Patent EP-1022278-A1 (EP)
Inventor: ASHKINAZI RIMMA ILIINICHNA
IPC: A61P31/12
Filed: 1997-04-02
Abstract: Biologically active substance on the basis of tetracyclic nitrogen heterocycles of pyrimidine
series (applicant - inventors R.I. Ashkinazi and K.A. Krasnov). The present invention relates
to medicine, and more specifically to pharmacology, veterinary cosmetology, and in particular
to synthetic biologically active compounds of a heterocycle series, which possess antimicrobial,
antiviral, antichlamydia and immune stimulating activities: derivatives of
5-oxo-5H-[1]-benzopyrano-[5,6-b]-4-oxo-4H-[1,2]-pyrimido-1,4,5,64-tetrahydro-1,3-thiazine.
The compounds are provided mainly for treating tuberculosis, mycobacteriosis, viral diseases,
infections caused by chlamydias, and diseases which are accompanied by immunodeficiency,
particularly malignant neoplasm. In addition, the above mentioned compounds can be used for
the same purposes in veterinary medicine and cosmetology. 
     An objective of the invention is to obtain new chemical compounds which have high
antimicrobial activity, particularly with respect to strains of mycobacteria that are resistant to
isoniazid, which is standardly used to treat mycobacteria. Compounds of the invention
simultaneously possess antiviral activity (relative to herpes simplex viruses), antichlamydial
activity, and also stimulate production of endogenic interferons in organisms. In other words,
the objective of the invention is a chemical synthesis of biologically active substances which are
superior to the prototype not only in a range of action on strains of tuberculosis and other
mycobacteria, but also possess antiviral, antichylamidial and immuno stimulating action. 
     The objective is solved by synthesis of new class of heterocyclic compounds-derivatives of
5-oxo-5H-[1]-benzopyrano[5,6-b]-4-oxo-4H-[1,2]-pyrimido-1,4,5,6-tetrahydro-1,3-thiazine
(1) of general formula (1).
  
   (I-X),where: R 1  = H or a halogen; R 2  = H, halogen, nitro, hydroxy, or methoxy. 
     The objective can be solved with R 1  = R 2  = H (I); R 1  = H and R 2  = Cl (II); R 1  = R 2  = Cl (III);
R 1  = H and R 2  = Br (IV); R 1  = R 2  = Br (V); R 1  = H and R 2  = NO 2  (VI); R 1  = Cl and R 2  = NO 2 
(VIIl); R 1  = Cl and R 2  = NO 2  (VII); R 1  = Br and R 2  = NO 2  (VIII); R 1  = H and R 2  = OCH 3  (IX);
R 1  = H and R 2  = OH (X). 
     The proposed synthesis of the claimed compounds includes two main stages:
   1. 4-oxo-4H-6-oxy-[1,2-d]-pyrimido-1, 4, 5, 6-tetrahydro-1,3-thiazine(XI) is synthesized
from 2-thiobarbituric acid (XII) and 1,3-dihalogenopropane(XIII); and   2. A target compound (I-X) is produced from the intermediate substance (XI) obtained in
the first stage and corresponding derivative of salicylaldehyde (XIV). The method is
common for all members of the group.    
     The subject matter of the present invention it explained by two examples of synthesis of the
intermediate substance and three examples of synthesis of claimed substances, two tables of
yield of intermediate and target products, two tables of characteristics of target products, and
data of seven experiments for determination of their biological properties.