ITMI940296A1 - DIAZOTATED HETEROCYCLIC DERIVATIVES WITH ACTIVITIES TO THE ANTAGONIST - Google Patents

Description

"DIAZOTATED HETEROCYCLIC DERIVATIVES HAVING ANTAGONIST ACTIVITIES

The present invention relates to imidazole derivatives with antagonist activity, a process for their preparation and pharmaceutical compositions containing them as active ingredients.

In particular, the invention relates to compounds of formula I

where R is C1-C5 alkyl or a C2-C5 alkenyl group;

3⁄4 is a COOR3, CN, -SO3H group or a tetrazole group of formula Ila or Ilb

N N

(THE

R2 is a pyrazine, pyrimidine or pyridazine ring optionally substituted by one or more 3⁄4-C5 alkyl groups, carboxy or C-j-Cg alkoxycarbonyl groups or their N-oxides;

R3 is hydrogen, C ^ -Cg alkyl or benzyl;

R4 is hydrogen, C 2 -Cg alkyl or triphenylmethyl and their salts with pharmaceutically acceptable acids or bases.

The term C1-C5 alkyl includes linear, branched or cyclic alkyl groups. Examples of such groups include methyl, ethyl, n-propyl, cyclopropyl, n-butyl, isobutyl, terbutyl, n-pentyl, isoamyl, cyclopentyl.

Examples of C2-C5 alkenyl groups are vinyl, allyl, isoprenyl, 2-butenyl, 3-pentenyl.

Examples of 3⁄4-C5 alkoxycarbonyl bonds include methoxycarbonyl, ethoxycarbonyl.

In the compounds of formula I R is preferably a C ^ -Cs alkyl group; Rj is preferably a tetrazole group of formula IIa or IIb wherein R4 is as defined above and preferably hydrogen; R2 is a 2-pyrimidinyl ring; 5-pyrimidinyl; 2-methyl-4-methoxycarbonyl-5-pyrimidinyl; 1-oxide-5-pyrimidinyl; 1-oxide-2-pyrimidinyl; 2-pyrazinyl; 2-pyrazinyl-4-oxide; 3-methoxycarbonyl-2-pyrazinyl; 3,6-dimethyl-2-pyrazinyl; 3-pyridazinyl; 3-methyl-6-pyridazinyl; 6-methoxycarbonyl-3-pyridazinyl; 2-oxide-3-methyl-6-pyridazinyl; 1-oxide-3-methyl-6-pyridazinyl, 1-oxide-3,6-dimethyl-2-pyrazinyl and 4-oxide-3,6-dimethyl-2-pyrazinyl.

The compounds of formula I are endowed with antagonistic activity of angiotensin II (All) and are therefore useful in the pharmacological treatment of cardio-vascular diseases such as hypertension, heart failure, intraocular hypertension, glaucoma, hyperaldosteronism, renal pathologies, myocardial infarction.

All antagonist activity compounds characterized by a completely substituted imidazole nucleus have been described in EP 253310, EP 324377, WO 91/00277, WO 91/00281, WO91 / 14367, WO 91/15206 and HO 92/00977.

The compounds of formula I are instead characterized by a 2,4-disubstituted imidazole group in which the substituent in position 4 is a 6-membered diazotated heterocyclic ring (pyrimidinyl, pyrazinyl or pyridazinyl) and by advantageous pharmaco-toxicological characteristics.

The compounds of formula I are prepared by reaction of a compound of formula III

CH X

where 3⁄4 has the same meanings as 3⁄4 or is a group convertible into 3⁄4 for the removal of protective bonds and X is an outgoing group such as halogen, mesyloxy, acetyloxy

with a compost of formula IV

where R and R2 are en defined above and M is H, acetyl, p-methoxybenzyl, trityl.

The alkylation reaction can be carried out by forming the imidazole IV salt, in which M is equal to H in an aprotic dipolar solvent such as IMF or DMSO by treatment with alkali and alkaline earth metal hydrides (Na, K, Ca) or alternatively by operating in lower alcohols (MeOH, EtOH, t-BuOH) in the presence of the corresponding Na or K alcoholate at temperatures between 20 “C and 100“ C.

The compounds of formula III can be prepared as reported in Carini et al., J. Med. Chem. 34, 2525, 1991 while the compounds of formula IV can be prepared by reacting imidazoles V, in turn prepared as described in R.M. Keenan et al., J. Med. Chem., 35, 3858 {1992)

No.

where R is as defined above, Y is ZnCl, BugSn, MegSn, B (C4I) 2 and Z is a protective group, with the appropriate halogen-pyrimidines, pyridazines or pyrazines. The reaction is carried out in a solvent, such as dioxane, at its reflux temperature, in the presence of transition metal complexes as catalysts, such as palladium complexes, for example palladium, tetrakistriphenylphosphine, platinum, nickel (as described for example by M. Peyreyre et al., Tin in organic synthesis, ButterWorks, London, 1987; R.F. Heck, Palladium reagente in organic chemistry, Academic Press, Orlando, Florida, 1985).

The heteroaryl imidazole compounds (IV), subjected to acid hydrolysis (both with methanolic HCl and aqueous HCl), in order to eliminate the protective group Z, are subsequently transformed into the corresponding sodium salts by reaction with hydrides of alkaline and alkaline earth metals (Na , K, Ca) in aprotic polar solvents (e.g., DMF, DMSO), then they are reacted with the derivative bromomethyl diphenyl tetrazole (III).

Compounds of formula (I), where R4 is different from hydrogen, finally provide the corresponding compounds (I) where R4 is hydrogen by heating in methanol with or without acid catalysis.

The compounds (I), where Rj is a corresponding N-oxide, can be prepared by oxidation with conventional reagents and subsequent deprotection, again by heating with methanol.

Conventional oxidation reagents are organic or inorganic peracids. Hydrogen peroxide in a 20-30% aqueous solution can be used in the presence of variable quantities of glacial acetic acid, and yet perbenzoic or m-chloroperbenzoic acid in solvents which are preferably dichloromethane or chloroform with temperatures ranging between 0 "C and 60'C and preferably between 0 ° C and 30 ° C.

The compounds described in the present invention act as antagollists at the A II receptor level. In vitro tests (such as inhibition of contraction induced by A II in rabbit aorta and displacement of ^ ■ 25I-Sarl_j ^ e8_AT JJ in rat adrenal cortex) were chosen for the characterization and evaluation of their efficacy. an in vivo test (inhibition of the pressure response induced by A II in the nonnotensive ganglion block rat). The compounds of the invention proved to be active in the above tests; for example, in the in vitro test of the rabbit aorta, several compounds showed pA2 values higher than 6.5, while in the receptor binding they showed a Ki <1 μΜ.

The compounds of general formula I or their pharmaceutically acceptable salts can be used in pharmaceutical preparations, alone or in admixture with pharmaceutically acceptable excipients, for oral or parenteral administration. Suitable excipients are, for example, starch, lactose, glucose, gum arabic, stearic acid and so on. Pharmaceutical preparations can be in solid form such as tablets, capsules or suppositories or in liquid form as solutions, suspensions or emulsions.

Furthermore, when administered parenterally, pharmaceutical preparations can be in the form of sterile solutions.

The compounds of general formula I can be administered in unitary doses ranging from 1 to 100 mg to patients suffering from cardiac and vascular pathologies such as hypertension, acute and chronic heart failure, intraocular hypertension. However, it is also expected to be used in other pathologies such as secondary aldosteronism, pulmonary hypertension, kidney diseases (glomerulonephritis, diabetic nephropathy) or vascular disorders (migraine, Raynoud's disease).

The following examples further illustrate the invention.

Example 1

6-TOethyl-3-r2-hjtil-rr2-trimethylsilyl ethoxy] methylimidazol-5-yl1pyridazine

A mixture of 2-butyl-1 - [[2- (trimethylsilyl) eto6si] methyl] -5- (tributylstannil) imidazole (6.4 g, 11.86 mmol) dog preparation described in R.M. Keenan et al., J. Med.Chem., 35, 3858 (1992), 3-chloro-6-methylpyridazine (1.52 g, 11.86 mmol), Pd (PPh3) 4 (0.68 g, 0.59 mmol), 2, 6-ditert-butyl-4-methylphenol (a tip of a spatula) in 130 ml of deaerated anhydrous dioxane was refluxed for 18 hours in an inert atmosphere.

The reaction mixture after being added with ethyl ether (180 ml) and 75 ml of a saturated aqueous solution of sodium fluoride was kept under stirring at room temperature for 20 hours, then it was filtered on a Celite panel and the filtrate was washed with saturated solution of NaCl (3 times), dried over MgS04 and evaporated under reduced pressure. The residue was purified by flash chromatography on silica gel (eluent acetone / CHCl3 = 2/8) giving 2.73 g of pure product (yield = 65%) in the form of liquid.

Similarly, the following were prepared:

2- [2-butyl-1 - [[2-trimethylsilyl] ethoxy] methyl] imidazol-5-yl] pyrimidine; 5- [2-butyl-1 - [[2-trimethylsilyl] ethoxy] methyl] imidazol-5-yl] pyrimidine; 2-methyl-4-ethoxycarbons 1-5- [2-butyl-1 - [[2-trimethylsilyl] ethoxy] methyl] imidazol-5-yl] pyrimidine;

2- [2-butyl-1-1 [2-trimethylsilyl] ethoxy] methyl] imidazol-5-yl] pyrazine;

3.6-dimethyl-2- [2-butyl-1 - [[2-trimethylsilyl] ethoxy] methyl] imidazol-5-ypirazine;

3-methoxycarbonyl-2- [2-butyl-1 - [[2-trimethylsily] ethoxy] methyl] imidazol-5-yl] pyrazine.

Example 2

6-methyl-3- [2-butylinridazol-5-yliniridazine

A solution of 6-methyl-3- [2-butyl-1 - [[2-trimethylsilyljetoxy] methyl] imidazol-5-yl] pyridazine (2.69 g, 7.76 ranols), 5N HCl (38 ml) was heated at 40-50 ° C for 3 hours, then it was alkalized with concentrated NaOH and repeatedly extracted with chloroform. The combined extracts were washed with a saturated solution of NaCl, dried over MgSO2 and evaporated under reduced pressure. The orange-colored resinous residue (1.66 g, quantitative yield) was used as such in the subsequent reaction.

Similarly, the following were prepared:

2- [2-butylimidazol-5-yl] pyrimidine;

5- [2-butylimidazol-5-yl] pyrimidine;

2-methyl-4-ethoxycarbonyl-5- [2-buti1imidazol-5-11] pyrimidine;

2- [2-butylimidazol-5-11] pyrazine;

3.6-dimethyl-2- [2-butylimidazol-5-yl] pyrazine;

3-methoxycarbonyl-2- [2-buti1imidazol-5-yl] pyrazine;

EXAMPLE 3

2-butyl-4- [6-methylpyridazin-3-in-1-rr2l-fl-triphenylmethyltetrazol-5-yl1biphenyl-4-ylmethyl1imidazole

NaH (93 mg, 3, 87 mmol) and the resulting suspension was kept under stirring at room temperature for 30 minutes, then a solution of N- (triphenylmethyl) -5- [4 '- (bromomethyl) biphenyl-2-yl] tetrazole 5 (2 , 16 g, 3.87 mmol) in DMF (35 ml).

The reaction mixture was kept under stirring always at room temperature for one night, then it was added with 180 ml of water and ice and repeatedly extracted with ethyl acetate. The combined organic extracts were washed with a saturated solution of NaCl, dried over MgSO 4 and evaporated under reduced pressure.

The residue was diluted with ethyl ether and after filtration 2.3 g of pure product were obtained in the form of an orange crystalline solid: m.p. = 163-166'C (Kofler).

Similarly, the following were prepared:

2-buti1-4- [pyrimidine-2-i1] -1 - [[2 '- [1-triphenylmethyltetrazol-5-yl] biphenyl-4-yl] methyl] imidazole;

2-butyl-4- [pyrimidine-5-yl] -1 - [[21- [1-triphenylmethyltetrazol-5-yl] biphenyl-4-yl] methyl] imidazole;

2-butyl-4- [2-methyl-4- (methoxycarbonyl) -pyrimidine-5-yl3-1 - [[21- [1-triphenylmethyltetrazol-5-i1] biphenyl-4-yl] methyl] imidazole;

2-butyl-4- [pyrazine-2-yl] -1 - [[2 '- [1-triphenylmethyltetrazol-5-yl] biphenyl-4-yl] methyl] imidazole;

2-butyl-4- [3,6-dimethylpyrazin-2-yl] -1 - [[21- [1-triphenylmethyltetrazol-5-yl] biphenyl-4-yl] methyl] imidazole;

2-but yl-4- [3- (methoxycarbonyl) pyrazine-2-yl] -1- [[21 - [1-triphenylroethyltetrazol-5-yl] biphenyl-4-yl] methyl] imidazole.

example 4

2-butyl-4-r6-methylpyridazine-3-yl-l-oxide1-l - [[21-ΓΙ-triphenylmethyltetrazol-5-inbiphenyl-4-inmethylpyridazole and 2-butyl-4-r6-methylpyridazin-3-yl- 2-oxidol-1-rΓ2 * -ΓΙ-triphenylmethyltetrazol-5-illbiphenyl-4-illmethylimidazole

To a solution cooled to 10 ° C, of 2-butyl-4- [6-methylpyridazin-3-yl] -1 - [[2f-11-triphenylmethyltetrazol-5-yl] biphenyl-4-yl] methyl] imidazole ( 1.35 g, 1.95 mmol) in 45 ml of CH2CI2 a solution of m-chloroperbenzoic acid (0.345 g, 2.0 mmol) in CH2CI2 was slowly dropped.The reaction mixture was kept under stirring at room temperature to 1 hour and then washed with a saturated aqueous solution of NaHC03 (2 x 75 ml) and with water. After drying on MgSO4 and evaporation under reduced pressure, the residue was purified by flash chromatography on silica gel (eluent mixture CHC ^ / acetone = 4/1) obtaining 430 mg (yield 31%) of 2-butyl-4- [6- methylpyridazin-3-yl-oxide] -1 - [[2 '[1-triphenylmethyltetrazol-5-yl] biphenyl-4-yl] methyl] imidazole and 370 mg (yield 27%) of 2-butyl-4- [6 -methylpyridazin-3-yl-2-oxide] -1 - [[2, - [1-triphenylmethyltetrazol-5-yl] biphenyl-4-yl] methyl] imidazole.

Similarly, the following were prepared:

2-butyl-4- [pyrimidine-2-yl-1-N-oxide] -1 - [[21- [1-triphenylmethyltetrazol-5-yl] biphenyl-4-yl] methyl] imidazole;

2-butyl-4- [pyrimidine-5-11-1-N-oxide] -1 - [[2 '- [1-triphenylmethyltetrazol-5-yl] biphenyl-4-yl] methyl] imidazole;

2-butyl-4- [pyrazine-2-yl-4-N-oxide] -1- [[2 '- [1-triphenylmethyltetrazol-S-yl] biphenyl-4-yl] methyl 3 imidazole;

2-butyl-4- [3,6-dimethylpyrazin-2-yl-1-N-oxide] -1- [[2 '- [1-tri-enylmethyltetrazol-5-yl] biphenyl-4-yl] methyl] imidazole;

2-butyl-4- [3,6-dimethylpyrazine-2-yl-4-N-oxide] -1 - [[2 '- [1-triphenylmethyltetrazol-5-yl] biphenyl-4-yl] methyl] imidazole;

2-butyl-4- [6-methylpyridazine-3-yl-1-oxide] -1 - [[21- [1-triphenylmethyltetrazol-5-yl] biphenyl-4-yl] methyl] imidazole;

2-butyl-4- [6-methylpyridazine-3-yl-2-oxide] -1 - [[2 '- [1-triphenylmethyltetrazol-5-yl] biphenyl-4-yl] methyl] imdazole.

example 5

2-butyl-4- [6-methylpyri n-3-ill-1-ΓΓ21-riH-tetrazol-5-yl] biphenyl-4-illmethylimidazole

A solution of 2-butyl-4- [6-methylpyridazin-3-yl] -l - [[2 '- [l-triphenylmethyltetrazol-5-yl] biphenyl-4-yl] methyl] imidazole (0.45 g, 0.65 limols) in 30 ml of methanol was refluxed for 16 hours, then it was evaporated to dryness and the residue was purified by flash chromatography on silica gel (eluent CHCI3 / CH3OH = 2/1) obtaining 160 mg of solid: m.p. = 196-199 "C (Kofler), ^ -H-NMR (CDCI3 + DMSO): 0.84 (t, 3H), 1.3 (sext, 2H), 1.60 (m, 2H), 2, 44 (s, 3H), 2.61 (t, 2H), 4.87 (s, 2H), 6.8 (d, 2H), 6.93 (d, 2H), 7.15-7.45 (m, 4H), 7.59 (s, 1H), 7.66 (d, 1H), 7.94 (d, 1H).

Similarly, the following were prepared:

2-butyl-4- [pyrimidine-2-yl] -1 - [[2 '- [1H-tetrazol-5-yl] biphenyl-4-yl] methyl] imidazole; white solid, m.p. = 141-144 * C,% -NMR {CDCI3): 0.87 (t, 3H), 1.35 (sext, 2H), 1.62 (quint, 2H), 2.50 (t, 2H), 5.00 (s, 2H), 6.85-7.05 (m, 5H), 7.28 (m, 1H), 7.49 (m, 3H), 7.92 (m, 1H), 8 , 40 (d, 1H);

2-butyl-4- [pyrimidine-5-yl] -1 - [[2, - [1H-tetrazol-5-yl] biphenyl-4-yl] raethyl] imidazole; solid straw yellow, m.p. = 117-118'C, ^ H-NMR (DMSO- <3⁄4): 0.84 (t, 3H), 1.31 (sext, 2H), 1.58 (quint, 2H), 2.65 (t, 2H), 5.25 (s, 2H), 7.13 (d app., 4H), 7.5-7.7 (m, 4H), 7.90 (s, 1H), 8, 98 (s, 1H), 9.09 (s, 2H);

2-butyl-4- [2-methyl-4- (methoxycarbonyl) -pyrimidin-5-yl] -1 - [[2 '[1H-tetrazol-5-yl] biphenyl-4-yl] methyl] imidazole; solid, m.p. = 125-126 "C, ^ H-NMR (DMSO-dg): 0.83 (t, 2H), 1.25 (sext, 2H), 1.55 (quint, 2H), 2.52 (t, 2H), 2.61 (s, 3H), 3.81 (s, 3H), 5.21 (s, 2H), 7.10 (s app., 4H), 7.5-7.71 (m , 5H), 9.11 (s, 1H);

2-but yl-4- [pyrazin-2-yl] -l- [[2 '- [1H-tetrazol-5-yl] biphenyl-4-yl] methyll] imidazole; solid ivory, m.p. = 117-120 * 0; 1⁄2-NMR (CDCI3 + DMSO): 0.92 (t, 3H), 1.40 (sext, 2H), 1.69 (quint, 2H), 2.70 (t, 2H), 5.13 (s, 2H), 7.1 (d app., 4H), 7.4-7.7 (m, 5H), 8.34 (d, 1H), 8.41 (d, 1H), 9, 1 (s, 1H); 2-butyl-4- [3,6-dimethylpyrazin-2-yl] —1 - [[21— [1H-tetrazol-5-11] biphenyl-4-yl] methyl] imidazole; light brown solid, m.p. = 118-121eC, 1⁄2-NMR (CDCI3): 0.85 (t, 3H), 1.31 (sext, 2H), 1.61 (quint, 2H), 2.36 (s, 3H), 2.55 (t, 2H), 2.66 (s, 3H), 5.04 (s, 2H), 6.86 (d, 2H), 6.95 (d, 2H), 7.24-7 , 55 (m, 4H), 7.73 (d, 1H), 8.07 (s, 1H);

2-butyl-4- [3- (methoxycarbonyl) pyrazine-2-yl] -1 - [[21- [1H-tetrazol-5-yl] biphenyl-4-yl] methyl] imidazole; solid, m.p. = 121-123'C, ^ H-NMR (DMSO-dg): 0.83 (t, 3H), 1.25 (sext, 2H), 1.51 (quint, 2H), 2.66 (t, 2H), 3.84 (s, 3H), 5.31 (s, 2H), 7.1-7.35 (m, 4H), 7.45-7.7 (m, 4H), 7.97 (s, 1H), 8.51 (d, 1H) 8.72 (d, 1H);

2-butyl-4- [pyrimidine-2-yl-1-N-oxide] -1- [[2 '- [1H-tetrazol-5-yl] biphenyl-4-yl] methyl] imidazole; solid ivory, m.p. = 237-243'C, 1⁄2-NMR (CDCI3): 0.90 (t, 3H), 1.38 (sext, 2H), 1.69 (quint, 2H), 2.69 {t, 2H ), 5.08 (s, 2H), 6.9-7.13 (m, 5H), 7.35-7.6 (m, 3H), 7.95 (m, 1H), 8.21 ( m, 1H), 8.40 (m, 2H);

2-butyl-4- [pyrimidine-5-yl-1-N-oxide] -1- [[2 '- [1H-tetrazol-5-yl] biphenyl-4-yl] raethyl] imidazole; solid straw yellow, m.p. = 112 ° C, 1⁄2-NMR (CD3OD): 0.90 (t, 3H), 1.38 (sext, 2H), 1.59 (quint, 2H), 2.70 (t, 2H), 5.25 (s, 2H), 7, 1-7, 7 (m, 8H), 7.80 (s, 1H), 8.78 (s, 1H), 8.89 (s, 2H); 2-butyl-4- [pyrazine-2-yl-4-N-oxide] -1- [[2 '- [1H-tetrazol-5-yl] biphenyl-4-yl] methyl] imidazole; ! H-NMR {CDCI3 + DMSO): 0.94 (t, 3H), 1.43 (sext, 2H), 1.72 (quint, 2H), 2.75 (t, 2H), 5.20 ( s, 2H), 7.05-7.5 (m, 9H), 8.4-8.5 (m, 2H), 9.4 (s, 1H).

2-but yl-4- [3,6-dimeth ylpyrazine-2-yl-1-N-oxide] - 1- [[21- [1H-tetrazol- 5-yl3biphenyl-4-yl] methyl] imidazole; solid pink, m.p. 109-113 * C, ^ H-NMR (CDCl ^): 0.95 (t, 3H), 1.44 (sext, 2H), 1.77 (quint, 2H), 2.43 (s, 3H) , 2.70 (t, 2H), 2.90 (s, 3H), 5.03 (s, 2H), 7.03 (s, app., 4H), 7.25-7.60 (m, 4H), 7.93 (m, 2H), 8.16 (s, 1H);

2-butyl-4- [3,6-dimethylpyrazine-2-yl-4-N-oxide] -1- [[2 '- [1H-tetrazol-5-yl] biphenyl-4-yl] methyl] imidazole ; solid pink, m.p. = 208-212eC, ^ H-NMR (CD3OD): 0.91 (t, 3H), 1.38 (sext, 2H), 1.69 (quint, 2H), 2.47 (s, 3H), 2 , 69 (t, 2H), 2.76 (s, 3H), 5.09 (s, 2H), 7.0 (d, 2H), 7.14 (d, 2H), 7.39-7, 65 (m, 6H), 7.98 (s, 1H);

2-butyl-4- [6-methylpyridazine-3-yl-1-oxide] -1- [[2 '- [1H-tetrazol-5-yl] biphenyl-4-yl] methyl] imidazole; crystalline solid, m.p. = 227-229'C, 3⁄4-NMR (CDCI3 + DMSO): 0.92 (t, 3H), 1.40 (sext, 2H), 1.70 (quint, 2H), 2.46 (s , 3H), 2.69 (t, 2H), 5.15 (s, 2H), 7.12 (s app., 4H), 7.48-7.68 (in, 7H); 2-butyl-4- [6-methylpyridazine-3-yl-2-oxide] -1- [[2 '- [1H-tetrazol-5-yl] biphenyl-4-yl] methyl] imidazole; ivory yellow crystalline solid, m.p. 133-135 * C, 1H-NMR (CDC13): 0.89 (t, 3H), 1.35 (sext, 2H), 1.65 (quint, 2H), 2.44 (s, 3H), 2 , 64 (t, 2H), 5.04 (s, 2H), 7.01 (m, 5H), 7.3-7.6 (m, 4H), 7.8 (d, 1H), 8, 15 (s, 1H), 8.48 (d, 1H).

Claims (8)

Claims 1. Compounds of general formula I where R is C1-C5 alkyl or a C2-C5 alkenyl group; 3⁄4 is a 00 * 3, CN, -SO3H group or a tetrazole group of formula Ila or Ilb (THE R2 is a pyrazine, pyrimidine or pyridazine ring optionally substituted by one or more 3⁄4-C5 alkyl groups, carboxy grains or C ^ -Cj alkoxycarbonyl groups or their N-oxides; R3 is hydrogen, 3⁄4-C5 alkyl or benzyl; R4 is hydrogen, C - ^ - Cj alkyl or triphenylmethyl and their salts with pharmaceutically acceptable acids or bases. 2. Compounds according to claim 1 wherein R is preferably a C1-C5 alkyl group; R ^ is preferably a tetrazole binding of formula IIa or IIb wherein R4 is as defined above and preferably hydrogen; R2 is a 2-pyrimidinyl ring; 5-pyrimidinyl; 2-methyl-4-methoxycarbonyl-5-pyrimidinyl; 1-oxide-5-pyrimidinyl; 1-oxide-2pyrimidinyl; 2-pyrazinyl; 2-pyr az ini 1- 4-oxide; 3-methoxycarbonyl-2-pyrazinyl; 3,6-diinethyl-2-pyrazinyl; 3-pyridazinyl; 3-methyl-6-pyridaz inyl; 6-methoxycarbonyl-3-pyridazinyl; 2-oxide-3-methyl-6-pyridazinyl; 1-oxide-3-methyl-6-pyridazinyl, 1-oxide-3, 6-dimethyl-2-pyrazinyl and 4-oxide-3,6-dimethyl-2-pyrazinyl. 3. A compound according to claims 1-2 selected from the group consisting of: 2-butyl-4- [6-methylpyridazin-3-yl] -1 - [[2 '- [1-triphenylmethyltetrazol-5-yl] biphenyl-4-yl] methyl] imidazole; 2-butyl-4- [pyrimidine-2-yl] —1 - [[21— [1-triphenylmethyltetrazol-5-yl] biphenyl-4-ylmethyl] imidazole; 2-butyl-4- [pyrimidine-5-yl] -1 - [[21- [1-triphenylmethyltetrazol-5-yl] biphenyl-4-yl] methyl] imidazole; 2-butyl-4- [2-methyl-4- (methoxycarbonyl) -pyrimidin-5-yl] -1 - [[2 '- [1-triphenylinethyltetrazol-5-yl] biphenyl-4-yl] methyl] imidazole; 2-butyl-4- [pyrazine-2-yl] -1 - [[21- [1-triphenylmethyltetrazol-5-yl] biphenyl-4-yl] methyl] imidazole; 2-butyl-4- [3,6-dimethylpyrazin-2-yl] -1 - [[2'-tl-triphenylmethyltetrazol-5-yl] biphenyl-4-yl] methyl] imidazole; 2-butyl-4- [3- (methoxycarbonyl) pyrazine-2-yl] -1 - [[2 '- [1-triphenylmethyltetrazol-5-yl] biphenyl-4-11] methyl] imidazole; 2-butyl-4- [6-methylpyridazine-3-yl-1-oxide] -1 - [[21- [1-triphenylmethyltetrazol-5-yl] biphenyl-4-yl] methyl] imidazole; 2-butyl-4- [6-methylpyridazine-3-yl-2-oxide] -1 - [[2 '- [1-triphenylmethyltetrazol-5-11] biphenyls 1-4-yl] methyl] imidazole; 2-butyl-4- [pyrimidine-2-yl-1-N-oxide] -1 - [[2 '- [1-trifanylinethyltetrazol-5-yl] biphenyl-4-yl] methyl] imidazole; 2-butyl-4- [pyrimidine-5-yl-1-N-oxide] -1 - [[21- [1-triphenylmethyltetrazol-5-yl] biphenyl-4-yl] methyl] imidazole; 2-butyl-4- [pyrazine-2-yl-4-N-oxide] -1 - [[21- [1-triphenylmethyltetrazol-5-yl] biphenyl-4-yl] methyl] imidazole; 2-butyl-4- [3,6-dimethylpyrazin-2-yl-1-N-oxide] -1- [[2 '- [1-tr if enylmethyl et razol- 5— yl] biphenyl-4-yl] methyl ] imidazole; 2-butyl-4- [3,6-dimethylpyrazine-2-yl-4-N-oxide] -1 - [[2 '- [1-triphenylmethyltetrazol-5-yl] biphenyl-4-yl] methyl] imidazole; 2-butyl-4- [6-methylpyridazine-3-yl-1-oxide] -1 - [[2 '- [1-triphenylmethyltetrazol-5-yl] biphenyl-4-yl] mBtyl] imidazole; 2-butyl-4- [6-methylpyridazine-3-yl-2-oxide] -1 - [[2 '- [1-triphenylmethyltetrazol-5-yl] biphenyl-4-yl] methyl3indazole; 2-butyl-4- [6-methylpyridazin-3-yl] -1 - [[2f— [1H-tetrazol-5-yl] biphenyl-4-yl] methyl] imidazole; 2-butyl-4- [pyrimidine-2-yl] -1 - [[2, - [1H-tetrazol-5-yl] biphenyl-4-yl] methyl3imidazole; 2-butyl-4- [pyrimidine-5-yl] -1 - [[2 '- [1H-tetrazol-5-yl] biphenyl-4-yl] methyl] imidazole; 2-butyl-4- [2-methyl-4- (methoxycarbonyl) -pyrimidin-5-yl] —1-C [21 [1H-tetrazol-5-yl] biphenyl-4-yl] methyl] imidazole; 2-butyl-4- [pyrazine-2-yl] -1 - [[2 '- [1H-tetrazol-5-yl] biphenyl-4-yl] methyl] imidazole; 2-butyl-4- [3,6-dimethylpyrazin-2-yl] -1 - [[21- [1H-tetrazol-5-yl] biphenyl-4yl] methyl] imidazole; 2-butyl-4- [3- {methoxycarbonyl) pyrazine-2-yl] -1 - [[2 '- [1H-tetrazol-5-yl] biphenyl-4-yl] methyl] imidazole; 2-butyl-4- [pyrimidine-2-yl-1-N-oxide] -1 - [[2 '- [1H-tetrazol-5-yl] biphenyl-4-yl] methyl] imidazole; 2-butyl-4- [pyrimidine-5-yl-1-N-oxide] -1 - [[2 '- [1H-tetrazol-5-yl] biphenyl-4-yl] methyl] imidazole; 2-butyl-4- [pyrazine-2-yl-4-N-oxide] -1 - [[2 '- [1H-tetrazol-5-yl] biphenyl-4-yl] methyl] imidazole; 2-butyl-4- [3,6-dimethylpyrazine-2-yl-1-N-oxide] -1 - [[2 <1> - [1H-tetrazol-5-yl] biphenyl-4-yl] methyl] imidazole; 2-butyl-4- [3,6-dimethylpyrazine-2-yl-4-N-oxide] -1 - [[2 '- [ΙΗ-tetrazol-5-yl] biphenyl-4-yl] methyl] imidazole; 2-butyl-4- [6-methylpyridazine-3-yl-1-oxide] -1 - [[2 <1> - [1H-tetrazol-5-yl] biphenyl-4-yl] methyl] imidazole; 2-butyl-4- [6-methylpyridazine-3-yl-2-oxide] -1 - [[2 <1> - [1H-tetrazol-5-yl] biphenyl-4-yl] methyl] imidazole. 4. Process for the preparation of compounds of claims 1-3 which comprises the reaction of a compound of formula III where 3⁄4 has the same meanings as 3⁄4 or is a group convertible to 3⁄4 by removing protective groups and X is a leaving group such as halogen, mesyloxy, acetyloxy with a compound of formula IV where R and R2 are as defined above and M is H, acetyl, p-methoxybenzyl, trityl. 5. Use of the compounds of claims 1-3 as therapeutic agents. 6. Use of the compounds of claims 1-3 as agents with All-antagonist activity. 7. Use of the compounds of claims 1-3 for the manufacture of a medicament useful in the treatment of cardiac or vascular or renal pathologies. 8. Pharmaceutical compositions containing an effective amount of one or more compounds of claims 1-7 as active principle in association with suitable carriers and excipients.