CA2477005A1 - Use of substituted 3-phenyl-5-alkoxy-1,3,4-oxdiazole-2-one for producing medicaments that inhibit pancreatic lipase - Google Patents

Abstract

The invention relates to the use of substituted 3-phenyl-5-alkoxy-1,3,4-oxdiazole-2-ones, in addition to their pharmacologically compatible salts and acid addition salts for producing medicaments, which exhibit an inhibiting action on pancreatic lipase, PL. The invention relates to the use of compounds of formula (I), in which the groups are defined as cited, in addition to their pharmacologically compatible salts and acid addition salts for producing a medicament for the prophylaxis or treatment of obesity or diabetes mellitus type 1 and 2.

Description

Description:
Use of substituted 3-phenyl-5-alkoxy-1,3,4-oxdiazol-2-ones for prodncinq medicaments with an inhibitory effect on pancreatic lipase The invention relates to the use of substituted 3-phenyl-5-alkoxy-1,3,4-oxdiazol-2-ones for producing medicaments which have an inhibitory effect on pancreatic lipase, PL.
Substituted 3-phenyl-5-alkoxy-1,3,4-oxdiazol-2-ones with an inhibitory effect on hormone-sensitive lipase are disclosed in WO 01/17981 (HMR 1999/L 052) and WO
01166531 (AVE-D 2000IA 015K).
It has now been found, surprisingly, that substituted 3-phenyl-5-alkoxy-1,3,4-oxdiazol-2-ones show an inhibitory effect on pancreatic lipase, PL.
The invention therefore relates to the use of substituted 3-phenyl-5-alkoxy-1,3,4-oxdiazol-2-ones of the formula 1 Ni ~ O
h--O
~~O

in which the meanings are:
R' C~-C6-alkyl, C3-C9-cycloalkyl, it being possible for both groups to be substituted one or more times by phenyl, C~-C4-alkyloxy, S-C~-C4-alkyl, N(C,-C4-alkyl)2, and far phenyl in turn to be substituted one or more times by halogen, C~-C4-alkyl, C~-C4-alkyloxy, nitro, CF3; and R2, R3, R4 and R5 independently of one another are hydrogen, halogen, vitro, C~-C4-alkyl; C~-C9-alkyloxy which is substituted by fluorine, C6-Coo-aryl, amino or C~-C4-alkyl-amino;
Cs-C,o-aryl-C,-C4-alkyfoxy, C6-~,o-aryloxy, C6-C,o-aryl, Cs-C,o-aryloxy-C,-C4-alkyl, Cs-C8-cycloalkyl or O-C3-C8-cycloalkyl, each of which may be substituted once, twice or three times by halogen, CF3, C~-C4-alkyloxy or C~-C4-alkyl;
SOZ-NH-C,-C6-alkyl, optionally substituted by N(C~-C6-alkyl)2, or SO~-NH-(2,2,6,6-tetramethylpiperidin-4-yl), S02-NH-C3-Cs-cycfoalkyl, optionally substituted one or more times by C~-C4-alkyl, or S02-N(C~-Cs-alkyl)2 or COX, 2-oxo-pyrrolidin-1-yl, 2,5-dimethylpyrrol-1-yl or NR6-A-R', with the proviso that R2, R3, R4 and R5 are not simultaneously hydrogen, with X ~ O-C~-Cs-alkyl, NH-C,-C6-alkyl, NH-C3-C8-cycloalkyl or N(C~-Cs-alkyl)2 and N(C,-C6-alkyl)2 may also be pyrrolidino, piperidino, morpholino, thiomorpholino or piperazino, each of which may optionally be substituted by C~-C4-alkyl, benzyf, Cs-Coo-aryl, CO-C~-C4-alkyl, CO-C6-C,o-aryl, CO-O-C~-C4-alkyl, S02-C~-C4-alkyl or S02-C6-Coo-aryl;
R6 hydrogen, C,-C~-alkyl or C6-Coo-aryl-C~-C4-alkyl, where aryl may be substituted by halogen, CF3, C~-C8-alkyloxy or C~-C4-alkyl;
A a single bond, CO~, SO~ or CONH;
n 1 or 2;
R' hydrogen;
C~-C~a-alkyl or C2-C~a-alkenyl, each of which may be substituted once to three times by C~-C4-alkyl, halogen, CF3, C~-C4-aikyloxy, N(C~-C4-alkyl)Z, -COOH, C~-C4-alkyloxycarbonyl, C6-C~2-aryl, C6-C~2-aryloxy, C6-C~2-arylcarbonyl, C6-C,o-aryl-C~-C4-alkyloxy or oxo, where aryl in turn may be substituted by halogen, C~-C4-alkyl, aminosuifonyl or methylmercapto;

C6-Coo-aryl-C~-C4-alkyl, C5-C8-cycloalkyl-C~-C4-alkyl, CS-C$-cycloalkyl, C6-C~o-aryl-CZ-Cs-alkenyl, Cs-Coo-aryl, biphenylyl, Biphenyl-C,-C4-alkyl, indanyl, each of which may be substituted once or twice by C,-C~$-alkyl, C,-C,8-alkyloxy, C3-C8-cycloalkyl, COOH, hydroxyl, C~-C4-alkylcarbonyl, C6-C,o-aryl-C~-C4-alkyl, C6-Coo-aryl-C~-C4-alkyloxy, C6-Coo-aryloxy, vitro, cyano, C~-Coo-aryl, fluorosulfonyl, C,-C6-alkyloxycarbonyl, Cs-Coo-arylsulfonyloxy, pyridyl, NHS02-C6-C,o-aryl, halogen, CF3 or OCF3, where alkyl may be substituted again by C~-C4-alkyloxycarbonyl, CF3 or carboxyl, and aryl by halogen, CF3 or C~-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 C~-C4-alkyl, C6-C,o-aryl, halogen, C~-C4-alkyloxy, C~-C4-alkyloxycarbonyl, C~-Coo-aryl-C,-C4-alkyl; C6-Coo-aryl-C,-C4-alkylmercapto or vitro, where benzo-fused aryl may in turn be substituted by halogen, C,-C4-alkyloxy or CF3 and alkyl in arylalkyl by methoxy and CF3, and of their pharmacologically acceptable salts and acid addition salts for producing a medicament with an inhibitory effect on pancreatic lipase.
Said aryl radicals may optionally be substituted one. or more times by C~-C9-alkyl, C~-Cg-alkyloxy, halogen, trifluoromethyl. Said cycloalkyl radicals may optionally be substituted one or more times by C~-C4-alkyl, C6-Coo-aryl, and said alkyl radicals may be substituted by hydroxyl, di-C~-C4-alkylamino and fluorine. Halogen is fluorine, chlorine, bromine, preferably fluorine and chlorine. Alkyl, alkenyl, alkyloxy etc. may be branched or unbranched.
The preferred use is of compounds of the formula 1 in which the meanings are:
R' C,-C6-alkyl which may optionally be substituted by phenyl; andlor R5 hydrogen; and/or R2 hydrogen, halogen, C~-C4-alkyl, C~-C9-alkyfoxy or amino, and of their pharmacologically acceptable salts and acid addition salts for producing a medicament with an inhibitory effect on pancreatic lipase.
A further preferred use is of compounds of the formula 1 in which R~ is hydrogen, C~-C4-alkyl, C6-Coo-aryl-C~-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 R' = Cs-Coo-aryl-C~-C4-alkyl which may be substituted by halogen, CF3, cyano, phenyl-C1-C4-alkyloxy, CF3-phenoxy, C5-Cg-cycloalkyl or fluorosulfonyloxy;
C~-C~2-alkyl which may be substituted by C~-C4-alkyloxy, phenyl, CF3 or phenyl-C~-C4-alkyloxy;
C2-C12-alkenyl or the group Het-(CHZ)r, with r = 0 or 1, and Het = saturated or unsaturated 5-7-membered heterocycle which may be benzo-fused and substituted by C~-C4-alkyl or halogen, or of the compounds of the formula 1 in which the meanings are:
R2' and R3 independently of one another hydrogen, C6-Coo-aryl, C3-C8-cycloalkyl, optionally C~-C4-alkyl-substituted C6-C,o-aryloxymethyl, optionally mono- or poly-C~-C4-alkyl- or halogen-substituted O-benzyl, O-C6-Coo-aryl or O-C3-Cs-cycloalkyl, mono- or poly-fluorine-, C6-Coo-aryl- or amino-substituted O-C~-C6-alkyl, where amino in turn may be substituted one or more times by C,-C4-alkyi, or S02-NH-C~-C6-alkyl, optionaNy substituted by N(C~-C6-alkyl)2, or SOZ-NH-(2,2,6,6-tetramethylpiperidin-4-yl), S02-NH-C3-C$-cycloalkyl, substituted by C~-C4-alkyl, S02-N(C,-C6-alkyl)2 or CO-N(C~-Cs-alkyl)2, and N(C,-Cs-alkyl)Z may also be piperidino, morphofino or piperazino, each of which may optionally be substituted by C~-C4-alkyl, and of their pharmacologically acceptable salts and acid addition salts for producing a medicament with an inhibitory effect on pancreatic lipase.

An additionally preferred use is of compounds of the formula 1 in which the meanings are:
R4 hydrogen, 2-oxo-pyrrolidin-1-yl, 2,5-dimethylpyrrol-1-yl or C6-C,o-aryl-C,-C4-alkyloxy, which may be substituted by halogen, and/or of the compounds of the formula 1 in which the meanings are:
R4 = NR6-A-R', with R6 = hydrogen or methyl, A = single bond and R' = hydrogen;
C~-C~2-alkyl which may be substituted once or twice by halogen;
C2-C,8-alkenyl which may be substituted once or twice by C~-C4-alkyl or C~-Ca-alkyloxycarbonyl;
C6-Coo-aryl-C~-C4-alkyl which may be substituted by halogen, C~-C6-alkyloxy, CF3, cyano, C5-Cs-cycloalkyl, C~-C4-alkyloxycarbonyl, C6-C,o-aryl-C,-C4-alkyl, C6-Coo-aryl-C~-C~-alkyloxy, where aryl may be substituted again by halogen or CF3;
C5-C8-cycloalkyl-C~-C4-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~-C4-alkyloxy or C~-C4-alkyfoxycarbonyl, andJor of compounds of the formula 1 in which the meanings are:
R4 = NR6-A-R' with R6 = hydrogen, A = -CO- and R' = C~-C,8-alkyl which may be substituted by halogen, phenyl, phenoxy, phenylcarbonyl or C,-Ca-alkyloxycarbonyl, where phenoxy in turn may be substituted by methyl, halogen or methylmercapto;
C2-C~$-alkenyf which may be substituted by C6-Coo-aryl;

Cs-Coo-aryl which may be substituted by halogen, C~-C$-alkyl, phenyl-C~-C4-alkyl, CF3, OCF3, fluorosulfonyl, C~-Ca-alkyloxycarbonyl, phenoxy, where aryl in turn may be substituted by C~-C4-alkyloxy;
Cs-Coo-aryl-C~-Ca-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 C~-C4-alkyl, halogen, C~-C4-alkyloxy, halophenyl or halobenzylmercapto, where benzo-fused aryl may in turn be substituted by halogen or methoxy, and/or of compounds of the formula 1 in which the meanings are:
R4 = N Rs-A-R', with Rs = hydrogen, A = -C02- and R' = C,-C,s-alkyl which is substituted by CF3 or phenyl; -Cs-C~o-arYl;
Cs-C,o-aryl-C~-C4-alkyl which is substituted by C~-C4-alkyl, halogen, CF3 or 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 C,-C4-alkyl or benzyl, and/or R4 = N Rs-A-R', with Rs = hydrogen, A = -SOZ- and -R' = C~-Cs-alkyl which may be substituted by CF3;
C2-C4-alkenyl which may be substituted by phenyl;
Cs-Coo-aryl which may be substituted by C,-Cs-alkyl, halogen, C~-C4-alkyloxy or benzyl;
biphenylyl-C~-C~-alkyl, substituted by halogen;
or the group Het-(CH2)r, with r = 0 and Het = saturated or unsaturated 5-7-membered heterocycle, and/or of compounds of the formula 1 in which the meanings are:
R4 = N R6-A-R', with Rs = hydrogen, A = -CO-NH- and R' = C~-Coo-alkyl which may be substituted by C~-C4-alkyloxycarbonyl, N(C,-C4-alkyl)2 or phenyl which may in tum be substituted by halogen or aminosulfonyl;
C~-C1o-aryl which may be substituted by C~-Cs-alkyl, C~-C6-alkyfoxy, C,-Cs-alkyloxycarbonyl, phenoxy, OCF3, benzyl or pyridyl, where alkyl may again be substituted by C~-C4-alkyloxycarbonyl or carboxyl;
C5-Cs-cycloalkyl which may be substituted by hydroxyl, 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, and of their pharmacologically acceptable salts and acid addition salts fog producing a medicament with an inhibitory effect on pancreatic lipase.
A further preferred use is of compounds of the formula 1 in which the meanings are:
R2 and R5 hydrogen, R3 hydrogen, C6-Coo-aryl, O-C6-Coo-aryl, optionally C~-C4-alkyl-substituted C6-Coo-aryloxymethyl, O-benzyl, mono- or poly-fluorine- or amino-substituted O-C~-C6-alkyl, where amino in turn may be substituted one or more times by C,-C4-alkyl, or optionally mono- or poly-C~-C4-alkyl-substituted O-C3-C8-cyclaalkyl and R4 hydrogen, C6-Coo-aryl, C3-C8-cycloalkyl, optionally mono- or poly-C~-C4-alkyl-or halogen-substituted O-C6-C,o-aryl or O-C3-C8-cycloalkyl, mono- or poly-fluorine-substituted O-C~-C6-alkyl, SOZ-NH-C~-Cs-alkyl, optionally substituted by N(C~-C6-alkyl)2, or S02-NH-(2,2,6,fi-tetramethylpiperidin-4-yl), S02-NH-C3-Ca-cycloalkyl, substituted one or more times by C~-C4-alkyl, S02-N(C,-C6-alkyl)2 or CO-N(C,-C6-alkyl)2, and N(C~-C6-alkyl)2 is also piperidino, morpholino or piperazino, each ofi which may optionally be substituted by C~-C4-alkyl, and of their pharmacologically acceptable salts and acid addition salts for producing a medicament with an inhibitory effect on pancreatic lipase.
The particularly preferred use is of compounds of the formula 1 in which R' is methyl, ethyl, butyl, isopropyl or benzyl, and RZ and R5 are hydrogen, and R3 is hydrogen, trifluoromethoxy, trifluorobutoxy, 3,3,5,5-tetramethylcyclohexyloxy, benzyloxy, phenoxy, phenyl, 2-diethylamino-ethyloxy or 3-methylphenoxymethyl, and R4 is hydrogen, trifluoromethoxy, 3,3,5,5-tetramethylcyclohexyloxy, phenoxy, 4-chlorophenoxy, cyclohexyl, phenyl, morpholinosulfonyl, 3,3,5-trimethylcyclohexylaminosulfonyl, 2,2,6,6-tetramethylpiperidin-4-ylaminosulfonyl, 2-(diisopropylaminoethyl)aminosulfonyl, 4-methylpiperazin-1-ylsulfonyl, 3,3-dimethylpiperidinocarbonyl or 3,5-dichlorophenoxy, or of compounds of the formula 1 in which R' is methyl, ethyl, butyl, isopropyl or benzyl, and RZ and R5 are hydrogen, and R3 is hydrogen, trifluoromethoxy, 3,3,5,5-tetramethylcyclohexyloxy, benzyloxy or phenoxy and R4 is hydrogen, trifluoromethoxy, 3,3,5,5-tetramethylcyclohexyloxy, phenoxy, cyclohexyl, phenyl, morpholinosulfonyl or 3,3,5-trimethylcyclohexyl-aminosulfonyl, and of their pharmacologically acceptable salts and acid addition salts for producing a medicament with an inhibitory effect on pancreatic lipase.
The very particularly preferred use is of compounds of the formula 1 in which R' is C~-C4-alkyl, R2 is hydrogen, R3 is hydrogen, trifluoromethoxy, benzyloxy, R4 is hydrogen, trifluoromethoxy, 4-chlorophenoxy, 4-trifluoromethylbenzoyl-amino, and R5 is hydrogen and of their pharmacologically acceptable salts and acid addition salts for producing a medicament with an inhibitory effect on pancreatic lipase.
A further very particularly preferred use is of compounds of the formula 1 in which R' is methyl, and of their pharmacologically acceptable salts and acid addition salts for producing a medicament with an inhibitory effect on pancreatic lipase.
An additional very particularly preferred use is of the compounds of the formula 1 which are mentioned in Examples 86, 210, 212, 213, 216, 218, 220 and 229.
The invention relates to the use of compounds of the formula 1 in the form of their racemates, racemic mixtures and pure enantiomers, and to their diastereomers and mixtures thereof.
Pharmaceutically acceptable salts are particularly suitable for medical applications because of their greater solubility in water compared with the initial compounds on which they are based. These salts must have a pharmaceutically acceptable anion or cation. Suitable pharmaceutically acceptable acid addition salts of the compounds of the formula 1 are salts of inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric, metaphosphoric, nitric, sulfonic and sulfuric acids, and of organic acids such as, for example, acetic acid, benzenesulfonic, benzoic, citric, ethanesulfonic, fumaric, gluconic, giycoiic, isethionic, lactic, lactobionic, malefic, malic, methanesuifonic, succinic, p-toluenesulfonic, tartaric and trifluoroacetic acids.
It is particularly preferred to use the chloride salt and the tartaric acid salt for medical purposes. Suitable pharmaceutically acceptable basic salts are ammonium salts, alkali metal salts (such as sodium and potassium salts) and alkaline earth metal salts (such as magnesium and calcium salts).

Salts with a pharmaceutically unacceptable anion likewise fall within the scope of the invention as useful intermediates for preparing or purifying pharmaceutically acceptable salts and/or for use in non-therapeutic, for example in vitro, applications.
5 The term "physiologically functional derivative" used herein refers to any physiologically tolerated derivative of a compound according to the invention, for example an ester, which is able on administration to a mammal, such as, for example, to humans, to form (directly or indirectly) such a compound or an active metabolite thereof.
A further aspect of this invention is the use of prodrugs of compounds of the formula 1. Such prodrugs can be metabolized in vivo to a compound of the formula 1.
These prodrugs may themselves be active or not.
The compounds of the formula 1 may also exist in various polymorphous forms, for example as amorphous and crystalline polymorphous forms. All polymorphous forms of the compounds of the formula 1 fall within the scope of the invention and are a further aspect of the invention.
A11 references hereinafter to "compound(s) of the formula 1" refer to compounds) of the formula 1 as described above and to the salts, solvates and physiologically functional derivatives thereof as described herein.
The amount of a compound of the formula 1 necessary to achieve the desired biological effect depends on a number of factors, for example the specific compound chosen, the intended use, the mode of administration and the clinical condition of the patient. The daily dose is generally in the range from 0.3 mg to 100 mg (typically from 3 mg to 50 mg) per day and per kilogram of body weight, for example 3-10 mg/kg/day. An intravenous dose may be, for example, in the range from 0.3 mg to 1.0 mg/kg, which can suitably be administered as infusion of 10 ng to 100 ng per kilogram and per minute. Infusion solutions suitable for these purposes may contain, for example, from 0.1 ng to 10 mg, typically from 1 ng to 10 mg, per milliliter. Single doses may contain, for example, from 1 mg to 10 g of the active ingredient.
Thus, ampoules for injections may 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, may contain, for example, from 1.0 to 1000 mg, typically from 10 to mg. In the case of pharmaceutically acceptable salts, the above weight data are based on the weight of the salt of the compound of the formula 1. The compounds of the formula 1 can be used for prophylaxis or therapy of the abovementioned states themselves as compound, but they are preferably in the form of a pharmaceutical composition with a compatible carrier. The carrier must, of course, be compatible in the sense of compatibility with other ingredients of the composition and not be harmful to the patient's health. The carrier may be a solid or a liquid or both and is preferably formulated with the compound as single dose, for example as tablet, which may contain from 0.05% to 95% by weight of the active ingredient.
Further pharmaceutically active substances may likewise be present, including further compounds of the formula 1. The pharmaceutical compositions according to the invention may be produced by one of the known pharmaceutical methods which essentially consist of mixing the ingredients with pharmacologically 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) administration, although the most suitable mode of administration depends in each individual case on the nature and severity of the condition to be treated and on the nature of the compound of the formula 1 used in each case. Coated formulations and coated slow-release formulations also fall within the scope of the invention. Acid- and gastric fluid-resistant formulations are preferred. Suitable gastric fluid-resistant coatings comprise cellulose acetate phthalate, polyvinyl acetate phthalate, hydroxypropylmethyl-cellulose phthalate and anionic polymers of methacrylic acid and methyl methacrylate.

Suitable pharmaceutical compounds for oral administration may be in the form of separate units such as, for example, capsules, cachets, pastilles or tablets, each of which contains a defined amount of the compound of the formula 1; as powder or granules; as solution or suspension in an aqueous or nonaqueous liquid; or as an oil-in-water or water-in-oil emulsion. T hese compositions may, as already mentioned, be prepared by any suitable pharmaceutical method which includes a step in which the active ingredient and the carrier (which may consist of one or more additional ingredients) are brought into contact. In general, the compositions are produced by uniform and homogeneous mixing of the active ingredient with a liquid and/or finely dispersed solid carrier, after which the product is shaped if necessary. Thus, for example, a tablet can be produced by compressing or shaping a powder or granules of the compound, where appropriate with one or more additional ingredients.
Compressed tablets may be produced by tabletting 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 one (or more) surface-active/dispersing agents in a suitable machine. Shaped tablets can be produced by shaping, in a suitable machine, the compound which is in powder form and has been moistened with an inert liquid diluent.
Pharmaceutical compositions suitable for peroral (sublingual) administration comprise suckable tablets which contain a compound of the formula 1 with a flavoring, normally sucrose, and gum arabic or tragacanth, and pastilles which contain the compound in an inert base such as gelatin and glycerol or sucrose and gum arabic.
Suitable pharmaceutical compositions for parenteral administration comprise preferably sterile aqueous preparations of a compound of the formula 1, which are preferably isotonic with the blood of the intended recipient. These preparations are preferably administered intravenously, although administration can also take place by subcutaneous, intramuscular or intradermal injection. These preparations can preferably be produced by mixing the compound with water and making the resulting solution sterile and isotonic with blood. Injectable compositions according to the invention generally contain from 0.1 to 5% by weight of the active compound.
Suitable pharmaceutical compositions for rectal administration are preferably in the form of single-dose suppositories. These can be produced by mixing a compound of the formula 1 with one or more conventional solid carriers, for example cocoa butter, and shaping the resulting mixture.
Suitable pharmaceutical compositions for topical use on the skin are preferably in the form of an ointment, cream, lotion, paste, spray, aerosol or oil. Carriers which can be used are petrolatum, lanolin, polyethylene glycols, alcohofs and combinations of two or more of these substances. The active ingredient is generally present in a concentration of from 0.1 to 15°l° by weight of the composition, for example from 0.5 to 2%.
Transdermal administration is also possible. Suitable pharmaceutical compositions for transdermal applications may be in the form of single plasters which are suitable for long-term close contact with the patient's epidermis. Plasters of this type suitably contain the active ingredient in an aqueous solution which is buffered where appropriate, 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 particular option, the active ingredient can be released by electrotransport or iontophoresis as described, for example, in Pharmaceutical Research, 2 (6):

(1986).
The following preparations serve to illustrate the invention without, however, restricting it.

Example A
Soft gelatin capsules containing 100 mg of active ingredient per capsule:
per capsule active ingredient 100 mg triglyceride mixture fractionated from coconut fat 400 mg capsule content 500 mg Example B

Emulsion containing 60 mg of active ingredient per 5 ml:

per 100 ml of emulsion active ingredient 1.2 g neutral oii q.s.

sodium carboxymethylcellulose 0.6 g polyoxyethylene stearate q.s.

glycerol, pure 0.2 to 2.0 g flavoring q.s.

water (deionized or distilled) ad 100 ml Example C
Rectal drug form containing 40 mg of active ingredient per suppository:
per suppository active ingredient 40 mg suppository base ad 2 g Example D
Tablets containing 40 mg of active ingredient per tablet:
per tablet active ingredient 40 mg lactose 600 mg corn starch 300 mg soluble starch 20 mg magnesium stearate 40 mg 1000 mg Example E

Coated tablets containing 50 mg of active ingredient per tablets:

per tablet active ingredient 50 mg 10 corn starch 100 mg lactose 60 mg sec. calcium phosphate 30 mg soluble starch 5 mg magnesium stearate 10 mg 15 colloidal silica 5 mg 260 mg EXample F

The following formulas are for producing the contents suitable of hard gelatin capsules:

a) active ingredient 100 mg corn starch 300 mg 400 mg b) active ingredient 140 mg lactose 180 mg com starch 180 mg 500 mg Example G
Drops can be produced in accordance with the following formula (100 mg of active ingredient in 1 ml = 20 drops):

active ingredient 10 g methyl benzoate 0.07 g ethyl benzoate 0.03 g ethanol, 96°f° 5 ml demineralized water ad 100 ml The compounds of the formula 1 can be prepared in various ways by methods known per se.

H O_R1 H
R4 f \ N + O~ ~ R4 ~ ~ N O-R1 = a ~CO_R1 --~ R4 ~ ~ N O

N--~ N O~R1 For example, substituted 3-phenyl-5-alkoxy-1,3,4-oxdiazol-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 R', R2, R3, R4 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 vitro 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 hydroxide 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 hydrazine hydrate R4 R4 x v NHz _ 2 subsequent reduction by known methods or by nucleophilic 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 formula 1 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 arylalkyf halides, or by reductive alkylation with aldehydes.
The following examples illustrate the preparation methods in detail without restricting them.
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:13.3 g rn.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-Methyl-4-nitrophenylhydrazine 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-nitrophenylhydrazine (intermediate) M.p.: 145°C
Example 7:
4-(4-Chlorophenoxy)-3-nitroaniline 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 ml of water under nitrogen and decomposed with 100 ml of 30°I° 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 mixture 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 stirred overnight 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) 5 M.p.:179°C
Example 11:
Methyl N'-(3-fluoro-4-nitrophenyl)hydrazinoformate M.p.: 127.4°C
Example 12:
Methyl N'-(3-methyl-4-nitrpphenyl)hydrazinoformate M.p.: 159°C
Example 13:
Methyl N'-(2-chloro-4-nitrophenyl)hydrazinoformate M.p.: 156°G
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.:193°C
Example 1 fi:
Methyl N'-(4-(4-chlorophenoxy)-3-nitrophenyl)hydrazinoformate M.p.: 147°C
Example 17:
Methyl N'-(3-piperidino-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 N'-(3-(N-benzylpiperazino)-4-nitrophenyl)hydrazinoformate M.p.: 15fi°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 overnight 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.: 151 °C
The following examples were prepared in analogy to Example 4:
Example 20:
5-Methoxy-3-(3-methyl-4-nitrophenyl)-3-H-(1,3,4)oxdiazol-2-one M.p.: 112°C
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.: 111°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-nitrophenyl)-3-H-(1,3,4)oxdiazol-2-one, 0.5 g of Pd/C and 20 ml 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 isopropanal and filtered off with suction.
Yield: 0.75 g; 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)oxdiazof-2-one M.p.: 114°C
Example 29:
5-Methoxy-3-(4-amino-3-(4-fluorobenzyfoxy)phenyl~3-H-(1,3,4)oxdiazol-2-one M.p.: 195°C
Example 30:
5-Methoxy-3-(4-(4-chlorophenylacetylamino)phenyl)-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.: 190pC
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)oxdiazol-2-one M.p.: 135°C
Example 35:
5-Methoxy-3-(4-(4-chlorobutanoylaminor3-methylphenyl)-3-H-(1,3,4)oxdiazol-2-one M.p.: 137°C
Example 36:
5-Methoxy-3-(4-pivaloylamino-3-methylphenyl)-3-H-(1,3,4)oxdiazol-2-one M.p.: 157°C
Example 37:
5-Methoxy-3-(4-(4-chlorophenylsulfonylamino)-3-methylphenyl)-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)oxdiazol-2-one M.p.: 123°C
Example 39:
5-Methoxy-3-(4-(2-phenylethenylsulfonylamino)-3-methylphenyl)-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-chforophenylsulfonylamino)phenyl)-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-(1,3,4)oxdiazol-2-one M.p.: 165°C
Example 4J:
5-Methoxy-3-(4-isopropylsulfonylaminophenyl)-3-H-(1,3,4~xdiazol-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 paraformaldehydeJformic 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-phenyf)-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 gel, ethyl 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-methylphenyl)-3-H-(1,3,4)oxdiazol-2-one M.p.: 143°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 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.: oif 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 80°C. 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)oxdiazol-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 above examples.
Example 56:
5-Methoxy-3-(3-aminophenyl)-3-H-(1,3,4~xdiazol-2-one M.p.: 95°C
Example 57:
5-Methoxy-3-(3-dibenzylaminophenyl)-3-H-(1,3,4)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-(3-(pyrid-2-yl)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-chlorophenyl)-3-H-(1,3,4)oxdiazol-2-one M.p.: 126°C
Example 64:
5-Methoxy-3-(2-chloro-4-nitrophenyl)-3-H-(1,3,4)oxdiazol-2-one M.p.:92°C
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-benzyloxycarbonylaminophenyl)-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
10 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:
15 5-Methoxy-3-(4-(3,4-dichlorobenzoyfamino)phenyl)-3-H-(1,3,4)oxdiazol-2-orie M.p.: 200°C
Example 73:
5-Methoxy-3-(4-(2-(4-chlorophenoxy)-2-methylpropionylamino)phenyl)-3-H-20 (1,3,4)oxdiazol-2-one M.p.: 153°C
Example 74:
5-Ethoxy-3-(3-methyl-4-benzyloxycarbonylaminophenyl}-3-H-(1;3,4)oxdiazol-2-one 25 M.p.:94°C
Example 75:
5-Isopropoxy-3-(3-methyl-4-benzyfoxycarbonylaminophenyl)-3-H-(1,3,4)oxdiazol-2-one M.p.: 119°C
Example 76:
5-Isopropoxy-3-(3-methyl-4-butyloxycarbonylaminophenyl)-3-H-.(1,3,4)oxdiazol-2-one M.p.: 114°C
Example 77:
5-Isopropoxy-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-benzyloxycarbonylaminophenyi)-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.: 206°C
Example 82:
5-Methoxy-3-(3-methyl-4-(pyrid-3-ylmethylaminocarbonylamino)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-trifluoromethyfbenzoylamino)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 No. Chemical name: M+1 Mol.
wt.
91 N-[4-(5-Methoxy-2-oxo-[1,3,4]oxdiazol-3-yl)phenyl]-362 361.4 3-methyl-benzenesulfonamide 92 3,4-Dimethoxy-N-[4-(5-methoxy-2-oxo- 408 407.4 [1,3,4]oxdiazol-3-yl)phenyl]benzenesulfonamide 93 Quinoline-8-sulfonic acid [4-(5-methoxy-2-oxo-399 398.4 [1,3,4]oxdiazol-3-yl)phenyl]amide 94 N-[4-(5-Methoxy-2-oxo-j1,3,4]oxdiazol-3-yl)phenyl]-415 414.3 5-nitro-isophthalic acid monomethyl ester 95 3-(2-Chlorophenyl)-5-methylisoxazole-4-carboxylic427 426.8 acid [4-(5-methoxy-2-oxo-[1,3,4]oxdiazol-3-yl)phenyl]amide 96 3,3,3-Trifluoro-2-methoxy-N-[4-(5-methoxy-2-oxo-424 423.3 [1,3,4]oxdiazol-3-yl)phenyl]-2-phenylpropionamide 97 2-Fluoro-N-[4-(5-methoxy-2-oxo-[1,3,4]oxdiazol-3-330 329.3 yl)phenyl]-benzamide 98 Tetradecanoic acid [4-(5-methoxy-2-oxo- 418 417.5 [1,3,4]oxdiazol-3-yl)phenyl]amide 99 N-[4-(5-Methoxy-2-oxo-[1,3,4]oxdiazol-3-yl)phenyl]-416 415.4 2-phenethyl-benzamide 100 N-[4-(5-Methoxy-2-oxo-[1,3,4]oxdiazol-3-yl)phenyl]-479 478.4 2-(4-methoxyphenoxy)-5-nitrobenzamide 101 2-(4-Benzyfoxyphenyl)-N-[4-(5-methoxy-2-oxo-432 431.4 [1,3,4]oxdiazol-3-yl)phenyl]acetamide 102 N-[4-(5-Methoxy-2-oxo-[1,3,4]oxdiazol-3-yl)phenyl]-492 491.5 3,3,3-triphenylpropionamide 103 N-(4-(5-Methoxy-2-oxo-[1,3,4]oxdiazol-3-yl)phenyl]-448 447.3 3,5-bistrifluoromethylbenzamide 104 4-Cyano-N-[4-(5-methoxy-2-oxo-[1,3,4]oxdiazol-3-337 336.3 yl)phenyl]-benzamide 105 Nonanoic acid [4-(5-methoxy-2-oxo-[1,3,4]oxdiazol-348 347.4 3-yl)phenyl]amide 106 Methyl 9-[4-(5-methoxy-2-oxo-[1,3,4]oxdiazol-3-406 405.4 yl)phenylcarbamoyl]nonanoate 107 Undecanoic acid [4-(5-methoxy-2-oxo- 376 375.5 [1,3,4Joxdiazol-3-yl)phenyl]amide 108 4-[4-(5-Methoxy-2-oxo-[1,3,4]oxdiazol-3- 394 393.3 yl)phenylcarbamoyl]-benzenesulfonyl fluoride 109 ~ 11-Phenoxyundecanoic acid [4-(5-methoxy-2-oxo-468 467.6 [1,3,4]oxdiazol-3-yl)phenyl]amide 110 N-[4-(5-Methoxy-2-oxo-[1,3,4]oxdiazol-3-yl)phenyl]-416. 415.4 2,3-diphenylpropionamide 111 4-Chloro-N-[4-(5-methoxy-2-oxo-[1,3,4Joxdiazol-3-360 359.8 yl)phenyl]-2-methylbenzamide 112 6-Chloro-N-[4-(5-methoxy-2-oxo-[1,3,4Joxdiazol-3-347 346.7 yl)phenyl]nicotinamide 113 5-Fluoro-N-[4-(5-methoxy-2-oxo-[1,3,4Joxdiazol-3-344 343.3 yl)phenyl]-2-methylbenzamide 114 N-[4-(5-Methoxy-2-oxo-[1,3,4]oxdiazol-3-yl)phenyl]-354 353.4 2,4,6-trimethylbenzamide 115 N-[4-(5-Methoxy-2-oxo-[1,3,4Joxdiazol-3-yl)phenyl]-388 387.4 3-naphthalen-2-ylacrylamide 116 5-Oxo-5-phenylpentanoic acid [4-(5-methoxy-2-382 381.4 oxo-[1,3,4]oxdiazol-3-yl)phenyl]amide 117 3-(2,4-Dichlorobenzylsulfanyl)thiophene-2-509 508.4 carboxylic acid [4-(5-methoxy-2-oxo-[1,3,4]oxdiazol-3-yl)phenyl]amide 118 2-Fluoro-N-[4-(5-methoxy-2-oxo-[1,3,4]oxdiazol-3-398 397.3 yl)phenyl]-4-trifluoromethyfbenzamide 119 1-Hexyl-3-[3-(5-methoxy-2-oxo-[1,3,4]oxdiazoi-3-335 334.4 yl)phenyl]urea 120 1-(4-Bromophenyl)-3-[3-(5-methoxy-2-oxo- 406 405.2 [1,3,4]oxdiazol-3-yl)phenyl]urea 121 1-[3-(5-Methoxy-2-oxo-[1,3,4Joxdiazol-3-yl)phenyl]-357 356.3 3-(2-methoxyphenyl)urea 122 Ethyl2-[3-[3-(5-methoxy-2-oxo-[1,3,4]oxdiazol-3-427 426.4 yl)phenyl]ureido]-3-phenylpropionate 123 1-(2,6-Diisopropylphenyl)-3-[3-(5-methoxy-2-oxo-411 410.5 [1,3,4]oxdiazol-3-yi)phenyl]urea 124 1-[3-(5-Methoxy-2-oxo-[1,3,4Joxdiazol-3-yl)phenyl]-363 362.4 3-octylurea 125 1-(4-Fluorobenzyl)-3-[3-(5-methoxy-2-oxo-359 358.3 [1,3,4Joxdiazol-3-yl)phenyl]urea 126 1-(2-Ethylphenyl)-3-[3-(5-methoxy-2-oxo- 355 354.4 [1,3,4]oxdiazol-3-yl)phenyl]urea 127 Ethyl 6-[3-[3-(5-methoxy-2-oxo-[1,3,4]oxdiazol-3-393 392.4 yl)phenyl]ureido]hexanoate 128 1-(2,6-Dimethoxyphenyl)-3-[3-(5-methoxy-2-oxo-387 386.4 [1,3,4Joxdiazol-3-yl)phenyl]urea 129 5-Methoxy-3-[4-[(thiophen-3- 304 303.3 ylmethyl)amino]phenyl]-3H-[1,3,4]oxdiazol-2-one 130 4-[[4-(5-Methoxy-2-oxo-[1,3,4)oxdiazol-3-437 436.3 yl)phenylamino]methyl]-benzonitrile trifluoroacetate 131 3-[4-(2-Bromo-4,5-dimethoxybenzylamino)phenyl]-437 436.3 5-methoxy-3H-[1,3,4]oxdiazol-2-one 132 3-[4-(3-Ethaxy-4-methoxybenzylamino)phenyl]-5-486 485.4 methoxy-3H-[1,3,4]oxdiazol-2-one trifluoroacetate 133 Methyl4-[[4-(5-methoxy-2-oxo-[1,3,4]oxdiazol-3-470 469.4 yl)phenylamino]methyl]benzoate trifluoroacetate 134 4-[[4-(5-Methoxy-2-oxo-[1,3,4]oxdiazol-3-356 355.3 yl)phenylamino]methyl]phenyf acetate 135 5-Methoxy-3-[4- 388 387.3 (pentafluorophenylmethylamino)phenyl]-3H-[1,3,4]oxdiazol-2-one 136 3-[4-(4-Benzyloxybenzylamino)phenyl]-5-methoxy-518 517.5 3H-[1,3,4]oxdiazol-2-one trifluoroacetate 137 3-[4-(3,3-Dichlorononylamino)phenyl]-5-methoxy-517 516.3 3H-[1,3,4]oxdiazol-2-one trifluoroacetate 138 2-[[4-(5-Methoxy-2-oxo-[1,3,4]oxdiazol-3-323 322.3 yl)phenylamino]methyl]benzonitrile 139 3-[4-(Cyclohexylmethylamino)phenyl]-5-methoxy-304 303.4 3H-[1,3,4]oxdiazol-2-one 140 5-Methoxy-3-[4-(2,3,5- 515 514.7 trichlorobenzylamino)phenyl]-3H-[1,3,4]oxdiazol-2-one trifluoroacetate 141 3-[4-(5-Bromo-2-fluorobenzylamino)phenyl]-5-509 508.2 methoxy-3H-[1,3,4]oxdiazol-2-one trifluoroacetate 142 3-[4-(4-Hexyloxybenzylamino)phenyl]-5-methoxy-512 511.5 3H-[1,3,4]oxdiazol-2-one trifluoroacetate 143 5-Methoxy-3-[4-[3-(3- 572 571.4 trifluoromethylphenoxy)benzyfamino]phenyl]-3H-[1,3,4]oxdiazol-2-one trifluoroacetate 144 3-[4-[(2-Chloroquinolin-3-ylmethyl)amino]phenyl]-5-497 496.8 methoxy-3H-[1,3,4]oxdiazol-2-one trifluoroacetate 145 Methyl3-methoxy-5-[[4-(5-methoxy-2-oxo- 501 500.4 [1,3,4]oxdiazol-3-yl)phenylamino]methyl]pyridine-2-carboxylate trifluoroacetate 146 4-[[4-(5-Methoxy-2-oxo-[1,3,4]oxdiazol-3-454 453.5 yl)phenylamino]methyl]phenyl benzenesulfonate 147 2-(2,6-Dirnethyl-4-methylsulfanylphenoxy)-N-[3-(5-416 415.5 methoxy-2-oxo-[1,3,4]oxdiazol-3-yl)phenyl]acetamide 148 1-(2,4-Difluorophenyl)-3-[4-(5-methoxy-2-oxo-363 362.3 [1,3,4]oxdiazol-3-yl)phenyl]urea 149 1-[4-(5-Methoxy-2-oxo-[1,3,4]oxdiazol-3-yl)phenylJ-419 418.4 3-(4-phenoxyphenyl)urea 150 1-{2,6-Difluorophenyl)-3-[4-(5-methoxy-2-oxo-363 362.3 [1,3,4]oxdiazol-3-yl)phenyl]urea 151 1-Butyl-3-[4-(5-methoxy-2-oxo-[1,3,4]oxdiazol-3-307 306.3 yl)phenyl]urea 152 1-(2-Ethoxyphenyl)-3-[4-(5-methoxy-2-oxo-371 370.4 [1,3,4]oxdiazol-3-yl)phenyl]urea 153 1-(2,6-Dibromo-4-fluorophenyl)-3-[4-(5-methoxy-2-503 502.1 oxo-[1,3,4]oxdiazoi-3-yf)phenyl]urea 154 1-(4-Butoxyphenyl)-3-[4-(5-methoxy-2-oxo-399 398.4 [1,3,4]oxdiazol-3-yl)phenyl]urea 155 1-[4-(5-Methoxy-2-oxo-[1,3,4]oxdiazol-3-yl)phenyl]-411 410.3 3-(4-trifluoromethoxyphenyl)urea 156 1-Benzyl-3-[4-(5-methoxy-2-oxo-[1,3,4]oxdiazol-3-341 340.3 yl)phenyl]urea 157 1-(3-Fluorophenyl~3-[4-(5-methoxy-2-oxo- 345 344.3 [1,3,4]oxdiazol-3-yl)phenyl]urea 158 Ethyl 6-[3-[4-(5-methoxy-2-oxo-[1,3,4]oxdiazol-3-393 392.4 yl)phenyl]ureido]hexanoate 159 1-Biphenyl-4-yl-3-[4-(5-methoxy-2-oxo- 403 402.4 [1,3,4]oxdiazol-3-yl)phenylJurea 160 Butyl 2-[3-(4-(5-methoxy-2-oxo-[1,3,4]oxdiazol-3-427 426.4 yl)phenyl]-ureido]benzoate 161 5-Methoxy-3-[3-(7-methoxy-3,7- 492 491.5 dimethyloctylamino)phenyl]-3H-[1,3,4]oxdiazol-2-one trifluoroacetate 162 5-Methoxy-3-[3-[(thiophen-2- 418 417.4 ylmethyl)amino]phenyl]-3H-[1,3,4]oxdiazol-2-one trifluoroacetate 163 3-(3-Hexylaminophenyl)-5-methoxy-3H- 406 405.4 [1,3,4]oxdiazol-2-one trifluoroacetate 164 5-Methoxy-3-[3-(3-phenylpropylamino)phenyl]-440 439.4 3H-[1,3,4]oxdiazoi-2-one trifluoroacetate 165 5-Methoxy-3-(3-undecylaminophenyl)-3H- 476 475.5 [1,3,4]oxdiazoi-2-one trifluoroacetate 166 5-Methoxy-3-[3-[3-(3- 572 571.4 trifluoromethylphenoxy)benzylamino]phenyl]-3H-[1,3,4]oxdiazol-2-one trifluoroacetate 167 3-[3-[(2-Chloroquinolin-3-ylmethyl)amino]phenyl]-5-497 496.8 methoxy-3H-[1,3,4]oxdiazol-2-one trifluoroacetate 168 4-[[3-(5-Methoxy-2-oxo-[1,3,4]oxdiazol-3-586 585.5 yl)phenylamino]methyl]phenyl 4-fluorobenzenesulfonate trifluoroacetate 169 5-Methoxy-3-[3-(3,4,5- 466 465.3 trifluorobenzylamino)phenyl]-3H-[1,3,4]oxdiazol-2-one trifluoroacetate 170 3-[3-(3,5-Bistrifluoromethylbenzylamino)phenyl]-5-548 547.3 methoxy-3H-[1,3,4]oxdiazol-2-one trifluoroacetate 171 3-(3-Dec-4-enylaminophenyi)-5-methoxy-3H- 460 459.5 [1,3,4]oxdiazol-2-one trifluoroacetate 172 3-[3-(3-Cyclopentyl-2- 600 599.6 phenethyloxybenzylamino)phenyl]-5-methoxy-3H-[1,3,4]oxdiazol-2-one trifluoroacetate 173 4-[[3-(5-Methoxy-2-oxo-[1,3,4]oxdiazol-3- 437 436.3 yl)phenylamino]methyl]benzonitrile trifluoroacetate 174 5-Methoxy-3-[3-[(6-methylpyridin-2- 427 426.3 ylmethyl)amino]phenyl]-3H-[1,3,4]oxdiazol-2-one trifluoroacetate 175 3-[3-(2-Benzyloxyethylamino)phenyl]-5-methoxy-455.4 3H-[1,3,4]oxdiazol-2-one trifluoroacetate 176 3-[3-(2,6-Difluorobenzylamino)phenyl]-5-methoxy-447.3 3H-[1,3,4]oxdiazol-2-one trifluoroacetate M.p. C

177 Dodecanoic acid [4-(5-methoxy-2-oxo-[1,3,4]oxdiazol-3-93 yl)phenyl]amide 178 Octadec-9-enoic acid [4-(5-methoxy-2-oxo- 67 [1,3,4]oxdiazol-3-y1)phenyl]amide 179 2-Methoxyethyl [4-(5-methoxy-2-oxo-[1,3,4]oxdiazol-3-117 yl)-2-methylphenyl]carbamate 180 1-(4-Hydroxycyclohexyl)-3-(4-(5-methoxy-2-oxo-220 [1,3,4]oxdiazol-3-yl)-2-methyfphenyl]urea 181 1,1-Dibutyl-3-[4-(5-methoxy-2-oxo-[1,3,4]oxdiazol-3-yl)-Oil 2-methylphenyl]urea 182 5-Methoxybenzofuran-2-carboxylic acid [4-(5-methoxy-2-199 oxo-(1,3,4]oxdiazol-3-yl)-2-methylphenyl]amide 183 4-Methylpiperazine-1-carboxylic acid [4-(5-methoxy-2-Oi1 oxo-[1,3,4]oxdiazol-3-yl)-2-methylphenyl]amide 184 1-Methyfpiperidin-4-yl [4-(5-methoxy-2-oxo- 235 [1,3,4]oxdiazol-3-yl)-2-methylphenyl]carbamate 185 Cyclohexyl [4-(5-methoxy-2-oxo-[1,3,4]oxdiazol-3-yl)-2-163 methylphenyl]carbamate 186 4-Benzylpiperidine-1-carboxylic acid (4-(5-methoxy-2-146 oxo-(1,3,4]oxdiazol-3-yl)-2-methylphenyl]amide 187 1-(2-Diisopropylaminoethyl)-3-[4-(5-methoxy-2-oxo-136 [1,3,4]oxdiazol-3-yl)-2-methylphenyl]urea 188 4-(2-{3-(4-(5-Methoxy-2-oxo-[1,3,4]oxdiazol-3-yl)-2-200 methylphenyl]-ureido}ethyl)benzenesulfonamide 189 1-(1-Benzylpiperidin-4-yl )-3-[4-(5-methoxy-2-oxo-198 (1,3,4]oxdiazol-3-y1)-2-methylphenyl]urea 190 1-(4-Isopropylphenyl)-3-[4-(5-methoxy-2-oxo- 200 [1,3,4]oxdiazol-3-yl)-2-methylphenyl]urea 191 2-{3-[4-(5-Methoxy-2-oxo-[1,3,4]oxd iazol-3-yl246 )-2-methylphenyl]ureido}-3-methylbutyric acid 192 1,2,3,4-Tetrahydronaphth-1-yl [4-(5-methoxy-2-oxo-159 (1,3,4]oxdiazol-3-yl)-2-methylphenyl]carbamate 193 1-Phenylethyl [4-(5-methoxy-2-oxo-[1,3,4]oxdiazol-3-yl)-Oi1 2-methylphenyl]carbamate 194 4-Isopropylbenzyl [4-(5-methoxy-2-oxo-[1,3,4]oxdiazol-3-88 yl)-2-methylphenyl]carbamate 195 4-Trifluoromethoxybenzyl [4-(5-methoxy-2-oxo- 82 [1,3,4]oxdiazol-3-yl)-2-methylphenyl]carbamate 196 3,5-Dichlorobenzyl [4-(5-methoxy-2-oxo-[1,3,4]oxdiazol-169 3-yl)-2-methylphenyl]carbamate 197 Biphenyl-2-ylmethyl [4-(5-methoxy-2-oxo-[1,3,4]oxdiazol-138 3-yl)-2-methylpheny!]carbamate 198 5-Chlorobenzofuran-2-carboxylic acid [4-(5-methoxy-2-210 oxo-[1,3,4]oxdiazol-3-yl)-2-methylphenyl]amide 199 5-Chlorobenzofuran-2-carboxylic acid [4-(5-methoxy-2-209 oxo-[1,3,4]oxdiazol-3-yl)phenyl]amide Example 200:
4-Fluorobenzenesulfonic acid mvrpholide (intermediate) 20 g of morpholine were added dropwise to a solution of 19.5 g 4-fluorobenzenesulfonyi chloride in 100 ml of toluene cooled in ice and the mixture was heated to reflux for 1 hour. After cooling, it was concentrated in vacuo and stirred with water, and the precipitate was filtered off with suction, washed with water and recrystallized from isopropanol.
Yield:16.9 g, melting point: 140°C
Example 201:
4-Hydrazinobenzenesulfonic acid morpholide (intermediate) 5 g of 4-fluorobenzenesulfonic acid morpholide were dissolved in 15 ml of N-methylpyrrolidone and, after addition of 2.5 g of hydrazine hydrate, heated at 100°C for 1 hour. After cooling to room temperature, 75 ml of water were added and the mixture was stirred at room temperature. After 2 hours, the solid was filtered off with suction and recrystallized from isopropanol.
Yield: 3.2 g, melting point: 164°C
The following example was prepared analogously:
Example 202:
4-Hydrazinobenzenesulfonic acid (3,3,5-trimethylcyclohexyl)amide (intermediate) melting point: 129°C
Example 203:
4-(3,3,5,5-Tetramethylcyclohexyloxy)nitrobenzene (intermediate) 1.3 g of sodium hydride are added to a solution of 7.8 g of 3,3,5,5-tetramethylcyclohexanol in 50 ml of dimethylformamide, and the mixture is stirred at 40-50°C for 30 min. Then a total of 7.0 g of 4-fluoronitrobenzene is added in portions, and the mixture is then heated at 100°C for 3 hours and cooled to room temperature. Addition of 250 ml of ice-water is followed by stirring, and the solid which has formed is filtered off with suction and dried in vacuo.
Yield: 8.6 g, melting point: 70°C
Example 204:
4-(3,3,5,5-Tetramethylcyclohexyloxy)aniline (intermediate) 8.3 g of 4-(3,3,5,5-tetramethylcyclohexyloxy)nitrobenzene are hydrogenated in 500 ml of methanol in the presence of 400 mg of platinum dioxide under atmospheric pressure until hydrogen uptake ceases. After removal of the catalyst by filtration, the solution is evaporated in a rotary evaporator, and the residue, a gradually solidifying brownish oil, is used without further purification for further reactions.
Yield: 7.3 g Example 205:
4-(3,3,5,5-Tetramethylcyclohexyloxy)phenylhydrazine hydrochloride (intermediate) A solution of 1.13 g of sodium nitrite in 7.5 ml of water is added dropwise to a stirred mixture, cooled to -10°C, consisting of 3.7 g of 4-(3,3,5,5-tetramethylcyclo-hexyloxy)aniiine, 7.5 m1 of water and 15.5 ml of concentrated HCI, and the mixture is then stirred at -10°C for 45 min and subsequently added dropwise to a suspension of 9.3 g of tin dichloride dihydrate in 7 ml of concentrated HCI. The precipitate is filtered off with suction, washed with water, suspended in 200 ml of water under nitrogen and decomposed with 100 ml of 30% strength sodium hydroxide solution at 10-15°C. The new precipitate which forms is filtered off with suction, washed with water, taken up in 200 ml of ether and dried with sodium sulfate. The product is then precipitated with ethereal HC1, filtered off with suction and dried in vacuo.
Yield: 2.1 g, melting point: 171 °C
5 Example 206:
Ethyl N'-(4-morpholinosulfonylphenyl)hydrazinoformate (intermediate) 114 mg of ethyl chloroformate were cautiously added dropwise to a mixture consisting of 0.275 g of 4-hydrazinobenzenesulfonic acid morpholide, 5 ml of methylene chloride and 1 ml of pyridine while cooling in ice, and the mixture was 10 then stirred while slowly warming to RT. After dilution with 10 ml of water, the product was extracted with ethyl acetate, and the ethyl acetate phase was washed several times with water, dried over sodium sulfate and concentrated. The oily crude product obtained in this way was reacted further without further purification.
Yield: 0.25 g Example 207:
3-(4-Morpholinosulfonylphenyl)-5-ethoxy-1,3,4-oxdiazol-2-one The oil from Example 206 was taken up in 5 ml of methylene chloride and, while stirring and cooling in ice, 1 ml of a 20% strength solution of phosgene in toluene was added. After standing at room temperature overnight, this mixture was diluted with a further 10 mi 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).
YieId:130 mg, melting point: 195°C
The following examples were prepared in analogy to Example 207:
Example 208:
3-(4-Morpholinosulfonylphenyl)-5-methoxy-1,3,4-oxdiazol-2-one melting point: 164°C

Example 209:
3-(4-Trifluoromethoxyphenyl)-5-methoxy-1,3,4-oxdiazol-2-one melting point: 52°C
Example 210:
3-(4-Trifluoromethoxyphenyl)-5-ethoxy-1,3,4-oxdiazol-2-one melting point: 63°C
Example 211:
3-(4-Trifluoromethoxyphenyl)-5-isopropoxy-1,3,4-oxdiazol-2-one melting point: oil Example 212:
3-(4-Trifluoromethoxyphenyl~5-butoxy-1,3,4-oxdiazol-2-one melting point: oil Example 213:
3-(4-Trifluoromethoxyphenyl)-5-benzyloxy-1,3,4-oxdiazol-2-one melting point: oil Example 214:
3-(4-(3,3,5-Trimethylcyclohexylaminosulfonyl)phenyl)-5-methoxy-1,3,4-oxdiazol-one melting point: 164°C
Example 215:
3-(4-(3,3,5,5-Tetramethylcyclohexyloxy)phenyl)-5-ethoxy-1,3,4-oxdiazol-2-one melting point: 111 °C
Example 216:
3-(3-Benzyloxyphenyl)-5-methoxy-1,3,4-oxdiazol-2-one melting point: oil Example 217:
3-(3-Benzyioxyphenyl)-5-ethoxy-1,3,4-oxdiazol-2-one melting point: 85°C
Example 218:
3-(3-Trifluoromethoxyphenyl)-5-ethoxy-1,3,4-oxdiazol-2-one melting point: oil Example 219:
3-(3-Trifluoromethoxyphenyl)-5-methoxy-1,3,4-oxdiazol-2-one melting point: oil Example 220:
3-(3-Trifluoromethoxyphenyl)-5-isopropoxy-1,3,4-oxdiazol-2-one melting point: oil Example 221:
3-(4-(2,2,6,6-Tetramethylpiperidin-4-yl-aminosulfonyl)phenyl)-5-methoxy-1,3,4-oxdiazol-2-one melting point: resin Example 222:
3-(4-(2,2,6,6-Tetramethylpiperidin-4-ylaminosulfonyl)phenyl)-5-isopropoxy-1,3,4-oxdiazol-2-one melting point: resin Example 223:
3-(4-(2-(Diisopropylaminoethyl)aminosulfonyl)phenyl)-5-methoxy-1,3,4-oxdiazol-one melting point: oil Example 224:

3-(4-(2-(Diisopropylaminoethyl)aminosulfonyl)phenyl)-5-isopropoxy-1,3,4-oxdiazol-2-one melting point: oil Example 225:
3-(4-(4-Methylpiperazin-1-yl-sulfonyl)phenyl)-5-isopropoxy-1,3,4-oxdiazol-2-one melting point: resin Example 226:
3-(4-(4-Methylpiperazin-1-yl-sul#onyi)phenyl)-5-methoxy-1,3,4-oxdiazol-2-one melting point: resin Example 227:
3-(3-(4,4,4-Trifluorobutyloxy)phenyl)-5-ethoxy-1,3,4-oxdiazol-2-one melting point: oil Example 228:
3-(3-(2-Diethylaminoethyloxy)phenyl)-5-ethoxy-1,3,4-oxdiazol-2-one melting point: resin Example 229:
3-(4-(4-Chlorophenoxy)phenyl)-5-methoxy-1,3,4-oxdiazol-2-one melting point: 68°C
Example 230:
3-(4-(4-Chlorophenoxy)phenyl)-5-isopropoxy-1,3,4-oxdiazol-2-one melting point: oil Example 231:
3-(4-(3,3,5-Trimethylcyclohexylaminosulfonyl)phenyl)-5-isopropoxy-1,3,4-oxdiazol-2-one melting point: oil Example 232:
3-(3-Phenoxyphenyl)-5-methoxy-1,3,4-oxdiazol-2-one melting point: 89°C
Example 233:
3-(3-Phenoxyphenyl)-5-ethoxy-1,3,4-oxdiazol-2-one melting point: 50°C
Example 234:
3-(3-Phenoxyphenyl)-5-isoproxy-1,3,4-oxdiazol-2-one melting point: 58°C
Example 235:
3-(4-Phenoxyphenyl)-5-methoxy-1,3,4-oxdiazol-2-one melting point: 83°C
Example 236:
3-(4-Cyclohexylphenyl)-5-methoxy-1,3,4-oxdiazol-2-one melting point: resin Example 237:
3-(3-(3,3,5,5-Tetramethylcyclohexyloxy)phenyl)-5-methoxy-1,3,4-oxdiazol-2-one melting point: 68°C
Example 238:
3-(4-Phenylphenyl)-5-methoxy-1,3,4-oxdiazol-2-one melting point: >260°C (decomp.) Example 239:
3-(3-(3-Methylphenoxymethyl)phenyl)-5-methoxy-1,3,4-oxdiazol-2-one melting point: 47°C

Example 240:
3-(3-Phenylphenyl)-5-methoxy-1,3,4-oxdiazol-2-one melting point: 80°C
5 Example 241:
3-(4-(3,3-Dimethylpiperidinocarbonyl)phenyl)-5-methoxy-1,3,4-oxdiazol-2-one melting point: resin Example 242:
10 3-(4-(3,3,5,5-Tetramethylcyclohexyloxy)phenyl)-5-isopropoxy-1,3,4-oxdiazol-2-one melting point: resin The compounds of the formula 1 show an inhibitory effect on pancreatic lipase (PL).
As PL inhibitors, they are able to prevent absorption of fat consumed with the diet 15 and thus lead to a reduction in the fat uptake and the body weight or prevent an increase in body weight. The compounds of the formula 1 are particularly suitable for producing medicaments for the treatment of obesity and of diabetes mellitus of type 1 and 2.
20 The activity of the compounds was assayed as follows:
1. Preparation of the substrate:
w 80 NI of tripalmitin (85 mM in chloroform) are mixed with 5,u1 of glycerol tri[9,10(nr 3H]oleate (5 mCilml in toluene) in a 12 ml polypropylene vessel. Evaporation in a 25 rotary evaporator (50°C) and addition of 4 ml of 200 mM TrislHCl (pH
7.6), 0.8% TX-100 are followed by ultrasound treatment of the mixture (Branson B-12 sonifier, output level 4, 3 X 2 min with 1 min intervals on ice) until a homogeneous milky suspension is produced.
30 2. Assay:
Lipase buffer: 80 mM TrislHCl (pH 7.6), 600 mM NaCI, 8 mM CaCl2, 8 mM
benzamidine, 2 mM Pefabloc (Roche Biochemicals) (add the inhibitors only on the day of the assay) Pancreatic lipase: Enriched preparation from porcine pancreas (Sigma order No.
L-0382) dissolved in lipase buffer (100 000 unitsl500,u1) Procedure:
5,u1 of test substance (in 100% DMSO) or DMSO (control) are mixed with 10 ~ul of substrate and 5 NI of lipase (in this sequence) and incubated at 30°C
(Eppendorf Thermomixer, 350 min-') for 30 min. After addition of 325,u1 of methanol/chloroform/n-heptane (10/9/7) and 105,u1 of 0.1 M K2C03, 0.1 M H3B03 (pH 10.5 adjusted with 1 M KOH) and vigorous mixing, the phases are separated by centrifugation (8000 rpm, Eppendorf centrifuge, 4°C). 140 NI portions of the aqueous supernatant {contains the liberated radiolabeled oleate; 70% recovery) are transferred into 20 ml scintillation vials and mixed with 6 ml of scintillation cocktail (Beckman ReadySafe). After vigorously mixing and incubating at room temperature for 2 h, the radioactivity is measured in a liquid scintillation counter (Beckman, L8008, tritium channel with quench curve, measurement time 20 min).
Evaluation:
Substances are routinely tested in each concentration in three independent incubation mixtures each with duplicate determination after phase separation (SD <
0.02). Background values (reaction under the same conditions but without lipase) are subtracted from all values (corresponds predominantly to the content of glycerol trioleate or free oleate in the substrate preparation in the aqueous phase, <
5% of the radioactivity employed). The inhibition of the pancreatic lipase enzymatic activity by a test substance is determined by comparison with an uninhibited control reaction (presence of lipase = 0% inhibition; absence of lipase 100% inhibition in each case after background correction). The lCSO is calculated from an inhibition plot with up to 8 concentrations of the test substance. The software package GRAPH IT
(Eisevier-BIOSOFT) is used for curve fitting and iCSO determination.

The compounds of the formula 1 showed the following effect in this assay system:
Compound from IC-50 Example: wM

_- _ _. _ 86 1.5 210 0.7 212 0.5 213 0.5 216 0.8 218 0.7 220 --_1.8 229 ~ 0.6

Claims (17)

claims:

1. The use of substituted 3-phenyl-5-alkoxy-1,3,4-oxdiazol-2-ones of the formula 1 in which the meanings are:
R1 C1-C6-alkyl, C3-C9-cycloalkyl, it being possible for both groups to be substituted one or more times by phenyl, C1-C4-alkyloxy, S-C1-C4-alkyl, N(C1-C4-alkyl)2, and for phenyl in turn to be substituted one or more times by halogen, C1-C4-alkyl, C1-C4-alkyloxy, nitro, CF3; and R2, R3, R4 and R5 independently of one another are hydrogen, halogen, nitro, C1-C4-alkyl; C1-C9-alkyloxy which is substituted by fluorine, C6-C10-aryl, amino or C1-C4-alkyl-amino;
C6-C10-aryl-C1-C4-alkyloxy, C6-C10-aryloxy, C6-C10-aryl, C6-C10-aryloxy-C1-C4-alkyl, C3-C8-cycloalkyl or O-C3-C8-cycloalkyl, each of which may be substituted once, twice or three times by halogen, CF3, C1-C4-alkyloxy or C1-C4-alkyl;
SO2-NH-C1-C6-alkyl, optionally substituted by N(C1-C6-alkyl)2, or SO2-NH-(2,2,6,6-tetramethylpiperidin-4-yl), SO2-NH-C3-C8-cycloalkyl, optionally substituted one or more times by C1-C4-alkyl, or SO2-N(C1-C6-alkyl)2 or COX, 2-oxo-pyrrolidin-1-yl, 2,5-dimethylpyrrol-1-yl or NR6-A-R7, with the proviso that R2, R3, R4 and R5 are not simultaneously hydrogen, with X O-C1-C6-alkyl, NH-C1-C6-alkyl, NH-C3-C8-cycloalkyl or N(C1-C6-alkyl)2 and N(C1-C6-alkyl)2 may also be pyrrolidino, piperidino, morpholino, thiomorpholino or piperazino, each of which may optionally be substituted by C1-C4-alkyl, benzyl, C6-C10-aryl, CO-C1-C4-alkyl, CO-C6-C10-aryl, CO-O-C1-C4-alkyl, SO2-C1-C4-alkyl or SO2-C6-C10-aryl;
R6 hydrogen, C1-C4-alkyl or C6-C10-aryl-C1-C4-alkyl, where aryl may be substituted by halogen, CF3, C1-C8-alkyloxy or C1-C4-alkyl;
A a single bond, CO n, SO n or CONH;
n 1 or 2;
R7 hydrogen;
C1-C18-alkyl or C2-C18-alkenyl, each of which may be substituted once to three times by C1-C4-alkyl, halogen, CF3, C1-C4-alkyloxy, N(C1-C4-alkyl)2, -COOH, C1-C4-alkyloxycarbonyl, C6-C12-aryl, C6-C12-aryloxy, C6-C12-arylcarbonyl, C6-C10-aryl-C1-C4-alkyloxy or oxo, where aryl in turn may be substituted by halogen, C1-C4-alkyl, aminosulfonyl or methylmercapto;
C6-C10-aryl-C1-C4-alkyl, C5-C8-cycloalkyl-C1-C4-alkyl, C5-C8-cycloalkyl, C6-aryl-C2-C6-alkenyl, C6-C10-aryl, biphenylyl, diphenyl-C1-C4-alkyl, indanyl, each of which may be substituted once or twice by C1-C18-alkyl, C1-C18-alkyloxy, C3-C6-cycloalkyl, COOH, hydroxyl, C1-C4-alkylcarbonyl, C6-C10-aryl-C1-C4-alkyl, C6-C10-aryl-C1-C4-alkyloxy, C6-C10-aryloxy, nitro, cyano, C6-C10-aryl, fluorosulfonyl, C1-C6-alkyloxycarbonyl, C6-C10-arylsulfonyloxy, pyridyl, NHSO2-C6-C10-aryl, halogen, CF3 or OCF3, where alkyl may be substituted again by C1-C4-alkyloxycarbonyl, CF3 or carboxyl, and aryl by halogen, CF3 or C1-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 C1-C4-alkyl, C6-C10-aryl, halogen, C1-C4-alkyloxy, C1-C4-alkyloxycarbonyl, C6-C10-aryl-C1-C4-alkyl, C6-C10-aryl-C1-C4-alkylmercapto or nitro, where benzo-fused aryl may in turn be substituted by halogen, C1-C4-alkyloxy or CF3 and alkyl in arylalkyl by methoxy and CF3, and of their pharmacologically acceptable salts and acid addition salts for producing a medicament with an inhibitory effect on pancreatic lipase.

2. The use of the compounds of the formula 1 as claimed in claim 1, in which the meanings are:
R1 C1-C6-alkyl which may optionally be substituted by phenyl; and/or R5 hydrogen; and/or R2 hydrogen, halogen, C1-C4-alkyl, C1-C9-alkyloxy or amino.

3. The use of the compounds of the formula 1 as claimed in claims 1 to 2, in which R3 is hydrogen, C1-C4-alkyl, C6-C10-aryl-C1-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 = C6-C10-aryl-C1-C4-alkyl which may be substituted by halogen, CF3, cyano, phenyl-C1-C4-alkyloxy, CF3-phenoxy, C5-C8-cycloalkyl or fluorosulfonyloxy;
C1-C12-alkyl which may be substituted by C1-C4-alkyloxy, phenyl, CF3 or phenyl-C1-C4-alkyloxy;
C2-C12-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 C1-C4-alkyl or halogen.

4. The use of the compounds of the formula 1 as claimed in claims 1 to 2, in which the meanings are:
R2 and R3 independently of one another hydrogen, C6-C10-aryl, C3-C8-cycloalkyl, optionally C1-C4-alkyl-substituted C6-C10-aryloxymethyl, optionally mono- or poly-C1-C4-alkyl- or halogen-substituted O-benzyl, O-C6-C10-aryl or O-C3-C8-cycloalkyl, mono- or poly-fluorine-, C6-C10-aryl- or amino-substituted O-C1-C6-alkyl, where amino in turn may be substituted one or more times by C1-C4-alkyl, or SO2-NH-C1-C6-alkyl, optionally substituted by N(C1-C6-alkyl)2, or NH-(2,2,6,6-tetramethylpiperidin-4-yl), SO2-NH-C3-C8-cycloalkyl, substituted by C1-C4-alkyl, SO2-N(C1-C6-alkyl)2 or CO-N(C1-C6-alkyl)2, and N(C1-C6-alkyl)2 may also be piperidino, morpholino or piperazino, each of which may optionally be substituted by C1-C4-alkyl.

5. The use of the compounds of the formula 1 as claimed in claims 1 to 4, in which the meanings are:
R4 hydrogen, 2-oxopyrrolidin-1-yl, 2,5-dimethylpyrrol-1-yl or C6-C10-aryl-C1-alkyloxy which may be substituted by halogen.

6. The use of the compounds of the formula 1 as claimed in claims 1 to 5, in which the meanings are:
R4 = NR6-A-R7, with R6 = hydrogen or methyl, A = single bond and R7 = hydrogen;
C1-C12-alkyl which may be substituted once or twice by halogen;
C2-C18-alkenyl which may be substituted once or twice by C1-C4-alkyl or C1-C4-alkyloxycarbonyl;
C6-C10-aryl-C1-C4-alkyl which may be substituted by halogen, C1-C6-alkyloxy, CF3, cyano, C5-C6-cycloalkyl, C1-C4-alkyloxycarbonyl, C6-C10-aryl-C1-C4-alkyl, C6-C10-aryl-C1-C4-alkyloxy, where aryl may be substituted again by halogen or CF3;
C5-C8-cycloalkyl-C1-C4-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, C1-C4-alkyloxy or C1-C4-alkyloxycarbonyl.

7. The use of the compounds of the formula 1 as claimed in claims 1 to 6, in which the meanings are:

R4 = NR6-A-R7 with R6 = hydrogen, A = -CO- and R7 = C1-C18-alkyl which may be substituted by halogen, phenyl, phenoxy, phenylcarbonyl or C1-C4-alkyloxycarbonyl, where phenoxy in turn may be substituted by methyl, halogen or methylmercapto;
C2-C18-alkenyl which may be substituted by C6-C10-aryl;
C6-C10-aryl which may be substituted by halogen, C1-C8-alkyl, phenyl-C1-C4-alkyl, CF3, OCF3, fluorosulfonyl, C1-C4-alkyloxycarbonyl, phenoxy, where aryl in turn may be substituted by C1-C4-alkyloxy;
C6-C10-aryl-C1-C4-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 C1-C4-alkyl, halogen, C1-C4-alkyloxy, halophenyl or halobenzylmercapto, where benzo-fused aryl may in turn be substituted by halogen or methoxy.

8. The use of the compounds of the formula 1 as claimed in claims 1 to 7, in which the meanings are:
R4 = NR6-A-R7, with R6 = hydrogen, A = -CO2- and R7 = C1-C18-alkyl which is substituted by CF3 or phenyl;
C6-C10-aryl;
C6-C10-aryl-C1-C4-alkyl which is substituted by C1-C4-alkyl, halogen, CF3 or 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 C1-C4-alkyl or benzyl.

9. The use of the compounds of the formula 1 as claimed in claims 1 to 8, in which the meanings are:
R4 = NR6-A-R7, with R6 = hydrogen, A = -SO2- and R7 = C1-C6-alkyl which may be substituted by CF3;
C2-C4-alkenyl which may be substituted by phenyl;
C6-C10-aryl which may be substituted by C1-C6-alkyl, halogen, C1-C4-alkyloxy or benzyl;
biphenylyl-C1-C4-alkyl, substituted by halogen;
or the group Het-(CH2)r-, with r = 0 and Het = saturated or unsaturated 5-7-membered heterocycle.

10. The use of the compounds of the formula 1 as claimed in claims 1 to 9, in which the meanings are:
R4 = NR6-A-R7, with R6 = hydrogen, A = -CO-NH- and R7 = C1-C10-alkyl which may be substituted by C1-C4-alkyloxycarbonyl, N(C1-C4-alkyl)2 or phenyl which may in turn be substituted by halogen or aminosulfonyl;
C6-C10-aryl which may be substituted by C1-C6-alkyl, C1-C6-alkyloxy, C1-C6-alkyloxycarbonyl, phenoxy, OCF3, benzyl or pyridyl, where alkyl may again be substituted by C1-C4-alkyloxycarbonyl or carboxyl;
C5-C8-cycloalkyl which may be substituted by hydroxyl, 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.

11. The use of the compounds of the formula 1 as claimed in claims 1 to 10, in which the meanings are:
R2 and R5 hydrogen, R3 hydrogen, C6-C10-aryl, O-C6-C10-aryl, optionally C1-C4-alkyl-substituted C6-C10-aryloxymethyl, O-benzyl, mono- or poly-fluorine- or amino-substituted O-C1-C6-alkyl, where amino in turn may be substituted one or more times by C1-C4-alkyl, or optionally mono- or poly-C1-C4-alkyl-substituted O-C3-C8-cycloalkyl and R4 hydrogen, C6-C10-aryl, C3-C8-cycloalkyl, optionally mono- or poly-C1-C4-alkyl-or halogen-substituted O-C6-C10-aryl or O-C3-C8-cycloalkyl, mono- or poly-fluorine-substituted O-C1-C6-alkyl, SO2-NH-C1-C6-alkyl, optionally substituted by N(C1-C6-alkyl)2, or SO2-NH-(2,2,6,6-tetramethylpiperidin-4-yl), SO2-NH-C3-C8-cycloalkyl, substituted one or more times by C1-C4-alkyl, SO2-N(C1-C6-alkyl)2 or CO-N(C1-C6-alkyl)2, and N(C1-C6-alkyl)2 is also piperidino, morpholino or piperazino, each of which may optionally be substituted by C1-C4-alkyl.

12. The use of the compounds of the formula 1 as claimed in claims 1 to 11, in which R1 is methyl, ethyl, butyl, isopropyl or benzyl, and R2 and R5 are hydrogen, and R3 is hydrogen, trifluoromethoxy, trifluorobutoxy, 3,3,5,5-tetramethylcyclohexyloxy, benzyloxy, phenoxy, phenyl, 2-diethylamino-ethyloxy or 3-methylphenoxymethyl, and R4 is hydrogen, trifluoromethoxy, 3,3,5,5-tetramethylcyclohexyloxy, phenoxy, 4-chlorophenoxy, cyclohexyl, phenyl, morpholinosulfonyl, 3,3,5-trimethylcyclohexylaminosulfonyl, 2,2,6,6-tetramethylpiperidin-4-ylaminosulfonyl, 2-(diisopropylaminoethyl)aminosulfonyl, 4-methylpiperazin-1-ylsulfonyl, 3,3-dimethylpiperidinocarbonyl or 3,5-dichlorophenoxy.

13. The use of the compounds of the formula 1 as claimed in claims 1 to 11, in which R1 is methyl, ethyl, butyl, isopropyl or benzyl, and R2 and R5 are hydrogen, and R3 is hydrogen, trifluoromethoxy, 3,3,5,5-tetramethylcyclohexyloxy, benzyloxy or phenoxy and R4 is hydrogen, trifluoromethoxy, 3,3,5,5-tetramethylcyclohexyloxy, phenoxy, cyclohexyl, phenyl, morpholinosulfonyl or 3,3,5-trimethylcyclohexyl-aminosulfonyl.

14. The use of the compounds of the formula 1 as claimed in claims 1 to 13, in which R1 is C1-C4-alkyl, R2 is hydrogen, R3 is hydrogen, trifluoromethoxy, benzyloxy, R4 is hydrogen, trifluoromethoxy, 4-chlorophenoxy, 4-trifluoromethylbenzoyl-amino, and R5 is hydrogen.

15. The use of the compounds of the formula 1 as claimed in claims 1 to 14, in which R1 is methyl.

16. The use of the compounds of the formula 1 as claimed in claims 1 to 15 in combination with one or more inhibitors of pancreatic lipase for producing a medicament for the prophylaxis or treatment of obesity.

17. The use of the compounds of the formula 1 as claimed in claims 1 to 15 in combination with one or more inhibitors of pancreatic lipase for producing a medicament for the prophylaxis or treatment of diabetes mellitus of type 1 and 2.