AU2003251001B2 - Diaryl-substituted cyclic urea derivatives having an MCH-modulatory effect - Google Patents

Diaryl-substituted cyclic urea derivatives having an MCH-modulatory effect Download PDF

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AU2003251001B2
AU2003251001B2 AU2003251001A AU2003251001A AU2003251001B2 AU 2003251001 B2 AU2003251001 B2 AU 2003251001B2 AU 2003251001 A AU2003251001 A AU 2003251001A AU 2003251001 A AU2003251001 A AU 2003251001A AU 2003251001 B2 AU2003251001 B2 AU 2003251001B2
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alkyl
aryl
independently
another
compound
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Thomas Boehme
Matthias Gossel
Gerhard Hessler
Gerard Rosse
Lothar Schwink
Siegfried Stengelin
Armin Walser
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Sanofi Aventis Deutschland GmbH
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Description

.1 Description Substituted diaryl heterocycles, process for their preparation and their use as medicaments 5 The invention relates to substituted diaryl heterocycles and to their physiologically tolerated salts and physiologically functional derivatives. Compounds having a pharmacological effect and similar in their overall 10 structure to the diaryl heterocycles described herein have already been described in the prior art (such as, for example, US006054590A). The invention was based on the object of providing compounds which bring about a weight reduction in mammals and which are suitable for the 15 prevention and treatment of obesity. The invention therefore relates to compounds of the formula I R1 W R5 N N R9 R2 A N R--B 0 R8 R10 R4 R6 R3 R7 20 in which R is (CO-C8)-alkylene-aryl, (C3-C 8 )-cycloalkyl, (C 1 -C4)-alkoxy-(C1 C4)-alkyl, (C2-C8)-alkenyl, (C2-C8)-alkynyl; 25 3-12 membered mono-, bi- or spirocyclic ring which may comprise one or two heteroatoms from the group of N, 0 and S, and the 3-12 membered ring may have further substituents, with the proviso that R is not tetrazolyl; 30 B is a linker consisting of one or two radicals from the group (C(R19)(R20))i, C(OR21)(R22), 0, N(R23), S, SO, S02, CO; 2 is 1, 2, 3; R19, R20, R21, R22, R23 are, independently of one another, H, (C1 -C6)-alkyl, aryl; 5 R1, R2, R3, R4 are, independently of one another, H, F, Cl, Br, I, OH, CF3, N02, CN, OCF3, 0-(C1-C6)-alkyl, 0-(Cl-C4)-alkoxy-(Cl-C4) alkyl, S-(Cl-C6)-alkyl, (C1-C6)-alkyl, (C2-C6)-alkenyl, (C3-C8) cycloalkyl, 0-(C3-C 8 )-cycloalkyl, (C3-C8)-cycloalkenyl, 0-(C3 10 C8)-cycloalkenyl, (C2-C6)-alkynyl, (C0-C8)-alkylene-aryl, 0-(C0 C8)-alkylene-aryl, S-aryl, N(R24)(R25), S02-CH3, CON(R26)(R27), N(R28)CO(R29), N(R30)SO2(R31), CO(R32); R24, R25, R26, R27, R28, R30 are, independently of one another, H, 15 (C1-C6)-alkyl; R29, R31, R32 are, independently of one another, H, (Cl-C6)-alkyl, aryl; W is -(CH2)n-, -CH=CH-, -CH=N-, -N=CH-; 20 n is 2, 3, 4, 5; R5, R6, R7, R8 are, independently of one another, H, F, CI, Br, I, OH, CF 3 , N02, CN, OCF3, 0-(C1-C6)-alkyl, 0-(C1-C4)-alkoxy-(C1-C4) 25 alkyl, S-(C1-C6)-alkyl, (C1-C 6 )-alkyl, (C2-C6)-alkenyl, (C3-C8) cycloalkyl, 0-(C3-C8)-cycloalkyl, (C3-C8)-cycloalkenyl, 0-(C3-C8)-cycloalkenyl, (C2-C6)-alkynyl, (CO-C8)-alkylene-aryl, 0-(CO-C8)-alkylene-aryl, S-aryl, N(R33)(R34), S0 2
-CH
3 , CON(R35)(R36), N(R37)CO(R38), N(R39)SO2(R40), CO(R41), 30 a 5-7 membered heterocycle having 1-4 heteroatoms from the group 0, N and S; R33, R34 are, independently of one another, H, (C1-C6)-alkyl; 35 or R33 and R34 form together with the nitrogen atom to which they are bonded a 5-6 membered ring, where in the case of the 6-membered ring one CH2 group may be replaced by 0 or S; 3 R35, R36, R37, R39 are, independently of one another, H, (C1-C6)-alkyl; R38, R40, R41 are, independently of one another, H, (C1-C6)-alkyl, aryl; 5 A is a chain -(C(R42)(R43))m- in which 0-2 members may be replaced by an element from the group of 0, S, N(R44), CO,
SO
2 ; m is 2, 3, 4, 5; 10 R42, R43, R44 are, independently of one another H, (C1-C6)-alkyl, aryl; R9, R10 are, independently of one another, H, (C1-C8)-alkyl, -(CH2)o-R45, (C1 C4)-alkoxy-(C1-C4)-alkyl, aryloxy-(C1-C4)-alkyl, (C3-C8)-alkenyl, 15 (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-C)-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 which, apart from the nitrogen atom, 20 may comprise 0 to 4 additional heteroatoms selected from the group of oxygen, nitrogen and sulfur, where the heterocyclic ring system may additionally be substituted by F, Cl, Br, CF 3 , N02, CN, (C1-C6)-alkyl, 0-(C1-C8)-alkyl, (C1-C4)-alkoxy-(C1-C4) alkyl, (CO-C8)-alkylene-aryl, oxo, CO(R46), CON(R47)(R48), 25 hydroxyl, COO(R49), N(R50)CO(C1-C6)-alkyl, N(R51)(R52) or
SO
2
CH
3 ; R46, R47, R48, R49, R50, R51, R52 are, independently of one another, H, (C1-C6)-alkyl; 30 o is 0, 1, 2, 3, 4, 5, 6; R45 is OH, CH(aryl)2, 3-12 membered mono- or bicyclic ring which may comprise one or more heteroatoms from the group of N, 0 and 35 S, and the 3-12 membered ring may comprise further substituents such as F, Cl, Br, I, OH, CF3, N02, 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, 0-(C3-C8)- 4 cycloalkyl, (C3-C8)-cycloalkenyl, 0-(C 3 -C8)-cycloalkenyl, (C2 C6)-alkynyl, (C 0 -C8)-alkylene-aryl, 0-(Co-C 8 )-alkylene-aryl, S-aryl, N(R51)(R52), S02-CH3 and COOH; 5 and the physiologically tolerated salts thereof. Preference is given to compounds of the formula I in which R is (CO-C2)-alkylene-aryl, (C3-C8)-cycloalkyl, (C 2 -C6)-alkenyl, 10 (C2-C6)-alkinyl; 3-7 numbered ring which may comprise one or two heteroatoms from the group of N, 0 and S, and the 3-7 membered ring may have further substituents, with the proviso that R is not tetrazolyl; 15 B is 0, S, SO2, CO, OCH(R20), N(R23), CH2, CH2CH2; R20, R23 are, independently of one another, H, (C1-C6)-alkyl; 20 R1, R2, R3, R4 are, independently of one another, H, F, Cl, Br, OH, CF3, N02, CN, OCF3, 0-(C1-C6)-alkyl, 0-(C 1
-C
4 )-alkoxy-(C1-C4) alkyl, S-(C 1 -C6)-alkyl, (C1-C6)-alkyl, (CO-C2)-alkylene-aryl, 0 (C0-C2)-alkylene-aryl, N(R24)(R25), S02-CH3, CON(R26)(R27), N(R28)CO(R29), CO(R32); 25 R24, R25, R26, R27, R28, R30 are, independently of one another, H, (C1-C6)-alkyl; R29, R32 are, independently of one another, H, (C1-C6)-alkyl, aryl; 30 W is -(CH2)n, -CH=CH-, -CH=N-, -N=CH-; n is 2, 3, 4; 35 R5, R6, R7, R8 are, independently of one another, H, F, Cl, Br, OH, CF3, N02, CN, OCF3, 0-(C1-C6)-alkyl, (C1-C6)-alkyl, (CO-C2) alkylene-aryl, 0-(C-C2)-alkylene-aryl, CO(R41); 5 R41 is (C1-C6)-alkyl, aryl; A is a chain -(C(R42)(R43))m- in which 0-2 members may be replaced by an element from the group of 0, N(R44), CO; 5 m is 2, 3, 4; R42, R43, R44 are, independently of one another, H, (C1-C6)-alkyl, aryl; 10 R9, R10 are, independently of one another, H, (C1-C8)-alkyl, (CH 2
)
0 -R45, (C1-C4)-alkoxy-(C1-C4)-alkyl, aryloxy-(C1-C4)-alkyl, (C3-C8) alkenyl, (C3-C8)-alkynyl, CO-(C1-C8)-alkyl, -CO-(CH 2
)
0 -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 15 which, apart from the nitrogen atom, may comprise 0 to 2 additional heteroatoms selected from the group of oxygen, nitrogen and sulfur, where the heterocyclic ring system may additionally be substituted by F, Cl, Br, CF3, CN, (C1-C6)-alkyl, O-(C1-C8)-alkyl, (C1-C 4 )-alkoxy-(C1-C4)-alkyl, (Co-C2)-alkylene 20 aryl, oxo, CO(R46), CON(R47)(R48), hydroxyl, COO(R49), N(R50)CO(C1-C6)-alkyl, N(R51)(R52) or SO2CH3; R46, R47, R 48, R49, R50, R51, R52 are, independently of one another, H, (C1 -C6)-alkyl; 25 0 is 0, 1, 2, 3, 4; R45 is OH, 3-12 membered mono- or bicyclic ring which may comprise one or two heteroatoms from the group of N, 0 and S, and the 3-12 30 membered ring may comprise further substituents such as F, Cl, Br, OH, CF3, NO 2 , CN, OCF3, oxo, 0-(C-C6)-alkyl, (C1-06) alkyl, (C2-C6)-alkenyl, (CO-C2)-alkylene-aryl, 0-(CO-C2) alkylene-aryl, N(R51)(R52), S0 2 -CH3 and COOH; 35 and the physiologically tolerated salts thereof. Particular preference is given to compounds of the formula I as defined previously in which 6 R is (C3-C8)-cycloalkyl; 5-6 membered ring which may comprise one or two heteroatoms from the group of N, 0 and S, and the 5-6 membered ring may 5 have further substituents such as F, Cl, Br, N02, CF3, OCF 3 , CN, (C1-C6)-alkyl, 0-(C1-C6)-alkyl; B is 0, S, CO, OCH2, N(R23), CH2; 10 R23 is H, (C1-C6)-alkyl; R1, R2, R3, R4 are, independently of one another, H, F, CI, Br, CF 3 , 0-(C1 C6)-alkyl; (C1-C6)-alkyl; 15 W is -CH=CH-, -N=CH-; R5, R6, R7, R8 are, independently of one another, H, F, CI, Br, OH, CF3, N02, CN, OCF 3 , 0-(C 1 -C6)-alkyl; 20 A is a chain -(C(R42)(R43))m-, in which one member may be replaced an element from the group of 0, N(R44); m is 3, 4; 7 R42, R43, R44 are, independently of one another, H, (C1 -C6)-alkyl, aryl; R9, R10 are, independently of one another, H, (C1-C8)-alkyl, -(CH 2
)
0 5 R45, CO-(C1-C8)-alkyl; or R9 and R10 form together with the nitrogen atom to which they are bonded a 4 to 1 0-membered mono-, bi- or spirocyclic ring which, apart from the nitrogen, may comprise 0 to 2 additional heteroatoms selected from the group of oxygen, nitrogen and sulfur, where the heterocyclic 10 ring system may additionally be substituted by F, (C1-C6) alkyl, O-(C1-Cs)-alkyl, oxo, CO(R46), CON(R47)(R48), hydroxyl, N(R50)CO(C1-C6)-alkyl or N(R51)(R52); R46, R47, R48, R50, R51, R52 are, independently of one another, H, 15 (C1-C6)-alkyl; 0 is 0, 1, 2, 3, 4; R45 is OH, 5-10 membered mono- or bicyclic ring which may 20 comprise one or two heteroatoms from the group of N, 0 and S, and the 3-12 membered ring may comprise further substituents such as F, Cl, Br, OH, CF 3 , oxo, O-(C1-C6)-alkyl, (C1-C6)-alkyl, (CO-C2)-alkylene-aryl, 0-(CO-C2)-alkylene-aryl, or N(R51)(R52); 25 A particular class within the particularly preferred compounds I is formed by the molecules for which W is -C=C-. 30 A further particular class within the particularly preferred compounds I is formed by the molecules for which m is 3; 35 R42, R43, R44 are H. A further particular class within the particularly preferred compounds I is 8 formed by the molecules for which R5, R6, R7, R8 are H. 5 A further particular class within the particularly preferred compounds I is formed by the molecules in which A and B are each disposed in the para position relative to the central heterocycle. If radicals or substituents can occur more than once in the compounds of 10 the formula 1, such as, for example, -(CH 2
)
0 -R45, they may all, independently of one another, have the stated meanings and be identical or different. The invention relates to compounds of the formula I in the form of their 15 racemates, enantiomer-enriched mixtures and pure enantiomers and to their diastereomers and mixtures thereof. 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, 20 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. 25 The term "aryl" means a phenyl or naphthyl group. Mono-, bi- or spirocyclic rings may be saturated, partially saturated or unsaturated and also bridged. 30 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 35 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, 9 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 5 (such as magnesium and calcium salts). 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 nontherapeutic, for 10 example in vitro, applications. The term "physiologically functional derivative" used herein refers to any physiologically tolerated derivative of a compound according to the invention of the formula 1, for example an ester, which is able on 15 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. The physiologically functional derivatives also include prodrugs of the compounds according to the invention. Such prodrugs can be metabolized 20 in vivo to a compound according to the invention. These prodrugs may themselves be active or not. The compounds according to the invention may also exist in various polymorphous forms, for example as amorphous and crystalline 25 polymorphous forms. All polymorphous forms of the compounds according to the invention lie within the scope of the invention and are a further aspect of the invention. All references hereinafter to "compound(s) of formula (I)" refer to 30 compound(s) of the formula (1) as described above, and the salts, solvates and physiologically functional derivatives thereof as described herein. 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 35 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 10 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 5 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 10 600 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 (1) can be used as the compound itself, but they are preferably in the form of a pharmaceutical 15 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 20 0.05% to 95% by weight of the active ingredient. Further pharmaceutically active substances may likewise be present, including other compounds of formula (1). 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 pharmacologically 25 acceptable carriers and/or excipients. 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) 30 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 (1) 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 35 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.
11 Suitable pharmaceutical compounds 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 5 of formula (1); 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 10 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 15 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 20 can be produced by molding the compound which is in powder form and is moistened with an inert liquid diluent in a suitable machine. Pharmaceutical compositions suitable for peroral (sublingual) administration comprise suckable tablets which contain a compound of 25 formula (1) 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. Suitable pharmaceutical compositions for parenteral administration 30 comprise preferably sterile aqueous preparations of a compound of formula (1), 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 35 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.
12 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 (1) with one or more conventional solid carriers, for example cocoa butter, and shaping the resulting mixture. 5 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. 10 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%. Transdermal administration is also possible. Suitable pharmaceutical compositions for transdermal uses can be in the form of single plasters 15 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 20 can be released as described, for example, in Pharmaceutical Research, 2(6): 318 (1986) by electrotransport or iontophoresis. The compounds of the formula I are distinguished by beneficial effects on lipid metabolism, and they are particularly suitable for weight reduction and 25 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. The compounds can be employed alone or in combination with other weight-reducing or anorectic active ingredients. Further anorectic active 30 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 35 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 13 suitable for the prophylaxis and, in particular, for the treatment of type 11 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 5 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. 10 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 15 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. The orally active hypoglycemic active ingredients preferably comprise 20 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 25 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 30 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. 35 In one embodiment of the invention, the present compounds are administered in combination with insulin. In a further embodiment, the present compounds are administered in combination with a sulfonylurea such as, for example, tolbutamide, 14 glibenclamide, glimepiride, glipizide, gliquidone, glisoxepide, glibornuride or gliclazide. In another embodiment, the present compounds are administered in 5 combination with a biguanide such as, for example, metformin. 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, 10 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. In a further embodiment, the present compounds are administered in 15 combination with an a-glucosidase inhibitor such as, for example, miglitol or acarbose. 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, 20 glibenclamide, glimepiride, glipizide, gliclazide or repaglinide. 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, 25 atorvastatin, cerivastatin, fluvastatin, probucol, ezetimibe or dextrothyroxine. 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 30 acarbose, repaglinide and metformin, insulin and a sulfonylurea, insulin and metformin, insulin and troglitazone, insulin and lovastatin, etc. The compounds of the invention may additionally be administered in combination with one or more antiobesity agents or appetite-regulating active ingredients. 35 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, P3 agonists, MSH (melanocyte-stimulating 15 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 5 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-P agonists. In one embodiment of the invention, the antiobesity agent is leptin or 10 modified leptin. In another embodiment, the antiobesity agent is dexamphetamine or amphetamine. In another embodiment, the antiobesity agent is fenfluramine or dexfenfluramine. 15 In yet another embodiment, the antiobesity agent is sibutramine or the mono- and bisdemethylated active metabolites of sibutramine. In a further embodiment, the antiobesity agent is orlistat. In another embodiment, the antiobesity agent is mazindol, diethylpropion or phentermine. 20 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, 25 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, 30 editor, Mack Publishing Co., Easton, PA, 1995. 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. 35 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- 16 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 5 formula I was therefore tested as follows. Functional measurements to establish IC50 values The cloning of the cDNA for the human MCH receptor, production of the 10 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 15 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), 20 using protocols of the manufacturer of the apparatus. The exemplary compounds showed IC50 values in the order of magnitude from 0.01 to > 10 RM. The efficacy of the compounds was additionally tested as follows: 25 Biological test model: The anorectic effect was tested on female NMRI mice. After withdrawal of food for 17 hours, the test product was administered by gavage. The animals were housed singly with free access to drinking water and were 30 offered condensed milk 30 minutes after administration of the product. The 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 35 milk consumption of treated compared with control animals.
17 Example Oral Number of Number of Reduction in the dose animals/ animals/ cumulative milk [mg/kg] cumulative milk cumulative milk consumption as consumption of consumption of % of the control the treated the control animals animals N/[ml] N/[ml] Example 1 30 5/1.7 5/4.1 58 The examples and preparation methods detailed below serve to illustrate the invention without, however, restricting it. 5 Example 1 1-[4-(2-Dimethylaminoethoxy)phenyl]-3-(4-phenoxyphenyl)-1,3-dihydro imidazol-2-one 10 0 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 15 dichloromethane (10 ml) and washed with sodium hydroxide solution (0.1 N; 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 20 molecular weight of 415.50 (C 25 H2 5
N
3 0 3 ); MS (ESI): 416 ([M+H]*), was obtained in this way. 1-(2,2-Dimethoxyethyl)-3-[4-(2-dimethylaminoethoxy)phenyl]-1 -(4-phenoxy phenyl)urea 25 A solution of triphosgene (178 mg) in chloroform (1 ml) was added to a 18 solution of 4-(2-dimethylaminoethoxy)aniline (324 mg) in chloroform (2 ml) and pyridine (0.182 ml) at 00C 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 5 chloroform (2 ml) and pyridine (0.182 ml) and shaken at 700C for 3 hours. Water (1 ml) was added. The mixture was extracted with dichloromethane (2 x 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 10 methanol). The product with the molecular weight of 479.58 (C 27
H
33
N
3 0 5 ); MS (ESI): 442 ([M-OMe]*), was obtained in this way. (2,2-Dimethoxyethyl)-(4-phenoxyphenyl)amine A solution of 4-phenoxyaniline (915 mg) in dimethylformamide (5 ml) was 15 mixed with bromoacetaldehyde dimethyl acetal (1.1 ml) and BEMP (1.9 ml). The reaction mixture was shaken at 100C 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 20 273.33 (C 16
H
19
NO
3 ); MS (ESI): 274 ([M+H]*), was obtained in this way. Example 2 1-[4-(2-Dimethylaminoethylamino)-3-nitrophenyl]-3-(4-phenoxyphenyl) 1,3-dihydroimidazol-2-one
SN
N N& 25 A solution of 1-(4-fluoro-3-nitrophenyl)-3-(4-phenoxyphenyl)-1,3-dihydro imidazol-2-one (100 mg) in dimethylformamide (2 ml) was shaken with 2-dimethylaminoethylamine (0.3 ml) at 700C for 2 hours. Volatiles were 30 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 (C 25
H
25
N
5 0 4 ); MS (ESI): 460 ([M+H]*), was obtained in this way.
19 1-(4-Fluoro-3-nitrophenyl)-3-(4-phenoxyphenyl)-1,3-dihydroimidazol-2-one 4-Fluoro-3-nitrophenyl isocyanate (0.45 ml) was added to a solution of (2,2-dimethoxyethyl)-(4-phenoxyphenyl)amine (750 mg) in chloroform 5 (10 ml). The reaction was shaken at 700C for 2 hours. A second portion of 4-fluoro-3-nitrophenyl isocyanate (0.45 ml) was added. After 16 hours at 70 0 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 10 product with the molecular weight of 391.36 (C2 1
H
14
FN
3 0 4 ); MS (ESI): 392 ([M+H]*), was obtained in this way. Example 3 1-[3-Amino-4-(2-dimethylaminoethylamino)phenyl]-3-(4-phenoxyphenyl) 15 1,3-dihydroimidazol-2-one
NH
2 H 0 N.-,-' N N\ 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 20 (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 (C 25
H
27
N
5 0 2 ); MS (ESI): 430 ([M+H]*), was obtained in 25 this way. Example 4 1-[3-Benzyl-4-(2-pyrrolidin-1 -ylethoxy)phenyl]-3-(4-phenoxyphenyl)-1,3 dihydroimidazol-2-one 20 0 O N N N 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 5 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 (C 34
H
33
N
3 0 3 ); MS (ESI): 532 ([M+H]*), was obtained as hydroformate in this way. 10 1-[3-Benzyl-4-(2-bromoethoxy)phenyl]-3-(4-phenoxyphenyl)-1,3-dihydro imidazol-2-one 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 15 mixed with sodium hydroxide solution (3N, 0.6 ml) and tetrabutylammonium hydrogen sulfate (12 mg). The mixture was heated at 80C for 2 hours. After cooling, the reaction mixture was diluted with dichloromethane and washed with sodium hydroxide solution (1 N), hydrochloric acid (1 N) and saturated brine. The organic phase was dried over magnesium sulfate and 20 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 (C30H 25
N
2 0 3 ); MS (ESI): 541 ([M+H]*), was obtained in this way. 25 1-(3-Benzyl-4-hydroxyphenyl)-3-(4-phenoxyphenyl)-1,3-dihydroimidazol 2-one 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 30 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 21 product with the molecular weight of 434.50 (C 2 8H 22
N
2 03); 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. 5 3-(4-Benzyloxyphenyl)-1 -(2,2-dimethoxyethyl)-1 -(4-phenoxyphenyl)urea 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 00C. After a reaction time at 0*C of 10 minutes, the reaction was allowed to continue at room temperature for 10 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 (C30H 3
ON
2 0 5 ); MS (ESI): 499 15 ([M+H]*), was obtained in this way. Example 5 1-[4-(2-Phenethylaminoethoxy)phenyl]-3-(4-phenoxyphenyl)-1,3-dihydro imidazol-2-one 20 0.0 O N NO N NN A solution of 1-[4-(2-bromoethoxy)phenyl]-3-(4-phenoxyphenyl)-1,3-dihydro imidazol-2-one (50 mg) in acetonitrile (1 ml) was mixed with 25 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 H 29
N
3 0 3 ); MS (ESI): 492 ([M+H]*), was obtained as hydroformate in this way. 30 1-[4-(2-Bromoethoxy)phenyl]-3-(4-phenoxyphenyl)-1,3-dihydroimidazol 2-one A solution of 1-(4-hydroxyphenyl)-3-(4-phenoxyphenyl)-1,3-dihydro imidazol-2-one (4.7 g) in 1,2-dibromoethane (23.6 ml) was mixed with 35 sodium hydroxide solution (3N, 9.1 ml) and tetrabutylammonium hydrogen 22 sulfate (232 mg). The mixture was heated at 750C for 2 hours. After cooling, the reaction mixture was mixed with dichloromethane and washed with sodium hydroxide solution (1 N), hydrochloric acid (1 N) and saturated brine. The organic phase was dried over magnesium sulfate and 5 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 (C 23
H
19
N
2 0 3 ); MS (ESI): 451 ([M+H]*), was obtained in this way. 10 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 00C. After 3 hours, saturated sodium bicarbonate solution was added and the organic phase was washed with saturated brine. The 15 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 H 1 6N 2 03); MS (ESI): 345 ([M+H]*), was obtained in this way. 20 1 -(4-Methoxyphenyl)-3-(4-phenoxyphenyl) -1,3-dihydroimidazol-2-one 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 25 over magnesium sulfate and concentrated. The product with the molecular weight of 358.40 (C 22
H
1
N
2 0 3 ); MS (ESI): 359 ([M+H]*), was obtained in this way. 1-(2,2-Dimethoxyethyl)-3-(4-methoxyphenyl)-1 -(4-phenoxyphenyl)urea 30 A solution of 4-methoxyaniline (1.9 g) in dimethylformamide (3 ml) was added dropwise to a solution of carbonyldiimidazole (2.51 g) in dimethylformamide (15 ml) at 0*C. After a reaction time at 00C 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 35 dimethylformamide (2 ml) was added, and the mixture was heated at 800C 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 23 concentrated. The product with the molecular weight of 422.49 (C2 4 H2 6 N20 5 ); MS (ESI): 423 ([M+H]*), was obtained in this way. Example 6 5 1-[4-(2-Methylaminoethoxy)phenyl]-3-(4-phenoxyphenyl)-1,3-dihydro imidazol-2-one Na N-C)-N 10 A solution of 1-[4-(2-bromoethoxy)phenyl]-3-(4-phenoxyphenyl)-1,3-dihydro imidazol-2-one (50 mg) in acetonitrile (1 ml) was left to stand with methylamine (1 M 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 15 401.47 (C 24
H
23
N
3 0 3 ); 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 20 2-one NkN-
NH
2 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 25 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 400C 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 (C2 4 H21N303); MS (ESI): 388 ([M+H]*), was 30 obtained as hydroformate in this way. Example 8 24 1-(4-Cyclopentyloxyphenyl)-3-[4-(3-dimethylaminopropoxy)phenyl] 1,3-dihydroimidazol-2-one O0 N- O 5 Carbonyldiimidazole (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 00C and 30 minutes at room temperature, a solution of (4-cyclopentyloxyphenyl)-(2,2-dimethoxyethyl)amine (265 mg) in dimethyl 10 formamide (1 ml) was added, and the mixture was heated at 800C 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 15 preparative HPLC. The product with the molecular weight of 421.54
(C
25 H3 1 N303); MS (ESI): 422 ([M+H]*), was obtained as hydrotrifluoro acetate in this way. 4-(3-Dimethylaminopropoxy)phenylamine 20 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 600C while evolving much gas. After a reaction time of 90 minutes, the catalyst was filtered off and the filtrate was 25 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
(C
11
H
18
N
2 0); MS (ESI):195 ([M+H]*), was obtained in this way. 30 Dimethyl-[3-(4-nitrophenoxy)propyl]amine A mixture of 4-fluoronitrobenzene (2.82 g), 3-dimethylaminopropanol (2.48 g), powdered potassium hydroxide (1.35 g) and aliquat 336 was heated at 850C for one hour. The cooled crude mixture was purified by chromatography on silica gel (eluent: ethyl acetate/methanol 9:1 mixed with 35 1% v/v triethylamine). The product with the molecular weight of 224.26 25
(C
11
H
16
N
2 0 3 ); MS (ESI): 225 ([M+H]*), was obtained in this way. (4-Cyclopentyloxyphenyl)-(2,2-dimethoxyethyl)amine A suspension of 4-cyclopentyloxyphenylamine (8.86 g), bromo 5 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 (C 15
H
23
NO
3 ); MS (ESI): 10 266 ([M+H]*), was obtained in this way. 4-Cyclopentyloxyphenylamine 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, 15 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 20 weight of 177.25 (C1 1 H1 5 NO); MS (ESI): 178 ([M+H]*), was obtained in this way. Example 9 1-(4-Cyclopentyloxyphenyl)-3-[4-((1 R,2S)-2-dimethylamino-1 -phenylpropoxy) 25 phenyl]-1,3-dihydroimidazol-2-one 0 0 0 O NAN O N The compound was prepared as described in example 8 but with use of 30 4-((1R,2S)-2-dimethylamino-1-phenylpropoxy)phenylamine. The product with the molecular weight of 497.64 (C 3 1
H
35
N
3 0 3 ); MS (ESI): 498 ([M+H]*), was obtained as hydrotrifluoroacetate in this way.
26 4-((1 R,2S)-2-Dimethylamino-1 -phenylpropoxy)phenylamine The compound was prepared as described in example 8 but with use of (1 R,2S)-dimethyl-[1 -methyl-2-(4-nitrophenoxy)-2-phenylethyl]amine. The product with the molecular weight of 270.38 (C 17
H
22
N
2 0); MS (ESI): 271 5 ([M+H]*), was obtained in this way. (1 R,2S)-Dimethyl-[1 -methyl-2-(4-nitrophenoxy)-2-phenylethyl]amine The compound was prepared as described in example 8 but with use of (1 R,2S)-dimethyl-[1 -methyl-2-hydroxy)-2-phenylethyl]amine. The product 10 with the molecular weight of 300.36 (C 17
H
20
N
2 0 3 ); MS (ESI): 301 ([M+H]*), was obtained in this way. Example 10 1-(4-Cyclopentyloxyphenyl)-3-{4-[(2-dimethylaminoethyl)methylamino] 15 phenyl}-1,3-dihydroimidazol-2-one 0 N N N A N 4:)/ The compound was prepared as described in example 8 but with use of 20 N-(2-dimethylaminoethyl)-N-methylbenzene-1,4-diamine. The product with the molecular weight of 420.56 (C 25
H
32
N
4 0 2 ); MS (ESI): 421 ([M+H]*), was obtained as hydrotrifluoroacetate in this way. N-(2-Dimethylaminoethyl)-N-methylbenzene-1,4-diamine 25 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. 30 N,N,N'-Trimethyl-N'-(4-nitrophenyl)ethane-1,2-diamine 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 35 and saturated brine, dried and concentrated. The product with the 27 molecular weight of 223.28 (C 11
H
17
N
3 0 2 ); MS (ESI): 224 ([M+H]*), was obtained in this way. Example 11 1-(4-Cyclopentyloxyphenyl)-3-[4-(3-dimethylaminopropyl)phenyl]-1,3-dihydro 5 imidazol-2-one 0 0 ON AN The compound was prepared as described in example 8 but with use of 10 4-(3-dimethylaminopropyl)phenylamine. The product with the molecular weight of 405.54 (C25H31N302); MS (ESI): 406 ([M+H]*), was obtained as hydrotrifluoroacetate in this way. 4-(3-Dimethylaminopropyl)phenylamine 15 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 20 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 25 (C1 1
H
18
N
2 ); MS (ESI): 179 ([M+H]*), was obtained in this way. 3-Dimethylamino-1 -(4-nitrophenyl)propan-1 -one A mixture of 4-nitroacetophenone (1.0 g), N,N-dimethylmethylene ammonium chloride (0.56 g) and acetonitrile (10 ml) was heated at 800C for 30 4 hours, and the precipitate which separated out after cooling was filtered off with suction. The product with the molecular weight of 222.25
(C
11
H
14
N
2 0 3 ); MS (ESI): 223 ([M+H]*), was obtained as hydrochloride in this way.
28 Examples 12-91 Further examples which were prepared as described in example 5 but with use of the appropriate amine are summarized in table 2 + o + -. L) cd c) cd on Lo : Lo Lo2 c co C ) C Co - c o co ODr co Cl, " C lr- ) 7l, Z 4U) It 10)Lf C3 E 0 0 C 0 0 coCfl0,q Cl, 0 z z zo z z I.- r- N- Z _o o~ o o oN z om Cf - o o a) NM c Cfo oCf o o z - o 0 0 0 00 o-v 8e ( E 00 * * 4 U 5 .! f'7C -o ' C 0 0 O E ~E > 5 C/.C U) 'go ).
C- N o 0z M'- CL 'N a. 0.u 0 ~ CL0 ) A -N - 0 N0 -0 400 U CL U =--' CD 0 Eu 7-C-l N 0 O E 8- 0 N1 zf y-z, C a) co COCl '- U) C6 CX C6 a), 0 D WZ- 12 00 O 0 O CF)0la Lo cD o co (. G L L6 LO LO tV 1r tO) cf) 0)t ~ CO O CO O CO COc0 co co cO o 0 0 0 0 Sc) CV) m co z z z z z o Cf) CV) a) mV Cf) CV) CV) N~ mV 7to c) toc\ c cV) CV)C C) CO) to o to 0o 0o z> 0 Z Z 0 0 rer C 00 y or4 rO orr 9 oI 'IE ' E Ii a.z z o c o- 0 zn c 0 .. o 0 0> o > I 0>. 00 0 ) C; = 0) =~V -5 0 N -r 0E +'e Nz N-C& ON) CL 0a) o o ~9 o o 0- OCU) Uc) e-U) e - a. .
- E N- 0 0 _____ N N oC co LO LO C) LO 0) 6CN C6 0) 0) 0r) T- LO o o 0 0 0 (Y) it t I Cf) z z z z z CV0) C) COC I I I I I o 0) 0 0 oo rio 0 0 Z O0 Cr Cr Cr Cr Cr z z o e , ,z 0 .E C o 0 0o E EE .-- C C . - CZ C0 C; C; 0 C C: CLC) c 7 0 (1) Cc 0- 0) ' o 0.,, -C N 'N 0)0~ a) 0 (D0 7 00 '- 0) _r_ CD c-~) CL a) - . C) 2;) L- 9C a No (D N -5N c\l c\l Ito o r- N 0 r- (0 LO t LO CD D C) (D a C O co cO co - tN 0 (0CD .* J* LO LO o 0 0 0 0 z z z z z 0D a) 0) Y csi csi csi) cl cY) I I I I I o- o br 0-2 0N 0) N IfO O C~ 2 O z O O C 0 0 0 0_ 0 a ') QCa)a .c 0 , CsII eo - - ~-' *C c c o , , r , I c , . .. a ) - c c C; ) 000) E; a) a-) . . Ac a). --
C_
E 0 -a o 2 V c -- C 9 5 ,'- ' c 3_C C (Da) 370 0 ~ 0 -5, 0 P >C V, % a) 0) c 0EV I 0 5. 4 r-cCV ; _l CL - .L '0-0 a) .o o > o >o c cc c0 No N) NC) 0') C\) C\l O LL a) 0 ) ODC*( CD (0 LO (D LO 1- C) cV) CV U Y) U) o 0 CV) 0cf) O O 0O z z c~)z f ) C) Z Z mCV) m) o CV) D Cr Cr C C oe 0 0 0 0) -o0 .E 0 c) a) ct 0. .C or -- C. 0 0NC . e E c CVg)r -Z _ oc _0 C C *CV LO COC C0 C a) N> c: . (IS C O _r_ CCV CN CO cr) C; cO 7C; > CE c; CD a) > NO CL c.. a) N. *cO L 0 U CV) N- U NC:) Cc C: 1 CV~CCo 7F) )C cD o 0 I to o N - o LA) N~ LO 00 co LO LO LO LO cri P. oi C6 o o N~ (0 0qC) t c) c) CrO o 0 0 0 0 O O O O O z z z z z T-LOA 0) c CV) cN cm cN I I I I I NM (0 0Y) N-0 Cv) NNNCv) Z- ZD -z 0 z o 0 0 0 or Cr CC rg 0. 0 ac '0o ,~ a 8 48 i v; Iq a)4 a .. N .; c Nc N c0 CCv 0% C: IC -L o-~ 0a ) 75 _0 X C 5 -C 4CL c% o mt CD C;C CZ* C C 0.. 1- .. I ' o E - E N-C 0 0 .. 0. -Ca.m a) co cEL C C) 0) Cf) 0)cl) (Y) Lt Cq CO Ct NM 0) CD a) 0 LO LO CD Iq C\l C) Ct Cl) Cfl ) I I I z z z z z N0 Cr NM Nm N cC (V) N CN C0 0) Rtco CD C\l CN CO C\l N o 0 0 0 0 to o O 2 00 *0 00 4 z LJON0 z* z EC2) 0 0 0C c~j 75 C;C 7E r L -L C\1 ar (1 c .c - C .c .c0 - CO CC CO N C ~ -01 E " E .E 70 a). 0V I - U) Il to-Ca C; > .ca. a):j C C\l Cf CO LO CO CO COL CO) 1-o co LO LO LO C) CV Cm c",) c") C"r) f z z z z T-0) C"r) N C) CN CO CN z 0 0 zz CCO C Ii CO C~ 00 0c0 0 ()0 O CI; a CO CO) COC Q-Co c c c 0 C -' C * - -C CU -r .c o~U ..- CeN - 0a c 0 EA r-V 4C CO - C m0 0 - -- *~ CD 0LO 0TE - 0 O 0 NO CI% NC~ CO 0) 0 C a)CM -5, o to V LO CO COr CO C0 C\l L.O LO LO LO i LO LIO 0 LO c\l c) Co Co 0n O iO to ci O 00 1- 4 o CY) Co D C\l LO LO LO O I LO LO Cf) c') CO) C') ItC') o 0 0 0 0 0 c') Rt e I C') c z z z z z z 0) C\l C CD N~ C'r) C') N~ CO) N~ I I I I I I cN c) LO 0 C N c') c') c') CO CO C o o 0 0 0 0 o z O z z 6 -0 z 0 .0 zo o 0 zl- C) c o- -5 z -czE -C c 0 -: ,ioo-I o-c tG o too LGL o C ~ ~ ~ C C ~ 1 0 0~ 70 C ( C .C 7E 0 7 CU) >1U (m N) C I 7E)c c ) o C 1oc) 0.- ca*~ co CLA o~ C E -8 - ~ 'N oL -r 0. C ~ U U 0 .cO (1 ) '0 c c o N0. c N C ) LI) CD 0I LIaI)L)-I
I
ODLO LO 0 ItItU LO LO 0O LA LO LO CD LO LO (0D( (D NiC - C6 0)i( coLO LO 0 0) 0 ,tIItLA LA LA cr) C) lqTcr) () (Y o 0 0 0 0 0 Itcl) (V) clr) ml ml z z z z z z C'~J r- r- a) LA LA ce) C\J CMJ CMJ cf) m 0) co - CMJ 01l OJ C\J CMJ CMJ Cl) ce) cf) 0 Or 0 0 zr~ Cl) Q) 0 06 36 C ~cr 0r 0 Cl Cl0l) C,, a) 0 C? ~ : 20 1 1oC: l-D o>%% 0C a) .0 .r C .C =C 0U CO i C; ) CL 0- CL0 C 0 )o 0) 04 0 0 0 L 0 CD > . >% C ) ~ >1 (D = 0lCI cz Cll as~ C. CLN C\?, a. 44 C C *C *C -~c O- 0 E 0 0 i LA LA LA cC > ~ CO C LO C CD LIC LO C C\l SC\lco LOLOO LO LO co It:j qTC co CD It1 C~ T (D I OC Lr LO O LO 10 0) 1) It qt Z Cl e o cl) 0 0 0 Cl ce) C, z z z z C\J 0 LO ce) Cl, Cl, It ( I: C'J 0~I T- I of 00 0r 00 Z z u0 O 0Z 0 ?1 0 , 0 0 T0 zc . c .c0) C). O cro GO 00 0) C >%; C; 0 I Q) - - -0 -6) Cli~ 17 0 *~ C,~ '.c I -U)1 CL .C >%.C 0COo0 O C; C' J 7 ) 0 a) s C Lc cU c' 0C' '5L vi NC( -- 0 a) O(1) N -7 C CJ) 0) CL~ '-0 ) &- " ) .- _r_ . - 0 ~ E- C . C,-U C\ D N C : CO CD CIS C6 C\l 0 CD CD a)r-.q LO LO 0) O0) LO LLO ClCO Lo LtLOL CO Z CE) CEd Cl Cf z L-z z z Cf) CD C) CM C\l LO o T-0 1 cy) IN 004N C)CE) C C) o* o 0 0 0 0 z zz f~I:0 0 Cc 0 -? -- ) 7EC (1 .- 0.C- CN .c 9-ac t) 9-c o 9 03 -. t?- E39 o o No .c 0 c 'yN ' -'N C - N ' 2-3-. CL 0 aC) 0~~~~~ -00 a0 75c 0 0 c a c: c 0o 9 9N ND CD N. N N. : o C: cc 4 C o -5 9 c o C Y( co CO tC co o LOo Co Co Co C_: CL C6l CO o LO o co LO CV) Ur) o 0 0 0 z z z z a) 0) 0) V Col Col N-l 0) o co - o r-- 0 czl '6 X _oZ - ZE 0 o z ? 000 00 00 z0 E CC o o 2 0 oC o o f~U -N 0 Z (a) &c aCD * COC - C CI" - 1 -L cA-r 0._ E 0) N 0. E 0 a-~ 0N -00 ~ 0 0 0 aC -5 " a) 7 E ) C ) U) ct C N- N- N- N-C;C o co To T CD CD cc LO LO LO T LO N - 0 CM CD LO LO r- CO I-LO (D co LO It tLO LC) ot NIoO U) Itcv) cf) qt0 z z z z c) N 0) 0) co Z 0) LO0) Cvr) N~ N~ cvr) N C v) C o0 000 o zz ? C ? ' e .5 Qe r - 0 0 1 e~ 0 0 o -> N.0 (,,. 0 orc o e.f f g . 0 C cc o T - 5+-- .ci o 'Ci- c D'.-. y~~~~~~ -1oe 05 >c 'it a) 0 cV 4-0 O _ c3 .. .- 0c c E 0 -C CL -0 Ca L ~ -- :. 4 OC 9 4. . 4 C Cc x' - E C: Tca .c 0 .- >4 a) . oXC -0 -C 'V (D. N 0 = C a) -0 N- C)v) C- 0 07 N- ca ' E 'T a)a -r- COj 00 0 N- N- N-0 CD C4 LO 0o C\l ( (C0 (0 CO LO LO LO LO LO in in i O in i 0) 0 C (0 (0 r- (0 co co CD N- 1- 4 i:L CD 0) co CrO14 LC) LO ItOr LO LO CO LO CO CO CO CO o 0 0 0 0 0 CO CO CO CO CO z z z z z z CO N- C\l - CO iO CO CO CO CO CO ' CO I I I I I I N 0 0) CO * O CO CO C\l CO CO CO o z z 0 zz 2 ZZ Z COO 4 0 Cr0 C 0 O 0 z z 0 00 0 0 6 * , 6 6 N c a)) a) -r E:G 0) - 7 -c 0 C a) * a) N 70 70 N .- E c E E C. 0- r ; C C..-CO - C a 0 a) 0 =C a) 0 C; a)CD- '- 0- 7 CLN E3~ NL C 0 N N N N * s TCc - 0 c CO In NO N cC6E c Ec Or- r c C) C\l LO LO LO C CO C CM co -CO " LO LO tO o a a c~r) CO t) U z z z * CI Cf) Z crl~) c~r, a) oCl) ItI C)clr) Ce) co o o o N 0 Z Z 0 0 0' 0V 0 0 6 0 >1 5a)l 0 IVC: C -C 15 C = C; o ; a o a)E C; C S C 0~ C:' 0 CCO 0 c 0 >, 04 a) a 'N CL C 0D ) -c± cl C; C E a) N = - 75. 0V 0 -0) 0 -1 7V ~ 0 _ ~E $E _ co 0) 0> co o 0)0 45 Example 92 1-(4-sec-Butoxyphenyl)-3-[4-(2-dimethylaminoethoxy)phenyl]-1,3-dihydro imidazol-2-one 5 0, 0 N N 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 10 cesium carbonate (100 mg) and 2-butyl bromide (25 mg) and heated at 80 0 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 (C 23
H
29
N
3 0 3 ); MS (ESI): 396 ([M+H]+), was obtained as hydrotrifluoroacetate in this way. 15 1-[4-(2-Dimethylaminoethoxy)phenyl]-3-(4-hydroxyphenyl)-1,3-dihydro imidazol-2-one A suspension of 1 -(4-benzyloxyphenyl)-1 -(2,2-dimethoxyethyl) 3-[4-(2-dimethylaminoethoxy)phenyl]urea (4.9 g), palladium (10% on 20 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 25 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 (C 19
H
21
N
3 0 3 ); MS (ESI): 340 ([M+H]+), was obtained in this way. 1-(4-Benzyloxyphenyl)-1 -(2,2-dimethoxyethyl)-3-[4-(2 30 dimethylaminoethoxy)phenyl]urea 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 35 at 800C for 30 minutes. After cooling, volatiles were removed and the 46 residue was purified by MPLC (eluent: heptane/ethyl acetate 9:1). The product with the molecular weight of 493.61 (C 28
H
35
N
3 0 5 ); MS (ESI): 494 ([M+H]+), was obtained in this way. 5 (4-Benzyloxyphenyl)-(2,2-dimethoxyethyl)amine 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 1000C for 5 hours. After cooling, the reaction solution was filtered and concentrated. The residue was purified by MPLC (eluent: 10 heptane/ethyl acetate 4:1). The product with the molecular weight of 287.36 (C1 7 H21 NO3); MS (ESI): 288 ([M+H]+), was obtained in this way. Examples 93-130 Further examples prepared as described in example 92 using the 15 appropriate alkyl bromide are summarized in table 3.
+ UI) -a LO C LO 5C=LC) LO LO)L C) 0)0)6 iC 2?- t0) 0 I 7 o ao af ae z z z z ~ 0 a) T-0) co N-l C~) CO o 0 0o 0l0 00 0)s 0) .cC2 -S aU) o C -1_ 0 C 0 0) C? C; ) U)S 4-. a)CZCc C-D a)(a C a c- E 0 ENc 4-~- >5 E~4 >C 9) C.) E 0 1 0c U) l N;~C a) ~ N N C\ J N E _: _ C 40 -E9 . 'E z .C - asCj -- C z-E ,- m 0'=< 0=O?<I1 z- = zI (D 0 -o 0n 0 U) -o cU X co J LO CD I- WZ 0 m) m It Rt 0 co q LO LO CQ ' C LO LO LO LO LO cli Cl, LliC 0tlq 0) N~ Ce, CO, CQ CO, CO o 0 0 0 0 CO, C 1 ) Cf Cf, Cf, z z z z z 0)0) a- ) CO N N Cf, N~ CY, It N CV) LA N~ N~ N~ N N~ 6 6 N 0 co 1 -0 c: z c C: C. 0) a) a) a) 0a -CL. o o C oL Qo o7 CUC~- CU c3) aa)a)C 0) CD-a) C 0 o 0 0 L0 00 E EN - v - E Err lt~~~~~~, czcC :c Cl C Dc -. 0 0 04 a) =3 CD0 (D __ __ 0) 0D - ) E 3 a 0a-7 co a) 11- CC ) CV) LO)cf C) cf) CO m) N-) N- V) Cfv I cv, r)C o 0 0 0 0 cr, CV) c~r CV)Cf z z z z z LO N CV) LO N N- NM Nm CMcl 6 0 0 (1) 'V" 0 0 c.. 0 1 L -7"as 5 7v , . -L CO CD0)- 0)* 0 7a E a) C. 4-V Z 0. =-C 4C CD'C a)- a) a)- % S . SU~ CU. - 5 m. U E_ ,cy :> + r -0 C 4- >C 0(a. 4C a)0. a 0 0)u , mE 0O 5EL -, CL L *% -- 4- N _ r E '-0 0-~. 0-Q 0 0 00 0 0 0 NM ct) LO co Co 0 Co C C CM C C ) C\l 0) C C Cf) C) CDOa Lfl 11) I CO 0) 0) C\ ) Cm C CIO CIO CO) CO) CO CO) CO) o 0 0 0 0 CO) CO) C') CO C') z z z z z C\l CN CN Co C I I I I I C\l C) C') LO CO CMl C\l CMl Cm C04 o1 0 0)- 0 00 -- 0 N N_ a - E - E Cil 4 7 Erv ()N N - C~ 5 _ N A 6 .c~~~~ o or- ' _0 -E s E :2 - >1 c E~ 0E or 5 E ar ac A 0 810 CLV a) a) 0 - - - 0 _ ~ 0 C) Ac E a O )- .. '. CL .a. a.) 0t C; 0 ) SO. o oEc a)) C C cE 9? E a) O 0 a GO W (U '0 ItC'0 'NE zO o0 0 -o Q O O 00 0 0 N CO 0 0 0 0 0 CC co ND N~ C N~ r- a) ItN I')OItUl LO p L6 L6 I- L Cf) CO) LO) (Y) CO) CO CV) co) ml ml z z z z z 0) clr) N-T Cl) ,i ClD NV CL) co) C CM Cl Cl COl 6 6 6 6 I _0 _ 4 -? = V co) 4 co ) co c I CD1 ) (1 D 0 C; a) CDU 0 ~ a)) E~ c a) 03~ a C CLN 0 0 = N 0 0N I CV 'NE E 0 _ 0 0 E 'E 'NcLE a) a) _x E a) _ C (D Co 0 z (3-. = - 5 1 -- 5 N, CD, 0L) > ) CO,(1 N N N N Cf, C) NM N~ 0 It Nl ~ (D N LOLO LO LO I - L6 C6, C6) 0 C0) C0) Nl N~ 0) Rt1 'cj. .It (Y)J C0) o 0o 0 Cf) c c") CE) C0) z z z z z T-Cf) 0) CflL Coj aE C) N) Ca) N ; I 1- rI iG r if) a0 N L C 0 Eo E 0 0 c CJ, 1) 6 0a a )C 0U 0 ) 0)-C~ - & I CM =1 0 CME 0EU E 9 cco ca C-, % ct03 0 N E9 E C\ Eo& (CN CU 0" (D UD C;. .cN m ECOC c Ezc E> 5E. -o 0 I 0 C0C 00 l- O 0) C0 CM C CC). CDIt CN CM LOI 0) LO LOAI LOAq N_ C6 , L6 cv, o N ~ tI 0) cv,) CO, Ct, 0 l o 0 CID 0 0 CIO cV) z cV CV) a) cv,) LL N-r N~ cl) CO Nr ~ ItLO m N Cf) N NM CO NM M 00 E~ 0 a)~v =% 1 = 0 0- 0 0 TU E_ )a - in ao 0 C CD a) ) 4- 3CI a a 0 0 C0 C 0 a) Q. = & cc C a)+_ .0- a) a) 0 1 E4.. 0
)
C LO0 0 Cc C2L ~ - 5E.N c E c: ~- . C' NE _ c N c-lV ' _0 EE5 ' 0 5,E*a)$ N5 Cl L N ~ N N~ Nt N MC~ E~ cz - -5, cra co c ,it Cf CO o o 0 CV CID ce) cf) zl zl z z cv,) Z T-LA LL CC) Cl) N ~ 0 ~ co ce) m m N~ N~ CW, o Z Z Z Ev c _ L- -E 0 C; aE) CL 04( 0a -E c) : C ( o SE~ E 6o.ce o . c C; I- C - c LA 00 0~ -) o ca- 6 E o E 0 Co L { Tz 0 -c . 0 9 E c Cc C? 5 '.50 Oa) c _ cc f4 co a)) E a) ' ; 0- '-(U ,-C ,
-
75V C 00 co 0) N N N Cl 55 Example 131 1-[4-(2-Dimethylaminoethoxy)phenyl]-3-[4-(2-nitrophenoxy)phenyl] 1,3-dihydroimidazol-2-one 5 O'Z'N.-O 0'.. a 0 O N N O N~ \== / 2-Nitrofluorobenzene (0.14 g) was added to a mixture of 1-[4-(2-dimethylaminoethoxy)phenyl]-3-(4-hydroxyphenyl)-1,3-dihydro 10 imidazol-2-one (0.34 g), Aliquat 336 (0.04 g), 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 (C 25
H
24
N
4 0 5 ); MS (ESI): 461 15 ([M+H]+), was obtained as hydrotrifluoroacetate in this way. Example 132 1-[4-(2-Dimethylaminoethoxy)phenyl]-3-(4-o-tolyloxyphenyl)-1,3-dihydro imidazol-2-one 20 0 O0 N N N Carbonyldiimidazole (40 mg) was added to a solution of 4-o-tolyloxy phenylamine (50 mg) in dimethylformamide (2 mL) at 00C. After 25 30 minutes, (2,2-dimethoxyethyl)-[4-(2-dimethylaminoethoxy)phenyl]amine (67 mg) was added, and the mixture was heated at 800C 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.
56 The organic phase was dried and concentrated. The residue was purified by preparative HPLC. The product with the molecular weight of 429.52 (C2 6 H2 7
N
3 0 3 ); MS (ESI): 430 ([M+H]+), was obtained as hydrotrifluoro acetate in this way. 5 (2,2-Dimethoxyethyl)-[4-(2-dimethylaminoethoxy)phenyl]amine 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 10 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
(C
14
H
24
N
2 0 3 ); MS (ESI): 269 ([M+H]+), was obtained in this way. 15 4-(2,2-Dimethoxyethylamino) phenol 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 20 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 25 Further examples prepared as described in example 132 using the appropriate aniline are summarized in table 4.
+ u 00 0 0i .(j. - 6 3i EA CfA 0 0 00 0:c c 0 Cl, CM 0 Ir N .J Z .J o= 0 c >0 I =0 I = U) LANNL 00 1 N 1 jZ j-0 fZO -0 z0 z 0 N 0f ( 0 0) a) 0 aU)a a) c a) oC) -CO .CD 0~~ 00 U) 0 .a O N ". CC 0 a) .c CE a) 0 0 0 2E 5 Ej _ -E' E~~~ a)C _- E EU _0 >1 : cl) LA w0 CU X 0o Wizo0 L co I C ~ ~ ~ c co0 t LO O LO LO cLi c6i ci cri cs 't aD ) 0) 0 t) c c* CV) cNl cm c) o 0 0 0 0 V~) C' () CV)I z z z z z N* LO a) c (D LO Cr) (D N N N N N o 0 0 o 0- o 0 NfZ z o o e o c c 4 .c o ccc 0 0 c .E 1 0 C0) >, E . - c c - t-o c. c- cC)0 a0) _% E1EE 0 .r- a) .- V. c o 00 0 a.% N.C 0 a C " a)) -0 -VC~ -0 C a)' I > > a -v x-j , IC; ? C E 02 cr* 0)o -c 5% ) 4- -2 E a) a. a '-0 >%-Ca)') C; 0) 0-N _: %C m' _7-C' ) ) CD 0LO 0 c\q CM , ~ CM c LO LO LO LO LO 0) ce 00cv le qt loe ct cei ,-l Ce cri co co O N CQ o a N z z z z z I O N N CO N Z LL C CO M M I o o O o m 2z O z z z z z I I 6 .EIC -g - ee . - N N c .cN >C Cu. CU o o A - o > E e' cE -coz o o o * c c =ON O z .c z- z >=a z c >= cl =O ~I -'- O (ze -' O 5 ~ () z o . 0 o LO I 0~C 03Uao e N. CA c e iN. <ic to <oo 6 0) . 0)) 0oN 4. C .0 .~-C m -1 _L N Ca ) CO (Dq*LfA CMC LO 0) N~ LO Nl- f (Y) N LOAI LO LO 0) LO LO CO) a) N~ LA r-co o 0 LA) 0 0 z Cl) T-I )0) 0 clr) NM N~ N~ Cl) N: N CM) N: N oi co N 0l L f 0 J\ z z z >= Cz 0 = zz Z )0 0- 0 0 * 03 0- 0 I 7 30o Co ( 0) CJO0 0 -C0 C C C.Cca CL Na)C N ?0 0N 0) _C OC o o 0) 1-~ 9 ZO aE C) XU C 4 0 c 0) 0 0 C.) 0 a0 C -Cl)4- EAN c-l' 0 N W .- c LA LA LA- C co 0 0 0 0) N N~ CM Cl4, Cl, N 0O CI C6, Ni o CO, 0 0l co) CY, co, of 0o 0 0 0 zl z-z oo NoC NN N0 0~ 0 0 l 0 z z = 00 1 0 0 _ - . .C z0 0-0- L-, D 0 0-Cl 00 000 0~_ -0.c > C: C 4 C 4- C CLc O 0Q. Q.C C - f 00 -~ 0 0 0' 0 E2% E 0 *0 C . . E ~ ~ 00 0E 0 0)( CC 6C N ~ NO c Nz=C L CO - a) . C 5l, 2) -o N%=. a) LO a)) 10 0 E~ 2 1 )C E0 N ~ Y I C IO 0 C)0) O) Cf) ItM Cf) It Cf) CIO U) U) 0 It CDl N 0 r ~ )I Uf) UO N N z z LL T-C NO Nf It Ir MIO It I OC ~ zz z 0 00 -=o >= - =o ( = >1:E I I >% I 0 1 c) c C I a) c a) .; a) (CD: a) cfQa ) 071 CL cx CD ) -a..Q _ 0 C 0 0c 4F C _ :5 0 C0 -0 -V O 0 >- 1~ a)) ., a)- > le 0 CI g d) Ea- 0E E 9 c: 9cz N.2 cL _0~ C13 N EV +- 4N-~ c: -C a) 0D N )4 a) ) a) a) CD a) 0 ~ --
-
CLa 63 Example 164 1-(4-Cyclopentyloxyphenyl)-3-{4-[(2-hydroxyethyl)methylamino]phenyl} 1,3-dihydroimidazol-2-one N Q N N N- OH 5 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 10 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 (C 23
H
27
N
3 0 3 ); MS (ESI): 394 ([M+H]+), was obtained in this way. 15 1-(4-Cyclopentyloxyphenyl)-1 -(2,2-dimethoxyethyl)-3-{4-[(2-hydroxyethyl) methylamino]phenyl}urea 2-[(4-Aminophenyl)methylamino]ethanol was reacted with carbonyl diimidazole and (4-cyclopentyloxyphenyl)-(2,2-dimethoxyethyl)amine by the 20 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 (C2 5
H
35
N
3 0 5 ); MS (ESI): 458 ([M+H]+), was obtained in this way. 25 2-[(4-Aminophenyl)methylamino]ethanol 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 30 concentrated. The product with the molecular weight of 166.22
(C
9
H
14
N
2 0); MS (ESI):167 ([M+H]+), was obtained in this way. 2-[Methyl-(4-nitrophenyl)amino]ethanol A mixture of 4-f luoronitrobenzene (20 g) and 2-methylaminoethanol 64 (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 (C 9 H12N20 3 ); MS (ESI):197 ([M+H]+), was obtained in this way. 5 Example 165 1-(4-Cyclopentyloxyphenyl)-3-{4-[(2-imidazol-1 -ylethyl)methylamino] phenyl}-1,3-dihydroimidazol-2-one N A N N N N 10 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 15 (5 mL) at 00C. 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 900C for 6 hours. Volatiles were removed and the residue was purified by preparative HPLC. The product with the molecular weight of 443.55 (C 2 6H 2 9N 5 02); MS (ESI): 444 ([M+H]+), was obtained as 20 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 25 0 / O NN NN\N N The compound was prepared as described in example 165 but with use of 2-methylimidazole. The product with the molecular weight of 457.58 30 (C27H31 N 5 0 2 ); MS (ESI): 458 ([M+H]+), was obtained as hydrotrifluoro acetate in this way.
65 Example 167 1 -(4-Cyclopentyloxyphenyl)-3-{4-[methyl-(2-methylaminoethyl)amino] phenyl}-1,3-dihydroimidazol-2-one 5 0 0/ II N ON N NH 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 10 (C 24
H
30
N
4 0 2 ); MS (ESI): 407 ([M+H]+), was obtained as hydrotrifluoro acetate in this way. Example 168 1- (4-Cyclopentyloxyphenyl)-3-{4-[methyl-(2-piperidin-1 -ylethyl)aminol 15 phenyl}- 1,3-dihydroimidazol-2-one 0 0I N AN N The compound was prepared as described in example 165 but with use of 20 piperidine. The product with the molecular weight of 460.62 (C 28
H
36
N
4 0 2 ); MS (ESI): 461 ([M+H]+), was obtained as hydrotrifluoroacetate in this way. Example 169 1 -(4-Cyclopentyloxyphenyl) -3-(4-{[2-(cyclopropylmethylamino)ethyl]methyl 25 amino}phenyl)-1,3-dihydroimidazol-2-one 0 0/ A
--
N N N N \--j H 66 The compound was prepared as described in example 165 but with use of cyclopropylamine. The product with the molecular weight of 446.60
(C
27
H
34
N
4 0 2 ); MS (ESI): 447 ([M+H]+), was obtained as hydrotrifluoro 5 acetate in this way. Example 170 N-[2-({4-[3-(4-Cyclopentyloxyphenyl)-2-oxo-2,3-dihydroimidazol-1 -yl] phenyl}methylamino)ethyl]-N-methylacetamide 10 0 0 0 N N N A solution of 1-(4-cyclopentyloxyphenyl)-3-{4-[methyl-(2-methylaminoethyl) amino] phenyl}-1,3-dihydroimidazol-2-one (50 mg) in dichloromethane 15 (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
(C
26
H
32
N
4 0 3 ); MS (ESI): 449 ([M+H]+), was obtained as hydrotrifluoro acetate in this way. 20 Example 171 1-[4-(2-Dimethylaminoethoxy)phenyl]-3-(4-phenoxyphenyl)imidazolidin 2-one 0 ~00 ON N N'' 25 Palladium(II) hydroxide (20 mg) was added to a solution of 1-(4-(2-dimethylaminoethoxy)phenyl]-3-(4-phenoxyphenyl)-1,3-dihydro imidazol-2-one (50 mg) in ethanol (5 mL) under nitrogen. The nitrogen 30 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 (C 25
H
27
N
3 0 3 ); MS (ESI): 418 67 ([M+H]+), was obtained in this way. Example 172 1-(4-Cyclopropylmethoxyphenyl)-3-[4-(2-dimethylaminoethoxy)phenyl] 5 imidazolidin-2-one 00 O N O N' The compound was prepared as described in example 171 by 10 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 (C 23
H
29
N
3 0 3 ); MS (ESI): 396 ([M+H]+), was obtained in this way.
68 Example 173 1-[4-(2-Dimethylaminoethoxy)phenyl]-3-(4-phenoxyphenyl)imidazolidin 2-one OK N N O 5 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 10 (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 (C 27
H
3 1
N
3 0 3 ); MS (ESI): 446 ([M+H]+), was obtained in this way. 15 1-(4-Hydroxyphenyl)-3-(4-phenoxyphenyl)-[1,3]-diazepan-2-one 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 20 374.44 (C 23
H
22
N
2 03); 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 The Grubbs catalyst was added to a solution of 1,3-diallyl 25 3-(4--benzyloxyphenyl)-1-(4-phenoxyphenyl)urea (145 mg) in dichloro methane (2 mL) at 00C. 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 (C 30
H
26
N
2 0 3 ); MS (ESI): 463 ([M+H]+), was obtained in this way. 30 1,3-Diallyl-3-(4-benzyloxyphenyl)-1 -(4-phenoxyphenyl)urea 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 [tL) was added. After 14 hours at 69 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 (C 32
H
30
N
2 0 3 ); MS (ESI): 491 ([M+H]+), was obtained in this way. 5 1 -Allyl-1 -(4-benzyloxyphenyl)-3-(4-phenoxyphenyl)urea 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 10 increased to 800C for 2 hours. A further 2 hours at 1200C, the reaction solution was cooled and then purified by preparative HPLC. The product with the molecular weight of 450.54 (C 29
H
26
N
2 0 3 ); MS (ESI): 451 ([M+H]+), was obtained in this way. 15 Allyl-(4-benzyloxyphenyl)amine 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 800C for 3 hours. After cooling, the reaction solution was filtered and concentrated. The residue was purified by MPLC. The product with the molecular weight 20 of 239.32 (C 16
H
17 NO); 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 25 00 O N N N'' N~ 1 -Formyl-2-(4-phenoxyphenyl)-4-[4-(2-dimethylaminoethoxy)phenyl]semi carbazide (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 30 heated at 400C 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
(C
24
H
24
N
4 0 3 ); MS (ESI): 417 ([M+H]+), was obtained in this way.
70 1 -Formyl-2-(4-phenoxyphenyl)-4-[4-(2-dimethylaminoethoxy)phenyl]semi carbazide 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 5 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 (C24H2 6
N
4 0 4 ); MS (ESI): 435 ([M+H]+), was obtained in this way. 10 1 -Benzylidene-2-(4-phenoxyphenyl)-4-[4-(2-dimethylaminoethoxy)phenyl] semicarbazide 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 15 00C. 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 (C 30
H
30
N
4 0 3 ); MS (ESI): 495 ([M+H]+), was obtained in this way. 20 N-Benzylidene-N'-(4-phenoxyphenyl)hydrazine 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 25 (C1 9
H
16
N
2 0); MS (ESI): 289 ([M+H]+), was obtained in this way. Example 175 1-(4-Cyclopentyloxyphenyl)-3-[4-(2-methylaminoethoxy)phenyl]-1,3 30 dihydroimidazol-2-one 00 N N O N 1-[4-(2-Bromoethoxy)phenyl]-3-(4-cyclopentyloxyphenyl)-1,3-dihydro 35 imidazol-2-one was reacted with methylamine as described in example 6.
71 The product with the molecular weight of 393.49 (C2 3
H
27
N
3 0 3 ); MS (ESI): 394 ([M+H]+) was obtained in this way. 1-[4-(2-Bromoethoxy)phenyl]-3-(4-cyclopentyloxyphenyl)-1,3-dihydro 5 imidazol-2-one 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 (C 22
H
2 3BrN 2 0 3 ); MS (ESI): 443 ([M+H]*) was obtained in this way. 10 1-(4-Cyclopentyloxyphenyl)-3-(4-hydroxyphenyl)-1,3-dihydroimidazol-2-one 3-(4-Benzyloxyphenyl)-1 -(4-cyclopentyloxyphenyl)-1 -(2,2-dimethoxyethyl) urea was reacted first with hydrogen and then with TFA as described in 15 example 92. The product with the molecular weight of 336.39
(C
20
H
20
N
2 0 3 ); MS (ESI): 337 ([M+H]*) was obtained in this way. 3-(4-Benzyloxyphenyl)-1 -(4-cyclopentyloxyphenyl)-1 (2,2-dimethoxyethyl urea 20 (4-Cyclopentyloxyphenyl)-(2,2-dimethoxyethyl)amine was reacted with carbonyldiimidazole and 4-benzyloxyaniline as described in example 5. The product with the molecular weight of 490.60 (C2 9
H
34
N
2 0 5 ); MS (ESI): 491 ([M+H]*) was obtained in this way. Example 176 25 N-(2-{4-[3-(4-Cyclopentyloxyphenyl)-2-oxo-2,3-dihydroimidazol-1 -yl) phenoxy}ethyl)-N-methylacetamide N N N 30 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 (C 25
H
29
N
3 0 4 ); MS (ESI): 436 ([M+H]+) was obtained in this way.
72 Example 177 1-(4-Cyclopentyloxyphenyl)-3-[4-(2-[1.2.4]triazol-4-ylethoxy)phenyl] 1,3-dihydroimidazol-2-one 5 C~rO 0 N N N N N 1-[4-.(2-Bromoethoxy)phenyl]-3-(4-cyclopentyloxyphenyl)-1,3-dihydro imidazol-2-one was reacted with 1,2,4-triazole as described in example 5. 10 The product with the molecular weight of 431.50 (C 24
H
25
N
5 0 3 ); MS (ESI): 432 ([M+H]+) was obtained in this way. Example 178 1 -(4-Cyclopentyloxyphenyl)-3-{4-[2-(cyclopropylmethyl(methyl)amino) 15 ethoxy]phenyl}-1,3-dihydroimidazol-2-one C ,ON, 00 N N O N 1-[4-(2-Bromoethoxy)phenyl]-3-(4-cyclopentyloxyphenyl)-1,3-dihydro 20 imidazol-2-one was reacted with cyclopropylmethyl(methyl)amine as described in example 5. The product with the molecular weight of 447.58
(C
27
H
33
N
3 0 3 ); MS (ESI): 448 ([M+H]+) was obtained in this way. Examples 179-216 25 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.
U,) FN + Fn + w- co c)C I a- c co0) 0) coc E0 0 0 Cf) CO I z z z 4cz c c * - N 75 om .&C S O *) 0) 010 I- Z J- -- -r CV0) a)) C 0 NyC N__ *~4 - c u -0 70 >1 . -r- N 7 0 C- CO C: a) -0 C a CL ~~ C: NL .9CuVa Z~ O 0) c$- 0 ) _r C 0 N CD 0 EC 0~ 0 0)0 * 00 E E 0N N~ 0 CM Co Coo C (0 (0 CMco LO (o LC) Co co Co Co o 0 0 0 z z z z Cf, LO )O co- to tr o CM, CM N1 Cv, oyco a )co oto 0 z 0 * .c oa .o oo C C ? a 0 E) 0 -C I c C o a .2o C N 0 N C .9- 5 - 02 ~5 cm C 5-E 5 p. CL I I QO o & a3 a& 00 N 0E N2 40N 0% _0 _0 0a)~- * cv )- C~ E - r a)~ .- a) E- a) Co~ * 0 - 0v E~ NL cv, QLO 5 co a Z 0 _0 _ C\l - C C\l COco(Y LO (D CLO C\l rCDCID CVO CO) CO CO' CN N CO c o 0 0 0 z z z z T- co tO CO) Cf) C O o o N( -o 0 0 - 09 z z 4 . 43a . 0) >- xO .I-, - o 0)00 000 C\CN CC~CLN CL 11 -, o COCL co ccco : 1 c) c N- (D N 0 0) C\l co LO Co( CDCOCO C G i (6 c; N- LO) Nl a) o 0 0 0 z z z z LO Cf, Co Cf, CO, CO Cf, I I I I Co co C\l C\l C\j C\l o0 0 0,r O z ZZ O O z z N0'cI 0 C l 00)) 0LQ 0- c (1) 40) cm5,C (Cl, = CI) _r e .- a.- o o0 0 s- N 0 N N . c o &s % C CO c -o CIcS 70 1-2E - .E o .E C. " .E _ >> 0C.) 0 0 o T --- ~ c >4 0 - C? 0. NC - C 00 O s E _ 0M -2 E E 75 t -60 C.) .. . .i O- r O-- '- O C E C l o00 LO LO1 '.0 0 Lf) LOcoCf CD LO LO (D LO IItLfO o 0 0 0 Cf, cQ cr) I z z z z r-7 CO, CD cC 00 0~) cl, N~ N~ N 0 o 0 Cl, e; a)' C; - C\10 7 1 _: a) ) c~V JR) y i- % - 4 E Ca)~C C- N V 0 c~ as 0 -r _0~~ a)CM 7 Cr = -r- - a) a) 0. CD N 0) 01) 0) 0) C a- _0- NM LO LO a CL It LO LI) LI) to to LI) LO) LO LO) coo I I i I o LO qT)c LI) CoCl Cl, cRT cf) c\\ COl o 0 0 o z z z z NY N~ CMcr, co co N N -NNC- N N co 0 0O NC c c C; CDl -~C CL N _t0" lqT a) a) II 00 C: ac): C- C 0 a)C4 E ( a CD a -r- o C a) ) a) 75 0I% _% %C 0) N 0) c 0 03c 2 C N NN 0) LO10 V N-o( 0) 0) LO 0) LO LO LO (0 r- I cI) cr I f o qTj 0 0 qt z q* R z z z z m 00 CCN Nj IO COl CO 0)0 z2 C CL CV *~0 a -'c C: CL 0~ 0. CO =C) C; 0 -. 1) 0 C 0 'z (1) U o N CD N -0 (L *d U) NV) =U) f as0_- 0T EQV 0 N 0 2 -0 N C~ +.
E-. :E Uz) V 0 ~0 CL " C>) E & 0 - "4- C> o o 0 0 C N: N 0 N N - r- N- 00 0) LO O L o 0 0 0 't 1O 10 U z z z z CC) NO NO No 00 0 (0 N0 oC o 0 q-_0 0 1c -,a 0c07E Q . N C3- a CL cc Z,. >% - 1 -L IE -L 25 O E ~ 0 0 - N 0 -, ~EE 0 -0 C (.0 NC) 0) C0 0 0 N~ N~ N~ N~ 0 0) N N a) a) 0 0 19T t LOLO (3 i (6 (6 0o ) 0 0 q tLO LO cf) LO 0 ce) ce) o q 0 0 Z N Z Z NM 0tC CO) Nl LO 0V 0) f- zZ zz C;) C;) C 0 a) &N>C cC CCr - I C ~ C C N >0 C- U E ~ 0CC V 0)~ 0) 9 0 0 E O-0 -0 0~7 Ocm _ 2 C C 22 5, 0 N N N N N N9 It CD LO co c6 oi It co o 0 Itj 'tj z z o C~j m m CD N C~J C\I 000 -co * 0) 7 0
AN
0 7 N ::.- E~ CL Z. E -'L M Q)L C; 0 0L0 CD a) E C C: CD a) 83 Example 216 1-(4-Aminophenyl)-3-(4-phenoxyphenyl)-1,3-dihydroimidazol-2-one N N N 5 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. 10 The precipitated solid was filtered off and dried in a vacuum oven at 400C. The product with the molecular weight of 343.39 (21 H 1 7
N
3 0 2 ); MS (ESI): 344 ([M+H]+) was obtained in this way. N-{4-[2-Oxo-3-(4-phenoxyphenyl)-2,3-dihydroimidazol-1 -yl]phenyl} 15 acetamide 4-Acetaminoaniline was reacted with carbonyldiimidazole and (2,2-dimethoxyethyl)-(4-phenoxyphenyl)amine as described in example 92, followed by treatment of the crude product with trifluoroacetic acid at 800C. 20 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 400C. The product with the molecular weight of 385.43 (C23H1 7 N302); MS (ESI): 386 ([M+H]+) was obtained in this way. 25 Example 217 2-Dimethylamino-N-{4-[2-oxo-3-(4-phenoxyphenyl)-2,3-dihydroimidazol 1 -yl]phenyl}acetamide Oa 0 N N \-/ 0 30 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.
84 After 10 minutes, Hbnig 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 5 bicarbonate solution, dried over magnesium sulfate and concentrated. The residue was purified by preparative HPLC. The product with the molecular weight of 428.50 (C 25
H
24
N
4 0 3 ); MS (ESI): 429 ([M+H]+) was obtained as hydrotrifluoroacetate in this way. 10 Example 218 N-{4-[2-Oxo-3-(4-phenoxyphenyl)-2,3-dihydroimidazol-1 -yl]phenyl} 2-piperidin-1 -ylacetamide 2-/ o 00 15 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 (C 2 8H 28
N
4 0 3 ); MS (ESI): 469 ([M+H]+) was obtained as hydrotrifluoroacetate in this way. 20 Example 219 3-Methylamino-N-{4-[2-oxo-3-(4-phenoxyphenyl)-2,3-dihydroimidazol 1 -yl]phenyl}propionamide O N N N 25 \- 0 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 (C 25
H
24
N
4 0 3 ); MS (ESI): 429 ([M+H]+) was obtained as hydrotrifluoroacetate in this way. 30 85 Example 220 3-(2-Methyl-4-nitroimidazol-1 -yl)-N-{ 4-[2-oxo-3-(4-phenoxyphenyl)-2,3 dihydroimidazol-1 -yI ] phenylpropionamide O A Na N NO \ o 5 I 1-(4-Aminophenyl)-3-(4-phenoxyphenyl)-1,3-dihydroimidazol-2-one was reacted with 2-methyl-4-nitrolmidazol-1-ylpropionic acid as described in example 217. The product with the molecular weight of 524.54 10 (C 28
H
24
N
6 0 5 ); MS (ESI): 524 ([M+H]+) was obtained in this way. Example 221 2-(2,5-Dioxolimidazolidin-1 -yl)-N-{4-[2-oxo-3-(4-phenoxyphenyl)-2,3 dihydroimidazol-1 -yl]phenyl}acetamide 15 0 0 ON NI N N -N 1-(4-Aminophenyl)-3-(4-phenoxyphenyl)-1,3-dihydroimidazol-2-one was reacted with 2,5-dioxoimidazolidin-1-ylacetic acid as described in example 20 217. The product with the molecular weight of 483.49 (C26H21N505); MS (ESI): 484 ([M+H]+) was obtained in this way. Example 222 Ethyl 1 -({4-[2-oxo-3-(4-phenoxyphenyl)-2,3-dihydroimidazol-1 -yl]phenyl 25 carbamoyl}ethyl)piperidine-4-carboxylate 0 0- 0 _ ) N0 ON N N O \ N 0 86 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 554.65
(C
32
H
34
N
4 0 5 ); MS (ESI): 555 ([M+H]+) was obtained as 5 hydrotrifluoroacetate in this way. Example 223 2-(Acetylmethylamino)-N-{4-[2-oxo-3-(4-phenoxyphenyl)-2,3-dihydro 10 imidazol-1 -yl]phenyl}acetamide 0IN 00 SNA N N Nj The product with the molecular weight of 428.50 (C 25
H
2 15 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 (C 26
H
24
N
4 0 4 ); MS (ESI): 457 ([M+H]+) was obtained as hydrotrifluoroacetate in this way.

Claims (21)

1. A compound of the formula I R1 W R5 N N R9 R2A N R- B 0 R8 R10 R4 R6 R3 R7 in which R is (Co-C8)-alkylene-aryl, (C3-C8)-cycloalkyl, (C1-C4)-alkoxy-(C1 10 C4)-alkyl, (C2-C8)-alkenyl, (C 2 -C8)-alkynyl;
3-12 membered mono-, bi- or spirocyclic ring which may comprise one or two heteroatoms from the group of N, 0 and S, and the 3-12 membered ring may have further substituents, with the proviso that 15 R is not tetrazolyl; B is a linker consisting of one or two radicals from the group (C(R19)(R20))i, C(OR21)(R22), 0, N(R23), S, SO, S02, CO; 20 i is 1, 2, 3; R19, R20, R21, R22, R23 are, independently of one another, H, (C1-C6)-alkyl, aryl; 25 R1, R2, R3, R4 are, independently of one another, H, F, Cl, Br, I, OH, CF3, N02, CN, OCF 3 , O-(C1-C6)-alkyl, O-(C1-C4)-alkoxy-(C1-C4) alkyl, S-(C-C6)alkyl, (C-C6)alkyl, (C2-C6)-alkenyl, (C3-C8) cycloalkyl, 0-(C3-C8)-cycloalkyl, (C3-C8)-cycloalkenyl, 0-(C3-C8) cycloalkenyl, (C2-C6)-alkynyl, (CO-C8)-alkylene-aryl, 0-(CO-C 8 ) 30 alkylene-aryl, S-aryl, N(R24)(R25), S02-CH3, CON(R26)(R27), N(R28)CO(R29), N(R30)SO2(R31), CO(R32); R24, R25, R26, R27, R28, R30 are, independently of one another, H, 88 (C1-C6)-alkyl; R29, R31, R32 are, independently of one another, H, (C1-C 6 )-alkyl, aryl; 5 W is -(CH2)n-, -CH=CH-, -CH=N-, -N=CH-; n is 2, 3, 4, 5; 10 R5, R6, R7, R8 are, independently of one another, H, F, CI, Br, I, OH, CF3, N02, CN, OCF3, 0-(C1-C6)-alkyl, 0-(C1-C 4 )-alkoxy-(C1-C4) alkyl, S-(C 1 -C6)-alkyl, (C1-C6)-alkyl, (C2-C6)-alkenyl, (C3-C8) cycloalkyl, 0-(C3-C8)-cycloalkyl, (C3-C8)-cycloalkenyl, 0-(C3-C8) cycloalkenyl, (C2-C6)-alkynyl, (CO-C8)-alkylene-aryl, 0-(CO-C8) 15 alkylene-aryl, S-aryl, N(R33)(R34), S02-CH3, CON(R35)(R36), N(R37)CO(R38), N(R39)SO 2 (R40), CO(R41), a 5-7 membered heterocycle having 1-4 heteroatoms from the group 0, N and S; 20 R33, R34 are, independently of one another, H, (C1-C6)-alkyl; or R33 and R34 form together with the nitrogen atom to which they are bonded a 5-6 membered ring, where in the case of the
6-membered ring one CH2 group may be replaced by 0 or S; 25 R35, R36, R37, R39 are, independently of one another, H, (C1-C6) alkyl; R38, R40, R41 are, independently of one another, H, (C1-C6)-alkyl, 30 aryl; A is a chain -(C(R42)(R43))m- in which 0-2 members may be replaced by an element from the group of 0, S, N(R44), CO, SO 2 ; 35 m is 2, 3, 4, 5; R42, R43, R44 are, independently of one another H, (C1-C6)-alkyl, aryl; 89 R9, R10 are, independently of one another, H, (C1-C 8 )-alkyl, -(CH2)o R45, (C1-C4)-alkoxy-(C1-C4)-alkyl, aryloxy-(C1-C4)-alkyl, (C 3 -C 8 ) alkenyl, (C3-C8)-alkynyl, CO-(C 1 -C)-alkyl, -CO-(CH2)o-R45, 5 CO-(C1-C4)-alkoxy-(Cl-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 which, apart from the nitrogen atom, may comprise 0 to 4 additional heteroatoms selected 10 from the group of oxygen, nitrogen and sulfur, where the heterocyclic ring system may additionally be substituted by F, Cl, Br, CF3, NO2, CN, (C-C6)alkyl, 0-(C-C8)alkyl, (C1-C4)-alkoxy-(C1 C4)-alkyl, (CO-C8)-alkylene-aryl, oxo, CO(R46), CON(R47)(R48), hydroxyl, COO(R49), N(R50)CO(C1-C6)-alkyl, N(R51)(R52) or 15 S02CH 3 ; R46, R47, R48, R49, R50, R51, R52 are, independently of one another, H, (C1-C6)-alkyl; 20 o is 0, 1, 2, 3, 4, 5, 6; R45 is OH, CH(aryl)2, 3-12 membered mono- or bicyclic ring which may comprise one or more heteroatoms from the group of N, 0 and S, and the 3-12 membered ring may comprise further 25 substituents such as F, Cl, Br, I, OH, CF3, N02, CN, OCF 3 , oxo, O-(C1-C6)-alkyl, (C1-C4)-alkoxy-(C1-C4)-alkyl, S-(C1-C6)-alkyl, (C1-C6)-alkyl, (C2-C6)-alkenyl, (C3-C8)-cycloalkyl, 0-(C 3 -C 8 ) cycloalkyl, (C3-C8)-cycloalkenyl, 0-(C3-C8)-cycloalkenyl, (C2-C6) alkynyl, (CO-C8)-alkylene-aryl, 0-(Co-C 8 )-alkylene-aryl, S-aryl, 30 N(R51)(R52), S0 2 -CH 3 and COOH; and the physiologically tolerated salts thereof. 2. A compound of formula I as claimed in claim 1, in which the further 35 substituents of the 3-12 membered ring in the definition for R are F, Cl, Br, N02, CF 3 , OCF3, CN, (C1-C6)-alkyl, aryl, CON(R11)(R12), N(R13)(R14), OH, 0-(C1 -C6)-alkyl, S-(C 1 -C6)-alkyl, N(R1 5)CO(C1 -C6)-alkyl, and 90 wherein R11, R1 2, R1 3, R1 4, R1 5 are, independently of one another, H, (C1-C6)-alkyl. 3. A compound of the formula I as claimed in claim 1, in which 5 R is (CO-C2)-alkylene-aryl, (C3-C8)-cycloalkyl, (C2-C6)-alkenyl, (C2 C6)-alkinyl; 3-7 numbered ring which may comprise one or two heteroatoms from the group of N, 0 and S, and the 3-7 membered ring may have further substituents, with the proviso that 10 R is not tetrazolyl; B is 0, S, SO2, CO, OCH(R20), N(R23), CH2, CH2CH2; R20, R23 are, independently of one another, H, (C1-C6)-alkyl; 15 R1, R2, R3, R4 are, independently of one another, H, F, Cl, Br, OH, CF3, N02, CN, OCF 3 , 0-(C1-C6)-alkyl, 0-(C 1 -C4)-alkoxy-(C1-C4) alkyl, S-(C1-C6)-alkyl, (C 1 -C6)-alkyl, (C0-C2)-alkylene-aryl, 0-(C0 C2)-alkylene-aryl, N(R24)(R25), S0 2 -CH3, CON(R26)(R27), 20 N(R28)CO(R29), CO(R32); R24, R25, R26, R27, R28, R30 are, independently of one another, H, (C1-C6)-alkyl; 25 R29, R32 are, independently of one another, H, (C1-C6)-alkyl, aryl; W is -(CH2)n, -CH=CH-, -CH=N-, -N=CH-; n is 2, 3, 4; 30 R5, R6, R7, R8 are, independently of one another, H, F, Cl, Br, OH, CF3, N02, CN, OCF3, 0-(C1-C6)-alkyl, (C1-C6)-alkyl, (CO-C2) alkylene-aryl, 0-(CO-C2)-alkylene-aryl, CO(R41); 35 R41 is (C1-C6)-alkyl, aryl; A is a chain -(C(R42)(R43))m- in which 0-2 members may be replaced by an element from the group of 0, N(R44), CO; 91 m is 2, 3, 4; R42, R43, R44 are, independently of one another, H, (C1-C6)-alkyl, 5 aryl; R9, R10 are, independently of one another, H, (C1-C8)-alkyl, (CH2)o R45, (C1-C4)-alkoxy-(C1-C4)-alkyl, aryloxy-(C1-C4)-alkyl, (C3-C8) alkenyl, (C3-C8)-alkynyl, CO-(C 1 -C8)-alkyl, -CO-(CH2)o-R45; or R9 10 and R10 form together with the nitrogen atom to which they are bonded a 4 to 10-membered mono-, bi- or spirocyclic ring which, apart from the nitrogen atom, may comprise 0 to 2 additional heteroatoms selected from the group of oxygen, nitrogen and sulfur, where the heterocyclic ring system may additionally be 15 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), hydroxyl, COO(R49), N(R50)CO(C1-C6)-alkyl, N(R51)(R52) or SO2CH3; 20 R46, R47, R 48, R49, R50, R51, R52 are, independently of one another, H, (C1-C6)-alkyl; o is 0, 1, 2, 3, 4; 25 R45 is OH, 3-12 membered mono- or bicyclic ring which may comprise one or two heteroatoms from the group of N, 0 and S, and the 3-12 membered ring may comprise further substituents such as F, Cl, Br, OH, CF 3 , NO 2 , CN, OCF3, oxo, O-(C1-C6)-alkyl, (01-06) alkyl, (C2-C6)-alkenyl, (CO-C2)-alkylene-aryl, 0-(C-C2)-alkylene 30 aryl, N(R51)(R52), S0 2 -CH3 and COOH; and the physiologically tolerated salts thereof. 4. A compound of the formula I as claimed in claim 2, in which the further 35 substituents of the 3-12 membered ring in the definition for R are F, Cl, Br, N02, CF3, OCF3, CN, (C1-06)-alkyl, CON(R11)(R12), N(R13)(R14), OH, 0-(C1-C6)-alkyl, N(R15)CO(C1-C6)-alkyl, and 92 wherein R11, R1 2, R1 3, R1 4, R1 5 are, independently of one another, H, (C1-C6)-alkyl. 5. A compound of the formula I as claimed in claims 1 to 2, in which 5 R is (C3-C8)-cycloalkyl; 5-6 membered ring which may comprise one or two heteroatoms from the group of N, 0 and S, and the 5-6 membered ring may have further substituents such as F, Cl, Br, N02, CF3, OCF3, CN, 10 (C1-C6)-alkyl, 0-(C1-C6)-alkyl; B is 0, S, CO, OCH2, N(R23), CH2; R23 is H, (C1-C6)-alkyl; 15 R1, R2, R3, R4 are, independently of one another, H, F, Cl, Br, CF 3 , 0 (C1-C6)-alkyl; (C1-C6)-alkyl; W is -CH=CH-, -N=CH-; 20 R5, R6, R7, R8 are, independently of one another, H, F, Cl, Br, OH, CF3, N02, CN, OCF3, O-(C 1 -C6)-alkyl; A is a chain -(C(R42)(R43))m-, in which one member may be 25 replaced an element from the group of 0, N(R44); m is 3, 4; R42, R43, R44 are, independently of one another, H, (C1-C6)-alkyl, 30 aryl; R9, R10 are, independently of one another, H, (C-C8)-alkyl, -(CH2)o R45, CO-(C1-C8)-alkyl; or R9 and R10 form together with the nitrogen atom to which they are bonded a 4 to 10-membered 35 mono-, bi- or spirocyclic ring which, apart from the nitrogen, may comprise 0 to 2 additional heteroatoms selected from the group of oxygen, nitrogen and sulfur, where the heterocyclic ring system may additionally be substituted by F, (C1-C6)-alkyl, 0-(C1-C8)- 93 alkyl, oxo, CO(R46), CON(R47)(R48), hydroxyl, N(R50)CO(C1 C6)-alkyl or N(R51)(R52); R46, R47, R48, R50, R51, R52 are, independently of one another, H, 5 (C1-C6)-alkyl; o is 0, 1, 2, 3, 4; R45 is OH, 5-10 membered mono- or bicyclic ring which may comprise 10 one or two heteroatoms from the group of N, 0 and S, and the 3-12 membered ring may comprise further substituents such as F, Cl, Br, OH, CF3, oxo, 0-(C1-C6)-alkyl, (C1-C6)-alkyl, (Co-C 2 ) alkylene-aryl, 0-(C0-C2)-alkylene-aryl, or N(R51)(R52). 15 6. A compound of the formula I as claimed in claims 1 to 5, in which W is -C=C-.
7. A compound of the formula I as claimed in claims 1 to 5, in which 20 m is 3; R42, R43, R44 are H.
8. A compound of the formula I as claimed in claims 1 to 5, in which 25 R5, R6, R7, R8 is hydrogen.
9. A compound of the formula I as claimed in claims 1 to 5, in which 30 A and B are each disposed in the para position relative to the central heterocycle.
10. A compound of the formula I as claimed in claim 1 and which is substantially as hereinbefore described with reference to the 35 Examples.
11. A medicament comprising one or more of the compounds as claimed in any one of claims 1 to 10. 94
12. A medicament comprising one or more of the compounds as claimed in any one of claims 1 to 10 and one or more anorectic active ingredients. 5
13. A pharmaceutical composition comprising a compound as claimed in any one of claims 1 to 10 together with a pharmaceutically suitable carrier. 10 14. The pharmaceutical composition as claimed in claim 13 further comprising one or more anorectic active ingredients.
15. A process for producing a medicament comprising any one or more of the compounds as claimed in claims 1 to 9, which process comprises 15 mixing the active ingredient with a pharmaceutically suitable carrier and converting this mixture into a form suitable for administration.
16. The use of a compound as claimed in any one of claims 1 to 10 for producing a medicament for weight reduction in mammals. 20
17. The use of a compound as claimed in any one of claims 1 to 10 for producing a medicament for the prophylaxis or treatment of obesity.
18. The use of a compound as claimed in any one of claims 1 to 10 for 25 producing a medicament for the prophylaxis or treatment of type 11 diabetes.
19. The use of a compound as claimed in any one of claims 1 to 10 for producing a medicament for the treatment of disturbances of wellbeing 30 and other psychiatric indications.
20. The use according to any one of claims 16 to 19 wherein the compound is used in combination with at least one other anorectic active ingredient. 35
21. A method for weight reduction in mammals, which method comprises administering to the mammal a therapeutically effective amount of a compound of the formula I as claimed in any one of claims 1 to 10 or of 95 a pharmaceutical composition as claimed in claim 13.
22. A method for weight reduction in mammals, which method comprises administering to the mammal a therapeutically effective amount of a 5 compound of the formula I as claimed in any one of claims 1 to 10 together with one or more anorectic active ingredients or of a pharmaceutical composition as claimed in claim 14.
23. A method for the prophylaxis and/or treatment of obesity or type II 10 diabetes in mammals, which method comprises administering to the mammal a therapeutically effective amount of a compound of the formula I as claimed in any one of claims 1 to 10 or of a pharmaceutical composition as claimed in claim 13. 15 24. A method for the prophylaxis and/or treatment of obesity or type 11 diabetes in mammals, which method comprises administering to the mammal a therapeutically effective amount of a compound of the formula I as claimed in any one of claims 1 to 10 together with one or more anorectic active ingredients or of a pharmaceutical composition 20 as claimed in claim 14.
25. A method for the treatment of disturbances of wellbeing and other psychiatric disturbances, which method comprises administering to the mammal a therapeutically effective amount of a compound of the 25 formula I as claimed in any one of claims 1 to 10 or of a pharmaceutical composition as claimed in claim 13.
26. A method for the treatment of disturbances of wellbeing and other psychiatric disturbances, which method comprises administering to the 30 mammal a therapeutically effective amount of a compound of the formula I as claimed in any one of claims 1 to 10 together with one or more anorectic active ingredients or of a pharmaceutical composition as claimed in claim 14. 35 SANOFI-AVENTIS DEUTSCHLAND GMBH WATERMARK PATENT & TRADE MARK ATTORNEYS P25150AUO0
AU2003251001A 2002-07-25 2003-07-18 Diaryl-substituted cyclic urea derivatives having an MCH-modulatory effect Ceased AU2003251001B9 (en)

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