MXPA99011455A - 13-dihydro-3'aziridino anthracyclines - Google Patents
13-dihydro-3'aziridino anthracyclinesInfo
- Publication number
- MXPA99011455A MXPA99011455A MXPA/A/1999/011455A MX9911455A MXPA99011455A MX PA99011455 A MXPA99011455 A MX PA99011455A MX 9911455 A MX9911455 A MX 9911455A MX PA99011455 A MXPA99011455 A MX PA99011455A
- Authority
- MX
- Mexico
- Prior art keywords
- formula
- demethoxy
- aziridinyl
- mixture
- daunorubicin
- Prior art date
Links
- 239000000203 mixture Substances 0.000 claims abstract description 14
- -1 Anthracycline glycosides Chemical class 0.000 claims abstract description 9
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims abstract description 4
- 239000002246 antineoplastic agent Substances 0.000 claims abstract description 3
- 150000001875 compounds Chemical class 0.000 claims description 14
- 229960000975 Daunorubicin Drugs 0.000 claims description 12
- 238000000034 method Methods 0.000 claims description 5
- STQGQHZAVUOBTE-VGBVRHCVSA-N DAUNOMYCIN Chemical compound O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(C)=O)[C@H]1C[C@H](N)[C@H](O)[C@H](C)O1 STQGQHZAVUOBTE-VGBVRHCVSA-N 0.000 claims description 4
- 239000003085 diluting agent Substances 0.000 claims description 3
- 239000003960 organic solvent Substances 0.000 claims description 3
- 239000008194 pharmaceutical composition Substances 0.000 claims description 3
- 239000003638 reducing agent Substances 0.000 claims description 3
- 238000000926 separation method Methods 0.000 claims description 3
- YOQDYZUWIQVZSF-UHFFFAOYSA-N sodium borohydride Substances [BH4-].[Na+] YOQDYZUWIQVZSF-UHFFFAOYSA-N 0.000 claims description 3
- 229910000033 sodium borohydride Inorganic materials 0.000 claims description 3
- ODGROJYWQXFQOZ-UHFFFAOYSA-N sodium;boron(1-) Chemical group [B-].[Na+] ODGROJYWQXFQOZ-UHFFFAOYSA-N 0.000 claims description 3
- 239000000969 carrier Substances 0.000 claims description 2
- 238000002560 therapeutic procedure Methods 0.000 claims description 2
- CSCPPACGZOOCGX-UHFFFAOYSA-N acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 6
- YMWUJEATGCHHMB-UHFFFAOYSA-N methylene dichloride Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 6
- 206010024324 Leukaemias Diseases 0.000 description 4
- 206010028980 Neoplasm Diseases 0.000 description 4
- OKKJLVBELUTLKV-UHFFFAOYSA-N methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 4
- YXFVVABEGXRONW-UHFFFAOYSA-N toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 4
- 210000004027 cells Anatomy 0.000 description 3
- 238000004128 high performance liquid chromatography Methods 0.000 description 3
- 210000001072 Colon Anatomy 0.000 description 2
- WEVYAHXRMPXWCK-UHFFFAOYSA-N acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 2
- 230000000259 anti-tumor Effects 0.000 description 2
- NOWKCMXCCJGMRR-UHFFFAOYSA-N aziridine Chemical compound C1CN1 NOWKCMXCCJGMRR-UHFFFAOYSA-N 0.000 description 2
- 230000003013 cytotoxicity Effects 0.000 description 2
- 231100000135 cytotoxicity Toxicity 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- 230000017066 negative regulation of growth Effects 0.000 description 2
- 239000012071 phase Substances 0.000 description 2
- 230000004083 survival Effects 0.000 description 2
- WYURNTSHIVDZCO-UHFFFAOYSA-N tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 2
- 210000004881 tumor cells Anatomy 0.000 description 2
- GVNVAWHJIKLAGL-UHFFFAOYSA-N 2-(cyclohexen-1-yl)cyclohexan-1-one Chemical compound O=C1CCCCC1C1=CCCCC1 GVNVAWHJIKLAGL-UHFFFAOYSA-N 0.000 description 1
- 101700067048 CDC13 Proteins 0.000 description 1
- 102100000129 CHURC1 Human genes 0.000 description 1
- 101710014631 CHURC1 Proteins 0.000 description 1
- 210000003734 Kidney Anatomy 0.000 description 1
- 210000004072 Lung Anatomy 0.000 description 1
- 206010025650 Malignant melanoma Diseases 0.000 description 1
- 210000002307 Prostate Anatomy 0.000 description 1
- 241000700159 Rattus Species 0.000 description 1
- 241000700605 Viruses Species 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 125000004432 carbon atoms Chemical group C* 0.000 description 1
- 238000004737 colorimetric analysis Methods 0.000 description 1
- 230000034994 death Effects 0.000 description 1
- 231100000517 death Toxicity 0.000 description 1
- RTZKZFJDLAIYFH-UHFFFAOYSA-N diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 1
- 229910000396 dipotassium phosphate Inorganic materials 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 231100000673 dose–response relationship Toxicity 0.000 description 1
- 239000003480 eluent Substances 0.000 description 1
- 238000004992 fast atom bombardment mass spectroscopy Methods 0.000 description 1
- 238000003818 flash chromatography Methods 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 201000001441 melanoma Diseases 0.000 description 1
- 239000012074 organic phase Substances 0.000 description 1
- 230000002611 ovarian Effects 0.000 description 1
- 239000008363 phosphate buffer Substances 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-N phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 1
- 235000011007 phosphoric acid Nutrition 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- FAPWRFPIFSIZLT-UHFFFAOYSA-M sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 230000002588 toxic Effects 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 238000002054 transplantation Methods 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
Abstract
Anthracycline glycosides of formula (I) wherein the wavy line means that the hydroxy group at 13-position may be at&agr;or&bgr;position, or a mixture thereof, are useful as anti-tumor agents.
Description
ANTRACICLINES OF 13-DIHYDRO-3 'AZIRIDINE DESCRIPTION OF THE INVENTION
The present invention relates to anthracycline glycosides, to a process for their preparation and to pharmaceutical compositions containing them. The present invention provides anthracycline glycosides having the formula I:
Formula I:
wherein the waved line means that the hydroxy group in position 13 may be in position a or ß, or a mixture thereof. REF. : 32180 The compounds of formula I comprise derivatives in which the hydroxy group at position 13, has the configuration 13 (S), 13 (R), or a mixture of diastereomers 13 (R) and 13 (S), i.e. : 4-demethoxy-13 (S / R) -3'-deamino-3 '-aziridini 1-4'-methanesulfonyl daunorubicin (la), 4-demethoxy-13 (S) -3'-deamino-3' -aziridinil -4'-methanesulfonyl daunorubicin (Ib) and 4-demethoxy-13 (R) -3 '-deamin-3' -aziridinyl-4 '-methanesulfonyl daunorubicin (le). More preferably, the present invention provides anthracycline glycosides having the formula I defined above, characterized in that the carbon atom 13 is S, ie 4-demethoxy-13 (S) -3'-deamin-3 '-aziridinyl- 4'-methanesulfonyl daunorubicin (Ib). The compounds of the formula I can be prepared by reducing the anthracycline of the formula II:
FORMULA II:
II in the presence of a reducing agent, such as sodium borohydride, in a mixture of organic solvents, such as methylene chloride and methanol, preferably at a temperature below 50 ° C, more preferably at a temperature of - 70 ° C, and, if conven and necessary, by separating the resulting mixture of the compounds 13 (R) and 13 (S) in the single diastereomer. For example, simple dihydro-13 diastereoisomers can be obtained through the separation of the mixture with high pressure liquid chromatography (HPLC). In particular, the HPLC separation can be carried out on a reverse phase column, using a phosphate buffer, such as 10 mM K2HP04 adjusted to a pH of 7.0 with 85% H3PO4, and an organic solvent as mobile phase , such as tetrahydrofuran or acetonitrile.
The starting material for the preparation of novel anthracycline glycosides is 4-demethoxy-3 '-deamin-3' -aziridinyl-4'-methanesulfonyl daunorubicin (II), and is described in US-A-5,532,218. The invention further provides a pharmaceutical composition comprising an anthracycline glucoside of formula I in combination with a pharmaceutically acceptable diluent or carrier. Conventional diluents and vehicles can be used. The composition can be formulated and administered in conventional manner. The compounds according to the present invention are used in methods of treating the human and animal body by means of therapy. They are useful as antitumor agents. They are useful in the treatment of leukemia and solid tumors, such as in the colon, rectal colon, ovarian tumors, mammary, prostate, lung, kidney and also melanoma tumors. Therefore, a human being can be treated with a method comprising administering thereto a therapeutically effective amount of a compound of the invention. In this way the condition of the human pat can be improved. The dose to be delivered can be ensured using the dosage ranges known in the anthracycline field, modified by reference to the activity known by the compounds of the present invention in antitumour tests in vi tro and in vi vo. Appropriate doses are generally in the range of 1 to 200 mg / m2 of the body surface, preferably 1 to 100 mg / m2, depending on the nature and severity of the disease to be treated and the general condition of the pat. The compounds of the formula I were tested and found to be active against a panel of murine and human tumor cell lines, and on murine P388 / DX disseminated leukemia.
Activity of the live virus In a panel of murine and human tumor cell lines, it presents a high cytotoxicity, as shown by the IC5U values of Table 1. The results of the in vi ve test of the envelope murine P388 / DX leukemia disseminated, as shown in Table 2. Table 1: Cytotoxicity in vi tro of the
1) Cells Incubated with the compound for 1 hour.
2) 50% of the inhibitory concentration represents the mean + SE of the dose response curves of at least two experiments. 3) Inhibition of growth determined by surviving counting cells. 4) Inhibition of growth determined by colorimetric analysis SRB.
Table 2: Anti-tumor activity ± n v ± v of the disseminated P388 / DX counter
1) P388 / DX Johnson leukemia IV cells (lOVraton) were injected on day 0. 2) IV treatment was given on day 1 after tumor transplantation (day 0). It was solubilized in [CremophorO / Ethanol = 6.5: 3.5] / [normal saline] = 20 / SO v / v. 3) Prolongation in the life period: [(mean survival time of treated rats / mean survival time of controls) x 100] -100. 4) Number of toxic deaths / number of mice.
) Long-term survivors (> 60 days) at the end of the experiments. The following example illustrates the present invention.
EXAMPLE 1: 13 (R / S) -dihydro-4-deme oxy-3 '-deamin-3' -aziridinyl-4'-ethanesulfonyl daunorubicin (Ia) Se. dissolved 4-demethoxy-3 '-deamin-3' -aziridinyl-methanesulfonyl daunorubicin (II, 600 mg, 1 mmol) in methylene chloride (50 ml) and cooled to a temperature of -70 ° C. The solution in the form of drops was added to the solution of sodium borohydride (120 mg, 3.2 mmol) dissolved in methanol (5 ml). After 15 minutes, acetone (10 ml) was added, then the reaction mixture was brought to room temperature, methylene chloride (500 ml) was added and washed with water (2 x 200 ml). The organic phase was separated, concentrated in a small volume and flash chromatography was applied on the silica gel using a mixture of toluene and acetone (8: 2 by volume). The fractions containing the title compound were pooled, concentrated in a small volume and precipitated with an exano ethyl ether mixture (85: 5 by volume) to give 13 (R / S) -dihydro-4-demethoxy-3. '-deamin-3' -aziridinyl-4'-methanesulfonyl daunorubicin (la, 400 mg).
TLC on the Kieselgel Plate (Merck) using as eluent a mixture of toluene and acetone (80:20 by volume), Rf = 0.3 H NMR (400 Mhz, CDC13) d: 1.14, 1.23, 1.72 (m, CHCH: aziridine , Ia + Ib); 1.27 (d, J = 6.3Hz, CH.i-13, Ib); 1.32 (d, J = 6.3Hz, CH3-13, la); 1.38 (d, J = 6.5Hz, CHa-5 ', Ia + Ib); 1.47 (ddd, J = 2.6, 4.5, 12.5Hz, CH.3-3 ', Ia + Ib); 1.78 (m, H-2'ax, Ia + Ib; H-8ax, la); 1.87 (dd, J = 4.1, 15. OHz, H-8ax, Ib); 2.07
(dd, J = 4.0, 13.4Hz, H-2'eq, la); 2.10 (dd, J = 4.0, 13.4Hz, H-2'eq, Ib); 2.12 (d, J = 7.8Hz, OH-13, la); 2.35 (ddd, J = 1.7, 2.6, 15. OHz, H-8eq, Ib); 2.40 (d, J = 3.8Hz, OH-13, Ib); 2.54 (ddd, J = 1.7, 2.6, 15. OHz, H8eq, la); 2.61 (d, J = 19.1Hz, H-lOax, la); 2.65 (d, J = 19.1Hz, H-lOax, Ib); 3.20 (dd, J = 1.9, 19.1Hz, H-lOeq, Ia + Ib); 3.21 (s, SO CH3); 3.67 (, CH-13, la); 3.82 (, CH-13, Ib); 4.11 (m, H-5 ', la + Ib); 4.22 (s, OH-9, la); 4.36 (s, OH-9, Ib); 4.74 (m, H-4 ', Ia + Ib); 5.27
(dd, J = 2.6, 4.4Hz, H-7, la); 5.29 (dd, J = 2.6, 4.4Hz, H-7, Ib); 5.55 (d, J = 3.8 Hz, H-1 ', Ia + Ib); 7.84 (, H-2 + H-3, Ia + Ib); 8.36 (m, H-1 + H-4, Ia + Ib); 13.38 (s, OH-11, la); 13.39 (s, OH-11, Ib); 13.59 (s; OH-6, la); 13.60 (s, OH-6, Ib). FAB-MS (+) m / z: 604 [MH] + It is noted that in relation to this date, the best method known by the applicant to carry out the aforementioned invention, is the conventional one for the manufacture of objects or products to which it refers.
Claims (10)
- Having described the invention as above, the content of the following claims is claimed as a priority: 1. An anthracycline glycoside of formula I: Formula I: characterized in that the waved line means that the hydroxy group in the 13 position can be in the a or β position, or a mixture thereof.
- 2. A compound according to claim 1, characterized in that it is 4-demethoxy-13 (S / R) -3 '-deamin-3' -aziridinyl-4'-methanesulfonyl daunorubicin, 4-demethoxy-13 (S) -3 ' deamino-3 '-aziridinyl-4'-methanesulfonyl daunorubicin or 4-demethoxy-13 (R) -3'-deamino-3' -aziridinyl-4'-methanesulfonyl daunorubicin.
- 3. A compound according to claim 1, characterized in that it is 4-demethoxy-13 (S) -3'-deamino-3 '-aziridinyl-4'-methanesulfonyl daunorubicin.
- 4. A process for the preparation of an anthracycline glycoside of formula (I) according to claim 1, characterized in that it comprises the anthracycline reduction of formula II: Formula II: II in the presence of a reducing agent in a mixture of organic solvents, and, if convenient and necessary, the separation of the resulting mixture of the compounds 13 (R) and 13 (S) in the single diastereomer.
- 5. A process according to claim 4, characterized in that the reducing agent is sodium borohydride.
- 6. A process according to claim 4 or 5, characterized in that the reduction is carried out at a temperature below 50 ° C.
- 7. A process according to claim 6, characterized in that the reduction is carried out at a temperature of -70 ° C.
- 8. A pharmaceutical composition characterized in that it comprises an anthracycline glycoside of formula I according to claim 1, and a pharmaceutically acceptable diluent or carrier.
- 9. A compound according to claim 1 or 2, characterized in that it is used in a method of treating the human or animal body by means of therapy.
- 10. A compound according to claim 9, characterized in that it is used as an antitumor agent.
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
GB9808027.8 | 1998-04-15 |
Publications (1)
Publication Number | Publication Date |
---|---|
MXPA99011455A true MXPA99011455A (en) | 2000-06-01 |
Family
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