JP6643545B2 - Trpm8拮抗剤としてのアザスピロ誘導体 - Google Patents
Trpm8拮抗剤としてのアザスピロ誘導体 Download PDFInfo
- Publication number
- JP6643545B2 JP6643545B2 JP2016557355A JP2016557355A JP6643545B2 JP 6643545 B2 JP6643545 B2 JP 6643545B2 JP 2016557355 A JP2016557355 A JP 2016557355A JP 2016557355 A JP2016557355 A JP 2016557355A JP 6643545 B2 JP6643545 B2 JP 6643545B2
- Authority
- JP
- Japan
- Prior art keywords
- decane
- diazaspiro
- difluoro
- dione
- oxoethyl
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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- 101150111302 Trpm8 gene Proteins 0.000 title claims description 44
- 239000005557 antagonist Substances 0.000 title description 20
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- 238000000034 method Methods 0.000 claims description 149
- -1 isothiazoloxy Chemical group 0.000 claims description 109
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 71
- 150000003839 salts Chemical class 0.000 claims description 54
- 208000035475 disorder Diseases 0.000 claims description 52
- 208000002193 Pain Diseases 0.000 claims description 42
- 208000004454 Hyperalgesia Diseases 0.000 claims description 40
- 125000000217 alkyl group Chemical group 0.000 claims description 40
- 150000002367 halogens Chemical class 0.000 claims description 40
- 230000036407 pain Effects 0.000 claims description 39
- 229910052736 halogen Inorganic materials 0.000 claims description 37
- 229910052739 hydrogen Inorganic materials 0.000 claims description 37
- 239000001257 hydrogen Substances 0.000 claims description 37
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 33
- 125000000008 (C1-C10) alkyl group Chemical group 0.000 claims description 32
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 32
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 32
- 125000001188 haloalkyl group Chemical group 0.000 claims description 32
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- 238000011282 treatment Methods 0.000 claims description 30
- 229910052757 nitrogen Inorganic materials 0.000 claims description 29
- 206010053552 allodynia Diseases 0.000 claims description 24
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 23
- 125000006376 (C3-C10) cycloalkyl group Chemical group 0.000 claims description 22
- 125000004438 haloalkoxy group Chemical group 0.000 claims description 21
- 229910052717 sulfur Inorganic materials 0.000 claims description 21
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- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 16
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- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 14
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 14
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- 239000003814 drug Substances 0.000 claims description 5
- 125000004043 oxo group Chemical group O=* 0.000 claims description 5
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- PRXNKYBFWAWBNZ-UHFFFAOYSA-N trimethylphenylammonium tribromide Chemical compound Br[Br-]Br.C[N+](C)(C)C1=CC=CC=C1 PRXNKYBFWAWBNZ-UHFFFAOYSA-N 0.000 description 1
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Classifications
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- C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
- C07D491/04—Ortho-condensed systems
- C07D491/056—Ortho-condensed systems with two or more oxygen atoms as ring hetero atoms in the oxygen-containing ring
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- C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
- C07D491/04—Ortho-condensed systems
- C07D491/044—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
- C07D491/048—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring the oxygen-containing ring being five-membered
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Description
したがって、TRPM8受容体拮抗活性を有する本発明のアザスピロ誘導体は、従来技術に開示されていない。
[1]以下の式(I)の化合物
Aは、アリール又はヘテロアリール;
Bは、アリール又はヘテロアリール;
Lは、化学結合、酸素、硫黄、-NR4-、-(CRCRD)t-、-O(CRCRD)t-、-(CRCRD)tO-、-N(R4)(CRCRD)t-、-(CRCRD)tN(R4)-、-N(R4)(CRCRD)tO-、および -O(CRCRD)t N(R4)-からなる群から独立に選ばれ;
Xは、-CH2-、酸素、硫黄、およびNHからなる群から独立に選ばれ;
RAおよびRBは、(1) 水素、(2) ハロゲン、(3) (C1-C10)アルキル、(4) (C3-C10)シクロアルキルおよび(5) (C1-C10)ハロアルキルからなる群から独立に選ばれ;またはRAおよびRBは、オキソ基(=O)を形成してもよく;またはRAおよびRBは、酸素原子、硫黄原子、および窒素原子から独立に選ばれる1つ以上のヘテロ原子を含んでもよい3〜8員環を形成してもよく;ここで該環は、(1) 水素、(2) ハロゲン、(3) ヒドロキシ、(4) (C1-C10)アルキル、(5) (C3-C10)シクロアルキル、(6) (C1-C10)ハロアルキル、(7) (C1-C10)アルコキシおよび(8) (C1-C10)ハロアルコキシから独立に選ばれる1〜6個の置換基で置換されていてもよく;
RCおよびRDは、(1) 水素、(2) ハロゲン、(3) (C1-C10)アルキル、(4) (C3-C10)シクロアルキルおよび(5) (C1-C10)ハロアルキルからなる群から独立に選ばれ;または、RCおよびRDは、酸素原子、硫黄原子、および窒素原子から独立に選ばれる1つ以上のヘテロ原子を含んでもよい3〜8員環を形成してもよく;ここで該環は、(1) 水素、(2) ハロゲン、(3) ヒドロキシ、(4) (C1-C10)アルキル、(5) (C3-C10)シクロアルキル、(6) (C1-C10)ハロアルキル、(7) (C1-C10)アルコキシおよび(8) (C1-C10)ハロアルコキシから独立に選ばれる1〜6個の置換基で置換されていてもよく;
R1は、(1) 水素、(2) ハロゲン、(3) アミノ、(4) シアノ、(5) ヒドロキシ、(6) (C1-C10)アルキル、(7) (C3-C10)シクロアルキル、(8) (C1-C10)ハロアルキル、(9) (C1-C10)アルコキシおよび(10) (C1-C10)ハロアルコキシからなる群から独立に選ばれ;同じ炭素または異なった炭素上の2つのR1は、酸素原子、硫黄原子、および窒素原子から選ばれる原子を含んでもよい3〜8員環を形成することが可能であり;ここで該環は、(1) 水素、(2) ハロゲン、(3) ヒドロキシ、(4) (C1-C10)アルキル、(5) (C3-C10)シクロアルキル、(6) (C1-C10)ハロアルキル、(7) (C1-C10)アルコキシ、および(8) (C1-C10)ハロアルコキシから独立に選ばれる1〜6個の置換基で置換されていてもよく;
R2は、(1) 水素、(2) ハロゲン、(3) アミノ、(4) -NH(C1-C6)アルキル、(5) -N[(C1-C6)アルキル]2 ここでアルキルは同じかまたは異なる、(6) シアノ、(7) ヒドロキシ、(8) ニトロ、(9) (C1-C6)アルキルチオ、(10) (C1-C10)アルキル、(11) (C3-C10)シクロアルキル、(12) (C1-C10)アルコキシ、(13) (C1-C10)ハロアルキルおよび(14) (C1-C10)ハロアルコキシからなる群から独立に選ばれ;
R3は、(1) 水素、(2) ハロゲン、(3) シアノ、(4) ニトロ、(5) ヒドロキシ、(6) (C1-C6)アルキルチオ、(7) (C1-C6)アルキルスルフィニル、(8) (C1-C6)アルキルスルホニル、(9) -NR5R6、(10) -C(=O)NR5R6、(11) トリ(C1-C6)アルキルシリル、(12) (C1-C10)アルキル、(13) (C3-C10)シクロアルキル、(14) (C1-C6)アルコキシ(C0-C6)アルキル、(15) (C3-C10)シクロアルコキシ、(16) -C(=O)(C1-C6)アルキル、(17) -C(=O)O(C1-C6)アルキルおよび(18) -C(=O)OHからなる群から独立に選ばれ;ここで (C1-C10)アルキル、(C3-C10)シクロアルキル、(C1-C6)アルコキシ(C0-C6)アルキルおよび(C3-C10)シクロアルコキシは、(1) 水素、(2) ハロゲン、(3) ヒドロキシ、(4) シアノ、(5) (C3-C10)シクロアルキル、(6) (C1-C10)ハロアルキル、(7) (C1-C10)アルコキシ、(8) (C1-C10)ハロアルコキシおよび (9) -NR6R5 から独立に選ばれる1〜6個の置換基で置換されていてもよく;
ここでR5およびR6は、それらの結合した窒素原子とともに3〜10員環(酸素、硫黄および窒素から選ばれる原子を含んでも良い)を形成してもよく;ここで該環は、(1) 水素、(2) ハロゲン、(3) ヒドロキシ、(4) (C1-C10)アルキル、(5) (C3-C10)シクロアルキル、(6) (C1-C10)ハロアルキル、(7) (C1-C10)アルコキシおよび(8) (C1-C10)ハロアルコキシから独立に選ばれる1〜6個の置換基で置換されていてもよく;
R4、R5およびR6は、(1) 水素、(2) (C1-C10)アルキル、(3) (C3-C10)シクロアルキル、(4) (C1-C10)ハロアルキル、(5) ヒドロキシ(C1-C10)アルキル、(6) (C1-C10)アルコキシ(C1-C10)アルキル、(7) H2N-(C1-C10)アルキル、(8) [(C1-C10)アルキル]NH-(C1-C10)アルキル、(9) [(C1-C10)アルキル]2N-(C1-C10)アルキル、(10) (C1-C10)アルキルカルボニルおよび(11) (C1-C10)アルキルスルホニルからなる群から独立に選ばれ;
pは、1、2、3または4であり;
qは、1、2、3または4であり;qが2以上のとき、R1は同じかまたは異なっており、
rは、1、2、3または4であり;rが2以上のとき、R2は同じかまたは異なっており、
sは、1、2、3、4、5、6または7であり;sが2以上のとき、R3は同じかまたは異なっており、
tは、1、2または3であり;tが2以上のとき、RCおよびRDは同じかまたは異なっている)または薬学的に許容されるその塩またはそのプロドラッグ;
または薬学的に許容されるその塩またはそのプロドラッグ;
3-(2-(2,5-ジメチル-1-フェニル-1H-イミダゾール-4-イル)-2-オキソエチル)-8,8-ジフルオロ-1,3-ジアザスピロ[4.5]デカン-2,4-ジオン;
6-(4-(2-(2,4-ジオキソ-1,3-ジアザスピロ[4.5]デカン-3-イル)アセチル)フェニル)ピコリノニトリル;
3-(2-(1-(3-クロロフェニル)-2,5-ジメチル-1H-イミダゾール-4-イル)-2-オキソエチル)-8,8-ジフルオロ-1,3-ジアザスピロ[4.5]デカン-2,4-ジオン;
8,8-ジフルオロ-3-(2-(1-(3-フルオロフェニル)-2,5-ジメチル-1H-イミダゾール-4-イル)-2-オキソエチル)-1,3-ジアザスピロ[4.5]デカン-2,4-ジオン;
3-(2-(1,4-ジメチル-5-フェニル-1H-ピラゾール-3-イル)-2-オキソエチル)-8,8-ジフルオロ-1,3-ジアザスピロ[4.5]デカン-2,4-ジオン;
8,8-ジフルオロ-3-(2-(4-(6-メチルピラジン-2-イル)フェニル)-2-オキソエチル)-1,3-ジアザスピロ[4.5]デカン-2,4-ジオン;
6-(4-(2-(8,8-ジフルオロ-2,4-ジオキソ-1,3-ジアザスピロ[4.5]デカン-3-イル)アセチル)フェニル)ピコリノニトリル;
8,8-ジフルオロ-3-(2-(2'-(ヒドロキシメチル)-[1,1'-ビフェニル]-4-イル)-2-オキソエチル)-1,3-ジアザスピロ[4.5]デカン-2,4-ジオン;
8,8-ジフルオロ-3-(2-(4-(3-メチルピラジン-2-イル)フェニル)-2-オキソエチル)-1,3-ジアザスピロ[4.5]デカン-2,4-ジオン;
3-(2-(2,5-ジメチル-1-フェニル-1H-イミダゾール-4-イル)-2-オキソエチル)-8,8-ジフルオロ-1-オキサ-3-アザスピロ[4.5]デカン-2,4-ジオン;
8,8-ジフルオロ-3-(2-(4-(2-(ヒドロキシメチル)ピリジン-3-イル)フェニル)-2-オキソエチル)-1,3-ジアザスピロ[4.5]デカン-2,4-ジオン;
8,8-ジフルオロ-3-(2-(4-(4-(ヒドロキシメチル)ピリジン-3-イル)フェニル)-2-オキソエチル)-1,3-ジアザスピロ[4.5]デカン-2,4-ジオン;
3-(2-(2,5-ジメチル-1-(5-メチルイソオキサゾール-3-イル)-1H-ピロール-3-イル)-2-オキソエチル)-8,8-ジフルオロ-1-オキサ-3-アザスピロ[4.5]デカン-2,4-ジオン;
8,8-ジフルオロ-3-(2-(5-(2-(ヒドロキシメチル)フェニル)-4-メチルチオフェン-2-イル)-2-オキソエチル)-1,3-ジアザスピロ[4.5]デカン-2,4-ジオン;
3-(2-(4-(3-(ヒドロキシメチル)ピラジン-2-イル)フェニル)-2-オキソエチル)-1,3-ジアザスピロ[4.5]デカン-2,4-ジオン;
3-(2-(1,4-ジメチル-5-フェニル-1H-ピラゾール-3-イル)-2-オキソエチル)-8,8-ジフルオロ-1-オキサ-3-アザスピロ[4.5]デカン-2,4-ジオン;
8,8-ジフルオロ-3-(2-(4-(4-メチルピリダジン-3-イル)フェニル)-2-オキソエチル)-1,3-ジアザスピロ[4.5]デカン-2,4-ジオン;
3-(4-(2-(8,8-ジフルオロ-2,4-ジオキソ-1,3-ジアザスピロ[4.5]デカン-3-イル)アセチル)フェニル)ピラジン-2-カルボニトリル;
3-(2-(1,4-ジメチル-5-フェニル-1H-ピロール-2-イル)-2-オキソエチル)-8,8-ジフルオロ-1,3-ジアザスピロ[4.5]デカン-2,4-ジオン;
8,8-ジフルオロ-3-(2-(4-(3-(ヒドロキシメチル)ピラジン-2-イル)フェニル)-2-オキソエチル)-1,3-ジアザスピロ[4.5]デカン-2,4-ジオン;
3-(2-(6-(メチル(ピリジン-2-イル)アミノ)ピリジン-3-イル)-2-オキソエチル)-1,3-ジアザスピロ[4.5]デカン-2,4-ジオン;
3-(4-(2-(8,8-ジフルオロ-2,4-ジオキソ-1,3-ジアザスピロ[4.5]デカン-3-イル)アセチル)フェニル)ピコリノニトリル;
8,8-ジフルオロ-3-(2-オキソ-2-(4-(キノリン-8-イル)フェニル)エチル)-1,3-ジアザスピロ[4.5]デカン-2,4-ジオン;
3-(2-(4-(1H-インドール-4-イル)フェニル)-2-オキソエチル)-8,8-ジフルオロ-1,3-ジアザスピロ[4.5]デカン-2,4-ジオン;
8,8-ジフルオロ-3-(2-オキソ-2-(4-(キノリン-2-イル)フェニル)エチル)-1,3-ジアザスピロ[4.5]デカン-2,4-ジオン;
8,8-ジフルオロ-3-(2-(4-(イソキノリン-8-イル)フェニル)-2-オキソエチル)-1,3-ジアザスピロ[4.5]デカン-2,4-ジオン;
8,8-ジフルオロ-3-(2-(4-(イソキノリン-1-イル)フェニル)-2-オキソエチル)-1,3-ジアザスピロ[4.5]デカン-2,4-ジオン;
8,8-ジフルオロ-3-(2-(4-(フロ[3,2-c]ピリジン-4-イル)フェニル)-2-オキソエチル)-1,3-ジアザスピロ[4.5]デカン-2,4-ジオン;
8,8-ジフルオロ-3-(2-(6-(メチル(ピリジン-2-イル)アミノ)ピリジン-3-イル)-2-オキソエチル)-1,3-ジアザスピロ[4.5]デカン-2,4-ジオン;
8,8-ジフルオロ-3-(2-(6-(メチル(フェニル)アミノ)ピリジン-3-イル)-2-オキソエチル)-1,3-ジアザスピロ[4.5]デカン-2,4-ジオン;
8,8-ジフルオロ-3-(2-(4-(3-フルオロピリジン-2-イル)フェニル)-2-オキソエチル)-1,3-ジアザスピロ[4.5]デカン-2,4-ジオン;
3-(4-(2-(8,8-ジフルオロ-2,4-ジオキソ-1,3-ジアザスピロ[4.5]デカン-3-イル)アセチル)フェニル)イソニコチノニトリル;
8,8-ジフルオロ-3-(2-(4-(2-メトキシピリジン-3-イル)フェニル)-2-オキソエチル)-1,3-ジアザスピロ[4.5]デカン-2,4-ジオン;
8,8-ジフルオロ-3-(2-(4-(4-メトキシピリジン-3-イル)フェニル)-2-オキソエチル)-1,3-ジアザスピロ[4.5]デカン-2,4-ジオン;
8,8-ジフルオロ-3-(2-オキソ-2-(4-(2-オキソインドリン-4-イル)フェニル)エチル)-1,3-ジアザスピロ[4.5]デカン-2,4-ジオン;
3-(2-(4-(7H-ピロロ[2,3-d]ピリミジン-4-イル)フェニル)-2-オキソエチル)-8,8-ジフルオロ-1,3-ジアザスピロ[4.5]デカン-2,4-ジオン;
3-(2-(4-(1H-ピロロ[3,2-c]ピリジン-4-イル)フェニル)-2-オキソエチル)-8,8-ジフルオロ-1,3-ジアザスピロ[4.5]デカン-2,4-ジオン;
3-(2-(4-(1H-ピロロ[2,3-b]ピリジン-4-イル)フェニル)-2-オキソエチル)-8,8-ジフルオロ-1,3-ジアザスピロ[4.5]デカン-2,4-ジオン;
3-(2-(4-(3-クロロピリジン-2-イル)フェニル)-2-オキソエチル)-8,8-ジフルオロ-1,3-ジアザスピロ[4.5]デカン-2,4-ジオン;
8,8-ジフルオロ-3-(2-(4-(2-メチル-1H-ベンゾ[d]イミダゾール-1-イル)フェニル)-2-オキソエチル)-1,3-ジアザスピロ[4.5]デカン-2,4-ジオン;
3-(2-(4-(1H-インダゾール-4-イル)フェニル)-2-オキソエチル)-8,8-ジフルオロ-1,3-ジアザスピロ[4.5]デカン-2,4-ジオン;
3-(2-(6-(1H-インダゾール-4-イル)ピリジン-3-イル)-2-オキソエチル)-8,8-ジフルオロ-1,3-ジアザスピロ[4.5]デカン-2,4-ジオン;
3-(2-(4-(1H-ベンゾ[d]イミダゾール-1-イル)フェニル)-2-オキソエチル)-8,8-ジフルオロ-1,3-ジアザスピロ[4.5]デカン-2,4-ジオン;
3-(5-(2-(8,8-ジフルオロ-2,4-ジオキソ-1,3-ジアザスピロ[4.5]デカン-3-イル)アセチル)-1,3-ジメチル-1H-ピロール-2-イル)ベンゾニトリル;
3-(2-(4-(1H-ピロロ[2,3-c]ピリジン-4-イル)フェニル)-2-オキソエチル)-8,8-ジフルオロ-1,3-ジアザスピロ[4.5]デカン-2,4-ジオン;
8,8-ジフルオロ-3-(2-(3-フルオロ-4-(キノリン-8-イル)フェニル)-2-オキソエチル)-1,3-ジアザスピロ[4.5]デカン-2,4-ジオン;
3-(5-(2-(8,8-ジフルオロ-2,4-ジオキソ-1,3-ジアザスピロ[4.5]デカン-3-イル)アセチル)-1-メチル-1H-ピロール-2-イル)ベンゾニトリル;
3-(5-(2-(8,8-ジフルオロ-2,4-ジオキソ-1,3-ジアザスピロ[4.5]デカン-3-イル)アセチル)-3-メチルチオフェン-2-イル)ベンゾニトリル;
8,8-ジフルオロ-3-(2-(4-(2-(2-ヒドロキシエトキシ)ピリジン-3-イル)フェニル)-2-オキソエチル)-1,3-ジアザスピロ[4.5]デカン-2,4-ジオン;
8,8-ジフルオロ-3-(2-(5-(3-フルオロフェニル)-1,4-ジメチル-1H-ピロール-2-イル)-2-オキソエチル)-1,3-ジアザスピロ[4.5]デカン-2,4-ジオン;
3-(2-(5-(3-クロロフェニル)-1,4-ジメチル-1H-ピロール-2-イル)-2-オキソエチル)-8,8-ジフルオロ-1,3-ジアザスピロ[4.5]デカン-2,4-ジオン;
3-(5-(2-(8,8-ジフルオロ-2,4-ジオキソ-1,3-ジアザスピロ[4.5]デカン-3-イル)アセチル)-1,3-ジメチル-1H-ピロール-2-イル)ベンズアミド;
8,8-ジフルオロ-3-(2-(5-(2-フルオロフェニル)-1,4-ジメチル-1H-ピロール-2-イル)-2-オキソエチル)-1,3-ジアザスピロ[4.5]デカン-2,4-ジオン;
3-(2-(4-(1H-ピラゾロ[3,4-b]ピリジン-4-イル)フェニル)-2-オキソエチル)-8,8-ジフルオロ-1,3-ジアザスピロ[4.5]デカン-2,4-ジオン;
3-(2-(4-(1H-ピラゾロ[4,3-c]ピリジン-4-イル)フェニル)-2-オキソエチル)-8,8-ジフルオロ-1,3-ジアザスピロ[4.5]デカン-2,4-ジオン;
3-(2-(4-(1H-インダゾール-1-イル)フェニル)-2-オキソエチル)-8,8-ジフルオロ-1,3-ジアザスピロ[4.5]デカン-2,4-ジオン;
8,8-ジフルオロ-3-(2-(5-(3-フルオロフェニル)-1-メチル-1H-イミダゾール-2-イル)-2-オキソエチル)-1,3-ジアザスピロ[4.5]デカン-2,4-ジオン;
8,8-ジフルオロ-3-(2-(4-(2-メチル-3H-イミダゾ[4,5-b]ピリジン-3-イル)フェニル)-2-オキソエチル)-1,3-ジアザスピロ[4.5]デカン-2,4-ジオン;
8,8-ジフルオロ-3-(2-オキソ-2-(4-(ピリジン-2-イルオキシ)フェニル)エチル)-1,3-ジアザスピロ[4.5]デカン-2,4-ジオン;
3-(2-(5-(3,5-ジフルオロフェニル)-1,4-ジメチル-1H-ピロール-2-イル)-2-オキソエチル)-8,8-ジフルオロ-1,3-ジアザスピロ[4.5]デカン-2,4-ジオン;
8,8-ジフルオロ-3-(2-(2'-メチル-[3,3'-ビピリジン]-6-イル)-2-オキソエチル)-1,3-ジアザスピロ[4.5]デカン-2,4-ジオン;
3-(2-(4-(1H-ピラゾロ[3,4-d]ピリミジン-4-イル)フェニル)-2-オキソエチル)-8,8-ジフルオロ-1,3-ジアザスピロ[4.5]デカン-2,4-ジオン;
3-(2-(6-(1H-ピロロ[2,3-c]ピリジン-4-イル)ピリジン-3-イル)-2-オキソエチル)-8,8-ジフルオロ-1,3-ジアザスピロ[4.5]デカン-2,4-ジオン;
8,8-ジフルオロ-3-(2-(4-(3-(2-ヒドロキシエトキシ)ピラジン-2-イル)フェニル)-2-オキソエチル)-1,3-ジアザスピロ[4.5]デカン-2,4-ジオン;
8,8-ジフルオロ-3-(2-オキソ-2-(4-(フタラジン-1-イル)フェニル)エチル)-1,3-ジアザスピロ[4.5]デカン-2,4-ジオン;
3-(2-(4-(3H-イミダゾ[4,5-b]ピリジン-3-イル)フェニル)-2-オキソエチル)-8,8-ジフルオロ-1,3-ジアザスピロ[4.5]デカン-2,4-ジオン;
3-(2-(2-(8,8-ジフルオロ-2,4-ジオキソ-1,3-ジアザスピロ[4.5]デカン-3-イル)アセチル)-4-メチルチアゾール-5-イル)ベンゾニトリル;
3-(2-(1,4-ジメチル-5-フェニル-1H-イミダゾール-2-イル)-2-オキソエチル)-8,8-ジフルオロ-1,3-ジアザスピロ[4.5]デカン-2,4-ジオン;
8,8-ジフルオロ-3-(2-(5-(3-フルオロフェニル)-1,4-ジメチル-1H-イミダゾール-2-イル)-2-オキソエチル)-1,3-ジアザスピロ[4.5]デカン-2,4-ジオン;
3-(2-(2-(8,8-ジフルオロ-2,4-ジオキソ-1,3-ジアザスピロ[4.5]デカン-3-イル)アセチル)-1,4-ジメチル-1H-イミダゾール-5-イル)ベンゾニトリル;
8,8-ジフルオロ-3-(2-(5-(イソキノリン-8-イル)-1,4-ジメチル-1H-イミダゾール-2-イル)-2-オキソエチル)-1,3-ジアザスピロ[4.5]デカン-2,4-ジオン;
8,8-ジフルオロ-3-(2-(5-(2-(ヒドロキシメチル)フェニル)-1,4-ジメチル-1H-イミダゾール-2-イル)-2-オキソエチル)-1,3-ジアザスピロ[4.5]デカン-2,4-ジオン;
8,8-ジフルオロ-3-(2-(4-(2-(ヒドロキシメチル)-1H-ベンゾ[d]イミダゾール-1-イル)フェニル)-2-オキソエチル)-1,3-ジアザスピロ[4.5]デカン-2,4-ジオン;
8,8-ジフルオロ-3-(2-(5-(3-フルオロフェニル)-1,4-ジメチル-1H-ピロール-3-イル)-2-オキソエチル)-1,3-ジアザスピロ[4.5]デカン-2,4-ジオン;
3-(4-(2-(8,8-ジフルオロ-2,4-ジオキソ-1,3-ジアザスピロ[4.5]デカン-3-イル)アセチル)-1,3-ジメチル-1H-ピロール-2-イル)ベンゾニトリル;
3-(2-(5-(1H-ベンゾ[d]イミダゾール-1-イル)ピラジン-2-イル)-2-オキソエチル)-8,8-ジフルオロ-1,3-ジアザスピロ[4.5]デカン-2,4-ジオン;
3-(2-(4-(2,7-ナフチリジン-1-イル)フェニル)-2-オキソエチル)-8,8-ジフルオロ-1,3-ジアザスピロ[4.5]デカン-2,4-ジオン;
8,8-ジフルオロ-3-(2-オキソ-2-(4-(2-オキソ-2,3-ジヒドロ-1H-ベンゾ[d]イミダゾール-1-イル)フェニル)エチル)-1,3-ジアザスピロ[4.5]デカン-2,4-ジオン;
8,8-ジフルオロ-3-(2-(5-(2-(ヒドロキシメチル)フェニル)ピラジン-2-イル)-2-オキソエチル)-1,3-ジアザスピロ[4.5]デカン-2,4-ジオン;
8,8-ジフルオロ-3-(2-(5-(4-メトキシピリジン-3-イル)ピラジン-2-イル)-2-オキソエチル)-1,3-ジアザスピロ[4.5]デカン-2,4-ジオン;
3-(5-(2-(8,8-ジフルオロ-2,4-ジオキソ-1,3-ジアザスピロ[4.5]デカン-3-イル)アセチル)-2,4-ジメチルチオフェン-3-イル)ベンズアミド;
3-(2-(5-(3,5-ジフルオロフェニル)-1,4-ジメチル-1H-イミダゾール-2-イル)-2-オキソエチル)-8,8-ジフルオロ-1,3-ジアザスピロ[4.5]デカン-2,4-ジオン;
8,8-ジフルオロ-3-(2-オキソ-2-(4-(ピリダジン-3-イルオキシ)フェニル)エチル)-1,3-ジアザスピロ[4.5]デカン-2,4-ジオン;
8,8-ジフルオロ-3-(2-オキソ-2-(4-(2-オキソ-1H-イミダゾ[4,5-b]ピリジン-3(2H)-イル)フェニル)エチル)-1,3-ジアザスピロ[4.5]デカン-2,4-ジオン;
3-(2-(5-(3,5-ジフルオロフェニル)-4-メチルチアゾール-2-イル)-2-オキソエチル)-8,8-ジフルオロ-1,3-ジアザスピロ[4.5]デカン-2,4-ジオン;
4'-(2-(8,8-ジフルオロ-2,4-ジオキソ-1,3-ジアザスピロ[4.5]デカン-3-イル)アセチル)-2'-メトキシ-[1,1'-ビフェニル]-2-カルボニトリル;
2-(4-(2-(8,8-ジフルオロ-2,4-ジオキソ-1,3-ジアザスピロ[4.5]デカン-3-イル)アセチル)フェノキシ)ニコチノニトリル;
3-(2-(4-((3-クロロピリジン-2-イル)オキシ)フェニル)-2-オキソエチル)-8,8-ジフルオロ-1,3-ジアザスピロ[4.5]デカン-2,4-ジオン;
8,8-ジフルオロ-3-(2-(4-(3-(ヒドロキシメチル)ピリジン-2-イル)フェニル)-2-オキソエチル)-1,3-ジアザスピロ[4.5]デカン-2,4-ジオン;
3-(2-(2'-(アミノメチル)-[1,1'-ビフェニル]-4-イル)-2-オキソエチル)-8,8-ジフルオロ-1,3-ジアザスピロ[4.5]デカン-2,4-ジオン;
8,8-ジフルオロ-3-(2-オキソ-2-(6-(キノリン-8-イル)ピリジン-3-イル)エチル)-1,3-ジアザスピロ[4.5]デカン-2,4-ジオン;
8,8-ジフルオロ-3-(2-(5-(2-メチルピリジン-3-イル)ピラジン-2-イル)-2-オキソエチル)-1,3-ジアザスピロ[4.5]デカン-2,4-ジオン;
3-(2-(4-(2,7-ナフチリジン-1-イル)フェニル)-2-オキソエチル)-8,8-ジフルオロ-1-オキサ-3-アザスピロ[4.5]デカン-2,4-ジオン;
3-(4-(2-(8,8-ジフルオロ-2,4-ジオキソ-1,3-ジアザスピロ[4.5]デカン-3-イル)アセチル)フェニル)-2-メチル-3H-イミダゾ[4,5-b]ピリジン-5-カルボニトリル;
8,8-ジフルオロ-3-(2-オキソ-2-(4-(2-オキソベンゾ[d]オキサゾール-3(2H)-イル)フェニル)エチル)-1,3-ジアザスピロ[4.5]デカン-2,4-ジオン;
3-(2-(4-(2,5-ジメチル-3H-イミダゾ[4,5-b]ピリジン-3-イル)フェニル)-2-オキソエチル)-8,8-ジフルオロ-1,3-ジアザスピロ[4.5]デカン-2,4-ジオン;
8,8-ジフルオロ-3-(2-(5-(2-メチル-1H-ベンゾ[d]イミダゾール-1-イル)ピラジン-2-イル)-2-オキソエチル)-1,3-ジアザスピロ[4.5]デカン-2,4-ジオン;
8,8-ジフルオロ-3-(2-(4-(2-メトキシ-5-メチル-3H-イミダゾ[4,5-b]ピリジン-3-イル)フェニル)-2-オキソエチル)-1,3-ジアザスピロ[4.5]デカン-2,4-ジオン;
8,8-ジフルオロ-3-(2-(4-(5-メチル-2-(トリフルオロメチル)-3H-イミダゾ[4,5-b]ピリジン-3-イル)フェニル)-2-オキソエチル)-1,3-ジアザスピロ[4.5]デカン-2,4-ジオン;
3-(2-(4-(2-(ジフルオロメチル)-5-メチル-3H-イミダゾ[4,5-b]ピリジン-3-イル)フェニル)-2-オキソエチル)-8,8-ジフルオロ-1,3-ジアザスピロ[4.5]デカン-2,4-ジオン;
8,8-ジフルオロ-3-(2-(4-(5-メチル-2-オキソ-1H-イミダゾ[4,5-b]ピリジン-3(2H)-イル)フェニル)-2-オキソエチル)-1,3-ジアザスピロ[4.5]デカン-2,4-ジオン;
6-(4-(2-(8,8-ジフルオロ-2,4-ジオキソ-1,3-ジアザスピロ[4.5]デカン-3-イル)アセチル)フェノキシ)ピコリノニトリル;
8,8-ジフルオロ-3-(2-(4-(5-メチル-3H-イミダゾ[4,5-b]ピリジン-3-イル)フェニル)-2-オキソエチル)-1,3-ジアザスピロ[4.5]デカン-2,4-ジオン;
8,8-ジフルオロ-3-(2-(4-(3-メトキシピラジン-2-イル)フェニル)-2-オキソエチル)-1,3-ジアザスピロ[4.5]デカン-2,4-ジオン;
3-(4-(2-(8,8-ジフルオロ-2,4-ジオキソ-1,3-ジアザスピロ[4.5]デカン-3-イル)アセチル)-3-フルオロフェニル)ピラジン-2-カルボニトリル;
8,8-ジフルオロ-3-(2-(4-(イミダゾ[1,2-b]ピリダジン-3-イル)フェニル)-2-オキソエチル)-1,3-ジアザスピロ[4.5]デカン-2,4-ジオン;
8,8-ジフルオロ-3-(2-(2'-(2-ヒドロキシエチル)-[1,1'-ビフェニル]-4-イル)-2-オキソエチル)-1,3-ジアザスピロ[4.5]デカン-2,4-ジオン;
2-(4'-(2-(8,8-ジフルオロ-2,4-ジオキソ-1,3-ジアザスピロ[4.5]デカン-3-イル)アセチル)-[1,1'-ビフェニル]-2-イル)アセトニトリル;
3-(2-(4-(1H-イミダゾ[4,5-b]ピラジン-1-イル)フェニル)-2-オキソエチル)-8,8-ジフルオロ-1,3-ジアザスピロ[4.5]デカン-2,4-ジオン;
8,8-ジフルオロ-3-(2-(4-(4-メチルピリダジン-3-イル)フェニル)-2-オキソエチル)-1-オキサ-3-アザスピロ[4.5]デカン-2,4-ジオン;
3-(4-(2-(8,8-ジフルオロ-2,4-ジオキソ-1,3-ジアザスピロ[4.5]デカン-3-イル)アセチル)フェノキシ)ピリダジン-4-カルボニトリル;
8,8-ジフルオロ-3-(2-(4-(2-(ヒドロキシメチル)-5-メチル-3H-イミダゾ[4,5-b]ピリジン-3-イル)フェニル)-2-オキソエチル)-1,3-ジアザスピロ[4.5]デカン-2,4-ジオン;
8,8-ジフルオロ-3-(2-オキソ-2-(4-(ピラゾロ[1,5-a]ピリミジン-3-イル)フェニル)エチル)-1,3-ジアザスピロ[4.5]デカン-2,4-ジオン;
4-(4-(2-(8,8-ジフルオロ-2,4-ジオキソ-1,3-ジアザスピロ[4.5]デカン-3-イル)アセチル)フェニル)ニコチノニトリル;
8,8-ジフルオロ-3-(2-(2-フルオロ-4-(4-メチルピリダジン-3-イル)フェニル)-2-オキソエチル)-1,3-ジアザスピロ[4.5]デカン-2,4-ジオン;
8,8-ジフルオロ-3-(2-(2-フルオロ-4-(3-(ヒドロキシメチル)ピラジン-2-イル)フェニル)-2-オキソエチル)-1,3-ジアザスピロ[4.5]デカン-2,4-ジオン;および
2-(4-(2-(8,8-ジフルオロ-2,4-ジオキソ-1,3-ジアザスピロ[4.5]デカン-3-イル)アセチル)フェニル)ニコチノニトリル
から選ばれる、[1]〜[3]のいずれか一項に記載された化合物または薬学的に許容されるその塩またはそのプロドラッグ;
すなわち、本明細書において、用語「ヘテロアリール」は、以下を意味する;
1)不飽和および部分的に飽和した炭素原子および窒素、リン、酸素および硫黄から選択される1〜5個のヘテロ原子からなる、5〜15員環、好ましくは6〜15員環。
2)不飽和および部分的に飽和した5〜15員環、好ましくは6〜15員環、そのようなヘテロシクリル環またはシクロアルキル環などの非芳香族環は、上記で定義されたヘテロアリールに縮合している。
3) アリール環がヘテロシクリル環に縮合している不飽和および部分的に飽和である5〜15員環、好ましくは6〜15員環。そのようなヘテロアリールの例としては、チオフェニル、チアゾリル、イソオキサゾリル、ピラゾリル、テトラゾリル、フラニル、ピロリル、イミダゾリル、オキサゾリル、イソチアゾリル、トリアゾリル、チアジアゾリル、ピリジル、ピリミジル、ピリダジニル、ピラジニル、トリアジニル、ベンゾフラニル、ベンゾチオフェニル、ベンゾトリアゾリル、インドリル、インダゾリル、ベンゾイミダゾリル、ピロロピリジル、ピロロピリミジニル、ピラゾロピリジル、ピラゾロピリミジニル、イミダゾピリジニル、フロピリジル、ベンゾイソオキサゾリル、イミダゾピラジニル、イミダゾピリダジニル、イミダゾピリミジニル、キノリル、イソキノリル、キナゾリニル、フタラジニル、キノキサリニル、ナフチリジニル、ピリドピリミジニル、およびこれらのN−オキシドおよびこれらのS-オキシドを含むが、これらに限定されない。
たとえば、α、β、およびδは、それぞれアルファ、ベータ、およびデルタである。
式(I)の化合物のいわゆる「プロドラッグ」も本発明の範囲内である。たとえば、それ自体は薬理活性をほとんどまたはまったくもたないかもしれない式(I)の化合物のある種の誘導体は、身体に投与されたとき、たとえば加水分解による切断によって、所望の活性を有する式(I)の化合物に変換され得る。このような誘導体を「プロドラッグ」と呼ぶ。プロドラッグの使用について、さらなる情報は「Pro-drugs as Novel Delivery Systems, Vol. 14, ACS Symposium Series(T HiguchiおよびW Stella)およびBioreversible Carriers in Drug Design, Pergamon Press, 1987(E B Roche編、American Pharmaceutical Association)で見ることができる。
(ii)式(I)の化合物がアミノ基、適切な酸ハライドまたは適切な酸無水物で反応することによって得られるアミド誘導体が、プロドラッグとして挙げられる。プロドラッグとして特に好ましいアミドは、-NHCO(CH2)2OCH3, -NHCOCH(NH2)CH3などである。
・鎮静薬、たとえばグルテチミド、メプロバメート、メタカロン、またはジクロラルフェナゾン;
・化学療法薬、たとえば、オキサリプラチン、5-フルオロウラシル、ロイコボリン、パクリタキセル;
・カルシトシン遺伝子関連タンパク(CGRP);
・ブラジキニン(BK1およびBK2)拮抗薬;
・電位依存性ナトリウム依存性チャネル遮断薬(Nav1.3, Nav1.7, Nav1.8);
・電位依存性カルシウムチャネル遮断薬 (N-型, T-型) ;
・P2X(イオンチャネル型ATP受容体)拮抗薬;
・酸感受性イオンチャネル(ASIC1a、ASIC3)拮抗薬;
・アンジオテンシンAT2拮抗薬;
・ケモカインCCR2B受容体拮抗薬;
・カテプシン(B、S、K)阻害薬;
・シグマ1受容体作動薬または拮抗薬;
本出願において、以下の略号は下記の意味で用いられる:
AcOH: 酢酸
aq.: 水の(aqueous)
BINAP: 2,2'-ビス(ジフェニルホスフィノ)-1,1'-ビナフチル
tBuXPhos: 2-ジ-tert-ブチルホスフィノ-2',4',6'-トリイソプロピルビフェニル
CDI: カルボニルジイミダゾール
Cs2CO3: 炭酸セシウム
DABCO: 1,4-ジアザビシクロ[2.2.2]オクタン
DavePhos: 2-ジシクロヘキシルホスフィノ-2 '?(N,N-ジメチルアミノ)ビフェニル
DBN: 1,5-ジアザビシクロ[4.3.0]ノン-5-エン
DBU: 1,8-ジアザビシクロ[5.4.0]ウンデカ-7-エン
DCM: ジクロロメタン
DEAD: アゾジカルボン酸ジエチル
DIPEA: ジイソプロピルエチルアミン
DMF: N,N-ジメチルホルムアミド
DMA: N,N-ジメチルアセトアミド
DME: 1,2-ジメトキシエタン
DMSO: ジメチルスルホキシド
デス-マーチン・ペルヨージナン: 1,1,1-トリス(アセチルオキシ)-1,1-ジヒドロ-1,2-ベンゾヨードキソール-3-(1H)-オン
ESI: エレクトロスプレーイオン化
Et: エチル
EtOAc: 酢酸エチル
EtOH: エタノール
eq.: 当量
HPLC: 高速液体クロマトグラフィー
INT: 中間体
IPE: イソプロピルエーテル
K2CO3: 炭酸カリウム
K3PO4: リン酸カリウム
KO t-Bu: カリウムtert-ブトキシド
LC: 液体クロマトグラフィー
LDA: リチウムジイソプロピルアミド
LG: 脱離基
tR: 保持時間
Me: メチル
MeCN: アセトニトリル
MeOH: メタノール
min: 分
NaHCO3: 炭酸水素ナトリウム
Na2SO4: 硫酸ナトリウム
Na2S2O3: チオ硫酸ナトリウム
NaO t-Bu: ナトリウムtert-ブトキシド
MHz: メガヘルツ
mp: 融点
MS: 質量分析計
NMP: N-メチル-2-ピロリドン
NMR: 核磁気共鳴
Oxone (登録商標): ペルオキシモノ硫酸カリウム
PG: 保護基
Pd2(dba)3: トリス(ジベンジリデンアセトン)ジパラジウム(0)
Pd(OAc)2: パラジウム(II)アセテート
PdCl2(dppf) CH2Cl2: [1,1'-ビス(ジフェニルホスフィノ)フェロセン]ジクロロパラジウム(II)ジクロロメタン付加物
PdCl2(Amphos)2: ビス(ジ-tert-ブチル(4-ジメチルアミノフェニル)ホスフィン)ジクロロパラジウム(II)
PEPPSI(商標)-IPr: [1,3-ビス(2,6-ジイソプロピルフェニル)イミダゾール-2-イリデン](3-クロロピリジン)パラジウム(II)ジクロリド
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)
POCl3: オキシ塩化リン(V)
quant.: 定量的
rt: 室温
sat.: 飽和
TEA: トリエチルアミン
TFA:トリフルオロ酢酸
THF:テトラヒドロフラン
THP: 2-テトラヒドロピラニル
p-TsOH: p-トルエンスルホン酸
XPhos: 2-ジシクロヘキシルホスフィノ-2 ',4',6'-トリイソプロピルビフェニル
Xantphos: 4,5-ビス(ジフェニルホスフィノ)-9,9-ジメチルキサンテン
装置;ウォーターズ(Waters)MS-trigger AutoPurification(登録商標)システム
カラム;ウォーターズ XTerra C18, 19X50 mm, 5μm粒子
方法A:メタノールまたはアセトニトリル/0.01%(v/v)アンモニア水溶液
方法B:メタノールまたはアセトニトリル/0.05%(v/v)ギ酸水溶液
低分解能マススペクトルデーター(ESI)は、以下の装置と条件で得る:装置;ZQまたはZMDマススペクトロメーターとUV検出器付きウォーターズ アライアンス(Alliance) HPLC システム。LC/MS/MSデータは、HPLC(Agilent 1100シリーズ)とオートサンプラー(AMR CTC-PAL)を備えたトリプル四重極質量分析計(AB SCIEXのAPI4000)で決定する。NMRデータは、特に明示しない限り、溶媒として重水素化クロロホルム(99.8%D)またはジメチルスルホキシド(99.9%D)を用いて27 0MHz((JEOL JNM-LA 270分光計)、または300 MHz(JEOL JNM-LA300分光計)または600 MHz (Bruker Avance 600)で測定し、データは、内部標準としてのテトラメチルシラン(TMS)に対して、parts per million(ppm)で示す。使用した慣用略語は、s=一重線、d=二重線、t=三重線、q=四重線、m=多重線、br.=ブロードなどである。化学記号は、M(モル/リットル)、L(リットル)、mL(ミリリットル)、g(グラム)、mg(ミリグラム)、mol(モル)、mmol(ミリモル)の通常の意味を示す。製造したそれぞれの化合物は、一般にChemBioDraw(Ultra, version 12.0, CambridgeSoft)によって命名する。
方法: QC1
装置:TUV検出器とZQ質量分析計を備えたWaters ACQUITY Ultra Performance LC
カラム:Waters ACQUITY C18、2.1x100mm、1.7μm粒子サイズ
カラム温度:60℃
流速:0.7 ml /分
実行時間:3分
UV検出:210 nm
MS検出:ESI陽イオン/陰イオンモード
移動相:
A1:10 mM酢酸アンモニウム
B1:アセトニトリル
濃度勾配プログラム:(QC_neutral_full_3分)
方法:QC2
装置: ZQ2000質量分析計と2996 PDA検出器とを備えたWaters 2795 Alliance HPLC
カラム:XBridge C18, 2.1 x 50 mm, 3.5μm粒子サイズ
カラム温度:45℃
流速:1.2 ml /分
実行時間:4.5分
UV検出:210から400 nmの走査
MS検出:ESI陽イオン/陰イオンモード
移動相:
A: 水
B: MeCN
C: 1% HCO2H水溶液
D: 1% NH3水溶液
濃度勾配プログラム:
適切な遷移金属触媒の例としては、テトラキス(トリフェニルホスフィン)パラジウム(0)、塩化ビス(トリフェニルホスフィン)パラジウム(II)、銅(0)、酢酸銅(I)、臭化銅(I)、塩化銅(I)、ヨウ化銅(I)、酸化銅(I)、トリフルオロメタンスルホン酸銅(II)、酢酸銅(II)、臭化銅(II)、塩化銅(II)、ヨウ化銅(II)、酸化銅(II)、トリフルオロメタンスルホン酸銅(II)、酢酸パラジウム(II)、塩化パラジウム(II)、ビス(アセトニトリル)ジクロロパラジウム(II)、ビス(ジベンジリデンアセトン)パラジウム(0)、トリス(ジベンジリデンアセトン)ジパラジウム(0)、および[1,1'-ビス(ジフェニルホスフィノ)フェロセン]パラジウム(II)ジクロリドが挙げられる。好ましい触媒は、テトラキス(トリフェニルホスフィン)パラジウム(0)、塩化ビス(トリフェニルホスフィン)パラジウム(II)、酢酸パラジウム(II)、塩化パラジウム(II)、ビス(アセトニトリル)ジクロロパラジウム(0)、ビス(ジベンジリデンアセトン)パラジウム(0)、トリス(ジベンジリデンアセトン)ジパラジウム(0)、および[1,1-ビス(ジフェニルホスフィノ)フェロセン]パラジウム(II)ジクロリドである。
無水溶媒および水−有機溶媒の共溶媒混合物のための好適な有機溶媒の例としては、THF;1,4-ジオキサン;DME;DMF; アセトニトリル;メタノールまたはエタノールなどのアルコール;DCM、1,2-ジクロロエタン、クロロホルムまたは四塩化炭素などのハロゲン化炭化水素;およびジエチルエーテルが挙げられる。この反応は、水酸化カリウム、水酸化ナトリウム、水酸化リチウム、炭酸水素ナトリウム、炭酸ナトリウム、炭酸カリウムおよびリン酸カリウムなどの塩基の存在下または非存在下に行われうる。この反応は、好適な添加剤の存在下または非存在下に行われうる。そのような添加剤としては、トリフェニルホスフィン、トリ-tert-ブチルホスフィン、1,1'-ビス(ジフェニルホスフィノ)フェロセン、トリ-2-フリルホスフィン、トリ-o-トリルホスフィン、2-(ジクロロヘキシルホスフィノ)ビフェニル、トリフェニルアルシン、テトラブチルアンモニウムクロリド、テトラブチルアンモニウムフルオリド、酢酸リチウム、塩化リチウム、トリエチルアミン、カリウムメトキシドまたはナトリウムメトキシド、水酸化ナトリウム, 炭酸セシウム、トリリン酸カリウム、炭酸ナトリウム、炭酸水素ナトリウム、および/またはヨウ化ナトリウムが挙げられる。反応は0℃〜200℃、より好ましくは、20℃〜150℃の温度で行われうる。反応時間は、一般的に5分〜96時間、より好ましくは、30分〜24時間である。あるいは、この反応は、塩基の存在下、不活性溶媒中において、マイクロ波システムで行われうる。この反応は100℃〜200℃、好ましくは、120℃〜150℃の温度で行われうる。反応時間は、一般的に10分〜3時間、好ましくは、15分〜1時間である。上記のスズキ‐ミヤハラカップリングの他、BR'w置換基のかわりにトリアルキルすずを用いたスティルクロスカップリング反応および亜鉛-ハロゲンを用いたネギシカップリング(ここでBR'w置換基のかわりにハロゲンとしては塩素、臭素、ヨウ素が用いられる)が使われうる。
1H-NMR (270MHz, DMSO-d6): δ10.77 (br.s, 1H), 8.53 (s, 1H), 2.20-1.65 (m, 8H).
1H-NMR (270 MHz, DMSO-d6): δ12.01 (br.s, 1H), 2.25-1.85 (m, 8H).
1H-NMR (270 MHz, CDCl3): δ5.79 (br.s, 1H), 3.38 (s, 2H), 2.35-1.75 (m, 8H).
1H-NMR (300 MHz, CDCl3): δ2.75 (s, 2H), 2.32-2.05 (m, 6H), 2.92-2.77 (m, 2H).
1H-NMR (300 MHz, CDCl3): δ8.08 (br s, 1H), 2.63 (s, 2H), 2.41-2.06 (m, 4H), 1.96-1.69 (m, 4H).
MS (ESI) m/z: 202.2 (M-H)-.
2-(4,4-ジフルオロ-1-ヒドロキシシクロヘキシル) -プロパン酸エチル
1H-NMR (270 MHz, CDCl3): δ4.19 (q, J = 7.3 Hz, 2H,), 3.33 (d, J = 2.0 Hz, 1H), 2.75-1.82 (m, 6H), 1.73-1.59 (m, 2H), 1.54-1.36 (m, 1H), 1.28 (t, J = 7.3 Hz, 3H), 1.23 (d, J = 7.3 Hz, 3H).
2-(4,4-ジフルオロ-1-ヒドロキシシクロヘキシル)プロパン酸
MS (ESI) m/z: 207.1 (M-H)-.
1H-NMR (270 MHz, CDCl3): δ5.61 (br s, 1H), 3.66 (q, J = 6.6 Hz, 1H), 2.38-1.95 (m, 6H), 1.88-1.59 (m, 2H), 1.20 (d, J = 6.6 Hz, 3H).
MS (ESI) m/z: 206.1 (M+H)+.
2-(4,4-ジフルオロ-1-ヒドロキシシクロヘキシル)-2-メチルプロパン酸エチル
MS (ESI) m/z: 249.1 (M-H)-.
2-(4,4-ジフルオロ-1-ヒドロキシシクロヘキシル)-2-メチルプロパン酸
MS (ESI) m/z: 221.1 (M-H)-.
1H-NMR (270 MHz, CDCl3): δ5.80 (br s, 1H), 2.33-2.02 (m, 6H), 1.80-1.60 (m, 2H), 1.27 (s, 3H), 1.27 (s, 3H).
MS (ESI) m/z: 220.2 (M+H)+.
2-(4,4-ジフルオロ-1-ヒドロキシシクロヘキシル)-3-メチルブタン酸エチル
2-(4,4-ジフルオロ-1-ヒドロキシシクロヘキシル)-3-メチルブタン酸
MS (ESI) m/z: 235.1 (M-H)-.
1H-NMR (270 MHz, CDCl3): δ6.37 (br s, 1H), 3.21 (d, J = 7.9 Hz, 1H), 2.35-2.18 (m, 1H), 2.18-1.98 (m, 5H), 1.98-1.73 (m, 3H), 1.00 (d, J = 6.6 Hz, 3H), 0.92 (d, J = 6.6 Hz, 3H).
MS (ESI) m/z: 234.2 (M+H)+.
1H-NMR (300 MHz, CDCl3): δ5.92 (s, 1H), 5.90 (s, 2H), 2.37 (s, 3H), 2.19 (s, 6H).
1H-NMR (270 MHz, CDCl3): δ 7.60-7.50 (m, 3H), 7.24-7.15 (m, 2H), 4.41 (q, J = 7.3 Hz, 2H), 2.32 (s, 3H), 2.23 (s, 3H), 1.42 (t, J = 7.3 Hz, 3H).
MS (ESI) m/z: 245.2 (M+H)+.
1H-NMR (270 MHz, CDCl3): δ9.07 (dd, J = 4.6, 1.3 Hz, 1H), 8.06 (d, J = 8.5 Hz, 2H), 7.84 (dd, J = 9.2, 4.6 Hz, 1H), 7.59-7.55 (m, 1H), 7.36 (d, J = 8.5 Hz, 2H), 2.60 (s, 3H).
MS (ESI) m/z: 246.3 (M+H)+.
2-クロロ-1-(2,5-ジメチル-1-(3-メチルイソオキサゾール-5-イル)-1H-ピロール-3-イル)エタノン
1H-NMR (270 MHz, CDCl3): δ6.31 (s, 1H), 6.10 (s, 1H), 4.45 (s, 2H), 2.46 (s, 3H), 2.41 (s, 3H), 2.15 (s, 3H).
MS (ESI) m/z: 253.17 (M+H)+ .
1H-NMR (270 MHz, CDCl3): δ7.62-7.52 (m, 3H), 7.24-7.17 (m, 2H), 4.88 (s, 2H), 2.35 (s, 3H), 2.21 (s, 3H).
MS (ESI) m/z: 249.2 (M+H)+.
(方法-A):ベンジルトリメチルアンモニウムジクロロヨウ素酸塩を用いた塩素化
中間体-6-1-A (INT-6-1-A: 1-(5-ブロモ-1-メチル-1H-ピロール-2-イル)-2-クロロエタノン
中間体-6-3-A (INT-6-3-A): 2-ブロモ-1-(1,4-ジメチル-5-フェニル-1H-ピロール-2-イル)エタノン
中間体-6-4-A (INT-6-4-A): 2-ブロモ-1-(5-ブロモ-1,4-ジメチル-1H-イミダゾール-2-イル)エタノン臭化水素酸塩
1H-NMR (270MHz, CDCl3): δ7.48-7.40 (m, 5H), 2.71 (s, 3H), 2.57 (s, 3H).
1H-NMR (270MHz, CDCl3): δ7.51-7.37 (m, 3H), 7.30-7.26 (m, 2H), 6.88 (s, 1H), 3.75 (s, 3H), 2.45 (s, 3H), 2.02 (s, 3H).
1H-NMR (270MHz, CDCl3): δ7.00 (s, 1H), 3.98 (s, 3H), 2.63 (s, 3H).
MS (ESI) m/z: 205.1 (M+H)+.
1H-NMR (270MHz, CDCl3): δ6.77 (s, 1H), 3.93 (s, 3H), 2.63 (s, 3H), 2.26 (s, 3H).
MS (ESI) m/z: 139.2 (M+H)+.
1H-NMR (270MHz, CDCl3): δ3.96 (s, 3H), 2.62 (s, 3H), 2.26 (s, 3H).
MS (ESI) m/z: 219.1 (M+H)+.
1H-NMR (600 MHz, CDCl3): δ6.70 (s, 1H), 3.91 (s, 3H), 2.61 (s, 3H), 1.88-1.82 (m, 1H), 0.91-0.86 (m, 2H), 0.73-0.69 (m, 2H).
MS (ESI) m/z: 165.2 (M+H)+.
1H-NMR (270MHz, CDCl3): δ3.94 (s, 3H), 2.57 (s, 3H), 1.92-1.80 (m, 1H), 0.95-0.88 (m, 4H).
MS (ESI) m/z: 243.1 (M+H)+.
1H-NMR (270MHz, CDCl3): δ7.11 (s, 1H), 3.95 (s, 3H), 2.63 (s, 3H).
MS (ESI) m/z: 159.2 (M+H)+.
1H-NMR (270 MHz, DMSO-d6): δ9.07 (dd, J = 4.6, 1.3 Hz, 1H), 8.06 (d, J = 8.5 Hz, 2H), 7.84 (dd, J = 9.2, 4.6 Hz, 1H), 7.59-7.55 (m, 1H), 7.36 (d, J = 8.5 Hz, 2H), 2.60 (s, 3H).
MS (ESI) m/z: 215.1 (M+H)+.
中間体-6-19 (INT-6-19): 1-(4-(2-メチル-3H-イミダゾ[4,5-b]ピリジン-3-イル)フェニル)エタノン
19-1 (INT-6-19-1): 1-(4-((2-ニトロフェニル)アミノ)フェニル)エタノン
1H-NMR (270 MHz, CDCl3): δ10.36 (br.s, 1H), 8.62-8.54 (m, 2H), 8.05-7.96 (m, 2H), 7.88-7.80 (m, 2H), 7.00-6.92 (m, 1H), 2.61 (s, 3H).
MS (ESI) m/z: 258.1 (M+H)+.
1H-NMR (270 MHz, DMSO-d6): δ8.28 (s, 1H), 7.85 (d, J = 8.5 Hz, 2H), 7.69 (d, J = 8.5 Hz, 2H), 7.57 (dd, J = 4.6, 1.3 Hz, 1H), 6.98 (dd, J = 7.9, 1.3 Hz, 1H), 6.75 (dd, J = 7.9, 4.6 Hz, 1H), 5.20 (s, 2H), 2.46 (s, 3H).
MS (ESI) m/z: 228.1 (M+H)+ .
1H-NMR (270 MHz, DMSO-d6): δ9.56 (s, 1H), 8.62 (s, 1H), 8.08 (d, J = 3.3 Hz, 1H), 7.89 (d, J = 9.2 Hz, 2H), 7.76-7.71 (m, 3H), 6.95 (dd, J = 7.3, 4.6 Hz, 1H), 2.50 (s, 3H), 2.12 (s, 3H).
MS (ESI) m/z: 270.1 (M+H)+.
1-(4-(2-メチル-3H-イミダゾ[4,5-b]ピリジン-3-イル)フェニル)エタノン
1H-NMR (270 MHz, DMSO-d6): δ8.25 (dd, J = 5.3, 1.3 Hz, 1H), 8.18 (d, J = 8.5 Hz, 2H), 8.06 (dd, J = 7.9, 1.3 Hz, 1H), 7.77 (d, J = 8.5 Hz, 2H), 7.32 (dd, J = 7.9, 5.3 Hz, 1H), 2.68 (s, 3H), 2.53 (s, 3H).
MS (ESI) m/z: 252.1 (M+H)+.
1H-NMR (270 MHz, DMSO-d6): δ9.07 (s, 1H), 8.49 (dd, J = 4.6, 1.3 Hz, 1H), 8.27-8.17 (m, 5H), 7.44 (dd, J = 7.9, 4.6 Hz, 1H), 2.66 (s, 3H).
MS (ESI) m/z: 238.1 (M+H)+.
1H-NMR (270 MHz, DMSO-d6): δ8.99 (s, 1H), 8.55 (d, J = 4.6 Hz, 1H), 8.22-8.19 (m, 3H), 7.92 (d, J = 8.6 Hz, 2H), 7.41 (dd, J = 7.9, 4.6 Hz), 2.67 (s, 3H).
MS (ESI) m/z: 238.3 (M+H)+.
1H-NMR (270 MHz, DMSO-d6): δ 9.19 (s, 1H), 9.12 (s, 1H), 8.51 (dd, J = 8.5, 1.3 Hz, 1H), 8.45 (d, J = 7.9 Hz, 1H), 8.13 (d, J = 8.5 Hz, 1H), 7.80 (d, J = 7.9 Hz, 1H), 7.46-7.35 (m, 2H), 2.68 (s, 3H).
MS (ESI) m/z: 238.1 (M+H)+.
1H-NMR (270 MHz, DMSO-d6): δ 9.25 (d, J = 2.0 Hz, 1H), 8.59-8.56 (m, 1H), 7.91 (d, J = 8.5 Hz, 1H), 7.68-7.65 (m, 1H), 7.55-7.52 (m, 1H), 7.29-7.25 (m, 2H), 2.72 (s, 3H), 2.65 (s, 3H).
MS (ESI) m/z: 252.0 (M+H)+.
1H-NMR (270 MHz, CDCl3): δ 10.46 (br. s, 1H), 8.45 (d, J = 7.9 Hz, 1H), 8.05-7.95 (m, 2H), 7.93-7.85 (m, 2H), 6.79 (d, J = 7.9 Hz, 1H), 2.61 (s, 3H), 2.59 (s, 3H).
MS (ESI) m/z: 272.1 (M+H)+.
1H-NMR (270 MHz, CDCl3): δ 7.90 (d, J = 8.6 Hz, 2H), 7.32 (d, J = 8.6 Hz, 2H), 7.01 (d, J = 7.9 Hz, 1H), 6.73 (d, J = 7.9 Hz, 1H), 6.65 (br.s, 1H), 3.33 (br.s, 2H), 2.55 (s, 3H), 2.43 (s, 3H).
MS (ESI) m/z: 242.2 (M+H)+.
1-(4-(2,5-ジメチル-3H-イミダゾ[4,5-b]ピリジン-3-イル)フェニル)エタノン
1H-NMR (270 MHz, CDCl3): δ 8.22-8.14 (m, 2H), 7.93 (d, J = 7.9 Hz, 1H), 7.77-7.69 (m, 2H), 7.17 (d, J = 7.9 Hz, 1H), 2.68 (s, 3H), 2.48 (s, 6H).
MS (ESI) m/z: 266.2 (M+H)+.
1H-NMR (270 MHz, CDCl3): δ 10.45 (br.s, 1H), 8.51 (d, J = 8.6 Hz, 1H), 8.08-7.97 (m, 2H), 7.87-7.75 (m, 2H), 6.92 (d, J = 8.6 Hz, 1H), 2.61 (s, 3H).
1H-NMR (270 MHz, DMSO-d6): δ8.45 (br.s, 1H), 7.90 (d, J = 8.6 Hz, 2H), 7.69 (d, J = 8.6 Hz, 2H), 7.01 (d, J = 7.9 Hz, 1H), 6.78 (d, J = 7.9 Hz, 1H), 5.35 (s, 2H), 2.50 (s, 3H).
MS (ESI) m/z: 262.2 (M+H)+.
1H-NMR (270 MHz, CDCl3): δ8.24-8.13 (m, 2H), 7.96 (d, J = 7.9 Hz, 1H), 7.60-7.50 (m, 2H), 7.27 (d, J = 7.9 Hz, 1H), 2.69 (s, 3H), 2.58 (s, 3H).
MS (ESI) m/z: 286.2 (M+H)+.
1H-NMR (270 MHz, DMSO-d6): δ8.29 (d, J = 7.9 Hz, 1H), 8.22 (d, J = 8.6 Hz, 2H), 7.95 (d, J = 7.9 Hz, 1H), 7.80 (d, J = 8.6 Hz, 2H), 2.69 (s, 3H), 2.58 (s, 3H).
MS (ESI) m/z: 277.3 (M+H)+.
1H-NMR (270 MHz, DMSO-d6): δ 10.37 (br.s, 1H), 8.74 (d, J = 8.6 Hz, 1H), 8.08-7.98 (m, 2H), 7.90-7.82 (m, 2H), 7.28 (dd, J = 8.6, 2.0 Hz, 1H), 2.62 (s, 3H).
MS (ESI) m/z: 296.2 (M+H)+.
1H-NMR (270 MHz, CDCl3): δ 8.24-8.16 (m 2H), 8.13 (d, J = 8.6 Hz, 1H), 7.70-7.64 (m, 1H), 7.62-7.55 (m, 2H), 2.70 (s, 3H), 2.65 (s, 3H).
MS (ESI) m/z: 320.1 (M+H)+.
1H-NMR (270 MHz, CDCl3): δ 8.39 (s, 1H), 8.35 (s, 3H), 8.04 (d, J = 8.6 Hz, 2H), 7.32 (d, J = 8.6 Hz, 2H), 2.59 (s, 3H), 2.36 (s, 3H).
MS (ESI) m/z: 229.13 (M+H)+.
1H-NMR (270 MHz, DMSO-d6): δ 9.04 (d, J = 4.6 Hz, 1H), 7.89 (d, J = 6.6 Hz, 1H), 7.84-7.76 (m, 2H), 7.63 (t, J = 7.9 Hz, 1H), 7.56-7.51 (m, 2H), 2.61 (s, 3H).
1H-NMR (270 MHz, CDCl3): δ 8.58-8.54 (m, 3H), 8.35 (d, J = 2.0 Hz, 1H), 7.61-7.53 (m, 1H), 7.41 (dd, J = 8.6, 4.6 Hz, 1H), 2.58 (s, 3H).
MS (ESI) m/z: 249.2 (M+H)+.
MS (ESI) m/z: 247.2 (M+H)+.
1H-NMR (270 MHz, DMSO-d6): δ 9.12 (d, J = 5.3 Hz, 1H), 8.11 (d, J = 8.6 Hz, 2H), 7.78 (d, J = 8.6 Hz, 2H), 7.69 (d, J = 5.3 Hz, 1H), 2.66 (s, 3H), 2.34 (s, 3H).
MS (ESI) m/z: 213.3 (M+H)+.
1H-NMR (270 MHz, DMSO-d6): δ 9.03 (s, 1H), 7.98 (d, J = 8.6 Hz, 2H), 7.81 (d, J = 8.6 Hz, 2H), 4.97 (s, 2H), 2.25-1.75 (m, 8H).
MS (ESI) m/z: 399.0 (M-H)-.
1H-NMR (270MHz, CDCl3): δ 4.48(s, 2H), 2.58 (s, 3H), 2.48 (s, 3H).
1H-NMR (270MHz, CDCl3): δ 6.88 (s, 1H), 4.42 (s, 2H), 3.95 (s, 3H), 2.07 (s, 3H).
1H-NMR (270MHz, CDCl3): δ 7.38 (s, 1H), 4.36 (s, 2H), 3.64 (s, 3H), 2.27 (s, 3H).
3-(2-(6-クロロピリジン-3-イル)-2-オキソエチル)-8,8-ジフルオロ-1,3-ジアザスピロ[4.5]デカン-2,4-ジオン
1H-NMR (270 MHz, DMSO-d6): δ 9.08 (d, J = 2.6 Hz, 1H), 9.04 (s, 1H), 8.41 (dd, J = 8.6, 2.6 Hz, 1H), 7.76 (d, J = 8.6 Hz, 1H), 5.05 (s, 2H), 2.25-1.65 (m, 8H).
MS (ESI) m/z: 358.2 (M+H)+.
MS (ESI) m/z: 282.9 (M+H)+.
1H-NMR (270 MHz, DMSO-d6): δ 8.82 (s, 1H), 8.77 (s, 1H), 8.71 (s, 1H), 6.19 (d, J = 5.3 Hz, 1H), 4.87 (td, J = 6.6, 5.3 Hz, 1H), 3.64 (ABqd, J = 13.8, 6.6 Hz, 2H), 2.20-1.65 (m, 8H).
MS (ESI) m/z: 406.8 (M+H)+.
1H-NMR (270 MHz, DMSO-d6): δ 9.09 (d, J = 1.3 Hz, 1H), 9.08 (s, 1H), 8.96 (s, 1H), 5.00 (s, 2H), 2.25-1.78 (m, 8H).
MS (ESI) m/z: 404.9 (M+H)+.
3-(2-(5-ブロモ-4-メチルチアゾール-2-イル)-2-オキソエチル)-8,8-ジフルオロ-1,3-ジアザスピロ[4.5]デカン-2,4-ジオン
MS (ESI) m/z: 258.0 (M+H)+.
1H-NMR (270MHz, DMSO-d6): δ 8.84 (br.s, 1H), 6.75 (d, J = 5.3 Hz, 1H), 4.95 (td, J = 7.2, 5.3 Hz, 1H), 3.58 (dd, J = 7.2, 1.3 Hz, 2H), 2.24 (s, 3H), 2.25-1.3 (m, 8H).
3-(2-(5-ブロモ-4-メチルチアゾール-2-イル)-2-オキソエチル)-8,8-ジフルオロ-1,3-ジアザスピロ[4.5]デカン-2,4-ジオン
1H-NMR (270MHz, CDCl3): δ 6.36 (br.s, 1H), 5.02 (s, 2H), 2.50 (s, 3H), 2.50-2.15 (m, 4H), 2.10-1.90 (m, 4H).
1H-NMR (270 MHz, DMSO-d6): δ 9.02 (s, 1H), 8.04 (d, J = 7.9 Hz, 2H), 7.84 (d, J = 7.9 Hz, 2H), 4.97 (s, 2H), 2.25-1.75 (m, 8H), 1.32 (s, 12H).
MS (ESI) m/z: 449.2 (M+H)+.
(2-オキソ-2-(4-(4,4,5,5-テトラメチル-1,3,2-ジオキサボロラン-2-イル)フェニル)エチル)-1-オキサ-3-アザスピロ[4.5]デカン-2-オン
1H-NMR (270 MHz, CDCl3): δ 7.51 (d, J = 7.9 Hz, 2H), 7.27 (d, J = 7.9 Hz, 2H), 5.03-4.92 (m, 1H), 3.59-3.23 (m, 4H), 2.90 (br.s, 1H), 2.31-1.95 (m, 6H), 1.83-1.68 (m, 2H).
MS (ESI) m/z: 390.1 (M+H)+.
1H-NMR (270 MHz, CDCl3): δ 7.80 (d, J = 8.6 Hz, 2H), 7.64 (d, J = 8.6 Hz, 2H), 4.67 (s, 2H), 3.47 (s, 2H), 2.38-2.00 (m, 6H), 2.00-1.80 (m, 2H).
MS (ESI) m/z: 390.1 (M+H)+.
INT-12-2-2(200 mg, 0.515 mmol)、ビス(ピナコラート)ジボロン(150 mg, 0.592 mmol)、PdCl2(dppf) CH2Cl2 (21 mg, 0.026 mmol)および酢酸カリウム(126 mg, 1.288 mmol)の混合物を1,4-ジオキサン(3 mL)中、80oCで3時間撹拌する。反応混合物(3 mLのジオキサン中)を次のスズキ-ミヤハラクロスカップリング反応に用いる。
3-(2-(4-(5,5-ジメチル-1,3,2-ジオキサボリナン-2-イル)フェニル)-2-オキソエチル)-1,3-ジアザスピロ[4.5]デカン-2,4-ジオン
3-(2-オキソ-2-(4-(4,4,5,5-テトラメチル-1,3,2-ジオキサボロラン-2-イル)フェニル)エチル)-1,3-ジアザスピロ[4.5]デカン-2,4-ジオン
8,8-ジフルオロ-3-(2-(3-フルオロ-4-(4,4,5,5-テトラメチル-1,3,2-ジオキサボロラン-2-イル)フェニル)-2-オキソエチル)-1,3-ジアザスピロ[4.5]デカン-2,4-ジオン
MS (ESI) m/z: 383.2 (M-H)- (ボロン酸誘導体として).
8,8-ジフルオロ-3-(2-(2-フルオロ-4-(4,4,5,5-テトラメチル-1,3,2-ジオキサボロラン-2-イル)フェニル)-2-オキソエチル)-1,3-ジアザスピロ[4.5]デカン-2,4-ジオン
8,8-ジフルオロ-3-(2-オキソ-2-(4-(4,4,5,5-テトラメチル-1,3,2-ジオキサボロラン-2-イル)フェニル)エチル)-1-オキサ-3-アザスピロ[4.5]デカン-2,4-ジオン
MS (ESI) m/z: 448.1 (M-H)-.
1H-NMR (270 MHz, CDCl3): δ 7.50 (d, J = 7.9 Hz, 2H), 7.28 (d, J = 7.9 Hz, 2H), 4.97 (dt, J = 7.9, 3.3 Hz, 1H), 3.52 (dd, J = 15.2, 3.3 Hz, 1H), 3.39 (dd, J = 15.2, 7.9 Hz, 1H), 3.19 (s, 2H), 3.20-3.14 (m, 1H), 1.85-1.63 (m, 4H), 1.60-1.32 (m, 6H).
MS (ESI) m/z: 356.0 (M+H)+.
1H-NMR (270 MHz, CDCl3): δ 7.81 (d, J = 8.5 Hz, 2H), 7.64 (d, J = 8.5 Hz, 2H), 4.65 (s, 2H), 3.39 (s, 2H), 2.00-1.32 (m, 10H).
MS (ESI) m/z: 354.0 (M+H)+.
MS (ESI) m/z: 387.9 (M+H-OH)+.
1H-NMR (270 MHz, CDCl3): δ 7.82 (d, J = 8.6 Hz, 2H), 7.65 (d, J = 8.6 Hz, 2H), 4.92 (d, J = 18.5 Hz, 1H), 4.33 (d, J = 18.5 Hz, 1H), 3.82 (q, J = 6.6 Hz, 1H), 2.40-1.98 (m, 6H), 1.93-1.66 (m, 2H), 1.15 (d, J = 6.6 Hz, 3H).
MS (ESI) m/z: 403.8 (M+H)+.
MS (ESI) m/z: 419.8 (M+H)+.
1H-NMR (270 MHz, CDCl3): δ 7.83 (d, J = 8.6 Hz, 2H), 7.65 (d, J = 8.6 Hz, 2H), 4.52 (s, 2H), 2.39-2.02 (m, 6H), 1.85-1.64 (m, 2H), 1.17 (s, 6H).
MS (ESI) m/z: 417.8 (M+H)+.
MS (ESI) m/z: 433.8 (M+H)+.
1H-NMR (270 MHz, CDCl3): δ 7.81 (d, J = 8.6 Hz, 2H), 7.65 (d, J = 8.6 Hz, 2H), 5.22 (d, J = 18.5 Hz, 1H), 4.40 (d, J = 18.5 Hz, 1H), 3.60 (d, J = 2.0 Hz, 1H), 2.62-2.49 (m, 1H), 2.41-1.72 (m, 8H), 1.04 (d, J = 6.6 Hz, 6H).
MS (ESI) m/z: 431.8 (M+H)+.
1H-NMR (270 MHz, DMSO-d6): δ 10.58 (br.s, 1H), 8.98 (s, 1H), 7.92 (d, J = 8.6 Hz, 2H), 6.89 (d, J = 8.6 Hz, 2H), 4.84 (s, 2H), 2.25-1.70 (m, 8H).
MS (ESI) m/z: 339.06 (M+H)+.
1H-NMR (270 MHz, DMSO-d6): δ 10.1 (s, 1H), 8.63-8.59 (m, 2H), 8.01 (d, J = 8.5 Hz, 2H), 7.90 (d, J = 8.5 Hz, 2H), 7.14 (dd, J = 7.9, 4.6 Hz, 1H), 4.89 (s, 2H).
MS (ESI) m/z: 337.9 (M+H)+.
1H-NMR (270 MHz, DMSO-d6): δ 10.2 (s, 1H), 9.02 (s, 1H), 8.62-8.57 (m, 2H), 8.05 (d, J = 8.5 Hz, 2H), 7.94 (d, J = 8.5 Hz, 2H), 7.15 (dd, J = 7.9, 4.6 Hz, 1H), 4.94 (s, 2H), 2.18-1.81 (m, 8H).
MS (ESI) m/z: 460.0 (M+H)+.
1H-NMR (270 MHz, DMSO-d6): δ 8.98 (s, 1H), 8.41 (s, 1H), 7.92 (d, J = 9.2 Hz, 2H), 7.72 (d, J = 9.2 Hz, 2H), 7.59 (dd, J = 4.6, 1.3 Hz, 1H), 7.02-6.98 (m, 1H), 6.78 (dd, J = 7.9, 4.6 Hz, 1H), 5.22 (s, 2H), 4.84 (s, 2H), 2.17-1.85 (m, 8H).
MS (ESI) m/z: 430.1 (M+H)+ .
1H-NMR (270 MHz, DMSO-d6): δ 10.23 (br.s, 1H), 8.53-8.45 (m, 1H), 8.06-7.92 (m, 4H), 7.04-6.96 (m, 1H), 4.90 (s, 2H), 2.52 (s, 3H).
MS (ESI) m/z: 350.1 (M+H)+.
1H-NMR (270 MHz, DMSO-d6): δ 10.25 (br.s, 1H), 9.02 (br.s, 1H), 8.53-8.46 (m, 1H), 8.10-7.95 (m, 4H), 7.05-6.97 (m, 1H), 4.94 (s, 2H), 2.53 (s, 3H), 2.27-1.75 (m, 8H).
MS (ESI) m/z: 474.0 (M+H)+.
1H-NMR (270 MHz, DMSO-d6): δ 8.98 (br.s, 1H), 8.37 (br.s, 1H), 7.92 (d, J = 8.6 Hz, 2H), 7.74 (d, J = 8.6 Hz, 2H), 6.93 (d, J = 7.9 Hz, 1H), 6.63 (d, J = 7.9 Hz, 1H), 4.98 (br.s, 2H), 4.84 (br.s, 2H), 2.29 (s, 3H), 2.26-1.75 (m, 8H).
MS (ESI) m/z: 444.0 (M+H)+.
1H-NMR (270 MHz, CDCl3): δ 8.00 (d, J = 7.9 Hz, 2H), 7.86 (d, J = 7.9 Hz, 1H), 7.53-7.46 (m, 4H), 7.30 (d, J = 7.3 Hz, 1H), 6.56 (s, 1H), 4.97 (s, 2H), 2.48-2.21 (m, 4H), 2.12-1.90 (m, 4H), 1.29 (s, 9H).
MS (ESI) m/z: 497.2 (M-H)-.
MS (ESI) m/z: 441.2 (M-H)-
MS (ESI) m/z: 480.3 (M-H)-.
1H-NMR (270 MHz, DMSO-d6): δ 9.05 (br.s, 1H), 8.30 (d, J = 8.6 Hz, 2H), 8.09 (d, J = 7.9 Hz, 1H), 7.85 (d, J = 8.6 Hz, 2H), 7.29 (d, J = 7.9 Hz, 1H), 5.09 (br.s, 2H), 4.96 (br.s, 2H), 2.52 (s, 3H), 2.28-1.78 (m, 8H).
MS (ESI) m/z: 502.2 (M+H)+.
MS (ESI) m/z: 512.0 (M+H)+.
MS (ESI) m/z: 526.3 (M+H)+.
1H-NMR (270 MHz, DMSO-d6): δ 8.95 (s, 1H), 6.70 (s, 1H), 6.65 (s, 1H), 4.59 (s, 2H), 2.52 (s, 3H), 2.36 (s, 3H), 2.12 (s, 3H), 2.25-1.70 (m, 8H).
MS (ESI) m/z: 421.3 (M+H)+.
1H-NMR (270 MHz, DMSO-d6): δ 8.79 (s, 1H), 8.15 (t, J = 7.2 Hz, 1H), 7.73 (d, J = 6.6 Hz 1H), 7.62 (d, J = 7.2 Hz, 1H), 6.61 (s, 1H), 4.56 (s, 2H), 2.29 (s, 3H), 2.06 (s, 3H), 1.72-1.57 (m, 8H).
MS (ESI) m/z: 415.2 (M+H)+.
観察されたMS: 451.2
tR/方法: 1.86分/(QC1)
観察されたMS: 480.2
tR/方法: 1.58分/(QC1)
1H-NMR (270 MHz, DMSO-d6): δ 8.71 (s, 1H), 7.89-7.74 (m, 3H), 7.36-7.17 (m, 8H), 6.74-6.70 (m, 2H), 6.27 (s, 1H), 4.50 (s, 2H), 4.09 (s, 2H), 2.51 (s, 3H).
MS (ESI) m/z: 375.1 (M+H)+.
1H-NMR (270 MHz, DMSO-d6): δ 8.18 (d, J = 8.5 Hz, 2H), 7.80-7.75 (m, 3H), 7.34-7.25 (m, 6H), 7.14-7.11 (m, 2H), 4.72 (s, 2H), 4.45 (s, 2H), 2.68 (s, 3H), 2.46 (s, 3H).
MS (ESI) m/z: .357.1 (M+H)+ .
MS (ESI) m/z: 270.1 (M+H)+.
1H-NMR (270 MHz, DMSO-d6): δ 9.06 (s, 1H), 8.30 (d, J = 8.5 Hz, 2H), 7.84 (d, J = 8.5 Hz, 2H), 7.32-7.28 (m, 4H), 5.61 (t, J = 5.9 Hz, 1H), 5.07 (s, 2H), 4.65 (d, J = 5.9 Hz, 2H), 2.19-1.76 (m, 8H).
MS (ESI) m/z: 469.1 (M+H)+.
MS (ESI) m/z: 493.9 (M+H)+.
観察されたMS: 466.5
tR/方法: 1.37分/(QC1)
中性化合物の精製:アミンシリカゲルを用いる短時間のろ過またはカラムクロマトグラフィーによる精製。
塩基性化合物の精製:残渣をSCXカートリッジ(Varian Bond Elute, 1 g/6 mL)上に供し、1mLのMeOHで調整し、5 mLのMeOHですすぎ、5 mLの1M NH3/MeOHで溶出する。揮発性物質を窒素気流で留去し、粗生成物を得る。必要ならば、SCXを用いる精製前にカラムクロマトグラフィーによる精製を行う。
さらなる精製は、LC-MS分取用システムにより常法で行う。HPLC-QC法による保持時間および観察されたMSは表20により記載されている。
1H-NMR (270 MHz, CDCl3): δ 8.01 (d, J = 2.7 Hz, 1H), 7.93 (d, J = 2.7 Hz, 1H), 4.75 (t, J = 3.0 Hz, 1H), 4.65-4.55 (m, 2H), 4.19-4.05 (m, 1H), 4.00-3.80 (m, 2H), 3.60-3.50 (m, 1H), 1.89-1.48 (m, 6H).
MS (ESI) m/z: 545.2 (M+H)+.
1H-NMR (270 MHz, CDCl3): δ 8.33 (d, J = 2.6 Hz, 1H), 8.24 (d, J = 8.6 Hz, 2H), 8.11 ( d, J = 2.6 Hz, 1H), 8.05 (d, J = 8.6 Hz, 2H), 6.05 (br.s, 1H), 4.97 (s, 2H), 4.65-4.57 (m, 2H), 4.08-4.00 (m, 2H), 2.58-2.19 (m, 5H), 2.12-1.90 (m, 4H).
観察されたMS: 459.3
tR/方法: 1.41分/(QC1)
1H-NMR (270 MHz, CDCl3): δ 8.04 (d, J = 8.5 Hz, 2H), 7.50-7.35 (m, 4H), 7.28-7.24 (m, 2H), 6.94 (br.s, 1H), 4.98 (s, 2H), 4.68 (br.s, 1H), 4.29 (d, J = 5.3 Hz, 2H), 2.38-2.24 (m, 4H), 2.04-1.98 (m, 4H), 1.63 (s, 3H), 1.43 (s, 9H).
MS (ESI) m/z: 526.4 (M-H)-.
1H-NMR (270 MHz, DMSO-d6): δ 9.05 (s, 1H), 8.33 (s, 2H), 8.16 (d, J = 8.5 Hz, 2H), 7.71 (d, J = 7.2 Hz, 1H), 7.62-7.48 (m, 4H), 7.37 (d, J = 7.2 Hz, 1H), 5.03 (s, 2H), 3.97 (s, 2H), 2.19-1.81 (m, 8H).
MS (ESI) m/z: 428.3 (M+H)-.
MS (ESI) m/z: 429.29 (M+H)+.
1H-NMR (270 MHz, CDCl3): δ 8.64-8.58 (m, 1H), 8.10-8.00 (m, 2H), 7.62-7.55 (m, 1H), 7.53-7.45 (m, 2H), 7.36-7.28 (m, 1H), 7.00 (br.s, 1H), 6.00 (br.s, 1H), 4.96 (s, 2H), 4.38 (d, J = 3.9 Hz, 2H), 2.50-1.90 (m, 8H), 1.65 (s, 3H), 1.43 (s, 9H).
MS (ESI) m/z: 529.41 (M+H)+.
1H-NMR (270 MHz, DMSO-d6): δ 9.03 (br.s, 1H), 8.65-8.60 (m, 1H), 8.18-8.10 (m, 2H), 7.75-7.40 (m, 3H), 7.44-7.35 (m, 1H), 5.02 (s, 2H), 3.73 (s, 2H), 2.30-1.75 (m, 8H). (NHに由来するシグナルは観測されない。)
観察されたMS: 427.3
tR/方法: 1.23分/(QC1)
さらなる精製は、LC-MS分取用システムにより常法で行う。
1H-NMR (270MHz, DMSO-d6): δ 9.03 (s, 1H), 8.65-8.60 (m, 1H), 8.24-8.20 (m, 1H), 8.18-8.10 (m, 2H), 7.75-7.60 (m, 3H), 7.48-7.40 (m, 1H), 5.03 (s, 2H), 4.32 (d, J = 4.3 Hz, 2H), 2.30-1.75 (m, 8H), 1.80 (s, 3H).
観察されたMS: 469.4
tR/方法: 1.33分/(QC1)
1H-NMR (270 MHz, DMSO-d6): δ 9.02 (s, 1H), 8.59 (d, J = 5.3 Hz, 1H), 8.43 (s, 1H), 8.14 (d, J = 7.9 Hz, 2H), 7.64 (d, J = 7.9 Hz, 2H), 7.51 (t, J = 5.3 Hz, 1H), 7.39 (d, J = 4.6 Hz, 1H), 5.02 (s, 2H), 4.11 (d, J = 5.3 Hz, 2H), 2.17-1.86 (m, 8H), 1.36 (s, 9H).
MS (ESI) m/z: 529.3 (M-H)-.
観察されたMS: 427.4
tR/方法: 1.19分/(QC1)
INT-8-3-A (30 mg, 0.093 mmol)のDME(1 mL)溶液にN-メチル-m-トルイジン(12 mg, 0.103mmol)、カリウムtert-ブトキシド(16 mg, 0.140 mmol)およびPd-PEPPSI(商標)-IPr (1.3 mg, 1.86 mmol)を加える。混合物を140oCで30分マイクロ波反応装置(Biotage Initiator)で照射する(または油浴中、100-150oCで3-15時間加熱する)。混合物を水で反応を停止し、セライトパッドを通してろ過する。ろ過ケーキをEtOAcで洗い、ろ液および洗液を食塩水で洗い、硫酸ナトリウムで乾燥し、ろ過し、減圧で濃縮する。残渣をヘキサン中10-100% EtOAcで溶出するシリカゲルカラムクロマトグラフィーにより精製し、表題化合物(13 mg, 34%収率)を得る。さらなる精製は、LC-MS分取用システムにより常法で行う。
観察されたMS: 405.4
tR/方法: 1.76分/(QC1)
観察されたMS: 417.7
tR/方法: 1.56分/(QC1)
観察されたMS: 439.3
tR/方法: 1.53分/(QC1)
3-(2-(4-((3-クロロピリジン-2-イル)オキシ)フェニル)-2-オキソエチル)-8,8-ジフルオロ-1,3-ジアザスピロ[4.5]デカン-2,4-ジオン
観察されたMS: 448.2
tR/方法: 1.68分/(QC1)
8,8-ジフルオロ-3-(2-(4-((4-メチルピリダジン-3-イル)オキシ)フェニル)-2-オキソエチル)-1,3-ジアザスピロ[4.5]デカン-2,4-ジオン
観察されたMS: 431.2
tR/方法: 1.43分/(QC1)
3-(4-(2-(8,8-ジフルオロ-2,4-ジオキソ-1,3-ジアザスピロ[4.5]デカン-3-イル)アセチル)フェノキシ)ピリダジン-4-カルボニトリル
観察されたMS: 442.2
tR/方法: 1.43分/(QC1)
8,8-ジフルオロ-3-(2-オキソ-2-(4-(チアゾール-2-イルオキシ)フェニル)エチル)-1,3-ジアザスピロ[4.5]デカン-2,4-ジオン
観察されたMS: 422.1
tR/方法: 1.56分/(QC1)
8,8-ジフルオロ-3-(2-オキソ-2-(4-(ピリジン-3-イルオキシ)フェニル)エチル)-1,3-ジアザスピロ[4.5]デカン-2,4-ジオン
観察されたMS: 416.4
tR/方法: 1.47分/(QC1)
8,8-ジフルオロ-3-(2-オキソ-2-(4-(ピリジン-3-イルメトキシ)フェニル)エチル)-1,3-ジアザスピロ[4.5]デカン-2,4-ジオン
観察されたMS: 430.1
tR/方法: 1.45分/(QC1)
8,8-ジフルオロ-3-(2-オキソ-2-(4-(ピリジン-4-イルメトキシ)フェニル)エチル)-1,3-ジアザスピロ[4.5]デカン-2,4-ジオン
観察されたMS: 430.2
tR/方法: 1.44分/(QC1)
8,8-ジフルオロ-3-(2-オキソ-2-(4-(ピリミジン-2-イルメトキシ)フェニル)エチル)-1,3-ジアザスピロ[4.5]デカン-2,4-ジオン
観察されたMS: 431.2
tR/方法: 1.34分/(QC1)
8,8-ジフルオロ-3-(2-オキソ-2-(4-(2-オキソ-1H-イミダゾ[4,5-b]ピリジン-3(2H)-イル)フェニル)エチル)-1,3-ジアザスピロ[4.5]デカン-2,4-ジオン
観察されたMS: 454.4
tR/方法: 1.34 分/(QC1)
8,8-ジフルオロ-3-(2-(4-(5-メチル-2-オキソ-1H-イミダゾ[4,5-b]ピリジン-3(2H)-イル)フェニル)-2-オキソエチル)-1,3-ジアザスピロ[4.5]デカン-2,4-ジオン
観察されたMS: 470.4
tR/方法: 1.42分/(QC1)
3-(2-(4-(2-(ジフルオロメチル)-1H-ベンゾ[d]イミダゾール-1-イル)フェニル)-2-オキソエチル)-8,8-ジフルオロ-1,3-ジアザスピロ[4.5]デカン-2,4-ジオン
観察されたMS: 490.1
tR/方法: 2.05分/(QC2)
8,8-ジフルオロ-3-(2-オキソ-2-(4-(2-(トリフルオロメチル)-3H-イミダゾ[4,5-b]ピリジン-3-イル)フェニル)エチル)-1,3-ジアザスピロ[4.5]デカン-2,4-ジオン
観察されたMS: 508.6
tR/方法: 1.58分/(QC1)
8,8-ジフルオロ-3-(2-(4-(5-メチル-2-(トリフルオロメチル)-3H-イミダゾ[4,5-b]ピリジン-3-イル)フェニル)-2-オキソエチル)-1,3-ジアザスピロ[4.5]デカン-2,4-ジオン
観察されたMS: 522.7
tR/方法: 1.67分/(QC1)
3-(2-(4-(2-((ジメチルアミノ)メチル)-5-メチル-3H-イミダゾ[4,5-b]ピリジン-3-イル)フェニル)-2-オキソエチル)-8,8-ジフルオロ-1,3-ジアザスピロ[4.5]デカン-2,4-ジオン
観察されたMS: 511.7
tR/方法: 1.48分/(QC1)
8,8-ジフルオロ-3-(2-(4-(2-メトキシ-3H-イミダゾ[4,5-b]ピリジン-3-イル)フェニル)-2-オキソエチル)-1,3-ジアザスピロ[4.5]デカン-2,4-ジオン
さらなる精製は、LC-MS分取用システムにより常法で行う。
観察されたMS: 470.2
tR/方法: 2.02分/(QC2)
3-(4-(2-(8,8-ジフルオロ-2,4-ジオキソ-1,3-ジアザスピロ[4.5]デカン-3-イル)アセチル)フェニル)-2-メチル-3H-イミダゾ[4,5-b]ピリジン-5-カルボニトリル
MS (ESI) m/z: 479.3 (M+H)+.
さらなる精製は、LC-MS分取用システムにより常法で行う。
観察されたMS: 479.2
tR/方法: 1.96分/(QC2)
3-(2-(4-(2-(ジメチルアミノ)-5-メチル-3H-イミダゾ[4,5-b]ピリジン-3-イル)フェニル)-2-オキソエチル)-8,8-ジフルオロ-1,3-ジアザスピロ[4.5]デカン-2,4-ジオン
観察されたMS: 497.8
tR/方法: 1.51分/(QC1)
N-(2-((4-(2-(8,8-ジフルオロ-2,4-ジオキソ-1,3-ジアザスピロ[4.5]デカン-3-イル)アセチル)フェニル)アミノ)ピリジン-3-イル)アセトアミド
1H-NMR (270 MHz, DMSO-d6): δ 9.56 (s, 1H), 8.98 (s, 1H), 8.71 (s, 1H), 8.14-8.08 (m, 1H), 7.97 (d, J = 8.6 Hz, 2H), 7.82-7.72 (m, 3H), 7.02-6.95 (m, 1H), 4.87 (s, 2H), 2.25-1.75 (m, 11H, δ 2.12 (s, 3H)).
MS (ESI) m/z: 472.2 (M+H)+.
さらなる精製は、LC-MS分取用システムにより常法で行う。
観察されたMS: 472.7
tR/方法: 1.35分/(QC1)
3-(2-(4-(2-アセチルイソインドリン-4-イル)フェニル)-2-オキソエチル)-8,8-ジフルオロ-1,3-ジアザスピロ[4.5]デカン-
2,4-ジオン
1H-NMR (270 MHz, CDCl3): δ 8.10-8.06 (m, 2H), 7.61-7.53 (m, 2H), 7.49-7.27 (m, 3H), 6.67 (br s, 1H), 5.00-4.93 (m, 2H), 4.93-4.80 (m, 4H), 2.50-1.90 (m, 11H).
MS (ESI) m/z: 482.0 (M+H)+.
さらなる精製は、LC-MS分取用システムにより常法で行う。
観察されたMS: 482.3
tR/方法: 1.51分/(QC1)
8,8-ジフルオロ-3-(2-(4-(2-(ヒドロキシメチル)-3H-イミダゾ[4,5-b]ピリジン-3-イル)フェニル)-2-オキソエチル)-1,3-ジアザスピロ[4.5]デカン-2,4-ジオン
観察されたMS: 470.3
tR/方法: 1.27分/(QC1)
8,8-ジフルオロ-3-(2-(4-(2-(ヒドロキシメチル)-5-メチル-3H-イミダゾ[4,5-b]ピリジン-3-イル)フェニル)-2-オキソエチル)-1,3-ジアザスピロ[4.5]デカン-2,4-ジオン
観察されたMS: 484.6
tR/方法: 1.33分/(QC1)
4'-(2-(8,8-ジフルオロ-2,4-ジオキソ-1,3-ジアザスピロ[4.5]デカン-3-イル)アセチル)-N,N-ジメチル-[1,1'-ビフェニル]-2-カルボキサミド
観察されたMS: 470.7
tR/方法: 1.49分/(QC1)
ヒトTRPM8を安定発現したHEK293細胞を5%CO2で加湿した培養器においてT175フラスコ内で37℃で約80%コンフルエントまで増殖させる。培地の組成は、Dulbecco改変イーグル培地(高グルコース)、10%ウシ胎仔血清(FCS)、100単位/mlペニシリン、100μg/mLストレプトマイシン、および600μg/mLジェネティシンからなった。アッセイの24時間前に、細胞(1ウェルに30,000細胞の密度で、ポリ-D-リジンでコートした384ウェルプレート(BDファルコン)に播き、5%CO2、37℃で培養する。アッセイ当日、培養培地を除き、細胞に0.5μM Fluo4-AM(モレキュラープローブ)および0.005% Pluronic F-127を含むアッセイ緩衝液(ハンクス平衡塩類溶液(HBSS)、19.4 mM HEPES pH7.4、2.5 mM プロベネシド)を加え室温に1時間置く。アッセイ緩衝液で洗浄した後、細胞を種々の化合物濃度で5分間予備培養した。30μMメントールの添加による細胞内カルシウム濃度の変化を、浜松ホトニクスの機能的薬物スクリーニングシステム(Functional Drug Screening System (FDSS))を用いた細胞イメージング技術によってモニターした。
本発明の化合物のIC50値は、11点の用量反応試験から決定する。曲線は、データの点ごとに2つのウエルの平均を使って描く。最後に、IC50値は、XLfit(IDビジネス・ソリューション社)により決定された最適用量曲線を用いて計算した。
G-361細胞を、5%CO2を含む加湿した培養器において、T175フラスコ内で37℃で約80%コンフルエントまで増殖させた。培地の組成は、マッコイの5A培地と10%のFCSからなる。アッセイの48時間前に、細胞を1ウェルに12,000細胞の密度で、ポリ-D-リジンでコートした98ウェルプレート(コーニング社)に播き、5%CO2、37℃で培養する。アッセイ当日、培養培地を除き、細胞に0.5μM Fluo4-AM(モレキュラープローブ)および0.005% Pluronic F-127を含むアッセイ緩衝液(HBSS、HBSS、2.5 mM プロベネシド)を加え室温に1時間置く。アッセイ緩衝液で洗浄した後、細胞を種々の化合物濃度で5分間予備培養する。300μMメントールの添加による細胞内カルシウム濃度の変化を、FDSSを用いた細胞イメージング技術によってモニターする。
本発明の化合物のIC50値は、用量反応試験から決定する。曲線は、データの点ごとに2つのウエルの平均を使って描く。最後に、IC50値は、XLfit(IDビジネス・ソリューション社)により決定された最適用量曲線を用いて計算した。
被験化合物の投与後60分間の排尿間隔から計算される排尿頻度を膀胱内圧測定データから分析した。被験化合物による排尿頻度の抑制は、ベヒクルに対してダネット検定を使用して評価した。有意水準5%以下を有意な差として認める。データは、8〜12匹のラットからの平均±SEMとして分析する。
ヒトHERG発現HEK293S細胞を施設内で調製し、増殖する。収集した細胞を、50 mM Tris-HCl(4℃でpH7.4)に懸濁し、全出力に設定した手持式Polytron PT1200粉砕装置を用いて、氷上で20秒間ホモジナイズする。そのホモジネートを48000×g、4℃で20分間遠心分離する。その後、ペレットを同じように再懸濁し、ホモジナイズし、遠心分離する。最終ペレットを、適量の50 mM Tris-HCl、10 mM KCl、1 mM MgCl2(4℃でpH7.4)に再懸濁し、ホモジナイズし、少量ずつ小分けし、使用するまで−80℃で貯蔵する。この膜画分のタンパク質濃度定量には、BCAタンパク質アッセイキット(PIERCE)、およびARVOsxプレートリーダー(Wallac)を用いる。結合アッセイは、384ウェルプレートにおいて総量30μLで行う。結合活性は、PHERAstar カウンタ(BMG LABTECH)で蛍光分極技術を用いて測定する。10μLの被験化合物を10μLの蛍光リガンド(Cy3Bで標識した6 nMのドフェチィライド誘導体)および10μLの膜ホモジネート(6μgタンパク)と室温120分間インキュベートする。非特異的な結合は、最終濃度で10μMのE4031によって求める。
本発明の全ての試験された化合物は、上記のTRPM8機能アッセイにおけるIC50値より、ヒトドフェチリド結合において高いIC50値を示す。
ヒト肝ミクロソーム(HLM)中の半減期
試験化合物(1μM)を、96ディープウェルプレートにおいて、37℃で100 mMリン酸カリウム緩衝液(pH7.4)中、1 mM MgCl2および0.78 mg/mL HLM(HL101)または0.74 mg/mL HLM (Gentest UltraPool 150)または0.61 mg/mL HLM (XenoTech XTreme 200)と共にインキュベートする。反応混合物を、必要に応じ非P450群とP450群の2群に分ける。P450群の反応混合物にのみNADPHを添加する。(NADPH生成システムもまた、NADPHの代わりに使用する。)P450群のサンプルの一部分を、0分、10分、30分、および60分の時点で採取するが、ここで0分の時点はP450群の反応混合物にNADPHを添加した時間を示す。非P450群のサンプルの一部分を、−10分および65分の時点で採取する。採取した一部分を、内部標準を含有するアセトニトリル溶液で抽出する。析出したタンパク質を遠心分離機(2000 rpm、15分)で沈降させる。上澄みの化合物濃度を、LC/MS/MSシステムで測定する。
この方法は、3 μMまたは0.4〜50 μMの各化合物における、プローブ(CYP1A2に対してタクリン2 μMまたはフェナセチン50μM、CYP2B6に対してブプロピオン3 μM、CYP2C8に対してアモジアキン2 μM、CYP2C9に対してジクロフェナック5 μMまたは10 μM、CYP2C19に対してS-メフェニトイン40 μM、CYP2D6に対してデキストロメトルファン5 μMまたはブフラロール5 μM、およびCYP3A4に対してミダゾラム2 μMまたは2.5 μM)からの代謝物生成の阻害率%を実質的に決める。
上清中の代謝物の濃度は、LC/MS/MSシステムにより測定する。薬物−薬物相互作用の程度は、試験化合物の存在下または非存在下で代謝物の生成%に基づいて解釈する。
本発明の化合物は、好ましい安定性を示し、これは上述の実用性を示す。
試験化合物(1 μM)の血漿タンパク結合は、96ウエルプレートタイプの装置を用いて平衡透析法により測定する。HTD96a(登録商標)、すなわち再生セルロース膜(分子量カットオフ12,000〜14,000、22 mm×120 mm)を蒸留水に一晩浸し、次いで30%エタノールに15分間、最後に透析緩衝液(ダルベッコのリン酸緩衝生理食塩水、CaCl2およびMgCl2不含有)に20分間浸す。ヒト、Sprague-Dawleyラット、およびビーグル犬の凍結血漿を使用する。透析装置を組み立て、各ウエルの片側に化合物を入れた血漿150μLを加え、その反対側のウエルに透析緩衝液150μLを加える。150 rpm、37℃で4時間インキュベーションした後、血漿と緩衝液の一部を採取する。血漿中および緩衝液中の化合物を分析用に内部標準化合物を含む、300μLのアセトニトリルまたはアセトニトリル/メタノール(1/1)で抽出する。化合物の濃度をLC/MS/MS分析で決定する。
化合物の非結合率は、次式(A)または(B)で計算する。
Cis,pは、血漿試料中の内部標準のピーク面積であり;
Cbは、緩衝液試料中の化合物のピーク面積であり;
Cis,bは、緩衝液試料の内部標準のピーク面積であり;
4および4/3は、それぞれ血漿および緩衝液で希釈率の逆数である。
本発明の化合物は、好ましい血漿タンパク結合を示し、これは上述の実用性を示す。
各化合物のDMSO溶液(2μL、30 mM)を96ウエルガラス底プレートの各ウエルに分注する。リン酸カリウム緩衝液(50mM、198 μL、pH6.5)を各ウエルに添加し、混合物を24時間、回転振とうしながら37℃でインキュベートする。2000×gで5分間遠心分離後、上清をポリカーボネートイソ−ポアメンブレンを通してろ過される。試料の濃度は、通常の勾配をかけたHPLC法(J. Pharm. Sci., 95, 2115-2122, 2006)によって決定する。
Claims (15)
- 式(I)の化合物
Aは、アリール又はヘテロアリール;
Bは、アリール又はヘテロアリール;
Lは、化学結合、酸素、硫黄、-NR4-、-(CRCRD)t-、-O(CRCRD)t-、-(CRCRD)tO-、-N(R4)(CRCRD)t-、-(CRCRD)tN(R4)-、-N(R4)(CRCRD)tO-、および -O(CRCRD)t N(R4)-からなる群から独立に選ばれ;
Xは、-CH2-、酸素、硫黄、およびNHからなる群から独立に選ばれ;
RAおよびRBは、(1) 水素、(2) ハロゲン、(3) (C1-C10)アルキル、(4) (C3-C10)シクロアルキルおよび(5) (C1-C10)ハロアルキルからなる群から独立に選ばれ;またはRAおよびRBは、オキソ基(=O)を形成してもよく;またはRAおよびRBは、酸素原子、硫黄原子、および窒素原子から独立に選ばれる1つ以上のヘテロ原子を含んでもよい3〜8員環を形成してもよく;ここで該環は、(1) 水素、(2) ハロゲン、(3) ヒドロキシ、(4) (C1-C10)アルキル、(5) (C3-C10)シクロアルキル、(6) (C1-C10)ハロアルキル、(7) (C1-C10)アルコキシおよび(8) (C1-C10)ハロアルコキシから独立に選ばれる1〜6個の置換基で置換されていてもよく;
RCおよびRD は、(1) 水素、(2) ハロゲン、(3) (C1-C10)アルキル、(4) (C3-C10)シクロアルキルおよび(5) (C1-C10) ハロアルキルからなる群から独立に選ばれ;または、RCおよびRDは、酸素原子、硫黄原子、および窒素原子から独立に選ばれる1つ以上のヘテロ原子を含んでもよい3〜8員環を形成してもよく;ここで該環は、(1) 水素、(2) ハロゲン、(3) ヒドロキシ、(4) (C1-C10)アルキル、(5) (C3-C10)シクロアルキル、(6) (C1-C10)ハロアルキル、(7) (C1-C10)アルコキシおよび(8) (C1-C10)ハロアルコキシから独立に選ばれる1〜6個の置換基で置換されていてもよく;
R1は、(2) ハロゲン、(3) アミノ、(4) シアノ、(5) ヒドロキシ、(7) (C3-C10)シクロアルキル、(8) (C1-C10)ハロアルキル、(9) (C1-C10)アルコキシおよび(10) (C1-C10)ハロアルコキシからなる群から独立に選ばれ;同じ炭素または異なった炭素上の2つのR1は、酸素原子、硫黄原子、および窒素原子から選ばれる原子を含んでもよい3〜8員のシクロアルキル環を形成することが可能であり;ここで該環は、(1) 水素、(2) ハロゲン、(3) ヒドロキシ、(4) (C1-C10)アルキル、(5) (C3-C10)シクロアルキル、(6) (C1-C10)ハロアルキル、(7) (C1-C10)アルコキシ、および(8) (C1-C10)ハロアルコキシから独立に選ばれる1〜6個の置換基で置換されていてもよく;
R2は、(1) 水素、(2) ハロゲン、(3) アミノ、(4) -NH(C1-C6)アルキル、(5) -N[(C1-C6)アルキル]2 ここでアルキルは同じかまたは異なる、(6) シアノ、(7) ヒドロキシ、(8) ニトロ、(9) (C1-C6)アルキルチオ、(10) (C1-C10)アルキル、(11) (C3-C10)シクロアルキル、(12) (C1-C10)アルコキシ、(13) (C1-C10)ハロアルキルおよび(14) (C1-C10)ハロアルコキシからなる群から独立に選ばれ;
R3は、(1) 水素、(2) ハロゲン、(3) シアノ、(4) ニトロ、(5) ヒドロキシ、(6) (C1-C6)アルキルチオ、(7) (C1-C6)アルキルスルフィニル、(8) (C1-C6)アルキルスルホニル、(9) -NR5R6、(10) -C(=O)NR5R6、(11) トリ(C1-C6)アルキルシリル、(12) (C1-C10)アルキル、(13) (C3-C10)シクロアルキル、(14) (C1-C6)アルコキシ(C0-C6)アルキル、(15) (C3-C10)シクロアルコキシ、(16) -C(=O)(C1-C6)アルキル、(17) -C(=O)O(C1-C6)アルキル および(18) -C(=O)OHからなる群から独立に選ばれ;ここで (C1-C10)アルキル、(C3-C10)シクロアルキル、(C1-C6)アルコキシ(C0-C6)アルキルおよび(C3-C10)シクロアルコキシは、(1) 水素、(2) ハロゲン、(3) ヒドロキシ、(4) シアノ、(5) (C3-C10)シクロアルキル、(6) (C1-C10)ハロアルキル、(7) (C1-C10)アルコキシ、(8) (C1-C10)ハロアルコキシおよび (9) -NR6R5 から独立に選ばれる1〜6個の置換基で置換されていてもよく;ここでR5およびR6は、それらの結合した窒素原子とともに3〜10員環(酸素、硫黄および窒素から選ばれる原子を含んでも良い)を形成してもよく;ここで該環は、(1) 水素、(2) ハロゲン、(3) ヒドロキシ、(4) (C1-C10)アルキル、(5) (C3-C10)シクロアルキル、(6) (C1-C10)ハロアルキル、(7) (C1-C10)アルコキシおよび(8) (C1-C10)ハロアルコキシから独立に選ばれる1〜6個の置換基で置換されていてもよく;
R4、R5およびR6は、(1) 水素、(2) (C1-C10)アルキル、(3) (C3-C10)シクロアルキル、(4) (C1-C10)ハロアルキル、(5) ヒドロキシ(C1-C10)アルキル、(6) (C1-C10)アルコキシ(C1-C10)アルキル、(7) H2N-(C1-C10)アルキル、(8) [(C1-C10)アルキル]NH-(C1-C10)アルキル、(9) [(C1-C10)アルキル]2N-(C1-C10)アルキル、(10) (C1-C10)アルキルカルボニルおよび(11) (C1-C10)アルキルスルホニルからなる群から独立に選ばれ;
pは、1、2、3または4であり;
qは、1、2、3または4であり;qが2以上のとき、R1は同じかまたは異なっており、
rは、1、2、3または4であり;rが2以上のとき、R2は同じかまたは異なっており、
sは、1、2、3、4、5、6または7であり;sが2以上のとき、R3は同じかまたは異なっており、
tは、1、2または3であり;tが2以上のとき、RCおよびRDは同じかまたは異なっている)
または薬学的に許容されるその塩。 - R1は、(2) ハロゲン、(3) アミノ、(4) シアノ、(5) ヒドロキシ、(8) (C1-C10)ハロアルキル、(9) (C1-C10)アルコキシおよび(10) (C1-C10)ハロアルコキシからなる群から独立に選ばれ; 同じ炭素または異なった炭素上の2つのR1は、酸素原子、硫黄原子、および窒素原子から選ばれる原子を含んでもよい3〜8員のシクロアルキル環を形成することが可能であり;ここで該環は、(1) 水素、(2) ハロゲン、(3) ヒドロキシ、(4) (C1-C10)アルキル、(5) (C3-C10)シクロアルキル、(6) (C1-C10)ハロアルキル、(7) (C1-C10)アルコキシ、および(8) (C1-C10)ハロアルコキシから独立に選ばれる1〜6個の置換基で置換されていてもよい、請求項1に記載された化合物または薬学的に許容されるその塩。
- R1は、(2) ハロゲン、(3) アミノ、(4) シアノ、(5) ヒドロキシ、(8) (C1-C10)ハロアルキル、(9) (C1-C10)アルコキシおよび(10) (C1-C10)ハロアルコキシから独立に選ばれる、請求項1に記載された化合物または薬学的に許容されるその塩。
- R1は、独立に(2) ハロゲンである、請求項1に記載された化合物または薬学的に許容されるその塩。
- Aが6員のアリールまたは5〜6員のヘテロアリールである請求項1〜請求項4のいずれか一項に記載された化合物または薬学的に許容されるその塩。
- Aが、フェニル、ピリジル、ピリダジニル、ピラジニル、ピリミジル、トリアジニル、チオフェニル、フラニル、ピロリル、イミダゾイル、ピラゾリル、チアゾリル、イソチアゾリル、オキサゾリル、イソオキサゾリル、およびトリアゾリルからなる群から独立に選ばれる、請求項1〜請求項5のいずれか一項に記載された化合物または薬学的に許容されるその塩。
- 式(I)の化合物
Aは、フェニル、ピリジル、ピリダジニル、ピラジニル、ピリミジル、トリアジニル、チオフェニル、フラニル、イミダゾリル、ピラゾリル、チアゾリル、イソチアゾリル、オキサゾリル、イソオキサゾリル、およびトリアゾリルからなる群から独立に選ばれ;
Bは、アリール又はヘテロアリール(但し、Aがフェニルのとき、Bがフェニルである場合を除く);
Lは、化学結合、酸素、硫黄、-NR 4 -、-(CR C R D ) t -、-O(CR C R D ) t -、-(CR C R D ) t O-、-N(R 4 )(CR C R D ) t -、-(CR C R D ) t N(R 4 )-、-N(R 4 )(CR C R D ) t O-、および -O(CR C R D ) t N(R 4 )-からなる群から独立に選ばれ;
Xは、-CH 2 -、酸素、硫黄、およびNHからなる群から独立に選ばれ;
R A およびR B は、(1) 水素、(2) ハロゲン、(3) (C 1 -C 10 )アルキル、(4) (C 3 -C 10 )シクロアルキルおよび(5) (C 1 -C 10 )ハロアルキルからなる群から独立に選ばれ;またはR A およびR B は、オキソ基(=O)を形成してもよく;またはR A およびR B は、酸素原子、硫黄原子、および窒素原子から独立に選ばれる1つ以上のヘテロ原子を含んでもよい3〜8員環を形成してもよく;ここで該環は、(1) 水素、(2) ハロゲン、(3) ヒドロキシ、(4) (C 1 -C 10 )アルキル、(5) (C 3 -C 10 )シクロアルキル、(6) (C 1 -C 10 )ハロアルキル、(7) (C 1 -C 10 )アルコキシおよび(8) (C 1 -C 10 )ハロアルコキシから独立に選ばれる1〜6個の置換基で置換されていてもよく;
R C およびR D は、(1) 水素、(2) ハロゲン、(3) (C 1 -C 10 )アルキル、(4) (C 3 -C 10 )シクロアルキルおよび(5) (C 1 -C 10 ) ハロアルキルからなる群から独立に選ばれ;または、R C およびR D は、酸素原子、硫黄原子、および窒素原子から独立に選ばれる1つ以上のヘテロ原子を含んでもよい3〜8員環を形成してもよく;ここで該環は、(1) 水素、(2) ハロゲン、(3) ヒドロキシ、(4) (C 1 -C 10 )アルキル、(5) (C 3 -C 10 )シクロアルキル、(6) (C 1 -C 10 )ハロアルキル、(7) (C 1 -C 10 )アルコキシおよび(8) (C 1 -C 10 )ハロアルコキシから独立に選ばれる1〜6個の置換基で置換されていてもよく;
R 1 は、(1) 水素、(2) ハロゲン、(6) (C 1 -C 10 )アルキルからなる群から独立に選ばれ;同じ炭素または異なった炭素上の2つのR 1 は、3〜8員のシクロアルキル環を形成することが可能であり;
R 2 は、(1) 水素、(2) ハロゲン、(3) アミノ、(4) -NH(C 1 -C 6 )アルキル、(5) -N[(C 1 -C 6 )アルキル] 2 ここでアルキルは同じかまたは異なる、(6) シアノ、(7) ヒドロキシ、(8) ニトロ、(9) (C 1 -C 6 )アルキルチオ、(10) (C 1 -C 10 )アルキル、(11) (C 3 -C 10 )シクロアルキル、(12) (C 1 -C 10 )アルコキシ、(13) (C 1 -C 10 )ハロアルキルおよび(14) (C 1 -C 10 )ハロアルコキシからなる群から独立に選ばれ;
R 3 は、(1) 水素、(2) ハロゲン、(3) シアノ、(4) ニトロ、(5) ヒドロキシ、(6) (C 1 -C 6 )アルキルチオ、(7) (C 1 -C 6 )アルキルスルフィニル、(8) (C 1 -C 6 )アルキルスルホニル、(9) -NR 5 R 6 、(10) -C(=O)NR 5 R 6 、(11) トリ(C 1 -C 6 )アルキルシリル、(12) (C 1 -C 10 )アルキル、(13) (C 3 -C 10 )シクロアルキル、(14) (C 1 -C 6 )アルコキシ(C 0 -C 6 )アルキル、(15) (C 3 -C 10 )シクロアルコキシ、(16) -C(=O)(C 1 -C 6 )アルキル、(17) -C(=O)O(C 1 -C 6 )アルキル および(18) -C(=O)OHからなる群から独立に選ばれ;ここで (C 1 -C 10 )アルキル、(C 3 -C 10 )シクロアルキル、(C 1 -C 6 )アルコキシ(C 0 -C 6 )アルキルおよび(C 3 -C 10 )シクロアルコキシは、(1) 水素、(2) ハロゲン、(3) ヒドロキシ、(4) シアノ、(5) (C 3 -C 10 )シクロアルキル、(6) (C 1 -C 10 )ハロアルキル、(7) (C 1 -C 10 )アルコキシ、(8) (C 1 -C 10 )ハロアルコキシおよび (9) -NR 6 R 5 から独立に選ばれる1〜6個の置換基で置換されていてもよく;ここでR 5 およびR 6 は、それらの結合した窒素原子とともに3〜10員環(酸素、硫黄および窒素から選ばれる原子を含んでも良い)を形成してもよく;ここで該環は、(1) 水素、(2) ハロゲン、(3) ヒドロキシ、(4) (C 1 -C 10 )アルキル、(5) (C 3 -C 10 )シクロアルキル、(6) (C 1 -C 10 )ハロアルキル、(7) (C 1 -C 10 )アルコキシおよび(8) (C 1 -C 10 )ハロアルコキシから独立に選ばれる1〜6個の置換基で置換されていてもよく;
R 4 、R 5 およびR 6 は、(1) 水素、(2) (C 1 -C 10 )アルキル、(3) (C 3 -C 10 )シクロアルキル、(4) (C 1 -C 10 )ハロアルキル、(5) ヒドロキシ(C 1 -C 10 )アルキル、(6) (C 1 -C 10 )アルコキシ(C 1 -C 10 )アルキル、(7) H 2 N-(C 1 -C 10 )アルキル、(8) [(C 1 -C 10 )アルキル]NH-(C 1 -C 10 )アルキル、(9) [(C 1 -C 10 )アルキル] 2 N-(C 1 -C 10 )アルキル、(10) (C 1 -C 10 )アルキルカルボニルおよび(11) (C 1 -C 10 )アルキルスルホニルからなる群から独立に選ばれ;
pは、1、2、3または4であり;
qは、1、2、3または4であり;qが2以上のとき、R 1 は同じかまたは異なっており、
rは、1、2、3または4であり;rが2以上のとき、R 2 は同じかまたは異なっており、
sは、1、2、3、4、5、6または7であり;sが2以上のとき、R 3 は同じかまたは異なっており、
tは、1、2または3であり;tが2以上のとき、R C およびR D は同じかまたは異なっている)
または薬学的に許容されるその塩。 - 3-(2-(2,5-ジメチル-1-(5-メチルイソオキサゾール-3-イル)-1H-ピロール-3-イル)-2-オキソエチル)-8,8-ジフルオロ-1,3-ジアザスピロ[4.5]デカン-2,4-ジオン;
3-(2-(2,5-ジメチル-1-フェニル-1H-イミダゾール-4-イル)-2-オキソエチル)-8,8-ジフルオロ-1,3-ジアザスピロ[4.5]デカン-2,4-ジオン;
6-(4-(2-(2,4-ジオキソ-1,3-ジアザスピロ[4.5]デカン-3-イル)アセチル)フェニル)ピコリノニトリル;
3-(2-(1-(3-クロロフェニル)-2,5-ジメチル-1H-イミダゾール-4-イル)-2-オキソエチル)-8,8-ジフルオロ-1,3-ジアザスピロ[4.5]デカン-2,4-ジオン;
8,8-ジフルオロ-3-(2-(1-(3-フルオロフェニル)-2,5-ジメチル-1H-イミダゾール-4-イル)-2-オキソエチル)-1,3-ジアザスピロ[4.5]デカン-2,4-ジオン;
3-(2-(1,4-ジメチル-5-フェニル-1H-ピラゾール-3-イル)-2-オキソエチル)-8,8-ジフルオロ-1,3-ジアザスピロ[4.5]デカン-2,4-ジオン;
8,8-ジフルオロ-3-(2-(4-(6-メチルピラジン-2-イル)フェニル)-2-オキソエチル)-1,3-ジアザスピロ[4.5]デカン-2,4-ジオン;
6-(4-(2-(8,8-ジフルオロ-2,4-ジオキソ-1,3-ジアザスピロ[4.5]デカン-3-イル)アセチル)フェニル)ピコリノニトリル;
8,8-ジフルオロ-3-(2-(2'-(ヒドロキシメチル)-[1,1'-ビフェニル]-4-イル)-2-オキソエチル)-1,3-ジアザスピロ[4.5]デカン-2,4-ジオン;
8,8-ジフルオロ-3-(2-(4-(3-メチルピラジン-2-イル)フェニル)-2-オキソエチル)-1,3-ジアザスピロ[4.5]デカン-2,4-ジオン;
3-(2-(2,5-ジメチル-1-フェニル-1H-イミダゾール-4-イル)-2-オキソエチル)-8,8-ジフルオロ-1-オキサ-3-アザスピロ[4.5]デカン-2,4-ジオン;
8,8-ジフルオロ-3-(2-(4-(2-(ヒドロキシメチル)ピリジン-3-イル)フェニル)-2-オキソエチル)-1,3-ジアザスピロ[4.5]デカン-2,4-ジオン;
8,8-ジフルオロ-3-(2-(4-(4-(ヒドロキシメチル)ピリジン-3-イル)フェニル)-2-オキソエチル)-1,3-ジアザスピロ[4.5]デカン-2,4-ジオン;
3-(2-(2,5-ジメチル-1-(5-メチルイソオキサゾール-3-イル)-1H-ピロール-3-イル)-2-オキソエチル)-8,8-ジフルオロ-1-オキサ-3-アザスピロ[4.5]デカン-2,4-ジオン;
8,8-ジフルオロ-3-(2-(5-(2-(ヒドロキシメチル)フェニル)-4-メチルチオフェン-2-イル)-2-オキソエチル)-1,3-ジアザスピロ[4.5]デカン-2,4-ジオン;
3-(2-(4-(3-(ヒドロキシメチル)ピラジン-2-イル)フェニル)-2-オキソエチル)-1,3-ジアザスピロ[4.5]デカン-2,4-ジオン;
3-(2-(1,4-ジメチル-5-フェニル-1H-ピラゾール-3-イル)-2-オキソエチル)-8,8-ジフルオロ-1-オキサ-3-アザスピロ[4.5]デカン-2,4-ジオン;
8,8-ジフルオロ-3-(2-(4-(4-メチルピリダジン-3-イル)フェニル)-2-オキソエチル)-1,3-ジアザスピロ[4.5]デカン-2,4-ジオン;
3-(4-(2-(8,8-ジフルオロ-2,4-ジオキソ-1,3-ジアザスピロ[4.5]デカン-3-イル)アセチル)フェニル)ピラジン-2-カルボニトリル;
3-(2-(1,4-ジメチル-5-フェニル-1H-ピロール-2-イル)-2-オキソエチル)-8,8-ジフルオロ-1,3-ジアザスピロ[4.5]デカン-2,4-ジオン;
8,8-ジフルオロ-3-(2-(4-(3-(ヒドロキシメチル)ピラジン-2-イル)フェニル)-2-オキソエチル)-1,3-ジアザスピロ[4.5]デカン-2,4-ジオン;
3-(2-(6-(メチル(ピリジン-2-イル)アミノ)ピリジン-3-イル)-2-オキソエチル)-1,3-ジアザスピロ[4.5]デカン-2,4-ジオン;
3-(4-(2-(8,8-ジフルオロ-2,4-ジオキソ-1,3-ジアザスピロ[4.5]デカン-3-イル)アセチル)フェニル)ピコリノニトリル;
8,8-ジフルオロ-3-(2-オキソ-2-(4-(キノリン-8-イル)フェニル)エチル)-1,3-ジアザスピロ[4.5]デカン-2,4-ジオン;
3-(2-(4-(1H-インドール-4-イル)フェニル)-2-オキソエチル)-8,8-ジフルオロ-1,3-ジアザスピロ[4.5]デカン-2,4-ジオン;
8,8-ジフルオロ-3-(2-オキソ-2-(4-(キノリン-2-イル)フェニル)エチル)-1,3-ジアザスピロ[4.5]デカン-2,4-ジオン;
8,8-ジフルオロ-3-(2-(4-(イソキノリン-8-イル)フェニル)-2-オキソエチル)-1,3-ジアザスピロ[4.5]デカン-2,4-ジオン;
8,8-ジフルオロ-3-(2-(4-(イソキノリン-1-イル)フェニル)-2-オキソエチル)-1,3-ジアザスピロ[4.5]デカン-2,4-ジオン;
8,8-ジフルオロ-3-(2-(4-(フロ[3,2-c]ピリジン-4-イル)フェニル)-2-オキソエチル)-1,3-ジアザスピロ[4.5]デカン-2,4-ジオン;
8,8-ジフルオロ-3-(2-(6-(メチル(ピリジン-2-イル)アミノ)ピリジン-3-イル)-2-オキソエチル)-1,3-ジアザスピロ[4.5]デカン-2,4-ジオン;
8,8-ジフルオロ-3-(2-(6-(メチル(フェニル)アミノ)ピリジン-3-イル)-2-オキソエチル)-1,3-ジアザスピロ[4.5]デカン-2,4-ジオン;
8,8-ジフルオロ-3-(2-(4-(3-フルオロピリジン-2-イル)フェニル)-2-オキソエチル)-1,3-ジアザスピロ[4.5]デカン-2,4-ジオン;
3-(4-(2-(8,8-ジフルオロ-2,4-ジオキソ-1,3-ジアザスピロ[4.5]デカン-3-イル)アセチル)フェニル)イソニコチノニトリル;
8,8-ジフルオロ-3-(2-(4-(2-メトキシピリジン-3-イル)フェニル)-2-オキソエチル)-1,3-ジアザスピロ[4.5]デカン-2,4-ジオン;
8,8-ジフルオロ-3-(2-(4-(4-メトキシピリジン-3-イル)フェニル)-2-オキソエチル)-1,3-ジアザスピロ[4.5]デカン-2,4-ジオン;
8,8-ジフルオロ-3-(2-オキソ-2-(4-(2-オキソインドリン-4-イル)フェニル)エチル)-1,3-ジアザスピロ[4.5]デカン-2,4-ジオン;
3-(2-(4-(7H-ピロロ[2,3-d]ピリミジン-4-イル)フェニル)-2-オキソエチル)-8,8-ジフルオロ-1,3-ジアザスピロ[4.5]デカン-2,4-ジオン;
3-(2-(4-(1H-ピロロ[3,2-c]ピリジン-4-イル)フェニル)-2-オキソエチル)-8,8-ジフルオロ-1,3-ジアザスピロ[4.5]デカン-2,4-ジオン;
3-(2-(4-(1H-ピロロ[2,3-b]ピリジン-4-イル)フェニル)-2-オキソエチル)-8,8-ジフルオロ-1,3-ジアザスピロ[4.5]デカン-2,4-ジオン;
3-(2-(4-(3-クロロピリジン-2-イル)フェニル)-2-オキソエチル)-8,8-ジフルオロ-1,3-ジアザスピロ[4.5]デカン-2,4-ジオン;
8,8-ジフルオロ-3-(2-(4-(2-メチル-1H-ベンゾ[d]イミダゾール-1-イル)フェニル)-2-オキソエチル)-1,3-ジアザスピロ[4.5]デカン-2,4-ジオン;
3-(2-(4-(1H-インダゾール-4-イル)フェニル)-2-オキソエチル)-8,8-ジフルオロ-1,3-ジアザスピロ[4.5]デカン-2,4-ジオン;
3-(2-(6-(1H-インダゾール-4-イル)ピリジン-3-イル)-2-オキソエチル)-8,8-ジフルオロ-1,3-ジアザスピロ[4.5]デカン-2,4-ジオン;
3-(2-(4-(1H-ベンゾ[d]イミダゾール-1-イル)フェニル)-2-オキソエチル)-8,8-ジフルオロ-1,3-ジアザスピロ[4.5]デカン-2,4-ジオン;
3-(5-(2-(8,8-ジフルオロ-2,4-ジオキソ-1,3-ジアザスピロ[4.5]デカン-3-イル)アセチル)-1,3-ジメチル-1H-ピロール-2-イル)ベンゾニトリル;
3-(2-(4-(1H-ピロロ[2,3-c]ピリジン-4-イル)フェニル)-2-オキソエチル)-8,8-ジフルオロ-1,3-ジアザスピロ[4.5]デカン-2,4-ジオン;
8,8-ジフルオロ-3-(2-(3-フルオロ-4-(キノリン-8-イル)フェニル)-2-オキソエチル)-1,3-ジアザスピロ[4.5]デカン-2,4-ジオン;
3-(5-(2-(8,8-ジフルオロ-2,4-ジオキソ-1,3-ジアザスピロ[4.5]デカン-3-イル)アセチル)-1-メチル-1H-ピロール-2-イル)ベンゾニトリル;
3-(5-(2-(8,8-ジフルオロ-2,4-ジオキソ-1,3-ジアザスピロ[4.5]デカン-3-イル)アセチル)-3-メチルチオフェン-2-イル)ベンゾニトリル;
8,8-ジフルオロ-3-(2-(4-(2-(2-ヒドロキシエトキシ)ピリジン-3-イル)フェニル)-2-オキソエチル)-1,3-ジアザスピロ[4.5]デカン-2,4-ジオン;
8,8-ジフルオロ-3-(2-(5-(3-フルオロフェニル)-1,4-ジメチル-1H-ピロール-2-イル)-2-オキソエチル)-1,3-ジアザスピロ[4.5]デカン-2,4-ジオン;
3-(2-(5-(3-クロロフェニル)-1,4-ジメチル-1H-ピロール-2-イル)-2-オキソエチル)-8,8-ジフルオロ-1,3-ジアザスピロ[4.5]デカン-2,4-ジオン;
3-(5-(2-(8,8-ジフルオロ-2,4-ジオキソ-1,3-ジアザスピロ[4.5]デカン-3-イル)アセチル)-1,3-ジメチル-1H-ピロール-2-イル)ベンズアミド;
8,8-ジフルオロ-3-(2-(5-(2-フルオロフェニル)-1,4-ジメチル-1H-ピロール-2-イル)-2-オキソエチル)-1,3-ジアザスピロ[4.5]デカン-2,4-ジオン;
3-(2-(4-(1H-ピラゾロ[3,4-b]ピリジン-4-イル)フェニル)-2-オキソエチル)-8,8-ジフルオロ-1,3-ジアザスピロ[4.5]デカン-2,4-ジオン;
3-(2-(4-(1H-ピラゾロ[4,3-c]ピリジン-4-イル)フェニル)-2-オキソエチル)-8,8-ジフルオロ-1,3-ジアザスピロ[4.5]デカン-2,4-ジオン;
3-(2-(4-(1H-インダゾール-1-イル)フェニル)-2-オキソエチル)-8,8-ジフルオロ-1,3-ジアザスピロ[4.5]デカン-2,4-ジオン;
8,8-ジフルオロ-3-(2-(5-(3-フルオロフェニル)-1-メチル-1H-イミダゾール-2-イル)-2-オキソエチル)-1,3-ジアザスピロ[4.5]デカン-2,4-ジオン;
8,8-ジフルオロ-3-(2-(4-(2-メチル-3H-イミダゾ[4,5-b]ピリジン-3-イル)フェニル)-2-オキソエチル)-1,3-ジアザスピロ[4.5]デカン-2,4-ジオン;
8,8-ジフルオロ-3-(2-オキソ-2-(4-(ピリジン-2-イルオキシ)フェニル)エチル)-1,3-ジアザスピロ[4.5]デカン-2,4-ジオン;
3-(2-(5-(3,5-ジフルオロフェニル)-1,4-ジメチル-1H-ピロール-2-イル)-2-オキソエチル)-8,8-ジフルオロ-1,3-ジアザスピロ[4.5]デカン-2,4-ジオン;
8,8-ジフルオロ-3-(2-(2'-メチル-[3,3'-ビピリジン]-6-イル)-2-オキソエチル)-1,3-ジアザスピロ[4.5]デカン-2,4-ジオン;
3-(2-(4-(1H-ピラゾロ[3,4-d]ピリミジン-4-イル)フェニル)-2-オキソエチル)-8,8-ジフルオロ-1,3-ジアザスピロ[4.5]デカン-2,4-ジオン;
3-(2-(6-(1H-ピロロ[2,3-c]ピリジン-4-イル)ピリジン-3-イル)-2-オキソエチル)-8,8-ジフルオロ-1,3-ジアザスピロ[4.5]デカン-2,4-ジオン;
8,8-ジフルオロ-3-(2-(4-(3-(2-ヒドロキシエトキシ)ピラジン-2-イル)フェニル)-2-オキソエチル)-1,3-ジアザスピロ[4.5]デカン-2,4-ジオン;
8,8-ジフルオロ-3-(2-オキソ-2-(4-(フタラジン-1-イル)フェニル)エチル)-1,3-ジアザスピロ[4.5]デカン-2,4-ジオン;
3-(2-(4-(3H-イミダゾ[4,5-b]ピリジン-3-イル)フェニル)-2-オキソエチル)-8,8-ジフルオロ-1,3-ジアザスピロ[4.5]デカン-2,4-ジオン;
3-(2-(2-(8,8-ジフルオロ-2,4-ジオキソ-1,3-ジアザスピロ[4.5]デカン-3-イル)アセチル)-4-メチルチアゾール-5-イル)ベンゾニトリル;
3-(2-(1,4-ジメチル-5-フェニル-1H-イミダゾール-2-イル)-2-オキソエチル)-8,8-ジフルオロ-1,3-ジアザスピロ[4.5]デカン-2,4-ジオン;
8,8-ジフルオロ-3-(2-(5-(3-フルオロフェニル)-1,4-ジメチル-1H-イミダゾール-2-イル)-2-オキソエチル)-1,3-ジアザスピロ[4.5]デカン-2,4-ジオン;
3-(2-(2-(8,8-ジフルオロ-2,4-ジオキソ-1,3-ジアザスピロ[4.5]デカン-3-イル)アセチル)-1,4-ジメチル-1H-イミダゾール-5-イル)ベンゾニトリル;
8,8-ジフルオロ-3-(2-(5-(イソキノリン-8-イル)-1,4-ジメチル-1H-イミダゾール-2-イル)-2-オキソエチル)-1,3-ジアザスピロ[4.5]デカン-2,4-ジオン;
8,8-ジフルオロ-3-(2-(5-(2-(ヒドロキシメチル)フェニル)-1,4-ジメチル-1H-イミダゾール-2-イル)-2-オキソエチル)-1,3-ジアザスピロ[4.5]デカン-2,4-ジオン;
8,8-ジフルオロ-3-(2-(4-(2-(ヒドロキシメチル)-1H-ベンゾ[d]イミダゾール-1-イル)フェニル)-2-オキソエチル)-1,3-ジアザスピロ[4.5]デカン-2,4-ジオン;
8,8-ジフルオロ-3-(2-(5-(3-フルオロフェニル)-1,4-ジメチル-1H-ピロール-3-イル)-2-オキソエチル)-1,3-ジアザスピロ[4.5]デカン-2,4-ジオン;
3-(4-(2-(8,8-ジフルオロ-2,4-ジオキソ-1,3-ジアザスピロ[4.5]デカン-3-イル)アセチル)-1,3-ジメチル-1H-ピロール-2-イル)ベンゾニトリル;
3-(2-(5-(1H-ベンゾ[d]イミダゾール-1-イル)ピラジン-2-イル)-2-オキソエチル)-8,8-ジフルオロ-1,3-ジアザスピロ[4.5]デカン-2,4-ジオン;
3-(2-(4-(2,7-ナフチリジン-1-イル)フェニル)-2-オキソエチル)-8,8-ジフルオロ-1,3-ジアザスピロ[4.5]デカン-2,4-ジオン;
8,8-ジフルオロ-3-(2-オキソ-2-(4-(2-オキソ-2,3-ジヒドロ-1H-ベンゾ[d]イミダゾール-1-イル)フェニル)エチル)-1,3-ジアザスピロ[4.5]デカン-2,4-ジオン;
8,8-ジフルオロ-3-(2-(5-(2-(ヒドロキシメチル)フェニル)ピラジン-2-イル)-2-オキソエチル)-1,3-ジアザスピロ[4.5]デカン-2,4-ジオン;
8,8-ジフルオロ-3-(2-(5-(4-メトキシピリジン-3-イル)ピラジン-2-イル)-2-オキソエチル)-1,3-ジアザスピロ[4.5]デカン-2,4-ジオン;
3-(5-(2-(8,8-ジフルオロ-2,4-ジオキソ-1,3-ジアザスピロ[4.5]デカン-3-イル)アセチル)-2,4-ジメチルチオフェン-3-イル)ベンズアミド;
3-(2-(5-(3,5-ジフルオロフェニル)-1,4-ジメチル-1H-イミダゾール-2-イル)-2-オキソエチル)-8,8-ジフルオロ-1,3-ジアザスピロ[4.5]デカン-2,4-ジオン;
8,8-ジフルオロ-3-(2-オキソ-2-(4-(ピリダジン-3-イルオキシ)フェニル)エチル)-1,3-ジアザスピロ[4.5]デカン-2,4-ジオン;
8,8-ジフルオロ-3-(2-オキソ-2-(4-(2-オキソ-1H-イミダゾ[4,5-b]ピリジン-3(2H)-イル)フェニル)エチル)-1,3-ジアザスピロ[4.5]デカン-2,4-ジオン;
3-(2-(5-(3,5-ジフルオロフェニル)-4-メチルチアゾール-2-イル)-2-オキソエチル)-8,8-ジフルオロ-1,3-ジアザスピロ[4.5]デカン-2,4-ジオン;
4'-(2-(8,8-ジフルオロ-2,4-ジオキソ-1,3-ジアザスピロ[4.5]デカン-3-イル)アセチル)-2'-メトキシ-[1,1'-ビフェニル]-2-カルボニトリル;
2-(4-(2-(8,8-ジフルオロ-2,4-ジオキソ-1,3-ジアザスピロ[4.5]デカン-3-イル)アセチル)フェノキシ)ニコチノニトリル;
3-(2-(4-((3-クロロピリジン-2-イル)オキシ)フェニル)-2-オキソエチル)-8,8-ジフルオロ-1,3-ジアザスピロ[4.5]デカン-2,4-ジオン;
8,8-ジフルオロ-3-(2-(4-(3-(ヒドロキシメチル)ピリジン-2-イル)フェニル)-2-オキソエチル)-1,3-ジアザスピロ[4.5]デカン-2,4-ジオン;
3-(2-(2'-(アミノメチル)-[1,1'-ビフェニル]-4-イル)-2-オキソエチル)-8,8-ジフルオロ-1,3-ジアザスピロ[4.5]デカン-2,4-ジオン;
8,8-ジフルオロ-3-(2-オキソ-2-(6-(キノリン-8-イル)ピリジン-3-イル)エチル)-1,3-ジアザスピロ[4.5]デカン-2,4-ジオン;
8,8-ジフルオロ-3-(2-(5-(2-メチルピリジン-3-イル)ピラジン-2-イル)-2-オキソエチル)-1,3-ジアザスピロ[4.5]デカン-2,4-ジオン;
3-(2-(4-(2,7-ナフチリジン-1-イル)フェニル)-2-オキソエチル)-8,8-ジフルオロ-1-オキサ-3-アザスピロ[4.5]デカン-2,4-ジオン;
3-(4-(2-(8,8-ジフルオロ-2,4-ジオキソ-1,3-ジアザスピロ[4.5]デカン-3-イル)アセチル)フェニル)-2-メチル-3H-イミダゾ[4,5-b]ピリジン-5-カルボニトリル;
8,8-ジフルオロ-3-(2-オキソ-2-(4-(2-オキソベンゾ[d]オキサゾール-3(2H)-イル)フェニル)エチル)-1,3-ジアザスピロ[4.5]デカン-2,4-ジオン;
3-(2-(4-(2,5-ジメチル-3H-イミダゾ[4,5-b]ピリジン-3-イル)フェニル)-2-オキソエチル)-8,8-ジフルオロ-1,3-ジアザスピロ[4.5]デカン-2,4-ジオン;
8,8-ジフルオロ-3-(2-(5-(2-メチル-1H-ベンゾ[d]イミダゾール-1-イル)ピラジン-2-イル)-2-オキソエチル)-1,3-ジアザスピロ[4.5]デカン-2,4-ジオン;
8,8-ジフルオロ-3-(2-(4-(2-メトキシ-5-メチル-3H-イミダゾ[4,5-b]ピリジン-3-イル)フェニル)-2-オキソエチル)-1,3-ジアザスピロ[4.5]デカン-2,4-ジオン;
8,8-ジフルオロ-3-(2-(4-(5-メチル-2-(トリフルオロメチル)-3H-イミダゾ[4,5-b]ピリジン-3-イル)フェニル)-2-オキソエチル)-1,3-ジアザスピロ[4.5]デカン-2,4-ジオン;
3-(2-(4-(2-(ジフルオロメチル)-5-メチル-3H-イミダゾ[4,5-b]ピリジン-3-イル)フェニル)-2-オキソエチル)-8,8-ジフルオロ-1,3-ジアザスピロ[4.5]デカン-2,4-ジオン;
8,8-ジフルオロ-3-(2-(4-(5-メチル-2-オキソ-1H-イミダゾ[4,5-b]ピリジン-3(2H)-イル)フェニル)-2-オキソエチル)1,3-ジアザスピロ[4.5]デカン-2,4-ジオン;
6-(4-(2-(8,8-ジフルオロ-2,4-ジオキソ-1,3-ジアザスピロ[4.5]デカン-3-イル)アセチル)フェノキシ)ピコリノニトリル;
8,8-ジフルオロ-3-(2-(4-(5-メチル-3H-イミダゾ[4,5-b]ピリジン-3-イル)フェニル)-2-オキソエチル)-1,3-ジアザスピロ[4.5]デカン-2,4-ジオン;
8,8-ジフルオロ-3-(2-(4-(3-メトキシピラジン-2-イル)フェニル)-2-オキソエチル)-1,3-ジアザスピロ[4.5]デカン-2,4-ジオン;
3-(4-(2-(8,8-ジフルオロ-2,4-ジオキソ-1,3-ジアザスピロ[4.5]デカン-3-イル)アセチル)-3-フルオロフェニル)ピラジン-2-カルボニトリル;
8,8-ジフルオロ-3-(2-(4-(イミダゾ[1,2-b]ピリダジン-3-イル)フェニル)-2-オキソエチル)-1,3-ジアザスピロ[4.5]デカン-2,4-ジオン;
8,8-ジフルオロ-3-(2-(2'-(2-ヒドロキシエチル)-[1,1'-ビフェニル]-4-イル)-2-オキソエチル)-1,3-ジアザスピロ[4.5]デカン-2,4-ジオン;
2-(4'-(2-(8,8-ジフルオロ-2,4-ジオキソ-1,3-ジアザスピロ[4.5]デカン-3-イル)アセチル)-[1,1'-ビフェニル]-2-イル)アセトニトリル;
3-(2-(4-(1H-イミダゾ[4,5-b]ピラジン-1-イル)フェニル)-2-オキソエチル)-8,8-ジフルオロ-1,3-ジアザスピロ[4.5]デカン-2,4-ジオン;
8,8-ジフルオロ-3-(2-(4-(4-メチルピリダジン-3-イル)フェニル)-2-オキソエチル)-1-オキサ-3-アザスピロ[4.5]デカン-2,4-ジオン;
3-(4-(2-(8,8-ジフルオロ-2,4-ジオキソ-1,3-ジアザスピロ[4.5]デカン-3-イル)アセチル)フェノキシ)ピリダジン-4-カルボニトリル;
8,8-ジフルオロ-3-(2-(4-(2-(ヒドロキシメチル)-5-メチル-3H-イミダゾ[4,5-b]ピリジン-3-イル)フェニル)-2-オキソエチル)-1,3-ジアザスピロ[4.5]デカン-2,4-ジオン;
8,8-ジフルオロ-3-(2-オキソ-2-(4-(ピラゾロ[1,5-a]ピリミジン-3-イル)フェニル)エチル)-1,3-ジアザスピロ[4.5]デカン-2,4-ジオン;
4-(4-(2-(8,8-ジフルオロ-2,4-ジオキソ-1,3-ジアザスピロ[4.5]デカン-3-イル)アセチル)フェニル)ニコチノニトリル;
8,8-ジフルオロ-3-(2-(2-フルオロ-4-(4-メチルピリダジン-3-イル)フェニル)-2-オキソエチル)-1,3-ジアザスピロ[4.5]デカン-2,4-ジオン;
8,8-ジフルオロ-3-(2-(2-フルオロ-4-(3-(ヒドロキシメチル)ピラジン-2-イル)フェニル)-2-オキソエチル)-1,3-ジアザスピロ[4.5]デカン-2,4-ジオン;
2-(4-(2-(8,8-ジフルオロ-2,4-ジオキソ-1,3-ジアザスピロ[4.5]デカン-3-イル)アセチル)フェニル)ニコチノニトリル;
3-(2-(2,5-ジメチル-1-フェニル-1H-イミダゾール-4-イル)-2-オキソエチル)-1-オキサ-3-アザスピロ[4.5]デカン-2,4-ジオン;
3-(2-(2,5-ジメチル-1-(m-トリル)-1H-イミダゾール-4-イル)-2-オキソエチル)-1,3-ジアザスピロ[4.5]デカン-2,4-ジオン;
3-(2-(1,4-ジメチル-5-フェニル-1H-ピラゾール-3-イル)-2-オキソエチル)-1,3-ジアザスピロ[4.5]デカン-2,4-ジオン;
3-(2-([2,3'-ビピリジン]-5-イル)-2-オキソエチル)-1,3-ジアザスピロ[4.5]デカン-2,4-ジオン;
3-(2-(4-(2-メチル-1H-ベンゾ[d]イミダゾール-1-イル)フェニル)-2-オキソエチル)-1,3-ジアザスピロ[4.6]ウンデカン-2,4-ジオン;
3-(2-オキソ-2-(4-(ピリジン-2-イルオキシ)フェニル)エチル)-1,3-ジアザスピロ[4.5]デカン-2,4-ジオン;
3-(2-(4-(2-メチル-3H-イミダゾ[4,5-b]ピリジン-3-イル)フェニル)-2-オキソエチル)-1,3-ジアザスピロ[4.6]ウンデカン-2,4-ジオン;
3-(2-(4-(2-メチル-3H-イミダゾ[4,5-b]ピリジン-3-イル)フェニル)-2-オキソエチル)-1,3-ジアザスピロ[4.5]デカン-2,4-ジオン;
3-(2-オキソ-2-(4-(ピリダジン-3-イルオキシ)フェニル)エチル)-1,3-ジアザスピロ[4.6]ウンデカン-2,4-ジオン;
3-(2-(4-(2-メチルピリジン-3-イル)フェニル)-2-オキソエチル)-1,3-ジアザスピロ[4.5]デカン-2,4-ジオン;
3-(2-(4-(4-メチルピリジン-3-イル)フェニル)-2-オキソエチル)-1,3-ジアザスピロ[4.5]デカン-2,4-ジオン;
3-(2-(4-(3-メチルチオフェン-2-イル)フェニル)-2-オキソエチル)-1,3-ジアザスピロ[4.5]デカン-2,4-ジオン;
3-(2-(4-(3,6-ジメチルピラジン-2-イル)フェニル)-2-オキソエチル)-1,3-ジアザスピロ[4.5]デカン-2,4-ジオン;
3-(4-(2-(2,4-ジオキソ-1,3-ジアザスピロ[4.5]デカン-3-イル)アセチル)フェニル)ピコリノニトリル;
3-(2-(4-(4-(ヒドロキシメチル)ピリジン-3-イル)フェニル)-2-オキソエチル)-1,3-ジアザスピロ[4.5]デカン-2,4-ジオン;
3-(2-(4-(3-メチルピラジン-2-イル)フェニル)-2-オキソエチル)-1,3-ジアザスピロ[4.5]デカン-2,4-ジオン;
3-(2-(4'-メチル-[2,3'-ビピリジン]-5-イル)-2-オキソエチル)-1,3-ジアザスピロ[4.5]デカン-2,4-ジオン;
3-(2-(2'-メチル-[2,3'-ビピリジン]-5-イル)-2-オキソエチル)-1,3-ジアザスピロ[4.5]デカン-2,4-ジオン;
3-(2-オキソ-2-(4-(ピリジン-3-イル)フェニル)エチル)-1,3-ジアザスピロ[4.5]デカン-2,4-ジオン;
3-(2-(2-フルオロ-4-(ピリジン-3-イル)フェニル)-2-オキソエチル)-1,3-ジアザスピロ[4.5]デカン-2,4-ジオン;
3-(2-(4-メチル-5-(ピリジン-3-イル)チオフェン-2-イル)-2-オキソエチル)-1,3-ジアザスピロ[4.5]デカン-2,4-ジオン;および
3-(2-(4-メチル-5-(4-メチルピリジン-3-イル)チオフェン-2-イル)-2-オキソエチル)-1,3-ジアザスピロ[4.5]デカン-2,4-ジオン
からなる群から選ばれる化合物または薬学的に許容されるその塩。 - TRPM8受容体拮抗活性を介した病態または障害の治療用薬剤を製造するための請求項1〜請求項8のいずれか一項に記載した化合物または薬学的に許容されるその塩の使用。
- 前記病態または障害が、慢性疼痛;冷アロディニアおよび糖尿病性神経障害を含む神経因性疼痛;術後疼痛;骨関節炎;リウマチ性関節炎痛;がん性疼痛;神経痛;神経障害;痛覚過敏;象牙質知覚過敏;神経損傷;偏頭痛;群発性および緊張性頭痛;虚血;過敏性腸症候群;レイノー病;神経変性;線維筋痛症;脳卒中;かゆみ;不安およびうつを含む精神疾患;喘息、慢性閉塞性肺、COPDを含む気道疾患、肺高血圧症を含む炎症性障害;他のストレス関連障害を含む不安;および排尿筋過活動または過活動膀胱、尿失禁、神経因性排尿筋過活動または排尿筋過反射、特発性排尿筋過活動または排尿筋不安定、良性前立腺肥大、および下部尿路症状を含む泌尿器疾患または障害;およびこれらの組み合わせを含む、1以上の炎症、疼痛、および泌尿器疾患または障害であることを特徴とする、請求項9に記載の使用。
- 哺乳動物(ヒトを除く)個体における、TRPM8受容体拮抗活性を介した病態または障害の治療方法であって、治療有効量の請求項1〜請求項8のいずれか一項に記載した化合物または薬学的に許容されるその塩を該治療が必要な哺乳動物(ヒトを除く)に投与することを含む方法。
- 前記病態または障害が、慢性疼痛;冷アロディニアおよび糖尿病性神経障害を含む神経因性疼痛;術後疼痛;骨関節炎;リウマチ性関節炎痛;がん性疼痛;神経痛;神経障害;痛覚過敏;象牙質知覚過敏;神経損傷;偏頭痛;群発性および緊張性頭痛;虚血;過敏性腸症候群;レイノー病;神経変性;線維筋痛症;脳卒中;かゆみ;不安およびうつを含む精神疾患;喘息、慢性閉塞性肺、COPDを含む気道疾患、肺高血圧症を含む炎症性障害;他のストレス関連障害を含む不安;および排尿筋過活動または過活動膀胱、尿失禁、神経因性排尿筋過活動または排尿筋過反射、特発性排尿筋過活動または排尿筋不安定、良性前立腺肥大、および下部尿路症状を含む泌尿器疾患または障害;およびこれらの組み合わせを含む、1以上の炎症、疼痛、および泌尿器疾患または障害であることを特徴とする、請求項11に記載の方法。
- 請求項1〜請求項8のいずれか一項に記載した化合物または薬学的に許容されるその塩と、該化合物の薬学的に許容される担体とを含む医薬組成物。
- 他の薬理学的に活性な薬剤をさらに含むことを特徴とする、請求項13に記載の医薬組成物。
- 請求項1〜請求項8のいずれか一項に記載した化合物または薬学的に許容されるその塩と、薬学的に許容される担体または賦形剤とを混合することを含む、医薬組成物の製造方法。
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CA2940621C (en) | 2022-03-15 |
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US20180339993A1 (en) | 2018-11-29 |
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US10093678B2 (en) | 2018-10-09 |
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MX2016011632A (es) | 2016-12-12 |
CA2940621A1 (en) | 2015-09-17 |
ES2850999T3 (es) | 2021-09-02 |
RU2683309C2 (ru) | 2019-03-28 |
TWI674257B (zh) | 2019-10-11 |
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