JPS61129194A - Anthracyclin deivatiave and its preparation - Google Patents

Abstract

NEW MATERIAL:A compound of formula I (R1 is H, methoxy; R2, R3 are H, hydroxyl; R4 is hydroxyl, when R<3> is H, or H, when R<3> is hydroxyl; X is divalent organic group; Y is the residue of the alcohol in activated ester). EXAMPLE:N-[4-(N-Succinimidyloxy) carbonylbutyryl] acetyldaunomycin. USE:A synthetic intermediate of a carcinostatic agent. PREPARATION:The esterification of a carboxylic acid of formula II gives a compound of formula I. The carboxylic acid of formula II as a a starting substance is obtained by allowing an anthracyclin of formula I with a haloacetyl N-succinimidyl ester of formula IV (Z is C1, Br, I), then allowing a monosodium salt of a dibasic acid of formula VI to act on the resultant alpha-halocarbonyl derivative of formula V.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to novel anthracycline derivatives. More specifically, the present invention relates to a novel anthracycline derivative having an active ester structure in its molecule, which is useful as a synthetic intermediate for anticancer drugs, and its manufacturing method.
Regarding.

Anthracyline drugs include dau/mycin, adriamycin, and other drugs that are important in the treatment of malignant shield tumors. In the course of intensive research to develop a new anticancer agent using anthracycline substances including downmycin and adriamycin as raw materials, the present inventors discovered a novel anthracycline derivative represented by the following formula (1). The compound is novel because it can react extremely easily with many other amide 7-containing substances through its active ester group while retaining the anticancer activity based on the structure of anthracycline substances. The present invention was achieved based on the discovery that the compound can be used as a synthetic intermediate for 7-antracycline anticancer drugs.

That is, the present invention is a method for producing anthracycline derivatives represented by the general formula CI] and a method for producing them, which is characterized by esterifying a carboxylic acid represented by the general formula [11] HOO.

In formula (1) and formula (II), X is a divalent organic group containing a lower alkylene group. When R is a lower fullkylene group, it preferably has 2 to 10 carbon atoms, and specific examples thereof include ethylene group, trimethylene group, 2-methyltrimethylene group, tetramethylene group, 2-methyltetramethylene group, and pentamethylene group. methylene group, hexamethylene group,
Heptamethylene group, octamethylene group.

Nonamethylene group, decamethylene group, etc. can be mentioned. Further, as the remainder of the alcohol moiety of the active ester represented by Y, N-succinimidyl, %, N-5-
norbornene-2,3-dicarboximidyl group, N-
7-talimine group, p-nitrophenyl group, 2,4.
5-) Lichlorophenyl graves, pentachlorophenyl groups, etc. are dug up by digging.

The carvone@S represented by the -e formula [11], which is used as a raw material for the production of the anthracycline derivative represented by the general formula (1) of this patent, is, for example, the general formula (III), in the formula , Rt, &, Rs and R4 are defined the same as in the case of formula [I).

The anthracycline substance represented by the formula (IV)
, [In the formula, 2 represents ct+Br, r. ] to obtain a halocarbonyl derivative represented by formula [V], formula CM), Na0CO-X-Co, H.・・・・・・・・・・・・
・・・・・・・・・(Vl) [In the formula, the definition of X is the formula [■]
The same is true for . It is manufactured by reacting with the monosodium salt of dibasic acid represented by ].

In the present invention, the derivative of the anthracycline substance represented by the formula [11] can be produced by esterifying the carboxylic acid represented by the formula (Il). It is achieved by condensing an acid and an alcohol.The condensation can be carried out, for example, by treating a mixture of a carboxylic acid and an alcohol with a dehydration condensation agent.The alcohol preferably used is N-hydroxysuccine. imide, N-human p-xy-5-norbornene-2,3-
N-hydroxyimides such as dicarboximide and N-hydroxy 7-talimide, and p-nitrophenol.

2.4-dinitrophenol, 2,4.5-)dichlorophenol1. Nophenols such as pentacrotuphenol can be praised. The dehydration condensation agents used in this reaction include dicyclohexylcarbodiimide,
Common examples include 1-2+-3-(3-dimethylaminopropyl)carbodiimide.

Generally, this reaction is carried out in the presence of a suitable solvent. Such a solvent is preferably one that is non-reactive in itself and has a high dissolving power, such as ether, ethers such as tetrahydrol, dioxane, dimethoxyethane, halogenated hydrocarbons such as methylene chloride, ethyl acetate, etc. esters, aprotic polar solvents such as acetonitrile, dimethylformamide, etc. are preferably used. In this reaction, preferably 0.8 to 1.5 mol of alcohol per 1 mol of carboxylic acid represented by general formula (I),
8 to 3.0 moles of dehydrated condensation polymer I O are used. The reaction temperature used in this reaction is -30°C to 50°C, preferably -0°C to room temperature. Reaction time is 1 hour to 4 days.

After the reaction is completed, the desired derivative of the anthracycline substance of the present invention represented by the general formula [■] can be obtained by performing conventional methods such as extraction, crystallization, and two-partition chromatography. I can do it.

For example, the anthracycline #A derivative of the present invention represented by the general formula CI) can be reacted with an anti-tumor antibody to impart cell-killing properties to the antibody, thereby making it a selective anti-cancer agent. can.

Hereinafter, the present invention will be explained in detail with reference to Reference Examples and Examples.

Reference Example 1 Production of N-(4-carboxybutyryloxy)acetyldaunomycin.

N-chromoacyldaunomycin 178, a known substance
Monosodium glutarate 423.51119 was dispersed in a solution of ~ dissolved in Efi dimethylformamide 20-, sodium macromide 42- was added, and the mixture was stirred at 80°C for 2 hours under a nitrogen atmosphere. Pour the reaction solution into ice water 150-
In addition, the extract was extracted three times with chloroform 50-ml, and the extract was dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure. The obtained residue was subjected to silica gel chromametry (jF[: chloroform-methanol-acetic acid system) to obtain N-(4-carboxybutyryloxy)acetyldaunomycin 891q.

Example 1 Preparation of N-(4-(N-succinimidyloxy)carbonylgtyryl)7cetyldaunomycin.

N-hydroxysuccinimide 7.7119 and N,N'-dicyclo 13.8iy4 of hexylcarbodiimide was added, and the mixture was stirred at room temperature for 20 hours. Add 0.1-mL of acetic acid and 0.2-mL of ice water; 1.
After stirring for 5 hours, the reaction solution was added to 50 liters of ice water and extracted with chloroform. The extract was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to obtain a residue. The residue was subjected to silica gel chromatography (solvent: chloroform-methanol system) and solidified with ether to obtain 301 nq of N-[4-(N-succinimidyloxy)carbonylbutyrylcoacetildau/mycin.

Physical properties of N-(4-(N-succinimidyloxy)carbonylphylyl)7cetyldaunomycin: m, p, 124 6°C uv: Xm1Lx in CHC!4 484, 4
99.

5 3 4 (sh) nm.

IR2D KBr 3 5 4 0 (br)
, 2950.

ax 1816.1785° 1 7 4 0 (S).

1720.1618,1580° 1411.1283.1206 (S).

983, Cm-', Proton NMR: δxom TMS in CDC4
The main signals are described along with their structure.

1.27 (3f (, d, 6.5Hz) 5'-C
H.

2.38 (3H, S) 14th place-C1 A.

2.85 (4f(,S) N-succinimidyl4.05 (3H,S') 4th-OC formula%
Formula % 1 3.1 6 (IH,S) 1 Reference Example 2゜N-(4-(N-succinimidyloxy)carbonylbutyryl coacetyl douts machine) obtained in Example 1 0
．． A solution of 814/jmole dissolved in 20011t of dimethylformamide was added to 1g of rabbit G1011I9
4.0-0.1 molar sodium phosphate buffer (p)
f 7.35 ) and allowed to stand at 4° C. for 12 hours. Remove a small amount of precipitate by centrifugation,
The resulting solution was subjected to gel filtration using Sephadex G-25 (Fine), and the high molecular fractions were pooled. Ultraviolet and visible absorbance measurements revealed that the benthic organisms obtained were IgG-daunomycin conjugates.

Patent applicant: Teijin Ltd. 15, agent: Patent attorney 1) Jun 4! ',
,",knee,,,,'

Claims (6)

[Claims] (1) The following formula [I] ▲There are mathematical formulas, chemical formulas, tables, etc.▼・・・・・・・・・
...... [I] In the formula, R_1 is a hydrogen atom or a methoxy group, R_2 and R_3 are each independently a hydrogen atom or a hydroxyl group, R_4 is a hydroxyl group when R_3 is a hydrogen atom, and R_3 is a hydroxyl group. represents a hydrogen atom. X
represents a divalent organic group. Y is a residue of the alcohol moiety of the active ester. (2) The anthracycline derivative according to claim 1, wherein X is a linear or branched alkylene group having 2 to 10 carbon atoms. (3) The anthracycline derivative according to claim 1 or 2, wherein Y is an N-succinimidyl group. (4) Claims 1 and 2, wherein R_1 is a methoxy group, R_2 and R_3 are hydrogen atoms, R_4 is a hydroxyl group, Y is a tritylene group, and Y is an N-succinimidyl group.
The daunomycin complex according to item 1 or 3. (5) R_1 is a methoxy group, R_2 and R_4 are hydroxyl groups, R_3 is a hydrogen atom, Y is a trimethylene group, Y is N-
The adriamycin derivative according to claim 1, 2 or 3, which is a succinimidyl group. (6) The following formula [II] ▲There are mathematical formulas, chemical formulas, tables, etc.▼・・・・・・・・・
・・・・・・[II] [In the formula, R_1, R_2, R_3, R
The definitions of _4 and X are the same as in the case of formula [II]. ] The following formula [I] is characterized by esterifying carboxylic acids represented by ▲There are mathematical formulas, chemical formulas, tables, etc.▼・・・・・・・・・
...... [I] [In the formula, R_1 is a hydrogen atom or a methoxy group, R_2 and R_3 are each independently a hydrogen atom or a hydroxyl group, R_4 is a hydroxyl group when R_3 is a hydrogen atom, R_3 When is a hydroxyl group, it represents a hydrogen atom. X represents a divalent organic group. Y is a residue of the alcohol moiety of the active ester. ] A method for producing an anthracycline derivative represented by: