DK150518B - Analogy process for preparing adriamycin derivatives - Google Patents

Description

The present invention relates to an analogous process for the preparation of novel antitumor glycosides belonging to the anthracycline series. Specifically, the glycosides having the general formula set forth in the preamble of the claim are such adriamycin derivatives in which a 3-amino-2,3,6-trideoxy-4-O-methyl-L-hexopyranose is glycosidically linked to adriamycin of the formula:! f 9 c-ch2oh

15 f yr JC JC X0E

DCH- 0 OH i * OH

The two compounds mentioned in the characterizing part of the formula of the formula - i.e. compounds V and VII - are obtained by condensation of daunomycinone with protected 1-halogen derivatives of aminodeoxy sugars, namely 2,3,6-trideoxy-3-trifluoroacetamido-4-O-methyl-L-lyxo-hexo-pyranosyl chloride II-E and 2 3,6-Trideoxy-3-trifluoroacetamido-4-O-methyl-Cfc-L-arabinohexopyranosyl chloride III

H3C / ^ 0-7 HjC ^ oJ

H3 C0 per -5 HH

oo éo 30 · 1 cf3 cf3 (ii-e) (III-E) to give the protected glycosides IV, respectively VI: 150518 2

* '0H

5 AND, 0 OH; * 0 vpZJ f 10 H3c P "'if. 1 -.- 0-0¾

V in R * - H

O OH yeah

00¾ 0 OH I

0 20 H ^ CT ^ -O -y VI 1 E * - -C-CF,

H, CO ^ JTW

3 11511 VII lE '. H

of which, by removing the protecting group, compounds V and VII are obtained.

25

The procedure. The invention is characterized in that the compounds V and VII respectively are converted into the 14-bromo derivative, which by hydrolysis gives the compounds VIII and IX respectively.

30

The condensation reaction between daunomycinone and the protected halogen sugars II-E and III-E, during which the glycoside bond is formed, is carried out in a suitable organic solvent, such as chloroform or methylene chloride, in the presence of a soluble silver salt as a catalyst such as silver trifluoride, such as silver trifluoride and molecular sieve as dehydrating agent, in accordance with the process described in GB patent 5,500,200.

The compounds methyl-2,3,6-trideoxy-3-trifluoroacetamido-oC-L-lyxo-hexopyranoside II-A and methyl-2,3,6-trideoxy-3-trifluoroacetamido-α-L-arabino -hexopyranoside III-A is described in GB patent no.

i · 457 · 559 · 0ch3 AND

VT '· 0' / h3 ° T ^ o-7 3 t ^ -SS-CT, S0 HE-CO-CF, RO i 3

15 ΙΙ-Α »E« Η ΙΙΙ-Α »H - H

Il-Βι R - CH3 III-Bi H. CH3 s3oo ra-oo-OPj 3 mi-cSlcr3

110 IIIO

h3c -y11 »0B h3c o ^» or 25 Li ---- J H, C0 ^ W

H3C0 nh-C0 ~ CF3 * NH-C0-CF3

II-D III-D

o wherein R

The treatment of compounds II-A and ΙΙΙ-Α, respectively, with diazomethane boron trifluoride etherate in methylene di-chloride (as described by J. O. Deferrari et al. I

Methods in Carbohydrate Chemistry, vol. VI, p. 365, 1972, Academic Press, New York and London) give the corresponding, previously unknown 4-O-methyl derivatives 5 II-B and III-B, respectively, in good yield. Acid hydrolysis gives the corresponding compounds II-C and III-C, respectively, which contain the free OH group at position 1, which are reacted with p-nitrobenzoyl chloride in pyridine; thereby obtaining the corresponding 10 1-O-p-nitrobenzoyl derivatives II-D and III-D, respectively, which upon treatment with dry hydrogen chloride in anhydrous methylene chloride give the corresponding 1-chloro derivatives II-E and III-E, respectively.

Preparation of Compounds V and VII, respectively

is initiated with coupling of daunomycinone αΛαλ ^ 1 I I "0Ϊ 20

OCH 2 O OH

as representative of the anthracyclinotype 25 reactants with 2,3,6-trideoxy-4-O-methyl-3-trifluoroacetamido-L-lyxo-hexopyranosyl chloride II-E and 2,3,6-trideoxy-4-O-methyl-3, respectively -trifluoroacetamido-e6-L-arabino-hexopyranosylchloride III-E as halogen sugar reagents. The coupling reaction gives the protected glycosides 30 IV and VI, respectively, from which, by mild alkaline treatment to remove the N-trifluoroacetyl group, 4'-O-methyldaunomycin V and 4'-epi-4'-O-methyldaunomyoin VII are isolated as hydrochlorides. Subsequently, compounds V, 5 and 5, respectively, are converted by the pathway indicated above to 4'-O-methyladriamycin VIII and 4'-epi-4'-O-methyladriamycin IX, respectively, using the U.S. Pat.

3,803,124 discloses the process described in a modified version to a certain extent, which modified method is set forth in Example 1.

'I I jH

IV * R- H * R '- COPP3

V | S.R <> R

VIII in R - OH, R '* II

H3CO NHB '

20 OH

COCH2R

^ I I j% <* 25 4ot3 6 X Η> <Ό VI «R- H'R * * COPP3

VIII R - R * - H

IX * R - OH, R '- H

? 3C7 ^ 0-7 30 ».CO 4 ^ T ^ J

30 J NHR '

The new compounds VIII and IX show antimitotic activity and are valuable therapeutic agents for the treatment of test tumors in animals.

The compounds have been tested on BDFi mice (C57BL / 6xDBA) in which i.p. was injected 105 cells / mice of L1210 ascitic leukemia. The treatment was carried out i.p. on day 1 after tumor inoculation; the substances were dissolved in distilled water as hydrochlorides.

The Adriamycin derivatives were tested against LI210 leukemia and not against P388 because P388 leukemia is too sensitive to adriamycin and therefore it is very difficult to assess the superiority of the new derivatives.

The data shown in Table 1 shows that in two separate experiments 4'-O-methyladriamycin was more active than adriamycin: at a dose of 4.4 and 6.6 mg / kg, this new derivative caused a lifetime increase of 130 to 212%, while at the optimal (non-toxic) dose of 6.6 mg / kg, adriamycin caused a lifetime increase of 75%.

This higher activity of 4'-O-methyladriamycin, as compared to adriamycin, against L1210 leukemia is particularly relevant. 41-epi-4'-O-methyladriamycin showed an antitumor activity of the same magnitude as adriamycin and a reduced toxicity.

Thus, the data presented herein show that substitution of the hydroxy group: in the 4-position of the amino sugar with a methoxy group produces a sharp increase in the antitumor activity epimerization of the 4 'substituent causes a reduction of the general toxicity, as shown in mice with tumors. .

TABLE X - Activity against L1210 leukemia

Compound Dose *> τ / C% in Tox 5 (mg / kg) 1st trial 2nd trial deaths / total

Adriamycin 4.4 169 10 6.6 175 175 10.0 187 187 3/20 4'-O-methyladri-4.4 2B7 312 amycin.HCl 6.6 231 275 1/20 15 (VIII) 10.0 75 62 17/18 41-epi-4'-O-me- 6.6. 169 thyladriamycin 10.0 187. HCl (IX) 15.0 181 2/10 20 22.5 87 9/10 *).

'Mean survival time of treated animals divided by mean survival time of control animals, x 100.

Example 1: 4'-O-methyladriamycin VIII (IMI 80).

A solution of compound V in a mixture of methanol and dioxane was treated with bromine to give the corresponding 14-bromine derivative. Following treatment with an aqueous sodium formate solution at room temperature for 4 days, 4'-O-methyladriamycin VIII, isolated as hydrochloride, was obtained, m.p. 177 ° C (decomp.), [T <] 33 = + 259 ° (c = 0.046 in CH 3 OH).

EXAMPLE 2: 4'-epi-4'-O-methyladriamycin IX (IMI

150518 δ 1 79).

The hydroxylation of compound VII via the 14-bromo derivative was achieved using the procedure described in Example 15. In this process, 4'-epi-4'-O-methyladriamycin IX was obtained as hydrochloride in the form of orange red crystals, m.p. 170 ° C (decomp.), [° G 33 = 0252 ° (c = 0.052 in CH 3 OH).