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WO2003047575A1 - Therapeutic benzamide derivatives - Google Patents

Therapeutic benzamide derivatives Download PDF

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Publication number
WO2003047575A1
WO2003047575A1 PCT/EP2002/013591 EP0213591W WO03047575A1 WO 2003047575 A1 WO2003047575 A1 WO 2003047575A1 EP 0213591 W EP0213591 W EP 0213591W WO 03047575 A1 WO03047575 A1 WO 03047575A1
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Prior art keywords
biphenyl
carboxylic acid
piperazin
amide
phenyl
Prior art date
Application number
PCT/EP2002/013591
Other languages
French (fr)
Inventor
Alain Claude-Marie Daugan
Nerina Dodic
Original Assignee
Glaxo Group Limited
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Filing date
Publication date
Application filed by Glaxo Group Limited filed Critical Glaxo Group Limited
Priority to AU2002358574A priority Critical patent/AU2002358574A1/en
Publication of WO2003047575A1 publication Critical patent/WO2003047575A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/30—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
    • C07D207/34—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D207/36—Oxygen or sulfur atoms
    • C07D207/40—2,5-Pyrrolidine-diones
    • C07D207/416—2,5-Pyrrolidine-diones with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to other ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
    • C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D277/22—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C07D277/28—Radicals substituted by nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
    • C07D295/12—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms
    • C07D295/135—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms with the ring nitrogen atoms and the substituent nitrogen atoms separated by carbocyclic rings or by carbon chains interrupted by carbocyclic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
    • C07D307/34—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D307/38—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D307/52—Radicals substituted by nitrogen atoms not forming part of a nitro radical
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
    • C07D307/34—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D307/56—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D307/68—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
    • C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
    • C07D333/06—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to the ring carbon atoms
    • C07D333/14—Radicals substituted by singly bound hetero atoms other than halogen
    • C07D333/20—Radicals substituted by singly bound hetero atoms other than halogen by nitrogen atoms

Definitions

  • the invention relates to therapeutic benzamide derivatives and 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.
  • 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.
  • MTP microsomal triglyceride transfer protein
  • triglyceride transfer protein 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 neosynthesized apoB-48 within the intestine, therefore leading to the production of triglyceride-rich lipoparticles such as VLDL and chylomicrons respectively.
  • 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.
  • R 1 represents C- ⁇ -4 alkyl, C 2-6 alkenyl, C 1-4 alkylsulfonyl, C 1-4 acyl or CH 2 -R 4 ;
  • R 2 represents isopropyl or trifluoromethyl
  • R 3 represents methyl or methoxy
  • R 4 represents: i) a 5 or 6-membered heteroaromatic group selected from thienyl, thiazolyl and furanyl, optionally substituted by halogen, cyano, C 1-4 alkyl, C 1-4 alkoxy or C 3- 7 cycloalkyl, ii) a 2-pyrrolyl substituted by either 4- or 5- cyano, iii) C 3-7 cycloalkyl, iv) cyano, v) hydroxycarbonyl or vi) C 1-4 alkoxyC 1-4 alkyl, hydroxyC 1- alkyl or vii) trifluoromethylC 1-4 alkyl; or a physiologically acceptable salt, solvate or derivative 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.
  • alkyl groups include methyl and ethyl groups.
  • alkyl, alkylene and alkoxy include both straight and branched chain saturated hydrocarbon groups.
  • alkyl groups include methyl and ethyl groups
  • examples of alkylene groups include methylene and ethylene groups
  • examples of alkoxy groups include methoxy and ethoxy groups.
  • alkenyl includes both straight and branched chain saturated hydrocarbon groups containing one double bond, e.g. 3- methyl-but-2-ene and propen-2-yl.
  • heteroaromatic group unless otherwise defined, means any single aromatic ring containing at least one ring heteroatom independently selected from O, N and S.
  • reference to a halogen group includes fluoro, chloro, bromo and iodo groups.
  • R 1 is suitably selected from C 1-4 alkyl, e.g. methyl, ethyl, isopropyl, propyl or isobutyl, C 2-
  • R 4 is suitably cyano, ethoxycarbonyl, hydroxycarbonyl, C 1-4 alkoxymethyl e.g. methoxymethyl, trifluoromethylC 1- alkyl, e.g. 1 ,1 ,1 -trif luoroethyl, C 3-7 cycloalkyl e.g.
  • R 1 is more suitably methyl, propyl, isopropyl, propen-2-yl, methoxyethyl, 1 ,1 ,1- trifluoropropyl, an optionally substituted 3-thienylmethyl or 2-furanylmethyl group, where optional substitution is effected by methyl or cyano, or a 2-pyrrolylmethyl, substituted by either 4- or 5- cyano.
  • R 1 is preferably propen-2-yl or 3-thienylmethyl. Alternatively, R 1 is preferably methyl, propyl, propen-2-yl, 2-furanylmethyl substituted by cyano or 3-thienylmethyl.
  • R 1 is most preferably propen-2-yl.
  • R 2 is preferably isopropyl.
  • R 3 is preferably methoxy. R 3 is equally preferably methyl.
  • 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 of the invention include:
  • physiologically functional derivative refers to any physiologically acceptable derivative of a compound of the present invention, for example, an ester or amide, which upon administration to a mammal, such as a human, is capable of providing (directly or indirectly) such a compound or an active metabolite thereof.
  • physiologically acceptable derivative of a compound of the present invention for example, an ester or amide, which upon administration to a mammal, such as a human, is capable of providing (directly or indirectly) such a compound or an active metabolite thereof.
  • Such derivatives are clear to those skilled in the art, without undue experimentation, and with reference to the teaching of Burger's Medicinal Chemistry
  • 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-
  • 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.
  • 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.
  • NIDDM non-insulin dependent diabetes mellitus
  • 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, solvate or derivative thereof for use in therapy, in particular in human medicine.
  • a method for the treatment of a mammal comprising administration of an effective amount of a compound of formula (I) or a physiologically acceptable salt, solvate or derivative thereof in particular in the treatment of conditions ameliorated by an apoB-100 and / or MTP inhibitor.
  • a mammal including man
  • administration of an effective amount of a compound of formula (I) or a physiologically acceptable salt, solvate or derivative thereof in particular in the treatment of conditions ameliorated by an apoB-100 and / or MTP inhibitor.
  • 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.
  • the invention also provides a pharmaceutical composition which comprises at least one compound of formula (I) or a physiologically acceptable salt, solvate or derivative thereof and formulated for administration by any convenient route.
  • a pharmaceutical composition which comprises at least one compound of formula (I) or a physiologically acceptable salt, solvate or derivative 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.
  • the 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.
  • 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, solvate or derivative thereof, may be prepared by the general methods outlined hereafter.
  • the groups R 1 ,R 2 and R 3 are as previously defined for compounds of formula (I), unless specified otherwise.
  • a compound of formula (I) may be prepared by reacting a compound of formula (II) with a compound of formula R 1 -L
  • 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)
  • 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.
  • a suitable leaving group such as chloride, or an OH group
  • P is a suitable amine protecting group, e.g. tert-butoxycarbonyl (Boc)
  • a compound of formula (IV) may be prepared by the two step reaction of a compound of formula (V)
  • compounds of formula (I) may be prepared by reaction of compounds of formula (III) and compounds of formula (VI)
  • Compounds of formula (VI) may be prepared by reaction of a compound of formula (V) with a compound of formula R 1 -L, where L is defined above, followed by reduction of the nitro group under hydrogenation or reductive tin chloride conditions.
  • a compound of formula (I) may be prepared by reacting a compound of formula (II) with a compound of formula (VII)
  • R 1 ' represents R 1 minus a methylene group, under standard reductive amination conditions, e.g. using sodium triacetoxyborohydride in a solvent such as dichloroethane.
  • 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 (VIII) and a compound of formula (IX)
  • 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.
  • 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.
  • a compound of formula (I) may be prepared from a different compound of formula (I), using standard techniques well known in the art.
  • compounds of formula (I) where R 3 comprises a group containing a carboxylic acid group may be prepared from the compound of formula (I) where the corresponding position comprises a carboxylic ester group.
  • Well known methods in the art may be employed to facilitate the transformation of an ester to an acid.
  • 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.
  • a specific enantiomer of a compound of general formula (I) when required, this may be obtained for example by resolution of a corresponding enantiomeric mixture of a compound of formula (I) using conventional methods.
  • 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.
  • 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.
  • 6-Methyl-4'-trifluoromethyl-biphenyl-2-carboxylic acid (4-piperazin-1 -yl-phenvD-amide as white crystals (0.9 g), m.p. : 155-157°C from 4- ⁇ 4-[(6-methyl-4'-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl ⁇ -piperazine- 1 -carboxylic acid tert-butyl ester (1.5 g).
  • Example 3 4'-lsopropyl-6-methyl-biphenyl-2-carboxylic acid r4-(4-allyl-piperazin-1 -vP-phenyll-amide as white crystals (110 mg), m.p. : 107-109°C mass spec m/z : 454 (M+1 ). from 4'-isopropyl-6-methyl-biphenyl-2-carboxylic acid (4-piperazin-1-yl-phenyl)-amide (500 mg) and 3-bromo-propene (160 mg).
  • Example 6 4'-lsopropyl-6-methoxy-biphenyl-2-carboxylic acid r4-(4-thiazol-2-ylmethyl-piperazin-1 - vP-phenyll-amide as a cream powder (104 mg), m.p. : 132°C mass spec m/z : 527 (M+1). from 4'-isopropyl-6-methoxy-biphenyl-2-carboxylic acid (4-piperazin-1-yl-phenyl)-amide (220 mg) and thiazole-2-carboxaldehyde (58 mg).
  • hepatocytes 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 ⁇ g/ml insulin, 100 nM dexamethasone and 50 ⁇ Ci/ml 35 S-methionine. Compounds were dissolved in DMSO and tested onto cells from 1 ⁇ M 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 1C 50 of each compound was determined on both apoproteins.
  • 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.
  • Examples of the invention were tested in vitro, using the biological assays described above. All of the compounds had an IC 50 value of 0.8 nM or below in the MTP assay.

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Abstract

Therapeutically active benzamide derivatives of formula (I) wherein R1-R3 are as defined in the specification, 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

Therapeutic Benzamide Derivatives
The invention relates to therapeutic benzamide derivatives and 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.
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 neosynthesized 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. International Patent Application no. PCT/EP99/09320 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 PCT/EP99/09320, and having a specific substitution pattern, exhibit improved properties over those compounds specifically disclosed in
PCT/EP99/09320. Thus, the present invention provides a compound of formula (I);
Figure imgf000003_0001
wherein R1 represents C-ι-4alkyl, C2-6alkenyl, C1-4alkylsulfonyl, C1-4acyl or CH2-R4;
R2 represents isopropyl or trifluoromethyl;
R3 represents methyl or methoxy;
R4 represents: i) a 5 or 6-membered heteroaromatic group selected from thienyl, thiazolyl and furanyl, optionally substituted by halogen, cyano, C1-4alkyl, C1-4alkoxy or C3- 7cycloalkyl, ii) a 2-pyrrolyl substituted by either 4- or 5- cyano, iii) C3-7cycloalkyl, iv) cyano, v) hydroxycarbonyl or
Figure imgf000003_0002
vi) C1-4alkoxyC1-4alkyl, hydroxyC1- alkyl or vii) trifluoromethylC1-4alkyl; or a physiologically acceptable salt, solvate or derivative 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), examples of alkyl groups include methyl and ethyl groups.
Referring to the general formula (I), alkyl, alkylene and alkoxy include both straight and branched chain saturated hydrocarbon groups. Examples of alkyl groups include methyl and ethyl groups, examples of alkylene groups include methylene and ethylene 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. 3- methyl-but-2-ene and propen-2-yl.
Referring to the general formula (I), reference to a heteroaromatic group, unless otherwise defined, means any single aromatic ring containing at least one ring heteroatom independently selected from O, N and S.
Referring to the general formula (I), reference to a halogen group includes fluoro, chloro, bromo and iodo groups.
R1 is suitably selected from C1-4alkyl, e.g. methyl, ethyl, isopropyl, propyl or isobutyl, C2-
6alkenyl, e.g. prop-2-enyl, acetyl, methylsulfonyl or -CH2-R4, wherein R4 is suitably cyano, ethoxycarbonyl, hydroxycarbonyl, C1-4alkoxymethyl e.g. methoxymethyl, trifluoromethylC1- alkyl, e.g. 1 ,1 ,1 -trif luoroethyl, C3-7cycloalkyl e.g. cyclopropyl, an optionally substituted 2-thienyl, 3-thienyl, 2-thiazolyl or 2-furanyl, where optional substitution is effected by bromo, methyl or cyano, or a 2-pyrrolyl substituted by either
4- or 5- cyano.
R1 is more suitably methyl, propyl, isopropyl, propen-2-yl, methoxyethyl, 1 ,1 ,1- trifluoropropyl, an optionally substituted 3-thienylmethyl or 2-furanylmethyl group, where optional substitution is effected by methyl or cyano, or a 2-pyrrolylmethyl, substituted by either 4- or 5- cyano.
R1 is preferably propen-2-yl or 3-thienylmethyl. Alternatively, R1 is preferably methyl, propyl, propen-2-yl, 2-furanylmethyl substituted by cyano or 3-thienylmethyl.
R1 is most preferably propen-2-yl.
R2 is preferably isopropyl.
R3 is preferably methoxy. R3 is equally preferably methyl.
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 of the invention include:
4'-lsopropyl-6-methoxy-biphenyl-2-carboxylic acid [4-(4-propyl-piperazin-1 -yl)-phenyl]- amide;
4'-lsopropyl-6-methoxy-biphenyl-2-carboxylic acid [4-(4-allyl-piperazin-1 -yl)-phenyl]- amide; 4'-lsopropyl-6-methyl-biphenyl-2-carboxylic acid [4-(4-allyl-piperazin-1-yl)-phenyl]- amide;
4'-lsopropyl-6-methoxy-biphenyl-2-carboxylic acid [4-(4-thiophen-3-ylmethyl-piperazin-
1-yl)-phenyl ]-amide;
4'-lsopropyl-6-methoxy-biphenyl-2-carboxylic acid {4-[4-(5-cyano-furan-2-ylmethyl)- piperazin-1 -yl]-phenyl}-amide;
4'-lsopropyl-6-methoxy-biphenyl-2-carboxylic acid [4-(4-thiazol-2-ylmethyl-piperazin-1 - yl)-phenyl]-amide;
4'-lsopropyl-6-methoxy-biphenyl-2-carboxylic acid [4-(4-thiophen-2-ylmethyl-piperazin-
1-yl)-phenyl]-amide; 4'-lsopropyl-6-methoxy-biphenyl-2-carboxylic acid [4-(4-furan-2-ylmethyl-piperazin-1-yl)- phenyl]-amide;
4'-lsopropyl-6-methyl-biphenyl-2-carboxylic acid [4-(4-propyl-piperazin-1 -yl)-phenyl]- amide;
4'-lsopropyl-6-methyl-biphenyl-2-carboxylic acid [4-(4-methyl-piperazin-1 -yl)-phenyl]- amide; 4'-lsopropyl-6-methoxy-biphenyl-2-carboxylic acid [4-(4-methyl-piperazin-1 -yl)-phenyl]- a ide;
4'-Isopropyl-6-methyl-biphenyl-2-carboxylic acid [4-(4-ethyl-piperazin-1 -yl)-phenyl]- amide ; 4'-lsopropyl-6-methyl-biphenyl-2-carboxylic acid [4-(4-isopropyl-piperazin-1-yl)-phenyl]- amide ;
4'-lsopropyl-6-methyl-biphenyl-2-carboxylic acid [4-(4-isobutyl-piperazin-1 -yl)-phenyl]- amide ;
4'-lsopropyl-6-methyl-biphenyl-2-carboxylic acid {4-[4-(3-methyl-but-2-enyl)-piperazin-1 - yl]-phenyl}-amide;
4'-lsopropyl-6-methyl-biphenyl-2-carboxylic acid {4-[4-(3,3,3-trifluoro-propyl)-piperazin-
1 -yl]-phenyl}-amide;
4'-lsopropyl-6-methyl-biphenyl-2-carboxylic acid {4-[4-(2-methoxy-ethyl)-piperazin-1 -yl]- phenyl}-amide ; 4'-lsopropyl~6-methyl-biphenyl-2-carboxylic acid {4-[4-(2-hydroxy-ethyl)-piperazin-1 -yl]- phenyl}-amide ;
4'-lsopropyl-6-methyl-biphenyl-2-carboxylic acid [4-(4-thiophen-3-ylmethyl-piperazin-1 - yl]-phenyl}-amide;
4'-lsopropyl-6-methyl-biphenyl-2-carboxylic acid [4-(4-furan-2-ylmethyl-piperazin-1 -yl]~ phenyl}-amide;
4'-lsopropyl-6-methyl-biphenyl-2-carboxylic acid {4-[4-(5-cyano-furan-2-ylmethyl)- piperazin-1 -yl]-phenyl}-amide;
4'-lsopropyl-6-methyl-biphenyl-2-carboxylic acid {4-[4-(4-cyano-1 H-pyrrol-2-ylmethyl)- piperazin-1 -yl]-phenyl}-amide; 4'-lsopropyl-6-methyl-biphenyl -2-carboxylic acid {4-[4-(5-cyano-1 H-pyrrol-2-ylmethyl)- piperazin-1 -yl]-phenyl}-amide;
4'-lsopropyl-6-methyl-biphenyl-2-carboxylic acid [4-(4-methanesulfonyl-piperazin-1 -yl)- phenylj-amide;
4'-lsopropyl-6-methyl-biphenyl-2-carboxylic acid [4-(4-acetyl-piperazin-1 -yl)-phenyl]- amide;
4'-lsopropyl-6-methyl-biphenyl-2-carboxylic acid [4-(4-propionyl-piperazin-1 -yl)-phenyl]- amide;
4'-lsopropyl-6-methoxy-biphenyl-2-carboxylic acid [4-(4-ethyl-piperazin-1 -yl)-phenyl]- amide; 4'-lsopropyl-6-methoxy-biphenyl-2-carboxylic acid [4-(4-isopropyl-piperazin-1 -yl)- phenyl]-amide ;
4'-lsopropyl-6-methoxy-biphenyl-2-carboxylic acid [4-(4-isobutyl-piperazin-1 -yl)-phenyl]- amide ; 4'-lsopropyl-6-methoxy-biphenyl-2-carboxylic acid {4-[4-(3-methyl-but-2-enyl)-piperazin-
1-yl]-phenyl}-amide;
4'-lsopropyl-6-methoxy-biphenyl-2-carboxylic acid {4-[4-(3,3,3-trifluoro-propyl)- piperazin-1 -yl]-phenyl}-amide;
4'-lsopropyl-6-methoxy-biphenyl-2-carboxylic acid {4-[4-(2-methoxy-ethyl)-piperazin-1 - yl]-phenyl}-amide;
4'-lsopropyl-6-methoxy-biphenyl-2-carboxylic acid {4-[4-(2-hydroxy-ethyl)-piperazin-1 - yl]-phenyl}-amide;
4'-Isopropyl-6-methoxy-biphenyl-2-carboxylic acid {4-[4-(4-cyano-1 H-pyrrol-2-ylmethyl)- piperazin-1 -yl]-phenyl}-amide; 4'-lsopropyl-6-methoxy-biphenyl -2-carboxylic acid {4-[4-(5-cyano-1 H-pyrrol-2-ylmethyl)- piperazin-1 -yl]-phenyl}-amide;
4'-lsopropyl-6-methoxy-biphenyl-2-carboxylic acid [4-(4-methanesulfonyl-piperazin-1 -yl)- phenylj-amide;
4'-lsopropyl-6-methoxy-biphenyl-2-carboxylic acid [4-(4-acetyl-piperazin-1 -yl)-phenyl]- amide;
4'-lsopropyl-6-methoxy-biphenyl-2-carboxylic acid [4-(4-propionyl-piperazin-1 -yl)- phenyl]-amide; or a physiologically acceptable salt, solvate or derivative thereof.
Most suitable compounds of the invention include:
4'-lsopropyl-6-methoxy-biphenyl-2-carboxylic acid [4-(4-propyl-piperazin-1 -yl)-phenyl]- amide;
4'-lsopropyl-6-methoxy-biphenyl-2-carboxylic acid [4-(4-allyl-piperazin-1 -yl)-phenyl]- amide; 4'-lsopropyl-6-methyl-biphenyl-2-carboxylic acid [4-(4-allyl-piperazin-1-yl)-phenyl]- amide;
4'-lsopropyl-6-methoxy-biphenyl-2-carboxylic acid [4-(4-thiophen-3-ylmethyl-piperazin-
1-yl)-phenyl ]-amide;
4'-lsopropyl-6-methoxy-biphenyl-2-carboxylic acid {4-[4-(5-cyano-furan-2-ylmethyl)- piperazin-1 -yl]-phenyl}-amide; 4'-lsopropyl-6-methoxy-biphenyl-2-carboxylic acid [4-(4-thiazol-2-ylmethyl-piperazin-1 - yl)-phenyl]-amide;
4'-lsopropyl-6-methoxy-biphenyl-2-carboxylic acid [4-(4-thiophen-2-ylmethyl-piperazin- 1-yl)-phenyl]-amide; 4'-lsopropyl-6-methoxy-biphenyl-2-carboxylic acid [4-(4-furan-2-ylmethyl-piperazin-1-yl)- phenyl]-amide;
4'-lsopropyl-6-methyl-biphenyl-2-carboxylic acid [4-(4-propyl-piperazin-1 -yl)-phenyl]- amide;
4'-lsopropyl-6-methyl-biphenyl-2-carboxylic acid [4-(4-methyl-piperazin-1-yl)-phenyl]- amide;
4'-lsopropyl-6-methoxy-biphenyl-2-carboxylic acid [4-(4-methyl-piperazin-1 -yl)-phenyl]~ amide; or a physiologically acceptable salt, solvate or derivative thereof.
The term "physiologically functional derivative" as used herein refers to any physiologically acceptable derivative of a compound of the present invention, for example, an ester or amide, which upon administration to a mammal, such as a human, is capable of providing (directly or indirectly) such a compound or an active metabolite thereof. Such derivatives are clear to those skilled in the art, without undue experimentation, and with reference to the teaching of Burger's Medicinal Chemistry
And Drug Discovery, 5th Edition, Vol 1 : Principles And Practice, which is incorporated herein by reference.
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, solvate or derivative 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, solvate or derivative 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, solvate or derivative 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, solvate or derivative 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.
The 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, solvate or derivative 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 R1-L
Figure imgf000011_0001
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)
Figure imgf000011_0002
(III) 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.
A compound of formula (IV), may be prepared by the two step reaction of a compound of formula (V)
Figure imgf000011_0003
(V)
comprising incorporation of the protecting group P using standard methodology followed by reduction of the nitro group, e.g. under hydrogenation conditions.
According to a second method (B), compounds of formula (I) may be prepared by reaction of compounds of formula (III) and compounds of formula (VI)
Figure imgf000012_0001
where L' is defined above, under standard coupling conditions.
Compounds of formula (VI) may be prepared by reaction of a compound of formula (V) with a compound of formula R1-L, where L is defined above, followed by reduction of the nitro group under hydrogenation or reductive tin chloride conditions.
According to a third general process (C), a compound of formula (I), may be prepared by reacting a compound of formula (II) with a compound of formula (VII)
Figure imgf000012_0002
where R1' represents R1 minus a methylene group, under standard reductive amination conditions, e.g. using sodium triacetoxyborohydride in a solvent such as dichloroethane.
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 (VIII) and a compound of formula (IX)
Figure imgf000012_0003
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 fourth process (D), a compound of formula (I) may be prepared from a different compound of formula (I), using standard techniques well known in the art. For example, compounds of formula (I) where R3 comprises a group containing a carboxylic acid group may be prepared from the compound of formula (I) where the corresponding position comprises a carboxylic ester group. Well known methods in the art may be employed to facilitate the transformation of an ester to an acid.
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 R1-L, (III), (V), (VI), (VIII) and (IX) 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: AcOEt-Ethyl acetate
BuLi - butyl lithium
BINAP-2,2'-bis(diphenylphosphino)-1 ,1'-binaphthyl
CH2CI2 - dichloromethane
CH3CN - acetonitrile DMSO - dimethylsulfoxide
EDCI-1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride
EtOH- Ethanol
Et3N- Triethylamine
Et2O - diethyl ether HOBt-1-Hydroxybenzotriazole
LiCI - lithium chloride
MS - LCMS mass spectrography
MeOH - Methanol
NaHCO3 - sodium hydrogencarbonate Na2CO3 - sodium carbonate
NiCI2(dppf) - nickel 1 ,1- bis(diphenylphosphino)ferrocene chloride
NaSO4 - sodium sulphate
Pd(PPh3)4 - tetrakis(triphenylphosphine)palladium(0)
SnCI2.2H2O - tin(ll) chloride dihydrate THF- Tetrahydrofuran Intermediate 1
4-(4-Nitro-phenyl)-piperazine-1 -carboxylic acid tert-butyl ester
To a solution of 1-(4-nitro-phenyl)-piperazine (15.5 g) in CH2CI2 (250 mL) was added Et3N (8.3 g). The solution was cooled to 0°C and di-tert-butyl dicarbonate (17.1 g) was added portionwise. After 16 hours at room temperature, the solution was washed with water, with a saturated solution of NaHCO3 and brine. The organic phase was dried over Na2SO4, filtered and evaporated under reduced pressure and the resulting solid was recrystallized from MeOH to give the title compound (21.5 g) as pale yellow crystals. m.p: 149-151 °C.
Intermediate 2
4-(4-Amino-phenyl)-piperazine-1 -carboxylic acid tert-butyl ester A solution of 4-(4-nitro-phenyl)-piperazine-1 -carboxylic acid tert-butyl ester (21.4 g) in
EtOH (250 mL) containing Pd/C 10% (0.5 g) was hydrogenated at room temperature.
After 16 hours, the catalyst was removed by filtration and the filtrate was evaporated under reduced pressure. The oily residue was then crystallized from cyclohexane to give the title compound (17.8 g) as pink crystals. m.p: 95-96°C.
Intermediate 3
4'-lsopropyl-6-methoxy-biphenyl-2-carboxylic acid methyl ester
To a stirred solution of 3-methoxy-2-(trifluoro-methanesulfonyloxy)-benzoic acid methyl ester (12.2 g) in toluene (300 mL) was added LiCI (5 g) and Pd(PPh3)4 (2.24 g). After few minutes at room temperature, a 2M solution of Na2CO3 (51 mL) was added followed by a solution of 4-isopropylphenyl boronic acid (7 g) in EtOH (50 mL). The resulting mixture was stirred under reflux for 16 hours. The mixture was cooled to room temperature and the phases were separated. The organic layer was then dried over Na2SO4, filtered and evaporated under reduced pressure. The residue was purified by flash chromatography eluting with petroleum ether/AcOEt (95/5) to give the title compound (10 g) as a colorless oil.
GCMS : m/z 284 (M+)
Similarly prepared were : Intermediate 4
4'-lsopropyl-6-methyl-biphenyl-2-carboxylic acid methyl ester as a colorless oil (15.3 g), GCMS : m/z 268 (M+) from 3-methyl-2-(trifluoro-methanesulfonyloxy)-benzoic acid methyl ester (15.7 g) and 4-isopropylphenyl boronic acid (10 g).
Intermediate 5
6-Methyl-4'-trifluoromethyl-biphenyl-2-carboxylic acid methyl ester as a colorless oil (13.7 g), GCMS : m/z 294 (M+) from 3-methyl-2-(trifluoro-methanesulfonyloxy)-benzoic acid methyl ester (15.7 g) and 4-trifluoromethylphenyl boronic acid (10 g).
Intermediate 6 4'-lsopropyl-6-methoxy-biphenyl-2-carboxylic acid
4'-lsopropyl-6-methoxy-biphenyl-2-carboxylic acid methyl ester (10 g) was placed in suspension in MeOH (150 mL) and a 1N solution of NaOH (70 mL) was added. The mixture was stirred under reflux for 5 hours and MeOH was evaporated under reduced pressure. The aqueous layer was then acidified with concentrated HCI and the resulting solid which formed was extracted with CH2CI2. The organic phase was washed with water, dried over Na2SO4, filtered and evaporated under reduced pressure to give the title compound (8.4 g) as white crystals, m.p. : 132-134°C
Similarly prepared were : Intermediate 7
4'-lsopropyl-6-methyl-biphenyl-2-carboxylic acid as white crystals (10 g), m.p. : 145-146°C from 4'-isopropyl-6-methyl-biphenyl-2-carboxylic acid methyl ester (15.3 g).
Intermediate 8
6-Methyl-4'-trifluoromethyl-biphenvi-2-carboxylic acid as white crystals (8.5 g), m.p. : 206-208°C from 6-methyl-4'-trifluoromethyl-biphenyl-2-carboxylic acid methyl ester (10 g). Intermediate 9
4-(4-r(4'-lsopropyl-6-methoxy-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 (2 g), 4'-isopropyl-6-methoxy-biphenyl-2-carboxylic acid (1.94 g), HOBt (1.26 g), and
Et3N (0.94 g) in CH2CI2 (30 mL) was added EDCI (1.77 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 and dried over Na2SO . After filtration and evaporation of the filtrate, the oily residue was crystallized from diisopropyl ether to give the tjfie compound (1.9 g) as white crystals, m.p. : 155-157°C.
Similarly prepared were :
Intermediate 10 4-f4-r(4'-lsopropyl-6-methyl-biphenyl-2-carbonyl)-aminol-phenvR-piperazine-1- carboxylic acid tert-butyl ester as white crystals (1.8 g), m.p. : 140-142°C from 4'-isopropyl-6-methyl-biphenyl-2-carboxylic acid (1.83 g) and 4-(4-amino-phenyl)- piperazine-1 -carboxylic acid tert-butyl ester (2 g).
Intermediate 11
4-{4-r(6-Methyl-4'-trifluoromethyl-biphenyl-2-carbonyl)-aminol-phenyl>-piperazine-1- carboxylic acid tert-butyl ester as white crystals (1.5 g), m.p. : 163-165°C from 6-methyl-4'-trifluoromethyl-biphenyl-2-carboxylic acid (2 g) and 4-(4-amino- phenyl)-piperazine-1 -carboxylic acid tert-butyl ester (2 g).
Intermediate 12
4'-lsopropyl-6-methoxy-biphenyl-2-carboxylic acid (4-piperazin-1 -yl-phenyl)-amide To a solution of 4-{4-[(4'-isopropyl-6-methoxy-biphenyl-2-carbonyl)-amino]-phenyl}- piperazine-1 -carboxylic acid tert-butyl ester (1.5 g) in CH2CI2 (3 mL) was added trifluoroacetic acid (3 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 dilute NaOH and extracted with CH2CI2. The organic phase was then washed with water, dried over Na2SO4, filtered and evaporated to dryness. The residue was crystallized from diisopropyl ether to give the title compound (1.3 g) as white crystals. m.p. : 157-159°C.
Similarly prepared were :
Intermediate 13
4'-lsopropyl-6-methyl-biphenyl-2-carboxylic acid (4-piperazin-1-yl-phenyl)-amide as white crystals (1.2 g), m.p. : 130°C from 4-{4-[(4'-isopropyl-6-methyl-biphenyl-2-carbonyl)-amino]-phenyl}-piperazine-1- carboxylic acid tert-butyl ester (1.8 g).
Intermediate 14
6-Methyl-4'-trifluoromethyl-biphenyl-2-carboxylic acid (4-piperazin-1 -yl-phenvD-amide as white crystals (0.9 g), m.p. : 155-157°C from 4-{4-[(6-methyl-4'-trifluoromethyl-biphenyl-2-carbonyl)-amino]-phenyl}-piperazine- 1 -carboxylic acid tert-butyl ester (1.5 g).
Example 1
4'-lsopropyl-6-methoxy-biphenyl-2-carboxylic acid r4-(4-propyl-piperazin-1-yl)-phenyl1- amide
To a stirred solution of 4'-isopropyl-6-methoxy-biphenyl-2-carboxylic acid (4-piperazin-1- yl-phenyl)-amide (intermediate 12) (220 mg) and potassium carbonate (106 mg) in acetone (15 ml) was added 1-bromopropane (76 mg). The mixture was heated under reflux overnight and then pourred into water. After extraction with CH CI2, the organic phase was dried over Na2SO4, filtered and evaporated under reduced pressure. The solid residue was crystallized from diethyl ether to give the title compound as a white powder (164 mg). m.p.: 144°C mass spec m/z : 472 (M+1).
Similarly prepared were : Example 2
4'-lsopropyl-6-methoxy-biphenyl-2-carboxylic acid r4-(4-allyl-piperazin-1 -vπ-phenyll- amide as a cream solid (80 mg), m.p. : 134-136°C mass spec m/z : 470 (M+1). from 4'-isopropyl-6-methoxy-biphenyl-2-carboxylic acid (4-piperazin-1-yl-phenyl)-amide (643 mg) and 3-bromo-propene (199 mg).
Example 3 4'-lsopropyl-6-methyl-biphenyl-2-carboxylic acid r4-(4-allyl-piperazin-1 -vP-phenyll-amide as white crystals (110 mg), m.p. : 107-109°C mass spec m/z : 454 (M+1 ). from 4'-isopropyl-6-methyl-biphenyl-2-carboxylic acid (4-piperazin-1-yl-phenyl)-amide (500 mg) and 3-bromo-propene (160 mg).
Example 4
4'-lsopropyl-6-methoxy-biphenyl-2-carboxylic acid r4-(4-thiophen-3-ylmethyl-piperazin- 1-yl)-phenyl 1-amide
To a solution of 4'-isopropyl-6-methoxy-biphenyl-2-carboxylic acid (4-piperazin-1-yl- phenyl)-amide (220 mg) in dichloromethane (15 mL) was added thiophene-3- carboxaldehyde (57 mg). The solution was cooled at O°C and sodium triacetoxy borohydride (109 mg) was added portionwise and the mixture was stirred at room temperature for 24 hours. The solution was then washed with a saturated solufion of
NaHCO3, with brine, dried over Na2SO , filtered and evaporated under reduced pressure. The residue was purified by flash chromatography eluting with CH2CI2/MeOH (96/4) and crystallized from diisopropyl ether to give the title compound (95 mg) as a white powder. m.p. : 158°C mass spec m/z : 526 (M+1).
Similarly prepared were : Example 5
4'-lsopropyl-6-methoxy-biphenyl-2-carboxylic acid {4-l4-(5-cvano-furan-2-ylmethyl)- piperazin-1 -yll-phenyll-amide as white crystals (300 mg), m.p. : 212-214°C mass spec m/z : 535 (M+1). from 4'-isopropyl-6-methoxy-biphenyl-2-carboxylic acid (4-piperazin-1-yl-phenyl)-amide (429 mg) and 5-formyl-furan-2-carbonitrile (121 mg).
Example 6 4'-lsopropyl-6-methoxy-biphenyl-2-carboxylic acid r4-(4-thiazol-2-ylmethyl-piperazin-1 - vP-phenyll-amide as a cream powder (104 mg), m.p. : 132°C mass spec m/z : 527 (M+1). from 4'-isopropyl-6-methoxy-biphenyl-2-carboxylic acid (4-piperazin-1-yl-phenyl)-amide (220 mg) and thiazole-2-carboxaldehyde (58 mg).
Example 7
4'-lsopropyl-6-methoxy-biphenyl-2-carboxylic acid r4-(4-thiophen-2-ylmethyl-piperazin- 1-viy-phenvH-amide as a cream powder (54 mg), m.p. : 126°C mass spec m/z : 526 (M+1).
From 4'-isopropyl-6-methoxy-biphenyl-2-carboxylic acid (4-piperazin-1-yl-phenyl)- amide (220 mg) and thiophene-2-carboxaldehyde (57 mg).
Example 8
4'-lsopropyl-6-methoxy-biphenyl-2-carboxylic acid r4-(4-furan-2-ylmethyl-piperazin-1 -vD- phenyll-amide as a cream powder (83 mg), m.p. : 68°C mass spec m/z : 510 (M+1). from 4'-isopropyl-6-methoxy-biphenyl-2-carboxylic acid-[4-piperazinyl-phenyl]-amide
(220 mg) and furan-2-carboxaldehyde (49 mg).
Example 9
4'-lsopropyl-6-methyl-biphenyl-2-carboxylic acid r4-(4-propyl-piperazin-1 -yl)-phenyl1- amide as a white solid (71 mg), m.p. : 98°C mass spec m/z : 456 (M+1). from 4'-isopropvl-6-methvl-biphenvl-2-carboxylic acid (4-piperazin-1 -yl-phenyl)-amide
(300 mg) and propionaldehyde (51 mg).
Example 10
4'-lsopropyl-6-methyl-biphenyl-2-carboxylic acid r4-(4-methyl-piperazin-1 -vD-phenyll- amide
To a stirred solution of 4-(4-methyl-piperazin-1-yl)-phenylamine (229 mg), 4'-isopropyl- 6-methyl-biphenyl-2-carboxylic acid (254 mg), HOBt (175 mg), and Et3N (131 mg) in
CH2CI2 (10 mL) was added at room temperature EDCI (249 mg) 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 and dried over Na2SO . After filtration and evaporation of the filtrate, the residue was purified by flash chromatography eluting with CH2CI2/MeOH (9/1) and crystallized from hexane to give the title compound (240 mg) as a white powder. m.p. : 108°C. mass spec m/z : 428 (M+1 ).
Similarly prepared was :
Example 11
4'-lsopropyl-6-methoxy-biphenyl-2-carboxylic acid r4-(4-methyl-piperazin-1 -vQ-phenvπ- amide as a white solid (200 mg), m.p. : 131-133°C mass spec m/z : 444 (M+1 ). from 4'-isopropyl-6-methoxy-biphenyl-2-carboxylic acid (270 mg) and 4-(4-methyl- piperazin-1-yl)-phenylamine (191 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 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 1C50 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.
Biological Data
Examples of the invention were tested in vitro, using the biological assays described above. All of the compounds had an IC50 value of 0.8 nM or below in the MTP assay.

Claims

Claims
1. A compound of formula (I)
Figure imgf000023_0001
wherein:
R1 represents C^alkyl, C2-6alkenyl, C1-4alkylsulfonyl, C1-4acyl or CH2-R4;
R2 represents isopropyl or trifluoromethyl;
R3 represents methyl or methoxy; R4 represents i) a 5 or 6 membered heteroaromatic group selected from thienyl, thiazolyl and furanyl, optionally substituted by halogen, cyano,
Figure imgf000023_0002
C1-4alkoxy or C3- 7cycloalkyl, ii) a 2-pyrrolyl substituted by either 4- or 5- cyano iii) C3-7cycloalkyl, iv) cyano, v) hydroxycarbonyl or C1-4alkoxycarbony'l, vi)
Figure imgf000023_0003
hydroxyC1-4alkyl or vii) trifluoromethylC1-4alkyl; or a physiologically acceptable salt, solvate or derivative thereof.
2. A compound of formula (I) according to claim 1 , wherein R1 represents methyl, propyl, isopropyl, propen-2-yl, methoxyethyl, 1 ,1 ,1-trifluoropropyl , an optionally substituted 3-thienylmethyl or 2-furanylmethyl group, wherein optional substitution is effected by methyl or cyano, or a 2-pyrrolylmethyl, substituted by either 4- or 5- cyano, or a physiologically acceptable salt, solvate or derivative thereof.
3. A compound of formula (I) according to claim 1 or claim 2, wherein R2 represents isopropyl, or a physiologically acceptable salt, solvate or derivative thereof.
4. A compound of formula (I) according to any one of claims 1 to 3, wherein R3 represents methyl or methoxy, or a physiologically acceptable salt, solvate or derivative thereof.
5. A compound of formula (I) according to claim 1 selected from the group comprising:
4'-lsopropyl-6-methoxy-biphenyl-2-carboxylic acid [4-(4-propyl-piperazin-1 -yl)-phenyl]- amide;
4'-lsopropyl-6-methoxy-biphenyl-2-carboxylic acid [4-(4-allyl-piperazin-1-yl)-phenyl]- amide; 4'-lsopropyl-6-methyl-biphenyl-2-carboxylic acid [4-(4-allyl-piperazin-1-yl)-phenyl]- amide;
4'-lsopropyl-6-methoxy-biphenyl-2-carboxylic acid [4-(4-thiophen-3-ylmethyl-piperazin-
1-yl)-phenyl ]-amide;
4'-Isopropyl-6-methoxy-biphenyl-2-carboxylic acid {4-[4-(5-cyano-furan-2-ylmethyl)- piperazin-1 -yl]-phenyl}-amide;
4'-lsopropyl-6-methoxy-biphenyl-2-carboxylic acid [4-(4-thiazol-2-ylmethyl-piperazin-1- yl)-phenyl]-amide;
4'-lsopropyl-6-methoxy-biphenyl-2-carboxylic acid [4-(4-thiophen-2-ylmethyl-piperazin-
1 -yl)-phenyl]-amide; 4'-lsopropyl-6-methoxy-biphenyl-2-carboxylic acid [4-(4-furan-2-ylmethyl-piperazin-1-yl)- phenyl]-amide;
4'-lsopropyl-6-methyl-biphenyl-2-carboxylic acid [4-(4-propyl-piperazin-1 -yl)-phenyl]- amide;
4'-lsopropyl-6-methyl-biphenyl-2-carboxylic acid [4-(4-methyl-piperazin-1 -yl)-phenyl]- amide;
4'-lsopropyl-6-methoxy-biphenyl-2-carboxylic acid [4-(4-methyl-piperazin-1 -yl)-phenyl]- amide;
4'-lsopropyl-6-methyl-biphenyl-2-carboxylic acid [4-(4-ethyl-piperazin-1 -yl)-phenyl]- amide ; 4'-lsopropyl-6-methyl-biphenyl-2-carboxylic acid [4-(4-isopropyl-piperazin-1-yl)-phenyl]- amide ;
4'-lsopropyl-6-methyl-biphenyl-2-carboxylic acid [4-(4-isobutyl-piperazin-1 -yl)-phenyl]- amide ;
4'-lsopropyl-6-methyl-biphenyl-2-carboxylic acid {4-[4-(3-methyl-but-2-enyl)-piperazin-1 - yl]-phenyl}-amide; 4'-lsopropyl-6-methyl-biphenyl-2-carboxylic acid {4-[4-(3,3,3-trifluoro-propyl)-piperazin-
1-yl]-phenyl}-amide;
4'-lsopropyl-6-methyl-biphenyl-2-carboxylic acid {4-[4-(2-methoxy-ethyl)-piperazin-1 -ylj- phenyl}-amide ; 4'-lsopropyl-6-methyl-biphenyl-2-carboxylic acid {4-[4-(2-hydroxy-ethyl)-piperazin-1-yl]- phenyl}-amide ;
4'-lsopropyl-6-methyl-biphenyl-2-carboxylic acid [4-(4-thiophen-3-ylmethyl-piperazin-1 - yl]-phenyl}-amide;
4'-Isopropyl-6-methyl-biphenyl-2-carboxylic acid [4-(4-furan-2-ylmethyl-piperazin-1 -yl]- phenyl}-amide;
4'-lsopropyl-6-methyl-biphenyl-2-carboxylic acid {4-[4-(5-cyano-furan-2-ylmethyl)- piperazin-1 -yl]-phenyl}-amide;
4'-lsopropyl-6-methyl-biphenyl-2-carboxylic acid {4-[4-(4-cyano-1 H-pyrrol-2-ylmethyl)- piperazin-1 -yl]-phenyl}-amide; 4'-lsopropyl-6-methyl-biphenyl -2-carboxylic acid {4-[4-(5-cyano-1 H-pyrrol-2-ylmethyl)- piperazin-1 -yl]-phenyl}-amide;
4'-lsopropyl-6-methyl-biphenyl-2-carboxylic acid [4-(4-methanesulfonyl-piperazin-1 -yl)- phenyl]-amide;
4'-lsopropyl-6-methyl-biphenyl-2-carboxylic acid [4-(4-acetyl-piperazin-1 -yl)-phenyl]- amide;
4'-lsopropyl-6-methyl-biphenyl-2-carboxylic acid [4-(4-propionyl-piperazin-1 -yl)-phenyl]- amide;
4'-lsopropyl-6-methoxy-biphenyl-2 -carboxylic acid [4-(4-ethyl-piperazin-1 -yl)-phenyl]- amide; 4'-lsopropyl-6-methoxy-biphenyl-2-carboxylic acid [4-(4-isopropyl-piperazin-1-yl)- phenyl]-amide ;
4'-lsopropyl-6-methoxy-biphenyl-2-carboxylic acid [4-(4-isobutyl-piperazin-1 -yl)-phenyl]- amide ;
4'-lsopropyl-6-methoxy-biphenyl-2-carboxylic acid {4-[4-(3-methyl-but-2-enyl)-piperazin- 1-yl]-phenyl}-amide;
4'-Isopropyl-6-methoxy-biphenyl-2-carboxylic acid {4-[4-(3,3,3-trifluoro-propyl)- piperazin-1 -yl]-phenyl}-amide;
4'-lsopropyl-6-methoxy-biphenyl-2-carboxylic acid {4-[4-(2-methoxy-ethyl)-piperazin-1- yl]-phenyl}-amide; 4'-lsopropyl-6-methoxy-biphenyl-2-carboxylic acid {4-[4-(2-hydroxy-ethyl)-piperazin-1 - yl]-phenyl}-amide;
4'-lsopropyl-6-methoxy-biphenyl-2-carboxylic acid {4-[4-(4-cyano-1 H-pyrrol-2-ylmethyl)- piperazin-1 -yl]-phenyl}-amide; 4'-lsopropyl-6-methoxy-biphenyl -2-carboxylic acid {4-[4-(5-cyano-1 H-pyrrol-2-ylmethyl)- piperazin-1 -yl]-phenyl}-amide;
4'-lsopropyl-6-methoxy-biphenyl-2-carboxylic acid [4-(4-methanesulfonyl-piperazin-1 -yl)- phenyl]-amide;
4'-lsopropyl-6-methoxy-biphenyl-2-carboxylic acid [4-(4-acetyl-piperazin-1 -yl)-phenyl]- amide;
4'-lsopropyl-6-methoxy-biphenyl-2-carboxylic acid [4-(4-propionyl-piperazin-1-yl)- phenyl]-amide; or a physiologically acceptable salt, solvate or derivative thereof.
6. A compound of formula (I) according to claim 1 selected from the group comprising:
4'-lsopropyl-6-methoxy-biphenyl-2-carboxylic acid [4-(4-propyl-piperazin-1 -yl)-phenyl]- amide;
4'-lsopropyl-6-methoxy-biphenyl-2-carboxylic acid [4-(4-allyl-piperazin-1 -yl)-phenyl]- amide; 4'-lsopropyl-6-methyl-biphenyl-2-carboxylic acid [4-(4-allyl-piperazin-1-yl)-phenyl]- amide;
4'-lsopropyl-6-methoxy-biphenyl-2-carboxylic acid [4-(4-thiophen-3-ylmethyl-piperazin-
1-yl)-phenyl ]-amide;
4'-lsopropyl-6-methoxy-biphenyl-2-carboxylic acid {4-[4-(5-cyano-furan-2-ylmethyl)- piperazin-1 -yl]-phenyl}-amide;
4'-lsopropyl-6-methoxy-biphenyl-2-carboxylic acid [4-(4-thiazol-2-ylmethyl-piperazin-1 - yl)-phenyl]-amide;
4'-lsopropyl-6-methoxy-biphenyl-2-carboxylic acid [4-(4-thiophen-2-ylmethyl-piperazin-
1-yl)-phenyl]-amide; 4'-lsopropyl-6-methoxy-biphenyl-2-carboxylic acid [4-(4-furan-2-ylmethyl-piperazin-1-yl)- phenyl]-amide;
4'-lsopropyl-6-methyl-biphenyl-2-carboxylic acid [4-(4-propyl-piperazin-1 -yl)-phenyl]- amide;
4'-lsopropyl-6-methyl-biphenyl-2-carboxylic acid [4-(4-methyl-piperazin-1 -yl)-phenyl]- amide; 4'~lsopropyl-6-methoxy-biphenyl-2-carboxylic acid [4-(4-methyl-piperazin-1 -yl)-phenyl]- amide; or a physiologically acceptable salt, solvate or derivative thereof.
7. A compound of formula (I) or a physiologically acceptable salt, solvate or derivative thereof according to any one of claims 1 to 6 for use in therapy.
8. Use of a compound of formula (I) or a physiologically acceptable salt, solvate or derivative thereof according to any one of claims 1 to 6 in the preparation of a medicament for use in the treatment of conditions ameliorated by an apoB-100 and/or
MTP inhibitor.
9. Use of a compound of formula (I) according to claim 8, or a physiologically acceptable salt, solvate or derivative thereof, for use in the preparation of a medicament for the treatment of atherosclerosis, pancreatitis, non-insulin dependent diabetes mellitus (NIDDM), coronary heart diseases and obesity.
10. A method of treating a mammal comprising administration of an effective amount of a compound of formula (I) according to any one of claims 1 to 6 or a physiologically acceptable salt, solvate or derivative thereof, in the treatment of conditions ameliorated by an apoB-100 and/or MTP inhibitor.
11. A pharmaceutical compositions comprising at least one compound of formula (I) according to any one of claims 1 to 6, or a physiologically acceptable salt, solvate or derivative thereof, together with one or more pharmaceutically acceptable carriers or excipients.
12. A process for the preparation of a compound of formula (I), or a physiologically acceptable salt, solvate or derivative thereof, comprising reacting a compound of formula (II) with a compound of formula with a compound of formula R1-L
Figure imgf000028_0001
where L represents a suitable halide leaving group under standard displacement conditions and R1 is as hereinbefore defined.
PCT/EP2002/013591 2001-12-04 2002-12-02 Therapeutic benzamide derivatives WO2003047575A1 (en)

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