Europäisches Patentamt *EP001336407A1* (19) European Patent Office Office européen des brevets (11) EP 1 336 407 A1 (12) EUROPEAN PATENT APPLICATION published in accordance with Art. 158(3) EPC (43) Date of publication: (51) Int Cl.7: A61K 31/4178, A61K 31/54, 20.08.2003 Bulletin 2003/34 A61K 45/00, A61P 9/12 (21) Application number: 01982846.6 (86) International application number: PCT/JP01/10095 (22) Date of filing: 19.11.2001 (87) International publication number: WO 02/041890 (30.05.2002 Gazette 2002/22) (84) Designated Contracting States: (72) Inventors: AT BE CH CY DE DK ES FI FR GB GR IE IT LI LU • SADA, Toshio SANKYO COMPANY, LIMITED MC NL PT SE TR Shinagawa-ku, Tokyo 140-8710 (JP) • MIZUNO, Makoto SANKYO COMPANY, LIMITED (30) Priority: 21.11.2000 JP 2000354327 Shinagawa-ku, Tokyo 140-8710 (JP) 31.05.2001 JP 2001164009 (74) Representative: (71) Applicant: Sankyo Company, Limited Gibson, Christian John Robert et al Tokyo 103-8426 (JP) MARKS & CLERK, 57/60 Lincoln’s Inn Fields London WC2A 3LS (GB) (54) MEDICINAL COMPOSITIONS (57) [Constitution] EP 1 336 407 A1 Printed by Jouve, 75001 PARIS (FR) (Cont. next page) EP 1 336 407 A1 A pharmaceutical composition comprises an angiotensin II receptor antagonist selected from among compounds having the above general formula (I), pharmacologically acceptable salts thereof, pharmacologically acceptable esters thereof and pharmacologically acceptable salts of said esters, and one or more diuretics. [Effects] The pharmaceutical composition of present invention has an excellent hypotensive effect and low toxicity, and therefore is useful as a medicament for preventing or treating hypertension or heart diseases. 2 EP 1 336 407 A1 Description [Technical field] 5 [0001] The present invention relates to a pharmaceutical composition containing a specific angiotensin II receptor antagonist and one or more diuretics as the active ingredients (particularly a pharmaceutical composition for preventing or treating hypertension), the use of a specific angiotensin II receptor antagonist and one or more diuretics for manu- facturing the pharmaceutical composition (particularly a pharmaceutical composition for preventing or treating hyper- tension), and a method for preventing or treating (particularly treating) diseases (particularly hypertension) by the ad- 10 ministration of a pharmaceutical composition to warm-blooded animals (particularly humans) comprising effective dos- es of a specific angiotensin II receptor antagonist and one or more diuretics. [Background art] 15 [0002] It is known that co-administration of an angiotensin II receptor antagonist and a diuretic is an effective therapy for the prevention or treatment of hypertension (particularly treatment). These pharmaceutical compositions are de- scribed, for example, in WO89/6233, Japanese Patent Application Kokai No. Hei 3-27362 and the like. [0003] However, the effects of a pharmaceutical composition containing a specific angiotensin II receptor antagonist, such as CS-866, and a diuretic remain unknown. 20 [Disclosure of the invention] [0004] Considering that prevention and/or treatment of hypertension are important, the present inventors investigated combinations of various drugs and found that a pharmaceutical composition containing a specific angiotensin II receptor 25 antagonist, such as CS-866, and one or more diuretics exerts excellent anti-hypertensive effects and hence may be useful as a preventative and/or therapeutic agent for hypertension. [0005] The present invention provides a pharmaceutical composition containing a specific angiotensin II receptor antagonist and one or more diuretics as the active ingredients (particularly pharmaceutical compositions for preventing or treating hypertension), the use of a specific angiotensin II receptor antagonist and one or more diuretics for manu- 30 facturing the pharmaceutical compositions (particularly pharmaceutical compositions for preventing or treating hyper- tension), a method for preventing or treating (particularly treating) diseases (particularly hypertension) by the admin- istration of a specific angiotensin II receptor antagonist and one or more diuretics to warm-blooded animals (particularly humans) at effective doses, and a pharmaceutical composition for administering simultaneously or sequentially a spe- cific angiotensin II receptor antagonist and one or more diuretics for preventing or treating hypertension. 35 [0006] The active ingredients of the pharmaceutical composition of this invention include an angiotensin II acceptor antagonist selected from the group consisting of a compound having the following formula (I), pharmacologically ac- ceptable salts thereof, pharmacologically acceptable esters thereof and pharmacologically acceptable salts of said esters; and one or more diuretics. 40 45 50 55 3 EP 1 336 407 A1 5 10 15 20 25 [0007] The compound of formula (I), a salt thereof and the like are known compounds, for example, described in the specification of Japanese Patent Application Kokai No. Hei 5-78328 etc. and the chemical name of the compound of formula (I) is 4-(1-hydroxy-1-methylethyl)-2-propyl-1-[2'-(1H-tetrazol-5-yl)biphenyl-4-ylmethyl]imidazol-5-carboxylic acid. 30 [0008] The "pharmacologically acceptable salt" of the compound of formula (I), which is an active ingredient of this invention, includes an alkali metal salt such as sodium salt, potassium salt or lithium salt; an alkaline earth metal salt such as calcium salt or magnesium salt; a metal salt such as aluminum salt, iron salt, zinc salt, copper salt, nickel salt or cobalt salt; or an amine salt such as ammonium salt, t-octylamine salt, dibenzylamine salt, morpholine salt, glu- cosamine salt, phenylglycine alkyl ester salt, ethylenediamine salt, N-methylglucamine salt, guanidine salt, diethyl- 35 amine salt, triethylamine salt, dicyclohexylamine salt, N,N'-dibenzylethylenediamine salt, chloroprocaine salt, procaine salt, diethanolamine salt, N-benzylphenethylamine salt, piperazine salt, tetramethylammonium salt or tris(hydroxyme- thyl)aminomethane salt. An alkali metal salt is preferable and the sodium salt is particularly preferable. [0009] The "pharmacologically acceptable ester" of the compound of formula (I), which is an active ingredient of this invention, is a compound esterified at the carboxyl moiety of the compound of formula (I). A group forming said ester 40 is a group which can be cleaved by a biological process such as hydrolysis in vivo. Such groups include, for example, a(C1-C4)alkoxy-(C1-C4)alkyl group such as methoxymethyl, 1-ethoxyethyl, 1-methyl-1-methoxyethyl, 1-(isopropoxy) ethyl, 2-methoxyethyl, 2-ethoxyethyl, 1,1-dimethyl-1-methoxymethyl, ethoxymethyl, propoxymethyl, isopropoxymethyl, butoxymethyl or t-butoxymethyl; a (C1-C4)alkoxylated (C1-C4)alkoxy-(C1-C4)alkyl group such as 2-methoxyethoxyme- thyl; a (C6-C10)aryloxy-(C1-C4)alkyl group such as phenoxymethyl; a halogenated (C1-C4)alkoxy-(C1-C4)alkyl group 45 such as 2,2,2-trichloroethoxymethyl or bis(2-chloroethoxy)methyl; a (C1-C4)alkoxycarbonyl-(C1-C4)alkyl group such as methoxycarbonylmethyl; a cyano-(C1-C4)alkyl group such as cyanomethyl or 2-cyanoethyl; a (C1-C4)alkylthiomethyl group such as methylthiomethyl or ethylthiomethyl; a (C6-C10)arylthiomethyl such as phenylthiomethyl or naphthylth- iomethyl; a (C1-C4)alkylsulfonyl-(C1-C4) lower alkyl group, which may be optionally substituted with a halogen atom (s), such as 2-methanesulfonylethyl or 2-trifluoromethanesulfonylethyl; a (C6-C10)arylsulfonyl-(C1-C4)alkyl group such 50 as 2-benzenesulfonylethyl or 2-toluenesulfonylethyl; an aliphatic (C1-C7)acyloxy-(C1-C4)alkyl group such as formy- loxymethyl, acetoxymethyl, propionyloxymethyl, butyryloxymethyl, pivaloyloxymethyl, valeryloxymethyl, isovaleryl- oxymethyl, hexanoyloxymethyl, 1-formyloxyethyl, 1-acetoxyethyl, 1-propionyloxyethyl, 1-butyryloxyethyl, 1-pivaloy- loxyethyl, 1-valeryloxyethyl, 1-isovaleryloxyethyl, 1-hexanoyloxyethyl, 2-formyloxyethyl, 2-acetoxyethyl, 2-propiony- loxyethyl, 2-butyryloxyethyl, 2-pivaloyloxyethyl, 2-valeryloxyethyl, 2-isovaleryloxyethyl, 2-hexanoyloxyethyl, 1-formy- 55 loxypropyl, 1-acetoxypropyl, 1-propionyloxypropyl, 1-butyryloxypropyl, 1-pivaloyloxypropyl, 1-valeryloxypropyl, 1-iso- valeryloxypropyl, 1-hexanoyloxypropyl, 1-acetoxybutyl, 1-propionyloxybutyl, 1-butyryloxybutyl, 1-pivaloyloxybutyl, 1-acetoxypentyl, 1-propionyloxypentyl, 1-butyryloxypentyl, 1-pivaloyloxypentyl, or 1-pivaloyloxyhexyl; a (C5-C6)cy- cloalkylcarbonyloxy-(C1-C4)alkyl group such as cyclopentylcarbonyloxymethyl, cyclohexylcarbonyloxymethyl, 1-cy- 4 EP 1 336 407 A1 clopentylcarbonyloxyethyl, 1-cyclohexylcarbonyloxyethyl, 1-cyclopentylcarbonyloxypropyl, 1-cyclohexylcarbonyloxy- propyl, 1-cyclopentylcarbonyloxybutyl or 1-cyclohexylcarbonyloxybutyl; a (C6-C10)arylcarbonyloxy-(C1-C4)alkyl group such as benzoyloxymethyl; a (C1-C6)alkoxycarbonyloxy-(C1-C4)alkyl group such as methoxycarbonyloxymethyl, 1-(methoxycarbonyloxy)ethyl, 1-(methoxycarbonyloxy)propyl, 1-(methoxycarbonyloxy)butyl, 1-(methoxycarbonyloxy) 5 pentyl, 1-(methoxycarbonyloxy)hexyl, ethoxycarbonyloxymethyl, 1-(ethoxycarbonyloxy)ethyl, 1-(ethoxycarbonyloxy) propyl, 1-(ethoxycarbonyloxy)butyl, 1-(ethoxycarbonyloxy)pentyl, 1-(ethoxycarbonyloxy)hexyl, propoxycarbony- loxymethyl, 1-(propoxycarbonyloxy)ethyl, 1-(propoxycarbonyloxy)propyl, 1-(propoxycarbonyloxy)butyl, isopropoxycar- bonyloxymethyl,1-(isopropoxycarbonyloxy)ethyl,1-(isopropoxycarbonyloxy)butyl,butoxycarbonyloxymethyl,1-(butox- ycarbonyloxy)ethyl, 1-(butoxycarbonyloxy)propyl, 1-(butoxycarbonyloxy)butyl,