GB2218087A - 4-Demethoxy-4'-deoxy-4' iodo anthracycline glycosides - Google Patents

4-Demethoxy-4'-deoxy-4' iodo anthracycline glycosides Download PDF

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GB2218087A
GB2218087A GB8809615A GB8809615A GB2218087A GB 2218087 A GB2218087 A GB 2218087A GB 8809615 A GB8809615 A GB 8809615A GB 8809615 A GB8809615 A GB 8809615A GB 2218087 A GB2218087 A GB 2218087A
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formula
pharmaceutically acceptable
deoxy
acid addition
demethoxy
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GB2218087B (en
GB8809615D0 (en
Inventor
Antonino Suarato
Michele Caruso
Sergio Penco
Fernando Giuliani
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Pfizer Italia SRL
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Farmitalia Carlo Erba SRL
Carlo Erba SpA
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Priority to GB8809615A priority Critical patent/GB2218087B/en
Publication of GB8809615D0 publication Critical patent/GB8809615D0/en
Priority to DE3912867A priority patent/DE3912867A1/en
Priority to IT8920197A priority patent/IT1230065B/en
Priority to JP1101521A priority patent/JPH01311095A/en
Publication of GB2218087A publication Critical patent/GB2218087A/en
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D309/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings
    • C07D309/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
    • C07D309/08—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D309/14—Nitrogen atoms not forming part of a nitro radical
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

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  • Organic Chemistry (AREA)
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  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
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  • Chemical Kinetics & Catalysis (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
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  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
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Description

n el ' : A. 18087 Ir 11 -1FC 382 4-DEMETHOXY-4'-DEOXY-4'-IODO
ANTHRACYCLINE GLYCOSIDES This invention relates to anthracycline glycosides, to their preparation and to pharmaceutical compositions containing them.
41-Deoxy41-iododaunorubicin and -doxorubicin have already been described in US-A-4 438 105. However, the present invention provides 4-demethoxy-41deoxy-41-iodo anthracycline glycosides having the general formula I:
0 OH -0 R 0 0 OH C 4 0 OH CH 0 41 NH 2 1 wherein R 1 represents a hydrogen atom or a hydroxy group and pharmaceutically acceptable acid addition salts thereof. The preferred salts are the hydrochloride salts.
The glycoside in which R 1 is hydrogen, compound Ia, is 4-demethoxy-41deoxy-41-iodo-daunorubicin. The glycoside in which R 1 is hydroxy, compound 1b, is 4demethoxy-41-deoxy-41-iodo-doxorubicin.
These anthracycline g1cosides differ from those described in US-A-4 438 105 in that the aglycone moiety lacks a methoxy group in the C-4 position.
The invention also provides a process for the preparation of an anthracycline glycoside of formula I or pharmaceutically acceptable acid addition salt thereof, which process comprises:
(i) converting the 4'-epi-hydroxy group of 4 demethoxy-41-epi-Ntrifluoroacetyldaunorubicin of formula IV:
0 OH 0 0 0 OH 0 OH 6 CH 0 3- - --j -71 0 HO NHCOCF, IV into a 41-epi-0-trifluoromethanesulfonyl group to form thereby the 4'-epi41-0-trifluoromethane sulfonate derivative of formula V:
0 OH 0 CO)b kOH 0 0 OH CH 0 -0 T 0 W so 0 3 2 NHCOCF V 3 Q (ii) reacting the C-epi-41-0-trifluoromethane sulfonate derivative of formula V with an iodide salt to form thereby 4-demethoxy-4'-deoxy-41-iodo-Ntrifluoroacetyl-daunorubicin of formula VI:
0 OH 0 @0 0 OH 0 OH U CH 3 0 7 &"" 1 NHCOCF 3 VI (iii) removing the N-trifluoroacetyl protecting group from the 4demethoxy-41-deoxy-41-iodo-Ntrifluoroacetyl-daunorubicin to form thereby 4-demethoxy41-deoxy-41-iododaunorubicin; (iv) if desired, converting the 4-demethoxy-4'deoxy-41-iododaunor.ubicin into a pharmaceutically acceptable acid addition salt thereof; (v) if desired, brominating the 4-demethoxy41-deoxy-41-iododaunorubicin or pharmaceutically acceptable acid addition salt thereof and hydrolysing the 14-bromo derivative thus obtained so as to form 4-demethoxy-41deoxy- 41-iododoxorubicin; and (vi) if desired, converting the 4-demethoxy-41deoxy-41-iododoxorubicin into a pharmaceutically acceptable acid addition salt thereof.
The preparation of compounds Ia and b is shown in the Reaction Scheme below.
The starting material for the preparation of the new anthracycline glycosides is 4-demethoxy-41-epi-Ntrifluoroacetyl-daunorubicin (IV) [see A DiMarco et al. Cancer Treat Rep, 62, 375 (1978)1. The 41-epi-hydroxy group of this compound is typically converted to a 41-epi0trifluoromethanesulfonyl group by reacting compound IV with trifluoromethanesulfonic anhydride in the presence of an organic base.
Compound IV is preferably treated with trifluoromethanesulfonic anhydride in anhydrous methylene dichloride and in the presence of an organic base such as dry pyridine, for example at about 0 0 C, to give the corresponding 4'-epi-41-0-trifluoromethanesulfonate V in almost quan titative yield (GB-A-2 159 518).
Reaction of compound V with an iodine salt, generally in an aprotic solvent such as acetone, gives 4demethoxy-41-deoxy-41-iodo-Ntrifluoroacetyldaunorubicin (VI). Compound V need not be isolated for this purpose. Sodium iodide may be employed. Reaction may be for about 1 hour at about 30 0 C. Compound VI can be obtained after purification by chromatography on a silica-gel column, using methylene dichloride as eluent.
Mild alkaline hydrolysis of the N-protecting group of compound VI, for example by 0.1N aqueous sodium hydroxide, gives the 4-demethoxy-41-iodo derivative Ia.
W 1.
Compound Ia can be converted, if desired, to the hydrochloride salt by treatment with a methanolic solution of hydrogen chloride. The conversion of compound Ia to the corresponding doxorubicin analog Ib can be performed as described in US-A-3 803 124. The daunorubicin derivative Ia or salt thereof can be reacted as desired with a chloroform solution of bromine followed by treatment with aqueous sodium formate to convert the so-obtained 14-bromo derivative to compound Ib. This can be treated with a methanolic solution of hydrogen chloride so that it may be isolated as the hydrochloride.
The present invention also provides pharmaceutical compositions comprising a pharmaceutically acceptable carrier or diluent and, as active ingredient, an anthracycline glycoside of formula I or pharmaceutically acceptable acid addition salt thereof. Conventional carriers or diluents may be used. The composition may be formulated and administered in conventional manner.
The anthracycline glycosides of formula I and pharmaceutically acceptable acid addition salts-thereof are antitumour agents. They may be used to treat a patient with a tumour by administration of a therapeutically effective amount thereof. The compounds thereof can be used to inhibit the growth of a tumour.
The following Examples illustrate the invention.
Reaction Scheme H CH 0 CH NHCO CF3 IV NaI acetone 1 H (9 'OH 1 = 3 so 2)20 pyridine/CH 2 cl 2 0, c H 0 0 'OH H CH3- 400p 0 NHCO CF, V1 Ia Br 21 aa. ECOONa - ib 0 CF35010 NHCO CF3 v aq. O.IN NaOH 1 11 Example 1 Preparation of: 4-demethoxy-41-deoxy-41-iodo-dauntrubicin (Ia) (R l=H) To a stirred solution of 2.96 g (5 mmole) of 4-demethoxy4'-epi-N-trifluoroacetyldaunorubicin (IV) in 70 ml of anhydrous methylene dichloride and 3.2 ml of dry pyridine, cooled at OOC, was added over a period af 15 minutes a solution of 2 ml of trifluoromethansulfonic anhydride in ml of anhydrous methylene dichloride. The organic phase was washed with a cooled 5% aqueous solution of sodium hydrogen carbonate, water, a 0.1N aqueous solution of hydrochloric acid and water in that order. The organic solution, containing the 4'-epi-41-0-trifluoromethane derivative IV, dried over anhydrous sodium sulphate, was filtered off and the solvent removed in vacuo.
TLC on Kieselgel plates (Merck F 254), using the system: methylentdichlaride / acetone (95: 5 by volume) Rf=0.60.
Compound IV was dissolved in 100 ml of acetone, added with 3 g of sodium iodide and kept at 300C for one hour under stirring. After that the mixture was poured in water and extracted with methylene dichloride, dried over anhydrous sodium sulphate, concentrated to small volume under vacum and chromatographed on a column of silica gel eluting with methylene dichloride to obtain 2.5 g of pure 4-demethoxy-41-deoxy...4'iodo-N-trifluoroacetyl-daunorubicin (V) - TLC on Kieselgel plates (Merck F 254) using the system methylene dichloride / acetone (95: 5 by volume) Rf=0.7.
F= EMt] 699. PMR (200 MHz, CDC1 3 J 13.55 (S, 1H, CH-6); 13.26 (s, 1H, OH-11); 8.27 (m, 2H, H-1 and H-4); 7.9- 7.8 (m, 2H, H-2 and H-3); 6.37 (d, j=8.1 Hz, 1H, NH); 5.49 (bd, j03.9 Hz, 1H, H-11); 5.22.(dd, j=4.2, 2.0 8 t Ez, 1H, M-7); 4.64 (m, 1H, H-41); 4.22 (s, 3H, ocH 3); 3.50 (dq, j=6.2, 1. 5 Ez, 1H, M-5'); 3.23 (dd, j=19.2, 1.7 Hz, 1H, ff-10eq); 2.94 (d, j=19.2 Hz, 1H, H-10ax); 2.42 (s, 3H, COCH 3); 2.34 (ddd, j=15.0, 2.0, 1.7 Hz, 1H, 11-8eq); 2.16 (bdd, j=15.0, 4.2 Hz, 1H, 11-8ax); 2.06 (td, j=13.3, 3.9 Hz, 1H, R-21ax); 1.88 (dd, J=13.3, 4.8 Hz, 1H, H-21eq); 1.28 (d, j=6.2 Ez, 3H, CH 3 CH).
To a solution of V in 20 ml of acetone, 150 mI of 0.1N aqueous sodium hydroxide solution was-added. After 2 hours at 0 C, the solution was adjusted to pH 8.6 with O.IN hydrochloric acid and extracted with methylene dichloride. The solvent was evaporated off, affording a residue that was converted by treatment with methanclic hydrogen chloride into the-hydrochloride of compound Ia, 1.7 g yield 61% TLC on Kieselgel plates (Merck F 254) using the solvent system methylene dichloride/methancl/acetic acid/water (30: 4: 1: 0.5 by volume) Rf=0.48. F= (Mt] 703 Example 2 Preparation of: 4-demethoxy-41-deoxy 4'-iododoxorubicin (Ib) (RI=OH) 1.3 g of 4-demethoxy-4'-deaxy-41-iododaunorubicin (Ia), prepared as described in Example 1, was dissolved in a mixture of methanol and dioxan. The solution was treated, as described in US Patent Specification No. 3, 803,124, first with bromine to give the 14-bromo-derivative-and then with aqueous sodium formate to give 4-demethoxy-41-deaxy-41-iododoxorubicin (Ib). This was converted into its hydrochloride by treatment with methanolic hydrogen chloride.
TLC on Kieselgel plates (Merck F 254) using the solvent system methylene dichloride/methanol/acetic acid/water (30: 4: 1: 0.5 by volume) Rf=0.36.
L -0m 1 0 F= W1 623 PMR (200 MHz, CDC1 3) 8.3-8.2 (m, 2H, -H-1 and H-4); 7.9-7.8 (m, 2H, H-2 and 5.43 (bd, j=3.2 Hz, 1E, H-11); 5.23 (dd, j=4.0, 2.2 Hz, lK, H-7); 4.73 (s, 2H, CH20,1); 4.48 (m, 1H, 11-4'); 3.36(bq, j=6.2 Hz, 1H, l[-51); 3.23 (dd, j=19.0, 1.4 Hz, 1H,11-10eq); 2.99 (d, j=19.0 Hz, 1H, H-10ax); 2.34 (ddd, j=14.5, 2.2, 1.4 Hz, 1H, H- 8eq); 2.14 (dd, j=14.5, 4.0 Hz, 1H, H-2ax); 2.2-2.1 (m, 1H, H-3'); 13-1.7 (m, 2H, CH 1); 1.31 (d, j=6.2 Hz, 3H, CH3CH).
-2 - 10 Biological Activitv The biological activity of compound lb was tested against several Cell Lines in vitro:
TABLE 1 Cytotoxicity of compound lb on different Tumor Cell Lines Cell Lines Hela (a) P388 (b) P388/Dx(c) ID (ng/ml) coso mpound lb 4.7 1.8 11.4 ID (ng/ml) do12rubicin 18 10.7 2050 (a) 24 hours treatment (b) 48 hours treatment (c) P388/doxorubicin resistent cell line; 48 hours treatment The activity of compound lb was also tested against several murine leukemias, by ip, iv and oral route.
Table 2 Antitumor activity against murine Leukemias (a) - (compound 'Ib) (b) (doxorubicin) (b) Tumor Treatment Dose(mg/Kg) T/C Dose(mg/Kg) T/C P388ip ip+1 6.6 265 10 265 P388/Dxiv iv+1 4.4 100 13 95 L1210iv iv+1 4.4 125 13 113 Grossiv iv+1 4.4 208 16.9 229 Grossiv os+l 6.6 192 -- -- (a) Experiments carried out on mice BDF 1 or CDF 1 injected ip or iv with 10 6 leukemic cells. (b) median survival time of treated mice/median survival time of controls x 100.
11 c n TABLE 3
ANTITUMOR ACTIVITY AGAINST P388/DX LEUKEMIA (a)_ (ip + 1) Compo 1 und optimal dose (b) T/C (c) (mg/kg) % ------------------------------------------ 1 ---------------------------------------- DNR 6.6 94 41-J-DNR 10 200 Ia (4dm-4'-J-DNR) 4.2 240 DX 10 100 41-J-DX 5.3 182 Ib (4dm-41-JDX) 6.6 220 a) Experiments were performed in BDF I or CDF I mice inoculated with 10 6 leukemia cells i.p.
b) Treatment i - p. on Day 1 a f ter tumor inoculum c) Median survival time of treated mice/median survival time of controls x 100

Claims (7)

  1. C L A I M S
    An anthracycline glycoside having the general formula I:
    0 OH 04 Q.
    0 OH 0 OH 1 0 CH 3 0 4'7 NH 2 0 R 1 I wherein R, represents a hydrogen atom or a hydroxy groupf and their pharmaceutically acceptable acid addition salts.
  2. 2. An anthracycline glycoside according to claim 1, which is 4-demethoxy41-deoxy-41-iododaunorubicin or its hydrochloride.
  3. 3. An anthracycline glycoside according to claim 1, which is 4-demethoxy41-deoxy-41-iododoxorubicin or its hydrochloride.
  4. 4. A process for the preparation of an anthracycline glycoside of formula I as defined in claim 1 or a pharmaceutically acceptable acid addition salt thereof, which process comprises:
    (i) converting the 4'-epi-hydroxy group of 4demethoxy-41-epi-Ntrifluoroacetyldaunorubicin of formula IV:
    11 9 0 OH 0 0 OH 0 OH JCH 3 0 3 NHCOCF IV into a 41-epi-0-trifluoromethanesulfonyl group to form thereby the V-epi41-0-trifluoromethane sulfonate derivative of formula V:
    0 OH 0 1 OH 1 0 0 11 0 OH 0 CH 3 0 W SO 0 3 2 NHCOCF,, V (ii) reacting the 41-epi-41-0-trifluoromethane sulfonate derivative of formula V with an iodide salt to form thereby 4-demethoxy-41-deoxy-41iodo-Ntrifluoroacetyl-daunorubicin of formula VI:
    0 0 OH OH 0 0 UH 0 CH 3 0 711--) j NHCOCF 3 vi (iii) removing the N-trifluoroacetyl protecting group from the 4demethoxy-41-deoxy-41-iodo-N trifluoroacetyl-daunorubicin to form thereby 4-demethoxy41-deoxy-41-iododaunorubicin; (iv) if desired, converting the 4-demethoxy-4'deoxy-41-iododaunorubicin into a pharmaceutically acceptable acid addition salt thereof; (v) if desired, brominating the 4-demethoxy41-deoxv-41-iododaunorubicin or pharmaceutically acceptable acid addition salt thereof and hydrolysing the 14-bromo derivative thus obtained so as to form 4-demethoxy-41deoxy- 41-iododoxorubicin; and (vi) if desired, converting the 4-demethoxy-41deoxy-41-iododoxorubicin into a pharmaceutically acceptable ac. id addition salt thereof.
  5. 5. A pharmaceutical composition comprising a pharmaceutically acceptale carrier or diluent and, as active ingredient, an anthracycline glycoside of formula I as defined in claim 1 or a pharmaceutically acceptable acid addition salt thereof.
  6. 6. An anthracycline glycos.ide of formula I as defined in claim 1 or a pharmaceutically acceptable acid addition salt thereof for use as an antitumour agent.
  7. 7. A process for the preparation of an anthracycline glycoside of formula I as defined in claim 1 or a pharmaceutically acceptable acid addition salt thereof, said process being substantially as hereinbefore described in Example 1 or 2.
    Published 1989atThePat-ent Office, S=e House. 66-7 1 High Hj!-Iar--. LcndonWCIR4TP. Further copies maybe obtained from The Patent Office. Sales Branch, St Mary Cray. Orpington. Kent BR5 3RD- Printed by Multiplex techniques Itd. St Mary Cray, Kent. Con. 1/87 1
GB8809615A 1988-04-22 1988-04-22 4-demethoxy-4'-deoxy-4'iodo anthracycline glycosides Expired - Fee Related GB2218087B (en)

Priority Applications (4)

Application Number Priority Date Filing Date Title
GB8809615A GB2218087B (en) 1988-04-22 1988-04-22 4-demethoxy-4'-deoxy-4'iodo anthracycline glycosides
DE3912867A DE3912867A1 (en) 1988-04-22 1989-04-19 4-DESMETHOXY-4'-DESOXY-4'-JODOANTHRACYCLINGLYCOSIDE AND METHOD FOR THE PRODUCTION THEREOF
IT8920197A IT1230065B (en) 1988-04-22 1989-04-19 4-DEMETOSSI-4'-DESOSSI-4'-IODO GLYCOSIDES OF ANTHRACYCLINE
JP1101521A JPH01311095A (en) 1988-04-22 1989-04-20 4-demethoxy-4'-deoxy-4'-iodoanthracycline glycoside

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GB8809615A GB2218087B (en) 1988-04-22 1988-04-22 4-demethoxy-4'-deoxy-4'iodo anthracycline glycosides

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GB8809615D0 GB8809615D0 (en) 1988-05-25
GB2218087A true GB2218087A (en) 1989-11-08
GB2218087B GB2218087B (en) 1991-01-30

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB9418260D0 (en) * 1994-09-09 1994-10-26 Erba Carlo Spa Anthracycline derivatives

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB2118540A (en) * 1982-04-19 1983-11-02 Erba Farmitalia Anthracycline glycosides
GB2169286A (en) * 1985-01-05 1986-07-09 Erba Farmitalia 4'-Deoxy-4'-halodoxorubicin-14-esters

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3803124A (en) * 1968-04-12 1974-04-09 Farmaceutici It Soc Process for the preparation of adriamycin and adriamycinone and adriamycin derivatives
GB8321676D0 (en) * 1983-08-11 1983-09-14 Erba Farmitalia 4'-haloanthrocycline glycosides

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB2118540A (en) * 1982-04-19 1983-11-02 Erba Farmitalia Anthracycline glycosides
GB2169286A (en) * 1985-01-05 1986-07-09 Erba Farmitalia 4'-Deoxy-4'-halodoxorubicin-14-esters

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
02 *
Dictionary of Antibiotic *

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GB2218087B (en) 1991-01-30
JPH01311095A (en) 1989-12-15
IT8920197A0 (en) 1989-04-19
GB8809615D0 (en) 1988-05-25
DE3912867A1 (en) 1989-11-02
IT1230065B (en) 1991-09-27

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