NOUVELLE COMPOSITION D'ANTAGONISTES DES RECEPTEURS DE L'ANGIOTENSINE II ET DE BLOQUEURS DES CANAUX CALCIQUES

NOVEL COMPOSITION OF ANGIOTENSIN-II RECEPTOR ANTAGONISTS AND CALCIUM CHANNEL BLOCKERS

Abrégé anglais

2103276 9220342 PCTABS00017
Novel pharmaceutical compositions containing a combination of an
angiotensin-II antagonist and a calcium channel blocker such as
2-butyl-4
chloro-1-[2-(1-H-tetrazol-5-yl)biphenyl-4-yl)methyl]-5-(hydroxymethyl)
imidazole, and diltiazem and the use of such compositions in the treatment of
hypertension and congestive heart failure.

Revendications

WO 92/20342 PCT/US92/03873
What is Claimed Is:
1. A pharmaceutical composition comprising a
pharmaceutically acceptable carrier and a
therapeutically effective amount of a combination
of an angiotensin-II receptor antagonist compound
of the formula:
<IMG>
wherein
R1 is CO2H; NHSO2CF3 and
<IMG>;
R2 is H, alkyl of 1 to 4 carbon atoms, halogen, or
alkoxy of 1 to 4 carbon atoms;
R3 is alkyl, alkenyl or alkynyl of 3 to 7 carbon
atoms;
R4 is H, Cl, Br, I; alkyl of 1 to 4 carbon atoms;
CVF2v+1, where v=1-3; or -?R6;

WO 92/20342 PCT/US92/03873
11
R5 is -(CH2)mOR7; -(CH2)mO?R7; <IMG>; -(CH2)m?R6;
-CH2NH?OR9; -(CH2)mNHSO2R9;
<IMG> ; or -COR6;
R6 is H, alkyl of 1 to 5 carbon atoms ox OR10;
R7 is H or alkyl of 1 to 4 carbon atoms;
R8 is H, alkyl of 1 to 4 carbon atoms, or acyl of 1 to
4 carbon atoms;
R9 is CF3, alkyl of 1 to 6 carbon atoms or phenyl;
R10 is H, alkyl of 1 to 6 carbon atoms, cycloalkyl of
3 to 6 carbon atoms, phenyl or benzyl;
m is 1 to 5
or a pharmaceutically acceptable salt thereof and a
calcium channel blocker compound selected from the group
consisting of: diltiazem, nifedipine, nitrendipine,
nimodipine, niludipine, niguldipine, nicardipine,
nisoldipine, amlodipine, felodipine, isradipine,
ryosidine, verapamil, gallopamil and tiapamil.
2. The composition of Claim 1 wherein the
angiotensin-II receptor antagonist is selected
from the group consisting of:
? 2-butyl-4-chloro-1-[(2'(1H-tetrazol-5-yl)biphenyl-
4-yl)methyl]-5-(hydroxymethyl)imidazole

WO 92/20342 PCT/US92/03873
12
? 2-butyl-4-chloro-1-[(2'-(1H-tetrazol-5-
yl)biphenyl-4-yl)methyl]imidazole-5-carboxylic
acid
? 2 propyl-4-trifluoromethyl-1-[(2'-(1H-tetrazol-5-
yl)biphenyl-4-yl)methyl]imidazole-5-carboxylic
acid
? 2 propyl-4-chloro-1-[2'-(1H-tetrazol-5-
yl)biphenyl-4-yl)methyl]imidazole-5-carboxaldehyde
? 2 propyl-4-ethyl-1-[(2'(1H-tetrazol-5-yl)biphenyl-
4-yl)methyl]imidazole-5-carboxylic acid
? 2 propyl-4-ethyl-1-[(2'-1H-tetrazol-5-yl)biphenyl-
4-yl)methyl]imidazole-5-carboxaldehyde
? 2-propyl-4-pentafluoroethyl-1-[(2'-(1H-tetrazol-5-
yl)biphenyl-4-yl)methyl]imidazole-5-carboxylic
acid
? 2-propyl-4-chloro-1-[2'-(1H-tetrazol-5-
yl)biphenyl-4-yl)methyl]imidazole-5-carboxylic
acid.
3. The composition of Claim 2 wherein the calcium
channel blocker is diltiazem.
4. The composition of Claim 3 wherein the
angiotensin-II receptor antagonist is 2-(butyl-4-
chloro-1-[2-(1H-tetrazol-5-yl)biphenyl-4-
yl)methyl]-5-(hydroxymethyl) imidazole.
5. The composition of Claim 3 wherein the
angiotensin-II receptor antagonist is 2-propyl-4-
pentafluoroethyl-1-[(2'-(1H-tetrazol-5-
yl)biphenyl-4-yl)methyl]imidazole-5-carboxylic
acid.

WO 92/20342 PCT/US92/03873
13
6. A method of treating hypertension which comprises
administering to a patient in need of such
treatment a therapeutically effective amount of a
composition of Claim 1.
7. The method of Claim 6 wherein the angtotensin-II
receptor antagonist is selected from the group
consisting of:
? 2-butyl-4-chloro-1-[(2'(1H-tetrazol-5-yl)biphenyl-
4-yl)methyl]-5-(hydroxymethyl)imidazole
? 2-butyl-4-chloro-1-[(2'-(1H-tetrazol-5-
yl)biphenyl-4-yl)methyl)imidazole-5-carboxylic
acid
? 2 propyl-4-trifluoromethyl-1-[(2'-(1H-tetrazol-5-
yl)biphenyl-4-yl)methyllimidazole-5-carboxylic
acid
? 2 propyl-4-chloro-1-[2'-(1H-tetrazol-5-
yl)biphenyl-4-yl)methyllimidazole-5-carboxaldehyde
? 2 propyl-4-ethyl-1-[(2'(1H-tetrazol-5-yl)biphenyl-
4-yl)methyl]imidazole-5-carboxylic acid
? 2 propyl-4-ethyl-1-[(2'-1H-tetrazol-5-yl)biphenyl-
4-yl)methyl]imidazole-5-carboxaldehyd
? 2-propyl-4-pentafluoroethyl-1-[(2'-(1H-tetrazol-5-
yl)biphenyl-4-yl)methyl]imidazole-5-carboxylic
acid
? 2-propyl-4-chloro-1-[2'-(1H-tetrazol-5-
yl)biphenyl-4-yl)methyl)imidazole-5-carboxylic
acid.
8. The method of Claim 6 wherein the calcium channel
blocker is diltiazem.

WO 92/20342 PCT/US92/03873
14
9. The method of Claim 8 wherein the angiotensin
receptor antagonist is 2-butyl-4-chloro-1-[2-(1H-
tetrazol-5-yl)biphenyl-4-yl)methyl]-5-
(hydroxymethyl)imidazole.
10. The method of Claim 8 wherein the angiotensin
receptor antagonist is 2-propyl-4-
pentafluoroethyl-1-[(2'-(1H-tetrazol-5
yl)biphenyl-4-yl)methyl]imidazole-5-carboxylic
acid.

Description

WO 92/20342 2 1 0 3 2 7 ~ PCI /~JS92/03873
NOVEL COMPOSITION OF ANGIOTENSIN-II RECEPTOR
ANTAGONISTS AND CALCIUM CHANNEL BLOCKERS
S Summa~y of th~ Invent~n
This invention relates to novel pharmaceutical
compositions containing an angiotensin-II receptor-
antagonist from a selected class in combination with a
calcium channel blocker from a selec~ed class useful for
the treatment of hypertension and for the treatment of
congestive heart failure.
,"~
The selected class of angiotensin-II receptor
antagonists and the selected class of calcium channel
blockers essential as compone~t parts of the novel
compositions of this invention are compounds already
known in the art as antihypertensive agents.
Angiotensin-II receptor antagonists useful in
compositions of the invention are included in those
compounds disclosed in publi~hed European Published
application 0 324 377 the disclosure of which is
incorporated herein by reference.
Calcium channel blockers useful in the compositions
of this invention are selected from the group consisting
of diltiazem, nifedipine, nitrendipine, nimodipine,
niludipine, niguldipine, nicardipine, nisoldipine,
amlodipine, felod~pine, isradipine, ryosidine,
verapamil, gallopamil and tiapamil.
30 1 ~
e~a~ es~ iQn of the InventLQn
The novel compositions of this invention contain ~`
calcium channel blocker of the group defined above in -
SIJBSTITUTE SHEET

W092/20342 PCT/US92/03873
2 7 S 2
combination with an angiotensin-II receptor antagonist
compound of the following formula:
R4
~Rs
R3
~q
~--R2
R1
wherein
R1 is CO2H; NHSO2CF3 and
N - N
/~N~
R2 is H, alkyl of 1 to 4 carbon atoms, halogen, or
alkoxy of 1 to 9 carbon atoms;
R3 is alkyl, alkenyl or alkynyl of 3 to 7 carbon
atoms;
R4 is H, Cl, Br, I; alkyl of 1 to 4 carbon atoms;
O
CVF2v~l, where v=1-3; or -CR6;
O O
R5 is -(CH2)moR7; -~CH2)moCR7; -CH=CH-CHOR8; ~(CH~)mCR6;
R7
SUBSTIT13TE SHEET

WO 92/2Q342 PCI/lJS92/03B73
2i~327~
-CH2NHCOR9, - ( CH2 ) mNHso2R9;
O
N -N
-CH2/~N
H ; or -COR~;
R6 is H, alkyl o~ 1 to 5 carbon atoms or OR10;
R7 is H or alkyl of 1 to 4 carbon atoms;
R8 i5 Hr alkyl of 1 to 4 carbon atoms, or acyl of 1 to
4 carbon atoms;
R9 is CF3, alkyl of 1 to 6 carbon atoms or phenyl;
~~ Rl0 is H, alkyl of 1 to 6 carbon atoms, cycloalkyl of
3 to 6 carbon atoms, phenyl or benzyl;
m is 1 to 5
or a phar~aceutically acceptable salt thereof.
Preferred compounds of the above formula are those
in which R1 is
N - N
N~
H
and R2 is H. Illustrati~e compound of this preferred
scope are:
2-butyl-4-chloro-1-[(2'~(lH-tetrazol-5-yl3biphenyl-
4-yl)methyl]-5-~hydroxymethyl)imidazole
?5 1 - 2-butyl-4-chloro-1-[(2'-tlH-tetrazol-5- j
yl)biphenyl-4-~yl)methyl]imidazole-5-carboxylic
acid
SUE~ST~TUTE SHEET

W092/20~2 PCT/US92/03873
~1~327~ 4
2 propyl-9-trifluoromethyl-1-[(2'-(lH-tetrazol-5-
yl)biphenyl-4-yl~methylJimidazole-5-carboxylic
acld
2 propyl-4-chloro-1-[2'-~lH-tetrazol-5-
yl)biphenyl-4-yl~methyl]imidazole-5-carboxaldehyde
2 propyl-4-ethyl-1-[(2'~lH-tetrazol-5-yl)biphenyl-
4-yl)methyl]imidazole-5-carboxylic acid
2 propyl-4-ethyl-1-[(2'-lH-tetrazol-5-yl)biphenyl-
4-yl)methyl~imidazole 5-carboxaldehyde
10 2-propyl-4-pentafluoroethyl~ 2'-~lH-tetrazol-5-
yl)biphenyl-4-yl)methyl~imidazole-5-carboxylic
acid
2-propyl-4-chloro-1-[2'-~lH-tetrazol-5-
yl)biphenyl-4-yl)methyl]imidazole-5-carboxylic
acid.
The potential antihypertensive effects of the
combination of compounds of this invention may be
demonstrated by admini~tering the combination of active
compounds to conscious spontaneously hypertensive rats.
Rats received either orally or ~ntrav~nously a dose of
0.1-30 mg/kg of the desired calcium channel blocker, or
a dose of 0.1-30 mg/kg of the desired angioten~in-II
receptor antagonist, or a combination of the two doses
of the calcium channel blocker and the angiotensin-II
receptor antagonist. Arterial blood pressure is
continuously measured directly through a carotid artery
catheter and rec~rded using a pressure transducer and a
, polygraph. Blood pressure level~ after treatment are
compared to pretreatme~t levels.
The combination of active compounds of this
in~ention are unexpectedly useful in treating
hypertension. They are also of value in the management
SUBSTITUTE SHEEr
.

W092/20~2 PC~US92/~3873
21 ~327~
.
of acute and chronic congestive heart failure. These
combinations also be expected to be useful in the
treatment of secondary hyperaldosteronism, primary and
secondary pulmonary hyperaldosteronism, primary and
secondary pulmonary hypertension, renal failure such as
diabetic nephropathyr glomerulonephritis, scleroderma,
glomerular sclerosis, proteinuria of primary renal
disease, end stage renal disease, renal transplant
therapy, and the like, renal vascular hypertension, left
ventricular dysfunction, diabetic retinopathy and in the
management of vascular disorders such as migraine,
Raynaud's disease, lumi~al hyperplasia, and to minimize
the atherosclerotic process.
The combinations of this invention can be
administered for the treatmen~ of hypertension according -
to the invention by any means that effects contact of
the active ingredient compounds with the site of action
in the body of a warm-blooded animal in need of such
treatment. For example, administration can be
parenteral, i.e., subcutaneous, intravenous,
intramuscular, or in~ra peritoneal. Alternatively, or
concurrently, in some cases administration can be by the
oral route.
The combinations of co~pounds can be administered
by any conventional means available for use in
con~unction with pharmaceuticals, either as individual
therapeutic agents or in a combination with additional
therapeutic agents. For example the combination of this
I invention of an angiotensin-II antagonist and calciym
channel blocker can be combined with other
antihypertensives and/or diuretics and/or angiotensin
converting enzyme inhibitors such as amiloride,
atenolol, bendroflumethiazide, chlorothalidone,
SUBSTITUTE SHEET

W092~20~2 PCT/US92/03873
21 i3~27~ i
chlorothiazide~ clonidine, cryptenamine acetates and
cryptenamine tannates, deserpidine, diazoxide,
guanethidene sulfate, hydralazine hydrochloride,
hydrochlorothiazide, metolazone, metoprolol tartate,
methyclothiazide, methyldopa, methyldopate
hydrochloride, minoxidil, pargyline hydrochlor~de,
polythiazide, prazosin, propranolol, ~L~Qlfia
~er~entina, rescinnamine, reserpine, sodium
nitroprusside, spironolactone, timolol maleate,
trichlormethiazide, trimethophan camsylate,
benzthiazide, quinethazone, tiorynafan, triamterene,
~_. acetazolamide, aminophyll~ne, cyclothiazide, ethacrynic
acid, furosemide! merethoxylline procaine, sodium
ethacrynate, captopril, delapril hydrochloride,
enalapril, enalaprilat, fosinopril sodium, lisinopril,
pentopril, quinapril hydrochloride, ramapril, teprotide,
zofenopril calcium, diflusinal and the l~ke.
The combinations of active oompounds can be
administered alone, but are generally administered with
a pharmaceutical carrier selected on the basis of the
chosen route of administration and standard
pharmaceutical practice.
For the purpose of this disclosurer a warm-blooded
animal is a member of the animal kingdom possessed of a
homeostatic mechanism and includes mammals and birds.
Pharmaceutical compositions of the invention may
contain from 10 to 30Q mg of the desired calcium channel
blocker and 1 to lO0 mg of the angiotensin-II receptor
I antagonist per unit dose one or more times daily.
The active ingredients can be administered orally :
in solid dosage forms, such as capsules, tablets, and
powders, or in l~quid dosage forms, such as elixirs
SUBSTITUTE SHEET

W092~20342 PCT/US~2~03873
21~327~
syrups, and suspensions. They can also be administered
parenterally, in sterile liquid dosag~ forms.
Gelatin capsules contain the active ingredients and
powdered carriers, such as lactose, starch, cellulose
derivatives, magnesium stearate, stearic acid, and the
like. Similar diluents can be used to make compres3ed
tablets. Both tablets and capsules can be manufactured
as sustained release products to provide for continuous
release of medication over a period of hours.
Compressed tablets can be sugar coated or film coated to
mask any unplea~ant taste and protect the tablet from
. the atmosphere, or enteric coated for selective
disintegration in the gastrointestinal tract.
Liquid dosage forms for oral administration can
contain coloring and flavoring to increase patient
acceptance.
In general, water, a suitable oil, saline, aqueous
dextrose (glucose), and related sugar solutions and
glycols such as propylene glycol or polyethylene glycols
are suitable carriers for parenteral solutions.
Solutions for parenteral administration preferably
contain a water soluble salt of the active ingredient,
suitable stabilizing agents, and if necessary, buffer
substances. Antioxidizing agents such as sodium
bisulfite, sodium sulfite, or ascorbic acid, either
alone or combined, are suitable stabilizing agents.
Also used are citric acid and its salts and sodium EDTA.
In addition, parenteral solutions can contain
, preservatives, such as benzàlkonium chloride, methyl- or
propylparaben, and~chlorobutanol.
Suitable pharmaceutical carriers are described in
~ , A. Osol, a standard
reference text in this field.
SUBSTITUTE SHEET

W092/20~2 PCT/US92/03B73
~1~327~ ~
Useful pharmaceutical dosage-forms for
administration of the compounds of this invention can be
illustrated as fQllOWS:
~ ~Ls~l~a
A large number of unit capsules are prepared by
filling standard two-piece hard gelatin capsules each as
with 100 milligrams of powdered active ingredients, 150
milligrams of lactose, 50 milligrams of cellulosers~lnd 6
milligrams magnesium stearate.
A mixture of active ingredients in a digestible oil
such as soybean oil, cottonseed oil or olive oil is
combinations prepared and injected by means of a
positive displacement pump into gelatin to form soft
gelatin capsules containing 100 milligrams of the active
ingred~ents. The capsules are washed and dried.
~ Y~a
A large number of tablets are prepared by
conventional procedures so that the dosage unit is 100
milligrams of active ingredients, 0.2 milligrams of
colloidal silicon dioxide, 5 milligrams of magnesium
stearate, 275 milligrams of microcrystalline cellulose,
11 milligrams of starch and 98.8 milligrams of lactose.
Appropriate coatings may be applied to increase
palatability or delay absorption.
;
Tniecta~le
A parenteral composition suitable for
administration by injection is prepared by stirring 1.5%
by weight of active ingredients in 10% by volume
SUBSTITUTE SHEET

W092/20342 PCT/US~2/03873
~ 1 ~ 3 2 7 fi
propylene glycol. The solution is made to volume with
water for injection and sterilized.
~a~
An aqueous suspension is prepared for oral
administration so that each 5 milliliters con~ain 100
milligrams of finely divided active ingredients, 100
milligrams of sodium carboxymethyl cellulose, 5
milligrams of sodium benzoate, 1.0 grams of sorbltol
solution, U.S.P~, and 0.025 milliliters of vanill~n.
SUBSTITUTE SHEET