Uracil derivatives, process for preparing same, and pharmaceutic

Details Uracil derivatives, process for preparing same, and pharmaceutic Uracil derivatives, process for preparing same, and pharmaceutic

1982-11-16

1985-06-18

Hollrah, Glennon H.

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Having -c-, wherein x is chalcogen, bonded directly to...

544229, 544296, A61K 31505, C07D40302

Patent

active

045241473

DESCRIPTION:

BRIEF SUMMARY
DESCRIPTION

1. Cross-Reference to Related Applications
This application is a national stage application of international application No. PCT/JP82/00081 filed Mar. 24, 1982.
2. Technical Field
This invention relates to novel uracil derivatives, a process for preparing the same, and pharmaceutical compositions comprising the same. More particularly, it relates to novel uracil derivatives which have such immunomodulatory activity as to make them effective against immune diseases (e.g., rheumatoid arthritis) and also useful in the treatment of viral diseases and in the immunotherapy of cancer and, moreover, are very desirable for therapeutic purposes because of their low toxicity, a process for preparing the same, and pharmaceutical compositions comprising the same.
3. Background Art
Conventionally, a large number of steroidal and non-steroidal anti-inflammatory agents have been used in the clinical treatment of autoimmune diseases such as rheumatism and the like. However, these numerous drugs are still not entirely satisfactory, judging from their pharmacological actions, side effects, toxicity, and the like.


DISCLOSURE OF THE INVENTION

It is an object of the present invention to provide a novel uracil derivative which exerts a specific effect on the cells participating in immune responses and thereby serves to modify the immune responses of the host, and a process for preparing this compound.
It is another object of the present invention to provide a pharmaceutical composition characterized by immunomodulatory activity and low toxicity.
In accordance with one feature of the present invention, there is provided a uracil derivative having the general formula ##STR2## where R represents a hydrogen atom or an alkyl radical having 1 to 4 carbon atoms.
In accordance with another feature of the present invention, compounds of the general formula (1) can be prepared by reacting a silylated pyrimidine of the general formula ##STR3## where R represents a hydrogen atom or an alkyl radical having 1 to 4 carbon atoms, with a compound of the general formula atoms.
In accordance with still another feature of the present invention, a pharmaceutical composition having immunomodulatory activity comprises a compound of the general formula (1) and a pharmaceutically acceptable carrier.


BEST MODE FOR CARRYING OUT THE INVENTION

Specific examples of the uracil derivatives represented by the general formula (1) include bis[2,4-dioxo-(1H,3H)pyrimidin-1-yl]ethanedione, bis[2-4-dioxo-5-methyl-(1H,3H)pyrimidin-1-yl]ethanedione, bis[2,4-dioxo-5-ethyl-(1H,3H)pyrimidin-1-yl]ethanedione, bis[2,4-dioxo-5-n-propyl-(1H,3H)pyrimidin-1-yl]ethanedione, bis[2,4-dioxo-5-isopropyl-(1H,3H)pyrimidin-1-yl]ethanedione, bis[2,4-dioxo-5-n-butyl(1H,3H)pyrimidin-1-yl]ethanedione, and bis[2,4-dioxo-5-tert-butyl-(1H,3H)pyrimidin-1yl]ethanedione. It is to be understood that the pyrimidine rings present in the general formula (1) can take various tautomeric forms.
In preparing such uracil derivatives according to the process of the present invention, not less than 2 moles, preferably 2 moles, of a silylated pyrimidine of the general formula (2) is reacted with 1 mole of a compound of the general formula (3) in the presence of a solvent. Generally, uracils are hardly soluble in solvents and hence fail to give a satisfactorily high reaction rate. For this reason, they are modified by silylation and used as active compounds soluble in solvents. Although such compounds can be isolated and purified by distillation or other suitable techniques, silylated pyrimidines of the general formula (2) may be used without purification.
Specific examples of the silylating agents suitable for this purpose include trimethylchlorosilane, hexamethyldisilazane, N,O-bis(trimethylsilyl)acetamide, N,O-bis(trimethylsilyl)-trifluoroacetamide, and the like. Where hexamethyldisilazane is used, it is usually advantageous to use it in combination with trimethylchlorosilane. The silylation of uracils with such a silylating agent can be carried out in the presence of a solvent such as

REFERENCES:
patent: 3532699 (1970-10-01), Kugele
Kugele, "Chemical Abstracts", vol. 71, 1961, col. 70628a.
"Chemical Abstracts", vol. 98, 1983, col. 98:126145t.

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