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WO2010151160A1 - O-substituted 3-n-heteroaryl-1,3,4-oxadiazolones for medical use - Google Patents

O-substituted 3-n-heteroaryl-1,3,4-oxadiazolones for medical use Download PDF

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Publication number
WO2010151160A1
WO2010151160A1 PCT/PT2009/000034 PT2009000034W WO2010151160A1 WO 2010151160 A1 WO2010151160 A1 WO 2010151160A1 PT 2009000034 W PT2009000034 W PT 2009000034W WO 2010151160 A1 WO2010151160 A1 WO 2010151160A1
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cio
alkyl
aryl
amino
chloro
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French (fr)
Inventor
David Alexander Learmonth
Patrício Manuel Vieira Araújo Soares da SILVA
Laszlo Erno Kiss
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Bial Portela and Cia SA
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Bial Portela and Cia SA
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    • 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
    • C07D413/04—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 directly linked by a ring-member-to-ring-member bond
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/12—Antihypertensives
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond

Definitions

  • the present invention relates to compounds having a 5-0-substituted
  • FAAH is an integral membrane protein (IMP) that hydrolyzes bioactive amides including the endocannabinoid anandamide which is an agonist of cannabinoid receptors and TRPVl vanilloid receptors to free fatty acid and ethanolamine, see e.g. McKinney M.K., Cravatt B.F., ⁇ 7m. Rev. Biochem. 74:411 (2005).
  • IMP integral membrane protein
  • FAAH Due to its ability to regulate anandamide levels, FAAH is currently viewed as an attractive draggable target.
  • non-selective inhibitors of FAAH include PMSF (phenylmethylsulfonylfluoride), MAFP (methoxyarachidonylfluorophosphonate), and ATMK (arachidonoyltrifluoromethylketone), while URB597
  • FAAH inhibition is considered to play an important role in many medical consitions, see e.g. Pacher et al, Pharmacol Rev 58:389-462 (2006). Particularly the following diseases and conditions may be mentioned:
  • Pain, in particular acute or chronic pain of neurogenic type migraine, neuropathic pain, including forms associated with the herpes virus and with diabetes; acute or chronic pain associated with inflammatory diseases: arthritis, rheumatoid arthritis, osteoarthritis, spondylitis, gout, vasculitis, Crohn's disease, irritable bowel syndrome;
  • eating disorders in particular anorexia and cachexia of various natures
  • neurological and psychiatric pathologies tremors, dyskinesias, dystonias, spasticity, obsessive-compulsive behaviour, Tourette's syndrome, all forms of depression and anxiety of any nature and origin, mood disorders, psychoses;
  • Parkinson's disease Alzheimer's disease, senile dementia, Huntington's chorea, lesions related to celebral ischaemia and to cranial and medullary trauma;
  • sleep disorders including sleep apnoea
  • cardiovascular diseases in particular hypertension, cardiac arrhythmias, arteriosclerosis, heart attack, cardiac ischaemia;
  • cancers benign skin tumours, brain tumours and papillomas, prostate tumours, cerebral tumours (glioblastomas, medulloepitheliomas, medulloblastomas, neuroblastomas, tumours of embryonic origin, astrocytomas, astroblastomas, ependymomas, oligodendrogliomas, plexus tumour, neuroepitheliomas, epiphyseal tumour, ependymoblastomas, malignant meningiomas, sarcomatosis, malignant melanomas, schwannomas);
  • autoimmune diseases in particular autoimmune diseases; psoriasis, lupus erythematosus, diseases of the connective tissue or collagen diseases, Sjogren's syndrome, ankylosing spondylitis, undifferentiated spondylitis, Behcet's disease, autoimmune haemolytic anaemia, multiple sclerosis, amyotrophic lateral sclerosis, amyloidosis, graft rejection, diseases affecting the plasmacytic line;
  • allergic diseases rhinitis or conjunctivitis, contact dermatitis;
  • inflammatory diseases in particular joint diseases: arthritis, rheumatoid arthritis, osteoarthritis, spondylitis, gout, vasculitis, Crohn's disease, irritable bowel syndrome;
  • eye conditions ocular hypertension, glaucoma;
  • pulmonary conditions diseases of the respiratory tracts, bronchospasm, coughing, asthma, chronic bronchitis, chronic obstruction of the respiratory tract, emphysema;
  • the compounds of the present invention have an unexpectedly high inhibition of FAAH, both in-vitro and in vivo, making these compounds promising candidates for medicaments for the treatment or prevention of FAAH-related medical conditions.
  • compounds of the present invention are characterized by peripheral selectivity over CNS in vivo, avoiding unwanted CNS effects.
  • the compounds of the present invention may be used to treat the above- mentioned conditions as well as in the preparation of medicaments to treat such methods.
  • the invention also includes methods of treating such diseases comprising administering a compound of the invention to a patient in need thereof, as well as pharmaceutical compositions containing a compound or compounds of the present invention.
  • treatment and variations such as 'treat' or 'treating' refers to any regime that can benefit a human or non-human animal.
  • the treatment may be in respect of an existing condition or may be prophylactic (preventative) treatment.
  • Treatment may include curative, alleviation or prophylactic effects.
  • Treatment may prevent or delay the onset, retard the progression or ameliorate the symptoms of the disease or condition.
  • the present invention relates to compounds of formula (I),
  • A represents a 5- or 6-membered heteroaromatic ring system containing up to 4 heteroatoms selected from O, S and N, which is optionally substituted once or several times by: hydrogen;
  • Ci-C ⁇ -alkyl Cs-Cs-cycloalkyl, C ⁇ -Cio-aryl, Ce-Cio-aryl-Ci-Cs-alkyl, Ci-Ce-alkoxy,
  • C6-Cio-aryl-Ci-C8-alkylcarbonyl Ci-C ⁇ -alkylcarboxy, C ⁇ -Cio-arylcarboxy, Ci-Ce- alkylmercaptyl, Ce-Cio-arylmercaptyl, Ci-C ⁇ -alkylmercaptocarbonyl, C3-C8- cycloalkylmercaptocarbonyl, C ⁇ -Cio-arylmercaptocarbonyl, Ci-C ⁇ -alkylmercaptocarboxy,
  • Ci-Ce-alkyl Ci-Ce-alkoxy; C ⁇ -Cio-aryloxy; CO 2 H; SOsH; CONEb; SO2NH2; CONH2 or SO2NH2 wherein the amino functionality is substituted one or more times with residues selected from Ci-C ⁇ -alkyl, Ce-Cio-aryl or C6-Cio-aryl-Ci-C4- alkyl and wherein in case of a di-Ci-Ce-alkyl-substituted amino functionality the alkyl residues may be combined to form 5 or 6-membered rings; amino; amino substituted one or more times with residues selected from Ci-C ⁇ -alkyl, Ce-C 10- aryl, Ci-C ⁇ -alkylcarbonyl, C ⁇ -Cio-arylcarbonyl, Ci-C ⁇ - alkylsulfonyl and C ⁇ -Cio-arylsulfonyl; thiol; hydroxyl; nitro; cyan
  • o represents O or 1 and W represents O, CEh, or NR 6 with R 6 being selected from hydrogen and Ci-C ⁇ -alkyl and wherein the methylene groups in formula (II) may optionally be substituted once or twice with Ci-C ⁇ -alkyl, fluoro or chloro; CONH 2 ;
  • OCFs or a saturated, unsaturated or aromatic heterocyclic ring system of up to 10 atoms, optionally substituted once or several times by
  • Ci-Ce-alkyl Ci-Ce-alkyl; Ci-Ce-alkoxy; COOH; SOsH; CONH 2; SO2NH2; CONH2 or SO2NH2 wherein the amino functionality is substituted one or more times with residues selected from Ci-C ⁇ -alkyl, C ⁇ -Cio-aryl or C6-Cio-aryl-Ci-C4-alkyl and wherein in case of a di-Ci-C ⁇ -alkyl-substituted amino functionality the alkyl residues may be combined to form 5 or 6-membered rings; amino; amino substituted one or more times with residues selected from Ci-C ⁇ -alkyl, C ⁇ -Cio-aryl, C6-Cio-aryl-Ci-C4-alkyl, Ci-C ⁇ -alkylcarbonyl, C ⁇ -Cio-arylcarbonyl, Ci-C ⁇ -alkylsulfonyl and C ⁇ -Cio- aryl
  • Ci-Ci8-alkyl mono or polyunsaturated C2-Cis-alkylene, C3-C8-cycloalkyl, C ⁇ -Cio-aryl, C ⁇ -Cio-aryl-Ci-Cs-alkyl, Ci-C ⁇ -alkoxy, C ⁇ -Cio-aryloxy, C ⁇ -Cio-aryl- Ci-Cs-alkoxy, Ci-C ⁇ -alkoxycarbonyl, C ⁇ -Cio-aryloxycarbonyl, C ⁇ -Cio-aryl-Ci-Cs- alkoxycarbonyl, Ci-Ce-alkylcarbonyl, C ⁇ -Cio-arylcarbonyl, Ce-Cio-aryl-Ci-Cs- alkylcarbonyl, Ci-Ce-alkylcarboxy, C ⁇ -Cio-arylcarboxy, Ci-Ce-alkylmercaptyl,
  • Ci-C ⁇ -alkylmercaptocarbonyl Ci-C ⁇ -alkylmercaptocarbonyl, C3-C8- cycloalkylmercaptocarbonyl, C ⁇ -Cio-arylmercaptocarbonyl, Ci-C ⁇ - alkylmercaptocarboxy, Ce-Cio-arylmercaptocarboxy, Ci-C ⁇ -alkylsulfonyl, C ⁇ -Cio- arylsulfonyl, O-C ⁇ -alkylsulfoxy, C ⁇ -Cio-arylsulfoxy, or a saturated, unsaturated or aromatic heterocyclic ring system of up to 10 atoms, wherein each is optionally substituted once or several times by: bl) Ci-C ⁇ -alkyl, Cs-Cs-cycloalkyl, C ⁇ -Cio-aryl, C ⁇ -Cio-aryl-Ci-Cs-alkyl, Ci-C ⁇ -alkoxy
  • o represents 0 or 1 and W represents O, CH2, or NR 6 with R 6 being selected from hydrogen and Ci-C ⁇ -alkyl and wherein the methylene groups in formula (II) may optionally be substituted once or twice with Ci-C ⁇ -alkyl, fluoro or chloro; or by b3) a saturated, unsaturated or aromatic heterocyclic ring system of up to 10 atoms, optionally substituted once or several times by Ci-Ce-alkyl; Ci-Ce- alkoxy; COOH; SOsH; CONH 2 ; SO2NH2; CONH2 or SO2NH2 wherein the amino functionality is substituted one or more times with residues selected from Ci-Ce-alkyl, Ce-Cio-aryl or C6-Cio-aryl-Ci-C4-alkyl and wherein in case of a di-Ci-C ⁇ -alkyl-substituted amino functionality the alkyl residues may be combined to form 5 or 6-membered rings
  • Suitable pharmaceutically acceptable salts include hydrochloride, dihydrochloride, and trifluoroacetate salts.
  • a representing a 5- or 6-membered heteroaromatic ring system containing up to 4 heteroatoms selected from O, S and N is preferably a heteroaromatic ring comprising 1, 2, 3 or 4, preferably 1 or 2, nitrogen atoms. It is also preferred that the heteroaromatic ring comprises 1 or 2 oxygen atoms. It is most preferred that the heteroaromatic ring is selected from pyridine, pyrazine, pyrimidine, pyridazine, triazine, tetrazine, thiophene, furane, oxazole, thiazole, oxazine, thiazine, and oxaadiazole. The most preferred heteroaromatic ring system is pyridine, in particular 2-pyridine, 3-pyridine and 4-pyridine derivatives.
  • Ci-C4-alkyl represents preferably methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, and tert-butyl.
  • G-C ⁇ -alkyl represents preferably methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, pentyl or hexyl.
  • Ci-Cis-alkyl represents preferably methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, pentyl, hexyl, octyl, decyl, dodecyl, tetradecyl and octadecyl.
  • mono or polyunsaturated C2-C18- alkylene preferably represents ethenyl, n-propenyl, isopropenyl, n-butenyl, sec-butenyl, tert-butenyl, pentenyl, hexenyl, octenyl, decenyl, dodecenyl, tetradecenyl, octadecenyl, dodecdienyl, tetradecdienyl and octadecdienyl.
  • C3-Cs-cycloalkyl preferably represents cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.
  • C ⁇ -Cio-aryl preferably represents phenyl, pentalenyl, indenyl, indanyl, isoindolinyl, chromanyl, naphthyl, fluorenyl, anthryl, phenanthryl or pyrenyl.
  • C ⁇ -Cio-aryl-Ci-Cs-alkyl, C ⁇ -Cio- aryl-Ci-Ce-alkyl and C6-Cio-aryl-Ci-C4-alkyl preferably represent phenyl or naphthyl being substituted with methyl, ethyl, propyl or butyl. Particularly preferred residues are benzyl and phenethyl.
  • Ci-C4-alkoxy preferably represents methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, and tert- butoxy.
  • Ci-C ⁇ -alkoxy preferably represents methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy, pentoxy or hexoxy.
  • C ⁇ -Cio-aryloxy preferably represents phenoxy, naphthoxy, indenoxy, fluorenoxy or phenanthroxy.
  • C ⁇ -do-aryl-Ci-Cs-alkoxy, C ⁇ -Cio-aryl-Ci-C ⁇ -alkoxy and preferably represent benzoxy, phenethoxy, phenpropoxy, or phenbutoxy. Particularly preferred residues are benzoxy and phenethoxy.
  • Ci-Ce-alkoxycarbonyl preferably represents methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl, isopropoxycarbonyl or butoxycarbonyl.
  • Ce-Cio-aryloxycarbonyl preferably represents phenoxycarbonyl or naphthoxycarbonyl.
  • Ce-Cio-aryl-Ci-Cs-alkoxycarbonyl preferably represents represents benzoxycarbonyl or phenethoxy carbonyl.
  • Ci-Ce-alkylcarbonyl preferably represents methylcarbonyl, ethylcarbonyl, n-propylcarbonyl, isopropylcarbonyl or butylcarbonyl.
  • C ⁇ -Cio-arylcarbonyl preferably represents phenylcarbonyl or naphthylcarbonyl.
  • C ⁇ -Cio-aryl-Ci-Cs-alkylcarbonyl preferably represents benzylcarbonyl or phenethylcarbonyl.
  • Ci-C ⁇ -alkylcarboxy preferably represents methylcarboy, ethylcarboxy, n-propylcarboxy, isopropylcarboxy or butylcarboxy.
  • C ⁇ -Cio-arylcarboxy preferably represents phenylcarboxy or naphthylcarboxy.
  • Ci-C ⁇ -alkylmercaptyl preferably represents methylmercaptyl, ethylmercaptyl, n-propylmercaptyl, isopropylmercaptyl or butylmercaptyl.
  • Ce-Cio-arylmercaptyl preferably represents phenylmercaptyl or naphthylmercaptyl.
  • Ci-C ⁇ -alkylmercaptocarbonyl preferably represents methylmercaptocarbonyl, ethylmercaptocarbonyl, n-propylmercaptocarbonyl, isopropylmercaptocarbonyl or butylmercaptocarbonyl.
  • C3-C8-cycloalkylmercapto- carbonyl preferably represents cyclopropylmercaptocarbonyl, cyclobutylmercaptocarbonyl, cyclopentylmercaptocarbonyl or cyclohexylmercaptocarbonyl.
  • C ⁇ -Cio-arylmercaptocarbonyl preferably represents phenylmercaptocarbonyl or naphthylmercaptocarbonyl.
  • Ci-Ce-alkylmercaptocarboxy preferably represents methylmercaptocarboxy, ethylmercaptocarboxy, n-propyl- mercaptocarboxy, isoproylmercaptocarboxy or butylmercaptocarboxy.
  • C ⁇ -Cio-arylmercaptocarboxy preferably represents phenylmercaptocarboxy or naphthylmercaptocarboxy.
  • Ci-C ⁇ -alkylsulfonyl preferably represents methylsulfonyl, ethylsulfonyl, n-propylsulfonyl, n-butylsulfonyl, sec- butylsulfonyl, tert-butylsulfonyl, pentylsulfonyl or hexylsulfonyl.
  • Ce-Cio-arylsulfonyl preferably represents phenylsulfonyl or naphthylsulfonyl.
  • Ci-Ce-alkylsulfoxy preferably represents methylsulfoxy, ethylsulfoxy, n-propylsulfoxy, n-butylsulfoxy, sec-butylsulfoxy or tert-butylsulfoxy.
  • C ⁇ -Cio-arylsulfoxy preferably represents phenylsulfoxy or naphthylsulfoxy.
  • substituents are optionally substituted once or several times by Ci-C ⁇ - alkyl, Ci-C ⁇ -alkoxy, Ce-Cio-aryloxy, CO2H, SCbH, amino, thiol, hydroxyl, nitro, cyano, fluoro, chloro, bromo, iodo, CF3 or OCF3.
  • Ci-C ⁇ -alkyl, Ci-C ⁇ -alkoxy, and C ⁇ -Cio-aryloxy preferably represent the same residues as mentioned above.
  • the term “optionally substituted once or several times by” is meant to include no substitution, single substitution or multiple substitution with one or more of the mentioned optional substituents. In case of a multiple substitution, the substituents can be selected independently from each other.
  • the term amino substituted one or more times with residues selected from Ci-C ⁇ -alkyl, C ⁇ -Cio-aryl, C6-Cio-aryl-Ci-C4-alkyl, Ci-C ⁇ -alkylcarbonyl, C ⁇ -Cio-arylcarbonyl, Ci-C ⁇ -alkylsulfonyl and C ⁇ -Cio-arylsulfonyl is preferably represented by an amino group that is once or twice and independently from each other substituted by methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert- butyl, pentyl or hexyl in case of Ci-Ce-alkyl; by phenyl, benzyl or phenethyl in case of C ⁇ -Cio-aryl and C6-Cio-aryl-Ci-C4-alkyl; by methylcarbon
  • the term CONH2 or SO2NH2 wherein the amino functionality is substituted one or more times with residues selected from Ci-Ce- alkyl, C ⁇ -Cio-aryl or C6-Cio-aryl-Ci-C4-alkyl and wherein in case of a di-Ci-C ⁇ -alkyl- substituted amino functionality the alkyl residues may be combined to form 5 or 6-membered rings, is preferably represented by residues derivable from N,N-dimethylamide, N-methylamide, N-ethylamide, N-phenylamide,
  • N,N-dimethylsulfonamide, N-methylsulfonamide, N-ethylsulfonamide, and N-phenylsulfonamide are also a preferred alternative that both residues are combined to form 5 or 6-membered rings.
  • amino functionalities include but are not limited to pyrrolidin and piperidine.
  • a saturated, unsaturated or aromatic heterocyclic ring system of up to 10 atoms is preferably represented by a saturated, unsaturated or aromatic heterocyclic ring system of up to 10 atoms containing one to four heteroatoms selected from N, O or S, particularly 5- or 6-membered heteroaromatic ring systems.
  • Examples of such preferred saturated, unsaturated or aromatic heterocycles of up to 10 atoms include but are not limited to benzimidazole, benzofuran, benzothiophene, benzoxazole, benzothiazole, carbazole, cinnoline, dioxin, dioxane, dioxolane, dithiane, dithiazine, dithiazole, dithiolane, furan, imidazole, imidazoline, imidazolidine, indole, indoline, indolizine, indazole, isoindole, isoquinoline, isoxazole, isothiazole, morpholine, napthyridine, oxazole, oxadiazole, oxathiazole, oxathiazolidine, oxazine, oxadiazine, phenazine, phenothiazine, phenoxazine, phthalazine, pipe
  • These heterocycles may be optionally substituted once or several times by Ci-C ⁇ -alkyl, Ci-Ce-alkoxy, COOH, SO3H, amino, thiol, hydroxyl, nitro, cyano, fluoro, chloro, bromo, iodo, CF3 or OCF3.
  • Particluarly preferred optional substituents are methyl, methoxy, amino, hydroxy, nitro, cyano, fluoro, chloro, bromo, iodo, CF3 and OCF 3 .
  • the most preferred aromatic heterocyclic ring systems of up to 10 atoms comprise the 6-membered heteroaryls 2-pyridine, 3-pyridine or 4-pyridine, all of which are optionally substituted with one or more residues selected from methyl, amino, fluoro, chloro or CF3; and pyrrole, which is optionally substituted with one or more residues selected from methyl, amino, fluoro, chloro or CF3.
  • A represents 2-pyridinyl, 3-pyridinyl or 4-pyridinyl.
  • A is substituted once or several times with hydrogen; hydroxyl;
  • OCF 3 amino; amino substituted one or more times with residues selected from Ci-Ce-alkyl, C ⁇ -Cio-aryl;
  • A is substituted once or several times with Ci-C ⁇ -alkyl, C ⁇ -Cio-aryl, wherein each is optionally substituted once or several times by Ci-C ⁇ -alkyl, Ci-C ⁇ -alkoxy, amino, Ci-C ⁇ -alkylamino, di-Ci-C ⁇ -alkylamino, hydroxy, fluoro, chloro, bromo, cyano, CF3 or OCF3.
  • A is substituted once or several times with fluoro or chloro. It is most preferred that, in the above formula (I), A is substituted with fluorine in ortho-position to the oxadiazolinone residue.
  • A is substituted once or several times with: hydroxy; or Ci-C ⁇ -alkoxy, Ce-Cio-aryloxy, Ce-Cio-aryl-Ci-C ⁇ -alkoxy, Ci-C ⁇ -alkylcarboxy, C ⁇ -Cio- arylcarboxy, Ci-Ce-alkylsulfonyl, Ce-Cio-arylsulfonyl, wherein each is optionally substituted once or several times by Ci-Ce-alkyl, Ci-C ⁇ -alkoxy, amino, Ci-C ⁇ -alkylamino, di-Ci-C ⁇ -alkylamino, CONH2 or SO2NH2 optionally substituted once or twice with Ci-Ce- alkyl or C ⁇ -Cio-aryl, hydroxy, fluoro, chloro, bromo, cyano, CF3 or OCF3.
  • A is in the meta- and/or para-position(s) to the oxadiazolinone ring substituted once or several times with: hydroxy; or
  • A is substituted once or several times with:
  • o represents 0 or 1 and W represents O, CEb, or NR 6 with R 6 being selected from hydrogen and Ci-Ce-alkyl and wherein the methylene groups in formula (II) may optionally be substituted once or twice with Ci-C ⁇ -alkyl, fluoro or chloro.
  • A is in the meta- and/or para-position(s) to the oxadiazolinone ring substituted once or several times with: amino; amino substituted once or twice with residues selected from Ci-C ⁇ -alkyl, C ⁇ -Cio-aryl; or a disubstituted amino of the following formula (II)
  • o represents O or 1 and W represents O, CBb, or NR 6 with R 6 being selected from hydrogen and Ci-C ⁇ -alkyl and wherein the methylene groups in formula (II) may optionally be substituted once or twice with Ci-C ⁇ -alkyl, fluoro or chloro.
  • o represents 0 or 1 and W represents O, CEh, or NR 6 with R 6 being selected from hydrogen and Ci-C4-alkyl and wherein the methylene groups in formula (II) may optionally be substituted once or twice with Ci-C ⁇ -alkyl, fluoro or chloro; or by c) a saturated, unsaturated or aromatic heterocyclic ring system of up to 10 atoms, optionally substituted once or several tunes by
  • Ci-Ce-alkyl Ci-C ⁇ -alkoxy; COOH; CONH 2 ; SO2NH2; CONH 2 or
  • n O
  • m O or 1
  • Y represents phenyl, or a 1-naphthyl, 2-naphthyl, 2-pyridinyl, 3-pyridinyl or 4-pyridinyl ring system.
  • Ci-Ce- alkyl phenyl; Ci-C ⁇ -alkoxy; hydroxy; fluoro; chloro; bromo; CF3; OCF3; amino; or CONH2 or SO2NH2 optionally substituted once or twice with Ci-Ce-alkyl wherein these optional Ci-Ce-alkyl residues may be combined to form 5 or 6-membered rings.
  • m represents O and Y represents phenyl which is substituted once or twice by hydroxy, fluoro, chloro or bromo.
  • m represents O and Y represents phenyl which is substituted in the 4-position by fluoro, in the 4-position by chloro, in the 2- and 4-position by fluoro, in the 2- and 4-position by chloro, or in the 4-position by phenyl. It is also most preferred in this embodiment, that, in above formula (I), Y also represents phenyl which is substituted in the 4-position by fluoro or by chloro, in the 2- and 4-position by fluoro, or in the 2- and 4-position by chloro.
  • Y represents phenyl which is substituted hi the 4-position by fluoro or by chloro, in the 2- and 4-position by fluoro, or in the 2- and 4-position by chloro.
  • A is substituted in the para-position to the oxadiazolone ring with hydrogen or fluorine.
  • A is substituted in the meta- or para-position or in the meta- and para-position with hydroxy.
  • A is a heterocycle comprising one, two, three or four nitrogen atoms, more preferably one or two nitrogen atoms.
  • A is selected from 2-pyridyl, 3-pyridyl or 4-pyridyl.
  • A is a heterocycle comprising one or two oxygen atoms.
  • the present invention also relates to a process for the preparation of a compound of formula (III),
  • A represents a 5- or 6-membered heteroaromatic ring system containing up to 4 heteroatoms selected from O, S and N, which is optionally substituted once or several times by: hydrogen; Ci-Ce-alkyl, C3-Cs-cycloalkyl, C ⁇ -Cio-aryl, Ce-Cio-aryl-Ci-Cs-alkyl, Ci-Ce-alkoxy, Ce-Cio-aryloxy, C ⁇ -Cio-aryl-Ci-Cs-alkoxy, Ci-C ⁇ -alkoxycarbonyl, Ce-Cio-aryloxy- carbonyl, C ⁇ -Cio-aryl-Ci-Cs-alkoxycarbonyl, Ci-C ⁇ -alkylcarbonyl, Ce-Cio-arylcarbonyl, C ⁇ -Cio-aryl-Ci-Cs-alkylcarbonyl, Ci-C ⁇ -alkylcarbonyl, Ce-Cio-arylcarbony
  • Ci-Ce-alkyl Ci-Ce-alkyl; Ci-Ce-alkoxy; Ce-Cio-aryloxy; CO 2 H; SOsH; CONH2; SO2NH2; CONH2 or SO2NH2 wherein the ammo functionality is substituted one or more times with residues selected from Ci-C ⁇ -alkyl, C ⁇ -Cio-aryl or C ⁇ -Cio- aryl-Ci-C4-alkyl and wherein in case of a di-Ci-C ⁇ -alkyl-substituted amino functionality the alkyl residues may be combined to form 5 or 6-membered rings; amino; amino substituted one or more times with residues selected from Ci-C ⁇ -alkyl, Ce-Cio-aryl, Ci-Ce-alkylcarbonyl,
  • o represents O or 1 and W represents O, CEb, or NR 6 with R 6 being selected from hydrogen and Ci-C ⁇ -alkyl and wherein the methylene groups in formula (II) may optionally be substituted once or twice with Ci-C ⁇ -alkyl, fluoro or chloro;
  • OCFs or a saturated, unsaturated or aromatic heterocyclic ring system of up to 10 atoms, optionally substituted once or several times by
  • Y represents: a) hydrogen; b) Ci-Ci8-alkyl, mono or polyunsaturated C2-Cis-alkylene, C3-C8-cycloalkyl, C ⁇ -Cio-aryl, Ce-Cio-aryl-Ci-Cs-alkyl, Ci-C ⁇ -alkoxy, Ce-Cio-aryloxy, Ce-Cio-aryl- Ci-Cs-alkoxy, Ci-Ce-alkoxycarbonyl, Ce-Cio-aryloxycarbonyl, C ⁇ -Cio-aryl-Ci-Cs- alkoxycarbonyl, Ci-Ce-alkylcarbonyl, C ⁇ -Cio-arylcarbonyl, C ⁇ -Cio-aryl-Ci-Cs- alkylcarbonyl, Ci-C ⁇ -alkylcarboxy, Ce-Cio-arylcarboxy, Ci-C ⁇ -alkyhnercaptyl, C ⁇ -C
  • Ci-C ⁇ -alkylcarbonyl C ⁇ -Cio-arylcarbonyl, C ⁇ -Cio-aryl-Ci-Cs-alkylcarbonyl,
  • Ci-Cio-arylsulfonyl Ci-C ⁇ -alkylsulfoxy, C6-Cio-arylsulfoxy; wherein each is optionally substituted once or several times by Ci-Ce-alkyl; Ci-C ⁇ -alkoxy; CONH 2 , SO2NH2; CONH2 or SO2NH2 wherein the amino functionality is substituted once or twice with Ci-Ce-alkyl; SChH; CO2H; amino; amino substituted one or more times with residues selected from Ci-C ⁇ -alkyl, C ⁇ -Cio-aryl, C ⁇ -Cio-aryl-Ci-C ⁇ -alkyl, Ci-Ce-alkylcarbonyl, C ⁇ -Cio- arylcarbonyl, Ci-C ⁇ -alkylsulfonyl and C6-Cio-arylsulfonyl; thiol; hydroxyl; nitro; cyano; fluoro; chloro; bromine
  • o represents O or 1 and W represents O, CH2, or NR 6 with R 6 being selected from hydrogen and Ci-Ce-alkyl and wherein the methylene groups in formula (II) may optionally be substituted once or twice with Ci-C ⁇ -alkyl, fluoro or chloro; or by b3) a saturated, unsaturated or aromatic heterocyclic ring system of up to 10 atoms, optionally substituted once or several times by Ci-Ce-alkyl; Ci-Ce- alkoxy; COOH; SO 3 H; CONH 2 , SO2NH2; CONH2 or SO2NH2 wherein the amino functionality is substituted one or more times with residues selected from Ci-C ⁇ -alkyl, C ⁇ -Cio-aryl or C ⁇ -Cio-aryl-Ci-C-t-alkyl and wherein in case of a di-Ci-C ⁇ -alkyl-substituted amino functionality the alkyl residues may be combined to form 5 or 6-membered
  • the cyclisation step to the oxadiazolone ring system is achieved by phosgene, carbonyldiimidazole, or a carbonic acid ester.
  • Suitable carbonic acid esters are in particular the Ci-C4-alkyl carbonic acid esters.
  • Phosgene and carbonyldiimidazole are the most preferred reagents to achieve cyclization.
  • the compounds according to the invention may be prepared by the following exemplary method of preparation: To an ice-cooled solution of 2-chloro-3-hydrazinylpyridine (0.67 g, 4.67 mmol) and pyridine (1.84 g, 23.33 mmol) in N-methylpyrrolidinone (7 mL) was added cyclohexyl carbonochloridate (0.911 g, 5.60 mmol). The resulting mixture was allowed to stir at room temperature for 1 hour, whereupon it was carefully quenched by the addition of ice and water. The mixture was extracted with ethyl acetate and the organic extracts were over MgSO ⁇ filtered and evaporated to leave an oil.
  • Frozen brains (without cerebellum) from Wistar rats were used, and each brain was homogenized in 15 ml 1 mM MgCh, 2OnM HEPES pH 7.0 with Potter Elvejhem (8 strokes at 500 rpm). Homogenates were centrifuged for 20 min at 3600Og at 4 0 C (Beckman, 70Ti rotor). Pellets were resuspended in 15 ml of the same buffer and centrifuged under the same conditions. Pellets were resuspended in 15 ml of the same buffer and incubated for 15 min at 37 0 C after which they were centrifuged for 20 min at 36000g at 4 0 C.
  • the FAAH activity was determined using AEA (labelled with 3 H in the ethanolamine part of the molecule) as substrate and measuring the 3 H-ethanolamine formed.
  • Reaction mix (total volume of 200 ⁇ l) contained: 2 ⁇ M AEA (2 ⁇ M AEA + 5 nM 3 H-AEA), 0.1 % fatty acid free BSA, 5 ⁇ g protein, in 1 mM EDTA, 10 mM Tris pH 7.6 and 10 ⁇ M or 100 mM compounds.
  • Stock solutions of the compounds to test (10 mM) were prepared in 100 % DMSO and the DMSO concentration in the assay was 0.1 % .
  • a selected compound was tested according to the following m-vrr ⁇ -protocol.
  • mice Male NMRI mice (weighing 27-44 g) obtained from Interfauna Iberica (Spain). Mice were kept 5 per cage, under controlled environmental conditions (12 hr light/dark cycle and room temperature 22+ 1 0 C). Food and tap water were allowed ad libitum and the experiments were all carried out during daylight hours.
  • Animals were administered 30 mg/kg BIA compounds via oral route (8 mL/kg; compound suspended m 0.5 % carboxymethylcellulose (CMC) or solubilized in water) or 8ml/kg 0.5 % CMC (controls) using animal feeding stainless steel curve needles (Perfectum, U.S.A.). Fifteen minutes before sacrifice animal were anesthetized with pentobarbital 60 mg/kg administered intraperitoneally. A fragment of liver, left lung lobe and brain without cerebellum were removed and put in plastic vials containing membrane buffer (3 niM MgCh, 1 mM EDTA, 50 mM Tris HCl pH 7.4). Tissues were stored at -3O 0 C until analysis. Animals were fasted overnight before administration of compounds except for time periods of > 18h, where food was removed on the morning of the day of administration and the compound was administered in the afternoon of the same day. Animals were then given water but nothing else.
  • CMC carboxymethylcellulose
  • Anandamide [ethanolamine -1- 3 H-] (40-60Ci/mmol) was obtained from American Radiochemicals. All other reagents were obtained from Sigma- Aldrich. Optiphase Supermix was obtained from Perkin Elmer and activated charcoal were obtained from Sigma- Aldrich.
  • Tissues were thawed on ice and were homogenized in 10 volumes of membrane buffer (3 mM MgCh, 1 mM EDTA, 50 mM Tris HCl pH 7.4) with either Potter- Elvejhem (brains - 8 strokes at 500 rpm) or Heidolph Diax (livers - 2 strokes at position 5 for 20 sec with 30 sec pauses).
  • membrane buffer 3 mM MgCh, 1 mM EDTA, 50 mM Tris HCl pH 7.4
  • Potter- Elvejhem brains - 8 strokes at 500 rpm
  • Heidolph Diax livers - 2 strokes at position 5 for 20 sec with 30 sec pauses
  • Reaction mix (total volume of 200 ⁇ l) contained: 2 ⁇ M AEA (2 ⁇ M AEA + 5 nM 3 H-AEA), 0.1 % fatty acid free BSA, 15 ⁇ g (brain), 5 ⁇ g (liver) or 50 ⁇ g (lung) protein, in 1 mM EDTA, 10 mM Tris pH 7.6. After a 15 min pre-incubation period at 37 0 C, reaction was started by the addition of the substrate solution (cold AEA + radiolabeled AEA + BSA).
  • the percentage of remaining enzymatic activity was calculated with respect to controls (no compound) and after blank subtraction.
  • a in formulae (I) and (III) is not substituted with
  • B-L-G wherein B represents a single bond, CH2, O, S or NR 1 , wherein R 1 is selected from hydrogen or a Ci-C ⁇ -alkyl group;
  • L represents a linker selected from:
  • Ci-C ⁇ -alkyl Ci-C ⁇ - alkoxy, CO2H, SO3H, amino, Ci-Ce-alkylamino, di-Ci-C ⁇ -alkylamino, thiol, hydroxy, nitro, cyano, fluoro, chloro, bromo, iodo, CF3 or OCF3; and
  • G represents a) NR 2 R 3 , wherein R 2 and R 3 independently from each other represent hydrogen; Ci-C ⁇ -alkyl, Cs-Cs-cycloalkyl, C ⁇ -Cio-aryl, aromatic heterocyclic ring system of up to 10 atoms, C ⁇ -Cio-aryl-d-C ⁇ -alkyl, Ci-C ⁇ -alkoxycarbonyl, C ⁇ -Cio-aryloxycarbonyl, C ⁇ -Cio-aryl-Ci-Cs-alkoxycarbonyl, Ci-Ce- alkylcarbonyl, C ⁇ -Cio-arylcarbonyl, C ⁇ -Cio-aryl-Ci-Cs-alkylcarbonyl, Ci-C ⁇ - alkyhnercaptocarbonyl, C3-C8-cycloalkylmercaptocarbonyl, C ⁇ -Cio- aryhnercaptocarbonyl, Ci-C ⁇ -alkylsulfonyl, or
  • o represents 0 or 1 and W represents O, CH2, or NR 6 with R 6 being selected from hydrogen, Ci-C ⁇ -alkyl, C ⁇ -Cio-aryl, and C ⁇ -Cio-aryl-Ci-Ce-alkyl, and wherein the methylene groups in formula (II) may optionally be substituted once or twice with Ci-C ⁇ -alkyl, fluoro or chloro;
  • G-C4-alkyl wherein these optional substituents may be combined to form 5- or 6-membered saturated, unsaturated or aromatic rings, or an isomer of said guanidine or amidine residue.
  • the compound of formula I is not:5-(benzyloxy)-3-(5-

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Abstract

The present invention relates to compound of formula (I), wherein A represents a 5- or 6-membered heteroaromatic ring system containing up to 4 heteroatoms selected from O, S and N, which is optionally substituted, and to a stereoisomer, pharmaceutically acceptable salt or ester, or prodrug thereof.

Description

O-SUBSTITUTED 3-N-HETEROARYL-I9S^-OXADIAZOLONES FOR MEDICAL
USE
The present invention relates to compounds having a 5-0-substituted
3-N-heteroaryl-l,3,4-oxadiazolone structural unit. These compounds exhibit an unexpectedly high inhibition of FAAH (fatty acid amide hydrolase), both in-vitro and in-vivo.
FAAH is an integral membrane protein (IMP) that hydrolyzes bioactive amides including the endocannabinoid anandamide which is an agonist of cannabinoid receptors and TRPVl vanilloid receptors to free fatty acid and ethanolamine, see e.g. McKinney M.K., Cravatt B.F., Λ7m. Rev. Biochem. 74:411 (2005).
Due to its ability to regulate anandamide levels, FAAH is currently viewed as an attractive draggable target. Examples of non-selective inhibitors of FAAH include PMSF (phenylmethylsulfonylfluoride), MAFP (methoxyarachidonylfluorophosphonate), and ATMK (arachidonoyltrifluoromethylketone), while URB597
([3-(3-carbamoylphenyl)phenyl] N-cyclohexylcarbamate) is widely regarded as the current "gold standard" FAAH inhibitor. In pre-clinical laboratory tests URB597 was found to increase the production of endocannabinoids resulting in measurable antidepressant and analgesic effects, see e.g. Russo R., et al, J Pharmacol Exp Ther. 322(l):236-42 (2007).
FAAH inhibition is considered to play an important role in many medical consitions, see e.g. Pacher et al, Pharmacol Rev 58:389-462 (2006). Particularly the following diseases and conditions may be mentioned:
Pain, in particular acute or chronic pain of neurogenic type: migraine, neuropathic pain, including forms associated with the herpes virus and with diabetes; acute or chronic pain associated with inflammatory diseases: arthritis, rheumatoid arthritis, osteoarthritis, spondylitis, gout, vasculitis, Crohn's disease, irritable bowel syndrome;
acute or chronic peripheral pain;
dizziness, vomiting, nausea, in particular resulting from chemotherapy;
eating disorders, in particular anorexia and cachexia of various natures;
neurological and psychiatric pathologies: tremors, dyskinesias, dystonias, spasticity, obsessive-compulsive behaviour, Tourette's syndrome, all forms of depression and anxiety of any nature and origin, mood disorders, psychoses;
acute and chronic neurodegenerative diseases: Parkinson's disease, Alzheimer's disease, senile dementia, Huntington's chorea, lesions related to celebral ischaemia and to cranial and medullary trauma;
epilepsy;
sleep disorders, including sleep apnoea;
cardiovascular diseases, in particular hypertension, cardiac arrhythmias, arteriosclerosis, heart attack, cardiac ischaemia;
renal ischaemia;
cancers: benign skin tumours, brain tumours and papillomas, prostate tumours, cerebral tumours (glioblastomas, medulloepitheliomas, medulloblastomas, neuroblastomas, tumours of embryonic origin, astrocytomas, astroblastomas, ependymomas, oligodendrogliomas, plexus tumour, neuroepitheliomas, epiphyseal tumour, ependymoblastomas, malignant meningiomas, sarcomatosis, malignant melanomas, schwannomas);
disorders of the immune system, in particular autoimmune diseases; psoriasis, lupus erythematosus, diseases of the connective tissue or collagen diseases, Sjogren's syndrome, ankylosing spondylitis, undifferentiated spondylitis, Behcet's disease, autoimmune haemolytic anaemia, multiple sclerosis, amyotrophic lateral sclerosis, amyloidosis, graft rejection, diseases affecting the plasmacytic line;
allergic diseases; immediate or delayed hypersensitivity, allergic rhinitis or conjunctivitis, contact dermatitis;
parasitic, viral or bacterial infectious diseases: AIDS, meningitis;
inflammatory diseases, in particular joint diseases: arthritis, rheumatoid arthritis, osteoarthritis, spondylitis, gout, vasculitis, Crohn's disease, irritable bowel syndrome;
osteoporosis;
eye conditions: ocular hypertension, glaucoma;
pulmonary conditions; diseases of the respiratory tracts, bronchospasm, coughing, asthma, chronic bronchitis, chronic obstruction of the respiratory tract, emphysema;
gastrointestinal diseases; irritable bowel syndrome, inflammatory intestinal disorders, ulcers, diarrhea,
urinary incontinence and bladder inflammation.
It was now surprisingly found that the compounds of the present invention have an unexpectedly high inhibition of FAAH, both in-vitro and in vivo, making these compounds promising candidates for medicaments for the treatment or prevention of FAAH-related medical conditions.
In addition, it was also surprisingly found that compounds of the present invention are characterized by peripheral selectivity over CNS in vivo, avoiding unwanted CNS effects. Thus, the compounds of the present invention may be used to treat the above- mentioned conditions as well as in the preparation of medicaments to treat such methods. The invention also includes methods of treating such diseases comprising administering a compound of the invention to a patient in need thereof, as well as pharmaceutical compositions containing a compound or compounds of the present invention.
As used herein, the term treatment and variations such as 'treat' or 'treating' refers to any regime that can benefit a human or non-human animal. The treatment may be in respect of an existing condition or may be prophylactic (preventative) treatment. Treatment may include curative, alleviation or prophylactic effects. Treatment may prevent or delay the onset, retard the progression or ameliorate the symptoms of the disease or condition.
The present invention relates to compounds of formula (I),
Figure imgf000005_0001
(D,
wherein
A represents a 5- or 6-membered heteroaromatic ring system containing up to 4 heteroatoms selected from O, S and N, which is optionally substituted once or several times by: hydrogen;
Ci-Cβ-alkyl, Cs-Cs-cycloalkyl, Cβ-Cio-aryl, Ce-Cio-aryl-Ci-Cs-alkyl, Ci-Ce-alkoxy,
Cδ-Cio-aryloxy, Cβ-Cio-aryl-G-Cs-alkoxy, Ci-Cβ-alkoxycarbonyl, Cβ-Cio-aryloxy- carbonyl, Cβ-Go-aryl-Ci-Cβ-alkoxycarbonyl, Ci-Cδ-alkylcarbonyl, Cδ-Cio-arylcarbonyl,
C6-Cio-aryl-Ci-C8-alkylcarbonyl, Ci-Cβ-alkylcarboxy, Cβ-Cio-arylcarboxy, Ci-Ce- alkylmercaptyl, Ce-Cio-arylmercaptyl, Ci-Cβ-alkylmercaptocarbonyl, C3-C8- cycloalkylmercaptocarbonyl, Cβ-Cio-arylmercaptocarbonyl, Ci-Cβ-alkylmercaptocarboxy,
Cδ-Cio-arylmercaptocarboxy, Ci-Cό-alkylsulfonyl, Cβ-Cio-arylsulfonyl, Ci-Cβ- alkylsulfoxy, Cβ-Cio-arylsulfoxy, wherein each is optionally substituted once or several times by
Ci-Ce-alkyl; Ci-Ce-alkoxy; Cβ-Cio-aryloxy; CO2H; SOsH; CONEb; SO2NH2; CONH2 or SO2NH2 wherein the amino functionality is substituted one or more times with residues selected from Ci-Cβ-alkyl, Ce-Cio-aryl or C6-Cio-aryl-Ci-C4- alkyl and wherein in case of a di-Ci-Ce-alkyl-substituted amino functionality the alkyl residues may be combined to form 5 or 6-membered rings; amino; amino substituted one or more times with residues selected from Ci-Cβ-alkyl, Ce-C 10- aryl,
Figure imgf000006_0001
Ci-Cβ-alkylcarbonyl, Cβ-Cio-arylcarbonyl, Ci-Cβ- alkylsulfonyl and Cβ-Cio-arylsulfonyl; thiol; hydroxyl; nitro; cyano; fluoro; chloro; bromo; iodo; CF3 or OCF3;
CO2H; SO3H; amino; amino substituted one or more times with residues selected from Ci-Cβ-alkyl, C6-Cio-aryl, Cβ-Cio-aryl-Ci-Ce-alkyl, Ci-Ce-alkylcarbonyl, Ce-Cio-arylcarbonyl, Ci-Cβ-alkylsulfonyl and Cβ-Cio-arylsulfonyl; a disubstituted amino of the following formula (II)
Figure imgf000006_0002
wherein o represents O or 1 and W represents O, CEh, or NR6 with R6 being selected from hydrogen and Ci-Cβ-alkyl and wherein the methylene groups in formula (II) may optionally be substituted once or twice with Ci-Cβ-alkyl, fluoro or chloro; CONH2;
CONH2 or SO2NH2 wherein the amino functionality is substituted once or twice with residues selected from Ci-Cβ-alkyl, Cβ-Cio-aryl or Cβ-Cio-aryl-Ci-Cβ-alkyl and wherein in the case of a di-Ci-Cβ-alkyl-substituted amino functionality the alkyl residues may be combined to form 5 or 6-membered rings; thiol; hydroxyl; nitro; cyano; fluorosulfonyl; halogen selected from fluoro, chloro, bromo or iodo;
CF3; oxo;
OCFs; or a saturated, unsaturated or aromatic heterocyclic ring system of up to 10 atoms, optionally substituted once or several times by
Ci-Ce-alkyl; Ci-Ce-alkoxy; COOH; SOsH; CONH2; SO2NH2; CONH2 or SO2NH2 wherein the amino functionality is substituted one or more times with residues selected from Ci-Cβ-alkyl, Cδ-Cio-aryl or C6-Cio-aryl-Ci-C4-alkyl and wherein in case of a di-Ci-Cβ-alkyl-substituted amino functionality the alkyl residues may be combined to form 5 or 6-membered rings; amino; amino substituted one or more times with residues selected from Ci-Cβ-alkyl, Cβ-Cio-aryl, C6-Cio-aryl-Ci-C4-alkyl, Ci-Cβ-alkylcarbonyl, Cβ-Cio-arylcarbonyl, Ci-Cβ-alkylsulfonyl and Cβ-Cio- arylsulfonyl; thiol; hydroxyl; nitro; cyano; fluoro; chloro; bromo; iodo; CF3 or OCF3; and wherein any two or more substituents of A may be combined to form anellated saturated, unsaturated or aromatic homo- or hetero-ring systems; n represents 0 or 1; m represents 0, 1, 2, 3, 4, 5 or 6; X represents O or S; Y represents:
a) hydrogen; b) Ci-Ci8-alkyl, mono or polyunsaturated C2-Cis-alkylene, C3-C8-cycloalkyl, Cβ-Cio-aryl, Cβ-Cio-aryl-Ci-Cs-alkyl, Ci-Cβ-alkoxy, Cβ-Cio-aryloxy, Cβ-Cio-aryl- Ci-Cs-alkoxy, Ci-Cβ-alkoxycarbonyl, Cβ-Cio-aryloxycarbonyl, Cδ-Cio-aryl-Ci-Cs- alkoxycarbonyl, Ci-Ce-alkylcarbonyl, Cδ-Cio-arylcarbonyl, Ce-Cio-aryl-Ci-Cs- alkylcarbonyl, Ci-Ce-alkylcarboxy, Cβ-Cio-arylcarboxy, Ci-Ce-alkylmercaptyl,
Cβ-Cio-arylmercaptyl, Ci-Cβ-alkylmercaptocarbonyl, C3-C8- cycloalkylmercaptocarbonyl, Cβ-Cio-arylmercaptocarbonyl, Ci-Cδ- alkylmercaptocarboxy, Ce-Cio-arylmercaptocarboxy, Ci-Cδ-alkylsulfonyl, Cβ-Cio- arylsulfonyl, O-Cβ-alkylsulfoxy, Cβ-Cio-arylsulfoxy, or a saturated, unsaturated or aromatic heterocyclic ring system of up to 10 atoms, wherein each is optionally substituted once or several times by: bl) Ci-Cβ-alkyl, Cs-Cs-cycloalkyl, Cβ-Cio-aryl, Cβ-Cio-aryl-Ci-Cs-alkyl, Ci-Cβ-alkoxy, Cβ-Cio-aryloxy, Cδ-Cio-aryl-Ci-Cs-alkoxy, Ci-Ce- alkoxycarbonyl, Cβ-Cio-aryloxycarbonyl, Cβ-Cio-aryl-Ci-Cs-alkoxycarbonyl, Ci-Cδ-alkylcarbonyl, Cβ-Cio-arylcarbonyl, Cβ-Cio-aryl-Ci-Cs-alkylcarbonyl,
Ci-Ce-alkylcarboxy, Ce-Cio-arylcarboxy, Ci-Cβ-alkylmercaptyl, Cβ-Cio- arylmercaptyl, Ci-Cβ-alkyhnercaptocarbonyl, C3-C8- cycloalkyhnercaptocarbonyl, Cβ-Cio-arylmercaptocarbonyl, Ci-Cδ- alkylmercaptocarboxy, Cβ-Cio-arylmercaptocarboxy, Ci-Cβ-alkylsulfonyl, Cβ-Cio-arylsulfonyl, Ci-Cβ-alkylsulfoxy, Cβ-Cio-arylsulfoxy; wherein each is optionally substituted once or several times by Ci-Cβ-alkyl; Ci-Cβ-alkoxy; CONH2, SO2NH2; COlSfH2 or SO2NH2 wherein the amino functionality is substituted once or twice with Ci-Cβ-alkyl; SO3H; CO2H; amino; amino substituted one or more times with residues selected from Ci-Cβ-alkyl, Cθ-Cio-aryl, Cβ-Cio-aryl-Ci-Cδ-alkyl, Ci-Cβ-alkylcarbonyl, Cβ-Cio- arylcarbonyl, Ci-Cβ-alkylsulfonyl and Cβ-Cio-arylsulfonyl; thiol; hydroxyl; nitro; cyano; fluoro; chloro; bromo; iodo; CF3; or OCF3; wherein several of the substituents in bl) may be combined to form anellated saturated, unsaturated or aromatic homo- or hetero-ring systems; or by b2) hydroxy; thiol; nitro; cyano; fluoro; chloro; bromo; iodo; CF3; CO2H;
SO3H; OCF3; CONH2; SO2NH2; CONH2 or SO2NH2 wherein the amino functionality is substituted once or twice with residues selected from Ci-Ce- alkyl, Cό-Cio-aryl or Cβ-Cio-aryl-Ci-Cβ-alkyl and wherein in the case of a di-Ci-Cβ-alkyl-substituted amino functionality, the alkyl residues may be combined to form 5 or 6-membered rings; amino; amino substituted one or more times with residues selected from Ci-Ce-alkyl, Cβ-Cio-aryl, Ce-Cio- aryl-Ci-Cs-alkyl, Ci-Ce-alkylcarbonyl, Ce-Cio-arylcarbonyl, Ci-Ce- alkylsulfonyl and Ce-Cio-arylsulfonyl; or a disubstituted amino of the following formula (II)
Figure imgf000009_0001
wherein o represents 0 or 1 and W represents O, CH2, or NR6 with R6 being selected from hydrogen and Ci-Cβ-alkyl and wherein the methylene groups in formula (II) may optionally be substituted once or twice with Ci-Cβ-alkyl, fluoro or chloro; or by b3) a saturated, unsaturated or aromatic heterocyclic ring system of up to 10 atoms, optionally substituted once or several times by Ci-Ce-alkyl; Ci-Ce- alkoxy; COOH; SOsH; CONH2; SO2NH2; CONH2 or SO2NH2 wherein the amino functionality is substituted one or more times with residues selected from Ci-Ce-alkyl, Ce-Cio-aryl or C6-Cio-aryl-Ci-C4-alkyl and wherein in case of a di-Ci-Cβ-alkyl-substituted amino functionality the alkyl residues may be combined to form 5 or 6-membered rings; amino; amino substituted one or more times with residues selected from Ci-Cβ-alkyl, Ce-Cio-aryl, Ce-Cio- aryl-Ci-C4-alkyl, Ci-Cβ-alkylcarbonyl, Cβ-Cio-arylcarbonyl, Ci-Ce- alkylsulfonyl and Cδ-Cio-arylsulfonyl; thiol; hydroxyl; nitxo; cyano; fluoro; chloro; bromo; iodo; CF3 or OCF3; c) SO3H; amino; amino substituted one or more times with residues selected from Ci-Ce-alkyl, Cβ-Cio-aryl, Ce-Cio-aryl-Ci-Cs-alkyl, Ci-Ce-alkylcarbonyl, Cβ-Cio- arylcarbonyl, G-Cδ-alkylsulfonyl and Ce-Cio-arylsulfonyl; CONH2; SO2NH2;
CONH2 or SO2NH2 wherein the amino functionality is substituted once or twice with residues selected from d-Cβ-alkyl, Cδ-Cio-aryl or Cθ-Cio-aryl-Ci-Cβ-alkyl and wherein in the case of a di-Ci-Cβ-alkyl-substituted amino functionality the alkyl residues may be combined to form 5 or 6-membered rings; thiol; hydroxyl; nitro; cyano; fluorosulfonyl; halogen selected from fluoro, chloro, bromo or iodo;
CFs; or OCFs; or a stereoisomer, pharmaceutically acceptable salt or ester, or prodrug thereof.
Suitable pharmaceutically acceptable salts include hydrochloride, dihydrochloride, and trifluoroacetate salts.
In the above formula (I), A representing a 5- or 6-membered heteroaromatic ring system containing up to 4 heteroatoms selected from O, S and N is preferably a heteroaromatic ring comprising 1, 2, 3 or 4, preferably 1 or 2, nitrogen atoms. It is also preferred that the heteroaromatic ring comprises 1 or 2 oxygen atoms. It is most preferred that the heteroaromatic ring is selected from pyridine, pyrazine, pyrimidine, pyridazine, triazine, tetrazine, thiophene, furane, oxazole, thiazole, oxazine, thiazine, and oxaadiazole. The most preferred heteroaromatic ring system is pyridine, in particular 2-pyridine, 3-pyridine and 4-pyridine derivatives.
Within the meaning of this application, the term Ci-C4-alkyl represents preferably methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, and tert-butyl.
Within the meaning of this application, the term G-Cβ-alkyl represents preferably methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, pentyl or hexyl. Within the meaning of this application, the term Ci-Cis-alkyl represents preferably methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, pentyl, hexyl, octyl, decyl, dodecyl, tetradecyl and octadecyl.
Within the meaning of this application, the term mono or polyunsaturated C2-C18- alkylene preferably represents ethenyl, n-propenyl, isopropenyl, n-butenyl, sec-butenyl, tert-butenyl, pentenyl, hexenyl, octenyl, decenyl, dodecenyl, tetradecenyl, octadecenyl, dodecdienyl, tetradecdienyl and octadecdienyl.
Within the meaning of this application, the term C3-Cs-cycloalkyl preferably represents cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.
Within the meaning of this application, the term Cβ-Cio-aryl preferably represents phenyl, pentalenyl, indenyl, indanyl, isoindolinyl, chromanyl, naphthyl, fluorenyl, anthryl, phenanthryl or pyrenyl.
Within the meaning of this application, the terms Cβ-Cio-aryl-Ci-Cs-alkyl, Cδ-Cio- aryl-Ci-Ce-alkyl and C6-Cio-aryl-Ci-C4-alkyl preferably represent phenyl or naphthyl being substituted with methyl, ethyl, propyl or butyl. Particularly preferred residues are benzyl and phenethyl.
Within the meaning of this application, the term Ci-C4-alkoxy preferably represents methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, and tert- butoxy.
Within the meaning of this application, the term Ci-Cβ-alkoxy preferably represents methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy, pentoxy or hexoxy.
Within the meaning of this application, the term Cβ-Cio-aryloxy preferably represents phenoxy, naphthoxy, indenoxy, fluorenoxy or phenanthroxy. Within the meaning of this application, the terms Cβ-do-aryl-Ci-Cs-alkoxy, Cβ-Cio-aryl-Ci-Cβ-alkoxy and
Figure imgf000012_0001
preferably represent benzoxy, phenethoxy, phenpropoxy, or phenbutoxy. Particularly preferred residues are benzoxy and phenethoxy.
Within the meaning of this application, the term Ci-Ce-alkoxycarbonyl preferably represents methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl, isopropoxycarbonyl or butoxycarbonyl.
Within the meaning of this application, the term Ce-Cio-aryloxycarbonyl preferably represents phenoxycarbonyl or naphthoxycarbonyl.
Within the meaning of this application, the term Ce-Cio-aryl-Ci-Cs-alkoxycarbonyl preferably represents represents benzoxycarbonyl or phenethoxy carbonyl.
Within the meaning of this application, the term Ci-Ce-alkylcarbonyl preferably represents methylcarbonyl, ethylcarbonyl, n-propylcarbonyl, isopropylcarbonyl or butylcarbonyl.
Within the meaning of this application, the term Cβ-Cio-arylcarbonyl preferably represents phenylcarbonyl or naphthylcarbonyl.
Within the meaning of this application, the term Cβ-Cio-aryl-Ci-Cs-alkylcarbonyl preferably represents benzylcarbonyl or phenethylcarbonyl.
Within the meaning of this application, the term Ci-Cβ-alkylcarboxy preferably represents methylcarboy, ethylcarboxy, n-propylcarboxy, isopropylcarboxy or butylcarboxy.
Within the meaning of this application, the term Cδ-Cio-arylcarboxy preferably represents phenylcarboxy or naphthylcarboxy. Within the meaning of this application, the term Ci-Cβ-alkylmercaptyl preferably represents methylmercaptyl, ethylmercaptyl, n-propylmercaptyl, isopropylmercaptyl or butylmercaptyl.
Within the meaning of this application, the term Ce-Cio-arylmercaptyl preferably represents phenylmercaptyl or naphthylmercaptyl.
Within the meaning of this application, the term Ci-Cβ-alkylmercaptocarbonyl preferably represents methylmercaptocarbonyl, ethylmercaptocarbonyl, n-propylmercaptocarbonyl, isopropylmercaptocarbonyl or butylmercaptocarbonyl.
Within the meaning of this application, the term C3-C8-cycloalkylmercapto- carbonyl preferably represents cyclopropylmercaptocarbonyl, cyclobutylmercaptocarbonyl, cyclopentylmercaptocarbonyl or cyclohexylmercaptocarbonyl.
Within the meaning of this application, the term Cβ-Cio-arylmercaptocarbonyl preferably represents phenylmercaptocarbonyl or naphthylmercaptocarbonyl.
Within the meaning of this application, the term Ci-Ce-alkylmercaptocarboxy preferably represents methylmercaptocarboxy, ethylmercaptocarboxy, n-propyl- mercaptocarboxy, isoproylmercaptocarboxy or butylmercaptocarboxy.
Within the meaning of this application, the term Cβ-Cio-arylmercaptocarboxy preferably represents phenylmercaptocarboxy or naphthylmercaptocarboxy.
Within the meaning of this application, the term Ci-Cδ-alkylsulfonyl preferably represents methylsulfonyl, ethylsulfonyl, n-propylsulfonyl, n-butylsulfonyl, sec- butylsulfonyl, tert-butylsulfonyl, pentylsulfonyl or hexylsulfonyl.
Within the meaning of this application, the term Ce-Cio-arylsulfonyl preferably represents phenylsulfonyl or naphthylsulfonyl. Within the meaning of this application, the term Ci-Ce-alkylsulfoxy preferably represents methylsulfoxy, ethylsulfoxy, n-propylsulfoxy, n-butylsulfoxy, sec-butylsulfoxy or tert-butylsulfoxy.
Within the meaning of this application, the term Cβ-Cio-arylsulfoxy preferably represents phenylsulfoxy or naphthylsulfoxy.
Furthermore, it is preferred in alternative embodiments of the invention that the above-mentioned substituents are optionally substituted once or several times by Ci-Cβ- alkyl, Ci-Cβ-alkoxy, Ce-Cio-aryloxy, CO2H, SCbH, amino, thiol, hydroxyl, nitro, cyano, fluoro, chloro, bromo, iodo, CF3 or OCF3. In this definition of optional substituents, Ci-Cό-alkyl, Ci-Cβ-alkoxy, and Cβ-Cio-aryloxy preferably represent the same residues as mentioned above.
Within the meaning of this application, the term "optionally substituted once or several times by" is meant to include no substitution, single substitution or multiple substitution with one or more of the mentioned optional substituents. In case of a multiple substitution, the substituents can be selected independently from each other.
Within the meaning of this application, the term amino substituted one or more times with residues selected from Ci-Cβ-alkyl, Cβ-Cio-aryl, C6-Cio-aryl-Ci-C4-alkyl, Ci-Cβ-alkylcarbonyl, Cβ-Cio-arylcarbonyl, Ci-Cβ-alkylsulfonyl and Cβ-Cio-arylsulfonyl is preferably represented by an amino group that is once or twice and independently from each other substituted by methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert- butyl, pentyl or hexyl in case of Ci-Ce-alkyl; by phenyl, benzyl or phenethyl in case of Cβ-Cio-aryl and C6-Cio-aryl-Ci-C4-alkyl; by methylcarbonyl, ethylcarbonyl, or phenylcarbonyl in case of Ci-Cθ-alkylcarbonyl and Ce-Cio-arylcarbonyl; and by methylsulfonyl, ethylsulfonyl or phenylsulfonyl in case of Ci-Cβ-alkylsulfonyl and Cβ-Cio-arylsulfonyl. Within the meaning of this application, the term CONH2 or SO2NH2, wherein the amino functionality is substituted one or more times with residues selected from Ci-Ce- alkyl, Cβ-Cio-aryl or C6-Cio-aryl-Ci-C4-alkyl and wherein in case of a di-Ci-Cβ-alkyl- substituted amino functionality the alkyl residues may be combined to form 5 or 6-membered rings, is preferably represented by residues derivable from N,N-dimethylamide, N-methylamide, N-ethylamide, N-phenylamide,
N,N-dimethylsulfonamide, N-methylsulfonamide, N-ethylsulfonamide, and N-phenylsulfonamide. In case of an alkyl-disubstitution of the amino functionality, it is also a preferred alternative that both residues are combined to form 5 or 6-membered rings. Examples of such amino functionalities include but are not limited to pyrrolidin and piperidine.
Within the meaning of this application, the term a saturated, unsaturated or aromatic heterocyclic ring system of up to 10 atoms, optionally substituted once or several times by Ci-Ce-alkyl, Ci-Cβ-alkoxy, COOH, SO3H, amino, thiol, hydroxyl, nitro, cyano, fluoro, chloro, bromo, iodo, CF3 or OCF3, is preferably represented by a saturated, unsaturated or aromatic heterocyclic ring system of up to 10 atoms containing one to four heteroatoms selected from N, O or S, particularly 5- or 6-membered heteroaromatic ring systems. Examples of such preferred saturated, unsaturated or aromatic heterocycles of up to 10 atoms include but are not limited to benzimidazole, benzofuran, benzothiophene, benzoxazole, benzothiazole, carbazole, cinnoline, dioxin, dioxane, dioxolane, dithiane, dithiazine, dithiazole, dithiolane, furan, imidazole, imidazoline, imidazolidine, indole, indoline, indolizine, indazole, isoindole, isoquinoline, isoxazole, isothiazole, morpholine, napthyridine, oxazole, oxadiazole, oxathiazole, oxathiazolidine, oxazine, oxadiazine, phenazine, phenothiazine, phenoxazine, phthalazine, piperazine, piperidine, pteridine, purine, pyran, pyrazine, pyrazole, pyrazoline, pyrazolidine, pyridazine, pyridine, pyrimidine, pyrrole, pyrrolidine, pyrroline, quinoline, quinoxaline, quinazoline, quinolizine, tetrahydrofuran, tetrazine, tetrazole, thiophene, thiadiazine, thiadiazole, thiatriazole, thiazine, thiazole, thiomorpholine, thianaphthalene, thiopyran, triazine, triazole, and trithiane in all their isomeric configurations. These heterocycles may be optionally substituted once or several times by Ci-Cβ-alkyl, Ci-Ce-alkoxy, COOH, SO3H, amino, thiol, hydroxyl, nitro, cyano, fluoro, chloro, bromo, iodo, CF3 or OCF3. Particluarly preferred optional substituents are methyl, methoxy, amino, hydroxy, nitro, cyano, fluoro, chloro, bromo, iodo, CF3 and OCF3.
The most preferred aromatic heterocyclic ring systems of up to 10 atoms comprise the 6-membered heteroaryls 2-pyridine, 3-pyridine or 4-pyridine, all of which are optionally substituted with one or more residues selected from methyl, amino, fluoro, chloro or CF3; and pyrrole, which is optionally substituted with one or more residues selected from methyl, amino, fluoro, chloro or CF3.
It is preferred that, in the above formula (I), A represents 2-pyridinyl, 3-pyridinyl or 4-pyridinyl.
In a preferred embodiment, A is substituted once or several times with hydrogen; hydroxyl;
Ci-Cβ-alkyl, Cβ-Cio-aryl, Ci-Cβ-alkoxy, Cό-Cio-aryloxy, Cβ-Cio-aryl-Ci-Ce-alkoxy, Ci-Ce- alkylcarboxy, Cβ-Cio-arylcarboxy, Ci-Cβ-alkylsulfonyl, Ce-Cio-arylsulfonyl, wherein each is optionally substituted once or several times by Ci-Ce-alkyl, Ci-Cδ-alkoxy, amino, Ci-Cβ-alkylamino, di-Ci-Cβ-alkylamino, hydroxy, fluoro, chloro, bromo, cyano, CF3 or
OCF3; amino; amino substituted one or more times with residues selected from Ci-Ce-alkyl, Cβ-Cio-aryl;
1-pyrrolyl, 2-pyrrolyl or 3-pyrrolyl, optionally substituted with one or more residues selected from Ci-Cβ-alkyl, amino, fluoro, chloro or CF3; or a disubstituted amino of the following formula (II)
Figure imgf000016_0001
(II) wherein o represents 0 or 1 and W represents O, CEb, or NR6 with R6 being selected from hydrogen and Ci-Cβ-alkyl and wherein the methylene groups in formula (II) may optionally be substituted once or twice with Ci-Cβ-alkyl, fluoro or chloro; CONH2;
CONH2 or SO2NH2 wherein the amino functionality is substituted once or twice with residues selected from Ci-Cβ-alkyl or Cβ-Cio-aryl; fluoro; chloro; bromo; CFs; or OCF3.
In a further preferred embodiment, A is substituted once or several times with Ci-Cβ-alkyl, Cβ-Cio-aryl, wherein each is optionally substituted once or several times by Ci-Cβ-alkyl, Ci-Cβ-alkoxy, amino, Ci-Cβ-alkylamino, di-Ci-Cβ-alkylamino, hydroxy, fluoro, chloro, bromo, cyano, CF3 or OCF3.
It is particularly preferred that, in the above formula (I), A is substituted once or several times with fluoro or chloro. It is most preferred that, in the above formula (I), A is substituted with fluorine in ortho-position to the oxadiazolinone residue.
In a further preferred embodiment, A is substituted once or several times with: hydroxy; or Ci-Cβ-alkoxy, Ce-Cio-aryloxy, Ce-Cio-aryl-Ci-Cδ-alkoxy, Ci-Cβ-alkylcarboxy, Cβ-Cio- arylcarboxy, Ci-Ce-alkylsulfonyl, Ce-Cio-arylsulfonyl, wherein each is optionally substituted once or several times by Ci-Ce-alkyl, Ci-Cβ-alkoxy, amino, Ci-Cβ-alkylamino, di-Ci-Cβ-alkylamino, CONH2 or SO2NH2 optionally substituted once or twice with Ci-Ce- alkyl or Cδ-Cio-aryl, hydroxy, fluoro, chloro, bromo, cyano, CF3 or OCF3.
It is more preferred that A is in the meta- and/or para-position(s) to the oxadiazolinone ring substituted once or several times with: hydroxy; or
Ci-Ce-alkoxy, Ce-Cio-aryloxy, or Ce-Cio-aryl-Ci-Cβ-alkoxy, each of which is optionally substituted once or several tunes by Ci-Cβ-alkyl, Ci-Cβ-alkoxy, amino, Ci-Cβ-alkylamino, di-Ci-Cβ-alkylamino, CONH2 or SO2NH2 optionally substituted once or twice with Ci-Ce- alkyl or Cβ-Cio-aryl, hydroxy, fluoro, chloro, or bromo.
In a further preferred embodiment, A is substituted once or several times with:
ammo; amino substituted one or more times with residues selected from Ci-Cβ-alkyl, Cβ-Cio-aryl; or a disubstituted amino of the following formula (II)
Figure imgf000018_0001
wherein o represents 0 or 1 and W represents O, CEb, or NR6 with R6 being selected from hydrogen and Ci-Ce-alkyl and wherein the methylene groups in formula (II) may optionally be substituted once or twice with Ci-Cβ-alkyl, fluoro or chloro.
It is more preferred that A is in the meta- and/or para-position(s) to the oxadiazolinone ring substituted once or several times with: amino; amino substituted once or twice with residues selected from Ci-Cβ-alkyl, Cβ-Cio-aryl; or a disubstituted amino of the following formula (II)
Figure imgf000018_0002
αi) wherein o represents O or 1 and W represents O, CBb, or NR6 with R6 being selected from hydrogen and Ci-Cβ-alkyl and wherein the methylene groups in formula (II) may optionally be substituted once or twice with Ci-Cβ-alkyl, fluoro or chloro.
With respect to the 5-oxy-substituent of the oxadiazolone ring, it is further preferred that, in the above formula (I), n represents 0; m represents 0, 1 , 2, 3, 4, 5 or 6; and Y represents C3-Cδ-cycloalkyl or Cδ-Cio-aryl, each of which is optionally substituted once or several times by: a) Ci-Cβ-alkyl, Ce-Cio-aryl, Cβ-Cxo-aryl-Ci-Q-alkyl, Ci-Ce-alkoxy, Cβ-Cio- aryloxy, Cβ-Cio-aryl-Ci-C-i-alkoxy, wherein each is optionally substituted once or several tunes by:
Ci-Ce-alkyl; Ci-Ce-alkoxy; COOH; CONH2; SO2NH2; CONH2 or SO2NH2 substituted once or twice with Ci-Ce-alkyl or Cβ-Cio-aryl; SO3H; ammo; amino substituted one or more tunes with residues selected from Ci-Cβ-alkyl, Cβ-Cio-aryl, C6-Cio-aryl-Ci-C4-alkyl,
Ci-Cβ-alkylcarbonyl, Cβ-Cio-arylcarbonyl, Ci-Cβ-alkylsulfonyl and Cβ-Cio-arylsulfonyl; thiol; hydroxyl; nitro; cyano; fluoro; chloro; bromo; iodo; CF3 or OCF3; or by b) hydroxy; thiol; nitro; cyano; fluoro; chloro; bromo; iodo; CF3; OCF3;
CO2H; SO3H; CONH2; SO2NH2; CONH2 or SO2NH2 wherein the amino functionality is substituted one or more times with residues selected from Ci-Cβ-alkyl, Cβ-Cio-aryl or C6-Cio-aryl-Ci-C4-alkyl and wherein in case of a di-Cx-Cβ-alkyl-substituted amino functionality the alkyl residues may be combined to form 5 or 6-membered rings; amino; amino substituted once or several tunes with Ci-Cβ-alkyl or phenyl; a disubstituted amino of the following formula (II)
Figure imgf000019_0001
wherein o represents 0 or 1 and W represents O, CEh, or NR6 with R6 being selected from hydrogen and Ci-C4-alkyl and wherein the methylene groups in formula (II) may optionally be substituted once or twice with Ci-Cψ-alkyl, fluoro or chloro; or by c) a saturated, unsaturated or aromatic heterocyclic ring system of up to 10 atoms, optionally substituted once or several tunes by
Ci-Ce-alkyl; Ci-Cβ-alkoxy; COOH; CONH2; SO2NH2; CONH2 or
SO2NH2 substituted once or twice with Ci-Cβ-alkyl or Ce-Cio-aryl; SO3H; amino; amino substituted one or more times with residues selected from Ci-Cό-alkyl, Ce-Cio-aryl, Ce-Cio-aryl-Ci-Ci-alkyl, Ci-Ce- alkylcarbonyl, Ce-Cio-arylcarbonyl, Ci-Ce-alkylsulfonyl and Ce-Oo- arylsulfonyl; thiol; hydroxyl; nitro; cyano; fluoro; chloro; bromo; iodo; CFs or OCFs.
It is more preferred that n represents O; m represents O or 1; and Y represents phenyl, or a 1-naphthyl, 2-naphthyl, 2-pyridinyl, 3-pyridinyl or 4-pyridinyl ring system.
It is even more preferred that Y is substituted once or several times by Ci-Ce- alkyl; phenyl; Ci-Cό-alkoxy; hydroxy; fluoro; chloro; bromo; CF3; OCF3; amino; or CONH2 or SO2NH2 optionally substituted once or twice with Ci-Ce-alkyl wherein these optional Ci-Ce-alkyl residues may be combined to form 5 or 6-membered rings.
It is still more preferred that m represents O and Y represents phenyl which is substituted once or twice by hydroxy, fluoro, chloro or bromo.
It is most preferred that m represents O and Y represents phenyl which is substituted in the 4-position by fluoro, in the 4-position by chloro, in the 2- and 4-position by fluoro, in the 2- and 4-position by chloro, or in the 4-position by phenyl. It is also most preferred in this embodiment, that, in above formula (I), Y also represents phenyl which is substituted in the 4-position by fluoro or by chloro, in the 2- and 4-position by fluoro, or in the 2- and 4-position by chloro.
In a further preferred embodiment, in the above formula (I), m is 0; n is 0; Y represents phenyl substituted once or twice by fluoro, chloro or bromo; and A is substituted in the meta- or para-position to the oxadiazolone ring with OR7 wherein R7 is selected from hydrogen and Ci-Cβ-alkyl.
It is more preferred that Y represents phenyl which is substituted hi the 4-position by fluoro or by chloro, in the 2- and 4-position by fluoro, or in the 2- and 4-position by chloro.
It is also preferred that A is substituted in the para-position to the oxadiazolone ring with hydrogen or fluorine.
It is also preferred that A is substituted in the meta- or para-position or in the meta- and para-position with hydroxy.
In a further preferred embodiment, A is a heterocycle comprising one, two, three or four nitrogen atoms, more preferably one or two nitrogen atoms.
It is most preferred that A is selected from 2-pyridyl, 3-pyridyl or 4-pyridyl.
In a further preferred embodiment, A is a heterocycle comprising one or two oxygen atoms.
In another aspect, the present invention also relates to a process for the preparation of a compound of formula (III),
Figure imgf000022_0001
(HI),
wherein
A represents a 5- or 6-membered heteroaromatic ring system containing up to 4 heteroatoms selected from O, S and N, which is optionally substituted once or several times by: hydrogen; Ci-Ce-alkyl, C3-Cs-cycloalkyl, Cό-Cio-aryl, Ce-Cio-aryl-Ci-Cs-alkyl, Ci-Ce-alkoxy, Ce-Cio-aryloxy, Cβ-Cio-aryl-Ci-Cs-alkoxy, Ci-Cθ-alkoxycarbonyl, Ce-Cio-aryloxy- carbonyl, Cβ-Cio-aryl-Ci-Cs-alkoxycarbonyl, Ci-Cβ-alkylcarbonyl, Ce-Cio-arylcarbonyl, Cδ-Cio-aryl-Ci-Cs-alkylcarbonyl, Ci-Cβ-alkylcarboxy, Cβ-Cio-arylcarboxy, Ci-Ce- alkylmercaptyl, Cό-Cio-arylmercaptyl, Ci-Ce-alkylmercaptocarbonyl, C3-C8- cycloalkylmercaptocarbonyl, Cδ-Cio-arylmercaptocarbonyl, Ci-Cβ-alkylmercaptocarboxy, Ce-Cio-arylmercaptocarboxy, Ci-Cβ-alkylsulfonyl, Ce-Cio-arylsulfonyl, Ci-Cβ- alkylsulfoxy, Ce-Cio-arylsulfoxy, wherein each is optionally substituted once or several times by
Ci-Ce-alkyl; Ci-Ce-alkoxy; Ce-Cio-aryloxy; CO2H; SOsH; CONH2; SO2NH2; CONH2 or SO2NH2 wherein the ammo functionality is substituted one or more times with residues selected from Ci-Cβ-alkyl, Cδ-Cio-aryl or Cθ-Cio- aryl-Ci-C4-alkyl and wherein in case of a di-Ci-Cβ-alkyl-substituted amino functionality the alkyl residues may be combined to form 5 or 6-membered rings; amino; amino substituted one or more times with residues selected from Ci-Cδ-alkyl, Ce-Cio-aryl,
Figure imgf000022_0002
Ci-Ce-alkylcarbonyl,
Cθ-Cio-arylcarbonyl, Ci-Cβ-alkylsulfonyl and Cβ-Cio-arylsulfonyl; thiol; hydroxyl; nitro; cyano; fluoro; chloro; bromo; iodo; CF3 or OCF3;
SO3H; amino; amino substituted one or more times with residues selected from Ci-Cδ-alkyl, Cβ-Cio-aryl, Cδ-Cio-aryl-Ci-Ce-alkyl, Ci-Cβ-alkylcarbonyl, Cβ-Cio-arylcarbonyl, Ci-Cδ-alkylsulfonyl and Cβ-Cio-arylsulfonyl; a disubstituted amino of the following formula (II)
Figure imgf000023_0001
wherein o represents O or 1 and W represents O, CEb, or NR6 with R6 being selected from hydrogen and Ci-Cβ-alkyl and wherein the methylene groups in formula (II) may optionally be substituted once or twice with Ci-Cβ-alkyl, fluoro or chloro;
CONH2;
CONH2 or SO2NH2 wherein the amino functionality is substituted once or twice with residues selected from Ci-Cβ-alkyl, Cβ-Cio-aryl or Ce-Cio-aryl-Ci-Ce-alkyl and wherein in the case of a di-Ci-Ce-alkyl-substituted amino functionality the alkyl residues may be combined to form 5 or 6-membered rings; thiol; hydroxyl; nitro; cyano; fluorosulfonyl; halogen selected from fluoro, chloro, bromo or iodo;
CF3; oxo;
OCFs; or a saturated, unsaturated or aromatic heterocyclic ring system of up to 10 atoms, optionally substituted once or several times by
Ci-Ce-alkyl; Ci-Ce-alkoxy; COOH; SOsH; CONH2; SO2NH2; CONH2 or SO2NH2 wherein the amino functionality is substituted one or more times with residues selected from Ci-Cβ-alkyl, Cβ-Cio-aryl or C6-Cio-aryl-Ci-C4-alkyl and wherein in case of a di-Ci-Ce-alkyl-substituted amino functionality the alkyl residues may be combined to form 5 or 6-membered rings; amino; amino substituted one or more times with residues selected from Ci-Ce-alkyl, Cβ-Cio-aryl, C6-Cio-aryl-Ci-C4- alkyl, G-Cβ-alkylcarbonyl, Ce-Cio-arylcarbonyl, Ci-Cβ-alkylsulfonyl and Cβ-Cio- arylsulfonyl; thiol; hydroxyl; nitro; cyano; fluoro; chloro; bromo; iodo; CF3 or OCF3; and wherein any two or more substituents of A may be combined to form anellated saturated, unsaturated or aromatic homo- or hetero-ring systems; m represents 0, 1, 2, 3, 4, 5 or 6; and
Y represents: a) hydrogen; b) Ci-Ci8-alkyl, mono or polyunsaturated C2-Cis-alkylene, C3-C8-cycloalkyl, Cδ-Cio-aryl, Ce-Cio-aryl-Ci-Cs-alkyl, Ci-Cό-alkoxy, Ce-Cio-aryloxy, Ce-Cio-aryl- Ci-Cs-alkoxy, Ci-Ce-alkoxycarbonyl, Ce-Cio-aryloxycarbonyl, Cβ-Cio-aryl-Ci-Cs- alkoxycarbonyl, Ci-Ce-alkylcarbonyl, Cβ-Cio-arylcarbonyl, Cβ-Cio-aryl-Ci-Cs- alkylcarbonyl, Ci-Cβ-alkylcarboxy, Ce-Cio-arylcarboxy, Ci-Cβ-alkyhnercaptyl, Cδ-Cio-aryhnercaptyl, Ci-Cβ-alkylmercaptocarbonyl, C3-C8- cycloalkylmercaptocarbonyl, Cό-Cω-arylmercaptocarbonyl, Ci-Cβ- alkyhnercaptocarboxy, Cβ-Cio-arylmercaptocarboxy, Ci-Cδ-alkylsulfonyl, Cβ-Cio- arylsulfonyl, Ci-Cό-alkylsulfoxy, Ce-Cio-arylsulfoxy, or a saturated, unsaturated or aromatic heterocyclic ring system of up to 10 atoms, wherein each is optionally substituted once or several times by: bl) Ci-Cό-alkyl, Cs-Cs-cycloalkyl, Ce-Cio-aryl, Cβ-Cio-aryl-Ci-Cs-alkyl, Ci-Ce-alkoxy, Cδ-Cio-aryloxy, Cβ-Cio-aryl-Ci-Cs-alkoxy, Ci-Ce- alkoxycarbonyl, Cβ-Cio-aryloxycarbonyl, Cβ-Cio-aryl-Ci-Cs-alkoxycarbonyl,
Ci-Cβ-alkylcarbonyl, Cβ-Cio-arylcarbonyl, Cδ-Cio-aryl-Ci-Cs-alkylcarbonyl,
Ci-Cβ-alkylcarboxy, Cβ-Cio-arylcarboxy, Ci-Ce-alkylmercaptyl, Cβ-Cio- arylmercaptyl, Ci-Cβ-alkylmercaptocarbonyl, C3-C8- cycloalkylmercaptocarbonyl, Cβ-Cio-arylmercaptocarbonyl, Ci-Ce- alkylmercaptocarboxy, Cβ-Cio-arylmercaptocarboxy, Ci-Ce-alkylsulfonyl,
Cβ-Cio-arylsulfonyl, Ci-Cβ-alkylsulfoxy, C6-Cio-arylsulfoxy; wherein each is optionally substituted once or several times by Ci-Ce-alkyl; Ci-Cβ-alkoxy; CONH2, SO2NH2; CONH2 or SO2NH2 wherein the amino functionality is substituted once or twice with Ci-Ce-alkyl; SChH; CO2H; amino; amino substituted one or more times with residues selected from Ci-Cβ-alkyl, Cδ-Cio-aryl, Cβ-Cio-aryl-Ci-Cό-alkyl, Ci-Ce-alkylcarbonyl, Cβ-Cio- arylcarbonyl, Ci-Cβ-alkylsulfonyl and C6-Cio-arylsulfonyl; thiol; hydroxyl; nitro; cyano; fluoro; chloro; bromo; iodo; CF3; or OCF3; wherein several of the substituents in bl) may be combined to form anellated saturated, unsaturated or aromatic homo- or hetero-ring systems; or by b2) hydroxy; thiol; nitro; cyano; fluoro; chloro; bromo; iodo; CF3; CO2H; SOsH; OCF3; CONH2; SO2NH2; CONH2 or SO2NH2 wherein the amino functionality is substituted once or twice with residues selected from G-Ce- alkyl, Ce-Cio-aryl or Cβ-Cio-aryl-Ci-Ce-alkyl and wherein in the case of a di- Ci-Cβ-alkyl-substituted amino functionality, the alkyl residues may be combined to form 5 or 6-membered rings; amino; amino substituted one or more times with residues selected from G-Ce-alkyl, Cθ-Cio-aryl, Cβ-Cio- aryl-Ci-Cs-alkyl, Ci-Ce-alkylcarbonyl, Ce-Cio-arylcarbonyl, Ci-Ce- alkylsulfonyl and Cβ-Cio-arylsulfonyl; or a disubstituted amino of the following formula (II)
Figure imgf000025_0001
wherein o represents O or 1 and W represents O, CH2, or NR6 with R6 being selected from hydrogen and Ci-Ce-alkyl and wherein the methylene groups in formula (II) may optionally be substituted once or twice with Ci-Cβ-alkyl, fluoro or chloro; or by b3) a saturated, unsaturated or aromatic heterocyclic ring system of up to 10 atoms, optionally substituted once or several times by Ci-Ce-alkyl; Ci-Ce- alkoxy; COOH; SO3H; CONH2, SO2NH2; CONH2 or SO2NH2 wherein the amino functionality is substituted one or more times with residues selected from Ci-Cό-alkyl, Cό-Cio-aryl or Cβ-Cio-aryl-Ci-C-t-alkyl and wherein in case of a di-Ci-Cβ-alkyl-substituted amino functionality the alkyl residues may be combined to form 5 or 6-membered rings; amino; amino substituted one or more times with residues selected from Ci-Cβ-alkyl, Cβ-Cio-aryl, Cβ-Cio- aryl-Ci-C4-alkyl, Ci-Cδ-alkylcarbonyl, Cβ-Cio-arylcarbonyl, Ci-Ce- alkylsulfonyl and Ce-Cio-arylsulfonyl; thiol; hydroxyl; nitro; cyano; fluoro; chloro; bromo; iodo; CF3 or OCF3; c) SO3H; amino; amino substituted one or more tunes with residues selected from
Ci-Cβ-alkyl, Cβ-Cio-aryl, Ce-Cio-aryl-Ci-Cs-alkyl, Ci-Ce-alkylcarbonyl, Cβ-Cio- arylcarbonyl, Ci-Cβ-alkylsulfonyl and Ce-Cio-arylsulfonyl; CONH2; SO2NH2; CONH2 or SO2NH2 wherein the amino functionality is substituted once or twice with residues selected from Ci-Cβ-alkyl, Cβ-Cio-aryl or Cβ-Cio-aryl-Ci-Cβ-alkyl and wherein in the case of a di-Ci-Cβ-alkyl-substituted amino functionality the alkyl residues may be combined to form 5 or 6-membered rings; thiol; hydroxyl; nitro; cyano; fluorosulfonyl; halogen selected from fluoro, chloro, bromo or iodo; CF3; or OCF3; is cyclised to form an oxadiazolone ring system.
It is preferred that the cyclisation step to the oxadiazolone ring system is achieved by phosgene, carbonyldiimidazole, or a carbonic acid ester.
Suitable carbonic acid esters are in particular the Ci-C4-alkyl carbonic acid esters.
Phosgene and carbonyldiimidazole are the most preferred reagents to achieve cyclization.
The compounds according to the invention may be prepared by the following exemplary method of preparation: To an ice-cooled solution of 2-chloro-3-hydrazinylpyridine (0.67 g, 4.67 mmol) and pyridine (1.84 g, 23.33 mmol) in N-methylpyrrolidinone (7 mL) was added cyclohexyl carbonochloridate (0.911 g, 5.60 mmol). The resulting mixture was allowed to stir at room temperature for 1 hour, whereupon it was carefully quenched by the addition of ice and water. The mixture was extracted with ethyl acetate and the organic extracts were over MgSOφ filtered and evaporated to leave an oil. Chromatography over silica gel (petroleum etheπethyl acetate, 3/1) gave cyclohexyl 2-(2-chloropyridin-3- yl)hydrazinecarboxylate as a pale yellow oil (1.22 g).
To an ice cooled solution of cyclohexyl 2-(2-chloropyridin-3- yl)hydrazinecarboxylate (1.2 g, 4.45 mmol) and pyridine (1.887 mL, 23.13 mmol) in dichloromethane (45 mL) was added a 20 % solution of phosgene (5.62 mL, 10.68 mmol) in toluene dropwise. The reaction was allowed to stir in the cooled solution for 15 min and was stirred for additional 45 min at room temperature. Nitrogen was bubbled through the mixture for 30 min and carefully quenched with water. The two phases were separated and the organic layer was washed with 1 N HCl solution and water respectively. The organic phase was dried over MgSC^ , filtered and recrystallized from hot isopropanol to give 3-(2-chloropyridin-3-yl)-5-(cyclohexyloxy)-l,3,4-oxadiazol- 2(3H)-one as a white solid, 408 mg, m.p. 78-79 0C.
Further 5-0-substituted 3-N-heteroaryl-l,3,4-oxadiazolones were prepared in similar fashion according to the reaction scheme outlined above:
Table 1
Figure imgf000028_0001
The compounds were tested according to the following in-vitro protocol:
Frozen brains (without cerebellum) from Wistar rats were used, and each brain was homogenized in 15 ml 1 mM MgCh, 2OnM HEPES pH 7.0 with Potter Elvejhem (8 strokes at 500 rpm). Homogenates were centrifuged for 20 min at 3600Og at 40C (Beckman, 70Ti rotor). Pellets were resuspended in 15 ml of the same buffer and centrifuged under the same conditions. Pellets were resuspended in 15 ml of the same buffer and incubated for 15 min at 370C after which they were centrifuged for 20 min at 36000g at 40C. Each pellet was then resuspended in 15 ml 3 mM MgCb, 1 mM EDTA, 50 mM Tris pH 7.4 and protein determined with BioRad Protein Assay (BioRad) using a standard curve of BSA (50-250 μg/ml). The membrane suspensions were aliquoted and stored at -8O0C.
The FAAH activity was determined using AEA (labelled with 3H in the ethanolamine part of the molecule) as substrate and measuring the 3H-ethanolamine formed. Reaction mix (total volume of 200 μl) contained: 2 μM AEA (2 μM AEA + 5 nM 3H-AEA), 0.1 % fatty acid free BSA, 5 μg protein, in 1 mM EDTA, 10 mM Tris pH 7.6 and 10 μM or 100 mM compounds. Stock solutions of the compounds to test (10 mM) were prepared in 100 % DMSO and the DMSO concentration in the assay was 0.1 % . After a 15 min preincubation period at 370C, reaction was started by the addition of the substrate solution (cold EAE + radiolabeled EAE + BSA). Reaction was carried out for 10 min before termination by the addition of 400 μl activated charcoal suspension (8 g charcoal in 32 ml 0.5 M HCI in continuous agitation). After a 30 min incubation period at room temperature with agitation, charcoal was sedimented by centrifugation in microfuge (10 min at 13000 rpm). 200 μl of the supernatant were added to 800 μl Optiphase Supermix scintillation cocktail previously distributed in 24- well plates. Counts per minute (cpm) were dertermined in Microbeta TriLux scintillation counter (10 min counting or until σ=2).
In each assay blanks (no protein, usually below 200 cpm) and controls (no compound) were present. The results are reported in the following table as % of control after blank subtraction.
Table 2
Figure imgf000030_0001
A selected compound was tested according to the following m-vrrø-protocol.
Animal treatment
The animals used for experiments were male NMRI mice (weighing 27-44 g) obtained from Interfauna Iberica (Spain). Mice were kept 5 per cage, under controlled environmental conditions (12 hr light/dark cycle and room temperature 22+ 10C). Food and tap water were allowed ad libitum and the experiments were all carried out during daylight hours.
Animals were administered 30 mg/kg BIA compounds via oral route (8 mL/kg; compound suspended m 0.5 % carboxymethylcellulose (CMC) or solubilized in water) or 8ml/kg 0.5 % CMC (controls) using animal feeding stainless steel curve needles (Perfectum, U.S.A.). Fifteen minutes before sacrifice animal were anesthetized with pentobarbital 60 mg/kg administered intraperitoneally. A fragment of liver, left lung lobe and brain without cerebellum were removed and put in plastic vials containing membrane buffer (3 niM MgCh, 1 mM EDTA, 50 mM Tris HCl pH 7.4). Tissues were stored at -3O0C until analysis. Animals were fasted overnight before administration of compounds except for time periods of > 18h, where food was removed on the morning of the day of administration and the compound was administered in the afternoon of the same day. Animals were then given water but nothing else.
All animal procedures were conducted in the strict adherence to the European
Directive for Protection of Vertebrate Animals Used for Experimental and Other
Scientific Purposes (86/609CEE) and Portuguese legislation (Decreto-Lei 129/92,
Portarias 1005/92 e 1131/97). The number of animals used was the minimum possible in compliance with current regulations and scientific integrity.
Reagents and Solutions
Anandamide [ethanolamine -1-3H-] (40-60Ci/mmol) was obtained from American Radiochemicals. All other reagents were obtained from Sigma- Aldrich. Optiphase Supermix was obtained from Perkin Elmer and activated charcoal were obtained from Sigma- Aldrich.
Tissue Preparation
Tissues were thawed on ice and were homogenized in 10 volumes of membrane buffer (3 mM MgCh, 1 mM EDTA, 50 mM Tris HCl pH 7.4) with either Potter- Elvejhem (brains - 8 strokes at 500 rpm) or Heidolph Diax (livers - 2 strokes at position 5 for 20 sec with 30 sec pauses).
Total protein in tissues was determined with the BioRad Protein Assay (BioRad) using a standard curve of BSA (50-250 μg/ml). Enzymatic assay
Reaction mix (total volume of 200 μl) contained: 2 μM AEA (2 μM AEA + 5 nM 3H-AEA), 0.1 % fatty acid free BSA, 15 μg (brain), 5 μg (liver) or 50 μg (lung) protein, in 1 mM EDTA, 10 mM Tris pH 7.6. After a 15 min pre-incubation period at 370C, reaction was started by the addition of the substrate solution (cold AEA + radiolabeled AEA + BSA). Reaction was carried out for 10 min (brain and lung) or 7 min (liver) before termination by the addition of 400 μl activated charcoal suspension (8 g charcoal in 32 mL 0.5 M HCl in continuous agitation). After a 30 min incubation period at room temperature with agitation, charcoal was sedimented by centrifugation in microfuge (10 min at 13000 rpm). 200 μl of the supernatant were added to 800 μl Optiphase Supermix scintillation cocktail previously distributed in 24-well plates. Counts per minute (cpm) were determined in a MicrobetaTriLux scintillation counter.
In each assay blanks (without protein) were prepared.
The percentage of remaining enzymatic activity was calculated with respect to controls (no compound) and after blank subtraction.
The following results were obtained:
Table 3
Figure imgf000032_0001
In alternative embodiments, A in formulae (I) and (III) is not substituted with
B-L-G wherein B represents a single bond, CH2, O, S or NR1, wherein R1 is selected from hydrogen or a Ci-Cβ-alkyl group;
L represents a linker selected from:
a) -(CEb)P-, wherein p is 1,2,3,4,5,6,7 or 8, b) -(C=O)- Or -O-(C=O)- , c) -(SO2)- or -0-(SO2)- , d) phenylene, cyclohexanylene or cyclopentanylene
wherein several of a) to d) may be used in combination and wherein a) and d) may be optionally substituted once or several times by Ci-Cβ-alkyl, Ci-Cβ- alkoxy, CO2H, SO3H, amino, Ci-Ce-alkylamino, di-Ci-Cό-alkylamino, thiol, hydroxy, nitro, cyano, fluoro, chloro, bromo, iodo, CF3 or OCF3; and
G represents a) NR2R3, wherein R2 and R3 independently from each other represent hydrogen; Ci-Cβ-alkyl, Cs-Cs-cycloalkyl, Cβ-Cio-aryl, aromatic heterocyclic ring system of up to 10 atoms, Cβ-Cio-aryl-d-Cδ-alkyl, Ci-Cβ-alkoxycarbonyl, Cβ-Cio-aryloxycarbonyl, Cβ-Cio-aryl-Ci-Cs-alkoxycarbonyl, Ci-Ce- alkylcarbonyl, Cβ-Cio-arylcarbonyl, Cδ-Cio-aryl-Ci-Cs-alkylcarbonyl, Ci-Cβ- alkyhnercaptocarbonyl, C3-C8-cycloalkylmercaptocarbonyl, Cβ-Cio- aryhnercaptocarbonyl, Ci-Cβ-alkylsulfonyl, or Cβ-Cio-arylsulfonyl, each of which is optionally substituted once or several times by Ci-Cδ-alkyl, Ci-Ce- alkoxy, Ce-Cio-aryloxy, CO2H, SO3H, amino, Ci-Ce-alkylamino, di-Ci-Cβ- alkylamino, thiol, hydroxyl, nitro, cyano, fluoro, chloro, bromo, iodo, CF3 or OCF3; and wherein one of R2 and R3 may be annelated to B or L to form a 5- or 6-membered ring; or b) NR4R5, wherein R4 and R5 form a saturated, unsaturated or aromatic homo- or hetero-cyclic ring system of up to 10 atoms, which is optionally substituted once or several times by Ci-Ce-alkyl, Ci-Ce-alkoxy, Ce-Cio-aryloxy, CO2H, SCbH, amino, Ci-Cδ-alkylamino, di-Ci-Ce-alkylamino, thiol, hydroxyl, nitro, cyano, fluoro, chloro, bromo, iodo, CF3 or OCF3; or c) a disubstituted amino of the following formula (II)
Figure imgf000034_0001
wherein o represents 0 or 1 and W represents O, CH2, or NR6 with R6 being selected from hydrogen, Ci-Cβ-alkyl, Cβ-Cio-aryl, and Cδ-Cio-aryl-Ci-Ce-alkyl, and wherein the methylene groups in formula (II) may optionally be substituted once or twice with Ci-Cβ-alkyl, fluoro or chloro;
or d) a guanidine or amidine residue, wherein said residue may optionally be substitued once or several times with Ci-Cβ-alkyl, Ce-Cio-aryl or Ce-Cio-aryl-
G-C4-alkyl, wherein these optional substituents may be combined to form 5- or 6-membered saturated, unsaturated or aromatic rings, or an isomer of said guanidine or amidine residue.
In alternative embodiments, the compound of formula I is not:5-(benzyloxy)-3-(5-
(trifluoromethyl)pyridin-2-yl)-l,3,4-oxadiazol-2(3H)-one, 5-phenoxy-3-(5-
(trifluoromethyl)pyridin-2-yl)-l ,3 ,4-oxadiazol-2(3H)-one,
5-(benzyloxy)-3-(pyridin-2-yl)-l ,3 ,4-oxadiazol-2(3H)-one,
3-(benzo[d]thiazol-2-yl)-5-(benzyloxy)-l,3,4-oxadiazol-2(3H)-one, 3-(benzo[d]thiazol-2-yl)-5-phenoxy-l ,3 ,4-oxadiazol-2(3H)-one,
3-(benzo[d]oxazol-2-yl)-5-(benzyloxy)-l,3,4-oxadiazol-2(3H)-one,
3-(benzo[d]oxazol-2-yl)-5-phenoxy-l ,3 ,4-oxadiazol-2(3H)-one,
5-(benzyloxy)-3-(6-chloropyridazin-3-yl)-l,3,4-oxadiazol-2(3H)-one,
3-(5-bromopyridin-2-yl)-5-phenoxy-l,3,4-oxadiazol-2(3H)-one, 3-(6-chloropyridin-3-yl)-5-(4-methoxyphenoxy)-l ,3 ,4-oxadiazol-2(3H)-one, 3-(6-chloropyridin-3-yl)-5-(4-hydroxyphenoxy)-l,3,4-oxadiazol-2(3H)-one, 3-(2-chloropyridin-3-yl)-5-(4-methoxyphenoxy)-l,3,4-oxadiazol-2(3H)-one hydrochloride, or 3-(2-chloropyridin-3-yl)-5-(cyclohexyloxy)-l ,3 ,4-oxadiazol-2(3H)-one.

Claims

1. Compound of formula (I) ,
Figure imgf000036_0001
(D, wherein
A represents a 5- or 6-membered heteroaromatic ring system containing up to 4 heteroatoms selected from O, S and N, which is optionally substituted once or several times by: hydrogen;
Ci-Ce-alkyl, C3-Cs-cycloalkyl, Cβ-Cio-aryl, Ce-Cio-aryl-Ci-Cs-alkyl, Ci-Ce-alkoxy, Cδ-Go-aryloxy, Cβ-Cio-aryl-Ci-Cs-alkoxy, Ci-Cβ-alkoxycarbonyl, Cβ-Cio-aryloxy- carbonyl, Cβ-Cio-aryl-Ci-Cs-alkoxycarbonyl, Ci-Ce-alkylcarbonyl, Cβ-Cio-aryl- carbonyl, Ce-Cio-aryl-Ci-Cs-alkylcarbonyl, Ci-Cβ-alkylcarboxy, Ce-Cio-aryl- carboxy, Ci-Cβ-alkylmercaptyl, Cβ-Cio-arylmercaptyl, Ci-Cβ-alkylmercapto- carbonyl, C3-C8-cycloalkyhnercaptocarbonyl, Cδ-Cio-aryhnercaptocarbonyl, Ci-Ce-alkylmercaptocarboxy, Ce-Cio-arylmercaptocarboxy, Ci-Ce-alkylsulfonyl, Ce-Cio-arylsulfonyl, Ci-Cβ-alkylsulfoxy, Ce-Cio-arylsulfoxy, wherein each is optionally substituted once or several times by
Ci-Ce-alkyl; Ci-Ce-alkoxy; Cβ-Cio-aryloxy; CO2H; SO3H; CONH2; SO2NH2; CONH2 or SO2NH2 wherein the amino functionality is substituted one or more times with residues selected from Ci-Cβ-alkyl, Ce-Cio-aryl or C6-Cio-aryl-Ci-C4-alkyl and wherein in case of a di-Ci-Cβ-alkyl-substituted amino functionality the alkyl residues may be combined to form 5 or 6-membered rings; amino; amino substituted one or more times with residues selected from Ci-Cδ-alkyl, Cβ-Cio-aryl, C6-Cio-aryl-Ci-C4-alkyl, Ci-Cδ-alkylcarbonyl, Cβ-Cio-arylcarbonyl, Ci-Cβ-alkylsulfonyl and Cβ-Cio- arylsulfonyl; thiol; hydroxyl; nitro; cyano; fluoro; chloro; bromo; iodo; CFs or OCFs;
CO2H; SO3H; amino; amino substituted one or more times with residues selected from Ci-Cβ-alkyl,
Cβ-Cio-aryl, Cό-Cio-aryl-Ci-Cβ-alkyl, Ci-Cβ-alkylcarbonyl, Cβ-Cio-arylcarbonyl,
Ci-Cβ-alkylsulfonyl and Cβ-Cio-arylsulfonyl; a disubstituted amino of the following formula (II)
Figure imgf000037_0001
wherein o represents 0 or 1 and W represents O, CH2, or NR6 with R6 being selected from hydrogen and Ci-Cβ-alkyl and wherein the methylene groups in formula (II) may optionally be substituted once or twice with Ci-Ce-alkyl, fluoro or chloro;
Figure imgf000037_0002
CONH2 or SO2NH2 wherein the amino functionality is substituted once or twice with residues selected from Ci-Ce-alkyl, Ce-Cio-aryl or Cδ-Cio-aryl-Ci-Cδ-alkyl and wherein in the case of a di-Ci-Cβ-alkyl-substituted amino functionality the alkyl residues may be combined to form 5 or 6-membered rings; thiol; hydroxyl; nitro; cyano; fluorosulfonyl; halogen selected from fluoro, chloro, bromo or iodo; CF3; oxo;
OCFs; or a saturated, unsaturated or aromatic heterocyclic ring system of up to 10 atoms, optionally substituted once or several times by Ci-Cβ-alkyl; Ci-Cβ-alkoxy; COOH; SOsH; CONH* SO2NH2; CONH2 or
SO2NH2 wherein the amino functionality is substituted one or more times with residues selected from Ci-Cβ-alkyl, Cδ-Cio-aryl or Ce-Cio-aryl-Ci-Gt- alkyl and wherein in case of a di-Ci-Cό-alkyl-substituted amino functionality the alkyl residues may be combined to form 5 or 6-membered rings; amino; amino substituted one or more times with residues selected from Ci-Cβ-alkyl, Ce-Cio-aryl, C6-Cio-aryl-Ci-C4-alkyl, Ci-Ce- alkylcarbonyl, Ce-Cio-arylcarbonyl, Ci-Cό-alkylsulfonyl and Cβ-Cio- arylsulfonyl; thiol; hydroxyl; nitro; cyano; fluoro; chloro; bromo; iodo; CFs or OCF3; and wherein any two or more substituents of A may be combined to form anellated saturated, unsaturated or aromatic homo- or heterocyclic ring systems;
n represents O or 1; m represents O, 1, 2, 3, 4, 5 or 6;
X represents O or S;
Y represents: a) hydrogen; b) Ci-Ciβ-alkyl, mono or polyunsaturated C2-Ci8-alkylene, C3-Cs-Cy cloalkyl, Cδ-Cio-aryl, Cβ-Cio-aryl-Ci-Cs-alkyl, Ci-Cβ-alkoxy, Ce-Cio-aryloxy, Cβ-Go-aryl-
Ci-Cs-alkoxy, Ci-Cβ-alkoxycarbonyl, Ce-Cio-aryloxycarbonyl, Cβ-Cio-aryl-Ci-Cβ- alkoxycarbonyl, Ci-Ce-alkylcarbonyl, Cβ-Cio-arylcarbonyl, Cβ-Cio-aryl-Ci-Cs- alkylcarbonyl, Ci-Cβ-alkylcarboxy, Cό-Cio-arylcarboxy, Ci-Cό-alkylmercaptyl, Cό-Cio-arylmercaptyl, Ci-Cό-alkylmercaptocarbonyl, C3-Cs- cycloalkylmercaptocarbonyl, Cβ-Cio-arylmercaptocarbonyl, Ci-Cβ- alkylmercaptocarboxy, Cδ-Cio-arylmercaptocarboxy, Ci-Cβ-alkylsulfonyl, Cβ-Cio- arylsulfonyl, Ci-Cβ-alkylsulfoxy, Cθ-Cio-arylsulfoxy, or a saturated, unsaturated or aromatic heterocyclic ring system of up to 10 atoms, wherein each is optionally substituted once or several times by: bl) Ci-Cβ-alkyl, Cs-Cs-cycloalkyl, Ce-Cio-aryl, Cβ-Cio-aryl-Ci-Cs-alkyl, Ci-Ce-alkoxy, Ce-Cio-aryloxy, Ce-Cio-aryl-Ci-Cs-alkoxy, Ci-Ce- alkoxycarbonyl, Cβ-Cio-aryloxycarbonyl, Cβ-Cio-aryl-Ci-Cs- alkoxycarbonyl, Ci-Cβ-alkylcarbonyl, Cβ-Cio-arylcarbonyl, Cβ-Cio-aryl-Ci- Cδ-alkylcarbonyl, Ci-Cδ-alkylcarboxy, Cβ-Cio-arylcarboxy, Ci-Ce- alkyhnercaptyl, Cβ-Cio-arylmercaptyl, Ci-Ce-alkylmercaptocarbonyl, C3-C8-cycloalkylmercaptocarbonyl, Cβ-Cio-aryhnercaptocarbonyl, Ci-Cβ- alkylmercaptocarboxy, Cβ-Cio-arylmercaptocarboxy, Ci-Cβ-alkylsulfonyl,
Cβ-Cio-arylsulfonyl, Ci-Cβ-alkylsulfoxy, Cβ-Cio-arylsulfoxy; wherein each is optionally substituted once or several times by Ci-Cβ-alkyl; Ci-Cβ- alkoxy; CONH2, SO2NH2; CONH2 or SO2NH2 wherein the amino functionality is substituted once or twice with d-Cβ-alkyl; SO3H; CO2H; amino; amino substituted one or more times with residues selected from
Ci-Cβ-alkyl, Cβ-Cio-aryl, Cβ-Cio-aryl-Ci-Ce-alkyl, Ci-Cβ-alkylcarbonyl, Cβ-Cio-arylcarbonyl, Ci-Cβ-alkylsulfonyl and Ce-Cio-arylsulfonyl; thiol; hydroxyl; nitro; cyano; fluoro; chloro; bromo; iodo; CF3; or OCF3; wherem several of the substituents in bl) may be combined to form anellated saturated, unsaturated or aromatic homo- or heterocyclic ring systems; or by b2) hydroxy; thiol; nitro; cyano; fluoro; chloro; bromo; iodo; CF3; CO2H; SO3H; OCF3; CONH2; SO2NH2; CONH2 or SO2NH2 wherein the amino functionality is substituted once or twice with residues selected from
Ci-Ce-alkyl, Ce-Cio-aryl or Cβ-Cio-aryl-Ci-Cό-alkyl and wherein in the case of a di-Ci-C6-alkyl-substituted amino functionality, the alkyl residues may be combined to form 5 or 6-membered rings; amino; amino substituted one or more times with residues selected from Ci-C6-alkyl, Ce-Cio-aryl, Ce-Cio-aryl-Ci-Cs-alkyl, Ci-Ce-alkylcarbonyl, Cβ-Cio-arylcarbonyl, Ci-Cβ- alkylsulfonyl and Ce-Cio-arylsulfonyl; or a disubstituted amino of the following formula (II)
Figure imgf000040_0001
wherein o represents O or 1 and W represents O, CEh, or NR6 with R6 being selected from hydrogen and Ci-Cβ-alkyl and wherein the methylene groups in formula (II) may optionally be substituted once or twice with Ci-Cβ-alkyl, fluoro or chloro; or by b3) a saturated, unsaturated or aromatic heterocyclic ring system of up to 10 atoms, optionally substituted once or several times by Ci-Cβ-alkyl;
Ci-C6-alkoxy; COOH; SOsH; CONH2; SO2NH2; CONH2 or SO2NH2 wherein the amino functionality is substituted one or more times with residues selected from Ci-Cβ-alkyl, Cβ-Cio-aryl or
Figure imgf000040_0002
and wherein in case of a di-Ci-Cβ-alkyl-substituted amino functionality the alkyl residues may be combined to form 5 or 6-membered rings; amino; amino substituted one or more times with residues selected from Ci-Cβ- alkyl, Ce-Cio-aryl, C6-Cio-aryl-Ci-C4-alkyl, Ci-Ce-alkylcarbonyl, Cβ-Cio- arylcarbonyl, Ci-Cβ-alkylsulfonyl and Cβ-Cio-arylsulfonyl; thiol; hydroxyl; nitro; cyano; fluoro; chloro; bromo; iodo; CF3 or OCF3; c) SO3H; amino; amino substituted one or more times with residues selected from
Ci-Cδ-alkyl, Ce-Cio-aryl, Ce-Cio-aryl-Ci-Cs-alkyl, Ci-Cβ-alkylcarbonyl, Ce-Cio- arylcarbonyl, Ci-Cβ-alkylsulfonyl and Ce-Cio-arylsulfonyl; CONH2; SO2NH2;
CONH2 or SO2NH2 wherein the ammo functionality is substituted once or twice with residues selected from Ci-Ce-alkyl, Ce-Cio-aryl or Cβ-Cio-aryl-Ci-Cβ-alkyl and wherein in the case of a di-Ci-Cβ-alkyl-substituted amino functionality the alkyl residues may be combined to form 5 or 6-membered rings; thiol; hydroxyl; nitro; cyano; fluorosulfonyl; halogen selected from fluoro, chloro, bromo or iodo;
CF3; or OCF3;
or a stereoisomer, pharmaceutically acceptable salt or ester, or prodrug thereof.
2. Compound according to claim 1 wherein A is substituted once or several times with hydrogen; hydroxyl;
Ci-Ce-alkyl, Cβ-Cio-aryl, G-Cβ-alkoxy, Cβ-Cio-aryloxy, Cβ-Cio-aryl-Ci-Ce-alkoxy,
Ci-Cβ-alkylcarboxy, Ce-Cio-arylcarboxy, Ci-Cβ-alkylsulfonyl, Ce-Cio-arylsulfonyl, wherein each is optionally substituted once or several times by Ci-Cβ-alkyl, Ci-Cδ- alkoxy, amino, Ci-Cβ-alkylamino, di-Ci-Ce-alkylamino, hydroxy, fluoro, chloro, bromo, cyano, CF3 or OCF3; amino; amino substituted one or more times with residues selected from Ci-Cβ-alkyl,
Figure imgf000041_0001
1-pyrrolyl, 2-pyrrolyl or 3-pyrrolyl, optionally substituted with one or more residues selected from Ci-Ce-alkyl, amino, fluoro, chloro or CF3; or a disubstituted amino of the following formula (II)
Figure imgf000041_0002
wherein o represents 0 or 1 and W represents O, CHb, or NR6 with R6 being selected from hydrogen and Ci-Cβ-alkyl and wherein the methylene groups in formula (II) may optionally be substituted once or twice with Ci-Cθ-alkyl, fluoro or chloro; CONH2;
CONH2 or SO2NH2 wherein the amino functionality is substituted once or twice with residues selected from Ci-Cβ-alkyl or Cβ-Cio-aryl; fluoro; chloro; bromo; CF3; or OCF3.
3. Compound according to claim 1 or 2 wherein A is substituted once or several times with hydrogen, fluorine or chlorine.
4. Compound according to claim 3 wherein A is substituted in the ortho-position to the oxadiazolinone ring with hydrogen or fluorine.
5. Compound according to any one of claims 1 to 4 wherein A is substituted once or several times with: hydroxy; or
Ci-Cβ-alkoxy, Ce-Cio-aryloxy, Cβ-Cio-aryl-Ci-Cβ-alkoxy, Ci-Ce-alkylcarboxy,
Ce-Cio-arylcarboxy, Ci-Cβ-alkylsulfonyl, Ce-Cio-arylsulfonyl, wherein each is optionally substituted once or several times by Ci-Cβ-alkyl, Ci-Cβ-alkoxy, amino,
Ci-Ce-alkylamino, di-Ci-Cβ-alkylamino, CONH2 or SO2NH2 optionally substituted once or twice with Ci-Cβ-alkyl or Cβ-Cio-aryl, hydroxy, fluoro, chloro, bromo, cyano, CF3 or OCF3.
6. Compound according to claim 5 wherein A is in the meta- and/or para-position(s) to the oxadiazolinone ring substituted once or several times with: hydroxy; or
Ci-Cθ-alkoxy, Ce-Cio-aryloxy, or Cβ-Cio-aryl-Ci-Ce-alkoxy, each of which is optionally substituted once or several times by Ci-Ce-alkyl, Ci-Cδ-alkoxy, amino, Ci-Ce-alkylamino, di-Ci-Cβ-alkylamino, CONH2 or SO2NH2 optionally substituted once or twice with Ci-Ce-alkyl or Cβ-Cio-aryl, hydroxy, fluoro, chloro, or bromo.
7. Compound according to any one of claims 1 to 6 wherein A is substituted once or several times with: amino; amino substituted one or more times with residues selected from Ci-Cβ-alkyl, Cβ- Cio-aryl; or a disubstituted amino of the following formula (II)
Figure imgf000043_0001
wherein o represents 0 or 1 and W represents O, CEb, or NR6 with R6 being selected from hydrogen and Ci-Cβ-alkyl and wherein the methylene groups in formula (II) may optionally be substituted once or twice with Ci-Cθ-alkyl, fluoro or chloro.
8. Compound according to claim 7 wherein A is is in the meta- and/or para- position(s) to the oxadiazolinone ring substituted once or several times with: ammo; amino substituted once or twice with residues selected from Ci-Cδ-alkyl, Ce-Cio- aryl; or a disubstituted amino of the following formula (II)
Figure imgf000043_0002
wherein o represents 0 or 1 and W represents O, CH2, or NR6 with R6 being selected from hydrogen and Ci-Cβ-alkyl and wherein the methylene groups in formula (II) may optionally be substituted once or twice with Ci-Cβ-alkyl, fluoro or chloro.
9. Compound according to any one of claims 1 to 8 wherein n represents 0; m represents 0, 1, 2, 3, 4, 5 or 6; and Y represents C3-Cδ-cycloalkyl or Cβ-Cio-aryl, each of which is optionally substituted once or several times by: a) Ci-Ce-alkyl, Cβ-Cio-aryl, C6-Cio-aryl-Ci-C4-alkyl, Ci-Ce-alkoxy, Cβ-Cio- aryloxy, Cβ-Go-aryl-Ci-C't-alkoxy, wherein each is optionally substituted once or several times by:
Ci-Oalkyl; Ci-Ce-alkoxy; COOH; CONH2; SO2NH2; CONH2 or SO2NH2 substituted once or twice with Ci-Cβ-alkyl or Cβ-Cio- aryl; SO3H; amino; amino substituted one or more times with residues selected from Ci-Cβ-alkyl, Cβ-Cio-aryl, Cβ-Cio-aryl-Ci- C4-alkyl, Ci-Cβ-alkylcarbonyl, Cβ-Cio-arylcarbonyl, Ci-Ce- alkylsulfonyl and Cβ-Cio-arylsulfonyl; thiol; hydroxyl; nitro; cyano; fluoro; chloro; bromo; iodo; CF3 or OCF3;
or by
b) hydroxy; thiol; nitro; cyano; fluoro; chloro; bromo; iodo; CF3; OCF3;
CO2H; SOsH; CONH2; SO2NH2; CONH2 or SO2NH2 wherein the amino functionality is substituted one or more times with residues selected from Ci-Ce-alkyl, Ce-Cio-aryl or Cβ-Cio-aryl-Ci-Gi-alkyl and wherein in case of a di-Ci-Cθ-alkyl-substituted amino functionality the alkyl residues may be combined to form 5 or 6-membered rings; amino; amino substituted once or several times with Ci-Cβ-alkyl or phenyl; a disubstituted amino of the following formula (II)
Figure imgf000044_0001
wherein o represents O or 1 and W represents O, CH2, or NR6 with R6 being selected from hydrogen and Ci-C4-alkyl and wherein the methylene groups in formula (II) may optionally be substituted once or twice with Ci- C4-alkyl, fluoro or chloro; or by
c) a saturated, unsaturated or aromatic heterocyclic ring system of up to 10 atoms, optionally substituted once or several times by
Ci-Cfr-alkyl; Ci-Cβ-alkoxy; COOH; CONH2; SO2NH2; CONH2 or SO2NH2 substituted once or twice with Ci-Cβ-alkyl or Cβ-Cio- aryl; SO3H; amino; amino substituted one or more times with residues selected from d-Cθ-alkyl, Cβ-Cio-aryl, Cβ-Cio-aryl-Ci- C4-alkyl, Ci-Ce-alkylcarbonyl, Ce-Cio-arylcarbonyl, Ci-Ce- alkylsulfonyl and Ce-Cio-arylsulfonyl; thiol; hydroxyl; nitro; cyano; fluoro; chloro; bromo; iodo; CF3 or OCF3.
10. Compound according to claim 9 wherein n represents 0; m represents 0 or 1; and Y represents a phenyl, 1-naphthyl, 2-naphthyl, 2-pyridinyl, 3-pyridinyl, or
4-pyridinyl ring system.
11. Compound according to claim 10 wherein Y is substituted once or several times by Ci-Cδ-alkyl; phenyl; Ci-Cβ-alkoxy; hydroxy; fluoro; chloro; bromo; CF3; OCF3; amino; or CONH2 or SO2NH2 optionally substituted once or twice with
Ci-Cβ-alkyl wherein these optional Ci-Cβ-alkyl residues may be combined to form 5 or 6-membered rings.
12. Compound according to claim 11 wherein m represents 0 and Y represents phenyl which is substituted once or twice by hydroxy, fluoro, chloro or bromo.
13. Compound according to claim 11 wherein m represents 0 and Y represents phenyl which is substituted in the 4-position by fluoro or by chloro, in the 2- and 4-position by fluoro, in the 2- and 4-position by chloro, or in the 4-position by phenyl.
14. Compound according to claim 1 wherein m is 0; n is 0; Y represents phenyl substituted once or twice by fluoro, chloro or bromo; and A is substituted in the meta- or para-position to the oxadiazolone ring with OR7 wherein R7 is selected from hydrogen and Ci-Cβ-alkyl.
15. Compound according to claim 14 wherein Y represents phenyl which is substituted in the 4-position by fluoro or by chloro, in the 2- and 4-position by fluoro, or in the 2- and 4-position by chloro.
16. Compound according to claim 14 or 15 wherein A is substituted in the para- position to the oxadiazolone ring with hydrogen or fluorine.
17. Compound according to any one of claims 14 to 16 wherein A is substituted in the meta- or para-position or in the meta- and para-position with hydroxy.
18. Compound according to any one of claims 1 to 17 wherein A is a heterocycle comprising one, two, three or four nitrogen atoms.
19. Compound according to any one of claims 1 to 18 wherein A is a heterocycle comprising one or two nitrogen atoms.
20. Compound according to any one of claims 1 to 19 wherein A is a heterocycle comprising one or two oxygen atoms.
21. Compound according to any one of claims 1 to 20 wherein A is 2-pyridyl, 3-pyridyl or 4-pyridyl.
22. Compound according to any one of claims 1 to 21 for the inhibition of FAAH.
23. Compound as claimed in any of claims 1 to 22 for treatment of a disorder that is positively influenced by inhibition of FAAH.
24. Compound as claimed in claim 23 wherein the disorder is selected from pain, dizziness, vomiting, and nausea, eating disorders, neurological and psychiatric pathologies, acute and chronic neurodegenerative diseases, epilepsy, sleep disorders, cardiovascular diseases, cancers, disorders of the immune system, parasitic, viral or bacterial infectious diseases, inflammatory diseases, osteoporosis, eye conditions, pulmonary conditions and gastrointestinal diseases.
25. Compound according to any one of claims 1 to 24 with the proviso that A is not substituted with B-L-G wherein
B represents a single bond, CH2, O, S or NR1, wherein R1 is selected from hydrogen or a Ci-Cδ-alkyl group;
L represents a linker selected from:
a. -(CEb)P-, wherein p is 1,2,3,4,5,6,7 or 8, b. -(C=O)- Or -O-(C=O)- , c. -(SO2)- or -0-(SO2)- , d. phenylene, cyclohexanylene or cyclopentanylene
wherein several of a) to d) may be used in combination and wherein a) and d) may be optionally substituted once or several times by Ci-Cβ-alkyl, CI-CO- alkoxy, CO2H, SO3H, ammo, Ci-Ce-alkylamino, di-Ci-Cβ-alkylamino, thiol, hydroxy, nitro, cyano, fluoro, chloro, bromo, iodo, CF3 or OCF3; and
G represents
a) NR2R3, wherein R2 and R3 independently from each other represent hydrogen; Ci-Ce-alkyl, C3-Cs-cycloalkyl, Ce-Cio-aryl, aromatic heterocyclic ring system of up to 10 atoms, Ce-Cio-aryl-Ci-Ce-alkyl, Ci-Ce- alkoxycarbonyl, Cβ-Cio-aryloxycarbonyl, Cδ-Cio-aryl-Ci-Cs-alkoxycarbonyl, Ci-Ce-alkylcarbonyl, Cβ-Cio-arylcarbonyl, Ce-Cio-aryl-Ci-Cs-alkylcarbonyl, Ci-Cδ-alkylmercaptocarbonyl, C3-C8-cycloalkylmercaptocarbonyl, Cβ-Cio- arylmercaptocarbonyl, Ci-Ce-alkylsulfonyl, or Ce-Cio-arylsulfonyl, each of which is optionally substituted once or several times by Ci-Ce-alkyl, Ci-Cδ- alkoxy, Ce-Cio-aryloxy, CO2H, SO3H, amino, Ci-Cβ-alkylamino, di-Ci-Cβ- alkylamino, thiol, hydroxyl, nitro, cyano, fluoro, chloro, bromo, iodo, CF3 or OCF3; and wherein one of R2 and R3 may be annelated to B or L to form a 5- or 6-membered ring; or
b) NR4R5, wherein R4 and R5 form a saturated, unsaturated or aromatic homo- or heterocyclic ring system of up to 10 atoms, which is optionally substituted once or several times by Ci-Ce-alkyl, Ci-Cβ-alkoxy, Cβ-Cio- aryloxy, CO2H, SO3H, amino, Ci-Cβ-alkylamino, di-Ci-Cβ-alkylamino, thiol, hydroxyl, nitro, cyano, fluoro, chloro, bromo, iodo, CF3 or OCF3; or
c) a disubstituted amino of the following formula (II)
Figure imgf000048_0001
wherein o represents 0 or 1 and W represents O, CEb, or NR6 with R6 being selected from hydrogen, Ci-Cβ-alkyl, Cό-Cio-aryl, and Cβ-Cio-aryl-Ci-Ce- alkyl, and wherein the methylene groups in formula (II) may optionally be substituted once or twice with Ci-Cδ-alkyl, fluoro or chloro;
or
d) a guanidine or amidine residue, wherein said residue may optionally be substitued once or several tunes with Ci-Cβ-alkyl, C6-Cio-aryl or Cδ-Cio-aryl- Ci-C4-alkyl, wherein these optional substituents may be combined to form 5- or 6-membered saturated, unsaturated or aromatic rings, or an isomer of said guanidine or amidine residue.
26. Compound according to any one of claims 1 to 24 with the proviso that the 5 compound of formula I is not:
5-(benzyloxy)-3-(5-(trifluoromethyl)pyridin-2-yl)-l,3,4-oxadiazol-2(3H)-one, 5-ρhenoxy-3-(5-(trifluoromethyl)pyridin-2-yl)-l,3,4-oxadiazol-2(3H)-one, 5-(benzyloxy)-3-(pyridin-2-yl)-l,3,4-oxadiazol-2(3H)-one, 3-(benzo[d]thiazol-2-yl)-5-(benzyloxy)-l,3,4-oxadiazol-2(3H)-one, o 3-(benzo[d]thiazol-2-yl)-5-phenoxy-l ,3 ,4-oxadiazol-2(3H)-one,
3-(benzo[d]oxazol-2-yl)-5-(benzyloxy)-l,3,4-oxadiazol-2(3H)-one, 3-(benzo[d]oxazol-2-yl)-5-phenoxy-l ,3 ,4-oxadiazol-2(3H)-one, 5-(benzyloxy)-3-(6-chloropyridazin-3-yl)-l,3,4-oxadiazol-2(3H)-one, 3-(5-bromopyridin-2-yl)-5-phenoxy-l ,3 ,4-oxadiazol-2(3H)-one, 5 3-(6-chloropyridin-3-yl)-5-(4-methoxyphenoxy)-l,3,4-oxadiazol-2(3H)-one,
3-(6-chloropyridin-3-yl)-5-(4-hydroxyphenoxy)-l,3,4-oxadiazol-2(3H)-one, 3-(2-chloropyridin-3-yl)-5-(4-methoxyphenoxy)-l,3,4-oxadiazol-2(3H)-one hydrochloride, or 0 3-(2-chloropyridin-3-yl)-5-(cyclohexyloxy)-l ,3 ,4-oxadiazol-2(3H)-one..
27. Use of a compound as claimed in any of claims 1 to 26 for inhibition of FAAH.
28. Use of a compound as claimed in any of claims 1 to 26 for treatment of a disorder5 that is positively influenced by inhibition of FAAH.
29. Use of a compound as claimed in any of claims 1 to 26 for manufacture of a medicament for the treatment of a disorder that is positively influenced by inhibition of FAAH. 0
30. Use as claimed in claim 28 or 29 wherein the disorder is selected from pain, dizziness, vomiting, and nausea, eating disorders, neurological and psychiatric pathologies, acute and chronic neurodegenerative diseases, epilepsy, sleep disorders, cardiovascular diseases, cancers, disorders of the immune system, parasitic, viral or bacterial infectious diseases, inflammatory diseases, osteoporosis, eye conditions, pulmonary conditions and gastrointestinal diseases.
31. Process for the preparation of a compound according to any one of claims 1 to 26 wherein a compound of formula (III),
Figure imgf000050_0001
(in),
wherein
A represents a 5- or 6-membered heteroaromatic ring system containing up to 4 heteroatoms selected from O, S and N, which is optionally substituted once or several times by: hydrogen;
Ci-Cδ-alkyl, C3-Cs-cycloalkyl, Cβ-Cio-aryl, Ce-Cio-aryl-Ci-Cs-alkyl, Ci-Cβ-alkoxy, Cδ-Cio-aryloxy, Cβ-Cio-aryl-Ci-Cs-alkoxy, Ci-Cδ-alkoxycarbonyl, Cβ-Cio-aryloxy- carbonyl, Cβ-Cio-aryl-Ci-Cs-alkoxycarbonyl, Ci-Cβ-alkylcarbonyl, Cδ-Cio-aryl- carbonyl, Cβ-Cio-aryl-Ci-Cs-alkylcarbonyl, Ci-Cβ-alkylcarboxy, Cβ-Cio-aryl- carboxy, Ci-Cβ-alkylmercaptyl, Cβ-Cio-arylmercaptyl, Ci-C6-alkylmercapto- carbonyl, C3-C8-cycloalkylmercaptocarbonyl, Cβ-Cio-arylmercaptocarbonyl, Ci-Cβ-alkylmercaptocarboxy, Cβ-Cio-arylmercaptocarboxy, Ci-Ce-alkylsulfonyl, Cβ-Cio-arylsulfonyl, Ci-Ce-alkylsulfoxy, Ce-Cio-arylsulfoxy, wherein each is optionally substituted once or several times by
Ci-Ce-alkyl; Ci-Cδ-alkoxy; Cβ-Cio-aryloxy; CO2H; SOsH; CONH2; SO2NH2; CONH2 or SO2NH2 wherein the amino functionality is substituted one or more times with residues selected from Ci-Cδ-alkyl, Cβ-Cio-aryl or C6-Cio-aryl-Ci-C4- alkyl and wherein in case of a di-Ci-Cβ-alkyl-substituted amino functionality the alkyl residues may be combined to form 5 or 6-membered rings; amino; amino substituted one or more times with residues selected from Ci-Cβ-alkyl, Cδ-Cio- aryl, C6-Cio-aryl-Ci-C4-alkyl, Ci-Cβ-alkylcarbonyl, Cβ-Cio-arylcarbonyl, Ci-Cβ- alkylsulfonyl and Ce-Cio-arylsulfonyl; thiol; hydroxyl; nitro; cyano; fluoro; chloro; bromo; iodo; CF3 or OCF3;
SOsH; amino; amino substituted one or more times with residues selected from Ci-Cβ-alkyl, Ce-Cio-aryl, Ce-Cio-aryl-Ci-Ce-alkyl, Ci-Cό-alkylcarbonyl, Ce-Cio-arylcarbonyl,
Ci-Cβ-alkylsulfonyl and Cδ-Cio-arylsulfonyl; a disubstituted amino of the following formula (II)
Figure imgf000051_0001
wherein o represents 0 or 1 and W represents O, CH2, or NR6 with R6 being selected from hydrogen and Ci-Cβ-alkyl and wherein the methylene groups in formula (II) may optionally be substituted once or twice with Ci-Cό-alkyl, fluoro or chloro;
Figure imgf000051_0002
CONH2 or SO2NH2 wherein the amino functionality is substituted once or twice with residues selected from Ci-Cβ-alkyl, Cβ-Cio-aryl or Cβ-Cio-aryl-Ci-Cό-alkyl and wherein in the case of a di-Ci-Cβ-alkyl-substituted amino functionality the alkyl residues may be combined to form 5 or 6-membered rings; thiol; hydroxyl; nitro; cyano; fluorosulfonyl; halogen selected from fluoro, chloro, bromo or iodo;
CF3; oxo; OCF3; or a saturated, unsaturated or aromatic heterocyclic ring system of up to 10 atoms, optionally substituted once or several times by
Ci-Ce-alkyl; Ci-Ce-alkoxy; COOH; SO3H; CONH2; SO2NH2; CONH2 or
SO2NH2 wherein the amino functionality is substituted one or more times with residues selected from Ci-Cβ-alkyl, Cδ-Cio-aryl or C6-Cio-aryl-Ci-C4- alkyl and wherein in case of a di-Ci-Cδ-alkyl-substituted amino functionality the alkyl residues may be combined to form 5 or 6-membered rings; amino; amino substituted one or more times with residues selected from Ci-Ce-alkyl, Ce-Cio-aryl, C6-Cio-aryl-Ci-C4-alkyl, Ci-Ce- alkylcarbonyl, Cβ-Cio-arylcarbonyl, Ci-Ce-alkylsulfonyl and Ce-Cio- arylsulfonyl; thiol; hydroxyl; nitro; cyano; fluoro; chloro; bromo; iodo;
CF3 or OCF3; and wherein any two or more substituents of A may be combined to form anellated saturated, unsaturated or aromatic homo- or heterocyclic ring systems;
m represents O, 1, 2, 3, 4, 5 or 6; and
Y represents:
a) hydrogen; b) Ci-Ci8-alkyl, mono or polyunsaturated C2-Ci8-alkylene, C3-Cs-Cy cloalkyl,
Cβ-Cio-aryl, Cδ-Cio-aryl-Ci-Cs-alkyl, Ci-Cβ-alkoxy, Cδ-Cio-aryloxy, Ce-Go-aryl- Ci-Cs-alkoxy, Ci-Ce-alkoxycarbonyl, Ce-Cio-aryloxycarbonyl, Cβ-Cio-aryl-Ci-Cs- alkoxycarbonyl, Ci-Ce-alkylcarbonyl, Cβ-Cio-arylcarbonyl, Cβ-Cio-aryl-Ci-Cs- alkylcarbonyl, Ci-Cβ-alkylcarboxy, Cβ-Cio-arylcarboxy, Ci-Ce-alkyhnercaptyl, Ce- Cio-arylmercaptyl, Ci-Cβ-alkylmercaptocarbonyl, C3-Ce- cycloalkylmercaptocarbonyl, Cβ-Cio-arylmercaptocarbonyl, Ci-Ce- alkylmercaptocarboxy, Ce-Cio-aryhnercaptocarboxy, Ci-Ce-alkylsulfonyl, Ce-Cio- arylsulfonyl, Ci-Cβ-alkylsulfoxy, Cβ-Cio-arylsulfoxy, or a saturated, unsaturated or aromatic heterocyclic ring system of up to 10 atoms, wherein each is optionally substituted once or several times by: bl) Ci-Ce-alkyl, C3-Cs-cycloalkyl, Ce-Cio-aryl, Ce-Cio-aryl-Ci-Cs-alkyl, Ci-Ce-alkoxy, Ce-Cio-aryloxy, Ce-Cio-aryl-Ci-Cs-alkoxy, Ci-Ce- alkoxycarbonyl, Cβ-Cio-aryloxycarbonyl, Ce-Cio-aryl-Ci-Cs-alkoxycarbonyl, Ci-Cβ-alkylcarbonyl, Ce-Cio-arylcarbonyl, Cβ-Cio-aryl-Ci-Cs-alkylcarbonyl, Ci-Ce-alkylcarboxy, Cβ-Cio-arylcarboxy, Ci-Cό-alkylmercaptyl, Ce-Cio- arylmercaptyl, Ci-Cβ-alkylmercaptocarbonyl, C3-C8- cycloalkylmercaptocarbonyl, Ce-Cio-arylmercaptocarbonyl, Ci-Ce- alkyhnercaptocarboxy, Cβ-Cio-arylmercaptocarboxy, Ci-Ce-alkylsulfonyl, Cβ-Cio-arylsulfonyl, Ci-Cβ-alkylsulfoxy, Cβ-Cio-arylsulfoxy; wherein each is optionally substituted once or several times by Ci-C6-alkyl; Ci-Cβ-alkoxy; CONH2, SO2NH2; CONH2 or SO2NH2 wherein the amino functionality is substituted once or twice with Ci-Ce-alkyl; SCbH; CO2H; amino; amino substituted one or more times with residues selected from Ci-Cβ-alkyl, Ce-Cio-aryl, Ce-Cio-aryl-Ci-Ce-alkyl, Ci-Ce-alkylcarbonyl, Ce-Cio- arylcarbonyl, Ci-Cβ-alkylsulfonyl and Ce-Cio-arylsulfonyl; thiol; hydroxyl; nitro; cyano; fluoro; chloro; bromo; iodo; CF3; or OCF3; wherein several of the substituents in bl) may be combined to form anellated saturated, unsaturated or aromatic homo- or heterocyclic ring systems; or by b2) hydroxy; thiol; nitro; cyano; fluoro; chloro; bromo; iodo; CF3; CO2H; SOsH; OCF3; CONH2; SO2NH2; CONH2 or SO2NH2 wherein the amino functionality is substituted once or twice with residues selected from Ci-Ce- alkyl, Cβ-Cio-aryl or Cβ-Cio-aryl-Ci-Ce-alkyl and wherein in the case of a di-Ci-Cβ-alkyl-substituted amino functionality, the alkyl residues may be combined to form 5 or 6-membered rings; amino; amino substituted one or more times with residues selected from Ci-Cβ-alkyl, Cβ-Cio-aryl, Cβ-Cio- aryl-Ci-Cβ-alkyl, Ci-Ce-alkylcarbonyl, Cβ-Cio-arylcarbonyl, Ci-Ce- alkylsulfonyl and Cό-Cio-arylsulfonyl; or a disubstituted amino of the following formula (II)
Figure imgf000054_0001
wherein o represents 0 or 1 and W represents O, CEh, or NR6 with R6 being selected from hydrogen and Ci-Ce-alkyl and wherein the methylene groups in formula (II) may optionally be substituted once or twice with Ci-Cδ-alkyl, fluoro or chloro; or by b3) a saturated, unsaturated or aromatic heterocyclic ring system of up to 10 atoms, optionally substituted once or several times by Ci-Cβ-alkyl; Ci-Ce- alkoxy; COOH; SO3H; C0NH2; SO2NH2; CONH2 or SO2NH2 wherein the amino functionality is substituted one or more times with residues selected from Ci-Cβ-alkyl, Ce-Cio-aryl or C6-Cio-aryl-Ci-C4-alkyl and wherein in case of a di-Ci-Cβ-alkyl-substituted amino functionality the alkyl residues may be combined to form 5 or 6-membered rings; amino; amino substituted one or more times with residues selected from Ci-Cβ-alkyl, Cό-Cio-aryl, Cβ-Cio- aryl-Ci-C4-alkyl, Ci-Ce-alkylcarbonyl, Cβ-Cio-arylcarbonyl, Ci-Ce- alkylsulfonyl and Ce-Cio-arylsulfonyl; thiol; hydroxyl; nitro; cyano; fluoro; chloro; bromo; iodo; CF3 or OCF3; c) SO3H; amino; amino substituted one or more times with residues selected from
Ci-Cβ-alkyl, Ce-Cio-aryl, Cβ-Cio-aryl-Ci-Cs-alkyl, Ci-Ce-alkylcarbonyl, Cβ-Cio- arylcarbonyl, Ci-Cδ-alkylsulfonyl and Cβ-Cio-arylsulfonyl; CONH2; SO2NH2; CONH2 or SO2NH2 wherein the amino functionality is substituted once or twice with residues selected from Ci-Cβ-alkyl, Cβ-Cio-aryl or Cβ-Cio-aryl-Ci-Cδ-alkyl and wherein in the case of a di-Ci-Ca-alkyl-substituted amino functionality the alkyl residues may be combined to form 5 or 6-membered rings; thiol; hydroxyl; nitro; cyano; fluorosulfonyl; halogen selected from fluoro, chloro, bromo or iodo; CF3; or OCF3; is cyclised to form an oxadiazolone ring system.
32. Process according to claim 31, wherein the cyclisation to the oxadiazolone ring system is achieved by phosgene, carbonyldiimidazole, or a carbonic acid ester.
33. Process according to claim 31 or 32 with the proviso that A is not substituted with B-L-G wherein
B represents a single bond, CEb, O, S or NR1, wherein R1 is selected from hydrogen or a Ci-Cδ-alkyl group;
L represents a linker selected from:
a) -(CKb)P-, wherein p is 1,2,3,4,5,6,7 or 8, b) -(C=O)- or -0-(C=O)- , c) -(SO2)- or -0-(SO2)- , d) phenylene, cyclohexanylene or cyclopentanylene
wherein several of a) to d) may be used in combination and wherein a) and d) may be optionally substituted once or several times by Ci-Cβ-alkyl, Ci-Cβ- alkoxy, CO2H, SO3H, amino, Ci-Cβ-alkylamino, di-Ci-Ce-alkylamino, thiol, hydroxy, nitro, cyano, fluoro, chloro, bromo, iodo, CF3 or OCF3; and
G represents
a) NR2R3, wherein R2 and R3 independently from each other represent hydrogen; Ci-Cό-alkyl, C3-C.-cycloalkyl, Ce-Cio-aryl, aromatic heterocyclic ring system of up to 10 atoms, Cβ-Cio-aryl-Ci-Cβ-alkyl, Ci-Ce- alkoxycarbonyl, Cβ-Cio-aryloxycarbonyl, Cβ-Cio-aryl-Ci-Cs-alkoxycarbonyl,
Ci-Cβ-alkylcarbonyl, Cβ-Cio-arylcarbonyl, Cβ-Cio-aryl-Ci-Cs-alkylcarbonyl, Ci-Cβ-alkylmercaptocarbonyl, C3-C8-cycloalkylmercaptocarbonyl, Cδ-Cio- arylmercaptocarbonyl, Ci-Ce-alkylsulfonyl, or Cβ-Cio-arylsulfonyl, each of which is optionally substituted once or several times by Ci-Cβ-alkyl, Ci-Ce- alkoxy, Cβ-Cio-aryloxy, CO2H, SO3H, amino, Ci-Cδ-alkylamino, di-Ci-Cβ- alkylamino, thiol, hydroxyl, nitro, cyano, fluoro, chloro, bromo, iodo, CF3 or OCF3; and wherein one of R2 and R3 may be annelated to B or L to form a
5- or 6-membered ring; or
b) NR4R5, wherein R4 and R5 form a saturated, unsaturated or aromatic homo- or heterocyclic ring system of up to 10 atoms, which is optionally substituted once or several times by Ci-Cβ-alkyl, Ci-Cβ-alkoxy, Cβ-Cio- aryloxy, CO2H, SCbH, amino, Ci-Cβ-alkylamino, di-Ci-Cβ-alkylamino, thiol, hydroxyl, nitro, cyano, fluoro, chloro, bromo, iodo, CF3 or OCF3; or
c) a disubstituted amino of the following formula (II)
Figure imgf000056_0001
wherein o represents 0 or 1 and W represents O, CH2, or NR6 with R6 being selected from hydrogen, Ci-Ce-alkyl, Cβ-Cio-aryl, and Cβ-Go-aryl-Ci-Ce- alkyl, and wherein the methylene groups in formula (II) may optionally be substituted once or twice with Ci-Cβ-alkyl, fluoro or chloro;
or
d) a guanidine or amidine residue, wherein said residue may optionally be substitued once or several times with Ci-Cδ-alkyl, Cβ-Cio-aryl or Cβ-Cio-aryl- Ci-C4-alkyl, wherein these optional substituents may be combined to form 5- or 6-membered saturated, unsaturated or aromatic rings, or an isomer of said guanidine or amidine residue.
34. Process according to any one of claims 31 to 33 with the proviso that the compound produced in the process is not:
5-(benzyloxy)-3-(5-(trifluoromethyl)pyridin-2-yl)-l,3,4-oxadiazol-2(3H)-one, 5-phenoxy-3-(5-(trifluoromethyl)pyridin-2-yl)-l,3,4-oxadiazol-2(3H)-one, 5-(benzyloxy)-3-(pyridin-2-yl)-l,3,4-oxadiazol-2(3H)-one, 3-(benzo[d]thiazol-2-yl)-5-(benzyloxy)-l,3,4-oxadiazol-2(3H)-one, 3-(benzo[d]thiazol-2-yl)-5-phenoxy-l ,3,4-oxadiazol-2(3H)-one,
3-(benzo[d]oxazol-2-yl)-5-(benzyloxy)-l,3,4-oxadiazol-2(3H)-one, 3-(benzo[d]oxazol-2-yl)-5-phenoxy-l ,3 ,4-oxadiazol-2(3H)-one, 5-(benzyloxy)-3-(6-chloropyridazin-3-yl)-l,3,4-oxadiazol-2(3H)-one, 3-(5-bromopyridin-2-yl)-5-phenoxy-l,3,4-oxadiazol-2(3H)-one, 3-(6-chloropyridin-3-yl)-5-(4-methoxyphenoxy)-l,3,4-oxadiazol-2(3H)-one,
3-(6-chloropyridin-3-yl)-5-(4-hydroxyphenoxy)-l,3,4-oxadiazol-2(3H)-one, 3-(2-chloropyridin-3-yl)-5-(4-methoxyphenoxy)-l,3,4-oxadiazol-2(3H)-one hydrochloride, or 3-(2-chloropyridin-3-yl)-5-(cyclohexyloxy)-l ,3 ,4-oxadiazol-2(3H)-one..
PCT/PT2009/000034 2009-06-24 2009-06-24 O-substituted 3-n-heteroaryl-1,3,4-oxadiazolones for medical use Ceased WO2010151160A1 (en)

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Citations (3)

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Publication number Priority date Publication date Assignee Title
WO2006044617A1 (en) * 2004-10-15 2006-04-27 The Scripps Research Institute Oxadiazole ketone inhibitors of fatty acid amide hydrolase
JP2007137834A (en) * 2005-11-21 2007-06-07 Hokko Chem Ind Co Ltd Oxadiazolinone derivatives and agricultural and horticultural fungicides
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WO2006044617A1 (en) * 2004-10-15 2006-04-27 The Scripps Research Institute Oxadiazole ketone inhibitors of fatty acid amide hydrolase
JP2007137834A (en) * 2005-11-21 2007-06-07 Hokko Chem Ind Co Ltd Oxadiazolinone derivatives and agricultural and horticultural fungicides
WO2009084970A1 (en) * 2007-12-27 2009-07-09 Bial-Portela & Companhia, S.A. 5-o-substituted 3-n-phenyl-1,3,4-oxadiazolones for medical use

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