ApoB-100 is the main protein component of low density lipoprotein-cholesterol (LDL-c).

High LDL-c plasmatic levels are a major risk factor for atherosclerosis and coronary artery diseases. ApoB-48 is the main protein component of chylomicrons.

The microsomal triglyceride transfer protein (MTP) catalyses the transfer of triglycerides, cholesteryl esters and phosphatidylcholine between small unilamellar vesicles. MTP is expressed in liver and intestine, both organs which produce lipoproteins. MTP is able to lipidate neosynthesized apoB-100 within the liver, and neosytthesized apoB-48 within the intestine, therefore leading to the production of triglyceride-rich lipoparticles such as VLDL and chylomicrons respectively. Thus, MTP inhibitors have the potential to decrease LDL-c and triglyceride plasmatic levels, and also intestinal lipid absorption. MTP inhibitors may be used in the treatment of non- insulin dependent diabetes mellitus, coronary heart disease, pancreatitis, mixed dyslipidemia, hypercholesterolemia, hypertriglyceridemia, hyperlipemia, post-prandial hyperlipemia, atherosclerosis and obesity.

Compounds having apoB-100 and MTP inhibition properties have been described in W096/40640. WO00/32582 describes therapeutic benzamid compounds for the treatment of conditions resulting from elevated circulating levels of apo-100.

Surprisingly, it has been found that compounds according to the present invention, generically disclosed in WO00/32582, and having a specific substitution pattern, exhibit improved properties over those compounds specifically disclosed in WOOO/32582.

Thus, the present invention provides a compound of formula (t) ;

wherein R1 represents CF3 or C1-6alkyl ; R2 represents halogen, C1-6alkyl or C1alkoxy ; and R3 represents C1-6alkyl or C2alkenyl. or a physiologically acceptable salt or solvate thereof.

Suitable physiologically acceptable salts of the compounds of general formula (I) include acid addition salts formed with pharmaceutically acceptable organic and inorganic acids for example, citrates, hydrochlorides, hydrobromides, or sulphates.

Particularly preferred salts are citrates or hydrochloride salts.

The solvates may, for example, be hydrates.

References hereinafter to a compound according to the invention include both compounds of formula (I) and their physiologically acceptable salts together with physiologically acceptable solvates.

Referring to the general formula (I), alkyl and alkoxy include both straight and branched chain saturated hydrocarbon groups. Examples of alkyl groups include methyl, ethyl, n- propyl, isopropyl and isobutyl groups, whilst examples of alkoxy groups include methoxy and ethoxy groups.

Referring to the general formula (1), reference to alkenyl includes both straight and branched chain saturated hydrocarbon groups containing one double bond, e. g. propen-2-yl.

Referring to the general formula tel), reference to a halogen group includes fluoro, chloro, bromo and iodo groups.

R'is preferably isopropyl, tert-butyl or trifluoromethyl.

R2 is suitably chloro, methyl or methoxy. R2 is preferably methyl or methoxy.

R3 is suitably n-propyl, isopropyl, isobutyl or prop-2-enyl.

A preferred sub-group of the invention is represented by a compound of formula (I) where R'is isopropyl, tert-butyl or trifluoromethyl, R is chloro, methyl or methoxy and R3 is n-propyl, isopropyl, isobutyl or prop-2-enyl.

Particularly preferred compounds of the invention include those in which each variable in formula (I) is selected from the preferred groups for each variable. Even more preferable compounds of the invention include those where each variable in formula (I) is selected from the more preferred or most preferred groups for each variable.

Suitable compounds according to the invention include : 5-Methyl-4'-trifluoromethyl-biphenyl-2-carboxylic acid [4- (4-allyl-piperazin-1-yl)-phenyl]- amide; 4'-tert-Butyl-5-methyl-biphenyl-2-carboxylic acid [4- (4-allyl-piperazin-1-yi)-phenyl]- amide; 4'-Isopropyl-5-methyl-biphenyl-2-carboxylic acid [4- (4-allyl-piperazin-1-yl)-phenyl]- amide; 5-Methoxy-4'-trifluoromethyl-biphenyl-2-carboxylic acid [4- (4-allyl-piperazin-1-yl)- phenyl]-amide ; 4'-Isopropyl-5-methoxy-biphenyl-2-carboxylic acid [4- (4-allyl-piperazin-1-yl)-phenyl]- amide; 5-Chloro-4'-trifluoromethyl-biphenyl-2-carboxylic acid [4- (4-isopropyl-piperazin-1-yl)- phenyl]-amide ; 4'-Isopropyl-5-methyl-biphenyl-2-carboxylic acid [4- (4-isobutyl-piperazin-1-yl)-phenyl]- amide; 4'-Isopropyl-5-methyl-biphenyl-2-carboxylic acid [4- (4-propyl-piperazin-1-yl)-phenyl]- amide; 5-Methyl-4'-trifluoromethyl-biphenyl-2-carboxylic acid [4- (4-isobutyl-piperazin-1-yi)- phenyll-amide ; 5-Methyl-4'-trifluoromethyl-biphenyl-2-carboxylic acid [4- (4-isopropyl-piperazin-1-yl)- phenyl]-amide ;

5-Chloro-4'-trifluoromethyl-biphenyl-2-carboxylic acid [4- (4-isobutyl-piperazin-1-yl)- phenyl]-amide ; 5-Chloro-4'-trifluoromethyl-biphenyl-2-carboxylic acid [4- (4-propyl-piperazin-1-yl)- phenyl]-amide ; 4'-Isopropyl-5-methyl-biphenyl-2-carboxylic acid [4- (4-isopropyl-piperazin-1-yl)-phenyl]- amide; 4'-Isopropyl-5-methoxy-biphenyl-2-carboxylic acid [4- (4-isobutyl-piperazin-1-yl)-phenyl]- amide; 4'-lsopropyl-5-methoxy-biphenyl-2-carboxylic acid [4- (4-isopropyl-piperazin-1-yl)- phenyl]-amide ; or a physiologically acceptable salt or solvate thereof.

The compounds of the invention are inhibitors of hepatic production of apoB-100 and MTP and are thus of use in the treatment of conditions ameliorated by an apoB-100 and/or MTP inhibitor.

The ability of the compounds of this invention to inhibit human MTP activity is measured by an in vitro assay where MTP transfers 3H-triolein between phosphatidylcholine liposomes. The specificity of the compounds of the invention is established by comparing the effects on apoB-100 and apoprotein A-1 production. A specificity of at least 100 is preferred.

The in vivo profile of the compounds is determined by acute oral administration of the compounds of the invention to DBA/2 mice and Wistar rats. Potency of the active compounds is evaluated by measuring plasmatic lipids (total cholesterol, triglyceride, LDL cholesterol and HDL cholesterol) and apoproteins (apoB-100, apoB-48 and apoA- 1).

The compounds of the invention are potent and specific inhibitors of hepatic production of apoB-100 and MTP, which furthermore exhibit good oral bioavailability and duration of action.

Furthermore, the compounds of the present invention exhibit significant oral activity compared with compounds of the prior art. They also possess favourable pharmacokinetic profiles compared with compounds of the prior art.

Compounds of the invention are of use in the treatment of atherosclerosis, pancreatitis, non-insulin dependent diabetes mellitus (NIDDM), coronary heart diseases and obesity.

Compounds of the invention are also useful in lowering serum lipid levels, cholesterol and/or triglycerides, and are of use in the treatment of hyperlipemia, hyperlipidemia, post-prandial hyperlipemia, mixed dislipidemia, hyperlipoproteinemia, hypercholesterolemia and/or hypertriglyceridemia.

The invention therefore provides a compound of formula (I) or a physiologically acceptable salt or solvate thereof for use in therapy, in particular in human medicine.

There is also provided as a further aspect of the invention the use of a compound of formula (I) or a physiologically acceptable salt or solvate thereof in the preparation of a medicament for use in the treatment of conditions ameliorated by an apoB-100 and/or MTP inhibitor.

In an alternative or further aspect, there is provided a method for the treatment of a mammal, including man, comprising administration of an effective amount of a compound of formula (I) or a physiologically acceptable salt or solvate thereof in particular in the treatment of conditions ameliorated by an apoB-100 and/or MTP inhibitor.

It will be appreciated that reference to treatment is intended to include prophylaxis as well as the alleviation of established symptoms. Compounds of formula (I) may be administered as the raw chemical but the active ingredient is preferably presented as a pharmaceutical formulation.

Accordingly, the invention also provides a pharmaceutical composition which comprises at least one compound of formula (I) or a physiologically acceptable salt or solvate thereof and formulated for administration by any convenient route. Such compositions are preferably in a form adapted for use in medicine, in particular human medicine, and can conveniently be formulated in a conventional manner using one or more pharmaceutical acceptable carriers or excipients.

Thus compounds of formula (I) may be formulated for oral, buccal, parenteral, transdermal, topical (including ophthalmic and nasal), depot or rectal administration or in a form suitable for administration by inhalation or insufflation (either through the mouth or nose).

The compounds of formula (I) may, if desired, be administered with one or more therapeutic agents and formulated for administration by any convenient route in a conventional manner. Appropriate doses will be readily appreciated by those skilled in the art. For example, the compounds of formula (I) may be administered in combination with an HMG CoA reductase inhibitor.

A compound of formula (I), or a physiologically acceptable salt or solvate thereof, may be prepared by the general methods outlined hereafter. In the following description, the groups R', R2 and R3 are as previously defined for compounds of formula ( !), unless specified otherwise.

According to a general process (A), a compound of formula (I) may be prepared by reacting a compound of formula (II) with a compound of formula R3-L where L represents a suitable halide leaving group, e. g. chloride, under standard displacement conditions.

A compound of formula (II) may be prepared by reaction of a compound of formula (ici) with a compound of formula (IV)

where L'is a suitable leaving group, such as chloride, or an OH group and P is a suitable amine protecting group, e. g. tert-butoxycarbonyl (Boc), under standard coupling conditions for an acid and amine coupling, followed by deprotection of the protecting group under suitable conditions, e. g. acidic removal of a Boc group.

Compounds of formula (III) and (IV) may be made by methods well-known in the art, in particular following the teaching of WO00/32582. For example, a compound of formula (III), where L'is a hydroxy group, may be prepared firstly by coupling a boronic acid with a suitable leaving group, represented by a compound of formula (V) and a compound of formula (V !) where PG represents a protected carboxylic acid and A and D represent either the boronic acid or the suitable leaving group, such as triflate or bromide, followed by deprotection of the protecting group under standard conditions, such as base removal of an ester group. Where L'represents a halide leaving group, the carboxylic acid product can be treated with a suitable reagent, such as thionyl chloride, to give the corresponding chloride leaving group.

According to a second method (B), compounds of formula (I) may be prepared by reaction of compounds of formula (III) and compounds of formula (Vil)

where L'is defined above, under standard coupling conditions.

Compounds of formula (VII) may be made by methods well-know on the art, in particular following the teaching of WO00/32582.

According to a third general process (C), a compound of formula (I), where there is an alkylen link to the piperazine group, may be prepared by reacting a compound of formula (II) with a compound of formula (VIII) where R3'represents R3 minus a methylene group, under standard reductive amination conditions, e. g. using sodium triacetoxyborohydride in a solvent such as dichloroethane.

The various general methods described above may be useful for the introduction of the desired groups at any stage in the stepwise formation of the required compound, and it will be appreciated that these general methods can be combined in different ways in such multi-stage processes. The sequence of the reactions in multi-stage processes should of course be chosen so that the reaction conditions used do not affect groups in the molecule which are desired in the final product.

Compounds of formula R3-L, (V), (VI) and (VIII) are known or may be prepared by standard methods well known in the art and/or herein described.

Physiologically acceptable salts may also be prepared from other salts, including other physiologically acceptable salts, of the compound of formula (I) using conventional methods.

The compounds of formula (l) may readily be isolated in association with solvent molecules by crystallisation from or evaporation of an appropriate solvent to give the corresponding solvates.

When a specific enantiomer of a compound of general formula (I) is required, this may be obtained for example by resolution of a corresponding enantiomeric mixture of a compound of formula (1) using conventional methods.

Thus, in one example an appropriate optically active acid may be used to form salts with the enantiomeric mixture of a compound of general formula (I). The resulting mixture of isomeric salts may be separated, for example, by fractional crystallisation into the diastereoisomeric salts from which the required enantiomer of a compound of general formula (I) may be isolated by conversion into the required free base.

Alternatively, enantiomers of a compound of general formula (I) may be synthesised from the appropriate optically active intermediates using any of the general processes described herein.

The invention is further illustrated by the following intermediates and examples. All temperatures are in degrees centigrade.

Abbreviations: MS-LCMS mass spectrography, HOBt-1-Hydroxybenzotriazole, AcOEt- Ethyl acetate, EDCI-1- (3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, BINAP-2, 2'-bis (diphenylphosphino)-1, 1'-binaphthyl, THF-Tetrahydrofuran, MeOH- Methanol, EtOH-Ethanol, Et3N-Triethylamine.

Intermediate 1 4-a, 4-f (5-Methyl-4'-triffuoromethvl-biphenvl-2-carbonvl)-aminol-afh envl-piperazine-1- carboxvlic acid tert-butyl ester To a stirred solution of 4- (4-amino-phenyl)-piperazine-l-carhoxylic acid ter-butyl ester (1.38 g), 5-methyl-4'-trifluoromethyl-biphenyl-2-carboxylic acid (1.4 g), HOBt (0.81 g), and Et3N (0.6 g) in CH2CI2 (60 mL) was added EDCI (1.15 g) and the mixture was stirred at room temperature for 16 hours. The organic solution was then washed with water, with a saturated solution of NaHCO3, with brine and dried over Na2SO4. After filtration and evaporation of the filtrate, the residue was purified by flash chromatography eluting with CH2CI2/AcOEt (85/15) and the solid obtained was recrystallized from ethanol to give the title compound (2.5 g) as a white solid. m. p.: 238-240°C.

Similarly prepared were:

Intermediate 2 4-{4-[(5-Methoxy-4'-trifluoromethyl-biphenyl-2-carbonyl)-ami no]-phenyl}-piperazine-1- carboxylic acid tert-butvl ester as a beige solid (3.8 g), m. p.: 114°C from 5-methoxy-4'-trifluoromethyl-biphenyl-2-carboxylic acid (2.43 g) and 4- (4-amino- phenyl)-piperazine-1-carboxylic acid tert-butyl ester (2.5 g).

Intermediate 3 4-{4-[(5-Chloro-4'-trifluoromethyl-biphenyl-2-carbonyl)-amin o]-phenyl}-piperazine-1- carboxylic acid tert-butvl ester as a white powder (5.7 g), m. p.: 222°C from 5-chloro-4'-trifluoromethyl-biphenyl-2-carboxylic acid (3.92 g) and 4- (4-amino- phenyl)-piperazine-1-carboxylic acid ter-butyl ester (3.98 g).

Intermediate 4 4-4-f (4'-Isopropyl-5-methoxv-biphenvl-2-carbonvl)-aminol-phenvl}- piperazine-1- carboxylic acid tert-butvl ester as a beige solid (2.3 g), LC/MS: m/z 530 (M+1) from 4'-isopropyl-5-methoxy-biphenyl-2-carboxylic acid (1.49 g) and 4- (4-amino- phenyl)-piperazine-1-carboxylic acid ter-butyl ester (1.53 g).

Intermediate 5 4-{4-[(4'-tert-Butyl-5-methyl-biphenyl-2-carbonyl)-amino]-ph enyl}-piperazine-1-carboxylic acid tert-butvl ester as a white solid (1.5 g), m. p.: 199-201 °C from 4'-tert-butyl-5-methyl-biphenyl-2-carboxylic acid (0.82 g) and 4- (4-amino- phenyl)- piperazine-1-carboxylic acid ter-butyl ester (0.85 g).

Intermediate 6 5-Methyl-4'-trifluoromethvl-biphenvl-2-carboxvlic acid (4-piperazin-1-vl-phenyl)-amide To a solution of 4- 4- [ (5-methyl-4'-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phe nyl}- piperazine-1-carboxylic acid ter-butyl ester (2.3 g) in CH2CI2 (25 mL) was added trifluoroacetic acid (5 mL) and the solution was stirred at room temperature for 16 hours. The mixture was then evaporated under reduced pressure and the residue was

basified with a saturated solution of NaHCO3. The resulting precipitate was extracted with CH2CI2 and the organic phase was washed with water, dried over Na2SO4, filtered and evaporated to dryness. The solid obtained was recrystallized from ethyl acetate to give the title compound (1.8 g) as a white solid. m. p.: 182-184°C.

Similarly prepared were: Intermediate 7 5-Methoxy-4'-trifluoromethyl-biphenyl-2-carboxylic acid (4-piperazin-1-vl-phenvl)-amide as a white solid (2.4 g), LC/MS: m/z456 (M+1) from 4- {4- [ (5-methoxy-4'-trifluoromethyl-biphenyl-2-carbonyl)-amino]-ph enyl}- piperazine-1-carboxylic acid tert-butyl ester (3.8 g).

Intermediate 8 5-Chloro-4'-trifluoromethvl-biphenvl-2-carboxvlic acid (4-piperazin-1-vl-phenvl)-amide as a pale yellow solid (4.14 g), m. p.: 196°C from 4- {4- [ (5-chloro-4'-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phe nyl}-piperazine- 1-carboxylic acid tert-butyl ester (5.7 g).

Intermediate 9 4'-Isopropvl-5-methoxy-biphenvl-2-carboxvlic acid (4-piperazin-1-vl-phenvl)-amide as a beige solid (1.56 g), LC/MS: m/z 430 (M+1) from 4- {4- [ (4'-isopropyl-5-methoxy-biphenyl-2-carbonyl)-amino]-phenyl}- piperazine-1- carboxylic acid ter-butyl ester (2.3 g).

Intermediate 10 4'-tert-Butyl-5-methyl-biphenyl-2-carboxylic acid (4-piperazin-1-vl-phenvl)-amide as a white solid (1.03 g), m. p.: 111-113°C from 4-{4-[(4'-tert-butyl-5-methyl-biphenyl-2-carbonyl)-amino]-ph enyl}-piperazine-1- carboxylic acid tert-butyl ester (1.44 g).

Example 1 5-Methvl-4'-trifluoromethvl-biphenvl-2-carboxvlic acid 4- (4-allvl-piperazin-1-vl)-phen amide To a solution of 5-methyl-4'-trifluoromethyl-biphenyl-2-carboxylic acid (4-piperazin-1-yl- phenyl)-amide (400 mg) in acetone (35 mL) containing Cs2CO3 (350 mg) was added allyl bromide (130 mg) and the mixture was heated at reflux for 16 hours. The mixture was then evaporated under reduced pressure and the residue was dissolved in CH2Cl2.

The organic phase was washed with water, brine, dried over Na2SO4, filtered and evaporated to dryness. The residue was purified by flash chromatography eluting with CH2CI2/MeOH (95/5) and the solid obtained was recrystallized from ethanol to give the title compound (230 mg) as white crystals. m. p.: 188°C GC/MS: m/z 479 (M+).

Example 2 4'-tert-Butyl-5-methyl-biphenyl-2-carboxylic acid f4- (4-allvl-piperazin-1-vl)-phenvil-amide To a solution of 4'-tert-butyl-5-methyl-biphenyl-2-carboxylic acid (4-piperazin-1-yl- phenyl)-amide (300 mg) in acetonitrile (25 mL) containing Cs2CO3 (655 mg) was added allyl bromide (93 mg) and the mixture was heated at reflux for 16 hours. The mixture was then evaporated under reduced pressure and the residue was dissolved in CH2CI2.

The organic phase was washed with water, brine, dried over Na2SO4, filtered and evaporated to dryness. The residue was purified by flash chromatography eluting with CH2CI2/MeOH (95/5) and the solid obtained was recrystallized from ethyl acetate to give the title compound (80 mg) as white crystals. m. p.: 164-166°C LC/MS: m/z 468 (M+1).

Example 3 4'-Isopropvl-5-methyl-biphenvl-2-carboxvlic acid f4- (4-allyl-piperazin-1-vl)-phenvll-amide To a solution of 4'-isopropyl-5-methyl-biphenyl-2-carboxylic acid (4-piperazin-1-yl- phenyl)-amide (250 mg) in acetonitrile (20 mL) containing Cs2CO3 (591 mg) was added allyl bromide (80 mg) and the mixture was heated at reflux for 16 hours. The mixture was then evaporated under reduced pressure and the residue was dissolved in CH2CI2. The organic phase was washed with water, brine, dried over Na2SO4, filtered and

evaporated to dryness. The residue was purified by flash chromatography eluting with CH2CI2/MeOH (95/5) and the solid obtained was recrystallized from diisopropyl ether to give the title compound (100 mg) as white crystals. m. p.: 134-136°C LC/MS: m/z 454 (M+1).

Similarly prepared were: Example 4 5-Methoxy-4'-trifluoromethvl-biphenvl-2-carboxvlic acid f4- (4-allyl-piperazin-1-vl)- phenyil-amide as white crystals (84 mg), m. p.: 192°C LC/MS: m/z496 (M+1) from 5-methoxy-4'-trifluoromethyl-biphenyl-2-carboxylic acid (4-piperazin-1-yl-phenyl)- amide (450 mg) and allyl bromide (143 mg).

Example 5 4'-Isopropvl-5-methoxv-biphenvl-2-carboxvlic acid f4- (4-allvl-piperazin-1-vl)-phenyll- amide as white crystals (70 mg), m. p.: 170-172°C LC/MS: m/z 470 (M+1) from 4'-isopropyl-5-methoxy-biphenyl-2-carboxylic acid (4-piperazin-1-yl-phenyl)-amide (300 mg) and allyl bromide (93 mg).

Example 6 5-Chloro-4'-trifluoromethvl-biphenvl-2-carboxylic acid (4- (4-isopropvl-piperazin-1-vl)- phenvll-amide To a solution of 5-chloro-4'-trifluoromethyl-biphenyl-2-carboxylic acid (4-piperazin-1-yl- phenyl)-amide (450 mg) in 1,2-dichloroethane (20 mL) was added acetone (113 mg) and acetic acid (59 mg). The solution was cooled at O°C and sodium triacetoxy borohydride (413 mg) was added portionwise and the mixture was stirred at room temperature for 16 hours. The solution was then washed with a saturated solution of NaHCO3, with brine, dried over Na2SO4, filtered and evaporated under reduced pressure. The residue was purified by flash chromatography eluting with CH2CI2/MeOH (95/5) and the solid obtained was recrystallized from ethanol to give the

title compound (310 mg) as white crystals. m. p.: 226°C GC/MS: m/z 501 (M+).

Example 7 4'-Isopropyl-5-methvl-biphenvl-2-carboxylic acid [4-(4-isobutyl-piperazin-1-yl)-phenyl]- amide To a solution of 4'-isopropyl-5-methyl-biphenyl-2-carboxylic acid (4-piperazin-1-yl- phenyl)-amide (300 mg) in 1,2-dichloroethane (10 mL) was added isobutyraldehyde (52 mg) and acetic acid (43 mg). The solution was cooled at O°C and sodium triacetoxy borohydride (230 mg) was added portionwise and the mixture was stirred at room temperature for 16 hours. The solution was then washed with a saturated solution of NaHCO3, with brine, dried over Na2SO4, filtered and evaporated under reduced pressure. The residue was purified by flash chromatography eluting with CH2CI2/MeOH (98/2) and the solid obtained was recrystallized from diisopropyl ether to give the title compound (130 mg) as white crystals. m. p.: 168-170°C LC/MS: m/z 470 (M+1).

Similarly prepared were: Example 8 4'-Isopropyl-5-methvl-biphenyl-2-carboxvlic acid [4-(4-propyl-piperazin-1-yl)-phenyl]- amide as white crystals (140 mg), m. p.: 149-151°C LC/MS: m/z 456 (M+1) from 4'-isopropyl-5-methyl-biphenyl-2-carboxylic acid (4-piperazin-1-yl-phenyl)-amide (300 mg) and propionaldehyde (42 mg).

Example 9 5-Methvl-4'-trifluoromethvl-biphenvl-2-carboxvlic acid [4- (4-isobutyl-piperazin-1-vl)- phenvll-amide as white crystals (239 mg), m. p.: 224°C LC/MS: m/z 496 (M+1) from 5-methyl-4'-trifluoromethyl-biphenyl-2-carboxylic acid (4-piperazin-1-yl-phenyl)-

amide (400 mg) and isobutyraidehyde (131 mg).

Example 10 5-Methvl-4'-trifluoromethvl-biphenyl-2-carboxvlic acid [4- (4-isopropvl-piperazin-1-vl)- phenvl1-amide as white crystals (104 mg), m. p.: 232°C GC/MS: m/z 481 (M+) from 5-methyl-4'-trifluoromethyl-biphenyl-2-carboxylic acid (4-piperazin-1-yl-phenyl)- amide (400 mg) and acetone (105 mg).

Example 11 5-Chloro-4'-trifluoromethyl-biphenyl-2-carboxylic acid [4-(4-isobutyl-piperazin-1-yl)- phenyll-amide as white crystals (290 mg), m. p.: 226°C GC/MS : m/z 516 (M+) from 5-chloro-4'-trifluoromethyl-biphenyl-2-carboxylic acid (4-piperazin-1-yi-phenyl)- amide (450 mg) and isobutyraldehyde (139 mg).

Example 12 5-Chloro-4'-trifluoromethvl-biphenvl-2-carboxvlic acid f4- (4-propvl-piperazin-1-vl)- phenvll-amide as white crystals (152 mg), m. p.: 198°C GC/MS: m/z 501 (M+) from 5-chloro-4'-trifluoromethyl-biphenyl-2-carboxylic acid (4-piperazin-1-yl-phenyl)- amide (300 mg) and propionaldehyde (75 mg).

Example 13 4'-fsopropvl-5-methvl-biphenvl-2-carboxvlic acid f4- (4-isopropyl-piperazin-1-vl)-phenyll- amide as white crystals (90 mg), m. p.: 168-170°C LC/MS: m/z 456 (M+1) from 4'-isopropyl-5-methyl-biphenyl-2-carboxylic acid (4-piperazin-1-yl-phenyl)-amide (300 mg) and acetone (84 mg).

Example 14

4'-Isopropvl-5-methoxv-biphenvl-2-carboxvlic acid T4- (4-isobutvl-piperazin-1-yl)-phenyll- amide as white crystals (230 mg), m. p.: 193-195°C LC/MS : m/z 486 (M+1) from 4'-isopropyl-5-methoxy-biphenyl-2-carboxylic acid (4-piperazin-1-yl-phenyl)-amide (300 mg) and isobutyraldehyde (51 mg).

Example 15 4'-lsopropvl-5-methoxv-biphenvl-2-carboxylic acid [4-(4-isoProPvl-Piperazin-1-vl) phenyl]-amide as white crystals (10 mg), m. p.: 192-194°C LC/MS: m/z 472 (M+1) from 4'-isopropyl-5-methoxy-biphenyl-2-carboxylic acid (4-piperazin-1-yl-phenyl)-amide (300 mg) and acetone (81 mg).

BiologicalAssay ApoB-100 Assay Primary human hepatocytes were seeded at 50 000 cells/well in 96 well plates. After an overnight adhesion phase, cells were incubated with compounds for 8 hours in RPMI medium containing 1% FCS 4 µg/ml insulin, 100 nM dexamethasone and 50 uCi/ml 35S-methionine. Compounds were dissolved in DMSO and tested onto cells from 1 uM to 1.6 nM. Production of radiolabeled apoB-100 and apoA-1 (used as a selectivity control) was quantified by analysis of supernatants using SDS PAGE and exposure of gels onto Phosphorlmager screens. Inhibition of apoB-100 and apoA-1 secretion by compounds was calculated taking untreated cells as controls, and IC50 of each compound was determined on both apoproteins.

MTPAssay The human MTP activity assay was established using SPA technology. Donor liposomes were prepared with 3H-triolein and phosphatidylcholine, while acceptor liposoms contained biotinylated phosphatidylethanolamine and phosphatidylcholine.

The MTP-mediated 3H-triolein transfer onto acceptor liposomes was allowed by a 25 min incubation at 37°C, and quantified by the addition of streptavidin-SPA beads. The results are shown in Table 1 below as the IC5o values in nM.

Table 1 Example No MT IC50 (nM 1 0. 1 2 0. 2 3 0. 25 4 1 5 0. 1 6 2. 2 7 0. 3 8 0. 3 9 0. 1 10 1.5 11 0. 3 12 0. 7 13 1. 3 14 1 15 1. 6