CZ235193A3 - Pharmaceutical preparation containing antagonist of angiotensin-ii receptor and calcium channels blocking compound - Google Patents

Abstract

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.

Description

A pharmaceutical composition comprising an angiotensin-II receptor antagonist and a calcium channel blocking compound

Technical field

The present invention relates to novel pharmaceutical compositions comprising angiotensin-II receptor antagonists selected from a particular class of substances in combination with calcium channel blockers selected from a particular class of substances. These preparations are suitable for the treatment of hypertension and congestive heart failure.

BACKGROUND OF THE INVENTION

The angiotensin-II receptor antagonist class and the calcium channel blocker class from which the compounds that form the essential components of the novel formulation of the invention are selected include those already known as antihypertensive agents.

Angiotensin-II receptor antagonists that are useful in the compositions of the invention are included among the compounds disclosed in European Patent Application No. 0 324 377. This citation is intended to replace the entire text of this specification.

Calcium channel blockers useful in the compositions of the invention are selected from the group consisting of:

diltiazem, nifedipine, nitrendipine, nimodipine, niludipine, niguldipine, nicardipine, nisoldipine, amlodipine, felodipine, isradipine, ryosidine, verapamil, gallopamil and tiapamil.

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SUMMARY OF THE INVENTION

The present invention provides a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of a combination of an angiotensin-II receptor antagonist of the formula:

R ⁴

R ¹ is CO ₂ H; NHSO ₂ CF ₃ or

R ² is hydrogen, C 1 -C 4 alkyl, halogen or C 1 -C 4 alkoxy;

R ³ is C 3 -C 7 alkyl, alkenyl or alkynyl;

R ⁴ is hydrogen, chlorine, bromine or iodine, C 1 -C 4 alkyl, ^c in ^F 2v + 1 'de; ^{v is} 1 to 3, or -C (= O) R ⁶ ;

R ⁶

R ⁷

R ⁸ is O

-CHCH-CHOR ⁸ ; - (CH ₂ ) _m CR 0;

AND

R ⁷

-CH ₂ NKCOR ⁹ ; - (CH ₂ ) _m NHSO ₂ R ⁹ ;

«I o

(CH ₂₎ m

- (CH ₂₎ ⁷ MOCR;

or

-CORO;

is hydrogen, C 1 -C 5 alkyl or OR ¹⁰ ;

is hydrogen or (C 1 -C 4) alkyl;

is hydrogen, (C1-C4) alkyl or (C1-C4) acyl;

R ⁹ is trifluoromethyl, C 1 -C 6 alkyl or phenyl;

R ¹⁰ is hydrogen, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, phenyl or benzyl; and m is from 1 to 5, or a pharmaceutically acceptable salt thereof, with a calcium channel blocking compound selected from diltiazem, nifedipine, nitrendipine, nimodipine, niludipine, niguldipine, nicardipine, nisoldipine, amlodipine, felodipine, isradipine, ryosidine, ryosidine, gallopamil and tiapamil.

Preferred angiotensin-II receptor antagonists in the compositions of the invention are those compounds of the above formula wherein R ¹ is a group of the formula

and R 7 'represents a hydrogen atom. Illustrative compounds falling within this preferred range include:

2-butyl-4-chloro-1 - [(2 '- (1H-tetrazol-5-yl) biphenyl-4-yl) methyl] -5- (hydroxymethyl) imidazole,

2-butyl-4-chloro-1 - [(2H-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; and

2-Propyl-4-chloro-1- [2 '- (1H-tetrazol-5-yl) biphenyl-4-yl) methyl] imidazole-5-carboxylic acid.

The potential antihypertensive effects of the combination of the compounds of this invention can be demonstrated by administering the combination of conscious drugs to spontaneously hypertensive rats. Rats receive either orally or intravenously a dose of 0.1 to 30 mg / kg of a desired calcium channel blocker or a dose of 0.1 to 30 mg / kg of a desired angiotensin-II receptor antagonist or a combination of both, i.e. a combination of a calcium channel blocker and a receptor antagonist. angiotensin-II. The arterial blood pressure is measured continuously using a catheter inserted into the carotid artery and recorded using a pressure gauge and a recording device. Post-treatment blood pressure values are compared to pre-treatment values.

The combination of the active compounds of the invention has unexpectedly proved to be useful in the treatment of hypertension. It also has a role in the management of acute and chronic congestive heart failure. Combinations of the invention are also expected to be useful in the treatment of secondary hyperaldosteronism, primary and secondary pulmonary hypertension, renal failure such as diabetic nephropathy, glomerulonephritis, scleroderma, glomerular sclerosis, proteinuria of primary renal disease, end stage renal disease, or kidney transplant states and the like , renal vascular hypertension, left ventricular dysfunction, diabetic retinopathy and in the management of vascular disorders such as migraine, Raynaud's disease, luminal hyperplasia, and minimizing the atherosclerosis process.

The combination of the present invention can be administered in the treatment of hypertension by any suitable means by contacting the active ingredients with the site of action in the body of a warm-blooded animal in need of such treatment. For example, administration may be parenteral, i.e., subcutaneous, intravenous, intramuscular, or intraperitoneal. Alternatively or concurrently, in some cases, oral administration may also be used. The combinations of the invention may be administered by any conventional means available for use in the pharmaceutical arts, either in the form of the combination itself or in the form of a combination that contains other therapeutically active ingredients. For example, a combination of the invention including an angiotensin-II antagonist and a calcium channel blocker may be combined with other antihypertensive agents and / or diuretics and / or angiotensin converting enzyme inhibitors such as amiloride, atenolol, bendroflumethiazide, chlorothalidone, chlorothiazide, clonidine, acetates and cryptenamine tannates, deserpidine, diazoxide, guanethidene sulphate, hydralazine hydrochloride, hydrochlorothiazide, metolazone, metoprolol tartrate, methylclothiazide, methyldopa, methyldadide hydrochloride, minoxidil, pargylin hydrochloride, polythiazide, prazosin, resolfin, propranoline, rupinoline, rupinoline, rupinoline, rupinoline, , timolol maleate, trichloromethiazide, trimethophan camsylate, benzthiazide, quinethazone, ticrynafan, triamterene, acetazolamide, aminophylline, cyclothiazide, ethacryniic acid, furosemide, merethoxylline procaine, sodium ethacrylate, enalaprililate, enalaprililate, capenalapril, fosinopril sodium, lisinopril, pentopril, quinapril hydrochloride, ramapril, teprotide, zofenopril calcium, diflusinal and the like.

Combinations of the active compounds of the invention may be administered alone, but are usually administered in conjunction with a pharmaceutically acceptable carrier selected according to the particular administration to be used in accordance with standard pharmaceutical practice.

For the purposes of this description, a warm-blooded animal is a member of an animal kingdom exhibiting a homeo static mechanism and including mammals and birds.

The pharmaceutical compositions of the invention may contain 10 to 300 mg of a desired calcium channel blocker and 1 to 100 mg of an angiotensin-II receptor antagonist in a unit dose to be administered once or more daily.

The active ingredient may be administered orally in the form of solid dosage forms, such as capsules, tablets and powders, or in the form of liquid dosage forms such as elixirs, syrups and suspensions. It can also be administered parenterally in the form of sterile liquid dosage forms.

Gelatin capsules contain the active ingredient and powdered carriers such as lactose, starch, cellulose derivatives, magnesium stearate, stearic acid, and the like. Similar diluents can also be used in the manufacture of compressed tablets. Both tablets and capsules can be formulated as delayed release forms to achieve continuous drug release over several hours. The compressed tablets may be provided with a sugar coating or film which serves to mask the unpleasant taste and protect the tablet from the atmosphere or to achieve selective disintegration in the gastrointestinal tract of the enteric coated tablets.

Liquid dosage forms for oral administration may contain coloring and flavoring agents to increase patient acceptance.

Suitable carriers for parenteral solutions are generally water, suitable oils, saline, aqueous dextrose: (glucose) and similar sugar solutions and glycols such as propylene glycol or polyethylene glycols.

Solutions for parenteral administration preferably comprise a water-soluble salt of the active ingredient, suitable stabilizing agents and, if desired, a suitable stabilizing agent. pH buffer. Suitable stabilizing agents are antioxidants, such as sodium bisulfite, sodium sulfite or ascorbic acid, which may be used alone or in the form of a mixture. Also used are citric acid and its salts and sodium ethylenediaminetetraacetic acid (EDTA). In addition, parenteral solutions may also contain preservatives such as benzalkonium chloride, methyl or propylparaben and chlorobutanol.

Suitable pharmaceutical carriers are described in Remington's Pharmaceutical Sciences, A. Osol, a standard reference in the art.

Suitable pharmaceutical dosage forms for administration of the compounds of this invention are illustrated below.

Capsule

A large number of unit capsules are prepared by filling standard two-piece hard gelatin capsules each with 100 mg of powdered active ingredients, 150 mg of lactose, 50 mg of cellulose and 6 mg of magnesium stearate.

Soft gelatin capsules

A mixture of the active ingredients and an edible oil such as soybean oil, cottonseed oil, olive oil or a combination thereof is prepared and injected into a gelatin using a positive displacement pump to form soft gelatin capsules containing 100 mg of active ingredients each. The capsules are washed and dried.

Tablets

A large number of tablets are prepared by conventional procedures such that the dosage unit contains 100 mg of active ingredients, 0.2 mg of colloidal silica, 5 mg of magnesium stearate, 275 mg of microcrystalline cellulose, 11 mg of starch and 98.8 mg of lactose. In order to increase ingestion acceptance or delay in absorption, the resulting tablets may be suitably coated.

Injectable preparation

A parenteral formulation suitable for injection is prepared by mixing 1.5% by weight of the active ingredient in 10% (v / v) propylene glycol in water. The solution is made up to volume with water for injection and then sterilized.

Suspension

An aqueous suspension is prepared for oral administration such that each 5 ml contains 100 mg of finely divided active ingredients, 100 mg of carboxymethylcellulose sodium, mg of sodium benzolate, 1.0 g of sorbitol solution according to U.S.P. and 0.025 ml vanillin.

Claims (5)

PATENT CLAIMS What is claimed is: 1. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of a combination of a compound which is an angiotensin-II receptor antagonist of the formula: wherein ad is ol is a group of formula CO ₂ H; NHSO ₂ CF ₃ or N — N <! \ / is hydrogen, C1-C4alkyl, halogen or C1-C4alkoxy; is C 3 -C 7 alkyl, alkenyl or alkynyl; R ⁴ is hydrogen, chlorine, bromine or iodine, C 1 -C 4 alkyl, ^C in ^F 2v + 1 ' ^{wherein v is} 1 to 3, or -C (= O) R ®; R 6 represents a group of the formula - (CH ₂ ) _m OR ⁷ ; - (CH2) MOCR ^7; -CH »CK-CHOR ^8; - (CH 2) _m CR ⁶ ; R ⁷ -CH ₂ NHCOR ⁹ ; - (CH ₂ ) _m NHSG ₂ R ⁹ ; 0 R ⁶ N-N // 7 AN or • ch / in H ^£ -COR; represents hydrogen, C sl to 5 carbon atoms or a group of the formula OR ^10; R ⁷ is hydrogen or (1-4C) alkyl carbon atoms; R ⁸ is hydrogen, (C1-C4) alkyl or (C1-C4) acyl; R ⁹ is trifluoromethyl, C1-C6 alkyl or phenyl; r1 ° is hydrogen, alkyl of 1 to 6 carbon atoms, cycloalkyl of 3 to 6 carbon atoms, phenyl or benzyl; and • m represents a number from 1 to 5 or a pharmaceutically acceptable salt thereof with a calcium channel blocking compound selected from the group consisting of diltiazem, nifedipine, nitrendipine, nimodipine, niludipine, niguldipine, nicardipine, nisoldipine, amlodipine, felodipine, felodipine, isradipine, ryosidine, verapamil, gallopamil, gallopamil, gallopamil, gallopamil, gallopamil, gallopamil. 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, 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; and 2-propyl-4-chloro-1- [2 '- (1H-tetrazol-5-yl) biphenyl-4-yl) methyl] imidazole-5-carboxylic acid. 3. A composition according to claim 2 wherein the calcium channel blocker is diltiazem. A composition according to 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. The composition of claim 3, wherein the angiotensin receptor antagonist II is 2-propyl-4-pentafluoroethyl-1-C (2 '- (1H-tetrazol-5-yl) biphenyl-4-yl) methyl] imidazole-5-carboxylic acid.