WO2010151160A1 - 3-n-hétéroaryl-1,3,4-oxadiazolones o substitué pour utilisation médicale - Google Patents

3-n-hétéroaryl-1,3,4-oxadiazolones o substitué pour utilisation médicale Download PDF

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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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PCT/PT2009/000034
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David Alexander Learmonth
Patrício Manuel Vieira Araújo Soares da SILVA
Laszlo Erno Kiss
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Bial - Portela & Ca., S.A.
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Priority to PCT/PT2009/000034 priority Critical patent/WO2010151160A1/fr
Publication of WO2010151160A1 publication Critical patent/WO2010151160A1/fr

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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

La présente invention porte sur un composé de formule (I), dans laquelle A représente un système de noyau hétéroaromatique à 5 ou 6 chaînons contenant jusqu'à 4 hétéroatomes choisis parmi O, S et N, qui est facultativement substitué, et sur un stéréo-isomère, un sel pharmaceutiquement acceptable ou un ester ou promédicament de celui-ci.
PCT/PT2009/000034 2009-06-24 2009-06-24 3-n-hétéroaryl-1,3,4-oxadiazolones o substitué pour utilisation médicale WO2010151160A1 (fr)

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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2006044617A1 (fr) * 2004-10-15 2006-04-27 The Scripps Research Institute Inhibiteurs oxadiazole cetone d'hydrolase d'amide d'acide gras
JP2007137834A (ja) * 2005-11-21 2007-06-07 Hokko Chem Ind Co Ltd オキサジアゾリノン誘導体および農園芸用殺菌剤
WO2009084970A1 (fr) * 2007-12-27 2009-07-09 Bial-Portela & Companhia, S.A. 3-n-phényl-1,3,4-oxadiazolones 5-o-substituées pour une utilisation médicale

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2006044617A1 (fr) * 2004-10-15 2006-04-27 The Scripps Research Institute Inhibiteurs oxadiazole cetone d'hydrolase d'amide d'acide gras
JP2007137834A (ja) * 2005-11-21 2007-06-07 Hokko Chem Ind Co Ltd オキサジアゾリノン誘導体および農園芸用殺菌剤
WO2009084970A1 (fr) * 2007-12-27 2009-07-09 Bial-Portela & Companhia, S.A. 3-n-phényl-1,3,4-oxadiazolones 5-o-substituées pour une utilisation médicale

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
DATABASE CAPLUS [online] CHEMICAL ABSTRACTS SERVICE, COLUMBUS, OHIO, US; 7 June 2007 (2007-06-07), XP002580331, Database accession no. 2007:614778 *

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