pharmaceutically effective amount of a compound according to claim 1 -8or claim 2 or λ compound prepared according to any of claims 3 to 6 in admixture with a pharmaceutically acceptable diluent or carrier,
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
IE93882A IE52913B1 (en) | 1982-04-21 | 1982-04-21 | Anthracycline glycosides |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
IE93882A IE52913B1 (en) | 1982-04-21 | 1982-04-21 | Anthracycline glycosides |
Publications (1)
Publication Number | Publication Date |
---|---|
IE52913B1 true IE52913B1 (en) | 1988-04-13 |
Family
ID=11020013
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
IE93882A IE52913B1 (en) | 1982-04-21 | 1982-04-21 | Anthracycline glycosides |
Country Status (1)
Country | Link |
---|---|
IE (1) | IE52913B1 (en) |
-
1982
- 1982-04-21 IE IE93882A patent/IE52913B1/en not_active IP Right Cessation
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