Benzofuran derivatives useful in treating diabetic complications

A benzofuran derivative having the general formula (I): ##STR1## wherein R.sup.1 is hydrogen atom, a benzyl group, unsubstituted or substituted with a halogen atom or an alkyloxy group, or an alkyl group having 1 to 3 carbon atoms, R.sup.2 is hydrogen atom or an alkyl group having 1 to 3 carbon atoms, R.sup.3 is acetyl group, ethyl group, carboxyl group or 4-methyl-2,5-dioxoimidazolidine-4-yl group, R.sup.4 is hydrogen atom, hydroxyl group, an alkyl group having 1 to 6 carbon atoms, an alkoxy group having 1 to 9 carbon atoms, carboxymethoxy group, nitro group, acetoamino group, a benzylozy group unsubstituted or substituted with a halogen atom, nitro group or an alkyloxy group or a group having the formula: --OR.sup.6, wherein R.sup.6 is an alkenyl group having 2 to 4 carbon atoms or an alkyl group having 2 to 3 carbon atoms having a halogen atom, cyano group or oxo group, R.sup.5 is hydrogen atom or methylenedioxy group together with R.sup.4 group, n is 1 or 2, and the unsubstituted or substituted N-carboxymethylsulfamoyl group, R.sup.4 and R.sup.5 are attached at 3-position, 4-position, 5-position, 6-position or 7-position of the benzofuran ring, or a nontoxic salt thereof, process for preparing the same and a pharmaceutical composition containing the same. The compounds of the present invention have powerful aldose reductase inhibiting activity, platelet aggregation inhibiting activity and arachidonic acid metabolism inhibiting activity and are useful for a remedy for treatment of diabetic complications.

BACKGROUND OF THE INVENTION 
The present invention relates to novel benzofuran derivatives, processes 
for preparing the same and a pharmaceutical composition, as a therapeutic 
agent for diabetic complications, containing the same. 
In recent years, a marked increase in the number of diabetic patients needs 
urgently the treatment thereof. 
As therapeutic agents for diabetes, insulin and blood sugar lowering agents 
have so far been used widely. However, diabetes is not a mere disorder of 
sugar metabolism but a disease also involving a variety of complications 
and therefore the therapeutic effects of the above-mentioned agents alone 
are not enough for the treatment of diabetes. 
Main complications are neuropathy, cataract, nephritis and retinopathy and 
in the development of these complications as abnormal metabolism of 
polyols is concerned (K. H. Gabbay, Adv. Metab. Disord., 2 (2), 424 
(1973)). That is, in the diabetic condition, polyols such as sorbitol are 
accumulated in the cell to an extraordinary extent, causing osmotic 
pressure increase and water swelling, which lead to cellular disturbance. 
Therefore, the above-mentioned diseases can be prevented and cured by 
inhibiting the aldose reductase activity which is essential to polyol 
synthesis (R. G. Judzewitsch et al., New Eng. J. Med., 308, 119 to 125 
(1983); J. H. Kinoshita et al., Metabolism, 28 (1), 462 to 469 (1979)). In 
Japanese Unexamined Patent Publication Nos. 28074/1982 and 40478/1982, 
there is described aldose reductase inhibiting agents used as a remedy for 
diabetic complications. 
In the complications such as cerebral and coronary vascular disturbances, 
accelerated platelet aggregation due to abnormal metabolism of arachidonic 
acid plays an important role for the development of the complications. 
That is, in the diabetic condition, the accelerated production of 
thromboxane A.sub.2 results in the platelet aggregation to induce 
thrombosis, which leads to microangiopathy (Ryutaro Takahashi, 
Purosutaguranzin to Byotai, Gendaikagaku Zokan, P 112 to 120 (1984)). 
Among the complications, nephritis and retinopathy are typical 
microangiopathies. These complications can be prevented and treated by 
inhibiting the metabolism of arachidonic acid to improve the accelerated 
platelet aggregation in addition to inhibiting the accumulation of 
polyols. 
SUMMARY OF THE INVENTION 
It is an object of the present invention to provide a novel compound useful 
as a therapeutic agent for diabetic complications including perceptual 
disorder, autonomic disturbance, diabetic nephropathy, and ocular diseases 
such as retinopathy and catarct. 
DETAILED DESCRIPTION 
The present invention provides a benzofuran derivative having the general 
formula (I): 
##STR2## 
wherein R.sup.1 is hydrogen atom, a benzyl group, unsubstituted or 
substituted with a halogen atom or an alkyloxy group, or an alkyl group 
having 1 to 3 carbon atoms, R.sup.2 is hydrogen atom or an alkyl group 
having 1 to 3 carbon atoms, R.sup.3 is acetyl group, ethyl group, carboxyl 
group or 4-methyl-2,5-dioxoimidazolidine-4-yl group, R.sup.4 is hydrogen 
atom, hydroxyl group, an alkyl group having 1 to 6 carbon atoms, an alkoxy 
group having 1 to 9 carbon atoms, carboxymethoxy group, nitro group, 
acetoamino group, a benzyloxy group unsubstituted or substituted with a 
halogen atom, nitro group or an alkyloxy group or a group having the 
formula: --OR.sup.6, wherein R.sup.6 is an alkenyl group having 2 to 4 
carbon atoms or an alkyl group having 2 to 3 carbon atoms having a halogen 
atom, cyano group or oxo group, R.sup.5 is hydrogen atom or methylenedioxy 
group together with R.sup.4 group, n is 1 or 2, and the unsubstituted or 
substituted N-carboxymethylsulfamoyl group, R.sup.4 and R.sup.5 are 
attached at 3-position, 4-position, 5-position, 6-position or 7-position 
of the benzofuran ring, or a nontoxic salt thereof and a process for 
preparing the same. 
The benzofuran derivatives having the general formula (I) of the present 
invention are prepared by reacting the compound having the general formula 
(II): 
##STR3## 
wherein X is a halogen atom, R.sup.5 is hydrogen atom or methylenedioxy 
group together with R.sup.6 group, R.sup.7 is hydrogen atom, an alkyl 
group having 1 to 6 carbon atoms, an alkoxy group having 1 to 9 carbon 
atoms, an alkoxycarbonylmethoxy group having 1 to 6 carbon atoms, nitro 
group, acetoamino group, benzyloxy group, unsustituted or substituted with 
a halogen atom, nitro group or an alkyloxy group, an alkenyloxy group 
having 2 to 4 carbon atoms, or an alkoxy group having 2 to 3 carbon atoms 
having a halogen atom, cyano group or oxo group, R.sup.8 is acetyl group, 
ethyl group, an alkoxycarbonyl group, an alkoxycarbonylmethoxycarbonyl 
group having 1 to 3 carbon atoms, cyano group or 
4-methyl-2,5-dioxoimidazolidine-4-yl group and n is 1 or 2, with amine 
compound having the general formula (III): 
##STR4## 
wherein R.sup.1 is hydrogen atom, a benzyl group, unsubstituted or 
substituted with a halogen atom or an alkyloxy group, or an alkyl group 
having 1 to 3 carbon atoms, R.sup.2 is hydrogen atom or alkyl group having 
1 to 3 carbon atoms and then either hydrolyzing the obtained ester or 
simultaneously conducting the hydrolysis and the ether bond-cleavage of 
the ester, thereby the compound having the general formula (II) can be 
obtained by reacting the benzofuran derivatives having the general formula 
(II'): 
##STR5## 
wherein R.sup.5, R.sup.7 and R.sup.8 are as above, with ClSO.sub.3 H. 
When the compound having the general formula (II') is reacted with 
ClSO.sub.3 H, either a solution of the compound having the general formula 
(II') dissolved in an aprotic solvent such as chloroform, carbon 
tetrachloride, dichloromethane or dichloroethane, or the compound having 
the general formula (II') is added to 5 or 20 times the amount of 
clSO.sub.3 H at -20.degree. to 10.degree. C. and the mixture is further 
stirred at -20.degree. to 25.degree. C. to complete the reaction. The 
resultant is then poured into ice-water to form precipitate, which is 
filtered or extracted with a solvent such as ethylacetate to give a 
chlorosulfonyl compound having the general formula (II). The 
chlorosulfonyl compound is added to an aprotic solvent such as chloroform, 
dichloromethane, dichloroethane or carbon tetrachloride, to which 1 to 2.5 
molar equivalents of the amine having the general formula (III) and 1 to 
2.5 molar equivalents of organic amine such as diethylamine or 
triethylamine are added dropwise. After the mixture is stirred at 
20.degree. to 50.degree. C. for 3 to 24 hours and poured into water, the 
resultant is extracted with a solvent such as ethylacetate or ether and 
the solvent is distilled away to give an ester compound, which is 
recrystallized from ethylacetate, ethanol, a mixture of ethylacetate and 
ethanol, a mixture of ethylacetate and petroleum benzin or a mixture of 
ethanol and water. The ester compound is hydrolyzed by stirring at 
10.degree. to 50.degree. C. for 1 to 5 hours either in an aqueous alkaline 
solution of sodium hydroxide, potassium hydroxide or the like, or in the 
aqueous alkaline solution in a solvent such as methanol, ethanol or 
dimethylsulfoxide, or by reacting in trifluoroacetic acid at 20.degree. to 
30.degree. C. for 1 to 3 hours. 
The crude crystalline material, which is obtained by acidifying the 
reaction solution when the hydrolysis is carried out with alkali or 
obtained by distilling away trifluoroacetic acid when the hydrolysis is 
carried out with trifluoroacetic acid, is recrystallized from ethanol, 
methanol, a mixture of ethanol and water, a mixture of dimethylsulfoxide 
and water, and the like to give the benzofuran derivatives having the 
general formula (I). Alternatively, a mixture of the ester compound and 
2.5 molar equivalent of AlCl.sub.3 is stirred in a solvent such as 
chlorobenzene or nitrobenzene at 100.degree. to 120.degree. C. for 1 to 7 
hours and the resultant is poured into an aqueous solution of hydrochloric 
acid to simultaneously carry out the hydrolysis and the cleavage of the 
ester, the obtained crude crystal being recrystallized from ethanol, 
methanol, water or dimethylsulfoxide to give the benzofuran derivatives 
having the general formula (I). 
Examples of the nontoxic salts of the benzofuran derivatives having the 
general formula (I) are pharmaceutically acceptable salts such as sodium 
salt, potassium salt, magnesium salt, calcium salt and salts with organic 
amine compounds. 
The following Table 1 shows typical compounds of the benzofuran derivatives 
having the general formula (I) of the present invention. 
TABLE 1 
__________________________________________________________________________ 
Compound 
No. Structural formula Compound name 
__________________________________________________________________________ 
1 
##STR6## 2-Acetyl-4-(Ncarboxy- methylsulfamoyl)-7- 
methoxybenzofuran 
2 
##STR7## 2-Acetyl-4-(Ncarboxy- methylsulfamoyl)-7- 
ethoxybenzofuran 
3 
##STR8## 2-Acetyl-4-(Ncarboxy- methylsulfamoyl)-7-n- 
propoxybenzofuran 
4 
##STR9## 2-Acetyl-4-(Ncarboxy- methylsulfamoyl)-7-n- 
butoxybenzofuran 
5 
##STR10## 2-Acetyl-4-(Ncarboxy- methylsulfamoyl)-7-n- 
pentyloxybenzofuran 
6 
##STR11## 2-Acetyl-4-(Ncarboxy- methylsulfamoyl)-7-n- 
hexyloxybenzofuran 
7 
##STR12## 2-Acetyl-4-(Ncarboxy- methylsulfamoyl)-7-n- 
heptyloxybenzofuran 
8 
##STR13## 2-Acetyl-4-(Ncarboxy- methylsulfamoyl)-7- 
carboxymethoxy- benzofuran 
9 
##STR14## 2-Acetyl-4-(Nmethyl-N carboxymethylsulfamoy 
l) 7-n- butoxybenzofuran 
10 
##STR15## 2-Acetyl-4-[Nmethyl- N(1-carboxyethyl- 
sulfamoyl)]-7-n- butoxybenzofuran 
11 
##STR16## 2-Acetyl-4-[N(1- carboxyethyl)sulfa- 
moyl)]-7-n-butoxy- benzofuran 
12 
##STR17## 2-Caboxy-4-(Ncarboxy- methylsulfamoyl)-7- 
carboxymethoxybenzofuran 
13 
##STR18## 2-Acetyl-4-(Ncarboxy- methylsulfamoyl)-7- 
methoxybenzofuran 
14 
##STR19## 2-Acetyl-4-(Ncarboxy- methylsulfamoyl)-7- 
ethoxybenzofuran 
15 
##STR20## 2-Acetyl-4-(Ncarboxy- methylsulfamoyl)-7- 
methylbenzofuran 
16 
##STR21## 2-Acetyl-4-(Ncarboxy- methylsulfamoyl)-7-se 
c- butylbenzofuran 
17 
##STR22## 2-Acetyl-4-(Ncarboxy- methylfulfamoyl)-5,6- 
methylenedioxybenzo- furan 
18 
##STR23## 2-Acetyl-4-methoxy-7- (Ncarboxymethyl- 
sulfamoyl)benzofuran 
19 
##STR24## 2-(4-methyl-2,5-dioxo- imidazolidine-4-yl)- 
4-(N carboxymethylsulfamoyl)- 7-methoxybenz 
ofuran 
20 
##STR25## 2-(4-methyl-2,5-dioxo- imidazolidine-4-yl)- 
4,6- di(Ncarboxymethyl)- sulfamoyl)-7-metho 
xy- benzofuran 
21 
##STR26## 2-Ethyl-3-(Ncarboxy- methylsulfamoyl)-5- 
nitrobenzofuran 
22 
##STR27## 2-Ethyl-3-(Ncarboxy- methylsulfamoyl)-5- 
acetylaminobenzofuran 
23 
##STR28## 2-Acetyl-4-(Ncarboxy- methylsulfamoyl)-7-p- 
nitrobenzyloxybenzofuran 
24 
##STR29## 2-Acetyl-4-(Ncarboxy- methylsulfamoyl)-7-p- 
methoxybenzyloxy- benzofuran 
25 
##STR30## 2-Acetyl-4-(Ncarboxy- methylsulfamoyl)-7- 
(2-chloropropyloxy)- benzofuran 
26 
##STR31## 2-Acetyl-4-(Ncarboxy- methylsulfamoyl)-7- 
acetonyloxybenzofuran 
27 
##STR32## 2-Acetyl-4-(Ncarboxy- methylsulfamoyl)-7- 
cyanomethyloxybenzofuran 
28 
##STR33## 2-Acetyl-4-(Ncarboxy- methylsulfamoyl)-7- 
hydroxybenzofuran 
29 
##STR34## 2-Acetyl-4-(Ncarboxy- methylsulfamoyl)-7- 
benzyloxybenzofuran 
30 
##STR35## 2-Acetyl-(Ncarboxy- methylsulfamoyl)-7-p 
chlorobenzyloxy- benzofuran 
31 
##STR36## 2-Acetyl-4-(Ncarboxy- methylsulfamoyl)-7- 
allyloxybenzofuran 
32 
##STR37## 2-Acetyl-4-(Ncarboxy- methylsulfamoyl)-7-(3 
- butenyloxy)benzofuran 
33 
##STR38## 2-Acetyl-4-(Np-methoxy- benzyl-Ncarboxymeth 
yl- sulfamoyl)-7-p-methoxy- benzyloxybenzof 
uran 
34 
##STR39## 2-Acetyl-4-(Np- chlorobenzyl-Ncarboxy- 
methylsulfamoyl)-7- p-chlorobenzyloxy- 
benzofuran 
35 
##STR40## 2-Acetyl-4-(Nbenzyl-N carboxymethylfulfamoy 
l)- 7-benzyloxybenzofuran 
__________________________________________________________________________ 
(Note)- 
A: SO.sub.2 NHCH.sub.2 COOH 
Pharmacological activities of the compound having the general formula (I) 
of the present invention are provided by the following detailed 
explanation. 
[ALDOSE REDUCTASE INHIBITING ACTIVITY] 
The compound having the general formula (I) of the present invention shows 
aldose reductase inhibiting activity and is useful for the prevention and 
treatment of neuropathy, diabetic retinopathy and cataract resulting from 
abnormal accumulation of polyols. For example, in the experiment in a 
laboratory, all the compounds of the present invention showed 50% 
inhibition against the activity of aldose reductase from rat lens in a 
concentration of from 10.sup.-8 to 10.sup.-6 M, which are presented in 
Table 2. 
TEST METHOD 
The test was carried out according to the method of Hayman et al. (S. Hyman 
and J. H. Kinoshita, J. Biol, Chem., 240, 877 to 882 (1965)). 
Wistar male rats were sacrificed by decapitation and the lenses were taken 
out to be homogenized with a 0.1M phosphate buffer [pH 6.8, containing 1 
mM of mercaptoethanol and 1 mM of nicotinamide-adenine dinucleotide 
phosphate (NADP)]. The homogenate was then centrifuged at 10,000 g for 15 
minutes and the supernatant was prepared as the crude enzyme solution. 
Separately, a 0.1M phosphate buffer (pH 6.2) containing 0.104 mM of NADPH 
(reduced form of NADP) and 10 mM of DL-glyceraldehyde was prepared, to 
which 15 .mu.l of each solution of test compound in varied concentrations 
was added, followed by addition of 25 .mu.l of the crude enzyme solution 
previously prepared, thereby initiating the reaction. The decrease in 
absorbance at 340 nm was measured using a high-sensitivity 
self-registering spectrophotometer (Model SM-401 made by Union Giken 
Kabushiki Kaisha). 
The results are shown in Table 2 in term of IC.sub.50 (50% inhibition 
concentration in M). 
TABLE 2 
______________________________________ 
Compound No. IC.sub.50 (M) 
______________________________________ 
1 2 .times. 10.sup.-7 
2 1 .times. 10.sup.-7 
3 6 .times. 10.sup.-8 
4 4 .times. 10.sup.-8 
5 5 .times. 10.sup.-8 
6 5 .times. 10.sup.-8 
7 3 .times. 10.sup.-8 
8 2 .times. 10.sup.-7 
9 1 .times. 10.sup.-6 
10 7 .times. 10.sup.-6 
11 5 .times. 10.sup.-6 
12 2 .times. 10.sup.-7 
13 1 .times. 10.sup.-7 
14 7 .times. 10.sup.-8 
15 5 .times. 10.sup.-7 
16 4 .times. 10.sup.-7 
17 2 .times. 10.sup.-6 
18 5 .times. 10.sup.-6 
19 2 .times. 10.sup.-6 
20 3 .times. 10.sup.-7 
21 5 .times. 10.sup.-8 
22 5 .times. 10.sup.-8 
23 5 .times. 10.sup.-8 
24 3 .times. 10.sup.-8 
25 2 .times. 10.sup.-7 
26 2 .times. 10.sup.-7 
27 1 .times. 10.sup.-7 
28 8 .times. 10.sup.-8 
29 5 .times. 10.sup.-8 
30 4 .times. 10.sup.-8 
31 5 .times. 10.sup.-8 
32 3 .times. 10.sup.-8 
33 8 .times. 10.sup.-7 
34 8 .times. 10.sup.-7 
35 7 .times. 10.sup.-7 
Sorbinil (Note) 2 .times. 10.sup.-7 
______________________________________ 
Note:- 
USAN (United States Adopted Names) of 
S6fluoro-spiro(chroman-4,4'-imidazolidine-2',5'-dione having the followin 
formula: 
##STR41## 
[PLATELET AGGREGATION INHIBITING ACTIVITY] 
The benzofuran derivatives having the general formula (I) of the present 
invention show platelet aggregation inhibiting activity and are useful for 
the prevention and treatment of diabetic complication such as 
cardiovascular disease. In the experiment in a laboratory, the benzofuran 
derivatives of the compound Nos. 5, 8, 9, 10, 11, 23, 29, 30 and 33 showed 
50% inhibition against the aggregation of the washed rabbit platelet by 
thrombin in a concentration of from 2.times.10.sup.-5 to 2.times.10.sup.-4 
M. The compounds of the present invention other than the above-mentioned 
compounds also showed platelet aggregation inhibiting activity, though the 
activity is somewhat lower than that of the above nine compounds which 
showed the activity equivalent to or more than that of the widely used 
platelet aggregation inhibiting agents, Persntin.RTM. (the registered 
trademark of dipyridamole made by Tanabe Seiyaku CO., LTD.). 
TEST METHOD 
Blood samples were collected from the auricular blood vessel of rabbits 
(white local breed), and washed platelets were prepared therefrom by the 
method of Baenziger et al. (N. L. Baenziger and P. W. Majerus, Methods 
Enzymol., 31, 149 to 155 (1974). The platelets were suspended in a 15 mM 
Tris-hydrochloric acid buffer with a final concentration of 
6.times.10.sup.8 cells/ml (Tris: tris(hydroxymethyl)aminomethane). Each 
test compound of the compound Nos. 5, 8, 9, 11, 23, 29, 30 and 33 and 
Persantin.RTM. was added thereto and incubation was carried out at 
37.degree. C. for 2 minutes. Then the platelets were stimulated by 
addition of thrombin (0.2 unit/ml of final concentration; made by Mochida 
Pharmaceutical Co.) and the aggregation inhibiting activity was estimated 
by the observation of the aggregation reaction using an aggregometer (made 
by Briston Co.). 
The results are shown in Table 3 in terms of IC.sub.50 (50% inhibiton 
concentration in M). 
TABLE 3 
______________________________________ 
Compound No. IC.sub.50 (M) 
______________________________________ 
7 1.5 .times. 10.sup.-4 
8 1.3 .times. 10.sup.-4 
9 6.0 .times. 10.sup.-4 
10 1.6 .times. 10.sup.-4 
11 1.6 .times. 10.sup.-4 
23 8.0 .times. 10.sup.-5 
29 3.5 .times. 10.sup.-5 
30 3.0 .times. 10.sup.-5 
33 2.0 .times. 10.sup.-5 
Persantin .RTM. 2.0 .times. 10.sup.-4 
______________________________________ 
[ACUTE TOXICITY] 
Acute toxicity test in mice was carried out on the benzofuran derivatives 
of the compound Nos. 3, 5, 9, 21, 23, 26, 29 and 34. The benzofuran 
derivatives of the compound Nos. 3, 5, 9 and 21 induced no death up to the 
dose of 3 g/kg body weight and had the LD.sub.50 value (oral) of more than 
3 g/kg body weight while the benzofuran derivatives of the compound Nos. 
23, 26, 29 and 34 induced no death up to 2 g/kg body weight and had the 
LD.sub.50 value (oral) of more than 2 g/kg body weight. This fact shows 
that the benzofuran derivatives of the present invention have quite low 
toxicity. 
TEST METHOD 
To groups of 4 male ddY mice (5 weeks of age) were orally administered by 
gavage each test compound (2, 3 and 4 g/kg body weight with respect to the 
compound Nos. 3, 5, 9 and 21, 1, 2 and 3 g/kg body weight with respect to 
the compound Nos. 23, 26, 29 and 34) suspended in a 10% gum arabic and the 
mice were observed for death or survival for 2 weeks. 
[ARACHIDONIC ACID METABOLISM INHIBITING ACTIVITY] 
The benzofuran derivatives of the compound Nos. 8, 13, 14, 19, 20, 23, 29, 
30 and 33 show arachidonic acid metabolism inhibiting activity; i.e. they 
showed 50% inhibition against the production of malondialdehyde from 
arachidonic acid by rabbit platelets in a concentration of 10.sup.-5 to 
10.sup.-4 M, which exhibits that the above compounds have an activity 2 to 
11 times stronger than that of the powerful cyclooxygenase inhibitor, 
indomethancin. Also in the experiment using 9000 G supernatant of lung 
homogenate taken from guinea pig, the above compounds showed an inhibition 
against the production of malonedialdehyde from arachidonic acid with an 
activity equivalent to or more than that of aspirin. 
TEST METHOD 
Washed rabbit platelets prepared as in the platelet aggregation inhibiting 
activity test were suspended in 15 mM Tris-hydrochloric acid buffer with a 
final concentration of 1.times.10.sup.8 cell/ml, to which each test 
compound of the compound Nos. 8, 13, 14, 19, 20, 23, 29, 30 and 33 were 
added and the resultant was preincubated at 37.degree. C. for five 
minutes. Then arachidonic acid (a final concentration: 0.2 mM, made by 
Sigma Chemical Co.) was added thereto and the mixture was preincubated for 
1 minute. An amount of the produced malondialdehyde was measured according 
to the thiobarbiturates method (Ed. Aoki and Shibata, Ketsuekigaku 
Kenkyukensaho, P 441 to 447). 
Lung from guinea pig was washed with physiological saline and homogenized 
in 0.1M Tris-hydrochloric acid buffer to prepare a supernatant by cooled 
centrifugation (9000 G). 
The inhibiting activity against cyclooxygenase was measured by using the 
9000 G supernatant as a source of cyclooxygenase in the presence of 1 mM 
epinephiline. 
The compounds of the present invention have powerful aldose reductase 
inhibiting activity, platelet aggregation inhibiting activity and 
arachidonic acid metabolism inhibiting activity and are useful for a 
remedy for treatment of diabetic complications. 
The compounds of the present invention can be formulated into 
pharmaceutical compositions in the form of tablets, capsules, injections, 
pills, granules, suppositories and eye drops. The pharmaceutical 
compositions of the present invention are administered with an effective 
dose of around 50 to around 500 mg/day for adults.