Antiallergically-active pyrimidine derivatives of the formula ##STR1## wherein R.sup.1 is hydrogen, chlorine, bromine or C.sub.1-4 -alkyl, and R.sup.2 is hydrogen or methyl, prepared starting from corresponding 4-oxothieno-[3,2-d]pyrimidine derivatives, are described.

BRIEF SUMMARY OF THE INVENTION 
The invention relates to antiallergically-active pyrimidine derivatives of 
the formula 
##STR2## 
wherein R.sup.1 is hydrogen, chlorine, bromine or C.sub.1-4 -alkyl, and 
R.sup.2 is hydrogen or methyl. 
The compounds of formula I are prepared from the corresponding 
4-oxothieno-[3,2-d]pyrimidine derivatives. 
In another aspect, the invention relates to compounds of the formula 
##STR3## 
wherein R.sup.1 is hydrogen, chlorine, bromine or C.sub.1-4 -alkyl and 
R.sup.2 is hydrogen or methyl and R.sup.3 and R.sup.4 are C.sub.1-4 
-alkyl, with ammonia. 
DETAILED DESCRIPTION OF THE INVENTION 
The invention relates to pyrimidine derivatives of the formula 
##STR4## 
wherein R.sup.1 is hydrogen, chlorine, bromine or C.sub.1-4 -alkyl and 
R.sup.2 is hydrogen or methyl. 
As used herein, the expression C.sub.1-4 -alkyl denotes straight-chain and 
branched groups, such as, methyl, ethyl, propyl and t-butyl. 
Examples of compounds of formula I are: 
Imidazo[1,2-a]thieno[3,2-d]pyrimidine-6,9(5H,7H)-dione; 
7-methyl-imidazo[1,2-a]thieno[3,2-d]pyrimidine-6,9-(5H,7H)-dione; and 
2- or 3-(methyl or 
chloro)-imidazo[1,2-a]thieno[3,2-d]-pyrimidine-6,9(5H,7H)-dione. The 
first-named compound is preferred. 
The invention also relates to a process for the preparation of the 
compounds of formula I as well as pharmaceutical preparations based on the 
compounds of formula I. 
The compounds of formula I can be prepared in accordance with the invention 
by reacting an ester of the formula 
##STR5## 
wherein R.sup.1 and R.sup.2 are as previously described and R.sup.3 and 
R.sup.4 are C.sub.1-4 -alkyl, with ammonia. 
The ester of formula II can be reacted with a solution of ammonia in water 
or in an alcohol, for example, an alkanol such as methanol, at a 
temperature in the range of 0.degree. to 150.degree. C., preferably at 
about 120.degree. C., conveniently under pressure. The reaction can also 
be carried out using liquid ammonia. 
The compounds of formula I can exist in various tautomeric forms. 
Therefore, the invention is not limited to compounds of formula I depicted 
above, but also includes the tautomers, for example, compounds of the 
formulas 
##STR6## 
wherein R.sup.1 and R.sup.2 are as previously described. 
The compounds of formula I wherein R.sup.2 is methyl and their tautomers 
can, moreover, exist in the form of racemates or in optically active form, 
i.e., as the enantiomers, all of these forms are also part of the 
invention. 
The esters of formula II can be prepared by reacting a compound of the 
formula 
##STR7## 
with a dialkyl sulfate of the formula (R.sup.4 O).sub.2 SO.sub.2 or a 
halide of the formula R.sup.4 Hal, wherein R.sup.1, R.sup.2, R.sup.3 and 
R.sup.4 are as previously described and Hal is halogen, preferably iodine. 
The reaction is conveniently carried out in the presence of a base, for 
example, an alkali metal carbonate such as potassium carbonate, in an 
aprotic solvent such as dimethylformamide, dimethyl sulfoxide or, when a 
dialkyl sulfate is used, also acetone, at a temperature in the range of 
0.degree. C. up to the reflux temperature of the reaction mixture, 
preferably while heating. 
The compounds of formula III can be prepared by reacting a compound of the 
formula 
##STR8## 
with an ester of the formula 
##STR9## 
wherein R.sup.1, R.sup.2 and R.sup.3 are as previously described and 
R.sup.5 is C.sub.1-4 -alkyl. The reaction is conveniently carried out in 
the presence of a base, for example, a trialkylamine such as 
triethylamine, in an aprotic solvent such as tetrahydrofuran, benzene or 
pyridine, at a temperature up to about 100.degree. C., preferably at room 
temperature. 
The compounds of formula IV can be prepared by reacting a compound of the 
formula 
##STR10## 
wherein R.sup.1 and R.sup.5 are as previously described, with 
thiophosgene, conveniently in the presence of a base, for example, an 
alkali metal carbonate, such as, sodium carbonate, or a trialkylamine, 
such as, triethylamine, in an apolar solvent such as, chloroform or carbon 
tetrachloride, at a temperature in the range of from between about 
-20.degree. and 0.degree. C. 
In the compounds of formulas II, III, IV and V, R.sup.3, R.sup.4 and 
R.sup.5 are preferably methyl. 
The compounds of formulas II and III also form part of the invention. 
The compounds of formula I are medicaments, particularly for the prevention 
of allergic reactions, for example, for the prophylactic treatment of 
bronchial asthma. The anti-allergic activity is demonstrated by the 
following experiment. 
Male rats were sensitized by an intravenous injection of plasma containing 
antiovalbumin antibody (1 ml per animal). An anaphylactic bronchial asthma 
reaction was induced in the sensitized rats 18 hours later by an i.v. 
injection of ovalbumin (5 mg per kg). The breathing frequency and the 
ratio between expiration time and inspiration time were measured with the 
aid of a pneumograph as the measurement for this reaction. The test 
substances were administered orally, in the case of 
imidazo[1,2-a]thieno[3,2-d]pyrimidine-6,9(5H,7H)-dione 1/2 hour before the 
injection of the ovalbumin. The ability of the test substance to reduce 
the breathing frequency and the ratio of expiration time to inspiration 
time was taken as the measurement for the activity. An ED.sub.50 of 32 
mg/kg was thus found for the above named pyrimidine derivative. The test 
results are set out in the Table which follows. 
______________________________________ 
Ratio 
Dosage expiration 
mg time/ 
per Breathing inspiration 
kg frequency Decrease time Decrease 
______________________________________ 
12.5 97.4 .+-. 13.7 
32.1 403.9 .+-. 94.9 
37.6 
25 88.5 .+-. 20.7 
38.0 357.5 .+-. 86.1 
40.1 
50 71.3 .+-. 53.9 
53.9 210.7 .+-. 68.1 
64.7 
______________________________________ 
The compounds of formula I can be administered enterally, especially 
orally, or parenterally as antiallergic agents; for example, for the 
prophylactic treatment of bronchial asthma, with dosages fitted to 
individual requirements. The compounds of formula I can be administered 
therapeutically, for example, enterally, especially orally, or 
parenterally, by incorporating a therapeutic dosage in a usual dosage form 
such as tablets, capsules, elixirs, suspensions or solutions. The 
compounds of formula I can be administered in admixture with usual 
pharmaceutical carriers or binders such as maize starch, potassium 
stearate, magnesium carbonate, potassium silicate, dicalcium phosphate, 
talc or lactose. Moreover, they can be administered in the presence of 
buffers or agents used for adjusting the isotony. The pharmaceutical 
dosage forms can, when desired, be subjected to the usual pharmaceutical 
operations such as sterilization and the like. The pharmaceutical dosage 
forms can also contain other therapeutically valuable substances. 
The amount of active substance, that is, a compound of formula I which is 
present in any of the dosage forms described above is variable. Capsules 
or tablets can contain, for example, about 10 mg to about 20 mg of a 
compound of formula I. 
The frequency with which such a dosage form is administered to a patient, 
i.e., warm-blooded animal, varies and is dependent on the amount of active 
substance present in the dosage form and the needs and requirements of the 
patient. Under normal conditions, however, up to about 20 mg/kg of a 
compound of formula I can be administered daily in several dosages. It 
will, however, be understood that the dosages indicated above are only 
given by way of example and that they in no way limit the scope of the use 
of this invention.

The Examples which follow further illustrate the invention. All 
temperatures are given in degrees Centigrade, unless otherwise stated. 
EXAMPLE 1 
Preparation of imidazo[1,2-a]thieno[3,2-d]pyrimidine-6,9-(5H,7H)-dione 
A mixture of 15 g of 
2-methylthio-4-oxothieno-[3,2-d]pyrimidine-3(4H)-acetic acid methyl ester 
and 300 ml of methanol saturated with ammonia at -10.degree. is stirred 
for 90 hours at 120.degree. and 28 atmospheres. After cooling, insoluble 
constituents are removed by filtration and the filtrate is made acid with 
hydrochloric acid. The product is then removed by filtration and 
recrystallized from glacial acetic acid. Yield: 7 g of 
imidazo[1,2-a]thieno[3,2-d]pyrimidine-6,9-(5H,7H)-dione, melting point 
&gt;250.degree.; IR (in KBr): 3094 (s), 2746 (s), 1785 (s), 1764 (s), 1700 
(s), 1644 (s), 1517 (s), 1440 (s), 1315 (m), 1219 (s), 1145 (m), 1049 (m), 
790 (m), 732 (m). 
The starting material can be prepared as follows: 
To a mixture of 320 ml of chloroform, 120 ml of water and 55.4 g of sodium 
carbonate, stirred at 0.degree., are added dropwise 20 ml of thiophosgene, 
followed in the course of 15 minutes by 38.7 g of 
3-amino-2-thiophenecarboxylic acid methyl ester hydrochloride. Then, the 
mixture is stirred at room temperature for 90 minutes. The organic phase 
is separated, dried and evaporated. The residue is recrystallized from 
chloroform-pentane. Yield: 42.5 g of 
3-isothiocyanato-2-thiophenecarboxylic acid methyl ester, melting point 
60.degree.-61.degree.. 
A mixture of 38 g of glycine methyl ester, 380 ml of tetrahydrofuran and 40 
ml of triethylamine is treated at room temperature with a solution of 42.5 
g of 3-isothocyanato-2-thiophenecarboxylic acid methyl ester and stirred 
at room temperature for 20 hours. Then, the mixture is poured into water 
and the precipitated product is removed by filtration. Yield: 46.5 g of 
1,4-dihydro-4-oxo-2-thioxothieno[3,2-d]-pyrimidine-3(2H)-acetic acid 
methyl ester, melting point 240.degree. (decomposition). 
A mixture of 46.5 g of 
1,4-dihydro-4-oxo-2-thioxo-thieno[3,2-d]pyrimidine-3(2H)-acetic acid 
methyl ester, 875 ml of acetone and 110 g of potassium carbonate is 
treated with 45 ml of dimethyl sulfate and boiled under reflux for 3 
hours. Then, the mixture is poured into water and the product is removed 
by filtration. Yield after recrystallization from ethyl acetate: 36 g of 
2-methylthio-4-oxothieno-[3,2-d]pyrimidine-3(4H)-acetic acid methyl ester, 
melting point 167.degree.-169.degree.. 
EXAMPLE 2 
Preparation of 
3-methylimidazo[1,2-a]thieno[3,2-d]pyrimidine-6,9-(5H,7)-dione 
In an analogous manner to Example 1, starting from 30 g of 
2-methylthio-7-methyl-4-oxothieno[3,2-d]pyrimidine-3-(4H)-acetic acid 
methyl ester there are prepared 15 g of 
3-methylimidazo[1,2-a]thieno[3,2-d]pyrimidine-6,9-(5H,7H)-dione, melting 
point 12.degree. (decomposition). 
The starting material can be prepared in an analogous manner to Example 1 
starting from 3-amino-4-methyl-2-thiophenecarboxylic acid methyl ester 
hydrochloride via 4-methyl-3-isothiocyanato-2-thiophenecarboxylic acid 
methyl ester (70 g, melting point 227.degree.-228.degree.) and 
1,4-dihydro-7-methyl-4-oxo-2-thioxothieno[3,2-d]pyrimidine-3(2H)-acetic 
acid methyl ester (69 g, melting point 227.degree.-228.degree.); yield 
68.9 g, melting point 131.degree.-132.degree.. 
EXAMPLE 3 
______________________________________ 
mg/capsule 
Capsule formulation 10 mg 20 mg 
______________________________________ 
Imidazo[1,2-a]thieno[3,2-d]pyrimidine- 
6,9(5H,7H)-dione 10.0 20 
Lactose 215.0 205.0 
Maize starch 60.0 60.0 
Magnesium stearate 3.0 3.0 
Talc 12.0 12.0 
Total 300 mg 300 mg 
______________________________________ 
The active substance 
imidazo[1,2-a]thieno[3,2-d]pyrimidine-6,9(5H,7H)-dione, lactose and maize 
starch are mixed in a suitable mixer. The mixture is ground through a 
suitable mill, mixed with the magnesium stearate and talc and filled on a 
capsule machine. 
EXAMPLE 4 
______________________________________ 
mg/tablet 
Tablet formulation: 10 mg 20 mg 
______________________________________ 
Imidazo[1,2-a]thieno[3,2-d]pyrimidine- 
6,9(5H,7H)-dione 10.0 20.0 
Lactose 182.0 172.0 
Microcrystalline cellulose 
60.0 60.0 
Modified starch 15.0 15.0 
Maize starch 30.0 30.0 
Magnesium stearate 3.0 3.0 
Total 300 mg 300 mg 
______________________________________ 
The active substance 
imidazo[1,2-a]thieno[3,2-d]pyrimidine-6,9(5H,7H)-dione, lactose, 
microcrystalline cellulose, modified starch and maize starch are mixed in 
a suitable mixer for 1 to 15 minutes. Then, the magnesium stearate is 
added and mixed for 5 minutes. The mixture is pressed on a suitable press. 
EXAMPLE 5 
______________________________________ 
mg/tablet 
Wet granulation tablet formulation: 
10 mg 20 mg 
Imidazo[1,2-a]thieno[3,2-d]pyrimidine- 
6,9(5H,7H)-dione 10.0 20.0 
Lactose 264.0 254.0 
Pregelatinized starch 17.5 17.5 
Maize starch 35.0 35.0 
Modified starch 17.5 17.5 
Magnesium stearate 6.0 6.0 
Total 350 mg 350 mg 
______________________________________ 
The active substance imidazo[1,2-a]thieno[3,2d]pyrimidine-6,9(5H,7H)-dione, 
lactose and pregelatinized starch are mixed in a suitable mixer. The 
mixture is ground through a suitable mill, mixed with the modified starch 
and magnesium stearate and filled on a capsule machine.