Note: Descriptions are shown in the official language in which they were submitted.
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
-- 5
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)
. .
-- 7
(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)
-- 8
(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~?~ :
-- 10 --
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*
-- 23 -
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)
- 24 -
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~
- 25 -
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~
- 26 -
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~
- 27 -
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~
- 28
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~
- 29 -
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~
- 30 -
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~
- 31 -
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
17 0 100 100
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
- 32 -
I Compound No. Liver Dnm~geIndex % Prophylaxis
p-GPT BSP
27 0 100 100
28 0 99 100
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
0 100 114
36 0 100 119
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~
- 33 -
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~
34
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~
,
- 35 -
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.
