CA1243031A - 1,3-dithiol-2-ylidene derivatives - Google Patents

Abstract

ABSTRACT OF THE DISCLOSURE
A 1,3-dithiol-2-yiidene derivative of the formula:

Description

Our Ref: BU-26 3~

I` 1,3-DIT~IOL-2-YLIDENE DERIVATIVES
The present invention relates to novel 1,3-dithiol derivatives, a process for their production and a pharmaceutical composition for treating the liver diseases.
It is known that there are a large number of patients who suffer from liver damages caused by various factors such as alcohol, malnutrition, viruses, chemicals, toxicants, etc. The liver diseases may generally be classified by their types into acute hepatitis, chronic hepatitis, liver cirrhosis, and fulminant hepatitis. It is said to be very difficult to treat these liver diseases. Namely, currently available methods for the treatment such as treatments with pharmaceuticals e.g. liver protective agents such as various vitamins, saccharides, amino acids, glutathione, glycyrrhizin, liver hydrolyzates or adrenocortical hormones; cholagogues; immunomodulaters; or antiviral substances against v.iral hepatitis, are all .

3~

- 2 -nothing more than symptomatic treatments, and they are not adequately effective or the treatment oE the existing liver damages.
It has recently been reported that 1,3-dithiol derivatives represented by Malotilate as identified below, are effective for the treatment of liver damages (see Japanese Examined Patent Publications No.
18,576/1981, No. 18,577/19gl and No. 18,578/1981).
S > /COOCH(CH3)2 \S \COOCH(CH3)2 Malotilate As a result of extensive researches, the present inventors have found that certain novel 1,3-dithiol derivatives represented by the after-mentioned formula I, I
exhibit excellent activities for the treatment of a wide l;
spectrum of liver damages, which are comparable or superior to the above-mentioned conventional l,3-dithiol derivatives. The present invention has been accomplished on the basis of this discovery.
Namely, the present invention provides a 1,3-dithiol-2-ylidene derivative of the formula:

C \ (I) OH /

,~, t ~1t wherein each of R and Rl which may be the same or different, is a lower alkyl group, a lower alkenyl group, a cycloalkyl group, a lower alkoxyalkyl group, or a substituted or unsubstituted aryl, aralkyl or heterocyclic group or R and Rl together form a substituted or unsubstituted ethylene or trimethylene group.
The compounds of the formula (I) of the present invention are effective for stimmulating, improving and recovering the liver functions, and are useful as preventive and curative drugs for various liver troubles.
The present invention also provides a process for producing the compound of the foLmula I, which comprises reacting a ~-diketone of the formula:

- R tII) ~H2 wherein R and Rl are as defined above, if necessary, protected by a suitable protective group, with a dithiolylium salt of the formula:

O + ~0_~2-X 9 (III) ,, aH /

wherein R2 is a lower alkyl group or an aralkyl group, and X is an anion residue, in the presence of a base, and, if necessary, removing the protective group.

Further, the present invention provides a pharmaceutical composition for treating the liver disease, which comprises an effective amount of the compound of the formula I and a pharmaceutically acceptable carrier or diluent.
Now/ the present invention will be described in detail with reference to the preferred embodiments.
Referring to the definitions of R and Rl in the formula I, the lower alkyl group includes methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl and hexyl; the lower alkenyl group includes vinyl or 2-methylvinyl; the cycloalkyl group includes cyclopentyl and cyclohexyl; the lower alkoxyalkyl group includes ethoxymethyl, 2-methoxyethyl, 3-ethoxypropyl,

3-propoxypropyl and 2-ethoxybutyl; and the substituted or unsubstituted aryl, aralkyl or heterocyclic group includes a phenyl, naphthyl, benzyl, naphthylmethyl, furyl, thienyl r pyrrolyl, imidazolyl, pyridyl, pyrazinyl, indolyl, quinolyl or benzimidazolyl group which may be substituted by e.g. halogen, hydroxyl, lower alkyl, lower alkoxy, nitro, cyano or lower alkoxy carbonyl.
Further, R and Rl may together form an ethylene or trimethylene group which may be substituted by e.g. a lower alkyl group, an aralkyl group and an aryl group.
Here, the lower alkyl group includes methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl and hexyl; the aralkyl group includes benzyl and naphthylmethyl; and the aryl group includes phenyl and naphthyl.
Specific examples of the compounds of the present invention may be mentioned as follows:
(1) 3-(1,3-dithiol-2-ylidene)-2,4-pentanedione (Compound 1) . ,.~ (2) 3-(1,3-dithiol-2-ylidene)-2,4-hexanedione (Compound 2) (3) 3-(1,3-dithiol-2-ylidene)-1-ethoxy-2,4-pentane-dione (Compound 3)

(4) 5-(1,3-dithiol-2-ylidene)-2,8-dimethyl-4,6-nonanedione (Compound 4)

(5) 2-(1,3-dithiol-2-ylidene)-1-cyclohexyl-1,3-butanedione (Compound 5)

(6) 2-(1,3-dithiol-2-ylidene)-1-phenyl-1,3-butane-dione (Compound 6)

(7) 2-(1,3-dithiol-2-ylidene)-1-phenyl-1,3-hexane-dione (Compound 7)

(8) 2-(1,3-dithiol-2-ylidene)-5-methyl-1-phenyl-1,3-hexanedione (Compound 8)

(9) 2-(1,3-dithiol-2-ylidene)-4,4-dimethyl-1-phenyl-1,3-pentanedione (Compound 9)

(10) 2-(1,3-dithiol-2-ylidene)-1-phenyl-1,3-octa-decanedione (Compound 10)

(11) 2-(1,3-dithiol-2-ylidene)-1-phenyl-4-hexene-1,3-dione (Compound 11) - pi t12) 2-(1,3-dithiol-2-ylidene)-1-(4-methylphenyl)-1,3-butanedione (Compound 12) (13) 2-(1,3-dithiol-2-ylidene)-1-(4-fluorophenyl)-1,3-butanedione (Compound 13) (14) 2-(1,3-dithiol-2-ylidene)-1-(4-chlorophenyl)-1,3-butanedione (Compound 14) (15) 2-(1,3-dithiol-2-ylidene)-1-(4-bromophenyl)-. , 1,3-butanedione (Compound 15) (16) 2-(1,3-dithiol-2-ylidene)-1-(2-methoxyphenyl)-1,3-butanedione (Compound 16) (17) 2-(1,3-dithiol-2-ylidene)-1-(4-methoxyphenyl)-1,3-butanedione (Compound 17) -(18) 2-(1,3-dithiol-2-ylidene)-1-(3,4-dimethoxy-phenyl)-1,3-butanedione (Compound 18) (19) 2-(1,3-dithiol-2-ylidene)-1-(4-nitrophenyl)-1,3-butanedione (Compound 19) (20) 2-(1,3-dithiol-2-ylidene)-1-(2-pyridyl)-1,3-butanedione (Compound 20) (21) 2-(1,3-dithiol-2-ylidene)-1-(3-pyridyl)-1,3-butanedione (Compound 21) (22) 2-(1,3-dithiol-2-ylidene)-1-(4-pyridyl)-1,3-butanedione (Compound 22) (23) 2-(1,3-dithiol-2-ylidene)-1-(2-furyl)-1,3-butanedione (Compound 23) (24) 2-(1,3-dithiol-2-ylidene)-1-(2-thienyl)-1,3-butanedione (Compound 24) (25) 2-(1,3-dithiol-2-ylidene)-1-(2-pyrrolyl)-1,3-butanedione (Compound 25) . .

(26) 2-(1,3-dithiol-2-ylidene)-1-pyrazinyl-1,3-butanedione (Compound 26) (27) 2-(1,3-di-thiol-2-ylidene)-1-(1-naphthyl)-1,-3-butanedione (Compound 27) 5(28) 2-(1,3-dithiol-2-ylidene)-1-(2-naphthyl)-1,3-butanedione (Compound 28) (29) 2-(1,3-dithiol-2-ylidene)-1-(2-indolyl)-1,3-butanedione (Compound 29) (30) 2-(1,3-dithiol-2-ylidene) 1-(2-qùinolyl)-1,3-10butanedione (Compound 30) (31) 2-(1,3-dithiol-2-ylidene)-1-phenyl-4,4,4-trifluoro-1,3-butanedione (Compound 31) (32) 3-(1,3-dithiol-2-ylidenej-1-phenyl-2,4-pentanedione (Compound 32) 15(33) 4-(1,3-dithiol-2-ylidene)-1-phenyl-1-hexene-3,5-dione (Compound 33) (34) 2-(1,3--dithiol-2-ylidene)-1,3-diphenyl-1,3-propanedione (Compound 34) (35) 2-(1,3-dithiol-2-ylidene)-1,3-di(4-chloro 20phenyl)-1,3-propanedione (Compound 35) (36) 2-(1,3-dithiol-2-ylidene)-1,3-di(4-methoxy-phenyl)-1,3-propanedione (Compound 36) (37) 2-(1,3-dithiol-2-ylidene)-1,4-diphenyl-1,3-butanedione (Compound 37) 25(38) 4 (1,3-dithiol-2-ylidene)-1,5-diphenyl-1-pentene-3,5-dione (Compound 38) (39) 4-(1,3-dithiol-2-ylidene)-1,7-diphenyl-1,6-heptadiene-3,5-dione (Compound 39) (40~ 2-(1,3-dithiol-2-ylidene)-1,3~cyclopentane-dione (Compound 40) (41) 2-(1,3-dithiol-2-ylidene)-1,3-cyclohexane-dione (Compound 41) (42) 2-(1,3-dithiol-2-ylidene)-4-methyl-1,3-cyclo-hexanedione (Compound 42) (43) 2-(1,3-dithiol-2-ylidene)-4-(2-methylethyl)-1,3-cyclohexanedione (Compound 43) (44) 2-(1,3-dithiol-2-ylidene)-5,5-dimethyl-1,3-cyclo-hexanedione (Compound 44) (45) 3-(1,3-dithiol-2-ylidene)-1-(4-hydroxylphenyl)-1,3-butanedione (Compound 45) . (46) 2-(1,3-dithiol-2-ylidene)-1-(4-aminophenyl)-1,3-butanedione (Compound 46) (47) 2-(1,3-dithiol-2-ylidene)-1-(2-benzimidazolyl)-1,3-butanedione (Compound 47) However, the present invention is not restricted to these specific examples.
According to the present invention, the compound of the formula I can be prepared by reacting the ~-diketone of the formula II, if necessary, protected by a suitable protective group, with the dithiolium salt of the formula III in the presence of a base, and, if necessary, removing the protective group.
As the ~-diketone of the formula II, there may be mentioned, for instance, 2,4-pentanedione, 2,4-hexanedione, 1-ethoxy-2,4-pentanedione, _ 9 2,8-dimethyl-4,G-nonanedione, l-cyclohexyl~1,3-butane-dione, l-phenyl-1,3-butanedione, 1-phenyl-1,3-hexane-dione, 5-methyl-1-phenyl-1,3-hexanedione, 4,4-dimethyl-l-phenyl-1,3-pentanedione, 1-phenyl-1,3-octadecanedione, 1-phenyl-4-hexene-1,3-dione, 1-(4-methylphenyl)-1,3-butanedione, l-t4-fluorophenyl)-1,3-butanedione, 1-(4-chlorophenyl)-1,3-butanedione, 1-t4-bromophenyl)-1,3-butanedione, 1-(2-methoxyphenyl)-1,3-butanedione, 1-(4-metho~yphenyl)-1,3-butanedione, 1-(3,4-methoxy-phenyl)-1,3-butanedione, 1-(4-nitrophenyl)-1,3-butane-dione, l-(2-pyridyl)-1,3-butanedione, 1-(3-pyridyl)-1,3-butanedione, 1-(4-pyridyl)-1,3-butanedione, 1-(2-furyl)-1,3-butanedione, 1-(2-thienyl)-1,3-butane-dione, 1-(2-pyrrolyl)-1,3-butanedione, 1-pyrazinyl-1,3-butanedione, 1-(1-naphthyl)-1,3-butanedione, 1-(2-naphthyl)-1,3-butanedione, 1-(2-indolyl)-1,3-butane-dione, l-(2-quinolyl)-1,3-butanedione, 1-pheny-4,4,4-trifluoro-1,3-butandedione, 1-phenyl-2,4-pentanedione, l-phenyl-l-hexene-3,5-dione, 1,3-diphenyl-1,3-propane-20 dione, 1,3-di(4-chlorophenyl)-1,3-propanedione, 1,3-di(4-methoxyphenyl)-1,3-propanedione, 1,4-diphenyl-1,3-butanedione, 1,5-diphenyl-1-pentene-3,5-dione, 1,7-diphenyl-1,6-heptadiene-3,5-dione, 1,3-cyclo-pentanedione, 1,3-cyclohexanedione, 4-methyl-1,3-cyclo-hexanedione, 4-(2-methylethyl)-1,3-cyclohexanedione, 5,5-dimethyl-1,3-cyclohexanedione, 1-(4-methoxy-methyloxyphenyl)-1,3-butanededione, 1-(4-t-butoxycarbonyl-o~?~ :

aminophenyl)-1,3-butanedione, and 1-t2-benzimidazolyl)-1,3-butanedione.
Such ~-diketones of the formula II may be available as commercial products, or may otherwise readily be prepared by one of the following two methods:
Method A

rid 11 11 1 Method B
O O base O
R-C-CH3 + Q-C-Rl id R-C-C~2-C-Rl (II) In the above formulas, R and R are as defined above, and Q is an active group of a carboxyl group.
The protective group for the ~-diketone may be of any type so long as it does not adversely affect the product when it is removed from the product. As specific examples of the protective group, there may be mentioned a tert-butoxycarbonyl group, a benzyloxycarbonyl group, a benzyl group, and a methoxymethyl group.
The dithiolylium salt of the formula III may be synthesized by alkylating 1,3-dithiol-2-thione by means of e.g. methyl iodide, ethyl iodide or dimethyl sulfate, or benzylating it with e.g. benzyl chloride.
In carrying out the process of the present invention, the reaction of the ~-diketone of the formula II with the dithiolylium salt of the formula III in the presence of a ~3~

base is preEerably conducted by using a suitable solvent.
As such a solvent, it is desirable to use a solvent inert to the reaction. For instance, there may be mentioned tetrahydrofuran, dioxane, methanol, acetic acid, dimethyl sulfoxide and dimethylformamide. These solvents may be used alone or in combination as a mixture.
The molar ratios of the dithiolylium salt and the base relative to the ~-diketone are not critical.
However, it is preferred to use the stoichiometric amount of dithiolylium salt and the stoichiometric amount or an excess amount of the base relative to the ~-diketone.
The reaction is conducted usually within a temperature range of from 0C to the boiling point of the solvent.
However, the reaction may be conducted at a temperature lower or higher than this range in order to control the reaction rate.
As the base to be used in the present invention, there may be mentioned inorganic bases such as metal sodium, sodium hydride, sodium methoxide, sodium hydroxide, potassium hydroxide, sodium carbonate and potassium carbonate, and organic bases such as pyridine, triethylamine and dimethylaniline.
The reaction produces no substantial by-products.
Therefore, after-treatment of the reaction is very simple. Namely, after the completion of the reaction, the desired product is extracted from the reaction mixture with a suitable solvent, followed by the removal

- 12 -of the solvent, whereby the desired product is obtained.
If necessary, the desired product can be separated and purified by recrystallization or by column chromatography.
When the compound of the present invention is to be used as a drug for treating the liver disease, its dose is usually from 0.1 to 25 mg a day per kg of the body weight in the case of oral administration, and from 0.01 to 10.0 mg a day per kg of the body weight in the case of parenteral administration, although it may vary depending upon the body weight, age, sex or health condition of the patient, the manner of administration or the degree of disease. r The compound of the present invention may be formulated into various forms such as tablets, granules, powders, suspensions, capsules, solutions for injection or isotonic solutions in accordance with the conventional methods which are commonly used in the technical fields for pharmaceutical formulations.
For the production of solid formulations for oral administration, the active ingredient is incorporated with a vehicle and necessary additives such as a condensing agent, a disintegrator, a lubricant, a coloring agent, or a taste- or odor-controlling agent, and then the mixture is formed into tablets, coated tablets, granules, powders or capsules by conventional methods.

- 13 -For the preparation of injection solutions, the active ingredient is incorporated with a pH controlling agent, a buffer, a suspending agent, a dissolving agent, a stabilizer, an isotonic agent, a storage assistant, etc., if required, and the mixture is formulated into hypodermic, intramuscular or intravenous injection solutions by conventional methods.
Now, the present invention will be described in further detail with reference to Examples. However, it should be understood that the present invention is by no means restricted to these specific Examples.
Example 1 To 20ml of dry tetrahydrofuran, 0.5g of 50% oil-based sodium hydride was suspended, and l.Og of 2,4-pentanedione was gradually added under cooling with ice. After the completion of the generation of hydrogen gas, 2.5g of 2-methylthio-1,3-dithiolylium perchlorate was added thereto, and the mixture was stirred at room temperature for three hours. Then, the solvent was removed from the reaction solution by distillation under reduced pressure. Ice water was added to the residue, and then the desired product was extracted with chloroform. The chloroform extract was concentrated under reduced pressure, and the residue was 25 recrystallized from benzene, whereby 1.8g (yield: 90%) of 3-(1,3-dithiol-2-ylidene)-2,4-pentanedione (Compound 1) was obtained as crystals having a melting point of from 159 to 160C.

; 3

- 14 -IRv m am 1 : 3010, 1570, 1370, 1320, 1270 NMR(CDC13)~ : 7.4t2H,s), 2.6~6H,s) Examples 2-44 In the same manner as in Example 1, the following compounds were obtained.
Example 2 3-(1,3-dithiol-2-ylidene)-2,4-hexanedione (Compound 2) mp~. : 90C (recrystallized from n-hexane) IRv Brcm 1 : 3000, 1570, 1365, 1320, 1270 max NMR(CDC13)~ o 7.3(2H,s), 2.8(2H,q), 2.6(3H,s), 1.2(3H,t) Example 3 3-(1,3-dithiol-2-ylidene)-1-ethoxy-2,4-pentane-dione (Compound 3) mp. : 85C (recrystallized from benzene-n-hexane) IRv maxcm 1 : 3020, 1580, 1380, 1320, 1280 NMR(CDCl )~ : 7.4(2H,s), 4.6(2H,s), 3.6(2H,q), 3 2.7(2H,s), 1.3(3H,t) Example 4 5-(1,3-dithiol-2-ylidene)-2,8-dimethyl-4,6-nonane--dione (Compound 4) mp. : 75-76C (recrystallized from benzene-n-hexane) IRv maxcm 1 : 3010, 1580, 1480, 1340, 1320 NMR(CDCl3)~ : 7.2(2H,s), 2.7(4H,d), 2.3(2H,m), 0.9(6H,d) 3-~

- 15 Example 5 2-(1,3-dithiol-2-ylidene)-1-cyclohexyl-1,3-butane--dione (Compound 5) mp. : 104-105C (recrystallized from methanol) IRv mBaxcm 1 : 2920, 1564, 1379, 1302 NMR(CDC13)~ : 7.5(2H,sl, 2.7(3H,s), ` ; 2.1-1.3(5H,m) Example 6 2-(1,3-dithiol-2-ylidene)-1-phenyl-1,3-butanedionee (Compound 6) mp. : 108-lo9oc (recrystallized from ethyl acetate-benzene) IRv mBxcm 1 : 3050, 1590, 1570, 1365, 1278 NMR(CDC13)~ : 7.5(5H,m), 7.3(2H,s), 1.9(3H,s) Example 7 2-(1,3-dithiol-2-ylidene)-1-phenyl~1,3-hexanedionee (Compound 7) mp. : 65C (recrystallized from benzene-n-hexane) IRv marcm 1 : 3070, 1570, 1450, 1370, 1340, 1280 NMR(CDC13)~ : 7.5(5H,m), 7.3(2H,s), 2.2(2H,t) 1.5(2H,m), 0.7(3H,t) Example 8 2-(1,3-dithiol-2-ylidene)-5-methyl-1-phenyl-1,3-hexanedlone (Compound 8) mp. : 63.5C (recrystallized from benzene-n-hexane) IRv mBaXCm : 1620, 1580, 1570, 1380, 1362 NMR(CDC13)~ : 7.5(5H,m), 7.3(2H,s), 2.0(2H,d) l.9(1H,m), 0.7(6H,d) go 3

- 16 -Example 9 2-~1,3-dithiol-2-ylidene)-4,4-dimethyl-1-phenyl-1,3-pentanedione (Compound 9) mp. : 91-92C (recrystallized from chloroform n-hexane) IRV maxcm 1 : 2900, 1630, 1580, 1560, 1382 NMR(CDC13)~ : 7.3-7.8(5H,m), 6.9(2H,s), I` ; l.O(9H,s) Example 10 2-(1,3-dithiol-2-ylidene)-1-phenyl-1,3-octadecanedione (Compound 10) mp. : 49-50C (recrystallized from chloroform-n-hexane) IRV maxcm 1 : 2920, 2850, 1615, 1560, 1338, 708 NMR(CDC13)~ : 7.3-7.7(5H,m), 7.25(2H,s), 2.2~2H,t) 0.7-1.7~29H,m) Example 11 2-(1,3-dithiol-2-ylidene)-1-phenyl-4-hexene-1,3-diione (Compound 11) mp. : 83-84.5C (recrystallized from ethyl ether-n-hexane) IR vKEarcm 1 : 2910, 1640, 1600 1565, 1363 NMR(CDC13)~ : 7.3-7.75(5H,m), 7.3(2H,s), 6.4-6.9 (lH,m), 5.75(1H,d.q), 1.51(3EI,d.d) ExamPle 12 2-(1,3-dithiol-2-ylidene)-1-(4-methylphenyl)-1,3-butanedione (Compound 12) ~s~

- 17 -mp. : 161-163C (recrystallized from acetone-n-hexane) IRV maxcm : 3080, 1610, 1560, 1340, 1278 NMR(CDC13)~ : 7.45(2H,d), 7.2(2H,s), 7.1(2H,d) 2.35(3H,s), 1.9(3H,s) Example 13 2-(1,3-dithiol-2-ylidene)-1-(4-fluorophenyl)-1,3-butanedione (Compound 13) mp. : 151-152C (recrystallized from methanol) KBrcm-l 3050, 1600, 1560, 1350, 1275, 1230 max NMR(CDC13)~ : 7.7(2H,d), 7.3(2H,s), 7.2(2H,d) 1.95(3H,s) Example 14 152-(1,3-dithiol-2-ylidene)-1-(4-chlorophenyl)-1,33-butanedione (Compound 14) mp. : 151-152C (recrystallized from acetone-n-hexane) v KBrcm 1 3080, 1580, 1370, 1322 max 1 95(3H,s) Example 15 2-(1,3-dithiol-2-ylidene)-1-(4-bromophenyl)-1,3-butanedione (Compound 15) 25mp. : 137-138C (recrystallized from benzene-n-hexane) IR vm xcm 1 : 3050, 1605, 1570, 1360, 1270, 1170

- 18 NMR(CDCl )~ : 7.8(2H,d), 7.5(2H,s), 7.35(2H,d) 3 1.9(3H,s) Example 16 2-(1,3-dithiol-2-ylidene)-1-(2-methoxyphenyl)-1,3--butanedione (Compound 16) mp. : 140.5C (recrystallized from acetone-petroleum ether) IRV mBaXCm : 3000, 1592, 1560, 1340, 1308 NMR(CDCl )~ : 6.6-7.5(6H,m), 3.7(3H,s), 1 3 1.9(3H,s) Example 17 2-(1,3-dithiol-2-ylidene)-1-(4-methoxyphenyl)-1,3--butanedione (Compound 17) mp. : 146C (recrystallized from methanol) IRV mBxrcm 1 : 3080, 1590, 1375, 1260, 1180 NMR(CDCl )~ : 7.5(2H,d), 7.1(2H,s), 6.9(2H,d), 3 3.7(3H,s), 1.9(3H,s) Example 18 2-(1,3-dithiol-2-ylidene)-1-(3,4-dimethoxyphenyl)--1,3-butanedione (Compound 18) mp. : 192-193C (recrystallized from ethanol) IRV mBxcm 1 : 3000, 1605, 1560, 1420, 1350, 1270 NMR(CDCl )~ : 7.15-7.35(7H,m), 7.2(2H,s), 25 3 6.85(1H,d), 3.9(6H,s), 2.0(3H,s)

- 19 -Example 19 2-(1,3-dithiol-2-ylidene)-1-(4-nitrophenyl)-1,3-butanedione (Compound 19) mp. : 151-153C (recrystallized from benzene-hexane) IRV m xcm : 3005, 1600, 1550, 1510, 1330, 1310 a 1280 NMR(CDC13)~ : 8.25(2H,d), 7.75(2H,d), ` 7.4(2H,s), 1.8(3H,s) Example 20 2-(1,3-dithiol-2-ylidene)-1-(2-pyridyl)~1,3-butanedione (Compound 20) mp. : 148-149C trecrystallized from benzene) maxcm : 3050, 1620, 1570, 1370, 1330 1265 NMR(CDC13)~ : 8.6(1H,d.d), 7.9(1H,d.d), 7.35(1H,m), 7.35(2H,s), 1.85 (3H,S) Example 21 2-(1,3-dithiol-2-ylidene)-1-(3-pyridyl)-1,3-butanedione (Compound 21) mp. : 124-125C (recrystallized from benzene-n-hexane) IRV m xCm : 1610, 1580, 1420, 1350, 1300 NMR(CDC13)~ : 8.7(2H,q), 8.0(1H,m), 7.4t2H,s), 7.3(1H,d), 2.0(3H,s) . .

f

20 --Example 22 2-(1,3-dithiol-2-ylidene)-1-(4-pyridyl)-1,3-butanedione (Compound 22) mp. : 146-146.5C (recrystallized from ethyl acetate-petroleum ether) IRv mBaxcm 1 : 3030, 1560, 1540, 1400, 1342, 1270 NMR(CDC13)~ : 8.7(2H,d), 7.4(2H,s), 7.35(2H,d) Example 23 2-(1,3-dithiol-2-ylidene)-1-(2-furyl)-1,3-butanedione (Compound 23) mp. : 154-155C recrystallized from benzene-n-hexane) IR v mBaxcm 1 : 3080, 1560, 1350, 1330, 1285 NMR(CDCl3)~ : 7.5(1H,d), 7.3(2H,s), 7.1(1H,d) 6.5(lH,q), 2.1(3H,s) Example 24 2-(1,3-dithiol-2-ylidene)-1-(2-thienyl)-1,3-butanedione (Compound 24) mp. : llO-111C (recrystallized from benzene-n-hexane) maxcm : 3050, 1600, 1545, 1415, 1360 NMR(CDCl )~ : 7.6(1H,d.d), 7.4(1H,d.d), 3 7.15(2H,s) 7.1(1H,m), 2.1(3H,s) Example 25 2-(1,3-dithiol-2-ylidene)-1-(2-pyrrolyl)-1,3-butanedione (Compound 25) mp. : 112-114C (recrystallized from benzene-n-hexane) 3~3

- 21 -IR vmaxcm 1 : 3000, 1605, 1550, 1403, 1363, 1320 NMR(CDC13)~ : 6.9(2H,s), 6.1-7.1(4H,m), 2.2(3H,s) Example 26 2-(1,3-dithiol-2-ylidene)-1-pyrazinyl-1,3-butanedione (Compound 26) mp. : 181-182C (rec!rystallized from ethyl acetate-benzene) IRV maxcm : 3050, 1620, 1590, 1570, 1360, 1020 NMR(CDC13)~ : 9.0(1H,s), 8.6(2H,m), 7.6(2H,s), 1.85(3H,s) Example 27 2-(1,3-dithiol-2-ylidene)-1-(1-naphthyl)-1,3-butanedione (Compound 27) lS mp. : 158-159C (recrystallized from benzene-n-hexane) maxcm : 12368~ 1600, 1555, 1420, 1340, NMR(CDC13)~ : 7.7-8.15(4H,m), 7.35-7.65(3H,m), 7.4(2H,s), 1.65(3H,s) Example 28 2-(1,3-dithiol-2-ylidene)-1-(2-naphthyl)-1,3-butanedione (Compound 28) mp. : 154-155C (recrystallized from benzene-n-hexane) 25 IRV maxcm : 3050, 1560, 1430, 1310, 1300, 880, f f

- 22 -NMR(CDC13)~ : 8.05(1H,br.s), 7.2-8.0(6H,m), 7.25(2H,s) 1.9(3H,s) Example 29 2-(1,3-dithiol-2-ylidene)-1-(2-indolyl)-1,2-butanedione (Compound 29) mp. : 98-99C (recrystallized from benzene-n-hexane) IRv m3arcm 1 : 3050, 1645, 1575, 1450, 1380, 1200 NMR(CDC13)~ : 7.2-7.6(5H,m) J 7.0(2H,s), 6.5(1H,br.s), 2.1(3H,s) Example 30 2-(1,3-dithiol-2-ylidene)-1-(2-quinolyl)-1,3-butanedione (Compound 30) mp. : 197-198C recrystallized from benzene-n-hexane) maxcm : 3050, 1570, 1435, 1365, 1320 NMR(CDC13)~ : 8.3(1H,d), 7.45-8.2(5H,m), 7.3(2H,s) 1.85(3H,s) Example 31 2-(1,3-dithiol-2-ylidene)-1-phenyl-4,4,4-trifluoro-1,3-butanedione (Compound 31) mp. : 77-79C (recrystallized from aqueous methanol) IR Vmaxcm : 3050, 1590, 1560, 1450, 1430, 1230 NMR(CDC13)~ : 7.9(2H,d.d), i.4(3H,m), 6.75(2H,s) 303*

E~ampl _ 3-(1,3-dithiol-2-ylidene)-1-phenyl-2,4-pentanedione (Compound 32) mp. : 157.5-158C (recrystallized from ethanol~acetone) IRv cm 1 : 3000, 1570, 1440, 1380, 1320, 1260 max NMR(d6~DMSO)~ : 7.65~2H,s), 7.15(5H,s), 4.25(2H,s), 2.6~3H,s) Example 33 4-(1,3-dithiol-2-ylidene)-1-phenyl-1-hexene-3,5-dione (Compound 33) mp. : 150C (recrystallized from benzene-n-hexane) IRv cm : 3050, 1640, 1600, 1540, 1370, max 1250, 1195 NMR(CDC13)~ : 7.7(1H,d), 7.1-7.7(5H,m), 7.3(2H,s), 7.2(1H,d), 2.55(3H,s) Example 34 2-(1,3-dithiol-2-ylidene)-1,3-diphenyl-1,3-propanedione (Compound 34) mp. : 155-156C (recrystallized from methanol) IRv maxcm 1 : 3080, 1588, 1560, 1360, 1271 NMR(CDC13)~ : 7.3(2H,s), 6.85-7.50(10H,m) Example 35 2-(1,3-dithiol-2-ylidene)-1,3-di(4-chlorophenyl)-1,3-propanedione (Compound 35) mp. : 147-148C (recrystallized from methanol) IR vRBrcm 1 3070, 1590, 1567, 1362, 1275 max NMR(CDC13)~ : 7.75(4H,d), 7.3(2H,s), 7.2(4H,d) Example 36 2-(1,3-dithiol-2-ylidene)-1,3-di(4-methoxyphenyl)--1,3-propanedione (Compound 36) mp. : 143C (recrystallized from ethyl acetate-benzene) IR VmBaXCm : 3060, 158", 1565, 1360, 1270 NMR(CDC13)~ : 7.55(4H,d), 7.1(2H,s), 6.9(4H,d), 3.6~6H,s) Example 37 2-(1,3-dithiol-2-ylidene)-1,4-diphenyl-1,3-butaneddione (Compound 37) mp. : 116C (recrystallized from ethyl acetate-benzene) v KBrcm 1 3040, 1595, 1585, 1360, 1270, 1000 max NMR(CDC13)~ : 7.8-6.8(10H,m), 7.2(2H,s), 3.6(2H,s) ~3~

Example 38 4-(1,3-dithiol-2-ylidene)-1,5-diphenyl-1-pentene-33,5-dione compound 38) mp. : 174C (recrystallized from benzene-n-hexane) IRv m~axcm 1 : 3030, 1640, 1600, 1550, 1380, 1290, 1000 NMR(CDC13)~ : 7.3(2H,s), 6.8-7.9(11H,m), - ` 6.4(lH,d) Example 39 4-(1,3-dithiol-2-ylidene)-1,7-diphenyl-1,6-heptadiiene-3,5-dione (Compound 39) mp. : 218C (recrystallized from benzene) v maxcm : 105' 1630, 1570, 1360, 1240, NMR(CDC13)~ : 7.74(2H,d), 7.35(2H,s), 7.1-7.6(12H,m) Example 40 2-(1,3-dithiol-2-ylidene)-1,3-cyclopentanedione (Compound 40) mp. : 205-207C (recrystallized from acetone-n-hexane) IRv maxcm : 2920, 1610, 1430, 1410, 1300, 1250 NMR(CDC13)~ : 7.9(2E~,s), 2.7(4H,s) ~3~

Example 41 2-(1 r 3-dithiol-2-ylidene)-1,3-cyclohexanedione (Compound 41) mp. : 225-226C (recrystallized from benzene IRV maxrcm : 3100, 1590, 1380, 1262, 1190 NMR(CDC13)~ : 7.4(2H,s), 2.7(4H,t), 2.0(2H,t) .

Example 42 2-(1,3-dithiol-2-ylidene)-4-methyl-1,3-cyclohexanedione (Compound 42) mp. : 147-148C (recrystallized from acetone IRv maxcm : 3050, 1590, 1380, 1270, 1225, 720 NMR(CDC13)~ : 7.45(2H,s), 1.7-2.9(5H,m), 1.3(3H,d) Example 43 2-(1,3-dithiol-2-ylidene?-4-isopropyl-1,3-cyclohexanedione (Compound 43) mp. : 115-117C (recrystallized from ethyl acetate-ether) IRv mBaxcm 1 : 2950, 1592, 1380, 1278, 1275, 700 NMR(CDC13)~ : 7.45t2H,s), 1.7-3.0(6H,m), 1.2(3H,d) ~4~

Example 44 2-~1,3-dithiol-2-ylidene)-5,5-dimethyl-1,3-cyclohexanedione (Compound 44) mp. : 201C (recrystallized from ', benzene-n-hexane) IRV KBrCm : 2950, 1585, 1380, 1338, 1280, 715 max NMR(CDC13) I: 7.45(2H,s), 2.5(4H,s), 1.1(6H,s) Example 45 To 50ml of dry tetrahydrofuran, 0.7g of 50% oil-based sodium hydride was suspended, and 2.2g of 1-(4-methoxymethyloxyphenyl)-1,3-butanedione was gradually added under cooling with ice. After the completion of the generation of hydrogen gas, 3.3g of 2-methylthio-1,3-dithiolylium perchlorate was added thereto, and the mixture was stirred for 1 hour. Then, the solvent was removed from the reaction solution by distillation under reduced pressure.
Ice water was added to the residue, and then the desired product was extracted with chloroform. The chloroform extract was concentrated under reduced pressure, and the residue was purified by silicagel chromatography, whereby 2.7g of 2-(1,3-dithiol-2-ylidene)-1-(4-methoxymethyloxyphenyl)-1,3-butaneedione I' was obtained. ,The above product was dissolved in 50ml of isopropyl alcohol containlng 0.7% (W/W) hydrogen chloride, and the solution was aged for 30 minutes at 60C. Then, the solvent was evaporated under 430~

reduced pressure, and the residue was recrystallized from benzene-n-hexane, whereby 2~5g (yield: 66%) of 2-(1,3-dithiol-2-ylidene)-1-(4-hydroxyphenyl)-1,3-butaneddione was obtained as crystals having a melting point of from 74 to 76C.

maxcm : 11655, 1620, 1590, 1280, 1220, NMR(CDC13)~ : 9.1(1H,s), 7.3(2H,d), 7.2(2H,s) 6.75(2H,d), 2.1(3H,s) Example 46 Two and six-tenth gram of 2-(1,3-dithiol-2-ylidene)- -1-(4-t-butoxy-carbonylaminophenyl~-1,3-butanedionee, obtained in the same manner as in Example 1 using 2.8g of 1-(4-t-butoxy-carbonylaminophenyl)-1,3-butanedionee and 15 2.8g of 2-methylthio-1,3-dithiolylium perchlorate, was dissolved in 5ml of trifluoroacetic acid. Then, the solution was aged for 3 hours at room temperature, and to its solution, 50ml of n-hexane was added under stirring.
The product was filtered and recrystallized from ethyl acetate, whereby 1.7g (yield: 89%) of 2-(1,3-dithiol-2-ylidene)-1-(4-aminophenyl)-1,3-butanedione was obtained as crystals having a melting point of from 168 to 169C.

IR v maxcm 1 : 3350, 1600, 1540, 1390, 1260, NMR(CDC13)~ : 7.45(2H,d), 7.1(2H,s), 6.6(2H,d) 5.0(2H,s), 2.0(3H,s) 3~

Example 47 By using 2.0g of 1-(2-benzimidazolyl)-1,3-butanedione and 2.5g of 2-methylthio 1,3-dithiolylium perchlorate, the treatment way conducted in the same manner as in Example 1. The product was purified by silicagel chromatography, whereby 0.87g (yield: 29%) of 2-(1,3-dithiol-2-ylidene)-1-(2-benzimidazolyl~-1,3-butanedione was obtained as crystals having a decomposition point of 254C.
IRV maxcm : 1615, 1565, 1427, 1335, 760, 700 NMR(CDC13)~ : 7.7(2H,s), 7.1-7.7(4H,m), 2.0(3H,s) Pharmacological Test 1. Protective Effect on Acute Liver Injury Induced by Carbon Tetrachloride A test compound was dissolved or suspended in olive oil and administered orally at a dose of 50mg/kg to mice (ddY mice, I, 23 + 2g, n=5). After 6 hours, carbon tetrachloride (0.05ml/kg) was administered orally. 24 Hours after the administration of carbon tetrachloride, BSP (sodium sulfobromophthalene; 75mg/kg) was administered intravenously. Thirty minutes later, the cardiac blood was collected, and GPT
(glutamic-pyruvic transaminase) activity and the 'i3~

retention rate of BSP in the plasma were measured.
Further, the liver injury immediately after the collection of the blood was visually observed and evaluated by the following score for liver damage index.

: normal 2: Slightly injured 4: distinctly injured 6: remarkably injured As shown in Table 1, the test compounds showed substantial effects for preventing the liver injury with respect to each of the test items.

1i ;3~3~33~

Table 1 Compound No. Liver Damage Index % Prophylaxis p-GPT ¦ BSP
.-1 5.0 25 80 . 2 1.4 72 85 ,`: 3 2.2 97 102 4 1.0 '100 108 2.8 89 96 6 0.4 100 103 7 1.6 100 108 8 1.2 100 110 9 0.4 100 103 2.0 42 78 11 0.8 100 105 12 0.6 100 114 14 0.4 100 113 3.2 100 105 16 0.6 99 95 18 0.4 54 100 19 1.6 100 100 21 0.8 98 100 ,. 22 0.2 100 120

23 1.0 94 110

24 0 100 102 2.2 76 88 26 0.4 96 I_ ~;d 3 I Compound No. Liver Dnm~geIndex % Prophylaxis p-GPT BSP

29 0.8 100 104 2.0 98 105 31 0.4 100 106 '' 32 0.4 95 124 33 4.2 77 86 34 0.8 100 1~2 37 1.8 100 99 38 3.2 66 96 41 6.0 29 66 42 6.0 29 60 43 5.6 67 95 44 1.2 95 111 0.2 100 111 46 ' 0.4 100 106 47 2.4 91 103 CC14 alone 6.0 0 0 (4413~455)* (57+8)*
Normal 0 100 100 . _ , (18+2)* (15+1)*

*The value in parentheses represents mean+ S.E.

~3~

2. Therapeu-tic Effect on Fatty Liver Induced by Carbon Tetrachloride Carbon tetrachloride (lml/kg) was subcutaneously administered to rats (SD strain, I, 38 week-oLd, n=5) for 4 days. Upon expiration of 3 days from the , administration of carbon tetrachloride, Compound 6 was orally given successively for 7 days at the dose of 50mg/kg. On the 8th day, the animals were sacrificed by exsanguination. The therapeutic effect was evaluated by examining the content of triglyceride in the liver and the concentration of apoprotein B in the plasma. As shown in Table 2, Compound 6 exhibited a significant effect for curing the fatty liver.

Table 2 I.
Triglyceride Apoprotein (mg/g-liver) (mg/ml-plasma) Compound 6 33+ 7 112+ 23 CC14 alone 99+ 6 66+ 2 Normal 33+ 5 125-+ 8 3. Protective Effect on Acute Liver Injury Induced by D-Galactosamine A test compound was dissolved or suspended in olive oil and orally administered twice daily for 6 days at a 30~

dose of 50mg/kg to rats (SD strain, I, 225 +15g, 7 weeks-old, n=5). On the 6th day, D~galactosamine (200mg/kg x 3) was intraperitoneally administered three times at 3-hour intervals. 48 Hours after the first injection of D-galactosamine, the animals were sacrificed by exsanguination from the abdominal aorta. The protective effect was evaluated by examining the biochemical parameters (p-GPT, glucose, alkaline phosphatase) in plasma.

As shown in Table 3, the test compounds showed substantial effects for preventing the liver injury.

Table 3 Test CompoundP-GPT Glucose ALP
(U/l)(mg/dl) (U/l) .

Compound 6908+248 81-9 ~398+45 Compound 472938+69455+2 287+25 D-Galactosamine 4825+590 32+4 176+6 alone Normal 29+2 142+4 500+63 4. Effect on Protein Synthesis in Liver Compound 6 was dissolved in olive oil and orally administered successively for 3 days at a dose of 100mg/kg to rats (Wister strain, I, 180+10g, 6 week-old, n=5). 24 Hours after the administration of the test 3~
, compound was completed, the animals were sacrificed. The effect on the protein synthesis in the liver was evaluated by determining the liver weight and protein content.
As shown in Table 4, compound 6 showed substantial effect for stimulating the protein metabolic function of I` the liver.

Table 4 _ Liver WeightLiver Protein (g/lOOg b.w.)(mg/lOOg b.w.) Control 6.3+0.1 883+79 Compound 6 8.6+0.3 1247+62 5. Acute Toxicity Test A test compound was dissolved or suspended in olive oil and administered orally to mice (ddY mice, , 23+2g, n=5). The acute toxicity value (LD50) was determined from the mortality one week after the administration.
The test compounds (Compound Nos. 4, 5, 6, 7, 8, 12, 17, 27, 28 and 45) showed low toxicity and their LD 50 values were at least 2g.

Claims (100)

THE EMBODIMENTS OF THE INVENTION IN WHICH AN EXCLUSIVE
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:

1. A process for producing a 1,3-dithiol-Z-ylidene derivative of the formula:

(I) wherein each of R and R1 may be the same or different, and is selected from the group consisting of a C1-6 alkyl group, a C2-4 alkenyl group, a C3-6 cycloalkyl group, a C1-3 alkoxy-C1-4-alkyl group, phenyl, naphthyl, benzyl, naphthylmethyl, furyl, thienyl, pyrollyl, imidazolyl, pyridyl, pyazinyl, indolyl, quinolyl, and benzimidazolyl group, which may be substituted by halogen, hydroxyl, lower alkyl, lower alkoxy, nitro, cyano, or lower alkoxycarbonyl or R and R1 together form an ethylene or trimethy-lene group which may be substituted by C1-4 alkyl, benzyl, naph-thyl, methyl, phenyl or naphthyl, which comprises reacting a .beta.-diketone of the formula:
(II) wherein R and R1 are as defined above, when required, protected by a suitable protective group, with a dithiolyllum salt of the formula:

(III) wherein R2 is a lower alkyl group or an aralkyl group, and X is an anion residue, in the presence of a base, and when required, removing the protective group.

2. A process as claimed in claim 1, which is conducted in the presence of a solvent inert to the reaction.

3. A process as claimed in c1aim 2, in which the .beta. -diketone is present in excess of stoichiometric.

4. A 1, 3-dithiol-2-ylidene derivative of the formula:

( I ) wherein each of R and R1 may be the same or different, and is selected from the group consisting of a C1-6 alkyl group, a C2-4 alkenyl group, a C3-6 cycloalkyl group, a C1-3 alkoxy-C1-4-alkyl group, phenyl, naphthyl, benzyl, naphthylmethyl, furyl, thienyl, pyroliyl, imidazoiyl, pyridyl, pyazinyl, indoiyl, quinoiyl, and benzimidazolyi group, which may be substituted by halogen, hydroxyl, lower alkyl, lower alkoxy, nitro, cyano, or lower alkoxycarbonyl or R and R1 together form an ethylene or trimethy-lene group which may be substituted by C1-4 alkyl, benzyl, naph-thyl, methyl, phenyl or naphthyl.

5. A process as claimed in claim 1, wherein each of R
and R1 is methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, hexyl, vinyl, 2-methylvinyl, cyclopentyl, cyclohexyl, ethoxymethyl, 2-methoxyethyl, 3-ethoxypropyl, 3-propoxypropyl, 2-ethoxybutyl, or a phenyl, naphthyl, benzyl, naphthylmethyl, furyl, thienyl, quinoiyl or benzimidazoiyl group which may be substituted by halogen, hydroxyl, lower alkyl, lower alkoxy, nitro, cyano or lower alkoxycarbonyl, or R and R1 together form an ethylene or trimethylene group which may be sub-stituted by lower alkyl, benzyl, naphthylmethyl, phenyl or naphthyl.

6. A compound of formula I given in claim 1, in which R and R1 are as in claim 5.

7. A process as claimed in claim 1, which comprises reacting 2,4-pentanedione in dry tetrahydrofuran and in the pres-ence of sodium hydride with 2-methylthio-1,3-dithiolylium per-chlorate at room temperature.

8. 3-(1,3-dithiol-2-ylidene)-2,4-pentanedione.

9. A process as claimed in claim 1, which comprises reacting 2,4-hexanedione in dry tetrahydrofuran and in the pres-ence of sodium hydride with 2-methylthio-1,3-diothiolylium per-chlorate at room temperature.

10. 3-(1,3-dithiol-2-ylidene)-2,4-hexanedione.

11. A process as claimed in claim 1, which comprises reacting 1-ethoxy-2,4-pentanedione in dry tetrahydrofuran and in the presence of sodium hydride with 2-methylthio-1,3-dithiolylium perchlorate at room temperature.

12. 3-(1,3-dithlol-2-ylidene)-1-ethoxy-2,4-pentanedione.

13. A process as claimed in claim 1, which comprises reacting 2,8-dimethyl-4,6-noxanedione in dry tetrahydrofuran and in the presence of sodium hydride with 2-methylthio-1,3-dithi-olylium perchlorate at room temperature.

14. 5-(1,3-dilthiol-2-ylidene)-2,8-dimethyl-4,6-nonanedione.

15. A process as claimed in claim 1, which comprises reacting 1-cyclohexyl-1,3-butanedione in dry tetrahydrofuran and in the presence of sodium hydride with 2-methylthio-1,3-dithi-olylium perchlorate at room temperature.

16. 2-(1,3-dithiol-2-ylidene)-1-cyclohexyl-1,3-butanedione.

17. A process as claimed in claim 1, which comprises reacting 1-phenyl-1,3-butanedione in dry tetrahydrofuran and in the presence of sodium hydride with 2-methylthio-1,3-dithiolylium perchlorate at room temperature.

18. 2-(1,3-dithiol-2-ylidene)-1-phenyl-1,3-butanedione.

19. A process as claimed in claim 1, which comprises reacting 1-phenyl-1,3-hexanedione in dry tetrahydrofuran and in the presence of sodium hydride with 2-methyithio-1,3-dithiolyllum perchlorate at room temperature.

20. 2-(1,3-dithiol-2-ylidene)-1-phenyl-1,3-hexanedione.

21. A process as claimed in claim 1, which comprises reacting 5-methyl-1-phenyl-1,3-hexanedione in dry tetrahydrofuran and in the presence of sodium hydride with 2-methylthio-1,3-dithiolylium perchlorate at room temperature.

22. 2-(1,3-dithiol-2-ylidene)-5-methyl-1-phenyl-1,3-hexanedione.

23. A process as claimed in claim 1, which comprises reacting 4,4-dimethyl-1-phenyl-1,3-pentanedione in dry tetrahy-drofuran and in the presence of sodium hydride with 2-methylthio-1,3-dithiolylium perchlorate at room temperature.

24. 2-(1,3-Dithiol-2-ylidene)-4,4-dimethyl-1-phenyl-1,3-pentanedione.

25. A process as claimed in claim 1, which comprises reacting 1-phenyl-1,3-octadecadione in dry tetrahydrofuran and in the presence of sodium hydride with 2-methylthio-1,3-dithiolylium perchlorate at room temperature.

26. 2-(1,3-Dithiol-2-ylidene)-1-phenyl-1,3-octadecanedione.

27. A process as claimed in claim 1, which comprises reacting 1-phenyl-4-hexene-1,3-dione in dry tetrahydrofuran and in the presence of sodium hydride with 2-methylthio-1,3-dithi-oiylium perchlorate at room temperature.

28. 2-(1,3-Dithiol-2-ylidene)-1-phenyl-4-hexene-1,3-dione.

29. A process as claimed in claim 1, which comprises reacting 1-(4-methylphenyl)-1,3-butanedione in dry tetrahydrofu-ran and in the presence of sodium hydride with 2-methylthio-1,3-dithiolylium perchlorate at room temperature.

30. 2-(1,3-Dithiol-2-ylidene)-1-(4-methylphenyl)-1,3-butanedione.

31. A process as claimed in claim 1, which comprises reacting 1-(4-chlorophenyl)-1,3-butanedlone in dry tetrahydrofu-ran and in the presence of sodium hydride with 2-methylthio-1,3-dithiolylium perchlorate at room temperature.

32. 2-(1,3-Dithiol-2-ylidene)-1-(4-fluorophenyl)-1,3-butanedione.

33. A process as claimed in claim 1, which comprises reacting 1-(4-fluorophenyl)-1,3-butanedione in dry tetrahydrofu-ran and in the presence of sodium hydride with 2-methylthio-1,3-dithiolylium perchlorate at room temperature.

34. 2-(1,3-dithiol-2-ylidene)-1-(4-chlorophenyl)-1,3-butanedione.

35. A process as claimed in claim 1, which comprises reacting 1-(4-bromophenyl)-1,3-butanedione in dry tetrahydrofuran and in the presence of sodium hydride with 2-methylthio-1,3-dithiolylium perchlorate at room temperature.

36. 2-(1,3-Dithiol-2-ylidene-1-(4-Bromophenyl)-1,3-butanedlone.

37. A process as claimed in claim 1, which comprises reacting 1-(2-methoxyphenyl)-1,3-butanedlone in dry tetrahydrofu-ran and in the presence of sodium hydride with 2-methylthio-1,3-dithiolylium perchlorate at room temperature.

38. 2-(1,3-Dithiol-2-ylidene)-1-(2-methoxyphenyl)-1,3-butanedione.

39. A process as claimed in claim 1, which comprises reacting 1-(2-methoxyphenyl)-1,3~butanedione in dry tetrahydrofu-ran and in the presence of sodium hydride with 2-methylthio-1,3-dithiolylium perchlorate at room temperature.

40. 2-(1,3-Dithiol-2-ylidene)-1-(4-methoxyphenyl)-1,3-butanedione.

41. A process as claimed in claim 1, which comprises reacting 1-(3,4-dimethoxyphenyl)-1,3-butanedione in dry tetrahy-drofuran and in the presence of sodium hydride with 2-methylthio-1,3-dithiolylium perchlorate at room temperature.

42. 2-(1,3-Dithiol-2-ylidene-1-(3,4-dimethoxyphenyl)-1,3-butanedione.

43. A process as claimed in claim 1, which comprises reacting 1-(4-nitrophenyl)-1,3-butanedione in dry tetrahydrofuran and in the presence of sodium hydride with 2-methylthio-1,3-dithiolylium perchlorate at room temperature.

44. 2-(1,3-Dithiol-2-ylidene)-1-(4-nitrophenyl)-1,3-butanedione.

45. A process as claimed in claim 1, which comprises reacting 1-(2-pyridyl)-1,3-butanedione in dry tetrahydrofuran and in the presence of sodium hydride with 2-methylthio-1,3-dithi-olylium perchlorate at room temperature.

46. 2-(1,3-Dithiol-2-ylidene)-1-(2-pyridyl)-1,3-butanedione.

47. A process as claimed in claim 1, which comprises reacting 1-(3-pyridyl)-1,3-butanedione in dry tetrahydrofuran and in the presence of sodium hydride with 2-methylthio-1,3-dithi-olylium perchlorate at room temperature.

48. 2-(1,3-Dithiol-2-ylidene)-1-(3-pyridyl)-1,3-butanedione.

49. A process as claimed in claim 1, which comprises reacting 1-(4-pyridyl)-1,3-butanedione in dry tetrahydrofuran and in the presence of sodium hydride with 2-methylthio-1,3-dithi-olylium perchlorate at room temperature.

50. 2-(1,3-Dithiol-2-ylidene)-1-(4-pyridyl)-1,3-butanedione.

51 . A process as claimed in claim 1, which comprises reacting 1-(2-furyl)-1,3-butanedione in dry tetrahydrofuran and in the presence of sodium hydride with 2-methylthio-1,3-dithi-olylium perchlorate at room temperature.

52. 2-(1,3-Dithiol-2-ylidene)-1-(2-furyl)-1,3-butanedione.

53. A process as claimed in claim 1, which comprises reacting 1-(2-thienyl)-1,3-butanedione in dry tetrahydrofuran and in the presence of sodium hydride with 2-methylthio-1,3-dithi-olylium perchlorate at room temperature.

54. 2-(1,3-Dithiol-2-ylidene)-1-(2-thienyl)-1,3-butanedione.

55. A process as claimed in claim 1, which comprises reacting 1-(2-pyrroiyl)-1,3-butanedione in dry tetrahydrofuran and in the presence of sodium hydride with 2-methylthio-1,3-dithioiylium perchlorate at room temperature.

56. 2-(1,3-Dithiol-2-ylidene)-1-(2-pyrroiyl)-1,3-butanedione.

57. A process as claimed in claim 1, which comprises reacting 1-pyrazinyl-1,3-butanedione in dry tetrahydrofuran and in the presence of sodium hydride with 2-methylthio-1,3-dithi-oiylium perchlorate at room temperature.

58. 2-(1,3-Dithiol-2-ylidene)-1-pyrazinyl-1,3-butanedione.

59. A process as claimed in claim 1, which comprises reacting 1-(1-naphthyl)-1,3-butanedione in dry tetrahydrofuran and in the presence of sodium hydride with 2-methylthio-1,3-dithiolylium perchlorate at room temperature.

60. 2-(1,3-Dithiol-2-ylidene)-1-(1-naphthyl)-1,3-butanedione.

61. A process as claimed in claim 1, which comprises reacting 1-(2-naphthyl)-1,3-butanedione in dry tetrahydrofuran and in the presence of sodium hydride with 2-methylthio-1,3-dithiolylium perchlorate at room temperature.

62. 2-(1,3-Dithiol-2-ylidene)-1-(2-naphthyl)-1,3-butanedione.

63. A process as claimed in claim 1, which comprises reacting 1-(2-indolyl)-1,2-butanedione in dry tetrahydrofuran and in the presence of sodium hydride with 2-methylthio-1,3-dithi-olylium perchlorate at room temperature.

64. 2-(1,3-Dithiol-2-ylidene)-1-(2-naphthyl)-1,3-butanedione.

65. A process as claimed in claim 1, which comprises reacting 1-(2-quinolyl)-1,3-butanedione in dry tetrahydrofuran and in the presence of sodium hydride with 2-methylthio-1,3-dithiolylium perchlorate at room temperature.

66. 2-(1,3-Dithiol-2-ylidene)-1-(2-quinolyl)-1,3-butanedione.

67. A process as claimed in claim 1, which comprises reacting 1-phenyl-4,4,4-trifluoro-1,3-butanedione in dry tetrahy-drofuran and in the presence of sodium hydride with 2-methylthio-1,3-dithiolylium perchlorate at room temperature.

68. 2-(1,3-Dithiol-2-ylidene)-1-phenyl-4,4,4-triflu-oro-1,3-butanedione.

69. A process as claimed in claim 1, which comprises reacting 1-phenyl-2,4-pentanedione in dry tetrahydrofuran and in the presence of sodium hydride with 2-methylthio-1,3-dithiolylium perchlorate at room temperature.

70. 3-(1,3-Dithiol-2-ylidene)-1-phenyl-2,4-pentanedione.

71. A process as claimed in claim 1, which comprises reacting 1-phenyl-1-hexene-3,5-dione in dry tetrahydrofuran and in the presence of sodium hydride with 2-methylthio-1,3-dithi-olylium perchlorate at room temperature.

72. 4-(1,3-Dithiol-2-ylidene)-1-phenyl-1-hexene-3,5-dione.

73. A process as claimed in claim 1, which comprises reacting 1,3-diphenyl-1,3-propanedione in dry tetrahydrofuran and in the presence of sodium hydride with 2-methylthio-1,3-dithi-olylium perchlorate at room temperature.

74. 2-(1,3-Dithiol-2-ylidene)-1,3-diphenyl-1,3-propanedione.

75. A process as claimed in claim 1, which comprises reacting 1,3-di(4-chlorophenyl)-1,3-propanedlone in dry tetrahy-drofuran and in the presence of sodium hydride with 2-methylthio-1,3-dithiolyllum perchlorate at room temperature.

76. 2-(1,3-Dithiol-2-ylidene)-1,3-di(4-chlorophenyl)-1,3-propanedione.

77. A process as claimed in claim 1, which comPrises reacting 1,3-di(4 methoxyphenyl)-1,3-propanedione in dry tetrahy-drofuran and in the presence of sodium hydride with 2-methylthio-1,3-dithiolylium perchlorate at room temperature.

78. 2-(1,3-Dithiol-2-ylidene)-1,3-di(4-methoxyphenyl)-1,3-propanedione.

79. A process as claimed in claim 1, which comprises reacting 1, 4-diphenyl-1,3-butanedione in dry tetrahydrofuran and in the presence of sodium hydride with 2-methylthio-1,3-dithi-olylium perchlorate at room temperature.

80. 2-(1,3-Dithiol-2-ylidene)-1,4-diphenyl-1,3-butanedione.

81. A process as claimed in claim 1, which comprises reacting 1,5-diphenyl-1-pentene-3,5-dione in dry tetrahydrofuran and in the presence of sodium hydride with 2-methylthio-1,3-dithioylium perchlorate at room temperature.

82. 4-(1,3-Dithiol-2-ylidene)-1,5-diphenyl-1-pentene-3,5-dione.

83. A process as claimed in claim 1, which comprises reacting 1,7-diphenyl-1,6-heptadiene-3,5-dione in dry tetrahydro-furan and in the presence of sodium hydride with 2-methylthio-1,3-dithiolylium perchlorate at room temperature.

84. 4-(1,3-Dithiol-2-ylidene)-1,7-diphenyl-1,6-hepta-diene-3,5-dione.

85. A process as claimed in claim 1, which comprises reacting 1,3-cyclopentanedione in dry tetrahydrofuran and in the presence of sodium hydride with 2-methylthio-1,3-dithiolylium perchlorate at room temperature.

86. 2-(1,3-Dithiol-2-ylidene)-1,3-cyclopentanedione.

87. A process as claimed in claim 1, which comprises reacting 1,3-cyclohexanedione in dry tetrahydrofuran and in the presence of sodium hydride with 2-methylthio-1,3-dithiolylium perchlorate at room temperature.

88. 2-(1,3-Dithiol-2-ylidene)-1,3-cyclohexanedione.

89. A process as claimed in claim 1, which comprises reacting 4-methyl-1,3-cyclohexanedlone in dry tetrahydrofuran and in the presence of sodium hydride with 2-methylthio-1,3-dithi-olylium perchlorate at room temperature.

90. 2-(1,3-Dithiol-2-ylidene)-4-methyl-1,3-cyclohex-anedione.

91. A process as claimed in claim 1, which comprises reacting 4-isopropyl-1,3-cyclohexanedione in dry tetrahydrofuran and in the presence of sodium hydride with 2-methylthio-1,3-dithiolylium perchlorate at room temperature.

92. 2-(1,3-Dithiol-2-ylidene)-4-isopropyl-1,3-cyclo-hexanedione.

93. A process as claimed in claim 1, which comprises reacting 5,5-dimethyl-1,3-cyclohexanedione in dry tetrahydrofuran and in the presence of sodium hydride with 2-methylthio-1,3-dithiolylium perchlorate at room temperature.

94. 2-(1,3-Dithiol-2-ylidene)-5,5-dimethyl-1,3-cyclo-hexanedione.

95. A process as claimed in claim 1, which comprises reacting 1-(4-methoxymethyloxyphenyl)-1,3-butanedione in dry tetrahydrofuran and in the presence of sodium hydride with 2-methylthio-1,3-dithiolylium perchlorate at room temperature.

96. 2-(1,3-dithiol-2-ylidene)-1-(4-methoxymethy-loxyphenyl)-1,3-butanedione.

97. A process as claimed in claim 1, which comprises reacting 1-(4-t-butoxy-carbonylaminophenyl)-1,3-butanedione in dry tetrahydrofuran and in the presence of sodium hydride with 2-methylthio-1,3-dithiolylium perchlorate at room temperature.

98. 2-(1,3-Dithiol-2-ylidene)-1-(4-t-butoxy-carbonylaminophenyl)-1,3-butanedione.

99. A process as claimed in claim 1, which comprises reacting 1-(2-benzimidazolyl)-1,3-butanedione in dry tetrahydrofuran and in the presence of sodium hydride with 2-methylthio-1,3-dithiolylium perchlorate at room temperature.

100. 2-(1,3-Dithiol-2-ylidene)-1-(2-benzimidazolyl)-1,3-butanedione.