Bl
`
`PCT
`WORLD INTELLECTIJAL PROPERTY ORGANIZATION
`International Bureau
`INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT)
`WO 96126948
`
`(51) International Patent Classification 6 :
`C07F 9n2, A61K 3U66, C07F 9/655
`
`Al
`
`(11) International Publication Number:
`
`(43) International Publication Date:
`
`6 September 1996 (06.09.96)
`
`(21) International Application Number:
`
`PCT/EP96/0078 l
`
`(22) International Filing Date:
`
`26 February 1996 (26.02.96)
`
`(30) Priority Data:
`9504066.3
`
`I March 1995 (01.03.95)
`
`GB
`
`(81) Designated States: AM, AU, BB, BG, BR, BY, CA, CN, CZ,
`EE, Fl, GE, HU, IS, JP, KE, KG, KP, KR, KZ, LK, LR, LT,
`LV, MD, MG, MN, MW, MX, NO, NZ, PL, RO, RU, SD,
`SG, SI, SK, TJ, TM, TT, UA, UG, US, UZ, VN, Eurasian
`patent (.Az, BY, KG, KZ, MD, RU, TJ, TM), European
`patent (AT, BE, CH, DE, DK, ES, FR, GB, GR, IE, IT, LU,
`MC, NL, PT, SE).
`
`(71) Applicant (for all designated States except US): PHARMACIA
`S.P.A. [IT/IT]; Via Robert Koch, 1.2, 1-20152 Milan (IT).
`
`(72) Inventors; and
`(75) Inventors/Applicants (for US only): FANCELLI, Daniele
`[IT/IT]; Via Gianella, 21, 1-20152 Milan (IT). SEVERINO,
`Dino [IT/IT]; Via A. Magnasco, 6, 1-20149 Milan (IT).
`CIIlARI, Augusto [IT/IT]; Piazza San Jacopino, 7, 1-
`50122 Florence (IT). LOVISOLO, PierPaolo [IT/IT]; Via
`Vigevano, 43, 1-20144 Milan (IT). GIIlSELLI, Giancarlo
`[IT/IT]; Via Cardinal Tosi, 5, 1-21052 Busto Arsizio (IT).
`
`Published
`With international search report.
`Before the expiration of the time limit for amending the
`claims and to be republished in the event of the receipt of
`amendments.
`
`(54) Title: PHOSPHATE DERIVATIVES OF DISUBSTITUTED UREAS AND TIIlOUREAS
`
`(57) Abstract
`
`The present invention relates to a novel compound having ACAT
`inhibitory activity of formula (I), wherein: the X substituent, being the same,
`arc 0 or S; Y is independently 0 or S; one of R1 and R2 is OPO(OH)2 and
`the other is hydrogen, C1-C6 alkyl, halo, hydroxy, C1-C4 alkoxy or OPO(OH)2;
`each of RJ and R4. being the same or different, is C1-C6 alkyl; or RJ and R4.
`taken together, form a C2-C4 alkylene chain in which each carbon atom can be
`optionally substitued by l or 2 substituents independently chosen from halo or
`C1-C3 alkyl; and the pharmaceutically acceptable salts thereof.
`
`(I)
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`FOR THE PURPOSES OF INFORMATION ONLY
`
`Codes used to identify States party to the PCT on the front pages of pamphlets publishing international
`applications under the PCT.
`
`AM
`AT
`AU
`BB
`BE
`BF
`BG
`BJ
`BR
`BY
`CA
`CF
`CG
`CH
`Cl
`CM
`CN
`cs
`CZ
`DE
`DK
`EE
`ES
`Fl
`FR
`GA
`
`Armenia
`Austtia
`Australia
`Barbados
`Belgium
`Burtina Faso
`Bulgaria
`Benin
`Brazil
`Belarus
`Canada
`Central African Republic
`Congo
`Switzerland
`COie d'Ivoire
`Cameroon
`China
`Czechoslovakia
`Cuch Republic
`Germany
`Denmark
`Estonia
`Spain
`Finland
`France
`Gabon
`
`GB
`GE
`GN
`GR
`HU
`IE
`IT
`JP
`KE
`KG
`KP
`
`KR
`KZ
`LI
`LK
`LR
`LT
`LU
`LV
`MC
`MD
`MG
`ML
`MN
`MR
`
`Uni!Cd Kingdom
`Georgia
`Guinea
`Gtttce
`HWlgary
`Ireland
`Italy
`Japan
`Kenya
`Kyrgystan
`Democratic People's Republic
`or Korea
`Republic of Korea
`Kazakhstan
`Liechtenstein
`Sri Lanka
`Liberia
`Lithuania
`Luxembourg
`Latvia
`Monaco
`Republic or Moldova
`Madagascar
`Mali
`Mongolia
`Mauritania
`
`MW
`MX
`NE
`NL
`NO
`NZ
`PL
`PT
`RO
`RU
`SD
`SE
`SG
`SI
`SK
`SN
`sz
`TD
`TG
`TJ
`1T
`UA
`UG
`us
`uz
`VN
`
`Malawi
`Mexico
`Niger
`Netherlands
`Norway
`New Zealand
`Poland
`Portugal
`Romania
`Russian Federation
`Sudan
`Sweden
`Singapore
`Slovenia
`Slovakia
`Senegal
`Swaziland
`Chad
`Togo
`Tajikistan
`Trinidad and Tobago
`Ukraine
`Uganda
`United Swes or America
`Uzbekistan
`Viet Nam
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`1
`
`Phosphate derivatives of disubstituted ureas and thioureas
`
`The present invention relates to novel compounds having ACAT inhibitory activity, to a
`process for their preparation and to pharmaceutical compositions containing them.
`The inhibition of the enzime acylCoA:cholesterol acyltransferase is generally considered one
`of the most appealing approaches to the treatment of dyslipidemias and to the prevention of
`the atherosclerotic process (Exp. Opin. Invest. Drugs (1994) 3(5) 427-436). ACAT
`inhibitors are well known in the art, for instance, the inventors of the present invention in
`EP 0500348 disclosed a new class of urea and thiourea derivatives endowed with high in
`vitro ACAT inhibitory activity. However such urea and thiourea derivatives, similarly to
`most of the known ACA T inhibitors, were characterized by high lipophilicity, extreme low
`aqueous solubility and low bioavailability; by consequence their effects on blood and tissutal
`cholesterol levels were indirect and appeared almost exclusively related to a reduction of the
`intestinal cholesterol absorption. Recently further experimental data demonstrated that the
`therapeutic potential of an ACA T inhibitor can be markedly enhanced when the compound
`directly affects ACA T activity in target tissues such as the liver and the arterial wall
`(Atherosclerosclerosis and Thrombosis (1994) 149(9) 1498). Therefore a hydrosolubility
`sufficient to achieve high systemic bioavailability is now considered a crucial requirement
`for an ACAT inhibitor to be developed as a hypolipidemic as well as an antiatherosclerotic
`agent. The task to combine in the same molecule a high affinity for ACAT enzime and an
`adequate hydrosolubility cannot be achieved by merely introducing hydrophilic groups into
`the structure of in vitro active ACA T inhibitors, as this strategy results in most cases in a
`significant loss of the inhibitory activity.
`It has now been discovered that new phosphate derivatives of a selected class of hydroxy
`compounds embraced by the general formula disclosed in EP 0500348, besides being highly
`hydrosoluble, are also potent in vivo ACA T inhibitors. By virtue of such properties the
`compounds of the present invention can be useful therapeutic agents in the treatment of
`dyslipidemias and atherosclerosis.
`Accordingly, the present invention provides new compounds having the following general
`formula (I).
`
`5
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`30
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`35
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`wherein:
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`
`the X substituen~::, being the same, are 0 or S;
`Y is independently 0 or S;
`one ofR 1 and R2 is OPO(OH)i and the other is hydrogen, C 1-C6 alkyl, halo, hydroxy, Ci(cid:173)
`C4 alkoxy or OPO(OH)i;
`each of R 3 and R4, being the same or different, is C 1-C6 alkyl; or R 3 and R 4, taken
`together, form a CrC4 alkylene chain in which each carbon atom can be optionally
`substituted by 1 or 2 substituents independently chosen from halo or C 1-C3 alkyl;
`and the pharmaceutically acceptable salts thereof.
`The alkyl and alkoxy groups may be branched or straight groups. Representative examples
`of C i-C6 alkyl groups include methyl, ethyl, n- and iso-propyl, n-, iso-, sec- and tert-butyl.
`Representative examples of C 1-C4 alkoxy groups include methoxy or ethoxy. A C 1-C3
`alkyl group is in particular methyl or ethyl. Halo includes fluoro, bromo, chlorine or iodine,
`in particular chlorine or bromine.
`When R3 and R4 , taken together, are a CrC4 alkylene chain and X is oxygen, then the
`resulting pentatomic, hexatomic or heptatomic 1,3-dioxalkyl ring is respectively a 1,3-
`dioxolan, 1,3-dioxan or 1,3-dioxepan ring which may be represented by the formula
`
`5
`
`10
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`15
`
`20
`
`25
`
`wherein RrR4 represents a CrC4 alkylene chain in which each carbon atom can be
`optionally substituted by I or 2 substituents independently chosen from halogen, m
`particular chlorine or C 1-C 3 alkyl, in particular methyl.
`When R 3 and R4 • taken together, are a CrC4 alkylene chain and X is sulfur, then the
`resulting pentatomic. hexatomic or heptatomic 1,3-dithialkyl ring is respectively a 1,3-
`dithiolan, 1,3-dithian or 1,3-dithiepan ring which may be represented by the formula
`
`30
`
`wherein RrR..i represents a Ci-C..i alkylene chain in which each carbon atom can be
`optionally substituted by
`I or 2 substituents independently chosen from halogen, m
`particular chlorine or C 1-C 3 alkyl, in particular methyl.
`The pharmaceutically acceptable salts of the compounds of formula (I) include the salts of
`inorganic bases, for example hydroxides of alkaly metals. e.g. sodium or potassium, or
`alkaline-heart metals, e.g. calcium or magnesium, and the salts of organic bases organic
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`bases, such as for example aliphatic amines, e.g. methylamine, ethylamine, diethylamine,
`trimethylamine, or heterocyclic amines, e.g. piperidine.
`The present invention also include within its scope all the possible isomers, stereoisomers,
`and their mixtures and both the metabolites and the pharmaceutically acceptable bio-
`precursors (otherwise known as pro-drugs} of the compounds of formula (I}.
`Preferred compounds of the invention are the compounds of formula (I} wherein:
`Xis 0;
`Y is 0;
`one ofR 1 and R2 is OPO(OH)i and the other is hydrogen;
`R3 and R4 , taken together, are a CrC 3 alkylene chain in which each carbon atom can be
`optionally substituted by I or 2 substituents independently chosen from halo or C 1-C2 alkyl;
`and the pharmaceutically acceptable salts thereof.
`Examples of preferred compounds of the invention are the following:
`4-{ 2-[3-(2, 6-diisopropylphenyl}ureidomethylJ-4, 5-dimethyl- l ,3-dioxolan-2-
`yl} phenyl phosphate;
`3-{ 2-[3-(2,6-diisopropylphenyl}ureidomethylJ-4,5-dimethyl- l ,3-dioxolan-2-
`yl }phenylphosphate~
`3-{ 2-[3-(2,6-diisopropylphenyl)ureidomethyl]-5,5-dimethyl-l ,3-dioxan-2-
`yl} phenylphospate;
`4-{ 2-[3-(2,6-diisopropylphenyl )ureidomethyl]-5, 5-diethyl- l ,3-dioxan-2-yl} phenylphospate;
`3-{ 2-[3-{2,6-diisopropylphenyl)ureidomethyl]-5,5-diethyl- l ,3-dioxan-2-yl} phenylphospate~
`and
`4-{ 2-[3-(2,6-diisopropylphenyl)ureidomethyl]-5,5-dimethyl-l ,3-dioxan-2-
`yl }phenylphospate:
`if the case either as a single isomer or as a mixture of isomers thereof, and the
`pharmaceutically acceptable salts thereof.
`The compounds of the invention and the salts thereof can be obtained by a process
`comprising the hydrogenolysis of a compound of formula (II)
`
`(II)
`
`wherein Bn means benzyl and R2• R3, R.1, Y and X are as defined above by reaction with
`hydrogen in the presence of a catalyst; and, if desired, converting a compound of formula
`(I) into another compound of formula (I), and/or resolving a mixture of compounds of
`
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`formula (I) into the single isomers and/or converting a compound of formula (I) into a
`pharmaceutically acceptable salt thereof
`The hydrogenolysis reaction of a compound of formula (II) to obtain a compound of
`formula (I) can be carried out according to well known methods in the art. For instance the
`reaction can be performed in a suitable organic solvent e.g. methyl alcohol. at room
`temperature, in the presence of a hydrogenation catalyst such as e.g. palladium on chaorcal
`or platinum black under a low pressure e.g. from I to 5 atm of hydrogen.
`The compounds of formula (II) can be prepared from the corresponding hydroxy derivatives
`of formula (III)
`
`(Ill)
`
`reaction with
`Y and X are as defined above, by
`dibenzylpyrophosphate in an opportune organic solvent such as e.g. dimethylformamide or
`acetonitrile in the presence of a base such as e.g. potassium tert-butylate or sodium hydride
`at a temperature ranging from 0 to 50°C, according to well known procedures.
`Hydroxy compounds of formula (III) can be prepared as described in EP 0 500 348 Al.
`The separation of a mixture of isomers of a compound of the invention into single isomers
`and the conversion of a compound of formula (I) into a pharmaceutically acceptable salt
`thereof can be carried out according to well known methods in the art.
`
`Pharmacology
`The compounds of the present invention show inhibitory activity of the enzyme acyl
`CoA:cholesterol acyltransferase (ACAT-EC 2.3.1.26) which regulates the intracellular
`esterification of cholesterol (J.Lip. Res.
`( 1985) 26 647) and
`thus the intracellular
`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 (B.B.A. ( 1980) 617 458). By
`virtue of their water solubility, compounds of the present invention, contrary to those
`disclosed in EP 0500348, can be included into injectable preparations; therefore they can
`reach high plasmatic levels, that are useful for the direct and efficient inhibition of the liver
`aortic enzyme. By this systemic ACA T inhibitory activity, the compounds of the
`and
`present
`invention, besides having antidyslipidemic activity, can also act as direct
`antiatherosclerotic agents. able to inhibit the development of the atheromatous plaque, and
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`therefore ti-~./ are useful in particular for the prevention of coronary heart disease (CHD),
`e.g. myocardial infarction and angina.
`
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`Biological results
`(-)-4-{(4R, 5R)2-[3-(2,6-
`invention
`The
`representative compound of the present
`diisopropyl-phenyl)ureidomethyl]-4,5-dimethyl-l.3-dioxolan-2-yl }phenylphosphate
`monosodium salt (internal code FCE 28654A) showed a good water solubility (8.5 mg/ml
`were dissolved into a pH 7.4 PBS buffer) in comparison with the compounds disclosed in
`EP 0 500 348 A 1 such as e.g. N-[2,6-bis(l-methylethyl)phenyl]-N'-(2-cyclohexyl-1,3-
`dithiolan-2-yl)methylurea (internal code FCE 27612) or N-[2,6-bis{l-methylethyl)phenyl](cid:173)
`N'-(2-cyclohexyl-5,5-dimethyl-l,3-dioxan-2-yl)methylurea
`(internal code FCE 27356)
`whose water solubility in the same conditions is less than 0. 1 mg/ml. The compound FCE
`28654A was tested in vivo in hypocholesterolemic r~ts according to the following
`experimental procedure: male rats (mean weight 300 g) were treated with a 1.5%
`cholesterol - 0. 5% cholic acid diet for 5 days. FCE 28654. dissolved in sterile PBS at pH
`7.4, was
`then intravenously administered through the tail vein. Six hours after dosing
`animals were sacrified and blood and hepatic (after extraction into chloroform/methanol
`according to the method of Folch [J. Biol. Chem. 1957, 226, 497])
`lipids were dosed by
`enzymatic methods. The results presented in the table indicate that the representative
`compound FCE
`28654
`significantly
`reduces
`plasmatic
`cholesterol
`levels
`in
`hypercholesterolemic rats after a single intravenous administration at the dose of 2 mg/kg.
`
`Table Effects of a single intravenous administration of compoWld FCE 28654A
`on plasma lipids of hypercholesterolemic rats.
`
`Treatment
`
`Plasma lipids (mg/dl)a
`
`Fe
`
`CE
`
`TG
`
`PL
`
`Control
`
`65±18
`
`22(1±51
`
`FCE 28654A
`
`J9±10*
`
`134±36**
`
`109±35
`
`126±34
`
`178±30
`
`138±19*
`
`* p < 0.05 . ** p < 0.0 I (Dunnelt's test}.
`a) Values are mean ±SD n = 7
`FC =free choksterol. CE= cholcstenil esters, TG = t1ig.lycerides. PL = phospholipids.
`
`25
`
`The dosage level suitable for administration to adult humans depends on the age, weight.
`conditions of t!1e patient and on the administration route: for example. the dosage adopted
`for oral administration e.g. for the representative compound of the invention FCE 28654A
`may range from about I 0 to about 500 mg pro dose, from 1 to 5 times daily.
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`The compounds cf the invention can be administered m a variety of dosage forms, e.g.
`orally, in the form of tablets, capsules, sugar or film coated tablets, liquid solutions or
`suspensions: rectally in the form of suppositories; parenterally, e.g. intramuscolarly, or by
`intravenous injection or infusion.
`The invention includes pharmaceutical compositions comprising a compound of the
`invention in association with a pharmaceutically acceptable excipient (which can be a carrier
`or a diluent).
`The pharmaceutical compositions containing the compounds of the invention are usually
`prepared following ...:onventlonal methods and are administered in a pharmaceutically
`suitable form.
`For example, the solid oral forms may contain, together with the active compound, diluents,
`e.g. lactose, destrose, 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. a starch, alginic acid, alginates or sodium
`starch glycolate: effervescing mixtures; dyestuffs; sweeteners: wetting agents such as
`lecithin, polysorbates, 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 dispersion for oral administration may be e.g. syrups, emulsions and suspension.
`The syrups may contain as carrier, for example, saccharose or saccharose with glycerine
`and/or mannitol and/or sorbitol.
`The suspension and the emulsion may contain as carrier. for example, a natural gum, agar.
`sodium alginate, pectin, methylcellulose, carboxymethylcellulose, or polyvinyl alcohol.
`The suspension or solutions for intramuscolar injections may contain, togethr with the
`active compound. a pharmaceutically acceptable carrier, e.g. sterile water, olive oil, ethyl·
`oleate, glycols, e.g. propylene glycol, and, if desidered, a suitable amount of lidocaine
`hydrochloride. The solutions for intravenous injections or infusion may contain as carrier,
`for example, sterile water or preferably they may be in the form of sterile, acqueous,
`isotonic saline solutions.
`The suppositories may contain together with the active compound a pharmacwtically
`acceptable carrier. e.g cocoa butter, polyethylene glycol, a polyoxyethylene sorbitan fatty
`acid ester surfactant or lecithin.
`
`5
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`1 O
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`25
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`30
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`35
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`The following examples illustrate but do not limit the invention.
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`Example I
`Preparation of (-)-4-{ (4R, 5R)2-{3-(2,6-diisopropyl-phenyl)ureidomethylj-
`4,5-dimethyl-J,3-dioxo/a11-2-yl}phenylpho!17>hate monosodium salt (FCE 28654A).
`A mixture of (-)-dibenzyl-4-{ ( 4R. 5R)2-[3-(2,6-diisopropyl-phenyl)ureidomethyl]-4,5-
`dimethyl-l ,3-dioxolan-2-yl} phenyl phosphate (0.800g, 1. l 6mmol) and 10% palladium on
`activated carbon (0.400g) in l 5ml of ethyl alcohol was shacken under a hydrogen pressure
`of 2 atm at 12°C for 0.25h. Solid catalyst was then filtered, the solvent evaporated under
`reduced pressure, and the residue partially purified by column chromatography over silica
`gel (eluent chloroform/methyl alcohol/acetic acid
`64: 16:20). The phosphate was
`conveniently isolated as the monosodium salt by adding to the acid in ethyl alcohol
`t
`equivalent of sodium acetate in acqueous ethyl alcohol. After evaporation of the solvent the
`residue was taken up with n-hexane/diethyl ether, filtered and dried yielding 450 mg of the
`title compound as a colorless powder.
`mp 142-144°C: [a]23D -13.2 (c = 0.980, MeOH); IH NMR (400 MHz, DMSO) 8 : 1.0-
`1.04 ( 1 SH, m), 3.09 (2H, m), 3.3-3.5 (3H, m), 3.81 (IH, m), 6.1 (IH, bs), 7 .0-7.3 (7H, m),
`7.5 (IH, bs); FAB MS: 551 (IOO, [M+Na]+), 529 (52.3, (M+H]+), 449 (49.1).
`
`Analogously the following products can be prepared :
`3-{ 2-[3-(2,6-diisopropylphenyJ)ureidomethyl]-4,5-dimethyl-l ,3-dioxoJan-2-
`yl} phenyl phosphate;
`3-{ 2-[3-(2,6-diisopropylphenyl)ureidomethyl]-5, 5-dimethyl-1,3-dioxan-2-
`yl} phenyl phosphate:
`4-{ 2-(3-(2,6-diisopropylphenyl)ureidomethyl]-5,5-diethyl- l ,3-dioxan-2-
`yl} phenylphosphate;
`3-{ 2-(3-(2,6-diisopropylphenyl)ureidomethyl]-5,5-diethyl- I ,3-dioxan-2-
`yl} phenyl phosphate;
`and
`4-{ 2-[3-(2,6-diisopropylphenyl)ureidomethyl]-5,5-dimethyl- I ,3-dioxan-2-
`yl }phenylphosphate.
`
`Example 2
`With the usual methods of pharmaceutical technique, preparation can be made of capsules
`having the following composition:
`(-)-4-{ ( 4R, 5R)2-[3-(2,6-diisopropyl-phenyl)ureidomethyl]-4,5-dimethyl-1,3
`-dioxolan-2-yl} phenylphosphate mono sodium salt
`talc
`starch
`microcristaJline cellulose
`magnesium stearate
`
`200mg
`8mg
`8mg
`23mg
`5mg
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`15
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`20
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`25
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`30
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`CLAIMS
`
`1.
`
`A compound of formula (I)
`
`PCT/EP96/00781
`
`8
`
`5
`
`10
`
`15
`
`20
`
`wherein:
`the X substituent, being the same, are 0 or S;
`Y is independently 0 or S;
`one of R l and R2 is OPO(OH)i and the other 1s hydrogen, C 1-C6 alkyl, halo,
`hydroxy, C 1-C4 alkoxy or OPO(OH)i;
`each of R 3 and R 4, being the same or different, is C 1-C6 alkyl; or R 3 and R4 , taken
`together, form a CrC4 alkylene chain in which each carbon atom can be optionally
`substituted by 1 or 2 substituents independently chosen from halo or C 1-C3 alkyl;
`and the pharmaceutically acceptable salts thereof
`
`2.
`
`A compound of formula (I), according to claim 1, wherein:
`Xis 0:
`Vis 0;
`one of R 1 and R 2 is OPO(OH}i and the other is hydrogen;
`R 3 and R4 , taken together, are a CrC3 alkylene chain in which each carbon atom can
`be optionally substituted by l or 2 substituents independently chosen from halo or C 1 -
`C 2 alkyl;
`and the pharmaceutically acceptable salts thereof
`
`25
`
`3.
`
`30
`
`A compound selected from :
`4-{ 2-[ 3-(2,6-diisopropylphenyl )ureidomethyl]-4,5-dimethyl- l ,3-dioxolan-2-
`yl }phenylphosphate;
`3-{ 2-[3-( 2.6-diisopropylphenyl)ureidomethyl]-4, 5-dimethyl- l ,3-dioxolan-2-
`yl} phenylphosphate;
`3-{ 2-(3-(2,6-diisopropylphenyl)ureidomethyl]-5,S-dimethyl- I ,3-dioxan-2-
`yl} phenylphospate;
`4-{ 2-(3-(2,6-diisopropylphenyl)ureidomethyl]-5,5-diethyl-l ,3-dioxan-2-
`yl} phenylphospate;
`
`10 of 14
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`IPR2015-01836
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`

`
`W096/26948
`
`PCT/EP96/00781
`
`9
`
`3-{ 2 ~..., -(2,6-diisopropylphenyl)ureidomethyl]-5,5-diethyl-l ,3-dioxan-2-
`yl }phenylphospate;
`and
`4-{ 2-[3-(2, 6-diisopropylphenyl)ureidomethyl]-5, 5-dimethyl- l ,3-dioxan-2-
`yl }phenylphospate;
`if the case either as a single isomer or as a mixture of isomers thereof, and the
`pharmaceutically acceptable salts thereof
`
`5
`
`4.
`
`10
`
`A process for the preparation of a compound of formula (I) as defined in claim 1, or
`salt thereof, said process comprising the hydrogenolysis of a compound of formula
`(II)
`
`(II)
`
`15
`
`wherein Bn means benzyl and R2, R 3, R 4, Y and X are as defined in claim 1 and, if
`desired, converting a compound of formula (I) into another compound of formula (I),
`and/or resolving a mixture of compounds of formula (I) into the single isomers and/or
`converting a compound of formula (I) into a pharmaceutically acceptable salt thereof
`
`20
`
`5.
`
`A pharmaceutical composition comprising a suitable carrier and/or diluent and, as an
`active principle, a compound of formula (I) as claimed
`in cJaim 1, or a
`pharmaceutically acceptable salt thereof
`
`25
`
`6.
`
`7.
`
`A compound of formula (I), as defined in claim I, or a pharmaceutically acceptable
`salt thereof, for use in the prevention of coronary heart disease.
`
`A compound of formula (I), as defined in claim I, or a pharmaceutically acceptable
`salt thereof, for use as antidyslipidaemic agent.
`
`30
`
`8.
`
`A compound of formula (J), as defined in claim 1, or a pharmaceutically acceptable
`salt thereof, for use as antiatherosclerotic agent.
`
`11 of 14
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`

`
`INTERNATIONAL SEARCH REPORT
`
`Intem~.,onal ApphcatJon No
`PC . 1 EP 96/00781
`
`A. CLASSlFICATIO:>; OF SUBJECT MATIER
`A61K31/66
`IPC 6 Ce7F9/12
`
`Ce7F9/655
`
`Accordln& to IntcmatJonal Patent OassificatJon (IPC) or to both national classification and IPC
`
`B. FIELDS SEARCHED
`Muumum documentanon searched (classificatlon system followed by cla.-mficallon symbols)
`IPC 6 Ce7F A61K
`
`Documcntanon sear:chcd other than mirumum documentallon to the extent that such documents are included m the fields searched
`
`ElectJ'oruc data base consulted dunn& the mtemanonal sear:ch (name of data base and, where pracllcal, search tenns used)
`
`C. DOCUMENTS CONSIDERED TO BE RELEVANT
`
`CateaorY • Citallon of document, wllh mdlcanon, where appropnalc, of the relevant passa&CS
`
`Relevant to daun No.
`
`A
`
`A
`
`EP,A,e see 348 (FARM ITALIA CARLO ERBA) 26
`August 1992
`cited in the application
`see the whole document
`---
`WO,A,95 e4e53 (PHARMACIA S.P.A.} 9
`February 1995
`see the whole document
`---
`
`-/--
`
`1-8
`
`1-8
`
`[R] Further documents an: listed m the conunuallon of box C.
`
`• Speaal ca1caones of ated documents :
`
`'A' document dcfuun& the 1eneral state of the art wtuch 1s not
`conSldcred to be of panicular relevance
`.E. earlier document but published on or after the intcrnanonal
`fihn& date
`.L. document wtuch may throw doubts on pnonty claim(s) or
`winch 1.~ ated to establish the publ1ca11on date of another
`ata11on or other speaal reason (as specified)
`·o· document refcrnn& to an oral dlsdosur:e, use, cxtub1tion or
`other means
`·p· document pubhshed pnor to the mtemanonal films date but
`later than the pnonty date cl&Jmcd
`
`[K] Patent family manba"S are listed m annex.
`·r later document published after the intcmallonal films date
`or pnonty dale and not m conflict with the appbcanon but
`ated to understand the pnnaple or theory undertym& the
`mvcnnon
`·x· document of parUcular: relevance; the claimed mvcnnon
`cannot be cons1dcr:ed novel or cannot be considered to
`mYOlve an mvcnnvc step when the document 1s talccn alone
`·y· document of parUcular relevance; the cl.urned mvcnnon
`cannot be congdcred to involve an mvcntl\IC step when the
`document 1s combined with one or more other such docu-
`mcnts, such comblnallon bcm& obvious to a person slalled
`1n the art.
`·&.· document member of the same patent family
`
`1
`
`Date of the actual completlon of the mtcrnatlonal search
`
`Date of rrwhn& of the mtemallonal sear:ch report
`
`28 June 1996
`
`0 3. 07. 96
`
`Same aru1 maihn& address of the ISA
`European Patent Office, P.B. SBl 8 Patenllaan 2
`:>;L - 2280 HV RIJSWIJk
`Td. ( ~ Jl-70) 340-2040, Tx. 31 6SI epo nl,
`Fax: ( + 31-70) 340-3016
`
`Authonzed officer
`
`Beslier, L
`
`Form PCT:tS,...llO l•ecorul sheet) (July 1992)
`
`page 1 of 2
`
`12 of 14
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`
`INTERNATIONAL SEARCH REPORT
`
`Pl../ EP 96/88781
`
`C.(Contmuation) DOCUMENT'S CONSIDERED TO BE RELEVANT
`
`Ca~gory • Gtatlon of docwnent., with mdlc.allon, where appropna~. of the relevant passages
`
`Relevant to claim So.
`
`P,X
`
`BIOORG. MED. CHEM. LETT.
`(BMCLE8,0968894X);95; VOL.5 (15);
`PP.1581-6, PHARM. PHARMACEUTICALS MILAN
`RES. INST.;NERVIANO; 28814; ITALY (IT),
`XP000573768
`"Synthesis and
`CHIARI A ET AL:
`pharmacological profile of FCE 28654: a
`water-soluble and injectable ACAT
`inhibitor"
`see the whole document
`
`1-8
`
`1
`
`Form PCT.JSA:J1D (conunuauon of second 1heet) (July 1992)
`
`page 2 of 2
`
`13 of 14
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`

`
`INTERNATIONAL SEARCH REPORT
`-.forma.non on pati:nt family members
`
`Patent document
`cited in search report
`
`EP-A-500348
`
`I
`
`Publication
`date
`
`26-08-92
`
`I
`
`Patent family
`member(s)
`AT-T(cid:173)
`122670
`AU-B(cid:173)
`648143
`AU-B(cid:173)
`1093692
`2061447
`CA-A(cid:173)
`DE-0-
`69202491
`DE-T -
`69202491
`ES-T(cid:173)
`2075610
`4338373
`JP-A(cid:173)
`NZ-A(cid:173)
`241595
`US-A-
`5264441
`
`lnti:rr··'Ional Apphcanon No
`PC.· I EP 96/00781
`
`I Publication
`
`date
`
`15-06-95
`14-04-94
`27-08-92
`20-88-92
`22-06-95
`12-10-95
`01-10-95
`25-11-92
`26-07-94
`23-11-93
`
`WO-A-9504053
`
`09-02-95
`
`EP-A-
`
`0662969
`
`19-07-95
`
`Form PCT:ISA;llO (patmnt famdy annH) (July 1992)
`
`14 of 14
`
`PENN EX. 2258
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`IPR2015-01836