HRP980174A2

HRP980174A2 - Phenoxymethyl piperidine derivatives

Phenoxymethyl piperidine derivatives

Info

Publication number: HRP980174A2
Authority: HR; Croatia
Prior art keywords: compound; formula; dimethylphenoxymethyl; methyl; hydrogen
Prior art date: 1997-04-03

Application number

Other languages

English (en)

Croatian (hr)

Inventor

Lee Allen Flippin

Xiao-Fa Lin

David Garrett Loughhead

Robert James Weikert

Original Assignee

Hoffmann La Roche

Priority date

1997-04-03

Filing date

1998-04-02

Publication date

1999-04-30

1998-04-02 Application filed by Hoffmann La Roche filed Critical Hoffmann La Roche

1999-04-30 Publication of HRP980174A2 publication Critical patent/HRP980174A2/hr

Links

ZZKAAWZQFPDZDW-UHFFFAOYSA-N 1-(phenoxymethyl)piperidine Chemical class C1CCCCN1COC1=CC=CC=C1 ZZKAAWZQFPDZDW-UHFFFAOYSA-N 0.000 title description 3
150000001875 compounds Chemical class 0.000 claims description 200
-1 (C 1-4 )-alkyl Inorganic materials 0.000 claims description 70
229910052739 hydrogen Inorganic materials 0.000 claims description 60
239000001257 hydrogen Substances 0.000 claims description 60
239000000203 mixture Substances 0.000 claims description 56
238000006243 chemical reaction Methods 0.000 claims description 47
238000000034 method Methods 0.000 claims description 42
125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 33
UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 32
VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical group Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 25
150000003839 salts Chemical class 0.000 claims description 23
125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 21
208000004296 neuralgia Diseases 0.000 claims description 18
208000021722 neuropathic pain Diseases 0.000 claims description 17
125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 16
201000010099 disease Diseases 0.000 claims description 16
208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 16
125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 15
125000006239 protecting group Chemical group 0.000 claims description 14
GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Chemical group BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 13
229910052794 bromium Inorganic materials 0.000 claims description 13
239000003195 sodium channel blocking agent Substances 0.000 claims description 13
150000001204 N-oxides Chemical class 0.000 claims description 11
229910052736 halogen Inorganic materials 0.000 claims description 11
125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 10
125000000217 alkyl group Chemical group 0.000 claims description 9
229940079593 drug Drugs 0.000 claims description 8
239000003814 drug Substances 0.000 claims description 8
150000002367 halogens Chemical class 0.000 claims description 8
125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 8
125000003545 alkoxy group Chemical group 0.000 claims description 7
125000001246 bromo group Chemical group Br* 0.000 claims description 7
229910052740 iodine Inorganic materials 0.000 claims description 7
UBHFGBSNTIMLPW-LBPRGKRZSA-N (3s)-3-[(4-bromo-2,6-dimethylphenoxy)methyl]piperidine Chemical compound CC1=CC(Br)=CC(C)=C1OC[C@@H]1CNCCC1 UBHFGBSNTIMLPW-LBPRGKRZSA-N 0.000 claims description 6
230000008569 process Effects 0.000 claims description 6
230000001225 therapeutic effect Effects 0.000 claims description 6
YDYKRTYDLMQIDI-UHFFFAOYSA-N 3-[(4-bromo-2,6-dimethylphenoxy)methyl]-1-methylpiperidine Chemical compound C1N(C)CCCC1COC1=C(C)C=C(Br)C=C1C YDYKRTYDLMQIDI-UHFFFAOYSA-N 0.000 claims description 5
WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical group [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 5
125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 5
125000004428 fluoroalkoxy group Chemical group 0.000 claims description 5
GEHBAXIFCZXOSO-AWEZNQCLSA-N (3s)-3-[(2,6-dimethylphenoxy)methyl]-1-methylpiperidine Chemical compound C1N(C)CCC[C@@H]1COC1=C(C)C=CC=C1C GEHBAXIFCZXOSO-AWEZNQCLSA-N 0.000 claims description 4
YDYKRTYDLMQIDI-ZDUSSCGKSA-N (3s)-3-[(4-bromo-2,6-dimethylphenoxy)methyl]-1-methylpiperidine Chemical compound C1N(C)CCC[C@@H]1COC1=C(C)C=C(Br)C=C1C YDYKRTYDLMQIDI-ZDUSSCGKSA-N 0.000 claims description 4
238000010511 deprotection reaction Methods 0.000 claims description 4
238000004519 manufacturing process Methods 0.000 claims description 4
125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 4
230000001629 suppression Effects 0.000 claims description 4
ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical group [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 3
230000010933 acylation Effects 0.000 claims description 3
238000005917 acylation reaction Methods 0.000 claims description 3
239000000460 chlorine Chemical group 0.000 claims description 3
229910052801 chlorine Chemical group 0.000 claims description 3
125000001153 fluoro group Chemical group F* 0.000 claims description 3
238000000926 separation method Methods 0.000 claims description 3
125000001424 substituent group Chemical group 0.000 claims description 3
FKXXLPPNHJXBNI-UHFFFAOYSA-N 3-[(2,6-dimethylphenoxy)methyl]-1-methyl-1-oxidopiperidin-1-ium Chemical compound CC1=CC=CC(C)=C1OCC1C[N+](C)([O-])CCC1 FKXXLPPNHJXBNI-UHFFFAOYSA-N 0.000 claims description 2
GEHBAXIFCZXOSO-UHFFFAOYSA-N 3-[(2,6-dimethylphenoxy)methyl]-1-methylpiperidine Chemical compound C1N(C)CCCC1COC1=C(C)C=CC=C1C GEHBAXIFCZXOSO-UHFFFAOYSA-N 0.000 claims description 2
LDNYJNSOBACMBY-UHFFFAOYSA-N 3-[(4-bromo-2,6-dimethylphenoxy)methyl]-1-methyl-1-oxidopiperidin-1-ium Chemical compound CC1=CC(Br)=CC(C)=C1OCC1C[N+](C)([O-])CCC1 LDNYJNSOBACMBY-UHFFFAOYSA-N 0.000 claims description 2
UBHFGBSNTIMLPW-UHFFFAOYSA-N 3-[(4-bromo-2,6-dimethylphenoxy)methyl]piperidine Chemical compound CC1=CC(Br)=CC(C)=C1OCC1CNCCC1 UBHFGBSNTIMLPW-UHFFFAOYSA-N 0.000 claims description 2
125000000738 acetamido group Chemical group [H]C([H])([H])C(=O)N([H])[*] 0.000 claims description 2
230000029936 alkylation Effects 0.000 claims description 2
238000005804 alkylation reaction Methods 0.000 claims description 2
SYSQUGFVNFXIIT-UHFFFAOYSA-N n-[4-(1,3-benzoxazol-2-yl)phenyl]-4-nitrobenzenesulfonamide Chemical class C1=CC([N+](=O)[O-])=CC=C1S(=O)(=O)NC1=CC=C(C=2OC3=CC=CC=C3N=2)C=C1 SYSQUGFVNFXIIT-UHFFFAOYSA-N 0.000 claims description 2
230000003647 oxidation Effects 0.000 claims description 2
238000007254 oxidation reaction Methods 0.000 claims description 2
150000002431 hydrogen Chemical class 0.000 claims 7
239000012752 auxiliary agent Substances 0.000 claims 1
XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 96
RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 78
YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 72
WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 66
238000002360 preparation method Methods 0.000 description 63
OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 51
238000002844 melting Methods 0.000 description 41
230000008018 melting Effects 0.000 description 41
LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 40
239000000243 solution Substances 0.000 description 39
ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 33
YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 33
XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 33
208000004454 Hyperalgesia Diseases 0.000 description 29
NQRYJNQNLNOLGT-UHFFFAOYSA-N tetrahydropyridine hydrochloride Natural products C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 25
241000700159 Rattus Species 0.000 description 23
VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 22
208000002193 Pain Diseases 0.000 description 19
239000002904 solvent Substances 0.000 description 19
150000002989 phenols Chemical class 0.000 description 18
230000036407 pain Effects 0.000 description 17
206010053552 allodynia Diseases 0.000 description 16
239000011541 reaction mixture Substances 0.000 description 16
HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 15
239000010410 layer Substances 0.000 description 15
238000012360 testing method Methods 0.000 description 15
239000003921 oil Substances 0.000 description 14
239000003960 organic solvent Substances 0.000 description 14
108010052164 Sodium Channels Proteins 0.000 description 13
102000018674 Sodium Channels Human genes 0.000 description 13
239000007787 solid Substances 0.000 description 13
CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 12
UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 12
CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 12
241001465754 Metazoa Species 0.000 description 12
VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 12
CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 12
239000000543 intermediate Substances 0.000 description 12
239000008194 pharmaceutical composition Substances 0.000 description 12
BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 12
230000001684 chronic effect Effects 0.000 description 11
230000000694 effects Effects 0.000 description 11
239000012044 organic layer Substances 0.000 description 11
239000000741 silica gel Substances 0.000 description 11
229910002027 silica gel Inorganic materials 0.000 description 11
QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 10
KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 10
208000027418 Wounds and injury Diseases 0.000 description 10
239000002253 acid Substances 0.000 description 10
238000009472 formulation Methods 0.000 description 10
239000004615 ingredient Substances 0.000 description 10
WBDPMSCRCLFVHH-ZOWNYOTGSA-N (3s)-3-[(4-bromo-2,6-dimethylphenoxy)methyl]-1-methylpiperidine;hydrochloride Chemical compound Cl.C1N(C)CCC[C@@H]1COC1=C(C)C=C(Br)C=C1C WBDPMSCRCLFVHH-ZOWNYOTGSA-N 0.000 description 9
QGJOPFRUJISHPQ-UHFFFAOYSA-N Carbon disulfide Chemical compound S=C=S QGJOPFRUJISHPQ-UHFFFAOYSA-N 0.000 description 9
PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 9
KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 9
231100000252 nontoxic Toxicity 0.000 description 9
230000003000 nontoxic effect Effects 0.000 description 9
208000024891 symptom Diseases 0.000 description 9
ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 description 8
IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 8
JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 8
UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 8
239000003795 chemical substances by application Substances 0.000 description 8
208000014674 injury Diseases 0.000 description 8
HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 8
NFHFRUOZVGFOOS-UHFFFAOYSA-N palladium;triphenylphosphane Chemical compound [Pd].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 NFHFRUOZVGFOOS-UHFFFAOYSA-N 0.000 description 8
239000002244 precipitate Substances 0.000 description 8
RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 8
230000006378 damage Effects 0.000 description 7
238000002474 experimental method Methods 0.000 description 7
210000000548 hind-foot Anatomy 0.000 description 7
239000007924 injection Substances 0.000 description 7
238000002347 injection Methods 0.000 description 7
201000005518 mononeuropathy Diseases 0.000 description 7
WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 6
WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 6
WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 description 6
SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 description 6
YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 6
ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 6
239000008346 aqueous phase Substances 0.000 description 6
239000012298 atmosphere Substances 0.000 description 6
239000012267 brine Substances 0.000 description 6
239000000835 fiber Substances 0.000 description 6
238000001914 filtration Methods 0.000 description 6
238000001727 in vivo Methods 0.000 description 6
229910052943 magnesium sulfate Inorganic materials 0.000 description 6
235000019341 magnesium sulphate Nutrition 0.000 description 6
239000000546 pharmaceutical excipient Substances 0.000 description 6
229910000027 potassium carbonate Inorganic materials 0.000 description 6
235000011181 potassium carbonates Nutrition 0.000 description 6
229910000029 sodium carbonate Inorganic materials 0.000 description 6
HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 6
238000003786 synthesis reaction Methods 0.000 description 6
BHKKSKOHRFHHIN-MRVPVSSYSA-N 1-[[2-[(1R)-1-aminoethyl]-4-chlorophenyl]methyl]-2-sulfanylidene-5H-pyrrolo[3,2-d]pyrimidin-4-one Chemical compound N[C@H](C)C1=C(CN2C(NC(C3=C2C=CN3)=O)=S)C=CC(=C1)Cl BHKKSKOHRFHHIN-MRVPVSSYSA-N 0.000 description 5
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
VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 5
KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 5
230000001154 acute effect Effects 0.000 description 5
239000000908 ammonium hydroxide Substances 0.000 description 5
230000015572 biosynthetic process Effects 0.000 description 5
239000003054 catalyst Substances 0.000 description 5
239000007788 liquid Substances 0.000 description 5
239000012280 lithium aluminium hydride Substances 0.000 description 5
210000005036 nerve Anatomy 0.000 description 5
238000010992 reflux Methods 0.000 description 5
239000012266 salt solution Substances 0.000 description 5
210000003497 sciatic nerve Anatomy 0.000 description 5
238000001356 surgical procedure Methods 0.000 description 5
239000003826 tablet Substances 0.000 description 5
WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 description 4
ZLVFYUORUHNMBO-UHFFFAOYSA-N 4-bromo-2,6-dimethylphenol Chemical compound CC1=CC(Br)=CC(C)=C1O ZLVFYUORUHNMBO-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
HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 4
VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 4
WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 4
206010020751 Hypersensitivity Diseases 0.000 description 4
GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Chemical class OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 4
FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 4
DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 4
150000004945 aromatic hydrocarbons Chemical class 0.000 description 4
WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 4
125000004744 butyloxycarbonyl group Chemical group 0.000 description 4
239000001913 cellulose Chemical class 0.000 description 4
229920002678 cellulose Chemical class 0.000 description 4
230000008878 coupling Effects 0.000 description 4
238000010168 coupling process Methods 0.000 description 4
238000005859 coupling reaction Methods 0.000 description 4
ZOOSILUVXHVRJE-UHFFFAOYSA-N cyclopropanecarbonyl chloride Chemical compound ClC(=O)C1CC1 ZOOSILUVXHVRJE-UHFFFAOYSA-N 0.000 description 4
FAMRKDQNMBBFBR-BQYQJAHWSA-N diethyl azodicarboxylate Substances CCOC(=O)\N=N\C(=O)OCC FAMRKDQNMBBFBR-BQYQJAHWSA-N 0.000 description 4
239000002552 dosage form Substances 0.000 description 4
FAMRKDQNMBBFBR-UHFFFAOYSA-N ethyl n-ethoxycarbonyliminocarbamate Chemical compound CCOC(=O)N=NC(=O)OCC FAMRKDQNMBBFBR-UHFFFAOYSA-N 0.000 description 4
239000000706 filtrate Substances 0.000 description 4
125000003709 fluoroalkyl group Chemical group 0.000 description 4
210000002683 foot Anatomy 0.000 description 4
150000008282 halocarbons Chemical class 0.000 description 4
239000008101 lactose Chemical class 0.000 description 4
239000003589 local anesthetic agent Substances 0.000 description 4
229960005015 local anesthetics Drugs 0.000 description 4
235000019359 magnesium stearate Nutrition 0.000 description 4
BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 4
LXCFILQKKLGQFO-UHFFFAOYSA-N methylparaben Chemical compound COC(=O)C1=CC=C(O)C=C1 LXCFILQKKLGQFO-UHFFFAOYSA-N 0.000 description 4
230000004048 modification Effects 0.000 description 4
238000012986 modification Methods 0.000 description 4
229910052757 nitrogen Inorganic materials 0.000 description 4
229910052763 palladium Inorganic materials 0.000 description 4
208000033808 peripheral neuropathy Diseases 0.000 description 4
UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 4
230000004044 response Effects 0.000 description 4
230000035945 sensitivity Effects 0.000 description 4
229910000030 sodium bicarbonate Inorganic materials 0.000 description 4
235000017557 sodium bicarbonate Nutrition 0.000 description 4
RSIJVJUOQBWMIM-UHFFFAOYSA-L sodium sulfate decahydrate Chemical compound O.O.O.O.O.O.O.O.O.O.[Na+].[Na+].[O-]S([O-])(=O)=O RSIJVJUOQBWMIM-UHFFFAOYSA-L 0.000 description 4
238000010561 standard procedure Methods 0.000 description 4
238000003756 stirring Methods 0.000 description 4
239000000829 suppository Substances 0.000 description 4
239000000725 suspension Substances 0.000 description 4
YAJOKURGJACHKD-ZOWNYOTGSA-N (3s)-3-[(2,6-dimethylphenoxy)methyl]piperidine;hydrochloride Chemical compound Cl.CC1=CC=CC(C)=C1OC[C@@H]1CNCCC1 YAJOKURGJACHKD-ZOWNYOTGSA-N 0.000 description 3
LJGHYPLBDBRCRZ-UHFFFAOYSA-N 3-(3-aminophenyl)sulfonylaniline Chemical group NC1=CC=CC(S(=O)(=O)C=2C=C(N)C=CC=2)=C1 LJGHYPLBDBRCRZ-UHFFFAOYSA-N 0.000 description 3
YAJOKURGJACHKD-UHFFFAOYSA-N 3-[(2,6-dimethylphenoxy)methyl]piperidine;hydrochloride Chemical compound Cl.CC1=CC=CC(C)=C1OCC1CNCCC1 YAJOKURGJACHKD-UHFFFAOYSA-N 0.000 description 3
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