WO2010074587A2 - 3-n-aryl-1,3,4-oxadiazolones 5-o-substituées destinées à une utilisation médicale - Google Patents

3-n-aryl-1,3,4-oxadiazolones 5-o-substituées destinées à une utilisation médicale Download PDF

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WO2010074587A2
WO2010074587A2 PCT/PT2009/000079 PT2009000079W WO2010074587A2 WO 2010074587 A2 WO2010074587 A2 WO 2010074587A2 PT 2009000079 W PT2009000079 W PT 2009000079W WO 2010074587 A2 WO2010074587 A2 WO 2010074587A2
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cio
alkyl
aryl
amino
fluoro
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PCT/PT2009/000079
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WO2010074587A3 (fr
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David Alexander Learmonth
Patrício Manuel Vieira Araújo Soares da SILVA
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Bial - Portela & Ca., S.A.
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D285/00—Heterocyclic compounds containing rings having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by groups C07D275/00 - C07D283/00
    • C07D285/01—Five-membered rings
    • C07D285/02—Thiadiazoles; Hydrogenated thiadiazoles
    • C07D285/04—Thiadiazoles; Hydrogenated thiadiazoles not condensed with other rings
    • C07D285/12—1,3,4-Thiadiazoles; Hydrogenated 1,3,4-thiadiazoles
    • C07D285/125—1,3,4-Thiadiazoles; Hydrogenated 1,3,4-thiadiazoles with oxygen, sulfur or nitrogen atoms, directly attached to ring carbon atoms, the nitrogen atoms not forming part of a nitro radical
    • C07D285/13—Oxygen atoms
    • 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
    • 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
    • A61P25/06—Antimigraine agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • 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
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings

Definitions

  • the present invention relates to compounds having a 5-0-substituted 3-N- (hetero)aryl-l,3,4-oxadiazolone structural unit having a aliphatic nitrogen containing sidegroup on the -(hetero)aryl moiety. These compounds exhibit an unexpectedly high inhibition of FAAH (fatty acid amide hydrolase).
  • 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., Ann. 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 (methoxyarachidonylfluorophos- phonate), and ATMK (arachidonoyltrifluoromethylketone), while URB597 ([3-(3- carbamoylphenyl)phenyl] N-cyclohexylcarbamate) is widely regarded as the current "gold standard" FAAH inhibitor.
  • FAAH inhibition is considered to play an important role in many medical conditions, see for example Pacher et al (2006) Pharmacol Rev 58:389-462. 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 ischae- mia 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 tu- mour, 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, amylotro- phic lateral sclerosis, amyloidosis, graft rejection, diseases affecting the plas- macytic 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 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.
  • the most preferred envisaged use for the compounds of the invention is the treatment of allergic diseases, such as immediate or delayed hypersensitivity, allergic rhinitis or conjunctivitis, contact dermatitis; inflammatory diseases, eye conditions, such as ocular hypertension or glaucoma; pulmonary conditions, and diseases of the respiratory tracts, bronchospasm, coughing, asthma, chronic bronchitis, chronic obstruction of the respiratory tract, and emphysema.
  • allergic diseases such as immediate or delayed hypersensitivity, allergic rhinitis or conjunctivitis, contact dermatitis
  • inflammatory diseases such as ocular hypertension or glaucoma
  • pulmonary conditions and diseases of the respiratory tracts, bronchospasm, coughing, asthma, chronic bronchitis, chronic obstruction of the respiratory tract, and emphysema.
  • 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 compounds of the invention may be used in combination with other pharmaceutically active compounds. Such use may be simultaneous administration, for example in a fixed combination composition containing the combined pharmaceutically active compounds, or sequential administration.
  • the present invention relates to compounds of formula (I),
  • A represents an phenyl or 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:
  • C-C ⁇ -alkyl C 3 -C 8 -cycloalkyl, C 6 -Cio-aryl, C r C ⁇ o-aryl-C r Cg-alkyi, Ci-C 6 - alkoxy, Ce-Cio-aryloxy, Cg-Cio-aryl-Ci-Cs-alkoxy, Ci-C ⁇ -alkylcarboxy, C 6 -Ci O - arylcarboxy, Ci-C ⁇ -alkylmercaptocarboxy, C6-Cio-arylmercaptocarboxy, Ci-Cg- alkylsulfoxy, C ⁇ -Cio-arylsulfoxy, wherein each is optionally substituted once or several times by
  • Ci-C ⁇ -alkyl C r C 6 -alkoxy; C 6 -Ci 0 -aryloxy; CO 2 H; SO 3 H; CONH 2 ; SO 2 NH2; CONH 2 or SO 2 NH 2 wherein the amino functionality is substituted one or more times with residues selected from Ci-C ⁇ -alkyl, Ce-Cio-aryl or C 6 -Cio-aryl-Ci-C 4 -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 d-C 6 -alkyl, C 6 -Cio-aryl, C 6 -Ci 0 -aryl-Ci-C 4 -alkyl, Cj-C 6 - alkylcarbonyl, Cg-Cio-arylearbonyl, Ci
  • Cio-aryl Cio-aryl, C ⁇ -Cio-aryl-Ci-C ⁇ -alkyl, Ci-Cg-alkylcarbonyl, C ⁇ -Cio-arylcarbonyi, Cp
  • o represents O or 1 and W represents O, CH 2 , or NR 6 with R 6 being selected from hydrogen and Q-Ce-alkyl and wherein the methylene groups in formula (II) may optionally be substituted once or twice with d-C ⁇ -alkyl, fluoro or chloro; CONH 2 ; SO 2 NH 2 ;
  • B represents a single bond, CH 2 , O, S or NR 1 , wherein R 1 is selected from hydrogen or a Cj-Ce-alkyl group;
  • L represents a linker selected from:
  • R 2 and R 3 independently from each other represent hydrogen; Ci-Ce-alkyl, C 3 -C 8 cycloalkyl, C ⁇ -Cio-aryl, saturated, unsaturated or aromatic heterocyclic ring system of up to 10 atoms, Ce-Cio-aryl-Ci-C ⁇ - alkyl, Ci-C ⁇ -alkoxycarbonyl, Co-Cio-aryloxycarbonyl, C ⁇ -Cio-aryl-Ci-Cg- alkoxycarbonyl, Ci-C ⁇ -alkylcarbonyl, C ⁇ -Cio-arylcarbonyl, Ce-Cio-aryl- Ci-C 8 -alkylcarbonyl, Ci-C ⁇ -alkylmercaptocarbonyl, C 3 -C 8 - cycloalkylmercaptocarbonyl, C 6 -Cio-arylmercaptocarbonyl, Ci-Ce- alkyls
  • R 4 , R 5 and N form a saturated, unsaturated or aromatic heterocyclic ring system of up to 10 atoms, which is optionally substituted once or several times by Ci-Cg-alkyl, Ci-C ⁇ -alkoxy, C ⁇ -Cio-aryloxy, CO 2 H, SChH, amino, Ci-C ⁇ -alkylamino, di-Ci-C 6 -alkylam.no, thiol, hy- droxyl, nitro, cyano, fluoro, chloro, bromo, iodo, CF 3 or OCF 3; or
  • o represents 0 or 1 and W represents O, CFfc, or NR 6 with R 6 being selected from hydrogen, Ci-C ⁇ -alkyl, Q-Cio-aryl, and Cg-Cio-aryl-Ci- C ⁇ -alkyl, and wherein the methylene groups in formula (II) may optionally be substituted once or twice with Ci-Ce-alkyl, fluoro or chloro;
  • guanidine or amidine residue wherein said residue may optionally be substitued once or several times with Ci-C ⁇ -alkyl, C ⁇ -Cjo-aryl or C ⁇ -Cio- aryl-Ci-C 4 -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;
  • n 0 or 1
  • m 0, 1, 2, 3, 4, 5 or 6;
  • X represents O or S
  • Y represents: a) hydrogen; b) Ci-Cig-alkyl, mono or polyunsaturated C 2 -Cig-alkylene, C 3 -Cg-cycloalkyl, Ce- Cio-aryl, Ce-Cio-aryl-Ci-Cg-alkyl, Ci-C ⁇ -alkoxy, C ⁇ -Cto-aryloxy, Ce-Cio-aryi-Ci- C 8 -alkoxy, Ci-C ⁇ -alkoxycarbonyl, C ⁇ -Cio-aryloxycarbonyl, C ⁇ -Cio-aryl-Ci-Cg- alkoxycarbonyl, Ci-C ⁇ -alkylcarbonyl, C ⁇ -Cio-arylcarbonyl, Ce-C io-aryi-Ci -Cg- alkylcarbonyl, Ci-C ⁇ -alkylcarboxy, Ce-Cio-arylearboxy, Ci-C
  • o represents O or 1 and W represents O, CH 2 , or NR 6 with R 6 being selected from hydrogen and d-Ce-alkyl and wherein the methylene groups in formula (II) may optionally be substituted once or twice with Ci-Ce- 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-C ⁇ -alkyl; Ci-Cg- alkoxy; COOH; SO 3 H; CONH 2, SO 2 NH 2 ; CONH 2 or SO 2 NH 2 wherein the amino functionality is substituted one or more times with residues selected from Ci-C ⁇ -alkyl, C ⁇ -Cio-aryl or Q-C io-aryl-Ci -C h alky 1 and wherein in case of a di-Cj-C ⁇ -alkyl-substituted amino functionality the alkyl residues may be combined
  • Typical pharmaceutically acceptable salts are known to the skilled person and preferably include the hydrochloride, dihydrochloride and trifluoroacetate salts.
  • the present invention relates also to a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of the above formula (I) or a pharmaceutically acceptable salt thereof or a prodrug thereof as well as to a method for treating the above-mentioned diseases and conditions by administering a pharmaceutically active amount of a compound of above formula (I) or a pharmaceutically acceptable salt thereof or a prodrug thereof.
  • the pharmaceutical composition of the invention additionally comprises one or more additional active pharmaceutical ingredients.
  • the compound of the invention may be administered with one or more additional active pharmaceutical ingredients. This may be in the form of a single composition comprising the compound of the invention and one or more additional active pharmaceutical ingredients. Alternatively, this may be in two or more separate compositions where the compound of the invention is contained in one composition and the one or more additional active pharmaceutical ingredients are contained in one or more separate compositions, for example for sequential administration.
  • 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 heteraromatic ring is selected from pyridine, pyrazine, pyrimidine, pyridazine, triazine, tetrazine, thiophene, furane, oxazole, thiazole, oxazine, thiazine, and oxadiazole. The most preferred heteroaromatic ring system is pyridine, in particular 2-pyridine, 3-pyridine and 4-pyridine derivatives.
  • L preferably represents a linker selected from:
  • linkers a) and d) are substituted once or several times by Ci-Ce-alkyl, Ci-C ⁇ -alkoxy, CO 2 H, SO 3 H, amino, Ci-C 6 -alkylamino, di-Ci-C 6 - alkylamino, thiol, hydroxy, nitro, cyano, fluoro, chloro, bromo, iodo, CF3 or OCF 3 .
  • substituents are Ci-C ⁇ -alkyl, Ci-C ⁇ -alkoxy, amino, Ci-C 6 -aikylamino, di-Ci-C ⁇ -alkylamino, hydroxy, fluoro, chloro, bromo, CF3 and OCF 3 .
  • substituents are Ci-C ⁇ -alkyl, Ci-C ⁇ -alkoxy, amino, Ci-C 6 -aikylamino, di-Ci-C ⁇ -alkylamino, hydroxy, fluoro, chloro, bromo, CF3 and OCF 3 .
  • a) to d) may be used in combination.
  • N the linker, and one of R 2 and R 3 form a pyrrolidine or piperidine moiety which is optionally substituted once or several times by Ci-C ⁇ -alkyl, CpC ⁇ -alkoxy, amino, Ci-C ⁇ -alkylamino, di-Ci-Ce-alkylamino, hydroxy, fluoro, chloro, bromo, CF 3 or OCF 3 .
  • the ring system may be substituted once or several times by Ci-Cg- alkyl, Ci-Cg-alkoxy, amino, Cj-C ⁇ -alkylamino, di-Ci-C ⁇ -alkylamino, hydroxy, fluoro, chloro, bromo, CF 3 or OCF 3
  • Ci-Cg- alkyl Ci-Cg-alkoxy
  • amino, Cj-C ⁇ -alkylamino, di-Ci-C ⁇ -alkylamino hydroxy, fluoro, chloro, bromo, CF 3 or OCF 3
  • H disubstituted amino of the following formula (H)
  • o represents 0 or 1 and W represents O, CH 2 , or NR 6 with R 6 being selected from hydrogen, C[-C 6 -alkyl, Ce-Cio-aryl, and C ⁇ -Cio-aryl-Ci-Ce-alkyl.
  • R 6 being selected from hydrogen, C[-C 6 -alkyl, Ce-Cio-aryl, and C ⁇ -Cio-aryl-Ci-Ce-alkyl.
  • the disubstituted amino represents pyrrolidinyl, piperidinyl, mor- pholinyl, or piperazinyl.
  • the nitrogen may also be substituted with Ci-C 4 -alkyl, phenyl or benzyl.
  • the methylene groups in formula (II) are substituted once or twice with Ci-C ⁇ -alkyl, fluoro or chloro.
  • C represents a guanidine or amidine residue
  • said residue is unsubstituted or substituted once or several times with Ci-C ⁇ -alkyl. It is also preferred that substituents are combined to form 5- or 6-membered saturated, unsaturated or aromatic rings such as pyrimidine. It is further preferred that, when C represents a guanidine or amidine residue, the nitrogen bonded to the linker L is further substituted with an alkyl residue that in turn forms a 5- or 6-membered ring with the linker L.
  • Ci-C 4 -alkyl represents preferably methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, and tert-butyl.
  • Ci-C ⁇ -alkyl represents preferably methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, pentyl or hexyl.
  • Ci-Cts-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, tetrade- cenyl, octadecenyl, dodecdienyl, tetradecdienyl and octadecdienyl.
  • C 3 -Cs-cycloalkyl preferably represents cyclopropyl, cyciobutyl, cyclopentyl or cyclohexyl.
  • Cg-Cio-aryl preferably represents phenyl, pentalenyl, indenyl, indanyl, isoindolinyl, chromanyl, naphthyl, fluorenyl, anthryl, phenanthryl or pyrenyl.
  • Ce-Cio-aryl-Ci-C ⁇ -alkyl preferably represent phenyl or naphthyl being substituted with methyl, ethyl, propyl or butyl. Particularly preferred residues are benzyl and phenethyi.
  • Ci-C 4 -alkoxy preferably represents methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, and tert- butoxy.
  • Ci-Ce-alkoxy preferably represents methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy, pentoxy or hexoxy.
  • C 6 -Cio-aryloxy preferably represents phenoxy, naphthoxy, indenoxy, fluorenoxy or phenanthroxy.
  • C ⁇ -Cio-aryl-Ci-Cs-alkoxy, C$- Cio-aryl-Ci-Ce-alkoxy and C 6 -Cio-aryl-C t -C 4 -alkoxy preferably represent ben- zoxy, phenethoxy, phenpropoxy, or phenbutoxy. Particularly preferred residues are benzoxy and phenethoxy.
  • Ci-Ce-alkoxycarbonyl preferably represents methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl, isopropoxycar- bonyl or butoxycarbonyl.
  • C ⁇ -Cio-aryloxycarbonyl preferably represents phenoxycarbonyl or naphthoxycarbonyl.
  • C ⁇ -Cio-aryl-Ci-Cg- 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-Cg-alkylcarbonyl preferably represents benzylcarbonyl or phenethylcarbonyl.
  • Ci-C ⁇ -alkylcarboxy preferably represents methylcarboy, ethylcarboxy, n-propylcarboxy, isopropylcarboxy or butylcarboxy.
  • Ce-Cio-arylcarboxy preferably represents phenylcarboxy or naphthylcarboxy.
  • Ci-Ce-alkylmercaptyl preferably represents methylmercaptyl, ethylmercaptyl, n-propylmercaptyl, isopropylmer- captyl or butylmercaptyl.
  • Ce-Cio-arylmercaptyl preferably represents phenylmercaptyl or naphthylmercaptyl.
  • Ci-C ⁇ -alkylmercaptocarbonyl preferably represents methylmercaptocarbonyl, ethylmercaptocarbonyl, n- propylmercaptocarbonyl, isopropylmercaptocarbonyl or butylmercaptocarbonyt.
  • Cj-Cs-cycloalkylmercapto- carbonyl preferably represents cyclopropylmercaptocarbonyl, cyclobutylmercap- tocarbonyl, cyclopentylmercaptocarbonyl or cyclohexylmercaptocarbonyl.
  • Cg-Cio-arylmercaptocarbonyl preferably represents phenylmercaptocarbonyl or naphthylmercaptocarbonyl.
  • Ci-C ⁇ -alkylmercaptocarboxy preferably represents methylmercaptocarboxy, ethylmercaptocarboxy, n-propyl- mercaptocarboxy, isoproylmercaptocarboxy or butylmercaptocarboxy.
  • C ⁇ -Qo-arylmercaptocarboxy preferably represents phenylmercaptocarboxy or naphthylmercaptocarboxy.
  • Ci-C ⁇ -alkylsulfonyl preferably represents methylsulfonyl, ethylsulfonyl, n-propylsulfonyl, n-butylsulfonyl, sec- butylsulfonyl, tert-butylsulfonyl, pentylsulfonyl or hexylsulfonyl.
  • C ⁇ -Cio-arylsulfonyl preferably represents phenylsulfonyl or naphthylsulfonyl.
  • d-Gs-alkylsulfoxy preferably represents methylsulfoxy, ethylsulfoxy, n-propylsulfoxy, n-butylsulfoxy, sec- butylsulfoxy or tert-butylsulfoxy.
  • Ce-Cio-arylsulfoxy preferably represents phenylsulfoxy or naphthylsulfoxy.
  • substituents are optionally substituted once or several times by C ⁇ -C 6 -alkyl, C ⁇ -C 6 -alkoxy, C 6 -Cio-aryloxy, CO 2 H, SO 3 H, amino, thiol, hydroxyl, nitro, cyano, fluoro, chloro, bromo, iodo, CF 3 or OCF 3 .
  • substituents Ci-C ⁇ -alkyl, Cj-C ⁇ -alkoxy, and C ⁇ -C t o-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, Cs-Cio-aryl, Ce-Cio-aryl-Ci-Gt- alkyl, Ci-C ⁇ -alkylcarbonyl, Ce-Cio-arylcarbonyl, Ci-C ⁇ -alkylsulfonyl and C O -CI 0 - 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 C)-C 6 -alkyl; by phenyl, benzyl or phenethyl in case of Q-Cio-aryl and C 6 -Cio-aryl-Ci-C 4 -alkyl;
  • the term CONH2 or SO 2 NH2 wherein the amino functionality is substituted one or more times with residues selected from Ci-C ⁇ -alkyl, Ce-Cio-aryl or C 6 -Cio-aryl-C ⁇ -C 4 -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.
  • 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
  • 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, benzothia- zole, carbazole, cinnoline, dioxin, dioxane, dioxolane, dithiane, dithiazine, dithia- zole, dithiolane, furan, imidazole, imidazoline, imidazolidine, indole, indoline, indolizine, indazole, isoindole, isoquinoline, isoxazole, isothiazole, morpholine, napthyridine, oxazole, oxadiazole, oxathiazole, oxathiazolidine, oxazine, oxadiaz- ine, phenazine, phenothiazine, phenoxazine
  • heterocycles may be optionally substituted once or several times by Ci-C 6 - alkyl, Cj-C ⁇ -alkoxy, COOH, SO 3 H, amino, thiol, hydroxyl, nitro, cyano, fluoro, chloro, bromo, iodo, CF 3 or OCF 3 .
  • 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 CF 3 ; and pyrrole, which is optionally substituted with one or more residues selected from methyl, amino, fluoro, chloro or CF3.
  • A represents phenyl, 2-pyridinyl, 3- pyridinyl or 4-pyridinyl.
  • A is substituted once or several times with Ci-C ⁇ -alkyl, C 3 -C 8 -cycloalkyl, C 6 -Ci 0 -aryl, C 6 -C
  • 0 represents O or 1 and W represents O, CH 2 , or NR 6 with R 6 being selected from hydrogen and C
  • A is substituted once or several times with fluoro, chloro, hydroxyl, or Cj-C ⁇ -alkoxy.
  • 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 oxadiazolone residue.
  • L represents -(CH2) P -, wherein p is 1,2,3, or 4, which may optionally be substituted once or several times by Ci-C ⁇ -alkyl, Ci-C ⁇ -alkoxy, amino, Ci-C ⁇ -alkylamino, di-Ci-C ⁇ -alkylamino, hydroxy, fluoro, chloro, bromo, CF 3 or OCF 3 .
  • L represents - ⁇ CH2)p-
  • L represents methylene, ethanylene or propanylene
  • C represents NR 2 R 3 , wherein R 2 and R 3 independently from each other represent hydrogen; or Ci-C ⁇ -alkyl, C 6 - Cio-aryl, Ce-Cio-aryl-Ci-C ⁇ -alkyl, Cj-C ⁇ -alkylcarbonyl, Cg-Cio-arylcarbonyl, C ⁇ - Cio-aryl-Ci-Cg-alkylcarbonyl, Ci-Cg-alkylsulfonyl, or Cs-Cio-arylsulfonyl, each of which is optionally substituted once or several times by Ci-Cg-alkyl, CpCe- alkoxy, amino, Ci-C ⁇ -alkylamino, di-Ci-C ⁇ -alkylamino, hydroxy, fluoro, chloro, bromo, CF 3 or OCF 3 .
  • L represents ethanylene and one of R 2 and R 3 represents propanylene that is annelated to L to form a 5- or 6- membered ring. It also preferred in this embodiment that R 2 and R 3 independently from each other represent hydrogen, Ci-C ⁇ -alkyl, C ⁇ -Cio-aryl, or C ⁇ -Cjo-aryl-d- C 6 -alkyl.
  • C represents NR 4 R 5 , wherein R 4 and R 5 form a saturated, unsaturated or aromatic homo- or heterocyclic ring system of up to 10 atoms. It also preferred that these ringsystems are substituted once or several times by Cj-C ⁇ -alkyl, Ci-C ⁇ -alkoxy, amino, Ci-C ⁇ -alkylamino, di- Cj-Ce-alkylamino, hydroxy, fluoro, chloro, bromo, CF 3 or OCF 3 .
  • NR 4 R 5 form an isoindolin ring system, which is optionally substituted once or several times by Ci-C ⁇ -alkyl, Ci-C ⁇ -alkoxy, amino, Ci-Ce-alkylamino, di-Ci-Ce-alkylamino, hydroxy, fluoro, chloro, bromo, CF 3 or OCF 3 .
  • C represents a disubstituted amino of the following formula (II)
  • o represents 0 or 1 and W represents O, CH 2 , or NR 6 with R being selected from hydrogen, Cj-C ⁇ -alkyl, C ⁇ -Cio-aryl, and C 6 -Cio-aryl-Ci-C 6 -alkyl. It is particularly preferred in these embodiments that C represents pyrrolidinyl, piperidinyl, morpholinyl, or piperazinyl optionally N-substituted with Ci-Gj-alkyl, phenyl or benzyl.
  • A represents phenyl that is at least substituted with fluorine in the ortho-position to the oxadiazolone residue.
  • n represents O
  • m represents 0, 1, 2, 3, 4, 5 or 6
  • Y represents Cj-C ⁇ -cycloalkyl or C 6 -Ci 0 -aryl, each of which is optionally substituted once or several times by:
  • Ci-Ce-alkyl C 6 -Cio-aryl, C 6 -Cio-aryl-Ci-C 4 -alkyl, Ci-C 6 -alkoxy, C 6 -Ci 0 - aryloxy, C ⁇ -Cio-aryl-Ci-Gralkoxy, wherein each is optionally substituted once or several times by:
  • n O
  • m O or 1
  • Y represents phenyl, or a 1-naphthyl, 2-naphthyl, 2-pyridinyl, 3-pyridinyl or 4-pyridinyl ring system.
  • Y is substituted once or several times by C1-C4- alkyl; phenyl; Ci-C 4 -alkoxy; hydroxy; fluoro; chloro; bromo; CF 3 ; OCF 3 ; CONH 2 , optionally substituted once or twice with Cj-C 4 -alkyl, wherein these optional Ci- C4-alkyl residues may be combined to form 5 or 6-membered rings; or amino.
  • 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.
  • 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.
  • a representing phenyl is at least substituted with fluorine in the ortho-position to the oxadia- zolone residue.
  • the present invention also relates to a process for the preparation of compounds according to invention wherein a compound of formula (III),
  • A represents an phenyl or 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:
  • o represents O or 1 and W represents O, CH 2 , or NR 6 with R 6 being selected from hydrogen and Ci-Q-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 ; SO 2 NH 2 ;
  • B represents a single bond, O, S or NR 1 , wherein R 1 is selected from hydrogen or a Ci-C ⁇ -alkyl group;
  • L represents a linker selected from:
  • R 2 and R 3 independently from each other represent hydrogen; Ci-C ⁇ -alkyl, C 3 -C 8 cycloalkyl, C ⁇ -C t o-aryl, saturated, unsaturated or aromatic heterocyclic ring system of up to 10 atoms, C ⁇ -Cio-aryl-Ci-Ce- alkyl, Ci-Cs-alkoxycarbonyl, C ⁇ -Cio-aryloxycarbonyl, Ce-C io-aryl-C
  • R 4 R 5 and N form a saturated, unsaturated or aromatic heterocyclic ring system of up to 10 atoms, which is optionally substituted once or several times by Cj-C ⁇ -alkyl, Ci-Ce-alkoxy, Ce-Cio-aryloxy, CO 2 H, SO 3 H, amino, Ci-C 6 -alkylamino, di-d-C ⁇ -alkylamino, thiol, hy- droxyl, nitro, cyano, fluoro, chloro, bromo, iodo, CF 3 or OCF 3 ; or
  • o represents 0 or 1 and W represents O, CH 2 , or NR 6 with R 6 being selected from hydrogen, Ci-C ⁇ -alkyl, Ce-Cio-aryl, and Ce-Cio-aryl-Ci- C ⁇ -alkyl, and wherein the methylene groups in formula (II) may optionally be substituted once or twice with Ci-Cs-alkyl, fluoro or chloro;
  • guanidine or amidine residue wherein said residue may optionally be substitued once or several times with Ci-C ⁇ -alkyl, Ce-Cio-aryl or C ⁇ -Cio- aryl-Ci-G t -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;
  • n 0, 1, 2, 3, 4, 5 or 6;
  • Y represents:
  • Ci-Ci 8 -alkyl mono or polyunsaturated C 2 -Cig-alkylene, C 3 -Cg-cycloaikyl, Ce- Cio-aryl, C 6 -Cio-aryl-Ci-Cg-alkyl, Ci-C 6 -alkoxy, C 6 -Cio-aryloxy, Ce-Cjo-aryl-Ci- Cg-alkoxy, Ci-Cg-alkoxycarbonyl, Cg-Cio-aryloxycarbonyl, Ce-C l o-aryl-Ci -Cg- alkoxycarbonyl, Cj-C ⁇ -alkylcarbonyl, C ⁇ -Cio-arylcarbonyl, C ⁇ -Cio-aryl-Ci-Cg- alkylcarbonyl, Ci-C ⁇ -alkylcarboxy, C ⁇ -Cio-arylcarboxy, Ci-C ⁇ -alkylcarboxy
  • o represents 0 or 1 and W represents O, CH 2 , 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 6 - 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 C t -C ⁇ -alkyl; Ci-Cg- alkoxy; COOH; SO 3 H; C0NH 2; SO 2 NH 2 ; CONH 2 or SO 2 NH 2 wherein the amino functionality is substituted one or more times with residues selected from Ci-C ⁇ -alkyl, C 6 -Cio-aryl or C 6 -Cio-aryl-C ⁇ -C 4 -alkyl and wherein in case of a di-Ci-C ⁇ -alkyl-substituted amino functionality
  • the cycllsation 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-C 4 -alkyl carbonic acid esters.
  • Phosgene and carbonyldiimidazole are the most preferred reagents to achieve cy- clization.
  • the method may also include the step of forming a salt and/or isolating any salt formed in the previous steps.
  • Table 1 shows compounds prepared in a similar manner. For solid materials, the melting point is given.
  • the FAAH inhibitory activity in tissues of animals administered with the compounds of the invention was determined accordingly to the following method:
  • mice Male NMRI mice (weighing 27-44 g) obtained from Interfauna Ib ⁇ rica (Spain). Mice were kept 5 per cage, under controlled environmental conditions (12 hr light/dark cycle and room temperature 22 ⁇ l°C). Food and tap water were allowed ad libitum and the experiments were all carried out during daylight hours.
  • BIA compounds were administered 30 mg/kg BIA compounds via oral route (8 ml/kg; compound suspended in 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 mM MgCl 2 , 1 mM EDTA, 50 mM Tris HCl pH 7.4). Tissues were stored at -3O 0 C until analysis.
  • membrane buffer 3 mM MgCl 2 , 1 mM EDTA, 50 mM Tris HCl pH 7.4
  • 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 MgCl 2 , 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 MgCl 2 , 1 mM EDTA, 50 mM Tris HCl pH 7.4
  • 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.
  • the compounds of the invention have unexpectedly high inhibition of FAAH, making these compounds promising candidates for medicaments for the treatment or prevention of FAAH-related medical conditions. Furthermore, a comparison of the data also demonstrates that compounds having a 5-0-substituted 3-N-phenyl-l,3,4-oxadiazolone structural unit are characterized by a peripheral selectivity over CNS in-vivo.
  • Y does not represent unsubstituted phenyl if A represents phenyl which is substituted in meta-position to the oxadiazolone ring with 2-dimethylaminoethyloxy 3,3,5-trimethylcyclohexylaminosulfonyl, 2,2,6,6-tetramethylpiperidin-4- ylaminosulfonyl, 2-(diisopropylaminoethyl)aminosulfonyl, 4-methylpiperazin-l- yl-sulfonyl, 3,3-dimethylpiperidinocarbonyl, or 2-dimethylaminoethyloxy.
  • Y is not represented by Cj-C ⁇ -alkyl, Cs-Crcycloalkyl, wherein both groups are optionally substituted one or more times by phenyl, Ci-C 4 -alkyloxy, S-C1-C4- alkyl, N(Ci-C4-alkyl)2, and wherein phenyl is optionally substituted one or more times by halogen, Ci-C4-alkyl, Ci-C 4 -alkyloxy, nitro, or CF 3 , when A, B and C represents phenyl substituted by amino which is substituted by Ci -C is alkyl or C2- C is -alkenyl which is substituted one to three times by N(Ci-C 4 -alkyl)2 or amino- sulfonyl; or by C 6 -Cio-aryl-Ci-C 4 -alkyl, Cs-Cg-cycloalkyl, Cs-Cg-cycloalkyl, C
  • all of these compounds can be substituted once or several times by C 1 -C 9 alkyl, C 1 -C 9 alkyloxy, halogen, and trifluoromethyl in case of aryl; and by C 1 -C 4 alkyl or aryl in case of cycioalkyl; and by hy- droxyl, and fluoro in case of alkyl.

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Abstract

La présente invention concerne un composé de formule (I), dans laquelle A représente un groupe phényl facultativement substitué ou un système cyclique hétéroaromatique à 5 ou 6 chaînons contenant jusqu'à 4 hétéroatomes choisis parmi O, S et N, B représente une liaison simple, O, S ou NR1, R1 étant choisi parmi un atome d'hydrogène ou un groupe alkyle en C1-C6; L représente un liant; C représente une fraction amino; n représente 0 ou 1; m représente 0, 1, 2, 3, 4, 5 ou 6; X représente O ou S; et Y représente un atome d'hydrogène ou une fraction carbone facultativement substituée; et leurs stéréoisomères, leurs sels ou esters pharmaceutiquement acceptables, ou leurs promédicaments. Les composés de l'invention sont de puissants inhibiteurs de la FAAH.
PCT/PT2009/000079 2008-12-23 2009-12-23 3-n-aryl-1,3,4-oxadiazolones 5-o-substituées destinées à une utilisation médicale WO2010074587A2 (fr)

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2011085216A2 (fr) 2010-01-08 2011-07-14 Ironwood Pharmaceuticals, Inc. Utilisation d'inhibiteurs de faah pour traiter la maladie de parkinson et le syndrome des jambes sans repos
WO2011123719A2 (fr) 2010-03-31 2011-10-06 Ironwood Pharmaceuticals, Inc. Utilisation d'inhibiteurs de faah pour le traitement des douleurs abdominales, viscérales et pelviennes

Citations (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS4858140A (fr) 1971-11-29 1973-08-15
US4076824A (en) 1975-02-03 1978-02-28 Rhone-Poulenc Industries Anthelmintic oxadiazolinone derivatives
US5093343A (en) 1989-09-23 1992-03-03 Bayer Aktiengesellschaft Substituted 1,3,4-oxa (thia) diazolinones process for their preparation and their use of combating endoparasites
US5236939A (en) 1989-09-23 1993-08-17 Bayer Aktiengesellschaft Substituted 1,3,4-oxa(thia)diazolinones process for their preparation and their use of combating endoparasites
WO2001017981A1 (fr) 1999-09-04 2001-03-15 Aventis Pharma Deutschland Gmbh 3-phenyl-5-alcoxi-1,3,4-oxdiazol-2-ones substituees, leur production et leur utilisation comme inhibiteurs de lipase
WO2003043997A1 (fr) 2001-11-15 2003-05-30 Eli Lilly And Company Agonistes de recepteurs alpha actives de la proliferation des peroxysomes
WO2003072555A1 (fr) 2002-02-28 2003-09-04 Aventis Pharma Deutschland Gmbh 3-phenyl-5-alcoxy-1,3,4-oxdiazol-2-ones substitues, ainsi que leur production et leur utilisation dans des medicaments
WO2003072098A1 (fr) 2002-02-28 2003-09-04 Aventis Pharma Deutschland Gmbh Utilisation de 3-phenyl-5-alcoxy-1,3,4-oxdiazol-2-one substituee pour la fabrication de medicaments a effet inhibiteur sur la lipase pancreatique
EP1263745B1 (fr) 2000-03-07 2004-05-19 Aventis Pharma Deutschland GmbH 3-phenyl-5-alcoxi-1,3,4-oxdiazol-2-ones substituees et leur utilisation pour inhiber la lipase sensible aux hormones

Family Cites Families (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR2605007A2 (fr) * 1986-05-07 1988-04-15 Rhone Poulenc Agrochimie Herbicides de type sulfonyluree, leur preparation, les compositions les contenant et leur utilisation
AU2003249937A1 (en) * 2002-07-12 2004-02-02 Sanofi-Aventis Deutschland Gmbh Heterocyclically substituted benzoylureas, method for their production and their use as medicaments
CN101959881A (zh) * 2007-12-27 2011-01-26 比艾尔-坡特拉有限公司 用于医疗用途的5-o-取代3-n-苯基-1,3,4-噁二唑酮

Patent Citations (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS4858140A (fr) 1971-11-29 1973-08-15
US4076824A (en) 1975-02-03 1978-02-28 Rhone-Poulenc Industries Anthelmintic oxadiazolinone derivatives
US5093343A (en) 1989-09-23 1992-03-03 Bayer Aktiengesellschaft Substituted 1,3,4-oxa (thia) diazolinones process for their preparation and their use of combating endoparasites
US5236939A (en) 1989-09-23 1993-08-17 Bayer Aktiengesellschaft Substituted 1,3,4-oxa(thia)diazolinones process for their preparation and their use of combating endoparasites
WO2001017981A1 (fr) 1999-09-04 2001-03-15 Aventis Pharma Deutschland Gmbh 3-phenyl-5-alcoxi-1,3,4-oxdiazol-2-ones substituees, leur production et leur utilisation comme inhibiteurs de lipase
EP1263745B1 (fr) 2000-03-07 2004-05-19 Aventis Pharma Deutschland GmbH 3-phenyl-5-alcoxi-1,3,4-oxdiazol-2-ones substituees et leur utilisation pour inhiber la lipase sensible aux hormones
WO2003043997A1 (fr) 2001-11-15 2003-05-30 Eli Lilly And Company Agonistes de recepteurs alpha actives de la proliferation des peroxysomes
WO2003072555A1 (fr) 2002-02-28 2003-09-04 Aventis Pharma Deutschland Gmbh 3-phenyl-5-alcoxy-1,3,4-oxdiazol-2-ones substitues, ainsi que leur production et leur utilisation dans des medicaments
WO2003072098A1 (fr) 2002-02-28 2003-09-04 Aventis Pharma Deutschland Gmbh Utilisation de 3-phenyl-5-alcoxy-1,3,4-oxdiazol-2-one substituee pour la fabrication de medicaments a effet inhibiteur sur la lipase pancreatique

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
MCKINNEY M.K.; CRAVATT B.F., ANN. REV. BIOCHEM., vol. 74, 2005, pages 411
PACHER ET AL., PHARMACOL REV, vol. 58, 2006, pages 389 - 462
RUSSO R. ET AL., J PHARMACOL EXP THER., vol. 322, no. L, 2007, pages 236 - 42

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2011085216A2 (fr) 2010-01-08 2011-07-14 Ironwood Pharmaceuticals, Inc. Utilisation d'inhibiteurs de faah pour traiter la maladie de parkinson et le syndrome des jambes sans repos
WO2011123719A2 (fr) 2010-03-31 2011-10-06 Ironwood Pharmaceuticals, Inc. Utilisation d'inhibiteurs de faah pour le traitement des douleurs abdominales, viscérales et pelviennes

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