Malonic acid derivatives

This invention relates to a malonic acid derivative represented by the general formula (I) ##STR1## wherein R.sup.1 and R.sup.2, which may be the same or different, represents hydrogen atom; C.sub.1 -C.sub.12 alkyl group; C.sub.1 -C.sub.8 alkyl group substituted with C.sub.1 -C.sub.5 alkoxy group, a tetrahydrofuryl group, a phenyl group or a phenyl group substituted with 1 to 3 groups selected from the group consisting of halogen atoms, C.sub.1 -C.sub.5 alkyl groups and C.sub.1 -C.sub.5 alkoxy groups; or C.sub.2 -C.sub.6 alkenyl group; R.sup.3 and R.sup.4, which may be the same or different, represent hydrogen atom, C.sub.1 -C.sub.6 alkyl group, C.sub.2 -C.sub.6 alkenyl group, C.sub.2 -C.sub.8 alkoxyalkyl group, benzoyl group, C.sub.2 -C.sub.8 alkylcarbonyl group, C.sub.2 -C.sub.8 alkoxycarbonyl group, C.sub.1 -C.sub.4 alkylsulfonyl group or aralkyl group including benzyl group, and R.sup.5, R.sup.6 and R.sup.7, which may be the same or different, represent hydrogen atom or C.sub.1 -C.sub.4 alkyl group, and its pharmaceutically acceptable salts, a process for producing the same and a pharmaceutical composition containing the same.

EXAMPLE 
This invention will be described in detail below with reference to 
Examples, but it is in no way limited thereto. 
First, synthesis examples of this invention are shown below. 
Example 1 
Diisopropyl(2,5-diaza-7,9-dithiabicyclo-[4,3,0]-nonane-8-ylidene)malonate 
(compound No. 2) 
To a suspension of 2.5 g of glyoxal-sodium bisulfite in 10 ml of water was 
added dropwise 0.5 g of ethylenediamine with ice-cooling and the mixture 
was stired for additional 1 hour. To this solution was added dropwise with 
ice-cooling the dithiolate aqueous solution which had been prepared 
previously by the reaction of 1.5 g of diisopropyl malonate with 0.8 g of 
carbon disulfide in the presence of 3.3 g of 30% aqueous potassium 
hydroxide. 
After the reaction mixture was stirred at 10.degree. C. for additional 1 
hour, the solid precipitated was collected by filtration, washed with 
water and n-hexane, and then recrystallized from chloroform-n-hexane to 
give 1.6 g of the desired product. 
Yield 58%; m.p. 99.degree.-100.degree. C. 
Example 2 
Diisopropyl(2,5-diacetyl-2,5-diaza-7,9-dithiabicyclo-[4,3,0]-nonane-8-ylide 
ne)malonate. (Compound No. 5) 
In the mixed solution of 10 ml of pyridine and 10 ml of tetrahydrofuran was 
dissolved 1.0 g of 
diisopropyl(2,5-diaza-7,9-dithiabicyclo-[4,3,0]-nonane-8-ylidene)malonate, 
and 0.8 g of acetyl chloride was added dropwise at 10.degree. C. and the 
mixture was stirred for 1 hour. 
After the solvents were evaporated in vacuo, the residue was extracted with 
ethyl acetate and dried over sodium sulfate. The extract was concentrated 
and purified by silica gel chromatography. The solid obtained was 
recrystalized from ethyl acetate-n-hexane to give 1.0 g of the desired 
product as a white crystal. 
Yield 80%; m.p. 147.degree.-149.degree. C. 
Example 3 
Diisopropyl(2,5-dimethyl-2,5-diaza-7,9-dithiabicyclo-[4,3,0]-nonane-8-ylien 
e)malonate. (Compound No. 16) 
To the solution of 1.9 g of N,N'-dimethylethylene diamine in 10 ml of water 
was added 3.2 g of 40% aqueous solution of glyoxal dropwise at 0.degree. 
C. and the mixture was stirred at 0.degree. C. for 30 minutes. To this 
solution was added dropwise at 0.degree. C. the dithiolate solution, which 
had been prepared previously by the reaction of 3.7 g of diisopropyl 
malonate with 1.8 g of carbon disulfide in the presence of 30% aqueous 
potassium hydroxide solution, and the mixture was stirred for additional 
16 hours. 
Then, 50 ml of water was added to the reaction solution. The solid 
precipitated was collected by filtration and recrystalized from ethyl 
acetate-n-hexane to give 5.1 g of the desired product. 
Yield 69%; m.p. 93.6.degree. C. 
Example 4 
Diisopropyl(2,5-diethyl-2,5-diaza-7,9-dithiabicyclo-[4,3,0]-nonane-8-yliden 
e)malonate. (Compound No. 24) 
To a suspension of 4.3 g of glyoxal sodium bisulfite in 10 ml of water was 
added 1.9 g of N,N'-diethylethylenediamine dropwise with ice-cooling and 
the mixture was stirred at 25.degree. C. until it became a homogeneous 
solution. The mixture was cooled to -10.degree. C. and the dithiolate 
solution which had been prepared previously by the reaction of 2.8 g of 
diisoopropyl malonate with 1.4 g of carbon disulfide in 10 ml of 
dimethylsulfoxide in the presence of 7.3 g of 30% aqueous potassium 
hydroxide, was added dropwise. After the reaction mixture was stirred for 
additional 1 hour, 50 ml of water was added to the reaction solution. The 
solid deposited was collected by filtration and recrystalized from ethyl 
acetate-n-hexane to give 4.1 g of the desired product. 
Yield 68%; m.p. 84.degree.-86.degree. C. 
Example 5 
Diethyl(1,2,5-trimethyl-2,5-diaza-7,9-dithiabicyclo-[4,3,0]-nonane-8-yliden 
e)malonate. (Compound No. 32) 
In 40 ml of water was suspended 11.2 g of pyruvic aldehyde sodium bisulfite 
addition compound, and 2.3 g of N,N'-dimethylethylenediamine was added 
dropwise at 0.degree. C. and the mixture was stirred for additional 1 
hour. To this solution was added dropwise at 0.degree. C. the dithiolate 
solution, which had been prepared previously by the reaction of 3.2 g of 
diethyl malonate with 1.8 g of carbon disulfide in 20 ml of 
dimethylsulfoxide in the presence of 9.7 g of 30% aqueous potassium 
hydroxide. After the reaction mixture was stirred for additional 1 hour, 
50 ml of water was added to the solution. The solid precipitated was 
collected by filtration and recrystallized from ethyl acetate-n-hexane to 
give 1.7 g of the desired product. 
Yield 24%; 103.degree.-106.degree. C. 
Example 6 
Diisopropyl(2,5-diisopropyl-2,5-diaza-7,9-dithiabicyclo-[4,3,0]-nonane-8-yl 
idene)malonate. (Compound No. 35) 
To a suspension of 1.7 g of glyoxal sodium bisulfite in 12 ml of water was 
added N,N'-diisopropylethylenediamine dropwise at room temperature and the 
mixture was stirred until it became a homogeneous solution. To this 
solution was added dropwise at 0.degree. C. the dithiolate solution which 
had been prepared previously by the reaction of 1.13 g of diisopropyl 
malonate with 0.55 g of carbon disulfide in the presence of 2.9 g of 30% 
aqueous potassium hydroxide. After the mixture was stirred for additional 
30 minutes, 50 ml of water was added to the reaction solution. The solid 
deposited was collected by filtration and recrystalized from ethyl 
acetate-n-hexane to give 1.16 g of the desired product. 
Yield 45%; m.p. 82.degree.-84.degree. C. 
Example 7 
Diisopropyl(2,5-diallyl-2,5-diaza-7,9-dithiabicyclo-[4,3,0]-nonane-8-yliden 
e)malonate. (Compound No. 44) 
To a suspension of 1.85 g glyoxal sodium bisulfite in 13 ml of water was 
added dropwise 1.0 g of N,N'-diallylethylenediamine with ice-cooling and 
the mixture was stirred until it became a homogeneous solution. To this 
solution was added dropwise with ice-cooling the dithiolate solution which 
had been prepared previously by the reaction of ;b 1.22 g of diisopropyl 
malonate with 0.59 g of carbon disulfide in the presence of 3.15 g of 30% 
aqueous potassium hydroxide. After the mixture was stirred for additional 
1 hour, the oily product deposited was extracted with ethyl acetate. The 
extract was dried over anhydrous sodium sulfate, concentrated and purified 
by column chromatography on silica gel to give 1.8 g of the desired 
product as a viscous oil. 
Yield 65%; n.sub.D.sup.25 : 1.5559. 
Example 8 
Isopropyl 
4-methoxybenzyl(2,5-dimethyl-2,5-diaza-7,9-dithiabicycl-[4,3,0]-nonane-8-y 
lidene)malonate. (Compound No. 75) 
To a suspension of 2.5 g of glyoxal sodium bisulfite in 20 ml of water 
N,N'-dimethylethylenediamine was added dropwise at 0.degree. C. and was 
stirred for 1 hour. To this solution was added at 0.degree. C. the 
dithiolate solution which had been prepared previously by the following 
method; To a solution of 2.0 g of isopropyl 4-methoxybenzyl malonate and 
0.8 g of carbon disulfide was added 3.3 g of 30% aqueous potassium 
hydroxide with ice-cooling and the mixture was stirred for 15 minutes at 
the same temperature and for 40 minutes at room temperature. 
The reaction mixture was stirred for additional 1 hour, and extracted with 
ethyl acetate. The extract was dried over anhydrous sulfate, concentrated 
and purified by column chromatography on silica gel to give 1.8 g of the 
desired product as paste. 
Yield 52%. 
NMR data (60 MHz, CDCl.sub.3, .delta. value) 1.18 (6H, d, J=7.0 Hz), 2.45 
(6H, s), 2.28-3.20 (4H, m), 3.75 (3H, s), 4.56 (2H, s), 5.03 (1H, m), 5.13 
(2H, s), 6.80 (2H, d, J=8.0 Hz), 7.26 (2H, d, J=8.0 Hz) 
Example 9 
Diisopropyl(2,5-dimethyl-2,5-diaza-7,9-dithiabicyclo-[4,3,0]-nonane-8-ylide 
ne)malonate. (Compound No. 16) 
In 10 ml of water was dissolved 3.2 g of 40% aqueous glyoxal and 1.9 g of 
N,N'-dimethylethylenediamine at 0.degree. C. To this solution was added 
4.4 g of sodium bisulfite dissolved in 20 ml of water and the mixture was 
stirred for 30 minutes. To this was added dropwise at 0.degree. C. the 
dithiolate solution which had been prepared previously by the reaction of 
3.7 g of diisopropyl malonate with 1.8 g of carbon disulfide in the 
presence of 8 g of 30% aqueous potassium hydroxide. After the reaction 
mixture was stirred for additional 3 hours, 50 ml of water was added to 
the reaction solution. The solid deposited was collected by filtration and 
recrystalized from ethyl acetate-n-hexane to give 5.5 g of the desired 
product. 
Yield 74%; m.p. 93.6.degree. C. 
Example 10 
Diisopropyl(3-methyl-2,5-diaza-7,9-dithiabicyclo-[4,3,0]-nonane-8-ylidene)m 
alonate. (Compound No. 90) 
To a suspension of 17.4 g of glyoxal sodium bisulfite in 120 ml of water 
was added dropwise 7.1 g of propylenediamine at 0.degree. C. and the 
mixture was stirred for 1 hour. Then to this solution was added dropwise 
at 0.degree. C. the dithiolate solution, which had been prepared 
previously as follow; To a mixture of 15.04 g of diisopropyl malonate and 
6.4 g of carbon disulfide was added dropwise with ice-cooling 23.8 g of 
45% aqueous potassium hydroxide solution and was stirred at the same 
temperature for 1 hour. 
After stirring for 15 minutes, the reaction mixture was extracted with 
dichloromethane and washed with water. The extract was dried over 
magnesium sulfate and concentrated to afford syrup, which was 
recrystallized from ether-n-hexane to give 11.5 g of the desired product 
as a white crystal. 
Yield 40%; m.p. 102.degree.-104.degree. C. 
Example 11 
Diisopropyl(3-methyl-2,5-diaza-7,9-dithiabicyclo-[4,3,0]-nonane-8-ylidene)m 
alonate sulfuric acid salt. (Compound No. 99) 
In 30 ml of dichloromethane was dissolved 1.8 g of 
diisopropyl(3-methyl-2,5-diaza-7,9dithiabicyclo-[4,3,0]-nonane-8-yidene)ma 
lonate, and a solution consist of 0.51 g of concentrated sulfuric acid and 
0.5 ml of ethanol was added dropwise with ice-cooling and stirred for 15 
minutes. The solution was evaporated in vacuo and the precipitated crystal 
was collected and washed with ether-n-hexane to give 2.0 g of the desired 
product as a white crystal. 
Yield 87.0%; m.p. 150.0.degree.-152.0.degree. C. 
Example 12 
Di-n-propyl(6-methyl-2,5-diaza-7,9-dithiabicyclo-[4,3,0]-nonane-8-ylidene)m 
alonate hydrochloride salt (compound No. 96) 
To a solution of 16.64 g of sodium bisulfite in 160 ml of water was added 
14.4 g of 40% aqueous pyruvic aldehyde and the mixture was stirred at room 
temperature for 30 minutes. After the solution was cooled down to 
0.degree. C., 5.8 g of ethylenediamine was added dropwise, and the mixture 
was stirred for 10 minutes. To this was added dropwise at 0.degree. C. the 
dithiolate solution, which had been prepared previously by the reaction of 
15.04 g of di-n-propyl malonate with 6.4 g of carbon disulfide in the 
presence of 23.8 g of 45% aqueous potassium hydroxide, and the mixture was 
stirred for 30 minutes at the same temperature. The reaction mixture was 
extracted three times with each 200 ml of chloroform. 
The combined extract was washed with water and dried over magnesium 
sulfate. Into this solution was bubbled dry hydrogen chloride with 
ice-cooling. After the solution was saturated with hydrogen chloride, the 
solvent was removed. The crystal precipitated was collected and washed 
with ether-n-hexane to give 12.4 g of the desired product. 
Yield 38.1%; m.p. 120.0-124.0 (dec.) 
Now, Examples regarding pharmaceutical compositions according to this 
invention will be described below. In the Examples, "part" is all part by 
weight. It is needless to say that the kinds and the proportions of the 
compounding ingredients used in the composition according to this 
invention can be changed variously without being restricted by these 
Examples. 
Example 13 
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Compound No. 2 10 parts 
Heavy magnesium oxide 
10 parts 
Lactose 80 parts 
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The above ingredients were mixed uniformly and made into a medicinal 
preparation in the form of powders or fine granules. 
Example 14 
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Compound No. 16 10 parts 
Synthetic aluminum silicate 
10 parts 
Calcium hydrogen phosphate 
5 parts 
Lactose 75 parts 
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The above ingredients were used to be made up into powders in a similar 
manner to that in Example. 
Example 15 
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Compound No. 23 50 parts 
Starch 10 parts 
Lactose 15 parts 
Crystalline cellulose 
20 parts 
polyvinyl alcohol 5 parts 
Water 30 parts 
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The above ingredients were uniformly mixed, kneaded, then crushed, 
granulated, dried and sieved to obtain granules. 
Example 16 
A mixture of 99 parts of the granules obtained in Example 15 and 1 part of 
calcium stearate was compression-formed into tablets of 10 mm diameter. 
Example 17 
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Compound No. 49 78 parts 
Polyvinyl alcohol 
2 parts 
Lactose 20 parts 
Water 30 parts 
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The above ingredients were made up into granules in the same manner as in 
Example 15. Ten parts of crystalline cellulose was added to 90 parts of 
the granules obtained above, and the mixture was compression-molded to 
obtain tablets of 8 mm diameter. The tablets may be further made up into 
dragee by using, in appropriate amounts, a mixed suspension of syrup 
gelatin and precipitated calcium carbonate, and a coloring agent. 
Example 18 
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Compound No. 56 0.5 part 
Nonionic surfactant 
2.5 parts 
Physiological saline 
97 parts 
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The above ingredients were mixed with warming, and then sterilized to 
obtain injections. 
Example 19 
The powders obtained in Example 13 were filled into capsule containers 
available on the market to obtain capsules. 
The effect of the compound of the present will be illustrated by the 
following Test Examples. 
Test Example 1 
Effect of suppressing hepatic disorder caused by carbon tetrachloride. 
Test Method 
The test compound was dissolved or suspended in olive oil, and orally 
administered at a dose of 30 mg/kg to mice (6 weeks of age, dd-strain, 
.male.). Six hours thereafter, carbon tetrachloride was orally 
administered in a proportion of 0.05 ml/kg. The animals were sacrificed 24 
hours after the administration of carbon tetrachloride, and the extent of 
liver injury was grossly examined. 
On the other hand, blood was collected from the animal at the time of the 
sacrifice, and centrifuged to obtain plasma. The plasma glutamic pyruvic 
transminase (GPT) activity was determined according to the method of 
Reitman-Frankel. The activity was expressed in terms of Karmen Units 
(K.U.). The conditions of the liver were expressed in terms of liver 
injury index as follows. 
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Liver injury index 
Condition of liver 
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0 Healthy liver 
2 Slightly affected 
4 Evidently observed injury 
6 Serious injury 
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Mice were used in groups of five and the results of test were represented 
by the mean value. When the GPT activity was 2,100 units or higher, or 
further determination was made, and the activity was calculated as 2,100 
units for reasons of convenience. 
The results obtained are shown in Table 3. 
TABLE 3 
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Effect of carbon tetrachloride on liver injury 
No. of compound Liver 
of this invention 
injury index 
p-GPT (K.U.) 
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Administration of carbon 
5.4 &gt;2,100 
tetrachloride alone 
No treatment 0 
1 2.0 225 
2 0.3 24.4 
3 0.1 53.0 
10 4.5 2,000 
16 0.6 32 
18 1.8 166 
19 1.6 99 
23 1.2 10.2 
25 0.4 13.2 
28 1.5 547 
30 0.8 22.8 
33 1.2 925 
37 1.4 143 
40 1.8 164 
43 0.2 51 
49 1.2 23.8 
51 0.4 18.2 
54 0 13.4 
56 0 16.8 
59 0.5 109.2 
63 0.5 32.8 
67 2.5 1,620 
68 1.5 914.6 
72 0.4 428.6 
74 0.6 25 
75 0 20 
79 1.4 1,060 
81 1.2 120 
83 0.8 38.6 
84 0.8 37 
87 0.2 21 
94 2.0 1,534 
96 0.1 28.0 
97 0.2 45.0 
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