FR2554450A1 - 4'-HALO-ANTHRACYCLINE GLYCOSIDES, PROCESS FOR THEIR PREPARATION AND THEIR USE AS A MEDICINAL PRODUCT - Google Patents

Abstract

4-HALO-ANTHRACYCLINE GLYCOSIDES, PROCESS FOR THE PREPARATION AND THEIR USE AS A MEDICINAL PRODUCT: (CF DRAWING IN BOPI) THESE COMPOUNDS HAVING THE ABOVE FORMULA (XH OR OH, RH, OH OR OCH, R BR, CL OR F) AND THEIR ACID ADDITIONAL SALTS ARE USEFUL AS ANTITUMOR AGENTS; THOSE IN WHICH XH ARE PREPARED BY AN EXCHANGE REACTION BETWEEN 4-EPI-4-O-TRIFLUOROMETHANESULFONYL-N-PROTEGE-DAUNORUBICIN (OR A CORRESPONDING 4-DEMETHYL OR 4-DEMETHOXY DERIVATIVE) AND (CH) NCL OR (CH) ) NBR OR CF; THOSE IN WHICH X OH ARE PREPARED FROM THE PREVIOUS BY BROMATION AND REACTION WITH AQUEOUS SODIUM FORMIATE.

Description

255445O

  The invention relates to 4'-halo-anthracycline glycosides, to a process for their preparation and

  to pharmaceutical compositions containing them.

  The invention makes it possible to obtain anthracycline glycosides having the general formula A

O OH

COCH 2X

Rl OH I!

O

A H, C

R I

2 2

  wherein X represents a hydrogen atom or a hydroxy group, R1 represents a hydrogen atom or a group

  hydroxy or a methoxy group, R2 represents a broach atom

  me, chlorine or fluorine. Acid-pharma-acid addition salts

  of these anthracycline glycosides

  are also included within the scope of the invention.

  The compounds of the invention in which X represents a hydrogen atom can be prepared by an exchange reaction between a compound of general formula

  2 in which R 1 and as defined above and R 3 represents.

  a group protecting an amino, and a fluoride, a

  chloride or bromide, followed by the deletion of the

  in the resulting compound of general formula 3. This

  The process is illustrated by the following reaction scheme.

  The compounds of the invention in which X represents a hydroxy group can be prepared from the compounds

  corresponding to the invention in which X is

  has a hydrogen atom by a bromination operation followed by the treatment of the resulting 14-bromo derivative with aqueous sodium formate according to the method described in US Pat. No. 3,803,124.

also in the context of the invention.

\ \ O OH COCH3

OH

Ri OH | I

R O 2OH

i C 3 7 "- one '

CF 3 SO2O_

1 5 hHR3

O | OH

X C O C HOC3

"

OO

A (H) C

30

NHR

A (X = H)

  When R2 represents a bromine or chlorine atom, the exchange reaction is preferably carried out between compound 2 and tetra (n-butyl) ammonium chloride or bromide respectively, and the R3 group protecting amine preferably a trifluoroacetyl group. The deprotection reaction can be a mild alkaline hydrolysis, for example with 0.1 N aqueous sodium hydroxide solution. When R2 represents a fluorine atom, the exchange reaction is preferably carried out between

  compound 2 and cesium fluoride, and the R3 group

  amine compound is preferably a trichloroethoxycar-

  bonyle. The deprotection reaction can then be hydrogenation, for example with zinc powder and acetic acid. The exchange reaction can be accomplished in an organic solvent such as dichlo-

  Methylene or acetonitrile.

  Starting materials 2 are either

  known compounds, for example, 4'-epi-4'-O-trifluoromethanesulphonate.

  fonyl-N-trifluoroacetyl-daunorubicin (2: R1 = OCH3, R3 = COCF3: 2C see European Patent Application No. 8117618.1), or compounds easily prepared from known derivatives

  4'-epi-daunorubicin by reaction with trihydric anhydride

  fluoromethanesulphonic. The compounds of the invention and their pharmaceutically acceptable acidic salts thereof are useful anti-tumor agents. These new compounds of formula

  were used in the same way as the compounds

  (ie, daunorubicin and doxorubicin)

  in the treatment of various experimental murine tumors

  for example L1210, P388, P388 / 04 and the like. It has been observed during selective preliminary tests that these new compounds are in certain circumstances more

  assets than the related compounds. As a result,

  It also relates to a pharmaceutical composition comprising: - DTD: 3 With an anthracycline qcycosice according to the invention or a pharmaceutically acceptable acid addition salt thereof

  this compound in admixture with a pharmaceutical vehicle or diluent

ceutically acceptable.

TESTING BIOLOGICAL ACTIVITY

  The compounds of Examples 1, 2 and 3 were tested in vitro in comparison with daunorubicin (DNR)

  and doxorubicin (DX) against Hela cells,

  P388 sensitive and resistant to DX (P388 / DX). The re-

  The results are reported in Table 1 below. All new derivatives appear to be more cytotoxic than

  related compounds against Hela and P388 cells

  to DX. However, this increased cytotoxicity is much more pronounced if we consider the activity of these compounds

  against P388 / DX. Here, we can note with these derivatives an ac-

  100 to 250-fold increase in cytotoxicity compared with

  related drug. In vivo the compounds have been

  tried against three different experimental leukemias.

  The antitumor activity obtained against ascitic leukemia

  that P388 is reported in Table 2 below. The activity exhibited by the compounds of Example 3 is equal to that of DNR, while the other derivative of DNR, the compound of

  Example 1 has a markedly superior anti-tumor activity.

  than that of DNR. The compound of Example 2 at the maximum tolerated dose (4.15 mg / kg) has about the same activity

than DX.

  All new compounds show activity against P388 / DX leukemia, as mentioned on the

  Table 3, however, that DNR and DX have no effectiveness.

  The three new compounds were also tested after ad-

  Intravenous administration against Gross disseminated leukemia, the results are reported in Table 4 below. In this case the compound of Example 3 is as active as DNR, while the compound of Example 1 appears more active than the parent compound. The compound of the example

  2 shows about the same efficiency as DX. Two of these

  poses were also tested after oral administration and showed interesting activity however that DNR and DX

  are not active when administered orally.

Table 1

  Cytotoxic activity of the compounds of Examples 1, 3 and 2 ID50 (ng / ml) Compound Hela + P388 ++ P388 / DX ++

DNR 12.3 2.8 980

  Example 1 6.8 0.5 4 Example 3 5.8 2.4 8.8

DX 12.5 4.25 1250

Example 2 3 0.2 7

  + Colony inhibition test after 24 hours of exposure

  to drugs ++ Cytotoxicity evaluated after 48 hours exposure to drugs

  Figures from several tests.

Table 2

  Effect against Ascitic Leukemia P388a Dose Compound T / Cc LTSd Deaths by (mg / kg)% Toxicity

DNR 2.9 165.155 0/20 0/20

4.4 170.135 0/18 0/18

6.6 130.115 0/20 12/20

Example 1 2.9 145 0/10 0/10

4.4 160 0/10 0/10

6.6 195 0/10 0/10

280 3/10 0/10

Example 3 2.9 130 0/10 0/10

4,4 155 0/10 0/10

6.6 145 0/10 0/10

85 0/8 6/8

DX 4.4 215 0/10 0/10

6.6 235 0/10 0/10

10 335 4/10 0/10

Example 2 2.4 200 0/10 0/10

2,88 230 0/10 0/10

3.46 210 0/10 0/10

4.15 325 4/10 1/10

  The assays were run on CDF1 mice, inoculated

  ip route of 106 leukemic cells.

  b Treat the day 1 after inoculation of the tumor.

  c Median survival time of the treated mice / median time of

Survival of witnessesx 100.

  d Long-term survivors (> 60 days).

  e Evaluation based on autopsy findings.

Table 3

  Effect against ascites leukemia P388 / DX Compound dose T / Cc Deaths pa (mg / kg)% toxicity

DNR 4.4 91 0/10

6.6 87 0/10

Example 1 4.4 143 0/10

143 0/10

Example 3 6.6 148 148 0/10

122 3/10

DlX 6.6 108 1/20

117 1/20

Example 2 2.88 122 0/20

3.48 125 0/20

4.15 137 1/20

  Tests were run on inoculated BDF1 mice

ip of 106 cells.

  b Treatment by ip on day 1 after inoculation of the tumor. c Median survival time of the treated mice / median time of

survival of witnesses, x 100.

  d Evaluation based on autopsy findings.

Table 4

  Effect against leukemia of Gross Compound Admpt dose pathway T / Cc Deaths by administration (mg / kg)% toxicity DNR iv 10 142.138 2/18

183.185 1/18

22.5 217.92 9/18

Example 1 iv 10 217 0/10

150 6/9

22.5 100 9/9

Example 3 iv 6.6 185 0/10

10 115 7/10

77 10/10

oral 6.6 154 0/10

169 0/10

92 7/8

DX iv 10 183 0/10

13,225 0/10

16.9 242 0/10

Example 2 iv 4.05 233 0/10

, 27,258 0/10

6.85 242 3/10

Oral 4.05 114 0/10

, 27 157 0/10

  Tests were run on C3H mice, inoculated

  ip with 2x106 leukemic cells.

  b Treatment ip or oral on day 1 after inoculation

tumor.

  c Median survival time of the treated mice / median time of

survival of witnesses x 100.

  d Evaluation based on autopsy findings.

  We will now give several examples to

  As an illustration of the invention.

Example 1

  4'-deoxy-4'-bromodaunorubicin (A: X = H, R1 = OCH3, R2 = Br) 2 g of tetra (n-butyl) bromide were added

  ammonium to a solution of 4 g of 4'-epi-4'-O-trifluoromethane

  nesulfonyl-N-trifluoroacetyldaunorubicin (2: R1 = OCH3, R3 = COCF3) in 80 ml of anhydrous methylene dichloride. After

  1 hour at room temperature, the reaction mixture

  The mixture was washed with water and the organic phase was evaporated in vacuo. The residue has been purified

  on silica gel, using the mixture of methyl dichloride

  lene: acetone as eluent and gave 3.5 g of 4'-deoxy-4'-

  bromo-N-trifluoroacetyldaunorubicin, m.p. 130 C; FD, MS 685 (M +), TLC on Kielselgel plates (Merck F 254) using the solvent mixture methylene dichloride: acetone

  (10: 1 by volume) Rf 0.5. To a solution of 3 g of 4'-deoxy-

  4'-bromo-N-trifluoroacetyldaunorubicin in 20 ml of acetic acid

  160 ml of a 0.1 N aqueous solution of hy-

  sodium droxide. After 4 hours at 0 C, the

  pH of the solution at the value 8.6 with hydrochloric acid

  0.1 N and extracted with dichlo-

  methylene chloride. The solvent was removed by evaporation

  which resulted in a residue that was converted by treatment

  with methanolic hydrochloric acid

  drate (2.2 g, mp 180 C with decomposition, TLC on

  Kieselgel (Merck F 254) using the solvent mixture methylene dichloride: methanol: water: acetic acid (80:20:

7: 3 by volume) Rf 0.32.

Example 2

  4'-deoxy-4'-bromodoxorubicin (A: X = OH, R1 = OCH3, R2 = Br)

  2 g of 4'-deoxy-4'-bromodaunorubicin, pre-

  prepared as described in Example 1, were dissolved in a mixture of methanol and dioxane. The solution was treated, as described in US Patent No. 3803124,

  first with bromine to give the 14-bromo derivative and

  continued with aqueous sodium formate to give the 4'-

  -deoxy-4'-bromo-doxorubicin. This one has been converted into

  hydrochloride by treatment with hydrochloric acid

  than methanolic. m.p. 170 C (with decomposition), FD-MS

  605 (M), TLC on Kieselgel plates (Merck F 254) to help

  of the solvent mixture methylene dichloride: methanol: water:

  acetic acid (80: 20: 7: 3 by volume) RF 0.20.

Example 3

  4'-deoxy-4'-chlorodaunorubicin (A: X = H, R1 = OCH3, R2 = Cl)

  Treatment of 4'-epi-4'-O-trifluoro-

  methanesulfonyl-N-trifluoroacetyldaunorubicin (2, R1 = OCH3,

  R3 = COCF3) with tetra (n-butyl) ammonium chloride, followed by

  vi of the process described in Example 1, provided the 4'-deoxygenase

  4'-chlorodamorunubicin, m.p. 175 C with decomposition, FD-MS 545 (M), TLC on Kielselgel plates (Merck F 254)

  with the aid of the solvent mixture methylene dichloride: metha-

  water: water: acetic acid (80: 20: 7: 3 by volume) RF 0.32.

Example 4

  4'-deoxy-4'-chlorodoxorubicin (A: X = OH, R1 = OCH3, R2 = C1) In accordance with the method described in Example 2, 4'-deoxy-4'-chlorodamorunicin was converted to 4 4'-deoxy-4'-chlorodoxorubicin, isolated in the form of its hydrochloride; m.p. 180 C (dec.); FC mass spectrum

  561 [M +] TLC on Kielselgel plates (Merck F 254) to the aid of

  of the solvent mixture methylene chloride / methanol / water /

  acetic acid (80: 20: 7: 3 by volume). RF 0.2.

Example 5

  4'-deoxy-4'-fluorodaunorubicin (A: X = H, R1 = OCH3, R2 = F)

  To a stirred solution of 26 g of 4'-

  epi-N-trichloroethoxycarbonyldaunorubicin, described in US Patent No. 4345068, in 650 ml of anhydrous methylene dichloride and 32 ml of anhydrous pyridine, cooled to 0 ° C., was added a solution of 11 ml of

  trifluoromethanesulfonic acid in 140 ml of methylene dichloride.

  anhydrous thylene. The reaction mixture was washed with cooled 5% aqueous sodium bicarbonate solution, with water, with 0.1 N hydrochloric acid and with water, in that order. The organic solution, dried over anhydrous sodium sulfate, was used in the

  following, without further purification.

  A solution of 2 g of 4'-epi-4'-O-trifluorone

  romethanesulfonyl-N-trichloroethoxycarbonyldaunorubicin in

  ml of acetonitrile was treated with 0.5 g of

  rure of cesium. After 10 min at room temperature, the mixture was poured into water and extracted with methylene dichloride. The organic phase, dried over anhydrous sodium sulfate, was evaporated in vacuo to dryness. The residue, dissolved in 30 ml of ethanol, was treated with 4 ml of acetic acid and 0.2 g of zinc powder at 0 ° C. After 1 hour, the mixture was filtered through Celite was diluted in water and extracted with methylene dichloride. The crude product, obtained by evaporation in vacuo of the solvent, was purified by chromatography on a

  column of silica gel, using methylene dichloride

  as an eluent, and gave the 4'-deoxy-4'-fluorodaunoru

  pure bicine, isolated as its hydrochloride: FD-MS

  529 (M +), TLC on Kieselgel plates (Merck F 2.54) to the aid of

  of the solvent mixture methylene dichloride: methanol: water:

  acetic acid (80: 20: 7: 3 by volume). RF 0.32.

Example 6

  4'-deoxy-4'-fluorodoxorubicin (A: X = OH, R1 = OCH3, R2 = F) Following the procedure described in Example 2,

  4'-deoxy-4'-fluorodaunorubicin has been converted to 4'-

  -desoxy-4'-fluorodoxorubicin isolated in the form of its chlorine

rhydrate.

Claims (18)

  1. Anthracycline glycoside having the following general formula A: O OH COCH2X -H 0 O  o H3 o A 2 H2   wherein X represents a hydrogen atom or a hydroxy group, R1 represents a hydrogen atom or a hydroxyl group or a methoxy group, R2 represents an atom of   bromine, chlorine or fluorine, and pharma acid   of this compound.   2. 4'-deoxy-4'-bromodaunorubicin.   3. 4'-deoxy-4'-chlorodaunorubicin.   4. 4'-deoxy-4'-fluorodaunorubicin.   5. 4'-deoxy-4'-bromodoxorubicin.   6. 4'-deoxy-4'-chlorodoxorubicin.   7. 4'-deoxy-4'-fluorodoxorubicin.   Process for the preparation of an anthracycline glycoside having the following general formula A: COCH X o OH {i {I R1 O OH I I o A H3 O R2 H2   wherein X represents a hydrogen atom, R1 represents   R 1 represents a hydrogen atom or a hydroxyl group or a methoxy group, R 2 represents a bromine, chlorine or fluorine atom, characterized in that an exchange reaction is carried out between a compound having the following general formula 2: O OH COCH3 i I R1 0 OH I 0 2 CF3 SO 2   Wherein R is as defined above and R3 is an amino protecting group, and a fluoride, bromide or   iodide, and the protection in the resulting compound is removed.   both having the following general formula 3: 0 OH COCH3 R1 H 1 o H3C O   NHR3 wherein R1, R2 and R3 are as above. 9. Process according to claim 8, characterized   in that the fluoride is cesium fluoride.   10. Process according to claim 8, characterized   in that the bromide is tetra (n-butyl) ammonium bromide.   CI11. Process according to Claim 8, characterized   in that the chloride is tetra (n-butyl) chloride ammonium.   12. Process according to any one of the claims   8 to 11, characterized in that the protecting group   the amine is the trichloroethoxycarbonyl group.   13. The method of claim 12 characterized in that the suppression reaction of the protection is a hydrogenation reaction.   14. Process according to any one of the claims   12, 13 characterized in that the suppression of the protection is carried out using zinc powder and of acetic acid.   15. Process according to any one of the claims   8 to 11, characterized in that the protecting group   the amine is a trifluoroacetyl group.   16. The method of claim 15 characterized in that the suppression reaction of the protection is a mild alkaline hydrolysis.   17. Process according to any one of the claims   15, 16 characterized in that the removal of the protection is carried out using an aqueous solution 0.1 N sodium hydroxide.   18. Process according to any one of the claims   1 to 17, characterized in that the exchange reaction is   carried out in methylene dichloride or acetonitrile.   19. Process for the preparation of an anthracycline glycoside having the following general formula A: COCH2 X OH he I R1 OH i 03 0) o A H3 R2 H2   in which X represents a hydroxyl group, R1 represents a hydrogen atom or a hydroxyl group or a methoxy group, R2 represents a bromine, chlorine or fluorine atom, characterized in that it consists in reacting with bromine an anthracycline glycoside having the general formula A of claim 1 wherein R1 and R2 are as defined in claim 1 and X is hydrogen and the resulting 14-bromo derivative is treated; with an aqueous solution of formate sodium.   20. Pharmaceutical composition characterized in that it comprises an anthracycline glycoside according to one of   any of claims 1 to 7 or an addition salt   pharmaceutically acceptable amount of this compound in admixture with   a pharmaceutically acceptable carrier or diluent.