IE76145B1 - 4-Pyrimidinone derivatives their preparation and their application in therapy - Google Patents

Abstract

1. Compounds, existing in three tautomeric forms, corresponding to the general formulae (I), (I') and (I'') <IMAGE> in which R1 = linear or branched (C1-7)alkyl, linear or branched (C3-9)alkenyl, cyclo(C3-7)alkyl(C1-6)alkyl, R2 = H, linear or branched (C1-7)alkyl, cyclo(C3-7)alkyl(C1-3)alkyl, aryl(C1-3)alkyl optionally substituted in the ring, aryloxy(C1-3)alkyl optionally substituted in the ring, arylthio(C1-3)alkyl optionally substituted in the ring, arylsulphonyl(C1-3)alkyl optionally substituted in the ring, heteroaryl(C1-3)alkyl optionally substituted in the ring, R3 = CO2H 1H-tetrazol-5-yl, NHCOR11, NHSO2R11, CONHSO2R11, CONHOR12, where R11 = CH3, CF3 or optionally substituted phenyl, R12 = H, CH3 or optionally substituted phenyl, as well as their pharmaceutically acceptable organic or inorganic salts. Therapeutic application.t

Description

The present invention relates to 4-pyriraidinone derivatives, to their preparation. and to their application ia therapy.

Several published patent applications describe pyrimidinone derivatives which are active as angiotensin XI antagonists and are useful in various forms of hypertensive pathology.

Thus, European Patent Application SP 0,424,317 filed on 10th October 1990 (priority date 19th October 1987) and published on 24th April 1991 describes pyrimidine derivatives of formula (a) in which R, can represent a hydroxyl group, R2 a 4-biphenyXylaaethyl group substituted with a -CO2H or 5~fcefcraeolyl group, R3 a butyl group and R4 a {0,-0,0 alkyl group.

European Patent Application EP 0,465,323 filed on 28th June 1991 (priority date 29th November 1990) and published on 8th January 1992 describes derivatives of formula (b) (b) in which Rx can represent a butyl group, R2 a (C^-C*) alkyl group or an aromatic ring system, Rf3 a hydrogen atom and R4 a phenyl group substituted with a -CO2S or -tetraaolyl group.

Patent Application WO 91/15209 filed on 27th March 1991 (priority date 30th March 1990) published on October 1991 describes, inter alia, derivatives of formula (c) in which R2 perhaps a (C^-C^) alkyl group optionally substituted with aa aryl group» European Patent Application EP 0,407,342 describes pyrimidine derivatives ox formula (d) in which can represent a 4-bipheayly lmethyl group substituted with a ~CO2H or 5-tetrazolyl group and Z aa oxygen atom» describes new are active as The present invention 4-pyrimidinone derivatives which angiotensin II antagonists and are useful in various forms of antihypertensive pathology.

The compounds of the invention correspond to the in which represents a *2 represents a r3 represents a (X) The compounds of the invention can occur in the three tautomeric forms The compounds can occur in free form or in the £o«a of pharmaceutically acceptable organic or inorganic salts.

The compounds of the invention may be prepared according to the following schema: (BI) (I) Isa a first step, a β-keto ester of general formula (II) , in which Rx is as defined above and R* represents a methyl or ethyl group, is reacted with a derivative of general formula (III), in which L represents a leaving group such as chloro, bromo, iodo, p-toluenesulphonyloxy or me thane-sulphonyl oxy and Rs represents either a carboxylic ester group CO2Rg, where Ris a methyl, ethyl, 1,1-dimethylethyl or benzyl group, or a 1H-tetrazol-5-yl group protected, for example, by a triphenylmefchyl or 1,1-dimethylethyl substituent, to give β-keto ester derivatives of general formula (IV), in which Rx, R4 and Rg ar® as defined above. The derivatives of general formula (III) are described in various European Patent Applications (253,310, 291,969, 323,841, 400,835, 400,974,. 401,030). The reaction is performed in a solvent such as methanol, ethanol, 1,1-dimethylethanol or dimethylformamide at a temperature of between -20°C and 4·80°Ο, in the presence of a base such as sodium methylate, potassium 1,1-dimethylethylate or sodium, hydride and optionally in the presence of a catalyst such as lithium, magnesium or sine bromide or iodide.

In a second step, a β-keto ester of general formula (IV) is reacted with an amidine of general formula (V) to obtain a pyrimidinone of general formula (VI), in which Rx, R, and R5 are ae defined above. The reaction is performed by heating a mixture of the two compounds to between 40° and 120°C, optionally in a solvent such as methanol, ethanol, butanol or toluene and optionally in the presence of a base such as sodium methylate, sodium acetate, potassium carbonate, pyridine, triethylamine or 4-dimethylaminopyridine.

In a third step, deprotection and/or conversion of the group Rs to a group R3 is carried out in accordance with the nature of this group: · when Rs is a carboxylic acid ester, the compounds of general formula (VI) are subjected to an acid or alkaline hydrolysis to obtain the compounds of general formula (I) in which Rx and R, are as defined above and R3 is a CO2S group • when Rs is a triphenylmethyl-lc?-tetrasol-5-yl group or a 1,1-dimethylethyl-Us-tetrazol-5-yl group, the compound® of general formula (VI) are subjected to a deprotection reaction in an acid medium, according to conventional conditions, to obtain the compounds of general formula (I) in which R3 is a 1£T-tetrazol5-yl group and and R, are as defined above.

The examples which follow illustrate the invention. The numbers relate to the table given later» Th© analyses confirm th© structure of the compounds.

Example 1 (compound no. 1) ft e - [ (6-Butyl-2~phenylmethyl-ft-oxo"l, 4-dihydr©-5~ pyrimidinyDmefchyl] - [1,1* -biphenyl] -2-carboxylic acid. 1.1. Methyl -[ (2-methoxycarbonyl) -3-oxoheptyl]- [1,1' biphenyl]-2-carboxylate.

A solution of 5.57 g of sodium methylate (prepared from 2.36 g of sodium in 60 ml of methanol) is added with stirring to a solution, cooled in an icebath, of 16 g of methyl 3-oxoheptanoate In 145 ml of methanol. When the addition is complete, stirring is continued at room temperature for one hour, and the mixture is then cooled again in an icebath. A solution of 40.12 g of methyl 4'-(bromomethyl)-[1,1*-biphenyl]-2-carboxylate in 60 ml of methanol is added dropwise. The reaction mixture is left stirring at room tswperature for 2ft hours. It Is concentrated under reduced pressure» The residue is taken up with dichloromethan®» It is washed with IN aqueous hydrochloric acid solution and, then with water? it is dried over sodium sulphate and evaporated under vacuum to obtain ft2.4 g of product, which is used in the next step without further treatment. 1.2 . 4 - ί (6-3utyl-2-pheaylmethyl-ft-oxo-l,ft-dihydro-5~ pyrimidinyl)methyl] - [Ι,Ι* -biphenyl] -2-carboxylic acid.

A mixture of 0.56 g of benzeneethanimidamide and 1.7 g of methyl 4*-[(2-methoxycarbonyl)-3-oxoheptyl][1,1*-biphenyl]-2-carboxylate is heated to 95°C under argon for 4 hour®. The product is purified by chromatography oa alumina, eluting with a mixture of diehloromethane and methanol, to obtain 1.0 g of product. This product is redissolved in a mixture of 30 ml of methanol and 3 mi of water in the presence of 1.0 g of sodium hydroxide. Th© resulting mixture is heated to reflux for 3 hours and then concentrated under reduced pressure. The residue is taken up with watex. The aqueous phase is washed with ether, filtered and acidified with 3M aqueous hydrochloric acid solution. The precipitate is filtered off and recrystallised in methanol to obtain 0.60 g of compound in the form of a white powder. Melting points 219°C Example 2_ (compound no. 2) 4'-[[6-3utyl-2-(2-phenylethyl)-4-oxo-l,4-dihydro-5pyrimidinyl] methyl] - [1,1' -biphenyl] -2 -carboxylic acid.

In accordance with Example 1, a mixture of 1.0 g of bensenepropanimidamide and 2.4 g of methyl 4' -(2methoxycarbonyl)-3-oxoheptyl) - [1,1'-biphenyl1-2carboxylafce is heated to 95°C for 6 hours.

The product obtained is purified by chromatography on a silica gel column, eluting with a mixture of diehloromethane and methanol, to obtain 1.0 g of product in the form of a syrup. This product is redissolved in a mixture of 30 ml of methanol and 3 ml of water containing 1.1 g of sodium hydroxide. The resulting mixture is heated to reflux for 3 hours and then concentrated under reduced pressure. The residue is taken up with water. Th© aqueous phase is washed with ether and then acidified with 3N aqueous hydrochloric acid solution. The precipitate is filtered off and recrystallised ia methanol to obtain 0.6 g of compound in the form of a white powder.

Melting points 194°C Example 3 (compound no. 3). 6-3utyl-2- (2-phenylethyl) -5 - [ [2' - (1H-fcetrazol-5-yl) [1,1' -biphenyl] -4-yl]methyl] -4 (li?) -pyrimidinone. 3.1. Methyl 3-oxo~2- E I2e - (l-fcripheaylaefchyl-isr-tefcrazol5-yl) - [1,1 -biphenyl] -4-yl]methyl)heptanoate.

A solution of 1.3 g of methyl 3-oxoheptanoate in. 13 ml of dimethylformamide is added to a solution, cooled in an icabath and under argon, of 0,97 g of potassium 1,1-dime thyl ethylate in IS ml of dimethylformamide, followed by 1.67 g of lithium bromide and then a solution of 5 g of 5-E4‘’-(bromomethyl)-El(,lf-biphenyl]-2-yl]-ltriphenylmethyl - 1J5T-tetrarole in 25 ml of dimethylformamide. The reaction mixture is stirred for 5 hours at room temperature and then diluted in 300 ml of ether. It is washed with twice 100 ml of water and then with 100 ml of saturated aqueous ammonium chloride solution, dried over magnesium sulphate and evaporated under vacuum to obtain 4.60 g of product in the form of a yellow oil,, which is used in the next step without further treatment, 3.2» 6-Butyl-2 -(2-phenylethyl)- 5 -E[21 -(1-triphenylmethyl-IH-tetrasol-5-yl) - (Ι,Γ -biphenyl] -4-yl]methyl] 4 (IH) -pyrimidinone.

A mixture of 0.7 g of benzenepropanimidamide and 3 g of the shove compound is heated to 90°C under argon for 2 hours. It is taken up with 120 ml of dichloromethane and the resulting mixture is washed with twice 50 ml of 1M aqueous potassium carbonate solution and then with 50 ml of Q.lli aqueous hydrochloric acid solution. The organic phase is dried over magnesium sulphate and evaporated. The residue is purified by chromatography on a silica gel column, eluting with a mixture of dichloromethane and methanol, to obtain 0.85 g of compound in the form of a whitish foam. 3.3. 6-Butyl-2- (2-phenylethyl) -5- ( (2' - (IH-tetrasol-5-yl) E1,V -biphenyl] -4-yl] methyl] -4 (IH) -pyrimidinoae. 0. S g of the above compound is dissolved in a mixture of 5 ml of methanol and 3 »1 of diethyl ether. 2.7 ml of 1.57 M solution of hydrochloric acid ia diethyl ether are added. The mixture is left for 2 hours at room temperature and then evaporated to dryness. The residue is taken up with 70 ml of 0.5 2? aqueous sodium hydroxide solution. The mixture is washed with three times 30 ml of ether and then acidified with hydrochloric acid solution. - 8 The precipitate formed ie filtered off and recrystallised in methanol to obtain 0.22 g of compound in the fona of a white powder.

Melting point: 226-228°C The following fable illustrates the structures and physical properties of the compounds according to the invention.

T.^jhl ft CompoundR1 cs ft b3 Melting point (°C) Ί oe C.iXg CgSg-CMg- co2h 219 2 CgSg-CH,),- co2h 194 3 c4h9 Γ9 TT »f^GS \ — *•*§***5 v»**2 / o jLH’13 €8υΧΗώΟΧ 5-yX 226-228 4 Γ W C W..-OTL··- X*a ~ ^B'CXS.SOX ™ 5-yX 226-228 Ths compounds of ths invention were subjected to pharmacological studies which demonstrated their angiotensin IX"antagonist properties.

Test of binding· of [3H] angiotensin II to rabbit adrenal cortex.

Male Pauve d® Bourgogne rabbits weighing 2 to 3 kg are used. After sacrifice by cervical dislocation, the adrenal glands are excised and the cortex Is dissected rapidly at 40"C. The tissue is homogenised in ml of an ice-cold 10 mM tris (hydroacymethyl) aminomethane buffer solution containing 0.33 M sucrose and 1 mS3 ethylenediaminetetraacetic acid, the pH of which has been adjusted to 7.4 with hydrochloric acid, using an electrical Potter apparatus at a speed of 1200 rpm. The volume of th® preparation is adjusted to 25 ml with the Tris-sucrose buffer solution before centrifuging for 15 min at 1075 x g. Ths supernatant is retained, and the pellet is rehomogenised in 10 sal of Tris-sucrose buffer, then centrifuged ss described above. The two supernatants are combined and centrifuged for 30 min at 47,800 x g. The pellet is taken up with 150 volumes (equivalent to 100 mg of tissue in 15 ml of buffer) of incubation buffer solution containing: 50 mM Tris-HCl, ISO mM NaCl, 5 mM ethylenediamine-tetraacetic acid, 1.25 μ-g per ml of bacitracin, 100 μί& phenylme thyl sulphonyl fluoride and 0.2 % of bovine serum albumin (pH 7.4 at 25°C) . 100 μΐ aliquot fractions of the " suspension containing the adrenal cortex aicrosoaes are then incubated for 30 minutes at 25°C in the presence of 2 nM [3H]angiotensin II (New England Nuclear, specific activity S Ci/mmol) ia a final volume of 0.5 al of incubation buffer. After incubation, the microaoaea are recovered by filtration on 0.45 μη Mxllipore HAW?™ cellulose nitrate filters pretreated with 1 % bovine serum albumin, and they are washed three times with 5 ml of ice-cold Tris-HCl buffer. The quantity of radioactivity bound to the tissue and retained on the filters is measured by scintillation spectrometry.

The specific binding of C3H] angiotensin II is defined as the quantity o£ radioactivity bound to the filter which cat be inhibited by incubation ia the presence of 1/na non-radioactive angiotensin II. This specific binding represents 90 to 95 % of the total quantity of radioactivity bound to the filter.

The specific binding of [3B] angiotensin II is measured in the presence of various concentrations of compounds under study» and the IC30,, the concentration of the test compound which inhibits 50 % of the specific binding of pH) angiotensin II» is determined graphically.

The ICS0 values of the compounds according to the invention lie between 5 aM and 10 μΜ.

Inhibition of fhe_ response to angiotensin II on rat arterial blood pressure.

Male rats (Sprague-Dawley» Charles River France) weighing 250 to 280 g are used» the rats being anaesthetised with pentobarbital sodium (55 mg/kg i.p.) and maintained under artificial respiration (Harvard™ Respirator - respiration rate 70 ml per minute» air volume 1 ml per 100 g of body weight) . The animals are pithed using a metal rod introduced via the orbit of the right eye and inserted over the length of the spinal column. The left and right vagus nerves are sectioned (bivagotomy) and the right carotid artery is ligated» the left carotid artery being catheterised in order to measure the arterial blood pressure using a pressure cell (Statham™ type P23Db) . A femoral vein is catheterised for the purpose of administration of various compounds.

The changes in mean arterial blood pressure induced by angiotensin II administered intravenously at a dose of 0.5 pg/kg are measured. The compounds of the invention or the vehicle are administered 5 min (for tests via th© i.v. routes) or 60 minutes (for tests via the oral route) before the administration of angiotensin II. The compounds of the invention are administered at doses ranging from 0.01 to 100 mg/kg.

The percentage inhibition of the control response to angiotensin II is used in order to assess th© angiotensin ΙΙ-antagonist potential of the compounds of the Invention.

The compounds of the invention xaay be used for the treatment of various forms of hypertensive pathologies and of coronary, cardiac, renal or pulmonary insufficiencies, as well as for the treatment of glaucoma.

The compounds of the invention may also be used In combination with other substances having cardiovascular activity, such as diuretics, es-blockers, β-blockers, calcium antagonists or angiotensin I-converting enzyme inhibitors.

The compounds of the invention may be presented in all pharmaceutical forms suited to the treatment, for oral, parenteral, intramuscular or rectal administration; tablets, capsules including hard gelatin capsules, sterile solutions or suspensions, suppositories, and the like.

For the treatment of glaucoma, the compounds of the invention may be presented in the form of tablets, hard gelatin capsules, injections or topical ocular formulations.

The compounds of the invention may be administered to patients in a quantity which can range from 1 to 1000 mg per day per patient, in one or more doses.

Claims (12)

1. CLAIMS;

1. Compounds, existing ' in three tautomeric forms, corresponding to the general formulae (I), (I s ) and (I) (0 (Γ) (Γ) 5 in which R x represents a linear butyl group, R 2 represents a phenylmethyl or phenylethyl group, and R 3 represents a CO 2 H or IH-tetrazol-S-yl group, as well as their pharmaceutically acceptable organic or 10 inorganic salt®.

2. S-Butyl-2- {2-phenylethyl) -5- [ (2 - (1H-tetrasol-5yl) -[1,1-biphenyl]-4-yl)methyl]-4(Is)-pyrimidinone, as well as its pharmaceutically acceptable organic or inorganic salts, according to Claim 1. 15

3. Process for preparing the compounds according to Claim 1, which process is characterised in that a ,5-keto ester of general formula (II) (II) in which R, is as defined In Claim 1 and R 4 represents a methyl or ethyl group, Is reacted with a derivative of 20 general formula (III) (III) in which L represents a leaving group and R s represents either a group CO 2 R 6 , in which R s is a methyl, ethyl, 1,1dimethylethyl or benxyl group, 5 or a protected IH-tetrasol-5-yl group, to obtain a compound of general formula (IV) in which R^, R^ and R 5 are as defined in Claim, 1 and above, which compound is reacted with an amidine of general 10 formula (v) (V) in -which R 2 is as defined in Claim 1, to obtain a compound of general formula (VI) (VI) I in which R lf R 2 and R s are as defined in Claim 1 and above, and the group S s is then deprotected and/or 15 coaverted in accordance with the nature of this group, to obtain, after conversion, a compound of general IS formula (I) .

4. Process according to Claim 3, characterised in that the compounds of general formula (VI) in which R s is a triphenylasthyl-IK-tetrasol-5-yl group or a 1,1-dimethylethyl-1H-tetrasol-5-yl group and R x and R 2 are as defined in Claim 1 are subjected to a deprotection reaction in an acid medium, to obtain the compounds of general formula (I) in which R 3 is a 1H-tetrazol-5-yl group and R x and R 2 ar® as defined in Claim 1.

5. Process according to Claim 3, characterised in that the compounds of general formula (VI) in which R s is a carboxylic acid ester group and R x and R 2 are as defined in Claim 1 are subjected to an acid or alkaline hydrolysis, to obtain the compounds of general formula (I) in which R x and R, are as defined in Claim 1 and R 3 is a CO 2 H group.

6. Medicinal product, characterised in that it contains a compound according to either of Claims 1 and 2.

7. » Pharmaceutical composition, characterised in that it contains a compound according to either of Claims 1 and 2, in combination with any suitable excipient.

8. A compound according to claim 1, substantially as hereinbefore described and exemplified.

9. A process for preparing a compound according to claim 1, substantially as hereinbefore described and exemplified.

10. A compound according to claim 1, whenever prepared by a process claimed in a preceding claim.

11. A medicinal product according to claim 6, substantially as hereinbefore described.

12. A pharmaceutical composition according to claim 7, substantially as hereinbefore described.