Method of producing anthracyclinic glycosides

专利摘要:
Anthracycline glycosides of the general formula (A'): <IMAGE> wherein R1 represents a hydrogen atom, a hydroxy group or a methoxy group; one of R2 and R3 represents a hydroxy group and the other of R2 and R3 represents a nitro group; and R4 represents a hydrogen atom or a hydroxy group; and their pharmaceutically acceptable salts; have anti-tumor activity.
公开号:SU1553015A3
申请号:SU864028510
申请日:1986-11-13
公开日:1990-03-23
发明作者:Анджелуччи Франческо；Гигли Мауро；Пенко Серджио；Джулиани Фернандо
申请人:Фармиталиа Карло Эрба С.П.А. (Фирма)；
IPC主号:

专利说明:


cm
The invention relates to a method for producing new derivatives of anthracyclic glycosides of the general formula
About R.,
he
 HCJ
I
where R1 is hydrogen; one of
KgK3 is a hydroxyl group; and the other of RJ and R, is a nitro group; R4 is hydrogen or hydroxyl
Group,
possessing antitumor activity.
The purpose of the invention is to obtain new anthracinolines. glycosides possessing higher antiviral activity than doxorubicin and downolicin structural analogues, and less
toxicity through the synthesis of these compounds.
35
Example 1: Preparation of (+) A-demethoxy-6-deoxy-6-nitrodaunomycin (compound 5).
a) Preparation of 4-cemetoxy-6-deoxy-7,9,11-triad of thil-daunomycin (intermediate 2).
4-demethoxy-6-deoxy-daunomycin 4d (compound 1), (1.7 g 4.8 mmol) is heated at 90 ° C with stirring together with acetic anhydride (25 ml) and pyridine (25 ml). After heating for 2 hours, the reaction mixture was poured.
The mixture is mixed with ice and water and allowed to stand for 30 seconds with stirring. The solid is filtered off, washed with water and crystallized from methanol to give the title compound - 2 (yield 2.19 g (.94%), mp. 225-226 ° C).
IR (KBZ), cm: 1770 (aromatic ester), 1740 (aliphatic slol ester), 1720 (aliphatic ketone), 1675 (aromatic ketone), 1590 (At).
UV (MeOH), XWOIKC, nm: 210,258,334.
High resolution maes spectrometry: t / 7. 478 (100, M).
55
0
five
0
five
0
five
d.,

five
I1MP (200 MHz, CDC13): 2.11 and 2.01 (singlets, 61), OCOCH3), 2.22 (sleep, MN, SISI), 2.52 (synget, 311, Ag - OS: OCH3 ), 2.4-3.3 (.muyplet, 4H), 6.17 (extended peak, 1H, / -H), 7.7- 8.25 (multiplet, 511).
) Preparation of 4-demethoxy-6-deoxy-7, 9-diacetyl-daunomycinone (soy ;; - - singing 3).
The obtained compound 2 (2.1 g
4.5 mmol) is dissolved in methanol (220 ml) and methylene (110 ml). Solution 1 and. morpholine in methanol (18 ml,
4 equivalents) is added and the pacisop is left to stand at 40 ° C for
5h After neutralization with water
1 and. HCl solution is removed in vacuo and the residue is crystallized from methanol to give the title compound 3 (yield 1.7 g (90%), i.e., 265 ° C with decomposition).
IR (KBG), cm-: 3440 (phenolic OH); 1745, 1720, 1670 (unchelated quinone), 1630 (chelated quinone), 1590.
High resolution mass spectromegri: m / Z 436 (M +).
UV and visible absorption spectra (MeOH), humag, nm: 204,220,258,336, 386,404.
PMR (200 MHz, CUClj): f 2.09 and 2.04 (singlets, 6H, OCOCHj), 2.25 (singlet, 3N, COCH3), 2.54 3-40 (mulletplet, AN), 6.19 (double duSlet,, 1 and
5.6 Hz, 1H, 7-H), 7.77-8.35 (mulhyplet, 5H), 13.11 (single t, 1H, 11-OH).
c) Preparation of 4-demethoxy-6-deoxy-6-nitro-7,9-diacystn-daunomyncinone (intermediate 4).
To the mixture obtained about compound 3 (1.6 g, 3.66 mmol), (1.6 g, 20 mmol) and (CF3CO). JO (18 ml) was added anhydrous (300 ml) under nitrogen atmosphere and with vigorous stirring at room temperature. After 90 seconds, methanol (Zl) is added to give a yellow precipitate, which is filtered off, washed with freshly distilled methanol and ethyl ether. After drying, the title compound 4 is obtained (yield 1.23 g (70%), mp. 263-2: 4 ° C).
IR (KBr), cm-1: 347D, 1745, 1720, 1675, 1635, 1585, 1540 (Лг - N0).
High resolution Mace spectrometry: m / Z 481 (M).
UV and visible spectra (M (H) N), xmax, nm: 216, 260, 338, 400.
515
G1MR (200 MHz, SG) S1E): 2.04 and 2.00 (singlets, 611, OCOCHj), 2.24 (single t, 3N, SOSNe), 2.43-3.51 (multiplet, 4H ), 6.22 (double doublet, J 2.3 and 5.4 Hz, HI, 7-H), 7.8-8.4
(multiplet 4H), 13.59 (singlet, 1H, 11-OH).
Compound 4 obtained above in step b (1.1 g, 2.3 mmop) was dissolved in THF (220 ml).
0.1 N is added to the solution. NaOH (220 ml) at room temperature under nitrogen and with stirring. After 1 hour, the solution is adjusted to a pH of about 7 with a 1 K solution of HC1 and the solvent is removed under vacuum. The residue is dissolved with CHgCl 3, the solution is washed with water until the mixture is neutralized, dried over L ag504 and the solvent is evaporated. After chromatography on silica gel, the title reaction product, Compound 5, is obtained (yield 0.77 g (90%), mp 233-234 ° C with decomposition).
IR (KBr), cm-1: 3570, 3470, 1710, 1680, 1630, 1585, 1535.
High resolution Mace spectrometry: m / Z 398 (MH +), 397 (Mf).
UV and visible spectra (MeOH), nm: 216, 260, 341, 384, 401.
PMR (200 MHz, CDC13); d 2.23-3.22 (multiplet, 4H), 2.41 (singlet, GZ, SOSI), 4.02 (doublet, 4 Hz, 7-OH), 4.67 (singlet, 1H, 9-OH), 5.02 (three doublets, 3,4,3 and 8,4 Hz, 1H, 7-H), 7.8-8.4 (multiplet, 4H), 13.51 (singlet, 1H, 11-OH).
PRI mme R 2. Obtaining 4 demetok SI-11-deoxy-11-nitrodaunomycin (compound 10).
“) Preparation of 4-demethoxy-6,7,9-triacetyl-11-deoxidaunomycin (intermediate 7).
4-Demetoxy-11-deoxy-daunomycinone (compound 6). (O, 7 g, 2 mmol) is stirred together with acetic anhydride (10 ml) and pyridine (10 ml) at
room temperature. After 24 hours, the reaction mixture was worked up as described in Example 1a to give the above-mentioned compound 7 (yield, 0.88 g (93%), mp 220-222 ° C).
IR (KBr), cm 1: 1780, 1730, 1720, 1675, 1590.
UV (MeOH), hmax, nm: 210, 258, 334.
156
High resolution Mace spectrometry: m / Z 479 (MH), 478 (M4).
PMR (200 MHz, CDCb,): s / 1 2.03 (singlet, 6H, OOSN), 2.23 (singlet, ZN, SOSNE), 2.44 (schletlet, ZN, Lg - OOSN,), 2, 44 - 3.39 (multiplet, 4H), 6.46 (broad peak, 1H 7-H), 7.75-8.3 (multiplet, 5H).
 6) Preparation of 4-demetocgy-7, 9-di-acetyl-11-deoxy daunomycin (intermediate 8).
Compound 7 obtained (0.83 g, 1.74 mmol) was treated in the manner described in Example 16 to give the title compound 8 (yield 0.67 g (88 / O, mp 244 ° C).
IR (KBr), cm-1: 3430, 1730, 1665, 1640, 1590.
UV and visible spectra (MeOH), Lm x nm: 208, 226, 254, 334, 384, 400.
High resolution Mace spectrometry: m / Z 436 (M).
GMR (200 MHz, SPS1E): f 2.04 (singlet, 6H, OCOCHj), 2.24 (singlet ZN, COCH3), 2.40-3.30 (multiplet, 4H), 6.47 (double doublet, , 0 and 5.5 Hz, 1H, 7-H), 7.8-8.3 (multiplet, 5H), 13.06 (singlet, 1H, 6-OH)
at). Preparation of 4-demethoxy-7,9-di-acetyl-11-deoxy-11-nitrodaunomycin (intermediate 9).
The resulting compound 8 (0.62 g, 1.42 mmol) is treated with NH4NOj (0.57 g, 7.1 mmol), (CF3CO) 20 (4 ml) in anhydrous CHgCl7 (90 ml). Using a procedure identical to Example 16, compound 9 was obtained (yield 0.5 g (73%), mp. With decomposition).
IR (KBG), 3450, 1740, 1710, 1680, 1635, 1590, 1545 (Ar - M02).
UV and visible spectra (MeOH),
, KC HM 208 254 334, 40 ° High Resolution Mace Spectrometry: m / Z 481 (M).
PMR (200 MHz, CDC13): d 2.06 and 2.04 (singlet, 6H, OOSN 3), 2.2 (singlet, 3N, COCH3), 2.42-3.03 (multiplet, 4H), 6 , 50 (double doublet, 7 and 5.5 Hz, 1H, 7-H), 7.8-8.4 (multiplet, 4H), 13.50 (singlet, 1H, 6-OH).
Compound 9 obtained in stage b (0.45 g, 0.94 mmol) is treated with 0.1 N. NaOH solution as described in Example 1 g, obtaining the reaction product — the above-named compound 10 (yield 0.34 g (91%), mp 231-233 ° C).
IR (KBr), cm 1: 3550, 1710, 1675, 1630, 1540.
UV and visible spectra (MeOH), l „aks, im: 210, 214, 218, 250, 326, 336, 400.
High resolution Mace spectrometry: m / Z 397 (M +).
Calculated for 5NO g 397, G7U8, found 397.0808.
PMR (200 MHz, CDC13): rf 2.18-3.1 (multiplet, 4H); 2.38 (singlet, ЗН, СОСН3), 3.85 (doublet, 2 Hz, 1H, 7-OH), 4.55 (singlet, 1H, 9-OH), 5.36 (three doublets), 8, 4.8 and 6.2 Hz, 1H, 7H), 7.8-8.4 (multiplet, 4H), 13.7 (singlet, 1H, 6-OH).
II p im e r. 3. Preparation of 4-demetoxy-6-deoxy-6-nitro-1-trifluoroacetyl-daunorubicin (compound 11).
To the cooled solution (15 ° C) of racemic 4-demethoxy-6-deoxy-6-nitrodaunomycinon 5 (0.7 g, 1.76 mmol) in anhydrous methylene chloride (140 ml) is simultaneously and quickly added with vigorous stirring and passing Nitrogen 1-chloro, N, 0- di- (trifluoroacetyl) -daunosamine (1.88 g, 5.28 mmol) in anhydrous (40 ml) and trifluoromethanesulfonate cepeb-ra (1.4 g, 5.28 mmol) in anhydrous ethyl ether (40 ml). After 20 seconds, a saturated aqueous solution of NaHCO3 (100 ml) is added and the mixture is left to stand with stirring for 10 seconds. The mixture is filtered through a zeolite, the organic layer is separated, washed with water, dried over and the solvent is removed under vacuum.
The yellow substance was dissolved in MeOH (300 ml) and left to stand overnight at room temperature to remove the 0-trifluoroacetyl group.
The residue obtained by evaporation of the solvent is chromatographed on silica gel with a puriating system: CH.jCl.j-EtOAC-CH COOH (90: 10: 1) v / v) to give o (α-glycosides 7 (5): 9 (8) with yield 0.43 g (39%) "and 7 (R): 9 (R) with a yield of 0.43 g (39%)
For 7 (S): 9 (S):
M.p. 245-246 ° C.
IR (KBr), 3470.3450, 1720, 1700 (N-trifluoroacetyl), 1680.1635, 1590.1535.
High resolution mass spectrometry: t / 7. 023 (MP4).
0
five
0
five
0
five
0
five
0
five
UV and visible spectra (MeOH), m: 208,260,341,384,401.
and, ° (0 0.05541 in MeOH).
CD (MeON): Of226, 31, df270, 94, uf 292, 67, / if 340, 68.
PMR (200 MHz, CDC1,): 1.24 (doublet, 8 Hz, 3N, 5 -SI.,); 1.82 (triple doublet, 1, 12.4 and 12.4 Hz, 1H, 2 ax - I), 1.94 (doublet, 2 Hz, 1H, 4 - OH), 1, 95 (double doublet ,, 0 and 12.4 Hz, 1H, 2 eq - H), 2.15 (double doublet, 3 and 15.1 Hz, 1H, 8 aq-H), 2.34 (singlet, 3N, SANE) , 2.48 (triple doublet, 8, 2.3, and 15.1 Hz, 1H, 8 equiv. Of H), 3.10 (doublet, 7 Hz, 1H, 10 ax-H), 3.27 (double doublet, J 1.8 and 18.7 Hz, 1H, 10 eq-H), 3.65 (double doublet, 7 and 8.2 Hz, 1H, 4 -H), 4.1-4.3 ( multiplet, 1H, 3H), 4.30 (quartet, 8 Hz, 1H, 5 -H), 5.00 (doublet, 1 Hz, 1H, 1 -H), 5.11 (double doublet, , 3 and 4.3 Hz, 1H, 7-H), 6.61 (doublet, 0 Hz, 1H, NHCOCFj), 7.8-7.9 (multiplet, 2H, 3-H), 8.2 -8.4 (multiplet, 2H, 1-H, 4-H), 13.55 (singlet, 1H, 11-OH).
For 7 (R): 9 (R):
M.p. 145-14b ° C.
High resolution Mace spectrometry: m / Z 623/10, (MN), 579 (100).
KD (MeOH): df 226, 9, & E 271 nm +7.26, dЈ 292 nm -0.27, YЈЈ 300, 56, l Ј 340 nm -5.1, GoP -293 ° (, 0635 and MeOH) .
PMR (200 MHz, CDC13): / 5, 1 4 (triplet, 0 Hz, 1H, 7-H), 5.27 (multiplet, 1H, 1-H).
PRI me R 4. Preparation of 4-demethoxy-6-deoxy-6-nitro-daunorubicin hydrochloride (compound 12).
4-Demetoxy-6-deoxy-6-nitro-K-trifluoroacetyl-daunorubicin (0.130 g, mmol) is dissolved in acetone (6 ml). At 0 ° C under nitrogen and stirring, 0.1 n is added. NaOH solution (60 ml). After 2 hours, the acetone is removed under vacuum and the pH is adjusted to 4.5 with 0.1N. HC1.
The aqueous solution is extracted with a pH adjusted to about 6.5-7.0 with 0.1N. NaOH and extracted with (L1; C1. The organic layer was washed with water, dried over Na, jS04 and the evaporator pan was evaporated. The residue was dissolved in MeOH (5 ml), acidified with drops of a solution of HC1 in MeOH and adding The hydrochloride is precipitated in ether and n-hexane. The solid is filtered, washed with diethyl ether until neutralized and dried to give the title compound 12 (yield 0.080 g (68%), mp. 173 ° C with decomposition) .
IR (KBG), cm: 3400.1710.1675, 1630.1590.1540.
High resolution Mace spectrometry: m / Z 527 (MH4).
Example 5: Preparation of 4-demetra si-11-deoxy-11-nitro-K-triforacetyl-daunorubicin (compound 13).
Racemic aglucon 11 (0.290 g, 0.73 mmol) is converted to the corresponding glycoside, as described in Example 3, Named reaction product 7 (S): 9 (S) with a yield of 0.1 g (24%) and its diastereomer 7 (R); 9 (R) J with a yield of 0.1 g (24% is obtained after a chromate-graphic separation.
For 7 (S): 9 (S):
M.p. 237-240 ° C with decomposition.
IR (KBG), 3500.3400.1720, 1675.1640.1540.
High resolution mass spectrometer: m / Z 579M-COOHE).
UV and Visible Spectra (MeOH), 207,259,335,400.
KD (MeON): 221, 1, D250, 0, 1, Л330 nm + 3, 1, Ј400, 0. (, 0623 in Meon).
PMR (200 MHz, CDC13): of 1.30 (doublet, 5 Hz, 3N, 5, -CH3), 1.86 (triple doublet,, 0; 13.0 and 13.0 Hz, 1H, 2 ax -N), 2.03 (double doublet, 4, and 13.0 Hz, 1H, 2 eq-H), 2.13 (double doublet, 3, and 14.9 Gu, 1H, 8 ax-K), 2.36 (three doublets, 6, 2.2 and 14.9 Hz, 1H, 8 eq-H), 2.37 (singlet, 3N, COCH3), 2.89 (double doublet, J 1,6n18, 2 Hz, 1H, 10 eq - H), 3.12 (doublet, J 18.2 Hz, 1H, 10 ax - H), 3.68 (the double doublet,, 0, and 8.0 Hz, 1H, 4 -TO)
4.15-4.30 (multiplet, 1H, 3 -H), 4.25 (quartet, 5 Hz, 1H, 5 -H, singlet, 1H, 9-OH), 5.30 (double doublet, 2 and 4.3 Hz, 1H, 7-H), 5.47 (doublet, 5 Hz, 1H, -H), 6.70 (doublet, 0 Hz, 1H, NHCOCF3), 7.8-7 , 9 (multiplet, 2H, 2-H, 3-H), 8.2-8.4 (multiplet, 2H, 1-H, 4-H), 13.72 (singlet, 1H, 6-OH). For 7 (R): 9 (R):
0
five
0
five
0
five
0
five
0
five
High resolution mass spectrometry: m / Z 579 (100, M -COCH3).
PMR (200 MHz, CDC13): S 5.35 (multiplet, 1H, 1 (-H), 5.59 (double doublet,, 0 and 3.5 Hz, 1H, 7-H).
Example 6. Preparation of 4-demethoxy-11-deoxy-1-nitro-daunoobl hydrochloride (compound 14).
The compound obtained in Example 5 (0.090 g, 0.145 mmol) was treated as described in Example 4 to give the title compound 14 (yield 0.061 g (75%), mp. With decomposition).
IR (KBG), cm-: 3400.2900.1710, 1670.1635.15.55.1540.
High resolution mass spectrometry: m / Z 527 (MH4).
UV and visible spectra (MeOH), awo, c, m: 208, 222, 256, 402.
Example. 4-Demetoxy-6-deoxy-6-nitro-doxorubicin (compound 15).
4-Demetoxy-6-deoxy-6-nitro daunobicicin hydrochloride from Example 4 (0.86 g, 1.52 mmol) is dissolved in 50 ml of methanol and 50 ml of dioxane. To the stirred solution are added trn-ethyl chlorofluormate (1.5 ml) and 0.92 ml of a solution of bromine in methipene chloride (30% by weight of the volume).
After 4 hours at room temperature, the solution was poured into a mixture of diethyl ether (300 ml) and n-hexane (500 ml) and precipitated 4-demethoxy-6-deoxy-6-nitro-1Z-diethyl ketal-14-bromo-daunorubicin collected and washed with ether.
The solid material is dissolved 6-120 ml 0.25 n. hydrobromic acid and 120 ml of acetone. After 16 hours at room temperature, 4.8 g of sodium formate, dissolved in 50 ml of water, are added and after 24 hours at 50 ° C, the solution is treated with a saturated aqueous solution of sodium bicarbonate until the pH is alkaline.
Upon shaking with methylene chloride, the reaction mixture gives a reddish precipitate of 4-demethoxy-6-deoxy-6-nitro-14-bromo-daunorubicin, which is filtered and washed with water. The mother liquor is extracted several times with methylene chloride, and the solvent is removed in vacuo to yield a second portion of the crude product.
I15
These two portions are combined and dissolved in methanol containing 10% acetic acid, 20 g of silica gel, added to this solution and the solvent is carefully removed in vacuo. The solid material is loaded on top of a column (5x30) prepared from silica gel and methylene chloride, and the mixture is eluted with a mixture (80:10 v / v) methylene chloride - 95% ethyl alcohol. The pure fractions are collected and the solvent is removed in vacuo. The residue is dissolved in methanol, cooled at OV, acidified with 0.5N. a solution of HCl in methano. to a pH value of about 3.
When diethyl ether is added, a yellow precipitate is formed, which is filtered and washed with ether. After drying under vacuum, 0.45 g (total yield 51%) of 4-demethoxy-6-deoxy-6-nitro-doxorubicin hydrochloride is obtained.
IR Spectrum (KBG), 3400, 1710, M675, 1630, 1590, 1540.
FD mass spectrum: m / e543 (MH +).
UV-Visible Spectrum (MeOH), ms, s. nm 208,260,341,384,401.
RЈ (plate with silica gel F 254 dichloromethane / methanol / acetic acid / water 80: 20: 7: 3) 0.37.
Try on 4-Demetoxy-11-deoxy-11-nitro-doxorubicin (compound 16).
4-Demetoxy-11-deoxy-11-nitro daunorubicin hydrochloride from Example 6 (0.35 g 0.62 mmol) was dissolved in 15 ml of methanol and 15 ml of dioxane. 0.5 ml of triethyl orthoformate and 0.34 ml of a solution of bromine in methylene chloride (30% by weight) are added to the stirred solution.
After 4 hours, the reaction mixture was poured into a mixture of 150 ml of diethyl ether and 300 ml of n-hexane, the precipitate formed of 4-demethoxy-11-deoxy-11-nitro-1Z-diethyl ketal-14-bromo-daunorubicin was filtered and washed with ether.
The solid material is dissolved in 25 ml of 0.25 n. hydrobromic acid and 25 ml of acetone and incubated overnight at room temperature. 1.5 g are added (sodium formate sodium dissolved in 15 ml of water and the temperature is raised to 50 ° C in 24 hours.
301512
A saturated aqueous solution of sodium bicarbonate is added to alkaline medium and the mixture is extracted with methylene chloride.
The organic layer is dried over sodium sulfate and the solvent 4-demethoxy-11-deoxy-11-nitro-14-bromo-daunorubicin is removed in vacuo. The crude n-yu material is purified on a chromatog, mastic with silica gel, which is eluted with a mixture of methylene chloride / / methanol / acetic acid 160: 20: 8. The pure fractions are collected, washed with a 15 saturated aqueous solution of sodium bicarbonate and water until neutral, then the product is extracted, washing it with a solution of water and 0.1N. hydrochloric acid at a pH of about 3.
2Q Aqueous solution was subjected to lyophilic drying, yielding 0.17 g (total yield 47%) of hydrochloride-4-demethoxy-11-deoxy-11-nitro-doxorubicin.
IR spectrum (KVg),: 3400.2900, 25 1710.1670.1635.155.1540.
FD mass spectrum: m / e543 (MHf).
UV and visible spectrum (MeOH), MnKC: nm: 208, 222, 256, 402.
Rf (plate with silica gel F 254 30 methylene chloride / methanol / / acetic acid / water 80: 20: 7: 3) 0.407.
The biological activity of the compounds of examples 6 and 4.
Compounds were tested against daunorubicin (DNP) against Hela cells and P 388 in vitro. The compounds are tested by dissolving them in the form of chlorohydrates in water.
35
In vivo action of the compound against
R 388 ascitic leukemia is presented in table. one.
The activity of these compounds is tested against disseminated (widespread) leukemia Cross. The results are presented in table. 2. In this system, two new compounds with the maximum tested dose (22.5 mg / kg and 50 microns / kg for the compounds in examples 6 and 4, respectively) were more active than DND at the maximum tolerated dose of PO mg / kg).
Data on toxicity are given in table. 5, for Compound 15 (Example 7) regarding Gross leukemia are extremely beneficial. No toxicity death at a dosage of 29.6 mg / kg compared with 4/10 fact
mi death from the toxicity of the original drug doxorogpgtsina gtri dosage of 16.9 mg / kg for both drugs.
It should also be noted that the activity of compound 16 (example 8) is relatively high with respect to disseminated throat-leukemia: 275/233 using almost equivalent doses of the test compound and the control drug.

权利要求:
Claims (1)
[1]
Invention Formula
The method of obtaining anthracycline glycosides of the general formula
About B-,
GHSH2R4 CHON
HCJ
BUT NH2
where R. is hydrogen;
one of R and R is hydroxyl
the group, and the other of RJ and RJ, nitrocrut;
R4 is hydrogen or hydroxyl
Group,
wherein the agylcon of the general formula
° ° (II)
where R ,, R, and R3 have the indicated meanings,
condense with 1-chloro-M, O-di (trifluoroacetyl) daunazamine of formula
five
H3S
C1
h4
sg
i
COCF5
R anhydrous methylene chloride in a nitrogen atmosphere at h ° C in the presence of silver trifluoromethanesulfonate to obtain a diastereomeric mixture of 7 (8), 9 (S) and 7 (R), 9 (R) anthracycline glycosides of the formula
 A 1 - 1
CHj
I -
but
ag-
aO- / -r-J (IV)
.CF5OCO AND
M, COCFj
where R1, R, R3 are as defined, then the protective 0-trifluoroacetyl group is removed by reacting with methanol for; nights at room
 7 (S), 9 (S) N-trifluoroacetyl anthradicline glycoside from 7 (R), 9 (R) anthracycline glycoside by silica gel chromatography, eluted with methylenedichloride-ethyl acetate-acetic acid in a 90 : 10: 1 (v / v), remove the N-trifluoroacetyl protective, group from the obtained 7 (5), 9 (5) anthracycline glycoside by medium alkaline hydrolysis of 0.1 N, sodium hydroxide with isolation of the target product of the formula (1) where R4 is hydrogen, in the form of its hydrochloride by reacting the free base
40 with a methanolic solution of hydrogen chloride and, if necessary, brominate the resulting compound at the 14-position with the subsequent treatment of the 14-bromo-45 derivative thus obtained with an aqueous solution of sodium formate) to obtain the target product of the formula (1), where R is a hydroxyl group, and releasing it in the form of its hydrochloride.
Table 1 Action against ascitic leukemia R 388
2.9 4.4 4 6 9 13.5
15 157 132 162 17 124
The tests were performed on mice of the SDH species infected with 10 intraperitoneal leukemia cells.
Treatment intraperitoneally once a day after the tumor inoculum.
The average survival time of cured mice / average survival time of control xOO mice.
Based on authentic conclusions.
Table2 Action against Gross leukemia
The tests were performed on mice of the species of OWS infected with 2x10 leukemia cells intravenously. Intravenous treatment once a day after
inoculating a tumor.
The average duration of survival of cured mice / the average duration of survival of control xOO mice.
It is judged on the basis of authentic (by dissecting the corpse) conclusions.
1/10 5/10 0/10 0/10 1/10 9/10
1715510151I
Tabletsa activity of cells in the cell is not la and 10 v0 outside the body
The inhibition of colony inhibition was carried out after 24 hours of treatment with the IDO0-dose, causing inhibition.
Table A: E activity against ascitic P 388 and disseminated Gross-Leukemia
P 388 - leukemia is inoculated with intraoral on day 0. Treatment is intraperitoneally on day 1.
Gross-leukemia was inoculated intravenously on day 0. Treatment - intravenously on day 1. 0 ratio of the average survival time of the treated mice to the average
the survival time of control animals x100. 0price based on unlocked data.
Table3 Activity in the body against gross-leukemia and breast cancer
Gross-leukemia was inoculated intravenously on day 0. Treatment intravenously on day 1. 0 treatment intravenously, the amount of 7c / x4, starting from the moment when
swelling felt by fingers. 0 ratio of the average survival time of the treated mice to the average
the survival time of control animals xyu. 0 based on data.

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US4025623A|1977-05-24|4&#39;-Epi-6&#39;-hydroxyadriamycin and method of use

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SU1553015A3|1990-03-23|Method of producing anthracyclinic glycosides

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DK160616B|1991-04-02|PROCEDURE FOR PREPARING ANTHRACYCLINE DERIVATIVES OR ACID ADDITIONAL SALTS THEREOF

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US4188377A|1980-02-12|Carminomycin derivatives, their preparation and use

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US4393052A|1983-07-12|Antitumor anthracycline glycosides, their preparation, intermediates therefor, and compositions and use thereof

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US4183919A|1980-01-15|Antitumor glycosides, process for their preparation including intermediates therefor and their use

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US4839346A|1989-06-13|Antitumor anthracycline glycosides, intermediates thereof, and composition and use thereof

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US4322412A|1982-03-30|Anthracycline glycosides, their preparation, use and compositions thereof

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US4133877A|1979-01-09|Anthracycline ethers and use therefor

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PT93071B|1996-01-31|METHOD FOR PREPARING NEW 4&#39;-EPI-4&#39;-AMINO-ANTHRACYCLINES AND PHARMACEUTICAL COMPOSITIONS CONTAINING THEM

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SU1277902A3|1986-12-15|Method of producing 4&#39;-deoxy-daunorubicyn or 4&#39;-deoxy-doxorubicyn

同族专利:

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公开号 | 公开日

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JPS62120395A|1987-06-01|

---

DE3638386C2|1995-09-14|

---

JPH0778073B2|1995-08-23|

---

SE8604870L|1987-05-20|

---

HUT42100A|1987-06-29|

---

GB2182926B|1989-10-04|

---

AT390618B|1990-06-11|

---

GB8528440D0|1985-12-24|

---

DK548086A|1987-05-20|

---

NL8602914A|1987-06-16|

---

FR2590260A1|1987-05-22|

---

GR862719B|1987-03-16|

---

ATA298586A|1989-11-15|

---

ZA868700B|1987-07-29|

---

DE3638386A1|1987-05-21|

---

HU195667B|1988-06-28|

---

NZ218256A|1988-11-29|

---

FI864566A0|1986-11-11|

---

PT83757B|1988-12-07|

---

IL80589D0|1987-02-27|

---

BE905751A|1987-03-02|

---

ES2002909A6|1988-10-01|

---

PT83757A|1986-12-01|

---

IT8622180D0|1986-10-29|

---

IT1206480B|1989-04-27|

---

FR2590260B1|1988-09-23|

---

US4749693A|1988-06-07|

---

DK548086D0|1986-11-17|

---

AU6510086A|1987-05-21|

---

GB2182926A|1987-05-28|

---

SE8604870D0|1986-11-13|

---

CA1296325C|1992-02-25|

---

FI864566A|1987-05-20|

---

AU590639B2|1989-11-09|

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WO1997034612A1|1996-03-22|1997-09-25|Waldemar Priebe|Bis-anthracyclines with high activity against doxorubicin resistant tumors|

法律状态:

优先权:

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申请号 | 申请日 | 专利标题

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GB8528440A|GB2182926B|1985-11-19|1985-11-19|Nitro anthracyclines, process for their preparation and use thereof|

---