EP1383753A1

EP1383753A1 - Piperazine-benzamide derivatives useful as apob-100 and/or mtp inhibitor

Info

Publication number: EP1383753A1
Application number: EP02732605A
Authority: EP
Inventors: Alain Claude-Marie Daugan
Original assignee: Glaxo Group Ltd
Current assignee: Glaxo Group Ltd
Priority date: 2001-04-12
Filing date: 2002-04-11
Publication date: 2004-01-28
Also published as: GB0109287D0; WO2002083658A1; JP2004525964A

Abstract

Therapeutically active benzamide derivatives of formula (I) wherein R1-R3 are as defined in the specification are disclosed as well as processes for the preparation thereof, the use thereof in therapy, particularly in the treatment or prophylaxis of conditions ameliorated by an apoB-100 and/or MTP inhibitor, and pharmaceutical compositions for use in such therapy.

Description

PIPERAZINE-BENZAMIDE DERIVATIVES USEFUL AS APOB-100 AND/OR MTP INHIBITOR

The invention relates to therapeutic benzamide derivatives, their use in inhibiting hepatic production of apoprotein B-100 (apoB-100) and intestinal production of chylomicrons or apoprotein B-48 (apoB-48) and MTP, and intermediates useful in the production of such derivatives.

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 neosyhthesized 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 WO96/40640. WO00/32582 describes therapeutic benzamide compounds for the treatment of conditions resulting from elevated circulating levels of apoB-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 WO00/32582.

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

wherein

R¹ represents CF₃ or C_1-6alkyl; R² represents halogen, C_1-6alkyl or C_1-6alkoxy; and R³ represents C_1-6alkyl or C_2-6alkenyl. 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 (I), 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 (I), reference to a halogen group includes fluoro, chloro, bromo and iodo groups.

R¹ is preferably isopropyl, tert-butyl or trifluoromethyl. R² is suitably chioro, methyl or methoxy. R 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 R¹ is isopropyl, tert-butyl or trifluoromethyl, R² 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-yl)-phenyl]- amide; 4'-lsopropyl-5-methyl-biphenyl-2-carboxylic acid [4-(4-allyl-piperazin-1-yl)-phenyl]- amide;

5-Methoxy-4'-trif luoromethyl-biphenyl-2-carboxylic acid [4-(4-allyl-piperazin-1 -yl)- phenyl]-amide;

4'-lsopropyl-5-methoxy-biphenyl-2-carboxylic acid [4-(4-allyl-piperazin-1 -yl)-phenylj- amide;

5-Chloro-4'-trifluoromethyl-biphenyl-2-carboxylic acid [4-(4-isopropyl-piperazin-1 -yl)- phenyl]-amide;

4'-lsopropyl-5-methyl-biphenyl-2-carboxylic acid [4-(4-isobutyl-piperazin-1 -yl)-phenyl]- amide; 4'-lsopropyl-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 -yl)- phenylj-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'-lsopropyl-5-methyl-biphenyl-2-carboxylic acid [4-(4-isopropyl-piperazin-1-yl)-phenyl]- amide;

4'-lsopropyl-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 pharmaceutically 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 R¹, R² and R³ are as previously defined for compounds of formula (I), 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 (III) 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 U 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 (VI)

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 (VII)

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

Compounds of formula (VII) may be made by methods well-known 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 alkylene 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 (I) 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 (I) 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, EtaN- Triethylamine.

Intermediate 1

4-f4-r(5-Methyl-4'-trifluoromethyl-biphenyl-2-carbonyl)-amino1-phenyl)-piperazine-1- carboxylic acid tert-butyl ester To a stirred solution of 4-(4-amino-phenyl)-piperazine-1 -carboxylic acid tert-butyl ester (1.38 g), δ-methyW-trifluoromethyl-biphenyl^-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-f(5-Methoxy-4'-trifluoromethyl-biphenyl-2-carbonyl)-aminol-phenyl -piperazine-1- carboxylic acid tert-butyl 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-f4-f(5-Chloro-4'-trifluoromethyl-biphenyl-2-carbonyl)-aminol-phenyl.-piperazine-1- carboxylic acid tert-butyl 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 tert-butyl ester (3.98 g).

Intermediate 4

4-f4-f(4'-lsopropyl-5-methoxy-biphenyl-2-carbonyl)-amino1-phenyl)-piperazine-1- carboxylic acid tert-butyl ester as a beige solid (2.3 g),

LC/MS : m/z 530 (M+1) from 4'-isopropyl-5-methoxy-biphenyl-2-carboxyiic acid (1.49 g) and 4-(4-amino- phenyl)-piperazine-1 -carboxylic acid tert-butyl ester (1.53 g).

Intermediate 5

4-{4-f(4'-tert-Butyl-5-methyl-biphenyl-2-carbonvπ-aminol-phenyl)-piperazine-1-carboxylic acid tert-butyl 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 tert-butyl ester (0.85 g).

Intermediate 6

5-Methyl-4'-trifluoromethyl-biphenyl-2-carboχylic acid (4-piperazin-1 -yl-phenyl .-amide To a solution of 4-{4-[(5-methyl-4'-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}- piperazine-1 -carboxylic acid tert-butyl ester (2.3 g) in CH₂CI₂ (25 mL) was added trifluoroacetic acid (5 L) 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 -yl-phenyl)-amide as a white solid (2.4 g),

LC/MS : m/z 456 (M+1) from 4-{4-[(5-methoxy-4'-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}- piperazine-1 -carboxylic acid tert-butyl ester (3.8 g).

Intermediate 8

5-Chloro-4'-trifluoromethyl-biphenyl-2-carboxylic acid (4-piperazin-1-yl-phenyl)-amide as a pale yellow solid (4.14 g), m.p. : 196°C from 4-{4-[(5-chloro-4'-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-piperazine-

1 -carboxylic acid tert-butyl ester (5.7 g).

Intermediate 9

4'-lsopropyl-5-methoxy-biphenyl-2-carboxylic acid (4-piperazin-1 -yl-phenyl)-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]-phenyI}-piperazine-1- carboxylic acid tert-butyl ester (2.3 g).

Intermediate 10

4'-tert-Butyl-5-methyl-biphenyl-2-carboxylic acid (4-piperazin-1 -yl-phenyl)-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]-phenyl}-piperazine-1- carboxylic acid tert-butyl ester (1.44 g). Example 1

5-Methyl-4'-trif luoromethyl-biphenyl-2-carboxylic acid f4-(4-allyl-piperazin-1 -yl)-phenvπ- 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 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 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 [4-(4-allyl-piperazin-1 -vD-phenyll-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.

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'-lsopropyl-5-methyl-biphenyl-2-carboxylic acid r4-(4-allyl-piperazin-1 -yl ,-phenyll-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 Na₂SO , 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'-trifluoromethyl-biphenyl-2-carboxylic acid r4-(4-allyl-piperazin-1 -yl )- phenyll-amide as white crystals (84 mg), m.p. : 192°C

LC/MS : m/z 496 (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'-lsopropyl-5-methoxy-biphenyl-2-carboxylic acid f4-(4-allyl-piperazin-1 -yl)-phenyl1- 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'-trifluoromethyl-biphenyl-2-carboxylic acid f4-(4-isopropyl-piperazin-1 -yl)- phenyll-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'-lsopropyl-5-methyl-biphenyl-2-carboxylic acid f4-(4-isobutyl-piperazin-1 -yl)-phenyl 1- 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'-lsopropyl-5-methyl-biphenyl-2-carboxylic acid r4-(4-propyl-piperazin-1 -vD-phenyll- 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-Methyl-4'-trifluor omethyl-biphenyl-2-carboxylic acid r4-(4-isobutyl-piperazin-1 -yl)- phenyll-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 isobutyraldehyde (131 mg).

Example 10

5-Methyl-4'-trifluoromethyl-biphenyl-2-carboxylic acid r4-(4-isopropyl-piperazin-1 -yl .- phenyll-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 r4-(4-isobutyl-piper azin-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-yl-phenyl)- amide (450 mg) and isobutyraldehyde (139 mg).

Example 12 5-Chloro-4'-trifluoromethyl-biphenyl-2-carboxylic acid r4-(4-propyl-piperazin-1 -yl .- phenyll-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'-lsopropyl-5-methyl-biphenyl-2-carboχylic acid r4-(4-isopropyl-piperazin-1 -vD-phenyl.- amide as white crystals (90 mg), m.p. : 168-170°C

(300 mg) and acetone (84 mg).

Example 14 4'-lsopropyl-5-methoxy-biphenyl-2-carboxylic acid r4-(4-isobutyl-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'-lsopropyl-5-methoxy-biphenyl-2-carboxylic acid r4-,4-isopropyl-piperazin-1-yl)- phenyll-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).

Biological Assay

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 μCi/ml ³⁵S-methionine. Compounds were dissolved in DMSO and tested onto cells from 1 μM to 1.6 nM. Production of radiolabeled apoB-100 and apoA-1 (used as a selectivity control) was quantified by analysis of supematants 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.

MTP Assay The human MTP activity assay was established using SPA technology. Donor liposomes were prepared with 3H-triolein and phosphatidylcholine, while acceptor liposomes 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 IC₅₀ values in nM. Table 1

Claims

A compound of formula (I);

wherein

R¹ represents CF₃ or C_1-6alkyl; R² represents halogen, C_1-6alkyl or C _-6alkoxy; and R³ represents Chalky! or C_2-6alkenyl. or a physiologically acceptable salt or solvate thereof.

2. A compound of formula (I) according to claim 1 , wherein R¹ represents isopropyl, tert-butyl or trifluoromethyl, or a physiologically acceptable salt or solvate thereof.

3. A compound of formula (I) according to claim 1 or claim 2, wherein R² represents chloro, methyl or methoxy, or a physiologically acceptable salt or solvate thereof.

4. A compound of formula (I) according to any one of claims 1 to 3, wherein R³ represents n-propyl, isopropyl, isobutyl, or prop-2-enyl, or a physiologically acceptable salt or solvate thereof.

5. A compound of formula (I) according to claim 1 selected from the group comprising: 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-yl)-phenyl]- amide;

4'-lsopropyl-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'-lsopropyl-5-methoxy-biphenyl-2-carboxylic acid [4-(4-allyl-piperazin-1 -yl)-phenyl]- amide;

4'-lsopropyl-5-methyl-biphenyl-2-carboxylic acid [4-(4-isobutyl-piperazin-1 -yl)- phenyl]-amide;

4'-lsopropyl-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 -yl)- phenyl]-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)- phenylj-amide;

5-Chloro-4'-trifluoromethyl-biphenyl-2-carboxylic acid [4-(4-propyl-piperazin-1-yl)- phenyl]-amide;

4'-lsopropyl-5-methyl-biphenyl-2-carboxylic acid [4-(4-isopropyl-piperazin-1 -yl)- phenyl]-amide;

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

6. A compound of formula (I) or a physiologically acceptable salt or solvate thereof according to any one of claims 1 to 5 for use in therapy.

7. Use of a compound of formula (I) or a physiologically acceptable salt or solvate thereof according to any one of claims 1 to 5 in the preparation of a medicament for use in the treatment of conditions ameliorated by an apoB-100 and/or MTP inhibitor.

8. Use of a compound of formula (I) according to claim 7, or a physiologically acceptable salt or solvate thereof, for use in the preparation of a medicament for the treatment of atherosclerosis, pancreatitis, non-insulin dependant diabetes mellitus (NIDDM), coronary heart diseases and obesity.

9. A method of treating a mammal comprising administration of an effective amount of a compound of formula (I) or a physiologically acceptable salt or solvate thereof in the treatment of conditions ameliorated by an apoB-100 and/or MTP inhibitor.

10. A pharmaceutical composition comprising at least one compound of formula (I) according to any of claims 1 to 5, or a physiologically acceptable salt or solvate thereof together with one or more pharmaceutically acceptable carriers or excipients.

11. A process for the preparation of a compound of formula (I) or a physiologically acceptable salt or solvate thereof comprising reacting a compound of formula (II) with a compound of formula R³-L.

wherein L represents a suitable halide leaving group under standard displacement conditions.