WO1995004053A1 - Urea and thiourea derivatives and process for their preparation - Google Patents

Urea and thiourea derivatives and process for their preparation Download PDF

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Publication number
WO1995004053A1
WO1995004053A1 PCT/EP1994/002058 EP9402058W WO9504053A1 WO 1995004053 A1 WO1995004053 A1 WO 1995004053A1 EP 9402058 W EP9402058 W EP 9402058W WO 9504053 A1 WO9504053 A1 WO 9504053A1
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Prior art keywords
phenyl
alkyl
formula
compound
halogen
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PCT/EP1994/002058
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English (en)
French (fr)
Inventor
Paolo Cozzi
Daniele Fancelli
Dino Severino
Augusto Chiari
Giancarlo Ghiselli
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Pharmacia S.P.A.
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Priority to EP94921623A priority Critical patent/EP0662969A1/en
Priority to JP7505512A priority patent/JPH08511269A/ja
Publication of WO1995004053A1 publication Critical patent/WO1995004053A1/en

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    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D405/00Heterocyclic 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
    • C07D405/02Heterocyclic 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
    • C07D405/10Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a carbon chain containing aromatic rings
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00Drugs for disorders of the cardiovascular system
    • A61P9/08Vasodilators for multiple indications
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00Drugs for disorders of the cardiovascular system
    • A61P9/10Drugs 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
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D317/00Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms
    • C07D317/08Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3
    • C07D317/10Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 not condensed with other rings
    • C07D317/14Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 not condensed with other rings with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D317/28Radicals substituted by nitrogen atoms
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D319/00Heterocyclic compounds containing six-membered rings having two oxygen atoms as the only ring hetero atoms
    • C07D319/041,3-Dioxanes; Hydrogenated 1,3-dioxanes
    • C07D319/061,3-Dioxanes; Hydrogenated 1,3-dioxanes not condensed with other rings
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D339/00Heterocyclic compounds containing rings having two sulfur atoms as the only ring hetero atoms
    • C07D339/02Five-membered rings
    • C07D339/06Five-membered rings having the hetero atoms in positions 1 and 3, e.g. cyclic dithiocarbonates
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D409/00Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/10Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing aromatic rings
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D413/00Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02Heterocyclic 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
    • C07D413/10Heterocyclic 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

Definitions

  • the present invention relates to new ureas and thioureas derivatives, to a process for their preparation and to pharmaceutical compositions containing them.
  • the invention provides compounds having the general formula (I)
  • Y is an aryl or heteroaryl group substituted by one group chosen from amino, C 1 -C 6 monoalkylamino.
  • 3- pyrrolin-1-yl, pyrrolidin-1-yl, morphclin-4-yl and piperidin-1-yl, being such aryl or heteroaryl group in addition, optionally substituted by 1 to 3 substituents independently chosen from halogen, C 1 -C 6 alkyl, trihalo-C 1 -C 3 alkyl; hydroxy, C 1 -C 6 alkoxy, C 1 -C 6 alkylthio and C 1 -C 6 alkylsulfonyl;
  • n is zero, 1 or 2;
  • X is oxygen or sulphur
  • R 1 and R 2 are each, independently, a C 1 -C 6 alkyl group or R 1 and R 2 taken together form a C 2 ⁇ C 4 alkylene chain in which each carbon atom is optionally substituted by 1 or 2 substituents independently chosen from halogen and C 1 -C 1 alkyl;
  • n 1, 2 or 3;
  • Q is oxygen or sulphur
  • W is an aryl or heteroaryl group unsubsti tuted or substituted by 1 to 4 substituents independently chosen from halogen, C 1 -C 6 alkyl, trihalo-C 1 -C 3 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 alkylthio and C 1 -C 6 alkylsulfonyl; or a pharmaceutically acceptable salt thereof.
  • the invention includes within its scope all the possible isomers, stereoisomers, both separately and in mixture and the metabolites and the metabolic precursors or bioprecursors of the compounds of formula (I).
  • alkyl groups as well as the aliphatic moieties of the alkoxy, alkylthio and alkylsulfonyl groups, may be branched or straight chains.
  • a C 1 -C 6 alkyl group is e.g. a C 1 -C 4 alkyl group, in particular methyl, ethyl, propyl or butyl.
  • a C 1 -C 4 alkyl group is preferably methyl or ethyl.
  • a C 1 -C 6 alkoxy group is preferably methoxy, ethoxy, propoxy or isopropoxy, in particular methoxy or ethoxy.
  • a C 1 -C 6 alkylthio group is e.g. methylthio, ethylthio, propylthio or butylthio, in particular methylthio or ethylthio.
  • a C 1 -C 6 alkylsulfonyl group is e.g. methylsulfonyl, ethylsulfonyl, propylsulfonyl, in particular methylsulfonyl.
  • a halogen atom is e.g. chlorine, bromine or fluorine, in particular bromine.
  • a trihalo-C 1 -C 3 alkyl group is e.g. a trichloro- or trifluoro C 1 -C 3 alkyl group, in particular trifluoromethyl.
  • Each of Y or W as an aryl group is preferably a phenyl or a naphthyl ring, in particular a phenyl ring.
  • Each of Y or W as a heteroaryl group is preferably a pentatomic or hexatomic heteromonocyclic ring containing from 1 to 3, preferably 1, heteroatoms independently chosen from nitrogen, sulphur and oxygen, in particular a thienyl or pyridyl ring.
  • each carbon atom may be optionally substituted by 1 or 2 substituents independently chosen from halogen, in particular fluorine, and C 1 -C 4 alkyl.
  • Pharmaceutically acceptable salts of the compounds of the invention include acid addition salts, with inorganic, e.g. nitric, hydrochloric, hydrobromic, sulphuric, perchloric and phosphoric acids, or organic, e.g. acetic, propionic, glycolic, lactic, oxalic, methanesulfonic, malonic, malic, maleic, tartaric, citric, benzoic, cinnamic, mandelic and salicylic acids.
  • the present invention also includes within its scope pharmaceutically acceptable bioprecursors (otherwise known as pro-drugs) of the compounds of formula (I), i.e. compounds which have a different formula to formula (I) above but which nevertheless upon administration to a human being are converted directly or indirectly in vivo into a compound of formula (I).
  • Preferred compounds of the invention are the compounds of formula (I), wherein
  • n zero or 1;
  • n 1, 2 or 3;
  • Q is oxygen or sulphur;
  • X is oxygen or sulphur
  • R 1 and R 2 taken together, form a C 2 -C 4 alkylene chain in which each carbon atom is unsubstituted or substituted by one or two substituents independently chosen from halogen and C 1 -C 4 alkyl;
  • Y is an aryl group substituted by a morpholin-4-yl, 3- pyrrolin-1-yl or pyrrolidin-1-yl group, the aryl group being optionally substituted in addition by 1 to 2 substituents independently chosen from halogen, C 1 -C 4 alkyl, trifluoromethyl, hydroxy, C 1 -C 4 alkoxy, C 1 -C 4 alkylthio and C 1 -C 4 alkylsulfonyl;
  • W is a phenyl or pyridyl ring substituted by 1 to 3 substituents independently chosen from halogen, C 1 -C 4 alkyl, C 1 -C 4 alkoxy and C 1 -C 4 alkylthio; or a pharmaceutically acceptable salt thereof.
  • More preferred compounds of the invention are the compounds of formula (I), wherein
  • n zero or 1;
  • n 1 or 2;
  • X is oxygen
  • R 1 and R 2 taken together form a C 2 -C 3 alkylene chain in which at least one carbon atom is substituted by one or two substituents independently chosen from halogen and C 1 -C 4 alkyl;
  • Y is an aryl group substituted by a morphol in-4-yl or 3- pyrrolin-1-yl group and, in addition, optionally substituted by 1 or 2 substituents independently chosen from halogen, C 1 -C 4 alkyl, trifluoromethyl, hydroxy, C 1 -C 4 alkoxy, C 1 -C 4 alkylthio and C 1 -C 4 alkylsulfonyl;
  • W is a phenyl or pyridyl ring substituted by one, two or three substituents independently chosen from halogen, C 1 -C 4 alkyl, C 1 -C 4 alkoxy and methylthio; or a pharmaceutically acceptable salt thereof.
  • Examples of preferred compounds of the present invention are the following:
  • the compounds of the present invention can be obtained by a process comprising:
  • n m, R 1 , R 2 , n , Q and W are as def i ned above and Z i s an aryl or heteroaryl group substi tuted by a nitro group and, in addition, optionally substituted by 1 to 3 substituents chosen from halogen, C 1 -C 6 alkyl, tri halo-C 1 -C 3 alkyl, hydroxy, C 1 -C 6 alkoxy, C 1 -C 6 alkylthio and C 1 -C 6 alkylsulfonyl, so obtaining a compound of formula (I) wherein m, X, R 1 , R 2 , n, Q and W are as defined above and Y is an aryl or heteroaryl group substituted by an amino grouo and, in addition, optionally substituted by 1 to 3 substituents chosen from halogen, C 1 -C 6 alkyl, trihalo-C 1 -C 3 alkyl, hydroxy,
  • reaction between a compound of formula (II) and a compound of formula (III), and the reaction between a compound of formula (IV) and a compound of formula (V), respectively, is an analogy process and can be carried out according to well known methods in the art.
  • these reactions can be performed in a suitable organic solvent, e.g. ethyl acetate or n-hexane, or in an appropriate mixture of the two, at a temperature ranging from about 0oC to reflux temperature of the reacting mixture.
  • a suitable organic solvent e.g. ethyl acetate or n-hexane, or in an appropriate mixture of the two, at a temperature ranging from about 0oC to reflux temperature of the reacting mixture.
  • the reduction of a compound of formula (VI) to give a compound of formula (I) as described under the above method c) may be, e.g., carried out in a conventional way by using, for example, NaBH 4 or KBH 4 together with NiCl 2 or CoCl 2 as reducing agents, in the presence of an organic solvent such as, for example, methanol, ethanol, tetrahydrofuran, dimethylformamide or a mixture thereof, at a temperature ranging from about 0oC to about 30oC; preferably by using NaBH 4 and NiCl 2 in the presence of a mixture of methanol and dimethylformamide at a temperature of about 20°C.
  • an organic solvent such as, for example, methanol, ethanol, tetrahydrofuran, dimethylformamide or a mixture thereof
  • the conversion of a compound of formula (I) into another compound of formula (I) with a different substitution pattern may be achieved by, for example: reacting a compound of formula (I) wherein m,
  • X, R 1 , R 2 , n, Q and W are as defined above and Y is an aryl or heteroaryl group substituted by an amino group and optionally substituted by 1 to 3 substituents independently chosen from halogen, C 1 -C 6 alkyl, trihalo-C 1 -C 3 alkyl, hydroxy, C 1 -C 6 alkoxy, C 1 -C 6 alkylthio and C 1 -C 6 alkylsulfonyl, with a compound of formula (VII) in the cis form
  • L-CH 2 -CH CH-CH 2 -L 1 (VII) where i n each of L and L 1 , be i ng the same or d i fferent , is a leaving group, so obtaining another compound of formula (I) wherein m, X, R 1 , R 2 , n, Q and W are as defined above and Y is an aryl or heteroaryl group substituted by a 3-pyrrolin-1-yl group and, in addition, optionally substituted by 1 to 3 substituents independently chosen from halogen, C 1 -C 6 alkyl, trihalo-C 1 -C 3 alkyl, hydroxy, C 1 -C 6 alkoxy, C 1 -C 6 alkylthio and C 1 -C 6 alkylsulfonyl; or
  • the leaving groups L and L 1 in the compound (VII) may be, for example, a halogen atom, e.g. chlorine or bromine, or an esterified hydroxy group such as, for example, a mesyloxy or tosyloxy group.
  • a halogen atom e.g. chlorine or bromine
  • an esterified hydroxy group such as, for example, a mesyloxy or tosyloxy group.
  • reaction between a compound of formula (I) and a compound of formula (VII) as described under method d) may be carried out according to known methods, for example in a polar organic solvent, e.g. dichloromethane, chloroform, dimethylformamide or dimethylsulfoxide, at a temperature ranging from about room temperature to about reflux temperature, optionally in the presence of a suitable proton scavenger, such as, for example triethylamine or potassium carbonate.
  • a polar organic solvent e.g. dichloromethane, chloroform, dimethylformamide or dimethylsulfoxide
  • the reduction of a compound of formula (I) as described under method e) may be carried out, e.g., by catalytic hydrogenation according to known procedures, using, for instance, palladium on charcoal or PtO, rhodium or Raney nickel as the catalyst, in an inert organic solvent such as, e.g., ethanol, methanol, ethyl acetate or dioxane, at a temperature ranging from about 20°C to about 60°C and under low pressure.
  • an inert organic solvent such as, e.g., ethanol, methanol, ethyl acetate or dioxane
  • the compounds of formula (II) may be obtained from the corresponding substituted aryl ketones, that are either commercially available or may be easily synthesized from commercially available starting materials by methods well known in the art, via halogen, e.g. bromine, replacement with alkali metal phthalimide, preferably potassium phthalimide, ketalization or thioketalization, and final hydrolysis of the phthalimido group, according to known methods in the art.
  • halogen e.g. bromine
  • alkali metal phthalimide preferably potassium phthalimide, ketalization or thioketalization
  • final hydrolysis of the phthalimido group according to known methods in the art.
  • a compound of formula (II) can be alternatively obtained by alkaline hydrolysis of a compound of formula (VIII) or ( VI I I a )
  • Y is an aryl or heteroaryl group substituted by one group chosen from C 1 -C 6 monoalkylamino, 3-pyrrolin-1-yl, pyrrolidin-1-yl and piperidin-1-yl, the aryl or heteroaryl group being optionally substituted in addition by 1 to 3 substituents independently chosen from halogen, C 1 -C 6 alkyl, trihalo-C 1 -C 3 alkyl, hydroxy, C 1 -C 6 alkoxy, C 1 -C 6 alkylthio and C 1 -C 6 alkylsulfonyl;
  • Z' is an aryl or heteroaryl group substituted by an amino group, the aryl or heteroaryl group, being optionally substituted in addition by 1 to 3 substituents independently chosen from halogen, C 1 -C 6 alkyl, trihalo-C 1 -C 3 alkyl, hydroxy, C 1 -C 6 alkoxy, C 1 -C 6 alkylthio and C 1 -C 6 alkylsulfonyl.
  • the alkaline hydrolysis of a compound of formula (VIII) or (VIIIa) to give a compound of formula (II) may be carried out by means of an aqueous alkali metal or alkaline earth metal hydroxide, for example NaOH, KOH or Ba(OH) 2 , in the presence of an appropriate co-solvent, for example ethanol, dioxane, diglyme and polyethylene glycol, at a temperature ranging from about 50°C to the reflux temperature of the mixture; preferred conditions are the use of concentrated aqueous sodium or potassium hydroxide and polyethylene glycol at a temperature ranging from about 100oC to about 140oC.
  • an aqueous alkali metal or alkaline earth metal hydroxide for example NaOH, KOH or Ba(OH) 2
  • an appropriate co-solvent for example ethanol, dioxane, diglyme and polyethylene glycol
  • a compound of formula (VI) can be obtained by reacting a compound of formula (IX)
  • This reaction may be carried out by following the same procedure described above in connection with the reaction of a compound of formula (II) with a compound of formula (III).
  • the present invention further provides a compound of formula (VIIIa): where i n
  • Z' is an aryl or heteroaryl group substituted by an amino group, the aryl or heteroaryl group being optionally substituted in addition by 1 to 3 substituents independently chosen from halogen, C 1 -C 6 alkyl, trihalo-C 1 -C 3 alkyl, hydroxy, C 1 -C 6 alkoxy, C 1 -C 6 alkylthio and C 1 -C 6 alkylsulfonyl;
  • n is zero, 1 or 2;
  • X is oxygen or sulphur
  • R 1 and R 2 are each, independently, a C 1 -C 6 alkyl group, or R 1 and R 2 taken together form a C 2 -C 4 alkylene chain in which each carbon atom is optionally substituted by 1 or 2 substituents independently chosen from halogen and C 1 -C 4 alkyl; and
  • n 1, 2 or 3.
  • Z is an aryl or heteroaryl group substituted by a nitro group, the aryl or heteroaryl group being optionally substituted in addition by 1 to 3 substituents independently chosen from halogen, C 1 - C 6 alkyl, trihalo-C 1 -C 3 alkyl, hydroxy, C 1 -C 6 alkylthio and C 1 -C 6 alkylsulfonyl;
  • n is zero, 1 or 2;
  • n 1, 2 or 3
  • R is a C 1 -C 6 alkyl group or a C 2 -C 4 alkylene chain in which each carbon atom is optionally substituted by
  • Z, m, X and n are as defined above, and R 1 and R 2 , being the same, are each a C 1 -C 6 alkyl group, and R 1 and R 2 together form a C 2 -C 4 alkylene chain in which each carbon atom is optionally substituted by 1 or 2 substituents independently chosen from halogen and C 1 - C 4 alkyl; and
  • reaction between a compound of formula (X) and a compound of formula (XI) or (XII) may be carried out in an organic solvent chosen, for example, from toluene, xylene, diglyme and nitromethane, in the presence of an acid catalyst such as, for example, p- toluene-sulfonic acid, methanesulfonic acid, trifluoromethane-sulfonic acid, trifluoroacetic acid, acidic ion exchange resins and mixture thereof, at a temperature ranging from about 50oC to the reflux temperature of the mixture.
  • an organic solvent chosen, for example, from toluene, xylene, diglyme and nitromethane
  • an acid catalyst such as, for example, p- toluene-sulfonic acid, methanesulfonic acid, trifluoromethane-sulfonic acid, trifluoroacetic acid, acidic ion exchange resins and mixture thereof, at a temperature
  • the water which is formed during the reaction can be removed, for example, either by azeotropic distillation, if the solvent is toluene or xylene or by using drying agents such as molecular sieves or Al 2 O 3 , or, alternatively, by reaction with a trialkylorthoformate such as, for example, trimethylorthoformate or triethylortho- formate.
  • a trialkylorthoformate such as, for example, trimethylorthoformate or triethylortho- formate.
  • this reaction may be carried out by using, for example, trifluoromethanesulfonic acid in toluene, in the presence of molecular sieves or by using trifluoromethanesulfonic acid in nitromethane, in the presence of trimethylorthoformate.
  • the reduction of a compound of formula (XIII), so obtaining a compound of formula (VIIIa) as defined under step 2) may be typically carried out by catalytic hydrogenation, for example in Pd/C or PtO, in the presence of an organic solvent such as, for example, ethyl acetate, dioxane, methanol or ethanol, at temperature ranging from about 20oC to about 60oC.
  • the compounds of formula (VIIIa) may be easily converted into compounds of formula (VIII).
  • the conversion of a compound of formula (VIIIa) into a compound of formula (VIII), and the optional conversion of a compound of formula (VIII) into another compound of formula (VIII) with different Y moieties may be carried out, for example:
  • step 3 4) reducing a compound of formula (VIII) as obtained under step 3), so obtaining another compound of formula (VIII) wherein m, X, R 1 , R 2 and n are as defined above and Y is an aryl or heteroaryl group substituted by a pyrrol idin-1-yl group the aryl or heteroaryl being optionally substituted in addition by 1 to 3 substituents independently chosen from halogen, C 1 -C 6 alkyl, trihalo-C 1 -C 3 alkyl, hydroxy, C 1 - C 6 alkoxy, C 1 -C 6 alkylthio and C 1 -C 6 alkylsulfonyl; or, if desired,
  • the reaction reported under step 3 may be carried out according to known methods, for example in a polar organic solvent such as, for example, dichloromethane, chloroform, dimethylformamide or dimethylsulfoxide, at a temperature ranging from room temperature to reflux temperature, in the presence of a suitable proton scavenger, typically triethylamine or potassium carbonate.
  • a polar organic solvent such as, for example, dichloromethane, chloroform, dimethylformamide or dimethylsulfoxide
  • the reduction as reported under step 4) may be carried out, for example, by low pressure catalytic hydrogenation, for example with Pd/C or PtO in an organic solvent such as, for example ethyl acetate, dioxane, methanol or ethanol, at a temperature ranging from about 20°C to about 60oC.
  • an organic solvent such as, for example ethyl acetate, dioxane, methanol or ethanol
  • the reaction as reported under step 5 may be carried out according to known methods, for example with a C 1 -C 5 alkyl aldehyde, in the presence of a reducing agent such as, for example hydrogen and Pd/C, or NaBH 3 CN and ZnCl 2 , or NaBH 4 and H 2 SO 4 (aq), at a temperature ranging from about 0oC to about 40oC.
  • a reducing agent such as, for example hydrogen and Pd/C, or NaBH 3 CN and ZnCl 2 , or NaBH 4 and H 2 SO 4 (aq)
  • the intermediate compounds of formula (VIIIa) can be also useful as intermediate compounds in a process for the preparation of known compounds such as, for example, a preferred class of compounds already disclosed in -EP-A-0 500 348, namely the compounds of formula (I)
  • A is an aryl group substituted by a C 1 -C 4 dialkylamino group
  • n is zero, 1 or 2;
  • X and Y being the same are oxygen or sulphur;
  • each of R 1 and R 2 independently is C 1 -C 6 alkyl or R 1 and R 2 taken together, are a C 2 -C 4 alkylene chain in which each carbon atom can be optionally substituted by 1 or 2 substituents independently chosen from halogen and C 1 -C 4 alkyl;
  • n 1, 2 or 3;
  • Q is oxygen or sulphur
  • B is an aryl group unsubstituted or substituted by 1 to
  • the isocyanates and isothiocyanates of formula (III) are known compounds or may be obtained by known methods from the corresponding amino-compounds.
  • Compounds of formula (IV) may be obtained by reacting compounds of formula (II) with phosgene or thiophosgene according to known processes.
  • the amines of formula (V) are known or commercially available compounds, or, if not previously known, may be easily synthesized from commercially available starting materials, by methods well known in the art.
  • Compounds of formula (IX), (X), (XI) and (XIII) are commercially available compounds, or may be easily synthesized from commercially available starting materials to the common knowledge in the art.
  • the compounds of the invention show inhibitory activity of the enzyme acyl CoA: cholesterol acyltransferase (ACAT-EC 2.3.1.26) which regulates the intracellular esterification of cholesterol (Suckling K.E. Stange E.F., J. Lip. Res. (1985) 26, 647) and thus the intracel lular accumulation of cholesteryl esters.
  • acyl CoA cholesterol acyltransferase
  • ACAT also plays a key role in the intestinal absorption of cholesterol and a significant activity of the enzyme has been observed in intestinal mucosa cells from several animal species (Heider J.G., Pickens C.E., Kelly LA., J. Lip. Res. (1983) 24, 1127).
  • the compounds of this invention have antidyslipidaemic activity and act also as direct antiatherosclerotic agents, able to inhibit the development of the atheromatous plaque. They are therefore useful in particular for the prevention of coronary heart disease (CHD), e.g. myocardial infarction and angina.
  • CHD coronary heart disease
  • the compounds of the invention are useful as antidyslipidaemic agents, indeed they show a high activity in lowering total serum cholesterol and triglycerides.
  • ACAT inhibitors of the compounds of the present invention has been evaluated in our laboratories on microsomal preparations from rabbit intestinal mucosa, essentially according to F. B. Bell (Atherosclerosis-1981- 38,81).
  • the following Table exemplifies the results obtained by testing for instance a representative group of compounds according to this invention:
  • a human or animal may thus be treated by a method comprising administering thereto a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.
  • the disease or disorder from which the human or animal is suffering may thereby be ameliorated.
  • the condition of the human or animal can thus be improved.
  • the dosage level suitable for oral administration to adult humans of the compounds of the invention may range from about 20 mg to about 500 mg per dose 1 to 3 times a day, depending on the disease, age and weight of the patients involved.
  • N-[2,6-bis(1-methylethyl)phenyl]-N'-[(4R,5R)-2-[4-(3-pyrrolin-1-yl)phenyl]-4,5-dimethyldioxolan-2-yl]methylurea is suitable administered orally at a dose in this range.
  • the toxicity of the compounds of the invention is negligible, therefore they can be safely used in therapy.
  • Nine hours food deprived mice and rats were treated orally with single administration of increasing doses, then housed and normally fed.
  • the orientative acute toxicity (LD 50 ) was assessed on the seventh day after the treatment, for instance in the mouse after oral administration.
  • the compounds of the invention can be administered in a variety of dosage forms, e.g. orally, in the form of tablets, capsules, sugar- or film-coated tablets, liquid solutions or suspensions.
  • the invention includes pharmaceutical compositions comprising a compound of the invention in association with a pharmaceutically acceptable excipient (which can be carrier or diluent).
  • a pharmaceutically acceptable excipient which can be carrier or diluent.
  • compositions comprising the compounds of the invention are typically prepared following conventional methods and are administered in a pharmaceutically suitable form.
  • the solid oral forms may comprise, together with the active compound, diluents, e.g. lactose, dextrose, saccharose, cellulose, corn starch or potato starch; lubricants, e.g. silica, talc, stearic acid, magnesium or calcium stearate, and/or polyethylene glycols; binding agents, e.g. starches, arabic gums, gelatin, methylcellulose, carboxymethylcellulose or polyvinyl pyrrolidone; disaggregating agents, e.g.
  • diluents e.g. lactose, dextrose, saccharose, cellulose, corn starch or potato starch
  • lubricants e.g. silica, talc, stearic acid, magnesium or calcium stearate, and/or polyethylene glycols
  • binding agents e.g. starches, arabic gums, gelatin, methylcellulose, carboxymethylcellulose or polyvinyl pyrrol
  • starch alginic acid, alginates or sodium starch glycolate; effervescing mixtures; dyestuffs; sweeteners; wetting agents, such as lecithin, polysorbates and laurylsulphates; and, in general, non-toxic and pharmacologically inactive substances used in pharmaceutical formulations.
  • Said pharmaceutical preparations may be manufactured in known manner, for example, by means of mixing, granulating, tabletting, sugar-coating, or film-coating processes.
  • the liquid dispersions for oral administration may be e.g. syrups, emulsions, and suspensions.
  • the syrups may contain as carrier, for example, saccharose or saccharose with glycerine and/or mannitol and/or sorbitol; in particular a syrup to be administered to diabetic patients can contain as carriers only products not metabolizable to glucose, or metabolizable in very small amount to glucose, for example sorbitol.
  • the suspensions and the emulsions may contain as carrier, for example, a natural gum, agar, sodium alginate, pectin, methylcellulose, carboxymethylcellulose, or polyvinyl alcohol.
  • carrier for example, a natural gum, agar, sodium alginate, pectin, methylcellulose, carboxymethylcellulose, or polyvinyl alcohol.
  • reaction mixture is then filtered and concentrated in vacuo to give a white solid that is purified by column chromatography (eluent n-hexane/ethyl acetate) and then crystallized from ethyl acetate yielding 3.50 gof (-)-N-[2,6-bis(1-methylethyl)phenyl]-N'-[(4R,5R)-2-[(4-pyrrolidin-1-yl)phenyl]-4,5-dimethyldioxolan-2-yl]methyl-urea;
  • reaction mixture is stirred for 90' and is then concentrated by distilling off at reduced pressure about 140 ml of solvent.
  • Diluted aqueous ammonium hydroxide and diethylether are added, the organic layer is separated, washed with water and brine, dried over anhydrous sodium sulphate, and the solvent is evaporated at reduced pressure.
  • the raw material is purified by column chromatography over silica-gel (eluent methyl alcohol /chloroform) and then crystallized from ethyl acetate yielding 2.5 g of (-)N-[2,6-bis(1-methylethyl)phenyl]-N'-[(4R,5R)-2-(4-aminophenyl)-4,5-dimethyldioxolan-2-yl]methylurea;
  • the raw material is purified by column chromatography over silica-gel (eluent chloroform/isopropyl alcohol) yielding 1.15 g of [5,5-dimethyl-2-[4-(3-pyrrolin-1-yl)phenyl]-1,3-dioxan-2-yl]methylamine; white powder m.p. 130-132oC.
  • reaction mixture After cooling the reaction mixture is poured into an ice-cooled solution of 0.5N aqueous sodium hydroxide and extracted with diehtylether.
  • the organic layer is washed with water and brine, dried over anhydrous sodium sulphate, and the solvent is evaporated at reduced pressure.
  • N-[2-(4-nitrophenyl)-1,3-dithian-2-yl] methylacetamide can be analogously prepared.
  • preparation can be made of capsules having the following composition:

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PCT/EP1994/002058 1993-08-03 1994-06-24 Urea and thiourea derivatives and process for their preparation WO1995004053A1 (en)

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1996026948A1 (en) * 1995-03-01 1996-09-06 Pharmacia & Upjohn S.P.A. Phosphate derivatives of disubstituted ureas and thioureas
WO2019024411A1 (zh) * 2017-08-04 2019-02-07 深圳新宙邦科技股份有限公司 一种消氢剂及其制备方法、铝电解电容器电解液

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
RO82905A2 (ro) * 1981-10-01 1984-01-14 Intreprinderea De Medicamente "Terapia",Ro Procedeu pentru prepararea p-nitro-omega-acetamidoacetofenonei
EP0500348A1 (en) * 1991-02-19 1992-08-26 PHARMACIA S.p.A. Disubstituted ureas and thioureas

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
RO82905A2 (ro) * 1981-10-01 1984-01-14 Intreprinderea De Medicamente "Terapia",Ro Procedeu pentru prepararea p-nitro-omega-acetamidoacetofenonei
EP0500348A1 (en) * 1991-02-19 1992-08-26 PHARMACIA S.p.A. Disubstituted ureas and thioureas

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
CHEMICAL ABSTRACTS, vol. 102, 1985, Columbus, Ohio, US; abstract no. 95397w, M. VALENTIN ET AL.: "p-Nitro-omega-acetamidoacetophenone" page 550; *

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1996026948A1 (en) * 1995-03-01 1996-09-06 Pharmacia & Upjohn S.P.A. Phosphate derivatives of disubstituted ureas and thioureas
WO2019024411A1 (zh) * 2017-08-04 2019-02-07 深圳新宙邦科技股份有限公司 一种消氢剂及其制备方法、铝电解电容器电解液

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