EP2238131A1 - 3-n-phényl-1,3,4-oxadiazolones 5-o-substituées pour une utilisation médicale - Google Patents
3-n-phényl-1,3,4-oxadiazolones 5-o-substituées pour une utilisation médicaleInfo
- Publication number
- EP2238131A1 EP2238131A1 EP08866782A EP08866782A EP2238131A1 EP 2238131 A1 EP2238131 A1 EP 2238131A1 EP 08866782 A EP08866782 A EP 08866782A EP 08866782 A EP08866782 A EP 08866782A EP 2238131 A1 EP2238131 A1 EP 2238131A1
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- Prior art keywords
- cio
- alkyl
- aryl
- amino
- fluoro
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- C07D271/02—Heterocyclic compounds containing five-membered rings having two nitrogen atoms and one oxygen atom as the only ring hetero atoms not condensed with other rings
- C07D271/10—1,3,4-Oxadiazoles; Hydrogenated 1,3,4-oxadiazoles
- C07D271/113—1,3,4-Oxadiazoles; Hydrogenated 1,3,4-oxadiazoles with oxygen, sulfur or nitrogen atoms, directly attached to ring carbon atoms, the nitrogen atoms not forming part of a nitro radical
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
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- C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
- C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
Definitions
- the present invention relates to compounds having a 5-0-substituted 3-N-phenyl- 1,3,4- oxadiazolone structural unit which have unexpectedly high level of inhibition of FAAH (fatty acid amide hydrolase).
- FAAH is an integral membrane protein (IMP) that hydrolyzes bioactive amides, such as 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).
- bioactive amides such as the endocannabinoid anandamide, which is an agonist of cannabinoid receptors and TRPVl vanilloid receptors to free fatty acid and ethanolamine
- FAAH Due to its ability to regulate anandamide levels, FAAH is currently viewed as an attractive drug target.
- inhibitors of FAAH include PMSF
- MAFP methoxyarachidonylfluorophosphonate
- ATMK arachidonoyltrifluoromethylketone
- FAAH inhibition is considered to play an important role in a wide variety of medical consitions, see for example Pacher et al Pharmacol. Rev. 58:389-462 (2006) which is fully incorporated into the description by reference thereto.
- pain in particular acute or chronic neurogenic pain such as migraine and neuropathic pain (for example diabetic neuropathic pain, post-herpetic neuralgia, trigeminal neauralgia); acute or chronic pain associated with inflammatory diseases such as arthritis, rheumatoid arthritis, osteoarthritis, spondylitis, gout, vasculitis, Crohn's disease, and irritable bowel syndrome; acute or chronic peripheral pain; (ii) dizziness, vomiting, and nausea, in particular resulting from chemotherapy;
- neurological and psychiatric pathologies such as tremors, dyskinesias, dystonias, spasticity, obsessive-compulsive behaviour, Tourette's syndrome, all forms of depression and anxiety of any nature and origin, mood disorders, and psychoses;
- cardiovascular diseases such as heart failure, hypertension, cardiac arrhythmias, arteriosclerosis, heart attack, cardiac ischaemia, and renal ischaemia;
- cancers for example benign skin tumours, brain tumours and papillomas, prostate tumours, and 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, and schwannomas);
- autoimmune diseases such as 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, amylotrophic lateral sclerosis, amyloidosis, graft rejection, diseases affecting the plasmacytic line, allergic diseases; immediate or delayed hypersensitivity, allergic rhinitis or conjunctivitis, contact dermatitis; (xi) parasitic, viral or bacterial infectious diseases such as AIDS, and meningitis;
- autoimmune diseases such as psoriasis, lupus erythematosus, diseases of the connective tissue or collagen diseases, Sjogren's syndrome, ankylosing spondylitis, undifferentiated spondylitis, Behcet's disease, autoimmune haemolytic anaemia,
- inflammatory diseases in particular joint diseases such as arthritis, rheumatoid arthritis, osteoarthritis, spondylitis, gout, vasculitis, Crohn's disease, irritable bowel syndrome;
- pulmonary conditions including diseases of the respiratory tracts, bronchospasm, coughing, asthma, chronic bronchitis, chronic obstruction of the respiratory tract, and emphysema;
- gastrointestinal diseases such as irritable bowel syndrome, inflammatory intestinal disorders, ulcers, diarrhoea, urinary incontinence and bladder inflammation.
- 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 pain, in particular:
- neuropathic pain for example, migraine
- neuropathic pain including diabetic neuropathic pain, post-herpetic neuralgia, trigeminal neauralgia
- 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 a compound of formula (I),
- R 1 to R 5 independently from each other represent: hydrogen
- Ci-Ce-alkylcarbonyl Ci-Co-alkylcarboxy, Ce-Cio-arylcarboxy, d-C ⁇ -alkylmercaptyl,
- o represents 0 or 1 and W represents O, CH 2 , 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;
- n 0 or 1
- m 0, 1, 2, 3, 4, 5 or 6;
- X represents O or S
- Y represents: a) hydrogen; b) Ci-Ci 8 -alkyl, mono or polyunsaturated C 2 -Cig-alkylene, C 3 -Cg-cycloalkyl, C ⁇ -Cio-aryl, C ⁇ -Cio-aryl-Ci-Cs-alkyl, Ci-C ⁇ -alkoxy, C ⁇ -Cio-aryloxy, C ⁇ -Cio-aryl-Ci-Cg-alkoxy, C 1 -C ⁇ -alkoxycarbonyl, CO-C 10 -aryloxycarbonyl, Ce-C 10 -aryl-C 1 -Cg-alkoxycarbonyl, Cj-C ⁇ -alkylcarbonyl, C ⁇ -Cio-arylcarbonyl, C ⁇ -Cio-aryl-Ci-Cg-alkylcarbonyl,
- Ci-C ⁇ -alkylsulfonyl C ⁇ -Cio-arylsulfonyl, Cj-C ⁇ -alkylsulfoxy, C 6 -Cio-arylsulfoxy; wherein each is optionally substituted once or several times by Ci-C 6 -alkyl; Ci-C 6 -alkoxy; COhJH 2 , SO 2 ISfH 2 ; CONH 2 or SO 2 NH 2 wherein the amino functionality is substituted once or twice with Ci-C 6 -alkyl; SO 3 H; CO 2 H; amino; amino substituted one or more times with residues g
- Ci-C ⁇ -alkyl selected from Ci-C ⁇ -alkyl, C ⁇ -Cio-aryl, C ⁇ -Cio-aryl-Ci-Ce-alkyl, Ci-C ⁇ -alkylcarbonyl, C ⁇ -Cio-arylcarbonyl, Ci-C ⁇ -alkylsulfonyl and
- 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 6 -Ci 0 -aryl, C 6 -Cio-aryl-Ci-C 8 -alkyl, Ci-Ce-alkylcarbonyl, C ⁇ -Cio-arylcarbonyl, Ci-C 6 -alkylsulfonyl and C ⁇ -Cio-arylsulfonyl; or a disubstituted amino of the following formula (II)
- o represents O or 1 and W represents O, CH 2 , or NR 6 with R 6 being selected from hydrogen and Ci-C 6 -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-C ⁇ -alkyl; Ci-C ⁇ -alkoxy; COOH;
- Ci-Ce-alkyl C 6 -Ci 0 -JUyI, C 6 -Ci 0 -aryl-Ci-C 8 -alkyl, Cj-Cs-alkylcarbonyl, C 6 -C
- a further embodiment relates to the use of the above-described compound for the inhibition of fatty acid amide hydrolase (FAAH) and also for the treatment of medical conditions which are positively influenced by the inhibition of FAAH.
- FAAH fatty acid amide hydrolase
- the above compounds are in particular indicated for the treatment of the above-mentioned diseases and medical conditions.
- the present invention relates also to a pharmaceutical composition
- a pharmaceutical composition comprising a compound of the above formula (I) or an enantiomer, pharmaceutically acceptable salt 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), an enantiomer, pharmaceutically acceptable salt or a prodrug thereof.
- Ci-C 4 -alkyl represents preferably methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, and tert-butyl.
- Ci-C 6 -alkyl represents preferably methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, pentyl or hexyl.
- Ci-Cig-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 C ⁇ -Cig-alkylene preferably represents ethenyl, n-propenyl, isopropenyl, n-butenyl, sec-butenyl, tert-butenyl, pentenyl, hexenyl, octenyl, decenyl, dodecenyl, tetradecenyl, octadecenyl, dodecdienyl, tetradecdienyl and octadecdienyl.
- Cs-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-d-Cg-alkyl, C 6 -Cio-aryl- Ci-C 6 -alkyl and C 6 -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-C 4 -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.
- the terms Co-Qo-aryl-Q-Cg-alkoxy, Ce-C w-aryl- Ci-C ⁇ -alkoxy and C 6 -Ci 0 -aryl-Ci-C 4 -alkoxy preferably represent benzoxy, phenethoxy, phenpropoxy, or phenbutoxy. Particularly preferred residues are benzoxy and phenethoxy.
- Ci-C ⁇ -alkoxycarbonyl preferably represents methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl, isopropoxycarbonyl or butoxycarbonyl.
- Ce-C ⁇ -aryloxycarbonyl preferably represents phenoxycarbonyl or naphthoxycarbonyl.
- C ⁇ -Cio-aryl-Ci-Cg-alkoxycarbonyl preferably represents represents benzoxycarbonyl or phenethoxycarbonyl.
- Ci-C ⁇ -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 methylcarboxy, ethylcarboxy, n-propylcarboxy, isopropylcarboxy or butylcarboxy.
- Ce-Cio-arylcarboxy preferably represents phenylcarboxy or naphthylcarboxy.
- the term d-C ⁇ -alkylmercaptyl preferably represents methylmercaptyl, ethylmercaptyl, n-propylmercaptyl, isopropylmercaptyl or butylmercaptyl.
- the term Ce-Cio-arylmercaptyl preferably represents phenylmercaptyl or naphthylmercaptyl.
- Ci-Ce-alkylmercaptocarbonyl preferably represents methylmercaptocarbonyl, ethylmercaptocarbonyl, n-propylmercaptocarbonyl, isopropylmercaptocarbonyl or butylmercaptocarbonyl.
- Cs-C ⁇ -cycloalkylmercaptocarbonyl preferably represents cyclopropylmercaptocarbonyl, cyclobutylmercaptocarbonyl, cyclopentylmercaptocarbonyl or cyclohexylmercaptocarbonyl.
- C ⁇ -Cio-arylmercaptocarbonyl preferably represents phenylmercaptocarbonyl or naphthylmercaptocarbonyl.
- Ci-C ⁇ -alkylmercaptocarboxy preferably represents methylmercaptocarboxy, ethylmercaptocarboxy, n-propylmercaptocarboxy, isopropylmercaptocarboxy or butylmercaptocarboxy.
- C ⁇ -Cio-arylmercaptocarboxy preferably represents phenylmercaptocarboxy or naphthylmercaptocarboxy.
- d-Ce-alkylsulfonyl preferably represents methylsulfonyl, ethylsulfonyl, n-propylsulfonyl, n-butylsulfonyl, sec-butylsulfonyl, tert- butylsulfonyl, pentylsulfonyl or hexylsulfonyl.
- C ⁇ -Cio-arylsulfonyl preferably represents phenylsulfonyl or naphthylsulfonyl.
- C]-C 6 -alkylsulfoxy preferably represents methylsulfoxy, ethylsulfoxy, n-propylsulfoxy, n-butylsulfoxy, sec-butylsulfoxy or tert- butylsulfoxy.
- C 6 -Cio-arylsulfoxy preferably represents phenylsulfoxy or naphthylsulfoxy.
- substituents are optionally substituted once or several times by Ci-C ⁇ -alkyl, d-C ⁇ -alkoxy, C 6 -C 10 -aryloxy, CO 2 H, CONH 2 , SO 2 NH 2 , SO 3 H, amino, thiol, hydroxyl, nitro, cyano, fluoro, chloro, bromo, iodo, CF 3 or OCF 3 .
- 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.
- amino substituted one or more times with residues selected from Ci-C 6 -alkyl, C 6 -C 10 -aryl, C 6 -Ci 0 -aryl-Ci-C 4 -alkyl, C 6 -Cio-aryl-Ci-C 6 -alkyl, Ce-Cio-aryl-Ci-Cs-alkyl jCi-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-C 6 -alkyl; by
- CONH 2 or SO2NH 2 wherein the amino functionality is substituted one or more times with residues selected from Ci-C ⁇ -alkyl, C ⁇ -Cio-aryl, C ⁇ -Cio-aryl-Ci-Gi-alkyl or C ⁇ -Cio-aryl-Ci-C ⁇ -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 the respective 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.
- C 6 -Cio-arylsulfonyl; thiol; hydroxyl; nitro; cyano; fluoro; chloro; bromo; iodo; CF 3 or OCF 3 " 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.
- 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
- heterocycles may be substituted once or several times by d-C 6 -alkyl, Ci-C 6 -alkoxy, COOH, SO 3 H, CONH 2 , SO 2 NHa. 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-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 Ci-C 6 -alkyl, C ⁇ -Cio-aryl, Ci-C ⁇ -alkylcarbonyl, C ⁇ -Cio-arylcarbonyl, Ci-C ⁇ -alkylsulfonyl and C ⁇ -Cio-ary
- the most preferred saturated, unsaturated or aromatic heterocyclic ring systems of up to 10 atoms comprise 2-pyridine, 3-pyridine and 4-pyridine, all three optionally substituted with one or more residues selected from methyl, amino, fluoro, chloro or CF 3 ; and N-linked pyrrole, optionally substituted with one or more residues selected from methyl, amino, fluoro, chloro or CF 3 .
- R 1 to R 5 may be combined to form anellated saturated, unsaturated or aromatic homo- or hetero-ring sytsems.
- ring systems include but are not limited to benzimidazole, benzofuran, benzothiophene, benzoxazole, and benzothiazole.
- R 1 to R 5 independently from each other represent hydrogen; hydroxyl; Ci-C ⁇ -alkyl, C ⁇ -Cio-aryl, Ci-C ⁇ -alkoxy, C ⁇ -Cio-aryloxy, C 6 -Cio-aryl-Ci-C 6 -alkoxy,
- Ci-C 6 -alkylcarboxy C ⁇ -Cio-arylcarboxy, Ci-C 6 -alkylsulfonyl, C 6 -Ci 0 -arylsulfonyl, wherein each is optionally substituted once or several times by Ci-C ⁇ -alkyl, Q-C ⁇ -alkoxy, amino, CrC ⁇ -alkylamino, di-Ci-C ⁇ -alkylamino, hydroxy, fluoro, chloro, bromo, cyano,
- o represents 0 or 1 and W represents O, CH 2 , 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 d-C ⁇ -alkyl, fluoro or chloro;
- R 1 to R 5 represent hydrogen, fluorine or chlorine. It is more preferred that either R 1 or R 5 represents hydrogen or fluorine. It is most preferred that either R 1 or R 5 represents fluorine.
- R 1 to R 5 represent hydroxy; Ci-C ⁇ -alkoxy, Co-Cio-aryloxy, C 6 -Cio-aryl-Ci-C 6 -alkoxy, Ci-C ⁇ -alkylcarboxy, C ⁇ -Cio-arylcarboxy, Ci-Ce-alkylsulfonyl, C ⁇ -Cio-arylsulfonyl, each of which is optionally substituted once or several times by Ci-C ⁇ -alkyl, Ci-C ⁇ -alkoxy, amino, C 1 -C h alky lamino, di-Ci-C 4 -alkylamino, CONH 2 or SO 2 NH 2 optionally substituted once or twice with Ci-C ⁇ -alkyl or C ⁇ -Cio-aryl, hydroxy, fluoro, chloro, bromo, cyano, CF 3 or OCF 3 .
- one of R 2 , R 3 or R 4 represents hydroxy; d-C ⁇ -alkoxy, C ⁇ -Cio-aryloxy, C ⁇ -Cio-aryl-d-C ⁇ -alkoxy, each of which is optionally substituted once or several times by Ci-C 4 -alkyl, Ci-C 4 -alkoxy, amino, Ci-C 4 -alkylamino, di- Ci-C4-alkylamino, CONH 2 or SO 2 NH 2 optionally substituted once or twice with d-C ⁇ -alkyl or C ⁇ -Cio-aryl, hydroxy, fluoro, chloro, or bromo.
- one or more of R 1 to R 5 represent amino; amino substituted one or more times with residues selected from Ci-C ⁇ -alkyl, Cg-Ci o-aryl; or a disubstituted amino of the following formula (II)
- o represents 0 or 1 and W represents O, CH 2 , or NR 6 with R 6 being selected from hydrogen and Ci-C 4 -alkyl and wherein the methylene groups in formula (II) may optionally be substituted once or twice with Ci-C4-alkyl, fluoro or chloro.
- one of R 2 , R 3 or R 4 represents amino; amino substituted once or twice with residues selected from d-Ce-alkyl, C 6 -Cio-aryl; or a disubstituted amino of the following formula (II)
- o represents 0 or 1 and W represents O, CH 2 , or NR 6 with R 6 being selected from hydrogen and Ci-Gj-alkyl and wherein the methylene groups in formula (II) may optionally be substituted once or twice with Ci-C 4 -alkyl, fluoro or chloro.
- Ci-C ⁇ -alkyl C 6 -Cio-aryl, C 6 -Cio-aryl-Ci-C 4 -alkyl, C r C 6 -alkoxy, C 6 -C 10 -aryloxy, C ⁇ -Cio-aryl-Ci-G t -alkoxy, wherein each is optionally substituted once or several times by;
- o represents 0 or 1 and W represents O, CH 2 , 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-G t -alkyl, fluoro or chloro;
- n O
- m O or 1
- Y represents a phenyl, 1-naphthyl, 2-naphthyl, 2-pyridinyl, 3-pyridinyl, or 4-pyridinyl ring system.
- Y is substituted once or several times by Ci-C 4 -alkyl; phenyl; Ci-C 4 -alkoxy; hydroxy; fluoro; chloro; bromo; CF 3 ; OCF 3 ; CONH 2 or SO 2 NH 2 , optionally substituted once or twice with Ci-C4-alkyl, wherein these optional Ci-C 4 -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 in this aspect 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 represents C6-Cio-aryl, preferably phenyl; benzyl, phenethyl, phenpropyl, phenbutyl or phenhexyl, which is optionally substituted once or several times by
- Ci-Ce-alkyl C 3 -C 8 -cycloalkyl, C 6 -Ci 0 -aryl, C ⁇ -Qo-aryl-Ci-Cg-alkyl, C r C 6 -alkoxy, C ⁇ -Cio-aryloxy, C ⁇ -Cio-aryl-Ci-C ⁇ -alkoxy, hydroxyl, CO 2 H, Ci-C ⁇ -alkoxycarbonyl,
- Ci-C6-alkyl each of which is optionally substituted once or several times by Ci-C6-alkyl, Ci-C ⁇ -alkoxy, COOH; CONH 2 , optionally substituted once or twice with Ci-C ⁇ -alkyl; SO 3 H, amino, thiol, hydroxyl, nitro, cyano, fluoro, chloro, bromo, iodo,
- Ci-C 6 -alkyl a saturated, unsaturated or aromatic heterocycle optionally substituted once or several times by Ci-C 6 -alkyl, Ci-C 6 -alkoxy, COOH; CONH 2 , optionally substituted once or twice with CpC ⁇ -alkyl; SO 3 H, amino, thiol, hydroxyl, nitro, cyano, fluoro, chloro, bromo, iodo, CF 3 or OCF 3 ;
- Ce-Cio-arylcarbonyl Ci-C 6 -alkylsulfonyl and C 6 -Cio-arylsulfonyl; CONH 2 , SO 2 NH 2 ,
- R 1 to R 5 independently from each other represent hydrogen, hydroxyl, Ci-C 4 -alkyl, C 6 -Ci 0 -aryl, C r C 4 -alkoxy, C 6 -Cio-aryloxy, C 6 -C 10 -aryl-
- Ce-C 10 -arylmercaptyl Ci-C ⁇ -alkylsulfonyl, C ⁇ -Cio-arylsulfonyl, Ci-C ⁇ -alkylsulfoxy,
- R 1 to R 5 are selected from hydroxyl, methyl, tert-butyl, phenyl, methoxy, ethoxy, phenoxy, amino, thiol, hydroxyl, cyano, fluoro, chloro, bromo, nitro, CF 3 , OCF 3 , pyridine, CONH 2 , SO 2 NH 2 , tetrazole or triazole.
- any one of R 1 to R 5 is phenyl further substituted once or several times by hydroxyl, Ci-C 6 -alkoxy, COOH, SO 3 H, amino, thiol, hydroxyl, nitro, cyano, fluoro, chloro, bromo, iodo, CF 3 or OCF 3 .
- Y represents phenyl or benzyl which is substituted in ortho-, meta- and/or para-positions by Ci-C ⁇ -alkoxy, C 6 -Ci 0 -aryloxy, hydroxyl, nitro, amino, CONH 2 , SO 2 NH 2 , fluoro, chloro or OCF 3 .
- Y represents phenyl which is substituted once, twice or three times in ortho- and/or para-positions with substituents independently selected from methoxy, ethoxy, tert-butoxy, phenoxy, hydroxy, nitro, CONH 2 , SO 2 NH 2 , fluoro, chloro or OCF 3 .
- R 1 to R 5 are selected from methyl, tert-butyl, phenyl, methoxy, ethoxy, phenoxy, amino, thiol, hydroxyl, cyano, fluoro, chloro, bromo, nitro, CF 3 , OCF 3 , pyridine, CONH 2 , SO 2 NH 2 , tetrazole, triazole or phenyl further substituted once or several times by Ci-C 6 -alkoxy, COOH, SO 3 H, amino, thiol, hydroxyl, nitro, cyano, fluoro, chloro, bromo, iodo, CF 3 or OCF 3 , and Y represents phenyl which is substituted in ortho- and/or para-positions by Cj-C ⁇ -alkoxy, C ⁇ -Cio-aryloxy, hydroxyl, nitro, CONH 2
- the present invention relates to a compound of formula (I),
- R 1 to R 5 independently from each other represent: hydrogen; Ci-C 6 -alkyI, C 3 -C 8 -cycloalkyl, C 6 -Ci 0 -aryl, C 6 -Cio-aryl-Ci-C 8 -alkyl, Ci-C 6 -alkoxy, C 6 -Cio-aryloxy, C ⁇ -Cio-aryl-Ci-C ⁇ -alkoxy, Ci-C ⁇ -alkoxycarbonyl, Ce-Cio-aryloxycarbonyl, C ⁇ -Cio-aryl-Ci-C ⁇ -alkoxycarbonyl, Ci-C ⁇ -alkylcarbonyl, C ⁇ -Cio-arylcarbonyl, C ⁇ -Cio-aryl- Ci-Cg-alkylcarbonyl, Ci-C 6 -alkylcarboxy, C ⁇ -Cio-arylcarboxy, Ci-Ce-alkylmercaptyl, Ce-Cio
- Ci-Gj-alkyl Ci-C ⁇ -alkylcarbonyl, Ce-Cio-arylcarbonyl, Ci-C ⁇ -alkylsulfonyl and C ⁇ -Cio-arylsulfonyl; thiol; hydroxyl; nitro; cyano; fluoro; chloro; bromo; iodo; CF3 or OCF 3 ;
- o represents O or 1 and W represents O, CH 2 , 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 ; SO 2 NH 2 ;
- Ci-C 6 -alkyl or a saturated, unsaturated or aromatic heterocyclic ring system of up to 10 atoms, optionally substituted once or several times by Ci-C 6 -alkyl; C,-C 6 -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 6 -Cio-aryl or C ⁇ -Cio-aryl-Ci-G t -alkyl and wherein in 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-C ⁇ -alkyl, C ⁇ -Cio-aryl, C ⁇ -Cio-aryl-Ci-C-i-alkyl,
- Ci-C ⁇ -alkylcarbonyl C ⁇ -Cio-arylcarbonyl, Ci-C ⁇ -alkylsulfonyl and
- Y represents phenyl which is optionally substituted once or several times by
- Ci-Ce-alkyl C 6 -Ci 0 -aryl, Ce-Cio-aryl-Ci-Cg-alkyl, C r C 6 -alkoxy, C 6 -C 10 -aryloxy, C ⁇ -Cio-aryl-d-Cg-alkoxy, Ci-C ⁇ -alkoxycarbonyl, C ⁇ -Cio-aryloxycarbonyl, C ⁇ -Cio-aryl- CpCe-alkoxycarbonyl, Ci-C ⁇ -alkylcarbonyl, C ⁇ -Cio-arylcarbonyl, C ⁇ -Cio-aryl- Ci-Cg-alkylcarbonyl, Ci-C ⁇ -alkylcarboxy, Co-Cw-arylcarboxy, Ci-C ⁇ -alkyhnercaptyl, C ⁇ -Cio-arylmercaptyl, Ci-C ⁇ -alkylmercaptocarbonyl, C 3
- o represents 0 or 1 and W represents O, CH 2 , or NR 6 with R 6 being selected from hydrogen and CrC 4 -alkyl and wherein the methylene groups in formula (II) may optionally be substituted once or twice with Ci-C 4 -alkyl, fluoro or chloro;
- R 1 to R 5 independently from each other do not represent hydrogen, fluoro, bromo, chloro, iodo or an alkyl radical when Y represents unsubstituted phenyl; that
- R 2 or R 4 do not represent a pyrazol-3-yl-derivative
- R 1 to R 5 independently from each other represent hydrogen; hydroxyl;
- o represents 0 or 1 and W represents O, CH 2 , or NR 6 with R 6 being selected from hydrogen and Cj-C 6 -alkyl and wherein the methylene groups in formula (II) may optionally be substituted once or twice with C ⁇ -C 6 -alkyl, fluoro or chloro; CONH 2 ;
- R 1 to R 5 represent hydrogen, fluorine or chlorine. It is most preferred that either R 1 or R 5 represents hydrogen or fluorine.
- R 1 to R 5 represent hydroxy
- one of R 2 , R 3 or R 4 represents hydroxy; or Ci-C ⁇ -alkoxy, Co-Cio-aryloxy, or C ⁇ -Cio-aryl-CrC ⁇ -alkoxy, each of which is optionally substituted once or several times by Ci-C ⁇ -alkyl, Ci-C 6 -alkoxy, amino, Ci-Ce-alkylamino, di-Ci-C ⁇ -a ⁇ cylamino, CONH 2 or SO 2 NH 2 optionally substituted once or twice with Ci-C 6 -alkyl or C ⁇ -Cio-aryl, hydroxy, fluoro, chloro, or bromo.
- one or more of R 1 to R 5 represent amino; amino substituted one or more times with residues selected from Ci-C ⁇ -alkyl, C ⁇ -Cio-aryl; or a disubstituted amino of the following formula (II)
- o represents 0 or 1 and W represents O, CH 2 , or NR 6 with R 6 being selected from hydrogen and Ci-C-j-alkyl and wherein the methylene groups in formula (II) may optionally be substituted once or twice with Ci-C 4 -alkyl, fluoro or chloro.
- one of R 2 , R 3 or R 4 represents amino; amino substituted once or twice with residues selected from Cj-C ⁇ -alkyl, C ⁇ -Cio-aryl; or a disubstituted amino of the following formula (II)
- o represents 0 or 1 and W represents O, CH 2 , or NR 6 with R 6 being selected from hydrogen and Ci-C 4 -alkyl and wherein the methylene groups in formula (II) may optionally be substituted once or twice with Ci-C 4 -alkyl, fluoro or chloro.
- Ci-C 6 -alkyl C 6 -C ⁇ 0 -aryl, C 6 -Cio-aryl-Ci-C 6 -alkyl, Ci-C ⁇ -alkoxy, C 6 -Cio-aryloxy,
- Ci-C ⁇ -alkyl Ci-C ⁇ -alkoxy
- SO 3 H Ci-C ⁇ -alkoxy
- CO 2 H amino; amino substituted one or more times with residues selected from Ci-C ⁇ -alkyl, C ⁇ -Cto-aryl, C ⁇ -Cio-aryl- d-C ⁇ -alkyl, Ci-C ⁇ -alkylcarbonyl, Ce-Cio-arylcarbonyl, Ci-C ⁇ -alkylsulfonyl and C ⁇ -Cio-arylsulfonyl; thiol; hydroxyl; nitro; cyano; fluoro; chloro; bromo; iodo; CF3;
- o represents 0 or 1 and W represents O, CH 2 , or NR 6 with R 6 being selected from hydrogen and d-C ⁇ -alkyl and wherein the methylene groups in formula (II) may optionally be substituted once or twice with C]-C 6 -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 d-C 6 -alkyl; d-C 6 -alkoxy; COOH; CONH 2 ; SO 2 NH 2 ; CONH 2 or SO 2 NH 2 wherein the amino functionality is substituted once or twice with Ci-C 6 -alkyl which may be combined to form 5 or 6-membered rings; SO 3 H; amino; amino substituted one or more times with residues selected from
- Y represents phenyl which is substituted once or several times by d-C 6 -alkyl; phenyl; d-C 6 -alkoxy; hydroxy; fluoro; chloro; bromo; CF 3 ; OCF 3 ; amino; or CONH 2 or SO 2 NH 2 optionally substituted once or twice with Cj-C 6 -alkyl wherein these optional Ci-C 6 -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. 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.
- m is 0; n is 0; 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, or in the 2- and 4-position by chloro; that any one of R 2 to R 4 represents OR 7 wherein R 7 is selected from hydrogen and Ci-C 4 -alkyl; and that R 1 represents fluorine.
- m is O; n is 0; Y represents phenyl substituted once or twice by fluoro, chloro or bromo; that R 3 or R 3 and R 4 represent hydroxyl; and that R 1 represents fluorine.
- R 1 to R 5 are selected from hydroxyl, methyl, tert-butyl, phenyl, methoxy, ethoxy, phenoxy, amino, thiol, hydroxyl, cyano, fluoro, chloro, bromo, nitro, CF 3 , OCF 3 , pyridine, CONH 2 , SO 2 NH 2 , tetrazole or triazole.
- R 1 to R 5 is a saturated, unsaturated or aromatic heterocycle optionally substituted once or several times by Ci-C ⁇ -alkyl, Q-C ⁇ -alkoxy, COOH, SO 3 H, amino, thiol, hydroxyl, nitro, cyano, fluoro, chloro, bromo, iodo, CF3 or OCF 3 or phenyl further substituted once or several times by Ci-C ⁇ -alkoxy, COOH, SO 3 H, amino, thiol, hydroxyl, nitro, cyano, fluoro, chloro, bromo, iodo, CF 3 or OCF3.
- R 1 to R 5 is CONH 2 ; SO 2 NH 2 ; or 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 C 6 -Cio-aryl-Ci-C 4 -alkyl.
- Y represents phenyl which is substituted in ortho- and/or para-positions by CpC ⁇ -alkoxy, C ⁇ -Cio-aryloxy, hydroxyl, nitro, amino, CONH 2 , SO 2 NH 2 , fluoro, chloro or OCF 3 .
- Y represents phenyl which is substituted once, twice or three times in ortho- and/or para-positions with substituents independently selected from methoxy, ethoxy, tert-butoxy, phenoxy, hydroxyl, nitro, CONH 2 , SO 2 NH 2 , fluoro, chloro or OCF 3 . It is also preferred that Y represents phenyl which is substituted in ortho- and/or para- positions by Ci-C ⁇ -alkoxy, C ⁇ -Cio-aryloxy, hydroxyl, nitro, CONH 2 , SO 2 NH 2 , fluoro, chloro or OCF 3 .
- R 1 to R 5 are selected from methyl, tert-butyl, phenyl, methoxy, ethoxy, phenoxy, amino, thiol, hydroxyl, cyano, fluoro, chloro, bromo, nitro, CF 3 , OCF 3 , pyridine, CONH 2 , SO 2 NH 2 , tetrazole, triazole or phenyl further substituted once or several times by Ci-C ⁇ -alkoxy, COOH, SO 3 H, amino, thiol, hydroxyl, nitro, cyano, fluoro, chloro, bromo, iodo, CF 3 or OCF 3 , and Y represents phenyl which is substituted in ortho- and/or para-positions by CrC ⁇ -alkoxy, C 6 -Cio-aryloxy, hydroxyl, nitro, CONH 2 , SO 2 NH 2 , fluoro, chloro or
- the present invention relates to a compound of formula
- R 1 to R 5 independently from each other represent: hydrogen
- o represents O or 1 and W represents O, CH 2 , 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 ; SO 2 NH 2 ; CONH 2 or SO 2 NH 2 wherein the amino functionality is substituted once or twice with residues selected from Ci-C ⁇ -alkyl, C ⁇ -Cio-aryl or C ⁇ -Cio-aryl-Cj-C ⁇ -alkyl and wherein in the case of a di-CrCo-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;
- Y represents phenyl which is optionally substituted once or several times by a) Ci-C ⁇ -alkyl, C ⁇ -Cio-aryl, C ⁇ -Cio-aryl-Ci-Cs-alkyl, Ci-C ⁇ -alkoxy, C ⁇ -Cio-aryloxy, C 6 -Cio-aryl-Ci-C 8 -alkoxy, d-C ⁇ -alkoxycarbonyl, C ⁇ -do-aryloxycarbonyl, C ⁇ -Cio-aryl- d-Cg-alkoxycarbonyl, Ci-C ⁇ -alkylcarbonyl, C ⁇ -Cio-arylcarbonyl, C ⁇ -Cio-aryl- d-Cg-alkylcarbonyl, d-C ⁇ s-alkylcarboxy, C ⁇ -Cio-arylcarboxy, Ci-Co-alkylmercapt
- Ci-C 6 -alkyl a saturated, unsaturated or aromatic heterocyclic ring system of up to 10 atoms, optionally substituted once or several times by Ci-C 6 -alkyl; Ci-C ⁇ -alkoxy; COOH; CONH 2 or S ⁇ 2NH 2 , optionally substituted once or twice with Ci-C ⁇ -alkyl; SO 3 H; amino; amino substituted one or more times with residues selected from Ci-C ⁇ -alkyl, C 6 -Ci O -aryl, C6-C 10 -aryl-Ci-C4-alkyl, Ci-C ⁇ -alkylcarbonyl, Co-Cio-arylcarbonyl, Ci-C 6 -aIkylsulfonyI and C ⁇ -Cio-arylsulfonyl; thiol; hydroxyl; nitro; cyano; fluoro; chloro; bromo; iodo; CF 3 or OCF 3 ; or
- o represents O or 1 and W represents O, CH 2 , or NR 6 with R 6 being selected from hydrogen and C ⁇ -C4-alkyl and wherein the methylene groups in formula (FV) may optionally be substituted once or twice with Ci-C 4 -alkyl, fluoro or chloro; with the proviso that Y does not represent unsubstituted phenyl if R 1 , R 2 and R 5 represent hydrogen, R 4 represents hydrogen, trifluoromethoxy, trifluorobutoxy, 3,3,5,5-tetramethylcyclohexyloxy, benzyloxy, phenoxy, phenyl, 2-dimethylaminoethyloxy or 3-methylphenoxy-methyl and R 3 represents hydrogen, trifluoromethoxy, trifluorobutoxy, 3,3,5,5-tetramethylcyclohexyloxy, phenoxy, 4-chlorophenoxy, cyclohexyl, phenyl, morpholinosulfonyl
- Y represents phenyl which is substituted once or several times by Ci-C ⁇ -alkyl; phenyl; Cj-C ⁇ -alkoxy; hydroxy; fluoro; chloro; bromo; CF 3 ; OCF 3 ; amino; or CONH 2 or SO 2 NH 2 optionally substituted once or twice with Ci-C6-alkyl wherein these optional Ci-C ⁇ -alkyl residues may be combined to form 5 or 6-membered rings.
- m represents 0 and Y represents phenyl which is substituted once or twice by hydroxy, fluoro, chloro or bromo.
- m represents 0 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.
- R 1 to R 5 are selected from methyl, tert- butyl, phenyl, methoxy, ethoxy, phenoxy, amino, thiol, hydroxyl, cyano, fluoro, chloro, bromo, nitro, CF 3 , OCF 3 , pyridine; CONH 2 , 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-Ci-C 4 -alkyl; tetrazole or triazole.
- any one of R 1 to R 5 is phenyl further substituted once or several times by Ci-C 6 -alkoxy, COOH, SO 3 H, amino, thiol, hydroxyl, nitro, cyano, fluoro, chloro, bromo, iodo, CF 3 or OCF 3 .
- Y represents phenyl which is substituted in ortho- and/or para-positions by Ci-C 6 -alkoxy, C ⁇ -Cio-aryloxy, hydroxyl, nitro, amino, CONH 2 , SO 2 NH 2 , fluoro, chloro or OCF 3 .
- Y represents phenyl which is substituted once, twice or three times in ortho- and/or para-positions with substituents independently selected from methoxy, ethoxy, tert-butoxy, phenoxy, hydroxyl, nitro, CONH 2 , SO 2 NH 2 , fluoro, chloro or OCF 3 .
- Y represents phenyl which is substituted in ortho- and/or para-positions by Ci-C ⁇ -alkoxy, C 6 -Ci 0 -aryloxy, hydroxyl, nitro, CONH 2 , SO 2 NH 2 , fluoro, chloro or OCF 3 .
- R 1 to R 5 are selected from methyl, tert-butyl, phenyl, methoxy, ethoxy, phenoxy, amino, thiol, hydroxyl, cyano, fluoro, chloro, bromo, nitro, CF 3 , OCF 3 , pyridine, CONH2, SO 2 NH 2 , tetrazole, triazole or phenyl further substituted once or several times by Ci-C ⁇ -alkoxy, COOH, SO 3 H, amino, thiol, hydroxyl, nitro, cyano, fluoro, chloro, bromo, iodo, CF 3 or OCF 3 , and Y represents phenyl which is substituted in ortho- and/or para-positions by Ci-C ⁇ -alkoxy, C ⁇ -Cio-aryloxy, hydroxyl, nitro, CONH 2 , SO 2 NH 2 , fluoro, chloro
- the present invention relates to a compound of formula (I),
- any one of R 2 to R 4 represents hydroxy, and remaining R residues are hydrogen; Ci-C 6 -alkyl, C 3 -C 8 -cycloalkyl, C 6 -C 10 -aryl, Ce-Cio-aryl-d-Cg-alkyl, Ci-C 6 -alkoxy, C ⁇ -Cio-aryloxy, C ⁇ -Cio-aryl-Ci-Cg-alkoxy, C
- o represents 0 or 1 and W represents O, CH 2 , 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 ; 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 6 -alkyl, C 6 -Cio-aryl or C ⁇ -Cio-aryl-Ci-C ⁇ -alkyl and wherein in the case of a di-Ci-C ⁇ -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 io
- CF 3 ; OCF 3 ; or a saturated, unsaturated or aromatic heterocyclic ring system of up to 10 atoms, optionally substituted once or several times by Ci-C ⁇ -alkyl, Ci-C ⁇ -alkoxy, COOH, SO 3 H, amino, thiol, hydroxyl, nitro, cyano, fluoro, chloro, bromo, iodo, CF3 or OCF 3 ; and wherein two or more of R 2 to R 4 may be combined to form anellated saturated, unsaturated or aromatic homo- or hetero-ring systems;
- n and m are 0;
- Y is phenyl substituted once or several times by Ci-C 6 -alkyl; phenyl; d-C ⁇ -alkoxy; hydroxy; fluoro; chloro; bromo; CF 3 ; OCF 3 ; amino; or CONH 2 optionally substituted once or twice with Ci-C ⁇ -alkyl wherein these optional Ci-C ⁇ -alkyl residues may be combined to form 5 or 6-membered rings; or a stereoisomer, pharmaceutically acceptable salt or ester, or prodrug thereof.
- the present invention relates to a compound of formula (I),
- any one of R 2 to R 4 represents amino and remaining R residues are hydrogen; Ci-C 6 -alkyl, C 3 -C 8 -cycloalkyl, C 6 -C ⁇ 0 -aryl, C 6 -Cio-aryl-Ci-C 8 -alkyl, Ci-C 6 -alkoxy, C ⁇ -Cio-aryloxy, C ⁇ -Cio-aryl-Ci-C ⁇ -alkoxy, Ci-C ⁇ -alkoxycarbonyl, C ⁇ -Cio-aryloxycarbonyl, C ⁇ -Cio-aryl-Ci-Cg-alkoxycarbonyl, Ci-C ⁇ -alkylcarbonyl, C ⁇ -Cio-arylcarbonyl, C 6 -Cio-aryl- Ci-Cg-alkylcarbonyl, Ci-C ⁇ -alkylcarboxy, C ⁇ -Cio-arylcarboxy, Ci-
- o represents 0 or 1 and W represents O, CH 2 , 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 ; 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 6 -alkyl, C 6 -Ci 0 -aryl or C 6 -C 10 -aryl-Ci-C 6 -alkyl and wherein in the case of a di-Ci-C ⁇ -alkyl-substituted amino functionality the alkyl residues may be combined to form 5 or 6-membered rings; thiol; hydroxy 1; nitro; cyano; fluorosulfonyl; halogen selected from fluoro, chloro, bromo or iodo
- CF 3 ; OCF 3 ; or a saturated, unsaturated or aromatic heterocyclic ring system of up to 10 atoms, optionally substituted once or several times by Ci-C ⁇ -alkyl, d-C ⁇ -alkoxy, COOH, SO 3 H, amino, thiol, hydroxyl, nitro, cyano, fluoro, chloro, bromo, iodo, CF 3 or OCF 3 ; and wherein any two or more of R 2 to R 4 may be combined to form anellated saturated, unsaturated or aromatic homo- or hetero-ring systems;
- n and m are 0;
- Y is phenyl substituted once or several times by Ci-C ⁇ -alkyl; phenyl; d-C ⁇ -alkoxy; hydroxy; fluoro; chloro; bromo; CF 3 ; OCF 3 ; amino; or CONH 2 optionally substituted once or twice with Ci-C 6 -alkyl wherein these optional d-C 6 -alkyl residues may be combined to form 5 or 6-membered rings, or a stereoisomer, pharmaceutically acceptable salt or ester, or prodrug thereof.
- the present invention relates to a compound of formula (I),
- R 3 or R 4 is Ci-C ⁇ -alkoxy, C 6 -Cio-aryloxy, C 6 -C t o-aryl-Ci-C8-alkoxy, Ci-C ⁇ -alkylcarboxy, C ⁇ -C t o-arylcarboxy, Ci-C 6 -alkylmercaptocarboxy, Q-Cio-arylmercaptocarboxy, Cj-C 6 -alkylsulfoxy, C ⁇ -Cjo-arylsulfoxy, wherein each is optionally substituted once or several times by Ci-C ⁇ -alkyl, Ci-C ⁇ -alkoxy, C ⁇ -Cio-aryloxy, CO 2 H, SO 3 H, amino, Ci-C ⁇ -alkylamino, di-Ci-C ⁇ -alkylamino, thiol, hydroxyl, nitro, cyano, fluoro, chloro, bromo, iodo
- R 3 or R 4 is amino substituted one or more times with residues selected from Ci-C 6 -aIkyl, C 6 -Ci 0 -aryl, C 6 -Cio-aryl-CrC 6 -alkyl, d-C ⁇ -alkylcarbonyl,
- R 2 is: hydrogen
- o represents 0 or 1 and W represents O, CH 2 , or NR 6 with R 6 being selected from hydrogen and Cj-C ⁇ -alkyl and wherein the methylene groups in formula (II) may optionally be substituted once or twice with Ci-C ⁇ -alkyl, fluoro or chloro;
- OCF 3 or a saturated, unsaturated or aromatic heterocyclic ring system of up to 10 atoms, optionally substituted once or several times by Ci-C ⁇ -alkyl, Cj-C ⁇ -alkoxy, COOH, SO 3 H, amino, thiol, hydroxyl, nitro, cyano, fluoro, chloro, bromo, iodo, CF 3 or OCF 3 ;
- n and m are 0;
- Y is phenyl substituted once or several times by Ci-C ⁇ -alkyl; phenyl; Ci-C ⁇ -alkoxy; hydroxy; fluoro; chloro; bromo; CF 3 ; OCF 3 ; amino; or CONH 2 optionally substituted once or twice with Ci-C ⁇ -alkyl wherein these optional Cj-Ce-alkyl residues may be combined to form 5 or 6-membered rings, or a stereoisomer, pharmaceutically acceptable salt or ester, or prodrug thereof.
- Y is phenyl substituted once or several times by Ci-C ⁇ -alkyl; phenyl; Ci-C ⁇ -alkoxy; hydroxy; fluoro; chloro; bromo; CF 3 ; OCF 3 ; amino; or CONH 2 optionally substituted once or twice with Q-Q-alkyl, wherein these optional Ci-C ⁇ -alkyl residues may be combined to form 5 or 6- membered rings.
- Y is phenyl substituted once or twice by hydroxy, fluoro, chloro or bromo.
- Y is phenyl 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.
- R 1 to R 5 independently from each other do not represent hydrogen, fluoro, bromo, chloro, iodo or an alkyl radical when Y represents unsubstituted phenyl
- R 2 or R 4 do not represent a pyrazol-3-yl-derivative
- the phenyl ring substituted with R 1 to R 5 and Y do not represent the following combinations:
- Y does not represent unsubstituted phenyl if R 1 , R 2 and R s represent hydrogen, R 4 represents hydrogen, trifluoromethoxy, trifluorobutoxy, 3,3,5,5-tetramethylcyclohexyloxy, benzyloxy, phenoxy, phenyl, 2-dimethylaminoethyloxy or 3-methylphenoxy-methyl and R 3 represents hydrogen, trifluoromethoxy, trifluorobutoxy,
- Y does not represent unsubstituted phenyl.
- R 1 or R 5 does not represent a substituent selected from halogen, in particular F, Cl, NO 2 , CHj, OCH 3 or CF 3 or CN, when at least one of the remainder of the substituents R 1 to R 5 represents a substituent selected from halogen, in particular F, Cl, Br, CH 3 , OCH 3 , NO 2 , CN and when the phenyl ring representing Y is substituted with F, Cl, Br, CH 3 , OCH 3 , NO 2 or CN.
- Y does not represent phenyl which is substituted by phenoxy or C ⁇ -Cu-alkyl.
- Y does not represent unsubstituted phenyl.
- Y does not represent phenyl or lower alkyl radical when R 1 to R 5 represent a hydrogen or halogen atom or a methyl radical.
- 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 C ⁇ -Cio aryl in case of cycloalkyl; and by hydroxyl, di-Ci-C 4 alkylamino and fiuoro in case of alkyl.
- Y does not represent phenyl substituted by alkyl having 1 to 4 carbon atoms; alkoxy having 1 to 4 carbon atoms; alkylthio having 1 to 4 carbon atoms; halogenoalkyl having 1 to 4 carbon atoms and 1 to 5 halogen atoms, the halogen atoms being identical or different; halogenoalkoxy having 1 to 4 carbon atoms and 1 to 5 halogen atoms, the halogen atoms being identical or different; or halogenoalkylthio having 1 to 4 carbon atoms and 1 to 5 halogen atoms, the halogen atoms being identical or different; alkylenedioxy having 1 or 2 carbon atoms; halogensubstituted alkylenedioxy having 1 or 2 carbon atoms and 1 to 4 halogen atoms, the halogen atoms being identical or different
- R 1 or R 5 does not represent a substituent selected from halogen, in particular F, CI, NO 2 , CH 3 , OCH 3 or CF 3 or CN, when at least one of the remainder of the substituents R 1 to R 5 represents a substituent selected from halogen, in particular F, Cl, Br, CH 3 , OCH 3 , NO 2 , CN and when the phenyl ring representing Y is substituted with F, Cl, Br, CH 3 , OCH 3 , NO 2 or CN.
- Y does not represent Cj-C ⁇ -alkyl or C 3 -C ⁇ >-cycloalkyl, optionally substituted once or several times by phenyl which in turn may be substituted once or several times by halogen, Ci-C 4 -alkyl, Ci-C 4 -alkyloxy, nitro, CF 3 ; or by O-d-C ⁇ alkyl, S-Ci-C 4 -alkyl, N(C,-C 4 -alkyl) 2 .
- Y does not represent Ci-C ⁇ -alkyl or C 3 -C 9 -cycloalkyl, optionally substituted once or several times by phenyl which in turn may be substituted once or several times by halogen, d-C 4 -alkyl, Ci-C 4 -alkyloxy, nitro, CF 3 ; or by O-C,-C 4 -alkyl, S-C,-C 4 -alkyl, N(Ci-C 4 -alkyl) 2 .
- the present invention also relates to the use of a pharmacophore of the following structure (III),
- FAAH fatty acid amide hydrolase
- the present invention also relates to compounds comprising a pharmacophore of the following structure (III),
- FAAH fatty acid amide hydrolase
- pharmacophore is to be understood as a molecular sub-unit, or substructure or part of the molecule which is essential for the interaction with the FAAH enzyme. It is to be understood that the pharmacophore of formula (III) may be further substituted.
- the present invention also relates to a process for the preparation of a compound according to any one of claims 1 to 17, and 24 to 79 wherein a compound of formula (IV), Y
- R 1 to R 5 independently from each other represent: hydrogen
- o represents 0 or 1 and W represents O, CH 2 , or NR 6 with R 6 being selected from hydrogen and Ci-C 6 -alkyl and wherein the methylene groups in formula (II) may optionally be substituted once or twice with Cj-C ⁇ -alkyl, fluoro or chloro; CONH 2 ;
- OCF 3 or a saturated, unsaturated or aromatic heterocyclic ring system of up to 10 atoms, optionally substituted once or several times by Ci-C ⁇ -alkyl, Ci-C ⁇ -alkoxy, COOH, SO 3 H, amino, thiol, hydroxyl, nitro, cyano, fluoro, chloro, bromo, iodo, CF 3 or OCF 3 ; and wherein any two or more of R 1 to R 5 may be combined to form anellated saturated, unsaturated or aromatic homo- or hetero-ring systems;
- n 0, 1, 2, 3, 4, 5 or 6;
- Y represents: a) hydrogen; b) Ci-Ci ⁇ -alkyl, mono or polyunsaturated C 2 -Cig-alkylene, Cs-C ⁇ -cycloalkyl, C ⁇ -Cio-aryl, C 6 -Cio-aryl-Ci-C 8 -alkyl, Ci-C 6 -alkoxy, C 6 -Ci 0 -aryloxy, C ⁇ -Cio-aryl-Ci-Cg-alkoxy, C 1 -C ⁇ -alkoxycarbonyl, C ⁇ -C 10 -aryloxycarbonyl, C ⁇ -C 1 o-aryl-C 1 -Cg-alkoxycarbonyl, Ci-C ⁇ -alkylcarbonyl, C ⁇ -Cio-arylcarbonyl, CO-CJ o-aryl-Ci-Cg-alkylcarbonyl,
- Ci-C ⁇ -alkylcarbonyl C ⁇ -Cio-arylcarbonyl, Ci-C 6 -alkylsulfonyl and
- o represents 0 or 1 and W represents O, CH 2 , or NR 6 with R 6 being selected from hydrogen and Cj-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-C ⁇ -alkyl; Cj-C ⁇ -alkoxy; COOH;
- Ci-Ce-alkylcarbonyl C ⁇ -Cio-arylcarbonyl, Ci-C ⁇ -alkylsulfonyl and
- 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 Cj -Chalky 1 carbonic acid esters.
- R 1 to R 5 independently from each other represent hydrogen; hydroxyl; Ci-C 6 -alkyl, C 6 -Cio-aryl, Ci-C 6 -alkoxy, C 6 -Cio-aryloxy, C6-Cio-aryl-Ci-C 6 -alkoxy, C
- o represents 0 or 1 and W represents O, CH 2 , 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 h alky I, fluoro or chloro; CONH 2 ; SO 2 NH 2 ; CONH 2 or SO 2 NH 2 wherein the amino functionality is optionally substituted one or more times with residues selected from Ci-C ⁇ -alkyl or C ⁇ -Cio-aryl; fluoro; chloro; bromo; CF 3 ; or OCF 3 .
- R 1 to R 5 represent fluorine or chlorine. It is most preferred that either R 1 or R 5 represents fluorine.
- R 1 to R 5 represent hydroxy; Ci-C ⁇ -alkoxy, C ⁇ -Cio-aryloxy, Ce-Cio-aryl-Ci-C ⁇ -alkoxy, Ci-C ⁇ -alkylcarboxy, C ⁇ -Cio-arylcarboxy, Ci-C ⁇ -alkylsulfonyl, C ⁇ -Cio-arylsulfonyl, each of which is optionally substituted once or several times by Ci-C ⁇ -alkyl, Ci-C ⁇ -alkoxy, CONH 2 or SO 2 NH 2 optionally substituted once or twice with Ci-C 6 -alkyl or C 6 -Cio-aryl; amino, Ci-C 4 -alkylamino, di-C 1 -C 4 -alkylam.no, hydroxy, fluoro, chloro, bromo, CF 3 or OCF 3 .
- one of R 2 , R 3 or R 4 represents hydroxy; Ci-C ⁇ -alkoxy, C ⁇ -Cio-aryloxy, C ⁇ -Cio-aryl-Ci-C ⁇ -alkoxy, each of which is optionally substituted once or several times by Ci-C4-alkyl, Ci-C 4 -alkoxy, CONH 2 or SO2NH2 optionally substituted once or twice with Ci-C ⁇ -alkyl or C ⁇ -Cio-aryl; amino, Ci-C 4 -alkylamino, di- Ci-C 4 -alkylamino, hydroxy, fluoro, chloro, or bromo.
- R 1 to R 5 represent amino; amino substituted one or more times with residues selected from Ci-C ⁇ -alkyl, C ⁇ -Cio-aryl; or a disubstituted amino of the following formula (II)
- o represents 0 or 1 and W represents O, CH 2 , or NR 6 with R 6 being selected from hydrogen and d-C 4 -alkyl and wherein the methylene groups in formula (II) may optionally be substituted once or twice with Ci-C 4 -alkyl, fluoro or chloro.
- one of R 2 , R 3 or R 4 represents 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 0 or 1 and W represents O, CH 2 , 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 4 -alkyl, fluoro or chloro.
- Ci-C ⁇ -alkyl C 6 -Ci 0 -aryl, C 6 -C 10 -aryl-Ci-C4-alkyl, Ci-C ⁇ -alkoxy, C ⁇ -Cw-aryloxy, C 6 -C 1 o-aryl-C 1 -C 4 -alkoxy , each of which is optionally substituted once or several times by Ci-C ⁇ -alkyl; Ci-C 6 -alkoxy; CONH 2 or SOaNH 2 , optionally substituted once or twice with Ci-C ⁇ -alkyl; SO3H; CO 2 H; amino; amino substituted one or more times with residues selected from Ci-C ⁇ -alkyl, C 6 -Cio-aryl, C6-Ci O -aryl-C 1 -C4-alkyl, Ci-C ⁇ -alkylcarbonyl, Ce-Cio-arylcarbonyl, Ci-C ⁇ -alkylsulfon
- Ci-C ⁇ -alkyl residues may be combined to form 5 or 6- membered rings; amino; amino substituted once or several times with Ci-C ⁇ -alkyl or phenyl; a disubstituted amino of the following formula (II)
- o represents O or 1 and W represents O, CH 2 , or NR 6 with R 6 being selected from hydrogen and Ci-C 4 -alkyl and wherein the methylene groups in formula (II) may optionally be substituted once or twice with Ci-C 4 -alkyl, fluoro or chloro;
- Ci-C ⁇ -alkyl a saturated, unsaturated or aromatic heterocyclic ring system of up to 10 atoms, optionally substituted once or several times by Ci-C ⁇ -alkyl; d-C ⁇ -alkoxy; COOH; CONH 2 or SO 2 NH 2 , optionally substituted once or twice with Ci-C ⁇ -alkyl, wherein these optional Ci-C ⁇ -alkyl residues may be combined to form 5 or 6-membered rings; SO 3 H; amino; amino substituted one or more times with residues selected from Ci-C 6 -alkyl, C 6 -Cio-aryl, Ci-Ce-alkylcarbonyl, C ⁇ -Cio-arylcarbonyl, Ci-C ⁇ -alkylsulfonyl and C ⁇ -C t o-arylsulfonyl; thiol; hydroxyl; nitro; cyano; fluoro; chloro; bromo; iodo; CF 3
- Y is substituted once or several times by Ci-C-j-alkyl; phenyl; Ci-C4-alkoxy; hydroxy; fluoro; chloro; bromo; CF 3 ; OCF 3 ; CONH 2 or SO 2 NH 2 , optionally substituted once or twice with Ci-C 4 -alkyl, wherein these optional Ci-C 4 -alkyl residues may be combined to form 5 or 6-membered rings; or amino.
- m represents 0 and Y represents phenyl which is substituted once or twice by hydroxy, fluoro, chloro or bromo.
- m represents 0 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.
- the reaction mixture was stirred at -5 0 C for 1 h and then allowed to warm to room temperature.
- the beige suspension was filtered, the filter cake was dissolved in water and the resulting solution was made basic by the addition of 3 N aqueous sodium hydroxide solution.
- the mixture was then extracted with dichloromethane and the combined extracts washed with water and brine, then dried (MgSO 4 ), filtered and evaporated.
- the resulting dark red-brown solid was was crystallized from diethyl ether/petroleum ether to afford (2-fluoro-4- methoxyphenyl)hydrazine as a dark pink solid (1.24 g, 53 %).
- Table 1 shows further compounds that were prepared in a similar manner. For solid materials, the melting point is given. For oils, the NMR data is given in Table 2. Table 1
- Frozen brains (without cerebellum) from Wistar rats were used, and each brain was homogenized in 15 mL 1 mM MgCl 2 , 2OnM HEPES pH 7.0 with Potter Elvejhem (8 strokes at 500 rpm). Homogenates were centrifuged for 20 min at 3600Og at 4°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 3600Og 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 (1OmM) were prepared in 100 % DMSO and the DMSO concentration in the assay was 0.1 %.
- 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°C). Food and tap water were allowed ad libitum and the experiments were all carried out during daylight hours.
- 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°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 all of which are characterized by a 5-0-substituted 3-N-phenyl-l,3,4-oxadiazolone structural unit, have unexpectedly high inhibition of FAAH, making these novel compounds promising candidates for medicaments for the treatment or prevention of FAAH-related medical conditions. Furthermore, the surprisingly high FAAH inhibition is evident not only in- vitro but also in-vivo. Furthermore, a comparison of the in-vivo data also demonstrates that the FAAH inhibitory activity of compounds having a 5-0-substituted 3-N-phenyl-l,3,4-oxadiazolone structural unit is characterized by a peripheral selectivity when compared with activity in the central nervous system (CNS).
- CNS central nervous system
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Abstract
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US930207P | 2007-12-27 | 2007-12-27 | |
PCT/PT2008/000054 WO2009084970A1 (fr) | 2007-12-27 | 2008-12-23 | 3-n-phényl-1,3,4-oxadiazolones 5-o-substituées pour une utilisation médicale |
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AR076687A1 (es) * | 2009-05-18 | 2011-06-29 | Infinity Pharmaceuticals Inc | Isoxazolinas como inhibidores de la amidahidrolasa de acidos grasos y com-posiciones farmaceuticas que los contienen |
WO2010151160A1 (fr) * | 2009-06-24 | 2010-12-29 | Bial - Portela & Ca., S.A. | 3-n-hétéroaryl-1,3,4-oxadiazolones o substitué pour utilisation médicale |
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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DE19942354A1 (de) * | 1999-09-04 | 2001-03-08 | Aventis Pharma Gmbh | Substituierte 3-Phenyl-5-alkoxi-1,3,4-oxdiazol-2-one, ihre Herstellung und Verwendung in Arzneimitteln |
AU2002347985A1 (en) * | 2001-11-15 | 2003-06-10 | Eli Lilly And Company | Peroxisome proliferator activated receptor alpha agonists |
DE10208987A1 (de) * | 2002-02-28 | 2003-09-11 | Aventis Pharma Gmbh | Substituierte 3-Phenyl-5-alkoxi-1,3,4-oxidiazol-2-one, ihre Herstellung und Verwendung in Arzneistoffen |
US20090111778A1 (en) * | 2005-11-18 | 2009-04-30 | Richard Apodaca | 2-Keto-Oxazoles as Modulators of Fatty Acid Amide Hydrolase |
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