Substituted diaryl heterocycles, process for their preparation and their use as medicaments

Abstract

This invention discloses and claims diary heterocycles of formula (I) 1

Description

BACKGROUND OF THE INVENTION

[0002] 1. Field of the Invention

[0003] The invention relates to substituted diaryl heterocycles and to their pharmaceutically acceptable salts and physiologically functional derivatives. The invention also relates to providing compounds which bring about a weight reduction in mammals and which are suitable for the prevention and treatment of obesity.

[0004] 2. Description of the Art

[0005] Compounds having a pharmacological effect and similar in their overall structure to the diaryl heterocycles described herein have already been described in the prior art (such as, for example, U.S. Pat. No. 6,054,590A).

SUMMARY OF THE INVENTION

[0006] The invention therefore relates to compounds of the formula I 2

[0007] wherein

[0008] R is (C1-C8)-alkyl, (C0-C8)-alkylene-aryl, (C3-C8)-cycloalkyl, (C1-C4)-alkoxy-(C1-C4)-alkyl, (C2-C8)-alkenyl, (C2-C8)-alkynyl, a 3- to 12-membered mono-, bi- or spirocyclic ring optionally containing one or more heteroatoms selected from the group consisting of N, O, and S, and wherein the 3- to 12-membered ring is optionally substituted by F, Cl, Br, NO2, CF3, OCF3, CN, (C1-C6)-alkyl, aryl, CON(R11)(R12), N(R13)(R14), OH, O—(C1-C6)-alkyl, S—(C1-C6)-alkyl, N(R15)CO(C1-C6)-alkyl or COO—(C1-C6)-alkyl;

[0009] R11, R12, R13, R14, R15 independently are H, or (C1-C6)-alkyl;

[0010] B is a bond or a linker consisting of one or two radicals selected from the group consisting of (C(R19)(R20))i, C(OR21)(R22), O, N(R23), S, SO, SO2 and CO;

[0011] i is 1, 2 or 3;

[0012] R19, R20, R21, R22, R23 independently are H, (C1-C6)-alkyl or aryl;

[0013] R1, R2, R3, R4 independently are H, F, Cl, Br, I, OH, CF3, NO2, CN, OCF3, O—(C1-C6)-alkyl, O—(C1-C4)-alkoxy-(C1-C4)-alkyl, S—(C1-C6)-alkyl, (C1-C6)-alkyl, (C2-C6)-alkenyl, (C3-C8)-cycloalkyl, O—(C3-C8)-cycloalkyl, (C3-C8)-cycloalkenyl, O—(C3-C8)-cycloalkenyl, (C2-C6)-alkynyl, (C0-C8)-alkylene-aryl, O—(C0-C8)-alkylene-aryl, S-aryl, N(R24)(R25), SO2—CH3, COOH, COO—(C1-C6)-alkyl, CON(R26)(R27), N(R28)CO(R29), N(R30)SO2(R31) or CO(R32);

[0014] R24, R25, R26, R27, R28, R30 independently are H or (C1-C6)-alkyl;

[0015] R29, R31, R32 independently are H, (C1-C6)-alkyl or aryl;

[0016] W is —(CH2)n—, —CH═CH—, —CH═N— or —N═CH—;

[0017] n is 2, 3, 4 or 5;

[0018] R5, R6, R7, R8 independently are H, F, Cl, Br, I, OH, CF3, NO2, CN, OCF3, O—(C1-C6)-alkyl, O—(C1-C4)-alkoxy-(C1-C4)-alkyl, S—(C1-C6)-alkyl, (C1-C6)-alkyl, (C2-C6)-alkenyl, (C3-C8)-cycloalkyl, O—(C3-C8)-cycloalkyl, (C3-C8)-cycloalkenyl, O—(C3-C8)-cycloalkenyl, (C2-C6)-alkynyl, (C0-C8)-alkylene-aryl, O—(C0-C8)-alkylene-aryl, S-aryl, N(R33)(R34), SO2—CH3, COOH, COO—(C1-C6)-alkyl, CON(R35)(R36), N(R37)CO(R38), N(R39)SO2(R40) or CO(R41), or a 5- to 7-membered heterocycle having 1 to 4 heteroatoms selected from the group consisting of O, N and S;

[0019] R33, R34 independently are H or (C1-C6)-alkyl;or

[0020] R33 and R34 form together with the nitrogen atom to which they are bonded a 5- or 6-membered ring, wherein when R33 and R34 form together with the nitrogen to which they are bonded a 6-membered ring, one CH2 group optionally is O or S;

[0021] R35, R36, R37, R39 independently are H or (C1-C6)-alkyl;

[0022] R38, R40, R41 independently are H, (C1-C6)-alkyl or aryl;

[0023] A is a chain —(C(R42)(R43))m- in which 0 to 2 members of the chain are optionally replaced by an element selected from the group consisting of O, S, N(R44), CO and SO2;

[0024] m is 0, 1, 2, 3, 4 or 5;

[0025] R42, R43, R44 independently are H, (C1-C6)-alkyl or aryl;

[0026] R9, R10 independently are H, (C1-C8)-alkyl, —(CH2)o—R45, (C1-C4)-alkoxy-(C1-C4)-alkyl, aryloxy-(C1-C4)-alkyl, (C3-C8)-alkenyl, (C3-C8)-alkynyl, CO—(C1-C8)-alkyl, —CO—(CH2)o—R45, CO—(C1-C4)-alkoxy-(C1-C4)-alkyl, CO-aryloxy-(C1-C4)-alkyl, CO—(C2-C8)-alkenyl, CO—(C2-C8)-alkynyl, or R9 and R10 form together with the nitrogen atom to which they are bonded a 4- to 10-membered mono-, bi- or spirocyclic ring wherein said ring, apart from the nitrogen atom, may optionally contain 0 to 4 additional heteroatoms selected from the group consisting of oxygen, nitrogen and sulfur and wherein said ring optionally is substituted by F, Cl, Br, CF3, NO2, CN, (C1-C6)-alkyl, O—(C1-C8)-alkyl, (C1-C4)-alkoxy-(C1-C4)-alkyl, (C0-C8)-alkylene-aryl, oxo, CO(R46), CON(R47)(R48), hydroxyl, COO(R49), N(R50)CO(C1-C6)-alkyl, N(R51)(R52) or SO2CH3;

[0027] R46, R47, R48, R49, R50, R51, R52 independently are H or (C1-C6)-alkyl;

[0028] o is 0, 1, 2, 3, 4, 5 or 6;

[0029] R45 is OH, CH(aryl)2, a 3- to 12-membered mono- or bicyclic ring which optionally contains one or more heteroatoms selected from the group consisting of N, O and S, wherein the 3- to 12-membered ring optionally is substituted by F, Cl, Br, I, OH, CF3, NO2, CN, OCF3, oxo, O—(C1-C6)-alkyl, (C1-C4)-alkoxy-(C1-C4)-alkyl, S—(C1-C6)-alkyl, (C1-C6)-alkyl, (C2-C6)-alkenyl, (C3-C8)-cycloalkyl, O—(C3-C8)-cycloalkyl, (C3-C8)-cycloalkenyl, O—(C3-C8)-cycloalkenyl, (C2-C6)-alkynyl, (C0-C8)-alkylene-aryl, O—(C0-C8)-alkylene-aryl, S-aryl, N(R51)(R52), SO2—CH3 or COOH; or

[0030] a pharmaceutically acceptable salt of the compound of formula I.

[0031] Preference is given to compounds of formula I wherein

[0032] R is (C1-C6)-alkyl, (C0-C2)-alkylene-aryl, (C3-C8)-cycloalkyl, (C2-C6)-alkenyl, (C5-C8)-cycloalkenyl, (C7-C8)-bicycloalkenyl, (C2-C6)-alkynyl; a 3- to 7-membered ring optionally containing one or more heteroatoms selected from the group consisting of of N, O and S, and wherein the 3- to 7-membered ring is optionally substituted by F, Cl, Br, NO2, CF3, OCF3, CN, (C1-C6)-alkyl, CON(R11)(R12), N(R13)(R14), OH, O—(C1-C6)-alkyl, N(R15)CO(C1-C6)-alkyl or COO(C1-C6)-alkyl;

[0033] R11, R12, R13, R14, R15 independently are H or (C1-C6)-alkyl;

[0034] B is a bond, O, S, SO2, CO, OCH(R20), N(R23), CH2 or CH2CH2

[0035] R20, R23 independently are H or (C1-C6)-alkyl;

[0036] R1, R2, R3, R4 independently are H, F, Cl, Br, OH, CF3, NO2, CN, OCF3, O—(C1-C6)-alkyl, O—(C1-C4)-alkoxy-(C1-C4)-alkyl, S—(C1-C6)-alkyl, (C1-C6)-alkyl, (C0-C2)-alkylene-aryl, O—(C0-C2)-alkylene-aryl, N(R24)(R25), SO2—CH3, COOH, COO—(C1-C6)-alkyl, CON(R26)(R27), N(R28)CO(R29) or CO(R32):

[0037] R24, R25, R26, R27, R28, R30 independently are H or (C1-C6)-alkyl;

[0038] R29, R32 independently are H, (C1-C6)-alkyl or aryl;

[0039] W is —(CH2)n, —CH═CH—, —CH═N— or —N═CH—;

[0040] n is 2, 3 or 4;

[0041] R5, R6, R7, R8 independently are H, F, Cl, Br, OH, CF3, NO2, CN, OCF3, O—(C1-C6)-alkyl, (C1-C6)-alkyl, (C0-C2)-alkylene-aryl, O—(C0-C2)-alkylene-aryl, COO—(C1-C6)-alkyl or CO(R41);

[0042] R41 is (C1-C6)-alkyl or aryl;

[0043] A is a chain —(C(R42)(R43))m- wherein 1 to 2 members are optionally replaced by an element selected from the group consisting of O, N(R44) and CO;

[0044] m is 3 or 4;

[0045] R42, R43, R44 independently are H, (C1-C6)-alkyl or aryl;

[0046] R9, R10 independently are H, (C1-C8)-alkyl, (CH2)o—R45, (C1-C4)-alkoxy-(C1-C4)-alkyl, aryloxy-(C1-C4)-alkyl, (C3-C8)-alkenyl, (C3-C8)-alkynyl, CO—(C1-C8)-alkyl, —CO—(CH2)o—R45, or R9 and R10 form together with the nitrogen atom to which they are bonded a 4- to 10-membered mono-, bi- or spirocyclic ring wherein said ring, apart from the nitrogen atom, may optionally contain 0 to 2 additional heteroatoms selected from the group consisting of oxygen, nitrogen and sulfur, and wherein said ring optionally is substituted by F, Cl, Br, CF3, CN, (C1-C6)-alkyl, O—(C1-C8)-alkyl, (C1-C4)-alkoxy-(C1-C4)-alkyl, (C0-C2)-alkylene-aryl, oxo, CO(R46), CON(R47)(R48), OH, COO(R49), N(R50)CO(C1-C6)-alkyl, N(R51)(R52) or SO2CH3;

[0047] R46, R47, R48, R49, R50, R51, R52 independently are H or (C1-C6)-alkyl;

[0048] o is 0, 1, 2, 3 or 4;

[0049] R45 is OH, a 3- to 12-membered mono- or bicyclic ring which optionally contains one or two heteroatoms selected from the group consisting of N, O and S, wherein the 3- to 12-membered ring optionally is substituted by F, Cl, Br, OH, CF3, NO2, CN, OCF3, oxo, O—(C1-C6)-alkyl, (C1-C6)-alkyl, (C2-C6)-alkenyl, (C0-C2)-alkylene-aryl, O—(C0-C2)-alkylene-aryl, N(R51)(R52), SO2—CH3 or COOH;

[0050] or the pharmaceutically acceptable salts thereof.

[0051] Particular preference is given to compounds of formula I in which

[0052] R is (C1-C6)-alkyl, (C3-C8)-cycloalkyl, or a 5- to 6-membered ring optionally containing one or two heteroatoms selected from the group consisting of N, O and S, wherein the 5- to 6-membered ring is optionally substituted by F, Cl, Br, NO2, CF3, OCF3, CN, (C1-C6)-alkyl or O—(C1-C6)-alkyl;

[0053] B is a bond, O, S, CO, OCH2, N(R23) or CH2;

[0054] R23 is H or (C1-C6)-alkyl;

[0055] R1, R2, R3, R4 independently are H, F, Cl, Br, CF3, O—(C1-C6)-alkyl or (C1-C6)-alkyl;

[0056] W is —CH═CH— or —N═CH—;

[0057] R5, R6, R7, R8 independently are H, F, Cl, Br, OH, CF3, NO2, CN, OCF3 or O—(C1-C6)-alkyl;

[0058] A is a chain —(C(R42)(R43))m-, wherein one member of the chain is optionally replaced by an element selected from the group consisting of O and N(R44);

[0059] m is 3 or 4;

[0060] R42, R43, R44 independently are H, (C1-C6)-alkyl or aryl;

[0061] R9, R10 independently are H, (C1-C8)-alkyl, —(CH2)o—R45, CO—(C1-C8)-alkyl, or

[0062] R9 and R10 form together with the nitrogen atom to which they are bonded a 4- to 10-membered mono-, bi- or spirocyclic ring wherein said ring, apart from the nitrogen atom, may optionally contain 0 to 2 additional heteroatoms selected from the group consisting of O, N and S, wherein said ring optionally is substituted by F, (C1-C6)-alkyl, O—(C1-C8)-alkyl, oxo, CO(R46), CON(R47)(R48), OH, N(R50)CO(C1-C6)-alkyl or N(R51)(R52);

[0063] R46, R47, R48, R50, R51, R52 independently are H or (C1-C6)-alkyl;

[0064] o is 0, 1, 2, 3 or 4;

[0065] R45 is OH, a 5- to 10-membered mono- or bicyclic ring which optionally contains one or two heteroatoms selected from the group consisting of N, O and S, wherein the 5- to 10-membered ring optionally is substituted by F, Cl, Br, OH, CF3, OXO, O—(C1-C6)-alkyl, (C1-C6)-alkyl, (C0-C2)-alkylene-aryl, O—(C0-C2)-alkylene-aryl, or N(R51)(R52);

[0066] A particular class within the particularly preferred compounds of formula I is formed by the molecules for which

[0067] W is —CH═CH—.

[0068] A further particular class within the particularly preferred compounds of formula I is formed by the molecules for which

[0069] m is 3;

[0070] R42, R43, R44 are H.

[0071] A further particular class within the particularly preferred compounds of formula I is formed by the molecules for which

[0072] R5, R6, R7, R8 are H.

[0073] A further particular class within the particularly preferred compounds of formula I is formed by the molecules in which A and B are each disposed in the para position relative to the central W-containing heterocycle.

[0074] If radicals or substituents can occur more than once in the compounds of formula 1, such as, for example, —(CH2)o—R45, they may all, independently of one another, have the stated meanings and be identical or different.

[0075] The invention relates to compounds of formula I in the form of their racemates, enantiomer-enriched mixtures and pure enantiomers and to their diastereomers and mixtures thereof.

[0076] The alkyl, alkenyl and alkynyl radicals in the substituents R, R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, R12, R13, R14, R15, R16, R17, R18, R19, R20, R21, R22, R23, R24, R25, R26, R27, R28, R29, R30, R31, R32, R33, R34, R35, R36, R37, R38, R39, R40, R41, R42, R43, R44, R45, R46, R47, R48, R49, R50, R51 and R52 may be either straight-chain, branched or optionally halogenated.

DETAILED DESCRIPTION OF THE INVENTION

[0077] The term “aryl” means a phenyl or naphthyl group.

[0078] Mono-, bi- or spirocyclic rings may be saturated, partially saturated or unsaturated and also bridged.

[0079] Pharmaceutically acceptable salts are particularly suitable for medical applications because their solubility in water is higher than the initial or basic compounds. These salts must have a pharmaceutically acceptable anion or cation. Suitable pharmaceutically acceptable acid addition salts of the compounds of the formula I are salts of inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric, metaphosphoric, nitric, sulfonic and sulfuric acids, and organic acids such as, for example, acetic acid, benzenesulfonic, benzoic, citric, ethanesulfonic, fumaric, gluconic, glycolic, isethionic, lactic, lactobionic, maleic, malic, methanesulfonic, succinic, p-toluenesulfonic, tartaric and trifluoroacetic acids. The chloride salt is particularly preferably used for medical purposes. Suitable pharmaceutically acceptable basic salts are ammonium salts, alkali metal salts (such as sodium and potassium salts) and alkaline earth metal salts (such as magnesium and calcium salts).

[0080] Salts with a pharmaceutically unacceptable anion likewise fall within the scope of the invention as useful intermediates for preparing or purifying pharmaceutically acceptable salts and/or for use in non-therapeutic, for example in vitro, applications.

[0081] The term “physiologically functional derivative” used herein refers to any physiologically tolerated derivative of a compound according to the invention of the formula I, for example an ester, which is able on administration to a mammal such as, for example, a human to form (directly or indirectly) a compound of the formula I or an active metabolite thereof.

[0082] The physiologically functional derivatives also include prodrugs of the compounds according to the invention. Such prodrugs can be metabolized in vivo to a compound according to the invention. These prodrugs may themselves be active or not.

[0083] The compounds according to the invention may also exist in various polymorphic forms, for example as amorphous and crystalline polymorphic forms. All polymorphic forms of the compounds according to the invention lie within the scope of the invention and are a further aspect of the invention.

[0084] All references hereinafter to “compound(s) of formula (I)” refer to compound(s) of the formula (I) as described above, and the salts, solvates and physiologically functional derivatives thereof as described herein.

[0085] The amount of a compound of formula (I) which is necessary to achieve the desired biological effect depends on a number of factors, for example the specific compound chosen, the intended use, the mode of administration and the clinical condition of the patient. In general, the daily dose is in the range from 0.3 mg to 100 mg (typically from 3 mg to 50 mg) per day and per kilogram of body weight, for example 3-10 mg/kg/day. An intravenous dose may be, for example, in the range from 0.3 mg to 1.0 mg/kg, which can most suitably be administered as infusion of from 10 ng to 100 ng per kilogram and per minute. Suitable infusion solutions for these purposes may contain, for example, from 0.1 ng to 10 mg, typically from 1 ng to 10 mg, per milliliter. Single doses may contain, for example, from 1 mg to 10 g of the active ingredient. It is thus possible for ampoules for injections to contain, for example, from 1 mg to 100 mg, and single-dose formulations which can be administered orally, such as, for example, tablets or capsules, to contain, for example, from 1.0 to 1000 mg, typically from 10 to 600 mg. In the case of pharmaceutically acceptable salts, the aforementioned weight data are based on the weight of the salt of the underlying free compound. For the prophylaxis or therapy of the abovementioned conditions, the compounds of formula (I) can be used as the compound itself, but they are preferably in the form of a pharmaceutical composition with an acceptable carrier. The carrier must, of course, be acceptable in the sense that it is compatible with the other ingredients of the composition and is not hazardous for the patient's health. The carrier may be a solid or a liquid or both and is preferably formulated with the compound as single dose, for example as tablet which may contain from 0.05% to 95% by weight of the active ingredient. Further pharmaceutically active substances may likewise be present, including other compounds of formula (I). The pharmaceutical compositions according to the invention can be produced by one of the known pharmaceutical methods which essentially consist of mixing the ingredients with pharmaceutically acceptable carriers and/or excipients.

[0086] Pharmaceutical compositions according to the invention are those suitable for oral, rectal, topical, peroral (for example sublingual) and parenteral (for example subcutaneous, intramuscular, intradermal or intravenous) administration although the most suitable mode of administration in each individual case depends on the nature and severity of the condition to be treated and on the nature of the compound of formula (I) used in each case. Coated formulations and coated slow-release formulations also lie within the scope of the invention. Formulations resistant to acid and gastric fluid are preferred. Suitable coatings resistant to gastric fluid comprise cellulose acetate phthalate, polyvinyl acetate phthalate, hydroxypropylmethylcellulose phthalate and anionic polymers of methacrylic acid and methyl methacrylate.

[0087] Suitable pharmaceutical compositions for oral administration may be in the form of separate units such as, for example, capsules, cachets, suckable tablets or tablets, each of which contain a defined amount of the compound of formula (I); as powders or granules; as solution or suspension in an aqueous or nonaqueous liquid; or as an oil-in-water or water-in-oil emulsion. These compositions may, as already mentioned, be prepared by any suitable pharmaceutical method which includes a step in which the active ingredient and the carrier (which may consist of one or more additional ingredients) are brought into contact. In general, the compositions are produced by uniform and homogeneous mixing of the active ingredient with a liquid and/or finely divided solid carrier, after which the product is shaped if necessary. Thus, for example, a tablet can be produced by compressing or molding a powder or granules of the compound, where appropriate with one or more additional ingredients. Compressed tablets can be produced by tableting the compound in free-flowing form, such as, for example, a powder or granules, where appropriate mixed with a binder, lubricant, inert diluent and/or a (plurality of) surface-active/dispersing agent(s) in a suitable machine. Molded tablets can be produced by molding the compound which is in powder form and is moistened with an inert liquid diluent in a suitable machine.

[0088] Pharmaceutical compositions suitable for peroral (sublingual) administration comprise suckable tablets which contain a compound of formula (I) with a flavoring, normally sucrose and gum arabic or tragacanth, and pastilles which comprise the compound in an inert base such as gelatin and glycerol or sucrose and gum arabic.

[0089] Suitable pharmaceutical compositions for parenteral administration comprise preferably sterile aqueous preparations of a compound of formula (I), which are preferably isotonic with the blood of the intended recipient. These preparations are preferably administered intravenously, although administration may also take place by subcutaneous, intramuscular or intradermal injection. These preparations can preferably be produced by mixing the compound with water and making the resulting solution sterile and isotonic with blood. Injectable compositions according to the invention generally contain from 0.1 to 5% by weight of the active compound.

[0090] Suitable pharmaceutical compositions for rectal administration are preferably in the form of single-dose suppositories. These can be produced by mixing a compound of formula (I) with one or more conventional solid carriers, for example cocoa butter, and shaping the resulting mixture.

[0091] Suitable pharmaceutical compositions for topical application to the skin are preferably in the form of ointment, cream, lotion, paste, spray, aerosol or oil. Carriers which can be used are petrolatum, lanolin, polyethylene glycols, alcohols and combinations of two or more of these substances. The active ingredient is generally present in a concentration of from 0.1 to 15% by weight of the composition, for example from 0.5 to 2%.

[0092] Transdermal administration is also possible. Suitable pharmaceutical compositions for transdermal uses can be in the form of single plasters which are suitable for long-term close contact with the patient's epidermis. Such plasters suitably contain the active ingredient in an optionally buffered aqueous solution, dissolved and/or dispersed in an adhesive or dispersed in a polymer. A suitable active ingredient concentration is about 1% to 35%, preferably about 3% to 15%. As a special possibility, the active ingredient can be released as described, for example, in Pharmaceutical Research, 2(6): 318 (1986) by electrotransport or iontophoresis.

[0093] The compounds of the formula I are distinguished by beneficial effects on lipid metabolism, and they are particularly suitable for weight reduction and for maintaining a reduced weight after weight reduction has taken place in mammals and as anorectic agents. The compounds are distinguished by their low toxicity and their few side effects.

[0094] The compounds can be employed alone or in combination with other weight-reducing or anorectic active ingredients. Further anorectic active ingredients of this type are mentioned, for example, in the Roten Liste, chapter 01 under weight-reducing agents/appetite suppressants, and may also include active ingredients which increase the energy turnover of the organism and thus lead to weight reduction or else those which influence the general metabolism of the organism in such a way that an increased calorie intake does not lead to an enlargement of the fat depots and a normal calorie intake leads to a reduction of the fat depots of the organism. The compounds are suitable for the prophylaxis and, in particular, for the treatment of excessive weight or obesity. The compounds are further suitable for the prophylaxis and, in particular, for the treatment of type II diabetes, of arteriosclerosis and for normalizing lipid metabolism and for the treatment of high blood pressure. The compounds act as MCH antagonists and are also suitable for the treatment of disturbances of wellbeing and other psychiatric indications such as, for example, depressions, anxiety states, anxiety neuroses, schizophrenia and for the treatment of disorders associated with the circadian rhythm and for the treatment of drug abuse.

[0095] In a further aspect of the invention, the compounds of the formula I can be administered in combination with one or more other pharmacologically active substances which are selected, for example, from antidiabetics, antiobesity agents, active ingredients which lower blood pressure, lipid-lowering agents and active ingredients for the treatment and/or prevention of complications caused by diabetes or associated with diabetes. Suitable antidiabetics include insulins, amylin, derivatives of GLP-1 and GLP-2 such as, for example, those disclosed in WO 98/08871 of Novo Nordisk A/S, and orally active hypoglycemic active ingredients.

[0096] The orally active hypoglycemic active ingredients preferably comprise sulfonylureas, biguanidines, meglitinides, oxadiazolidinediones, thiazolidinediones, glucosidase inhibitors, glucagon receptor antagonists, GLP-1 agonists, potassium channel openers such as, for example, those disclosed in WO 97/26265 and WO 99/03861 of Novo Nordisk A/S, insulin sensitizers, activators of insulin receptor kinase, inhibitors of liver enzymes involved in the stimulation of gluconeogenesis and/or glycogenolysis, for example inhibitors of glycogen phosphorylase, modulators of glucose uptake and glucose excretion, compounds which alter lipid metabolism, such as antihyperlipidemic active ingredients and antilipidemic active ingredients, for example HMGCoA reductase inhibitors, inhibitors of cholesterol transport/of cholesterol uptake, inhibitors of bile acid reabsorption or inhibitors of the microsomal triglyceride transfer protein (MTP), compounds which reduce food intake, PPAR and RXR agonists and active ingredients which act on the ATP-dependent potassium channel of the beta cells.

[0097] In one embodiment of the invention, the present compounds are administered in combination with insulin.

[0098] In a further embodiment, the present compounds are administered in combination with a sulfonylurea such as, for example, tolbutamide, glibenclamide, glimepiride, glipizide, gliquidone, glisoxepide, glibornuride or gliclazide.

[0099] In another embodiment, the present compounds are administered in combination with a biguanide such as, for example, metformin.

[0100] In yet another embodiment, the present compounds are administered in combination with a meglitinide such as, for example, repaglinide. In yet a further embodiment, the present compounds are administered in combination with a thiazolidinedione such as, for example, troglitazone, ciglitazone, pioglitazone, rosiglitazone or the compounds disclosed in WO 97/41097 of Dr. Reddy's Research Foundation, in particular 5-[[4-[(3,4-dihydro-3-methyl-4-oxo-2-quinazolinylmethoxy]phenyl]methyl]-2,4-thiazolidinedione.

[0101] In a further embodiment, the present compounds are administered in combination with an (x-glucosidase inhibitor such as, for example, miglitol or acarbose.

[0102] In another embodiment, the present compounds are administered in combination with an active ingredient which acts on the ATP-dependent potassium channel of the beta cells, such as, for example, tolbutamide, glibenclamide, glimepiride, glipizide, gliclazide or repaglinide.

[0103] In yet another embodiment, the present compounds are administered in combination with an antihyperlipidemic active ingredient or an antilipidemic active ingredient such as, for example, cholestyramine, colestipol, clofibrate, fenofibrate, gemfibrozil, lovastatin, pravastatin, simvastatin, atorvastatin, cerivastatin, fluvastatin, probucol, ezetimibe or dextrothyroxine.

[0104] In a further embodiment, the present compounds are administered in combination with more than one of the aforementioned compounds, e.g. in combination with a sulfonylurea and metformin, a sulfonylurea and acarbose, repaglinide and metformin, insulin and a sulfonylurea, insulin and metformin, insulin and troglitazone, insulin and lovastatin, etc.

[0105] The compounds of the invention may additionally be administered in combination with one or more antiobesity agents or appetite-regulating active ingredients.

[0106] Active ingredients of these types may be selected from the group consisting of CART agonists, NPY antagonists, MC4 agonists, orexin antagonists, H3 agonists, TNF agonists, CRF agonists, CRF BP antagonists, urocortin agonists, β3 agonists, MSH (melanocyte-stimulating hormone) agonists, CCK agonists, serotonin-reuptake inhibitors, mixed sertonin- and noradrenaline-reuptake inhibitors, 5HT modulators, MAO inhibitors, bombesin agonists, galanin antagonists, growth hormone, growth hormone-releasing compounds, TRH agonists, modulators of uncoupling proteins 2 or 3, leptin agonists, dopamine agonists (bromocriptine, Doprexin), lipase/amylase inhibitors, antagonists of cannabinoid receptor 1, modulators of acylation-stimulating protein (ASP), PPAR modulators, RXR modulators, hCNTF agonists or TR-β agonists.

[0107] In one embodiment of the invention, the antiobesity agent is leptin or modified leptin.

[0108] In another embodiment, the antiobesity agent is dexamphetamine or amphetamine.

[0109] In another embodiment, the antiobesity agent is fenfluramine or dexfenfluramine.

[0110] In yet another embodiment, the antiobesity agent is sibutramine or the mono- and bisdemethylated active metabolites of sibutramine.

[0111] In a further embodiment, the antiobesity agent is orlistat.

[0112] In another embodiment, the antiobesity agent is mazindol, diethylpropion or phentermine.

[0113] The present compounds may additionally be administered in combination with one or more antihypertensive active ingredients. Examples of antihypertensive active ingredients are beta blockers such as alprenolol, atenol, timolol, pindolol, propanolol and metoprolol, ACE (angiotensin converting enzyme) inhibitors such as, for example, benazepril, captopril, enalapril, fosinopril, lisinopril, quinapril and rampril, calcium channel blockers such as nifedipine, felodipine, nicardipine, isradipine, nimodipine, diltiazem and verapamil, and alpha blockers such as doxazosin, urapidil, prazosin and terazosin. Reference may furthermore be made to Remington: The Science and Practice of Pharmacy, 19th edition, Gennaro, editor, Mack Publishing Co., Easton, Pa., 1995.

[0114] It will be appreciated that every suitable combination of the compounds of the invention with one or more of the aforementioned compounds and optionally one or more other pharmacologically active substances is to be regarded as covered by the scope of protection of the present invention.

Experimental

[0115] In two articles which appeared simultaneously in Nature (Nature 400, 261-264,1999; Nature 400, 265-269,1999, see annex), two research groups separately described a highly specific receptor for the melanin-concentrating hormone (MCH). MCH undertakes important functions in the control of food intake. Compounds which act on the MCH receptor therefore have an anorectic effect and are suitable for the treatment of obesity. The anorectic effect of the compounds of the invention of the formula I was therefore tested as follows.

[0116] Functional measurements to establish IC50 values

[0117] The cloning of the cDNA for the human MCH receptor, production of the recombinant HEK293 cell line which expresses the human MCH receptor, and functional measurements using the recombinant cell line took place in analogy to the description by Audinot et al. (J. Biol. Chem. 276,13554-13562, 2001). However, a difference from the reference was that the plasmid pEAK8 from EDGE Biosystems (USA) was used for constructing the expression vector. The host used for the transfection was a transformed HEK cell line named “PEAK Stable Cells” (likewise from EDGE Biosystems). The functional measurements of the cellular calcium flux after addition of agonist (MCH) in the presence of ligand of the invention took place with the aid of the FLIPR apparatus from Molecular Devices (USA), using protocols of the manufacturer of the apparatus. The exemplary compounds showed IC50 values in the order of magnitude from 0.01 to >10 μM.

[0118] The efficacy of the compounds was additionally tested as follows:

[0119] Biological Test Model:

[0120] The anorectic effect was tested on female NMRI mice. After withdrawal of food for 17 hours, the test compound was administered by gavage. The animals were housed singly with free access to drinking water and were offered condensed milk 30 minutes after administration of the compound. Condensed milk consumption was determined every half hour for 7 hours, and the general wellbeing of the animals was observed. The measured milk consumption was compared with the vehicle-treated control animals.

TABLE 1
Anorectic effect measured as the reduction in the cumulative
milk consumption of treated compared with control animals.
		Number of	Number of	Reduction
		animals/	animals/	in the
		cumulative milk	cumulative milk	cumulative
		consumption of	consumption of	milk
	Oral	the treated	the control	consumption
	dose	animals	animals	as % of the
Example	[mg/kg]	N/[ml]	N/[ml]	control
Example 1	30	5/1.7	5/4.1	58

[0121] The examples and preparation methods detailed below serve to illustrate the invention without, however, restricting it.

EXAMPLE 1

1-[4-(2-Dimethylaminoethoxy)phenyl]-3-(4-phenoxyphenyl)-1,3-dihydroimidazol-2-one

[0122] 3

[0123] 1-(2,2-Dimethoxyethyl)-3-[4-(2-dimethylaminoethoxy)phenyl]-1-(4-phenoxy-phenyl)urea (0.33 g) was shaken with trifluoroacetic acid (5 ml) for 16 hours. Volatiles were removed and the residue was taken up in dichloromethane (10 ml) and washed with sodium hydroxide solution (0.1N; 1 ml). The aqueous phase was extracted with dichloromethane (10 ml), and the combined organic phases were concentrated. The residue was purified by chromatography on silica gel (eluent: dichloromethane/methanol 98:2 with 1% v/v 7N ammonia solution in methanol). The product with the molecular weight of 415.50 (C25H25N3O3); MS (ESI): 416 ([M+H]+), was obtained in this way.

1-(2,2-Dimethoxyethyl)-3-[4-(2-dimethylaminoethoxy)phenyl]-1-(4-phenoxy-phenyl)urea

[0124] A solution of triphosgene (178 mg) in chloroform (1 ml) was added to a solution of 4-(2-dimethylaminoethoxy)aniline (324 mg) in chloroform (2 ml) and pyridine (0.182 ml) at 0° C. under nitrogen. The reaction was then shaken at room temperature for 30 minutes. The solution was then added to a solution of (2,2-dimethoxyethyl)-(4-phenoxyphenyl)amine (410 mg) in chloroform (2 ml) and pyridine (0.182 ml) and shaken at 70° C. for 3 hours. Water (1 ml) was added. The mixture was extracted with dichloromethane (2×15 ml). The combined organic phases were concentrated and the residue was purified by chromatography on silica gel (eluent: dichloromethane/methanol 98:2 with 1% v/v 7N ammonia solution in methanol). The product with the molecular weight of 479.58 (C27H33N3O5); MS (ESI): 442 ([M-OMe]+), was obtained in this way.

(2,2-Dimethoxyethyl)-(4-phenoxyphenyl)amine

[0125] A solution of 4-phenoxyaniline (915 mg) in dimethylformamide (5 ml) was mixed with bromoacetaldehyde dimethyl acetal (1.1 ml) and BEMP (1.9 ml). The reaction mixture was shaken at 100° C. for 16 hours. Volatiles were removed and the residue was purified by chromatography on silica gel (eluent: dichloromethane/hexane 1:2, later 1:1 with in each case 1% v/v 7N ammonia solution in methanol). The product with the molecular weight of 273.33 (C16H19NO3); MS (ESI): 274 ([M+H]+), was obtained in this way.

EXAMPLE 2

1-[4-(2-Dimethylaminoethylamino)-3-nitrophenyl]-3-(4-phenoxyphenyl)-1,3-dihydroimidazol-2one

[0126] 4

[0127] A solution of 1-(4-fluoro-3-nitrophenyl)-3-(4-phenoxyphenyl)-1,3-dihydroimidazol-2-one (100 mg) in dimethylformamide (2 ml) was shaken with 2-dimethylaminoethylamine (0.3 ml) at 70° C. for 2 hours. Volatiles were removed and the residue was partitioned between dichloromethane and water. The organic phase was dried and concentrated. The product with the molecular weight of 459.51 (C25H25N5O4); MS (ESI): 460 ([M+H]+), was obtained in this way.

1-(4-Fluoro-3-nitrophenyl)-3-(4-phenoxyphenyl)-1,3-dihydroimidazol-2-one

[0128] 4-Fluoro-3-nitrophenyl isocyanate (0.45 ml) was added to a solution of (2,2-dimethoxyethyl)-(4-phenoxyphenyl)amine (750 mg) in chloroform (10 ml). The reaction was shaken at 70° C. for 2 hours. A second portion of 4-fluoro-3-nitrophenyl isocyanate (0.45 ml) was added. After 16 hours at 70° C., volatiles were removed and TFA.(10 ml) was added. After shaking for 16 hours, volatiles were removed and the residue was purified by chromatography on silica gel (eluent: dichloromethane/hexane 8:1). The product with the molecular weight of 391.36 (C21 H14FN3O4); MS (ESI): 392 ([M+H]+), was obtained in this way.

EXAMPLE 3

1-[3-Amino-4-(2-dimethylaminoethylamino)phenyl]-3-(4-phenoxyphenyl)-1,3-dihydroimidazol-2-one

[0129] 5

[0130] Zinc dust (250 mg) was added to a solution of 1-[4-(2-dimethylamino-ethylamino)-3-nitrophenyl]-3-(4-phenoxyphenyl)-1,3-dihydroimidazol-2-one (50 mg) in dichloromethane (10 ml) and glacial acetic acid (1 ml). After 10 minutes, solids were removed by filtration and the filtrate was washed with saturated sodium carbonate solution. The organic phase was dried over magnesium sulfate and concentrated. The product with the molecular weight of 429.53 (C25H27N5O2); MS (ESI): 430 ([M+H]+), was obtained in this way.

EXAMPLE 4

1-[3-Benzyl-4-(2-pyrrolidin-1-ylethoxy)phenyl]-3-(4-phenoxyphenyl)-1,3-dihydroimidazol-2-one

[0131] 6

[0132] A solution of 1-[3-benzyl-4-(2-bromoethoxy)phenyl]-3-(4-phenoxyphenyl)-1,3-dihydroimidazol-2-one (60 mg) in acetonitrile (1 ml) was mixed with pyrrolidine (0.2 ml) and sodium iodide (5 mg) and boiled under reflux for 2 hours. The cooled solution was filtered and concentrated. The residue was purified by preparative HPLC. The product with the molecular weight of 531.66 (C34H33N3O3); MS (ESI): 532 ([M+H]+), was obtained as hydroformate in this way.

1-[3-Benzyl-4-(2-bromoethoxy)phenyl]-3-(4-phenoxyphenyl)-1,3-dihydroimidazol-2-one

[0133] A solution of 1-(3-benzyl-4-hydroxyphenyl)-3-(4-phenoxyphenyl)-1,3-dihydroimidazol-2-one (233 mg) in 1,2-dibromoethane (1.7 ml) was mixed with sodium hydroxide solution (3N, 0.6 ml) and tetrabutylammonium hydrogen sulfate (12 mg). The mixture was heated at 80° C. for 2 hours. After cooling, the reaction mixture was diluted with dichloromethane and washed with sodium hydroxide solution (1N), hydrochloric acid (1N) and saturated brine. The organic phase was dried over magnesium sulfate and concentrated, and the residue was purified by chromatography on silica gel (eluent: heptane/ethyl acetate 3:2). The product with the molecular weight of 541.45 (C30H25BrN2O3); MS (ESI): 541 ([M+H]+), was obtained in this way.

1-(3-Benzyl-4-hydroxyphenyl)-3-(4-phenoxyphenyl)-1,3-dihydroimidazol-2-one

[0134] A solution of 3-(4-benzyloxyphenyl)-1-(2,2-dimethoxyethyl)-1-(4-phenoxy-phenyl)urea (498 mg) in trifluoroacetic acid (5 ml) was left to stand for 3 days and then neutralized with saturated sodium carbonate solution. The mixture was extracted with ethyl acetate. The organic phase was dried over magnesium sulfate and concentrated, and the residue was purified by chromatography on silica gel (eluent: dichloromethane/methanol 9:1). The product with the molecular weight of 434.50 (C28H22N2O3); MS (ESI): 435 ([M+H]+), was obtained in this way. 1-(4-Hydroxyphenyl)-3-(4-phenoxy-phenyl)-1,3-dihydroimidazol-2-one was obtained as a further product.

3-(4-Benzyloxyphenyl)-1-(2,2-dimethoxyethyl)-1-(4-phenoxyphenyl)urea

[0135] A solution of 4-benzyloxyaniline (199 mg) in dimethylformamide (1 ml) was added dropwise to a solution of carbonyldiimidazole (162 mg) in dimethylformamide (1 ml) at 0° C. After a reaction time at 0° C. of 10 minutes, the reaction was allowed to continue at room temperature for 20 minutes. Then (2,2-dimethoxyethyl)-(4-phenoxyphenyl)amine (273 mg) was added, and the mixture was heated at 80° C. for 1.5 hours. Cooling was followed by dilution with water and extraction with ethyl acetate. The organic phase was dried over magnesium sulfate and concentrated. The product with the molecular weight of 498.58 (C30H30N2O5); MS (ESI): 499 ([M+H]+), was obtained in this way.

EXAMPLE 5

1-[4-(2-Phenethylaminoethoxy)phenyl]-3-(4-phenoxyphenyl)-1,3-dihydroimidazol-2-one

[0136] 7

[0137] A solution of 1-[4-(2-bromoethoxy)phenyl]-3-(4-phenoxyphenyl)-1,3-dihydroimidazol-2-one (50 mg) in acetonitrile (1 ml) was mixed with phenethylamine (47 mg), potassium carbonate (70 mg) and sodium iodide (5 mg) and boiled under reflux for 2 hours. The cooled solution was filtered and concentrated. The residue was purified by preparative HPLC. The product with the molecular weight of 491.60 (C31 H29N3O3); MS (ESI): 492 ([M+H]+), was obtained as hydroformate in this way.

1-[4-(2-Bromoethoxy)phenyl]-3-(4-phenoxyphenyl)-1,3-dihydroimidazol-2-one

[0138] A solution of 1-(4-hydroxyphenyl)-3-(4-phenoxyphenyl)-1,3-dihydroimidazol-2-one (4.7 g) in 1,2-dibromoethane (23.6 ml) was mixed with is sodium hydroxide solution (3N, 9.1 ml) and tetrabutylammonium hydrogen sulfate (232 mg). The mixture was heated at 75° C. for 2 hours. After cooling, the reaction mixture was mixed with dichloromethane and washed with sodium hydroxide solution (1N), hydrochloric acid (1N) and saturated brine. The organic phase was dried over magnesium sulfate and concentrated, and the residue was purified by chromatography on silica gel (eluent: dichloromethane/methanol 9:1). The product with the molecular weight of 451.32 (C23H19BrN2O3); MS (ESI): 451 ([M+H]+), was obtained in this way.

[0139] 1-(4-Hydroxyphenyl)-3-(4-phenoxyphenyl)-1,3-dihydroimidazol-2-one Boron tribromide (2.5 ml) was added to a solution of 1-(4-methoxyphenyl)-3-(4-phenoxyphenyl)-1,3-dihydroimidazol-2-one (6.0 g) in dichloromethane (75 ml) at 0° C. After 3 hours, saturated sodium bicarbonate solution was added and the organic phase was washed with saturated brine. The organic phase was dried over magnesium sulfate and concentrated, and the residue was purified by chromatography on silica gel (eluent: dichloromethane/methanol 9:1). The product with the molecular weight of 344.37 (C21 H16N2O3); MS (ESI): 345 ([M+H]+), was obtained in this way.

1-(4-Methoxyphenyl)-3-(4-phenoxyphenyl)-1,3-dihydroimidazol-2-one

[0140] A solution of 1-(2,2-dimethoxyethyl)-3-(4-methoxyphenyl)-1-(4-phenoxy-phenyl)urea (6.8 g) in trifluoroacetic acid (20 ml) was left to stand for 16 hours and then neutralized with saturated sodium carbonate solution. The mixture was extracted with ethyl acetate. The organic phase was dried over magnesium sulfate and concentrated. The product with the molecular weight of 358.40 (C22H18N2O3); MS (ESI): 359 ([M+H]+), was obtained in this way.

1-(2,2-Dimethoxyethyl)-3-(4-methoxyphenyl)-1-(4-phenoxyphenyl)urea

[0141] A solution of 4-methoxyaniline (1.9 g) in dimethylformamide (3 ml) was added dropwise to a solution of carbonyidiimidazole (2.51 g) in dimethylformamide (15 ml) at 0° C. After a reaction time at 0° C. of 15 minutes, the reaction was allowed to continue at room temperature for 45 minutes. Then (2,2-dimethoxyethyl)-(4-phenoxyphenyl)amine (4.1 g) in dimethylformamide (2 ml) was added, and the mixture was heated at 80° C. for 2 hours. After cooling, volatiles were removed and the residue was taken up in ethyl acetate. The organic phase was washed with water and saturated brine. The organic phase was dried over magnesium sulfate and concentrated. The product with the molecular weight of 422.49 (C24H26N2O5); MS (ESI): 423 ([M+H]+), was obtained in this way.

EXAMPLE 6

1-[4-(2-Methylaminoethoxy)phenyl]-3-(4-phenoxyphenyl)-1,3-dihydroimidazol-2-one

[0142] 8

[0143] A solution of 1-[4-(2-bromoethoxy)phenyl]-3-(4-phenoxyphenyl)-1,3-dihydroimidazol-2-one (50 mg) in acetonitrile (1 ml) was left to stand with methylamine (1M in THF, 1 ml) and sodium iodide (5 mg) and 24 hours. The reaction solution was filtered and concentrated. The residue was purified by preparative HPLC. The product with the molecular weight of 401.47 (C24H23N3O3); MS (ESI): 402 ([M+H]+), was obtained as hydroformate in this way.

EXAMPLE 7

1-[4-(2-Aminoethoxy)phenyl]-3-(4-phenoxyphenyl)-1,3-dihydroimidazol-2-one

[0144] 9

[0145] A solution of 1-[4-(2-bromoethoxy)phenyl]-3-(4-phenoxyphenyl)-1,3-dihydroimidazol-2-one (50 mg) in acetonitrile (1 ml) was left to stand with ammonia solution (1 ml) and sodium iodide (5 mg) and 24 hours. After repeated addition of the ammonia solution, the reaction was kept at 40° C. for 5 hours. The cooled reaction solution was filtered and concentrated. The residue was purified by preparative HPLC. The product with the molecular weight of 387.44 (C24H21N3O3); MS (ESI): 388 ([M+H]+), was obtained as hydroformate in this way.

EXAMPLE 8

1-(4-Cyclopentyloxyphenyl)-3-[4-(3-dimethylaminopropoxy)phenyl]-1,3-dihydroimidazol-2-one

[0146] 10

[0147] Carbonyidiimidazole (163 mg) was added to a solution of 4-(3-dimethyl-aminopropoxy)phenylamine (194 mg) in dimethylformamide (5 ml) at 0° C. After 10 minutes at 0° C. and 30 minutes at room temperature, a solution of (4-cyclopentyloxyphenyl)-(2,2-dimethoxyethyl)amine (265 mg) in dimethyl-formamide (1 ml) was added, and the mixture was heated at 80° C. for 2 hours. After cooling to room temperature, trifluoroacetic acid (1 ml) was added. After 72 hours, the mixture was diluted with water and extracted with ethyl acetate. The organic phase was washed with saturated sodium bicarbonate solution, dried and concentrated. The residue was purified by preparative HPLC. The product with the molecular weight of 421.54 (C25H31N3O3); MS (ESI): 422 ([M+H]+), was obtained as hydrotrifluoro-acetate in this way.

4-(3-Dimethylaminopropoxy)phenylamine

[0148] Palladium(II) hydroxide (20% on carbon; 0.4 g) was added to a solution of dimethyl-[3-(4-nitrophenoxy)propyl]amine (3.75 g) in ethanol (75 ml) under argon. Then formic acid (4 ml) was added dropwise, during which the reaction mixture heated to 60° C. while evolving much gas. After a reaction time of 90 minutes, the catalyst was filtered off and the filtrate was concentrated. The residue was partitioned between methyl tert-butyl ether and sodium hydroxide solution (2N). The organic phase was dried and concentrated. The product with the molecular weight of 194.28 (C11H18N2O); MS (ESI):195 ([M+H]+), was obtained in this way.

Dimethyl-[3-(4-nitrophenoxy)propyl]amine

[0149] A mixture of 4-fluoronitrobenzene (2.82 g), 3-dimethylaminopropanol (2.48 g), powdered potassium hydroxide (1.35 g) and Aliquat® 336 (tricaprylylmethylammonium chloride) was heated at 85° C. for one hour. The cooled crude mixture was purified by chromatography on silica gel (eluent: ethyl acetate/methanol 9:1 mixed with 1% v/v triethylamine). The product with the molecular weight of 224.26 (C11H16N2O3); MS (ESI): 225 ([M+H]+), was obtained in this way.

(4-Cyclopentyloxyphenyl)-(2,2-dimethoxyethyl)amine

[0150] A suspension of 4-cyclopentyloxyphenylamine (8.86 g), bromo-acetaldehyde dimethyl acetal (12.2 g), potassium carbonate (13.8 g) and dimethylformamide (100 ml) was heated at 100° C. for 5 hours. Cooling was followed by filtration and concentration of the filtrate. The residue was purified by chromatography on silica gel (eluent: heptane/ethyl acetate 4:1). The product with the molecular weight of 265.36 (C15H23NO3); MS (ESI): 266 ([M+H]+), was obtained in this way.

4-Cyclopentyloxyphenylamine

[0151] Sodium hydride (50% in oil; 4.8 g) was added in portions to a solution of 4-aminophenol (10.9 g) in dimethylformamide (150 ml). After 20 minutes, cyclopentyl bromide (14.9 g) was added dropwise. After 2 hours at room temperature, the reaction mixture was diluted with water and extracted with ethyl acetate. The organic phase was washed with water and brine, dried and concentrated. The residue was purified by chromatography on silica gel (eluent: heptane/ethyl acetate 3:1). The product with the molecular weight of 177.25 (C11H15NO); MS (ESI): 178 ([M+H]+), was obtained in this way.

EXAMPLE 9

1-(4-Cyclopentyloxyphenyl)-3-[4-((1 R,2S)-2-dimethylamino-1-phenylpropoxy)-phenyl]-1,3-dihydroimidazol-2-one

[0152] 11

[0153] The compound was prepared as described in example 8 but with use of 4-((1R,2S)-2-dimethylamino-1-phenylpropoxy)phenylamine. The product with the molecular weight of 497.64 (C31H35N3O3); MS (ESI): 498 ([M+H]+), was obtained as hydrotrifluoroacetate in this way.

4-((1R,2S)-2-Dimethylamino-1-phenylpropoxy)phenylamine

[0154] The compound was prepared as described in example 8 but with use of (1R,2S)-dimethyl-[1-methyl-2-(4-nitrophenoxy)-2-phenylethyl]amine. The product with the molecular weight of 270.38 (C17H22N2O); MS (ESI): 271 ([M+H]+), was obtained in this way.

(1R,2S)-Dimethyl-[1-methyl-2-(4-nitrophenoxy)-2-phenylethyl]amine

[0155] The compound was prepared as described in example 8 but with use of (1R,2S)-dimethyl-[1-methyl-2-hydroxy)-2-phenylethyl]amine. The product with the molecular weight of 300.36 (C17H20N2O3); MS (ESI): 301 ([M+H]+), was obtained in this way.

EXAMPLE 10

1-(4-Cyclopentyloxyphenyl)-3-{4-[(2-dimethylaminoethyl)methylamino]-phenyl}-1,3-dihydroimidazol-2-one

[0156] 12

[0157] The compound was prepared as described in example 8 but with use of N-(2-dimethylaminoethyl)-N-methylbenzene-1,4-diamine. The product with the molecular weight of 420.56 (C25H32N4O2); MS (ESI): 421 ([M+H]+), was obtained as hydrotrifluoroacetate in this way.

N-(2-Dimethylaminoethyl)-N-methylbenzene-1,4-diamine

[0158] The compound was prepared by zinc dust reduction of N,N,N′-trimethyl-N′-(4-nitrophenyl)ethane-1,2-diamine in analogy to the method in example 3. The product with the molecular weight of 193.29 (C11H19N3); MS (ESI): 194 ([M+H]+), was obtained in this way.

N,N,N′-Trimethyl-N′-(4-nitrophenyl)ethane-1,2-diamine

[0159] A mixture of N,N,N′-trimethylethane-1,2-diamine (2.17 g), potassium carbonate (3.0 g), 4-nitrofluorobenzene and dimethylformamide (30 ml) was stirred for 72 hours. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic phase was washed with water and saturated brine, dried and concentrated. The product with the molecular weight of 223.28 (C11H17N3O2); MS (ESI): 224 ([M+H]+), was obtained in this way.

EXAMPLE 11

1-(4-Cyclopentyloxyphenyl)-3-[4-(3-dimethylaminopropyl)phenyl]-1,3-dihydroimidazol-2-one

[0160] 13

[0161] The compound was prepared as described in example 8 but with use of 4-(3-dimethylaminopropyl)phenylamine. The product with the molecular weight of 405.54 (C25H31N3O2); MS (ESI): 406 ([M+H]+), was obtained as hydrotrifluoroacetate in this way.

4-(3-Dimethylaminopropyl)phenylamine

[0162] A solution of 3-dimethylamino-1-(4-nitrophenyl)propan-1-one (hydrochloride, 0.25 g) in glacial acetic acid (10 ml) was adjusted to pH 1 with concentrated hydrochloric acid and, under nitrogen, palladium(II) hydroxide (20% on carbon, 0.1 g) was added. The nitrogen atmosphere was replaced by hydrogen, and the suspension was shaken for 6 hours. The catalyst was filtered off and the filtrate was concentrated. The residue was partitioned between saturated sodium bicarbonate solution and ethyl acetate. The aqueous phase was adjusted to pH>12 with sodium hydroxide solution and extracted with ethyl acetate. The combined organic phases were dried and concentrated. The product with the molecular weight of 178.28 (C11H18N2); MS (ESI): 179 ([M+H]+), was obtained in this way.

3-Dimethylamino-1-(4-nitrophenyl)propan-1-one

[0163] A mixture of 4-nitroacetophenone (1.0 g), N,N-dimethylmethylene-ammonium chloride (0.56 g) and acetonitrile (10 ml) was heated at 80° C. for 4 hours, and the precipitate which separated out after cooling was filtered off with suction. The product with the molecular weight of 222.25 (C11H14N2O3); MS (ESI): 223 ([M+H]+), was obtained as hydrochloride in this way.

EXAMPLES 12-91

[0164] Further examples which were prepared as described in example 5 but with use of the appropriate amine are summarized in table 2

TABLE 2
Ex.				Molecular	[M + H]+
No.	Name	Structure	Molecular formula	weight	ESI-MS
12	1-{4-[2-(2- Methoxyethylamino)ethoxy]phenyl}- 3-(4-phenoxyphenyl)-1,3- dihydroimidazol-2-one	14	C26H27N3O4	445.52	446
13	1-(4-Phenoxyphenyl)-3-{4-[2- ((1S,5R)-1,3,3-trimethyl-6- azabicyclo[3.2.1]oct-6-yl)ethoxy]- phenyl}-1,3-dihydroimidazol-2-one	15	C33H37N3O3	523.68	524
14	1-(4-Phenoxyphenyl)-3-[4-(2- thiomorpholin-4-ylethoxy)phenyl]- 1,3-dihydroimidazol-2-one	16	C27H27N3O3S	473.60	474
15	1-(2-{4-[2-Oxo-3-(4- phenoxyphenyl)-2,3- dihydroimidazol-1- yl]phenoxy}ethyl)piperidine-3- carboxylic acid diethylamide	17	C33H38N4O4	554.70	555
16	1-{4-[2-(1,4-Dioxa-8- azaspiro[4.5]dec-8-yl)- ethoxy]phenyl}-3-(4- phenoxyphenyl)-1,3- dihydroimidazol-2-one	18	C30H31N3O5	513.60	514
17	1-(4-{2-[Methyl-(2-pyridin-2- ylethyl)amino]ethoxy}phenyl)-3-(4- phenoxyphenyl)-1,3- dihydroimidazol-2-one	19	C31H30N4O3	506.61	507
18	1-(4-Phenoxyphenyl)-3-{4-[2-(4- phenylbutylamino)ethoxy]phenyl}- 1,3-dihydroimidazol-2-one	20	C33H33N3O3	519.65	520
19	1-{4-[2- (Allylcyclopentylamino)ethoxy]phenyl}- 3-(4-phenoxyphenyl)-1,3- dihydroimidazol-2-one	21	C31H33N3O3	495.63	496
20	1-{4-[2-(2- Phenoxyethylamino)ethoxy]phenyl}- 3-(4-phenoxyphenyl)-1,3- dihydroimidazol-2-one	22	C31H29N3O4	507.59	508
21	1-{4-[2-(2-Cyclohex-1- enylethylamino)ethoxy]phenyl}-3-(4- phenoxyphenyl)-1,3-dihydro- imidazol-2-one	23	C31H33N3O3	495.63	496
22	1-(4-{2-[(1- Hydroxycyolohexylmethyl)amino]- ethoxy}phenyl)-3-(4- phenoxyphenyl)-1,3- dihydroimidazol-2-one	24	C30H33N3O4	499.62	500
23	(S)-3-(2-{4-[2-Oxo-3-(4- phenoxyphenyl)-2,3- dihydroimidazol-1- yl]phenoxy}ethylamino)azepan-2- one	25	C29H30N4O4	498.59	499
24	1-{4-[2-(4-Acetylpiperazin-1- yl)ethoxy]phenyl}-3-(4- phenoxy)phenyl)-1,3- dihydroimidazol-2-one	26	C29H30N4O4	498.59	499
25	1-(4-{2-[3-(2-Oxopyrrolidin-1- yl)propylamino]ethoxy}phenyl)-3-(4- phenoxyphenyl)-1,3- dihydroimidazol-2-one	27	C30H32N4O4	512.61	513
26	1-{4-[2-(5- Hydroxypentylamino)ethoxy]- phenyl}-3-(4-phenoxyphenyl)-1,3- dihydroimidazol-2-one	28	C28H31N3O4	473.58	474
27	1-(4-Phenoxyphenyl)-3-(4-{2- [(tetrahydrofuran-2- ylmethyl)amino]ethoxy}phenyl)-1,3- dihydroimidazol-2-one	29	C28H29N3O4	471.56	472
28	1-{4-[2-(4-Hydroxypiperidin-1-yl)- ethoxy]phenyl}-3-(4- phenoxyphenyl)-1,3- dihydroimidazol-2-one	30	C28H29N3O4	471.56	472
29	1-{4-[2-(3,4-Dihydro-1H-isoquinolin- 2-yl)ethoxy]phenyl}-3-(4- phenoxyphenyl)-1,3- dihydroimidazol-2-one	31	C32H29N3O3	503.61	504
30	1-{4-[2-(4-Methylpiperidin-1- yl)ethoxy]phenyl}-3-(4- phenoxyphenyl)-1,3- dihydroimidazol-2-one	32	C29H31N3O3	469.59	470
31	1-{4-[2-(2,2- Diphenylethylamino)ethoxy]phenyl}- 3-(4-phenoxyphenyl)-1,3-dihydro- imidazol-2-one	33	C37H33N3O3	567.69	568
32	1-[4-(2- Phenethylaminoethoxy)phenyl]-3- (4-phenoxyphenyl)-1,3- dihydroimidazol-2-one	34	C31H29N3O3	491.60	492
33	1-{4-[2- (Benzylmethylamino)ethoxy]phenyl}- 3-(4-phenoxyphenyl)-1,3- dihydroimidazol-2-one	35	C31H29N3O3	491.60	492
34	1-(4-Phenoxyphenyl)-3-(4-{2- [(thiophen-2-yl- methyl)amino]ethoxy}phenyl)-1,3- dihydroimidazol-2-one	36	C28H25N3O3S	483.59	484
35	1-{4-[2-(4-Benzylpiperidin-1- yl)ethoxy]phenyl}-3-(4- phenoxyphenyl)-1,3- dihydroimidazol-2-one	37	C35H35N3O3	545.69	546
36	1-(4-Phenoxyphenyl)-3-[4-(2- thiazolidin-3-ylethoxy)phenyl]-1,3- dihydroimidazol-2-one	38	C26H25N3O3S	459.57	460
37	1-{4-[2- (Methylphenethylamino)ethoxy]- phenyl}-3-(4-phenoxyphenyl)-1,3- dihydroimidazol-2-one	39	C32H31N3O3	505.62	506
38	1-[4-(2- Cyclopropylaminoethoxy)phenyl]-3- (4-phenoxyphenyl)-1,3- dihydroimidazol-2-one	40	C26H25N3O3	427.51	428
39	1-[4-(2- Cyclohexylaminoethoxy)phenyl]-3- (4-phenoxyphenyl)-1,3- dihydroimidazol-2-one	41	C29H31N3O3	469.59	470
40	1-[4-(2-tert- Butylaminoethoxy)phenyl]-3-(4- phenoxyphenyl)-1,3- dihydroimidazol-2-one	42	C27H29N3O3	443.55	444
41	1-(4-Phenoxyphenyl)-3-{4-[2-(2- pyridin-4- ylethylamino)ethoxy]phenyl}-1,3- dihydroimidazol-2-one	43	C30H28N4O3	492.58	493
42	1-[4-(2- isopropyiaminoethoxy)phenyl]-3-(4- phenoxyphenyl)-1,3- dihydroimidazol-2-one	44	C26H27N3O3	429.52	430
43	N-[1-(2-{4-[2-Oxo-3-(4- phenoxyphenyl)-2,3- dihydroimidazol-1- yl]phenoxy}ethyl)pyrrolidin-3- yl]acetamide	45	C29H30N4O4	498.59	499
44	1-{4-[2-(4-Hydroxy-4- phenylpiperidin-1-yl)ethoxy]phenyl}- 3-(4-phenoxyphenyl)-1,3- dihydroimidazol-2-one	46	C34H33N3O4	547.66	548
45	1-[4-(2-Imidazol-1-ylethoxy)phenyl]- 3-(4-phenoxyphenyl)-1,3- dihydroimidazol-2-one	47	C26H22N4O3	438.49	439
46	1-(4-Phenoxyphenyl)-3-[4-(2- pyrazol-1-yl-ethoxy)phenyl]-1,3- dihydroimidazol-2-one	48	C26H22N4O3	438.49	439
47	(S)-1-(2-{4-[2-Oxo-3-(4- phenoxyphenyl)-2,3- dihydroimidazol-1- yl]phenoxy}ethyl)pyrrolidine-2- carboxylic acid ethyl ester	49	C30H31N3O5	513.60	514
48	1-{4-[2-(Indan-2- ylamino)ethoxy]phenyl}-3-(4- phenoxyphenyl)-1,3- dihydroimidazol-2-one	50	C32H29N3O3	503.61	504
49	1-{4-[2-(2-Ethylpiperidin-1- yl)ethoxy]phenyl}-3-(4- phenoxyphenyl)-1,3- dihydroimidazol-2-one	51	C30H33N3O3	483.62	484
50	1-{4-[2- (Cyclopropylmethylamino)ethoxy]- phenyl}-3-(4-phenoxyphenyl)-1,3- dihydroimidazol-2-one	52	C27H27N3O3	441.53	442
51	1-{4-[2-(Indan-1- ylamino)ethoxy]phenyl}-3-(4- phenoxyphenyl)-1,3- dihydroimidazol-2-one	53	C32H29N3O3	503.61	504
52	1-(4-Phenoxyphenyl)-3-{4-[2-(4- phenylpiperazin-1- yl)ethoxy]phenyl}-1,3-dihydro- imidazol-2-one	54	C33H32N4O3	532.65	533
53	1-{4-[2-(4-Phenethylpiperazin-1- yl)ethoxy]phenyl}-3-(4- phenoxyphenyl)-1,3-dihydro- imidazol-2-one	55	C35H36N4O3	560.70	561
54	1-[4-(2-Benzoimidazol-1- yl)ethoxy)phenyl]-3-(4- phenoxyphenyl)-1,3- dihydroimidazol-2-one	56	C30H24N4O3	488.55	489
55	1-(4-{2-[2-(3- Methoxyphenyl)ethylamino]- ethoxy}phenyl)-3-(4- phenoxyphenyl)-1,3- dihydroimidazol-2-one	57	C32H31N3O4	521.62	522
56	1-{4-[2-(2-Methyl-4,5- dihydroimidazol-1- yl)ethoxy]phenyl}-3-(4- phenoxyphenyl)-1,3- dihydroimidazol-2-one	58	C27H26N4O3	454.53	455
57	1-{4-[2-(4-Ethylpiperazin-1- yl)ethoxy]phenyl}-3-(4- phenoxyphenyl)-1,3- dihydroimidazol-2-one	59	C29H32N4O3	484.60	485
58	1-{4-[2-(3,6-Dihydro-2H-pyridin-1- yl)ethoxy]phenyl}-3-(4- phenoxyphenyl)-1,3-dihydro- imidazol-2-one	60	C28H27N3O3	453.55	454
59	1-{4-[2-(3-Hydroxypyrrolidin-1- yl)ethoxy]phenyl}-3-(4- phenoxyphenyl)-1,3-dihydro- imidazol-2-one	61	C27H27N3O4	457.53	458
60	1-(4-Phenoxyphenyl)-3-{4-[2- ((1S,2R)-2- phenylcyclopropylamino)ethoxy]phenyl}- 1,3-dihydroimidazol-2-one	62	C32H29N3O3	503.61	504
61	1-{4-[(4aR,8aS)-2- (Octahydroisoquinolin-2- yl)ethoxy]phenyl}-3-(4- phenoxyphenyl)-1,3- dihydroimidazol-2-one	63	C32H35N3O3	509.65	510
62	1-{4-[(4aS,8aS)-2- (Octahydroisoquinolin-2- yl)ethoxy]phenyl}-3-(4- phenoxyphenyl)-1,3- dihydroimidazol-2-one	64	C32H35N3O3	509.65	510
63	1-[4-(2-{[2-(1H-Indol-3- yl)ethyl]methylamino}- ethoxy)phenyl]-3-(4- phenoxyphenyl)-1,3- dihydroimidazol-2-one	65	C34H32N4O3	544.66	545
64	1-(4-{2-[2-(2- Chlorophenyl)ethylamino]- ethoxy}phenyl)-3-(4- phenoxyphenyl)-1,3- dihydroimidazol-2-one	66	C31H28ClN3O3	526.04	526
65	1-(4-{2-[(5-Chlorothiophen-2- ylmethyl)amino]ethoxy}phenyl)-3-(4- phenoxyphenyl)-1,3- dihydroimidazol-2-one	67	C28H24ClN3O3S	518.04	518
66	1-{4-[2-((1R,2R)-2- Benzyloxycyclopentyl- amino)ethoxy]phenyl}-3-(4- phenoxyphenyl)-1,3- dihydroimidazol-2-one	68	C35H35N3O4	561.69	562
67	1-{4-[2-((S)-8-Methoxy-1,2,3,4- tetrahydronaphthalen-2- ylamino)ethoxy]phenyl}-3-(4- phenoxyphenyl)-1,3- dihydroimidazol-2-one	69	C34H33N3O4	547.66	548
68	1-{4-[2-(4-Benzyl-4- hydroxypiperidin-1-yl)- ethoxy]phenyl}-3-(4- phenoxyphenyl)-1,3- dihydroimidazol-2-one	70	C35H35N3O4	561.69	562
69	1-{4-[2-(5-Bromo-2,3-dihydroindol- 1-yl)ethoxy]phenyl}-3-(4- phenoxyphenyl)-1,3- dihydroimidazol-2-one	71	C31H26BrN3O3	568.48	568
70	1-{4-[2-(5-Ethyl-2-methylpiperidin-1- yl)ethoxy]phenyl}-3-(4- phenoxyphenyl)-1,3- dihydroimidazol-2-one	72	C31H35N3O3	497.64	498
71	1-{4-[2-(2,5-Dimethylpyrrolidin-1- yl)ethoxy]phenyl}-3-(4- phenoxyphenyl)-1,3-dihydro- imidazol-2-one	73	C29H31N3O3	469.59	470
72	1-{4-[2- (Methylpropylamino)ethoxy]phenyl}- 3-(4-phenoxyphenyl)-1,3- dihydroimidazol-2-one	74	C27H29N3O3	443.55	444
73	1-{4-[2-([1,3]-Dioxolan-2- ylmethylmethyl- amino)ethoxy]phenyl}-3-(4- phenoxyphenyl)-1,3- dihydroimidazol-2-one	75	C28H29N3O5	487.56	488
74	1-{4-[2-(2-Methylpyrrolidin-1- yl)ethoxyphenyl}-3-(4- phenoxyphenyl)-1,3- dihydroimidazol-2-one	76	C28H29N3O3	455.56	456
75	1-{4-[2- (Isopropylmethylamino)ethoxy]phenyl}- 3-(4-phenoxyphenyl)-1,3- dihydroimidazol-2-one	77	C27H29N3O3	443.55	444
76	1-{4-[2-((R)-2- Methoxymethylpyrrolidin- 1-yl)ethoxy]phenyl}-3-(4- phenoxyphenyl)- 1,3-dihydroimidazol-2-one	78	C29H31N3O4	485.59	486
77	(S)-1-(2-{4-[2-Oxo-3-(4- phenoxyphenyl)- 2,3-dihydroimidazol-1- yl]phenoxy}ethyl)pyrrolidine-2- carboxylic acid dimethylamide	79	C30H32N4O4	512.61	513
78	1-(4-{2-[(2- Methoxyethyl)methylamino]- ethoxy}phenyl)-3-(4- phenoxyphenyl)- 1,3-dihydroimidazol-2-one	80	C27H29N3O4	459.55	460
79	1-{4-[2-(7-Azabicyclo[2.2.1]hept-7- yl)ethoxy]phenyl}-3-(4- phenoxyphenyl)-1,3-dihydro- imidazol-2-one	81	C29H29N3O3	467.57	468
80	1-(4-{2-[(1-Benzylpyrrolidin-3- yl)methylamino]ethoxy}phenyl)-3-(4- phenoxyphenyl)-1,3- dihydroimidazol-2-one	82	C35H36N4O3	560.70	561
81	1-(4-{2-[(1,1-Dioxotetrahydro- 1lambda6-thiophen-3- yl)methylamino]ethoxy}phenyl)-3-(4- phenoxyphenyl)-1,3- dihydroimidazol-2-one	83	C28H29N3O5S	519.62	520
82	1-{4-[2- (Benzhydrylmethylamino)ethoxy]- phenyl}-3-(4-phenoxyphenyl)-1,3- dihydroimidazol-2-one	84	C37H33N3O3	567.69	568
83	1-(4-{2-[((4S,5S)-2,2-Dimethyl-4- phenyl-[1,3]-dioxan-5- yl)methylamino]ethoxy}phenyl)-3-(4- phenoxyphenyl)-1,3- dihydroimidazol-2-one	85	C36H37N3O5	591.71	592
84	1-{4-[2-(3-Dimethylaminopyrrolidin- 1-yl)ethoxy]phenyl}-3-(4- phenoxyphenyl)- 1,3-dihydroimidazol-2-one	86	C29H32N4O3	484.60	485
85	1-(4-Phenoxyphenyl)-3-{4-[2-(2- phenylpyrrolidin-1- yl)ethoxy]phenyl}-1,3-dihydro- imidazol-2-one	87	C33H31N3O3	517.63	518
86	1-{4-[2-(2-Benzylpyrrolidin-1- yl)ethoxy]phenyl}-3-(4- phenoxyphenyl)-1,3-dihydro- imidazol-2-one	88	C34H33N3O3	531.66	532
87	1-{4-[2-(2-Phenethylpyrrolidin-1- yl)ethoxy]phenyl}-3-(4- phenoxyphenyl)-1,3-dihydro- imidazol-2-one	89	C35H35N3O3	545.69	546
88	1-{4-[2-(2-Isopropylpyrrolidin-1- yl)ethoxy]phenyl}-3-(4- phenoxyphenyl)-1,3-dihydro- imidazol-2-one	90	C30H33N3O3	483.62	484
89	1-(4-Phenoxyphenyl)-3-{4-[2-(3- phenylpyrrolidin-1- yl)ethoxy]phenyl}-1,3-dihydro- imidazol-2-one	91	C33H31N3O3	517.63	518
90	1-{4-[2-(3-Benzylpyrrolidin-1- yl)ethoxy]phenyl}-3-(4- phenoxyphenyl)-1,3-dihydro- imidazol-2-one	92	C34H33N3O3	531.66	532
91	1-{4-[2-(3- Methanesulfonylpyrrolidin-1-yl)- ethoxy]phenyl}-3-(4- phenoxyphenyl)-1,3- dihydroimidazol-2-one	93	C28H29N3O5S	519.62	520

EXAMPLE 92

1-(4-sec-Butoxyphenyl)-3-[4-(2-dimethylaminoethoxy)phenyl]-1,3-dihydroimidazol-2-one

[0165] 94

[0166] A solution of 1-[4-(2-dimethylaminoethoxy)phenyl]-3-(4-hydroxyphenyl)-1,3-dihydroimidazol-2-one (50 mg) in propionitrile (1 mL) was mixed with cesium carbonate (100 mg) and 2-butyl bromide (25 mg) and heated at 80° C. for 2 hours. The reaction solution was filtered and the concentrated. The residue was purified by preparative HPLC. The product with the molecular weight of 395.51 (C23H29N3O3); MS (ESI): 396 ([M+H]+), was obtained as hydrotrifluoroacetate in this way.

1-[4-(2-Dimethylaminoethoxy)phenyl]-3-(4-hydroxyphenyl)-1,3-dihydroimidazol-2-one

[0167] A suspension of 1-(4-benzyloxyphenyl)-1-(2,2-dimethoxyethyl)-3-[4-(2-dimethylaminoethoxy)phenyl]urea (4.9 g), palladium (10% on carbon, 1.0 g) and ethanol (40 mL) was stirred under hydrogen for 5 hours. The catalyst was filtered off and the filtrate was concentrated. The residue was taken up in trifluoroacetic acid (20 mL) and the solution was stirred for 48 hours. The reaction mixture was diluted with dichloromethane and washed with saturated sodium bicarbonate solution. The organic phase was dried and concentrated. The solid residue was stirred with acetonitrile, and the product was filtered off. The product with the molecular weight of 339.40 (C19H21N3O3); MS (ESI): 340 ([M+H]+), was obtained in this way.

1-(4-Benzyloxyphenyl)-1-(2,2-dimethoxyethyl)-3-[4-(2-dimethylaminoethoxy)phenyl]urea

[0168] Carbonyldiimidazole (2.7 g) was added to a solution of 4-(2-dimethylaminoethoxy)phenylamine (3.01 g) in dimethylformamide (40 mL) cooled in ice. After 30 minutes, (4-benzyloxyphenyl)-(2,2-dimethoxyethyl)amine (4.8 g) was added, and the mixture was heated at 80° C. for 30 minutes. After cooling, volatiles were removed and the residue was purified by MPLC (eluent: heptane/ethyl acetate 9:1). The product with the molecular weight of 493.61 (C28H35N3O5); MS (ESI): 494 ([M+H]+), was obtained in this way.

(4-Benzyloxyphenyl)-(2,2-dimethoxyethyl)amine

[0169] A mixture of 4-benzyloxyaniline (10 g), bromoacetaldehyde dimethyl acetal (12.2 g), potassium carbonate (13.8 g) and dimethylformamide (150 mL) was heated at 100° C. for 5 hours. After cooling, the reaction solution was filtered and concentrated. The residue was purified by MPLC (eluent: heptane/ethyl acetate 4:1). The product with the molecular weight of 287.36 (C17H21NO3); MS (ESI): 288 ([M+H]+), was obtained in this way.

EXAMPLES 93-130

[0170] Further examples prepared as described in example 92 using the appropriate alkyl bromide are summarized in table 3.

TABLE 3
Ex. No.	Structure	Name	Molecular formula	Molecular weight	[M + H]+ ESI-MS
93	95	1-[4-(2-Dimethylaminoethoxy)phenyl]- 3-[4-(1-phenylethoxy)phenyl]-1,3- dihydroimidazol-2-one	C27H29N3O3	443.55	444
94	96	1-(4-sec-Butoxyphenyl)-3-[4- (2-dimethyl]aminoethoxy)phenyl]-1,3- dihydroimidazol-2-one	C23H29N3O3	395.51	396
95	97	1-[4-(2-Dimethylaminoethoxy)phenyl]- 3-[4-(1-methylbutoxy)phenyl]-1,3- dihydroimidazol-2-one	C24H31N3O3	409.53	410
96	98	1-[4-(2-Dimethylaminoethoxy)phenyl]- 3-[4-(2-methylbenzyloxy)phenyl]-1,3- dihydroimidazol-2-one	C27H29N3O3	443.55	444
97	99	1-[4-(2-Dimethylaminoethoxy)phenyl]- 3-[4-(3-methylbenzyloxy)phenyl]-1,3- dihydroimidazol-2-one	C27H29N3O3	443.55	444
98	100	1-[4-(2-Dimethylaminoethoxy)phenyl]- 3-[4-(4-methylbenzyloxy)phenyl]-1,3- dihydroimidazol-2-one	C27H29N3O3	443.55	444
99	101	1-[4-(2-Dimethylaminoethoxy)phenyl]- 3-[4-(2,2-dimethylpropoxy)phenyl]-1,3- dihydroimidazol-2-one	C24H31N3O3	409.53	410
100	102	1-[4-(2-Dimethylaminoethoxy)phenyl]- 3-(4-isobutoxyphenyl)-1,3- dihydroimidazol-2-one	C23H29N3O3	395.51	396
101	103	1-[4-(2-Dimethylaminoethoxy)phenyl]- 3-[4-(2-ethylbutoxy)phenyl]-1,3-dihydro- imidazol-2-one	C25H33N3O3	423.56	424
102	104	1-[4-(2-Dimethylaminoethoxy)phenyl]- 3-(4-ethoxyphenyl)-1,3-dihydroimidazol- 2-one	C21H25N3O3	367.45	368
103	105	1-[4-(2-Dimethylaminoethoxy)phenyl]- 3-[4-(2-methoxyethoxy)phenyl]-1,3- dihydroimidazol-2-one	C22H27N3O4	397.48	398
104	106	1-[4-(2-Dimethylaminoethoxy)phenyl]- 3-(4-prop-2-ynyloxyphenyl)-1,3-dihydro- imidazol-2-one	C22H23N3O3	377.45	378
105	107	1-(4-Allyloxyphenyl)-3-[4-(2- dimethylaminoethoxy)phenyl]-1,3- dihydroimidazol-2-one	C22H25N3O3	379.46	380
106	108	1-{4-[((E)-But-2-enyl)oxy]phenyl}-3-{4- [(2-dimethylaminoethyl)oxy]phenyl}-1,3- dihydroimidazol-2-one	C23H27N3O3	393.49	394
107	109	1-[4-(2-Dimethylaminoethoxy)phenyl]- 3-(4-propoxyphenyl)-1,3- dihydroimidazol-2-one	C22H27N3O3	381.48	382
108	110	1-(4-But-3-enyloxyphenyl)-3-[4-(2- dimethylaminoethoxy)phenyl]-1,3- dihydroimidazol-2-one	C23H27N3O3	393.49	394
109	111	1-(4-Butoxyphenyl)-3-[4-(2- dimethylaminoethoxy)phenyl]-1,3- dihydroimidazol-2-one	C23H29N3O3	395.51	396
110	112	1-[4-(2-Dimethylaminoethoxy)phenyl]- 3-(4-hexyloxyphenyl)-1,3- dihydroimidazol-2-one	C25H33N3O3	423.56	424
111	113	1-(4-Cyclopropylmethoxyphenyl)-3-[4- (2-dimethylaminoethoxy)phenyl]-1,3- dihydroimidazol-2-one	C23H27N3O3	393.49	394
112	114	1-(4-Cyclopentyloxyphenyl)-3-[4- (2-dimethylaminoethoxy)phenyl]-1,3- dihydroimidazol-2-one	C24H29N3O3	407.52	408
113	115	1-(4-Cyclohexylmethoxyphenyl)-3-[4- (2-dimethylaminoethoxy)phenyl]-1,3- dihydroimidazol-2-one	C26H33N3O3	435.57	436
114	116	1-[4-(2-Dimethylaminoethoxy)phenyl]- 3-[4-([1,3]dioxolan-2-ylmethoxy)phenyl]- 1,3-dihydroimidazol-2-one	C23H27N3O5	425.49	426
115	117	1-(4-Cyclohexyloxyphenyl)-3-[4- (2-dimethylaminoethoxy)phenyl]-1,3- dihydroimidazol-2-one	C25H31N3O3	421.54	422
116	118	1-(4-Cycloheptyloxyphenyl)-3-[4- (2-dimethylaminoethoxy)phenyl]-1,3- dihydroimidazol-2-one	C26H33N3O3	435.57	436
117	119	1-[4-(2-Dimethylaminoethoxy)phenyl]- 3-[4-(tetrahydropyran-2- ylmethoxy)phenyl]-1,3-dihydroimidazol- 2-one	C25H31N3O4	437.54	438
118	120	1-[4-(2-Dimethylaminoethoxy)phenyl]- 3-[4-(4-methylcyclohexyloxy)phenyl]- 1,3-dihydroimidazol-2-one	C26H33N3O3	435.57	436
119	121	1-[4-(2-Dimethylaminoethoxy)phenyl]- 3-[4-(tetrahydrofuran-2- ylmethoxy)phenyl]-1,3-dihydroimidazol- 2-one	C24H29N3O4	423.52	424
120	122	1-[4-(2-Dimethylaminoethoxy)phenyl]- 3-[4-(1-ethylbutoxy)phenyl]-1,3-dihydro- imidazol-2-one	C25H33N3O3	423.56	424
121	123	1-[4-(2-Dimethylaminoethoxy)phenyl]- 3-[4-(3-fluoropropoxy)phenyl]-1,3- dihydroimidazol-2-one	C22H26FN3O3	399.47	400
122	124	1-(4-Cyclobutylmethoxyphenyl)-3-[4- (2-dimethylaminoethoxy)phenyl]-1,3- dihydroimidazol-2-one	C24H29N3O3	407.52	408
123	125	1-[4-(2-Dimethylaminoethoxy)phenyl]- 3-[4-(3,3-dimethylbutoxy)phenyl]-1,3- dihydroimidazol-2-one	C25H33N3O3	423.56	424
124	126	1-[4-(2-Dimethylaminoethoxy)phenyl]- 3-[4-(4,4,4-trifluorobutoxy)phenyl]-1,3- dihydroimidazol-2-one	C23H26F3N3O3	449.48	450
125	127	1-[4-(Bicyclo[2.2.1]hept-5-en-2- ylmethoxy)phenyl]-3-[4-(2- dimethylaminoethoxy)phenyl]-1,3- dihydroimidazol-2-one	C27H31N3O3	445.57	446
126	128	1-[4-(2-Dimethylaminoethoxy)phenyl]- 3-[4-(2-methylallyloxy)phenyl]-1,3- dihydroimidazol-2-one	C23H27N3O3	393.49	394
127	129	1-[4-((1S,2R,4R)-Bicyclo[2.2.1]hept-2- yloxy)phenyl]-3-[4- (2-dimethylaminoethoxy)phenyl]-1,3- dihydroimidazol-2-one	C26H31N3O3	433.56	434
128	130	1-(4-But-2-ynyloxyphenyl)-3-[4- (2-dimethylaminoethoxy)phenyl]-1,3- dihydroimidazol-2-one	C23H25N3O3	391.47	392
129	131	1-[4-(2-Dimethylaminoethoxy)phenyl]- 3-[4-(4,4,4-trifluoro-2- methylbutoxy)phenyl]-1,3- dihydroimidazol-2-one	C24H28F3N3O3	463.50	464
130	132	1-[4-(2-Dimethylaminoethoxy)phenyl]- 3-[4-(4-fluorobutoxy)phenyl]-1,3- dihydroimidazol-2-one	C23H28FN3O3	413.50	414

EXAMPLE 131

1-[4-(2-Dimethylaminoethoxy)phenyl]-3-[4-(2-nitrophenoxy)phenyl]-1,3-dihydroimidazol-2-one

[0171] 133

[0172] 2-Nitrofluorobenzene (0.14 g) was added to a mixture of 1-[4-(2-dimethylaminoethoxy)phenyl]-3-(4-hydroxyphenyl)-1,3-dihydroimidazol-2-one (0.34 g), Aliquat® 336 (0.04 g, tricaprylylmethylammonium chloride), potassium hydroxide (0.077 g) and toluene (10 mL). The mixture was heated under reflux for 3 hours. After cooling, the reaction solution was washed with water, dried and concentrated. The residue was purified by preparative HPLC. The product with the molecular weight of 460.49 (C25H24N4O5); MS (ESI): 461 ([M+H]+), was obtained as hydrotrifluoroacetate in this way.

EXAMPLE 132

1-[4-(2-Dimethylaminoethoxy)phenyl]-3-(4-o-tolyloxyphenyl)-1,3-dihydroimidazol-2-one

[0173] 134

[0174] Carbonyldiimidazole (40 mg) was added to a solution of 4-o-tolyloxyphenylamine (50 mg) in dimethylformamide (2 mL) at 0° C. After 30 minutes, (2,2-dimethoxyethyl)-[4-(2-dimethylaminoethoxy)phenyl]amine (67 mg) was added, and the mixture was heated at 80° C. for 2 hours. After cooling to room temperature, trifluoroacetic acid (0.5 mL) was added and the mixture was left to stand for 72 hours. The reaction solution was diluted with ethyl acetate and washed with saturated sodium bicarbonate solution. The organic phase was dried and concentrated. The residue was purified by preparative HPLC. The product with the molecular weight of 429.52 (C26H27N3O3); MS (ESI): 430 ([M+H]+), was obtained as hydrotrifluoroacetate in this way.

(2,2-Dimethoxyethyl)-[4-(2-dimethylaminoethoxy)phenyl]amine

[0175] Sodium hydride (1.57 g) was added to a solution of 4-(2,2-dimethoxyethyl-amino)phenol (4.3 g) in dimethylformamide (25 mL). After 30 minutes, 2-dimethylaminoethyl chloride (hydrochloride, 3.14 g) was added. After 12 hours, the reaction solution was diluted with ethyl acetate and washed with water. The organic phase was dried and concentrated. The residue was purified by MPLC (eluent: dichloromethane/methanol/ammonia solution 95:4.9:0.1). The product with the molecular weight of 268.36 (C14H24N2O3); MS (ESI): 269 ([M+H]+), was obtained in this way.

4-(2,2-Dimethoxyethylamino)phenol

[0176] Palladium(II) hydroxide (20% on carbon, 0.5 g) was added to a solution of (4-benzyloxyphenyl)-(2,2-dimethoxyethyl)amine (3.5 g) in ethanol (50 mL) under nitrogen. The nitrogen atmosphere was replaced by hydrogen and the mixture was shaken for 3 hours. The catalyst was filtered off and the filtrate was concentrated. The crude product was reacted further without purification.

EXAMPLES 133-166

[0177] Further examples prepared as described in example 132 using the appropriate aniline are summarized in table 4.

TABLE 4
Ex. No.	Name	Structure	Molecular formula	Molecular weight	[M + H]+ ESI
133	1-[4-(2-Chlorophenoxy)phenyl]-3-[4- (2-dimethylaminoethoxy)phenyl]- 1,3-dihydroimidazol-2-one	135	C25H24ClN3O3	449.94	450
134	1-[4-(2- Dimethylaminoethoxy)phenyl]- 3-[4-(2-methoxyphenoxy)phenyl]- 1,3-dihydroimidazol-2-one	136	C26H27N3O4	445.52	446
135	1-[4-(2- Dimethylaminoethoxy)phenyl]- 3-(4-m-tolyloxyphenyl)-1,3- dihydroimidazol-2-one	137	C26H27N3O3	429.52	430
136	1-[4-(3-Chlorophenoxy)phenyl]-3-[4- (2-dimethylaminoethoxy)phenyl]- 1,3-dihydroimidazol-2-one	138	C25H24ClN3O3	449.94	450
137	1-[4-(2-Dimethylaminoethoxy)phenyl]- 3-[4-(3-methoxyphenoxy)phenyl]- 1,3-dihydroimidazol-2-one	139	C26H27N3O4	445.52	446
138	1-[4-(2-Dimethylaminoethoxy)phenyl]- 3-[4-(pyridin-3-yloxy)phenyl]-1,3- dihydroimidazol-2-one	140	C24H24N4O3	416.48	417
139	1-Biphenyl-4-yl-3-[4-(2- dimethylaminoethoxy)phenyl]-1,3- dihydroimidazol-2-one	141	C25H25N3O2	399.50	400
140	1-(4-Butylphenyl)-3-[4-(2- dimethylaminoethoxy)phenyl]-1,3- dihydroimidazol-2-one	142	C23H29N3O2	379.51	380
141	1-[4-(2-Dimethylaminoethoxy)phenyl]- 3-(2-methoxy-4- phenylaminophenyl)- 1,3-dihydroimidazol-2-one	143	C26H28N4O3	444.54	445
142	1-(4-Benzyloxyphenyl)-3-[4-(2- dimethylaminoethoxy)phenyl]-1,3- dihydroimidazol-2-one	144	C26H27N3O3	429.52	430
143	1-(4-Benzylphenyl)-3-[4-(2- dimethylaminoethoxy)phenyl]-1,3- dihydroimidazol-2-one	145	C26H27N3O2	413.52	414
144	1-[4-(2-Dimethylaminoethoxy)phenyl]- 3-(4-pyridin-4-ylmethylphenyl)-1,3- dihydroimidazol-2-one	146	C25H26N4O2	414.51	415
145	1-[4-(2-Dimethylaminoethoxy)phenyl]- 3-(4-p-tolyloxyphenyl)-1,3- dihydroimidazol-2-one	147	C26H27N3O3	429.52	430
146	1-[4-(2-Dimethylaminoethoxy)phenyl]- 3-(4-phenylsulfanylphenyl)-1,3- dihydroimidazol-2-one	148	C25H25N3O2S	431.56	432
147	1-[4-(2-Dimethylaminoethoxy)phenyl]- 3-[4-(3-trifluoromethylphenoxy)phenyl]- 1,3-dihydroimidazol-2-one	149	C26H24F3N3O3	483.49	484
148	1-(4-Butyl-2-methylphenyl)-3-[4-(2- dimethylaminoethoxy)phenyl]-1,3- dihydroimidazol-2-one	150	C24H31N3O2	393.53	394
149	4′-{3-[4-(2-Dimethylaminoethoxy)phenyl]- 2-oxo-2,3-dihydroimidazol-1- yl}biphenyl-4-carbonitrile	151	C26H24N4O2	424.51	425
150	1-[3-Chloro-4-(pyrimidin-2- yloxy)phenyl]-3-[4-(2- dimethylaminoethoxy)phenyl]- 1,3-dihydroimidazol-2-one	152	C23H22ClN5O3	451.92	452
151	5-(4-{3-[4- (2-Dimethylaminoethoxy)phenyl]- 2-oxo-2,3-dihydroimidazol-1- yl}phenyl)-2-methylfuran-3- carboxylic acid ethyl ester	153	C27H29N3O5	475.55	476
152	1-[4-(2- Dimethylaminoethoxy)phenyl]- 3-[4-(piperidine-1-carbonyl)phenyl]- 1,3-dihydroimidazol-2-one	154	C25H30N4O3	434.54	435
153	1-[4-(2- Dimethylaminoethoxy)phenyl]- 3-(4-heptafluoropropylsulfanylphenyl)- 1,3-dihydroimidazol-2-one	155	C22H20F7N3O2S	523.48	524
154	1-[4-(2-Dimethylaminoethoxy)phenyl]- 3-[4-(4-fluorophenoxy)phenyl]-1,3- dihydroimidazol-2-one	156	C25H24FN3O3	433.49	434
155	1-[4-(2-Dimethylaminoethoxy)phenyl]- 3-[4-(pyrimidin-2-yloxy)phenyl]-1,3- dihydroimidazol-2-one	157	C23H23N503	417.47	418
156	1-[4-(2-Dimethylaminoethoxy)phenyl]- 3-(2-methoxybiphenyl-4-yl)-1,3- dihydroimidazol-2-one	158	C26H27N3O3	429.52	430
157	1-[4-(2-Dimethylaminoethoxy)phenyl]- 3-(6-methoxybiphenyl-3-yl)-1,3- dihydroimidazol-2-one	159	C26H27N3O3	429.52	430
158	1-[4-(2-Dimethylaminoethoxy)phenyl]- 3-(4-[1,3]dithiolan-2-ylphenyl)-1,3- dihydroimidazol-2-one	160	C22H25N3O2S2	427.59	428
159	1-[4-(2-Dimethylaminoethoxy)phenyl]- 3-[4-(thiophen-2-ylsulfanyl)phenyl]- 1,3-dihydroimidazol-2-one	161	C23H23N3O2S2	437.59	438
160	1-(3-Chloro-4-piperidin-1-ylphenyl)- 3-[4-(2-dimethylaminoethoxy)phenyl]- 1,3-dihydroimidazol-2-one	162	C24H29ClN4O2	440.98	441
161	1-[4-(2-Dimethylaminoethoxy)phenyl]- 3-[4-(2-fluorophenoxy)phenyl]-1,3- dihydroimidazol-2-one	163	C25H24FN3O3	433.49	434
162	1-(3-Cyclopentyloxy-4-methoxyphenyl)- 3-[4-(2-dimethylaminoethoxy)phenyl]- 1,3-dihydroimidazol-2-one	164	C25H31N3O4	437.54	438
163	1-[4-(2-Dimethylaminoethoxy)phenyl]- 3-(4-piperidin-1-ylphenyl)-1,3- dihydroimidazol-2-one	165	C24H30N4O2	406.53	407

EXAMPLE 164

1-(4-Cyclopentyloxyphenyl)-3-{4-[(2-hydroxyethyl)methylamino]phenyl}-1,3-dihydroimidazol-2-one

[0178] 166

[0179] A solution of 1-(4-cyclopentyloxyphenyl)-1-(2,2-dimethoxyethyl)-3-{4-[(2-hydroxyethyl)methylamino]phenyl}urea (0.4 g) in dimethyl-formamide (6 mL) was mixed with trifluoroacetic acid (2 mL) and left to stand for 48 hours. The mixture was diluted with water and extracted with ethyl acetate. The organic phase was washed with water and sodium carbonate solution, dried and concentrated. The product with the molecular weight of 393.49 (C23H27N3O3); MS (ESI): 394 ([M+H]+), was obtained in this way.

1-(4-Cyclopentyloxyphenyl)-1-(2,2-dimethoxyethyl)-3-{4-[(2-hydroxyethyl)-methylamino]phenyl}urea

[0180] 2-[(4-Aminophenyl)methylamino]ethanol was reacted with carbonyldiimidazole and (4-cyclopentyloxyphenyl)-(2,2-dimethoxyethyl)amine by the method given in example 4. The crude product was purified by chromatography on silica gel (eluent: ethyl acetate). The product with the molecular weight of 457.57 (C25H35N3O5); MS (ESI): 458 ([M+H]+), was obtained in this way.

2-[(4-Aminophenyl)methylamino]ethanol

[0181] Palladium (10% on carbon, 1 g) was added to a solution of 2-[methyl-(4-nitrophenyl)amino]ethanol (6 g) in methanol (100 mL) under nitrogen. The nitrogen atmosphere was replaced by hydrogen and the mixture was shaken for 4 hours. The catalyst was filtered off and the filtrate was concentrated. The product with the molecular weight of 166.22 (C9H14N2O); MS (ESI):167 ([M+H]+), was obtained in this way.

2-[Methyl-(4-nitrophenyl)amino]ethanol

[0182] A mixture of 4-fluoronitrobenzene (20 g) and 2-methylaminoethanol (56 mL) was left to stand for 12 hours and then diluted with ethyl acetate. It was washed with water. The organic phase was dried and concentrated. The product with the molecular weight of 196.21 (C9H12N2O3);

[0183] MS (ESI):197 ([M+H]+), was obtained in this way.

EXAMPLE 165

1-(4-Cyclopentyloxyphenyl)-3-{4-[(2-imidazol-1-ylethyl)methylamino]-phenyl}-1,3-dihydroimidazol-2-one

[0184] 167

[0185] Triethylamine (0.13 g) and methanesulfonyl chloride (0.1 mL) were added to a solution of 1-(4-cyclopentyloxyphenyl)-3-{4-[(2-hydroxyethyl)methyl-amino]phenyl}-1,3-dihydroimidazol-2-one (0.20 g) in dichloromethane (5 mL) at 0° C. After 2 hours, volatiles were removed and the residue was taken up in propionitrile (5 mL). Imidazole (0.25 g) was added and the mixture was heated at 90° C. for 6 hours. Volatiles were removed and the residue was purified by preparative HPLC. The product with the molecular weight of 443.55 (C26H29N5O2); MS (ESI): 444 ([M+H]+), was obtained as hydrotrifluoroacetate in this way.

EXAMPLE 166

1-(4-Cyclopentyloxyphenyl)-3-(4-{methyl-[2-(2-methylimidazol-1-yl)ethyl]-amino}phenyl)-1,3-dihydroimidazol-2-one

[0186] 168

[0187] The compound was prepared as described in example 165 but with use of 2-methylimidazole. The product with the molecular weight of 457.58 (C27H31N5O2); MS (ESI): 458 ([M+H]+), was obtained as hydrotrifluoro-acetate in this way.

EXAMPLE 167

1-(4-Cyclopentyloxyphenyl)-3-{4-[methyl-(2-methylaminoethyl)amino]-phenyl}-1,3-dihydroimidazol-2-one

[0188] 169

[0189] The compound was prepared as described in example 165 but with use of methylamine (1 M in THF). The product with the molecular weight of 406.53 (C24H30N4O2); MS (ESI): 407 ([M+H]+), was obtained as hydrotrifluoroacetate in this way.

EXAMPLE 168

1-(4-Cyclopentyloxyphenyl)-3-{4-[methyl-(2-piperidin-1-ylethyl)amino]-phenyl}-1,3-dihydroimidazol-2-one

[0190] 170

[0191] The compound was prepared as described in example 165 but with use of piperidine. The product with the molecular weight of 460.62 (C28H36N4O2); MS (ESI): 461 ([M+H]+), was obtained as hydrotrifluoroacetate in this way.

EXAMPLE 169

1-(4-Cyclopentyloxyphenyl)-3-(4-{[2-(cyclopropylmethylamino)ethyl]methylamino}phenyl)-1,3-dihydroimidazol-2-one

[0192] 171

[0193] The compound was prepared as described in example 165 but with use of cyclopropylmethylamine. The product with the molecular weight of 446.60 (C27H34N4O2); MS (ESI): 447 ([M+H]+), was obtained as hydrotrifluoro-acetate in this way.

EXAMPLE 170

N-[2-({4-[3-(4-Cyclopentyloxyphenyl)-2-oxo-2,3-dihydroimidazol-1-yl]-phenyl}methylamino)ethyl]-N-methylacetamide

[0194] 172

[0195] A solution of 1-(4-cyclopentyloxyphenyl)-3-{4-[methyl-(2-methylaminoethyl)-amino]phenyl}-1,3-dihydroimidazol-2-one (50 mg) in dichloromethane (2 mL) was mixed with triethylamine (25 mg) and acetyl chloride (15 mg). After 2 hours, volatiles were removed and the residue was purified by preparative HPLC. The product with the molecular weight of 448.57 (C26H32N4O3); MS (ESI): 449 ([M+H]+), was obtained as hydrotrifluoro-acetate in this way.

EXAMPLE 171

1-[4-(2-Dimethylaminoethoxy)phenyl]-3-(4-phenoxyphenyl)imidazolidin-2-one

[0196] 173

[0197] Palladium(II) hydroxide (20 mg) was added to a solution of 1-(4-(2-dimethylaminoethoxy)phenyl]-3-(4-phenoxyphenyl)-1,3-dihydroimidazol-2-one (50 mg) in ethanol (5 mL) under nitrogen. The nitrogen atmosphere was replaced by hydrogen and the mixture was shaken for 8 hours. The catalyst was filtered off and the filtrate was concentrated. The product with the molecular weight of 417.51 (C25H27N3O3); MS (ESI): 418 ([M+H]+), was obtained in this way.

EXAMPLE 172

1-(4-Cyclopropylmethoxyphenyl)-3-[4-(2-dimethylaminoethoxy)phenyl]-imidazolidin-2-one

[0198] 174

[0199] The compound was prepared as described in example 171 by hydrogenation of 1-(4-cyclopropylmethoxyphenyl)-3-[4-(2-dimethylamino-ethoxy)phenyl]-1,3-dihydroimidazol-2-one. The product with the molecular weight of 395.51 (C23H29N3O3); MS (ESI): 396 ([M+H]+), was obtained in this way.

EXAMPLE 173

1-[4-(2-Dimethylaminoethoxy)phenyl]-3-(4-phenoxyphenyl)-[1,3]-diazepan-2-one

[0200] 175

[0201] A solution of 1-(4-hydroxyphenyl)-3-(4-phenoxyphenyl)-[1,3]-diazepan-2-one (26 mg) was dissolved in THF (2 mL), and sodium hydride (80% in oil, 3 mg) was added. After 30 minutes, 2-dimethylaminoethyl chloride (hydrochloride, 11 mg) was added. After 16 hours, the reaction mixture was diluted with water and extracted with ethyl acetate. The organic phase was dried and concentrated. The residue was purified by preparative HPLC. The product with the molecular weight of 445.57 (C27H31 N3O3); MS (ESI): 446 ([M+H]+), was obtained in this way.

1-(4-Hydroxyphenyl)-3-(4-phenoxyphenyl)-[1,3]-diazepan-2-one

[0202] The compound was prepared by hydrogenation of 1-(4-benzyloxyphenyl)-3-(4-phenoxyphenyl)-1,3,4,7-tetrahydro[1,3]diazepin-2-one in analogy to the method in example 171. The product with the molecular weight of 374.44 (C23H22N2O3); MS (ESI): 375 ([M+H]+), was obtained in this way.

1-(4-Benzyloxyphenyl)-3-(4-phenoxyphenyl)-1,3,4,7-tetrahydro-[1,3]-diazepin-2-one

[0203] The Grubbs catalyst was added to a solution of 1,3-diallyl-3-(4-benzyloxyphenyl)-1-(4-phenoxyphenyl)urea (145 mg) in dichloro-methane (2 mL) at 0° C. After 3 days at room temperature, volatiles were removed and the residue was purified by preparative HPLC. The product with the molecular weight of 462.55 (C30H26N2O3); MS (ESI): 463 ([M+H]+), was obtained in this way.

1,3-Diallyl-3-(4-benzyloxyphenyl)-1-(4-phenoxyphenyl)urea

[0204] Potassium hydride (30% in oil, 40 mg) was added to a solution of 1-allyl-1-(4-benzyloxyphenyl)-3-(4-phenoxyphenyl)urea (133 mg) in THF (3 mL) at −78° C. After 30 minutes, allyl bromide (30 μL) was added. After 14 hours at room temperature, the solution was diluted with dichloromethane and washed with saturated sodium bicarbonate solution. The organic phase was dried and concentrated. The product with the molecular weight of 490.61 (C32H30N2O3); MS (ESI): 491 ([M+H]+), was obtained in this way.

1-Allyl-1-(4-benzyloxyphenyl)-3-(4-phenoxyphenyl)urea

[0205] Carbonyldiimidazole (136 mg) was added to a solution of 4-phenoxyaniline (155 mg) in dimethylformamide (3 mL) at 0° C. After 30 minutes, allyl-(4-benzyloxyphenyl)amine (200 mg) was added and the temperature was increased to 80° C. for 2 hours. A further 2 hours at 120° C., the reaction solution was cooled and then purified by preparative HPLC. The product with the molecular weight of 450.54 (C29H26N2O3); MS (ESI): 451 ([M+H]+), was obtained in this way.

Allyl-(4-benzyloxyphenyl)amine

[0206] A mixture of 4-benzyloxyaniline (3.0 g), allyl bromide (1.27 mL), potassium carbonate (4.2 g) and dimethylformamide (15 mL) was heated at 80° C. for 3 hours. After cooling, the reaction solution was filtered and concentrated. The residue was purified by MPLC. The product with the molecular weight of 239.32 (C16H17NO); MS (ESI):240 ([M+H]+), was obtained in this way.

EXAMPLE 174

4-[4-(2-Dimethylaminoethoxy)phenyl]-2-(4-phenoxyphenyl)-2,4-dihydro-[1,2,4]triazol-3-one

[0207] 176

[0208] 1-Formyl-2-(4-phenoxyphenyl)-4-[4-(2-dimethylaminoethoxy)phenyl]semicarbazide (60 mg) was added to a solution of potassium hydroxide (15 mg) in methanol (20 mL). After 4 hours at room temperature, the mixture was heated at 40° C. for 24 hours. After cooling, the reaction solution was diluted with water and extracted with ethyl acetate. The organic phase was dried and concentrated. The product with the molecular weight of 416.48 (C24H24N4O3); MS (ESI): 417 ([M+H]+), was obtained in this way.

1-Formyl-2-(4-phenoxyphenyl)-4-[4-(2-dimethylaminoethoxy)phenyl]semicarbazide

[0209] Palladium(II) hydroxide (60 mg) and formic acid (4.6 g) were added to a solution of 1-benzylidene-2-(4-phenoxyphenyl)-4-[4-(2-dimethylamino-ethoxy)phenyl]semicarbazide (600 mg) in tetrahydrofuran/ethanol (1:1, 30 mL). The mixture was heated under reflux for five hours and then filtered. The filtrate was concentrated and the residue was purified by HPLC. The product with the molecular weight of 434.50 (C24H26N4O4); MS (ESI): 435 ([M+H]+), was obtained in this way.

1-Benzylidene-2-(4-phenoxyphenyl)-4-[4-(2-dimethylaminoethoxy)phenyl]-semicarbazide

[0210] Phosgene (20% in toluene; 0.091 mL) was added dropwise to a solution of N-benzylidene-N′-(4-phenoxyphenyl)hydrazine (50 mg) in toluene (1 mL) at 0° C. After 24 hours at room temperature, 4-(2-dimethylaminoethoxy)aniline (31 mg) was added. After two hours, the crystals which had separated out were filtered off with suction. The product with the molecular weight of 494.60 (C30H30N4O3); MS (ESI): 495 ([M+H]+), was obtained in this way.

N-Benzylidene-N′-(4-phenoxyphenyl)hydrazine

[0211] A suspension of (4-phenoxyphenyl)hydrazine (J. Org. Chem. 1956, 395; 1.5 g) in methanol (10 mL) was mixed with benzaldehyde (0.76 mL) and heated to reflux. The crystals which separated out on cooling were filtered off with suction. The product with the molecular weight of 288.35 (C19H16N2O); MS (ESI): 289 ([M+H]+), was obtained in this way.

EXAMPLE 175

1-(4-Cyclopentyloxyphenyl)-3-[4-(2-methylaminoethoxy)phenyl]-1,3-dihydroimidazol-2-one

[0212] 177

[0213] 1-[4-(2-Bromoethoxy)phenyl]-3-(4-cyclopentyloxyphenyl)-1,3-dihydroimidazol-2-one was reacted with methylamine as described in example 6. The product with the molecular weight of 393.49 (C23H27N3O3); MS (ESI): 394 ([M+H]+) was obtained in this way.

1-[4-(2-Bromoethoxy)phenyl]-3-(4-cyclopentyloxyphenyl)-1,3-dihydroimidazol-2-one

[0214] 1-(4-Cyclopentyloxyphenyl)-3-(4-hydroxyphenyl)-1,3-dihydroimidazol-2-one was reacted with 1,2-dibromoethane as described in example 5. The product with the molecular weight of 443.34 (C22H23BrN2O3); MS (ESI): 443 ([M+H]+) was obtained in this way.

1-(4-Cyclopentyloxyphenyl)-3-(4-hydroxyphenyl)-1,3-dihydroimidazol-2-one

[0215] 3-(4-Benzyloxyphenyl)-1-(4-cyclopentyloxyphenyl)-1-(2,2-dimethoxyethyl)-urea was reacted first with hydrogen and then with TFA as described in example 92. The product with the molecular weight of 336.39 (C20H20N2O3); MS (ESI): 337 ([M+H]+) was obtained in this way.

3-(4-Benzyloxyphenyl)-1-(4-cyclopentyloxyphenyl)-1 (2,2-dimethoxyethyl-urea

[0216] (4-Cyclopentyloxyphenyl)-(2,2-dimethoxyethyl)amine was reacted with carbonyidiimidazole and 4-benzyloxyaniline as described in example 5. The product with the molecular weight of 490.60 (C29H34N2O5); MS (ESI): 491 ([M+H]+) was obtained in this way.

EXAMPLE 176

N-(2-{4-[3-(4-Cyclopentyloxyphenyl)-2-oxo-2,3-dihydroimidazol-1-yl)-phenoxy}ethyl)-N-methylacetamide

[0217] 178

[0218] 1-(4-Cyclopentyloxyphenyl)-3-[4-(2-methylaminoethoxy)phenyl]-1,3-dihydroimidazol-2-one was reacted with acetyl chloride and triethylamine as described in example 170. The product with the molecular weight of 435.53 (C25H29N3O4); MS (ESI): 436 ([M+H]+) was obtained in this way.

EXAMPLE 177

1-(4-Cyclopentyloxyphenyl)-3-[4-(2-[1,2,4]triazol-4-ylethoxy)phenyl]-1,3-dihydroimidazol-2-one

[0219] 179

[0220] 1-[4-(2-Bromoethoxy)phenyl]-3-(4-cyclopentyloxyphenyl)-1,3-dihydroimidazol-2-one was reacted with 1,2,4-triazole as described in example 5. The product with the molecular weight of 431.50 (C24H25N5O3); MS (ESI): 432 ([M+H]+) was obtained in this way.

EXAMPLE 178

1-(4-Cyclopentyloxyphenyl)-3-{4-[2-(cyclopropylmethyl(methyl)amino)-ethoxy]phenyl}-1,3-dihydroimidazol-2-one

[0221] 180

[0222] 1-[4-(2-Bromoethoxy)phenyl]-3-(4-cyclopentyloxyphenyl)-1,3-dihydroimidazol-2-one was reacted with cyclopropylmethyl(methyl)amine as described in example 5. The product with the molecular weight of 447.58 (C27H33N3O3); MS (ESI): 448 ([M+H]+) was obtained in this way.

EXAMPLES 179-216

[0223] Further examples were obtained by reacting 1-[4-(2-bromoethoxy)phenyl]-3-(4-cyclopentyloxyphenyl)-1,3-dihydroimidazol-2-one with the appropriate amines. The results are summarized in table 5.

TABLE 5
				Molecu-
Ex.			Molecular	lar
No.	Name	Structure	formula	weight
179	1-(4-Cyclopentyloxyphenyl)-3-{4- [2-(2-methoxyethylamino)ethoxy]- phenyl}-1,3-dihydroimidazol-2-one	181	C25H31N3O4	437.54
180	1-(4-Cyclopentyloxyphenyl)-3-(4- {2-[(1- hydroxycyclohexylmethyl)amino]ethoxy}phenyl)- 1,3-dihydroimidazol-2-one	182	C29H37N3O4	491.64
181	1-{4-[2-(4-Acetylpiperazin-1- yl)ethoxyphenyl}-3-(4- cyclopentyloxyphenyl)- 1,3-dihydroimidazol-2-one	183	C28H34N4O4	490.61
182	1-(4-Cyclopentyloxyphenyl)-3-{4- [2-(4-hydroxypiperidin-1- yl)ethoxy]phenyl)- 1,3-dihydroimidazol-2-one	184	C27H33N3O4	463.58
183	1-(4-Cyclopentyloxyphenyl)-3-{4- [2-(4-methylpiperidin-1- yl)ethoxy]phenyl}- 1,3-dihydroimidazol-2-one	185	C28N35N3O3	461.61
184	1-(4-Cyclopentyloxyphenyl)-3-[4- (2- cyclopropylaminoethoxy)phenyl]- 1,3-dihydroimidazol-2-one	186	C25H29N3O3	419.53
185	1-[4-(2- Cyclohexylaminoethoxy)phenyl]- 3-(4-cyclopentyloxyphenyl)- 1,3-dihydroimidazol-2-one	187	C28H35N3O3	461.61
186	1-(4-Cyclopentyloxyphenyl)-3-[4- (2-isopropylaminoethoxy)phenyl]- 1,3-dihydroimidazol-2-one	188	C25H31N3O3	421.54
187	1-(4-Cyclopentyloxyphenyl)-3-{4- [2-(4-ethylpiperazin-1- yl)ethoxy]phenyl}- 1,3-dihydroimidazol-2-one	189	C28H36N4O3	476.62
188	1-(4-Cyclopentyloxyphenyl)-3-{4- [2-(2,5-dimethylpyrrolidin-1- dihydroimidazol-2-one	190	C28H35N3O3	461.61
189	1-(4-Cyclopentyloxyphenyl)-3-{4- [2- (isopropylmethylamino)ethoxyl]ph enyl)-1,3-dihydroimidazol-2-one	191	C26H33N3O3	435.57
190	1-(4-Cyclopentyloxyphenyl)-3-{4- [2-((R)-2- methoxymethylpyrrolidin-1- yl)ethoxy]phenyl}- 1,3-dihydroimidazol-2-one	Chiral 192	C28H35N3O4	477.61
191	1-{4-[2-(7-Azabicyclo[2.2.1]hept- 7-yl)ethoxyl]phenyl}-3-(4- cyclopentyloxyphenyl)-1,3- dihydroimidazol-2-one	193	C28H33N3O3	459.59
192	1-(4-Cyclopentyloxyphenyl)-3-{4- [2-(3-dimethylaminopyrrolidin-1- yl)ethoxy]phenyl}-1,3- dihydroimidazol-2-one	194	C28H36N4O3	476.62
193	N-[1-(2-{4-[3-(4- Cyclopentyloxyphenyl)-2-oxo-2,3- dihydroimidazol-1-yl]phenoxy}- ethyl)pyrrolidin-3-yl]acetamide	195	C28H34N4O4	490.61
194	1-(4-Cyclopentyloxyphenyl)-3-{4- [2-(4-hydroxy-4-phenylpiperidin-1- yl)ethoxy]phenyl}-1,3- dihydroimidazol-2-one	196	C33H37N3O4	539.68
195	1-(4-Cyclopentyloxyphenyl)-3-{4- [2-(3-hydroxypyrrolidin-1- yl)ethoxy]phenyl}-1,3- dihydroimidazol-2-one	197	C26H31N3O4	449.55
196	1-(4-Cyclopentyloxyphenyl)-3-{4- [2-(2-methylpyrrolidin-1- yl)ethoxy]phenyl}-1,3- dihydroimidazol-2-one	198	C27H33N3O3	447.58
197	Dimethyl (S)-1-(2-{4-[3-(4- cyclopentyloxyphenyl)-2-oxo-2,3- dihydroimidazol-1- yl]phenoxy}ethyl)pyrrrolidin-2- carboxamide	Chiral 199	C29H36N4O4	504.63
198	1-(4-Cyclopentyloxyphenyl)-3-(4- {2-[(2- methoxyethyl)methylamino]ethoxy }phenyl)-1,3-dihydroimidazol-2- one	200	C26H33N3O4	451.57
199	1-(4-Cyclopentyloxyphenyl)-3-{4- [2-(2-methylimidazol-1- yl)ethoxy]phenyl}-1,3- dihydroimidazol-2-one	201	C26H28N4O3	444.54
200	1-(4-Cyclopentyloxyphenyl)-3-{4- [2-(4-methylimidazol-1- yl)ethoxy]phenyl}-1,3- dihydroimidazol-2-one	202	C26H28N4O3	444.54
201	1-(4-Cyclopentyloxyphenyl)-3-{4- [2-(2-ethylimidazol-1- yl)ethoxy]phenyl}-1,3- dihydroimidazol-2-one	203	C27H30N403	458.57
202	1-(4-Cyclopentyloxyphenyl)-3-{4- [2-(2,4-dimethylimidazol-1- yl)ethoxy]phenyl}-1,3- dihydroimidazol-2-one	204	C27H30N4O3	458.57
203	1-{4-[2-(2-Chloroimidazol-1- yl)ethoxy]phenyl}-3-(4- cyclopentyloxyphenyl)-1,3- dihydroimidazol-2-one	205	C25H25Cl N4O3	464.96
204	1-(4-Cyclopentyloxyphenyl)-3-{4- [2-(2-ethyl-4-methylimidazol-1- yl)ethoxy]phenyl}-1,3- dihydroimidazol-2-one	206	C28H32N4O3	472.59
205	1-(4-Cyclopentyloxyphenyl)-3-{4- [2-(2-isopropylimidazol-1- yl)ethoxy]phenyl}-1,3- dihydroimidazol-2-one	207	C28H32N4O3	472.59
206	1-(4-Cyclopentyloxyphenyl)-3-{4- [2-(2,4,5-trimethylimidazol-1- yl)ethoxy]phenyl}-1,3- dihydroimidazol-2-one	208	C28H32N4O3	472.59
207	1-(4-Cyclopentyloxyphenyl)-3-{4- [2-(2-nitroimidazol-1-yl)ethoxy]- phenyl}-1,3-dihydroimidazol-2-one	209	C25H25N5O5	475.51
208	1-(4-Cyclopentyloxyphenyl)-3-{4- [2-(4-nitroimidazol-1-yl)ethoxy]- phenyl}-1,3-dihydroimidazol-2-one	210	C25H25N5O5	475.51
209	1-(4-Cyclopentyloxyphenyl)-3-{4- [2-(2-methyl-4-nitroimidazol-1- yl)ethoxy]phenyl}-1,3- dihydroimidazol-2-one	211	C26H27N5O5	489.54
210	1-(4-Cyclopentyloxyphenyl)-3-{4- [2-(5-methyl-4-nitroimidazol-1- yl)ethoxy]phenyl}-1,3- dihydroimidazol-2-one	212	C26H27N5O5	489.54
211	1-(4-Cyclopentyloxyphenyl)-3-{4- [2-(4,5-dichloroimidazol-1- yl)ethoxy]phenyl}-1,3- dihydroimidazol-2-one	213	C25H24Cl2 N4O3	499.40
212	1-(4-Cyclopentyloxyphenyl)-3-{4- [2-(2-phenylimidazol-1-yl)ethoxy]- phenyl}-1,3-dihydroimidazol-2-one	214	C31H30N4O3	506.61
213	1-(4-Cyclopentyloxyphenyl)-3-{4- [2-(4-phenylimidazol-1-yl)ethoxy]- phenyl}-1,3-dihydroimidazol-2-one	215	C31H30N4O3	506.61
214	1-(4-Cyclopentyloxyphenyl)-3-{4- [2-(2-methyl-4,5-dihydroimidazol- 1-yl)ethoxy]phenyl}-1,3- dihydroimidazol-2-one	216	C26H30N4O3	446.55
215	1-(4-Cyclopentyloxyphenyl)-3-{4- [2-(4,4-dimethyl-4,5- dihydroimidazol-1-yl)ethoxy]- phenyl]-1,3-dihydroimidazol-2-one	217	C27H32N4O3	460.58

EXAMPLE 216

1-(4-Aminophenyl)-3-(4-phenoxyphenyl)-1,3-dihydroimidazol-2-one

[0224] 218

[0225] A solution of N-{4-[2-oxo-3-(4-phenoxyphenyl)-2,3-dihydroimidazol-1-yl]phenyl}acetamide (4.0 g) in ethanol (100 ml) was heated to reflux with hydrochloric acid (20% strength, 30 ml) for 16 hours. After cooling, ammonia solution (10% strength) was added until the reaction was basic. The precipitated solid was filtered off and dried in a vacuum oven at 40° C. The product with the molecular weight of 343.39 (C21H17N3O2); MS (ESI): 344 ([M+H]+) was obtained in this way.

N-{4-[2-Oxo-3-(4-phenoxyphenyl)-2,3-dihydroimidazol-1-yl]phenyl}acetamide

[0226] 4-Acetaminoaniline was reacted with carbonyidiimidazole and (2,2-dimethoxyethyl)-(4-phenoxyphenyl)amine as described in example 92, followed by treatment of the crude product with trifluoroacetic acid at 80° C. The product is precipitated on addition of ethyl acetate/heptane 1:1. The precipitated solid was filtered off and dried in a vacuum oven at 40° C. The product with the molecular weight of 385.43 (C23H17N3O2); MS (ESI): 386 ([M+H]+) was obtained in this way.

EXAMPLE 217

2-Dimethylamino-N-{4-[2-oxo-3-(4-phenoxyphenyl)-2,3-dihydroimidazol-1-yl]phenyl}acetamide

[0227] 219

[0228] TOTU (327 mg) was added to a solution of 1-(4-aminophenyl)-3-(4-phenoxyphenyl)-1,3-dihydroimidazol-2-one (343 mg) in DMF (3 ml) at 0° C. After 10 minutes, Hünig base (130 mg) and then a solution of dimethylglycine (103 mg) in DMF (1 ml) was added. After a reaction time of 12 hours at room temperature, the mixture was mixed with water and extracted with ethyl acetate. The organic phase was washed with sodium bicarbonate solution, dried over magnesium sulfate and concentrated. The residue was purified by preparative HPLC. The product with the molecular weight of 428.50 (C25H24N4O3); MS (ESI): 429 ([M+H]+) was obtained as hydrotrifluoroacetate in this way.

EXAMPLE 218

N-{4-[2-Oxo-3-(4-phenoxyphenyl)-2,3-dihydroimidazol-1-yl]phenyl}-2-piperidin-1-ylacetamide

[0229] 220

[0230] 1-(4-Aminophenyl)-3-(4-phenoxyphenyl)-1,3-dihydroimidazol-2-one was reacted with piperidin-1-ylacetic acid as described in example 217. The product with the molecular weight of 468.56 (C28H28N4O3); MS (ESI): 469 ([M+H]+) was obtained as hydrotrifluoroacetate in this way.

EXAMPLE 219

3-Methylamino-N-14-[2-oxo-3-(4-phenoxy-phenyl)-2,3-dihydroimidazol-1-yl]-phenyl}-propionamide

[0231] 221

[0232] 1-(4-Aminophenyl)-3-(4-phenoxyphenyl)-1,3-dihydroimidazol-2-one was reacted with methylaminopropionic acid as described in example 217. The product with the molecular weight of 428.50 (C25H24N4O3); MS (ESI): 429 ([M+H]+) was obtained as hydrotrifluoroacetate in this way.

EXAMPLE 220

3-(2-Methyl-4-nitro-imidazol-1-yl)-N-{4-[2-oxo-3-(4-phenoxy-phenyl)-2,3-dihydroimidazol-1-yl]-phenyl-propionamide

[0233] 222

[0234] 1-(4-Aminophenyl)-3-(4-phenoxyphenyl)-1,3-dihydroimidazol-2-one was reacted with 2-methyl-4-nitro-imidazol-1-yl-propionic acid as described in example 217. The product with the molecular weight of 524.54 (C28H24N6O5); MS (ESI): 525 ([M+H]+) was obtained as hydrotrifluoroacetate in this way.

EXAMPLE 221

2-(2,5-Dioxo-imidazolidin-1-yl)-N-{4-[2-oxo-3-(4-phenoxy-phenyl)-2,3-dihydroimidazol-1-yl]-phenyl}-acetamide

[0235] 223

[0236] 1-(4-Aminophenyl)-3-(4-phenoxyphenyl)-1,3-dihydroimidazol-2-one was reacted with 2-(2,5-dioxo-imidazolidin-1-yl acetic acid as described in example 217. The product with the molecular weight of 483.49 (C26H21N5O5); MS (ESI): 484 ([M+H]+) was obtained as hydrotrifluoroacetate in this way.

EXAMPLE 222

Ethyl 1-({4-[2-oxo-3-(4-phenoxy-phenyl)-2,3-dihydro-imidazol-1-yl]-phenylcarbamoyl}-ethyl)-piperidine-4-carboxylate

[0237] 224

[0238] 1-(4-Aminophenyl)-3-(4-phenoxyphenyl)-1,3-dihydroimidazol-2-one was reacted with ethyl 1-carboxyethylpiperidine-4-carboxylate as described in example 217. The product with the molecular weight of 544.65 (C32H34N4O5); MS (ESI): 555 ([M+H]+) was obtained as hydrotrifluoroacetate in this way.

EXAMPLE 223

2-(Acetylmethylamino)-N-{4-[2-oxo-3-(4-phenoxyphenyl)-2,3-dihydroimidazol-1-yl]phenyl}acetamide

[0239] 225

[0240] 1-(4-Aminophenyl)-3-(4-phenoxyphenyl)-1,3-dihydroimidazol-2-one was reacted with (acetylmethylamino)acetic acid as described in example 217. The product with the molecular weight of 456.51 (C26H24N4O4); MS (ESI): 457 ([M+H] ) was obtained as hydrotrifluoroacetate in this way.

Claims

1. A compound of formula (I)

2. The compound according to claim 1 wherein R is (C1-C6)-alkyl, (C0-C2)-alkylene-aryl, (C3-C8)-cycloalkyl, (C2-C6)-alkenyl, (C5-C8)-cycloalkenyl, (C7-C8)-bicycloalkenyl, (C2-C6)-alkynyl or a 3- to 7-membered ring optionally containing one or more heteroatoms selected form the group consisting of N, O, and S, and wherein the 3- to 7-membered ring is optionally substituted by F, Cl, Br, NO2, CF3, OCF3, CN, (C1-C6)-alkyl, CON(R11)(R12), N(R13)(R14), OH, O—(C1-C6)-alkyl or N(R15)CO(C1-C6)-alkyl or COO—(C1-C6)-alkyl; B is a bond O, S, SO2, CO, OCH(R20), N(R23), CH2 or CH2CH2; R20 and R23 independently are H or (C1-C6)-alkyl; R1, R2, R3, and R4 independently are H, F, Cl, Br, OH, CF3, NO2, CN, OCF3, O—(C1-C6)-alkyl, O—(C1-C4)-alkoxy-(C1-C4)-alkyl, S—(C1-C6)-alkyl, (C1-C6)-alkyl, (C0-C2)-alkylene-aryl, O—(C0-C2)-alkylene-aryl, N(R24)(R25), SO2—CH3, COOH, COO—(C1-C6)-alkyl, CON(R26)(R27), N(R28)CO(R29) or CO(R32); R29 and R32 independently are H, (C1-C6)-alkyl or aryl; n is 2, 3 or 4; R5, R6, R7 and R8 independently are H, F, Cl, Br, OH, CF3, NO2, CN, OCF3, O—(C1-C6)-alkyl, (C1-C6)-alkyl, (C0-C2)-alkylene-aryl, O—(C0-C2)-alkylene-aryl, COO—(C1-C6)-alkyl or CO(R41); R41 is (C1-C6)-alkyl or aryl; A is a chain —(C(R42)(R43))m- wherein 1 to 2 members of the chain are optionally replaced by an element selected from the group consisting of O, N(R44) and CO; m is 3 or4; R9 and R10 independently are H, (C1-C8)-alkyl, —(CH2)o—R45, (C1-C4)-alkoxy-(C1-C4)-alkyl, aryloxy-(C1-C4)-alkyl, (C3-C8)-alkenyl, (C3-C8)-alkynyl, CO—(C1-C8)-alkyl or CO—(CH2)oR45; or R9 and R10 form together with the nitrogen atom to which they are bonded a 4- to 10-membered mono-, bi- or spirocyclic ring wherein said ring, apart from the nitrogen atom, may optionally contain 0 to 2 additional heteroatoms selected from the group consisting of O, N and S and wherein said ring optionally is substituted by F, Cl, Br, CF3, CN, (C1-C6)-alkyl, O—(C1-C8)-alkyl, (C1-C4)-alkoxy-(C1-C4)-alkyl, (C0-C2)-alkylene-aryl, oxo, CO(R46), CON(R47)(R48), OH, COO(R49), N(R50)CO(C1-C6)-alkyl, N(R51)(R52) or SO2CH3; o is 0, 1, 2, 3 or 4; R45 is OH, a 3- to 12-membered mono- or bicyclic ring which optionally contains one or two heteroatoms selected from the group consisting of N, O and S wherein the 3- to 12-membered ring optionally is substituted by F, Cl, Br, OH, CF3, NO2, CN, OCF3, oxo, O—(C1-C6)-alkyl, (C1-C6)-alkyl, (C2-C6)-alkenyl, (C0-C2)-alkylene-aryl, O—(C0-C2)-alkylene-aryl, N(R51)(R52), SO2—CH3 or COOH.

3. The compound according to claim 2 wherein R is (C1-C6)-alkyl, (C3-C8)-cycloalkyl, or a 5- to 6-membered mono- or bicyclic ring optionally containing one or two heteroatoms selected from the group consisting of N, O, and S, wherein the 5- to 6-membered ring is optionally substituted by F, Cl, Br, NO2, CF3, OCF3, CN, (C1-C6)-alkyl or O—(C1-C6)-alkyl; B is a bond, O, S, CO OCH2, N(R23) or CH2; R23 is H or (C1-C6)-alkyl; R1, R2, R3, and R4 independently are H, F, Cl, Br, CF3, O—(C1-C6)-alkyl or (C1-C6)-alkyl; W is —CH═CH— or —N═CH—; R5, R6, R7 and R8 independently are H, F, Cl, Br, OH, CF3, NO2, CN, OCF3 or O—(C1-C6)-alkyl; A is a chain —(C(R42)(R43))m- wherein 1 member of the chain is optionally replaced by an element selected from the group consisting of O and N(R44); R9 and R10 independently are H, (C1-C8)-alkyl, —(CH2)o—R45 or CO—(C1-C8)-alkyl; or R9 and R10 form together with the nitrogen atom to which they are bonded a 4- to 10-membered mono-, bi- or spirocyclic ring wherein said ring, apart from the nitrogen atom, may optionally contain 0 to 2 additional heteroatoms selected from the group consisting of O, N and S, and wherein said ring optionally is substituted by F, (C1-C6)-alkyl, O—(C1-C8)-alkyl, oxo, CO(R46), CON(R47)(R48), OH, N(R50)CO(C1-C6)-alkyl or N(R51)(R52); R45 is OH, a 5- to 10-membered mono- or bicyclic ring which optionally contains one or two heteroatoms selected from the group consisting of N, O and S, wherein the 5- to 10-membered ring optionally is substituted by F, Cl, Br, OH, CF3, oxo, O—(C1-C6)-alkyl, (C1-C6)-alkyl, (C0-C2)-alkylene-aryl, O—(C0-C2)-alkylene-aryl or N(R51)(R52).

4. The compound according to claim 3 wherein W is —CH═CH—.

5. The compound according to claim 3 wherein m is 3 and R42, R43 and R44 are H.

6. The compound according to claim 3 wherein R5, R6, R7 and R8 are H.

7. The compound according to claim 3 wherein A and B are each disposed in the para position relative to the central W-containing heterocycle.

8. The compound according to claim 7 which is 1-[4-(2-dimethylaminoethoxy)-phenyl]-3-(4-phenoxyphenyl)-1,3-dihydroimidazol-2-one.

9. A method for the treatment or prevention of excessive weight or obesity in mammals comprising administering to said mammal a therapeutically effective amount of a compound, or a pharmaceutically acceptable salt thereof, of formula (I)

10. A method of treating a disease or psychiatric indication in mammals which comprises administering to said mammal a therapeutically effective amount of a compound, or a pharmaceutically acceptable salt thereof, of formula (I)

11. The method of claim 10 wherein the disease or psychiatric indication is selected from the group consisting of Type II diabetes, arteriosclerosis, high blood pressure, depression, anxiety, anxiety neuroses and schizophrenia.

12. The method of claim 11 wherein the disease is Type II diabetes.

13. The method of claim 11 wherein the disease is arteriosclerosis.

14. The method of claim 11 wherein the disease is high blood pressure.

15. The method of claim 11 wherein the psychiatric indication is depression.

16. The method of claim 11 wherein the psychiatric indication is anxiety or anxiety neuroses.

17. The method of claim 11 wherein the psychiatric indication is schizophrenia.

18. A method for the treatment or prevention of excessive weight or obesity in mammals comprising administering to said mammal a therapeutically effective amount of a mixture of one or more antiobesity agents or appetite-regulating active ingredients and a compound, or a pharmaceutically acceptable salt thereof, of formula (I)

19. The method of claim 18 wherein the antiobesity agent or appetite-regulating active ingredient is selected from the group consisting of leptin, modified leptin, dexamphetamine, amphetamine, fenfluramine, dexfenfluramine, sibutramine, the mono- and bis-demethylated active metabolites of sibutramine, orlistat, mazindol, diethylpropion and phenteramine.

20. A method for the treatment or prevention of Type II diabetes in mammals comprising administering to said mammal a therapeutically effective amount of a mixture of one or more antidiabetics or hypoglycemic active ingredients and a compound, or a pharmaceutically acceptable salt thereof, of formula (I)

21. The method of claim 20 wherein said antidiabetic or hypoglycemic active ingredient is selected from the group consisting of insulin, a sulfonylurea, a biguanide, a meglitinide, a thiazolidinedione, an oxadiazolidinedione and an α-glucosidase inhibitor.

22. A pharmaceutical composition comprising a pharmaceutical carrier and a therapeutically effective amount of a compound, or a pharmaceutically acceptable salt thereof, of formula (I)

23. A pharmaceutical composition according to claim 22 further comprising a therapeutically effective amount of one or more compounds selected from the group consisting of an antiobesity agent, an appetite-regulating active ingredient, an antidiabetic and a hypoglycemic active ingredient.

24. A pharmaceutical composition according to claim 23 wherein said antiobesity agent or appetite-regulating active ingredient is selected from the group consisting of of leptin, modified leptin, dexamphetamine, amphetamine, fenfluramine, dexfenfluramine, sibutramine, the mono- and bis-demethylated active metabolites of sibutramine, orlistat, mazindol, diethylpropion and phenteramine.

25. A pharmaceutical composition according to claim 23 wherein said antidiabetic or hypoglycemic active ingredient is selected from the group consisting of insulin, a sulfonylurea, a biguanide, a meglitinide, a thiazolidinedione, an oxadiazolidinedione and an α-glucosidase inhibitor.