COMPOUNDS HAVING ANGIOTENSINE II ANTAGONISTIC ACTIVITY

The present invention refers to heterocyclic com¬ pounds having angiotensine II antagonistic activity.

The renin-angiotensine system (RAS) is a proteoly- tic cascade playing a fundamental role in regulating blood pressure and is apparently involved in the onset and maintenance of some cardiovascular pathologies, such as hypertension or heart failure.

The octapeptide hormone angiotensine II (All) fi¬ nal product of RAS, is mainly formed in blood by the degradation of angiotensine I by the ACE enzyme which is localized in the endothelium of blood vessels, lungs, kidneys and many other organs. This hormone exerts on the arteries a powerful vasoconstrictive ac¬ tion as a consequence of its interaction with specific receptors, present on the cell membranes.

One of the possible control modes of RAS is the All antagonism at the receptorial level. Some peptide analogues of All (e.g. saralasine, sarmesine) are known to antagonize competitively the interactions of the hormone, but their clinical or experimental use has been limited by a partial agonist activity and by the lack of oral activity.

Recently, several non-peptide 5- or 6-membered he¬ terocyclic compounds were disclosed as All receptor an- tagonists. Example of these compounds are claimed in EP 253310, EP 323841, EP 324377, EP 409332, EP 411507, EP 412594 A, EP 419048 A. The present invention refers to heterocyclic derivatives having All antagonist proper¬ ties which may be therefore used for the treatment of

different cardiovascular pathologies such as hyperten¬ sion, heart failure and intraocular hypertension. The compounds of the invention have the general formula I

wherein:

R is linear or branched alkyl;

R, is hydrogen; C _j ^ linear or branched alkyl; aryl or arylalkyl wherein aryl is phenyl, naphthyl, 2-thienyl, 2-furanyl optionally substituted by one or more halogens, C^_ ₄ alkyl, C _1-4 alkoxy, hydroxy, carboxy or ^c ^_ linear or branched alkoxycarbonyl groups; when N and X are connected by a double bond, R. is obviously not present;

R ₂ is hydrogen, C^_ ₄ linear or branched alkyl, hydroxy, amino, aryl, wherein aryl is as defined above, or a group of formula NHA wherein A is C ₂ -C ₇ acyl, CN, NO,, CONHB or CSNHB wherein B is hydrogen, C,_c ₄ linear or branched alkyl", Cg_ ₇ cycloalkyl, aryl as defined above; ₃ is hydrogen or one o more halogen atoms; X is CO or a C-R ₄ group wherein R ₄ may be OR^ (wherein R^ must be obviously present and has the above mentio¬ ned meanings) , aryl optionally substituted by carboxy or hydroxy groups or CH ₂ OR ₅ wherein R _g is hydrogen, lower alkyl, arylalkyl wherein the aryl portion is as defined above;

Z is a COORg group wherein R _g is hydrogen or C ₁ _ ₄

linear or branched alkyl or a tetrazol-5-yl group of formula

wherein R _? is hydrogen or C ₁ __ ₄ alkyl with the proviso that, when X is CO and R ₁ = H, phenyl or phenethyl, R ₂ is different from hydrogen or alkyl. The disclaimed compounds are known from EP 0435827.

Preferred compounds of formula I are those wherein X is CO; ^ is preferably hydrogen; C _j -C ₄ alkyl; phenyl, benzyl, thienyl or furanyl optionally substituted by carboxy or C,-C ₄ alkoxycarbonyl groups;

R ₂ is preferally hydrogen; C,-C ₄ alkyl; amino; phenyl, 2-thienyl, 2-furanyl optionally sustituted by carboxy or C,-C ₄ alkoxycarbonyl groups; R. is preferably hydrogen.

Another group of preferred compounds, is that where R ₂ is hydrogen or C _1- _ ₄ alkyl and R^ is C ₁ _ ₄ alkyl, phenyl, benzyl, furanyl or thienyl optionally, substituted by carboxy or alkoxy carbonyl group. Parti- cularly preferred are the compounds wherein R ₂ is amino. Particularly preferred compounds are: 4-butyl-l- [(2-carboxyphenyl)methyl]-2-methyl-5-[[2'-(IH-tetrazol- 5-yl)biphenyl-4-]methyl]pyrimidin-6-one and 2-amino-6- butyl-5-[[2'-(lH-tetrazol-5-yl)biphenyl-4-yl]methyl]- pyrimidin-4-one.

The compounds I are characterized by a methyl-

biphenyl group on a carbon atom instead of a nitrogen atom as in the prior art.

The invention concerns also the pharmaceutically acceptable salts of the compounds I with organic or inorganic bases or acids. These salts include ammonium salts, alkali metal salts such as sodium and potassium, alkaline-earth metal salts such as calcium and magne¬ sium, organic bases salts, e.g. with dicyclohexylamine, N-methyl-D-glucamine, with a inoacids such as arginine, lysine and so on. Examples of salts with organic or inorganic acids, are those with hydrochloric, hydrobro- mide, sulfuric, phosphoric, methanesulfonic, toluensul- fonic, maleic, fumaric, camphorsulfonic acids, etc.

The invention refers also to the process for the preparation of the compounds I.

The compounds of formula I wherein Z is a COOR _g group ( g is a C^^ alkyl) or a substituted tetrazolyl group, are prepared by reacting a 1,3-dicarbonyl deri¬ vative or a β-ketoacid derivative of formula II

wherein:

R and Rg are as defined for the formula I

Rg is an 0R ₉ group ( ₉ is methyl or ethyl) or a CH ₂ 0R _ς group wherein R _g is as defined for the formula I

Y is COORg group (Rg is C^_ ₄ alkyl group) or a sub- stituted tetrazol-5-yl group, with compounds of for¬ mula III

*2 I (III)

HN-C-NH-R,

wherein R ₁ and R ₂ are as defined for the formula I, with the proviso that R ₁ is at least hydrogen.

The reaction is carried out in a protic solvent such as a lower alcohol (e.g. methanol, ethanol, iso- propanol) or in water or in mixtures there of or in an aprotic solvent such as benzene or toluene, optionally in the presence of bases such as an alcoholate (CH ₃ ONa,

C ₂ H ₅ ONa, ter-ButOK) , an alkali or alkaline-earth metal hydroxide or carbonate. The temperature may range from the room temperature to the reflux temperature.

The formation of the heterocycle may be carried out also in the presence of acids such as acetic acid or hydrochloric acid, at a temperature from 20 to 80 ^β C. Alternatively, the compounds I are prepared starting from compounds of formula IV

wherein:

R, R. , R ₂ and R ₃ are as defined above

Y is a COORg group (Rg being a C _1-4 alkyl), CN or a tetrazol-5-yl group substituted by a triphenylmethyl group.

When Y is an alkoxycarbonyl group, the compound IV may be subjected to acid (i.e. hydrochloric, tri- fluoroace ic, formic, acetic acids in protic solvents such as water-alcohol mixtures or in aprotic solvents such as CF_ ₂ C1 ₂ , dioxane) or alkaline (alkali hydroxides in water-alcohol mixtures at temperatures from 20 to 80°C) hydrolysis.

When Y is a CN group, it may be hydrolyzed with strong acids or bases, preferably with 1:1 aqueous hy- drochloric acid and glacial acetic acid mixture at re¬ flux, or with NaOH in ethanol or ethylene glycol at temperatures from 20° to the reflux temperature. The CN group may be converted into the tetrazolyl derivative by treatment with NaN ₃ and NH ₄ C1 in DMP at temperatures from 30 to 120 ^β C, or by 1,3-dipolar addition of trialkyl or triaryl stannyl azides in solvents such as toluene o xylene at temperatures from 110 to 130 ^β C.

When Y is a tetrazole group protected by a triphenylmethyl group, the latter may be removed by treatment with acetic, trifluoroacetic or hydrochloric acid or by hydrogenolysis.

The compounds IV wherein R, is hydrogen may be alkylated in the presence of bases such as K ₂ co ₃ , NaH,

NaNH ₂ , butillithium, LDA in aprotic polar solvents such as DMP, DMSO, THF at temperature from -20 to +30°Cm with compounds of formula V

X-CIL _J -R- _^ (V) wherein:

R, is as defined above and X is a leaving groups such as chlorine, bromine, iodine or a mesylate or tosylate groups.

The compounds IV wherein X is C-R ₄ wherein R ₄ is CH ₂ 0CH ₂ -phenyl may be transformed into the correspon¬ ding hydroxy derivatives by catalytic hydrogenolysis in a hydroxylated solvent such as methanol, ethanol in the presence of platinum or palladium as a catalyst.

The compounds IV are prepared by reacting com¬ pounds II wherein Y is as defined for the formula IV, with compounds III according to the previously reported method. Compounds II are obtained by alkylating known β- diketones or β-ketoesters, as according to the exam¬ ples.

The compounds herein described have antagonist ac¬ tivity at All receptor. Iii vitro (inhibition of All-induced contraction in rabbit aorta and ^{1 5} I-Sar ¹ -Ile ⁸ -AT II displacement in rat adrenal cortex) and aln vivo test (inhibition of A II induced pressure response in normotensive rat under ganglionic block). The compounds of the invention proved to be active in the above tests; for example in the zLn vitro test on rabbit aorta, several compounds showed pA ₂ higher than 6,5.

The compounds I or the pharmaceutically acceptable salts thereof con be used in pharmaceutical composi¬ tions alone or in admixture with pharmaceutically ac¬ ceptable adjutants, for oral or parenteral administra¬ tion. The pharmaceutical compositions can be in the so¬ lid form, such as tablets, capsules or suppositories or in the liquid form, such as solutions, suspensions or emulsions.

Further, when parenterally administered, the phar maceutical composition can be in the form of sterile solutions.

The compounds I can be administered in unitary do- ses ranging from 1 to 100 mg to patients suffering from cardiovascular pathologies such as hypertension, acute or chronic cardiac failure, intraocular hypertension. The use in other pathologies, such as secondary hype- raldostero ism, pulmonary hypertension, renal disease (glomerulonephritis, diabetic nephropaty) or vascular disorders (hemiσrania, Raynaud's syndrome) may also be possible.

The following examples further illustrate the in¬ vention. M.p. are uncorrected; the structure and purity of the compounds were assessed by elementary analysis (C, H, N) and UV, IR, NMR and mass spectroscopy.

Flash chromatography (FC) was carried out on si¬ lica gel according to the method described in W. C. Still, J. Org. Chem. 4_3, 2923 (1978).

EXAMPLE 1 l-Benzyloxy-2, -octadione

Under nitrogen atmosphere, 0,9 g of CH ₃ ONa, fol¬ lowed after 10 minutes by 2 ml of 2-hexanone, were ad- ded to a solution containing 4,9 g of methyl benzy- loxyacetate in 50 ml of anhydrous toluene. After stir¬ ring for 10 hours at room temperature, 10 ml of water were added and acetic acid was added to pH 5. The to- luenic phase was separated and the aqueous phase was extracted with ethyl acetate. The organic phases, poo¬ led with the toluene phase, were washed with a NaCl sa-

turated solution, dried over Na ₂ S0 ₄ and evaporated to dryness. The residue was purified by FC (eluent: hexane/AcOEt 9:1). 2.5 g of a pale yellow oil were ob¬ tained (yield 63%); ^Η ^' NMR (200 MHz, CDC1 ₃ ) i 0.92 (t, 3H), 1.22-1.68 (m, 4H) , 2.33 (t, 2H) , 4.07 (s, 2H) , 4.60 (s, 2H), 5.85 (s, 1H) , 7.30-7.45 (m, 5H) .

Similarly, the following compounds were prepared:

- l-benzyloxy-2,4-heptadione;

- l-methoxy-2,4-octadione; - l-methoxy-2,4-heptadione;

- l-[(4-methoxycarbonylphenyl)methoxy]-2,4-octadione.

EXAMPLE 2 l-Benzyloxy-3-[(2'-methoxycarbonylbiphenyl-4- yl)methyl]-2,4-octadione under nitrogen atmosphere, 1.3 g of 1-benzyloxy- 2,4-octadione, dissolved in 5 ml of anhydrous DMF were dropped into a suspension containing 0.16 g of 80% NaH in 15 ml of anhydrous DMF. After effervescence was over, 2 g of Nal were added and 1.6 g of 4-bromomethyl- 2•-methoxycarbonylbiphenyl, dissolved in 5 ml of anhy¬ drous DMF, were added dropwise to the mixture. After stirring for 6 hours at room temperature and for 6 hours at 70°C, the solvent was evaporated, the residue was treated with H ₂ o and extracted with Et ₂ 0. The orga- nic phase was washed with a NaCl saturated solution, dried on Na ₂ S0 ₄ and evaporated to dryness. The residue was purified by FC (eluent: hexane/AcOEt 75:25). 1.3 g of a pale yellow oil were obtained (yield 52%); ^■ " ^• 'H-NMR (200 MHz, CDCl ₃ ) <f: 0.80 (t, 3H) , 1.08-1.50 (m, 4H) , 2.17 (dt, 1H), 2.47 (dt, 1H) , 3.02 (dd, 1H) , 3.22 (dd, 1H), 3.62 (s, 3H), 3.99 (s, 2H) , 4.19 (t, 1H) , 4.48 (s,

2H) , 7.10-7.55 (m, 12H) , 7.82 ( dd, 1H) .

Similarly, the following compounds were prepared:

- l-benzyloxy-3-[(2'-methoxycarbonylbiphenyl-4- yl)methyl]-2,4-heptadione; - l-methoxy-3-[(2*-methoxycarbonylbiphenyl-4-yl)me¬ thyl]-2,4-octadione;

- l-[(4-methoxycarbonylphenyl)methoxy]-3-[(2'-methoxy- carbonylbiphenyl-4-yl)methyl]-2,4-octadione;

- l-benzyloxy-3-[(2'-cyanobiphenyl-4-yl)methyl]-2,4-oc- tadione;

- l-benzyloxy-3-[[2'-[N-triphenylmethyl-(lH-tetrazol-5- yl) ]biphenyl-4-yl]-methyl]-2,4-octadione

EXAMPLE 3 Methyl 3-oxoheptanoate under nitrogen atmosphere, 59 ml of butyllithium 1.6 M in hexane were added to a solution containing 14 ml of diisopropylamine in 200 ml of anhydrous THF, at 0 ^β C.

After stirring for 20 minutes, 9.3 ml of methyl acetoacetato were dropped, stirring was continued for 30 minutes at 0"C and further 54 ml of butyllithium 1.6 M in hexane were dropped. After further 30 minutes 8.4 ml of propyl iodide were dropped into the dark orange solution. The temperature was allowed to raise to room temperature and after 30 minutes, 50 ml of 37% HC1 di¬ luted with 100 ml of H ₂ o were continously dropped while keeping the temperature under 15 ^β C. The reaction mix¬ ture was extracted with Et ₂ o. The organic phase was wa¬ shed with a NaCl saturated solution, dried on Na ₂ S0 ₄ and evaporated to dryness. The residue was purified by FC (eluent: AσOEt/hexane 1:9). 8.3 g of a clear oil

were obtained (yield 61%); ^-NMR (200 MHz, CDC1 ₃ ) 5 ^" : 0.90 (t, 3H), 1.22 - 1.65 (m, 4H) , 2.53 (t, 2H) , 3.44 (s, 2H), 3.73 (s, 3H).

Similarly, methyl 3-oxohexanoate was prepared. EXAMPLE 4

Methyl 2-[ (2'-Methoxycarbonylbiphenyl-4-yl)methyl]-3- oxoheptanoate

Under nitrogen atmosphere, 2.3 of methyl 3-oxohep- tanoate, dissolved into 10 ml of anhydrous THF were dropped into a suspension containing 0.22 g of 80% NaH in 30 ml g of anhydrous THF. After the effervescence was over, 2.22 g of 4-bromomethyl-2'-methoxycar- bonylbiphenyl, dissolved in 10 ml of anhydrous THF, were slowly dropped into the clear solution. After 15 minutes, water was added and acetic acid was added till acidic pH. The reaction mixture was extracted with AcOEt. The organic phase was washed with a NaCl satura¬ ted solution, dried on Na ₂ sθ ₄ and evaporated to dry¬ ness. The residue was purified by FC (eluent: hexane/AcOEt 8:2). 2.6 g of a clear oil were obtained (yield 93%); ^-NMR (200 MHz, CDC1 ₃ ) 6 : 0.86 (t, 3H) , 1.15-1.62 (m, 4H), 2.25-2.65 (m, 2H) , 3.20 (d, 2H) , 3.63 (s, 3H) , 3.71 (s, 3H) , 3.84 (t, 1H) , 7.12-7.58 (m, 7H), 7.78 (dd, 1H) . Similarly, the following compounds were prepared:

- methyl 2-[ (2--cyanobiphenyl-4-yl)methyl]-3-oxohep- tanoate; ^X H-NMR (CDC1 ₃ ) 6 : 0.85 (t, 3H) , 1.15-1.63 (m, 4H), 2.27-2.67 (m, 2H) , 3.22 (d, 2H) , 3.71 (s, 3H), 3.85 (t, 1H), 7.23-7.79 (m, 8H) ; - methyl 2-[[2 ^» -[N-triphenylmethyl-(lH-tetrazol-5- yl) ]biphenyl-4-yl]-methyl]-3-oxoheptanoate; ^H-NMR

(CDC1 ₃ ) - : 0.84 (t , 3H) , 1.12-1.61 (m, 4H) , 2.18-2. 62 ( , 2H) , 3.06 (d, 2H) , 3. 66 ( s , 3H) , 3.69 (t, 1H) , 6.81-7.52 (m, 22H) , 7.90 (dd, 1H) ;

- methyl 2-[(2*-methoxycarbonylbiphenyl-4-yl)methyl]-3- oxohexanoate;

- methyl 2-[(5*-chloro-2--methoxycarbonylbiphenyl-4- yl)methyl]-3-oxoheptanoate;

- methyl 2-[(2'-terbutoxycarbonylbiphenyl-4-yl)methyl]- 3-oxoheptanoate.

EXAMPLE 5

6-Butyl-5-[(2'-methoxycarbonylbiphenyl-4-yl)methyl]py- rimidin-4-one

Under nitrogen atmosphere and while cooling, 0.18 g of formamide hydrochloride, followed by 0.87 g of methyl 2-[(2'-methoxycarbonylbiphenyl-4-yl)methyl]-3- oxoheptanoate dissolved into 2 ml of anhydrous MeOH, were added to a solution containing 0.37 g of CH ₃ ONa in 8 ml of anhydrous MeOH.

After stirring for 20 hours at room temperature, the solvent was evaporated, the residue was recovered with H ₂ o and pH was adjusted to 5 with diluted HCl. The aqueous phase was extracted with Et ₂ o and the white so¬ lid, which had separated at the interphase, was fil¬ trated off. 0.45 g of product was obtained (yield 53%; m.p. « 135 - 137 ^β C).

Similarly, the following compounds were prepared:

- 5-[(2•-methoxycarbonylbiphenyl-4-ylJmethyl]-6-propyl- pyrimidin-4-one;

- 6-butyl-5-[(2'-methoxycarbonylbiphenyl-4-yl)methyl]- 2-methylpyrimidin-4-one (m.p. - 144 - 147 ^# C);

- 4-benzyloxymethyl-6-butyl-5-[(2'-methoxycarbonylbi-

phenyl-4-yl)methyl]-2-methylpyrimidine;

- 4-butyl-5-[ (2 ^l -methoxycarbonylbiphenyl-4-yl)methyl]-

6-methoxymethyl-2-methylpyrimidine;

- 4-butyl-5-[ (2"-methoxycarbonylbiphenyl-4-yl)methyl]- 6-[(4-methoxycarbonylphenyl)methoxymethyl]-2-methyl- pyrimidine;

- 6-butyl-5-[(2•-cyanobiphenyl-4-yl)methyl]pyrimidin-4- one;

- 6-butyl-5-[[2'-[N-triphenylmethyl-(lH-tetrazol-5- yl) ]biphenyl-4-yl]methyl]pyrimidin-4-one;

- 2-amino-6-butyl-5-[ (2•-methoxycarbonylbiphenyl-4-yl)- methyl]pyrimidin-4-one (m.p. - 252-254 ^β C);

- 6-butyl-2-hydroxy-5-[(2'-methoxycarbonylbiphenyl-4- yl)methyl]pyrimidin-4-one; - 6-butyl-[(5'-chloro-2•-methoxycarbonylbiphenyl-4-yl)- methyl]pyrimidin-4-one;

- 6-butyl-2-cyanoamino-5-[ (2'-methoxycarbonylbiphenyl-

4-yl)methyl]pyrimidin-4-one (m.p. 222-224 ^β C);

- 6-butyl-5-[(2'-methoxycarbonylbiphenyl-4-yl)methyl]- 2-nitroaminopyrimidin-4-one;

- 6-butyl-2-methyl-5-[[2•-[N-triphenylmethyl-(lH-tetra- zol-5-yl) ]biphenyl-4-yl]methyl]pyrimidin-4-one (m.p. 98-100 ^β C);

- 2-amino-6-butyl-5-[[2 ^« -[lH-tetrazol-5-yl)biphenyl-4- yl]methyl]pyrimidin-4-one (m.p. 234-236°C).

EXAMPLE 6 4-Butyl-6-hydroxymethyl-2-methyl-5-[(2'-methoxycarbo- nylbiphenyl-4-yl)methyl]pyrimidine

A solution containing 0.5 g of 4-benzyloxymethyl- 6-butyl-2-methyl-5-[(2'-methoxycarbonylbiphenyl-4-yl)- methyl _. pyrimidine in 50 ml of EtOH was hydrogenated in

presence of 0.1 g of 10% palladium on charcoal at at¬ mospheric pressure and room temperature. After the the¬ oretical hydrogen absorption the reaction mixture was filtered on Celite ^v _R' and the solvent was evaporated obtaining 0.38 g of a clear oil, which was directly used without further purification (yield 95%).

EXAMPLE 7 6-Butyl-5-[(2'-carboxybiphenyl-4-yl)methyllpyrimidin-4- one

0.13 g of NaOH dissolved in 2 ml of H ₂ o were added to a solution containing 0.42 g of 6-butyl-5-[(2•- methoxycarbonylbiphenyl-4-yl)methyl]pyrimidin-4-one in 10 ml of MeOH. After refluxing for 24 hours under stir¬ ring the solvent was evaporated. The residue was reco- vered with H ₂ o and extracted with Et ₂ 0. The aqueous phase was acidified to pH 3. The so obtained waxy solid was treaded with a H ₂ o/Et ₂ 0 mixture. After filtering, 0.35 g of a white solid was obtained (yield 88%; m.p. - 197 - 200 ^β C). Similarly, the following compounds were prepared:

- 5-C(2'-carboxybiphenyl-4-yl)methyl]-6-propylpyrimi- din-4-one;

- 6-butyl-5-[(2'-carboxybiphenyl-4-yl)methyl]-2-methyl- pyrimidin-4-one (m.p. - 208-210 ^β C); - 4-butyl-5-[(2--carboxybiphenyl-4-yl)methyl]-6-hydroxy methyl-2-methylpyrimidine;

- 4-butyl-5-[(2•-carboxybiphenyl-4-yl)methyl]-2-methyl- 6-methoxymethylpyrimidine;

- 4-butyl-5-[(2'-carboxybiphenyl-4-yl)methyl]-6-[(4- carboxyphenyDmethoxymethyl]pyrimidine;

- 2-amino-6-butyl-5-[(2*-carboxybiphenyl-4-yl)methyl]

pyrimidin-4-one (m.p. 190-195 ^β C dec);

- 6-butyl-5-[ (2'-carboxybiphenyl-4-yl)methyl]-2-hydroxy pyrimidin-4-one;

- 4-butyl-5-[(2•-carboxybiphenyl-4-yl)methyl]-1-[(4- carboxyphenyl)methyl]pyrimidin-6-one (m.p. 141- 144 ^β C);

- l-benzyl-4-butyl-5-[(2'-carboxybiphenyl-4-yl)methyl] pyrimidin-6-one (m.p. 198-200 ^β C);

- 4-butyl-5-[ (2'-carboxybiphenyl-4-yl)methyl]-1-[ (4-hy- droxyphenyl)methyl]pyrimidin-6-one;

- 6-butyl-5-[(2'-carboxy-5'-chlorobiphenyl-4-yl)methyl] pyrimidin-4-one.

- 4-butyl-5-[ (2'-carboxybiphenyl-4-yl)methyl]-6-[(3- carboxythien-2-yl)methoxy]-2-methylpyrimidine (m.p. 180-185 ^β C dec);

- 4-butyl-5-[ (2'-carboxybiphenyl-4-yl)methyl]-6-[(3- carboxyfuran-2-yl)methyl]-2-methylpyrimidine (m.p. 149-152°C);

- 4-butyl-5-[ (2'-carboxybiphenyl-4-yl)methyl]-l-[(2- carboxyphenyl)methyl]pyrimidin-6-one (m.p. 185- 187 ^β C);

- 4-butyl-5-[(2'-carboxybiphenyl-4-yl)methyl]-1-[(3- carboxythien-2-yl)methyl]-2-methylpyrimidin-6-one (m.p. 175-178 ^β C dec); - 4-butyl-5-[(2'-carboxybiphenyl-4-yl)methyl]-l-[(3- carboxyfuran-2-yl)methyl]-2-methylpyrimidin-6-one (m.p. 143-148 ^β C dec);

- 4-butyl-5-[ (2'-carboxybiphenyl-4-yl)methyl]-l-[(thi- en-2-yl)methyl]pyrimidin-6-one (m.p. 205-208 ^β C); - 6-butyl-5-[(2'-carboxybiphenyl-4-yl)methyl]-2-cyanoa- minopyrimidin-4-one (m.p. 230-232°C) ;

- 6-butyl-5-[(2'-carboxybiphenyl-4-yl)methyl]-2-nitroa- minopyrimidin-4-one;

- 6-butyl-5-[(2'-carboxybiphenyl-4-yl)methyl]-2-phenyl- aminocarbonylaminopyrimidin-4-one (m.p. 229-231 ^β C); - 6-butyl-5-[(2'-carboxybiphenyl-4-yl)methyl]-2-cyclo- hexylaminocarbonylaminopyrimidin-4-one (m.p. 234- 236 ^β C);

- 6-butyl-5-[(2•-carboxybiphenyl-4-yl)methyl]-2-methy- laminothiocarbonylaminopyrimidin-4-one (m.p. 179- 181 ^β C);

- 2-aminocarbonylamino-6-butyl-5-[(2•-carboxybiphenyl- 4-yl)methyl]pyrimidin-4-one;

- 4-butyl-l-[(3-carboxythien-2-yl)methyl]-5-[[2•-(1H- tetrazol-5-yl)biphenyl-4-yl)methyl]pyrimidin-6-one (m.p. 154-156 ^β C);

- 4-butyl-l- i ( 3-carboxyf uran-2-yl ) methyl ] -5- [ [ 2 ' - ( 1H- tetrazol-5-yl)biphenyl-4-yl)methyl]pyrimidin-6-one;

- 4-butyl-5-[ (2 ' -carboxybiphenyl-4-yl) methyl ] -6- [ [ 4- carboxyphenyl ) me thyl lpyrimi dine (m.p. 208-211 ^β C ) . EXAMPLE 8

4-butyl-5-[(2'-methoxycarbonylbiphenyl-4-yl)methyl]-1- C(4-methoxycarbonylphenyl)methyllpyrimidin-6-one

0.6 g of 6-butyl-5-[(2'-methoxycarbonylbiphenyl-4- yl)methyl]pyrimidin-4-one dissolved in 3 ml of anhy- drous DMF was added to a suspension containing 0.05 g of 80% NaH in 5 ml of anhydrous DMF, while stirring at room temperature. After the effervescence was over, 0.7 ml of methyl 4-bromomethylbenzoate, dissolved in 2 ml of anhydrous DMF, was dropped. After stirring of 3 hours, the solvent was evaporated and the residue was purified by FC (eluent: AcoEt-hexane 1:1). 0.7 g of a

clear oil was obtained (yield 85%); ¹ H-NMR (200 MHz, CDC1 ₃ ) _: 0.91 (t, 3H) , 1.15-1.65 (m, 4H) , 2.62 (t, 2H), 3.62 (s, 3H), 3.91 (s, 3H) , 3.97 (s, 2H) , 5.15 (s, 2H), 7.12-7.52 (m, 9H), 7.78 (dd, 1H) , 7.98-8.10 (m, 2H), 8.07 (s, 1H).

Similarly, the following compounds were prepared:

- l-benzyl-4-butyl-5-[(2•-methoxycarbonylbiphenyl-4- yl)methyl]pyrimidin-6-one; ^H-NMR (CDCl ₃ )<f _: 0.91 (t, 3H), 1.20-1.65 (m, 4H) , 2.61 (t, 2H) , 3.61 (s, 3H) , 3.98 (s, 2H), 5.10 (s, 2H) , 7.15-7.52 (m, 12H) , 7.78 (dd, 1H), 8.05 (s, 1H);

- 4-butyl-l-[ (4-hydroxyphenyl)methyl]-5-[ (2 '-methoxy- carbonylbiphenyl-4-yl ) -methyl ]pyrimidin-6-one ;

- 4-butyl-5- [ ( 2 ' -methoxycarbonylbiphenyl-4-yl ) methyl ] - l-[ (2-methoxycarbonylphenyl)methyl]pyriτnidin-6-one;

^■ T-H-NMR (CDC1 ₃ ) S '. 0.91 (t, 3H) , 1.25-1.65 (m, 4H) , 2.63 (t, 2H), 3.61 (s, 3H) , 3.91 (s, 3H) , 3.97 (s, 2H), 5.55 (s, 2H), 7.12-7.57 (m, 10H) , 7.78 (dd, 1H) , 8.03 (dd, 1H), 8.15 (S, 1H) ; - 4-butyl-5-[ (2'-methoxycarbonylbiphenyl-4-yl)methyl]- l-[(thien-2-yl)methyl]pyrimidin-6-one; ^H-NMR (CDC1 ₃ ) 5: 0.96 (t, 3H), 1.15-1.65 (m, 4H) , 2.60 (t, 2H) , 3.62 (s, 3H), 3.98 (s, 2H) , 5.25 (s, 2H) , 6.89 (dd, 1H), 7.08-7.53 (m, 9H) , 7.78 (dd, 1H) , 8.08 (s, 1H) ; - 4-butyl-5-[(2'-methoxycarbonylbiphenyl-4-yl)methyl]- 1-[(3-methoxycarbonylthien-2-yl)methyl]-2-methylpyri- midin-6-one; ^X H-NMR (CDC1 ₃ ) $ : 0.90 (t, 3H) , 1.20- 1.65 (m, 4H), 2.47 (s, 3H) , 2.58 (t, 2H) , 3.61 (s, 3H), 3.90 (s, 3H), 3.99 (s, 2H) , 5.91 (s, 2H) , 7.08- 7.53 (m, 9H) , 7.78 (dd, 1H) ;

- 4-butyl-5-[(2 ^» -methoxycarbonylbiphenyl-4-yl)methyl]-

1-[(3-methoxycarbonylfuran-2-yl)methyl]-2-methylpyri- midin-6-one; ^X H-NMR (CDC1 ₃ ) 6 : 0.90 (t, 3H) , 1.15- 1.65 (m, 4H), 2.47 (s, 3H) , 2.57 (t, 2H) , 3.61 (s, 3H>, 3.88 (s, 3H) , 3.98 (s, 2H) , 5.69 (s, 2H) , 6.69 (d, IH). 7.12-7.55 (m, 8H) , 7.78 (dd, IH);

- 4-butyl-l-[(2-methoxycarbonylbiphenyl)methyl1-2- methyl-5-[[2'-[N-triphenylmethyl-(lH-tetrazol-5- yl) ]biphenyl-4-yl]methyl]pyrimidin-6-one; ¹ H-NMR (CDC1 ₃ )^ ^" : 0.91 (t, 3H) , 1.15-1.65 (m, 4H) , 2.36 (s, 3H), 2.53 (t, 2H), 3.85 (s, 2H), 3.93 (s, 3H), 5.73 (s, 2H), 6.75 (dd, IH) , 6.82-7.10 (m, 8H) 7.18-7.48 (m, 16H), 7.78 (dd, IH), 8.08 (dd, IH) ;

- 4-butyl-l-[(3-methoxycarbonylthien-2-yl)methyl]-2- methyl-5-[[2•-[N-triphenylmethyl-(lH-tetrazol-5- yl)]biphenyl-4-yl]methyl]pyrimidin-6-one; ^H-NMR (CDC1 ₃ ) ^ _: 0.88 (t, 3H) , 1.20-1.65 (m, 4H) , 2.46 (s, 3H), 2.50 (t, 2H), 3.86 (s, 2H), 3.90 (s, 3H), 5.87 (s, 2H), 6.80-7.55 (m, 24H) 7.88 (dd, IH) ;

- 4-butyl-l-[(3-methoxycarbonylfuran-2-yl)methyl]-2- methyl-5-[[2'-[N-triphenylmethyl-(lH-tetrazol-5- yl) ]biphenyl-4-yl]methyl]pyrimidin-6-one; ^-N R (CDC1 ₃ ) ^: 0.90 (t, 3H) , 1.15-1.65 (m, 4H) , 2.46 (s, 3H), 2.50 (t, 2H), 3.86 (s, 2H), 3.88 (s, 3H), 5.66 (s, 2H), 6.69 (d, IH), 6.80-7.55 (m, 23H) 7.88 (dd, IH) ;

- 4-butyl-l-[(4-methoxycarbonylphenyl)methyl]-2-methyl- 5-[[2•-[N-triphenylmethyl-(lH-tetrazol-5- yl) ]biphenyl-4-yl]methyl]pyrimidin-6-one; -^H-NMR

(CDC1 ₃ )^: 0.91 (t, 3H), 1.15-1.65 (m, 4H) , 2.36 (s, 3H), 2.53 (t, 2H), 3.85 (s, 2H), 3.93 (s, 3H), 5.33

(s, 2H), 6.75 (dd, IH) , 6.82-7.10 (m, 8H) 7.18-7.48

(m, 16H), 7.78 (dd, IH) , 8.08 (dd, IH) ;

- 4-butyl-5-[ (2 ' -methoxycarbonylbiphenyl-4-yl) methyl ]- 6-[ (4-methoxycarbonylphenyl)methoxy]pyrimidine; -^H- NMR (CDC1 ₃ ) ≤: 0.91 (t, 3H) , 1.20-1.70 (m, 4H) , 2.77 (t, 2H), 3.61 (s, 3H), 3.90 (s, 3H) , 4.08 (s, 2H) ,

5.48 (s, 2H), 7.05-7.55 (m, 9H) 8.81 (dd, IH) , 7.93- 8.01 (m, 2H), 8.63 (s, IH);

- 4-butyl-5-[ (2 '-methoxycarbonylbiphenyl-4-yl) methyl ]- 6-[ (2-methoxycarbonylphenyl)methoxy]pyrimidine; H- NMR (CDC1 ₃ ) S: 0.91 (t, 3H) , 1.20-1.70 (m, 4H) , 2.77

(t, 2H), 3.58 (s, 3H), 3.86 (s, 3H) , 4.09 (s, 2H) , 5.86 (s, 2H), 7.06-7.56 (m, 10H) 7.78 (dd, IH) , 7.98 (dd, IH), 8.63 (s, IH);

- 4-butyl-5-[(2'-methoxycarbonylbiphenyl-4-yl)methyl]- 6-[(3-methoxycarbonylthien-2-yl)methoxy]-2- methylpyrimidine; ^Ε-NMR (CDC1 ₃ ) 6 : 0.89 (t, 3H) , 1.20-1.65 (m, 4H) , 2.59 (s, 3H) , 2.71 (t, 2H) , 3.59 (s, 3H) , 3.87 (s, 3H), 4.06 (s, 2H) , 5.96 (s, 2H) , 7.12-7.52 (m, 9H) 7.78 (dd, IH) ; - 4-butyl-5-[(2'-methoxycarbonylbiphenyl-4-yl)methyl]- 6-[(3-methoxyσarbonylfuran-2-yl)methoxy]-2-methylpy- rimidine; ^X H-NMR (CDC1 ₃ ) S : 0.88 (t, 3H) , 1.20-1.65 (m, 4H), 2.58 (s, 3H) , 2.65 (t, 2H) , 3.60 (s, 3H) , 3.81 (s, 3H), 3.96 (s, 2H) , 5.71 (s, 2H) , 6.72 (d, IH), 7.02-7.55 (m, 8H) , 7.78 (dd, IH) ;

- 4-butyl-6-[ (4-methoxycarbonylphenyl)methoxy]-2- methyl-5-[[2'-[N-triphenylmethyl-(lH-tetrazol-5- yl)]biphenyl-4-yl]methyl]pyrimidine; 1H-NMR (CDC13) $: 0.86 (t, 3H), 1.20-1.70 (m, 4H) , 2.56 (s, 3H) , 2.62 (t, 2H) , 3.88 (s, 3H) , 3.90 (s, 2H) , 5.42 (s,

2H), 6.82-7.03 (m, 8H) , 7.15-7.52 (m, 17H) , 7.85-8.00

(m, 2H) ;

- 4-butyl-6-[(2-methoxycarbonylphenyl)methoxy]-2- methyl-5-[[2'-[N-triphenylmethyl-(lH-tetrazol-5- yl) ]biphenyl-4-yl]methyl]pyrimidine; 1H-NMR (CDC13) &: 0.86 (t, 3H), 1.15-1.60 (m, 4H) , 2.56 (s, 3H) , 2.62 (t, 2H), 3.84 (s, 3H) , 3.91 (s, 2H) , 5.80 (s, 2H), 6.82-7.03 (m, 8H) , 7.15-7.52 (m, 17H) , 7.85-8.00 (m, 2H);

- 4-butyl-6-[(3-methoxycarbonylthien-2-yl)methoxy]-2- methyl-5-[[2•-[N-triphenylmethyl-(lH-tetrazol-5- yl)]biphenyl-4-yl]methyl]pyrimidine; 1H-NMR (CDC13) Si 0.86 (t, 3H), 1.20-1.60 (m, 4H), 2.59 (s, 3H), 2.61 (t, 2H), 3.85 (s, 3H) , 3.93 (s, 2H) , 5.93 (s, 2H), 6.82-7.48 (m, 24H) , 7.87 (dd, IH); - 4-butyl-6-[(3-methoxycarbonylfuran-2-yl)methoxy]-2- methyl-5-[[2 ^• -[N-triphenylmethyl-(lH-tetrazol-5- yl)]biphenyl-4-yl]methyl]pyrimidine; 1H-NMR (CDC13) 8: 0.86 (t, 3H), 1.20-1.60 (m, 4H), 2.55 (s, 2H) , 2.59 (s, 3H), 3.80 (s, 3H) , 3.85 (s, 2H) , 5.69 (s, 2H), 6.70 (d, IH), 6.80-7.50 (m, 23H), 7.87 (dd, IH).

EXAMPLE 9 6-Butyl-5-[(2'-(lH-tetrazol-5-yl)biphenyl-4-yl]me- thy lpyrimidin-4-one Method A Under nitrogen atmosphere, 0.11 g of sodium azide and 0.09 g of ammonium chloride were added to a solu¬ tion containing 0.2 g di 6-butyl-5-[(2•-cyanobiphenyl- 4-yl)-methyl]pyrimidin-4-one in 2 ml of anhydrous DMF. After reacting for 16 hours at 100 ^β C and 60 hours at 120 ^β C the reaction mixture was let to cool down and a further amount equal to the former of sodium azide and

ammonium chloride was added. After further 50 hours at 120 ^β C the solid was filtered off and the solvent was distilled under vacuum. The residue was recovered with H ₂ o and extracted with AcOEt, the organic phase was dried on Na ₂ so ₄ and the solvent was evaporated. The crude material was purified by FC (eluent: AcOEt/MeOH) obtaining 12 g of a white solid (yield 53%) . Method B

1 ml of trifluoroacetic acid and 1 ml of H ₂ o were added to a solution containing 0.3 g of 6-butyl-5-[[2'- [N-triphenylmethyl-(lH-tetrazol-5-yl) ]biphenyl-4-yl]- methyl] pyrimidin-4-one in 5 ml of THF. After stirring for 2 hours at room temperature, the reaction mixture was treated with NaOH to neutrality and the solvent was evaporated. The residue was purified by FC, according to Method A. 0.11 g of a white solid was obtained (yield 60%).

Similarly, the following compounds were prepared:

- 6-butyl-2-methyl-5-[[2•-(lH-tetrazol-5-yl)biphenyl-4- yl] methyl]pyrimidin-4-one (m.p. 238-240°C dec);

- l-benzyl-4-butyl-5-[[2•-(lH-tetrazol-5-yl)biphenyl-4- yl] methyl]pyrimidin-6-one;

- 4-butyl-l-[ (2-carboxyphenyl)methyl]-2-methyl-5-[[2'- (lH-tetrazol-5-yl)biphenyl-4-yl]methyl]pyrimidin-6- one (m.p. 193-196 ^β C);

- 4-butyl-6-[(2-methoxycarbonylphenyl)methoxy]-2- methyl-5-[[2•-(lH-tetrazol-5-yl)bipheny1-4- yl]methyl]pyri-midine (m.p. 103-105 ^β C);

- 4-butyl-l-[(3-methoxycarbonylthien-2-yl)methyl]-2-me- thyl-5-[[2•-(lH-tetrazol-5-yl)biphenyl-4-yl]methyl]- pyrimidin-6-one (m.p. 100-105 ^β C);

- 4-butyl-6-[(3-methoxycarbonylthien-2-yl)methoxy]-2- me-thyl-5-[[2'-(lH-tetrazol-5-yl)biphenyl-4- yl]methyl]-pyrimidine (m.p. 100-105 ^β C);

- 4-butyl-l-[(3-methoxycarbonylfuran-2-yl) ethyl]-2- methyl-5-[[2'-(lH-tetrazol-5-yl)biphenyl-4-yl]rae- thyllpyrimidin-6-one;

- 4-butyl-6-[(3-methoxycarbonylfuran-2-yl)methoxy]-2- methyl-5-[[2'-(lH-tetrazol-5-yl)biphenyl-4-yl]me¬ thylJpyrimidine; - 4-butyl-l-[(4-carboxyphenyl)methyl]-2-methyl-5-[[2'- (lH-tetrazo1-5-yl)bipheny1-4-y1]methyl]pyrimidin-6- one;

- 4-butyl-6-[(4-methoxycarbonylphenyl)methoxy]-2-me- thyl-5-[[2'-(lH-tetrazol-5-yl)biphenyl-4-yl]methyl]- pyrimidine.

EXAMPLE 10 6-Butyl-5-[(2'-methoxycarbonylbiphenyl-4-yl)methyl]-2- phenylaminocarbonylaminopyrimidin-4-one

0.27 g of phenylisocyanate were added to a solu- tion containing 0.3 g of 2-amino-6-butyl-5-[(2'- methoxycarbonylbiphenyl-4-yl)-methyl]pyrimidin-4-one in 6 ml of dry DMF at 0°C. After stirring at room tempera¬ ture for 30 minutes the mixture was evaporated to dry¬ ness and the residue was crystallized from DMF; 0.22 g of a white solid was obtained (yield 56%, m.p. 217- 219 ^β C).

Similarly, the following compounds were prepared:

- 6-butyl-2-cyclohexylaminocarbonylamino-5-[(2'-metho- xycarbonylbiphenyl-4-yl)methyl]pyrimidin-4-one (m.p. 220-222°C);

- 6-butyl-5-[(2 ^« -methoxycarbonylbiphenyl-4-yl)methyl]-

2-methylaminothiocarbonylaminopyrimidin-4-one (m.p. 186-188°C); - 2-aminocarbonylamino-6-butyl-[(2'-methoxycarbonylbi- phenyl-4-yl)methyl]pyrimidin-4-one. EXAMPLE 11

2-Acetylamino-6-butyl-5-[[2'-(lH-tetrazol-5-yl)biphe- nyl-4-ylImethyl]pyrimidin-4-one

10 ml of Ac ₂ o were added to a sospension of 2- amino-6-butyl-5-[(2'-(lH-tetrazol-5-yl)biphenyl-4-yl]- methyllpyrimidin-4-one in toluene. After other addi¬ tions of Aco the solution was evaporated to dryness. The residue was purified by FC (eluent: CH ₂ ci ₂ /MeOH/AcOH 89.9:10:0.1). 15 mg of a white solid was obtained (yield 32%, m.p. 205-208°C).