WO1998047877A1 - 2-benzoyl-1,2,3,4-tetrahydroisoquinoline-3-carboxamide derivatives and their use as inhibitors of hepatic production of apob-100 - Google Patents

2-benzoyl-1,2,3,4-tetrahydroisoquinoline-3-carboxamide derivatives and their use as inhibitors of hepatic production of apob-100 Download PDF

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Publication number
WO1998047877A1
WO1998047877A1 PCT/EP1998/002244 EP9802244W WO9847877A1 WO 1998047877 A1 WO1998047877 A1 WO 1998047877A1 EP 9802244 W EP9802244 W EP 9802244W WO 9847877 A1 WO9847877 A1 WO 9847877A1
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Prior art keywords
naphthalen
tetrahydro
tetrahydroisoquinoline
benzoyl
carboxamide
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PCT/EP1998/002244
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French (fr)
Inventor
Alain Claude-Marie Daugan
Pascal Maurice Charles Pianetti
Original Assignee
Glaxo Group Limited
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Publication date
Application filed by Glaxo Group Limited filed Critical Glaxo Group Limited
Priority to AU75265/98A priority Critical patent/AU7526598A/en
Publication of WO1998047877A1 publication Critical patent/WO1998047877A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/06—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
    • C07D217/22—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems 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 carbon atoms of the nitrogen-containing ring
    • C07D217/26—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
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • This invention relates to novel compounds which inhibit hepatic production of apoprotein B-100 (apoB-100), and to processes for their preparation, pharmaceutical compositions containing them and their medical use. More particularly, the invention relates to novel 1 ,2,3,4-tetrahydroisoquinolines and their use in therapy. Certain tetrahydroisoquinolines with a therapeutic utility have been described in WO9800403.
  • 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-100 plasmatic levels correlate with LDL-C plasmatic levels and also constitute a cardiovascular risk factor in themselves. ApoB-100 is exclusively produced by hepatocytes and reducing hepatic production of ApoB-100 should induce a decrease of LDL-C plasmatic levels. Compounds which act as inhibitors of ApoB-100 have been described in PCT.EP97.05636.
  • the present invention provides a compound of formula (I)
  • R° represents hydrogen, halogen, C ⁇ alkyl, C ⁇ alkoxy or a methylenedioxy group, and n represents an integer from 1-4;
  • R 1 represents hydrogen, halogen, C ⁇ alkyl, C 1-4 alkoxy, trifluoromethoxy or a methylenedioxy group, and p represents an integer from 1-4;
  • R 2 represents one or more groups selected from hydrogen, halogen, C 1-4 alkyl, C ⁇ alkoxy, a methylenedioxy group,NR 4 R 5 , -(C 1 . 4 alkylene)-NR 6 R 7 , -NR 4 - or -O- (C ⁇ alkylene)-NR 8 R 9 , 4-morpholino,
  • R 3 represents hydrogen or C M alkyl
  • R 4 -R 10 independently represent hydrogen or C 1-4 alkyl; or a pharmaceutically acceptable salt or solvate thereof.
  • Suitable pharmaceutically acceptable salts of the compounds of general formula (I) include acid addition salts formed with pharmaceutically acceptable inorganic acids for example, hydrochlorides, hydrobromides, or sulphates.
  • the solvates may, for example, be hydrates.
  • references hereinafter to a compound according to the invention include both compounds of formula (I) and their pharmaceutically acceptable salts together with pharmaceutically acceptable solvates.
  • the compounds of formula (I) contain at least two chiral centres (shown as * and ** in formula (I)).
  • the compounds of formula (I) are preferably in their (R) form at centre * .
  • the compounds of formula (I) are preferably in the form which is obtained from use of a (+)-1,2,3,4-tetrahydro-1-naphthalenamine intermediate.
  • alkyl and alkylene includes both straight and branched chain saturated hydrocarbon groups.
  • alkyl groups include methyl, ethyl, isopropyl and tert-butyl groups
  • alkylene groups include methylene, ethylene, isopropylene and tert-butylene groups.
  • a halogen atom may be a fluorine, chlorine, bromine or iodine atom.
  • a methylenedioxy group indicates a -0-CH 2 -0-
  • R° is suitably a hydrogen, methoxy or methylenedioxy group and n is suitably 1.
  • R° is suitably substituted in either the 6- or 7- position of the bicyciic ring, or where R° is methylenedioxy, in the 6- and 7- positions of the ring.
  • R° is preferably hydrogen.
  • R 1 is suitably hydrogen, C 1-4 alkyl, e.g methyl or isopropyl, halogen, e.g fluorine or chlorine, methoxy or trifluoromethoxy, and p is suitably 1 , 2 or 3.
  • R 1 is substituted on any one, two or three of the 3-, 4-, 5-, 6- , 7- and 8- positions of the bicyciic ring, including gem substitution where appropriate.
  • R 1 is preferably methyl, methoxy or isopropyl substituted in the 7- position of the bicyciic ring.
  • R 1 is most preferably isopropyl substituted in the 7- position of the bicyciic ring.
  • R 2 is suitably hydrogen, C 1-4 alkyl, e.g methyl, halogen, e.g. chlorine, methoxy, methylenedioxy, NMe 2 , -0-(C 1-4 alkylene)-NR 6 R 7 , e.g. 2-dimethylamino-ethoxy, 2-dimethylamino-propoxy, 2-dimethylamino-1 -methyl-ethoxy, 2-dimethylamino-2- methyl-propoxy or 2-dimethylamino-1 ,1-dimethyl-ethoxy, 4-morpholino
  • m is suitably 1 , 2 or 3.
  • R 2 is mono-, di- or tri- substituted on the 2-, 3- or 4- positions of the phenyl ring, or where R 2 is methylendioxy, on the 3- and 4- positions of the phenyl ring.
  • R 2 is mono-substituted on the 3- position of the phenyl ring.
  • R 2 is methyl, dimethylamino or 4-morpholino.
  • R 2 is 2-dimethylamino-ethoxy substituted in the 3-position of the phenyl ring.
  • R 3 is suitably hydrogen.
  • Suitable compounds according to the invention include:
  • Preferred compounds of the invention include:
  • Particularly preferred compounds of the invention include 2-[3-(2-dimethylamino- ethoxy)-benzoyl]-N-(7-isopropyl-1,2,3,4-tetrahydro-naphthalen-1-yl)-1 ,2,3,4- tetrahydroisoquinoline-3-carboxamide; or a pharmaceutically acceptable salt or solvate thereof.
  • the compounds of the invention are inhibitors of hepatic production of apoB-100 and are thus of use in the treatment of conditions resulting from elevated circulating levels of apoB-100.
  • the ability of the compounds of the invention to inhibit the production of apoB- 100 by human hepatocytes in vitro is determined using a human hepatocarcinoma cell line, Hep G 2 , as a model system.
  • the specificity of the compounds of the invention is established by comparing the effects on apoB- 100, apoprotein A-1 , and fibrinogen production. A specificity of at least 100 is preferred.
  • the in vivo profile of the compounds was determined by acute oral administration of the compounds of the invention to DBA/2 mice and Wistar rats with measurement of apoB-100 plasmatic levels as percentage of control values. Active compounds are further evaluated in Wistar rats by repeated oral administration (once a day) with measurement of total cholesterol, low density lipoprotein-cholesterol, triglycerides, apoB-100 and apoA-l plasmatic levels as a percentage of control values.
  • the compounds of the invention are potent and specific inhibitors of hepatic production of apoB-100, which furthermore exhibit good oral bioavailability and duration of action.
  • Compounds of the invention are of use in the treatment of atherosclerosis, pancreatitis, non-insulin dependent diabetes mellitus (NIDDM), and coronary heart diseases.
  • 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, hyperlipoproteinemia, hypercholesterolemia and/or hypertriglyceridemia.
  • the invention therefore provides a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof for use in therapy, in particular in human medicine.
  • a method for the treatment of a mammal including man, in particular in the treatment of conditions resulting from elevated circulating levels of apoB-100, comprising administration of an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.
  • the invention also provides a pharmaceutical composition which comprises at least one compound of formula (I) or a pharmaceutically acceptable salt 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 pharmaceutical compositions may take the form of, for example, tablets or capsules prepared by conventional means with pharmaceutically acceptable excipients such as binding agents (e.g. pregelatinised maize starch, polyvinylpyrrolidone or hydroxypropyl methylcellulose); fillers (e.g. lactose, microcrystalline cellulose or calcium hydrogen phosphate); lubricants (e.g. magnesium stearate, talc or silica); disintegrants (e.g. potato starch or sodium starch glycollate); or wetting agents (e.g. sodium lauryl sulphate).
  • binding agents e.g. pregelatinised maize starch, polyvinylpyrrolidone or hydroxypropyl methylcellulose
  • fillers e.g. lactose, microcrystalline cellulose or calcium hydrogen phosphate
  • lubricants e.g. magnesium stearate, talc or silica
  • disintegrants e.g. potato starch or sodium starch glycollate
  • Liquid preparations for oral administration may take the form of, for example, solutions, syrups or suspensions, or they may be presented as a dry product for constitution with water or other suitable vehicle before use.
  • Such liquid preparations may be prepared by conventional means with pharmaceutically acceptable additives such as suspending agents (e.g. sorbitol syrup, cellulose derivatives or hydrogenated edible fats); emulsifying agents (e.g. lecithin or acacia); non-aqueous vehicles (e.g. almond oil, oily esters, ethyl alcohol or fractionated vegetable oils); and preservatives (e.g. methyl or propyl- p-hydroxybenzoates or sorbic acid).
  • the preparations may also contain buffer salts, flavouring, colouring and sweetening agents as appropriate.
  • Preparations for oral administration may be suitably formulated to give controlled release of the active compound.
  • composition may take the form of tablets or lozenges formulated in conventional manner.
  • the compounds according to the invention may be formulated as creams, gels, ointments or lotions or as a transdermal patch.
  • Such compositions may for example be formulated with an aqueous or oily base with the addition of suitable thickening, gelling, emulsifying, stabilising, dispersing, suspending, and/or colouring agents.
  • the compounds of the invention may be formulated for parenteral administration by bolus injection or continuous infusion.
  • Formulations for injection may be presented in unit dosage form e.g. in ampoules or in multi-dose containers, with an added preservative.
  • the compositions may take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles, and may contain formulatory agents such as suspending, stabilising and/or dispersing agents.
  • the active ingredient may be in powder form for constitution with a suitable vehicle, e.g. sterile pyrogen-free water, before use.
  • the compounds of the invention may be formulated for topical administration in the form of ointments, creams, gels, lotions, pessaries, aerosols or drops (e.g. eye, ear or nose drops).
  • Ointments and creams may, for example, be formulated with an aqueous or oily base with the addition of suitable thickening and/or gelling agents.
  • Ointments for administration to the eye may be manufactured in a sterile manner using sterilised components.
  • Lotions may be formulated with an aqueous or oily base and will in general also contain one or more emulsifying agents, stabilising agents, dispersing agents, suspending agents, thickening agents, or colouring agents. Drops may be formulated with an aqueous or non aqueous base also comprising one or more dispersing agents, stabilising agents, solubilising agents or suspending agents. They may also contain a preservative.
  • the compounds of the invention may also be formulated in rectal compositions such as suppositories or retention enemas, e.g. containing conventional suppository bases such as cocoa butter or other glycerides.
  • the compounds of the invention may also be formulated as depot preparations. Such long acting formulations may be administered by implantation (for example subcutaneously or intramuscularly) or by intramuscular injection.
  • the compounds of the invention may be formulated with suitable polymeric or hydrophobic materials (for example as an emulsion in an acceptable oil) or ion exchange resins, or as sparingly soluble derivatives, for example, as a sparingly soluble salt.
  • the compounds of the invention may be formulated as solutions for administration via a suitable metered or unit dose device or alternatively as a powder mix with a suitable carrier for administration using a suitable delivery device.
  • compositions may contain from 0.1% upwards, e.g. 0.1 - 99% of the active material, depending on the method of administration.
  • a proposed dose of the compounds of the invention is 0.25mg/kg to about 125mg/kg bodyweight per day e.g. 20mg/kg to 100mg/kg per day. It will be appreciated that it may be necessary to make routine variations to the dosage, depending on the age and condition of the patient and the precise dosage will be ultimately at the discretion of the attendant physician or veterinarian. The dosage will also depend on the route of administration and the particular compound selected.
  • 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 withp an HMG CoA reductase inhibitor or an agent for inhibition of bile acid transport.
  • a compound of formula (I) may be prepared by reacting a compound of formula (II) with a compound of formula (III)
  • X represents a suitable halide leaving group, e.g. chloride, or X represents a hydroxy group.
  • the reaction is conveniently carried out under standard coupling conditions for acid or acid halide couplings with amines.
  • a compound of formula (II) may be prepared by reaction of a compound of formula (IV) with a compound of formula (V)
  • Y is a suitable amine protecting group, e.g. tert-butoxycarbonyl (Boc), under standard coupling conditions for an acid/amine coupling, followed by deprotection of the protecting group under suitable conditions.
  • a suitable amine protecting group e.g. tert-butoxycarbonyl (Boc)
  • compounds of formula (I) may be prepared by reaction of compounds of formula (VI) and compounds of formula (V)
  • compositions may also be prepared from other salts, including other pharmaceutically 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.
  • 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.
  • (+)-7-lsopropyl-1 ,2,3,4-tetrahydro-naphthalen-1 -ylamine hydrochloride A mixture of (7-isopropyl-1 ,2,3,4-tetrahydro-naphthalen-1-yl)-(1-phenyl-ethyl)- amine ( 20.2 g ; 69 mmol), ammonium formate (13 g ; 206 mmol) and 10% Pd/C (1 g) in methanol (300 mL) was refluxed for 3 hours. The reaction mixture was cooled at room temperature, the catalyst was filtered off and the filtrate was evaporated under reduced pressure.
  • the mixture was cooled to 0°C and treated with 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.25 g) followed by stirring for 3 hours at room temperature.
  • the reaction mixture was washed successively with water, 1 N HCI, an aqueous solution of NaHC03 and brine, and then was dried over sodium sulfate, filtered and evaporated.
  • HepG2 cells were seeded at 30 000 cells/well in 96 well plates. After 4 days, confluent cells were incubated with compounds for 24 hours in RPMI medium containing 1% FCS and 50 ⁇ Ci/ml 35S-methionine. Compounds were dissolved in DMSO and tested onto cells from 5 ⁇ M to 0.32 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 calculted taking untreated cells as controsl, and IC50 of each compound was determined on both apoproteins.
  • compositions A and B can be prepared by wet granulation of ingredients (a) to (c) and (a) to (d) with a solution of povidone, followed by addition of the magnesium stearate and compression.
  • Composition A mg/tablet mg/tablet
  • Composition B mg/tablet mg/tablet
  • composition C mg/tablet
  • compositions D and E can be prepared by direct compression of the admixed ingredients.
  • the lactose used in composition E is of the direct compression type.
  • composition D mg/tablet Active ingredient 250
  • composition E mg/tablet
  • Composition F Controlled release composition mg/tablet
  • composition can be prepared by wet granulation of ingredients (a) to (c) with a solution of povidone, followed by addition of the magnesium stearate and compression.
  • Composition G Enteric-coated tablet
  • Enteric-coated tablets of Composition C can be prepared by coating the tablets with 25mg/tablet of an enteric polymer such as cellulose acetate phthalate, polyvinylacetate phthalate, hydroxypropylmethyl- cellulose phthalate, or anionic polymers of methacrylic acid and methacrylic acid methyl ester (Eudragit L). Except for Eudragit L, these polymers should also include 10% (by weight of the quantity of polymer used) of a plasticizer to prevent membrane cracking during application or on storage. Suitable plasticizers include diethyl phthalate, tributyl citrate and triacetin.
  • enteric polymer such as cellulose acetate phthalate, polyvinylacetate phthalate, hydroxypropylmethyl- cellulose phthalate, or anionic polymers of methacrylic acid and methacrylic acid methyl ester (Eudragit L). Except for Eudragit L, these polymers should also include 10% (by weight of the quantity of polymer used) of a
  • Composition H Enteric-coated controlled release tablet
  • Enteric-coated tablets of Composition F can be prepared by coating the tablets with 50mg/tablet of an enteric polymer such as cellulose acetate phthalate, polyvinylacetate phthalate, hydroxypropylmethyl- cellulose phthalate, or anionic polymers of methacrylic acid and methacrylic acid methyl ester (Eudragit L).
  • an enteric polymer such as cellulose acetate phthalate, polyvinylacetate phthalate, hydroxypropylmethyl- cellulose phthalate, or anionic polymers of methacrylic acid and methacrylic acid methyl ester (Eudragit L).
  • these polymers should also include 10% (by weight of the quantity of polymer used) of a plasticizer to prevent membrane cracking during application or on storage.
  • Suitable plasticizers include diethyl phthalate, tributyl citrate and triacetin.
  • composition A Capsules can be prepared by admixing the ingredients of Composition D above and filling two-part hard gelatin capsules with the resulting mixture.
  • Composition B infra may be prepared in a similar manner.
  • composition B mg/capsule
  • composition C mg/capsule
  • Capsules can be prepared by melting the Macrogol 4000 BP, dispersing the active ingredient in the melt and filling two-part hard gelatin capsules therewith.
  • Composition D mg/capsule Active ingredient 250 Lecithin 100
  • Capsules can be prepared by dispersing the active ingredient in the lecithin and arachis oil and filling soft, elastic gelatin capsules with the dispersion.
  • Composition E Controlled release capsule
  • Active ingredient 250 (b) Microcrystalline Cellulose 125
  • the controlled release capsule composition can be prepared by extruding mixed ingredients (a) to (c) using an extruder, then spheronising and drying the extrudate. The dried pellets are coated with a release controlling membrane (d) and filled into two-part, hard gelatin capsules.
  • Composition F Enteric capsule mg/capsule
  • the enteric capsule composition can be prepared by extruding mixed ingredients (a) to (c) using an extruder, then spheronising and drying the extrudate. The dried pellets are coated with an enteric membrane (d) containing a plasticizer (e) and filled into two-part, hard gelatin capsules.
  • Composition G Enteric-coated controlled release capsule
  • Enteric capsules of Composition E can be prepared by coating the controlled-release pellets with 50mg/capsule of an enteric polymer such as cellulose acetate phthalate, polyvinylacetate phthalate, hydroxypropylmethylcellulose phthalate, or anionic polymers of methacrylic acid and methacrylic acid methyl ester (Eudragit L). Except for Eudragit L, these polymers should also include 10% (by weight of the quantity of polymer used) of a plasticizer to prevent membrane cracking during application or on storage. Suitable plasticizers include diethyl phthalate, tributyl citrate and triacetin.
  • enteric polymer such as cellulose acetate phthalate, polyvinylacetate phthalate, hydroxypropylmethylcellulose phthalate, or anionic polymers of methacrylic acid and methacrylic acid methyl ester (Eudragit L). Except for Eudragit L, these polymers should also include 10% (by weight of the quantity of polymer used) of a plasticizer
  • the active ingredient is dissolved in most of the phosphate buffer at 35-40°C, then made up to volume and filtered through a sterile micropore filter into sterile 10 ml glass vials (Type 1) which are sealed with sterile closures and overseals.
  • the sodium benzoate is dissolved in a portion of the purified water and the sorbitol solution added.
  • the active ingredient is added and dissolved.
  • the resulting solution is mixed with the glycerol and then made up to the required volume with the purified water.
  • Witepsol H15 is melted in a steam-jacketed pan at 45°C maximum.
  • the active ingredient is sifted through a 200lm sieve and added to the molten base with mixing, using a Silverson fitted with a cutting head, until a smooth dispersion is achieved. Maintaining the mixture at 45°C, the remaining Witepsol H15 is added to the suspension which is stirred to ensure a homogenous mix.
  • the entire suspension is then passed through a 250lm stainless steel screen and, with continuous stirring, allowed to cool to 40°C. At a temperature of 38-40°C, 2.02g aliquots of the mixture are filled into suitable plastic moulds and the suppositories allowed to cool to room temperature,
  • Active ingredient 200mg Alcohol USP 0.1ml Hydroxyethyl cellulose
  • the active ingredient and alcohol USP are gelled with hydroxyethyl cellulose ⁇ and packed in a transdermal device with a surface area of 10 cm .

Abstract

The present invention relates to a compound of formula (I), wherein R0 représents hydrogen, halogen, C¿1-4?alkyl, C1-4alkoxy or a methylenedioxy group, and n represents an integer from 1-4; R?1¿ represents hydrogen, halogen, C¿1-4?alkyl, C1-4alkoxy, trifluoromethoxy or a methylenedioxy group, and p represents an integer from 1-4; R?2¿ represents one or more groups selected from hydrogen, halogen, C¿1-4? alkyl, C1-4 alkoxy, a methylenedioxy group, NR?4R5¿, -(C¿1-4?alkylene)-NR?6R7, -NR4¿- or -O-(C¿1-4? alkylene)-NR?8R9¿, 4-morpholino, or formula (II), and m represents an integer from 1-4; R3 represents hydrogen or C¿1-4? alkyl; R?4-R¿10 independently represent hydrogen or C1-4 alkyl; or a pharmaceutically acceptable salt or solvate thereof, to processes for their preparation; and their use in the treatment of conditions mediated by ApoB-100 regulation.

Description

2-BENZOYL-l ,2,3,4-TETRAHYDROISOQUINOLINE-3-CARBOXAMIDE DERIVATIVES AND THEIR USE AS INHIBITORS OF HEPATIC PRODUCTION OF APOB-100
This invention relates to novel compounds which inhibit hepatic production of apoprotein B-100 (apoB-100), and to processes for their preparation, pharmaceutical compositions containing them and their medical use. More particularly, the invention relates to novel 1 ,2,3,4-tetrahydroisoquinolines and their use in therapy. Certain tetrahydroisoquinolines with a therapeutic utility have been described in WO9800403.
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-100 plasmatic levels correlate with LDL-C plasmatic levels and also constitute a cardiovascular risk factor in themselves. ApoB-100 is exclusively produced by hepatocytes and reducing hepatic production of ApoB-100 should induce a decrease of LDL-C plasmatic levels. Compounds which act as inhibitors of ApoB-100 have been described in PCT.EP97.05636.
The present invention provides a compound of formula (I)
Figure imgf000003_0001
wherein
R° represents hydrogen, halogen, C^alkyl, C^alkoxy or a methylenedioxy group, and n represents an integer from 1-4;
R1 represents hydrogen, halogen, C^alkyl, C1-4alkoxy, trifluoromethoxy or a methylenedioxy group, and p represents an integer from 1-4; R2 represents one or more groups selected from hydrogen, halogen, C1-4 alkyl, C^ alkoxy, a methylenedioxy group,NR4R5, -(C1.4alkylene)-NR6R7, -NR4- or -O- (C^ alkylene)-NR8R9, 4-morpholino,
Figure imgf000004_0001
, and m represents an integer from 1-4; R3 represents hydrogen or CM alkyl;
R4-R10 independently represent hydrogen or C1-4 alkyl; or a pharmaceutically acceptable salt or solvate thereof.
Suitable pharmaceutically acceptable salts of the compounds of general formula (I) include acid addition salts formed with pharmaceutically acceptable inorganic acids for example, hydrochlorides, hydrobromides, or sulphates.
The solvates may, for example, be hydrates.
References hereinafter to a compound according to the invention include both compounds of formula (I) and their pharmaceutically acceptable salts together with pharmaceutically acceptable solvates.
It will be appreciated by those skilled in the art that the compounds of formula (I) contain at least two chiral centres (shown as * and ** in formula (I)). The compounds of formula (I) are preferably in their (R) form at centre * . At centre **, the compounds of formula (I) are preferably in the form which is obtained from use of a (+)-1,2,3,4-tetrahydro-1-naphthalenamine intermediate.
Referring to the general formula (I), alkyl and alkylene includes both straight and branched chain saturated hydrocarbon groups. Examples of alkyl groups include methyl, ethyl, isopropyl and tert-butyl groups, and examples of alkylene groups include methylene, ethylene, isopropylene and tert-butylene groups.
Referring to general formula (I), a halogen atom may be a fluorine, chlorine, bromine or iodine atom.
Referring to general formula (I), a methylenedioxy group indicates a -0-CH2-0-
SUBSTΓΓUTE SHEET (RULE 26) group attached to adjacent carbons on an aromatic ring.
R° is suitably a hydrogen, methoxy or methylenedioxy group and n is suitably 1.
R° is suitably substituted in either the 6- or 7- position of the bicyciic ring, or where R° is methylenedioxy, in the 6- and 7- positions of the ring. R° is preferably hydrogen.
R1 is suitably hydrogen, C1-4 alkyl, e.g methyl or isopropyl, halogen, e.g fluorine or chlorine, methoxy or trifluoromethoxy, and p is suitably 1 , 2 or 3. Suitably, R1 is substituted on any one, two or three of the 3-, 4-, 5-, 6- , 7- and 8- positions of the bicyciic ring, including gem substitution where appropriate. R1 is preferably methyl, methoxy or isopropyl substituted in the 7- position of the bicyciic ring. R1 is most preferably isopropyl substituted in the 7- position of the bicyciic ring.
R2 is suitably hydrogen, C1-4 alkyl, e.g methyl, halogen, e.g. chlorine, methoxy, methylenedioxy, NMe2, -0-(C1-4alkylene)-NR6R7, e.g. 2-dimethylamino-ethoxy, 2-dimethylamino-propoxy, 2-dimethylamino-1 -methyl-ethoxy, 2-dimethylamino-2- methyl-propoxy or 2-dimethylamino-1 ,1-dimethyl-ethoxy, 4-morpholino
/ \ or — N N N N— Me
\ \ / — / , and m is suitably 1 , 2 or 3.
Suitably, R2 is mono-, di- or tri- substituted on the 2-, 3- or 4- positions of the phenyl ring, or where R2 is methylendioxy, on the 3- and 4- positions of the phenyl ring. Preferably, R2 is mono-substituted on the 3- position of the phenyl ring.
Preferably, R2 is methyl, dimethylamino or 4-morpholino.
Most preferably, R2 is 2-dimethylamino-ethoxy substituted in the 3-position of the phenyl ring.
R3 is suitably hydrogen. Suitable compounds according to the invention include:
2-(4-Methyl benzoyl)-N-(7-methyl-1 ,2,3,4-tetrahydro-naphthalen-1-yl)-1 ,2,3,4- tetrahydroisoquinoline-3-carboxamide;
2-(3-Dimethylamino-4-methyl benzoyl)-N-(7-methyl-1,2,3,4-tetrahydro- naphthalen-1 -yl)-1 ,2,3,4-tetrahydroisoquinoline-3-carboxamide;
2-(3-Dimethylamino benzoyl)-N-(7-methyl-1 ,2,3,4-tetrahydro-naphthalen-l -yl)-
1 ,2,3,4-tetrahydroisoquinoline-3-carboxamide;
2-(3-(Morpholin-4-yl)benzoyl)-N-(7-methyl-1,2,3,4-tetrahydro-naphthalen-1-yl)-
1,2,3,4-tetrahydroisoquinoline-3-carboxamide; 2-(3-(Morpholin-4-yl)benzoyl)- N-(7-methoxy-1 ,2,3,4-tetrahydro-naphthalen-1-yl)-
1 ,2,3,4-tetrahydroisoquinoline-3-carboxamide;
2-(3-Dimethylamino benzoyl)-N-(7-methoxy-1,2,3,4-tetrahydro-naphthalen-1- yl)-1,2,3,4-tetrahydroisoquinoline-3-carboxamide;
2-[3-(2-Dimethylamino-ethoxy)-benzoyl]-N-(7-isopropyl-1 ,2,3,4-tetrahydro- naphthalen-1 -yl)-1 ,2,3,4-tetrahydroisoquinoline-3-carboxamide;
2-[3-(2-Dimethylamino-ethoxy)-benzoyl]-N-(7-methyl-1 ,2,3,4-tetrahydro- naphthalen-1-yl)-1,2,3,4-tetrahydroisoquinoline-3-carboxamide;
2-[3-(2-Dimethylamino-ethoxy)-benzoyl]-N-(5,7-dimethyl-1 ,2,3,4-tetrahydro- naphthalen-1-yl)-1 ,2,3,4-tetrahydroisoquinoline-3-carboxamide; 2-(4-Methyl-benzoyl)-N-(7-isopropyl-1 ,2,3,4-tetrahydro-naphthalen-1 -yl)-
1,2,3,4-tetrahydroisoquinoline-3-carboxamide;
2-(3,4-Methylenedioxy-benzoyl)-N-(7-methyl-1 ,2,3,4-tetrahydro-naphthalen -
1 -yl)-1 ,2,3,4-tetrahydroisoquinoline-3-carboxamide;
2-(3-Morpholin-4-yl-benzoyl)-N-(7-isopropyl-1 ,2,3,4-tetrahydro-naphthalen-1- yl)-1 ,2,3,4-tetrahydroisoquinoline-3-carboxamide;
2-[3-(2-Diethylamino-ethoxy)-benzoyl]-N-(7-isopropyl-1 ,2,3,4-tetrahydro- naphthalen-1-yl)-1 ,2,3,4-tetrahydroisoquinoline-3-carboxamide;
2-(3-Morpholin-4-yl-benzoyl)-N-(7-tert-butyl-1 ,2,3,4-tetrahydro-naphthalen-1- yl)-1,2,3,4-tetrahydroisoquinoline-3-carboxamide; 2-[3-(2-Dimethylamino-ethoxy)-benzoyl]-N-(7-tert-butyl-1 ,2,3,4-tetrahydro- naphthalen-1-yl)-1,2,3,4-tetrahydroisoquinoline-3-carboxamide;
2-[3-(3-Dimethylamino-propoxy)-benzoyl]-N-(7-isopropyl-1 ,2,3,4-tetrahydro- naphthalen-1-yl)-1 ,2,3,4-tetrahydroisoquinoline-3-carboxamide;
2-[3-(2-Diisopropylamino-ethoxy)-benzoyl]-N-(7-isopropyl-1,2,3,4-tetrahydro-
SUBST1TUTE SHEET (RULE 26) naphthalen-1-yl)-1 ,2,3,4-tetrahydroisoquinoline-3-carboxamide;
2-(4-Methyl-benzoyl)-N-(6,7-methylenedioxy-1 ,2,3,4-tetrahydro-naphthalen-
1-yl)-1,2,3,4-tetrahydroisoquinoline-3-carboxamide;
2-(3-Moφholin-4-yl-benzoyl)-N-(6,7-methylenedioxy-1 ,2,3,4-tetrahydro- naphthalen-1-yl)-1,2,3,4-tetrahydroisoquinoline-3-carboxamide;
2-(4-Methyl-benzoyl)-N-(5,7-dimethyl-1 ,2,3,4-tetrahydro-naphthalen -1 -yl)-
1,2,3,4-tetrahydroisoquinoline-3-carboxamide;
2-(4-Methyl-benzoyl)-N-(6-fluoro-7-methoxy-1 ,2,3,4-tetrahydro-naphthalen -
1-yl)-1,2,3,4-tetrahydroisoquinoline-3-carboxamide; 2-(3-Methoxy-benzoyl)-N-(7-methyl-1 ,2,3,4-tetrahydro-naphthalen -1 -yl)-
1 ,2,3,4-tetrahydroisoquinoline-3-carboxamide;
2-[3-(4-Methyl-piperazin-1-yl)-benzoyl]-N-(7-methoxy-1 ,2,3,4-tetrahydro- naphthalen-1-yl)-1,2,3,4-tetrahydroisoquinoline-3-carboxamide;
2-(3-Dimethylamino-4-methoxy-benzoyl)-N-(7-methyl-1 ,2,3,4-tetrahydro- naphthalen -1-yl)-1 ,2,3,4-tetrahydroisoquinoline-3-carboxamide;
2-(4-Chloro-benzoyl)-N-(7-methyl-1,2,3,4-tetrahydro-naphthalen -1-yl)-
1,2,3,4-tetrahydroisoquinoline-3-carboxamide;
2-(3-Morpholin-4-yl-benzoyl)-N-(1 ,2,3,4-tetrahydro-naphthalen -1-yl)-1 ,2,3,4- tetrahydroisoquinoline-3-carboxamide; 2-(2-Dimethylamino-benzoyl)-N-(1 ,2,3,4-tetrahydro-naphthalen -1-yl)-
1 ,2,3,4-tetrahydroisoquinoline-3-carboxamide;
2-(3-Morpholin-4-yl-benzoyl)-N-(4,4,7-trimethyl-1,2,3,4-tetrahydro- naphthalen-1-yl)-1 ,2,3,4-tetrahydroisoquinoline-3-carboxamide;
2-(3-Morpholin-4-yl-benzoyl)-N-(4,4)6-trimethyl-1 ,2,3,4-tetrahydro- naphthalen-1-yl)-1,2,3,4-tetrahydroisoquinoline-3-carboxamide;
2-(3-Morpholin-4-yl-benzoyl)-N-(7-methoxy-4,4-dimethyl-1 ,2,3,4-tetrahydro- naphthalen-1-yl)-1 ,2,3,4-tetrahydroisoquinoline-3-carboxamide;
2-(3-Morpholin-4-yl-benzoyl)-N-(3,3-dimethyl-1,2,3,4-tetrahydro-naphthalen-
1-yl)-1,2,3,4-tetrahydroisoquinoline-3-carboxamide isomer 1 ; 2-(3-Dimethylamino-benzoyl)-N-(7-methoxy-4,4-dimethyl-1 ,2,3,4-tetrahydro- naphthalen-1-yl)-1,2,3,4-tetrahydroisoquinoline-3-carboxamide;
2-(3-Morpholin-4-yl-benzoyl)-N-(5,7-dimethyl-1 ,2,3,4-tetrahydro-naphthalen-
1-yl)-1,2,3,4-tetrahydroisoquinoline-3-carboxamide;
2-(3-Moφholin-4-yl-benzoyl)-N-(7-trifluoromethoxy-1 ,2,3,4-tetrahydro-
SUBSTΓΓUTE SHEET (RULE 26) naphthalen-1-yl)-1 ,2,3,4-tetrahydroisoquinoline-3-carboxamide; 2-(3-Moφholin-4-yl-benzoyl)-N-(7-fluoro-1,2,3,4-tetrahydro-naphthalen-1-yl)- I^.S^-tetrahydroisoquinoiine-S-carboxamide;
2-[3-(2-dimethylamino-2-methyl-propoxy)-benzoyl]-N-(7-isopropyl-1 ,2,3,4- tetrahydro-naphthalen-1-yl)-1 ,2,3,4-tetrahydroisoquinoline-3-carboxamide; 2-[3-(2-dimethylamino-1,1-dimethyl-ethoxy)-benzoyl]-N-(7-isopropyl-1 , 2,3,4- tetrahydro-naphthalen-1-yl)-1 ,2,3,4-tetrahydroisoquinoline-3-carboxamide; or a pharmaceutically acceptable salt or solvate thereof.
Preferred compounds of the invention include:
2-[3-(2-dimethylamino-ethoxy)-benzoyl]-N-(7-isopropyl-1 ,2,3,4-tetrahydro- naphthalen-1-yl)-1 ,2,3,4-tetrahydroisoquinoline-3-carboxamide;
2-[3-(2-Dimethylamino-ethoxy)-benzoyl]-N-(7-methyl-1,2,3,4-tetrahydro- naphthalen-1-yl)-1 ,2,3,4-tetrahydroisoquinoline-3-carboxamide; 2-[3-(2-Dimethylamino-ethoxy)-benzoyl]-N-(5,7-dimethyl-1 ,2,3,4-tetrahydro- naphthalen-1-yl)-1,2,3,4-tetrahydroisoquinoline-3-carboxamide;
2-(4-Methyl-benzoyl)-N-(7-isopropyl-1 ,2,3,4-tetrahydro-naphthalen-1-yl)-
1,2,3,4-tetrahydroisoquinoline-3-carboxamide;
2-(3,4-Methylenedioxy-benzoyl)-N-(7-methyl-1,2,3,4-tetrahydro-naphthalen - 1-yl)-1 ,2,3,4-tetrahydroisoquinoline-3-carboxamide;
2-(3-Morpholin-4-yl-benzoyl)-N-(7-isopropyl-1 ,2,3,4-tetrahydro-naphthalen-1- yl)-1 ,2,3,4-tetrahydroisoquinoiine-3-carboxamide;
2-[3-(2-Diethylamino-ethoxy)-benzoyl]-N-(7-isopropyl-1 ,2,3,4-tetrahydro- naphthalen-1-yl)-1,2,3,4-tetrahydroisoquinoline-3-carboxamide; 2-(3-Moφholin-4-yl-benzoyl)-N-(7-tert-butyl-1 ,2,3,4-tetrahydro-naphthalen-1- yl)-1 ,2,3.4-tetrahydroisoquinoline-3-carboxamide;
2-[3-(2-Dimethylamino-ethoxy)-benzoyl]-N-(7-tert-butyl-1 ,2,3,4-tetrahydro- naphthalen-1-yl)-1,2,3,4-tetrahydroisoquinoline-3-carboxamide;
2-[3-(3-Dimethylamino-propoxy)-benzoyl]-N-(7-isopropyl-1,2,3,4-tetrahydro- naphthalen-1 -yl)-1 ,2,3,4-tetrahydroisoquinoline-3-carboxamide;
2-[3-(2-Diisopropylamino-ethoxy)-benzoyl]-N-(7-isopropyl-1,2,3,4-tetrahydro- naphthalen-1-yl)-1,2,3,4-tetrahydroisoquinoline-3-carboxamide;
2-[3-(2-dimethylamino-propoxy)-benzoyl]-N-(7-isopropyl-1 ,2,3,4-tetrahydro- naphthalen-1-yl)-1,2,3,4-tetrahydroisoquinoline-3-carboxamide; 2-[3-(2-dimethylamino-1-methyl-ethoxy)-benzoyl]-N-(7-isopropyl-1, 2,3,4- tetrahydro-naphthalen-1-yl)-1,2,3,4-tetrahydroisoquinoline-3-carboxamide; or a pharmaceutically acceptable salt or solvate thereof.
Particularly preferred compounds of the invention include 2-[3-(2-dimethylamino- ethoxy)-benzoyl]-N-(7-isopropyl-1,2,3,4-tetrahydro-naphthalen-1-yl)-1 ,2,3,4- tetrahydroisoquinoline-3-carboxamide; or a pharmaceutically acceptable salt or solvate thereof.
The compounds of the invention are inhibitors of hepatic production of apoB-100 and are thus of use in the treatment of conditions resulting from elevated circulating levels of apoB-100.
The ability of the compounds of the invention to inhibit the production of apoB- 100 by human hepatocytes in vitro is determined using a human hepatocarcinoma cell line, Hep G2, as a model system. The specificity of the compounds of the invention is established by comparing the effects on apoB- 100, apoprotein A-1 , and fibrinogen production. A specificity of at least 100 is preferred.
The in vivo profile of the compounds was determined by acute oral administration of the compounds of the invention to DBA/2 mice and Wistar rats with measurement of apoB-100 plasmatic levels as percentage of control values. Active compounds are further evaluated in Wistar rats by repeated oral administration (once a day) with measurement of total cholesterol, low density lipoprotein-cholesterol, triglycerides, apoB-100 and apoA-l plasmatic levels as a percentage of control values.
The compounds of the invention are potent and specific inhibitors of hepatic production of apoB-100, which furthermore exhibit good oral bioavailability and duration of action.
Compounds of the invention are of use in the treatment of atherosclerosis, pancreatitis, non-insulin dependent diabetes mellitus (NIDDM), and coronary heart diseases.
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, hyperlipoproteinemia, hypercholesterolemia and/or hypertriglyceridemia.
The invention therefore provides a compound of formula (I) or a pharmaceutically 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 pharmaceutically acceptable salt or solvate thereof in the preparation of a medicament for use in the treatment of conditions resulting from elevated circulating levels of apoB-100.
In an alternative or further aspect there is provided a method for the treatment of a mammal, including man, in particular in the treatment of conditions resulting from elevated circulating levels of apoB-100, comprising administration of an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.
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 pharmaceutically acceptable salt 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).
For oral administration, the pharmaceutical compositions may take the form of, for example, tablets or capsules prepared by conventional means with pharmaceutically acceptable excipients such as binding agents (e.g. pregelatinised maize starch, polyvinylpyrrolidone or hydroxypropyl methylcellulose); fillers (e.g. lactose, microcrystalline cellulose or calcium hydrogen phosphate); lubricants (e.g. magnesium stearate, talc or silica); disintegrants (e.g. potato starch or sodium starch glycollate); or wetting agents (e.g. sodium lauryl sulphate). The tablets may be coated by methods well known in the art. Liquid preparations for oral administration may take the form of, for example, solutions, syrups or suspensions, or they may be presented as a dry product for constitution with water or other suitable vehicle before use. Such liquid preparations may be prepared by conventional means with pharmaceutically acceptable additives such as suspending agents (e.g. sorbitol syrup, cellulose derivatives or hydrogenated edible fats); emulsifying agents (e.g. lecithin or acacia); non-aqueous vehicles (e.g. almond oil, oily esters, ethyl alcohol or fractionated vegetable oils); and preservatives (e.g. methyl or propyl- p-hydroxybenzoates or sorbic acid). The preparations may also contain buffer salts, flavouring, colouring and sweetening agents as appropriate.
Preparations for oral administration may be suitably formulated to give controlled release of the active compound.
For buccal administration the composition may take the form of tablets or lozenges formulated in conventional manner.
For transdermal administration the compounds according to the invention may be formulated as creams, gels, ointments or lotions or as a transdermal patch. Such compositions may for example be formulated with an aqueous or oily base with the addition of suitable thickening, gelling, emulsifying, stabilising, dispersing, suspending, and/or colouring agents.
The compounds of the invention may be formulated for parenteral administration by bolus injection or continuous infusion. Formulations for injection may be presented in unit dosage form e.g. in ampoules or in multi-dose containers, with an added preservative. The compositions may take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles, and may contain formulatory agents such as suspending, stabilising and/or dispersing agents. Alternatively, the active ingredient may be in powder form for constitution with a suitable vehicle, e.g. sterile pyrogen-free water, before use.
The compounds of the invention may be formulated for topical administration in the form of ointments, creams, gels, lotions, pessaries, aerosols or drops (e.g. eye, ear or nose drops). Ointments and creams may, for example, be formulated with an aqueous or oily base with the addition of suitable thickening and/or gelling agents. Ointments for administration to the eye may be manufactured in a sterile manner using sterilised components.
Lotions may be formulated with an aqueous or oily base and will in general also contain one or more emulsifying agents, stabilising agents, dispersing agents, suspending agents, thickening agents, or colouring agents. Drops may be formulated with an aqueous or non aqueous base also comprising one or more dispersing agents, stabilising agents, solubilising agents or suspending agents. They may also contain a preservative.
The compounds of the invention may also be formulated in rectal compositions such as suppositories or retention enemas, e.g. containing conventional suppository bases such as cocoa butter or other glycerides.
The compounds of the invention may also be formulated as depot preparations. Such long acting formulations may be administered by implantation (for example subcutaneously or intramuscularly) or by intramuscular injection. Thus, for example, the compounds of the invention may be formulated with suitable polymeric or hydrophobic materials (for example as an emulsion in an acceptable oil) or ion exchange resins, or as sparingly soluble derivatives, for example, as a sparingly soluble salt.
For intranasal administration, the compounds of the invention may be formulated as solutions for administration via a suitable metered or unit dose device or alternatively as a powder mix with a suitable carrier for administration using a suitable delivery device.
The compositions may contain from 0.1% upwards, e.g. 0.1 - 99% of the active material, depending on the method of administration. A proposed dose of the compounds of the invention is 0.25mg/kg to about 125mg/kg bodyweight per day e.g. 20mg/kg to 100mg/kg per day. It will be appreciated that it may be necessary to make routine variations to the dosage, depending on the age and condition of the patient and the precise dosage will be ultimately at the discretion of the attendant physician or veterinarian. The dosage will also depend on the route of administration and the particular compound selected.
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 withp an HMG CoA reductase inhibitor or an agent for inhibition of bile acid transport.
Compounds of formula (I), and salts and solvates thereof, may be prepared by the general methods outlined hereafter. In the following description, the groups R°, R , R2 and R3 are as previously defined for compounds of formula (I). According to a general process, a compound of formula (I) may be prepared by reacting a compound of formula (II) with a compound of formula (III)
Figure imgf000014_0001
where X represents a suitable halide leaving group, e.g. chloride, or X represents a hydroxy group. The reaction is conveniently carried out under standard coupling conditions for acid or acid halide couplings with amines.
A compound of formula (II) may be prepared by reaction of a compound of formula (IV) with a compound of formula (V)
Figure imgf000014_0002
where Y is a suitable amine protecting group, e.g. tert-butoxycarbonyl (Boc), under standard coupling conditions for an acid/amine coupling, followed by deprotection of the protecting group under suitable conditions.
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.
Thus, according to a second method, compounds of formula (I) may be prepared by reaction of compounds of formula (VI) and compounds of formula (V)
Figure imgf000015_0001
under standard conditions for amine and acid couplings.
Compounds of formula (VI) may be prepared by reaction of compounds of formula (VII) with compounds of formula (III)
Figure imgf000015_0002
(vii) (in) where Z is a suitable C^ alkyl protecting group, e.g. methyl, and X is OH, under standard conditions for acid and amine couplings, followed by removal of the acid protecting group.
It will be appreciated that certain intermediates, e.g. compounds of formula (II) and (VI), are novel and may, therefore, provide a further aspect of the present invention. Compounds of formula (III), (IV), (V) and (VII) are known or may be prepared by standard methods.
Pharmaceutically acceptable salts may also be prepared from other salts, including other pharmaceutically 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.
Intermediate 1 (+)-7-Methyl-1 ,2,3,4-tetrahydro-naphthalen-1 -ylamine
To a solution of racemic 7-methyl-1 ,2, 3,4-tetrahydro-naphthalen-1 -ylamine (12.1 g) in methanol (70 mL) was added a solution (L)-(+)-tartaric acid (11.2 g) in methanol (70 mL) and the resulting solution was kept overnight at room temperature. The crystalline salt was filtered off and dried to give the tartrate salt (9.7g) as white crystals (m.p.: 189-191 °C). The salt was treated with 1N aqueous NaOH, extracted with diethyl ether and the resulting organic phase was dried over sodium sulphate, filtered and evaporated under reduced pressure to give the title compound as a pale yellow liquid (4.7 g). [α]D = +46.8° (c = 0.5; CHCI3) Intermediate 2
(+ )-7-Methoxy-1 ,2,3,4-tetrahydro-naphthalen-1 -ylamine
To a stirred suspension of racemic 7-methoxy-1,2,3,4-tetrahydro-naphthalen-1- ylamine (20 g) in water (80 mL) was added (L)-(+)-tartaric acid (16.9 g) and the resulting suspension was warmed to effect complete solution. After 3 hours at room temperature, the crystalline salt was filtered off and then recrystallised twice from methanol to give the tartrate salt (8 g) as white crystals (m.p.: 211- 212°C). The salt (1g) was treated with 1 N aqueous NaOH, extracted with diethyl ether, and the resulting organic phase was dried over sodium sulphate, filtered and evaporated under reduced pressure to give the title compound as a pale yellow liquid (0.5 g). [α]D = +45.9° (c = 1.12; MeOH)
Intermediate 3
3-Dimethylamino-4-methyl benzoic acid methyl ester
To a stirred suspension of 3-amino-4-methyl benzoic acid methyl ester (6.6 g) in methanol (60 mL) was added a 37% aqueous formaldehyde solution (8 mL) and 10% palladium on charcoal (0.66 g) and the mixture was stirred under hydrogen atmospher for 16 hours at room temperature. The catalyst was filtered off, the filtrate was evaporated under reduced pressure and the residue was then purified by chromatography eluting with dichloromethane/ethyl acetate (90/10) to give the title compound as a colourless liquid (6.7 g). GC/MS (El, 70 eV): m/z = 193
Intermediate 4
3-Dimethylamino-4-methyl benzoic acid
A 1 N solution of NaOH (48.9 mL) was added to a solution of 3-dimethylamino-4- methyl benzoic acid methyl ester (6.3 g) in methanol (60 mL) and the solution was stirred at room temperature for 16 hours. The reaction mixture was evaporated under reduced pressure and 1N HCI (48.9 mL) was added. The aqueous layer was extracted with dichloromethane and the organic phase was washed with brine, dried over sodium sulphate and evaporated. The white solid obtained was recrystallised from hexane to give the title compound as white crystals (5g). m.p.: 131-133°C.
Intermediate 5 2-(tert-Butoxycarbonyl)-N-(7-methyl-1 ,2,3,4-tetrahydro-naphthalen-1-yl)-1 ,2,3,4- tetrahydroisoquinoline-3-carboxamide
To a solution of (+)-7-methyl-1 , 2, 3,4-tetrahydro-naphthalen-1 -ylamine (4.8 g) in dichloromethane (100 mL) were added Boc-D-1 ,2,3,4-tetrahydroisoquinoline-3- carboxylic acid (8.24 g), 1-hydroxybenzotriazole (5.21 g) and triethylamine (3.86 g). The mixture was cooled at 0°C and treated with 1-(3-dimethylamino propyl)- 3-ethylcarbodiimide hydrochloride (7.37 g) followed by stirring for 3 hours at room temperature. The reaction mixture was washed successively with water, 1N HCI, an aqueous solution of NaHC03 and brine, and then was dried over sodium sulphate and evaporated. The oily residue was crystallised from diisopropyi ether to give the title compound as white crystals (9.7 g). m.p.:140-142°C.
Similarly prepared was:
Intermediate 6 2-(tert-Butoxycarbonyl)-N-(7-methoxy-1 ,2,3,4-tetrahydro-naphthalen-1-yl)-
1,2,3,4-tetrahydroisoquinoline-3-carboxamide as white crystals (16g), m.p.:149-151°C from (+)-7-methoxy-1,2,3,4-tetrahydro-naphthalen-1 -ylamine (8.5 g), and Boc-D-
1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid (13.3g).
Intermediate 7
N-(7-methyl-1 ,2,3,4-tetrahydro-naphthalen-1-yl)-1 ,2,3,4-tetrahydroisoquinoline-
3-carboxamide
To a stirred solution of 2-(tert-butoxycarbonyl)-N-(7-methyl-1,2,3,4-tetrahydro- naphthalen-1-yl)-1 ,2,3,4-tetrahydroisoquinoline-3-carboxamide (intermediate 5)
(9.7 g) in anhydrous dichloromethane (70 mL) cooled at 0°C was added trifluoroacetic acid (32 mL) and the solution was allowed to react at room temperature. After 4 hours, the reaction mixture was evaporated to dryness under reduced pressure and the residue was taken up in water, basified with a saturated aqueous solution of NaHC03 and extracted with dichloromethane. The resulting organic phase was washed with brine, dried over sodium sulphate, filtered and evaporated to dryness. The white solid obtained was recrystallised from diisopropyl ether to give the title compound as white crystals (6.7 g). m.p.: 132-134 .
Similarly prepared was: Intermediate 8
N-(7-Methoxy-1 ,2,3,4-tetrahydro-naphthalen-1-yl)-1 ,2,3,4-tetrahydroisoquinoline- 3-carboxamide as white crystals (11.8 g), m.p.: 131-133X from 2-(tert-butoxycarbonyl)-N-(7-methoxy-1 ,2,3,4-tetrahydro-naphthalen-1 -yl)- 1,2,3,4-tetrahydroisoquinoline-3-carboxamide (16 g) (intermediate 6).
Intermediate 9
4,4,7-Trimethyl-3,4-dihydro-2H-naphthalen-1 -one oxime
To a solution of 4,4,7-trimethyl-3,4-dihydro-2H-naphthalen-1-one (1.7 g) in ethanol (30 mL) was added a solution of hydroxylamine hydrochloride (1 g) in water (20 mL) and sodium acetate (2.2 g). After 48 hours at room temperature, the solvents are removed under reduced pressure and the residue was taken up in water and extracted with diethyl ether. The organic layer was washed with water, dried over sodium sulfate and evaporated to dryness to give the title compound as an oil (2 g). GC/MS (El, 70 eV) : m/z=203 (M+)
Similarly prepared were:
Figure imgf000019_0001
12 7-Trifluoromethoxy 245 (M )
Intermediate 13
7-Methoxy-4,4-dimethyl-1 , 2, 3,4-tetrahydro-naphthalen-1 -ylamine hydrochloride A solution of 7-methoxy-4,4-dimethyl-3,4-dihydro-2H-naphthalen-1-one oxime (3.5 g) in methanol (60 mL) was hydrogenated in the presence of 10% Pd/C (0.3 g) for 16 hours at room temperature. After removal of the catalyst, the solvent was evaporated in vacuo and the residue was dissolved in diethyl ether and treated with a solution of hydrochloric acid in diethyl ether. The precipitate obtained was filtered and washed with diethyl ether to give the title compound as white crystals (3.7 g). m.p.: 234-236°C.
Similarly prepared were
Figure imgf000020_0001
Intermediate 19
7-Fluoro-1 , 2, 3,4-tetrahydro-naphthalen-1 -ylamine
A solution of 7-fluoro-3,4-dihydro-2H-naphthalen-1-one oxime (0.56 g) in acetic acid (15 mL) was hydrogenated in the presence of 10% Pd/C (0.06 g) for 16 hours at 40°C. After removal of the catalyst, the solvent was evaporated in vacuo and the residue was basified with a solution of sodium hydroxide, and extracted with dichloromethane. The organic layer was washed with brine, dried over sodium sulfate and evaporated under reduced pressure. The residue was purified by flash chromatography eluting with dichloromethane/methanol (90/10) to give the title compound as white crystals (0.07 g). m.p.: 62-64X.
Intermediate 20
(7-lsopropyl-1 ,2,3,4-tetrahydro-naphthalen-1 -yl)-(1 -phenyl-ethyl)-amine A solution of 7-isopropyl-3,4-dihydro-2H-naphthalen-1-one (14.5 g), (S)-(-)-α- methyl benzylamine (27.9 g) and a catalytic amount of p-toluenesulfonic acid in toluene (150 mL) was refluxed under a dean-stark trap until conversion was complete (48 hours). The solvent was then evaporated under reduced pressure and the oily residue (22.5 g) was dissolved in methanol (300 mL). The solution was cooled at 0°C and treated portionwise with sodium borohydride (1.8 g) and then stirred for 0.5 hour at the same temperature. Water was then added and the mixture was evaporated to dryness and filtered on silica gel eluting with dichloromethane / methanol (95/5) to give the title compound (20.4 g) as an oil. GC/MS (El, 70 eV) : m/z= 293 (M+)
Similarly prepared was:
Intermediate 21
(7-tert-Butyl-1 ,2,3,4-tetrahydro-naphthalen-1 -yl)-(1 -phenyl-ethyl)-amine as an oil (15.2 g),
GC/MS (El, 70 eV) : m/z= 307 (M+) from 7-tert-butyl-3,4-dihydro-2H-naphthalen-1-one (10.1 g) and (S)-(-)- α-methyl benzylamine (18.15 g).
Intermediate 22
(+)-7-lsopropyl-1 ,2,3,4-tetrahydro-naphthalen-1 -ylamine hydrochloride A mixture of (7-isopropyl-1 ,2,3,4-tetrahydro-naphthalen-1-yl)-(1-phenyl-ethyl)- amine ( 20.2 g ; 69 mmol), ammonium formate (13 g ; 206 mmol) and 10% Pd/C (1 g) in methanol (300 mL) was refluxed for 3 hours. The reaction mixture was cooled at room temperature, the catalyst was filtered off and the filtrate was evaporated under reduced pressure. The residue was treated with 1N sodium hydroxide , extracted with diethyl ether, and the organic phase was dried over sodium sulfate and filtered. The organic solution was then treated with hydrochloric acid and the precipitate was filtered and dried to give the title compound ( 10.5 g) as a white solid. m.p . : > 250°C
[α]D = +29.4° (C=0.52 ;MeOH).
Similarly prepared was:
Intermediate 23
(+)-7-tert-butyl-1 , 2, 3,4-tetrahydro-naphthalen-1 -ylamine hydrochloride as a white solid (10.2 g), m.p . : > 250°C
[α]D = +28° (C=0.58 ;MeOH) from (7-tert-Butyl-1 ,2,3,4-tetrahydro-naphthalen-1 -yl)-(1 -phenyl-ethyl)-amine
(15.2 g).
Similarly prepared as Intermediate 5:
Figure imgf000022_0001
Intermediate 27 2-(tert-Butoxycarbonyl)-N-(5,7-dimethyl-1,2,3,4-tetrahydro-naphthalen-1-yl)- 1 ,2,3,4-tetrahydroisoquinoline-3-carboxamide as a mixture of diastereoisomers To a solution of racemic 5,7-dimethyl-1 , 2, 3,4-tetrahydro-naphthalen-1 -ylamine hydrochloride (1.1 g) in dichloromethane (20 mL) were added Boc-D-1 ,2,3,4- tetrahydroisoquinoline-3-carboxylic acid (1.4 g), 1-hydroxybenzotriazole (0.9 g) and triethylamine (1.1 g). The mixture was cooled at 0°C and treated with 1-(3- dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (1.3 g) followed by stirring for 3 hours at room temperature. The reaction mixture was washed successively with 1N HCI, an aqueous solution of NaHC03 and brine, and then was dried over sodium sulfate and evaporated. The residue was crystallised from diisopropyl ether to give the title compound (2 g) as white crystals, m.p.: 152-154°C.
Similarly prepared were :
Figure imgf000023_0001
Similarly prepared to Intermediate 7:
Figure imgf000023_0002
Intermediate 39 3-(4-Methyl-piperazin-1-yl)-benzoic acid ethyl ester A mixture of 3-amino-benzoic acid ethyl ester (19.7 g), bis-(2-chloro-ethyl)- methylamine (23 g) and sodium carbonate (63 g) in butanol (450 mL) was stirred and heated under reflux for 16 hours. The mixture was evaporated under reduced pressure and the residue was taken up in water and extracted with ethyl acetate. The organic layer was dried over sodium sulfate, evaporated under reduced pressure and the residue was purified by flash chromatography eluting with dichloromethane/methanol (95/5) to give the title compound as a pale yellow oil (3.8 g). GC/MS (EI.70 eV) : m/z=248 (M+)
Intermediate 40
3-(3-Dimethylamino-propoxy)-benzoic acid ethyl ester
A mixture of 3-hydroxy-benzoic acid ethyl ester (3.32 g), (3-chloro-propyl)- dimethylamine hydrochloride (3.79 g) and anhydrous potassium carbonate (6.62 g) in acetone (150 mL) was stirred and heated under reflux for 24 hours. It was then cooled, and the solid material was filtered off and washed with acetone. The filtrate was evaporated under reduced pressure and the residue was purified by flash chromatography eluting with dichloromethane/methanol (95/5) to give the title compound (4 g) as a pale yellow oil. GC/MS (EI.70 eV) : m/z=251 (M+)
Similarly prepared were
Figure imgf000024_0001
Intermediate 43
3-(2-dimethylamino-1-methyl-ethoxy)-benzoic acid ethyl ester and 3-(2- dimethylamino-propoxy)-benzoic acid ethyl ester
A mixture of 3-hydroxy-benzoic acid ethyl ester (16.6 g), (2-chloro-propyl)- dimethylamine hydrochloride (21.6 g) and anhydrous potassium carbonate (41.1 g) in acetone (400 mL) was stirred and heated under reflux for 16 hours. It was then cooled, and the solid material was filtered off and washed with acetone. The filtrate was evaporated under reduced pressure and the residue was purified by flash chromatography eluting with dichloromethane/methanol (95/5) to give first 3-(2-dimethylamino-1-methyl-ethoxy)-benzoic acid ethyl ester (7 g) as a pale yellow oil,
GC/MS (El, 70eV) : m/z= 251 (M+) followed by 3-(2-dimethylamino-propoxy)-benzoic acid ethyl ester (10 g) as a pale yellow oil,
GC/MS (El, 70eV) : m/z= 251 (M+)
Intermediate 44
3-(2-dimethylamino-1 ,1-dimethyl-ethoxy)-benzoic acid ethyl ester and 3-(2- dimethylamino-2-methyl-propoxy)-benzoic acid ethyl ester
A solution of 3-hydroxy-benzoic acid ethyl ester (1.6 g) in tetrahydrofuran (50 mL) containing triphenyl phosphine (2.9 g) was stirred at room temperature while diethyl azodicarboxylate ( 1.9 g) was added dropwise. To this solution was added 2-dimethylamino-2-methyl-propan-1-ol (1.2 g) and the mixture was stirred at room temperature for 16 hours. Evaporation of the solvent in vacuo gave an oil which was dissolved in diethyl ether and the organic layer was washed with water, dried over sodium sulfate, evaporated and purified by flash chromatography eluting with dichloromethane/methanol (90/10) to give first : 3- (2-dimethylamino-1 ,1-dimethyl-ethoxy)-benzoic acid ethyl ester (1.2 g) as a pale yellow oil,
GC/MS (EI,70eV) : m/z= 265 (M+) followed by 3-(2-dimethylamino-2-methyl-propoxy)-benzoic acid ethyl ester (0.3 g) as a pale yellow oil,
GC/MS (EI,70eV) : m/z= 265 (M+)
Intermediate 45
3-Morpholin-4-yl-benzoic acid
To a solution of 3-morpholin-4-yl-benzoic acid ethyl ester (6.1 g) in ethanol (40 mL) was added a 1N solution of sodium hydroxide (55 mL) and the mixture was heated under reflux for 1 hour. Ethanol was then evaporated under reduced pressure and the aqueous solution was extracted with diethyl ether and neutralised with a 1N solution of hydrochloric acid (55 mL). The aqueous layer was then extracted with dichloromethane, and the organic layer was dried over sodium sulfate and evaporated to dryness. The solid obtained was recrystallised from acetonitrile to give the title compound (3.6 g) as white crystals, m.p. : 168-170°C.
Similarly prepared were
Int. R^ M.P. °C No.
o OH 46 3-Dimethylamino-4- 150-152 methoxy
R1- < _>. 47 3-(4-Methyl-piperazin-1 ■ 190-192 yi)
Intermediate 48
3-(3-Dimethylamino-propoxy)-benzoic acid hydrochloride
To a solution of 3-(3-dimethylamino-propoxy)-benzoic acid ethyl ester (4 g) in ethanol (50 mL) was added a solution of sodium hydroxide (1.3 g) in water (50 mL) and the mixture was heated at 60°C for 1.5 hours. Ethanol was then evaporated under reduced pressure and the solution was acidified with concentrated hydrochloric acid. The aqueous solution was evaporated to dryness and the resulting solid residue was extracted with hot ethanol and the solution was filtered and evaporated. The solid obtained was recrystallised from propanol-2 to give the title compound (3.5 g) as white crystals, m.p. : 180-182°C.
Similarly prepared were:
Figure imgf000027_0001
Intermediate 52
3-(2-dimethylamino-propoxy)-benzoic acid hydrochloride
To a solution of 3-(2-dimethylamino-propoxy)-benzoic acid ethyl ester (10 g) in ethanol (100 mL) was added a normal solution of sodium hydroxide (80 mL) and the mixture was heated under reflux for 0.5 hour. Ethanol was then evaporated under reduced pressure and the solution was acidified with concentrated hydrochloric acid. The aqueous solution was evaporated to dryness and the resulting solid residue was extracted with hot ethanol and the solution was filtered and evaporated. The solid obtained was washed with diisopropyl ether to give the title compound (9.5 g) as white crystals, m.p. : 177-179°C.
Similarly prepared were :
Figure imgf000027_0002
dimethyl-ethoxy)
Intermediate 56
(R)-2-(3-Dimethylamino-benzoyl)-1 ,2,3,4-tetrahydroisoquinoline-3-carboxylic acid ethyl ester To a solution of (R)-1 ,2,3,4-tetrahydroisoquinoline-3-carboxylic acid ethyl ester hydrochloride (5.8 g) in dichloromethane (170 mL) were added 3-dimethylamino- benzoic acid (4 g), 1 -hydroxy benzotriazole (4.2 g) and triethylamine (5.4 g). The mixture was cooled at 0°C and treated with 1-(3-dimethylaminopropyl)-3- ethylcarbodiimide hydrochloride (5.9 g) followed by stirring for 4 hours at room temperature. The reaction mixture was washed successively with water, an aqueous solution of NaHC03 and brine, and then was dried over sodium sulfate and evaporated. The residue was purified by flash chromatography eluting with dichloromethane/ethyl acetate (90/10) to give the title compound as a yellow oil (6.5 g). GC/MS(EI, 70eV) : m/z=352 (M+)
Similarly prepared was :
Intermediate 57 (R)-2-(3-Morpholin-4-yl-benzoyl)-1 ,2,3,4-tetrahydroisoquinoline-3-carboxylic acid ethyl ester as a yellow oil (2.2 g),
GC/MS(EI, 70eV) : m/z=394 (M+) from (R)-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid ethyl ester hydrochloride (1.8 g) and 3-morpholin-4-yl-benzoic acid (1.6 g).
Intermediate 58
(R)-2-(3-Dimethylamino-benzoyl)-1 ,2,3,4-tetrahydroisoquinoline-3-carboxylic acid
A stirred solution of (R)-2-(3-dimethylamino-benzoyl)-1,2,3,4-tetrahydro isoquinoline-3-carboxylic acid ethyl ester (6.5 g) in a mixture of THF, MeOH,
H20 (30/10/10 mL) cooled to 5°C, was treated with UOH.H20 (1.2 g) and the mixture was stirred at the same temperature for 8 hours. The solvents were removed under reduced pressure and the residue was neutralized with 1 N HCI, and extracted with dichloromethane. The organic phase was washed with water, dried over sodium sulfate and evaporated under reduced pressure. The solid obtained was recrystallised from ethyl acetate to give the title compound as white crystals (5 g), m.p.: 202-204°C.
Similarly prepared was :
Intermediate 59 (R)-2-(3-Morpholin-4-yl-benzoyl)-1 ,2,3,4-tetrahydroisoquinoline-3-carboxylic acid as white crystals (1.7 g) m.p.: 106-108°C from (R)-2-(3-morpholin-4-yl-benzoyl)-1 ,2,3,4-tetrahydroisoquinoline-3- carboxylic acid ethyl ester (2.2 g).
Example 1
2-(4-Methyl benzoyl)-N-(7-methyl-1 ,2,3,4-tetrahydro-naphthaien-1-yl)-1 ,2,3,4- tetrahydroisoquinoline-3-carboxamide
Method A: To a solution of N-(7-methyl-1 ,2,3,4-tetrahydro-naphthalen-1-yl)-1 ,2,3,4- tetrahydroisoquinoline-3-carboxamide (Intermediate 7) (160 mg) in dichloromethane (8 mL) were added 4-methyl benzoic acid (68 mg), 1- hydroxybenzotriazole (81 mg) and triethylamine (61 mg). The mixture was cooled at 0°C and treated with 1-(3-dimethylaminopropyl)-3-ethyicarbodiimide hydrochloride (114 mg) followed by stirring for 16 hours at room temperature.
The reaction mixture was diluted with dichloromethane and washed successively with 1 N HCI, an aqueous solution of NaHC03 and brine, and then was dried over sodium sulphate and evaporated. The residue was purified by flash chromatography eluting with dichloromethane/ ethyl acetate (90/10) and crystallised from dichloromethane / hexane to give the title compound as white crystals (150 mg). m.p.:161-162°C. [α]D = + 47.1° (C=1.1 ; CHCI3)
Analysis for C29H30N2θ2 Calculated: C,79.42;H,6.89;N,6.39; Found: C,79.01 ;H,7.1 ;N,6.43%.
Method B
A solution of 4-methyl benzoyi chloride (913 mg) in dry dichloromethane (10 mL) was added dropwise to a solution of N-(7-methyl-1 ,2,3,4-tetrahydro- naphthalen-1-yl)-1 ,2,3,4-tetrahydroisoquinoline-3-carboxamide (Intermediate 7) (1.8 g) and triethylamine (597 mg) while being stirred under an nitrogen atmosphere with ice-bath cooling. After 0.5h, the solution was washed with 1N HCI, an aqueous solution of NaHC03 and brine and then dried over sodium sulphate, filtered, and evaporated. The residue was purified by flash chromatography eluting with dichloromethane/ethyl acetate (90/10) and crystallised from dichloromethane/ hexane to give the title compound as white crystals (2 g). m.p.:157-159°C [α]D = + 46° (C=1.2 ; CHCI3)
Analysis for C29H30N2O2: Calculated: C,79.42;H,6.89;N,6.39;
Found: C,78.99;H,7.01 ;N,6.31%.
Similarly prepared were:
Example 2
2-(3-Dimethylamino-4-methyl benzoyl)-N-(7-methyl-1 ,2,3,4-tetrahydro- naphthalen-1 -yl)-1 ,2,3,4-tetrahydroisoquinoline-3-carboxamide as white crystals, m.p.: 140-141°C [α]D= + 43.6° (C=1.2 ; CHCI3)
Analysis for C31H35N302: Calculated: C.77.31 ;H,7.32;N,8.72;
Found: C,77.04;H,7.54;N,8.66%. from N-(7-methyl-1 ,2,3,4-tetrahydro-naphthalen-1-yl)-1 ,2,3,4- tetrahydroisoquinoline-3-carboxamide (Intermediate 7) and 3-dimethylamino-4- methyl benzoic acid.
Example 3
2-(3-Dimethylamino benzoyl)-N-(7-methyl-1 ,2,3,4-tetrahydro-naphthalen-1-yl)-
1,2,3,4-tetrahydroisoquinoline-3-carboxamide as white crystals, m.p.: 186-187°C [α]D= + 41° (C=0.4 ; CHCI3)
Analysis for C30H33N3O2: Calculated: C,77.06;H,7.11 ;N,8.99;
Found: C,77.22;H,7.04;N,9.03%. from N-(7-methyl-1 ,2,3,4-tetrahydro-naphthalen-1-yl)-1 ,2,3,4- tetrahydroisoquinoline-3-carboxamide (Intermediate 7) and 3-dimethylamino benzoic acid.
Example 4 2-(3-(Morpholin-4-yl)benzoyl)- N-(7-methyl-1 ,2,3,4-tetrahydro-naphthalen-1-yl)-
1,2,3,4-tetrahydroisoquinoline-3-carboxamide as a white solid, m.p.: 96-101°C
[α]D= + 33.6° (C=1 ; CHCI3)
Analysis for C32H35N303: Calculated: C,75.41 ;H,6.92;N,8.24; Found: C,75.69;H,7.19;N,7.99% from N-(7-methyl-1 ,2,3,4-tetrahydro-naphthalen-1-yl)-1 ,2,3,4- tetrahydroisoquinoline-3-carboxamide (Intermediate 7) and 3-(morpholin-4- yl)benzoic acid.
Example 5
2-(3-(Morpholin-4-yl)benzoyl)- N-(7-methoxy-1 ,2,3,4-tetrahydro-naphthalen-1 -yl)-
1 ,2,3,4-tetrahydroisoquinoline-3-carboxamide as white crystals, m.p.: 124-126°C
[α]D = + 23.9° (C=0.4 ; CHCI3) Analysis for C32H35N304: Calculated: C,73.12;H,6.71 ;N,7.99;
Found: C,73.32;H,7.13;N,8.05% from N-(7-Methoxy-1 ,2,3,4-tetrahydro-naphthalen-1-yl)-1 ,2,3,4- tetrahydroisoquinoline-3-carboxamide (Intermediate 8) and 3-(morpholin-4- yl)benzoic acid.
Example 6
2-(3-Dimethylamino benzoyl)-N-(7-methoxy-1 ,2,3,4-tetrahydro-naphthalen-1-yl)- 1,2,3,4-tetrahydroisoquinoline-3-carboxamide as white crystals, m.p.: 164-166°C [α]D = + 25.6° (C=0.5 ; CHCI3) Analysis for C30H33N3O3: Calculated: C.74.51 ;H,6.88;N,8.69;
Found: C,74.42;H,7.26;N,8.72%. from N-(7-Methoxy-1 ,2,3,4-tetrahydro-naphthalen-1-yl)-1 ,2,3,4- tetrahydroisoquinoline-3-carboxamide (Intermediate 8) and 3-dimethylamino benzoic acid.
Example 7 2-[3-(2-Dimethylamino-ethoxy)-benzoyl1-N-(7-isopropyl-1 ,2,3,4-tetrahydro- naphthalen-1-yl)-1 ,2,3,4-tetrahydroisoquinoline-3-carboxamide
To a solution of N-(7-isopropyl-1 ,2,3,4-tetrahydro-naphthalen-1-yl)-1 ,2,3,4- tetrahydroisoquinoline-3-carboxamide (Intermediate 30) (2.84 g) in dichloromethane (100 mL) were added 3-(2-dimethylamino-ethoxy)-benzoic acid hydrochloride (2 g), 1-hydroxybenzotriazole (1.43 g) and triethylamine (1.89 g). The mixture was cooled at 0°C and treated with 1-(3-dimethylaminopropyl)-3- ethylcarbodiimide hydrochloride (2 g) followed by stirring for 16 hours at room temperature. The reaction mixture was diluted with dichloromethane and washed successively with water, an aqueous solution of NaHC03 and brine, and then was dried over sodium sulfate, filtered and evaporated. The residue was purified by flash chromatography eluting with dichloromethane / methanol (96/4) and crystallised from diisopropyl ether to give the title compound as a white solid (3.2 g). m.p.: 88-90°C [α]D = + 27.2° (C=1 ; CHCI3) Analysis for C34H41 N303 : Calculated: C,75.66;H,7.66;N,7.79;
Found: C,75.21 ;H,7.85;N,7.71%.
Similarly prepared were:
Figure imgf000033_0001
Figure imgf000033_0002
Figure imgf000034_0001
Figure imgf000035_0001
Figure imgf000036_0001
Figure imgf000037_0001
Example 32
2-(3-Morpholin-4-yl-benzoyl)-N-(4,4,7-trimethyl-1 ,2,3,4-tetrahydro-naphthalen-1- yl)-1,2,3,4-tetrahydroisoquinoline-3-carboxamide isomer 1 and isomer 2. To a solution of (R)-2-(3-morpholin-4-yl-benzoyl)-1 ,2,3,4-tetrahydro isoquinoline- 3-carboxylic acid (0.33 g) in dichloromethane (10 mL) were added racemic 4,4,7-trimethyl-1,2,3,4-tetrahydro-naphthalen-1 -ylamine hydrochloride (0.22 g), 1 -hydroxy benzotriazole (0.17 g) and triethylamine (0.23 g). The mixture was cooled to 0°C and treated with 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.25 g) followed by stirring for 3 hours at room temperature. The reaction mixture was washed successively with water, 1 N HCI, an aqueous solution of NaHC03 and brine, and then was dried over sodium sulfate, filtered and evaporated. The residue was purified by flash chromatography eluting with dichloromethane/methanol (99/1) to give the title compound Isomer 1 as a white solid (0.12 g), m.p.: 113-115°C [α]D= + 20° (C=0.4 ; CHCI3) Analysis for C34H39N303 : Calculated: C,75.95;H,7.31;N,7.81;
Found: C,75.80;H,7.59;N,7.61%. followed by
Example 33 Isomer 2 as a white solid (0.08 g), m.p.: 117-119°C [α]D = + 25.4° (C=0.4 ; CHCI3) Analysis for C34H39N303 : Calculated: C,75.95;H,7.31;N,7.81 ;
Found: C,75.47;H,7.23;N,7.87%.
Similarly prepared were :
Figure imgf000038_0001
Figure imgf000038_0002
3,3-dimethyl 3-morpholin-4-yl- C33H37N303 118- (isomer 1) C,75.69;H,7.12;N,8.02 120 C,75.76;H,7.57;N,7.79 + 33.5° (C=0.5; CHCI3)
3,3-dimethyl 3-morpholin-4-yl- C33H37N303 120- (isomer 2) C,75.69;H,7.12;N,8.02 122 C,75.71 ;H,7.43;N,7.84 + 16° (C=1; CHCI3)
7-methoxy-4,4- 3-dimethylamino C32H37N303 174- dimethyl C,75.12;H,7.29;N,8.21 176
(isomer 1) C,75.03;H,7.43;N,8.12 + 13.4° (C=0.5; CHCI3)
7-methoxy-4,4- 3-dimethylamino C32H37N303 97-99 dimethyl C,75.12;H,7.29;N,8.21;
(isomer 2) C,74.57;H,7.75;N,8.02 + 12.6° (C=0.4; CHCI3)
5,7-di-Me 3-morpholin-4-yl C33H37N303 183- (isomer 1) C,75.69;H,7.12;N,8.02; 185 C,75.60;H,7.35;N,7.86 + 28° (C=0.4; CHCI3)
5,7-di-Me 3-morpholin-4-yl C33H37N303 96-98 (isomer 2) C,75.69;H,7.12;N,8.02; C,75.99;H,7.62;N,7.85 + 33.7° (C=0.6; CHCI3)
- trifluoromethoxy 3-morpholin-4-yl C32H32F3N304 102-
(mixture of isomer C,66.31 ;H,5.56;N,7.25 107
1 and 2) C,66.37;H,5.83;N,7.18
Figure imgf000040_0001
Biological Assay
HepG2 cells were seeded at 30 000 cells/well in 96 well plates. After 4 days, confluent cells were incubated with compounds for 24 hours in RPMI medium containing 1% FCS and 50 μCi/ml 35S-methionine. Compounds were dissolved in DMSO and tested onto cells from 5 μM to 0.32 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 calculted taking untreated cells as controsl, and IC50 of each compound was determined on both apoproteins.
Biological Results
The following table illustrates the activity of the compounds of the invention in the assay described above:
Figure imgf000040_0002
Tablet compositions The following compositions A and B can be prepared by wet granulation of ingredients (a) to (c) and (a) to (d) with a solution of povidone, followed by addition of the magnesium stearate and compression.
Composition A mg/tablet mg/tablet
(a) Active ingredient 250 250
(b) Lactose B.P. 210 26
(c) Sodium Starch Glycoilate 20 12
(d) Povidone B.P. 15 9
(e) Magnesium Stearate _5 _3
500 300
Composition B mg/tablet mg/tablet
(a) Active ingredient 250 250
(b) Lactose 150 150 -
(c) Avicel PH 101 60 26
(d) Sodium Starch Glycoilate 20 12
(e) Povidone B.P. 15 9
(f) Magnesium Stearate 5 _3
500 300
Composition C mg/tablet
Active ingredient 100
Lactose 200
Starch 50
Povidone 5
Magnesium Stearate _4 359
The following compositions D and E can be prepared by direct compression of the admixed ingredients. The lactose used in composition E is of the direct compression type.
Composition D mg/tablet Active ingredient 250
Magnesium Stearate 4
Pregeiatinised Starch NF15 146
400
Composition E mg/tablet
Active ingredient 250
Magnesium Stearate 5
Lactose 145
Avicel 100
500
Composition F (Controlled release composition) mg/tablet
(a) Active ingredient 500
(b) Hydroxypropylmethylcellulose 112 (Methocel K4M Premium)
(c) Lactose B.P. 53
(d) Povidone B.P.C. 28
(e) Magnesium Stearate _7
700
The composition can be prepared by wet granulation of ingredients (a) to (c) with a solution of povidone, followed by addition of the magnesium stearate and compression.
Composition G (Enteric-coated tablet)
Enteric-coated tablets of Composition C can be prepared by coating the tablets with 25mg/tablet of an enteric polymer such as cellulose acetate phthalate, polyvinylacetate phthalate, hydroxypropylmethyl- cellulose phthalate, or anionic polymers of methacrylic acid and methacrylic acid methyl ester (Eudragit L). Except for Eudragit L, these polymers should also include 10% (by weight of the quantity of polymer used) of a plasticizer to prevent membrane cracking during application or on storage. Suitable plasticizers include diethyl phthalate, tributyl citrate and triacetin.
Composition H (Enteric-coated controlled release tablet)
Enteric-coated tablets of Composition F can be prepared by coating the tablets with 50mg/tablet of an enteric polymer such as cellulose acetate phthalate, polyvinylacetate phthalate, hydroxypropylmethyl- cellulose phthalate, or anionic polymers of methacrylic acid and methacrylic acid methyl ester (Eudragit L).
Except for Eudragit L, these polymers should also include 10% (by weight of the quantity of polymer used) of a plasticizer to prevent membrane cracking during application or on storage. Suitable plasticizers include diethyl phthalate, tributyl citrate and triacetin.
(ϋ) Capsule compositions Composition A Capsules can be prepared by admixing the ingredients of Composition D above and filling two-part hard gelatin capsules with the resulting mixture. Composition B (infra) may be prepared in a similar manner.
Composition B mg/capsule
(a) Active ingredient 250
(b) Lactose B.P. 143
(c) Sodium Starch Glycoilate 25
(d) Magnesium Stearate _2
420
Composition C mg/capsule
(a) Active ingredient 250 (b) Macrogol 4000 BP 350
600
Capsules can be prepared by melting the Macrogol 4000 BP, dispersing the active ingredient in the melt and filling two-part hard gelatin capsules therewith.
Composition D mg/capsule Active ingredient 250 Lecithin 100
Arachis Oil H)
450
Capsules can be prepared by dispersing the active ingredient in the lecithin and arachis oil and filling soft, elastic gelatin capsules with the dispersion.
Composition E (Controlled release capsule) mg/capsule (a) Active ingredient 250 (b) Microcrystalline Cellulose 125
(c) Lactose BP 125
(d) Ethyl Cellulose _13
513
The controlled release capsule composition can be prepared by extruding mixed ingredients (a) to (c) using an extruder, then spheronising and drying the extrudate. The dried pellets are coated with a release controlling membrane (d) and filled into two-part, hard gelatin capsules.
Composition F (Enteric capsule) mg/capsule
(a) Active ingredient 250
(b) Microcrystalline Cellulose 125
(c) Lactose BP 125
SUBSTITUTE SHEET (RULE 25) (d) Cellulose Acetate Phthalate 50
(e) Diethyl Phthalate _5
555 The enteric capsule composition can be prepared by extruding mixed ingredients (a) to (c) using an extruder, then spheronising and drying the extrudate. The dried pellets are coated with an enteric membrane (d) containing a plasticizer (e) and filled into two-part, hard gelatin capsules.
Composition G (Enteric-coated controlled release capsule)
Enteric capsules of Composition E can be prepared by coating the controlled-release pellets with 50mg/capsule of an enteric polymer such as cellulose acetate phthalate, polyvinylacetate phthalate, hydroxypropylmethylcellulose phthalate, or anionic polymers of methacrylic acid and methacrylic acid methyl ester (Eudragit L). Except for Eudragit L, these polymers should also include 10% (by weight of the quantity of polymer used) of a plasticizer to prevent membrane cracking during application or on storage. Suitable plasticizers include diethyl phthalate, tributyl citrate and triacetin.
(iii) Intravenous injection composition
Active ingredient 0.200g
Sterile, pyrogen-free phosphate buffer (pH 9.0) to 10 ml
The active ingredient is dissolved in most of the phosphate buffer at 35-40°C, then made up to volume and filtered through a sterile micropore filter into sterile 10 ml glass vials (Type 1) which are sealed with sterile closures and overseals.
(iv) Intramuscular injection composition
Active ingredient 0.20 g
Benzyl Alcohol 0.10 g
Glycofurol 75 1.45 g
Water for Injection q.s. to 3.00 ml The active ingredient is dissolved in the glycofurol. The benzyl alcohol is then added and dissolved, and water added to 3 ml. The mixture is then filtered through a sterile micropore filter and sealed in sterile 3 ml glass vials (Type 1).
(v) Syrup composition
Active ingredient 0.25g
Sorbitol Solution 1.50g Glycerol 1.00g
Sodium Benzoate 0.005g
Flavour 0.0125ml
Purified Water q.s. to 5.0ml
The sodium benzoate is dissolved in a portion of the purified water and the sorbitol solution added. The active ingredient is added and dissolved. The resulting solution is mixed with the glycerol and then made up to the required volume with the purified water.
(vi) Suppository composition
mg/suppository Active ingredient 250
Hard Fat, BP (Witepsol H15 - Dynamit NoBel) 1770 2020
One-fifth of the Witepsol H15 is melted in a steam-jacketed pan at 45°C maximum. The active ingredient is sifted through a 200lm sieve and added to the molten base with mixing, using a Silverson fitted with a cutting head, until a smooth dispersion is achieved. Maintaining the mixture at 45°C, the remaining Witepsol H15 is added to the suspension which is stirred to ensure a homogenous mix. The entire suspension is then passed through a 250lm stainless steel screen and, with continuous stirring, allowed to cool to 40°C. At a temperature of 38-40°C, 2.02g aliquots of the mixture are filled into suitable plastic moulds and the suppositories allowed to cool to room temperature,
(vii) Pessary composition mg/pessary
Active ingredient (631m) 250
Anhydrous Dextrose 380
Potato Starch 363
Magnesium Stearate _7
1000
The above ingredients are mixed directly and pessaries prepared by compression of the resulting mixture.
(viii) Transdermal composition
Active ingredient 200mg Alcohol USP 0.1ml Hydroxyethyl cellulose
The active ingredient and alcohol USP are gelled with hydroxyethyl cellulose ό and packed in a transdermal device with a surface area of 10 cm .

Claims

Claims
1. A compound of formula (I)
Figure imgf000048_0001
wherein
R ╬╣0 represents hydrogen, halogen, C^alkyl, C1-4alkoxy or a methylenedioxy group, and n represents an integer from 1-4;
R1 represents hydrogen, halogen, C1-4alkyl, C1-4alkoxy, trifluoromethoxy or a methylenedioxy group, and p represents an integer from 1-4; R2 represents one or more groups selected from hydrogen, halogen, C1-4 alkyl, C-,.4 alkoxy, a methylenedioxy group,NR4R5, -(C1-4alkylene)-NR6R7, -NR4- or -O- (C1-4 alkylene)-NR8R9, 4-morpholino,
Figure imgf000048_0002
, and m represents an integer from 1-4;
R represents hydrogen or C1-4 alkyl;
R -R ,10 independently represent hydrogen or C1-4 alkyl; or a pharmaceutically acceptable salt or solvate thereof.
2. A compound as claimed in claim 1 wherein R is hydrogen.
3. A compound according to Claim 1 or Claim 2 where R1 hydrogen, C-M alkyl, halogen, methoxy, or trifluoromethoxy, p is 1 , 2 or 3, and R1 is substituted on any one, two or three of the 3-, 4-, 5-, 6- , 7- and 8- positions of the bicyciic ring, including gem substitution.
4. A compound as claimed in any one of claims 1 to 3 where R1 is isopropyl substituted in the 7- position of the bicyciic ring.
5. A compound as claimed in any one of claims 1 to 4 where R is hydrogen, C^ 4 alkyl, halogen, methoxy, methylenedioxy, NMe2, -0-(C1^ alkylene)-NMe2, 4- morpholino
or -N N l--MMee and m is suitably 1 , 2 or 3.
6. A compound as claimed in any one of claims 1 to 5 wherein R2 is 2- dimethylamino-ethoxy substituted in the 3-position of the phenyl ring.
7. A compound as claimed in any one of claims 1 to 6 wherein R3 is hydrogen.
8. A compound selected from:
2-(4-Methyl benzoyl)-N-(7-methyl-1 ,2,3,4-tetrahydro-naphthalen-1-yl)-1 ,2,3,4- tetrahydroisoquinoline-3-carboxamide;
2-(3-Dimethylamino-4-methyl benzoyl)-N-(7-methyl-1,2,3,4-tetrahydro- naphthalen-1-yl)-1,2,3,4-tetrahydroisoquinoline-3-carboxamide;
2-(3-Dimethylamino benzoyl)-N-(7-methyl-1 ,2,3,4-tetrahydro-naphthalen-1-yl)-
1,2,3,4-tetrahydroisoquinoiine-3-carboxamide; 2-(3-(Morpholin-4-yl)benzoyl)- N-(7-methyl-1 ,2,3,4-tetrahydro-naphthalen-1 -yl)-
1,2,3,4-tetrahydroisoquinoline-3-carboxamide;
2-(3-(Morpholin-4-yl)benzoyl)-N-(7-methoxy-1 ,2,3,4-tetrahydro-naphthalen-1-yl)-
1 ,2,3,4-tetrahydroisoquinoline-3-carboxamide;
2-(3-Dimethylamino benzoyl)-N-(7-methoxy-1 ,2,3,4-tetrahydro-naphthalen-1- yl)-1 ,2,3,4-tetrahydroisoquinoline-3-carboxamide;
2-[3-(2-Dimethylamino-ethoxy)-benzoyl]-N-(7-isopropyl-1 ,2,3,4-tetrahydro- naphthalen-1-yl)-1,2,3,4-tetrahydroisoquinoline-3-carboxamide;
2-[3-(2-Dimethylamino-ethoxy)-benzoyl]-N-(7-methyl-1 ,2,3,4-tetrahydro- naphthalen-1-yl)-1,2,3,4-tetrahydroisoquinoline-3-carboxamide; 2-[3-(2-Dimethylamino-ethoxy)-benzoyl]-N-(5,7-dimethyl-1 ,2,3,4-tetrahydro- naphthalen-1-yl)-1 ,2,3,4-tetrahydroisoquinoline-3-carboxamide;
2-(4-Methyl-benzoyl)-N-(7-isopropyl-1 ,2,3,4-tetrahydro-naphthalen-1-yl)-
1 ,2,3,4-tetrahydroisoquinoline-3-carboxamide; 2-(3 ,4-Methy lened ioxy-benzoyl)-N-(7-methy 1-1 ,2 , 3 ,4-tetrahyd ro-naphthalen -
1 -yl)-1 ,2,3,4-tetrahydroisoquinoline-3-carboxamide;
2-(3-Morpholin-4-yl-benzoyl)-N-(7-isopropyl-1 ,2,3,4-tetrahydro-naphthalen-1- yl)-1,2,3,4-tetrahydroisoquinoline-3-carboxamide; 2-[3-(2-Diethylamino-ethoxy)-benzoyl]-N-(7-isopropyl-1 ,2,3,4-tetrahydro- naphthalen-1-yl)-1 ,2,3,4-tetrahydroisoquinoline-3-carboxamide;
2-(3-Morpholin-4-yl-benzoyl)-N-(7-tert-butyl-1 ,2,3,4-tetrahydro-naphthalen-1- yl)-1 ,2,3,4-tetrahydroisoquinoline-3-carboxamide;
2-[3-(2-Dimethylamino-ethoxy)-benzoyl]-N-(7-tert-butyl-1 ,2,3,4-tetrahydro- naphthalen-1-yl)-1,2,3,4-tetrahydroisoquinoline-3-carboxamide;
2-[3-(3-Dimethylamino-propoxy)-benzoyl]-N-(7-isopropyl-1 ,2,3,4-tetrahydro- naphthalen-1-yl)-1 ,2,3,4-tetrahydroisoquinoline-3-carboxamide;
2-[3-(2-Diisopropylamino-ethoxy)-benzoyl]-N-(7-isopropyl-1 ,2,3,4-tetrahydro- naphthalen-1-yl)-1 ,2,3,4-tetrahydroisoquinoline-3-carboxamide; 2-(4-Methyl-benzoyl)-N-(6,7-methylenedioxy-1 ,2,3,4-tetrahydro-naphthalen-
1-yl)-1 ,2,3,4-tetrahydroisoquinoline-3-carboxamide;
2-(3-Morpholin-4-yl-benzoyl)-N-(6,7-methylenedioxy-1 ,2,3,4-tetrahydro- naphthalen-1-yl)-1 ,2,3,4-tetrahydroisoquinoline-3-carboxamide;
2-(4-Methyl-benzoyl)-N-(5,7-dimethyl-1 ,2,3,4-tetrahydro-naphthalen -1 -yl)- 1 ,2,3,4-tetrahydroisoquinoline-3-carboxamide;
2-(4-Methyl-benzoyl)-N-(6-fluoro-7-methoxy-1 ,2,3,4-tetrahydro-naphthalen -
1-yl)-1 ,2,3,4-tetrahydroisoquinoline-3-carboxamide;
2-(3-Methoxy-benzoyl)-N-(7-methyl-1 ,2,3,4-tetrahydro-naphthalen -1-yl)-
1 ,2,3,4-tetrahydroisoquinoline-3-carboxamide; 2-[3-(4-Methyl-piperazin-1 -yl)-benzoyl]-N-(7-methoxy-1 ,2,3,4-tetrahydro- naphthalen-1-yl)-1 ,2,3,4-tetrahydroisoquinoline-3-carboxamide;
2-(3-Dimethylamino-4-methoxy-benzoyl)-N-(7-methyl-1 ,2,3,4-tetrahydro- naphthalen -1 -yl)-1 ,2,3,4-tetrahydroisoquinoline-3-carboxamide;
2-(4-Chloro-benzoyl)-N-(7-methyl-1,2,3,4-tetrahydro-naphthalen -1-yl)- 1 ,2,3,4-tetrahydroisoquinoline-3-carboxamide;
2-(3-Mθφholin-4-yi-benzoyl)-N-(1 ,2,3,4-tetrahydro-naphthalen -1-yl)-1 ,2,3,4- tetrahydroisoquinoline-3-carboxamide;
2-(2-Dimethylamino-benzoyl)-N-(1 ,2,3,4-tetrahydro-naphthalen -1 -yl)-
1 ,2,3,4-tetrahydroisoquinoline-3-carboxamide; 2-(3-Morpholin-4-yl-benzoyl)-N-(4,4,7-trimethyl-1 ,2,3,4-tetrahydro- naphthalen-1-yl)-1 ,2,3,4-tetrahydroisoquinoiine-3-carboxamide isomer 1 ; 2-(3-Moφholin-4-yl-benzoyl)-N-(4,4,7-trimethyl-1,2I3,4-tetrahydro- naphthalen-1 -yl)-1 ,2,3,4-tetrahydroisoquinoline-3-carboxamide isomer 2; 2-(3-Morpholin-4-yl-benzoyl)-N-(4,4,6-trimethyl-1 ,2,3,4-tetrahydro- naphthalen-1-yl)-1 ,2,3,4-tetrahydroisoquinoline-3-carboxamide isomer 1 ; 2-(3-Morpholin-4-yl-benzoyl)-N-(4,4,6-trimethyl-1 ,2,3,4-tetrahydro- naphthalen-1-yl)-1 ,2,3,4-tetrahydroisoquinoline-3-carboxamide isomer 2; 2-(3-Morpholin-4-yl-benzoyl)-N-(7-methoxy-4,4-dimethyl-1 ,2,3,4-tetrahydro- naphthalen-1 -yl)-1 ,2,3,4-tetrahydroisoquinoline-3-carboxamide isomer 1 ;
2-(3-Morpholin-4-yl-benzoyl)-N-(7-methoxy-4,4-dimethyl-1 ,2,3,4-tetrahydro- naphthalen-1-yl)-1 ,2,3,4-tetrahydroisoquinoline-3-carboxamide isomer 2; 2-(3-Morpholin-4-yl-benzoyl)-N-(3,3-dimethyl-1,2,3,4-tetrahydro-naphthalen- 1-yl)-1 ,2,3,4-tetrahydroisoquinoline-3-carboxamide isomer 1 ; 2-(3-Morpholin-4-yl-benzoyl)-N-(3,3-dimethyl-1 ,2,3,4-tetrahydro-naphthalen- 1 -yl)-1 ,2,3,4-tetrahydroisoquinoline-3-carboxamide isomer 2; 2-(3-Dimethylamino-benzoyl)-N-(7-methoxy-4,4-dimethyl-1 ,2,3,4-tetrahydro- naphthalen-1-yl)-1 ,2,3,4-tetrahydroisoquinoline-3-carboxamide isomer 1 ; 2-(3-Dimethylamino-benzoyl)-N-(7-methoxy-4,4-dimethyl-1 ,2,3,4-tetrahydro- naphthalen-1-yl)-1 ,2,3,4-tetrahydroisoquinoline-3-carboxamide isomer 2;
2-(3-Morpholin-4-yl-benzoyl)-N-(5,7-dimethyl-1 ,2,3,4-tetrahydro-naphthalen- 1-yl)-1 ,2,3,4-tetrahydroisoquinoline-3-carboxamide isomer 1 ; 2-(3-Mθφholin-4-yl-benzoyl)-N-(5,7-dimethyl-1 ,2,3,4-tetrahydro-naphthalen- 1-yl)-1,2,3,4-tetrahydroisoquinoline-3-carboxamide isomer 2; 2-(3-Morpholin-4-yl-benzoyl)-N-(7-trifluoromethoxy-1 ,2,3,4-tetrahydro- naphthalen-1-yl)-1,2,3,4-tetrahydroisoquinoline-3-carboxamide; 2-(3-Morpholin-4-yl-benzoyl)-N-(7-fluoro-1 ,2,3,4-tetrahydro-naphthalen-1-yl)- 1 ,2,3,4-tetrahydroisoquinoline-3-carboxamide; 2-[3-(2-dimethylamino-propoxy)-benzoyl]-N-(7-isopropyl-1 ,2,3,4-tetrahydro- naphthalen-1-yl)-1,2,3,4-tetrahydroisoquinoline-3-carboxamide;
2-[3-(2-dimethylamino-1-methyl-ethoxy))-benzoyl]-N-(7-isopropyl-1 , 2,3,4- tetrahydro-naphthalen-1-yl)-1 ,2,3,4-tetrahydroisoquinoline-3-carboxamide; 2-[3-(2-dimethylamino-2-methyl-propoxy))-benzoyl]-N-(7-isopropyl-1 , 2,3,4- tetrahydro-naphthalen-1-yl)-1 ,2,3,4-tetrahydroisoquinoline-3-carboxamide; 2-[3-(2-dimethylamino-1 , 1 -dimethyl-ethoxy))-benzoyl]-N-(7-isopropyl-1 ,2,3,4- tetrahydro-naphthalen-1-yl)-1 ,2,3,4-tetrahydroisoquinoline-3-carboxamide; or a pharmaceutically acceptable salt or solvate thereof.
9. 2-[3-(2-Dimethylamino-ethoxy)-benzoyl]-N-(7-isopropyl-1,2,3,4-tetrahydro- naphthalen-1-yl)-1,2,3,4-tetrahydroisoquinoline-3-carboxamide; or a pharmaceutically acceptable salt or solvate thereof.
10. A compound according to any one of Claims 1 to 9 for use in therapy.
11. A method for the treatment of a mammal, including man, of conditions resulting from elevated circulating levels of apoB-100 comprising administration of an effective amount of a compound according to any one of claims 1 to 9 or a pharmaceutically acceptable derivative thereof.
12. The use of a compound according to any one of claims 1 to 9 or a pharmaceutically acceptable salt or solvate thereof in the manufacture of a medicament for use in the treatment of conditions resulting from elevated circulating levels of apoB-100.
13. A pharmaceutical composition comprising a compound according to any one of claims 1 to 9 or a pharmaceutically acceptable derivative thereof, together with one or more pharmaceutically acceptable carriers.
14. A process for preparing a compound of formula (I) as claimed in claim 1 which comprises:
(a) reacting a compound of formula (II) with a compound of formula (III)
Figure imgf000053_0001
(III)
("I)
where X represents a suitable halide leaving group or X represents a hydroxy group, or
(b) by reaction of compounds of formula (VI) and compounds of formula (V)
Figure imgf000053_0002
under standard conditions for amine and acid couplings.
15. An intermediate represented by formula (II)
Figure imgf000054_0001
(ll) wherein
R┬░ represents hydrogen, halogen, C1-4alkyl, C1-4alkoxy or a methylenedioxy group, and n represents an integer from 1-4; R1 represents hydrogen, halogen, C^alkyl, C1-4alkoxy, trifluoromethoxy or a methylenedioxy group, and p represents an integer from 1-4; R3 represents hydrogen or C alkyl; or a pharmaceutically acceptable salt or solvate thereof.
16. An intermediate represented by formula (VI)
Figure imgf000054_0002
wherein R┬░ represents hydrogen, halogen, C1-4alkyl, C alkoxy or a methylenedioxy group, and n represents an integer from 1-4;
R2 represents one or more groups selected from hydrogen, halogen, C1-4 alkyl, C1-4 alkoxy, a methylenedioxy group,NR R5, -(C1-4alkylene)-NR6R7, N or -0-(C1-4 alkylene)-NR8R9, 4-morpholino,
Figure imgf000054_0003
and m represents an integer from 1-4; R3 represents hydrogen or C1-4 alkyl;
R4-R10 independently represent hydrogen or C1-4 alkyl; or a pharmaceutically acceptable salt or solvate thereof.
PCT/EP1998/002244 1997-04-22 1998-04-20 2-benzoyl-1,2,3,4-tetrahydroisoquinoline-3-carboxamide derivatives and their use as inhibitors of hepatic production of apob-100 WO1998047877A1 (en)

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US8114991B2 (en) 2003-02-05 2012-02-14 Bayer Cropscience Ag Amino-1,3,5-triazines N-substituted with chiral bicyclic radicals, process for their preparation, compositions thereof, and their use as herbicides and plant growth regulators
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AP1960A (en) * 2003-02-05 2009-02-26 Bayer Cropscience Ag amino 1,3,5-triazines N-substituted with chiral bicyclic radicals, process for their preparation, compositions thereof and their use as herbicides andplant growth regulators
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WO2004096774A1 (en) * 2003-05-01 2004-11-11 Glaxo Group Limited Acyl isoindoline derivatives and acyl isoquinoline derivatives as anti-viral agents
US8445408B2 (en) 2008-12-30 2013-05-21 Bayer Cropscience Ag Pyrimidine derivatives and their use for controlling undesired plant growth
US11254658B2 (en) 2017-09-13 2022-02-22 Amgen Inc. Bisamide sarcomere activating compounds and uses thereof
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US11780826B2 (en) 2017-09-13 2023-10-10 Amgen Inc. Bisamide sarcomere activating compounds and uses thereof

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