JP2018511627A - Nmda受容体のモジュレーターとしてのピリドピリミジノン及びその使用 - Google Patents
Nmda受容体のモジュレーターとしてのピリドピリミジノン及びその使用 Download PDFInfo
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- JP2018511627A JP2018511627A JP2017553877A JP2017553877A JP2018511627A JP 2018511627 A JP2018511627 A JP 2018511627A JP 2017553877 A JP2017553877 A JP 2017553877A JP 2017553877 A JP2017553877 A JP 2017553877A JP 2018511627 A JP2018511627 A JP 2018511627A
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Abstract
Description
本発明は、特定のピリドピリミジノン化合物と、かかる化合物を含む医薬組成物と、かかる化合物及び医薬組成物を用いて神経学的及び精神医学的病態ならびに他の疾患及び病状を処置する方法とに関する。また、本発明は、NMDA受容体活性の調節における使用のための特定のピリドピリミジノン化合物に関する。
N−メチル−D−アスパラギン酸(NMDA)受容体は、シナプス伝達及びシナプス可塑性のような様々な中枢神経系機能、ならびに長期増強、長期抑圧、及び経験依存的シナプス微調整の制御のような根底をなす機能において重要な役割を果たしている。Costaら、「A Novel Family of Negative and Positive Allosteric Modulators of NMDA Receptors」、J. Pharmacol. Exp. Ther. 2010年335号、614〜621、614頁。これら受容体における興奮性神経伝達は、神経伝達物質、L−グルタミン酸、及びアゴニストであるNMDAによって制御される。国際公開公報第2007/006175号、段落2〜3。NMDA受容体は、7つのサブユニット:GluN1、GluN2A〜D、及びGluN3A〜Bを含むリガンド開口型イオンチャネルである。Costa、615頁。NR2A及びNR2Bサブユニットは、グルタミン酸の受容体への結合に関与しているが、一方で、NR1サブユニットは、受容体コアゴニストであるグリシンの結合において役割を果たし得る。NMDA受容体のグルタミン酸結合ポケット及びグリシン結合ポケットの三次元構造は、特徴付けられており、より多くのサブタイプ特異的モジュレーターの設計が可能になっている。
本発明は、式I:
[式中、
Xは:−O−Ar;
−NRa−Ar;又は
−Arであり;
R1は:水素;
C1−6アルキル;
ハロ;
C1−6アルコキシ;
シアノ;
フラニル、チエニル、ピロリル、ピラゾリル、イミダゾリル、ピリジニル及びピリミジニル(これらの各々は、非置換であっても、又はRbで1若しくは2回置換されていてもよい)より選択される、ヘテロアリール;
−C(O)−NHRc;
−C(O)−Rc;又は
シクロプロピル(これは、非置換であっても、又はRdで1若しくは2回置換されていてもよい)であり;
R2は:水素;
C1−6アルキル;
C1−6アルコキシ;
ハロ;又は
ハロ−C1−6アルキルであり;
R3は:水素;
C1−6アルキル;
C1−6アルコキシ;
ハロ;又は
ハロ−C1−6アルキルであり;
R4は:水素;又は
C1−6アルキルであり;
R5は:水素;又は
C1−6アルキルであり;そして
R6は:水素;
C1−6アルキルであり;
Arは:フェニル、又はフラニル、チエニル、ピロリル、ピラゾリル、イミダゾリル、ベンゾイミダゾリル、ピリジニル及びピリミジニルより選択されるヘテロアリールであり、ここで、該フェニル又はヘテロアリールは、非置換であっても、又はReで1、2若しくは3回置換されていてもよく;
Raは:水素;又は
C1−6アルキルであり;
Rbは:C1−6アルキル;
ハロ;
ハロ−C1−6アルキル;又は
シクロプロピルであり;
Rcは:C1−6アルキル;又は
ハロ−C1−6アルキルであり;
各Rdは、独立して:
C1−6アルキル;
ハロ;
ハロ−C1−6アルキル;
ヒドロキシ−C1−6アルキル;
C1−6アルコキシ−C1−6アルキル;又は
シアノであり;
各Reは、独立して:
C1−6アルキル;
ハロ;
ハロ−C1−6アルキル;
−NH−C(O)−Rf;
シアノ;又は
シクロプロピルであり;そして
Rfは、フラニル、チエニル、ピロリル、ピラゾリル又はイミダゾリルである]
で示される化合物、又はその薬学的に許容し得る塩を提供する。
大部分の化学名は、本明細書においてIUPAC命名法を用いて作成した。一部の化学名は、異なる命名法を用いて作成したか、又は当技術分野において公知の別の名称若しくは商品名であった。名称と構造とが矛盾する場合、構造が優先される。
上記で使用する場合、及び本開示全体を通して、以下の用語は、特に指定しない限り、以下の意味を有すると理解されるものとする。定義が見当たらない場合、当業者に公知の従来の定義を適用する。本明細書に提供される定義が、任意の引用した刊行物に提供される定義と矛盾するか又は異なっている場合、本明細書に提供される定義を適用する。
本明細書で使用する場合、「アルキル」とは、1〜10個の炭素原子を有する飽和の、直鎖状又は分枝鎖状の炭化水素基を指す。代表的なアルキル基は、メチル、エチル、n−プロピル、イソプロピル、2−メチル−1−プロピル、2−メチル−2−プロピル、2−メチル−1−ブチル、3−メチル−1−ブチル、2−メチル−3−ブチル、2,2−ジメチル−1−プロピル、2−メチル−1−ペンチル、3−メチル−1−ペンチル、4−メチル−1−ペンチル、2−メチル−2−ペンチル、3−メチル−2−ペンチル、4−メチル−2−ペンチル、2,2−ジメチル−1−ブチル、3,3−ジメチル−1−ブチル、2−エチル−1−ブチル、ブチル、イソブチル、t−ブチル、n−ペンチル、イソペンチル、ネオペンチル、n−ヘキシルなど、及びヘプチル、オクチルなどのようなより長鎖のアルキル基を含むが、これらに限定されない。本明細書で使用する場合、「低級アルキル」とは、1〜6個の炭素原子を有するアルキルを意味する。
ヘテロシクロアルキル基は、それらが炭素原子を介して分子の残部に結合していることを意味する炭素結合していてもよいし、又は、それらが窒素原子を介して分子の残部に結合していることを意味する窒素結合していてもよい。
本発明は、式I:
[式中、
Xは:−O−Ar;
−NRa−Ar;又は
−Arであり;
R1は:水素;
C1−6アルキル;
ハロ;
C1−6アルコキシ;
シアノ;
フラニル、チエニル、ピロリル、ピラゾリル、イミダゾリル、ピリジニル及びピリミジニル(これらの各々は、非置換であっても、又はRbで1若しくは2回置換されていてもよい)より選択される、ヘテロアリール;
−C(O)−NHRc;
−C(O)−Rc;又は
シクロプロピル(これは、非置換であっても、又はRdで1若しくは2回置換されていてもよい)であり;
R2は:水素;
C1−6アルキル;
C1−6アルコキシ;
ハロ;又は
ハロ−C1−6アルキルであり;
R3は:水素;
C1−6アルキル;
C1−6アルコキシ;
ハロ;又は
ハロ−C1−6アルキルであり;
R4は:水素;又は
C1−6アルキルであり;
R5は:水素;又は
C1−6アルキルであり;そして
R6は:水素;
C1−6アルキルであり;
Arは:フェニル、又はフラニル、チエニル、ピロリル、ピラゾリル、イミダゾリル、ベンゾイミダゾリル、ピリジニル及びピリミジニルより選択されるヘテロアリールであり、ここで、該フェニル又はヘテロアリールは、非置換であっても、又はReで1、2若しくは3回置換されていてもよく;
Raは:水素;又は
C1−6アルキルであり;
各Rbは、独立して:
C1−6アルキル;
ハロ;
ハロ−C1−6アルキル;又は
シクロプロピルであり;
Rcは:C1−6アルキル;又は
ハロ−C1−6アルキルであり;
Rdは、C1−6アルキル;
ハロ;
ハロ−C1−6アルキル;
ヒドロキシ−C1−6アルキル;
C1−6アルコキシ−C1−6アルキル;又は
シアノであり;
各Reは、独立して:
C1−6アルキル;
ハロ;
ハロ−C1−6アルキル;
−NH−C(O)−Rf;
シアノ;又は
シクロプロピルであり;そして
Rfは、フラニル、チエニル、ピロリル、ピラゾリル又はイミダゾリルである]
で示される化合物、又はその薬学的に許容し得る塩を提供する。
本発明はまた、NR2A陽性アロステリックモジュレーターによって媒介されるか、さもなければNR2A陽性アロステリックモジュレーターに関連する疾患又は病態を処置する方法であって、それを必要としている対象に有効量の本発明の化合物を投与することを含む方法を提供する。
本発明の化合物は、以下に示され説明される例示的合成反応スキームに描かれる様々な方法によって生成することができる。
追加の実施態様は、式IIIの少なくとも1つの化合物又はその薬学的に許容し得る塩及び薬学的に許容し得る賦形剤を含む医薬組成物と、NMDA受容体活性によって媒介される疾患又は病状に罹患している対象を処置する方法であって、かかる処置を必要としている対象に有効量の式IIIの少なくとも1つの化合物又はその薬学的に許容し得る塩を投与することを含む方法とを含む。
本明細書で使用する場合、用語「対象」とは、哺乳類及び非哺乳類を包含する。哺乳類の例は、哺乳綱の任意のメンバー:ヒト;非ヒト霊長類(例えば、チンパンジー及び他の類人猿、ならびにサルの種);家畜(例えば、ウシ、ウマ、ヒツジ、ヤギ、ブタ);飼育動物(例えば、ウサギ、イヌ、及びネコ);及び実験動物(ラット、マウス、及びモルモットなどのげっ歯類を含む)などを含むが、これらに限定されない。非哺乳類の例は、鳥類、魚類などを含むが、これらに限定されない。本発明の1つの実施態様において、哺乳類は、ヒトである。
次に、本発明の化合物の調製において有用な例示的で非限定的な化学実体及び方法について、以下の具体的な実施例を参照して説明する。当業者であれば、他の合成経路を用いて本発明による化合物を合成し得ることを理解するであろう。具体的な出発物質及び試薬を本明細書に図示し、説明するが、他の出発物質及び試薬に容易に置き換えて、様々な誘導体及び/又は反応条件を提供することができる。加えて、記載する方法によって調製される例示的な化合物の多くは、当業者に周知の従来の化学を用いて本開示を考慮して更に改変することができる。
特に指定しない限り、1H NMRスペクトルは、三重共鳴5mmプローブを備えるVarian Unity Inova(400MHz)分光計を用いて、周囲温度で記録した。化学シフトは、テトラメチルシランに対してppmで表す。以下の略記を用いた: br=ブロードシグナル(幅広い信号)、s=シングレット(1重線)、d=ダブレット(2重線)、dd=ダブルダブレット(2重−2重線)、t=トリプレット(3重線)、q=カルテット(4重線)、m=マルチプレット(多重線)。
窒素の不活性雰囲気でパージし維持した30-mLの封管中、テトラヒドロフラン(12.2mL)中のシクロプロパンカルボニトリル(1.0g、14.9mmol)の溶液に、[Ir(COD)OMe]2(320mg、0.25mmol)、ビス(ピナコラト)ジボロン(1.59g、12.5mmol)及びジメチルフェン(50.5mg、0.49mmol)を加えた。反応混合物を90℃で18時間撹拌し、減圧下で濃縮した。残留物を酢酸エチル/石油エーテル(1:4)を用いるクロマトグラフィーにより精製して、2−(テトラメチル−1,3,2−ジオキサボロラン−2−イル)シクロプロパン−1−カルボニトリルを明黄色の油状物(1g、粗)として与えた。この反応を180回繰り返して、2−(テトラメチル−1,3,2−ジオキサボロラン−2−イル)シクロプロパン−1−カルボニトリル 180gを明黄色の油状物として与えた。
メタノール(4.5L)中の2−(テトラメチル−1,3,2−ジオキサボロラン−2−イル)シクロプロパン−1−カルボニトリル(180g、粗)の溶液に、H2O(2L)中のジフルオランカリウム(difluorane potassium)(9.98g、129mmol)を加えた。得られた反応混合物を室温で12時間撹拌し、減圧下で濃縮した。残留物をプロパン−2−オン(6×1.5L)で洗浄した。濾液を減圧下で濃縮し、水(5L)で溶解し、DCM(3×3L)及びEA(3×3L)で洗浄した。水層を凍結乾燥させて、カリウム2−(トリフルオロボラート)シクロプロパンカルボニトリルを白色の固体(151.9g、2つの工程で33%)として与えた。 1H-NMR (400 MHz, DMSO-d6, ppm): δ 0.88-0.82 (m, 1H), 0.76-0.72 (m, 1H), 0.59-0.51 (m, 1H), 0.03-0.10 (m, 1H).
アセトニトリル(50mL)中の6−クロロピリジン−2−アミン(5g、38.9mmol)の溶液に、N−クロロスクシンイミド(5.25g、39.3mmol)を加えた。反応物を80℃で18時間撹拌し、次に減圧下で濃縮した。残留物を、酢酸エチル/石油エーテル(1/3)を用いるクロマトグラフィーにより精製して、5,6−ジクロロピリジン−2−アミン(4g、63%)を白色の固体として与えた。LCMS (ESI): M+H+= 163.0. 1HNMR (300 MHz, CDCl3) δ 7.42 (d, J = 4.0 Hz, 1H), 6.63 (d, J = 4.0 Hz, 1H), 5.10 (brs, 2H).
5,6−ジクロロピリジン−2−アミン(4g、24.5mmol)、4−クロロ−3−オキソブタン酸エチル(8.1g、49.2mmol)及びPPA(21g、182mmol)の混合物を、110℃で1時間撹拌した。反応物を水(50mL)に注ぎ、水酸化ナトリウム(1mol/L)を用いて溶液のpH値を7に調整した。得られた溶液をジクロロメタン(3×200mL)で抽出し、次に減圧下で濃縮した。残留物を、酢酸エチル/石油エーテル(1/3)を用いるクロマトグラフィーにより精製して、6,7−ジクロロ−2−(クロロメチル)−4H−ピリド[1,2−a]ピリミジン−4−オン(2g、31%)を褐色の固体として与えた。LCMS (ESI): M+H+= 263.0. 1HNMR (300 MHz, CDCl3) δ 7.58 (d, J = 4.8 Hz, 1H), 7.37 (d, J = 4.8 Hz, 1H), 6.57 (s, 1H), 4.45 (s, 2H).
アセトニトリル(50mL)中の6,7−ジクロロ−2−(クロロメチル)−4H−ピリド[1,2−a]ピリミジン−4−オン(1g、3.80mmol)の溶液に、5−クロロ−3−(トリフルオロメチル)−1H−ピラゾール(519mg、3.04mmol)、ヨウ化カリウム(317mg、1.91mmol)及び炭酸カリウム(1.05g、7.60mmol)を加えた。反応物を80℃で1時間撹拌した。次に得られた混合物を減圧下で濃縮した。残留物を、酢酸エチル/石油エーテル(1/9)を用いるクロマトグラフィーにより精製して、6,7−ジクロロ−2−[[5−クロロ−3−(トリフルオロメチル)−1H−ピラゾール−1−イル]メチル]−4H−ピリド[1,2−a]ピリミジン−4−オン(600mg、40%)を黄色の油状物として与えた。LCMS (ESI): M+H+ = 397.1; 1HNMR (300 MHz, CDCl3) δ 7.60 (d, J = 4.8 Hz, 1H), 7.34 (d, J = 4.8 Hz, 1H), 6.60 (s, 1H), 5.85 (s, 1H), 5.31 (s, 2H).
1,4−ジオキサン/H2O(6mL/0.6mL)中の6,7−ジクロロ−2−[[5−クロロ−3−(トリフルオロメチル)−1H−ピラゾール−1−イル]メチル]−4H−ピリド[1,2−a]ピリミジン−4−オン(440mg、1.11mmol)の溶液に、カリウム2−(トリフルオロボラート)シクロプロパンカルボニトリル(577mg、3.34mmol)、1,1’−ビス(ジフェニルホスフィノ)フェロセンパラジウムジクロリド(250mg、0.342mmol)及びリン酸カリウム(707mg、3.34mmol)を加えた。得られた溶液を90℃で15時間撹拌し、次に減圧下で濃縮した。残留物を、酢酸エチル/石油エーテル(1/9)で精製して、ラセミ生成物(100mg、21%)を与えた。次にこの生成物をキラル分取HPLCにより下記の条件で精製して、2つの異性体を与えた:カラム、Chiralpak IC-3、0.46×5cm、3um;移動相、Hex及びEtOH(8分で30.0%EtOHを保持);検出器、UV 254nm:
エナンチオマー1: (保持時間、2.767分)(1R,2R)−2−(7−クロロ−2−[[5−クロロ−3−(トリフルオロメチル)−1H−ピラゾール−1−イル]メチル]−4−オキソ−4H−ピリド[1,2−a]ピリミジン−6−イル)シクロプロパン−1−カルボニトリル(42.3mg、9%)を黄色の固体として。LCMS (ESI): M+H+ = 428.0; 1HNMR (300 MHz, CDCl3) 7.52 (d, J = 4.8 Hz, 1H), 7.37 (d, J = 4.8 Hz, 1H), 6.64 (s, 1H), 5.86 (s, 1H), 5.34 (s, 2H), 3.32-3.24 (m, 1H), 1.88-1.77 (m, 1H), 1.57-1.50 (m, 1H), 1.28-1.22 (m, 1H).
及び
エナンチオマー2: (保持時間、4.082分)(1S,2S)−2−(7−クロロ−2−[[5−クロロ−3−(トリフルオロメチル)−1H−ピラゾール−1−イル]メチル]−4−オキソ−4H−ピリド[1,2−a]ピリミジン−6−イル)シクロプロパン−1−カルボニトリルを黄色の固体(40.7mg、9%)として。 LCMS (ESI): M+H+ = 428.0; 1HNMR (300 MHz, CDCl3) 7.54 (d, J = 4.8 Hz, 1H), 7.41 (d, J = 4.8 Hz, 1H), 6.64 (s, 1H), 5.85 (s, 1H), 5.35 (s, 2H), 3.32-3.25 (m, 1H), 1.89-1.82 (m, 1H), 1.57-1.51 (m, 1H), 1.27-1.20 (m, 1H).
テトラサイクリン誘導性hNR1及びhNR2Aで安定的にトランスフェクトしたHEK細胞を、底が透明な384ウェルのポリ−D−リジンでコーティングされたプレート内の7.5μg mL−1 デオキシサイクリン及び500μM (+)−ケタミンを含む最小必須培地(MEM;L−不含)に播種した(2.5×104細胞/ウェル)。細胞を、5%CO2中37℃で24時間インキュベートした。細胞質カルシウムの変化を測定するために、播種培地を除去し、そして、ハンクス平衡塩類溶液(HBSS;マグネシウム無し、1.8mM カルシウム、0.65mg mL−1 プロベネシド、及び10μM (+)−ケタミンを含む、pH7.15)中、1X Becton Dickinson Calcium Assay Kit試薬を用いて、細胞を37℃で60分間インキュベートし、次いで、室温で30分間平衡化させた。様々なウェルのHBSSに様々な濃度(30μM グリシン及び300nM L−グルタミン酸を含む(EC30))を添加することによって、陽性アロステリックモジュレーター(PAM)に対する濃度−効果曲線を作成した。10秒間のベースライン読み取り後に化合物を添加し、そして、相対蛍光単位(RFU)の最高レベルを5分間にわたって測定した。100μM L−グルタミン酸最大応答(100%)及び0μM L−グルタミン酸(0%)に対して応答をスケーリングした。最大応答プラトーに達する化合物についてはEC50値が与えられ、そして、プラトーに達しなかった場合のみ、最大%(EC50(--))が与えられる。
Claims (22)
- 式I:
[式中、
Xは:−O−Ar;
−NRa−Ar;又は
−Arであり;
R1は:水素;
C1−6アルキル;
ハロ;
C1−6アルコキシ;
シアノ;
フラニル、チエニル、ピロリル、ピラゾリル、イミダゾリル、ピリジニル及びピリミジニル(これらの各々は、非置換であっても、又はRbで1若しくは2回置換されていてもよい)より選択される、ヘテロアリール;
−C(O)−NHRc;
−C(O)−Rc;又は
シクロプロピル(これは、非置換であっても、又はRdで1若しくは2回置換されていてもよい)であり;
R2は:水素;
C1−6アルキル;
C1−6アルコキシ;
ハロ;又は
ハロ−C1−6アルキルであり;
R3は:水素;
C1−6アルキル;
C1−6アルコキシ;
ハロ;又は
ハロ−C1−6アルキルであり;
R4は:水素;又は
C1−6アルキルであり;
R5は:水素;又は
C1−6アルキルであり;そして
R6は:水素;
C1−6アルキルであり;
Arは:フェニル、又はフラニル、チエニル、ピロリル、ピラゾリル、イミダゾリル、ベンゾイミダゾリル、ピリジニル及びピリミジニルより選択されるヘテロアリールであり、ここで、該フェニル又はヘテロアリールは、非置換であっても、又はReで1、2若しくは3回置換されていてもよく;
Raは:水素;又は
C1−6アルキルであり;
各Rbは、独立して:
C1−6アルキル;
ハロ;
ハロ−C1−6アルキル;又は
シクロプロピルであり;
Rcは:C1−6アルキル;又は
ハロ−C1−6アルキルであり;
Rdは:C1−6アルキル;
ハロ;
ハロ−C1−6アルキル;
ヒドロキシ−C1−6アルキル;
C1−6アルコキシ−C1−6アルキル;又は
シアノであり;
各Reは、独立して:
C1−6アルキル;
ハロ;
ハロ−C1−6アルキル;
−NH−C(O)−Rf;
シアノ;又は
シクロプロピルであり;そして
Rfは、フラニル、チエニル、ピロリル、ピラゾリル又はイミダゾリルである]
で示される化合物、又はその薬学的に許容し得る塩。 - Xが、Arである、請求項1記載の化合物。
- R1が:C1−6アルキル;ハロ;C1−6アルコキシ;シアノ;又はシクロプロピル(これは、非置換であっても、又はRdで1若しくは2回置換されていてもよい)である、請求項1記載の化合物。
- R1が、シクロプロピル(これは、非置換であっても、又はRdで1若しくは2回置換されていてもよい)である、請求項1記載の化合物。
- R2が、水素、ハロ又はC1−6アルキルである、請求項1記載の化合物。
- R3が、水素、C1−6アルキル又はハロ−C1−6アルキルである、請求項1記載の化合物。
- R4が、水素である、請求項1記載の化合物。
- R5が、水素である、請求項1記載の化合物。
- R6が、水素である、請求項1記載の化合物。
- Arが、フェニル又はピラゾリルであり、これらの各々が、非置換であっても、又はReで1若しくは2回置換されていてもよい、請求項1記載の化合物。
- Arが、Reで1又は2回置換されているピラゾリルである、請求項1記載の化合物。
- Arが、3−クロロ−5−(トリフルオロメチル)ピラゾール−1−イルである、請求項1記載の化合物。
- 各Rdが、独立して、シアノ、C1−6アルキル又はヒドロキシ−C1−6アルキルである、請求項1記載の化合物。
- Rdが、シアノである、請求項1記載の化合物。
- 各Reが、独立して、ハロ又はハロ−C1−6アルキルである、請求項1記載の化合物。
- Rdが、シアノ、C1−6アルキル又はヒドロキシ−C1−6アルキルである、請求項18記載の化合物。
- 各Reが、独立して、ハロ又はハロ−C1−6アルキルである、請求項1記載の化合物。
- (a)有効量の、請求項1記載の少なくとも1つの化合物、及び(b)薬学的に許容し得る担体を含む、医薬組成物。
- N2RA活性によって媒介される疾患若しくは病状に罹患しているか又は該疾患若しくは病状と診断された対象を処置する方法であって、かかる処置を必要としている対象に有効量の、請求項1記載の少なくとも1つの化合物を投与することを含む、方法。
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