GB2233326A - N-Acryloyl anthracyclin glycosides - Google Patents

N-Acryloyl anthracyclin glycosides Download PDF

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GB2233326A
GB2233326A GB8914947A GB8914947A GB2233326A GB 2233326 A GB2233326 A GB 2233326A GB 8914947 A GB8914947 A GB 8914947A GB 8914947 A GB8914947 A GB 8914947A GB 2233326 A GB2233326 A GB 2233326A
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compound
hydrogen atom
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GB2233326B (en
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Nicola Mongelli
Giovanni Biasoli
Antonino Suarato
Gabriella Pezzoni
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Pfizer Italia SRL
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Farmitalia Carlo Erba SRL
Carlo Erba SpA
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Priority to JP2166556A priority patent/JPH0338595A/en
Priority to DE4020332A priority patent/DE4020332A1/en
Priority to IT02077490A priority patent/IT1249003B/en
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    • 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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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents

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Abstract

N-Acryloyl anthracycline glycosides having the general formula A: <IMAGE> wherein R1 represents a hydrogen atom or a methoxy group; R2 represents a hydrogen atom or a hydroxy group; one of R3 and R4 represents a hydrogen atom, the other of R3 and R4 represents a hydrogen atom or a hydroxy group; R5 represents a hydroxy atom, a halogen atom, a cyano or a nitro group, are useful as antitumor agents.

Description

FIC 439 OG/M9 PP 4547 NeACRYLOYL-ANTHRACYCLINE-GLYCOSIDES The Invention
relates to N-acryloyl anthracycline glycosidess to methods for their preparation and to pharmaceutica.l. compositions containing them.
The invention provides N-acryloyl glycosides, having the formula (A) 0 OH 0 R 2 OH lxx=-5 R 0 OH 0 CH 3 R 3 R NH 11\ CH 2 0 / R 5 anthracycline A wherein R represents a hydrogen atom or a methoxy group, R 2 represents a hydrogen atom or a hydroxy group, one of R 3 and R4 represents a hydrogen atom, the other of R 3 and R 4 represents a hydrogen atom or a hydroxy group, R 5 represents a hydrogen atom, a halogen atom, a 1 1 C cyano or a nitro group.
The anthracycline glycosides of formula (A) include: N-(oL bromoacryloyl)-daunorubicin. N-( eL -bromoacryloyl)-41-epidaunorubicin. N(01 -bromoacryloyl)-doxorubicin. N-( k -bromoacryloyl)-41-epidoxorubicin. 4-demethoxy-N-( OL -bromoacryloyl)-daunorubicin. N-( & ?-chloroacryloyl)doxorubicin. N- acryloyl-doxorubicin.
The invention further provides a process for the preparation of the anthracycline 9 lycosides of formula A, the process comprising reacting an anthracycline glycoside having the formula (B) 0 OTH 0 -R GH R 0 OH 0 C'S E2 R A j B wherein RIS R 29 R 3 and R4 are as defined above, with a compound of formula (C) 1 4 k, CH 2 >-i -X R.5 0 c wherein R 5 is as defined above and X is a hydroxy or a leaving group.
The leaving group X in the compounds (C) may be, for example a halogen atom, preferably chlorine,,or another easily displaceable groups such as ethyloxy formate ú--OC-OCH(CH)2-7, 11 3 0 2,4-dinitrophenoxy, pivaloyloxy J-0-C-C(CH 0 3)37 0 (-0-C-OEt),isopropyloxy formate 11 0 2,4,5-trichlorophenoxy, succinimido -N-oxy or an imidazolyl group.
The reaction between a compound of formula (B) and a compound of formula (C), wherein X is a leaving groups as defined above, is usually carried out in a molecular ratio from 1:1 to 1:3 in an organic solvent. Tipically useful solvents include dimethyl formamide, pyridine, dimethylsulphoxide, dimethyl acetamide, tetrahydrofuran, acetone or acetonitrile. The reaction is carried out in the presence of an organic base, e.g. triethylamine or dilsopropylethylamine, at.a temperature from about -100C to 400C and for a period of from about two f 4_ hours to ten hours.
The reaction between a compound of formula (B) and a compound of formula (C), wherein X is OH, is preferably carried out in a molecular ratio from 1:1 to 1:3 in an organic solvent. Tipically useful solvents include dimethylformamide, pyridine, dimethylsuphoxide, dimethylacetamide, tetrahydrofuran, acetone or acetonitrile, in the presence of an..organic base such as triethylamine or diisopropylethylamine or inorganic base such as sodium bicarbonate and of a condensing agent such as, e.g., N,NIdicyclohexylcarbodlimide or N-ethy]-N'-(31-dimethylaminopropyl)carbodiimide.
The reaction temperature may vary from about -101C to 501C and the reaction time four about 1 to 12 hours.
The compounds of formula (A) prepared according to the above described procedures may be purified by conventional methods such as, e.g., silica gel or alumina column chromatography, and/or by crystallization from organic solvents such as, e.g. ethyl ether-hexane, methylenechloridehexane, dimethyl formamide-water and lower aliphatic alcohols-water.
The following examples illustrate but not limit 1 -0, k the Invention.
The abbreviations DMF and THF stand. respectively, for dimethylformamide and tetrahydrofuran.
EXAMPLE-] Ne( & cbromoacryloyl)cdaunorubicin (Formula A: (R 1= OCH3; R2=R3=H;R4=0H; ReBr) To a solution of & -bromo acrylic acid (225 mg) in dry DMF (30 M), cooled to -100C. triethylamine (0,42 M) was added, and then pivaloyl chloride (0, 147 M).
The resulting suspension was stirred at -101C for 30 minutes, and then daunorubicin hydrochloride (300 mg) was added.
The mixture was stirred for 30' at OOC, and then for 3 hours at room temperature.
The solvent was evaporated in vacuum to dryness, the residue dissolved in methylene chloride and washed with water. The solvent was dried on anhydrous sodium sulphate and evaporated to dryness under vacuum.
The residue was chromatographed on silica with methylene chloride-methane 98:2 (v/v) eluant.
The fractions containing the product combined and evaporated under vacuum and gel a s were the i if k_ residue recrystallizated from methylene chloride -hexane affording N-(0(bromoacryloyl)-daunorubicin (160 mg).
U.V. A max (CH 30H) G5): 496 (11682), 251 (27918) 233 (39402) FAB-MS: m/z 660, M + +1; 398 (aglycone); 262 (acilated sugar).
PMR (200 MHz RSO-d6): ppm 14.00 (s,]H, ON6); 13.25 (s,]H, ONM 8 (m, 2H, M] e H2) (d, J= 8.0 Hz,]H, NWC0) (m,]H, H3) (d, J 2.4 Hz, 1 j]H j 73-7 7.72 7.61 6.64 6.09 (d, 5.53 (s, 5.22 (d, 5.00 (d, 4.91 (m, 4.20 (-q 3.98 (m, 3.95 3.43 2.92 (s, 2.25 ( s.
].H) CH-H) ]H, = CH-H) 2.4Hz, 3.5 Hz, U, HP) J 6.0 Hz, IH, 0H41) 1 H W7) J 6.9 Hz, U, W) 1H, H3) 3H, OCH 3) U, W) 2H9 CH 210) 3H, COCH 3) f k 23-2.0 (m, 2H, CH281 1.90 (ddd, J=3.5, 11.09 12.9 Hz. 1H, H21 ax) 1.51 (dd,J=4.9; 12.9 Hz,]H, 11 eq) 1.13 (d, J = 6.9 Hz, 3H. CH35').
EXAMPLE-2
Ne-cZ,cbromoacryloyl)c41.cepidaunorubicin Formula A (R 1 = OCH3; R2=R4=H; R3=0H; R5=Br).
Following the procedure described in Example 1, 300 mg of 41-epidaunorubicin hydrochloride were treated with 225 mg of r)--bromoacrylic acid and 0,147 m] of pivaloyl chloride to give after chromatographic separation and recrystallization from methylene chloride-hexane, 185 mg of pure N-( C--bromoacryloyl)-41-epi-daunorubicin.
U.V.)\ max (CH 3 OH 496 (1418); 251 (26268); 233 (38214).
FAB-MS; m/z 660, M + + 1; 398 (aglycone); 262 (acilated sugar).
PMR (200 MHz), CDC1 3);J ppm 14.00 (s,]H, OH-6); 13.25 (s,]H, OH-II) 8.02 (d, J = 7.0 Hz,]H, M) 7.77 (t, J = 7.0, 8.1 Hz, 1H, H2) 7.38 (d, J = 8.1 Hz, 1H, W3) 6.97 (d, i = 1.7 Hz,]H, = CH-H) (1 4 j 6.53 (d; J = 6.8 Hz; 1H, NUCO) 6.03 (dg J = 1.7 Hz. l[H, = CH-H) 5.51 (d, J = 3.2 Hz, 1H, HP) 5.26 (dds J = 2.09 4.2 Hz,]H, M7) 4.07 (s, 3H. OCH...3 33-4.0 (ms 2H.. M31 e M58) 3.20 (t$ J = 9.4 Hz.1H, H41) 3.22 (dd, J = 1.7, 18.8 Hz, 1H, M10eq) Z.91 (d, J = 18.8 Hz, 1H, M10ax) 2.43 (s, 3H, COCH -3 2.35 (ddd, J = 1.7, 2.0, 14.9 Hz,]H, H js) 2.0-2.2 (m, 2H, H8ax e H21eq) 1.80 (ddd, 3.2, 11.0, 13.0 Hz,]H, H21ax) 1.36 (d, J=6.3 Hz, 3H, CH 3 -51) EXAMPLE-3
Nc(01,cbromoacryloyl)cdoxorubicin Formula A (R 1 =OCH 3; R 3 =H; R 2 =R 4 =OH; R 5 =Br) To a solution of OL-bromoacrylic acid (225 mg) in dry THF (15 m]), cooled to - lOQC, triethylamind (0.42 M) was added, and then pivaloyl chloride (0,147 mli.
The resulting suspension was stirred at -100C for 30 minutes and then was added to a cooled solution of doxorubicin hydrochloride (og 293.) in dry DMF (35 M).
4 k 1 The mixture was stirred for 30lat 00C. and them for 2 hours at room temperature.
The.solvent was evaporated in vacuum to dryness. the residue dissolved in chloroform and washed with water. The solvent was dried on anhydrous sodium sulphate and evaporated to dryness under vacuum.
The residue was chromatographed on silica gel, with methylene chloridemethanol 98:2 as eluent.
After evaporation of the solvent, the solid was stirred with little ethyl ether, filtered and washed with hexane, affording N-(dL-bromoacryloyl)-doxorubicin (125 mg).
U.V.,k max (CH 3 OH) 496 (11500); 251 (26247); 233 (39776).
FAS-MS: m/z 676, M + +1 414 (aglycone); 262 (acilated sugar). PMR (200 MH, CDC] 3):.ppm 13.98 (s,]H, OHc6) 13.25 (s, ]H, 0Well) 8.04 (d, J = 7.6 Hz, 1H, M) 7.79 (dd, J 7.6, 8.4 Hz, 1H, W2) 7.39 (d, J = 8.4 Hz, 1H9 H3) 6.96 (d, J = 8.4 Hz,]H, NHCO) 6.92 (d, i = 1.5 Hz, 1H -CH-H) 5.99 (d, J = 1.5 Hz, H = CH-H) 5.52 (d, J = 3.4 Hz,]H,, H11) i 5.30 (dds J=2.4s 4.2 HZ, U, H7) 4.76 (d, J = 4.6 Hz, 2H, CH,OH) 4.51 (s, lHq ON9) 4.2-4.1 (m, 2H. M31 e M51) 4.08 (s. 3H. OCH3) 3.68 (dds J=1.7.8.1 Hz, U, W) 3.29 (dd, J 1.59 19.1 Hz, 1H, W10eq) 3.03 (d, J = 19.1 Hz, 1H, M10ax) 2.99 (t, J = 4.6 Hz, 1H, CH 20M) 2.34 (ddd, J 1.5, 2.4, 15.2 Hz, 1H, H8eq) 2.18 (dd, J 4.2, 15.2 Hz, 1H, W8ax) 1.97 (d, J = 8.1 Hz, 1H, 0H41) 13-1.8 (m, 2H, CH 2 c21) 1.30 (d, J = 6.6 Hz, 3H, C23 -51) EXAMPLr_4 M.
Nc(-4cbromp-acryloyl-)c41---eoidoxorubicin Formula A: (R 1 =OCH 3; R 2 =R 3 =OH; R 4=H; R,=Br) Following the procedure described in Example 3, 300 mg of 41- epidoxorubicin hydrochloride were treated with 225 mg of &-bromoacrylic acid and 0,147mol of pivaloyl chloride to give, after chromatographic separation and treatment with ethyl ether-hexane, 138 mg of pure N-( OL -bromoacryloyl)-41- epidoxorubicin.
U.V.;k, max (CH 3 OH) GE'): 496 (11500); 251 (27464); IL - 11 233 (40588).
FAB-MS: mlz (acilated sugar).
PMR (200MHz, DMSO): ppm 13.99 (s, 1H, OH-6) 13.25 (s, 1H, OH-1 73-7.8 (m, 3H, MI, M2, NHCO) 7.7-7.6 (m,]H, M3) 6.58 (d, J = 2.4 Hz, M, = CH-H) 6.06 (d, J = 2.4 Hz, 1H, = CH-H) 5.40 (s, U, 0M9) 5.22 (d, J = 3.0 Hz, M, W) 4.99 (m, 4.88 (d, 4.68 (t, 4.55 (d, 3.98 (s, 33-3.8 3.00 (m, 2.21 (m, 1.8-1.3 1.20 (d 676, M + +1; 1H, j = J= i:
M7) 6.3 Hz,]H, ON41) 4.6. Hz, 1H, CH 2 OM) 4.6 Hz, 2H, C220m) 3H, OCH 3) (m, 2H, M3! e 051) 2H, CH 210) 2H; CH28) (ms 2H9 CH 2L) J = 6.2 Hz, 3H, CH 351) 414 (aglycone); 262 EXAMPLE-5 4edemetboxycNc(-ri-cbromoacryloylledaunorubicin Formula A (R 1 =R 2=RJ-H; R4=0H; R,=Br) (1 Following the procedure described in Example 3,284 mg of 4-demethoxy- daunorubicin hydrochloride were treated with 225 mg of d,-bromoacrylic acid and 0,147 m] of pival.oyl chloride to give, after chromatographic separation and recrystallization from methylene chloride-hexane 158 mg of pure 4-demethoxy-N-( 01 -bromoacryloyl)-daunorubicin.
U.V X max (CH 3 OH) 496 (11582); 251 (27888); 233 (39394).
FAB-MS: m/z 630, M + + 1, 368 (aglycone) 262 (acilated sugar). PMR (200 MHz DMSO): 13.92 (s, 1H, ON6); 13.20 (s,]H, ON]]) 8.2-7.8 7.72 (d, 6.64 (d, 6.09 (d, 5.53 (s, 5.22 (d, 5.00 (d, J 4. 91 (m,]H$ 4.20 (q, J = 3.98 (m,]H, 3.95 (s, 3H, < PPM 4H, M] H2 9 H 3 e H 4) 8.0 Hz, U, NWC0) J 2.4Hz, J= 2.4 Hz, 1H, ON9) J=3.5 Hz,]H,, H]!) 6.0 Hz,]H, OH41) M7) 6.9 Hz, U, H3-1) OCH 3) ]H, = CH-H) IHS = CH-H) J' k 1 V.
3.43 (m, 1H, MC) 2.92 (s, 2H._ CH210) 2.25 (s. 3H. COCH 3) 2.3-2.0 (ms 2HsCH28) 1.90 (ddd, J = 3.5, 11.0$ 12.9 Hz. 1H. H21ax) 1.51 (ddJ= 4.9; 12.9 Hz. 1H,HVeq) 1.13 (d$ J = 6.9 Hz, 3H. CH 351). EXAMPLE-6 Nc(oLcchloroacryloyl)cdoxorubicin Formula A (R 1 = OCH 3; R 2 =R 4 =OH; R 3 =H; R 5=Cl) To a solution of:--chloroacrylic acid (106 M) in dry DMF (20 M), N,N- dicyclohexylcarbodiimide (165 mg) was added and the r.esulting suspension was stirred at room temperature for 20 minutes.
The mixture was treated with triethylamine (0,2 ml) and doxorubicin hydrochloride (200 mg),. and the whole stirred for 6 hours at room temperature.
The solvent was evaporated in vacuum to dryness, the residue dissolved in chloroform and washed with water. The solvent was dried on anhydrous sodium sulphate and evadorated to dryness under vacuum.
The residue was chromatographed on silica gel, with methylene chloridemethanol 98:2 (v/v) as eluant.
After evaporation of the solvent. the solid was f It- 1 t stirred with little ethyl ether, filtered and washed with hexane, affording N-( OL -chloro- acryloyl)-doxorubicin (102 mg)._ U.V.- A max (CH 3 OH).-((f):.496 (11.582); 251 (26403); 233 (40024).
FAB-MS: mlz (acilated PMR (200 13.98 (s, (S, (d, (dd (d, (d, (d, (d, 5.52 (d, 5.30 (dd 4.76 (d, 4.51 (s, 4.2-4.1 13.25 8.04 7.79 7.39 6.86 6.70 5.89 6323 M +1; sugar).
MHz, CDC13):]H,]H, J=7.6 1 PPM HZ,]H, H]) J= 7.6, 8.4 Hz, U, M2) J= 8.4 Hz, 1H,-M3) J= 8.4 Hz,]H, NMC0) J= 1.5 Hz,1H, CM-H) J= 1.5 Hz,]H, =CW-H) J= 3.4 Hz, U, H]!) J=2.4,4.2 Hz,]H, M7) J=4.6 HZ, 2H, CH 2 OH) U, 0M9) (m, 2H, M31 e M5-1) 4.08 (s, 3H, OCH 3) 3.68 (dd, J = 1.7, 8.1 HZ,1H, H4' 3.29 (dds J= 1.5, 19.1 Hz,AH, M10eq) 3.03 (d, i = 19.1 Hz, 1H, H10ax) 414 (aglycone); 218 f 2.99 (t, J= 4.6 Hz, 1H, CH ON) 2 2.34 (ddds J=1.59 2,4,-15.2 Hz, 1H, N8eq) 2.18 (ddg J= 4.2. 15.2Hz.]H, W8ax) 19.7 (d, J= 8.1 Hz 1H OH41) 2H, CH2c21 1.30 (d, J=6.6 Hz, 3H, CH 3- 5 ) EXAMPLE-7 Heacryloyledoxorubicin Formula A (R 1 =OCH 39 R 2= R 4= OH; R 3=R5 =H) Following the procedure described in Example 6, 200 mg of doxorubicin hydrochloride were treated with and 165 mg of give, after chromatographic 72 mg of acrylic acid N,N'-dicyclo-hexylcarbodiimide, to separation, 96 N-acryloyl-doxorubicin.
U.V. /k max (CH OH) 496 (11382 . 3 251 (26223); 233 (39642).
FAB-MS: m/z 598, M + + 414 (agl'ycone); 184 (acilated sugar).
PMR (200 MHz, CDC] 3 13.98 (s,]H, ONe6); 13.25 (s,]H, 0Well) 8.04 (d; J= 7.6 Hz,]H, H]) 7.79 (dd, J 7.6, 8.4 Hz,]H, H2) 7.39 (d, 1 8.4 Hz. 1H, H3) ): ppm mg of pure i - 6.80 (d, J = 8.4 Hz,]H, NUCO) 6.46 (dd, 1H, -CM=CH 2) 6.19 (dds 1H, -CH=CH 2) 5.60 Idd, 1H,.-CH=CH 2); 5.52 (d, J = 3.4 Hz,]H, M11) 5.30 (dd, J=2.49 4.2 Hz,1H, M7) 4.76 (d, J=4.6 Hz,2H, CH 20H) 4.51 (S,]H, ON9) 4.2-4.1 (m, 2H, WVe W5t) 4.08 (s, 3H, OCH 3) 3.68 (dd, J= 1.7, 8A Hz,1H, H41 3.29 (dd, J= 1.5, 19.1 Hz, 1H, W10eq) 3.03 (d, J= 19.1 Hz, 1H, H10ax) 2.99 (t, J= 4.6 Hz,]H, CH 20N) 2.34 (ddd, J= 1.5, 2.4, 15.2 Hz,]H, H8eq) 2.18 (dd, J=4.2, 15.2 Hz,]H, H8ax) 19.7 (d, J= 8.1 Hz, M, 0H41) 1.9-1.8 (m,ZH, CH--21) 1.30 (d, J=6.6 Hz,3H, CW 3- s').
1

Claims (10)

  1. WHAT WE CLAIM IS
    An anthracycline glycoside having the formula (A) 0 CH 0 R 2 0 0 CH 3 R3 --? R 4 NH CH 2 0 R A wherein R 1 represents a hydrogen atom or a methoxy group; R 2 represents a hydrogen atom or a hydroxy group; one of R 3 and R 4 represents a hydrogen atom, the other of R 3 and R 4 represents a hydrogen atom or a hydroxy group; R 5 represents a hydrogen atom, a halogen atom, a cyano or a nitro group.
  2. 2) A compound according to claim 1, which is N-(rL-bromoacryloyl)daunorubicin.
  3. 3) A compound according to claim 1. which is N-( d,-bromoacryloyl)-41-epidaunorubicin.
  4. if %C_. 1 4) A compound according to claim 19 which Is 4-demethoxy-N- ( G - bromoacrylOY1)-daunorubicin.
  5. 5) A compound according to claim 1, which is N-( Q -bro.moacryloyl)doxorubfcln.
  6. 6) A compound according to claim 19 which Is N-( C -bromoacryloyl)-49-epidoxorubicin.
  7. 7) A compound according to claim 1 which is N-('Y--chloroacryloyl)doxorubicin.
  8. 8) A compound according to claim 1, which is N-acryloyl -doxorubicin.
  9. 9) A process for preparing a glycosidic compound of general formula (A) as defined In claim 1, characterized in that an anthracycline glycoside of general formula (B).
    0 CH 0 "2 CH 0 F.
    2 R E 0 wherein Rj. R 21 R 3 and R 4 have the meaningsas defined In claim 1. dissolved in an organic solvent such as pyridine) dimethylsulphoxide, dimethylacetamide. tetrahydrofurane acetone or acetonitrile, is reacted at a temperature of -101C to 401C and from a period of from about 2 hours to hours, with a compound of formula (C):
    CH C-X % U C wherein R 5 is as above defined and X is a halogen atom, preferably a chlorine atom, a -0-C-C(CH 3)31 0 #1 3 2 0 clorophenoxy group, 2,4-dinitrophenoxy, succini-' mido-N-oxy-, an imidazoly] group, in the presence of an organic base such as triethylamine to give a compound of formula (A) as defined above which is eventually purified by methods known in the art.
  10. 10) A process for preparing a glycosidic compound of general formula (A) as defined in claim 1, h characterized in that an anthracycline glycoside of formula (B) as defined in claim 9, dissolved in an organic solvent such as dimethylformamide, dimethylsulphoxides hexamethylphosphotriamideg acetone, tetrahydrofuran is reacted at a temperature of from -100C to 500C and for 1 to 2 hours, with a compound of formula (C):
    CH 2 >---ii-x C R5 0 wherein R 5 is as defined above and X is a hydroxy group, in the presence of an organic base such as triethylamine and of a condensing agent such as N,N'-dicyclohexyl)carbodiimide or N-ethy]-N'-(3-dimethylaminopropyl)carbodlimide, to give the desired compound of formula (A) which is eventual ly purified by methods known in the art.
    Published 1991 atThe Patent Office. State House. 66171 HighHolborn, London WC1R47P. Further copies- M.y be obtained from The Patent Office. Sales Branch. St Mary Cray, Orpington. Kent BR5 3RD. Printed by Multiplex technique& ltd. St Y ray. Kent Con. 1187
GB8914947A 1989-06-29 1989-06-29 N-acryloyl anthracycline glycosides Expired - Fee Related GB2233326B (en)

Priority Applications (4)

Application Number Priority Date Filing Date Title
GB8914947A GB2233326B (en) 1989-06-29 1989-06-29 N-acryloyl anthracycline glycosides
JP2166556A JPH0338595A (en) 1989-06-29 1990-06-25 N-acryloyl-anthracyclin glycoside
DE4020332A DE4020332A1 (en) 1989-06-29 1990-06-26 N-ACRYLOYLANTHRACYCLINGLYCOSIDE
IT02077490A IT1249003B (en) 1989-06-29 1990-06-26 ANTHRACYCLINIC N-ACRILOIL GLYCOSIDES

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GB8914947A GB2233326B (en) 1989-06-29 1989-06-29 N-acryloyl anthracycline glycosides

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GB8914947D0 GB8914947D0 (en) 1989-08-23
GB2233326A true GB2233326A (en) 1991-01-09
GB2233326B GB2233326B (en) 1993-02-03

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0136938A2 (en) * 1983-09-05 1985-04-10 Etablissement Public dit: CENTRE NATIONAL DE LA RECHERCHE SCIENTIFIQUE (CNRS) Derivatives of furanes, their preparation and application

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0136938A2 (en) * 1983-09-05 1985-04-10 Etablissement Public dit: CENTRE NATIONAL DE LA RECHERCHE SCIENTIFIQUE (CNRS) Derivatives of furanes, their preparation and application

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IT9020774A1 (en) 1991-12-26
DE4020332A1 (en) 1991-01-10
IT1249003B (en) 1995-02-11
JPH0338595A (en) 1991-02-19
IT9020774A0 (en) 1990-06-26
GB8914947D0 (en) 1989-08-23
GB2233326B (en) 1993-02-03

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