EP2280951A2 - Processes for the preparation of benzo-fused dioxin derivatives - Google Patents
Processes for the preparation of benzo-fused dioxin derivativesInfo
- Publication number
- EP2280951A2 EP2280951A2 EP08732845A EP08732845A EP2280951A2 EP 2280951 A2 EP2280951 A2 EP 2280951A2 EP 08732845 A EP08732845 A EP 08732845A EP 08732845 A EP08732845 A EP 08732845A EP 2280951 A2 EP2280951 A2 EP 2280951A2
- Authority
- EP
- European Patent Office
- Prior art keywords
- formula
- compound
- yield
- group
- reacting
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Withdrawn
Links
- 238000000034 method Methods 0.000 title claims abstract description 147
- 230000008569 process Effects 0.000 title claims abstract description 109
- 238000002360 preparation method Methods 0.000 title claims abstract description 44
- 150000002013 dioxins Chemical class 0.000 title 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 26
- 206010015037 epilepsy Diseases 0.000 claims abstract description 26
- 150000001875 compounds Chemical class 0.000 claims description 389
- 239000003960 organic solvent Substances 0.000 claims description 107
- 150000007529 inorganic bases Chemical class 0.000 claims description 67
- 239000000203 mixture Substances 0.000 claims description 52
- 150000007530 organic bases Chemical class 0.000 claims description 43
- 229910052739 hydrogen Inorganic materials 0.000 claims description 37
- -1 t-butyl-diphenylsilyl Chemical group 0.000 claims description 36
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 36
- 239000001257 hydrogen Substances 0.000 claims description 35
- 239000007800 oxidant agent Substances 0.000 claims description 35
- 239000003937 drug carrier Substances 0.000 claims description 25
- 239000008194 pharmaceutical composition Substances 0.000 claims description 25
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 22
- 125000000217 alkyl group Chemical group 0.000 claims description 22
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 claims description 20
- NHQDETIJWKXCTC-UHFFFAOYSA-N 3-chloroperbenzoic acid Chemical group OOC(=O)C1=CC=CC(Cl)=C1 NHQDETIJWKXCTC-UHFFFAOYSA-N 0.000 claims description 19
- 150000003839 salts Chemical class 0.000 claims description 19
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 15
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 14
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 claims description 13
- 125000006241 alcohol protecting group Chemical group 0.000 claims description 13
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 13
- 238000002156 mixing Methods 0.000 claims description 12
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 12
- 238000000634 powder X-ray diffraction Methods 0.000 claims description 12
- 229910052736 halogen Inorganic materials 0.000 claims description 11
- 150000002367 halogens Chemical group 0.000 claims description 11
- NOQXXYIGRPAZJC-UHFFFAOYSA-N oxiran-2-ylmethyl 4-methylbenzenesulfonate Chemical compound C1=CC(C)=CC=C1S(=O)(=O)OCC1OC1 NOQXXYIGRPAZJC-UHFFFAOYSA-N 0.000 claims description 8
- 125000004217 4-methoxybenzyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1OC([H])([H])[H])C([H])([H])* 0.000 claims description 5
- 125000005448 ethoxyethyl group Chemical group [H]C([H])([H])C([H])([H])OC([H])([H])C([H])([H])* 0.000 claims description 5
- 150000002431 hydrogen Chemical group 0.000 claims description 5
- 125000006503 p-nitrobenzyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1[N+]([O-])=O)C([H])([H])* 0.000 claims description 4
- 125000005745 ethoxymethyl group Chemical group [H]C([H])([H])C([H])([H])OC([H])([H])* 0.000 claims 4
- 125000004184 methoxymethyl group Chemical group [H]C([H])([H])OC([H])([H])* 0.000 claims 4
- 150000007522 mineralic acids Chemical class 0.000 claims 4
- 150000007524 organic acids Chemical class 0.000 claims 4
- 238000003786 synthesis reaction Methods 0.000 abstract description 13
- 230000015572 biosynthetic process Effects 0.000 abstract description 9
- 125000001072 heteroaryl group Chemical group 0.000 abstract description 4
- 239000000543 intermediate Substances 0.000 abstract description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N methanol Substances OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 90
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 50
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 46
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 42
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 40
- RTZKZFJDLAIYFH-UHFFFAOYSA-N ether Substances CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 31
- 239000007787 solid Substances 0.000 description 30
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 28
- 206010010904 Convulsion Diseases 0.000 description 27
- 239000011541 reaction mixture Substances 0.000 description 25
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 24
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 23
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 description 20
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 20
- 235000019441 ethanol Nutrition 0.000 description 20
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 18
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 18
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 18
- 239000012043 crude product Substances 0.000 description 18
- 238000005160 1H NMR spectroscopy Methods 0.000 description 17
- 239000000047 product Substances 0.000 description 17
- 229910052757 nitrogen Inorganic materials 0.000 description 16
- 125000006239 protecting group Chemical group 0.000 description 16
- 235000002639 sodium chloride Nutrition 0.000 description 16
- 239000003826 tablet Substances 0.000 description 15
- 238000006243 chemical reaction Methods 0.000 description 14
- 229910000027 potassium carbonate Inorganic materials 0.000 description 14
- 238000010992 reflux Methods 0.000 description 14
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 13
- 239000002585 base Substances 0.000 description 13
- 208000035475 disorder Diseases 0.000 description 13
- 239000003921 oil Substances 0.000 description 13
- 235000019198 oils Nutrition 0.000 description 13
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 12
- 239000000243 solution Substances 0.000 description 12
- 239000000725 suspension Substances 0.000 description 11
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 10
- 239000012267 brine Substances 0.000 description 10
- 239000002775 capsule Substances 0.000 description 10
- DEQYTNZJHKPYEZ-UHFFFAOYSA-N ethyl acetate;heptane Chemical compound CCOC(C)=O.CCCCCCC DEQYTNZJHKPYEZ-UHFFFAOYSA-N 0.000 description 10
- 239000003223 protective agent Substances 0.000 description 10
- 229910000029 sodium carbonate Inorganic materials 0.000 description 10
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 10
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 9
- 238000002844 melting Methods 0.000 description 9
- 230000008018 melting Effects 0.000 description 9
- 230000003287 optical effect Effects 0.000 description 9
- 239000002904 solvent Substances 0.000 description 9
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 8
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 8
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 8
- KFSLWBXXFJQRDL-UHFFFAOYSA-N Peracetic acid Chemical compound CC(=O)OO KFSLWBXXFJQRDL-UHFFFAOYSA-N 0.000 description 8
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 8
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 8
- 239000004480 active ingredient Substances 0.000 description 8
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 description 8
- 239000002552 dosage form Substances 0.000 description 7
- 239000007788 liquid Substances 0.000 description 7
- 239000012071 phase Substances 0.000 description 7
- 239000000843 powder Substances 0.000 description 7
- 238000000746 purification Methods 0.000 description 7
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 6
- 229920002472 Starch Polymers 0.000 description 6
- 229910052794 bromium Inorganic materials 0.000 description 6
- 239000000969 carrier Substances 0.000 description 6
- 239000003153 chemical reaction reagent Substances 0.000 description 6
- 239000000460 chlorine Substances 0.000 description 6
- 229910052801 chlorine Inorganic materials 0.000 description 6
- 229910052740 iodine Inorganic materials 0.000 description 6
- USSBDBZGEDUBHE-UHFFFAOYSA-L magnesium;2-oxidooxycarbonylbenzoate Chemical compound [Mg+2].[O-]OC(=O)C1=CC=CC=C1C([O-])=O USSBDBZGEDUBHE-UHFFFAOYSA-L 0.000 description 6
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 6
- 235000019698 starch Nutrition 0.000 description 6
- NVBFHJWHLNUMCV-UHFFFAOYSA-N sulfamide Chemical compound NS(N)(=O)=O NVBFHJWHLNUMCV-UHFFFAOYSA-N 0.000 description 6
- 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 5
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 5
- OAKJQQAXSVQMHS-UHFFFAOYSA-N Hydrazine Chemical compound NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 0.000 description 5
- 239000002253 acid Substances 0.000 description 5
- 239000000654 additive Substances 0.000 description 5
- AGEZXYOZHKGVCM-UHFFFAOYSA-N benzyl bromide Chemical compound BrCC1=CC=CC=C1 AGEZXYOZHKGVCM-UHFFFAOYSA-N 0.000 description 5
- 239000011230 binding agent Substances 0.000 description 5
- 239000003814 drug Substances 0.000 description 5
- 239000000706 filtrate Substances 0.000 description 5
- 239000004615 ingredient Substances 0.000 description 5
- 239000000463 material Substances 0.000 description 5
- 239000012074 organic phase Substances 0.000 description 5
- 239000006187 pill Substances 0.000 description 5
- 239000000741 silica gel Substances 0.000 description 5
- 229910002027 silica gel Inorganic materials 0.000 description 5
- 125000001424 substituent group Chemical group 0.000 description 5
- 235000000346 sugar Nutrition 0.000 description 5
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 description 4
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 4
- YNJSNEKCXVFDKW-UHFFFAOYSA-N 3-(5-amino-1h-indol-3-yl)-2-azaniumylpropanoate Chemical compound C1=C(N)C=C2C(CC(N)C(O)=O)=CNC2=C1 YNJSNEKCXVFDKW-UHFFFAOYSA-N 0.000 description 4
- YYROPELSRYBVMQ-UHFFFAOYSA-N 4-toluenesulfonyl chloride Chemical compound CC1=CC=C(S(Cl)(=O)=O)C=C1 YYROPELSRYBVMQ-UHFFFAOYSA-N 0.000 description 4
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 4
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 4
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 4
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 4
- BHELZAPQIKSEDF-UHFFFAOYSA-N allyl bromide Chemical compound BrCC=C BHELZAPQIKSEDF-UHFFFAOYSA-N 0.000 description 4
- 229910000024 caesium carbonate Inorganic materials 0.000 description 4
- 239000003795 chemical substances by application Substances 0.000 description 4
- 201000010099 disease Diseases 0.000 description 4
- 229940079593 drug Drugs 0.000 description 4
- 238000001914 filtration Methods 0.000 description 4
- JMMWKPVZQRWMSS-UHFFFAOYSA-N isopropanol acetate Natural products CC(C)OC(C)=O JMMWKPVZQRWMSS-UHFFFAOYSA-N 0.000 description 4
- 239000000314 lubricant Substances 0.000 description 4
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 4
- NSPJNIDYTSSIIY-UHFFFAOYSA-N methoxy(methoxymethoxy)methane Chemical compound COCOCOC NSPJNIDYTSSIIY-UHFFFAOYSA-N 0.000 description 4
- 239000003755 preservative agent Substances 0.000 description 4
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 4
- 239000000377 silicon dioxide Substances 0.000 description 4
- 239000011734 sodium Substances 0.000 description 4
- 239000008107 starch Substances 0.000 description 4
- 150000008163 sugars Chemical class 0.000 description 4
- 239000000375 suspending agent Substances 0.000 description 4
- 238000012360 testing method Methods 0.000 description 4
- FPGGTKZVZWFYPV-UHFFFAOYSA-M tetrabutylammonium fluoride Chemical compound [F-].CCCC[N+](CCCC)(CCCC)CCCC FPGGTKZVZWFYPV-UHFFFAOYSA-M 0.000 description 4
- LNAZSHAWQACDHT-XIYTZBAFSA-N (2r,3r,4s,5r,6s)-4,5-dimethoxy-2-(methoxymethyl)-3-[(2s,3r,4s,5r,6r)-3,4,5-trimethoxy-6-(methoxymethyl)oxan-2-yl]oxy-6-[(2r,3r,4s,5r,6r)-4,5,6-trimethoxy-2-(methoxymethyl)oxan-3-yl]oxyoxane Chemical compound CO[C@@H]1[C@@H](OC)[C@H](OC)[C@@H](COC)O[C@H]1O[C@H]1[C@H](OC)[C@@H](OC)[C@H](O[C@H]2[C@@H]([C@@H](OC)[C@H](OC)O[C@@H]2COC)OC)O[C@@H]1COC LNAZSHAWQACDHT-XIYTZBAFSA-N 0.000 description 3
- 241000416162 Astragalus gummifer Species 0.000 description 3
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- 235000010643 Leucaena leucocephala Nutrition 0.000 description 3
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- 229920001615 Tragacanth Polymers 0.000 description 3
- NOQXXYIGRPAZJC-SECBINFHSA-N [(2r)-oxiran-2-yl]methyl 4-methylbenzenesulfonate Chemical compound C1=CC(C)=CC=C1S(=O)(=O)OC[C@@H]1OC1 NOQXXYIGRPAZJC-SECBINFHSA-N 0.000 description 3
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- 238000001228 spectrum Methods 0.000 description 3
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- GIGRWGTZFONRKA-UHFFFAOYSA-N 1-(bromomethyl)-4-methoxybenzene Chemical compound COC1=CC=C(CBr)C=C1 GIGRWGTZFONRKA-UHFFFAOYSA-N 0.000 description 2
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- 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
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- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
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- AIHIHVZYAAMDPM-MRVPVSSYSA-N [(2r)-oxiran-2-yl]methyl 3-nitrobenzenesulfonate Chemical compound [O-][N+](=O)C1=CC=CC(S(=O)(=O)OC[C@@H]2OC2)=C1 AIHIHVZYAAMDPM-MRVPVSSYSA-N 0.000 description 2
- 150000001298 alcohols Chemical class 0.000 description 2
- 150000001408 amides Chemical class 0.000 description 2
- 239000007900 aqueous suspension Substances 0.000 description 2
- 229910052786 argon Inorganic materials 0.000 description 2
- 239000007894 caplet Substances 0.000 description 2
- 125000001309 chloro group Chemical group Cl* 0.000 description 2
- 238000000576 coating method Methods 0.000 description 2
- 239000013078 crystal Substances 0.000 description 2
- IIJREXIVDSIOFR-UHFFFAOYSA-N dichloromethane;heptane Chemical compound ClCCl.CCCCCCC IIJREXIVDSIOFR-UHFFFAOYSA-N 0.000 description 2
- 239000003085 diluting agent Substances 0.000 description 2
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- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 230000001179 pupillary effect Effects 0.000 description 1
- 239000008213 purified water Substances 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 230000000306 recurrent effect Effects 0.000 description 1
- 230000008929 regeneration Effects 0.000 description 1
- 238000011069 regeneration method Methods 0.000 description 1
- 230000004044 response Effects 0.000 description 1
- 208000026451 salivation Diseases 0.000 description 1
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 239000008159 sesame oil Substances 0.000 description 1
- 235000011803 sesame oil Nutrition 0.000 description 1
- 239000004208 shellac Substances 0.000 description 1
- ZLGIYFNHBLSMPS-ATJNOEHPSA-N shellac Chemical compound OCCCCCC(O)C(O)CCCCCCCC(O)=O.C1C23[C@H](C(O)=O)CCC2[C@](C)(CO)[C@@H]1C(C(O)=O)=C[C@@H]3O ZLGIYFNHBLSMPS-ATJNOEHPSA-N 0.000 description 1
- 229940113147 shellac Drugs 0.000 description 1
- 235000013874 shellac Nutrition 0.000 description 1
- 239000001632 sodium acetate Substances 0.000 description 1
- 235000017281 sodium acetate Nutrition 0.000 description 1
- WXMKPNITSTVMEF-UHFFFAOYSA-M sodium benzoate Chemical compound [Na+].[O-]C(=O)C1=CC=CC=C1 WXMKPNITSTVMEF-UHFFFAOYSA-M 0.000 description 1
- 239000004299 sodium benzoate Substances 0.000 description 1
- 235000010234 sodium benzoate Nutrition 0.000 description 1
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 description 1
- 229920001027 sodium carboxymethylcellulose Polymers 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 235000010267 sodium hydrogen sulphite Nutrition 0.000 description 1
- RYYKJJJTJZKILX-UHFFFAOYSA-M sodium octadecanoate Chemical compound [Na+].CCCCCCCCCCCCCCCCCC([O-])=O RYYKJJJTJZKILX-UHFFFAOYSA-M 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- 239000008247 solid mixture Substances 0.000 description 1
- 239000000600 sorbitol Substances 0.000 description 1
- 235000010356 sorbitol Nutrition 0.000 description 1
- 239000007921 spray Substances 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 229940032147 starch Drugs 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 239000008174 sterile solution Substances 0.000 description 1
- 210000002784 stomach Anatomy 0.000 description 1
- 230000035882 stress Effects 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- QAHVHSLSRLSVGS-UHFFFAOYSA-N sulfamoyl chloride Chemical compound NS(Cl)(=O)=O QAHVHSLSRLSVGS-UHFFFAOYSA-N 0.000 description 1
- 238000013268 sustained release Methods 0.000 description 1
- 239000012730 sustained-release form Substances 0.000 description 1
- 230000002889 sympathetic effect Effects 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 235000012222 talc Nutrition 0.000 description 1
- ILMRJRBKQSSXGY-UHFFFAOYSA-N tert-butyl(dimethyl)silicon Chemical group C[Si](C)C(C)(C)C ILMRJRBKQSSXGY-UHFFFAOYSA-N 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- 210000001519 tissue Anatomy 0.000 description 1
- 125000003944 tolyl group Chemical group 0.000 description 1
- 230000036977 tonic contraction Effects 0.000 description 1
- 230000000699 topical effect Effects 0.000 description 1
- 230000037317 transdermal delivery Effects 0.000 description 1
- 125000000026 trimethylsilyl group Chemical group [H]C([H])([H])[Si]([*])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 238000003828 vacuum filtration Methods 0.000 description 1
- 239000003981 vehicle Substances 0.000 description 1
- 239000000230 xanthan gum Substances 0.000 description 1
- 229920001285 xanthan gum Polymers 0.000 description 1
- 235000010493 xanthan gum Nutrition 0.000 description 1
- 229940082509 xanthan gum Drugs 0.000 description 1
- 229930195724 β-lactose Natural products 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D319/00—Heterocyclic compounds containing six-membered rings having two oxygen atoms as the only ring hetero atoms
- C07D319/10—1,4-Dioxanes; Hydrogenated 1,4-dioxanes
- C07D319/14—1,4-Dioxanes; Hydrogenated 1,4-dioxanes condensed with carbocyclic rings or ring systems
- C07D319/16—1,4-Dioxanes; Hydrogenated 1,4-dioxanes condensed with carbocyclic rings or ring systems condensed with one six-membered ring
- C07D319/20—1,4-Dioxanes; Hydrogenated 1,4-dioxanes condensed with carbocyclic rings or ring systems condensed with one six-membered ring with substituents attached to the hetero ring
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/08—Antiepileptics; Anticonvulsants
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
Definitions
- the present invention is directed to processes for the preparation of benzo-fused heteroaryl derivatives, useful for the treatment of epilepsy and related disorders.
- the present invention is further directed to processes for the preparation of intermediates in the synthesis of the benzo-fused heteroaryl derivatives.
- Epilepsy describes a condition in which a person has recurrent seizures due to a chronic, underlying process.
- Epilepsy refers to a clinical phenomenon rather than a single disease entity, since there are many forms and causes of epilepsy.
- epilepsy Using a definition of epilepsy as two or more unprovoked seizures, the incidence of epilepsy is estimated at approximately 0.3 to 0.5 percent in different populations throughout the world, with the prevalence of epilepsy estimated at 5 to 10 people per 1000.
- An essential step in the evaluation and management of a patient with a seizure is to determine the type of seizure that has occurred.
- the main characteristic that distinguishes the different categories of seizures is whether the seizure activity is partial (synonymous with focal) or generalized.
- Partial seizures are those in which the seizure activity is restricted to discrete areas of the cerebral cortex. If consciousness is fully preserved during the seizure, the clinical manifestations are considered relatively simple and the seizure is termed a simple-partial seizure. If consciousness is impaired, the seizure is termed a complex-partial seizure. An important additional subgroup comprises those seizures that begin as partial seizures and then spread diffusely throughout the cortex, which are known as partial seizures with secondary generalization.
- Generalized seizures involve diffuse regions of the brain simultaneously in a bilaterally symmetric fashion. Absence or petit mal seizures are characterized by sudden, brief lapses of consciousness without loss of postural control. Atypical absence seizures typically include a longer duration in the lapse of consciousness, less abrupt onset and cessation, and more obvious motor signs that may include focal or lateralizing features.
- Generalized Tonic- clonic or grand mal seizures the main type of generalized seizures, are characterized by abrupt onset, without warning. The initial phase of the seizure is usually tonic contraction of muscles, impaired respiration, a marked enhancement of sympathetic tone leading to increased heart rate, blood pressure, and pupillary size.
- the tonic phase of the seizure typically evolves into the clonic phase, produced by the superimposition of periods of muscle relaxation on the tonic muscle contraction.
- the periods of relaxation progressively increase until the end of the ictal phase, which usually lasts no more than 1 min.
- the postictal phase is characterized by unresponsiveness, muscular flaccidity, and excessive salivation that can cause sthdorous breathing and partial airway obstruction.
- Atonic seizures are characterized by sudden loss of postural muscle tone lasting 1-2 s. Consciousness is briefly impaired, but there is usually no postictal confusion.
- Myoclonic seizures are characterized by a sudden and brief muscle contraction that may involve one part of the body or the entire body, (harrisonsonline.com, March 29, 2001 )
- McComsey, D., et al. in US Patent Publication US 2006/0041008 A1 , published February 23, 2006 and McComsey, D., et al. in US Patent Publication US 2005/0282887 A1 , published December 22, 2005 disclose compounds of formula (I) and their use in the treatment of epilepsy and related disorders.
- McComsey, D., et al. in US Patent Publication US 2006/0041008 A1 and McComsey, D., et al. in US Patent Publication US 2005/0282887 A1 further disclose a process for the preparation of the compounds of formula (I) comprising reacting a suitable substituted amine with sulfamide.
- the present invention is directed to a process for the preparation of compounds of formula (I)
- b is an integer from 0 to 4; and wherein c is an integer from 0 to 2; each R 5 is independently selected from the group consisting of halogen, lower alkyl and nitro;
- R 4 is selected from the group consisting of hydrogen and lower alkyl; R 1 and R 2 are each independently selected from the group consisting of hydrogen and lower alkyl; or pharmaceutically acceptable salts thereof; comprising
- the present invention is further directed to a process for the preparation of a compound of formula (V)
- each R 5 is independently selected from the group consisting of halogen, lower alkyl and nitro; comprising
- the present invention is directed to a process for the preparation of a compound of formula (I-S)
- the present invention is directed to a process for the preparation of a compound of formula (V-S)
- the present invention is further directed to a process for the preparation of a compound of formula (I)
- b is an integer from 0 to 4; and wherein c is an integer from 0 to 2; each R 5 is independently selected from the group consisting of halogen, lower alkyl and nitro;
- R 4 is selected from the group consisting of hydrogen and lower alkyl; R 1 and R 2 are each independently selected from the group consisting of hydrogen and lower alkyl; or pharmaceutically acceptable salts thereof; comprising
- the present invention is further directed to a process for the preparation of a compound of formula (V)
- b is an integer from 0 to 4; and wherein c is an integer from 0 to 2; each R 5 is independently selected from the group consisting of halogen, lower alkyl and nitro;
- the present invention is directed to processes for the preparation of a compound of formula (I-S)
- the present invention is directed to processes for the preparation of the compound of formula (V-S)
- the present invention is further directed to crystalline forms of the compound of formula (I-S)
- the present invention is directed to crystalline form (I- SA), as hereinafter defined. In another embodiment, the present invention is directed to crystalline form (I-SB), as hereinafter defined.
- the present invention is further directed to a product prepared according to any of the processes described herein.
- Illustrative of the invention is a pharmaceutical composition comprising a pharmaceutically acceptable carrier and any of the crystalline forms as described herein or a product prepared according to any of the processes described herein.
- An illustration of the invention is a pharmaceutical composition made by mixing any of the crystalline forms as described herein or a product prepared according to any of the processes described herein and a pharmaceutically acceptable carrier.
- Illustrating the invention is a process for making a pharmaceutical composition comprising mixing any of the crystalline forms as described herein or a product prepared according to any of the processes described herein and a pharmaceutically acceptable carrier.
- Exemplifying the invention are methods of treating epilepsy or a related disorder comprising administering to a subject in need thereof, a therapeutically effective amount of any of the compounds or pharmaceutical compositions described above.
- FIGURES Figure 1 illustrates representative XRD Spectra for representative samples of Crystalline Form (I-SA) (labeled b and c) and Crystalline form (I-SB) (labeled a).
- R 1 , R 2 , R 4 and v — y are as herein defined.
- the compounds of the present invention are useful in the treatment of epilepsy and related disorders.
- the present invention is further directed to processes for the preparation of compounds of formula (V), which can be represented herein by either of the following formulas
- the compounds of formula (V) are useful as intermediates in the synthesis of the compounds of formula (I).
- the present invention is directed to processes for the preparation of the compound of formula (I-S) or pharmaceutically acceptable salts thereof. In another embodiment, the present invention is directed to processes for the preparation of the compound of formula (V-S)
- the present invention is directed to processes for the synthesis of compounds of formula (I-A)
- b and R 5 are as herein defined.
- b is an integer from O to 2; more preferably, b is an integer from O to 1 .
- R 5 is halogen, more preferably, R 5 is chloro.
- R 1 is selected from the group consisting of hydrogen and methyl.
- R 2 is selected from the group consisting of hydrogen and methyl.
- R 1 and R 2 are each hydrogen or R 1 and R 2 are each methyl.
- R 4 is selected from the group consisting of hydrogen and methyl, preferably, R 4 is hydrogen.
- b is an integer from O to 2.
- c is an integer from O to 2.
- b is an integer from O to 1 .
- c is an integer from O to 1.
- the sum of b and c is an integer form O to 2, preferably an integer from O to 1.
- b is an integer from O to 2 and c is O.
- R 5 is selected from the group consisting of halogen and lower alkyl. In another embodiment of the present invention R 5 is selected from chloro, fluoro, bromo and methyl.
- a ring structure selected from the group consisting of 2-(6-chloro-2,3-dihydro- benzo[1 ,4]dioxinyl), 2-(5-chloro-2,3-dihydro-benzo[1 ,4]dioxinyl), 2-(7-nitro-2,3- dihydro-benzo[1 ,4]dioxinyl), 2-(6,7-dichloro-2,3-dihydro-benzo[1 ,4]dioxinyl) and 2-(2,3-dihydro-naphtho[2,3-b][1 ,4]dioxinyl).
- 2-(6-chloro-2,3-dihydro- benzo[1 ,4]dioxinyl) 2-(5-chloro-2,3-dihydro-benzo[1 ,4]dioxinyl)
- present invention is a ring structure selected from the group consisting of 2-(5-chloro-2,3-dihydro-benzo[1 ,4]dioxinyl), 2-(7-nitro-2,3-dihydro- benzo[1 ,4]dioxinyl), 2-(6,7-dichloro-2,3-dihydro-benzo[1 ,4]dioxinyl) and 2-(2,3- dihydro-naphtho[2,3-b][1 ,4]dioxinyl).
- Another embodiment of the present invention is selected from the group consisting of 2-(2,3-dihydro-benzo[1 ,4]dioxinyl), 2-(7-methyl-2,3-dihydro- benzo[1 ,4]dioxinyl) and 2-(6-bromo-2,3-dihydro-benzo[1 ,4]dioxinyl).
- the stereo-center on the compound of formula (I) is in the S-configuration. In another embodiment of the present invention, the stereo-center on the compound of formula (I) is in the
- the compound of formula (I) is present as an enantiomerically enriched mixture, wherein the % enantiomeric enrichment (%ee) is greater than about 75%, preferably greater than about
- Additional embodiments of the present invention include those wherein the substituents selected for one or more of the variables defined herein (e.g. R 1 , R 2 , R 4 , b and R 5 , etc.) are independently selected to be any individual substituent or any subset of substituents selected from the complete list as defined herein.
- halogen shall mean chlorine, bromine, fluorine and iodine.
- alkyl whether used alone or as part of a substituent group, includes straight and branched chains.
- alkyl radicals include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, t-butyl, pentyl and the like.
- lower when used with alkyl means a carbon chain composition of 1-4 carbon atoms.
- alkoxy shall denote an oxygen ether radical of the above described straight or branched chain alkyl groups. For example, methoxy, ethoxy, n-propoxy, sec-butoxy, t-butoxy, n-hexyloxy and the like.
- the term "enantiomerically enriched" when used to describe a compound with one stereogenic center shall mean that one stereo-configuration of the compound is present in a greater amount than the opposite stereo-configuration of said compound.
- the desired enantiomer of said compound is present in an enantiomeric excess of at least about 75 percent ee, more preferably at least 85 percent ee, more preferably at least 90 percent ee, more preferably at least 95 percent ee, more preferably at least 98 percent ee, most preferably at least 99 percent ee.
- epilepsy and related disorders shall mean any disorder in which a subject (preferably a human adult, child or infant) experiences one or more seizures and / or tremors.
- Suitable examples include, but are not limited to, epilepsy (including, but not limited to, localization-related epilepsies, generalized epilepsies, epilepsies with both generalized and local seizures, and the like), seizures as a complication of a disease or condition (such as seizures associated with encephalopathy, phenylketonuria, juvenile Gaucher's disease, Lundborg's progressive myoclonic epilepsy, stroke, head trauma, stress, hormonal changes, drug use or withdrawal, alcohol use or withdrawal, sleep deprivation, and the like), essential tremor, restless limb syndrome, and the like.
- epilepsy including, but not limited to, localization-related epilepsies, generalized epilepsies, epilepsies with both generalized and local seizures, and the like
- seizures as a complication of a disease or condition such as seizures associated with encephalopathy, phenylketonuria, juvenile Gaucher's disease, Lundborg's progressive myoclonic epi
- the disorder is selected from epilepsy (regardless of type, underlying cause or origin), essential tremor or restless limb syndrome, more preferably, the disorder is epilepsy (regardless of type, underlying cause or origin) or essential tremor.
- subject refers to an animal, preferably a mammal, most preferably a human, who is or has been the object of treatment, observation or experiment.
- terapéuticaally effective amount means that amount of active compound or pharmaceutical agent that elicits the biological or medicinal response in a tissue system, animal or human that is being sought by a researcher, veterinarian, medical doctor or other clinician, which includes alleviation of the symptoms of the disease or disorder being treated.
- composition is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product which results, directly or indirectly, from combinations of the specified ingredients in the specified amounts.
- reaction step(s) in the specification and claims are performed under suitable conditions (e.g. temperature, pressure, with appropriate solvents and/or reactants), according to known methods, to provide the desired product.
- suitable conditions e.g. temperature, pressure, with appropriate solvents and/or reactants
- suitable conditions shall mean a reaction step is performed under appropriate conditions (e.g. temperature, pressure, with appropriate solvents and/or reactants) according to known methods to provide the desired product.
- reagent or reagent class/type/ e.g. base, solvent, etc.
- the individual reagents are independently selected for each reaction step and may be the same of different from each other.
- the organic or inorganic base selected for the first step may be the same or different than the organic or inorganic base of the second step.
- aprotic solvent shall mean any solvent that does not yield a proton. Suitable examples include, but are not limited to DMF, dioxane, THF, acetonitrile, pyridine, dichloroethane, dichloromethane, MTBE, toluene, and the like.
- leaving group shall mean a charged or uncharged atom or group which departs during a substitution or displacement reaction. Suitable examples include, but are not limited to, Br, Cl, I, mesylate, tosylate, and the like.
- nitrogen protecting group shall mean a group which may be attached to a nitrogen atom to protect said nitrogen atom from participating in a reaction and which may be readily removed following the reaction.
- alcohol protecting group shall mean a group which may be attached to the oxygen of a hydroxy group (OH)) to protect said hydroxy group from participating in a reaction, and which may be readily removed following the reaction.
- Suitable alcohol protecting groups include, but are not limited to, t-butyl-dimethylsilyl, trimethylsilyl (TMS), MOM, ethoxyethyl, THP, SEM, benzyl, 4-nitrobenzyl, 4- methoxybenzyl, allyl, and the like.
- TMS trimethylsilyl
- MOM trimethylsilyl
- ethoxyethyl THP
- SEM benzyl
- 4-nitrobenzyl 4- methoxybenzyl
- allyl and the like.
- Other suitable alcohol protecting groups may be found in texts such as T. W. Greene & P. G. M. Wuts, Protective Groups in Organic Synthesis, John Wiley & Sons, 1991 , which is herein incorporated by reference in its
- the compounds according to this invention may accordingly exist as enantiomers. Where the compounds possess two or more chiral centers, they may additionally exist as diastereomers. It is to be understood that all such isomers and mixtures thereof are encompassed within the scope of the present invention.
- the enantiomer is present at an enantiomeric excess of greater than or equal to about 75%, more preferably, the enantiomer is present at an enantiomeric excess of greater than or equal to about 85%, more preferably, at an enantiomeric excess of greater than or equal to about 90%, more preferably still, at an enantiomeric excess of greater than or equal to about 95%, more preferably still, at an enantiomeric excess of greater than or equal to about 98%, most preferably, at an enantiomeric excess of greater than or equal to about 99%.
- the diastereomer is present at an diastereomeric excess of greater than or equal to about 75%, more preferably, the diastereomer is present at an diastereomehc excess of greater than or equal to about 85%, more preferably, at an diastereomehc excess of greater than or equal to about 90%, more preferably still, at an diastereomeric excess of greater than or equal to about 95%, more preferably still, at an diastereomeric excess of greater than or equal to about 98%, most preferably, at an diastereomeric excess of greater than or equal to about 99%.
- crystalline forms for the compounds of the present invention may exist as polymorphs and as such are intended to be included in the present invention.
- some of the compounds of the present invention may form solvates with water (i.e., hydrates) or common organic solvents, and such solvates are also intended to be encompassed within the scope of this invention.
- reaction step of the present invention may be carried out in a variety of solvents or solvent systems, said reaction step may also be carried out in a mixture of the suitable solvents or solvent systems.
- the processes for the preparation of the compounds according to the invention give rise to mixture of stereoisomers
- these isomers may be separated by conventional techniques such as preparative chromatography.
- the compounds may be prepared in racemic form, or individual enantiomers may be prepared either by enantiospecific synthesis or by resolution.
- the compounds may, for example, be resolved into their component enantiomers by standard techniques, such as the formation of diastereomeric pairs by salt formation with an optically active acid, such as (-)-di-p-toluoyl-D-tartahc acid and/or (+)-di-p-toluoyl-L-tartahc acid followed by fractional crystallization and regeneration of the free base.
- the compounds may also be resolved by formation of diastereomeric esters or amides, followed by chromatographic separation and removal of the chiral auxiliary. Alternatively, the compounds may be resolved using a chiral HPLC column.
- it may be necessary and/or desirable to protect sensitive or reactive groups on any of the molecules concerned. This may be achieved by means of conventional protecting groups, such as those described in Protective Groups in Organic Chemistry, ed. J. F. W. McOmie, Plenum Press, 1973; and T. W. Greene & P. G. M. Wuts, Protective Groups in Organic Synthesis, John Wiley & Sons, 1991.
- the protecting groups may be removed at a convenient subsequent stage using methods known from the art.
- the salts of the compounds of this invention refer to non-toxic "pharmaceutically acceptable salts. " Other salts may, however, be useful in the preparation of compounds according to this invention or of their pharmaceutically acceptable salts. Suitable pharmaceutically acceptable salts of the compounds include acid addition salts which may, for example, be formed by mixing a solution of the compound with a solution of a pharmaceutically acceptable base (preferably a strong base) such as NaOH, KOH, NaH, chloline hydroxide, and the like.
- a pharmaceutically acceptable base preferably a strong base
- the present invention is directed to a process for the preparation of compounds of formula (V) as described in more detail in Scheme 1 below.
- a known compound or compound prepared by known methods is protected, by reacting with a suitable protecting agent (i.e. a protecting agent stable under subsequent reaction condition, e.g. hydrolysis, oxidation) such as benzyl bromide, allyl bromide, 2-(thmethylsilyl)ethoxymethyl chloride (SEM-CI), t-butyl-diphenylsilyl chloride, methoxy or nitro-substituted benzyl bromides (for example, 4-nitro-benzyl bromide, 4-methoxybenzyl bromide, and the like), 1-(Ci -4 alkoxy)methyl halide or 1-(Ci -4 alkoxy)ethyl halide, wherein the halide is Cl, Br or I (for example, MOM-CI, ethoxyethylchlohde, and the like), and the like; in the presence of an organic or inorganic base such as K 2 CO 3 , Na 2 CO 3 , C
- protecting agent is benzyl bromide
- Pg 1 is benzyl
- the protecting agent is allyl bromide
- Pg 1 is allyl
- the protecting agent is MOM-CI
- Pg 1 is methoxy methyl ether (MOM).
- additional protecting groups and methods for incorporating said protecting groups are known in the art, as for example, described in T. W. Greene & P. G. M. Wuts, Protective Groups in Organic Synthesis, John Wiley & Sons, 1991 , which is herein incorporated by reference in its entirety.
- the compound of formula (Xl) is reacted with a suitably selected oxidizing agent such as m-CPBA, perbenzoic acid, peracetic acid, monomagnesium peroxyphthalate and the like, preferably m-CPBA; wherein the oxidizing agent is present in an amount of at least about 1 molar equivalent, preferably about 1 to 2 molar equivalents; in an organic solvent such as DCE, DCM, chloroform, acetonithle, NMP, and the like, preferably DCM; preferably, at about room temperature; to yield the corresponding compound of formula (XII).
- a suitably selected oxidizing agent such as m-CPBA, perbenzoic acid, peracetic acid, monomagnesium peroxyphthalate and the like, preferably m-CPBA; wherein the oxidizing agent is present in an amount of at least about 1 molar equivalent, preferably about 1 to 2 molar equivalents; in an organic solvent such as DCE, DCM, chloroform, ace
- the compound of formula (XII) is reacted with an organic or inorganic base such as NaOCH 3 , K-t-butoxide, sodium carbonate, potassium bicarbonate, and the like, preferably NaOCH 3 ; wherein the base is preferably present in an amount in the range of from about 1 to about 5 molar equivalents, more preferably in an amount in the range of from about 2 to about 3 molar equivalents; in an organic solvent or mixture thereof such as methanol, ethanol, propanol, a mixture of THF and an alcohol, and the like, or in a mixture of one or more organic solvents and water; preferably in an alcohol, more preferably in methanol; preferably at a temperature in the range of from about room temperature to about reflux temperature, more preferably at about room temperature; to yield the corresponding compound of formula (XIII).
- the compound of formula (XIII) is reacted with is reacted with a source
- epoxy-methylene such as glycidyl-m-nosylate, glycidyl- tosylate, epichlorohydhn, epibromohydhn, and the like, preferably glycidyl-m- nosylate or glycidyl-tosylate, preferably enantiomerically enriched source of epoxy-methylene, more preferably ⁇ -glycidyl-m-nosylate or ⁇ -glycidyl- tosylate; wherein the source of epoxy-methylene is preferably present in an amount in an amount in the range of from about 1 to about 5 molar equivalents, more preferably present in an amount in an amount in the range of from about 1 to about 2 molar equivalents, more preferably in an amount in the range of from about 1.1 to about 1.5 molar equivalent; in the presence of an inorganic base such as K 2 CO 3 , Na 2 CO 3 , Cs 2 CO 3 , NaH,
- the inorganic base is preferably present in an amount greater than or equal to about 1 molar equivalent, more preferably, an excess amount; at a temperature greater than about room temperature, preferably at a temperature in the range of form about room temperature to about 10O 0 C, more preferably, at a temperature in the range of from about 40 0 C to about 60 0 C, most preferably, at a temperature of about 40 0 C; in an organic solvent such as DMF, THF, N-methylpyrrolidinone, and the like, preferably DMF; to yield the corresponding compound of formula (XIV).
- an organic solvent such as DMF, THF, N-methylpyrrolidinone, and the like, preferably DMF
- the compound of formula (XIV) is de-protected according to known methods, to yield the corresponding compound of formula (XV).
- the compound of formula (XIV) may be de-protected by reacting with hydrogen or a source of hydrogen, preferably with hydrogen gas in the presence of a catalyst such as Pd/C, Pt, Pd(sulfide)/C, and the like; wherein the hydrogen gas is introduced at a pressure in the range of from about 10 psi to about 15 psi; in an organic solvent such as ethyl acetate, THF, isopropyl acetate, 2-methyl-THF, methyl-t-butyl ether, ethanol, and the like.
- the compound of formula (XIV) may be de-protected by reacting with a source of fluoride such as tetrabutylammonium fluoride, and the like, in an organic solvent such as THF, and the like.
- a source of fluoride such as tetrabutylammonium fluoride, and the like
- organic solvent such as THF, and the like.
- the reagent(s) selected for the de-protection of the compound of formula (XIV) are selected to be substantially un-reactive to the epoxy group on the compound of formula (XIV).
- the compound of formula (XV) is reacted with an organic or inorganic base such as NaOCH 3 , K-t-butoxide, sodium carbonate, and the like, preferably NaOCH 3 ; wherein the base is preferably present in an amount greater than or equal to about 1 molar equivalent, more preferably an excess amount; in a organic solvent such as methanol, ethanol, THF, acetonithle, and the like, preferably methanol; preferably at about room temperature; to yield the corresponding compound of formula (V).
- an organic or inorganic base such as NaOCH 3 , K-t-butoxide, sodium carbonate, and the like, preferably NaOCH 3 ; wherein the base is preferably present in an amount greater than or equal to about 1 molar equivalent, more preferably an excess amount;
- the compound of formula (V) may be prepared from the corresponding compound of formula (V) wherein the substituent group at the position at which one or more nitro groups is desired, is hydrogen, by converting said hydrogen(s) to the corresponding nitro group(s) according to known methods, for example by reacting with a mixture of nitric acid and sulfuric acid, a mixture of nitric acid and acetic acid or by reacting with potassium nitrate and sulfuric acid.
- the present invention is further directed to a process for the preparation of compounds of formula (V), as described in more detail in Scheme 2, below.
- source of epoxy-methylene such as glycidyl-m-nosylate, glycidyl-tosylate, epichlorohydhn, epibromohydrin, and the like, preferably glycidyl-m-nosylate or glycidyl-tosylate, preferably enantiomerically enriched source of epoxy-methylene, more preferably ⁇ -glycidyl-m-nosylate or (R)- glycidyl-tosylate; wherein the source of epoxy-methylene is preferably present in an amount in an amount in the range of from about 1 to about 5 molar equivalents, more preferably present in an amount in an amount in the range of from about 1 to about 2 molar equivalents, more preferably in an amount in the range of from about 1.1 to about 1.5 molar equivalent; in the presence of an inorganic base such as K 2 CO3, Na 2 COs, CS 2 CO3, NaH, KH,
- the compound of formula (XVII) is reacted with a suitably selected oxidizing agent such as m-CPBA, perbenzoic acid, peracetic acid, monomagnesium peroxyphthalate and the like, preferably m-CPBA; wherein the oxidizing agent is present in an amount of at least about 1 molar equivalent, preferably about 1 to 2 molar equivalents; in an organic solvent such as DCE, DCM, chloroform, acetonithle, NMP, and the like, preferably DCM; preferably, at about room temperature; to yield the corresponding compound of formula (XVIII).
- a suitably selected oxidizing agent such as m-CPBA, perbenzoic acid, peracetic acid, monomagnesium peroxyphthalate and the like, preferably m-CPBA; wherein the oxidizing agent is present in an amount of at least about 1 molar equivalent, preferably about 1 to 2 molar equivalents; in an organic solvent such as DCE, DCM, chloroform,
- the compound of formula (XVIII) is reacted with an organic or inorganic base such as NaOCH 3 , K-t-butoxide, sodium carbonate, and the like, preferably NaOCH 3 ; wherein the base is preferably present in an amount greater than or equal to about 1 molar equivalent, more preferably an excess amount; in a organic solvent such as methanol, ethanol, THF, acetonithle, and the like, preferably methanol; preferably at about room temperature; to yield the corresponding compound of formula (V).
- an organic or inorganic base such as NaOCH 3 , K-t-butoxide, sodium carbonate, and the like, preferably NaOCH 3 ; wherein the base is preferably present in an amount greater than or equal to about 1 molar equivalent, more preferably an excess amount; in a organic solvent such as methanol, ethanol, THF, acetonithle, and the like, preferably methanol; preferably at about room temperature; to yield the corresponding
- the compound of formula (V) may be further reacted according to known methods (for example, as disclosed in McComsey, D., et al. in US Patent Publication US 2006/0041008 A1 , published February 23, 2006; McComsey, D., et al. in US Patent Publication US 2005/0282887 A1 , published December 22, 2005) to yield the corresponding compound of formula (I).
- a suitably substituted compound of formula (V), prepared as for example outlined in Scheme 1 or 2 above, is activated, according to known method, to yield the corresponding compound of formula (XIX), wherein J is a suitable leaving group, such tosylate, Cl, Br, I, mesylate, thflate, and the like.
- the compound of formula (XIX) is reacted with a phthalimide salt such as potassium phthlimide, sodium phthalimide, and the like, in an organic solvent such as DMF, DMSO, acetonithle, and the like, preferably, at an elevated temperature in the range of from 50 0 C to about 200 0 C, more preferably, wherein the organic solvent is DMF, DMSO and the like, at temperature in the range of from about 50 0 C to about 150 0 C and wherein the organic solvent is acetonitrile, and the like, at about reflux temperature, to yield the corresponding compound of formula (XX).
- a phthalimide salt such as potassium phthlimide, sodium phthalimide, and the like
- the compound of formula (XX) is reacted with ISbH 4 , a known compound, in an organic solvent such as ethanol, methanol, and the like, preferably, at an elevated temperature in the range of from about 50 0 C to about 100 0 C, more preferably, at about reflux temperature, and the like, to yield the corresponding compound of formula (XXI).
- the compound of formula (XXI) is reacted with sulfamide (NH 2 -SO 2 -
- NH 2 a known compound, preferably wherein the sulfamide is present in an amount in the range of about 2 to about 5 equivalents, in an organic solvent such as THF, dioxane, and the like, preferably at an elevated temperature in the range of about 50 0 C to about 100 0 C, more preferably at about reflux temperature, to yield the corresponding compound of formula (Ia), a compound of formula (I) wherein R 1 and R 2 are each hydrogen.
- the compound of formula (XXI) is reacted with a suitably substituted compound of formula (XXII), a known compound or compound prepared by known methods, in the presence of a base such as TEA, DIPEA, pyridine, and the like, in an organic solvent such as DMF, DMSO, and the like, to yield the corresponding compound of formula (Ib).
- a base such as TEA, DIPEA, pyridine, and the like
- organic solvent such as DMF, DMSO, and the like
- a suitably substituted compound of formula (X-S) a known compound or compound prepared by known methods is protected by reacting with a suitable protecting agent (i.e. a protecting agent stable under subsequent reaction condition, e.g. hydrolysis, oxidation) such as benzyl bromide, allyl bromide, 2-(trimethylsilyl)ethoxymethyl chloride (SEM-CI), t-butyl- diphenylsilyl chloride, methoxy or nitro-substituted benzyl bromides (for example, 4-nitro-benzyl bromide, 4-methoxybenzyl bromide, and the like), 1- (Ci- 4 alkoxy)methyl halide or 1-(Ci -4 alkoxy)ethyl halide, wherein the halide is Cl, Br or I (for example, MOM-CI, ethoxyethylchlohde, and the like), and the like; in the presence of an organic or inorganic base such
- protecting agent is benzyl bromide
- Pg 1 is benzyl
- the protecting agent is allyl bromide
- Pg 1 is allyl
- the protecting agent is MOM-CI
- Pg 1 is methoxy methyl ether.
- additional protecting groups and methods for incorporating said protecting groups are known in the art, as for example, described in T. W. Greene & P. G. M. Wuts, Protective Groups in Organic Synthesis, John Wiley & Sons, 1991 , which is herein incorporated by reference in its entirety.
- the compound of formula (Xl-S) is reacted with a suitably selected oxidizing agent such as m-CPBA, perbenzoic acid, peracetic acid, monomagnesium peroxyphthalate and the like, preferably m-CPBA; wherein the oxidizing agent is present in an amount of at least about 1 molar equivalent, preferably about 1 to 2 molar equivalents; in an organic solvent such as DCE, DCM, chloroform, acetonithle, NMP, and the like, preferably DCM; preferably, at about room temperature; to yield the corresponding compound of formula (XII-S).
- a suitably selected oxidizing agent such as m-CPBA, perbenzoic acid, peracetic acid, monomagnesium peroxyphthalate and the like, preferably m-CPBA; wherein the oxidizing agent is present in an amount of at least about 1 molar equivalent, preferably about 1 to 2 molar equivalents; in an organic solvent such as DCE, DCM, chloro
- the compound of formula (XII-S) is reacted with an organic or inorganic base such as NaOCH 3 , K-t-butoxide, sodium carbonate, potassium bicarbonate, and the like, preferably NaOCH 3 ; wherein the base is preferably present in an amount in the range of from about 1 to about 5 molar equivalents, more preferably in an amount in the range of from about 2 to about 3 molar equivalents; in an organic solvent or mixture thereof such as methanol, ethanol, propanol, a mixture of THF and an alcohol, and the like, or in a mixture of one or more organic solvents and water; preferably in an alcohol, more preferably in methanol; preferably at a temperature in the range of from about room temperature to about reflux temperature, more preferably at about room temperature; to yield the corresponding compound of formula (XIII-S).
- the compound of formula (XIII) is reacted with is reacted with a source
- (fy-epoxy-methylene i.e. 1 ⁇ ) such as (RJ-glycidyl-m-nosylate, (R)- glycidyl-tosylate, (T?,)-epichlorohydrin, (7?,)-epibromohydhn, and the like, preferably (fy-glycidyl-m-nosylate or (fy-glycidyl-tosylate,; wherein the source of epoxy-methylene is preferably present in an amount in an amount in the range of from about 1 to about 5 molar equivalents, more preferably present in an amount in an amount in the range of from about 1 to about 2 molar equivalents, more preferably in an amount in the range of from about 1.1 to about 1.5 molar equivalent; in the presence of an inorganic base such as K 2 CO 3 , Na 2 CO 3 , Cs 2 CO 3 , NaH, KH, and the like, preferably K 2 CO 3 ;
- the compound of formula (XIV-S) is de-protected according to known methods, to yield the corresponding compound of formula (XV-S).
- the compound of formula (XIV-S) Pg 1 is benzyl, allyl, and the like
- the compound of formula (XIV-S) may be de-protected by reacting with hydrogen or a source of hydrogen, preferably with hydrogen gas in the presence of a catalyst such as Pd/C, Pt, Pd(sulfide)/C, and the like; wherein the hydrogen gas is introduced at a pressure in the range of from about 10 psi to about 15 psi; in an organic solvent such as ethyl acetate, THF, isopropyl acetate, 2-methyl-THF, methyl-t-butyl ether, ethanol, and the like.
- the compound of formula (XIV-S) may be de- protected by reacting with a source of fluoride such as tetrabutylammonium fluoride, and the like, in an organic solvent such as THF, and the like.
- a source of fluoride such as tetrabutylammonium fluoride, and the like
- organic solvent such as THF, and the like.
- the reagent(s) selected for the de-protection of the compound of formula (XIV-S) are selected to be substantially un-reactive to the epoxy group on the compound of formula (XIV- S).
- the compound of formula (XV-S) is reacted with an organic or inorganic base such as NaOCH3, K-t-butoxide, sodium carbonate, and the like, preferably NaOCHs; wherein the base is preferably present in an amount greater than or equal to about 1 molar equivalent, more preferably an excess amount; in a organic solvent such as methanol, ethanol, THF, acetonithle, and the like, preferably methanol; preferably at about room temperature; to yield the corresponding compound of formula (V-S).
- an organic or inorganic base such as NaOCH3, K-t-butoxide, sodium carbonate, and the like, preferably NaOCHs
- a organic solvent such as methanol, ethanol, THF, acetonithle, and the like, preferably methanol; preferably at about room temperature; to yield the corresponding compound of formula (V-S).
- the present invention is directed to a process for the preparation of the compound of formula (V-S), as outlined in Scheme 5 below.
- ⁇ -epoxy-methylene i.e. 1 ⁇
- source of ⁇ -epoxy-methylene such as (RJ-glycidyl-m- nosylate, ⁇ -glycidyl-tosylate, (7?,)-epichlorohydrin, (7?,)-epibromohydrin, and the like, preferably ⁇ -glycidyl-m-nosylate or (7 ⁇ -glycidyl-tosylate
- the source of epoxy-methylene is preferably present in an amount in an amount in the range of from about 1 to about 5 molar equivalents, more preferably present in an amount in an amount in the range of from about 1 to about 2 molar equivalents, more preferably in an amount in the range of from about 1.1 to about 1.5 molar equivalent; in the presence of an inorganic base such as K 2 CO 3 , Na 2 CO 3 , Cs 2 CO 3 , NaH, KH, and the like, preferably K 2 CO 3 ;
- the compound of formula (XVIII-S) is reacted with a suitably selected oxidizing agent such as m-CPBA, perbenzoic acid, peracetic acid, monomagnesium peroxyphthalate and the like, preferably m-CPBA; wherein the oxidizing agent is present in an amount of at least about 1 molar equivalent, preferably about 1 to 2 molar equivalents; in an organic solvent such as DCE, DCM, chloroform, acetonithle, NMP, and the like, preferably DCM; preferably, at about room temperature; to yield the corresponding compound of formula (XVIII-S).
- a suitably selected oxidizing agent such as m-CPBA, perbenzoic acid, peracetic acid, monomagnesium peroxyphthalate and the like, preferably m-CPBA; wherein the oxidizing agent is present in an amount of at least about 1 molar equivalent, preferably about 1 to 2 molar equivalents; in an organic solvent such as DCE, DCM, chlor
- the compound of formula (XVIII-S) is reacted with an organic or inorganic base such as NaOCH 3 , K-t-butoxide, sodium carbonate, and the like, preferably NaOCH 3 ; wherein the base is preferably present in an amount greater than or equal to about 1 molar equivalent, more preferably an excess amount; in a organic solvent such as methanol, ethanol, THF, acetonithle, and the like, preferably methanol; preferably at about room temperature; to yield the corresponding compound of formula (V-S).
- an organic or inorganic base such as NaOCH 3 , K-t-butoxide, sodium carbonate, and the like, preferably NaOCH 3 ; wherein the base is preferably present in an amount greater than or equal to about 1 molar equivalent, more preferably an excess amount; in a organic solvent such as methanol, ethanol, THF, acetonithle, and the like, preferably methanol; preferably at about room temperature; to
- the compound of formula (V-S) may be further reacted to yield the corresponding compound of formula (I-S) according to known methods (for example, as disclosed in McComsey, D., et al. in US Patent Publication US 2006/0041008 A1 , published February 23, 2006; McComsey, D., et al. in US Patent Publication US 2005/0282887 A1 , published December 22, 2005).
- the compound of formula (I-S) may be prepared according to the process outlined in Scheme 6, below.
- the compound of formula (XIX-S) is reacted with a phthalimide salt such as potassium phthlimide, sodium phthalimide, and the like, in an organic solvent such as DMF, DMSO, acetonithle, and the like, preferably, at an elevated temperature in the range of from 50 0 C to about 200 0 C, more preferably, wherein the organic solvent is DMF, DMSO and the like, at temperature in the range of from about 50 0 C to about 150 0 C and wherein the organic solvent is acetonitrile, and the like, at about reflux temperature, to yield the corresponding compound of formula (XX-S).
- a phthalimide salt such as potassium phthlimide, sodium phthalimide, and the like
- the compound of formula (XX-S) is reacted with N 2 H 4 , a known compound, in an organic solvent such as ethanol, methanol, and the like, preferably, at an elevated temperature in the range of from about 50 0 C to about 100 0 C, more preferably, at about reflux temperature, and the like, to yield the corresponding compound of formula (XXI-S).
- the compound of formula (XXI-S) is reacted with sulfamide (NH 2 -SO 2 - NH2), a known compound, preferably wherein the sulfamide is present in an amount in the range of about 2 to about 5 equivalents, in an organic solvent such as THF, dioxane, and the like, preferably at an elevated temperature in the range of about 50 0 C to about 100 0 C, more preferably at about reflux temperature, to yield the corresponding compound of formula (I-S).
- sulfamide NH 2 -SO 2 - NH2
- organic solvent such as THF, dioxane, and the like
- compound of formula (XXI-S) is reacted with compound of formula (XXII-S), a known compound, also known as sulfamoyl chloride, in the presence of a base such as TEA, DIPEA, pyridine, and the like, in an organic solvent such as DMF, DMSO, and the like, to yield the corresponding compound of formula (I-S).
- a base such as TEA, DIPEA, pyridine, and the like
- organic solvent such as DMF, DMSO, and the like
- the present invention is further directed to crystalline forms of the compound of formula (I-S), hereinafter referred to as crystalline form (I-SA) and (I-SB).
- the crystalline forms of the compound of formula (I-S) may be characterized by their corresponding Powder X-ray Diffraction (PXRD) spectra.
- the crystalline forms of the compound of formula (I-S) may be characterized by their corresponding PXRD peaks, wherein the peaks have a relative intensity of greater than or equal to about 10% relative intensity; preferably, wherein the peaks have a relative intensity of greater than or equal to about 25% relative intensity.
- the crystalline form of the compound of formula (I-S) may be characterized by its corresponding PXRD peaks, wherein the peaks are defined by their position (°2 ⁇ ), d-spacing (A) and relative intensity (%).
- the crystalline form of the compound of formula (I-S) may be characterized by its corresponding PXRD peaks, wherein the peaks are defined by their position (°2 ⁇ ) and d-spacing (A). Powder XRD spectra were measured for representative samples of the crystalline forms of the compound of formula (I-S) with peaks as listed in Tables 2 and 3 below.
- the PXRD spectra were measured using an X-Celerator detector, scanning form 3 to 35°2 ⁇ , at a step size of 0.0165°2 ⁇ , a time per step of 10.16 sec, an effective scan speed of 0.2067°/sec, instrument voltage of 45 kV and a current setting of 40 mA.
- Crystalline form (I-SA) may be prepared for example, as described in Example 13 below.
- the melting point of crystalline form (I-SA) was measured for a representative sample and showed a melting point onset of 98.6°C and a 100.8 0 C.
- Crystalline form (I-SA) may be characterized by its powder XRD peaks, as listed in Table XRD-1 below.
- Crystalline form (I-SB) may be prepared by re-crystallizing the compound of formula (I-S) from water, according to known methods, for example as described in Example 14 below.
- the melting point of crystalline form (I-SA) was measured for a representative sample and showed a melting point onset of 100.7 0 C and a 102.8 0 C.
- Crystalline form (I-SB) may be characterized by its powder XRD peaks, as listed in Table 3 below.
- Figure 1 illustrates representative powder X-ray diffraction patterns corresponding to the following samples: (a) the topmost scan corresponds to a representative sample of crystalline form (I-SB); (b) the middle and bottom scans correspond to two separately prepared samples of crystalline form (I- SA).
- the present invention further comprises pharmaceutical compositions containing one or more of the compounds prepared according to any of the processes described herein with a pharmaceutically acceptable carrier.
- compositions containing one or more of the compounds of the invention described herein as the active ingredient can be prepared by intimately mixing the compound or compounds with a pharmaceutical carrier according to conventional pharmaceutical compounding techniques.
- the carrier may take a wide variety of forms depending upon the desired route of administration (e.g., oral, parenteral).
- suitable carriers and additives include water, glycols, oils, alcohols, flavoring agents, preservatives, stabilizers, coloring agents and the like;
- suitable carriers and additives include starches, sugars, diluents, granulating agents, lubricants, binders, disintegrating agents and the like.
- Solid oral preparations may also be coated with substances such as sugars or be enteric-coated so as to modulate major site of absorption.
- the carrier will usually consist of sterile water and other ingredients may be added to increase solubility or preservation.
- injectable suspensions or solutions may also be prepared utilizing aqueous carriers along with appropriate additives.
- compositions of this invention one or more compounds of the present invention as the active ingredient is intimately admixed with a pharmaceutical carrier according to conventional pharmaceutical compounding techniques, which carrier may take a wide variety of forms depending of the form of preparation desired for administration, e.g., oral or parenteral such as intramuscular.
- a pharmaceutical carrier may take a wide variety of forms depending of the form of preparation desired for administration, e.g., oral or parenteral such as intramuscular.
- any of the usual pharmaceutical media may be employed.
- suitable carriers and additives include water, glycols, oils, alcohols, flavoring agents, preservatives, coloring agents and the like;
- suitable carriers and additives include starches, sugars, diluents, granulating agents, lubricants, binders, disintegrating agents and the like. Because of their ease in administration, tablets and capsules represent the most advantageous oral dosage unit form, in which case solid pharmaceutical carriers are obviously employed. If desired, tablets may be sugar coated or enteric coated by standard techniques.
- the carrier will usually comprise sterile water, through other ingredients, for example, for purposes such as aiding solubility or for preservation, may be included.
- injectable suspensions may also be prepared, in which case appropriate liquid carriers, suspending agents and the like may be employed.
- the pharmaceutical compositions herein will contain, per dosage unit, e.g., tablet, capsule, powder, injection, teaspoonful and the like, an amount of the active ingredient necessary to deliver an effective dose as described above.
- compositions herein will contain, per unit dosage unit, e.g., tablet, capsule, powder, injection, suppository, teaspoonful and the like, of from about 1-1000 mg and may be given at a dosage of from about 0.01-300 mg/kg/day, or any range therein, preferably from about 0.5-100 mg/kg/day, or any range therein, more preferably from about 1.0-25.0 mg/kg/day, or any range therein.
- the dosages may be varied depending upon the requirement of the patients, the severity of the condition being treated and the compound being employed. The use of either daily administration or post- periodic dosing may be employed.
- compositions are in unit dosage forms from such as tablets, pills, capsules, powders, granules, sterile parenteral solutions or suspensions, metered aerosol or liquid sprays, drops, ampoules, autoinjector devices or suppositories; for oral parenteral, intranasal, sublingual or rectal administration, or for administration by inhalation or insufflation.
- the composition may be presented in a form suitable for once-weekly or once- monthly administration; for example, an insoluble salt of the active compound, such as the decanoate salt, may be adapted to provide a depot preparation for intramuscular injection.
- a pharmaceutical carrier e.g.
- a solid preformulation composition containing a homogeneous mixture of a compound of the present invention, or a pharmaceutically acceptable salt thereof.
- preformulation compositions as homogeneous, it is meant that the active ingredient is dispersed evenly throughout the composition so that the composition may be readily subdivided into equally effective dosage forms such as tablets, pills and capsules.
- This solid preformulation composition is then subdivided into unit dosage forms of the type described above containing from 0.1 to about 500 mg of the active ingredient of the present invention.
- the tablets or pills of the novel composition can be coated or otherwise compounded to provide a dosage form affording the advantage of prolonged action.
- the tablet or pill can comprise an inner dosage and an outer dosage component, the latter being in the form of an envelope over the former.
- the two components can be separated by an enteric layer which serves to resist disintegration in the stomach and permits the inner component to pass intact into the duodenum or to be delayed in release.
- enteric layers or coatings such materials including a number of polymeric acids with such materials as shellac, cetyl alcohol and cellulose acetate.
- liquid forms in which the novel compositions of the present invention may be incorporated for administration orally or by injection include, aqueous solutions, suitably flavoured syrups, aqueous or oil suspensions, and flavoured emulsions with edible oils such as cottonseed oil, sesame oil, coconut oil or peanut oil, as well as elixirs and similar pharmaceutical vehicles.
- Suitable dispersing or suspending agents for aqueous suspensions include synthetic and natural gums such as tragacanth, acacia, alginate, dextran, sodium carboxymethylcellulose, methylcellulose, polyvinyl-pyrrolidone or gelatin.
- the method of treating epilepsy or a related disorder described in the present invention may also be carried out using a pharmaceutical composition comprising any of the compounds as defined herein and a pharmaceutically acceptable carrier.
- the pharmaceutical composition may contain between about 0.1 mg and 1000 mg, preferably about 50 to 500 mg, of the compound, or any range therein, and may be constituted into any form suitable for the mode of administration selected.
- Carriers include necessary and inert pharmaceutical excipients, including, but not limited to, binders, suspending agents, lubricants, flavorants, sweeteners, preservatives, dyes, and coatings.
- compositions suitable for oral administration include solid forms, such as pills, tablets, caplets, capsules (each including immediate release, timed release and sustained release formulations), granules, and powders, and liquid forms, such as solutions, syrups, elixers, emulsions, and suspensions.
- forms useful for parenteral administration include sterile solutions, emulsions and suspensions.
- compounds of the present invention may be administered in a single daily dose, or the total daily dosage may be administered in divided doses of two, three or four times daily.
- compounds for the present invention can be administered in intranasal form via topical use of suitable intranasal vehicles, or via transdermal skin patches well known to those of ordinary skill in that art.
- the dosage administration will, of course, be continuous rather than intermittent throughout the dosage regimen.
- the active drug component can be combined with an oral, non-toxic pharmaceutically acceptable inert carrier such as ethanol, glycerol, water and the like.
- suitable binders include, without limitation, starch, gelatin, natural sugars such as glucose or beta- lactose, corn sweeteners, natural and synthetic gums such as acacia, tragacanth or sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride and the like.
- Disintegrators include, without limitation, starch, methyl cellulose, agar, bentonite, xanthan gum and the like.
- the liquid forms in suitably flavored suspending or dispersing agents such as the synthetic and natural gums, for example, tragacanth, acacia, methyl- cellulose and the like.
- suspending or dispersing agents such as the synthetic and natural gums, for example, tragacanth, acacia, methyl- cellulose and the like.
- sterile suspensions and solutions are desired.
- Isotonic preparations which generally contain suitable preservatives are employed when intravenous administration is desired.
- a compound of formula (I) as the active ingredient is intimately admixed with a pharmaceutical carrier according to conventional pharmaceutical compounding techniques, which carrier may take a wide variety of forms depending of the form of preparation desired for administration (e.g. oral or parenteral).
- a pharmaceutical carrier may take a wide variety of forms depending of the form of preparation desired for administration (e.g. oral or parenteral).
- Suitable pharmaceutically acceptable carriers are well known in the art. Descriptions of some of these pharmaceutically acceptable carriers may be found in The Handbook of Pharmaceutical Excipients, published by the American
- Compounds of this invention may be administered in any of the foregoing compositions and according to dosage regimens established in the art whenever treatment of epilepsy or related disorders is required.
- the daily dosage of the products may be varied over a wide range from 0.01 to 10,000 mg per adult human per day, or any range therein.
- the compositions are preferably provided in the form of tablets containing, 0.01 , 0.05, 0.1 , 0.5, 1.0, 2.5, 5.0, 10.0, 15.0, 25.0, 50.0, 100, 150, 200, 250, 500 and 1000 milligrams of the active ingredient for the symptomatic adjustment of the dosage to the patient to be treated.
- An effective amount of the drug is ordinarily supplied at a dosage level of from about 0.01 mg/kg to about 500.0 mg/kg of body weight per day, or any range therein.
- the range is from about 0.5 to about 100.0 mg/kg of body weight per day, or any range therein, more preferably, from about 1.0 to about 50.0 mg/kg of body weight per day, or any range therein.
- the compounds may be administered on a regimen of 1 to 4 times per day.
- Optimal dosages to be administered may be readily determined by those skilled in the art, and will vary with the particular compound used, the mode of administration, the strength of the preparation, the mode of administration, and the advancement of the disease condition. In addition, factors associated with the particular patient being treated, including patient age, weight, diet and time of administration, will result in the need to adjust dosages.
- a one-neck flask (equipped with magnetic stirring, and a nitrogen inlet), was charged with crude formic acid, 2-benzyloxy-5-chloro-phenyl ester (9, 28 g, 0.107 mol), sodium methoxide (25% (w/w) in methanol, 26.5 mL, 0.123 mol), and methanol (175 mL).
- the reaction mixture was stirred for 18 h (overnight).
- the reaction mixture was concentrated to a red oil that was partitioned between saturated ammonium chloride (200 mL) and ethyl ether (200 mL).
- the aqueous layer was extracted with ethyl ether (2 x 100 mL), and the combined organics were washed with 1 M aqueous sodium hydroxide (150 mL), brine (2 x 100 mL), dried (MgSO 4 ), and concentrated to yield crude product.
- the crude product was dissolved in dichloromethane and loaded onto a Biotage 4OM (90 g silica gel) and eluted with dichloromethane (250 mL) and 1 :19 ethyl acetate-dichloromethane (1 L) to yield the title compound as a white solid (19415-132A). Melting Point: 73 - 75°C.
- reaction mixture was then allowed to cool overnight to yield a white slurry upon cooling.
- the white solid was removed by filtration and the filtrate was split into four portions. Each portion was washed with 10% (w/w) sodium bisufite (1 L) and both phases were tested by starch iodide paper to see if any oxidant remained. This test was negative and the aqueous phase was back extracted with dichloromethane (2 x 250 mL) and the combined organic phases (four portions) were washed with saturated sodium bicarbonate (3 x 500 mL), dried (MgSO 4 ), and concentrated to yield crude product, which was used in subsequent steps without further purification.
- reaction mixture was stirred under nitrogen at room temperature for 10 days (reaction appeared complete after ⁇ 4 days).
- the reaction mixture was filtered to remove amine hydrochloride and split into two portions. Each portion was stirred with 20% aqueous potassium bicarbonate (3 L) for 2.5 h. Each portion was then extracted with /-propyl acetate (2 x 1 .5 L) and the organics were washed with 2 M hydrochloric acid (2 x 1 L), saturated sodium bicarbonate (2 x 1 L), brine (500 mL), and dried (MgSO 4 ). The resulting mixture was concentrated to yield crude product.
- the mixed fractions were re- chromatographed on a Biotage 75L (800 g silica) using heptane (1 L), 1 :9 ethyl acetate-heptane (2 L), 3:7 ethyl acetate-heptane (6 L), and 1 :1 ethyl acetate- heptane (8 L) to yield additional product.
- the two lots of product were combined to yield the title compound as an off-white solid.
- the title compound prepared according to the procedure as described in this Example yielded form (I-SA).
- reaction mixture was then cooled in an ice bath and 1 N HCI (750 mL) was added.
- the reaction mixture was extracted with diethyl ether (3x, 200 mL).
- the combined diethyl ether was washed with 1 N HCI (2x, 250 mL), water, brine (2x) and dried (MgSO 4 ) and evaporated in vacuo to yield the title compound as a white solid..
- the compound of formula (I-S), prepared for example as described above, was formulated according to known methods into liquid formulations of 25 mg and 100 mg, respectively, with components as listed in Table 4 below.
- Hypromellose also known as HPMC or Suspending hydroxypropylmethylcellulose
- an oral composition 100 mg of the compound prepared as in Example 18 is formulated with sufficient finely divided lactose to provide a total amount of 580 to 590 mg to fill a size O hard gel capsule.
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Abstract
The present invention is directed to processes for the preparation of benzo-fused heteroaryl derivatives, useful for the treatment of epilepsy and related disorders. The present invention is further directed to processes for the preparation of intermediates in the synthesis of the benzo-fused heteroaryl derivatives.
Description
PROCESS FOR PREPARATION OF BENZO-FUSED HETEROARYL
DERIVATIVES
FIELD OF THE INVENTION
The present invention is directed to processes for the preparation of benzo-fused heteroaryl derivatives, useful for the treatment of epilepsy and related disorders. The present invention is further directed to processes for the preparation of intermediates in the synthesis of the benzo-fused heteroaryl derivatives.
BACKGROUND OF THE INVENTION
Epilepsy describes a condition in which a person has recurrent seizures due to a chronic, underlying process. Epilepsy refers to a clinical phenomenon rather than a single disease entity, since there are many forms and causes of epilepsy. Using a definition of epilepsy as two or more unprovoked seizures, the incidence of epilepsy is estimated at approximately 0.3 to 0.5 percent in different populations throughout the world, with the prevalence of epilepsy estimated at 5 to 10 people per 1000. An essential step in the evaluation and management of a patient with a seizure is to determine the type of seizure that has occurred. The main characteristic that distinguishes the different categories of seizures is whether the seizure activity is partial (synonymous with focal) or generalized.
Partial seizures are those in which the seizure activity is restricted to discrete areas of the cerebral cortex. If consciousness is fully preserved during the seizure, the clinical manifestations are considered relatively simple and the seizure is termed a simple-partial seizure. If consciousness is impaired, the seizure is termed a complex-partial seizure. An important additional subgroup comprises those seizures that begin as partial seizures and then spread diffusely throughout the cortex, which are known as partial seizures with secondary generalization.
Generalized seizures involve diffuse regions of the brain simultaneously in a bilaterally symmetric fashion. Absence or petit mal seizures are
characterized by sudden, brief lapses of consciousness without loss of postural control. Atypical absence seizures typically include a longer duration in the lapse of consciousness, less abrupt onset and cessation, and more obvious motor signs that may include focal or lateralizing features. Generalized Tonic- clonic or grand mal seizures, the main type of generalized seizures, are characterized by abrupt onset, without warning. The initial phase of the seizure is usually tonic contraction of muscles, impaired respiration, a marked enhancement of sympathetic tone leading to increased heart rate, blood pressure, and pupillary size. After 10-20 s, the tonic phase of the seizure typically evolves into the clonic phase, produced by the superimposition of periods of muscle relaxation on the tonic muscle contraction. The periods of relaxation progressively increase until the end of the ictal phase, which usually lasts no more than 1 min. The postictal phase is characterized by unresponsiveness, muscular flaccidity, and excessive salivation that can cause sthdorous breathing and partial airway obstruction. Atonic seizures are characterized by sudden loss of postural muscle tone lasting 1-2 s. Consciousness is briefly impaired, but there is usually no postictal confusion. Myoclonic seizures are characterized by a sudden and brief muscle contraction that may involve one part of the body or the entire body, (harrisonsonline.com, March 29, 2001 )
McComsey, D., et al. in US Patent Publication US 2006/0041008 A1 , published February 23, 2006 and McComsey, D., et al. in US Patent Publication US 2005/0282887 A1 , published December 22, 2005 disclose compounds of formula (I) and their use in the treatment of epilepsy and related disorders. McComsey, D., et al. in US Patent Publication US 2006/0041008 A1 and McComsey, D., et al. in US Patent Publication US 2005/0282887 A1 further disclose a process for the preparation of the compounds of formula (I) comprising reacting a suitable substituted amine with sulfamide.
In the process(es) as disclosed in McComsey D., et al. compounds of formula (I) wherein R1 and R2 are each hydrogen describes the use of sulfamoyl chloride ( CI-SO2-NH2) as a reagent, which reagent is unsuitable for large scale / commercial preparation. There remains, however, a need for a
process suitable for the preparation of large scale material and / or for commercial preparation of the compounds of formula (I).
SUMMARY OF THE INVENTION
The present invention is directed to a process for the preparation of compounds of formula (I)
wherein
is selected from the group consisting of
b is an integer from 0 to 4; and wherein c is an integer from 0 to 2; each R5 is independently selected from the group consisting of halogen, lower alkyl and nitro;
R4 is selected from the group consisting of hydrogen and lower alkyl; R1 and R2 are each independently selected from the group consisting of hydrogen and lower alkyl; or pharmaceutically acceptable salts thereof; comprising
protecting a compound of formula (X) wherein
is selected
from the group consisting of
to yield the corresponding compound of formula (Xl), wherein Pg1 is an alcohol protecting group;
reacting the compound of formula (Xl) with an oxidizing agent; in an organic solvent; to yield the corresponding compound of formula (XII);
reacting the compound of formula (XII) with an organic or inorganic base; in an organic solvent, in a mixture of organic solvents or in a mixture of one or more organic solvents and water; to yield the corresponding compound of formula (XIII);
reacting the compound of formula (XIII) with a source of epoxy- methylene; in the presence of an inorganic base; at a temperature greater than about room temperature; in an organic solvent; to yield the corresponding compound of formula (XIV);
de-protecting the compound of formula (XIV); to yield the corresponding compound of formula (XV);
reacting the compound of formula (XV) with an organic or inorganic base; in a organic solvent; to yield the corresponding compound of formula (V);
reacting the compound of formula (V); to yield the corresponding compound of formula (I).
The present invention is further directed to a process for the preparation of a compound of formula (V)
(V) wherein
is selected from the group consisting of
and
b is an integer from 0 to 4; and wherein c is an integer from 0 to 2; each R5 is independently selected from the group consisting of halogen, lower alkyl and nitro; comprising
protecting a compound of formula (X); to yield the corresponding compound of formula (Xl), wherein Pg1 is an alcohol protecting group;
reacting the compound of formula (Xl) with an oxidizing agent; in an organic solvent; to yield the corresponding compound of formula (XII);
reacting the compound of formula (XII) with an organic or inorganic base; in an organic solvent, in a mixture of organic solvents or in a mixture of one or more organic solvents and water; to yield the corresponding compound of formula (XIII);
reacting the compound of formula (XIII) with a source of epoxy- methylene; in the presence of an inorganic base; at a temperature greater than about room temperature; in an organic solvent; to yield the corresponding compound of formula (XIV);
de-protecting the compound of formula (XIV); to yield the corresponding compound of formula (XV);
reacting the compound of formula (XV) with an organic or inorganic base; in a organic solvent; to yield the corresponding compound of formula (V).
In an embodiment, the present invention is directed to a process for the preparation of a compound of formula (I-S)
or a pharmaceutically acceptable salt thereof (wherein the compound of formula (I-S) is also known as Λ/-[[(2S)-6-chloro-2,3-dihydro-1 ,4-benzodioxin-2- yl]methyl]-sulfamide); comprising
protecting a compound of formula (X-S); to yield the corresponding compound of formula (Xl-S), wherein Pg1 is an alcohol protecting group;
reacting the compound of formula (Xl-S) with an oxidizing agent; in an organic solvent; to yield the corresponding compound of formula (XII-S);
reacting the compound of formula (XII-S) with an organic or inorganic base; in an organic solvent, in a mixture of organic solvents or in a mixture of one or more organic solvents and water; to yield the corresponding compound of formula (XIII-S);
reacting the compound of formula (XIII-S) with a source of (R)-epoxy- methylene; in the presence of an inorganic base; at a temperature greater than about room temperature; in an organic solvent; to yield the corresponding compound of formula (XIV-S);
de-protecting the compound of formula (XIV-S); to yield the corresponding compound of formula (XV-S);
reacting the compound of formula (XV-S) with an organic or inorganic base; in a organic solvent; to yield the corresponding compound of formula (V- S);
reacting the compound of formula (V-S); to yield the corresponding compound of formula (I-S).
In another embodiment, the present invention is directed to a process for the preparation of a compound of formula (V-S)
also known as (6-chloro-2,3-dihydro-benzo[1 ,4]dioxin-2-yl)-('S/)-methanol; comprising
protecting a compound of formula (X-S); to yield the corresponding compound of formula (Xl-S), wherein Pg1 is an alcohol protecting group;
reacting the compound of formula (Xl-S) with an oxidizing agent; in an organic solvent; to yield the corresponding compound of formula (XII-S);
reacting the compound of formula (XII-S) with an organic or inorganic base; in an organic solvent, in a mixture of organic solvents or in a mixture of one or more organic solvents and water; to yield the corresponding compound of formula (XIII-S);
reacting the compound of formula (XIII-S) with a source of (R)-epoxy- methylene; in the presence of an inorganic base; at a temperature greater than about room temperature; in an organic solvent; to yield the corresponding compound of formula (XIV-S);
de-protecting the compound of formula (XIV-S); to yield the corresponding compound of formula (XV-S);
reacting the compound of formula (XV-S) with an organic or inorganic base; in a organic solvent; to yield the corresponding compound of formula (V- S).
The present invention is further directed to a process for the preparation of a compound of formula (I)
wherein
is selected from the group consisting of
b is an integer from 0 to 4; and wherein c is an integer from 0 to 2; each R5 is independently selected from the group consisting of halogen, lower alkyl and nitro;
R4 is selected from the group consisting of hydrogen and lower alkyl; R1 and R2 are each independently selected from the group consisting of hydrogen and lower alkyl; or pharmaceutically acceptable salts thereof; comprising
reacting a
compound of formula (XVI) wherein is selected
from the group consisting of
and and wherein Q is selected from the group consisting of -C(O)-(Ci-4alkyl); with a source of epoxy-methylene; in the presence of an inorganic base; at a temperature greater than about room temperature; in an organic solvent; to yield the corresponding compound of formula (XVII);
reacting the compound of formula (XVII) with an oxidizing agent; in an organic solvent; to yield the corresponding compound of formula (XVIII);
reacting the compound of formula (XVIII) with an organic or inorganic base; in a organic solvent; to yield the corresponding compound of formula (V);
*
reacting the compound of formula (V); to yield the corresponding compound of formula (I).
The present invention is further directed to a process for the preparation of a compound of formula (V)
(V) wherein
is selected from the group consisting of
b is an integer from 0 to 4; and wherein c is an integer from 0 to 2; each R5 is independently selected from the group consisting of halogen, lower alkyl and nitro;
reacting a compound of formula (XVI) wherein Q is selected from the group consisting of -C(0)-(d-4alkyl); with a source of epoxy-methylene; in the presence of an inorganic base; at a temperature greater than about room temperature; in an organic solvent; to yield the corresponding compound of formula (XVII);
reacting the compound of formula (XVII) with an oxidizing agent; in an organic solvent; to yield the corresponding compound of formula (XVIII);
reacting the compound of formula (XVIII) with an organic or inorganic base; in a organic solvent; to yield the corresponding compound of formula (V).
In an embodiment, the present invention is directed to processes for the preparation of a compound of formula (I-S)
or a pharmaceutically acceptable salt thereof (wherein the compound of formula (I-S) is also known as Λ/-[[(2S)-6-chloro-2,3-dihydro-1 ,4-benzodioxin-2- yl]methyl]-sulfamide); comprising
reacting a compound of formula (XVI-S) wherein Q is selected from the group consisting of -C(O)-(Ci-4alkyl); with a source of (T?,)-epoxy-methylene; in the presence of an inorganic base; at a temperature greater than about room temperature; in an organic solvent; to yield the corresponding compound of formula (XVII-S);
reacting the compound of formula (XVII-S) with an oxidizing agent; in an organic solvent; to yield the corresponding compound of formula (XVIII-S);
reacting the compound of formula (XVIII-S) with an organic or inorganic base; in a organic solvent; to yield the corresponding compound of formula (V- S);
reacting the compound of formula (V-S); to yield the corresponding compound of formula (I-S).
In another embodiment, the present invention is directed to processes for the preparation of the compound of formula (V-S)
also known as (6-chloro-2,3-dihydro-benzo[1 ,4]dioxin-2-yl)-('S/)-methanol; comprising
reacting a compound of formula (XVI-S) wherein Q is selected from the group consisting of -C(O)-(Ci-4alkyl); with a source of (7?,)-epoxy-methylene; in the presence of an inorganic base; at a temperature greater than about room temperature; in an organic solvent; to yield the corresponding compound of formula (XVII-S);
reacting the compound of formula (XVII-S) with an oxidizing agent; in an organic solvent; to yield the corresponding compound of formula (XVIII-S);
reacting the compound of formula (XVIII-S) with an organic or inorganic base; in a organic solvent; to yield the corresponding compound of formula (V- S).
The present invention is further directed to crystalline forms of the compound of formula (I-S)
In an embodiment, the present invention is directed to crystalline form (I- SA), as hereinafter defined. In another embodiment, the present invention is directed to crystalline form (I-SB), as hereinafter defined.
The present invention is further directed to a product prepared according to any of the processes described herein. Illustrative of the invention is a pharmaceutical composition comprising a pharmaceutically acceptable carrier and any of the crystalline forms as described herein or a product prepared according to any of the processes described herein. An illustration of the invention is a pharmaceutical composition made by mixing any of the crystalline forms as described herein or a product prepared according to any of the processes described herein and a pharmaceutically acceptable carrier. Illustrating the invention is a process for making a pharmaceutical composition comprising mixing any of the crystalline forms as described herein or a product prepared according to any of the processes described herein and a pharmaceutically acceptable carrier. Exemplifying the invention are methods of treating epilepsy or a related disorder comprising administering to a subject in need thereof, a therapeutically
effective amount of any of the compounds or pharmaceutical compositions described above.
BRIEF DESCRIPTION OF THE FIGURES Figure 1 illustrates representative XRD Spectra for representative samples of Crystalline Form (I-SA) (labeled b and c) and Crystalline form (I-SB) (labeled a).
DETAILED DESCRIPTION OF THE INVENTION The present invention is directed to processes for the preparation of compound of formula (I)
wherein R1, R2, R4 and v — y are as herein defined. The compounds of the present invention are useful in the treatment of epilepsy and related disorders.
The present invention is further directed to processes for the preparation of compounds of formula (V), which can be represented herein by either of the following formulas
The compounds of formula (V) are useful as intermediates in the synthesis of the compounds of formula (I).
In an embodiment, the present invention is directed to processes for the preparation of the compound of formula (I-S)
or pharmaceutically acceptable salts thereof. In another embodiment, the present invention is directed to processes for the preparation of the compound of formula (V-S)
In embodiment, the present invention is directed to processes for the synthesis of compounds of formula (I-A)
and pharmaceutically acceptable salts thereof, wherein b and R5 are as herein defined. Preferably, b is an integer from O to 2; more preferably, b is an integer from O to 1 . Preferably R5 is halogen, more preferably, R5 is chloro.
In an embodiment of the present invention R1 is selected from the group consisting of hydrogen and methyl. In another embodiment of the present invention R2 is selected from the group consisting of hydrogen and methyl. In yet another embodiment of the present invention R1 and R2 are each hydrogen or R1 and R2 are each methyl.
In an embodiment of the present R4 is selected from the group consisting of hydrogen and methyl, preferably, R4 is hydrogen.
In an embodiment of the present invention b is an integer from O to 2. In another embodiment of the present invention c is an integer from O to 2. In another embodiment of the present invention b is an integer from O to 1 . In another embodiment of the present invention c is an integer from O to 1. In yet another embodiment of the present invention the sum of b and c is an integer form O to 2, preferably an integer from O to 1. In yet another embodiment of the present invention b is an integer from O to 2 and c is O.
In an embodiment of the present invention R5 is selected from the group consisting of halogen and lower alkyl. In another embodiment of the present invention R5 is selected from chloro, fluoro, bromo and methyl.
In an embodiment of the present invention,
is a ring structure
selected from the group consisting of
and
embodiment of the present
consisting of
In an embodiment of the present invention,
is a ring structure selected from the group consisting of 2-(6-chloro-2,3-dihydro- benzo[1 ,4]dioxinyl), 2-(5-chloro-2,3-dihydro-benzo[1 ,4]dioxinyl), 2-(7-nitro-2,3- dihydro-benzo[1 ,4]dioxinyl), 2-(6,7-dichloro-2,3-dihydro-benzo[1 ,4]dioxinyl) and 2-(2,3-dihydro-naphtho[2,3-b][1 ,4]dioxinyl). In another embodiment of the
present invention,
is a ring structure selected from the group consisting of 2-(5-chloro-2,3-dihydro-benzo[1 ,4]dioxinyl), 2-(7-nitro-2,3-dihydro- benzo[1 ,4]dioxinyl), 2-(6,7-dichloro-2,3-dihydro-benzo[1 ,4]dioxinyl) and 2-(2,3- dihydro-naphtho[2,3-b][1 ,4]dioxinyl).
In an embodiment of the present invention,
is selected from the group consisting of 2-(2,3-dihydro-benzo[1 ,4]dioxinyl),-2-(6-chloro-2,3-dihydro- benzo[1 ,4]dioxinyl), 2-(6-fluoro-2,3-dihydro-benzo[1 ,4]dioxinyl), 2-(5-fluoro-2,3- dihydro-benzo[1 ,4]dioxinyl), 2-(7-chloro-2,3-dihydro-benzo[1 ,4]dioxinyl), 2-(7- nitro-2,3-dihydro-benzo[1 ,4]dioxinyl), 2-(7-methyl-2,3-dihydro- benzo[1 ,4]dioxinyl), 2-(5-chloro-2,3-dihydro-benzo[1 ,4]dioxinyl), 2-(6-bromo- 2,3-dihydro-benzo[1 ,4]dioxinyl), 2-(6,7-dichloro-2,3-dihydro-benzo[1 ,4]dioxinyl), 2-(8-chloro-2,3-dihydro-benzo[1 ,4]dioxinyl) and 2-(2,3-dihydro-naphtho[2,3- b][1 ,4]dioxinyl).
In another embodiment of the present invention,
is selected from the group consisting 2-(2,3-dihydro-benzo[1 ,4]dioxinyl), 2-(6-chloro-2,3- dihydro-benzo[1 ,4]dioxinyl), 2-(7-chloro-2,3-dihydro-benzo[1 ,4]dioxinyl), 2-(7- methyl-2,3-dihydro-benzo[1 ,4]dioxinyl), 2-(6-bromo-2,3-dihydro- benzo[1 ,4]dioxinyl) and 2-(6,7-dichloro-2,3-dihydro-benzo[1 ,4]dioxinyl). In
another embodiment of the present invention,
is selected from the group consisting of 2-(2,3-dihydro-benzo[1 ,4]dioxinyl), 2-(7-methyl-2,3-dihydro- benzo[1 ,4]dioxinyl) and 2-(6-bromo-2,3-dihydro-benzo[1 ,4]dioxinyl).
In an embodiment of the present invention, the stereo-center on the compound of formula (I) is in the S-configuration. In another embodiment of the present invention, the stereo-center on the compound of formula (I) is in the
R-configuration.
In an embodiment of the present invention the compound of formula (I) is present as an enantiomerically enriched mixture, wherein the % enantiomeric enrichment (%ee) is greater than about 75%, preferably greater than about
85%, more preferably greater than about 90%, more preferably greater than about 95%, more preferably greater than about 98%, most preferably greater than about 99%.
Representative compounds of the present invention, are as listed in Tables 1 and 2, below. In Tables 1 and 2 below, the column headed "stereo" defines the stereo-configuration at the carbon atom of the heterocycle attached at the starred bond. Where no designation is listed, the compound was prepared as a mixture of stereo-configurations. Where an "R" or "S" designation is listed, the stereo-configuration was based on the enantiomerically enriched starting material.
Table 1 : Representative Compounds of Formula (I)
Additional embodiments of the present invention, include those wherein the substituents selected for one or more of the variables defined herein (e.g. R1, R2, R4, b and R5, etc.) are independently selected to be any individual substituent or any subset of substituents selected from the complete list as defined herein.
As used herein, unless otherwise noted, "halogen" shall mean chlorine, bromine, fluorine and iodine.
As used herein, unless otherwise noted, the term "alkyl" whether used alone or as part of a substituent group, includes straight and branched chains. For example, alkyl radicals include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, t-butyl, pentyl and the like. Unless otherwise noted, "lower" when used with alkyl means a carbon chain composition of 1-4 carbon atoms.
As used herein, unless otherwise noted, "alkoxy" shall denote an oxygen ether radical of the above described straight or branched chain alkyl groups. For example, methoxy, ethoxy, n-propoxy, sec-butoxy, t-butoxy, n-hexyloxy and the like.
As used herein, the notation "*" shall denote the presence of a stereogenic center.
As used herein, unless otherwise noted, the term "enantiomerically enriched" when used to describe a compound with one stereogenic center, shall mean that one stereo-configuration of the compound is present in a greater amount than the opposite stereo-configuration of said compound. Preferably, when the compound is said to be enantiomerically enriched, the desired enantiomer of said compound is present in an enantiomeric excess of at least about 75 percent ee, more preferably at least 85 percent ee, more preferably at least 90 percent ee, more preferably at least 95 percent ee, more preferably at least 98 percent ee, most preferably at least 99 percent ee.
Abbreviations used in the specification, particularly the Schemes and Examples, are as follows:
As used herein, unless otherwise noted, the terms "epilepsy and related disorders" or "epilepsy or related disorder" shall mean any disorder in which a subject (preferably a human adult, child or infant) experiences one or more seizures and / or tremors. Suitable examples include, but are not limited to, epilepsy (including, but not limited to, localization-related epilepsies, generalized epilepsies, epilepsies with both generalized and local seizures, and the like), seizures as a complication of a disease or condition (such as seizures associated with encephalopathy, phenylketonuria, juvenile Gaucher's disease, Lundborg's progressive myoclonic epilepsy, stroke, head trauma, stress, hormonal changes, drug use or withdrawal, alcohol use or withdrawal, sleep deprivation, and the like), essential tremor, restless limb syndrome, and the like. Preferably, the disorder is selected from epilepsy (regardless of type, underlying cause or origin), essential tremor or restless limb syndrome, more preferably, the disorder is epilepsy (regardless of type, underlying cause or origin) or essential tremor.
The term "subject" as used herein, refers to an animal, preferably a mammal, most preferably a human, who is or has been the object of treatment, observation or experiment.
The term "therapeutically effective amount" as used herein, means that amount of active compound or pharmaceutical agent that elicits the biological or medicinal response in a tissue system, animal or human that is being sought by a researcher, veterinarian, medical doctor or other clinician, which includes alleviation of the symptoms of the disease or disorder being treated.
As used herein, the term "composition" is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product which results, directly or indirectly, from combinations of the specified ingredients in the specified amounts.
One skilled in the art will recognize that, where not otherwise specified, the reaction step(s) in the specification and claims are performed under
suitable conditions (e.g. temperature, pressure, with appropriate solvents and/or reactants), according to known methods, to provide the desired product. The term "suitable conditions" shall mean a reaction step is performed under appropriate conditions (e.g. temperature, pressure, with appropriate solvents and/or reactants) according to known methods to provide the desired product.
One skilled in the art will also recognize that, in the specification and claims as presented herein, wherein a reagent or reagent class/type/ (e.g. base, solvent, etc.) is recited in more than one step of a process, the individual reagents are independently selected for each reaction step and may be the same of different from each other. For example wherein two steps of a process recite an organic or inorganic base as a reagent, the organic or inorganic base selected for the first step may be the same or different than the organic or inorganic base of the second step.
To provide a more concise description, some of the quantitative expressions given herein are not qualified with the term "about". It is understood that whether the term "about" is used explicitly or not, every quantity given herein is meant to refer to the actual given value, and it is also meant to refer to the approximation to such given value that would reasonably be inferred based on the ordinary skill in the art, including approximations due to the experimental and/or measurement conditions for such given value.
As used herein, unless otherwise noted, the term "aprotic solvent" shall mean any solvent that does not yield a proton. Suitable examples include, but are not limited to DMF, dioxane, THF, acetonitrile, pyridine, dichloroethane, dichloromethane, MTBE, toluene, and the like. As used herein, unless otherwise noted, the term "leaving group" shall mean a charged or uncharged atom or group which departs during a substitution or displacement reaction. Suitable examples include, but are not limited to, Br, Cl, I, mesylate, tosylate, and the like.
As used herein, unless otherwise noted, the term "nitrogen protecting group" shall mean a group which may be attached to a nitrogen atom to protect said nitrogen atom from participating in a reaction and which may be readily removed following the reaction. Suitable nitrogen protecting groups include, but are not limited to carbamates - groups of the formula -C(O)O-R
wherein R is for example methyl, ethyl, t-butyl, benzyl, phenylethyl, CH2=CH- CH2-, and the like; amides - groups of the formula -C(O)-R' wherein R' is for example methyl, phenyl, thfluoromethyl, and the like; N-sulfonyl derivatives - groups of the formula -SO2-R" wherein R" is for example tolyl, phenyl, thfluoromethyl, 2,2,5,7,8-pentamethylchroman-6-yl-, 2,3,6-thmethyl-4- methoxybenzene, and the like. Other suitable nitrogen protecting groups may be found in texts such as T. W. Greene & P. G. M. Wuts, Protective Groups in Organic Synthesis, John Wiley & Sons, 1991.
As used herein, unless otherwise noted, the term "alcohol protecting group" shall mean a group which may be attached to the oxygen of a hydroxy group (OH)) to protect said hydroxy group from participating in a reaction, and which may be readily removed following the reaction. Suitable alcohol protecting groups include, but are not limited to, t-butyl-dimethylsilyl, trimethylsilyl (TMS), MOM, ethoxyethyl, THP, SEM, benzyl, 4-nitrobenzyl, 4- methoxybenzyl, allyl, and the like. Other suitable alcohol protecting groups may be found in texts such as T. W. Greene & P. G. M. Wuts, Protective Groups in Organic Synthesis, John Wiley & Sons, 1991 , which is herein incorporated by reference in its entirety.
Where the compounds according to this invention have at least one chiral center, they may accordingly exist as enantiomers. Where the compounds possess two or more chiral centers, they may additionally exist as diastereomers. It is to be understood that all such isomers and mixtures thereof are encompassed within the scope of the present invention. Preferably, wherein the compound is present as an enantiomer, the enantiomer is present at an enantiomeric excess of greater than or equal to about 75%, more preferably, the enantiomer is present at an enantiomeric excess of greater than or equal to about 85%, more preferably, at an enantiomeric excess of greater than or equal to about 90%, more preferably still, at an enantiomeric excess of greater than or equal to about 95%, more preferably still, at an enantiomeric excess of greater than or equal to about 98%, most preferably, at an enantiomeric excess of greater than or equal to about 99%. Similarly, wherein the compound is present as a diastereomer, the diastereomer is present at an diastereomeric excess of greater than or equal to about 75%, more preferably,
the diastereomer is present at an diastereomehc excess of greater than or equal to about 85%, more preferably, at an diastereomehc excess of greater than or equal to about 90%, more preferably still, at an diastereomeric excess of greater than or equal to about 95%, more preferably still, at an diastereomeric excess of greater than or equal to about 98%, most preferably, at an diastereomeric excess of greater than or equal to about 99%.
Furthermore, some of the crystalline forms for the compounds of the present invention may exist as polymorphs and as such are intended to be included in the present invention. In addition, some of the compounds of the present invention may form solvates with water (i.e., hydrates) or common organic solvents, and such solvates are also intended to be encompassed within the scope of this invention.
One skilled in the art will recognize that wherein a reaction step of the present invention may be carried out in a variety of solvents or solvent systems, said reaction step may also be carried out in a mixture of the suitable solvents or solvent systems.
Where the processes for the preparation of the compounds according to the invention give rise to mixture of stereoisomers, these isomers may be separated by conventional techniques such as preparative chromatography. The compounds may be prepared in racemic form, or individual enantiomers may be prepared either by enantiospecific synthesis or by resolution. The compounds may, for example, be resolved into their component enantiomers by standard techniques, such as the formation of diastereomeric pairs by salt formation with an optically active acid, such as (-)-di-p-toluoyl-D-tartahc acid and/or (+)-di-p-toluoyl-L-tartahc acid followed by fractional crystallization and regeneration of the free base. The compounds may also be resolved by formation of diastereomeric esters or amides, followed by chromatographic separation and removal of the chiral auxiliary. Alternatively, the compounds may be resolved using a chiral HPLC column. During any of the processes for preparation of the compounds of the present invention, it may be necessary and/or desirable to protect sensitive or reactive groups on any of the molecules concerned. This may be achieved by means of conventional protecting groups, such as those described in Protective
Groups in Organic Chemistry, ed. J. F. W. McOmie, Plenum Press, 1973; and T. W. Greene & P. G. M. Wuts, Protective Groups in Organic Synthesis, John Wiley & Sons, 1991. The protecting groups may be removed at a convenient subsequent stage using methods known from the art.
For use in medicine, the salts of the compounds of this invention refer to non-toxic "pharmaceutically acceptable salts. " Other salts may, however, be useful in the preparation of compounds according to this invention or of their pharmaceutically acceptable salts. Suitable pharmaceutically acceptable salts of the compounds include acid addition salts which may, for example, be formed by mixing a solution of the compound with a solution of a pharmaceutically acceptable base (preferably a strong base) such as NaOH, KOH, NaH, chloline hydroxide, and the like.
The present invention is directed to a process for the preparation of compounds of formula (V) as described in more detail in Scheme 1 below.
Scheme 1 Accordingly, a suitably substituted compound of formula (X), wherein
is selected from the group consisting of and
, a known compound or compound prepared by known methods is protected, by reacting with a suitable protecting agent (i.e. a
protecting agent stable under subsequent reaction condition, e.g. hydrolysis, oxidation) such as benzyl bromide, allyl bromide, 2-(thmethylsilyl)ethoxymethyl chloride (SEM-CI), t-butyl-diphenylsilyl chloride, methoxy or nitro-substituted benzyl bromides (for example, 4-nitro-benzyl bromide, 4-methoxybenzyl bromide, and the like), 1-(Ci-4alkoxy)methyl halide or 1-(Ci-4alkoxy)ethyl halide, wherein the halide is Cl, Br or I (for example, MOM-CI, ethoxyethylchlohde, and the like), and the like; in the presence of an organic or inorganic base such as K2CO3, Na2CO3, Cs2CO3, tetramethylguanidine, TEA, and the like; preferably K2CO3; wherein the base is preferably present in an amount greater than or equal to about 1 molar equivalent, more preferably an excess amount; at a temperature greater than about room temperature, preferably at a temperature in the range of form about 400C to about 10O0C, more preferably, at a temperature in the range of from about 600C to about 800C, most preferably, at a temperature of about 600C; in an organic solvent such as DMF, THF, N- methylpyrrolidinone, and the like; to yield the corresponding compound of formula (Xl), wherein Pg1 is the corresponding alcohol protecting group. For example, wherein the protecting agent is benzyl bromide, Pg1 is benzyl; wherein the protecting agent is allyl bromide, Pg1 is allyl; wherein the protecting agent is MOM-CI, Pg1 is methoxy methyl ether (MOM). One skilled in the art will recognize that additional protecting groups and methods for incorporating said protecting groups are known in the art, as for example, described in T. W. Greene & P. G. M. Wuts, Protective Groups in Organic Synthesis, John Wiley & Sons, 1991 , which is herein incorporated by reference in its entirety.
The compound of formula (Xl) is reacted with a suitably selected oxidizing agent such as m-CPBA, perbenzoic acid, peracetic acid, monomagnesium peroxyphthalate and the like, preferably m-CPBA; wherein the oxidizing agent is present in an amount of at least about 1 molar equivalent, preferably about 1 to 2 molar equivalents; in an organic solvent such as DCE, DCM, chloroform, acetonithle, NMP, and the like, preferably DCM; preferably, at about room temperature; to yield the corresponding compound of formula (XII).
The compound of formula (XII) is reacted with an organic or inorganic base such as NaOCH3, K-t-butoxide, sodium carbonate, potassium
bicarbonate, and the like, preferably NaOCH3; wherein the base is preferably present in an amount in the range of from about 1 to about 5 molar equivalents, more preferably in an amount in the range of from about 2 to about 3 molar equivalents; in an organic solvent or mixture thereof such as methanol, ethanol, propanol, a mixture of THF and an alcohol, and the like, or in a mixture of one or more organic solvents and water; preferably in an alcohol, more preferably in methanol; preferably at a temperature in the range of from about room temperature to about reflux temperature, more preferably at about room temperature; to yield the corresponding compound of formula (XIII). The compound of formula (XIII) is reacted with is reacted with a source
of epoxy-methylene (i.e.
) such as glycidyl-m-nosylate, glycidyl- tosylate, epichlorohydhn, epibromohydhn, and the like, preferably glycidyl-m- nosylate or glycidyl-tosylate, preferably enantiomerically enriched source of epoxy-methylene, more preferably ^-glycidyl-m-nosylate or ^-glycidyl- tosylate; wherein the source of epoxy-methylene is preferably present in an amount in an amount in the range of from about 1 to about 5 molar equivalents, more preferably present in an amount in an amount in the range of from about 1 to about 2 molar equivalents, more preferably in an amount in the range of from about 1.1 to about 1.5 molar equivalent; in the presence of an inorganic base such as K2CO3, Na2CO3, Cs2CO3, NaH, KH, and the like, preferably
K2CO3; wherein the inorganic base is preferably present in an amount greater than or equal to about 1 molar equivalent, more preferably, an excess amount; at a temperature greater than about room temperature, preferably at a temperature in the range of form about room temperature to about 10O0C, more preferably, at a temperature in the range of from about 400C to about 600C, most preferably, at a temperature of about 400C; in an organic solvent such as DMF, THF, N-methylpyrrolidinone, and the like, preferably DMF; to yield the corresponding compound of formula (XIV).
The compound of formula (XIV) is de-protected according to known methods, to yield the corresponding compound of formula (XV). For example, wherein the compound of formula (XIV) Pg1 is benzyl, allyl, and the like, the compound of formula (XIV) may be de-protected by reacting with hydrogen or a
source of hydrogen, preferably with hydrogen gas in the presence of a catalyst such as Pd/C, Pt, Pd(sulfide)/C, and the like; wherein the hydrogen gas is introduced at a pressure in the range of from about 10 psi to about 15 psi; in an organic solvent such as ethyl acetate, THF, isopropyl acetate, 2-methyl-THF, methyl-t-butyl ether, ethanol, and the like. Wherein Pg1 is SEM or a silyl protecting group, the compound of formula (XIV) may be de-protected by reacting with a source of fluoride such as tetrabutylammonium fluoride, and the like, in an organic solvent such as THF, and the like. One skilled in the art will recognize that additional methods for removing protecting groups are known in the art, as for example, described in T. W. Greene & P. G. M. Wuts, Protective Groups in Organic Synthesis, John Wiley & Sons, 1991.
One skilled in the art will recognize that the reagent(s) selected for the de-protection of the compound of formula (XIV) are selected to be substantially un-reactive to the epoxy group on the compound of formula (XIV). The compound of formula (XV) is reacted with an organic or inorganic base such as NaOCH3, K-t-butoxide, sodium carbonate, and the like, preferably NaOCH3; wherein the base is preferably present in an amount greater than or equal to about 1 molar equivalent, more preferably an excess amount; in a organic solvent such as methanol, ethanol, THF, acetonithle, and the like, preferably methanol; preferably at about room temperature; to yield the corresponding compound of formula (V).
One skilled in the art will recognize that when the source of epoxy- methylene is enatiomehcally enriched with one of the enantiomers, then on opening the epoxide, the compound of formula (V) is prepared as the corresponding enantiomerically enriched compound. For example, wherein enantiomerically enriched ('R)-glycicyl-m-nosylate or (R)-glycidyl tosylate is reacted with the compound of formula (XIII), then the process as described in Scheme 1 above yield the corresponding compound of formula (V)
as the enantiomehcaly enriched (S) enantiomer at the starred ("*") position.
Preferably, the process as described in Scheme 1 above is applied to the preparation of compounds of formula (V) wherein each R5 is other than nitro. One skilled in the art will recognize that wherein one or more of the R5 groups are nitro, the compound of formula (V) may be prepared from the corresponding compound of formula (V) wherein the substituent group at the position at which one or more nitro groups is desired, is hydrogen, by converting said hydrogen(s) to the corresponding nitro group(s) according to known methods, for example by reacting with a mixture of nitric acid and sulfuric acid, a mixture of nitric acid and acetic acid or by reacting with potassium nitrate and sulfuric acid.
The present invention is further directed to a process for the preparation of compounds of formula (V), as described in more detail in Scheme 2, below.
Scheme 2
Accordingly, a suitably substituted compound of formula (XVI) wherein Q is selected from the group consisting of -C(O)-(Ci-4alkyl), wherein the Ci-4 alkyl is preferably a primary Ci-4alkyl, more preferably -C(O)-CH3, and the like, a known compound or compound prepared by known methods is reacted with a
source of epoxy-methylene (i.e. ^ ) such as glycidyl-m-nosylate, glycidyl-tosylate, epichlorohydhn, epibromohydrin, and the like, preferably glycidyl-m-nosylate or glycidyl-tosylate, preferably enantiomerically enriched source of epoxy-methylene, more preferably ^-glycidyl-m-nosylate or (R)- glycidyl-tosylate; wherein the source of epoxy-methylene is preferably present in an amount in an amount in the range of from about 1 to about 5 molar
equivalents, more preferably present in an amount in an amount in the range of from about 1 to about 2 molar equivalents, more preferably in an amount in the range of from about 1.1 to about 1.5 molar equivalent; in the presence of an inorganic base such as K2CO3, Na2COs, CS2CO3, NaH, KH, and the like, preferably K2CO3; wherein the inorganic base is preferably present in an amount greater than or equal to about 1 molar equivalent, more preferably, an excess amount; at a temperature greater than about room temperature, preferably at a temperature in the range of form about room temperature to about 10O0C, more preferably, at a temperature in the range of from about 400C to about 6O0C, most preferably, at a temperature of about 400C; in an organic solvent such as DMF, THF, N-methylpyrrolidinone, and the like, preferably DMF; to yield the corresponding compound of formula (XVII).
The compound of formula (XVII) is reacted with a suitably selected oxidizing agent such as m-CPBA, perbenzoic acid, peracetic acid, monomagnesium peroxyphthalate and the like, preferably m-CPBA; wherein the oxidizing agent is present in an amount of at least about 1 molar equivalent, preferably about 1 to 2 molar equivalents; in an organic solvent such as DCE, DCM, chloroform, acetonithle, NMP, and the like, preferably DCM; preferably, at about room temperature; to yield the corresponding compound of formula (XVIII). Wherein Q is -C(O)-(CH3) the compound of formula (XVII) is reacted under conditions other than with monomagnesium peroxyphthalate in DMF.
The compound of formula (XVIII) is reacted with an organic or inorganic base such as NaOCH3, K-t-butoxide, sodium carbonate, and the like, preferably NaOCH3; wherein the base is preferably present in an amount greater than or equal to about 1 molar equivalent, more preferably an excess amount; in a organic solvent such as methanol, ethanol, THF, acetonithle, and the like, preferably methanol; preferably at about room temperature; to yield the corresponding compound of formula (V).
One skilled in the art will recognize that when the source of epoxy- methylene is enatiomehcally enriched with one of the enantiomers, then on opening the epoxide, the compound of formula (V) is prepared as the corresponding enantiomerically enriched compound. For example, wherein enantiomerically enriched ('R)-glycicyl-m-nosylate or (RJ-glycidyl-tosylate is
reacted with the compound of formula (XIII), then the process as described in Scheme 2 above yield the corresponding compound of formula (Va)
as the enantiomehcaly enriched (S) enantiomer at the starred ("*") position.
The compound of formula (V) may be further reacted according to known methods (for example, as disclosed in McComsey, D., et al. in US Patent Publication US 2006/0041008 A1 , published February 23, 2006; McComsey, D., et al. in US Patent Publication US 2005/0282887 A1 , published December 22, 2005) to yield the corresponding compound of formula (I).
For example, compounds of formula (I) wherein R4 is hydrogen may be prepared according to the process outlined in Scheme 3.
(V) (XIX) (XX)
(XXII)
Scheme 3
Accordingly, a suitably substituted compound of formula (V), prepared as for example outlined in Scheme 1 or 2 above, is activated, according to known method, to yield the corresponding compound of formula (XIX), wherein J is a suitable leaving group, such tosylate, Cl, Br, I, mesylate, thflate, and the like.
The compound of formula (XIX) is reacted with a phthalimide salt such as potassium phthlimide, sodium phthalimide, and the like, in an organic solvent such as DMF, DMSO, acetonithle, and the like, preferably, at an elevated temperature in the range of from 500C to about 2000C, more preferably, wherein the organic solvent is DMF, DMSO and the like, at temperature in the range of from about 500C to about 1500C and wherein the organic solvent is acetonitrile, and the like, at about reflux temperature, to yield the corresponding compound of formula (XX). The compound of formula (XX) is reacted with ISbH4, a known compound, in an organic solvent such as ethanol, methanol, and the like, preferably, at an elevated temperature in the range of from about 500C to about 1000C, more preferably, at about reflux temperature, and the like, to yield the corresponding compound of formula (XXI). The compound of formula (XXI) is reacted with sulfamide (NH2-SO2-
NH2), a known compound, preferably wherein the sulfamide is present in an amount in the range of about 2 to about 5 equivalents, in an organic solvent such as THF, dioxane, and the like, preferably at an elevated temperature in the range of about 500C to about 1000C, more preferably at about reflux temperature, to yield the corresponding compound of formula (Ia), a compound of formula (I) wherein R1 and R2 are each hydrogen.
Alternatively, the compound of formula (XXI), is reacted with a suitably substituted compound of formula (XXII), a known compound or compound prepared by known methods, in the presence of a base such as TEA, DIPEA, pyridine, and the like, in an organic solvent such as DMF, DMSO, and the like, to yield the corresponding compound of formula (Ib).
In an embodiment, the present invention is directed to a process for the preparation of the compound of formula (V-S), as outlined in Scheme 4 below.
Scheme 4
Accordingly, a suitably substituted compound of formula (X-S), a known compound or compound prepared by known methods is protected by reacting with a suitable protecting agent (i.e. a protecting agent stable under subsequent reaction condition, e.g. hydrolysis, oxidation) such as benzyl bromide, allyl bromide, 2-(trimethylsilyl)ethoxymethyl chloride (SEM-CI), t-butyl- diphenylsilyl chloride, methoxy or nitro-substituted benzyl bromides (for example, 4-nitro-benzyl bromide, 4-methoxybenzyl bromide, and the like), 1- (Ci-4alkoxy)methyl halide or 1-(Ci-4alkoxy)ethyl halide, wherein the halide is Cl, Br or I (for example, MOM-CI, ethoxyethylchlohde, and the like), and the like; in the presence of an organic or inorganic base such as K2CO3, Na2CU3, CS2CO3, tetramethylguanidine, TEA, and the like; preferably K2CO3; wherein the base is preferably present in an amount greater than or equal to about 1 molar equivalent, more preferably an excess amount; at a temperature greater than about room temperature, preferably at a temperature in the range of form about 400C to about 10O0C, more preferably, at a temperature in the range of from about 6O0C to about 8O0C, most preferably, at a temperature of about 6O0C; in
an organic solvent such as DMF, THF, N-methylpyrrolidinone, and the like; to yield the corresponding compound of formula (Xl-S), wherein Pg1 is the corresponding alcohol protecting group. For example, wherein the protecting agent is benzyl bromide, Pg1 is benzyl; wherein the protecting agent is allyl bromide, Pg1 is allyl; wherein the protecting agent is MOM-CI, Pg1 is methoxy methyl ether. One skilled in the art will recognize that additional protecting groups and methods for incorporating said protecting groups are known in the art, as for example, described in T. W. Greene & P. G. M. Wuts, Protective Groups in Organic Synthesis, John Wiley & Sons, 1991 , which is herein incorporated by reference in its entirety.
The compound of formula (Xl-S) is reacted with a suitably selected oxidizing agent such as m-CPBA, perbenzoic acid, peracetic acid, monomagnesium peroxyphthalate and the like, preferably m-CPBA; wherein the oxidizing agent is present in an amount of at least about 1 molar equivalent, preferably about 1 to 2 molar equivalents; in an organic solvent such as DCE, DCM, chloroform, acetonithle, NMP, and the like, preferably DCM; preferably, at about room temperature; to yield the corresponding compound of formula (XII-S).
The compound of formula (XII-S) is reacted with an organic or inorganic base such as NaOCH3, K-t-butoxide, sodium carbonate, potassium bicarbonate, and the like, preferably NaOCH3; wherein the base is preferably present in an amount in the range of from about 1 to about 5 molar equivalents, more preferably in an amount in the range of from about 2 to about 3 molar equivalents; in an organic solvent or mixture thereof such as methanol, ethanol, propanol, a mixture of THF and an alcohol, and the like, or in a mixture of one or more organic solvents and water; preferably in an alcohol, more preferably in methanol; preferably at a temperature in the range of from about room temperature to about reflux temperature, more preferably at about room temperature; to yield the corresponding compound of formula (XIII-S). The compound of formula (XIII) is reacted with is reacted with a source
of (fy-epoxy-methylene (i.e. 1^ ) such as (RJ-glycidyl-m-nosylate, (R)- glycidyl-tosylate, (T?,)-epichlorohydrin, (7?,)-epibromohydhn, and the like,
preferably (fy-glycidyl-m-nosylate or (fy-glycidyl-tosylate,; wherein the source of epoxy-methylene is preferably present in an amount in an amount in the range of from about 1 to about 5 molar equivalents, more preferably present in an amount in an amount in the range of from about 1 to about 2 molar equivalents, more preferably in an amount in the range of from about 1.1 to about 1.5 molar equivalent; in the presence of an inorganic base such as K2CO3, Na2CO3, Cs2CO3, NaH, KH, and the like, preferably K2CO3; wherein the inorganic base is preferably present in an amount greater than or equal to about 1 molar equivalent, more preferably, an excess amount; at a temperature greater than about room temperature, preferably at a temperature in the range of form about room temperature to about 10O0C, more preferably, at a temperature in the range of from about 400C to about 600C, most preferably, at a temperature of about 400C; in an organic solvent such as DMF, THF, N- methylpyrrolidinone, and the like, preferably DMF; to yield the corresponding compound of formula (XIV-S).
The compound of formula (XIV-S) is de-protected according to known methods, to yield the corresponding compound of formula (XV-S). For example, wherein the compound of formula (XIV-S) Pg1 is benzyl, allyl, and the like, the compound of formula (XIV-S) may be de-protected by reacting with hydrogen or a source of hydrogen, preferably with hydrogen gas in the presence of a catalyst such as Pd/C, Pt, Pd(sulfide)/C, and the like; wherein the hydrogen gas is introduced at a pressure in the range of from about 10 psi to about 15 psi; in an organic solvent such as ethyl acetate, THF, isopropyl acetate, 2-methyl-THF, methyl-t-butyl ether, ethanol, and the like. Wherein Pg1 is SEM or a silyl protecting group, the compound of formula (XIV-S) may be de- protected by reacting with a source of fluoride such as tetrabutylammonium fluoride, and the like, in an organic solvent such as THF, and the like. One skilled in the art will recognize that additional methods for removing protecting groups are known in the art, as for example, described in T. W. Greene & P.G.M. Wuts, Protective Groups in Organic Synthesis, John Wiley & Sons, 1991 .
One skilled in the art will recognize that the reagent(s) selected for the de-protection of the compound of formula (XIV-S) are selected to be
substantially un-reactive to the epoxy group on the compound of formula (XIV- S).
The compound of formula (XV-S) is reacted with an organic or inorganic base such as NaOCH3, K-t-butoxide, sodium carbonate, and the like, preferably NaOCHs; wherein the base is preferably present in an amount greater than or equal to about 1 molar equivalent, more preferably an excess amount; in a organic solvent such as methanol, ethanol, THF, acetonithle, and the like, preferably methanol; preferably at about room temperature; to yield the corresponding compound of formula (V-S).
In another embodiment, the present invention is directed to a process for the preparation of the compound of formula (V-S), as outlined in Scheme 5 below.
Scheme 5
Accordingly, a suitably substituted compound of formula (XVI-S) wherein Q is selected from the group consisting of -C(O)-(Ci-4alkyl), wherein the Ci-4 alkyl is preferably a primary Ci-4alkyl, more preferably -C(O)-CHs, and the like, a known compound or compound prepared by known methods is reacted with a
source of ^-epoxy-methylene (i.e. 1^ ) such as (RJ-glycidyl-m- nosylate, ^-glycidyl-tosylate, (7?,)-epichlorohydrin, (7?,)-epibromohydrin, and the like, preferably ^-glycidyl-m-nosylate or (7^-glycidyl-tosylate; wherein the source of epoxy-methylene is preferably present in an amount in an amount in the range of from about 1 to about 5 molar equivalents, more preferably
present in an amount in an amount in the range of from about 1 to about 2 molar equivalents, more preferably in an amount in the range of from about 1.1 to about 1.5 molar equivalent; in the presence of an inorganic base such as K2CO3, Na2CO3, Cs2CO3, NaH, KH, and the like, preferably K2CO3; wherein the inorganic base is preferably present in an amount greater than or equal to about 1 molar equivalent, more preferably, an excess amount; at a temperature greater than about room temperature, preferably at a temperature in the range of form about room temperature to about 10O0C, more preferably, at a temperature in the range of from about 400C to about 600C, most preferably, at a temperature of about 400C; in an organic solvent such as DMF, THF, N- methylpyrrolidinone, and the like, preferably DMF; to yield the corresponding compound of formula (XVII-S).
The compound of formula (XVIII-S) is reacted with a suitably selected oxidizing agent such as m-CPBA, perbenzoic acid, peracetic acid, monomagnesium peroxyphthalate and the like, preferably m-CPBA; wherein the oxidizing agent is present in an amount of at least about 1 molar equivalent, preferably about 1 to 2 molar equivalents; in an organic solvent such as DCE, DCM, chloroform, acetonithle, NMP, and the like, preferably DCM; preferably, at about room temperature; to yield the corresponding compound of formula (XVIII-S). Wherein Q is -C(O)-(CH3) the compound of formula (XVII-S) is reacted under conditions other than with monomagnesium peroxyphthalate in DMF.
The compound of formula (XVIII-S) is reacted with an organic or inorganic base such as NaOCH3, K-t-butoxide, sodium carbonate, and the like, preferably NaOCH3; wherein the base is preferably present in an amount greater than or equal to about 1 molar equivalent, more preferably an excess amount; in a organic solvent such as methanol, ethanol, THF, acetonithle, and the like, preferably methanol; preferably at about room temperature; to yield the corresponding compound of formula (V-S). The compound of formula (V-S) may be further reacted to yield the corresponding compound of formula (I-S) according to known methods (for example, as disclosed in McComsey, D., et al. in US Patent Publication US
2006/0041008 A1 , published February 23, 2006; McComsey, D., et al. in US Patent Publication US 2005/0282887 A1 , published December 22, 2005).
For example, the compound of formula (I-S) may be prepared according to the process outlined in Scheme 6, below.
Scheme 6
Accordingly, a suitably substituted compound of formula (V-S), prepared as for example outlined in Scheme 1 , 2, 4 or 5 above, is activated, according to known method, to yield the corresponding compound of formula (XIX-S), wherein J is a suitable leaving group, such as tosylate, Cl, Br, I, mesylate, thflate, and the like.
The compound of formula (XIX-S) is reacted with a phthalimide salt such as potassium phthlimide, sodium phthalimide, and the like, in an organic solvent such as DMF, DMSO, acetonithle, and the like, preferably, at an elevated temperature in the range of from 500C to about 2000C, more preferably, wherein the organic solvent is DMF, DMSO and the like, at temperature in the range of from about 500C to about 1500C and wherein the organic solvent is acetonitrile, and the like, at about reflux temperature, to yield the corresponding compound of formula (XX-S).
The compound of formula (XX-S) is reacted with N2H4, a known compound, in an organic solvent such as ethanol, methanol, and the like, preferably, at an elevated temperature in the range of from about 500C to about 1000C, more preferably, at about reflux temperature, and the like, to yield the corresponding compound of formula (XXI-S).
The compound of formula (XXI-S) is reacted with sulfamide (NH2-SO2- NH2), a known compound, preferably wherein the sulfamide is present in an amount in the range of about 2 to about 5 equivalents, in an organic solvent such as THF, dioxane, and the like, preferably at an elevated temperature in the range of about 500C to about 1000C, more preferably at about reflux temperature, to yield the corresponding compound of formula (I-S).
Alternatively, the compound of formula (XXI-S), is reacted with compound of formula (XXII-S), a known compound, also known as sulfamoyl chloride, in the presence of a base such as TEA, DIPEA, pyridine, and the like, in an organic solvent such as DMF, DMSO, and the like, to yield the corresponding compound of formula (I-S).
The present invention is further directed to crystalline forms of the compound of formula (I-S), hereinafter referred to as crystalline form (I-SA) and (I-SB). The crystalline forms of the compound of formula (I-S) may be characterized by their corresponding Powder X-ray Diffraction (PXRD) spectra. In an embodiment, the crystalline forms of the compound of formula (I-S) may be characterized by their corresponding PXRD peaks, wherein the peaks have a relative intensity of greater than or equal to about 10% relative intensity; preferably, wherein the peaks have a relative intensity of greater than or equal to about 25% relative intensity. In an embodiment, the crystalline form of the compound of formula (I-S) may be characterized by its corresponding PXRD peaks, wherein the peaks are defined by their position (°2Θ), d-spacing (A) and relative intensity (%). In another embodiment, the crystalline form of the compound of formula (I-S) may be characterized by its corresponding PXRD peaks, wherein the peaks are defined by their position (°2Θ) and d-spacing (A). Powder XRD spectra were measured for representative samples of the crystalline forms of the compound of formula (I-S) with peaks as listed in Tables
2 and 3 below. The PXRD spectra were measured using an X-Celerator detector, scanning form 3 to 35°2Θ, at a step size of 0.0165°2θ, a time per step of 10.16 sec, an effective scan speed of 0.2067°/sec, instrument voltage of 45 kV and a current setting of 40 mA.
Crystalline form (I-SA) may be prepared for example, as described in Example 13 below. The melting point of crystalline form (I-SA) was measured for a representative sample and showed a melting point onset of 98.6°C and a 100.80C. Crystalline form (I-SA) may be characterized by its powder XRD peaks, as listed in Table XRD-1 below.
Table 2: Form (I-SA)
Crystalline form (I-SB) may be prepared by re-crystallizing the compound of formula (I-S) from water, according to known methods, for example as described in Example 14 below. The melting point of crystalline form (I-SA) was measured for a representative sample and showed a melting point onset of 100.70C and a 102.80C. Crystalline form (I-SB) may be characterized by its powder XRD peaks, as listed in Table 3 below.
Table 3: Form (I-SB)
Figure 1 illustrates representative powder X-ray diffraction patterns corresponding to the following samples: (a) the topmost scan corresponds to a representative sample of crystalline form (I-SB); (b) the middle and bottom scans correspond to two separately prepared samples of crystalline form (I- SA).
The present invention further comprises pharmaceutical compositions containing one or more of the compounds prepared according to any of the processes described herein with a pharmaceutically acceptable carrier.
Pharmaceutical compositions containing one or more of the compounds of the invention described herein as the active ingredient can be prepared by intimately mixing the compound or compounds with a pharmaceutical carrier according to conventional pharmaceutical compounding techniques. The carrier may take a wide variety of forms depending upon the desired route of administration (e.g., oral, parenteral). Thus for liquid oral preparations such as suspensions, elixirs and solutions, suitable carriers and additives include water, glycols, oils, alcohols, flavoring agents, preservatives, stabilizers, coloring agents and the like; for solid oral preparations, such as powders, capsules and tablets, suitable carriers and additives include starches, sugars, diluents, granulating agents, lubricants, binders, disintegrating agents and the like. Solid oral preparations may also be coated with substances such as sugars or be enteric-coated so as to modulate major site of absorption. For parenteral administration, the carrier will usually consist of sterile water and other ingredients may be added to increase solubility or preservation. Injectable suspensions or solutions may also be prepared utilizing aqueous carriers along with appropriate additives.
To prepare the pharmaceutical compositions of this invention, one or more compounds of the present invention as the active ingredient is intimately admixed with a pharmaceutical carrier according to conventional
pharmaceutical compounding techniques, which carrier may take a wide variety of forms depending of the form of preparation desired for administration, e.g., oral or parenteral such as intramuscular. In preparing the compositions in oral dosage form, any of the usual pharmaceutical media may be employed. Thus, for liquid oral preparations, such as for example, suspensions, elixirs and solutions, suitable carriers and additives include water, glycols, oils, alcohols, flavoring agents, preservatives, coloring agents and the like; for solid oral preparations such as, for example, powders, capsules, caplets, gelcaps and tablets, suitable carriers and additives include starches, sugars, diluents, granulating agents, lubricants, binders, disintegrating agents and the like. Because of their ease in administration, tablets and capsules represent the most advantageous oral dosage unit form, in which case solid pharmaceutical carriers are obviously employed. If desired, tablets may be sugar coated or enteric coated by standard techniques. For parenterals, the carrier will usually comprise sterile water, through other ingredients, for example, for purposes such as aiding solubility or for preservation, may be included. Injectable suspensions may also be prepared, in which case appropriate liquid carriers, suspending agents and the like may be employed. The pharmaceutical compositions herein will contain, per dosage unit, e.g., tablet, capsule, powder, injection, teaspoonful and the like, an amount of the active ingredient necessary to deliver an effective dose as described above. The pharmaceutical compositions herein will contain, per unit dosage unit, e.g., tablet, capsule, powder, injection, suppository, teaspoonful and the like, of from about 1-1000 mg and may be given at a dosage of from about 0.01-300 mg/kg/day, or any range therein, preferably from about 0.5-100 mg/kg/day, or any range therein, more preferably from about 1.0-25.0 mg/kg/day, or any range therein. The dosages, however, may be varied depending upon the requirement of the patients, the severity of the condition being treated and the compound being employed. The use of either daily administration or post- periodic dosing may be employed.
Preferably these compositions are in unit dosage forms from such as tablets, pills, capsules, powders, granules, sterile parenteral solutions or suspensions, metered aerosol or liquid sprays, drops, ampoules, autoinjector
devices or suppositories; for oral parenteral, intranasal, sublingual or rectal administration, or for administration by inhalation or insufflation. Alternatively, the composition may be presented in a form suitable for once-weekly or once- monthly administration; for example, an insoluble salt of the active compound, such as the decanoate salt, may be adapted to provide a depot preparation for intramuscular injection. For preparing solid compositions such as tablets, the principal active ingredient is mixed with a pharmaceutical carrier, e.g. conventional tableting ingredients such as corn starch, lactose, sucrose, sorbitol, talc, stearic acid, magnesium stearate, dicalcium phosphate or gums, and other pharmaceutical diluents, e.g. water, to form a solid preformulation composition containing a homogeneous mixture of a compound of the present invention, or a pharmaceutically acceptable salt thereof. When referring to these preformulation compositions as homogeneous, it is meant that the active ingredient is dispersed evenly throughout the composition so that the composition may be readily subdivided into equally effective dosage forms such as tablets, pills and capsules. This solid preformulation composition is then subdivided into unit dosage forms of the type described above containing from 0.1 to about 500 mg of the active ingredient of the present invention. The tablets or pills of the novel composition can be coated or otherwise compounded to provide a dosage form affording the advantage of prolonged action. For example, the tablet or pill can comprise an inner dosage and an outer dosage component, the latter being in the form of an envelope over the former. The two components can be separated by an enteric layer which serves to resist disintegration in the stomach and permits the inner component to pass intact into the duodenum or to be delayed in release. A variety of material can be used for such enteric layers or coatings, such materials including a number of polymeric acids with such materials as shellac, cetyl alcohol and cellulose acetate.
The liquid forms in which the novel compositions of the present invention may be incorporated for administration orally or by injection include, aqueous solutions, suitably flavoured syrups, aqueous or oil suspensions, and flavoured emulsions with edible oils such as cottonseed oil, sesame oil, coconut oil or peanut oil, as well as elixirs and similar pharmaceutical vehicles. Suitable
dispersing or suspending agents for aqueous suspensions, include synthetic and natural gums such as tragacanth, acacia, alginate, dextran, sodium carboxymethylcellulose, methylcellulose, polyvinyl-pyrrolidone or gelatin.
The method of treating epilepsy or a related disorder described in the present invention may also be carried out using a pharmaceutical composition comprising any of the compounds as defined herein and a pharmaceutically acceptable carrier. The pharmaceutical composition may contain between about 0.1 mg and 1000 mg, preferably about 50 to 500 mg, of the compound, or any range therein, and may be constituted into any form suitable for the mode of administration selected. Carriers include necessary and inert pharmaceutical excipients, including, but not limited to, binders, suspending agents, lubricants, flavorants, sweeteners, preservatives, dyes, and coatings. Compositions suitable for oral administration include solid forms, such as pills, tablets, caplets, capsules (each including immediate release, timed release and sustained release formulations), granules, and powders, and liquid forms, such as solutions, syrups, elixers, emulsions, and suspensions. Forms useful for parenteral administration include sterile solutions, emulsions and suspensions.
Advantageously, compounds of the present invention may be administered in a single daily dose, or the total daily dosage may be administered in divided doses of two, three or four times daily. Furthermore, compounds for the present invention can be administered in intranasal form via topical use of suitable intranasal vehicles, or via transdermal skin patches well known to those of ordinary skill in that art. To be administered in the form of a transdermal delivery system, the dosage administration will, of course, be continuous rather than intermittent throughout the dosage regimen.
For instance, for oral administration in the form of a tablet or capsule, the active drug component can be combined with an oral, non-toxic pharmaceutically acceptable inert carrier such as ethanol, glycerol, water and the like. Moreover, when desired or necessary, suitable binders; lubricants, disintegrating agents and coloring agents can also be incorporated into the mixture. Suitable binders include, without limitation, starch, gelatin, natural sugars such as glucose or beta- lactose, corn sweeteners, natural and synthetic gums such as acacia, tragacanth or sodium oleate, sodium stearate, magnesium stearate, sodium benzoate,
sodium acetate, sodium chloride and the like. Disintegrators include, without limitation, starch, methyl cellulose, agar, bentonite, xanthan gum and the like.
The liquid forms in suitably flavored suspending or dispersing agents such as the synthetic and natural gums, for example, tragacanth, acacia, methyl- cellulose and the like. For parenteral administration, sterile suspensions and solutions are desired. Isotonic preparations which generally contain suitable preservatives are employed when intravenous administration is desired.
To prepare a pharmaceutical composition of the present invention, a compound of formula (I) as the active ingredient is intimately admixed with a pharmaceutical carrier according to conventional pharmaceutical compounding techniques, which carrier may take a wide variety of forms depending of the form of preparation desired for administration (e.g. oral or parenteral). Suitable pharmaceutically acceptable carriers are well known in the art. Descriptions of some of these pharmaceutically acceptable carriers may be found in The Handbook of Pharmaceutical Excipients, published by the American
Pharmaceutical Association and the Pharmaceutical Society of Great Britain.
Methods of formulating pharmaceutical compositions have been described in numerous publications such as Pharmaceutical Dosage Forms: Tablets, Second Edition, Revised and Expanded, Volumes 1-3, edited by Lieberman et al; Pharmaceutical Dosage Forms: Parenteral Medications, Volumes 1-2, edited by Avis et al; and Pharmaceutical Dosage Forms: Disperse Systems, Volumes 1-2, edited by Lieberman et al; published by Marcel Dekker, Inc.
Compounds of this invention may be administered in any of the foregoing compositions and according to dosage regimens established in the art whenever treatment of epilepsy or related disorders is required.
The daily dosage of the products may be varied over a wide range from 0.01 to 10,000 mg per adult human per day, or any range therein. For oral administration, the compositions are preferably provided in the form of tablets containing, 0.01 , 0.05, 0.1 , 0.5, 1.0, 2.5, 5.0, 10.0, 15.0, 25.0, 50.0, 100, 150, 200, 250, 500 and 1000 milligrams of the active ingredient for the symptomatic adjustment of the dosage to the patient to be treated. An effective amount of the
drug is ordinarily supplied at a dosage level of from about 0.01 mg/kg to about 500.0 mg/kg of body weight per day, or any range therein. Preferably, the range is from about 0.5 to about 100.0 mg/kg of body weight per day, or any range therein, more preferably, from about 1.0 to about 50.0 mg/kg of body weight per day, or any range therein. The compounds may be administered on a regimen of 1 to 4 times per day.
Optimal dosages to be administered may be readily determined by those skilled in the art, and will vary with the particular compound used, the mode of administration, the strength of the preparation, the mode of administration, and the advancement of the disease condition. In addition, factors associated with the particular patient being treated, including patient age, weight, diet and time of administration, will result in the need to adjust dosages.
One skilled in the art will recognize that, both in vivo and in vitro trials using suitable, known and generally accepted cell and / or animal models are predictive of the ability of a test compound to treat or prevent a given disorder.
One skilled in the art will further recognize that human clinical trails including first-in-human, dose ranging and efficacy trials, in healthy patients and / or those suffering from a given disorder, may be completed according to methods well known in the clinical and medical arts.
The following Examples are set forth to aid in the understanding of the invention, and are not intended and should not be construed to limit in any way the invention set forth in the claims which follow thereafter.
In the Examples which follow, some synthesis products are listed as having been isolated as a residue. It will be understood by one of ordinary skill in the art that the term "residue" does not limit the physical state in which the product was isolated and may include, for example, a solid, an oil, a foam, a gum, a syrup, and the like.
Example 1 2-Benzyloxy-5-chloro-benzaldehyde
A 2 L three-necked flask (equipped with mechanical stirrer, nitrogen inlet, and a thermocouple) was charged with 5-chlorosalicylaldehyde (7, 23 g, 0.147 mol), benzyl bromide (25.1 g, 0.147 mol), potassium carbonate (20.3 g, 0.147 mol), and Λ/,Λ/-dimethylformamide (650 ml_). The reaction mixture was heated to 600C for 18 h (overnight). The reaction mixture was poured into water (700 mL) and then extracted with ethyl ether (3 x 300 ml_). The combined organics were washed with brine (2 x 200 mL), dried (MgSO4), and concentrated to yield a crude product. The crude product was dissolved in 1 :1 heptane-dichloromethane and loaded onto a Biotage 75S (200 g silica gel) and eluted with heptane (1 L), then 1 :9 (3L), and 3:7 (2 L) ethyl acetate-heptane to yield the title compound as a solid 1H NMR (CDCI3) δ ppm: 10.48 (s, 1 H), 7.81 (d, J= 3.1 Hz, 1 H), 7.42 (m,
6H), 7.01 (d, J = 8.9 Hz, 1 H), 5.19 (s, 2H).
Example 2 Formic acid, 2-benzyloxy-5-chloro-phenyl ester
In a 1 L one-neck flask (equipped with magnetic stirrer, and nitrogen inlet, was charged 2-benzyloxy-5-chloro-benzaldehyde (8, 28.1 g, 0.1 14 mol) and dichloromethane (360 ml_). To this solution was added m-CPBA (-75%, 31.4 g, 0.137 mol). The reaction mixture was stirred at room temperature for 17 h (overnight) to yield a white slurry. The white solid was removed by filtration, then the filtrate was washed with 10% (w/w) sodium bisufite (200 mL) and each phase was tested by starch iodide paper to see if any oxidant remained. This test was negative and the organic phase was washed with saturated sodium bicarbonate (2 x 150 mL), dried (MgSO4), and concentrated to yield crude product, as a solid. The crude product was used in subsequent steps without further purification.
1H NMR (CDCI3) δ ppm: 8.25 (s, 1 H), 7.37 (m, 5H), 7.15 (m, 2H), 6.95 (d, J = 8.7 Hz, 1 H), 5.09 (s, 2H).
Example 3
2-Benzyloxv-5-chloro-phenol
C
A one-neck flask (equipped with magnetic stirring, and a nitrogen inlet), was charged with crude formic acid, 2-benzyloxy-5-chloro-phenyl ester (9, 28 g, 0.107 mol), sodium methoxide (25% (w/w) in methanol, 26.5 mL, 0.123 mol), and methanol (175 mL). The reaction mixture was stirred for 18 h (overnight). The reaction mixture was concentrated to a red oil that was partitioned between saturated ammonium chloride (200 mL) and ethyl ether (200 mL). The aqueous was extracted with ethyl ether (100 mL) and the combined organics were washed with brine (100 mL), dried (MgSO4), and concentrated to yield the title compound as a oil. The product was used in subsequent steps without further purification.
1H NMR (CDCI3) δ ppm: 7.41 (m, 5H), 6.95 (d, J = 1.8Hz, 1 H), 6.82 (m, 2H), 5.71 (s, 1 H), 5.09 (s, 2H).
Example 4 (/?)-2-(2-Benzyloxy-5-chloro-phenoxymethyl)-oxirane
In a 500 ml_, three-necked flask (equipped with a magnetic stir bar, thermocouple, and a nitrogen inlet) was charged 2-benzyloxy-5-chloro-phenol (10, 1 1 .3 g, 48.2 mmol), (R)-glycidyl m-nitrophenylsulfonate (1 1.3 g, 43.8 mmol), and Λ/,Λ/-dimethylformamide (200 ml_). The reaction mixture was heated to 400C for 12hrs, then cooled to room temperature and poured into water (300 ml_). The aqueous phase was extracted with ethyl ether (3 x 200 ml_). The combined organic phases were washed with 1 M sodium hydroxide (aq), brine (3 x 100 ml_), dried (MgSO4), and concentrated in vacuo to yield crude product as an oil. The oil was dissolved in 1 :1 heptane-dichloromethane and loaded onto an lsco cartridge (120 g silica gel) and eluted to yield the title compound as an oil.
1H NMR (CDCI3) δ ppm: 7.38 (m, 5H), 6.94 (d, J = 2.5Hz, 1 H), 6.85 (m, 2H), 5.1 1 (s, 2H), 4.28 (dd, J = 1 1.4, 3.3 Hz, 1 H), 4.01 (dd, J = 1 1.3, 5.5 Hz, 1 H), 3.38 (m, 1 H), 2.89 (dd, J = 5.1 , 4.9 Hz, 1 H), 2.77 (dd, J = 5.0, 2.6 Hz, 1 H).
Example 5 (/?)-4-Chloro-2-oxiranylmethoxy-phenol
A Parr reaction bottle was charged with 5% palladium on carbon (dry, 1.0 g), (f?)-2-(2-benzyloxy-5-chloro-phenoxymethyl)-oxirane (1 1 , 1 1 .7 g, 40.2 mmol), and ethyl acetate (250 ml_). The reaction mixture was agitated on a Parr shaker at room temperature under 5-7 psi of hydrogen gas for 2.5 h. The catalyst was removed by filtration and the ethyl acetate removed in vacuo to yield the title compound as an oil that solidified upon standing. The product was used in subsequent steps without further purification.
1H NMR (CDCI3) δ ppm: 6.87 (m, 3H), 6.09 (bs, 1 H), 4.25 (dd, J = 1 1.4, 2.6 Hz, 1 H), 3.98 (dd, J = 1 1.3, 5.7 Hz, 1 H), 3.39 (m, 1 H), 2.96 (t, J = 4.6 Hz, 1 H), 2.85 (dd, J = 5.2, 2.7 Hz, 1 H).
Example 6 (S)-(6-Chloro-2,3-dihvdro-benzoπ ,41dioxin-2-vl)-methanol
A one-neck flask (equipped with magnetic stirring, and a nitrogen inlet), was charged (f?)-4-chloro-2-oxiranylmethoxy-phenol (12, 8.1 g, 40.4 mmol), sodium methoxide (25% (w/w) in methanol, 10.5 ml_, 48.4 mmol), and methanol (90 ml_). The reaction was stirred for 18 h (overnight). The reaction mixture was concentrated to a red oil that was partitioned between water (250 mL) and ethyl ether (200 mL). The aqueous layer was extracted with ethyl ether (2 x 100 mL), and the combined organics were washed with 1 M aqueous sodium hydroxide (150 mL), brine (2 x 100 mL), dried (MgSO4), and concentrated to yield crude product. The crude product was dissolved in dichloromethane and loaded onto a Biotage 4OM (90 g silica gel) and eluted with dichloromethane (250 mL) and 1 :19 ethyl acetate-dichloromethane (1 L) to yield the title compound as a white solid (19415-132A). Melting Point: 73 - 75°C.
Optical rotation: [α]D = -58.0° (c 1 .99, MeOH, 23°C) 1H NMR (CDCI3) δ ppm: 6.82 (m, 3H), 4.30 (dd, J = 1 1.1 , 2.2 Hz, 1 H), 4.24 (m, 1 H), 4.10 (dd, J = 1 1 .2, 7.4 Hz, 1 H), 3.87 (m, 2H), 1.95 (t, J = 6.6 Hz, 1 H).
Example 7 (/?)-1 -(4-Chloro-2-oxiranylmethoxy-phenyl)-ethanone
In a 22 L, four-necked flask (equipped with a mechanical stirrer, thermocouple, Teflon stopper, and a argon inlet) was charged 4-chloro-2- hydroxy-acetophenone (13, 687.2 g, 4.03 mol) and Λ/,Λ/-dimethylformamide (14.0 L). To this solution was added potassium carbonate (613 g, 4.43 mol) and (R)-glycidyl m-nitrophenylsulfonate (1 .045 kg, 4.03 mol). The reaction mixture was heated to 400C for 20 h (overnight) then cooled to room temperature and split into two portions. Each portion was poured into water (9 L) and extracted with methyl terf-butyl ether (3 x 2 L) and ethyl ether (2L). The two organic phases were each washed with brine (2 x 4 L), dried (MgSO4), and concentrated in vacuo to yield crude product, which was used in subsequent steps without further purification.
1H NMR (CDCI3) δ ppm: 7.71 (d, J = 8.5 Hz, 1 H), 7.02 (dd, J = 8.8, 1.7 Hz, 1 H), 6.95 (d, J = 1.8 Hz, 1 H), 4.39 (dd, J = 1 1 .0, 2.8 Hz, 1 H), 3.98 (dd, J = 10.8, 6.1 Hz, 1 H), 3.41 (m, 1 H), 2.96 (t, J = 4.4 Hz, 1 H), 2.78 (dd, J = 5.1 , 2.7 Hz, 1 H), 2.64 (s, 3H). A small portion of the product prepared as described above was chromatographed (Isco silica - 40 g) to yield a white powder: MP: 79-800C.
Optical Rotation: [α]D = -19.4° (c 2.02, MeOH, 23°C). High-Resolution MS: (as CnH12O3CI, M+H) : Calculated: 227.48; Measured: 227.05
Example 8 (/?)-Acetic acid, 4-chloro-2-oxiranylmethoxv-phenyl ester
In a 22 L four-necked flask (equipped with mechanical stirrer, two stoppers, and a condenser with a argon inlet), was charged (f?)-1 -(4-chloro-2- oxiranylmethoxy-phenyl)-ethanone (14, 815 g, 3.60 mol) and dichloromethane (8.8 L). To this solution was added m-CPBA (-75% Lancaster, 993 g, 4.31 mol oxidant). The reaction mixture was heated at mild reflux for 22 h over 3 days (heat was only applied with supervision). We then added additional m-CPBA (100 g, -0.36 mol) and continued reflux for 8 h. The reaction mixture was then allowed to cool overnight to yield a white slurry upon cooling. The white solid was removed by filtration and the filtrate was split into four portions. Each portion was washed with 10% (w/w) sodium bisufite (1 L) and both phases were tested by starch iodide paper to see if any oxidant remained. This test was negative and the aqueous phase was back extracted with dichloromethane (2 x 250 mL) and the combined organic phases (four portions) were washed with saturated sodium bicarbonate (3 x 500 mL), dried (MgSO4), and concentrated to yield crude product, which was used in subsequent steps without further purification.
1H NMR (CDCI3) δ ppm: 6.96 (m, 3H), 4.25 (dd, J = 10.9, 2.4 Hz, 1 H), 3.94 (dd, J = 1 1.5, 5.6 Hz, 1 H), 3.30 (m, 1 H), 2.88 (t, J = 4.8 Hz, 1 H), 2.71 (dd, J = 4.8, 2.6 Hz, 1 H), 2.31 (s, 3H).
A small portion of the crude product prepared as described above was chromatographed (Isco silica - 12 g) to yield a clear oil:
Optical Rotation: [α]D = -8.29° (c 2.05, MeOH, 23°C). High-Resolution MS: (as CnH11O3CI, M+): Calculated: 242.03; Measured: 242.03
Example 9 (S)-(6-Chloro-2,3-dihvdro-benzori ,41dioxin-2-yl)-methanol
A four-necked 12 L flask (equipped with mechanical stirring, two stoppers, and a nitrogen inlet), was charged (R)-acetic acid, 4-chloro-2- oxiranylmethoxy-phenyl ester (15, 1 .019 kg impure, assumed 874 g, 3.60 mol), sodium methoxide (25% (w/w) in methanol, 972 ml_, 4.50 mol), and methanol (6.0 L). The reaction mixture was stirred for 20 h (overnight) and then treated with 3 M aqueous sodium hydroxide (500 mL) and stirred for an additional 6 days. The reaction mixture was concentrated to a red oil that was diluted with water to a volume of 4.0 L. This material was split into two portions and each aqueous phase was extracted with methyl ferf-butyl ether (2 x 1 .0 L) and ethyl ether (1 L). The organic phases were washed with 10% aqueous sodium bisulfite (500 mL), saturated sodium bicarbonate (500 mL), brine (2 x 500 mL), dried (MgSO4), and concentrated to yield crude product. The crude product was used in subsequent steps without further purification. 1H NMR (CDCI3) δ ppm: 6.89 (m, 1 H), 6.2 (m, 2H), 4.30 (dd, J = 1 1.3,
2.2 Hz, 1 H), 4.23 (m, 1 H), 4.10 (dd, J = 10.9, 7.6 Hz, 1 H), 3.91 (dd, J = 12.0, 4.2 Hz, 1 H), 3.83 (dd, J = 12.1 , 5.4 Hz, 1 H).
A small portion of the crude product prepared as decshbed above was chromatographed (Isco silica - 12 g) to yield a white solid: Melting Point: 79-810C.
Optical rotation: [α]D = -58.2° (c 2.05, MeOH, 23°C); Chiral HPLC: Chiralpak AS-H, Hexane/IPA (97:3), Rt = 16.095 min, >99%ee.
High-Resolution MS: (as C9H9O3CI, M+): Calculated: 200.02 : Measured: 200.02
Example 10
(/?)-Toluene-4-sulfonic acid, 6-chloro-2,3-dihvdro-benzoH ,41dioxin-2-yl- methvl ester
To a 12 L, four necked flask (equipped with mechanical stirrer, nitrogen inlet, and two stoppers) was charged (S)-(6-chloro-2,3-dihydro- benzo[1 ,4]dioxin-2-yl)-methanol (2, 300 g, 1.50 mol) and 4.5 L of tetrahydrofuran/dichloromethane (9:1 ). This solution was treated with N- methylmorpholine (362 ml_, 3.29 mol), Λ/,Λ/-dimethylaminopyridine (36.4 g, 0.298 mol), and p-toluenesulfonyl chloride (341 g, 1 .79 mol). The reaction mixture was stirred under nitrogen at room temperature for 10 days (reaction appeared complete after ~4 days). The reaction mixture was filtered to remove amine hydrochloride and split into two portions. Each portion was stirred with 20% aqueous potassium bicarbonate (3 L) for 2.5 h. Each portion was then extracted with /-propyl acetate (2 x 1 .5 L) and the organics were washed with 2 M hydrochloric acid (2 x 1 L), saturated sodium bicarbonate (2 x 1 L), brine (500 mL), and dried (MgSO4). The resulting mixture was concentrated to yield crude product. The crude product was dissolved in dichloromethane/heptane (1 :3) and loaded onto a Biotage 150L (5 kg silca gel) and eluted (30 psi) with heptane (8 L), 1 :9 ethyl acetate-heptane (24 L), 15:85 ethyl acetate-heptane (48 L), and 1 :2 ethyl acetate-heptane (18 L) to yield the title compound as an off-white solid. 1H NMR (DMSO-d6) δ ppm: 7.79 (d, J = 7.9 Hz, 2H), 7.47 (d, J = 8.0 Hz,
2H), 6.94 (d, J = 2.5 Hz, 1 H), 6.87 (dd, J = 8.8, 2.5 Hz, 1 H), 6.8 (d, J = 8.8 Hz, 1 H), 4.46 (m, 1 H), 4.35 (dd, J = 1 1.7, 3.1 Hz, 1 H), 4.29 (dd, J = 1 1 .7, 2.5 Hz, 1 H), 4.20 (dd, J = 1 1.3, 6.4 Hz, 1 H), 3.99 (dd, J = 1 1.5, 6.2 Hz, 1 H), 2.42 (s, 1 H). Optical rotation: [α]D = -34.73° (c 2.02, MeOH, 23°C).
Example 11
(S)-2-(6-Chloro-2.3-dihvdro-benzori .41dioxin-2-ylmethyl)-isoindole-1.3- dione
A 12-L four necked flask (equipped with mechanical stirrer, air condenser topped with a nitrogen inlet, and two stoppers) was charged with (f?)-toluene-4-sulfonic acid, 6-chloro-2,3-dihydro-benzo[1 ,4]dioxin-2-yl-methyl ester (3, 443 g, 1.25 mol), potassium phthalimide (301 g, 1.62 mol), and N,N- dimethylformamide (5 L). The reaction mixture was heated to 1000C for 2 h then cooled to room temperature over 16 h (overnight). The reaction mixture was diluted into water (6 L) and stirred for 2.5 h. The resulting white solid was collected by vacuum filtration and dried in a vacuum oven at 55°C to yield the title compound as an off-white solid.
1H NMR (DMSO-d6) δ ppm: 7.84 (m, 4H), 6.98 (d, J = 2.9 Hz, 1 H), 6.87 (dd, J = 8.4, 2.8 Hz, 1 H), 6.83 (d, J = 8.3 Hz, 1 H), 4.49 (qd, J = 6.1 , 2.2, 1 H), 4.36 (dd, J = 1 1.4, 2.7 Hz, 1 H), 4.13 (dd, J = 1 1 .9, 2.5 Hz, 1 H), 3.88 (m, 2H).
Melting Point: 126-127°C.
Example 12 (S)-(6-Chloro-2,3-dihvdro-benzoπ ,41dioxin-2-yl)-methylamine
A 12-L four necked flask (equipped with mechanical stirrer, water condenser topped with a nitrogen inlet, and two stoppers) was charged with (S)-2-(6-chloro-2,3-dihydro-benzo[1 ,4]dioxin-2-ylmethyl)-isoindole-1 ,3-dione (4, 370 g, 1.12 mol), hydrazine (65.2 mL, 2.08 mol), and ethanol (4 L). The reaction mixture was heated to reflux for 1.5 h and then cooled to room temperature. The reaction mixture was acidified with 1 M hydrochloric acid (2 L) and filtered. The filtrate was concentrated to remove ethanol then basified with 3 M sodium hydroxide (1 L) and extracted with ethyl ether (2 L, then 2 x 1 L). The combined organics were washed with brine (2 x 600 mL), dried
(MgSO4), and concentrated to yield the title compound as a white solid, which was used in subsequent steps without further purification.
1H NMR (DMSO-d6) δ ppm: 6.95 (d, J = 1 .9 Hz, 1 H), 6.87 (m, 2H), 4.37 (dd, J = 1 1.5, 2.6, 1 H), 4.07 (m, 1 H), 3.98 (dd, J = 10.9, 7.7 Hz, 1 H), 2.83 (dd, J = 12.7, 5.4, 1 H), 2.77 (dd, J = 12.7, 6.1 , 1 H).
Melting Point: 70-710C.
Optical rotation: [α]D = -81.0° (c 2.00, MeOH, 23°C).
Example 13 (S)-Λ/-(6-Chloro-2,3-dihvdro-benzoH ,41dioxin-2-ylmethyl)-sulfamide
A 12-L four necked flask (equipped with mechanical stirrer, water condenser topped with a nitrogen inlet, and two stoppers) was charged with (S)-(6-chloro-2,3-dihydro-benzo[1 ,4]dioxin-2-yl)-methylamine (5, 214 g, 1.07 mol), sulfamide (412 g, 4.29 mol), and /so-propyl acetate (4 L). The reaction mixture was then heated to reflux for a total of 15 h over 3 days and then cooled to room temperature. The reaction mixture was chilled in an ice-bath and the residues were collected by filtration and washed with /so-propyl acetate. The filtrate was washed with 1 M hydrochloric acid (3 L), dried (MgSO4), and concentrated to yield crude product. The entire portion of crude product was dissolved in ethyl acetate and absorbed onto silica gel (600 g) and loaded into a Biotage sample induction module, then eluted onto a Biotage 150M (2.5 g silica gel) using heptane (2 L), 1 :9 ethyl acetate-heptane (4 L), 3:7 ethyl acetate-heptane (12 L), and 1 :1 ethyl acetate-heptane (16 L) to yield the product along with mixed fractions. The mixed fractions were re- chromatographed on a Biotage 75L (800 g silica) using heptane (1 L), 1 :9 ethyl acetate-heptane (2 L), 3:7 ethyl acetate-heptane (6 L), and 1 :1 ethyl acetate- heptane (8 L) to yield additional product. The two lots of product were combined to yield the title compound as an off-white solid.
The title compound prepared according to the procedure as described in this Example yielded form (I-SA).
1H NMR (DMSO-d6) δ ppm: 6.98 (d, J = 1 .9 Hz, 1 H), 6.89 (m, 3H), 6.67 (bs, 2H), 4.36 (dd, J = 1 1.7, 1.6, 1 H), 4.28 (m, 1 H), 4.00 (dd, J = 1 1.5, 6.8 Hz, 1 H), 3.19 (m, 1 H), 3.1 1 (m, 1 H).
Melting Point: 99-1000C.
Optical rotation: [α]D = -57.6° (c 2.14, MeOH, 23°C).
Chiral HPLC: Chiralpak AD-H, Hex(0.1 % TEA)/IPA (80:20), R1 = 1 1.407 min, >99%ee. Elemental Analysis for C9H11CIN2O4S:
Calculated: %C 38.78, %H 3.98, %CI 12.72, %N 10.05, %S 1 1 .51.
Measured: %C 38.81 , %H 3.74, %CI 12.83, %N 9.93, %S 1 1.53.
Example 14 Water Recrystallization of (S)-Λ/-(6-Chloro-2,3-dihydro-benzori ,41dioxin-2- ylmethvD-sulfamide
Distilled water (5 ml.) was added to (S)-Λ/-(6-Chloro-2,3-dihydro- benzo[1 ,4]dioxin-2-ylmethyl)-sulfamide (0.05Og) in a test tube and the resulting mixture was heated. The white solid was observed to dissolve in the water before the water boiled. As the water cooled, material dropped out as a suspension and formed white needle-like crystals over two hours. The crystals were filtered off, rinsed with water, air dried, and collected to yield crystalline form (I-SB) as herein defined.
Example 15
(/?)-Toluene-4-sulfonic acid, (7-chloro-2,3-dihvdro-benzoH ,41dioxin-2-yl)- methvl ester
(S)-(7-Chloro-2,3-dihydro-1 ,4-benzodioxin-2-yl)methanol {[α]D = -35.6 ° (c=1.45, EtOH), 7.12 g, 35.4 mmol}, prepared according to the method as disclosed in A. M. Birch et al. Journal of Medicinal Chemistry 1999, 42, 3342- 3355, was dissolved in pyridine (50 mL) and cooled to 00C. To the resulting mixture was added p-toluenesulfonyl chloride (6.68 g, 35.5 mmol) and the reaction mixture stirred at room temperature for 2Oh. The reaction mixture was then cooled in an ice bath and 1 N HCI (750 mL) was added. The reaction mixture was extracted with diethyl ether (3x, 200 mL). The combined diethyl ether was washed with 1 N HCI (2x, 250 mL), water, brine (2x) and dried (MgSO4) and evaporated in vacuo to yield the title compound as a white solid..
1H NMR (CDCI3) δ 7.79 (d, J = 8.4 Hz, 2H), 7.37 (d, J = 8.5 Hz, 2H), 6.76 (m, 3H), 4.40 (m, 1 H), 4.21 (m, 3H), 4.03 (dd, J = 6.2, 1 1 .6 Hz, 1 H), 2.61 (s, 3H).
Example 16
(S)-2-(7-Chloro-2,3-dihvdro-benzoπ ,41dioxin-2-ylmethyl)- isoindole-1 ,3-dione
(f?)-Toluene-4-sulfonic acid, (7-chloro-2,3-dihydro-benzo[1 ,4]dioxin-2-yl)- methyl ester (10.65 g), prepared as in Example 15 above) was combined with potassium phthalimide (8.90 g, 48 mmol) in DMF (100 mL) and the resulting mixture was heated to reflux for 1 h, then cooled to room temperature and poured into vigorously stirring ice water (750 mL) and stirred 30 min. The resulting white solid was filtered and washed several times with water, then dried under vacuum (16h) to yield the title compound as white powdery solid.
1H NMR (CDCI3) δ 7.89 (m, 2H), 7.75 (m, 2H), 6.82 (m, 3H), 4.50 (m, 1 H), 4.29 (dd, J = 2.3, 1 1.6 Hz, 1 H), 4.05 (m, 2H), 3.89 (dd, J = 5.4, 14.2 Hz, 1 H).
Example 17 (S)-(7-Chloro-2,3-dihvdro-benzori ,41dioxin-2-yl)-methylamine
(S)-2-(7-chloro-2,3-Dihydro-benzo[1 ,4]dioxin-2-ylmethyl)-isoindole-1 ,3- dione (8.1 g, 24.6 mmol; prepared as in Example 16 above) was combined with hydrazine (1 .57 g, 49 mmol) in EtOH (120 ml.) and heated at reflux for 2 h, then cooled to room temperature. To the reaction mixture was then added 1 N HCI to pH 2.0 and the resulting mixture was stirred for 45 min. The resulting white solid was filtered and washed several times with fresh EtOH and the solid discarded. The filtrate was evaporated in vacuo to yield a solid, which was partitioned between diethyl ether and dilute aqueous NaOH. The diethyl ether solution was washed once with brine, dried (Na2SO4) and evaporated in vacuo to yield the title compound as a clear viscous oil. MS 200 (MH+)
1H NMR (CDCI3) δ 6.90 (dd, J = 1.54, 1.1 Hz, 1 H), 6.79 (m, 2H), 4.26 (dd, J = 1 1.2, 2.2 Hz, 1 H), 4.13 (m, 1 H), 3.98 (dd, J = 1 1.3, 7.5 Hz, 1 H), 2.98 (m, 2H), 1.25 (bd s, NH2)
Optical Rotation [α]D = -54.2 ° (c = 1.55, CHCI3)
Example 18
(S)-Λ/-(7-Chloro-2,3-dihvdro-benzoH ,41dioxin-2-ylmethyl)-sulfamide (Compound of Formula (1-S))
(S)-(7-chloro-2,3-dihydro-benzo[1 ,4]dioxin-2-yl)-methylamine (4.7 g, 23.5 mmol) and sulfamide (4.51 g, 47 mmol) were refluxed in dioxane (125 mL) for 3 h, then cooled to room temperature, filtered and evaporated in vacuo to yield a solid. The solid (crude product) was purified by flash column chromatography
(DCM:MeOH 20:1 ) to yield a white solid, which was recrystallized from ethyl acetate/hexane to yield the title compound as a white crystalline solid. mp 1 18-1 19°C
MS 277 (M-1 )
Optical Rotation [α]D = -40.0° (c = 1.20, MeOH)
1H NMR (DMSOd6) δ 6.97 (d, J = 2.2 Hz, 1 H), 6.90 (m, 3H), 6.67 (s, 2H, NH2), 4.35 (m, 2H), 4.01 (m, 1 H), 3.15 (m, 2 H)
Chemical Analysis:
Calculated C, 38.78; H, 3.98; N, 10.05; S, 1 1 .51 Measured: C, 38.83; H, 3.88; N, 10.08; S, 1 1 .31
Example 19 Liquid Formulation
The compound of formula (I-S), prepared for example as described above, was formulated according to known methods into liquid formulations of 25 mg and 100 mg, respectively, with components as listed in Table 4 below.
Table 4: Liquid Formulations
25 mg/mL 100 mg/mL
Component Role Suspension Suspension
Compound of formula (I-S) Active 25 mg 100 mg
Hypromellose (also known as HPMC or Suspending hydroxypropylmethylcellulose) agent 5 mg 5 mg
Purified water Solvent q.s. ad. 1 ml_ q.s. ad. 1 ml.
Example 20 - Prophetic Example
As a specific embodiment of an oral composition, 100 mg of the compound prepared as in Example 18 is formulated with sufficient finely divided lactose to provide a total amount of 580 to 590 mg to fill a size O hard gel capsule. While the foregoing specification teaches the principles of the present invention, with examples provided for the purpose of illustration, it will be
understood that the practice of the invention encompasses all of the usual variations, adaptations and/or modifications as come within the scope of the following claims and their equivalents.
Claims
1. A process for the preparation of a compound of formula (V)
(V) wherein
is selected from the group consisting of
and b is an integer from 0 to 4; and wherein c is an integer from 0 to 2; each R5 is independently selected from the group consisting of halogen, lower alkyl and nitro; comprising
protecting a compound of formula (X); to yield the corresponding compound of formula (Xl), wherein Pg1 is an alcohol protecting group;
reacting the compound of formula (Xl) with an oxidizing agent; in an organic solvent; to yield the corresponding compound of formula (XII); reacting the compound of formula (XII) with an organic or inorganic base; in an organic solvent, in a mixture of organic solvents or in a mixture of one or more organic solvents and water; to yield the corresponding compound of formula (XIII);
reacting the compound of formula (XIII) with a source of epoxy- methylene; in the presence of an inorganic base; at a temperature greater than about room temperature; in an organic solvent; to yield the corresponding compound of formula (XIV);
de-protecting the compound of formula (XIV); to yield the corresponding compound of formula (XV);
reacting the compound of formula (XV) with an organic or inorganic base; in a organic solvent; to yield the corresponding compound of formula (V).
2. A process as in Claim 1 , wherein Pg1 is selected from the group consisting of benzyl, allyl, 2-(thmethylsilyl)ethoxymethyl, t-butyl-diphenylsilyl, A- nitro-benzyl, 4-methoxybenzyl, methoxymethyl and ethoxyethyl.
3. A process as in Claim 2, wherein Pg1 is selected from the group consisting of benzyl and allyl.
4. A process as in Claim 1 , wherein the oxidizing agent is m-CPBA.
5. A process as in Claim 1 , wherein the organic or inorganic base reacted with compound of formula (XII) is NaOCHs.
6. A process as in Claim 1 , wherein the source of epoxy-methylene is selected form the group consisting of glycidyl-m-nosylate and glycidyl-tosylate.
7. A process as in Claim 1 , wherein the source of epoxy-methylene is selected from the group consisting of ^-glycidyl-m-nosylate and (T?,)-glycidyl tosylate.
8. A process as in Claim 3, wherein the compound of formula (XIV) is de- protected by reacting the compound of formula (XIV) with hydrogen or a source of hydrogen.
9. A process as in Claim 1 , wherein the organic or inorganic base reacted with the compound of formula (V) is NaOCHs.
10. A process as in Claim 1 , wherein is
1 1. A process for the preparation of compounds of formula (I)
wherein is selected from the group consisting of
b is an integer from 0 to 4; and wherein c is an integer from 0 to 2; each R5 is independently selected from the group consisting of halogen, lower alkyl and nitro;
R4 is selected from the group consisting of hydrogen and lower alkyl; R1 and R2 are each independently selected from the group consisting of hydrogen and lower alkyl; or pharmaceutically acceptable salts thereof; comprising
protecting a com pound of formula (X) wherein is selected
from the group consisting of to yield the corresponding compound of formula (Xl), wherein Pg1 is an alcohol protecting group; reacting the compound of formula (Xl) with an oxidizing agent; in an organic solvent; to yield the corresponding compound of formula (XII);
reacting the compound of formula (XII) with an organic or inorganic base; in an organic solvent, in a mixture of organic solvents or in a mixture of one or more organic solvents and water; to yield the corresponding compound of formula (XIII);
reacting the compound of formula (XIII) with a source of epoxy- methylene; in the presence of an inorganic base; at a temperature greater than about room temperature; in an organic solvent; to yield the corresponding compound of formula (XIV);
de-protecting the compound of formula (XIV); to yield the corresponding compound of formula (XV);
reacting the compound of formula (XV) with an organic or inorganic base; in a organic solvent; to yield the corresponding compound of formula (V).
reacting the compound of formula (V); to yield the corresponding compound of formula (I).
12. A process as in Claim 1 1 , wherein PG1 is selected from the group consisting of benzyl, allyl, 2-(thmethylsilyl)ethoxymethyl, t-butyl-diphenylsilyl, 4- nitro-benzyl, 4-methoxybenzyl, methoxymethyl and ethoxyethyl.
13. A process as in Claim 12, wherein Pg1 is selected from the group consisting of benzyl and allyl.
14. A process as in Claim 1 1 , wherein the oxidizing agent is m-CPBA.
15. A process as in Claim 1 1 , wherein the organic or inorganic base reacted with compound of formula (XII) is NaOCHs.
16. A process as in Claim 1 1 , wherein the source of epoxy-methylene is selected from the group consisting of glycidyl-m-nosylate and glycidyl-tosylate.
17. A process as in Claim 1 1 , wherein the source of epoxy-methylene is selected from the group consisting of ^-glycidyl-m-nosylate and (T?,)-glycidyl tosylate.
18. A process as in Claim 13, wherein the compound of formula (XIV) is de- protected by reacting the compound of formula (XIV) with hydrogen or a source of hydrogen.
19. A process as in Claim 1 1 , wherein the organic or inorganic base reacted with the compound of formula (V) is NaOCHs.
20. A process as in Claim 1 , wherein is R1 is hydrogen, R2 is hydrogen and R4 is hydrogen.
21. A process for the preparation of a compound of formula (V-S)
comprising
protecting a compound of formula (X-S); to yield the corresponding compound of formula (Xl-S), wherein Pg1 is an alcohol protecting group;
reacting the compound of formula (Xl-S) with an oxidizing agent; in an organic solvent; to yield the corresponding compound of formula (XII-S);
reacting the compound of formula (XII-S) with an organic or inorganic base; in an organic solvent, in a mixture of organic solvents or in a mixture of one or more organic solvents and water; to yield the corresponding compound of formula (XIII-S);
reacting the compound of formula (XIII-S) with a source of (R)-epoxy- methylene; in the presence of an inorganic base; at a temperature greater than about room temperature; in an organic solvent; to yield the corresponding compound of formula (XIV-S);
de-protecting the compound of formula (XIV-S); to yield the corresponding compound of formula (XV-S);
reacting the compound of formula (XV-S) with an organic or inorganic base; in a organic solvent; to yield the corresponding compound of formula (V- S).
22. A process as in Claim 21 , wherein Pg1 is selected from the group consisting of benzyl, allyl, 2-(thmethylsilyl)ethoxymethyl, t-butyl-diphenylsilyl, 4- nitro-benzyl, 4-methoxybenzyl, methoxymethyl and ethoxyethyl.
23. A process as in Claim 22, wherein Pg1 is selected from the group consisting of benzyl and allyl.
24. A process as in Claim 21 , wherein the oxidizing agent is m-CPBA.
25. A process as in Claim 21 , wherein the organic or inorganic base reacted with compound of formula (XII-S) is NaOCHs.
26. A process as in Claim 21 , wherein the source of ^-epoxy-methylene is selected from the group consisting of ^-glycidyl-m-nosylate and (T?,)-glycidyl tosylate.
27. A process as in Claim 23, wherein the compound of formula (XIV-S) is de-protected by reacting the compound of formula (XIV) with hydrogen or a source of hydrogen.
28. A process as in Claim 21 , wherein the organic or inorganic base reacted with the compound of formula (V-S) is NaOCHs.
29. A process for the preparation of a compound of formula (I-S) comprising the process of Claim 21 ; and further comprising
reacting the compound of formula (V-S); to yield the corresponding compound of formula (I-S).
30. A process for the preparation of a compound of formula (I-S)
or a pharmaceutically acceptable salt thereof comprising protecting a compound of formula (X-S); to yield the corresponding compound of formula (Xl-S), wherein Pg1 is an alcohol protecting group;
reacting the compound of formula (Xl-S) with an oxidizing agent; in an organic solvent; to yield the corresponding compound of formula (XII-S);
reacting the compound of formula (XII-S) with an organic or inorganic base; in an organic solvent, in a mixture of organic solvents or in a mixture of one or more organic solvents and water; to yield the corresponding compound of formula (XIII-S);
reacting the compound of formula (XIII-S) with a source of (R)-epoxy- methylene; in the presence of an inorganic base; at a temperature greater than about room temperature; in an organic solvent; to yield the corresponding compound of formula (XIV-S); de-protecting the compound of formula (XIV-S); to yield the corresponding compound of formula (XV-S);
reacting the compound of formula (XV-S) with an organic or inorganic base; in a organic solvent; to yield the corresponding compound of formula (V- S);
reacting the compound of formula (V-S); to yield the corresponding compound of formula (I-S).
31. A process as in Claim 30, wherein Pg1 is selected from the group consisting of benzyl, allyl, 2-(thmethylsilyl)ethoxymethyl, t-butyl-diphenylsilyl, 4- nitro-benzyl, 4-methoxybenzyl, methoxymethyl and ethoxyethyl.
32. A process as in Claim 31 , wherein Pg1 is selected from the group consisting of benzyl and allyl.
33. A process as in Claim 30, wherein the oxidizing agent is m-CPBA.
34. A process as in Claim 30, wherein the organic or inorganic base reacted with compound of formula (XII-S) is NaOCHs.
35. A process as in Claim 30, wherein the source of ^-epoxy-methylene is selected from the group consisting of (fy-glycidyl-m-nosylate and (T?,)-glycidyl tosylate.
36. A process as in Claim 32, wherein the compound of formula (XIV-S) is de-protected by reacting the compound of formula (XIV) with hydrogen or a source of hydrogen.
37. A process as in Claim 30, wherein the organic or inorganic base reacted with the compound of formula (V-S) is NaOCHs.
38. A product prepared according to the process of Claim 1 1.
39. A product prepared according to the process of Claim 30.
40. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and the product of Claim 39.
41. A pharmaceutical composition made by mixing the product of Claim 39 and a pharmaceutically acceptable carrier.
42. A process for making a pharmaceutical composition comprising mixing the product of Claim 39 and a pharmaceutically acceptable carrier.
43. A method of treating epilepsy or a related disorder comprising administering to a subject in need thereof a therapeutically effective amount of the product of Claim 39.
44. The method of Claim 43, wherein the disorder is epilepsy.
45. A process for the preparation of a compound of formula (V)
(V) wherein
is selected from the group consisting of
b is an integer from O to 4; and wherein c is an integer from O to 2; each R5 is independently selected from the group consisting of halogen, lower alkyl and nitro;
reacting a compound of formula (XVI) wherein Q is selected from the group consisting of -C(0)-(d-4alkyl); with a source of epoxy-methylene; in the presence of an inorganic base; at a temperature greater than about room temperature; in an organic solvent; to yield the corresponding compound of formula (XVII);
reacting the compound of formula (XVII) with an oxidizing agent; in an organic solvent; to yield the corresponding compound of formula (XVIII); reacting the compound of formula (XVIII) with an organic or inorganic base; in a organic solvent; to yield the corresponding compound of formula (V).
46. A process as in Claim 45, wherein Q is -C(O)-CHs.
47. A process as in Claim 45, wherein the source of epoxy-methylene is selected from the group consisting of glycidyl-m-nosylate and glycidyl tosylate.
48. A process as in Claim 47, wherein the source of epoxy-methylene is selected from the group consisting of ^-glycidyl-m-nosylate and ^-glycidyl tosylate.
49. A process as in Claim 45, wherein the oxidizing agent is m-CPBA.
50. A process as in Claim 45, wherein the organic or inorganic acid reacted with the compound of formula (XVIII) is NaOCH3.
51. A process as in Claim 45, wherein is Cl
52. A process for the preparation of a compound of formula (I)
wherein is selected from the group consisting of
b is an integer from 0 to 4; and wherein c is an integer from 0 to 2; each R5 is independently selected from the group consisting of halogen, lower alkyl and nitro;
R4 is selected from the group consisting of hydrogen and lower alkyl; R1 and R2 are each independently selected from the group consisting of hydrogen and lower alkyl; or pharmaceutically acceptable salts thereof; comprising
reacting a compound of formula (XVI) wherein ^ v is selected
from the group consisting of and wherein Q is selected from the group consisting of -C(O)-(Ci-4alkyl); with a source of epoxy-methylene; in the presence of an inorganic base; at a temperature greater than about room temperature; in an organic solvent; to yield the corresponding compound of formula (XVII); reacting the compound of formula (XVII) with an oxidizing agent; in an organic solvent; to yield the corresponding compound of formula (XVIII);
reacting the compound of formula (XVIII) with an organic or inorganic base; in a organic solvent; to yield the corresponding compound of formula (V);
reacting the compound of formula (V); to yield the corresponding compound of formula (I).
53. A process as in Claim 52, wherein Q is -C(O)-CHs.
54. A process as in Claim 52, wherein the source of epoxy-methylene is selected from the group consisting of glycidyl-m-nosylate and glycidyl tosylate.
55. A process as in Claim 54, wherein the source of epoxy-methylene is selected from the group consisting of ^-glycidyl-m-nosylate and (RJ-glycidyl tosylate.
56. A process as in Claim 52, wherein the oxidizing agent is m-CPBA.
57. A process as in Claim 52, wherein the organic or inorganic acid reacted with the compound of formula (XVIII) is NaOCHs.
58. A process as in Claim 52, wherein is R1 is hydrogen, R2 is hydrogen and R4 is hydrogen.
59. A process for the preparation of the compound of formula (V-S)
comprising
reacting a compound of formula (XVI-S) wherein Q is selected from the group consisting of -C(O)-(Ci-4alkyl); with a source of (T?,)-epoxy-methylene; in the presence of an inorganic base; at a temperature greater than about room temperature; in an organic solvent; to yield the corresponding compound of formula (XVII-S);
reacting the compound of formula (XVII-S) with an oxidizing agent; in an organic solvent; to yield the corresponding compound of formula (XVIII-S);
reacting the compound of formula (XVIII-S) with an organic or inorganic base; in a organic solvent; to yield the corresponding compound of formula (V- S).
60. A process as in Claim 15, wherein Q is -C(O)-CH3.
61. A process as in Claim 15, wherein the source of (7?,)-epoxy-methylene is selected from the group consisting of ^-glycidyl-m-nosylate and (T?,)-glycidyl tosylate.
62. A process as in Claim 15, wherein the oxidizing agent is m-CPBA.
63. A process as in Claim 15, wherein the organic or inorganic acid reacted with the compound of formula (XVIII-S) is NaOCH3.
64. A process for the preparation of a compound of formula (I-S)
or a pharmaceutically acceptable salt thereof comprising
reacting a compound of formula (XVI-S) wherein Q is selected from the group consisting of -C(O)-(Ci-4alkyl); with a source of (7?,)-epoxy-methylene; in the presence of an inorganic base; at a temperature greater than about room temperature; in an organic solvent; to yield the corresponding compound of formula (XVII-S); reacting the compound of formula (XVII-S) with an oxidizing agent; in an organic solvent; to yield the corresponding compound of formula (XVIII-S);
reacting the compound of formula (XVIII-S) with an organic or inorganic base; in a organic solvent; to yield the corresponding compound of formula (V- S);
reacting the compound of formula (V-S); to yield the corresponding compound of formula (I-S).
65. A process as in Claim 64, wherein Q is -C(O)-CH3.
66. A process as in Claim 64, wherein the source of ^-epoxy-methylene is selected from the group consisting of ^-glycidyl-m-nosylate and (T?,)-glycidyl tosylate.
67. A process as in Claim 64, wherein the oxidizing agent is m-CPBA.
68. A process as in Claim 64, wherein the organic or inorganic acid reacted with the compound of formula (XVIII-S) is NaOCH3.
69. A product prepared according to the process of Claim 52.
70. A product prepared according to the process of Claim 64.
71. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and the product of Claim 70.
72. A pharmaceutical composition made by mixing the product of Claim 70 and a pharmaceutically acceptable carrier.
73. A process for making a pharmaceutical composition comprising mixing the product of Claim 70 and a pharmaceutically acceptable carrier.
74. A method of treating epilepsy or a related disorder comprising administering to a subject in need thereof a therapeutically effective amount of the product of Claim 70.
75. The method of Claim 74, wherein the disorder is epilepsy.
76. Crystalline form I-SA of the compound of formula (I-S)
77. The crystalline form I-SA where in the crystalline form I-SA has the following powder X-ray diffraction peaks
78. Crystalline form I-SB of the compound of formula (I-S)
79. The crystalline form I-SB of claim 78 wherein the crystalline form I-SA has the following powder X-ray diffraction peaks:
80. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and the product of Claim 76.
81. A pharmaceutical composition made by mixing the product of Claim 76 and a pharmaceutically acceptable carrier.
82. A process for making a pharmaceutical composition comprising mixing the product of Claim 76 and a pharmaceutically acceptable carrier.
83. A method of treating epilepsy or a related disorder comprising administering to a subject in need thereof a therapeutically effective amount of the product of Claim 76.
84. The method of Claim 83, wherein the disorder is epilepsy.
85. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and the product of Claim 78.
86. A pharmaceutical composition made by mixing the product of Claim 78 and a pharmaceutically acceptable carrier.
87. A process for making a pharmaceutical composition comprising mixing the product of Claim 78 and a pharmaceutically acceptable carrier.
88. A method of treating epilepsy or a related disorder comprising administering to a subject in need thereof a therapeutically effective amount of the product of Claim 78.
89. The method of Claim 88, wherein the disorder is epilepsy.
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| KR20080012360A (en) | 2005-05-20 | 2008-02-11 | 얀센 파마슈티카 엔.브이. | Process for preparing sulfamide derivatives |
| US8497298B2 (en) | 2005-12-19 | 2013-07-30 | Janssen Pharmaceutica Nv | Use of benzo-fused heterocycle sulfamide derivatives for lowering lipids and lowering blood glucose levels |
| US8937096B2 (en) | 2005-12-19 | 2015-01-20 | Janssen Pharmaceutica Nv | Use of benzo-fused heterocyle sulfamide derivatives for the treatment of mania and bipolar disorder |
| US8691867B2 (en) | 2005-12-19 | 2014-04-08 | Janssen Pharmaceutica Nv | Use of benzo-fused heterocycle sulfamide derivatives for the treatment of substance abuse and addiction |
| EA200870556A1 (en) | 2006-05-19 | 2009-06-30 | Янссен Фармацевтика Н.В. | COMBINED THERAPY IN THE TREATMENT OF EPILEPSY AND RELATED DISORDERS |
| EA018567B1 (en) | 2008-06-23 | 2013-08-30 | Янссен Фармацевтика Нв | Crystalline form of (2s)-(-)-n-(6-chloro-2,3-dihydrobenzo[1,4]dioxin-2-ylmethyl)sulfamide |
| US8815939B2 (en) | 2008-07-22 | 2014-08-26 | Janssen Pharmaceutica Nv | Substituted sulfamide derivatives |
| JP2014528953A (en) * | 2011-09-29 | 2014-10-30 | ヤンセン ファーマシューティカ エヌ．ベー． | Process for the preparation of sulfamide derivatives |
| KR20140082762A (en) * | 2011-09-29 | 2014-07-02 | 얀센 파마슈티카 엔.브이. | Improved process for the preparation of sulfamide derivatives |
Family Cites Families (2)
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|---|---|---|---|---|
| US5120758A (en) * | 1991-02-08 | 1992-06-09 | Ciba-Geigy Corporation | Certain benzodioxole, benzodioxane and benzodioxepin derivatives useful as 5-lipoxygenase inhibitors |
| MY147767A (en) * | 2004-06-16 | 2013-01-31 | Janssen Pharmaceutica Nv | Novel sulfamate and sulfamide derivatives useful for the treatment of epilepsy and related disorders |
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2008
- 2008-03-26 EA EA201071121A patent/EA201071121A1/en unknown
- 2008-03-26 BR BRPI0822396A patent/BRPI0822396A2/en not_active IP Right Cessation
- 2008-03-26 CN CN2008801285523A patent/CN101981023A/en active Pending
- 2008-03-26 KR KR1020107023449A patent/KR20100126536A/en not_active Withdrawn
- 2008-03-26 WO PCT/US2008/058247 patent/WO2009120192A2/en not_active Ceased
- 2008-03-26 CA CA2719402A patent/CA2719402A1/en not_active Abandoned
- 2008-03-26 JP JP2011501762A patent/JP2011517448A/en not_active Withdrawn
- 2008-03-26 AU AU2008353492A patent/AU2008353492A1/en not_active Abandoned
- 2008-03-26 MX MX2010010597A patent/MX2010010597A/en unknown
- 2008-03-26 EP EP08732845A patent/EP2280951A2/en not_active Withdrawn
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2010
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- 2010-09-24 EC EC2010010498A patent/ECSP10010498A/en unknown
- 2010-10-25 ZA ZA2010/07610A patent/ZA201007610B/en unknown
Non-Patent Citations (1)
| Title |
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| See references of WO2009120192A2 * |
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| EA201071121A1 (en) | 2011-04-29 |
| AU2008353492A1 (en) | 2009-10-01 |
| JP2011517448A (en) | 2011-06-09 |
| BRPI0822396A2 (en) | 2019-09-24 |
| WO2009120192A2 (en) | 2009-10-01 |
| IL208223A0 (en) | 2010-12-30 |
| WO2009120192A3 (en) | 2010-01-21 |
| ZA201007610B (en) | 2012-04-25 |
| ECSP10010498A (en) | 2010-10-30 |
| KR20100126536A (en) | 2010-12-01 |
| CN101981023A (en) | 2011-02-23 |
| CA2719402A1 (en) | 2009-10-01 |
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