WO2003015786A1 - 2, 5-substituted 1-(aminocarbonylalkyl) -pyrimidin-4-one derivatives with lp-pla2 inhinitory activity for the treatment of atherosclerosis - Google Patents

Abstract

Pyrimidinone compounds of the formula (I) are inhibitors of the enzyme Lp-PLA2 and are of use in therapy, in particular for treating atherosclerosis.

Description

, 5-SUBSTITUTED 1- (AMINOCARBONYLALKYL) -PYRIMIDIN-4-0NE DERIVATIVES WITH LP-PLA2 INHINITORY ACTIVITY FOR THE TREATMENT OF ATHEROSCLEROSIS

The present invention relates to certain novel pyrimidinone compounds, processes for their preparation, intermediates useful in their preparation, pharmaceutical compositions containing 5 them and their use in therapy, in particular in the treatment of atherosclerosis.

WO 95/00649 (SmithKline Beecham pic) describe the phospholipase A2 enzyme Lipoprotein Associated Phospholipase A2 (Lp-PLA2), the sequence, isolation and purification thereof, isolated nucleic acids encoding the enzyme, and recombinant host cells transformed with DNA

10 encoding the enzyme. Suggested therapeutic uses for inhibitors of the enzyme included atherosclerosis, diabetes, rheumatoid arthritis, stroke, myocardial infarction, reperfusion injury and acute and chronic inflammation. A subsequent publication from the same group further describes this enzyme (Tew D et al, Arterioscler Thromb Vas Biol 1996:16;591-9) wherein it is referred to as LDL-PLA2. A later patent application (WO 95/09921, Icos Corporation) and a

15 related publication in Nature (Tjoelker et al, vol 374, 6 April 1995, 549) describe the enzyme PAF-AH which has essentially the same sequence as Lp-PLA2 and suggest that it may have potential as a therapeutic protein for regulating pathological inflammatory events.

It has been shown that Lp-PLA2 is responsible for the conversion of phosphatidylcholine to 20 lysophosphatidylcholine, during the conversion of low density lipoprotein (LDL) to its oxidised form. The enzyme is known to hydrolyse the sn-2 ester of the oxidised phosphatidylcholine to give lysophosphatidylcholine and an oxidatively modified fatty acid. Both products of Lp-PLA2 action are biologically active with lysophosphatidylcholine, a component of oxidised LDL, known to be a potent chemoattractant for circulating monocytes. As such, 25 lysophosphatidylcholine is thought to play a significant role in atherosclerosis by being responsible for the accumulation of cells loaded with cholesterol ester in the arteries. Inhibition of the Lp-PLA2 enzyme would therefore be expected to stop the build up of these macrophage enriched lesions (by inhibition of the formation of lysophosphatidylcholine and oxidised free fatty acids) and so be useful in the treatment of atherosclerosis. 30

A recently published study (WOSCOPS-Packard et al, N. Eng. J. Med. 343 (2000) 1148-1155) has shown that the level of the enzyme Lp-PLA2 is an independent risk factor in coronary artery disease.

35 The increased lysophosphatidylcholine content of oxidatively modified LDL is also thought to be responsible for the endothelial dysfunction observed in patients with atherosclerosis. Inhibitors of Lp-PLA2 could therefore prove beneficial in the treatment of this phenomenon. An Lp-PLA2 inhibitor could also find utility in other disease states that exhibit endothelial dysfunction including diabetes, hypertension, angina pectoris and after ischaemia and reperfusion.

40

In addition, Lp-PLA2 inhibitors may also have a general application in any disorder that involves activated monocytes, macrophages or lymphocytes, as all of these cell types express Lp-PLA₂. Examples of such disorders include psoriasis. Furthermore, L -PLA2 inhibitors may also have a general application in any disorder that involves lipid oxidation in conjunction with Lp-PLA2 activity to produce the two injurious products, lysophosphatidylcholine and oxidatively modified fatty acids. Such conditions include the aforementioned conditions atherosclerosis, diabetes, rheumatoid arthritis, stroke, myocardial infarction, reperfusion injury and acute and chronic inflammation.

Patent applications WO 96/12963, WO 96/13484, WO96/19451, WO 97/02242, WO97/217675, WO97/217676, WO 96/41098, and WO97/41099 (SmithKline Beecham pic) disclose inter alia various series of 4-thionyl/sulfinyl/sulfonyl azetidinone compounds which are inhibitors of the enzyme Lp-PLA2- These are irreversible, acylating inhibitors (Tew et al, Biochemistry, 37, 10087, 1998).

Patent applications WO 99/24420, WO 00/10980, WO 00/66567, WO 00/66566 and WO 00/68208 (SmithKline Beecham pic) describe a new class of reversible, non-acylating inhibitors of the enzyme Lp-PLA2, in particular classes of pyrimidinone compounds. The early

2-(alkyltMo)pyrirnidin-4-one chemical lead is described in Bioorganic and Medicinal Chemistry Letters, 2000, 10, 395-8. The early Nl-substituted pyrimidinone leads are described in Bioorganic and Medicinal Chemistry Letters, 2000, 10, 2557-2561.

A further class of pyrimidinone compounds has now been identified which are inhibitors of the enzyme Lp-PLA2-

Accordingly, the present invention provides a compound of formula (I):

in which:

R¹ is an aryl or heteroaryl group, optionally substituted by 1, 2, 3 or 4 substituents which may be the same or different selected from Cn.\ 8)^aH ϊ_> C(l-1 g- alkoxy, Cn -l 8)alkylthio,

C(i _4)alkoxy, or, as a single substituent, optionally in combination with a further substituent as hereinbefore defined, CH COOH or a salt thereof, CH₂COOR⁸, CH2CONR⁹R¹⁰, CH₂CN, (CH₂)_mNR⁹R¹⁰, (CH₂)_mOH or (CH₂)_mOR⁶ where m is an integer from 1 to 3;

R is an aryl or heteroaryl group, optionally substituted by 1, 2, 3 or 4 substituents which may be the same or different selected from C -18)^alkyl_s C _ι 8)alkoxy, Cn _j g-jalkylthio, arylC(i_₁₈)alkoxy, hydroxy, halogen, CN, COR⁶, carboxy, COOR⁶, CONR⁹R¹⁰, NR⁶COR⁷, SO₂NR⁹R¹⁰, NR⁶SO₂R⁷, NR⁹R¹⁰, mono to perfluoro-C(i_4)alkyl, mono to perfluoro- Cn _4)alkoxy, and arylCn_4)alkyl;

R3 is Het-C(o_4)alkyl in which Het is a 5- to 7- membered heterocyclyl ring, bonded directly through a ring carbon atom, comprising N and optionally O or S, and in which N may be substituted by COR⁷, COOR⁷, CONR⁹R¹⁰, or C(₁_₆)alkyl optionally substituted by 1, 2 or 3 substituents selected from hydroxy, halogen, OR⁷, COR⁷, carboxy, COOR⁷, COOR⁸, CONR⁹R10 or R RlO, for instance, piperidin-4-yl or pyrrolidin-3-yl;

R4 is an aryl or a heteroaryl ring optionally substituted by 1, 2, 3 or 4 substituents which may be the same or different selected from Cn_i8)alkyL Cn _ι^\alkoxy, Cn.^g^alkylthio, arylC(₁.₁8)alkoxy, hydroxy,

SO2NR⁹R¹⁰, NR⁶S0₂R⁷, NR⁹R¹⁰, mono to perfluoro-C(i_4)alkyl and mono to perfluoro- Cn_4)alkoxy;

R5 is an aryl ring which is further optionally substituted by 1, 2, 3 or 4 substituents which may be the same or different selected from Cn_ιg\alkyl, Cn __}g\alkoxy, Cn_ιg)alkylthio,

Cn_4)alkoxy;

R⁶ and R⁷ are independently hydrogen or Cn _20)alkyl, for instance

(e.g. methyl or ethyl); R⁸ is Cn _4)alkyl or a pharmaceutically acceptable in vivo hydrolysable ester group;

R⁹ and RlO which may be the same or different is each selected from hydrogen, C(i_i2)alkyl, CH2R^{1 1}, CHR¹²CO2H or a salt thereof, or R⁹ and R¹⁰ together with the nitrogen to which they are attached form a 4- to 7-, preferably 5- to 7-, membered ring optionally containing one or more further heteroatoms selected from oxygen, nitrogen and sulphur, and optionally substituted by one or two substituents selected from hydroxy, oxo, Cn _4)alky Cn _ 4)alkylCO, aryl, e.g. phenyl, or aralkyl, e.g benzyl, for instance morpholine or piperazine;

R¹1 is COOH or a salt thereof, COOR⁸, CONR⁶R⁷, CN, CH₂OH or CH OR⁶;

R!2 is an amino acid side chain such as CH/TOH from serine; n is an integer from 1 to 4, preferably 1 or 3; X is O or S; and

Z is CR¹³R¹⁴ where R ³ and R^ are each hydrogen or Cπ _4)alkyl, or R" and R*4 together with the intervening carbon atom form a C(3_6)cycloalkyl ring.

Preferably, Z is CH2.

Examples of R1 when an aryl group include phenyl and naphthyl.

Examples of R when a heteroaryl group include a 5- or 6- membered, monocyclic heteroaryl group comprising 1 or 2 nitrogen heteroatoms.

Preferably, R* is pyrimidyl optionally substituted by 1 or 2 substituents preferably selected from oxo, arylCn 4)alkyl (e.g. benzyl), Cn_6)alkyl (e.g. methyl or ethyl), C(3_6)cycloalkyl, hydroxy, Cn_4)alkoxy (e.g. methoxy), carboxyCn 6)alkyl, Cn gΛalltylcarboxyCn g^alkyl, di- Cn _6)alkylamino, and morpholino; or pyrazolyl optionally substituted by Cn g^alkyl (e.g. methyl or ethyl).

Preferably, ZR* is pyrimid-5-ylmethyl optionally substituted by 2-methoxy, 2-trifluoromethyl, 2- (4-morpholino) or 2-dimethylamino; 2-oxo-pyrimid-5-ylmethyl or l-methyl-4-pyrazolylmethyl.

Preferably X is S.

Examples of R^ when an aryl group include phenyl and naphthyl. Examples of R² when a heteroaryl group include pyridyl, pyrimidinyl, pyrazolyl, furanyl, thienyl, thiazolyl, quinolyl, benzothiazolyl, pyridazolyl and pyrazinyl. Preferably, R-2 is phenyl optionally substituted by halogen.

Examples of R^CB^X include 4-fluorobenzylthio and 2,3-difluorobenzylthio.

Examples of R^ include Het-C(0-4)alkyl in which Het is a 5- to 7- membered heterocyclyl ring, bonded directly through a ring carbon atom, comprising N and in which N may be substituted by C(ι_g)alkyl. optionally substituted by C(ι_4)alkoxy. Preferably R^ is l-(2- methoxyethyl)piperidin-4-yl, 1 -methylpiperidin-4-yl, 1 -ethylpiperidin-4-yl, 1 -isopropylpiperidin- 4-yl and l-ethylpyrrolidin-2-ylmethyl.

Examples of R^ include phenyl optionally substituted by halogen; thiophene; pyridine; and pyrimidine.

Examples of R^ include phenyl optionally substituted by halogen, trifluoromethyl, or trifluoromethoxy, preferably at the 4-position.

Preferably, R^ and R^ together form a 4-(phenyl)phenyl substituent in which the remote phenyl ring may be optionally substituted by halogen or trifluoromethyl, preferably at the 4-position.

Pharmaceutically acceptable in vivo hydrolysable ester groups for R⁸ include those which break down readily in the human body to leave the parent acid or its salt.

Examples of values of pharmaceutically acceptable in vivo hydrolysable ester groups for R⁸ include:

-CH(R^a)O.CO.R ;

-CH(R^a)O.CO.OR^c;

-CH(R^a)CO.NR^eR^f

-R^dNR^eR^f; -CH₂ORg;

in which: R^a is hydrogen, (Cι-6)alkyl, in particular methyl, (C3-7)cycloalkyl, or phenyl, each of which may be optionally substituted;

R^D is (Cι-g)alkyl, (Cι-6)alkoxy(Cι-6)alkyl, phenyl, benzyl, (C3-7)cycloalkyl,

(Cι-6)alkyl(C3-7)cycloalkyl, l-amino(Cι-6)alkyl, or l-(Cι-6alkyl)amino(Cι-6)alkyl, each of which may be optionally substituted; or R^a and R^D together form a 1,2-phenylene group optionally substituted by one or two methoxy groups;

R^c is (Cι-₆)alkyl, (C₃-₇)cycloalkyL (C₁-₆)alkyl(C₃-₇)cycloalkyl;

R" is (Cι-6)alkylene optionally substituted with a methyl or ethyl group;

R^e and R^ which may be the same or different is each (Ci -g)alkyl; or aryl(Cι-4) alkyl, optionally substituted with e.g. hydroxy;

Rg is (Cι-₆)alkyl;

R" is hydrogen, (Cj-^alkyl or phenyl;

R¹ is hydrogen or phenyl optionally substituted by up to three groups selected from halogen,

(Ci -6)-alkyl, or (Ci -g)alkoxy; and

Y* is oxygen orNH; for instance:

(a) acyloxyalkyl groups such as acetoxymethyl, isobutyryloxymethyl, pivaloyloxymethyl, benzoyloxymethyl, α-acetoxyethyl, α-pivaloyloxyethyl, l-(cyclohexylcarbonyloxy)ethyl, (1 -aminoethyl)carbonyloxymethyl, 2-methoxyprop-2-ylcarbonyloxymethyl, phenylcarbonyloxymethyl and 4-methoxyphenyl-carbonyloxymethyl;

(b) alkoxy/cycloalkoxycarbonyloxyalkyl groups, such as ethoxycarbonyloxymethyl, t- butyloxycarbonyloxymethyl, cyclohexyloxycarbonyloxymethyl, 1- methylcyclohexyloxycarbonyloxymethyl and α-ethoxycarbonyloxyethyl; (c) dialkylaminoalkyl, especially di-loweralkylamino alkyl groups such as dimethylaminomethyl, dimethylaminoethyl, diethylaminomethyl or diethylaminoethyl;

(d) acetamido groups such as N-N-dimethylaminocarbonylmethyl, N,N-(2- hydroxyethyl)aminocarbonylmethyl;

(e) lactone groups such as phthalidyl and dimethoxyphthalidyl; (f) (5-methyl-2-oxo-l,3-dioxolen-4-yl)methyl; and

(g) (2-methoxycarbonyl-E-but-2-en-yl)methyl. Examples of pharmaceutically acceptable in vivo hydrolysable ester groups for R⁸ include: (2-methoxycarbonyl-E-but-2-en-yl)methyl, isobutyryloxymethyl, 2-methoxyprop-2- ylcarbonyloxymethyl, phenylcarbonyloxymethyl, 4-methoxyphenyl-carbonyloxymethyl, t- butyloxycarbonyloxymethyl, cyclohexyloxy-carbonyloxymethyl, 1- methylcyclohexyloxycarbonyloxymethyl, N,N-dimethylaminocarbonylmethyl, and (5-methyl-2- oxo-l,3-dioxolen-4-yl)methyl.

It will be appreciated that in some instances, compounds of the present invention may include a basic function such as an amino group as a substituent. Such basic functions may be used to form acid addition salts, in particular pharmaceutically acceptable salts. Pharmaceutically acceptable salts include those described by Berge, Bighley, and Monkhouse, J. Pharm. Sci., 1977, 66, 1-19. Such salts may be formed from inorganic and organic acids. Representative examples thereof include maleic, fumaric, benzoic, ascorbic, pamoic, succinic, bismethylenesalicylic, methanesulfonic, p-toluenesulfonic, ethanedisulfonic, acetic, propionic, tartaric, salicylic, citric, gluconic, aspartic, stearic, palmitic, itaconic, glycolic, p-aminobenzoic, glutamic, taurocholic acid, benzenesulfonic, hydrochloric, hydrobromic, sulfuric, cyclohexylsulfamic, phosphoric and nitric acids.

It will be appreciated that in some instances, compounds of the present invention may include a carboxy group as a substituent. Such carboxy groups may be used to form salts, in particular pharmaceutically acceptable salts. Pharmaceutically acceptable salts include those described by Berge, Bighley, and Monkhouse, J. Pharm. Sci., 1977, 66, 1-19. Preferred salts include alkali metal salts such as the sodium and potassium salts.

When used herein, the term "alkyl" and similar terms such as "alkoxy" includes all straight chain and branched isomers. Representative examples thereof include methyl, ethyl, κ-propyl, iso- propyl, «-butyl, -fee-butyl, iso-butyl, t-butyl, «-pentyl and «-hexyl.

When used herein, the term "aryl" refers to, unless otherwise defined, a mono- or bicyclic aromatic ring system containing up to 10 carbon atoms in the ring system, for instance phenyl or naphthyl.

When used herein, the term "heteroaryl" refers to a mono- or bicyclic heteroaromatic ring system comprising up to four, preferably 1 or 2, heteroatoms each selected from oxygen, nitrogen and sulphur. Each ring may have from 4 to 7, preferably 5 or 6, ring atoms. A bicyclic heteroaromatic ring system may include a carbocyclic ring.

When used herein, the terms "halogen" and "halo" include fluorine, chlorine, bromine and iodine and fluoro, chloro, bromo and iodo, respectively.

Representative compounds of formula (I) are:

1 -(N-( 1 -(2-methoxy ethyl)piperidin-4-yl)-N-(4-(4- fluoromethylphenyl)benzyl)aminocarbonyl- methyl)-2-(2,3-difluorobenzyl)thio-5-(l-methyl-4-pyrazolylmethyl)pyrimidin-4-one bitartrate; 1 -(N-( 1 -ethylpiperidin-4-yl)-N-(4-(4-trifluoromethylphenyl)benzyl)aminocarbonylmethyl)-2- (2,3-difluorobenzyl)mio-5-(l-methyl-4-pyrazolylmemyl)pyrimidin-4-one bitartrate; 1 -(N-( 1 -memylpiperidin-4-yl)-N-(4-(4-trifluoromethylphenyl)benzyl)aminocarbonylmethy l)-2- (2,3-difluorobenzyl)thio-5-( 1 -methyl-4-pyrazolylmethyl)pyrimidin-4-one bitartrate; N-(l-wopropylpiperidin-4-yl)-N-(4-(4-trifluorome ylphenyl)benzyl)aminocarbonylmethyl)-2- (2,3-difluorobenzyl)thio-5-( 1 -methyl-4-pyrazolylmethyl)pyrimidin-4-one bitartrate; 1 -(N-( 1 -(2-methoxyethyl)piperidin-4-yl)-N-(4-(4-trifluoromethylphenyl)benzyl)aminocarbonyl- methyl)-2-(4-fluorobenzyl)thio-5-(l-methyl-4-pyrazolylmethyl)pyrimidin-4-one bitartrate; 1 -(N-( 1 -methylpiperidin-4-yl)-N-(4-(4-trifluoromethylρhenyl)benzyl)aminocarbonylmethyl)-2- (4-fluorobenzyl)thio-5-(l-methyl-4-pyrazolylmethyl)pyrimidin-4-one bitartrate;

1 -(N-( 1 -ethylpiperidin-4-yl)-N-(4-(4-trifluoromethylphenyl)benzyl)aminocarbonylmethyl)-2-(4- fluorobenzyl)tWo-5-(l-methyl-4-pyrazolylmethyl)ρyrimidin-4-one bitartrate; 1 -(N-( 1 -wc>propylpiperidin-4-yl)-N-(4-(4-trifluoromethylphenyl)benzyl)aminocarbonyhnethyl)- 2-(4-fluorobenzyl)thio-5-(l-methyl-4-ρyrazolylmethyl)pyrimidin-4-one bitartrate; 1 -(N-( 1 -ethylpyrrolidin-2-ylmethyl)-N-(4-(4-cUorophenyl)benzyl)aminocarbonylmethyl)-2-(4- fluorobenzyl)thio-5-(l-methylpyrazol-4-ylmethyl)pyrimidin-4-one or a pharmaceutically acceptable salt thereof, including the hydrochloride, bitartrate, citrate and tosylate salts.

Since the compounds of the present invention, in particular compounds of formula (I), are intended for use in pharmaceutical compositions, it will be understood that they are each provided in substantially pure form, for example at least 50% pure, more suitably at least 75% pure and preferably at least 95% pure (% are on a wt/wt basis). Impure preparations of the compounds of formula (I) may be used for preparing the more pure forms used in the pharmaceutical compositions. Although the purity of intermediate compounds of the present invention is less critical, it will be readily understood that the substantially pure form is preferred as for the compounds of formula (I). Preferably, whenever possible, the compounds of the present invention are obtained in crystalline form.

When some of the compounds of this invention are allowed to crystallise or are recrystallised from organic solvents, solvent of crystallisation may be present in the crystalline product. This invention includes within its scope such solvates. Similarly, some of the compounds of this invention may be crystallised or recrystallised from solvents containing water. In such cases water of hydration may be formed. This invention includes within its scope stoichiometric hydrates as well as compounds containing variable amounts of water that may be produced by processes such as lyophilisation. In addition, different crystallisation conditions may lead to the formation of different polymorphic forms of crystalline products. This invention includes within its scope all polymorphic forms of the compounds of formula (I).

Compounds of the present invention are inhibitors of the enzyme lipoprotein associated phospholipase A2 (Lp-PLA2) and as such are expected to be of use in therapy, in particular in the treatment of atherosclerosis. In a further aspect therefore the present invention provides a compound of formula (I) for use in therapy. The compounds of formula (I) are inhibitors of lysophosphatidylcholine production by Lp-PLA2 and may therefore also have a general application in any disorder that involves endothelial dysfunction, for example atherosclerosis, diabetes, hypertension, angina pectoris and after ischaemia and reperfusion. In addition, compounds of formula (I) may have a general application in any disorder that involves lipid oxidation in conjunction with enzyme activity, for example in addition to conditions such as atherosclerosis and diabetes, other conditions such as rheumatoid arthritis, stroke, inflammatory conditions of the brain such as Alzheimer's Disease, myocardial infarction, reperfusion injury, sepsis, and acute and chronic inflammation. Further such conditions include various neuropsychiatric disorders such as schizophrenia (see Psychopharmacology Bulletin, 31, 159-165, 1995).

Further applications include any disorder that involves activated monocytes, macrophages or lymphocytes, as all of these cell types express Lp-PLA₂. Examples of such disorders include psoriasis.

Accordingly, in a further aspect, the present invention provides for a method of treating a disease state associated with activity of the enzyme Lp-PLA₂ which method involves treating a patient in need thereof with a therapeutically effective amount of an inhibitor of the enzyme. The disease state may be associated with the increased involvement of monocytes, macrophages or lymphocytes; with the formation of lysophosphatidylcholine and oxidised free fatty acids; with lipid oxidation in conjunction with Lp-PLA2 activity; or with endothelial dysfunction.

Compounds of the present invention may also be of use in treating the above mentioned disease states in combination with an anti-hyperlipidaemic, anti-atherosclerotic, anti-diabetic, anti- anginal, anti-inflammatory, or anti-hypertension agent or an agent for lowering Lp(a). Examples of the above include cholesterol synthesis inhibitors such as statins, anti-oxidants such as probucol, insulin sensitisers, calcium channel antagonists, and anti-inflammatory drugs such as NSAIDs. Examples of agents for lowering Lp(a) include the aminophosphonates described in WO 97/02037, WO 98/28310, WO 98/28311 and WO 98/28312 (Symphar SA and SmithKline Beecham).

A preferred combination therapy will be the use of a compound of the present invention and a statin. The statins are a well known class of cholesterol lowering agents and include atorvastatin, simvarstatin, pravastatin, cerivastatin, fluvastatin, lovastatin and ZD 4522 (also referred to as S- 4522, rosuvastatin, Astra Zeneca). The two agents may be administered at substantially the same time or at different times, according to the discretion of the physician.

A further preferred combination therapy will be the use of a compound of the present invention and an anti-diabetic agent or an insulin sensitiser, as coronary heart disease is a major cause of death for diabetics. Within this class, preferred compounds for use with a compound of the present invention include the PPARgamma activators, for instance GI262570 (GlaxoSmithKline) and also the glitazone class of compounds such as rosiglitazone (Avandia, GlaxoSmithKline), troglitazone and pioglitazone. In therapeutic use, the compounds of the present invention are usually administered in a standard pharmaceutical composition. The present invention therefore provides, in a further aspect, a pharmaceutical composition comprising a compound of formula (I) and a pharmaceutically acceptable carrier.

Suitable pharmaceutical compositions include those which are adapted for oral or parenteral administration or as a suppository. Compounds of formula (I) which are active when given orally can be formulated as liquids, for example syrups, suspensions or emulsions, tablets, capsules and lozenges. A liquid formulation will generally consist of a suspension or solution of the compound or pharmaceutically acceptable salt in a suitable liquid carrier(s) for example, ethanol, glycerine, non-aqueous solvent, for example polyethylene glycol, oils, or water with a suspending agent, preservative, flavouring or colouring agent. A composition in the form of a tablet can be prepared using any suitable pharmaceutical carrier(s) routinely used for preparing solid formulations. Examples of such carriers include magnesium stearate, starch, lactose, sucrose and cellulose. A composition in the form of a capsule can be prepared using routine encapsulation procedures. For example, pellets containing the active ingredient can be prepared using standard carriers and then filled into a hard gelatin capsule; alternatively, a dispersion or suspension can be prepared using any suitable pharmaceutical carrier(s), for example aqueous gums, celluloses, silicates or oils and the dispersion or suspension then filled into a soft gelatin capsule. Typical parenteral compositions consist of a solution or suspension of the compound of formula (I) in a sterile aqueous carrier or parenterally acceptable oil, for example polyethylene glycol, polyvinyl pyrrolidone, lecithin, arachis oil or sesame oil. Alternatively, the solution can be lyophilised and then reconstituted with a suitable solvent just prior to administration. A typical suppository formulation comprises a compound of formula (I) which is active when administered in this way, with a binding and/or lubricating agent such as polymeric glycols, gelatins or cocoa butter or other low melting vegetable or synthetic waxes or fats.

Preferably the composition is in unit dose form such as a tablet or capsule. Each dosage unit for oral administration contains preferably from 1 to 500 mg (and for parenteral administration contains preferably from 0.1 to 25 mg) of a compound of the formula (I). The daily dosage regimen for an adult patient may be, for example, an oral dose of between 1 mg and 1000 mg, preferably between 1 mg and 500 mg, or an intravenous, subcutaneous, or intramuscular dose of between 0.1 mg and 100 mg, preferably between 0.1 mg and 25 mg, of the compound of the formula (I), the compound being administered 1 to 4 times per day. Suitably the compounds will be administered for a period of continuous therapy, for example for a week or more.

A compound of formula (I) may be prepared by a number of processes which include:

(a) reacting a compound of formula (13):

(π) in which X, Z, R*, R^ and n are as hereinbefore defined, with a compound of formula (HI):

R⁵-R⁴-CH₂NHR³

OH) in which R³, R⁴ and R^ are as hereinbefore defined; under amide forming conditions. Amide forming conditions are well known in the art, see for instance Comprehensive Organic Synthesis 6, 382-399, and include reacting the acid compound of formula (H) and the amine compound of formula (HI) in an inert solvent such as dichloromethane, at ambient temperature, in the presence of a coupling agent. Preferred coupling agents include those developed for use in peptide chemistry, such as l-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride ("EDC"), preferably in the presence of an additive such as 1-hydroxybenzotriazole, or 0-(7-azabenzotriazol-l-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate ("HATU"), preferably in the presence of di-isopropylethylamine.

(b) reacting a compound of formula (IV):

(TV) in which X, Z, R and R² are as hereinbefore defined, with a compound of formula (V):

R⁵-R⁴-CH₂NR³-CO-(CH₂)_n-L¹

(V) in which n, R³, ⁴ and R^ are as hereinbefore defined, and L* is a leaving group such as halogen, for instance bromo or iodo, in the presence of a base such as a secondary or tertiary amine, for instance di-isopropylethylamine, in an inert solvent such as dichloromethane;

(c) when X is S, reacting a compound of formula (VI):

(VI) in which n, Z, R , R³, R⁴ and R^ are as hereinbefore defined, with a compound of formula (VII):

(vπ) in which R^ and L* are as hereinbefore defined, in the presence of a base such as a secondary or tertiary amine, for instance di-isopropyl- ethylamine, in an inert solvent such as dichloromethane; or

(d) when X is O, reacting a compound of formula (VDT):

(vm) in which n, Z, R*, R³, R⁴ and R^ are as hereinbefore defined, and !?^■ is a leaving group such as halogen or alkylthio, for instance methylthio, with a compound of formula (LX):

R -CH₂-OH

(IX) in which B? is as hereinbefore defined, in the presence of a base such as 4-dimethylaminopyridine, in an inert solvent such as pyridine.

Compounds of formulae (Tf), (IV), (VI) and (VIII) for use in the above processes may be prepared by processes illustrated in the following scheme I:

Scheme I in which:

L³ is a C(l-6)alkyl group, for instance methyl;

R!5 is a Cn _6)alkyl group, for instance methyl, ethyl, or t-butyl, and

L¹, L², R¹, R2, R³, R⁴, R⁵, n, X and Z are as hereinbefore defined.

With reference to Scheme I:

Amide forming conditions for step (a) are well known in the art. Preferably, the acid of formula (II) is reacted with the amine of formula (HI) in an inert solvent, such as dichloromethane, at ambient temperature and in the presence of a coupling agent such as 0-(7-azabenzotriazol-l-yl)- N,N,N',N'-tetramethyluronium hexafluorophosphate and di-isopropylethylamine or l-(3- dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride in the presence of 1- hydroxybenzotriazole.

Alkylation conditions for step (b) include reaction in the presence of a base such as a secondary or tertiary amine, for instance di-wo-propylethylamine, in an inert solvent such as dichloromethane, forming an intermediate ester which is converted to the acid of formula (13) by hydrolysis, for instance using aqueous sodium hydroxide in a solvent such as dioxan or by alternative deprotection, for instance using trifluoracetic acid in a solvent such as dichloromethane.

Conditions for step (c) include under thioether forming conditions. Advantageously, the reaction is carried out in the presence of a base such as sodium ethoxide or potassium carbonate, preferably in a solvent such as ethanol or dimethyl formamide, or a secondary or tertiary amine base such as di-isopropylethyl amine, in solvent such as dichloromethane.

In step (d), a compound of formula (XV13) is reacted with thiourea, in the presence of sodium ethoxide (preferably generated in situ from sodium and ethanol).

In step (e), a compound of formula (XVIII) is reacted with ethyl formate in the presence of a base such as sodium hydride or potassium isopropoxide.

In step (f), a compound of formula (IN) is reacted with a compound of formula (V) in the presence of a base such as a secondary or tertiary amine, for instance di-isopropylethylamine, in an inert solvent such as dichloromethane

In step (g), a compound of formula (XH3) is reacted with a compound of formula (X1N) in a solvent such as dimethylformamide to form an intermediate thiourea, which is then treated with a base such as sodium methoxide.

In step (h), a compound of formula (XVI) is reacted with a metal thiocyanate, for example potassium thiocyanate, in a solvent such as acetonitrile.

In step (i), a compound of formula (XVII) is reacted with a methylating agent such as dimethyl sulphate in the presence of a base such as potassium carbonate, followed by hydrolysis of the intermediate ester in conventional manner e.g. by basic hydrolysis using sodium hydroxide to give the corresponding carboxylic acid which may then be converted into the acyl chloride, for instance by treatment with oxalyl chloride.

In step (j), a catalyst such as 4-dimethylaminopyridine, and in a solvent such as pyridine are used.

In step (k), a compound of formula (XH3) is reacted with a compound of formula (XV) in a solvent such as dimethylformamide to form an intermediate thiourea, which is then treated with a base such as sodium methoxide. The present invention will now be illustrated by the following examples.

Examples

The structure and purity of the intermediates and examples was confirmed by 1H-NMR and (in nearly all cases) mass spectroscopy, even where not explicitly indicated below.

Intermediate Al - l-(2-Methoxyethyl)piperidin-4-one

MeO — / —

A mixture of l-bromo-2-methoxy ethane (38.95mL), piperidin-4-one hydrochloride (56.2g), triethylamine (116mL), and dry dichloromethane (500mL) was stirred and heated at reflux under argon for 90 h, then cooled and washed with water. The aqueous layer was extracted with dichloromethane and the combined organic layers dried over (MgS0₄) and solvent evaporated. The residue was chromatographed on silica gel using NH_j/MeOH/CH-Cl_j to give the title compound. ^-NMR (CDC1₃) δ 2.48 (4H,m), 2.70 (2H,t), 2.82 (4H,m), 3.38 (3H,s), 3.55 (2H,t); MS (APCI+) found (M+l) = 158; C₈H₁₅N0₂ requires 157.

Intermediate A2 4-(4'-TrifluoromethyIphenyl)benzonitrile

A mixture of 4-trifluoromethylbenzeneboronic acid (60g) and 4-bromobenzonitrile (57.5g) was suspended in PrOH (500mL) and a solution of Na₂C0₃ (67g) in water (500mL) added with stirring under argon. 10% Pd/C (8.2g) was added and the mixture stirred and heated at reflux for 65 h. The mixture was filtered hot through celite and the celite washed with a small amount of /PrOH. Water (lOOOmL) was added to the hot combined filtrates and the solution was cooled in ice. The title compound was collected by filtration. Further title compound was obtained by washing the celite pad with CH₂C1₂ (2x25 OmL), combining and evaporating the solvent. Total yield (64.4g). 1H-NMR (CDCI3) δ 7.8-7.9 (2H,m), 7.9-8.05 (6H,m); MS (APCI+) found (M+l) = 248, Cι H₈F N requires 247.

Intermediate A3 4-(4-Trifluoromethylphenyl)benzyIamine hydrochloride

H,N

To a solution of intermediate A2 (96.7g) in absolute ethanol (5L) and concentrated hydrochloric acid (200mL) was added 10% palladium on charcoal (30.0g, 54% H₂0 paste). The mixture was stirred under 50psi hydrogen for 16h. Additional 10% palladium on charcoal (25.0g, 54% H₂0 paste) was added and the mixture was stirred under 50psi hydrogen for further 16 h. The mixture was filtered through celite and the solvent evaporated to give the title compound as a cream solid (102.5g). Η-NMR (d₆ DMSO) δ 8.61 (3H,s), 7.93 (2H,d), 7.83 (2H,d), 7.80 (2H,d), 7.65 (2H,d), 4.08 (2H,s); MS (APCI+) found (M-NH₂) = 237, C₁₄H₁₂F₃N requires 251. Intermediate A4 - N-(l-(2-Methoxyethyl)-piperidin-4-yI)-4-(4- trifluoromethylphenyl)benzylamine

A solution of intermediate Al (14.16g) and intermediate A3 (25g) in 1,2-dichloroethane

(240mL) was treated portionwise with sodium triacetoxyborohydride (42.05g) and acetic acid (5mL) in an ice bath over 1 h. The mixture was allowed to warm to room temperature over 2 h and further intermediate Al (0.7 lg) was added and the mixture sonicated with stirring for 1.5 h. After stirring overnight, the reaction was added slowly to sodium hydroxide (2M, 600mL) (CARE gas evolution) and extracted with diethyl ether. The organic phase was dried (MgS0₄) and the solvent evaporated to afford a residue, which was chromatographed on silica gel using NH_j/MeOH/CH-Cl, to give the title compound (31.6g). Η-NMR (CDCL) δ 1.44-1.54 (2H,m), 1.91 (2H,br.d), 2.06 (2H,t), 2.51-2.58 (3H,m), 2.90-2.94 (2H,m), 3.35 (3H,s), 3.51 (3H,t), 3.87 (2H,s), 7.43 (2H,d), 7.55 (2H,d) 7.68 (4H,s); MS (APCI+) found (M+l) = 393; C22H27F3N2O requires 392.

The following intermediates were made by the method of Intermediate A4:

Intermediate A8 — N-((l-EthyIpyrrolidin-2-yl)methyl)-4-(4-chlorophenyl)benzylamine

A mixture of 4-(4-chloroρhenyl)benzaldehyde (lg),¹ 2-aminomethyl-l-ethylpyrrolidine (0.59g), 4A molecular sieves (lOg), and dry dichloromethane (30mL) was swirled at room temperature under argon for 16 h The solid was filtered off and washed with dichloromethane, and the combined filtrates evaporated to a green solid (1.3g). This imine intermediate was suspended in ethanol (30mL), cooled in ice and sodium borohydride (0.15g) added portionwise. The ice bath was removed, and the mixture stirred for 45min at room temperature then at 50°C for 1 h. The solvent was removed in vacuo, water was added to the residue, and the product extracted into dichloromethane. Drying and evaporation of the solvent gave a light green oil (1.2g). Η-NMR (CDCI3) δ 1.08 (3H,t), 1.5-2.0 (5H,m), 2.0-2.3 (2H,m), 2.4-2.65 (2H,m), 2.65-2.9 (2H,m), 3.1- 3.25 (lH,m), 3.85 (2H,2xd), 7.3-7.6 (8H,m); MS (APCI+) found (M+l) = 329, C20H25CIN2 requires 328. ¹ WO 00/66567

Intermediate Bl - 2-(2,3-DifluorobenzyIthio)-5-((l-methylpyrazol-4-yl)methyl)pyrimidin- 4-one

A mixture of 5-((l-methylpyrazol-4-yl)methyl)-2-thiouracil (15g),' 2,3-difluorobenzyl bromide (13.99g), potassium carbonate (23.08g), and dry DMF (150mL) was stirred under argon at 80°C for 17.5 h, then cooled and evaporated. The solid residue was suspended in water (200mL) with vigorous stirring, then acidified to pH2 with hydrochloric acid and stirred for a further 1 h. The white solid was filtered off and washed with water and ether to obtain the title compound (18.36g). -NMR (d6-DMSO) δ 3.43 (2H,s), 3.76 (3H,s), 4.45 (2H,s), 7.05-7.4 (5H,m), 7.45 (lH,m), 7.72 (lH,br.s); MS (APCI+) found (M+l) = 349; C₁₆H₁₄F₂N₄OS requires 348. ¹ WO 00/66567

Intermediate B2 - l-(tert-ButoxycarbonylmethyI)-2-(2,3-difluorobenzyIthio)-5-((l-methyl- pyrazol-4-yl)methyl)pyrimidin-4-one

A mixture of intermediate Bl (lOg), tert-butyl iodoacetate (7.33g), diisopropylethylamine (5.8mL) and dichloromethane (120mL) was stirred at room temperature under argon for 66 h. The solution was washed with aq. sodium bicarbonate then with aq. ammonium chloride, dried and evaporated to a pale viscous oil. Ethyl acetate (300mL) was added, the precipitate was filtered off and discarded, and the solution was chromatographed (silica, 2.5%-10% methanol / ethyl acetate + 0.5% aq. ammonia in dichloromethane). Product fractions were evaporated to give the title compound (9.39g). *H-NMR (d₆-DMSO) δ 1.36 (9H,s), 3.37 (2H,s), 3.76 (3H,s), 4.51 (2H,s), 4.67 (2H,s), 7.05-7.25 (lH,m), 7.23 (lH.m), 7.25-7.55 (4H,m); MS (APCI+) found (M+l) = 463; C22H24F2N4O3S requires 462. Intermediate B3 - l-(Carboxymethyl)-2-(2,3-difluorobenzylthio)-5-((l-methylpyrazol-4- yl)methyl)pyrimidin-4-one

Intermediate B2 (5g) was dissolved in dichloromethane (4.5mL), cooled in ice/water, and trifluoroacetic acid (6.5mL) added slowly with rapid stirring. After 42 h further trifluoroacetic acid (3mL) was added. After a further 24 h stirring, the mixture was diluted with toluene and the solvent was evaporated. Further toluene was added and the mixture evaporated. The residue was triturated with ether to give the title compound as a white solid (3.72g). 1H-NMR (d6-DMSO) δ 3.36 (2H,s), 3.76 (3H,s), 4.50 (2H,s), 4.68 (2H,s), 7.0-7.25 (2H,m), 7.25-7.55 (4H,m); MS (APCI+) found (M+l) = 407; C₁₈H₁₆F2N₄θ3S requires 406.

Example 1 — l-(N-(l-(2-Methoxyethyl)piperidin-4-yl)-N-(4-(4- trifluoromethylphenyl)benzyl)aminocarbonylmethyl)-2-(2,3-difluorobenzyl)thio-5-(l- methyl-4-pyrazoIylmethyl)pyrimidin-4-one bitartrate

A mixture of Intermediate A4 (0.3g), Intermediate B3 (0.29g), 0-(7-azabenzotriazol-l-yl)- N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU) (0.34g) and diisopropylamine (0.3 lmL) in dimethylformamide (20mL) was stirred at room temperature for 42 h. The solvent was evaporated and the residue partioned between dichloromethane and water. The organic layer was washed with brine and dried over K-C0₃. The majority of the solvent was evaporated and the residue applied directly to a lOg silica cartridge, which was eluted with 5% (2M ammonia in methanol) in dichloromethane. Product fractions were evaporated and triturated with ether to obtain the free base of the title compound (0.3 lg). This material was dissolved in methanol (lOmL) and tartaric acid (0.06g) added. The mixture was shaken at room temperature for 2 h and the solvent evaporated. The residue was triturated with diethyl ether and dried to give the title compound (0.35g). ^-NMR (d₆-DMSO) δ 1.5-1.9 (4H,m), 2.3 (2H,br.t), 2.6-2.75 (2H,m),

2.95-3.15 (2H,m), 3.22 (3H,s), 3.3-3.5 (4H,2xt), 3.76 (3H,s), 3.7-3.9 + 4.2-4.35 (lH,2xbm), 4.20 (2H,s), 4.46 + 4.54 + 4.58 + 4.65 + 4.77 + 5.15 (6H,6xs), 7.05-7.2 (lH,m), 7.2-7.5 (7H,m), 7.5- 7.7 (2H,m),7.83 (4H,s); MS (APCI+) found (M+l) = 781; C4oH₄₁F₅N₆03S requires 780. Example 2 — l-(N-(l-Ethylpiperidin-4-yl)-N-(4-(4-trifluoromethylphenyI)benzyI)- aminocarbonylmethyI)-2-(2,3-difluorobenzyI)thio-5-(l-methyI-4-pyrazoIyI- methyl)pyrimidin-4-one bitartrate

A mixture of Intermediate A6 (0.3g), Intermediate B3 (0.27g), 0-(7-azabenzotriazol-l-yl)- N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU) (0.34g) and diisopropylamine (0.3 lmL) in dimethylformamide (20mL) was stirred at room temperature for 42 h. The solvent was evaporated and the residue partioned between dichloromethane and water. The organic layer was washed with brine and dried over K-C0₃. The majority of the solvent was evaporated and the residue applied directly to a lOg silica cartridge, which was eluted with 5% (2M ammonia in methanol) in dichloromethane. Product fractions were evaporated and triturated with ether to obtain the free base of the title compound (0.2g). This material was dissolved in methanol (lOmL) and tartaric acid (0.039g) added. The mixture was shaken at room temperature for 2 h and the solvent evaporated. The residue was triturated with diethyl ether and dried to give the title compound (0.22g). -NMR (d₆-DMSO) δ 1.1 (3H,t), 1.6-2.0 (4H,m), 2.4-2.6 (2H,m), 2.6- 2.8 (2H,m), 3.1-3.3 (2H,m), 3.3-3.5 (2H,m), 3.76 (3H,s), 3.8-4.0 + 4.2-4.4 (lH,2xbm), 4.13 (2H,s), 4.46 + 4.54 + 4.58 + 4.66 + 4.78 + 5.16 (6H,6xs), 7.05-7.2 QH,m), 7.2-7.5 (5H,m), 7.5- 7.6 (2H,m), 7.6-7.7 (2H,m), 7.83 (4H,s); MS (APCI+) found (M+l) = 751; C39H3₉F5N₆0₂S requires 750.

The following examples were made by the method of Example 1:

Replacing intermediate B3 in Example 1 with l-(carboxymethyl)-2-(4-fluorobenzylthio)-5-((l- methylpyrazol-4-yl)methyl)pyrimidin-4-one (compound Z) (see WO 00/66567) gave the following examples:

Example 9 — l-(N-(l-Ethylpyrrolidin-2-y!methyl)-N-(4-(4- chlorophenyl)benzyl)aminocarbonylmethyl)-2-(4-fluorobenzyl)thio-5-(l-methylpyrazoI-4- y!methyl)pyrimidin-4-one

A mixture of Intermediate A8 (0.34g), compound Z (0.4g), 0-(7-azabenzotriazol-l-yl)- N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU) (0.47 ) and diisopropylamine (0.41mL) in dimethylformamide (20mL) was stirred at room temperature for 2 h. The solvent was evaporated and the residue partioned between dichloromethane and saturated sodium bicarbonate. The organic layer was washed with saturated ammonium chloride and brine and applied directly to a lOg silica cartridge, which was eluted with 0-15% methanol in dichloromethane. Product fractions were evaporated and triturated with ether to obtain the title compound (0.33g). -NMR (d₆-DMSO) δ 0.94 and 1.10 (3H,2xt), 1.3-2.1 (4H,m), 2.2-2.7 (3H,m), 2.8-3.75 (6H,m), 3.84 (3H,s), 4.35-4.6 (3H,m), 4.65-5.15 (3H,5xs), 6.79 (lH.br.s), 6.85- 7.05(2H,m), 7.15-7.5 (12H,m); MS (APCI+) found (M+l) = 699; C₃8H₄₀ClFN₆θ2S requires 698.

Biological Data

1. Screen for Lp-PLA2 inhibition.

Enzyme activity was determined by measuring the rate of turnover of the artificial substrate 1- decanoyl-2-(p-nitrophenyl glutaryl)phosphatidylcholine (A) at 37 °C in 50 mM HEPES (N-2- hydroxyethylpiperazine-N'-2-ethanesulphonic acid) buffer containing 150 mM NaCl, pH 7.4.

(A)

Assays were performed in 96 well titre plates. Recombinant Lp PLA2 was purified to homogeneity from baculovirus infected Sf9 cells, using a zinc chelating column, blue sepharose affinity chromatography and an anion exchange column. Following purification and ultrafiltration, the enzyme was stored at 6 mg/ml at 4°C. Assay plates of compound or vehicle plus buffer were set up using automated robotics to a volume of 170 μl. The reaction was initiated by the addition of 20μl of lOx substrate (A) to give a final substrate concentration of 20 μM and 10 μl of diluted enzyme to a final 0.2 nM LpPLA2.

The reaction was followed at 405 nm and 37 °C for 20 minutes using a plate reader with automatic mixing. The rate of reaction was measured as the rate of change of absorbance.

Results

The compounds described in the Examples were tested as described above and had IC50 values in the range 1 to 0.01 nM.

Claims

Claims

1. A compound of formula (I):

in which:

R¹ is an aryl or heteroaryl group, optionally substituted by 1, 2, 3 or 4 substituents which may be the same or different selected from Cn_ι 8)alkyl, Cn _ι 8)alkoxy, Cn_ι 8)alkylthio, arylC(i_i8 alkoxy, hydroxy, halogen, CN, COR⁶, carboxy, COOR⁶, CONR⁹R¹⁰, NR⁶COR⁷, Sθ2NR⁹R¹⁰, NR⁶Sθ2R⁷, NR⁹R¹⁰, mono to perfluoro-C(i_4)alkyl and mono to perfluoro-

Cn _4)alkoxy, or, as a single substituent, optionally in combination with a further substituent as hereinbefore defined, CH₂COOH or a salt thereof, CH₂COOR⁸, CH₂CONR⁹R¹⁰, CH₂CN, (CH2)_mNR⁹R¹⁰, (CH₂)_mOH or (CH )_mOR⁶ where m is an integer from 1 to 3;

R^ is an aryl or heteroaryl group, optionally substituted by 1, 2, 3 or 4 substituents which may be the same or different selected from C _i8)alkyl, Cn_ι 8)alkoxy, Cn_ι 8)alkylthio, arylC(₁.₁₈)^alkoχy_> hydroxy, halogen, CN, COR⁶, carboxy, COOR⁶, CONR⁹R¹⁰, NR⁶COR⁷, Sθ2NR⁹R¹⁰, NR⁶S02R⁷, NR⁹R¹⁰, mono to perfluoro-C(i_4)alkyl, mono to perfluoro- Cn_4Λalkoxy, and arylCπ_4)alkyl;

R3 is Het-C(ø-4)alkyl in which Het is a 5- to 7- membered heterocyclyl ring, bonded directly through a ring carbon atom, comprising N and optionally O or S, and in which N may be substituted by COR⁷, COOR⁷, CONR⁹R¹⁰, or C(i_6)alkyl optionally substituted by 1, 2 or 3 substituents selected from hydroxy, halogen, OR⁷, COR⁷, carboxy, COOR⁷, COOR*, CONR⁹R¹⁰ orNR R¹⁰;

R4 is an aryl or a heteroaryl ring optionally substituted by 1, 2, 3 or 4 substituents which may be the same or different selected from Cn _1 )alkyl, Cn _18)alkoxy, Cn _ι g\alkylthio,

Cn_4)alkoxy;

R^ is an aryl ring which is further optionally substituted by 1, 2, 3 or 4 substituents which may be the same or different selected from Cn _j 8)^alkyl_> ι_ι 8)alkoxy, Cn _ι 8)alkylthio, arylC(₁.₁₈)alkoxy, hydroxy, halogen, CN, COR⁶, carboxy, COOR⁶, CONR⁹R¹⁰, NR°COR⁷, S0₂NR⁹R¹⁰, NR⁶Sθ2R⁷, NR⁹R¹⁰, mono to perfluoro-C(₁.4)alkyl and mono to perfluoro- C(i_4)alkoxy;

R⁶ and R⁷ are independently hydrogen or Cn _20)alkyl, for instance C(i_4)alkyl (e.g. methyl or ethyl);

R⁸ is or a pharmaceutically acceptable in vivo hydrolysable ester group;

R⁹ and R*0 which may be the same or different is each selected from hydrogen, ^c(l-12)^al y CH2R¹¹, CHR¹²Cθ2H or a salt thereof, or R⁹ and R¹⁰ together with the nitrogen to which they are attached form a 4- to 7-, preferably 5- to 7-, membered ring optionally containing one or more further heteroatoms selected from oxygen, nitrogen and sulphur, and optionally substituted by one or two substituents selected from hydroxy, oxo, Cn.^alkyl, Cn _ 4)alkylCO, aryl, e.g. phenyl, or aralkyl, e.g benzyl, for instance morpholine or piperazine;

R¹1 is COOH or a salt thereof, COOR⁸, CONR⁶R⁷, CN, CH₂OH or CH OR⁶;

R*2 is an amino acid side chain such as CH2OH from serine; n is an integer from 1 to 4, preferably 1 or 3; X is O or S; and

Z is CR¹³R¹⁴ where R¹³ and R¹⁴ are each hydrogen or C -4)alkyl, or R^³ and R 4 together with the intervening carbon atom form a Cπ^cycloalkyl ring.

2. A compound of formula (I) as claimed in claim 1 in which Z is CH2.

3. A compound of formula (I) as claimed in claim 1 or 2 in which R is an aryl group selected from phenyl and naphthyl or a heteroaryl group which comprises a 5- or 6- membered, monocyclic heteroaryl group comprising 1 or 2 nitrogen heteroatoms.

4. A compound of formula (I) as claimed in any one of claims 1 to 3 in which R is pyrimidyl optionally substituted by 1 or 2 substituents selected from oxo,

Cπ_6)cycloalkyl, hydroxy,

Cn.6)alkylcarboxyCn.g)alkyl, di-Cn _6)alkylamino, and morpholino; or pyrazolyl optionally substimted by Cn gΛalkyl.

5. A compound as claimed in claim 4 in which ZR is pyrimid-5-ylmethyl optionally substimted by 2-methoxy, 2-trifluoromethyl, 2-(4-morpholino) or 2-dimethylamino; 2-oxo-pyrimid-5- ylmethyl or l-methyl-4-pyrazolylmethyl.

6. A compound of formula (I) as claimed in any one of claims 1 to 5 in which X is S.

7. A compound of formula (I) as claimed in any one of claims 1 to 6 in which R² is an aryl group selected from phenyl and naphthyl or a heteroaryl group selected from pyridyl, pyrimidinyl, pyrazolyl, furanyl, thienyl, thiazolyl, quinolyl, benzothiazolyl, pyridazolyl and pyrazinyl.

8. A compound of formula (I) as claimed in claim 7 in which R² is phenyl optionally substimted by halogen

9. A compound of formula (I) as claimed in any one of claims 1 to 8 in which R³ is Het-C(ø_ 4)alkyl in which Het is a 5- to 7- membered heterocyclyl ring, bonded directly through a ring carbon atom, comprising N and in which N may be substimted by C(ι_6)alkyl, optionally substituted by C(ι _4)alkoxy.

10. A compound of formula (I) as claimed in any one of claims 1 to 9 in which R^ is selected from phenyl optionally substimted by halogen; thiophene; pyridine; and pyrimidine.

11. A compound of formula (I) as claimed in any one of claims 1 to 10 in which R is phenyl optionally substimted by halogen, trifluoromethyl, or trifluoromethoxy.

12. A compound of formula (I) as claimed in claim 10 or 11 in which R^ and R^ together form a 4-(phenyl)phenyl substituent in which the remote phenyl ring may be optionally substimted by halogen or trifluoromethyl.

13. A compound of formula (I) as claimed in claim 1 and as named in any one of Examples 1 to 9.

14. A pharmaceutical composition comprising a compound of formula (I) as claimed in any one of the preceding claims and a pharmaceutically acceptable carrier.

15. A compound of formula (I) as claimed in claim 1 for use in therapy.

16. The use of a compound of formula (I) as claimed in claim 1 for the manufacture of a medicament for treating atherosclerosis.

17. A method of treating a disease state associated with activity of the enzyme Lp-PLA₂ which method involves treating a patient in need thereof with a therapeutically effective amount of a compound of formula (I) as claimed in claim 1.

18. A method of treating atherosclerosis which method comprises administering to a patient in need thereof an effective amount of a compound of formula (I) as claimed in claim 1 and a statin.

19. A process for preparing a compound of formula (I) as defined in claim 1 which process comprises:

(a) reacting a compound of formula (TJ):

p₂ ⁾ _n

COOH (13) in which X, Z, Rl, R2 and n are as defined in claim 1, with a compound of formula (HI): R⁵-R -CH₂NHR³ m in which R³, R⁴ and R^ are as defined in claim 1; under amide forming conditions;

(b) reacting a compound of formula (IV):

(IN) in which X, Z, R* and R² are as defined in claim 1, with a compound of formula (V):

R⁵-R⁴-CH₂ΝR³-CO-(CH2)_n-L¹

(V) in which n, R³, R⁴ and R^ are as defined in claim 1, and L^ is a leaving group such as halogen; in the presence of a base such as a secondary or tertiary amine, in an inert solvent;

(c) when X is S, reacting a compound of formula (VI):

(VI) in which n, Z, R*, R³, R⁴ and R^ are as defined in claim 1, with a compound of formula (VET):

(vπ) in which R² and L* are as defined in claim 1, in the presence of a base such as a secondary or tertiary amine, in an inert solvent; or

(d) when X is O, reacting a compound of formula (VET):

(VH3) in which n, Z, R , R³, R⁴ and R-^> are as defined in claim 1, and lX is a leaving group, with a compound of formula (IX):

R²-CH₂-OH

(DQ in which R² is as defined in claim 1, in the presence of a base, in an inert solvent.