+

WO1998016526A1 - Tetrahydro-6h-pyrazino[1,2-b]isoquilone 1,4-diones en tant qu'inhibiteurs de l'apoproteine b-100 - Google Patents

Tetrahydro-6h-pyrazino[1,2-b]isoquilone 1,4-diones en tant qu'inhibiteurs de l'apoproteine b-100 Download PDF

Info

Publication number
WO1998016526A1
WO1998016526A1 PCT/EP1997/005636 EP9705636W WO9816526A1 WO 1998016526 A1 WO1998016526 A1 WO 1998016526A1 EP 9705636 W EP9705636 W EP 9705636W WO 9816526 A1 WO9816526 A1 WO 9816526A1
Authority
WO
WIPO (PCT)
Prior art keywords
tetrahydro
pyrazino
dione
isoquinoline
methoxy
Prior art date
Application number
PCT/EP1997/005636
Other languages
English (en)
Inventor
Richard Frederic Labaudiniere
Paul Martres
Nerina Dodic
Bernard Andre Dumaitre
Original Assignee
Glaxo Group Limited
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority claimed from GBGB9621576.9A external-priority patent/GB9621576D0/en
Application filed by Glaxo Group Limited filed Critical Glaxo Group Limited
Priority to AU49471/97A priority Critical patent/AU4947197A/en
Publication of WO1998016526A1 publication Critical patent/WO1998016526A1/fr

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems

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.
  • 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.
  • LDL-C low density lipoprotein-cholesterol
  • 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 inhibit production of ApoB-100 have been described, for example, in DE19602989 and EP765878.
  • Tetrahydro-6H-pyrazino[1 ,2- b]isoquinoline-1 ,4-diones have been described previously in the literature, for example, in WO97/17344 and Eur. J. Biochem. (1997), 247 (1), 66-73.
  • R° represents C 3-8 cycloalkyl, optionally substituted by C 1-4 alkyl
  • R 1 represents hydrogen, halogen, NO 2 , CN, CHO, NHS0 2 R 3 , NR 4 R 5 , NR 6 COR 7 , a 5-membered heteroaromatic ring optionally substituted by C ⁇ alkyl, or a group X-Z ;
  • R 2 represents hydrogen or a prop-2-enyl group;
  • Y represents methylene or difluoromethylene
  • X represents a C 1-6 alkylene, C 2-6 alkenylene, C 3 . 6 alkynylene or an N-linked imine group
  • Z represents hydrogen, C 1-4 alkoxy, C0 2 R 6 , or an optionally substituted 5- or 6- membered heteroaromatic or phenyl group, where optional substitution is selected from a group consisting of C0 2 R 6 , NR 4 R 5 , and N0 2 ;
  • Ar represents a phenyl or 5- or 6- membered heteroaromatic group optionally substituted by one or more groups selected from halogen, cyano, C 1-4 alkyl, C 1-4 alkoxy, CF 3 , S(0) n R 5 , NHS0 2 R 5 , N0 2 , NR 4 R 5 , NR 6 COR 8 , C0 2 R 6 , CONR 4 R 5 ,
  • R 3 represents C ⁇ alkyl or trifluoromethyl
  • R 4 and R 5 independently represent hydrogen or C 1-4 alkyl, or together R 4 and R 5 form a 3- to 6- membered cycloalkylamine ring;
  • R 6 and R 8 independently represent hydrogen or C 1-4 alkyl
  • R 7 represents C 1-4 alkyl or (CH 2 ) m E, where m is 0 or 1 and E is a 5- or 6- membered heteroaromatic group; n is an integer from 0-3; and pharmaceutically acceptable salts and solvates 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.
  • alkyl and alkylene groups include both straight and branched chain saturated hydrocarbon groups.
  • alkyl groups include methyl, ethyl, propyl and iso-butyl groups
  • alkylene groups include methylene and ethylene groups.
  • alkenyl and alkenylene groups include both straight and branched chain saturated hydrocarbon groups containing a double bond.
  • alkenylene groups include ethenylene, propenylene groups.
  • alynyl and alkynylene groups include both straight and branched chain hydrocarbon groups with at least one triple bond. Examples of such groups include ethynylene and propynylene groups.
  • C 3 . 8 cycloalkyl includes bridged cycloalkyl groups e.g. norbornyl, as well as unbridged cycloalkyl groups, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl.
  • a 5-membered heteroaromatic ring includes rings containing one or more heteroatoms selected from nitrogen, sulphur and oxygen atoms.
  • heteroatoms selected from nitrogen, sulphur and oxygen atoms. Examples of such groups include thiophene, thiazole, thiphene, pyrrole, pyrazole, imidazole and furan.
  • a 6-membered heteroaromatic ring includes rings containing one or more nitrogen atoms.
  • An example of such a group is pyridyl.
  • a 5- membered heterocyclic group includes aromatic and non-aromatic rings containing one or more heteroatoms selected from nitrogen, sulphur and oxygen atoms and includes groups such as thiadiazole and thiazole.
  • a halogen atom may be a fluorine, chlorine, bromine or iodine atom.
  • the compounds of formula (I) contain at least one chiral centre (shown as * in formula (I)).
  • the compounds of formula (I) are preferably in their (R) form at centre * .
  • R° is suitably cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl, optionally substituted by C 1-4 alkyl, e.g. methyl.
  • R° is preferably cyclohexyl or cyclopentyl.
  • E is suitably a pyridyl group.
  • R 1 represents a 5-membered heteroaromatic ring
  • R 1 is suitably a furyl, thienyl, or a pyrrolyl group, optionally substituted by methyl.
  • R 1 represents an X-Z group
  • X is suitably a C 1-6 alkylene, e.g. methylene or ethylene, C 2 . 6 alkenylene, e.g. ethenylene or prop-2-enylene or an N-linked imino group.
  • X is an N-linked imino group, this is suitably substituted by pyridyl, or a phenyl group substituted by a dimethylamino group.
  • X is preferably a C ⁇ e alkylene, e.g. methylene or ethylene or C 2 . 6 alkenylene, e.g. ethenylene or prop-2-enylene.
  • R 1 represents an X-Z group
  • Z is suitably hydrogen, methoxy, CO 2 Me, N0 2 or an optionally substituted phenyl or 5- or 6-membered hetroaromatic e.g. pyridyl or imidazolyl, where optional substitution is suitably by C0 2 Me or NMe 2 .
  • Z is preferably hydrogen.
  • R a represents 5-membered hetroaromatic ring optionally substituted by C-,, 4 alkyl, this is suitably furyl, thienyl, pyrrolyl, pyrazolyl or thiazolyl.
  • R 1 is suitably hydrogen, halogen, e.g bromo, chloro or iodo, C ⁇ alkyl, e.g. methyl, ethyl or n-propyl, C 2 . 6 alkenyl, e.g. ethenyl or prop-2-enyl, N0 2 , CN, CHO, NR R 5 , e.g. NH 2 , NHS0 2 R 3 , e.g. NHS0 2 CH 3 , CH 2 thienyl, thienyl, thiazolyl, N-methylpyrrolyl, or NHCOR 7 , e.g. NHCOMe or NHCOpyridyl.
  • R 1 is a prop-2-enyl or ethyl group.
  • R 1 is a prop-2-enyl group.
  • R 1 is a prop-2-enyl group.
  • R is preferably hydrogen.
  • Ar is selected from a phenyl, pyridyl, pyrazinyl, pyrazolyl, pyrrolyl, thiazolyl or thienyl group optionally substituted by one or more groups selected from cyano, halogen, e.g. fluorine, bromine or chlorine, C 1-4 alkyl, e.g. methyl or tert-butyl, methoxy, N0 2 , a 5-membered heterocyclic group, e.g. thiazole or thiadiazole, or SO 2 CF 3 .
  • Ar is a phenyl or pyridyl group optionally substituted by a cyano group.
  • R° represents C 3-8 cycloalkyl, optionally substituted by C ⁇ alkyl
  • R 1 represents hydrogen, halogen, C 1-6 alkyl, C 2-6 alkenyl, C 3 . 6 alkynyl, or a 5- membered heteroaromatic ring;
  • Y represents methylene or difluoromethylene
  • Ar represents a phenyl, pyridine, pyrimidine or pyrazine ring optionally substituted by one or more groups selected from halogen, cyano, C ⁇ alkyl, trifluoromethyl, nitro, trifluoromethoxy, trifluoromethylsulfonyl, and a 5- membered heterocyclic group containing one or more heteroatoms selected from nitrogen, sulphur and oxygen atoms; and pharmaceutically acceptable salts and solvates thereof.
  • a further preferred sub-class of compounds of formula (I) are those wherein R° is cyclohexyl or cyclopentyl optionally substituted by a methyl group, R 1 is ethyl or prop-2-enyl, Y is methylene, and Ar is a phenyl or pyridyl group optionally substituted by a cyano group.
  • Suitable compounds according to the invention include: [11a-R]-8-[(5-cyanopyridin-2-yl)difIuoromethoxy]-2-cyclohexyl-2,3,11 ,11a- tetrahydro-6H-pyrazino[1 ,2-b]isoquinoline-1 ,4-dione;
  • Preferred compounds of the invention include:
  • 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, most particularly in the treatment of conditions resulting from elevated circulating levels of apoB-100.
  • a method for the treatment of a mammal comprising administration of an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.
  • reference to treatment is intended to include prophylaxis as well as the alleviation of established symptoms.
  • Compounds of formula (I) may be administered as the raw chemical but the active ingredient is preferably presented as a pharmaceutical formulation.
  • the invention also provides a pharmaceutical composition which comprises at least one compound of formula (I) or a pharmaceutically acceptable salt thereof and formulated for administration by any convenient route.
  • 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 with an HMG CoA reductase inhibitor or a bile acid transport inhibitor.
  • Compounds of formula (I) where R represents hydrogen, and salts and solvates thereof, may be prepared by the general methods outlined hereafter. In the following description, the groups R°, R 1 , R 2 ,Y and Ar are as previously defined for compounds of formula (I).
  • a compound of formula (I) may be prepared by reacting a compound of formula (II)
  • L is a suitable leaving group such as a bromine or chlorine atom.
  • the reaction conveniently takes place in the presence of a suitable base such as cesium or potassium carbonate in a solvent such as N,N-dimethylformamide or acetone.
  • a compound of formula (II) where R 1 or R 2 represent a prop-2-enyl group may be prepared from a compound of formula (lla)
  • a compound of formula (lla) may be prepared from a compound of formula (II) where R 1 and R 2 represent hydrogen, by alkylation using the corresponding prop-2-enyl halide, suitably the bromide, with a base such as cesium carbonate, in a suitable solvent such as acetone.
  • a compound of formula (lla) may be prepared from a compound of formula (lie)
  • a compound of formula (II) where R 1 is a halogen may be prepared from a compound of formula (II) where R 1 is hydrogen, using a suitable halogenating agent such as the N-halo-succinimide in a suitable solvent such as N,N- dimethylformamide.
  • a compound of formula (II) where R 1 is nitro may be prepared by nitration of a compound of formula (II) where R 1 is hydrogen, using a suitable nitrating agent such as nitric acid.
  • Compounds of formula (II) where R 1 is N-linked may be prepared from a compound of formula (II) where R 1 is nitro by normal methods.
  • L' is a suitable protecting group, e.g. tert-butyldimethylsilyl, suitably using tetrakis (triphenyl phosphine) palladium (0) and the trialkylstannyl or boronic acid derivative of R 1 in a solvent such as N,N-dimethylformamide, followed by removal of the protecting group under standard conditions.
  • protecting group e.g. tert-butyldimethylsilyl
  • Compounds of formula (lib) may be prepared from compounds of formula (II) where R 1 is hydrogen by methods outlined above.
  • R 9 is an alkyl protection group for a carboxylic acid e.g methyl or ethyl ester.
  • the reaction is conveniently carried out in ethanol at elevated temperature.
  • R 9 is previously defined, using, suitably, chloroacetyl chloride and sodium bicarbonate or an organic base in an organic solvent at elevated temperature.
  • Compounds of formula (VI) are known or are available by standard methods.
  • the reaction is conveniently carried out using a suitable halogenating agent and radical initiator in carbon tetrachloride.
  • suitable brominating agents include 1 ,3- dibromo-5,5-dimethylhydantoin or N-bromo-succinimide and radical initiators include benzoyl peroxide, azo-isobutyronitrile and light.
  • Ar- ⁇ H ( Vl ) by reacting with diethylaminosulfurtrifluoride in a halogenated solvent such as carbon tetrachloride at room temperature.
  • Ar- CH 3 ( ⁇ x ) by treatment with iodine in a solvent such as dimethyl sulfoxide at elevated temperature followed by quenching with aqueous base.
  • a compound of formula (I) may be prepared from another compound of formula (I) employing suitable conditions and reagents as herein described.
  • the protecting groups used in the preparation of compounds of formula (I) may be used in conventional manner. See for example 'Protective Groups in Organic Chemistry' Ed. J. F. W. McOmie (Plenum Press 1973) or 'Protective Groups in Organic Synthesis' by Theodora W Greene and P M G Wuts (John Wiley and Sons 1991).
  • a compound of formula (I) as a salt for example a pharmaceutically acceptable salt, this may be achieved by reacting the compound of formula (I) in the form of the free base with an appropriate amount of suitable acid and in a suitable solvent such as an alcohol (e.g. ethanol or methanol), an ester (e.g. ethyl acetate) or an ether (e.g diethyl ether or tetrahydrofuran).
  • a suitable solvent such as an alcohol (e.g. ethanol or methanol), an ester (e.g. ethyl acetate) or an ether (e.g diethyl
  • 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.
  • a specific enantiomer of a compound of general formula (I) when required, this may be obtained for example by resolution of a corresponding enantiomeric mixture of a compound of formula (I) using conventional methods.
  • an appropriate optically active acid may be used to form salts with the enantiomeric mixture of a compound of general formula (I).
  • the resulting mixture of isomeric salts may be separated, for example, by fractional crystallisation into the diastereoisomeric salts from which the required enantiomer of a compound of general formula (I) may be isolated by conversion into the required free base.
  • enantiomers of a compound of general formula (I) may be synthesised from the appropriate optically active intermediates using any of the general processes described herein.
  • [11a-R]-7-chloro-2cyclopentyl-8-hydroxy-2,3,11 ,11a-tetrahydro-6H- pyrazino[1 ,2b]isoquinoline-1 ,4dione as white crystals (130 mg) mp 238-240°C from [11a-R]-2-cyciopentyl-8-hydroxy-2,3,11 ,11a-tetrahydro-6H- pyrazino[1 ,2b]isoquinoline-1 ,4-dione (300 mg) using N-chlorosuccinimide instead of N-bromosuccinimide.
  • a mixture of [11a-R]-2-cyclopentyl-8-hydroxy-7-iodo-2,3,11 ,11a-tetrahydro-6H- pyrazino[1 ,2b] isoquinoline-1 ,4-dione (2,4 g), potassium cyanide (0,44 g), 18-C- 6 (1 ,79 g) and tetrakis (triphenylphosphine) palladium [0] in tetrahydrofuran (200 ml) was heated under reflux ovemight and then filtered on a celite pad.
  • [11a-R]-2-cyclopentyl-8-(prop-2-enyloxy)-2,3,11 ,11a-tetrahydro-6H- pyrazino[1 ,2b]isoquinolin-1 ,4-dione 50 g was heated at 240°C for 10 minutes. The mixture was cooled to room temperature and [11a-R]-2-cyciopentyl-8- hydroxy-7-(prop-2-enyl)-2,3,11 ,11a-tetrahydro-6H-pyrazino[1 ,2b]isoquinoline-
  • [11 a-R]-2-cyclopentyl-8-hydroxy-7-(prop-2-enyl) -2,3,11 ,11a- tetrahydro-6H-pyrazino[1 ,2b]isoquinoline-1 ,4-dione (10g) in acetone (100 ml) was added cesium carbonate (11 ,5 g) and 4-bromotoluonitrile (6,34 g).
  • [11a-R]-2-cyclopentyl -8-hydroxy-7-(prop-2-enyl)- 2,3,11 ,11a- tetrahydro-6H-pyrazino[1 ,2b]isoquinoline-1 ,4-d ⁇ one (2 g) in acetone (30 ml) was added cesium carbonate (5.75 g) and 2-chloromethyl pyridine hydrochloride (1 ,06 g).
  • Methylboronic acid (0,24 g), sodium bicarbonate (0,17 g) and tetrakis (triphenylphosphine) palladium [0] (0,05 g) were added and the mixture was stirred 4 hours at 120°C.
  • the mixture was filtered on a celite pad, and the filtrate concentrated in vacuo.
  • the residue was treated with water and extracted with dichloromethane.
  • the organic layer was dried (Na 2 S0 4 ) and concentrated under reduced pressure to leave a solid residue which was washed with acetonitrile and filtered.
  • a mixture of [11a-R]-8-[(4-cyanophenyl)methoxy]-2-cyclopentyl-7-[2-(pyridin-2- yl)ethenyl]-2,3,11 ,11 a-tetrahydro-6H-pyrazino[1 ,2b] isoquinoiine-1 ,4-dione (0,23 g) and palladium/C (0,05 g) in ethanol (50 ml) was hydrogenated at room temperature.
  • HepG2 cells are seeded in Eagle medium containing 10% FCS at a density of 35 000 cells/well in 96-well plates. After 4 days, confluent cells are incubated with compounds for 24 hours in RPMI medium containing 1% FCS. Compounds are dissolved in DMSO and tested onto cells from 25 ⁇ M to 0,32 nM. Production of apoB-100 and apoA-1 (used as a selectivity control) in the supernatants is quantified by specific ELISAs using antibodies from Biodesign International. Inhibition of apoB-100 and apoA-1 secretion by compounds is calculated taking untreated cells as controls, and IC 50 of each compound is 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
  • 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 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).
  • 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 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).
  • 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.
  • 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.
  • 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).
  • 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.
  • Witepsoi H15 - Dynamit NoBel 1770 2020 One-fifth of the Witepsoi 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 Witepsoi 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

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)

Abstract

La présente invention a trait à des composés de la formule suivante (I): dans lesquels R0 représente un C¿3-8? cycloalkyle, éventuellement substitué par un C1-4 alkyle; R?1¿ représente un hydrogène, un halogène, NO¿2?, CN, CHO, NHSO2R?3, NR4R5, NR6COR7¿, un noyau hétéroaromatique doté de 5 chaînons éventuellement substitué par un C¿1-4? alkyle, ou un groupe X-Z; R?2¿ représente un hydrogène ou un groupe prop-2-ényle; Y représente un méthylène ou un difluorométhylène; X représente un C¿1-6? alkylène, un C2-6 alkénylène, un C3-6 alkynylène ou un groupe imine à liaison en N; Z représente un hydrogène, un C1-4 alkoxy, CO2R?6¿, un groupe hétéroaromatique doté de 5 ou 6 chaînons éventuellement substitué ou un groupe phényle, dans lequel une substitution éventuelle est sélectionnée dans un groupe constitué par CO¿2?R?6, NR4R5¿, et NO¿2?; Ar représente un phényle ou un groupe hétéroaromatique doté de 5 ou 6 chaînons éventuellement substitué par un ou plusieurs groupes sélectionnés parmi un halogène, un cyano, un C1-4 alkyle, un C1-4 alkoxy, CF3, S(O)nR?5¿, NHSO¿2R?5, NO2, NR?4R5, NR6COR8, CO¿2R?6, CONR4R5, OCF¿3, et un groupe hétérocyclique doté de 5 chaînons éventuellement substitué par un C1-4 alkyle; R3 représente un C¿1-4? alkyle ou trifluorométhyle; R?4 et R5¿ représentent indépendamment un hydrogène ou un C¿1-4? alkyle, ou R?4 et R5¿ forment ensemble un noyau cycloalkylamine doté de 3 à 6 chaînons; R6 et R8 représentent indépendamment un hydrogène ou un C¿1-4? alkyle; R?7¿ représente un C¿1-4? alkyle ou (CH2)mE, où m est égal à 0 ou 1, et E est un groupe hétéroaromatique doté de 5 ou 6 chaînons; n est un nombre entier compris entre 0 et 3; l'invention a également trait à des dérivés, pharmaceutiquement acceptables, de ces composés, à leurs procédés de préparation, et à leur utilisation dans le traitement d'états liés à la régulation d'ApoB-100.
PCT/EP1997/005636 1996-10-16 1997-10-15 Tetrahydro-6h-pyrazino[1,2-b]isoquilone 1,4-diones en tant qu'inhibiteurs de l'apoproteine b-100 WO1998016526A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU49471/97A AU4947197A (en) 1996-10-16 1997-10-15 Tetrahydro-6h-pyrazino{1,2-b}isoquinoline 1,4-diones as apoprotein b-100 inhibitors

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
GB9621576.9 1996-10-16
GBGB9621576.9A GB9621576D0 (en) 1996-10-16 1996-10-16 Chemical compounds
GBGB9711966.3A GB9711966D0 (en) 1996-10-16 1997-06-10 Chemical compounds
GB9711966.3 1997-06-10

Publications (1)

Publication Number Publication Date
WO1998016526A1 true WO1998016526A1 (fr) 1998-04-23

Family

ID=26310241

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/EP1997/005636 WO1998016526A1 (fr) 1996-10-16 1997-10-15 Tetrahydro-6h-pyrazino[1,2-b]isoquilone 1,4-diones en tant qu'inhibiteurs de l'apoproteine b-100

Country Status (3)

Country Link
AU (1) AU4947197A (fr)
HR (1) HRP970555A2 (fr)
WO (1) WO1998016526A1 (fr)

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6608193B2 (en) * 2001-12-21 2003-08-19 The Procter & Gamble Company Methods for synthesis of amino-tetrahydroisoquinoline ring compounds
RU2527526C2 (ru) * 2009-06-25 2014-09-10 Эверест Байосайенсиз Инк. Индолил-замещенные пиразино-хинолины и их применение для лечения рака
JP2015067547A (ja) * 2013-09-27 2015-04-13 公益財団法人相模中央化学研究所 （ブロモジフルオロメチル）ベンゼン誘導体及びそれらの製造方法
CN114728959A (zh) * 2019-11-12 2022-07-08 豪夫迈·罗氏有限公司 用于治疗自身免疫性疾病的氢吡嗪并[1,2-b]异喹啉化合物

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1996024588A1 (fr) * 1995-02-11 1996-08-15 Astra Aktiebolag Isothiourees bicycliques utiles en therapie
WO1997017344A1 (fr) * 1995-11-07 1997-05-15 Astra Aktiebolag Derives d'amidine et d'isothio-uree en tant qu'inhibiteurs de la synthase de l'oxyde nitrique

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1996024588A1 (fr) * 1995-02-11 1996-08-15 Astra Aktiebolag Isothiourees bicycliques utiles en therapie
WO1997017344A1 (fr) * 1995-11-07 1997-05-15 Astra Aktiebolag Derives d'amidine et d'isothio-uree en tant qu'inhibiteurs de la synthase de l'oxyde nitrique

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
T. FUKUYAMA ET AL.: "Synthesis of unsymmetrically substituted 2,5-piperazinediones: regioselective alkylation of piperazinedione derivatives", TETRAHEDRON LETT., vol. 26, no. 25, 1985, pages 2955 - 2958, XP002054450 *

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6608193B2 (en) * 2001-12-21 2003-08-19 The Procter & Gamble Company Methods for synthesis of amino-tetrahydroisoquinoline ring compounds
RU2527526C2 (ru) * 2009-06-25 2014-09-10 Эверест Байосайенсиз Инк. Индолил-замещенные пиразино-хинолины и их применение для лечения рака
US9066947B2 (en) 2009-06-25 2015-06-30 Everest Biosciences, Inc. Indolyl-substituted pyrazino[1,2-b]isoquinolines for cancer treatment
JP2015067547A (ja) * 2013-09-27 2015-04-13 公益財団法人相模中央化学研究所 （ブロモジフルオロメチル）ベンゼン誘導体及びそれらの製造方法
CN114728959A (zh) * 2019-11-12 2022-07-08 豪夫迈·罗氏有限公司 用于治疗自身免疫性疾病的氢吡嗪并[1,2-b]异喹啉化合物

Also Published As

Publication number Publication date
AU4947197A (en) 1998-05-11
HRP970555A2 (en) 1998-08-31

Similar Documents

Publication Publication Date Title
DE69030206T2 (de) Pyrazolopyridinverbindungen und Verfahren zu ihrer Herstellung
US7452899B2 (en) Gamma-secretase inhibitors
DE69331888T2 (de) Bicyclische Pyridinderivate, Verfahren zu ihrer Herstellung, Zwischenprodukte, ihre Anwendung als Arzneimittel und diese enthaltende pharmazeutische Zusammensetzungen
EP0430709A2 (fr) Dérivés de benzothiophène
US5840732A (en) Imidazopyridine or imidazopyrimidine compounds, their production and use
SK31793A3 (en) Pyridine and pyridine n-oxide derivatives of diaryl methyl piperidines and piperazines and compositions and methods of use thereof
CS277445B6 (en) Novel heteroazepines, process of their preparation and pharmaceutical preparations comprising them
WO1991009029A1 (fr) Benzimidazoles chloro-substitues therapeutiquement actifs, leurs procedes de preparation et leur utilisation
KR20170012404A (ko) 히스톤 데아세틸라제 억제제 및 그것의 조성물 및 사용 방법
GB2196962A (en) Substituted 2-benzyl-mercapto-imidazoles and analogs useful as anti-inflammatory agents
EP0586560A1 (fr) Nouveaux composes de benzopyrido piperidylidene, compositions, procedes de preparation et d'utilisation
EP0503471A1 (fr) Hétrazépines acylaminosubstituées
WO1996020936A1 (fr) Nouveaux derives de thiazolidin-4-one
US5310927A (en) Benzofuran derivatives
EP2968207A1 (fr) Inhibiteurs d'histone désacétylase, et compositions et méthodes d'utilisation de ceux-ci
JPS63139167A (ja) ジヒドロピリジン抗アレルギー及び抗炎症剤
JPH02209876A (ja) イミダゾール誘導体
KR940006633B1 (ko) 광학 활성 티에노트리아졸로디아제핀 화합물
US6093714A (en) Tricyclic benzazepine compounds
JPH06503083A (ja) ベンゾフラン及びベンゾチオフェン誘導体
EP0475204A2 (fr) Amides hétéroazépinoides
WO1998016526A1 (fr) Tetrahydro-6h-pyrazino[1,2-b]isoquilone 1,4-diones en tant qu'inhibiteurs de l'apoproteine b-100
KR870001681B1 (ko) 히단토인 유도체의 제조방법
US5212186A (en) Cardioactive pyrrolobenzimidazoles
KR20010031839A (ko) 한 개의 질소원자를 함유하는 5, 6 또는 7원헤테로사이클릭 환으로 치환된 이미다조일알킬

Legal Events

Date Code Title Description
AK Designated states

Kind code of ref document: A1

Designated state(s): AL AM AT AU AZ BA BB BG BR BY CA CH CN CU CZ DE DK EE ES FI GB GE GH HU ID IL IS JP KE KG KP KR KZ LC LK LR LS LT LU LV MD MG MK MN MW MX NO NZ PL PT RO RU SD SE SG SI SK SL TJ TM TR TT UA UG US UZ VN YU ZW AM AZ BY KG KZ MD RU TJ TM

AL Designated countries for regional patents

Kind code of ref document: A1

Designated state(s): GH KE LS MW SD SZ UG ZW AT BE CH DE DK ES FI FR GB GR IE IT LU MC

DFPE Request for preliminary examination filed prior to expiration of 19th month from priority date (pct application filed before 20040101)
121 Ep: the epo has been informed by wipo that ep was designated in this application
REG Reference to national code

Ref country code: DE

Ref legal event code: 8642

122 Ep: pct application non-entry in european phase
NENP Non-entry into the national phase

Ref country code: CA

点击 这是indexloc提供的php浏览器服务，不要输入任何密码和下载