CA1310322C - Cyclohexanedione derivative and a process for producing the same - Google Patents

Abstract

ABSTRACT OF THE DISCLOSURE
A cyclohexanedione derivative represented by the general formula (I);

(I) wherein R1, R4 and R7 represent independently hydrogen atom or C1 - C8 alkyl group, R2 represents hydrogen atom;
C1 - C8 alkyl group; C2 - C6 alkenyl group; C3 - C8 cycloalkyl group; C2 - C7 alkoxycarbonyl group; C1 - C6 alkylthio C1 - C6 alkyl group; a phenyl group; a phenyl group substituted with 1 to 3 groups selected from the group consisting of halogen atom, C1 - C6 alkyl group, C1 - C6 haloalkyl group, C1 - C6 alkoxy group, C1 - C6 alkylthio group, C3 - C8 cycloalkoxy group, a benzyloxy group and a benzyloxy group substltuted with C1 - C6 alkoxy group; naphthyl group or a heterocyclic group, R3 represents hydrogen atom, C1 - C8 alkyl group or C2 - C7 alkoxycarbonyl group, and R5 and R6, which may be the same or different, represent hydrogen atom, C1 - C6 alkyl groups, C2 - C6 alkenyl group, C2 - C7 alkylcarbonyl group or C2- C7 haloalkylcarbonyl group or its pharmaceutically acceptable salts; a pharmaceutical composition containing the same; and a process for producing the same.

Description

13~ ~322 FIELD OE THE INVENTION
This invention relates to a cyclohexanedione derivative represented by the general formula ~r~- J

wherein Rl, R4 and R7 represent independently hydrogen atom or Cl - C8 alkyl group, R2 represents hydrogen atom;
Cl - C8 alkyl group; C2 - C16 alkenyl group; C3 - C8 cycloalkyl group; C2 - C7 alkoxycarbonyl group; Cl - C6 alkylthio Cl - C6 alkyl group; a phenyl group; a phenyl group substituted with 1 to 3 groups selected from the group consisting o~ halogen atom, Cl ~ C6 alkyl group, Cl -C6 haloalkyl group, Cl - C6 alkoxy group, Cl - C6 alkylthio group, C3 - C8 cycloallcoxy group, a benzyloxy group and a benzyloxy group subst~ituted w~ith C - C6 ~ ry/ ~r ~ ,~n~ :
alkoxy group; naphthyl group or a-~e~e~e~e~ group, R3 represents hydrogen atom, Cl: - C8 alkyl group or C2 - C7 alkoxycarbonyl group, and R5~and R6j which may be the same or different, represent hydrogen atom, Cl - C6 alkyl group, C2 - C6 alkenyl group, C2 - C7 alkylcarbonyl group : or C2 - C7 haloalkylcarbonyl group and its pharmaceutically -- 1 -- .

3~

~ 3:~ ~322 1 acceptable salts, a process for producing the same and a pharmacel~tical composition containing the same.

BACKGROUND OF THE INVENTION
It has been disclosed tnat cyclohexanedione ~- 5 derivatives shown below are effective for the treatment of ~v~ damage (See U.S. Patent Mo. 4,668,799) 1. 2-(1,3-dithiol-2-ylidene)-1,3-cyclohexanedione.

2. 2-(1,3-dithiol-2-ylidene)-4-methyl-1,3-cyclohexane-dione.

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

4. 2-(1,3-dithiol-2-ylidene)-5,5-dimet]lyl-1,3-cyclohexane-dione.
There is still a desire, however, for a compound capable of curing and/or preventing liver disorders at a conside-rably lower dosage which will provide a more safety margin for treating both men and animals.

SUMMARY OF THE INVENTION
~ The object of the present invention is to provide a cyclohexanedione derivative represented by the aforementioned general formula (Ij.
The other object of the present invention is to provide a pharmaceutical composition containing as an active ingredient a compound shown by said general formula (I).
The furt'ner other object of the present 3 ~ ~

1 invention is to provide a method for treating liverdisorders in men and animals by administrating said composition to them parenterally or orally.
The further other object of the present inven-tion is to provide a method for producing a compoundrepresented by said general formula (I).
The terms ~alkyl and allcenyl" as used herein denote both straight-chain and branched alkyl and alkenyl groups, respectively.
.
DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS
The compounds represented by the afore-mentioned ~-general formula (I) and their salts are novel compounds not described in the literatures; they have, for example, a liver function activating effect, and hence is useful as active ingredient for a pharmaceutical composition for treating hepatic disorders in men and animals.
The compound of general formula (I) can be produced, for example, by methods A and B as shown in the following scheme:

:: :
Method A
. ~.

R
R ~1) R HNCCH2NHR (III) O\ ¦ ~S03Na H
C
HO 53Na MS ~ R2 .

~ 3 ~ 2 R7 1 O R (I) l R2 R3 R4 R5 R6 and R7 have the same meanings as defined above, M represents alkali metal atom.
That is, the compound of the general formula (I) can be produced by reacting the compound of the general formula (II) with the compound of the general formula (III) in a suitable solvent at a temperature in the range of from -20C to 50C and followed by the reaction with the compound of the general formula (IV) at a temperature in the range oE from -20C to 80C.
The solvents which can be used in the present reaction are preferably water or solvents consist of water and an organic solvent. For the organic solvent, there can be exemplified, for example, dimethylforamide, dimethy1sulfoxide, hexamethylphosphoroamide and N,N-dimethylethyleneurea or in combination oE these solvents.
The reaction time depends upon the~reaction temperature and reaction scale, but it may properly be selected from l to 2~hours. As to the molar rati~o of the reagents in pract1c1ng the present reaction, they are used in equi-mola~r amounts because the present reaction are anequimolar reaction, but e1ther one of them may be used in ~ excess of the other.

: ~ : :
~ - 4 -~L3~3~

1 The compound of general formula (II) shown below can be obtained by reacting a compound of general formula (V) with an equivalent or a slightly excess of sodium bisulfite in water at a temperature in the range of from 0C to 80C.

~ C~ HO \¦ ~SO3Na + 2NaHS03 >
~,C~ Ho~ CH~So N

(V) (II) wherein R4 has tne same meaning as defined above. The compound of the general formula (IV) shown below can be obtained by reacting a cornpound of general formula (VI) with carbon disulfide in a suitable solvent in the presence of a base at a temperature in the range of from -20C to 60C:

R base MS ~ R

(VI) (IV) whereln Rl, R2, R3 and M have the same meaning as defined above.
In most case, the compound of the general formula (IV) can be used without being separated from the : - 5 -~31~3~

1 reactiOn mixture.
For a base usable in preparing the compound of the general formula (IV), there can be exemplified, for example, a hydroxide such as sodium hydroxide, potassium hydroxide and a carbonate such as sodium carbonate, potassium carbonate.
~ or a solvent, there can be exemplified, for example, dimethylformamide, dimethylsulfoxide, hexamethyl-phosphoroamide and N,N-dimethylethyleneurea etc., and in combination of these solvents or in combination of water with above organic solvents.

Method B

RSX (VII) or N S 3 R R6X (VIII) ~ N ~ S Rl : N S ~ R2 R6 (or ~8) o R

- (I) 1 h ein Rl R2 R3 R4, R5, R6 and R7 have the same meanings as defined above, R8 represents hydrogen atom or Cl - C5 alkyl group, and X represents halogen atom.
That is, the compound of the general ormula (I) can be produced by reacting the compound of the general formula (I'), which was prepared by the method A with the compound of the general formula (VII) or (VIII) in an inert solvent at a temperature in the range of from -20C
to the boiling point of the solvent used.
Solvents which can be used in this reaction may be any of those not disturbing the reaction, and include for example ethers (e.g. diethyl ether, tetrahydrofuran, dioxane), aromatic hydrocarbons (e.g. benzene, toluene, xylene), halogenated hydrocarbons (e.g. chloroform, carbon tetrachloride). These solvents may be used alone or in combination. Bases which can be used in this reaction are inorganic bases such as sodium hydroxide, potassium hydroxide, lithium hydride, sodium hydride, etc. and organic bases such as, triethylamine, pyridine etc.
As to the amount of the base and the compound of the general formula (VII) or (VIII) used in this reaction, it suffices to use 2 mole per mole of the compound of the general formula (I') when R8 represents hydrogen atom in general formula (I') and an amount equimolar to the com-pound of the general formula (I') when R8 represents Cl - C5 alkyl group, but amounts in excess thereof will do.
T'ne reaction time depends upon the reaction temperature and reaction scale, but lt may properly be q ~3~

1 selected from a range of 30 minutes to 8 hours.
Further, the salt of the compound of the general formula tI) was obtained by reacting the compound of the general formula (I) with the acid.
The salt of the compound of the general formula (I) may be any of pharmaceutically acceptable salt. For the acids usable in preparing the salt, there are exempli-fied, for example, inorganic acids such as hydrogen chloride, sulfuric acid, phosphoric acid etc., organic carboxylic acids such as acetic acid, succinic acid, fumaric acid, tartaric acid and organic sulfonic acids such as methanesulfonic acid, heptanesulfonic acid, benzenesulfonic acid, toluenesulfonic acid. For the solvents, there are exemplified, alcohol, chloroform, dichloromethane, ethyl acetate and the like.
The compound of the general formula (I) and its salt can be separated by a conventional method.
Representative examples of the compound of the general ~ormula (I) and their salts will be shown in Table 1, but the derivatives are not limited to these examples.
Among the compound of the present invention of which the typical example are shown in Table 1 below, the prefered compounds are those whose R2 represents hydrogen atom; lower (Cl - C6) alkyl group; alkenyl group; cyclo-alkyl group; a phenyl group; a phenyl group substitutedwith 1 to 3 groups selected from the group consisting of halogen atom, lower (Cl - C6) alkyl group, lower (Cl - C6) haloalkoxy group, lower (Cl - C6) alkoxy group, cycloalkoxy group, a benzyloxy group and a benzyloxy group substituted with lower (Cl-C6) alkoxy group; naphthyl group or a heterocyclic group, and R5 and R6, which may be the same or different, represent hydrogen atom, lower (Cl-C6) alkyl, lower (C2-C6) alkenyl group, alkylcarbonyl group or haloalkylcarbonyl group and R , R , R4 and R represent hydrogen or lower (Cl-C6) alkyl. More preferred ones are those whose R2 represents hydrogen atom; Cl-C4 alkyl group; a phenyl group; a phenyl group substituted with 1 to 2 groups selected from the group consisting of halogen atom, Cl-C4 alkyl group and Cl-C4 alkoxy group; or furyl group, Rl, R3, R4, R5, R6 and R7 represents hydrogen atom or Cl-C4 alkyl group.

~, _ g _ ~3~QJ~2~

~ ~ ~ ~J ~
C) In U~ U~ ~ ~
~ ~ ~ ~ c~ ~ ~ ~ c ~ O'JJ l O l O l l l O
C~ ~ C ~ u~ ~ Ll~ ~r Lr) ~r ~
J- ~ X It ~ o ~ . . . . . .
S ~ O a) C CIJ R~ ~J Q~ Q~ Q~
_ _ E E __ E E E

m m m m m m _._ _ ~1 _ , _ ~`
X
X :C
~ ~ ~ ~ ~ ~ C~ C
. __ _ _ __ In ~ U~
~ ~ ~ ~ m u~ 3: ~ ~ m ~ v ~; c~ v ~ v m ~ c ... _ _ a~ ~; ~5 ~ ~ ~ ~ m tc _ _ P~ m m m m m m m m ~ ~ ~ 5: x~ m :: :: ~ ~ : : :
:: .. - - -~ ~ ~ ~ m m ~ m m u m m ~: : __ _ ~: ~ ~Z ~ _ ~ r In ~D ~_ 3 ~ 2 2 . V V ~,v ov ov V V V
In ~g ~ ~ ~ ~ O ~
~r ~r ~ In U~ ~r u~ I_ ~ ~ ~ ~ ~ ~ V l l C
U~ o U~ ~ ~ o ~r ~ ~ n ~D ~ Ln ~r ~1 ~ ~ ~ ~ ~ ~ ~ ~
~ Ql ~ R~ ~ o Q. ~
E E E E~ E E E~ E E~
_ ~ 'X~ ._ ::C ~ ~ ~ ~r: V V
_ _ _ U~ ~ Ln ~C r~ ~ ~ ~:
V ~5 ~ ~ ~ ~r V l ~ V V ~C V V
~ ~:: O=V O=c) _ _ . _ .. _ . _ _ _ ~ :C~ U~
r~ r~ ~ ~
V ~ :C ~ ~ ~r V V V ~ V V
~5 ~ C O=V
C ' _ -r~ ~ !~7~ _ ..
::~ ~ X V V V X ~ ~C
_ _ _ _ _ __ ~ ~ ~C :C ~:: ~n :~ ~ ~ ~
Q _ ___ El a v ~ ~ v :
: :
:
~ ~ ~ ~ ~ ~ .
V V :I: :3: V V V V ~C
- -: ~ --~ ~ _l ~ ~ ~1 ~ U>

~ ~ o - u ~ ~ ~
03 ~r I ~D CO l ~ O
~ ''1' ~ C~ ~ ~ I_ ~ l S~
co ~ L(~ L~ o Ln u~ ~r . . ~ ~ ~ ~ ~ ~ u~ l l- o~ Q~
. . . ~ a ~ a . ~ a ~ a .
C C ~ C C
__ _ . __ m 3:: m 5: m 5: x :~ 3::
_ _ __ ~ ~ ~ ~7 ~ ~ ~
E4 ~ ~C m ~ ~ :~: ~::
0=~1 C~ V _ O _~ V V
_ ~ r~7 ~~7 ~ ~ ~ ~ r~
~ ~C ~ X _ ~ :C :C ~C
~ C~ C~ C~ ~ C~ V V O V
C _ ... __ _ O X ~ X m ~ ~ ~ ~ ~
_ _ _ ~ ~ ~C~
R ::C ~ :C ~ ::C m m m V
~ _ _ ~ m ~ ~ ~ \/

I ~7 ~ ~ ~ U ~ ~ ~
::~ ~T~ ~ l o ~ U
C~ V : C ; ~)~ ~ :
: ; c~-vv V-V~
. 1_ 1 , .
:~
v ~r m ::c m ~ t:C ~n ~
: : __ l_ CO a~ o ~ ~ ~ ~r u~
~ ~ ~ : ~ ~ ~ ~ ~
~ _ _ ._ . .

~ 3 ~
ov V V V V V V V
U,~ ~D ~ l C~ ~, l I
.D ~ ~ ~ ~ ) U~
P~P~ P~ P~ P~ PJ ~ P~
._ __ .__ . _ .. __ __ m ~ m ,~ m m ~ m ~", ~ ____ _ 3: u ~ o m 5: o ~) .._ ~ ~ ~ _ .

r~5 ~ ~ ~ ~ m m m ~ . _ _ _ . _ __ ._ C) ~ ~ ~ ~ :C
.__ _ .._ .._ . _ ._ Q m m ~ m m m ~ x ~ ~ ~ ~ v ~ ~v ~ ~v ~ ~--- --- ---- - --P: m ~ ~ ~:: 3:: ~ m _ -_ _ . _ .
~D I~ ) ~ O
._. _ _ _ .._ ._ ..__ ~31~J2 ou ov u u u l l l l o ~ v o ~: ~ o ~ co ~ ~: ~
~ P~ ~ n~ P~ ~ ~ Q~
- - -- ~ - ---- --- --:~ m m ~ ::a m ::c _~ ... _ ~ .
m c~ ~ m ~ ._ . , _ _ m ~ ~ ~ :r ~ .
~ m c~ ~ ~ m ._ ._ o m m m x m ~ m ' _ ._ ::c ~c m E~ . __ ._ ~ ~ ~ ~ ~ ~ ~E4 o _~__ ~ - _ _ m ~ ~ ~: ~:: ::~ ~
_ _~ _ _ .. _ U~ U~ ~ CO C~ o ~ ~ ~ ~ ~ - _ . V V V V ~5 ~ ~ ~ In O
~ ~, V ~ ~ ~. ~ ~
~ ~ U~ ~ ~ ~ o ~ ~ ~ ~ ~ ~ ~ l . ~ ~ Q~
~ E~ ~ ~ ~ e ~
~ ~_ . _ x m ~ ~ ~
... ._ W~

5: ~ ~ ~-::C ~ ~ V ~, X
V V V V ~ ~ U
. .. . .__ m ~
V ~ ::C
. .. V V ,~_ V
s:~
X ~ ~ ~ :~ ~ V
.. .__ _ .. _ a) ~ ~ ~ ~ P~ :c ~
R .. _ _ .__ __ V V V V X~ V
~ ~ ~ ~ ~ ~ '~
..__ -._. _ 5: X ~ ~ ~C :r:
.__ : .
~ ~ ~ ~ U~ ~t7 ~, ~r ~ ~ ~ .~

~ 3 ~ ~ ?~ J
~ ~ ~ ~ ~

~ F co ~ ~ ~ ~ l _ .. .__ m ~ ~ m ~ m m ~ . ._ .
~ 3: ~ r~ r~ r~
3 u~ c~ ~ c~ 5 ._ _ ._ . _ .

C~ C~ h~ C~ m ~:: c~
._ .._ :.._ _ ..
C~ X ~ X ~C ~ ~ ::C
._ . ._ r~
Q ~ !T! 3:~ X ~:C ~:: C) E~ __ ........... ._ :C~ :C~ ~tc~ ~ ~
N N ~r~ ) ' _ ~
e~ ~ :I: ~C m ~
_ ._ ~ a~ o ~ ~ r~ ~
~r ~r In U~ ~ In n ~3~ ~v~2 ov CJ ~. ~, ~ ~, o V
o r~ ~o ~ ~ ~ l Q~ Q~ L~ Q~ Q~ Q~ ~J Q~
. ~ ~ ~ ~ ~ ~ ~ ~
_ __ _ ._ . ._ ..
X X ~ ~ ~ ~: ~ ~C
._ .__ . . __ _ , _ ~ ~ x ~ ~ ~ :~ m ~ ~>~' l ,i ~ ~: ~
._ ._ . ___ _ ~ m x~ ~ ~ ~ ~u~ ,_ 5: ~ ~ ~ X ~ ~ ~
_ l V ._ _ ~C ~ 3~ ~ :C~) ::C X X
. _ _ _ :~ ~ :C ~' X :~ ~ ~
E~ _ _ ... _ _ .. _ ._ ~C~ ~U~
~C C~ C~ ~>~
o o o o o o o o ~D ~ ~ ~ ~ ~ ~ ~
: ~. _ ~C ~ ~: ~ P~ 5: ~q ...__ ~ ~ ~ n c~ o ~ ~

~ 3 a~
.~ Q. Q. ~ Q

~ ~ ~ ~ ~ ~.
:~ :C X V V m ._ ~ , _ ~ X m V V ~
_ __ .
o V ~ ~ X ~C 5:
_ __ . __ ~ ~ ~r ~C m ~:C m Q ._ ~_ ~ m :~ ~ ~ ~ ~ r~
O O U O ~ O U O

_, __ .__ : ~ m ~c~: :~ !r : ._ . .__ ~ ~ U~ U~ ~ CO
:; ~ ~ ~ ~ ~- __ _ ~ 18 -~ (-~ c~ u ~ ~J c~
~ ~ ~ ~ O ~D I~ o ~
~ ~ ~ o ~ ~ ~ ~ o r~ c~ I t~ ~ ~1 l 'J
~1 ~ o a~ o ~ ~ ~
~ ~ ~ G~ ~ ~ ~ l_ l R~ ~ Q~R~ R~ R~ R~ C~
. ~ ~ ~ ~ ~ ~ ~
__ __ . .__ ~ :c ~:~:: m ~ x ~
._ .. _ 11:~ _ ~ ~ ~ .~ ~ ~ ~ ~
V~ ~ ~ ~ ~C C~ C~
.. _ .
U~ ~ ~
~:
X ~) ~ ~C ::C ~C
t~ ~ ~ ~ ~ V
_ _ ._ o ~ ~ ~ ~ ~ 5~ 5:
: ~ _ _ ...
~ ~7 ~ ~ :C ~C 5: X
E~ __ .. _ _ __ _ .
l ~ ~ ~ x~ ~c~ ~ ~
~ ~ v ~ ~

~:: :~ :~ 5:
-- ~----- -a~ o I_ ~ ~ ~r L~
~ - ~ -- --2 ~

V U V V N V
O ~ V C~ ~~ ~ ~ ~~ V
t~ Lt~ n ~r ,_ u~ ~ ~r c.
o Ln ~ u~ r~ ~ ~r ~
~' P~ P~ P~ P~ P~ P~ P~ P~
.. _ ._ ___ 3~ V ~ 5: ~ ~C ~ ~::
._ .___ _ _ .___ r~
~C ~ ~ ~ 3:
~ X V V ~ ~ O O
' _ ~ _ ~ .____ ~ r~ X ~ :C
m ~ ~ x ~ rr V ~ ~ C~ V ~ o C~
._ _ . ._ _ . ._ O ~C ~C X !rl 3 !T! X !r r-l _......................... .. ____ Q ~:C h:~ ~:C 5: T! ~:C ~ ~1 .

~ N~ Vj ~ ~ ~ $ j ~

:
.._ 5~ :r: :~ ~~ ~ X ~C
~ _ _ ..___ ~ c~ ~ ~ o ~ ~ r~ ~
~ ~ I , 0 , .

~ v - ~ ~ :J ~ o u~u:~ ~ r- ~ ~ u~ ~ ~ :
a) ~ ~ a) ~ a) ~ ~:
l l l o l l o l o l o u~ ~r ~ ~ ~ ~o ~ l P~ Q~ ~a) Q~ PJ~ ~ Q~
~ ~ ~ -~ ~ ~ ~ ~ ~--- - -- -- -- --m m m m x m x .. ... .

~) ~: ~: ~C ~ :C !r _ . .
r~ ~ ~ ~
...... ...... .__ ::c ~: m m ~ m :~
.. .__ ~ . ..__ .._ _ Q ~C m :c m m ~ x E~ ... .._ .._ .

o~ o V ~ ~o: ~o ~o : :
: _ .. ___ :.. __ . ~.. _ ~ _ 5: ~ ~ x : m m :c :...... _ : _ U~ U:) I C~ ~ O
. .~ ... __ :

- ---- ~ l o o o o ~
l ~ l l- - o - ~ ~ v a) o ~ s::
. l . I ~n I u~ ~ l o nu~ Oo~ O l L~ C~
r~ ~r ~ ~~ ~~ ~ u~
~ ~ ~ o~ 8~ ~ ~ ~ l . o ~ ~ ~~ ~,. ~, .
P~ ~ ~ ~ ~~ a~~ a)R~
. ~ ~ ~ ~ ~ ~ ~
.. _ . .. ....
X~
:~ V V ~:
. . _ _ .. _ __ ,., ::C ~ ~C :C ~ ~
._ .__ . . ...

~:: ~ X ~ ~ ~ ~
._ _ .__ . _ ~o, ~ ~ ~C ~ ~C 3~ ~C

~ . _ .. _ . ._ Q 5~ ~C :C ~:C ::C ~: ~C

~:: 5: ~ : ~ P~ ~' ~
. , ~ r ~ ~D t- 0 a~ ~ ~ o~ o~
- - -.._ ~ o ~, V
~ _ ~ ~r co c~ ~
U~ U~ ~ o ~ ~
, U~ l l l l l o o ~ ~ ~ o ~ o ~, ~C~ ~ ~ ~ ~ ~ ~ l . ~ ~ ~IS 1:~J ~ P~- ~1 ~1 E~ -- Q.E~ E Ei ~ E~
. .. _ _ . .__ ... _ m ~ ~ ~ ~c _ . ...__ .._ ~~ ~ ~ ~ ~
h:: ~~ C~ ~ ~C
_ _ .._ .

~ ~ .~ ~ r~
:C X ~ X X :~
C> C~ C~ t~ ~ C~
._ ._ o 5: ~ X ~ ~C ~: t~
. ._ ._ . _ . . _ In U~ Lr~n :C ~ tc~ ~
Q~ ~:C x O O ~O) O ::C
E~

:~ ~ :c ~ x ~
- ~ --- --- --- ---- ---o ~ ~ ~7 ~r u~
~ o o o o o o --- --- ~ - - -- -~ ~ ~ ~ o l ~J

~ ~ ~ ~ ~ ~: ~
~ ~ Q~ ~ ~ ~
E ___ E E E

m m m m m ~:
_ _ .. _ .

m m ~ m x 5:
y ~) ~ ~) c> m m ~) . __ :~
m m o ~ 3 ~C ~:: m o :-1 ~ ~a D:: 3 _ .. _ ~ . _ ~U~

R ~:C m m m m m o E~ ... _ _ : ~ ~ ~ ~ ~ a~.
m ~m, o . ~/ x ~ ~c ~ l . . .. _ ~ - . _ : ~ :: ~ :r m ~ x r~ .__:_ .. . __ ~____ ~__ ~ ~ ~D O O~ ~ O ~_ `

~ 3 ~ 2 U U U U U V
o a ~ o o ~D ~1 ~ ~1 V
~ ~ ~ ~ ~ ~, ~, U ~
~ In ~ l ~ ~ ~ CO L/ C~
O ~ ~ ~ I~ ~ > U~
r ~ ~ >1' Q~ Q~ R~ ~~ ~ X ~ Q~ x E E E E E E ~ O o? E ~ c) ~,q _ _ _._ .. _ _ _ m r m ~ m m m _ . . _ . .
m ~ r~ ~7 m U :C V ~ V :~:
c ID~ .. _ .. ___ . .___ m c v m m m m -c . .
v m ~ m m m m ~r . .. _ _ . _ . . .
u~ u~ u~ ~ u~
,~ ~ m ~ m Q 8 o o 8 o m m ~ ~J v ~ v ~

~ ~ ~ 1 ~o ~
~-m ~ m m ¦ m m . _ ._ _ ~7 ~ In ~ r- Q~ ~
: ~ ~ ~ ~ ~ ._ o- ~ ~ ~
CO ~ ~1 In ~1 a~
a~ ll I c) ~ ~ I u I u~ o ~ I o ~ I tn o r~
O 0 4 r-l ~ In 0 ~1 Q,~ ~ u~ ~ o ~D ~'1:1 C) E~ ~ ~ rl ~ ~ ~ ~
O ,C S~ ~ ~ 0 5:: ~1 . C,) O ~ ~ O V . ~ O
12~ a~ x -1 ~ ~ X ~ Q~ X
. ~ ~ ~ . ~ ~
~ U D~ ~ ~ V ~ ~ ~ ~ V ~q _ __. .__ _ ~C ~
_ ._ ._ .. _ .__ ~ ~C ~
._ - .. -- _ ~C~
~5 ~ ~ ~) - .. _ .
C) ~ :C ~::
._ _ ~ ~C ~
Q .
E~

c~ ~ ~D~ a : : . . .:_ ~. :
: ~ 3~ ~::
: ~0 _ _ ._ ~ ~ .

~ 3 ~ 2 1 The respective melting point of the compound numbers 118-122 in Table 1 shows the value of hydrochloric acid salt of said compounds.
~ext, NMR spectra data of compound No. 100 is sho~n below.
NMR data (60 MHz, CDC13, ~ value) 1.12(3H, t, J=7.0Hz), 1.24(3H, d, J=7.0~z) 1.20~1.70(3H), 2.40(6H, S), 2.0-3.10(11H) 4.35(2H, S) Cyclohexanedione derivatives represented by the general formula (I~ and their salts caused no toxic symptom nor death in mice or rats even after administrated continually for two weeks at a does of 300 mg/kg/day to the mice or rats, which reveals the marlcedly low toxicity of the compound of this invention. For example, LD50 value (acute oral toxicity to male rat) of the compound No. 55 is more than 1,000 mg/kg.
The compounds represented by the general formula (I) and their salts are useful as a medicinal agent for t~eating liver diseases. For example, while it is Icnown that hepatic disorders can be experimentally produced in healthy test animals by administering various agents such as carbon tetrachloride to the animals, as d1sclosed for example in U.S. Patent Mo. 4,118,506, it has been found that the compounds represented by the general formula (I) 5 and th~eir salts give a marked e~fect of suppressing the :
lowering o~ liver functions when administered orally or parenterally (for example by injection) to test animals which have hepatic disorders of var1ous pathologic models ~ 3 ~
1 experimentally produced therein. Accordingly, the compounds represented by the general formula (I) and their salts are useful as a medicinal agent for curing or preventing hepatic disorders in men and animals. Thus, it can be used as a curative for acute or chronic hepatic disorders of men and animals produced by various causes, for example, jecure adiposum, alcoholic hepatitis, hepatitis, toxic liver disorders, cardic cirrhosls, cholestatic liver disorder, or hepatocirrhosis which is the final state of these diseases.
Accordingly, the term "a pharmaceutical composition for treating hepatic disorders" as used in this lnvention means a medicinal agent for curing and/or preventing various disorders in liver by utilizing the pharmacological actions manifested in liver as mentioned above including the action of activating liver functions and the action of preventing and curing hepatic disorders.
The compound represented by the general formula (I) or its salt can be used as a medicinal agent for treating hepatic disorders in the form as it is; it may also be formulated, according to conventional pharma-ceutical procedures, as a mixture thereof with a pharma-ceutically acceptable diIuents and/or other pharmacologi-cally active substances. Further, it may be formulated into a dose unit form. Examples of the form which the compound can take as a medicinal agent include: powders, granules, tablets, dragée, capsules, pills, suspensions, solutions, liquid, emulsions, ampulesr injections, and 1 3 ~

1 isotonic solutionsO
The modes of preparing the compound of tnis invention into a pharmaceutical composition include one wherein the compound represented by the general rormula (I~ or its salt is contained as a mixture thereof with one or more pharmaceutically acceptable diluents.
The "diluent" referred to herein means a material other than the compound represented by the general forJnula (I) and their salts. It may be in the form of solid, semisolid, liquid, or ingestible capsules.
Examples of the diluents include excipients, fillers, binders, moistening agents, disintegrators, surfactants, lubricants, dispersants, buffering agents, flavoring agents, odor correctives, coloring agents, flavors, preservatives, solubilizing aids, solvents, coating agents, and sugar-coating agents. However, they are not limited to these. Further, they may be used as a mixture of one or rnore kinds thereof. Sometimes, these pharma-ceutically acceptable diluents are used as a mixture thereof with other pharmacologicalLy active substances.
The pharmaceutical composition according to this invention may be prepared by any method known in the art.
For instance, the active ingredie~nt is mixed wi~h a diluent and made up, for example, into granules. The resulting composition is then formed, for example, into tablets. Preparations to be administered parenterally should be made aseptic. Further, as occasion demands, they should be made isotonic with blood.

1 In this invention, since the compound represent-ed by the genera] formula (I) and their salts mentioned above can be itself make a medicinal agent for treating liver diseases, the active ingredient is generally S contained in the composition in a proportion of 0.01 to 100% by weight.
~ hen the compound is made into a preparation in the form of dose unit, the individual parts of the prepa-ration which form said preparation may be either in the same shape or in shapes different from each other. For example, the following shapes are often adopted: tablets, granules, pills, powders, dragée, capsules, ampules, and the lil<e.
The medicinal agent for treating hepatic disorders according to this invention can be applied to men and animals for the purpose of preventing and treating hepatic disorders therein, in a manner conventional in the art. It is administered orally or parenterally. Oral administration referred to herein includes sublingual administration. Parenteral administration includes herein administrations conducted by means of injections (includ-ing, for example, subcutaneous, intramuscular or intravenous injection and instillation).
The dose of the medicinal~agent of this invention varies depending upon various factors including whether it is applied to animals or men, difference in susceptibility, age, sex, body weight, the method, time, and interval of administration, the condition of diseases, ~ 30 -~ 3 ~ 2 1 physical condition, the properties of the pharmaceutical composition, the kind of the preparation, and the kind OL
the active ingredient.
Accordingly, sometimes those doses may be sufficient which are lower than the minimum of the dose range shown below, whereas sometimes it becomes necessary to administer an amount exceeding the upper limit of the dose shown below.
When the pharmaceutical composition is to be administered in a large amount, it is preferably administered divided in several doses per day.
In order to obtain effective results in application to animals, the agent is advantageously administered at a dose, in terms of the active ingredient, 15 in the range of 0.1 to 500 mg, preferably 0.1 to 30 mg, per 1 kg of body weight per day in oral adminsitration, and 0.01 to 250 mg, preferably 0.1 to 25 mg, per 1 kg of body weight per day in the case of parenteral administration.
The doses necessary for obtaining effective results in application to men are, judged from the effec-tive doses in animals and in consideration of difference ln susceptibility and safety, advantageously selected, for example, from the following dose range. In oral admini-25 stration the dose is Ool to 200 mg, preferably 0.5 to 50 mg, per kg o~ body weight per day, and in parenteral administration it is 0.01 to 100 mg, preferably 0.1 to 25 mg, per kg of body weight per day.

~3~^s 1 Example This invention will be described in detail belo~
with reference to Example.s, but it is in no way limited thereto.
First, synthesis examples of this invention are shown below.

Example 1 2-~2,5-dimethyl-2,5~diaza-7,9~dithiabicyclo-(4,3,0)-nonane-8-ylidene]-1,3-cyclohexanedione.
~compound No. 1) To a suspension of 5.75 g (0.02 mole) of glyoxal-sodium bisulfite in 20 ml of water was added drop-wise 1.92 g`(0.02 mole) of N,N'-dimethylethylenediamine with ice-cooling and the mixture was stirred until it became a homogeneous solution. Then to this solution was added with ice-cooling the dithiolate solution prepared in the manner shown below: To a mixture of 2.24 g (0.02 mole) of cyclohexanedione and 1.6 g (0.021 mole) of carbon disulfide in 15 ml of dimethylsulfoxide was added with ice-cooling 2.8 g (0.05 mole) of powdered potassium hydroxide and the mixture was stirred for 1 hour.
The reaction mixture was stirredl for addition-al 30 minutes and the crystalline precipitated was collected by filtration. This crystalline was washed with water, isopropylalcohol and~hexane, and then recrystalized from isopropylalcohol to give 3.0 g of the desired product.
Yield 50~; m.p. 158-159C.

1 Example 2 2-[2-methyl-2,5-diaza-7,9-dit'niabicyclo-(4,3,0)-nonane-8-ylidene]-5,5-dimethyl-1,3-cyclohexanedione. (compound No. 5) To a suspension of 5.68 g (0.02 mole) of glyoxal-sodium bisulfite in 30 ml of water was added drop-wise with ice-cooling 1.5 g 10.02 mole) of N-methyl-ethylenediamine. Then to this solution was added dropwise with ice-cooling the dithiolate solution prepared in the manner shown below; To mixture of 2.8 g (0.02 mole) of dimedone and 1.6 g (0.021 mole) of carbon disulfide in 20 ml or dimethylsulfoxide was added at room temperature 2.7 g (0.044 mole) of powdered potassium hydroxide and the mixture was stirred for 1 hour.
The reaction mixture was stirred for additional one hour at room temperature. The crystalline precipitat-ed was collected by filtration and washed with water and hexane and recrystalized from chloroform-ether to give 1.5 g of the desired product.
Yield 24%; m.p. 156-157C.

0 Example 3 2-[2,5-dimethyl-2,5-diaza-7,9-dithiabicyclo-(4,3,0)-nonane-8-ylidene]-5-phenyl-1,3-cyclo-hexanedione. (compound No. 26~
: : To a suspension of 3.4 g (0.01 mole) of glyoxal-sodium bisulfite in 20 ml of water was added drop~ise at 0C N,N'-dimethylethylenediamine and the mixture was stirred for 1 hour.
Then to this solution was added at 0C the J ~

1 dithiolate solution prepared in the manner sho~7n below; To a solution of 1.9 g (0.01 mole) of 5-phenyl-1,3-cyclo-hexanedione and 0.9 g (0.012 mole) of carbon disulfide in 10 ml of dimethylsulfoxide was added at 10C l.S g of powdered potassium hydroxide and stirred for 1 hour.
After the completion of addition, the mixture was stirred for 1 hour. The solid precipitated was collected by filtration and washed with water and then recrystalized ethyl acetate-hexane to give 2.0 g of desired product.
Yield 53%; m.p. 149-153C.

Example 4 2-[2,5-di-n-butyl-2,5-diaza-7,9-dithiabicyclo-(4,3,0)-nonane-8-ylidene]-5-phenyl-1,3-cyclo-hexanedione. (Compound No. 29) The mixture of 3.4 g (0.01 mole) of glyoxal-sodium bisulfite and 3.0 g (0.018 mole) of N,N'-di-n-butylethylenediamine in 30 ml of water was stirred for 1 hour at 0C. Then to this solution was added dropwise at 0C the dithiolate solution prepared by the reaction of 1.9 g (0.01 mole) of 5-phenylcyclohexane-1,3-dione with 0.9 g (0.012 mole) of carbon disulfide in 10 ml of dimethylsulfoxide in the presence of 1.5 g (0.027 mole) of powdered potassium hydroxide.
The reaction m1xture was st1rred for 2 hours.
Then 50 ml of water was added to the reaction solution.
The crystalline precipitated was collected by filtration, washed with water and dried up and then recrystalized from - 3~ -1 ethyl acetate-n-hexane to give 1.7 g of the desired product.
Yield 37~; m.p. 130-132C.

Example 5 2-[2,5-diaza-7,9-dithiabicyclo-(4,3,0)-nonane-8-ylidene]-5-(4-methoxyphenyl)-1,3-cyclo-hexanedione. (Compound No. 53) To a suspension of 5.68 g (0.02 mole) of glyoxal-sodium bisulfite in 30 ml of water was added drop-wise at room temperature 1.44 g (0.024 mole) of ethylene-diamine and the mixture was stirred until it became a homogeneous solution.
Then to this solution was added with ice-cooling the dithiolate solution prepared in the manner shown below; To a solution of 4.09 g (0.02 mole) of 5-(4-methoxyphenyl)-1,3-cyclohexanedione and 1.6 g (0.021 mole) of carbon disulfide in 20 ml of dimethylsulfoxide was added 2~8 g (0.05 mole) of powdered potassium hydroxide, and the mixture was stirred for one hour.
The reaction mixture was stirred for additional 30 minutes at 0C. The crystalline precipitated was collected by filtration, washed with water, and~dried and recrystalized from chloroform-ether to give 1.45 g of the desired product.
Yield 2~%, m.p 160-162r.

~ 3 ~ 2 1 Example 6 2-[2,5-dimethyl-2,5-diaza-7,9-dithiabicyclo-(4,3,0)-nonane-8-ylidene]-5-(2-thienyl)-1,3-cyclo hexanedione. (cornpound No. 82) To a suspension of 2.84 g (0.01 mole) of glyoxal-sodium bisulEite in 20 ml of water was added dropwise at room temperature 1.05 g (0.01 mole) of N,N'-dimethylethylenediamine and the mixture was stirred until it became a homogeneous solution. Then to this solution was added with ice-cooling the dithiolate solution prepar-ed in the manner mentioned below; To a solution of 1.94 g(0.01 mole) of 5-thienyl-1,3-cyclohexanedione and 0.8 g (0 01 mole) of carbon disulfide in 10 ml of dimethylform-amide was added with ice-cooling 1.4 g (0.025 mole) of powdered potassium hydroxide, and the mixture was stirred for one hour.
The reaction mixture was stirred for additional 30 minutes. The crystalline precipitated was collected by filtration, washed with water, dried and then recrystalized from chloroform-ether to give 1.07 g of the desired product.
Yield 28%; m.p. 165-166C.

Example 7 2-[1,2,5-trimethyl-2,5-diaza-7,9~dithiabicyclo-( 4 r 3~o)-nonane-8-ylidenei-5l5-dimetllyl-l~3-:,:
~ cyclohexanedione. (compound ~o. 12) ~ To a solution of 4.58 g (0.04 mole) of sodium bisulrlte was added 3.96 g (0.02 mole) of 40% methyl-glyoxal and the mixture was stlrred for 1 hour at room ~ 3 ~

1 temperature.
To this solution was added dropwise with ice-cooling 1.94 g (0.022 mole) of N,N'-dimethylethylene-; diamine and tne mixture was stirred for 1 hour. Then to this solution was added with ice-cooling the dithiolate solution prepared in the manner shown below; To a mixture of 2.8 g (0.02 mole) of dimedone and 1.6 g (0.02 mole) of carbon disulfide in 15 ml of dimethylsulfoxide was added 2.7 g (0.044 mole) of powdered potassium hydroxide, and the mixture was stirred for one hour.
The reaction solution was stirred for additional 20 minutes and the solid precipitated was collected by filtration. The solid was dissolved in chloroform, and the solution was washed with water and dried over anhydrous sodium sulfate. After chIoroform was evaporated in vacuo, the residue was recrystalized from chloroform-ether to give 0.55 g of the desired product.
Yield 8%; m.p. 161-162C.

Example 8 2-[3-methyl-2,5-diaza-7,9-dithiabicyclo-(4,3,0)-nonane-8-ylidene]-5,5-dimethyl-1,3-cyclohexane-dione. (compound No. 14) To a suspension of 5.68 g (0.02 mole) o~
glyoxal-sodium bisul~ite in 20 ml of water was added - dropwlse with ice-cooling 1.49 g (0.02 mole) of ; 25 1,2-propanediamine and the mixture was stirred until it hecame a homogeneous solution. Then to this solution was added with ice-cooling the dithiolate solution prepared in ~ 37 -~ 3 ~ 2 1 the manner shown below; To a solution of 2.8 g (0.02 mole) of dimedone and 1.6 g (0.02 mole) of carbon disulfide in 20 ml of dimethylsulfoxide was added with ice-cooling 2.7 g (0.044 mole) of powdered potassium hydroxide, and the mixture was stirred for one hour.
The reaction mixture was extracted with ethyl acetate, washed three times with ice-water and dried over anhydrous magnesium sulfate. The solvent was evaporated and the residue was recrystalized from ethyl 10~ acetate-hexane to give 0.8 g of the desired product.
Yield 13%; m.p. 150.0C.

:
Example 9 2-~2,5-acetyl-3-methyl-2,5 diaza-7,9-dithiabi-cyclo-(4,3,0)-nonane-8-ylidene]-5,5-dimethyl-1,3-cyclohexanedione. (compound No. 15) To a solution of 0.4 g (0.0013 mole) of 2-[3-methyl-2,5-diaza-7,9-dithiabicyclo-(4,3,0)-nonane-8-ylidene]-5,5-dimethyl-1,3-cyclohexanedione in 5 ml of pyridine was added dropwise with ice-cooling 0.79 g (0.01 mole) of acetyl chloride and the mixture was stirred for 1 hour.
The reaction solution was~extracted with ethyl ~acetate, washed with 2 N hydrochloric acid and water, and then~dried over magnesium~sulfate. The solvent was removed and the residue was washed with ether and recrystalized from ethyl acetate-hexane to give 0 35 g of the;desired product.
Yield 68%; m.p. 146-150C.
:

:
: :: :

~ 3 ~ d 2 1 Example 10 2-[2-metllyl-2,5-diaza-7,9-dithiabicyclo-(4,3,0)-nonane-8-ylidene]-5,5-dimethyl-1,3-cyclohexanedione dihydrochloride salt.
(compound 118) Into a solution of l.n g (0.0032 mole) of 2-[2-methyl-2,5-diaza-7,9-dithiabicyclo-(4,3,0)-nonane-~-ylidene] 5,5-dimethyl-1,3-cyclohexanedione in 20 ml of acetone was bubbled dry hydrogen chloride with ice-cooling. After the crystalline was precipitated, to this solution was added 20 ml of ether to crystalize further the product dissolved in acetone.
The crystalline was collected by filtration and was washed with ether to give 1.1 g of the desired product.
Yield 90~; m.p. 162-164C.
Now, Examples regarding pharmaceutical composi-tions 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 11 Compound No. 4 ........................... 10 parts ~Heavy magnesium oxide ................... 10 parts Lactone .................................. 80 parts The above ingredients were mixed uniformly and made into a medicinal preparation in the form of powders or ~ 3 ~ 2 1 fine granules.

Example 12 Compound No. 43 .......................... 10 parts Synthetic aluminum silicate .............. 10 parts Calcium hydrogen phosphate ................ 5 parts Lactose .................................. 75 parts The above ingredients were used to be rnade up into powders in a similar manner to that in Example 11.

Example 13 Compound No. 53 .......................... 50 parts Starch ................................... 10 parts Lactose .................................. 15 parts Crystalline cellulose .................... 20 parts Polyvinyl alcohol ......................... 5 parts ~ater ................................... 30 parts The above ingredients were uniformly mixed, kneaded, then crushed, granulated, dried and sieved to obtain granules.

Example 14 A mixture of 99 parts of the granules obtained : in Example 13 and 1 parts of calcium stearate was compression-formed into tablets of 10 mm diameter.

Example 15 Compound No. 79 .......................... 78 parts .

~ 3 ~

1 Polyvinyl alcohol ....................... .2 parts Lactose ..................... ........... 20 parts Water ~ 30 parts T'ne above ingredients were made up into granules in the same manner as in Example 13. Ten parts o~
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 dra~ée by using, in appro-priate amounts, a mixed suspension of syrup, gel~tin andprecipitated calcium carbonate, and a coloring agent.

Example 16 Compound No. 95 ......................... Ø5 part Nonionic surfactant ..................... .2.5 parts Physiological saline ........ ........... 97 parts The above ingredients were mixed with warming, then sterilized to obtain injections.

Example 17 The powders obtained in Example 11 were filled into capsule containers available on the market to obtain capsules.

The effect of the compound of the present inven-tion will be illustrated by the following Test Example.

l ~est Example l 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 t6 weeks of age, dd-strain, d), Six hours there-after, carbon tetrachloride was orally administered in a proportion of 0.05 ml/kg. The animals were sacriEiced 24 hours after the administration of carbon tetrachloride, and the extent of liver injury was examined.
On the other hand, blood was collected from the animal at the time of the sacrifice, and centriEuged to obtain plasma. The plasma glutamic pyruvic transminase (GPT) activity was determined according ot the method of Reitman-Frankel. The activity was expressed in terms of Karmen Units (R.U.). The conditions of the liver were expressed in terms of liver injury index as follows.
Liver injury index Condition of liver 20 0 Healthy liver 2 Slightly affected 4 Evidently observed injury , 6 ; Serious injury Mice were used in groups of rive and the results of test were represent~ed by the mean value. When the GPT
activity was 2,000 onits or higher, or further determina-tion was made, the activity was calculated as 2,000 1 3 ~

1 ~nits for reasons of convenience.
Trle results obtained are shown in Table 2.

:
:

- . :
:
- 43 _ , z~ ~ ~

Table 2 Effect of carbon tetrachloride on liver injury No. of compound Liver of this invention ln~uryP-GPT (K.U.) .. __ Administration of carbon 6.02000 tetrachloride alone No treatment 0 12 . .___ 1 0.2 14 .. _ _. _ .. _ 2 0.4 15 : 4 0 11 . . ._ . _ . _ ._ ..

. _ . _ ._ .__ __ .

. _ _ . . . _ 11 0.5 - 16 . ~ ..
12 0.4 33 14 0.4 18 _ _. .. __ 18 1.2 22 21 0.1 23 0.8 15 _ ... ~ _.
~ 28 0.2 39 ~ ~ .. _ 32 0.3 22 . ._ .. __ ~ 36 1.5 268 - - . .. _ . .__ : ~: 41 0.4 213 . _ _ _ - cont'd -1 3 ~ 2 Table 2 ( cont ' d ) , ._ _ . . __ 43 0.2 24 ... _ . _ .

.. _ _ .. _ .. ._ 48 0.3 18 _ _~ .___ .. _ . ___ . ...... _ 52 0.1 14 _ . _ 53 0.1 13 . .. ~ _ _ ._ 0.3 107 _ : ._ _..__ .. ._ 56 2.5 50 . . . _ _ _ .. _ __ _ _ .. _ _ 57 0.2 142 . . _. _ ._ 59 0.1 - 16 0.1 26 . . . __ ._ 61 1.5 494 . __ .. ___ .. _ 1.6 347 . . ._ ~ . . _ 78 0.2 18 . . . . __ . _ ._ . . . . .
1.0 405 ._ ._ .__ ._ 82 0.3 16 _._ .. __ .. __ .. _ ._ 92 - 0.4 15 ._ . __ .. _ _ ..
102 1.5 319 _ _ -- __ _ . _ 103 _ 18 104 1.7 345 . . _ __ . _ ... . . .
: 105 0 _ 15 106 1.2 242 - cont ' d -3 ?J 2 Table 2 ( cont ' d ) _ __ . .
108 1 . 0 24 . __ __ _ . _ . _ ._ _ . _ , .
111 ,___ 1 0 . .. _ 114 2 . 2 26 . ... __ ..... ._ .. __ .. ._ . _ . . __ .....

.. __ ._ _._ . . . ._ .... _ _ .. __ _ .. __ _ _ _ . __ ~ __ 1 22 . . 231

Claims (22)

1. A cyclohexanedione derivative represented by the general formula (I):

(I) wherein R1, R4 and R7 represent independently hydrogen or C1-C8 alkyl, R2 represents hydrogen; C1-C8 alkyl; C2-C6 alkenyl; C3-C8 cycloalkyl; C2-C7 alkoxycarbonyl; C1-C6 alkylthio C1-C6 alkyl;
phenyl; phenyl substituted with 1 to 3 groups selected from the group consisting of halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 alkylthio, C3-C8 cycloalkoxy, benzyloxy and benzy-loxy substituted with C1-C6 alkoxy; naphthyl, furyl or thienyl, R3 represents hydrogen, C1-C8 alkyl or C2-C7 alkoxycarbonyl, and R5 and R6, which may be the same or different, represent hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C7 alkylcarbonyl or C2-C7 halo-alkylcarbonyl or a pharmaceutically acceptable salt thereof.

2. A cyclohexanedione derivative or pharmaceutically acceptable salt thereof according to claim 1, wherein R1, R3, R4 and R7 represent independently hydrogen or lower alkyl, R2 repre-sents hydrogen; lower alkyl; alkenyl; cycloalkyl; phenyl; phenyl substituted with 1 to 3 groups selected from the group consisting of halogen, lower alkyl, lower haloalkyl, lower alkoxy, cyclo-alkoxy, benzyloxy and benzyloxy substituted with lower alkoxy;
naphthyl, furyl or thienyl, and R5 and R6, which may be the same or different, represent hydrogen, lower alkyl, lower alkenyl, alkylcarbonyl or haloalkylcarbonyl.

3. A cyclohexanedione derivative or pharmaceutically acceptable salt thereof according to claim 1, wherein R1, R3, R4, R5, R6 and R7 represent independently hydrogen or C1-C4 alkyl, and R2 represents hydrogen; C1-C4 alkyl; phenyl; phenyl substituted with 1 to 2 groups selected from the group consisting of halogen, C1-C4 alkyl and C1-C4 alkoxy; or furyl.

4. The compound 2-[2,5-dimethyl-2,5-diaza-7,9-dithia-bicyclo-(4,3,0)-nonane-8-ylidene]-1,3-cyclohexanedione or a pharmaceutically acceptable salt thereof.

5. The compound 2-[2,5-dimethyl-2,5-diaza-7,9-dithia-bicyclo-(4,3,0)-nonane-8-ylidene]-5,5-dimethyl-1,3-cyclohexane-dione or a pharmaceutically acceptable salt thereof.

6. The compound 2-[2-methyl-2,5-diaza-7,9-dithiabicyclo-(4,3,0)-nonane-8-ylidene]-5-(2-chlorophenyl)-1,3-cyclohexanedione or a pharmaceutically acceptable salt thereof.

7. The compound 2-[2,5-dimethyl-2,5-diaza-7,9-dithia-bicyclo-(4,3,0)-nonane-8-ylidene]-5-(4-tolyl)-1,3-cyclohexanedione or a pharmaceutlcally acceptable salt thereof.

8. The compound 2-[2,5-dimethyl-2,5-diaza-7,9-dithiabicyclo-(4,3,0)-nonane-8-ylidene]-5-(4-methoxyphenyl)-1,3-cyclohexane-dione or a pharmaceutically acceptable salt thereof.

9. The compound 2-[2,5-diaza-7,9-dithiabicyclo-(4,3,0)-nonane-8-ylidene]-5-(4-methoxyphenyl)-1,3-cyclohexanedione or a pharmaceutically acceptable salt thereof.

10. The compound 2-[2,5-dimethyl-2,5-diaza-7,9-dithiabicyclo-(4,3,0)-nonane-8-ylidene]-5-(2-furyl)-1,3-cyclohexanedione or a pharmaceutically acceptable salt thereof.

11. The compound 2-[1,2,5-trimethyl-2,5-diaza-7,9-dithiabi-cyclo-(4,3,0)-nonane-8-ylidene]-5-(2-furyl)-1,3-cyclohexanedione or a pharmaceutically acceptable salt thereof.

12. The compound 2-[1 methyl-2,5-diaza-7,9-dithiabicyclo-(4,3,0)-nonane-8-ylidene]-5-(4-methoxyphenyl)-1,3-cyclohexanedione or a pharmaceutically acceptable salt thereof.

13. The compound 2-[3-methyl-2,5-diaza-7,9-dithiabicyclo-(4,3,0)-nonane-8-ylidene]-5-(4-methoxyphenyl)-1,3-cyclohexanedione or a pharmaceutically acceptable salt thereof.

14. A cyclohexane derivative according to any one of claims 1 to 13 wherein the salt is a salt of hydrogen chloride, sulfuric acid, phosphoric acid, acetic acid, succinic acid, fumaric acid, tartaric acid, methanesulfonic acid, heptanesulfonic acid, benzenesulfonic acid or toluenesulfonic acid.

15. A process for preparing a compound of formula (I) as defined in claim 1, wherein R1, R2, R3, R4, R5, R6 and R7 are as defined in claim 1 or a pharmaceutically acceptable salt thereof, which process comprises reacting a compound of the formula (II):
(II) wherein R4 is as defined above, with a compound of the formula (III):

(III) wherein R5, R6 and R7 are as defined above, followed by reacting the product so obtained with a compound of the formula (IV):
(IV) wherein R1, R2 and R3 are as defined above, and M represents an alkali metal atom and, where required, forming a pharmaceutically acceptable salt thereof.

16. A process according to claim 15 wherein the salt is a salt of hydrogen chloride, sulfuric acid, phosphoric acid, acetic acid, succinic acid, fumaric acid, tartaric acid, methanesulfonic acid, heptanesulfonic acid, benzenesulfonic acid or toluene-sulfonic acid.

17. A pharmaceutical composition for treating a hepatic disorder comprising a compound of formula (I) as defined in any one of claims 1 to 13 or a pharmaceutically acceptable salt thereof in admixture with a pharmaceutically acceptable diluent or carrier.

18. A composition according to claim 17 wherein the salt is a salt of hydrogen chloride, sulfuric acid, phosphoric acid, acetic acid, succinic acid, fumaric acid, tartaric acid, methane-sulfonic acid, heptanesulfonic acid, benzenesulfonic acid or toluenesulfonic acid.

19. A use of a compound of formula (I) as defined in any one of claims 1 to 13 or a pharmaceutically acceptable salt thereof in the treatment of a hepatic disorder.

20. A use according to claim 19 wherein the salt is a salt of hydrogen chloride, sulfuric acid, phosphoric acid, acetic acid, succinic acid, fumaric acid, tartaric acid, methanesulfonic acid, heptanesulfonic acid, benzenesulfonic acid or toluene-sulfonic acid.

21. A commercial package comprising as an active ingredient thereof a compound of formula (I) as defined in any one of claims 1 to 13 or a pharmaceutically acceptable salt thereof together with instructions for the use thereof in the treatment of a hepatic disorder.

22. A package according to claim 21 wherein the salt is a salt of hydrogen chloride, sulfuric acid, phosphoric acid, acetic acid, succinic acid, fumaric acid, tartaric acid, methanesulfonic acid, heptanesulfonic acid, benzenesulfonic acid or toluene-sulfonic acid.