Pharmaceutical composition

To provide a pharmaceutical composition which performs a remarkable effect with a relatively decreased dosage, and, with less side effects, a pharmaceutical composition formulated by combination of an angiotensin II-mediated compound or a salt thereof with at least one species of a compound having the activity of increasing insulin-sensitivity, a compound having the activity of improving postprandial hyperglycemia in diabetes mellitus, an indane derivative having the activity of inhibiting angiotensin converting enzyme, a pyridine derivative having the activity of inhibiting HMG-Co A reductase or salts thereof are advantageously employed.

TECHNICAL FIELD 
This invention relates to a pharmaceutical composition comprising a 
compound having angiotensin II antagonistic activity or a salt thereof in 
combination with at least one species selected from the group consisting 
of a compound having the activity of increasing insulin-sensitivity, a 
compound having the activity of improving postprandial hyperglycemia in 
diabetes mellitus, an indane derivative having the activity of inhibiting 
angiotensin converting enzyme, a pyridine derivative having the activity 
of inhibiting HMG-Co A reductase or salts of them, and to the use of the 
composition. 
BACKGROUND ART 
Angiotensin II has a strong vasoconstrictive action, 
aldosterone-synthesizing action and cell-propagating action, which has 
been considered as one of the mediators of various circulatory diseases. 
An angiotensin II antagonistic drug suppressing the action of angiotensin, 
which antagonizes to this angiotensin II at angiotensin II receptor, is 
useful for the prophylaxis and therapy of circulatory diseases including 
hypertension, cardiac diseases (e.g. heart failure, myocardial infarction, 
etc.), cerebral apoplexy, nephritis, arteriosclerosis, etc. And, an 
angiotensin converting enzyme drug suppresses conversion of angiotensin I 
to angiotensin II, which is considered, like angiotensin II antagonistic 
drugs, as useful for the prophylaxis and therapy of circulatory diseases 
including hypertension, cardiac diseases (e.g. heart failure, myocardial 
infarction, etc.), cerebral apoplexy, nephritis, arteriosclerosis, etc. 
However, since angiotensin converting enzyme is the same enzyme as 
kininase II which destructs kinin, and it has no substrate specificity, it 
has such an undesirable side effect as depositing inflammatory peptide 
including kinin and the substance P to cause occurrence of cough. 
On the other hand, in the therapy of diabetes mellitus, there has been 
given treatment with a medicine to improve postprandial hyperglycemia in 
diabetes mellitus or treatment with a medicine to increase insulin 
sensitivity for preventing lowering of insulin sensitivity to the intake 
of glucose in peripheral tissue. 
Further, in the therapy of hyperlipemia, a medicine of inhibiting HMG-Co A 
reductase (3-hydroxy-3-methylglutaryl coenzyme A reductase) is employed to 
suppress the biosynthesis of cholesterol. 
Above all, such diseases as hypertension, abnormal carbohydrate tolerance 
and abnormal lipid metabolism have been known to be complicated with one 
another. Especially, hypertension and insulin resistance, or hypertension 
and arteriosclerosis are considered to aggravate the respective 
counterpart diseases. 
This invention is intended, by combination of a compound having angiotensin 
II antagonistic action or a salt thereof with a compound having action 
mechanism other than the above, to perform especially remarkable effects 
in angiotensin II-mediated diseases, especially hypertension, 
hyperlipemia, arteriosclerosis and so on, singly or complications of these 
diseases and to cover up various defects observed in administration of a 
medicine consisting of a single component. 
Circumstances being such as above, the present inventors have actually 
combined, for the first time, a compound having angiotensin antagonistic 
activity or a salt thereof, which is the essential component, with at 
least one species selected from the group consisting of a compound having 
an insulin sensitivity increasing action, a compound having the activity 
of improving postprandial hyperglycoplasmia in diabetes mellitus, an 
indane derivative having the action of inhibiting angiotensin converting 
enzyme, a pyridine derivative having the action of HMG-Co A reductase or 
salts thereof, and, as a result, they have found that the co-use performs 
especially remarkable effects (e.g. in the treatment effect, safety, 
stability, dose, administration route, method of use, etc.) which were not 
observed in the administration of the respective compounds singly, and 
they have conducted further studies to accomplish the present invention. 
SUMMARY OF THE INVENTION 
More specifically, the present invention relates to 
(1) a pharmaceutical composition comprising a compound having angiotensin 
II antagonistic activity or a salt thereof in combination with at least 
one species selected from the group consisting of a compound having the 
activity of increasing insulin-sensitivity, a compound having the activity 
of lowering postprandial hyperglycemia in diabetes mellitus, an indane 
derivative having the activity of inhibiting angiotensin converting 
enzyme, a pyridine derivative having the activity of inhibiting HMG-Co A 
reductase and their salts; 
(2) the composition as described in the above (1), which is a prophylactic 
(preventing) or therapeutic (treating) agent of angiotensin II-mediated 
diseases; 
(3) the composition as described in the above (2), which is directed to the 
prophylaxis or therapy of circulatory diseases; 
(4) the composition as described in the above (2), which is directed to the 
prophylaxis (prevention) or therapy (treatment) of hypertension, cardiac 
insufficiency, cerebral apoplexy, ischemic peripheral circulation 
disturbances, myocardial ischemia, venous insufficiency, progressive 
cardiac insufficiency after myocardial infarction, diabetic nephropathy, 
nephritis, glomerulonephritis, arteriosclerosis, angiohypertrophy, 
vascular hypertrophy or obstruction after percutaneous transluminal 
coronary angioplasty, vascular reobstruction after bypass surgery, 
hyperaldosteronism, glomerulosclerosis, renal insufficiency, glaucoma, 
occular hypertension, hyperlipemia, myocardial infarction, angina 
pectoris, aneurysm, coronary arteriosclerosis, cerebral arteriosclerosis, 
peripheral arteriosclerosis, thrombosis, diseases of central nervous 
system, Alzheimer's disease, deficiency of memory, depression, amnesia, 
senile dementia, sensory disturbances, multiple system organ failure or 
scleroderma, or to the prevention or amelioration of anxiety neurosis, 
catatonia, indisposition or dyspeptic symptoms; 
(5) the composition as described in the above (2), which is directed to the 
prophylaxis or therapy of complications of hypertension; 
(6) the composition as described in the above (2), which is directed to the 
prophylaxis or therapy of arteriosclerosis; 
(7) the composition as described in the above (5), which is directed to the 
prophylaxis or therapy of arteriosclerosis; 
(8) the composition as described in the above (1), wherein the compound 
having angiotensin II antagonistic activity is a compound of the formula: 
##STR1## 
wherein R.sup.1 stands for H or an optionally substituted hydrocarbon 
residue; R.sup.2 stands for an optionally esterified carboxyl group; 
R.sup.3 stands for a group capable of forming anion or a group convertible 
thereto; X shows that phenylene group and phenyl group are bonded directly 
or through a spacer having a chain length of 1 to 2 atoms; n denotes 1 or 
2; the ring A is a benzene ring optionally having further substituents 
other than the group shown by R.sup.2 ; and Y stands for a bond, --O--, 
--S(O)m-- (m denotes 0, 1 or 2) or --N(R.sup.4)-- (R.sup.4 stands for H or 
an optionally substituted alkyl group); 
(9) the composition as described in the above (1), wherein the compound 
having angiotensin II antagonistic activity is 
(.+-.)-1-(cyclohexyloxycarbonyloxy)ethyl 2-ethoxy-1-[[2'-(1 
H-tetrazol-5-yl)biphenyl-4-yl]methyl]-1 H-benzimidazole-7-carboxylate, 
2-ethoxy-1-[[2'-(1 H-tetrazol-5-yl)biphenyl-4-yl]methyl]-1 
H-benzimidazole-7-carboxylic acid or 
2-ethoxy-1-[[2'-(2,5-dihydro-5-oxo-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]meth 
yl]-1 H-benzimidazole-7-carboxyalic acid; 
(10) the composition as described in the above (1), wherein the compound 
having the activity of increasing insulin-sensitivity is 
5-[4-[2-(5-ethyl-2-pyridyl)ethoxy]-benzyl]-2,4-thiazolidinedione or 
(R)-(.+-.)-5-[3-[4-(2-(2-furyl)-5-methyl-4-oxazolylmethoxyj-3-methoxypheny 
l]-propyl]-2,4-oxazolidinedione; 
(11) the composition as described in the above (1), wherein the compound 
having the activity of improving post-prandial hyperglycemia in diabetes 
mellitus is N-(1,3-dihydroxy-2-propyl)valiolamine; 
(12) the composition as described in the above (1), wherein the indane 
derivative having the activity of inhibiting angiotensin converting enzyme 
is 
N-[N-[(S)-1-ethoxy-carbonyl-3-phenylpropyl]-L-alanyl]-N-(indan-2-yl)-glyci 
ne; 
(13) the composition as described in the above (1), wherein the pyridine 
derivative having the activity of inhibiting HMG-Co A reductase is 
(+)-3R,5S-erythro-(E)-7-[4-(4-fluorophenyl)-2,6-diisopropyl-5-methoxymethy 
l-pyridin-3-yl]-3,5-dihydroxyhept-6-enoic acid 
[(3R,5S,6E)-7-[4-(p-fluorophenyl)-2,6-diisopropyl-5-(methoxymethyl)-3-pyri 
dyl]-3,5-dihydroxy-6-heptenoic acid]; 
(14) the composition as described in the above (1), wherein the compound 
having angiotensin II antagonistic activity is 
(.+-.)-1-(cyclohexyloxycarbonyloxy)ethyl 
2-ethoxy-1-[[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl]-1H-benzimidazole-7 
-carboxylate, 
2-ethoxy-1-[[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl]-1H-benzimidazole-7 
-carboxylic acid or 
2-ethoxy-1-[[2'-(2,5-dihydro-5-oxo-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]meth 
yl]-1H-benzimidazole-7-carboxylic acid; 
the compound having the activity of increasing insulin-sensitivity is 
5-[4-[2-(5-ethyl-2-pyridyl)ethoxy]-benzyl]-2,4-thiazolidinedione or 
(R)-(+)-5-[3-[4-[2-(2-furyl)-5-methyl-4-oxazolylmethoxy]-3-methoxyphenyl]- 
propyl]-2,4-oxazolidinedione; 
the compound having the activity of improving post-prandial hyperglycemia 
in diabetes mellitus is N-(1,3-dihydroxy-2-propyl)valiolamine; 
the indane derivative having the activity of inhibiting angiotensin 
converting enzyme is 
N-[N-[(S)-1-ethoxy-carbonyl-3-phenylpropyl]-L-alanyl]-N-(indan-2-yl)-glyci 
ne; and 
the pyridine derivative having the activity of inhibiting HMG-Co A 
reductase is 
(+)-3R,5S-erythro-(E)-7-[4-(4-fluorophenyl)-2,6-diisopropyl-5-methoxymethy 
l-pyridin-3-yl]-3,5-dihydroxyhept-6-enoic acid; 
(15) the composition as described in the above (1) comprising the compound 
having angiotensin II antagonistic activity or a salt thereof in 
combination with the compound having the activity of increasing 
insulin-sensitivity or a salt thereof; 
(16) the composition as described in the above (1) comprising the compound 
having angiotensin II antagonistic activity or a salt thereof in 
combination with the compound having the activity of lowering postprandial 
hyperglycemia in diabetes mellitus or a salt thereof; 
(17) a pharmaceutical composition for the prevention or treatment of 
hypertension, arteriosclerosis or hyperlipemia comprising 
(.+-.)-1-(cyclohexyloxycarbonyloxy)ethyl 
2-ethoxy-1-[[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl]-1H-benzimidazole-7 
-carboxylate or a salt thereof in combination with at least one species 
selected from the group consisting of 
5-[4-[2-(5-ethyl-2-pyridyl)ethoxy]benzyl]-2,4-thiazol-idinedione, 
(R)-(+)-5-[3-[4-[2-(2-furyl)-5-methyl-4-oxazolylmethoxy]-3-methoxyphenyl]p 
ropyl]-2,4-oxazol-idinedione, N-(1,3-dihydroxy-2-propyl)valiolamine, 
N-[N-[(S)-1-ethoxycarbonyl-3-phenylpropyl]-L-alanyl]-N--(indan-2-yl)glycin 
e, 
(+)-3R,5S-erythro-(E)-7-[4-(4-fluorophenyl)-2,6-diisopropyl-5-methoxymethy 
lpyridin-3-yl]-3,5-dihydroxyhept-6-enoic acid and their salts; 
(18) a pharmaceutical composition for the prevention or treatment of 
hypertension, arteriosclerosis or hyperlipemia comprising 
2-ethoxy-1-[[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl]-1H-benzimidazole-7 
-carboxylic acid or a salt thereof in combination with at least one species 
selected from the group consisting of 
5-[4-[2-(5-ethyl-2-pyridyl)ethoxy]-benzyl]-2,4-thiazolidine-dione, 
(R)-(+)-5-[3-[4-[2-(2-furyl)-5-methyl-4-oxazolylmethoxy]-3-methoxyphenyl]- 
propyl]-2,4-oxazolidinedione, N-(1,3-dihydroxy-2-propyl)valiolamine, 
N-[N-[(S)-1-ethoxycarbonyl-3-phenylpropyl]-L-alanyl]-N-(indan-2-yl)glycine 
, (+)-3R,5S-erythro-(E)-7-[4-(4-fluorophenyl)-2,6-diiso-propyl-5-methoxymet 
hylpyridin-3-yl]-3,5-dihydroxyhept-6-enoic acid and their salts; 
(19) a pharmaceutical composition for the prevention or treatment of 
hypertension, arteriosclerosis or hyperlipemia comprising 
2-ethoxy-1-[[2'-(2,5-dihydro-5-oxo-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]meth 
yl]-1H-benzimidazole-7-carboxylic acid or a salt thereof in combination 
with at least one species selected from the group consisting of 
5-[4-[2-(5-ethyl-2-pyridyl)ethoxy]benzyl]-2,4-thiazolidinedi-one, 
(R)-(+)-5-[3-[4-[2-(2-furyl)-5-methyl-4-oxazolyl-methoxy]-3-methoxyphenyl] 
propyl]-2,4-oxazolidinedione, N-(1,3-dihydroxy-2-propyl)valiolamine, 
N-[N-[(S)-1-ethoxycarbonyl-3-phenylpropyl]-L-alanyl]-N-(indan-2-yl)glycine 
, (+)-3R,5S-erythro-(E)-7-[4-(4-fluoro--phenyl)-2,6-diisopropyl-5-methoxyme 
thylpyridin-3-yl]-3,5-dihydroxyhept-6-enoic acid and their salts; 
(20) a method for preventing or treating angiotensin II-mediated diseases 
in a mammal, which comprises administering to said mammal a compound 
having angiotensin II antagonistic activity or a salt thereof in 
combination with at least one species selected from the group consisting 
of a compound having the activity of increasing insulin-sensitivity, a 
compound having the activity of lowering postprandial hyperglycemia in 
diabetes mellitus, an indane derivative having the activity of inhibiting 
angiotensin converting enzyme, a pyridine derivative having the activity 
of inhibiting HMG-Co A reductase and their salts; and 
(21) use of a compound having angiotensin II antagonistic activity or a 
salt thereof in combination with at least one species selected from the 
group consisting of a compound having the activity of increasing 
insulin-sensitivity, a compound having the activity of lowering 
postprandial hyperglycemia in diabetes mellitus, an indane derivative 
having the activity of inhibiting angiotensin converting enzyme, a 
pyridine derivative having the activity of inhibiting HMG-Co A reductase 
and their salts, for the manufacture of a medicament for preventing or 
treating angiotensin II-mediated diseases. 
DETAILED EXPLANATION OF THE INVENTION 
Specific examples of the compound having the angiotensin II antagonistic 
activity or salts thereof include benzimidazol-7-carboxylic acid 
derivatives and salts thereof disclosed in, for example, JP-A [Japanese 
Patent Application Laid-open No.] H4(1992)-9373, EP-A- 425921, JP-A 
H4(1992)-364171, EP-A-459136 and EP-A- 520423, preferably compounds 
represented by the following formula (I) or salts thereof (preferably, 
pharmacologically acceptable salts). Formula (I) 
##STR2## 
wherein R.sup.1 stands for H or an optionally substituted hydrocarbon 
residue; R.sup.2 stands for an optionally esterified carboxyl group; 
R.sup.3 stands for a group capable of forming anion or a group convertible 
thereto; X shows that phenylene group and phenyl group are bonded directly 
or through a spacer having a chain length of 1 to 2 atoms; n denotes 1 or 
2; the ring A is a benzene ring optionally having further substituents 
other than groups shown by R.sup.2 ; and Y stands for a bond, --O--, 
--S(O)m-- (wherein m denotes 0, 1 or 2) or --N(R .sup.4)-- (wherein 
R.sup.4 stands for H or an optionally substituted alkyl group). 
In the above formula (I), examples of the hydrocarbon residue shown by 
R.sup.1 include alkyl, alkenyl, alkynyl, cycloalkyl, aryl and aralkyl 
groups. Among them, alkyl, alkenyl and cycloalkyl groups are preferable. 
The alkyl group shown by R.sup.1 is a straight chain or branched lower 
alkyl group having 1 to about 8 carbon atoms, as exemplified by methyl, 
ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, t-butyl, pentyl, 
i-pentyl, hexyl, heptyl and octyl. 
The alkenyl group shown by R.sup.1 is a straight chain or branched lower 
alkenyl group having 2 to about 8 carbon atoms, as exemplified by vinyl, 
propenyl, 2-butenyl, 3-butenyl, isobutenyl and 2-octenyl. 
The alkynyl group shown by R.sup.1 is a straight chain or branched lower 
alkynyl group having 2 to about 8 carbon atoms, as exemplified by ethynyl, 
2-propynyl, 2-butynyl, 2-pentynyl and 2-octynyl. 
The cycloalkyl group shown by R.sup.1 is a lower cycloalkyl group having 3 
to about 6 carbon atoms, as exemplified by cyclopropyl, cyclobutyl, 
cyclopentyl and cyclohexyl. 
The above-mentioned alkyl, alkenyl, alkynyl or cycloalkyl group may 
optionally be substituted with hydroxyl group, an optionally substituted 
amino group (e.g. amino, N-lower (C.sub.1-4)alkylamino, N,N-dilower 
(C.sub.1-4) alkylamino, etc.), halogen, a lower (C.sub.1-4) alkoxy group 
or a lower (C.sub.1-4) alkylthio group. 
The aralkyl group shown by R.sup.1 is exemplified by a phenyl-lower 
(C.sub.1-4) alkyl such as benzyl, phenethyl, etc. and the aryl group shown 
by R.sup.1 is exemplified by phenyl, etc. 
The above-mentioned aralkyl or aryl group may optionally have, on any 
position of its benzene ring, for example, halogen (e.g. F, Cl, Br, etc.), 
nitro, an optionally substituted amino group (e.g. amino, N-lower 
(C.sub.1-4) alkylamino, N,N-dilower (C.sub.1-4) alkylamino, etc.), lower 
(C.sub.1-4) alkoxy (e.g. methoxy, ethoxy, etc.), lower (C.sub.1-4) 
alkylthio (e.g. methylthio, ethylthio, etc.), lower (C.sub.1-4) alkyl 
(e.g. methyl, ethyl, etc.), etc. 
Among the above-mentioned groups shown by R.sup.1, optionally substituted 
alkyl, alkenyl or cycloalkyl groups [e.g. a lower (C.sub.1-5) alkyl, lower 
(C.sub.2-5) alkenyl or lower (C.sub.3-6) cycloalkyl group optionally 
substituted with hydroxyl group, amino group, halogen or a lower 
(C.sub.1-4) alkoxy group] are preferable. 
Y stands for a bond, --O--, --S(O)m-- (wherein m denotes 0, 1 or 2) or 
--N(R.sup.4)-- (wherein R.sup.4 stands for H or an optionally lower alkyl 
group), preferably a bond, --O--, --S-- or --N(R.sup.4)-- [wherein R.sup.4 
stands for H or a lower (C.sub.1-4) alkyl (e.g. methyl, ethyl, propyl, 
isopropyl, butyl, sec-butyl, t-butyl, etc.)]. 
With respect to the above-mentioned formula (I), the group shown by 
R.sup.3, capable of forming anion (a group having a hydrogen atom capable 
of leaving as proton), or a group capable of changing thereto, is 
exemplified by 5- to 7-membered (preferably 5- to 6-membered) monocyclic 
optionally substituted heterocyclic ring residue which contain one or more 
of N, S and O (preferably N-containing heterocyclic ring residue having a 
hydrogen atom capable of leaving as proton) or groups capable of changing 
thereto in vivo. Such groups include the following: 
##STR3## 
The chemical bond between the group shown by R.sup.3 and the partner phenyl 
group may be a carbon-carbon bond as shown above, or a nitrogen-carbon 
bond via one of the several nitrogen atoms when the symbol g stands for 
--NH-- in the above formulae. For instance, when R.sup.3 is shown by 
##STR4## 
, specific examples include: 
##STR5## 
Other examples of R.sup.3 bonded through nitrogen atom include: 
##STR6## 
In the above formulae, g stands for 
##STR7## 
&gt;=Z, &gt;=Z' and &gt;=Z" each stands for a carbonyl group, a thiocarbonyl group 
or an optionally oxidized sulfur atom (e.g. S, S(O), S(O).sub.2, etc.; 
preferably a carbonyl or thiocarbonyl group; more preferably, a carbonyl 
group); m denotes 0, 1 or 2; R.sup.7 stands for H or an optionally 
substituted lower alkyl group (e.g. a lower (C.sub.1-4) alkyl such as 
methyl, ethyl, propyl, isopropyl, butyl, sec-butyl and t-butyl). 
Preferable examples of R.sup.3 include 2,5-dihydro-5-oxo-1,2,4-oxadiazole 
ring residue, 2,5-dihydro-5-thioxo-1,2,4-oxadiazole ring residue or 
2,5-dihydro-5-oxo-1,2,4-thiadiazole ring residue having --NH or --OH group 
as proton donor and carbonyl group, thiocarbonyl group or sulfinyl group 
as proton acceptor simultaneously. 
And, while the heterocyclic residue shown by R.sup.3 may form a condensed 
ring by connecting the substituents on the ring, it is preferably a 5- to 
6-membered ring, more preferably a 5-membered heterocyclic residue. As 
R.sup.3, groups represented by the formula 
##STR8## 
wherein i stands for --O-- or --S--; j stands for &gt;C=O, -&gt;C=S or &gt;S(O)m; 
and m is of the same meaning as defined above (especially, 
2,5-dihydro-5-oxo-1,2,4-oxadiazol-3-yl, 
2,5-dihydro-5-thioxo-1,2,4-oxadiazol-3-yl or 
2,5-dihydro-5-oxo-1,2,4-thiadiazol-3-yl) are preferable. R.sup.3 can be 
substituted at any of the ortho, meta and para position of the phenyl 
group, most preferably at the ortho position. 
In addition, the above-mentioned heterocyclic residue (R.sup.3) have the 
following tautomeric isomers. 
For example, 
In 
##STR9## 
, when Z=O and g=O, 
##STR10## 
the three tautomeric isomers a, b and c exist. And, the heterocyclic 
residue represented by the formula 
##STR11## 
include all of the above-mentioned a, b and c. 
Moreover, R.sup.3 may be a carboxyl group, tetrazolyl group, 
trifluoromethanesulfonamide group (--NHSO.sub.2 CF.sub.3), phosphoric acid 
group, sulfonic acid group, cyano group or lower (C.sub.1-4) 
alkoxycarbonyl group; these groups each may be protected with an 
optionally substituted lower alkyl group or acyl group, and, any group 
capable of forming an anion biologically or physiologically (e.g. through 
biological reactions such as oxidation, reduction or hydrolysis caused by 
enzymes in the body) or chemically, or a group capable of changing thereto 
is acceptable. 
As R.sup.3, a tetrazolyl or carboxyl (preferably tetrazolyl) group 
optionally protected with an optionally substituted lower (C.sub.1-4) 
alkyl (e.g. methyl, triphenylmethyl, methoxymethyl, ethoxymethyl, 
p-methoxybenzyl, p-nitrobenzyl, etc.) or acyl group (e.g. lower 
(C.sub.2-5) alkanoyl, benzoyl, etc.) is preferable. R.sup.3 can be 
substituted at any of ortho-, meta- and para- positions, preferably at the 
ortho-position. 
X shows the linkage of phenylene group and phenyl group adjacent to each 
other directly or through a spacer having a chain length of 1 to 2 atoms 
(preferably direct linkage). The spacer having a chain length of 1 to 2 
atoms may consist of a divalent chain in which the number of atoms 
composing the straight chain portion is either 1 or 2, and may have a side 
chain, as exemplified by a lower (C.sub.1-4) alkylene, --CO--, --O--, 
--S--, --NH--, --CO--NH--, --O--CH.sub.2 --, --S--CH.sub.2 --, 
--CH.dbd.CH--, etc. 
The symbol n denotes an integer of 1 or 2 (preferably 1). 
The formula represented by the above-mentioned R.sup.3, X and n: 
##STR12## 
is preferably the following one: 
##STR13## 
In the formula (I), the optionally esterified carboxyl group shown by 
R.sup.2 is exemplified by groups represented by the formula --CO--D 
[wherein D stands for a hydroxyl group or an optionally substituted alkoxy 
group {e.g. (i) a lower (C.sub.1-6) alkoxyl group whose alkyl moiety is 
optionally substituted with (1) a hydroxyl group, (2) an optionally 
substituted amino (e.g. amino, N-lower (C.sub.1-4) alkylamino, N,N-lower 
(C.sub.1-4) alkylamino, piperidino, morpholino, etc.), (3) halogen, (4) a 
lower (C.sub.1-6) alkoxy, (5) a lower (C.sub.1-6) alkylthio or (6) an 
optionally substituted dioxolenyl (e.g. 5-methyl-2-oxo-1,3-dioxolen-4-yl) 
group, or (ii) alkoxyl group shown by the formula --O--CH(R 
.sup.6)--OCOR.sup.5 [wherein R.sup.6 stands for (1) H, (2) a lower 
(C.sub.1-6) straight chain or branched alkyl group (e.g. methyl, ethyl, 
n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, n-pentyl, isopentyl, 
neopentyl, etc.), (3) a lower (C.sub.2-6) straight chain or branched 
alkenyl group (e.g. vinyl, allyl, butenyl, i-butenyl, 2-hexenyl, etc.) or 
(4) (C.sub.3-8) cycloalkyl group (e.g. cyclopentyl, cyclohexyl, 
cycloheptyl, etc.); and R.sup.5 stands for (1) a lower (C.sub.1-6) 
straight chain or branched alkyl group (e.g. methyl, ethyl, n-propyl, 
isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl, isopentyl, 
neopentyl, etc.), (2) a lower (C.sub.2-6) straight chain or branched 
alkenyl group (e.g. vinyl, allyl, butenyl, i-butenyl, 2-hexenyl, etc.), 
(3) a (C.sub.3-8) cycloalkyl group (e.g. cyclopentyl, cyclohexyl, 
cycloheptyl, etc.), (4) a lower (C.sub.1-3) alkyl group substituted with 
(C.sub.3-8) cycloalkyl group (e.g. cyclopentyl, cyclohexyi, cycloheptyl, 
etc.) or an optionally substituted aryl group such as phenyl and naphthyl 
optionally substituted with halogen, nitro or a lower (C.sub.1-4) alkyl 
(e.g. benzyl, p-chlorobenzyl, phenethyl, cyclopentylmethyl, 
cyclohexylmethyl, etc.), (5) a lower (C.sub.2-3) alkenyl group optionally 
substituted with C.sub.3-8 cycloalkyl or an optionally substituted aryl 
group such as phenyl and naphthyl optionally substituted with halogen, 
nitro or a lower (C.sub.1-4) alkyl (e.g. cinnamyl, etc. having alkenyl 
moiety such as vinyl, propenyl, allyl and isopropenyl), (6) an optionally 
substituted aryl group such as phenyl and naphthyl optionally substituted 
with halogen, nitro or a lower (C.sub.1-4) alkyl (e.g. phenyl, p-tolyl, 
naphthyl, etc.), (7) a lower (C.sub.1-6) straight chain or branched alkoxy 
group (e.g. methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, 
sec-butoxy, t-butoxy, n-pentyloxy, isopentyloxy, neopentyloxy, etc.), (8) 
a lower (C.sub.2-8) straight chain or branched alkenyloxy group (e.g. 
allyloxy, isobutenyloxy, etc.), (9) a (C.sub.3-8) cycloalkyloxy group 
(e.g. cyclopentyloxy, cyclohexyloxy, cycloheptyloxy, etc.), (10) a lower 
(C.sub.1-3) alkoxy group substituted with (C.sub.3-8) cycloalkyl (e.g. 
cyclopentyl, cyclohexyl, cycloheptyl, etc.) or an optionally substituted 
aryl group such as phenyl and naphthyl optionally substituted with 
halogen, nitro or lower (C.sub.1-4) alkyl (e.g. benzyloxy, phenethyloxy, 
cyclohexylmethoxy, etc. having alkoxy moiety such as methoxy, ethoxy, 
n-propoxy, isopropoxy, etc.), (11) a lower (C.sub.2-3) lower alkenyloxy 
group substituted with a C.sub.3-8 cycloalkyl (e.g. cyclopentyl, 
cyclohexyl, cycloheptyl, etc.) or with an optionally substituted aryl 
group such as phenyl and naphthyl optionally substituted with halogen, 
nitro or lower (C.sub.1-4) alkyl (e.g. cinnamyloxy, etc. having alkenyloxy 
moiety such as vinyloxy, propenyloxy, allyloxy, isopropenyloxy, etc.) or 
(12) an optionally substituted aryloxy group such as phenoxy and naphthoxy 
optionally substituted with halogen, nitro or lower (C.sub.1-4) alkyl 
(e.g. phenoxy, p-nitrophenoxy, naphthoxy, etc.)]}]. The substituent shown 
by R.sup.2 may be a group actually or potentially capable of forming anion 
[e.g. tetrazolyl group, trifluoromethanesulfonamide group, phosphoric acid 
group or sulfonic acid group optionally protected with an optionally 
substituted alkyl (e.g. lower (C.sub.1-4) alkyl, etc.) or acyl (e.g. lower 
(C.sub.2-5) alkanoyl, optionally substituted benzoyl, etc.)]. 
Examples of the substituent R.sup.2 include --COOH and its salts, --COOMe, 
--COOEt, --COOtBu, --COOPr, pivaloyloxymethoxycarbonyl, 
1-(cyclohexyloxycarbonyloxy)ethoxycarbonyl, 
(5-methyl-2-oxo-1,3-dioxolen-4-yl)methoxycarbonyl, acetoxymethoxycarbonyl, 
propionyloxymethoxycarbonyl, n-butyryloxymethoxycarbonyl, 
isobutyryloxymethoxycarbonyl, (1-ethoxycarbonyloxyethoxy)carbonyl, 
(1-acetoxyethoxy)carbonyl, (1-isobutyryloxyethoxy)carbonyl, 
cyclohexylcarbonyloxymethoxycarbonyl, benzoyloxymethoxycarbonyl, 
cinnamyloxycarbonyl and cyclopentylcarbonyloxymethoxycarbonyl. 
Furthermore, R.sup.2 may be any of the groups actually or potentially 
capable of forming anion (e.g. COO.sup.- or its derivatives) under 
biologic or physiologic conditions (e.g. oxidation or reduction induced by 
enzyme present in the living body, or in vivo reaction such as hydrolysis) 
or chemically. R.sup.2 may be carboxyl group or its prodrug. R.sup.2 may 
be a group capable of being biologically or chemically transformed, for 
example, in vivo to anion. 
Among the groups described above as R.sup.2, preferable ones include 
carboxyl, esterified carboxyl (e.g. methyl ester, ethyl ester or an ester 
formed by binding of a group shown by the formula 
--O--CH(R.sup.6)--OCOR.sup.5 to carbonyl) and optionally protected 
tetrazolyl, carboaldehyde and hydroxymethyl. 
In the formula (I), ring A may have, in addition to the group shown by 
R.sup.2, further substituents as exemplified by halogen (e.g. F, Cl, Br, 
etc.), cyano, nitro, lower (C.sub.1-4) alkyl, lower (C.sub.1-4) alkoxy, an 
optionally substituted amino group {e.g. amino, N-lower (C.sub.1-4) 
alkylamino (e.g. methylamino, etc.), N,N-di-lower (C.sub.1-4) alkylamino 
(e.g. dimethylamino, etc.), N-arylamino (e.g. phenylamino, etc.), 
alicyclic amino (e.g. morpholino, piperidino, piperazino, 
N-phenylpiperazino, etc.)}, a group shown by the formula --CO--D' [wherein 
D' stands for hydroxyl group or a lower (C.sub.1-4) alkoxy group whose 
alkyl moiety may optionally be substituted with hydroxyl group, lower 
(C.sub.1-4) alkoxy, lower (C.sub.2-6) alkanoyloxy (e.g. acetoxy, 
pivaloyloxy, etc.) or lower (C.sub.1-6) alkoxycarbonyloxy (e.g. chain-like 
alkoxycarbonyloxy such as methoxycarbonyloxy, ethoxycarbonyloxy, etc. or 
cyclic alkoxycarbonyloxy such as cyclohexyloxycarbonyloxy)], or a 
tetrazolyl group, a trifluoromethanesulfonamide group, a phosphoric acid 
group or a sulfonic acid group which may optionally be protected with 
lower (C.sub.1-4)alkyl or acyl (e.g. lower (C.sub.2-5) alkanoyl, 
optionally substituted benzoyl, etc.); among them, a lower (C.sub.1-4) 
alkyl and halogen are preferable. Of these substituents, one or two may 
simultaneously be substituted at available positions in the ring. 
Among the compounds represented by the formula (I) mentioned above, 
compounds represented by the formula (I') or salts thereof are preferred: 
##STR14## 
wherein ring A stands for a benzene ring optionally having further 
substituents besides groups shown by R.sup.2 ; R.sup.1 stands for H or an 
optionally substituted lower (C.sub.1-6) alkyl (preferably lower alkyl 
(C.sub.1-4) alkyl); Y stands for --O--, --S-- or --N(H)--; R.sup.2 is a 
group represented by the formula --CO--D" [wherein D" stands for hydroxyl 
group, or a lower (C.sub.1-4) alkoxy whose alkyl moiety is optionally 
substituted with hydroxyl group, amino, halogen, a lower (C.sub.2-6) 
alkanoyloxy (e.g. acetyloxy, pivaloyloxy, etc.), a lower (C.sub.4-7) 
cycloalkanoyloxy, (lower (C.sub.1-6)alkoxy)carbonyloxy (e.g. 
methoxycarbonyloxy, ethoxycarbonyloxy, etc.), (lower 
(C.sub.3-7)cycloalkoxy)carbonyloxy (e.g. cyclohexyloxycarbonyl, etc.) or a 
lower (C.sub.1-4)alkoxy; R.sup.3 stands for a tetrazolyl, carboxyl group 
or groups represented by the formula 
##STR15## 
[wherein i stands for --O-- or --S--; j stands for &gt;C=O, &gt;C=S or &gt;S(O)m, m 
denotes 0, 1 or 2] each of which is optionally protected with optionally 
substituted lower (C.sub.1-4) alkyl (e.g. methyl, triphenylmethyl, 
methoxymethyl, acetyloxymethyl, methoxycarbonyloxymethyl, 
ethoxycarbonyloxymethyl, 1-(cyclohexyloxycarbonyloxy)ethyl, 
pivaloyloxymethyl, etc.) or an acyl group (e.g. a lower (C.sub.2-5) 
alkanoyl, benzoyl, etc.); n denotes 1 or 2 (preferably 1)]. 
In the formula (I'), as substituents on the optionally substituted,.lower 
alkyl shown by R.sup.1, mention is made of a hydroxyl group, an amino 
group, halogen or a lower (C.sub.1-4) alkoxy group. 
In the formula (I'), as substituents other than those shown by R.sup.2 on 
the ring A, mention is made of halogen (e.g. F, Cl, Br, etc.), lower 
(C.sub.1-4) alkyl, lower (C.sub.1-4) alkoxy, nitro, a group represented by 
the formula --CO--D' [wherein D' stands for a hydroxyl group or lower 
(C.sub.1-4) alkoxy whose alkyl moiety may optionally be substituted with 
hydroxyl group, lower (C.sub.1-4) alkoxy, lower (C.sub.2-6) alkanoyloxy 
(e.g. acetoxy, pivaloyloxy, etc.) or lower (C.sub.1-6) alkoxycarbonyloxy 
(e.g. methoxycarbonyloxy, ethoxycarbonyloxy, cyclohexyloxycarbonyloxy, 
etc.)] or amino optionally substituted with a lower (C.sub.1-4) alkyl 
(preferably lower (C.sub.1-4) alkyl or halogen). As the ring A, a benzene 
ring, which has no substituent other than the group represented by the 
formula R.sup.2, is more preferable. 
As the salts mentioned above, mention is made of pharmaceutically 
acceptable ones, as exemplified by a salt with an inorganic base, an 
organic base, an iorganic acid, an organic acid, or a basic or acidic 
amino acid. Preferable examples of a salt with an inorganic base include 
alkali metal salts such as sodium salts, potassium salts, and so on; 
alkaline earth metal salts such as calcium salts, magnesium salts, and so 
on; as well as aluminum salts, ammonium salts, etc. Preferable examples of 
a salt with an organic base include salts with trimethylamine, 
triethylamine, pyridine, picoline, ethanolamine, diethanolamine, 
triethanolamine, dicyclohexylamine, N,N'-dibenzylethylenediamine, 
N-methylmorpholine, etc. Preferable examples of a salt with an inorganic 
acid include salts with hydrochloric acid, hydrobromic acid, nitric acid, 
sulfuric acid, phosphoric acid, etc. Preferable examples of the salt with 
an organic acid include salts with formic acid, acetic acid, 
trifluoroacetic acid, fumaric acid, oxalic acid, tartaric acid, maleic 
acid, citric acid, succinic acid, malic acid, methanesulfonic acid, 
benzenesulfonic acid, p-toluenesulfonic acid, etc. Preferable examples of 
a salt with a basic amino acid include salts with arginine, lysine, 
ornithine, etc. Preferable examples of a salt with an acidic amino acid 
include salts with aspartic acid, glutamic acid, etc. 
Preferable compounds to be employed as the active ingredient of the present 
invention include those described in the Examples of JP-A 
H4(1992)-364171/1992, EP-A-459136 and EP-A-520423. Among them, 
(.+-.)-1-(cyclohexyloxycarbonyloxy)ethyl 
2-ethoxy-1-[[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl]-1H-benzimidazole-7 
-carboxylate, 
2-ethoxy-1-[[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl]-1H-benzimidazole-7 
-carboxylic acid, 
2-ethoxy-1-[[2'-(2,5-dihydro-5-oxo-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]meth 
yl]-1H-benzimidazole-7-carboxylic acid or pharmaceutically acceptable salts 
thereof are preferable. 
The compounds represented by the general formula (I) are disclosed in, for 
example, JP-A H4(1992)-9373, EP-A-425921, JP-A H4(1992)-364171, 
EP-A-459136 and EP-A-520423, which can be produced by the methods 
disclosed in these official publications or methods analogous thereto. 
As the compound having the activity of increasing insulin-sensitivity to be 
used for the present invention or salts thereof, mention is made of a 
compound having the activity of normalizing the function of the receptor 
whose insulin-activity is damaged, namely a compound having the activity 
of releasing the insulin-resistance, or salts thereof. Specific examples 
of such compounds as above include 2,4-thiazolidinedione, 
2,4-oxazolidinedione derivatives or salts thereof described in 
EP-A-193256, Japan Patent Application No. H7(1995)-284106 (EP-A-710659), 
JP-A S60(1985)-51189, or known compounds having the activity of increasing 
insulin-sensitivity, for example, 
5-[[3,4-dihydro-2-(phenylmethyl)-2H-1-benzopyran-6-yl]methyl]-2,4-thiazoli 
dinedione (generic name: englitazone); 
5-[[4-[3-(5-methyl-2-phenyl-4-oxazolyl)-1-oxopropyl]phenyl]methyl]-2,4-thi 
azolidinedione (generic name: darglitazone; CP-86325); 
5-[2-(5-methyl-2-phenyl-4-oxazolylmethyl)benzofuran-5-ylmethyl]-2,4-oxazol 
idinedione (CP-92768); 5-(2-naphthalenylsulfonyl)-2,4-thiazolidinedione 
(AY-31637); 4-[(2-naphthaleneyl)methyl]-3H-1,2,3,5-oxathiadiazol-2-oxide 
(AY-30711); and 
5-[[4-[2-(methyl-2-pyridylamino)ethoxy]phenyl]methyl]-2,4-thiazolinedione 
(BRL-49653). Preferable compounds include those described as Working 
Examples in EP-A-193256, Japan Patent Application No. H7(1995)-284106 
(EP-A-710659) or JP-A S60(1985)-51189. Among them, 2,4-thiazolidinedione 
or 2,4-oxazolidinedione derivatives such as 
5-[4-[2-(3-ethyl-2-pyridyl)ethoxy]benzyl]-2,4-thiazolidinedione, 
5-[4-[2-(5-ethyl-2-pyridyl)ethoxy]benzyl]-2,4-thiazolidin-edione, 
5-[4-[2-(5-ethyl-2-pyridyl)ethoxy]benzyl]-2,4-thiazolidinedione, 
5-[4-[2-(5-ethyl-2-pyridyl)ethoxy]benzyl]-2,4-thiazolidinedione, 
(R)-(+)-5-[3-[4-[2-(2-furyl)-5-methyl-4-oxazolylmethoxy]-3-methoxyphenyl]p 
ropyl]-2,4-oxazolidinedione and CS-045 are preferable, especially, 
5-[4-[2-(5-ethyl-2-pyridyl)ethoxy]benzyl]-2,4-thiazolidinedione or 
(R)-(+)-5-[3-[4-[2-(2-furyl)-5-methyl-4-oxazolylmethoxy]-3-methoxyphenyl]p 
ropyl]-2,4-oxazolidinedione is preferable. 
Preferable examples of salts of a compound having the activity of 
increasing (enhancing) insulin-sensitivity include pharmaceutically 
acceptable salts, which are specifically exemplified by substantially the 
same ones as pharmaceutically acceptable salts of the above-mentioned 
compounds having the angiotensin II antagonistic activity. 
As the compound having the activity of improving postprandial hyperglycemia 
in diabetes mellitus or salts thereof to be used in the present invention, 
mention is made of a compound having the activity of inhibiting 
.alpha.-glucosidase and having the activity of inhibiting a digestive 
enzyme such as amilase, maltase, .alpha.-dextrinase, sucrase and so on to 
delay the digestion of starch or sucrose, or salts thereof. As examples of 
them, mention is made of valiolamine derivatives or salts thereof 
described in EP-A-56194, etc., acarbose or salts thereof described in U.S. 
Pat. No. 4,062,950, etc. As preferable examples of them, mention is made 
of compounds described in Examples of EP-A-56194, and, among them, 
N-(1,3-dihydroxy-2-propyl)valiolamine is preferable. 
Preferable examples of salts of a compound having the activity of improving 
postprandial hyperglycemia in diabetes mellitus include pharmaceutically 
acceptable salts, which are specifically exemplified by substantially the 
same ones as pharmaceutically acceptable salts of the above-mentioned 
compounds having the angiotensin II antagonistic activity. 
As indane derivatives having the activity of inhibiting angiotensin 
converting enzyme or salts thereof to be used in the present invention, 
mention is made of indane derivatives or salts thereof having the 
antihypertensive activity by inhibiting angiotensin converting enzyme 
which converts angiotensin I to angiotensin II. Specific examples of them 
include indane derivatives or salts thereof described in, for example, 
JP-A S57(1982)-179141 and EP-A-51391. As preferable compounds, mention is 
made of those described as Working Examples in JP-A S57(1982)-179141 or 
EP-A-51391. Among them, 
N-[N-[(S)-1-ethoxycarbonyl-3-phenylpropyl]-L-alanyl]-N-(indan-2-yl)glycine 
or salts thereof are preferable, and especially, 
N-[N-[(S)-1-ethoxycarbonyl-3-phenylpropyl]-L-alanyl]-N-(indan-2-yl)glycine 
hydrochloride is preferable. 
As preferable examples of salts of indane derivatives having the activity 
of inhibiting angiotensin converting enzyme, mention is made of 
pharmaceutically acceptable salts. As specific examples of them, mention 
is made of those which are substantially the same as pharmaceutically 
acceptable salts of the above-mentioned compound having the angiotensin II 
antagonistic activity. 
In the present invention, a compound having the angiotensin II antagonistic 
activity or a salt thereof is used in combination with an indane 
derivative having the activity of inhibiting angiotensin converting enzyme 
or a salt thereof. In place of the above-mentioned indane derivative 
having the activity of inhibiting angiotensin converting enzyme, other 
angiotensin converting enzyme inhibiting agents (e.g. captopril, 
enalapril, alacepril, ramipril, lisinopril imidapril, etc.) may optionally 
be used, and, any other antihypertensive agent such as .alpha.-blocker, 
.beta.-blocker, a diuretic or a calcium antagonist may optionally be used 
in combination with an angiotensin II antagonist. 
As the pyridine derivative having the activity of inhibiting HMG-Co A 
reductase or a salt thereof to be used in the present invention, mention 
is made of a pyridine derivative having the activity of inhibiting HMG-Co 
A reductase, which is a rate-limiting enzyme of cholesterol synthesis, or 
a salt thereof. Specific example of them include pyridine derivatives or 
salts thereof described in, for example, JP-A H1(1989)-216974, 
EP-A-325130, JP-A H4(1992)-308573, U.S. Pat. No. 5,177,080, JP-B [Japanese 
Patent Examined Publication No.] H6(1994)-41448, EP-A-307342, JP-A 
H1(1989)-121266 and EP-A-306929. As preferable compounds, mention is made 
of, for example, pyridine derivatives described as Working Examples in 
these official publications, and, among them, pyridine derivatives 
described as Working Examples in JP-A H4(1992)-308573 are more preferable, 
especially preferable one being 
(+)-3R,5S-erythro-(E)-7-[4-(4-fluorophenyl)-2,6-diisopropyl-5-methoxymethy 
lpyridin-3-yl]-3,5-dihydroxyhept-6-enoic acid or salts thereof and most 
preferable one being 
(+)-3R,5S-erythro-(E)-7-[4-(4-fluorophenyl)-2,6-diisopropyl-5-methoxymethy 
lpyridin-3-yl]-3,5-dihydroxyhept-6-enoate sodium. 
As preferable examples of salts of a pyridine derivative having the 
activity of inhibiting HMG-Co A reductase, mention is made of 
pharmaceutically acceptable salts, which are specifically exemplified by 
substantially the same ones as pharmaceutically acceptable salts of the 
above-mentioned angiotensin II antagonistic compounds. 
In the present invention, an angiotensin II antagonistic compound or a salt 
thereof is used in combination with a pyridine derivative having the 
activity of inhibiting HMG-Co A reductase or a salt thereof. And, in place 
of the above-mentioned pyridine derivatives having the activity of 
inhibiting HMG-Co A reductase, any other agent of inhibiting HMG-Co A 
reductase (e.g. pravastatin, simvastatin, lovastatin or fluvastatin may 
optionally. be employed. And, any other antihyperlipemic drug including an 
agent of inhibiting squalene synthesis and a fibrate compound having the 
activity of lowering triglyceride (e.g. bezafibrate) may optionally be 
used in combination with an angiotensin II antagonistic drug. 
In the present invention, a compound having the angiotensin II antagonistic 
activity or a salt thereof is employed in combination with at least one 
species of a compound having the activity of increasing 
insulin-sensitivity, a compound having the activity of improving 
postprandial hyperglycemia in diabetes mellitus, an indane derivative 
having the activity of inhibiting angiotensin converting enzyme, a 
pyridine derivative having the activity of inhibiting HMG-Co A reductase 
or salts thereof. And, a combination of one or more species of a compound 
having the activity of increasing insulin-sensitivity, a compound having 
the activity of improving postprandial hyperglycemia in diabetes mellitus, 
an indane derivative having the activity of inhibiting angiotensin 
converting enzyme, a pyridine derivative having the activity of inhibiting 
HMG-Co A reductase or salts of them may optionally be employed. And, any 
other drugs (e.g. an antihypertensive drug, an antihyperlipemic drug, 
etc.) may optionally be combined appropriately with any one of the above 
compound. 
To state further, in the case of using a compound having the angiotensin 
antagonistic activity or a salt thereof in combination with at least one 
species of a compound having the activity of increasing 
insulin-sensitivity, a compound having the activity of improving 
postprandial hyperglycemia in diabetes mellitus, an indane derivative 
having the activity of inhibiting angiotensin converting enzyme, a 
pyridine derivative having the activity of inhibiting HMG-Co A reductase 
or salts thereof, these drugs can be formulated by mixing individually or 
simultaneously with pharmaceutically acceptable carriers, excipients, 
binders, diluents or the like, which can be administered orally or 
non-orally. In the case of formulating these effective components 
individually, while thus individually formulated agents can be 
administered in the form of their mixture prepared by using, for example, 
a diluent when administered, the individually formulated agents can also 
be administered separately or simultaneously or with time intervals to the 
one and same subject. A kit for administering the individually formulated 
effective components in the form of their mixture prepared by using, for 
example, a diluent when administered (e.g. a kit for injection which 
comprises two or more ampoules each comprising a powdery component and a 
diluent for mixing and dissolving two or more components when 
administered, etc.), a kit for administering the individually formulated 
agents simultaneously or with time intervals to the one and same subject 
(e.g. a kit for tablets to be administered simultaneously or with time 
intervals, characterized by having two or more tablets each comprising an 
agent and said tablets being put in one or separate bags and, if 
necessary, a column to describe time to be administered each agent, etc.) 
are also included by the pharmaceutical composition of the present 
invention. 
Preferable combinations of the pharmaceutical composition of the present 
invention are as follows: 
(1) a combination of (.+-.)-1-(cyclohexyloxycarbonyloxy)ethyl 
2-ethoxy-1-[[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl]-1H-benzimidazole-7 
-carboxylate or a salt thereof with at least one species of 
5-[4-[2-(5-ethyl-2-pyridyl)ethoxy]benzyl]-2,4-thiazolidinedione, 
(R)-(+)-5-[3-[4-[2-(2-furyl)-5-methyl-4-oxazolylmethoxy]-3-methoxyphenyl]p 
ropyl]-2,4-oxazolidinedione, N-(1,3-dihydroxy-2-propyl)valiolamine, 
N-[N-[(S)-1-ethoxycarbonyl-3-phenylpropyl]-L-alanyl]-N-(indan-2-yl)glycine 
, (+)-3R,5S-erythro-(E)-7-[4-(4-fluorophenyl)-2,6-diisoprop-yl-5-methoxymet 
hylpyridin-3-yl]-3,5-dihydroxyhept-6-enoic acid or salts thereof; 
(2) a combination of 
2-ethoxy-1-[[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl]-1H-benzimidazole-7 
-carboxylic acid or a salt thereof with at least one species of 
5-[4-[2-(5-ethyl-2-pyridyl)ethoxy]benzyl]-2,4-thiazolidinedione, 
(R)-(+)-5-[3-[4-[2-(2-furyl)-5-methyl-4-oxazolylmethoxy]-3-methoxyphenyl]p 
ropyl]-2,4-oxazolidinedione, N-(1,3-dihydroxy-2-propyl)valiolamine, 
N-[N-[(S)-1-ethoxycarbonyl-3-phenylpropyl]-L-alanyl]-N-(indan-2-yl)glycine 
, (+)-3R,5S-erythro-(E)-7-[4-(4-fluorophenyl)-2,6-diisoprop-yl-5-methoxymet 
hylpyridin-3-yl]-3,5-dihydroxyhept-6-enoic acid or salts thereof, and 
(3) a combination of 
2-ethoxy-1-[[2'-(2,5-dihydro-5-oxo-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]meth 
yl]-1H-benzimidazole-7-carboxylic acid or a salt thereof with at least one 
species of 
5-[4-[2-(5-ethyl-2-pyridyl)ethoxy]benzyl]-2,4-thiazolidinedione, (R)-(+)-5 
-[3-[4-[2-(2-furyl)-5-methyl-4-oxazolylmethoxy]-3-methoxyphenyl]propyl]-2,4 
-oxazolidinedione, N-(1,3-dihydroxy-2-propyl)valiolamine, 
N-[N-[(S)-1-ethoxycarbonyl-3-phenylpropyl]-L-alanyl]-N-(indan-2-yl)glycine 
, (+)-3R,5S-erythro-(E)-7-[4-(4-fluorophenyl)-2,6-diisopropyl-5-methoxymeth 
ylpyridin-yl]-3,5-dihydroxyhept-6-enoic acid or salts thereof. These 
preferred combinations (1) to (3) are preferably used for the prevention 
or treatment of hypertension, arteriosclerosis or hyperlipemia, in 
particular, arteriosclerosis accompanied with hypertension. 
Among them, a combination of a compound having the angiotensin II 
antagonistic activity or a salt thereof with at least one species of a 
compound having the activity of increasing insulin-sensitivity, a compound 
having the activity of improving postprandial hyperglycemia in diabetes 
mellitus or salts of them is preferably used. 
The pharmaceutical composition of this invention is used as a prophylactic 
or therapeutic agent of, for example, angiotensin II-mediated diseases of 
animals, especially mammals (e.g. man, dog, rabbit, rat, mouse, etc.), as 
exemplified by circulatory diseases including hypertension, cardiac 
insufficiency, cerebral apoplexy, ischemic peripheral circulation 
disturbances, myocardial ischemia, venous insufficiency, progressive 
cardiac insufficiency after myocardial infarction, diabetic nephropathy, 
nephritis, glomerulonephritis, arteriosclerosis, angiohypertrophy, 
vascular hypertrophy or obstruction after percutaneous transluminal 
coronary angioplasty, vascular reobstruction after bypass surgery, 
hyperaldosteronism, glomerulosclerosis, renal insufficiency, glaucoma, 
occular hypertension, hyperlipemia, myocardial infarction, angina 
pectoris, aneurysm, coronary arteriosclerosis, cerebral arteriosclerosis, 
peripheral arteriosclerosis, thrombosis; diseases of sensory disturbances 
including Alzheimer's disease, deficiency of memory, depression, amnesia, 
senile dementia; diseases of central nervous system including anxiety 
neurosis, catatonia and indisposition; dyspeptic symptoms, multiple system 
organ failure, and scleroderma. The pharmaceutical composition of this 
invention is preferably used as a prophylactic or therapeutic agent for, 
especially, circulatory diseases including diseases of central nervous 
system caused by circulatory disturbances. Among the circulatory diseases, 
for the prophylaxis or therapy of arteriosclerosis and hyperlipemia, use 
of the pharmaceutical composition of this invention is preferable, 
especially, use of it for the prophylaxis or therapy of artereiosclerosis 
is preferable. Further, also for the therapeutic method for lowering 
cholesterol, the pharmaceutical composition of this invention can be used. 
And, the pharmaceutical composition of this invention performs remarkable 
effects for the prophylaxis or therapy of diseases accompanied with 
diabetic, obesitic, hyperlipemic or essential hypertension. It is 
preferably used, especially, for the prophylaxis or therapy of 
arteriosclerosis accompanied with hypertension. 
The pharmaceutical composition of this invention can be administered orally 
or non-orally in the form of, for example, granules, powdery preparations, 
dust preparations, tablets, capsules, syrup, emulsions, suppositories 
(e.g. rectal suppositories and vaginal suppositories), injections (e.g. 
subcutaneous, intravenous, intramuscular or intraperitoneal injections), 
instillation, medicines for external application (e.g. preparations to be 
administered through nasal route, transdermally administrable preparations 
and ointments), emulsions, elixir, suspensions and solutions. These 
preparations can be formulated in accordance with per se known methods 
usually employed in the formulation process. In the present specification, 
the term "non-orally" includes subcutaneous injection, intravenous 
injection intramuscular injection, intraperitoneal injection or 
instillation. 
Injectable preparations, for example, sterile injectable aqueous 
suspensions or oil suspensions can be prepared by known procedures in the 
relevant fields, using a suitable dispersant or wetting agent and 
suspending agent. The sterile injections may be in the state of, for 
example, a solution or a suspension, which is prepared with a non-toxic 
diluent administrable non-orally, e.g. an aqueous solution, or with a 
solvent employable for sterile injection. Examples of usable vehicles or 
acceptable solvents include water, Ringer's solution and an isotonic 
aqueous saline solution. Further, a sterile non-volatile oil can usually 
be employed as solvent or suspending agent. 
Any non-volatile oil and a fatty acid can be used for this purpose, which 
include natural or synthetic or semi-synthetic fatty oil or fatty acid, 
and natural or synthetic or semi-synthetic mono- or di- or tri-glycerides. 
Furthermore, additives including a preservative, an isotonizer, a 
solubilizer, a stabilizer and a pain-soothing agent may adequately be 
employed. 
Rectal suppositories can be prepared by mixing the drug with a suitable 
non-irritable vehicle, for example, cocoa butter and polyethylene glycols, 
which are in the solid state at ordinary temperatures, but, in the liquid 
state at temperatures in intestinal tubes and melt in rectum to release 
the drug. 
As a solid formulation for oral administration, mention is made of powdery 
preparations, granules, tablets, pills and capsules as referred to in the 
above. In such formulations as exemplified above, the active components 
can be mixed with at least one additive, for example, sucrose, lactose, 
cellulose sugar, mannitol, maltitol, dextran, starch, agar, alginates, 
chitins, chitosans, pectins, tragacanth gum, gum arabic, gelatins, 
collagens, casein, albumin, synthetic or semi-synthetic polymers or 
glycerides. These formulations can contain, as in conventional cases, 
further additives, for example, an inactive diluent, a lubricant such as 
magnesium stearate, a preservative such as parabens and sorbic acid, an 
anti-oxidant such as ascorbic acid, .alpha.-tocopherol or cysteine, an 
excipient, a disintegrator, a binder, a thickening agent, a buffer, a 
sweetener, a flavoring agent, a perfuming agent and a coating agent. 
Tablets and pills can further be prepared with enteric coating. Examples 
of liquid preparations for oral administration include pharmaceutically 
acceptable emulsions, syrups, elixirs, suspensions and solutions, which 
may contain an inactive diluent, for example, water, which is 
conventionally employed in the relevant field. 
A formulation used for the pharmaceutical composition of this invention 
preferably comprises, as an effective component, about 0.6 to 39 weight % 
(more preferably about 0.7 to 27 weight %) of a compound having 
angiotensin II antagonistic activity or a salt thereof, about 0.06 to 35 
weight % (more preferably about 0.6 to 23 weight %) of a compound having 
the activity of increasing insulin-sensitivity or a salt thereof, 
about 0.06 to 0.39 weight % (more preferably about 0.06 to 0.24 weight %) 
of a compound having the activity of improving postprandial hyperglycemia 
in diabetes mellitus or a salt thereof, 
about 3 to 46 weight % (more preferably about 3 to 23 weight %) of an 
indane derivative having the activity of inhibiting angiotensin converting 
enzyme or a salt thereof and/or 
about 0.006 to 0.77 weight % (more preferably about 0.006 to 0.39 weight %) 
of a pyridine derivative having the activity of inhibiting HMG-Co A 
reductase or salt thereof. 
This formulation may be prepared by formulating two or more components 
individually or simultaneously. 
The pharmaceutical composition of this invention is less toxic, which is 
safely used for animals, especially mammals (e.g. man, dog, rabbit, rat, 
mouse, etc.) and can be used advantageously for prophylaxis or therapy of 
angiotensin II-mediated diseases. 
The dose of the pharmaceutical composition of this invention is determined 
in accordance with the dose of individual drugs, and can be selected 
dependent on the age, body weight, symptom, dose interval, administration 
routes, type of the formulation, and combination of drugs. 
The dose to be administered to a specific patient is dependent on the age, 
body weight, general health conditions, sex, diet, dose interval, 
administration routes, excretion rate, combination of drugs and conditions 
of the diseases then treated, while taking the minimal recommendable 
clinical dose or these and other necessary factors into consideration. 
Typical daily doses of the compositions having various combinations of an 
angiotensin II antagonistic compound or a salt thereof with at least one 
species of a compound having the activity of increasing 
insulin-sensitivity, a compound having the activity of improving 
postprandial hyperglycemia in diabetes mellitus, an indane derivative 
having the activity of inhibiting angiotensin converting enzyme, a 
pyridine derivative having the activity of inhibiting HMG-Co A reductase 
and salts thereof are within the range of from about 1/50 of the minimal 
recommendable clinical dose to maximal recommendable dose (preferably 
minimum recommendable dose, more preferably about 1/2 of minimum 
recommendable dose) in the case of practical administration of these 
compounds individually. 
For example, in case of the treatment of arteriosclerosis in human adult 
(body weight: about 60 kg), (.+-.)-1-(cyclohexyloxycarbonyloxy)ethyl 
2-ethoxy-[[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl]-1H-benzimidazole-7-c 
arboxylate in a dose ranging from about 1 to 50 mg/patient/day (preferably 
from about 1 to 35 mg/patient/day) can be effectively combined with, for 
example, 5-[4-[2-(5-ethyl-2-pyridyl)ethoxy]benzyl]-2,4-thiazolidindione in 
a dose ranging from about 0.1 to 30 mg/patient/day (preferably from about 
2 to 30 mg/patient/day) or N-(1,3-dihydroxy-2-propyl)valiolamine in a dose 
ranging from about 0.1 to 2 mg/patient/day. Needless to state, while these 
dosage ranges can be adjusted by a necessary unit base for dividing a 
daily dose, such doses are decided by taking into consideration the 
diseases to be treated, conditions of such diseases, the age, body weight, 
general health conditions, sex and diet of the patient then treated, dose 
internals, administration routes, excretion rate, combinations of drugs or 
any other necessary factors into consideration. In the prophylactic or 
therapeutic agents of this invention, the unit dose is administered once 
or twice daily (preferably once). 
In case of the prevention or treatment of arteriosclerosis of human adult 
(body weight: about 60 kg), preferred embodiments of the above-mentioned 
preferred combinations (1) to (3) are shown below: 
(1) A tablet comprising about 1 to 50 mg (preferably about 1 to 35 mg) of 
(.+-.)-1-(cyclohexyloxycarbonyloxy)ethyl 
2-ethoxy-1-[[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl]-1H-benzimidazole-7 
-carboxylate is orally administered to one and same subject in the form of 
combination use with a tablet comprising about 0.1 to 45 mg (preferably 
about 2 to 30 mg) of 
5-[4-[2-(5-ethyl-2-pyridyl)ethoxy]benzyl]-2,4-thiazolidinedione, a tablet 
comprising about 1 to 20 mg (preferably about 1 to 15 mg) of 
(R)-(+)-5-[3-[4-[2-(2-furyl)-5-methyl-4-oxazolylmethoxy]-3-methoxyphenyl]p 
ropyl]-2,4-oxazolidinedione, a tablet comprising about 0.1 to 0.5 mg 
(preferably about 0.1 to 0.3 mg) of N-(1,3-dihydroxy-2-propyl)valiolamine, 
a tablet comprising about 5 to 60 mg (preferably about 5 to 30 mg) of 
N-[N-[(S)-1-ethoxycarbonyl-3-phenylpropyl]-L-alanyl]-N-(indan-2-yl)glycine 
hydrochloride or a tablet comprising about 0.01 to 1 mg (preferably about 
0.01 to 0.5 mg) of 
(+)-3R,5S-erythro-(E)-7-[4-(4-fluorophenyl)-2,6-diisopropyl-5-methoxymethy 
lpyridin-3-yl]-3,5-dihydroxyhept-6-enoate sodium. Each tablet is preferably 
administered once a day and may be administered to one and same subject 
simultaneously or with time intervals of 12 hours or less (preferably 6 
hours or less). 
(2) A tablet comprising about 1 to 50 mg (preferably about 1 to 35 mg) of 
2-ethoxy-1-[[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl]-1H-benzimidazole-7 
-carboxylic acid is orally administered to one and same subject in the form 
of combination use with a tablet comprising about 0.1 to 45 mg (preferably 
about 2 to 30 mg) of 
5-[4-[2-(5-ethyl-2-pyridyl)ethoxy]benzyl]-2,4-thiazolidinedione, a tablet 
comprising about 1 to 20 mg (preferably about 1 to 15 mg) of 
(R)-(+)-5-[3-[4-[2-(2-furyl)-5-methyl-4-oxazolylmethoxy]-3-methoxyphenyl]- 
propyl]-2,4-oxazolidinedione, a tablet comprising about 0.1 to 0.5 mg 
(preferably about 0.1 to 0.3 mg) of N-(1,3-dihydroxy-2-propyl)valiolamine, 
a tablet comprising about 5 to 60 mg (preferably about 5 to 30 mg) of 
N-[N-[(S)-1-ethoxycarbonyl-3-phenylpropyl]-L-alanyl]-N-(indan-2-yl)glycine 
hydrochloride or a tablet comprising about 0.01 to 0.1 mg (preferably 
about 0.01 to 0.5 mg) of 
(+)-3R,5S-erythro-(E)-7-[4-(4-fluorophenyl)-2,6-diisopropyl-5-methoxymethy 
lpyridin-3-yl]-3,5-dihydroxyhept-6-enoate sodium. Each tablet is preferably 
administered once a day and may be administered to one and same subject 
simultaneously or with time intervals of 12 hours or less (preferably 6 
hours or less). 
(3) A tablet comprising about 1 to 50 mg (preferably about 1 to 35 mg) of 
2-ethoxy-1-[[2'-(2,5-dihydro-5-oxo-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]meth 
yl]-1H-benzimidazole-7-carboxylic acid is orally administered to one and 
same subject in the form of combination use with a tablet comprising about 
0.1 to 45 mg (preferably about 2 to 30 mg) of 
5-[4-[2-(5-ethyl-2-pyridyl)ethoxy]benzyl]-2,4-thiazolidinedione, a tablet 
comprising about 1 to 20 mg (preferably about 1 to 15 mg) of 
(R)-(+)-5-[3-[4-[2-(2-furyl)-5-methyl-4-oxazolylmethoxy]-3-methoxyphenyl]p 
ropyl]-2,4-oxazolidinedione, a tablet comprising about 0.1 to 0.5 mg 
(preferably about 0.1 to 0.3 mg) of N-(1,3-dihydroxy-2-propyl)valiolamine, 
a tablet comprising about 5 to 60 mg (preferably about 5 to 30 mg) of 
N-[N-[(S)-1-ethoxycarbonyl-3-phenylpropyl]-L-alanyl]-N-(indan-2-yl)glycine 
hydrochloride or a tablet comprising about 0.01 to 1 mg (preferably about 
0.01 to 0.5 mg) of 
(+)-3R,5S-erythro-(E)-7-[4-(4-fluorophenyl)-2,6-diisopropyl-5-methoxymethy 
lpyridin-3-yl]-3,5-dihydroxyhept-6-enate sodium. Each tablet is preferably 
administered once a day and may be administered to one and same subject 
simultaneously or with time intervals of 12 hours or less (preferably 6 
hours or less). 
BEST MODE FOR CARRYING OUT THE INVENTION 
By the following formulation examples, the present invention will be 
illustrated in more detail, and they should not be construed as limiting 
the invention thereto.