GB2201419A - Anthracycline-oestrone derivatives - Google Patents
Anthracycline-oestrone derivatives Download PDFInfo
- Publication number
- GB2201419A GB2201419A GB08704236A GB8704236A GB2201419A GB 2201419 A GB2201419 A GB 2201419A GB 08704236 A GB08704236 A GB 08704236A GB 8704236 A GB8704236 A GB 8704236A GB 2201419 A GB2201419 A GB 2201419A
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- United Kingdom
- Prior art keywords
- formula
- compound
- oestrone
- salt
- pharmaceutically acceptable
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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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J41/00—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring
- C07J41/0005—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring the nitrogen atom being directly linked to the cyclopenta(a)hydro phenanthrene skeleton
- C07J41/0016—Oximes
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Engineering & Computer Science (AREA)
- Biochemistry (AREA)
- Biotechnology (AREA)
- Genetics & Genomics (AREA)
- Molecular Biology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
Anthracycline glycoside derivatives of formula I: <IMAGE> wherein n is an integer of from 1 to 4, R1 is hydrogen or hydroxy and R2 is hydrogen or methoxy; and pharmaceutically acceptable acid addition salts thereof; are antitumor agents.
Description
DESCRIPTION
ANTHRACYCLINE-OESTRONE DERIVATIVES
The invention relates to anthracycline glycoside derivatives, to their preparation and to pharmaceutical composition containing them.
The present invention provides anthracycline glycosides of general formula I
wherein
R1 represents a hydrogen atom or hydroxyl group,
R2 represents a hydrogen atom or ta methoxy group and
n is an integer of from 1 to 4; and pharmaceutically acceptable acid addition salts thereof.
The present invention also provides a process for the preparation of compounds of formula I and their pharmaceutically acceptable acid addition salts, which process comprises coupling the 3'-amino group of an anthracycline glycoside of formula II:
wherein R1 and R2 are as defined above, to the carboxy group of the oestrone derivative of formula
III:
and, if desired, converting the resulting compound of formula I into a pharmaceutically acceptable acid addition salt thereof.
Thus, the compounds of the invention can be prepared by reacting the 3'-amino group of daunorubicin or doxorubicin with the carboxy group of the carboxy-alkyloxime at position C-17 of oestrone. The process can be effected according to the mixed anhydride method, for example as described by Anderson et al. [J.Am.Chem.Soc., 89 5012 (1967)]. The compound of formula II may be employed in the form of a salt, for example the hydrochloride. The oestrone derivative III is prepared according to the method described by Huffman et al. [J.
Bio.Chem., 134 591 (1940)]. Preferably:
(i) the 17-carboxyalkyloxime-oestrone of formula
III, dissolved in dry dimethylformamide, is reacted, at a temperature of from -100C to 5 0C under a nitrogen atmosphere and in the presence of triethylamine, with isobutylchloroformate and
(ii) the so formed mixed anhydride is reacted with daunorubicin or 4-demethoxy-daunorubicin hydrochloride or with an analogous doxorubicin derivative, at from -100C to room temperature and in the presence of triethylamine, to obtain a desired product of formula I.
Typically, the compound of formula I is purified by chromatography on silica gel using as the eluting system methylene dichloride -CH30H (97:3 v/v) and crystallisation.
A preferred embodiment of the invention is illustrated by the following reaction scheme:
REACTION SCHEME
The present invention also provides a pharmaceutical composition comprising as active ingredient an anthracycline glycoside of formula I or a pharmaceutically acceptable salt thereof together with a pharmaceutically acceptable carrier or diluent.
Conventional carriers and diluents may be used and the composition may be formulated in a conventional manner.
The compounds of the invention are useful in methods of treatment of the human or animal body by therapy. The compounds are useful for increasing the specificity of the anthracyclines against mammary tumors.
Because of the large number of oestrogen receptors expressed in these tumor types, the oestrogen moiety acts as a carrier to transport the anthracycline to the cell nucleus. Thus, the compounds of the invention are useful as antitumor agents by administering a therapeutically effective amount of the compound to a patient.
The invention is illustrated by the following
Examples.
Example 1 Daunorubicin-3 '-NH- [oestrone-17' '-oxime-ethyl- carbonyl] (Ia)
0.357g (1 mmol) of 17-carboxyethyloxime-oestrone
(III) was dissolved in 25ml of dry dimethylformamide and stirred under a constant stream of nitrogen at -10 C Subsequently, 0.14ml (1 mmol) of triethylamine and 0.17ml (1.25 mmol) of isobutylchloroformate was added, and the reaction mixture was stirred for 20 minutes. Then a mixture of 0.480g (0.85 mmol) of daunorubicin hydrochloride and O.12m1 of triethylamine in 50ml of dimethylformamide was added and the mixture was stirred for 1 hr at -100, after which the reaction was left to equilibrate with room temperature.Distilled water was added to this mixture, and it was extracted with methylene dichloride. The organic phase ws washed with 3% aqueous sodium hydrogen carbonate, followed by a saturated sodium chloride solution wash. It was dried over anhydrous sodium sulphate and the residue was purified by flash chromatography using for elution methylene dichloride and 3% methanol.
After removal of the solvent, the product was crystallised from ethyl ether to give 0.63g of Ia, yield 73%
TLC on Kieselgel plate F254 (Merck) using methylene dichloride methanol (95:5 by volume) Rf: 0.3. mp: 209 C, FDMS [M+] 866 1HNMR (200 MHz, CDC13/DMSO-d6): i.a.
0.85 (s, 3H, CH3-18'') 1.24 (d, J=6.8 Hz, 3H, CH3-5') 1.7-1.9 (m, 2H, CH2-2') 2.04 (dd, J=4.2, 14.8Hz, 1H, H-8ax) 2.28 (dd, J=1.0, 14.8Hz, 1H, H-8e) 2.36 (s, 3H, COCH3) 2.45 (m, 2H, CH2-CO-NH-) 2.92 (d, J=18.6 Hz, 1H, H-10ax) 3.22 (d, J=18.6Hz, 1H, H-10e) 3.59 (m, 1H, H-4') 4.01 (s, 3H, CH3O-4) 4.1-4.2 (m, 4H, CH2-O-N=, H-5', H-3') 5.22 (dd, J=1.0, 4.2Hz, 1H, H-7) 5.45 (m, 1H, H-1') 6.37 (d, J=7.9Hz, 1H, NH-3') 6.52 (d, J=2.7Hz, 1H, H-4'') 6.59 (dd, J=2.7, 8.3Hz, 1H, H-2'') 7.05 (d, J=8.3Hz, 1H, H-1'') 7.33 (d, J=8.OHz, 1H, N-3) 7.73 (t, J=8.0Hz, 1H, H-2) 7.98 (d, J=8.0Hz, 1H, H-1) 13.25 (s, 1H, OH-11) 13.94 (s, 1H, OH-6)
Example 2
Doxorubicin-3'-NH-[oestrone-17''-oxime-ethyl-carbonyl] (Ib) 0.490g (0.85 mmol) of doxorubicin hydrochloride was transformed into derivative Ib, following the proceding outlined in the example 1.
Yield 69% (0.600g). TLC on Xieseigei plate F254 (Merck) using methylene dichloride - methanol (95 : 5 by volume)
Rf:0.25. mp:176 C. FDMS tM ]: 882 1HNMR (200MHz, CDC13/DMSO-d6) i.a.
0.83 (s, 3H, CH3-18'') 1.22 (d, J=6.4Hz, 3H, CH3-5') 1.7-2.3 (m, 4H, CH2-8, CH2-2') 2.4-2.5 (m, 2H, CH2-CO-NH-) 2.93 (d, J=18.9Hz, 1H, H-10e) 3.18 (d, J=18.9Hz, 1H, H-10e) 3.24 (t, J=S.OHz, 1H, CH2-OH) 3.32 (d, J=6.0Hz, 1H, OH-4') 3.56 (m, 1H, H-4') 3.62 (s, 1H, OH-9) 4.00 (s, 3H, CH3O) 4.1-4.2 (m, 4H, CH2-O-N=, H-5', H-3') 4.70 (m, 2H, CH2-OH) 5.20 (m, 1H, H-i') 6.46 (d, J=8.4Hz, NH-) 6.5 (d, J=2.6Hz, 1H, H-4'') 6.57 (dd, J=2.6, 8.3Hz, 1H, H-2'') 7.02 (d, J=8.3Hz, 1H, H-1'') 7.32 8dd, J=i.0, 8.3Hz, 1H, H-3) 7.71 (t, J=8.3Hz, 1H, H-2) 7.93 (s, 1H, OH-3'') 7.95 (dd, J=1.0, 8.3Hz, 1H, H-1) 13.18 (s, 1H, OH-11) 13.90 (s, 1H, OH-6)
Claims (14)
1. An anthracycline glycoside derivative of formula I:
n is an integer of from 1 to 4, R1 S hydrogen or hydroxy and R2 is hydrogen or methoxy; and the pharmaceutically acceptable acid addition salts thereof.
2. A compound according to claim 1, which is 3'-NH-[oestrone-17"-oxime -ethyl-carbonyl]-daunorubicin.
3. A compound according to claim 1, which is 3'-NH-[oestrone-17"-oxime-ethyl-carbonyl]-doxorubicin.
4. A compound according to claim 1, which is 4-demethoxy-3'-NH-[oestrone-17"-oxime-ethyl-caronyl]daunorubicin.
5. A compound according to claim 1, which is 4-demethoxy-3'-NH-[oestrone-17"-oxime-ethyl-carbonyl]doxorubicin.
6. A process for the preparation of a compound of formula I as defined in claim 1 or a pharmaceutically acceptable acid addition salt thereof, which process comprises coupling the 3'-amino group of an anthracycline Ivcoside of formula II:
wherein R1 and R2 are as defined in claim 1, to the carboxy group of the oestrone derivative of formula
III:
and, if desired, converting the resulting compound of formula I into a pharmaceutically acceptable acid addition salt thereof.
7. A process according to claim 6, wherein the anthracycline glycoside of formula II is in the form of a salt.
8. A process according to claim 7, wherein the salt is the hydrochloride.
9. A process according to any one of claims 6 to 8, wherein the coupling is effected by the mixed anhydride method.
10. A process according to any one of claims 6 to 9, wherein
(i) the i7-carboxyalkyloxime-oestrone of formula
III, dissolved in dry dimethylformamide, is reacted, at a temperature of from -10 C to 5 C under a nitrogen atmosphere and in the presence of triethylamine, with isobutylchloroformate and
(ii) the so formed mixed anhydride is reacted with daunorubicin or 4-demethoxy-daunorubicin hydrochloride or with an analogous doxorubicin derivative, at from -100C to room temperature and in the presence of triethylamine, to obtain a desired product of formula I.
11. A process according to any one of claims 6 to 10, wherein the compound of formula I is purified by chromatography on silica gel using as the eluting system methylene dichloride -CH30H (97:3 v/v) and crystallisation.
12. A compound of formula (I) 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.
13. A compound of formula (I) or salt thereof according to claim 12 for use as an anti-tumor agent.
14. A process for the preparation of a compound of formula (I), said process being substantially as hereinbefore described in Example 1 or with reference to
Example 2.
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
GB08704236A GB2201419A (en) | 1987-02-24 | 1987-02-24 | Anthracycline-oestrone derivatives |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
GB08704236A GB2201419A (en) | 1987-02-24 | 1987-02-24 | Anthracycline-oestrone derivatives |
Publications (2)
Publication Number | Publication Date |
---|---|
GB8704236D0 GB8704236D0 (en) | 1987-04-01 |
GB2201419A true GB2201419A (en) | 1988-09-01 |
Family
ID=10612793
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
GB08704236A Withdrawn GB2201419A (en) | 1987-02-24 | 1987-02-24 | Anthracycline-oestrone derivatives |
Country Status (1)
Country | Link |
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GB (1) | GB2201419A (en) |
Cited By (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1990010638A1 (en) * | 1989-03-07 | 1990-09-20 | Gerhard Eisenbrand | Antitumoral agents with an affinity for steroid hormone receptors |
WO1994029327A1 (en) * | 1993-06-07 | 1994-12-22 | British Technology Group Limited | Anticancer compounds |
WO1995018141A1 (en) * | 1993-12-29 | 1995-07-06 | Iskra Industry Co., Ltd. | Medicinal composition for bone resorption inhibition and osteogenesis acceleration |
-
1987
- 1987-02-24 GB GB08704236A patent/GB2201419A/en not_active Withdrawn
Cited By (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1990010638A1 (en) * | 1989-03-07 | 1990-09-20 | Gerhard Eisenbrand | Antitumoral agents with an affinity for steroid hormone receptors |
WO1994029327A1 (en) * | 1993-06-07 | 1994-12-22 | British Technology Group Limited | Anticancer compounds |
WO1995018141A1 (en) * | 1993-12-29 | 1995-07-06 | Iskra Industry Co., Ltd. | Medicinal composition for bone resorption inhibition and osteogenesis acceleration |
US5698542A (en) * | 1993-12-29 | 1997-12-16 | Iskra Industry Co., Ltd. | Bone resorption inhibition/osteogenesis promotion pharmaceutical composition |
Also Published As
Publication number | Publication date |
---|---|
GB8704236D0 (en) | 1987-04-01 |
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WAP | Application withdrawn, taken to be withdrawn or refused ** after publication under section 16(1) |