JP2014141480A - Pharmaceuticals containing methylpiperidine derivatives - Google Patents
Pharmaceuticals containing methylpiperidine derivatives Download PDFInfo
- Publication number
- JP2014141480A JP2014141480A JP2013270612A JP2013270612A JP2014141480A JP 2014141480 A JP2014141480 A JP 2014141480A JP 2013270612 A JP2013270612 A JP 2013270612A JP 2013270612 A JP2013270612 A JP 2013270612A JP 2014141480 A JP2014141480 A JP 2014141480A
- Authority
- JP
- Japan
- Prior art keywords
- methanone
- methylpiperidin
- benzoxazol
- phenyl
- methyl
- 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.)
- Pending
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- PAMIQIKDUOTOBW-UHFFFAOYSA-N 1-methylpiperidine Chemical class CN1CCCCC1 PAMIQIKDUOTOBW-UHFFFAOYSA-N 0.000 title claims abstract description 23
- 239000003814 drug Substances 0.000 title claims description 18
- 150000001875 compounds Chemical class 0.000 claims abstract description 155
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 92
- 201000010099 disease Diseases 0.000 claims abstract description 64
- 150000003839 salts Chemical class 0.000 claims abstract description 28
- 208000024827 Alzheimer disease Diseases 0.000 claims abstract description 25
- 208000019901 Anxiety disease Diseases 0.000 claims abstract description 25
- 208000023105 Huntington disease Diseases 0.000 claims abstract description 25
- 206010020772 Hypertension Diseases 0.000 claims abstract description 25
- 206010061218 Inflammation Diseases 0.000 claims abstract description 25
- 208000019695 Migraine disease Diseases 0.000 claims abstract description 25
- 208000002193 Pain Diseases 0.000 claims abstract description 25
- 208000018737 Parkinson disease Diseases 0.000 claims abstract description 25
- 230000002124 endocrine Effects 0.000 claims abstract description 25
- 206010015037 epilepsy Diseases 0.000 claims abstract description 25
- 230000004054 inflammatory process Effects 0.000 claims abstract description 25
- 206010027599 migraine Diseases 0.000 claims abstract description 25
- 208000019116 sleep disease Diseases 0.000 claims abstract description 25
- 206010013663 drug dependence Diseases 0.000 claims abstract description 24
- 208000019906 panic disease Diseases 0.000 claims abstract description 24
- 208000020685 sleep-wake disease Diseases 0.000 claims abstract description 24
- 208000011117 substance-related disease Diseases 0.000 claims abstract description 24
- 201000000980 schizophrenia Diseases 0.000 claims abstract description 23
- 239000004480 active ingredient Substances 0.000 claims abstract description 20
- 230000001225 therapeutic effect Effects 0.000 claims abstract description 11
- 208000018522 Gastrointestinal disease Diseases 0.000 claims abstract description 8
- 208000010643 digestive system disease Diseases 0.000 claims abstract description 6
- 208000018685 gastrointestinal system disease Diseases 0.000 claims abstract description 6
- -1 5-chloro-1,3-benzoxazol-2-yl Chemical group 0.000 claims description 89
- 239000000203 mixture Substances 0.000 claims description 62
- WSFSSNUMVMOOMR-BJUDXGSMSA-N methanone Chemical compound O=[11CH2] WSFSSNUMVMOOMR-BJUDXGSMSA-N 0.000 claims description 41
- 125000005843 halogen group Chemical group 0.000 claims description 37
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 35
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 29
- 208000030814 Eating disease Diseases 0.000 claims description 24
- 208000019454 Feeding and Eating disease Diseases 0.000 claims description 24
- 235000014632 disordered eating Nutrition 0.000 claims description 24
- 208000035475 disorder Diseases 0.000 claims description 22
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 20
- 125000004191 (C1-C6) alkoxy group Chemical group 0.000 claims description 19
- 230000001079 digestive effect Effects 0.000 claims description 17
- 229940079593 drug Drugs 0.000 claims description 15
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 13
- 229910052757 nitrogen Inorganic materials 0.000 claims description 12
- 125000000246 pyrimidin-2-yl group Chemical group [H]C1=NC(*)=NC([H])=C1[H] 0.000 claims description 11
- 125000000714 pyrimidinyl group Chemical group 0.000 claims description 10
- 125000001072 heteroaryl group Chemical group 0.000 claims description 9
- 230000003449 preventive effect Effects 0.000 claims description 9
- 230000002265 prevention Effects 0.000 claims description 8
- 125000001425 triazolyl group Chemical group 0.000 claims description 8
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 7
- 125000004105 2-pyridyl group Chemical group N1=C([*])C([H])=C([H])C([H])=C1[H] 0.000 claims description 6
- LTGVIMBNYBDWGE-HUUCEWRRSA-N [(2r,5r)-5-(5-chloro-1,3-benzoxazol-2-yl)-2-methylpiperidin-1-yl]-[6-methyl-3-(triazol-2-yl)pyridin-2-yl]methanone Chemical compound C([C@@H](CC[C@H]1C)C=2OC3=CC=C(Cl)C=C3N=2)N1C(=O)C1=NC(C)=CC=C1N1N=CC=N1 LTGVIMBNYBDWGE-HUUCEWRRSA-N 0.000 claims description 5
- GXCBYDCDBQWJFX-UHFFFAOYSA-N 2-(triazol-2-yl)benzaldehyde Chemical compound O=CC1=CC=CC=C1N1N=CC=N1 GXCBYDCDBQWJFX-UHFFFAOYSA-N 0.000 claims description 4
- JRLUKOVCDNSLJA-UHFFFAOYSA-N 2-pyrimidin-2-ylbenzaldehyde Chemical compound O=CC1=CC=CC=C1C1=NC=CC=N1 JRLUKOVCDNSLJA-UHFFFAOYSA-N 0.000 claims description 4
- WKDHORIIWZFUCN-UHFFFAOYSA-N 5-fluoro-2-pyrimidin-2-ylbenzaldehyde Chemical compound O=CC1=CC(F)=CC=C1C1=NC=CC=N1 WKDHORIIWZFUCN-UHFFFAOYSA-N 0.000 claims description 4
- RDBXBVVGBXXYNE-UHFFFAOYSA-N 5-methyl-2-(triazol-2-yl)benzaldehyde Chemical compound O=CC1=CC(C)=CC=C1N1N=CC=N1 RDBXBVVGBXXYNE-UHFFFAOYSA-N 0.000 claims description 4
- BYWWIDLMCZNAIS-UHFFFAOYSA-N 6-methyl-3-pyrimidin-2-ylpyridine-2-carbaldehyde Chemical compound O=CC1=NC(C)=CC=C1C1=NC=CC=N1 BYWWIDLMCZNAIS-UHFFFAOYSA-N 0.000 claims description 4
- NOIRPBCONVSVMR-HUUCEWRRSA-N [(2r,5r)-5-(5-chloro-1,3-benzoxazol-2-yl)-2-methylpiperidin-1-yl]-(5-chloro-2-pyrimidin-2-ylphenyl)methanone Chemical compound C([C@@H](CC[C@H]1C)C=2OC3=CC=C(Cl)C=C3N=2)N1C(=O)C1=CC(Cl)=CC=C1C1=NC=CC=N1 NOIRPBCONVSVMR-HUUCEWRRSA-N 0.000 claims description 4
- SOBBTAWPHJEHLX-CHWSQXEVSA-N [(2r,5r)-5-(6-chloro-[1,3]oxazolo[5,4-b]pyridin-2-yl)-2-methylpiperidin-1-yl]-[4-fluoro-2-(triazol-2-yl)phenyl]methanone Chemical compound C([C@@H](CC[C@H]1C)C=2OC3=NC=C(Cl)C=C3N=2)N1C(=O)C1=CC=C(F)C=C1N1N=CC=N1 SOBBTAWPHJEHLX-CHWSQXEVSA-N 0.000 claims description 4
- BXASEUXJISXETE-HUUCEWRRSA-N [(2r,5r)-5-(6-chloro-[1,3]oxazolo[5,4-b]pyridin-2-yl)-2-methylpiperidin-1-yl]-[5-methyl-2-(triazol-2-yl)phenyl]methanone Chemical compound C([C@@H](CC[C@H]1C)C=2OC3=NC=C(Cl)C=C3N=2)N1C(=O)C1=CC(C)=CC=C1N1N=CC=N1 BXASEUXJISXETE-HUUCEWRRSA-N 0.000 claims description 4
- 239000003795 chemical substances by application Substances 0.000 claims description 4
- 125000001424 substituent group Chemical group 0.000 claims description 4
- KWXXYJTVZUNOOG-HUUCEWRRSA-N (5-chloro-2-pyrimidin-2-ylphenyl)-[(2r,5r)-2-methyl-5-[5-(trifluoromethyl)-1,3-benzoxazol-2-yl]piperidin-1-yl]methanone Chemical compound C([C@@H](CC[C@H]1C)C=2OC3=CC=C(C=C3N=2)C(F)(F)F)N1C(=O)C1=CC(Cl)=CC=C1C1=NC=CC=N1 KWXXYJTVZUNOOG-HUUCEWRRSA-N 0.000 claims description 3
- XTLWVQBJKPVFEJ-HUUCEWRRSA-N (5-chloro-2-pyrimidin-2-ylphenyl)-[(2r,5r)-5-(5-fluoro-1,3-benzoxazol-2-yl)-2-methylpiperidin-1-yl]methanone Chemical compound C([C@@H](CC[C@H]1C)C=2OC3=CC=C(F)C=C3N=2)N1C(=O)C1=CC(Cl)=CC=C1C1=NC=CC=N1 XTLWVQBJKPVFEJ-HUUCEWRRSA-N 0.000 claims description 3
- VQQSXMICRNLDDU-IAGOWNOFSA-N (5-methyl-2-pyrimidin-2-ylphenyl)-[(2r,5r)-2-methyl-5-[5-(trifluoromethyl)-1,3-benzoxazol-2-yl]piperidin-1-yl]methanone Chemical compound C([C@@H](CC[C@H]1C)C=2OC3=CC=C(C=C3N=2)C(F)(F)F)N1C(=O)C1=CC(C)=CC=C1C1=NC=CC=N1 VQQSXMICRNLDDU-IAGOWNOFSA-N 0.000 claims description 3
- DUHXORFTDVELMU-IEBWSBKVSA-N 2-[(3r,6r)-6-methyl-1-(5-methyl-2-pyrimidin-2-ylbenzoyl)piperidin-3-yl]-1,3-benzoxazole-5-carbonitrile Chemical compound C([C@@H](CC[C@H]1C)C=2OC3=CC=C(C=C3N=2)C#N)N1C(=O)C1=CC(C)=CC=C1C1=NC=CC=N1 DUHXORFTDVELMU-IEBWSBKVSA-N 0.000 claims description 3
- PNCMVTWYNKEPGV-SJLPKXTDSA-N 2-[(3r,6r)-6-methyl-1-[5-methyl-2-(triazol-2-yl)benzoyl]piperidin-3-yl]-1,3-benzoxazole-5-carbonitrile Chemical compound C([C@@H](CC[C@H]1C)C=2OC3=CC=C(C=C3N=2)C#N)N1C(=O)C1=CC(C)=CC=C1N1N=CC=N1 PNCMVTWYNKEPGV-SJLPKXTDSA-N 0.000 claims description 3
- BDIYZDDQOQDSFL-HZPDHXFCSA-N [(2r,5r)-5-(4,6-difluoro-1,3-benzoxazol-2-yl)-2-methylpiperidin-1-yl]-(5-methyl-2-pyrimidin-2-ylphenyl)methanone Chemical compound C([C@@H](CC[C@H]1C)C=2OC3=CC(F)=CC(F)=C3N=2)N1C(=O)C1=CC(C)=CC=C1C1=NC=CC=N1 BDIYZDDQOQDSFL-HZPDHXFCSA-N 0.000 claims description 3
- HFTSBIQERRDTOK-HUUCEWRRSA-N [(2r,5r)-5-(4-chloro-1,3-benzoxazol-2-yl)-2-methylpiperidin-1-yl]-(5-fluoro-2-pyrimidin-2-ylphenyl)methanone Chemical compound C([C@@H](CC[C@H]1C)C=2OC3=CC=CC(Cl)=C3N=2)N1C(=O)C1=CC(F)=CC=C1C1=NC=CC=N1 HFTSBIQERRDTOK-HUUCEWRRSA-N 0.000 claims description 3
- AJVBSJHAKPEZBR-IAGOWNOFSA-N [(2r,5r)-5-(4-chloro-1,3-benzoxazol-2-yl)-2-methylpiperidin-1-yl]-(5-methyl-2-pyrimidin-2-ylphenyl)methanone Chemical compound C([C@@H](CC[C@H]1C)C=2OC3=CC=CC(Cl)=C3N=2)N1C(=O)C1=CC(C)=CC=C1C1=NC=CC=N1 AJVBSJHAKPEZBR-IAGOWNOFSA-N 0.000 claims description 3
- ZSFSAEXOZCUEIK-HZPDHXFCSA-N [(2r,5r)-5-(4-fluoro-1,3-benzoxazol-2-yl)-2-methylpiperidin-1-yl]-[5-methyl-2-(triazol-2-yl)phenyl]methanone Chemical compound C([C@@H](CC[C@H]1C)C=2OC3=CC=CC(F)=C3N=2)N1C(=O)C1=CC(C)=CC=C1N1N=CC=N1 ZSFSAEXOZCUEIK-HZPDHXFCSA-N 0.000 claims description 3
- CWGKRFLVTUKSPJ-ZIAGYGMSSA-N [(2r,5r)-5-(5,6-difluoro-1,3-benzoxazol-2-yl)-2-methylpiperidin-1-yl]-(5-fluoro-2-pyrimidin-2-ylphenyl)methanone Chemical compound C([C@@H](CC[C@H]1C)C=2OC3=CC(F)=C(F)C=C3N=2)N1C(=O)C1=CC(F)=CC=C1C1=NC=CC=N1 CWGKRFLVTUKSPJ-ZIAGYGMSSA-N 0.000 claims description 3
- WQKZAVICPKONHT-HZPDHXFCSA-N [(2r,5r)-5-(5,6-difluoro-1,3-benzoxazol-2-yl)-2-methylpiperidin-1-yl]-(5-methyl-2-pyrimidin-2-ylphenyl)methanone Chemical compound C([C@@H](CC[C@H]1C)C=2OC3=CC(F)=C(F)C=C3N=2)N1C(=O)C1=CC(C)=CC=C1C1=NC=CC=N1 WQKZAVICPKONHT-HZPDHXFCSA-N 0.000 claims description 3
- CKMMIKDRHQZEHQ-HZPDHXFCSA-N [(2r,5r)-5-(5,7-difluoro-1,3-benzoxazol-2-yl)-2-methylpiperidin-1-yl]-(5-methyl-2-pyrimidin-2-ylphenyl)methanone Chemical compound C([C@@H](CC[C@H]1C)C=2OC3=C(F)C=C(F)C=C3N=2)N1C(=O)C1=CC(C)=CC=C1C1=NC=CC=N1 CKMMIKDRHQZEHQ-HZPDHXFCSA-N 0.000 claims description 3
- UPBDBBDMNGPZTG-HUUCEWRRSA-N [(2r,5r)-5-(5-chloro-1,3-benzoxazol-2-yl)-2-methylpiperidin-1-yl]-(2-fluoro-6-pyrimidin-2-ylphenyl)methanone Chemical compound C([C@@H](CC[C@H]1C)C=2OC3=CC=C(Cl)C=C3N=2)N1C(=O)C1=C(F)C=CC=C1C1=NC=CC=N1 UPBDBBDMNGPZTG-HUUCEWRRSA-N 0.000 claims description 3
- BCPYIFDFGLBCFI-HUUCEWRRSA-N [(2r,5r)-5-(5-chloro-1,3-benzoxazol-2-yl)-2-methylpiperidin-1-yl]-(4-fluoro-2-pyrimidin-2-ylphenyl)methanone Chemical compound C([C@@H](CC[C@H]1C)C=2OC3=CC=C(Cl)C=C3N=2)N1C(=O)C1=CC=C(F)C=C1C1=NC=CC=N1 BCPYIFDFGLBCFI-HUUCEWRRSA-N 0.000 claims description 3
- HYCOJYOEZMVPLV-ZIAGYGMSSA-N [(2r,5r)-5-(5-chloro-1,3-benzoxazol-2-yl)-2-methylpiperidin-1-yl]-[2-fluoro-6-(triazol-2-yl)phenyl]methanone Chemical compound C([C@@H](CC[C@H]1C)C=2OC3=CC=C(Cl)C=C3N=2)N1C(=O)C1=C(F)C=CC=C1N1N=CC=N1 HYCOJYOEZMVPLV-ZIAGYGMSSA-N 0.000 claims description 3
- HIBDUGVEJVHVBD-ZIAGYGMSSA-N [(2r,5r)-5-(5-chloro-1,3-benzoxazol-2-yl)-2-methylpiperidin-1-yl]-[3-fluoro-2-(triazol-2-yl)phenyl]methanone Chemical compound C([C@@H](CC[C@H]1C)C=2OC3=CC=C(Cl)C=C3N=2)N1C(=O)C1=CC=CC(F)=C1N1N=CC=N1 HIBDUGVEJVHVBD-ZIAGYGMSSA-N 0.000 claims description 3
- QBHPBUFJKACQAY-ZIAGYGMSSA-N [(2r,5r)-5-(5-chloro-1,3-benzoxazol-2-yl)-2-methylpiperidin-1-yl]-[4-fluoro-2-(triazol-2-yl)phenyl]methanone Chemical compound C([C@@H](CC[C@H]1C)C=2OC3=CC=C(Cl)C=C3N=2)N1C(=O)C1=CC=C(F)C=C1N1N=CC=N1 QBHPBUFJKACQAY-ZIAGYGMSSA-N 0.000 claims description 3
- DEGDKCRYRVFWFW-HZPDHXFCSA-N [(2r,5r)-5-(5-chloro-1,3-benzoxazol-2-yl)-2-methylpiperidin-1-yl]-[4-methyl-2-(triazol-2-yl)phenyl]methanone Chemical compound C([C@@H](CC[C@H]1C)C=2OC3=CC=C(Cl)C=C3N=2)N1C(=O)C1=CC=C(C)C=C1N1N=CC=N1 DEGDKCRYRVFWFW-HZPDHXFCSA-N 0.000 claims description 3
- JNZPDTIJNSUNOW-HUUCEWRRSA-N [(2r,5r)-5-(5-chloro-1,3-benzoxazol-2-yl)-2-methylpiperidin-1-yl]-[5-fluoro-2-(5-methoxypyrimidin-2-yl)phenyl]methanone Chemical compound N1=CC(OC)=CN=C1C1=CC=C(F)C=C1C(=O)N1[C@H](C)CC[C@@H](C=2OC3=CC=C(Cl)C=C3N=2)C1 JNZPDTIJNSUNOW-HUUCEWRRSA-N 0.000 claims description 3
- ZKRWEUKQLHTEJJ-HZPDHXFCSA-N [(2r,5r)-5-(5-fluoro-1,3-benzoxazol-2-yl)-2-methylpiperidin-1-yl]-(2-pyrimidin-2-ylphenyl)methanone Chemical compound C([C@@H](CC[C@H]1C)C=2OC3=CC=C(F)C=C3N=2)N1C(=O)C1=CC=CC=C1C1=NC=CC=N1 ZKRWEUKQLHTEJJ-HZPDHXFCSA-N 0.000 claims description 3
- CAZRGCGHEOCKLV-HUUCEWRRSA-N [(2r,5r)-5-(5-fluoro-1,3-benzoxazol-2-yl)-2-methylpiperidin-1-yl]-(5-fluoro-2-pyrimidin-2-ylphenyl)methanone Chemical compound C([C@@H](CC[C@H]1C)C=2OC3=CC=C(F)C=C3N=2)N1C(=O)C1=CC(F)=CC=C1C1=NC=CC=N1 CAZRGCGHEOCKLV-HUUCEWRRSA-N 0.000 claims description 3
- YAHDLBXXEGKPKL-HUUCEWRRSA-N [(2r,5r)-5-(5-fluoro-1,3-benzoxazol-2-yl)-2-methylpiperidin-1-yl]-[2-(triazol-2-yl)phenyl]methanone Chemical compound C([C@@H](CC[C@H]1C)C=2OC3=CC=C(F)C=C3N=2)N1C(=O)C1=CC=CC=C1N1N=CC=N1 YAHDLBXXEGKPKL-HUUCEWRRSA-N 0.000 claims description 3
- ZVFJYBKPLWRACQ-ZIAGYGMSSA-N [(2r,5r)-5-(5-fluoro-1,3-benzoxazol-2-yl)-2-methylpiperidin-1-yl]-[5-fluoro-2-(triazol-2-yl)phenyl]methanone Chemical compound C([C@@H](CC[C@H]1C)C=2OC3=CC=C(F)C=C3N=2)N1C(=O)C1=CC(F)=CC=C1N1N=CC=N1 ZVFJYBKPLWRACQ-ZIAGYGMSSA-N 0.000 claims description 3
- QRWUHWVNVUTITA-HZPDHXFCSA-N [(2r,5r)-5-(6,7-difluoro-1,3-benzoxazol-2-yl)-2-methylpiperidin-1-yl]-(5-methyl-2-pyrimidin-2-ylphenyl)methanone Chemical compound C([C@@H](CC[C@H]1C)C=2OC3=C(F)C(F)=CC=C3N=2)N1C(=O)C1=CC(C)=CC=C1C1=NC=CC=N1 QRWUHWVNVUTITA-HZPDHXFCSA-N 0.000 claims description 3
- VTSASDPVEUQDPY-HUUCEWRRSA-N [(2r,5r)-5-(6-chloro-1,3-benzoxazol-2-yl)-2-methylpiperidin-1-yl]-(5-fluoro-2-pyrimidin-2-ylphenyl)methanone Chemical compound C([C@@H](CC[C@H]1C)C=2OC3=CC(Cl)=CC=C3N=2)N1C(=O)C1=CC(F)=CC=C1C1=NC=CC=N1 VTSASDPVEUQDPY-HUUCEWRRSA-N 0.000 claims description 3
- UETJKKXRKNELKY-IAGOWNOFSA-N [(2r,5r)-5-(6-chloro-1,3-benzoxazol-2-yl)-2-methylpiperidin-1-yl]-(5-methyl-2-pyrimidin-2-ylphenyl)methanone Chemical compound C([C@@H](CC[C@H]1C)C=2OC3=CC(Cl)=CC=C3N=2)N1C(=O)C1=CC(C)=CC=C1C1=NC=CC=N1 UETJKKXRKNELKY-IAGOWNOFSA-N 0.000 claims description 3
- AQFXSFHAIKNJES-ZIAGYGMSSA-N [(2r,5r)-5-(6-chloro-1,3-benzoxazol-2-yl)-2-methylpiperidin-1-yl]-[2-fluoro-6-(triazol-2-yl)phenyl]methanone Chemical compound C([C@@H](CC[C@H]1C)C=2OC3=CC(Cl)=CC=C3N=2)N1C(=O)C1=C(F)C=CC=C1N1N=CC=N1 AQFXSFHAIKNJES-ZIAGYGMSSA-N 0.000 claims description 3
- BYFKGFCQVGGYBQ-ZIAGYGMSSA-N [(2r,5r)-5-(6-chloro-1,3-benzoxazol-2-yl)-2-methylpiperidin-1-yl]-[4-fluoro-2-(triazol-2-yl)phenyl]methanone Chemical compound C([C@@H](CC[C@H]1C)C=2OC3=CC(Cl)=CC=C3N=2)N1C(=O)C1=CC=C(F)C=C1N1N=CC=N1 BYFKGFCQVGGYBQ-ZIAGYGMSSA-N 0.000 claims description 3
- AVSJYLGLCUKFQB-HZPDHXFCSA-N [(2r,5r)-5-(6-chloro-1,3-benzoxazol-2-yl)-2-methylpiperidin-1-yl]-[5-methyl-2-(triazol-2-yl)phenyl]methanone Chemical compound C([C@@H](CC[C@H]1C)C=2OC3=CC(Cl)=CC=C3N=2)N1C(=O)C1=CC(C)=CC=C1N1N=CC=N1 AVSJYLGLCUKFQB-HZPDHXFCSA-N 0.000 claims description 3
- KDQGNNDPQRWRHU-HUUCEWRRSA-N [(2r,5r)-5-(6-chloro-1,3-benzoxazol-2-yl)-2-methylpiperidin-1-yl]-[6-methyl-3-(triazol-2-yl)pyridin-2-yl]methanone Chemical compound C([C@@H](CC[C@H]1C)C=2OC3=CC(Cl)=CC=C3N=2)N1C(=O)C1=NC(C)=CC=C1N1N=CC=N1 KDQGNNDPQRWRHU-HUUCEWRRSA-N 0.000 claims description 3
- IOMVORXMZSGYAU-HZPDHXFCSA-N [(2r,5r)-5-(7-fluoro-1,3-benzoxazol-2-yl)-2-methylpiperidin-1-yl]-[5-methyl-2-(triazol-2-yl)phenyl]methanone Chemical compound C([C@@H](CC[C@H]1C)C=2OC3=C(F)C=CC=C3N=2)N1C(=O)C1=CC(C)=CC=C1N1N=CC=N1 IOMVORXMZSGYAU-HZPDHXFCSA-N 0.000 claims description 3
- RBXCARZAWJKBGI-ZIAGYGMSSA-N [5-bromo-2-(triazol-2-yl)phenyl]-[(2r,5r)-5-(5-chloro-1,3-benzoxazol-2-yl)-2-methylpiperidin-1-yl]methanone Chemical compound C([C@@H](CC[C@H]1C)C=2OC3=CC=C(Cl)C=C3N=2)N1C(=O)C1=CC(Br)=CC=C1N1N=CC=N1 RBXCARZAWJKBGI-ZIAGYGMSSA-N 0.000 claims description 3
- SLQDEIHULNIKSZ-ZIAGYGMSSA-N [5-chloro-2-(triazol-2-yl)phenyl]-[(2r,5r)-5-(5-fluoro-1,3-benzoxazol-2-yl)-2-methylpiperidin-1-yl]methanone Chemical compound C([C@@H](CC[C@H]1C)C=2OC3=CC=C(F)C=C3N=2)N1C(=O)C1=CC(Cl)=CC=C1N1N=CC=N1 SLQDEIHULNIKSZ-ZIAGYGMSSA-N 0.000 claims description 3
- KLMYHTBSEBGMNF-HZPDHXFCSA-N [5-methyl-2-(triazol-2-yl)phenyl]-[(2r,5r)-2-methyl-5-[5-(trifluoromethyl)-1,3-benzoxazol-2-yl]piperidin-1-yl]methanone Chemical compound C([C@@H](CC[C@H]1C)C=2OC3=CC=C(C=C3N=2)C(F)(F)F)N1C(=O)C1=CC(C)=CC=C1N1N=CC=N1 KLMYHTBSEBGMNF-HZPDHXFCSA-N 0.000 claims description 3
- 125000003545 alkoxy group Chemical group 0.000 claims description 3
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- 239000008101 lactose Substances 0.000 description 1
- 210000003796 lateral hypothalamic area Anatomy 0.000 description 1
- 238000001294 liquid chromatography-tandem mass spectrometry Methods 0.000 description 1
- GLXDVVHUTZTUQK-UHFFFAOYSA-M lithium hydroxide monohydrate Substances [Li+].O.[OH-] GLXDVVHUTZTUQK-UHFFFAOYSA-M 0.000 description 1
- 229940040692 lithium hydroxide monohydrate Drugs 0.000 description 1
- 210000004185 liver Anatomy 0.000 description 1
- 210000000627 locus coeruleus Anatomy 0.000 description 1
- 231100000053 low toxicity Toxicity 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 229910001629 magnesium chloride Inorganic materials 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- 239000011976 maleic acid Substances 0.000 description 1
- 239000001630 malic acid Substances 0.000 description 1
- 235000011090 malic acid Nutrition 0.000 description 1
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- 239000000594 mannitol Substances 0.000 description 1
- 235000010355 mannitol Nutrition 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 230000037323 metabolic rate Effects 0.000 description 1
- VAUIDGILAZCFMS-UHFFFAOYSA-N methyl 6-methyl-1-[5-methyl-2-(triazol-2-yl)benzoyl]piperidine-3-carboxylate Chemical compound C1C(C(=O)OC)CCC(C)N1C(=O)C1=CC(C)=CC=C1N1N=CC=N1 VAUIDGILAZCFMS-UHFFFAOYSA-N 0.000 description 1
- 235000010755 mineral Nutrition 0.000 description 1
- 239000011707 mineral Substances 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000001280 n-hexyl group Chemical group C(CCCCC)* 0.000 description 1
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- KVBGVZZKJNLNJU-UHFFFAOYSA-N naphthalene-2-sulfonic acid Chemical compound C1=CC=CC2=CC(S(=O)(=O)O)=CC=C21 KVBGVZZKJNLNJU-UHFFFAOYSA-N 0.000 description 1
- 125000005244 neohexyl group Chemical group [H]C([H])([H])C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000001971 neopentyl group Chemical group [H]C([*])([H])C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 210000000653 nervous system Anatomy 0.000 description 1
- 238000006386 neutralization reaction Methods 0.000 description 1
- 229930027945 nicotinamide-adenine dinucleotide Natural products 0.000 description 1
- 229910017604 nitric acid Inorganic materials 0.000 description 1
- 230000008452 non REM sleep Effects 0.000 description 1
- 230000002474 noradrenergic effect Effects 0.000 description 1
- 239000002674 ointment Substances 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 210000001672 ovary Anatomy 0.000 description 1
- 235000006408 oxalic acid Nutrition 0.000 description 1
- 125000002971 oxazolyl group Chemical group 0.000 description 1
- KDLHZDBZIXYQEI-UHFFFAOYSA-N palladium Substances [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 1
- 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 1
- 125000003538 pentan-3-yl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])C([H])([H])[H] 0.000 description 1
- 239000008194 pharmaceutical composition Substances 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 230000000704 physical effect Effects 0.000 description 1
- 150000003053 piperidines Chemical class 0.000 description 1
- 125000003386 piperidinyl group Chemical group 0.000 description 1
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 1
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 1
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- WSHYKIAQCMIPTB-UHFFFAOYSA-M potassium;2-oxo-3-(3-oxo-1-phenylbutyl)chromen-4-olate Chemical compound [K+].[O-]C=1C2=CC=CC=C2OC(=O)C=1C(CC(=O)C)C1=CC=CC=C1 WSHYKIAQCMIPTB-UHFFFAOYSA-M 0.000 description 1
- DBABZHXKTCFAPX-UHFFFAOYSA-N probenecid Chemical compound CCCN(CCC)S(=O)(=O)C1=CC=C(C(O)=O)C=C1 DBABZHXKTCFAPX-UHFFFAOYSA-N 0.000 description 1
- 229960003081 probenecid Drugs 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 125000003373 pyrazinyl group Chemical group 0.000 description 1
- 125000003226 pyrazolyl group Chemical group 0.000 description 1
- 125000002098 pyridazinyl group Chemical group 0.000 description 1
- 125000004076 pyridyl group Chemical group 0.000 description 1
- 238000011002 quantification Methods 0.000 description 1
- 230000002285 radioactive effect Effects 0.000 description 1
- 210000001609 raphe nuclei Anatomy 0.000 description 1
- 239000002464 receptor antagonist Substances 0.000 description 1
- 229940044551 receptor antagonist Drugs 0.000 description 1
- 230000015355 regulation of circadian sleep/wake cycle, sleep Effects 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 238000012552 review Methods 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 229940076279 serotonin Drugs 0.000 description 1
- 238000004904 shortening Methods 0.000 description 1
- 239000000377 silicon dioxide Substances 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 229910000033 sodium borohydride Inorganic materials 0.000 description 1
- 239000012279 sodium borohydride Substances 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 239000012312 sodium hydride Substances 0.000 description 1
- 230000002269 spontaneous effect Effects 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 230000000638 stimulation Effects 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 229910052717 sulfur Inorganic materials 0.000 description 1
- 125000004434 sulfur atom Chemical group 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 239000000725 suspension Substances 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
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 125000001973 tert-pentyl group Chemical group [H]C([H])([H])C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 125000000335 thiazolyl group Chemical group 0.000 description 1
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 1
- 210000004515 ventral tegmental area Anatomy 0.000 description 1
Landscapes
- Plural Heterocyclic Compounds (AREA)
- Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
Description
本発明は、オレキシン(OX)受容体拮抗作用を有する化合物及びその医薬上許容される塩、並びにそれらを有効成分として含有することを特徴とする医薬組成物、特に、睡眠障害、うつ病、不安障害、パニック障害、統合失調症、薬物依存症、アルツハイマー病、パーキンソン病、ハンチントン舞踏病、摂食障害、頭痛、片頭痛、疼痛、消化器疾患、てんかん、炎症、免疫関連疾患、内分泌関連疾患、高血圧等の疾患の治療又は予防薬に関する。 The present invention relates to a compound having orexin (OX) receptor antagonistic activity and a pharmaceutically acceptable salt thereof, and a pharmaceutical composition comprising them as active ingredients, particularly sleep disorders, depression, anxiety Disorder, panic disorder, schizophrenia, drug addiction, Alzheimer's disease, Parkinson's disease, Huntington's disease, eating disorder, headache, migraine, pain, digestive disorders, epilepsy, inflammation, immune related diseases, endocrine related diseases, The present invention relates to a therapeutic or preventive drug for diseases such as hypertension.
オレキシンは、視床下部外側野に特異的に発現するプレプロオレキシンからスプライシングされる神経ペプチドである。これまでに、33個のアミノ酸からなるOX−Aおよび28個のアミノ酸からなるOX−Bが同定されており、これらはいずれも睡眠・覚醒パターンの調節や摂食の調節に深く関与している。 Orexin is a neuropeptide spliced from preproorexin that is specifically expressed in the lateral hypothalamic area. So far, OX-A consisting of 33 amino acids and OX-B consisting of 28 amino acids have been identified, both of which are deeply involved in the regulation of sleep / wake patterns and the regulation of food intake. .
OX−AおよびOX−Bは、いずれもOX受容体に作用する。OX受容体は、これまでにOX1およびOX2受容体の2つのサブタイプがクローニングされており、いずれも主として脳内に発現する7回膜貫通Gタンパク質共役型受容体であることが知られている。OX1受容体は、Gタンパク質サブクラスのうちGqと特異的に共役しており、一方でOX2受容体はGqおよびGi/oに共役している(非特許文献1及び非特許文献2参照)。
OX受容体のサブタイプによって組織分布は異なっており、OX1受容体はノルアドレナリン作動性神経の起始核である青斑核、OX2受容体はヒスタミン神経の起始核である結節乳頭核に高密度に発現している(非特許文献3、非特許文献4及び非特許文献5参照)。セロトニン神経の起始核である縫線核や、ドパミン神経の起始核である腹側被蓋野にはOX1受容体とOX2受容体両方の発現がみられる(非特許文献3参照)。オレキシン神経は脳幹と視床下部のモノアミン神経系に投射し、それらの神経に対して興奮性の影響を与えており、さらにREM睡眠の制御に関わる脳幹のアセチルコリン神経にもOX2受容体の発現がみられ、これらの神経核の活性にも影響を及ぼしている(非特許文献3及び非特許文献4参照)。
Both OX-A and OX-B act on the OX receptor. The OX receptor has been cloned so far in two subtypes of OX1 and OX2 receptors, both of which are known to be 7-transmembrane G protein-coupled receptors that are mainly expressed in the brain. . The OX1 receptor is specifically conjugated to Gq in the G protein subclass, while the OX2 receptor is conjugated to Gq and Gi / o (see Non-Patent Document 1 and Non-Patent Document 2).
The tissue distribution varies depending on the subtype of the OX receptor. The OX1 receptor has a high density in the locus coeruleus, the origin of noradrenergic nerves, and the OX2 receptor in the nodule papillary nucleus, the origin of histamine neurons. (See Non-Patent Document 3, Non-Patent Document 4 and Non-Patent Document 5). Expression of both the OX1 receptor and the OX2 receptor is observed in the raphe nucleus which is the origin nucleus of the serotonin nerve and the ventral tegmental area which is the origin nucleus of the dopamine nerve (see Non-Patent Document 3). Orexin neurons project to the brain stem and the monoamine nervous system in the hypothalamus and have an excitatory effect on those nerves. Furthermore, the expression of OX2 receptors is also seen in the acetylcholine neurons of the brain stem involved in REM sleep control. It also affects the activity of these nerve nuclei (see Non-Patent Document 3 and Non-Patent Document 4).
近年、OX1およびOX2受容体と睡眠・覚醒調節との関連が注目されており、OX受容体拮抗作用を有する化合物の有用性が研究されている。OX−Aをラットの脳室内に投与すると、自発運動量の亢進(非特許文献6及び非特許文献7参照)、常同行動の亢進(非特許文献7参照)、覚醒時間の延長(非特許文献6参照)などが認められる。OX−Aの投与によるREM睡眠時間の短縮作用は、OX受容体拮抗物質の前処置により完全に拮抗される(非特許文献8参照)。さらに、経口投与が可能なOX1およびOX2受容体を同程度に拮抗する物質の投与により、運動量の減少、入眠潜時の短縮、non−REM睡眠量およびREM睡眠の増加が報告されている(非特許文献9および非特許文献10参照)。
OX受容体拮抗作用化合物としては、例えば総説として非特許文献11に記載の種々の構造を有する化合物が知られている。また、特許文献1〜3には、置換ピペリジン誘導体が開示されているが、本願記載のピペリジン環にベンゾオキサゾール環が直接結合している化合物についての開示はない。
In recent years, attention has been focused on the relationship between OX1 and OX2 receptors and sleep / wake regulation, and the usefulness of compounds having OX receptor antagonistic activity has been studied. When OX-A is administered into the cerebral ventricles of rats, the amount of spontaneous exercise is increased (see Non-Patent Document 6 and Non-Patent Document 7), the normal behavior is increased (see Non-Patent Document 7), and the awakening time is extended (Non-Patent Document). 6). The action of shortening REM sleep time by administration of OX-A is completely antagonized by pretreatment with an OX receptor antagonist (see Non-Patent Document 8). Furthermore, administration of substances that antagonize OX1 and OX2 receptors to the same extent that can be administered orally has been reported to reduce exercise, shorten sleep onset latency, increase non-REM sleep and REM sleep (non-) (See Patent Document 9 and Non-Patent Document 10).
As OX receptor antagonistic compounds, for example, compounds having various structures described in Non-Patent Document 11 as a review are known. Patent Documents 1 to 3 disclose substituted piperidine derivatives, but do not disclose a compound in which a benzoxazole ring is directly bonded to the piperidine ring described in the present application.
本発明の目的は、OX受容体拮抗作用を有する新規化合物を有効成分として含有することを特徴とする睡眠障害、うつ病、不安障害、パニック障害、統合失調症、薬物依存症、アルツハイマー病、パーキンソン病、ハンチントン舞踏病、摂食障害、頭痛、片頭痛、疼痛、消化器疾患、てんかん、炎症、免疫関連疾患、内分泌関連疾患、高血圧等の疾患の治療又は予防薬を提供することにある。さらに詳しくは、優れたOX受容体拮抗作用と共に優れた薬物動態及び安全性を示す新規化合物を有効成分として含有することを特徴とする医薬を提供することにある。 An object of the present invention is to provide a sleep disorder, depression, anxiety disorder, panic disorder, schizophrenia, drug dependence, Alzheimer's disease, Parkinson, characterized by containing a novel compound having an OX receptor antagonistic action as an active ingredient It is to provide a therapeutic or prophylactic agent for diseases such as diseases, Huntington's chorea, eating disorders, headache, migraine, pain, digestive disorders, epilepsy, inflammation, immune-related diseases, endocrine-related diseases, and hypertension. More specifically, it is intended to provide a medicament characterized by containing a novel compound exhibiting excellent pharmacokinetics and safety as well as excellent OX receptor antagonism as an active ingredient.
本発明者らはオレキシン受容体に対し拮抗作用を有する新規な骨格の化合物につき鋭意検討した結果、下記に示す式で表されるある種のメチルピペリジン誘導体に優れたOX受容体拮抗作用があることを見出し、本発明を完成した。
以下、本発明を詳細に説明する。本発明の態様(以下、「本発明化合物」という)は以下に示すものである。
(1)式(IA)
As a result of intensive studies on a novel skeletal compound having an antagonistic action on the orexin receptor, the present inventors have found that a certain methylpiperidine derivative represented by the following formula has an excellent OX receptor antagonistic action. The present invention has been completed.
Hereinafter, the present invention will be described in detail. The embodiment of the present invention (hereinafter referred to as “the compound of the present invention”) is shown below.
(1) Formula (IA)
Xは、窒素原子、又は式CHを示し、
Yは、窒素原子、又は式CHを示し、
R1は、水素原子、ハロゲン原子、シアノ基、C1-6アルキル基(該C1-6アルキル基は、1〜3個のハロゲン原子で置換されてもよい)、又はC1-6アルコキシ基を示し、
R2は、ヘテロアリール基(該ヘテロアリール基は、ハロゲン原子及びC1-6アルコキシ基からなる群から選ばれる同一又は異なった1〜3個の置換基で置換されてもよい)を示し、
R3及びR4は、同一に又は異なって、水素原子、ハロゲン原子、シアノ基、C1-6アルキル基、又はC1-6アルコキシ基(該C1-6アルキル基、及びC1-6アルコキシ基は1〜3個のハロゲン原子で置換されてもよい)を示す。)
で表されるメチルピペリジン誘導体、又はその医薬上許容される塩を有効成分として含有することを特徴とする睡眠障害、うつ病、不安障害、パニック障害、統合失調症、薬物依存症、アルツハイマー病、パーキンソン病、ハンチントン舞踏病、摂食障害、疼痛、片頭痛、消化器疾患、てんかん、炎症、免疫関連疾患、内分泌関連疾患、高血圧等の疾患の治療又は予防薬、
(2)上記式(IA)において、
R3が、ハロゲン原子、シアノ基、C1-6アルキル基、又はC1-6アルコキシ基(該C1-6アルキル基、及びC1-6アルコキシ基は1〜3個のハロゲン原子で置換されてもよい)であり、
R4が、水素原子、又はハロゲン原子である(1)に記載のメチルピペリジン誘導体、又はその医薬上許容される塩を有効成分として含有することを特徴とする睡眠障害、うつ病、不安障害、パニック障害、統合失調症、薬物依存症、アルツハイマー病、パーキンソン病、ハンチントン舞踏病、摂食障害、疼痛、片頭痛、消化器疾患、てんかん、炎症、免疫関連疾患、内分泌関連疾患、高血圧等の疾患の治療又は予防薬、
(3)上記式(IA)において、
R2が、トリアゾリル基、又はピリミジニル基(該ピリミジニル基は、ハロゲン原子及びC1-6アルコキシ基からなる群から選ばれる同一又は異なった1〜3個の置換基で置換されてもよい)である(1)又は(2)いずれかに記載のメチルピペリジン誘導体、又はその医薬上許容される塩を有効成分として含有することを特徴とする睡眠障害、うつ病、不安障害、パニック障害、統合失調症、薬物依存症、アルツハイマー病、パーキンソン病、ハンチントン舞踏病、摂食障害、疼痛、片頭痛、消化器疾患、てんかん、炎症、免疫関連疾患、内分泌関連疾患、高血圧等の疾患の治療又は予防薬、
(4)上記式(IA)において、
R1が、水素原子、ハロゲン原子、又はC1-6アルキル基である(1)〜(3)いずれか1つに記載のメチルピペリジン誘導体、又はその医薬上許容される塩を有効成分として含有することを特徴とする睡眠障害、うつ病、不安障害、パニック障害、統合失調症、薬物依存症、アルツハイマー病、パーキンソン病、ハンチントン舞踏病、摂食障害、疼痛、片頭痛、消化器疾患、てんかん、炎症、免疫関連疾患、内分泌関連疾患、高血圧等の疾患の治療又は予防薬、
(5)上記式(IA)において、
Yが、式CHであり、
R2が、トリアゾリル基、又はピリミジニル基である(1)〜(4)いずれか1つに記載のメチルピペリジン誘導体、又はその医薬上許容される塩を有効成分として含有することを特徴とする睡眠障害、うつ病、不安障害、パニック障害、統合失調症、薬物依存症、アルツハイマー病、パーキンソン病、ハンチントン舞踏病、摂食障害、疼痛、片頭痛、消化器疾患、てんかん、炎症、免疫関連疾患、内分泌関連疾患、高血圧等の疾患の治療又は予防薬、
(6)上記式(IA)において、
Xが、窒素原子であり、
R4が、水素原子である(1)〜(5)いずれか1つに記載のメチルピペリジン誘導体、又はその医薬上許容される塩を有効成分として含有することを特徴とする睡眠障害、うつ病、不安障害、パニック障害、統合失調症、薬物依存症、アルツハイマー病、パーキンソン病、ハンチントン舞踏病、摂食障害、疼痛、片頭痛、消化器疾患、てんかん、炎症、免疫関連疾患、内分泌関連疾患、高血圧等の疾患の治療又は予防薬、
(7)上記式(IA)が、式(IIA)
X represents a nitrogen atom or the formula CH;
Y represents a nitrogen atom or the formula CH;
R 1 is a hydrogen atom, a halogen atom, a cyano group, a C 1-6 alkyl group (the C 1-6 alkyl group may be substituted with 1 to 3 halogen atoms), or C 1-6 alkoxy Group,
R 2 represents a heteroaryl group (the heteroaryl group may be substituted with 1 to 3 identical or different substituents selected from the group consisting of a halogen atom and a C 1-6 alkoxy group);
R 3 and R 4 are the same or different and each represents a hydrogen atom, a halogen atom, a cyano group, a C 1-6 alkyl group, or a C 1-6 alkoxy group (the C 1-6 alkyl group and C 1-6 An alkoxy group may be substituted with 1 to 3 halogen atoms). )
A sleep disorder, depression, anxiety disorder, panic disorder, schizophrenia, drug dependence, Alzheimer's disease, characterized by containing a methylpiperidine derivative represented by the formula: Parkinson's disease, Huntington's chorea, eating disorders, pain, migraine, digestive disorders, epilepsy, inflammation, immune related diseases, endocrine related diseases, therapeutic or preventive drugs for diseases such as hypertension,
(2) In the above formula (IA),
R 3 is a halogen atom, a cyano group, a C 1-6 alkyl group, or a C 1-6 alkoxy group (the C 1-6 alkyl group and the C 1-6 alkoxy group are substituted with 1 to 3 halogen atoms) May be)
A sleep disorder, depression, anxiety disorder, wherein R 4 contains the methylpiperidine derivative according to (1) or a pharmaceutically acceptable salt thereof as an active ingredient, which is a hydrogen atom or a halogen atom; Diseases such as panic disorder, schizophrenia, drug addiction, Alzheimer's disease, Parkinson's disease, Huntington's disease, eating disorders, pain, migraine, digestive disorders, epilepsy, inflammation, immune related diseases, endocrine related diseases, hypertension Treatment or prevention of
(3) In the above formula (IA),
R 2 is a triazolyl group or a pyrimidinyl group (the pyrimidinyl group may be substituted with 1 to 3 identical or different substituents selected from the group consisting of a halogen atom and a C 1-6 alkoxy group). A sleep disorder, depression, anxiety disorder, panic disorder, schizophrenia characterized by containing the methylpiperidine derivative according to any one of (1) and (2) or a pharmaceutically acceptable salt thereof as an active ingredient , Drug dependence, Alzheimer's disease, Parkinson's disease, Huntington's disease, eating disorders, pain, migraine, digestive disorders, epilepsy, inflammation, immune-related diseases, endocrine-related diseases, hypertension, etc. ,
(4) In the above formula (IA),
The methyl piperidine derivative or the pharmaceutically acceptable salt thereof according to any one of (1) to (3), wherein R 1 is a hydrogen atom, a halogen atom, or a C 1-6 alkyl group as an active ingredient Sleep disorder, depression, anxiety disorder, panic disorder, schizophrenia, drug addiction, Alzheimer's disease, Parkinson's disease, Huntington's chorea, eating disorders, pain, migraine, digestive disorders, epilepsy , Therapeutic or prophylactic agent for diseases such as inflammation, immune related diseases, endocrine related diseases, hypertension,
(5) In the above formula (IA),
Y is the formula CH;
R 2 is a triazolyl group or a pyrimidinyl group and contains the methylpiperidine derivative according to any one of (1) to (4), or a pharmaceutically acceptable salt thereof as an active ingredient. Disorder, depression, anxiety disorder, panic disorder, schizophrenia, drug addiction, Alzheimer's disease, Parkinson's disease, Huntington's chorea, eating disorders, pain, migraine, digestive disorders, epilepsy, inflammation, immune related diseases, Endocrine related diseases, therapeutic or preventive drugs for diseases such as hypertension
(6) In the above formula (IA),
X is a nitrogen atom,
A sleep disorder or depression characterized by containing, as an active ingredient, the methylpiperidine derivative according to any one of (1) to (5), or a pharmaceutically acceptable salt thereof, wherein R 4 is a hydrogen atom. , Anxiety disorder, panic disorder, schizophrenia, drug addiction, Alzheimer's disease, Parkinson's disease, Huntington's disease, eating disorder, pain, migraine, digestive disorders, epilepsy, inflammation, immune related diseases, endocrine related diseases, Therapeutic or preventive drugs for diseases such as hypertension,
(7) The above formula (IA) is converted to formula (IIA)
(8)式(I)
(8) Formula (I)
Xは、窒素原子、又は式CHを示し、
R1は、水素原子、ハロゲン原子、又はC1-6アルキル基を示し、
R2は、ヘテロアリール基(該ヘテロアリール基は、1〜3個のハロゲン原子で置換されてもよい)を示し、
R3は、水素原子、ハロゲン原子、C1-6アルキル基、又はC1-6アルコキシ基(該C1-6アルキル基、及びC1-6アルコキシ基は1〜3個のハロゲン原子で置換されてもよい)を示す。)
で表されるメチルピペリジン誘導体、又はその医薬上許容される塩を有効成分として含有することを特徴とする睡眠障害、うつ病、不安障害、パニック障害、統合失調症、薬物依存症、アルツハイマー病、パーキンソン病、ハンチントン舞踏病、摂食障害、疼痛、片頭痛、消化器疾患、てんかん、炎症、免疫関連疾患、内分泌関連疾患、高血圧等の疾患の治療又は予防薬、
(9)上記式(I)において、
Xが、窒素原子であり、
R1が、水素原子、又はC1-6アルキル基であり、
R2が、トリアゾリル基、又はピリミジニル基であり、
R3が、ハロゲン原子である(8)に記載のメチルピペリジン誘導体、又はその医薬上許容される塩を有効成分として含有することを特徴とする睡眠障害、うつ病、不安障害、パニック障害、統合失調症、薬物依存症、アルツハイマー病、パーキンソン病、ハンチントン舞踏病、摂食障害、疼痛、片頭痛、消化器疾患、てんかん、炎症、免疫関連疾患、内分泌関連疾患、高血圧等の疾患の治療又は予防薬、
(10)上記式(I)が、式(II)
X represents a nitrogen atom or the formula CH;
R 1 represents a hydrogen atom, a halogen atom, or a C 1-6 alkyl group,
R 2 represents a heteroaryl group (the heteroaryl group may be substituted with 1 to 3 halogen atoms);
R 3 represents a hydrogen atom, a halogen atom, a C 1-6 alkyl group, or a C 1-6 alkoxy group (the C 1-6 alkyl group and the C 1-6 alkoxy group are substituted with 1 to 3 halogen atoms) May be). )
A sleep disorder, depression, anxiety disorder, panic disorder, schizophrenia, drug dependence, Alzheimer's disease, characterized by containing a methylpiperidine derivative represented by the formula: Parkinson's disease, Huntington's chorea, eating disorders, pain, migraine, digestive disorders, epilepsy, inflammation, immune related diseases, endocrine related diseases, therapeutic or preventive drugs for diseases such as hypertension,
(9) In the above formula (I),
X is a nitrogen atom,
R 1 is a hydrogen atom or a C 1-6 alkyl group,
R 2 is a triazolyl group or a pyrimidinyl group;
Sleep disorder, depression, anxiety disorder, panic disorder, integration characterized by containing, as an active ingredient, the methylpiperidine derivative according to (8), wherein R 3 is a halogen atom, or a pharmaceutically acceptable salt thereof Treatment or prevention of diseases such as ataxia, drug addiction, Alzheimer's disease, Parkinson's disease, Huntington's disease, eating disorders, pain, migraine, digestive disorders, epilepsy, inflammation, immune related diseases, endocrine related diseases, hypertension medicine,
(10) The above formula (I) is converted to formula (II)
(11)上記(1)に記載される下記化合物群及びその医薬上許容される塩から選ばれるいずれか1種又は2種以上の混合物を有効成分として含有することを特徴とする睡眠障害、うつ病、不安障害、パニック障害、統合失調症、薬物依存症、アルツハイマー病、パーキンソン病、ハンチントン舞踏病、摂食障害、疼痛、片頭痛、消化器疾患、てんかん、炎症、免疫関連疾患、内分泌関連疾患、高血圧等の疾患の治療又は予防薬。
[(2R,5R)−5−(5−クロロ−1,3−ベンゾオキサゾール−2−イル)−2−メチルピペリジン−1−イル][6−メチル−3−(2H−1,2,3−トリアゾール−2−イル)ピリジン−2−イル]メタノン、
[(2R*,5R*)−5−(5−クロロ−1,3−ベンゾオキサゾール−2−イル)−2−メチルピペリジン−1−イル][5−フルオロ−2−(2H−1,2,3−トリアゾール−2−イル)フェニル]メタノン、
[(2R*,5R*)−5−(5−クロロ−1,3−ベンゾオキサゾール−2−イル)−2−メチルピペリジン−1−イル][2−(2H−1,2,3−トリアゾール−2−イル)フェニル]メタノン、
[(2R*,5R*)−5−(5−クロロ−1,3−ベンゾオキサゾール−2−イル)−2−メチルピペリジン−1−イル][6−メチル−3−(ピリミジン−2−イル)ピリジン−2−イル]メタノン、
[(2R*,5R*)−5−(5−クロロ−1,3−ベンゾオキサゾール−2−イル)−2−メチルピペリジン−1−イル][5−メチル−2−(ピリミジン−2−イル)フェニル]メタノン、
[(2R*,5R*)−5−(5−クロロ−1,3−ベンゾオキサゾール−2−イル)−2−メチルピペリジン−1−イル][5−フルオロ−2−(ピリミジン−2−イル)フェニル]メタノン、
[(2R*,5R*)−5−(5−クロロ−1,3−ベンゾオキサゾール−2−イル)−2−メチルピペリジン−1−イル][2−(ピリミジン−2−イル)フェニル]メタノン、
[(2R*,5R*)−5−(5−フルオロ−1,3−ベンゾオキサゾール−2−イル)−2−メチルピペリジン−1−イル][5−メチル−2−(ピリミジン−2−イル)フェニル]メタノン、
[(2R*,5R*)−5−(5−クロロ−1,3−ベンゾオキサゾール−2−イル)−2−メチルピペリジン−1−イル][5−メチル−2−(2H−1,2,3−トリアゾール−2−イル)フェニル]メタノン、
[(2R*,5R*)−5−(5−フルオロ−1,3−ベンゾオキサゾール−2−イル)−2−メチルピペリジン−1−イル][5−メチル−2−(2H−1,2,3−トリアゾール−2−イル)フェニル]メタノン、
[(2R*,5R*)−5−(5−フルオロ−1,3−ベンゾオキサゾール−2−イル)−2−メチルピペリジン−1−イル][6−メチル−3−(2H−1,2,3−トリアゾール−2−イル)ピリジン−2−イル]メタノン、
[(2R,5R)−5−(5−クロロ−1,3−ベンゾオキサゾール−2−イル)−2−メチルピペリジン−1−イル][5−クロロ−2−(ピリミジン−2−イル)フェニル]メタノン、
[(2R,5R)−5−(5−クロロ−1,3−ベンゾオキサゾール−2−イル)−2−メチルピペリジン−1−イル][4−フルオロ−2−(2H−1,2,3−トリアゾール−2−イル)フェニル]メタノン、
[(2R,5R)−5−(5−クロロ−1,3−ベンゾオキサゾール−2−イル)−2−メチルピペリジン−1−イル][3−フルオロ−2−(2H−1,2,3−トリアゾール−2−イル)フェニル]メタノン、
[(2R,5R)−5−(5−クロロ−1,3−ベンゾオキサゾール−2−イル)−2−メチルピペリジン−1−イル][2−フルオロ−6−(2H−1,2,3−トリアゾール−2−イル)フェニル]メタノン、
[(2R,5R)−5−(5−クロロ−1,3−ベンゾオキサゾール−2−イル)−2−メチルピペリジン−1−イル][4−フルオロ−2−(ピリミジン−2−イル)フェニル]メタノン、
[(2R,5R)−5−(5−クロロ−1,3−ベンゾオキサゾール−2−イル)−2−メチルピペリジン−1−イル][2−フルオロ−6−(ピリミジン−2−イル)フェニル]メタノン、
[5−ブロモ−2−(2H−1,2,3−トリアゾール−2−イル)フェニル][(2R,5R)−5−(5−クロロ−1,3−ベンゾオキサゾール−2−イル)−2−メチルピペリジン−1−イル]メタノン、
[(2R,5R)−5−(5−クロロ−1,3−ベンゾオキサゾール−2−イル)−2−メチルピペリジン−1−イル][5−フルオロ−2−(5−メトキシピリミジン−2−イル)フェニル]メタノン、
[(2R,5R)−5−(5−クロロ−1,3−ベンゾオキサゾール−2−イル)−2−メチルピペリジン−1−イル][4−メチル−2−(2H−1,2,3−トリアゾール−2−イル)フェニル]メタノン、
[(2R,5R)−5−(5−フルオロ−1,3−ベンゾオキサゾール−2−イル)−2−メチルピペリジン−1−イル][2−(2H−1,2,3−トリアゾール−2−イル)フェニル]メタノン、
[(2R,5R)−5−(5−フルオロ−1,3−ベンゾオキサゾール−2−イル)−2−メチルピペリジン−1−イル][5−フルオロ−2−(2H−1,2,3−トリアゾール−2−イル)フェニル]メタノン、
[5−クロロ−2−(2H−1,2,3−トリアゾール−2−イル)フェニル][(2R,5R)−5−(5−フルオロ−1,3−ベンゾオキサゾール−2−イル)−2−メチルピペリジン−1−イル]メタノン、
[(2R,5R)−5−(5−フルオロ−1,3−ベンゾオキサゾール−2−イル)−2−メチルピペリジン−1−イル][2−(ピリミジン−2−イル)フェニル]メタノン、
[(2R,5R)−5−(5−フルオロ−1,3−ベンゾオキサゾール−2−イル)−2−メチルピペリジン−1−イル][5−フルオロ−2−(ピリミジン−2−イル)フェニル]メタノン、
[5−クロロ−2−(ピリミジン−2−イル)フェニル][(2R,5R)−5−(5−フルオロ−1,3−ベンゾオキサゾール−2−イル)−2−メチルピペリジン−1−イル]メタノン、
[(2R,5R)−5−(5−フルオロ−1,3−ベンゾオキサゾール−2−イル)−2−メチルピペリジン−1−イル][4−フルオロ−2−(2H−1,2,3−トリアゾール−2−イル)フェニル]メタノン、
[(2R,5R)−5−(5−フルオロ−1,3−ベンゾオキサゾール−2−イル)−2−メチルピペリジン−1−イル][2−フルオロ−6−(2H−1,2,3−トリアゾール−2−イル)フェニル]メタノン、
[5−メチル−2−(2H−1,2,3−トリアゾール−2−イル)フェニル]{(2R,5R)−2−メチル−5−[5−(トリフルオロメチル)−1,3−ベンゾオキサゾール−2−イル]ピペリジン−1−イル}メタノン、
[5−メチル−2−(ピリミジン−2−イル)フェニル]{(2R,5R)−2−メチル−5−[5−(トリフルオロメチル)−1,3−ベンゾオキサゾール−2−イル]ピペリジン−1−イル}メタノン、
[5−クロロ−2−(ピリミジン−2−イル)フェニル]{(2R,5R)−2−メチル−5−[5−(トリフルオロメチル)−1,3−ベンゾオキサゾール−2−イル]ピペリジン−1−イル}メタノン、
[(2R,5R)−5−(6−クロロ−1,3−ベンゾオキサゾール−2−イル)−2−メチルピペリジン−1−イル][5−メチル−2−(2H−1,2,3−トリアゾール−2−イル)フェニル]メタノン、
[(2R,5R)−5−(6−クロロ−1,3−ベンゾオキサゾール−2−イル)−2−メチルピペリジン−1−イル][5−メチル−2−(ピリミジン−2−イル)フェニル]メタノン、
[(2R,5R)−5−(6−クロロ−1,3−ベンゾオキサゾール−2−イル)−2−メチルピペリジン−1−イル][5−フルオロ−2−(ピリミジン−2−イル)フェニル]メタノン、
[(2R,5R)−5−(6−クロロ−1,3−ベンゾオキサゾール−2−イル)−2−メチルピペリジン−1−イル][6−メチル−3−(2H−1,2,3−トリアゾール−2−イル)ピリジン−2−イル]メタノン、
[(2R,5R)−5−(6−クロロ−1,3−ベンゾオキサゾール−2−イル)−2−メチルピペリジン−1−イル][4−フルオロ−2−(2H−1,2,3−トリアゾール−2−イル)フェニル]メタノン、
[(2R,5R)−5−(6−クロロ−1,3−ベンゾオキサゾール−2−イル)−2−メチルピペリジン−1−イル][2−フルオロ−6−(2H−1,2,3−トリアゾール−2−イル)フェニル]メタノン、
[(2R,5R)−5−(5,6−ジフルオロ−1,3−ベンゾオキサゾール−2−イル)−2−メチルピペリジン−1−イル][5−メチル−2−(2H−1,2,3−トリアゾール−2−イル)フェニル]メタノン、
[(2R,5R)−5−(5,6−ジフルオロ−1,3−ベンゾオキサゾール−2−イル)−2−メチルピペリジン−1−イル][5−メチル−2−(ピリミジン−2−イル)フェニル]メタノン、
[(2R,5R)−5−(5,6−ジフルオロ−1,3−ベンゾオキサゾール−2−イル)−2−メチルピペリジン−1−イル][5−フルオロ−2−(ピリミジン−2−イル)フェニル]メタノン、
[5−クロロ−2−(ピリミジン−2−イル)フェニル][(2R,5R)−5−(5,6−ジフルオロ−1,3−ベンゾオキサゾール−2−イル)−2−メチルピペリジン−1−イル]メタノン、
[(2R,5R)−5−(5,6−ジフルオロ−1,3−ベンゾオキサゾール−2−イル)−2−メチルピペリジン−1−イル][6−メチル−3−(2H−1,2,3−トリアゾール−2−イル)ピリジン−2−イル]メタノン、
[(2R,5R)−5−(5,6−ジフルオロ−1,3−ベンゾオキサゾール−2−イル)−2−メチルピペリジン−1−イル][4−フルオロ−2−(2H−1,2,3−トリアゾール−2−イル)フェニル]メタノン、
2−{(3R,6R)−6−メチル−1−[5−メチル−2−(2H−1,2,3−トリアゾール−2−イル)ベンゾイル]ピペリジン−3−イル}−1,3−ベンゾオキサゾール−5−カルボニトリル、
2−{(3R,6R)−6−メチル−1−[5−メチル−2−(ピリミジン−2−イル)ベンゾイル]ピペリジン−3−イル}−1,3−ベンゾオキサゾール−5−カルボニトリル、
[(2R,5R)−5−(6,7−ジフルオロ−1,3−ベンゾオキサゾール−2−イル)−2−メチルピペリジン−1−イル][5−メチル−2−(2H−1,2,3−トリアゾール−2−イル)フェニル]メタノン、
[(2R,5R)−5−(6,7−ジフルオロ−1,3−ベンゾオキサゾール−2−イル)−2−メチルピペリジン−1−イル][5−メチル−2−(ピリミジン−2−イル)フェニル]メタノン、
[(2R,5R)−5−(4,6−ジフルオロ−1,3−ベンゾオキサゾール−2−イル)−2−メチルピペリジン−1−イル][5−メチル−2−(2H−1,2,3−トリアゾール−2−イル)フェニル]メタノン、
[(2R,5R)−5−(4,6−ジフルオロ−1,3−ベンゾオキサゾール−2−イル)−2−メチルピペリジン−1−イル][5−メチル−2−(ピリミジン−2−イル)フェニル]メタノン、
[(2R,5R)−5−(5,7−ジフルオロ−1,3−ベンゾオキサゾール−2−イル)−2−メチルピペリジン−1−イル][5−メチル−2−(2H−1,2,3−トリアゾール−2−イル)フェニル]メタノン、
[(2R,5R)−5−(5,7−ジフルオロ−1,3−ベンゾオキサゾール−2−イル)−2−メチルピペリジン−1−イル][5−メチル−2−(ピリミジン−2−イル)フェニル]メタノン、
[(2R,5R)−5−(7−フルオロ−1,3−ベンゾオキサゾール−2−イル)−2−メチルピペリジン−1−イル][5−メチル−2−(2H−1,2,3−トリアゾール−2−イル)フェニル]メタノン、
[(2R,5R)−5−(4−フルオロ−1,3−ベンゾオキサゾール−2−イル)−2−メチルピペリジン−1−イル][5−メチル−2−(2H−1,2,3−トリアゾール−2−イル)フェニル]メタノン、
[(2R,5R)−5−(4−フルオロ−1,3−ベンゾオキサゾール−2−イル)−2−メチルピペリジン−1−イル][5−メチル−2−(ピリミジン−2−イル)フェニル]メタノン、
[(2R,5R)−5−(4−クロロ−1,3−ベンゾオキサゾール−2−イル)−2−メチルピペリジン−1−イル][5−メチル−2−(2H−1,2,3−トリアゾール−2−イル)フェニル]メタノン、
[(2R,5R)−5−(4−クロロ−1,3−ベンゾオキサゾール−2−イル)−2−メチルピペリジン−1−イル][5−メチル−2−(ピリミジン−2−イル)フェニル]メタノン、
[(2R,5R)−5−(4−クロロ−1,3−ベンゾオキサゾール−2−イル)−2−メチルピペリジン−1−イル][5−フルオロ−2−(ピリミジン−2−イル)フェニル]メタノン、
[(2R,5R)−5−(6−クロロ[1,3]オキサゾロ[5,4−b]ピリジン−2−イル)−2−メチルピペリジン−1−イル][5−メチル−2−(2H−1,2,3−トリアゾール−2−イル)フェニル]メタノン、及び
[(2R,5R)−5−(6−クロロ[1,3]オキサゾロ[5,4−b]ピリジン−2−イル)−2−メチルピペリジン−1−イル][4−フルオロ−2−(2H−1,2,3−トリアゾール−2−イル)フェニル]メタノン。
(11) A sleep disorder or depression characterized by containing as an active ingredient any one or a mixture of two or more selected from the following compound group described in (1) above and a pharmaceutically acceptable salt thereof: Disease, anxiety disorder, panic disorder, schizophrenia, drug addiction, Alzheimer's disease, Parkinson's disease, Huntington's chorea, eating disorder, pain, migraine, gastrointestinal disease, epilepsy, inflammation, immune related diseases, endocrine related diseases Therapeutic or preventive drugs for diseases such as hypertension.
[(2R, 5R) -5- (5-chloro-1,3-benzoxazol-2-yl) -2-methylpiperidin-1-yl] [6-methyl-3- (2H-1,2,3 -Triazol-2-yl) pyridin-2-yl] methanone,
[(2R *, 5R *)-5- (5-chloro-1,3-benzoxazol-2-yl) -2-methylpiperidin-1-yl] [5-fluoro-2- (2H-1,2, , 3-Triazol-2-yl) phenyl] methanone,
[(2R *, 5R *)-5- (5-chloro-1,3-benzoxazol-2-yl) -2-methylpiperidin-1-yl] [2- (2H-1,2,3-triazole -2-yl) phenyl] methanone,
[(2R *, 5R *)-5- (5-chloro-1,3-benzoxazol-2-yl) -2-methylpiperidin-1-yl] [6-methyl-3- (pyrimidin-2-yl ) Pyridin-2-yl] methanone,
[(2R *, 5R *)-5- (5-chloro-1,3-benzoxazol-2-yl) -2-methylpiperidin-1-yl] [5-methyl-2- (pyrimidin-2-yl) ) Phenyl] methanone,
[(2R *, 5R *)-5- (5-chloro-1,3-benzoxazol-2-yl) -2-methylpiperidin-1-yl] [5-fluoro-2- (pyrimidin-2-yl ) Phenyl] methanone,
[(2R *, 5R *)-5- (5-chloro-1,3-benzoxazol-2-yl) -2-methylpiperidin-1-yl] [2- (pyrimidin-2-yl) phenyl] methanone ,
[(2R *, 5R *)-5- (5-fluoro-1,3-benzoxazol-2-yl) -2-methylpiperidin-1-yl] [5-methyl-2- (pyrimidin-2-yl) ) Phenyl] methanone,
[(2R *, 5R *)-5- (5-chloro-1,3-benzoxazol-2-yl) -2-methylpiperidin-1-yl] [5-methyl-2- (2H-1,2, , 3-Triazol-2-yl) phenyl] methanone,
[(2R *, 5R *)-5- (5-fluoro-1,3-benzoxazol-2-yl) -2-methylpiperidin-1-yl] [5-methyl-2- (2H-1,2, , 3-Triazol-2-yl) phenyl] methanone,
[(2R *, 5R *)-5- (5-fluoro-1,3-benzoxazol-2-yl) -2-methylpiperidin-1-yl] [6-methyl-3- (2H-1,2, , 3-Triazol-2-yl) pyridin-2-yl] methanone,
[(2R, 5R) -5- (5-chloro-1,3-benzooxazol-2-yl) -2-methylpiperidin-1-yl] [5-chloro-2- (pyrimidin-2-yl) phenyl ] Methanone,
[(2R, 5R) -5- (5-chloro-1,3-benzoxazol-2-yl) -2-methylpiperidin-1-yl] [4-fluoro-2- (2H-1,2,3 -Triazol-2-yl) phenyl] methanone,
[(2R, 5R) -5- (5-chloro-1,3-benzoxazol-2-yl) -2-methylpiperidin-1-yl] [3-fluoro-2- (2H-1,2,3 -Triazol-2-yl) phenyl] methanone,
[(2R, 5R) -5- (5-chloro-1,3-benzoxazol-2-yl) -2-methylpiperidin-1-yl] [2-fluoro-6- (2H-1,2,3 -Triazol-2-yl) phenyl] methanone,
[(2R, 5R) -5- (5-Chloro-1,3-benzoxazol-2-yl) -2-methylpiperidin-1-yl] [4-fluoro-2- (pyrimidin-2-yl) phenyl ] Methanone,
[(2R, 5R) -5- (5-Chloro-1,3-benzoxazol-2-yl) -2-methylpiperidin-1-yl] [2-fluoro-6- (pyrimidin-2-yl) phenyl ] Methanone,
[5-Bromo-2- (2H-1,2,3-triazol-2-yl) phenyl] [(2R, 5R) -5- (5-chloro-1,3-benzoxazol-2-yl)- 2-methylpiperidin-1-yl] methanone,
[(2R, 5R) -5- (5-chloro-1,3-benzoxazol-2-yl) -2-methylpiperidin-1-yl] [5-fluoro-2- (5-methoxypyrimidin-2- Yl) phenyl] methanone,
[(2R, 5R) -5- (5-chloro-1,3-benzoxazol-2-yl) -2-methylpiperidin-1-yl] [4-methyl-2- (2H-1,2,3 -Triazol-2-yl) phenyl] methanone,
[(2R, 5R) -5- (5-fluoro-1,3-benzoxazol-2-yl) -2-methylpiperidin-1-yl] [2- (2H-1,2,3-triazol-2 -Yl) phenyl] methanone,
[(2R, 5R) -5- (5-fluoro-1,3-benzoxazol-2-yl) -2-methylpiperidin-1-yl] [5-fluoro-2- (2H-1,2,3 -Triazol-2-yl) phenyl] methanone,
[5-Chloro-2- (2H-1,2,3-triazol-2-yl) phenyl] [(2R, 5R) -5- (5-fluoro-1,3-benzoxazol-2-yl)- 2-methylpiperidin-1-yl] methanone,
[(2R, 5R) -5- (5-fluoro-1,3-benzoxazol-2-yl) -2-methylpiperidin-1-yl] [2- (pyrimidin-2-yl) phenyl] methanone,
[(2R, 5R) -5- (5-Fluoro-1,3-benzoxazol-2-yl) -2-methylpiperidin-1-yl] [5-fluoro-2- (pyrimidin-2-yl) phenyl ] Methanone,
[5-Chloro-2- (pyrimidin-2-yl) phenyl] [(2R, 5R) -5- (5-fluoro-1,3-benzoxazol-2-yl) -2-methylpiperidin-1-yl ] Methanone,
[(2R, 5R) -5- (5-fluoro-1,3-benzoxazol-2-yl) -2-methylpiperidin-1-yl] [4-fluoro-2- (2H-1,2,3 -Triazol-2-yl) phenyl] methanone,
[(2R, 5R) -5- (5-fluoro-1,3-benzoxazol-2-yl) -2-methylpiperidin-1-yl] [2-fluoro-6- (2H-1,2,3 -Triazol-2-yl) phenyl] methanone,
[5-Methyl-2- (2H-1,2,3-triazol-2-yl) phenyl] {(2R, 5R) -2-methyl-5- [5- (trifluoromethyl) -1,3- Benzoxazol-2-yl] piperidin-1-yl} methanone,
[5-Methyl-2- (pyrimidin-2-yl) phenyl] {(2R, 5R) -2-methyl-5- [5- (trifluoromethyl) -1,3-benzoxazol-2-yl] piperidine -1-yl} methanone,
[5-Chloro-2- (pyrimidin-2-yl) phenyl] {(2R, 5R) -2-methyl-5- [5- (trifluoromethyl) -1,3-benzoxazol-2-yl] piperidine -1-yl} methanone,
[(2R, 5R) -5- (6-chloro-1,3-benzoxazol-2-yl) -2-methylpiperidin-1-yl] [5-methyl-2- (2H-1,2,3 -Triazol-2-yl) phenyl] methanone,
[(2R, 5R) -5- (6-Chloro-1,3-benzoxazol-2-yl) -2-methylpiperidin-1-yl] [5-methyl-2- (pyrimidin-2-yl) phenyl ] Methanone,
[(2R, 5R) -5- (6-Chloro-1,3-benzoxazol-2-yl) -2-methylpiperidin-1-yl] [5-fluoro-2- (pyrimidin-2-yl) phenyl ] Methanone,
[(2R, 5R) -5- (6-chloro-1,3-benzoxazol-2-yl) -2-methylpiperidin-1-yl] [6-methyl-3- (2H-1,2,3 -Triazol-2-yl) pyridin-2-yl] methanone,
[(2R, 5R) -5- (6-chloro-1,3-benzoxazol-2-yl) -2-methylpiperidin-1-yl] [4-fluoro-2- (2H-1,2,3 -Triazol-2-yl) phenyl] methanone,
[(2R, 5R) -5- (6-chloro-1,3-benzoxazol-2-yl) -2-methylpiperidin-1-yl] [2-fluoro-6- (2H-1,2,3 -Triazol-2-yl) phenyl] methanone,
[(2R, 5R) -5- (5,6-difluoro-1,3-benzoxazol-2-yl) -2-methylpiperidin-1-yl] [5-methyl-2- (2H-1,2, , 3-Triazol-2-yl) phenyl] methanone,
[(2R, 5R) -5- (5,6-difluoro-1,3-benzoxazol-2-yl) -2-methylpiperidin-1-yl] [5-methyl-2- (pyrimidin-2-yl ) Phenyl] methanone,
[(2R, 5R) -5- (5,6-difluoro-1,3-benzoxazol-2-yl) -2-methylpiperidin-1-yl] [5-fluoro-2- (pyrimidin-2-yl ) Phenyl] methanone,
[5-Chloro-2- (pyrimidin-2-yl) phenyl] [(2R, 5R) -5- (5,6-difluoro-1,3-benzoxazol-2-yl) -2-methylpiperidine-1 -Il] methanone,
[(2R, 5R) -5- (5,6-difluoro-1,3-benzoxazol-2-yl) -2-methylpiperidin-1-yl] [6-methyl-3- (2H-1,2, , 3-Triazol-2-yl) pyridin-2-yl] methanone,
[(2R, 5R) -5- (5,6-difluoro-1,3-benzoxazol-2-yl) -2-methylpiperidin-1-yl] [4-fluoro-2- (2H-1,2, , 3-Triazol-2-yl) phenyl] methanone,
2-{(3R, 6R) -6-methyl-1- [5-methyl-2- (2H-1,2,3-triazol-2-yl) benzoyl] piperidin-3-yl} -1,3- Benzoxazole-5-carbonitrile,
2-{(3R, 6R) -6-methyl-1- [5-methyl-2- (pyrimidin-2-yl) benzoyl] piperidin-3-yl} -1,3-benzoxazole-5-carbonitrile,
[(2R, 5R) -5- (6,7-difluoro-1,3-benzoxazol-2-yl) -2-methylpiperidin-1-yl] [5-methyl-2- (2H-1,2, , 3-Triazol-2-yl) phenyl] methanone,
[(2R, 5R) -5- (6,7-difluoro-1,3-benzoxazol-2-yl) -2-methylpiperidin-1-yl] [5-methyl-2- (pyrimidin-2-yl ) Phenyl] methanone,
[(2R, 5R) -5- (4,6-difluoro-1,3-benzoxazol-2-yl) -2-methylpiperidin-1-yl] [5-methyl-2- (2H-1,2, , 3-Triazol-2-yl) phenyl] methanone,
[(2R, 5R) -5- (4,6-difluoro-1,3-benzoxazol-2-yl) -2-methylpiperidin-1-yl] [5-methyl-2- (pyrimidin-2-yl ) Phenyl] methanone,
[(2R, 5R) -5- (5,7-difluoro-1,3-benzoxazol-2-yl) -2-methylpiperidin-1-yl] [5-methyl-2- (2H-1,2, , 3-Triazol-2-yl) phenyl] methanone,
[(2R, 5R) -5- (5,7-difluoro-1,3-benzoxazol-2-yl) -2-methylpiperidin-1-yl] [5-methyl-2- (pyrimidin-2-yl ) Phenyl] methanone,
[(2R, 5R) -5- (7-fluoro-1,3-benzoxazol-2-yl) -2-methylpiperidin-1-yl] [5-methyl-2- (2H-1,2,3 -Triazol-2-yl) phenyl] methanone,
[(2R, 5R) -5- (4-fluoro-1,3-benzoxazol-2-yl) -2-methylpiperidin-1-yl] [5-methyl-2- (2H-1,2,3 -Triazol-2-yl) phenyl] methanone,
[(2R, 5R) -5- (4-Fluoro-1,3-benzoxazol-2-yl) -2-methylpiperidin-1-yl] [5-methyl-2- (pyrimidin-2-yl) phenyl ] Methanone,
[(2R, 5R) -5- (4-chloro-1,3-benzoxazol-2-yl) -2-methylpiperidin-1-yl] [5-methyl-2- (2H-1,2,3 -Triazol-2-yl) phenyl] methanone,
[(2R, 5R) -5- (4-Chloro-1,3-benzoxazol-2-yl) -2-methylpiperidin-1-yl] [5-methyl-2- (pyrimidin-2-yl) phenyl ] Methanone,
[(2R, 5R) -5- (4-Chloro-1,3-benzoxazol-2-yl) -2-methylpiperidin-1-yl] [5-fluoro-2- (pyrimidin-2-yl) phenyl ] Methanone,
[(2R, 5R) -5- (6-Chloro [1,3] oxazolo [5,4-b] pyridin-2-yl) -2-methylpiperidin-1-yl] [5-methyl-2- ( 2H-1,2,3-triazol-2-yl) phenyl] methanone and [(2R, 5R) -5- (6-chloro [1,3] oxazolo [5,4-b] pyridin-2-yl ) -2-Methylpiperidin-1-yl] [4-fluoro-2- (2H-1,2,3-triazol-2-yl) phenyl] methanone.
本発明のメチルピペリジン誘導体は、OX受容体に対して親和性を示すと共に生理的リガンドによる受容体への刺激に対して拮抗作用を示すことが明らかになった。 The methylpiperidine derivative of the present invention has been shown to exhibit affinity for the OX receptor and antagonize the stimulation of the receptor by a physiological ligand.
本明細書において用いる用語は、以下の意味である。
「ハロゲン原子」とは、フッ素原子、塩素原子、臭素原子、ヨウ素原子である。
「C1-6アルキル基」とは直鎖状又は分岐鎖状の炭素数1〜6個のアルキル基を意味し、例えばメチル、エチル、n−プロピル、イソプロピル、n−ブチル、イソブチル、sec−ブチル、tert−ブチル、n−ペンチル、イソペンチル、ネオペンチル、tert−ペンチル、1−エチルプロピル、n−ヘキシル、イソヘキシル、ネオヘキシル基等を挙げることができる。
「C1-6アルコキシ基」とは直鎖状又は分岐鎖状の炭素数1〜6個のアルコキシ基を意味し、例えばメトキシ、エトキシ、n−プロポキシ、イソプロポキシ、n−ブトキシ、イソブトキシ、sec−ブトキシ、tert−ブトキシ、n−ペンチルオキシ、イソペンチルオキシ、ネオペンチルオキシ、tert−ペンチルオキシ、1−エチルプロポキシ、n−ヘキシルオキシ基等を挙げることができる。
「ヘテロアリール」とは窒素原子、酸素原子及び硫黄原子からなる群より選ばれる同一又は異なる1個以上の複素原子と1〜5個の炭素原子からなる5員又は6員のヘテロアリールを意味し、例えばピラゾリル、イミダゾリル、トリアゾリル、オキサゾリル、チアゾリル、ピリジル、ピラジニル、ピリミジニル、ピリダジニル基等を挙げることができる。
The terms used in the present specification have the following meanings.
The “halogen atom” is a fluorine atom, a chlorine atom, a bromine atom, or an iodine atom.
The “C 1-6 alkyl group” means a linear or branched alkyl group having 1 to 6 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec- Examples include butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, tert-pentyl, 1-ethylpropyl, n-hexyl, isohexyl, neohexyl group and the like.
“C 1-6 alkoxy group” means a linear or branched alkoxy group having 1 to 6 carbon atoms, such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec -Butoxy, tert-butoxy, n-pentyloxy, isopentyloxy, neopentyloxy, tert-pentyloxy, 1-ethylpropoxy, n-hexyloxy group and the like can be mentioned.
“Heteroaryl” means a 5- or 6-membered heteroaryl consisting of one or more heteroatoms selected from the group consisting of a nitrogen atom, an oxygen atom and a sulfur atom, and 1 to 5 carbon atoms. Examples include pyrazolyl, imidazolyl, triazolyl, oxazolyl, thiazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl group and the like.
本明細書中における「睡眠障害」とは、入眠時、睡眠持続相又は覚醒時の障害であり、例えば、不眠症等を挙げることができる。また、不眠症の分類としては、入眠障害、中途覚醒、早朝覚醒、熟眠障害等を挙げることができる。 The “sleep disorder” in the present specification is a disorder at the time of falling asleep, a sleep continuation phase, or awakening, and examples thereof include insomnia. Examples of insomnia classification include sleep onset disorder, mid-wake awakening, early morning awakening, and deep sleep disorder.
本明細書中における「医薬上許容される塩」とは、薬剤的に許容することのできる酸付加塩を意味し、用いられる酸としては、硫酸、塩酸、臭化水素酸、リン酸、硝酸等の無機酸との塩、或いは、酢酸、安息香酸、シュウ酸、乳酸、リンゴ酸、酒石酸、フマル酸、マレイン酸、クエン酸、マロン酸、マンデル酸、グルコン酸、ガラクタル酸、グルコヘプトン酸、グリコール酸、グルタミン酸、メタンスルホン酸、エタンスルホン酸、ベンゼンスルホン酸、p−トルエンスルホン酸、カンファースルホン酸、ナフタレン−2−スルホン酸等の有機酸との塩が含まれる。遊離体から当該塩への変換は従来の方法で行うことができる。 As used herein, “pharmaceutically acceptable salt” means a pharmaceutically acceptable acid addition salt, and the acid used includes sulfuric acid, hydrochloric acid, hydrobromic acid, phosphoric acid, nitric acid. Salts with inorganic acids such as acetic acid, benzoic acid, oxalic acid, lactic acid, malic acid, tartaric acid, fumaric acid, maleic acid, citric acid, malonic acid, mandelic acid, gluconic acid, galactaric acid, glucoheptonic acid, glycol Salts with organic acids such as acid, glutamic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, camphorsulfonic acid, naphthalene-2-sulfonic acid are included. Conversion from the educt to the salt can be performed by conventional methods.
本発明化合物において、好ましい態様を以下にあげる。
Yは、式CHである化合物が好ましい。
Xは、窒素原子である化合物が好ましい。
R1は、水素原子、ハロゲン原子(ただし、ヨウ素原子を除く)、又はC1-6アルキル基である化合物が好ましく、ここでハロゲン原子はフッ素原子である化合物がより好ましく、C1-6アルキル基はメチル基である化合物がより好ましい。
R2は、トリアゾリル基、又はピリミジニル基である化合物が好ましく、1,2,3−トリアゾール−2−イル基、又はピリミジン−2−イル基である化合物がより好ましい。
R3は、ハロゲン原子、シアノ基、C1-6アルキル基、又はC1-6アルコキシ基(該C1-6アルキル基、及びC1-6アルコキシ基は1〜3個のハロゲン原子で置換されてもよい)である化合物が好ましく、ハロゲン原子、又はC1-6アルキル基(該C1-6アルキル基は1〜3個のフッ素原子で置換されている)である化合物がより好ましく、フッ素原子、塩素原子、又はトリフルオロメチル基である化合物がさらに好ましく、フッ素原子、又は塩素原子である化合物が特に好ましい。
R4は、水素原子、又はハロゲン原子である化合物が好ましく、水素原子、又はフッ素原子である化合物がより好ましい。
本発明化合物中の好ましい化合物の例として、
[(2R,5R)−5−(5−クロロ−1,3−ベンゾオキサゾール−2−イル)−2−メチルピペリジン−1−イル][6−メチル−3−(2H−1,2,3−トリアゾール−2−イル)ピリジン−2−イル]メタノン、
[(2R*,5R*)−5−(5−クロロ−1,3−ベンゾオキサゾール−2−イル)−2−メチルピペリジン−1−イル][5−フルオロ−2−(2H−1,2,3−トリアゾール−2−イル)フェニル]メタノン、
[(2R*,5R*)−5−(5−クロロ−1,3−ベンゾオキサゾール−2−イル)−2−メチルピペリジン−1−イル][2−(2H−1,2,3−トリアゾール−2−イル)フェニル]メタノン、
[(2R*,5R*)−5−(5−クロロ−1,3−ベンゾオキサゾール−2−イル)−2−メチルピペリジン−1−イル][6−メチル−3−(ピリミジン−2−イル)ピリジン−2−イル]メタノン、
[(2R*,5R*)−5−(5−クロロ−1,3−ベンゾオキサゾール−2−イル)−2−メチルピペリジン−1−イル][5−メチル−2−(ピリミジン−2−イル)フェニル]メタノン、
[(2R*,5R*)−5−(5−クロロ−1,3−ベンゾオキサゾール−2−イル)−2−メチルピペリジン−1−イル][5−フルオロ−2−(ピリミジン−2−イル)フェニル]メタノン、
[(2R*,5R*)−5−(5−クロロ−1,3−ベンゾオキサゾール−2−イル)−2−メチルピペリジン−1−イル][2−(ピリミジン−2−イル)フェニル]メタノン、
[(2R*,5R*)−5−(5−フルオロ−1,3−ベンゾオキサゾール−2−イル)−2−メチルピペリジン−1−イル][5−メチル−2−(ピリミジン−2−イル)フェニル]メタノン、
[(2R*,5R*)−5−(5−クロロ−1,3−ベンゾオキサゾール−2−イル)−2−メチルピペリジン−1−イル][5−メチル−2−(2H−1,2,3−トリアゾール−2−イル)フェニル]メタノン、
[(2R*,5R*)−5−(5−フルオロ−1,3−ベンゾオキサゾール−2−イル)−2−メチルピペリジン−1−イル][5−メチル−2−(2H−1,2,3−トリアゾール−2−イル)フェニル]メタノン、
[(2R*,5R*)−5−(5−フルオロ−1,3−ベンゾオキサゾール−2−イル)−2−メチルピペリジン−1−イル][6−メチル−3−(2H−1,2,3−トリアゾール−2−イル)ピリジン−2−イル]メタノン、
[(2R,5R)−5−(5−クロロ−1,3−ベンゾオキサゾール−2−イル)−2−メチルピペリジン−1−イル][5−クロロ−2−(ピリミジン−2−イル)フェニル]メタノン、
[(2R,5R)−5−(5−クロロ−1,3−ベンゾオキサゾール−2−イル)−2−メチルピペリジン−1−イル][4−フルオロ−2−(2H−1,2,3−トリアゾール−2−イル)フェニル]メタノン、
[(2R,5R)−5−(5−クロロ−1,3−ベンゾオキサゾール−2−イル)−2−メチルピペリジン−1−イル][3−フルオロ−2−(2H−1,2,3−トリアゾール−2−イル)フェニル]メタノン、
[(2R,5R)−5−(5−クロロ−1,3−ベンゾオキサゾール−2−イル)−2−メチルピペリジン−1−イル][2−フルオロ−6−(2H−1,2,3−トリアゾール−2−イル)フェニル]メタノン、
[(2R,5R)−5−(5−クロロ−1,3−ベンゾオキサゾール−2−イル)−2−メチルピペリジン−1−イル][4−フルオロ−2−(ピリミジン−2−イル)フェニル]メタノン、
[(2R,5R)−5−(5−クロロ−1,3−ベンゾオキサゾール−2−イル)−2−メチルピペリジン−1−イル][2−フルオロ−6−(ピリミジン−2−イル)フェニル]メタノン、
[5−ブロモ−2−(2H−1,2,3−トリアゾール−2−イル)フェニル][(2R,5R)−5−(5−クロロ−1,3−ベンゾオキサゾール−2−イル)−2−メチルピペリジン−1−イル]メタノン、
[(2R,5R)−5−(5−クロロ−1,3−ベンゾオキサゾール−2−イル)−2−メチルピペリジン−1−イル][5−フルオロ−2−(5−メトキシピリミジン−2−イル)フェニル]メタノン、
[(2R,5R)−5−(5−クロロ−1,3−ベンゾオキサゾール−2−イル)−2−メチルピペリジン−1−イル][4−メチル−2−(2H−1,2,3−トリアゾール−2−イル)フェニル]メタノン、
[(2R,5R)−5−(5−フルオロ−1,3−ベンゾオキサゾール−2−イル)−2−メチルピペリジン−1−イル][2−(2H−1,2,3−トリアゾール−2−イル)フェニル]メタノン、
[(2R,5R)−5−(5−フルオロ−1,3−ベンゾオキサゾール−2−イル)−2−メチルピペリジン−1−イル][5−フルオロ−2−(2H−1,2,3−トリアゾール−2−イル)フェニル]メタノン、
[5−クロロ−2−(2H−1,2,3−トリアゾール−2−イル)フェニル][(2R,5R)−5−(5−フルオロ−1,3−ベンゾオキサゾール−2−イル)−2−メチルピペリジン−1−イル]メタノン、
[(2R,5R)−5−(5−フルオロ−1,3−ベンゾオキサゾール−2−イル)−2−メチルピペリジン−1−イル][2−(ピリミジン−2−イル)フェニル]メタノン、
[(2R,5R)−5−(5−フルオロ−1,3−ベンゾオキサゾール−2−イル)−2−メチルピペリジン−1−イル][5−フルオロ−2−(ピリミジン−2−イル)フェニル]メタノン、
[5−クロロ−2−(ピリミジン−2−イル)フェニル][(2R,5R)−5−(5−フルオロ−1,3−ベンゾオキサゾール−2−イル)−2−メチルピペリジン−1−イル]メタノン、
[(2R,5R)−5−(5−フルオロ−1,3−ベンゾオキサゾール−2−イル)−2−メチルピペリジン−1−イル][4−フルオロ−2−(2H−1,2,3−トリアゾール−2−イル)フェニル]メタノン、
[(2R,5R)−5−(5−フルオロ−1,3−ベンゾオキサゾール−2−イル)−2−メチルピペリジン−1−イル][2−フルオロ−6−(2H−1,2,3−トリアゾール−2−イル)フェニル]メタノン、
[5−メチル−2−(2H−1,2,3−トリアゾール−2−イル)フェニル]{(2R,5R)−2−メチル−5−[5−(トリフルオロメチル)−1,3−ベンゾオキサゾール−2−イル]ピペリジン−1−イル}メタノン、
[5−メチル−2−(ピリミジン−2−イル)フェニル]{(2R,5R)−2−メチル−5−[5−(トリフルオロメチル)−1,3−ベンゾオキサゾール−2−イル]ピペリジン−1−イル}メタノン、
[5−クロロ−2−(ピリミジン−2−イル)フェニル]{(2R,5R)−2−メチル−5−[5−(トリフルオロメチル)−1,3−ベンゾオキサゾール−2−イル]ピペリジン−1−イル}メタノン、
[(2R,5R)−5−(6−クロロ−1,3−ベンゾオキサゾール−2−イル)−2−メチルピペリジン−1−イル][5−メチル−2−(2H−1,2,3−トリアゾール−2−イル)フェニル]メタノン、
[(2R,5R)−5−(6−クロロ−1,3−ベンゾオキサゾール−2−イル)−2−メチルピペリジン−1−イル][5−メチル−2−(ピリミジン−2−イル)フェニル]メタノン、
[(2R,5R)−5−(6−クロロ−1,3−ベンゾオキサゾール−2−イル)−2−メチルピペリジン−1−イル][5−フルオロ−2−(ピリミジン−2−イル)フェニル]メタノン、
[(2R,5R)−5−(6−クロロ−1,3−ベンゾオキサゾール−2−イル)−2−メチルピペリジン−1−イル][6−メチル−3−(2H−1,2,3−トリアゾール−2−イル)ピリジン−2−イル]メタノン、
[(2R,5R)−5−(6−クロロ−1,3−ベンゾオキサゾール−2−イル)−2−メチルピペリジン−1−イル][4−フルオロ−2−(2H−1,2,3−トリアゾール−2−イル)フェニル]メタノン、
[(2R,5R)−5−(6−クロロ−1,3−ベンゾオキサゾール−2−イル)−2−メチルピペリジン−1−イル][2−フルオロ−6−(2H−1,2,3−トリアゾール−2−イル)フェニル]メタノン、
[(2R,5R)−5−(5,6−ジフルオロ−1,3−ベンゾオキサゾール−2−イル)−2−メチルピペリジン−1−イル][5−メチル−2−(2H−1,2,3−トリアゾール−2−イル)フェニル]メタノン、
[(2R,5R)−5−(5,6−ジフルオロ−1,3−ベンゾオキサゾール−2−イル)−2−メチルピペリジン−1−イル][5−メチル−2−(ピリミジン−2−イル)フェニル]メタノン、
[(2R,5R)−5−(5,6−ジフルオロ−1,3−ベンゾオキサゾール−2−イル)−2−メチルピペリジン−1−イル][5−フルオロ−2−(ピリミジン−2−イル)フェニル]メタノン、
[5−クロロ−2−(ピリミジン−2−イル)フェニル][(2R,5R)−5−(5,6−ジフルオロ−1,3−ベンゾオキサゾール−2−イル)−2−メチルピペリジン−1−イル]メタノン、
[(2R,5R)−5−(5,6−ジフルオロ−1,3−ベンゾオキサゾール−2−イル)−2−メチルピペリジン−1−イル][6−メチル−3−(2H−1,2,3−トリアゾール−2−イル)ピリジン−2−イル]メタノン、
[(2R,5R)−5−(5,6−ジフルオロ−1,3−ベンゾオキサゾール−2−イル)−2−メチルピペリジン−1−イル][4−フルオロ−2−(2H−1,2,3−トリアゾール−2−イル)フェニル]メタノン、
2−{(3R,6R)−6−メチル−1−[5−メチル−2−(2H−1,2,3−トリアゾール−2−イル)ベンゾイル]ピペリジン−3−イル}−1,3−ベンゾオキサゾール−5−カルボニトリル、
2−{(3R,6R)−6−メチル−1−[5−メチル−2−(ピリミジン−2−イル)ベンゾイル]ピペリジン−3−イル}−1,3−ベンゾオキサゾール−5−カルボニトリル、
[(2R,5R)−5−(6,7−ジフルオロ−1,3−ベンゾオキサゾール−2−イル)−2−メチルピペリジン−1−イル][5−メチル−2−(2H−1,2,3−トリアゾール−2−イル)フェニル]メタノン、
[(2R,5R)−5−(6,7−ジフルオロ−1,3−ベンゾオキサゾール−2−イル)−2−メチルピペリジン−1−イル][5−メチル−2−(ピリミジン−2−イル)フェニル]メタノン、
[(2R,5R)−5−(4,6−ジフルオロ−1,3−ベンゾオキサゾール−2−イル)−2−メチルピペリジン−1−イル][5−メチル−2−(2H−1,2,3−トリアゾール−2−イル)フェニル]メタノン、
[(2R,5R)−5−(4,6−ジフルオロ−1,3−ベンゾオキサゾール−2−イル)−2−メチルピペリジン−1−イル][5−メチル−2−(ピリミジン−2−イル)フェニル]メタノン、
[(2R,5R)−5−(5,7−ジフルオロ−1,3−ベンゾオキサゾール−2−イル)−2−メチルピペリジン−1−イル][5−メチル−2−(2H−1,2,3−トリアゾール−2−イル)フェニル]メタノン、
[(2R,5R)−5−(5,7−ジフルオロ−1,3−ベンゾオキサゾール−2−イル)−2−メチルピペリジン−1−イル][5−メチル−2−(ピリミジン−2−イル)フェニル]メタノン、
[(2R,5R)−5−(7−フルオロ−1,3−ベンゾオキサゾール−2−イル)−2−メチルピペリジン−1−イル][5−メチル−2−(2H−1,2,3−トリアゾール−2−イル)フェニル]メタノン、
[(2R,5R)−5−(4−フルオロ−1,3−ベンゾオキサゾール−2−イル)−2−メチルピペリジン−1−イル][5−メチル−2−(2H−1,2,3−トリアゾール−2−イル)フェニル]メタノン、
[(2R,5R)−5−(4−フルオロ−1,3−ベンゾオキサゾール−2−イル)−2−メチルピペリジン−1−イル][5−メチル−2−(ピリミジン−2−イル)フェニル]メタノン、
[(2R,5R)−5−(4−クロロ−1,3−ベンゾオキサゾール−2−イル)−2−メチルピペリジン−1−イル][5−メチル−2−(2H−1,2,3−トリアゾール−2−イル)フェニル]メタノン、
[(2R,5R)−5−(4−クロロ−1,3−ベンゾオキサゾール−2−イル)−2−メチルピペリジン−1−イル][5−メチル−2−(ピリミジン−2−イル)フェニル]メタノン、
[(2R,5R)−5−(4−クロロ−1,3−ベンゾオキサゾール−2−イル)−2−メチルピペリジン−1−イル][5−フルオロ−2−(ピリミジン−2−イル)フェニル]メタノン、
[(2R,5R)−5−(6−クロロ[1,3]オキサゾロ[5,4−b]ピリジン−2−イル)−2−メチルピペリジン−1−イル][5−メチル−2−(2H−1,2,3−トリアゾール−2−イル)フェニル]メタノン、及び
[(2R,5R)−5−(6−クロロ[1,3]オキサゾロ[5,4−b]ピリジン−2−イル)−2−メチルピペリジン−1−イル][4−フルオロ−2−(2H−1,2,3−トリアゾール−2−イル)フェニル]メタノン、
又はそれらの医薬上許容される塩が挙げられる。
なお、本発明化合物が水和物又は溶媒和物を形成する場合、それらも本発明の範囲内に含まれる。同様に、本発明化合物の水和物又は溶媒和物の医薬上許容される塩も本発明の範囲内に含まれる。
Preferred embodiments of the compound of the present invention are listed below.
Y is preferably a compound of formula CH.
A compound in which X is a nitrogen atom is preferable.
R 1 is preferably a hydrogen atom, a halogen atom (excluding an iodine atom) or a C 1-6 alkyl group, wherein the halogen atom is more preferably a fluorine atom, and a C 1-6 alkyl group. More preferably, the group is a methyl group.
R 2 is preferably a compound that is a triazolyl group or a pyrimidinyl group, and more preferably a compound that is a 1,2,3-triazol-2-yl group or a pyrimidin-2-yl group.
R 3 represents a halogen atom, a cyano group, a C 1-6 alkyl group, or a C 1-6 alkoxy group (the C 1-6 alkyl group and the C 1-6 alkoxy group are substituted with 1 to 3 halogen atoms). And a compound that is a halogen atom or a C 1-6 alkyl group (the C 1-6 alkyl group is substituted with 1 to 3 fluorine atoms) is more preferable, A compound that is a fluorine atom, a chlorine atom, or a trifluoromethyl group is more preferable, and a compound that is a fluorine atom or a chlorine atom is particularly preferable.
R 4 is preferably a compound that is a hydrogen atom or a halogen atom, and more preferably a compound that is a hydrogen atom or a fluorine atom.
Examples of preferred compounds in the compounds of the present invention include
[(2R, 5R) -5- (5-chloro-1,3-benzoxazol-2-yl) -2-methylpiperidin-1-yl] [6-methyl-3- (2H-1,2,3 -Triazol-2-yl) pyridin-2-yl] methanone,
[(2R *, 5R *)-5- (5-chloro-1,3-benzoxazol-2-yl) -2-methylpiperidin-1-yl] [5-fluoro-2- (2H-1,2, , 3-Triazol-2-yl) phenyl] methanone,
[(2R *, 5R *)-5- (5-chloro-1,3-benzoxazol-2-yl) -2-methylpiperidin-1-yl] [2- (2H-1,2,3-triazole -2-yl) phenyl] methanone,
[(2R *, 5R *)-5- (5-chloro-1,3-benzoxazol-2-yl) -2-methylpiperidin-1-yl] [6-methyl-3- (pyrimidin-2-yl ) Pyridin-2-yl] methanone,
[(2R *, 5R *)-5- (5-chloro-1,3-benzoxazol-2-yl) -2-methylpiperidin-1-yl] [5-methyl-2- (pyrimidin-2-yl) ) Phenyl] methanone,
[(2R *, 5R *)-5- (5-chloro-1,3-benzoxazol-2-yl) -2-methylpiperidin-1-yl] [5-fluoro-2- (pyrimidin-2-yl ) Phenyl] methanone,
[(2R *, 5R *)-5- (5-chloro-1,3-benzoxazol-2-yl) -2-methylpiperidin-1-yl] [2- (pyrimidin-2-yl) phenyl] methanone ,
[(2R *, 5R *)-5- (5-fluoro-1,3-benzoxazol-2-yl) -2-methylpiperidin-1-yl] [5-methyl-2- (pyrimidin-2-yl) ) Phenyl] methanone,
[(2R *, 5R *)-5- (5-chloro-1,3-benzoxazol-2-yl) -2-methylpiperidin-1-yl] [5-methyl-2- (2H-1,2, , 3-Triazol-2-yl) phenyl] methanone,
[(2R *, 5R *)-5- (5-fluoro-1,3-benzoxazol-2-yl) -2-methylpiperidin-1-yl] [5-methyl-2- (2H-1,2, , 3-Triazol-2-yl) phenyl] methanone,
[(2R *, 5R *)-5- (5-fluoro-1,3-benzoxazol-2-yl) -2-methylpiperidin-1-yl] [6-methyl-3- (2H-1,2, , 3-Triazol-2-yl) pyridin-2-yl] methanone,
[(2R, 5R) -5- (5-chloro-1,3-benzooxazol-2-yl) -2-methylpiperidin-1-yl] [5-chloro-2- (pyrimidin-2-yl) phenyl ] Methanone,
[(2R, 5R) -5- (5-chloro-1,3-benzoxazol-2-yl) -2-methylpiperidin-1-yl] [4-fluoro-2- (2H-1,2,3 -Triazol-2-yl) phenyl] methanone,
[(2R, 5R) -5- (5-chloro-1,3-benzoxazol-2-yl) -2-methylpiperidin-1-yl] [3-fluoro-2- (2H-1,2,3 -Triazol-2-yl) phenyl] methanone,
[(2R, 5R) -5- (5-chloro-1,3-benzoxazol-2-yl) -2-methylpiperidin-1-yl] [2-fluoro-6- (2H-1,2,3 -Triazol-2-yl) phenyl] methanone,
[(2R, 5R) -5- (5-Chloro-1,3-benzoxazol-2-yl) -2-methylpiperidin-1-yl] [4-fluoro-2- (pyrimidin-2-yl) phenyl ] Methanone,
[(2R, 5R) -5- (5-Chloro-1,3-benzoxazol-2-yl) -2-methylpiperidin-1-yl] [2-fluoro-6- (pyrimidin-2-yl) phenyl ] Methanone,
[5-Bromo-2- (2H-1,2,3-triazol-2-yl) phenyl] [(2R, 5R) -5- (5-chloro-1,3-benzoxazol-2-yl)- 2-methylpiperidin-1-yl] methanone,
[(2R, 5R) -5- (5-chloro-1,3-benzoxazol-2-yl) -2-methylpiperidin-1-yl] [5-fluoro-2- (5-methoxypyrimidin-2- Yl) phenyl] methanone,
[(2R, 5R) -5- (5-chloro-1,3-benzoxazol-2-yl) -2-methylpiperidin-1-yl] [4-methyl-2- (2H-1,2,3 -Triazol-2-yl) phenyl] methanone,
[(2R, 5R) -5- (5-fluoro-1,3-benzoxazol-2-yl) -2-methylpiperidin-1-yl] [2- (2H-1,2,3-triazol-2 -Yl) phenyl] methanone,
[(2R, 5R) -5- (5-fluoro-1,3-benzoxazol-2-yl) -2-methylpiperidin-1-yl] [5-fluoro-2- (2H-1,2,3 -Triazol-2-yl) phenyl] methanone,
[5-Chloro-2- (2H-1,2,3-triazol-2-yl) phenyl] [(2R, 5R) -5- (5-fluoro-1,3-benzoxazol-2-yl)- 2-methylpiperidin-1-yl] methanone,
[(2R, 5R) -5- (5-fluoro-1,3-benzoxazol-2-yl) -2-methylpiperidin-1-yl] [2- (pyrimidin-2-yl) phenyl] methanone,
[(2R, 5R) -5- (5-Fluoro-1,3-benzoxazol-2-yl) -2-methylpiperidin-1-yl] [5-fluoro-2- (pyrimidin-2-yl) phenyl ] Methanone,
[5-Chloro-2- (pyrimidin-2-yl) phenyl] [(2R, 5R) -5- (5-fluoro-1,3-benzoxazol-2-yl) -2-methylpiperidin-1-yl ] Methanone,
[(2R, 5R) -5- (5-fluoro-1,3-benzoxazol-2-yl) -2-methylpiperidin-1-yl] [4-fluoro-2- (2H-1,2,3 -Triazol-2-yl) phenyl] methanone,
[(2R, 5R) -5- (5-fluoro-1,3-benzoxazol-2-yl) -2-methylpiperidin-1-yl] [2-fluoro-6- (2H-1,2,3 -Triazol-2-yl) phenyl] methanone,
[5-Methyl-2- (2H-1,2,3-triazol-2-yl) phenyl] {(2R, 5R) -2-methyl-5- [5- (trifluoromethyl) -1,3- Benzoxazol-2-yl] piperidin-1-yl} methanone,
[5-Methyl-2- (pyrimidin-2-yl) phenyl] {(2R, 5R) -2-methyl-5- [5- (trifluoromethyl) -1,3-benzoxazol-2-yl] piperidine -1-yl} methanone,
[5-Chloro-2- (pyrimidin-2-yl) phenyl] {(2R, 5R) -2-methyl-5- [5- (trifluoromethyl) -1,3-benzoxazol-2-yl] piperidine -1-yl} methanone,
[(2R, 5R) -5- (6-chloro-1,3-benzoxazol-2-yl) -2-methylpiperidin-1-yl] [5-methyl-2- (2H-1,2,3 -Triazol-2-yl) phenyl] methanone,
[(2R, 5R) -5- (6-Chloro-1,3-benzoxazol-2-yl) -2-methylpiperidin-1-yl] [5-methyl-2- (pyrimidin-2-yl) phenyl ] Methanone,
[(2R, 5R) -5- (6-Chloro-1,3-benzoxazol-2-yl) -2-methylpiperidin-1-yl] [5-fluoro-2- (pyrimidin-2-yl) phenyl ] Methanone,
[(2R, 5R) -5- (6-chloro-1,3-benzoxazol-2-yl) -2-methylpiperidin-1-yl] [6-methyl-3- (2H-1,2,3 -Triazol-2-yl) pyridin-2-yl] methanone,
[(2R, 5R) -5- (6-chloro-1,3-benzoxazol-2-yl) -2-methylpiperidin-1-yl] [4-fluoro-2- (2H-1,2,3 -Triazol-2-yl) phenyl] methanone,
[(2R, 5R) -5- (6-chloro-1,3-benzoxazol-2-yl) -2-methylpiperidin-1-yl] [2-fluoro-6- (2H-1,2,3 -Triazol-2-yl) phenyl] methanone,
[(2R, 5R) -5- (5,6-difluoro-1,3-benzoxazol-2-yl) -2-methylpiperidin-1-yl] [5-methyl-2- (2H-1,2, , 3-Triazol-2-yl) phenyl] methanone,
[(2R, 5R) -5- (5,6-difluoro-1,3-benzoxazol-2-yl) -2-methylpiperidin-1-yl] [5-methyl-2- (pyrimidin-2-yl ) Phenyl] methanone,
[(2R, 5R) -5- (5,6-difluoro-1,3-benzoxazol-2-yl) -2-methylpiperidin-1-yl] [5-fluoro-2- (pyrimidin-2-yl ) Phenyl] methanone,
[5-Chloro-2- (pyrimidin-2-yl) phenyl] [(2R, 5R) -5- (5,6-difluoro-1,3-benzoxazol-2-yl) -2-methylpiperidine-1 -Il] methanone,
[(2R, 5R) -5- (5,6-difluoro-1,3-benzoxazol-2-yl) -2-methylpiperidin-1-yl] [6-methyl-3- (2H-1,2, , 3-Triazol-2-yl) pyridin-2-yl] methanone,
[(2R, 5R) -5- (5,6-difluoro-1,3-benzoxazol-2-yl) -2-methylpiperidin-1-yl] [4-fluoro-2- (2H-1,2, , 3-Triazol-2-yl) phenyl] methanone,
2-{(3R, 6R) -6-methyl-1- [5-methyl-2- (2H-1,2,3-triazol-2-yl) benzoyl] piperidin-3-yl} -1,3- Benzoxazole-5-carbonitrile,
2-{(3R, 6R) -6-methyl-1- [5-methyl-2- (pyrimidin-2-yl) benzoyl] piperidin-3-yl} -1,3-benzoxazole-5-carbonitrile,
[(2R, 5R) -5- (6,7-difluoro-1,3-benzoxazol-2-yl) -2-methylpiperidin-1-yl] [5-methyl-2- (2H-1,2, , 3-Triazol-2-yl) phenyl] methanone,
[(2R, 5R) -5- (6,7-difluoro-1,3-benzoxazol-2-yl) -2-methylpiperidin-1-yl] [5-methyl-2- (pyrimidin-2-yl ) Phenyl] methanone,
[(2R, 5R) -5- (4,6-difluoro-1,3-benzoxazol-2-yl) -2-methylpiperidin-1-yl] [5-methyl-2- (2H-1,2, , 3-Triazol-2-yl) phenyl] methanone,
[(2R, 5R) -5- (4,6-difluoro-1,3-benzoxazol-2-yl) -2-methylpiperidin-1-yl] [5-methyl-2- (pyrimidin-2-yl ) Phenyl] methanone,
[(2R, 5R) -5- (5,7-difluoro-1,3-benzoxazol-2-yl) -2-methylpiperidin-1-yl] [5-methyl-2- (2H-1,2, , 3-Triazol-2-yl) phenyl] methanone,
[(2R, 5R) -5- (5,7-difluoro-1,3-benzoxazol-2-yl) -2-methylpiperidin-1-yl] [5-methyl-2- (pyrimidin-2-yl ) Phenyl] methanone,
[(2R, 5R) -5- (7-fluoro-1,3-benzoxazol-2-yl) -2-methylpiperidin-1-yl] [5-methyl-2- (2H-1,2,3 -Triazol-2-yl) phenyl] methanone,
[(2R, 5R) -5- (4-fluoro-1,3-benzoxazol-2-yl) -2-methylpiperidin-1-yl] [5-methyl-2- (2H-1,2,3 -Triazol-2-yl) phenyl] methanone,
[(2R, 5R) -5- (4-Fluoro-1,3-benzoxazol-2-yl) -2-methylpiperidin-1-yl] [5-methyl-2- (pyrimidin-2-yl) phenyl ] Methanone,
[(2R, 5R) -5- (4-chloro-1,3-benzoxazol-2-yl) -2-methylpiperidin-1-yl] [5-methyl-2- (2H-1,2,3 -Triazol-2-yl) phenyl] methanone,
[(2R, 5R) -5- (4-Chloro-1,3-benzoxazol-2-yl) -2-methylpiperidin-1-yl] [5-methyl-2- (pyrimidin-2-yl) phenyl ] Methanone,
[(2R, 5R) -5- (4-Chloro-1,3-benzoxazol-2-yl) -2-methylpiperidin-1-yl] [5-fluoro-2- (pyrimidin-2-yl) phenyl ] Methanone,
[(2R, 5R) -5- (6-Chloro [1,3] oxazolo [5,4-b] pyridin-2-yl) -2-methylpiperidin-1-yl] [5-methyl-2- ( 2H-1,2,3-triazol-2-yl) phenyl] methanone and [(2R, 5R) -5- (6-chloro [1,3] oxazolo [5,4-b] pyridin-2-yl ) -2-methylpiperidin-1-yl] [4-fluoro-2- (2H-1,2,3-triazol-2-yl) phenyl] methanone,
Or a pharmaceutically acceptable salt thereof.
In addition, when this invention compound forms a hydrate or a solvate, they are also contained in the scope of the present invention. Similarly, pharmaceutically acceptable salts of hydrates or solvates of the compounds of the invention are also included within the scope of the invention.
本発明の化合物は、エナンチオマー、ジアステレオマー、平衡化合物、これらの任意の割合の混合物、ラセミ体等を全て含む。
本発明に係る化合物には、一つ以上の水素原子、炭素原子、窒素原子、酸素原子、フッ素原子が放射性同位元素や安定同位元素と置換された化合物も含まれる。これらの標識化合物は、代謝や薬物動態研究、受容体のリガンド等として生物学的分析等に有用である。
本発明に係る化合物は、経口又は非経口的に投与することができる。その投与剤型は錠剤、カプセル剤、顆粒剤、散剤、粉剤、トローチ剤、軟膏剤、クリーム剤、皮膚貼付剤、乳剤、懸濁剤、坐剤、注射剤等であり、いずれも慣用の製剤技術(例えば、第15改正日本薬局方に規定する方法等)によって製造することができる。これらの投与剤型は、患者の症状、年齢、体重、及び治療の目的に応じて適宜選択することができる。
これらの製剤は、本発明の化合物を含有する組成物に薬理学的に許容されるキャリヤー、すなわち、賦形剤(例えば、結晶セルロース、デンプン、乳糖、マンニトール)、結合剤(例えば、ヒドロキシプロピルセルロース、ポリビニルピロリドン)、滑沢剤(例えば、ステアリン酸マグネシウム、タルク)、崩壊剤(例えば、カルボキシメチルセルロースカルシウム)、その他薬理学的に許容される各種添加剤を配合し、製造することができる。
本発明の化合物は、成人患者に対して1回の投与量として0.001〜500mgを1日1回又は数回に分けて経口又は非経口で投与することが可能である。なお、この投与量は治療対象となる疾病の種類、患者の年齢、体重、症状等により適宜増減することができる。
The compounds of the present invention include all enantiomers, diastereomers, equilibrium compounds, mixtures of these in any proportion, racemates and the like.
The compounds according to the present invention also include compounds in which one or more hydrogen atoms, carbon atoms, nitrogen atoms, oxygen atoms and fluorine atoms are substituted with radioactive isotopes or stable isotopes. These labeled compounds are useful for metabolic and pharmacokinetic studies, biological ligands, etc. as receptor ligands.
The compound according to the present invention can be administered orally or parenterally. The dosage forms are tablets, capsules, granules, powders, powders, troches, ointments, creams, skin patches, emulsions, suspensions, suppositories, injections, etc., all of which are conventional formulations It can be manufactured by technology (for example, the method prescribed in the 15th revision Japanese Pharmacopoeia). These dosage forms can be appropriately selected according to the patient's symptoms, age, weight, and purpose of treatment.
These formulations are pharmaceutically acceptable carriers for the compositions containing the compounds of the invention, ie excipients (eg crystalline cellulose, starch, lactose, mannitol), binders (eg hydroxypropylcellulose). , Polyvinylpyrrolidone), lubricants (for example, magnesium stearate, talc), disintegrants (for example, carboxymethyl cellulose calcium), and other various pharmacologically acceptable additives.
The compound of the present invention can be orally or parenterally administered to an adult patient in an amount of 0.001 to 500 mg once a day or divided into several times a day. The dose can be appropriately increased or decreased depending on the type of disease to be treated, the age, weight, symptoms, etc. of the patient.
本発明の化合物における望ましいプロファイルとしては、薬効が優れていること、体内動態が優れていること(経口吸収性が良い等)、物性が優れていること、低毒性であること、等が挙げられる。
本発明の化合物(IA)の代表的な製造法を以下のスキームA〜Cに示す。以下の方法は、本発明化合物の製造法の例示であり、これに限定されるものではない。なお、以下の製造法の例示において、化合物は反応に支障にならない塩を形成していてもよい。
スキームA
Desirable profiles in the compounds of the present invention include excellent drug efficacy, excellent pharmacokinetics (eg, good oral absorption), excellent physical properties, low toxicity, and the like. .
A typical production method of the compound (IA) of the present invention is shown in the following schemes AC. The following method is an illustration of the production method of the compound of the present invention, and is not limited thereto. In the following examples of production methods, the compound may form a salt that does not hinder the reaction.
Scheme A
(式中、Bocはtert−ブトキシカルボニル基を示し、X、Y、R1、R2、R3及びR4は前記と同義である。Pはヒドロキシ基の一般的な保護基、例えばJ. F. W. McOmie 著、Protective Groups in Organic Chemistry、およびT. W. Greene 及びP.G.M.Wuts著、Protective Groups in Organic Synthesis等に記載されている基を示し、例えばトリエチルシリル基等を示す。) (In the formula, Boc represents a tert-butoxycarbonyl group, and X, Y, R 1 , R 2 , R 3 and R 4 have the same meanings as described above. P represents a general protecting group for a hydroxy group such as The groups described in F. W. McOmie, Protective Groups in Organic Chemistry, and T. W. Greene and PGM Wuts, Protective Groups in Organic Synthesis, etc. are shown. Show.)
工程A−1:化合物(2)は、化合物(1)のエステルの加水分解反応により得ることができる。工程A−1における反応は、塩基として水酸化リチウム、水酸化ナトリウム、水酸化カリウム等の水溶液を用い、基質の溶解度増加または反応温度調節のために、メタノール、エタノール、テトラヒドロフラン等を混合溶媒として使用することもできる。本反応は、0℃〜還流温度の条件下にて行うことができる。
工程A−2:化合物(4)は、化合物(2)と化合物(3)との縮合反応により得ることができる。工程A−2の縮合反応には、脱水縮合剤を用いた方法等が挙げられる。脱水縮合剤には、DMT−MM(4−(4,6−ジメトキシ−1,3,5−トリアジン−2−イル)−4−メチルモルホリニウムクロリド)、1−エチル−3−(3−ジメチルアミノプロピル)カルボジイミド・塩酸塩、プロパンホスホニックアシッドアンハイドライド、HATU[O−(7−アザベンゾトリアゾール−1−イル)−N,N,N’,N’−テトラメチルウロニウム ヘキサフルオロホスファート]、TBTU(O−(ベンゾトリアゾール−1−イル)−N,N,N’,N’−テトラメチルウロニウム テトラフルオロボレート)、ジシクロヘキシルカルボジイミド、ジフェニルホスホニルアジド、カルボニルジイミダゾール等が挙げられ、必要に応じて1−ヒドロキシベンゾトリアゾール、ヒドロキシスクシンイミド等の活性化剤を用いることができる。反応溶媒としては、N,N−ジメチルホルムアミド、テトラヒドロフラン、ジクロロメタン、クロロホルム、トルエン、酢酸エチル、メタノール、エタノール、水等や、それらの混合溶媒が挙げられる。この際、塩基を用いて行うことができ、塩基の例としては、ピリジン、トリエチルアミン、ジイソプロピルエチルアミン等の有機アミン類、炭酸カリウム等の無機塩基等が挙げられる。反応は0℃〜還流温度で行うことができる。
工程A−3:化合物(5)は、化合物(4)から閉環反応により得ることができる。工程A−3における反応は、無溶媒下、若しくはアセトニトリル、テトラヒドロフラン、クロロホルム等の溶媒中、又はそれらの混合溶媒中、塩化チオニル、オキシ塩化リン、ポリリン酸、酢酸、トリフェニルホスフィン/DEAD(ジエチルアゾジカルボキシラート)、トリフェニルホスフィン/ヘキサクロロエタン等を使用し、0℃〜還流温度条件下で行うことができる。
工程A−4:化合物(6)は、化合物(5)を、塩酸、硫酸、トリフルオロ酢酸、p−トルエンスルホン酸、メタンスルホン酸等の酸と反応させることにより得ることができる。工程A−4における反応に関する包括的概観は、J. F. W. McOmie 著、Protective Groups in Organic Chemistry、及びT. W. Greene 及びP.G.M.Wuts著、Protective Groups in Organic Synthesisに見出され得る。
工程A−5:化合物(8)は、化合物(6)と化合物(7)との縮合反応により得ることができる。工程A−5の縮合反応は、工程A−2と同様の反応条件に従って行うことができる。
スキームB
Step A-1: Compound (2) can be obtained by hydrolysis reaction of ester of compound (1). The reaction in Step A-1 uses an aqueous solution of lithium hydroxide, sodium hydroxide, potassium hydroxide or the like as a base, and uses methanol, ethanol, tetrahydrofuran or the like as a mixed solvent for increasing the solubility of the substrate or adjusting the reaction temperature. You can also This reaction can be performed under conditions of 0 ° C. to reflux temperature.
Step A-2: Compound (4) can be obtained by a condensation reaction between compound (2) and compound (3). Examples of the condensation reaction in Step A-2 include a method using a dehydrating condensing agent. Examples of the dehydrating condensing agent include DMT-MM (4- (4,6-dimethoxy-1,3,5-triazin-2-yl) -4-methylmorpholinium chloride), 1-ethyl-3- (3- Dimethylaminopropyl) carbodiimide / hydrochloride, propanephosphonic acid anhydride, HATU [O- (7-azabenzotriazol-1-yl) -N, N, N ′, N′-tetramethyluronium hexafluorophosphate ], TBTU (O- (benzotriazol-1-yl) -N, N, N ′, N′-tetramethyluronium tetrafluoroborate), dicyclohexylcarbodiimide, diphenylphosphonyl azide, carbonyldiimidazole, etc. If necessary, an activator such as 1-hydroxybenzotriazole or hydroxysuccinimide is added. It is possible to have. Examples of the reaction solvent include N, N-dimethylformamide, tetrahydrofuran, dichloromethane, chloroform, toluene, ethyl acetate, methanol, ethanol, water and the like, and mixed solvents thereof. In this case, the reaction can be carried out using a base. Examples of the base include organic amines such as pyridine, triethylamine and diisopropylethylamine, and inorganic bases such as potassium carbonate. The reaction can be carried out at 0 ° C. to reflux temperature.
Step A-3: Compound (5) can be obtained from compound (4) by a ring-closing reaction. The reaction in Step A-3 is carried out in the absence of a solvent, in a solvent such as acetonitrile, tetrahydrofuran, chloroform, or a mixed solvent thereof, thionyl chloride, phosphorus oxychloride, polyphosphoric acid, acetic acid, triphenylphosphine / DEAD (diethylazo Dicarboxylate), triphenylphosphine / hexachloroethane and the like can be used, and the reaction can be performed at 0 ° C. to reflux temperature.
Step A-4: Compound (6) can be obtained by reacting Compound (5) with an acid such as hydrochloric acid, sulfuric acid, trifluoroacetic acid, p-toluenesulfonic acid, methanesulfonic acid and the like. A comprehensive overview of the reaction in step A-4 can be found in F. W. McOmie, Protective Groups in Organic Chemistry, and T. W. Greene and P.A. G. M. Can be found in Wuts, Protective Groups in Organic Synthesis.
Step A-5: Compound (8) can be obtained by a condensation reaction of compound (6) and compound (7). The condensation reaction in Step A-5 can be performed according to the same reaction conditions as in Step A-2.
Scheme B
工程B−1:化合物(10)は、化合物(9)と化合物(7)との縮合反応より得ることができる。工程B−1の縮合反応は工程A−2と同様の反応条件に従って行うことができる。
工程B−2:化合物(11)は、化合物(10)のエステルの加水分解反応により得ることができる。工程B−2の反応は工程A−1と同様の反応条件に従って行うことができる。又は塩酸、硫酸等の鉱酸の水溶液を用いた酸加水分解によっても得ることができる。溶媒はメタノール、エタノール、1,4‐ジオキサン等を混合溶媒として使用することができる。本反応は、0℃〜還流温度の条件下にて行うことができる。
工程B−3:化合物(12)は、化合物(11)と化合物(3’)との縮合反応により得ることができる。工程B−3の縮合反応は工程A−2と同様の反応条件に従って行うことができる。
工程B−4:化合物(13)は、化合物(12)の閉環反応により得ることができる。工程B−4における反応は工程A−3と同様の反応条件に従って行うことができる。
スキームC
Step B-1: The compound (10) can be obtained by a condensation reaction of the compound (9) and the compound (7). The condensation reaction in Step B-1 can be performed according to the same reaction conditions as in Step A-2.
Step B-2: Compound (11) can be obtained by hydrolysis reaction of ester of compound (10). The reaction in Step B-2 can be performed according to the same reaction conditions as in Step A-1. Alternatively, it can also be obtained by acid hydrolysis using an aqueous solution of a mineral acid such as hydrochloric acid or sulfuric acid. As the solvent, methanol, ethanol, 1,4-dioxane and the like can be used as a mixed solvent. This reaction can be performed under conditions of 0 ° C. to reflux temperature.
Step B-3: The compound (12) can be obtained by a condensation reaction of the compound (11) and the compound (3 ′). The condensation reaction in Step B-3 can be performed according to the same reaction conditions as in Step A-2.
Step B-4: The compound (13) can be obtained by a ring closure reaction of the compound (12). The reaction in Step B-4 can be performed according to the same reaction conditions as in Step A-3.
Scheme C
工程C−1:化合物(14)は、化合物(2)と化合物(3’)との環化反応により得ることができる。工程C−1における反応は、酸触媒としてEaton試薬を用い、80〜120℃の条件下にて行うことができる。
工程C−2:化合物(15)は、化合物(14)と化合物(7)との縮合反応より得ることができる。工程C−2の縮合反応は工程A−2と同様の反応条件に従って行うことができる。
Step C-1: The compound (14) can be obtained by a cyclization reaction between the compound (2) and the compound (3 ′). The reaction in Step C-1 can be performed under conditions of 80 to 120 ° C. using an Eaton reagent as an acid catalyst.
Step C-2: Compound (15) can be obtained from the condensation reaction of compound (14) and compound (7). The condensation reaction in Step C-2 can be performed according to the same reaction conditions as in Step A-2.
以下、参考例、実施例及び試験例を挙げて本発明を更に詳細に説明するが、これらは本発明を限定するものではなく、また本発明の範囲を逸脱しない範囲で変化させてもよい。
以下の参考例及び実施例においてカラムクロマトグラフィーを使用して精製した際の「KP−Sil」にはBiotage社SNAPCartridge KP−Sil、「HP−Sil」にはBiotage社SNAPCartridge HP−Sil、「KP−NH」にはBiotage社SNAPCartridge KP−NHを使用した。
Hereinafter, the present invention will be described in more detail with reference examples, examples, and test examples. However, the present invention is not limited to these examples, and may be changed without departing from the scope of the present invention.
In the following Reference Examples and Examples, “KP-Sil” when purified using column chromatography is Biotage SNAPPartridge KP-Sil, “HP-Sil” is Biotage SNAPPartridge HP-Sil, “KP-Sil”. For NH, Biotage SNAP cartridge KP-NH was used.
以下の参考例および実施例において、分取高速液体クロマトグラフィー(HPLC)による精製は以下の条件により行った。ただし、塩基性官能基を有する化合物の場合、本操作でトリフルオロ酢酸を用いたときには、フリー体を得るための中和操作等を行う場合がある。
機械:Gilson社 preparative HPLC system
カラム:資生堂 Capcelpak C18 MGII 5μm 20×150mm
溶媒:A液;0.1%トリフルオロ酢酸含有水、B液;0.1%トリフルオロ酢酸含有アセトニトリル
グラジエント:0分(A液/B液=90/10)、22分(A液/B液=20/80)、25分(A液/B液=10/90)
流速:20mL/min、検出法:UV 254nm
In the following Reference Examples and Examples, purification by preparative high performance liquid chromatography (HPLC) was performed under the following conditions. However, in the case of a compound having a basic functional group, when trifluoroacetic acid is used in this operation, a neutralization operation for obtaining a free form may be performed.
Machine: Gilson preparative HPLC system
Column: Shiseido Capcelpak C18 MGII 5 μm 20 × 150 mm
Solvent: A solution; 0.1% trifluoroacetic acid-containing water, B solution; 0.1% trifluoroacetic acid-containing acetonitrile gradient: 0 minutes (A solution / B solution = 90/10), 22 minutes (A solution / B Liquid = 20/80), 25 minutes (A liquid / B liquid = 10/90)
Flow rate: 20 mL / min, detection method: UV 254 nm
以下の参考例および実施例において、高速液体クロマトグラフィーマススペクトル(LCMS)は以下の4種類の条件のいずれかにより測定した。
・条件1
測定機械:MicroMass社 Platform LCおよびAgilent社 Agilent1100
カラム:Waters社 SunFire C18 2.5μm4.6x50mm
溶媒:0.1%トリフルオロ酢酸含有水、B液;0.1%トリフルオロ酢酸含有アセトニトリル
グラジエント:0分(A液/B液=90/10)、0.5分(A液/B液=90/10)、5.5分(A液/B液=20/80)、6.0分(A液/B液=1/99)、6.3分(A液/B液=1/99)
流速:1mL/min、検出法:254nm
イオン化法:エレクトロンスプレー法(ESI:Electron Spray Ionization)
・条件2
測定機械:SHIMADZU社 LCMS−2010EV
カラム:SHIMADZU社 Shimpack XR−ODS 2.2μm 2.0x30mm
溶媒:A液0.1%ギ酸含有水、B液;0.1%ギ酸含有アセトニトリル
グラジエント:0分(A液/B液=90/10)、1分(A液/B液=60/40)、2分(A液/B液=0/100)、2.5分(A液/B液=0/100)
流速:0.6mL/min、検出法:254nm
イオン化法:エレクトロンスプレー法(ESI:Electron Spray Ionization)及び大気圧化学イオン法(APCI:Atomospheric Pressure Chemical Ionization)
・条件3
測定機械:SHIMADZU社 LCMS−2010EV
カラム:SHIMADZU社 Shimpack XR−ODS 2.2μm 2.0x30mm
溶媒:A液0.1%ギ酸含有水、B液;0.1%ギ酸含有アセトニトリル
グラジエント:0分(A液/B液=90/10)、3分(A液/B液=60/40)、5.5分(A液/B液=0/100)、6.5分(A液/B液=0/100)
流速:0.6mL/min、検出法:254nm
イオン化法:エレクトロンスプレー法(ESI:Electron Spray Ionization)及び大気圧化学イオン法(APCI:Atomospheric Pressure Chemical Ionization)
・条件4
測定機械:Agilent社 Agilent2900及びAgilent6150
カラム:Waters社 Acquity CSH C18 1.7μm 2.1x50mm
溶媒:A液;0.1%ギ酸含有水、B液;0.1%ギ酸含有アセトニトリル
グラジエント:0分(A液/B液=80/20)、1.2〜1.4分(A液/B液=1/99)
流速:0.8mL/min、検出法:UV 254nm
イオン化法:エレクトロンスプレー法(ESI:Electron Spray Ionization)
以下の実施例において、ラセミ体の分割は以下の3種類の条件のいずれかにより実施した。
・条件1
カラム:CHIRALPAK AD(ダイセル化学工業)、20mm×250mm
移動相:ヘキサン/エタノール=40/60(v/v)
流速:5.0mL/min
・条件2
カラム:CHIRALPAK AD(ダイセル化学工業)、20mm×250mm
移動相:ヘキサン/エタノール=80/20(v/v)〜0/100(v/v)
流速:5.0mL/min
・条件3
カラム:CHIRALPAK IC(ダイセル化学工業)、10cm×25cm
移動相:ヘキサン/2−プロパノール=90/10(v/v)
流速:142mL/min.
以下の実施例において、キラル分析は以下条件により実施した。
・条件A
カラム:CHIRALPAK AD−H(ダイセル)、4.6mm×250mm
流速:1.0mL/min
移動相:ヘキサン/エタノール=50/50
In the following Reference Examples and Examples, high performance liquid chromatography mass spectrum (LCMS) was measured under any of the following four conditions.
・ Condition 1
Measuring machine: Micromass Platform LC and Agilent Agilent 1100
Column: Waters SunFire C18 2.5 μm 4.6 × 50 mm
Solvent: water containing 0.1% trifluoroacetic acid, liquid B; acetonitrile gradient containing 0.1% trifluoroacetic acid: 0 minutes (liquid A / liquid B = 90/10), 0.5 minutes (liquid A / liquid B = 90/10), 5.5 minutes (A liquid / B liquid = 20/80), 6.0 minutes (A liquid / B liquid = 1/99), 6.3 minutes (A liquid / B liquid = 1) / 99)
Flow rate: 1 mL / min, detection method: 254 nm
Ionization method: Electron Spray Ionization (ESI: Electron Spray Ionization)
・ Condition 2
Measuring machine: SHIMADZU LCMS-2010EV
Column: SHIMADZU Shimpack XR-ODS 2.2 μm 2.0 × 30 mm
Solvent: A solution 0.1% formic acid-containing water, B solution; 0.1% formic acid-containing acetonitrile gradient: 0 minutes (A solution / B solution = 90/10), 1 minute (A solution / B solution = 60/40) ) 2 minutes (A liquid / B liquid = 0/100), 2.5 minutes (A liquid / B liquid = 0/100)
Flow rate: 0.6 mL / min, detection method: 254 nm
Ionization method: Electron Spray Ionization (ESI) and Atmospheric Pressure Chemical Ionization (APCI)
・ Condition 3
Measuring machine: SHIMADZU LCMS-2010EV
Column: SHIMADZU Shimpack XR-ODS 2.2 μm 2.0 × 30 mm
Solvent: A solution 0.1% formic acid-containing water, B solution; 0.1% formic acid-containing acetonitrile gradient: 0 minutes (A solution / B solution = 90/10), 3 minutes (A solution / B solution = 60/40) ) 5.5 minutes (A liquid / B liquid = 0/100), 6.5 minutes (A liquid / B liquid = 0/100)
Flow rate: 0.6 mL / min, detection method: 254 nm
Ionization method: Electron Spray Ionization (ESI) and Atmospheric Pressure Chemical Ionization (APCI)
・ Condition 4
Measuring machine: Agilent Agilent 2900 and Agilent 6150
Column: Waters Acquity CSH C18 1.7 μm 2.1 × 50 mm
Solvent: A liquid; 0.1% formic acid-containing water, B liquid; 0.1% formic acid-containing acetonitrile gradient: 0 minutes (A liquid / B liquid = 80/20), 1.2 to 1.4 minutes (A liquid / B liquid = 1/99)
Flow rate: 0.8 mL / min, detection method: UV 254 nm
Ionization method: Electron Spray Ionization (ESI: Electron Spray Ionization)
In the following examples, racemic resolution was performed under any of the following three conditions.
・ Condition 1
Column: CHIRALPAK AD (Daicel Chemical Industries), 20 mm x 250 mm
Mobile phase: hexane / ethanol = 40/60 (v / v)
Flow rate: 5.0 mL / min
・ Condition 2
Column: CHIRALPAK AD (Daicel Chemical Industries), 20 mm x 250 mm
Mobile phase: hexane / ethanol = 80/20 (v / v) to 0/100 (v / v)
Flow rate: 5.0 mL / min
・ Condition 3
Column: CHIRALPAK IC (Daicel Chemical Industries), 10cm x 25cm
Mobile phase: hexane / 2-propanol = 90/10 (v / v)
Flow rate: 142 mL / min.
In the following examples, chiral analysis was performed under the following conditions.
・ Condition A
Column: CHIRALPAK AD-H (Daicel), 4.6 mm x 250 mm
Flow rate: 1.0 mL / min
Mobile phase: hexane / ethanol = 50/50
以下の参考例および実施例において、マススペクトル(MS)は以下の条件により測定した。
MS測定機器:SHIMADZU社LCMS−2010EVあるいはmicromass社 Platform LC
以下の参考例および実施例において、化合物名はACD/Name (ACD/Labs 12.01, Advanced Chemistry Development Inc.)により命名した。
In the following Reference Examples and Examples, mass spectra (MS) were measured under the following conditions.
MS measuring instrument: SHIMADZU LCMS-2010EV or micromass Platform LC
In the following Reference Examples and Examples, compound names were named by ACD / Name (ACD / Labs 12.01, Advanced Chemistry Development Inc.).
参考例及び実施例中、以下の用語及び試薬は下記のように表記した。
Na2SO4(無水硫酸ナトリウム)、MgSO4(無水硫酸マグネシウム)、Na2CO3(炭酸ナトリウム)、Cs2CO3(炭酸セシウム)、NaHCO3(炭酸水素ナトリウム)、NaOH(水酸化ナトリウム)、LiOH・H2O(水酸化リチウム・一水和物)、MeOH(メタノール)、EtOH(エタノール)、Et2O(ジエチルエーテル)、THF(テトラヒドロフラン)、DMF(N,N−ジメチルホルムアミド)、MeCN(アセトニトリル)、EtOAc(酢酸エチル)、CHCl3(クロロホルム)、HOBt・H2O(1−ヒドロキシベンゾトリアゾール・一水和物)、EDC・HCl[1−(3−ジメチルアミノプロピル)−3−エチルカルボジイミド・一塩酸塩]、HATU[O−(7−アザベンゾトリアゾール−1−イル)−N,N,N’,N’−テトラメチルウロニウム ヘキサフルオロホスファート]、DMT−MM(4−(4,6−ジメトキシ−1,3,5−トリアジン−2−イル)−4−メチルモルホリニウムクロリド)、Pd(PPh3)4[テトラキストリフェニルホスフィンパラジウム(0)]、brine(飽和食塩水)、Boc(tert−ブトキシカルボニル)、THP(テトラヒドロピラニル)、DIPEA(N,N−ジイソプロピルエチルアミン)、TEA(トリエチルアミン)、MeI(ヨウ化メチル)、EtI(ヨウ化エチル)、TBAF(テトラブチルアンモニウムフルオリド)、TBTU(O−(ベンゾトリアゾール−1−イル)−N,N,N’,N’−テトラメチルウロニウム テトラフルオロボレート)、MsCl(塩化メタンスルホニル)、NaBH4(水素化ホウ素ナトリウム)、NaH(水素化ナトリウム)、HCl(塩化水素)、H2O(水)、PPA(ポリリン酸)、PTLC(分取薄層クロマトグラフィー)。
In the Reference Examples and Examples, the following terms and reagents are expressed as follows.
Na 2 SO 4 (anhydrous sodium sulfate), MgSO 4 (anhydrous magnesium sulfate), Na 2 CO 3 (sodium carbonate), Cs 2 CO 3 (cesium carbonate), NaHCO 3 (sodium bicarbonate), NaOH (sodium hydroxide) , LiOH.H 2 O (lithium hydroxide monohydrate), MeOH (methanol), EtOH (ethanol), Et 2 O (diethyl ether), THF (tetrahydrofuran), DMF (N, N-dimethylformamide), MeCN (acetonitrile), EtOAc (ethyl acetate), CHCl 3 (chloroform), HOBt · H 2 O (1-hydroxybenzotriazole monohydrate), EDC · HCl [1- (3-dimethylaminopropyl) -3 -Ethylcarbodiimide monohydrochloride], HATU [O- (7-azabenzotria 1-yl) -N, N, N ′, N′-tetramethyluronium hexafluorophosphate], DMT-MM (4- (4,6-dimethoxy-1,3,5-triazine-2) -Yl) -4-methylmorpholinium chloride), Pd (PPh 3 ) 4 [tetrakistriphenylphosphine palladium (0)], brine (saturated saline), Boc (tert-butoxycarbonyl), THP (tetrahydropyranyl) ), DIPEA (N, N-diisopropylethylamine), TEA (triethylamine), MeI (methyl iodide), EtI (ethyl iodide), TBAF (tetrabutylammonium fluoride), TBTU (O- (benzotriazole-1- Yl) -N, N, N ′, N′-tetramethyluronium tetrafluoroborate), MsC (Methanesulfonyl chloride), NaBH 4 (sodium borohydride), NaH (sodium hydride), HCl (hydrogen chloride), H 2 O (water), PPA (polyphosphoric acid), PTLC (preparative thin layer chromatography) .
参考例1 (3RS,6RS)−1−(tert−ブトキシカルボニル)−6−メチルピペリジン−3−カルボン酸 Reference Example 1 (3RS, 6RS) -1- (tert-butoxycarbonyl) -6-methylpiperidine-3-carboxylic acid
(3RS,6RS)−1−(tert−ブトキシカルボニル)−6−メチルピペリジン−3−カルボン酸メチル(16.0g、62.2mmol)のTHF(497mL)、H2O(124mL)混合溶液にLiOH・H2O(2.74g、65.3mmol)を加え、室温で一晩攪拌した。H2Oを加えEt2Oで抽出後、水層に2mol/L 塩酸を加え、EtOAcを用いて抽出した。得られた有機層をMgSO4で乾燥後、乾燥剤を濾別し、減圧下溶媒留去し、表題化合物(12.7g)を得た(無色固体)。
MS (ESI neg.) m/z : 242 [M-H]-
(3RS, 6RS) -1- (tert-butoxycarbonyl) -6-methylpiperidine-3-carboxylate (16.0 g, 62.2 mmol) in THF (497 mL) and H 2 O (124 mL) mixed solution was mixed with LiOH. H 2 O (2.74 g, 65.3 mmol) was added and stirred at room temperature overnight. After adding H 2 O and extracting with Et 2 O, 2 mol / L hydrochloric acid was added to the aqueous layer, and the mixture was extracted with EtOAc. The obtained organic layer was dried over MgSO 4 , the desiccant was filtered off, and the solvent was distilled off under reduced pressure to obtain the title compound (12.7 g) (colorless solid).
MS (ESI neg.) M / z: 242 [MH]-
参考例2 tert−ブチル (2RS,5RS)−5−[(5−クロロ−2−ヒドロキシフェニル)カルバモイル]−2−メチルピペリジン−1−カルボキシラート Reference Example 2 tert-butyl (2RS, 5RS) -5-[(5-chloro-2-hydroxyphenyl) carbamoyl] -2-methylpiperidine-1-carboxylate
4−クロロ−2−アミノフェノール(254mg、1.77mmol)及び参考例1で得られた(3RS,6RS)−1−(tert−ブトキシカルボニル)−6−メチルピペリジン−3−カルボン酸(331mg、1.36mmol)のEtOH溶液(18mL)にDMT−MM(521mg、1.77mmol)を加え室温で3日間撹拌した。反応溶液を濃縮後、H2Oを加え、EtOAcを用いて抽出した。MgSO4で乾燥後、乾燥剤を濾別し、減圧下溶媒留去した。得られた残渣をカラムクロマトグラフィー(HP−Sil 25g、hexane/EtOAc)にて精製することにより表題化合物(331mg)を得た(褐色非晶質)。
MS (ESI pos.) m/z : 369 [M+H]+
4-Chloro-2-aminophenol (254 mg, 1.77 mmol) and (3RS, 6RS) -1- (tert-butoxycarbonyl) -6-methylpiperidine-3-carboxylic acid (331 mg, obtained in Reference Example 1) 1.36 mmol) EtOH solution (18 mL) was added DMT-MM (521 mg, 1.77 mmol) and stirred at room temperature for 3 days. The reaction solution was concentrated, H 2 O was added, and the mixture was extracted with EtOAc. After drying over MgSO 4 , the desiccant was filtered off and the solvent was distilled off under reduced pressure. The obtained residue was purified by column chromatography (HP-Sil 25 g, hexane / EtOAc) to obtain the title compound (331 mg) (brown amorphous).
MS (ESI pos.) M / z: 369 [M + H] +
参考例3 tert−ブチル (2RS,5RS)−5−(5−クロロ−1,3−ベンゾオキサゾール−2−イル)−2−メチルピペリジン−1−カルボキシラート Reference Example 3 tert-Butyl (2RS, 5RS) -5- (5-Chloro-1,3-benzoxazol-2-yl) -2-methylpiperidine-1-carboxylate
tert−ブチル (2RS,5RS)−5−[(5−クロロ−2−ヒドロキシフェニル)カルバモイル]−2−メチルピペリジン−1−カルボキシラート(317mg、0.86mmol)のトルエン溶液(8.6mL)にピリジン(1.39mL、17.2mmol)、塩化チオニル(0.626mL、8.6mmol)を加え、100℃で2時間撹拌した。さらに反応溶液にピリジン(1.39mL、17.2mmol)、塩化チオニル(0.626mL、8.6mmol)を加え、100℃で2時間撹拌した。室温に放冷後、反応混合物にH2Oを加え、EtOAcを用いて抽出した。得られた有機層をMgSO4で乾燥後、乾燥剤を濾別し、減圧下溶媒留去した。得られた残渣をカラムクロマトグラフィー(HP−Sil 25g、hexane/EtOAc)にて精製し、表題化合物(158mg)を得た(無色非晶質)。
MS (ESI pos.) m/z : 351 [M+H]+
To a toluene solution (8.6 mL) of tert-butyl (2RS, 5RS) -5-[(5-chloro-2-hydroxyphenyl) carbamoyl] -2-methylpiperidine-1-carboxylate (317 mg, 0.86 mmol) Pyridine (1.39 mL, 17.2 mmol) and thionyl chloride (0.626 mL, 8.6 mmol) were added and stirred at 100 ° C. for 2 hours. Further, pyridine (1.39 mL, 17.2 mmol) and thionyl chloride (0.626 mL, 8.6 mmol) were added to the reaction solution, and the mixture was stirred at 100 ° C. for 2 hours. After allowing to cool to room temperature, H 2 O was added to the reaction mixture, and the mixture was extracted with EtOAc. The obtained organic layer was dried over MgSO 4 , the desiccant was filtered off, and the solvent was distilled off under reduced pressure. The obtained residue was purified by column chromatography (HP-Sil 25 g, hexane / EtOAc) to obtain the title compound (158 mg) (colorless amorphous).
MS (ESI pos.) M / z: 351 [M + H] +
参考例4 5−クロロ−2−[(3RS,6RS)−6−メチルピペリジン−3−イル]−1,3−ベンゾオキサゾール Reference Example 4 5-chloro-2-[(3RS, 6RS) -6-methylpiperidin-3-yl] -1,3-benzoxazole
tert−ブチル (2RS,5RS)−5−(5−クロロ−1,3−ベンゾオキサゾール−2−イル)−2−メチルピペリジン−1−カルボキシラート(160.7mg、0.46mmol)のEtOAc溶液(4.6mL)に4mol/L HCl−EtOAc溶液(2.3mL、9.16mmol)を加え、室温で一晩撹拌した。反応混合物を減圧下濃縮し、2mol/L NaOH水溶液を加え、EtOAcを用いて抽出した。得られた有機層をMgSO4で乾燥後、乾燥剤を濾別し、減圧下溶媒留去した。得られた残渣をカラムクロマトグラフィー(HP−Sil 10g、hexane/EtOAc)にて精製し、表題化合物(108mg)を得た(無色非晶質)。
MS (ESI pos.) m/z : 251 [M+H]+
tert-Butyl (2RS, 5RS) -5- (5-chloro-1,3-benzoxazol-2-yl) -2-methylpiperidine-1-carboxylate (160.7 mg, 0.46 mmol) in EtOAc ( (4.6 mL) was added 4 mol / L HCl-EtOAc solution (2.3 mL, 9.16 mmol), and the mixture was stirred overnight at room temperature. The reaction mixture was concentrated under reduced pressure, 2 mol / L aqueous NaOH solution was added, and the mixture was extracted with EtOAc. The obtained organic layer was dried over MgSO 4 , the desiccant was filtered off, and the solvent was distilled off under reduced pressure. The obtained residue was purified by column chromatography (HP-Sil 10 g, hexane / EtOAc) to obtain the title compound (108 mg) (colorless amorphous).
MS (ESI pos.) M / z: 251 [M + H] +
参考例5 tert−ブチル (2RS,5RS)−5−[(5−フルオロ−2−ヒドロキシフェニル)カルバモイル]−2−メチルピペリジン−1−カルボキシラート Reference Example 5 tert-butyl (2RS, 5RS) -5-[(5-fluoro-2-hydroxyphenyl) carbamoyl] -2-methylpiperidine-1-carboxylate
参考例1で得られた(3RS,6RS)−1−(tert−ブトキシカルボニル)−6−メチルピペリジン−3−カルボン酸(810mg、3.33mmol)及び4−フルオロ−2−アミノフェノール(1.1g、8.66mmol)を原料にして、参考例2と同様の手法により、表題化合物(799mg)を得た(褐色非晶質)。
MS (ESI pos.) m/z : 431 [M+H]+
(3RS, 6RS) -1- (tert-butoxycarbonyl) -6-methylpiperidine-3-carboxylic acid (810 mg, 3.33 mmol) and 4-fluoro-2-aminophenol (1. 1 g, 8.66 mmol) was used as a starting material, and the title compound (799 mg) was obtained in the same manner as in Reference Example 2 (brown amorphous).
MS (ESI pos.) M / z: 431 [M + H] +
参考例6 tert−ブチル (2RS,5RS)−5−(5−フルオロ−1,3−ベンゾオキサゾール−2−イル)−2−メチルピペリジン−1−カルボキシラート Reference Example 6 tert-butyl (2RS, 5RS) -5- (5-fluoro-1,3-benzoxazol-2-yl) -2-methylpiperidine-1-carboxylate
参考例5で得られたtert−ブチル (2RS,5RS)−5−[(5−フルオロ−2−ヒドロキシフェニル)カルバモイル]−2−メチルピペリジン−1−カルボキシラート(763mg、2.07mmol)、ピリジン(6.68mL、41.4mmol)及び塩化チオニル(3.02mL、41.4mmolを用いて、参考例2と同様の手法により、表題化合物(329mg)を得た(無色非晶質)。
MS (ESI pos.) m/z : 335 [M+H]+
Tert-Butyl (2RS, 5RS) -5-[(5-fluoro-2-hydroxyphenyl) carbamoyl] -2-methylpiperidine-1-carboxylate (763 mg, 2.07 mmol) obtained in Reference Example 5 and pyridine (6.68 mL, 41.4 mmol) and thionyl chloride (3.02 mL, 41.4 mmol) were used in the same manner as in Reference Example 2 to obtain the title compound (329 mg) (colorless amorphous).
MS (ESI pos.) M / z: 335 [M + H] +
参考例7 5−フルオロ−2−[(3RS,6RS)−6−メチルピペリジン−3−イル]−1,3−ベンゾオキサゾール Reference Example 7 5-Fluoro-2-[(3RS, 6RS) -6-methylpiperidin-3-yl] -1,3-benzoxazole
参考例6で得られたtert−ブチル (2RS,5RS)−5−(5−フルオロ−1,3−ベンゾオキサゾール−2−イル)−2−メチルピペリジン−1−カルボキシラート (329mg、0.94mmol)及び4mol/L HCl−EtOAc溶液(4.7mL、18.8mmol)を用いて、参考例4と同様の手法により、表題化合物(190mg)を得た(無色非晶質)。
MS (ESI pos.) m/z : 235 [M+H]+
Tert-Butyl (2RS, 5RS) -5- (5-fluoro-1,3-benzoxazol-2-yl) -2-methylpiperidine-1-carboxylate obtained in Reference Example 6 (329 mg, 0.94 mmol) ) And 4 mol / L HCl-EtOAc solution (4.7 mL, 18.8 mmol) were obtained in the same manner as in Reference Example 4 to obtain the title compound (190 mg) (colorless amorphous).
MS (ESI pos.) M / z: 235 [M + H] +
参考例8 メチル (3RS,6RS)−6−メチル−1−[5−メチル−2−(2H−1,2,3−トリアゾール−2−イル)ベンゾイル]ピペリジン−3−カルボキシラート Reference Example 8 Methyl (3RS, 6RS) -6-methyl-1- [5-methyl-2- (2H-1,2,3-triazol-2-yl) benzoyl] piperidine-3-carboxylate
(3RS,6RS)−6−メチルピペリジン−3−カルボン酸メチル(4.64g、29.5mmol)及び5−メチル−2−(2H−1,2,3−トリアゾール−2−イル)安息香酸(6.00g、29.5mmol)のDMF溶液(295mL)にDIPEA(20.6mL、118mmol)及びHATU(10.6g、32.5mmol)を加え室温で一晩撹拌した。反応混合物に水を加え、EtOAcを用いて抽出し、有機層を減圧下溶媒留去した。得られた残渣をカラムクロマトグラフィー(HP−Sil 100g、Hexane/EtOAc)にて精製し、表題化合物(2.83g)を得た(無色油状物)。
MS (ESI pos.) m/z : 297 [M+H]+
(3RS, 6RS) -6-methylpiperidine-3-carboxylate methyl (4.64 g, 29.5 mmol) and 5-methyl-2- (2H-1,2,3-triazol-2-yl) benzoic acid ( DIPEA (20.6 mL, 118 mmol) and HATU (10.6 g, 32.5 mmol) were added to a DMF solution (295 mL) of 6.00 g, 29.5 mmol), and the mixture was stirred overnight at room temperature. Water was added to the reaction mixture, extraction was performed using EtOAc, and the organic layer was evaporated under reduced pressure. The obtained residue was purified by column chromatography (HP-Sil 100 g, Hexane / EtOAc) to obtain the title compound (2.83 g) (colorless oil).
MS (ESI pos.) M / z: 297 [M + H] +
参考例9 (3RS,6RS)−6−メチル−1−[5−メチル−2−(2H−1,2,3−トリアゾール−2−イル)ベンゾイル]ピペリジン−3−カルボン酸 Reference Example 9 (3RS, 6RS) -6-methyl-1- [5-methyl-2- (2H-1,2,3-triazol-2-yl) benzoyl] piperidine-3-carboxylic acid
参考例8で得られたメチル (3RS,6RS)−6−メチル−1−[5−メチル−2−(2H−1,2,3−トリアゾール−2−イル)ベンゾイル]ピペリジン−3−カルボキシラート(329mg、0.94mmol)の1,4−ジオキサン(497mL)溶液に2mol/L 塩酸(57.0mL)を加え、80℃で6時間攪拌した。反応混合物を減圧下濃縮し、得られた残渣をカラムクロマトグラフィー(HP−Sil 50g、hexane/EtOAc)にて精製し、表題化合物(1.41g)を得た(無色非晶質)。
MS (ESI pos.) m/z : 329 [M+H]+
Methyl (3RS, 6RS) -6-methyl-1- [5-methyl-2- (2H-1,2,3-triazol-2-yl) benzoyl] piperidine-3-carboxylate obtained in Reference Example 8 To a solution of (329 mg, 0.94 mmol) in 1,4-dioxane (497 mL) was added 2 mol / L hydrochloric acid (57.0 mL), and the mixture was stirred at 80 ° C. for 6 hours. The reaction mixture was concentrated under reduced pressure, and the resulting residue was purified by column chromatography (HP-Sil 50 g, hexane / EtOAc) to obtain the title compound (1.41 g) (colorless amorphous).
MS (ESI pos.) M / z: 329 [M + H] +
参考例10 (3RS,6RS)−N−(5−クロロ−2−ヒドロキシフェニル)−6−メチル−1−[5−メチル−2−(2H−1,2,3−トリアゾール−2−イル)ベンゾイル]ピペリジン−3−カルボキサミド Reference Example 10 (3RS, 6RS) -N- (5-chloro-2-hydroxyphenyl) -6-methyl-1- [5-methyl-2- (2H-1,2,3-triazol-2-yl) Benzoyl] piperidine-3-carboxamide
参考例9で得られた(3RS,6RS)−6−メチル−1−[5−メチル−2−(2H−1,2,3−トリアゾール−2−イル)ベンゾイル]ピペリジン−3−カルボン酸(300mg、0.91mmol)及び4−クロロ−2−アミノフェノール(157mg、1.10mmol)を原料にして、参考例8と同様の手法により、表題化合物(118mg)を得た(褐色油状物)。
MS (ESI pos.) m/z : 454 [M+H]+
(3RS, 6RS) -6-methyl-1- [5-methyl-2- (2H-1,2,3-triazol-2-yl) benzoyl] piperidine-3-carboxylic acid obtained in Reference Example 9 ( 300 mg, 0.91 mmol) and 4-chloro-2-aminophenol (157 mg, 1.10 mmol) were used as raw materials in the same manner as in Reference Example 8 to obtain the title compound (118 mg) (brown oil).
MS (ESI pos.) M / z: 454 [M + H] +
参考例11 (3RS,6RS)−N−(5−フルオロ−2−ヒドロキシフェニル)−6−メチル−1−[5−メチル−2−(2H−1,2,3−トリアゾール−2−イル)ベンゾイル]ピペリジン−3−カルボキサミド Reference Example 11 (3RS, 6RS) -N- (5-fluoro-2-hydroxyphenyl) -6-methyl-1- [5-methyl-2- (2H-1,2,3-triazol-2-yl) Benzoyl] piperidine-3-carboxamide
4−フルオロ−2−アミノフェノール(85.2mg、0.67mmol)、及び参考例9で得られた(3RS,6RS)−6−メチル−1−[5−メチル−2−(2H−1,2,3−トリアゾール−2−イル)ベンゾイル]ピペリジン−3−カルボン酸(200mg、0.61mmol)のDMF溶液(6mL)にHOBt・H2O(109mg、0.80mmol)及びEDC・HCl(140mg、0.73mmol)を加え室温で一晩撹拌した。反応溶液にNaHCO3水溶液を加え、EtOAcを用いて抽出した。有機層をMgSO4で乾燥後、乾燥剤を濾別し、減圧下溶媒留去した。得られた残渣をカラムクロマトグラフィー(HP−Sil 25g、hexane/EtOAc)にて精製した(67mg)。得られた化合物の一部(26mg)のDMF溶液(0.6mL)にDIPEA(0.6mL)を加え100℃で一晩撹拌した。室温に放冷後H2Oを加え、EtOAcを用いて抽出した。得られた有機層をMgSO4で乾燥後、乾燥剤を濾別し、減圧下溶媒留去した。得られた残渣をカラムクロマトグラフィー(HP−Sil 10g、hexane/EtOAcの後、KP−NH 11g、CHCl3/MeOH)にて精製することにより表題化合物(18mg)を得た(無色非晶質)。
MS (ESI pos.) m/z : 438 [M+H]+
4-Fluoro-2-aminophenol (85.2 mg, 0.67 mmol) and (3RS, 6RS) -6-methyl-1- [5-methyl-2- (2H-1, 2,3-triazol-2-yl) benzoyl] piperidine-3-carboxylic acid (200 mg, 0.61 mmol) in DMF solution (6 mL) and HOBt · H 2 O (109 mg, 0.80 mmol) and EDC · HCl (140 mg) , 0.73 mmol) was added and stirred at room temperature overnight. To the reaction solution was added an aqueous NaHCO 3 solution, and the mixture was extracted with EtOAc. After drying the organic layer with MgSO 4 , the desiccant was filtered off and the solvent was distilled off under reduced pressure. The obtained residue was purified by column chromatography (HP-Sil 25 g, hexane / EtOAc) (67 mg). DIPEA (0.6 mL) was added to a DMF solution (0.6 mL) of a part of the obtained compound (26 mg), and the mixture was stirred at 100 ° C. overnight. After allowing to cool to room temperature, H 2 O was added, and the mixture was extracted with EtOAc. The obtained organic layer was dried over MgSO 4 , the desiccant was filtered off, and the solvent was distilled off under reduced pressure. The obtained residue was purified by column chromatography (HP-Sil 10 g, hexane / EtOAc followed by KP-NH 11 g, CHCl 3 / MeOH) to obtain the title compound (18 mg) (colorless amorphous) .
MS (ESI pos.) M / z: 438 [M + H] +
参考例12 5−フルオロ−2−[(3RS,6RS)−6−メチルピペリジン−3−イル]−1,3−ベンゾオキサゾール Reference Example 12 5-Fluoro-2-[(3RS, 6RS) -6-methylpiperidin-3-yl] -1,3-benzoxazole
4−フルオロ−2−アミノフェノール(575mg、4.52mmol)、参考例1で得られた(3RS,6RS)−1−(tert−ブトキシカルボニル)−6−メチルピペリジン−3−カルボン酸(1.0g、4.11mmol)及びPPA(2.5g)の混合物を180℃で30分間撹拌した。室温まで放冷後、反応溶液に飽和NaHCO3水溶液を加え、EtOAcを用いて抽出した。有機層をMgSO4で乾燥後、乾燥剤を濾別し、減圧下溶媒留去した。得られた残渣をカラムクロマトグラフィー(HP−Sil 50g、hexane/EtOAc)にて精製した(672mg)。得られた化合物の一部(608mg)のCHCl3溶液(13mL)にTEA(0.70mL、5.02mmol)及びBoc2O(1.1g、5.02mmol)を加え50℃で1.5時間撹拌した。室温に放冷後2mol/L 塩酸を加え、EtOAcを用いて抽出した。得られた有機層をMgSO4で乾燥後、乾燥剤を濾別し、減圧下溶媒留去した。得られた残渣をカラムクロマトグラフィー(HP−Sil 50g、hexane/EtOAc)にて精製した(333mg)。得られた化合物(333mg、1.00mmol)のEtOAc溶液(5.0mL)に4mol/L HCl−EtOAc溶液(5.0mL、19.9mmol)を加え、室温で2時間撹拌した。反応混合物を減圧下濃縮し、2mol/L NaOH水溶液を加え、EtOAcを用いて抽出した。得られた有機層をMgSO4で乾燥後、乾燥剤を濾別し、減圧下溶媒留去した。得られた残渣をカラムクロマトグラフィー(KP−NH 10g、hexane/EtOAc)にて精製し、表題化合物(196mg)を得た(無色非晶質)。
MS (ESI pos.) m/z : 235 [M+H]+
4-fluoro-2-aminophenol (575 mg, 4.52 mmol), (3RS, 6RS) -1- (tert-butoxycarbonyl) -6-methylpiperidine-3-carboxylic acid (1. 0 g, 4.11 mmol) and PPA (2.5 g) were stirred at 180 ° C. for 30 min. After allowing to cool to room temperature, saturated aqueous NaHCO 3 solution was added to the reaction solution, and the mixture was extracted with EtOAc. After drying the organic layer with MgSO 4 , the desiccant was filtered off and the solvent was distilled off under reduced pressure. The obtained residue was purified by column chromatography (HP-Sil 50 g, hexane / EtOAc) (672 mg). TEA (0.70 mL, 5.02 mmol) and Boc 2 O (1.1 g, 5.02 mmol) were added to a CHCl 3 solution (13 mL) of a part of the obtained compound (608 mg) and added at 50 ° C. for 1.5 hours. Stir. After allowing to cool to room temperature, 2 mol / L hydrochloric acid was added, and the mixture was extracted with EtOAc. The obtained organic layer was dried over MgSO 4 , the desiccant was filtered off, and the solvent was distilled off under reduced pressure. The obtained residue was purified by column chromatography (HP-Sil 50 g, hexane / EtOAc) (333 mg). A 4 mol / L HCl-EtOAc solution (5.0 mL, 19.9 mmol) was added to an EtOAc solution (5.0 mL) of the obtained compound (333 mg, 1.00 mmol), and the mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure, 2 mol / L aqueous NaOH solution was added, and the mixture was extracted with EtOAc. The obtained organic layer was dried over MgSO 4 , the desiccant was filtered off, and the solvent was distilled off under reduced pressure. The obtained residue was purified by column chromatography (KP-NH 10 g, hexane / EtOAc) to obtain the title compound (196 mg) (colorless amorphous).
MS (ESI pos.) M / z: 235 [M + H] +
参考例13 6−フルオロ−2−[(3RS,6RS)−6−メチルピペリジン−3−イル]−1,3−ベンゾオキサゾール 塩酸塩 Reference Example 13 6-Fluoro-2-[(3RS, 6RS) -6-methylpiperidin-3-yl] -1,3-benzoxazole hydrochloride
4−フルオロ−2−アミノフェノール(575mg、4.52mmol)、参考例1で得られた(3RS,6RS)−1−(tert−ブトキシカルボニル)−6−メチルピペリジン−3−カルボン酸(1.0g、4.11mmol)及びPPA(2.5g)の混合物を180℃で30分間撹拌した。室温まで放冷後、反応溶液にNaHCO3水溶液を加え、EtOAcを用いて抽出した。有機層をMgSO4で乾燥後、乾燥剤を濾別し、減圧下溶媒留去した。得られた残渣をカラムクロマトグラフィー(HP−Sil 50g、hexane/EtOAc)にて精製した(560mg)。得られた化合物の全量(560mg)のTHF溶液(20mL)にTEA(0.37mL、2.63mmol)及びBoc2O(0.57g、2.63mmol)を加え室温で2時間、50℃で1時間撹拌した。室温に放冷後2mol/L 塩酸を加え、EtOAcを用いて抽出した。得られた有機層をMgSO4で乾燥後、乾燥剤を濾別し、減圧下溶媒留去した。得られた残渣をカラムクロマトグラフィー(HP−Sil 50g、hexane/EtOAc)にて精製した(464mg)。得られた化合物の全量(464mg、1.39mmol)のEtOAc溶液(5.6mL)に4mol/L HCl−EtOAc溶液(7.0mL、27.8mmol)を加え、室温で3時間撹拌した。生じた固体をろ取し、表題化合物(343mg)を得た(無色固体)。
MS (ESI pos.) m/z : 235 [M+H]+
4-fluoro-2-aminophenol (575 mg, 4.52 mmol), (3RS, 6RS) -1- (tert-butoxycarbonyl) -6-methylpiperidine-3-carboxylic acid (1. 0 g, 4.11 mmol) and PPA (2.5 g) were stirred at 180 ° C. for 30 min. After allowing to cool to room temperature, an aqueous NaHCO 3 solution was added to the reaction solution, and the mixture was extracted with EtOAc. After drying the organic layer with MgSO 4 , the desiccant was filtered off and the solvent was distilled off under reduced pressure. The obtained residue was purified by column chromatography (HP-Sil 50 g, hexane / EtOAc) (560 mg). TEA (0.37 mL, 2.63 mmol) and Boc 2 O (0.57 g, 2.63 mmol) were added to a THF solution (20 mL) of the total amount of the obtained compound (560 mg) and 1 hour at 50 ° C. at room temperature. Stir for hours. After allowing to cool to room temperature, 2 mol / L hydrochloric acid was added, and the mixture was extracted with EtOAc. The obtained organic layer was dried over MgSO 4 , the desiccant was filtered off, and the solvent was distilled off under reduced pressure. The obtained residue was purified by column chromatography (HP-Sil 50 g, hexane / EtOAc) (464 mg). A 4 mol / L HCl-EtOAc solution (7.0 mL, 27.8 mmol) was added to an EtOAc solution (5.6 mL) of the total amount of the obtained compound (464 mg, 1.39 mmol), and the mixture was stirred at room temperature for 3 hours. The resulting solid was collected by filtration to give the title compound (343 mg) (colorless solid).
MS (ESI pos.) M / z: 235 [M + H] +
参考例14 (3R,6R)−1−(tert−ブトキシカルボニル)−6−メチルピペリジン−3−カルボン酸メチル Reference Example 14 (3R, 6R) -1- (tert-butoxycarbonyl) -6-methylpiperidine-3-carboxylic acid methyl
(3RS,6RS)−1−(tert−ブトキシカルボニル)−6−メチルピペリジン−3−カルボン酸メチル(80.0g、329mmol)のラセミ混合物を前記のラセミ体分割条件(条件3)で分割し、2つのピーク(保持時間:28.5min、 35.8min)を分離した。このうち相対保持時間が長い化合物(保持時間:35.8min)として表題化合物(34.9g)を得た(無色油状物)。得られた表題化合物は参考例1、16、24、32及び実施例1と同様の手法を用いて[(2R,5R)−5−(5−クロロ−1,3−ベンゾオキサゾール−2−イル)−2−メチルピペリジン−1−イル][6−メチル−3−(2H−1,2,3−トリアゾール−2−イル)ピリジン−2−イル]メタノンへと導き、X線結晶構造解析によってその絶対立体構造を決定した。
MS (ESI pos.) m/z : 244 [M+H]+
A racemic mixture of methyl (3RS, 6RS) -1- (tert-butoxycarbonyl) -6-methylpiperidine-3-carboxylate (80.0 g, 329 mmol) was resolved under the above racemic resolution conditions (condition 3), Two peaks (retention time: 28.5 min, 35.8 min) were separated. Of these, the title compound (34.9 g) was obtained as a compound having a long relative retention time (retention time: 35.8 min) (colorless oil). The obtained title compound was prepared using the same procedure as in Reference Examples 1, 16, 24, 32 and Example 1 [(2R, 5R) -5- (5-chloro-1,3-benzoxazol-2-yl ) -2-methylpiperidin-1-yl] [6-methyl-3- (2H-1,2,3-triazol-2-yl) pyridin-2-yl] methanone and analyzed by X-ray crystal structure analysis Its absolute steric structure was determined.
MS (ESI pos.) M / z: 244 [M + H] +
参考例15 (3R,6R)−1−(tert−ブトキシカルボニル)−6−メチルピペリジン−3−カルボン酸 Reference Example 15 (3R, 6R) -1- (tert-butoxycarbonyl) -6-methylpiperidine-3-carboxylic acid
(3R,6R)−1−(tert−ブトキシカルボニル)−6−メチルピペリジン−3−カルボン酸メチル(5.9g、22.9mmol)のTHF(183mL)、H2O(46mL)混合溶液にLiOH・H2O(1.01g、24.1mmol)を加え、室温で一晩攪拌した。H2Oを加えEt2Oで抽出後、水層に2mol/L 塩酸を加え、EtOAcを用いて抽出した。得られた有機層をMgSO4で乾燥後、乾燥剤を濾別し、減圧下溶媒留去し、表題化合物(5.41g)を得た(無色固体)。
MS (ESI neg.) m/z : 242 [M-H]-
To a mixed solution of methyl (3R, 6R) -1- (tert-butoxycarbonyl) -6-methylpiperidine-3-carboxylate (5.9 g, 22.9 mmol) in THF (183 mL) and H 2 O (46 mL) was added LiOH. · H 2 O (1.01g, 24.1mmol ) was added and stirred at room temperature overnight. After adding H 2 O and extracting with Et 2 O, 2 mol / L hydrochloric acid was added to the aqueous layer, and the mixture was extracted with EtOAc. The obtained organic layer was dried over MgSO 4 , the desiccant was filtered off, and the solvent was distilled off under reduced pressure to obtain the title compound (5.41 g) (colorless solid).
MS (ESI neg.) M / z: 242 [MH]-
参考例16 tert−ブチル (2R,5R)−5−{[2−ヒドロキシ−5−(トリフルオロメチル)フェニル]カルバモイル}−2−メチルピペリジン−1−カルボキシラート Reference Example 16 tert-butyl (2R, 5R) -5-{[2-hydroxy-5- (trifluoromethyl) phenyl] carbamoyl} -2-methylpiperidine-1-carboxylate
5−トリフルオロメチル−2−トリエチルシリルオキシアニリン(395mg、1.36mmol)、及び参考例15で得られた(3R,6R)−1−(tert−ブトキシカルボニル)−6−メチルピペリジン−3−カルボン酸(300mg、1.23mmol)のDMF溶液(12mL)にHOBt・H2O(225mg、1.48mmol)及びEDC・HCl(283mg、1.48mmol)を加え室温で一晩撹拌した。反応溶液にH2Oを加え、Et2Oを用いて抽出した。有機層をMgSO4で乾燥後、乾燥剤を濾別し、減圧下溶媒留去した。得られた残渣をTHF(30mL)に溶解させ、室温にてTBAF(1.0mol/L THF溶液、2.5mL、2.5mmol)を加え2時間撹拌した。H2Oを加え、EtOAcを用いて抽出し、減圧下溶媒留去した。得られた残渣をカラムクロマトグラフィー(HP−Sil 100g、hexane/EtOAc)にて精製することにより表題化合物(562mg)を得た(淡黄色油状物)。
MS (ESI pos.) m/z : 425 [M+Na]+
5-trifluoromethyl-2-triethylsilyloxyaniline (395 mg, 1.36 mmol) and (3R, 6R) -1- (tert-butoxycarbonyl) -6-methylpiperidine-3- 3 obtained in Reference Example 15 To a DMF solution (12 mL) of carboxylic acid (300 mg, 1.23 mmol) were added HOBt · H 2 O (225 mg, 1.48 mmol) and EDC · HCl (283 mg, 1.48 mmol), and the mixture was stirred overnight at room temperature. H 2 O was added to the reaction solution, and extraction was performed using Et 2 O. After drying the organic layer with MgSO 4 , the desiccant was filtered off and the solvent was distilled off under reduced pressure. The obtained residue was dissolved in THF (30 mL), TBAF (1.0 mol / L THF solution, 2.5 mL, 2.5 mmol) was added at room temperature, and the mixture was stirred for 2 hours. H 2 O was added, extraction was performed with EtOAc, and the solvent was distilled off under reduced pressure. The obtained residue was purified by column chromatography (HP-Sil 100 g, hexane / EtOAc) to give the title compound (562 mg) (pale yellow oil).
MS (ESI pos.) M / z: 425 [M + Na] +
以下の参考例17〜23を参考例16と同様の手法により得た。得られた化合物の構造式、化合物名及びMSデータを表1に示す。 The following Reference Examples 17 to 23 were obtained in the same manner as in Reference Example 16. Table 1 shows the structural formula, compound name, and MS data of the obtained compound.
参考例24 tert−ブチル (2R,5R)−2−メチル−5−[5−(トリフルオロメチル)−1,3−ベンゾオキサゾール−2−イル]ピペリジン−1−カルボキシラート Reference Example 24 tert-butyl (2R, 5R) -2-methyl-5- [5- (trifluoromethyl) -1,3-benzoxazol-2-yl] piperidine-1-carboxylate
tert−ブチル (2R,5R)−5−{[2−ヒドロキシ−5−(トリフルオロメチル)フェニル]カルバモイル}−2−メチルピペリジン−1−カルボキシラート(494mg、1.23mmol)とPPh3(710mg、2.71mmol)のTHF溶液(12mL)に氷浴下DEAD(2.2mol/L、1.23mL、2.71mmol)を加え、室温で一晩撹拌した。減圧下、濃縮後HPLCにて精製し、表題化合物(244mg)を得た(淡黄色油状物)。
MS (ESI pos.) m/z : 385 [M+H]+
tert-Butyl (2R, 5R) -5-{[2-hydroxy-5- (trifluoromethyl) phenyl] carbamoyl} -2-methylpiperidine-1-carboxylate (494 mg, 1.23 mmol) and PPh 3 (710 mg DEAD (2.2 mol / L, 1.23 mL, 2.71 mmol) was added to a THF solution (12 mL) of (2.71 mmol) in an ice bath and stirred overnight at room temperature. After concentration under reduced pressure, the residue was purified by HPLC to give the title compound (244 mg) (pale yellow oil).
MS (ESI pos.) M / z: 385 [M + H] +
以下の参考例25〜31を参考例24と同様の手法により得た。得られた化合物の構造式、化合物名及びMSデータを表2に示す。 The following Reference Examples 25 to 31 were obtained in the same manner as in Reference Example 24. Table 2 shows the structural formula, compound name, and MS data of the obtained compound.
参考例32 2−[(3R,6R)−6−メチルピペリジン−3−イル]−5−(トリフルオロメチル)−1,3−ベンゾオキサゾール 塩酸塩 Reference Example 32 2-[(3R, 6R) -6-methylpiperidin-3-yl] -5- (trifluoromethyl) -1,3-benzoxazole hydrochloride
tert−ブチル (2R,5R)−2−メチル−5−[5−(トリフルオロメチル)−1,3−ベンゾオキサゾール−2−イル]ピペリジン−1−カルボキシラート(244mg、0.635mmol)のEtOAc溶液(6.3mL)に4mol/L HCl−EtOAc溶液(6.3mL)を加え、室温で30分撹拌した。反応混合物を減圧下濃縮し、表題化合物(195mg)を得た(無色固体)。
MS (ESI pos.) m/z : 285 [M+H]+
tert-Butyl (2R, 5R) -2-methyl-5- [5- (trifluoromethyl) -1,3-benzoxazol-2-yl] piperidine-1-carboxylate (244 mg, 0.635 mmol) in EtOAc A 4 mol / L HCl-EtOAc solution (6.3 mL) was added to the solution (6.3 mL), and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was concentrated under reduced pressure to obtain the title compound (195 mg) (colorless solid).
MS (ESI pos.) M / z: 285 [M + H] +
以下の参考例33〜39を参考例32と同様の手法により得た。得られた化合物の構造式、化合物名及びMSデータを表3に示す。 The following Reference Examples 33 to 39 were obtained in the same manner as in Reference Example 32. Table 3 shows the structural formula, compound name, and MS data of the obtained compound.
参考例40 5,7−ジフルオロ−2−[(3R,6R)−6−メチルピペリジン−3−イル]−1,3−ベンゾオキサゾール Reference Example 40 5,7-Difluoro-2-[(3R, 6R) -6-methylpiperidin-3-yl] -1,3-benzoxazole
MS (ESI pos.) m/z : 253 [M+H]+
MS (ESI pos.) M / z: 253 [M + H] +
以下の参考例41〜43を参考例40と同様の手法により得た。得られた化合物の構造式、化合物名及びMSデータを表4に示す。 The following reference examples 41 to 43 were obtained in the same manner as in reference example 40. Table 4 shows the structural formula, compound name, and MS data of the obtained compound.
参考例44 (3R,6R)−N−(5−クロロ−2−ヒドロキシピリジン−3−イル)−6−メチル−1−[5−メチル−2−(2H−1,2,3−トリアゾール−2−イル)ベンゾイル]ピペリジン−3−カルボキサミド Reference Example 44 (3R, 6R) -N- (5-chloro-2-hydroxypyridin-3-yl) -6-methyl-1- [5-methyl-2- (2H-1,2,3-triazole-) 2-yl) benzoyl] piperidine-3-carboxamide
(3R,6R)−1−(tert−ブトキシカルボニル)−6−メチルピペリジン−3−カルボン酸メチルから導かれた(3R,6R)−6−メチルピペリジン−3−カルボン酸メチル塩酸塩(165mg、0.78mmol)及び3−アミノ−5−クロロ−2−ヒドロキシピリジン塩酸塩(143mg、0.79mmol)を原料にして、参考例8〜10と同様の手法により、表題化合物(50mg)を得た(褐色油状物)。
MS (ESI pos.) m/z : 455 [M+H]+
(3R, 6R) -1- (tert-butoxycarbonyl) -6-methylpiperidine-3-carboxylate derived from methyl (3R, 6R) -6-methylpiperidine-3-carboxylate (165 mg, 0.78 mmol) and 3-amino-5-chloro-2-hydroxypyridine hydrochloride (143 mg, 0.79 mmol) as starting materials, and the title compound (50 mg) was obtained in the same manner as in Reference Examples 8-10. (Brown oil).
MS (ESI pos.) M / z: 455 [M + H] +
参考例45 メチル (3R,6R)−1−[4−フルオロ−2−(2H−1,2,3−トリアゾール−2−イル)ベンゾイル]−6−メチルピペリジン−3−カルボキシラート Reference Example 45 Methyl (3R, 6R) -1- [4-fluoro-2- (2H-1,2,3-triazol-2-yl) benzoyl] -6-methylpiperidine-3-carboxylate
(3R,6R)−1−(tert−ブトキシカルボニル)−6−メチルピペリジン−3−カルボン酸メチルから導かれた(3R,6R)−6−メチルピペリジン−3−カルボン酸メチル(41.0mg、0.261mmol)及び4−フルオロ−2−(2H−1,2,3−トリアゾール−2−イル)安息香酸(54.0mg、0.261mmol)のDMF(2.61mL)溶液にDIPEA(0.182mL、1.04mmol)及びHATU(102.0mg、0.313mmol)を加え室温で一晩撹拌した。反応混合物にNaHCO3水溶液を加え、CHCl3を用いて抽出し、有機層を減圧下溶媒留去した。得られた残渣をカラムクロマトグラフィー(HP−Sil 、Hexane/EtOAc)にて精製し、表題化合物(73.0mg)を得た(無色非晶質)。
MS (ESI pos.) m/z : 347 [M+H]+
(3R, 6R) -1- (tert-Butoxycarbonyl) -6-methylpiperidine-3-carboxylate derived from methyl (3R, 6R) -6-methylpiperidine-3-carboxylate (41.0 mg, 0.261 mmol) and 4-fluoro-2- (2H-1,2,3-triazol-2-yl) benzoic acid (54.0 mg, 0.261 mmol) in DMF (2.61 mL) solution in DIPEA (0. 182 mL, 1.04 mmol) and HATU (102.0 mg, 0.313 mmol) were added and stirred at room temperature overnight. Aqueous NaHCO 3 solution was added to the reaction mixture, extraction was performed using CHCl 3 , and the organic layer was evaporated under reduced pressure. The obtained residue was purified by column chromatography (HP-Sil, Hexane / EtOAc) to obtain the title compound (73.0 mg) (colorless amorphous).
MS (ESI pos.) M / z: 347 [M + H] +
参考例46 (3R,6R)−1−[4−フルオロ−2−(2H−1,2,3−トリアゾール−2−イル)ベンゾイル]−6−メチルピペリジン−3−カルボン酸 Reference Example 46 (3R, 6R) -1- [4-Fluoro-2- (2H-1,2,3-triazol-2-yl) benzoyl] -6-methylpiperidine-3-carboxylic acid
参考例45で得られたメチル (3R,6R)−1−[4−フルオロ−2−(2H−1,2,3−トリアゾール−2−イル)ベンゾイル]−6−メチルピペリジン−3−カルボキシラート(73.0mg、0.21mmol)の1,4−ジオキサン(2.1mL)溶液に2mol/L 塩酸(2.1mL)を加え、80℃で6時間攪拌した。反応混合物を減圧下濃縮し、表題化合物を得た(無色非晶質)。
MS (ESI pos.) m/z : 333 [M+H]+
Methyl (3R, 6R) -1- [4-fluoro-2- (2H-1,2,3-triazol-2-yl) benzoyl] -6-methylpiperidine-3-carboxylate obtained in Reference Example 45 To a 1,4-dioxane (2.1 mL) solution of (73.0 mg, 0.21 mmol) was added 2 mol / L hydrochloric acid (2.1 mL), and the mixture was stirred at 80 ° C. for 6 hours. The reaction mixture was concentrated under reduced pressure to obtain the title compound (colorless amorphous).
MS (ESI pos.) M / z: 333 [M + H] +
参考例47 (3R,6R)−N−(5−クロロ−2−ヒドロキシピリジン−3−イル)−1−[4−フルオロ−2−(2H−1,2,3−トリアゾール−2−イル)ベンゾイル]−6−メチルピペリジン−3−カルボキサミド Reference Example 47 (3R, 6R) -N- (5-chloro-2-hydroxypyridin-3-yl) -1- [4-fluoro-2- (2H-1,2,3-triazol-2-yl) Benzoyl] -6-methylpiperidine-3-carboxamide
参考例46で得られた(3R,6R)−6−メチル−1−[5−メチル−2−(2H−1,2,3−トリアゾール−2−イル)ベンゾイル]ピペリジン−3−カルボン酸 (0.21mmol)及び3−アミノ−5−クロロ−2−ヒドロキシピリジン塩酸塩(41.82mg、0.23mmol)を原料にして、参考例44と同様の手法により、表題化合物(25.5mg)を得た(褐色油状物)。
MS (ESI pos.) m/z : 459 [M+H]+
(3R, 6R) -6-methyl-1- [5-methyl-2- (2H-1,2,3-triazol-2-yl) benzoyl] piperidine-3-carboxylic acid obtained in Reference Example 46 0.21 mmol) and 3-amino-5-chloro-2-hydroxypyridine hydrochloride (41.82 mg, 0.23 mmol) as a starting material, and the title compound (25.5 mg) was prepared in the same manner as in Reference Example 44. Obtained (brown oil).
MS (ESI pos.) M / z: 459 [M + H] +
参考例48 5−クロロ−2−[(3R,6R)−6−メチルピペリジン−3−イル]−1,3−ベンゾオキサゾール Reference Example 48 5-chloro-2-[(3R, 6R) -6-methylpiperidin-3-yl] -1,3-benzoxazole
(3R,6R)−1−(tert−ブトキシカルボニル)−6−メチルピペリジン−3−カルボン酸(5.34g、21.95mmol)を原料として、参考例16、24、32と同様の手法により順次反応を行い、表題化合物(2.49g)を得た(淡黄色固体)。
MS (ESI pos.) m/z : 251 [M+H]+
Using (3R, 6R) -1- (tert-butoxycarbonyl) -6-methylpiperidine-3-carboxylic acid (5.34 g, 21.95 mmol) as a raw material, the same procedure as in Reference Examples 16, 24, and 32 was sequentially performed. Reaction was performed to obtain the title compound (2.49 g) (pale yellow solid).
MS (ESI pos.) M / z: 251 [M + H] +
実施例1 [(2R,5R)−5−(5−クロロ−1,3−ベンゾオキサゾール−2−イル)−2−メチルピペリジン−1−イル][6−メチル−3−(2H−1,2,3−トリアゾール−2−イル)ピリジン−2−イル]メタノン Example 1 [(2R, 5R) -5- (5-Chloro-1,3-benzoxazol-2-yl) -2-methylpiperidin-1-yl] [6-methyl-3- (2H-1, 2,3-triazol-2-yl) pyridin-2-yl] methanone
5−クロロ−2−[(3RS,6RS)−6−メチルピペリジン−3−イル]−1,3−ベンゾオキサゾール(0.30g、1.6mmol)のCHCl3溶液(5mL)にDIPEA(0.228mL、1.31mmol)、6−メチル−3−(2H−1,2,3−トリアゾール−2−イル)ピリジン−2−カルボン酸(66.9mg、0.33mmol)、プロパンホスホニックアシッドアンハイドライド(1.7mol/L EtOAc溶液、0.93mL、1.57mmol)を加え、50℃で4.5時間撹拌した。反応混合物を減圧下濃縮し、2mol/L NaOH水溶液を加え、EtOAcを用いて抽出した。得られた有機層をMgSO4で乾燥後、乾燥剤を濾別し、減圧下溶媒留去した。得られた残渣をカラムクロマトグラフィー(HP−Sil 10g、hexane/EtOAc)にて精製し、表題化合物のラセミ混合物(163mg)を得た(無色固体)。
得られたラセミ混合物を前記のラセミ体分割条件(条件2)で分割し、2つのピーク(前記の分析条件における保持時間:5.67min、 8.58min)を分割した。このうち相対保持時間が長い化合物(保持時間:8.58min)として表題化合物を得た(無色固体)。得られた表題化合物は、参考例14で導いて、絶対立体構造を決定した[(2R,5R)−5−(5−クロロ−1,3−ベンゾオキサゾール−2−イル)−2−メチルピペリジン−1−イル][6−メチル−3−(2H−1,2,3−トリアゾール−2−イル)ピリジン−2−イル]メタノンと、前記キラル分析(条件A)における保持時間が一致したことから、その絶対立体構造を確認した。
LCMS retention time 3.80 min.(条件3)
MS (ESI pos.) m/z : 437 [M+H]+
5-chloro -2 - [(3RS, 6RS) -6- methyl-piperidin-3-yl] -1,3- DIPEA (0 to CHCl 3 solution (5 mL) benzoxazole (0.30g, 1.6mmol). 228 mL, 1.31 mmol), 6-methyl-3- (2H-1,2,3-triazol-2-yl) pyridine-2-carboxylic acid (66.9 mg, 0.33 mmol), propanephosphonic acid anhydride (1.7 mol / L EtOAc solution, 0.93 mL, 1.57 mmol) was added and stirred at 50 ° C. for 4.5 hours. The reaction mixture was concentrated under reduced pressure, 2 mol / L aqueous NaOH solution was added, and the mixture was extracted with EtOAc. The obtained organic layer was dried over MgSO 4 , the desiccant was filtered off, and the solvent was distilled off under reduced pressure. The obtained residue was purified by column chromatography (HP-Sil 10 g, hexane / EtOAc) to obtain a racemic mixture (163 mg) of the title compound (colorless solid).
The obtained racemic mixture was divided under the above racemic resolution conditions (condition 2), and two peaks (retention times under the above analysis conditions: 5.67 min, 8.58 min) were resolved. Among these, the title compound was obtained as a compound having a long relative retention time (retention time: 8.58 min) (colorless solid). The obtained title compound was derived in Reference Example 14 and the absolute steric structure was determined [(2R, 5R) -5- (5-chloro-1,3-benzoxazol-2-yl) -2-methylpiperidine. -1-yl] [6-methyl-3- (2H-1,2,3-triazol-2-yl) pyridin-2-yl] methanone and the retention time in the chiral analysis (Condition A) matched. The absolute steric structure was confirmed.
LCMS retention time 3.80 min. (Condition 3)
MS (ESI pos.) M / z: 437 [M + H] +
実施例2 [(2R*,5R*)−5−(5−クロロ−1,3−ベンゾオキサゾール−2−イル)−2−メチルピペリジン−1−イル][5−フルオロ−2−(2H−1,2,3−トリアゾール−2−イル)フェニル]メタノン Example 2 [(2R *, 5R *)-5- (5-chloro-1,3-benzoxazol-2-yl) -2-methylpiperidin-1-yl] [5-fluoro-2- (2H- 1,2,3-triazol-2-yl) phenyl] methanone
5−クロロ−2−[(3RS,6RS)−6−メチルピペリジン−3−イル]−1,3−ベンゾオキサゾール(50.0mg、0.20mmol)及び5−フルオロ−2−(2H−1,2,3−トリアゾール−2−イル)安息香酸(82.6mg、0.40mmol)を原料にして、実施例1と同様の手法により、表題化合物のラセミ混合物(34mg)を得た(無色固体)。
得られたラセミ混合物を前記のラセミ体分割条件(条件1)で分割し、相対保持時間が長い化合物として表題化合物を得た(無色固体)。
LCMS retention time 4.28 min.(条件3)
MS (ESI pos.) m/z : 440 [M+H]+
5-chloro-2-[(3RS, 6RS) -6-methylpiperidin-3-yl] -1,3-benzoxazole (50.0 mg, 0.20 mmol) and 5-fluoro-2- (2H-1, A racemic mixture (34 mg) of the title compound was obtained in the same manner as in Example 1 using 2,3-triazol-2-yl) benzoic acid (82.6 mg, 0.40 mmol) as a raw material (colorless solid) .
The obtained racemic mixture was divided under the above-mentioned racemic resolution conditions (condition 1) to obtain the title compound as a compound having a long relative retention time (colorless solid).
LCMS retention time 4.28 min. (Condition 3)
MS (ESI pos.) M / z: 440 [M + H] +
実施例3 [(2R*,5R*)−5−(5−クロロ−1,3−ベンゾオキサゾール−2−イル)−2−メチルピペリジン−1−イル][2−(2H−1,2,3−トリアゾール−2−イル)フェニル]メタノン Example 3 [(2R *, 5R *)-5- (5-chloro-1,3-benzoxazol-2-yl) -2-methylpiperidin-1-yl] [2- (2H-1,2, 3-Triazol-2-yl) phenyl] methanone
5−クロロ−2−[(3RS,6RS)−6−メチルピペリジン−3−イル]−1,3−ベンゾオキサゾール(32.8mg、0.13mmol)及び2−(2H−1,2,3−トリアゾール−2−イル)安息香酸(49.5mg、0.26mmol)を原料にして、実施例1と同様の手法により、表題化合物のラセミ混合物(37mg)を得た(無色固体)。
得られたラセミ混合物を前記のラセミ体分割条件(条件1)で分割し、相対保持時間が長い化合物として表題化合物を得た(無色固体)。
LCMS retention time 4.12 min.(条件3)
MS (ESI pos.) m/z : 422 [M+H]+
5-Chloro-2-[(3RS, 6RS) -6-methylpiperidin-3-yl] -1,3-benzoxazole (32.8 mg, 0.13 mmol) and 2- (2H-1,2,3- A racemic mixture (37 mg) of the title compound was obtained in the same manner as in Example 1 using triazol-2-yl) benzoic acid (49.5 mg, 0.26 mmol) as a raw material (colorless solid).
The obtained racemic mixture was divided under the above-mentioned racemic resolution conditions (condition 1) to obtain the title compound as a compound having a long relative retention time (colorless solid).
LCMS retention time 4.12 min. (Condition 3)
MS (ESI pos.) M / z: 422 [M + H] +
実施例4 [(2R*,5R*)−5−(5−クロロ−1,3−ベンゾオキサゾール−2−イル)−2−メチルピペリジン−1−イル][6−メチル−3−(ピリミジン−2−イル)ピリジン−2−イル]メタノン Example 4 [(2R *, 5R *)-5- (5-chloro-1,3-benzoxazol-2-yl) -2-methylpiperidin-1-yl] [6-methyl-3- (pyrimidine- 2-yl) pyridin-2-yl] methanone
5−クロロ−2−[(3RS,6RS)−6−メチルピペリジン−3−イル]−1,3−ベンゾオキサゾール(98.8mg、0.39mmol)及び6−メチル−3−(ピリミジン−2−イル)ピリジン−2−カルボン酸(84.8mg、0.39mmol)を原料にして、実施例1と同様の手法により、表題化合物のラセミ混合物(58mg)を得た(無色固体)。
得られたラセミ混合物を前記のラセミ体分割条件(条件2)で分割し、相対保持時間が長い化合物として表題化合物を得た(無色固体)。
LCMS retention time 3.52 min.(条件3)
MS (ESI pos.) m/z : 448 [M+H]+
5-Chloro-2-[(3RS, 6RS) -6-methylpiperidin-3-yl] -1,3-benzoxazole (98.8 mg, 0.39 mmol) and 6-methyl-3- (pyrimidine-2- Yl) A racemic mixture (58 mg) of the title compound was obtained in the same manner as in Example 1 using pyridine-2-carboxylic acid (84.8 mg, 0.39 mmol) as a raw material (colorless solid).
The obtained racemic mixture was divided under the above racemic resolution conditions (Condition 2) to give the title compound as a compound with a long relative retention time (colorless solid).
LCMS retention time 3.52 min. (Condition 3)
MS (ESI pos.) M / z: 448 [M + H] +
実施例5 [(2R*,5R*)−5−(5−クロロ−1,3−ベンゾオキサゾール−2−イル)−2−メチルピペリジン−1−イル][5−メチル−2−(ピリミジン−2−イル)フェニル]メタノン Example 5 [(2R *, 5R *)-5- (5-chloro-1,3-benzoxazol-2-yl) -2-methylpiperidin-1-yl] [5-methyl-2- (pyrimidine- 2-yl) phenyl] methanone
5−クロロ−2−[(3RS,6RS)−6−メチルピペリジン−3−イル]−1,3−ベンゾオキサゾール(55.0mg、0.22mmol)及び5−メチル−2−(ピリミジン−2−イル)安息香酸(94.0mg、0.44mmol)を原料にして、実施例1と同様の手法により、表題化合物のラセミ混合物(84mg)を得た(無色固体)。
得られたラセミ混合物を前記のラセミ体分割条件(条件1)で分割し、相対保持時間が長い化合物として表題化合物を得た(無色固体)。
LCMS retention time 4.20 min.(条件3)
MS (ESI pos.) m/z : 447 [M+H]+
5-chloro-2-[(3RS, 6RS) -6-methylpiperidin-3-yl] -1,3-benzoxazole (55.0 mg, 0.22 mmol) and 5-methyl-2- (pyrimidine-2- Il) A racemic mixture (84 mg) of the title compound was obtained in the same manner as in Example 1 using benzoic acid (94.0 mg, 0.44 mmol) as a raw material (colorless solid).
The obtained racemic mixture was divided under the above-mentioned racemic resolution conditions (condition 1) to obtain the title compound as a compound having a long relative retention time (colorless solid).
LCMS retention time 4.20 min. (Condition 3)
MS (ESI pos.) M / z: 447 [M + H] +
実施例6 [(2R*,5R*)−5−(5−クロロ−1,3−ベンゾオキサゾール−2−イル)−2−メチルピペリジン−1−イル][5−フルオロ−2−(ピリミジン−2−イル)フェニル]メタノン Example 6 [(2R *, 5R *)-5- (5-chloro-1,3-benzoxazol-2-yl) -2-methylpiperidin-1-yl] [5-fluoro-2- (pyrimidine- 2-yl) phenyl] methanone
5−クロロ−2−[(3RS,6RS)−6−メチルピペリジン−3−イル]−1,3−ベンゾオキサゾール(50.0mg、0.20mmol)及び5−フルオロ−2−(ピリミジン−2−イル)安息香酸(87.0mg、0.40mmol)を原料にして、実施例1と同様の手法により、表題化合物のラセミ混合物(66mg)を得た(無色固体)。
得られたラセミ混合物を前記のラセミ体分割条件(条件1)で分割し、相対保持時間が長い化合物として表題化合物を得た(無色固体)。
LCMS retention time 4.19 min.(条件3)
MS (ESI pos.) m/z : 451 [M+H]+
5-Chloro-2-[(3RS, 6RS) -6-methylpiperidin-3-yl] -1,3-benzoxazole (50.0 mg, 0.20 mmol) and 5-fluoro-2- (pyrimidine-2- Il) A racemic mixture (66 mg) of the title compound was obtained in the same manner as in Example 1 using benzoic acid (87.0 mg, 0.40 mmol) as a raw material (colorless solid).
The obtained racemic mixture was divided under the above-mentioned racemic resolution conditions (condition 1) to obtain the title compound as a compound having a long relative retention time (colorless solid).
LCMS retention time 4.19 min. (Condition 3)
MS (ESI pos.) M / z: 451 [M + H] +
実施例7 [(2R*,5R*)−5−(5−クロロ−1,3−ベンゾオキサゾール−2−イル)−2−メチルピペリジン−1−イル][2−(ピリミジン−2−イル)フェニル]メタノン Example 7 [(2R *, 5R *)-5- (5-chloro-1,3-benzoxazol-2-yl) -2-methylpiperidin-1-yl] [2- (pyrimidin-2-yl) Phenyl] methanone
5−クロロ−2−[(3RS,6RS)−6−メチルピペリジン−3−イル]−1,3−ベンゾオキサゾール(50.0mg、0.20mmol)及び2−(ピリミジン−2−イル)安息香酸(79.8mg、0.40mmol)を原料にして、実施例1と同様の手法により、表題化合物のラセミ混合物(83mg)を得た(無色固体)。
得られたラセミ混合物を前記のラセミ体分割条件(条件1)で分割し、相対保持時間が長い化合物として表題化合物を得た(無色固体)。
LCMS retention time 3.98 min.(条件3)
MS (ESI pos.) m/z : 433 [M+H]+
5-Chloro-2-[(3RS, 6RS) -6-methylpiperidin-3-yl] -1,3-benzoxazole (50.0 mg, 0.20 mmol) and 2- (pyrimidin-2-yl) benzoic acid A racemic mixture (83 mg) of the title compound was obtained in the same manner as in Example 1 using (79.8 mg, 0.40 mmol) as a starting material (colorless solid).
The obtained racemic mixture was divided under the above-mentioned racemic resolution conditions (condition 1) to obtain the title compound as a compound having a long relative retention time (colorless solid).
LCMS retention time 3.98 min. (Condition 3)
MS (ESI pos.) M / z: 433 [M + H] +
実施例8 [(2R*,5R*)−5−(5−フルオロ−1,3−ベンゾオキサゾール−2−イル)−2−メチルピペリジン−1−イル][5−メチル−2−(ピリミジン−2−イル)フェニル]メタノン Example 8 [(2R *, 5R *)-5- (5-fluoro-1,3-benzoxazol-2-yl) -2-methylpiperidin-1-yl] [5-methyl-2- (pyrimidine- 2-yl) phenyl] methanone
5−フルオロ−2−[(3RS,6RS)−6−メチルピペリジン−3−イル]−1,3−ベンゾオキサゾール(53.0mg、0.23mmol)及び5−メチル−2−(ピリミジン−2−イル)安息香酸(96.9mg、0.45mmol)を原料にして、実施例1と同様の手法により、表題化合物のラセミ混合物(55mg)を得た(無色固体)。
得られたラセミ混合物を前記のラセミ体分割条件(条件1)で分割し、相対保持時間が長い化合物として表題化合物を得た(無色固体)。
LCMS retention time 3.93 min.(条件3)
MS (ESI pos.) m/z : 431 [M+H]+
5-Fluoro-2-[(3RS, 6RS) -6-methylpiperidin-3-yl] -1,3-benzoxazole (53.0 mg, 0.23 mmol) and 5-methyl-2- (pyrimidine-2- Il) A racemic mixture (55 mg) of the title compound was obtained in the same manner as in Example 1 using benzoic acid (96.9 mg, 0.45 mmol) as a raw material (colorless solid).
The obtained racemic mixture was divided under the above-mentioned racemic resolution conditions (condition 1) to obtain the title compound as a compound having a long relative retention time (colorless solid).
LCMS retention time 3.93 min. (Condition 3)
MS (ESI pos.) M / z: 431 [M + H] +
実施例9 [(2R*,5R*)−5−(5−クロロ−1,3−ベンゾオキサゾール−2−イル)−2−メチルピペリジン−1−イル][5−メチル−2−(2H−1,2,3−トリアゾール−2−イル)フェニル]メタノン Example 9 [(2R *, 5R *)-5- (5-chloro-1,3-benzoxazol-2-yl) -2-methylpiperidin-1-yl] [5-methyl-2- (2H- 1,2,3-triazol-2-yl) phenyl] methanone
参考例10で得られた(3RS,6RS)−N−(5−クロロ−2−ヒドロキシフェニル)−6−メチル−1−[5−メチル−2−(2H−1,2,3−トリアゾール−2−イル)ベンゾイル]ピペリジン−3−カルボキサミド(118mg、0.26mmol)を原料にして、参考例2と同様の手法により、表題化合物のラセミ混合物(65mg)を得た(無色固体)。
得られたラセミ混合物を前記のラセミ体分割条件(条件1)で分割し、相対保持時間が長い化合物として表題化合物を得た(無色固体)。
LCMS retention time 4.32 min.(条件3)
MS (ESI pos.) m/z : 436 [M+H]+
(3RS, 6RS) -N- (5-chloro-2-hydroxyphenyl) -6-methyl-1- [5-methyl-2- (2H-1,2,3-triazole-) obtained in Reference Example 10 2-Ryl) benzoyl] piperidine-3-carboxamide (118 mg, 0.26 mmol) was used as a starting material to give a racemic mixture (65 mg) of the title compound (colorless solid) in the same manner as in Reference Example 2.
The obtained racemic mixture was divided under the above-mentioned racemic resolution conditions (condition 1) to obtain the title compound as a compound having a long relative retention time (colorless solid).
LCMS retention time 4.32 min. (Condition 3)
MS (ESI pos.) M / z: 436 [M + H] +
実施例10 [(2R*,5R*)−5−(5−フルオロ−1,3−ベンゾオキサゾール−2−イル)−2−メチルピペリジン−1−イル][5−メチル−2−(2H−1,2,3−トリアゾール−2−イル)フェニル]メタノン Example 10 [(2R *, 5R *)-5- (5-fluoro-1,3-benzoxazol-2-yl) -2-methylpiperidin-1-yl] [5-methyl-2- (2H- 1,2,3-triazol-2-yl) phenyl] methanone
参考例11で得られた(3RS,6RS)−N−(5−フルオロ−2−ヒドロキシフェニル)−6−メチル−1−[5−メチル−2−(2H−1,2,3−トリアゾール−2−イル)ベンゾイル]ピペリジン−3−カルボキサミド(18mg、0.04mmol)を原料にして、参考例2と同様の手法により、表題化合物のラセミ混合物(65mg)を得た(無色固体)。
得られたラセミ混合物を前記のラセミ体分割条件(条件1)で分割し、相対保持時間が長い化合物として表題化合物を得た(無色固体)。
LCMS retention time 4.05 min.(条件3)
MS (ESI pos.) m/z : 420 [M+H]+
(3RS, 6RS) -N- (5-fluoro-2-hydroxyphenyl) -6-methyl-1- [5-methyl-2- (2H-1,2,3-triazole-) obtained in Reference Example 11 2-Ryl) benzoyl] piperidine-3-carboxamide (18 mg, 0.04 mmol) was used as a starting material to give a racemic mixture (65 mg) of the title compound (colorless solid) in the same manner as in Reference Example 2.
The obtained racemic mixture was divided under the above-mentioned racemic resolution conditions (condition 1) to obtain the title compound as a compound having a long relative retention time (colorless solid).
LCMS retention time 4.05 min. (Condition 3)
MS (ESI pos.) M / z: 420 [M + H] +
実施例11 [(2R*,5R*)−5−(5−フルオロ−1,3−ベンゾオキサゾール−2−イル)−2−メチルピペリジン−1−イル][6−メチル−3−(2H−1,2,3−トリアゾール−2−イル)ピリジン−2−イル]メタノン Example 11 [(2R *, 5R *)-5- (5-fluoro-1,3-benzoxazol-2-yl) -2-methylpiperidin-1-yl] [6-methyl-3- (2H- 1,2,3-triazol-2-yl) pyridin-2-yl] methanone
5−フルオロ−2−[(3RS,6RS)−6−メチルピペリジン−3−イル]−1,3−ベンゾオキサゾール(53.0mg、0.23mmol)及び6−メチル−3−(2H−1,2,3−トリアゾール−2−イル)ピリジン−2−カルボン酸(96.9mg、0.45mmol)を原料にして、実施例1と同様の手法により、表題化合物のラセミ混合物(55mg)を得た(無色固体)。
得られたラセミ混合物を前記のラセミ体分割条件(条件2)分割し、相対保持時間が長い化合物として表題化合物を得た(無色固体)。
LCMS retention time 3.38 min.(条件3)
MS (ESI pos.) m/z : 421 [M+H]+
5-Fluoro-2-[(3RS, 6RS) -6-methylpiperidin-3-yl] -1,3-benzoxazole (53.0 mg, 0.23 mmol) and 6-methyl-3- (2H-1, A racemic mixture (55 mg) of the title compound was obtained in the same manner as in Example 1 using 2,3-triazol-2-yl) pyridine-2-carboxylic acid (96.9 mg, 0.45 mmol) as a starting material. (Colorless solid).
The obtained racemic mixture was divided under the above racemic resolution conditions (Condition 2) to give the title compound as a compound with a long relative retention time (colorless solid).
LCMS retention time 3.38 min. (Condition 3)
MS (ESI pos.) M / z: 421 [M + H] +
実施例12 [(2R*,5R*)−5−(6−フルオロ−1,3−ベンゾオキサゾール−2−イル)−2−メチルピペリジン−1−イル][6−メチル−3−(2H−1,2,3−トリアゾール−2−イル)ピリジン−2−イル]メタノン Example 12 [(2R *, 5R *)-5- (6-Fluoro-1,3-benzoxazol-2-yl) -2-methylpiperidin-1-yl] [6-methyl-3- (2H- 1,2,3-triazol-2-yl) pyridin-2-yl] methanone
6−フルオロ−2−[(3RS,6RS)−6−メチルピペリジン−3−イル]−1,3−ベンゾオキサゾール 塩酸塩(88.0mg、0.33mmol)、TEA(0.05mL、0.36mmol)のDMF溶液(3mL)に6−メチル−3−(2H−1,2,3−トリアゾール−2−イル)ピリジン−2−カルボン酸(73.0mg、0.36mmol)、HOBt・H2O(74.0mg、0.49mmol)、及びEDC・HCl(93.0mg、0.49mmol)を加え、室温で3時間撹拌した。反応溶液にNaHCO3水溶液を加え、EtOAcを用いて抽出した。有機層をMgSO4で乾燥後、乾燥剤を濾別し、減圧下溶媒留去した。得られた残渣をカラムクロマトグラフィー(HP−Sil 25g、hexane/EtOAc)にて精製し表題化合物のラセミ混合物(32mg)を得た(無色固体)。
得られたラセミ混合物を前記のラセミ体分割条件(条件2)で分割し、相対保持時間が長い化合物として表題化合物を得た(無色固体)。
LCMS retention time 3.36 min.(条件3)
MS (ESI pos.) m/z : 421 [M+H]+
6-Fluoro-2-[(3RS, 6RS) -6-methylpiperidin-3-yl] -1,3-benzoxazole hydrochloride (88.0 mg, 0.33 mmol), TEA (0.05 mL, 0.36 mmol) ) In DMF solution (3 mL) to 6-methyl-3- (2H-1,2,3-triazol-2-yl) pyridine-2-carboxylic acid (73.0 mg, 0.36 mmol), HOBt · H 2 O (74.0 mg, 0.49 mmol) and EDC.HCl (93.0 mg, 0.49 mmol) were added, and the mixture was stirred at room temperature for 3 hours. To the reaction solution was added an aqueous NaHCO 3 solution, and the mixture was extracted with EtOAc. After drying the organic layer with MgSO 4 , the desiccant was filtered off and the solvent was distilled off under reduced pressure. The obtained residue was purified by column chromatography (HP-Sil 25 g, hexane / EtOAc) to obtain a racemic mixture (32 mg) of the title compound (colorless solid).
The obtained racemic mixture was divided under the above racemic resolution conditions (Condition 2) to give the title compound as a compound with a long relative retention time (colorless solid).
LCMS retention time 3.36 min. (Condition 3)
MS (ESI pos.) M / z: 421 [M + H] +
実施例13 [(2R,5R)−5−(5−クロロ−1,3−ベンゾオキサゾール−2−イル)−2−メチルピペリジン−1−イル][5−クロロ−2−(ピリミジン−2−イル)フェニル]メタノン Example 13 [(2R, 5R) -5- (5-Chloro-1,3-benzoxazol-2-yl) -2-methylpiperidin-1-yl] [5-chloro-2- (pyrimidin-2- Yl) phenyl] methanone
5−クロロ−2−[(3R,6R)−6−メチルピペリジン−3−イル]−1,3−ベンゾオキサゾール(20mg、0.080mmol)及び5−クロロ−2−(ピリミジン−2−イル)安息香酸(19mg、0・080mmol)のCHCl3溶液(1mL)にDIPEA(34.7μL、0.20mmol)及びプロパンホスホニックアシッドアンハイドライド(1.7mmol/L、EtOAc溶液、141μL、0.24mmol)を加え、50℃で9時間撹拌した。反応溶液にNaHCO3水溶液を加え、CHCl3を用いて抽出した。反応混合物を減圧下、濃縮後HPLCにて精製し、表題化合物(4.9mg)を得た(黄色固体)。
LCMS retention time 1.16 min.(条件4)
MS (ESI pos.) m/z : 467 [M+H]+
5-chloro-2-[(3R, 6R) -6-methylpiperidin-3-yl] -1,3-benzoxazole (20 mg, 0.080 mmol) and 5-chloro-2- (pyrimidin-2-yl) Benzoic acid (19 mg, 0.080 mmol) in CHCl 3 solution (1 mL) with DIPEA (34.7 μL, 0.20 mmol) and propanephosphonic acid anhydride (1.7 mmol / L, EtOAc solution, 141 μL, 0.24 mmol) And stirred at 50 ° C. for 9 hours. To the reaction solution was added an aqueous NaHCO 3 solution, and the mixture was extracted with CHCl 3 . The reaction mixture was concentrated under reduced pressure and purified by HPLC to give the title compound (4.9 mg) (yellow solid).
LCMS retention time 1.16 min. (Condition 4)
MS (ESI pos.) M / z: 467 [M + H] +
以下実施例14〜70を実施例13と同様の手法により得た。得られた化合物の構造式、化合物名及びLCMSデータを表5−1〜5−10に示す。 Examples 14 to 70 were obtained in the same manner as in Example 13 below. The structural formulas, compound names and LCMS data of the obtained compounds are shown in Tables 5-1 to 5-10.
実施例71 [(2R,5R)−5−(6−クロロ[1,3]オキサゾロ[5,4−b]ピリジン−2−イル)−2−メチルピペリジン−1−イル][5−メチル−2−(2H−1,2,3−トリアゾール−2−イル)フェニル]メタノン Example 71 [(2R, 5R) -5- (6-chloro [1,3] oxazolo [5,4-b] pyridin-2-yl) -2-methylpiperidin-1-yl] [5-methyl- 2- (2H-1,2,3-triazol-2-yl) phenyl] methanone
(3R,6R)−N−(5−クロロ−2−ヒドロキシピリジン−3−イル)−6−メチル−1−[5−メチル−2−(2H−1,2,3−トリアゾール−2−イル)ベンゾイル]ピペリジン−3−カルボキサミド(50mg、0.11mmol)、PPh3(87mg、0.33mmol)、C2Cl6(65mg、0.27mmol)、TEA(120μL、0.88mmol)のCHCl3溶液(2mL)を室温で一晩撹拌した。減圧下、濃縮後HPLCにて精製し、表題化合物(17mg)を得た(無色固体)。
LCMS retention time 1.03 min.(条件4)
MS (ESI pos.) m/z : 437(M+H)+
(3R, 6R) -N- (5-Chloro-2-hydroxypyridin-3-yl) -6-methyl-1- [5-methyl-2- (2H-1,2,3-triazol-2-yl) ) Benzyl] piperidine-3-carboxamide (50 mg, 0.11 mmol), PPh 3 (87 mg, 0.33 mmol), C 2 Cl 6 (65 mg, 0.27 mmol), TEA (120 μL, 0.88 mmol) in CHCl 3 (2 mL) was stirred at room temperature overnight. After concentration under reduced pressure, the residue was purified by HPLC to give the title compound (17 mg) (colorless solid).
LCMS retention time 1.03 min. (Condition 4)
MS (ESI pos.) M / z: 437 (M + H) +
実施例72 [(2R,5R)−5−(6−クロロ[1,3]オキサゾロ[5,4−b]ピリジン−2−イル)−2−メチルピペリジン−1−イル][4−フルオロ−2−(2H−1,2,3−トリアゾール−2−イル)フェニル]メタノン Example 72 [(2R, 5R) -5- (6-chloro [1,3] oxazolo [5,4-b] pyridin-2-yl) -2-methylpiperidin-1-yl] [4-fluoro- 2- (2H-1,2,3-triazol-2-yl) phenyl] methanone
LCMS retention time 1.01 min.(条件4)
MS (ESI pos.) m/z : 463 (M+Na)+
LCMS retention time 1.01 min. (Condition 4)
MS (ESI pos.) M / z: 463 (M + Na) +
試験例1 (オレキシン拮抗活性の測定)
試験化合物のヒトオレキシン1型受容体(hOX1R)、オレキシン2型受容体(hO
X2R)に対する拮抗活性は文献(Toshikatsu Okumura et al., Biochemical and Biophysical Research Communications 280, 976-981, 2001)に記載された方法を改変して行った。hOX1R、hOX2Rを強制発現させたChinese hamster ovary(CHO)細胞を96wellのBlack clear bottomプレート(Nunc)の各ウェルに20,000個となるように播種し、0.1mM MEM非必須アミノ酸、0.5mg/ml G418、10% 牛胎児血清を含むHam’s F−12培地(以上インビトロジェン)で、37℃、5% CO2の条件下で16時間培養した。培地を除去後、0.5μM Fluo−3AM エステル(同仁)を含むアッセイ用緩衝液(25mM HEPES(同仁)、Hanks’ balanced salt solution(インビトロジェン)、0.1% 牛血清アルブミン、2.5mM プロベネシド、200μg/ml Amaranth(以上Sigma−Aldrich)、pH7.4)を100μL添加し60分間、37℃、5% CO2にインキュベートした。Fluo−3AM エステルを含むアッセイ用緩衝液を除去したのち、試験化合物は10mMとなるようにジメチルスルホキシドで溶解してアッセイ用緩衝液で希釈後、150μLを添加し、30分間インキュベートした。
リガンドであるヒトオレキシン-Aの2アミノ酸を置換したペプチド(Pyr-Pro-Leu-Pro-Asp-Ala-Cys-Arg-Gln-Lys-Thr-Ala-Ser-Cys-Arg-Leu-Tyr-Glu-Leu-Leu-His-Gly-Ala-Gly-Asn-His-Ala-Ala-Gly-Ile-Leu-Thr-Leu-NH2;ペプチド研究所)はhOX1Rに対しては終濃度300pM、hOX2Rに対しては3nMとなるようにアッセイ用緩衝液で希釈し、このリガンド溶液50μLを添加して反応を開始した。反応はFunctional Drug Screening System(FDSS;浜松ホトニクス社製)を用いて各wellの蛍光値を1秒毎に3分間測定し、最大蛍光値を細胞内Ca2+濃度の指標として拮抗活性を求めた。試験化合物の拮抗活性は希釈緩衝液のみを添加したウェルの蛍光値を100%、リガンドおよび化合物を含まない緩衝液を添加したウェルの蛍光値を0%として算出し、種々の濃度の試験化合物を添加した際の蛍光値から、50%阻害濃度(IC50値)を求めた。
Test Example 1 (Measurement of orexin antagonistic activity)
Test compounds human orexin type 1 receptor (hOX1R), orexin type 2 receptor (hO
The antagonistic activity against (X2R) was performed by modifying the method described in the literature (Toshikatsu Okumura et al., Biochemical and Biophysical Research Communications 280, 976-981, 2001). Chinese hamster ovary (CHO) cells in which hOX1R and hOX2R are forcibly expressed were seeded at 20,000 in each well of a 96-well Black clear bottom plate (Nunc), and 0.1 mM MEM non-essential amino acids, 0. The cells were cultured in Ham's F-12 medium (Invitrogen) containing 5 mg / ml G418, 10% fetal calf serum for 16 hours under conditions of 37 ° C. and 5% CO 2. After removing the medium, assay buffer containing 25 μM Fluo-3AM ester (Dojin) (25 mM HEPES (Dojin), Hanks' balanced salt solution (Invitrogen), 0.1% bovine serum albumin, 2.5 mM probenecid, 100 μL of 200 μg / ml Amaranth (above Sigma-Aldrich), pH 7.4) was added and incubated for 60 minutes at 37 ° C., 5% CO 2 . After removing the assay buffer containing Fluo-3AM ester, the test compound was dissolved in dimethyl sulfoxide to 10 mM, diluted with assay buffer, 150 μL was added, and the mixture was incubated for 30 minutes.
Peptide substituted with 2 amino acids of human orexin-A ligand (Pyr-Pro-Leu-Pro-Asp-Ala-Cys-Arg-Gln-Lys-Thr-Ala-Ser-Cys-Arg-Leu-Tyr-Glu -Leu-Leu-His-Gly-Ala-Gly-Asn-His-Ala-Ala-Gly-Ile-Leu-Thr-Leu-NH2 (Peptide Institute) is a final concentration of 300 pM for hOX1R and hOX2R Each was diluted with an assay buffer so as to be 3 nM, and 50 μL of this ligand solution was added to initiate the reaction. For the reaction, the fluorescence value of each well was measured for 3 minutes every second using a Functional Drug Screening System (FDSS; manufactured by Hamamatsu Photonics), and the antagonistic activity was determined using the maximum fluorescence value as an index of intracellular Ca 2+ concentration. . The antagonistic activity of the test compound was calculated by setting the fluorescence value of the well to which only the dilution buffer was added to 100% and the fluorescence value of the well to which the buffer solution containing no ligand and compound was added to 0%. The 50% inhibitory concentration (IC 50 value) was determined from the fluorescence value upon addition.
本発明化合物のIC50値を表6に示す。 The IC 50 values of the compounds of the present invention are shown in Table 6.
試験例2(代謝安定性試験)
被験化合物のヒト肝ミクロソーム(Ms)における安定性試験は以下の方法に従って行った。
被験化合物を、NADPH 生成系(0.16mM NADP+、2.5mM MgCl2、1.5mM glucose−6−phosphate)存在下、ヒト肝ミクロソーム画分(Xenotech/H630B/lot.0810472)とともに0.1M リン酸緩衝液(pH7.4)中でインキュベートした(37℃,15分間)。被験化合物、肝Msタンパクの終濃度は,それぞれ1μM及び0.25mg protein/mLとした。インキュベート後の反応混液は、2倍容量のDMSOを添加、攪拌したのち2150xgで遠心分離した(4℃,10分間)。得られた上清は、液体クロマトグラフィータンデム質量分析(LC−MS/MS)システムによる分析に供した。定量下限は、0.1μMであった。その結果、実施例1の化合物の代謝率は27.8%であった。
Test Example 2 (Metabolic stability test)
The stability test of the test compound in human liver microsomes (Ms) was performed according to the following method.
The test compound was mixed with 0.1 M phosphoric acid together with human liver microsome fraction (Xenotech / H630B / lot.0810472) in the presence of NADPH production system (0.16 mM NADP +, 2.5 mM MgCl2, 1.5 mM glucose-6-phosphate). Incubated in buffer (pH 7.4) (37 ° C., 15 minutes). The final concentrations of the test compound and liver Ms protein were 1 μM and 0.25 mg protein / mL, respectively. The reaction mixture after the incubation was added with 2 volumes of DMSO, stirred, and then centrifuged at 2150 × g (4 ° C., 10 minutes). The obtained supernatant was subjected to analysis by a liquid chromatography tandem mass spectrometry (LC-MS / MS) system. The lower limit of quantification was 0.1 μM. As a result, the metabolic rate of the compound of Example 1 was 27.8%.
本発明化合物は、OX受容体拮抗作用を有することが示された。従って、本発明化合物又はその医薬上許容される塩は、OX受容体拮抗作用によって調節される病気、例えば、睡眠障害、うつ病、不安障害、パニック障害、統合失調症、薬物依存症、アルツハイマー病、パーキンソン病、ハンチントン舞踏病、摂食障害、頭痛、片頭痛、疼痛、消化器疾患、てんかん、炎症、免疫関連疾患、内分泌関連疾患、高血圧等の治療又は予防薬として使用することが可能である。 The compound of the present invention was shown to have OX receptor antagonistic action. Therefore, the compound of the present invention or a pharmaceutically acceptable salt thereof is a disease modulated by OX receptor antagonism, such as sleep disorder, depression, anxiety disorder, panic disorder, schizophrenia, drug dependence, Alzheimer's disease , Parkinson's disease, Huntington's disease, eating disorders, headache, migraine, pain, digestive disorders, epilepsy, inflammation, immune related diseases, endocrine related diseases, hypertension, etc. .
Claims (11)
Xは、窒素原子、又は式CHを示し、
Yは、窒素原子、又は式CHを示し、
R1は、水素原子、ハロゲン原子、シアノ基、C1-6アルキル基(該C1-6アルキル基は、1〜3個のハロゲン原子で置換されてもよい)、又はC1-6アルコキシ基を示し、
R2は、ヘテロアリール基(該ヘテロアリール基は、ハロゲン原子及びC1-6アルコキシ基からなる群から選ばれる同一又は異なった1〜3個の置換基で置換されてもよい)を示し、
R3及びR4は、同一に又は異なって、水素原子、ハロゲン原子、シアノ基、C1-6アルキル基、又はC1-6アルコキシ基(該C1-6アルキル基、及びC1-6アルコキシ基は1〜3個のハロゲン原子で置換されてもよい)を示す。)
で表されるメチルピペリジン誘導体、又はその医薬上許容される塩を有効成分として含有することを特徴とする睡眠障害、うつ病、不安障害、パニック障害、統合失調症、薬物依存症、アルツハイマー病、パーキンソン病、ハンチントン舞踏病、摂食障害、疼痛、片頭痛、消化器疾患、てんかん、炎症、免疫関連疾患、内分泌関連疾患、高血圧の疾患の治療又は予防薬。 Formula (IA)
X represents a nitrogen atom or the formula CH;
Y represents a nitrogen atom or the formula CH;
R 1 is a hydrogen atom, a halogen atom, a cyano group, a C 1-6 alkyl group (the C 1-6 alkyl group may be substituted with 1 to 3 halogen atoms), or C 1-6 alkoxy Group,
R 2 represents a heteroaryl group (the heteroaryl group may be substituted with 1 to 3 identical or different substituents selected from the group consisting of a halogen atom and a C 1-6 alkoxy group);
R 3 and R 4 are the same or different and each represents a hydrogen atom, a halogen atom, a cyano group, a C 1-6 alkyl group, or a C 1-6 alkoxy group (the C 1-6 alkyl group and C 1-6 An alkoxy group may be substituted with 1 to 3 halogen atoms). )
A sleep disorder, depression, anxiety disorder, panic disorder, schizophrenia, drug dependence, Alzheimer's disease, characterized by containing a methylpiperidine derivative represented by the formula: Treatment or prevention of Parkinson's disease, Huntington's chorea, eating disorders, pain, migraine, digestive disorders, epilepsy, inflammation, immune-related diseases, endocrine-related diseases, hypertension diseases.
R3が、ハロゲン原子、シアノ基、C1-6アルキル基、又はC1-6アルコキシ基(該C1-6アルキル基、及びC1-6アルコキシ基は1〜3個のハロゲン原子で置換されてもよい)であり、
R4が、水素原子、又はハロゲン原子である請求項1に記載のメチルピペリジン誘導体、又はその医薬上許容される塩を有効成分として含有することを特徴とする睡眠障害、うつ病、不安障害、パニック障害、統合失調症、薬物依存症、アルツハイマー病、パーキンソン病、ハンチントン舞踏病、摂食障害、疼痛、片頭痛、消化器疾患、てんかん、炎症、免疫関連疾患、内分泌関連疾患、高血圧の疾患の治療又は予防薬。 In the above formula (IA),
R 3 is a halogen atom, a cyano group, a C 1-6 alkyl group, or a C 1-6 alkoxy group (the C 1-6 alkyl group and the C 1-6 alkoxy group are substituted with 1 to 3 halogen atoms) May be)
A sleep disorder, depression, anxiety disorder, characterized by comprising, as an active ingredient, the methylpiperidine derivative according to claim 1, or a pharmaceutically acceptable salt thereof, wherein R 4 is a hydrogen atom or a halogen atom. Panic disorder, schizophrenia, drug addiction, Alzheimer's disease, Parkinson's disease, Huntington's disease, eating disorder, pain, migraine, digestive disorders, epilepsy, inflammation, immune related diseases, endocrine related diseases, hypertension Therapeutic or prophylactic agent.
R2が、トリアゾリル基、又はピリミジニル基(該ピリミジニル基は、ハロゲン原子及びC1-6アルコキシ基からなる群から選ばれる同一又は異なった1〜3個の置換基で置換されてもよい)である請求項1又は2いずれかに記載のメチルピペリジン誘導体、又はその医薬上許容される塩を有効成分として含有することを特徴とする睡眠障害、うつ病、不安障害、パニック障害、統合失調症、薬物依存症、アルツハイマー病、パーキンソン病、ハンチントン舞踏病、摂食障害、疼痛、片頭痛、消化器疾患、てんかん、炎症、免疫関連疾患、内分泌関連疾患、高血圧の疾患の治療又は予防薬。 In the above formula (IA),
R 2 is a triazolyl group or a pyrimidinyl group (the pyrimidinyl group may be substituted with 1 to 3 identical or different substituents selected from the group consisting of a halogen atom and a C 1-6 alkoxy group). A sleep disorder, depression, anxiety disorder, panic disorder, schizophrenia characterized by containing the methylpiperidine derivative according to any one of claims 1 and 2 or a pharmaceutically acceptable salt thereof as an active ingredient, Drugs for treatment, prevention of Alzheimer's disease, Parkinson's disease, Huntington's disease, eating disorders, pain, migraine, digestive disorders, epilepsy, inflammation, immune related diseases, endocrine related diseases, hypertension.
R1が、水素原子、ハロゲン原子、又はC1-6アルキル基である請求項1〜3いずれか1項に記載のメチルピペリジン誘導体、又はその医薬上許容される塩を有効成分として含有することを特徴とする睡眠障害、うつ病、不安障害、パニック障害、統合失調症、薬物依存症、アルツハイマー病、パーキンソン病、ハンチントン舞踏病、摂食障害、疼痛、片頭痛、消化器疾患、てんかん、炎症、免疫関連疾患、内分泌関連疾患、高血圧の疾患の治療又は予防薬。 In the above formula (IA),
R 1 is a hydrogen atom, a halogen atom, or a C 1-6 alkyl group, containing the methylpiperidine derivative according to any one of claims 1 to 3 or a pharmaceutically acceptable salt thereof as an active ingredient. Sleep disorder, depression, anxiety disorder, panic disorder, schizophrenia, drug addiction, Alzheimer's disease, Parkinson's disease, Huntington's chorea, eating disorders, pain, migraine, digestive disorders, epilepsy, inflammation Drugs for treating or preventing immune related diseases, endocrine related diseases, and hypertension diseases.
Yが、式CHであり、
R2が、トリアゾリル基、又はピリミジニル基である請求項1〜4いずれか1項に記載のメチルピペリジン誘導体、又はその医薬上許容される塩を有効成分として含有することを特徴とする睡眠障害、うつ病、不安障害、パニック障害、統合失調症、薬物依存症、アルツハイマー病、パーキンソン病、ハンチントン舞踏病、摂食障害、疼痛、片頭痛、消化器疾患、てんかん、炎症、免疫関連疾患、内分泌関連疾患、高血圧の疾患の治療又は予防薬。 In the above formula (IA),
Y is the formula CH;
R 2 is a triazolyl group or a pyrimidinyl group, comprising the methylpiperidine derivative according to any one of claims 1 to 4 or a pharmaceutically acceptable salt thereof as an active ingredient, Depression, anxiety disorder, panic disorder, schizophrenia, drug dependence, Alzheimer's disease, Parkinson's disease, Huntington's chorea, eating disorder, pain, migraine, gastrointestinal disease, epilepsy, inflammation, immune related diseases, endocrine related Therapeutic or preventive drug for diseases and hypertension.
Xが、窒素原子であり、
R4が、水素原子である請求項1〜5いずれか1項に記載のメチルピペリジン誘導体、又はその医薬上許容される塩を有効成分として含有することを特徴とする睡眠障害、うつ病、不安障害、パニック障害、統合失調症、薬物依存症、アルツハイマー病、パーキンソン病、ハンチントン舞踏病、摂食障害、疼痛、片頭痛、消化器疾患、てんかん、炎症、免疫関連疾患、内分泌関連疾患、高血圧の疾患の治療又は予防薬。 In the above formula (IA),
X is a nitrogen atom,
R 4 is a hydrogen atom. Sleep disorder, depression, anxiety characterized by containing the methylpiperidine derivative according to any one of claims 1 to 5 or a pharmaceutically acceptable salt thereof as an active ingredient. Disorder, panic disorder, schizophrenia, drug addiction, Alzheimer's disease, Parkinson's disease, Huntington's disease, eating disorder, pain, migraine, digestive disorders, epilepsy, inflammation, immune related diseases, endocrine related diseases, hypertension Disease treatment or prevention drugs.
Xは、窒素原子、又は式CHを示し、
R1は、水素原子、ハロゲン原子、又はC1-6アルキル基を示し、
R2は、ヘテロアリール基(該ヘテロアリール基は、1〜3個のハロゲン原子で置換されてもよい)を示し、
R3は、水素原子、ハロゲン原子、C1-6アルキル基、又はC1-6アルコキシ基(該C1-6アルキル基、及びC1-6アルコキシ基は1〜3個のハロゲン原子で置換されてもよい)を示す。)
で表されるメチルピペリジン誘導体、又はその医薬上許容される塩を有効成分として含有することを特徴とする睡眠障害、うつ病、不安障害、パニック障害、統合失調症、薬物依存症、アルツハイマー病、パーキンソン病、ハンチントン舞踏病、摂食障害、疼痛、片頭痛、消化器疾患、てんかん、炎症、免疫関連疾患、内分泌関連疾患、高血圧の疾患の治療又は予防薬。 Formula (I)
X represents a nitrogen atom or the formula CH;
R 1 represents a hydrogen atom, a halogen atom, or a C 1-6 alkyl group,
R 2 represents a heteroaryl group (the heteroaryl group may be substituted with 1 to 3 halogen atoms);
R 3 represents a hydrogen atom, a halogen atom, a C 1-6 alkyl group, or a C 1-6 alkoxy group (the C 1-6 alkyl group and the C 1-6 alkoxy group are substituted with 1 to 3 halogen atoms) May be). )
A sleep disorder, depression, anxiety disorder, panic disorder, schizophrenia, drug dependence, Alzheimer's disease, characterized by containing a methylpiperidine derivative represented by the formula: Treatment or prevention of Parkinson's disease, Huntington's chorea, eating disorders, pain, migraine, digestive disorders, epilepsy, inflammation, immune-related diseases, endocrine-related diseases, hypertension diseases.
Xが、窒素原子であり、
R1が、水素原子、又はC1-6アルキル基であり、
R2が、トリアゾリル基、又はピリミジニル基であり、
R3が、ハロゲン原子である請求項8に記載のメチルピペリジン誘導体、又はその医薬上許容される塩を有効成分として含有することを特徴とする睡眠障害、うつ病、不安障害、パニック障害、統合失調症、薬物依存症、アルツハイマー病、パーキンソン病、ハンチントン舞踏病、摂食障害、疼痛、片頭痛、消化器疾患、てんかん、炎症、免疫関連疾患、内分泌関連疾患、高血圧の疾患の治療又は予防薬。 In the above formula (I),
X is a nitrogen atom,
R 1 is a hydrogen atom or a C 1-6 alkyl group,
R 2 is a triazolyl group or a pyrimidinyl group;
The sleep disorder, depression, anxiety disorder, panic disorder, integration characterized by containing as an active ingredient the methylpiperidine derivative according to claim 8, or a pharmaceutically acceptable salt thereof, wherein R 3 is a halogen atom. Ataxia, drug dependence, Alzheimer's disease, Parkinson's disease, Huntington's disease, eating disorders, pain, migraine, gastrointestinal disease, epilepsy, inflammation, immune related diseases, endocrine related diseases, treatment for or prevention of hypertension .
[(2R,5R)−5−(5−クロロ−1,3−ベンゾオキサゾール−2−イル)−2−メチルピペリジン−1−イル][6−メチル−3−(2H−1,2,3−トリアゾール−2−イル)ピリジン−2−イル]メタノン、
[(2R*,5R*)−5−(5−クロロ−1,3−ベンゾオキサゾール−2−イル)−2−メチルピペリジン−1−イル][5−フルオロ−2−(2H−1,2,3−トリアゾール−2−イル)フェニル]メタノン、
[(2R*,5R*)−5−(5−クロロ−1,3−ベンゾオキサゾール−2−イル)−2−メチルピペリジン−1−イル][2−(2H−1,2,3−トリアゾール−2−イル)フェニル]メタノン、
[(2R*,5R*)−5−(5−クロロ−1,3−ベンゾオキサゾール−2−イル)−2−メチルピペリジン−1−イル][6−メチル−3−(ピリミジン−2−イル)ピリジン−2−イル]メタノン、
[(2R*,5R*)−5−(5−クロロ−1,3−ベンゾオキサゾール−2−イル)−2−メチルピペリジン−1−イル][5−メチル−2−(ピリミジン−2−イル)フェニル]メタノン、
[(2R*,5R*)−5−(5−クロロ−1,3−ベンゾオキサゾール−2−イル)−2−メチルピペリジン−1−イル][5−フルオロ−2−(ピリミジン−2−イル)フェニル]メタノン、
[(2R*,5R*)−5−(5−クロロ−1,3−ベンゾオキサゾール−2−イル)−2−メチルピペリジン−1−イル][2−(ピリミジン−2−イル)フェニル]メタノン、
[(2R*,5R*)−5−(5−フルオロ−1,3−ベンゾオキサゾール−2−イル)−2−メチルピペリジン−1−イル][5−メチル−2−(ピリミジン−2−イル)フェニル]メタノン、
[(2R*,5R*)−5−(5−クロロ−1,3−ベンゾオキサゾール−2−イル)−2−メチルピペリジン−1−イル][5−メチル−2−(2H−1,2,3−トリアゾール−2−イル)フェニル]メタノン、
[(2R*,5R*)−5−(5−フルオロ−1,3−ベンゾオキサゾール−2−イル)−2−メチルピペリジン−1−イル][5−メチル−2−(2H−1,2,3−トリアゾール−2−イル)フェニル]メタノン、
[(2R*,5R*)−5−(5−フルオロ−1,3−ベンゾオキサゾール−2−イル)−2−メチルピペリジン−1−イル][6−メチル−3−(2H−1,2,3−トリアゾール−2−イル)ピリジン−2−イル]メタノン、
[(2R,5R)−5−(5−クロロ−1,3−ベンゾオキサゾール−2−イル)−2−メチルピペリジン−1−イル][5−クロロ−2−(ピリミジン−2−イル)フェニル]メタノン、
[(2R,5R)−5−(5−クロロ−1,3−ベンゾオキサゾール−2−イル)−2−メチルピペリジン−1−イル][4−フルオロ−2−(2H−1,2,3−トリアゾール−2−イル)フェニル]メタノン、
[(2R,5R)−5−(5−クロロ−1,3−ベンゾオキサゾール−2−イル)−2−メチルピペリジン−1−イル][3−フルオロ−2−(2H−1,2,3−トリアゾール−2−イル)フェニル]メタノン、
[(2R,5R)−5−(5−クロロ−1,3−ベンゾオキサゾール−2−イル)−2−メチルピペリジン−1−イル][2−フルオロ−6−(2H−1,2,3−トリアゾール−2−イル)フェニル]メタノン、
[(2R,5R)−5−(5−クロロ−1,3−ベンゾオキサゾール−2−イル)−2−メチルピペリジン−1−イル][4−フルオロ−2−(ピリミジン−2−イル)フェニル]メタノン、
[(2R,5R)−5−(5−クロロ−1,3−ベンゾオキサゾール−2−イル)−2−メチルピペリジン−1−イル][2−フルオロ−6−(ピリミジン−2−イル)フェニル]メタノン、
[5−ブロモ−2−(2H−1,2,3−トリアゾール−2−イル)フェニル][(2R,5R)−5−(5−クロロ−1,3−ベンゾオキサゾール−2−イル)−2−メチルピペリジン−1−イル]メタノン、
[(2R,5R)−5−(5−クロロ−1,3−ベンゾオキサゾール−2−イル)−2−メチルピペリジン−1−イル][5−フルオロ−2−(5−メトキシピリミジン−2−イル)フェニル]メタノン、
[(2R,5R)−5−(5−クロロ−1,3−ベンゾオキサゾール−2−イル)−2−メチルピペリジン−1−イル][4−メチル−2−(2H−1,2,3−トリアゾール−2−イル)フェニル]メタノン、
[(2R,5R)−5−(5−フルオロ−1,3−ベンゾオキサゾール−2−イル)−2−メチルピペリジン−1−イル][2−(2H−1,2,3−トリアゾール−2−イル)フェニル]メタノン、
[(2R,5R)−5−(5−フルオロ−1,3−ベンゾオキサゾール−2−イル)−2−メチルピペリジン−1−イル][5−フルオロ−2−(2H−1,2,3−トリアゾール−2−イル)フェニル]メタノン、
[5−クロロ−2−(2H−1,2,3−トリアゾール−2−イル)フェニル][(2R,5R)−5−(5−フルオロ−1,3−ベンゾオキサゾール−2−イル)−2−メチルピペリジン−1−イル]メタノン、
[(2R,5R)−5−(5−フルオロ−1,3−ベンゾオキサゾール−2−イル)−2−メチルピペリジン−1−イル][2−(ピリミジン−2−イル)フェニル]メタノン、
[(2R,5R)−5−(5−フルオロ−1,3−ベンゾオキサゾール−2−イル)−2−メチルピペリジン−1−イル][5−フルオロ−2−(ピリミジン−2−イル)フェニル]メタノン、
[5−クロロ−2−(ピリミジン−2−イル)フェニル][(2R,5R)−5−(5−フルオロ−1,3−ベンゾオキサゾール−2−イル)−2−メチルピペリジン−1−イル]メタノン、
[(2R,5R)−5−(5−フルオロ−1,3−ベンゾオキサゾール−2−イル)−2−メチルピペリジン−1−イル][4−フルオロ−2−(2H−1,2,3−トリアゾール−2−イル)フェニル]メタノン、
[(2R,5R)−5−(5−フルオロ−1,3−ベンゾオキサゾール−2−イル)−2−メチルピペリジン−1−イル][2−フルオロ−6−(2H−1,2,3−トリアゾール−2−イル)フェニル]メタノン、
[5−メチル−2−(2H−1,2,3−トリアゾール−2−イル)フェニル]{(2R,5R)−2−メチル−5−[5−(トリフルオロメチル)−1,3−ベンゾオキサゾール−2−イル]ピペリジン−1−イル}メタノン、
[5−メチル−2−(ピリミジン−2−イル)フェニル]{(2R,5R)−2−メチル−5−[5−(トリフルオロメチル)−1,3−ベンゾオキサゾール−2−イル]ピペリジン−1−イル}メタノン、
[5−クロロ−2−(ピリミジン−2−イル)フェニル]{(2R,5R)−2−メチル−5−[5−(トリフルオロメチル)−1,3−ベンゾオキサゾール−2−イル]ピペリジン−1−イル}メタノン、
[(2R,5R)−5−(6−クロロ−1,3−ベンゾオキサゾール−2−イル)−2−メチルピペリジン−1−イル][5−メチル−2−(2H−1,2,3−トリアゾール−2−イル)フェニル]メタノン、
[(2R,5R)−5−(6−クロロ−1,3−ベンゾオキサゾール−2−イル)−2−メチルピペリジン−1−イル][5−メチル−2−(ピリミジン−2−イル)フェニル]メタノン、
[(2R,5R)−5−(6−クロロ−1,3−ベンゾオキサゾール−2−イル)−2−メチルピペリジン−1−イル][5−フルオロ−2−(ピリミジン−2−イル)フェニル]メタノン、
[(2R,5R)−5−(6−クロロ−1,3−ベンゾオキサゾール−2−イル)−2−メチルピペリジン−1−イル][6−メチル−3−(2H−1,2,3−トリアゾール−2−イル)ピリジン−2−イル]メタノン、
[(2R,5R)−5−(6−クロロ−1,3−ベンゾオキサゾール−2−イル)−2−メチルピペリジン−1−イル][4−フルオロ−2−(2H−1,2,3−トリアゾール−2−イル)フェニル]メタノン、
[(2R,5R)−5−(6−クロロ−1,3−ベンゾオキサゾール−2−イル)−2−メチルピペリジン−1−イル][2−フルオロ−6−(2H−1,2,3−トリアゾール−2−イル)フェニル]メタノン、
[(2R,5R)−5−(5,6−ジフルオロ−1,3−ベンゾオキサゾール−2−イル)−2−メチルピペリジン−1−イル][5−メチル−2−(2H−1,2,3−トリアゾール−2−イル)フェニル]メタノン、
[(2R,5R)−5−(5,6−ジフルオロ−1,3−ベンゾオキサゾール−2−イル)−2−メチルピペリジン−1−イル][5−メチル−2−(ピリミジン−2−イル)フェニル]メタノン、
[(2R,5R)−5−(5,6−ジフルオロ−1,3−ベンゾオキサゾール−2−イル)−2−メチルピペリジン−1−イル][5−フルオロ−2−(ピリミジン−2−イル)フェニル]メタノン、
[5−クロロ−2−(ピリミジン−2−イル)フェニル][(2R,5R)−5−(5,6−ジフルオロ−1,3−ベンゾオキサゾール−2−イル)−2−メチルピペリジン−1−イル]メタノン、
[(2R,5R)−5−(5,6−ジフルオロ−1,3−ベンゾオキサゾール−2−イル)−2−メチルピペリジン−1−イル][6−メチル−3−(2H−1,2,3−トリアゾール−2−イル)ピリジン−2−イル]メタノン、
[(2R,5R)−5−(5,6−ジフルオロ−1,3−ベンゾオキサゾール−2−イル)−2−メチルピペリジン−1−イル][4−フルオロ−2−(2H−1,2,3−トリアゾール−2−イル)フェニル]メタノン、
2−{(3R,6R)−6−メチル−1−[5−メチル−2−(2H−1,2,3−トリアゾール−2−イル)ベンゾイル]ピペリジン−3−イル}−1,3−ベンゾオキサゾール−5−カルボニトリル、
2−{(3R,6R)−6−メチル−1−[5−メチル−2−(ピリミジン−2−イル)ベンゾイル]ピペリジン−3−イル}−1,3−ベンゾオキサゾール−5−カルボニトリル、
[(2R,5R)−5−(6,7−ジフルオロ−1,3−ベンゾオキサゾール−2−イル)−2−メチルピペリジン−1−イル][5−メチル−2−(2H−1,2,3−トリアゾール−2−イル)フェニル]メタノン、
[(2R,5R)−5−(6,7−ジフルオロ−1,3−ベンゾオキサゾール−2−イル)−2−メチルピペリジン−1−イル][5−メチル−2−(ピリミジン−2−イル)フェニル]メタノン、
[(2R,5R)−5−(4,6−ジフルオロ−1,3−ベンゾオキサゾール−2−イル)−2−メチルピペリジン−1−イル][5−メチル−2−(2H−1,2,3−トリアゾール−2−イル)フェニル]メタノン、
[(2R,5R)−5−(4,6−ジフルオロ−1,3−ベンゾオキサゾール−2−イル)−2−メチルピペリジン−1−イル][5−メチル−2−(ピリミジン−2−イル)フェニル]メタノン、
[(2R,5R)−5−(5,7−ジフルオロ−1,3−ベンゾオキサゾール−2−イル)−2−メチルピペリジン−1−イル][5−メチル−2−(2H−1,2,3−トリアゾール−2−イル)フェニル]メタノン、
[(2R,5R)−5−(5,7−ジフルオロ−1,3−ベンゾオキサゾール−2−イル)−2−メチルピペリジン−1−イル][5−メチル−2−(ピリミジン−2−イル)フェニル]メタノン、
[(2R,5R)−5−(7−フルオロ−1,3−ベンゾオキサゾール−2−イル)−2−メチルピペリジン−1−イル][5−メチル−2−(2H−1,2,3−トリアゾール−2−イル)フェニル]メタノン、
[(2R,5R)−5−(4−フルオロ−1,3−ベンゾオキサゾール−2−イル)−2−メチルピペリジン−1−イル][5−メチル−2−(2H−1,2,3−トリアゾール−2−イル)フェニル]メタノン、
[(2R,5R)−5−(4−フルオロ−1,3−ベンゾオキサゾール−2−イル)−2−メチルピペリジン−1−イル][5−メチル−2−(ピリミジン−2−イル)フェニル]メタノン、
[(2R,5R)−5−(4−クロロ−1,3−ベンゾオキサゾール−2−イル)−2−メチルピペリジン−1−イル][5−メチル−2−(2H−1,2,3−トリアゾール−2−イル)フェニル]メタノン、
[(2R,5R)−5−(4−クロロ−1,3−ベンゾオキサゾール−2−イル)−2−メチルピペリジン−1−イル][5−メチル−2−(ピリミジン−2−イル)フェニル]メタノン、
[(2R,5R)−5−(4−クロロ−1,3−ベンゾオキサゾール−2−イル)−2−メチルピペリジン−1−イル][5−フルオロ−2−(ピリミジン−2−イル)フェニル]メタノン、
[(2R,5R)−5−(6−クロロ[1,3]オキサゾロ[5,4−b]ピリジン−2−イル)−2−メチルピペリジン−1−イル][5−メチル−2−(2H−1,2,3−トリアゾール−2−イル)フェニル]メタノン、及び
[(2R,5R)−5−(6−クロロ[1,3]オキサゾロ[5,4−b]ピリジン−2−イル)−2−メチルピペリジン−1−イル][4−フルオロ−2−(2H−1,2,3−トリアゾール−2−イル)フェニル]メタノン。 A sleep disorder, depression, anxiety disorder characterized by containing as an active ingredient any one or a mixture of two or more selected from the following compound group described in claim 1 and pharmaceutically acceptable salts thereof , Panic disorder, schizophrenia, drug addiction, Alzheimer's disease, Parkinson's disease, Huntington's disease, eating disorder, pain, migraine, gastrointestinal disease, epilepsy, inflammation, immune related diseases, endocrine related diseases, hypertension diseases Treatment or prevention drug.
[(2R, 5R) -5- (5-chloro-1,3-benzoxazol-2-yl) -2-methylpiperidin-1-yl] [6-methyl-3- (2H-1,2,3 -Triazol-2-yl) pyridin-2-yl] methanone,
[(2R *, 5R *)-5- (5-chloro-1,3-benzoxazol-2-yl) -2-methylpiperidin-1-yl] [5-fluoro-2- (2H-1,2, , 3-Triazol-2-yl) phenyl] methanone,
[(2R *, 5R *)-5- (5-chloro-1,3-benzoxazol-2-yl) -2-methylpiperidin-1-yl] [2- (2H-1,2,3-triazole -2-yl) phenyl] methanone,
[(2R *, 5R *)-5- (5-chloro-1,3-benzoxazol-2-yl) -2-methylpiperidin-1-yl] [6-methyl-3- (pyrimidin-2-yl ) Pyridin-2-yl] methanone,
[(2R *, 5R *)-5- (5-chloro-1,3-benzoxazol-2-yl) -2-methylpiperidin-1-yl] [5-methyl-2- (pyrimidin-2-yl) ) Phenyl] methanone,
[(2R *, 5R *)-5- (5-chloro-1,3-benzoxazol-2-yl) -2-methylpiperidin-1-yl] [5-fluoro-2- (pyrimidin-2-yl ) Phenyl] methanone,
[(2R *, 5R *)-5- (5-chloro-1,3-benzoxazol-2-yl) -2-methylpiperidin-1-yl] [2- (pyrimidin-2-yl) phenyl] methanone ,
[(2R *, 5R *)-5- (5-fluoro-1,3-benzoxazol-2-yl) -2-methylpiperidin-1-yl] [5-methyl-2- (pyrimidin-2-yl) ) Phenyl] methanone,
[(2R *, 5R *)-5- (5-chloro-1,3-benzoxazol-2-yl) -2-methylpiperidin-1-yl] [5-methyl-2- (2H-1,2, , 3-Triazol-2-yl) phenyl] methanone,
[(2R *, 5R *)-5- (5-fluoro-1,3-benzoxazol-2-yl) -2-methylpiperidin-1-yl] [5-methyl-2- (2H-1,2, , 3-Triazol-2-yl) phenyl] methanone,
[(2R *, 5R *)-5- (5-fluoro-1,3-benzoxazol-2-yl) -2-methylpiperidin-1-yl] [6-methyl-3- (2H-1,2, , 3-Triazol-2-yl) pyridin-2-yl] methanone,
[(2R, 5R) -5- (5-chloro-1,3-benzooxazol-2-yl) -2-methylpiperidin-1-yl] [5-chloro-2- (pyrimidin-2-yl) phenyl ] Methanone,
[(2R, 5R) -5- (5-chloro-1,3-benzoxazol-2-yl) -2-methylpiperidin-1-yl] [4-fluoro-2- (2H-1,2,3 -Triazol-2-yl) phenyl] methanone,
[(2R, 5R) -5- (5-chloro-1,3-benzoxazol-2-yl) -2-methylpiperidin-1-yl] [3-fluoro-2- (2H-1,2,3 -Triazol-2-yl) phenyl] methanone,
[(2R, 5R) -5- (5-chloro-1,3-benzoxazol-2-yl) -2-methylpiperidin-1-yl] [2-fluoro-6- (2H-1,2,3 -Triazol-2-yl) phenyl] methanone,
[(2R, 5R) -5- (5-Chloro-1,3-benzoxazol-2-yl) -2-methylpiperidin-1-yl] [4-fluoro-2- (pyrimidin-2-yl) phenyl ] Methanone,
[(2R, 5R) -5- (5-Chloro-1,3-benzoxazol-2-yl) -2-methylpiperidin-1-yl] [2-fluoro-6- (pyrimidin-2-yl) phenyl ] Methanone,
[5-Bromo-2- (2H-1,2,3-triazol-2-yl) phenyl] [(2R, 5R) -5- (5-chloro-1,3-benzoxazol-2-yl)- 2-methylpiperidin-1-yl] methanone,
[(2R, 5R) -5- (5-chloro-1,3-benzoxazol-2-yl) -2-methylpiperidin-1-yl] [5-fluoro-2- (5-methoxypyrimidin-2- Yl) phenyl] methanone,
[(2R, 5R) -5- (5-chloro-1,3-benzoxazol-2-yl) -2-methylpiperidin-1-yl] [4-methyl-2- (2H-1,2,3 -Triazol-2-yl) phenyl] methanone,
[(2R, 5R) -5- (5-fluoro-1,3-benzoxazol-2-yl) -2-methylpiperidin-1-yl] [2- (2H-1,2,3-triazol-2 -Yl) phenyl] methanone,
[(2R, 5R) -5- (5-fluoro-1,3-benzoxazol-2-yl) -2-methylpiperidin-1-yl] [5-fluoro-2- (2H-1,2,3 -Triazol-2-yl) phenyl] methanone,
[5-Chloro-2- (2H-1,2,3-triazol-2-yl) phenyl] [(2R, 5R) -5- (5-fluoro-1,3-benzoxazol-2-yl)- 2-methylpiperidin-1-yl] methanone,
[(2R, 5R) -5- (5-fluoro-1,3-benzoxazol-2-yl) -2-methylpiperidin-1-yl] [2- (pyrimidin-2-yl) phenyl] methanone,
[(2R, 5R) -5- (5-Fluoro-1,3-benzoxazol-2-yl) -2-methylpiperidin-1-yl] [5-fluoro-2- (pyrimidin-2-yl) phenyl ] Methanone,
[5-Chloro-2- (pyrimidin-2-yl) phenyl] [(2R, 5R) -5- (5-fluoro-1,3-benzoxazol-2-yl) -2-methylpiperidin-1-yl ] Methanone,
[(2R, 5R) -5- (5-fluoro-1,3-benzoxazol-2-yl) -2-methylpiperidin-1-yl] [4-fluoro-2- (2H-1,2,3 -Triazol-2-yl) phenyl] methanone,
[(2R, 5R) -5- (5-fluoro-1,3-benzoxazol-2-yl) -2-methylpiperidin-1-yl] [2-fluoro-6- (2H-1,2,3 -Triazol-2-yl) phenyl] methanone,
[5-Methyl-2- (2H-1,2,3-triazol-2-yl) phenyl] {(2R, 5R) -2-methyl-5- [5- (trifluoromethyl) -1,3- Benzoxazol-2-yl] piperidin-1-yl} methanone,
[5-Methyl-2- (pyrimidin-2-yl) phenyl] {(2R, 5R) -2-methyl-5- [5- (trifluoromethyl) -1,3-benzoxazol-2-yl] piperidine -1-yl} methanone,
[5-Chloro-2- (pyrimidin-2-yl) phenyl] {(2R, 5R) -2-methyl-5- [5- (trifluoromethyl) -1,3-benzoxazol-2-yl] piperidine -1-yl} methanone,
[(2R, 5R) -5- (6-chloro-1,3-benzoxazol-2-yl) -2-methylpiperidin-1-yl] [5-methyl-2- (2H-1,2,3 -Triazol-2-yl) phenyl] methanone,
[(2R, 5R) -5- (6-Chloro-1,3-benzoxazol-2-yl) -2-methylpiperidin-1-yl] [5-methyl-2- (pyrimidin-2-yl) phenyl ] Methanone,
[(2R, 5R) -5- (6-Chloro-1,3-benzoxazol-2-yl) -2-methylpiperidin-1-yl] [5-fluoro-2- (pyrimidin-2-yl) phenyl ] Methanone,
[(2R, 5R) -5- (6-chloro-1,3-benzoxazol-2-yl) -2-methylpiperidin-1-yl] [6-methyl-3- (2H-1,2,3 -Triazol-2-yl) pyridin-2-yl] methanone,
[(2R, 5R) -5- (6-chloro-1,3-benzoxazol-2-yl) -2-methylpiperidin-1-yl] [4-fluoro-2- (2H-1,2,3 -Triazol-2-yl) phenyl] methanone,
[(2R, 5R) -5- (6-chloro-1,3-benzoxazol-2-yl) -2-methylpiperidin-1-yl] [2-fluoro-6- (2H-1,2,3 -Triazol-2-yl) phenyl] methanone,
[(2R, 5R) -5- (5,6-difluoro-1,3-benzoxazol-2-yl) -2-methylpiperidin-1-yl] [5-methyl-2- (2H-1,2, , 3-Triazol-2-yl) phenyl] methanone,
[(2R, 5R) -5- (5,6-difluoro-1,3-benzoxazol-2-yl) -2-methylpiperidin-1-yl] [5-methyl-2- (pyrimidin-2-yl ) Phenyl] methanone,
[(2R, 5R) -5- (5,6-difluoro-1,3-benzoxazol-2-yl) -2-methylpiperidin-1-yl] [5-fluoro-2- (pyrimidin-2-yl ) Phenyl] methanone,
[5-Chloro-2- (pyrimidin-2-yl) phenyl] [(2R, 5R) -5- (5,6-difluoro-1,3-benzoxazol-2-yl) -2-methylpiperidine-1 -Il] methanone,
[(2R, 5R) -5- (5,6-difluoro-1,3-benzoxazol-2-yl) -2-methylpiperidin-1-yl] [6-methyl-3- (2H-1,2, , 3-Triazol-2-yl) pyridin-2-yl] methanone,
[(2R, 5R) -5- (5,6-difluoro-1,3-benzoxazol-2-yl) -2-methylpiperidin-1-yl] [4-fluoro-2- (2H-1,2, , 3-Triazol-2-yl) phenyl] methanone,
2-{(3R, 6R) -6-methyl-1- [5-methyl-2- (2H-1,2,3-triazol-2-yl) benzoyl] piperidin-3-yl} -1,3- Benzoxazole-5-carbonitrile,
2-{(3R, 6R) -6-methyl-1- [5-methyl-2- (pyrimidin-2-yl) benzoyl] piperidin-3-yl} -1,3-benzoxazole-5-carbonitrile,
[(2R, 5R) -5- (6,7-difluoro-1,3-benzoxazol-2-yl) -2-methylpiperidin-1-yl] [5-methyl-2- (2H-1,2, , 3-Triazol-2-yl) phenyl] methanone,
[(2R, 5R) -5- (6,7-difluoro-1,3-benzoxazol-2-yl) -2-methylpiperidin-1-yl] [5-methyl-2- (pyrimidin-2-yl ) Phenyl] methanone,
[(2R, 5R) -5- (4,6-difluoro-1,3-benzoxazol-2-yl) -2-methylpiperidin-1-yl] [5-methyl-2- (2H-1,2, , 3-Triazol-2-yl) phenyl] methanone,
[(2R, 5R) -5- (4,6-difluoro-1,3-benzoxazol-2-yl) -2-methylpiperidin-1-yl] [5-methyl-2- (pyrimidin-2-yl ) Phenyl] methanone,
[(2R, 5R) -5- (5,7-difluoro-1,3-benzoxazol-2-yl) -2-methylpiperidin-1-yl] [5-methyl-2- (2H-1,2, , 3-Triazol-2-yl) phenyl] methanone,
[(2R, 5R) -5- (5,7-difluoro-1,3-benzoxazol-2-yl) -2-methylpiperidin-1-yl] [5-methyl-2- (pyrimidin-2-yl ) Phenyl] methanone,
[(2R, 5R) -5- (7-fluoro-1,3-benzoxazol-2-yl) -2-methylpiperidin-1-yl] [5-methyl-2- (2H-1,2,3 -Triazol-2-yl) phenyl] methanone,
[(2R, 5R) -5- (4-fluoro-1,3-benzoxazol-2-yl) -2-methylpiperidin-1-yl] [5-methyl-2- (2H-1,2,3 -Triazol-2-yl) phenyl] methanone,
[(2R, 5R) -5- (4-Fluoro-1,3-benzoxazol-2-yl) -2-methylpiperidin-1-yl] [5-methyl-2- (pyrimidin-2-yl) phenyl ] Methanone,
[(2R, 5R) -5- (4-chloro-1,3-benzoxazol-2-yl) -2-methylpiperidin-1-yl] [5-methyl-2- (2H-1,2,3 -Triazol-2-yl) phenyl] methanone,
[(2R, 5R) -5- (4-Chloro-1,3-benzoxazol-2-yl) -2-methylpiperidin-1-yl] [5-methyl-2- (pyrimidin-2-yl) phenyl ] Methanone,
[(2R, 5R) -5- (4-Chloro-1,3-benzoxazol-2-yl) -2-methylpiperidin-1-yl] [5-fluoro-2- (pyrimidin-2-yl) phenyl ] Methanone,
[(2R, 5R) -5- (6-Chloro [1,3] oxazolo [5,4-b] pyridin-2-yl) -2-methylpiperidin-1-yl] [5-methyl-2- ( 2H-1,2,3-triazol-2-yl) phenyl] methanone and [(2R, 5R) -5- (6-chloro [1,3] oxazolo [5,4-b] pyridin-2-yl ) -2-Methylpiperidin-1-yl] [4-fluoro-2- (2H-1,2,3-triazol-2-yl) phenyl] methanone.
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US20140228377A1 (en) * | 2011-07-05 | 2014-08-14 | Taisho Pharmaceutical Co., Ltd. | Methylpiperidine derivative |
US20160068510A1 (en) * | 2013-04-23 | 2016-03-10 | Merck Sharp & Dohme Corp. | Hydroxy-substituted orexin receptor antagonists |
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US11059828B2 (en) | 2009-10-23 | 2021-07-13 | Janssen Pharmaceutica Nv | Disubstituted octahydropyrrolo[3,4-C]pyrroles as orexin receptor modulators |
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US20140228377A1 (en) * | 2011-07-05 | 2014-08-14 | Taisho Pharmaceutical Co., Ltd. | Methylpiperidine derivative |
US20160068510A1 (en) * | 2013-04-23 | 2016-03-10 | Merck Sharp & Dohme Corp. | Hydroxy-substituted orexin receptor antagonists |
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