Title of Invention

SUBSTITUTED 3-PHENYL-5-ALKOXI-1,3,4-OXDIAZOL-2-ONE AND USE THEREOF FOR INHIBITING HORMONE-SENSITIVE LIPASE

Abstract

The invention relates to substituted 3-phenyl-5-alkoxi-I,3,4-oxdiazol-2-ones of formula (I), wherein R 1 means substituted C1-C6 -alkyl and C3 and C9-cycloalkyl, R2, R3, R4 and Rs mean hydrogen,nitro, C1-C4-alkyl, C1-C9-alkyloxy, substituted C6-C1o-aryl- C1-C4-alkyloxy, C6-C1o-aryl,C3-Cg-cycloalkyl or O-C3-Cg-cycloalkyl or 2-oxo-pyrrolidin- I-yl, 2,5-dimethypyrrol-l-yl or NR6_A-R-7, on the condition that R2, R3, R4 and Rs do not mean simultaneously mean hydrogen and at least one of the radicals R2, R3, R4 or RS represents the radical 2-oxo-pyrrolidin-l-yl,2,5-dimethylpyttol-l-yl orNR6-A-R7, with R6 = hydrogen, C1-C4-alkyl or substituted C6-C1o-aryl-C1-C4-alkyl, A = a simple bond,Con, Son or CONH, n = 1 or 2 R 7 = hydrogen, substituted C1-C1g-alkyl, C2-C1g-alkenyl, C6-C1O- aryl-C I-C4-alkyl, CS-Cg-cycloalkyl-C I-C4-alkyl, CS-Cg-cycloalkyl, C6-C1o-aryl-C2-C6- alkenyl, C6-C1O-aryl, diphenyl, diphenyl-C1-C4-alkyl, indanyl or he group Het-(CH2), with r = 0, I, 2 or 3 and Het = a saturated and unsaturated 5-7 membered heterocycle which can be benzoanellated and substituted. The invention also relates to a method for producing the same. The inventive compounds have an inhibitory effect on hormones- sensitive lipase, HSL

Full Text

The invention relates to substituted 3-phenyl-5-alkoxy-1,3,4-oxdiazol-2-ones which show an inhibitory effect on hormone-sensitive lipase, HSL. Certain 5-alkoxy-1,3,4-oxdiazol-2-ones with an ortho-substituted phenyl ring as substituent or with fused-on five- or six-membered rings have anthelmintic (DE-A 26 04 110) and insecticidal effects (DE-A 26 03 877, EP-B 0 048 040, EP-B 0 067 471). "Certain 5-phenoxy-1,3,4-oxdiazol-2-ones with an ortho-substituied phenyl ring as substituents show an endoparasiticidal effect (EP-A 0 419 918). The aim of the invention was now to find compounds which show an inhibitory effect on hormone-sensitive lipase, HSL. or the group Het-(CH2),-, substituted by Ci-Cj-alkyl or halogen. Additionally preferred compounds of the formula 1 are those in which: R4 is hydrogen, 2-oxopyrrolidin-1-yl, 2,5-dimethylpyrrol-1-yl or C6-Ci0-aryl-Ci-C4-a!kyloxy which may be substituted by halogen, and/or compounds of the formula 1 in which: R4 is NR6-A-R7, with R6 = hydrogen or methyl, A = single bond and R7 - hydrogen; Ci-Ci2-alkyl which may be substituted once or twice by halogen; C2-CiB-aIkenyl which may be substituted once or twice by CrC4-alkyl or Ci-C4-alkyloxycarbonyl; C6-Cio-aryl-Ci-C4-alkyl which may be substituted by halogen, d-Cg-alkyloxy, CF3, cyano, C5-C6-cycloalkyl, CrC4-alkyloxycarbonyl, C6-C10-aryl-C--C4-aikyl, Ce-Cicraryl-Ci-C4-alkyloxy, where aryl may again be substituted by halogen or CF3; C5-C8-cycloalkyl-CrC4-alkyl; or the group Het-(CH2)r, with r = 1, 2 or 3 and Het = saturated or unsaturated 5-7-membered heterocycle which may be substituted by halogen, C-i-C4-alkyloxy or Ci-C4-alkyloxycarbonyl, and/or compounds of the formula 1 in which: R4 is NR6-A-R7, with R6 = hydrogen, A = -CO-and R7 = Ci-Cie-alkyI which may be substituted by halogen, phenyl, phenoxy, phenylcarbonyl or Ci-C4-alkyloxycarbonyl, where phenoxy in turn may be substituted by methyl, halogen or methylmercapto; C2-Cie-alkenyl which may be substituted by C6-Cto-aryl; Ce-Cio-aryl which may be substituted by halogen, Ci-C8-alkyl, phenyl- CrC4-alkyl, CF3, OCF3, fluorosulfonyl, C1-C4-a!kyloxycarbonyl, phenoxy, where aryl in turn may be substituted by CrC4-alkyloxy; C6-Cio-aryl-CrC4-alkyl where alkyl may be substituted by methoxy or CF3 and aryl by halogen; or the group Het-(CH2)r, with r = 0 and Het = saturated or unsaturated 5-7-membered heterocycle which may be benzo-fused and substituted by Ci-C Ci-C4-alkyloxy, halophenyl or halobenzylmercapto, where benzo-fused aryl may in turn be substituted by halogen or methoxy, and/or compounds of the formula 1 in which: R4 is NR6-A-R7, with R6 = hydrogen, A = -C02- and R7 = Ci-Cia-alkyl which is substituted by CF3 or phenyl; C6-Cio-aryl; C6-Cio-aryl-CrC4-alkyl which is substituted by d-Ct-alkyl, halogen, CFsor OCF3, benzyloxy or phenyl; or the group Het-(CH2)r, with r = 0 or 1 and Het = saturated or unsaturated 5-7-membered heterocycle which may be benzo-fused and substituted by d-Oralkyl or benzyl, and/or R4 is NR6-A-R7, with R6 = hydrogen, A = -SO2- and R7 = Ci-C6-alkyl which may be substituted by CF3; C2-C4-alkenyl which may be substituted by phenyl; C6-Cio-aryl which may be substituted by Ci-CB-alkyl, halogen, Ci-C4-alkyloxy or benzyl; diphenyl-C 1-C.t-alkyl substituted by halogen; or the group Het-(CH2)r, with r = 0 and Het = saturated or unsaturated 5-7-membered heterocycle, and/or compounds of the formula 1 in which: R4 is NR6-A-R7, with R6 = hydrogen, damage to the pancreas. For example, substituted 3-phenyl-5-alkoxy-1,3,4-oxadiazol-2-ones of the formula 1 can be prepared by reacting hydrazines of the formula 2 with chloroformic esters of the formula 3 or other reactive carbonic ester derivatives, in which R1, R2, R3, R* and R5 are as defined above, to give the compounds of the formula 4, which are acylated with phosgene, carbonyldiimidazole, diphosgene or triphosgene, cyclized and converted where appropriate by further chemical modification of the radicals R2-R5, such as, for example, by reduction of nitro to amino radicals by known processes, and subsequent acylation or alkylation, into compounds of the formula 1. Since acids are usually liberated in these reactions, promotion is advisable by adding bases such as pyridine, triethylamine, sodium hydroxyde solution or alkali metal carbonates. The reactions can be carried out in wide temperature ranges. It has proved advantageous as a rule to operate at 0°C to the boiling point of the solvent used. Examples of solvents employed are methylene chloride, THF, DMF, toluene, ethyl acetate, n-heptane, dioxane, diethyl ether. The hydrazines of the formula 2 can be prepared by known methods, for example by diazotization of the corresponding anilines and subsequent reduction by known methods or by nucleophific substitution of suitably substituted phenyl derivatives 6 (X = F, CI, Br, I, OS02CF3) with hydrazine hydrate. Such suitable phenyl derivatives may be nitro-substituted halobenzenes, preferably fluoro- and chloronitrobenzenes, from which the compounds of the invention can be prepared by known methods at a suitable point in the synthetic route by reduction and reaction with acylating or alkylating agents such as, for example, acid chlorides, anhydrides, isocyanates, chloroformic esters, sulfonyl chlorides or alkyl and arylalkyl halides, or by reductive alkylation with aldehydes. The effect of the compounds of the invention, of the formula 1, was tested using the following enzyme assay system: Enzyme preparation: Preparation of partially purified HSL: Isolated rat fat cells are obtained from epididymal adipose tissue from untreated male rats (Wistar, 220-250 g) by collagenase treatment according to published methods (e.g. S. Nilsson et al., Anal. Biochem. 158,1986, 399 - 407; G. Fredrikson etal., J. Biol. Chem. 256,1981,6311 -6320; H. Tornquistet al., J. Biol. Chem. 251, 1976, 813 - 819). The fat cells from 10 rats are washed three times by flotation with 50 ml each time of homogenization buffer (25 ml tris/HCI, pH 7.4, 0.25 M sucrose, 1 mM EDTA, 1 mM DTT, 10 ug/ml leupeptin, 10 ug/ml antipain, 20 ug/ml pepstatin) and finally taken up in 10 ml of homogenization buffer. The fat cells are homogenized in a Teflon-in-glass homogenizer (Braun-Melsungen) by 10 strokes at 1 500 rpm and 15°C. The homogenate is centrifuged (Sorvall SM24 tubes, 5 000 rpm, 10 min, 4°C). The subnatant between the fatty layer at the top and the pellet is removed and the centrifugation is repeated. The subnatant resulting therefrom is recentrifuged (Sorvall SM24 tubes, 20 000 rpm, 45 min, 4°C). The subnatant is removed and mixed with 1 g of heparin-Sepharose (Pharmacia-Biotech, CL-6B, 5 x washed with 25 mM tris/HCI, pH 7.4, 150 mM NaCI). After the mixture has been incubated at 4°C for 60 min (shaking at 15-min intervals), it is centrifuged (Sorvall SM24 tubes, 3 000 rpm, 10 min, 4°C). The supernatant is adjusted to pH 5.2 by adding glacial acetic acid and incubated at 4°C for 30 min. The precipitates are collected by centrifugation (Sorvall SS34,12 000 rpm, 10 min, 4°C) and suspended in 2.5 ml of 20 mM tris/HCI, pH 7.0, 1 mM EDTA, 65 mM NaCI, 13% sucrose, 1 mM DTT, 10 ug/ml leupeptin/pepstatin/antipain. The suspension is dialyzed against 25 mM tris/HCI, pH 7.4, 50% glycerol, 1 mM DTT, 10 ug/ml leupepttn, pepstatin, antipain at 4°C overnight and then loaded onto a hydroxy apatite column (0.1 g per 1 ml of-suspension, equilibrated with 10 mM potassium phosphate, pH 7.0, 30% glycerol, 1 mM DTT). The column is washed with four volumes of equilibration buffer at a flow rate of 20 to 30 ml/h. The HSL is etuted with one volume of equilibration buffer containing 0.5 M potassium phosphate, and then dialyzed (see above) and concentrated 5- to 10-fold by ultrafiltration (Amicon Diaflo PM 10 filter) at 4°C. The partially purified HSL can be stored at -70°C for 4 to 6 weeks. Assay: To prepare the substrate, 25-50 pCi of [3H]trioleoylg!ycerol (in toluene), 6.8 umol of unlabeled trioleoylglycerol and 0.6 mg of phospholipids (phosphatidylcholine/ phosphatidylinositol 3:1 w/v) are mixed, dried with N2 and then taken up in 2 ml of 0.1 M KPi (pH 7.0) by ultrasonic treatment (Branson 250, microtip, setting 1 -2, 2 x 1 min at 1-min intervals). After addition of 1 ml of KPi and renewed ultrasonic treatment (4 x 30 sec on ice in 30-sec intervals), 1 ml of 20% BSA (in KPi) is added (final concentration of trioleoylglycerol 1.7 mM). For the reaction, 100 pi of substrate solution are pipetted into 100 ul of HSL solution (HSL prepared as above, diluted in 20 mM KPi, pH 7.0, 1 mM EDTA, 1 mM DTT, 0.02% BSA, 20 ug/ml pepstatin, 10 ug/ml leupeptin) and incubated at 37°C for 30 min. Addition of 3.25 ml of methanol/chloroform/heptane (10:9:7) and of 1.05 ml of 0.1 M K2C03, 0.1 M boric acid (pH 10.5) is followed by thorough mixing and finally centrifugation (800 x g, 20 min). After phase separation, one equivalent of the upper phase (1 ml) is removed and the radioactivity is determined by liquid scintillation measurement. Evaluation: Examples: Example 1: 3-Methyl-4-nitrophenylhydrazine 5 g of hydrazine hydrate are slowly added dropwise to a solution of 15.9 g of 2-methyl-4-fluoronitrobenzene in 10 ml of N-methylpyrrolidone at room temperature, and the mixture is heated with stirring at 65°C for 4 hours. The product is precipitated by adding 70 ml of water and is filtered off with suction and recrystallized from isopropanol. Yield:13.3g m.p.:138°C The following examples were prepared in an analogous way: Example 2: 3-Fluoro-4-nitrophenylhydrazine M.p.: 130°C Example 3: 2-Chloro-4-nitrophenylhydrazine M.p.:144°C Example 4: 2 -Methyi-4-nitropheny (hydrazine M.p.:135°C Example 5: 3-(4-Fluorobenzyloxy)-2-nitrophenylhydrazine M.p.:164°C The starting compound 2-fluoro-4-(4-fluorobenzyloxy)nitrobenzene (m.p.: 99°C) was prepared by alkylation of 3-fluoro-4-nitrophenol with 4-fluorobenzyl chloride in DMF in the presence of potassium carbonate. Example 6: 3-(4-Fluorobenzyloxy)-4-nitropheny I hydrazine (intermediate) M.p.: 145°C Example 7: 4-(4-Chlorophenoxy)-3-nitroaniiine 1.4 g of potassium carbonate are added to a solution of 1.29 g of 4-chlorophenol in 8 ml of DMF and, after stirring for 30 minutes, 1.6 g of 4-fluoro-3-nitroaniline are added, and the mixture is stirred at 100°C for 3 hours. After cooling, 80 ml of water are added and, after briefly stirring, the precipitate is filtered off with suction and dried in vacuo at 40°C. Yield: 2.0 g; m.p.: 101°C Example 8: 4-{4-Chlorophenoxy)-3-nitrophenylhydrazine A solution of 0.52 g of sodium nitrite in 5 ml of water is added dropwise to a stirred mixture consisting of 1.9 g of 4-(4-chlorophenoxy)-3-nitroaniline, 25 ml of concentrated hydrochloric acid and 25 ml of ethanol cooled to 0°C, and the mixture is then stirred at 0°C for 60 min and subsequently added dropwise to a suspension of 8.5 g of tin dichloride dihydrate in 8 ml of concentrated HCI. The precipitate is filtered off with suction, washed with water, suspended in 200 mt of water under nitrogen and decomposed with 100 ml of 30% strength sodium hydroxide solution at 10-15°C. The oil which forms is extracted by shaking with ethyl acetate and washed with water, and the organic phase is dried with sodium sulfate. The product is then precipitated with isopropanolic HCI, filtered off with suction and dried in vacuo. Yield: 1.1 g; m.p.: 221°C Example 9: Methyl N"-{4-nitro-2-methylphenyl)hydrazinoformate 0.43 ml of methyl chloroformate was cautiously added dropwise to a mixtare consisting of 0.84 g of 2-methyl-4-nitrophenylhydrazine, 15 ml of NMP and 2 ml of pyridine while cooling in ice, and the mixture was then stirred for 2 hours while slowly warming to RT. After dilution with 50 ml of water, the mixture was sitrred over night and the solid was dried in vacuo at 40°C. Yield: 0.81 g; m.p.:153°C The following examples were prepared in an analogous way: Example 10: Methyl N"-(4-nitrophenyl)hydrazinoformate (intermediate) M.p.: 179X Example 11: Methyl N"-{3-fluoro-4-nitrophenyl)hydrazinoformate M.p.: 127.4°C Example 12: Methyl N"-(3-methyl-4-nitrophenyl)hydrazinoforrnate M.p.: 159°C Example 13: Methyl N"-(2-chloro-4-nitrophenyl)hydrazinoformate M.p.:156°C Example 14: Methyl N"-(3-(4-fluorobenzyloxy)-4-nitrophenyl)hydrazinoformate (intermediate) M.p.: 166°C Example 15: Methyl N"-(3-(4-fluorobenzyloxy)-2-nitrophenyl)hydrazinoformate M.p.: 193DC Example 16: Methyl N"-(4-(4-chlorophenoxy)-3-nitrophenyl)hydrazinoformate M.p.: 147°C Example 17: Methyl N"-(3-piperidmo-4-nitrophenyl)hydrazinoformate (-) M.p.: 131°C The latter compound and the compound of Example 18 were prepared by reacting methyl N"-{3-fluoro-4-nitrophenyl)hydrazinoformate with piperidine and N-benzyl-piperazine, respectively, in NMP at 80°C. Example 18: Methyl >T-(3-(N-benzylpiperazino)-4-nitrophenyl)hydrazinoformate M.p.: 156°C Example 19: 5-Methoxy-3-(4-nitrophenyl)-3-H-(1,3,4)oxdiazol-2-one 2.5 g of methyl N"-(4-nitrophenyl)hydrazinoformate and 5 ml of pyridine were taken up in 15 ml of methylene chloride and, while stirring and cooling in ice. 3 ml of a 20% strength solution of phosgene in toluene were added dropwise. This mixture was left to stand at room temperature over night and was diluted with a further 10 ml of methylene chloride and then washed 3 times with water. After drying over sodium sulfate, the mixture was concentrated in vacuo, and the product was purified by column chromatography (silica gel, solvents: methanol:methylene chloride = 2:98) and recrystallized from isopropanol. Yield: 1.5 g m.p.: 151DC The following examples were prepared in analogy to Example 4: Example 20: 5-Methoxy-3-(3-methy!-4-nitrophenyl)-3-H-(1,3,4)oxdtazol-2-one M.p.: 112DC Example 21: 5-Methoxy-3-(4-(4-chlorophenoxy-3-nitrophenyl)-3-H-(1,3,4)oxdiazol-2-one M.p.: oil Example 22: 5-Methoxy-3-(3-(4-fluorobenzyloxy)-2-nitrophenyl)-3-H-(1,3,4)oxdiazol-2-one M.p.: 99°C Example 23: 5-Methoxy-3-(2-methyl-4-nitrophenyl)-3-H-(1,3,4)oxdiazol-2-one M.p.: m°C Example 24: 5-Methoxy-3-(3-(4-fluorobenzyloxy)-4-nitrophenyl)-3-H-(1,3,4)oxdiazol-2-one M.p.: 137°C Example 25: 5-Methoxy-3-(4-aminophenyl)-3-H-{1,3,4)oxdiazol-2-one A mixture consisting of 1.4 g of 5-methoxy-3-(4-nftrophenyI)-3-H-(1,3l4)oxdia2ol- 2-one, 0.5 g of Pd/C and 20ml of methanol is hydrogenated under atmospheric pressure at room temperature until the calculated amount of hydrogen has been taken up. The catalyst is then filtered off, and the solution is concentrated in vacuo. The remaining semisolid residue is stirred with isopropanol and filtered off with suction. Yield: 0.75g; m.p.: 85°C Example 26: 5-Methoxy-3-(2-amino-4-(4-fluorobenzyloxy)phenyl)-3-H-(1,3,4)oxdiazol-2-one M.p.: oil Example 27: 5-Methoxy-3-(3-amino-4-{4-chlorophenoxy)phenyl)-3-H-(1,3,4)oxdiazol-2-one M.p.:133°C Example 28: 5-Methoxy-3-(4-amino-3-methylphenyl)-3-H-(1,3,4)oxdiazol-2-one M.p.: 114°C Example 29: 5-Methoxy-3-(4-amino-3-(4-fluorobenzyloxy)phenyl)-3-H-(1,3,4)oxdiazol-2-one M.p.: 195°C Example 30: 5-Methoxy-3-(4-(4-chlorophenylacetylamino)phenyI)-3-H-(1,3,4)oxdiazol-2-one 201 mg of 4-chlorophenylacetyl chloride are added dropwise to a mixture consisting of 200 mg of 5-methoxy-3-(4-aminophenyl)-3-H-(1,3,4)oxdiazol-2-one, 20 ml of methylene chloride and 0.1 ml of pyridine cooled in ice, and the mixture is stirred at room temperature for 5 hours. Volatiles are removed in vacuo, and the residue is stirred with water and the solid is filtered off with suction and dried at 40°C in vacuo. Yield: 318 mg; m.p.:161°C The following examples were prepared in an analogous way: Example 31: 5-Methoxy-3-(4-(4-chlorophenylacetylamino)-3-methylphenyl)-3-H-(1,3,4)oxdiazol- 2-one M.p.:190°C Example 32: 5-Methoxy-3-{4-octanoylamino-3-methylphenyl)-3-H-(1,3,4)oxdiazol-2-one M.p.:110°C Example 33: 5-Methoxy-3-(4-(4-heptylbenzoylamino)phenyl)-3-H-(1,3,4)oxdiazol-2-one M.p.; 155°C Example 34: 5-Methoxy-3-(4-(4-butylphenylsulfonylamino)phenyl)-3-H-(1,3,4)oxdia20l-2-one M.p.: 135°C Example 35: 5-Methoxy-3-(4-(4-chlorobutanoylamino)-3-methylphenyl)-3-H-(1,3,4)oxdiazol-2-one M.p.: 137°C Example 36: 5-Methoxy-3-(4-piva!oylamino-3-methylphenyl)-3-H-(1,3,4)oxdiazol-2-one M.p.: 157°C Example 37: 5-Methoxy-3-(4-(4-chlorophenylsulfonylamino)-3-methy|phenyl)-3-H-(1,3,4)oxdiazol- 2-one M.p.: 147°C Example 38: 5-Methoxy-3-{4-(1-naphthylsulfonylamino)-3-methylphenyl)-3-H-(1,3,4)oxdiazoi-2- one M.p.: 123°C Example 39: 5-Methoxy-3-(4-(2-phenylethenylsulfonylamino)-3-methylphenyI)-3-H-(1,3,4)oxdiazol-2-one M.p.: 129°C Example 40: 5-Methoxy-3-(4-{2,2,2-trifluoroethylsulfonylamino)-3-methylphenyl)-3-H-(1,3,4)oxdiazol-2-one M.p.: 151°C Example 41: 5-Methoxy-3-(4-(benzyloxycarbonylamino)-3-methylphenyl)-3-H-(1,3,4)oxdiazol-2-one M.p.: 115°C Example 42: 5-Methoxy-3-(4-(3,4-dichlorophenylaminocarbonylamino)-3-methylphenyl)-3-H- (1,3,4)oxdiazol-2-one M.p.: 210°C The latter compound was obtained by reacting 5-methoxy-3-(4-amino-3-methyl-phenyl)-3-H-(1,3,4)oxdiazol-2-one with equimolar amounts of 3,4-dichlorophenyl isocyanate in toluene at 50°C. Example 43: 5-Methoxy-3-(4-(4-chlorophenylsu!fonylamino)pheny!)-3-H-(1,3,4)oxdiazol-2-one M.p.: 169°C Example 44: 5-Methoxy-3-(4-(2-chlorophenylsulfonylamino)phenyl)-3-H-(1,3,4)oxdiazol-2-one M.p.: 171°C Example 45: 5-Methoxy-3-(4-(3-chlorophenylsulfonylamino)phenyl)-3-H-(1,3,4)oxdiazol-2-one M.p.: 141"C Example 46: 5-Methoxy-3-(4-(4-chlorophenylacetylamino)-3-(4-fluorobenzyloxy)phenyl)-3-H-(1,3,4)oxdiazol-2-one M.p.: 167°C Example 47: 5-Methoxy-3-(4-benzylsulfonylaminophenyl)-3-H-(1,3,4)oxdiazol-2-one M.p.: 153°C Example 48: 5-Methoxy-3-(4-(-2-(4"-chlorobiphenyl)ethyl)sulfonylamino)phenyl)-3-H-(1 .S^Joxdiazol^-one M.p.; 165°C Example 49: 5-Methoxy-3-(4-isopropylsulfonylaminophenyl)-3-H-(1,3,4)oxdiazol-2-one M.p.; 190"C Example 50: 5-Methoxy-3-(4-dimethylamino-3-methylphenyl)-3-H-(1,3,4)oxdiazol-2-one M.p.:71°C The latter compound was obtained by reacting 5-methoxy-3-{4-amino-3-methyl-phenyl)-3-H-(1,3,4)oxdiazol-2-one with paraformaldehyde/formic acid in DMF at room temperature and was purified by column chromatography (silica gel, ethyl acetate:n-heptane = 1:1). Example 51: 5-Methoxy-3-(4-(4-chlorobenzylamino)-3-methylphenyl)-3-H-(1,3,4)oxdiazol-2-one M.p.: oil The latter compound was obtained by reacting 5-methoxy-3-(4-amino-3-methyl-phenyl)-3-H-(1,3,4)oxdiazol-2-one with 4-chlorobenzaldehyde/sodium borohydride in methanol/methylene chloride at room temperature and was purified by column chromatography (silica get, ethyi acetate:n-heptane = 1:1). Example 52: 5-Methoxy-3-(4-(2-oxopyrrolidin-1-yl)-3-methylphenyl)-3-H-(1,3,4)oxdiazol-2-one M.p.: oil The latter compound was prepared by reacting 5-methoxy-3-(4-(4-chlorobutanoylamino)-3-methylphenyl)-3-H-(1,3,4)oxdiazol-2-one with sodium hydride in dioxane at room temperature and purifying the crude product by column chromatography (siilca gel, methylene chloride:methanol = 98:2). Example 53: 5-Methoxy-3-(4-(4-oxopent-2-en-2-ylamino)-3-methylphenyi)-3-H-(1,3,4)oxdia2ol-2-o ne M.p.: 143°C The latter compound was obtained by reacting 5-methoxy-3-(4-amino-3-methyl-phenyl)-3-H-(1,3,4)oxdia20l-2-one with equimolar amounts of acetylacetone in glacial acetic acid at 80°C and was isolated by precipitation by adding water and filtration. Example 54: 5-Methoxy-3-(4-(2,5-dimethylpyrrol-1-yl)-3-methylphenyl)-3-H-(1,3,4)oxdiazol-2-one M.p.: oil The latter compound was obtained by reacting 5-methoxy-3-(4-amino-3-methyl-phenyl)-3-H-(1,3,4)oxdiazol-2-one with equimolar amounts of acetonylacetone in glacial acetic acid at 80CC. Working up took place by dilution with water, extraction by shaking with ethyl acetate and column chromatography (silica gel, methylene chloride) of the crude product obtained after concentration of the dried organic phase. Example 55: 5-Methoxy-3-(3-(4-fluorobenzyloxy)-4-methylaminophenyl)-3-H-(1,3,4)oxdia20l-2-one M.p.: 98°C The latter compound was obtained as by-product of the hydrogenation of 5-methoxy-3-{3-(4-fluorobenzyloxy)-4-nitrophenyl)-3-H-(1,3,4)oxdiazol-2-one with platinum dioxide as catalyst in methanol at room temperature under atmospheric pressure and after filtering off the catalyst, concentrating the reaction mixture and column chromatography (silica gel, methylene chloride). The compounds of Examples 56-199 were prepared analogously to the previous examples. Example 56: 5-Methoxy-3-(3-aminophenyl)-3-H-(1,3,4)oxdiazol-2-one M.p.: 95°C Example 57: 5-Methoxy-3-(3-dibenzylaminophenyl)-3-H-(t,3,4)oxdiazol-2-one M.p.:71°C Example 58: 5-Methoxy-3-(3-benzylaminophenyl)-3-H-(1,3,4)oxdiazol-2-one M.p.: oil Example 59: 5-Methoxy-3-(4-(pyrid-2-y[)aminocarbonylaminophenyl)-3-H-(1,3,4)oxdiazol-2-one M.p.:81°C Example 60: 5-Methoxy-3-(3-{4-fluorobenzyloxy)-4-benzyloxycarbonylaminophenyl)-3-H-(1,3,4)oxdiazol-2-one M.p.: oil Example 61: 5-Methoxy-3-(4-amino-2-methylphenyl)-3-H-(1,3,4)oxdiazol-2-one M.p.: oil Example 62: 5-Methoxy-3-{3-methyl-4-(2-chlorobenzyloxycarbonylamino)phenyl)-3-H- (1,3,4)oxdiazol-2-one M.p.: 161°C Example 63: 5-Methoxy-3-(4-amino-2-chlorophenyi)-3-H-(1,3,4)oxdiazol-2-one M.p.: 126°C Example 64: 5-Methoxy-3-(2-chloro-4-nitrophenyt)-3-H Example 65: 5-Methoxy-3-(2-methyl-4-benzyloxycarbonylaminophenyl)-3-H-(1,3,4)oxdiazol-2-one M.p.: 112°C Example 66: 5-Methoxy-3-(2-methyl-4-(4-trifluoromethoxybenzoylamino)phenyl)-3-H-(1,3,4)oxdiazol-2-one M.p.: 150°C Example 67: 5-Methoxy-3-(2-chloro-4-benzyloxycarbonylaminophenyr)-3-H-(1,3,4)oxdiazol-2-one M.p.: 150°C Example 68: 5-Methoxy-3-(3-fluoro-4-nitrophenyl)-3-H-(1,3,4)oxdiazol-2-one M.p.: 127°C Example 69: 5-Methoxy-3-(4-(4-t-butylbenzoylamino)phenyl)-3-H-(1,3,4)oxdiazol-2-one M.p.: 173°C Example 70: 5-Methoxy-3-(4-(4-chlorobenzyloxycarbonylamino)phenyl)-3-H-(1,3,4)oxdiazol-2-one M.p.: 177°C Example 71: 5-Methoxy-3-(2-chloro-4-(4-heptylbenzoylamino}phenyl)-3-H-(1,3,4)oxdiazol-2-one M.p.: 135°C Example 72: 5-Methoxy-3-(4-(3,4-dichlorobenzoylamino)phenyl)-3-H-(1,3,4}oxdiazol-2-one M.p.: 200°C Example 73: 5-Methoxy-3-(4-(2-(4-chlorophenoxy)-2-methylpropionylamino)phenyl)-3-H-(1,3,4)oxdiazol-2-one M.p.: 153°C Example 74: 5-Ethoxy-3-(3-methyM-benzyloxycarbonylaminophenyl)-3-H-(1,3,4)oxdiazol-2-one M.p.: 94°C Example 75: 5-lsopropoxy-3-(3-methyl-4-benzyloxycarbonylaminophenyl)-3-H-(1,3,4)oxdiazol- 2-one M.p.:119°C Example 76: 5-lsopropoxy-3-(3-methyl-4-butyloxycarbonylaminophenyl)-3-H-(1,3,4)oxdiazol-2-one M.p.:114°C Example 77: 5-lsopropoxy-3-(3-methyl-4-(3-chlorophenylaminocarbonylamino)phenyl)-3-H-(1,3,4)oxdiazol-2-one M.p.: 201°C Example 78: 5-tert-Butoxy-3-(3-methyl-4-benzyioxycarbonylaminopheny])-3-H-(1,3,4)oxdiazol- 2-one M.p.: 113°C Example 79: 5-Methoxy-3-(3-methyl-4-phenoxycarbonylaminophenyl)-3-H-(1,3,4)oxdiazol-2-one M.p.: 145°C Example 80: 5-Methoxy-3-(3-methyl-4-(pyrid-3-ylcarbonylamino)phenyl)-3-H-(1,3,4)oxdiazol-2-one M.p.: oil Example 81: 5-Methoxy-3-(3-methyl-4-(indan-2-ylaminocarbonylamino)phenyl)-3-H-(1,3,4)oxdiazol-2-one M.p.: 206X Example 82: 5-Methoxy-3-(3-methyl-4-(pyrid-3-ylmethylaminocarbony]amino)phenyl)-3-H-(1,3,4)oxdiazol-2-one M.p.: 229°C Example 83: 5-Methoxy-3-(3-methyl-4-(pyrid-3-ylmethoxycarbonylamino)phenyl)-3-H-(1,3,4)oxdiazol-2-one M.p.: 232°C Example 84: 5-Methoxy-3-(3-fluoro-4-benzyloxycarbonylaminophenyl)-3-H-(1,3,4)oxdiazol-2-one M.p.: oil Example 85: 5-Methoxy-3-{3-fluoro-4-{4-trifluoromethylbenzoylamino)phenyl)-3-H-(1,3,4)oxdiazol-2-one M.p.: oil Example 86: 5-Methoxy-3-(3-benzyloxy-4-(4-trifluoromethylbenzoylamino)phenyl)-3-H- (1,3,4)oxdiazol-2-one M.p.: 159°C Example 87: 5-Methoxy-3-(3-fluoro-4-(4-tert-butylbenzoylamino)phenyl)-3-H-(1,3,4)oxdiazol-2-one M.p.: 144°C Example 88: 5-Methoxy-3-(3-methyl-4-(2,2,2-trifluoroethoxycarbonylamino)phenyl)-3-H-(1,3,4)oxdiazol-2-one M.p.: 141"C Example 89: 5-Methoxy-3-(3-methyl-4-piperidinocarbonylaminophenyl)-3-H-(1,3,4)oxdiazol-2-one M.p.: 154°C Example 90: 5-Methoxy-3-(4-(6-methoxybenzofuran-2-yl-carbonylamino)phenyl)-3-H-(1,3,4)oxdiazol-2-one M.p.: 191°C Further examples which were prepared by the processes described above and were characterized by mass spectroscopy (M+1): Example Chemical name: M+1 Mol. wt. No. 91 N-[4-(5-Metrioxy-2-oxo-{1,3,4]oxdiazol-3-yl)phenyl]-3-methyl- 362 361.4 benzenesulfonamide 92 3,4-Dimethoxy-N-[4-(5-metrioxy-2-oxo-[1,3,4]oxdiazol-3-yl)- 408 407.4 phenyljbenzenesulfonamide 93 Quinoline-B-sulfonic acid [4-(5-methoxy-2-oxo-[1,3,4]oxdiazol- 399 396.4 3-yl)pheny!]amide 94 N-[4-{5-Methoxy-2-oxo-[1,3,4]oxdiazol-3-yl)phenyl]-5-nitro- 415 414.3 isophthalic acid monomethyl ester in which the meanings are: R1 Ci-C6-alkyl, C3-C9-cycloalkyl, it being possible for both groups to be substituted one or more times by phenyl, C-i-Chalkyloxy, S-Ci-C4-alkyl, N(CrC4-alkyl)2, and for phenyl in turn to be substituted one or more times by halogen, Ci-C4-alkyl, Ci-C4-alkyloxy, nrtro, CF3; and R2, R3, R4 and R5 independently of one another hydrogen, halogen, nitro, Ci-C4-alkyl, Ci-Cg-alkyloxy; C6-Cio-aryl-Ci-C4-alkyloxy, C6-C10-aryloxy, C6-C10-aryl, C3-CB-cycloalkyl or 0-C3-Ce-cycloalkyl, each of which may be substituted once, twice or three times by halogen, CF3, Ci-C4-alkyloxy or Ci-C4-alkyl; 2-oxopyrrolidin-1-yl, 2,5-dimethylpyrrol-1-yl or NR6-A-R7, with the proviso that R2, R3, R4 and R5 are not simultaneously hydrogen, and at least one of the radicals R2, R3, R4 or R5 is the radical 2-oxopyrrolidin-1-yl, 2,5-dimethylpyrrol-1-yl or NR6-A-R7, with R6 hydrogen, Ci-C„-alkyl or C6-Ci0-aryl-C1-C4-alkyl, where aryl may be substituted by halogen, CF3, Ci-C8-alkyloxy or Ci-C4-alkyl; A a single bond, COn, SOn or CONH; n 1 or 2; R7 hydrogen; Ci-Cia-alkyI or C2-Ci8-alkenyl, each of which may be substituted once to three times by CrC4-alkyl, halogen, CF3. CrC4-alkyloxy, N(Ci-C4-alkyl)2, -COOH, CrC4-alkyloxycarbony!, C6-Ci2-aryl, C6-Ci2-aryloxy, C6-Ci2-arylcarbonyl, C6-C10-aryl-Ci-C4-alkyloxy or oxo, where aryl in turn may be substituted by halogen, Ci-C4-alkyl, aminosulfonyl or methylmercapto; C6-Ci0-aryl-Ci-C4-alkyl, C5-C8-cycloalkyl-Ci-C4-alkyi, Cs-Cs-cycloalkyl, C6-Cio-aryl-C2-C6-alkenyl, C6-Cio-aryl, diphenyl, diphenyl-d-Cv-alkyi, indanyl, each of which may be substituted once or twice by Ci-Ci6-alkyl, Ci-Cia-alkyloxy, C3-C8-cycloalkyl, COOH, hydroxyl, CrC4-alkylcarbonyl, C6-Cio-aryl-CrC4-alkyt, C6-Cio-aryl-Ci-C4-alkyloxy, C6-Cio-aryloxy, nttro, cyano, C6-Ci0-aryl, fluorosulfonyl, Ci-C6-alkyloxycarbonyl, C6-Cio-arylsulfonyloxy, pyridyl, NHS02-C6-Cio-aryl, halogen, CF3orOCF3, where alkyl may be substituted again by Ci-C4-a)kyloxycarbonyl, CF3 or carboxyl, and aryl by halogen, CF3 or Ci-C4-alkyloxy; or the group Het-(CH2)r, with r = 0,1, 2 or 3 and Het = saturated or unsaturated 5-7-membered heterocycle which may be benzo-fused and substituted by Ci-C4-alkyl, C6-Cio-aryl, halogen, Ci-C4-alkyloxy, Ci-C4-alkyloxycarbonyl, C6-Cio-aryl-Ci-C4-alkyl, Ce-Cio-aryl-CT^-alkylmercapto or nitro, where benzo-fused aryl may in turn be substituted by halogen, d-C4-alkyloxy or CF3 and alkyl in arylalkyl by methoxy and CF3, and the pharmacologically suitable salts and acid addition salts thereof. 2. A compound of the formula 1 as claimed in claim 1, in which R1 is Ci-C4-alkyl. 3. A compound of the formula 1 as claimed in claim 1 or 2, in which R1 is methyl. 4. A compound of the formula 1 as claimed in claims 1 to 3, in which R5 is hydrogen. 5. A compound of the formula 1 as claimed in claims 1 to 4, in which R2 is hydrogen, halogen, CrCd-alkyl, Ci-C9-alkyloxy or amino. 6. A compound of the formula 1 as claimed in claims 1 to 5, in which R3 is hydrogen, Ci-C4-alkyl, C6-Cio-aryl-Ci-C4-alkyloxy which may optionally be substituted in the aryl moiety by halogen, or is NR6-A-R7 with R6= hydrogen or benzyl, A = single bond and R7 = Ce-Cio-aryl-CrC^alkyl which may be substituted by halogen, CF3l cyano, phenyI~Ci-C4-alkyloxy, CF3-phenoxy, C5-Cfl-cycloalkyl or fluorosulfonyloxy; Ci-Ci2-aIkyl which may be substituted by CrC4-alkyloxy, phenyl, CF3 or phenyl-Ci-C4-alkyloxy; CrCi2-alkenyl or the group Het-(CH2)r, with r = 0 or 1, and Het = saturated or unsaturated 5-7-membered heterocycle which may be benzo-fused and substituted by d-C4-alkyl or halogen. 7. A compound of the formula 1 as claimed in claims 1 to 6, in which R4 is hydrogen, 2-oxopyrrolidin-1-yl, 2,5-dimethylpyrrol-1-yl or C6-C10-aryl-Ci-C4-alkyloxy which may be substituted by halogen. 8. A compound of the formula 1 as claimed in claims 1 to 7, in which R* is NR6-A-R7, with R6 = hydrogen or methyl, A = single bond and R7= hydrogen; Ci-Ci2-alkyl which may be substituted once or twice by halogen; C2-Ci8-alkenyl which may be substituted once or twice by Ci-C4-alkyl or C1 -Chalky loxycarbonyl; C6-Cio-aryl-CrC4-alkyl which may be substituted by halogen, Ci-C6-alkyloxy, CF3, cyano, C5-C6-cycloalkyl, CrC4-alkyloxycarbonyl, C6-Ci0-aryl-Ci-C4-alkyl, C6-Cio-aryl-CrC4-alkyloxy, where aryl may again be substituted by halogen or CF3; C5-C6-cycloalkyl-CrC4-alkyl; or the group Het-(CH2)r, 11. A compound of the formula 1 as claimed in claims 1 to 10, in which R4 is NRe-A-R7, with R6 = hydrogen, A = -S02- and R7 = Ci-C6-alkyl which may be substituted by CF3; C2-C4-alkenyl which may be substituted by phenyl; C6-Cio-aryl which may be substituted by Ci-C6-alkyl, halogen, Ci-C4-alkyloxy or benzyl; diphenyl-Ci-C4-alkyl substituted by halogen; QJ the group HeHChfeJr, with r = 0 and Het = saturated or unsaturated 5-7-membered heterocycle. 12. A compound of the formula 1 as claimed in claims 1 to 11, in which R4tsNR6-A-R7,with R6= hydrogen, A = -CO-NH- and R7 = Ci-Cio-alkyl which may be substituted by Ci-C4-alky!oxycarbonyl, N(CrC4-alkyI)2 or phenyl which may in turn be substituted by halogen or aminosuifonyl; C6-Cio-aryl which may be substituted by Ci-Ce-alkyl, CrC6-alkyloxy, Ci-C6-alkyloxycarbonyl, phenoxy, OCF3, benzyl or pyridyl, where alkyl may again be substituted by Ci-C^-alkyloxycarbonyl or carboxyl; C5-Ce-cycloalkyl which may be substituted by hydroxy!, or indanyl; or the group Het-(CH2)r, with r = 0 or 1 and Het = saturated or unsaturated 5-7-membered heterocycle which may be substituted by benzyl. 13. A process for preparing compounds of the formula 1 as claimed in claims 1 to 12, which comprises reacting hydrazines of the formula 2 with chloroformic esters of the formula 3 or other reactive carbonic ester derivatives in which R1, R2, R3, R4 and Rs are as defined in claims 1 to 12 to give the compounds of the formula 4, which are acytated with phosgene, carbonyldiimidazole, diphosgene or triphosgene, cyclized and, where appropriate, converted by further chemical modification of the radicals R2-R5 such as, for example, by reduction of nitro to amino radicals and subsequent acylation or alkylation into the compounds of the formula 1.

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