Anti-tumor DC-52 compounds

Details Anti-tumor DC-52 compounds Anti-tumor DC-52 compounds

1988-05-25

1989-11-07

Berch, Mark L.

Organic compounds -- part of the class 532-570 series

Organic compounds

Nitrogen attached directly or indirectly to the purine ring...

A61K 31495, C07D47118, C07D49822

Patent

active

048793868

DESCRIPTION:

BRIEF SUMMARY
cl TECHNICAL FIELD
The present invention relates to novel DC-52 derivatives having anti-tumor activity.


BACKGROUND ART

DC-52 is an antibiotic represented by the following formula: ##STR2##
It shows antibacterial activity against a variety of bacteria, and also has anti-tumor activity against lymphocytic leukemia P-388 and the like (Japanese Published Unexamined Patent Application No. 170189/82).
As a derivative thereof, DX-52-1 represented by the following formula and having anti-tumor activity is known (Japanese Published Unexamined Patent Application No. 210086/84). ##STR3##
Derivatives of DC-52 having higher anti-tumor activity are always in demand, as is the case with other types of anti-tumor antibiotics.


DISCLOSURE OF THE INVENTION

The derivatives of DC-52 of the present invention having high anti-tumor activity are compounds represented by the following formula (I): ##STR4## wherein X is chlorine, bromine, iodine, hydroxyl, formyl, hydroxyiminomethyl, cyano, nitro, amino or lower alkanoylamino; and Y is hydroxyl and Z is cyano, or Y and Z represent --O-- in the form of --Y--Z-- [The compounds are hereinafter referred to as compounds (I). The same shall apply to compounds of other formula Nos]
The lower alkanoylamino in the definition of X in formula (I) means a straight chain or branched alkanoylamino group having 1 to 4 carbon atoms such as formamide, acetamide, propionamide, butyramide and isobutyramide.
Pharmacologically acceptable salts of compounds (I) have high anti-tumor activity as well as compounds (I). These salts include pharmacologically acceptable acid addition salts, alkali metal salts, alkaline earth metal salts, ammonium salts and pharmacologically acceptable organic base addition salts. The pharmacologically acceptable acid addition salts include pharmacologically acceptable inorganic acid addition salts such as hydrochloride, hydrobromide, hydroiodide, sulfate, phosphate and nitrate; and pharmacologically acceptable organic acid addition salts such as acetate, benzoate, maleate, fumarate, succinate, tartrate, citrate, oxalate, glyoxylate, aspartate, methanesulfonate, ethanesulfonate, propanesulfonate, methanedisulfonate, .alpha., .beta.-ethanedisulfonate and benzenesulfonate. The alkali metal salts include sodium salt, potassium salt, etc. and the alkaline earth metal salts include calcium salt, magnesium salt, etc. The pharmacologically acceptable organic base addition salts include salts with ethanolamine, triethylamine, morpholine, piperidine, etc.
The process for preparing compounds (I) is described below.
Compounds represented by the following formula (I-1) are prepared by reaction of DX-52-1 with a halogenating agent in an inert solvent: ##STR5## (wherein X.sub.1 is chlorine, bromine or iodine).
Chlorination is carried out usually at 0.degree. to 80.degree. C. for one to eight hours using chlorine, N-chlorosuccinimide or the like as the chlorinating agent, and acetic acid, DMF or the like as the inert solvent.
Bromination is carried out usually at 0.degree. to 50.degree. C. for one to six hours using bromine, N-bromosuccinimide or the like as the brominating agent, and acetic acid, DMF or the like as the inert solvent.
Iodination is carried out usually at 20.degree. to 80.degree. C. for one to eight hours using iodine-periodic acid as the iodinating agent, and water, acetic acid or the like as the inert solvent.
Compounds of formula (I) in which X is formyl or hydroxyiminomethyl, Y is hydroxyl and Z is cyano can be prepared by the following reaction steps: ##STR6##
DX-52-1 is first esterified with methanol in the presence of an acid catalyst to form compound (II). The acid catalyst includes mineral acids such as hydrogen chloride and sulfuric acid and Lewis acids such as BF.sub.3 -OEt.sub.2, and is usually used in an amount of 2 to 20 equivalents based on DX-52-1. The reaction is usually carried out at 20.degree. to 60.degree. C. and is complete in 3 to 24 hours. Compound (II) may also be prepared by dropwise addition of a diethyl ether solution of diazomethane to a sol

REFERENCES:
patent: 4650869 (1987-03-01), Hirata et al.
Translation of Claims of Japanese Unexamined Pat. Application 170189/82.

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