EP1383753A1 - Derives de piperazine-benzamide pouvant etre utilises en tant qu'inhibiteurs de apob-100 et/ou mtp - Google Patents

Derives de piperazine-benzamide pouvant etre utilises en tant qu'inhibiteurs de apob-100 et/ou mtp

Info

Publication number
EP1383753A1
EP1383753A1 EP02732605A EP02732605A EP1383753A1 EP 1383753 A1 EP1383753 A1 EP 1383753A1 EP 02732605 A EP02732605 A EP 02732605A EP 02732605 A EP02732605 A EP 02732605A EP 1383753 A1 EP1383753 A1 EP 1383753A1
Authority
EP
European Patent Office
Prior art keywords
biphenyl
carboxylic acid
amide
piperazin
phenyl
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP02732605A
Other languages
German (de)
English (en)
Inventor
Alain Claude-Marie Daugan
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Glaxo Group Ltd
Original Assignee
Glaxo Group Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Glaxo Group Ltd filed Critical Glaxo Group Ltd
Publication of EP1383753A1 publication Critical patent/EP1383753A1/fr
Withdrawn legal-status Critical Current

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Classifications

    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/18—Drugs for disorders of the alimentary tract or the digestive system for pancreatic disorders, e.g. pancreatic enzymes
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/10—Drugs for disorders of the urinary system of the bladder
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/04—Anorexiants; Antiobesity agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis

Definitions

  • 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.
  • 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 neosyhthesized 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.
  • WO96/40640 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.
  • R 1 represents CF 3 or C 1-6 alkyl
  • R 2 represents halogen, C 1-6 alkyl or C 1-6 alkoxy
  • R 3 represents C 1-6 alkyl 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.
  • alkyl and alkoxy include both straight and branched chain saturated hydrocarbon groups.
  • alkyl groups include methyl, ethyl, n- propyl, isopropyl and isobutyl groups, whilst 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. propen-2-yl.
  • reference to a halogen group includes fluoro, chloro, bromo and iodo groups.
  • R 1 is preferably isopropyl, tert-butyl or trifluoromethyl.
  • R 2 is suitably chioro, methyl or methoxy.
  • R is preferably methyl or methoxy.
  • R 3 is suitably n-propyl, isopropyl, isobutyl or prop-2-enyl.
  • a preferred sub-group of the invention is represented by a compound of formula (I) where R 1 is isopropyl, tert-butyl or trifluoromethyl, R 2 is chloro, methyl or methoxy and R 3 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:
  • 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 LDL cholesterol and HDL cholesterol
  • 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.
  • 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 or solvate 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 or solvate thereof in particular in the treatment of conditions ameliorated by an apoB-100 and / or MTP inhibitor.
  • 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.
  • 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 or solvate 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 3 -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 (III) and (IV) may be made by methods well-known in the art, in particular following the teaching of WO00/32582.
  • 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)
  • 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.
  • compounds of formula (I) may be prepared by reaction of compounds of formula (III) and compounds of formula (VII)
  • 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)
  • R 3 ' represents R 3 minus a methylene group
  • R 3 ' represents R 3 minus a methylene group
  • standard reductive amination conditions e.g. using sodium triacetoxyborohydride in a solvent such as dichloroethane.
  • 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) is 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.
  • 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 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).
  • 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 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 IC 50 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 IC 50 values in nM. Table 1

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  • Health & Medical Sciences (AREA)
  • Organic Chemistry (AREA)
  • Chemical & Material Sciences (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • General Health & Medical Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Medicinal Chemistry (AREA)
  • Diabetes (AREA)
  • Hematology (AREA)
  • Cardiology (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Urology & Nephrology (AREA)
  • Obesity (AREA)
  • Child & Adolescent Psychology (AREA)
  • Vascular Medicine (AREA)
  • Emergency Medicine (AREA)
  • Endocrinology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention concerne des dérivés de benzamide actifs d'un point de vue thérapeutique se caractérisant par la formule (I) dans laquelle R1-R3 sont tels que définis dans la spécification, des procédés permettant leur préparation, leur utilisation en thérapie, notamment dans le cadre du traitement ou de la prévention d'états pathologiques améliorés par un inhibiteur de apoB-100 et/ou MTP, ainsi que des compositions pharmaceutiques destinées à être utilisées dans le cadre d'une thérapie de ce type.
EP02732605A 2001-04-12 2002-04-11 Derives de piperazine-benzamide pouvant etre utilises en tant qu'inhibiteurs de apob-100 et/ou mtp Withdrawn EP1383753A1 (fr)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
GBGB0109287.3A GB0109287D0 (en) 2001-04-12 2001-04-12 Therapeutic benzamide derivatives
GB0109287 2001-04-12
PCT/EP2002/004061 WO2002083658A1 (fr) 2001-04-12 2002-04-11 Derives de piperazine-benzamide pouvant etre utilises en tant qu'inhibiteurs de apob-100 et/ou mtp

Publications (1)

Publication Number Publication Date
EP1383753A1 true EP1383753A1 (fr) 2004-01-28

Family

ID=9912827

Family Applications (1)

Application Number Title Priority Date Filing Date
EP02732605A Withdrawn EP1383753A1 (fr) 2001-04-12 2002-04-11 Derives de piperazine-benzamide pouvant etre utilises en tant qu'inhibiteurs de apob-100 et/ou mtp

Country Status (4)

Country Link
EP (1) EP1383753A1 (fr)
JP (1) JP2004525964A (fr)
GB (1) GB0109287D0 (fr)
WO (1) WO2002083658A1 (fr)

Families Citing this family (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE60228447D1 (de) 2001-06-28 2008-10-02 Pfizer Prod Inc Triamidsubstituierte indole, benzofurane und benzothiophene als inhibitoren des mikrosomalen triglyceridtransferproteins (mtp) und/oder der sekretion von apolipoprotein b (apo b)
UA83510C2 (en) * 2003-12-09 2008-07-25 Янссен Фармацевтика Н.В. N-aryl piperidine substituted biphenylcarboxamides as inhibitors of apolipoprotein b
WO2008143127A1 (fr) * 2007-05-17 2008-11-27 Ajinomoto Co., Inc. Procédé de mesure de l'activité d'une enzyme modifiée par un lipide

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB9826412D0 (en) * 1998-12-03 1999-01-27 Glaxo Group Ltd Chemical compounds
GB0013346D0 (en) * 2000-06-01 2000-07-26 Glaxo Group Ltd Therapeutic benzamide derivatives

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO02083658A1 *

Also Published As

Publication number Publication date
GB0109287D0 (en) 2001-05-30
WO2002083658A1 (fr) 2002-10-24
JP2004525964A (ja) 2004-08-26

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