JPH01311095A - 4-demethoxy-4'-deoxy-4'-iodoanthracycline glycoside - Google Patents

Abstract

NEW MATERIAL: A compound of formula I (R₁ is H, hydroxy) or its salt.

EXAMPLE: 4-Demethoxy4'-deoxy-4'-iododaunorubicin.

USE: An antitumor agent.

PROCESS: First, the 4'-epi-hydroxy group of 4demethoxy-4'-epiN-trifluoroacetyl daunorubicin of formula II is converted into a 4'-epi-O-trifluoromethane sulfonyl group by being reacted with anhydrous trifluoromethane sulfonic acid preferably in anhydrous methylene dichloride in the presence of an organic base to obtain the 4'-epi-4'-O-triluoromethane sulfonate derivative of formula III. Next, the product is reacted with an iodide salt to produce 4'-demethoxy4'-deoxy-4'-iodo- Ntrifluoroacetyl-daunorubicin of formula IV, from which the N-trifluoroacetyl protective group is removed.

COPYRIGHT: (C)1989,JPO

Description

[Detailed description of the invention]

The present invention relates to anthracycline glycosides, their production and pharmaceutical compositions containing them. 4'-deoxy-41-iododaunorubicin and -
Doxorubicin has already been described in US-A-4438105. However, the present invention provides 4-demethoxy-4'-deoxy-4'-B having the general formula I: (wherein R1 represents a hydrogen atom or a hydroxyl group)
-Doanthracyclyl glycoside and its pharmaceutically acceptable acid addition salts are provided. The preferred salt is the hydrochloride. The glycoside in which R1 is hydrogen (compound 1a) is 4-demethoxy-4'-deoxy-4'-iodo-daunorubicin. Gly'cyto (compound 1b) in which R1 is anddo[1xy] is 4-demethoxy-4'-geoxy-4'-iotote: t-sorbitan. These anthracycline glycosides differ from LJS-A in that the aglycone moiety does not have a methoxy group at the C-4 position.
-4438105. The present invention further provides a method for producing an anthracycline glycoside of formula I or a pharmaceutically acceptable acid addition salt thereof, which method comprises (+) 4-demethoxy-4'-shrimp-N-tri The 41-epi-hydroxy group of fluoroacetyl daunorubicin is
-e and 10-trifluoromethanesulfonyl groups to produce a 4'-epi-4'-0-trifluoromethanesulfonate derivative of formula V: (ii) 42-epi-4'- of formula V; A 0-trifluoromethanesulfonate derivative is reacted with an iodide salt to form 4-demethoxy-4'-deoxy-4'-iodo-N of the formula ■:
-trifluoroacetyl-daunorubicin is produced (iii) 4-demethoxy-4'-deoxy-4''
-iodo-N=trifluoroacetyl-removal of the N-trifluoroacetyl protecting group from daunorubicin to produce 4-demethoxy-4'-deoxy-4'-iododoxorubicin, (iv) optionally 4-demethoxy- (V) optionally 4-demethoxy-4'-deoxy-
41-]-Dadaunorubicin or a pharmaceutically acceptable acid addition salt thereof is brominated, and the resulting 14-bromo derivative is hydrolyzed to give 4-demethoxy-41-deoxy-4'.
(vi) optionally converting 4-demethoxy-4'-deoxy-4'-iododoxorubicin into a pharmaceutically acceptable acid addition salt thereof. The production of compounds 1a and 1b is shown in the reaction scheme below. The starting material for preparing the novel anthracycline glycosides is 4-demethoxy-4'-shrimp-N-trifluoroacetyl-daunorubicin NV) (A
DiHarco et al, CancerTrea
t Rap, p. 62.375 (19711))
. The 4'-ebi-hydroxy group of this compound is typically converted to the 4'-ebi-trifluoromethanesulfonyl group by reacting compound (1) with trifluoromethanesulfonic anhydride in the presence of an organic base 1S. Preferably, compound 1 is treated with trifluoromethanesulfonic anhydride in anhydrous methylene dichloride in the presence of an organic base (e.g. dry pyridine) at, e.g. -Produces 〇-trifluoromethanesulfonate V with almost constant yield (GB-A
-2159518). Generally, the reaction of compound V with '3+-L, compound salt in an aprotic solvent (e.g. acetone) is
-cy4'-lafoxy-41-iodo-N-trino-o-aretyldaunorubicin (Vl) is given. Compound V does not need to be isolated for this purpose. Sodium iodide "cum" can be used. The reaction is about 3
The heating time can be about 1 hour at 0°C. Compound (1) 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 (1), for example with 0.1N aqueous sodium hydroxide, provides the 4-demethoxy-4'-iodo derivative 1a. Compound 1a can optionally be converted to the hydrochloride salt by treatment with a methanol solution of hydrogen chloride. Conversion of compound 1a to the corresponding doquinrubicin congener 1a can be carried out as described in US-A.-3803124k:2. Daunorubicin derivative 1
If desired, a or a salt thereof can be reacted with a chloroform solution of bromine and then treated with mAl1 aqueous sodium solution to convert the resulting 14-bromo derivative to compound 1b. This can be isolated as a hydrochloride salt by treatment with a methanol solution of hydrogen chloride. In general, the present invention also provides a pharmaceutical composition comprising a pharmaceutically acceptable carrier or diluent and an anthracycline glycoside having formula 1 or a pharmaceutically acceptable acid addition salt thereof as the active ingredient. Conventional carriers or diluents can be used. This composition can be formulated and administered in a conventional manner. Anthracycline glycosides of Formula 1 and their pharmaceutically acceptable acid addition salts are antitumor agents. These compounds can be used to inhibit tumor growth by administering a therapeutically effective amount of the present invention. Ten 1111 Dodaunorubicin (Ia) (R, == H) Small IL: 2,969 (5 mmol) of 4-amy-1-xy-4' in 70 ml of silent aqueous methylene dichloride and 3.2 mmol of dry pyridine. -Ebby N-Trifluo

A stirred solution of coapidyldaunorubicin (IV) cooled to 0°C was added with
d solution of triflic anhydrous comethanesulfonic acid was added. The organic phase was treated with a cooled 5% aqueous solution of sodium bicarbonate,
It was washed with water, a 0.1N aqueous solution of hydrochloric acid, and water in this order. The solution containing 4'-E and 4'-0-1 trifluoro I comethane derivatives IV was dried over anhydrous sodium sulfate, the organic solution was filtered, and the solvent was removed under reduced pressure. Kieselgel plate (Merck FM'C'+7) using a system of methylene dichloride/acetone (95:5 volume ratio) TIC: Rf=
0.60° Compound ■ is dissolved in 100 m of acetone,
3 g of sodium iodide was added and kept under stirring at 30° C. for 1 hour. The mixture was then poured into water, extracted with methylene dichloride, and anhydrous lil! 2. dried over sodium chloride, evaporated under reduced pressure to a small volume, and further chromatographed on silica gel eluting with membrane dichloride.
5g l1114-demethoxy-4'-deoxy-4'
-Iodo-N-trifluoroacedel-daunorubicin (V) was obtained. TLC on Gieselgel plates (Merck F) using a system of methylene dichloride/acetone (95:5 volume ratio): Rf = 0.7° 1:DN
S (M”, ) 699, PHR (200HII
z, CD CI 3) δ13.55 (8,1)1.
O-6): 13.26 (s, 11], α-11): 8.27 (m, 2H, Dan-1 and Dan-
4) Near, 9-7.8 (m, 2H, Dan-2 and H-3): 6.37 (d, j = 8.1 Hz, 1t-
1, N11): 5.49 (b d,
j 03.9 Hz, 1 to 1
H-1'): 5.22 (dd,
j = 4.2, 2. ON2. 1 f-1, H-7)
: 4.64 (m, 1H, dan-4'): 4.22 (S
, 3H. OCH3): 3.50 (dQ, j=6.2
, 1.5 N2゜1[1,tan-5'): 3.23
(dd, j = 19.2.1.7H2, IN, dan-1
0e q ): 2.94 (d , j = 19.
2Hz, 11-1. 10ax): 2.4
2(s, 3H. CO island 1i3): 2.34(ddd, j=1
5.0.2.0. 1.7 Hz, IH, 1l-8el; 2.16(
bdd. j=15.0.4.2 Hz, 1H, 1l-8ax
) :2.06(td, j -13,3,3,9H
z, I H, dan-2'ax); 1.88 (dd,
j = 13.3. 4.8 Hl, 11-1
゜dan-2' eq)1.28(d,j-6,2Hz
, 3H. Suburbs 3CH). To a solution of compound ■ in 20rd acetone, add 150d
0.1N aqueous sodium hydroxide solution was added. After 2 hours at 0°C, the solution was adjusted to pH 8 with 0.1N hydrochloric acid.
6 and extracted with methylene dichloride. Evaporation of the solvent gave a residue which was converted to the salt IIS of formula Ia by treatment with hydrogen chloride in methanol (1.7t
J, yield 61%). Methylene dichloride/methanol/vinegar l! /Wed (30:4:
TLC on Kieselgel plates (Merck F) using a solvent system with a volume ratio of 1:o, 5: Rf = 0.48
゜FDMS (M: ) 703゜Todo"F')Ruhishi> (Ib) (R1-OH)
4-demethoxy-4'-deoxy-4'-iododaunorubicin (produced as described in Example 1)
1.3 g of Ia) was dissolved in a mixture of methanol and dioxane. This solution was added to U.S. Patent No. 3.803.124.
@ As described in the publication, first treat with bromine and
The 4-bromo-derivative was obtained and then treated with an aqueous sodium vA acid solution to give 4-demethoxy-4'-deAxy4'-
Iododoxorubicin (Ib) was produced. This was converted to its hydrochloride salt by treatment with a methanol solution of hydrogen chloride. Mevlene dichloride/methanol/vinegar I! ! /Wed (30:4
: 1:0.5 volume ratio) TLC at Merck [): Rf-0,36゜roosuv++,) b2a PHR (200Hllz, CDC13) δ8.3-
8.2 (m, 2H, dan-1 and dan-4) near,
9-7.8 (m, 2H, Dan-2 and Dan-3): 5
．． 43 (bd, j=3.2 Hz, 1N,) l-1'
):5.23(dd, j −4,0,2,2N
2. IN, 1l-7):4,73(S
, 2H, CH20H): 4.48 (m, 1H, H-4'
): 3.36 (bq, j = 6.2 Hz, 1H2dan-5'): 3.23 (dd, j-1
9,0,1,41'-1Z, IH, Dan-10e q)
: 2.99 (d, j = 19.0+-+z, 1
H, Dan-10aX): 2.34 (ddd, j=14.5
．． 2.2, 1.4 Hz, IH, dan-8eq)
:2.14(dd, j -14,5,4,ON
2. IH, H-2ax): 2.2-2.1
(m, 1 H, dan-3'); 1.9 -1.7
(m, 2H, CH'): 1,31 (d. □2 j-6,2Hz, 311. 3 CH). 11'' and the biological activity of compound 1b in several cell lines.
Tested with VitrO: I of Compound Ib against Second Different Tumor Illlll1 Strains
I cytotoxic cell line IO(no/If) 10sO(n(]/
ml) tlela(”) 4.7
18P388(b) 1.8
10.7P388/DX (C)11.4
2050 (a) 24 hour treatment (b) 48 hour treatment (c) P388/doxorgocin resistant cell line; 4
Processed for 8 hours. The activity of compound 1b was also tested against several murine leukemias by intraperitoneal, intravenous and oral routes. 115 Antitumor activity against murine leukemia (compound 1b) (doxorubicin) administration 1! i1(
II1g/Dose (ll1g/kg) P388ip
it)+1 6.6 265 10 265P
38B/Dxiv iv+1 4.4 100 13
9511210iv iv+1 4.4
125 13 113Grossiv
iv+1 4.4 208 16.9 229Gros
siv 0341 6.6 192 -- --(
a) Experiments performed on mice BDF 1 or CDF 1 injected intraperitoneally or intravenously with 10 6 leukemia cells. (b) 50% survival time of treated mice (mad 1a
nsurvival title)/50% survival time of control x 100°* In Table 2, “1p” represents intraperitoneal administration;
J represents intravenous administration and "O3" represents oral administration.

Claims (7)

[Claims] (1) General formula: ▲There are mathematical formulas, chemical formulas, tables, etc.▼ [In the formula, R_1 represents a hydrogen atom or a hydroxy group] An anthracycline glycoside or a pharmaceutically acceptable acid addition salt thereof. (2) The anthracycline glycoside according to claim 1, which is 4-demethoxy-4'-deoxy-4'-iododaunorubicin or its hydrochloride. (3) The anthracycline glycoside according to claim 1, which is 4-demethoxy-4'-deoxy-4'-iododoxorubicin or its hydrochloride. (4) A method for producing an anthracycline glycoside of formula I or a pharmaceutically acceptable acid addition salt thereof according to claim 1, comprising (i) formula IV: ▲There are mathematical formulas, chemical formulas, tables, etc.▼ The 4'-epi-hydroxy group of 4-demethoxy-4'-epi-N-trifluoroacetyldaunorubicin was replaced with 4'
-Epi-O-trifluoromethanesulfonyl group is converted to form a 4'-epi-4'-O-trifluoromethanesulfonate derivative of formula V: ▲There are mathematical formulas, chemical formulas, tables, etc.▼V, and the formula (ii) A 4'-epi-4'-O-trifluoromethanesulfonate derivative of V is reacted with an iodide salt to form the formula V
I: ▲There are mathematical formulas, chemical formulas, tables, etc.▼ of 4-demethoxy-4'-deoxy-4'-iodo-N
(iii) removing the N-trifluoroacetyl protecting group from 4-demethoxy-4'-deoxy-4'-iodo-N-trifluoroacetyl-daunorubicin to produce 4-demethoxy- (iv) optionally converting 4-demethoxy-4'-deoxy-4'-iododaunorubicin to a pharmaceutically acceptable acid addition salt thereof; (v) ) Optionally, 4-demethoxy-4'-deoxy-
4'-iododaunorubicin or a pharmaceutically acceptable acid addition salt thereof is brominated and the resulting 14-bromo derivative is hydrolyzed to give 4-demethoxy-4'-deoxy-4'.
(vi) optionally converting 4-demethoxy-4'-deoxy-4'-iododoxorubicin into a pharmaceutically acceptable acid addition salt thereof. (5) A pharmaceutical composition comprising a pharmaceutically acceptable carrier or diluent and an anthracycline glycoside having the formula I according to claim 1 or a pharmaceutically acceptable acid addition salt thereof as an active ingredient. (6) An anthracycline glycoside having formula I according to claim 1 or a pharmaceutically acceptable acid addition salt thereof for use as an antitumor agent. (7) A method for producing an anthracycline glycoside having formula I according to claim 1 or a pharmaceutically acceptable acid addition salt thereof, the method substantially as described in Example 1 or 2.