AU650319B2

AU650319B2 - 4-pyrimidinone derivatives, their preparation and their application in therapy

Info

Publication number: AU650319B2
Application number: AU11059/92A
Authority: AU
Inventors: Michel Aletru; Marc Daumas; Christian Hoornaert; Jean-Claude Muller
Original assignee: Synthelabo SA
Current assignee: Synthelabo SA
Priority date: 1991-02-20
Filing date: 1992-02-19
Publication date: 1994-06-16
Anticipated expiration: 2012-02-19
Also published as: NO920648L; ATE135695T1; PL168617B1; JP2529798B2; IL101014A0; FI920720A0; KR920016434A; IE920525A1; AU1105992A; EP0500409A1; JPH04346980A; IE76145B1; NZ241659A; ES2086090T3; FI920720A; HU9200532D0; IL101014A; FR2672892A1; PL293531A1; RU2073675C1

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

I rr~-aanasa=r~--~-: ii S--0319

AUSTRALIA

PATENTS ACT 1990 COMPLETE SPECIFICATION NAME OF APPLICANT(S): Synthelabo ADDRESS FOR SERVICE: DAVIES COLLISON CAVE Patent Attorneys 1 Little Collins Street, Melbourne, 3000.

INVENTION TITLE: 4-pyrimidinone derivatives, their preparation and their application in therapy The following statement is a full description of this invention, including of performing it known to me/us:the best method -nr-rp~ The present invention relates to novel substituted 4pyrimidinone compounds, derivatives thereof, their preparation and their application in therapy.

The compounds of the invention have the formula (I) wherein R, represents a straight butyl group,

R

2 represents a phenylmethyl group, a 4-carboxyphenylmethyl group, a phenylethyl group, a 4-methoxyphenylethyl group, a 4-fluorophenylethyl group, a 3,4,5--trimethoxyphenylethyl group, a 3-fluoro-4-methoxyphenylethyl group,

R

3 is a CO 2 H or a 1H-tetrazol-5-yl group.

The compounds of formjla can be expressed as tautomeric forms 931208,p:\oper\dab,11059-92.340,2 3

R

2 2 N~N H NH_

N

R1- 0 Z RI OH Z Ri 0 which are part of the invention.

The compounds of the invention may be present either in a free form or in the form of organic or inorganic pharmaceutically acceptable salts.

The following scheme provides the preparation of the compounds of the invention: 0 0

R.'GOR

4

(I)

R

2 HN;

NH-

2 In a first step, a S-ketoester of the general formula (II), in which R, is as defin-d above and R 4 r .vresents a methyl or ethyl group, is condensed with a derivative of the general formula (III), wherein L represents a leaving group such as chloro, bromo, iodo, p-toluenesulfonyloxy ou methanesulfonyloxy and R s represents either a carboxylic group COpR 6 wherein R 6 is a methyl, ethyl, 1,1-dimethylethyl or benzyl group, either a nitro group, either a 1H-tetrazolgroup protected, for example, by a triphenylmethyl substituent or 1,1-dimethylethyl substituent, to yield B-ketoester derivatives of the general formula in which

R

1

R

4 et R s are as defined above. The derivatives of general formula (III) are described in various European patent applications (253310, 291969, 323841, 400835, 400974, 401030). The reaction is carried out in a solvent such as methanol, ethanol, 1,1-dimethylethanol or dimethylformamide at a temperature between 20 0 C and 80 0 C, in the presence of a base such as sodium hydride, or sodium methylate or potassium 1,1-dimethylethylate and optionally in the presence of a catalyst such as lithium, magnesium or zinc bromide or iodide.

In a second step, a B-ketoester of the general formula (IV) is condensed with an amidine of the general formula to give a pyrimidinone of the general formula wherein R and R 5 are as defined above. The reaction is carried out by heating, between 40 0 C and 120 0 C, a mixture of the two compounds, optionally in a solvent such as methanol, ethanol, butanol or toluene, and optionally in the presence of a base such as sodium methylate, potassium carbonate, sodium acetate, pyridine, triethylamine or 4-dimethylaminopyridine.

In a third step, the deprotection and/or the transformation of the group R 5 into the group R 3 is performed, depending on the nature of the group: when R 5 is a carboxylic ester, the compounds of general formula (VI) are converted, by an acidic or a basic hydrolysis, to the compounds of general formula wherein R 1 and R 2 are as defined above and R 3 is a CO 2 H group; the CO 2

H

group can further be transformed, under classical conditions, by activation by means of various reagents and then by reaction with amines or sulfonamides, to obtain compounds of general formula wherein R 3 is a CONHSO 2

R

11 or CONHOR 12 group and R 1

R

2

R

11

R

12 are as defined above.

*when Rs is a triphenylmethyl-1H-tetrazol-5-yl or a 1,1-dimethylethyl-1H-tetrazol-5-yl group, it is deprotected in an acidic medium, under classical conditions, to yield compounds of general formula wherein R 3 is the group and R 1 and R 2 are as defined above.

*when Rg is a nitro group, it is transformed into an amino group by reduction, to yield the compounds of general formula (VI) which are converted, by acylation or sulfonylation under classical conditions, to compounds of general formula (I) wherein R 3 is a NHCOR 11 or a NHSO 2 R11 group and R 1

R

2 and Ri 1 are as defined above.

The following examples illustrate the preparation of the compounds of general formula The analysis confirm their structure.

Example 1 (6-butyl-2-phenylmethyl-4-oxo-1 yl)methyl][1,1'-biphenyl]-2-carboxylic acid.

A mixture of 0.56 g of benzeneethanimideamide and 1.7 of methyl 4'-[(2-methoxycarbonyl)- 3-oxoheptyl][1,1'-biphenyl]-2-carboxylate is heated at 95 0

C,

under an atmosphere of argon, for 4 hours. The product is purified by chromatography on alumina., by eluting with a mixture of dichloromethane and methanol, to obtain 1.0 g of the product. This product is redissolved in a mixture of 30 ml of methanol and 3 ml of water in the presence of 1.0 g of sodium hydroxide. It is refluxed for 3 hours and concentrated under reduced pressure. The residue is taken up in water. The aqueous phase is washed with ether, filtered and acidified with an aqueous 3 N solution of hydrochloric acid. The precipitate is filtered and recristallized in methanol to obtain 0.60 g of the compound in the form of a white powder.

Melting point 219 0

C

Example 2 4'-([6-butyl-2-(2-phenylethyl)-4-oxo-1,4-dihydro-pyrimidin-5yl]methyl][1,1'-biphenyle]-2-carboxyli acid.

A mixture of 1.0 g of benzenepropanimideamide 35 and 2.4 g of methyl 4'-[(2-methoxycarbonyl)-3- 7 oxoheptyl][1,1'-biphenyl]-2-carboxylate is heated at 95 0

C,

for 6 hours. The product is purified by chromatography on silica gel column, by eluting with a mixture of dichloromethane and methanol, to obtain 1.0 g of the product in the form of a syrup. This product is redissolved in a mixture of 30 ml of methanol and 3 ml of water in the presence of 1.1 g of sodium hydroxide. It is refluxed for 3 hours and concentrated under reduced pressure. The residue is taken up in water. The aqueous phase is washed with ether, filtered and acidified with an aqueous 3 N solution of hydrochloric acid. The precipitate is filtered and recristallized in methanol to obtain 0.60 g of the compound in the form of a white powder.

Melting point 194°C Example 3 6-butyl-2-(2-phenylethyl)-5-[[2'-(1H-tetrazol-5-yl)[1,1'biphenyl]-4-yl]methyl]-pyrimidin-4(1H)-one.

3.1. methyl 3-oxo-2-[[2'-(1-triphenylmethyl-1H-tetrazol-5yl)[1,1'-biphenyl]-4-yl]methyl]heptanoate.

To a solution of 0.97 g of potassium 1,1-dimethylethylate in ml of dimethylformamide, chilled on an ice bath, under an atmosphere of argon, a solution of 1.3 g of methyl 3-oxoheptanoate in 13 ml of dimethylformamide is added, followed by 1.67 g of lithium bromide and a solution of 5 g of (bromomethyl)[1,1'-biphenyl]-2-yl]-1-triphenylmethyl-1Htetrazole in 25 ml of dimethylformamide. The reaction mixture is stirred for 5 hours at room temperature and then diluted with 300 ml of ether. The mixture is washed twice with 100 ml of water and then with 100 ml of a saturated aqueous solution of ammonium chloride. It is dried on magnesium sulfate and evaporated in vacuo to obtain 4.6 g of the product in the form of a yellow oil used as such in the following step.

3.2. 6-butyl-2-(2-phenylethyl)-5-[[2'-(1-triphenylmethyl-1H- -tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-pyrimidin-4 one.

A mixture of 0.7 g of benzenepropanimidamide and 3 g of the 8 foregoing compound is heated, under an atmosphere of argon, at 90°C, for 2 hours. The residue is taken up in 120 ml of dichloromethane and the mixture is washed twice with 50 ml of an aqueous 1 M solution of potassium carbonate and then with 50 ml of an aqueous 0.1 N solution of hydrochloric acid. It is dried on magnesium sulfate and evaporated. The residue is purified by chromatography on silica gel column by eluting with a mixture of dichloromethane and methanol, to obtain 0.85 g of the compound in the form of a whitish foam.

3.3. 6-butyl-2-(2-phenylethyl)-5-[[2'-(1H-tetrazol-5yi)[1,1'-biphenylJ-4-yl]methyi]-pyrimidin-4(1H)-one.

0.6 g of the foregoing compound is dissolved in a mixture of ml of methanol and 3 ml of diethylether. 2.7 ml of a 1.57 M solution of hydorchloric acid in diethylether are added. The mixture is left at room temperature for 2 hours and then evaporated. The residue is taken up in 70 ml of an aqueous solution of sodium hydroxide. It is washed three times with ml of ether and acidified with hydrochloric acid. The precipitate is filtered and recristallized in methanol to obtain 0.22 g of the compound in the form of a white powder.

Melting point 226-228 0

C

The following table illustrates the structures and physical properties of some compounds according to the invention.

6 ;1 v ii

A-.

Ito Table R2~ 0 Compound I R Me] tincj uoiiL I

I

1 2 3 4 6 CA11

C

4 11 9

C

4

H

9 c 4 11 9

CAH

C

6 11 5

-CH

2

C

6

H-

5

(CH

2 2 7

C

6

H

5

(CH

2 2-

C

6 I C I27 4-C11 3 0-C 6

H

4 (C'1 2 2 4-F-C 6 !!1 4 (C'1 2 2c 2 if C0 2 11 1 II-tetrazol-5-yl 1ll -tLecLrazol 5-y 1 111-i-etrazol -5-yi- 111I- tetrazoi.-5-yl 219 194 226-228 226-228 194-198 198-203 Compound J

R

T

7 8 9

C

4 H 9 C 4 H 9

C

4

H

9 3, 4, 5- (CH 3 o 3

-C

6 11 2

(CH

2 2- 3-F, 4-CH 3

O-C

6

H

3

(CH

2 2 4-HO 2

C-C

6

H

4

-CH

2 1I--tetrazol-5-yl 1 II-Letrpzo1-5-yl Melting point 198-200 21 3-21 4 1 H-LeLr~ .zol-5-yl 27 2-27 L I i.

U

lf The compounds of the invention have been the subject of pharmacological studies which have demonstrated their antagonistic properties to angiotensin II.

Test of binding of Hi-angiotensin II to rabbit adrenal cortex.

Male Fauves de Bourgogne rabbits (2-3 kg body weight) are used. Rabbits are sacrificed by cervical dislocation, the adrenal gland excised and the cortex rapidly dissected at 4 0 C. Tissues are homogenized in 10 ml of ice-cold 10 mM tris(hydroxymethyl)aminomethane buffer solution, containing 0.33 M sucrose and 1 mM ethylenediaminetetraacetic acid, adjusted to pH 7.4 with hydrochloric acid, in an electrical Potter apparatus at a speed of 1200 revolutions per minute.

The volume of the preparation is adjusted to 25 ml with trissucrose buffer, before centrifuging for 15 min at 1075 g. The supernatant is kept, the pellet is rehomogenized in 10 ml of tris-sucrose buffer and centrifuged as described above. Both supernatants are pooled and centrifuged for 30 min at 47 800 g. The resulting pellet is resuspended in 150 volumes 100 mg of tissue in 15 ml of buffer) of an incubation buffer containing 50 mM tris-HCl, 150 mM NaCI, 5 mM ethylenediaminetetraacetic acid, 1.25 pg/ml bacitracin, 100 uM phenylmethylsulfonylfluoride and 0.2 bovine serum albumin (pH 7.4 at 25 0

C).

Corticoadrenal microsomes (100 ul of suspension) are incubated in the presence of 2 nM [3H]-angiotensin II (New England Nuclear, specific activity 61 Ci/mmol) in a final volume of 0.5 ml of incubation buffer for 30 min at 25 0

C.

Following incubation, the microsomes are harvested by filtration on 0.45 pm Millipore HAWP" cellulose nitrate filters, pretreated with bovine serum albumin, and washed using three 5 ml aliquots of ice-cold tris-HCl buffer.

Membrane bound radioactivity retained by the filters is quantified using liquid scintillation spectrometry.

Specific 3 H]-angiotensin II binding is defined as the amount of filter-retained radioactivity that could be inhibited by S incubation in the presence of 1 pM of unlabelled angiotensin 7i 12 .II. It represents 90 to 95 of the total amount of filterretained radioactivity.

Specific [3HI-angiotensin II binding is measured in the presence of various concentrations of the test compounds and the IC., the concentration of the test compound which inhibits 50 of specific 3 H]-angiotensin II binding, is graphically determined.

The IC. values of the compounds of the invention are between nM and 10 uM.

Inhibition of pressor response to angiotensin II in rat.

Male Sprague-Dawley rats (250-280 g body weight; Charles River France) are anesthetized with sodium pentobarbital (55 mg/kg and maintained under artificial respiration (Harvard T M respirator; rate 70 ml per minute, volume of air 1 ml per 100 g body weight). The animals are pithed through the orbit of the right eye with a metal rod. The right and left vagus nerves are sectionned (bivagotomy); the right carotid artery is ligatured, the left carotid artery being catheterized in order to measure the blood pressure using a pressure cell (Statham T P23Db type). A femoral vein is catheterized for i.v. administration of drug.

Blood pressure is measured after i.v. administration of 0.5 jg/kg angiotensin II. Compounds of the invention or saline vehicle are administered 5 min (for i.v. studies) or min (for p.o. studies) before injection 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 Sangiotensin II is used to evaluate the antagonistic potential of the compounds of the invention to angiotensin II.

The compounds of the invention or their suitable salts may 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 or their suitable salts may

I

also be used in combination with other substances possesing cardiovascular activity such as diuretics, a-blockers, B-blockers, calcium antagonists or angiotensine I converting enzyme inhibitors.

The compounds of the invention or their suitable salt6 may be provided in any pharmaceutical form suitable for treatment by oral, parenteral, intramuscular or rectal administration tablets, capsules, hard gelatin capsules, sterile solutions or suspensions, suppositories etc..

For the treatment of glaucoma, tie compounds of the invention or their suitable salts may be provided in the form of tablets, hard gelatin capsules, injectable solutions or topical ocular formulations.

The compositions of the invention may be administered to patients in an amount which may range from 1 to 1000 mg per day and per patient, in one or more doses.

o #0 C 1oo Q (*oo

Claims

1. A compound in the three tautomeric forms, having the formulas and 'OH wherein RI represents a straight butyl group, R 2 represents a phenylmethyl group, a 4-carboxyphenylmethyl group, a phenylethyl group, a 4-methoxyphenylethyl group, a

4-fluorophenylethyl group, a 3,4,5-trimethoxyphenylethyl group, a 3-fluoro-4-methoxyphenylethyl group, R 3 is a CO 2 H or a 1H-tetrazol-5-yl group. 2. A method for preparing compounds as defined in claim 1, characterized in that a p-ketoester of the formula (II), 0 0 RI' OR 4 (II) in which R, is as defined in claim 1 and R 4 represents a methyl or an ethyl group, is reacted with a derivative of the 931208,p:\oper\dab,11059-92.340,23 15 formula (III) (III) wherein L represents a leaving group and R S represents either a carboxylic group C0 2 R 6 wherein R 6 is a methyl, ethyl, 1,1-dimethylethyl or benzyl group, either a nitro group, either a protected 1H-tetrazol-5-yl group, to yield a compound of formula (IV), o 0 Ri OR 4 (IV) wherein R 1 R 4 and Rg are as defined in claim 1 and ahove, which compound is reacted with an amidine of formula (V) R 2 HN;K NH 2 -j wherein R 2 is as defined in claim 1, to obtain a compound of formula (VI) ^ts^ (VI) I p i wherein R 1 R 2 and R 5 are as defined in claim 1 and above, then the R 5 group is transformed and/or deprotected, in accordance with the nature of this group, to obtain, after transformation, a compound of formula 3. The method as defined in claim 2, characterized in that the compounds of formula (VI) wherein R 5 is a triphenylmethyl- or a group, are subjected to a deprotection in an acidic medium, to yield compounds of general formula wherein R 3 is the group and R, and R 2 are as defined above. 4. The method as defined in claim 2, characterized in that the compounds of formula (VI) wherein R, is a carboxylic ester and R 1 and R 2 are as defined in claim 1 are converted, by an acidic or a basic hydrolysis, to the compounds of general formula wherein R, and R 2 are as defined above and R 3 is a CO 2 H group.

5. A pharmaceutical composition, characterized in that it contains a compound defined in claim 1, in association with any appropriate excipient.

6. Compounds of formula methods for their preparation or pharmaceutical compositions of methods of treatment involving them, substantially as hereinbefore described with reference to the Examples. DATED this 8th day of November, 1993. SYNTHELABO By its Patent Attorneys DAVIES COLLISON CAVE 931208,p:\oper\dab,11059-92340,25 4-PYRIMIDINONE DERIVATIVES, THEIR PREPARATION AND THEIR APPLICATION IN THERAPY SYNTHELABO Inventors Christian HOORNAERT Marc DAUMAS Michel ALETRU Jean-Claude MULLER Abstract 1. Compounds which can be expressed as tautomeric forms and having the formulas and R2 2 R 2 N-NH N N H1N'N R 3 23 R 3 wherein RI a straight or branched 7 )alkyl group or a straight or branched (C3_ 9 )alkenyl group or a cyclo(C 3 7 )alkyl(C_ 6)alkyl group, R 2 an atom of hydrogen, or a straight or branched (C,_7)alkyl group, or a cyclo(C 3 _)alkyl(C1_ 3 )alkyl group, or an aryl(C 1 3 )alkyl group optionally substituted on the ring, or an aryloxy(C,_ 3 )alkyl group optionally substituted on the ring, or an arylthio(C 3 )alkyl group optionally substituted on the ring, or an arylsulfonyl(C1- 3 )alkyl group optionally substituted on the ring, or a heteroaryl(Cl_ 3 )alkyl group optionally substituted on the ring, R 3 C02H, 1H-tetrazol-5-yl, NHCOR11, NHSO 2 R,1, CONHSO 2 R 11 or CONHOR, 2 group where a methyl, trifluoromethyl, or phenyl group optionally substituted, R 12 a hydrogen atom, or a methyl or a phenyl group optionally substituted. Therapeutic application.