GB1572998A - 3'-epi-6'-hdroxy-dauno-mycin and -adriamycin - Google Patents
3'-epi-6'-hdroxy-dauno-mycin and -adriamycin Download PDFInfo
- Publication number
- GB1572998A GB1572998A GB4098276A GB4098276A GB1572998A GB 1572998 A GB1572998 A GB 1572998A GB 4098276 A GB4098276 A GB 4098276A GB 4098276 A GB4098276 A GB 4098276A GB 1572998 A GB1572998 A GB 1572998A
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- Prior art keywords
- epi
- hydroxy
- adriamycin
- daunomycin
- imi
- Prior art date
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H13/00—Compounds containing saccharide radicals esterified by carbonic acid or derivatives thereof, or by organic acids, e.g. phosphonic acids
- C07H13/02—Compounds containing saccharide radicals esterified by carbonic acid or derivatives thereof, or by organic acids, e.g. phosphonic acids by carboxylic acids
- C07H13/04—Compounds containing saccharide radicals esterified by carbonic acid or derivatives thereof, or by organic acids, e.g. phosphonic acids by carboxylic acids having the esterifying carboxyl radicals attached to acyclic carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H13/00—Compounds containing saccharide radicals esterified by carbonic acid or derivatives thereof, or by organic acids, e.g. phosphonic acids
- C07H13/02—Compounds containing saccharide radicals esterified by carbonic acid or derivatives thereof, or by organic acids, e.g. phosphonic acids by carboxylic acids
- C07H13/08—Compounds containing saccharide radicals esterified by carbonic acid or derivatives thereof, or by organic acids, e.g. phosphonic acids by carboxylic acids having the esterifying carboxyl radicals directly attached to carbocyclic rings
-
- 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
- C07H15/02—Acyclic radicals, not substituted by cyclic structures
- C07H15/04—Acyclic radicals, not substituted by cyclic structures attached to an oxygen atom of the saccharide radical
-
- 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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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Engineering & Computer Science (AREA)
- Health & Medical Sciences (AREA)
- Biochemistry (AREA)
- Biotechnology (AREA)
- General Health & Medical Sciences (AREA)
- Genetics & Genomics (AREA)
- Molecular Biology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Crystallography & Structural Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Saccharide Compounds (AREA)
Description
(54) 3'-EPI-6'-HYDROXY-DAUNOMYCIN AND -ADRIAMYCIN
(71) We, SOCIETA FARMACEUTICI ITALIA S.p.A., a body corporate organised and existing under the laws of Italy, of 1/2 Largo Guido Donegani-1 20121 Milan, Italy, do hereby declare the invention for which we pray that a patent may be granted to us, and the method by which it is to be performed, to be particularly described in and by the following statement:
The invention relates to antitumour glycosides of the anthracycline series and to processes for their preparation.
The invention provides 3'-epi-6'-hydroxy-daunomycin which has the formula V below
and 3'-epi-6'-hydroxy-adriamycin which has the formula VI below
The invention further provides a process for the preparation of 3'-epi-6'-hydroxydaunomycin V, which process comprises condensing daunomycin with 2,3-dideoxy-3 trifluoroacetamido-4,6-di-O-p-nitrobenzoyl-L-xylo-hexopyranosyl chloride in an organic solvent in the presence of a soluble silver salt catalyst and a molecular sieve as a dehydrating agent to obtain a protected a-glycoside of the formula II below
and removing the protecting groups by hydrolysis.
Preferred organic solvents are chloroform and methylene dichloride. As soluble silver salt, the trifluoromethanesulphonate (AgSO3CF3) is preferred. The condensation reaction goes to completion in a short time (about 1 hour) and is stereospecific, yielding only the protected a-glycoside II. Similar condensation reactions we described in our British Patent
Specification No. 1506200. The 3'-epi-6'-hydroxy-daunomycin can be isolated as its hydrochloride.
Subsequent treatment of 3'-epi-6'-hydroxy-daunomycin V with bromine followed by treatment of the intermediate 14-bromo-derivative with sodium formate gives the corresponding 3'-epi-6'-hydroxy-adriamycin VI, which can be isolated as its hydrochloride.
This process is also within the scope of the invention.
3'-epi-6'-hydroxy-daunomycin V and 3'-epi-6'-hydroxy-adriamycin Vl are effective in the treatment of certain experimental tumours in animals.
The 2,3-dideoxy-3-trifluoroacetamido-4,6-di-O-p-nitrobenzoyl-L-xylo-hexopyranosyl chloride used in the process of the invention has the formula III-B below and its parent amino sugar, 3-amino-2,3-dideoxy-L-xylo-hexose has the formula III-A below.
These compounds were previously unknown in the L-series and may be prepared starting from methyl 2,3-dideoxy-3-trifluoroacetamido-a-L-nbo-hexopyranoside VII:
The hexopyranoside VII can be prepared as described in our British Patent Specification 1506200. The process comprises reacting the hexopyranoside VII with methane-sulphonyl chloride in dry pyridine to obtain its crystalline 4,6-di-O-methanesulphonyl derivative VIII, treatment of the derivative VIII with sodium benzoate in N,N-dimethylformamide to obtain the corresponding 4,6-di-O-benzoyl derivative IX, treatment of the derivative IX with a catalytic amount of sodium in dry methanol to obtain methyl 2,3-dideoxy-3 tnfluoroacetamido-a-L-xylohexopyranoside X. reacting the compound with p-nitro benzovl chloride in dry pyridine to obtain the corresponding crystalline 4.6-di-O-pnitrobenzoate XI, reaction of the compound XI in acetic acid and chloroform with hydrogen chloride followed by treatment with p-nitrobenzoyl chloride in dry pyridine to obtain 1,4,6-tri-O-p-nitrobenzoyl-2,3-dideoxy-3-trifluoroacetamido-L-xylo-hexopyranose XII, and treatment of compound XII with dry hydrogen chloride in chloroform to give the compound III-B. The compound III-A can be obtained by acid hydrolysis of the compound
X. The treatment with sodium benzoate in N,N-dimethylformamide is preferably carried out for 5 hours at 1200C. The reaction of compound XI in acetic acid and chloroform with hydrogen chloride is preferably performed at O C for 1 hour. The final treatment of compound XII with dry hydrogen chloride in chloroform is preferably for 1 hour at O"C to obtain the desired protected derivative I1I-B.
The terms daunomycin and adriamycin, which are our Trade Marks, are used herein respectively to mean daunorubicin and doxorubicin or 14-hydroxy-daunorubicin (see
Pharmacological and Chemical Synonyms, 5th Edition, 1973, pages 118 and 167).
The invention is illustrated by the following Examples.
Example 1
4 g (14.6 mmols of methyl 2,3-dideoxy-3-trifluoro-acetamido-o-L-ribo-hexopyranoside VII dissolved in 40 ml dry pyridine is treated at 0 C with 5 ml methane sulphonyl chloride.
After 16 hours standing at 20"C, the reaction mixture is poured into iced water, and then extracted with chloroform. The crude product obtained is purified by chromatography over a silica gel column using a 95:5 chloroform:acetone as eluant. 5.2 g (83%) of crystalline methyl 2,3-dideoxy-4,6-di-O-methanesulphonyl-3-trifluoro-acetamido-a-L-ribo- hexopyranoside VIII are obtained: m.p. 126-128"C; [0:]D 51.30 (c=0.43 in chloroform); m/e 430.
4.7 g (10.4 mmols) of compound VIII so obtained and 7.4 g sodium benzoate in 300 ml dry N,N-dimethylformamide are heated for 5 hours at 1200C. The resulting mixture is then poured into iced water and extracted with chloroform. The extract is purified by chromatography over a silica gel column using chloroform as eluant. 4 g (80%) of pure methyl 4,6-di-O-benzoyl-2,3-dideoxy-3-trifluoroacetamido-o-L-xylo-hexopyranoside IX are obtained as a syrup: [a] -28.5 (c=0.5 in chloroform); p.m.r. spectrum absorptions: 1.6-2.7 (m, C-2-H2), 3.57 (s, -OCH3), 5.10 (broad s, WH 8 Hz. C-4-H), 5.33 (broad s,
WH 8 Hz, C-1-H) and 8-8.4 (m, 10 aromatic H).
3 g ( 6.23 mmols) of this compound IX are dissolved in 42 ml dry methanol containing 10 mg of sodium.
After 16 hours standing at 20"C, and neutralization by the addition of solid carbon dioxide, the resulting solution is evaporated to dryness. The residue is extracted with chloroform, and chromatographed over a silica gel column by elution with 95/5 chloroform/methanol. 1.54 g (90aXs) methyl 2,3-dideoxy-3-trifluoro-acetamido-a-L-xylohexopyranoside X are obtained as a syrup: [a]D -42" (c=l in methanol); m/e 274; p.m.r.
spectrum absorptions: 1.4-1.9 (m. C-2- H,,,), 2.1-2.7 (m,C-2-Het,), 3.42 (s, -O-CH?,) and 4.87 b (dd, J' 1 Hz, J" 3Hz, C-1-H).
1.5 g (5.46 mmols) of this compound X in 30 ml dry pyridine is treated with 2.76 g p-nitrobenzoyl chloride at OOC. After 3 hours at 20"C, the reaction mixture is poured into iced water, and the precipitate is filtered off and washed with water to neutrality.
Crystallization from chloroform:diethyl ether gives 2.58 g (82%) of methyl 2,3-dideoxy 4,di-O-p-nitrobenzoyl-3-trifluoro-acetamido-a-L-xylo-hexopyranoside XI: m.p.
153-155"C: [aiD +1.4 (c=0.5 in chloroform); p.m.r. spectrum absorptions 1.5-2.6 (m, c-2-H2), 3.50 (s, -OCH3), 5.06 (broad s. WH 6Hz, C-4-H), 5.30 (broad s, WH 6Hz, C-1-H) and 8.0-8.4 b (m, 8 aromatic H).
2 g of this compound Xl dissolved in 7.5 ml chloroform containing acetic acid is saturated with dry hydrogen chloride at 0 c. After 1 hour standing. the solution is evaporated to dryness under vacuum. The residue is dissolved in 32 ml dry pyridine and treated with 1 g p-nitrobenzoyl chloride at 0 c. After 14 hours standing at 20"C, the reaction mixture is poured into iced water. The precipitate is filtered off, washed with water to neutrality, and crystallized from chloroform:diethyl ether. 2.1 g (85%) 1,4.6-tri-O-p-nitrobenzoyl-3trifluoroacetamido-L-xylo-hexopyranoside XII are obtaind: m.p. 118-120"C.
2 g of this compound XII dissolved in 60 ml methylene dichloride is saturated with dry hydrogen chloride at 00c for 1 hour. p-Nitrobenzoic acid precipitates and is filtered off. The filtrate is evaporated to dryness under vacuum until the removal of acidity is completed.
The resulting 1.6 g (95C/c) of crude 2.3-dideoxy-4,6-di-O-p-nitrobenzoyl-3 trifluoroacetamido-L-xylo-hexopyranosyl chloride III is not further purified. Its p.m.r.
spectrum shows among other things absorption of C-1H at 6.46 5.
Example 2
1 g daunomycinone in 100 ml dry methylene dichloride is treated with 0.7 g of compound
III, obtained as in Example 1, in the presence of 10 g molecular sieve (4 )Merck) and of 0.33 g silver trifluoromethane sulphonate with strong stirring for 1 hour at room temperature. The reaction mixture is neutralized with a saturated aqueous solution of sodium bicarbonate. The organic phase is separated and evaporated under vacuum. The crude residue is purified by chromatography over a column of silicic acid using 2:1 benzene-ethyl acetate as eluant. 1.1 g (73%) of compound II: m.p. 150-153"C are obtained.
0.5 g of this compound II dissolved in 30 ml acetone is treated with 30 ml 0.2N aqueous sodium hydroxide at 0 c. After 45 minutes standing, the pH of the reaction mixture is adjusted to 4.5 by addition of N hydrochloric acid. The mixture is extracted with chloroform to eliminate some impurities. The pH of the remaining aqueous phase is adjusted to 8.5. The aqueous phase is repeatedly extracted with chloroform. The extracts are combined, dried over anhydrous sodium sulphate and evaporated to a volume of 5 ml.
A stoichiometric amount of methanolic hydrogen chloride and excess diethyl ether are added. 0.24 SJ (81%) 3'-epi-6'-hydroxydaunomycin are obtained as hydrochloride: m.p.
176-178"C; ain +235 (c=0.05 in methanol).
Example 3
0.2 g of compound V, obtained as in Example 2, in 2.8 ml dry methanol and 8 ml dioxan is treated with 0.2 ml ethyl orthoformate and 0.73 ml of a solution of 0.93 g bromine in 10 ml dry chloroform. After 1 hour at room temperature, the reaction mixture is poured into a mixture of 40 ml diethyl ether and 20 ml petroleum ether. The resulting precipitate is filtered and washed with diethyl ether, dissolved in 4 ml acetone and treated with 4 ml 0.25
N hydrobromic acid. After 15 hours standing at room temperature, the reaction mixture is added to 4 ml water, and repeatedly extracted with chloroform to remove some degradation products. The aqueous phase is then extracted with n-butanol. The n-butanol extracts are concentrated under vacuum to a small volume, and treated with diethyl ether to obtain 0.17 g of the 14-bromo derivative. This product is dissolved in 4 ml 0.25 N hydrobromic acid and treated with 0.3 g sodium formate in 4.5 ml water. The reaction mixture is stirred for 4 days at room temperature and then evaporated to dryness. The residue is dissolved in 80 ml of 2:1 chloroform-methanol, and washed twice with 35 ml each time of a 2.59 aqueous solution of sodium bicarbonate. The aqueous phase is extracted with chloroform until the extracts are no longer coloured. Then the organic phase is combined with the chloroform extracts. dried over anhydrous sodium sulphate and evaporated under vacuum to 20 ml volume. The pH of the resulting red solution is adjusted to 3.5 (Congo Red) by addition of anhydrous methanolic hydrogen chloride mixed with excess diethyl ether. 0.08 g 3'-epi-3'-hydroxyadriamycin VI is obtained as hydrochloride: m.p. 169-170"C; [alD +165 (c=0.05 in methanol).
Biological activity
TABLE 1
Activity of 3'-epi-6'-hydroxy-derivatives of Daunomycin and Adriamycin on cloning, efficency of HeLa cells (treatment for 24 hours).
Dose Number of colonies ID50
Compound (ng/ml) % Compared with the (ng/ml)
controls
Daunomycin 12.5 3
6.25 43 4.5
3.12 64 IMI-61 3-epi-6' -hydroxy-Daunomycin 3200 46
1600 92 3200
800 99
Adriamycin 12.5 22
6.25 52 6 IMI-65 3'-epi-6'hydroxy-Adriamycin 1600 30
400 87 1000 100 117
25 117
TABLE 2
Antitumoural activity of 3'epi-6'-hydroxy-derivatives of Daunomycin and Adriamycin on
L1210 Leukemia.
Scheme of Dose T/C
Tumor Treatment Compound (mg/Kg) % LTS Toxicity
L1210 i.p. +1 Daunomycin(") 2.9 162,144 2/20
4.4 162,144 2/20
6.6 137,133 11/20
10 125 10/10 IMI-61 3'-epi
hydroxy-Dauno
mycin ( ) . 2.9 106 3/10
4.4 100 3/10
6.6 100 1/10
10 113
50 100
75 100
L 1210 i.p., +1 Adriamycin 4.4 133 1/8
6.6 138 1/8
10 144 1/8
IMI-65 3'-epi
-6'-hydroxy
Adriamycin 25 88 1/7
50 88
100 88 ( ) Data of 2 experiments
WHAT WE CLAIM IS:
1. 3'-Epi-6'-hydroxydaunomycin.
2. 3'-Epi-6'-hydroxyadriamycin.
3. A process for the preparation of 3'-epi-6'-hydroxy-daunomycin. the process
**WARNING** end of DESC field may overlap start of CLMS **.
Claims (10)
1. 3'-Epi-6'-hydroxydaunomycin.
2. 3'-Epi-6'-hydroxyadriamycin.
3. A process for the preparation of 3'-epi-6'-hydroxy-daunomycin. the process
comprising condensing daunomycinone with 2,3-dideoxy-3-trifluoroacetamido-4.6-di- nitro benzoyl-L-xylo-hexopyranosyl chloride in an organic solvent in the presence of a soluble silver salt catalyst and a molecular sieve as a dehydrating agent, and removing the protecting groups by hydrolysis.
4. A process according to claim 3 in which the silver salt is silver trifluoromethanesulphonate.
5. A process according to claim 3 or claim 4 in which the organic solvent is chloroform or methylene dichloride.
6. A process for the preparation of 3'-epi-6'-hydroxy-daunomycin, the process being substantially as described herein with reference to Example 2.
7. 3'-Epi-6'-hydroxydaunomycin prepared by a process according to any of claims 3 to 6.
8. A process for the preparation of 3'-epi-6'-hydroxy-adriamycin, the process comprising reacting 3'-cpi-6'-hydroxydaunomycin with bromine and subjecting the resultant
14-bromo derivative to treatment with sodium formate.
9. A process for the preparation of 3'-epi-6'-hydroxy-adriamycin, the process being substantially as described herein with reference to Example 3.
10. 3'-Epi-6'-hydroxyadriamycin prepared by a process according to claim X or claim 9.
Priority Applications (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB4098276A GB1572998A (en) | 1976-10-01 | 1976-10-01 | 3'-epi-6'-hdroxy-dauno-mycin and -adriamycin |
| DE19772743675 DE2743675A1 (en) | 1976-10-01 | 1977-09-28 | NEW ANTITUMOR GLYCOSIDES |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB4098276A GB1572998A (en) | 1976-10-01 | 1976-10-01 | 3'-epi-6'-hdroxy-dauno-mycin and -adriamycin |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| GB1572998A true GB1572998A (en) | 1980-08-13 |
Family
ID=10417557
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| GB4098276A Expired GB1572998A (en) | 1976-10-01 | 1976-10-01 | 3'-epi-6'-hdroxy-dauno-mycin and -adriamycin |
Country Status (2)
| Country | Link |
|---|---|
| DE (1) | DE2743675A1 (en) |
| GB (1) | GB1572998A (en) |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| NL8001417A (en) * | 1979-03-17 | 1980-09-19 | Erba Farmitalia | ANTITUMORGLYCOSIDES. |
-
1976
- 1976-10-01 GB GB4098276A patent/GB1572998A/en not_active Expired
-
1977
- 1977-09-28 DE DE19772743675 patent/DE2743675A1/en not_active Withdrawn
Also Published As
| Publication number | Publication date |
|---|---|
| DE2743675A1 (en) | 1978-04-06 |
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PS | Patent sealed | ||
| PCNP | Patent ceased through non-payment of renewal fee |