EP1482929A1 - 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-one for the production of medicaments with an inhibitory effect on the pancreatic lipase

The invention relates to the use of substituted 3-phenyl-5-alkoxy-1, 3,4-oxdiazol-2-ones for the production of medicaments which have an inhibitory effect on the pancreatic lipase, PL.

Substituted 3-phenyl-5-alkoxy-1, 3,4-oxdiazol-2-ones with an inhibitory effect on the hormone-sensitive lipase are known from WO 01/17981 (HMR 1999 / L 052) and WO 01/66531 (AVE-D 2000 / A 015K).

Surprisingly, it has now been found that substituted 3-phenyl-5-alkoxy-1, 3,4-oxdiazol-2-ones show an inhibitory effect on the pancreatic lipase, PL.

The invention therefore relates to the use of substituted 3-phenyl-5-alkoxy-1,3,4-oxdiazol-2-ones of the general formula 1,

1

in which mean:

R ¹ Ci-C-β-alkyl, C ₃ -C ₉ cycloalkyl, both groups by phenyl, CC ₄ - alkyloxy, S-Cι-C ₄ alkyl, N (CrC ₄ alkyl) ₂ one or more times can be substituted and phenyl in turn by halogen, -CC ₄ alkyl, CrC alkyloxy, nitro,

CF ₃ , can be substituted one or more times; and R ² , R ³ , R ⁴ and R ⁵ independently of one another hydrogen, halogen, nitro, -CC alkyl; Ci-Cg-alkyloxy, which is substituted by fluorine, C ₆ -Cιo-aryl, amino or CrC -alkyl-amino; C ₆ -Cιo-aryl -CC ₄ -alkyloxy, C ₆ -Cιo-aryloxy, C ₆ -Cιo-aryl, C ₆ -Cι ₀ -aryloxy-Cι-C ₄ - alkyl, C ₃ -C ₈ cycloalkyl or OC ₃ -C ₈ cycloalkyl, which can be mono-, tri-or trisubstituted by halogen, CF _3> CrC ₄ -alkyloxy or C ₁ -C ₈ -alkyl;

S0 ₂ -NH-CrC ₆ -alkyl, optionally substituted by N (C ₁ -C ₆ -alkyl) ₂ , SO ₂ - NH- (2.2 _I 6.6 ₎ -tetramethylpiperidin-4-yl), SO ₂ - NH-C ₃ -C ₈ -cycloalkyl, optionally mono- or polysubstituted by CrC-alkyl, SO ₂ -N (-C-C ₆ -

Alkyl) ₂ or COX,

2-oxopyrrolidin-1-yl, 2,5-dimethylpyrrol-1-yl or NR ⁶ -AR ⁷ ,

with the proviso that R ² , R ³ , R ⁴ and R ⁵ do not simultaneously mean hydrogen with

X O-CrC-e-alkyl, NH-C C ₆ alkyl, NH-C ₃ -C ₈ cycloalkyl or NCd-Ce-alkyl ^ and N (CrC ₆ alkyl) ₂ also for pyrrolidino, piperidino, morpholino. Thiomorpholino or piperazino, which may be substituted by C 1 -C ₄ alkyl, benzyl, Cβ-

C ₁₀ aryl, CO-Crd-alkyl, CO-C ₆ -Cι ₀ aryl, CO-OC C ₄ alkyl, SO ₂ -CC ₄ alkyl or SO ₂ -C ₆ -Cιo-aryl may be substituted; R ^{6 is} hydrogen, CC ₄ alkyl or. C ₆ -C ₁₀ aryl -CC ₄ -alkyl, where aryl can be substituted by halogen, CF ₃ , CrC ₈ alkyloxy or CrC alkyl; A is a simple bond, CO _n , SO _n or CONH; n 1 or 2;

R ^{7 is} hydrogen;

C ₁ -C 8 -alkyl or C ₂ -C ₁₈ -alkenyl which is mono- to triple-substituted by CC ₄ -alkyl, halogen, CF ₃ , dC ₄ -alkyloxy, N (CrC ₄ -alkyl) ₂ , -COOH, dd Alkyloxycarbonyl, C ₆ -C ₁₂ aryl, C ₆ -C ₂ aryloxy, C ₆ -Cι ₂ arylcarbonyl, Ce-do-aryl-dd-alkyloxy or oxo can be substituted, aryl in turn being substituted by halogen, C- ι-C ₄ - alkyl, aminosulfonyl or methyl mercapto may be substituted; Ce-do-aryl-dd-alkyl, Cs-Cs-cycloalkyl-dd-alkyl, C ₅ -C ₈ cycloalkyl, C ₆ -C ₁₀ - aryl-C ₂ -C ₆ -alkenyl, C ₆ -Cι ₀ - Aryl, biphenylyl, diphenyl -CC-C alkyl, indanyl by CC ₁₈ alkyl, d-ds-alkyloxy, C ₃ -C ₈ cycloalkyl, COOH, hydroxy, CC ₄ - alkylcarbonyl, C ₆ -Cιo-aryl -C-C ₄ -alkyl, C ₆ -C ₁₀ -aryl-Cι-C ₄ -alkyloxy, C ₆ -C ₁₀ -

Aryloxy, nitro, cyano, C6-C ₁₀ -aryl, fluorosulfonyl, -C ₆ alkyloxycarbonyl, C ₆ - Cio-arylsulfonyloxy, pyridyl, NHSO ₂ -C ₆ -Cι mono- or _0-aryl, halogen, CF ₃ or OCF ₃ can be substituted twice, where alkyl can be substituted again by C 1 -C ₄ -alkyloxycarbonyl, CF ₃ or carboxy and aryl by halogen, CF ₃ or dC ₄ -alkyloxy; or the group Het- (CH ₂ ) _r -, with r = 0, 1, 2 or 3 and Het = saturated or unsaturated 5-7-membered heterocycle, which fuses with benzo and with CrC ₄ -alkyl, C ₆ -Cio-aryl , Halogen, CC -alkyloxy, -CC ₄ -alkyloxycarbonyl, Ce-do-aryl-dd-alkyl, Ce-Cio-aryl-dd-alkylmercapto or nitro may be substituted, with benzo-fused aryl in turn by halogen, dC -alkyloxy or CF ₃ and alkyl in arylalkyl can be substituted by methoxy and CF ₃ ,

and their pharmacologically acceptable salts and acid addition salts for the manufacture of a medicament with an inhibitory effect on the pancreatic lipase.

The aryl radicals mentioned can optionally be substituted one or more times with d-Cg-alkyl, Ci-Cs-alkyloxy, halogen, trifluoromethyl. The cycloalkyl radicals mentioned can optionally be substituted one or more times with C 1 -C ₄ -alkyl, C ₆ -do-aryl and the alkyl radicals mentioned can be substituted by hydroxy, di-C ₄ -C ₄ -alkylamino and fluorine. Halogen represents fluorine, chlorine, bromine, preferably fluorine and chlorine. Alkyl, alkenyl, alkyloxy, etc. can be branched or unbranched. Preferred is the use of the compounds of formula 1, in which: R ¹ denotes Ci-Ce-alkyl, which may optionally be substituted by phenyl; and / or R ^{5 is} hydrogen; and or R ^{2 is} hydrogen, halogen, -CC ₄ -alkyl, -C-Cg-alkyloxy or amino, and their pharmacologically tolerable salts and acid addition salts for the manufacture of a medicament with an inhibitory effect on the pancreatic lipase.

Preference is furthermore given to the use of the compounds of the formula 1 in which R ^{3 is} hydrogen, CrC ₄ -alkyl, C ₆ -C ₀ -aryl-dC -alkyloxy which may optionally be substituted in the aryl part by halogen or NR ⁶ -AR ⁷ with R ⁶ = hydrogen or benzyl,

A = simple binding and

R ⁷ = C ₆ -Cι-aryl-Cι-C ₄ alkyl, which can be substituted by halogen, CF ₃ , cyano, phenyl-CrC ₄ - alkyloxy, CF ₃ -phenoxy, C ₅ -C ₈ cycloalkyl or fluorosulfonyloxy ; -CC ₂ -alkyl which can be substituted by -C ₄ -alkyloxy, phenyl, CF ₃ or phenyl-CrC -alkyloxy;

C ₂ -Ci ₂ alkenyl or the group Het- (CH ₂ ) r, with r = 0 or 1, and Het = saturated or unsaturated 5-7-membered heterocycle, which is benzo-fused and substituted with dC ₄ -alkyl or halogen can, means, or

of the compounds of formula 1, in which:

R ² and R ³ independently of one another are hydrogen, C ₆ -C ₁₀ aryl, C ₃ -C ₈ cycloalkyl, optionally substituted by CrC ₄ alkyl, C ₆ -Cι ₀ aryloximethyl, optionally substituted by dC ₄ alkyl or halogen. or poly-substituted O-benzyl OC ₆ -C ₁₀ aryl or OC ₃ -C ₈ cycloalkyl, one or more substituted by fluorine, C _δ -Cio-aryl or amino 0-dC ₆ alkyl, wherein amino in turn by Cι -C ₄ alkyl can be mono- or polysubstituted, SO ^ NH-d-Ce alkyl, optionally substituted by N (dC ₆ alkyl) ₂ , SO ₂ -NH- (2,2,6,6-tetramethylpiperidine -4-yl), SO ₂ -NH-C ₃ -C ₈ -cycloalkyl, substituted by CC ₄ -alkyl, SO ₂ -N (CC ₆ -alkyl) ₂ or CO-N (dC ₆ -alkyl) 2, and N (-C ₆ alkyl) _{2 can} also represent piperidino, morpholino or piperazino, which may optionally be substituted by C ₄ alkyl, and their pharmacologically acceptable salts and acid addition salts for the preparation of a medicament with an inhibitory effect on the pancreatic lipase.

In addition, the use of the compounds of the formula 1 is preferred, in which:

R ^{4 is} hydrogen, 2-oxopyrrolidin-1-yl, 2,5-dimethylpyrrol-1-yl or C ₆ -C ₁₀ aryl-CrC ₄ -alkyloxy, which may be substituted by halogen, and / or

of the compounds of formula 1, in which:

R ⁴ = NR ⁶ -AR ⁷ , with

R ⁶ = hydrogen or methyl, A = single bond and

R ⁷ = hydrogen;

C 1 -C ₂ alkyl, which can be mono- or disubstituted by halogen;

C ₂ -C ₁₈ -Alkenyl, the one or two times by -CC ₄ alkyl or CC -

Alkyloxycarbonyl may be substituted; Cβ-do-aryl-dd-alkyl, which is substituted by halogen, dC ₆ -alkyloxy, CF ₃ , cyano, C ₅ -C ₆ -

Cycloalkyl, -CC ₄ -alkyloxycarbonyl, C ₆ -C -o-aryl-CrC -alkyl, C ₆ -C ₁₀ -aryl-C C ₄ - alkyloxy may be substituted, where aryl may be substituted again by halogen or CF ₃ ;

C ₅ -C ₈ cycloalkyl-C C alkyl; or the group Het- (CH ₂ ) _r -, with r = 1, 2 or 3 and Het = saturated or unsaturated 5-7-membered

Heterocycle which can be substituted by halogen, dC ₄ -alkyloxy or dC ₄ -alkyloxycarbonyl, and / or

of the compounds of formula 1, in which:

R ⁴ = NR ⁶ -AR ⁷ , with R ⁶ = hydrogen, A = -CO- and

R ⁷ = d-cis-alkyl, which can be substituted by halogen, phenyl, phenoxy, phenylcarbonyl or C 1 -C ₄ -alkyloxycarbonyl, where phenoxy can in turn be substituted by methyl, halogen or methylmercapto; C ₂ -C ₈ alkenyl, which can be substituted by C ₆ -Cιo aryl;

Ce-do-aryl, which can be substituted by halogen, dC ₈ -alkyl, phenyl-dC ₄ -alkyl, CF ₃ , OCF ₃ , fluorosulfonyl, Cι-C -alkyloxycarbonyl, phenoxy, aryl in turn being substituted by Cι-C ₄ - Alkyloxy may be substituted; C ₆ -Cιo-aryl-Cι-C ₄ -alkyl, where alkyl can be substituted by methoxy or CF ₃ and aryl by halogen; or the group Het- (CH ₂ ) _r -, with r = 0 and Het = saturated or unsaturated 5-7-membered heterocycle, which is benzo-fused and with C 1 -C ₄ -alkyl, halogen, C 1 -C ₄ -alkyloxy, halogen - Phenyl or halogen-benzylmercapto can be substituted, wherein benzo-fused aryl can in turn be substituted by halogen or methoxy, and / or

of the compounds of formula 1, in which:

R ⁴ = NR ⁶ -AR ⁷ , with R ⁶ = hydrogen,

A = -CO ₂ - and

R ⁷ = d-cis-alkyl which is substituted by CF ₃ or phenyl;

C ₆ do aryl;

Ce-Cio-aryl-dd-alkyl, which is substituted by -CC ₄ alkyl, halogen, CF ₃ , or OCF ₃ , benzyloxy or phenyl; or the group Het- (CH ₂ ) _r , with r = 0 or 1 and Het = saturated or unsaturated 5-7-membered

Heterocycle, which can be benzo-fused and substituted with C 1 -C ₄ -alkyl or benzyl, and / or R ⁴ = NR ⁶ -AR ⁷ , with

R ⁶ = hydrogen,

A = -SO ₂ - and R ⁷ = CrC ₆ -AlkyI, which can be substituted with CF ₃ ; C ₂ -C alkenyl, which may be substituted by phenyl; C _ö -Cio-aryl, which can be substituted by Ci-Cβ-alkyl, halogen, CrC -alkyloxy or benzyl; Biphenylyl-dC ₄ alkyl substituted with halogen; or the group Het- (CH ₂ ) _r , with r = 0 and Het = saturated or unsaturated 5-7-membered heterocycle, and / or

of the compounds of formula 1, in which:

R ⁴ = NR ⁶ -AR ⁷ , with

R ⁶ = hydrogen,

A = -CO-NH- and

R ⁷ = Ci-Cio-alkyl, which may be substituted by dC ₄ -alkyloxycarbonyl, N (CC ₄ -alkyl) ₂ or phenyl, which in turn may be substituted by halogen or aminosulfonyl;

Ce-Cio-aryl, the by -CC ₆ alkyl, dC ₆ alkyloxy, dC ₆ alkyloxycarbonyl,

Phenoxy, OCF ₃ , benzyl or pyridyi, with alkyl again by Cι-C -

Alkyloxycarbonyl or carboxy may be substituted; C ₅ -C ₈ cycloalkyl, which can be substituted by hydroxy or indanyl; or the group Het- (CH ₂ ) r, with r = 0 or 1 and Het = saturated or unsaturated 5-7-membered

Heterocycle, which may be substituted with benzyl, and their pharmacologically acceptable salts and acid addition salts for the manufacture of a medicament with an inhibitory effect on the pancreatic lipase.

Preference is furthermore given to the use of the compounds of the formula 1, in which: R ² and R ^{5 are} hydrogen,

R ^{3 is} hydrogen, C ₆ -C ₁₀ aryl, OC ₆ -C ₁₀ aryl, optionally substituted by CC ₄ alkyl C ₆ -Cιo-aryloximethyl, O-benzyl, one or more times by fluorine or amino-substituted O-C ₆ alkyl, where amino can in turn be substituted one or more times by C ₁ -C ₄ alkyl, optionally substituted by C ₁ -C ₄ alkyl one or more times substituted OC ₃ -C ₈ cycloalkyl and R ^{4 is} hydrogen, C ₆ -C ₁ -aryl, C ₃ -C ₈ -cycloalkyl, optionally substituted by CrC -alkyl or halogen OC ₆ -C ₁ -aryl or OC ₃ -C ₈ - mono- or polysubstituted

Cycloalkyl, one or more fluorine-substituted OdC ₆ alkyl, SO ₂ - NH-CrC ₆ alkyl, optionally substituted by N (-C ₆ -alkyl) ₂ , SO ₂ -NH- (2,2,6, 6-tetramethylpiperidin-4-yl), SO ₂ -NH-C ₃ -C ₈ -cycloalkyl, mono- or polysubstituted by CC ₄ -alkyl, SO ₂ -N (dC ₆ -alkyl) ₂ or CO-N (dC _6- alkyl) ₂ mean, and

N (-C ₆ alkyl) ₂ also represents piperidino, morpholino or piperazino, which may optionally be substituted by C 1 -C alkyl, and their pharmacologically acceptable salts and acid addition salts for the preparation of a medicament with an inhibitory effect on the pancreatic lipase.

Particular preference is given to the use of the compounds of the formula 1 in which R ^{1 is} methyl, ethyl, butyl, isopropyl or benzyl and R ² and R ^{5 are} hydrogen and R ^{3 is} hydrogen, trifluoromethoxy, trifluorobutoxy, 3,3,5, 5

Tetramethylcyclohexyloxy, benzyloxy, phenoxy, phenyl, 2-diethylaminoethyloxy or 3-methylphenoxymethyl, and R ⁴ for hydrogen, trifluoromethoxy, 3,3,5,5-tetramethylcyclohexyloxy, phenoxy, 4-

Chlorophenoxy, cyclohexyl, phenyl, morpholinosulfonyl, 3,3,5-trimethylcyclohexyl-aminosulfonyl, 2,2,6,6, -tetramethyl-piperidin-4-yl-aminosulfonyl, 2- (diisopropylaminoethyl) aminosulfonyl, 4-methyl- piperazin-1 -yl-sulfonyl, 3,3, -Dimethylpiperidino-carbonyl or 3,5-dichlorophenoxy, or the compounds of formula 1, wherein R ^{1 is} methyl, ethyl, butyl, isopropyl or benzyl and R ² and R ⁵ stand for hydrogen and

R ³ for hydrogen, trifluoromethoxy, 3,3,5,5-tetramethylcyclohexyloxy, benzyloxy or phenoxy and R ^{4 represents} hydrogen, trifluoromethoxy, 3,3,5,5-tetramethylcyclohexyloxy, phenoxy, cyclohexyl, phenyl, morpholinosulfonyl or 3,3,5-trimethylcyclohexylaminosulfonyl, and their pharmacologically acceptable salts and acid addition salts for the preparation of a medicament with an inhibitory effect on the pancreatic lipase.

The use of the compounds of the formula 1 in which

R ¹ CτC-4-alkyl, R ² hydrogen,

R ^{3 is} hydrogen, trifluoromethoxy, benzyloxy,

R ^{4 is} hydrogen, trifluoromethoxy, 4-chlorophenoxy, 4-trifluoromethylbenzoylamino, and

R ^{5 is} hydrogen and their pharmacologically acceptable salts and acid addition salts for the manufacture of a medicament with an inhibitory effect on the pancreatic

Lipase.

It is also very particularly preferred to use the compounds of the formula 1 in which R ^{1 is} methyl and their pharmacologically tolerable salts and acid addition salts for the preparation of a medicament with an inhibitory effect on the pancreatic

Lipase.

The use of the compounds of the formula 1 mentioned in Examples 86, 210, 212, 213, 216, 218, 220 and 229 is also very particularly preferred.

The invention relates to the use of the compounds of 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 due to their higher water solubility compared to the starting or basic compounds. These salts must have a pharmaceutically acceptable anion or cation. Suitable pharmaceutically acceptable acid addition salts of the compounds of formula 1 are salts of inorganic acids, such as hydrochloric acid, hydrobromic, phosphoric, metaphosphoric, nitric, sulfonic and sulfuric acid, and organic acids, such as, for example, acetic acid, benzenesulfonic acid, benzoic acid, citric acid, Ethanesulfonic, fumaric, gluconic, glycol, isethionic, lactic, lactobionic, maleic, apple, methanesulfonic, succinic, p-toluenesulfonic, tartaric and trifluoroacetic acid. The chloride salt and the tartaric acid salt are used in a particularly preferred manner 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 non-pharmaceutically acceptable anion are also within the scope of the invention as useful intermediates for the production or purification of pharmaceutically acceptable salts and / or for use in non-therapeutic, for example in vitro, applications.

The term "physiologically functional derivative" as used herein means any physiologically acceptable derivative of a compound of the invention, e.g. an ester which, when administered to a mammal, e.g. humans, is able (directly or indirectly) to form such a compound or an active metabolite thereof.

Another aspect of this invention is the use of prodrugs of the compounds of formula 1. Such prodrugs can be metabolized in vivo to a compound of formula 1. These prodrugs may or may not be effective themselves.

The compounds of formula 1 can also exist in various polymorphic forms, for example as amorphous and crystalline polymorphic forms. All polymorphic Forms of the compounds of formula 1 are within the scope of the invention and are a further aspect of the invention.

In the following, all references to "compound (s) according to formula 1" refer to compound (s) of formula 1 as described above, and their salts, solvates and physiologically functional derivatives as described herein.

The amount of a compound of Formula 1 required to achieve the desired biological effect depends on a number of factors, e.g. the specific compound chosen, the intended one

Use, route of administration and clinical condition of the patient. In general, the daily dose is in the range from 0.3 mg to 100 mg (typically from 3 mg to 50 mg) per day per kilogram of body weight, for example 3-10 mg / kg / day. An intravenous dose can be, for example, in the range from 0.3 mg to 1.0 mg / kg, which can suitably be administered as an infusion of 10 ng to 100 ng per kilogram per minute. Suitable infusion solutions for these purposes can contain, for example, from 0.1 ng to 10 mg, typically from 1 ng to 10 mg, per milliliter. Single doses can contain, for example, from 1 mg to 10 g of the active ingredient. Thus, ampoules for injections can contain, for example, from 1 mg to 100 mg, and orally administrable single dose formulations, such as tablets or capsules, can contain, for example, from 1.0 to 1000 mg, typically from 10 to 600 mg. In the case of pharmaceutically acceptable salts, the aforementioned weight data relate to the weight of the salt of the compound of the formula 1. For the prophylaxis or therapy of the abovementioned conditions, the compounds of the formula 1 themselves can be used as a compound, but they are preferably in a compatible carrier Form of a pharmaceutical composition. The carrier must of course be compatible, in the sense that it is compatible with the other components of the composition and is not harmful to the health of the patient. The carrier can be a solid or a liquid or both and is preferably formulated with the compound as a single dose, for example as a tablet, which can contain from 0.05% to 95% by weight of the active ingredient. Other pharmaceutically active substances can also be present, including further compounds of the formula 1. The pharmaceutical compositions according to the invention can be prepared by one of the known pharmaceutical methods, which consist essentially in the fact that the constituents are mixed with pharmacologically acceptable carriers and / or auxiliaries.

Pharmaceutical compositions according to the invention are those which are suitable for oral, rectal, topical, peroral (for example sublingual) and parenteral (for example subcutaneous, intramuscular, intradermal or intravenous) administration, although the most suitable mode of administration in each individual case depends on the type and severity of the to be treated State and on the type of compound used according to formula 1 is dependent. Coated formulations and coated slow-release formulations also fall within the scope of the invention. Formulations which are resistant to acid and gastric juice are preferred. Suitable enteric coatings include cellulose acetate phthalate, polyvinyl acetate phthalate,

Hydroxypropylmethylcellulose phthalate and anionic polymers of methacrylic acid and methyl methacrylate.

Suitable pharmaceutical compounds for oral administration can be present in separate units, such as capsules, wafer capsules,

Lozenges or tablets, each containing a certain amount of the compound of formula 1; as powder or granules; as a solution or suspension in an aqueous or non-aqueous liquid; or as an oil-in-water or water-in-oil emulsion. As already mentioned, these compositions can be prepared by any suitable pharmaceutical method which comprises 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 prepared by uniformly and homogeneously mixing the active ingredient with a liquid and / or finely divided solid carrier, after which the product is shaped if necessary. For example, a tablet can be made by compressing or molding a powder or granules of the compound, optionally with one or more additional components. Compressed tablets can be prepared by tabletting the compound in free flowing form, such as a powder or granules, optionally mixed with a binder, lubricant, inert diluent and / or a (several) surface active / dispersing agent in a suitable machine. Molded tablets can be made by molding the powdered compound moistened with an inert liquid diluent in a suitable machine.

Pharmaceutical compositions suitable for oral (sublingual) administration include lozenges containing a compound of Formula 1 with a flavor, usually sucrose and acacia or tragacanth, and lozenges containing the compound in an inert base such as gelatin and glycerin or sucrose and gum arabic.

Suitable pharmaceutical compositions for parenteral administration preferably comprise sterile aqueous preparations of a compound according to formula 1, which are preferably isotonic with the blood of the intended recipient. These preparations are preferably administered intravenously, although they can also be administered subcutaneously, intramuscularly or intradermally as an injection. These preparations can preferably be prepared by mixing the compound with water and making the solution obtained sterile and isotonic with the 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 prepared 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. Vaseline, lanolin, polyethylene glycols, alcohols and combinations of two or more of these substances can be used as carriers. The active ingredient is generally present in a concentration of 0.1 to 15% by weight of the composition, for example 0.5 to 2%.

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

Triglyceride mixture 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 oil qs Sodium carboxymethyl cellulose 0.6 g

Polyoxyethylene stearate q.s.

Pure glycerin 0.2 to 2.0 g

Flavor q.s. Water (desalinated or distilled) to 100 ml

Example C

Rectal dosage form, containing 40 mg of active ingredient per suppository: per suppository

Active ingredient 40 mg

Suppository base mass ad 2 g

Example D tablets containing 40 mg of active ingredient per tablet: 40 mg of active ingredient per tablet

Lactose 600 mg

Corn starch 300 mg soluble starch 20 mg

Magnesium stearate 40 mg

1000 mg

Example E

Dragee, containing 50 mg of active substance per dragees: 50 mg of active substance per dragee

Corn starch 100 mg lactose 60 mg sec.calcium phosphate 30 mg soluble starch 5 mg Magnesium stearate 10 mg colloidal silica 5 mg

260 mg

Example F

The following recipes are suitable for producing the contents of hard gelatin capsules: a) Active ingredient 100 mg corn starch 300 mg

400 mg b) active ingredient 140 mg milk sugar 180 mg corn starch 180 mg 500 mg

Example G

Drops can be prepared according to the following recipe (100 mg active ingredient in 1 ml

= 20 drops): active ingredient 10 g

Methyl benzoate 0.07 g

Ethyl benzoate 0.03 g

Ethanol 96% 5 ml demineralized water ad 100 ml

The compounds of general formula 1 can be prepared by methods known per se in various ways.

For example, the substituted 3-phenyl-5-alkoxy-1, 3,4-oxdiazol-2-ones of general formula 1 can be prepared by reacting hydrazines of general formula 2 with chloroformic acid esters of formula 3 or other reactive carbonic acid ester derivatives, in which R ¹ , R ² , R ³ , R ⁴ and R ^{5 are} as defined above, to the compounds of formula 4, which acylated with phosgene, carbonyldiimidazole, diphosgene or triphosgene, cyclized and optionally by further chemical modification of the radicals R ² -R ⁵ , such as, for example, by reduction of nitro to amino residues by known processes, and subsequent acylation or alkylation, to give the compounds of the formula 1. Since acids are usually released during these reactions, it is advisable to add bases such as pyridine, triethylamine, sodium hydroxide solution or alkali carbonates to accelerate them. The reactions can be carried out over a wide temperature range. In general, it has proven to be advantageous to work at 0 ° C. up to the boiling point of the solvent used. Examples of solvents used are methylene chloride, THF, DMF, toluene, ethyl acetate, n-heptane, dioxane and 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 according to known methods or by nucleophilic substitution of appropriately substituted phenyl derivatives 6 (X = F, Cl, Br, I, OSO ₂ CF ₃ ) with hydrazine hydrate. Such suitable phenyl derivatives can be nitro-substituted halogenobenzenes, preferably fluoro- and chloro-nitrobenzenes, from which, at a suitable point in the synthesis route, reduction and reaction with acylating or alkylating agents, such as, for example, acid chlorides, anhydrides, isocyanates, chloroformates, sulfonic acid chlorides or alkyl and Arylalkyl halides, or by reductive alkylation with aldehydes according to known methods to prepare the compounds of formula 1.

The following examples explain the manufacturing methods in more detail without restricting them.

Examples:

Example 1 :

3-methyl-4-nitro-phenylhydrazine

5 g of hydrazine hydrate are slowly added dropwise at room temperature to the solution of 15.9 g of 2-methyl-4-fluoro-nitrobenzene in 10 ml of N-methylpyrrolidone, and the mixture is heated at 65 ° C. for 4 hours while stirring. The product is precipitated by adding 70 ml of water, filtered off with suction and recrystallized from isopropanol.

Yield: 13.3 g mp: 138 ° C The following examples were prepared in an analogous manner: Example 2:

3-fluoro-4-nitro-phenylhydrazine mp: 130 ° C

Example 3:

2-chloro-4-nitro-phenylhydrazine mp: 144 ° C

Example 4:

2-methyl-4-nitro-phenylhydrazine mp: 135 ° C

Example 5:

3- (4-fluorobenzyloxy) -2-nitro-phenylhydrazine mp: 164 ° C

The starting compound, 2-fluoro-4- (4-fluorobenzyloxy) nitrobenzene (mp: 99 ° C.) was prepared by alkylation of 3-fluoro-4-nitro-phenol with 4-fluorobenzyl chloride in DMF in the presence of potash.

Example 6:

3- (4-fluorobenzyloxy) -4-nitro-phenylhydrazine (intermediate) mp: 145 ° C

Example 7: 4- (4-chlorophenoxy) -3-nitro-aniline

1.4 g of potash are added to the 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-nitro-aniline are added and the mixture is stirred at 100 ° C. for 3 hours touched. After cooling, 80 ml of water added and the precipitate is filtered off after brief stirring and dried in vacuo at 40 ° C. Yield: 2.0 g; Mp .: 101 ° C

Example 8: 4- (4-chlorophenoxy) -3-nitro-phenylhydrazine

To the cooled to 0 ° C, stirred mixture consisting of 1.9 g of 4- (4-chlorophenoxy) -3-nitro-aniline, 25 ml of conc. Hydrochloric acid and 25 ml of ethanol, the solution of 0.52 g of sodium nitrite in 5 ml of water is added dropwise and the mixture is stirred at -0.degree. C. for 60 minutes and then a suspension of 8.5 g of tin dichloride dihydrate in 8 ml of conc. HCI added dropwise. The precipitate is filtered off, washed with water, slurried in nitrogen in 200 ml of water and decomposed at 100 ° -15 ° C. with 100 ml of 30% sodium hydroxide solution. The oil that forms is shaken out with ethyl acetate, washed with water, and the organic phase is dried with sodium sulfate. Then the product is precipitated with isopropanolic HCl, suction filtered and dried in vacuo. Yield: 1.1 g; Mp: 221 ° C

Example 9: N '- (4-nitro-2-methylphenyl) hydrazino-formic acid methyl ester

To the mixture consisting of 0.84 g of 2-methyl-4-nitro-phenylhydrazine, 15 ml of NMP and 2 ml of pyridine, 0.43 ml of methyl chloroformate was carefully added dropwise with ice cooling and then stirred with slow warming to RT for 2 hours. 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; Fp.:153°C

The following examples were made in a similar manner:

Example 10: N '- (4-nitro-phenyl) -hydrazino-formic acid methyl ester (intermediate) mp: 179 ° C.

Example 11: N '- (3-fluoro-4-nitro-phenyl) hydrazino-formic acid methyl ester, mp: 127.4 ° C

Example 12:

N '- (3-methyl-4-nitro-phenyl) hydrazino-formic acid methyl ester mp: 159 ° C

Example 13:

N '- (2-chloro-4-nitro-phenyl) hydrazino-formic acid methyl ester mp: 156 ° C

Example 14:

N '- (3- (4-fluorobenzyloxy) -4-nitro-phenyl) hydrazino-formic acid methyl ester (intermediate) mp: 166 ° C

Example 15:

N '- (3- (4-fluorobenzyloxy) -2-nitro-phenyl) hydrazino-formic acid methyl ester, mp: 193 ° C

Example 16: N '- (4- (4-chlorophenoxy) -3-nitro-phenyl) -hydrazino-formic acid methyl ester, mp: 147 ° C.

Example 17:

N '- (3-piperidino-4-nitro-phenyl) hydrazino-formic acid methyl ester (-) mp: 131 ° C This compound and the compound of Example 18 were prepared by reacting N '- (3-fluoro-4-nitro-phenyl) -hydrazino-formic acid methyl ester with piperidine or N-benzyl-piperazine in NMP at 80 ° C.

Example 18:

N '- (3- (N-Benzylpiperazino) -4-nitro-phenyl) hydrazino-formic acid methyl ester, mp: 156 ° C

Example 19: 5-Methoxi-3- (4-nitro-phenyl) -3-H- (1, 3,4) oxdiazol-2-one

2.5 g of N '- (4-nitro-phenyl) -hydrazino-formic acid methyl ester and 5 ml of pyridine were taken up in 15 ml of methylene chloride and, while stirring and cooling with ice, 3 ml of a 20% toluene phosgene solution were added dropwise. This mixture stood 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, solvent: methanol: methylene chloride = 2:98) and recrystallized from isopropanol. Yields, 5g mp: 151 ° C

The following examples were prepared analogously to Example 4:

Example 20: 5-methoxy-3- (3-methyl-4-nitro-phenyl) -3-H- (1,3,4) oxdiazol-2-one, mp: 112 ° C

Example 21:

5-methoxy-3- (4- (4-chlorophenoxy-3-nitro-phenyl) -3-H- (1,3,4) oxdiazol-2-one m.p .: oil Example 22:

5-methoxy-3- (3- (4-fluorobenzyloxy) -2-nitro-phenyl) -3-H- (1,3,4) oxdiazol-2-one mp: 99 ° C

Example 23: 5-methoxy-3- (2-methyl-4-nitro-phenyl) -3-H- (1, 3,4) oxdiazol-2-one mp: 111 ° C

Example 24: 5-methoxy-3- (3- (4-fluorobenzyloxy) -4-nitro-phenyl) -3-H- (1, 3,4) oxdiazol-2-one mp: 137 ° C

Example 25: 5-methoxy-3- (4-aminophenyl) -3-H- (1, 3,4) oxdiazol-2-one

The mixture consisting of 1.4 g of 5-methoxy-3- (4-nitro-phenyl) -3-H- (1,3,4) oxdiazol-2-one, 0.5 g of Pd / C and 20 ml of methanol is used hydrogenated under normal pressure at room temperature until the calculated amount of hydrogen was taken up. The catalyst is then filtered off and the solution is concentrated in vacuo. The remaining semi-solid residue is stirred with isopropanol and suction filtered. Yield: 0.75 g; Mp .: 85 ° C

Example 26:

5-Methoχi-3- (2-amino-4- (4-fluorobenzyloxy) phenyl) -3-H- (1, 3,4) oxdiazol-2-one Mp .: oil

Example 27:

5-Methoxi-3- (3-amino-4- (4-chlorophenoxy) phenyl) -3-H- (1, 3,4) oxdiazol-2-one mp: 133 ° C

Example 28: 5-methoxy-3- (4-amino-3-methylphenyI) -3-H- (1, 3,4) oxdiazol-2-one Mp .: 114 ° C

Example 29:

5-methoxi-3- (4-amino-3- (4-fluorobenzyloxy) phenyl) -3-H- (1, 3,4) oxdiazol-2-one mp: 195 ° C

Example 30: 5-Methoxi-3- (4- (4-chlorophenylacetylamino) phenyl) -3-H- (1, 3,4) oxdiazol-2-one

To the ice-cooled 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, 201 mg 4- Chlorphenylacetic acid chloride added dropwise and the mixture was stirred for 5 hours at room temperature. The volatile constituents 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; Mp: 161 ° C

The following examples were prepared in an analogous manner:

Example 31: 5-Methoxi-3- (4- (4-chlorophenylacetylamino) -3-methylphenyl) -3-H- (1, 3,4) oxdiazol-2-one mp: 190 ° C

Example 32:

5-Methoxi-3- (4-octanoylamino-3-methylphenyl) -3-H- (1, 3,4) oxdiazoI-2-one mp: 110 ° C

Example 33:

5-methoxy-3- (4- (4-heptyl-benzoylamino) phenyl) -3-H- (1, 3,4) oxdiazoI-2-one mp: 155 ° C

Example 34: 5-methoxy-3- (4- (4-butylphenylsulfonylamino) phenyl) -3-H- (1, 3,4) oxdiazol-2-one Mp: 135 ° C

Example 35:

5-Methoxi-3- (4- (4-chlorobutanoylamino) -3-methylphenyl) -3-H- (1, 3,4) oxdiazol-2-one mp: 137 ° C

Example 36:

5-methoxy-3- (4-pivaloylamino-3-methylphenyl) -3-H- (1,3,4) oxdiazol-2-one

Mp: 157 ° C

Example 37:

5-methoxy-3- (4- (4-chlorophenylsulfonylamino) -3-methylphenyl) -3-H- (1, 3,4) oxdiazol-2-one

Mp .: 147 ° C

Example 38:

5-methoxy-3- (4- (1-naphthylsulfonylamino) -3-methylphenyl) -3-H- (1, 3,4) oxdiazol-2-one

Mp .: 123 ° C

Example 39:

5-methoxy-3- (4- (2-phenylethenylsulfonylamino) -3-methylphenyl) -3-H- (1, 3,4) oxdiazole-

2-one

Mp: 129 ° C

Example 40:

5-methoxy-3- (4- (2,2,2-trifluoroethylsulfonylamino) -3-methylphenyl) -3-H- (1, 3,4) oxdiazole-

2-one

Mp .: 151 ° C

Example 41:

5-Methoxi-3- (4- (benzyloxicarbonylamino) -3-methylphenyl) -3-H- (1, 3,4) oxdiazol-2-one mp: 115 ° C Example 42:

5-Methoxi-3- (4- (3,4-dichlorophenylamino-carbonylamino) -3-methyl-phenyl) -3-H- (1, 3,4) oxdiazol-2-one mp: 210 ° C

This compound was obtained by reacting 5-methoxy-3- (4-amino-3-methylphenyl) -3-H- (1, 3,4) oxdiazol-2-one with equimolar amounts of 3,4-dichlorophenyl isocyanate in toluene obtained at 50 ° C.

Example 43:

5-Methoxi-3- (4- (4-chlorophenylsulfonylamino) phenyl) -3-H- (1, 3,4) oxdiazöl-2-one mp: 169 ° C

Example 44:

5-Methoxi-3- (4- (2-chlorophenylsulfonylamino) phenyl) -3-H- (1, 3,4) oxdiazol-2-one, mp: 171 ° C

Example 45: 5-methoxi-3- (4- (3-chlorophenylsulfonylamino) phenyl) -3-H- (1, 3,4) oxdiazol-2-one mp: 141 ° C

Example 46:

5-Methoxi-3- (4- (4-chlorophenylacetylamino) -3- (4-fluorobenzyloxi) phenyl) -3-H- (1, 3,4) oxdiazol-2-one mp: 167 ° C

Example 47:

5-methoxy-3- (4-benzylsulfonylaminophenyl) -3-H- (1, 3,4) oxdiazol-2-one mp: 153 ° C

Example 48: 5-methoxy-3- (4 - (- 2- (4'-chlorobiphenyl) ethyl) sulfonylamino) phenyl) -3-H- (1, 3,4) oxdiazol-2-one mp: 165 ° C

Example 49: 5-Methoxi-3- (4-isopropylsulfonylamino-phenyl) -3-H- (1, 3,4) oxdiazol-2-one mp: 190 ° C

Example 50: 5-methoxy-3- (4-dimethylamino-3-methyl-phenyl) -3-H- (1,3,4) oxdiazol-2-one, mp: 71 ° C

This compound was obtained by reacting 5-methoxy-3- (4-amino-3-methylphenyl) -3- H- (1, 3,4) oxdiazol-2-one with paraformaldehyde / formic acid in DMF at room temperature and by Column chromatography (silica gel, ethyl acetate-heptane = 1: 1) purified.

Example 51:

5-methoxi-3- (4- (4-chlorobenzylamino) -3-methylphenyl) -3-H- (1, 3,4) oxdiazol-2-one mp: oil

This compound was reacted with 5-methoxy-3- (4-amino-3-methylphenyl) -3- H- (1, 3,4) oxdiazol-2-one with 4-chlorobenzaldehyde / sodium borohydride in methanol / methylene chloride Obtain room temperature and purified by column chromatography (silica gel, ethyl acetate: n-heptane = 1: 1).

Example 52:

5-methoxi-3- (4- (2-oxopyrrolidin-1-yl) -3-methylphenyl) -3-H- (1, 3,4) oxdiazol-2-one mp: oil

This compound was obtained by reacting 5-methoxi-3- (4- (4-chlorobutanoylamino) -3-methylphenyl) -3-H- (1, 3,4) oxdiazol-2-one with sodium hydride Dioxane at room temperature and purification of the crude product by column chromatography (silica gel, methylene chloride: methanol = 98: 2).

Example 53: 5-methoxy-3- (4- (4-oxopent-2-en-2-yl-amino) -3-methylphenyl) -3-H- (1, 3,4) oxdiazole- 2- on mp: 143 ° C

This compound was obtained by reaction of 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 isolated by precipitation by adding water and filtration.

Example 54:

5-methoxy-3- (4- (2,5-diethylethyl-pyrrol-1-yl) -3-methylphenyl) -3-H- (1,3,4) oxdiazol-2-one mp: oil

This compound was obtained by reaction of 5-methoxy-3- (4-amino-3-methylphenyI) -3- H- (1, 3,4) oxdiazol-2-one with equimolar amounts of acetonylacetone in glacial acetic acid at 80 ° C , The mixture was worked up by dilution with water, shaking with ethyl acetate and column chromatography (silica gel, methylene chloride) of the crude product obtained after concentrating the dried organic phase.

Example 55:

5-methoxy-3- (3- (4-fluorobenzyloxy) -4-methylaminophenyl) -3-H- (1,3,4) oxdiazol-2-one, mp: 98 ° C

This compound was used as a by-product in the hydrogenation of 5-methoxy-3- (3- (4-fluorobenzyloxy) -4-nitro-phenyl) -3-H- (1, 3,4) oxdiazol-2-one with platinum dioxide Obtain catalyst in methanol at room temperature under normal 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 examples above.

Example 56: 5-methoxy-3- (3-aminophenyl) -3-H- (1, 3,4) oxdiazol-2-one mp: 95 ° C

Example 57:

5-methoxy-3- (3-dibenzylamino-phenyl) -3-H- (1, 3,4) oxdiazol-2-one mp: 71 ° C

Example 58:

5-methoxi-3- (3-benzylaminophenyl) -3-H- (1, 3,4) oxdiazol-2-one mp: oil

Example 59:

5-Methoxi-3- (4- (pyrid-2-yl) amino-carbonylamino-phenyl) -3-H- (1,3,4) oxdiazol-2-one, mp: 81 ° C

Example 60:

5-methoxi-3- (3- (4-fluorobenzyloxy) -4-benzyloxicarbonylamino-phenyl) -3-H- (1, 3,4) oxdiazol-2-one mp: 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-chlorobenzyloxicarbonylamino) phenyl) -3-H- (1,3,4) oxdiazol-2-one mp: 161 ° C Example 63:

5-methoxy-3- (4-amino-2-chlorophenyl) -3-H- (1, 3,4) oxdiazol-2-one mp: 126 ° C

Example 64:

5-methoxy-3- (2-chloro-4-nitro-phenyl) -3-H- (1, 3,4) oxdiazol-2-one mp: 92 ° C

Example 65:

5-Methoxi-3- (2-methyl-4-benzyloxicarbonylamino-phenyl) -3-H- (1, 3,4) oxdiazol-2-one mp: 112 ° C

Example 66: 5-Methoxi-3- (2-methyl-4- (4-trifluoromethoxibenzoylamino) phenyl) -3-H- (1, 3,4) oxdiazol-2-one mp: 150 ° C

Example 67: 5-Methoxi-3- (2-chloro-4-benzyloxicarbonylamino-phenyl) -3-H- (1, 3,4) oxdiazol-2-one mp: 150 ° C

Example 68:

5-methoxy-3- (3-fluoro-4-nitro-phenyl) -3-H- (1, 3,4) oxdiazol-2-one mp: 127 ° C

Example 69:

5-Methoxi-3- (4- (4-t-butylbenzoylamino) phenyl) -3-H- (1, 3,4) oxdiazol-2-one mp: 173 ° C

Example 70: 5-Methoxi-3- (4- (4-chloro-benzyloxicarbonylamino) phenyl) -3-H- (1, 3,4) oxdiazol-2-one Mp: 177 ° C

Example 71:

5-Methoxi-3- (2-chloro-4- (4-heptylbenzoylami ^' no) phenyl) -3-H- (1, 3,4) oxdiazol-2-one mp: 135 ° C

Example 72: -

5-methoxy-3- (4- (3,4-dichlorobenzoylamino) phenyl) -3-H- (1,3,4) oxdiazol-2-one

Mp .: 200 ° C

Example 73:

5-methoxy-3- (4- (2- (4-chlorophenoxy) -2-methyl-propionylamino) phenyl) -3-H-

(1, 3,4) oxdiazol-2-one

Mp: 153 ° C

Example 74:

5-Ethoxi-3- (3-methyl-4-benzyloxicarbonylamino-phenyl) -3-H- (1, 3,4) oxdiazol-2-one

Mp .: 94 ° C

Example 75:

5-isopropoxy-3- (3-methyl-4-benzyloxycarbonyamino-phenyl) -3-H- (1, 3,4) oxdiazol-2-one mp: 119 ° C

Example 76: 5-Isopropoxy-3- (3-methyl-4-butyloxicarbonylaminophenyl) -3-H- (1,3,4) oxdiazol-2-one mp: 114 ° C

Example 77:

5-Isopropoxy-3- (3-methyl-4- (3-chlorophenylamino-carbonylamino) -phenyl) -3-H- (1, 3,4) oxdiazol-2-one mp: 201 ° C Example 78:

5-tert.butoxi-3- (3-methyl-4-benzyloxicarbonylamino-phenyl) -3-H- (1, 3,4) oxdiazol-2-one mp: 113 ° C

Example 79: 5-Methoxi-3- (3-methyl-4-phenoxicarbonylamino-phenyl) -3-H- (1, 3,4) oxdiazol-2-one mp: 145 ° C

Example 80: 5-methoxy-3- (3-methyl-4- (pyrid-3-yl-carbonylamino) phenyl) -3-H- (1,3,4) oxdiazol-2-one mp: oil

Example 81: 5-methoxy-3- (3-methyl-4- (indan-2-yl-aminocarbonylamino) phenyl) -3-H- (1, 3,4) oxdiazol-2-one

Mp: 206 ° C

Example 82:

5-Methoxi-3- (3-methyl-4- (pyrid-3-yl-methylaminocarbonylamino) phenyl) -3-H- (1, 3,4) oxdiazol-2-one mp: 229 ° C

Example 83

5-Methoxi-3- (3-methyl-4- (pyrid-3-yl-methoxycarbonyamino) phenyl) -3-H- (1, 3,4) oxdiazol-2-one mp: 232 ° C

Example 84:

5-methoxi-3- (3-fluoro-4-benzyloxicarbonylamino-phenyl) -3-H- (1, 3,4) oxdiazol-2-one mp: oil

Example 85: 5-methoxy-3- (3-fluoro-4- (4-trifluoromethylbenzoylamino) phenyl) -3-H- (1, 3,4) oxdiazol-2-one mp: oil

Example 86: 5-methoxy-3- (3-benzyloxy-4- (4-trifluoromethylbenzoylamino) phenyI) -3-H- (1,3,4) oxdiazol-2-one mp: 159 ° C

Example 87: 5-methoxy-3- (3-fluoro-4- (4-tert-butyl-benzoylamino) phenyl) -3-H- (1, 3,4) oxdiazol-2-one mp: 144 ° C

Example 88:

5-Methoxi-3- (3-methyl-4- (2,2,2-trifluoroethoxycarbonylamino) phenyl) -3-H- (1,3,4) oxdiazol-2-one, mp: 141 ° C

Example 89:

5-Methoxi-3- (3-methyl-4-piperidinocarbonylamino-phenyl) -3-H- (1, 3,4) oxdiazol-2-one mp: 154 ° C

Example 90:

5-methoxy-3- (4- (6-methoxy-benzofuran-2-yl-carbonylamino) phenyl) -3-H- (1,3,4) oxdiazol-2-one mp: 191 ° C

Further examples, which were prepared by the methods described above and were characterized by mass spectroscopy (M + 1):

Example chemical name: M + 1 molge

No. w. 91 N- [4- (5-methoxy-2-oxo [1, 3,4] oxdiazol-3-yl) phenyl] -3- 362 361, 4 methyl-benzenesulfonamide

92 3,4-Dimethoxi-N- [4- (5-methoxy-2-oxo [1,3,4] oxdiazol-3- 408 407.4 yl) phenyl] benzenesulfonamide

93 Quinolin-8-sulfonic acid [4- (5-methoxy-2-oxo-399 398.4 [1, 3.4] oxdiazol-3-yl) phenyl] amide

94 N- [4- (5-Methoxi-2-oxo [1, 3,4] oxdiazol-3-yl) -p enyI] -5- 415 414.3 monomethyl nitro-isophthalate

95 3- (2-chlorophenyl) -5-methyl-isoxazole-4-carboxylic acid 427 426.8 [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- phenyl-propionamide

97 2-Fluoro-N- [4- (5-methoxy-2-oxo [1,3,4] oxdiazol-3-yl) -330,329.3 phenylj-benzamide

98 tetradecanoic acid [4- (5-methoxy-2oxo [1, 3,4] oxdiazol-418,417,5 3-yl) phenyl] amide

99 N- [4- (5-methoxy-2-oxo [1, 3,4] oxdiazol-3-yl) phenyl] -2- 416 415.4 phenethyl benzamide

100 N- [4- (5-methoxy-2-oxo [1, 3,4] oxdiazol-3-yl) phenyl] -2- 479,478.4 (4-methoxyphenoxy) -5-nitro- benzamide

101 2- (4-Benzyloxy-phenyl) -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-triphenyl-propionamide

103 N- [4- (5-methoxy-2-oxo [1, 3,4] oxdiazol-3-yl) phenyl] -3,5- 448,447,3 bis-trifluoromethyl-benzamide

104 4-Cyano-N- [4- (5-methoxy-2-oxo [1, 3,4] oxdiazol-3-yl) - 337,336.3 phenylj-benzamide

105 nonanoic acid [4- (5-methoxy-2-oxo [1, 3,4] oxdiazol-3-yl) - 348,347.4 phenyl] amide

106 9- [4- (5-Methoxi-2-oxo [1, 3,4] oxdiazol-3-yl) - 406 405.4 phenyl carbamoylj nonanoic acid methyl ester 107 Undecanoic acid [4- (5-methoxy-2-oxo [1,3,4] oxdiazol-3-376,375.5 yl) phenyl] amide

108 4- [4- (5-methoxy-2-oxo [1, 3,4] oxdiazol-3-yl) - 394,393.3 phenylcarbamoylj-benzenesulfonyl fluoride

109 11-phenoxy-undecanoic 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-joxydiazol-3-yl) phenyl] -2,3-416,415.4 diphenyl-propionamide

111 4-Chloro-N- [4- (5-methoxy-2-oxo [1, 3,4] oxdiazol-3-yI) -360,359.8 phenyl] -2-methyl-benzamide

112 6-Chloro-N- [4- (5-methoxy-2-oxo [1, 3,4] oxdiazol-3-yI) - 347 346.7 phenylj-nicotinamide

113 5-Fluoro-N- [4- (5-methoxy-2-oxo [1, 3,4] oxdiazol-3-yl) - 344,343.3 phenyl] -2-methyl-benzamide

114 N- [4- (5-methoxy-2-oxo [1, 3,4] oxdiazol-3-yl) phenylj- 354,353,4 2,4,6-trimethyl-benzamide

115 N- [4- (5-methoxy-2-oxo [1, 3,4] oxdiazol-3-yl) phenyl] -3- 388 387.4 naphthalene-2-yl-acrylamide

116 5-Oxo-5-phenylpentanoic acid [4- (5-methoxy-2-oxo-382 381,4 [1, 3,4] oxdiazol-3-yl) phenyl] amide

117 3- (2,4-dichlorobenzylsulfanyl) thiophene-2-carboxylic acid 509 508.4 [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-yl) - 398,397.3 phenyl] -4-trifluoromethyl-benzamide

119 1-Hexyl-3- [3- (5-methoxy-2-oxo [1, 3,4] oxdiazol-3-yl) - 335 334.4 phenylj-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, 3,4] oxdiazol-3-yl) phenyl] -3- 357,356.3 (2-methoxyphenyl) urea

122 2- [3- [3- (5-Methoxi-2-oxo [1, 3,4] oxdiazol-3-yl) phenyl] - 427 426.4 ureido] -3-phenyl-propionic acid ethyl ester 123 1- (2,6-diisopropylphenyl) -3- [3- (5-methoxy-2-oxo-411 410.5 [1, 3,4] oxdiazol-3-yl) phenyl] urea

124 1- [3- (5-methoxy-2-oxo [1, 3,4] oxdiazol-3-yl) phenyl] -3- 363 362.4 octylurea

125 1- (4-Fluoro-benzyl) -3- [3- (5-methoxy-2-oxo-359 358.3 [1, 3,4] oxdiazol-3-yl) phenyl] urea

126 - 1- (2-Ethylphenyl) -3- [3- (5-methoxy-2-oxo-355 354.4

[1, 3,4joxdiazol-3-yl) phenyl] urea

127 6- [3- [3- (5-Methoxi-2-oxo [1, 3,4] oxdiazol-3-yl) phenylj- 393 392.4 ureidoj-hexanoic acid, ethyl ester

128 1- (2,6-Dimethoxyphenyl) -3- [3- (5-methoxy-2-oxo-387 386.4 [1,3,4] oxdiazol-3-yl) phenyl] urea

129 5-Methoxi-3- [4 - [(thiophen-3-ylmethyl) aminoj-phenylj-304 303.3 3H- [1, 3,4] oxdiazol-2-one

130 4 - [[4- (5-Methoxii2-oxo [1, 3,4] oxdiazol-3-yl) - 437 436.3 phenylaminoj-methylj-benzonitrile trifluoroacetate

131 3- [4- (2-Bromo-4,5-dimethoxybenzylamino) phenyl] -5- 437 436.3 methoxy-3H- [1, 3.4] oxdiazoI-2-one

132 3- [4- (3-Ethoxy-4-methoxy-benzylamino) phenyl] -5- 486 485.4 methoxy-3H- [1,3,4] oxdiazol-2-one-trifluoroacetate

133 4 - [[4- (5-Methoxi-2-oxo [1, 3,4] oxdiazol-3-yl.) - 470 469.4 phenylaminoj-methylj-benzoic acid methyl ester trifluoroacetate

134 Acetic acid 4 - [[4- (5-methoxy-2-oxo [1,3,4] oxdiazol-3 356 355.3 yl) phenylamino] methyl] phenyl ester

135 5-methoxy-3- [4- (pentafluorophenylmethylamino) - 388 387.3 phenyl] -3H- [1, 3,4] oxdiazol-2-one

136 3- [4- (4-Benzyloxy-benzylamino) phenyl] -5-methoxy-3H-518 517.5 [1, 3,4] oxdiazole-2-όn-trifluoroacetate

137 3- [4- (3,3-dichloro-nonylamino) phenyl] -5-methoxy-3H-517 516.3 [1,3,4-oxydiazol-2-one-trifluoroacetate

138 2 - [[4- (5-methoxy-2-oxo [1, 3,4] oxdiazol-3-yl) - 323,322.3

, _ i - -, ι: xi_. .n ■ ._: -: x ..: ι - phenylaminoj-methylj-benzonitrile

139 3- [4- (Cyclohexylmethylamino) phenyl] -5-methoxy-3H-304. 303.4 [1, 3.4] oxdiazol-2-one

140 5-methoxy-3- [4- (2,3,5-trichlorobenzylamino) phenyl] -3H- 515 514.7 [1, 3.4] oxdiazol-2-one trifluoroacetate

141 3- [4- (5-Bromo-2-fluoro-benzylamino) phenyl] -5-methoxy-509 508.2 3H- [1, 3,4] oxdiazol-2-one trifluoroacetate

142 3- [4- (4-Hexyloxy-benzylamino) phenyl] -5-methoxy-3H-512 511, 5 [1, 3,4] oxdiazol-2-one trifluoroacetate

143 5-methoxy-3- [4- [3- (3-trifluoromethylphenoxy) - 572 571, 4 benzylamino] phenyl] -3H- [1, 3,4] oxdiazoI-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 3-Methoxy-5 - [[4- (5-methoxy-2-oxo [1, 3,4] oxdiazol-3-yl) - 501,500.4 phenylamino] methyl] pyridine-2-carboxylic acid methyl ester trifluoroacetate

146-4-benzenesulfonic acid - [[4- (5-methoxy-2-oxo-454 453.5 [1,3,4] oxdiazol-3-yl) phenylamino] methylJ-phenyl ester

147 2- (2,6-Dimethyl-4-methylsulfanyl-phenoxy) -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) phenyl] -3- 419 418.4 (4-phenoxyphenyl) urea

150 1- (2,6-difluorophenyl) -3- [4- (5-methoxy-2-oxo-363,362.3 [1,3,4] oxdiazol-3-yl) phenyI] urea

151 1-Butyl-3- [4- (5-methoxy-2-oxo [1, 3,4-joxydiazol-3-yl) - 307 306.3 phenylj-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-oxo-503 502.1 [1, 3.4] oxdiazol-3-yl) 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-Methoxi-2-oxo [1, 3,4] oxdiazol-3-yl) phenyl] -3- 411 410.3 (4-trifluoromethoxyphenyl) urea

156 1-Benzyl-3- [4- (5-methoxy-2-oxo [1, 3,4] oxdiazol-3-yl) - 341 340.3 phenylj-urea

157 1- (3-Fluoro-phenyl) -3- [4- (5-methoxy-2-oxo-345 344.3 [1, 3.4] oxdiazol-3-yl) phenyl] urea

158 6- [3- [4- (5-Methoxi-2-oxo [1, 3,4] oxdiazol-3-yl) phenylj- 393 392.4 ureidoj-hexanoic acid ethyl ester

159 1-Biphenyl-4-yl-3- [4- (5-methoxy-2-oxo [1, 3,4] oxdiazol-403 402,4 3-yl) phenyl] urea

160 2- [3- [4- (5-Methoxy-2-oxo [1, 3,4] oxdiazol-3-yl) phenyl] - 427 426.4 ureidoj-benzoic acid butyl ester

161 5-methoxy-3- [3- (7-methoxy-3,7-dimethyl-octylamino) - 492 491, 5 phenyl] -3H- [1,3,4] oxdiazol-2-one-trifluoroacetate

162 5-Methoxi-3- [3 - [(thiophene-2-ylmethyl) amino] phenylj- 418 417.4 3H- [1, 3,4] oxdiazol-2-one trifluoroacetate

163 3- (3-Hexylamino-phenyl) -5-methoxy-3H- [1,3,4] oxdiazole-406,405,4 2-one-trifluoroacetate

164 5-Methoxi-3- [3- (3-phenyl-propylamino) phenyl] -3H- 440 439.4 [1, 3,4] oxdiazol-2-one trifluoroacetate

165 5-methoxy-3- (3-undecylamino-phenyl) -3H- 476 475.5 [1, 3.4] oxdiazol-2-one trifluoroacetate

166 5-methoxy-3- [3- [3- (3-trifluoromethylphenoxy) - 572 571, 4 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-Fluoro-benzenesulfonic acid 4 - [[3- (5-methoxy-2-oxo-586 585.5 [1,3,4] oxdiazol-3-yl) phenylamino] methyl] phenyl ester trifluoroacetate

169 5-methoxy-3- [3- (3,4,5-trifluoro-benzylamino) phenyl] -3H- 466 465.3 [1, 3,4] oxdiazol-2-one trifluoroacetate

170 3- [3- (3,5-bis-trifluoromethylbenzylamino) phenyl] -5- 548 547.3 methoxy-3H- [1, 3,4] oxdiazol-2-one trifluoroacetate

171 3- (3-Dec-4-enylaminophenyl) -5-methoxy-3H- 460 459.5 [1, 3,4] oxdiazol-2-one trifluoroacetate

172 3- [3- (3-Cyclopentyl-2-phenethyloxy-benzylamino) - 600 599.6 phenyl] -5-methoxy-3H- [1, 3,4] oxdiazol-2-one trifluoroacetate

173 4 - [[3- (5-Methoxi-2-oxo [1, 3,4] oxdiazol-3-yl) - 437 436.3 phenylaminoj-methylj-benzonitrile trifluoroacetate

174 5-Methoxi-3- [3 - [(6-methyl-pyridin-2-ylmethyl) amino] - 427 426.3 phenyl] -3H- [1, 3,4] oxdiazol-2-one-trifluoroacetate

175 3- [3- (2-Benzyloxy-ethylamino) phenyl] -5-methoxy-3H-456 455.4 [1, 3,4] oxdiazol-2-one trifluoroacetate

176 3- [3- (2,6-Difluorobenzylamino) phenyl] -5-methoxy-3H- 448 447.3 [1, 3,4] oxdiazol-2-one trifluoroacetate

Mp ° C

177 Dodecanoic acid [4- (5-methoxy-2-oxo [1, 3,4] oxdiazol-3-yl) - 93 phenyl] amide

178 octadec-9-enoic acid [4- (5-methoxy-2-oxo [1,3,4] oxdiazol-3-67 yl) phenyl] amide

179 [4- (5-methoxy-2-oxo [1, 3,4] oxdiazol-3-yl) -2-imethylphenyl] - 17 carbamic acid 2-methoxyethyl ester

180 1- (4-Hydroxy-cyclohexyl) -3- [4- (5-methoxy-2-oxo-220 [1,3,4] oxdiazol-3-yl) -2-methylphenyl] urea

181 1, 1-dibutyl-3- [4- (5-ιmethoxi-2-oxo [1, 3,4] oxdiazol-3-yl) -2-oil methyl-phenylj-urea 182 5-methoxy-benzofran-2-carboxylic acid- [4- (5-methoxy-2-oxo-199 [1, 3,4] oxdiazol-3-yl) -2-methyl-phenylj-amide

183 4-Methylpiperazine-1-carboxilicic acid [4- (5-methoxy-2-oxo oil [1, 3,4] oxdiazol-3-yl) -2-methylphenyl] amide

184 [4- (5-methoxy-2-oxo [1,3,4] oxdiazol-3-yl) -2-methylphenyl] - 235 carbamic acid 1-methylpiperidin-4-yl ester

185 [4- (5-methoxy-2-oxo [1, 3,4] oxdiazol-3-yl) -2-methylphenyl] - 163 carbamic acid cyclohexyl ester

186 4-Benzyl-piperidine-1-carboxylic acid- [4- (5-methoxy-2-oxo-146 [1,3,4] oxdiazol-3-yl) -2-methylphenylj-amide

187 1- (2-Diisopropylamino-ethyl) -3- [4- (5-methoxy-2-oxo-136 [1,3,4] oxdiazol-3-yl) -2-methylphenylj-urea

188 4- (2- {3- [4- (5-Methoxy-2-oxo [1,3,4] oxdiazol-3-yl) -2-methyl-200 phenyl] -ureido} ethyl) benzenesulfonamide

189 1- (1-benzyl-piperidin-4-yl) -3- [4- (5-methoxy-2-oxo-198 [1, 3,4] oxdiazol ~ 3-yl) -2-methyl-phenylj- urea

190 1- (4-isopropylphenyl) -3- [4- (5-methoxy-2-oxo [1, 3,4] oxdiazol-200 3-yl) -2-methylphenyljurea

191 2- {3- [4- (5-Methoxy-2-oxo [1,3,4] oxdiazol-3-yl) -2-methyl-246 phenyl] -ureido} -3-methyl-butyric acid

192 [4- (5-methoxy-2-oxo [1, 3,4] oxdiazol-3-yl) -2-methylphenyl] - 159 carbamic acid 1, 2,3,4-tetrahydro-naphth-1 - yl ester

193 [4- (5-Methoxy-2-oxo [1, 3,4] oxdiazol-3-yl) -2-methylphenyl] - oil carbamic acid 1-phenyl ethyl ester

194 [4- (5-Methoxy-2-oxo [1, 3,4] oxdiazol-3-yl) -2-methylphenylj-88 carbamic acid 4-isopropyl benzyl ester

195 [4- (5-methoxy-2-oxo [1,3,4] oxdiazol-3-yl) -2-methylphenyl] - 82 carbamic acid 4-trifluoromethoxy benzyl ester

196 [4- (5-methoxy-2-oxo [1, 3,4] oxdiazol-3-yl) -2-methylphenyl] - 169 carbamic acid 3,5-dichlorobenzyl ester

197 [4- (5-methoxy-2-oxo [1, 3,4] oxdiazol-3-yl) -2-methylphenyl] - 138 carbamic acid biphenyl-2-ylmethyl ester 198 5-chloro-benzofuran-2-carboxylic acid- [4- (5-methoxy-2-oxo-210 [1,3,4] oxdiazol-3-yl) -2-methylphenylj amide

199 5-chloro-benzofuran-2-carboxylic acid- [4- (5-methoxy-2-oxo-209 [1, 3,4] oxdiazol-3-yl) phenyl] amide

Example 200:

4-fluoro-benzenesulfonic acid morpholide (intermediate)

20 g of morpholine were added dropwise to the ice-cooled solution of 19.5 g of 4-fluoro-benzenesulfonic acid chloride in 100 ml of toluene and the mixture was heated under reflux for 1 hour. After cooling, the mixture was concentrated in vacuo, stirred with water, the precipitate was filtered off with suction, washed with water and recrystallized from isopropanol. Yield: 16.9 g mp: 140 ° C

Example 201:

4-hydrazino-benzenesulfonic acid-morpholide (intermediate) 5 g of 4-fluoro-benzenesulfonic acid-morpholide were dissolved in 15 ml of N-methylpyrrolidone, mixed with 2.5 g of hydrazine hydrate and heated to 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 suction filtered and recrystallized from isopropanol. Yield: 3.2 g mp: 164 ° C

The following example was produced analogously:

Example 202:

4-hydrazino-benzoisulfonic acid- (3,3,5-trimethyl-cyclohexyl) -amide (intermediate) mp: 129 ° C

Example 203: 4- (3,3,5,5-tetramethylcyclohexyl-oxi) nitrobenzene (intermediate)

1.3 g of sodium hydride are added to the 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 minutes. Then a total of 7.0 g of 4-fluoro-nitrobenzene are added in portions and the The mixture was then heated to 100 ° C. for 3 hours and cooled to room temperature. After adding 250 ml of ice water, the mixture is stirred and the solid formed is filtered off with suction and dried in vacuo. Yield: 8.6 g. Mp .: 70 ° C. 5 Example 204:

4- (3,3,5,5-tetramethylcyclohexyloxy) aniline (intermediate) 8.3 g of 4- (3,3,5,5-tetramethylcyclohexyloxy) nitrobenzene are dissolved in 500 ml of methanol in the presence of 400 mg of platinum dioxide hydrogenated under normal pressure until the end of the hydrogen uptake. After filtering off the catalyst, the solution is spun in and the residue, a gradually solidifying, brownish oil, is used for the further reactions without further purification. Yield: 7.3 g

15 Example 205:

4- (3,3,5,5-Tetramethylcyclohexyl-oxi) -phenylhydrazine hydrochloride (intermediate) To the stirred mixture, cooled to -10 ° C, consisting of 3.7 g 4- (3, 3,5,5-Tetramethylcyclohexyl -oxi) -aniline, 7.5 ml water and 15.5 ml conc. HCI, the solution of 1.13 g sodium nitrite in 7.5 ml water is added dropwise and the mixture at -

20 10 ° C stirred for 45 min and then to the suspension of 9.3 g of tin dichloride dihydrate in 7 ml conc. HCI added dropwise. The precipitate is filtered off, washed with water, slurried in nitrogen in 200 ml of water and decomposed at 100 ° -15 ° C. with 100 ml of 30% sodium hydroxide solution. The precipitate which forms again is filtered off with suction, washed with water, taken up in 200 ml of ether and with

25 dried sodium sulfate. Then the product is precipitated with ethereal HCI, suction filtered and dried in vacuo. Yield: 2.1 g mp: 171 ° C

Example 206: 30 N '- (4-Morpholinosulfonyl-phenyl) -hydrazino-formic acid ethyl ester (intermediate) To the mixture consisting of 0.275 g of 4-hydrazino-benzenesulfonic acid morpholide, 5 ml of methylene chloride and 1 ml of pyridine, 114 mg of ethyl chloroformate were carefully added dropwise with ice cooling and the mixture was then stirred with slow warming to RT. After dilution with 10 ml of water, the product was shaken out with ethyl acetate, the ethyl acetate phase was washed several times with water, dried over sodium sulfate and concentrated. The oily crude product thus obtained was reacted further without further purification. Yield: 0.25 g

Example 207:

3- (4-Morpholinosulfonyl-phenyl) -5-ethoxi-1, 3,4-oxdiazol-2-one The oil from example 206 was taken up in 5 ml of methylene chloride and under

Stir and ice cooling with 1 ml of a 20% toluene phosgene solution. This mixture stood 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 by column chromatography (silica gel, solvent:

MethanokMethylenchlorid = 2: 98) cleaned.

Yield: 130 mg mp: 195 ° C

The following examples were produced analogously to example 207:

Example 208:

3- (4-Morpholinosulfonyl-phenyl) -5-methoxy-1, 3,4-oxdiazol-2-one mp: 164 ° C

Example 209:

3- (4-trifluoromethoxyphenyl) -5-methoxy-1, 3,4-oxdiazol-2-one mp: 52 ° C Example 210:

3- (4-Trifluoromethoxi-phenyl) -5-ethoxi-1, 3,4-oxdiazol-2-one mp: 63 ° C

Example 211:

3- (4-trifluoromethoxyphenyl) -5-isopropoxy-1, 3,4-oxdiazol-2-one mp: oil

Example 212:

3- (4-trifluoromethoxyphenyl) -5-butoxy-1, 3,4-oxdiazol-2-one mp: oil

Example 213: 3- (4-trifluoromethoxyphenyl) -5-benzyloxi-1, 3,4-oxdiazol-2-one mp: oil

Example 214:

3- (4- (3,3,5-Trimethyl-cyclohexylaminosulfonyl) phenyl) -5-methoxy-1, 3,4-oxdiazol-2-one mp: 164 ° C

Example 215:

3- (4- (3,3,5,5-Tetramethylcycloohexyl-oxi) phenyl) -5-ethoxy-1, 3,4-oxdiazol-2-one, mp: 111 ° C

Example 216:

3- (3-Benzyloxi-phenyl) -5-methoxi-1, 3,4-oxdiazoI-2-one mp: oil

Example 217

3- (3-Benzyloxiphenyl) -5-ethoxi-1, 3,4-oxdiazol-2-one mp: 85 ° C Example 218:

3- (3-trifluoromethoxyphenyl) -5-ethoxi-1, 3,4-oxdiazol-2-one mp: oil

Example 219:

3- (3-trifluoromethoxyphenyl) -5-methoxi-1,3,4-oxdiazol-2-one mp: oil

Example 220:

3- (3-trifluoromethoxyphenyl) -5-isopropoxy-1, 3,4-oxdiazol-2-one mp: oil

Example 221:, 3- (4- (2,2,6,6-Tetramethyl-piperidin-4-yl-aminosulfonyl) phenyl) -5-methoxy-1, 3,4-oxdiazol-2-one

Mp .: resin

Example 222:

3- (4- (2,2,6,6-Tetramethyl-piperidin-4-yl-aminosulfonyl) phenyl) -5-isopropoxy-1, 3,4-oxdiazol-2-one

Mp .: resin

Example 223

3- (4- (2- (Diisopropylaminoethyl) aminosulfonyl) phenyl) -5-methoxy-1, 3,4-oxdiazol-2-one mp: oil

Example 224:

3- (4- (2- (Diisopropylaminoethyl) aminosulfonyl) phenyl) -5-isopropoxy-1, 3,4-oxdiazol-2- one mp: oil

Example 225: 3- (4- (4-Methyl-piperazin-1-yl-sulfonyl) phenyl) -5-isopropoxy-1, 3,4-oxdiazol-2-one m.p .: Resin

Example 226: 3- (4- (4-Methyl-piperazin-1-yl-sulfonyl) -phenyl) -5-methoxy-1, 3,4-oxdiazol-2-one mp: resin

Example 227:

3- (3- (4,4,4-Trifluorobutyl-oxi) phenyl) -5-ethoxi-1, 3,4-oxdiazol-2-one Mp .: oil

Example 228:

3- (3- (2-Diethylamino-ethyl-oxi) phenyl) -5-ethoxi-1, 3,4-oxdiazol-2-one mp: resin

Example 229:

3- (4- (4-chlorophenoxy) phenyl) -5-methoxy-1, 3,4-oxdiazol-2-one

Mp: 68 ° C

Example 230:

3- (4- (4-chlorophenoxy) phenyl) -5-isopropoxy-1, 3,4-oxdiazol-2-one Mp .: oil

Example 231: 3- (4- (3,3,5-Trimethyl-cyclohexylaminosulfonyl) phenyl) -5-isopropoxy-1,3,4-oxdiazol-2-one mp: oil

Example 232: 3- (3-phenoxyphenyl) -5-methoxy-1, 3,4-oxdiazol-2-one mp: 89 ° C Example 233

3- (3-phenoxyphenyl) ~ 5-ethoxy-1, 3,4-oxdiazol-2-one mp: 50 ° C

Example 234: 3- (3-phenoxyphenyl) -5-isoproxi-1, 3,4-oxdiazol-2-one mp: 58 ° C

Example 235: 3- (4-phenoxyphenyl) -5-methoxy-1, 3,4-oxdiazol-2-one mp: 83 ° C

Example 236

3- (4-cyclohexylphenyl) -5-methoxy-1, 3,4-oxdiazol-2-one Mp .: resin

Example 237

3- (3- (3,3,5,5-Tetramethyl-cyclohexyl-oxi) phenyl) -5-methoxy-1, 3,4-oxdiazol-2-one mp: 68 ° C

Example 238:

3- (4-phenyl-phenyl) -5-methoxy-1, 3,4-oxdiazol-2-one mp:> 260 ° C (dec.)

Example 239

3- (3- (3-Methylphenoxi-methyI) -phenyI) -5-methoxi-1, 3,4-oxdiazol-2-one mp: 47 ° C

Example 240: 3- (3-phenylphenyl) -5-methoxy-1, 3,4-oxdiazol-2-one mp: 80 ° C Example 241

3- (4- (3,3-Dimethylpiperidinocarbonyl) phenyl) -5-methoxy-1, 3,4-oxdiazol-2-one Mp .: resin

Example 242: 3- (4- (3,3,5,5-tetramethyl-cyclohexyloxy) phenyl) -5-isopropoxy-1,3,4-oxdiazol-2-one mp: resin

The compounds of formula 1 show an inhibitory effect on pancreatic lipase (PL). As inhibitors of PL, they can prevent the absorption of the fat consumed with food and thus lead to a reduction in fat intake and body weight or prevent an increase in body weight. The compounds of formula 1 are particularly suitable for the production of medicaments for the treatment of obesity and of type 1 and 2 diabetes mellitus.

The effectiveness of the compounds was tested as follows:

1. Preparation of the substrate:

80 μl tripalmitin (85 mM in chloroform) are mixed with 5 μl glycerol tri [9.10 (n) - ³ H] oleate (5 mCi / ml in toluene) in a 12 ml polypropylene vessel. After spinning in (50 ° C.) and adding 4 ml of 200 mM Tris / HCl (pH 7.6), 0.8% TX-100, the mixture is treated with ultrasound (Branson Sonifier B-12, power level 4, 3 times 2 min with 1- min intervals on ice) until a homogeneous, milky, cloudy suspension has formed.

2. Assay:

Lipase buffer: 80 mM Tris / HCl (pH 7.6), 600 mM NaCl, 8 mM CaCl ₂ , 8 mM benzamidine, 2 mM Pefabloc (Röche Biochemicals) (add inhibitors only on the day of the test)

Pancreatic lipase: Enriched preparation from pig pancreas (Sigma Order No. L-0382) dissolved in lipase buffer (100000 units / 500 μl)

Execution:

5 μl of test substance (in 100% DMSO) or DMSO (control) are mixed with 10 μl of substrate and 5 μl of lipase (in this order) and incubated for 30 min at 30 ° C. (Eppendorf Thermomixer, 350 min ^“1 ). After addition of 325 μl methanol / chloroform / n-heptane (10/9/7) and 105 μl 0.1 MK ₂ CO ₃ , 0 1 MH ₃ BO ₃ (pH 10.5 adjusted with 1 M KOH) and vigorous mixing is centrifuged to separate the phases (8000 rpm, Eppendorf centrifuge, 4 ° C.) 140 μl of the aqueous supernatant (contains the released radiolabeled oleate; 70% recovery) are transferred to 20 ml scintillation vessels and mixed with 6 ml scintillation cocktail (Beckman ReadySafe) after vigorous mixing and incubation for 2 h at room temperature, the radioactivity measurement is carried out in the liquid scintillation counter (Beckman, L8008, tritium channel with quench curve, 20 min measuring time).

Evaluation:

At every concentration, substances are routinely tested in three independent incubation approaches, each with double 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 proportion of glycerol trioleate or free oleate in the substrate preparation in the aqueous phase, <5% of the radioactivity used). The inhibition of the enzymatic activity of the pancreatic lipase by a test substance is determined by comparison with an uninhibited control reaction (presence of lipase = 0% inhibition; absence of lipase 100% inhibition after background correction). The IC ₅₀ value is calculated using an inhibition curve with up to 8 concentrations of the test substance. The software package GRAPHIT (Elsevier-BIOSOFT) is used for curve fitting and IC ₅ 0-Ermitt.lu.ng.

In this test system, the compounds of formula 1 had the following effects:

Claims

claims:

1. Use of substituted 3-phenyl-5-alkoxy-1, 3,4-oxdiazol-2-ones of the general formula 1,

1

in which mean:

R ¹ -C ₆ -alkyl, C ₃ -Cg-cycloalkyl, both groups by phenyl, C -C -

Alkyloxy, S-C 1 -C ₄ -alkyl, N (CrC ₄ -alkyl) ₂ can be substituted one or more times and phenyl can in turn be substituted by halogen, CrC ₄ -alkyl, CrC -alkyloxy, nitro, CF ₃ , one or more times can be; and

R ² , R ³ , R ⁴ and R ⁵ independently of one another hydrogen, halogen, nitro, -CC ₄ alkyl;

-CC ₉ alkyloxy which is substituted by fluorine, C ₆ -C ₀ -aryl, amino or CrC ₄ -alkylI-amino;

C ₆ -C-aryl-Cι-C -alkyloxy, C ₆ -Cι ₀ -aryloxy, C ₆ -Cι ₀ -aryl, C ₆ -Cι ₀ -aryloxy-Cι-C ₄ - alkyl, C ₃ -C ₈ - Cycloalkyl or OC ₃ -C ₈ cycloalkyl by halogen, CF _3ι CC ₄ -

Alkyloxy or -CC ₄ alkyl can be substituted once, twice or three times;

SO ₂ -NH-Cι-C ₆ alkyl, optionally substituted by N (CC ₆ alkyl) ₂ , SO ₂ -

NH- (2,2,6,6, -Tetramethylpiperidin-4-yl), SO ₂ -NH-C ₃ -C ₈ -cycloalkyl, optionally substituted one or more times by -C-alkyl, S0 ₂ -N ( CC ₆ -

Alkyl) ₂ or COX,

2- oxo-pyrrolidin-1-yl, 2,5-dimethylpyrrol-1-yl or.NR ⁶ -AR ⁷ ,

with the proviso that R ² , R ³ , R ⁴ and R ⁵ do not simultaneously mean hydrogen with X 0-Cι-C ₆ alkyl, NH-Cι-C ₆ alkyl, NH-C ₃ -C ₈ -cycloalkyl or N _(Cι-C6 alkyl) _2, and N _(C-C6 alkyl) ₂ can also represent pyrrolidino, piperidino, morpholino, thiomorpholino or piperazino, which may optionally be substituted by Ci-d-alkyl, benzyl, C ₆ -do-aryl, CO-Cι-C ₄ alkyl, CO-C ₆ -Cι ₀ aryl , CO-OdC ₄ -alkyl, SO ₂ -dC ₄ -alkyl or SO ₂ -C ₆ -Cιo-aryl may be substituted;

R ^{6 is} hydrogen, -CC ₄ -alkyl or C ₆ -C -o-aryl-C ₄ -C ₄ -alkyl, where aryl is through

Halogen, CF ₃ , -CC ₈ alkyloxy or dC -alkyl may be substituted; A is a simple bond, CO _n , SO _n or CONH; n 1 or 2; R ^{7 is} hydrogen;

-C-Cιs alkyl or C ₂ -Cι ₈ alkenyl, the mono- to triple by C -C ₄ alkyl, halogen, CF _3, CC ₄ -alkyloxy, N (-C-C ₄ alkyl) ₂ , -COOH , dC ₄ -alkyloxycarbonyl, C ₆ -C ₂ aryl, C ₆ -Cι ₂ aryloxy, C ₆ -Cι ₂ arylcarbonyl, C ₆ -Cι ₀ aryl -CC -alkyloxy or oxo may be substituted, wherein Aryl can in turn be substituted by halogen, -CC ₄ - alkyl, aminosulfonyl or methyl mercapto;

C ₆ -aryl -Cι _0-Cι-C4 alkyl, Cs-Cs-cycloalkyl-dd-alkyl, C ₅ -C ₈ -CycloalkyI, C ₆ -C ₁₀ - aryl-C ₂ -C ₆ alkenyl, C _ö -Cio-aryl, biphenylyl, diphenyl-Cι-C alkyl, indanyl, _r by Cι C ₈ alkyl, C Cι ₈ alkyloxy, C ₃ -C ₈ -Qycloalkyl, COOH, hydroxy, CC ₄ - alkylcarbonyl, C ₆ -Cιo-aryl-Cι-C ₄ -alkyl, C ₆ -Cι ₀ -aryl-CrC ₄ -alkyloxy, C ₆ -Cι ₀ - aryloxy, nitro, cyano, Ce-Cio-aryl, fluorosulfonyl, CrC ₆ - Alkyloxycarbonyl, CQ-

Cio-arylsulfonyloxy, pyridyl, NHSO ₂ -C ₆ -Cιo-aryl, halogen, CF ₃ or OCF ₃ can be mono- or disubstituted, where alkyl can be substituted again by dd-alkyloxycarbonyl, CF ₃ or carboxy and aryl by halogen , CF ₃ or -CC alkyloxy; or the group Het- (CH ₂ ) _r , with r = 0, 1, 2 or 3 and Het = saturated or unsaturated 5-7-membered heterocycle, which benzo-fused and with -CC alkyl, C ₆ -CIO aryl , halogen, d- _C4-alkyloxy, CC ₄ alkyloxycarbonyl, C ₆ -Cιo-aryl-Cι-C ₄ -alkyl, C ₆ -aryl -Cι _{0-Cι-C 4} - may be substituted alkylmercapto or nitro, wherein benzo-fused aryl in turn by halogen, dd-alkyloxy or CF ₃ and alkyl in arylalkyl by

Methoxy and CF ₃ can be substituted, and their pharmacologically acceptable salts and acid addition salts for the manufacture of a medicament with an inhibitory effect on the pancreatic lipase.

2. Use of the compounds of formula 1 according to claim 1, in which:

R ¹ -C ₆ alkyl, which may optionally be substituted by phenyl; and / or R ^{5 is} hydrogen; and / or R ^{2 is} hydrogen, halogen, CC-alkyl, Ci-Cg-alkyloxy or amino.

3. Use of the compounds of formula 1 according to claims 1 to 2, in which

R ^{3 is} hydrogen, CrC ₄ alkyl, C ₆ -Cιo-AryI-Cι-C ₄ alkyloxy, which may optionally be substituted in the aryl part by halogen or NR ⁶ -AR ⁷ with

R ⁶ = hydrogen or benzyl,

A = simple binding and

R ⁷ = C ₆ -Cιo-aryl-Cι-C ₄ alkyl, which can be substituted by halogen, CF ₃ , cyano, phenyl-dd-alkyloxy, CF ₃ -phenoxy, Cs-Cs-cycloalkyl or fluorosulfonyloxy;

-CC ₂ -alkyl which can be substituted by CrC ₄ -alkyloxy, phenyl, CF ₃ or PhenyI -CC-C ₄ -alkyIoxy;

C ₂ -C ₂ alkenyl or the group Het- (CH ₂ ) _r , with r = 0 or 1, and Het = saturated or unsaturated 5-7-membered heterocycle, which is benzo-fused and with C 1 -C ₄ -alkyl or halogen can be substituted means.

4. Use of the compounds of formula 1 according to claims 1 to 2, in which:

R ² and R ³ are independently hydrogen, C ₆ -Cι ₀ aryl, C ₃ -C ₈ -CycloaIkyl, optionally substituted by Cι-C ₄ alkyl-substituted C ₆ -Cιo-Aryloximethyl, optionally substituted by C -C ₄ alkyl or mono- halogen, or poly-substituted O-benzyl OC ₆ -Cι ₀ -aryl or OC ₃ -C ₈ -cycloalkyl, mono- or 0-C ₁ -C ₆ alkyl substituted several times by fluorine, Ce-Cio-aryl or amino, where amino in turn may be substituted one or more times by CrC ₄ alkyl, SO ₂ -NH-C ₁ -C ₆ -alkyl, if appropriate substituted by N (C -C ₆ alkyl) ₂ , SO ₂ -NH- (2,2,6,6-tetramethylpiperidin-4-yl), SO ₂ -NH-C ₃ -C ₈ cycloalkyl substituted by CC ₄ -alkyl, S0 ₂ -N (CC ₆ -alkyl) ₂ or CO-N (CC ₆ -alkyl) ₂ mean, and

N (-C ₆ alkyl) _{2 can} also represent piperidino, morpholino or piperazino, which can optionally be substituted by C 1 -C alkyl.

Use of the compounds of formula 1 according to claims 1 to 4, in which:

R ^{4 is} hydrogen, 2-oxo-pyrrolidin-1-yl, 2,5-dimethylpyrrol-1-yl or C ₆ -C o-aryl -CC-C ₄ alkyloxy, which can be substituted by halogen.

Use of the compounds of formula 1 according to claims 1 to 5, in which:

R ⁴ = NR ⁶ -AR ⁷ , with • R ⁶ = hydrogen or methyl,

A = single bond and R ⁷ = hydrogen;

CrCι ₂ alkyl, which can be substituted once or twice by halogen;

C ₂ -C ₈ alkenyl which is mono- or disubstituted by C ₄ -C ₄ alkyl or C -C -

Alkyloxycarbonyl may be substituted;

C _{6 -Cιo-aryl-Cι-C4-alkyl} substituted by halogen, Cι-C ₆ -AIkyloxy, CF _3, cyano, C ₅ -C- ₆ - cycloalkyl, dC ₄ alkyloxycarbonyl, C ₆ -Cι ₀ - Aryl-C ₄ -alkyl, C ₆ -C ₀ -aryl-C ₄ -C ₄ -alkyloxy may be substituted, whereby aryl may be substituted again by halogen or CF ₃ ;

C ₅ -C ₈ cycloalkyl -CC ₄ alkyl; or the group Het- (CH ₂ ) _r , with r = 1, 2 or 3 and Het = saturated or unsaturated 5-7-membered

Heterocycle with halogen, -CC -AlkyIoxy _. or C 1 -C ₄ alkyloxycarbonyI can be substituted. Use of the compounds of formula 1 according to claims 1 to 6, in which:

R ⁴ = NR ⁶ -AR ⁷ , with R ⁶ = hydrogen,.

A = -CO- and

R ⁷ = -C ₈ alkyl, which can be substituted by halogen, phenyl, phenoxy, phenylcarbonyl or C -C ₄ alkyloxycarbonyl, where phenoxy can in turn be substituted by methyl, halogen or methyl mercapto; C ₂ -C ₈ alkenyl, which can be substituted by Cβ-Cio-aryl;

Ce-Cio-aryl, which can be substituted by halogen, -CC ₈ alkyl, phenyl -CC ₄ -alkyl, CF ₃ , OCF ₃ , fluorosulfonyl, -CC ₄ -alkyloxycarbonyl, phenoxy, aryl in turn by dC ₄ alkyloxy may be substituted; C ₆ -Cιo-aryl-Cι-C ₄ alkyl, where alkyl can be substituted by methoxy or CF ₃ and aryl by halogen; or the group Het- (CH ₂ ) _r , with r = 0 and Het = saturated or unsaturated 5-7-membered heterocycle, which fuses with benzo and with C -C ₄ -alkyl, halogen, dC ₄ -alkyloxy, halophenyl or Halogen-benzylmercapto can be substituted, wherein benzo-fused aryl can in turn be substituted by halogen or methoxy.

Use of the compounds of formula 1 according to claims 1 to 7, wherein: R ⁴ = NR ⁶ -AR ⁷ , with

R ⁶ = hydrogen,

A = -CO ₂ - and

R ⁷ = CrCι ₈ alkyl, which is substituted by CF ₃ or phenyl; C ₆ -Cιo-aryl-CrC ₄ -alkyl, which by Cι-C ₄ alkyl, halogen, CF ₃ , or OCF ₃ ,

Benzyioxy or phenyl is substituted; or the group Het- (CH ₂ ) _r -, with r = 0 or 1 and Het = saturated or unsaturated 5-7-membered heterocycle, which can be benzo-fused and substituted with -CC alkyl or benzyl.

Use of the compounds of formula 1 according to claims 1 to 8, in which:

R ⁴ = NR ⁶ -AR ⁷ , with

R ⁶ = hydrogen,

A = -SO ₂ - and R ⁷ = -C-C ₆ alkyl, which can be substituted with CF ₃ ;

C ₂ -C ₄ alkenyl, which may be substituted by phenyl;

C ₆ -C ₀ aryl, which may be substituted by -C ₆ alkyl, halogen, dC ₄ alkyloxy or benzyl;

Biphenylyl -CC -alkyl, substituted with halogen; or the group Het- (CH ₂ ) _r -, with r = 0 and Het = saturated or unsaturated 5-7-membered heterocycle.

Use of the compounds of formula 1 according to claims 1 to 9, wherein: R ⁴ = NR ⁶ -AR ⁷ , with

R ⁶ = hydrogen,

A = -CO-NH- and

R ⁷ = -C-Cιo-alkyl by dd-alkyloxycarbonyl, N (-C-C ₄ alkyl) ₂ or

Phenyl can be substituted, which in turn can be substituted by halogen or aminosulfonyl;

Ce-do-aryl, which by CrC ₆ -AlkyI, d-Ce-alkyloxy, Ci-Ce -alkyloxycarbonyl,

Phenoxy, OCF ₃ , benzyl or pyridyl, alkyl being again by C 1 -C ₄ -

Alkyloxycarbonyl or carboxy may be substituted;

C ₅ -C ₈ cycloalkyl, which can be substituted by hydroxy or indanyl; or the group Het- (CH ₂ ) _r , with r = 0 or 1 and Het = saturated or unsaturated 5-7-membered

Heterocycle, which can be substituted with benzyl.

11. Use of the compounds of formula 1 according to claims 1 to 10, in which:

R ² and R ⁵ is hydrogen, R ³ is hydrogen, C ₆ -Cι ₀ -aryl, OC ₆ -Cι ₀ aryl, optionally substituted by C -C ₄ alkyl-substituted C ₆ -Cιo-Aryloximethyl, O-benzyl, mono- or O-Ci-Cβ-alkyl substituted several times by fluorine or amino, where amino can in turn be substituted one or more times by C -C ₄ alkyl, optionally substituted by C ₁ -C ₄ alkyl or OC ₃ -C ₈ -Cycloalkyl and R ⁴ hydrogen, Ce-Cio-aryl, C ₃ -C ₈ cycloalkyl, optionally substituted by CC ₄ alkyl or halogen mono- or polysubstituted OC ₆ -do-aryl or OC ₃ -C ₈ - cycloalkyl - or poly-substituted O--C ₆ alkyl, SO ₂ - NH-Ci-Ce-alkyl, optionally substituted by N (CC ₆ alkyl) ₂ , SO ₂ -NH- (2,2,6, 6-tetramethylpiperidin-4-yl), SO ₂ -NH-C ₃ -C ₈ -cycloalkyl, mono- or polysubstituted by -C-C ₄ alkyl, SO ₂ -N (CC ₆ -alkyl) ₂ or CO-N (dC ₆ alkyl) ₂ mean, and

N (dC ₆ -alkyl) _{2 is} also piperidino, morpholino or piperazino, which can optionally be substituted by dd-alkyl.

12. Use of the compounds of formula 1 according to claims 1 to 11, wherein R ^{1 is} methyl, ethyl, butyl, isopropyl or benzyl and R ² and R ^{5 are} hydrogen and R ^{3 is} hydrogen, trifluoromethoxy, trifluorobutoxy, 3, 3,5,5-tetramethylcyclohexyloxy, benzyloxy, phenoxy, phenyl, 2-diethylamino-ethyloxy or 3-methylphenoxy-methyl, and R ⁴ for hydrogen, trifluoromethoxy, 3,3,5,5-tetramethylcyclohexyloxy, phenoxy, 4-chlorophenoxy, Cyclohexyl, phenyl, morpholinosulfonyl, 3,3,5-trimethylcyclohexyl-aminosulfonyl, 2,2,6,6, -tetramethyl-piperidin-4-yl-aminosulfonyl, 2- (diisopropylaminoethyl) aminosulfonyl, 4-methyl-piperazine- 1-yl-sulfonyl, 3,3, -dimethylpiperidino-carbonyl or 3,5-dichlorophenoxy are available.

13. Use of the compounds of formula 1 according to claims 1 to 11, wherein

R ^{1 represents} methyl, ethyl, butyl, isopropyl or benzyl and R ² and R ^{5 represent} hydrogen and R ^{3 represents} hydrogen, trifluoromethoxy, 3,3,5,5-tetramethylcyclohexyloxy, benzyloxy or phenoxy and R ^{4 represents} hydrogen, trifluoromethoxy , 3,3,5, 5-tetramethylcyclohexyloxy, phenoxy, cyclohexyl, phenyl, morpholinosulfonyl or 3,3,5-trimethylcyclohexylaminosulfonyl.

14. Use of the compounds of formula 1 according to claims 1 to 13, wherein

R ¹ CrC- ₄ alkyl,

R ² hydrogen, R ³ hydrogen, trifluoromethoxy, benzyloxy,

R ^{4 is} hydrogen, trifluoromethoxy, 4-chlorophenoxy, 4-trifluoromethylbenzoylamino, and

R ^{5 is} hydrogen.

15. Use of the compounds of formula 1 according to claims 1 to 14, wherein R ^{1 is} methyl.

16. Use of the compounds of formula 1 according to claims 1 to 15 in combination with one or more inhibitors of pancreatic lipase for the manufacture of a medicament for the prophylaxis or treatment of

, Obesity.

17. Use of the compounds of formula 1 according to claims 1 to 15 in combination with one or more inhibitors of pancreatic lipase for the manufacture of a medicament for the prophylaxis or treatment of

Diabetes mellitus types 1 and 2.