JP6835668B2 - シクロヘキシルアミン類 - Google Patents
シクロヘキシルアミン類 Download PDFInfo
- Publication number
- JP6835668B2 JP6835668B2 JP2017108579A JP2017108579A JP6835668B2 JP 6835668 B2 JP6835668 B2 JP 6835668B2 JP 2017108579 A JP2017108579 A JP 2017108579A JP 2017108579 A JP2017108579 A JP 2017108579A JP 6835668 B2 JP6835668 B2 JP 6835668B2
- Authority
- JP
- Japan
- Prior art keywords
- oxy
- propyl
- iodide
- dimethylcyclohexaneaminium
- compound
- 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.)
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- 150000003946 cyclohexylamines Chemical class 0.000 title 1
- 150000001875 compounds Chemical class 0.000 claims description 258
- 239000000203 mixture Substances 0.000 claims description 83
- -1 xinafoate Chemical compound 0.000 claims description 81
- 125000000217 alkyl group Chemical group 0.000 claims description 44
- 229910052757 nitrogen Inorganic materials 0.000 claims description 33
- 238000002347 injection Methods 0.000 claims description 28
- 239000007924 injection Substances 0.000 claims description 28
- 125000001072 heteroaryl group Chemical group 0.000 claims description 23
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 20
- 238000011282 treatment Methods 0.000 claims description 20
- 239000003795 chemical substances by application Substances 0.000 claims description 17
- 238000009472 formulation Methods 0.000 claims description 15
- 229910052736 halogen Inorganic materials 0.000 claims description 15
- 150000002367 halogens Chemical class 0.000 claims description 15
- 229910052799 carbon Inorganic materials 0.000 claims description 12
- 239000000460 chlorine Substances 0.000 claims description 12
- 239000003195 sodium channel blocking agent Substances 0.000 claims description 12
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 claims description 8
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 claims description 8
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 8
- 150000003839 salts Chemical class 0.000 claims description 8
- BDHFUVZGWQCTTF-UHFFFAOYSA-M sulfonate Chemical compound [O-]S(=O)=O BDHFUVZGWQCTTF-UHFFFAOYSA-M 0.000 claims description 8
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 claims description 8
- 229910052801 chlorine Inorganic materials 0.000 claims description 7
- 229910052739 hydrogen Inorganic materials 0.000 claims description 7
- 239000002253 acid Substances 0.000 claims description 6
- PXBRQCKWGAHEHS-UHFFFAOYSA-N dichlorodifluoromethane Chemical compound FC(F)(Cl)Cl PXBRQCKWGAHEHS-UHFFFAOYSA-N 0.000 claims description 6
- 239000002552 dosage form Substances 0.000 claims description 6
- 229940125794 sodium channel blocker Drugs 0.000 claims description 6
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 claims description 5
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 claims description 5
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 claims description 5
- 229910052794 bromium Inorganic materials 0.000 claims description 5
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 claims description 5
- ZQPPMHVWECSIRJ-KTKRTIGZSA-N oleic acid Chemical compound CCCCCCCC\C=C/CCCCCCCC(O)=O ZQPPMHVWECSIRJ-KTKRTIGZSA-N 0.000 claims description 5
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 claims description 5
- FCEHBMOGCRZNNI-UHFFFAOYSA-N 1-benzothiophene Chemical class C1=CC=C2SC=CC2=C1 FCEHBMOGCRZNNI-UHFFFAOYSA-N 0.000 claims description 4
- KAESVJOAVNADME-UHFFFAOYSA-N 1H-pyrrole Natural products C=1C=CNC=1 KAESVJOAVNADME-UHFFFAOYSA-N 0.000 claims description 4
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical group [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 4
- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 claims description 4
- DSLZVSRJTYRBFB-LLEIAEIESA-N D-glucaric acid Chemical compound OC(=O)[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C(O)=O DSLZVSRJTYRBFB-LLEIAEIESA-N 0.000 claims description 4
- FEWJPZIEWOKRBE-LWMBPPNESA-L D-tartrate(2-) Chemical compound [O-]C(=O)[C@@H](O)[C@H](O)C([O-])=O FEWJPZIEWOKRBE-LWMBPPNESA-L 0.000 claims description 4
- YTPLMLYBLZKORZ-UHFFFAOYSA-N Divinylene sulfide Natural products C=1C=CSC=1 YTPLMLYBLZKORZ-UHFFFAOYSA-N 0.000 claims description 4
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 claims description 4
- AEMRFAOFKBGASW-UHFFFAOYSA-M Glycolate Chemical compound OCC([O-])=O AEMRFAOFKBGASW-UHFFFAOYSA-M 0.000 claims description 4
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 claims description 4
- JVTAAEKCZFNVCJ-REOHCLBHSA-N L-lactic acid Chemical compound C[C@H](O)C(O)=O JVTAAEKCZFNVCJ-REOHCLBHSA-N 0.000 claims description 4
- FEWJPZIEWOKRBE-JCYAYHJZSA-L L-tartrate(2-) Chemical compound [O-]C(=O)[C@H](O)[C@@H](O)C([O-])=O FEWJPZIEWOKRBE-JCYAYHJZSA-L 0.000 claims description 4
- OFOBLEOULBTSOW-UHFFFAOYSA-L Malonate Chemical compound [O-]C(=O)CC([O-])=O OFOBLEOULBTSOW-UHFFFAOYSA-L 0.000 claims description 4
- PVNIIMVLHYAWGP-UHFFFAOYSA-N Niacin Chemical compound OC(=O)C1=CC=CN=C1 PVNIIMVLHYAWGP-UHFFFAOYSA-N 0.000 claims description 4
- 229910019142 PO4 Inorganic materials 0.000 claims description 4
- LCTONWCANYUPML-UHFFFAOYSA-M Pyruvate Chemical compound CC(=O)C([O-])=O LCTONWCANYUPML-UHFFFAOYSA-M 0.000 claims description 4
- DTQVDTLACAAQTR-UHFFFAOYSA-M Trifluoroacetate Chemical compound [O-]C(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-M 0.000 claims description 4
- WNLRTRBMVRJNCN-UHFFFAOYSA-L adipate(2-) Chemical compound [O-]C(=O)CCCCC([O-])=O WNLRTRBMVRJNCN-UHFFFAOYSA-L 0.000 claims description 4
- 229940072107 ascorbate Drugs 0.000 claims description 4
- 235000010323 ascorbic acid Nutrition 0.000 claims description 4
- 239000011668 ascorbic acid Substances 0.000 claims description 4
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Chemical group BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 4
- BKFUVCPECXBYNG-UHFFFAOYSA-M cyclohexyl-[2-(2,6-dimethylbenzoyl)oxypropyl]-dimethylazanium;iodide Chemical compound [I-].CC=1C=CC=C(C)C=1C(=O)OC(C)C[N+](C)(C)C1CCCCC1 BKFUVCPECXBYNG-UHFFFAOYSA-M 0.000 claims description 4
- 229910052731 fluorine Inorganic materials 0.000 claims description 4
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical group II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 claims description 4
- SUMDYPCJJOFFON-UHFFFAOYSA-N isethionic acid Chemical compound OCCS(O)(=O)=O SUMDYPCJJOFFON-UHFFFAOYSA-N 0.000 claims description 4
- 229940049920 malate Drugs 0.000 claims description 4
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 claims description 4
- BJEPYKJPYRNKOW-UHFFFAOYSA-N malic acid Chemical compound OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 claims description 4
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 4
- 235000001968 nicotinic acid Nutrition 0.000 claims description 4
- 239000011664 nicotinic acid Substances 0.000 claims description 4
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 claims description 4
- 229940049964 oleate Drugs 0.000 claims description 4
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 claims description 4
- 239000010452 phosphate Substances 0.000 claims description 4
- LBLYYCQCTBFVLH-UHFFFAOYSA-M toluenesulfonate group Chemical group C=1(C(=CC=CC1)S(=O)(=O)[O-])C LBLYYCQCTBFVLH-UHFFFAOYSA-M 0.000 claims description 4
- 230000003442 weekly effect Effects 0.000 claims description 4
- 229950000339 xinafoate Drugs 0.000 claims description 4
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 claims description 3
- 150000007513 acids Chemical class 0.000 claims description 3
- DCXYFEDJOCDNAF-UHFFFAOYSA-M asparaginate Chemical compound [O-]C(=O)C(N)CC(N)=O DCXYFEDJOCDNAF-UHFFFAOYSA-M 0.000 claims description 3
- 125000001309 chloro group Chemical group Cl* 0.000 claims description 3
- 150000003840 hydrochlorides Chemical class 0.000 claims description 3
- QAOWNCQODCNURD-UHFFFAOYSA-M hydrogensulfate Chemical compound OS([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-M 0.000 claims description 3
- 229940116871 l-lactate Drugs 0.000 claims description 3
- AFVFQIVMOAPDHO-UHFFFAOYSA-M methanesulfonate group Chemical group CS(=O)(=O)[O-] AFVFQIVMOAPDHO-UHFFFAOYSA-M 0.000 claims description 3
- 150000002823 nitrates Chemical class 0.000 claims description 3
- 125000005498 phthalate group Chemical group 0.000 claims description 3
- 125000005346 substituted cycloalkyl group Chemical group 0.000 claims description 3
- 229930192474 thiophene Natural products 0.000 claims description 3
- ITMCEJHCFYSIIV-UHFFFAOYSA-M triflate Chemical compound [O-]S(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-M 0.000 claims description 3
- 238000002679 ablation Methods 0.000 claims description 2
- 125000001231 benzoyloxy group Chemical group C(C1=CC=CC=C1)(=O)O* 0.000 claims description 2
- DRULPMMUVUNPNT-UHFFFAOYSA-M cyclohexyl-dimethyl-[2-(2,4,6-trimethylbenzoyl)oxypropyl]azanium;iodide Chemical compound [I-].CC=1C=C(C)C=C(C)C=1C(=O)OC(C)C[N+](C)(C)C1CCCCC1 DRULPMMUVUNPNT-UHFFFAOYSA-M 0.000 claims description 2
- UOFZDNRHBZKKSO-UHFFFAOYSA-M cyclohexyl-dimethyl-[2-(2-propan-2-ylbenzoyl)oxypropyl]azanium;iodide Chemical compound [I-].C=1C=CC=C(C(C)C)C=1C(=O)OC(C)C[N+](C)(C)C1CCCCC1 UOFZDNRHBZKKSO-UHFFFAOYSA-M 0.000 claims description 2
- DPCLVXMHBWASEU-UHFFFAOYSA-M cyclohexyl-dimethyl-[2-(4-propan-2-ylbenzoyl)oxypropyl]azanium;iodide Chemical compound [I-].C=1C=C(C(C)C)C=CC=1C(=O)OC(C)C[N+](C)(C)C1CCCCC1 DPCLVXMHBWASEU-UHFFFAOYSA-M 0.000 claims description 2
- 238000009792 diffusion process Methods 0.000 claims description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 2
- 238000007917 intracranial administration Methods 0.000 claims description 2
- 230000001788 irregular Effects 0.000 claims description 2
- 150000003233 pyrroles Chemical class 0.000 claims description 2
- 150000003577 thiophenes Chemical class 0.000 claims description 2
- LSNNMFCWUKXFEE-UHFFFAOYSA-M Bisulfite Chemical compound OS([O-])=O LSNNMFCWUKXFEE-UHFFFAOYSA-M 0.000 claims 2
- 150000003892 tartrate salts Chemical class 0.000 claims 2
- LUKCGRBQOXWVGZ-UHFFFAOYSA-M 1-(1-cyclohexylpiperidin-1-ium-1-yl)propan-2-yl 2-propan-2-ylbenzoate;bromide Chemical compound [Br-].C=1C=CC=C(C(C)C)C=1C(=O)OC(C)C[N+]1(C2CCCCC2)CCCCC1 LUKCGRBQOXWVGZ-UHFFFAOYSA-M 0.000 claims 1
- JIDYIDWHPKOSFT-UHFFFAOYSA-M 1-(1-cyclohexylpiperidin-1-ium-1-yl)propan-2-yl 4-tert-butylbenzoate;bromide Chemical compound [Br-].C=1C=C(C(C)(C)C)C=CC=1C(=O)OC(C)C[N+]1(C2CCCCC2)CCCCC1 JIDYIDWHPKOSFT-UHFFFAOYSA-M 0.000 claims 1
- QIWPSQMDMNVYDX-UHFFFAOYSA-M 1-(1-cyclohexylpyrrolidin-1-ium-1-yl)propan-2-yl 2-propan-2-ylbenzoate;bromide Chemical compound [Br-].C=1C=CC=C(C(C)C)C=1C(=O)OC(C)C[N+]1(C2CCCCC2)CCCC1 QIWPSQMDMNVYDX-UHFFFAOYSA-M 0.000 claims 1
- UALFMSXJBJWGQA-UHFFFAOYSA-M 1-(1-cyclohexylpyrrolidin-1-ium-1-yl)propan-2-yl 3-chloro-1-benzothiophene-2-carboxylate;bromide Chemical compound [Br-].S1C2=CC=CC=C2C(Cl)=C1C(=O)OC(C)C[N+]1(C2CCCCC2)CCCC1 UALFMSXJBJWGQA-UHFFFAOYSA-M 0.000 claims 1
- YSGPGWOTPOTOET-UHFFFAOYSA-M 1-(1-cyclohexylpyrrolidin-1-ium-1-yl)propan-2-yl 4-tert-butylbenzoate;bromide Chemical compound [Br-].C=1C=C(C(C)(C)C)C=CC=1C(=O)OC(C)C[N+]1(C2CCCCC2)CCCC1 YSGPGWOTPOTOET-UHFFFAOYSA-M 0.000 claims 1
- SZWCMUWSKPBFKT-UHFFFAOYSA-M 2-(1-benzothiophene-2-carbonyloxy)propyl-cyclohexyl-dimethylazanium;iodide Chemical compound [I-].C=1C2=CC=CC=C2SC=1C(=O)OC(C)C[N+](C)(C)C1CCCCC1 SZWCMUWSKPBFKT-UHFFFAOYSA-M 0.000 claims 1
- CUUUHDTTWYRDLX-UHFFFAOYSA-M 2-(2,6-dimethylbenzoyl)oxypropyl-dimethyl-(4-methylcyclohexyl)azanium;iodide Chemical compound [I-].CC=1C=CC=C(C)C=1C(=O)OC(C)C[N+](C)(C)C1CCC(C)CC1 CUUUHDTTWYRDLX-UHFFFAOYSA-M 0.000 claims 1
- AGOGOZONSZCDMW-UHFFFAOYSA-M 2-(2-chlorobenzoyl)oxypropyl-cyclohexyl-dimethylazanium;iodide Chemical compound [I-].C=1C=CC=C(Cl)C=1C(=O)OC(C)C[N+](C)(C)C1CCCCC1 AGOGOZONSZCDMW-UHFFFAOYSA-M 0.000 claims 1
- GBDHRLZEGFYNCS-UHFFFAOYSA-M 2-(3-chloro-1-benzothiophene-2-carbonyl)oxypropyl-cyclohexyl-dimethylazanium;iodide Chemical compound [I-].S1C2=CC=CC=C2C(Cl)=C1C(=O)OC(C)C[N+](C)(C)C1CCCCC1 GBDHRLZEGFYNCS-UHFFFAOYSA-M 0.000 claims 1
- HCCXHYRVBMJIAW-UHFFFAOYSA-M 2-(4-chlorobenzoyl)oxypropyl-cyclohexyl-dimethylazanium;iodide Chemical compound [I-].C=1C=C(Cl)C=CC=1C(=O)OC(C)C[N+](C)(C)C1CCCCC1 HCCXHYRVBMJIAW-UHFFFAOYSA-M 0.000 claims 1
- YLBDXJKKNGCVCN-UHFFFAOYSA-M 2-(4-tert-butylbenzoyl)oxyethyl-cyclohexyl-dimethylazanium;iodide Chemical compound [I-].C1=CC(C(C)(C)C)=CC=C1C(=O)OCC[N+](C)(C)C1CCCCC1 YLBDXJKKNGCVCN-UHFFFAOYSA-M 0.000 claims 1
- XLNIZLLVNBORQX-UHFFFAOYSA-M 2-(4-tert-butylbenzoyl)oxypropyl-cyclohexyl-dimethylazanium;iodide Chemical compound [I-].C=1C=C(C(C)(C)C)C=CC=1C(=O)OC(C)C[N+](C)(C)C1CCCCC1 XLNIZLLVNBORQX-UHFFFAOYSA-M 0.000 claims 1
- QITHEKJHQSEUFX-UHFFFAOYSA-M 2-(4-tert-butylbenzoyl)oxypropyl-dimethyl-(4-methylcyclohexyl)azanium;iodide Chemical compound [I-].C=1C=C(C(C)(C)C)C=CC=1C(=O)OC(C)C[N+](C)(C)C1CCC(C)CC1 QITHEKJHQSEUFX-UHFFFAOYSA-M 0.000 claims 1
- LJQBLTHEPDCYHK-UHFFFAOYSA-M 2-(cyclohexanecarbonyloxy)propyl-cyclohexyl-diethylazanium;iodide Chemical compound [I-].C1CCCCC1[N+](CC)(CC)CC(C)OC(=O)C1CCCCC1 LJQBLTHEPDCYHK-UHFFFAOYSA-M 0.000 claims 1
- AVRWEULSKHQETA-UHFFFAOYSA-N Thiophene-2 Chemical compound S1C=2CCCCCC=2C(C(=O)OC)=C1NC(=O)C1=C(F)C(F)=C(F)C(F)=C1F AVRWEULSKHQETA-UHFFFAOYSA-N 0.000 claims 1
- XFHSHQYKWVYVNX-UNTBIKODSA-M [(2r)-2-(4-tert-butylbenzoyl)oxypropyl]-cyclohexyl-dimethylazanium;bromide Chemical compound [Br-].C([C@@H](C)OC(=O)C=1C=CC(=CC=1)C(C)(C)C)[N+](C)(C)C1CCCCC1 XFHSHQYKWVYVNX-UNTBIKODSA-M 0.000 claims 1
- XLNIZLLVNBORQX-UNTBIKODSA-M [(2r)-2-(4-tert-butylbenzoyl)oxypropyl]-cyclohexyl-dimethylazanium;iodide Chemical compound [I-].C([C@@H](C)OC(=O)C=1C=CC(=CC=1)C(C)(C)C)[N+](C)(C)C1CCCCC1 XLNIZLLVNBORQX-UNTBIKODSA-M 0.000 claims 1
- XFHSHQYKWVYVNX-LMOVPXPDSA-M [(2s)-2-(4-tert-butylbenzoyl)oxypropyl]-cyclohexyl-dimethylazanium;bromide Chemical compound [Br-].C([C@H](C)OC(=O)C=1C=CC(=CC=1)C(C)(C)C)[N+](C)(C)C1CCCCC1 XFHSHQYKWVYVNX-LMOVPXPDSA-M 0.000 claims 1
- XLNIZLLVNBORQX-LMOVPXPDSA-M [(2s)-2-(4-tert-butylbenzoyl)oxypropyl]-cyclohexyl-dimethylazanium;iodide Chemical compound [I-].C([C@H](C)OC(=O)C=1C=CC(=CC=1)C(C)(C)C)[N+](C)(C)C1CCCCC1 XLNIZLLVNBORQX-LMOVPXPDSA-M 0.000 claims 1
- BKFUVCPECXBYNG-UNTBIKODSA-M cyclohexyl-[(2r)-2-(2,6-dimethylbenzoyl)oxypropyl]-dimethylazanium;iodide Chemical compound [I-].C([C@@H](C)OC(=O)C=1C(=CC=CC=1C)C)[N+](C)(C)C1CCCCC1 BKFUVCPECXBYNG-UNTBIKODSA-M 0.000 claims 1
- BKFUVCPECXBYNG-LMOVPXPDSA-M cyclohexyl-[(2s)-2-(2,6-dimethylbenzoyl)oxypropyl]-dimethylazanium;iodide Chemical compound [I-].C([C@H](C)OC(=O)C=1C(=CC=CC=1C)C)[N+](C)(C)C1CCCCC1 BKFUVCPECXBYNG-LMOVPXPDSA-M 0.000 claims 1
- UPMOQCRKUSQFMP-UHFFFAOYSA-M cyclohexyl-[2-(2,3-dichlorobenzoyl)oxypropyl]-dimethylazanium;iodide Chemical compound [I-].C=1C=CC(Cl)=C(Cl)C=1C(=O)OC(C)C[N+](C)(C)C1CCCCC1 UPMOQCRKUSQFMP-UHFFFAOYSA-M 0.000 claims 1
- PIOXMNQDJRNCNQ-UHFFFAOYSA-M cyclohexyl-[2-(2,4-dichlorobenzoyl)oxypropyl]-dimethylazanium;iodide Chemical compound [I-].C=1C=C(Cl)C=C(Cl)C=1C(=O)OC(C)C[N+](C)(C)C1CCCCC1 PIOXMNQDJRNCNQ-UHFFFAOYSA-M 0.000 claims 1
- LRAOIOJPKAFHEB-UHFFFAOYSA-M cyclohexyl-[2-(2,4-dimethylbenzoyl)oxypropyl]-dimethylazanium;iodide Chemical compound [I-].C=1C=C(C)C=C(C)C=1C(=O)OC(C)C[N+](C)(C)C1CCCCC1 LRAOIOJPKAFHEB-UHFFFAOYSA-M 0.000 claims 1
- VUTCDLCJGWUIGB-UHFFFAOYSA-M cyclohexyl-[2-(2,6-dichlorobenzoyl)oxypropyl]-dimethylazanium;iodide Chemical compound [I-].ClC=1C=CC=C(Cl)C=1C(=O)OC(C)C[N+](C)(C)C1CCCCC1 VUTCDLCJGWUIGB-UHFFFAOYSA-M 0.000 claims 1
- HRTUGRVTLQGDEJ-UHFFFAOYSA-M cyclohexyl-[2-(2,6-dimethoxybenzoyl)oxypropyl]-dimethylazanium;iodide Chemical compound [I-].COC1=CC=CC(OC)=C1C(=O)OC(C)C[N+](C)(C)C1CCCCC1 HRTUGRVTLQGDEJ-UHFFFAOYSA-M 0.000 claims 1
- UQZLVHTVBVMDRL-UHFFFAOYSA-M cyclohexyl-[2-(2,6-dimethylbenzoyl)oxyethyl]-dimethylazanium;iodide Chemical compound [I-].CC1=CC=CC(C)=C1C(=O)OCC[N+](C)(C)C1CCCCC1 UQZLVHTVBVMDRL-UHFFFAOYSA-M 0.000 claims 1
- ITFUXQXQCVZRAZ-UHFFFAOYSA-M cyclohexyl-[2-(2-ethylbenzoyl)oxypropyl]-dimethylazanium;iodide Chemical compound [I-].CCC1=CC=CC=C1C(=O)OC(C)C[N+](C)(C)C1CCCCC1 ITFUXQXQCVZRAZ-UHFFFAOYSA-M 0.000 claims 1
- XIZAYWXCHUHCMF-UHFFFAOYSA-M cyclohexyl-[2-(2-fluorobenzoyl)oxypropyl]-dimethylazanium;iodide Chemical compound [I-].C=1C=CC=C(F)C=1C(=O)OC(C)C[N+](C)(C)C1CCCCC1 XIZAYWXCHUHCMF-UHFFFAOYSA-M 0.000 claims 1
- WJPOKYGLTLVXEF-UHFFFAOYSA-M cyclohexyl-[2-(3,5-dichlorobenzoyl)oxypropyl]-dimethylazanium;iodide Chemical compound [I-].C=1C(Cl)=CC(Cl)=CC=1C(=O)OC(C)C[N+](C)(C)C1CCCCC1 WJPOKYGLTLVXEF-UHFFFAOYSA-M 0.000 claims 1
- DNGSPNFAOVVBPL-UHFFFAOYSA-M cyclohexyl-[2-(3-fluorobenzoyl)oxypropyl]-dimethylazanium;iodide Chemical compound [I-].C=1C=CC(F)=CC=1C(=O)OC(C)C[N+](C)(C)C1CCCCC1 DNGSPNFAOVVBPL-UHFFFAOYSA-M 0.000 claims 1
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- OHAFXFZOESPSDV-UHFFFAOYSA-M cyclohexyl-[2-[4-fluoro-2-(trifluoromethyl)benzoyl]oxypropyl]-dimethylazanium;iodide Chemical compound [I-].C=1C=C(F)C=C(C(F)(F)F)C=1C(=O)OC(C)C[N+](C)(C)C1CCCCC1 OHAFXFZOESPSDV-UHFFFAOYSA-M 0.000 claims 1
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- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 239000003053 toxin Substances 0.000 description 1
- 231100000765 toxin Toxicity 0.000 description 1
- OAHWPNUPCSDOGU-UHFFFAOYSA-N trans-10-shogaol Natural products CCCCCCCCCC=CC(=O)CCc1ccc(O)c(CO)c1 OAHWPNUPCSDOGU-UHFFFAOYSA-N 0.000 description 1
- 238000002646 transcutaneous electrical nerve stimulation Methods 0.000 description 1
- 238000013271 transdermal drug delivery Methods 0.000 description 1
- 230000001052 transient effect Effects 0.000 description 1
- 230000007704 transition Effects 0.000 description 1
- GOZBHBFUQHMKQB-UHFFFAOYSA-N trimecaine Chemical compound CCN(CC)CC(=O)NC1=C(C)C=C(C)C=C1C GOZBHBFUQHMKQB-UHFFFAOYSA-N 0.000 description 1
- 229950002569 trimecaine Drugs 0.000 description 1
- 229960001491 trospium Drugs 0.000 description 1
- OYYDSUSKLWTMMQ-JKHIJQBDSA-N trospium Chemical compound [N+]12([C@@H]3CC[C@H]2C[C@H](C3)OC(=O)C(O)(C=2C=CC=CC=2)C=2C=CC=CC=2)CCCC1 OYYDSUSKLWTMMQ-JKHIJQBDSA-N 0.000 description 1
- RVCSYOQWLPPAOA-QKYUOBHYSA-M trospium chloride Chemical compound [Cl-].[N+]12([C@@H]3CC[C@H]2C[C@H](C3)OC(=O)C(O)(C=2C=CC=CC=2)C=2C=CC=CC=2)CCCC1 RVCSYOQWLPPAOA-QKYUOBHYSA-M 0.000 description 1
- 229960001005 tuberculin Drugs 0.000 description 1
- 238000009281 ultraviolet germicidal irradiation Methods 0.000 description 1
- 238000011144 upstream manufacturing Methods 0.000 description 1
- 210000003708 urethra Anatomy 0.000 description 1
- 238000002255 vaccination Methods 0.000 description 1
- BDIAUFOIMFAIPU-UHFFFAOYSA-N valepotriate Natural products CC(C)CC(=O)OC1C=C(C(=COC2OC(=O)CC(C)C)COC(C)=O)C2C11CO1 BDIAUFOIMFAIPU-UHFFFAOYSA-N 0.000 description 1
- 239000005526 vasoconstrictor agent Substances 0.000 description 1
- 229960003726 vasopressin Drugs 0.000 description 1
- 235000015112 vegetable and seed oil Nutrition 0.000 description 1
- 239000008158 vegetable oil Substances 0.000 description 1
- FVECELJHCSPHKY-YFUMOZOISA-N veratridine Chemical compound C1=C(OC)C(OC)=CC=C1C(=O)O[C@@H]1[C@@]2(O)O[C@@]34C[C@@]5(O)[C@H](CN6[C@@H](CC[C@H](C)C6)[C@@]6(C)O)[C@]6(O)[C@@H](O)C[C@@]5(O)[C@@H]4CC[C@H]2[C@]3(C)CC1 FVECELJHCSPHKY-YFUMOZOISA-N 0.000 description 1
- 229940063390 vesicare Drugs 0.000 description 1
- 239000013603 viral vector Substances 0.000 description 1
- 230000009278 visceral effect Effects 0.000 description 1
- 238000011179 visual inspection Methods 0.000 description 1
- 230000001755 vocal effect Effects 0.000 description 1
- 238000010792 warming Methods 0.000 description 1
- 239000003643 water by type Substances 0.000 description 1
- 230000037303 wrinkles Effects 0.000 description 1
- 210000000707 wrist Anatomy 0.000 description 1
- 229960002911 zonisamide Drugs 0.000 description 1
- UBQNRHZMVUUOMG-UHFFFAOYSA-N zonisamide Chemical compound C1=CC=C2C(CS(=O)(=O)N)=NOC2=C1 UBQNRHZMVUUOMG-UHFFFAOYSA-N 0.000 description 1
Images
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- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
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- A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
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- A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
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- A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
- A61K31/351—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom not condensed with another ring
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- C07C219/04—Compounds containing amino and esterified hydroxy groups bound to the same carbon skeleton having esterified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated
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- C07C219/14—Compounds containing amino and esterified hydroxy groups bound to the same carbon skeleton having esterified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having at least one of the hydroxy groups esterified by a carboxylic acid having the esterifying carboxyl group bound to a carbon atom of a six-membered aromatic ring
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- C07C65/24—Compounds having carboxyl groups bound to carbon atoms of six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups containing ether groups, groups, groups, or groups polycyclic
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- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/30—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
- C07D207/34—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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- C07D309/08—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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- C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
- C07D333/26—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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Description
さらなる形態において、過活動膀胱を治療するための方法が提供され、この方法は、治療を必要とする患者に、R1、R2、A、X、及びYが本明細書で定義されるものである式(I)の化合物を投与することを含む。
さらに別の形態において上記方法のいずれも、TRPV1受容体アクチベーターの投与を含む。
本発明の他の形態及び利点は、以下の発明の詳細な説明から容易に明らかとなるであろう。
式(I)中のR2は、C1〜C6アルキルである。ある態様において、R2はCH3である。さらなる態様において、R2はCH2CH3である。さらに別の態様において、2つのR2基は一緒に連結されて、5又は6員環を形成する。
R3成分は、H又はC1〜C6アルキルである。ある態様において、R3はHである。別の態様において、R3はCH3である。
この構造において、R4、R5、R6、R7、及びR8は、独立に、H、任意に置換されたC1〜C6アルキル、任意に置換されたC1〜C6アルコキシ、ハロゲン、C1〜C3ペルフルオロアルキル、及びNO2から選択される。
v.さらに別の態様において、Aは、
これらの構造において、R9、R10、及びR11は、独立に、H、任意に置換されたC1〜C6アルキル、又はハロゲンである;及び、R12は、H又はC1〜C6アルキルである。
viii.さらに別の態様において、Aは、任意に置換されたチオフェンである。
xii.別の態様において、Aは任意に置換されたベンゾチオフェンである。
用語「ヘテロ原子」は、硫黄、窒素、又は酸素原子を指す。
式(I)の化合物は、注入のために又は局所鎮痛剤又は抗掻痒薬として使用される場合、グルコース又はデキストロースと組み合わせることができる。
また式(I)の化合物は、ゼリーを形成するために増粘剤と組み合わされるか、又は、泌尿生殖器の局所的な手順用のような局所又は経皮用途での使用のために、透過増強剤を含有してもよい。
口腔及び咽頭の局所麻酔用スプレー剤は、式(I)の化合物、サッカリン及び/又はアルコールを含有してもよい。
最後に、式(I)の化合物は、アクセス可能な粘膜への投与のための軟膏として製剤化することができる。
「中心性疼痛」は、脳の外傷、脳卒中、脊髄損傷の結果として生じる疼痛を含む。
「内臓痛」は、呼吸器や消化管及び膵臓、尿路及び生殖器などの内臓からの痛みを含む。ある態様において内臓痛は、器官被膜(organ capsule)の腫瘍浸潤から生じる。別の態様において内臓痛は、中空臓器の閉塞に起因する。さらなる態様において内臓痛は、膀胱炎又は逆流性食道炎のような炎症から生じる。
「機能不全性疼痛」は、神経系への侵害刺激、組織損傷又は病変が存在しない場合に発生する疼痛を指す。ある態様において、機能不全の疼痛は、関節炎及び線維筋痛、緊張型頭痛、過敏性腸障害、及び肢端紅痛症などのリウマチ症状から生じる疼痛を指す。
「片頭痛」とは、脳の髄膜を刺激する感覚線維の活性化に起因する。
疼痛−切迫性−高頻度症状スケールは、排尿障害、骨盤痛、及び性交に関連する症状のバランスの取れた評価であり、しばしば膀胱内塩化カリウム投与と組合せて使用される。
UWIは、頻度、切迫性、夜間頻尿、及び痛みについて7つのIC関連の質問を利用する。
カラムW:Zorbax(登録商標)Extend C18 カラム, 4.6 x 50 mm, 5μ
カラムX:Gemini(登録商標)NX C18 カラム, 4.6 x 50 mm, 5μ
カラムY:Xbridge(登録商標)C18 カラム, 4.6 x 50 mm, 5μ
カラムZ:Reprosil(登録商標)カラム, 4.6 x 50 mm, 5μ
Aチャネル:(i)0.05%ギ酸水溶液;
(ii)10mM酢酸アンモニウム水溶液;又は
(iii)0.05%TFA水溶液。
Bチャネル:アセトニトリル(有機相)。
1.LCMS反応モニタリングと最終化合物の分析法(一般的極性化合物)
勾配条件:5分の運転時間
時間プログラム:P1:10mM酢酸アンモニウム、水/アセトニトリル中
Q1:0.05%TFA、水/アセトニトリル中
R1:0.05%ギ酸、水/アセトニトリル中
勾配は、アセトニトリルが10%〜90%〜10%に変化した。
流速: 1.2mL/分。
勾配条件:12分の運転時間
時間プログラム:P2:10mM酢酸アンモニウム、水/アセトニトリル中
Q2:0.05%TFA、水/アセトニトリル中
R2:0.05%ギ酸、水/アセトニトリル中
勾配は、アセトニトリルが5%〜90%〜5%に変化した。
流速: 1.0mL/分。
質量スペクトルデータは以下を使用して得られた:
イオン化法: API(大気圧イオン化)源を使用するESI(電子噴霧イオン化)
デクラスタリング電位:化合物のイオン化に応じて10〜70V
質量範囲:100〜800amu
スキャンの種類: Q1
極性: +/−ve
イオン源: ターボ噴霧
イオン噴霧電圧: +モード用の5500、−モード用の−4500
質量源温度:200℃。
B.アセトニトリル又はメタノール(有機相)。
A.水中の0.05%TFA、水中の0.05%HCOOH
B.アセトニトリル。
エタノール(300ml)中の1−アミノ−2−プロパノール(15g,0.199モル)の溶液に、シクロヘキサノン(31.4mL,0.299モル)を加えた。反応混合物を0〜−10℃で10分間撹拌した。0℃で水素化ホウ素ナトリウム(10.8g,0.285モル)を、室温で15分間撹拌した。得られた反応混合物を水でクエンチし、Celite(登録商標)試薬に通して濾過し、溶媒を蒸発させた。残渣を2N HClに溶解し、酢酸エチルで洗浄した;水層のpHを飽和炭酸水素ナトリウム溶液を用いて8に調整した。化合物を酢酸エチルで抽出した。有機層を硫酸ナトリウム上で乾燥し、濃縮乾固し、粗物質をカラムクロマトグラフィーにかけて、1−(シクロヘキシルアミノ)プロパン−2−オールを得た。収率:22g(70.1%);1H NMR (400 MHz, DMSO-d6) δ 8.25 (bs, 1 H), 5.25 (bs, 1 H), 3.95-3.91 (m, 1 H), 2.89-2.88 (dd, J = 6, 9 Hz, 2 H), 2.71-2.66 (m, 1 H), 2.00-1.99 (m, 2 H), 1.75-1.72 (m, 2 H), 1.60-1.57 (m, 1 H), 1.36-0.93 (m, 8 H).。
THF(300ml)中の1−(シクロヘキシルアミノ)プロパン−2−オール(15g,95.5ミリモル)の溶液に、0℃でTEA(19.9mL,143.2ミリモル)を加えた。次にBoc無水物(22.8g,104.46ミリモル)を加えた。得られた反応混合物を室温で6時間攪拌した。反応混合物を水でクエンチし、酢酸エチルで希釈し、水及び食塩水で洗浄した。有機層を硫酸ナトリウムで乾燥させ、濃縮乾固した。粗化合物をカラムクロマトグラフィー(10〜15%酢酸エチル/ヘキサン)により精製して、tert−ブチルシクロヘキシル(2−ヒドロキシプロピル)カルバメートを得た。収率:16g(65%);1H NMR (400 MHz, CDCl3) δ 4.41-4.25 (bs, 1 H), 3.81-3.96 (m, 1 H), 3.71-3.59 (m, 1 H), 3.11-3.34 (m, 1 H), 2.99-3.02 (m, 1 H), 1.79-1.76 (m, 3 H), 1.68-1.64 (m, 1 H), 1.60 (m, 1H), 1.46-1.45 (s, 9 H), 1.37-1.26 (m, 4 H), 1.14-1.12 (d, J = 6 Hz, 3 H), 1.07-1.03 (m, 1H)。
無水トルエン(10ml)中のtert−ブチルシクロヘキシル(2−ヒドロキシプロピル)カルバメート(1g,3.89ミリモル)の溶液に、2,4,6−トリメチル−ベンゾイルクロリド(0.510mL,4.280ミリモル)を加えた。得られた反応混合物を室温で16時間撹拌した。反応混合物を酢酸エチルで希釈し、水及び食塩水で洗浄した。有機層を硫酸ナトリウムで乾燥させ、濃縮乾固して、1−((tert−ブトキシカルボニル)(シクロヘキシル)アミノ)プロパン−2−イル2,4,6−トリメチルベンゾエートを得た。収率:1g(64.10%);LCMS:m/z=404.4[M+H]、RT=2.76分、(カラム:Y、プログラム:P1)
1−((tert−ブトキシカルボニル)(シクロヘキシル)アミノ)プロパン−2−イル2,4,6−トリメチルベンゾエート(1.0g,2.48ミリモル)を、ジオキサン−塩酸(15mL)に溶解した。反応混合物を室温で2時間撹拌した。溶媒を蒸発させた。粗固体をDCE(10ml)とホルムアルデヒド(0.34mL,3.96ミリモル)に溶解し、及びトリアセトキシ水素化ホウ素ナトリウム(1.67g,7.92ミリモル)と酢酸(0.5mL)を0℃で加えた。得られた反応混合物を室温で16時間撹拌した。反応混合物をDCMで希釈し、1N NaOH、水及び食塩水で洗浄した。有機層を硫酸ナトリウムで乾燥し、濃縮乾固した。粗化合物をカラムクロマトグラフィーにより精製して、1−(シクロヘキシル(メチル)アミノ)プロパン−2−イル2,4,6−トリメチルベンゾエートを得た。収率:0.6(76%);1H NMR (400 MHz, CDCl3) δ 6.82 (s, 2 H), 5.27-5.25 (m, 1 H), 2.64-2.62 (m, 1 H), 2.51-2.46 (m, 1 H), 2.29 (s, 9 H), 2.25 (s, 3 H), 1.75-1.74 (m, 4 H), 1.33-1.31 (d, J = 6 Hz, 3 H), 1.18-1.13 (m, 4 H), 1.09-1.03 (m, 1H); LCMS:m/z=317.8[M+H]、RT=2.98分(カラム:X、プログラム:P1)。
DCE(5mL)中の1−(シクロヘキシル(メチル)アミノ)プロパン−2−イル2,4,6−トリメチルベンゾエート(0.30g,0.946ミリモル)の溶液に、ヨウ化メチル(0.12mL,1.892ミリモル)を加えた。得られた反応混合物を室温で16時間撹拌した。反応混合物をDCMで希釈し、濃縮乾固した。粗生成物をカラムクロマトグラフィーにかけて、N,N−ジメチル−N−[2−((2,4,6−トリメチルベンゾイル)オキシ)プロピル]シクロヘキサンアミニウムヨージドを得た。収率:0.109g(25%)。1H NMR (400 MHz, CDCl3) δ 6.86 (s, 2 H), 5.70-5.67 (m, 1 H), 4.52-4.48 (d, J = 14 Hz, 1 H), 3.83-3.77 (m, 1 H), 3.70-3.64 (m, 1 H), 3.34 (s, 3 H), 3.28 (s, 3 H), 2.29-2.01 (m, 10 H), 2.01-1.98 (m, 1 H), 1.84 (m, 1 H), 1.64-1.62 (d, J = 6 Hz, 4 H), 1.47-1.38 (m, 4 H), 1.13-1.08 (m, 2 H)。LCMS:m/z=332.2[M+]、RT=3.01分(カラム:Y、プログラム:P1)。HPLC:99.53%(200nm)、RT4.11分(移動相:A:ACN、B:水中の0.05%TFA、カラム:Zorbax(登録商標)SBC18(50*4.6mm)1.8μ。
エタノール(15mL)中の1−アミノ−2−プロパノール(1.0mL,13.31ミリモル)の撹拌溶液に、0℃でシクロヘキサノン(1.9g,19.9ミリモル)を加えた。反応混合物を0℃で15分間撹拌し、次にNaBH4(0.725g,19.17ミリモル)を加えた。反応混合物を室温で15分間攪拌し、次に水でクエンチした。反応混合物をCelite(登録商標)パッドを通して濾過し、濾液を濃縮した。残渣をDCMに溶解し、Na2SO4で乾燥させ、濾過し、濃縮して、1−(シクロヘキシルアミノ)プロパン−2−オールを得た。収率:2.6g(粗物質)。1H NMR (DMSO-d6) δ 4.39-4.36 (m, 1 H), 3.61-3.57 (m, 1 H), 2.47-2.30 (m, 3 H), 1.78-1.75 (m, 2 H), 1.66-1.63 (m, 2 H), 1.55-1.52 (m, 1 H), 1.23-1.12 (m, 3 H), 1.03-0.89 (m, 5 H)。1−(シクロヘキシルアミノ)プロパン−2−オールはまた、実施例1の手順に従って調製することができる。
DCE(30mL)中の1−(シクロヘキシルアミノ)−プロパン−2−オール(粗2.6g)の攪拌溶液に、HCHO(水中35%、2.1mL,24.8ミリモル)、Na(OAc)3BH(10.5g,49.6ミリモル)及び酢酸(1mL)を、氷冷条件で連続的に加えた。得られた混合物を室温で16時間撹拌した。反応物を酢酸エチルで希釈し、1N NaOHで塩基性化した。有機層を分離し、水及び食塩水で洗浄し、Na2SO4で乾燥させ、濾過し、濃縮した。粗物質をシリカゲル(230〜400メッシュ)のクロマトグラフィーにより5%MeOH/DCMで溶出して精製することにより、1−(シクロヘキシル(メチル)アミノ)プロパン−2−オールを得た。収率:1.0g、1H NMR (DMSO-d6) δ 4.11 (brs, 1 H), 3.65-3.57 (m, 1 H), 2.35-2.20 (m, 3 H), 2.19 (s, 3 H), 1.72-1.68 (m, 4 H), 1.57-1.54 (m, 1 H), 1.24-1.05 (m, 5 H), 1.01 (d, J = 6 Hz, 3 H)。
塩化チオニル(0.8mL,10.52ミリモル)を0℃で2−イソプロピル安息香酸(0.864g,5.26ミリモル)に加え、得られた混合物を3時間還流した。反応混合物を減圧下で濃縮して酸塩化物を得た。無水トルエン(15mL)中の酸塩化物の撹拌溶液に、0℃の無水トルエン(10mL)中の1−(シクロヘキシル(メチル)アミノ)プロパン−2−オール(0.75g,4.38ミリモル)の溶液を添加し、反応混合物を16時間還流した。反応混合物を酢酸エチルで希釈し、有機層を飽和NaHCO3、水及び食塩水で洗浄し、Na2SO4で乾燥させ、濾過し、濃縮した。粗物質をCombiflash(登録商標)クロマトグラフィーにより9〜11%の酢酸エチル/ヘキサンで溶出して、1−(シクロヘキシル(メチル)アミノ)プロパン−2−イル2−イソプロピルベンゾエートを得た。収率:0.88g(63.38%)。1H NMR (DMSO-d6) δ 7.56 (d, J = 8 Hz, 1 H), 7.51-7.44 (m, 2 H), 7.26 (t, J = 7 Hz, 1 H), 5.15-5.12 (m, 1 H), 3.61-3.54 (m, 1 H), 2.67-2.59 (m, 1 H), 2.33-2.31 (m, 1 H), 2.23 (s, 3 H), 1.71-1.67 (m, 4 H), 1.57-1.54 (m, 1 H), 1.25 (d, J = 6 Hz, 3 H), 1.21-1.05 (m, 11 H)。LCMS:m/z=318.4[M+H]、RT=2.51分(カラム:Y、プログラム:P1)
DCE(3mL)中の1−(シクロヘキシル(メチル)アミノ)プロパン−2−イル2−イソプロピルベンゾエート(0.45g,1.41ミリモル)の攪拌溶液に、ヨウ化メチル(0.35mL,5.67ミリモル)を加え、反応混合物を封管中で室温で16時間攪拌した。反応混合物を濃縮し、粗物質をCombiflash(登録商標)クロマトグラフィーにより3〜4% CH3OH/DCMで溶出して固体を得て、これをメタノール−エーテルから結晶化して、白色のN−[2−((2−イソプロピルベンゾイル)オキシ)プロピル]−N,N−ジメチルシクロヘキサンアミニウムヨージドを得た。収率:0.415g(64%)。1H NMR (DMSO-d6) δ 7.71 (d, J = 8 Hz, 1 H), 7.58-7.50 (m, 2 H), 7.31 (t, J = 7 Hz, 1 H), 5.57-5.54 (m, 1 H), 3.93-3.87 (m, 1 H), 3.67-3.57 (m, 2 H), 3.38-3.34 (m, 1 H), 3.05 (s, 3 H), 3.02 (s, 3 H), 2.17-2.08 (m, 2 H), 1.87-1.84 (m, 1 H), 1.75-1.72 (m, 1 H), 1.54-1.42 (m, 3 H), 1.40 (d, J = 6 Hz, 3 H), 1.24-1.19 (m, 7 H), 1.13-0.99 (m, 2 H)。LCMS:m/z=332.0[M+]、RT=3.01分、(カラム:Y、プログラム:P1)。UPLC:98.43%(200nm)、RT=3.60分(移動相A、水中の0.05%TFA、B、アセトニトリル;カラム:Zorbax(登録商標)SB−C18(4.6×50mm)1.8μ)
DCE(20mL)中の安息香酸2−シクロヘキシルアミノ−1−メチル−エチルエステル(1.0g,3.8ミリモル)の撹拌溶液に、K2CO3(2.11g,15.2ミリモル)及びヨウ化エチル(1.8mL,22ミリモル)を連続して添加した。得られた混合物を封管中で50℃で16時間加熱した。ヨウ化エチル(1.8mL)を再度加え、反応混合物をさらに60℃で24時間加熱した。反応混合物を濾過し、5%メタノール−DCMで洗浄した。濾液を濃縮し、粗物質をCombiflash(登録商標)クロマトグラフィーにより6〜7%メタノール/DCMで溶出して、1−(シクロヘキシル(エチル)アミノ)プロパン−2−イルベンゾエートを得た。収率:1.04g(94.70%)。1H NMR (DMSO-d6) δ 7.95 (d, J = 7 Hz, 2 H), 7.64 (t, J = 7 Hz, 1 H), 7.52 (t, J = 8 Hz, 2 H), 5.08-5.04 (m, 1 H), 2.68-2.62 (m, 1 H), 2.55-2.40 (m, 4 H), 1.70-1.53 (m, 5 H), 1.26 (d, J = 6 Hz, 3 H), 1.19-1.07 (m, 5 H), 0.93 (t, J = 7 Hz, 3 H)。LCMS:m/z=290.4[M+H]、RT=3.93分、(カラム:Y、プログラム:P1)
乾燥DCM(20mL)中の1−(シクロヘキシル(エチル)アミノ)プロパン−2−イルベンゾエート(0.427g,1.47ミリモル)の撹拌溶液に、エチルトリフレート(0.25mL,1.92ミリモル)を氷冷条件下で滴下して添加した。得られた混合物を、封管中で室温で16時間攪拌した。反応混合物を濃縮し、粗物質をCombiflash クロマトグラフィーにより3〜4%メタノール/DCMで溶出して、粘性の液体を得た。アンバーライト(登録商標)IRA−400(Cl)の塩化物型樹脂(3.0g)を、メタノール(15mL)中の液体化合物(15)の溶液に添加し、6時間攪拌した。次に溶液を濾過し、濃縮し、凍結乾燥して固体を得た。フッ素NMRスペクトルは不完全な対イオン交換を示したため、固体を再び水中のアンバーライト(登録商標)IRA−400(Cl)の塩化物型樹脂で処理し、濾過した。濾液を濃縮し、粗物質を凍結乾燥して、N−[2−(ベンゾイルオキシ)プロピル]−N,N−ジエチルシクロヘキサンアミニウムクロリドをオフホワイト色の固体として得た。収率:0.05g(9.62%)。1H NMR (DMSO-d6) δ 7.98 (d, J = 8 Hz, 2 H), 7.68 (t, J = 7 Hz, 1 H), 7.54 (t, J = 8 Hz, 2 H), 5.52-5.49 (m, 1 H), 3.95-3.89 (m, 1 H), 3.55 (d, J = 15 Hz, 1 H), 3.44-3.35 (m, 5 H), 2.19-2.17 (m, 1 H), 2.09-2.06 (m, 1 H), 1.80-1.78 (m, 2 H), 1.54-1.51 (m, 3 H), 1.36 (d, J = 6 Hz, 3 H), 1.25-1.07 (m, 9 H)。LCMS:m/z=318.0[M+]、RT=2.88分、(カラム:Y、プログラム:P1)。UPLC:98.70%(200nm)で、RT=3.59分、(移動相A、水中0.05%TFA、B、アセトニトリル;カラム:Zorbax(登録商標)SB−C18(4.6×50mm)1.8μ)
DCM(10mL)中の4−イソプロピル−安息香酸(1g,6.09ミリモル)の溶液に、クロロギ酸イソブチル(0.7mL,7.31ミリモル)を−20℃〜−30℃で添加した。反応混合物を、同じ温度で30分攪拌して、混合無水物の溶液を得た。別の丸底フラスコに、1−(シクロヘキシル(メチル)アミノ)プロパン−2−オール(1.04g,6.09ミリモル)をDCM(15mL)に溶解し、TEA(2.1mL,15.24ミリモル)を加えた。この反応混合物に、得られた混合酸無水物溶液を0℃で加えた。得られた反応混合物を同じ温度で45分間撹拌した。反応混合物をDCMで抽出し、水及び食塩水で洗浄した。有機層を硫酸ナトリウムで乾燥し、濃縮乾固した。粗固体をカラムクロマトグラフィーを用いて精製して、1−(シクロヘキシル(メチル)アミノ)プロパン−2−イル4−イソプロピルベンゾエートを得た。収率:0.6g(32.4%)。1H NMR (400 MHz, CDCl3) δ 7.95-7.93 (d, J = 8 Hz, 2 H), 7.27-7.25 (d, J = 8 Hz, 2 H), 5.20-5.18 (m, 1 H), 2.96-2.92 (m, 1 H), 2.72-2.67 (m, 1 H), 2.53-2.48 (m, 1 H), 2.33-2.28 (m, 4 H), 1.76-1.74 (bs, 4 H), 1.32-1.30 (d, J = 6 Hz, 3 H), 1.25 (bs, 6 H), 1.24-1.18 (m, 5 H)。
DCE(5mL)中の1−(シクロヘキシル(メチル)アミノ)プロパン−2−イル4−イソプロピルベンゾエート(0.5g,1.57ミリモル)の溶液に、ヨウ化メチル(0.2mL,3.15ミリモル)を加えた。得られた反応混合物を室温で16時間攪拌した。溶媒を蒸発させ、粗生成物をカラムクロマトグラフィーにより精製した。単離された生成物を、メタノール/エーテルから再結晶化した。収率:134.9mg(18.65%)。1H NMR (400 MHz, DMSO-d6) δ 7.94-7.92 (d, J = 8 Hz, 2 H), 7.43-7.41 (d, J = 8 Hz, 2 H), 5.54-5.50 (m, 1 H), 3.95-3.89 (m, 1 H), 3.61-3.58 (d, J = 14 Hz, 1 H), 3.40-3.34 (m, 1 H), 3.03-2.95 (m, 7 H), 2.22-2.20 (d, J = 11 Hz, 1 H), 2.10-2.07 (d, J = 11 Hz, 1 H), 1.86-1.83 (m, 2 H), 1.57-1.43 (m, 3 H), 1.36-1.35 (d, J = 6 Hz, 3 H), 1.16-1.11 (m, 9 H)。LCMS:m/z=331.8[M+]、RT=3.08分(カラム:Y、プログラム:P1)。UPLC:99.65%(200nm)、室温3.09分(移動相:A.ACN、B.水中の0.05% HCOOH、カラム:Gemini(登録商標)NXC18(50×4.6mm)3μ。
無水THF(700ml)中の(S)−1−(シクロヘキシル(メチル)アミノ)プロパン−2−オール(38.0g,222.22ミリモル)の攪拌溶液に、0℃でNaH(油中60%、9.77g,244.22ミリモル)を加え、室温で20分間攪拌した。次に、4−tert−ブチルベンゾイルクロリド(52.1ml、266.67ミリモル)を0℃を添加し、反応混合物を室温で4時間撹拌した。反応混合物を飽和NH4Cl溶液でクエンチし、酢酸エチルで希釈した。有機層を水及び食塩水で洗浄し、Na2SO4で乾燥させ、濾過し、濃縮した。粗物質を中性アルミナ上のクロマトグラフィーにより4〜0%酢酸エチル−ヘキサンで溶出して、粘性の化合物1−(シクロヘキシル(メチル)アミノ)プロパン−2−イル4−(tert−ブチル)ベンゾエートを得た。収率:26.0g(35.7%)。1H NMR (DMSO-d6) δ 7.86 (d, J = 8 Hz, 2 H), 7.52 (d, J = 8 Hz, 2 H), 5.12-5.07 (m, 1 H), 2.66-2.61 (m, 1 H), 2.46 (d, J = 5 Hz, 1 H), 2.31-2.28 (m, 1 H), 2.24 (s, 3 H), 1.68-1.65 (m, 4 H), 1.55-1.53 (m, 1 H), 1.29 (s, 9 H), 1.25 (d, J = 6 Hz, 3 H), 1.18-1.02 (m, 5 H); LCMS:m/z=332.2[M+H]、RT=2.85分、(カラム:Y、プログラム:P1)
DCE(150ml)中の1−(シクロヘキシル(メチル)アミノ)プロパン−2−イル4−(tert−ブチル)ベンゾエート(22.5g,67.98ミリモル)の攪拌溶液に、臭化メチル(トルエン中25%溶液、103ml、271.90ミリモル)を加え、反応混合物を室温で16時間撹拌した。TLCは、非常に少量の未反応の出発材料を示した。そのため、別の0.5当量の臭化メチルを加え、室温で8時間攪拌した。反応混合物を濃縮し、粗物質を中性アルミナ上のクロマトグラフィーにより2〜8%メタノール−DMCで溶出して、オフホワイトの固体を得た。固体材料をDCM−エーテルから結晶化して、[2−(4−(tert−ブチル−ベンゾイルオキシ)プロピル]−シクロヘキシル−ジメチル−アンモニウムブロミドを得た。収率:15.5g(53.5%)。1H NMR (DMSO-d6) δ 7.94 (d, J = 8 Hz, 2 H), 7.57 (d, J = 8 Hz, 2 H), 5.54-5.51 (m, 1 H), 3.93 (dd, J = 15, 9 Hz, 1 H), 3.63 (d, J = 14 Hz, 1 H), 3.42-3.36 (m, 1 H), 3.05 (s, 6 H), 2.23-2.20 (m, 1 H), 2.11-2.08 (m, 1 H), 1.87-1.83 (m, 2 H), 1.57-1.43 (m, 3 H), 1.36 (d, J = 6 Hz, 3 H), 1.30 (s, 9 H), 1.23-1.08 (m, 3 H); LCMS:m/z=346.4[M+]、RT=3.00分、(カラム:Y、プログラム:P1)。UPLC:99.90%(200nm)、RT=4.04分(移動相A.水中の0.05%TFA、B.アセトニトリル;カラム:Zorbax(登録商標)SB−C18(4.6×50mm)1.8μ)。
hTRPV1を発現する細胞で、熱(47℃)による刺激後に、化合物を用いてナトリウムチャネル応答の抑制を評価するためのインビトロアッセイを開発した。
インビボアッセイでのさらなる評価に進むであろう化合物を選択することを補助する予備スクリーンとして、以下の細胞が開発された。
(i)hTRPV1を細胞に送達するためのプラスミド
細胞株を調製するために、ヒト神経芽腫細胞株IMR322[NCBI dbEST ID:18353]に基づくcDNAライブラリーからPCRにより、以下のプライマーを使用して、hTRPV1をコードする読みとり枠を増幅した:
(a)TRPV1_KpnIF(前進プライマー)[配列番号2]
5’-ATAAACGGTACCGCCGCCACCATGAAGAAATGGAGCAGCAC-3’
(b)TRPV1_PmeIR(逆進プライマー)[配列番号3]
5’-ATCGGTTTAAACTCACTTCTCTCCGGAAGCGGC-3’
前進プライマーは、KpnI部位[GGTACC(上記(a)で下線を引いてある]とコザック配列[GCCGCCACC((a)で2重下線を引いてある]を含む。逆進プライマーは、PmeI部位[GTTTAAAC,(b)で下線を引いてある]を含む。
hTRPV1の読みとり枠(NCBI NM_080706.3に対応する)は、配列番号4である:
TGA:遺伝子の停止コドン(ORFの最後)
GGG→GGA:逆進プライマー中のふらつき(グリシンからグリシン)
ATG→ATC:Genecardで報告された単一ヌクレオチド多型(SNP)、Met−−−>Ile,SNP ID:rs222747。
以下の材料がこの方法のために使用された:
リポフェクタミン2000(Invitrogen, Cat # 11668-019)、ポリエチレンイミン(Aldrich, Cat # J40872)、ヒグロマイシン−B(Invitrogen, Cat# 10687-010)。Ultra pureキットによりスーパーコイルドDNAが調製され、トランスフェクションは抗生物質不含無血清DMEMで行われた。
細胞を継代するために、上記のように上記の細胞継代プロトコールを行った、限界希釈法によるクローン単離は、以下のように行った。
カルシウムアッセイのために、細胞を、384透明底ポリ−D−リジン被覆プレート中のウェル当たり50μlのDMEM+10%FBS+300μg/mLヒグロマイシンにつき、5000個をプレーティングし、37℃、5%CO2で48時間インキュベートした。アッセイの日に、静かに培地を捨て、修飾タイロード(Tyrodes)(登録商標)緩衝液(20μL/ウェル)で洗浄し、次にこれを静かに捨てた。表3を参照。
384透明底ポリ−D−リジン被覆プレート中のウェル当たり50μl[DMEM+10%FBS+300μg/mL H\ヒグロマイシン]につき、細胞5000個をプレーティングし、37℃、5%CO2で48時間インキュベートした。アッセイの日に、静かに培地を捨て、ウェル当たり30μLの色素[FMPブルー色素をアッセイ緩衝液で調製した]を加え、室温で20分間、色素ローディングを進行させた。製造業者の説明書に従ってFLIPR(登録商標)装置のための、「アゴニスト」薬剤添加プレートを調製した。このプレートは、ベラチジン(Sigma-Aldrich, Cat No V5754)とアネモニア・スルカータ(Anemonia sulcata)からのトキシン-II(ATX-II, Sigma-Aldrich Cat No T3268)を含有した。FLIPR装置を使用して10μLの組合せ溶液を細胞プレートに分注した時、100μMと3μMの最終アッセイ濃度が達成できるように、薬剤添加プレート中のベラトリジンとATX−IIの濃度は、それぞれ400μMと12μMであった。蛍光シグナルの読みの開始と一致するように、そしてそのような読みが10分間の継続中規則的な間隔で取れるように、アゴニスト添加をFLIPR(登録商標)でプログラムした。
175mLのフラスコ(Nunc)中で増殖培地[1×DMEM(Sigma)+10%FBS(Gibco)+1%ペニシリン−ストレプトマイシン(Gibco)+300μg/mLヒグロマイシンB(Invitrogen、選択マーカーとして)を含有する]中で培養することにより、hTRPV1−N1E115を継代した。細胞を1:10に分割した。フラスコからの使用済み培地を吸引し、手のひらでフラスコの側面をたたいて、フラスコの底から細胞をはがした。増殖培地(10mL)を加えて細胞を懸濁し、増殖培地(35mL)を含む新鮮なT−175フラスコに懸濁細胞(1mL)を接種した。アッセイ用の細胞のプレーティングのために、50μLの増殖培地中の5000細胞を、蓋(Greiner-bio one)が層流空気中にある384ウェルの透明底の無菌ポリ−D−リジン被覆プレートの各ウェルに加えた。プレートをCO2インキュベーター(Thermo)中で37℃、5%CO2でインキュベートした。48時間後、アッセイの日に、細胞接種プレートを顕微鏡で観察して、アッセイの前に単層の健康、付着、及びコンフルエンスをチェックした。
主要な心臓ナトリウムチャネルアイソフォームを遮断する試験化合物の傾向を評価するために、以下のアッセイを使用した。Nav1.5ナトリウムチャンネルは、例えばQX−314のような4級ナトリウムチャネル遮断薬に対して透過性であることが知られており、従って、このアッセイは、化学的TRPV1アゴニストの非存在下で行われた。
このアッセイは、化合物が、単独で又はリドカインと組合せて坐骨神経の近傍に直接注射された時の、鎮痛の経時変化を追跡するために実施された。
上記で得られた要約とアッセイを使用して、以下の表8の製剤を調製し試験した。これらのアッセイの結果は図1と2に示され、以下の表に要約される。具体的には、図1と2は、足引っ込め/発声力(g)対時間(時間)のプロットである。
注射液は、上記に従って調製し、(i)0.5%の実施例6の化合物と2%のリドカインとを含む溶液100μlと、(ii)0.5%の実施例6の化合物と2%のリドカインとを含む溶液200μlを含んだ。これらの注射液を上記したように投与し、こうして、100μl対200μl容量の製剤の影響の解析を可能にした。
試験溶液のアリコート(0.25mL)を、意識あるウサギ(両方の性、2〜4kg)の結膜嚢に適用し、目蓋を約20秒間閉じて維持した。試験溶液の塗布前及びその後5分毎に、角膜反射がチェックされる。角膜反射を試験するために、柄のある弾性剛毛で角膜を6回タッチする。麻酔の持続時間は、剛毛による6回のタッチのいずれも感じない時点から、6回のタッチの3つに動物が反応する時点までの期間として計算される。局所麻酔効果の可逆性を検証するために、動物が少なくとも15分間毛のすべての6回のタッチに反応するまで、試験が続行される。
実施例53:皮膚麻酔活性
各実施例の約18〜24時間前に、オスのモルモットの背中の皮膚の毛を剃り、市販の毛リムーバーで脱毛する。経皮適用後の各薬剤の麻酔作用は、Aberg (Acta Pharmacol Toxicol, 273-286) に記載されたように「ピンプリック」法を用いて決定される。処理前及び処理後の種々の間隔で、皮膚の領域が、10gの所定の最大負荷時で尖った金属の「痛覚計」を用いて、6回の標準化された皮膚プロービングに応答した皮膚収縮の有無について試験される。皮膚の収縮応答を生成しないプロービングの平均数を「麻酔薬スコア」とする。
各実験前の約18〜24時間、雄のモルモットの背中の皮膚を、実施例53に従って準備する。皮内注射後の各薬剤の麻酔作用は、実施例53に記載の方法と同様の「ピンプリック(pin-prick)」法を用いて測定される。処理前及び処理後の種々の間隔で、皮膚の領域が、20gの所定の最大負荷で尖った金属の「痛覚計」を用いて、6回の標準化された皮膚プロービングに応答した皮膚収縮の有無について試験される。皮膚の収縮応答を生成しないプロービングの平均数が、「麻酔薬スコア」として指定される。このシステムで6回の刺激に対して6回の応答は「麻酔薬活性無し」を表し、6回の刺激に対して応答が無いことは、「最大麻酔活性」を表す。薬剤の皮内注射を用いた実験において、モルモットの背中はマーキングペンを使用して4つのセクションに分割され、4つの分割された領域のそれぞれに1回、生理食塩水中の試験化合物、ビヒクル(生理食塩水)、及び少なくとも1つの参照化合物の0.25%、0.5%、及び1.0%溶液の0.1mLの注射が行われる。
試験施設での少なくとも10日間と実験室での少なくとも1時間の安定化期間の後、NMRI系統ののマウス(雄)(体重20〜22g)が使用される。試験前16時間は、すべての動物に水以外の食物は与えられない。薬剤投与の2時間後からは、動物は食物に自由にアクセスでき、これは、ほぼ午前9.00頃である。すべての動物は、投与後7日間、毎日観察される。
この試験は、孤立した排尿筋の収縮応答に対する本明細書に記載の試験化合物の作用を評価する(Iravani & Zar, British Journal of Pharmacology 1994, 113: 95-102)。
膀胱平滑筋片は、雌モルモットから得られる(Dunkin-Hartley系統、体重300〜350g)。膀胱片を調製し、クレブス−ヘンゼライト溶液(95%O2/5%CO2のガスを供給して37℃、pH7.4で維持される)を含有する5mlの臓器浴中で張力変換器に接続される。片は、1.0gの静止張力で少なくとも60分間平衡化され、その間組織は15分毎に洗浄される。次に、各片は、生存率を確認するために80mM KClに暴露される。30分の期間の平衡化とウォッシュアウト期間後、排尿筋片は電界刺激(EFSパラメータ:800mA、周波数15Hz、パルス持続時間0.1ms、2分毎に4秒のパルス列)に供される。
リドカインと本明細書に記載の化合物の両方とも、EFS誘導性排尿筋収縮の濃度依存的抑制を生じることが予想される。また、リドカインと試験化合物の組み合わせに排尿筋組織を暴露することは、濃度−抑制関係を引き起こしことが予測され、これは、2つの薬剤が付加的に作用して収縮応答を抑制することを示唆する。
この例は、EFS誘導性膀胱収縮の抑制における本明細書に記載の化合物の持続性を示すために実施された。
EFS処理した膀胱平滑筋片が、実施例58の第1段落に記載のように調製される。約20〜25分(安定化)後、リドカインの単一濃度(0.01又は0.003%)、本明細書に記載の化合物(0.01%又は0.0004%)又は溶媒が添加される。最大作用(約15分)を得た後、すべての調製物は4回洗浄される。次にEFS誘導性収縮が、120分間記録される。回復期間中のEFS誘導性収縮の大きさは、基礎EFS誘導性収縮(処理前)の%として表される。分析は、休薬期間の終了後5分、15分、30分、60分、及び120分に行われる。
データは、試験化合物が膀胱排尿筋に作用して収縮を抑制し、この作用は逆転するのに時間がかかるであろうことを示唆すると予測される。
この試験は、意識のあるラットにおいて膀胱機能の様々な面について本明細書に記載の化合物の作用を評価する。
ラットは、ドームを通って膀胱内に配置された留置ポリエチレンカテーテルを用いて準備され、肩甲骨のレベルで体外に出る。膀胱内圧力は、溶液及び薬物の注入を可能にするT−コネクタを介して、市販の歪みゲージにカテーテルを接続することによって追跡される。膀胱内圧記録は、カテーテル移植後48時間以内に開始されるであろう。動物は、連続的に2mL/時の速度でカテーテルを介して、試験化合物有り又は無しで生理食塩水を投与される。尿を採取し、力変換器を用いて計量し、膀胱内圧を連続的に追跡して、排尿振幅、排尿頻度、排尿量及び膀胱容量を評価する。生理食塩水灌流物に試験化合物を補充して、上記の膀胱機能パラメータのそれぞれに対する作用を測定する。
Claims (30)
- 式(I):
R1は、H又はC1〜C6アルキルであり;
R2は、C1〜C6アルキルであり;
又は、2つのR2は、一緒に連結されて、5又は6員環を形成し;
Yは、O又はCHR3であり;
R3は、H又はC1〜C6アルキルであり;
Aは、任意に置換されたフェニル、任意に置換されたヘテロアリール、又は任意に置換されたシクロアルキルであるが、ただし、Aが置換されていないフェニルである場合、R1及びR2はメチルではなく、かつR3はHではなく、また、Aはトリメトキシフェニルではなく;
Xは、塩素、臭素、ヨウ素、トリフルオロ酢酸塩、硫酸塩、リン酸塩、酢酸塩、フマル酸塩、マレイン酸塩、クエン酸塩、ピルビン酸塩、コハク酸塩、シュウ酸塩、スルホン酸塩、重硫酸塩、マロン酸塩、キシナホ酸塩、アスコルビン酸塩、オレイン酸塩、ニコチン酸塩、サッカリン酸塩、アジピン酸塩、蟻酸塩、グリコール酸塩、L−乳酸塩、D−乳酸塩、アスパラギン酸塩、リンゴ酸塩、L−酒石酸塩、D−酒石酸塩、ステアリン酸塩、2−フロ酸塩、3−フロ酸塩、ナパジシル酸塩、エジシル酸塩、イセチオン酸塩、D−マンデル酸塩、L−マンデル酸塩、プロピオン酸塩、酒石酸塩、フタル酸塩、塩酸塩、臭化水素酸塩、硝酸塩、メタンスルホン酸塩、ナフタレンスルホン酸塩、ベンゼンスルホン酸塩、トルエンスルホン酸塩、樟脳スルホン酸塩、又はトリフルオロメタンスルホン酸塩である]
の化合物、又はその医薬として許容される塩を含む、少なくとも1つの剤型であるナトリウムチャネル遮断薬;あるいは
式(I):
R 1 は、CH 3 であり;
R 2 は、C 1 〜C 6 アルキルであり;
又は、2つのR 2 は、一緒に連結されて、5又は6員環を形成し;
Yは、O又はCHR 3 であり;
R 3 は、H又はC 1 〜C 6 アルキルであり;
Aは、任意に置換されたフェニル、任意に置換されたヘテロアリール、又は任意に置換されたシクロアルキルであるが、ただし、Aが置換されていないフェニルである場合、R 1 及びR 2 はメチルではなく、かつR 3 はHではなく;
Xは、塩素、臭素、ヨウ素、トリフルオロ酢酸塩、硫酸塩、リン酸塩、酢酸塩、フマル酸塩、マレイン酸塩、クエン酸塩、ピルビン酸塩、コハク酸塩、シュウ酸塩、スルホン酸塩、重硫酸塩、マロン酸塩、キシナホ酸塩、アスコルビン酸塩、オレイン酸塩、ニコチン酸塩、サッカリン酸塩、アジピン酸塩、蟻酸塩、グリコール酸塩、L−乳酸塩、D−乳酸塩、アスパラギン酸塩、リンゴ酸塩、L−酒石酸塩、D−酒石酸塩、ステアリン酸塩、2−フロ酸塩、3−フロ酸塩、ナパジシル酸塩、エジシル酸塩、イセチオン酸塩、D−マンデル酸塩、L−マンデル酸塩、プロピオン酸塩、酒石酸塩、フタル酸塩、塩酸塩、臭化水素酸塩、硝酸塩、メタンスルホン酸塩、ナフタレンスルホン酸塩、ベンゼンスルホン酸塩、トルエンスルホン酸塩、樟脳スルホン酸塩、又はトリフルオロメタンスルホン酸塩である]
の化合物、又はその医薬として許容される塩を含む、少なくとも1つの剤型であるナトリウムチャネル遮断薬、並びに
式(I)の化合物を、それを必要とする患者に投与するステップを含む治療のための指示書
を含む、ナトリウムチャネル遮断のために用いられるキット。 - R1がHである、請求項1に記載のキット。
- R1がCH3である、請求項1に記載のキット。
- R2がCH3である、請求項1に記載のキット。
- R2がCH2CH3である、請求項1に記載のキット。
- YがOである、請求項1に記載のキット。
- YがCHR3である、請求項1に記載のキット。
- R3がHである、請求項7に記載のキット。
- R3がCH3である、請求項7に記載のキット。
- R4、R5、R6、R7、及びR8が、独立に、OCH3、CH3、CH2CH3、CH(CH3)2、C(CH3)3、Cl、F、CF3、及びNO2からなる群から選択される、請求項11に記載のキット。
- Aが任意に置換されたピロールである、請求項1に記載のキット。
- R12がCH3である、請求項15に記載のキット。
- Aが任意に置換されたチオフェンである、請求項1に記載のキット。
- R15がCH3である、請求項19に記載のキット。
- Aが、任意に置換されたベンゾチオフェンである、請求項1に記載のキット。
- R17がハロゲンである、請求項23に記載のキット。
- 化合物が、
N−[2−((2,6−ジメチルベンゾイル)オキシ)プロピル]−N,N−ジメチルシクロヘキサンアミニウムヨージド;
N−[2−(ベンゾイルオキシ)プロピル]−N,N−ジエチルシクロヘキサンアミニウムクロリド;
N,N−ジメチル−N−[2−((2,4,6−トリメチルベンゾイル)オキシ)プロピル]シクロヘキサンアミニウムヨージド;
N−[2−((2,6−ジメトキシベンゾイル)オキシ)プロピル]−N,N−ジメチルシクロヘキサンアミニウムヨージド;
N−[2−((2−フルオロベンゾイル)オキシ)プロピル]−N,N−ジメチルシクロヘキサンアミニウムヨージド;
N−[2−((2−クロロベンゾイル)オキシ)プロピル]−N,N−ジメチルシクロヘキサンアミニウムヨージド;
N−[2−((2,4−ジクロロベンゾイル)オキシ)プロピル]−N,N−ジメチルシクロヘキサンアミニウムヨージド;
N,N−ジメチル−N−[2−((2−メチルベンゾイル)オキシ)プロピル]シクロヘキサンアミニウムヨージド;
N−[2−((2−イソプロピルベンゾイル)オキシ)プロピル]−N,N−ジメチルシクロヘキサンアミニウムヨージド;
N−[2−((4−(tert−ブチル)ベンゾイル)オキシ)プロピル]−N,N−ジメチルシクロヘキサンアミニウムヨージド;
N−[2−((4−クロロベンゾイル)オキシ)プロピル]−N,N−ジメチルシクロヘキサンアミニウムヨージド;
N−[2−((3−フルオロベンゾイル)オキシ)プロピル]−N,N−ジメチルシクロヘキサンアミニウムヨージド;
N−[2−((4−フルオロ−2−(トリフルオロメチル)ベンゾイル)オキシ)プロピル]−N,N−ジメチルシクロヘキサンアミニウムヨージド;
N,N−ジメチル−N−[2−((3−(トリフルオロメチル)ベンゾイル)オキシ)プロピル]シクロヘキサンアミニウムヨージド;
N−[2−((2−(トリフルオロメチル)ベンゾイル)オキシ)プロピル]−N,N−ジメチルシクロヘキサンアミニウムヨージド;
N,N−ジメチル−N−[2−((2−ニトロベンゾイル)オキシ)プロピル]シクロヘキサンアミニウムヨージド;
N−[2−((3,5−ジクロロベンゾイル)オキシ)プロピル]−N,N−ジメチルシクロヘキサンアミニウムヨージド;
N−[2−((4−エチルベンゾイル)オキシ)プロピル]−N,N−ジメチルシクロヘキサンアミニウムヨージド;
N,N−ジメチル−N−[2−((4−(トリフルオロメチル)ベンゾイル)オキシ)プロピル]シクロヘキサンアミニウムヨージド;
(S)−N,N−ジメチル−N−[2−((2,4,6−トリメチルベンゾイル)オキシ)プロピル]シクロヘキサンアミニウムヨージド;
(S)−N−[2−((2,6−ジメチルベンゾイル)オキシ)プロピル]−N,N−ジメチルシクロヘキサンアミニウムヨージド;
(R)−N−[2−((2,6−ジメチルベンゾイル)オキシ)プロピル]−N,N−ジメチルシクロヘキサンアミニウムヨージド;
(R)−N,N−ジメチル−N−[2−((2,4,6−トリメチルベンゾイル)オキシ)プロピル]シクロヘキサンアミニウムヨージド;
N−[2−((3−イソプロピルベンゾイル)オキシ)プロピル]−N,N−ジメチルシクロヘキサンアミニウムヨージド;
N−[2−((2,6−ジクロロベンゾイル)オキシ)プロピル]−N,N−ジメチルシクロヘキサンアミニウムヨージド;
N,N−ジメチル−N−[2−((2,4,6−トリメチルベンゾイル)オキシ)プロピル]テトラヒドロ−2H−ピラン−4−アミニウムヨージド;
N−[2−((2,3−ジクロロベンゾイル)オキシ)プロピル]−N,N−ジメチルシクロヘキサンアミニウムヨージド;
N−[2−((シクロヘキサンカルボニル)オキシ)プロピル]−N,N−ジエチルシクロヘキサンアミニウムヨージド;
N−[2−((3−クロロベンゾ[b]チオフェン−2−カルボニル)オキシ)プロピル]−N,N−ジメチルシクロヘキサンアミニウムヨージド;
N,N−ジメチル−N−[2−((チオフェン−2−カルボニル)オキシ)プロピル]シクロヘキサンアミニウムヨージド;
N−[2−((4−イソプロピルベンゾイル)オキシ)プロピル]−N,N−ジメチルシクロヘキサンアミニウムヨージド;
N,N−ジメチル−N−[2−((チオフェン−3−カルボニル)オキシ)プロピル]シクロヘキサンアミニウムヨージド;
N,N−ジメチル−N−[2−((1−メチル−1H−ピロール−2−カルボニル)オキシ)プロピル]シクロヘキサンアミニウムヨージド;
N−[2−((ベンゾ[b]チオフェン−2カルボニル)オキシ)プロピル]−N,N−ジメチルシクロヘキサンアミニウムヨージド;
N−[2−((2,6−ジメチルベンゾイル)オキシ)プロピル]−N,N,4−トリメチルシクロヘキサンアミニウムヨージド;
N,N−ジメチル−N−[2−((3−メチルチオフェン−2−カルボニル)オキシ)プロピル]シクロヘキサンアミニウムヨージド;
N−[2−((4−(tert−ブチル)ベンゾイル)オキシ)プロピル]−N,N,4−トリメチルシクロヘキサンアミニウムヨージド;
N,N,4−トリメチル−N−[2−((2,4,6−トリメチルベンゾイル)オキシ)プロピル]シクロヘキサンアミニウムヨージド;
N−[2−((2,6−ジメチルベンゾイル)オキシ)エチル]−N,N−ジメチルシクロヘキサンアミニウムヨージド;
N−[2−((2,4,6−トリメチルベンゾイル)オキシ)エチル]−N,N−ジメチルシクロヘキサンアミニウムヨージド;
N,N−ジメチル−N−[2−((4−メチルベンゾイル)オキシ)プロピル]シクロヘキサンアミニウムヨージド;
N−[2−((4−(tert−ブチル)ベンゾイル)オキシ)エチル]−N,N−ジメチルシクロヘキサンアミニウムヨージド;
N−[2−((2−エチルベンゾイル)オキシ)プロピル]−N,N−ジメチルシクロヘキサンアミニウムヨージド;
N−[2−((2,4−ジメチルベンゾイル)オキシ)プロピル]−N,N−ジメチルシクロヘキサンアミニウムヨージド;
(S)−N−[2−((4−(tert−ブチル)ベンゾイル)オキシ)プロピル]−N,N−ジメチルシクロヘキサンアミニウムヨージド;
(R)−N−[2−((4−(tert−ブチル)ベンゾイル)オキシ)プロピル]−N,N−ジメチルシクロヘキサンアミニウムヨージド;
(S)−N−[2−((4−(tert−ブチル)ベンゾイル)オキシ)プロピル]−N,N−ジメチルシクロヘキサンアミニウムブロミド;
(R)−N−[2−((4−(tert−ブチル)ベンゾイル)オキシ)プロピル]−N,N−ジメチルシクロヘキサンアミニウムブロミド;
1−シクロヘキシル−1−[2−((2−イソプロピルベンゾイル)オキシ)プロピル]ピロリジン−1−イウムブロミド;
1−シクロヘキシル−1−[2−((2−イソプロピルベンゾイル)オキシ)プロピル]ピペリジン−1−イウムブロミド;
1−[2−((4−(tert−ブチル)ベンゾイル)オキシ)プロピル]−1−シクロヘキシルピロリジン−1−イウムブロミド;
1−[2−((4−(tert−ブチル)ベンゾイル)オキシ)プロピル]−1−シクロヘキシルピペリジン−1−イウムブロミド;
1−[2−((3−クロロベンゾ[b]チオフェン−2−カルボニル)オキシ)プロピル]−1−シクロヘキシルピロリジン−1−イウムブロミド;及び
1−[2−((3−クロロベンゾ[b]チオフェン−2−カルボニル)オキシ)プロピル]−1−シクロヘキシルピペリジン−1−イウムブロミド
からなる群から選択される化合物を含む、少なくとも1つの剤型であるナトリウムチャネル遮断薬を含む、ナトリウムチャネル遮断のために用いられるキット。 - 化合物が、経口;注射:経口、鼻腔内、及び気管内を含む吸入;眼内;単純な受動拡散処方による、又はイオントフォレーシス、マイクロニードルを用いるマイク穿孔法、若しくは高周波アブレーションを使用する促進された送達による経皮;血管内、皮膚、皮下、筋肉内、舌下、頭蓋内、硬膜外、直腸内、膀胱内、又は膣内で患者に投与される、請求項1に記載のキット。
- 化合物が、日毎に、週毎に、月毎に、若しくは年毎に、又は不規則なスケジュールで投与される、請求項1に記載のキット。
- 化合物の1回目の投与の治療的有効量は、化合物の1回又はそれ以上の以後の投与の治療的有効量より多い、請求項1に記載のキット。
- 化合物の1回目の投与の治療的有効量は、化合物の1回又はそれ以上の以後の投与の治療的有効量より少ない、請求項1に記載のキット。
- 化合物の等しい用量が、約2時間毎、約6時間毎、約8時間毎、約12時間毎、約24時間毎、約36時間毎、約48時間毎、約72時間毎、約1週間毎、約2週間毎、約3週間毎、約1ヶ月毎、約2ヶ月毎、約3ヶ月毎、又は約6ヶ月毎に投与される、請求項1に記載のキット。
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EP2771320A1 (en) | 2014-09-03 |
US20130101667A1 (en) | 2013-04-25 |
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EP2771320B1 (en) | 2016-06-22 |
DK2771320T3 (en) | 2016-10-03 |
JP2015501320A (ja) | 2015-01-15 |
ES2596215T3 (es) | 2017-01-05 |
HUE032240T2 (en) | 2017-09-28 |
US20140213552A1 (en) | 2014-07-31 |
JP2017214376A (ja) | 2017-12-07 |
WO2013063127A1 (en) | 2013-05-02 |
US8685418B2 (en) | 2014-04-01 |
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US9180115B2 (en) | 2015-11-10 |
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