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WO1991009030A1 - 2-substituted 4,5-diphenyl-imidazoles - Google Patents

2-substituted 4,5-diphenyl-imidazoles

Info

Publication number
WO1991009030A1
WO1991009030A1 PCT/EP1990/002147 EP9002147W WO9109030A1 WO 1991009030 A1 WO1991009030 A1 WO 1991009030A1 EP 9002147 W EP9002147 W EP 9002147W WO 9109030 A1 WO9109030 A1 WO 9109030A1
Authority
WO
WIPO (PCT)
Prior art keywords
group
formula
symbols
atom
carbon atoms
Prior art date
Application number
PCT/EP1990/002147
Other languages
French (fr)
Inventor
Andrew William Bridge
Neil Victor Harris
David John Lythgoe
Christopher Smith
Original Assignee
Rhone-Poulenc Sante
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 GB898928028A external-priority patent/GB8928028D0/en
Priority claimed from GB909000698A external-priority patent/GB9000698D0/en
Priority claimed from GB909000697A external-priority patent/GB9000697D0/en
Application filed by Rhone-Poulenc Sante filed Critical Rhone-Poulenc Sante
Priority to JP91502395A priority Critical patent/JPH05502235A/en
Publication of WO1991009030A1 publication Critical patent/WO1991009030A1/en

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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
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • 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
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/10—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • This invention relates to therapeutically useful imidazole derivatives, to processes for their
  • the present invention provides compounds of the general formula:-
  • R and R 1 are the same or different and each represents a hydrogen or halogen atom or a straight- or branched-chain alkyl group containing from 1 to about 5 carbon atoms
  • W represents a methylene group or a straight alkylene chain containing from 2 to about 5 carbon atoms and is optionally substituted with one or more straight- or branched-chain alkyl groups containing from 1 to about 4 carbon atoms
  • Y represents a group of formula (II),
  • R 4 represents a hydrogen atom or a straight- or branched- chain alkyl group containing from 1 to about 4 carbon atoms
  • the symbols R 4 each represent a hydrogen atom or else together the two symbols R 4 and the carbon atom to which they are both joined form a carbonyl group
  • R 5 represents a hydrogen atom or a hydroxy group
  • Z represents an oxygen or sulphur atom or a group of formula [C(R 3 ) 2 ] q or NR 3
  • m represents zero or an integer from 1 to about 5
  • n represents zero or an integer from 1 to about 5
  • ACAT acyl coenzyme-A:- cholesterol-O-acyl transferase
  • the invention also provides a method for the treatment of a human or animal patient suffering from, or subject to, conditions which can be ameliorated by the administration of an inhibitor of acyl coenzyme-A:- cholesterol-O-acyl transferase, such as
  • Atherosclerosis hyperlipidaemia
  • cholesterol ester storage disease or atheroma in vein grafts, which comprises administering to the patient an effective amount of a compound of formula (I), or a
  • the invention also provides a compound of formula (I), or a pharmaceutically acceptable acid addition salt thereof, as hereinbefore defined, for use in a new method of treatment, of the human or animal body, by therapy, of conditions which can be
  • acyl coenzyme-A:cholesterol-O-acyl transferase such as atherosclerosis, hyperlipidaemia, cholesterol ester storage disease or atheroma in vein grafts.
  • the present invention also provides
  • the present invention also provides new
  • R and R 1 are the same or different and each represents a hydrogen or halogen atom or a
  • W represents a methylene group or a straight alkylene chain containing from 2 to 4 carbon atoms
  • Y represents a group of formula (V), as
  • R 3 are the same or different and each represents a hydrogen atom or a straight- or branched-chain alkyl group containing from
  • R 4 represent hydrogen atoms and Z represents an oxygen atom or a group of formula [C(R 3 ) 2 ] q , wherein q
  • compositions could be useful as inhibitors of acyl coenzyme-A: cholesterol-O-acyl transferase or in the treatment of conditions such as atherosclerosis, hyperlipidaemia, cholesterol ester storage disease and atherrma in vein grafts.
  • acyl coenzyme-A cholesterol-O-acyl transferase
  • R represents a hydrogen or chlorine atom or a methyl group
  • R 1 represents a hydrogen or chlorine atom or a methyl group
  • W represents a methylene group or an alkylene chain of 2, 3 or 4 carbon atoms
  • Y represents a phthalimido group or an optionally substituted maleimido, pyrrolidinyl, piperidyl, perhydroazepinyl, piperazinyl, or morpholino group;
  • R 3 represents a hydrogen atom or a methyl or ethyl group
  • Important compounds according to the present invention include:
  • the codes 1A to 4B are allocated to compounds for easy reference later in the specification.
  • microsomes prepared from the livers of rats fed a diet
  • radiolabelled oleoyl-CoA in the presence of compounds according to the invention at a concentration of 0.5, 1 or 10 ⁇ g/ml.
  • concentration of 0.5, 1 or 10 ⁇ g/ml The degree of ACAT inhibition produced is shown in Table I.
  • 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 amounts as shown, for example, in Table II.
  • [DPIM] is as hereinbefore defined and M is an alkali metal, preferably a sodium or potassium, atom, with a compound of the general formula:-
  • X is a group displaceable by a thiolate salt, such as a halogen, e.g. a chlorine, atom or an alkyl- or aryl-sulphonyloxy group (e.g. methanesulphonyloxy or 4-toluene- sulphonyloxy) and W and Y are as hereinbefore defined.
  • a thiolate salt such as a halogen, e.g. a chlorine, atom or an alkyl- or aryl-sulphonyloxy group (e.g. methanesulphonyloxy or 4-toluene- sulphonyloxy) and W and Y are as hereinbefore defined.
  • a thiolate salt such as a halogen, e.g. a chlorine, atom or an alkyl- or aryl-sulphonyloxy group (e.g. methanesulphonyloxy or 4-toluene-
  • a proton acceptor which may be organic, such as an amine (e.g. triethylamine), or inorganic, such as a carbonate of an alkali metal (e.g. potassium carbonate).
  • a proton acceptor such as organic, such as an amine (e.g. triethylamine), or inorganic, such as a carbonate of an alkali metal (e.g. potassium carbonate).
  • reaction is generally carried out in an inert organic solvent, for example xylene, and optionally in the presence of an acidic catalyst, such as 4-toluenesulphonic acid, at the reflux temperature, with azeotropic removal of water.
  • an inert organic solvent for example xylene
  • an acidic catalyst such as 4-toluenesulphonic acid
  • the starting materials and intermediates can be prepared by the application or adaptation of known methods.
  • compounds of formula (VII) can be prepared by the reaction of a base such as sodium hydride with compounds of the general formula:-
  • Compounds of formula (IX) can also be prepared by the reaction of compounds of formula (I), wherein Y represents a phthalimido group, with hydrazine, in a solvent such as ethanol at temperatures up to reflux.
  • salts as used in this specification is meant acid addition salts the anions of which are relatively innocuous to the animal organism when used in
  • pharmaceuticals may be selected from salts derived from inorganic acids, for example hydrochlorides,
  • hydrobromides hydrobromides, phosphates, sulphates and nitrates, and organic acids, for example oxalates, lactates,
  • acid addition salts of compounds of formula (I) are prepared by reaction of the parent compounds of formula (I) with the appropriate acid, by the application or adaptation of known methods.
  • salts of compounds of formula (I) are useful for the purposes of purification of the parent
  • the parent compounds of formula (I) can be regenerated from their salts by the application or adaptation of known methods.
  • parent compounds of general formula (I) can be regenerated from their acid addition salts by treatment with an alkali, e.g. aqueous sodium bicarbonate solution or aqueous ammonia solution.
  • alkali e.g. aqueous sodium bicarbonate solution or aqueous ammonia solution.
  • reference to compounds of formula (I) is intended to include reference to their pharmaceutically acceptable acid addition salts, where the context so permits.
  • Acetyl chloride (20ml) was added dropwise to cold (10oC) ethanol (90ml) with stirring, maintaining the temperature below 30°C. After stirring for 0.5hr, a solution of N-[2-(4,5-diphenylimidazol-2-ylthio)- ethyl]morpholine (1.5g, 4.1mmol) in ethanol (10ml) was added and stirring continued for 0.5hr. The mixture was then evaporated and the residue recrystallised from ethanol to give N-[2-(4,5-diphenylimidazol-2-ylthio)- ethyl]morpholine dihydrochloride (1.46g), as a
  • Acetyl chloride 25ml was added dropwise to cold ( ⁇ 10oC) ethanol (70ml) with stirring, maintaining the temperature below 10°C.
  • a solution of N-[3-(4,5-diphenylimidazol-2-ylthio)- propyl]piperidine (3.98g) in ethanol (10ml) was added and stirring continued for 0.5hr.
  • the mixture was then evaporated and the residue crystallised from ethanol / ether to give N-[3-(4,5-diphenylimidazol-2-ylthio)- propyl]piperidine dihydrochloride (2.62g), as a
  • N-[2-(4,5-diphenylimidazol-2-ylthio)ethyl]phthalimide (5.05g), as a very pale cream solid, m.p. 165-166oC;
  • Diglycolic anhydride (8.34g, 32.3mmol) was added to boiling xylene (500ml) with stirring.
  • the iodomethyllactam starting materials were prepared by the method of S. Knapp et al,
  • N-[4-(4,5-Diphenylimidazol-2-ylthio)butyl]- phthalimide (10.2g, 22.5mmol) [prepared as in Example 1(iii)] was heated under reflux in a mixture of ethanol (250ml) and hydrazine hydrate (1.25g, 25mmol) for 22hr. An aqueous solution of hydrochloric acid (2N; 50ml) was then added and boiling continued for 0.5hr. The mixture was then chilled (10°C) and the solid filtered and discarded. The filtrate was evaporated and the residue dissolved in water (250ml) and filtered.
  • Example 2 but using a mixture of cis- and trans-N-(4-chlorobutanoyl)-2,6-dimethylmorpholine as a starting material, there was prepared a nixture of cis- and trans-2,6-dimethyl-N-[4-(4,5-diphenylimidazol-2-yl- thio)butan-1-oyl]morpholine, m.p.147-149°C.
  • compounds of the present invention may be administered parenterally, rectally or orally.
  • Solid compositions for oral administration include compressed tablets, pills, powders and
  • 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,
  • compositions according to the invention for oral administration also include capsules of absorbable material such as gelatin, containing one or more of the active
  • 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 propylene 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).
  • compositions of the invention may be varied, it being necessary that it should constitute a proportion such that a suitable dosage shall be obtained. Obviously, several unit dosage forms may be administered at about the same time. The dose employed will be determined by the physician, and depends upon the desired
  • the doses are generally from about 0.5 to about 70, preferably about 1 to about 10, mg/kg body weight per day by oral administration.
  • compositions according to the present invention illustrate pharmaceutical compositions according to the present invention.
  • No. 2 size gelatin capsules each containing:- N-[2-(4,5-diphenylimidazol-2-ylthio)ethyl]- morpholine 20 mg lactose 100 mg starch 60 mg dextrin 40 mg magnesium stearate 1 mg were prepared in accordance with the usual procedure.
  • No. 2 size gelatin capsules each containing:- 3,5-dimethyl-N-[3-(4,5-diphenylimidazol-2-ylthio)propyl]piperidine-2,6-dione 20 mg lactose 100 mg starch 60 mg dextrin 40 mg magnesium stearate 1 mg were prepared in accordance with the usual procedure.
  • No. 2 size gelatin capsules each containing:- [3-R,S]-3-[(4,5-diphenylimidazol-2-ylthio)- methyl]-1-methylpiperidine 20 mg lactose 100 mg starch 60 mg dextrin 40 mg magnesium stearate 1 mg were prepared in accordance with the usual procedure.

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Abstract

Imidazole derivatives of the formula (I): [DPIM]-S-W-Y, wherein [DPIM] represents a group of formula (DPIM), wherein R and R1 represent hydrogen, halogen or alkyl, W represents straight chain alkylene of 1 to 6 carbon atoms optionally substituted by alkyl, Y represents a group of formulas (II), (III), (IV), (V), (VI) and salts thereof, are inhibitors of acyl coenzyme-A:cholesterol-O-acyl transferase useful for the conditions such as atherosclerosis, hyperlipidaemia, cholesterol or ester storage disease and atheroma in vein grafts.

Description

2-substituted 4,5-diphenyl-imidazoles
This invention relates to therapeutically useful imidazole derivatives, to processes for their
production, to pharmaceutical compositions containing them, and to their use in a method of treatment of the human or animal body.
The present invention provides compounds of the general formula:-
[DPIM]-S-W-Y (I)
wherein [DPIM] is as hereinafter depicted, R and R1 are the same or different and each represents a hydrogen or halogen atom or a straight- or branched-chain alkyl group containing from 1 to about 5 carbon atoms, W represents a methylene group or a straight alkylene chain containing from 2 to about 5 carbon atoms and is optionally substituted with one or more straight- or branched-chain alkyl groups containing from 1 to about 4 carbon atoms, Y represents a group of formula (II),
(III), (IV), (V) or (VI) hereinafter depicted, wherein the symbols R2 are the same or different and each represents a hydrogen atom or a methyl group, the symbols R3 are the same or different and each
represents a hydrogen atom or a straight- or branched- chain alkyl group containing from 1 to about 4 carbon atoms, the symbols R4 each represent a hydrogen atom or else together the two symbols R4 and the carbon atom to which they are both joined form a carbonyl group, R5 represents a hydrogen atom or a hydroxy group, Z represents an oxygen or sulphur atom or a group of formula [C(R3) 2 ]q or NR3 , m represents zero or an integer from 1 to about 5, n represents zero or an integer from 1 to about 5, and p represents zero or 1, such that m + n + p = about 3, 4 or 5, q represents 0,
1 or 2, and pharmaceutically acceptable acid addition salts thereof, for use in the preparation of a
pharmaceutical composition for the treatment of
conditions which can be ameliorated by the
administration of an inhibitor of acyl coenzyme-A:- cholesterol-O-acyl transferase (ACAT; EC 2.3.1.26), such as atherosclerosis, hyperlipidaemia, cholesterol ester storage disease and atheroma in vein grafts.
The invention also provides a method for the treatment of a human or animal patient suffering from, or subject to, conditions which can be ameliorated by the administration of an inhibitor of acyl coenzyme-A:- cholesterol-O-acyl transferase, such as
atherosclerosis, hyperlipidaemia, cholesterol ester storage disease or atheroma in vein grafts, which comprises administering to the patient an effective amount of a compound of formula (I), or a
pharmaceutically acceptable acid addition salt thereof, as hereinbefore defined, to secure an improvement in the condition of the patient. The invention also provides a compound of formula (I), or a pharmaceutically acceptable acid addition salt thereof, as hereinbefore defined, for use in a new method of treatment, of the human or animal body, by therapy, of conditions which can be
ameliorated by the administration of an inhibitor of acyl coenzyme-A:cholesterol-O-acyl transferase, such as atherosclerosis, hyperlipidaemia, cholesterol ester storage disease or atheroma in vein grafts.
The present invention also provides
pharmaceutical formulations which contain at least one of the compounds of formula (I), or a pharmaceutically acceptable acid addition salt thereof, as hereinbefore defined, provided that when W represents a methylene group or a straight alkylene chain containing from 2 to 4 carbon atoms, Y represents other than a group of formula (V), as hereinafter depicted, wherein the symbols R4 represent hydrogen atoms and Z represents an oxygen atom or a group of formula [C(R3)2]q, wherein q represents 0 or 1, or NR 3, or the symbols R4 and the carbon atom to which they are both joined form a carbonyl group and Z represents a group of formula
[ C(R 3 ) 2 ]q , wherein 2 represents 0, R, R1 and R3 being as hereinbefore defined, in association with a
pharmaceutically acceptable carrier or coating. The present invention also provides new
imidazole derivatives of general formula (I), and pharmaceutically acceptable acid addition salts
thereof, as hereinbefore defined, subject to the proviso that when W represents a methylene group or a straight alkylene chain containing from 2 to 4 carbon atoms, Y represents other than a group of formula (V), as hereinafter depicted, wherein the symbols R4 represent hydrogen atoms and Z represents an oxygen atom or a group of formula [C(R3)2]q, wherein q
represents 0 or 1, or NR 3, or the symbols R4 and the carbon atom to which they are both joined form a carbonyl group and Z represents a group of formula
[C(R3) 2 ]q, wherein q represents 0, R, R1 and R3 being as hereinbefore defined.
Compounds within the scope of general formula
(I), wherein R and R1 are the same or different and each represents a hydrogen or halogen atom or a
straight- or branched-chain alkyl group containing from
1 to 5 carbon atoms, W represents a methylene group or a straight alkylene chain containing from 2 to 4 carbon atoms, Y represents a group of formula (V), as
hereinafter depicted, the symbols R3 are the same or different and each represents a hydrogen atom or a straight- or branched-chain alkyl group containing from
1 to 4 carbon atoms, and wherein the symbols R4 represent hydrogen atoms and Z represents an oxygen atom or a group of formula [C(R3)2]q, wherein q
represents 0 or 1, or NR 3, or the symbols R4 and the carbon atom to which they are both joined form a carbonyl group and Z represents a group of formula
[C(R3)2]q, wherein q represents 0, and their
pharmaceutically acceptable acid addition salts, alone and in association with pharmaceutically acceptable carriers or coatings, have been disclosed in the specification of Japanese Patent O.P.I. No. 64-40467 (Application No. 62-196117).
However, in that specification, those compounds and their pharmaceutical compositions are described as having anti-ulcer and anti-inflammatory activity.
Nowhere in that specification is there any suggestion that the compounds and their pharmaceutical
compositions could be useful as inhibitors of acyl coenzyme-A: cholesterol-O-acyl transferase or in the treatment of conditions such as atherosclerosis, hyperlipidaemia, cholesterol ester storage disease and atherrma in vein grafts. Thus, the utilities disclosed in the present specification are entirely unexpected.
Especially important features of the present invention are, or involve, compounds of general formula (I) wherein at least one of the symbols has a value selected from the following: -
( i ) R represents a hydrogen or chlorine atom or a methyl group;
(ii) R1 represents a hydrogen or chlorine atom or a methyl group;
(iii) W represents a methylene group or an alkylene chain of 2, 3 or 4 carbon atoms;
(iv) Y represents a phthalimido group or an optionally substituted maleimido, pyrrolidinyl, piperidyl, perhydroazepinyl, piperazinyl, or morpholino group; and/or
(v) R3 represents a hydrogen atom or a methyl or ethyl group;
the other symbols being as hereinbefore defined, and their pharmaceutically acceptable acid addition salts.
Important compounds according to the present invention include:
1A N-[2-(4,5-diphenylimidazol-2-ylthio)ethyl]- morpholine
1AA N-[2-(4,5-diphenylimidazol-2-ylthio)ethyl]- morpholine hydrochloride 1B N-[3-(4,5-diphenylimidazol-2-ylthio)propyl]- morpholine
1BA N-[3-(4,5-diphenylimidazol-2-ylthio)propyl]- morpholine dihydrochloride
1C N-[2-(4,5-diphenylimidazol-2-ylthio)ethyl]- piperidine
1CA N-[2-(4,5-diphenylimidazol-2-ylthio)ethyl]- piperidine dihydrochloride
1D N-[3-(4,5-diphenylimidazol-2-ylthio)propyl]-
N'-methylpiperazine
1E N-[2-(4,5-diphenylimidazol-2-ylthio)ethyl]- pyrrolidine-2-one
1F N-[2-(4,5-diphenylimidazol-2-ylthio)ethyl]- pyrrolidine
1G N-[3-(4,5-diphenylimidazol-2-ylthio)propyl]- piperidine
1GA N-[3-(4,5-diphenylimidazol-2-ylthio)propyl]- piperidine dihydrochloride
1H N-[2-(4,5-diphenylimidazol-2-ylthio)ethyl]- perhydroazepine
1HA N-[2-(4,5-diρhenylimidazol-2-ylthio)ethyl]- perhydroazepine dihydrochloride
1I cis- and trans-2,6-dimethyl-N-[4-(4,5-diphenyl- imidazol-2-ylthio)butyl]morpholine
1IA cis- and trans-2,6-dimethyl-N-[4-(4.5-diphenyl- imidazol-2-ylthio)butyl]morpholine dihydrochloride
2A N-[2-(4,5-diphenylimidazol-2-ylthio)ethyl]- phthalimide
2B N-[3-(4,5-diρhenylimidazol-2-ylthio)propyl]- phthalimide
2C N-[4-(4,5-diphenylimidazol-2-ylthio)butyl]- phthalimide
2D N-[3-(4,5-diphenylimidazol-2-ylthio)propyl]- morpholine-3,5-dione
2E 3,5-dimethyl-N-[3-(4,5-diphenylimidazol-2-yl- thio)propyl]piperidine-2,6-dione
2F N-[2-(4,5-diphenylimidazol-2-ylthio)ethyl]- maleimide
2G N-[3-(4,5-diphenylimidazol-2-ylthio)propyl]-
4-methylmaleimide
2H N-[2-(4,5-diphenylimidazol-2-ylthio)ethyl]- pyrrolidine-2,5-dione
2l N-[3-(4,5-diphenylimidazol-2-ylthio)propyl]- pyrrolidine-2,5-dione
2J N-[3-(4,5-diphenylimidazol-2-ylthio)propyl]- piperidine-2,6-dione
2K 4,4-dimethyl-N-[2-(4,5-diphenylimidazol-2-yl- thio)ethyl]piperidine-2,6-dione
2L 4,4-dimethyl-N-[3-(4,5-diphenylimidazol-2-yl- thio)propyl]piperidine-2,6-dione 2M N-[3-(4,5-diphenylimidazol-2-ylthio)propyl]-4- methylpiperidine-2,6-dione
2N N-[3-(4,5-diphenylimidazol-2-ylthio)propyl]-4- ethyl-4-methylpiperidine-2,6-dione
2O N-[3-(4,5-diphenylimidazol-2-ylthio)propyl]- thiomorpholine-3,5-dione
2P 4,4-dimethyl-N-[3-(4,5-di-p-tolylimidazol-2-yl- thio)propyl]piperidine-2,6-dione
2Q N-[3-(4,5-di-p-tolylimidazol-2-ylthio)propyl]- morpholine-3,5-dione
2R N-[3-(4,5-di-2-chlorophenylimidazol-2-ylthio)- propyl]-4,4-dimethylpiperidine-2,6-dione
2S N-[4-(4,5-diphenylimidazol-2-ylthio)butyl]- morpholine-2,6-dione
2T 3,3-dimethyl-N-[3-(4,5-diphenylimidazol-2-yl- thio)propyl]piperidine-2,6-dione
3A [3-R,S]-3-[(4,5-diphenylimidazol-2-ylthio)- methyl]-1-methylρiperidine
3AA [3-R,S]-3-[(4,5-diphenylimidazol-2-ylthio)- methyl]-1-methylpiperidine hydrochloride
3B [5-R,S]-5-[(4,5-diphenylimidazol-2-ylthio)- methyl-2-pyrrolidinone
3C [6-R,S]-6-[(4,5-diphenylimidazol-2-ylthio)- methyl]-2-piperidinone
3D [6-R,S]-4,4-dimethyl-6-[(4,5-diphenylimidazol-
2-ylthio)methyl]-2-piperidinone 3E [4-R,S]-4-[2-(4,5-diphenylimidazol-2-ylthio)- ethyl]-1-methylpiperidine
3F [2-R,S]-2-[(4,5-diphenylimidazol-2-ylthio)- methyl]-1-methylpiperidine
4A N-[3-(4,5-diphenylimidazol-2-ylthio)propyl]-
5-hydroxypyrrolidin-2-one
4B N-[3-(4,5-diphenylimidazol-2-ylthio)propyl]- 5-hydroxymorpholin-3-one
The codes 1A to 4B are allocated to compounds for easy reference later in the specification.
Compounds within the scope of the present invention exhibit positive pharmacological activities as demonstrated by the following in vivo and in vitro tests which are believed to correlate to
pharmacological activity in humans and other mammals.
In assays performed in vitro, microsomes, prepared from the livers of rats fed 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, 1 or 10μg/ml. The degree of ACAT inhibition produced is shown in Table I.
In in vivo tests, using rats fed on a similar diet to that above and further supplemented by 0.03% w/w of test compound, 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 amounts as shown, for example, in Table II.
Figure imgf000014_0001
Figure imgf000015_0001
Compounds of formula (I) can be prepared by the application or adaptation of known methods, by which is meant methods used heretofore or described in the literature.
Thus, according to a feature of the present invention, compounds of formula (I), as hereinbefore defined, are prepared by the reaction of a salt of the general formula:-
[DPIM]-S- M+ (VII)
wherein [DPIM] is as hereinbefore defined and M is an alkali metal, preferably a sodium or potassium, atom, with a compound of the general formula:-
X-W-Y (VIII)
or an acid addition salt thereof, wherein X is a group displaceable by a thiolate salt, such as a halogen, e.g. a chlorine, atom or an alkyl- or aryl-sulphonyloxy group (e.g. methanesulphonyloxy or 4-toluene- sulphonyloxy) and W and Y are as hereinbefore defined. The reaction is carried out in an inert organic
solvent, such as dimethylformamide or tetrahydrofuran, at from room temperature to 100°C, optionally in the presence of a proton acceptor, which may be organic, such as an amine (e.g. triethylamine), or inorganic, such as a carbonate of an alkali metal (e.g. potassium carbonate). According to a further feature of the present invention, compounds of general formula (I) wherein Y represents a group of formula (II), (III) or (IV), the other symbols being as hereinbefore defined, are prepared by the reaction of a compound of the general formula:-
[DPIM]-S-W-NH2 (IX)
wherein the symbols are as hereinbefore defined, with a compound of the general formula (X), (XI) or (XII), hereinafter depicted, wherein Z, R 2 and R3 are as hereinbefore defined. The reaction is generally carried out in an inert organic solvent, for example xylene, and optionally in the presence of an acidic catalyst, such as 4-toluenesulphonic acid, at the reflux temperature, with azeotropic removal of water.
According to a further feature of the present invention, compounds of formula (I), wherein Y
represents a group of formula (V) and the other symbols are as hereinbefore defined, are prepared from the corresponding compounds of formula (I) wherein Y represents a group of formula (IV) and the other symbols are as hereinbefore defined, by reduction with a metal hydride reducing agent, such as lithium
aluminium hydride, in an inert solvent, such as an ether, e.g. diethyl ether or tetrahydrofuran, at 0°C to room temperature. According to a further feature of the present invention, compounds of formula (I), wherein Y
represents a group of formula (V) in which the symbols R4 represent hydrogen atoms and the other symbols are as hereinbefore defined, are prepared by reduction of the corresponding compounds of formula (I) wherein Y represents a group of formula (V) in which the two symbols R4 and the carbon atom to which they are both joined form a carbonyl group and the other symbols are as hereinbefore defined, in conditions similar to those described hereinbefore for the reduction of compounds of formula I wherein Y represents a group of formula
(IV) to corresponding compounds wherein Y represents a group of formula (V).
According to a further feature of the present invention, compounds of the general formula:-
[DPIM]-S-W1-CH2-Y (XIV) within formula (I), wherein W1 represents a methylene group or a straight alkylene chain containing from 2 to
4 carbon atoms, optionally substituted with one or more straight- or branched-chain alkyl groups containing from 1 to 4 carbon atoms, the other symbols being as hereinbefore defined, are prepared by reduction of compounds of the general formula:-
[DPIM]-S-W1-CO-Y (XV)
wherein the symbols are as hereinbefore defined, in conditions similar to those described hereinbefore for the reduction of compounds of formula (I) wherein Y represents a group of formula (IV) to corresponding compounds wherein Y represents a group of formula (V).
The starting materials and intermediates can be prepared by the application or adaptation of known methods.
Thus, compounds of formula (VII) can be prepared by the reaction of a base such as sodium hydride with compounds of the general formula:-
[DPIM]-SH (XVI)
wherein [DPIM] is as hereinbefore defined. This reaction is conveniently carried out in situ.
Compounds of formula (IX) can be prepared by the reaction of a compound of formula (VII), as hereinbefore defined, with a compound of the general formula:-
X-W-NH2 (XIII) or a salt thereof, wherein X and W are as hereinbefore defined, under conditions similar to those described above for the reaction of a compound of formula (VII) with a compound of formula (VIII).
Compounds of formula (IX) can also be prepared by the reaction of compounds of formula (I), wherein Y represents a phthalimido group, with hydrazine, in a solvent such as ethanol at temperatures up to reflux.
Compounds of formula (XV) can be prepared by the reaction of compounds of formula (VII) with compounds of the general formula:-
X-W1-CO-Y (XVII)
wherein the symbols are as hereinbefore defined, under conditions similar to those described above for the reaction of a compound of formula (VII) with a compound of formula (VIII).
By the term "pharmaceutically acceptable acid addition salts" as used in this specification is meant acid addition salts the anions of which are relatively innocuous to the animal organism when used in
therapeutic doses so that the beneficial pharmaceutical properties of the parent compounds of general formula (I) are not vitiated by side-effects ascribable to those anions.
Suitable acid addition salts for use in
pharmaceuticals may be selected from salts derived from inorganic acids, for example hydrochlorides,
hydrobromides, phosphates, sulphates and nitrates, and organic acids, for example oxalates, lactates,
tartrates, acetates, salicylates, citrates,
propionates, succinates, fumarates, maleates,
methylene-bis-β-hydroxynaphthoates, gentisates and di-p-toluoyltartrates.
According to a further feature of the invention, acid addition salts of compounds of formula (I) are prepared by reaction of the parent compounds of formula (I) with the appropriate acid, by the application or adaptation of known methods.
As well as being useful in themselves as active compounds, salts of compounds of formula (I) are useful for the purposes of purification of the parent
compounds of formula (I)I for example by exploitation of the solubility differences between the salts and the parent compounds, by techniques well known to those skilled in the art.
The parent compounds of formula (I) can be regenerated from their salts by the application or adaptation of known methods.
For example, parent compounds of general formula (I) can be regenerated from their acid addition salts by treatment with an alkali, e.g. aqueous sodium bicarbonate solution or aqueous ammonia solution. In this specification reference to compounds of formula (I) is intended to include reference to their pharmaceutically acceptable acid addition salts, where the context so permits.
Compounds of formula (I) can be purified by the usual physical means, for example by crystallisation or chromatography.
The following Examples illustrate the
preparation of compounds according to the invention and the Reference Examples illustrate the preparation of intermediates .
N.M.R. spectra were recorded at 200MHz or 400MHz. Chemical shifts are expressed in ppm relative to tetramethylsilane. Abbreviations have the following significances:- s = singlet, d = doublet, t = triplet, q = quartet, quin = quintet, m = multiplet, dd = doublet of
doublets, dt = doublet of triplets, br = broad signal.
Infra-red spectra were recorded in potassium bromide discs. The positions of the major absorption peaks are given.
Figure imgf000023_0001
Figure imgf000024_0001
EXAMPLE 1
Compounds 1A, 1B, 1C and 1D
Sodium hydride (1.2g, 40mmol of an 80%
dispersion in oil) was added to a stirred suspension of 4,5-diphenylimidazol-2-thiol (5.04g, 20mmol) in dry tetrahydrofuran (180ml) at ambient temperature. After stirring for 0.5hr, N-(2-chloroethyl)morpholine
hydrochloride (3.72g, 20mmol) was added followed by triethylamine (3ml). The mixture was heated under reflux for 48hr, then poured into water (300ml) and extracted with ether (2 x 200ml). The ethereal
solution was then extracted with aqueous 2N
hydrochloric acid (200ml). The acidic aqueous solution was then basified (NaOH) and extracted with ether (2 x 150 ml). This ethereal solution was dried (MgSO4), evaporated, and the residue recrystallised from toluene to give N-[2-(4,5-diphenylimidazol-2-ylthio)ethyl]- morpholine (4.9g), as a colourless solid, m.p.
129-132°C;
[Elemental analysis:- C, 68.9; H, 6.3; N, 11.6%;
Calculated for C21H23N3OS:- C, 69.0; H, 6.3;
N, 11.5%;
N.M.R.(CDCl3 & D2O): 2.55 (4H, br t, J=4Hz), 2.86 (2H, t, J=6Hz), 3.11 (2H, t, J=6Hz), 3.5 (4H, br t, J=4Hz), 7.2-7.6 (10H, m)]. By proceeding in the same manner, but replacing the N-(2-chloroethyl)morpholine by:
i) N-(3-chloropropyl)morpholine;
ii) N-(2-chloroethyl)piperidine; and
iii) N-(3-chloropropyl)-N'-methylpiperazine there were prepared:
i) N-[3-(4,5-diphenylimidazol-2-ylthio)propyl]- morpholine, m.p. 135-137°C;
ii) N-[2-(4,5-diphenylimidazol-2-ylthio)ethyl]- piperidine, m.p. 143-145°C; and
iii) N-(4,5-diphenylimidazol-2-ylthio)propyl]-
N'-methylpiperazine, m.p. 175-178ºC.
EXAMPLE 2
Compound 1AA
Acetyl chloride (20ml) was added dropwise to cold (10ºC) ethanol (90ml) with stirring, maintaining the temperature below 30°C. After stirring for 0.5hr, a solution of N-[2-(4,5-diphenylimidazol-2-ylthio)- ethyl]morpholine (1.5g, 4.1mmol) in ethanol (10ml) was added and stirring continued for 0.5hr. The mixture was then evaporated and the residue recrystallised from ethanol to give N-[2-(4,5-diphenylimidazol-2-ylthio)- ethyl]morpholine dihydrochloride (1.46g), as a
colourless solid, m.p. 247ºC;
[Elemental analysis:- C, 55.1; H, 5.95; Cl, 15.3; N, 8.9%; Calculated for C21H23N3S .2HCl .H2O: - C , 55.3 ; H, 5.96 ; Cl , 15.5 ; N, 9.2% ;
N.M.R. ( CD3SOCD3 & D2O) : 3.23-3 . 95 ( 12H, m) , 7.34-7.56 ( 10H, m) ] .
EXAMPLE 3
Compound 1E
Sodium hydride ( 0.48g, 16mmol of an 80% dispersion in oil) was added to a stirred suspension of 4,5-diphenylimidazol-2-thiol (3.78g, 15mmol) in dry tetrahydrofuran at ambient temperature. After stirring for 0.5hr, N-(2-tosyloxyethyl)pyrrolidin-2-one (5.66g, 20mmol) was added and stirring continued for 3hr. The mixture was then poured into water (500ml) and
extracted with ether (2 x 200ml). The ethereal
solution was dried (MgSO4), evaporated, and purified by flash chromatography (19:1 dichloromethane / methanol as eluent). The product was crystallised from 1:1 ethyl acetate / petroleum ether ( 60-80°C) to give N-[2-(4,5- diphenylimidazol-2-ylthio)ethyl]pyrrolidin-2-one
(4.2g), as a colourless solid, m.p. 128-130 °C;
[Elemental analysis:- C, 69.4; H, 5.75; N, 11.7%
Calculated for C21H21N3OS:- C, 69.4; H, 5.82; N, 11.6%; N.M.R. (CDCl3): 2.14 (2H, q, J=7Hz), 2.58 (2H, t, J=7Hz), 2.96 (2H, t, J=6Hz), 3.46 (2H, t, J=7Hz), 3.64 (2H, t, J=6Hz), 7.1-7.45 (6H, m), 7.46-7.74 (4H, m), 12.3 (1H, br s)].
EXAMPLE 4
Compound 1F
A solution of N-[2-(4,5-diphenylimidazol-2-yl- thio)ethyl]pyrrolidin-2-one (3.2g, 9mmol ) in dry tetrahydrofuran (20ml) was added to a stirred
suspension of lithium aluminium hydride (1.07g, 28mmol) in diethyl ether (300ml) at ambient temperature under an argon atmosphere. Stirring was continued for 0.5hr, then ethyl acetate (50ml) was added slowly with ice cooling followed by water (300ml) and stirring then continued for 0.5hr. The organic layer was separated, dried (MgSO4), and evaporated to a gum which was purified by flash chromatography (9:1 dichloromethane / methanol as eluent). The product was dissolved in ethyl acetate (5ml) and petroleum ether (60-80°C; 50ml) was added to give N-[2-(4,5-diphenylimidazol-2-ylthio)- ethyl]pyrrolidine (1.9g), as a colourless crystalline solid, m.p. 102-103°C;
[Elemental analysis:- C, 72.3; H, 6.4; N, 12.1%
Calculated for C21H23N3S:- C, 72.2; H, 6.6;
N, 12.0% N.M.R. ( CDCl3 & D2O) : 1.53-1.64 (4H, m) ,
2.6-2.68 (4H, m) , 3.03-3.1 (4H, m) , 7.2-7.33 (6H, m) , 7.41-7.55 ( 4H, m) ] .
EXAMPLE 5
Compounds 1G and 1GA
Potassium tert.-butoxide (4.44g, 39.6mmol) was added to a stirred suspension of 4,5-diphenylimidazol- 2-thiol (10g, 39.6mmol) at ambient temperature to give a yellow solution. After stirring for 0.5hr, N-(3- chloropropyl)piperidine hydrochloride (11.77g,
59.4mmol) was added. The mixture was stirred for 18hr and evaporated, and the residue mixed with ethyl acetate (200ml) and washed with water (250ml),
saturated aqueous sodium bicarbonate solution (200ml) and water (200ml). The organic phase was dried (MgSO4) and evaporated and the orange residue was crystallised from aqueous ethanol to give N-[3-(4,5-diphenyl- imidazol-2-ylthio)propyl]piperidine (3.98g), as a colourless solid, m.p. 118-120ºC.
Acetyl chloride (25ml) was added dropwise to cold (<10ºC) ethanol (70ml) with stirring, maintaining the temperature below 10°C. After stirring for 0.5hr, a solution of N-[3-(4,5-diphenylimidazol-2-ylthio)- propyl]piperidine (3.98g) in ethanol (10ml) was added and stirring continued for 0.5hr. The mixture was then evaporated and the residue crystallised from ethanol / ether to give N-[3-(4,5-diphenylimidazol-2-ylthio)- propyl]piperidine dihydrochloride (2.62g), as a
colourless solid, m.p. 180-185°C;
[Elemental analysis:- C, 59.3; H, 6.5; Cl, 14.8; N, 9.1; S, 6.6%
Calculated for C23H27N3S.2HCl.H2O:- C, 59.0; H, 6.67; Cl, 15.1; N, 8.97; S, 6.84%]
EXAMPLE 6
Compounds 1H and 1HA
Potassium tert.-butoxide (4.44g, 39.6mmol) was added to a stirred suspension of 4,5-diphenylimidazol- 2-thiol (10g, 39.6mmol) at ambient temperature to give a yellow solution. After stirring for 0.5hr, 2-(hexamethyleneimino)ethyl chloride monohydrochloride (11.9g, 60mmol) was added. The mixture was stirred for 18hr filtered, and the solid washed with small portions of dimethylformamide until the washings were colourless. The insoluble material was shaken with a mixture of ethyl acetate (500ml) and aqueous potassium carbonate solution (10%, 250ml) until complete solution occurred. The organic phase was washed with water (2x100ml), dried (MgSO4) and evaporated to give N-[2-(4,5- diphenylimidazol-2-ylthio)ethyl]perhydroazepine
(10.8g), as a colourless solid. Acetyl chloride (25ml) was added dropwise to cold (<10ºC) methanol (150ml) with stirring,
maintaining the temperature below 10ºC. After stirring for 0.5hr, a solution of N-[2-(4,5-diphenylimidazol- 2-ylthio)ethyl]perhydroazepine (10.8g) in methanol (100ml) was added and stirring continued for 5min.
Decolourising charcoal (1g) was added, stirring
continued for 15min and the mixture was filtered. The filtrate was evaporated to low volume and ether added to give N-[2-(4,5-diphenylimidazol-2-ylthio)ethyl]- perhydroazepine dihydrochloride (11.5g), as a
colourless solid, m.p. 225-230ºC;
[Elemental analysis:- C, 59.8; H, 6.7; Cl, 15.4; N, 9.2; S, 7.4%
Calculated for C23H27N3S.2HCl.½H2O:- C, 60.1; H, 6.58; Cl, 15.4; N, 9.15; S, 6.98%]
EXAMPLE 7
Compounds 2A, 2B and 2C
i) Sodium hydride (0.6g, 20mmol of an 80% dispersion in oil) was added to a stirred suspension of 4,5-diphenylimidazol-2-thiol (4.45g, 17.7mmol) in dry tetrahydrofuran (130ml) at ambient temperature. After stirring for 0.5hr, N-(2-bromoethyl)phthalimide (5.08g, 20mmol) was added and the solution heated under reflux for 6hr. The mixture was then poured into water
(500ml) and extracted with ethyl acetate (2 x 200ml). The extract was dried (MgSO4) and evaporated to a gum which was crystallised from toluene to give
N-[2-(4,5-diphenylimidazol-2-ylthio)ethyl]phthalimide (5.05g), as a very pale cream solid, m.p. 165-166ºC;
[Elemental analysis:- C, 70.8; H, 4.5; N, 9.8%;
Calculated for C25H19N3O2S:- C, 70.6; H, 4.5; N, 9.9%
N.M.R. (CDCl3 & D2O): 3.22 (2H, t, J=5Hz), 3.98 (2H, t, J=5Hz), 7.23-7.45 (6H, m), 7.54 (2H, d, J=7Hz), 7.62 (2H, d, J=7Hz), 7.73-7.78 (2H, m) 7.86-7.92 (2H, m)].
By proceeding in a similar manner, but replacing the N-(2-bromoethyl)phthalimide by N-(3-bromopropyl)- phthalimide and N-(4-bromobutyl)phthalimide there were prepared:
ii) N-[3-(4,5-diphenylimidazol-2-ylthio)- propyl]phthalimide, a colourless solid, m.p. 188-190°C;
[Elemental analysis:- C, 70.7; H, 4.7; N, 9.2%
Calculated for C26H21N3O2S:- C, 71.05; H, 4.8; N, 9.6%
N.M.R. (CDCl3 & D2O): 2.03 (2H, guin, J=7Hz), 3.05 (2H, t, J=7Hz), 3.96 (2H, t, J=7Hz), 7.2-7.4 (6H, m), 7.42-7.62 (4H, m), 7.73 (2H, dd, J=6 and 3Hz), 7.82 (2H, dd, J=6 and 3Hz)]; and
iii) N-[4-(4,5-diphenylimidazol-2-ylthio)butyl]- phthalimide, a colourless solid, m.p. 170-171°C; [Elemental analysis:- C, 71.7; H, 5.0; N, 9.3; S, 7.4%
Calculated for C27H23N3O2S:- C, 71.5; H, 5.1; N, 9.3; S, 7.1%
N.M.R. (CDCl3 & D2O): 1.62-1.93 (4H, m), 3.15 (2H, t, J=6Hz), 3.74 (2H, t, J=6Hz), 7.2-7.39 (6H, m), 7.4-7.6 (4H, m), 7.62-7.78 (4H, m)].
EXAMPLE 8
Compound 2D
Diglycolic anhydride (8.34g, 32.3mmol) was added to boiling xylene (500ml) with stirring.
2-(3-Aminopropylthio)-4,5-diphenylimidazole (5.0g, 16.2mmol) was then added in lg portions at 45 minute intervals with vigorous stirring to the boiling
mixture, removing any water formed azeotropically.
After the final addition, heating under reflux was continued for 1.5hr and the mixture was allowed to cool and decanted. The solution was evaporated and the residue purified by flash chromatography on silica gel (39:1 dichloromethane / methanol as eluent). The product was recrystallised from acetonitrile to give N-[3-(4,5-diphenylimidazol-2-ylthio)propyl]morpholine- 3,5-dione (3.7g), as a colourless solid, m.p.
164-166°C; [Elemental analysis :- C, 64.6; H, 5.1; N, 10.2; S, 8.0%
Calculated for C22H21N3O3S:- C, 64.9; H, 5.2; N, 10.3; S, 7.9% ;
N.M.R. (CDCl3 & D2O): 1.98 (2H, quin, J=7Hz), 3.09 (2H, t, J=7Hz), 4.02 (2H, t, J=7Hz), 4.34 (4H, s), 7.2-7.37 (6H, m), 7.45-7.57 (4H, m)].
EXAMPLE 9
Compounds 2E to 2T
2,4-Dimethylglutaric anhydride (7.35g, 51.7mmol) was added to boiling xylene (500ml) with stirring.
2-(3-Aminopropylthio)-4,5-diphenylimidazole (4.0g, 12.9mmol) was added in lg portions at 1 hour intervals, with vigorous stirring, to the boiling mixture removing any water formed azeotropically. Reflux was continued for 2hr and then toluenesulphonic acid monohydrate (0.4g, 2.1mmol) was added and reflux continued for 8hr. The mixture was allowed to cool and decanted and the solution was then evaporated. The resulting residue was purified by flash chromatography on silica gel
(97:3 dichloromethane / methanol as eluent). The product was recrystallised from acetonitrile to give 3,5-dimethyl-N-[3-(4,5-diphenylimidazol-2-ylthio)- propyl]piperidine-2, 6-dione (3.23g), as a colourless solid, m.p. 132-134ºC;
[Elemental analysis :- C, 69.0; H, 6.2; N, 9.8; S, 7.4%
Calculated for C25H27N3O2S:- C, 69.3; H, 6.3; N, 9.7; S, 7.4%
N.M.R. (CDCl3 & D2O): 1.27 (6H, d, J=7Hz), 1.49 (1H, g, J=12Hz), 1.73-2.04 (4H, m), 2.02 (1H, dt, J=4 and 12Hz), 2.53-2.82 (2H, m), 2.93 (2H, t, J=6Hz), 4.13 (2H, t, J=7Hz), 7.22-7.34 (6H, m), 7.48-7.62 (4H, m)].
The N.M.R. spectrum indicated that this was a 9:1 mixture of syn and anti isomers .
By proceeding in a similar manner, but replacing the 2,4-dimethylglutaric anhydride by the appropriate anhydride and the 2-(3-aminopropylthio)-4,5-diphenyl- imidazole by the appropriate amine, there were
prepared:- ii) N-[2-(4,5-diphenylimidazol-2-ylthio)ethyl]- maleimide, a yellow solid, m.p. 132-133°C;
[Elemental analysis:- C, 67.0; H, 4.5; N, 11.1%
Calculated for C21H17N3O2S:- C, 67.2; H, 4.53; N, 11.2%]; N.M.R. (CDCl3 & D2O): 3.13 (2H, t, J=6Hz), 3.82 (2H, t, J=6Hz), 7.2-7.45 (6H, m), 7.46-7.7 (4H, m)].
iii) N-[3-(4,5-diphenylimidazol-2-ylthio)- propyl]-4-methylmaleimide, a buff solid, m.p.
136-138ºC;
[Elemental analysis:- C, 68.2; H, 5.15; N, 10.4; S, 8.1%
Calculated for C23H21N3O2S:- C, 68.5; H, 5.2; N, 10.4; S, 7.94%];
N.M.R. (CDCl3 & D2O): 1.94 (2H, quin, J=7Hz), 2.06 (3H, d, J=4Hz), 3.02 (2H, t, J=7Hz), 3.78 (2H, t, J=7Hz), 6.32 (1H, d, J=4Hz), 7.22-7.38 (6H, m),
7.45-7.56 (4H, m)];
iv) N-[2-(4,5-diρhenylimidazol-2-ylthio)- ethyl]pyrrolidine-2,5-dione, a colourless solid, m.p. 189-191°C;
[Elemental analysis:- C, 66.8; H, 5.1; N, 11.1; S, 8.5%
Calculated for C21H19N3O2S:- C, 66.8; H, 5.04; N, 11.14; S, 8.5%];
v) N-[3-(4,5-diphenylimidazol-2-ylthio)- propyl]pyrrolidine-2,5-dione, a colourless solid, m.p. 177-179°C;
[Elemental analysis:- C, 67.6; H, 5.4; N, 10.6%
Calculated for C22H21N3O2S:- C, 67.5; H, 5.4 ; N, 10.7%]; vi) N-[3-(4,5-diphenylimidazol-2-ylthio)propyl]- piperidine-2,6-dione, a colourless solid, m.p.
154-155°C;
[Elemental analysis:-C, 68.2; H, 5.8; N, 10.4%
Calculated for C23H23N3O2S:- C, 68.1; H, 5.7; N, 10.36%];
vii) 4 , 4-dimethyl-N- [ 2- ( 4 , 5-diphenylimidazol- 2-ylthio) ethyl ]piperidine-2,6-dione, a buff solid, m.p. 86-88°C;
[Elemental analysis:- C, 68.2; H, 6.27; N, 9.6; S, 7.5%
Calculated for C24H25N3O2S:- C, 68.7; H, 6.0; N, 10.0; S, 7.6%];
viii) 4,4-dimethyl-N-[3-(4,5-diphenylimidazol- 2-ylthio)propyl]piperidine-2,6-dione, a colourless solid, m.p. 155-157ºC;
[Elemental analysis:- C, 69.0; H, 6.24; N, 9.6; S, 7.4%
Calculated for C25H27N3O2S:- C, 69.26; H, 6.28; N, 9.7; S, 7.4%];
ix) N-[3-(4,5-diphenylimidazol-2-ylthio)- propyl]-4-methylpiperidine-2,6-dione, a colourless solid, m.p. 160-162°C;
[Elemental analysis:- C, 68.9; H, 6.03; N, 9.9%
Calculated for C24H25N3O2S:- C, 68.7; H, 6.0; N, 10.0% ]; x) N-[3-(4,5-diphenylimidazol-2-ylthio)- propyl]-4-ethyl-4-methylpiperidine-2,6-dione, a buff solid, m.p. 134-136ºC;
[Elemental analysis:- C, 69.6; H, 6.5; N, 9.3; S, 7.3%
Calculated for C26H29N3O2S:- C, 69.77; H, 6.53; N, 9.4; S, 7.16%];
xi) N-[3-(4,5-diphenylimidazol-2-ylthio)propyl]- thiomorpholine-3,5-dione, a cream solid, m.p.
164-166ºC;
[Elemental analysis:- C,62.3; H, 4.84; N, 9.8; S, 15.0%
Calculated for C22H21N3O2S2 :- C, 62.4; H, 5.0; N, 9.9; S, 15.14%];
xii) 4,4-dimethyl-N-[3-(4,5-di-p-tolyl- imidazol-2-ylthio)propyl]piperidine-2,6-dione, a cream solid, m.p. 175-177ºC;
[Elemental analysis:- C, 69.8; H, 6.65; N, 9.1; S, 6.95%
Calculated for C27H31N3O2S:- C, 70.25; H, 6.77; N, 9.1; S, 6.95%];
xiii) N-[3-(4,5-di-p-tolylimidazol-2-ylthio)- propyl]morpholine-3,5-dione, a buff solid, m.p.
148-149ºC; [Elemental analysis:- C, 66.4; H, 5.7; N, 9.5; S, 7.4%;
Calculated for C24H25N3O3S:- C, 66.18; H, 5.8; N, 9.65; S, 7.36%];
xiv) N-[3-(4,5-di-2-chlorophenylimidazol- 2-ylthio)propyl]-4,4-dimethylpiperidine-2,6-dione;
xv) N-[4-(4,5-diρhenylimidazol-2-ylthio)butyl]- morpholine-3,5-dione, a colourless solid, m.p.
153-155°C;
[Elemental analysis:- C, 65.1; H, 5.45; N, 10.0; S, 7.5%
Calculated for C23H23N3O3S:- C, 65.5; H, 5.5; N, 9.97; S, 7.61%]; and
xvi) 3,3-dimethyl-N-[3-(4,5-diphenylimidazol- 2-ylthio)propyl]piperidine-2,6-dione, a colourless solid, m.p. 168-170°C;
[Elemental analysis:- C, 69.3; H, 6.3; N, 9.7; S, 7.2%
Calculated for C25H27N3O2S:- C, 69.26; H, 6.28; N, 9.69; S, 7.4%].
EXAMPLE 10
Compounds 3A and 3AA
i) A suspension of 4,5-diphenylimidazole-2-thiol (5.04g, 20mmol) in anhydrous THF (180ml) was treated with sodium hydride (80% dispersion in oil, 1.2g, 40mmol) and the mixture stirred at room temperature for 30min. A mixture of (+)-3-chloromethyl-1-methyl- piperidine hydrochloride (3.68g, 20mmol) and sodium hydride (80% dispersion in oil, 0.6g, 20mmol) in anhydrous THF (20ml) was also stirred at room
temperature for 30min. The two mixtures were mixed together, triethylamine (3.0ml) was added, and the whole mixture stirred at reflux overnight. After cooling to room temperature the reaction mixture was poured onto iced water (300ml) and extracted with ether (3x200ml). The combined ethereal extracts were
extracted with 2M hydrochloric acid (3x100ml). The acidic solution was basified with 50% sodium hydroxide solution with ice cooling and the product extracted into ether (3x100ml). The combined extracts were dried (MgSO4) and evaporated to give a white solid (2.0g). Crystallisation from toluene gave [3-R,S]- 3-[(4,5-diphenylimidazol-2-ylthio)methyl]-1-methylpiperidine (1.5g), as a white crystalline solid, mp 167-169ºC;
[Found:-C, 72.6; H, 6.9; N, 11.5; S, 8.8.%
Calculated for C22H25N3S:- C, 72.7; H. 6.9;
N, 11.6; S, 8.8%
N.M.R. (CDCl3): 1.92 (3H, s), 1.40-2.70, (9H, m), 3.20 (2H, m), 7.20-7.50 (10H, m)
IR (KBr): 696, 765, 1445, 1494, 2926 and 3433 cm-1].
ii) A solution of [3-R,S]-3-[(4,5-diphenyl- imidazol-2-ylthio)methyl]-1-methylpiperidine (4.1g, 11.3mmol) in ethanol (30ml) was added with stirring and ice cooling to a solution of hydrogen chloride in ethanol [prepared by adding acetyl chloride (40ml) dropwise to cold (10°C) ethanol (180ml) with stirring, maintaining the temperature below 30°C]. The mixture was allowed to warm to room temperature and stirred for 2hr. Ether (200ml) was added and the white precipitate was collected by filtration and washed thoroughly with fresh ether to give [3-R,S]-3-[(4,5-diphenyl- imidazol-2-ylthioJmethyl]-1-methylpiperidine
hydrochloride (4.6g), as a white powder, mp 175-177°C;
[Found:- C, 59.7; H, 6.5; N, 9.0; Cl, 14.3;
S, 6.8%
Calculated for C22H25N3S.1.8HCl.H2O:- C, 59.2; H, 6.5; N, 9.4; Cl, 14.3; S, 7.2%].
EXAMPLE 11
Compounds 3B, 3C and 3D
i) A mixture of 5-iodomethyl-2-pyrrolidinone (1.83g, 8.1mmol), 4,5-diphenylimidazole-2-thiol (1.83g, 7.3mmol) and anhydrous potassium carbonate (0.70g, 5.1mmol) in DMF (35ml) was stirred at room temperature overnighh. The mixture was evaporated to low bulk and the residue suspended in water (70ml). The product was collected by filtration, dried, and crystallised from ethanol / ether to give [5-R,S]-5-[(4,5-diρhenyl- imidazol-2-ylthio)methyl]-2-pyrrolidinone (0.98g) as a white crystalline solid, mp 218ºC;
[Found:- C, 68.6; H, 5.5; N, 12.0; S, 9.1%
Calculated for C20H19N3OS:- C, 68.7; H, 5.5;
N, 12.0; S, 9.2%
N.M.R. (CDCl3): 1.85 & 2.35 (4H, 2m), 3.00 & 3.27 (2H, 2dd, J=14Hz and 4Hz), 3.91 (1H, m), 7.2-7.7 (10H, m)
IR (KBr): 698, 762 and 1680 cm-1]
ii) By proceeding in the same manner, but replacing the 5-iodomethyl-2-pyrrolidinone by
6-iodomethyl-2-piperidinone and purifying the crude product by flash chromatography (10% ethanol in ethyl acetate) followed by crystallisation from ethanol / ether, there was prepared [6-R,S]-6-[(4,5-diphenyl- imidazol-2-ylthio)methyl]-2-piperidinone, as a white solid, mp 209-210°C;
[Found:- C, 69.4; H, 5.8; N, 11.6; S, 8.6.%
Calculated for C21H21N3OS:- C, 69.4; H, 5.8;
N, 11.6; S, 8.8%
N.M.R. (CD3SOCD3): 1.4-2.0 & 2.05-2.10 (6H, 2m), 3.24 (2H, m), 3.63 (1H, m). 7.20-7.55 (10H, m,)
IR (KBr): 697, 763 and 1634 cm-1]. iii) By proceeding in the same manner, but replacing the 5-iodomethyl-2-pyrrolidinone by
4,4-dimethyl-6-iodomethyl-2-piperidinone and purifying the crude product by flash chromatography (ethyl acetate), there was prepared [6-R,S]-4,4-dimethyl- 6- [ ( 4 ,5-diphenylimidazol-2-ylthio)methyl]-2- piperidinone as a white solid, mp 148-150°C;
[Found:- C, 70.3; H, 6.6; N, 10.4.%
Calculated for C23H25N3OS:- C, 70.6; H, 6.4; N, 10.7%.
N.M.R. (CD3SOCD3): 0.94 & 0.98 (6H, 2s), 1.2-1.8 (2H, m), 1.96 (2H, m), 3.26 (2H, m), 3.73 (1H, m), 7.20-7.58 (10H, m)
IR (KBr): 695, 763, 1488 and 1636 cm-1].
The iodomethyllactam starting materials were prepared by the method of S. Knapp et al,
J. Org. Chem., 1988, 53, 4006.
EXAMPLE 12
Compounds 3E and 3F
i) A suspension of 4,5-diphenylimidazole-2-thiol (8g, 31.7mmol) in anhydrous THF (250ml) was treated with sodium hydride (80% in oil, 0,97g, 32.7mmol) and the mixture stirred at room temperature for 30min. A mixture of (+)-4-[2-(p-toluenesulphonyloxy)ethyl]- 1-methylpiperidine (9.4g, 31.6mmol) in anhydrous THF (20ml) was added and the mixture stirred at room temperature for 18hr, followed by refluxing for 24hr. After cooling to room temperature, the reaction mixture was poured into iced water (500ml) and extracted with ether (4x100ml). The combined ethereal extracts were extracted with hydrochloric acid (2M, 4x100ml). The acidic solution was basified with 50% sodium hydroxide solution with ice cooling and the product extracted into ether (3x500ml). The combined extracts were dried (MgSO4) and evaporated and the residual solid (5.4g) was purified by flash chromatography on silica gel (9:1 dichloromethane / methanol as eluent) to give [4-R,S]- 4-[2-(4,5-diphenylimidazol-2-ylthio)ethyl]-1-methylpiperidine (2.28g), as a colourless solid, m.p.
74-76ºC;
[Found:- C, 73.3; H, 7.4; N, 10.8; S, 8.6% Calculated for C23H27N3S:- C, 73.16; H, 7.2; N, 11.3; S, 8.5%].
ii) By proceeding in a similar manner, but replacing the (±)-4-[2-(p-toluenesulphonyloxy)ethyl]- 1-methylpiρeridine by (±)-2-(p-toluenesulphonyloxy)- methyl-1-methylpiperidine and purifying the crude product by crystallisation from toluene followed by conversion to the hydrochloride salt and subsequent regeneration of the free base, there was prepared
[2-R,S]-2-[(4,5-diphenylimidazol-2-ylthio)methyl]- 1-methylpiperidine, as a colourless solid, m.p.
62-64°C;
[Found:- C, 71.4; H, 6.9; N, 11.2; S, 8.2%
Calculated for C22H25N3S.¼H2O:- C, 71.7; H, 6.98; N, 11.42; S, 8.71%].
EXAMPLE 13
Compound 1I
By proceeding in a manner similar to that described in Example 4, but replacing the N-[2-(4,5- diphenylimidazol-2-ylthio)ethyl]pyrrolidin-2-one, used as a starting material, by a mixture of cis- and
trans-2,6-dimethyl-N-[4-(4,5-diphenylimidazol-2-yl- thio)butan-1-oyl]morpholine, carrying out the reaction for 4 hours, followed by the addition of water and then aqueous sodium hydroxide solution for the work-up, there was prepared a mixture of cis- and trans-2,6- dimethyl-N-[4-(4,5-diphenylimidazol-2-ylthio)butyl]- morpholine, m.p. 50-60°C (slowly melts). [Elemental analysis:- C,70.0;H,7.4;N,9.8;S,7.6;H2O,1.4%;
calculated for C25H31N3OS:0.5H2:- C,69.73;H,7.49;N,9.76;S,7.44;H2O,2.09%].
EXAMPLE 14
Compounds 1BA, 1CA and 1IA
By proceeding in a manner similar to that described in Example 2, but starting with:- i) N-[3-(4,5-diphenylimidazol-2-ylthio)propyl]- morpholine;
ii) N-[2-(4,5-diphenylimidazol-2-ylthio)ethyl]- piperidine; and
iii) a mixture of cis- and trans-2,6-dimethyl-
N-[4-(4,5-diphenylimidazol-2-ylthio)butyl]- morpholine;
there were prepared:- i) N-[3-(4,5-diphenylimidazol-2-ylthio)propyl]- morpholine dihydrochloride, m.p. 173-175°C [Elemental analysis:- C,54.7;H,6.02;C1,14.9;N,9.1;S,6.41;H2O,6.4%; calculated for C22H25N3OS:2HCl:1.75H2O:- C,54.7;H,5.94; Cl,15.09;N,8.7;S,6.64;H2O,6.52%];
ii) N-[2-(4,5-diphenylimidazol-2-ylthio)ethyl]- piperidine dihydrochloride, m.p. 237-240°C [Elemental analysis:- C,60.06;H,6.4;Cl,16.0;N,9.6;S,7.3%;
calculated for C22H25N3S:2HCl:- C,60.54;H,6.24;
C1,16.25;N,9.63;S,7.35%]; and
iii) a mixture of cis- and trans-2,6-dimethyl- N-[4-(4,5-diphenylimidazol-2-ylthio)butyl]morpholine dihydrochloride, m.p. 208-210ºC [Elemental analysis:- C,60.6;H,6.9;C1,13.9;N,8.5;S,6.47%; calculated for
C252H3125N3OS:2HCl:- C,60-72;H,6.73;Cl,14.34;N,8.5;
S,6.48%]. EXAMPLE 15
Compounds 4A and 4B
By proceeding in a manner similar to that described in Example 4 but starting with:- i) N-[3-(4,5-diphenylimidazol-2-ylthio)propyl]- pyrrolidin-2,5-dione; and
ii) N-[3-(4,5-diphenylimidazol-2-ylthio)propyl]- morpholin-3,5-dione;
there were prepared:- i) N-[3-(4,5-diphenylimidazol-2-ylthio)propyl]- 5-hydroxypyrrolidin-2-one, m.p. 185-187ºC; and
ii) N-[3-(4,5-diphenylimidazol-2-ylthio)propyl]- 5-hydroxymorpholin-3-one; m.p. 105°C (shrinks at 87°C).
REFERENCE EXAMPLE 1
i) Sodium hydride (1.4g, 46mmol of an 80% dispersion in oil) was added to a stirred suspension of 4,5-diphenylimidazol-2-thiol (5.04g, 20mmol) in dry THF (150ml) at ambient temperature. After stirring for 0.25hr, 3-bromopropylamine hydrobromide (4.38g, 20mmol) was added. The mixture was then heated under reflux for lhr then poured into water (1000ml) and extracted with ethyl acetate (2 x 500ml). The combined extract was dried (MgSO4) and evaporated. The residue was triturated with ethyl acetate / ether (1:1; 70ml) and the solid collected to give 2-(3-aminopropylthio)- 4,5-diphenylimidazole (4.8g). An analytical sample was prepared by recrystallisation from toluene to give colourless crystals, m.p 162-163°C;
[Elemental analysis:- C, 70.1; H, 6.3; N, 13.5%
Calculated for C18H19N3S:- C, 69.9; H, 6.2;
N, 13.6%
N.M.R (CDCl3 & D2O): 1.88 (2H, quin, J=7Hz), 2.93 (2H, t, J=7Hz), 3.2 (2H, t, J=7Hz), 7.2-7.32 (6H, m), 7.47-7.53 (4H, m)].
ii) By proceeding in a similar manner, but replacing the 3-bromopropylamine hydrobromide by
2-bromoethylamine hydrobromide there was prepared
2-(2-aminoethylthio)-4,5-diphenylimidazole,
m.p.152-154°C; [Elemental analysis:- C, 68.6; H, 5.8; N, 14.1; S, 10.5%
Calculated for C17H17N3S:- C, 69.1; H, 5.8;
N, 14.2; S, 10.85%
N.M.R. (CDCl3 & D2O): 3.1 (4H, br s), 7.16-7.36 (6H, m), 7.42-7.56 (4H, m)].
REFERENCE EXAMPLE 2
N-[4-(4,5-Diphenylimidazol-2-ylthio)butyl]- phthalimide (10.2g, 22.5mmol) [prepared as in Example 1(iii)] was heated under reflux in a mixture of ethanol (250ml) and hydrazine hydrate (1.25g, 25mmol) for 22hr. An aqueous solution of hydrochloric acid (2N; 50ml) was then added and boiling continued for 0.5hr. The mixture was then chilled (10°C) and the solid filtered and discarded. The filtrate was evaporated and the residue dissolved in water (250ml) and filtered. The filtrate was then basified (>pH10) with aqueous sodium hydroxide solution (2N) and the mixture extracted with ethyl acetate (3 x 200ml). The combined extract was dried (MgSO4), evaporated and recrystallised from
acetonitrile to give 2-(4-aminobutylthio)-4,5-diphenylimidazole (4.5g), as colourless crystals, m.p.
138-139ºC;
[Elemental analysis :- C,70.7; H,6.6; N,13.0;
Calculated for C19H21N3S :- C, 70.6; H, 6.5; N, 13.0%]. REFERENCE EXAMPLE 3
By proceeding in a manner similar to that
described in Example 1, but using a mixture of cis- and trans-N-(4-chlorobutanoyl)-2,6-dimethylmorpholine as a starting material, there was prepared a nixture of cis- and trans-2,6-dimethyl-N-[4-(4,5-diphenylimidazol-2-yl- thio)butan-1-oyl]morpholine, m.p.147-149°C.
In clinical practice compounds of the present invention may be administered parenterally, rectally or orally.
Solid compositions for oral administration include compressed tablets, pills, powders and
granules. In such solid compositions, 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. Examples of organic solvents or suspending media are propylene 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).
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. Obviously, several unit dosage forms may be administered at about the same time. The dose employed will be determined by the physician, and depends upon the desired
therapeutic effect, the route of administration and the duration of the treatment, and the condition of the patient. In the adult, the doses are generally from about 0.5 to about 70, preferably about 1 to about 10, mg/kg body weight per day by oral administration.
The following Composition Examples illustrate pharmaceutical compositions according to the present invention.
COMPOSITION EXAMPLE 1
No. 2 size gelatin capsules each containing:- N-[2-(4,5-diphenylimidazol-2-ylthio)ethyl]- morpholine 20 mg lactose 100 mg starch 60 mg dextrin 40 mg magnesium stearate 1 mg were prepared in accordance with the usual procedure.
COMPOSITION EXAMPLE 2
No. 2 size gelatin capsules each containing:- 3,5-dimethyl-N-[3-(4,5-diphenylimidazol-2-ylthio)propyl]piperidine-2,6-dione 20 mg lactose 100 mg starch 60 mg dextrin 40 mg magnesium stearate 1 mg were prepared in accordance with the usual procedure.
COMPOSITION EXAMPLE 3
No. 2 size gelatin capsules each containing:- [3-R,S]-3-[(4,5-diphenylimidazol-2-ylthio)- methyl]-1-methylpiperidine 20 mg lactose 100 mg starch 60 mg dextrin 40 mg magnesium stearate 1 mg were prepared in accordance with the usual procedure.

Claims

1. Compounds which are of the general formula :
[DPIM]-S-W-Y (I) wherein [DPIM] is of the general formula :
(DPIM)
Figure imgf000055_0002
R and R1 are the same or different and each represents a hydrogen or halogen atom or a straight- or branched-chain alkyl group containing from 1 to 5 carbon atoms, W
represents a methylene group or a straight alkylene chain containing from 2 to 5 carbon atoms and is optionally substituted with one or more straight- or branched-chain alkyl groups containing from l to 4 carbon atoms, Y
represents a group of the formula :
Figure imgf000055_0001
Figure imgf000056_0001
wherein the symbols R2 are the same or different and each represents a hydrogen atom or a methyl group, the symbols R3 are the same or different and each represents a hydrogen atom or a straight- or branched-chain alkyl group
containing from 1 to 4 carbon atoms, the symbols R4 each represent a hydrogen atom or else together the two symbols R4 and the carbon atom to which they are both joined form a carbonyl group, R5 represents a hydrogen atom or a hydroxy group, Z represents an oxygen or sulphur atom or a group of formula [C(R3)2]q or NR3, m represents zero or an integer from 1 to 5, n represents zero or an integer from 1 to 5, and p represents zero or 1, such that m + n + p = 3, 4 or 5, q represents 0, 1 or 2, or a pharmaceutically acceptable acid addition salt thereof, for use in the preparation of a pharmaceutical composition for the treatment of conditions which can be ameliorated by the administration of an inhibitor of acyl coenzyme-A: cholesterol-O-acyl
transferase.
2. A compound according to claim 1 for use in the preparation of a pharmaceutical composition for the treatment of atherosclerosis, hyperlipidaemia, cholesterol ester storage disease or atheroma in vein grafts.
3. A compound of formula (I) as defined in claim 1, or a pharmaceutically acceptable acid addition salt thereof, provided that when W represents a methylene group or a straight alkylene chain containing from 2 to 4 carbon atoms, Y represents other than a group of formula (V), wherein the symbols R4 represent hydrogen atoms and Z represents an oxygen atom or a group of formula [C(R3)2]q, wherein q represents 0 or 1, or NR3, or the symbols R4 and the carbon atom to which they are both joined form a carbonyl group and Z represents a group of formula
[C(R3)2]q, wherein q represents 0, R, R1 and R3 being as hereinbefore defined, for use in a method of treatment of the human or animal body by therapy.
4. A compound according to claim 3 for use in a method of treatment of the human or animal body by therapy of atherosclerosis, hyperlipidaemia, cholesterol ester storage disease or atheroma in vein grafts.
5. An imidazole derivative of general formula (I), as defined in claim 1 or a pharmaceutically acceptable acid addition salt thereof, subject to the proviso that when W represents a methylene group or a straight alkylene chain containing from 2 to 4 carbon atoms, Y represents other than a group of formula (V), wherein the symbols R4 represent hydrogen atoms and Z represents an oxygen atom or a group of formula [C(R3)2]q, wherein q represents 0 or 1, or NR3, or the symbols R4 and the carbon atom to which they are both joined form a carbonyl group and Z represents a group of formula [C(R3)2]q, wherein q represents 0, R, R1 and R3 being as hereinbefore defined.
6. A compound according to claim 5 wherein at least one of the symbols has a value selected from the following :-
(i) R represents a hydrogen or chlorine atom or a methyl group;
(ii) R1 represents a hydrogen or chlorine atom or a methyl group;
(iii) W represents a methylene group or an alkylene chain of 2, 3 or 4 carbon atoms;
(iv) Y represents a phthalimido group or an optionally substituted maleimido, pyrrolidinyl, piperidyl. perhydroazepinyl, piperazinyl or morpholino group; and/or
(v) R3 represents a hydrogen atom or a methyl or ethyl group;
the other symbols being as hereinbefore defined, and their pharmaceutically acceptable acid addition salts.
7. A process for the preparation of a compound of general formula (I) as defined in claim 5 which
comprises:
(A) the reaction of a salt of the formula
[DPIM]-S- M+ (VII) wherein [DPIM] is as defined in claim 1 and M is an alkali metal atom, with a compound of the general formula:-
X-W-Y (VIII) or an acid addition salt thereof wherein X is a group displaceable by a thiolate salt and W and Y are as defined in claim 5;
(B) when Y represents a group of formula (II), (III) or (IV), the other symbols being as defined in claim 5, by the reaction of a compound of the formula :-
[DPIM]-S-W-NH2 (IX) wherein the various symbols are as defined in claim 5, with a compound of the general formula :
(X)
Figure imgf000059_0001
Figure imgf000060_0001
wherein Z, R2 and R3 are as defined in claim 5;
(C) when Y represents a group of formula (V) and the other symbols are as defined in claim 5, the reduction with a metal hydride reducing agent of a compound of formula (I) wherein Y represents a group of formula (IV) and the other symbols are as defined in claim 5;
(D) when Y represents a group of formula (V) in which the symbols R4 represent hydrogen atoms and the other symbols are as defined in claim 5, the reduction with a metal hydride reducing agent of a compound of formula (I) wherein Y represents a group of formula (V) in which the two symbols R4 and the carbon atom to which they are both joined form a carbonyl group and the other symbols are as defined in claim 5; (E) when the compound of formula (I) conforms to the formula :
[DPIM]-S-W1-CH2-Y (XIV) wherein W1 represents a methylene group or straight
alkylene chain containing from 2 to 4 carbon atoms
optionally substituted with one or more a straight- or branched-chain alkyl groups containing from 1 to 4 carbon atoms, the other symbols being as defined in claim 5 , the reduction with a metal hydride reducing agent of a compound of the formula :
[DPIM]-S-W1CO-Y (XV) wherein the various symbols are as defined in claim 5;
optionally followed by the conversion of a compound of general formula (I) into a pharmaceutically acceptable acid addition salt thereof.
8. A pharmaceutical composition which comprises an imidazole derivative of formula (I) as defined in claim 5, or a pharmaceutically acceptable acid addition salt thereof, in association with a pharmaceutically acceptable carrier or coating.
9. A pharmaceutical composition useful in the treatment of a condition which can be ameliorated by administration of an inhibitor of acyl coenzyme-A:
cholesterol-O-acyl transferase which comprises an amount effective to ameliorate said condition of a compound of general formula (I) as defined in claim 1 or a pharmaceutically acceptable acid addition salt thereof.
10. A method for the treatment of a human or animal host suffering from, or subject to, a condition which can be ameliorated by administration of an inhibitor of acyl coenzyme-A: cholesterol-O-acyl transferase which comprises the administration to said host of an amount effective to ameliorate said condition of an imidazole derivative of general formula (I) as defined in claim 1, or a pharmaceutically acceptable acid addition salt thereof.
11. An agent for use in the treatment of a condition which can be ameliorated by administration of an inhibitor of acyl coenzyme-A: cholesterol-O-acyl
transferase which comprises an imidazole derivative of the general formula :
[DPIM]-S-W-Y (I) wherein [DPIM] is of the general formula
(DPIM)
Figure imgf000062_0001
R and R1 are the same or different and each represents a hydrogen or halogen atom or straight- or branched-chain alkyl group containing from 1 to 5 carbon atoms, W
represents a methylene group or a straight alkylene chain containing from 2 to 5 carbon atoms and is optionally substituted with one or more a straight- or branched-chain alkyl groups containing from 1 to 4 carbon atoms, Y represents a group of the formula :
Figure imgf000063_0001
(VI)
Figure imgf000064_0001
wherein the symbols R2 are the same or different and each represents a hydrogen atom or a methyl group, the symbols R3 are the same or different and each represents a hydrogen atom or a straight- or branched-chain alkyl group
containing from 1 to 4 carbon atoms, the symbols R4 each represent a hydrogen atom or else together the two symbols R4 and the carbon atom to which they are both joined form a carbonyl group, R5 represents a hydrogen atom or a hydroxy group, Z represents an oxygen or sulphur atom or a group of formula [C(R3)2]q or NR3, m represents zero or an integer from 1 to 5, n represents zero or an integer from 1 to 5, and p represents zero or 1, such that m+ n + p = 3, 4 or 5, q represents 0, 1 or 2, or a pharmaceutically acceptable acid addition salt thereof.
PCT/EP1990/002147 1989-12-12 1990-12-11 2-substituted 4,5-diphenyl-imidazoles WO1991009030A1 (en)

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GB8928028.3 1989-12-12
GB898928028A GB8928028D0 (en) 1989-12-12 1989-12-12 New use
GB9000698.2 1990-01-12
GB909000698A GB9000698D0 (en) 1990-01-12 1990-01-12 New compositions of matter
GB9000697.4 1990-01-12
GB909000697A GB9000697D0 (en) 1990-01-12 1990-01-12 New compositions of matter

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WO1992015562A3 (en) * 1991-03-04 1992-10-29 Eastman Kodak Co Preparation of omega-substituted alkanamide
WO1993023392A1 (en) * 1992-05-11 1993-11-25 The Du Pont Merck Pharmaceutical Company Imidazoles linked to bicyclic heterocyclic groups for the treatment of atherosclerosis
US5310748A (en) * 1992-05-11 1994-05-10 The Du Pont Merck Pharmaceutical Company Imidazoles for the treatment of atherosclerosis
WO1995014673A1 (en) * 1993-11-22 1995-06-01 Pharmacia S.P.A. 4,5-diphenylimidazole derivatives, their preparation and their use as acyl coenzyme a: cholesterol-0-acyl-transferase (acat) inhibitor
FR2751647A1 (en) * 1996-07-25 1998-01-30 Synthelabo BENZIMIDAZOLE DERIVATIVES, THEIR PREPARATIONS AND THEIR THERAPEUTIC APPLICATIONS
EP0862435A4 (en) * 1995-11-22 1999-02-03 Merck & Co Inc Inhibitors of farnesyl-protein transferase

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JP2933739B2 (en) * 1990-04-09 1999-08-16 明治製菓株式会社 Thiazole or imidazole derivatives and anti-ulcer agents

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Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1992015562A3 (en) * 1991-03-04 1992-10-29 Eastman Kodak Co Preparation of omega-substituted alkanamide
WO1993023392A1 (en) * 1992-05-11 1993-11-25 The Du Pont Merck Pharmaceutical Company Imidazoles linked to bicyclic heterocyclic groups for the treatment of atherosclerosis
US5310748A (en) * 1992-05-11 1994-05-10 The Du Pont Merck Pharmaceutical Company Imidazoles for the treatment of atherosclerosis
US5364875A (en) * 1992-05-11 1994-11-15 The Du Pont Merck Pharmaceutical Company Imidazoles linked to bicyclic heterocyclic groups for the treatment of atherosclerosis
WO1995014673A1 (en) * 1993-11-22 1995-06-01 Pharmacia S.P.A. 4,5-diphenylimidazole derivatives, their preparation and their use as acyl coenzyme a: cholesterol-0-acyl-transferase (acat) inhibitor
EP0862435A4 (en) * 1995-11-22 1999-02-03 Merck & Co Inc Inhibitors of farnesyl-protein transferase
FR2751647A1 (en) * 1996-07-25 1998-01-30 Synthelabo BENZIMIDAZOLE DERIVATIVES, THEIR PREPARATIONS AND THEIR THERAPEUTIC APPLICATIONS
WO1998004546A1 (en) * 1996-07-25 1998-02-05 Synthelabo Benzimidazole derivatives, preparation thereof, and therapeutical uses thereof

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