JP2011520834A - Nk1受容体アンタゴニストとしての5−[5−[2−(3,5−ビス(トリフルオロメチル)フェニル)−2−メチルプロパノイルメチルアミノ]−4−(4−フルオロ−2−メチルフェニル)]−2−ピリジニル−2−アルキル−プロリンアミド - Google Patents
Nk1受容体アンタゴニストとしての5−[5−[2−(3,5−ビス(トリフルオロメチル)フェニル)−2−メチルプロパノイルメチルアミノ]−4−(4−フルオロ−2−メチルフェニル)]−2−ピリジニル−2−アルキル−プロリンアミド Download PDFInfo
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- JP2011520834A JP2011520834A JP2011508893A JP2011508893A JP2011520834A JP 2011520834 A JP2011520834 A JP 2011520834A JP 2011508893 A JP2011508893 A JP 2011508893A JP 2011508893 A JP2011508893 A JP 2011508893A JP 2011520834 A JP2011520834 A JP 2011520834A
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- Prior art keywords
- methyl
- phenyl
- compound
- pharmaceutically acceptable
- bis
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
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Abstract
Description
国際公開第02/16324号(F. Hoffmann-La Roche AG)には、NK1受容体アンタゴニストとしての4−フェニルピリジン誘導体について記載されている。
本発明の化合物の幾つかは、水性および有機溶媒のような溶媒から結晶化、または再結晶化され得る。このような場合には溶媒和物が形成され得る。本発明はその範囲内に、水和物を含む化学量論的な溶媒和物、および、凍結乾燥のような過程により産生され得る可変量の水を含む化合物を含む。
それ故、式(I)で表される化合物の塩、溶媒和物、および水和物は本発明の態様を形づくる。
(5R)−5−[5−[{2−[3,5−ビス(トリフルオロメチル)フェニル]−2−メチルプロパノイル}(メチル)アミノ]−4−(4−フルオロ−2−メチルフェニル)−2−ピリジニル]−2−メチル−D−プロリンアミド(Ie);
で表される化合物を、20〜70℃のような適切な温度においてメタノールのような適切な溶媒中でアンモニアと共に反応させることと、それに続く任意の薬学上許容される塩への変換を含んでなる。
で表される化合物のアルキル化と、それに続く保護基Pの除去によって調製され得る。アルキル化反応は典型的には、式(IV)で表される化合物を、THFのような適切な溶媒中のリチウムビス(トリメチル)アミドのような適切な塩基と共に−78℃ないし室温の範囲の適切な温度において数分ないし数時間の範囲の間反応させ、続いて適切な求電子試薬R−X[式中、RはC1−4アルキルを表し、Xは適切な脱離基、例えばハロゲン (すなわちヨード)、メシル、トシル、トリフルオロメタンスルホニルを表す]を、−78℃ないし高温の範囲の適切な温度においてin situ添加することを含んでなる。保護基pの除去は、N保護基除去のための公知の手順を用いて実行できる。従って例えば、PがBocを表す場合、前記脱保護反応はジクロロメタンのような適切な溶媒中のトリフルオロ酢酸により、室温のような適切な温度において実行できる。
との、CuI存在下での薗頭カップリングにより調製され得る。この反応はパラジウム(0)の存在下に不活性溶媒中で行われてよい。適切なパラジウム触媒の例は、テトラキス(トリフェニルホスフィン)パラジウム(0)およびトリス(ジベンジリデンアセトン)ジパラジウム(0)を含むがこれらに限定されない。パラジウム(II)源を用い、in situでパラジウム(0)触媒を発生させることもまた可能である。適切なパラジウム(II)源の例は、酢酸パラジウム(II)、塩化パラジウム(II)、トリフルオロ酢酸パラジウム(II)、ジクロロビス(トリフェニル−ホスフィン)パラジウム(II)、および二塩化ビス(ジフェニルホスフィノ−フェロセン)パラジウム(II)を含むがこれらに限定されない。この反応に適切な溶媒は、トリエチルアミン、ジイソプロピルアミン、N,N−ジメチルホルムアミド、テトラヒドロフラン、ジオキサン、トルエン、ベンゼン、1,2−ジメトキシエタン、および1−メチル−2−ピロリジノンを含むがこれらに限定されない。所望により、反応内に塩基およびホスフィンが添加物として含まれてよい。適切な塩基の例は、例えばトリエチルアミン、ジイソプロピルアミン、およびそれらの混合物のような、トリアルキルアミンを含む。適切なホスフィン添加物の例は、トリフェニルホスフィン、トリブチルホスフィン、およびエチレンビス(ジフェニルホスフィン)を含むがこれらに限定されない。
工程(ii)は、典型的には式(XI)で表される化合物とNa2CO3の、アルコールすなわちメタノールのような適切な溶媒の存在下での塩基により触媒される加水分解を含んでなる。
工程(iii)は、典型的には式(XII)で表される化合物とメタンスルホニルクロリドとをジクロロメタンのような適切な溶媒、およびトリエチルアミンのような適切な塩基の存在下で反応させることを含んでなる。
により、酸からのエステルの取得および窒素基の保護についての当業者に公知の、従来の方法を用いて調製され得る。Floris P.J.T. Rutjes, Advanced Synthesis & Catalysis, 346(7), 823-834; 2004.を参照のこと。
あるいは、ここに記載される一般的方法と、それに続く、該方法の好都合な点でのジアステレオ異性体混合物の分離を用いることにより、例えばジアステレオ異性体(Ia)(Ib)(Ic)および(Id)は、(XIVa)または(XIVb)(式中、Raは水素を表す)から開始して取得され得る。
工程(i)および(ii)はまた、保護基Pの除去も含んでなる。
工程(ii)は、保護基Pの除去を含んでなる。
工程(ii)は、保護基Pの除去を含んでなる。
タキキニン受容体の三つの型、すなわちNK1(SP選択的)、NK2(NKA選択的)およびNK3(NKB選択的)が同定されており、これらは中枢神経系(CNS)および末梢神経系にわたって広く分布する。
大うつ病エピソード、躁病エピソード、混合性エピソードおよび軽躁病エピソードを含むうつ病および気分障害;大うつ病性障害、気分変調性障害(300.4)、他に特定されないうつ病性障害(311)を含むうつ病性障害;双極I型障害、双極II型障害(軽躁病エピソードを伴う反復性大うつ病エピソード)(296.89)、気分循環性障害(301.13)および他に特定されない双極性障害(296.80)を含む双極性障害;うつ病性の特徴、大うつ病様エピソード、躁病性の特徴、および混合性の特徴を伴う亜型を含む、一般身体疾患による気分障害(293.83)を含むその他の気分障害、うつ病性の特徴、躁病性の特徴、および混合性の特徴を伴う亜型を含む物質誘発性気分障害;および特定不能の気分障害(296.90)、
i)妄想型(295.30)、***型(295.10)、緊張型(295.20)、識別不能型(295.90)および残遺型(295.60)の亜型を含む、統合失調症;統合失調症様障害(295.40);双極型およびうつ型の亜型を含む、統合失調感情障害(295.70);色情型、誇大型、嫉妬型、被害型、身体型、混合型および不特定型の亜型を含む、妄想性障害(297.1);短期精神病性障害(298.8);共有精神病性障害(297.3);妄想を伴う、および幻覚を伴う亜型を含む、一般的な症状に起因する精神病性障害;物質誘発性妄想を伴う(293.81)、および幻覚を伴う(293.82)亜型を含む、精神病性障害;および特定不能の精神病性障害(298.9)を含む。
大うつ病エピソード、躁病エピソード、混合性エピソードおよび軽躁病エピソードを含むうつ病および気分障害;大うつ病性障害、気分変調性障害(300.4)、他に特定されないうつ病性障害(311)を含むうつ病性障害;双極I型障害、双極II型障害(軽躁病エピソードを伴う反復性大うつ病エピソード)(296.89)、気分循環性障害(301.13)および他に特定されない双極性障害(296.80)を含む双極性障害;うつ病性の特徴、大うつ病様エピソード、躁病性の特徴、および混合性の特徴を伴う亜型を含む、一般身体疾患による気分障害(293.83)を含むその他の気分障害、うつ病性の特徴、躁病性の特徴、および混合性の特徴を伴う亜型を含む物質誘発性気分障害;および特定不能の気分障害(296.90)を含む。
3,5−ジアミノ−6−(2,3−ジクロロフェニル)−1,2,4−トリアジン;
R(−)−2,4−ジアミノ−5−(2,3−ジクロロフェニル)−6−フルオロメチルピリミジン;
(2R,5R)−2−(4−{[(2−フルオロフェニル)メチル]オキシ}フェニル)−1,7−ジアザスピロ[4.4]ノナン−6−オン;
(2R,5R)−2−(4−{[(2−フルオロフェニル)メチル]オキシ}フェニル)−7−メチル−1,7−ジアザスピロ[4.4]ノナン−6−オン;
(5R)−5−(4−{[(2−フルオロフェニル)メチル]オキシ}フェニル)−L−プロリンアミド、
またはそれらの薬学上許容される塩もしくは溶媒和物からなる群より選択されるNaチャネル遮断薬を含んでなる。
化合物3,5−ジアミノ−6−(2,3−ジクロロフェニル)−1,2,4−トリアジンおよびその薬学上許容される塩および溶媒和物は、付与された欧州特許第0021121B号および米国特許第4,602,017号に記載される。化合物3,5−ジアミノ−6−(2,3−ジクロロフェニル)−1,2,4−トリアジンおよびその薬学上許容される塩および溶媒和物は、欧州特許第0021121B号および米国特許第4,602,017号に記載されるいずれの方法を用いても調製され得る。
化合物R(−)−2,4−ジアミノ−5−(2,3−ジクロロフェニル)−6−フルオロメチルピリミジンおよびその薬学上許容される塩および溶媒和物は、1997年3月13日に公開されたPCT公報、国際公開第97/9317号に記載される。化合物R(−)−2,4−ジアミノ−5−(2,3−ジクロロフェニル)−6−フルオロメチルピリミジンおよびその薬学上許容される塩および溶媒和物は、国際公開第97/9317号に記載されるいずれの方法を用いても調製され得る。
化合物(5R)−5−(4−{[(2−フルオロフェニル)メチル]オキシ}フェニル)−L−プロリンアミドおよびその薬学上許容される塩および溶媒和物は、PCT公報、国際公開第2007/042239号に記載される。化合物(5R)−5−(4−{[(2−フルオロフェニル)メチル]オキシ}フェニル)−L−プロリンアミドおよびその薬学上許容される塩および溶媒和物は、国際公開第2007/042239号に記載されるいずれの方法を用いても調製され得る。
化合物(2R,5R)−2−(4−{[(2−フルオロフェニル)メチル]オキシ}フェニル)−7−メチル−1,7−ジアザスピロ[4.4]ノナン−6−オンおよびその薬学上許容される塩および溶媒和物は、PCT公報、国際公開第2007/042240号に記載される。化合物(2R,5R)−2−(4−{[(2−フルオロフェニル)メチル]オキシ}フェニル)−7−メチル−1,7−ジアザスピロ[4.4]ノナン−6−オンおよびその薬学上許容される塩および溶媒和物は、国際公開第2007/042240号に記載されるいずれの方法を用いても調製され得る。
以下の中間体および実施例は、本発明の化合物の調製を例証する。
AgOTf トリフルオロメタンスルホン酸銀(I)
BH3.THF ボランテトラヒドロフラン複合体
Boc-無水物 二炭酸ジ−tert−ブチル
CDCl3 クロロホルム−d
DCM ジクロロメタン
DiPA ジイソプロピルアミン
DIPEA ジイソプロピルエチルアミン
DMF ジメチルホルムアミド
DMSO ジメチルスルホキシド
EtOAc 酢酸エチル
HCl 塩酸
MeOH メタノール
Na2SO4 硫酸ナトリウム
NaHCO3 炭酸水素ナトリウム
THF テトラヒドロフラン
TFA トリフルオロ酢酸
TEA トリエチルアミン
CD 円二色性
HPLC 高速液体クロマトグラフィー
UPLC 超高速液体クロマトグラフィー
DAD ダイオードアレイ検出器
TBME ボランテトラヒドロフラン複合体
h 時間
min 分
r.t. 室温
メチル(2S)−2−({[(1,1−ジメチルエチル)オキシ]カルボニル}アミノ)−4−ペンチノアート
メチル(2S)−5−[5−[{2−[3,5−ビス(トリフルオロメチル)フェニル]−2−メチルプロパノイル}(メチル)アミノ]−4−(4−フルオロ−2−メチルフェニル)−2−ピリジニル]−2−({[(1,1−ジメチルエチル)オキシ]カルボニル}アミノ)−4−ペンチノアート
メチル(2S)−5−[5−[{2−[3,5−ビス(トリフルオロメチル)フェニル]−2−メチルプロパノイル}(メチル)アミノ]−4−(4−フルオロ−2−メチルフェニル)−2−ピリジニル]−3,4−ジヒドロ−2H−ピロール−2−カルボキシレート
メチル(5S)−5−[5−[{2−[3,5−ビス(トリフルオロメチル)フェニル]−2−メチルプロパノイル}(メチル)アミノ]−4−(4−フルオロ−2−メチルフェニル)−2−ピリジニル]−L−プロリナート(4)およびメチル(5R)−5−[5−[{2−[3,5−ビス(トリフルオロメチル)フェニル]−2−メチルプロパノイル}(メチル)アミノ]−4−(4−フルオロ−2−メチルフェニル)−2−ピリジニル]−L−プロリナート(5)
二つの産物を分離した。
(第1溶出)(中間体4):メチル(5S)−5−[5−[{2−[3,5−ビス(トリフルオロメチル)フェニル]−2−メチルプロパノイル}(メチル)アミノ]−4−(4−フルオロ−2−メチルフェニル)−2−ピリジニル]−L−プロリナート(160mg,0.256mmol,収率24.92%)白色の固体、1H NMR (500 MHz, DMSO-d6) δ (ppm): 8.30 (s, 1 H) 8.03 (s, 1 H) 7.75 (br. s., 2 H) 7.39 (s, 1 H) 7.17 (d, 1 H) 7.10 (br. s., 1 H) 7.06 (br. s., 1 H) 4.37 - 4.46 (m, 1 H) 3.91 - 3.99 (m, 1 H) 3.64 (s, 3 H) 2.29 (br. s., 3 H) 2.18 - 2.24 (m, 1 H) 2.08 - 2.13 (m, 1 H) 2.10 (br. s., 3 H) 1.80 - 1.91 (m, 1 H) 1.74 (br. s., 1 H) 1.50 (br. s., 3 H) 1.36 (br. s., 3 H)、相対立体化学はROESY(双極子相関:H−2,H−5に対するH−11;H−11,H−3,−3’,−4’に対するH−2;H−11,H−3’,−4,−4’ に対するH−5)により決定した。以下の構造に示す原子の番号付けはNMRデータとの関連の目的のみのために含まれる。UPLC:Rt0.81分(ブロードシグナル),m/z626[M+H]+。
1−(1,1−ジメチルエチル)2−メチル(2S,5R)−5−[5−[{2−[3,5−ビス(トリフルオロメチル)フェニル]−2−メチルプロパノイル}(メチル)アミノ]−4−(4−フルオロ−2−メチルフェニル)−2−ピリジニル]−1,2−ピロリジンジカルボキシレート
1−(1,1−ジメチルエチル)2−メチル(2R,5R)−5−[5−[{2−[3,5−ビス(トリフルオロメチル)フェニル]−2−メチルプロパノイル}(メチル)アミノ]−4−(4−フルオロ−2−メチルフェニル)−2−ピリジニル]−2−メチル−1,2−ピロリジンジカルボキシレート(7)および1−(1,1−ジメチルエチル)2−メチル(2S,5R)−5−[5−[{2−[3,5−ビス(トリフルオロメチル)フェニル]−2−メチルプロパノイル}(メチル)アミノ]−4−(4−フルオロ−2−メチルフェニル)−2−ピリジニル]−2−メチル−1,2−ピロリジンジカルボキシレート(8)
二つの産物を分離した:
(第1溶出)1−(1,1−ジメチルエチル)2−メチル(2R,5R)−5−[5−[{2−[3,5−ビス(トリフルオロメチル)フェニル]−2−メチルプロパノイル}(メチル)アミノ]−4−(4−フルオロ−2−メチルフェニル)−2−ピリジニル]−2−メチル−1,2−ピロリジンジカルボキシレート(中間体7、31mg,0.042mmol,収率10.14%)、白色の固体。1H NMR (400 MHz, CHLOROFORM-d) δ ppm 8.29 - 8.46 (m, 1 H) 7.74 - 7.85 (m, 1 H) 7.63 - 7.75 (m, 2 H) 6.84 - 7.35 (m, 4 H) 5.10 - 5.36 (m, 1 H) 3.66 - 3.87 (m, 3 H) 0.75 - 2.73 (m, 28 H). MS: m/z 740 [M+H]+ and 762 [M+Na]+。キラル分析、クロマトグラフィー条件:[カラムChiralcel AD-H(25x0.46cm);移動相:n−ヘキサン/2−プロパノール 85/15%v/v;流速1.0ml/分;DAD210〜340nm,CD230nm]Rt4.21分,94.6%e.e。
(第2溶出)1−(1,1−ジメチルエチル)2−メチル(2S,5R)−5−[5−[{2−[3,5−ビス(トリフルオロメチル)フェニル]−2−メチルプロパノイル}(メチル)アミノ]−4−(4−フルオロ−2−メチルフェニル)−2−ピリジニル]−2−メチル−1,2−ピロリジンジカルボキシレート(中間体8、200mg,0.27mmol,収率65.4%)、白色の固体。1H NMR (400 MHz, CHLOROFORM-d) δ ppm 8.24 - 8.46 (m, 1 H) 7.59 - 7.98 (m, 4 H) 6.77 - 7.36 (m, 3 H) 5.00 - 5.27 (m, 1 H) 3.47 - 3.75 (m, 3 H) 0.83 - 2.73 (m, 28 H). MS: m/z 740 [M+H]+ and 762 [M+Na]+。
メチル(5R)−5−[5−[{2−[3,5−ビス(トリフルオロメチル)フェニル]−2−メチルプロパノイル}(メチル)アミノ]−4−(4−フルオロ−2−メチルフェニル)−2−ピリジニル]−2−メチル−D−プロリナート
メチル(5R)−5−[5−[{2−[3,5−ビス(トリフルオロメチル)フェニル]−2−メチルプロパノイル}(メチル)アミノ]−4−(4−フルオロ−2−メチルフェニル)−2−ピリジニル]−2−メチル−L−プロリナート
メチル(2R)−2−({[(1,1−ジメチルエチル)オキシ]カルボニル}アミノ)−4−ペンチノアート
メチル(2R)−5−[5−[{2−[3,5−ビス(トリフルオロメチル)フェニル]−2−メチルプロパノイル}(メチル)アミノ]−4−(4−フルオロ−2−メチルフェニル)−2−ピリジニル]−2−({[(1,1−ジメチルエチル)オキシ]カルボニル}アミノ)−4−ペンチノアート
メチル(2R)−2−アミノ−5−[5−[{2−[3,5−ビス(トリフルオロメチル)フェニル]−2−メチルプロパノイル}(メチル)アミノ]−4−(4−フルオロ−2−メチルフェニル)−2−ピリジニル]−4−ペンチノアート
メチル(2R)−5−[5−[{2−[3,5−ビス(トリフルオロメチル)フェニル]−2−メチルプロパノイル}(メチル)アミノ]−4−(4−フルオロ−2−メチルフェニル)−2−ピリジニル]−3,4−ジヒドロ−2H−ピロール−2−カルボキシレート
無水アセトニトリル(25ml)中のメチル(2R)−2−アミノ−5−[5−[{2−[3,5−ビス(トリフルオロメチル)フェニル]−2−メチルプロパノイル}(メチル)アミノ]−4−(4−フルオロ−2−メチルフェニル)−2−ピリジニル]−4−ペンチノアート溶液(中間体13、1.85g,2.97mmol)にトリフルオロメタンスルホン酸銀(0.381g,1.483mmol)を少しずつ加え、得られた反応混合物を室温で一晩撹拌した。揮発物を、室温、真空下で蒸発させた。残基をジクロロメタン中に取得し、セライトのプラグを通して濾過した後、2.2gの表題化合物を茶色の固体として得た(この物質は残余のアセトニトリルを幾らか含んでいたため、全体としての回収量は理論的な量よりも高めであった)。UPLC:Rt0.95分,m/z624[M+H+]。
ジクロロメタン(15ml)中のメチル(2R)−5−[5−[{2−[3,5−ビス(トリフルオロメチル)フェニル]−2−メチルプロパノイル}(メチル)アミノ]−4−(4−フルオロ−2−メチルフェニル)−2−ピリジニル]−2−({[(1,1−ジメチルエチル)オキシ]カルボニル}アミノ)−4−ペンチノアート溶液(中間体12、1g,1.382mmol)にTFA(5ml,64.9mmol)を加え、反応混合物を室温で1時間攪拌した。溶媒および過剰のTFAを蒸発させ、残渣をSPE−SCXカートリッジにより精製して、中間体13を得た。この残渣をアセトニトリル(14ml)に溶解してトリフルオロメタンスルホン酸銀(0.036g,0.138mmol)を加え;反応混合物を60℃で6時間攪拌した。溶媒を蒸発させて残渣をDCM(15ml)中に溶解し、金属触媒を濾過して除いた。
有機溶液を蒸発させ、表題化合物をオレンジ色の固体として得た(800mg,1.283mmol,収率93%)。UPLC:Rt0.95分,m/z624[M+H+]。
メチル(5R)−5−[5−[{2−[3,5−ビス(トリフルオロメチル)フェニル]−2−メチルプロパノイル}(メチル)アミノ]−4−(4−フルオロ−2−メチルフェニル)−2−ピリジニル]−D−プロリナート(15)およびメチル(5S)−5−[5−[{2−[3,5−ビス(トリフルオロメチル)フェニル]−2−メチルプロパノイル}(メチル)アミノ]−4−(4−フルオロ−2−メチルフェニル)−2−ピリジニル]−D−プロリナート(16)
THF(20.85ml)中のメチル(2R)−5−[5−[{2−[3,5−ビス(トリフルオロメチル)フェニル]−2−メチルプロパノイル}(メチル)アミノ]−4−(4−フルオロ−2−メチルフェニル)−2−ピリジニル]−3,4−ジヒドロ−2H−ピロール−2−カルボキシレート溶液(方法Aにより得られた中間体14、1.3g,2.085mmol)に、THF(6.25ml,6.25mmol)中の1M BH3THF溶液を−40℃においてゆっくりと加え、反応混合物を同じ温度で2時間攪拌した。反応をMeOH(2ml)により消失させ、室温で2時間攪拌した。溶液を塩水(50ml)で希釈して、酢酸エチル(3x80ml)で抽出した。有機層を乾燥(Na2SO4)、濾過、および蒸発させて、残渣を、カラム40+M、および溶出剤としてシクロヘキサン/酢酸エチル 7:3ないし酢酸エチルを用いる、シリカゲル上のフラッシュクロマトグラフィー(Biotage system)により精製して二つの化合物を得た:
(第1溶出)(中間体15)メチル(5R)−5−[5−[{2−[3,5−ビス(トリフルオロメチル)フェニル]−2−メチルプロパノイル}(メチル)アミノ]−4−(4−フルオロ−2−メチルフェニル)−2−ピリジニル]−D−プロリナート(350mg,0.559mmol,収率26.8%)1H NMR (400 MHz, DMSO-d6) δ(ppm): 8.30 (s, 1H), 8.03 (s, 1H), 7.75 (br.s, 2H), 7.39 (s, 1H), 7.17 (d, 1H), 7.10 (br.s, 1H), 7.06 (br.s, 1H), 4.37 - 4.46 (m, 1H), 3.91 - 3.99 (m, 1H), 3.64 (s, 3H), 2.29 (br.s, 3H), 2.18 - 2.24 (m, 1H), 2.08 - 2.13 (m, 1H), 2.10 (br.s., 3H), 1.80 - 1.91 (m, 1H), 1.68 - 1.81 (br.s, 1H), 1.50 (br.s., 3H), 1.36 (br.s, 3H)。相対立体化学は、対応する鏡像異性体(中間体4)とのNMRスペクトルの比較により特定された。UPLC:Rt0.76分(ブロードシグナル),m/z626[M+H+]。
(第2溶出)(中間体16)メチル(5S)−5−[5−[{2−[3,5−ビス(トリフルオロメチル)フェニル]−2−メチルプロパノイル}(メチル)アミノ]−4−(4−フルオロ−2−メチルフェニル)−2−ピリジニル]−D−プロリナート(355mg,0.567mmol,収率27.2%)。1H NMR (500 MHz, DMSO-d6) δ(ppm): 8.30 (s, 1H), 8.03 (s, 1H), 7.76 (br.s, 2H), 7.57 (br.s, 1H), 7.19 (d, 1H), 6.92 - 7.26 (m, 2H), 4.26 - 4.36 (m, 1H), 3.83 - 3.92 (m, 1H), 3.60 (s, 3H), 2.20 - 2.36 (m, 3H), 2.15 - 2.24 (m, 1H), 2.03 - 2.16 (m, 4H), 1.79 - 1.90 (m, 1H), 1.66 - 1.76 (m, 1H), 1.12 - 1.57 (m, 6H)。相対立体化学は、対応する鏡像異性体(中間体5)とのNMRスペクトルの比較により特定された。UPLC:Rt0.78分(ブロードシグナル),m/z626[M+H+]。
方法B
メタノール(10ml)中のメチル(2R)−5−[5−[{2−[3,5−ビス(トリフルオロメチル)フェニル]−2−メチルプロパノイル}(メチル)アミノ]−4−(4−フルオロ−2−メチルフェニル)−2−ピリジニル]−3,4−ジヒドロ−2H−ピロール−2−カルボキシレート溶液(方法Bにより得られた中間体14、650mg,1.042mmol)に、水素化ホウ素ナトリウム(43.4mg,1.147mmol)を0℃において加え、反応混合物を同じ温度で2時間攪拌した。反応をNaHCO3 5%溶液(1ml)により消失させ、溶媒を蒸発させた。残渣を水(20ml)で希釈して、酢酸エチル(3x50ml)で抽出した。有機層を乾燥(Na2SO4)、濾過、および蒸発させて、残渣を、カラム40+M、および溶出剤として7:3 シクロヘキサン/酢酸エチルないし酢酸エチルを用いる、シリカゲル上のフラッシュクロマトグラフィー(Biotage system)により精製した。二つの異なる産物が分離された:
(第2溶出)(中間体16)メチル(5S)−5−[5−[{2−[3,5−ビス(トリフルオロメチル)フェニル]−2−メチルプロパノイル}(メチル)アミノ]−4−(4−フルオロ−2−メチルフェニル)−2−ピリジニル]−D−プロリナート(160mg,0.256mmol,収率24.54%)白色の固体。
1−(1,1−ジメチルエチル)2−メチル(2R,5S)−5−[5−[{2−[3,5−ビス(トリフルオロメチル)フェニル]−2−メチルプロパノイル}(メチル)アミノ]−4−(4−フルオロ−2−メチルフェニル)−2−ピリジニル]−1,2−ピロリジンジカルボキシレート
1−(1,1−ジメチルエチル)2−メチル(2S,5S)−5−[5−[{2−[3,5−ビス(トリフルオロメチル)フェニル]−2−メチルプロパノイル}(メチル)アミノ]−4−(4−フルオロ−2−メチルフェニル)−2−ピリジニル]−2−メチル−1,2−ピロリジンジカルボキシレート(18)および1−(1,1−ジメチルエチル)2−メチル(2R,5S)−5−[5−[{2−[3,5−ビス(トリフルオロメチル)フェニル]−2−メチルプロパノイル}(メチル)アミノ]−4−(4−フルオロ−2−メチルフェニル)−2−ピリジニル]−2−メチル−1,2−ピロリジンジカルボキシレート(19)
(第1溶出)1−(1,1−ジメチルエチル)2−メチル(2S,5S)−5−[5−[{2−[3,5−ビス(トリフルオロメチル)フェニル]−2−メチルプロパノイル}(メチル)アミノ]−4−(4−フルオロ−2−メチルフェニル)−2−ピリジニル]−2−メチル−1,2−ピロリジンジカルボキシレート(中間体18、7mg,9.46μmol,収率4.58%).UPLC:Rt1.09分,m/z740[M+H]+。
(第2溶出)1−(1,1−ジメチルエチル)2−メチル(2R,5S)−5−[5−[{2−[3,5−ビス(トリフルオロメチル)フェニル]−2−メチルプロパノイル}(メチル)アミノ]−4−(4−フルオロ−2−メチルフェニル)−2−ピリジニル]−2−メチル−1,2−ピロリジンジカルボキシレート(中間体19、70mg,0.095mmol,収率45.8%).UPLC:Rt1.06分,m/z740[M+H]+。
メチル(5S)−5−[5−[{2−[3,5−ビス(トリフルオロメチル)フェニル]−2−メチルプロパノイル}(メチル)アミノ]−4−(4−フルオロ−2−メチルフェニル)−2−ピリジニル]−2−メチル−D−プロリナート
メチル(2R)−2−[(tert−ブトキシカルボニル)アミノ]−2−メチルペンタ−4−イノアート
メチル(2R)−5−[5−[{2−[3,5−ビス(トリフルオロメチル)フェニル]−2−メチルプロパノイル}(メチル)アミノ]−4−(4−フルオロ−2−メチルフェニル)ピリジン−2−イル]−2−[(tert−ブトキシカルボニル)アミノ]−2−メチルペンタ−4−イノアート
1H NMR (500MHz, DMSO-d6) δppm: 1.36-1.45 (18H, m), 2.12 (3H, s), 2.86-2.91 (1H, d), 3.18-3.24 (1H, br. d.), 3.64 (3H, s), 7.09-7.19 (3H, m), 7.41 (1H, s), 7.75 (2H, s) 8.01 (1H, s), 8.37 (1H, s)。
メチル(2R)−5−[5−[{2−[3,5−ビス(トリフルオロメチル)フェニル]−2−メチルプロパノイル}(メチル)アミノ]−4−(4−フルオロ−2−メチルフェニル)ピリジン−2−イル]−2−メチル−3,4−ジヒドロ−2H−ピロール−2−カルボキシレート
1H NMR (500MHz, 333K, DMSO-d6) δppm: 1.42 (6H, br. s.), 1.47 (3H, s), 1.90-1.96 (1H, m), 2.11 (3H, s), 2.36-2.44 (1H, m), 2.52 (3H, s), 3.18-3.25 (3H, m), 3.65 (3H, s), 7.05-7.10 (1H, m), 7.13-7.19 (2H, m), 7.77 (2H, s), 7.90 (1H, s), 7.99 (1H, s), 8.49 (1H, s)。
(2R)−5−[5−[{2−[3,5−ビス(トリフルオロメチル)フェニル]−2−メチルプロパノイル}(メチル)アミノ]−4−(4−フルオロ−2−メチルフェニル)ピリジン−2−イル]−2−メチル−3,4−ジヒドロ−2H−ピロール−2−カルボキサミド
1H NMR (500MHz, 333K, DMSO-d6) δppm: 1.39 (3H, s), 1.43 (6H, br. s.), 1.91-1.97 (1H, m), 2.15 (3H, s), 2.21-2.28 (1H, m), 2.53 (3H, s), 3.07-3.20 (2H, m), 6.79-6.94 (2H, br. d.), 7.06-7.11 (1H, br. t.), 7.15-7.20 (2H, m), 7.78 (2H,s), 7.99 (1H, s), 8.14 (1H,s), 8.47 (1H, s)。
(5R)−5−[5−[{2−[3,5−ビス(トリフルオロメチル)フェニル]−2−メチルプロパノイル}(メチル)アミノ]−4−(4−フルオロ−2−メチルフェニル)−2−ピリジニル]−2−メチル−D−プロリンアミド
1H NMR (400 MHz, DMSO-d6) δ ppm 8.32 - 8.42 (m, 1 H) 8.02 - 8.09 (m, 1 H) 7.68 - 7.87 (m, 2 H) 7.50 - 7.58 (m, 1 H) 7.43 (s, 1 H) 6.95 - 7.28 (m, 4 H) 4.19 - 4.38 (m, 1 H) 3.04 - 3.24 (m, 1 H) 2.54 (s, 3 H) 2.19 (s, 3 H) 1.99 - 2.42 (m, 2 H) 1.56 - 1.87 (m, 2 H) 1.37 (s, 3 H) 1.42 (s, 6 H)。相対立体化学アンチは、シンジアステレオ異性体(実施例3)のNMRスペクトルとの比較により特定された:スペクトルは異なっていた。HPLC:Rt5.49分.MS:m/z625[M+H]+および647[M+Na]+。
(5R)−5−[5−[{2−[3,5−ビス(トリフルオロメチル)フェニル]−2−メチルプロパノイル}(メチル)アミノ]−4−(4−フルオロ−2−メチルフェニル)−2−ピリジニル]−2−メチル−D−プロリンアミド塩酸塩
(5R)−5−[5−[{2−[3,5−ビス(トリフルオロメチル)フェニル]−2−メチルプロパノイル}(メチル)アミノ]−4−(4−フルオロ−2−メチルフェニル)−2−ピリジニル]−2−メチル−L−プロリンアミド
(5R)−5−[5−[{2−[3,5−ビス(トリフルオロメチル)フェニル]−2−メチルプロパノイル}(メチル)アミノ]−4−(4−フルオロ−2−メチルフェニル)−2−ピリジニル]−2−メチル−L−プロリンアミド塩酸塩
(5S)−5−[5−[{2−[3,5−ビス(トリフルオロメチル)フェニル]−2−メチルプロパノイル}(メチル)アミノ]−4−(4−フルオロ−2−メチルフェニル)−2−ピリジニル]−2−メチル−D−プロリンアミド
(5S)−5−[5−[{2−[3,5−ビス(トリフルオロメチル)フェニル]−2−メチルプロパノイル}(メチル)アミノ]−4−(4−フルオロ−2−メチルフェニル)−2−ピリジニル]−2−メチル−D−プロリンアミド塩酸塩
(5R)−5−[5−[{2−[3,5−ビス(トリフルオロメチル)フェニル]−2−メチルプロパノイル}(メチル)アミノ]−4−(4−フルオロ−2−メチルフェニル)−2−ピリジニル]−2−メチル−D−プロリンアミド無水結晶形1
次にこの化合物(598.8g)を室温で酢酸エチル(1.2L)に懸濁し、次に熱して還流した。得られた熱い溶液を濾過/浄化して、いずれの粒状の物質も除去した。メチルシクロヘキサン(6.0L)を還流時に濾過物へゆっくりと添加すると、添加の終わりまでには白色の懸濁液が生じた。熱い懸濁液を4時間にわたって20℃に冷却し、次に20℃のままで一晩攪拌した。懸濁液を濾過し、メチルシクロヘキサン(1.2L)ですすぎ、次に真空下で40℃、26時間乾燥させ、表題化合物が、約99%の純度である白色の結晶性固体として供給された(527g)。
1H NMR (500MHz, 353K, DMSO-d6) δppm: 1.40 (3H, s), 1.42 (6H, s), 1.65-1.70 (1H, m), 1.78-1.85 (1H, m), 2.11-2.24 (5H, m) 3.08 (1H, br. s.), 4.31-4.34 (1H, t), 7.03-7.07 (1H, m), 7.13-7.17 (2H, m), 7.37 (1H, s) 7.76 (2H, s), 7.96 (1H, s), 8.32(1H, s)。
DSCによる融解開始、198.7℃。
DSCサーモグラムは、TA Instruments Q2000示差走査熱量計を用いて得た。サンプルはアルミニウムパン内へ秤量し、蓋を上に載せ、密閉することなく軽く圧着した。実験は10℃/分の加熱率を用いて行った。
[(5R)−5−[5−[{2−[3,5−ビス(トリフルオロメチル)フェニル]−2−メチルプロパノイル}(メチル)アミノ]−4−(4−フルオロ−2−メチルフェニル)−2−ピリジニル]−2−メチル−D−プロリンアミド酒石酸塩]
酸を溶解させるため、酒石酸(126.15mg,1当量)にアセトン(7ml)を加えた。次に該酸溶液を500mgの(5R)−5−[5−[{2−[3,5−ビス(トリフルオロメチル)フェニル]−2−メチルプロパノイル}(メチル)アミノ]−4−(4−フルオロ−2−メチルフェニル)−2−ピリジニル]−2−メチル−D−プロリンアミド(実施例1)に加えた。得られたスラリーを500rpmで撹拌しながら温度サイクル(0〜40℃)へと設定した。1時間後、濃厚なゲル用の物質が形成された。次に物質の可動性を改善するため、アセトン(13ml)をさらに加えた。反応を撹拌しながら、さらに3日間温度サイクルに供した。固体を分離し、45℃で一晩乾燥させ、表題化合物を結晶形として得た(463mg)。DSCによる融解開始、211℃。
[(5R)−5−[5−[{2−[3,5−ビス(トリフルオロメチル)フェニル]−2−メチルプロパノイル}(メチル)アミノ]−4−(4−フルオロ−2−メチルフェニル)−2−ピリジニル]−2−メチル−D−プロリンアミド安息香酸塩]
酸を溶解させるため、安息香酸(102.65mg,1当量)にトルエン(3.5ml)を加えた。次に該酸溶液を500mgの(5R)−5−[5−[{2−[3,5−ビス(トリフルオロメチル)フェニル]−2−メチルプロパノイル}(メチル)アミノ]−4−(4−フルオロ−2−メチルフェニル)−2−ピリジニル]−2−メチル−D−プロリンアミド(実施例1)に加えた。40℃に熱し、次に20℃に冷却した後、反応にトルエンからの小スケール蒸発実験により得られた(50mg)実施例1の安息香酸塩結晶を播種した。次に反応を3日間温度サイクルに供した。形成された固体を分離し、45℃で一晩乾燥させ、表題化合物を結晶形として得た(374mg)。DSCによる融解開始、131℃。
[(5R)−5−[5−[{2−[3,5−ビス(トリフルオロメチル)フェニル]−2−メチルプロパノイル}(メチル)アミノ]−4−(4−フルオロ−2−メチルフェニル)−2−ピリジニル]−2−メチル−D−プロリンアミドクエン酸塩]
HPLCバイアル中に、25mgの(5R)−5−[5−[{2−[3,5−ビス(トリフルオロメチル)フェニル]−2−メチルプロパノイル}(メチル)アミノ]−4−(4−フルオロ−2−メチルフェニル)−2−ピリジニル]−2−メチル−D−プロリンアミド(実施例1)、続いて7.6mg(1当量)のクエン酸を分配した。次に250μLのトルエンを固体の上に分注し、反応を500rpmで撹拌しながら温度サイクル(0〜40℃)へと設定した。2.5日後、固体を周囲温度にて濾過して分離した。DSCによる融解開始は90℃であり、それに分解が続く。
(5R)−5−[5−[{2−[3,5−ビス(トリフルオロメチル)フェニル]−2−メチルプロパノイル}(メチル)アミノ]−4−(4−フルオロ−2−メチルフェニル)−2−ピリジニル]−2−メチル−D−プロリンアミドビス−塩酸塩
揮発物を真空下で蒸発させた。表題化合物を白色の固体として得た(118.7g,収率99%)。
HPLC:Rt=5.168分。
1H NMR (400 MHz, DMSO-d6) δ ppm 9.43 (br. s., 1 H), 9.10 (br. s., 1 H), 8.52 (s, 1 H), 7.99 - 8.15 (m, 2 H), 7.84 (s, 1 H), 7.64 - 7.89 (m, 2 H), 7.54 (s, 1 H), 6.96 - 7.29 (m, 3 H), 4.87 - 5.09 (m, 1 H), 2.50 (s, 3 H), 2.35 (br. s., 3 H), 2.01 - 2.43 (m, 4 H), 1.72 (s, 3 H), 1.42 (br. s., 6 H)。
本発明の化合物は以下のアッセイに従い、in vitro生物活性を試験されてよい。
本発明の化合物のNK1結合親和性は、CHO(チャイニーズハムスター卵巣)細胞に安定的に発現するヒトNK1受容体に対する放射性リガンドとして[3H]−GR205171を用いる、以下の濾過結合アッセイを用いて決定した(C. Griffante et al, Br. J. Pharmacol. 2006, 148, 39-45; H. M. Sarau et al, J. Pharmacol. Experimental Therapeutics 2000, 295(1), 373-381 and D.T. Beattie et al., Br. J. Pharmacol. 1995, 116, 3149-3157を参照)。
特異的結合は、1μM GR205171存在下での結合として判断された非特異的結合から、総結合を差し引くことにより決定された。特異的結合のパーセント阻害は、本発明の化合物の各濃度、および特異的結合を50%阻害するために必要とされる濃度として定義され、濃度反応曲線から得られるIC50に対して決定された。
親和性の値は阻害定数(pKi,)の負の対数として表され、放射リガンドの解離定数(KD)およびそのアッセイにおける濃度を用いるCheng-Prusoff方程式により、IC50から算出された。
NK受容体とその予想されるリガンドとの相互作用により誘導される細胞内カルシウム放出の阻害に対する本発明の化合物の効果を決定するために、FLIPR技術を用いる機能的アッセイにより本発明の化合物をさらに特徴付けた。ヒトNK1、NK2、およびNK3受容体を発現する組み換えBacMamウィルスにより一過性に形質転換されたヒトU2OS細胞を研究に使用した(J. P. Condreay et al, Proc. Natl. Acad. Sci. USA 1999, 96(1): 127-132を参照)。簡単に述べると、U2OS細胞を組織培養フラスコから回収し、細胞濃度200〜300K/mlに再懸濁して、NKR遺伝子を保有するBacMamウィルスと1%(v/v)のウィルス/細胞比において混合した。次に10〜15K細胞/ウェルを、384ウェルGreiner bio-oneプレート内の培地(10%FBSを含むDMEM)中にまき、37℃、5%CO2で一晩インキュベートした。培地を吸引した後、18〜24時間後に、30μL/ウェル緩衝液(20mM HEPESを含むハンクス液)中の細胞質カルシウム指示薬Fluo−4カルシウム3色素(Molecular Devices Co.)を細胞に負荷し、CO2中で37℃60分間インキュベートした。次に、様々な濃度の化合物を含む10μL/ウェルアッセイ緩衝液(20mM HEPESを含むハンクス液)を細胞に加え、37℃で30分間インキュベートした。最後に、0.1%BSAを含むアッセイ緩衝液中のNKRリガンド10μL/ウェルを細胞に加え、蛍光シグナルをFLIPRシステムで読み取った。サブスタンスP、NKA、およびNKBペプチドを、それぞれNK1、NK2、およびNK3受容体のリガンドとして使用した。各化合物のIC50値を、11点の3x希釈阻害曲線により決定した。各アンタゴニストの効力(fpKi)を、別の実験により決定されたリガンドのEC50を用いるCheng-Prusoff方程式により、pIC50から算出した。
GR73632により誘導されるフットタッピング行動は、0.3、1.0、および3.0mg/kg p.o.の実施例11によって有意に減弱され(P<0.01)、算出されたID50は約0.2mg/kg(ID50、約5ng/ml血漿)であった。
Claims (12)
- Rが、メチルである、請求項1に記載の化合物。
- (5R)−5−[5−[{2−[3,5−ビス(トリフルオロメチル)フェニル]−2−メチルプロパノイル}(メチル)アミノ]−4−(4−フルオロ−2−メチルフェニル)−2−ピリジニル]−2−メチル−D−プロリンアミドである化合物。
- 請求項1〜4のいずれか一項に記載の式(I)で表される化合物またはそれらの薬学上許容される塩と薬学上許容される担体または賦形剤とを含んでなる、医薬組成物。
- 治療法における使用のための、請求項1〜4のいずれか一項に記載の化合物。
- NK1受容体への拮抗作用が有益である状態の治療における使用のための、請求項1〜4のいずれか一項に記載の化合物。
- うつ病、不安症、睡眠障害、または嘔吐の治療における使用のための、請求項1〜4のいずれか一項に記載の化合物。
- NK1受容体への拮抗作用が有益である状態を治療するための薬剤の製造における、請求項1〜4のいずれか一項に記載の化合物の使用。
- うつ病、不安症、睡眠障害、または嘔吐を治療するための薬剤の製造における、請求項1〜4のいずれか一項に記載の化合物の使用。
- ヒトを含む哺乳類におけるNK1受容体への拮抗作用が有益である状態の治療または予防の方法であって、治療的に有効な量の式(I)で表される化合物またはその薬学上許容される塩を患者へ投与することを含んでなる方法。
- ヒトを含む哺乳類におけるうつ病、不安症、睡眠障害、または嘔吐の治療または予防の方法であって、治療的に有効な量の式(I)で表される化合物またはその薬学上許容される塩を患者へ投与することを含んでなる方法。
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WO2018197638A1 (en) | 2017-04-27 | 2018-11-01 | Nerre Therapeutics Limited | Novel use of (5r)-5-[5-[{2-[3,5-bis(trifluoromethyl)phenyl]-2-methylpropanoyl}(methyl)amino]-4-(4-fluoro-2-methylphenyl)-2-pyridinyl]-2-methyl-d-prolinamide |
WO2021154631A1 (en) * | 2020-01-30 | 2021-08-05 | Javed Mohammad | Combination drug therapies for cns disorders |
CA3177477A1 (en) | 2020-06-02 | 2021-12-09 | Nerre Therapeutics Limited | Neurokinin (nk)-1 receptor antagonists for use in the treatment of pulmonary fibrosis conditions promoted by mechanical injury to the lungs |
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