RU2331637C2 - Производные алкилпиперазин- и алкилгомопиперазинкарбоксилатов, их получение и применение в качестве ингибиторов фермента faah - Google Patents
Производные алкилпиперазин- и алкилгомопиперазинкарбоксилатов, их получение и применение в качестве ингибиторов фермента faah Download PDFInfo
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- RU2331637C2 RU2331637C2 RU2006134047/04A RU2006134047A RU2331637C2 RU 2331637 C2 RU2331637 C2 RU 2331637C2 RU 2006134047/04 A RU2006134047/04 A RU 2006134047/04A RU 2006134047 A RU2006134047 A RU 2006134047A RU 2331637 C2 RU2331637 C2 RU 2331637C2
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- Prior art keywords
- phenyl
- base
- radical
- general formula
- radicals
- Prior art date
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- 239000003940 fatty acid amidase inhibitor Substances 0.000 title abstract 2
- 150000001875 compounds Chemical class 0.000 claims abstract description 81
- 238000000034 method Methods 0.000 claims abstract description 10
- 125000001570 methylene group Chemical group [H]C([H])([*:1])[*:2] 0.000 claims abstract description 6
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 5
- 208000015122 neurodegenerative disease Diseases 0.000 claims abstract description 4
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims abstract 2
- -1 benzyloxy, naphthalenyl Chemical group 0.000 claims description 105
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 28
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 20
- 150000003839 salts Chemical class 0.000 claims description 18
- 239000002253 acid Substances 0.000 claims description 17
- 239000012453 solvate Substances 0.000 claims description 14
- 101000918494 Homo sapiens Fatty-acid amide hydrolase 1 Proteins 0.000 claims description 10
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- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 9
- 230000007170 pathology Effects 0.000 claims description 9
- 125000006272 (C3-C7) cycloalkyl group Chemical group 0.000 claims description 8
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Chemical compound BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 7
- 239000000460 chlorine Substances 0.000 claims description 7
- 229910052801 chlorine Inorganic materials 0.000 claims description 7
- 125000005843 halogen group Chemical group 0.000 claims description 7
- 125000001041 indolyl group Chemical group 0.000 claims description 7
- 125000001624 naphthyl group Chemical group 0.000 claims description 7
- 238000011282 treatment Methods 0.000 claims description 7
- 230000001154 acute effect Effects 0.000 claims description 6
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 6
- 239000003814 drug Substances 0.000 claims description 6
- 125000000842 isoxazolyl group Chemical group 0.000 claims description 6
- 206010028980 Neoplasm Diseases 0.000 claims description 5
- 125000000217 alkyl group Chemical group 0.000 claims description 5
- 229910052794 bromium Inorganic materials 0.000 claims description 5
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 5
- 125000004430 oxygen atom Chemical group O* 0.000 claims description 5
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 5
- 230000002265 prevention Effects 0.000 claims description 5
- 125000000714 pyrimidinyl group Chemical group 0.000 claims description 5
- 125000002733 (C1-C6) fluoroalkyl group Chemical group 0.000 claims description 4
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical group [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 claims description 4
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- 125000003545 alkoxy group Chemical group 0.000 claims description 4
- 150000001412 amines Chemical class 0.000 claims description 4
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- 229910052740 iodine Inorganic materials 0.000 claims description 4
- 125000003226 pyrazolyl group Chemical group 0.000 claims description 4
- 125000002943 quinolinyl group Chemical group N1=C(C=CC2=CC=CC=C12)* 0.000 claims description 4
- 239000000758 substrate Substances 0.000 claims description 4
- 238000007098 aminolysis reaction Methods 0.000 claims description 3
- 125000005982 diphenylmethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])(*)C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 claims description 3
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- 125000001424 substituent group Chemical group 0.000 claims description 3
- 208000024172 Cardiovascular disease Diseases 0.000 claims description 2
- KZBUYRJDOAKODT-UHFFFAOYSA-N Chlorine Chemical compound ClCl KZBUYRJDOAKODT-UHFFFAOYSA-N 0.000 claims description 2
- 208000018522 Gastrointestinal disease Diseases 0.000 claims description 2
- 208000019693 Lung disease Diseases 0.000 claims description 2
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 claims description 2
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- 208000001132 Osteoporosis Diseases 0.000 claims description 2
- 206010063897 Renal ischaemia Diseases 0.000 claims description 2
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- 125000002947 alkylene group Chemical group 0.000 claims description 2
- 208000026935 allergic disease Diseases 0.000 claims description 2
- 208000022362 bacterial infectious disease Diseases 0.000 claims description 2
- 201000011510 cancer Diseases 0.000 claims description 2
- 150000005560 carbamic acid amides Chemical class 0.000 claims description 2
- 230000001684 chronic effect Effects 0.000 claims description 2
- 208000002173 dizziness Diseases 0.000 claims description 2
- 230000007937 eating Effects 0.000 claims description 2
- 206010015037 epilepsy Diseases 0.000 claims description 2
- 208000030533 eye disease Diseases 0.000 claims description 2
- 125000004428 fluoroalkoxy group Chemical group 0.000 claims description 2
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- 230000004770 neurodegeneration Effects 0.000 claims description 2
- 230000000926 neurological effect Effects 0.000 claims description 2
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- 208000023504 respiratory system disease Diseases 0.000 claims description 2
- 208000019116 sleep disease Diseases 0.000 claims description 2
- 125000000335 thiazolyl group Chemical group 0.000 claims description 2
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 claims description 2
- JOYRKODLDBILNP-UHFFFAOYSA-N urethane group Chemical group NC(=O)OCC JOYRKODLDBILNP-UHFFFAOYSA-N 0.000 claims description 2
- 230000003612 virological effect Effects 0.000 claims description 2
- 230000008673 vomiting Effects 0.000 claims description 2
- 206010063057 Cystitis noninfective Diseases 0.000 claims 1
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- 230000000694 effects Effects 0.000 abstract description 5
- 229910052760 oxygen Inorganic materials 0.000 abstract description 3
- 239000000126 substance Substances 0.000 abstract description 3
- 239000001301 oxygen Substances 0.000 abstract description 2
- 206010061218 Inflammation Diseases 0.000 abstract 2
- 230000004054 inflammatory process Effects 0.000 abstract 2
- 230000003119 painkilling effect Effects 0.000 abstract 2
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 abstract 1
- 239000002585 base Substances 0.000 description 156
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 81
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 69
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 51
- 125000000250 methylamino group Chemical group [H]N(*)C([H])([H])[H] 0.000 description 42
- 239000000203 mixture Substances 0.000 description 29
- 239000000243 solution Substances 0.000 description 25
- 239000000047 product Substances 0.000 description 23
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 20
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 15
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 15
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 15
- RFIOZSIHFNEKFF-UHFFFAOYSA-M piperazine-1-carboxylate Chemical compound [O-]C(=O)N1CCNCC1 RFIOZSIHFNEKFF-UHFFFAOYSA-M 0.000 description 15
- 230000002829 reductive effect Effects 0.000 description 15
- 229920006395 saturated elastomer Polymers 0.000 description 13
- 238000010898 silica gel chromatography Methods 0.000 description 13
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 12
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 12
- 125000003854 p-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Cl 0.000 description 12
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- 239000007864 aqueous solution Substances 0.000 description 11
- GLUUGHFHXGJENI-UHFFFAOYSA-N diethylenediamine Natural products C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 description 11
- 238000002844 melting Methods 0.000 description 11
- 230000008018 melting Effects 0.000 description 11
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 10
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 10
- 239000011780 sodium chloride Substances 0.000 description 10
- 125000004179 3-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C(Cl)=C1[H] 0.000 description 9
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 9
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 9
- 239000012074 organic phase Substances 0.000 description 9
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 9
- 229910052938 sodium sulfate Inorganic materials 0.000 description 9
- 235000011152 sodium sulphate Nutrition 0.000 description 9
- 239000007787 solid Substances 0.000 description 9
- HZAXFHJVJLSVMW-UHFFFAOYSA-N 2-Aminoethan-1-ol Chemical compound NCCO HZAXFHJVJLSVMW-UHFFFAOYSA-N 0.000 description 8
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 8
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- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 7
- 125000004432 carbon atom Chemical group C* 0.000 description 7
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- 238000001816 cooling Methods 0.000 description 6
- 229910052731 fluorine Inorganic materials 0.000 description 6
- 238000012360 testing method Methods 0.000 description 6
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 description 5
- JTOWYPLFWBIAPN-UHFFFAOYSA-N [2-(methylamino)-2-oxoethyl] piperazine-1-carboxylate;hydrochloride Chemical compound Cl.CNC(=O)COC(=O)N1CCNCC1 JTOWYPLFWBIAPN-UHFFFAOYSA-N 0.000 description 5
- LGEQQWMQCRIYKG-DOFZRALJSA-N anandamide Chemical compound CCCCC\C=C/C\C=C/C\C=C/C\C=C/CCCC(=O)NCCO LGEQQWMQCRIYKG-DOFZRALJSA-N 0.000 description 5
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- 125000004182 2-chlorophenyl group Chemical group [H]C1=C([H])C(Cl)=C(*)C([H])=C1[H] 0.000 description 4
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical group [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 4
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 4
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 4
- 125000001931 aliphatic group Chemical group 0.000 description 4
- 229910021529 ammonia Inorganic materials 0.000 description 4
- LGEQQWMQCRIYKG-UHFFFAOYSA-N arachidonic acid ethanolamide Natural products CCCCCC=CCC=CCC=CCC=CCCCC(=O)NCCO LGEQQWMQCRIYKG-UHFFFAOYSA-N 0.000 description 4
- 125000000319 biphenyl-4-yl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1C1=C([H])C([H])=C([*])C([H])=C1[H] 0.000 description 4
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- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonium chloride Substances [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 3
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- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 3
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- APXOQEJUTPZKAC-UHFFFAOYSA-N [2-(methylamino)-2-oxoethyl] (4-nitrophenyl) carbonate Chemical compound CNC(=O)COC(=O)OC1=CC=C([N+]([O-])=O)C=C1 APXOQEJUTPZKAC-UHFFFAOYSA-N 0.000 description 2
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- 208000018198 spasticity Diseases 0.000 description 1
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- 125000004434 sulfur atom Chemical group 0.000 description 1
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- CWXPZXBSDSIRCS-UHFFFAOYSA-N tert-butyl piperazine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CCNCC1 CWXPZXBSDSIRCS-UHFFFAOYSA-N 0.000 description 1
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Classifications
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
- C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
- C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D215/20—Oxygen atoms
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
- C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
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- C07D215/20—Oxygen atoms
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- C07D215/26—Alcohols; Ethers thereof
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- C07D243/00—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms
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- C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
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Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
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| FR0401953A FR2866888B1 (fr) | 2004-02-26 | 2004-02-26 | Derives de alkylpiperazine- et alkylhomopiperazine- carboxylates, leur preparation et leur application en therapeutique |
| FR0401953 | 2004-02-26 | ||
| PCT/FR2005/000450 WO2005090322A1 (fr) | 2004-02-26 | 2005-02-25 | Derives de alkylpiperazine- et alkylhomopiperazine- carboxylates, leur preparation et leur application en tant qu’inhibiteurs de l’enzyme faah |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| RU2006134047A RU2006134047A (ru) | 2008-04-10 |
| RU2331637C2 true RU2331637C2 (ru) | 2008-08-20 |
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| RU2006134047/04A RU2331637C2 (ru) | 2004-02-26 | 2005-02-25 | Производные алкилпиперазин- и алкилгомопиперазинкарбоксилатов, их получение и применение в качестве ингибиторов фермента faah |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| RU2376305C2 (ru) * | 2004-02-26 | 2009-12-20 | Санофи-Авентис | Производные арил- и гетероарилпиперидинкарбоксилатов, их получение и их применение в качестве ингибиторов фермента faah |
| RU2539595C2 (ru) * | 2009-05-18 | 2015-01-20 | Инфинити Фармасьютикалз, Инк. | Изоксазолины в качестве ингибиторов амидгидролазы жирных кислот |
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| SE0102299D0 (sv) | 2001-06-26 | 2001-06-26 | Astrazeneca Ab | Compounds |
| US7269708B2 (en) * | 2004-04-20 | 2007-09-11 | Rambus Inc. | Memory controller for non-homogenous memory system |
| AU2006215080B2 (en) | 2005-02-17 | 2011-03-10 | Astellas Pharma Inc. | Pyridyl non-aromatic nitrogenated heterocyclic-1-carboxylate ester derivative |
| US7918848B2 (en) | 2005-03-25 | 2011-04-05 | Maquet Cardiovascular, Llc | Tissue welding and cutting apparatus and method |
| US8197472B2 (en) | 2005-03-25 | 2012-06-12 | Maquet Cardiovascular, Llc | Tissue welding and cutting apparatus and method |
| US7541359B2 (en) | 2005-06-30 | 2009-06-02 | Janssen Pharmaceutica N.V. | N-heteroarylpiperazinyl ureas as modulators of fatty acid amide hydrolase |
| EP2065369A4 (en) * | 2006-08-23 | 2011-12-28 | Astellas Pharma Inc | UREA CONNECTION OR SALT THEREOF |
| US9968396B2 (en) | 2008-05-27 | 2018-05-15 | Maquet Cardiovascular Llc | Surgical instrument and method |
| JP2011521723A (ja) | 2008-05-27 | 2011-07-28 | マッケ カーディオバスキュラー，エルエルシー | 外科用器具および方法 |
| US9402680B2 (en) | 2008-05-27 | 2016-08-02 | Maquet Cardiovasular, Llc | Surgical instrument and method |
| CN101712655B (zh) * | 2008-10-08 | 2012-05-23 | 秦引林 | 一种乙酰胺类衍生物及其在制药中的应用 |
| CN101503394B (zh) * | 2009-03-11 | 2010-05-12 | 深圳市湘雅生物医药研究院 | 高哌嗪乙酰肼类衍生物及其制备方法和用途 |
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| WO2012015704A2 (en) * | 2010-07-28 | 2012-02-02 | The Regents Of The University Of California | Peripherally restricted faah inhibitors |
| MX354772B (es) | 2011-08-19 | 2018-03-21 | Univ California | Inhibidores de la amida de acidos grasos (faah) restringidos perifericamente por bifenil metasustituido. |
| EP3988540A1 (en) | 2014-04-07 | 2022-04-27 | The Regents of the University of California | Inhibitors of fatty acid amide hydrolase (faah) enzyme with improved oral bioavailability and their use as medicaments |
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| FR2865205B1 (fr) * | 2004-01-16 | 2006-02-24 | Sanofi Synthelabo | Derives de type aryloxyalkylcarbamates, leur preparation et leur application en therapeutique |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| RU2376305C2 (ru) * | 2004-02-26 | 2009-12-20 | Санофи-Авентис | Производные арил- и гетероарилпиперидинкарбоксилатов, их получение и их применение в качестве ингибиторов фермента faah |
| RU2539595C2 (ru) * | 2009-05-18 | 2015-01-20 | Инфинити Фармасьютикалз, Инк. | Изоксазолины в качестве ингибиторов амидгидролазы жирных кислот |
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