Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
  • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
  • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P11/00—Drugs for disorders of the respiratory system
• • 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
  • 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
  • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
  • A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P9/00—Drugs for disorders of the cardiovascular system
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P9/00—Drugs for disorders of the cardiovascular system
  • A61P9/08—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
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
  • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
  • C07D233/66—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
  • C07D233/84—Sulfur atoms
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
  • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
  • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
• • 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

• the present invention relates to new therapeutically useful imidazole derivatives, to a process for their preparation, to pharmaceutical compositions containing them, and to their use as pharmaceuticals.
• the imidazole derivatives of the present invention are the compounds of the general formula:-
• A-S(0) k -Q-Z I wherein A represents a group of general formula II shown hereinafter in the present specification, wherein the symbols R may be the same or different and each represents hydrogen or one or more substituents, for example substituents selected from halogen atoms, and straight- or branched-chain alkyl and alkoxy groups containing from 1 to about 6 carbon atoms, and trifluoromethyl groups; k represents 0, 1 or 2;
• Q represents a methylene group or alkylene chain containing from 2 to about 5 carbon atoms, optionally substituted with one or more alkyl groups containing from 1 to about 4 carbon atoms;
• Z represents a hydrogen atom; a hydroxy group; an alkoxy group optionally substituted by, for example, an alkoxy or alkoxyalkoxy group; an aryl, for example phenyl, group optionally substituted by, for example. one or more alkoxy, e.g. methoxy, groups; a dialkyl- amino group wherein the alkyl groups may be the same or different and each is straight- or branched-chain and contains from 1 to about 4 carbon atoms; a group of the formula -NHR 2, wherein R2 represents an acyl group, for example a straight- or branched-chain alkanoyl group containing up to about 6 carbon atoms and which may be
• R4 represents a straight- or branched-chain alkyl group containing from
• R 5 represents a 5- or 6-membered nitrogen-containing heterocyclic ring which may also contain an oxygen atom, optionally substituted by one or more substituents selected from, for example, straight- or branched-chain alkyl groups containing from 1 to about
• R represents a straight- or branched-chain alkenyl or alkoxy group containing up to
• R represents a straight- or branched-chain alkyl group containing from 1 to about 4 carbon atoms, optionally substituted by one or more substituents selected from, for example, hydroxy groups; a group of the general formula III shown hereinafter, wherein m is 0 or 1, n is 0 or 1 and p is
• R each represent a hydrogen atom, or a methyl group substituted by a straight- or branched-chain alkoxyy or alkanoyloxy group containing up to about 6 carbon atoms; a group of the general formula IV shown hereinafter wherein m is as hereinbefore defined; a group of the general formula V shown hereinafter wherein R 9 represents a hydrogen atom or a straight- or branched-chain alkyl group containing from 1 to about 4 carbon atoms and R represents a hydrogen atom or a hydroxy group or a straight- or branched-chain alkyl group containing from 1 to about 4 carbon atoms; or a group of the general formula VI
• R 9 shown hereinafter wherein R is as hereinbefore defined; a group of the general formula VII shown hereinafter wherein R 9 and R10 are as hereinbefore defined, the symbols R 11 may be the same or different and each represents a hydrogen atom or a hydroxy group and R12 represents a hydrogen atom or a straight- or branched-chain alkyl group containing from
• alkyl groups and moieties are straight- or branched- chain and contain from 1 to about 6 carbon atoms.
• the symbols R may be different or, preferably, the same and each represents a hydrogen or halogen, e.g. chlorine or fluorine, atom or a straight- or branched-chain alkyl group containing from 1 to 6, preferably from 1 to 4, carbon atoms, or a straight- or branched-chain alkoxy group containing from 1 to 3 carbon atoms, e.g. methoxy, or a trifluoro ethyl group; (ii) k represents 0;
• Z represents a hydrogen atom; a hydroxy grou an alkoxy, e.g. ethoxy, group optionally substituted by, for example, an alkoxyalkoxy, e.g. methoxyethoxy, group; an aryl, for example phenyl, group optionally substituted by, for example, one or more alkoxy, e.g. methoxy, groups; a dialkylamino group wherein the alkyl groups may be the same or different and each is straight- or branched-chain and contains from 1 to 4, preferably from 1 to 3, carbon atoms; an ethynyl group, or a cycloalkyl, e.g.
• R 2 represents an acyl group, for example a straight- or branched chain alkanoyl group containing up to about 6 carbon atoms and which may be substituted, for example, by a carboxy group; or a pyridyl or triazolyl group optionally substituted by one or more, preferably one or two, substituents selected from amino groups and straight- or branched-chain alkyl, e.g. methyl, groups; 3 (v) R represents a methyl group;
• R represents a methyl group
• R represents a imidazolyl, morpholinyl or pyridyl group optionally substituted by one or two alkyl, e.g. methyl, groups;
• R represents an allyl group, or an alkoxy group containing from 1 to 3 carbon atoms, e.g. methoxy or ethoxy;
• R 7 represents an alkyl group contai.ni.ng from 1 to 3 carbon atoms, e.g. methyl or ethyl, optionally substituted by a hydroxy group;
• R represents a hydrogen atom or a hydroxymethyl, ethoxymethyl or acetoxymethyl group
• R represents a hydrogen atom or a methyl group
• R represents a hydrogen atom or a hydroxy or methyl group
• R12 represents a hydrogen atom or a methyl group
• R represents an alkoxy or alkylamino group containing from 1 to 4 carbon atoms; the other symbols being as hereinbefore defined, and pharmaceutically acceptable salts thereof.
• Particularly important features of the present invention are, or involve, at least one of the following compounds:-
• the letters A to CO are allocated to the compounds for easy reference.
• the compounds according to the invention are inhibitors of acyl coenzyme-A:cholesterol-O-acyl transferase (ACAT; EC 2.3.1.26). They are therefore of value as anti-atherosclerotic agents and have utility in the treatment of atherosclerosis, hyperlipidaemia, cholesterol ester storage disease and atheroma in vein grafts.
• ACAT acyl coenzyme-A:cholesterol-O-acyl transferase
• thromboxane xA 2 are also inhibitors of the binding of thromboxane xA 2 to its receptors. They are therefore of utility in the treatment of conditions such as thrombosis and myocardial infarction, vasospastic disorders, for example associated with angina, and bronchospasm, for example associated with asthma, or in reperfusion salvage therapy, for example after ischaemic injury.
• compounds of the invention produced up to 50% inhibition of the binding of thromboxane TxA_ to its receptors at concentrations down to about 600 nano olar or less.
• assays performed in-vitro microsomes, obtained from the livers of rats fed on a diet supplemented with 0.5%w/w cholesterol and 0.25%w/w cholic acid for 7 days, were incubated with radiolabelled oleoyl-CoA in the presence of compounds according to the invention at a concentration of 0.5 or 1 ⁇ g/ml. The degree of ACAT inhibition produced was up to 90% or more.
• the compounds according to the invention inhibited increases in plasma cholesterol concentrations, measured after 3 days, relative to control animals fed on the cholesterol supplemented diet without the drug, by up to 90% or more.
• the intermediates and starting materials from which they are prepared can also be prepared by the application or adaptation of known methods.
• X is a group displaceable by a thiolate salt, such as a halogen e.g. a chlorine, bromine or iodine, atom or an alkyl- or aryl- sulphonyloxy group (e.g. methanesulphonyloxy or 4-toluenesulphonyloxy) and Q and Z are as hereinbefore defined.
• a thiolate salt such as a halogen e.g. a chlorine, bromine or iodine, atom or an alkyl- or aryl- sulphonyloxy group (e.g. methanesulphonyloxy or 4-toluenesulphonyloxy) and Q and Z are as hereinbefore defined.
• the reaction is generally carried out in an inert organic solvent such as tetrahydrofuran, dimethylformamide, a lower alkanol such as methanol or ethanol, at a temperature from ambient to 110°C and optionally in the presence of a proton acceptor, such as an amine (e.g. triethylamine or pyridine) or an alkali metal hydroxide, carbonate or alkoxide.
• a proton acceptor such as an amine (e.g. triethylamine or pyridine) or an alkali metal hydroxide, carbonate or alkoxide.
• the salt of formula IX or the compound of formula X can optionally be prepared m situ by the application or adaptation of known methods.
• compounds of formula I wherein k is 0 and Z represents a group of the formula -NHR 2 wherein R2 represents an acyl group, A and Q being as hereinbefore defined, are prepared by the acylation by known methods of compounds of formula XII as hereinbefore defined, for example by reaction with the appropriate acid anhydride or acid halide.
• compounds of formula I wherein k is 0 and Z represents a group of the formula -CH(OH)CH 2 (CR 9 R 10 ) CH COR 14 wherein R 9, R10 and r are as hereinbefore defined and R 14 represents a straight- or branched-chain alkoxy group containing from 1 to 4 carbon atoms, A and Q being as hereinbefore defined, are prepared by the reaction of a compound of formula IX as hereinbefore defined, optionally prepared in situ, with a compound of the general formula:-
• R 15 CH 2 (CR 9 R 10 ) r CH 2 COR 14 XIII wherein R 9, R10, r and R14 are as hereinbefore defined and R 15 represents a 1,2-epoxyethyl group, in an inert solvent such as methanol.
• compounds of general formula I are prepared by the interconversion of other compounds of general formula I.
• the cyclisation can be carried out by reaction with a base, e.g. sodium methoxide in methanol, followed by reaction with trifluoroacetic acid.
• a base e.g. sodium methoxide in methanol
• Z represents a group of formula III wherein n is 0, m is 1, and the symbols R preferably represent hydrogen atoms.
• A, Q and p being as hereinbefore defined, are prepared by the reaction of a compound of the general formula:-
• a metal hydride such as lithium aluminium hydride
• A, R and R represent hydrogen atoms
• A, R and R being as hereinbefore defined are prepared by the reduction of compounds of general formula I wherein k is 0 and Z represents a group of formula V, A, R 9 and R10 being as hereinbefore defined, for example by reaction with a metal hydride such as di-isobutylaluminium hydride, in an ether such as tetrahydrofuran.
• a metal hydride such as di-isobutylaluminium hydride
• Z represents a group of formula -CH(0H)R , A, Q and R 5 being as hereinbefore defined, are prepared by the reduction of compounds of general formula I wherein
• Z represents a group of formula -COR , A, Q and R 5 being as hereinbefore defined, for example by reaction with a metal borohydride such as sodium borohydride in a solvent system such as aqueous ethanol.
• a metal borohydride such as sodium borohydride in a solvent system such as aqueous ethanol.
• A, Q and R being as hereinbefore defined are prepared by the elimination of the elements of water from compounds of general formula I wherein k is 0 and Z represents a group of formula V wherein R represents g a hydroxy group, A, Q and R being as hereinbefore defined, e.g. by reaction with trifluoroacetic acid.
• R 16 represents a straight- or branched -chain alkylamino group contain- mg from 1 to 4 carbon atoms
• A, Q, R 9, R10 and r being as hereinbefore defined, are prepared from compounds of formula I wherein k is 0 and Z represents a group of formula V wherein R 9 and R10 are as hereinbefore defined, A and Q being as hereinbefore defined, for example by reaction with the appropriate alkylamine of formula R NH I-_,, R being as hereinbefore defined, preferably at an elevated temperature, e.g. at reflux, in a solvent such as ethanol.
• compounds of formula I containing one or more lower alkoxy groups are prepared by the alkylation of compounds of formula I containing one or more hydroxy groups, for example by reaction with the appropriate lower alkanol, preferably in the presence of a catalyst such as boron trifluoride diethyl etherate.
• R5 is as hereinbefore defined, preferably an optionally substituted imidazole group
• a and Q being as hereinbefore defined, are prepared by reaction of corresponding compounds of formula I wherein Z represents a morpholinocarbonyl group with the product of the reaction between lithium diisopropylamide (preferably complexed with mono-tetrahydrofuran) with a compound of formula R 5 'H wherein R 5' represents a group wi.thi.n the defi.ni.ti.on of R 5 but wherein any free lmmo groups are temporarily protected, e.g. by dimethylaminomethyl groups.
• compounds of formula I wherein k represents 1 or 2 are prepared by the oxidation of compounds of formula I wherein A, Q and Z are as hereinbefore defined and p is less than in the desired product .
• the oxidation may be performed by using a conventional oxidant, such as hydrogen peroxide, sodium metaperiodate, a hypochlorite, an acyl nitrite, sodium perborate, peracids, such as percarboxylic acids (e.g. m-chloroperbenzoic acid) , potassium permanganate or potassium hydrogen persulphate, or a ruthenium (VIII) compound, in an inert solvent, at or below room temperature.
• a conventional oxidant such as hydrogen peroxide, sodium metaperiodate, a hypochlorite, an acyl nitrite, sodium perborate, peracids, such as percarboxylic acids (e.g. m-chloroperbenzoic acid) , potassium permanganate or potassium hydrogen persulphate, or a ruthenium (VIII) compound, in an inert solvent, at or below room temperature.
• a conventional oxidant such as hydrogen peroxide, sodium metaperi
• Suitable solvents may include water, alcohols, water-alcohol mixtures, chlorinated hydrocarbons, such as dichloromethane, and organic acids.
• compounds of formula I containing one or more carboxy groups are prepared by the hydrolysis by known methods of compounds of formula I containing one or more alkoxycarbonyl groups.
• Preferred salts are acid addition salts such as the hydrochlorides or, where the compound of formula I contains an acidic hydrogen atom, for example when Z contains a carboxy group, salts formed with alkali metals, e.g. sodium and potassium, or alkaline earth metals, e.g. calcium and magnesium, or with ammonia or with pharmaceutically acceptable amines.
• alkali metals e.g. sodium and potassium
• alkaline earth metals e.g. calcium and magnesium
• NMR nuclear magnetic resonance
• a stirred suspension of 4,5-diphenylimidazole- 2-thiol (3.2g) and anhydrous potassium carbonate (1.8g) in anhydrous dimethylforma ide (50ml) was stirred at room temperature for 15 minutes. It was then treated with 2-bromoethyl ethyl ether (2.4g) and the mixture was stirred at room temperature overnight. The mixture was filtered through silica gel and the bright yellow filtrate was evaporated to low bulk. The residue was shaken with ethyl acetate (100ml) and water (50ml) . The layers were separated and the organic layer was washed with water (50ml) , dried (magnesium sulphate) and evaporated.
• Example 12 Compounds AO, AK, AN and AP
• N-(pyrid-2-yl)-4-(4,5-diphenylimidazol-2- ylthio)butanamide (0.8g) in the form of a colourless solid, m.p. 167-169°C.
• the white insoluble solid was collected by filtration and washed with a little fresh methanol.
• the solution was treated with fresh methanol (100ml) and IM sodium hydroxide solution (50ml) . After standing at room temperature for 2 hours the clear solution was evaporated to dryness and shaken with ethyl acetate (200ml) and 2M acetic acid solution (150ml) . The layers were separated and the organic layer dried (magnesium sulphate) and evaporated.
• the oily residue was dissolved in dichloromethane (300ml) and treated with trifluoroacetic acid (10ml) .
• 4,5-diphenylimidazole-2-thiol (12.99g) was dissolved in dry dimethylformamide (200ml) , and then it was treated with potassium carbonate (5.44g) and methyl 6-deoxy-6-iodo-A-D-mannopyranoside (15.66g) and stirred at room temperature for 18 hours.
• the solid was crystallised from a mixture of t-butyl methyl ether (300ml) and ethanol (150ml) by concentrating to about 200ml and cooling overnight, to give 4-[4-(4,5-diphenylimidazol- 2-ylthio)butanoyl]morpholine (10.92g) in the form of colourless crystals, m.p. 168-173°C.
• a solution of morpholine (13.0g) and pyridine (13.Og) in dimethylformamide (50ml) was added during 10 minutes to a stirred solution of 5-chlorovaleryl chloride (22.Og) in dimethylformamide (150ml).
• the mixture was stirred at ambient temperature for 2 hours then 4,5-diphenylimidazole-2-thiol (37.Og) was added.
• the mixture was stirred at 125-135°C for 2 hours. After cooling to 80°C, the mixture was poured into water (500ml) and acidified to pHl by treatment with dilute hydrochloric acid . The mixture was stirred and the resulting solid was filtered off.
• the present invention also includes within its scope pharmaceutical formulations which comprise at least one of the compounds of formula I or a pharmaceutically acceptable salt thereof in association with a pharmaceutically acceptable carrier or coating. In clinical practice the compounds of the present invention may be administered parenterally, rectally or orally.
• Solid compositions for oral administration include compressed tablets, pills, powders and granules.
• one or more of the active compounds is, or are, admixed with at least one inert diluent such as starch, sucrose or lactose.
• the compositions may also comprise, as is normal practice, additional substances other than inert diluents, e.g. lubricating agents, such as magnesium stearate.
• Liquid compositions for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups and elixirs containing inert diluents commonly used in the art such as water and liquid paraffin. Besides inert diluents such compositions may comprise adjuvants, such as wetting and suspending agents, and sweetening, flavouring, perfuming and preserving agents.
• the compositions according to the invention for oral administration also include capsules of absorbable material such as gelatin, containing one or more of the active substances with or without the addition of diluents or excipients.
• compositions according to the invention for parenteral administration include sterile aqueous, aqueous-organic, and organic solutions, suspensions and emulsions.
• organic solvents or suspending media are propyiene glycol, polyethylene glycol, vegetable oils such as olive oil and injectable organic esters such as ethyl oleate.
• the compositions may also contain adjuvants such as stabilising, preserving, wetting, emulsifying and dispersing agents. They may be sterilised, for example, by filtration through a bacteria-retaining filter, by incorporation in the compositions of sterilising agents, by irradiation or by heating. They may also be manufactured in the form of sterile solid compositions, which can be dissolved in sterile water or some other sterile injectable medium immediately before use.
• Solid compositions for rectal administration include suppositories formulated in accordance with known methods and containing at least one compound of formula I or a pharmaceutically acceptable salt thereof.
• the percentage of active ingredient in the compositions of the invention may be varied, it being necessary that it should constitute a proportion such that a suitable dosage shall be obtained.
• several unit dosage forms may be administered at about the same time.
• the size and frequency of the dose employed will be determined by the physician, and depends upon the desired therapeutic effect, the route of administration, the duration of the treatment and the age, sex, size and condition of the patient.
• the doses are generally from 0.01 to 100, preferably 0.1 to 70, more especially 0.5 to 10, mg/kg body weight per day by oral administration, and from 0.001 to 10, preferably 0.01 to 1 , mg/kg body weight per day by intravenous administration.
• Example illustrates a pharmaceutical composition according to the present invention.
• COMPOSITION EXAMPLE No. 2 size gelatin capsules each containing:- Compound A 20 mg lactose 100 mg starch 60 mg dextrin 40 mg magnesium stearate 1 mg were prepared in accordance with the usual procedure. Capsules can also be made up in a similar manner using any other of the compounds B to CO, or a pharmaceutically acceptable salt thereof.

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