JPWO2009136625A1 - 環状アミン−1−カルボン酸エステル誘導体およびそれを含有する医薬組成物 - Google Patents
環状アミン−1−カルボン酸エステル誘導体およびそれを含有する医薬組成物 Download PDFInfo
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- JPWO2009136625A1 JPWO2009136625A1 JP2010511078A JP2010511078A JPWO2009136625A1 JP WO2009136625 A1 JPWO2009136625 A1 JP WO2009136625A1 JP 2010511078 A JP2010511078 A JP 2010511078A JP 2010511078 A JP2010511078 A JP 2010511078A JP WO2009136625 A1 JPWO2009136625 A1 JP WO2009136625A1
- Authority
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- Prior art keywords
- carboxylate
- methoxybenzylcarbamoyl
- hydroxy
- piperidine
- group
- 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.)
- Granted
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- 239000003814 drug Substances 0.000 claims abstract description 42
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 35
- 208000004296 neuralgia Diseases 0.000 claims abstract description 34
- 208000021722 neuropathic pain Diseases 0.000 claims abstract description 31
- 206010061218 Inflammation Diseases 0.000 claims abstract description 30
- 230000004054 inflammatory process Effects 0.000 claims abstract description 30
- 125000003118 aryl group Chemical group 0.000 claims abstract description 18
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims abstract description 17
- 125000001424 substituent group Chemical group 0.000 claims abstract description 16
- 125000001072 heteroaryl group Chemical group 0.000 claims abstract description 12
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims abstract description 12
- 229910052736 halogen Chemical group 0.000 claims abstract description 10
- 150000002367 halogens Chemical group 0.000 claims abstract description 10
- 125000004448 alkyl carbonyl group Chemical group 0.000 claims abstract description 9
- 125000005129 aryl carbonyl group Chemical group 0.000 claims abstract description 5
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- 238000000034 method Methods 0.000 claims description 35
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- QKOMAZVWWDIAMW-UHFFFAOYSA-N (4,4-dimethylcyclohexyl) 4-[(4-hydroxy-3-methoxyphenyl)methylcarbamoyl]piperidine-1-carboxylate Chemical compound C1=C(O)C(OC)=CC(CNC(=O)C2CCN(CC2)C(=O)OC2CCC(C)(C)CC2)=C1 QKOMAZVWWDIAMW-UHFFFAOYSA-N 0.000 claims description 8
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- KWDVKRXFWVYEQZ-JTQLQIEISA-N (3S)-3-[(4-hydroxy-3-methoxyphenyl)methylcarbamoyl]pyrrolidine-1-carboxylic acid Chemical compound C1=C(O)C(OC)=CC(CNC(=O)[C@@H]2CN(CC2)C(O)=O)=C1 KWDVKRXFWVYEQZ-JTQLQIEISA-N 0.000 claims description 6
- LBODSNSFSPEQLE-YJBOKZPZSA-N [(1s,3s)-3-methylcyclohexyl] 4-[(4-hydroxy-3-methoxyphenyl)methylcarbamoyl]piperidine-1-carboxylate Chemical compound C1=C(O)C(OC)=CC(CNC(=O)C2CCN(CC2)C(=O)O[C@@H]2C[C@@H](C)CCC2)=C1 LBODSNSFSPEQLE-YJBOKZPZSA-N 0.000 claims description 6
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- CWRYNOOGAXQTGV-RUCARUNLSA-N C1C[C@@H](CC)CC[C@@H]1OC(=O)N1CCC(C(=O)NCC=2C=C(OC)C(O)=CC=2)CC1 Chemical compound C1C[C@@H](CC)CC[C@@H]1OC(=O)N1CCC(C(=O)NCC=2C=C(OC)C(O)=CC=2)CC1 CWRYNOOGAXQTGV-RUCARUNLSA-N 0.000 claims description 5
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- IRZDXGCNZQRVBE-UHFFFAOYSA-N cyclohexyl 4-[(4-hydroxy-3-methoxyphenyl)methylcarbamoyl]piperidine-1-carboxylate Chemical compound C1=C(O)C(OC)=CC(CNC(=O)C2CCN(CC2)C(=O)OC2CCCCC2)=C1 IRZDXGCNZQRVBE-UHFFFAOYSA-N 0.000 claims description 5
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- MZVUVLZEZCUDOA-UHFFFAOYSA-N cycloheptyl 4-[(4-hydroxy-3-methoxyphenyl)methylcarbamoyl]piperidine-1-carboxylate Chemical compound C1=C(O)C(OC)=CC(CNC(=O)C2CCN(CC2)C(=O)OC2CCCCCC2)=C1 MZVUVLZEZCUDOA-UHFFFAOYSA-N 0.000 claims description 4
- XDSPKGJYTFALQS-UHFFFAOYSA-N cyclohexylmethyl 4-[(4-hydroxy-3-methoxyphenyl)methylcarbamoyl]piperidine-1-carboxylate Chemical compound C1=C(O)C(OC)=CC(CNC(=O)C2CCN(CC2)C(=O)OCC2CCCCC2)=C1 XDSPKGJYTFALQS-UHFFFAOYSA-N 0.000 claims description 4
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- MCCDVTLLMFMBNV-UHFFFAOYSA-N (2-methylcyclohexyl) 4-[(4-hydroxy-3-methoxyphenyl)methylcarbamoyl]piperidine-1-carboxylate Chemical compound C1=C(O)C(OC)=CC(CNC(=O)C2CCN(CC2)C(=O)OC2C(CCCC2)C)=C1 MCCDVTLLMFMBNV-UHFFFAOYSA-N 0.000 claims description 3
- UAEAUWVVVOWCHO-UHFFFAOYSA-N (2-propan-2-ylphenyl) 3-[(4-hydroxy-3-methoxyphenyl)methylcarbamoyl]azetidine-1-carboxylate Chemical compound C1=C(O)C(OC)=CC(CNC(=O)C2CN(C2)C(=O)OC=2C(=CC=CC=2)C(C)C)=C1 UAEAUWVVVOWCHO-UHFFFAOYSA-N 0.000 claims description 3
- KYOKKWZRIYGUNW-UHFFFAOYSA-N (2-propan-2-ylphenyl) 4-[(4-hydroxy-3-methoxyphenyl)methylcarbamoyl]piperidine-1-carboxylate Chemical compound C1=C(O)C(OC)=CC(CNC(=O)C2CCN(CC2)C(=O)OC=2C(=CC=CC=2)C(C)C)=C1 KYOKKWZRIYGUNW-UHFFFAOYSA-N 0.000 claims description 3
- LBODSNSFSPEQLE-UHFFFAOYSA-N (3-methylcyclohexyl) 4-[(4-hydroxy-3-methoxyphenyl)methylcarbamoyl]piperidine-1-carboxylate Chemical compound C1=C(O)C(OC)=CC(CNC(=O)C2CCN(CC2)C(=O)OC2CC(C)CCC2)=C1 LBODSNSFSPEQLE-UHFFFAOYSA-N 0.000 claims description 3
- YVGZLHYAPDBRAX-INIZCTEOSA-N (4,4-dimethylcyclohexyl) (3s)-3-[(4-hydroxy-3-methoxyphenyl)methylcarbamoyl]pyrrolidine-1-carboxylate Chemical compound C1=C(O)C(OC)=CC(CNC(=O)[C@@H]2CN(CC2)C(=O)OC2CCC(C)(C)CC2)=C1 YVGZLHYAPDBRAX-INIZCTEOSA-N 0.000 claims description 3
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- LEOGTFJKBXSUCN-UHFFFAOYSA-N (4-ethylcyclohexyl) 3-[(4-hydroxy-3-methoxyphenyl)methylcarbamoyl]pyrrolidine-1-carboxylate Chemical compound C1CC(CC)CCC1OC(=O)N1CC(C(=O)NCC=2C=C(OC)C(O)=CC=2)CC1 LEOGTFJKBXSUCN-UHFFFAOYSA-N 0.000 claims description 3
- CWRYNOOGAXQTGV-UHFFFAOYSA-N (4-ethylcyclohexyl) 4-[(4-hydroxy-3-methoxyphenyl)methylcarbamoyl]piperidine-1-carboxylate Chemical compound C1CC(CC)CCC1OC(=O)N1CCC(C(=O)NCC=2C=C(OC)C(O)=CC=2)CC1 CWRYNOOGAXQTGV-UHFFFAOYSA-N 0.000 claims description 3
- IRAMMCKYVGIHCU-UHFFFAOYSA-N (4-methylcyclohexyl) 4-[(4-hydroxy-3-methoxyphenyl)methylcarbamoyl]piperidine-1-carboxylate Chemical compound C1=C(O)C(OC)=CC(CNC(=O)C2CCN(CC2)C(=O)OC2CCC(C)CC2)=C1 IRAMMCKYVGIHCU-UHFFFAOYSA-N 0.000 claims description 3
- ZQNJEMNHNZJDLP-UHFFFAOYSA-N (4-tert-butylcyclohexyl) 3-[(4-hydroxy-3-methoxyphenyl)methylcarbamoyl]azetidine-1-carboxylate Chemical compound C1=C(O)C(OC)=CC(CNC(=O)C2CN(C2)C(=O)OC2CCC(CC2)C(C)(C)C)=C1 ZQNJEMNHNZJDLP-UHFFFAOYSA-N 0.000 claims description 3
- HVWAPEGXSNPCCN-UHFFFAOYSA-N (4-tert-butylcyclohexyl) 3-[(4-hydroxy-3-methoxyphenyl)methylcarbamoyl]pyrrolidine-1-carboxylate Chemical compound C1=C(O)C(OC)=CC(CNC(=O)C2CN(CC2)C(=O)OC2CCC(CC2)C(C)(C)C)=C1 HVWAPEGXSNPCCN-UHFFFAOYSA-N 0.000 claims description 3
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- ALGMJCXWGKJHLP-UHFFFAOYSA-N (2-ethylcyclohexyl) 4-[(4-hydroxy-3-methoxyphenyl)methylcarbamoyl]piperidine-1-carboxylate Chemical compound CCC1CCCCC1OC(=O)N1CCC(C(=O)NCC=2C=C(OC)C(O)=CC=2)CC1 ALGMJCXWGKJHLP-UHFFFAOYSA-N 0.000 claims description 2
- GGFIQBUMOSZCEL-UHFFFAOYSA-N (3,5-dimethylcyclohexyl) 4-[(4-hydroxy-3-methoxyphenyl)methylcarbamoyl]piperidine-1-carboxylate Chemical compound C1=C(O)C(OC)=CC(CNC(=O)C2CCN(CC2)C(=O)OC2CC(C)CC(C)C2)=C1 GGFIQBUMOSZCEL-UHFFFAOYSA-N 0.000 claims description 2
- XUNWSPBODPKJKZ-UHFFFAOYSA-N (3-methylcyclohexyl) 3-[(4-hydroxy-3-methoxyphenyl)methylcarbamoyl]azetidine-1-carboxylate Chemical compound C1=C(O)C(OC)=CC(CNC(=O)C2CN(C2)C(=O)OC2CC(C)CCC2)=C1 XUNWSPBODPKJKZ-UHFFFAOYSA-N 0.000 claims description 2
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- 239000004094 surface-active agent Substances 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 125000006253 t-butylcarbonyl group Chemical group [H]C([H])([H])C(C(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 239000003826 tablet Substances 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
- 229940095064 tartrate Drugs 0.000 description 1
- MFPWEWYKQYMWRO-UHFFFAOYSA-N tert-butyl carboxy carbonate Chemical compound CC(C)(C)OC(=O)OC(O)=O MFPWEWYKQYMWRO-UHFFFAOYSA-N 0.000 description 1
- GKCBAIGFKIBETG-UHFFFAOYSA-N tetracaine Chemical compound CCCCNC1=CC=C(C(=O)OCCN(C)C)C=C1 GKCBAIGFKIBETG-UHFFFAOYSA-N 0.000 description 1
- 229960002494 tetracaine hydrochloride Drugs 0.000 description 1
- TUNFSRHWOTWDNC-HKGQFRNVSA-N tetradecanoic acid Chemical compound CCCCCCCCCCCCC[14C](O)=O TUNFSRHWOTWDNC-HKGQFRNVSA-N 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- 125000003718 tetrahydrofuranyl group Chemical group 0.000 description 1
- 125000001412 tetrahydropyranyl group Chemical group 0.000 description 1
- 208000012720 thalamic disease Diseases 0.000 description 1
- 230000000542 thalamic effect Effects 0.000 description 1
- 229940126585 therapeutic drug Drugs 0.000 description 1
- 239000002562 thickening agent Substances 0.000 description 1
- OGIDPMRJRNCKJF-UHFFFAOYSA-N titanium oxide Inorganic materials [Ti]=O OGIDPMRJRNCKJF-UHFFFAOYSA-N 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 1
- 239000012929 tonicity agent Substances 0.000 description 1
- 238000011200 topical administration Methods 0.000 description 1
- 125000002088 tosyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1C([H])([H])[H])S(*)(=O)=O 0.000 description 1
- 239000003053 toxin Substances 0.000 description 1
- 231100000765 toxin Toxicity 0.000 description 1
- 108700012359 toxins Proteins 0.000 description 1
- 235000010487 tragacanth Nutrition 0.000 description 1
- 239000000196 tragacanth Substances 0.000 description 1
- 229940116362 tragacanth Drugs 0.000 description 1
- 229960004380 tramadol Drugs 0.000 description 1
- TVYLLZQTGLZFBW-GOEBONIOSA-N tramadol Natural products COC1=CC=CC([C@@]2(O)[C@@H](CCCC2)CN(C)C)=C1 TVYLLZQTGLZFBW-GOEBONIOSA-N 0.000 description 1
- 230000001052 transient effect Effects 0.000 description 1
- 230000008736 traumatic injury Effects 0.000 description 1
- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 description 1
- WEAPVABOECTMGR-UHFFFAOYSA-N triethyl 2-acetyloxypropane-1,2,3-tricarboxylate Chemical compound CCOC(=O)CC(C(=O)OCC)(OC(C)=O)CC(=O)OCC WEAPVABOECTMGR-UHFFFAOYSA-N 0.000 description 1
- 239000001069 triethyl citrate Substances 0.000 description 1
- VMYFZRTXGLUXMZ-UHFFFAOYSA-N triethyl citrate Natural products CCOC(=O)C(O)(C(=O)OCC)C(=O)OCC VMYFZRTXGLUXMZ-UHFFFAOYSA-N 0.000 description 1
- 235000013769 triethyl citrate Nutrition 0.000 description 1
- RYFMWSXOAZQYPI-UHFFFAOYSA-K trisodium phosphate Chemical compound [Na+].[Na+].[Na+].[O-]P([O-])([O-])=O RYFMWSXOAZQYPI-UHFFFAOYSA-K 0.000 description 1
- 239000012588 trypsin Substances 0.000 description 1
- 208000001072 type 2 diabetes mellitus Diseases 0.000 description 1
- 210000001364 upper extremity Anatomy 0.000 description 1
- 210000002438 upper gastrointestinal tract Anatomy 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
- 229920002554 vinyl polymer Polymers 0.000 description 1
- 230000003612 virological effect Effects 0.000 description 1
- 239000004034 viscosity adjusting agent Substances 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
- 239000003871 white petrolatum Substances 0.000 description 1
- 235000010493 xanthan gum Nutrition 0.000 description 1
- 239000000230 xanthan gum Substances 0.000 description 1
- 229920001285 xanthan gum Polymers 0.000 description 1
- 229940082509 xanthan gum Drugs 0.000 description 1
- 239000011787 zinc oxide Substances 0.000 description 1
- UHVMMEOXYDMDKI-JKYCWFKZSA-L zinc;1-(5-cyanopyridin-2-yl)-3-[(1s,2s)-2-(6-fluoro-2-hydroxy-3-propanoylphenyl)cyclopropyl]urea;diacetate Chemical compound [Zn+2].CC([O-])=O.CC([O-])=O.CCC(=O)C1=CC=C(F)C([C@H]2[C@H](C2)NC(=O)NC=2N=CC(=CC=2)C#N)=C1O UHVMMEOXYDMDKI-JKYCWFKZSA-L 0.000 description 1
- 229960002860 zucapsaicin Drugs 0.000 description 1
Classifications
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- C07—ORGANIC CHEMISTRY
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- C07D205/04—Heterocyclic compounds containing four-membered rings with one nitrogen 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
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Abstract
Description
R1は、メチル基または水素原子を示し、
R2は、水素原子、C1〜4アルキル基、C1〜4アルキルカルボニル基またはアリールカルボニル基を示し、
Aは、C3〜8シクロアルキル基、C3〜8シクロアルケニル基、アリール基またはヘテロアリール基(該各基は、C1〜6アルキル、C2〜6アルケニル、C3〜8シクロアルキル及びハロゲンからなる群から選ばれる、同一又は相異なった1個〜5個の置換基で置換されていてもよい。)を示し、
nおよびmは、同一または相異なって1、2または3の整数を示し、
pは、0、1、2または3の整数を示す。]
で表される化合物またはその生理的に許容される塩。
4−エチルシクロヘキシル 4−(4−ヒドロキシ−3−メトキシベンジルカルバモイル)−ピペリジン−1−カルボキシレート、
4,4−ジメチルシクロヘキシル 4−(4−ヒドロキシ−3−メトキシベンジルカルバモイル)−ピペリジン−1−カルボキシレート、
3−メチルシクロヘキシル 4−(4−ヒドロキシ−3−メトキシベンジルカルバモイル)−ピペリジン−1−カルボキシレート、
2−メチルシクロヘキシル 4−(4−ヒドロキシ−3−メトキシベンジルカルバモイル)−ピペリジン−1−カルボキシレート、
4,4−ジエチルシクロヘキシル 3−(4−ヒドロキシ−3−メトキシベンジルカルバモイル)−アゼチジン−1−カルボキシレート、
4−t−ブチルシクロヘキシル 3−(4−ヒドロキシ−3−メトキシベンジルカルバモイル)−アゼチジン−1−カルボキシレート、
4−t−ブチルシクロヘキシル 3−(4−ヒドロキシ−3−メトキシベンジルカルバモイル)−ピロリジン−1−カルボキシレート、
4−メチルシクロヘキシル 4−(4−ヒドロキシ−3−メトキシベンジルカルバモイル)−ピペリジン−1−カルボキシレート、
3,3,5,5−テトラメチルシクロヘキシル 3−(4−ヒドロキシ−3−メトキシベンジルカルバモイル)−アゼチジン−1−カルボキシレート、
2−イソプロピル−5−メチルシクロヘキシル 3−(4−ヒドロキシ−3−メトキシベンジルカルバモイル)−アゼチジン−1−カルボキシレート、
4−エチルシクロヘキシル 3−(4−ヒドロキシ−3−メトキシベンジルカルバモイル)−ピロリジン−1−カルボキシレート、
4,4−ジメチルシクロヘキシル 3−(4−ヒドロキシ−3−メトキシベンジルカルバモイル)−ピロリジン−1−カルボキシレート、
4,4−ジエチルシクロヘキシル 3−(4−ヒドロキシ−3−メトキシベンジルカルバモイル)−ピロリジン−1−カルボキシレート、
4−t−ブチルシクロヘキシル 4−(4−ヒドロキシ−3−メトキシベンジルカルバモイル)−ピペリジン−1−カルボキシレート、
4−ブチルシクロヘキシル 3−(4−ヒドロキシ−3−メトキシベンジルカルバモイル)−アゼチジン−1−カルボキシレート、
4,4−ジエチルシクロヘキシル 4−(4−ヒドロキシ−3−メトキシベンジルカルバモイル)−ピペリジン−1−カルボキシレート、
3,5−ジメチルシクロヘキシル 4−(4−ヒドロキシ−3−メトキシベンジルカルバモイル)−ピペリジン−1−カルボキシレート、
2−エチルシクロヘキシル 4−(4−ヒドロキシ−3−メトキシベンジルカルバモイル)−ピペリジン−1−カルボキシレート、
4−エチルシクロヘキシル 3−(4−ヒドロキシ−3−メトキシベンジルカルバモイル)−アゼチジン−1−カルボキシレート、
3−メチルシクロヘキシル 3−(4−ヒドロキシ−3−メトキシベンジルカルバモイル)−アゼチジン−1−カルボキシレート、
4−イソプロピルシクロヘキシル 3−(4−ヒドロキシ−3−メトキシベンジルカルバモイル)−アゼチジン−1−カルボキシレート、
2−イソプロペニル−5−メチルシクロヘキシル 3−(4−ヒドロキシ−3−メトキシベンジルカルバモイル)−アゼチジン−1−カルボキシレート、
シクロヘプチル 4−(4−ヒドロキシ−3−メトキシベンジルカルバモイル)−ピペリジン−1−カルボキシレート、
シクロヘキシルメチル 4−(4−ヒドロキシ−3−メトキシベンジルカルバモイル)−ピペリジン−1−カルボキシレート、
2−イソプロピルフェニル 4−(4−ヒドロキシ−3−メトキシベンジルカルバモイル)−ピペリジン−1−カルボキシレート、
2−シクロペンチルフェニル 4−(4−ヒドロキシ−3−メトキシベンジルカルバモイル)−ピペリジン−1−カルボキシレート、
3−イソプロピルフェニル 4−(4−ヒドロキシ−3−メトキシベンジルカルバモイル)−ピペリジン−1−カルボキシレート、
4−イソプロピルフェニル 4−(4−ヒドロキシ−3−メトキシベンジルカルバモイル)−ピペリジン−1−カルボキシレート、
2−イソプロピルフェニル 3−(4−ヒドロキシ−3−メトキシベンジルカルバモイル)−アゼチジン−1−カルボキシレート、
2−シクロペンチルフェニル 3−(4−ヒドロキシ−3−メトキシベンジルカルバモイル)−アゼチジン−1−カルボキシレート、および
シクロヘキシル 4−(4−ヒドロキシ−3−メトキシベンジルカルバモイル)−ピペリジン−1−カルボキシレート
からなる群から選択される化合物である、項1記載の化合物またはその生理的に許容される塩。
4−エチルシクロヘキシル 4−(4−ヒドロキシ−3−メトキシベンジルカルバモイル)−ピペリジン−1−カルボキシレート、
4,4−ジメチルシクロヘキシル 4−(4−ヒドロキシ−3−メトキシベンジルカルバモイル)−ピペリジン−1−カルボキシレート、
3−メチルシクロヘキシル 4−(4−ヒドロキシ−3−メトキシベンジルカルバモイル)−ピペリジン−1−カルボキシレート、
2−メチルシクロヘキシル 4−(4−ヒドロキシ−3−メトキシベンジルカルバモイル)−ピペリジン−1−カルボキシレート、
4,4−ジエチルシクロヘキシル 3−(4−ヒドロキシ−3−メトキシベンジルカルバモイル)−アゼチジン−1−カルボキシレート、
4−t−ブチルシクロヘキシル 3−(4−ヒドロキシ−3−メトキシベンジルカルバモイル)−アゼチジン−1−カルボキシレート、
4−t−ブチルシクロヘキシル 3−(4−ヒドロキシ−3−メトキシベンジルカルバモイル)−ピロリジン−1−カルボキシレート、
4−メチルシクロヘキシル 4−(4−ヒドロキシ−3−メトキシベンジルカルバモイル)−ピペリジン−1−カルボキシレート、
3,3,5,5−テトラメチルシクロヘキシル 3−(4−ヒドロキシ−3−メトキシベンジルカルバモイル)−アゼチジン−1−カルボキシレート、
2−イソプロピル−5−メチルシクロヘキシル 3−(4−ヒドロキシ−3−メトキシベンジルカルバモイル)−アゼチジン−1−カルボキシレート、
4−エチルシクロヘキシル 3−(4−ヒドロキシ−3−メトキシベンジルカルバモイル)−ピロリジン−1−カルボキシレート、
4,4−ジメチルシクロヘキシル 3−(4−ヒドロキシ−3−メトキシベンジルカルバモイル)−ピロリジン−1−カルボキシレート、および
4,4−ジエチルシクロヘキシル 3−(4−ヒドロキシ−3−メトキシベンジルカルバモイル)−ピロリジン−1−カルボキシレート
からなる群から選択される化合物である、項1記載の化合物またはその生理的に許容される塩。
シス−4−エチルシクロヘキシル 4−(4−ヒドロキシ−3−メトキシベンジルカルバモイル)−ピペリジン−1−カルボキシレート、
トランス−4−エチルシクロヘキシル 4−(4−ヒドロキシ−3−メトキシベンジルカルバモイル)−ピペリジン−1−カルボキシレート、
4,4−ジメチルシクロヘキシル 4−(4−ヒドロキシ−3−メトキシベンジルカルバモイル)−ピペリジン−1−カルボキシレート、
トランス−3−メチルシクロヘキシル 4−(4−ヒドロキシ−3−メトキシベンジルカルバモイル)−ピペリジン−1−カルボキシレート、
シス−2−メチルシクロヘキシル 4−(4−ヒドロキシ−3−メトキシベンジルカルバモイル)−ピペリジン−1−カルボキシレート、
4,4−ジエチルシクロヘキシル 3−(4−ヒドロキシ−3−メトキシベンジルカルバモイル)−アゼチジン−1−カルボキシレート、
シス−4−t−ブチルシクロヘキシル 3−(4−ヒドロキシ−3−メトキシベンジルカルバモイル)−アゼチジン−1−カルボキシレート、
シス−4−t−ブチルシクロヘキシル (S)−3−(4−ヒドロキシ−3−メトキシベンジルカルバモイル)−ピロリジン−1−カルボキシレート、
シス−4−メチルシクロヘキシル 4−(4−ヒドロキシ−3−メトキシベンジルカルバモイル)−ピペリジン−1−カルボキシレート、
3,3,5,5−テトラメチルシクロヘキシル 3−(4−ヒドロキシ−3−メトキシベンジルカルバモイル)−アゼチジン−1−カルボキシレート、
(1S,2S,5R)−2−イソプロピル−5−メチルシクロヘキシル 3−(4−ヒドロキシ−3−メトキシベンジルカルバモイル)−アゼチジン−1−カルボキシレート、
シス−4−エチルシクロヘキシル (S)−3−(4−ヒドロキシ−3−メトキシベンジルカルバモイル)−ピロリジン−1−カルボキシレート、
4,4−ジメチルシクロヘキシル (S)−3−(4−ヒドロキシ−3−メトキシベンジルカルバモイル)−ピロリジン−1−カルボキシレート、および
4,4−ジエチルシクロヘキシル (S)−3−(4−ヒドロキシ−3−メトキシベンジルカルバモイル)−ピロリジン−1−カルボキシレート
からなる群から選択される化合物である、項1記載の化合物またはその生理的に許容される塩。
シス−4−エチルシクロヘキシル 4−(4−ヒドロキシ−3−メトキシベンジルカルバモイル)−ピペリジン−1−カルボキシレート、
トランス−4−エチルシクロヘキシル 4−(4−ヒドロキシ−3−メトキシベンジルカルバモイル)−ピペリジン−1−カルボキシレート、
4,4−ジメチルシクロヘキシル 4−(4−ヒドロキシ−3−メトキシベンジルカルバモイル)−ピペリジン−1−カルボキシレート、
トランス−3−メチルシクロヘキシル 4−(4−ヒドロキシ−3−メトキシベンジルカルバモイル)−ピペリジン−1−カルボキシレート、
シス−2−メチルシクロヘキシル 4−(4−ヒドロキシ−3−メトキシベンジルカルバモイル)−ピペリジン−1−カルボキシレート、
4,4−ジエチルシクロヘキシル 3−(4−ヒドロキシ−3−メトキシベンジルカルバモイル)−アゼチジン−1−カルボキシレート、
シス−4−t−ブチルシクロヘキシル 3−(4−ヒドロキシ−3−メトキシベンジルカルバモイル)−アゼチジン−1−カルボキシレート、
シス−4−t−ブチルシクロヘキシル (S)−3−(4−ヒドロキシ−3−メトキシベンジルカルバモイル)−ピロリジン−1−カルボキシレート、
シス−4−メチルシクロヘキシル 4−(4−ヒドロキシ−3−メトキシベンジルカルバモイル)−ピペリジン−1−カルボキシレート、
トランス−4−メチルシクロヘキシル 4−(4−ヒドロキシ−3−メトキシベンジルカルバモイル)−ピペリジン−1−カルボキシレート、
シス−4−t−ブチルシクロヘキシル 4−(4−ヒドロキシ−3−メトキシベンジルカルバモイル)−ピペリジン−1−カルボキシレート、
シクロヘプチル 4−(4−ヒドロキシ−3−メトキシベンジルカルバモイル)−ピペリジン−1−カルボキシレート、
シクロヘキシルメチル 4−(4−ヒドロキシ−3−メトキシベンジルカルバモイル)−ピペリジン−1−カルボキシレート、
シス−3−メチルシクロヘキシル 4−(4−ヒドロキシ−3−メトキシベンジルカルバモイル)−ピペリジン−1−カルボキシレート、
トランス−2−メチルシクロヘキシル 4−(4−ヒドロキシ−3−メトキシベンジルカルバモイル)−ピペリジン−1−カルボキシレート、
トランス−4−t−ブチルシクロヘキシル 3−(4−ヒドロキシ−3−メトキシベンジルカルバモイル)−アゼチジン−1−カルボキシレート、
3,3,5,5−テトラメチルシクロヘキシル 3−(4−ヒドロキシ−3−メトキシベンジルカルバモイル)−アゼチジン−1−カルボキシレート、
シス−4−ブチルシクロヘキシル 3−(4−ヒドロキシ−3−メトキシベンジルカルバモイル)−アゼチジン−1−カルボキシレート、
シクロヘキシル 4−(4−ヒドロキシ−3−メトキシベンジルカルバモイル)−ピペリジン−1−カルボキシレート
からなる群から選択される化合物である、項1記載の化合物またはその生理的に許容される塩。
シス−4−エチルシクロヘキシル 4−(4−ヒドロキシ−3−メトキシベンジルカルバモイル)−ピペリジン−1−カルボキシレート、
トランス−4−エチルシクロヘキシル 4−(4−ヒドロキシ−3−メトキシベンジルカルバモイル)−ピペリジン−1−カルボキシレート、
4,4−ジメチルシクロヘキシル 4−(4−ヒドロキシ−3−メトキシベンジルカルバモイル)−ピペリジン−1−カルボキシレート、
トランス−3−メチルシクロヘキシル 4−(4−ヒドロキシ−3−メトキシベンジルカルバモイル)−ピペリジン−1−カルボキシレート、
シス−2−メチルシクロヘキシル 4−(4−ヒドロキシ−3−メトキシベンジルカルバモイル)−ピペリジン−1−カルボキシレート、
4,4−ジエチルシクロヘキシル 3−(4−ヒドロキシ−3−メトキシベンジルカルバモイル)−アゼチジン−1−カルボキシレート、
シス−4−t−ブチルシクロヘキシル 3−(4−ヒドロキシ−3−メトキシベンジルカルバモイル)−アゼチジン−1−カルボキシレート、および
シス−4−t−ブチルシクロヘキシル (S)−3−(4−ヒドロキシ−3−メトキシベンジルカルバモイル)−ピロリジン−1−カルボキシレート
からなる群から選択される化合物である、項1記載の化合物またはその生理的に許容される塩。
A’は、1個〜4個の同一又は異なるC1〜6アルキル、C2〜6アルケニルまたはC3〜8シクロアルキルで置換されていてもよいC5〜7シクロアルキル基であり、
nおよびmは、共に1または2の整数を示すか、または一方が1で他方が2を示す。]
で表される化合物またはその生理的に許容される塩である。
式(I)で表される化合物またはその生理的に許容される塩は、新規化合物であり、例えば、以下に述べる方法、後述する実施例または公知の方法に準じた方法によって製造することができる。
式(IV)の化合物は、市販されているか、或いは公知の方法、例えば、J. Org. Chem., 45, 5399 (1980)、J. Chem. Soc., Perkin Trans. 1, 3015 (1999)等に記載の方法、あるいはこれらに準じた方法に従って製造することができる。以下その代表的な製造方法を例示する。
シス−4−エチルシクロヘキシル 4−(4−ヒドロキシ−3−メトキシベンジルカルバモイル)−ピペリジン−1−カルボキシレートの製造:
1H-NMR(CDCl3, δ): 0.88(3H,t), 1.14-1.32(5H,m), 1.44-1.79(6H,m), 1.81-1.94(4H,m), 2.21-2.34(1H,m), 2.69-2.96(2H,m), 3.88(3H,s), 4.11-4.31(2H,m), 4.36(2H,d), 4.87-4.96(1H,m), 5.60(1H,s), 5.68(1H,brs), 6.75(1H,dd), 6.79(1H,d), 6.86(1H,d)。m.p.109℃。XRD:2θ=6.5, 10.6, 13.0, 18.0, 20.0°
実施例1におけるシス−4−エチルシクロヘキサノールの代わりに各種置換シクロヘキサノールを用い、実施例1と同様に反応及び処理して、表1および表2に示す化合物を得た。
シス−2−エチルシクロヘキシル 4−(4−ヒドロキシ−3−メトキシベンジルカルバモイル)−ピペリジン−1−カルボキシレートの製造:
1H-NMR (CDCl3, δ):0.88(3H,t), 1.15-1.84(11H,m), 1.85-1.98(4H,m), 2.21-2.34(1H,m), 2.68-2.94(2H,m), 3.88(3H,s), 4.11-4.30(2H,m), 4.36(2H,d), 4.89-4.97(1H,m), 5.59(1H,s), 5.66(1H,brs), 6.75(1H,dd), 6.78(1H,d), 6.87(1H,d)。
4,4−ジエチルシクロヘキシル 3−(4−ヒドロキシ−3−メトキシベンジルカルバモイル)−アゼチジン−1−カルボキシレートの製造:
1H-NMR(CDCl3, δ): 0.74(3H,t), 0.75(3H,t), 1.10-1.40(6H,m), 1.41-1.59(4H,m), 1.61-1.80(2H,m), 3.12-3.27(1H,m), 3.89(3H,s), 4.03-4.22(4H,m), 4.38(2H,d), 4.55-4.66(1H,m), 5.60(1H,s), 5.67(1H,brs), 6.76(1H,dd), 6.80(1H,d), 6.87(1H,d)。m.p.95℃。XRD:2θ=5.6, 11.2, 13.4, 14.5, 16.8°。
実施例14における4,4−ジエチルシクロヘキサノールの代わりに各種置換シクロヘキサノールを用い、実施例14と同様に反応及び処理して表3に示す化合物を得た。
実施例14における4,4−ジエチルシクロヘキサノールの代わりに4−ブチルシクロヘキサノールまたは4−(イソプロピル)シクロヘキサノールを用い、実施例14と同様に反応および処理した。その後、シス体とトランス体をシリカゲルカラムクロマトグラフィー(溶出溶媒:ヘキサン/酢酸エチル=100/0から0/100のグラジエント)で分離精製して表4に示す化合物を得た。
(1R,2S,5R)−2−イソプロペニル−5−メチルシクロヘキシル 3−(4−ヒドロキシ−3−メトキシベンジルカルバモイル)−アゼチジン−1−カルボキシレートの製造:
1H-NMR(CDCl3,δ): 0.81-1.12(2H,m), 0.92(3H,s), 1.30-1.71(4H,m), 1.67(3H,s), 1.89-2.10(2H,m), 3.11-3.26(1H,m), 3.89(3H,s), 4.00-4.21(4H,m), 4.38(2H,d), 4.61(1H,dt), 4.69-4.80(2H,m), 5.60(1H,s), 5.66(1H,brs), 6.76(1H,dd), 6.80(1H,d), 6.87(1H,d)。
4,4−ジメチルシクロヘキシル (S)−3−(4−ヒドロキシ−3−メトキシベンジルカルバモイル)−ピロリジン−1−カルボキシレートの製造:
1H-NMR(CDCl3, δ):0.92(6H,s), 1.19-1.34(3H,m), 1.37-1.62(3H,m), 1.68-1.79(2H,m), 2.06-2.28(2H,m), 2.77-2.94(1H,m), 3.32-3.45(1H,m), 3.52-3.76(3H,m), 3.89(3H,s), 4.37(2H,d), 4.58-4.69(1H,m), 5.61(1H,s), 5.72(1H,brs), 6.77(1H,dd), 6.79(1H,d), 6.88(1H,d)。
実施例27における4,4−ジメチルシクロヘキサノールの代わりに各種置換シクロヘキサノールを用い、実施例27と同様に反応および処理して表5に示す化合物を得た。
4,4−ジメチルシクロヘキシル (R)−3−(4−ヒドロキシ−3−メトキシベンジルカルバモイル)−ピロリジン−1−カルボキシレートの製造:
1H-NMR(CDCl3, δ):0.92(6H,s), 1.19-1.32(3H,m), 1.37-1.62(3H,m), 1.68-1.79(2H,m), 2.05-2.27(2H,m), 2.77-2.94(1H,m), 3.32-3.45(1H,m), 3.52-3.76(3H,m), 3.89(3H,s), 4.37(2H,d), 4.58-4.69(1H,m), 5.60(1H,s), 5.72(1H,brs), 6.77(1H,dd), 6.79(1H,d), 6.88(1H,d)。
実施例31における4,4−ジメチルシクロヘキサノールの代わりに各種置換シクロヘキサノールを用い、実施例31と同様に反応および処理して表6に示す化合物を得た。
(1R,3R)−3−メチルシクロヘキシル 4−(4−ヒドロキシ−3−メトキシベンジルカルバモイル)−ピペリジン−1−カルボキシレートの製造:
1H-NMR(CDCl3, δ):0.88(3H,d), 0.89-1.24(2H,m), 1.35-1.90(11H,m), 2.21-2.33(1H,m), 2.69-2.87(2H,m), 3.88(3H,s), 4.11-4.31(2H,m), 4.36(2H,d), 4.95-5.02(1H,m), 5.59(1H,s), 5.65(1H,brs), 6.75(1H,dd), 6.79(1H,d), 6.87(1H,d)。m.p.155℃。XRD:2θ=6.9, 12.8, 14.8, 18.0, 20.7°。
(1S,3S)−3−メチルシクロヘキシル 4−(4−ヒドロキシ−3−メトキシベンジルカルバモイル)−ピペリジン−1−カルボキシレートの製造:
1H-NMR(CDCl3, δ):0.88(3H,d), 0.89-1.24(2H,m), 1.35-1.90(11H,m), 2.20-2.32(1H,m), 2.69-2.87(2H,m), 3.88(3H,s), 4.12-4.31(2H,m), 4.36(2H,d), 4.94-5.01(1H,m), 5.59(1H,s), 5.65(1H,brs), 6.75(1H,dd), 6.79(1H,d), 6.87(1H,d)。
(1R,2S)−2−メチルシクロヘキシル 4−(4−ヒドロキシ−3−メトキシベンジルカルバモイル)−ピペリジン−1−カルボキシレートの製造:
1H-NMR(CDCl3, δ):0.88(3H,d), 1.23-1.50(6H,m), 1.53-1.91(7H,m), 2.19-2.32(1H,m), 2.69-2.91(2H,m), 3.88(3H,s), 4.14-4.29(2H,m), 4.36(2H,d), 4.79-4.85(1H,m), 5.60(1H,s), 5.68(1H,brs), 6.75(1H,dd), 6.79(1H,d), 6.87(1H,d)。結晶A m.p.125℃,XRD:2θ=6.0, 10.5, 12.0, 15.6, 21.1°。結晶B m.p.118℃,XRD:2θ=6.2, 7.1, 9.0, 10.6, 16.8°。結晶C m.p.124℃。XRD:2θ=6.1, 6.6, 7.5, 8.6, 15.7°。
(1S,2R)−2−メチルシクロヘキシル 4−(4−ヒドロキシ−3−メトキシベンジルカルバモイル)−ピペリジン−1−カルボキシレートの製造:
1H-NMR(CDCl3, δ):0.88(3H,d), 1.23-1.50(6H,m), 1.53-1.91(7H,m), 2.20-2.33(1H,m), 2.70-2.91(2H,m), 3.88(3H,s), 4.15-4.30(2H,m), 4.36(2H,d), 4.78-4.85(1H,m), 5.61(1H,s), 5.68(1H,brs), 6.75(1H,dd), 6.79(1H,d), 6.87(1H,d)。
実施例1におけるシス−4−エチルシクロヘキサノールの代わりにシクロヘプタノールまたはシクロヘキシルメタノールを用い、実施例1と同様に反応及び処理して表7に示す化合物を得た。
2−イソプロピルフェニル 4−(4−ヒドロキシ−3−メトキシベンジルカルバモイル)−ピペリジン−1−カルボキシレートの製造:
1H-NMR(CDCl3, δ):1.22(6H,d), 1.70-1.99(4H,m), 2.28-2.38(1H,m), 2.80-2.96(1H,m), 2.99-3.12(2H,m), 3.88(3H,s), 4.20-4.39(2H,m), 4.37(2H,d), 5.65(1H,s), 5.77(1H,brs), 6.77(1H,dd), 6.80(1H,d), 6.87(1H,d), 6.99-7.10(1H,m), 7.14-7.21(2H,m), 7.25-7.31(1H,m)。
実施例41における2−イソプロピルフェノールの代わりに各種置換フェノールを用い、実施例41と同様に反応及び処理して表8に示す化合物を得た。
2−イソプロピルフェニル 3−(4−ヒドロキシ−3−メトキシベンジルカルバモイル)−アゼチジン−1−カルボキシレートの製造:
1H-NMR(CDCl3, δ):1.22(6H,d), 3.05-3.17(1H,m), 3.23-3.35(1H,m), 3.89(3H,s), 4.12-4.35(3H,m), 4.40(2H,d), 4.41-4.55(1H,m), 5.65(1H,s), 5.79(1H,brs), 6.77(1H,dd), 6.80(1H,d), 6.87(1H,d), 7.02-7.10(1H,m), 7.13-7.21(2H,m), 7.25-7.33(1H,m)。
2−シクロペンチルフェニル 3−(4−ヒドロキシ−3−メトキシベンジルカルバモイル)−アゼチジン−1−カルボキシレートの製造:
1H-NMR(CDCl3, δ):1.51-1.84(6H,m), 1.93-2.09(2H,m), 3.06-3.18(1H,m), 3.21-3.32(1H,m), 3.88(3H,s), 4.10-4.32(3H,m), 4.39(2H,d), 4.40-4.55(1H,m), 5.67(1H,s), 5.86(1H,brs), 6.77(1H,dd), 6.81(1H,d), 6.87(1H,d), 7.01-7.09(1H,m), 7.12-7.21(2H,m), 7.25-7.32(1H,m)。
(1S*,2S*)−2−メチルシクロヘキシル 4−(4−ヒドロキシ−3−メトキシベンジルカルバモイル)−ピペリジン−1−カルボキシレートの製造:
1H-NMR(CDCl3, δ):0.91(3H,d), 0.98-1.50(5H,m), 1.52-2.03(8H,m), 2.18-2.32(1H,m), 2.69-2.84(2H,m), 3.88(3H,s), 4.12-4.35(3H,m), 4.36(2H,d), 5.60(1H,s), 5.67(1H,brs), 6.75(1H,dd), 6.79(1H,d), 6.87(1H,d)。
シクロヘキシル 4−(4−ヒドロキシ−3−メトキシベンジルカルバモイル)−ピペリジン−1−カルボキシレートの製造:
1H-NMR(CDCl3, δ):1.22-1.58(6H,m), 1.60-1.88(8H,m), 2.18-2.33(1H,m), 2.68-2.85(2H,m), 3.88(3H,s), 4.10-4.28(2H,m), 4.35(2H,d), 4.61-4.73(1H,m), 5.61(1H,s), 5.67(1H,brs), 6.75(1H,dd), 6.77(1H,d), 6.86(1H,d)。
以下に、本発明の代表的化合物の薬理試験結果を示し、本発明の化合物についての薬理作用を説明する。ただし、本発明はこれらの試験例に限定されるものではない。
本試験は本発明の化合物を経皮投与することによって、神経因性疼痛モデルにおける機械的痛覚過敏がどの程度改善されるかを指標に鎮痛効果を測定するものであり、Kim and Chungの方法[Pain, 50, 355-363(1992)]や、Tsuda等の方法[Nature, 424, 778-783, 2003]に準じて実施した。
結果を以下の表9に示す。
本試験は本発明の化合物が、どの程度の刺激性を有するかを検討するものであり、Jancso等の方法[Acta. Physiol. Acad. Sci. Hung.,19, 113-131(1961)]およびSzallasi等の方法[Brit. J. Pharmacol.,119, 283-290(1996)]に準じて実施した。具体的には、5%Tween 80および5%エタノールを含有する生理食塩液に、各濃度(10または30μg/ml)になるように試験化合物を溶解させ、得られた溶液をStd:ddy系雄性マウス(一群5匹,体重20〜30g)の眼へ一滴滴下し,前肢での防御的拭い取り動作(protective wiping behavior)の回数を一分毎に投与後5分まで数えた。試験終了後、各分毎の回数の平均値を求め,最大回数を代表値とした。また、溶媒対照として5%Tween 80および5%エタノールを含有する生理食塩液を用い、同様の試験を行った。
結果を表10に示す。
Crl:CD系雄性ラットに、エタノールおよびTween 80を含有する生理食塩水に溶解した実施例2、16および37の化合物を、24時間間隔2回皮下投与し、小核誘発能を評価した。
本試験は、TRPV1の発現が豊富なラット後根神経節培養細胞を用いて、細胞内カルシウム濃度上昇を指標に、試験化合物のTRPV1のアゴニスト活性を測定するものであり、Jerman等の方法(Jerman,J.C.,et al., Comparison of effects of anandamide at recombinant and endogenous rat vanilloid receptors. Br J Anaesth, 2002. 89(6): p.882-7)に準じて試験を実施した。即ち、生後7日目のWistar系ラットから後根神経節を摘出し、コラゲナーゼ―トリプシン処置により細胞を単離した。その後、5%CO2、37℃に設定したCO2インキュベーターで2日間の初代培養を行った。培養液として、NeurobasalTM mediumにL-glutamine、nerve growth factor、N-2 Supplement、Penicillin−Streptomycin、5−Fluoro−2’−deoxyuridine(培養1日目のみ)を添加したものを用いた。
試験化合物の投与方法を除き、試験例1と同じ試験系および評価方法を用いて検討を行った(試験例1を参照)。
(1)%=(試験化合物投与後逃避閾値/試験化合物投与前逃避閾値)×100
(2)%=(試験化合物およびプレガバリン投与後逃避閾値/試験化合物投与前逃避閾値)×100
結果を以下の表12に示す。
Claims (21)
- 下記式(I):
R1は、メチル基または水素原子を示し、
R2は、水素原子、C1〜4アルキル基、C1〜4アルキルカルボニル基またはアリールカルボニル基を示し、
Aは、C3〜8シクロアルキル基、C3〜8シクロアルケニル基、アリール基またはヘテロアリール基(該各基は、C1〜6アルキル、C2〜6アルケニル、C3〜8シクロアルキルまたはハロゲンで置換可能な位置にて置換されていてもよい。)を示し、
nおよびmは、同一または相異なって1、2または3の整数を示し、pは、0、1、2または3の整数を示す。]
で表される化合物またはその生理的に許容される塩。 - 式(I)において、Aが、C3〜8シクロアルキル基またはアリール基(該各基は、C1〜6アルキル、C2〜6アルケニル、C3〜8シクロアルキル及びハロゲンからなる群から選ばれる、同一又は相異なった1個〜5個の置換基で置換されていてもよい。)を示す請求項1記載の化合物またはその生理的に許容される塩。
- 式(I)において、Aが、C3〜8シクロアルキル基またはアリール基(該各基は、C1〜6アルキル、C2〜6アルケニル及びC3〜8シクロアルキルからなる群から選ばれる、同一又は相異なった1個〜5個の置換基で置換されていてもよい。)を示す請求項1記載の化合物またはその生理的に許容される塩。
- 式(I)において、nおよびmが、同一または相異なって1または2の整数を示す請求項1〜3のいずれかに記載の化合物またはその生理的に許容される塩。
- 式(I)において、nおよびmが、共に2である請求項4に記載の化合物またはその生理的に許容される塩。
- 式(I)において、pが、0または1の整数を示す請求項1〜5のいずれかに記載の化合物またはその生理的に許容される塩。
- 式(I)において、pが、0の整数を示す請求項6に記載の化合物またはその生理的に許容される塩。
- 式(I)において、R1がメチル基を示す、請求項1〜7のいずれかに記載の化合物またはその生理的に許容される塩。
- 式(I)において、R2が水素原子を示す、請求項1〜8のいずれかに記載の化合物またはその生理的に許容される塩。
- 式(I)で表される化合物が、
4−エチルシクロヘキシル 4−(4−ヒドロキシ−3−メトキシベンジルカルバモイル)−ピペリジン−1−カルボキシレート、
4,4−ジメチルシクロヘキシル 4−(4−ヒドロキシ−3−メトキシベンジルカルバモイル)−ピペリジン−1−カルボキシレート、
3−メチルシクロヘキシル 4−(4−ヒドロキシ−3−メトキシベンジルカルバモイル)−ピペリジン−1−カルボキシレート、
2−メチルシクロヘキシル 4−(4−ヒドロキシ−3−メトキシベンジルカルバモイル)−ピペリジン−1−カルボキシレート、
4,4−ジエチルシクロヘキシル 3−(4−ヒドロキシ−3−メトキシベンジルカルバモイル)−アゼチジン−1−カルボキシレート、
4−t−ブチルシクロヘキシル 3−(4−ヒドロキシ−3−メトキシベンジルカルバモイル)−アゼチジン−1−カルボキシレート、
4−t−ブチルシクロヘキシル 3−(4−ヒドロキシ−3−メトキシベンジルカルバモイル)−ピロリジン−1−カルボキシレート、
4−メチルシクロヘキシル 4−(4−ヒドロキシ−3−メトキシベンジルカルバモイル)−ピペリジン−1−カルボキシレート、
3,3,5,5−テトラメチルシクロヘキシル 3−(4−ヒドロキシ−3−メトキシベンジルカルバモイル)−アゼチジン−1−カルボキシレート、
2−イソプロピル−5−メチルシクロヘキシル 3−(4−ヒドロキシ−3−メトキシベンジルカルバモイル)−アゼチジン−1−カルボキシレート、
4−エチルシクロヘキシル 3−(4−ヒドロキシ−3−メトキシベンジルカルバモイル)−ピロリジン−1−カルボキシレート、
4,4−ジメチルシクロヘキシル 3−(4−ヒドロキシ−3−メトキシベンジルカルバモイル)−ピロリジン−1−カルボキシレート、
4,4−ジエチルシクロヘキシル 3−(4−ヒドロキシ−3−メトキシベンジルカルバモイル)−ピロリジン−1−カルボキシレート、
4−t−ブチルシクロヘキシル 4−(4−ヒドロキシ−3−メトキシベンジルカルバモイル)−ピペリジン−1−カルボキシレート、
4−ブチルシクロヘキシル 3−(4−ヒドロキシ−3−メトキシベンジルカルバモイル)−アゼチジン−1−カルボキシレート、
4,4−ジエチルシクロヘキシル 4−(4−ヒドロキシ−3−メトキシベンジルカルバモイル)−ピペリジン−1−カルボキシレート、
3,5−ジメチルシクロヘキシル 4−(4−ヒドロキシ−3−メトキシベンジルカルバモイル)−ピペリジン−1−カルボキシレート、
2−エチルシクロヘキシル 4−(4−ヒドロキシ−3−メトキシベンジルカルバモイル)−ピペリジン−1−カルボキシレート、
4−エチルシクロヘキシル 3−(4−ヒドロキシ−3−メトキシベンジルカルバモイル)−アゼチジン−1−カルボキシレート、
3−メチルシクロヘキシル 3−(4−ヒドロキシ−3−メトキシベンジルカルバモイル)−アゼチジン−1−カルボキシレート、
4−イソプロピルシクロヘキシル 3−(4−ヒドロキシ−3−メトキシベンジルカルバモイル)−アゼチジン−1−カルボキシレート、
2−イソプロペニル−5−メチルシクロヘキシル 3−(4−ヒドロキシ−3−メトキシベンジルカルバモイル)−アゼチジン−1−カルボキシレート、
シクロヘプチル 4−(4−ヒドロキシ−3−メトキシベンジルカルバモイル)−ピペリジン−1−カルボキシレート、
シクロヘキシルメチル 4−(4−ヒドロキシ−3−メトキシベンジルカルバモイル)−ピペリジン−1−カルボキシレート、
2−イソプロピルフェニル 4−(4−ヒドロキシ−3−メトキシベンジルカルバモイル)−ピペリジン−1−カルボキシレート、
2−シクロペンチルフェニル 4−(4−ヒドロキシ−3−メトキシベンジルカルバモイル)−ピペリジン−1−カルボキシレート、
3−イソプロピルフェニル 4−(4−ヒドロキシ−3−メトキシベンジルカルバモイル)−ピペリジン−1−カルボキシレート、
4−イソプロピルフェニル 4−(4−ヒドロキシ−3−メトキシベンジルカルバモイル)−ピペリジン−1−カルボキシレート、
2−イソプロピルフェニル 3−(4−ヒドロキシ−3−メトキシベンジルカルバモイル)−アゼチジン−1−カルボキシレート、
2−シクロペンチルフェニル 3−(4−ヒドロキシ−3−メトキシベンジルカルバモイル)−アゼチジン−1−カルボキシレート、および
シクロヘキシル 4−(4−ヒドロキシ−3−メトキシベンジルカルバモイル)−ピペリジン−1−カルボキシレート
からなる群から選択される化合物である、請求項1記載の化合物またはその生理的に許容される塩。 - 式(I)で表される化合物が、
シス−4−エチルシクロヘキシル 4−(4−ヒドロキシ−3−メトキシベンジルカルバモイル)−ピペリジン−1−カルボキシレート、
トランス−4−エチルシクロヘキシル 4−(4−ヒドロキシ−3−メトキシベンジルカルバモイル)−ピペリジン−1−カルボキシレート、
4,4−ジメチルシクロヘキシル 4−(4−ヒドロキシ−3−メトキシベンジルカルバモイル)−ピペリジン−1−カルボキシレート、
トランス−3−メチルシクロヘキシル 4−(4−ヒドロキシ−3−メトキシベンジルカルバモイル)−ピペリジン−1−カルボキシレート、
シス−2−メチルシクロヘキシル 4−(4−ヒドロキシ−3−メトキシベンジルカルバモイル)−ピペリジン−1−カルボキシレート、
4,4−ジエチルシクロヘキシル 3−(4−ヒドロキシ−3−メトキシベンジルカルバモイル)−アゼチジン−1−カルボキシレート、
シス−4−t−ブチルシクロヘキシル 3−(4−ヒドロキシ−3−メトキシベンジルカルバモイル)−アゼチジン−1−カルボキシレート、
シス−4−t−ブチルシクロヘキシル (S)−3−(4−ヒドロキシ−3−メトキシベンジルカルバモイル)−ピロリジン−1−カルボキシレート、
シス−4−メチルシクロヘキシル 4−(4−ヒドロキシ−3−メトキシベンジルカルバモイル)−ピペリジン−1−カルボキシレート、
3,3,5,5−テトラメチルシクロヘキシル 3−(4−ヒドロキシ−3−メトキシベンジルカルバモイル)−アゼチジン−1−カルボキシレート、
(1S,2S,5R)−2−イソプロピル−5−メチルシクロヘキシル 3−(4−ヒドロキシ−3−メトキシベンジルカルバモイル)−アゼチジン−1−カルボキシレート、
シス−4−エチルシクロヘキシル (S)−3−(4−ヒドロキシ−3−メトキシベンジルカルバモイル)−ピロリジン−1−カルボキシレート、
4,4−ジメチルシクロヘキシル (S)−3−(4−ヒドロキシ−3−メトキシベンジルカルバモイル)−ピロリジン−1−カルボキシレート、および
4,4−ジエチルシクロヘキシル (S)−3−(4−ヒドロキシ−3−メトキシベンジルカルバモイル)−ピロリジン−1−カルボキシレート
からなる群から選択される化合物である、請求項1記載の化合物またはその生理的に許容される塩。 - 式(I)で表される化合物が、
シス−4−エチルシクロヘキシル 4−(4−ヒドロキシ−3−メトキシベンジルカルバモイル)−ピペリジン−1−カルボキシレート、
トランス−4−エチルシクロヘキシル 4−(4−ヒドロキシ−3−メトキシベンジルカルバモイル)−ピペリジン−1−カルボキシレート、
4,4−ジメチルシクロヘキシル 4−(4−ヒドロキシ−3−メトキシベンジルカルバモイル)−ピペリジン−1−カルボキシレート、
トランス−3−メチルシクロヘキシル 4−(4−ヒドロキシ−3−メトキシベンジルカルバモイル)−ピペリジン−1−カルボキシレート、
シス−2−メチルシクロヘキシル 4−(4−ヒドロキシ−3−メトキシベンジルカルバモイル)−ピペリジン−1−カルボキシレート、
4,4−ジエチルシクロヘキシル 3−(4−ヒドロキシ−3−メトキシベンジルカルバモイル)−アゼチジン−1−カルボキシレート、
シス−4−t−ブチルシクロヘキシル 3−(4−ヒドロキシ−3−メトキシベンジルカルバモイル)−アゼチジン−1−カルボキシレート、
シス−4−t−ブチルシクロヘキシル (S)−3−(4−ヒドロキシ−3−メトキシベンジルカルバモイル)−ピロリジン−1−カルボキシレート、
シス−4−メチルシクロヘキシル 4−(4−ヒドロキシ−3−メトキシベンジルカルバモイル)−ピペリジン−1−カルボキシレート、
トランス−4−メチルシクロヘキシル 4−(4−ヒドロキシ−3−メトキシベンジルカルバモイル)−ピペリジン−1−カルボキシレート、
シス−4−t−ブチルシクロヘキシル 4−(4−ヒドロキシ−3−メトキシベンジルカルバモイル)−ピペリジン−1−カルボキシレート、
シクロヘプチル 4−(4−ヒドロキシ−3−メトキシベンジルカルバモイル)−ピペリジン−1−カルボキシレート、
シクロヘキシルメチル 4−(4−ヒドロキシ−3−メトキシベンジルカルバモイル)−ピペリジン−1−カルボキシレート、
シス−3−メチルシクロヘキシル 4−(4−ヒドロキシ−3−メトキシベンジルカルバモイル)−ピペリジン−1−カルボキシレート、
トランス−2−メチルシクロヘキシル 4−(4−ヒドロキシ−3−メトキシベンジルカルバモイル)−ピペリジン−1−カルボキシレート、
トランス−4−t−ブチルシクロヘキシル 3−(4−ヒドロキシ−3−メトキシベンジルカルバモイル)−アゼチジン−1−カルボキシレート、
3,3,5,5−テトラメチルシクロヘキシル 3−(4−ヒドロキシ−3−メトキシベンジルカルバモイル)−アゼチジン−1−カルボキシレート、
シス−4−ブチルシクロヘキシル 3−(4−ヒドロキシ−3−メトキシベンジルカルバモイル)−アゼチジン−1−カルボキシレート、
シクロヘキシル 4−(4−ヒドロキシ−3−メトキシベンジルカルバモイル)−ピペリジン−1−カルボキシレート
からなる群から選択される化合物である、請求項1記載の化合物またはその生理的に許容される塩。 - 活性成分として請求項1〜12のいずれかに記載の化合物またはその生理的に許容される塩を含有する医薬組成物。
- 請求項1〜12のいずれかに記載の化合物またはその生理的に許容される塩を有効成分として含有する、疼痛および/または炎症の治療剤または予防剤。
- 請求項1〜12のいずれかに記載の化合物またはその生理的に許容される塩の有効量を患者に投与することを含む、疼痛および/または炎症を治療または予防するための方法。
- 疼痛および/または炎症の治療剤または予防剤を製造するための、請求項1〜12のいずれかに記載の化合物またはその生理的に許容される塩の使用。
- 請求項1〜12のいずれかに記載の化合物またはその生理的に許容される塩と、
麻薬性鎮痛薬、神経因性疼痛治療薬、非ステロイド性抗炎症薬、ステロイド性抗炎症薬、抗うつ薬、抗てんかん薬、抗攣縮薬、麻酔薬、抗不整脈薬、局所麻酔薬及び抗不安薬からなる群より選択される少なくとも1種の他の薬剤とを備える医薬。 - 活性成分として請求項17記載の医薬を含有する医薬組成物。
- 請求項17記載の医薬を有効成分として含有する、疼痛および/または炎症の治療剤または予防剤。
- 請求項17記載の医薬の有効量を患者に投与することを含む、疼痛および/または炎症を治療または予防するための方法。
- 疼痛および/または炎症の治療剤または予防剤を製造するための、請求項17記載の医薬の使用。
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JP2008121701 | 2008-05-07 | ||
JP2008121701 | 2008-05-07 | ||
PCT/JP2009/058644 WO2009136625A1 (ja) | 2008-05-07 | 2009-05-07 | 環状アミン-1-カルボン酸エステル誘導体およびそれを含有する医薬組成物 |
JP2010511078A JP4746713B2 (ja) | 2008-05-07 | 2009-05-07 | 環状アミン−1−カルボン酸エステル誘導体およびそれを含有する医薬組成物 |
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JPWO2009136625A1 true JPWO2009136625A1 (ja) | 2011-09-08 |
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US (1) | US8367835B2 (ja) |
EP (2) | EP2277861A4 (ja) |
JP (1) | JP4746713B2 (ja) |
KR (1) | KR101409651B1 (ja) |
CN (1) | CN102089277B (ja) |
AU (1) | AU2009245121B2 (ja) |
CA (1) | CA2721815C (ja) |
ES (1) | ES2433008T3 (ja) |
HK (1) | HK1168089A1 (ja) |
WO (1) | WO2009136625A1 (ja) |
Families Citing this family (10)
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CA2771592A1 (en) * | 2009-09-04 | 2011-03-10 | Zalicus Pharmaceuticals Ltd. | Substituted heterocyclic derivatives for the treatment of pain and epilepsy |
JP2013028536A (ja) * | 2009-11-11 | 2013-02-07 | Dainippon Sumitomo Pharma Co Ltd | 環状アミン−1−カルボン酸エステル誘導体およびそれを含有する医薬組成物 |
BR112014024382B1 (pt) | 2012-04-18 | 2022-08-09 | SpecGx LLC | Composições farmacêuticas de contenção de abuso de liberação imediata e seu processo de preparação |
US10208023B2 (en) | 2013-03-01 | 2019-02-19 | Mark G. DeGiacomo | Heterocyclic inhibitors of the sodium channel |
US9301918B2 (en) | 2013-03-15 | 2016-04-05 | Mallinckrodt Llc | Abuse deterrent solid dosage form for immediate release with functional score |
AU2015284078B2 (en) | 2014-07-03 | 2020-01-30 | SpecGx LLC | Abuse deterrent immediate release formulations comprising non-cellulose polysaccharides |
CN107709314A (zh) * | 2015-06-11 | 2018-02-16 | 巴斯利尔药物国际股份公司 | 外排泵抑制剂及其治疗性用途 |
EP3856160A4 (en) | 2018-09-25 | 2022-07-06 | SpecGx LLC | ANTI-ABUSE IMMEDIATE RELEASE CAPSULES DOSAGE FORMS |
GB2584471A (en) * | 2019-06-05 | 2020-12-09 | James Frank Thomas Peter | Improvements in or relating to organic material |
MX2023002683A (es) | 2020-09-07 | 2023-04-03 | Sumitomo Pharma Co Ltd | Derivado de fenol. |
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TWI239942B (en) | 2001-06-11 | 2005-09-21 | Dainippon Pharmaceutical Co | N-arylphenylacetamide derivative and pharmaceutical composition containing the same |
TWI283665B (en) * | 2001-09-13 | 2007-07-11 | Smithkline Beecham Plc | Novel urea compound, pharmaceutical composition containing the same and its use |
WO2004087646A2 (de) | 2003-04-03 | 2004-10-14 | Merck Patent Gmbh | Pyrrolidin -1,2-dicarbonsäure-1-(phenylamid) -2- (4-(3-oxo-morpholin-4-yl)-phenylamid) derivate und verwandte verbindungen als inhibitoren des koagulationsfaktors xa zur behandlung von thromboembolischen erkrankungen |
GB0319150D0 (en) * | 2003-08-14 | 2003-09-17 | Glaxo Group Ltd | Novel compounds |
DE602004019294D1 (de) * | 2003-10-01 | 2009-03-19 | Xention Ltd | Tetrahydronaphthalin- und harnstoffderivate |
GB0325287D0 (en) | 2003-10-29 | 2003-12-03 | Merck Sharp & Dohme | Therapeutic agents |
JP4250582B2 (ja) * | 2004-09-30 | 2009-04-08 | 株式会社東芝 | 携帯端末 |
JP5159604B2 (ja) | 2005-03-19 | 2013-03-06 | アモーレパシフィック コーポレイション | バニロイド受容体拮抗薬としての新規な化合物、その異性体又はその薬剤学的に許容される塩、及びこれを含む医薬組成物 |
CN101203483A (zh) | 2005-04-21 | 2008-06-18 | 大日本住友制药株式会社 | N-取代的苯乙酰胺衍生物和包含该衍生物的药物组合物 |
BRPI0613505A2 (pt) | 2005-06-30 | 2011-01-11 | Prosidion Ltd | agonistas de gpcr |
US20080227823A1 (en) | 2007-03-12 | 2008-09-18 | Hassan Pajouhesh | Amide derivatives as calcium channel blockers |
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2009
- 2009-05-07 JP JP2010511078A patent/JP4746713B2/ja not_active Expired - Fee Related
- 2009-05-07 WO PCT/JP2009/058644 patent/WO2009136625A1/ja active Application Filing
- 2009-05-07 US US12/991,224 patent/US8367835B2/en active Active
- 2009-05-07 AU AU2009245121A patent/AU2009245121B2/en not_active Ceased
- 2009-05-07 CN CN200980126428.8A patent/CN102089277B/zh not_active Expired - Fee Related
- 2009-05-07 KR KR1020107026843A patent/KR101409651B1/ko not_active IP Right Cessation
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- 2009-05-07 ES ES12166546T patent/ES2433008T3/es active Active
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- 2009-05-07 EP EP12166546.7A patent/EP2484664B1/en not_active Not-in-force
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Also Published As
Publication number | Publication date |
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KR101409651B1 (ko) | 2014-06-18 |
US8367835B2 (en) | 2013-02-05 |
ES2433008T3 (es) | 2013-12-05 |
KR20110010620A (ko) | 2011-02-01 |
JP4746713B2 (ja) | 2011-08-10 |
HK1168089A1 (en) | 2012-12-21 |
EP2277861A1 (en) | 2011-01-26 |
CA2721815C (en) | 2014-06-10 |
EP2484664A1 (en) | 2012-08-08 |
US20120028937A1 (en) | 2012-02-02 |
EP2484664B1 (en) | 2013-09-04 |
AU2009245121B2 (en) | 2013-08-01 |
EP2277861A4 (en) | 2012-05-02 |
AU2009245121A1 (en) | 2009-11-12 |
CN102089277B (zh) | 2014-02-12 |
CA2721815A1 (en) | 2009-11-12 |
WO2009136625A1 (ja) | 2009-11-12 |
CN102089277A (zh) | 2011-06-08 |
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