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• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
  • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
  • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P13/00—Drugs for disorders of the urinary system
  • A61P13/02—Drugs for disorders of the urinary system of urine or of the urinary tract, e.g. urine acidifiers
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P9/00—Drugs for disorders of the cardiovascular system
  • A61P9/08—Vasodilators for multiple indications
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P9/00—Drugs for disorders of the cardiovascular system
  • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
  • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
  • C07D233/66—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
  • C07D233/84—Sulfur atoms
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
  • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
  • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
  • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
  • C07D487/04—Ortho-condensed systems

Definitions

• the present invention relates to new diphenylimidazoles having ACAT inhibiting activity , to a process for their preparation and to pharmaceutical compositions containing them. It is well known that high levels of plasma cholesterol represent a primary risk factor in the development of lesions of the arterial wall and induction of atherosclerotic disease .
• acyl coenzyme A During the process of storage acyl coenzyme A is involved: cholesterol -O-acyl-transferase (ACAT; EC 2.3.1.2.6) which, catalyzing the transfer of a fatty acid from coenzyme A to cholesterol is able to regulate intracellular esterification of cholesterol itself.
• ACAT cholesterol -O-acyl-transferase
• This enzyme still not completely purified and characterized, with molecular weight of approximately 180 kDa, plays an important role not only in absorption of exogenous cholesterol in the intestinal district but also in other tissues.
• the present invention provides compounds having the following formula (I)
• Ph is phenyl; p is zero or 1;
• Y is a bond or a—(CH 2 ) m —X—(CH 2 ) n — group, wherein m and n being the same are 1 or 2 and X is a—(CH A) ⁇ — group wherein A is hydrogen or hydroxy and t is zero or an integer of 1 to
• Z is a group selected from 4,5-diphenylimidazol-2-ylthio; an aryloxy group unsubstituted or onosubstituted by a substituent chosen independently from C]-C 6 alkyl, halo-C,- C 6 alkyl C,-C 6 alkoxy, halogen, amino and nitro; an aryloxy group substituted by two substituents chosen independently from C,-C 6 alkyl, halo-C,-C 6 alkyl, C,-C 6 alkoxy, halogen, amino, nitro, C,-C 6 alkoxy-carbonyl, di(C,-C 6 alkyl) amino and -NHCONH-C,-C 6 alkyl; an aryloxy or arylthio group substituted by three substituents chosen independently from hydroxy and C,-C 6 alkyl;
• each of R 2 , R 3 and R 4 independently is hydrogen, C,-C 4 alkyl or C,-C 4 alkoxy; and the pharmaceutically acceptable forming salts thereof, and wherein
• Z is an aryloxy group unsubstituted or substituted by a substituent chosen from C,-C 6 alkyl, halo—C,-C 6 alkyl, C,-C 6 alkoxy, halogen, amino or an aryloxy group substituted by two substituents chosen from C,-C 6 alkyl, halo-C,-C 6 alkyl, C,-C 6 alkoxy, halogen, amino, nitro, C !
• p is zero or 1 and Y is a—(CH 2 ) m —X—(CH 2 ) n — group wherein m and n are 1, X is a—(CH A) t — group wherein A and t are as defined above, or a group chosen from -CO—, in which R is as defined above; or
• the invention includes within its scope all the possible isomers, stereoisomers, and their mixtures and the metabolites and the metabolic precursors or bio-precursors of the compounds of formula (I) .
• alkyl, alkoxy, di-alkylamino and haloalkyl, hydroxy- alkyl, ureido-alkyl and alkoxy-carbonyl groups may be branched or straight chain groups.
• A-(CH 2 ) m —, —(CH 2 ) n —, —(CHA)j- or —(CH 2 ),— group, when m, n or t, respectively, is an integer higher than 1 can provide independently a branched or straight alkylene chain.
• a C ! -C I0 alkyl chain is preferably a C]-C 6 alkyl chain, typically methyl, ethyl, propyl, isopropyl, butyl and tert- butyl.
• a C,-C 6 alkyl group is e.g. a C,-C 4 alkyl group, in particular methyl, ethyl, propyl or butyl.
• a C,-C 4 alkyl is typically methyl, ethyl, propyl, isopropyl, butyl and tert-butyl.
• a halo—C,-C 6 alkyl group is e.g. a halo—, dihalo— or trihalo—alkyl, in which the halogen atom is e.g. chlorine, bromine or fluorine, preferably it is a halo—C,-C 4 alkyl, typically trifluoromethyl.
• a C,-C 6 alkoxy is preferably methoxy, ethoxy, propoxy, isopropoxy, in particular methoxy or ethoxy.
• a C,-C 4 alkoxy is typically methoxy, ethoxy, propoxy, isopropoxy, butoxy and tert-butoxy.
• a halogen atom is e.g. chlorine, bromine or fluorine, in particular chlorine or fluorine, typically fluorine.
• An aryloxy group is e.g. a naphthyl-oxy or phenoxy group, preferably a phenoxy group.
• An arylthio is e.g. a naphthyl-thio or phenylthio group, preferably a phenyl-thio group.
• An imidazo[l,2-b]pyrazol-l-yl group when substituted is typically substituted by one or two substituents at the 2,3 and/or 6 positions, the substituent being preferably a phenyl group.
• a C,-C 6 alkoxy-carbonyl group is preferably a Cj- alkoxy- carbonyl group, wherein the C,-C 4 alkoxy moiety is typically as defined above.
• a di(C ! -C 6 alkyl) amino group is preferably a di(C,-C 4 alkyl) amino group, in particular dimethylamino and diethylamino.
• Pharmaceutically acceptable salts of the compounds of the invention include acid addition salts, with inorganic, e.g. nitric, hydrochloric, hydrobromic, sulfuric, perchloric and phosphoric acids, or organic, e.g. acetic, propionic, glycolic, lactic, oxalic, malonic, malic, maleic, tartaric, citric, benzoic, cinnamic, mandelic and salicylic acids.
• the present invention also includes within its scope pharmaceutically acceptable bio-precursors (otherwise known as pro-drug) of the compounds of formula (I) , i.e. compounds which have a different formula to formula (I) above but which converted directly or indirectly in-vivo into a compound of formula (I) .
• Preferred compounds of the invention are the compounds of formula (I) , wherein subject to the above proviso Ph is phenyl; p is zero or 1; Y is a bond or a—(CH 2 ),,—X—(CH 2 ) n — group, wherein each of m and n is 1 or 2 and X is a group —(CHA) t — wherein A is as defined above and t is zero or an integer of 1 group in which R is as defined above, or
• Z is a group selected from
• More preferred compounds of the invention are the compounds of formula (I) wherein Ph is phenyl; p is zero;
• Z is 4,5-diphenylimidazol-2-ylthio
• Y is a—(CH 2 ) wherein m and n are as defined above and X R is hydrogen or C,-C 6 alkyl,
• More preferred compounds of the invention are also the compounds of formula (I) wherein Ph is phenyl; p is zero or 1; Z is a group selected from: a phenoxy group substituted by a substituent chosen from halogen, C ⁇ -O. ⁇ alkyl, C,-C 4 alkoxy, trifluoromethyl and nitro; a phenoxy group substituted by two substituents independently chosen from halogen, C,-C 4 alkyl, C,-C 4 alkoxy, C,-C 4 alkoxy-carbonyl, di(C,-C 4 alkyl)amino, and
• Y is a—(CH 2 ) m —X—(CH 2 ) n — group wherein m and n are as defined above and X is —(CHA) t — in which t is zero or an integer of 1 to 4 and A is as defined above; and the pharmaceutically acceptable salts thereof.
• More preferred compounds of the invention are also the compounds of formula (I) wherein
• Ph is phenyl; p is zero;
• Z is thiazolidin—2,4—dione—5—yl; and Y is a bond or a—(CH 2 ) m —X—(CH 2 ) n — group wherein m and n are as defined above and X is —(CH 2 ) t — in which t is an integer of 1 to 4; and the pharmaceutically acceptable salts thereof.
• Examples of preferred compounds of the invention are the following, herebelow numbered according to the relevant occurring experimental preparation example: 1) 2-oxyimino-l,3-bis-(4 , 5-diphenylimidazole-2-ylthio) - propane;
• Hal is halogen, m, n, X and Z are as defined above, thus obtaining a compound of the invention wherein p is zero; or
• Ph, m, n, p and Z are as defined above, with a compound selected from the group (V) consisting of
• W is an activated derivative of an hydroxy group and m, n, and X are as defined above, thus obtaining a compound of the invention wherein Z is 4, 5-diphenylimidazol-2-ylthio; or
• Ph, Y and Z are as defined above, thus obtaining a compound of formula (I) wherein p is 1; and, if desired, converting a compound of formula (I) into another compound of formula (I) , and/or resolving a mixture of isomers of a compound of formula (I) into the single isomers, and/or converting a compound of formula (I) into a pharmaceutically acceptable salt thereof.
• Hal in a compound of formula (III) is a chlorine, bromine or iodine atom, preferably a bromine atom.
• reaction of a compound of formula (II) with a compound of formula (III) or of formula (VI) can be carried out in the presence of polar, organic, protic or aprotic solvents ⁇ e.g. a C,-C 4 alkanol, dimetylformamide and dimethylsulfoxide, preferably in the presence of a basic catalyst, substantially belonging to the class of sterically hindered tertiary amines, such as trialkylamine, 2,6-lutidine and pyridine.
• polar, organic, protic or aprotic solvents e.g. a C,-C 4 alkanol, dimetylformamide and dimethylsulfoxide
• a basic catalyst substantially belonging to the class of sterically hindered tertiary amines, such as trialkylamine, 2,6-lutidine and pyridine.
• the reaction is preferably carried out at room temperature, even if sometimes it is more convenient to heat it, to accelerate the course, at a temperature ranging between room temperature and 100°C and preferably at reflux temperature of a lower alcohol, such as ethanol and isopropanol.
• the reaction is generally complete after a period of time which may vary from 1 to 24 hours according to the substrate and catalyst used.
• the crystallized product is filtered off or the solvent removed and the residue purified according to the traditional methods of crystallization using appropriate solvents or by chromatography.
• reaction of compound of formula (IV) with a compound selected from the group (V) , as defined above can be carried out according to known methods. For instance, by reacting the appropriate hydroxylamine compound or ⁇ micarbazide in a protic solvent e.g. water or C,-C 4 alkanol at room temperature.
• a protic solvent e.g. water or C,-C 4 alkanol at room temperature.
• W as an activated derivative of an hydroxy group is e.g. a mesyloxy or tosyloxy group.
• reaction of a compound of formula (II) with a compound of formula (VII) is an analogy process that can be performed according to known methods.
• W is a tosyloxy group
• the reaction can be performed in a protic solvent e.g. a lower alkanol, typically C,-C 4 alkanol, in the presence of a basic agent e.g. 2,6-lutidine, at reflux temperature.
• a protic solvent e.g. a lower alkanol, typically C,-C 4 alkanol
• a basic agent e.g. 2,6-lutidine
• oxidation of a compound of formula (VIII) to obtain a compound of formula (I) in which p is 1 is an analogy process.
• Said oxidation is preferably carried out by reaction with a suitable oxidizing agent e.g. m-chloro- perbenzoic acid, in an inert organic solvent e.g. dichloromethane, under cooling.
• the optional conversion of a compound of formula (I) into another compound of formula (I) can be carried out according to well known methods in the art.
• Examples of conversion of a compound of formula (I) into another compound of formula (I) are for instance the conversion of an nitro-derivative into the respective amino- derivative and the conversion of an amino-derivative into the respective di (alkyl) amino-derivative.
• the intermediate compounds of formula (II) , (III) , (V) , (VI) and (VII) are known products or can be obtained according to known methods from known compounds.
• the compounds of formula (III) can be obtained respectively, by reaction of the appropriate hydroxyaryl, arylmercaptan, 2-hydroxypyridine, or imidazo[1,2-b]pyrazol with epichlorohydrin or chiral glycidyl tosylates or with a suitable alpha-omega-dihaloalkane.
• the haloketones are obtained by proceeding via epoxide, opening the haloidric acid and subsequent oxidation of the hydroxy group to carbonyl.
• a compound of formula (III) in which X is —(CH 2 ) t — wherein t is as defined above can be prepared from diethylmalonate via alkylation with a compound of formula
• Hal-CH 2 -(CH 2 )..-CHr-B in which Hal and n are as defined above in the presence of sodium hydride at room temperature in anhydrous tetrahydrofuran; chlorination of the alpha carbon atom at the ester functions with ⁇ ulfuryl chloride at 70°C; decarboxylation and hydrolysis of the ester functions in the presence of glacial acetic acid and 37% HC1 at reflux; reaction of the resulting alpha-chloro acid with thiourea in 2-methoxyethanol at reflux and treatment with 2N HC1.
• the compounds of formula (IV) are compounds of formula (I) according to the present invention wherein Y is a
• the compounds of formula (VIII) are compounds of formula (I) in which p is zero.
• a compound of formula (VIII) can be obtained according to anyone of processes a) , b) , c) and d) described above.
• the compounds of the invention show inhibitory activity of the enzyme acyl CoA: cholesterol acyltransferase (ACAT-EC).
• the compounds of this invention besides having antidyslipidaemic activity, act also as direct antiatherosclerotic agents, able to inhibit the development of the atheromatous plaque, and therefore are useful in particular for the prevention of coronary heart disease (CHD) , e.g. myocardial infarction, angina and cardiac insufficiency, thrombosis, cerebral ischemia, renal insufficiency and nephrotic syndromes.
• CHD coronary heart disease
• the activity of the enzyme and its regulation by the compounds of the invention has been evaluated in our laboratories both in-vitro and in-vivo tests, for instance as described herebelow.
• the activity of the ACAT enzyme was measured in-vitro evaluating the transfer of oleic acid from coenzyme A to cholesterol, during the process of formation of cholesterol oleate.
• As substrates endogenous cholesterol, deriving from the microsomial fraction and [14-C]-oleoyl-CoA. were used.
• the microsomial fraction was prepared from the liver of SD male rats (Charles River) , weighing 150-300 g, fed "ad libitum" with a normal standard diet. The rats were killed by decapitation and the liver of the animals removed and homogenized in 2.5 volumes of 0.25 M sucrose buffer containing ImM EDTA (pH 7.4) .
• the icrosomes were then obtained by differential centrifugation: the supernatant of an initial centrifugation at 10000 x g for 20 minutes (4°C) was centrifuged again in 0.1 M phosphate buffer (pH 7.4) at 105000 x g for 1 hour in order to sediment the required fraction. The microsomes thus obtained were resuspended in the same buffer, centrifuged again and maintained at -80°C until ready for use.
• test was carried out in test tubes using a final incubation volume of 200 ⁇ l.
• test tubes were preincubated for 10 minutes at 37° C and successively 100 ⁇ l of [14-C]oleoyl-CoA (0.1 mCi, final concentration 50 ⁇ M) were added. The incubation was stopped after 10 minutes by the addition of a mixture of (4 ml) of chloroform : ethanol (2:1 v/v) .
• the band thus visualized was scraped from the plate and placed in a vial to which scintillation liquid was added.
• the total radioactivity was evaluated by means of liquid scintillation counter (Beckman) .
• the background counts were evaluated by preparing controls submitted to 10 minutes boiling.
• the inhibitory percentage of the activity of the ACAT enzyme obtained in the presence of the compounds under study was calculated in terms of percentage compared to control values.
• the control values, determined in the presence of the dissolution vehicle correspond on average to 50 nmol [14-C] cholesterol oleate formiate/h/mg of microsomial protein.
• the inhibitory efficacy of the ACAT enzyme for the compounds representative of the invention and for the reference ones (CI-976 and RP-70676) is shown in Table 1 and is expressed as the concentration at which the ACAT activity is inhibited by 50% (IC 50 ) .
• mice Male Sprague-Dawley rats (Charles River, Calco, Italy) , weighing 120-180 g, 8 per group, maintained at 22+l°C temperature and 65+10% relative humidity, were fed ad libitum with a modified Nath's diet supplemented with 1% cholesterol (w/w) , 1 % cholic acid (w/w) (Dottor Piccioni, Gessate, Italy) for 5 days, concomitantly with test compound administration. Test compounds were suspended in 0.5% w/v carboxymethylcellulose and administered daily by gavage between 9-11 a.m. On the fifth day, 2 hours after the last treatment, the rats were exsanguinated by decapitation and blood samples collected. The following analyses were performed on serum obtained by low speed centrifugation:
• Reference prior-art compound RP-70676 is 2-[5-(3,5- dimethylpyrazol-1-yl)penthylthio]-4, 5-diphenylimidazole and is disclosed by WO 9110662.
• Reference compound CI-976 is 2,2- dimethy1-N-(2,4, 6-trimethoxypheny1)dodecanamide and is know from EP-283742.
• the dosage level suitable for oral administration to adult humans of the compounds of the invention may range from about 10 mg to about 1000 mg per dose 1 to 3 times a day, depending on the disease, age and weight of the patients involved.
• 2-[5- (4-terbutylphenoxy)pentylthio]-4, 5-diphenyl imidazole and 2-oxyimino-l, 3-bis-(4,5-diphenylimidazole-2-yl thio)propane can be suitably 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.
• 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 solution or suspension.
• the invention includes pharmaceutical compositions comprising a compound of the invention in association with a pharmaceutically acceptable excipient (which can be a carrier or diluent) .
• a pharmaceutically acceptable excipient which can be a carrier or diluent
• compositions comprising the compounds of the invention are typically prepared following conventional methods and are administered in a pharmaceutically suitable form.
• the solid oral forms may comprise, together with the active compound, diluents, e.g. lactose, dextrose, saccharose, cellulose, corn starch or potato starch; lubricants, e.g. silica, talc, stearic acid, magnesium or calcium stearate, and/or polyethylene glycols; binding agents, e.g. starches, arabic gums, gelatin, methylcellulose, carboxymethylcellulose or polyvinyl pyrrolidone; desegregating agents, e.g.
• diluents e.g. lactose, dextrose, saccharose, cellulose, corn starch or potato starch
• lubricants e.g. silica, talc, stearic acid, magnesium or calcium stearate, and/or polyethylene glycols
• binding agents e.g. starches, arabic gums, gelatin, methylcellulose, carboxymethylcellulose or polyvinyl pyr
• 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 dispersions for oral administration may be e.g. syrups, emulsions, and suspensions.
• the syrups may contain as carrier, for example, saccharose or saccharose with glycerine and/or mannitol and /or sorbitol; in particular a syrup to be administered to diabetic patients can contain as carriers only products not metabolizable to glucose, or metabolizable in very small amount to glucose, for example sorbitol.
• carrier for example, saccharose or saccharose with glycerine and/or mannitol and /or sorbitol
• a syrup to be administered to diabetic patients can contain as carriers only products not metabolizable to glucose, or metabolizable in very small amount to glucose, for example sorbitol.
• the suspensions and the emulsions may contain as carrier, for example, a natural gum, agar, sodium alginate, pectin, methylcellulose, carboxymethylcellulose, or polyvinyl alcohol.
• carrier for example, a natural gum, agar, sodium alginate, pectin, methylcellulose, carboxymethylcellulose, or polyvinyl alcohol.
• 2-oxo-l, 3-bis-(4 , 5-diphenylimidazole-2-yl-thio) -propane (500 mg, 0.89 mmol) and hydroxylamine hydrochloride (310 mg, 4.48 mmol) are dissolved in isobuthanol (50 ml) .
• the solution is stirred at room temperature until precipitation of a white solid. It is stirred for a further 30', then the solvent is evaporated.
• 2,6-lutidine is added (0.1 ml, 0.9 mmol) and then a solution of 3-[p-(2, 6-diisopropylphenylcarboxamido) phenoxy]-1-bromo propane (350 mg, 0.77 mmol) in absolute ethanol (10 ml) is added dropwise. The mixture is refluxed for 24 hours. Then filtered hot over dicalite and concentrated to dryness. The residue is taken up with ethyl acetate and water. The organic layer is washed several times with water, dried over Na 2 S0 4 and concentrated. The crude substance is crystallized from ethyl acetate/acetone (1:1), obtaining 270 mg (0.43 mmol, yield 56%) . m.p. > 235°C.
• preparation can be made of capsules having the following composition:

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• 1993
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