US20010031772A1 - Substituted 3-phenyl-5-alkoxy-1,3,4-oxadiazol-2-ones, their preparation and their use as pharmaceuticals - Google Patents

Substituted 3-phenyl-5-alkoxy-1,3,4-oxadiazol-2-ones, their preparation and their use as pharmaceuticals Download PDF

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US20010031772A1
US20010031772A1 US09/799,082 US79908201A US2001031772A1 US 20010031772 A1 US20010031772 A1 US 20010031772A1 US 79908201 A US79908201 A US 79908201A US 2001031772 A1 US2001031772 A1 US 2001031772A1
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alkyl
aryl
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halogen
alkyloxy
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Karl Schoenafinger
Stefan Petry
Guenter Mueller
Karl-Heinz Baringhaus
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Sanofi Aventis Deutschland GmbH
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Aventis Pharma Deutschland GmbH
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D271/00—Heterocyclic compounds containing five-membered rings having two nitrogen atoms and one oxygen atom as the only ring hetero atoms
    • C07D271/02—Heterocyclic compounds containing five-membered rings having two nitrogen atoms and one oxygen atom as the only ring hetero atoms not condensed with other rings
    • C07D271/10—1,3,4-Oxadiazoles; Hydrogenated 1,3,4-oxadiazoles
    • C07D271/113—1,3,4-Oxadiazoles; Hydrogenated 1,3,4-oxadiazoles with oxygen, sulfur or nitrogen atoms, directly attached to ring carbon atoms, the nitrogen atoms not forming part of a nitro radical
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/18—Drugs for disorders of the alimentary tract or the digestive system for pancreatic disorders, e.g. pancreatic enzymes
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/10—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • This invention relates to substituted 3-phenyl-5-alkoxy-1,3,4-oxadiazol-2-ones, which show an inhibitory effect on hormone-sensitive lipase (HSL), and their pharmaceutically acceptable salts or acid addition salts.
  • HSL hormone-sensitive lipase
  • the present invention further relates to processes for the preparation of 3-phenyl-5-alkoxy-1,3,4-oxadiazol-2-ones, to the use of 3-phenyl-5-alkoxy-1,3,4-oxadiazol-2-ones and their pharmaceutically acceptable salts or acid addition salts as pharmaceuticals, including their use as inhibitors of HSL, and to pharmaceutical compositions comprising 3-phenyl-5-alkoxy-1,3,4-oxadiazol-2-ones and their pharmaceutically acceptable salts or acid addition salts, including their use in the treatment of non-insulin dependent diabetes mellitus and diabetic syndrome.
  • An aim of the invention was to find compounds which show an inhibitory effect on hormone-sensitive lipase, HSL.
  • the present invention relates to substituted 3-phenyl-5-alkoxy-1,3,4-oxadiazol-2-ones of the formula 1:
  • R 1 is C 1 -C 6 -alkyl, C 3 -C 9 -cycloalkyl, wherein both groups are optionally substituted one or more times by phenyl, C 1 -C 4 -alkyloxy, S—C 1 —C 4 -alkyl, N(C 1 -C 4 -alkyl) 2 , and wherein phenyl is optionally substituted one or more times by halogen, C 1 -C 4 -alkyl, C 1 -C 4 -alkyloxy, nitro, CF 3 ; and
  • R 2 , R 3 , R 4 and R 5 independently of one another are hydrogen, halogen, nitro, C 1 -C 4 -alkyl, C 1 -C 9 -alkyloxy; C 6 -C 10 -aryl-C 1 -C 4 -alkyloxy, C 6 -C 10 -aryloxy, C 6 -C 10 -aryl, C 3 -C 8 -cycloalkyl or O—C 3 -C 8 -cycloalkyl, each of which is optionally substituted once, twice or three times by halogen, CF 3 , C 1 -C 4 -alkyloxy or C 1 -C 4 -alkyl; 2-oxopyrrolidin-1-yl, 2,5-dimethylpyrrol-1-yl or NR 6 -A-R 7 , with the proviso that R 2 , R 3 , R 4 and R 5 are not simultaneously hydrogen, and at least one of the radicals R 2 ,
  • R 6 is hydrogen, C 1 -C 4 -alkyl or C 6 -C 10 -aryl-C 1 -C 4 -alkyl, wherein aryl may be substituted by halogen, CF 3 , C 1 -C 8 -alkyloxy or C 1 -C 4 -alkyl;
  • A is a single bond, CO n , SO n , or CONH;
  • n 1 or 2;
  • R 7 is hydrogen, C 1 -C 18 -alkyl or C 2 -C 18 -alkenyl, wherein C 1 -C 18 -alkyl or C 2 -C 18 alkenyl are optionally substituted one to three times by C 1 -C 4 -alkyl, halogen, CF 3 , C 1 -C 4 -alkyloxy, N(C 1 -C 4 -alkyl) 2 , —COOH, C 1 -C 4 -alkyloxycarbonyl, C 6 -C 12 -aryl, C 6 -C 12 -aryloxy, C 6 -C 12 -arylcarbonyl, C 6 -C 10 -aryl-C 1 -C 4 -alkyloxy or oxo, wherein aryl is in turn optionally substituted by halogen, C 1 -C 4 -alkyl, aminosulfonyl or methylmercapto;
  • Said aryl radicals are optionally substituted one or more times by C 1 -C 9 -alkyl, C 1 -C 8 -alkyloxy, halogen, and trifluoromethyl.
  • Said cycloalkyl radicals are optionally substituted one or more times by C 1 -C 4 -alkyl, C 6 -C 10 -aryl, and said alkyl radicals are optionally substituted by hydroxyl, di-C 1 -C 4 -alkylamino and fluorine.
  • Halogen is fluorine, chlorine, bromine, generally fluorine and chlorine.
  • Alkyl, alkenyl, alkyloxy, etc. are branched or unbranched. The phrase “is optionally substituted” means that the relevant group is or is not substituted.
  • Pharmaceutically acceptable salts of compounds of the formula 1 include their organic and inorganic salts, as described in Remington's Pharmaceutical Sciences (A. R. Gennard Editor, Mack Publishing Co., Easton, Pa., USA, 17 th Ed., p 1418, (1985)).
  • acidic groups include, inter alia, sodium, potassium, calcium and ammonium salts.
  • basic groups include, inter alia, salts of hydrochloric acid, sulfuric acid, phosphoric acid, or of carboxylic acids or sulfonic acids, such as, for example, acetic acid, citric acid, benzoic acid, maleic acid, fumaric acid, tartaric acid and p-toluenesulfonic acid.
  • Typical compounds of the formula 1 are those in which:
  • R 1 is C 1 -C 4 -alkyl
  • R 5 is hydrogen
  • R 2 is hydrogen, halogen, C 1 -C 4 -alkyl, C 1 -C 9 -alkyloxy or amino.
  • R 3 is hydrogen, C 1 -C 4 -alkyl, C 6 -C 10 -aryl-C 1 -C 4 -alkyloxy, which is optionally substituted in the aryl moiety by halogen, or is NR 6 -A-R 7 wherein
  • R 6 hydrogen or benzyl
  • R 7 C 6 -C 10 -aryl-C 1 -C 4 -alkyl, which is optionally substituted by halogen, CF 3 , cyano, phenyl-C 1 -C 4 -alkyloxy, CF 3 -phenoxy, C 5 -C 8 -cycloalkyl or fluorosulfonyloxy;
  • C 1 -C 12 -alkyl which is optionally substituted by C 1 -C 4 -alkyloxy, phenyl, CF 3 or phenyl-C 1 -C 4 -alkyloxy; C 2 -C 12 -alkenyl;
  • Het a saturated or unsaturated 5-7-membered heterocycle, which is optionally benzo-fused and optionally substituted by C 1 -C 4 -alkyl or halogen.
  • R 4 is hydrogen, 2-oxopyrrolidin-1-yl, 2,5-dimethylpyrrol-1-yl or C 6 -C 10 -aryl-C 1 -C 4 -alkyloxy, which is optionally substituted by halogen, and/or: compounds of the formula 1 in which: R 4 is NR 6 -A-R 7 , wherein
  • R 6 hydrogen or methyl
  • C 2 -C 18 -alkenyl which is optionally substituted once or twice by C 1 -C 4 -alkyl or C 1 -C 4 -alkyloxycarbonyl;
  • C 6 -C 10 -aryl-C 1 -C 4 -alky which is optionally substituted by halogen, C 1 -C 6 -alkyloxy, CF 3 , cyano, C 5 -C 6 -cycloalkyl, C 1 -C 4 -alkyloxycarbonyl, C 6 -C 10 -aryl-C 1 -C 4 -alkyl, C 6 -C 10 -aryl-C 1 -C 4 -alkyloxy, wherein aryl is further optionally substituted by halogen or CF 3 ;
  • R 4 is NR 6 -A-R 7 , wherein
  • R 7 C 1 -C 18 -alkyl, which is optionally substituted by halogen, phenyl, phenoxy, phenylcarbonyl or C 1 -C 4 -alkyloxycarbonyl, wherein phenoxy is optionally substituted by methyl, halogen or methylmercapto;
  • C 6 -C 10 -aryl which is optionally substituted by halogen, C 1 -C 8 -alkyl, phenyl-C 1 -C 4 -alkyl, CF 3 , OCF 3 , fluorosulfonyl, C 1 -C 4 -alkyloxycarbonyl, phenoxy, wherein aryl is optionally substituted by C 1 -C 4 -alkyloxy;
  • R 4 is NR 6 -A-R 7 , wherein
  • R 7 C 1 -C 18 -alkyl, which is substituted by CF 3 or phenyl;
  • C 6 -C 10 -aryl-C 1 -C 4 -alkyl which is substituted by C 1 -C 4 -alkyl, halogen, CF 3 or OCF 3 , benzyloxy or phenyl;
  • R 4 is NR 6 -A-R 7 , wherein
  • R 7 C 1 -C 6 -alky, which is optionally substituted by CF 3 ;
  • R 4 is NR 6 -A-R 7 , wherein
  • R 7 C 1 -C 10 -alkyl, which is optionally substituted by C 1 -C 4 -alkyloxycarbonyl, N(C 1 -C 4 -alkyl) 2 or phenyl, which is in turn optionally substituted by halogen or aminosulfonyl;
  • C 6 -C 10 -aryl which is optionally substituted by C 1 -C 6 -alkyl, C 1 -C 6 -alkyloxy, C 1 -C 6 -alkyloxycarbonyl, phenoxy, OCF 3 , benzyl or pyridyl, wherein alkyl is optionally substituted by C 1 -C 4 -alkyloxycarbonyl or carboxyl;
  • C 5 -C 8 -cycloalky which is optionally substituted by hydroxyl, or indanyl;
  • Representative compounds of the formula 1 are those mentioned in Examples 21, 22, 27, 28, 30 to 34, 36 to 42, 53, 54, 58, 60, 62, 65, 69, 71, 74, 92, 97,107,116,128, 130, 136,139,142,152,166 and 171.
  • the compounds of the invention have a surprising inhibitory effect on hormone-sensitive lipase, HSL, an allosteric enzyme in adipocytes, which is inhibited by insulin and is responsible for the breakdown of fats in fat cells and for the transfer of fat constituents into the blood stream. Inhibition of this enzyme thus corresponds to an insulin-like effect of the compounds of the invention, which eventually leads to a reduction of free fatty acids in the blood and of blood glucose. Therefore, the compounds of the invention can be employed in the treatment of metabolic disturbances such as, for example, non-insulin-dependent diabetes mellitus, diabetic syndrome, and direct damage to the pancreas.
  • metabolic disturbances such as, for example, non-insulin-dependent diabetes mellitus, diabetic syndrome, and direct damage to the pancreas.
  • the compounds of the invention can be prepared in various ways by methods known per se.
  • substituted 3-phenyl-5-alkoxy-1,3,4-oxadiazol-2-ones of the formula 1 can be prepared by reacting hydrazines of the formula 2 with chloroformic esters of the formula 3 or other reactive carbonic ester derivatives, in which R 1 , R 2 , R 3 , R 4 and R 5 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 R 2 -R 5 , such as, for example, by reduction of nitro to amino radicals by known processes, and subsequent acylation or alkylation, into compounds of the formula 1.
  • the hydrazines of the formula 2 can be prepared by known methods, for example by diazotization of the corresponding anilines and
  • suitable phenyl derivatives may be nitro-substituted halobenzenes, such as fluoro- and chloronitrobenzenes, from which the compounds of the invention can be prepared by known methods at a suitable point in the synthetic route by reduction and reaction with acylating or alkylating agents such as, for example, acid chlorides, anhydrides, isocyanates, chloroformic esters, sulfonyl chlorides or alkyl and arylalkyl halides, or by reductive alkylation with aldehydes.
  • acylating or alkylating agents such as, for example, acid chlorides, anhydrides, isocyanates, chloroformic esters, sulfonyl chlorides or alkyl and arylalkyl halides, or by reductive alkylation with
  • Isolated rat fat cells were obtained from epididymal adipose tissue from untreated male rats (Wistar, 220-250 g) by collagenase treatment according to published methods (e.g., S. Nilsson et al., Anal. Biochem. 158:399-407 (1986); G. Fredrikson et al., J. Biol. Chem. 256:6311-6320 (1981); H. Tornquist et al., J. Biol. Chem. 251:813-819 (1976)).
  • the fat cells from 10 rats were washed three times by flotation with 50 ml each time of homogenization buffer (25 ml tris/HCl, pH 7.4, 0.25 M sucrose, 1 mM EDTA, 1 mM DTT, 10 ⁇ g/ml leupeptin, 10 ⁇ g/ml antipain, 20 ⁇ g/ml pepstatin) and finally taken up in 10 ml of homogenization buffer.
  • the fat cells were homogenized in a Teflon-in-glass homogenizer (Braun-Mels Institute) by 10 strokes at 1500 rpm and 15° C. The homogenate was centrifuged (Sorvall SM24 tubes, 5000 rpm, 10 min, 4° C.).
  • the subnatant between the fatty layer at the top and the pellet was removed and the centrifugation was repeated.
  • the subnatant resulting therefrom was recentrifuged (Sorvall SM24 tubes, 20000 rpm, 45 min, 4° C.).
  • the subnatant was removed and mixed with 1 g of heparin-Sepharose (Pharmacia-Biotech, CL-6B, 5 ⁇ washed with 25 mM tris/HCl, pH 7.4,150 mM NaCl). After the mixture had been incubated at 4° C. for 60 min (shaking at 15-min intervals), it was centrifuged (Sorvall SM24 tubes, 3000 rpm, 10 min, 4° C.).
  • the supernatant was adjusted to pH 5.2 by adding glacial acetic acid and incubated at 4° C. for 30 min.
  • the precipitates were collected by centrifugation (Sorvall SS34, 12000 rpm, 10 min, 4° C.) and suspended in 2.5 ml of 20 mM tris/HCl, pH 7.0,1 mM EDTA, 65 mM NaCl, 13% sucrose, 1 mM DTT, 10 ⁇ g/ml leupeptin/pepstatin/antipain.
  • the suspension was dialyzed against 25 mM tris/HCl, pH 7.4, 50% glycerol, 1 mM DTT, 10 ⁇ g/ml leupeptin, pepstatin, antipain at 4° C. overnight and then loaded onto a hydroxy apatite column (0.1 g per 1 ml of suspension, equilibrated with 10 mM potassium phosphate, pH 7.0, 30% glycerol, 1 mM DTT). The column was washed with four volumes of equilibration buffer at a flow rate of 20 to 30 ml/h.
  • the HSL was eluted with one volume of equilibration buffer containing 0.5 M potassium phosphate, and then dialyzed (see above) and concentrated 5- to 10-fold by ultrafiltration (Amicon Diaflo PM 10 filter) at 4° C.
  • the partially purified HSL can be stored at ⁇ 70° C. for 4 to 6 weeks.
  • Substances were normally tested in four independent mixtures.
  • the inhibition of the HSL enzymatic activity by a test substance was determined by comparison with an uninhibited control reaction.
  • the IC 50 was calculated via an inhibition plot with at least 10 concentrations of the test substance.
  • the data was analyzed using the software package GRAPHIT, Elsevier-BIOSOFT.
  • Selected compounds of the invention showed the following effect, as measured by this assay: Compound of Example No. IC 50 ( ⁇ M) 21 10 22 1 27 10 28 6 30 1 31 10 32 3 33 0.2 34 1 36 10 37 1 38 1 39 1 40 10 41 0.1 42 1 53 1 54 1 58 0.8 60 0.2 62 0.3 65 1 69 0.03 71 0.02 74 0.04 92 0.25 97 0.03 107 0.12 116 0.1 128 0.6 130 0.5 136 0.5 139 0.4 142 0.2 152 0.2 166 0.2 171 0.6
  • 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.
  • a solution of 0.52 g of sodium nitrite in 5 ml of water was 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 was 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 HCl. The precipitate was 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 oil formed was extracted by shaking with ethyl acetate and washed with water, and the organic phase was dried with sodium sulfate. The product was then precipitated with isopropanolic HCl, filtered off with suction and dried in vacuo.
  • the latter compound was obtained by reacting 5-methoxy-3-(4-amino-3-methylphenyl)-3H-(1,3,4)oxadiazol-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.

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Abstract

Substituted 3-phenyl-5-alkoxy-1,3,4-oxadiazol-2-ones of the formula 1 are described,
Figure US20010031772A1-20011018-C00001
in which R1 is substituted C1-C6-alkyl and C3-C9-cycloalkyl, R2, R3, R4 and R5 are hydrogen, halogen, nitro, C1-C4-alkyl, C1-C9-alkyloxy, substituted C6-C10-aryl-C1-C4-alkyloxy, C6-C10-aryloxy, C6-C10-aryl, C3-C8-cycloalkyl or O—C3—C8-cycloalkyl, or 2-oxopyrrolidin-1-yl, 2,5-dimethylpyrrol-1-yl or NR6-A-R7, with the proviso that R2, R3, R4 and R5 are not simultaneously hydrogen, and at least one of the radicals R2, R3, R4 or R5 is the radical 2-oxopyrrolidin-1-yl, 2,5-dimethylpyrrol-1-yl or NR6-A-R7, wherein R6=hydrogen, C1-C4-alkyl or substituted C6-C10-aryl-C1-C4-alkyl, A=a single bond, COn, SOn or CONH, n=1 or 2, R7=hydrogen, substituted C1-C18-alkyl, C2-C18-alkenyl, C6-C10-aryl-C1-C4-alkyl, C5-C8-cycloalkyl-C1-C4-alkyl, C5-C8-cycloalkyl, C6-C10-aryl-C2-C6-alkenyl, C6-C10-aryl, biphenylyl, biphenylyl-C1-C4-alkyl, indanyl, or the group Het-(CH2)r—, wherein r=0, 1, 2 or 3 and Het=a saturated or unsaturated 5-7-membered heterocycle, which may be optionally benzo-fused and optionally substituted, and proceses for their preparation. The compounds of formula 1 show an inhibitory effect on hormone-sensitive lipase, HSL.

Description

  • This invention relates to substituted 3-phenyl-5-alkoxy-1,3,4-oxadiazol-2-ones, which show an inhibitory effect on hormone-sensitive lipase (HSL), and their pharmaceutically acceptable salts or acid addition salts. The present invention further relates to processes for the preparation of 3-phenyl-5-alkoxy-1,3,4-oxadiazol-2-ones, to the use of 3-phenyl-5-alkoxy-1,3,4-oxadiazol-2-ones and their pharmaceutically acceptable salts or acid addition salts as pharmaceuticals, including their use as inhibitors of HSL, and to pharmaceutical compositions comprising 3-phenyl-5-alkoxy-1,3,4-oxadiazol-2-ones and their pharmaceutically acceptable salts or acid addition salts, including their use in the treatment of non-insulin dependent diabetes mellitus and diabetic syndrome. [0001]
  • Certain 5-alkoxy-1,3,4-oxadiazol-2-ones substituted with an ortho-substituted phenyl ring or with fused-on five- or six-membered rings have anthelmintic (DE-A 26 04 110) and insecticidal effects (DE-A 26 03 877, EP-B 0 048 040, EP-B 0 067 471). [0002]
  • Certain 5-phenoxy-1,3,4-oxadiazol-2-ones with an ortho-substituted phenyl ring as substituents show an endoparasiticidal effect (EP-A 0 419 918). [0003]
  • An aim of the invention was to find compounds which show an inhibitory effect on hormone-sensitive lipase, HSL. [0004]
  • The present invention relates to substituted 3-phenyl-5-alkoxy-1,3,4-oxadiazol-2-ones of the formula 1: [0005]
    Figure US20010031772A1-20011018-C00002
  • in which: [0006]
  • R[0007] 1 is C1-C6-alkyl, C3-C9-cycloalkyl, wherein both groups are optionally substituted one or more times by phenyl, C1-C4-alkyloxy, S—C1—C4-alkyl, N(C1-C4-alkyl)2, and wherein phenyl is optionally substituted one or more times by halogen, C1-C4-alkyl, C1-C4-alkyloxy, nitro, CF3; and
  • R[0008] 2, R3, R4 and R5 independently of one another are hydrogen, halogen, nitro, C1-C4-alkyl, C1-C9-alkyloxy; C6-C10-aryl-C1-C4-alkyloxy, C6-C10-aryloxy, C6-C10-aryl, C3-C8-cycloalkyl or O—C3-C8-cycloalkyl, each of which is optionally substituted once, twice or three times by halogen, CF3, C1-C4-alkyloxy or C1-C4-alkyl; 2-oxopyrrolidin-1-yl, 2,5-dimethylpyrrol-1-yl or NR6-A-R7, with the proviso that R2, R3, R4 and R5 are not simultaneously hydrogen, and at least one of the radicals R2, R3, R4 or R5 is the radical 2-oxopyrrolidin-1-yl, 2,5-dimethylpyrrol-1-yl, or NR6-A-R7, and wherein:
  • R[0009] 6 is hydrogen, C1-C4-alkyl or C6-C10-aryl-C1-C4-alkyl, wherein aryl may be substituted by halogen, CF3, C1-C8-alkyloxy or C1-C4-alkyl;
  • A is a single bond, CO[0010] n, SOn, or CONH;
  • n is 1 or 2; [0011]
  • R[0012] 7 is hydrogen, C1-C18-alkyl or C2-C18-alkenyl, wherein C1-C18-alkyl or C2-C18alkenyl are optionally substituted one 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, wherein aryl is in turn optionally substituted by halogen, C1-C4-alkyl, aminosulfonyl or methylmercapto;
  • C[0013] 6-C10-aryl-C1-C4-alkyl, C5-C8-cycloalkyl-C1-C4-alkyl, C5-C8-cycloalkyl, C6-C10-aryl-C2-C6-alkenyl, C6-C10-aryl, biphenylyl, biphenylyl-C1-C4-alkyl, indanyl, each of which is optionally substituted once or twice by C1-C18-alkyl, C1-C1 8-alkyloxy, C3-C8-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, wherein alkyl is in turn optionally substituted by C1-C4-alkyloxycarbonyl, CF3 or carboxyl, and aryl is also optionally substituted by halogen, CF3 or C1-C4-alkyloxy;
  • or the group Het-(CH[0014] 2)r—,
  • wherein r=0, 1, 2 or 3 and Het=a saturated or unsaturated 5-7-membered heterocycle, optionally benzo-fused and optionally substituted by C[0015] 1-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, wherein the benzo-fused aryl is in turn optionally substituted by halogen, C1-C4-alkyloxy or CF3 and the alkyl in arylalkyl is also optionally by methoxy and CF3,
  • and their pharmaceutically acceptable salts and acid addition salts. [0016]
  • Said aryl radicals are optionally substituted one or more times by C[0017] 1-C9-alkyl, C1-C8-alkyloxy, halogen, and trifluoromethyl. Said cycloalkyl radicals are optionally substituted one or more times by C1-C4-alkyl, C6-C10-aryl, and said alkyl radicals are optionally substituted by hydroxyl, di-C1-C4-alkylamino and fluorine. Halogen is fluorine, chlorine, bromine, generally fluorine and chlorine. Alkyl, alkenyl, alkyloxy, etc. are branched or unbranched. The phrase “is optionally substituted” means that the relevant group is or is not substituted.
  • Pharmaceutically acceptable salts of compounds of the formula 1 include their organic and inorganic salts, as described in Remington's Pharmaceutical Sciences (A. R. Gennard Editor, Mack Publishing Co., Easton, Pa., USA, 17[0018] th Ed., p 1418, (1985)). Examples of acidic groups include, inter alia, sodium, potassium, calcium and ammonium salts. Examples of basic groups include, inter alia, salts of hydrochloric acid, sulfuric acid, phosphoric acid, or of carboxylic acids or sulfonic acids, such as, for example, acetic acid, citric acid, benzoic acid, maleic acid, fumaric acid, tartaric acid and p-toluenesulfonic acid.
  • Typical compounds of the formula 1 are those in which: [0019]
  • R[0020] 1 is C1-C4-alkyl; and/or
  • R[0021] 5 is hydrogen; and/or
  • R[0022] 2 is hydrogen, halogen, C1-C4-alkyl, C1-C9-alkyloxy or amino.
  • Further examples of compounds of the formula 1 are those in which: [0023]
  • R[0024] 3 is hydrogen, C1-C4-alkyl, C6-C10-aryl-C1-C4-alkyloxy, which is optionally substituted in the aryl moiety by halogen, or is NR6-A-R7 wherein
  • R[0025] 6=hydrogen or benzyl,
  • A=single bond and [0026]
  • R[0027] 7=C6-C10-aryl-C1-C4-alkyl, which is optionally substituted by halogen, CF3, cyano, phenyl-C1-C4-alkyloxy, CF3-phenoxy, C5-C8-cycloalkyl or fluorosulfonyloxy;
  • C[0028] 1-C12-alkyl, which is optionally substituted by C1-C4-alkyloxy, phenyl, CF3 or phenyl-C1-C4-alkyloxy; C2-C12-alkenyl;
  • or the group Het-(CH[0029] 2)r—,
  • wherein r=0 or 1, and Het=a saturated or unsaturated 5-7-membered heterocycle, which is optionally benzo-fused and optionally substituted by C[0030] 1-C4-alkyl or halogen.
  • Additional compounds of the formula 1 are those in which: [0031]
  • R[0032] 4 is hydrogen, 2-oxopyrrolidin-1-yl, 2,5-dimethylpyrrol-1-yl or C6-C10-aryl-C1-C4-alkyloxy, which is optionally substituted by halogen, and/or: compounds of the formula 1 in which: R4 is NR6-A-R7, wherein
  • R[0033] 6=hydrogen or methyl,
  • A=single bond and [0034]
  • R[0035] 7=hydrogen;
  • C[0036] 1-C12-alky, which is optionally substituted once or twice by halogen;
  • C[0037] 2-C18-alkenyl, which is optionally substituted once or twice by C1-C4-alkyl or C1-C4-alkyloxycarbonyl;
  • C[0038] 6-C10-aryl-C1-C4-alky, which is optionally 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, wherein aryl is further optionally substituted by halogen or CF3;
  • C[0039] 5-C8-cycloalkyl-C1-C4-alkyl;
  • or the group Het-(CH[0040] 2)r—,
  • wherein r=1, 2 or 3 and Het=a saturated or unsaturated 5-7-membered heterocycle, which is optionally substituted by halogen, C[0041] 1-C4-alkyloxy or C1-C4-alkyloxycarbonyl, and/or compounds of the formula 1 in which:
  • R[0042] 4 is NR6-A-R7, wherein
  • R[0043] 6=hydrogen,
  • A=—CO— and [0044]
  • R[0045] 7=C1-C18-alkyl, which is optionally substituted by halogen, phenyl, phenoxy, phenylcarbonyl or C1-C4-alkyloxycarbonyl, wherein phenoxy is optionally substituted by methyl, halogen or methylmercapto;
  • C[0046] 2-C18-alkenyl, which is optionally substituted by C6-C10-aryl;
  • C[0047] 6-C10-aryl, which is optionally substituted by halogen, C1-C8-alkyl, phenyl-C1-C4-alkyl, CF3, OCF3, fluorosulfonyl, C1-C4-alkyloxycarbonyl, phenoxy, wherein aryl is optionally substituted by C1-C4-alkyloxy;
  • C[0048] 6-C10-aryl-C1-C4-alkyl, wherein alkyl is optionally substituted by methoxy or CF3 and aryl by halogen;
  • or the group Het-(CH[0049] 2)r—,
  • wherein r=0 and Het=a saturated or unsaturated 5-7-membered heterocycle, which is optionally benzo-fused and optionally substituted by C[0050] 1-C4-alkyl, halogen, C1-C4-alkyloxy, halophenyl or halobenzylmercapto, wherein benzo-fused aryl is optionally substituted by halogen or methoxy, and/or compounds of the formula 1 in which:
  • R[0051] 4 is NR6-A-R7, wherein
  • R[0052] 6=hydrogen,
  • A=—CO[0053] 2— and
  • R[0054] 7=C1-C18-alkyl, which is substituted by CF3 or phenyl;
  • C[0055] 6-C10-aryl;
  • C[0056] 6-C10-aryl-C1-C4-alkyl, which is substituted by C1-C4-alkyl, halogen, CF3 or OCF3, benzyloxy or phenyl;
  • or the group Het-(CH[0057] 2)r—,
  • wherein r=0 or 1 and Het=a saturated or unsaturated 5-7-membered heterocycle, which is optionally benzo-fused and optionally substituted by C[0058] 1-C4-alkyl or benzyl, and/or compounds of the formula 1 in which:
  • R[0059] 4 is NR6-A-R7, wherein
  • R[0060] 6=hydrogen,
  • A=—SO[0061] 2— and
  • R[0062] 7=C1-C6-alky, which is optionally substituted by CF3;
  • C[0063] 2-C4-alkenyl, which is optionally substituted by phenyl;
  • C[0064] 6-C10-aryl, which is optionally substituted by C1-C6-alkyl, halogen,
  • C[0065] 1-C4-alkyloxy or benzyl;
  • biphenylyl-C[0066] 1-C4-alkyl substituted by halogen;
  • or the group Het-(CH[0067] 2)r—,
  • wherein r=0 and Het=a saturated or unsaturated 5-7-membered heterocycle, and/or compounds of the formula 1 in which: [0068]
  • R[0069] 4 is NR6-A-R7, wherein
  • R[0070] 6=hydrogen,
  • A=—CO—NH— and [0071]
  • R[0072] 7=C1-C10-alkyl, which is optionally substituted by C1-C4-alkyloxycarbonyl, N(C1-C4-alkyl)2 or phenyl, which is in turn optionally substituted by halogen or aminosulfonyl;
  • C[0073] 6-C10-aryl, which is optionally substituted by C1-C6-alkyl, C1-C6-alkyloxy, C1-C6-alkyloxycarbonyl, phenoxy, OCF3, benzyl or pyridyl, wherein alkyl is optionally substituted by C1-C4-alkyloxycarbonyl or carboxyl;
  • C[0074] 5-C8-cycloalky, which is optionally substituted by hydroxyl, or indanyl;
  • or the group Het-(CH2)[0075] r—,
  • wherein r=0 or 1 and Het=a saturated or unsaturated 5-7-membered heterocycle, which is optionally substituted by benzyl. [0076]
  • Other typical compounds of the formula 1 are those in which R[0077] 1 is methyl.
  • Representative compounds of the formula 1 are those mentioned in Examples 21, 22, 27, 28, 30 to 34, 36 to 42, 53, 54, 58, 60, 62, 65, 69, 71, 74, 92, 97,107,116,128, 130, 136,139,142,152,166 and 171. [0078]
  • The compounds of the invention have a surprising inhibitory effect on hormone-sensitive lipase, HSL, an allosteric enzyme in adipocytes, which is inhibited by insulin and is responsible for the breakdown of fats in fat cells and for the transfer of fat constituents into the blood stream. Inhibition of this enzyme thus corresponds to an insulin-like effect of the compounds of the invention, which eventually leads to a reduction of free fatty acids in the blood and of blood glucose. Therefore, the compounds of the invention can be employed in the treatment of metabolic disturbances such as, for example, non-insulin-dependent diabetes mellitus, diabetic syndrome, and direct damage to the pancreas. [0079]
  • The compounds of the invention can be prepared in various ways by methods known per se. [0080]
    Figure US20010031772A1-20011018-C00003
  • For example, substituted 3-phenyl-5-alkoxy-1,3,4-oxadiazol-2-ones of the formula 1 can be prepared by reacting hydrazines of the formula 2 with chloroformic esters of the formula 3 or other reactive carbonic ester derivatives, in which R[0081] 1, 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 nitro to amino radicals by known processes, and subsequent acylation or alkylation, into compounds of the formula 1. Since acids are usually liberated in these reactions, neutralization 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 to operate in the temperature range from 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, and diethyl ether.
  • The hydrazines of the formula 2 can be prepared by known methods, for example by diazotization of the corresponding anilines and [0082]
    Figure US20010031772A1-20011018-C00004
  • subsequent reduction by known methods or by nucleophilic substitution of suitably substituted phenyl derivatives of the formula 6 (X=F, Cl, Br, l, OSO[0083] 2CF3) with hydrazine hydrate. Such suitable phenyl derivatives may be nitro-substituted halobenzenes, such as fluoro- and chloronitrobenzenes, from which the compounds of the invention can be prepared by known methods at a suitable point in the synthetic route by reduction and reaction with acylating or alkylating agents such as, for example, acid chlorides, anhydrides, isocyanates, chloroformic esters, sulfonyl chlorides or alkyl and arylalkyl halides, or by reductive alkylation with aldehydes.
  • The effect of the compounds of the invention on HSL was tested using the following enzyme assay system: [0084]
  • Enzyme Preparation: [0085]
  • Preparation of Partially Purified HSL: [0086]
  • Isolated rat fat cells were obtained from epididymal adipose tissue from untreated male rats (Wistar, 220-250 g) by collagenase treatment according to published methods (e.g., S. Nilsson et al., Anal. Biochem. 158:399-407 (1986); G. Fredrikson et al., J. Biol. Chem. 256:6311-6320 (1981); H. Tornquist et al., J. Biol. Chem. 251:813-819 (1976)). The fat cells from 10 rats were washed three times by flotation with 50 ml each time of homogenization buffer (25 ml tris/HCl, pH 7.4, 0.25 M sucrose, 1 mM EDTA, 1 mM DTT, 10 μg/ml leupeptin, 10 μg/ml antipain, 20 μg/ml pepstatin) and finally taken up in 10 ml of homogenization buffer. The fat cells were homogenized in a Teflon-in-glass homogenizer (Braun-Melsungen) by 10 strokes at 1500 rpm and 15° C. The homogenate was centrifuged (Sorvall SM24 tubes, 5000 rpm, 10 min, 4° C.). The subnatant between the fatty layer at the top and the pellet was removed and the centrifugation was repeated. The subnatant resulting therefrom was recentrifuged (Sorvall SM24 tubes, 20000 rpm, 45 min, 4° C.). The subnatant was removed and mixed with 1 g of heparin-Sepharose (Pharmacia-Biotech, CL-6B, 5×washed with 25 mM tris/HCl, pH 7.4,150 mM NaCl). After the mixture had been incubated at 4° C. for 60 min (shaking at 15-min intervals), it was centrifuged (Sorvall SM24 tubes, 3000 rpm, 10 min, 4° C.). The supernatant was adjusted to pH 5.2 by adding glacial acetic acid and incubated at 4° C. for 30 min. The precipitates were collected by centrifugation (Sorvall SS34, 12000 rpm, 10 min, 4° C.) and suspended in 2.5 ml of 20 mM tris/HCl, pH 7.0,1 mM EDTA, 65 mM NaCl, 13% sucrose, 1 mM DTT, 10 μg/ml leupeptin/pepstatin/antipain. The suspension was dialyzed against 25 mM tris/HCl, pH 7.4, 50% glycerol, 1 mM DTT, 10 μg/ml leupeptin, pepstatin, antipain at 4° C. overnight and then loaded onto a hydroxy apatite column (0.1 g per 1 ml of suspension, equilibrated with 10 mM potassium phosphate, pH 7.0, 30% glycerol, 1 mM DTT). The column was washed with four volumes of equilibration buffer at a flow rate of 20 to 30 ml/h. The HSL was eluted with one volume of equilibration buffer containing 0.5 M potassium phosphate, and then dialyzed (see above) and concentrated 5- to 10-fold by ultrafiltration (Amicon Diaflo PM 10 filter) at 4° C. The partially purified HSL can be stored at −70° C. for 4 to 6 weeks. [0087]
  • Assay: [0088]
  • To prepare the substrate, 25-50 μCi of [[0089] 3H]trioleoylglycerol (in toluene), 6.8 μmol of unlabeled trioleoylglycerol and 0.6 mg of phospholipids (phosphatidylcholine/phosphatidylinositol 3:1 w/v) were mixed, dried with N2 and then taken up in 2 ml of 0.1 M KPi (pH 7.0) by ultrasonic treatment (Branson 250, microtip, setting 1-2, 2×1 min at 1-min intervals). After addition of 1 ml of KPi and renewed ultrasonic treatment (4×30 sec on ice in 30-sec intervals), 1 ml of 20% BSA (in KPi) was added (final concentration of trioleoylglycerol 1.7 mM). For the reaction, 100 μl of substrate solution were pipetted into 100 82 l of HSL solution (HSL prepared as above, diluted in 20 mM KPi, pH 7.0, 1 mM EDTA, 1 mM DTT, 0.02% BSA, 20 μg/ml pepstatin, 10 μg/ml leupeptin) and incubated at 37° C. for 30 min. Addition of 3.25 ml of methanol/chloroform/heptane (10:9:7) and of 1.05 ml of 0.1 M K2CO3, 0.1 M boric acid (pH 10.5) was followed by thorough mixing and finally centrifugation (800×g, 20 min). After phase separation, one equivalent of the upper phase (1 ml) was removed and the radioactivity was determined by liquid scintillation measurement.
  • Evaluation: [0090]
  • Substances were normally tested in four independent mixtures. The inhibition of the HSL enzymatic activity by a test substance was determined by comparison with an uninhibited control reaction. The IC[0091] 50 was calculated via an inhibition plot with at least 10 concentrations of the test substance. The data was analyzed using the software package GRAPHIT, Elsevier-BIOSOFT.
  • Selected compounds of the invention showed the following effect, as measured by this assay: [0092]
    Compound of Example No. IC50 (μM)
    21 10
    22 1
    27 10
    28 6
    30 1
    31 10
    32 3
    33 0.2
    34 1
    36 10
    37 1
    38 1
    39 1
    40 10
    41 0.1
    42 1
    53 1
    54 1
    58 0.8
    60 0.2
    62 0.3
    65 1
    69 0.03
    71 0.02
    74 0.04
    92 0.25
    97 0.03
    107  0.12
    116  0.1
    128  0.6
    130  0.5
    136  0.5
    139  0.4
    142  0.2
    152  0.2
    166  0.2
    171  0.6
  • The following examples illustrate the preparation methods in detail without restricting them. [0093]
    • EXAMPLE 1
  • 3-Methyl-4-nitrophenylhydrazine [0094]
  • 5 g of hydrazine hydrate were 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 was heated with stirring at 65° C. for 4 hours. The product was precipitated by adding 70 ml of water and was filtered off with suction and then recrystallized from isopropanol. [0095]
  • Yield:13.3 g m.p.: 138° C. [0096]
  • The following examples were prepared in an analogous way: CL EXAMPLE 2 [0097]
  • 3-Fluoro-4-nitrophenylhydrazine [0098]
  • M.p.: 130° C. [0099]
    • EXAMPLE 3
  • 2-Chloro-4-nitrophenylhydrazine [0100]
  • M.p.:144° C. [0101]
    • EXAMPLE 4
  • 2-Methyl-4-nitrophenylhydrazine [0102]
  • M.p.:135° C. [0103]
    • EXAMPLE 5
  • 3-(4-Fluorobenzyloxy)-2-nitrophenylhydrazine [0104]
  • M.p.:164° C. [0105]
  • 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. [0106]
    • EXAMPLE 6
  • 3-(4-Fluorobenzyloxy)-4-nitrophenylhydrazine (intermediate) [0107]
  • M.p.: 145° C. [0108]
    • EXAMPLE 7
  • 4-(4-Chlorophenoxy)-3-nitroaniline [0109]
  • 1.4 g of potassium carbonate were 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 were added, and the mixture was stirred at 100° C. for 3 hours. After cooling, 80 ml of water were added and, after brief stirring, the precipitate was filtered off with suction and dried in vacuo at 40° C. [0110]
  • Yield: 2.0 g; m.p.: 101° C. [0111]
    • EXAMPLE 8
  • 4-(4-Chlorophenoxy)-3-nitrophenylhydrazine [0112]
  • A solution of 0.52 g of sodium nitrite in 5 ml of water was 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 was 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 HCl. The precipitate was 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 oil formed was extracted by shaking with ethyl acetate and washed with water, and the organic phase was dried with sodium sulfate. The product was then precipitated with isopropanolic HCl, filtered off with suction and dried in vacuo. [0113]
  • Yield: 1.1 g; m.p.: 221° C. [0114]
    • EXAMPLE 9
  • Methyl N′-(4-nitro-2-methylphenyl)hydrazinoformate [0115]
  • 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 over night and the solid was dried in vacuo at 40° C. [0116]
  • Yield: 0.81 g; m.p.:153° C. [0117]
  • The following examples were prepared in an analogous way: [0118]
    • EXAMPLE 10
  • Methyl N′-(4-nitrophenyl)hydrazinoformate (intermediate) [0119]
  • M.p.: 179° C. [0120]
    • EXAMPLE 11
  • Methyl N′-(3-fluoro-4-nitrophenyl)hydrazinoformate [0121]
  • M.p.: 127.4° C. [0122]
    • EXAMPLE 12
  • Methyl N′-(3-methyl-4-nitrophenyl)hydrazinoformate [0123]
  • M.p.: 159° C. [0124]
    • EXAMPLE 13
  • Methyl N′-(2-chloro-4-nitrophenyl)hydrazinoformate [0125]
  • M.p.: 156° C. [0126]
    • EXAMPLE 14
  • Methyl N′-(3-(4-fluorobenzyloxy)-4-nitrophenyl)hydrazinoformate (intermediate) [0127]
  • M.p.: 166° C. [0128]
    • EXAMPLE 15
  • Methyl N′-(3-(4-fluorobenzyloxy)-2-nitrophenyl)hydrazinoformate [0129]
  • M.p.: 193° C. [0130]
    • EXAMPLE 16
  • Methyl N′-(4-(4-chlorophenoxy)-3-nitrophenyl)hydrazinoformate [0131]
  • M.p.: 147° C. [0132]
    • EXAMPLE 17
  • Methyl N′-(3-piperidino-4-nitrophenyl)hydrazinoformate (-) [0133]
  • M.p.: 131° C. [0134]
  • 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. [0135]
    • EXAMPLE 18
  • Methyl N′-(3-(N-benzylpiperazino)-4-nitrophenyl)hydrazinoformate [0136]
  • M.p.: 156° C. [0137]
    • EXAMPLE 19
  • [0138] 5-Methoxy-3-(4-nitrophenyl)-3H-(1,3,4)oxadiazol-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. [0139]
  • Yield:1.5 g m.p.: 151° C. [0140]
  • The following examples were prepared analogously to Example 4: [0141]
    • EXAMPLE 20
  • 5-Methoxy-3-(3-methyl-4-nitrophenyl)-3H-(1,3,4)oxadiazol-2-one [0142]
  • M.p.: 112° C. [0143]
    • EXAMPLE 21
  • 5-Methoxy-3-(4-(4-chlorophenoxy-3-nitrophenyl)-3H-(1,3,4)oxadiazol-2-one [0144]
  • M.p.: oil [0145]
    • EXAMPLE 22
  • 5-Methoxy-3-(3-(4-fluorobenzyloxy)-2-nitrophenyl)-3H-(1,3,4)oxadiazol-2-one [0146]
  • M.p.: 99° C. [0147]
    • EXAMPLE 23
  • 5-Methoxy-3-(2-methyl-4-nitrophenyl)-3H-(1,3,4)oxadiazol-2-one [0148]
  • M.p.: 111° C. [0149]
    • EXAMPLE 24
  • 5-Methoxy-3-(3-(4-fluorobenzyloxy)-4-nitrophenyl)-3H-(1,3,4)oxadiazol-2-one [0150]
  • M.p.: 137° C. [0151]
    • EXAMPLE 25
  • 5-Methoxy-3-(4-aminophenyl)-3H-(1,3,4)oxadiazol-2-one [0152]
  • A mixture consisting of 1.4 g of 5-methoxy-3-(4-nitrophenyl)-3H-(1,3,4)oxadiazol-2-one, 0.5 g of Pd/C and 20ml of methanol was hydrogenated under atmospheric pressure at room temperature until the calculated amount of hydrogen had been taken up. The catalyst was then filtered off, and the solution was concentrated in vacuo. The remaining semisolid residue was stirred with isopropanol and filtered off with suction. [0153]
  • Yield: 0.75g; m.p.: 85° C. [0154]
    • EXAMPLE 26
  • 5-Methoxy-3-(2-amino-4-(4-fluorobenzyloxy)phenyl)-3H-(1,3,4)oxadiazol-2-one [0155]
  • M.p.: oil [0156]
    • EXAMPLE 27
  • 5-Methoxy-3-(3-amino-4-(4-chlorophenoxy)phenyl)-3H-(1,3,4)oxadiazol-2-one [0157]
  • M.p.: 133° C. [0158]
    • EXAMPLE 28
  • 5-Methoxy-3-(4-amino-3-methylphenyl)-3H-(1,3,4)oxadiazol-2-one [0159]
  • M.p.: 114° C. [0160]
    • EXAMPLE 29
  • 5-Methoxy-3-(4-amino-3-(4-fluorobenzyloxy)phenyl)-3H-(1,3,4)oxadiazol-2-one [0161]
  • M.p.: 195° C. [0162]
    • EXAMPLE 30
  • 5-Methoxy-3-(4-(4-chlorophenylacetylamino)phenyl)-3H-(1,3,4)oxadiazol-2-one [0163]
  • 201 mg of 4-chlorophenylacetyl chloride were added dropwise to a mixture consisting of 200 mg of 5-methoxy-3-(4-aminophenyl)-3H-(1,3,4)oxadiazol-2-one, 20 ml of methylene chloride and 0.1 ml of pyridine cooled in ice, and the mixture was stirred at room temperature for 5 hours. Volatiles were removed in vacuo. The residue was stirred with water and the solid was filtered off with suction and dried at 40° C. in vacuo. [0164]
  • Yield: 318 mg; m.p.:161° C. [0165]
  • The following examples were prepared in an analogous way: [0166]
    • EXAMPLE 31:
  • 5-Methoxy-3-(4-(4-chlorophenylacetylamino)-3-methylphenyl)-3H-(1,3,4)oxadiazol-2-one [0167]
  • M.p.: 190° C. [0168]
    • EXAMPLE 32
  • 5-Methoxy-3-(4-octanoylamino-3-methylphenyl)-3H-(1,3,4)oxadiazol-2-one [0169]
  • M.p.: 110° C. [0170]
    • EXAMPLE 33
  • 5-Methoxy-3-(4-(4-heptylbenzoylamino)phenyl)-3H-(1,3,4)oxadiazol-2-one [0171]
  • M.p.: 155° C. [0172]
    • EXAMPLE 34
  • 5-Methoxy-3-(4-(4-butylphenylsulfonylamino)phenyl)-3H-(1,3,4)oxadiazol-2-one [0173]
  • M.p.: 135° C. [0174]
    • EXAMPLE 35
  • 5-Methoxy-3-(4-(4-chlorobutanoylamino)-3-methylphenyl)-3H-(1,3,4)oxadiazol-2-one [0175]
  • M.p.: 137° C. [0176]
    • EXAMPLE 36
  • 5-Methoxy-3-(4-pivaloylamino-3-methylphenyl)-3H-(1,3,4)oxadiazol-2-one [0177]
  • M.p.: 157° C. [0178]
    • EXAMPLE 3
  • 5-Methoxy-3-(4-(4-chlorophenylsulfonylamino)-3-methylphenyl)-3H-(1,3,4)oxadiazol-2-one [0179]
  • M.p.: 147° C. [0180]
    • EXAMPLE 38
  • 5-Methoxy-3-(4-(1-naphthylsulfonylamino)-3-methylphenyl)-3H-(1,3,4)oxadiazol-2-one [0181]
  • M.p.: 123° C. [0182]
    • EXAMPLE 39
  • 5-Methoxy-3-(4-(2-phenylethenylsulfonylamino)-3-methylphenyl)-3H-(1,3,4)oxadiazol-2-one [0183]
  • M.p.: 129° C. [0184]
    • EXAMPLE 40
  • 5-Methoxy-3-(4-(2,2,2-trifluoroethylsulfonylamino)-3-methylphenyl)-3H-(1,3,4)oxadiazol-2-one [0185]
  • M.p.: 151° C. [0186]
  • EXAMPLE 41 [0187]
  • 5-Methoxy-3-(4-(benzyloxycarbonylamino)-3-methylphenyl)-3H-(1,3,4)oxadiazol-2-one [0188]
  • M.p.: 115° C. [0189]
    • EXAMPLE 42
  • 5-Methoxy-3-(4-(3,4-dichlorophenylaminocarbonylamino)-3-methylphenyl)-3H-(1,3,4)oxadiazol-2-one [0190]
  • M.p.: 210° C. [0191]
  • The latter compound was obtained by reacting 5-methoxy-3-(4-amino-3-methylphenyl)-3H-(1,3,4)oxadiazol-2-one with equimolar amounts of 3,4-dichlorophenyl isocyanate in toluene at 50° C. [0192]
    • EXAMPLE 43
  • 5-Methoxy-3-(4-(4-chlorophenylsulfonylamino)phenyl)-3H-(1,3,4)oxadiazol-2-one [0193]
  • M.p.: 169° C. [0194]
    • EXAMPLE 44
  • 5-Methoxy-3-(4-(2-chlorophenylsulfonylamino)phenyl)-3H-(1,3,4)oxadiazol-2-one [0195]
  • M.p.: 171° C. [0196]
    • EXAMPLE 45
  • 5-Methoxy-3-(4-(3-chlorophenylsulfonylamino)phenyl)-3H-(1,3,4)oxadiazol-2-one [0197]
  • M.p.: 141° C. [0198]
    • EXAMPLE 46
  • 5-Methoxy-3-(4-(4-chlorophenylacetylamino)-3-(4-fluorobenzyloxy)phenyl)-3H-(1,3,4)oxadiazol-2-one [0199]
  • M.p.: 167° C. [0200]
    • EXAMPLE 47
  • [0201] 5-Methoxy-3-(4-benzylsulfonylaminophenyl)-3H-(1,3,4)oxadiazol-2-one
  • M.p.: 153° C. [0202]
    • EXAMPLE 48
  • 5-Methoxy-3-(4-(-2-(4′-chlorobiphenyl)ethyl)sulfonylamino)phenyl)-3H-(1,3,4)oxadiazol-2-one [0203]
  • M.p.: 165° C. [0204]
    • EXAMPLE 49
  • 5-Methoxy-3-(4-isopropylsulfonylaminophenyl)-3H-(1,3,4)oxadiazol-2-one [0205]
  • M.p.: 190° C. [0206]
    • EXAMPLE 50
  • 5-Methoxy-3-(4-dimethylamino-3-methylphenyl)-3H-(1,3,4)oxad iazol-2-one [0207]
  • M.p.: 71° C. [0208]
  • The latter compound was obtained by reacting 5-methoxy-3-(4-amino-3-methylphenyl)-3H-(1,3,4)oxadiazol-2-one with paraformaldehyde/formic acid in DMF at room temperature and was purified by column chromatography (silica gel, ethyl acetate:n-heptane=1:1). [0209]
    • EXAMPLE 51
  • 5-Methoxy-3-(4-(4-chlorobenzylamino)-3-methylphenyl)-3H-(1,3,4)oxadiazol-2-one [0210]
  • M.p.: oil [0211]
  • The latter compound was obtained by reacting 5-methoxy-3-(4-amino-3-methylphenyl)-3H-(1,3,4)oxadiazol-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). [0212]
    • EXAMPLE 52
  • 5-Methoxy-3-(4-(2-oxopyrrolidin-1-yl)-3-methylphenyl)-3H-(1,3,4)oxad iazol-2-one [0213]
  • M.p.: oil [0214]
  • The latter compound was prepared by reacting 5-methoxy-3-(4-(4-chlorobutanoylamino)-3-methylphenyl)-3H-(1,3,4)oxadiazol-2-one with sodium hydride in dioxane at room temperature and purifying the crude product by column chromatography (silica gel, methylene chloride:methanol=98:2). [0215]
    • EXAMPLE 53
  • 5-Methoxy-3-(4-(4-oxopent-2-en-2-ylamino)-3-methylphenyl)-3H-(1,3,4)oxadiazol-2-one [0216]
  • M.p.: 143° C. [0217]
  • The latter compound was obtained by reacting 5-methoxy-3-(4-amino-3-methylphenyl)-3H-(1,3,4)oxadiazol-2-one with equimolar amounts of acetylacetone in glacial acetic acid at 80° C. and was isolated by precipitation by adding water and filtration. [0218]
    • EXAMPLE 54
  • 5-Methoxy-3-(4-(2,5-dimethylpyrrol-1-yl)-3-methylphenyl)-3H-(1,3,4)oxadiazol-2-one [0219]
  • M.p.: oil [0220]
  • The latter compound was obtained by reacting 5-methoxy-3-(4-amino-3-methylphenyl)-3H-(1,3,4)oxadiazol-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. [0221]
    • EXAMPLE 55
  • 5-Methoxy-3-(3-(4-fluorobenzyloxy)-4-methylaminophenyl)-3H-(1,3,4)oxadiazol-2-one [0222]
  • M.p.: 98° C. [0223]
  • The latter compound was obtained as a by-product of the hydrogenation of 5-methoxy-3-(3 -(4-fluorobenzyloxy)-4-nitrophenyl)-3H-(1,3,4)oxadiazol-2-one with platinum dioxide as catalyst, in methanol, at room temperature under atmospheric pressure. Purification proceeded by column chromatography (silica gel, methylene chloride) after filtering off the catalyst and concentrating the reaction mixture. [0224]
  • The compounds of Examples 56-199 were prepared analogously to the above-mentioned examples. [0225]
    • EXAMPLE 56
  • 5-Methoxy-3-(3-aminophenyl)-3H-(1,3,4)oxadiazol-2-one [0226]
  • M.p.: 95° C. [0227]
    • EXAMPLE 57
  • 5-Methoxy-3-(3-dibenzylaminophenyl)-3H-(1,3,4)oxadiazol-2-one [0228]
  • M.p.: 71° C. [0229]
    • EXAMPLE 58
  • 5-Methoxy-3-(3-benzylaminophenyl)-3H-(1,3,4)oxadiazol-2-one [0230]
  • M.p.: oil [0231]
    • EXAMPLE 59
  • 5-Methoxy-3-(4-(pyrid-2-yl)aminocarbonylaminophenyl)-3H-(1,3,4)oxadiazol-2-one [0232]
  • M.p.: 81° C. [0233]
    • EXAMPLE 60
  • 5-Methoxy-3-(3-(4-fluorobenzyloxy)-4-benzyloxycarbonylaminophenyl)-3H-(1,3,4)oxadiazol-2-one [0234]
  • M.p.: oil [0235]
    • EXAMPLE 61
  • 5-Methoxy-3-(4-amino-2-methylphenyl)-3H-(1,3,4)oxadiazol-2-one [0236]
  • M.p.: oil [0237]
    • EXAMPLE 62
  • 5-Methoxy-3-(3-methyl-4-(2-chlorobenzyloxycarbonylamino)phenyl)-3H-(1,3,4)oxadiazol-2-one [0238]
  • M.p.: 161° C. [0239]
    • EXAMPLE 63
  • 5-Methoxy-3-(4-amino-2-chlorophenyl)-3H-(1,3,4)oxadiazol-2-one [0240]
  • M.p.: 126° C. [0241]
    • EXAMPLE 64
  • 5-Methoxy-3-(2-chloro-4-nitrophenyl)-3H-(1,3,4)oxadiazol-2-one [0242]
  • M.p.: 92° C. [0243]
    • EXAMPLE 65
  • 5-Methoxy-3-(2-methyl-4-benzyloxycarbonylaminophenyl)-3H-(1,3,4)oxadiazol-2-one [0244]
  • M.p.: 112° C. [0245]
    • EXAMPLE 66
  • 5-Methoxy-3-(2-methyl-4-(4-trifluoromethoxybenzoylamino)phenyl)-3H-(1,3,4)oxadiazol-2-one [0246]
  • M.p.: 150° C. [0247]
    • EXAMPLE 67
  • 5-Methoxy-3-(2-chloro-4-benzyloxycarbonylaminophenyl)-3H-(1,3,4)oxadiazol-2-one [0248]
  • M.p.: 150° C. [0249]
    • EXAMPLE 68
  • 5-Methoxy-3-(3-fluoro-4-nitrophenyl)-3H-(1,3,4)oxadiazol-2-one [0250]
  • M.p.: 127° C. [0251]
    • EXAMPLE 69
  • 5-Methoxy-3-(4-(4-t-butylbenzoylamino)phenyl)-3H-(1,3,4)oxadiazol-2-one [0252]
  • M.p.: 173° C. [0253]
    • EXAMPLE 70
  • 5-Methoxy-3-(4-(4-chlorobenzyloxycarbonylamino)phenyl)-3H-(1,3,4)oxadiazol-2-one [0254]
  • M.p.: 177° C. [0255]
    • EXAMPLE 71
  • 5-Methoxy-3-(2-chloro-4-(4-heptylbenzoylamino)phenyl)-3H-(1,3,4)oxadiazol-2-one [0256]
  • M.p.: 135° C. [0257]
    • EXAMPLE 72
  • 5-Methoxy-3-(4-(3,4-dichlorobenzoylamino)phenyl)-3H-(1,3,4)oxadiazol-2-one [0258]
  • M.p.: 200° C. [0259]
    • EXAMPLE 73
  • 5-Methoxy-3-(4-(2-(4-chlorophenoxy)-2-methylpropionylamino)phenyl)-3H-(1,3,4)oxadiazol-2-one [0260]
  • M.p.: 153° C. [0261]
    • EXAMPLE 74
  • 5-Ethoxy-3-(3-methyl-4-benzyloxycarbonylaminophenyl)-3H-(1,3,4)oxadiazol-2-one [0262]
  • M.p.: 94° C. [0263]
    • EXAMPLE 75
  • 5-isopropoxy-3-(3-methyl-4-benzyloxycarbonylaminophenyl)-3H-(1,3,4)oxadiazol-2-one [0264]
  • M.p.: 119° C. [0265]
    • EXAMPLE 76
  • 5-isopropoxy-3-(3-methyl-4-butyloxycarbonylaminophenyl)-3H-(1,3,4)oxadiazol-2-one [0266]
  • M. p.: 114° C. [0267]
    • EXAMPLE 77
  • 5-isopropoxy-3-(3-methyl-4-(3-chlorophenylaminocarbonylamino)phenyl)-3H-(1,3,4)oxadiazol-2-one [0268]
  • M.p.: 201° C. [0269]
    • EXAMPLE 78
  • 5-tert-Butoxy-3-(3-methyl-4-benzyloxycarbonylaminophenyl)-3H-(1,3,4)oxadiazol-2-one [0270]
  • M.p.: 113° C. [0271]
    • EXAMPLE 79
  • 5-Methoxy-3-(3-methyl-4-phenoxycarbonylaminophenyl)-3H-(1,3,4)oxadiazol-2-one [0272]
  • M.p.: 145° C. [0273]
    • EXAMPLE 80
  • 5-Methoxy-3-(3-methyl-4-(pyrid-3-ylcarbonylamino)phenyl)-3H-(1,3,4)oxadiazol-2-one [0274]
  • M.p.: oil [0275]
    • EXAMPLE 81
  • 5-Methoxy-3-(3-methyl-4-(indan-2-ylaminocarbonylamino)phenyl)-3H-(1,3,4)oxadiazol-2-one [0276]
  • M.p.: 206° C. [0277]
    • EXAMPLE 82
  • 5-Methoxy-3-(3-methyl-4-(pyrid-3-ylmethylaminocarbonylamino)phenyl)-3H-(1,3, 4)oxadiazol-2-one [0278]
  • M.p.: 229° C. [0279]
    • EXAMPLE 83
  • [0280] 5-Methoxy-3-(3-methyl-4-(pyrid-3-ylmethoxycarbonylamino)phenyl)-3H-(1,3,4)oxadiazol-2-one
  • M.p.: 232° C. [0281]
    • EXAMPLE 84
  • 5-Methoxy-3-(3-fluoro-4-benzyloxycarbonylaminophenyl)-3H-(1,3,4)oxadiazol-2-one [0282]
  • M.p.: oil [0283]
    • EXAMPLE 85
  • 5-Methoxy-3-(3-fluoro-4-(4-trifluoromethylbenzoylamino)phenyl)-3H-(1,3,4)oxadiazol-2-one [0284]
  • M.p.: oil [0285]
    • EXAMPLE 86
  • 5-Methoxy-3-(3-benzyloxy-4-(4-trifluoromethylbenzoylamino)phenyl)-3H-(1,3,4)oxadiazol-2-one [0286]
  • M.p.: 159° C. [0287]
    • EXAMPLE 87
  • 5-Methoxy-3-(3-fluoro-4-(4-tert-butylbenzoylamino)phenyl)-3H-(1,3,4)oxadiazol-2-one [0288]
  • M.p.: 144° C. [0289]
    • EXAMPLE 88
  • 5-Methoxy-3-(3-methyl-4-(2,2,2-trifluoroethoxycarbonylamino)phenyl)-3H-(1,3, 4)oxadiazol-2-one [0290]
  • M.p.: 141° C. [0291]
    • EXAMPLE 89
  • 5-Methoxy-3-(3-methyl-4-piperidinocarbonylaminophenyl)-3H-(1,3,4)oxadiazol-2-one [0292]
  • M.p.: 154° C. [0293]
    • EXAMPLE 90
  • 5-Methoxy-3-(4-(6-methoxybenzofuran-2-yl-carbonylamino)phenyl)-3H-(1,3,4)oxadiazol-2-one [0294]
  • M.p.: 191° C. [0295]
  • Further examples of the invention were prepared by the processes described above and characterized by mass spectroscopy (M+1): [0296]
    Example Mol.
    No. Chemical name: M + 1 wt.
     91 N-[4-(5-Methoxy-2-oxo-[1,3,4]oxadiazol-3- 362 361.4
    yl)phenyl]-3-methyl-benzenesulfonamide
     92 3,4-Dimethoxy-N-[4-(5-methoxy-2-oxo-[1,3, 408 407.4
    4]oxadiazol-3-yl)-phenyl]benzenesulfon-
    amide
     93 Quinoline-8-sulfonic acid [4-(5-methoxy-2- 399 398.4
    oxo-[1,3,4]oxadiazol-3-yl)phenyl]amide
     94 N-[4-(5-Methoxy-2-oxo-[1,3,4]oxadiazol-3- 415 414.3
    yl)phenyl]-5-nitro-isophthalic acid mono-
    methyl ester
     95 3-(2-Chlorophenyl)-5-methylisoxazole-4- 427 426.8
    carboxylic acid [4-(5-methoxy-2-oxo-[1,3,
    4]oxadiazol-3-yl)phenyl]amide
     96 3,3,3-Trifluoro-2-methoxy-N-[4-(5-methoxy- 424 423.3
    2-oxo-[1,3,4]oxadiazol-3-yl)phenyl]-2-
    phenylpropionamide
     97 2-Fluoro-N-[4-(5-methoxy-2-oxo-[1,3,4] 330 329.3
    oxadiazol-3-yl)phenyl]-benzamide
     98 Tetradecanoic acid [4-(5-methoxy-2-oxo-[1, 418 417.5
    3,4]oxadiazol-3-yl)phenyl]amide
     99 N-[4-(5-Methoxy-2-oxo-[1,3,4]oxadiazol-3- 416 415.4
    yl)phenyl]-2-phenethyl-benzamide
    100 N-[4-(5-Methoxy-2-oxo-[1,3,4]oxadiazol-3- 479 478.4
    yl)phenyl]-2-(4-methoxyphenoxy)-5-nitro-
    benzamide
    101 2-(4-Benzyloxyphenyl)-N-[4-(5-methoxy-2- 432 431.4
    oxo-[1,3,4]oxadiazol-3-yl)phenyl]acetamide
    102 N-[4-(5-Methoxy-2-oxo-[1,3,4]oxadiazol-3- 492 491.5
    yl)phenyl]-3,3,3-triphenylpropionamide
    103 N-[4-(5-Methoxy-2-oxo-[1,3,4]oxadiazol-3- 448 447.3
    yl)phenyl]-3,5-bis-trifluoromethylbenzamide
    104 4-Cyano-N-[4-(5-methoxy-2-oxo-[1,3,4] 337 336.3
    oxadiazol-3-yl)phenyl]-benzamide
    105 Nonanoic acid [4-(5-methoxy-2-oxo-[1,3,4] 348 347.4
    oxadiazol-3-yl)phenyl]amide
    106 Methyl 9-[4-(5-methoxy-2-oxo-[1,3,4] 406 405.4
    oxadiazol-3-yl)phenyl-carbamoyl]nonanoate
    107 Undecanoic acid [4-(5-methoxy-2-oxo-[1,3, 376 375.5
    4]oxadiazol-3-yl)phenyl]amide
    108 4-[4-(5-Methoxy-2-oxo-[1,3,4]oxadiazol-3- 394 393.3
    yl)phenylcarbamoyl]-benzenesulfonyl
    fluoride
    109 11-Phenoxyundecanoic acid [4-(5-methoxy- 468 467.6
    2-oxo-[1,3,4]-oxadiazol-3-yl)phenyl]amide
    110 N-[4-(5-Methoxy-2-oxo-[1,3,4]oxadiazol-3- 416 415.4
    yl)phenyl]-2,3-diphenylpropionamide
    111 4-Chloro-N-[4-(5-methoxy-2-oxo-[1,3,4] 360 359.8
    oxadiazol-3-yl)phenyl]-2-methylbenzamide
    112 6-Chloro-N-[4-(5-methoxy-2-oxo-[1,3,4] 347 346.7
    oxadiazol-3-yl)phenyl]nicotinamide
    113 5-Fluoro-N-[4-(5-methoxy-2-oxo-[1,3,4] 344 343.3
    oxadiazol-3-yl)phenyl]-2-methylbenzamide
    114 N-[4-(5-Methoxy-2-oxo-[1,3,4]oxadiazol-3- 354 353.4
    yl)phenyl]-2,4,6-trimethylbenzamide
    115 N-[4-(5-Methoxy-2-oxo-[1,3,4]oxadiazol-3- 388 387.4
    yl)phenyl]-3-naphthalen-2-ylacrylamide
    116 5-Oxo-5-phenylpentanoic acid [4-(5- 382 381.4
    methoxy-2-oxo-[1,3,4]-oxadiazol-3-yl)
    phenyl]amide
    117 3-(2,4-Dichlorobenzylsulfanyl)thiophene-2- 509 508.4
    carboxylic acid [4-(5-methoxy-2-oxo-[1,3,4]
    oxadiazol-3-yl)phenyl]amide
    118 2-Fluoro-N-[4-(5-methoxy-2-oxo-[1,3,4] 398 397.3
    oxadiazol-3-yl)phenyl]-4-trifluoromethyl-
    benzamide
    119 1-Hexyl-3-[3-(5-methoxy-2-oxo-[1,3,4] 335 334.4
    oxadiazol-3-yl)phenyl]urea
    120 1-(4-Bromophenyl)-3-[3-(5-methoxy-2-oxo- 406 405.2
    [1,3,4]oxadiazol-3-yl)phenyl]urea
    121 1-[3-(5-Methoxy-2-oxo-[1,3,4]oxadiazol-3- 357 356.3
    yl)phenyl]-3-(2-methoxyphenyl)urea
    122 Ethyl 2-[3-[3-(5-methoxy-2-oxo-[1,3,4]oxa- 427 426.4
    diazol-3-yl)phenyl]-ureido]-3-phenyl-
    propionate
    123 1-(2,6-Diisopropylphenyl)-3-[3-(5-methoxy- 411 410.5
    2-oxo-[1,3,4]oxadiazol-3-yl)phenyl]urea
    124 1-[3-(5-Methoxy-2-oxo-[1,3,4]oxadiazol-3- 363 362.4
    yl)phenyl]-3-octylurea
    125 1-(4-Fluorobenzyl)-3-[3-(5-methoxy-2-oxo- 359 358.3
    [1,3,4]oxadiazol-3-yl)phenyl]urea
    126 1-(2-Ethylphenyl)-3-[3-(5-methoxy-2-oxo- 355 354.4
    [1,3,4]oxadiazol-3-yl)phenyl]urea
    127 Ethyl 6-[3-[3-(5-methoxy-2-oxo-[1,3,4] 393 392.4
    oxadiazol-3-yl)phenyl]-ureido]hexanoate
    128 1-(2,6-Dimethoxyphenyl)-3-[3-(5-methoxy- 387 386.4
    2-oxo-[1,3,4]oxadiazol-3-yl)phenyl]urea
    129 5-Methoxy-3-[4-[(thiophen-3-ylmethyl) 304 303.3
    amino]phenyl]-3H-[1,3,4]oxadiazol-2-one
    130 4-[[4-(5-Methoxy-2-oxo-[1,3,4]oxadiazol-3- 437 436.3
    yl)phenylamino]methyl]-benzonitrile tri-
    fluoroacetate
    131 3-[4-(2-Bromo-4,5-dimethoxybenzylamino) 437 436.3
    phenyl]-5-methoxy-3H-[1,3,4]oxadiazol-2-
    one
    132 3-[4-(3-Ethoxy-4-methoxybenzylamino) 486 485.4
    phenyl]-5-methoxy-3H-[1,3,4]oxadiazol-
    2-one trifluoroacetate
    133 Methyl 4-[[4-(5-methoxy-2-oxo-[1,3,4] 470 469.4
    oxadiazol-3-yl)phenylamino]methyl]benzoate
    trifluoroacetate
    134 4-[[4-(5-Methoxy-2-oxo-[1,3,4]oxadiazol-3- 356 355.3
    yl)phenylamino]-methyl]phenyl acetate
    135 5-Methoxy-3-[4-(pentafluorophenylmethyl- 388 387.3
    amino)phenyl]-3H-[1,3,4]oxadiazol-2-one
    136 3-[4-(4-Benzyloxybenzylamino)phenyl]-5- 518 517.5
    methoxy-3H-[1,3,4]oxadiazol-2-one
    trifluoroacetate
    137 3-[4-(3,3-Dichlorononylamino)phenyl]-5- 517 516.3
    methoxy-3H-[1,3,4]oxadiazol-2-one
    trifluoroacetate
    138 2-[[4-(5-Methoxy-2-oxo-[1,3,4]oxadiazol-3- 323 322.3
    yl)phenylamino]-methyl]benzonitrile
    139 3-[4-(Cyclohexylmethylamino)phenyl]-5- 304 303.4
    methoxy-3H-[1,3,4]oxadiazol-2-one
    140 5-Methoxy-3-[4-(2,3,5-trichlorobenzyl- 515 514.7
    amino)phenyl]-3H-[1,3,4]oxadiazol-2-one
    trifluoroacetate
    141 3-[4-(5-Bromo-2-fluorobenzylamino) 509 508.2
    phenyl]-5-methoxy-3H-[1,3,4]oxadiazol-2-
    one trifiuoroacetate
    142 3-[4-(4-Hexyloxybenzylamino)phenyl]-5- 512 511.5
    methoxy-3H-[1,3,4]oxadiazol-2-one
    trifluoroacetate
    143 5-Methoxy-3-[4-[3-(3-trifluoromethyl- 572 571.4
    phenoxy)benzylamino]-phenyl]-3H-[1,3,
    4]oxadiazol-2-one trifluoroacetate
    144 3-[4-[(2-Chloroquinolin-3-ylmethyl)amino] 497 496.8
    phenyl]-5-methoxy-3H-[1,3,4]oxadiazol-2-
    one trifluoroacetate
    145 Methyl 3-methoxy-5-[[4-(5-methoxy-2-oxo- 501 500.4
    [1,3,4]oxadiazol-3-yl)phenylamino]methyl]
    pyridine-2-carboxylate trifluoroacetate
    146 4-[[4-(5-Methoxy-2-oxo-[1,3,4]oxadiazol-3- 454 453.5
    yl)phenylamino]-methyl]phenyl
    benzenesulfonate
    147 2-(2,6-Dimethyl-4-methylsulfanylphenoxy)- 416 415.5
    N-[3-(5-methoxy-2-oxo-[1,3,4]oxadiazol-3-
    yl)phenyl]acetamide
    148 1-(2,4-Difluorophenyl)-3-[4-(5-methoxy-2- 363 362.3
    oxo-[1,3,4]oxadiazol-3-yl)phenyl]urea
    149 1-[4-(5-Methoxy-2-oxo-[1,3,4]oxadiazol-3- 419 418.4
    yl)phenyl]-3-(4-phenoxyphenyl)urea
    150 1-(2,6-Difluorophenyl)-3-[4-(5-methoxy-2- 363 362.3
    oxo-[1,3,4]oxadiazol-3-yl)phenyl]urea
    151 1-Butyl-3-[4-(5-methoxy-2-oxo-[1,3,4] 307 306.3
    oxadiazol-3-yl)phenyl]urea
    152 1-(2-Ethoxyphenyl)-3-[4-(5-methoxy-2-oxo- 371 370.4
    [1,3,4]oxadiazol-3-yl)phenyl]urea
    153 1-(2,6-Dibromo-4-fluorophenyl)-3-[4-(5- 503 502.1
    methoxy-2-oxo-[1,3,4]oxadiazol-3-yl)
    phenyl]urea
    154 1-(4-Butoxyphenyl)-3-[4-(5-methoxy-2-oxo- 399 398.4
    [1,3,4]oxadiazol-3-yl)phenyl]urea
    155 1-[4-(5-Methoxy-2-oxo-[1,3,4]oxadiazol-3- 411 410.3
    yl)phenyl]-3-(4-trifluoromethoxyphenyl)urea
    156 1-Benzyl-3-[4-(5-methoxy-2-oxo-[1,3,4] 341 340.3
    oxadiazol-3-yl)phenyl]urea
    157 1-(3-Fluorophenyl)-3-[4-(5-methoxy-2-oxo- 345 344.3
    [1,3,4]oxadiazol-3-yl)phenyl]urea
    158 Ethyl 6-[3-[4-(5-methoxy-2-oxo-[1,3,4] 393 392.4
    oxadiazol-3-yl)phenyl]-ureido]hexanoate
    159 1-Biphenyl-4-yl-3-[4-(5-methoxy-2-oxo-[1,3, 403 402.4
    4]oxadiazol-3-yl)phenyl]urea
    160 Butyl 2-[3-[4-(5-methoxy-2-oxo-[1,3,4] 427 426.4
    oxadiazol-3-yl)phenyl]-ureido]benzoate
    161 5-Methoxy-3-[3-(7-methoxy-3,7-dimethyl- 492 491.5
    octylamino)phenyl]-3H-[1,3,4]oxadiazol-2-
    one trifluoroacetate
    162 5-Methoxy-3-[3-[(thiophen-2-ylmethyl) 418 417.4
    amino]phenyl]-3H-[1,3,4]oxadiazol-2-one
    trifluoroacetate
    163 3-(3-Hexylaminophenyl)-5-methoxy-3H-[1, 406 405.4
    3,4]oxadiazol-2-one trifluoroacetate
    164 5-Methoxy-3-[3-(3-phenylpropylamino) 440 439.4
    phenyl]-3H-[1,3,4]oxadiazol-2-one
    trifluoroacetate
    165 5-Methoxy-3-(3-undecylaminophenyl)-3H- 476 475.5
    [1,3,4]oxadiazol-2-one trifluoroacetate
    166 5-Methoxy-3-[3-[(3-trifluoromethylphenoxy) 572 571.4
    benzylamino]phenyl]-3H-[1,3,4]oxadiazol-2-
    one trifluoroacetate
    167 3-[3-[(2-Chloroquinolin-3-ylmethyl)amino] 497 496.8
    phenyl]-5-methoxy-3H-[1,3,4]oxadiazol-2-
    one trifluoroacetate
    168 4-[[3-(5-Methoxy-2-oxo-[1,3,4]oxadiazol-3- 586 585.5
    yl)phenylamino]-methyl]phenyl 4-fluoro-
    benzenesulfonate trifluoroacetate
    169 5-Methoxy-3-[3-(3,4,5-trifluorobenzylamino) 466 465.3
    phenyl]-3H-[1,3,4]oxadiazol-2-one
    trifluoroacetate
    170 3-[3-(3,5-Bistrifluoromethylbenzylamino) 548 547.3
    phenyl]-5-methoxy-3H-[1,3,4]oxadiazol-2-
    one trifluoroacetate
    171 3-(3-Dec-4-enylaminophenyl)-5-methoxy- 460 459.5
    3H-[1,3,4]oxadiazol-2-one trifluoroacetate
    172 3-[3-(3-Cyclopentyl-2-phenethyloxybenzyl- 600 599.6
    amino)phenyl]-5-methoxy-3H-[1,3,4]
    oxadiazol-2-one trifluoroacetate
    173 4-[[3-(5-Methoxy-2-oxo-[1,3,4]oxadiazol-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]
    oxadiazol-2-one trifluoroacetate
    175 3-[3-(2-Benzyloxyethylamino)phenyl]-5- 456 455.4
    methoxy-3H-[1,3,4]oxadiazol-2-one
    trifluoroacetate
    176 3-[3-(2,6-Difluorobenzylamino)phenyl]-5- 448 447.3
    methoxy-3H-[1,3,4]oxadiazol-2-one
    trifluoroacetate
    M.p. ° C.
    177 Dodecanoic acid [4-(5-methoxy-2-oxo-[1,3,4]  93
    oxadiazol-3-yl)phenyl]amide
    178 Octadec-9-enoic acid [4-(5-methoxy-2-oxo-[1,3,4]  67
    oxadiazol-3-yl)phenyl]-amide
    179 2-Methoxyethyl [4-(5-methoxy-2-oxo-[1,3,4] 117
    oxadiazol-3-yl)-2-methylphenyl]carbamate
    180 1-(4-Hydroxycyclohexyl)-3-[4-(5-methoxy-2-oxo- 220
    [1,3,4]oxadiazol-3-yl)-2-methylphenyl]urea
    181 1,1-Dibutyl-3-[4-(5-methoxy-2-oxo-[1,3,4] Oil
    oxadiazol-3-yl)-2-methyl-phenyl]urea
    182 5-Methoxybenzofuran-2-carboxylic acid [4-(5- 199
    methoxy-2-oxo-[1,3,4]oxadiazol-3-yl)-2-
    methylphenyl]amide
    183 4-Methylpiperazine-1-carboxylic acid [4-(5- Oil
    methoxy-2-oxo-[1,3,4]oxadiazol-3-yl)-2-
    methylphenyl]amide
    184 1-Methylpiperidin-4-yl [4-(5-methoxy-2-oxo-[1,3, 235
    4]oxadiazol-3-yl)-2-methylphenyl]carbamate
    185 Cyclohexyl [4-(5-methoxy-2-oxo-[1,3,4] 163
    oxadiazol-3-yl)-2-methylphenyl]-carbamate
    186 4-Benzylpiperidine-1-carboxylic acid [4-(5- 146
    methoxy-2-oxo-[1,3,4]oxadiazol-3-yl)-2-methyl-
    phenyl]amide
    187 1-(2-Diisopropylaminoethyl)-3-[4-(5- 136
    methoxy-2-oxo-[1,3,4]oxadiazol-3-yl)-2-
    methylphenyl]urea
    188 4-(2-{3-[4-(5-Methoxy-2-oxo-[1,3,4]oxadiazol-3- 200
    yl)-2-methylphenyl]-ureido}ethyl)benzenesulfon-
    amide
    189 1-(1-Benzylpiperidin-4-yl)-3-[4-(5-methoxy-2- 198
    oxo-[1,3,4]oxadiazol-3-yl)-2-methylphenyl]urea
    190 1-(4-Isopropylphenyl)-3-[4-(5-methoxy-2-oxo-[1, 200
    3,4]oxadiazol-3-yl)-2-methylphenyl]urea
    191 2-{3-[4-(5-Methoxy-2-oxo-[1,3,4]oxadiazol-3-yl)- 246
    2-methylphenyl]ureido}-3-methylbutyric acid
    192 1,2,3,4-Tetrahydronaphth-1-yl [4-(5-methoxy-2- 159
    oxo-[1,3,4]oxadiazol-3-yl)-2-methylphenyl]
    carbamate
    193 1-Phenylethyl [4-(5-methoxy-2-oxo-{1,3,4] Oil
    oxadiazol-3-yl)-2-methyl-phenyl]carbamate
    194 4-Isopropylbenzyl [4-(5-methoxy-2-oxo-[1,3,4]  88
    oxadiazol-3-yl)-2-methylphenyl]carbamate
    195 4-Trifluoromethoxybenzyl [4-(5-methoxy-2-oxo-  82
    [1,3,4]oxadiazol-3-yl)-2-methylphenyl]carbamate
    196 3,5-Dichlorobenzyl [4-(5-methoxy-2-oxo-[1,3,4] 169
    oxadiazol-3-yl)-2-methylphenyl]carbamate
    197 Biphenyl-2-ylmethyl [4-(5-methoxy-2-oxo-[1,3,4] 138
    oxadiazol-3-yl)-2-methylphenyl]carbamate
    198 5-Chlorobenzofuran-2-carboxylic acid-[4-(5- 210
    methoxy-2-oxo-[1,3,4]oxadiazol-3-yl)-2-methyl-
    phenyl]amide
    199 5-Chlorobenzofuran-2-carboxylic acid [4-(5- 209
    methoxy-2-oxo-[1,3,4]oxadiazol-3-yl)phenyl]
    amide

Claims (19)

We claim:
1. Compounds of the formula 1
Figure US20010031772A1-20011018-C00005
in which:
R1 is C1-C6-alkyl, C3-C9-cycloalkyl, wherein both groups are optionally substituted one or more times by phenyl, C1-C4-alkyloxy, S—C1-C4-alkyl, N(C1-C4-alkyl)2, and wherein phenyl is optionally 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; C6-C10-aryl-C1-C4-alkyloxy, C6-C10-aryloxy, C6-C10-aryl, C3-C8-cycloalkyl or O—C3-C8-cycloalkyl, each of which is optionally substituted once, twice or three times by halogen, CF3, C1-C4-alkyloxy or C1-C4-alkyl; 2-oxopyrrolidin-1-yl, 2,5-dimethylpyrrol-1-yl or NR6-A-R7,
with the proviso that R2, R3, R4 and R5 are not simultaneously hydrogen, and at least one of the radicals R2, R3, R4 or R5 is the radical 2-oxopyrrolidin-1-yl, 2,5-dimethylpyrrol-1-yl, or NR6-A-R7, and wherein:
R6 is 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 is a single bond, COn, SOn, or CONH;
n is 1 or 2;
R7 is hydrogen;
C1-C18-alkyl or C2-C18-alkenyl, wherein C1-C18-alkyl or C2-C18-alkenyl are optionally substituted one 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, wherein aryl is in turn optionally 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-C10-aryl-C2-C6-alkenyl, C6-C10-aryl, biphenylyl, biphenylyl-C1-C4-alkyl, indanyl, each of which is optionally substituted once or twice by C1-C18-alkyl, C1-C18-alkyloxy, C3-C8-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, wherein alkyl is in turn optionally substituted by C1-C4-alkyloxycarbonyl, CF3 or carboxyl, and aryl is also optionally substituted by halogen, CF3 or C1-C4-alkyloxy;
or the group Het-(CH2)r—,
wherein r=0, 1, 2 or 3 and Het=a saturated or unsaturated 5-7-membered heterocycle, optionally benzo-fused and optionally 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, wherein the benzo-fused aryl is in turn optionally substituted by halogen, C1-C4-alkyloxy or CF3 and the alkyl in arylalkyl is also optionally by methoxy and CF3,
and their pharmaceutically acceptable salts and acid addition salts.
2. Compounds of the formula 1 as claimed in
claim 1
, in which R1 is C1-C4-alkyl.
3. Compounds of the formula 1 as claimed in
claim 1
, in which R1 is methyl.
4. Compounds of the formula 1 as claimed in
claim 1
, in which R5 is hydrogen.
5. Compounds of the formula 1 as claimed in
claim 1
, in which R2 is hydrogen, halogen, C1-C4-alkyl, C1-C9-alkyloxy or amino.
6. Compounds of the formula 1 as claimed in
claim 1
, in which R3 is hydrogen, C1-C4-alkyl, C6-C10-aryl-C1-C4-alkyloxy, which is optionally substituted in the aryl moiety by halogen, or is NR6-A-R7 wherein
R6=hydrogen or benzyl,
A=single bond and
R7=C6-C10-aryl-C1-C4-alkyl, which is optionally substituted by halogen, CF3, cyano, phenyl-C1-C4-alkyloxy, CF3-phenoxy, C5-C8-cycloalkyl or fluorosulfonyloxy;
C1-Ci2-alkyl, which is optionally substituted by C1-C4-alkyloxy, phenyl, CF3 or phenyl-C1-C4-alkyloxy;
C2-C12-alkenyl or the group Het-(CH2)r—,
wherein r=0 or 1, and Het=a saturated or unsaturated 5-7-membered heterocycle, which is optionally benzo-fused and optionally substituted by C1-C4-alkyl or halogen.
7. Compounds of the formula 1 as claimed in
claim 1
, in which R4 is hydrogen, 2-oxopyrrolidin-1-yl, 2,5-dimethylpyrrol-1-yl, or C6-C10-aryl-C1-C4-alkyloxy, which is optionally substituted by halogen.
8. Compounds of the formula 1 as claimed in
claim 1
, in which:
R4 is NR6-A-R7, wherein
R6=hydrogen or methyl,
A=single bond and
R7=hydrogen;
C1-C12-alky, which is optionally substituted once or twice by halogen;
C2-C18-alkenyl, which is optionally substituted once or twice by C1-C4-alkyl or C1-C4-alkyloxycarbonyl;
C6-C10-aryl-C1-C4-alky, which is optionally substituted by halogen, C1-C6-alkyloxy, CF3, cya no, C5-C6-cycloalkyl, C1-C4-alkyloxycarbonyl, C6-C10-aryl-C1-C4-alkyl, C6-C10-aryl-C1-C4-alkyloxy, wherein aryl is further optionally substituted by halogen or CF3;
C5-C8-cycloalkyl-C1-C4-alkyl ; or
the group Het-(CH2)r—,
wherein r=1, 2 or 3 and Het=a saturated or unsaturated 5-7-membered heterocycle, which is optionally substituted by halogen, C1-C4-alkyloxy or C1-C4-alkyloxycarbonyl.
9. Compounds of the formula 1 as claimed in
claim 1
, in which:
R4 is NR6-A-R7 wherein
R6=hydrogen,
A=—CO— and
R7 C1-C18-alkyl, which is optionally substituted by halogen, phenyl, phenoxy, phenylcarbonyl or C1-C4-alkyloxycarbonyl, wherein phenoxy is optionally substituted by methyl, halogen or methylmercapto;
C2-C18-alkenyl, which is optionally substituted by C6-C10-aryl;
C6-C10-aryl, which is optionally substituted by halogen, C1-C8-alkyl, phenyl-C1-C4-alkyl, CF3, OCF3, fluorosulfonyl, C1-C4-alkyloxycarbonyl, phenoxy, wherein aryl is optionally substituted by C1-C4-alkyloxy;
C6-C10-aryl-C1-C4-alkyl, wherein alkyl is optionally substituted by methoxy or CF3 and aryl by halogen; or
the group Het-(CH2)r—,
wherein r=0 and Het=a saturated or unsaturated 5-7-membered heterocycle, which is optionally benzo-fused and optionally substituted by C1-C4-alkyl, halogen, C1-C4-alkyloxy, halophenyl or halobenzylmercapto, wherein benzo-fused aryl is optionally substituted by halogen or methoxy.
10. Compounds of the formula 1 as claimed in
claim 1
, in which:
R4 is NR6-A-R7, wherein
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—,
wherein r=0 or 1 and Het=a saturated or unsaturated 5-7-membered heterocycle, which is optionally benzo-fused and optionally substituted by C1-C4-alkyl or benzyl.
11. Compounds of the formula 1 as claimed in
claim 1
, in which:
R4 is NR6-A-R, wherein
R6=hydrogen,
A=—SO2— and
R7=C1-C6-alky, which is optionally substituted by CF3;
C2-C4-alkenyl, which is optionally substituted by phenyl;
C6-C10-aryl, which is optionally substituted by C1-C6-alkyl, halogen, C1-C4-alkyloxy or benzyl;
biphenylyl-C1-C4-alkyl substituted by halogen; or
the group Het-(CH2)r—,
wherein r=0 and Het=a saturated or unsaturated 5-7-membered heterocycle.
12. Compounds of the formula 1 as claimed in
claim 1
, in which:
R4 is NR6-A-R7, wherein
R6=hydrogen,
A=—CO—NH— and
R7=C1-C10-alkyl, which is optionally substituted by C1-C4-alkyloxycarbonyl, N(C1-C4-alkyl)2 or phenyl, which is in turn optionally substituted by halogen or aminosulfonyl;
C6-C10-aryl, which is optionally substituted by C1-C6-alkyl, C1-C6-alkyloxy, C1-C6-alkyloxycarbonyl, phenoxy, OCF3, benzyl or pyridyl, wherein alkyl is optionally substituted by C1-C4-alkyloxycarbonyl or carboxyl;
C5-C8-cycloalky, which is optionally substituted by hydroxyl, or indanyl; or
the group Het-(CH2)r—,
wherein r=0 or 1 and Het=a saturated or unsaturated 5-7-membered heterocycle, which is optionally substituted by benzyl.
13. A process for preparing compounds of the formula 1 as claimed in any one of
claims 1
 to
12
, comprising the steps of:
Figure US20010031772A1-20011018-C00006
reacting hydrazines of the formula 2 with chloroformic esters of the formula 3 or other reactive carbonic ester derivatives in which R1, R2, R3, R4 and R5 are as defined in
claim 1
 to give the compounds of the formula 4,
acylating the compounds of the formula 4 with phosgene, carbonyldiimidazole, diphosgene or triphosgene, to give the compounds of the formula 5, and
cyclizing the compounds of the formula 5 into the compounds of the formula 1.
14. A process according to
claim 13
 further comprising the step of reacting said compounds of formula 1 with a suitable agent to form pharmaceutically acceptable salts or acid addition salts.
15. A process according to
claim 13
, further comprising the step of chemical modification of the radicals R2-R5 by reduction of nitro to amino radicals, acylation or alkylation.
16. A process according to
claim 15
 further comprising the step of reacting said compounds of formula 1 with a suitable agent to form pharmaceutically acceptable salts or acid addition salts.
17. Compounds of the formula 1 as claimed in any one of claims 1 to 12 for use in a pharmaceutical composition having an inhibitory effect on hormone-sensitive lipase, HSL.
18. Compounds of the formula 1 as claimed in any one of
claims 1
 to
12
 for use in a pharmaceutical composition useful for treating non-insulin-dependent diabetes mellitus or diabetic syndrome.
19. A pharmaceutical composition for treating non-insulin-dependent diabetes mellitus or diabetic syndrome, comprising at least one of the compounds of formula 1 as claimed in any one of
claims 1
 to
12
.
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US9150505B2 (en) 2010-03-04 2015-10-06 Ajinomoto Co., Inc. Prophylactic or therapeutic agent for diabetes or obesity
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