Treating arteriosclerosis using benzimidazole compositions

13 Pages·2013·1.19 MB·English

USO05387600A
United States Patent [19] [11] Patent Number: 5,387,600
Aikawa et a1. [45] Date of Patent: Feb. 7, 1995
[54] TREATING ARTERIOSCLEROSIS USING 0167943 l/1986 European Pat. Off. .
BENZIMIDAZOLE COMPOSITIONS 0352864 1/ 1990 European Pat. Off. .
[75] Inventors: Kazuhiro Aikawa; Kozo Aoki, both of OTHER PUBLICATIONS
Minami-ashigara, Japan
American Journal of Pathology, vol. 139. N0. 1, Jul. 1,
[73] Assignee: Fuji Photo Film Co., Ltd., Kanagawa, 1991, pp. 217-229, McGuire et a1, “Peroxisome Induc
Japan tion Potential and Lipid-Regulating Activity in Rats”.
The Merck Index, 1989, Merck & Co., Rahway USA, p.
[21] Appl. No.: 94,321
1156, No. 7245; 1462-3, No. 9217; and pp. 168-169, Nos.
[22] Filed: Jul. 21, 1993 1091, 1092.
International Journal of Obesity, vol. 11, 1987, pp.
[30] Foreign Application Priority Data
619-629, F. M. Whittington et al, “Effect of Sodium
Jul. 30, 1992 [JP] Japan ................................ .. 4-2o4122
2-n-pentadecyl-benzimidazole-S-carboxy1ate . . . and
Sep. 2, 1992 [JP] Japan ................................ .. 4234767 lean mice”.
[51] Int. Cl.6 ................ .. A61K 31/415; A61K 31/535 Primary Examiner-Raymond J. Henley, III
[52] US. Cl. ............................... .. 514/395; 514/235.8;
Assistant Examiner-T. J. Criares
514/237.5; 514/237.8; 514/387; 514/394;
Attorney, Agent, or Firm-Sughrue, Mion, Zinn,
514/392; 514/398; 514/400; 514/396
Macpeak & Seas
[58] Field of Search ............. .. 514/387, 395, 384, 392,
514/398, 400, 356, 235.8, 237.5, 237.8 [57] ABSTRACT
[56] References Cited Disclosed are an antihyperlipidemia or antiarterios
U.S. PATENT DOCUMENTS clerosis agent comprising a certain benzimidazole or
2,2'-methylenebispheno1 derivative such as 5
3,658,822 4/1972 Fauran et a1. .............. .. 260/268 BC dodecanoylamino-2-mercaptobenzimidazole or 2,2’
4,814,329 3/1989 Harsanyl et a1. .................. .. 514/211 isobuty1idenebis(4,6-dimethyphenol).
FOREIGN PATENT DOCUMENTS
0074341 3/1983 European Pat. Off. . 6 Claims, No Drawings
5,387,600
1 2
-continued
TREATING ARTERIOSCLEROSIS USING
(111)
BENZIMIDAZOLE COMPOSITIONS
BACKGROUND OF THE INVENTION 5 R3
The present invention relates to a novel pharmaceuti
cal composition and method for treating hyperlipidemia Maggie
and arteriosclerosis, more speci?cally to an antihyper R2 (111)
|
lipidemia agent having a blood cholesterol lowering
effect or an antiarteriosclerosis agent having a macro
phage-foaming reaction suppressing effect and a
method for treating hyperlipidemia and arteriosclerosis
using this composition.
OH Kg R12 OR13 (IV)
As people have become more affluent, their eating /
habits have changed toward increased intake of foods R9 C
with high cholesterol content and high caloric value.
As a result, hyperlipidemia and arteriosclerosis are in
creasing rapidly in conjunction with the aging of the
population. This has become a major social problem. R10 ‘R2
Hitherto, drug therapy for hyperlipidemia and arteri
osclerosis has been directed only to lowering blood wherein
cholesterol. No drug capable of reversing the effects of
R1 represents a hydrogen atom, an alkyl, an aryl, a
arteriosclerosis is available.
mercapto, an alkylthio, an alkenylthio, an arylthio
Arteriosclerosis is characterized by thickening of the
or a heterocyclo group;
blood vessel intima and lipid deposition within the
R2 represents a hydrogen atom or an alkyl group,
blood vessel. Therefore, for drug therapy of the disease,
provided that the alkyl group is not substituted by
drugs capable of lowering blood cholesterol have been
a hydroxyl group;
used. However, it has been found that the macrophage
foaming reaction plays an important role in forming the R3 and R4 each independently represents a hydrogen
focus of arteriosclerosis. Thus, it is expected that sup atom, a halogen atom, a nitro group, R5O—,
pression of this reaction would result in regression of R5CONH——, R5NHCO—, (R5)2NCO—,
the arteriosclerosis foci. R5SO2NH—, R5NHSO2—, R5OCO—, R5COO—
or R5NHCONH—- where R5 represents an alkyl or
SUMMARY OF THE INVENTION
an aryl group;
A primary object of the present invention is to pro R5 represents a divalent group;
vide a novel and low toxic pharmaceutical composition R7, R3, R9 and R10 each independently represents an
capable of lowering blood cholesterol and suppressing
alkyl, a cycloalkyl group, --(C(CH3)2)k—(CH2)
macrophage-foaming reaction by way of inhibiting
mCOOR14 01' —(C(CH3)2)I<—(CH2)mC0N(R14)2
acyl-CoA cholesterolacyltransferase (ACAT) activity
where k represents 0 or 1, m represents an integer
and intracellular cholesterol transport.
of 0 to 4 and R14 represents a lower alkyl group;
Another object of the present invention is to provide
R11 and R12 each independently represents a hydro
a method for treating hyperlipidemia and arteriosclero
gen atom, an alkyl, an aryl or an aralkyl group; and
srs.
These and other objects of the present invention will R13 represents a hydrogen atom, a lower alkyl, an
45
be apparent from the following description and Exam aralkyl, an acyl, an alkyl- or arylsulfonyl group, or
ples. —-(CH2),,COOR15 where n represents an integer of
The above objects were achieved based on the dis 0 to 2 and R15 represents a lower alkyl group.
covery that certain benzimidazole and 2,2’ The second aspect of the present invention relates to
methylenebisphenol derivatives have not only an a use of a compound of the formula (I), (II) or (III), or
ACAT activity-inhibiting effect, an intracellular choles a pharmaceutically-acceptable salt thereof, or a com
terol transport-inhibiting effect and an excellent blood pound of the formula (IV) for preparing an antihyper
cholesterol lowering effect but also a macrophage lipidemia or antiarteriosclerosis agent.
foaming reaction suppressing effect, and, as such, are
able to achieve the aforesaid object. 55 DETAILED EXPLANATION OF PREFERRED
The ?rst aspect of the present invention relates to a EMBODIMENTS
pharmaceutical composition comprising a compound of
The present invention provides a pharmaceutical
the following formula (I), (II) or (III), or a pharmaceuti
composition which has an excellent blood cholesterol
cally-acceptable salt thereof, or a compound of the.
lowering effect and macrophagefoaming reaction sup
following formula (IV) as an active ingredient together 60
pressing effect and is low in toxicity, it therefore exhib
with a pharmaceutical-acceptable carrier or diluent:
its an excellent therapeutic effect on hyperlipidemia and
arteriosclerosis and is administrable over a long period.
R2 (1)
Among the compounds of the formulae (1), (II), (III)
R3 N and (IV), the compounds of the formulae (I) and (IV)
w 65
are preferable and, in the compounds of the formula (I),
the compounds of the following formula (V) are partic
R4 N
ularly preferable;
5,387,600
3 4
atoms (such as methyl, butyl and hexyl groups), which
may be straight or branched chains, are preferable.
NH ~ (V) The alkyl group represented by R; may be optionally
R3 >— R1 substituted. Examples of the substituents include aryl,
amino and acylamino groups. The alkyl group is not
N
substituted by hydroxy group.
Preferred groups represented by R2 are hydrogen
wherein
atom and the alkyl groups having 1 to 6 carbon atoms,
R1 represents a hydrogen atom, an alkyl, a mercapto particularly hydrogen atom.
or an alkylthio group; and
When R3 in the formulae (1), (II) and (V) and R4 in
R3 represents a hydrogen atom, a halogen atom, a the formula (I) contain R5, examples of the alkyl groups
nitro group,‘ R5O—, R5CONH—, R5NHCO—,
represented by R5 include alkyl groups having 1 to 20
RsNHSOz- or R5SO2NH— where R5 represents carbon atoms (such as methyl, butyl, octyl, dodecyl and
an alkyl group. octadecyl groups). Alkyl groups having 4 to 18 carbon
The compounds of the formulae (I), (II), (III) and (V)
15 atoms (such as methyl, butyl, octyl, dodecyl and octa
of the present invention will now be described in detail.
decyl groups), which may be straight or branched
Examples of the alkyl groups represented by R1 in the
chains, are preferable. Examples of the aryl groups
formulae (I), (III) and (V) include alkyl groups having
include phenyl and naphthyl groups. Phenyl group is
lto 18 carbon atoms (such as methyl, ethyl, butyl, octyl, particularly preferable.
dodecyl and octadecyl groups). Alkyl groups having 1
20 The alkyl and aryl groups represented by R5 may be
to 8 carbon atoms (such as methyl, ethyl, butyl and
optionally substituted. Examples of the substituents
octyl groups), which may be straight or branched
include halogen atoms, alkyl, aryl, acylamino and aryl
chains, are preferable. Examples of the aryl groups
oxy groups.
include phenyl and naphthyl groups. Phenyl group is
Preferred groups represented by R3 and R4 are the
particularly preferable. Examples of the alkyl groups of 25
above-described groups containing R5, that is, R5O—,
the alkylthio groups include alkyl groups having 1 to 18
R5CONH—, R5NHCO——, R5SO2NH-—, R5NHS02—,
carbon atoms (such as methyl, ethyl, butyl, octyl, dode~
R5OCO—-—, R5COO— and R5NHCONH-—, particularly
cyl and octadecyl groups). Alkyl groups having 1 to 8
R5O--, R5CONH—-, R5NHCO——, R5NHSO2— and
carbon atoms (such as methyl, ethyl, butyl and octyl
R5SO2NH-—. Speci?c examples of the preferred groups
groups), which may be straight or branched chains, are 30 include octyloxy, hexadecyloxy, dodecanoyloxy, dode
preferable. Examples of the alkenyl groups of the alke cylcarbamoyl, octylsulfonylamino, dodecylsulfamoyl
nylthio groups include alkenyl groups having 2 to 18
groups.
carbon atoms (such as allyl and octadecenyl groups).
Examples of the divalent groups represented by R5 in
Examples of the aryl groups of the arylthio groups
the formulae (II) and (III) include —-(CH2),,—,
include phenyl and naphthyl groups. Phenyl group is
—O(CH2),,O-, —NHCO(CH2),, CONH——, —NH
particularly preferable. Examples of the heterocyclo
SO2(CH2),,SO2NH— where n represents an integer of l
groups of the heterocyclothio groups include pyridyl
to 10.
and hexahydropyridyl groups. 2- and 4-pyridyl groups
—(CH;),,—— and —NHCO(CH2),,CONH—— where n
are particularly preferable.
is 2 to 8 are particularly preferable.
Each of the alkyl, aryl, alkylthio, alkenylthio,
Among the above-described compounds having R1 to
arylthio and heterocyclothio groups represented by R1
R6, preferred are the compounds in which at least one
may be optionally substituted. Examples of the substitu
substituents have not less than 4 carbon atoms, particu
ents include halogen atoms, alkyl, aryl, alkoxy, aryloxy,
larly those in which at least one substituents except for
acylamino and nitro groups.
R2 have 4 to 20 carbon atoms, preferably 8 to 18 carbon
Preferred groups represented by R1 are hydrogen
45 atoms.
atom, alkyl groups, mercapto group and alkylthio
Examples of the parmaceutically-acceptable salts of
groups. Speci?c examples of the preferred groups rep
the compounds represented by the formulae (I), (II) and
resented by R1 include methyl, butyl, mercapto and
(III) include hydrochloride, hydrobromide, nitrate,
methylthio groups.
sulfate and toluenesulfonate. Hydrochloride is particu
Next, examples of the alkyl groups represented by R; larly preferable.
in the formulae (I) to (III) include alkyl groups having
Examples of the compounds of the formulae (I), (II)
1 to 12 carbon atoms (such as methyl, butyl, hexyl, octyl
and (III) or the formula (V) of the present invention are
and dodecyl groups). Alkyl groups having 1 to 6 carbon
listed below.
(1) (2)
(3) (4)

5,387,600
9 10
-continued
(40) (41)
N 0C1sH3s 0-(— cHzcl-lzoigCHg
HS—<
N
H N NHCO
HS—<
: O-(-CHZCH20-)§CH3
o (42) H (43)
II N
CH3\ 01
N H cocnzs—<
A
N ‘ N
O N S \
l N OH
CH3
N (44) 0H (45)
CH2S—< CONH-(-CH2-)§O csnua)
N
\ N
/N S—< CsHUO)
N OH N
| H
co
01
N NHCONHC18H37 (46) N NHCOC11H23 (47)
HS—< H..(
N N
H H
N NHCONHCl 1H23 (48) N OCOC11H23 (49)
CH;;—( CH;-—(
N N
H H
(50) (51)
CH3O CONH N CH 3 NHCONH N
>- C11H23 >- (111F123
N CH3 N
H H
Next, the detailed description will be made on the
compounds of the formula (IV) of the present inven Examples of the substituents include lower alkyl groups
tion. such as methyl and ethyl groups and halogen atoms
The alkyl groups represented by R7 to R10 in the such as chlorine, bromine, ?uorine and iodine. Cycloal
formula (IV) include alkyl groups having 1 to 12 carbon kyl groups substituted by methyl group are preferred.
atoms which may be straight or branched chains. Exam When R7 to R10 represent —(C(CH3)2)1r—(CH2)
ples of the alkyl groups include methyl, ethyl, n-propyl, mCOOR14 O1‘ —-(C(CH3)2)k——(CH2)mCON(R14)2, the
isopropyl, isobutyl, sec-butyl, tert-butyl, tert-pentyl, lower alkyl groups represented by R14 include alkyl
hexyl, octyl, decyl and dodecyl groups. Among these, groups having 1 to 4 carbon atoms which may be
alkyl groups having 1 to 8 carbon atoms are preferred straight or branched chains. Examples of the alkyl
and those having 1 to 4 carbon atoms are particularly groups include methyl, ethyl, n-propyl, isopropyl, iso
preferred. However, alkyl groups having not less than 4 butyl, sec-butyl and tert-butyl groups, preferably
carbon atoms are also preferred insofar as they are ter methyl and ethyl groups. k is preferably 1 and m is
tiary alkyl groups (such as tert-butyl, tert-pentyl, tert preferably 3.
hexyl, tert-octyl groups and the like). These alkyl Preferable groups represented by R7 to R10 are alkyl
groups may be optionally substituted. Examples of the groups having 1 to 4 carbon atoms and cycloalkyl
substituents include halogen atoms such as chlorine, groups substituted by methyl group, particularly methyl
bromine, ?uorine and iodine. 65 and tert-butyl groups.
The cycloalkyl groups represented by R7 to R10 in The alkyl groups represented by R11 and R12 in the
clude cyclopentyl, cyclohexyl and cycloheptyl groups. formula (IV) include alkyl groups having 1 to 13 carbon
These cycloalkyl groups may be optionally substituted. atoms which may be straight or branched chains. Exam
5,387,600
11 12
ples of the alkyl groups include methyl, ethyl, n-propyl,
-continued
isopropyl, isobutyl, sec-butyl, tert-butyl, hexyl, octyl,
OH 0H (53)
decyl and dodecyl groups. Among these, alkyl groups
having 1 to 8 carbon atoms are preferred and those
having 1 to 4 carbon atoms are particularly preferred.
The aryl groups represented by R11 and R12 include CH3 CH CH3
/
phenyl, tolyl, xylyl and naphthyl groups. Phenyl group
CH3 CH3
is preferable.
The aralkyl groups represented by R11 and R12 in CHL O: H OH CH3 (54)
clude benzyl and phenethyl groups.
In the preferable combination of R11 and R12, one is a
hydrogen atom and the other is a lower alkyl group CH2
CH3 I CH3
having 1 to 4 carbon atoms.
The lower alkyl groups represented by R13 in the CH
formula (IV) include alkyl groups having 1 to 4 carbon / \
CH3 CH2
atoms which may be straight or branched chains. Exam
ples of the alkyl groups include methyl, ethyl, n-propyl, C(CH3)s
isopropyl, isobutyl, sec-butyl and tert-butyl groups.
Methyl and ethyl groups are preferable. OH OH (55)
CH3 TH CH3
The aralkyl groups represented by R13 include benzyl
(n)C11H23 l
and phenethyl groups.
The acyl groups represented by R13 include aliphatic
CH3 CH3
and aromatic acyl groups. Examples of the aliphatic 25
acyl groups include acyl groups having 2 to 6 carbon OH OH (56)
atoms (such as acetyl, propionyl, pentanoyl and the
like), which may be straight or branched chains. Exam
ples of the aromatic acyl groups include benzoyl group.
These acyl groups may be optionally substituted. Exam
ples of the substituents of the aliphatic acyl groups in
clude lower alkoxy groups and phenoxy group. These (0641319, O: H ,ICPL iO H ,C4H9(t) (57)
substituents may further be substituted by one or more
substituents including lower alkyl groups such as
35
methyl, ethyl, mpropyl, isopropyl, isobutyl, sec-butyl (I1)C7H15
CH3 CH3
and tert-butyl groups and halogen atoms such as chlo
rine, bromine, ?uorine and iodine. Examples of the
OH OCOCH3 (58)
substituents of the aromatic acyl groups include lower (t)C4H9\¢/CHL i .cmga)
alkyl groups such as methyl, ethyl, n-propyl, isopropyl,
isobutyl, sec-butyl and tert-butyl groups and halogen
atoms such as chlorine, bromine, ?uorine and iodine. CH3 CH3
Examples of the alkylsulfonyl groups represented by
R13 include alkylsulfonyl groups having 2 to 4 carbon (0C4H9, iO H ,CH2. Oi CH3, C4H9(t) (59)
45
atoms (such as methanesulfonyl, ethanesulfonyl,
propanesulfonyl and the like), which may be straight or
branched chains. Examples of the arylsulfonyl groups
CH3 CH3
represented by R13 include benzenesulfonyl and p
toluenesulfonyl groups.
(OCH-I9. Ot H ,CH. Oi H ,C4H9(t) (60)
When R13 represents —-(CH2),,COOR15, the lower
alkyl groups represented by R15 include alkyl groups
having 1 to 4 carbon atoms which may be straight or
branched chains. Examples of the alkyl groups include CH3 CH3
methyl, ethyl, n-propyl, isopropyl, isobutyl, sec-butyl 55
and tert-butyl groups. Methyl and ethyl groups are OH OH (61)
preferable. n is preferably 0 or 1. CH
R13 is preferably a hydrogen atom.
CH3
Examples of the compounds of the general formula CH3 (H)C1H1s
60
(IV) of the present invention are listed below. CH3 CH3
(62)
OH OH (52) CH3‘ o: n 1|f: m OH CH3
65
CH3
CH3 CH3 CH3 CH3
5,387,600
13 14
-continued -continued
OH H OH (63) (72)
(0051111 C csnna) C235 $113 ‘[313 CZHS
’ 5 lwco-ecumc OH CH2 0H (|3-(-CH2-)§CON\ '
CH3
(t)CsI-I11 (005ml CZHS we“ CZHS
CH3
OH H OH (64) CH3 CH3
tC H C
() 8 17 l Cal-I170) 10 COOC2H5 (73)
CH3 0H
(OCsHW (t)CsH17 CH3 CH CH3
OH OH (65) 15
(s)C4H9 CH C4H9(s) CH3 CH CH
/ \ 3
CH3 CH3
(5)0411; CH (5)04119 OH OH (74)
/ \ 2O (UC4H9 (‘3H C4H9(t)
CH3 CH3 CH2
|
OH OH (66) CH3 CH2 CH3
CH3 CH2 C4H9(t) @
25
CH3 (t)C4H9 (75)
,cmo
(‘1H3 OH OH (‘3H3 (67) OH O
CH3OCO(CH2')§-C CH2 (lT-(-CH2')§COOCH3 30 CH2
l CH3 CH3
CH3 CH3
CH3 CH3 CH3 CH3
CH3 O: H on; O: H c113 (68) 35 (t)C4H9_ iO H ,CH2_ iO H ,C4H9(t) (76)
(OCsHU (t)CsH17 (‘1H2 (‘3H2
40 CH
/SO2CH3 (69) | 2 (EH2
OH COOC4H9 COOC4H9
CH3 CH CH3 . .
The method for preparing these compounds will now
45 be described in detail.
CH3 CH CH3 Benzimidazole ring which is basic skeleton of the
Cg CH compounds of the formulae (I), (II) and (III) is gener
3 3 ally synthesized using a o-phenylenediamine as a start
cHzcooczHs (70) ing material. That is Z-mercaptobenzimidazoles are gen
50 erally syntheslzed by reactmg o-phenylenedlammes
CH OH with carbon disul?de under a basic condition and 2
3 CH CH3 alkyl- or 2-aryl benzimidazoles are generally synthe
sized by reacting o-phenylenediamines with carboxyl
ate or orthocarboxylate under an acidic condition.
CH3/ CH CH3 55 On the other hand, 2,2’-methylenebis P henol deriva
CH3 CH3 tives of the compounds of the formula (IV) are gener
ally synthesized by subjecting a phenol and an aldehyde
C1 (71) or ketone to dehydrocondensation under an acidic con
coc H 60 dition. However, it is possible to obtain the compounds
H20 C5 "(0 by sub'ecting a henol derivative and an aldehyde or
/ J p ,
0H ketone to equimolar addition reaction under a basic
CH3 CH CH3 condition to obtain a methylol intermediate and then
reacting this intermediate with the equimolar phenol
65 under an acidic condition. The latter method is particu
CH3 CH CH3 larly useful for preparing an unsymmetrical 2,2’
CH3 CH3 methylenebisphenol derivative.
5,387,600
15 16
Synthesis Example 1 Synthesis Example 5
Synthesis of 2-metyl-5-nitrobenzimidazole (5) Synthesis of
5-dodecanoylamino-2-mercaptobenzimidazole (8)
15.3 g of 3,4-dinitrobenzene was added to 64 ml of
acetic anhydride and 2 ml of cone. hydrochloric acid 5 g of 5~amino~2-mercaptobenzimidazole was dis
and the mixture was re?uxed for 3 hours. After cooling, solved in 50 ml of pyridine and 7.95 g of dodecanoyl
the formed crystals were dispersed in 10% sodium hy chloride was added dropwise thereto under cooling
droxide aqueous solution and then ?ltered off. The with ice. After stirring, for 3 hours at room tempera
crystals were recrystallized from water-containing eth ture, the solution was poured into ice-water. The
anol to obtain 6 g of compound (5). formed crystals were ?ltered off and recrystallized from
Melting point: 220°~221° C. Elemental analysis (%): water-containing methanol to obtain 10.9 g of com
pound (8).
Anal. C 54.42 H 4.03 N 23.62 Cal. C 54.23 H 3.98 N
Melting point: 266°—267° C. Elemental analysis (%):
23.72
Anal. C 66.38 H 8.54 N 11.34 Cal. C 65.71 H 8.36 N
Synthesis Example 2 15 12.10
Synthesis of l,8-bis(5-nitrobenzimidazol-2-yl) octane (6) Synthesis Example 6
10.8 g of o-phenylenediamine and 10.1 g of sebacic Synthesis of 2-morpholinomethylbenzimidazole (36)
acid were added to 120 ml of 4N hydrochloric acid and
To 108 g of o-phenylenediamine, l l of 4N hydrochlo—
the mixture was re?uxed for 6 hours. After cooling, the
ric acid and 142 g of chloroacetic acid were added and
formed crystals were ?ltered off and washed with 1N
re?uxed for 1.5 hours. After allowing to stand over
sodium carbonate aqueous solution until the washing
night, the solution was diluted with 2 l of water and
solution maitained an alkalinity. After separating and
neutralized with dilute ammonia water. The formed
drying the crystals, they were dissolved in 35 ml of
25 crystals were ?ltered off to obtain 113 g of 2-chlorom
cone. sulfuric acid and 3.8 g of potassium nitrate was
ethylbenzimidazole.
added thereto little by little while stirring under cooling
10 g of 2-chloromethy1benzimidazole thus obtained
with ice. After stirring for 2 hours under cooling with
and 10.5 g of morpholine were dissolved in 75 ml of
ice, the solution was poured into ice-water and the
alcohol and the solution was refluxed for 3 hours. After
formed crystals were washed with 1N sodium carbon
cooling, ether was added to the solution and the precipi
ate aqueous solution until the washing solution mait
tated crystals were ?ltered off. The ?ltrate was washed
ained an alkalinity. The crystals were recrystallized
with water and satulated with hydrogen chloride to
from water-containing ethanol to obtain 3.4 g of com
form an oily matter. The oily matter was crystallized by
pound (6).
adding a smoll amount of alcohol and the crystals were,
Melting point: l35°-137° C. Elemental analysis ( % ):
?ltered off. The crystals were recrystallized from alco
Anal. C 60.62 H 19.25 N 5.41 Cal. C 60.54 H 19.26 N
hol to obtain 2.5 g of compound (36).
5.54
Melting point: 235°—236° C. Elemental analysis (%):
Synthesis Example 3 Anal. C 49.48 H 5.88 N 14.27 Cal. C 49.66 H 5.91 N
14.48
Synthesis of 2-mercapto-S-methoxybenzimidazole (13)
Synthesis Example 7
70 ml of ethanol and 15 ml of carbon disul?de were
added to 2.6 g of 3,4-diaminoanisole and then a solution Synthesis of 2,2'-isobutylidenebis(4,6-dimethyphenol)
of 1.5 g of sodium hydroxide in 5 ml of water was added (53)
thereto. After heating with a water bath for 3.5 hours,
36 g of isobutylaldehyde and 122 g of 2,4-dimethy
the mixture was cooled with ice, ?ltered and then the 45
phenol were mixed and 77 g of anhydrous calcium chlo
solvent in the ?ltrate was distilled off under reduced
ride was added to this mixture. The resulting mixture
pressure. The residue was dissolved in ethanol. The
was heated to 60° C. and 46 ml of conc. hydrochloric
solution was fltrated to remove the insoluble matter acid was added dropwise over 2 hours. After stirring
and then the solvent in the ?ltrate was distilled off for 6 hours, the reaction mixture was cooled and then
under reduced pressure. The residue was recrystallized water and methanol were added to disperse solid mat
from water-containing methanol to obtain 2.0 g of the
ter. After ?ltration, the solid matter was washed with
titled compound (13). water, dried and recrystallized from hexane under cool
Melting point: 254°—255° C. Elemental analysis (%): ing to obtain 102 g of compound (53).
Anal. C 53.06 H 4.52 N 15.27 Cal. C 53.33 H 4.44 N Melting point: l63°—l65° C. Elemental analysis (%):
55
15.56 Anal. C 80.67 H 8.88 Cal. C 80.49 H 8.78
Synthesis Example 4 Synthesis Example 8
Synthesis of 2-benzylthiobenzimidazole (7) Synthesis of 2,2’-methylenebis
(6-tert-butyl-4-methylphenol) monomethyl ether (59)
15 g of Z-mercaptobenzimidazole and 16.5 g of ben 60
zylbromide were dissolved in 50 ml of ethanol and the 34 g of 2,2'-methylenebis(6-tert-butyl-4-methyl
mixture was re?uxed with a water bath for 5 hours. phenol) was dissolved in 50 ml of acetone and 27.6 g of
After cooling, the formed crystals were collected and anhydrous calcium chloride was added to this solution.
recrystallized from ethanol to obtain 18 g of compound 15 g of methyl iodide was slowly added dropwise
(7). 65 thereto while stirring under re?ux. After stirring for 6
Melting point: 185°—186° C. Elemental analysis (%): hours, the reaction mixture was cooled and solid matter
Anal. C 69.59 H 5.30 N 11.74 Cal. C 69.99 H 5.03 N was ?ltered off. The ?ltrate was poured into ice-water
11.66 and the formed crystals were ?ltered off. The crystals
5,387,600
17 18
were recrystallized from water-containing methanol to The pharmaceutical composition of the present in
obtain 28.2 g of compound (59). vention may be administered, for example, orally or by
Melting point: l63°-l65° C. Elemental analysis (%): injection (mainly intramuscular, intravenous or subcuta
Anal. C 81.06 H 9.54 Cal. C 81.31 H 9.67 ' neous route) and is usually prepared in the form of a
formulation suitable for the administration route. Thus,
Synthesis Example 9
the pharmaceutical composition can be used as an oral
Synthesis of 2,2’-ethylidenebis(4,6-di-tert-pentylphenol) formulation such as tablet, powder, granule, capsule,
(63) syrup, emulsion, suspension or solution, or injection.
The formulations can be prepared by mixing the com
70.4 g of 2,4-di-tert-pentylphenol and 9.9 g of para
formaldehyde were dissolved in 100 ml of toluene and 10 pound of the present invention with a pahrmaceutical
acceptable carrier, diluent and/or bioactive substance.
5.7 g of p-toluenesulfonic acid was added thereto. The
Examples of pharmaceutical carriers or diluents suit
solution was heated to 70° C. and 30 ml of toluene was
able for combining with the compound of formula (I) to
distilled off over 3 hours under reduced pressure of
(IV) include glucose; saccharose; lactose; ethanol; glyc
100-135 mmHg. After cooling, water was added to the
15 erin; mannitol; sorbitol; pentaerythritol; diethylene gly
. solution and the water phase was neutralized with so
col, triethylene glycol, ethylene glycol, propylene gly
dium hydrogen carbonate. Then, the toluene phase was
col, dipropylene glycol, polyethylene glycol 400, other
washed with water, the solvent was distilled off under
polyethylene glycols than polyethylene glycol 400;
reduced pressure and the residue was recrystallized
mono-, di- and triglycerides of saturated fatty acids such
from water-containing methanol to obtain 52 g of com
pound (63). 20 as trilauryl glyceride, monostearoyl glyceride, tristear
oyl glyceride and distearoyl glyceride; pectin; starch;
Melting point: 1l6°-1l8° C. Elemental analysis (%):
corn starch; arginic acid; xylose; talc, lycopodium; oils
Anal. C 82.67 H 10.92 Cal. C 82.53 H 11.00
The following compounds were synthesized accord and fats such as olive oil, peanut oil, castor oil, corn oil,
wheat malt oil, sesame oil, cottonseed oil, sun?ower oil
ing to the method above described. The melting points
of the crystalline compounds are as follows: 25 and cod-liver oil; gelatin; lecithin; silica; cellulose; cellu
lose derivatives such as hydroxypropyl methyl cellu
lose, methylcellulose, hydroxyethyl cellulose and cal
Compound Compound cium carboxymethyl cellulose; magnesium or calcium
No. m.p.(°C.) No. m.p.(°C.) salts of fatty acids having 12 to 22 carbon atoms such as
(1) 195-200 (HCI salt) (2) 200-203 30 calcium stearate, calcium laurate, magnesium oleate,
(3) 133-135 (HBr salt) (4) 167-170 calcium palmitate, calcium behenate and magnesium
(5) 220-221 (6) 135-137 stearate; cyclodextrins such as a-cyclodextrin, B
(7) 190-191 (a) 226-267
cyclodextrin, 'r-cyclodextrin, hydroxyethyl-B
(9) 266-268 (10) 275-276
cyclodextrin, hydroxypropyl-B-cyclodextrin, dihy
(11) >300 (12) >280
(13) 254-255 (14) 128-129 35 droxypropyl-B-cyclodextrin, carboxymethyl ethyl-B
(15) 95-97 (16) 106-108 cyclodextrin and dimethyl-B-cyclodextrin; emulsi?ers
(17) 181-183 (18) 119-123
(20) 84-87 (21) 183-186 such as esters of saturated and unsaturated fatty acids
(23) 250-252 (24) 214-217 having 2 to 22, particularly 10 to 18 carbon atoms, with
(25) 200 (decomp.) (26) 284-286 monovalent aliphatic alcohols (for example, alkanols
(27) 230-232 (23) 132-134 having 1 to 20 carbon atoms such as glycol, glycerin,
(29) 217 (decomp.) (30) 243-245
diethylene glycol, pentaerythritol, ethanol, butanol and
(31) 143-144 (32) >250
(33) 124-125 (34) 218-220 octadecanol) or polyvalent alcohols; silicones such as
(35) 215-217 (HCl salt) (36) 235 (decomp.) dimethyl polysiloxane; and pyrogen-free distilled Water.
(HCl salt) The dosage of the pharmaceutical composition of the
(37) 162-164 (38) 215-216
(39) 202-203 (42) 230-231 45 present invention varies depending on age, body
(43) 155-156 (44) 163-164 weight, severity of the disease of the patient and the
(45) 146 (decomp.) (46) 197- 199 administration route. However, in general, the quantity
(47) 54-56 (48) 60-63 of the compound of formula (I), (II), (III) and/o r (IV)
(49) 82-85 (50) 188-191
(51) 209-212 to be administered ranges from 0.1 to 500 mg, prefera
(52) 123-124 (53) 163-165 50 bly from 0.2 to 100 mg per day per kg of body weight
(54) 171-173 (55) 124-125 for adult.
(56) 117-118 (57) 105-106
(53) 93-101 (59) 120-123 Pharmaceutical Test
(60) 171-172 (61) 92-95
(62) 122-131 (63) 116-118 (1) In vitro test for suppressing effect of macrophage
(64) 101-102 (67) 53-56 55 foaming reaction using mouse abdominal cavity macro
(68) 162-165 (74) 139-140 phage
A 15-week old ICR female mouse (Japan SLC) was
Compounds (65), (72) and (73) are oily and com amputated at its neck and exsanguinated. Then, Hanks
pounds (66), (69), (70), (71), (75) and (76) are non-crys buffer (Nissui Pharmaceutical Co., Ltd.) was injected
talline. Accordingly, they have no melting point. intraperitoneally. After massaging the abdominal part,
The pharmaceutical composition of the present in the buffer was recovered rapidly and centrifuged at
vention may contain one or more compounds of formu 1,000 rpm for 5 minutes to collect the abdominal cavity
lae (I) to (IV) and may be used in combination with the macrophage. Then, the collected abdominal cavity
known antihyperlipidemia and antiarteriosclerosis macrophage was suspended in GIT medium (Wako
agents that are conventionally used and are compatible 65 Pure Chemical Industry) and inoculated on a 24-well
~ with the compounds of the present invention. Examples microplate. After culturing the macrophage for 2 hours
of known a ntihyperlipidemia and antiarteriosclerosis at 37° C. in 5% CO2, the medium was changed into
agents include Melinamide, Probucol and Mevalotin. Dulbecco modi?ed Eagle’s MEM medium (Nissui