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WO1993018039A1 - Derives de cetal cycliques - Google Patents

Derives de cetal cycliques Download PDF

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Publication number
WO1993018039A1
WO1993018039A1 PCT/EP1993/000486 EP9300486W WO9318039A1 WO 1993018039 A1 WO1993018039 A1 WO 1993018039A1 EP 9300486 W EP9300486 W EP 9300486W WO 9318039 A1 WO9318039 A1 WO 9318039A1
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Prior art keywords
compound
group
formula
compounds
chch
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PCT/EP1993/000486
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English (en)
Inventor
Peter John Sharratt
Nigel Stephen Watson
Panayiotis Alexandrou Procopiou
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Glaxo Group Ltd
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Glaxo Group Ltd
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Priority to JP5515317A priority Critical patent/JPH07504421A/ja
Priority to AU37457/93A priority patent/AU3745793A/en
Priority to EP93906480A priority patent/EP0630378A1/fr
Publication of WO1993018039A1 publication Critical patent/WO1993018039A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D493/00—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system
    • C07D493/02—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system in which the condensed system contains two hetero rings
    • C07D493/08—Bridged systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/06—Antihyperlipidemics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/08—Vasodilators for multiple indications
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
    • C07H19/01—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing oxygen
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H9/00—Compounds containing a hetero ring sharing at least two hetero atoms with a saccharide radical
    • C07H9/02—Compounds containing a hetero ring sharing at least two hetero atoms with a saccharide radical the hetero ring containing only oxygen as ring hetero atoms
    • C07H9/04—Cyclic acetals

Definitions

  • This invention relates to novel compounds having hypocholesterolemic, hypolipidemic and/or antifungal activity, to processes for their preparation, to pharmaceutical compositions containing them and to their use in medicine, particularly in the treatment and/or prevention of atherosclerosis and associated cardiovascular diseases.
  • the invention also relates to novel compounds which are useful as intermediates for the preparation of compounds having hypocholesterolemic, hypolipidemic and/or antifungal activity.
  • High levels of blood cholesterol and blood lipids are conditions which are implicated in the onset of vessel wall disease. Methods for effective reduction of plasma cholesterol levels are therefore of high interest. Cholesterol concentrations can be reduced, for example, by lowering the dietary intake of the sterol, by enhancing its metabolism and elimination or by decreasing its rate of biosynthesis. The most effective approaches to lowering physiological cholesterol level are likely to include inhibition of cholesterol biosynthesis as a component since cholesterol synthesis is subject to feedback regjulation, so that decreases in cholesterol levels tend to be compensated for by increased biosynthesis.
  • the synthesis of squalene from farnesyl diphosphate involves an isolable intermediate, presqualene diphosphate, and the entire synthetic sequence is catalysed by squalene synthase (farnesyldiphosphate: farnesyldiphosphate farnesyltransferase, EC 2.5.1.21), a membrane-bound enzyme.
  • squalene synthase farnesyldiphosphate: farnesyldiphosphate farnesyltransferase, EC 2.5.1.21
  • Agents which act to inhibit the enzyme squalene synthase are therefore potential drugs for the regulation of choiesterogenesis. The use of such agents is attractive as non-steroidal pathways should be minimally affected.
  • R 1 represents a hydroxyl group or a group selected from
  • R 2 represents a hydroxyl group
  • R 3 represents a group selected from
  • R 8 is a hydrogen atom or an acetyl group
  • R 4 and R 5 may each independently represent a hydrogen atom or a methyl group
  • R 1 preferably represents a group
  • R 3 preferably represents a group
  • R 8 is a hydrogen atom or an acetyl group
  • a particularly preferred compound of formula (I) is [1S-[1 ⁇ (4R*,5S*), 3 ⁇ ,4 ⁇ ,5 ⁇ ,6 ⁇ (2E,4R*,6R*),7 ⁇ ]]1-(4-acetyloxy-5-methyl-3-methylene-6-phenylhexyl)-3-(aminomethyl)-4,6,7-trihydroxy-2,8-dioxabicyclo[3.2.1]octane-4,5 -dicarboxylic acid, 6-(4,6-dimethyl-2-octenoate) and salts and protected derivatives thereof.
  • Physiologically acceptable base salts include inorganic base salts such as alkali metal salts (e.g. sodium and potassium salts including the disodium and dipotassium salts), alkaline earth metal salts (e.g. calcium salts) and ammonium salts.
  • Suitable organic base salts include amine salts such as trialkylamine (e.g. triethylamine), dialkylamine (e.g. d ⁇ cyclohexylamine), optionally substituted benzylamine (e.g. p-bromobenzylamine), tris(hydroxymethyl)methylamine salts and amino acid salts (e.g.
  • physiologically acceptable acid addition salts include salts derived from organic or inorganic acids such as hydrochlorides, hydrobromides, sulphates, alkyl- or arylsulphonates (e.g. methanesulphonates or p-toluenesulphonates), phosphates, acetates, citrates, succinates, lactates, tartrates, fumarates and maleates.
  • Other salts which are not physiologically acceptable may be useful in the preparation of compounds of formula (I) and these form a further aspect of the invention.
  • Compounds of the invention have been found to inhibit the enzyme squalene synthase and cholesterol biosynthesis and are therefore of use in medicine, particularly in a variety of conditions where a lowering of the level of blood plasma cholesterol in animals (especially humans) would be beneficial.
  • diseases associated with hypercholesterolemia and hyperlipoproteinemia especially atherosclerosis and cardiovascular diseases (such as cardiac ischaemic diseases, cerebral ischaemic diseases and peripheral arterial disease).
  • Compounds of the invention which inhibit squalene synthase may also be of use in combating fungal infections in animals, including humans. For example, they may be useful in the treatment of systemic infections caused by,. for example Candida (e.g. Candida albicans. Candida qiabrata. Candida parapsilosis and Candida pseudotrop). Crvptococcus neoformans. Aspergillus Sp (e.g. Aspergillus flavus and Aspergillus fumigatus). Coccidioides (e.g. Coccidioides immitis.. Paracoccidioides (e.g. Paracoccidioides brasiliensis.. Histoplasma (e.g.
  • compositions may also be formulated for topical administration in the form of ointments, creams, gels, lotions, shampoos, powders (including spray powders), pessaries, tampons, sprays, dips, aerosols, drops (e.g. eye, ear or nose drops) or pour-ons.
  • 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.
  • Pour-ons may, for example, be formulated for veterinary use in oils containing organic solvents, optionally with formulatory agents, e.g.
  • Pessaries and tampons for vaginal insertion may be formulated using conventional techniques and, where appropriate, may contain an effervescent vehicle. Such compositions may also contain other active ingredients such as corticosteroids, antibiotics or antiparasitics as appropriate.
  • Liquid preparations for intranasal delivery may take the form of solutions or suspensions and may contain conventional excipients such as tonicity adjusting agents, for example, sodium chloride, dextrose or mannitol; preservatives, for example benzalkonium chloride, thiomersal, phenylethyl alcohol; and other formulating agents such as suspending, buffering, stabilising and/or dispersing agents.
  • tonicity adjusting agents for example, sodium chloride, dextrose or mannitol
  • preservatives for example benzalkonium chloride, thiomersal, phenylethyl alcohol
  • other formulating agents such as suspending, buffering, stabilising and/or dispersing agents.
  • Transdermal administration may be affected by the design of a suitable system which promotes adsorption of the active compound through the skin and would typically consist of a base formulation enclosed within an adhesive stick-on patch comprising backing films, membranes and release liners.
  • composition according to the invention may also be formulated as a depot preparation.
  • Such long acting formulations may be administered by implantation (for example subcutaneously or intramuscularly) or by intramuscular injection.
  • a compound 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.
  • each unit will preferably contain 0.001 mg to 1000mg, advantageously 0.01 mg to 400mg, of active ingredient where a compound of the invention is to be administered orally.
  • the daily dosage as employed for adult human treatment will preferably range from 0.001 mg to 5000mg of active ingredient, most preferably from 0.01 mg to 2000mg which may be administered in 1 to 4 daily doses, for example, depending on the route of administration and on the condition of the patient and the disease to be treated.
  • the compound may be administered by intravenous infusion using, for example, up to 50mg/kg/day of the active ingredient.
  • the duration of treatment will be dictated by the rate of response rather than by arbitrary numbers of days.
  • Compounds of the invention which inhibit squalene synthase may also be used in combination with other therapeutic agents, and- the invention thus provides, in a further aspect, a combination comprising a compound of the invention which inhibits squalene synthase together with another therapeutically active agent r such as an inhibitor of 3-hydroxy-3-methylglutaryl coenzyme A (HMG CoA) reductase or another agent which reduces serum cholesterol and/or inhibits cholesterol biosynthesis, for example a bile acid sequestrant or an antihypieripoproteinemic or antihyperlipemic agent such as probucol, gemfibrozil, clofibrate, dextrothyroxine or its sodium salt, colestipol or its hydrochloride salt, cholestyramine,
  • compositions comprising a combination as defined above together with a pharmaceutically acceptable carrier thereof comprise a further aspect of the invention.
  • the individual components of such combinations may be administered either sequentially or simultaneously in separate or combined pharmaceutical formulations.
  • each compound of the invention When a compound of the invention is used in combination with a second therapeutic agent against the same condition the dose of each compound may differ from that when the compound is used alone. Appropriate doses will be readily appreciated by those skilled in the art.
  • a compound of formula (I) or a physiologically acceptable salt thereof or a pharmaceutical composition comprising a compound of formula (I) or a physiologically acceptable salt thereof as defined above for use in therapy, particularly for the treatment of conditions where a lowering of the level of blood plasma cholesterol in animals (especially humans) would be beneficial, or for the treatment of fungal infections in animals (especially humans).
  • a compound of formula (I) or a physiologically acceptable salt thereof or a pharmaceutical composition comprising a compound of formula (I) or a physiologically acceptable salt thereof as defined above for use in the treatment of diseases associated with hypercholesterolemia and/or hyperlipoproteinemia, especially atherosclerosis and cardiovascular diseases (such as cardiac ischaemic diseases, cerebral ischaemic diseases and peripheral arterial disease).
  • diseases associated with hypercholesterolemia and/or hyperlipoproteinemia especially atherosclerosis and cardiovascular diseases (such as cardiac ischaemic diseases, cerebral ischaemic diseases and peripheral arterial disease).
  • a compound of formula (I) or a physiologically acceptable salt thereof in the manufacture of a medicament for the treatment of diseases associated with hypercholesterolemia and/or hyperlipoproteinemia, especially atherosclerosis and cardiovascular diseases (such as cardiac ischaemic diseases, cerebral ischaemic diseases and peripheral arterial disease).
  • a method of treatment of the human or non-human animal body to combat diseases associated with hypercholesterolemia and/or hyperlipoproteinemia especially atherosclerosis and cardiovascular diseases (such as cardiac ischaemic diseases, cerebral ischaemic diseases and peripheral arterial disease) or to combat fungal diseases, which method comprises administering to said body an effective amount of a compound of formula (I) or a physiologically acceptable salt thereof.
  • references herein to treatment extend to prophylaxis as well as the treatment of established conditions or infections.
  • reaction to introduce an alkyl- or arylsulphonyloxy group such as trifluoromethanesulphonyloxy may conveniently be effected by treating a compound of formula (IV) with a suitable anhydride such as trifluoromethanesulphonic anhydride preferably in the presence of an organic base (e.g. 2,4,6-collidine) and in a solvent such as . a halogenated hydrocarbon (e.g. dichloromethane) at a temperature of about -10° to +20°C.
  • a suitable anhydride such as trifluoromethanesulphonic anhydride
  • organic base e.g. 2,4,6-collidine
  • solvent such as a halogenated hydrocarbon (e.g. dichloromethane) at a temperature of about -10° to +20°C.
  • reaction may conveniently be effected by activation of the 3-carboxyl group followed by reduction with a suitable reducing agent such as a borohydride (e.g. sodium borohydride) in a solvent such as dimethylformamide or an ether (e.g. tetrahydrofuran) optionally in the presence of water at a suitable temperature, for example in the range of 0° to 50°C (e.g. about room temperature).
  • a suitable reducing agent such as a borohydride (e.g. sodium borohydride) in a solvent such as dimethylformamide or an ether (e.g. tetrahydrofuran) optionally in the presence of water at a suitable temperature, for example in the range of 0° to 50°C (e.g. about room temperature).
  • a suitable reducing agent such as a borohydride (e.g. sodium borohydride) in a solvent such as dimethylformamide or an ether (e.g. tetrahydrofuran
  • Activation of the 3-carboxyl group may be effected, for example, by conversion to an active ester by reaction with a reagent such as N-hydroxysuccinimide in a suitable solvent such as an ether (e.g. tetrahydrofuran) at a temperature in the range 0°-20°C and in the presence of a carbodiimide [e.g.
  • a suitable solvent such as a halogenated hydrocarbon (e.g. dichloromethane)
  • a non-nucfeophilic organic base such as triethylamine
  • activation may be effected by reaction with oxalyl chloride in dimethylformamide conveniently in the presence of a suitable solvent such as dichloromethane, and if appropriate in admixture with a solvent such as an ether (e.g. tetrahydrofuran) or a nitrile (e.g. acetonitrile) or a mixture thereof conveniently at a temperature of about 0°C.
  • a suitable solvent such as dichloromethane
  • a solvent such as an ether (e.g. tetrahydrofuran) or a nitrile (e.g. acetonitrile) or a mixture thereof conveniently at a temperature of about 0°C.
  • Another process (B) for the preparation of compounds of formula (I) comprises converting a compound of formula (I) to a different compound of formula (I).
  • a compound of formula (I) in which at least one of R 6 and R 7 represents a C 1-4 alkyl group may be prepared by treating a compound of formula (I) in which R 6 and R 7 both represent hydrogen atoms with an appropriate amount of an aldehyde such as formaldehyde and a reducing agent such as a borohydride (e.g. sodium borohydride, sodium cyanoborohydride or sodium triacetoxyborohydride), preferably in an organic solvent such as acetonitrile.
  • a borohydride e.g. sodium borohydride, sodium cyanoborohydride or sodium triacetoxyborohydride
  • a compound of formula (I) in which R 1 represents a hydroxyl group may be prepared by deacylation of a corresponding compound of formula (I) in which R 1 represents an acyloxy group as defined in formula (I) above using the general deacylation conditions described hereinafter.
  • Suitable carboxylic acid protecting groups and hydroxyl protecting groups for use herein include any conventional protecting group, for example as described in 'Protective Groups in Organic Chemistry', Ed. J. F. W. McOmie (Plenum Press, 1973) or 'Protective Groups in Organic Synthesis' by Theodora W. Greene (John Wiley and Sons, 1991).
  • suitable carboxylic acid protecting groups include alkyl groups such as methyl or t-butyl, 2-methoxyethoxymethyl or aralkyl groups such as diphenylmethyl or p-nitrobenzyl.
  • suitable hydroxyl protecting groups include groups such as 2-methoxyethoxymethyl and silyl groups (e.g. t-butyldimethylsilyl).
  • Amino groups may be protected by, for example, a group selected from an aralkoxycarbonyl (e.g. benzyloxycarbonyl) or an alkoxycarbonyl (e.g. t-butoxycarbonyl) group.
  • aralkoxycarbonyl e.g. benzyloxycarbonyl
  • alkoxycarbonyl e.g. t-butoxycarbonyl
  • the protecting groups may be removed using conventional techniques.
  • an alkyl group such as t-butyl may, for example, be removed under anhydrous acid conditions (for example using hydrogen chloride in a solvent such as an ether, e.g. dioxan).
  • a p-nitrobenzyl group may conveniently be removed using zinc metal and hydrochloric acid in a solvent such as an ether (e.g. tetrahydrofuran or aqueous tetrahydrofuran).
  • a diphenylmethyl group or a 2-methoxyethoxymethyl group may conveniently be removed using aqueous formic acid or trifluoroacetic acid.
  • Silyl groups such as t-butyldimethylsilyl may conveniently be removed using fluoride ions.
  • the removal of an amino protecting group as defined hereinabove may be effected by hydrolysis under standard conditions. The conditions described above for the removal of a t-butyl group may also be conveniently used to remove a t-
  • Esterification of carboxylic acid groupings of appropriate intermediate compounds to the corresponding methyl esters groupings may conveniently be effected by treatment with a methylating agent such as a methyl halide (e.g. methyl iodide) or dimethyl sulphate in a suitable organic solvent such as an amide (e.g. dimethylacetamide or preferably dimethylformamide) in the presence of a base such as a bicarbonate (e.g. sodium bicarbonate).
  • the reaction may conveniently be carried out at a temperature ranging from 0° to 100°C, preferably 20° to 30°C.
  • the esterification may be effected by treatment with an ethereal solution of diazomethane in a suitable solvent such as methanol.
  • the esterification may also be effected by treatment with methanol in the presence of a suitable acid such as a mineral acid (e.g. hydrochloric acid) at about room temperature.
  • a suitable acid such as a mineral acid (
  • Conversion of one t-butyl ester into a different t-butyl ester may be carried out by an appropriate deesterification step.
  • the deesterification may be effected under acid conditions, for example by hydrolysis using anhydrous hydrogen chloride in a suitable solvent such as dioxan.
  • Compounds of formula (VII) may be prepared according to the fermentation process described hereinafter or may be prepared from products of the fermentation process by acylation or deacylation at the 6-position as appropriate according to suitable acylation and deacylation methods. Suitable acylation methods are described hereinafter. Deacylation may conveniently be effected by base catalysed hydrolysis using a base such as aqueous sodium hydroxide in a solvent such as an alcohol (e.g. methanol). Alternatively, deacylation of ⁇ , ⁇ -unsaturated esters may be carried out using a hydroxylamine (e.g. N-methylhydroxylamine hydrochloride) optionally in the presence of a suitable base (e.g.
  • a hydroxylamine e.g. N-methylhydroxylamine hydrochloride
  • a suitable base e.g.
  • the fermentation process comprises cultivating a microorganism capable of producing one or more of the appropriate compounds of formula (VII). Thereafter the desired compound from the culture may be isolated and, if desired, acylated or deacylated and/or esterified to the corresponding methyl ester.
  • the products of the fermentation process may also be isolated and purified by the use of a liquid anion exchanger such as LA 2.
  • the cell extracts may be loaded directly without removal of solvent.
  • the extract may either be loaded directly at about pH3 or at about pH8 following filtration of solid impurities.
  • Suitable solvents/eluants for the chromatographic purification/ separation of appropriate compounds of formula (VII) will, of course, depend on the nature of the column type and support.
  • a solvent system comprising ethyl acetate, hexane, methanol and an aqueous acid (e.g. aqueous sulphuric acid) to be particularly suitable.
  • an anion exchanger such as IRA-35 the resin may conveniently be washed with aqueous acetone followed by elution with sulphuric acid in aqueous acetone.
  • the presence of the products of the fermentation process during the extraction/isolation procedures may be monitored by conventional techniques such as h.p.l.c. or UV spectroscopy or by utilising the properties of the compounds.
  • the R 1 group may be introduced by treating a compound of formula (VII) in which R 1 is a hydroxy group with an acid of formula (VIII)
  • the compound of formula (VIII) may conveniently be prepared by hydrolysis of a compound of formula (VII) in which R 1 represents
  • Acid addition salts may be prepared by treating a compound of formula (I) with an appropriate acid in the presence of a suitable solvent such as water and/or a cosolvent such as an alcohol (e.g. methanol) or a nitrile (e.g. acetonitrile).
  • a suitable solvent such as water and/or a cosolvent such as an alcohol (e.g. methanol) or a nitrile (e.g. acetonitrile).
  • Physiologically acceptable salts may also be prepared from other salts, including other physiologically acceptable salts of the compounds of formula (I), using conventional methods.
  • IMI 332962 was grown on agar plates of the following composition: Malt extract (Oxoid L39) 30g
  • Agar (Oxoid No 3) 20g Distilled water to 1 litre
  • the pH of the medium before autoclaving was in the range of 5.3-5.5.
  • the inoculated plates were incubated at 28°C for 14 days.
  • Several 6mm diameter plugs of agar covered with fungal mycelium were cut from the growing edge of the culture and two plugs were transferred into each of several cryotubes containing 1.6ml of sterile distilled water.
  • the tubes were capped and stored at room temperature until required.
  • Seed medium (A) Peptone (Oxoid L34) 10g
  • the pH of the medium was adjusted to 6.3-6.5 with aqueous sodium hydroxide before autoclaving.
  • the flasks of inoculated seed medium were incubated at 25°C on a shaker platform, which rotated at 250rpm with a 50mm diameter orbital motion, for 5 days.
  • Fermentation medium (B) Glycerol 50g
  • the pH of the medium before autoclaving was in the range 6.1 - 6.3.
  • the flasks were incubated as above with shaking for 8 days.
  • the aqueous back extracts were bulked, adjusted to pH 2.8 as above and re-extracted into 2 ⁇ 800ml of ethyl acetate. These extracts were combined and evaporated to dryness to yield a brown oil.
  • This oil was further processed by countercurrent chromatography using an Ito Multi-layer Coil Extractor (P. C. Inc., Potomac, Maryland, USA).
  • the coil used was the standard preparative coil consisting of approximately 70 metres of 2.6mm internal diameter PTFE tubing giving a total volume of about 380ml.
  • the solvent system used was a mixture of ethyl acetate, hexane, methanol and N/100 sulphuric acid (6:5:5:6 by volume).
  • the lower phase was kept stationary.
  • the coil was filled with the lower phase using a Gilson Model 303 pump and a Model 804C Manometric Module (Gilson,
  • the oil (578mg) was further processed by high peformance liquid chromatography (HPLC) using a Gilson autopreparative system composed of 3 Gilson solvent delivery pumps (model 303), an 811 Dynamic mixer and an 802C manometric module.
  • HPLC high peformance liquid chromatography
  • the chromatography was carried out on a Dynamax Microsorb C18 (5 ⁇ m) semi-preparative column (250 ⁇ 10mm).
  • the mobile phase was a gradient composed of acetonitrile and 0.1% v/v formic acid to pH 3.15 with ammonium acetate (1 :3 to 4:1 to 1 :3) pumped at 2.8-5.6ml/min with a run time of 65 minutes.
  • the homogenised seed culture was used at 3% (v/v) to inoculate 120, 50ml aliquots of fermentation medium (B) in 250ml Erlenmeyer flasks. The flasks were incubated with shaking as above for 10 days.
  • the flasks were incubated at 25°C on a shaker platform, which rotated at 250rpm with a 50mm diameter orbital motion, for 4 days.
  • the contents of the seed flasks were pooled and used at 3% (v/v) to inoculate 120 50ml aliquots of fermentation medium (B) in 250 ml Erlenmeyer flasks.
  • the flasks were incubated with shaking as above for 9 days.
  • the ethyl acetate extract was concentrated under reduced pressure to a yellow oil which was dissolved in methanol (10ml). This solution was evaporated to 3ml and applied to a column (32 ⁇ 2.5cm) of ODS-3 (Whatman Partisil Bioprep 40, 75 Angstrom, slurry packed in acetonitrile-water, 20:80). The column was eluted with a stepwise gradient of a mixture of acetonitrile and water, increasing the proportion of acetonitrile as follows : 1 :4, 3:7, 2:3, 1 :1 , 3:2. Fractions were monitored by HPLC and those containing the title compound were evaporated to remove acetonitrile. The resulting aqueous suspensions were pooled and freeze dried overnight to yield the title compound (59mg) as an off-white solid.
  • proton N.m.r- (CDCI 3 ) includes ⁇ 0.05 (s,(CH 3 ) 2 Si), 0.8-0.9 (m,CH 3 and
  • Example 2 A solution of Example 2 (50mg) in dioxan (5ml) was treated with a solution of potassium bicarbonate (14mg) in water (1 ml). The resulting solution was freeze-dried to give the title compound as a white powder (59mg), proton N.m.r.
  • Example 2 A solution of Example 2 (25mg), N-methylhydroxylamine hydrochloride (7mg) and triethylamine (28 ⁇ l, 19mg) in dimethylformamide (1ml) was stirred at room temperature for 5h. It was then evaporated to dryness and the residue was partitioned between ethyl acetate (50ml) and 2M-hydrochloric acid (20ml). The organic phase was washed with acid (20ml) and brine (2 ⁇ 20ml), dried (MgSO 4 ) and evaporated to a white solid.
  • Example 1 A solution of Example 1 (61.3mg) in methanol (1ml) was treated with triethylamine (0.051ml), followed by (aminoiminomethane)sulphonic acid (17mg) and the mixture was stirred at 20° for 18h. The solvent was removed under reduced pressure and the residue was partitioned between ethyl acetate and 2M hydrochloric acid. The organic phase was washed with 2M hydrochloric acid, brine,- dried and evaporated to dryness to give the title compound (62mg) as a glass, proton N.m.r.
  • Example 1 A suspension of Example 1 (20mg) in acetonitrile (1 ml) was stirred at room temperature under nitrogen and treated with aqueous formaldehyde (2 ⁇ l of 40% solution) and sodium triacetoxyborohydride (19mg) to give a clear solution. After 3h 10min further formaldehyde solution was added (4 ⁇ l) and after 6h the reaction solution was evaporated. The residue was stirred with ethyl acetate and filtered. The filtrate was evaporated to a white solid which was purified by preparative HPLC using a Spherisorb ODS-2 (2x25cm) column eluting with 70% acetonitrile in water containing trifluoroacetic acid (1 ml/L), flow rate 15ml/min.
  • Active Ingredient refers to a compound of the present invention, for example a compound described in the Examples hereinabove.
  • Example 1 - Tablets a) Active Ingredient 5.0mg
  • composition 200.0mg
  • the active ingredient, microcrystalline cellulose, lactose and cross-linked polyvinylpyrrolidone are sieved through a 500 micron sieve and blended in a suitable mixer.
  • the magnesium stearate is sieved though a 250 micron sieve and blended with the active blend.
  • the blend is compressed into tablets using suitable punches.
  • the active ingredient and lactose are blended together and granulated with a solution of polyvinylpyrrolidone.
  • the wet mass is dried and milled.
  • the magnesium stearate and cross-linked polyvinylpyrrolidone are screened through a 250 micron sieve and blended with the granule.
  • the resultant blend is filled into hard gelatin capsules of a suitable size.
  • the solution may be provided as a sterile unit dose

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Abstract

L'invention concerne des composés de la formule (I) dans laquelle R1 représente un groupe hydroxyle ou un groupe choisi parmi -OCOCH=ECHCH(CH3)(CH2)3CH3, -OCOCH=ECHC(CH3)=ECHCH(CH3)CH2CH3 ou -OCO-X-CH2CH(CH3)CH2CH3[où X représente -CH=ECHCH(CH3)-, -CH2CH(OH)CH(CH3)-, -CH=ECHC(OH)(CH3)-, -CH2CH(OH)CH2- ou -CH2CH2CH(CH3-]; R2 représente un groupe hydroxyle; R3 représente un groupe choisi parmi (a) (dans laquelle R8 représente un atome d'hydrogène ou un groupe acétyle), -C(CH3)=ECHCH(CH2R9)CH2Ph (où R9 représente un groupe hydrogène ou un groupe hydroxyle), -C(CH2OH)=ZCHCH(CH3CH2Ph, -C(=CH2)CH(OH)CH(CH2OH)CH2Ph, -C(=CH2)CH(NHCOCH3)CH(CH3)CH2Ph, -C(CH2NHCOCH3)=ECHCH(CH3)CH2Ph, et (b); R4 et R5 peuvent représenter chacun indépendamment un atome d'hydrogène ou un groupe méthyle; R6 ainsi que R7 peuvent représenter chacun indépendamment un atome d'hydrogène ou un groupe alkyle C1-4; ou R6 représente un atome d'hydrogène et R7 représente un groupe -C(=Y)NH2 dans lequel Y représente un atome d'oxygène ou de soufre ou NH; ainsi que leurs sels. Ces composés inhibent la synthase de squalène et/ou constituent des intermédiaires de préparation de composés inhibant la synthase de squalène. Des composés de l'invention peuvent être formulés pour une utilisation dans divers états dans lesquels un abaissement de la cholestérolémie chez des animaux présente un caractère bénéfique, et afin de combattre des mycoses chez des animaux.
PCT/EP1993/000486 1992-03-10 1993-03-02 Derives de cetal cycliques Ceased WO1993018039A1 (fr)

Priority Applications (3)

Application Number Priority Date Filing Date Title
JP5515317A JPH07504421A (ja) 1992-03-10 1993-03-02 環状ケタール誘導体
AU37457/93A AU3745793A (en) 1992-03-10 1993-03-02 Cyclic ketal derivatives
EP93906480A EP0630378A1 (fr) 1992-03-10 1993-03-02 Derives de cetal cycliques

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
GB9205140.8 1992-03-10
GB929205140A GB9205140D0 (en) 1992-03-10 1992-03-10 Chemical compounds

Publications (1)

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WO1993018039A1 true WO1993018039A1 (fr) 1993-09-16

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PCT/EP1993/000486 Ceased WO1993018039A1 (fr) 1992-03-10 1993-03-02 Derives de cetal cycliques

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EP (1) EP0630378A1 (fr)
JP (1) JPH07504421A (fr)
GB (1) GB9205140D0 (fr)
WO (1) WO1993018039A1 (fr)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5468771A (en) * 1991-08-07 1995-11-21 Merck & Co., Inc. Cholesterol lowering compound
US5506262A (en) * 1991-05-10 1996-04-09 Merck & Co., Inc. Cholesterol lowering compounds

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0448393A1 (fr) * 1990-03-21 1991-09-25 Merck & Co. Inc. Antihypercholestérolémiques
EP0450812A1 (fr) * 1990-03-21 1991-10-09 Merck & Co. Inc. Antihypercholesterolemiques
EP0494622A1 (fr) * 1991-01-09 1992-07-15 Glaxo Group Limited Dérivés de cétals cycliques pontés
WO1992012156A1 (fr) * 1991-01-09 1992-07-23 Glaxo Group Limited Derives cycliques pontes d'acetal
EP0497091A1 (fr) * 1991-01-09 1992-08-05 Glaxo Group Limited Dérivés de cétals cycliques pontés

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0448393A1 (fr) * 1990-03-21 1991-09-25 Merck & Co. Inc. Antihypercholestérolémiques
EP0450812A1 (fr) * 1990-03-21 1991-10-09 Merck & Co. Inc. Antihypercholesterolemiques
EP0494622A1 (fr) * 1991-01-09 1992-07-15 Glaxo Group Limited Dérivés de cétals cycliques pontés
WO1992012156A1 (fr) * 1991-01-09 1992-07-23 Glaxo Group Limited Derives cycliques pontes d'acetal
EP0497091A1 (fr) * 1991-01-09 1992-08-05 Glaxo Group Limited Dérivés de cétals cycliques pontés

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5506262A (en) * 1991-05-10 1996-04-09 Merck & Co., Inc. Cholesterol lowering compounds
US5468771A (en) * 1991-08-07 1995-11-21 Merck & Co., Inc. Cholesterol lowering compound

Also Published As

Publication number Publication date
JPH07504421A (ja) 1995-05-18
GB9205140D0 (en) 1992-04-22
EP0630378A1 (fr) 1994-12-28

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