The present invention provides thienopyrimidine derivatives of the formula (I) ##STR1## wherein R.sub.1 and R.sub.2 are the same or different and each represent hydrogen, halogen, lower alkyl, cycloalkyl or phenyl, R.sub.1 and R.sub.2 taken together may form a ring of an alkylene chain, R.sub.3 represents lower alkyl or a group of the formula ##STR2## (in which R.sub.4 is a lower alkyl, lower alkoxy or halogen, m is 0, 1 or 2, and R.sub.5 is hydrogen or halogen) and Z is oxygen or sulfur, or pharmaceutically acceptable salts thereof, pharmaceutical compositions containing them as an active principle and aldose-reductase inhibitors.

DESCRIPTION 
1. Technical Field 
The present invention relates to novel thienopyrimidine derivatives or 
pharmaceutically acceptable salts thereof, pharmaceutical compositions 
containing the same and aldose-reductase inhibitors. 
2. Background Art 
Kinoshita et al. reported that the aldose-reductase participates in crisis 
and development of complications of diabetes such as diabetic cataract, 
diabetic neuropathy, diabetic nephropathy and diabetic retinopathy (J. H. 
Kinoshita et al., Journal of the American Medical Association, 246, 257, 
(1981)). The aldose-reductase reduces aldoses such as glucose and 
galactose to polyols such as sorbitols. The polyol produced is relatively 
stable and rarely passes extracellularly, consequently accumulating 
intracellularly. Since the hyperglycemic status as in diabetes, promotes 
the activity of aldose-reductase, the polyols accumulate excessively in 
the lenses, neurons, vascular tissues, etc. Therefore, the osmotic 
pressure increases in these tissue cells, which results in swell of the 
tissues, damaged cellular function and tissue disorders. In view of these 
situations, it has been desired to develop compounds useful for remedy and 
prevention of various diabetic complications and excellent in 
aldose-reductose inhibiting activity by inhibiting the aldose-reductase 
and thus avoiding abnormal intracellular accumulation of polyols. 
DISCLOSURE OF THE INVENTION 
The inventors conducted extensive research in view of the above problems of 
the prior art and found that the novel thienopyrimidine derivatives 
represented below by the formula (I) and their salts exhibit outstanding 
aldose-reductase inhibitory effect and are useful as medicaments. 
Therefore, the invention has been accomplished.

The present invention provides thienopyrimidine derivatives of the formula 
(I) 
##STR3## 
wherein R.sub.1 and R.sub.2 are the same or different and each represent 
hydrogen, halogen, lower alkyl, cycloalkyl or pheny, R.sub.1 and R.sub.2 
taken together may form a ring with an alkylene chain, R.sub.3 represents 
lower alkyl or a group of the formula 
##STR4## 
(in which R.sub.4 is lower alkyl, lower alkoxy or halogen, m is 0, 1 or 2, 
and R.sub.5 is hydrogen or halogen) and Z is oxygen or sulfur, or 
pharmaceutically acceptable salts thereof. 
Examples of halogen atoms represented by R.sub.1, R.sub.2, R.sub.4 and 
R.sub.5 in the formula (I) are fluorine, chlorine, bromine and iodine. 
Examples of lower alkyl groups represented by R.sub.1, R.sub.2, R.sub.3 
and R.sub.4 are straight chain or branched chain C.sub.1 -C.sub.6 alkyl 
groups such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, 
sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, tert-pentyl, hexyl 
and isohexyl. Examples of cycloalkyl groups represented by R.sub.1 and 
R.sub.2 are C.sub.3 -C.sub.7 cyclopropyl, cyclobutyl, cyclohexyl, etc. 
Examples of rings with an alkylene chain formed by R.sub.1 and R.sub.2 
taken together are 
##STR5## 
etc. Examples of lower alkoxy groups represented by R.sub.4 are straight 
chain or branched chain C.sub.1 -C.sub.6 alkoxy groups such as methoxy, 
ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, tert-butoxy, pentoxy and 
hexyloxy. 
The salts of the compounds of the present invention are pharmaceutically 
acceptable salts thereof including salts of alkali metals such as sodium, 
potassium and lithium; salts of alkaline earth metals such as calcium and 
magnesium; salts of ammonium; salts of tetraalkylammoniums such as 
tetramethylammonium, tetraethylammonium, tetrapropylammonium and 
tetrabutylammonium; salts of mono-, di- or trialkylamines such as 
methylamine, ethylamine, isopropylamine, tert-butylamine, dimethtylamine, 
diethylamine, trimethylamine and triethylamine; salts of cycloalkylamines 
such as cyclopentylamine and cyclohexylamine; salts of phenyl(lower 
alkyl)amines such as benzylamine, phenethylamine and phenylpropylamine; 
salts of 5- or 6-membered heterocyclic compounds containing in its ring 
structure one or two nitrogen atoms as the heteroatom such as piperidine, 
piperazine, imidazoline and pyrrole; salts of mono-, di- or 
trialkanolamines such as monoethanolamine, monopropanolamine, 
diethanolamine and triethanolamine; salts of basic amino acids such as 
lysine, arginine and histidine; organic amines such as 
tris(hydroxymethyl)aminomethane; etc. 
Of the compounds of the formula (I), preferable are the compounds in which 
R.sub.1 is hydrogen, methyl, isopropyl or halogen, R.sub.2 is hydrogen or 
methyl, R.sub.3 is 3,4-dichlorobenzyl, 2,4-dichlorobenzyl or 
4-bromo-2-fluorobenzyl, and Z is oxygen or sulfur. Most preferable are the 
compounds of the formula (I) in which R.sub.1 is isopropyl, chlorine or 
bromine, R.sub.2 is hydrogen, R.sub.3 is 4-bromo-2-fluorobenzyl, and Z is 
oxygen. 
The compounds of the present invention of the formula (I) and the 
pharmaceutically acceptable salts thereof display excellent 
aldose-reductase inhibitory effects and are useful as a medicament, 
especially for treating chronic syndromes and complications due to 
diabetes. 
Therefore, the present invention provides an aldose-reductase inhibitor 
containing an effective amount of the compound of the formula (I) or a 
pharmaceutically acceptable salt thereof and a pharmacological carrier. 
The present invention also provides a method of inhibiting aldose-reductase 
comprising administrating to patients an effective amount of the compound 
of the formula (I) or a pharmaceutically acceptable salt thereof. 
The thienopyrimidine derivative of the present invention of the formula (I) 
in which Z is oxygen can be prepared by the process as shown below in 
Reaction scheme (1). When one or both of R.sub.1 and R.sub.2 in the above 
formula (I) are halogen, the compound can be prepared by the process as 
showm below in Reaction scheme (1) or (2). The compound of the formula (I) 
wherein Z is sulfur can be prepared by the process as shown below in 
Reaction scheme (3). 
##STR6## 
In the foregoing formulas, R.sub.1, R.sub.2 and R.sub.3 are as defined 
above, and R.sub.7 is a carboxyl-protecting group. 
The compound of the formula (II) is known and described, for example, in 
"Heterocyclic Compounds", vol. 44. part 3, pp 565-973 "Thiophene and its 
derivatives", written by John M. Barker and Patrick R. Huddleston, edited 
by Salo Gronowitz, published by John Wiley & Sons, Inc., New York (1986). 
Generally used as carboxyl-protecting groups represented by R.sub.7 are 
known groups, for example, subtituted or unsubstituted alkyl groups such 
as methyl, ethyl, propyl, butyl, tert-butyl and trichloroethyl; 
substituted or unsubstituted aralkyl groups such as benzyl, 
diphenylmethyl, p-nitrobenzyl and p-methoxybenzyl; acyloxyalkyl groups 
such as acetoxymethyl, acetoxyethyl, propionyloxyethyl, pivaloyloxymethyl, 
pivaloyloxypropyl, benzoyloxymethyl, benzoyloxyethyl, 
benzylcarbonyloxymethyl and cyclohexylcarbonyloxymethyl; alkoxyalkyl 
groups such as methoxymethyl, ethoxymethyl and benzyloxymethyl; and other 
groups such as tetrahydropyranyl, dimethylaminoethyl, dimethylchlorosilyl 
and trichlorosilyl. 
Each step in the above scheme can be done as described below in more 
detail. 
Step A 
The thiophene derivative of the formula (II) is allowed to react with an 
amine of the formula 
EQU R.sub.3 NH.sub.2 (V) 
(in which R.sub.3 is as defined above) in the presence or absence of a base 
in a suitable solvent, giving the thienopyrimidine derivative of the 
formula (III). 
Examples of the amine of the formula (V) are methylamine, ethylamine, 
propylamine, isopropylamine, pentylamine, hexylamine, benzylamine, 
4-chlorobenzylamine, 2,4-dichlorobenzylamine, 3,4-dichlorobenzylamine, 
4-methoxybenzylamine, 4-methylbenzylamine, 2-fluoro-4-bromobenzylamine, 
2,4-difluorobenzylamine, etc. Although the solvent is not specifically 
limited insofar as it does not participate in this reaction, it is 
preferred to use alcohols such as methanol, ethanol, propanol and 
isopropanol; N,N-dimethylformamide; N,N-acetylacetamide; ethers such as 
tetrahydrofuran and dioxane; or the mixture of these solvents. Examples of 
bases useful in this reaction are alkoxides of alkali metals or alkaline 
earth metals such as sodium methoxide, potassium methoxide, potassium 
t-butoxide, sodium ethoxide, sodium isopropoxide and magnesium methoxid; 
hydrides such as sodium hydride, potassium hydride and lithium hydride; 
amide compounds such as lithium diisopropylamide, lithium 
dicyclohexylamide, sodium amide and potassium amide; organic bases such as 
triethylamine, 4-(N,N-dimethylamino)pyridine and hydroxypyridine; etc. The 
base is preferably used in an amount of about 1.0-1.5 moles per mole of 
the amine (V). Although the proportions of the thiophene derivative (II) 
and the amine (V) may be appropriately determined, in general the amine 
(V) is preferably used in an amount of about 1.0-2.0 moles per mole of the 
thiophene derivative (II). The reaction is usually conducted with heating 
at a temperatuare of about 60.degree.-300.degree. C., preferably at a 
temperature of about 200.degree.-250.degree. C. 
Step B 
The thienopyrimidine derivative of the formula (III) is allowed to react 
with an acetic acid derivative of the formula 
EQU XCH.sub.2 COOR.sub.7 (VI) 
(in which R.sub.7 is as defined above, and X is chlorine, bromine or 
iodine) in the presence of a base in a suitable solvent, giving the 
thienopyrimidine acetate derivative of the formula (IV). Although the 
solvent is not specifically limited insofar as it does not participate in 
this reaction, it is preferred to use ethers such as diethyl ether, 
tetrahydrofuran, dimethoxyethane and dioxane, aromatic hydrocarbons such 
as benzene, toluene and xylene, N,N-dimethylformamide, 
N,N-dimethylacetamide, dimethylsulfoxide or the like. 
Examples of useful bases are alkoxides of alkali metals or alkaline earth 
metals such as potassium methoxide, potassium ethoxide, potassium 
t-butoxide, sodium methoxide, sodium ethoxide, sodium propoxide, sodium 
isopropoxide, lithium methoxide and magnesium ethoxide; hydrides such as 
potassium hydride, sodium hydride and lithium hydride; amide compounds 
such as sodium amide, lithium amide, potassium amide and lithium 
diisopropylamide; hydroxides such as potassium hydroxide, sodium 
hydroxide, lithium hydroxide and calcium hydroxide; carbonates such as 
potassium carbonate and sodium carbonate; etc. The base is preferably used 
in an amount of about 1.0-1.5 moles per mole of the acetic acid derivative 
(VI). Although the proportions of the thienopyrimidine derivative (III) 
and the acetic acid derivative (VI) can be appropriately determined, in 
general the acetic acid derivative (VI) is preferably used in an amount of 
about 1.0-2.0 moles per mole of the thienopyrimidine derivative (III). 
Although the reaction temperature is not specifically limited, the 
reaction is usually conducted with cooling or at room temperature. 
Step C 
The thienopyrimidine acetate derivative of the formula (IV) obtained is 
subjected to de-esterification reaction with or without isolation from the 
reaction system of Step B, giving the thienopyrimidine derivative of the 
formula (I). The de-esterification is conducted by a conventional method, 
for example, by a method using acid or base, etc. 
Examples of acids useful in a method using acid are lower fatty acids such 
as formic acid, acetic acid and propionic acid, trihaloacetic acids such 
as trichloroacetic acid and trifluoroacetic acid, halogenated hydroacids 
such as hydrochloric acid, hydrobromic acid and hydrofluoric acid, organic 
sulfonic acids such as p-toluenesulfonic acid and trifluoromethanesulfonic 
acid; and mixtures thereof. 
When an acid in the liquid form is used in the above reaction with an acid, 
no other solvent is required, but a solvent which does not participate in 
the reaction can be used, for example, halogenated hydrocarbons such as 
dichloromethane, chloroform and 1,2-dichloroethane, cyclic ethers such as 
tetrahydrofuran and dioxane, N,N-dimethylformamide, acetone, water and 
mixtures thereof. 
Examples of bases useful in a method using a base are hydroxides of alkali 
metals or alkaline earth metals such as lithium hydroxide, sodium 
hydroxide, potassium hydroxide, barium hydroxide, calcium hydroxide and 
magnesium hydroxide, carbonates such as potassium carbonate and sodium 
carbonate, 1,8-diazabicyclo[5,4,0]-7-undecene, etc. As a solvent, those 
which do not participate in the reaction are used, for example, alcohols 
such as methanol, ethanol and isopropanol, ethers such as tetrahydrofuran, 
dimethoxyethane and dioxane, N,N-dimethylformamide, mixtures of the 
aforementioned solvents and/or water, etc. 
In the above Reaction scheme (1), the compound (III) can be also 
synthesized from the thiophene derivative of the formula (II') by the 
process as shown in the following reaction scheme. 
##STR7## 
In the foregoing formulas, R.sub.1, R.sub.2 and R.sub.3 are as defined 
above. 
The compound of the formula (II') is knowm and described, for example, in 
"Heterocyclic Compounds", vol. 44. part 3, pp 565-973 "Thiophene and its 
derivatives", written by John M. Barker and Patrick R. Huddleston, edited 
by Salo Gronowitz, published by John Wiley & Sons, Inc., New York (1986). 
The thiophene derivative of the formula (II') is heated to 
50.degree.-120.degree. C. in the presence of phosgene or trichloromethyl 
chloroformate in a suitable solvent, and then the solvent is distilled 
off, giving the isocyanate derivative (II"). Examples of useful solvents 
are aromatic hydrocarbons such as xylene, toluene and benzene, halogenated 
hydrocarbons such as chloroform, 1,2-dichloroethane and 
tetrachloromethane, esters such as ethyl acetate and isopropyl acetate, 
cyclic ethers such as dioxane and tetrahydrofuran, dimethoxyethane and 
like solvents which do not participate in the reaction. The compound (II") 
is allowed to react with the amine of formula (V) in a solvent, giving the 
ureide derivative (II"'). Solvents suitable for the reaction are ethers 
such as diethyl ether, diisopropyl ether, tetrahydrofuran and dioxane, 
aromatic hydrocarbons such as xylene, toluene, benzene and chlorobenzene, 
halogenated hydrocarbons such as chloroform, 1,2-dichloroethane, 
tetrachloromethane and dichloromethane, etc. Although the reaction usually 
proceeds exothermically at room temperature, at the conclusion of the 
reaction the reaction system may be heated or such as a base may be as 
4-(N,N-dimethylamino)pyridine, pyridine, triethylamine, 
N-methylpiperidine, diisopropylethylamine, dicyclohexylethylamine, etc. 
The base is used in an amount of 0.1-3.0 equivalents per equivalent of the 
amine (V). The amount of the amine (V) is appropriately determined, but it 
is usually preferable to use the amine (V) in an amount of about 1.0 to 
about 2.0 moles per mole of the thiophene derivative (II"). The resulting 
ureide derivative (II"') is subjected to cyclization in a suitable solvent 
as it is or in the presence of a base, giving the thienopyrimidine 
derivative of the formula (III). As a base are exemplified organic amines 
such as triethylamine, pyridine, N-methylpiperidine, diisopropylethylamine 
and dicyclohexylethylamine, hydroxides of alkali metals such as sodium 
hydroxide and potassium hydroxide, alkoxides of alkali metals such as 
sodium methoxide, sodium ethoxide, sodium isopropoxide, potassium 
methoxide, potassium ethoxide, potassium t-butoxide and lithium methoxide, 
hydrides of alkali metals such as potassium hydride, lithium hydride and 
sodium hydride and other usual bases. Suitably used as a solvent are 
alcohols such as methanol, ethanol, propanol, isopropanol and butanol, 
ethers such as tetrahydrofuran, dimethoxyethane and dioxane, amides such 
as N,N-dimethylformamide and N,N-dimethylacetamide, dimethylsulfoxide or 
mixtures thereof. The base is preferably used in an amount of about 
1.0-3.0 moles per mole of the ureide derivative. The reaction is carried 
out usually at a temperature of about 50.degree. to about 150.degree. C. 
##STR8## 
In the foregoing formulas, R.sub.1 ' and R.sub.2 ' are the same as R.sub.1 
and R.sub.2 provided that at least one of them is hydrogen, R.sub.7 ' is 
hydrogen or the same as R.sub.7, R.sub.1 " and R.sub.2 " and the same as 
R.sub.1 and R.sub.2 provided that at least one of them is halogen, and 
R.sub.3 and R.sub.7 are as defined above. 
Step D 
The compound of the formula (IV') in which one or two hydrogen atoms exist 
in the thiophene ring moiety of the compound (IV) can be halogenated at 
the thiophene ring by a conventional method generally used in halogenating 
a thiophene. This procedure gives the compound of the formula (IV") or (I) 
in which one or two halogen atoms exist in the thiophene ring moiety. The 
halogenation is conducted by causing such a halogenating agent to act as 
chlorine, sulfuryl chloride, bromine and iodine in the presence or the 
absence of a catalyst in a solvent which does not participate in the 
reaction. Suitable solvents include acetic acid, ethers such as ethyl 
ether and dioxane, halogenated hydrocarbons such as chloroform, 
1,2-dichloroethane, tetrachloromethane and dichloromethane, water or 
mixtures thereof. In this case, the reaction temperature is not limited 
specifically. Examples of catalysts are inorganic acids such as sulfuric 
acid and periodic acid, Lewis acids such as alminium chloride, mercury 
chloride and tin chloride and the like. The halogenation is also suitably 
carried out by reacting the compound (IV') with a N-halogenosuccinimide 
such as N-chlorosuccinimide or N-bromosuccinimide as a halogenating agent 
in the above solvent at a temperature between room temperature and the 
reflux temperature of the solvent. The halogenating agent is generally 
used in an amount of about 1.0 to about 2.5 moles per mole of the compound 
(IV'). The compound of the formula (IV") can be made into the compound (I) 
by the method at Step C in Reaction scheme (1). 
##STR9## 
In the foregoing formulas, R.sub.1, R.sub.2, R.sub.3 and R.sub.7 are as 
defined above. 
Step E 
One to two equivalents of sodium hydride is added to a solution of the 
compound of the formula (VII) in N,N-dimethylformamide at a temperature of 
below room temperature, and the mixture is allowed to react with the 
acetic acid derivative (VI). Then the amine of the formula (V) is added 
and the mixture is allowed to react at a temperature between room 
temperature and 100.degree. C. to obtain the compound of the formula 
(VIII). The compounds of the formulas (VI) and (V) are preferably used in 
amounts of about 1.0 to about 2.0 moles per mole of the compound (VII). 
The compound of the formula (VII) can be prepared according to a 
conventional method for preparing isatonic anhydride by reacting the known 
corresponding 2-amino-3-thiophenecarboxylic acid ("Heterocyclic Compounds" 
vol. 44. part 3, pp 565-973 "Thiophene and its derivatives", written by 
John M. Barker and Patrick R. Huddleston, edited by Salo Gronowitz, 
published by John Wiley & Sons, Inc., New York (1986)) with phosgene or 
trichloromethyl chloroformate. The method using phosgene is described, for 
example, in E. C. Wagner and M. F. Fegley. Organic Synthesis, vol. III, 
488 (1955). The method using trichloromethyl chloroformate is described, 
for example, in K. Kurita, T. Matsumura and Y. Iwakura, Journal of Organic 
Chemistry, vol. 41, 2070 (1976). 
Step F 
One mole of the compound of the formula (VIII) and 2 to 3 moles of 
1,1'-thiocarbonyldiimidazole are dissolved in dioxane. The solution is 
heated to a bath temperature of 150.degree. C. and allowed to react for 
one to four hours, giving the thienopyrimidine derivative of the formula 
(IV"'). The compound can be treated in the same manner as in Step C in 
Reaction scheme (1) to give a compound of the formula (I). 
The novel thienopyrimidine derivative of the present invention produced by 
the above reaction can be easily isolated by a conventional separation 
method, for example, recrystallization, column chromatography or the like. 
For use in preventing or treating the diseases caused by aldose-reductase, 
e.g., diabetic cataract, neuropathy, nephropathy, diabetic retinopathy, 
the thienopyrimidine derivatives of the present invention are administered 
to mammals including humans in any of pharmaceutical dosage forms 
including oral preparation, injection, suppository and eye drop. Such 
preparations can be formulated in a manner already known in the art. 
For the formulation of solid preparations for oral administration such as 
tablets, coated tablets, granules, powders and capsules, an excipient and, 
when required, a binder, disintegrator, lubricant, coloring agent, 
corrigent, flavor, etc. are added to the compound of the invention, and 
then a preparation is formulated in a usual manner. Such additives are 
those already known in the art, and usuful examples are excipients such as 
lactose, sucrose, sodium chloride, glucose solution, starch, calcium 
carbonate, kaolin, crystalline cellulose and silicic acid; binders such as 
water, ethanol, propanol, glucose, carboxymethyl cellulose, hydroxymethyl 
cellulose, methyl cellulose, ethyl cellulose, schellac, potassium 
phosphate and polyvinyl pyrrolidone; disintegrators such as dried starch, 
sodium alginate, agar powder, sodium hydrogencarbonate, calcium carbonate, 
sodium lauryl sulfate, glyceryl monostearate and lactose; lubricants such 
as purified talc, stearic acid salt, boric acid powder and polyethylene 
glycol; corrigents such as sucrose, orange peel, citric acid and tartaric 
acid, etc. 
For the formulation of liquid preparations for oral administration such as 
oral liquid preparations and syrups, a corrigent, buffer, stabilizer, 
flavor, etc. can be added to the compound of the present invention, 
whereafter a preparation can be formulated in a usual manner. Examples of 
useful corrigents are those exemplified above. Examples of buffers are 
sodium citrate, etc. Examples of stabilizers are tragacanth, gum arabic, 
gelatin, etc. 
Parenteral preparations such as a subcutaneous injection, intramuscular 
injection, intravenous injection or the like can be prepared in a usual 
manner by adding to the comopound of the invention a pH adjusting agent, 
buffer, stabilizer, isotonic agent, local anesthetic, etc. Examples of pH 
adjusting agents and buffers are sodium citrate, sodium acetate, sodium 
phosphate, etc. Examples of stabilizers are sodium pyrosulfite, EDTA, 
thioglycolic acid, thiolactic acid, etc. Examples of local anesthetics are 
procaine hydrochloride, lidocaine hydrochloride, etc. 
Suppositories can be prepared in a usual manner by adding excipients such 
as unsaturated fatty acid triglycerides and, if required, surfactants such 
as Tween. 
Eye drops can be prepared in a usual manner by using a diluent such as 
distilled water and physiological saline. Eye drops should preferably be 
made isotonic by using a pH adjusting agent, buffer, etc. 
The amount of the compound of the present invention to be incorporated into 
each dosage form varies with the symptoms of the patient or with the type 
of the preparation. Preferably the amount per administration unit is about 
10 to about 300 mg for oral administration, about 10 to about 50 mg for 
pareteral administration, about 10 to 200 mg for intrarectal 
administration and about 5 to about 50 mg for administration to eyes. The 
dosage per day of such preparations is variable with the symptoms, body 
weight, age, sex and the like of the patient. Usually the preparation is 
adminstered to an adult in an amount of about 5 to about 900 mg per day 
based on the compound, preferably in one or two to four devided doses. 
The present invention will be described below in more detail with reference 
to Reference Examples and Examples. 
REFERENCE EXAMPLE 1 
Preparation of 
3-(4-chlorobenzyl)-5,6-dimethylthieno[2,3-d]pyrimidin-2,4(1H,3H)-dione 
(Compound III-1) 
A 1 g quantity of ethyl 
2-ethoxycarbonylamino-4,5-dimethyl-3-thiophenecarboxylate and 1 g of 
4-chlorobenzylamine were dissolved in a mixture of 3 ml of ethanol and 1 
ml of N,N-dimethylformamide and the mixture was allowed to react in a 
sealed tube at 230.degree. C. for 7 hours. The reaction mixture was 
concentrated and the residue was recrystallized from an 
acetone-ethanol-dimethylformamide mixture, giving 0.8 g of 
3-(4-chlorobenzyl)-5,6-dimethylthieno[2,3-d]pyrimidin-2,4(1H,3H)-dione 
having a melting point of 291.degree. to 292.degree. C. in a yield of 68%. 
______________________________________ 
Elemental Analysis (for C.sub.15 H.sub.13 N.sub.2 O.sub.2 SCl) 
C H N 
______________________________________ 
Calcd. (%): 
56.16 4.08 8.73 
Found (%): 56.12 4.00 8.83 
______________________________________ 
REFERENCE EXAMPLE 2 
The compounds III-2 to III-9 as shown below in Table 1 were prepared in the 
same manner as in Reference Example 1. 
REFERENCE EXAMPLE 3 
Preparation of 
3-(4-bromo-2-fluorobenzyl)-5-methylthieno[2,3-d]-pyrimidine-2,4(1H,3H)-dio 
ne (Compound III-17) 
A solution of 3.71 g of ethyl 2-amino-4-methyl-3-thiophenecarboxylate and 
7.91 g of trichloromethyl chloroformate in 50 ml of dioxane was stirred at 
a bath temperature of 80.degree. to 100.degree. C. for 3 hours, and the 
solvent was evaporated off under reduced pressure. The residue was 
dissolved in 30 ml of diethyl ether and 4.49 g of 
4-bromo-2-fluorobenzylamine was added dropwise thereto with ice-cooling. 
After the temperature of the mixture was raised to room temperature, the 
mixture was stirred for three hours, 20 ml of n-hexane was added dropwise 
thereto and a colorless precipitate was collected, giving 5.4 g of the 
ureide compound of the following formula in a yield of 68%. 
##STR10## 
A 5.3 g quantity of the ureide compound was dissolved in 70 ml of ethanol 
and 1.58 g of sodium methoxide was added thereto. The mixture was refluxed 
for 5 hours, concentrated to a half of volume, and then homogeneously 
mixed with 20 ml of water. The resulting solution was neutralized and 
acidified with concentrated hydrochloric acid to precipitate colorless 
crystals. The crystals were collected by filtration, washed with water and 
dried in vacuo, giving 4.75 g of the compound III-17 having a melting 
point of 296.degree. to 297.5.degree. C. in a yield of 97%. 
______________________________________ 
Elemental Analysis (for C.sub.14 H.sub.10 N.sub.2 O.sub.2 SBrF) 
C H N 
______________________________________ 
Calcd. (%): 
45.54 2.73 7.59 
Found (%): 45.51 2.61 7.64 
______________________________________ 
REFERENCE EXAMPLE 4 
The compounds III-10 to III-16, III-18 and III-19 as shown below in Table 1 
were prepared in the same manner as in Reference Example 3. 
TABLE 1 
__________________________________________________________________________ 
##STR11## 
__________________________________________________________________________ 
Compound No. 
R.sub.1 
R.sub.2 
R.sub.3 Yield (%) 
mp (.degree.C.) 
__________________________________________________________________________ 
III-1 CH.sub.3 
CH.sub.3 
##STR12## 68 291.about.292 
III-2 CH.sub.3 
CH.sub.3 
##STR13## 70 275.about.276 
III-3 (CH.sub.3).sub.2 CH 
H 
##STR14## 43 252.5.about. 253.5 
III-4 (CH.sub.3).sub.2 CH 
H 
##STR15## 12 223.about.226 
III-5 H CH.sub.3 
##STR16## 70 299.about.300 
III-6 
##STR17## 
##STR18## 29 230.about.232 
III-7 
##STR19## 
##STR20## 40 240.about.241 
III-8 
##STR21## 
##STR22## 45 255.about.256 
III-9 
##STR23## 
(CH.sub.2).sub.5 CH.sub.3 
24 132.about. 132.5 
III-10 CH.sub.3 
H 
##STR24## 55 304.about.305 
III-11 CH.sub.3 
CH.sub.3 
##STR25## 47 258.about. 258.5 
III-12 
##STR26## 
##STR27## 49 225.about.230 
III-13 
##STR28## 
H 
##STR29## 69 257.about.259 
III-14 (CH.sub.3).sub.2 CH 
H 
##STR30## 76 227.about.228 
III-15 (CH.sub.3).sub.3 C 
H 
##STR31## 43 263.5.about. 265 
III-16 H H 
##STR32## 71 290.about.291 
III-17 H CH.sub.3 
##STR33## 66 296.about. 297.5 
III-18 (CH.sub.3).sub.2 CH 
H 
##STR34## 64 219.about.221 
III-19 
##STR35## 
H 
##STR36## 50 257.about.259 
__________________________________________________________________________ 
Elemental Analysis(%): Calcd. in parenthesis 
Compound No. 
Molecular Formula 
C H N 
__________________________________________________________________________ 
III-1 C.sub.15 H.sub. 13 N.sub.2 O.sub.2 ClS 
(56.16) (4.08) 
(8.73) 
56.12 4.00 
8.83 
III-2 C.sub.15 H.sub.12 N.sub.2 O.sub.2 Cl.sub.2 S 
(50.72) (3.40) 
(7.89) 
50.43 3.26 
7.80 
III-3 C.sub.16 H.sub.14 N.sub.2 O.sub.2 Cl.sub.2 S 
(52.04) (3.83) 
(7.59) 
52.01 3.87 
7.60 
III-4 C.sub.16 H.sub.14 N.sub.2 O.sub.2 Cl.sub.2 S 
(52.04) (3.83) 
(7.59) 
51.75 3.81 
7.51 
III-5 C.sub.14 H.sub.10 N.sub.2 O.sub.4 S 
(62.21) (3.73) 
(10.36) 
62.10 3.54 
10.20 
III-6 C.sub.18 H.sub.18 N.sub.2 O.sub.3 S 
(63.14) (5.30) 
(8.18) 
63.28 5.11 
8.17 
III-7 C.sub.18 H.sub.18 N.sub.2 O.sub.2 S 
(66.23) (5.56) 
(8.58) 
66.30 5.42 
8.50 
III-8 C.sub.17 H.sub.14 Cl.sub.2 N.sub.2 O.sub.2 S 
(53.55) (3.70) 
(7.35) 
53.45 3.77 
7.37 
III-9 C.sub.16 H.sub.22 N.sub.2 O.sub.2 S 
(62.72) (7.24) 
(9.14) 
62.50 7.12 
9.02 
III-10 C.sub.14 H.sub.10 BrFN.sub.2 O.sub.2 S 
(45.54) (2.73) 
(7.59) 
45.86 3.04 
7.51 
III-11 C.sub.15 H.sub.12 BrFN.sub.2 O.sub.2 S 
(47.01) (3.16) 
(7.31) 
47.11 3.18 
7.41 
III-12 C.sub.17 H.sub.14 FBrN.sub.2 O.sub.2 S 
(49.89) (3.45) 
(6.84) 
49.49 3.20 
6.76 
III-13 C.sub.18 H.sub.16 BrFN.sub.2 O.sub.2 S 
(51.07) (3.81) 
(6.62) 
50.86 3.84 
6.63 
III-14 C.sub.16 H.sub.14 BrFN.sub.2 O.sub.2 S 
(48.38) (3.55) 
(7.05) 
48.18 3.56 
7.11 
III-15 C.sub.17 H.sub.16 Cl.sub.2 N.sub.2 O.sub.2 S 
(53.27) (4.21) 
(7.31) 
53.58 4.37 
7.31 
III-16 C.sub.13 H.sub.8 BrFN.sub.2 O.sub.2 S 
(43.96) (2.27) 
(7.89) 
44.05 2.30 
7.83 
III-17 C.sub.14 H.sub.10 BrFN.sub.2 O.sub.2 S 
(45.54) (2.73) 
(7.59) 
45.51 2.61 
7.64 
III-18 C.sub.16 H.sub.14 F.sub.2 N.sub.2 O.sub.2 S 
(57.13) (4.20) 
(8.33) 
57.63 4.42 
8.53 
III-19 C.sub.16 H.sub.18 Cl.sub.2 N.sub.2 O.sub.2 S 
(54.69) (4.08) 
(7.09) 
54.70 4.18 
6.99 
__________________________________________________________________________ 
REFERENCE EXAMPLE 5 
Preparation of 
3-(4-chlorobenzyl)-1-ethoxycarbonylmethyl-5,6-dimethylthieno[2,3-d]pyrimid 
in-2,4(1H,3H)-dione (Compound IV-1) 
A 0.6 g quantity of 
3-(4-chlorobenzyl)-5,6-dimethylthieno[2,3-d]pyrimidin-2,4(1H,3H)-dione 
(Compound III-1) was dissolved in 20 ml of anhydrous 
N,N-dimethylformamide. To the solution were added at room temperature 0.1 
g of 50% sodium hydride and then 0.4 g of ethyl bromoacetate. The mixture 
was stirred at room temperature for 17 hours, concentrated and acidified 
by adding diluted hydrochloric acid with ice-cooling. The crystals 
precipitated were collected by filtration and recrystallized from ethanol, 
giving 0.7 g of 
3-(4-chlorobenzyl)-1-ethoxycarbonylmethyl-5,6-dimethylthieno[2,3-d]pyrimid 
in-2,4(1H,3H)-dione having a melting point of 151.degree. to 152.degree. C. 
in a yield of 92%. 
______________________________________ 
Elemental Analysis (for C.sub.19 H.sub.19 N.sub.2 O.sub.4 SCl) 
C H N 
______________________________________ 
Calcd. (%): 
56.09 4.71 6.88 
Found (%): 55.84 4.50 6.89 
______________________________________ 
REFERENCE EXAMPLE 6 
The compounds IV-2 to IV-8 and IV-12 to IV-22 as shown below in Table 2 
were prepared in the same manner as in Reference Example 5. 
REFERENCE EXAMPLE 7 
Preparation of 
1-ethoxycarbonylmethyl-3-hexyl-5,6,7,8-tetrahydrobenzothieno[2,3-d]pyrimid 
in-2,4(1H,3H)-dione (Compound IV-9) 
A 1.2 g quantity of 
3-hexyl-5,6,7,8-tetrahydrobenzothieno[2,3-d]pyrimidin-2,4(1H,3H)-dione 
(Compound III-9), 0.14 g of 50% sodium hydride and 1.0 g of ethyl 
bromoacetate were allowed to react with each other in the same manner as 
in Reference Example 5. The residue obtained by concentration was 
subjected to silica gel column chromatography using chloroform as an 
eluent. Then 1.2 g of 
1-ethoxycarbonylmethyl-3-hexyl-5,6,7,8-tetrahydrobenzothieno[2,3-d]pyrimid 
in-2,4(1H,3H)-dione was obtained in a yield of 77%. 
Nuclear Magnetic Resonance (DMSO-d.sub.6): .delta.(ppm): 0.85 (3H, t), 
1.0-2.0 (12H, m), 1.21 (3H, t), 2.5-2.9 (4H, m), 3.84 (2H, t), 4.17 (2H, 
q), 4.7 (2H, s) 
REFERENCE EXAMPLE 8 
Preparation of 
1-ethoxycarbonylmethyl-3-(3,4-dichlorobenzyl)-6-bromo-5-methylthieno[2,3-d 
]pyrimidin-2,4(1H,3H)-dione (Compound IV"-10) 
A 0.3 g quantity of 
1-ethoxycarbonylmethyl-3-(3,4-dichlorobenzyl)-5-methylthieno[2,3-d]pyrimid 
in-2,4(1H,3H)-dione (compound IV-5) synthesized in Reference Example 6 and 
0.137 g of N-bromosuccinimide were dissolved in 30 ml of anhydrous 
tetrachloromethane, and the mixture was refluxed for 2 hours. The solvent 
was distilled off under reduced pressure and the residual solid obtained 
was purified by silica gel column chromatography 
(eluent:chloroform:n-hexane=2:1) to afford 0.30 g of 
1-ethoxycarbonylmethyl-3-(3,4-dichlorobenzyl)-6-bromo-5-methylthieno[2,3-d 
]pyrimidin-2,4(1H,3H)-dione having m.p. of 165.5.degree. to 167.degree. C. 
in a yield of 85%. 
______________________________________ 
Elemental Analysis (for C.sub.18 H.sub.15 N.sub.2 O.sub.4 SBrCl.sub.2) 
C H N 
______________________________________ 
Calcd. (%): 
47.21 2.99 5.53 
Found (%): 47.50 2.84 5.42 
______________________________________ 
REFERENCE EXAMPLE 9 
The compound IV"-23 as shown in Table 2 was prepared in the same manner as 
in Reference Example 8. 
REFERENCE EXAMPLE 10 
Preparation of 
1-ethoxycarbonylmethyl-3-(3,4-dichlorobenzyl)-6-chloro-5-methylthieno[2,3- 
d]pyrimidin-2,4(1H,3H)-dione (Compound IV"-11) 
A 0.427 g quantity of 
1-ethoxycarbonylmethyl-3-(3,4-dichlorobenzyl)-5-methylthieno[2,3-d]pyrimid 
in-2,4(1H,3H)-dione (compound IV-5) synthesized in Reference Example 6 and 
0.162 g of sulfuryl chloride were dissolved in 30 ml of anhydrous 
tetrachloromethane, and the mixture was allowed to react at 50.degree. to 
70.degree. C. for 6 hours. The residue obtained by concentration of the 
reaction mixture was subjected to silica gel column chromatography using a 
2:1 mixture of chroloform and n-hexane as an eluent to afford 0.30 g of 
1-ethoxycarbonylmethyl-3-(3,4-dichlorobenzyl)-6-chloro-5-methylthieno[2,3- 
d]pyrimidin-2,4(1H,3H)-dione having m.p. of 141.degree. to 145.degree. C. 
in a yield of 65%. 
______________________________________ 
Elemental Analysis (for C.sub.18 H.sub.15 N.sub.2 O.sub.4 SCl.sub.3) 
C H N 
______________________________________ 
Calcd. (%): 
46.82 3.27 6.07 
Found (%): 46.65 3.12 5.92 
______________________________________ 
REFERENCE EXAMPLE 11 
The compound IV"-24 as shown in Table 2 was prepared in the same manner as 
in Reference Example 10. 
REFERENCE EXAMPLE 12 
Preparation of 
1-ethoxycarbonylmethyl-3-(4-bromo-2-fluorobenzyl)-6-isopropyl-4(3H)-oxo-2( 
1H)-thioxothieno[2,3-d]pyrimidine (Compound IV"'-25) 
A 7.8 g quantity of 2-amino-5-isopropylthiophenecarboxylic acid and 25 g of 
trichloromethyl chloroformate were dissolved in 80 ml of dioxane. The 
resulting solution was refluxed for 6 hours and then the solvent was 
evaporated off under reduced pressure. The pale brown solids obtained were 
crushed in ether and the pieces were collected by filtration and dried in 
vacuo. As pale color solids was obtained 5.6 g of the compound of the 
following formula in a yield of 74%. 
##STR37## 
M.p.: 180.degree.-181.degree. C. (CO.sub.2 generated). 
______________________________________ 
Elemental Analysis (for C.sub.9 H.sub.9 NO.sub.3 S) 
C H N 
______________________________________ 
Calcd. (%): 
51.17 4.29 6.63 
Found (%): 51.21 4.36 6.65 
______________________________________ 
A 5.4 g quantity of this compound was dissolved in 40 ml of 
N,N-dimethylformamide and 1.45 g of 60% sodium hydride was added to the 
solution with ice-cooling. After stirring for 40 minutes, 4.34 ml of ethyl 
bromoacetate was added thereto. The temperature of the mixture was raised 
to room temperature, and the reaction was conducted for 2 hours. Then 7.96 
g of 4-bromo-2-fluorobenzylamine was added to the reaction mixture, the 
mixture was allowed to react at 80.degree. C. for two hours, 5.4 ml of 
triethylamine was added thereto and the reaction mixture was allowed to 
react for 1 hour. The solvent was distilled off under reduced pressure and 
the residue was extracted with 120 ml of chloroform. The extract was 
washed with water, dried over anhydrous sodium carbonate and then 
concentrated. The residue obtained was recrystallized from a mixture of 
chloroform, iropropyl ether and n-hexane, giving 8.92 g of the compound of 
the following formula as pale yellow needle crystals in a yield of 65%. 
##STR38## 
M.p.: 135.5.degree.-137.5.degree. C. 
______________________________________ 
Elemental Analysis (for C.sub.19 H.sub.22 N.sub.2 O.sub.3 SBrF) 
C H N 
______________________________________ 
Calcd. (%): 
49.90 4.85 6.13 
Found (%): 49.63 4.65 6.16 
______________________________________ 
A 2.29 quantity of this compound and 1.96 g of 1,1'-thiocarbonyldiimidazole 
were dissolved in 20 ml of dioxane. The dioxane was distilled off with 
stirring on the bath at 150.degree. C. and the mixture was allowed to 
react for 2 hours. Ethanol was added to the reaction mixture when hot and 
the solution was cooled to room temperature. The crystals precipitated 
were collected and purified by silica gel (75 g) column chromatography 
using chloroform as an eluent, giving as colorless crystals 2.11 g of 
Compound IV"'-25 having m.p. of 177.degree. to 179.degree. C. in a yield 
of 85%. 
______________________________________ 
Elemental Analysis (for C.sub.20 H.sub.20 N.sub.2 O.sub.3 S.sub.2 BrF) 
C H N 
______________________________________ 
Calcd. (%): 
48.10 4.04 5.61 
Found (%): 48.30 3.94 5.64 
______________________________________ 
TABLE 2 
__________________________________________________________________________ 
##STR39## (IV) 
__________________________________________________________________________ 
Compound No. 
R.sub.1 
R.sub.2 
R.sub.3 Z R.sub.7 
Yield (%) 
mp (.degree.C.) 
__________________________________________________________________________ 
IV-1 CH.sub.3 
CH.sub.3 
##STR40## O C.sub.2 H.sub.5 
92 151.about.152 
IV-2 CH.sub.3 
CH.sub.3 
##STR41## O C.sub.2 H.sub.5 
96 150.about.151 
IV-3 (CH.sub.3).sub.2 CH 
H 
##STR42## O C.sub.2 H.sub.5 
89 91.about.92 
IV-4 (CH.sub.3).sub.2 CH 
H 
##STR43## O C.sub.2 H.sub.5 
61 146.about.148 
IV-5 H CH.sub.3 
##STR44## O C.sub.2 H.sub.5 
46 124.about.126 
IV-6 
##STR45## 
##STR46## O C.sub.2 H.sub.5 
60 153.5.about. 154 
IV-7 
##STR47## 
##STR48## O C.sub.2 H.sub.5 
65 147.about.149 
IV-8 
##STR49## 
##STR50## O C.sub.2 H.sub.5 
66 169.about.170 
IV-9 
##STR51## 
(CH.sub.2).sub.5 CH.sub.3 
O C.sub.2 H.sub.5 
77 Oil 
IV"-10 Br CH.sub.3 
##STR52## O C.sub.2 H.sub.5 
85 165.5.about. 167 
IV"-11 Cl CH.sub.3 
##STR53## O C.sub.2 H.sub.5 
65 141.about.145 
IV-12 CH.sub.3 
H 
##STR54## O C.sub.2 H.sub.5 
58 145.about.147 
IV-13 
##STR55## 
H 
##STR56## O C.sub.2 H.sub.5 
70 234.about.235 
IV-14 CH.sub.3 
CH.sub.3 
##STR57## O C.sub.2 H.sub.5 
88 144.about.146 
IV-15 
##STR58## 
##STR59## O C.sub.2 H.sub.5 
60 141.about.143 
IV-16 
##STR60## 
H 
##STR61## O C.sub.2 H.sub.5 
83 96.about.97 
IV-17 (CH.sub.3).sub.2 CH 
H 
##STR62## O C.sub.2 H.sub.5 
88 99.about.101 
IV-18 (CH.sub.3).sub.3 C 
H 
##STR63## O C.sub.2 H.sub.5 
68 115.about.116 
IV-19 H H 
##STR64## O C.sub.2 H.sub.5 
63 117.about.119 
IV-20 H CH.sub.3 
##STR65## O C.sub.2 H.sub.5 
87 153.about.154 
IV-21 (CH.sub.3).sub.2 CH 
H 
##STR66## O C.sub.2 H.sub.5 
50 111.about.112 
IV-22 
##STR67## 
H 
##STR68## O C.sub.2 H.sub.5 
73 135.about.136 
IV"-23 Br H 
##STR69## O C.sub.2 H.sub.5 
62 169.about.170 
IV"-24 Cl H 
##STR70## O C.sub.2 H.sub.5 
93 132.5.about. 133.5 
IV"'-25 (CH.sub.3).sub.2 CH 
H 
##STR71## S C.sub.2 H.sub.5 
85 177.about.179 
__________________________________________________________________________ 
Elemental Analysis(%): Calcd. in parenthesis 
Compound No. 
Molecular Formula 
C H N 
__________________________________________________________________________ 
IV-1 C.sub.19 H.sub.19 N.sub.2 O.sub.4 ClS 
(56.09) (4.71) (6.88) 
55.84 4.50 6.89 
IV-2 C.sub.19 H.sub.18 N.sub.2 O.sub.4 Cl.sub.2 S 
(51.71) (4.11) (6.35) 
51.42 4.19 6.14 
IV-3 C.sub.20 H.sub.20 N.sub.2 O.sub.4 Cl.sub.2 S 
(52.75) (4.43) (6.15) 
52.85 4.45 6.15 
IV-4 C.sub.20 H.sub.20 N.sub.2 O.sub.4 Cl.sub.2 S 
(52.75) (4.43) (6.15) 
52.86 4.44 6.11 
IV-5 C.sub.18 H.sub.16 N.sub.2 O.sub.4 Cl.sub.2 S 
(50.60) (3.77) (6.56) 
50.70 3.77 6.62 
IV-6 CHN.sub.2 O.sub.5 S 
(61.67) (5.65) (6.54) 
61.70 5.77 6.49 
IV-7 C.sub.22 H.sub.24 N.sub.2 O.sub. 4 S 
(64.06) (5.86) (6.79) 
64.14 5.81 6.75 
IV-8 C.sub.21 H.sub.20 Cl.sub.2 N.sub.2 O.sub.4 S 
(53.97) (4.31) (5.99) 
53.80 4.32 5.99 
IV-9 C.sub.20 H.sub.28 N.sub.2 O.sub.4 S 
(61.20) (7.19) (7.14) 
60.95 7.38 6.95 
IV"-10 C.sub.18 H.sub.15 BrCl.sub.2 N.sub.2 O.sub.4 S 
(47.21) (2.99) (5.53) 
47.50 2.84 5.42 
IV"-11 C.sub.18 H.sub.15 Cl.sub.3 N.sub.2 O.sub.4 S 
(46.82) (3.27) (6.07) 
46.65 3.12 5.92 
IV-12 C.sub.18 H.sub.16 BrFN.sub.2 O.sub.4 S 
(47.48) (3.54) (6.15) 
47.35 3.62 6.15 
IV-13 C.sub.23 H.sub.18 BrFN.sub.2 O.sub.4 S 
(53.39) (3.51) (5.41) 
53.57 3.32 5.46 
IV-14 C.sub.19 H.sub.18 BrFN.sub.2 O.sub.4 S 
(48.62) (3.87) (5.97) 
48.48 3.85 5.96 
IV-15 C.sub.21 H.sub.20 BrFN.sub.2 O.sub.4 S 
(50.92) (4.07) (5.66) 
50.70 4.09 5.60 
IV-16 C.sub.22 H.sub.22 BrFN.sub.2 O.sub.4 S 
(51.87) (4.35) (5.50) 
52.35 4.42 5.47 
IV-17 C.sub.20 H.sub.20 BrFN.sub.2 O.sub.4 S 
(49.70) (4.17) (5.80) 
49.77 4.31 5.72 
IV-18 C.sub. 21 H.sub.22 Cl.sub.2 N.sub.2 O.sub.4 S 
(53.74) (4.72) (5.97) 
53.70 4.85 6.07 
IV-19 C.sub.17 H.sub.14 BrFN.sub.2 O.sub.4 S 
(46.27) (3.20) (6.35) 
46.35 3.32 6.18 
IV-20 C.sub.18 H.sub.16 BrFN.sub.2 O.sub.4 S 
(47.48) (3.54) (6.15) 
47.50 3.54 6.18 
IV-21 C.sub.20 H.sub.20 F.sub.2 N.sub.2 O.sub.4 S 
(56.86) (4.77) (6.63) 
56.46 5.10 6.77 
IV-22 C.sub.22 H.sub.22 Cl.sub.2 N.sub.2 O.sub.4 S 
(54.89) (4.61) (5.82) 
55.06 4.56 5.86 
IV"-23 C.sub.17 H.sub.13 Br.sub.2 FN.sub.2 O.sub.4 S 
(39.25) (2.52) (5.39) 
39.28 2.60 5.21 
IV"-24 C.sub.17 H.sub.13 BrClFN.sub.2 O.sub.4 S 
(42.92) (2.75) (5.89) 
43.01 2.67 5.91 
IV"'-25 C.sub.20 H.sub.20 BrFN.sub.2 O.sub.3 S.sub.2 
(48.10) (4.04) (5.61) 
48.30 3.94 5.64 
__________________________________________________________________________ 
EXAMPLE 1 
Preparation of 
1-carboxymethyl-3-(4-chlorobenzyl)-5,6-dimethylthieno[2,3-d]pyrimidin-2,4( 
1H, 3H)-dione (Compound I-1) 
A 0.7 g quantity of 
3-(4-chlorobenzyl)-1-ethoxycarbonylmethyl-5,6-dimethylthieno[2,3-d]pyrimid 
in-2,4(1H, 3H)-dione (Compound IV-1) prepared in Reference Example 5 was 
dissolved in 30 ml of methanol. To the solution was added 0.3 g of sodium 
hydroxide dissolved in 2 ml of water. The mixture was allowed to react at 
60.degree. C. for 30 minutes, and then the reaction mixture was 
concentrated. Diluted hydrochloric acid was added thereto with ice-cooling 
to acidify the resulting solution. The solution was filtrated and the 
separated crystals were recrystallized from methanol, giving 0.4 g of 
1-carboxymethyl-3-(4-chlorobenzyl)-5,6-dimethylthieno[2,3-d]pyrimidin-2,4( 
1H, 3H)-dione having m.p. of 173.degree. to 176.degree. C. in a yield of 
61%. 
______________________________________ 
Elemental Analysis (for C.sub.17 H.sub.15 N.sub.2 O.sub.4 SCl) 
C H N 
______________________________________ 
Calcd. (%): 
53.90 3.99 7.39 
Found (%): 53.75 4.04 7.31 
______________________________________ 
EXAMPLE 2 
The compounds I-2 to I-11 as shown below in Table 3 were prepared in the 
same manner as in Example 1. 
EXAMPLE 3 
Preparation of 
1-carboxymethyl-3-(4-bromo-2-fluorobenzyl)-5-methylthieno[2,3-d]pyrimidin- 
2,4(1H, 3H)-dione (Compound I-20) 
A 4.60 quantity of Compound IV-20 prepared in Reference Example 6, 20 ml of 
acetic acid and 10 ml of concentrated hydrochloric acid were refluxed for 
4 hours, and then 10 ml of concentrated hydrochloric acid was added. The 
solution was further refluxed for 4 hours, and 10 ml of water was added. 
The mixture was allowed to stand overnight at room temperature. The 
crystals precipitated were collected, washed with water and recrystallized 
from 80% ethanol, giving 3.75 g of Compound I-20 having m.p. of 
206.5.degree. to 208.degree. C. in a yield of 87%. 
______________________________________ 
Elemental Analysis (for C.sub.16 H.sub.12 N.sub.2 O.sub.4 SBrF) 
C H N 
______________________________________ 
Calcd. (%): 
44.98 2.83 6.56 
Found (%): 45.02 2.78 6.38 
______________________________________ 
EXAMPLE 4 
The compounds I-12 to I-19 and I-21 to I-25 as shown below in Table 3 were 
prepared in the same manner as in Example 3. 
EXAMPLE 5 
Preparation of L-arginine salt of 
1-carboxymethyl-3-(4-bromo-2-fluorobenzyl)-6-chlorothieno[2,3-d]pyrimidin- 
2,4(1H,3H)-dione (Compound I-24) 
A 0.45 g quantity of Compound I-24 was dissolved in 10 ml of ethanol with 
refluxing, and an aqueous solution (1 ml) of 0.174 g of L-arginine was 
added to the solution. Then the solution was cooled and allowed to stand 
at room temperature for one day. The crystals precipitated were collected, 
washed with ethanol and dried in vacuo at 100.degree. C. for 6 hours, 
giving 0.49 g of the L-arginine salt of Compound I-24 having m.p. of 
224.degree. to 225.5.degree. C. in a yield of 76%. 
______________________________________ 
Elemental Analysis (for C.sub.21 H.sub.23 N.sub.6 O.sub.6 SBrClF) 
C H N 
______________________________________ 
Calcd. (%): 
40.56 3.73 13.51 
Found (%): 40.27 3.65 13.51 
______________________________________ 
EXAMPLE 6 
The L-lysine salt of Compound I-24 was prepared in the same manner as in 
Example 5 in a yield of 82%. 
M.p.: 213.degree.-214.degree. C. 
______________________________________ 
Elemental Analysis (for C.sub.21 H.sub.23 N.sub.4 O.sub.6 SBrClF.lH.sub.2 
O) 
C H N 
______________________________________ 
Calcd. (%): 
41.22 4.12 9.16 
Found (%): 41.55 4.04 9.19 
______________________________________ 
EXAMPLE 7 
Preparation of 
1-carboxymethyl-3-(4-bromo-2-flurobenzyl)-6-chloro-4(3H)-oxo-2(1H)-thioxot 
hieno[2,3-d]pyrimidine (I-26) 
According to the method described in Reference Example 12, 2.5 g of 
N-(4-bromo-2-fluorobenzyl)-5-chloro-2-ethoxycarbonylmethylamino-3-thiophen 
ecarboxamide, 2.0 g of 1,1'-thiocarbonyldiimidazole and 20 ml of dioxane 
were mixed together and the mixture was allowed to react on a bath at a 
temperature of 150.degree. C. for 2 hours. A 80 ml quantity of ethanol was 
added and the solution was cooled to room temperature. The crystals 
precipitated were collected to prepare 1.4 g of 
1-ethoxycarbonylmethyl-3-(4-bromo-2-fluorobenzyl)-6-chloro-4(3H)-oxo-2(1H) 
-thioxothieno[2,3-d]pyrimidine as a crude product. This crude product was 
hydrolyzed in the same manner as in Example 3. That is, 15 ml of acetic 
acid and 15 ml of concentrated hydrochloric acid were added to this crude 
product, and the mixture was refluxed for 8 hours. Thereto 15 ml of water 
was added and the solution was cooled to room temperature. The crystals 
precipitated were collected by filtration and recrystallized from 80% 
ethanol, giving 0.54 g of 
1-carboxymethyl-3-(4-bromo-2-fluorobenzyl)-6-chloro-4(3H)-oxo-2(1H)-thioxo 
thieno[2,3-d]pyrimidine in a yield of 41%. 
______________________________________ 
Elemental Analysis (for C.sub.15 H.sub.9 N.sub.2 O.sub.3 S.sub.2 BrClF) 
C H N 
______________________________________ 
Calcd. (%): 
38.85 1.95 6.04 
Found (%): 38.47 2.10 5.77 
______________________________________ 
TABLE 3 
__________________________________________________________________________ 
##STR72## (I) 
__________________________________________________________________________ 
Compound No. 
R.sub.1 
R.sub.2 
R.sub.3 Z Yield (%) 
mp (.degree.C.) 
__________________________________________________________________________ 
I-1 CH.sub.3 
CH.sub.3 
##STR73## O 61 173.about.176 
I-2 CH.sub.3 
CH.sub.3 
##STR74## O 53 266.about.267 
I-3 (CH.sub.3).sub.2 CH 
H 
##STR75## O 61 189.about.191 
I-4 (CH.sub.3).sub.2 CH 
H 
##STR76## O 44 228.about.229 
I-5 H CH.sub.3 
##STR77## O 48 &gt;300 
I-6 
##STR78## 
##STR79## O 65 230.about.234 
I-7 
##STR80## 
##STR81## O 65 253.about.256 
I-8 
##STR82## 
##STR83## O 63 265.about.266 
I-9 
##STR84## 
(CH.sub.2).sub.5 CH.sub.3 
O 65 204.about.206 
I-10 Br CH.sub.3 
##STR85## O 37 &gt;300 
I-11 Cl CH.sub.3 
##STR86## O 19 &gt;300 
I-12 CH.sub.3 
H 
##STR87## O 66 242.about.243 
I-13 
##STR88## 
H 
##STR89## O 71 249.about.251 
I-14 CH.sub.3 
CH.sub.3 
##STR90## O 80 233.about.235 
I-15 
##STR91## 
##STR92## O 85 228.about.290 
I-16 
##STR93## 
H 
##STR94## O 49 160.about.162 
I-17 (CH.sub.3).sub.2 CH 
H 
##STR95## O 55 203.about.205 
I-18 (CH.sub.3).sub.3 C 
H 
##STR96## O 67 194.about.197 
I-19 H H 
##STR97## O 77 200.about.202 
I-20 H CH.sub.3 
##STR98## O 87 206.5.about. 208 
I-21 (CH.sub.3).sub.2 CH 
H 
##STR99## O 75 194.about.196 
I-22 
##STR100## 
H 
##STR101## O 34 222.about.226 
I-23 Br H 
##STR102## O 93 244.about. 246.5 
I-24 Cl H 
##STR103## O 96 221.about.223 
I-25 (CH.sub.3).sub.2 CH 
H 
##STR104## S 93 220.about.221 
I-26 Cl H 
##STR105## S 41 -- 
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Elemental Analysis (%): Calcd. in parenthesis 
Compound No. 
Molecular Formula 
C H N 
__________________________________________________________________________ 
I-1 C.sub.17 H.sub.15 N.sub.2 O.sub.4 ClS 
(53.90) 
(3.99) (7.39) 
53.75 4.04 7.31 
I-2 C.sub.17 H.sub.14 N.sub.2 O.sub.4 Cl.sub.2 S 
(49.41) 
(3.41) (6.78) 
49.17 3.38 6.82 
I-3 C.sub.18 H.sub.16 N.sub.2 O.sub.4 Cl.sub.2 S 
(50.60) 
(3.77) (6.56) 
50.62 3.91 6.54 
I-4 C.sub.18 H.sub.16 N.sub.2 O.sub.4 Cl.sub.2 S 
(50.60) 
(3.77) (6.56) 
50.58 3.86 6.55 
I-5 C.sub.16 H.sub.12 N.sub.2 O.sub.4 Cl.sub.2 S 
(48.13) 
(3.03) (7.02) 
48.10 2.98 7.12 
I-6 C.sub.20 H.sub.20 N.sub.2 O.sub.5 S 
(59.99) 
(5.03) (7.00) 
60.11 5.14 7.03 
I-7 C.sub.20 H.sub.20 N.sub.2 O.sub.4 S 
(62.48) 
(5.24) (7.29) 
62.61 5.17 7.32 
I-8 C.sub.19 H.sub.16 Cl.sub.2 N.sub.2 O.sub.4 S 
(51.95) 
(3.67) (6.38) 
51.99 3.75 6.42 
I-9 C.sub.18 H.sub.24 N.sub.2 O.sub.4 S 
(59.32) 
(6.64) (7.69) 
59.12 6.44 7.58 
I-10 C.sub.16 H.sub.11 N.sub.2 O.sub.4 BrCl.sub.2 S 
(42.71) 
(2.99) (5.53) 
42.52 3.12 5.36 
I-11 C.sub.16 H.sub.11 N.sub.2 O.sub.4 Cl.sub.3 S 
(44.31) 
(2.56) (6.46) 
44.22 2.38 6.34 
I-12 C.sub.16 H.sub.12 BrFN.sub.2 O.sub.4 S 
(44.98) 
(2.83) (6.56) 
45.09 2.89 6.53 
I-13 C.sub.21 H.sub.14 BrFN.sub.2 O.sub.4 S 
(51.55) 
(2.88) (5.72) 
51.13 3.09 5.43 
I-14 C.sub.17 H.sub.14 BrFN.sub.2 O.sub.4 S 
(46.27) 
(3.20) (6.35) 
46.17 3.12 6.34 
I-15 C.sub.19 H.sub.16 BrFN.sub.2 O.sub.4 S 
(48.83) 
(3.45) (5.99) 
48.70 3.41 6.03 
I-16 C.sub.20 H.sub.18 BrFN.sub.2 O.sub.4 S 
(49.91) 
(3.77) (5.82) 
49.83 3.71 5.76 
I-17 C.sub.18 H.sub.16 BrFN.sub.2 O.sub.4 S 
(47.48) 
(3.54) (6.15) 
47.25 3.83 6.17 
I-18 C.sub.21 H.sub.22 Cl.sub.2 N.sub.2 O.sub.4 S 
(51.71) 
(4.11) (6.35) 
51.87 4.20 6.38 
I-19 C.sub.15 H.sub.10 BrFN.sub.2 O.sub.4 S 
(43.60) 
(2.44) (6.78) 
43.55 2.50 6.67 
I-20 C.sub.16 H.sub.12 BrFN.sub.2 O.sub.4 S 
(44.98) 
(2.83) (6.56) 
45.02 2.78 6.38 
I-21 C.sub.18 H.sub.16 F.sub.2 N.sub.2 O.sub.4 S 
(54.82) 
(4.09) (7.10) 
55.32 4.17 7.13 
I-22 C.sub.20 H.sub.18 Cl.sub.2 N.sub.2 O.sub.4 S 
(52.99) 
(4.00) (6.18) 
52.65 3.81 5.85 
I-23 C.sub.15 H.sub.9 Br.sub.2 FN.sub.2 O.sub.4 S 
(36.61) 
(1.84) (5.69) 
36.80 1.82 5.61 
I-24 C.sub.15 H.sub.9 BrClFN.sub.2 O.sub.4 S 
(40.24) 
(2.03) (6.26) 
40.63 1.96 6.28 
I-25 C.sub.18 H.sub.16 BrFN.sub.2 O.sub.3 S.sub.2 
(45.87) 
(3.42) (5.94) 
46.28 3.29 5.97 
I-26 C.sub.15 H.sub.9 BrClFN.sub.2 O.sub.3 S.sub.2 
(38.85) 
(1.95) (6.04) 
38.47 2.10 5.77 
__________________________________________________________________________ 
PHARMACOLOGICAL TEST 
Pharmacological test was carried out on the compound (I) of the present 
invention as follows. 
Aldose-Reductase Inhibitory Activity 
The aldose-reductase (AR) activity was evaluated by determining 
spectrophotometrically the decrease in absorbance of NADPH at 340 nm due 
to the reduction of the substrate, i.e., glyceraldehyde according to the 
method described in Biochemical Pharmacology 25, pp 2505-2513 (1976). 
The lenses of Wister male rats was homogenized with 0.5 ml of 0.1M 
phosphate buffer (pH 6.2) per lens by a glass homogenizer and the 
homogenate was centrifuged at 10000 rpm for 10 minutes. The supernatant 
obtained was used as AR. 
The determination of the AR activity was conducted as follows. A 700 .mu.l 
quantity of 0.1M phosphate buffer (pH 6.2), 100 .mu.l of 2.21 mM NADPH, 
100 .mu.l of AR and 5 .mu.l of DMSO containing each of test compounds in 
varying concentrations were placed in a cell for test sample, and 800 
.mu.l of 0.1M phosphate buffer (pH 6.2), 100 .mu.l of 2.21 mM NADPH, 100 
.mu.l of AR and 5 .mu.l of DMSO were placed in a cell for control. Then 
the solutions in the cells were thoroughly mixed together and the mixtures 
were maintained at 30.degree. C. Then 100 .mu.l of 100 mM glyceraldehyde 
maintained at 30.degree. C. was added to a cell for test sample and 
quickly blended to initiate the reaction. The AR activity was determined 
from the rate of change of absorbance per minute in the linear part of 
variations of absorbance during a period of from 1 minute to three minutes 
after the start of the reaction, and a dose-response curve was drawn. An 
IC.sub.50, i.e., a concentration exhibiting 50% inhibition, was calculated 
from the dose-response curve. 
______________________________________ 
Compound IC.sub.50 (.times. 10.sup.-8 mole/l) 
______________________________________ 
I-1 7.5 
I-2 2.0 
I-3 2.6 
I-4 1.7 
I-5 3.0 
I-8 4.2 
I-10 2.6 
I-11 2.5 
I-13 3.4 
I-14 2.1 
I-15 2.3 
I-16 3.0 
I-17 2.2 
I-19 2.0 
I-20 2.4 
I-24 (Lysine salt) 2.5 
______________________________________ 
Preparation of pharmaceutical compositions containing the compounds of the 
present invention is described below in Preparation Examples. 
PREATION EXAMPLE 1 (TABLETS) 
A tablet was prepared from the following composition. 
______________________________________ 
Compound I-17 100 mg 
Lactose 47 mg 
Corn starch 50 mg 
Crystalline cellulose 50 mg 
Hydroxypropyl cellulose 15 mg 
Talc 2 mg 
Magnesium stearate 2 mg 
Ethyl cellulose 30 mg 
Unsaturated fatty acid glyceride 
2 mg 
Titanium dioxide 2 mg 
Total 300 mg 
______________________________________ 
PREATION EXAMPLE 2 (CAPSULES) 
An encapsulated preparation was formulated from the following composition. 
______________________________________ 
Compound I-24 50 mg 
Lactose 50 mg 
Corn Starch 47 mg 
Crystalline cellulose 50 mg 
Talc 2 mg 
Magnesium stearate 1 mg 
Total 200 mg 
______________________________________