EP0662969A1 - Urea and thiourea derivatives and process for their preparation - Google Patents

Urea and thiourea derivatives and process for their preparation

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Publication number
EP0662969A1
EP0662969A1 EP94921623A EP94921623A EP0662969A1 EP 0662969 A1 EP0662969 A1 EP 0662969A1 EP 94921623 A EP94921623 A EP 94921623A EP 94921623 A EP94921623 A EP 94921623A EP 0662969 A1 EP0662969 A1 EP 0662969A1
Authority
EP
European Patent Office
Prior art keywords
phenyl
alkyl
formula
compound
halogen
Prior art date
Legal status (The legal status 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 status listed.)
Withdrawn
Application number
EP94921623A
Other languages
German (de)
French (fr)
Inventor
Paolo Cozzi
Daniele Fancelli
Dino Severino
Augusto Chiari
Giancarlo Ghiselli
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Pfizer Italia SRL
Original Assignee
Pharmacia and Upjohn SpA
Pharmacia SpA
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Filing date
Publication date
Application filed by Pharmacia and Upjohn SpA, Pharmacia SpA filed Critical Pharmacia and Upjohn SpA
Publication of EP0662969A1 publication Critical patent/EP0662969A1/en
Withdrawn legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/10—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a carbon chain containing aromatic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/08—Vasodilators for multiple indications
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D317/00—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms
    • C07D317/08—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3
    • C07D317/10—Heterocyclic 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
    • C07D317/14—Heterocyclic 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
    • C07D317/28—Radicals substituted by nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D319/00—Heterocyclic compounds containing six-membered rings having two oxygen atoms as the only ring hetero atoms
    • C07D319/04—1,3-Dioxanes; Hydrogenated 1,3-dioxanes
    • C07D319/06—1,3-Dioxanes; Hydrogenated 1,3-dioxanes not condensed with other rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D339/00—Heterocyclic compounds containing rings having two sulfur atoms as the only ring hetero atoms
    • C07D339/02—Five-membered rings
    • C07D339/06—Five-membered rings having the hetero atoms in positions 1 and 3, e.g. cyclic dithiocarbonates
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/10—Heterocyclic 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
    • 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

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 ⁇ -Cg monoalky 1amino.
  • 3- pyrrol in-1-yl , pyrrol idin-1- l , morphcl in-4-yl and piperidin-1-yl being such aryl or heteroaryl group in addition, optionally substituted by 1 to 3 substi ⁇ tuents independently chosen from halogen, C ⁇ -C.
  • alkyl trihalo-C j -C j alkyl; hydroxy, C j -Cg alkoxy, c ⁇ c 6 alkylthio and J-CJ alkylsulfonyl; m is zero, 1 or 2; X is oxygen or sulphur;
  • R j and R 2 are each, independently, a C ⁇ -Cg alkyl group or R. j and 2 taken together form a alkylene chain in _ 9 -
  • W is an aryl or heteroaryl group unsubstituted or substituted by 1 to 4 substituents independently chosen from halogen, 0,-Cg alkyl , trihalo-C ⁇ -C ⁇ alkyl,
  • the invention includes within its scope all the possible isomers, stereoisomers, both separately and in mixture and the metabolites and the metabolic precursors or bio- precursors of the compounds of formula (I).
  • the alkyl groups as well as the aliphatic moieties of the alkoxy, alkylthio and alkylsulfon l groups, may be branched or straight chains.
  • a C -CJ alkyl group is e.g. a C_
  • a C_,-C ⁇ alkyl group is preferably methyl or ethyl.
  • a Cg alkoxy group is preferably methoxy, ethoxy, propoxy or isopropoxy, in particular methoxy or ethoxy.
  • a C ⁇ -Cg alkylthio group is e.g. methylthio, ethylthio, propylthio or butylthio, in particular methylthio or ethylthio.
  • a C ⁇ -Cg alkylsulfonyl group is e.g. ethylsulfonyl , ethylsulfonyl , propy1 sulfony1 , in particular methyl ⁇ sulfonyl .
  • a halogen atom is e.g. chlorine, bromine or fluorine, in particular bromine.
  • a trihalo-C-C alkyl group is e.g. a trichloro- or trifluoro C ⁇ -C j alkyl group, in particular trifluoro- methyl .
  • 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 eteromonocycl ic ring containing from 1 to 3 , preferably 1, heteroato s independently chosen from nitrogen, sulphur and oxygen, in particular a thienyl or pyridyl ring.
  • R. and R taken together form a C.-C, alkylene chain and X is sulfur then the pentatomic, hexatomic or heptatomic resulting 1 , 3-dithioalkyl ring is respectively a 1 , 3-dithiolan, 1,3-dithian or 1,3- dithiepan ring which may be represented by the following chemical formula "*C , wherein / R ⁇ represents a C.-C, alkylene chain in which each carbon atom may be optionally substituted by 1 or 2 substituents independentl chosen from halogen, in particular fluorine, and C j -C ⁇ alkyl.
  • Preferred compounds of the invention are the compounds of formula (I), wherein m is zero or 1 ; n is 1 , 2 or 3; o -
  • Q is oxygen or sulphur
  • X is oxygen or sulphur
  • R, and R 7 taken together, form a C.-C ⁇ alkylene chain in which each carbon atom is unsubstituted or substituted by one or two substituents independently chosen from halogen and C.-C ⁇ alkyl;
  • Y is an aryl group substituted by a morphol in-4-y1 , 3- pyrrol in-1-yl or pyrrol idin-1-y1 group, the aryl group being optionally substituted in addition by 1 to 2 substituents independently chosen from halogen, C..-C alkyl, trif1uoromethy1 , hydroxy, C j -C ⁇ alkoxy, j -C ⁇ alkylthio and
  • W is a phenyl or pyridyl ring substituted by 1 to 3 substituents independently chosen from halogen, C ⁇ -C ⁇ alkyl, 0,,-C ⁇ alkoxy and C j -C ⁇ alkylthio; or a pharma ⁇ ceutically acceptable salt thereof.
  • X is oxygen
  • Examples of preferred compounds of the present invention are the following:
  • n m, R>. , 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 ⁇ c ⁇ alkyl, trihalo-C ⁇ -C j alky1 , hydroxy, C.-Cg alkoxy, Ci-C j alkylthio and C_ j -Cg alkylsulfonyl, so obtaining a compound of formula (I) wherein m, X, R.
  • 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 4 ⁇ c ⁇ alkyl, trihalo-C j -C, alkyl, hydroxy, c ⁇ c ' alkoxy, C 4 ⁇ "Cg alkylthio and .-Cg alkylsulfon 1 ; and, if desired, converting a compound of formula (I) into another compound of formula (I) and/or, if desired, salifying a compound ' of formula (I), and/or, if desired, resolving a mixture of isomers of formula (I) into the single isomers.
  • 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 0 C C to reflux temperature of the reacting mixture.
  • a suitable organic solvent e.g. ethyl acetate or n- hexane
  • 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.
  • NiCl ⁇ or CDC1 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 0 ! C to about 30'C; preferably by using aBH ⁇ 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, at a temperature ranging from about 0 ! C to about 30'C; preferably by using aBH ⁇ and NiCl 2 in the presence of a mixture of methanol and dimethylformamide at a temperature of about 20°C.
  • 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 ,
  • , R 2 , n, 0 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.-Cg alkyl, trihalo-C j -C j alkyl , hydroxy, C ⁇ -Cg alkoxy, C,-Cg alkylthio and C_J-CJ alkylsulfonyl, with a compound of formula (VII) in the cis form
  • i n each of L and L, , 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-pyrrol in-1-yl group and, in addition, optionally substituted by 1 to 3 substituents independently chosen from halogen, C.-Cg alkyl, trihalo- ⁇ -C j alkyl , hydroxy, C j -Cg alkoxy, C j -Cg alkylthio and C j -Cg alkylsulfonyl; or e) reducing a compound of formula (I) obtained following the procedure described under method d), so obtaining another compound of formula (I) wherein m, X, R_, , R 2 , n, Q and W are as defined above and Y is an
  • the leaving groups L and L ⁇ 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.
  • the 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 suitable proton scavenger such as, for example triethylamine or potassium carbonate.
  • the reduction of a compound of formula (I) as described under method e) may be carried out, e.g.
  • 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, Ci-Cg alkyl, trihalo-C_ j -C j alkyl, hydroxy, j -Cg alkoxy, C ⁇ -Cg alkylthio and ⁇ -Cg alkylsulfonyl.
  • the alkaline hydrolysis of a compound of formula (VIII) or (Villa) 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 100 * C to about 140 : C.
  • a compound of formula (VI) can be obtained by reacting a compound of formula (IX)
  • the present invention further provides a compound of formula (Villa): X R .
  • 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.-C- ⁇ alkyl, trihalo-C ⁇ -C j alkyl , hydroxy, C ⁇ -Cg alkoxy, C ⁇ Cg alkyltnio and j -Cg alkylsulfonyl; m is zero, 1 or 2; X is oxygen or sulphur,
  • R j and R 2 are each, independently, a C ⁇ -C alkyl group, or R, and R 2 taken together form a C 2 -Ci alkylene chain in which each carbon atom is optionally substituted by 1 or 2 substituents independently chosen from halogen and C ⁇ -C ⁇ alkyl; and n is 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,-
  • R is a C ⁇ -Cg alkyl group or a C ⁇ -C ⁇ alkylene chain in ' which each carbon atom is optionally substituted by
  • Z, , X and n are as defined above, and R 1 and R 2 , being the same, are each a C j -C fi alkyl group, and R, 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 ndependently chosen from halogen and C.- Ci 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, tri- fluoromethane-sulfonic acid, trif1uoroacetic acid, acidic ion exchange resins and mixture thereof, at a temperature ranging from about 50'C 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, tri- fluoromethane-sulfonic acid, trif1uoroacetic acid, acidic ion exchange resins and mixture thereof
  • 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 A ⁇ O j , 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, trif1uoromethanesulfonic 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 (Villa) 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 20'C to about 60'C.
  • the compounds of formula (Villa) may be easily converted into compounds of formula (VIII).
  • the conversion of a compound of formula (Villa) 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 , X, R, , 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 j -Cg alkyl , trihalo-C.-C, al ky1 , hydroxy, C ⁇ - C j alkoxy, C ⁇ -Cg alkylthio and C_ ⁇ -Cg 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 hydro- genation, 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 60'C.
  • 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.-C- alkyl aldehyde, in the presence of a reducing agent such as, for example hydrogen and Pd/C, or NaBH j CN and ZnCl 2 , or aBH ⁇ and H j SO ⁇ aq), at a temperature ranging from about 0"C to about 40'C.
  • a reducing agent such as, for example hydrogen and Pd/C, or NaBH j CN and ZnCl 2 , or aBH ⁇ and H j SO ⁇ aq
  • the intermediate compounds of formula (Villa) 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 j -C, dialkylamino group; is zero, 1 or 2; X and Y being the same are oxygen or sulphur; each of R, and R 2 , independently is C.-Cg alkyl or R_ ⁇ and R 2 taken together, are a C ⁇ -C ⁇ alkylene chain in which each carbon atom can be optionally substituted by 1 or 2 substituents independently chosen from halogen and C,- C 4 alkyl ; n is 1 , 2 or 3;
  • Said pharmaceutical preparations may be manufactured in known manner, for example, by means of mixing, granulat ⁇ ing, tabletting, sugar-coating, or film-coating processes.
  • the liquid dispersions for oral adminis ⁇ tration 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 metabol izable to glucose, or metabol izable in very small amount to glucose, for example sorbito! .
  • the suspensions and the emulsions may contain as carrier, for example, a natural gum, agar, sodium alginate, pectin, methylcel 1 lose, carboxymethyl- cellulose, or polyvinyl alcohol.
  • carrier for example, a natural gum, agar, sodium alginate, pectin, methylcel 1 lose, carboxymethyl- cellulose, or polyvinyl alcohol.
  • N'-[(4R,5R)-2-[4-(3-pyrrol in-1-yl )pheny1 ]-4 , 5-dimethy1- dioxolan-2-yl ]methylurea (6.50 g) in ethyl alcohol (100 ml) is added Pd-C 0% (350 mg) and the mixture is hydrogenated at a Parr apparatus at room temperature until the theoretical amount of hydrogen is taken up.
  • 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.
  • reaction mixture After cooling the reaction mixture is poured into an ice-cooled solution of 0.5N aqueous sodium hydroxide and extracted with diehtylether.
  • N-[2-(4-nitrophenyl )-1 ,3-dithian-2-yl ] methylacetamide can be analogously prepared.

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Abstract

The invention provides a compound of formula (I), wherein Y is an aryl or heteroaryl group substituted by a group chosen from amino, C1-C6 monoalkylamino, 3-pyrrolin-1-yl, pyrrolidin-1-yl, morpholin-4-yl and piperidin-1-yl, the aryl or heteroaryl being optionally substituted in addition by 1 to 3 substituents independently chosen from halogen, C1-C6 alkyl, trihalo-C1-C3 alkyl, hydroxy, C1-C6 alkoxy, C1-C6 alkylthio and C1-C6 alkylsulfonyl; m is zero, 1 or 2; X is oxygen or sulphur; R1 and R2 are each, independently, a C1-C6 alkyl group or R1 and R2 taken together form a C2-C4 alkylene chain in which each carbon atom is optionally substituted by 1 or 2 substituents independently chosen from halogen and C1-C4 alkyl; n is 1, 2 or 3; Q is oxygen or sulphur; W is an aryl or heteroaryl group unsubstituted or substituted by 1 to 4 substituents independently chosen from halogen, C1-C6 alkyl, trihalo-C1-C3 alkyl, C1-C6 alkoxy, C1-C6 alkylthio and C1-C6 alkylsulfonyl; or a pharmaceutically acceptable salt thereof. The compounds of the invention show inhibitory activity of the enzyme acyl CoA: cholesterol acyltransferase (ACAT-EC 2.3.1.26) and thus have utility as antiatherosclerotic and antidyslipidaemic agents and in the prevention of coronary heart disease.

Description

UREA AND THIOUREA DERIVATIVES AND PROCESS FOR THEIR
PREPARATION
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)
(CH, ) -C-(CH9)n-NH-C-NH-W (I)
XR.
wherein
Y is an aryl or heteroaryl group substituted by one group chosen from amino, C^-Cg monoalky 1amino. 3- pyrrol in-1-yl , pyrrol idin-1- l , morphcl in-4-yl and piperidin-1-yl , being such aryl or heteroaryl group in addition, optionally substituted by 1 to 3 substi¬ tuents independently chosen from halogen, C^-C. alkyl, trihalo-Cj-Cj alkyl; hydroxy, Cj-Cg alkoxy, cι~c6 alkylthio and J-CJ alkylsulfonyl; m is zero, 1 or 2; X is oxygen or sulphur;
Rj and R2 are each, independently, a C^-Cg alkyl group or R.j and 2 taken together form a alkylene chain in _ 9 -
which each carbon atom is optionally substituted by 1 or 2 substituents i dependently chosen from halogen and C_|-C^ alkyl ; n is 1 , 2 or 3; Q is oxygen or sulphur;
W is an aryl or heteroaryl group unsubstituted or substituted by 1 to 4 substituents independently chosen from halogen, 0,-Cg alkyl , trihalo-C^-C^ alkyl,
0,-Cg alkoxy, C^-Cj alkylthio and C.,-C6 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 bio- precursors of the compounds of formula (I). In the specification the alkyl groups as well as the aliphatic moieties of the alkoxy, alkylthio and alkylsulfon l groups, may be branched or straight chains. A C -CJ alkyl group is e.g. a C_|-C4 alkyl group, in particular methyl, ethyl, propyl or butyl.
A C_,-Cι alkyl group is preferably methyl or ethyl. A Cg alkoxy group is preferably methoxy, ethoxy, propoxy or isopropoxy, in particular methoxy or ethoxy. A C^-Cg alkylthio group is e.g. methylthio, ethylthio, propylthio or butylthio, in particular methylthio or ethylthio. A C^-Cg alkylsulfonyl group is e.g. ethylsulfonyl , ethylsulfonyl , propy1 sulfony1 , in particular methyl¬ sulfonyl .
A halogen atom is e.g. chlorine, bromine or fluorine, in particular bromine.
A trihalo-C-C alkyl group is e.g. a trichloro- or trifluoro C^-Cj alkyl group, in particular trifluoro- methyl . 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 eteromonocycl ic ring containing from 1 to 3 , preferably 1, heteroato s independently chosen from nitrogen, sulphur and oxygen, in particular a thienyl or pyridyl ring.
When R_< and R, taken together form a C,-C4 alkylene chain and X is oxygen, then the pentatomic, hexatomic or heptatomic resulting 1 , 3-dioxalkyl ring is respectively a 1 , 3-dioxolan, 1 ,3-dioxan or 1 , 3-dioxepan ring which may be represented by the following chemical formula
alkylene chain in which each carbon atom may be optionally substituted by 1 or 2 substituents independently chosen from halogen, in particular fluorine, and C^-C^ alkyl . Analogously, when R. and R taken together form a C.-C, alkylene chain and X is sulfur, then the pentatomic, hexatomic or heptatomic resulting 1 , 3-dithioalkyl ring is respectively a 1 , 3-dithiolan, 1,3-dithian or 1,3- dithiepan ring which may be represented by the following chemical formula "*C , wherein /R^ represents a C.-C, alkylene chain in which each carbon atom may be optionally substituted by 1 or 2 substituents independentl chosen from halogen, in particular fluorine, and Cj-C^ 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, ethanesulfonic, malonic, malic, maleic, tartaric, citric, benzoic, cinnamic, mandelic and salicylic acids. As stated above, the present invention also includes within its scope pharmaceutically acceptable bio- precursors (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 m is zero or 1 ; n is 1 , 2 or 3; o -
Q is oxygen or sulphur;
X is oxygen or sulphur;
R, and R7, taken together, form a C.-C^ alkylene chain in which each carbon atom is unsubstituted or substituted by one or two substituents independently chosen from halogen and C.-C^ alkyl;
Y is an aryl group substituted by a morphol in-4-y1 , 3- pyrrol in-1-yl or pyrrol idin-1-y1 group, the aryl group being optionally substituted in addition by 1 to 2 substituents independently chosen from halogen, C..-C alkyl, trif1uoromethy1 , hydroxy, Cj-C^ alkoxy, j-C^ alkylthio and |-Ci alkylsulfony ;
W is a phenyl or pyridyl ring substituted by 1 to 3 substituents independently chosen from halogen, C^-C^ alkyl, 0,,-C^ alkoxy and Cj-C^ alkylthio; or a pharma¬ ceutically acceptable salt thereof.
More preferred compounds of the invention are the compounds of formula (I), wherein m is zero or 1 ; n is 1 or 2;
Q is oxygen;
X is oxygen;
R. and 2 taken together form a C2-C. alkylene chain in which at least one carbon atom is substituted by one or two substituents independently chosen from halogen and C..-Ci alky1 ; Y is an aryl group substituted by a morphol in-4-yl or 3- pyrrol in-1-yl group and, in addition, optionally substituted by 1 or 2 substituents independently chosen from halogen, C]~C A alkyl , trif1uoromethyl , hydroxy, cι_C. alkoxy, cι~c_ alkylthio and '-ι~Ci al kylsulfon 1 ;
W is a phenyl or pyridyl ring substituted by one, two or three substituents independently chosen from halogen, C<-Ci alkyl, .-C4 alkoxy and methylthio; or a pharma- ceutically acceptable salt thereof.
Examples of preferred compounds of the present invention are the following:
N-[2,6-bis( 1-methylethyl Ipheny1]-N' -{2-[4-.'3-pyrrol ιn-1- yl )phenyl ]-4,5-dimethy1dioxolan-2-y1 }methylurea; N-[2,6-bis( 1-methylethyl )pheny1]-M' -{2-[4-(pyrrolidin-1- yl )phenyl j- , 5-dimethy!dioxolan-2-y1 }methylurea;
N-[2,6-bis( 1-methylethyl )pheny1 ]- ' - {5 , 5-dimethy1-2-[4-
(3-pyrrol in-1-yl )phenyl ]-1 , 3-dioxan-2-y1 }methylurea;
N-[2,6-bis( 1-methylethyl )phenyl ]-N'-{5 , 5-dimethy1-2-[4- (pyrrol idin-1-yl )phenyl ]-1 ,3-dioxan-2-yl }methylurea;
N-[2,6-bis( 1-methylethyl )phenyl ]- '- {5 , 5-dimethy1-2-[4-
(piperidin-1-yl )phenyl ]-1 ,3-dioxan-2- 1 }methylurea;
N-[2,6-bis( 1-methylethyl )phenyl]- '-{2-[4-(3-pyrrol i -1- yl )phenyl ]dithiolan-2-yl }methylurea; N- [2, 6-bis( methyl thio phenyl ] -N'-{2-[4-( 3-pyrro1 in-1- yl )phenyl ]- , 5-dimethyldioχolan-2-y1 }methylurea; N-[2, 6-bis( 1-methylethyl )phenyl]-N'-{2-[4-(3-pyrrol i -1- yl ) phenyl ]-1 , 3-di thi an-2-yl } methyl urea;
N-[2,6-bis( 1-methylethyl )pheny 1]-N ' -{2-[4-(pyrrolidi n-1- yl ) phenyl ]di thiolan-2-y 1 }methylurea; N- [ 2, 6- is( methylthio) phenyl ]-N '- {5 , 5-di methyl -2- [4-( 3- pyrrol in-1-yl ) phenyl ]- 1 , 3-dioxan-2-yl } ethyl urea;
N- [2, 6-bis( methyl thi o) phenyl ] -N ' - {2- [4- ( 3-pyrro in-1 - l ) phenyl ]di hiolan-2-yl }methylu ea;
N- [ 2, 6-bis( 1-methylethyl )pheny 1 ]-N '-[ 5 , 5-dimethy 1-2- ( 3- bromo-4-morphol in-4-yl ) phenyl -1 , 3-d ioxan-2-yl ] ethyl - urea; if the case, either as single isomer or a mixture of isomers, and the pharmaceutically acceptable salts thereof. The compounds of the present invention can be obtained by a process comprising: a) reacting a compound of formula (II)
XR.
Y-(CH2)rn-C-(CHl)n-NH2 (II)
XR,
wherein Y, m, X, R1, R2 and n are as defined above, with an isocyanate or isothiocyanate of formula (III)
Q=C=N-W (III) wherein Q and W are as defined above, so obtaining a compound of formula (I) wherein Y, m, X, R^ , R2 , n, Q and W are as defined above; or b) reacting a compound of formula (IV)
XR, i I
Y-(CH2 )m-C-(CH2 )n-N=C=Q (IV) XR„
wherein Y, m, X, R_j , R,, n and Q are as defined above, with an amine of formula (V)
H2N-W (V)
wherein W is as defined above, so obtaining a compound of formula (I) wherein i, m, X. R. , R», n, 0 and W are as defined above; or
c) reducing a compound of formula (VI)
XR, I 1
Z-(CH2)m-C-(CHl)n-NH-C-NH-W (VI)
XR2 Q
wherei n m, R>. , R2 , 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\~c~ alkyl, trihalo-C^-Cj alky1 , hydroxy, C.-Cg alkoxy, Ci-Cj alkylthio and C_j-Cg alkylsulfonyl, so obtaining a compound of formula (I) wherein m, X, R. , R« , 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 4~c β alkyl, trihalo-Cj-C, alkyl, hydroxy, c ~c' alkoxy, C 4~"Cg alkylthio and .-Cg alkylsulfon 1 ; and, if desired, converting a compound of formula (I) into another compound of formula (I) and/or, if desired, salifying a compound ' of formula (I), and/or, if desired, resolving a mixture of isomers of formula (I) into the single isomers.
The 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.
For example, 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 0CC 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. or KBH, together with NiCl^ or CDC12 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 0!C to about 30'C; preferably by using aBH^ and NiCl2 in the presence of a mixture of methanol and dimethylformamide at a temperature of about 20°C.
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 ,
X, R<| , R2, n, 0 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.-Cg alkyl, trihalo-Cj-Cj alkyl , hydroxy, C^-Cg alkoxy, C,-Cg alkylthio and C_J-CJ alkylsulfonyl, with a compound of formula (VII) in the cis form
L-CH2-CH=CH-CH2-Lj (VII)
where i n each of L and L, , be i ng the same or d i fferent , is a leaving group, so obtaining another compound of formula (I) wherein m, X, R1 , R2, n, Q and W are as defined above and Y is an aryl or heteroaryl group substituted by a 3-pyrrol in-1-yl group and, in addition, optionally substituted by 1 to 3 substituents independently chosen from halogen, C.-Cg alkyl, trihalo-^-Cj alkyl , hydroxy, Cj-Cg alkoxy, Cj-Cg alkylthio and Cj-Cg alkylsulfonyl; or e) reducing a compound of formula (I) obtained following the procedure described under method d), so obtaining another compound of formula (I) wherein m, X, R_, , R2, n, Q and W are as defined above and Y is an aryl or heteroaryl group substituted by a pyrrol idin-1-yl group and, in addition, optionally substituted by 1 to 3 substituents chosen from halogen, C.-C^ alkyl, trihalo-C^Cj alkyl, hydroxy, C^-Cg alkoxy, C.,-Cg alkylthio and C^-Cg alkylsulfonyl.
The leaving groups L and L^ 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.
The 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. 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.
The salification of a compound of formula ( I ) as well as the separation of a mixture of isomers of a compound of the invention into the single isomers may be carried out according to conventional procedures.
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 phthal imide, ketal i zation or thioketal ization, and final hydrolysis of the phthal imido 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 (Villa)
XR. Y-(CH2)m-C-(CH2)n-NHCOCH3 (VIII)
XR2
XR.
I ]
Z ' - ( CH2 ) -C- ( CH2 )n-NHCOCH3 (Villa)
XR2
wherein m, X, R^ , R2 and n are as defined above, Y is an aryl or heteroaryl group substituted by one group chosen from C_j-Cg monoal kylamino, 3-pyrrol in-1-yl , pyrrol idin-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_j-Cg alkyl, trihalo-C^-Cj alkyl, hydroxy, C,-Cg alkoxy, C,-Cg alkylthio and C^-C-. alkylsulfonyl; and 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, Ci-Cg alkyl, trihalo-C_j-Cj alkyl, hydroxy, j-Cg alkoxy, C^-Cg alkylthio and ^-Cg alkylsulfonyl.
The alkaline hydrolysis of a compound of formula (VIII) or (Villa) 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 100*C to about 140:C. A compound of formula (VI) can be obtained by reacting a compound of formula (IX)
Z-(CH2 )n-NH2 (IX)
wherein Z, m, X, R1 , R2 and n are as defined above with a compound of formula (III) as defined above. 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 (Villa): X R .
I i
- ( CH2 )m-C- ( CH2 )n-NHCOCH3 ( Vi l la ) R „
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.-C-^ alkyl, trihalo-C^-Cj alkyl , hydroxy, C^-Cg alkoxy, C^Cg alkyltnio and j-Cg alkylsulfonyl; m is zero, 1 or 2; X is oxygen or sulphur,
Rj and R2 are each, independently, a C^-C alkyl group, or R, and R2 taken together form a C2-Ci alkylene chain in which each carbon atom is optionally substituted by 1 or 2 substituents independently chosen from halogen and C^-C^ alkyl; and n is 1 , 2 or 3.
Compounds of formula (Villa) are novel intermediates in the preparation of compounds of formula (I).
The compounds of formula (Villa) .can be obtained by a new process which represents further object of the present invention, said process comprising:
1) reacting a compound of formula (X) Z- ( CH, ) -C- ( CH, ) -NHCOCH, ( X )
. tn j, - n i
0 wherei n
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,-
Cg alkyl, trihalo-Cj-Cj alkyl , hydroxy, c ι~Cg alkylthio and C^-Cg alkylsulfonyl; m is zero, 1 or 2; and n is 1 , 2 or 3 , with a compound of formula (XI) or (XII)
R-XH (XI) HX-R-XH (XII)
wherein
R is a C^-Cg alkyl group or a C^-C^ alkylene chain in ' which each carbon atom is optionally substituted by
1 or 2 substituents independently chosen from halogen and C^-C^ alkyl, so obtaining a compound of formula (XIII)
Z-
wherei n
Z, , X and n are as defined above, and R1 and R2, being the same, are each a Cj-Cfi alkyl group, and R, and R2 together form a C2~C4 alkylene chain in which each carbon atom is optionally substituted by 1 or 2 substituents ndependently chosen from halogen and C.- Ci alkyl ; and
2) reducing a compound of formula (XIII).
The 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, tri- fluoromethane-sulfonic acid, trif1uoroacetic acid, acidic ion exchange resins and mixture thereof, at a temperature ranging from about 50'C to the reflux temperature of the mixture. 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 A^Oj, or, alternatively, by reaction with a trialkylorthoformate such as, for example, trimethylorthoformate or triethylortho- formate. Preferably this reaction may be carried out by using, for example, trif1uoromethanesulfonic 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 (Villa) 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 20'C to about 60'C. The compounds of formula (Villa) may be easily converted into compounds of formula (VIII). The conversion of a compound of formula (Villa) 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:
3) reacting a compound of formula (Villa) as defined above, with a compound of formula (VII) as defined above, so obtaining a compound of formula (VIII) wherein m, X, Rj,R and n are as defined above and Y is an aryl or heteroaryl group substituted by a 3- pyrrol in-1-yl group and, in addition, optionally substituted by 1 to 3 substituents independently chosen from halogen, C^-Cg alkyl, trihalo-Cj-Cj alkyl, hydroxy, c\ ~c~ alkoxy, C-Cg alkylthio and Cj-Cg alkylsulfonyl and, if desired,
4) reducing a compound of formula (VIII) as obtained under step 3), so obtaining another compound of formula (VIII) wherein , X, R, , R2 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, Cj-Cg alkyl , trihalo-C.-C, al ky1 , hydroxy, C^- Cj alkoxy, C^-Cg alkylthio and C_<-Cg alkylsulfonyl; or, if desired,
5) reacting a compound of formula (Villa) with a Cj-Cg alkyl aldehyde, in the presence of a reducing agent, so obtaining another compound of formula (VIII) wherein m, X, R^ , 2 and n are as defined above and Y is an aryl or heteroaryl group substituted by a Cj-Cg monoa kylamino group, the aryl or heteroaryl group being optionally substituted in addition by 1 to 3 substituents independently chosen from halogen, C_|-C8 alkyl, trihalo-C_|-C3 alky1 , hydroxy, Cj-C- alkoxy, C^-Cg alkylthio and C^-Cg alkylsulfonyl.
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.
The reduction as reported under step 4) may be carried out, for example, by low pressure catalytic hydro- genation, 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 60'C.
The reaction as reported under step 5) may be carried out according to known methods, for example with a C.-C- alkyl aldehyde, in the presence of a reducing agent such as, for example hydrogen and Pd/C, or NaBHjCN and ZnCl2, or aBH^ and HjSO^aq), at a temperature ranging from about 0"C to about 40'C.
The intermediate compounds of formula (Villa) 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)
wherei n
A is an aryl group substituted by a j-C, dialkylamino group; is zero, 1 or 2; X and Y being the same are oxygen or sulphur; each of R, and R2 , independently is C.-Cg alkyl or R_< and R2 taken together, are a C^-C^ alkylene chain in which each carbon atom can be optionally substituted by 1 or 2 substituents independently chosen from halogen and C,- C4 alkyl ; n is 1 , 2 or 3;
Q is oxygen or sulphur and
B is an aryl group unsubstituted or substituted by 1 to
4 substituents independently chosen from halogen, j-C6 alkyl, a halo-Cj-C3 alkyl, C -Cg alkoxy, C_,-C6 alkylthio and C -Cg alkylsulfonyl; and the pharmaceutically acceptable salts thereof. 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.
PHARMACOLOGY
The compounds of the invention show inhibitory activity of the enzyme acyl CoA:cholesterol acyltransferase (ACAT-EC 2.3.1.26) which regulates the i tracel 1ular esterification of cholesterol (Suckling K.E. Stange E.F. , J. Lip. Res. (1985) 26., 647) and thus the intracel lular accumulation of cholesteryl esters. The activity of this enzyme increases to the greatest extent during the atherosclerotic process in which the accumulation of esterified cholesterol in the atherosclerotic plaque is one of the predominant events (Brecher P. , Chan C , B.B.A. (1980) 6T7. 458). 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).
By virtue of their ACAT inhibitory activity 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. Moreover, the compounds of the invention are useful as antidyslipi aemic agents, indeed they show a high activity in lowering total serum cholesterol and triglycerides.
The activity as 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 (Athero- sclerosis-1981- 38,81). The following Table exemplifies the results obtained by testing for instance a representative group of compounds according to this invention:
(-)-N-[2, 6-bis( 1-methylethyl )phenyl]-N'-[(4R,5R)-2~[4- (3-pyrroli n-1 -yl )phenyl]-4,5-dimethyl-di oxolan-2-yl] methylurea (internal code FCE 28110); (-)-N-[2,6-bis(1-methylethyl )phenyl ]-N'-[(4R,5R)-2-[(4- p rroli in-1-y1 )pheny1 ]-4 ,5-dimethyl-dioxolan-2- l] methylurea (internal code FCE 28228);
N-[2,6-bis(1-methylethyl )phenyl]-N'-[5,5-dimethyl-2-[4- ( 3-p rrol in-1 -yl )pheny1 -1 , 3-dioxan-2y1 ]methylurea (internal code FCE 28326); N-[2,6-bis( 1-methylethyl )phenyl]-N'-[5,5-dimethyl-2-[3- bromo-4-morpholin-4-yl )phenyl]-1 ,3-dioxan-2yl]methylurea (internal code FCE 27913); in comparison with the known compound CL 277082 whose inhibitory activity in vitro on the ACAT enzyme has been already demonstrated (J. Med. Chem. , 1986, 29, 1131, 1133).
Table
The values of IC50 (concentration producing 50 % inhibition of enzyme activity) for the ACAT inhibition in microsomes from rabbit intestinal mucosa provide evidence that the compounds of the invention are more potent that CL 277082.
A human or animal may thus be treated by a method comprising administering thereto a therapeuticall 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. For example, N-[2 ,6-bis("1-methyle- thy1 )phenyl ]- '-[(4R,5R)-2-[4-(3-pyrrolin-1-yl )phenyl]- 4,5-dimethyldioxolan-2-yl ]methylu rea 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 ( LDJQ) 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).
The pharmaceutical compositions comprising the compounds of the invention are typically prepared following conventional methods and are administered in a pharma¬ ceutically suitable form.
For example, 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, methylcel 1ulose, carboxymethylcel lulose or polyvinyl pyrrolidone; disaggregating agents, e.g. 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 pharma- cologically inactive substances used in pharmaceutical formulations.
Said pharmaceutical preparations may be manufactured in known manner, for example, by means of mixing, granulat¬ ing, tabletting, sugar-coating, or film-coating processes. The liquid dispersions for oral adminis¬ tration 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 metabol izable to glucose, or metabol izable in very small amount to glucose, for example sorbito! .
The suspensions and the emulsions may contain as carrier, for example, a natural gum, agar, sodium alginate, pectin, methylcel 1 lose, carboxymethyl- cellulose, or polyvinyl alcohol. The following examples illustrate but do not limit the invention:
Example 1
To a solution of cis-2-butene-1 ,4-diol dimesylate (1.10 g, 4.5 mmol ) in 50 ml of anhydrous d chloro ethane, at room temperature under nitrogen, (-)-N-[2 , 6-bis( 1- ethylethyl )phenyl ]-N'-[ (4R, 5R )-2-(4-aminophenyl )-4,5- dimethyldioxolan-2-yl ]methyl urea (5.75 g, 13.5 mmol) is added portionwise. The resulting solution is stirred for 20 hours and then extracted with 50 ml of water. The organic layer is separated and dried over sodium sulphate. After removal of the solvent, the residue is purified by column chromatography over silica gel (eluent n-hexane/ethyl acetate) and crystallized from ethyl acetate yielding 2.0 g of (- )-N-[2 , 6-bis( 1- methylethyl )pheny 1]-N '- [( 4R , 5R)-2-[ 4- (3-pyr ro1 i n- 1- yl )phenyl ]-4, 5-dimethyl-dioxolan-2-yl-]methylurea; white powder m.p. 172-173'C αc = -14.6 (c = 1.03,EtOH). Analogously the following compounds can be prepared: N-[2,6-bis( 1-methylethyl )pheny1 ]-N '-[5 ,5-dimethy1-2-[4- (3-py rol in-1-yl )phenyl ]-1 ,3-dioxan-2-yl ]methylurea; white powder, m.p. 177-178'C;
N-[2,6-bis( 1-methylethyl )phenyl]-N'-[2-[4-(3-pyrrol in-1- yl )phenyl ]-1 , 3-dithiolan-2-y1 ]methylurea; and N-[2,6-bis( 1-methyl thi o)phenyl ] -N' -[ ( 4R, 5R) -2- [4- (3- pyrrol in-1-yl )phenyl 3-4, 5-dimethyldioxolan-2-y1 ]methyl¬ urea.
Example 2
To a solution of (- )-N-[2 , 6-bis( 1-methylethyl )phenyl ]-
N'-[(4R,5R)-2-[4-(3-pyrrol in-1-yl )pheny1 ]-4 , 5-dimethy1- dioxolan-2-yl ]methylurea (6.50 g) in ethyl alcohol (100 ml) is added Pd-C 0% (350 mg) and the mixture is hydrogenated at a Parr apparatus at room temperature until the theoretical amount of hydrogen is taken up. The reaction mixture is then filtered and concentrated in vacuo to give a white solid that is purified by column chro atography (eluent n-hexane/ethy1 acetate) and then crystallized from ethyl acetate yielding 3.50 gof (- )-N-[2, 6-bis( 1-methylethyl )phenyl ]- '-[ (4R, 5R)-2- [(4-pyrrolidin-1-yl )pheny1]-4 ,5-dimethyldioxolan-2- yl ]methyl-urea; white powder m.p. 193-195°C αD = -8.7 (c=1.00, EtOH).
Analogously, the following compound can be prepared:
N-[2,6-bis( 1-methylethyl )phenyl ]- '-[5 ,5-dimethyl-2-[4- (pyrrol idin-1-yl )phenyl]-1 ,3-dioxa -2-yl ]rnethylurea; white powder, m.p. 167-168°C,
Example 3
To a stirred suspension of (- )-N-[2 , 6-bis( 1-methylethyl ) phenyl]-NT- [ (4R, 5R) -2-( 4-ni t opheny 1 ) -4 , 5-dimethy 1- dioxolan-2-yl ]methylurea (3.64 g, 7.99 mmol ) and sodium borohydride (1.20 g, 31.7 mmol) in methyl alcohol (100 ml) and dimethylformamide (100 ml ) at room temperature is added portionwise nickel chloride hexahydrate (3.78 g, 15.9 mmol) in about 10' . The 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; white powder m.p. 174-175.5°C αD = -15.8 (c=0.79, EtOH). Analogously the following compounds can be prepared: N-[2,6-bis( 1-methylethyl )pheny1 ]-N'-[5 , 5-dimethyl-2-(4- aminophenyl )-1 ,3-dioxan-2-yl]methylurea; N-[2,6-bis(1-methylethyl )phenyl]-N'-[(4R,5R)-2-(4-amino- phenyl )-4,5-dimeth ldioxolan-2-yl]methylurea; and N- [2, 6-bis(methylthio)phenyl]-N'-[(4R,5R)-2-(4-amino- phenyl )-4,5-di ethyldioxolan-2-yl]methylurea.
Example 4
To a solution of [2-[4-(3-pyrrol in-1-yl )phenyl]-5,5- dimethyl-1 ,3-dioxan-2-yl]methylamine (5.0 g, 17.3 mmol) in ethyl acetate (75 ml) is added dropwise at room temperature2,6-bis(1-methylethyl )phenylisocyanate (3.71 ml, 17.3 mmol). The reaction mixture is stirred at room temperature for five hours. Volatiles are removed under reduced pressure and the residue is purified by column chromatography over silica gel (eluent n-hexane/ethyl acetate 70:30) and then crystallized from n-hexane/ethyl acetate yielding 7.2 g of N-[2,6-bis(1-methylethyl )phenyl]-N'-[5,5-dimethyl-2- [4-(3-pyrrol in-1-yl )phenyl]-1 ,3-dioxan-2-yl]methylurea, m.p. 177-178'C.
Analogously, by making use of a suitable compound of formula (III), the following compounds can be prepared: N-[2,6-bis(1-methylethyl )phenyl]-N'-[5,5-dimethy1-2-[4- (pyrrol idi n-1 -yl )phenyl]-1 ,3-dioxan-2-yl ]methylurea, m.p. 167-168*C;
N- [2, 6-bi s( 1 -methyl ethyl ) phenyl ]-N ' - [5 , 5-dimethyl -2- [4- (piperidin-1-yl )phenyl ]-1 , 3-dioxan-2-yl ]methylurea; N-[2,6-bis( 1-methylethyl )pheny1]-N'-[2-[4-(3-pyrrol in-1- yl )phenyl ]dithioIan-2-yl ]methylurea;
N-[2,6-di (methylthio)phenyl]-N'-[(4S,5S)-2-[4-(3- pyrrol in-1-yl )phenyl ]-4 , 5-d methy1dioxolan-2-yl ]methyl¬ urea, m.p. 172-173°C cu = +14.7 (c=1.01 , EtOH ) ; N- [2, 6-bis( methyl ethyl ) phenyl ]-N'-[ 5 ,5-di methyl -2-(3- bromo-4-morphol in-4-yl )phenyl -1 , 3-dioxan-2yl ]methylurea, m.p. 128-130'C; N- [2, 6-bis( 1-methylethyl )phe yl]-N' -[ (4R, 5R)-2- [4-( 3- pyrrol in-1-yl )phenyl ]-4, 5-dimethy!dioxolan-2-yl ]methyl¬ urea;
N-[2,6-bis( 1-methylethyl )pheny1]- '-[(4R, 5R)-2-[4-nitro- phenyl ]-4, 5-dimethy1dioxolan-2-yl ]methylurea; N-[2,6-bis( 1-methylethyl )pheny1]-N '-{2-[4-(3-pyrrol i -1- yl )phenyl ]-1 ,3-dithian-2-yl }methylurea;
N-[2,6-bis( 1-methylethyl )pheny1]- '-{2-[4-(pyrrolidin-1- yl )phenyl ]dithiolan-2-y1 }methylurea; N-[2,6-bis(methylthio)phenyl ]-N '-{5, 5-dimethyl-2-[4-( 3- pyrrol in-1-yl )phenyl ]-1 , 3-dioxan-2-yl }methylurea;
N- [2, 6-bis( methyl thio)phenyl ] -N'-{2-[4-( 3-pyrro 1 in-1- yl )phenyl]dithiolan-2-yl }methylurea;
N-[2,6-bis( 1-methylethyl )phenyl ]-N'-[5 , 5-dimethy1-2-(4- nitrophenyl )-1 , 3-dioxan-2-yl ]methylurea; and N-[2,6-bis( 1-methylethyl )phenyl ]-N'-[2-(4-n trophenyl )- 1 ,3-dithiolan-2-yl ]methylurea. Example 5
A mixture of N-[5 , 5-dimethy1-2-[4-(3-pyrrol in-1-yl ) phenyl ]-1 , 3-dioxan-2-yl ]methylacetamide (1.5 g, 4.5 mmol), aqueous NaOH 35% (10 ml) and PEG-400 (10 ml) is refluxed with stirring under nitrogen atmosphere for 4 hours. After cooling, the reaction mixture is poured into water (200 ml) and extracted with diethylether . The organic layer is 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 chloroform/isopropyl alcohol) yielding 1.15 g of [5,5- dimethyl-2-[4-(3-p rro 1 in-1-yl ) phenyl ]-1 ,3-dioxan-2- yl ]methylamine; white powder m.p. 130-132'C. Analogously the following compounds can be prepared: [(4R.5R )-2-[4-(3-pyrrol in-1-yl ) phenyl ]-4 , 5-dimethyl- dioxolan-2-yl ]methylamine,
H-NMR (CDC13, 80MHz)
1.22 d 3 H J=7.06 Hz CH-CHCHCH3
1.29 d 3 H J=7.17 Hz CH-CHCHCH,
2.85 broad s 2 H CH2NH2
3.41-3.93 CH,CHCHCH.
4.12 CH,N(Ar)CH2
5.95 CH.CH=CHCH2
6.45-6.60 aromatics
7.31-7.50 aromatics
[5, 5-di ethy1-2-[4-(pyrrol d n-1-yl )phenyl ]-1 , 3-dioxan- 2-yl ]methylamine;
[5 , 5-d i methy 1-2- [4-( pi peri din- 1-yl ) phenyl ]-1 , 3-d ioxan- 2- yl ]methylamine;
[2- [4-( 3-pyrrol i n-1 -yl )pheny 1 ] d i th i ol an- 2-y 1 ]meth y 1- amine;
[(4R,5R)-2-[4-(pyrrolidin-1-yl) phenyl ]-4 , 5-di methy 1- dioxo Ian- 2-yl ] methyl amine; (4R,5R)-2-( 4-ni rophenyl ) -4, 5-d i ethyldioxo Ian- 2- yl ]methylamine ; [5, 5-dimethyl-2-(4-ni trophenyl )-1 ,3-dioxan-2-yl] methyl amine; and [2- (4-ni trophenyl )-1 , 3-di thiol an-2-y 1 ] me thy! amine .
Example 6
To a solution of cis-2-butene-1 ,4-diol dimesylate (8.55 g, 35 mmol) in 500 ml of anhydrous dichloromethane at room temperature under nitrogen atmosphere, (-)-N- [(4R,5R)-2-(4-aminophenyl)-4,5-dimethyldio olan-2- yl ]methylacetamide (28.5 g, 10.8 mmol) is added portionwise. The resulting solution is stirred for 20 hours and then extracted with 400 ml of water. The organic layer is separated and dried over sodium sulphate. After removal of the solvent, the residue is purified by column chromatography over silica gel (eluent n-hexane/ethyl acetate) and crystallized from iPrOH yielding 8.2 g of (-)-N-[ (4R,5R)-2-[4-(3-pyrrol in-1-yl)phe yl ]-4, 5- di methy 1 dioxol an- 2-yl ] methy lace tarn ide ; white powder m.p. 148-149'C α- = -17.9 (c=1.00 MeOH ) . Analogously the following compounds can be prepared: N- [2-[4- (3-pyrrol i n- 1-yl )pheny 1 ] di thiolan-2- yl jmethylacetamide; and
N-[5 ,5-dimethyl-2-[4-( 3-pyrrol in-1-yl )pheny1 ]-1 , 3- d io an- 2-yl ] methy lace tarn ide ; white powder m.p. 131-132 * C .
Example 7
A solution of (-)-N-[(4R, 5R)-2-( -aminopheny1 )-4, 5- dimethyldioxolan-2-yl ]acetamide (5.0 g, 18.9 mmol) and finely crushed sodium borohydride (4.40 g, 116 mmol) in digly e (116 ml) is added to a stirred mixture of 3 molar sulfuric acid (20 ml, 60 mmol), 40% aqueous formaldehyde (9.5 ml, 137 mmol) and diglyme (10 ml) at a rate compatible with temperature control (+16"' to +19*C). After the addition is complete, the mixture is concentrated at reduced pressure, the residue is taken up with 6N aqueous sodium hydroxide and extracted with diethylether . The organic solution is washed with saturated sodium chloride solution, dried with sodium sulfate and the solvent is removed at reduced pressure. The residue is taken up with hexane, filtered and washed with hexane, giving 5.0 g of (-)-N-[(4R,5R)-2-(4-dimethy1aminopheny1 )-4,5-dimethy1- dioxolan-2-yl]acetarnide; white powder m.p. 124-126'C αD= -18.6 (c=1.01, MeOH) . Analogously the following compounds can be prepared: N-[2-(4-dimethylaminophenyl )-5,5-dimethyl-1 ,3-dioxan-2- yl]acetamide; and N-[2-(4-dimethylaminopheny1 )dithiolan-2-yl] acetamide.
Example 8
To a stirred suspension of 2-acetamido-4'-nitroaceto- phenone (16.6 g, 7.48 mmol), D(-)2,3-butanediol (17.0 ml, 18.7 mmol), trimethylo^thoformate (32.7 ml, 29.9 mmol) in dry nitromethane (20 ml) warmed at 60°C is added trifluoromethanesulfonic acid (6.6 ml, 7.48 mmol). The resulting solution is refluxed for 60'. After cooling the reaction mixture is poured into an ice- cooled aqueous solution of potassium carbonate and extracted with diethylether. The organic layer is 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 diisopropyl- ether/ethyl acetate) yielding 14.0 g of (-)-N-[(4R,5R)- 2-(4-nitrophenyl )-4,5-dimethyl-dioxolan]methylacetamide; white powder m.p. 112-114*C αD= -18.7 (c=1.10, MeOH) Analogously the following compounds can be prepared: N-[5,5-dimethyl-2-[4-(piperidin-1-yl )phenyl]-1 ,3-dioxan- 2-yl ]methylacetamide; and
N-[5,5-dimethyl-2-(4-nitrophenyl )- 1 ,3-dioxan-2- yl ]methyl-acetamide.
Example 9
To a stirred suspension of 2-acetamido-4'-nitroaceto- phenone (9.78 g, 44.0 mmol) and L(+)2,3-butanediol (4.0 ml, 44.0 mmol) in dry toluene warmed at 60°C is added trifluoromethanesulfonic acid (3.0 ml, 34.1 mmol). The resulting solution is warmed at 130*C for 60' while about 10 ml of a mixture of toluene, water and a little butanediol is distilled off.
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. The raw material is purified by column chromatography over silica gel (eluent diisopropylether/ethyl acetate) yielding 7.10 g of (+)N-[(4S,5S)-2-(4-nitrophenyl )-4,5- dimethyldioxolan]meth lacetamide; white powder m.p. 112-114'C α0= +18.8 (c=1.00, MeOH) ELEMENTAL ANALYSIS C H N calculated for C,4H18N205 57.14 6.16 9.52
57.14 6.20 9.47 3
- 37 -
The compound N-[2-(4-nitrophenyl )dithiolan-2-yl]methyl- acetamide and
N-[2-(4-nitrophenyl )-1 ,3-dithian-2-yl ] methylacetamide can be analogously prepared.
Example 10
With the usual methods of pharmaceutical technique, preparation can be made of capsules having the following composition:
(-)-N-[2,6-bis(1-methylethyl )ρhenyl]-N'- [(4R,5R)-2-[4-(3-pyrrolin-1-yl )phenyl]-
4,5-dimethyldioxolan-2-yl )methyl-urea 200 mg
Starch 8 mg
Microcrystal1ine cellulose 23 mg
Talc 8 mg Magnesium stearate 5 mg

Claims

1. A compound of formula (I)
wherein
Y is an aryl or heteroaryl group substituted by one group chosen from amino, C1-C6 monoalkylamino, 3- pyrrolin-1-yl, pyrrolidin-1-yl, morpholin-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, C1-C6 alkyl, trihalo-C1-C3 alkyl, hydroxy, C1-C6 alkoxy, C1-C6 alkylthio and C1-C6 alkylsulfonyl; m is zero, 1 or 2;
X is oxygen or sulphur;
R1 and R2 are each, independently, a C1-C6 alkyl group or R1 and R2 taken together form a C2-C4 alkylene chain in which each carbon atom is optionally substituted by 1 or 2 substituents independently chosen from halogen and C1-C4 alkyl; n is 1, 2 or 3;
Q is oxygen or sulphur; W is an aryl or heteroaryl group unsubstituted or substituted by 1 to 4 substituents independently chosen from halogen, C1-C6 alkyl, trihalo-C1-C3 alkyl, C1-C6 alkoxy, C1-C6 alkylthio and C1-C6 alkylsulfonyl; or a pharmaceutically acceptable salts thereof.
2. A compound of formula (I), according to claim 1, wherein
m is zero or 1;
n is 1, 2 or 3;
Q is oxygen or sulphur;
X is oxygen or sulphur;
R1 and R2, taken together, form a C2-C4 alkylene chain in which each carbon atom is unsubstituted or substituted by one or two substituents independently chosen from halogen and C1-C4 alkyl; Y is an aryl group substituted by a morpholin-4-yl, 3-pyrrolin-1-yl or a pyrrolidin-1-yl group, the aryl group being optionally substituted in addition by 1 to 3 substituents independently chosen from halogen, C1-C4 alkyl, trifluoromethyl, hydroxy, C1-C4 alkoxy, C1-C4 alkylthio and C1-C4 alkylsulfonyl;
W is a phenyl or pyridyl ring substituted by 1 to 3 substituents independently chosen from halogen, C1- C4 alkyl, C1-C4 alkoxy and C1-C4 alkylthio; or a pharmaceutically acceptable salt thereof.
3. A compound of formula (I), according to claim 1, wherein
m is zero or 1;
n is 1 or 2;
Q is oxygen;
X is oxygen;
R1 and R2 taken together, form a C2-C3 alkylene chain in which at least one carbon atom is susbtituted by 1 or 2 substituents independently chosen from halogen and C1-C4 alkyl;
Y is an aryl group substituted by a morphol i n-4-yl or 3-pyrrolin-1-yl group and, in addition, optionally substituted by one or two substituents chosen from halogen, C1-C4 alkyl, trifluoromethy 1, hydroxy, C1-C4 alkoxy, C1-C4 alkylthio and C1-C4 alkylsulfonyl;
W is a phenyl or a pyridyl ring substituted by 1, 2 or 3 substituents independently chosen from halogen, C1-C4 alkyl, C1-C4 alkoxy and
methylthio; or a pharmaceutically acceptable salt thereof.
4. A compound selected from:
N-[2,6-bis(1-methylethyl)phenyl]-N'-{2-[4-(3-pyrrolin-1-yl)phenyl]-4,5-dimethyldioxolan-2-yl}methyl urea;
N-[2,6-bi s( 1-methylethyl )phenyl]-N'- {2- [4- (pyrrolidin-1-yl)phenyl]-4,5-dimethyldioxolan-2-y]}methylurea;
N-[2,6-bis(1-methylethyl)phenyl]-N'-{5,5-dimethyl-2- [4-(3-pyrrolin-1-yl )phenyl]-1 ,3-dioxan-2-yl}methylurea;
N-[2,6-bis(1-methylethyl)phenyl]-N'-{5,5-dimethyl-2- [4-(pyrrolidin-1-yl )phenyl]-1 ,3-dioxan-2-yl}methylurea;
N-[2,6-bis(1-methylethyl)phenyl]-N'-{5,5-dimethyl-2- [4-(piperidin-1-yl )phenyl ]-1 ,3-dioxan-2-yl}methylurea;
N-[2,6-bis(1-methylethyl )phenyl]-N'-{2-[4-(3-pyrrolin-1-yl)phenyl]-1,3-dithiolan-2-yl}methylurea;
N-[2,6-bis( 1-methylthio)phenyl ]-N'-{2-[4-(3-pyrrol in-1-yl )phenyl]-4,5-dimethyldioxolan-2-yl}methylurea;
N-[2,6-bis(1-methylethyl )phenyl]-N'-{2-[4-(3-pyrrolin-1-yl)phenyl]-1,3-dithian-2-yl}methylurea;
N- [2 , 6-bi s ( 1 -methyl ethyl )phenyl ]-N ' -{2- [4(pyrrolidin-1-yl)phenyl]dithiolan-2-yl}methylurea;
N-[2,6-bis(methylthio)phenyl]-N'-{5,5-dimethyl-2-[4- (3-pyrrolin-1-yl)phenyl]-1,3-dioxan-2-yl}methylurea; N-[2,6-bis(methylthio)phenyl]-N'-{2-[4-(3-pyrrolin- 1-yl}phenyl]dithiolan-2-yl}methylurea;
N-[2,6-bis(1-methylethyl)phenyl]-N'-[5,5-dimethyl-2- (3-bromo-4-morpholin-4-yl)phenyl-1,3-dioxan-2- yl]methylurea;
if the case, either as single isomer or as mixture of isomers thereof, and the pharmaceutically acceptable salts thereof.
5. A process for the preparation of a compound of formula (I), as defined in claim 1, or a pharmaceutically acceptable salt thereof, the process comprising
a) reacting a compound of formula (II)
wherein Y, m, X, R1 and R2 and n are as defined in claim 1, with an isocyanate or an isothiocyanate of formula (III) Q=C=N-W (III)
wherein W and Q are as defined in claim 1, so obtaining a compound of formula (I) as defined in claim 1; or b ) reacti ng a compound of formu l a ( IV )
wherein Y, m, X, R1 , R2 , n and Q are as defined in claim 1, with an amine of formula (V)
H2N-W (V) wherein W is as defined in claim 1, so obtaining a compound of formula (I) as defined in claim 1, or reducing a compound of formula (VI)
wherein m, X, R1, R2, n, Q and W are as defined in claim 1 and 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, C1-C6 alkyl, trihalo-C1-C3 alkyl, hydroxy, C1-C6 alkoxy, C1-C6 alkylthio and C1-C6 alkylsulfonyl, so obtaining a compound of formula (I) wherein m, X, R1, R2, n, Q and W are as defined above and Y 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 chosen from halogen, C1-C6 alkyl, trihalo-C1-C3 alkyl, hydroxy, C1-C6 alkoxy, C1-C6 alkylthio and C1-C6 alkylsulfonyl; and, if desired, converting a compound of formula (I) into another compound of formula (I), and/or, if desired, salifying of a compound of formula (I), and/or, if desired, resolving a mixture of isomers of compounds of formula (I) into the single isomers.
6. A pharmaceutical composition comprising a suitable carrier and/or diluent and, as an active principle, a compound of formula (I) as defined in claim 1, or a pharmaceutically acceptable salt thereof.
7. A compound of formula (I), as defined in claim 1, or a pharmaceutically acceptable salt thereof for use as an inhibitor of the enzyme acyl CoA:Cholesterol acyltransferase.
8. A compound or salt as claimed in claim 7 for use in the prevention of coronary heart disease.
9. A compound or salt as claimed in claim 7 for use as an antidislipidaemic agent or an antiatherosclerotic agent.
10. A compound of formula (VIIIa)
wherein
Z' is an aryl or heteroaryl group substituted by an ami no group, the aryl or heteroaryl group being, optionally substituted in addition by 1 to 3 substituents independently chosen from halogen,
C1-C6 alkyl, trihalo-C1-C3 alkyl, hydroxy, C1-C6 alkoxy, C1-C6 alkylthio and C1-C6 alkylsulfonyl; m is zero, 1 or 2;
X is oxygen or sulphur,
R1 and R2 are each, independently, a C1-C6 alkyl group or R1 and R2, taken together, form a C2-C4 alkylene chain in which each carbon atom is optionally substituted by 1 or 2 substituents independently chosen from halogen and C1-C4 alkyl; and
n is 1, 2 or 3.
11. A process for preparing a compound of formula (VIIIa), as defined in claim 10, the process comprising
1) reacting a compound of formula (X)
wherein
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, C1-C6 alkyl, trihalo-C1-C3 alkyl, hydroxy, C1-C6 alkoxy, C1-C6 alkylthio and C1-C6 alkylsulfonyl; m is zero, 1 or 2; and
n is 1 , 2 or 3,
with a compound of formula (XI) or (XII)
R-XH (XI) HX-R-XH (XII) wherein
R is a C1-C6 alkyl group or a C2-C4 alkylene chain in which each carbon atom is optionally substituted by 1 or 2 substituents independently chosen from halogen and C1-C4 alkyl, so obtaining a compound of formula (XIII)
wherein
Z, m, X, R1, R2 and n are as defined above; and
2) reducing a compound of formula (XIII).
EP94921623A 1993-08-03 1994-06-24 Urea and thiourea derivatives and process for their preparation Withdrawn EP0662969A1 (en)

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