JP2018500371A - ヘテロシクリルアルキン誘導体およびそれらのmGluR5受容体のモジュレーターとしての使用 - Google Patents
ヘテロシクリルアルキン誘導体およびそれらのmGluR5受容体のモジュレーターとしての使用 Download PDFInfo
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- JP2018500371A JP2018500371A JP2017534834A JP2017534834A JP2018500371A JP 2018500371 A JP2018500371 A JP 2018500371A JP 2017534834 A JP2017534834 A JP 2017534834A JP 2017534834 A JP2017534834 A JP 2017534834A JP 2018500371 A JP2018500371 A JP 2018500371A
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Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- 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
- A61K31/42—Oxazoles
- A61K31/424—Oxazoles condensed with heterocyclic ring systems, e.g. clavulanic acid
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
- C07D498/04—Ortho-condensed systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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Abstract
Description
R1は、アルキル基、任意には置換されていてもよい一環式、二環式または三環式の、N、OおよびSから選択される1〜5個のヘテロ原子を含むC1〜C13のヘテロ環基、任意には置換されていてもよい一環式、二環式または三環式のC6〜C14のアリール基、任意には置換されていてもよいC3〜C6のシクロアルキル基、任意には置換されていてもよいC3〜C6のシクロアルケニル基、結合、または、任意には置換されていてもよいCO、CS、CH、CH2もしくはSO2基であり、
R2は、非存在であるか、または、任意には置換されていてもよい一環式または二環式の、N、OおよびSから選択される1〜3個のヘテロ原子を含むC1〜C9のヘテロ環基、任意には置換されていてもよい一環式、二環式または三環式のC6〜C14のアリール基、または、アルキル基、シクロアルキル基、アルコキシ基、シクロアルキルオキシ基、アリールオキシ基、シクロアルキル基、シクロアルキルオキシ基、ヘテロアリールオキシ基、アルキルチオ基、アミノ基、N−アルキルアミノ基、N,N−ジアルキルアミノ基、N−アルキル−N−アルコキシアミノ基、もしくはN−アルキル−N−アルキルオキシアミノ基から選択される任意には置換されていてもよい基であり、
R3は、任意には置換されていてもよいアルキル基、任意には置換されていてもよい一環式、二環式または三環式の、N、OおよびSから選択される1〜5個のヘテロ原子を含むC1〜C13のヘテロ環基、任意には置換されていてもよい一環式、二環式または三環式のC6〜C14のアリール基、任意には置換されていてもよいC3〜C6のシクロアルキル基、または、任意には置換されていてもよいC3〜C6のシクロアルケニル基であり、ならびに
nは1〜3である。
−OR4
を有する基を示しており、ここで、
R4は、C1〜C10の直鎖のまたは分岐のアルキル基、C1〜C10のシクロアルキル基、または、NもしくはOから選択される少なくとも一つのヘテロ原子を含むC1〜C10のヘテロ環基である。
例えば、R4が、C1〜C10のシクロアルキル基である場合、R4は、好ましくは、シクロプロピルメチルまたはシクロペンチル基であり、したがって、R2は、好ましくは、シクロプロピルメトキシまたはシクロペントキシ基である。
−NR5R6
を有する基を示しており、ここで、
R5は、C1〜C10の直鎖もしくは分岐のアルキルもしくはアルコキシ基または水素原子であり、R6は、C1〜C10の直鎖もしくは分岐のアルキルもしくはアルコキシ基であって、R5およびR6は、同一の基でもよく、また異なる基であってもよい、または
R5およびR6は、窒素原子ともに、5員環もしくは6員環のヘテロ環式の環を形成する。
R1は、アルキル基、任意には置換されていてもよい一環式、二環式または三環式の、N、OおよびSから選択される1〜5個のヘテロ原子を含むC1〜C13のヘテロ環基、任意には置換されていてもよい一環式、二環式または三環式のC6〜C14のアリール基、任意には置換されていてもよいC3〜C6のシクロアルキル基、もしくは任意には置換されていてもよいC3〜C6のシクロアルケニル基、または、結合、一または複数のR2基または置換基によって任意には置換されていてもよいCO、CS、CH、CH2、SO2基であり、
R2は、非存在であるか、または、任意には置換されていてもよい一環式または二環式の、窒素、酸素および硫黄から選択される1〜3個のヘテロ原子を含むC1〜C9のヘテロ環基、任意には置換されていてもよい一環式、二環式または三環式のC6〜C14のアリール基、または、アルキル基、シクロアルキル基、アルコキシ基、シクロアルキルオキシ基、アリールオキシ基、ヘテロアリールオキシ基、アルキルチオ基、アミノ基、N−アルキルアミノ基、N,N−ジアルキルアミノ基、もしくはN−アルキル−N−アルコキシアミノ基から選ばれる任意には置換されていてもよい基であり、
R3は、任意には置換されていてもよいアルキル基、任意には置換されていてもよい一環式、二環式または三環式の、N、OおよびSから選択される1〜5個のヘテロ原子を含むC1〜C13のヘテロ環基、任意には置換されていてもよい一環式、二環式または三環式の、C6〜C14のアリール基、任意には置換されていてもよいC3〜C6のシクロアルキル基、または、任意には置換されていてもよいC3〜C6のシクロアルケニル基であり、ならびに
nは1〜3である。
R1は、アルキル基、任意には置換されていてもよい一環式、二環式または三環式の、N、OおよびSから選択される1〜5個のヘテロ原子を含むC1〜C13のヘテロ環基、任意には置換されていてもよい一環式、二環式または三環式のC6〜C14のアリール基、任意には置換されていてもよいC3〜C6のシクロアルキル基、もしくは任意には置換されていてもよいC3〜C6のシクロアルケニル基、または、結合、一または複数のR2基または置換基によって任意には置換されていてもよいCO、CS、CH、CH2、SO2基であり、
R2は、非存在であるか、または、任意には置換されていてもよい一環式または二環式の、窒素、酸素および硫黄から選択される1〜3個のヘテロ原子を含むC1〜C9のヘテロ環基、任意には置換されていてもよい一環式、二環式または三環式のC6〜C14のアリール基、または、アルキル基、シクロアルキル基、アルコキシ基、シクロアルキルオキシ基、アリールオキシ基、ヘテロアリールオキシ基、アルキルチオ基、アミノ基、N−アルキルアミノ基、N,N−ジアルキルアミノ基、もしくはN−アルキル−N−アルコキシアミノ基から選択される任意には置換されていてもよい基であり、
R3は、任意には置換されていてもよいアルキル基、任意には置換されていてもよい一環式、二環式または三環式の、N、OおよびSから選択される1〜5個のヘテロ原子を含むC1〜C13のヘテロ環基、任意には置換されていてもよい一環式、二環式または三環式のC6〜C14のアリール基、任意には置換されていてもよいC3〜C6のシクロアルキル基、または、任意には置換されていてもよいC3〜C6のシクロアルケニル基であり、ならびに
nは1〜3である。
他に明記されない限り、以下の定義は本明細書およびクレームを通して適用される。これらの定義は、用語がそのまま使用されるかまたは他の用語と組み合わせて使用されるかに関わらず適用される。例えば、「アルキル基(alkyl)」との定義は、アルキル基そのものにのみ適用されるだけではなく、アルコキシ基、アルキルアミノ基、アルキルチオ基またはアルキルカルボニル基などのアルキル部分にもまた適用される。さらに、化学的な基について記載される全ての範囲、例えば、「1〜13個の炭素原子(from 1 to 13 carbon atoms)」または「C1〜C6アルキル基(C1-C6 alkyl)」は、範囲の全ての組み合わせおよび部分的な組み合わせならびにそこに入る炭素原子の特定の数を包含している。
特に示されない限り、明細書およびクレームを通して、示されている化学式または名称は、互変異性体および全ての立体、光学および幾何異性体(例えば、エナンチオマー、ジアステレオマー、E/Zアイソマーなど)ならびにそれらのラセミ体を包含する。これは、個々のエナンチオマーを種々の割合で含む混合物、ジアステレオマーの混合物、または、そのようなアイソマーおよびエナンチオマーが存在するような任意の前述の形態の混合物、ならびに、薬学的に許容可能な塩およびそれらの溶媒和物、例えば水和物、遊離の化合物の溶媒和物または化合物の塩の溶媒和物などの塩を包含する。
本発明は、さらに、式Iの化合物の塩、溶媒和物、水和物、N−オキサイド、プロドラッグおよび活性な代謝物を包含する。
化合物Iがバルクの物質として投与されることが可能であるかもしれない一方、活性な成分を、例えば、薬剤が、意図される投与ルートおよび標準的な薬務の観点から選択される薬学的に許容可能な担体との混合物中に存在するような、薬学的な製剤の形で存在させることが好ましい。
投与のためのルートとしては、例えば、経口(例えば、タブレット、カプセルとして、または、摂取可能な溶液として、など)、局所的、粘膜的(例えば、鼻孔スプレーまたは吸入のためのエアロゾルとしてなど)、経鼻の、非経口(例えば、注入可能なフォームによって)、胃腸菅内、髄腔内、腹腔、筋肉内、静脈内、子宮内、眼内、皮内、頭蓋内、気管内、膣内、脳室内、大脳内、皮下、眼科的(硝子体中または前房内を含む)、経皮的、直腸内、口腔の、硬膜外および舌下が挙げられる。本発明の組成物は、任意のこれらの投与ルートのために特に製剤される。好ましい実施形態において、本発明の医薬組成物は、経口デリバリーに適切である形態に製剤される。
式Iの化合物、および、エナンチオマー、ジアステレオマー、N−オキサイド、および、それらの薬学的に許容可能な塩は、以降に概略される一般的な方法によって調整され得、この方法は、本発明のさらなる態様を構成する。
他に特に記載しない限り、以降で記載される例の化合物の一または複数の互変異性の形態が、in situで合成され、および/または、単離される。以降で記載される例の化合物の互変異性の全ての形態が開示されていると理解されるべきである。
AN アセトニトリル
BOC tert−ブチルオキシカルボニル
conc. 濃縮された
DCM ジクロロメタン
DIPEA N,N−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
DMSO ジメチルスルフォキシド
DPPF 1,1’−bis(ジフェニル−ホスフィノ)フェロセン
EI 電子イオン化
ESI エレクトロスプレーイオン化
EtOAc 酢酸エチル
EtOH エタノール
HATU 2−(7−アザ−1H−ベンゾトリアゾール−1−イル)−1,1,3,3−テトラメチルウロニウムヘキサフルオロホスファート
HCl 塩酸
HCOOH ギ酸
HPLC 高速液体クロマトグラフィー
HPLC−MS 質量分析と連結された高速液体クロマトグラフィー
i.vac. 真空下
MeOH メタノール
MS 質量分析法
MW 分子量
NaOH 水酸化ナトリウム
NH4OH 水酸化アンモニウム(水中30%アンモニア)
PE 石油エーテル
Rf 保持値(薄層クロマトグラフィーによる)
RT 室温
R.sub.t 保持時間(HPLCによる)
TBTU 2−(1H−ベンゾトリアゾール−1−イル)−1,1,3,3−テトラメチルユーロニウム テトラフルオロボレート
THF テトラヒドロフラン
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
3−(3−クロロフェニルエチニル)−3a,4,5,6a−テトラヒドロピロロ[3,2−d]イソキサゾール−6−イル−(モルフォリン−4−イル)メタノン
MS:[M+H]+=239.32。
MS:[M+H]+=165.35。
MS:[M+H]+=180.16。
1H NMR (400MHz、クロロホルム−d) δppm 2.10 - 2.23 (m, 1H) 2.30 (dd, 1H) 3.18 (td, 1H) 3.43 - 3.50 (m, 4H) 3.73 (m, 4H) 3.87 - 3.98 (m, 2H) 6.57 (d, 1H) 7.33 (dd, 1H) 7.43 (m, 2H) 7.54 (s, 1H)
MS:[M+H]+=239.32。
3−(3−クロロフェニルエチニル)−3a,4,5,6a−テトラヒドロピロロ[3,2−d]イソキサゾール−6−イル−モルフォリノメタノンの極性の小さいエナンチオマー
3−(3−クロロフェニルエチニル)−3a,4,5,6a−テトラヒドロピロロ[3,2−d]イソキサゾール−6−イル−モルフォリノメタノンの極性の大きいエナンチオマー
エチル−3−[(6−メチル−2−ピリジル)エチニル]−3a,4,5,6a−テトラヒドロピロロ[3,2−d]イソキサゾール−6−カルボキシレート
1H NMR (400MHz、クロロホルム−d) δppm 1.28 - 1.38 (m, 3H) 2.11 - 2.28 (m, 1H) 2.40 (dd, 1H) 2.60 (s, 3H) 3.22 (td, 1H) 3.73 - 3.93 (m, 1H) 3.93 - 4.08 (m, 1H) 4.24 (d, 2H) 6.28 - 6.52 (m, 1H) 7.20 (d, 1H) 7.40 (d, 1H) 7.57 - 7.66 (m, 1H)
t−ブチル−3−エチニル−3a,4,5,6a−テトラヒドロピロロ[3,2−d]イソキサゾール−6−カルボキシレート(中間体20e)
イソプロピル−3−(3−クロロフェニルエチニル)−3a,4,5,6a−テトラヒドロピロロ[3,2−d]イソキサゾール−6−カルボキシレート
MS:[M+H]+=333.1、[2M+Na]=687.3。
1H NMR (400MHz、DMSO−d6) δ 7.77 - 7.73 (m, 1H), 7.63 - 7.57 (m, 2H), 7.53 - 7.47 (m, 1H), 6.35 - 6.26 (m, 1H), 4.89 - 4.78 (m, 1H), 4.21 - 4.12 (m, 1H), 3.73 - 3.65 (m, 1H), 3.08 - 2.97 (m, 1H), 2.26 - 2.18 (m, 2H), 1.23 (d, 6H)
シクロプロピルメチル−3−(3−クロロフェニルエチニル)−3a,4,5,6a−テトラヒドロピロロ[3,2−d]イソキサゾール−6−カルボキシレート
MS:[M+H]+=345.8。
1H NMR (400MHz、DMSO−d6) δ 7 7.77 - 7.74 (m, 1H), 7.64 - 7.56 (m, 2H), 7.51 (dd, 1H), 6.33 (d, 1H), 4.23 - 4.11 (m, 2H), 3.76 - 3.67 (m, 1H), 3.14 - 2.97 (m, 2H), 2.29 - 2.16 (m, 2H), 1.21 - 1.07 (m, 1H), 0.53 (d, 2H), 0.35 - 0.26 (m, 2H)
シクロペンチル−3−(3−クロロフェニルエチニル)−3a,4,5,6a−テトラヒドロピロロ[3,2−d]イソキサゾール−6−カルボキシレート
MS:[2M+Na]=739.4。
1H NMR (400MHz、DMSO−d6) δ 7.78 - 7.73 (m, 1H), 7.63 - 7.57 (m, 2H), 7.53 - 7.47 (m, 1H), 6.29 (dd, 1H), 5.05 (s, 1H), 4.26 - 4.1 1 (m, 1H), 3.73 - 3.62 (m, 1H), 3.14 - 2.95 (m, 1H), 2.27 - 2.15 (m, 2H), 1.90 - 1.75 (m, 2H), 1.75 - 1.50 (m, 6H)
2,2−ジメチルプロピル−3−(3−クロロフェニルエチニル)−3a,4,5,6a−テトラヒドロピロロ[3,2−d]イソキサゾール−6−カルボキシレート
1H NMR (400MHz、DMSO−d6) δ 7.76 (s, 1H), 7.66 - 7.56 (m, 2H), 7.54 - 7.45 (m, 1H), 6.40 - 6.26 (m, 1H), 4.28 - 4.10 (m, 1H), 3.89 - 3.62 (m, 3H), 3.22 - 2.95 (m, 1H), 2.24 (s, 2H), 0.97 - 0.90 (m, 9H)
3−(3−クロロフェニルエチニル)−N−(プロパン−2−イル)−3a,4,5,6a−テトラヒドロピロロ[3,2−d]イソキサゾール−6−カルボキシアミド
MS:[M+H]+=332.1。
1H NMR (400MHz、DMSO−d6) δ 7.75 (t, 1H), 7.63 - 7.56 (m, 2H), 7.53 - 7.46 (m, 1H), 6.44 (d, 1H), 6.35 (d, 1H), 4.14 - 4.06 (m, 1H), 3.84 - 3.75 (m, 1H), 3.70 - 3.61 (m, 1H), 3.00 - 2.89 (m, 1H), 2.24 - 2.10 (m, 2H), 1.09 (dd, 6H)
N−t−ブチル−3−(3−クロロフェニルエチニル)−3a,4,5,6a−テトラヒドロピロロ[3,2−d]イソキサゾール−6−カルボキシアミド
MS:[M+H]+=346。
1H NMR (400MHz、DMSO−d6) δ 7.75 (t, 1H), 7.62 - 7.57 (m, 2H), 7.53 - 7.47 (m, 1H), 6.48 (d, 1H), 5.82 (s, 1H), 4.14 - 4.05 (m, 1H), 3.69 - 3.60 (m, 1H), 3.03 - 2.90 (m, 1H), 2.22 - 2.1 1 (m, 2H), 1.29 (s, 9H)
3−(3−クロロフェニルエチニル)−N−シクロペンチル−3a,4,5,6a−テトラヒドロピロロ[3,2−d]イソキサゾール−6−カルボキシアミド
MS:[M+H]+=358.1。
1H NMR (400MHz、DMSO−d6) δ 7.77 - 7.73 (m, 1H), 7.59 (m, 2H), 7.53 - 7.46 (m, 1H), 6.46 (d, 1H), 6.41 (d, 1H), 4.10 (t, 1H), 4.00 - 3.88 (m, 1H), 3.71 - 3.62 (m, 1H), 3.00 - 2.89 (m, 1H), 2.23 - 2.09 (m, 2H), 1.86 - 1.74 (m, 2H), 1.68 - 1.60 (m, 2H), 1.53 - 1.37 (m, 4H)
3−(3−クロロフェニルエチニル)−3a,4,5,6a−テトラヒドロピロロ[3,2−d]イソキサゾール−6−イル−(フラン−3−イル)メタノン
MS:[M+H]+=341.5。
1H NMR (400MHz、DMSO) δ 8.30 - 8.14 (m, 1H), 7.86 - 7.74 (m, 2H), 7.66 - 7.57 (m, 2H), 7.51 (t, 1H), 6.85 - 6.78 (m, 1H), 6.69 - 6.54 (m, 1H), 4.36 - 4.07 (m, 2H), 3.14 - 2.98 (m, 1H), 2.38 - 2.15 (m, 2H)
3−(3−クロロフェニルエチニル)−3a,4,5,6a−テトラヒドロピロロ[3,2−d]イソキサゾール−6−イル−(5−メチルフラン−2−イル)メタノン
MS:[M+H]+=355.1、[2M+Na]=731.4。
1H NMR (400MHz、DMSO−d6) δ 7.78 (t, 1H), 7.66 - 7.56 (m, 2H), 7.55 - 7.46 (m, 1H), 7.1 1 (d, 1H), 6.81 (s, 1H), 6.33 (dd, 1H), 4.30 (s, 1H), 4.21 - 3.86 (m, 2H), 3.08 (s, 1H), 2.36 (s, 3H), 2.30 (s, 1H)
3−(3−クロロフェニルエチニル)−3a,4,5,6a−テトラヒドロピロロ[3,2−d]イソキサゾール−6−イル−(シクロペンチル)メタノン
MS:[M+H]+=343.1。
1H NMR (400MHz、DMSO−d6、回転異性体の混合物) δ 7.78 - 7.75 (m, 1H), 7.64 - 7.58 (m, 2H), 7.50 (t, 1H), 6.60 (d, lH多い方の回転異性体), 6.45 (d, lH少ない方の回転異性体), 4.28 (t, lH多い方の回転異性体), 4.13 (t, 1 H少ない方の回転異性体), 3.92 - 3.82 (m, 1H), 3.24 - 3.14 (m, l H多い方の回転異性体), 3.09 - 3.00 (m, 1 H少ない方の回転異性体), 2.99 - 2.87 (m, 1H), 2.29 - 2.1 1 (m, 2H), 1.93 - 1.77 (m, 2H), 1.73 - 1.52 (m, 6H)
3−(3−クロロフェニルエチニル)−3a,4,5,6a−テトラヒドロピロロ[3,2−d]オキサゾール−6−イル−(オキサン−4−イル)メタノン
MS:[M+H]+=359.1。
1H NMR (400MHz、DMSO−d6、回転異性体の混合物) δ 7.78 - 7.75 (m, 1H), 7.64 - 7.57 (m, 1H), 7.51 (t, 1H), 6.67 (d, lH多い方の回転異性体), 6.46 (d, lH少ない方の回転異性体), 4.29 (t, lH多い方の回転異性体), 4.13 (t, lH少ない方の回転異性体), 3.94 - 3.77 (m, 4H), 3.44 - 3.33 (m, 3H), 3.00 - 2.87 (m, 1H), 2.35 - 2.08 (m, 2H), 1.71 - 1.52 (m, 4H)
3−(3−クロロフェニルエチニル)−3a,4,5,6a−テトラヒドロピロロ[3,2−d]イソキサゾール−6−イル−(4−メチルピペラジン−1−イル)メタノン
MS:[M+H]+=373.3。
1H NMR (400MHz、DMSO−d6) δ 7.77 - 7.73 (m, 1H), 7.62 - 7.57 (m, 2H), 7.53 - 7.46 (m, lH), 6.52 (d, lH), 4.12 (t, 1H), 3.59 (dd, 1H), 3.36 - 3.28 (m, 2H, シグナルは水のシグナルと部分的に重なっている), 3.28 - 3.19 (m, 2H), 3.16 - 3.07 (m, 1H), 2.36 - 2.24 (m, 4H), 2.23 - 2.16 (m, 4H), 2.15 - 2.05 (m, 1H)
4−オキサニル−3−(3−クロロフェニルエチニル)−3a,4,5,6a−テトラヒドロピロロ[3,2−d]イソキサゾール−6−カルボキシレート
MS:[2M+Na]+=771.3。
1H NMR (400MHz、DMSO−d6) δ 7.75 (s, 1H), 7.65 - 7.56 (m, 2H), 7.53 - 7.47 (m, 1H), 6.35 (t, 1H), 4.83 (s, 1H), 4.20 (s, 1H), 3.87 - 3.63 (m, 3H), 3.50 (d, 2H), 3.05 (s, 1H), 2.24 (s, 2H), 1.87 (s, 2H), 1.59 (s, 2H)
3−メチルブチル−3−(3−クロロフェニルエチニル)−3a,4,5,6a−テトラヒドロピロロ[3,2−d]イソキサゾール−6−カルボキシレート
MS:[2M+Na]+=743.3。
1H NMR (400MHz、DMSO−d6) δ 7.76 (s, 1H), 7.64 - 7.56 (m, 2H), 7.55 - 7.46 (m, 1H), 6.37 - 6.23 (m, 1H), 4.24 - 4.14 (m, 1H), 4.16 - 4.05 (m, 2H), 3.77 - 3.61 (m, 1H), 3.12 - 2.97 (m, 1H), 2.22 (m, 2H), 1.79 - 1.58 (m, 1H), 1.49 (dt, 2H), 0.91 (d, 6H)
3−(3−クロロフェニルエチニル)−N−(ペンタン−3−イル)−3a,4,5,6a−テトラヒドロピロロ[3,2−d]イソキサゾール−6−カルボキシアミド
MS:[M+H]+=360.0。
1H NMR (400MHz、DMSO−d6) δ 7.75 (t, 1H), 7.63 - 7.56 (m, 2H), 7.54 - 7.46 (m, 1H), 6.48 (d, 1H), 6.19 (d, 1H), 4.17 - 4.07 (m, 1H), 3.73 - 3.62 (m, 1H), 3.50 - 3.41 (m, 1H), 3.03 - 2.92 (m, 1H), 2.24 - 2.13 (m, 2H), 1.52 - 1.31 (m, 4H), 0.83 (td, 6H)
3−(3−クロロフェニルエチニル)−N−(ピリジン−3−イル)−3a,4,5,6a−テトラヒドロピロロ[3,2−d]イソキサゾール−6−カルボキシアミド
MS:[M+H]+=367.2、[2M+Na]+=755.2。
1H NMR (400MHz、DMSO−d6) δ 8.86 (s, 1H), 8.70 (d, 1H), 8.22 (dd, 1H), 7.94 (dd, 1H), 7.77 (t, 1H), 7.65 - 7.58 (m, 2H), 7.55 - 7.48 (m, 1H), 7.32 (dd, 1H), 6.60 (d, 1H), 4.24 (t, 1H), 3.91 - 3.82 (m, 1H), 3.21 - 3.10 (m, 1H), 2.37 - 2.24 (m, 2H)
3−(3−クロロフェニルエチニル)−N−(2,2−ジメチルプロピル)−3a,4,5,6a−テトラヒドロピロロ[3,2−d]イソキサゾール−6−カルボキシアミド
MS:[M+H]+=360.2。
1H NMR (400MHz、DMSO−d6) δ 7.75 (t, 1H), 7.63 - 7.56 (m, 2H), 7.53 - 7.47 (m, 1H), 6.53 - 6.45 (m, 2H), 4.16 - 4.09 (m, 1H), 3.71 - 3.64 (m, 1H), 3.07 - 2.96 (m, 2H), 2.78 (dd, 1H), 2.23 - 2.16 (m, 2H), 0.84 (s, 9H)
3−(3−クロロフェニルエチニル)−3a,4,5,6a−テトラヒドロピロロ[3,2−d]イソキサゾール−6−イル−(1,5−ジメチル−1H−ピラゾール−3−イル)メタノン
MS:[M+H]+=369.1、[2M+H]+=759.2。
1H NMR (400MHz、DMSO−d6) δ 7.77 (t, 1H), 7.66 - 7.56 (m, 2H), 7.50 (t, 1H), 7.34 (d, 1H), 6.50 (d, 1H), 4.30 (t, 1H), 4.01 (dd, 1H), 3.80 (d, 3H), 3.06 (td, 1H), 2.36 - 2.10 (m, 5H)
3−(3−クロロフェニルエチニル)−3a,4,5,6a−テトラヒドロピロロ[3,2−d]イソキサゾール−6−イル−(チアゾール−4−イル)メタノン
MS:[M+H]+=358.1。
1H NMR (400MHz、DMSO−d6) δ 9.30 - 9.16 (m, 1H), 8.44 (d, 1H), 7.78 (t, 1H), 7.61 (tt, 2H), 7.55 - 7.45 (m, 1H), 7.35 (d, 1H), 4.34 - 4.23 (d, 1H), 4.03 (dd, 1H), 3.15 (dd, 1H), 2.32 - 2.22 (m, 2H)
3−(3−クロロフェニルエチニル)−3a,4,5,6a−テトラヒドロピロロ[3,2−d]イソキサゾール−6−イル−(4,4−ジフルオロシクロヘキシル)メタノン
MS:[2M+Na]+=807.3。
1H NMR (400MHz、DMSO−d6) δ 7.78 - 7.75 (m, 1H), 7.64 - 7.58 (m, 2H), 7.54 - 7.48 (m, 1H), 6.65 (d, l H多い方の回転異性体), 6.45 (d, l H少ない方の回転異性体), 4.36 - 4.27 (m, lH多い方の回転異性体), 4.17 - 4.10 (m, l H少ない方の回転異性体), 3.96− 3.89 (m, l H少ない方の回転異性体), 3.89− 3.80 (m, lH多い方の回転異性体), 2.95 (td, 1H), 2.88 - 2.79 (m, 1H), 2.31 - 2.20 (m, 2H), 2.18 - 2.00 (m, 2H), 1.98 - 1.75 (m, 4H), 1.69 - 1.52 (m, 2H)
3−(3−クロロフェニルエチニル)−3a,4,5,6a−テトラヒドロピロロ[3,2−d]イソキサゾール−6−イル−(1−メチル−ピペリジン−4−イル)メタノン
MS:[M+H]+=372.3。
1H NMR (400MHz、DMSO−d6) δ 7.78 - 7.74 (m, 1H), 7.64 - 7.58 (m, 2H), 7.54 - 7.47 (m, 1H), 6.64 (d, lH多い方の回転異性体), 6.45 (d, lH少ない方の回転異性体), 4.35 - 4.28 (m, lH多い方の回転異性体), 4.18 - 4.11 (m, lH少ない方の回転異性体), 3.96 - 3.80 (m, 1H), 3.27 - 3.00 (m, 3H), 3.00 - 2.89 (m, 1H), 2.84 - 2.71 (m, 1H), 2.31 - 2.23 (m, 1H), 2.21 - 2.08 (m, 1H), 1.92 - 1.58 (m, 4H), 1.21 - 1.1 1 (m, 1H)。CH3基由来のシグナルは、DMSO−d6のシグナルと重なっている。
3−(3−クロロフェニルエチニル)−N−(2−メトキシエチル)−N−メチル−3a,4,5,6a−テトラヒドロピロロ[3,2−d]イソキサゾール−6−カルボキシアミド
MS:[2M+Na]+=745.3。
1H NMR (400MHz、DMSO−d6) δ 7.75 (t, 1H), 7.64 - 7.55 (m, 2H), 7.54 - 7.46 (m, 1H), 6.52 (d, 1H), 4.12 (t, 1H), 3.61 - 3.39 (m, 4H), 3.31 - 3.27 (m, 1H), 3.26 (s, 3H), 3.18 - 3.05 (m, 1H), 2.88 (s, 3H), 2.25 - 2.01 (m, 2H)
3−(3−フルオロフェニルエチニル)−3a,4,5,6a−テトラヒドロピロロ[3,2−d]イソキサゾール−6−イル−モルフォリン−4−イル−メタノン
MS:[M+H]+=331.65。
MS:[M+H]+=231.54。
MS:[M+H]+=344.54。
1H NMR (400MHz、DMSO−d6) ppm 7.45 - 7.58 (m, 3H) 7.34 - 7.43 (m, 1H) 6.54 (d, 1H) 4.10 - 4.19 (m, 1H) 3.51 - 3.69 (m, 5H) 3.30 - 3.38 (m, 2H) 3.19 - 3.28 (m, 2H) 3.12 (td, 1H) 2.05 - 2.25 (m, 2H)
3−(3−フルオロフェニルエチニル)−3a,4,5,6a−テトラヒドロピロロ[3,2−d]イソキサゾール−6−イル−(ピロリジン−1−イル)メタノン
MS:[M+H]+=328.54。
1H NMR (400MHz、DMSO−d6) ppm 7.45 - 7.58 (m, 3H) 7.29 - 7.44 (m, 1H) 6.54 (d, 1H) 4.19 (dd, 1H) 3.68 (dd, 1H) 3.35 - 3.46 (m, 2H) 3.23 - 3.28 (m, 2H) 3.11 (td, 1H) 2.04 - 2.28 (m, 2H) 1.59 - 1.93 (m, 4H)
3−フェニルエチニル−3a,4,5,6a−テトラヒドロピロロ[3,2−d]イソキサゾール−6−イル−(モルフォリン−4−イル)メタノン
MS:[M+H]+=313.51。
MS:[M+H]+=213.54。
MS:[M+H]+=326.55。
1H NMR (400MHz、DMSO−d6) ppm 7.59 - 7.66 (m, 2H) 7.43 - 7.56 (m, 3H) 6.53 (d, 1H) 4.13 (dd, 1H) 3.52 - 3.69 (m, 5H) 3.33 - 3.41 (m, 2H) 3.19 - 3.28 (m, 2H) 3.13 (td, 1H) 2.05 - 2.24 (m, 2H)
3−(3−ブロモフェニルエチニル)−3a,4,5,6a−テトラヒドロピロロ[3,2−d]イソキサゾール−6−イル−(ピロリジン−1−イル)メタノン
MS:[M+H]+=392.66。
MS:[M+H]+=292.78。
MS:[M+H]+=389.71。
1H NMR (400MHz、DMSO−d6) ppm 7.87 (m, 1H), 7.72 (m, 1H), 7.64 (m, 1H), 7.39-7.48 (m, lH), 6.54 (d, 1H), 4.07-4.18 (m, 1H), 3.60-3.72 (m, 1H), 3.34-3.44 (m, 2H), 3.31 (d, 2H), 3.1 1 (m, 1H), 2.03-2.30 (m, 2H), 1.64-1.94 (m, 4H)
安定にトランスフェクトされるセルラインが、テトラサイクリン調節発現システム(T- REx(登録商標) system, Invitrogen, Life Technologies)を用いて、ヒトmGluR5受容体をエンコードする発現誘導ベクターを用いて作製された。ヒトmGluR5のオープンリーディングフレーム(ORF)、網羅的なストップコドンが、TetO2を有するpcDNA4/TO/myc−His(登録商標) A ベクターにクローニングされた。mGluR5受容体のための挿入サイトは、HIndIII−PstIであった。得られた構築物は、その後、FuGENEプロトコール(Roche)を用いて、T−REx CHO(登録商標)セルラインへとトランスフェクトされた。CHO T−REx(登録商標)セルラインは、ブラストサイジン、10μg/mLのセレクション下、安定的にTetリプレッサーを発現する(pcDNA6/TR プラスミドから)。安定なクローンは、1mg/mLのzeocin(登録商標)を用いて選択し、透析FBS、zeocin(登録商標)、ブラストサイジンで補充されたULTRA CHO培地(LONZA)中で5% CO2雰囲気中、37℃で維持することにより得られた。h−mGluR5受容体の発現は、結合実験の前、18時間、1μg/mLのテトラサイクリンで抑制解除され、一方、h−mGluR5受容体の発現は、蛍光ベースのカルシウム実験の前、18時間、それぞれ3ng/mLおよび10ng/mLのテトラサイクリンを用いて抑制解除された。
膜貫通型グルタミン酸代謝型のmGluR5受容体サブタイプのアフィニティーは、いくつかの変更を加えたAndersonの方法にしたがって、評価された(Anderson ら、J Pharmacol. Exp. Ther.、2002年、第303(3)巻、1044〜51頁)。クローニングされたmGluR5は、20mM HEPES、2mM MgCl2、2mM CaCl2、pH7.4中にCHO T−REx(登録商標)h−mGluR5セルを再懸濁させ(50μg/ウェル)、その後、最終的な体積が1mLで、25℃で60分間、4nM [3H]MPEPとともに、競合薬剤の存在下または非存在下でインキュベートすることによって得られた。非特異的バインディングは、10μM MPEPの存在下で測定された。インキュベーションは、pH7.4の冷トリスバッファーの添加によって停止され、そして、0.2%ポリエチレンイミンで前処理されたFiltermat 1204−401(Perkin Elmer)フィルターで素早くろ過された。その後フィルターが冷バッファーで洗浄され、そして、フィルター上に保持された放射活性が液体シンチレーションスペクトロメトリー(Betaplate 1204 BS-Wallac)によってカウントされた。
セルは、10%透析FBSで補充されたRPMI(フェノールレッドなし、L−グルタミンなし、Gibco LifeTechnologies, CA)中、80000セル/ウェルの密度で、黒色フレーム、透明底の96ウェルプレート内に播種された。テトラサイクリンとの18時間のインキュベーション後、セルは、37℃で1時間、20μm Hepes(Sigma)および2.5mM プロベネシド(Sigma)を含むハンクス平衡生理的塩溶液(HBSS、Gibco LifeTechnologies, CA)中に、2mMのCa2+感受性蛍光色素Fluo−4/AM(Molecular Probes)とともにロードされた。セルは、細胞外の色素を除去するために、HBSSを用いて3回洗浄された。蛍光シグナルは、1.5秒〜60秒のサンプリング間隔で、蛍光マイクロプレートリーダー Flexstation(登録商標)3(Molecular Devices)を使用して測定された。
天然およびクローニングされたmGluR5およびmGluR5サブタイプにおける試験された化合物の阻害カーブは、Prism 4.0(Graphpad, San Diego, CA)ソフトウェアを用いて非線形回帰分析によって決定された。IC50値および擬Hillスロープ係数がプログラムによって見積もられた。阻害定数Kiの値は、式 Ki=IC50/(1+[L]/Kd)(ここで、[L]は、放射性リガンドの濃度であり、Kdは、放射性リガンド−受容体錯体の平衡解離定数である)にしたがって計算された(Chengら、Biochem. Pharmacol.、1973年、第22巻、3099〜3108頁)。
Claims (15)
- 以下の式I:
(R1は、アルキル基、任意には置換されていてもよい一環式、二環式または三環式の、N、OおよびSから選択される1〜5個のヘテロ原子を含むC1〜C13のヘテロ環基、任意には置換されていてもよい一環式、二環式または三環式のC6〜C14のアリール基、任意には置換されていてもよいC3〜C6のシクロアルキル基、もしくは任意には置換されていてもよいC3〜C6のシクロアルケニル基、または、結合、一または複数のR2基または置換基によって任意には置換されていてもよいCO、CS、CH、CH2、SO2基であり、
R2は、非存在であるか、または、任意には置換されていてもよい一環式または二環式の、窒素、酸素および硫黄から選択される1〜3個のヘテロ原子を含むC1〜C9のヘテロ環基、任意には置換されていてもよい一環式、二環式または三環式のC6〜C14のアリール基、または、アルキル基、シクロアルキル基、アルコキシ基、シクロアルキルオキシ基、アリールオキシ基、ヘテロアリールオキシ基、アルキルチオ基、アミノ基、N−アルキルアミノ基、N,N−ジアルキルアミノ基、もしくはN−アルキル−N−アルコキシアミノ基から選ばれる任意には置換されていてもよい基であり、
R3は、任意には置換されていてもよいアルキル基、任意には置換されていてもよい一環式、二環式または三環式の、N、OおよびSから選択される1〜5個のヘテロ原子を含むC1〜C13のヘテロ環基、任意には置換されていてもよい一環式、二環式または三環式の、C6〜C14のアリール基、任意には置換されていてもよいC3〜C6のシクロアルキル基、または、任意には置換されていてもよいC3〜C6のシクロアルケニル基であり、ならびに
nは1〜3である。) - 任意の置換基が、ハロゲン原子、および、C1〜C6アルキル基、C1〜C6アルコキシ基、水酸基、メルカプト基、ニトロ基、シアノ基、オキソ基、ハロ(C1〜C6)アルキル基、ハロ(C1〜C6)アルコキシ基、C1〜C6アルキルチオ基、C1〜C6のアルキルスルホニル基、C1〜C6アルキルカルボニル基、スルファモイル基、C1〜C6アルキルスルファモイル基、ジ(C1〜C6)アルキルスルファモイル基、(C1〜C6)アルコキシカルボニル基、および、(C1〜C6)アルキルカルボニル(C1〜C6)アルキル基からなる群より、ならびに、−NR*R*、−C(=O)−NR*R*、−A、−O−A、−C(=O)−A、−(CH2)q−A、−NR**−A、−C(=O)−NR**−A、−NR**C(=O)−A、および、−0−C(=O)−Aで示される式であって、ここで、それぞれのR*は、独立して、水素原子、または、C1〜C6アルキル基、C1〜C6アルコキシ基、C1〜C6アルキルカルボニル基、フェニル基、または、ベンゾイル基を示し、R**は、水素原子、または、C1〜C6アルキル基を示し、qは1〜6の整数であり、ならびに、Aは、フェニル基、または、N、OおよびSから選択される1〜3個のヘテロ原子を含むC1〜C8のヘテロ環基、C1〜C6シクロアルキル基であって、それぞれの基のAは、任意には、ハロ基、水酸基、シアノ基、ニトロ基およびC1〜C6アルキル基から独立して選択される1〜3の基で置換されていてもよい、式である群より、独立して選択される置換基であり、好ましくは、ハロゲン原子およびC1〜C6アルキル基からなる群より選択される置換基である請求項1記載の化合物。
- n=1である請求項1または2記載の化合物。
- R1がCO基である請求項1記載の化合物。
- R2が、任意には置換されていてもよい一環式もしくは二環式の、窒素、酸素および硫黄から選択される1〜3個のヘテロ原子を含むC1〜C9のヘテロ環基、または、シクロアルキル基、アルコキシ基、シクロアルキルオキシ基、アリールオシ基、ヘテロアリールオキシ基、アミノ基、N−アルキルアミノ基、N,N−ジアルキルアミノ基、もしくは、N−アルキル−N−アルコキシアミノ基から選ばれる任意には置換されていてもよい基である請求項1〜4のいずれか1項に記載の化合物。
- R2が、以下の式:
−OR4
(ここで、R4は、C1〜C10の直鎖のまたは分岐のアルキル基、C1〜C10のシクロアルキル基、または、NもしくはOから選択される少なくとも一つのヘテロ原子を含むC1〜C10のヘテロ環基である)
である請求項5記載の化合物。 - R2が、飽和または不飽和の、任意には置換されていてもよい、5員環もしくは6員環である同素環基またはNもしくはOから選択される少なくとも一つのヘテロ原子を含むヘテロ環基である。請求項5記載の化合物。
- R2が、以下の式:
−NR5R6
(ここで、R5は、C1〜C10の直鎖もしくは分岐のアルキルもしくはアルコキシ基または水素原子であり、R6は、C1〜C10の直鎖もしくは分岐のアルキルもしくはアルコキシ基であって、R5およびR6は、同一の基でもよく、また異なる基であってもよい、または
R5およびR6は、窒素原子ともに、5員環もしくは6員環のヘテロ環式の環を形成する)
である請求項5記載の化合物。 - R3が、任意には置換されていてもよい一環式、二環式または三環式のC6〜C14のアリール基、NまたはOより選択される少なくとも一つのヘテロ原子を含む任意には置換されていてもよい5員環または6員環のヘテロ環基、任意には置換されていてもよいC3〜C6シクロアルキル基、または、任意には置換されていてもよいC3〜C6シクロアルケニル基である請求項1〜8のいずれか1項に記載の化合物。
- R3が、フェニルまたはピリジニル基であり、前記任意的な置換基が、C1〜C10アルキル基またはハライド基より選択される請求項9記載の化合物。
- 以下の式I:
(R1は、アルキル基、任意には置換されていてもよい一環式、二環式または三環式の、N、OおよびSから選択される1〜5個のヘテロ原子を含むC1〜C13のヘテロ環基、任意には置換されていてもよい一環式、二環式または三環式のC6〜C14のアリール基、任意には置換されていてもよいC3〜C6のシクロアルキル基、もしくは任意には置換されていてもよいC3〜C6のシクロアルケニル基、または、結合、一または複数のR2基または置換基によって任意には置換されていてもよいCO、CS、CH、CH2、SO2基であり、
R2は、非存在であるか、または、任意には置換されていてもよい一環式または二環式の、窒素、酸素および硫黄から選択される1〜3個のヘテロ原子を含むC1〜C9のヘテロ環基、任意には置換されていてもよい一環式、二環式または三環式のC6〜C14のアリール基、または、アルキル基、シクロアルキル基、アルコキシ基、シクロアルキルオキシ基、アリールオキシ基、ヘテロアリールオキシ基、アルキルチオ基、アミノ基、N−アルキルアミノ基、N,N−ジアルキルアミノ基、もしくはN−アルキル−N−アルコキシアミノ基から選ばれる任意には置換されていてもよい基であり、
R3は、任意には置換されていてもよいアルキル基、任意には置換されていてもよい一環式、二環式または三環式の、N、OおよびSから選択される1〜5個のヘテロ原子を含むC1〜C13のヘテロ環基、任意には置換されていてもよい一環式、二環式または三環式の、C6〜C14のアリール基、任意には置換されていてもよいC3〜C6のシクロアルキル基、または、任意には置換されていてもよいC3〜C6のシクロアルケニル基であり、ならびに
nは1〜3である。) - それを必要とする被験者における神経学的障害、精神病性障害またはグルタミン酸機能不全に関連する精神医学的な障害の処置および/または予防における使用のための、以下の式I:
(R1は、アルキル基、任意には置換されていてもよい一環式、二環式または三環式の、N、OおよびSから選択される1〜5個のヘテロ原子を含むC1〜C13のヘテロ環基、任意には置換されていてもよい一環式、二環式または三環式のC6〜C14のアリール基、任意には置換されていてもよいC3〜C6のシクロアルキル基、もしくは任意には置換されていてもよいC3〜C6のシクロアルケニル基、または、結合、一または複数のR2基または置換基によって任意には置換されていてもよいCO、CS、CH、CH2、SO2基であり、
R2は、非存在であるか、または、任意には置換されていてもよい一環式または二環式の、窒素、酸素および硫黄から選択される1〜3個のヘテロ原子を含むC1〜C9のヘテロ環基、任意には置換されていてもよい一環式、二環式または三環式のC6〜C14のアリール基、または、アルキル基、シクロアルキル基、アルコキシ基、シクロアルキルオキシ基、アリールオキシ基、ヘテロアリールオキシ基、アルキルチオ基、アミノ基、N−アルキルアミノ基、N,N−ジアルキルアミノ基、もしくはN−アルキル−N−アルコキシアミノ基から選ばれる任意には置換されていてもよい基であり、
R3は、任意には置換されていてもよいアルキル基、任意には置換されていてもよい一環式、二環式または三環式の、N、OおよびSから選択される1〜5個のヘテロ原子を含むC1〜C13のヘテロ環基、任意には置換されていてもよい一環式、二環式または三環式の、C6〜C14のアリール基、任意には置換されていてもよいC3〜C6のシクロアルキル基、または、任意には置換されていてもよいC3〜C6のシクロアルケニル基であり、ならびに
nは1〜3である。) - 前記グルタミン酸機能不全に関連する障害が、統合失調症、統合失調感情障害、物質誘発精神病性障害、加齢に伴う学習および記憶の障害または損失、脳卒中後の認知症、集中力欠如、中程度の認知機能障害、アルツハイマー病における認知機能障害、統合失調症における認知機能障害、認知低下、認知症または認知機能障害、脆弱X症候群、レット症候群、フェラン−マクダーミド症候群、または結節性硬化である請求項13記載の化合物。
- 前記障害が、脆弱X症候群、レット症候群、フェラン−マクダーミド症候群、または結節性硬化である請求項13記載の化合物。
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