IL201472A - Intermediates for the preparation of dioxane-2-alkyl carbamates - Google Patents
Intermediates for the preparation of dioxane-2-alkyl carbamatesInfo
- Publication number
- IL201472A IL201472A IL201472A IL20147209A IL201472A IL 201472 A IL201472 A IL 201472A IL 201472 A IL201472 A IL 201472A IL 20147209 A IL20147209 A IL 20147209A IL 201472 A IL201472 A IL 201472A
- Authority
- IL
- Israel
- Prior art keywords
- dioxan
- naphthalen
- trans
- general formula
- phenyl
- Prior art date
Links
- 238000002360 preparation method Methods 0.000 title description 8
- 239000000543 intermediate Substances 0.000 title description 3
- -1 (pyridin-4-yl) methyl group Chemical group 0.000 claims description 67
- 150000001875 compounds Chemical class 0.000 claims description 58
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 14
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 9
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 8
- 125000000217 alkyl group Chemical group 0.000 claims description 6
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 54
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 36
- 239000000243 solution Substances 0.000 description 32
- 239000000203 mixture Substances 0.000 description 29
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 26
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 24
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 16
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 14
- 238000000034 method Methods 0.000 description 14
- 125000003854 p-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Cl 0.000 description 14
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 12
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 12
- 239000012074 organic phase Substances 0.000 description 12
- 239000000047 product Substances 0.000 description 12
- 125000004206 2,2,2-trifluoroethyl group Chemical group [H]C([H])(*)C(F)(F)F 0.000 description 11
- 238000002844 melting Methods 0.000 description 11
- 230000008018 melting Effects 0.000 description 11
- 150000003839 salts Chemical class 0.000 description 10
- 239000002904 solvent Substances 0.000 description 10
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 10
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 9
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 9
- 150000001412 amines Chemical class 0.000 description 9
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 9
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 9
- 229920006395 saturated elastomer Polymers 0.000 description 9
- HZAXFHJVJLSVMW-UHFFFAOYSA-N 2-Aminoethan-1-ol Chemical compound NCCO HZAXFHJVJLSVMW-UHFFFAOYSA-N 0.000 description 8
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 8
- 238000004587 chromatography analysis Methods 0.000 description 8
- 239000000741 silica gel Substances 0.000 description 8
- 229910002027 silica gel Inorganic materials 0.000 description 8
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 8
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 7
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 7
- 201000010099 disease Diseases 0.000 description 7
- 239000000706 filtrate Substances 0.000 description 7
- 229910052938 sodium sulfate Inorganic materials 0.000 description 7
- 235000011152 sodium sulphate Nutrition 0.000 description 7
- 239000007787 solid Substances 0.000 description 7
- 125000006274 (C1-C3)alkoxy group Chemical group 0.000 description 6
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 6
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 6
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 6
- 238000005481 NMR spectroscopy Methods 0.000 description 6
- 208000002193 Pain Diseases 0.000 description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- 239000008346 aqueous phase Substances 0.000 description 6
- ZMXDDKWLCZADIW-UHFFFAOYSA-N dimethylformamide Substances CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 6
- 239000011780 sodium chloride Substances 0.000 description 6
- 239000012453 solvate Substances 0.000 description 6
- 125000003944 tolyl group Chemical group 0.000 description 6
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 5
- 102000004190 Enzymes Human genes 0.000 description 5
- 108090000790 Enzymes Proteins 0.000 description 5
- 206010028980 Neoplasm Diseases 0.000 description 5
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 5
- 239000002253 acid Substances 0.000 description 5
- 125000005843 halogen group Chemical group 0.000 description 5
- YNTOKMNHRPSGFU-UHFFFAOYSA-N n-Propyl carbamate Chemical compound CCCOC(N)=O YNTOKMNHRPSGFU-UHFFFAOYSA-N 0.000 description 5
- 230000001575 pathological effect Effects 0.000 description 5
- 239000000725 suspension Substances 0.000 description 5
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 5
- 125000001622 2-naphthyl group Chemical group [H]C1=C([H])C([H])=C2C([H])=C(*)C([H])=C([H])C2=C1[H] 0.000 description 4
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 4
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 description 4
- 230000001154 acute effect Effects 0.000 description 4
- 239000012298 atmosphere Substances 0.000 description 4
- 229910052794 bromium Inorganic materials 0.000 description 4
- 125000004432 carbon atom Chemical group C* 0.000 description 4
- 229910052801 chlorine Inorganic materials 0.000 description 4
- 239000000460 chlorine Substances 0.000 description 4
- 125000004093 cyano group Chemical group *C#N 0.000 description 4
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 4
- 229910052740 iodine Inorganic materials 0.000 description 4
- 239000000546 pharmaceutical excipient Substances 0.000 description 4
- 238000003756 stirring Methods 0.000 description 4
- 238000005406 washing Methods 0.000 description 4
- 125000006273 (C1-C3) alkyl group Chemical group 0.000 description 3
- 125000006555 (C3-C5) cycloalkyl group Chemical group 0.000 description 3
- 125000001255 4-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1F 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical group [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 3
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 description 3
- KZBUYRJDOAKODT-UHFFFAOYSA-N Chlorine Chemical compound ClCl KZBUYRJDOAKODT-UHFFFAOYSA-N 0.000 description 3
- 201000002661 Spondylitis Diseases 0.000 description 3
- 150000007513 acids Chemical class 0.000 description 3
- 238000007098 aminolysis reaction Methods 0.000 description 3
- 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 3
- LGEQQWMQCRIYKG-UHFFFAOYSA-N arachidonic acid ethanolamide Natural products CCCCCC=CCC=CCC=CCC=CCCCC(=O)NCCO LGEQQWMQCRIYKG-UHFFFAOYSA-N 0.000 description 3
- 239000001569 carbon dioxide Substances 0.000 description 3
- 229910002092 carbon dioxide Inorganic materials 0.000 description 3
- 150000004649 carbonic acid derivatives Chemical class 0.000 description 3
- 230000001684 chronic effect Effects 0.000 description 3
- 235000014113 dietary fatty acids Nutrition 0.000 description 3
- 239000003814 drug Substances 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 239000000194 fatty acid Substances 0.000 description 3
- 229930195729 fatty acid Natural products 0.000 description 3
- 150000004665 fatty acids Chemical class 0.000 description 3
- 239000011521 glass Substances 0.000 description 3
- 230000007062 hydrolysis Effects 0.000 description 3
- 238000006460 hydrolysis reaction Methods 0.000 description 3
- 208000027866 inflammatory disease Diseases 0.000 description 3
- 230000002401 inhibitory effect Effects 0.000 description 3
- 238000007912 intraperitoneal administration Methods 0.000 description 3
- 208000002551 irritable bowel syndrome Diseases 0.000 description 3
- 229940126601 medicinal product Drugs 0.000 description 3
- 239000008194 pharmaceutical composition Substances 0.000 description 3
- WSDQIHATCCOMLH-UHFFFAOYSA-N phenyl n-(3,5-dichlorophenyl)carbamate Chemical compound ClC1=CC(Cl)=CC(NC(=O)OC=2C=CC=CC=2)=C1 WSDQIHATCCOMLH-UHFFFAOYSA-N 0.000 description 3
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 3
- 238000001953 recrystallisation Methods 0.000 description 3
- 210000001519 tissue Anatomy 0.000 description 3
- NXLNNXIXOYSCMB-UHFFFAOYSA-N (4-nitrophenyl) carbonochloridate Chemical compound [O-][N+](=O)C1=CC=C(OC(Cl)=O)C=C1 NXLNNXIXOYSCMB-UHFFFAOYSA-N 0.000 description 2
- KYVBNYUBXIEUFW-UHFFFAOYSA-N 1,1,3,3-tetramethylguanidine Chemical compound CN(C)C(=N)N(C)C KYVBNYUBXIEUFW-UHFFFAOYSA-N 0.000 description 2
- SCYULBFZEHDVBN-UHFFFAOYSA-N 1,1-Dichloroethane Chemical compound CC(Cl)Cl SCYULBFZEHDVBN-UHFFFAOYSA-N 0.000 description 2
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 2
- 125000001637 1-naphthyl group Chemical group [H]C1=C([H])C([H])=C2C(*)=C([H])C([H])=C([H])C2=C1[H] 0.000 description 2
- RCRCTBLIHCHWDZ-UHFFFAOYSA-N 2-Arachidonoyl Glycerol Chemical compound CCCCCC=CCC=CCC=CCC=CCCCC(=O)OC(CO)CO RCRCTBLIHCHWDZ-UHFFFAOYSA-N 0.000 description 2
- 125000000979 2-amino-2-oxoethyl group Chemical group [H]C([*])([H])C(=O)N([H])[H] 0.000 description 2
- 125000004204 2-methoxyphenyl group Chemical group [H]C1=C([H])C(*)=C(OC([H])([H])[H])C([H])=C1[H] 0.000 description 2
- 125000004179 3-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C(Cl)=C1[H] 0.000 description 2
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 description 2
- 208000024827 Alzheimer disease Diseases 0.000 description 2
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 2
- 208000003174 Brain Neoplasms Diseases 0.000 description 2
- 101150041968 CDC13 gene Proteins 0.000 description 2
- BPYUAAOXJAQFAX-PPUGGXLSSA-N COc1ccc2c(cccc2c1)[C@H]1CO[C@H](CCCN)OC1 Chemical compound COc1ccc2c(cccc2c1)[C@H]1CO[C@H](CCCN)OC1 BPYUAAOXJAQFAX-PPUGGXLSSA-N 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- 208000000094 Chronic Pain Diseases 0.000 description 2
- 208000011231 Crohn disease Diseases 0.000 description 2
- 201000005569 Gout Diseases 0.000 description 2
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 2
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 2
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 2
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 2
- BAVYZALUXZFZLV-UHFFFAOYSA-N Methylamine Chemical compound NC BAVYZALUXZFZLV-UHFFFAOYSA-N 0.000 description 2
- LINDOXZENKYESA-UHFFFAOYSA-N TMG Natural products CNC(N)=NC LINDOXZENKYESA-UHFFFAOYSA-N 0.000 description 2
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 2
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 2
- 206010047115 Vasculitis Diseases 0.000 description 2
- 208000005298 acute pain Diseases 0.000 description 2
- 125000001931 aliphatic group Chemical group 0.000 description 2
- 125000003545 alkoxy group Chemical group 0.000 description 2
- QGZKDVFQNNGYKY-UHFFFAOYSA-N ammonia Natural products N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 2
- 206010003246 arthritis Diseases 0.000 description 2
- 238000003556 assay Methods 0.000 description 2
- 239000000872 buffer Substances 0.000 description 2
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 description 2
- 238000006243 chemical reaction Methods 0.000 description 2
- 238000005859 coupling reaction Methods 0.000 description 2
- 239000013078 crystal Substances 0.000 description 2
- 208000035475 disorder Diseases 0.000 description 2
- 238000001035 drying Methods 0.000 description 2
- 238000006911 enzymatic reaction Methods 0.000 description 2
- 150000002148 esters Chemical class 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 150000004677 hydrates Chemical class 0.000 description 2
- 230000002209 hydrophobic effect Effects 0.000 description 2
- 238000007918 intramuscular administration Methods 0.000 description 2
- 238000007913 intrathecal administration Methods 0.000 description 2
- 238000001990 intravenous administration Methods 0.000 description 2
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
- 239000012528 membrane Substances 0.000 description 2
- CXHHBNMLPJOKQD-UHFFFAOYSA-M methyl carbonate Chemical compound COC([O-])=O CXHHBNMLPJOKQD-UHFFFAOYSA-M 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 125000001624 naphthyl group Chemical group 0.000 description 2
- 201000008482 osteoarthritis Diseases 0.000 description 2
- 150000001475 oxazolidinediones Chemical class 0.000 description 2
- 230000036407 pain Effects 0.000 description 2
- 230000000144 pharmacologic effect Effects 0.000 description 2
- 239000012071 phase Substances 0.000 description 2
- AHWALFGBDFAJAI-UHFFFAOYSA-N phenyl carbonochloridate Chemical compound ClC(=O)OC1=CC=CC=C1 AHWALFGBDFAJAI-UHFFFAOYSA-N 0.000 description 2
- 230000002265 prevention Effects 0.000 description 2
- 208000029340 primitive neuroectodermal tumor Diseases 0.000 description 2
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
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- 206010039073 rheumatoid arthritis Diseases 0.000 description 2
- 239000011734 sodium Substances 0.000 description 2
- 229910052708 sodium Inorganic materials 0.000 description 2
- 235000017557 sodium bicarbonate Nutrition 0.000 description 2
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 2
- MFRIHAYPQRLWNB-UHFFFAOYSA-N sodium tert-butoxide Chemical compound [Na+].CC(C)(C)[O-] MFRIHAYPQRLWNB-UHFFFAOYSA-N 0.000 description 2
- 238000007920 subcutaneous administration Methods 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 230000000699 topical effect Effects 0.000 description 2
- 125000005490 tosylate group Chemical group 0.000 description 2
- 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 description 2
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 2
- YCVURLGFTSUYQJ-UHFFFAOYSA-N (1-tritylimidazol-2-yl)methanol Chemical compound OCC1=NC=CN1C(C=1C=CC=CC=1)(C=1C=CC=CC=1)C1=CC=CC=C1 YCVURLGFTSUYQJ-UHFFFAOYSA-N 0.000 description 1
- RYWGPCLTVXMMHO-UHFFFAOYSA-N (4-chlorophenyl) carbonochloridate Chemical compound ClC(=O)OC1=CC=C(Cl)C=C1 RYWGPCLTVXMMHO-UHFFFAOYSA-N 0.000 description 1
- XGDZAPUEJRQPOD-ZLCLUPBPSA-N (5z,8z,11z,14z)-n-(2-hydroxyethyl)icosa-5,8,11,14-tetraenamide Chemical compound CCCCC\C=C/C\C=C/C\C=C/C\C=C/CCCC(=O)NCCO.CCCCC\C=C/C\C=C/C\C=C/C\C=C/CCCC(=O)NCCO XGDZAPUEJRQPOD-ZLCLUPBPSA-N 0.000 description 1
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 description 1
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 description 1
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 description 1
- BDERNNFJNOPAEC-UHFFFAOYSA-N 1-propanol Substances CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 1
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- ZFFMLCVRJBZUDZ-UHFFFAOYSA-N 2,3-dimethylbutane Chemical group CC(C)C(C)C ZFFMLCVRJBZUDZ-UHFFFAOYSA-N 0.000 description 1
- RDDXOPGLTRAHGE-UHFFFAOYSA-N 2-(4-chloronaphthalen-1-yl)propane-1,3-diol Chemical compound C1=CC=C2C(C(CO)CO)=CC=C(Cl)C2=C1 RDDXOPGLTRAHGE-UHFFFAOYSA-N 0.000 description 1
- QKNYBSVHEMOAJP-UHFFFAOYSA-N 2-amino-2-(hydroxymethyl)propane-1,3-diol;hydron;chloride Chemical compound Cl.OCC(N)(CO)CO QKNYBSVHEMOAJP-UHFFFAOYSA-N 0.000 description 1
- GOJUJUVQIVIZAV-UHFFFAOYSA-N 2-amino-4,6-dichloropyrimidine-5-carbaldehyde Chemical group NC1=NC(Cl)=C(C=O)C(Cl)=N1 GOJUJUVQIVIZAV-UHFFFAOYSA-N 0.000 description 1
- 125000004182 2-chlorophenyl group Chemical group [H]C1=C([H])C(Cl)=C(*)C([H])=C1[H] 0.000 description 1
- RLQZIECDMISZHS-UHFFFAOYSA-N 2-phenylcyclohexa-2,5-diene-1,4-dione Chemical compound O=C1C=CC(=O)C(C=2C=CC=CC=2)=C1 RLQZIECDMISZHS-UHFFFAOYSA-N 0.000 description 1
- VSBPFIKNUJWISH-UHFFFAOYSA-N 3-[5-[6-(cyclopropylmethoxy)naphthalen-1-yl]-1,3-dioxan-2-yl]propan-1-amine Chemical compound C1OC(CCCN)OCC1C1=CC=CC2=CC(OCC3CC3)=CC=C12 VSBPFIKNUJWISH-UHFFFAOYSA-N 0.000 description 1
- 125000004172 4-methoxyphenyl group Chemical group [H]C1=C([H])C(OC([H])([H])[H])=C([H])C([H])=C1* 0.000 description 1
- 208000030507 AIDS Diseases 0.000 description 1
- DLFVBJFMPXGRIB-UHFFFAOYSA-N Acetamide Chemical compound CC(N)=O DLFVBJFMPXGRIB-UHFFFAOYSA-N 0.000 description 1
- 102000004092 Amidohydrolases Human genes 0.000 description 1
- 108090000531 Amidohydrolases Proteins 0.000 description 1
- 229920000856 Amylose Polymers 0.000 description 1
- 206010002556 Ankylosing Spondylitis Diseases 0.000 description 1
- 208000019901 Anxiety disease Diseases 0.000 description 1
- 206010003210 Arteriosclerosis Diseases 0.000 description 1
- 206010003571 Astrocytoma Diseases 0.000 description 1
- 208000023275 Autoimmune disease Diseases 0.000 description 1
- 208000009137 Behcet syndrome Diseases 0.000 description 1
- 108091003079 Bovine Serum Albumin Proteins 0.000 description 1
- 201000006474 Brain Ischemia Diseases 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- 208000009079 Bronchial Spasm Diseases 0.000 description 1
- 206010006458 Bronchitis chronic Diseases 0.000 description 1
- MDNAKOIYLYRLKZ-SGNKCFNYSA-N COc1ccc2c(cccc2c1)[C@H]1CO[C@H](CCCNC(=O)OCC(O)=O)OC1 Chemical compound COc1ccc2c(cccc2c1)[C@H]1CO[C@H](CCCNC(=O)OCC(O)=O)OC1 MDNAKOIYLYRLKZ-SGNKCFNYSA-N 0.000 description 1
- 206010006895 Cachexia Diseases 0.000 description 1
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Description
201472/3 ιτΒΚ&Κ-ηρ p17K-2- Dj?T,7 imtf? Q^ra nam INTERMEDIATES FOR THE PREPARATION OF DIOXANE-2-ALKYL CARBAMATES SANOFI-AVENTIS C: 69425 The present application is a divisional application of IL 166882.
Summary of the Invention The present invention relates to compounds corresponding to general formula (III) (III) in which: R2 is a group of general formula CHR3CONHR4 in which R3 is a hydrogen atom or a methyl group and R is a hydrogen atom or a Ci-3-alkyl, C3_5-cycloalkyl or (pyridin-4-yl) methyl group; and U is a hydrogen atom or a nitro group.
Statement in accordance with Paragraph 1 of Commissioner' s Circular 23 (P) : Inasmuch as the invention is defined in the appended claims, it will be apparent that the portions of the present specification, which fall outside the scope of the claims, do not relate directly to the claimed invention . This Notice is not meant to disclaim any legitimate rights to which the Patentee is legally entitled, especially any rights in accordance with Section 49 of the Israel Patent Law.
Additional Aspects of the Application The invention relates to 1 , 3-d.ioxan-2-ylalkylcarbamate derivatives, to their preparation and to rheir use in therapeutics.
The compounds of the invention correspond to general formula (I) 201472/1 la 0 !D in which Ri represents a phenyl or naphthalenyl group optionally substituted with one or more halogen atoms or hydroxyl, cyano, nitro, {Ci~C3) alkyl , (C1-C3) alkoxy, trifluoromethyl, trifluoromethoxy, benzyloxy, (C3-C6) cycloalkyl-O- or (C3-C6> cycloalkyl (C1-C3) alkoxy groups; R2 represents either a group of general formula .CHR3CONHR4■ in which R3 represents a hydrogen atom or a methyl group and R4 represents a hydrogen atom or a (C1-C3) alkyl, (C3-C5) cycloalkyl or (pyridin-4-ylJiriethyl group, or a 2, 2, 2-trxfluoroethyl · group, or an { imidazol-2-yl ) methyl group, or a (benzimidazol-2~yl)methyl group, or a phenyl group optionally substituted with one or 2 more halogen atoms or cyano, nitro, {C1-C3) alkyl, (C1-C3) alkoxy, trifluoromethyl or trifluoromethoxy groups; and n represents a number ranging from 1 to 3.
The compounds of general formula (I) may comprise one or more asymmetric carbons. They may exist in the form of enantiomers or of diastereoisomers . The compounds of general formula (I) may also exist in the form of cis or trans stereoisomers. These enantiomers, diastereoisomers and stereoisomers, and also their mixtures, including the racemic mixtures, are part of the invention.
The compounds of formula (I) may exist in the form of bases or of addition salts with acids. Such addition salts are part of the invention.
These salts are advantageously prepared with pharmaceutically acceptable acids, but the salts of other acids which are of use, for example, for purifying or isolating the compounds of formula (I) are also part of the invention. The compounds of general formula (I) may be in the form of hydrates or of solvates, namely in the form of associations or of combinations with one or more molecules of water or with a solvent. Such hydrates and solvates are also part of the invention.
Compounds similar to those of the invention, for which R2 represents a linear or branched (C1-C4) alkyl group, have been described as 3 anticonvulsants in documents EP 0461958 and FR 2714056.
In the context of the invention: - the term " (Ct-C») where t and z can take the values of 1 to 6" is intended to mean a carbon chain which can have from t to z carbon atoms, for example , (C1-C3) " is intended to mean a carbon chain which can have from 1 to 3 carbon atoms; - the term "alkyl" is intended to mean a linear or branched, saturated aliphatic group; for example a (C3.-C3) alkyl group represents a linear or branched carbon chain of 1 to 3 carbon atoms, more particularly a methyl, ethyl, propyl or isopropyl; - the term "cycloalkyl" is intended to mean a cyclic alkyl group; for example, a (C3-C5) cycloalkyl group represents a cyclic carbon chain of 3 to 5 carbon atoms, more particularly a cyclopropyl, cyclobutyl or cyclopentyl ; - the term "alkoxy" is intended to mean an alkyloxy group containing a linear or branched, saturated aliphatic chain; - the term "halogen atom" is intended to mean a fluorine, a chlorine, a bromine or an iodine.
Among the compounds of general formula (I) , mention may be made of preferred compounds, which are defined as follows: Ri represents a naphthalenyl group optionally substituted with one or more halogen atoms or hydroxyl, cyano, nitro, (C1-C3) alkyl, (C1-C3) alkoxy , 4 trifluoromethyl , trifluoromethoxy, benzyloxy, (C3-C6) cycloalkyl-O- or (C3-C6) cycloalkyl (C1-C3) alkoxy groups; and/or R2 represents either a group of general formula CHR3CONHR4 in which R3 represents a hydrogen atom and R4 represents a hydrogen atom or a (Ci-C3)alkyl group, preferably a methyl or an ethyl, or (pyridin- 4-yl) methyl group, or a 2, 2, 2-trifluoroethyl group, or a phenyl group optionally substituted with one or more halogen atoms or cyano, nitro, (C1-C3) alkyl, (C1-C3) alkoxy, trifluoromethyl or trifluoromethoxy groups; and/or n represents 2 or 3.
The compounds for which both Ri, R2 and n are as defined above are particularly preferred.
By way of example of preferred compounds, mention may be made of the following compounds: 2-amino-2-oxoethyl trans-3- [5- (naphthalen-l-yl) -1 , 3-dioxan-2-yl] propylcarbamate 2- (rnethylamino) -2-oxoethyl trans-2- [ 5- (naphthalen-l-yl) -1, 3-dioxan-2-yl] ethylcarbamate 2- (rnethylamino) -2-oxoethyl trans-3- [5- (naphthalen-1-yl) -1, 3-dioxan-2~yl] ropylcarbamate 2, 2, 2-trifluoroethyl trans-2- [5- (naphthalen-l-yl) -1, 3-dioxan-2-yl] ethylcarbamate 2,2, 2-trifluoroethyl trans-3- [5- (naphthalen-l-yl ) - 1, 3-dioxan-2-yl] propylcarbamate phenyl trans-2- [5- (naphthalen-l-yl) -1, 3-dioxan-2-yl] ethylcarbamate phenyl trans-3- [5- (naphthalen-l-yl) -1, 3-dioxan-2-yl] ropylcarbamate 2-amino-2~oxoethyl trans-3- [5- ( 4-chloronaphthalen- 1-yl) -1, 3-dioxan-2-yl] propylcarbamate 2- (methylamino) -2-oxoethyl trans-3- [5- (4-chloro-naphthalen-l-yl) -1, 3-dioxan-2-yl] propylcarbamate 2- (methylamino) -2-oxoethyl trans-3- [ 5- ( 6-chloro-naphthalen-l-yl) -1, 3-dioxan-2-yl] propylcarbamate 2-amino-2-oxoethyl trans-3- [5- ( 6-methoxynaphthalen- 1-yl) -1, 3-dioxan-2-yl] propylcarbamate 2-amino-2-oxoethyl cis-3- [5- ( 6-raethoxynaphthalen-l-yl ) -1 , 3-dioxan-2-yl ] ropylcarbamate 2- (methylamino) -2-oxoethyl trans-2- [5- (6-methoxynaphthalen-l-yl) -1, 3-dioxan-2-yl] ethylcarbamate 4-chlorophenyl trans-2- [5- ( 6-methoxynaphthalen-l-yl ) -1, 3-dioxan-2-yl] ethylcarbamate 2 , 2, 2-trifluoroethyl trans-2- [5- ( 6-methoxynaphthalen-l-yl) -1 , 3~dioxan~2-yl] ethylcarbamate 2- (methylamino) -2-oxoethyl trans-3- [5- (6-methoxynaphthalen-l-yl ) -1 , 3-dioxan-2 -yl ] propylcarbamate 2- (ethylamino) -2-oxoethyl trans-3- [5- ( 6-methoxy-naphthalen-l-yl) -1, 3-dioxan-2-yl] propylcarbamate 2- [ (pyridin-4-yl) methylamino] -2-oxoethyl trans-3- [5- (6-methoxynaphthalen-l-yl) -1, 3-dioxan-2-yl ] propylcarbamate 2,2, 2-trifluoroethyl trans-3- [5- ( 6-methoxynaphthalen- 1-yl) -1, 3-dioxan-2-yl] ropylcarbamate phenyl trans-3- [5- { 6-methoxynaphthalen-l-yl) -1 , 3-dioxan-2-ylJ propylcarbamate 2~amino-2-oxoethyl trans-3- [ 5- ( 6-cyclopropylmethoxy-naphthalen-l-yl) -1, 3-dioxan~2-yl ] propylcarbamate 4-chlorophenyl trans-3- [5- ( 6-cyclopropylmethoxy-naphthalen-l-yl) -1, 3-dioxan-2-yl ] ropylcarbamate 2,2, 2-trifluoroethyl trans-3- [5- ( 6-cyclopropylmethoxy-napht alen-l-yl) -1, 3-dioxan-2-yl ] propylcarbamate 2-amino-2-oxoethyl trans-3- [ 5- ( 6-phenylmethoxy-naphthalen-l-yl) -1, 3-dioxan-2-yl ] propylcarbamate 2-amino-2-oxoethyl trans-3- [5- ( 6-hydroxynaphthalen- 1-yl) -1, 3-dioxan-2-yl] propylcarbamate 2- (methylamino ) -2-oxoethyl trans-3- [ 5- ( 6-hydroxy-naphthalen-l-yl) -1, 3-dioxan-2-yl]propylcarbamate 2-amino-2-oxoethyl trans-3- [ 5- (7-methoxynaphthalen- 1-y ) -1, 3-dioxan-2-yl] ropylcarbamate 2- (methylamino) -2-oxoethyl trans-3- [5- (7-methoxy-naphthalen-l-yl) -1, 3-dioxan-2-yl ] propylcarbamate 2, 2 2-trifluoroethyl trans-3- [5- (7-methoxynaphthalen- 1-yl) -1, 3-dioxan-2-yl] ropylcarbamate phenyl trans-3- [5- ( 7-methoxynaphthalen-l-yl) - 1, 3-dioxan-2-yl] propylcarbamate phenyl trans-3- [5- (naphthalen-2-yl) -1, 3-dioxan-2-yl] propylcarbamate 2- (methylamino) -2-oxoethyl trans-3- [5- (naphthalen-2-yl) -1, 3-dioxan-2-yl] propylcarbamate 2, 2, 2-trifluoroethyl trans-3- [5- (naphthalen-2-yl) - 7 1, 3-dioxan-2-yl] propylcarbamate .
The compounds of the invention can be prepared according to various methods, illustrated by the following schemes.
Thus, a method of preparation (Scheme 1) consists in reacting an amine of general formula (II), in which Rx and n are as defined in general formula (I), with a carbonate of general formula (III) , in which U represents a hydrogen atom or a nitro group and R2 is as defined in general formula (I), in a solvent such as toluene or dichloroethane, at a temperature of between 0 and 80°C.
Scheme 1 The carbonates of general formula (III) can be prepared according to any method described in the literature, for example by reacting an alcohol of general formula HOR2 with phenyl or 4 -nitrophenyl chloroformate, in the presence of a base such as triethylamine or diisopropylethylamine.
The compounds of general formula (I) for which R2 represents more particularly an optionally substituted phenyl group (Ar) can be prepared by reacting an amine of general formula (II), as defined 8 above, with an aryl chloroformate of general formula (Ilia) in a solvent such as dichloromethane or dichloroethane, in the presence of a base such as triethylamine or diisopropylethylamine, at a temperature of between 0°C and the reflux temperature of the solvent . 0 (Ilia) According to Scheme 2, the compounds of general formula (I) for which R2 represents more particularly a group of general formula CHR3CO HR4 can be prepared by reacting an amine of general formula (II), as defined above, with carbon dioxide in the presence of a base such as caesium ^ carbonate and a phase-transfer agent such as tetra-n-butyl ammonium iodide, in a solvent such as iV, AJ-dimethylformamide or W-methylpyrrolidone, and then with a haloacetamide of general formula (IV) in which V represents a chlorine, bromine or iodine atom and R3 and R¾ are as defined in general formula (I) .
Scheme 2 (I) R. 9 A variant (Scheme 3) for obtaining the compounds of general formula (I) in which R2 represents more particularly a group of general formula CHR3GONHR4 consists in reacting an amine of general formula (II), as defined above, with a carbonate of general formula (Illb) in which U represents a hydrogen atom or a nitro group, R3 is as defined in general formula (I) and R5 represents a methyl or ethyl group. The carbamate ester of general formula (la) thus obtained is then converted to a compound of general formula (I) , either by direct aminolysis by means of- an amine of general formula R4NH2 in which R4 is as defined in general formula (I) , or by hydrolysis to an acid of general formula (la), in which R5 represents a hydrogen atom, followed by coupling with an amine of general formula R4NH2 in which Rt is as. defined in general formula (I) . The aminolysis reaction can be carried out in a solvent such as methanol or a mixture of solvents such as methanol and tetrahydrofuran . The coupling reaction can be carried out according to any known method from the literature, for example using isobutyl chloroforrtiate in the presence of a base such as diisopropylethylamine .
Scheme 3 The carbonates of general formula (Illb) can be prepared in a manner similar to the carbonates of formula (III) .
Another variant (Scheme 4) for obtaining the compounds of general formula (I) in which R2 represents more particularly a group of general formula CHR3CONHR4 consists in reacting a derivative of general formula (Ila) , in which Z represents a hydroxyl, mesylate or tosylate group, or a chlorine, bromine or iodine atom, and Ri and n are as defined in general formula (I) , with an oxazolidinedione of general structure (V) in which R3 is as defined in general formula (I), to provide the oxazolidinedione derivative of general structure (VI) . When Z represents a hydroxyl group, the reaction can be carried out according to the conditions of Mitsunobu (Synthesis, 1981, 1-28) , for example by the action of diethyl or diisopropyl azodicarboxylate in the presence of triphenylphosphine . When Z represents a chlorine, bromine or iodine atom, or a mesylate or tosylate group, the reaction can be carried cut in the presence of a base such as 1, 1, 3, 3-tetramethylguanidine, sodium hydride or sodium tert-butoxide in a solvent such as tetrahydrofuran, acetonitrile or dimethylformamide, at a temperature of between 0°C and the reflux temperature of the solvent. The oxazolidinedione derivative of general formula {VI} thus obtained is then converted to a compound of general formula (I) by aminolysis by means of an amine of general formula R4 H2 where R4 is as defined in general formula (I) .
Scheme 4 0 (VI) t (I) The amines of general formula (II) can be prepared according to the methods of preparation described in patent applications EP 0461958, WO 97/20836 and WO 98/55474, optionally adapted 12 according to techniques known to those skilled in the art .
The compounds of general formulae (Ila) , (Ilia), (IV) and (V), and also the amines ¾NH2, when their method of preparation is not described, are commercially available or described in the literature, or else can be prepared according to methods which are described therein or which are known to those skilled in the art.
The compounds of general formula (la), in which Ri, R.3 and n are as defined in general formula (I) and R5 represents a hydrogen atom or a methyl or ethyl group, and the compounds of general formula (VI), in which Ri, R3 and n are as defined in general formula (I), are novel and are also part of the invention. They are of use as synthetic intermediates for preparing the compounds of general formula (I) .
The following examples illustrate the preparation of some compounds of the invention. These examples are not limiting and merely illustrate the invention. The microanalyses, the IR and NMR spectra and/or the LC-MS (liquid chromatography coupled to mass spectroscopy) confirm the structures and the purities of the compounds obtained.
The numbers indicated in brackets in the titles of the examples correspond to those of the 1st column of the table hereinafter. 13 Example 1 (Compound No. 61} 2- (Cyclopropylamino) -2-oxoethyl trans-3- [ 5- ( 6-methoxy-naphthalen-l-yl) -1, 3-dioxan-2-yl] propylcarbamate 1.1. Ethyl [ (phenoxycarbonyl)'oxy] acetate 13.5 ml (105.6 mmol) of phenyl chloroformate are added, dropwise, at ambient temperature to a solution of 10 g (96.15 mmol) -of ethyl glycolate and 27 ml (192.3 mmol) of triethylamine in 20 ml of toluene and the mixture is stirred at ambient temperature for 2 h. The salt formed is separated and the filtrate is concentrated under reduced pressure. g of oily product are obtained, which are used without modification in the following step. 1.2. Ethyl trans- [ [ [ [3- [5- ( 6-methoxynaphthalen-l-yl) - 1, 3-dioxan-2-yl]propyl] amino] carbonyl] oxy] acetate A solution of 10 g (33 mmol) of trans-3-[5-( 6-methoxynaphthalen-l-yl) -1, 3-dioxan-2-yl] ropanamine and 8.9 g (39.8 mmol) of ethyl [ (phenoxycarbonyl ) oxy] -acetate, obtained in step 1.1, in 500 ml of toluene, is heated at 50°C for 12 h. The mixture is allowed to return to ambient temperature, the insoluble material is separated by filtration and the filtrate is concentrated under reduced pressure. The residue is taken up with dichloromethane and water, the aqueous phase is separated and extracted three times with dichloromethane, and the pooled organic phases are washed with a saturated aqueous sodium chloride1 solution and dried over sodium sulphate. After 14 evaporation of the solvent, the residue is purified by chromatography on silica gel, eluting with a 20/80 mixture of ethyl acetate and cyclohexane.
Finally, 7 g of pure product are obtained, in the form of an oil which crystallizes: Melting point: 74-76°C. 1.3. trans- [ [ [ [3- [5- ( 6-Methoxynaphthalen-l-yl ) -1, 3- dioxan-2-yl] propyl] amino] carbonyl] oxy] acetic acid 40 ml of a IN aqueous sodium hydroxide solution are added, dropwise, to a solution of 4 g {9.27 mmol) of ethyl trans- [[[ [3- [5- ( 6-methoxy-naphthalen-l-yl) -1, 3-dioxan-2-yl] propyl] amino] -carbonyl] oxy] cetate, obtained in step 1.2, in 40 ml of dimethoxyethane, and the mixture is stirred at ambient temperature for 2 h. The mixture is concentrated under reduced pressure, the residue is dissolved in a minimum of water, IN hydrochloric acid is added until a pH equal to 4 is obtained, the aqueous phase is extracted three times with dichloromethane , the organic phase is separated and dried over sodium sulphate, and concentration is carried out at reduced pressure. 3 g of acid are obtained.
Melting point: 114-116°C. 1.4. 2- (Cyclopropylamino) -2-oxoethyl trans-3- [5- ( 6-methoxynaphthalen-l-yl } -1, 3-dioxan- 2-yl] propylcarbamate A solution of 0.169 g (1.24 mmol) of isobutylchloxoformate in 5 ml of tetrahydrofuran is added, dropwise, under an inert atmosphere, to a solution of 0.5 g (1.24 mmol} of trans- [ [ [ [3- [ 5- (6-methoxynaphthalen-l-yl) -1, 3-dioxan~2-yl] propyl] amino] -carbonyl] oxy] acetic acid, obtained in step 1.3, and 0.65 ml (3.70 mmol) of N, iV-diisopropylethylamine in 10 ml of tetrahydrofuran, cooled to approximately -20°C, while at the same time maintaining the temperature of the reaction medium below -15°C.
Stirring is maintained at this temperature for 1 h, then a solution of 0.078 g (1.36 mmol) of cyclopropylamine in 5 ml of tetrahydrofuran is slowly added, and the stirring is continued at -15°C for 1 hr and then at 20°C for 10 h. Concentration is carried out under reduced pressure, the residue is taken up with ethyl acetate and water, the organic phase is separated, washed with a saturated aqueous sodium chloride solution and dried over sodium sulphate, concentration is carried out under reduced pressure, and the solid is recrystallized from ethanol.
Finally, 0.25B g of pure product is obtained.
Melting point: 176°C.
XH NMR: (CDC13) δ (ppm) 8.10 (d, 1H) ; 7.65 (d, 1H) ; 7.35 (dd, 1H); 7.25 (d, 1H) ; 7.15 (dd, 1H) ; 7.05 (d, 1H) ; 6.20 (broad m, 1H) ; 5.05 (broad m, 1H) 4.70 (t, 1H) ; 4.55 (s, 2H) ; 4.35 (m, 2H) ; 3.95-3.90 (m, 6H) ; 3.30 (m, 2H); 2.75 (m, 1H) ; 1.75 (m, 4H) ; 0.80 {m, 2H) 0.55 (m, 2H) .
Example 2 (Compound No. 49} 2-Amino-2-oxoethyl trans-3- [5- ( 6-methoxynaphthalen- 1-yl) -1/ 3-dioxan-2-yl] propylcarbamate g (66 mmol) of trans-3- [ 5- ( 6-methoxynaphthalen-l-yl) -1, 3-dioxan-2-yl ] propanamine, 64 g (198 mmol) of caesium carbonate and 73.14 g (198 mmol) of tet ra-n-butylammonium iodide in suspension in 400 ml of N/iV-dimethylformamide are introduced into a l l three-necked round-bottomed flask placed under an inert atmosphere. A stream of carbon dioxide is passed through the suspension, with vigorous stirring, for 2 h. 18.5 g (198 mmol) of chloroacetamide in solution in 70 ml of ii,N-dimethylformamide are then added dropwise, and the stream of carbon dioxide is maintained for 5 h, and the stirring is continued at ambient temperature overnight. The salts are separated by filtration, the filtrate is concentrated under reduced pressure, the residue is taken up with ethyl acetate and water, and the organic phase is separated and washed with a 0. IN aqueous hydrochloric acid solution, then a saturated aqueous sodium hydrogen carbonate solution and a saturated aqueous sodium chloride solution. The organic phase is dried over sodium sulphate and the filtrate is concentrated under reduced pressure, the residue is purified by chromatography on silica gel, eluting with a 95/5 mixture of ethyl acetate and methanol, and the solid obtained is recrystallized from ethyl acetate. 6-5 g of pure product are obtained.
Melting point: 148-150°C.
H NMR: (DMSO) 5 (ppm) 8.15 {d, 1H) ; 7.75 (d, 1H) ; 7.4 (dd, 1H) ; 7.35 (d, 1H) ; 7.25 (m, 4H) ; 7.15 (broad m, 1H) ; 4.75 (t, 1H) ; 4.35 (s, 2H) ; 4.25 (dd, 2H) ; 3.95 (dd, 2H); 3.90 (s+m, 4H) ; 3.05 (m, 2H) ; 1.60 (m, 4H) . Example 3 (Compound No. 3} 2- (Methyiamino} -2-oxoethyl trans-2- (5-phenyl-1 , 3-dioxan-2-yl } ethylcarbamate 3.1. Ethyl trans- [[[ [2- ( 5-phenyl-l , 3-dioxan- 2-yl) ethyl] amino] carbonyl] oxy] acetate The method of Example 1.2 is used. From 1 g (4.8 mmol) of trans-2- (5-phenyl-l, 3-dioxan-2-yl) ethanamine and 1.1 g (4.8 mmol) of ethyl [ (phenoxycarbonyl ) oxy] acetate, 0.740 g of ester is obtained/ in the form of an oil. 3.2. 2- (Methyiamino) -2-oxoethyl trans-2- ( 5-phenyl- 1 , 3-dioxan-2-yl ) ethylcarbamate 3.3 ml (6.7 mmol) of a solution of methylamine (2M in tetrahydrofuran) are added, dropwise, to a solution of 0.70 g (2.1 mmol) of ethyl trans- [ [ [ [2- (5-phenyl-l, 3-dioxan-2-yl) ethyl] amino] -carbonyl] oxy] acetate, obtained in step 3.1, in 4 ml of methanol, and the mixture is stirred at ambient temperature for 12 h. Concentration is carried out at reduced pressure, and the residue is purified by chromatography on silica gel, eluting with a 90/10 mixture of dichloromethane and methanol. The oil obtained is triturated in diisopropyl erher and 0.450 g of pure product is obtained.
Melting point: 89°C. 1H NMR: (CDCI3) δ (ppm) 7.35-7.20 (m, 3H) ; 7.15 (dd, 2H) ; 6.15 [broad m, 1H) 5.45 (broad m, 1H) 4.75 (t, 1H); 4.60 {s, 2H) ; 4.20 (dd, 2H) ; 3.80 (dd, 2H) ; 3.40 (m, 2H); 3.20 {m, 1H) ; 2.85 (d, 3H) ; 1.90 (ra, 2H) .
Example 4 (Compound No. 63) lif-Imidazol-2-ylmethyl trans-3- [5- ( 6-methoxynaphthalen-1-yl) -1, -dioxan-2-yl] propylcarbamate 4.1. Phenyl ( l-triphenylmethyl-lii-imidazol- 2-yl ) methylcarbonate The procedure is carried out as described in Example 1.1. From 3 g (8.80 mmol ) of 1-triphenylmethyl-lH-imidazole-2-methanol (J. Het. Cham. , (1995), 32, 903-906) and 1.1 ml (8.80 mmol) of phenyl chloroformate , 3.9 g of product are obtained, which is used unmodified in the following step. 4.2. (l-Triphenylmethyl-lii-imidazol-2-yl)methyl trans- 3- [5- (6-methoxynaphthalen-l-yl) -1, 3-dioxan- 2-yl 3 propylcarbamate The procedure is carried out as described in Example 1.2. From 2.5 g (8.28 mmol) of trans-3- [ 5- ( 6-methoxynaphthalen-l-yl) -1, 3-dioxan-2-yl]propanamine and 3.8 g (8.28 mmol) f phenyl ( l~triphenylmethyl~l#-imidazol-2-yl) methylcarbonate, obtained in step 4.1, 3.2 g of a solid are obtained, in amorphous form. 19 4.3. lif-Imidazol-2-ylmethyi trans-3- [ 5- ( 6-methoxy-naphthalen-l-yl ) -1 , 3-dioxan-2-yl] propylcarbamate R solution of 0.6 ml (2.83 mmol) of trifluoroacetic acid in 2 ml of dichloromethane is added, dropwise, at ambient temperature, to a solution of 1.9 g (2.83 mmol) of (1-triphenylmethyl-lff-imidazol-2-yl) methyl trans-3- [5- ( 6-methoxynaphthalen-l-yl) -1, 3-dioxan-2-yl]propylcarbamate, obtained in step 4.2, in 150 ml of dichloromethane, and the mixture is stirred at ambient temperature for 12 h. Concentration is carried out under reduced pressure, the residue is taken up with dichloromethane and a saturated aqueous sodium hydrogen carbonate solution, the organic phase is separated, washed with a saturated aqueous sodium chloride solution and dried over sodium sulphate, concentration is carried out under reduced pressure, and the residue is purified by chromatography on silica gel, eluting with a 98/2/0.2 mixture of dichloromethane, methanol and aqueous ammonia.
After recrystallization from ethyl acetate, 0.820 g of pure product is finally obtained.
Melting point: 130-132°C.
XH NMR: (CDCla) δ (ppm) 10.0 (broad ra, 1H) ; 8.10 (d, 1H); 7.65 (d, 1H) ; 7.35 (dd, 1H) ; 7.25 (d, 1H) ; 7.15 (dd, 1H) ; 7.05 (dd, 1H) ; 7.00 (s, 2H) ; 5.15 (m+s, 3H} ; 4.70 (t, 1H) ; 4.30 (m, 2H} ; 3.95-3.90 (m, 6H) ; 3.30 (m, 2H) ; 1.85 (m, 4H) .
Example 5 (Compound No. 46) 2-Amino~2-oxoethyl trans-3- [5- ( 4~chloronaphthalen- 1-yl) -1, 3-dioxan-2-yl]propylcarbamate .1. trans-3- [5- (4-Chloronaphthalen-l-yl ) -1 , 3-dioxan- 2-ylJ -1-propanol 0.75 ml (10 mrnol) of 2 , -dihydrofuran and then 0.25 ml of a concentrated aqueous hydrochloric acid solution (37%) are added to a solution of 1.18 g (5 mrnol) of 2- (4-chloronaphthalen-l-yl) -1, 3-propanediol in 10 ml of dioxane. The mixture is allowed to react overnight at ambient temperature and then 5 ml of water are added. The mixture is stirred for 5 hours and is then diluted in 25 ml of water and 50 ml of dichloromethane . The mixture is separated after settling out and the aqueous phase is extracted with 50 ml of dichloromethane. The organic phases are washed with 25 ml of a saturated aqueous sodium chloride solution, drying is carried out over sodium sulphate and concentration is carried out under reduced pressure. The residue is purified by chromatography on silica gel, eluting with a 70/30 and then 60/40 mixture of cyclohexane and ethyl acetate. After recrystallization from diisopropyl ether, 0.557 g of product is obtained, in the form of white crystals. Melting point: 127-129°C. .2. trans-3- [5- (4-Chloronaphthalen-l-yl) -1, 3-dioxan- 2^yl J propyl methanesulphonate A solution of 0.256 g (2.23 mrnol) of mesyl 21 chloride in 2 ml of dichloromethane is added, dropwise, to a solution of 0.530 g (1.72 mmol ) of trans-3- [5- ( 4-chloronaphthalen-l-yl) -1, 3-dioxan-2-yl ] -l-propanol prepared in step 5.1 and of 0.48 ml (3.45 mmol) of triethylamine in 8 ml of dichloromethane cooled to 0°C under an inert atmosphere. The reaction mixture is stirred at 0°C for 1 hour. 25 ml of water and 50 ml of dichloromethane are added. The mixture is separated off after settling out and the aqueous phase is extracted with 50 ml of dichloromethane. The organic phases are washed with 25 ml of a saturated aqueous sodium chloride solution, drying is carried out over magnesium sulphate and concentration is carried out under vacuum, to obtain 0.66 g of product in the form of a white solid used without modification in the following step. 5.3. trans-3- [3- (5- ( 4-Chloronaphthalen-l-yl ) -1, 3- dioxan-2-yl ) propyl] -1 , 3-oxazolidine-2, 4-dione A mixture of 0.660 g (1.71 mmol) of trans-3- [ 5- (4-chloronaphthalen-l-yl) -1, 3-dioxan-2-yl ] ropyl methanesulphonate, obtained in step 5.2, of 0.208 g (2.05 mmol) of 1, 3-oxazoIidine-2 , 4-dione (J. Med.
Chem., 1991, 34, 1542-1543) and of 0.396 g (3.43 mmol) of 1, 1, 3, 3-tetramethylguanidine in 10 ml of tetrahydrofuran is refluxed overnight under an inert atmosphere. The residue is taken up in 100 ml of ethyl acetate and 25 ml of water. Separation is carried out after settling out. The organic phase is washed with 25 ml of water and then 25 ml of a saturated aqueous 22 sodium chloride solution. The aqueous phases are re-extracted with 50 ml of ethyl acetate. The organic phases are pooled, dried over sodium sulphate and concentrated under reduced pressure. The residue is purified by chromatography on silica gel, eluting with a 70/30 and then 60/40 mixture of cyclohexane and ethyl acetate, to obtain 0.483 g of product in the form of a white solid.
Melting point: 125-127 °C. .4. 2-Amino-2-oxoethyl trans-3- [5- ( -chloronaphthalen- 1-yl) -1, 3-dioxan-2-yl] ropylcarbamate 0.470 g (1.20 mmol) of trans-3~ [3- ( 5- ( 4-chloronaphthalen-l-yl) -1, 3-dioxan-2-yl ) propyl] -1, 3-oxazolidine-2, 4-dione, . obtained in step 5.3, is dissolved in 3.5 ml of tetrahydrofuran and 7 ml of a 7N solution of aqueous ammonia in methanol are added. The mixture is allowed to react overnight at ambient temperature and is then evaporated to dryness, and recrystallization is carried out from a mixture of isopropanol and diisopropyl ether, to obtain 0.388 g of product in the form of white crystals.
Melting point: 1 6-178 °C.
LC-MS: M+H == 407 XH NMR (DMSO) δ (ppm) : 8.35 (d, 1H) ; 8.25 (d, 1H) ; 7.8 (m, 3H); 7.4 (d, 1H) ; 7.25 (m, 2H) ; 7.15 (s, 1H) 4.75 (t, 1H); 4.3 {s, 2H); 4.2 (m, 2H) ; 4.0-3.9 (m, 3H) ; 3.05 (t, 2H); 1.65 (m, 2H) ; 1.6 (m, 2H) . 23 Example 6 (Compound No. 67) 4-Chlorophenyl trans-3- [5- ( 6-cyclopropylmethoxy-naphthalen-l-yl ) -1, 3-dioxan-2-yl] ropylcarbamate 0.205 g (0.60 mmol) of trans-3- [5- (6-cylcopropylmethoxynaphthalen-l-yl } -1, 3-dioxan- 2-yl ] ropylamine is added, in small portions and at ambient temperature, to a solution of 0.110 ml (0.78 mmol) of 4-chlorophenyl chloroformate and 0.205 ml (1.2 mmol) of W, W-diisopropylethylamine in 6 ml of dichloromethane . The mixture is stirred at ambient temperature for 16 hours, then washing is carried out with 5 ml of a saturated sodium bicarbonate solution. The phases are separated and the organic phase is filtered through a hydrophobic sintered glass funnel. The filtrate is concentrated under reduced pressure and the residue is purified by chromatography on silica gel, eluting with an 80/20 mixture of cyclohexane and ethyl acetate. After washing in 5 ml of diisopropyl ether, 0.176 g of a white solid is obtained.
LC-MS: M+H - 496 Melting point: 159-162°C :H NMR (CDC13) 6 (ppm) : 8.10 (d, 1H) ; 7.65 (d, 1H) ; 7.45-7.20 (m, 4H) ; 7.20-7.00 (m, 4H) ; 5.30 (broad m, 1H) ; 4.75 (t, 1H) 4.35 (dd, 2H) ; 4.10-3.80 (m, 5H) ; 3.50-3.25 (m, 2H) ; 1.95-1.70 (m, 4H) ; 1.45-1.20 (m, 1H) ; 0.80-0.65 (m, 2H) ; 0.50-0.30 (m, 2H) . 24 Example 7 (Compound No. 68) 2, 2, 2-Trifluoroethyl trans-3- [5- ( 6-cyclopropylmethoxy-naphthalen-l-yl) -1, 3-dioxan-2-yl] propylcarbamate 0.075 ml (1.01 mmol) of 2, 2 , 2-trifluoroethanol is added, dropwise and at ambient temperature, to a suspension of 0.205 g (1.01 mmol) of 4-nitrophenyl chloroformate and 0.555 g (2.02 mmol) of N/N-diisopropylaminoethylpolystyrene (Ps-DIEA, 2% DVB, titre = 3.66 mmol/g) in 7.1 ml of dichloromethane . The mixture is stirred with orbital shaking and at ambient temperature for 16 hours. The resin is filtered through a cartridge equipped with a sintered glass funnel and rinsing is carried out with 4 ml of dichloromethane. The filtrate is concentrated under reduced pressure and the oily residue thus obtained is taken up in 3.5 ml of 1, 2-dichloroethane. 0.134 ml (0.78 mmol) of N, IV-diisopropylethylamine and 0.205 g (0.6 mmol) of 3- [5- ( 6-cyclopropylmethoxynaphthalen-l-yl) -1, 3-dioxan-2-yl] propylamine are successively added. This reaction mixture is heated at 60 °C for 16 hours.. After cooling, washing is carried out with 20 ml of a IN sodium hydroxide solution. The phases are separated and the organic phase is filtered through a hydrophobic sintered glass funnel. The filtrate is concentrated under reduced pressure and the residue is purified by chromatography on silica gel, eluting with an 80/20 mixture of cyclohexane and ethyl acetate. After washing in 5 ml of diisopropyl ether, 0.076 g of white solid is obtained .
LC-MS: +H = 468 Melting point: 105-1Q7°C ¾ NMR: (CDCI3) δ (ppm) : 8.15 (d, 1H) ; 7.65 (d, 1H) ; 7.35 (dd, 1H) ; 7.25 {m, 1H) ; 7.15 (d, 1H) ; 7.10 (d, 1H); 5.15 (broad m, 1H) ; 4.75 (t, 1H) ; 4.50 (q, 2H) ; 4.30 (dd, 2H) ; 4.10-3.80 (m, 5H) ; 3.40-3.20 (m, 2H) ; 1.90-1.65 (m, 4H) ; 1.45-1.20 (m, 1H) ; 0.75-0.60 (m, 2H) ; 0.50-0.35 (2H) .
The following table illustrates the chemical structures and the physical properties of some compounds according to the invention. The compounds in the table exhibit the trans relative configuration on the dioxane ring, with the exception of compounds No. 37 and 50, which exhibit the cis relative configuration, and compounds No. 6, 9, 11, 13, 18, 20, 21 and 43, which are in the form of a mixture of the cis and trans stereoisomers. All the compounds in the table are in the form of bases.
Table 0 o. Ri n 2 M+H M.p.
(°C) 1. phenyl 2 CH2CONH2 - 172-174 2. phenyl 3 C¾CONH, - 116-118 3. phenyl 2 CHCONHCHa - 89 4. phenyl 3 CH2CONHCH3 _ 116 . phenyl 2 CH2CF3 334 77-80 6. phenyl 3 CH2CF3 348 83-85 7. phenyl 2 phenyl 328 131-134 8. phenyl 3 phenyl 342 100-103 9. phenyl 2 2-chlorophenyl 362 95-98 0. phenyl 3 2-chlorophenyl 376 129-131 1. phenyl 2 4-chlorophenyl 362 134-136 2. phenyl 3 4-chlorophenyl 376 117-121 3. phenyl 2 4-fluorophenyl 346 132-134 4. phenyl 3 4-fluorophenyl 360 106-109 . phenyl 2 4-methylphenyl 342 112-115 6. phenyl 3 4-methylphenyl 356 87-90 7. phenyl 2 2-methoxyphenyl 358 - 8. phenyl 3 2-methoxyphenyl 372 84-87 9. phenyl 2 4-methoxyphenyl 358 130-132 0. phenyl 3 4-methoxyphenyl 372 99-101 1. phenyl 2 3-trifluoro- 396 87-90 methylphenyl 2. phenyl 3 3-trifluoro- 410 128-131 methylphenyl 3. -fluorophenyl 1 -c loropheny1 - 139-141 4. 4-fluorophenyl 2 CH2CONHCH3 - 124-126 5. 4-fluorophenyl 3 CH2CONHC¾ - 150-152 6. 3-chlorophenyl 2 4-chlorophenyl - 123-125 27 Ri n R2 M+H j M.p. rc) 3-chlorophenyl 3 4-chlorophenyl - 89-91 4-chlorophenyl 1 4-chlorophenyl - 146-148 4-chlorophenyl 1 CH2CF3 - 99-101 2-methoxyphenyl 2 4-chlorophenyl - 144-146 3-rnethoxyphenyl 2 4 -chlorophenyl - 116-118 -methoxyphen 1 3 4-chlorophenyl - 128-131 3-trifluoro- 1 4-chlorophenyl - 116-119 methylphenyl 3-trifluoro- 1 CH:CF3 - 66-67 methylphenyl 3-trifluoro- 3 4-chlorophenyl - 93-96 methylphenyl 3-trifluoro- 2 CH2CONHCH3 - 118-120 methylphenyl 3-trifluoro- 2 CH2CONHCH3 - 82-84 methylphenyl naphthalen-l-yl 3 CH2CONH2 112-114 naphthalen-l-yl 2 CH2CONHCH3 - 86-88 naphthalen-l-yl 3 CH2CONHCH3 - 154 naphthalen-l-yl 2 CH2CF3 384 111-113 naphthalen-l-yl 3 CH2CF3 398 89-92 naphthalen-l-yl 2 CH2-benzimidazol- 432 - 2-yl naphthalen-l-yl 2 phenyl 378 131-133 naphthalen-l-yl 3 phenyl 392 125-127 4-chloro- 3 CH2CONH2 407 176-178 naphthalen-l-yl 4-chloro- 3 CH2CONHCH3 - 190-192 naphthalen-l-yl 6-chloro- 3 CH2CONHCH3 - 182-184 naphthalen-l-yl 6-methoxy- 3 CH2CONH2 - 148-150 naphthalen-l-yl 28 n R2 - H M.p.
C°c) 6-methoxy- 3 CH2CONH2 - 144-147 naphthalen-l-yl 6-methoxy- 1 CHCONHCH3 - 194-196 naphthalen-l-yl 6-methoxy- 1 4-chlorophenyl - 133-136 naphthalen-l-yl 6-methoxy- 1 CH2CF3 - 142-144 naphthalen-l-yl 6-methoxy- 2 CH CONHCH3 - 136-138 naphthalen-l-yl 6-methoxy- 2 4-chlorophenyl - 129-131 naphthalen-l-yl 6-methoxy~ 2 C¾CF3 - 93-95 naphthalen-l-yl 6-itiethoxy- 3 CH2CONHCH3 - 126-130 naphthalen-l-yl 6-methoxy- 3 CH2CONHCH2CH3 - 170-172 naphthalen-l-yl 6-methoxy- 3 CH (CH3) CONHCH3 - 154 naphthalen-l-yl 6-methoxy- 3 CH2CONHCH2-pyridin- - 152 naphthalen-l-yl 4-yl 6-methoxy- 3 CH2CONH~cyclo- - 176 naphthalen-l-yl propyl 6-methoxy- 3 CH2CF3 - 111 naphthalen-l-yl 6-methoxy- 3 CH2-imidazol-2-yl - 130-132 naphthalen-l-yl 6-methoxy- 3 CH2-benziitiidazol- - 175-176 naphthalen-l-yl 2-yl 6-methoxy- 3 phenyl - 128 naphthalen-l-yl 6-cyclopropyl- 3 CH3CONH2 137-139 methoxynaphthalen- 1-yl 29 No. Ri n R2 M+H M.p.
(°C) 67. 6-cyclopropyl- 3 -chlorophenyl 496 159-162 methoxynaphthalen- 1-yl 68. 6-cyclopropyl- 3 CH2CF2 468 105-107 methoxynaphthalen- 1-yl 69. 6-phenylitiethoxy- 1 CH2CONH2 - 154-156 naphthalen-l-yl 70. 6-hydroxy- 3 CH2CONH2 - 166-170 napht alen-l-yl 71. 6-hydroxy- 3 CH2CONHCH3 - 140-148 naphthalen-1-yl 72. 7-methoxy- 3 CH2C0NH2 156-158 naphthalen-l-yl 73. 7-methoxy- 3 CH2CONHCH3 - 144-146 naphthalen-l-yl 74. 7-methoxy- 3 CH2CF3 428 93-96 naphthalen-l-yl 75. 7-methoxy- 3 phenyl 422 151-153 naphthalen-l-yl 76. naphthalen-2-yl 3 phenyl 392 130-131 77. naphthalen-2-yl 3 CH2CONHCH3 - 144-146 7B. naphthalen-2-yl 3 CK2CF3 398 130-132 The compounds of the invention have been the subject of pharmacological tests to determine their inhibitory effect on the enzyme FAAH (Fatty Acid Amido Hydrolase) .
The inhibitory activity was demonstrated in a radioenzymatic assay based on measuring the product of hydrolysis (ethanolamine [1-3H] ) of anandamide [ethanolamine 1-3H] by FAAH (Life Sciences (1995), 56, 1999-2005 and Journal of Pharmacology and Experimented Therapeutics (1997), 283, 729-734). Thus, mouse brains (minus the cerebellum) are removed and stored at -80 °C. Membrane homogenates are prepared extemporaneously by homogenization of the tissues with a Polytron in a 10 mM Tris-HCl buffer (pH 8.0) containing 150 mM NaCl and 1 mM EDTA. The enzyme reaction is then carried out in 70 μΐ of buffer containing bovine serum albumin without fatty acids (1 g/ml) . The compounds tested, at various concentrations, the anandamide [ethanolamine 1-3H] (specific activity of 15-20 Ci/mmol} diluted to 10 μΜ with non-radiolabelled anandamide and the membrane preparation (400 pg of frozen tissue per assay) are added successively. After 15 minutes at 25°C, the enzyme reaction is stopped by adding 140 μΐ of chloroform/methanol (2:1). The mixture is stirred for 10 minutes and then centrifuged for 15 minutes at 3 500 g. An aliquot' (30 μΐ) of the aqueous phase containing the ethanolamine [1-3H] is counted by liquid scintillation .
Under these conditions, the most active compounds of the invention exhibit IC5o values {concentration which inhibits by 501 the control enzyme activity of FAAH) of between 0.005 and 1 μΜ.
It therefore appears that the compounds according to the invention have an inhibitory activity on the FAAH enzyme.
The in vivo activity of the compounds of the invention was evaluated in a test for analgesia. 31 Thus, intraperitoneal (i.p.) administration of PBQ (phenylbenzoquinone, 2 mg/kg in a solution of 0.9% aCl containing 5% of ethanol) to male OFl mice weighing 25 to 30 g causes abdominal pulls, on average 30 twists or contractions during the 5 to 15 minute period after injection. The compounds tested are administered orally or i.p. in suspension in Tween 80 at .0.5%, 30 minutes, 60 minutes or 120 minutes before administration of PBQ.
Under these conditions, the most potent compounds of the invention reduce by 50 to 70% the number of pulls induced by the PBQ, within a dose range of between 1 and 30 mg/kg.
The FAAH enzyme {Chemistry and Physics of Lipids, (2000), 108, 107-121) catalyses the hydrolysis of endogenous derivatives of amides and of esters of various fatty acids such as N-arachidonoylethanolamine (anandamide) , N-palrnitoylethanolamine , N-oleoylethanolamine, oleamide or 2-arachidonoylglycerol . These derivatives exercise various pharmacological activities by interacting, inter alia, with cannabinoid and vanilloid receptors. The compounds of the invention block this degradation pathway and increase the tissue level of these endogenous substances. They can be used in this respect in the prevention and treatment of any pathological condition in which endogenous cannabinoids and/or any other substrate metabolized by the FAAH enzyme are involved . 32 The following diseases and conditions may, for example, be mentioned: pain, in particular acute or chronic pain of the neurogenic type: migraine, neuropathic pain including forms associated with the herpes virus and with diabetes ; acute or chronic pain associated with inflammatory diseases: arthritis, rheumatoid arthritis, osteoarthritis, spondylitis, gout, vasculitis, Crohn's disease, irritable bowel syndrome; acute or chronic peripheral pain; dizziness, vomiting, nausea, in particular subsequent to chemotherapy; eating disorders, in particular anorexia and cachexia of various natures; neurological and psychiatric pathological conditions: shaking, dyskinesia, dystonia, spasticity, obsessive-compulsive behaviour, Tourette's syndrome, all forms of depression and of anxiety of any nature and cause, mood disorders, psychoses; acute, or chronic neurodegenerative diseases: Parkinson's disease, Alzheimer's disease, senile dementia, Huntington's chorea, lesions associated with cerebral ischemia and with cranial and medullary trauma; epilepsy; sleep disorders including sleep apnoea; cardiovascular diseases, in particular hypertension, 33 cardiac arrhythmias, arteriosclerosis, heart attack, cardiac ischemias; renal ischemia; cancers: benign skin tumours, papillomas .and brain tumours, prostate tumours, brain tumours (glioblastomas, medulloepitheliomas , medulloblastomas , neuroblastomas, tumours of embryonic origin, astrocytomas, astroblastomas, ependyomas, oligodendroglyomas , plexus tumour, neuroepitheliomas, epiphyseal tumour, ependymoblastomas, malignant meningiomas, sarcomatosis , malignant melanomas, schwannomas) disorders of the immune system, in particular autoimmune diseases: psoriasis, lupus erythematosus, diseases of the connective tissue or collagen diseases, Sjogren's syndrome, ankylosing spondylarthritis, undifferentiated spondylarthritis, Behcet's disease, haemolytic autoimmune anaemias, multiple sclerosis, amyotrophic lateral sclerosis, amyloses, transplant rejection, diseases affecting the plasmocytic line; allergic diseases: immediate or delayed hypersensitivity, allergic rhinitis or conjunctivitis, contact dermatitis; parasitic, viral or bacterial infectious diseases: AIDS: meningitis inflammatory diseases, in particular diseases of the joints: arthritis, rheumatoid arthritis, osteoarthritis, spondylitis, gout, vasculitis, Crohn's 34 disease, irritable bowel syndrome; osteoporosis ; ocular conditions: ocular hypertension, glaucoma; pulmonary conditions: diseases of the respiratory tracts, bronchospasms , coughing, asthma, chronic bronchitis, chronic obstruction of the respiratory tracts, emphysema; gastrointestinal diseases: irritable bowel syndrome, intestinal inflammatory disorders, ulcers, diarrhoea, gastrooesophageal reflux; urinary incontinence and bladder inflammation.
The use of the compounds according to the invention, for preparing a medicinal product intended to prevent or treat the abovementioned pathological conditions, is an integral part of the invention.
A subject of the invention is also medicinal products which comprise a compound of formula (I), or a salt, or else a hydrate or a solvate, which is pharmaceutically acceptable, of the compound of formula (I). These medicinal products find their use in therapeutics, in particular in the prevention and treatment of the abovementioned pathological conditions .
According to another of its aspects, the present invention concerns pharmaceutical compositions containing, as active principle, at least one compound according to the invention. These pharmaceutical compositions contain an effective dose of a compound according to the invention, or a salt, or a hydrate, or a solvate, which is pharmaceutically acceptable, of said compound and, optionally, one or more pharmaceutically acceptable excipients.
Said excipients are chosen, depending on the pharmaceutical form and the method of administration desired, from the usual excipients which are known to those skilled in the. art.
In the pharmaceutical compositions of the present invention for oral, sublingual, subcutaneous, intramuscular, intravenous, topical, local, intrathecal, intranasal, transdermal, pulmonary, ocular or rectal administration, the active principle of formula (I) above, or its optional salt, solvate or hydrate, can be administered in a single-dose administration form, as a mixture with conventional pharmaceutical excipients, to animals and to humans, for preventing or treating the abovementioned disorders or diseases.
Suitable single-dose administration forms comprise oral forms such as tablets, soft or hard gelatin capsules, powders, granules, chewing gums and oral solutions or suspensions, forms for sublingual, buccal, intratracheal, intraocular and intranasal administration and for administration by inhalation, forms for subcutaneous, intramuscular, intravenous or intrathecal administration and forms for rectal or vaginal administration. For topical application, the compounds according to the invention can be used in 36 creams, ointments or lotions.
By way of example, a single-dose administration form for a compound according to the invention in tablet form can comprise the following components: compound according to the invention 50.0 mg mannitol 223.75 mg sodium croscaramellose 6.0 mg corn starch 15.0 mg hydroxypropylmethylcellulose 2.25 mg magnesium stearate 3.0 mg Said single-dose forms contain a dose so as to allow daily administration of 0.01 to 20 mg of active principle per. kg of body weight, depending on the pharmaceutical form.
There may be particular cases in which higher or lower doses are suitable; such doses also belong to the invention. According to usual practice, the appropriate dose for each patient is determined by the physician, depending on the method of administration, and the weight and response of said patient.
According to another of its aspects, the invention also concerns a method for treating the pathological conditions indicated above, which comprises administering an effective dose of a compound according to the invention, of one of its pharmaceutically acceptable salts, or of a solvate or of a hydrate of said compound.
Claims (1)
1. Compound corresponding to general formula (III) 0 {III in which: A- R2 is a group of general formula CHR3CONHR4 in which R3 is a hydrogen atom or a methyl group and R4 is a hydrogen atom or a Ci-3.alkyl, C3-s~cycloalkyl or (pyridin-4-yl) methyl group; and U is a hydrogen atom or a nitro group. For the Applicant, Sanford T. Colb C: 69425
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