JPWO2013187467A1 - ヘテロ芳香環メチル環状アミン誘導体 - Google Patents
ヘテロ芳香環メチル環状アミン誘導体 Download PDFInfo
- Publication number
- JPWO2013187467A1 JPWO2013187467A1 JP2014521401A JP2014521401A JPWO2013187467A1 JP WO2013187467 A1 JPWO2013187467 A1 JP WO2013187467A1 JP 2014521401 A JP2014521401 A JP 2014521401A JP 2014521401 A JP2014521401 A JP 2014521401A JP WO2013187467 A1 JPWO2013187467 A1 JP WO2013187467A1
- Authority
- JP
- Japan
- Prior art keywords
- methyl
- methanone
- pyrazol
- phenyl
- triazol
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
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- -1 Heteroaromatic methyl cyclic amine Chemical class 0.000 title claims abstract description 52
- 150000003839 salts Chemical class 0.000 claims abstract description 28
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 20
- 201000010099 disease Diseases 0.000 claims abstract description 14
- 208000019116 sleep disease Diseases 0.000 claims abstract description 7
- 208000020685 sleep-wake disease Diseases 0.000 claims abstract description 6
- 208000024827 Alzheimer disease Diseases 0.000 claims abstract description 5
- 208000019901 Anxiety disease Diseases 0.000 claims abstract description 5
- 208000030814 Eating disease Diseases 0.000 claims abstract description 5
- 208000019454 Feeding and Eating disease Diseases 0.000 claims abstract description 5
- 206010019233 Headaches Diseases 0.000 claims abstract description 5
- 208000023105 Huntington disease Diseases 0.000 claims abstract description 5
- 206010020772 Hypertension Diseases 0.000 claims abstract description 5
- 206010061218 Inflammation Diseases 0.000 claims abstract description 5
- 208000019695 Migraine disease Diseases 0.000 claims abstract description 5
- 208000002193 Pain Diseases 0.000 claims abstract description 5
- 208000018737 Parkinson disease Diseases 0.000 claims abstract description 5
- 235000014632 disordered eating Nutrition 0.000 claims abstract description 5
- 206010013663 drug dependence Diseases 0.000 claims abstract description 5
- 230000002124 endocrine Effects 0.000 claims abstract description 5
- 206010015037 epilepsy Diseases 0.000 claims abstract description 5
- 231100000869 headache Toxicity 0.000 claims abstract description 5
- 230000004054 inflammatory process Effects 0.000 claims abstract description 5
- 206010027599 migraine Diseases 0.000 claims abstract description 5
- 208000019906 panic disease Diseases 0.000 claims abstract description 5
- 208000011117 substance-related disease Diseases 0.000 claims abstract description 5
- 150000001875 compounds Chemical class 0.000 claims description 194
- 239000000203 mixture Substances 0.000 claims description 82
- 125000005843 halogen group Chemical group 0.000 claims description 24
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 19
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 14
- WSFSSNUMVMOOMR-BJUDXGSMSA-N methanone Chemical compound O=[11CH2] WSFSSNUMVMOOMR-BJUDXGSMSA-N 0.000 claims description 14
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 13
- 125000001425 triazolyl group Chemical group 0.000 claims description 10
- 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 9
- 125000000714 pyrimidinyl group Chemical group 0.000 claims description 9
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 8
- 229910052757 nitrogen Inorganic materials 0.000 claims description 7
- 239000004480 active ingredient Substances 0.000 claims description 5
- 125000004076 pyridyl group Chemical group 0.000 claims description 5
- HWEPGAHHAQYJAV-UHFFFAOYSA-N [2-[[3-(5-fluoropyridin-2-yl)pyrazol-1-yl]methyl]-1,3-oxazolidin-3-yl]-[5-methyl-2-(triazol-2-yl)phenyl]methanone Chemical compound C=1C(C)=CC=C(N2N=CC=N2)C=1C(=O)N1CCOC1CN(N=1)C=CC=1C1=CC=C(F)C=N1 HWEPGAHHAQYJAV-UHFFFAOYSA-N 0.000 claims description 4
- 201000000980 schizophrenia Diseases 0.000 claims description 4
- XIJFGHZYWVCPFJ-AOMKIAJQSA-N [(2s,5s)-2-[[4-(5-fluoropyridin-2-yl)pyrazol-1-yl]methyl]-5-methyl-1,3-oxazolidin-3-yl]-[5-methyl-2-(triazol-2-yl)phenyl]methanone Chemical compound C([C@H]1N(C[C@@H](O1)C)C(=O)C=1C(=CC=C(C)C=1)N1N=CC=N1)N(N=C1)C=C1C1=CC=C(F)C=N1 XIJFGHZYWVCPFJ-AOMKIAJQSA-N 0.000 claims description 3
- CWBJXWWFPDALKJ-UHFFFAOYSA-N [2-[[1-(5-fluoropyridin-2-yl)pyrazol-3-yl]methyl]-1,3-oxazolidin-3-yl]-[5-methyl-2-(triazol-2-yl)phenyl]methanone Chemical compound Cc1ccc(c(c1)C(=O)N1CCOC1Cc1ccn(n1)-c1ccc(F)cn1)-n1nccn1 CWBJXWWFPDALKJ-UHFFFAOYSA-N 0.000 claims description 3
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- NCKZYCBDYGDFRC-UHFFFAOYSA-N [2-[[1-(5-fluoropyridin-2-yl)pyrazol-4-yl]methyl]-1,3-oxazolidin-3-yl]-[5-methyl-2-(triazol-2-yl)phenyl]methanone Chemical compound Cc1ccc(c(c1)C(=O)N1CCOC1Cc1cnn(c1)-c1ccc(F)cn1)-n1nccn1 NCKZYCBDYGDFRC-UHFFFAOYSA-N 0.000 claims description 3
- LRBYYJMSSHIJKG-UHFFFAOYSA-N [2-[[3-(4-fluorophenyl)pyrazol-1-yl]methyl]-1,3-oxazinan-3-yl]-(5-methyl-2-pyrimidin-2-ylphenyl)methanone Chemical compound Cc1ccc(c(c1)C(=O)N1CCCOC1Cn1ccc(n1)-c1ccc(F)cc1)-c1ncccn1 LRBYYJMSSHIJKG-UHFFFAOYSA-N 0.000 claims description 3
- AEZZJXJIJFSUEM-UHFFFAOYSA-N [2-[[3-(5-fluoropyridin-2-yl)pyrazol-1-yl]methyl]-1,3-oxazinan-3-yl]-[5-methyl-2-(triazol-2-yl)phenyl]methanone Chemical compound C=1C(C)=CC=C(N2N=CC=N2)C=1C(=O)N1CCCOC1CN(N=1)C=CC=1C1=CC=C(F)C=N1 AEZZJXJIJFSUEM-UHFFFAOYSA-N 0.000 claims description 3
- 125000004105 2-pyridyl group Chemical group N1=C([*])C([H])=C([H])C([H])=C1[H] 0.000 claims description 2
- ACWUXIWHMGKPIR-UHFFFAOYSA-N 5-methyl-2-pyrimidin-2-ylbenzaldehyde Chemical compound O=CC1=CC(C)=CC=C1C1=NC=CC=N1 ACWUXIWHMGKPIR-UHFFFAOYSA-N 0.000 claims description 2
- CILZHXDOAWGUSS-SBUREZEXSA-N [(2S,4S)-2-[[4-(5-fluoropyridin-2-yl)pyrazol-1-yl]methyl]-4-methyl-1,3-oxazinan-3-yl]-[5-methyl-2-(triazol-2-yl)phenyl]methanone Chemical compound C[C@H]1CCO[C@@H](CN2C=C(C=N2)C2=NC=C(F)C=C2)N1C(=O)C1=CC(C)=CC=C1N1N=CC=N1 CILZHXDOAWGUSS-SBUREZEXSA-N 0.000 claims description 2
- DPVRTJAYOKJIFQ-ZHRRBRCNSA-N [(2s,4r)-2-[[3-(5-fluoropyridin-2-yl)pyrazol-1-yl]methyl]-4-methyl-1,3-oxazolidin-3-yl]-[5-methyl-2-(triazol-2-yl)phenyl]methanone Chemical compound C([C@@H]1OC[C@H](N1C(=O)C=1C(=CC=C(C)C=1)N1N=CC=N1)C)N(N=1)C=CC=1C1=CC=C(F)C=N1 DPVRTJAYOKJIFQ-ZHRRBRCNSA-N 0.000 claims description 2
- DPVRTJAYOKJIFQ-AOMKIAJQSA-N [(2s,4s)-2-[[3-(5-fluoropyridin-2-yl)pyrazol-1-yl]methyl]-4-methyl-1,3-oxazolidin-3-yl]-[5-methyl-2-(triazol-2-yl)phenyl]methanone Chemical compound C([C@@H]1OC[C@@H](N1C(=O)C=1C(=CC=C(C)C=1)N1N=CC=N1)C)N(N=1)C=CC=1C1=CC=C(F)C=N1 DPVRTJAYOKJIFQ-AOMKIAJQSA-N 0.000 claims description 2
- XIJFGHZYWVCPFJ-ZHRRBRCNSA-N [(2s,5r)-2-[[4-(5-fluoropyridin-2-yl)pyrazol-1-yl]methyl]-5-methyl-1,3-oxazolidin-3-yl]-[5-methyl-2-(triazol-2-yl)phenyl]methanone Chemical compound C([C@H]1N(C[C@H](O1)C)C(=O)C=1C(=CC=C(C)C=1)N1N=CC=N1)N(N=C1)C=C1C1=CC=C(F)C=N1 XIJFGHZYWVCPFJ-ZHRRBRCNSA-N 0.000 claims description 2
- HVYGOEAVNOYJPX-UHFFFAOYSA-N [2-[[1-(5-fluoropyridin-2-yl)pyrazol-4-yl]methyl]-1,3-oxazinan-3-yl]-(5-fluoro-2-pyrimidin-2-ylphenyl)methanone Chemical compound Fc1ccc(nc1)-n1cc(CC2OCCCN2C(=O)c2cc(F)ccc2-c2ncccn2)cn1 HVYGOEAVNOYJPX-UHFFFAOYSA-N 0.000 claims description 2
- XREXIMFORJAGEV-UHFFFAOYSA-N [2-[[1-(5-fluoropyridin-2-yl)pyrazol-4-yl]methyl]-1,3-oxazinan-3-yl]-(5-methyl-2-pyrimidin-2-ylphenyl)methanone Chemical compound Cc1ccc(c(c1)C(=O)N1CCCOC1Cc1cnn(c1)-c1ccc(F)cn1)-c1ncccn1 XREXIMFORJAGEV-UHFFFAOYSA-N 0.000 claims description 2
- XMTCRKRHFLBROW-UHFFFAOYSA-N [2-[[3-(4-fluorophenyl)pyrazol-1-yl]methyl]-1,3-oxazinan-3-yl]-(6-methyl-3-pyrimidin-2-ylpyridin-2-yl)methanone Chemical compound C1CCOC(CN2N=C(C=C2)C=2C=CC(F)=CC=2)N1C(=O)C1=NC(C)=CC=C1C1=NC=CC=N1 XMTCRKRHFLBROW-UHFFFAOYSA-N 0.000 claims description 2
- BZZDKUXANMBARX-UHFFFAOYSA-N [2-[[3-(4-fluorophenyl)pyrazol-1-yl]methyl]-1,3-oxazinan-3-yl]-[6-methyl-3-(triazol-2-yl)pyridin-2-yl]methanone Chemical compound N=1C(C)=CC=C(N2N=CC=N2)C=1C(=O)N1CCCOC1CN(N=1)C=CC=1C1=CC=C(F)C=C1 BZZDKUXANMBARX-UHFFFAOYSA-N 0.000 claims description 2
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- QTGVVJKIDVNSKU-UHFFFAOYSA-N [2-[[3-(4-fluorophenyl)pyrazol-1-yl]methyl]-1,3-oxazolidin-3-yl]-[6-methyl-3-(triazol-2-yl)pyridin-2-yl]methanone Chemical compound N=1C(C)=CC=C(N2N=CC=N2)C=1C(=O)N1CCOC1CN(N=1)C=CC=1C1=CC=C(F)C=C1 QTGVVJKIDVNSKU-UHFFFAOYSA-N 0.000 claims description 2
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Classifications
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- C07—ORGANIC CHEMISTRY
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- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
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- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
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- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
- A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
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- A61K31/5355—Non-condensed oxazines and containing further heterocyclic rings
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Abstract
Description
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)。
OX受容体拮抗作用化合物として、特許文献1にはヘテロ芳香環誘導体が開示されているが、本願記載のヘテロ芳香環メチル環状アミン骨格を有する化合物についての開示はない。また、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が、本願記載のヘテロ芳香環メチル環状アミン骨格を有する化合物についての開示はない。
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)
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、トリアゾリル基、ピリジル基、又はピリミジニル基を示し、
R3は、水素原子、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個のハロゲン原子で置換されてもよい)を示し、
R4は、水素原子、又はC1-6アルキル基を示す)
で表される化合物、又はその医薬上許容される塩。
(2)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であり、
R3が、ハロゲン原子である(1)に記載の化合物、又はその医薬上許容される塩。
(3)上記式(IA)において、
nが2である(1)又は(2)いずれかに記載の化合物、又はその医薬上許容される塩。
(4)式(I)
X1及びX2は、同一に又は異なって窒素原子、又は式CHを示し、
Y1及びY2は、いずれか一方が窒素原子、他方がCHを示し、
nは1又は2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、トリアゾリル基、ピリジル基、又はピリミジニル基を示し、
R3は、水素原子、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個のハロゲン原子で置換されてもよい)を示し、
R4は、水素原子、又はC1-6アルキル基を示す)
で表される化合物、又はその医薬上許容される塩。
(5)上記式(I)において、
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(4)に記載の化合物、又はその医薬上許容される塩。
(6)上記式(I)において、
nが2である(4)又は(5)いずれかに記載の化合物、又はその医薬上許容される塩。
(7)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。
(−)−(2−{[3−(5−フルオロピリジン−2−イル)−1H−ピラゾール−1−イル]メチル}−1,3−オキサゾリジン−3−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、
(−)−(2−{[4−(5−フルオロピリジン−2−イル)−1H−ピラゾール−1−イル]メチル}−1,3−オキサゾリジン−3−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、
(−)−(2−{[3−(5−フルオロピリジン−2−イル)−1H−ピラゾール−1−イル]メチル}−1,3−オキサジナン−3−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、
(−)−(2−{[4−(5−フルオロピリジン−2−イル)−1H−ピラゾール−1−イル]メチル}−1,3−オキサジナン−3−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、
(−)−[(2S,5S)−2−{[4−(5−フルオロピリジン−2−イル)−1H−ピラゾール−1−イル]メチル}−5−メチル−1,3−オキサゾリジン−3−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、
(−)−[(2S,5R)−2−{[4−(5−フルオロピリジン−2−イル)−1H−ピラゾール−1−イル]メチル}−5−メチル−1,3−オキサゾリジン−3−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、
[(2S,4R)−2−{[3−(5−フルオロピリジン−2−イル)−1H−ピラゾール−1−イル]メチル}−4−メチル−1,3−オキサゾリジン−3−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、
(−)−[(2S,4S)−2−{[3−(5−フルオロピリジン−2−イル)−1H−ピラゾール−1−イル]メチル}−4−メチル−1,3−オキサゾリジン−3−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、
(±)−2−{[3−(5−フルオロピリジン−2−イル)−1H−ピラゾール−1−イル]メチル}−1,3−オキサゾリジン−3−イル][5−メチル−2−(ピリミジン−2−イル)フェニル]メタノン、
(±)−(2−{[3−(5−フルオロピリジン−2−イル)−1H−ピラゾール−1−イル]メチル}−1,3−オキサゾリジン−3−イル)[5−フルオロ−2−(ピリミジン−2−イル)フェニル]メタノン、
(±)−(2−{[3−(4−フルオロフェニル)−1H−ピラゾール−1−イル]メチル}−1,3−オキサゾリジン−3−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、
(±)−(2−{[4−(4−フルオロフェニル)−1H−ピラゾール−1−イル]メチル}−1,3−オキサゾリジン−3−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、
(±)−(2−{[4−(4−フルオロフェニル)−1H−ピラゾール−1−イル]メチル}−1,3−オキサゾリジン−3−イル)[5−メチル−2−(ピリミジン−2−イル)フェニル]メタノン、
(−)−(2−{[3−(4−フルオロフェニル)−1H−ピラゾール−1−イル]メチル}−1,3−オキサゾリジン−3−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、
(−)−(2−{[3−(4−フルオロフェニル)−1H−ピラゾール−1−イル]メチル}−1,3−オキサジナン-3-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、
(−)−(2−{[3−(4−フルオロフェニル)−1H−ピラゾール−1−イル]メチル}−1,3−オキサジナン-3-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、
(−)−(2−{[3−(5−フルオロピリジン−2−イル)−1H−ピラゾール−1−イル]メチル}−1,3−オキサジナン−3−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、
(−)−(2−{[3−(5−フルオロピリジン−2−イル)−1H−ピラゾール−1−イル]メチル}−1,3−オキサジナン−3−イル)[5−メチル−2−(ピリミジン−2−イル)フェニル]メタノン、
(−)−(2−{[4−(4−フルオロフェニル)−1H−ピラゾール−1−イル]メチル}−1,3−オキサジナン−3−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、
(−)−(2−{[4−(4−フルオロフェニル)−1H−ピラゾール−1−イル]メチル}−1,3−オキサジナン−3−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、
(−)−[2−{[3−(5−フルオロピリジン−2−イル)−1H−ピラゾール−1−イル]メチル}−1,3−オキサジナン−3−イル][5−フルオロ−2−(ピリミジン−2−イル)フェニル]メタノン、
(−)−[2−{[4−(4−フルオロフェニル)−1H−ピラゾール−1−イル]メチル}−1,3−オキサジナン−3−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、
(−)−[2−{[5−(5−フルオロピリジン−2−イル)−1,2,4−オキサジアゾール−3−イル]メチル}−1,3−オキサジナン−3−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、
(−)−[2−{[5−(4−フルオロフェニル)−1,2,4−オキサジアゾール−3−イル]メチル}−1,3−オキサジナン−3−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、
(−)−[2−{[5−(4−フルオロフェニル)−1,2,4−オキサジアゾール−3−イル]メチル}−1,3−オキサジナン−3−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、
[(2S,4S)−2−{[4−(5−フルオロピリジン−2−イル)−1H−ピラゾール−1−イル]メチル}−4−メチル−1,3−オキサジナン−3−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、
(−)−[(2S*,5S*)−2−{[4−(5−フルオロピリジン−2−イル)−1H−ピラゾール−1−イル]メチル}−5−メチル−1,3−オキサジナン−3−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、
(−)−[2−{[3−(4−フルオロフェニル)−1H−ピラゾール−1−イル]メチル}−1,3−オキサジナン−3−イル][5−メチル−2−(ピリミジン−2−イル)フェニル]メタノン、
(±)−[2−{[1−(5−フルオロピリジン−2−イル)−1H−ピラゾール−4−イル]メチル}−1,3−オキサジナン-3-イル][5-メチル-2-(ピリミジン-2-イル)フェニル]メタノン、
(−)−[2−{[4−(4−フルオロフェニル)−1H−ピラゾール−1−イル]メチル}−1,3−オキサジナン−3−イル][5−メチル−2−(ピリミジン−2−イル)フェニル]メタノン、
(−)−[2−{[1−(5−フルオロピリジン−2−イル)−1H−ピラゾール−4−イル]メチル}−1,3−オキサジナン−3−イル][5−フルオロ−2−(ピリミジン−2−イル)フェニル]メタノン、
(−)−[2−{[1−(5−フルオロピリジン−2−イル)−1H−ピラゾール−3−イル]メチル}−1,3−オキサゾリジン−3−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、
(−)−[2−{[1−(5−フルオロピリジン−2−イル)−1H−ピラゾール−4−イル]メチル}−1,3−オキサゾリジン−3−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、
(−)−[2−{[1−(5−フルオロピリジン−2−イル)−1H−ピラゾール−4−イル]メチル}−1,3−オキサジナン−3−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(−)−[(2S*,5R*)−2−{[4−(5−フルオロピリジン−2−イル)−1H−ピラゾール−1−イル]メチル}−5−メチル−1,3−オキサジナン−3−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。
(8)上記(1)〜(7)いずれか1つに記載の化合物、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医薬。
(9)上記(1)〜(7)いずれか1つに記載の化合物、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、又は高血圧の疾患の治療又は予防薬。
「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。
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。
R1は、ハロゲン原子又はC1-6アルキル基である化合物が好ましく、フッ素原子又はメチル基である化合物がより好ましく、メチル基である化合物がさらに好ましい。
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−イル基がより好ましい。
R3は、ハロゲン原子である化合物が好ましく、フッ素原子、又は塩素原子である化合物がより好ましく、フッ素原子である化合物がさらに好ましい。
R4は、水素原子又はメチル基である化合物が好ましい。
nは、2である化合物が好ましい。
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。
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、ハロゲン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。
スキームA
スキームB
工程B−2:化合物(13)は、化合物(12)より得ることができる。工程B−2における反応は、含水メタノールや含水エタノール等の含水アルコール系溶媒、テトラヒドロフランや1,4−ジオキサン等のエーテル系溶媒、ジクロロメタン、クロロホルム等のハロゲン系溶媒アセトン等のケトン系溶媒、水又はそれらの混合溶媒中、塩酸、トリフルオロ酢酸、p‐トルエンスルホン酸等の酸と反応させる条件で実施できる。本反応は0℃〜80℃で行う事ができる。
工程B−4:化合物(16)は、化合物(4)と化合物(15)の縮合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−2と同様の反応条件に従って実施できる。
スキームC
スキームD
スキームE
スキームF
スキームG
工程G−2:化合物(43)は、化合物(32)と化合物(42)のカップリング反応により得ることができる。工程G−2における反応は工程D−5と同様の反応条件に従って実施できる。
スキームH
機械:Gilson社 TrilutionLC
カラム:Waters社 SunFire prep C18 OBD 5.0μm 30x50mm 又はYMC社 YMC−Actus Triant 5.0μm 50x30mm
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)、11分(A液/B液=20/80)、12〜13.5分(A液/B液=5/95)
流速:40mL/min
検出法:UV 254nm
条件1
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:電子衝撃イオン化法(ESI:Electron Spray Ionization)
条件2
測定機械:SHIMADZU社 LCMS−2010EV
カラム:SHIMADZU社 Shim−pack XR−ODS 2.2μm 2.0mmI.D.x30mm
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:UV 254nm
イオン化法:電子衝撃イオン化法(ESI:Electron Spray Ionization)及び大気圧化学イオン法(APCI:Atomospheric Pressure Chemical Ionization)
MS測定機器:SHIMADZU社 LCMS−2010EVあるいはmicromass社 Platform LC
条件1
測定機械:Agilent社 Agilent1100
カラム:CHIRALPAK AD−3(ダイセル、4.6mm*250mm)
流速:1.0mL/min
移動相:ヘキサン/エタノール=30/70
条件2
測定機械:Waters社 Waters2695及び2998
カラム:CHIRALPAK IB(ダイセル、4.6mm*250mm)
流速:1.0mL/min
移動相:ヘキサン/エタノール=90/10
条件3
測定機械:Waters社 Waters2695及び2998
カラム:CHIRALPAK IB(ダイセル、4.6mm*250mm)
流速:1.0mL/min
移動相:ヘキサン/2−プロパノール=30/70
条件4
測定機械:Agilent社 Agilent1100
カラム:CHIRALPAK AD−3(ダイセル、4.6mm*150mm)
流速:1.0mL/min
移動相:ヘキサン/エタノール=20/80
条件5
測定機械:Agilent社 Agilent1100
カラム:CHIRALPAK IB−3(ダイセル、4.6mm*150mm)
流速:1.0mL/min
移動相:ヘキサン/エタノール=50/50
条件6
測定機械:Waters社 Waters996及び2795
カラム:CHIRALPAK AD−3(ダイセル、4.6mm*150mm)
流速:1.0mL/min
移動相:ヘキサン/2−プロパノール=0/100
条件7
測定機械:Agilent社 Agilent1100
カラム:CHIRALPAK IB−3(ダイセル、4.6mm*150mm)
流速:1.0mL/min
移動相:ヘキサン/エタノール=70/30
条件8
測定機械:Waters社 Waters996及び2795
カラム:CHIRALPAK IB−3(ダイセル、4.6mm*150mm)
流速:1.0mL/min
移動相:ヘキサン/2−プロパノール=30/70
条件9
測定機械:Agilent社 Agilent1100
カラム:CHIRALPAK AD−3(ダイセル、4.6mm*150mm)
流速:1.0mL/min
移動相:ヘキサン/エタノール=30/70
条件10
測定機械:Agilent社 Agilent1100
カラム:CHIRALPAK IB−3(ダイセル、4.6mm*150mm)
流速:1.0mL/min
移動相:ヘキサン/エタノール=90/10
条件11
測定機械:Agilent社 Agilent1100
カラム:CHIRALPAK IB−3(ダイセル、4.6mm*150mm)
流速:1.0mL/min
移動相:ヘキサン/エタノール=80/20
条件12
測定機械:Waters社 Waters996及び2795
カラム:CHIRALPAK ID−3(ダイセル、4.6mm*150mm)
流速:1.0mL/min
移動相:ヘキサン/2−プロパノール=50/50
条件13
測定機械:Waters社 Waters996及び2795
カラム:CHIRALPAK IA−3(ダイセル、4.6mm*150mm)
流速:1.0mL/min
移動相:ヘキサン/2−プロパノール=20/80
測定機械:日本分光社 JASCO P−2300
Na2SO4(無水硫酸ナトリウム)、MgSO4(無水硫酸マグネシウム)、Cs2CO3(炭酸セシウム)、NaHCO3(炭酸水素ナトリウム)、TFA(トリフルオロ酢酸)、THF(テトラヒドロフラン)、DMF(N,N−ジメチルホルムアミド)、NMP(N−メチル−2−ピロリドン)EtOAc(酢酸エチル)、CHCl3(クロロホルム)、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]、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)、MsCl(塩化メタンスルホニル)、NaBH4(水素化ホウ素ナトリウム)、LiBH4(水素化ホウ素リチウム)。
MS (ESI/APCI Dual pos.) m/z : 331 [M+H]+
MS (ESI/APCI Dual pos.) m/z : 289 [M+H]+
MS (ESI pos.) m/z : 367 [M+Na]+
MS (ESI pos.) m/z : 303 [M+H]+
MS (ESI/APCI Dual pos.) m/z : 345 [M+H]+
MS (ESI/APCI Dual pos.) m/z : 345 [M+H]+
MS (ESI pos.) m/z : 303 [M+H]+
MS (ESI pos.) m/z : 303 [M+H]+
MS (ESI pos.) m/z : 248 [M+H]+
MS (ESI pos.) m/z : 164 [M+H]+
MS (ESI pos.) m/z : 164 [M+H]+
MS (ESI pos.) m/z : 280 [M+H]+
MS (ESI pos.) m/z : 359 [M+H]+
MS (ESI pos.) m/z : 317 [M+H]+
MS (ESI pos.) m/z : 359 [M+H]+
MS (ESI pos.) m/z : 171 [M+Na]+
MS (ESI pos.) m/z : 254 [M+H]+
MS (ESI pos.) m/z : 253 [M+H]+
MS (ESI pos.) m/z : 208 [M+H]+
MS (ESI pos.) m/z : 506 [M+H]+
MS (ESI pos.) m/z : 506 [M+H]+
MS (ESI pos.) m/z : 507 [M+H]+
MS (ESI pos.) m/z : 511 [M+H]+
MS (ESI pos.) m/z : 236 [M+H]+
MS (ESI pos.) m/z : 194 [M+H]+
MS (ESI pos.) m/z : 192 [M+H]+
MS (ESI pos.) m/z : 206 [M+H]+
MS (ESI pos.) m/z : 303 [M+H]+
参考例4で得られた(±)−[2−(ヒドロキシメチル)−1,3−オキサジナン−3−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(1.0mg、0.0033mmol)、酢酸ビニル(0.05mL)、t−ブチルメチルエーテル(1mL)溶液にブタ膵臓由来リパーゼ(9.5mg、商品名 Lipase from porcine pancreas Type II、SIGMA社製)を加え、35℃でスクリューバイアル中、250rpmで24時間振盪撹拌した。反応液をエキクロディスク13CR(日本ポール社製)で濾過した。濾液を減圧下濃縮し、得られた残渣を前述のラセミ体分析条件10にてHPLC分析したところ酢酸{3−[5−メチル−2−(2H−1,2,3−トリアゾール−2−イル)ベンゾイル]−1,3−オキサジナン−2−イル}メチル(54.5%、81.2%ee、Rt1=7.3 min、Rt2=8.9 minのうち保持時間の長い化合物が過剰、無色油状物)と表題化合物(45.5%、>99.9%ee、Rt1=10.2 min、Rt2=11.6 minのうち保持時間の短い化合物が過剰、無色油状物)を得た。
MS (ESI pos.) m/z : 303 [M+H]+
トリフルオロメタンスルホン酸銅(II)(0.013g、0.040mmol)と(R,R)−2,2‘−イソプロピリデンビス(4−フェニル−2−オキサゾリン)(0.012g、0.040mmol)のTHF溶液(1.5mL)に参考例4で得られた(±)−[2−(ヒドロキシメチル)−1,3−オキサジナン−3−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(0.36g、1.2mmol)、炭酸カリウム(0.16g、1.2mmol)、塩化ベンゾイル(0.069g、0.59mmol)を加え室温で3時間撹拌した。反応混合物に水を加えCHCl3で抽出した。有機層を飽和塩化ナトリウム水溶液で洗浄し、Na2SO4で乾燥後、乾燥剤を濾別し、減圧下溶媒を留去した。得られた残渣をカラムクロマトグラフィー(HP−Sil 10g、hexane/EtOAc=75/25〜0/100)にて精製することにより、安息香酸 {3−[5−メチル−2−(2H−1,2,3−トリアゾール−2−イル)ベンゾイル]−1,3−オキサジナン−2−イル}メチル(0.16g、55%ee)を得た(無色油状物)。光学純度は前述のラセミ体分析条件(条件10、Rt1=6.9 min、Rt2=7.9 min)に基づき分析し、相対保持時間が短い(Rt1=6.9 min)化合物を過剰に得た。得られた無色油状物(0.020g、0.049mmol)のMeOH溶液(0.5mL)に炭酸カリウム(0.010g、0.074mmol)を加え室温で2時間撹拌した。反応混合物に水を加えEtOAcで抽出した。有機層を飽和塩化ナトリウム水溶液で洗浄し、Na2SO4で乾燥後、乾燥剤を濾別し、減圧下溶媒を留去した。得られた残渣をカラムクロマトグラフィー(HP−Sil 10g、hexane/EtOAc=75/25〜0/100)にて精製することにより表題化合物(0.011g、55%ee)を得た(無色油状物)。光学純度は前述のラセミ体分析条件(条件10、Rt1=10.2 min、Rt2=11.6 min)に基づき分析し、相対保持時間が短い(Rt1=10.2 min)化合物を過剰に得た。
MS (ESI pos.) m/z : 303 [M+H]+
MS (ESI pos.) m/z : 321 [M+H]+
MS (ESI pos.) m/z : 359 [M+H]+
MS (ESI pos.) m/z : 317 [M+H]+
MS (ESI pos.) m/z : 335 [M+H]+
LCMS retention time 0.90 min.
MS (ESI pos.)m/z : 434 [M+H]+
[α]D 25 = −71.0 (c = 0.0994, CHCl3)
LCMS retention time 0.92 min.
MS (ESI pos.) m/z : 448 [M+H]+
[α]D 25 = −80.4 (c = 0.0828, CHCl3)
LCMS retention time 0.83 min.
MS (ESI pos.) m/z : 420 [M+H]+
LCMS retention time 0.96 min.
MS (ESI pos.) m/z : 462 [M+H]+
LCMS retention time 0.94 min.
MS (ESI pos.) m/z : 462 [M+H]+
[α]D 23 = −44.1 (c = 0.0704, CHCl3)
LCMS retention time 1.0 min.
MS (ESI pos.) m/z : 458 [M+H]+
[α]D 23 = −34.1 (c = 0.0914, CHCl3)
Rt1=4.6 min、Rt2=13.8 min)に基づきセミ分取カラムを用いて分割し、相対保持時間が短い(Rt1=4.6 min)表題化合物(0.017g)を得た(無色固体)。
LCMS retention time 1.0 min.
MS (ESI pos.)m/z : 434 [M+H]+
[α]D 23 = −104.0 (c = 0.0566, CHCl3)
LCMS retention time 0.97 min.
MS (ESI pos.)m/z : 434 [M+H]+
[α]D 23 = −80.9 (c = 0.0478, CHCl3)
LCMS retention time 0.97 min.
MS (ESI pos.)m/z : 448 [M+H]+
[α]D 23 = −21.4 (c = 0.109, CHCl3)
LCMS retention time 0.90 min.
MS (ESI pos.) m/z : 448 [M+H]+
LCMS retention time 0.95 min.
MS (ESI pos.) m/z : 462 [M+H]+
[α]D 25 = −14.1(c = 0.0870, CHCl3)
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(hOX2R)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。
本発明化合物のIC50値を表6に示す。
Claims (9)
- 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であり、
R3が、ハロゲン原子である請求項1に記載の化合物、又はその医薬上許容される塩。 - 上記式(IA)において、
nが2である請求項1又は2いずれかに記載の化合物、又はその医薬上許容される塩。 - 式(I)において、
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4に記載の化合物、又はその医薬上許容される塩。 - 上記式(I)において、
nが2である請求項4又は5いずれかに記載の化合物、又はその医薬上許容される塩。 - 請求項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。
(−)−(2−{[3−(5−フルオロピリジン−2−イル)−1H−ピラゾール−1−イル]メチル}−1,3−オキサゾリジン−3−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、
(−)−(2−{[4−(5−フルオロピリジン−2−イル)−1H−ピラゾール−1−イル]メチル}−1,3−オキサゾリジン−3−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、
(−)−(2−{[3−(5−フルオロピリジン−2−イル)−1H−ピラゾール−1−イル]メチル}−1,3−オキサジナン−3−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、
(−)−(2−{[4−(5−フルオロピリジン−2−イル)−1H−ピラゾール−1−イル]メチル}−1,3−オキサジナン−3−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、
(−)−[(2S,5S)−2−{[4−(5−フルオロピリジン−2−イル)−1H−ピラゾール−1−イル]メチル}−5−メチル−1,3−オキサゾリジン−3−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、
(−)−[(2S,5R)−2−{[4−(5−フルオロピリジン−2−イル)−1H−ピラゾール−1−イル]メチル}−5−メチル−1,3−オキサゾリジン−3−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、
[(2S,4R)−2−{[3−(5−フルオロピリジン−2−イル)−1H−ピラゾール−1−イル]メチル}−4−メチル−1,3−オキサゾリジン−3−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、
(−)−[(2S,4S)−2−{[3−(5−フルオロピリジン−2−イル)−1H−ピラゾール−1−イル]メチル}−4−メチル−1,3−オキサゾリジン−3−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、
(±)−2−{[3−(5−フルオロピリジン−2−イル)−1H−ピラゾール−1−イル]メチル}−1,3−オキサゾリジン−3−イル][5−メチル−2−(ピリミジン−2−イル)フェニル]メタノン、
(±)−(2−{[3−(5−フルオロピリジン−2−イル)−1H−ピラゾール−1−イル]メチル}−1,3−オキサゾリジン−3−イル)[5−フルオロ−2−(ピリミジン−2−イル)フェニル]メタノン、
(±)−(2−{[3−(4−フルオロフェニル)−1H−ピラゾール−1−イル]メチル}−1,3−オキサゾリジン−3−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、
(±)−(2−{[4−(4−フルオロフェニル)−1H−ピラゾール−1−イル]メチル}−1,3−オキサゾリジン−3−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、
(±)−(2−{[4−(4−フルオロフェニル)−1H−ピラゾール−1−イル]メチル}−1,3−オキサゾリジン−3−イル)[5−メチル−2−(ピリミジン−2−イル)フェニル]メタノン、
(−)−(2−{[3−(4−フルオロフェニル)−1H−ピラゾール−1−イル]メチル}−1,3−オキサゾリジン−3−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、
(−)−(2−{[3−(4−フルオロフェニル)−1H−ピラゾール−1−イル]メチル}−1,3−オキサジナン-3-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、
(−)−(2−{[3−(4−フルオロフェニル)−1H−ピラゾール−1−イル]メチル}−1,3−オキサジナン-3-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、
(−)−(2−{[3−(5−フルオロピリジン−2−イル)−1H−ピラゾール−1−イル]メチル}−1,3−オキサジナン−3−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、
(−)−(2−{[3−(5−フルオロピリジン−2−イル)−1H−ピラゾール−1−イル]メチル}−1,3−オキサジナン−3−イル)[5−メチル−2−(ピリミジン−2−イル)フェニル]メタノン、
(−)−(2−{[4−(4−フルオロフェニル)−1H−ピラゾール−1−イル]メチル}−1,3−オキサジナン−3−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、
(−)−(2−{[4−(4−フルオロフェニル)−1H−ピラゾール−1−イル]メチル}−1,3−オキサジナン−3−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、
(−)−[2−{[3−(5−フルオロピリジン−2−イル)−1H−ピラゾール−1−イル]メチル}−1,3−オキサジナン−3−イル][5−フルオロ−2−(ピリミジン−2−イル)フェニル]メタノン、
(−)−[2−{[4−(4−フルオロフェニル)−1H−ピラゾール−1−イル]メチル}−1,3−オキサジナン−3−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、
(−)−[2−{[5−(5−フルオロピリジン−2−イル)−1,2,4−オキサジアゾール−3−イル]メチル}−1,3−オキサジナン−3−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、
(−)−[2−{[5−(4−フルオロフェニル)−1,2,4−オキサジアゾール−3−イル]メチル}−1,3−オキサジナン−3−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、
(−)−[2−{[5−(4−フルオロフェニル)−1,2,4−オキサジアゾール−3−イル]メチル}−1,3−オキサジナン−3−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、
[(2S,4S)−2−{[4−(5−フルオロピリジン−2−イル)−1H−ピラゾール−1−イル]メチル}−4−メチル−1,3−オキサジナン−3−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、
(−)−[(2S*,5S*)−2−{[4−(5−フルオロピリジン−2−イル)−1H−ピラゾール−1−イル]メチル}−5−メチル−1,3−オキサジナン−3−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、
(−)−[2−{[3−(4−フルオロフェニル)−1H−ピラゾール−1−イル]メチル}−1,3−オキサジナン−3−イル][5−メチル−2−(ピリミジン−2−イル)フェニル]メタノン、
(±)−[2−{[1−(5−フルオロピリジン−2−イル)−1H−ピラゾール−4−イル]メチル}−1,3−オキサジナン-3-イル][5-メチル-2-(ピリミジン-2-イル)フェニル]メタノン、
(−)−[2−{[4−(4−フルオロフェニル)−1H−ピラゾール−1−イル]メチル}−1,3−オキサジナン−3−イル][5−メチル−2−(ピリミジン−2−イル)フェニル]メタノン、
(−)−[2−{[1−(5−フルオロピリジン−2−イル)−1H−ピラゾール−4−イル]メチル}−1,3−オキサジナン−3−イル][5−フルオロ−2−(ピリミジン−2−イル)フェニル]メタノン、
(−)−[2−{[1−(5−フルオロピリジン−2−イル)−1H−ピラゾール−3−イル]メチル}−1,3−オキサゾリジン−3−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、
(−)−[2−{[1−(5−フルオロピリジン−2−イル)−1H−ピラゾール−4−イル]メチル}−1,3−オキサゾリジン−3−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、
(−)−[2−{[1−(5−フルオロピリジン−2−イル)−1H−ピラゾール−4−イル]メチル}−1,3−オキサジナン−3−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、
(−)−[(2S*,5R*)−2−{[4−(5−フルオロピリジン−2−イル)−1H−ピラゾール−1−イル]メチル}−5−メチル−1,3−オキサジナン−3−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。 - 請求項1〜7いずれか1項に記載の化合物、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医薬。
- 請求項1〜7いずれか1項に記載の化合物、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、又は高血圧の疾患の治療又は予防薬。
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