JP2012528113A - ネプリリシン阻害剤としての置換アミノプロピオン酸誘導体 - Google Patents
ネプリリシン阻害剤としての置換アミノプロピオン酸誘導体 Download PDFInfo
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- JP2012528113A JP2012528113A JP2012512359A JP2012512359A JP2012528113A JP 2012528113 A JP2012528113 A JP 2012528113A JP 2012512359 A JP2012512359 A JP 2012512359A JP 2012512359 A JP2012512359 A JP 2012512359A JP 2012528113 A JP2012528113 A JP 2012528113A
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Classifications
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Abstract
Description
内因性心房性ナトリウム利尿ペプチド(ANP)は、心房性ナトリウム利尿因子(ANF)とも呼ばれ、哺乳動物で利尿、ナトリウム利尿および血管弛緩機能を有する。天然ANFペプチドは代謝により、特に、例えばエンケファリン類の代謝不活化に係わる酵素中性エンドペプチダーゼ(NEP)EC3.4.24.11に対応することが認識されている分解酵素により、不活性化される。
本発明の目的は、哺乳動物において中性エンドペプチダーゼ阻害剤、例えば、ANF分解酵素阻害剤として有用であり、従って哺乳動物におけるANFの利尿、ナトリウム利尿および血管拡張特性を、低活性代謝物への分解を阻害することにより延長し、かつ強める、新規化合物を提供することである。
本発明の化合物は、故に、特に中性エンドペプチダーゼ(NEP)EC3.4.24.11の阻害に応答する状態および障害の処置に有用である。
R1はH、C1−7アルキル、ヒドロキシ、C1−7アルコキシ、ハロゲン、−SH、−S−C1−7アルキルまたはNRaRbであり;
各R2は独立してC1−7アルキル、ハロ、NO2、CN、C1−7アルカノイルアミノ、C3−7シクロアルキル、ヒドロキシ、C1−7アルコキシ、ハロC1−7アルキル、−NRaRb、C6−10アリール、ヘテロアリールまたはヘテロシクリルであり;ここで、各RaおよびRbは独立してHまたはC1−7アルキルであり;
R3はA1−C(O)X1またはA2−R4であり;
R4はC6−10アリールまたはヘテロアリールであり、これらは、単環でも二環でもよく、場合によりヒドロキシ、ヒドロキシC1−7アルキル、ニトロ、−NRaRb、−C(O)C1−7アルキル、C(O)−O−C1−7アルキル、C1−7アルコキシ、ハロ、C1−7アルキル、ハロ−C1−7アルキル(akyl)、C2−7アルケニル、C6−10アリール、ヘテロアリール、−NHSO2−C1−7アルキルおよびベンジルからなる群から独立して選択される1個以上の置換基で置換されていてよく;またはR4は場合によりオキソ、ヒドロキシ、ヒドロキシC1−7アルキル、アミノ、C(O)−O−C1−7アルキル、C1−7アルコキシ、ハロ、C1−7アルキル、ハロ−C1−7アルキル(akyl)、C6−10アリール、ヘテロアリール、−NHSO2−C1−7アルキルおよびベンジルからなる群から独立して選択される1個以上の置換基で置換されていてよいヘテロシクリルであり;
R5はH、ハロ、ヒドロキシ、C1−7アルコキシ、ハロ、C1−7アルキルまたはハロ−C1−7アルキル(akylであり);
XおよびX1は独立してOH、−O−C1−7アルキル、−NRaRb、−NHS(O)2−C1−7アルキル、−NHS(O)2−ベンジルまたは−O−C6−10アリールであり、ここで、アルキルは場合によりC6−10アリール、ヘテロアリール、ヘテロシクリル、C(O)NH2、C(O)NH−C1−6アルキルおよびC(O)N(C1−6アルキル)2からなる群から独立して選択される1個以上の置換基で置換されていてよく;
B1は−C(O)NH−または−NHC(O)−であり;
A1は結合であるかまたは直鎖もしくは分枝鎖C1−7アルキレンであり;これは、場合によりハロ、C3−7シクロアルキル、C1−7アルコキシ、ヒドロキシおよびO−アセテートからなる群から独立して選択される1個以上の置換基で置換されていてよく;ここで、2個のジェミナルアルキルは場合により一体となってC3−7シクロアルキルを形成してよく;または
A1は直鎖もしくは分枝鎖C1−7アルケニレンであるか;または
A1は直鎖C1−4アルキレンであり、ここで、1個以上の炭素原子がO、NRcから選択されるヘテロ原子で置き換えられており;そしてA1は場合によりハロおよびC1−7アルキルからなる群から独立して選択される1個以上の置換基で置換されていてよく;ここで、各Rcは、独立してH、C1−7アルキル、−C(O)−O−C1−7アルキルまたは−CH2C(O)OHであるか;または
A1はフェニルまたはヘテロアリールであり;この各々は場合によりC1−7アルキル、C3−7シクロアルキル、ハロ−C1−7アルキル、ヒドロキシ、C1−7アルコキシ、ハロ、−NRaRb、−OCH2CO2Hおよび−OCH2C(O)NH2からなる群から独立して選択される1個以上の置換基で置換されていてよく;または
A1はC3−7シクロアルキルであり;
A1は−C1−4アルキレン−C6−10−アリール−、−C1−4アルキレン−ヘテロアリール−または−C1−4アルキレン−ヘテロシクリル−であり、ここで、A1はいずれの方向でもよく;
A2は結合または直鎖もしくは分枝鎖C1−7アルキレンであり;これは、場合によりハロ、C1−7アルコキシ、ヒドロキシ、O−アセテートおよびC3−7シクロアルキルからなる群から独立して選択される1個以上の置換基で置換されていてよく;
nは0、1、2、3、4または5であり;
ここで、各ヘテロアリールは、炭素原子および1〜5個のヘテロ原子から選択される5−10環原子を含む単環または二環芳香環であり、そして
各ヘテロシクリルは、炭素原子および1〜5個のヘテロ原子から選択を含む4−7環原子を含む単環の飽和もしくは部分的に飽和であるが、非芳香族性の基であり、ここで、ヘテロアリールまたはヘテロシクリルの各ヘテロ原子は独立してO、NおよびSから選択される。〕
の化合物またはその薬学的に許容される塩を提供する。
R1はHまたはC1−7アルキルであり;
各R2は独立してC1−7アルキル、ハロ、NO2、CN、C1−7アルカノイルアミノ、C3−7シクロアルキル、ヒドロキシ、C1−7アルコキシ、ハロC1−7アルキル、−NRaRb、C6−10アリール、ヘテロアリールまたはヘテロシクリルであり;ここで、各RaおよびRbは独立してHまたはC1−7アルキルであり;
R3はA1−C(O)X1またはA2−R4であり;
R4はC6−10アリールまたはヘテロアリールであり、これらは、単環でも二環でもよく、場合によりヒドロキシ、ヒドロキシC1−7アルキル、アミノ、C(O)−O−C1−7アルキル、C1−7アルコキシ、ハロ、C1−7アルキル、ハロ−C1−7アルキル(akyl)、C6−10アリール、ヘテロアリール、−NHSO2−C1−7アルキルおよびベンジルからなる群から独立して選択される1個以上の置換基で置換されていてよく;またはR4は場合によりオキソ、ヒドロキシ、ヒドロキシC1−7アルキル、アミノ、C(O)−O−C1−7アルキル、C1−7アルコキシ、ハロ、C1−7アルキル、ハロ−C1−7アルキル(akyl)、C6−10アリール、ヘテロアリール、−NHSO2−C1−7アルキルおよびベンジルからなる群から独立して選択される1個以上の置換基で置換されていてよいヘテロシクリルであり;
R5はH、ハロ、ヒドロキシ、C1−7アルコキシ、ハロ、C1−7アルキルまたはハロ−C1−7アルキル(akyl)であり;
XおよびX1は独立してOH、−O−C1−7アルキル、NRaRbまたは−O−C6−10アリールであり、ここで、アルキルは場合によりC6−10アリール、ヘテロアリール、ヘテロシクリル、C(O)NH2、C(O)NH−C1−6アルキルおよびC(O)N(C1−6アルキル)2からなる群から独立して選択される1個以上の置換基で置換されていてよく;
B1は−C(O)NH−または−NHC(O)−であり;
A1は結合または直鎖もしくは分枝鎖C1−7アルキレンであり;これは、場合によりハロ、C3−7シクロアルキル、C1−7アルコキシ、ヒドロキシおよびO−アセテートからなる群から独立して選択される1個以上の置換基で置換されていてよく;ここで、2個のジェミナルアルキルは場合により一体となってC3−7シクロアルキルを形成してよく;または
A1はフェニルまたはヘテロアリールであり;この各々は場合によりC1−7アルキル、C3−7シクロアルキル、ハロ−C1−7アルキル、ヒドロキシ、C1−7アルコキシ、ハロ、−NRaRb、−OCH2CO2Hおよび−OCH2C(O)NH2からなる群から独立して選択される1個以上の置換基で置換されていてよく;または
A1はC3−7シクロアルキルであり;
A1は−C1−4アルキレン−C6−10−アリール−、−C1−4アルキレン−ヘテロアリール−または−C1−4アルキレン−ヘテロシクリル−であり、ここで、A1はいずれの方向でもよく;
A2は結合または直鎖もしくは分枝鎖C1−7アルキレンであり;これは、場合によりハロ、C1−7アルコキシ、ヒドロキシ、O−アセテートおよびC3−7シクロアルキルからなる群から独立して選択される1個以上の置換基で置換されていてよく;
nは0、1、2、3、4または5であり;
ここで、各ヘテロアリールは、炭素原子および1〜5個のヘテロ原子から選択される5−10環原子を含む単環または二環芳香環であり
各ヘテロシクリルは、炭素原子および1〜5個のヘテロ原子から選択を含む4−7環原子を含む単環の飽和もしくは部分的に飽和であるが、非芳香族性の基であり、ここで、ヘテロアリールまたはヘテロシクリルの各ヘテロ原子は独立してO、NおよびSから選択される。〕
の化合物またはその薬学的に許容される塩を提供する。
本発明の化合物
次の式IまたはI’に関する引用は、式IA〜VIICの化合物に等しく適用される。
以下の本発明の態様に関する引用は、該態様が存在する限り、式Iの化合物および式IA〜VIICの化合物に等しく適用される。
本発明の種々の態様を記載する。各態様において特定される性質を他の特定される性質と組み合わせて、さらなる態様を提供し得ることは当然である。
R1がHまたはC1−7アルキルであり;
各R2が独立してC1−7アルキル、ハロ、C3−7シクロアルキル、ヒドロキシ、C1−7アルコキシ、ハロC1−7アルキル、−NRaRb、C6−10アリール、ヘテロアリールまたはヘテロシクリルであり;ここで、各RaおよびRbが独立してHまたはC1−7アルキルであり;
R3がA1−C(O)X1またはA2−R4であり;
R4がC6−10アリールまたはヘテロアリールであり、これらは単環でも二環でもよく、場合によりヒドロキシ、C1−7アルコキシ、ハロ、C1−7アルキル、ハロ−C1−7アルキル、C6−10アリール、ヘテロアリール、−NHSO2−C1−7アルキルおよびベンジルからなる群から独立して選択される1個以上の置換基で置換されていてよく;
R5がHであり;
XおよびX1が独立してOH、−O−C1−7アルキルまたはNRaRbであり;
B1が−C(O)NH−または−NHC(O)−であり;
A1が直鎖もしくは分枝鎖C1−7アルキレンであり;これは、場合によりハロ、C3−7シクロアルキル、C1−7アルコキシ、ヒドロキシおよびO−アセテートからなる群から独立して選択される1個以上の置換基で置換されていてよく;ここで、2個のジェミナルアルキルは場合により一体となってC3−7シクロアルキルを形成してよく;または
A1がフェニルまたはヘテロアリールであり;この各々は場合によりC1−7アルキル、C3−7シクロアルキル、ハロ−C1−7アルキル、ヒドロキシ、C1−7アルコキシ、ハロ、−NRaRb、−OCH2CO2Hおよび−OCH2C(O)NH2からなる群から独立して選択される1個以上の置換基で置換されていてよく;
A2が結合または直鎖もしくは分枝鎖C1−7アルキレンであり;これは、場合によりハロ、C1−7アルコキシ、ヒドロキシ、O−アセテートおよびC3−7シクロアルキルからなる群から独立して選択される1個以上の置換基で置換されていてよく;
nが0、1、2、3、4または5であり;
ここで、各ヘテロアリールは、炭素原子および1〜5個のヘテロ原子から選択される5−10環原子を含む単環または二環芳香環であり
各ヘテロシクリルは、炭素原子および1〜5個のヘテロ原子から選択を含む4−7環原子を含む単環の飽和もしくは部分的に飽和であるが、非芳香族性の基であり、ここで、ヘテロアリールまたはヘテロシクリルの各ヘテロ原子は独立してO、NおよびSから選択される
式IまたはI’の化合物またはその薬学的に許容される塩を提供する。
の化合物またはその薬学的に許容される塩を含む。
の化合物またはその薬学的に許容される塩により説明される。
の化合物またはその薬学的に許容される塩により説明される。
の化合物またはその薬学的に許容される塩を含む。
の化合物またはその薬学的に許容される塩により説明される。
の化合物またはその薬学的に許容される塩を含む。
である、ここに記載する式I’、I〜IC、II〜IICおよびII〜IIICまたは任意の群もしくは下位群の化合物またはその薬学的に許容される塩を含む。この態様の一つの面において、A1は次のものの一つである:
の一つである、ここに記載する式I’、I〜IC、II〜IICおよびII〜IIICまたは任意の群もしくは下位群の化合物またはその薬学的に許容される塩を含む。さらなる態様において、A1は次のものの一つである:
の化合物またはその薬学的に許容される塩により説明される。
の化合物またはその薬学的に許容される塩に関する。
の化合物またはその薬学的に許容される塩を含む。この態様の一つの面において、A1はフェニル、ピリジンまたはピリミジンである。
の化合物またはその薬学的に許容される塩に関する。
の化合物またはその薬学的に許容される塩を含む。さらなる態様は、式VIIA:
の化合物またはその薬学的に許容される塩を含む。
の化合物またはその薬学的に許容される塩を有する。
本明細書を解釈する目的で、以下の定義を、特にことわらない限り、そして、適当である限り、適用すべきであり、単数で使用している用語は複数も含み、その逆もそうである。
塩基性基および酸性基の両方が同じ分子に存在するとき、本発明の化合物は分子内塩、例えば、双性イオン分子も形成し得る。
本発明の化合物は、以下のスキーム、実施例に記載の方法を使用し、当分野で認識されている方法を使用して、合成できる。ここに記載する全ての化合物は、化合物として本発明に包含される。本発明の化合物は、スキーム1−4に記載する方法の少なくともひとつに従い合成し得る。
上に記載する全ての方法工程は、特に記載のものを含むそれ自体既知の反応条件下、例えば、使用する反応材に対しして不活性であり、それらを溶解する溶媒または希釈剤を含む、溶媒または希釈剤の非存在下または慣用的に存在下、触媒、縮合材または中和剤、例えば、イオン交換体、例えば、H+形態の、例えばカチオン交換体の非存在下または存在下、反応および/または反応体の性質によって、低温、常温または高温で、例えば、約−100〜190℃の範囲で、例えば、約−80〜約150℃、例えば、−80〜−60℃の範囲を含み、室温で、−20〜40℃でまたは還流温度で、大気圧下または密閉容器中、適当であれば加圧下および/または不活性雰囲気、例えばアルゴンまたは窒素雰囲気下、行い得る。
工程(2c)において、アルキル化のための標準的方法を用いることができる。この化学の説明的例は、Chemical Reviews 1996, 96(2), 835 - 876およびその中の引用文献に概説されている。
工程(2d)において、N−アシルオキサゾリジノンまたはN−アシルオキサジナノンn開裂のための標準的方法を用いることができる。この化学の説明的例は、Aldrichchimica Acta 1997, Vo. 30, pp. 3 - 12およびその中の引用文献に概説されている。
工程(4b)において、R1LGを塩基、例えばLDA、NHMDS、LHMDSまたはKHMDSの存在下で用いるようなアルキル化のための標準的方法を使用できる。
あるいは、中間体HまたはIを、Tetrahedron: Asymmetry, 2006, Vol. 17, No. 2, pp. 205-209に直接的にまた包括的に略記されている方法により製造してよい。
あるいは、中間体HまたはIをエノラート付加により製造し得る。この化学の説明的例は、“Enantioselective synthesis of β-amino acids, 2nd Edition”, John Wiley and Sons, Inc., NJ (2005)に直接的にまた包括的に概説されている。
あるいは、中間体HまたはIをSynlett, 2006, No. 4, pp. 539-542に略記された合成経路に、直接的に従いまたは準じて製造し得る。
a) 希釈剤、例えば、ラクトース、デキストロース、スクロース、マンニトール、ソルビトール、セルロースおよび/またはグリシン;
b) 滑剤、例えば、シリカ、タルク、ステアリン酸、そのマグネシウムまたはカルシウム塩および/またはポリエチレングリコール;錠剤についてはまた
c) 結合剤、例えば、ケイ酸アルミニウム・マグネシウム、デンプンペースト、ゼラチン、トラガカント、メチルセルロース、ナトリウムカルボキシメチルセルロースおよび/またはポリビニルピロリドン;所望により
d) 崩壊剤、例えば、デンプン類、寒天、アルギン酸またはそのナトリウム塩または起沸性混合物;および/または
e) 吸収剤、着色剤、香味剤および甘味剤
と共に含む錠剤およびゼラチンカプセルである。
組み換えヒト中性エンドペプチダーゼ(標準的方法を使用して昆虫細胞で発現させ、精製した、最終濃度7pM)を種々の濃度の試験化合物と、1時間、室温で150mM NaClおよび0.05%(w/v) CHAPSを含む10mM リン酸ナトリウム緩衝液中、pH7.4でプレインキュベートする。酵素反応を合成ペプチド基質Cys(PT14)−Arg−Arg−Leu−Trp−OHを0.7μMの最終濃度まで添加することにより開始させる。Doering et al. (2009)に記載の通り基質加水分解が、PT14の蛍光寿命(FLT)を、FLTリーダーで測定して延長させる。酵素活性に対する本化合物の影響を、室温で1時間(t=60分)インキュベーション後に決定した。阻害剤の非存在下で測定したFLT値の50%減少を示す阻害剤濃度に対応するIC50値を、阻害パーセント対阻害剤濃度の非線形回帰分析ソフトウェアを使用したプロットから計算する。
用語“ApoA−I摸倣剤”は、D4Fペプチド類(例えば、式D−W−F−K−A−F−Y−D−K−V−A−E−K−F−K−E−A−F)を含む。
市販のアルドステロンシンターゼ阻害剤または保健当局が承認しているアルドステロンシンターゼ阻害剤が好ましい。
用語“CETP阻害剤”は、種々のコレステイルエステル類およびトリグリセリド類のHDLからLDLおよびVLDLへのコレステリルエステル輸送タンパク質(CETP)仲介輸送を阻害する化合物を意味する。かかるCETP阻害活性は、標準アッセイ(例えば米国特許6,140,343)に従い、当業者により容易に決定できる。例は、米国特許6,140,343および米国特許6,197,786に開示されている化合物(例えば、[2R,4S]4−[(3,5−ビス−トリフルオロメチル−ベンジル)−メトキシカルボニル−アミノ]−2−エチル−6−トリフルオロメチル−3,4−ジヒドロ−2H−キノリン−1−カルボン酸エチルエステル(トルセトラピブ);米国特許6,723,752に開示されている化合物(例えば、(2R)−3−{[3−(4−クロロ−3−エチル−フェノキシ)−フェニル]−[[3−(1,1,2,2−テトラフルオロ−エトキシ)−フェニル]−メチル]−アミノ}−1,1,1−トリフルオロ−2−プロパノール);米国特許出願10/807,838に開示されている化合物;米国特許5,512,548に開示されているポリペプチド誘導体;それぞれJ. Antibiot., 49(8): 815-816 (1996)およびBioorg. Med. Chem. Lett.; 6: 1951-1954 (1996)に開示されているロセノノラクトン誘導体およびコレステリルエステル類のホスフェート含有アナログを含む。さらに、CETP阻害剤はまたWO2000/017165、WO2005/095409およびWO2005/097806に開示されているものも含む。
特に興味深い第二剤は、エンドセリンアンタゴニスト、レニン阻害剤、アンギオテンシンII受容体アンタゴニスト、カルシウムチャネルブロッカー、利尿剤、抗糖尿病剤、例えばDPPIV阻害剤およびアルドステロンシンターゼ阻害剤を含む。
本発明の合成に使用する全ての出発物質、中間体、反応材、酸類、塩基類、脱水剤、溶媒および触媒は市販のものであるか、当業者に既知の有機合成法により製造できる(Houben-Weyl 4th Ed. 1952, Methods of Organic Synthesis, Thieme, Volume 21)。さらに、本発明の化合物を以下の実施例に示す当業者に既知の有機合成法により製造できる。
HPLC条件A:
カラム:INERTSIL C8-3、3μm×33mm×3.0mm、40℃
流速:2ml/分
移動相:A)5mM 水性HCOONH4、B)MeOH/CH3CN(1/1、v/v)
勾配:2分間で5%Aから95%Bの直線勾配
検出:200−400nmでDAD−UV
カラム:INERTSIL C8-3、3μm×33mm×3.0mm、40℃
流速:2ml/分
移動相:A)5mM 水性HCOONH4、B)MeOH/CH3CN(1/1、v/v)
勾配:2分間で40%Aから95%Bの直線勾配
検出:200−400nmでDAD−UV
カラム:INERTSIL C8-3、3μm×33mm×3.0mm、40℃
流速:2ml/分
移動相:A)(5mM NH4 +HCOO−)/水、B)MeOH/CH3CN(1/1、v/v)
勾配:2分間で5から95%Bの直線勾配
検出:200−400nmでDAD−UV
カラム:INERTSIL C8-3、3μm×33mm×3.0mm、40℃
流速:2ml/分
移動相:A)0.1%水性ギ酸、B)MeOH/CH3CN(1/1、v/v)
勾配:2分間で5%Bから95%Bの直線勾配
検出:200−400nmでDAD−UV
カラム:Inertsil C8-3、3μm×33mm×3.0mm、40℃
流速:2ml/分
移動相:A)メタノール/アセトニトリル(1/1、v/v)、B)5mM水性HCOONH4
勾配:2分間で40%Bから95%Aの直線勾配
検出:214nmでUV
キラルHPLC保持時間=3.59分。カラム:Daicel CHIRALPAK AD-H(4.6×100mm);流速=1ml/分;溶離剤:EtOH(0.1%TFA含有)/ヘプタン=4/6。
得られた残留物をRP−HPLC(SunFire C18、H2O(0.1%TFA)/CH3CN)で精製し、凍結乾燥して、(R)−6−(1−(ビフェニル−4−イル)−4−エトキシ−4−オキソブタン−2−イルカルバモイル)ピリミジン−4−カルボン酸(84.8mg)を得る。HPLC保持時間=1.32分(条件B);MS (m+1)=434.1; 1H NMR (400 MHz, DMSO-d6) δ ppm 1.12 (t, J=7.0 Hz, 3 H) 2.65 (A of ABX, Jab=15.4 Hz, Jax=5.8 Hz, 1 H) 2.73 (B of ABX, Jab=15.4 Hz, Jbx=7.9 Hz) 2.91 (A of ABX, Jab=13.6 Hz, Jax=6.1 Hz, 1 H) 3.01 (B of ABX, Jab=13.6 Hz, Jbx=8.2 Hz, 1 H) 4.01 (q, J=7.0 Hz, 2 H) 4.59 - 4.68 (m, 1 H) 7.29 - 7.35 (m, 3 H) 7.41 - 7.45 (m, 2 H) 7.55 - 7.63 (m, 4 H) 8.32 (d, J=1.35 Hz, 1 H) 9.19 (d. J=9.1 Hz, 1 H) 9.50 (d, J=1.35 Hz, 1 H) 14.11 (br s, 1 H)。
キラルHPLC保持時間=4.33分。カラム:Daicel CHIRALPAK IA(4.6×100mm);流速=1ml/分;溶離剤:EtOH(0.1%TFA含有)/ヘプタン=10分間で10/90〜70/30。(直線勾配)。
次に、粗物質(39mg)およびPd/C(16.6mg、7.8μmol)のEtOH(1ml)懸濁液を、水素下、室温で4時間撹拌する。反応混合物を濾過し、濃縮して、粗物質を得る。得られた残留物を20%MeCN/水(0.1%TFA)から100%MeCNの勾配を使用する分取HPLCで精製して、4−(ビフェニル−4−イル)−3−(1−(カルボキシメチル)シクロペンタンカルボキサミド)酪酸(12.7mg)を得る;HPLC保持時間=1.16分(条件B);MS (m+1)=410.1; 1H NMR (400 MHz, DMSO-d6) δ ppm 1.39 - 1.53 (m, 6 H) 1.83 - 1.98 (m, 2 H) 2.34 - 2.45 (m, 2 H) 2.53 (s, 2 H) 2.73 - 2.86 (m, 2 H) 4.21 - 4.33 (m, 1 H) 7.27 (d, J=8.1 Hz, 2 H) 7.32 - 7.37 (m, 2 H) 7.43 - 7.46 (m, 2 H) 7.55 - 7.58 (m, 2 H) 7.62 - 7.64 (m, 2 H) 7.84 (br d, J=8.9 Hz, 1 H)。
次に、上記ジエステル(70mg、0.147mmol)の塩化メチレン(2mL)溶液にTFA(4mL)を添加し、混合物を室温で18時間撹拌する。溶媒を減圧下除去し、残留物を35%MeCN/水〜100%MeCN(+0.1%TFA)の勾配を使用する分取HPLCで精製する。適当なフラクションの凍結乾燥により、表題化合物を得る;HPLC保持時間=1.42分(条件C);MS 419.1 (M+1); 1H NMR (400 MHz, DMSO-d6): δ ppm 1.17 (t, J=7.07 Hz, 3H), 2.41 (d, J=7.07 Hz, 2H), 2.77-2.79 (m, 2H), 3.66-3.68 (m, 2H), 4.04 (q, J=7.07 Hz, 2H), 4.08-4.15 (m, 1H), 6.13 (t, J=5.81 Hz, 1H), 6.24 (d, J=8.59 Hz, 1H), 7.28-7.30 (m, 2H), 7.39-7.42 (m, 1H), 7.48 (t, J=7.83 Hz, 1H), 7.62-7.64 (m, 3H), 7.71 (t, J=1.77 Hz, 1H), 12.42 (s, 1H)。
次に、(R)−3−アミノ−4−ビフェニル−4−イル−酪酸エチルエステルトリフルオロ酢酸塩(0.074g、0.261mmol)のDCM(10mL)懸濁液に、室温で1H−テトラゾール−5−酢酸(0.050g、0.392mmol)を添加する。混合物に、氷浴温度で、ビス(2−オキソ−3−オキサゾリジニル)ホスフィニッククロライド(0.100g、0.392mmol)、そして直ぐにDIPEA(0.137ml、0.783mmol)を添加する。反応混合物をゆっくり室温に温め、一夜撹拌する。反応物をDCMで抽出する。合わせた有機層を飽和NaHCO3、飽和NH4Cl、塩水で洗浄し、無水硫酸ナトリウムで乾燥させ、濾過し、減圧下濃縮して、(R)−4−ビフェニル−4−イル−3−(2−1H−テトラゾール−5−イル−アセチルアミノ)−酪酸エチルエステルを得る。HPLC保持時間=1.04分(条件E);MS (m+1)=394。
実施例4−21:(R)−3−[(5−カルボキシメチル−フラン−2−カルボニル)−アミノ]−4−(3’−クロロ−ビフェニル−4−イル)−酪酸
次に、上記ジエステル(235mg、0.486mmol)のEtOH(5mL)溶液に1N NaOH(0.486mL)を添加し、混合物を室温で4時間撹拌する。溶媒を減圧下除去し、水(4mL)を添加する。溶液を1N HClにより酸性化し、混合物をEtOAcで抽出する。有機相を硫酸ナトリウムにより乾燥させ、溶媒を減圧下除去する。残留物を10%MeCN/水〜100%MeCN(+0.1%TFA)の勾配を使用する分取HPLCで精製する。適当なフラクションの凍結乾燥により、表題化合物を得る。(R)−3−[(5−カルボキシメチル−フラン−2−カルボニル)−アミノ]−4−(3’−クロロ−ビフェニル−4−イル)−酪酸エチルエステル。HPLC保持時間=1.35分(条件C);MS 470.0 (M+1); 1H NMR (400 MHz, DMSO-d6) δ ppm 1.13 (t, J=7.07 Hz, 3H), 2.50-2.64 (m, 2H), 2.81-2.95 (m, 2H), 3.74 (s, 2H), 4.01 (q, J=7.07 Hz, 2H), 4.51 (m, 1H), 6.99 (d, J=3.28 Hz, 1H), 7.31 (d, J=8.34 Hz, 2H), 7.38-7.41 (m, 1H), 7.47 (t, 1H), 7.62 (d, J=8.08 Hz, 3H), 7.69 (t, 1H), 8.24 (d, J=8.84 Hz, 1H)。
HPLC保持時間=1.31分(条件B);MS (m+1)=414.1;1H NMR (400 MHz, DMSO-d6) δ ppm 1.11 (t, J=7.1 Hz, 3 H), 2.63 (dd, J=15.4, 5.6 Hz, 1 H), 2.72 (dd, J=15.4, 8.3 Hz, 1 H), 2.86 - 2.99 (m, 2 H), 4.02 (q, J=7.1 Hz, 2 H), 4.55 - 4.67 (m, 1 H), 7.32 (d, J=8.1 Hz, 2 H), 7.37 - 7.42 (m, 1 H), 7.46 (t, J=7.8 Hz, 1 H), 7.60 (d, J=8.1 Hz, 3 H), 7.68 (t, J=1.8 Hz, 1 H), 9.37 (d, J=8.8 Hz, 1 H)。
次に、(2R,4R)−7−ビフェニル−4−イルメチル−2,4−ジメチル−6−オキソ−ノナン二酸9−tert−ブチルエステル1−エチルエステルのEtOH(4mL)溶液に水性1M NaOH(4mL)を添加し、混合物を室温で30分間撹拌する。混合物を水性1M HClでpH2−3に酸性化し、酢酸エチルで抽出する。溶媒を減圧下除去し、残留物を10−100%MeCN/水(0.1%TFA)の勾配を使用する分取HPLCで精製する。適切なフラクションの凍結乾燥により(R)−4−(2−ビフェニル−4−イルメチル−3−カルボキシ−プロピオニルアミノ)−2−メチル−ペンタン酸を得る。HPLC保持時間=1.13分(条件C);MS 398.2 (M+1); 1H- NMR (400 MHz, DMSO-d6) δ ppm 0.93 (m, 6H), 1.23 (m, 1H), 1.59 (m, 1H), 2.17 (m, 1H), 2.63 (m, 1H), 2.82 (m, 1H), 3.72 (m, 1H), 7.27 (m, 2H), 7.33 (m, 1H), 7.45 (m, 2H), 7.56 (m, 2H), 7.62 (m, 2H), 7.71 (m, 1H), 12.07 (s, 1H)。
キラルHPLC保持時間=5.64分。カラム:Daicel CHIRALCEL OJ-H(4.6×100mm);流速=1ml/分;溶離剤:EtOH(0.1%TFA含有)/ヘプタン=2/8。
(R)−3−[(S)−2−(カルボキシメチル−アミノ)−プロピオニルアミノ]−4−(3’−クロロ−ビフェニル−4−イル)−酪酸:1H NMR (400 MHz, DMSO-d6) δ ppm 1.28 (d, J=7.1 Hz, 3 H), 2.40 (dd, J=15.7, 8.3 Hz, 1 H), 2.51 - 2.56 (m, 1 H), 2.76 (dd, J=13.4, 8.1 Hz, 1 H), 2.87 (dd, J=13.4, 5.3 Hz, 1 H), 3.43 - 3.52 (m, 3 H), 3.67 (q, J=6.7 Hz, 1 H), 4.25 - 4.36 (m, 1 H), 7.30 (d, J=8.3 Hz, 2 H), 7.38 - 7.43 (m, 1 H), 7.48 (t, J=7.8 Hz, 1 H), 7.59 - 7.65 (m, 3 H), 7.70 (t, J=1.8 Hz, 1 H), 8.41 (d, J=8.3 Hz, 1 H). HRMS: C21H23ClN2O5の計算値: 418.1295; 実測値: m/z 418.1307. LCMS (条件A): 419 (M+1);保持時間=0.93分;(R)−3−[(R)−2−(カルボキシメチル−アミノ)−プロピオニルアミノ]−4−(3’−クロロ−ビフェニル−4−イル)−酪酸:1H NMR (400 MHz, DMSO-d6) δ ppm 1.17 (d, J=6.8 Hz, 3 H), 2.41 - 2.49 (m, 0 H), 2.51 - 2.57 (m, 1 H), 2.73 (dd, J=13.4, 9.1 Hz, 1 H), 2.91 (dd, J=13.4, 4.8 Hz, 1 H), 3.55 - 3.67 (m, 2 H), 3.67 - 3.74 (m, 1 H), 4.26 - 4.40 (m, 1 H), 7.29 (d, J=8.3 Hz, 2 H), 7.39 - 7.44 (m, 0 H), 7.48 (t, J=7.8 Hz, 0 H), 7.59 - 7.65 (m, 3 H), 7.69 (t, J=1.8 Hz, 1 H), 8.43 (d, J=8.6 Hz, 1 H). HRMS: C21H23ClN2O5の計算値: 418.1295; 実測値: m/z 418.1305. LCMS (条件A): 419 (M+1);保持時間=0.99分間。
実施例13−2:(R)−2−(1−(ビフェニル−4−イル)−3−カルボキシプロパン−2−イルカルバモイル)イソニコチン酸の合成
次に、上記残留物をEtOH(1mL)に溶解し、1N NaOH(3mL、3mmol)を添加する。混合物を室温で2時間撹拌し、1N HClで酸性化する。混合物をEtOAcで抽出する有機相を水、塩水で洗浄し、硫酸ナトリウムにより乾燥させる。溶媒を減圧下除去し、残留物10%MeCN/水〜100%MeCN(+0.1%TFA)の勾配を使用する分取HPLCで精製する。適当なフラクションの凍結乾燥により、表題化合物を得る;HPLC保持時間=0.98分(条件C);MS 391.3 (M+1); 1H NMR (400 MHz, DMSO-d6): δ ppm 2.34 (d, J=7.33 Hz, 2H), 2.79 (d, J=6.57 Hz, 2H), 3.67 (d, J=5.56 Hz, 2H), 4.04-4.12 (m, 1H), 6.15 (t, J=5.81 Hz, 1H), 6.23 (d, J=8.34 Hz, 1H), 7.28-7.30 (m, 2H), 7.39-7.42 (m, 1H), 7.48 (t, J=7.83 Hz, 1H), 7.62-7.65 (m, 3H), 7.71 (t, J=1.77 Hz, 1H), 12.32 (s, br, 2H)。
中間体1:(R)−エチル4−(4−ブロモフェニル)−3−(4−メトキシ−4−オキソブタンアミド)ブタノエート
次に、(R)−4−ビフェニル−4−イル−3−(3−カルボキシ−プロピオニルアミノ)−酪酸エチルエステル(200mg、0.522mmol)のTHF(10mL)溶液に、室温でEDC・HCl(120mg、0.626mmol)およびHOBT(96mg、0.626mmol)を添加する。反応物を室温で10分間撹拌し、3−アミノプロピオニトリル(0.046ml、0.626mmol)およびTEA(0.087ml、0.626mmol)を添加する。1時間後、0.5当量のEDC・HCl、HOBTおよび3−アミノプロピオニトリルを添加し、16時間撹拌する。反応混合物を塩水でクエンチし、酢酸エチルで抽出する。合わせた有機層を塩水で洗浄し、無水硫酸ナトリウムで乾燥させ、濾過し、減圧下濃縮する。得られた残留物をフラッシュクロマトグラフィー(シリカゲル、2%〜5%EtOH/DCM)で精製して、(R)−4−ビフェニル−4−イル−3−[3−(2−シアノ−エチルカルバモイル)−プロピオニルアミノ]−酪酸エチルエステル(218mg、96%収率)を得る。HPLC保持時間=0.77分(条件E);MS=436 (m+1)。
次に、(R)−4−ビフェニル−4−イル−3−[3−(2−シアノ−エチルカルバモイル)−プロピオニルアミノ]−酪酸エチルエステル(204mg、0.468mmol)のTHF(10mL)溶液に、室温でPh3P(307mg、1.17mmol)を添加し、混合物を室温で10分間撹拌する。混合物に氷浴温度でDIAD(0.228ml、1.171mmol)およびトリメチルシリルアジド(0.155ml、1.171mmol)を添加する。得られた混合物をゆっくり室温に温め、16時間撹拌する。反応混合物を減圧下濃縮する。得られた残留物をフラッシュクロマトグラフィー(シリカゲル、1%〜3%EtOH/DCM)で精製して、(R)−4−ビフェニル−4−イル−3−{3−[1−(2−シアノ−エチル)−1H−テトラゾール−5−イル]−プロピオニルアミノ}−酪酸エチルエステル(137mg、64%収率)を得る。HPLC保持時間=1.61分(条件C);MS=461 (m+1)。
次に、(E)−(R)−4−tert−ブトキシカルボニルアミノ−2−メチル−ペント−2−エン酸エチルエステル(1.83g、7.11mmol)の酢酸エチル(75mL)溶液を、10%Pt/C(183mg)で、1気圧で18時間水素化する。触媒をセライトを通して濾過し、溶媒を減圧下除去する。残留物をキラルHPLCで精製して、(2R,4R)−4−tert−ブトキシカルボニルアミノ−2−メチル−ペンタン酸エチルエステルを得る;1H-NMR (400 MHz, CDCl3); δ ppm 1.13 (t, 3H), 1.18 (m, 3H), 1.26 (t, 3H), 1.43 (s, 9H), 1.81 (s, 1H), 2.50 (m, 1H), 3.72 (m broad, 1H), 4.14 (m, 2H), 4.33 (m broad, 1H)。
次に、(2R,4R)−4−tert−ブトキシカルボニルアミノ−2−メチル−ペンタン酸エチルエステル(142mg、0.548mmol)をトリフルオロ酢酸(5mL)に添加する。10分間後、溶媒を減圧下除去する。塩化メチレンを添加し、溶媒を減圧下除去して、(2R,4R)−4−アミノ−2−メチル−ペンタン酸エチルエステルトリフルオロアセテートを得る。この物質を直接続くカップリング反応に使用する。
次に、2−(トリフェニルホスファニリデン)−コハク酸4−tert−ブチルエステル1−メチルエステル(700mg、1.561mmol)およびビフェニル−4−カルボキシアルデヒド(278mg、1.419mmol)のトルエン(20mL)中の混合物を4日間還流する。溶媒を減圧下除去し、残留物を0−30%ヘプタン/EtOAcの勾配を使用するカラムクロマトグラフィーで精製して、2−[1−ビフェニル−4−イル−メト−(Z)−イリデン]−コハク酸4−tert−ブチルエステル1−メチルエステルを油状物として得る;1H-NMR (400 MHz, CDCl3); δ ppm 1.47 (s, 9H), 3.52 (s, 2H), 3.84 (s, 3H), 7.37 (t, 1H), 7.46 (t, 4H), 7.62 (t, 4H), 7.89 (s, 1H)。
2−[1−ビフェニル−4−イル−メト−(Z)−イリデン]−コハク酸4−tert−ブチルエステル1−メチルエステル(410mg、1.163mmol)の酢酸エチル(20mL)溶液を、Pt/C(40mg)で、1気圧で18時間水素化する。触媒をセライトを通して濾過し、溶媒を減圧下除去して、2−ビフェニル−4−イルメチル−コハク酸4−tert−ブチルエステル1−メチルエステル。エナンチオマーをキラルHPLCにより分離する。
次に、2−ビフェニル−4−イルメチル−コハク酸4−tert−ブチルエステル1−メチルエステル(160mg、0.451mmol)をトリフルオロ酢酸(5mL)に添加する。10分間後、溶媒を減圧下除去する。塩化メチレンを添加し、溶媒を減圧下除去して、2−ビフェニル−4−イルメチル−コハク酸1−メチルエステルを得る。この物質を直接続くカップリング反応に使用する。
粗物質に、1,4−ジオキサン中4M HCl溶液(1.583ml、6.33mmol)を添加する。1時間撹拌後、沈殿した固体を回収し、減圧下乾燥させて、(R)−3−アミノ−4−(3’−クロロビフェニル−4−イル)酪酸ヒドロクロライド(60.2mg)を白色固体として得る;HPLC保持時間=0.52分(条件B);MS (m+1)=290.22; 1H NMR (400 MHz, CD3OD) δ ppm 2.58 - 2.74 (m, 2 H) 2.99 - 3.11 (m, 2 H) 3.80 - 3.85 (m, 1 H) 7.34 - 7.45 (m, 4 H) 7.54 - 7.57 (m, 1 H) 7.62 - 7.65 (m, 3 H)。
(R)−エチル3−(tert−ブトキシカルボニルアミノ)−4−(5’−フルオロ−2’−メトキシビフェニル−4−イル)ブタノエート、(2.86g、6.62mmol)の1,4−ジオキサン中4M HCl溶液(33.1ml、132mmol)中の溶液を室温で撹拌する。1時間撹拌後、反応混合物を減圧下濃縮して、(R)−エチル3−アミノ−4−(5’−フルオロ−2’−メトキシビフェニル−4−イル)ブタノエート塩酸塩(2.44g)を得る。HPLC保持時間=1.46分(条件A);MS (m+1)=332.3; 1H NMR (400 MHz, クロロホルム-d) δ ppm 1.15 (t, J=6.4 Hz, 3 H) 2.66 - 2.77 (m, 1 H) 2.78 - 2.91 (m, 1 H) 2.94 - 3.10 (m, 1 H) 3.42 - 3.53 (m, 1 H) 3.67 (s, 3 H) 3.83 - 3.96 (m, 1 H) 4.07 (q, J=6.8 Hz, 2 H) 6.77 - 6.84 (m, 1 H) 6.87 - 6.96 (m, 2 H) 7.23 (d, J=7.1 Hz, 2 H) 7.38 (d, J=7.1 Hz, 2 H) 8.64 (br. s., 2 H)
次に、上記二酸(220mg、1.29mmol)のメタノール(8mL)溶液に、Amberlyst-15樹脂(50mg)を添加し、混合物を室温で18時間撹拌する。樹脂を濾過し、溶媒を減圧下除去して、生成物を得て、それをそのまま次反応に使用する。1H NMR (400 MHz, クロロホルム-d) δ ppm 3.75 (s, 3H), 3.82 (s, 2H), 6.45 (d, J=3.54 Hz, 1H), 7.29 (d, J=3.54 Hz, 1H), 10.17 (s, broad, 1H)。
次に、2−(4−メトキシ−ベンジル)−2H−テトラゾール−5−カルボン酸のトルエン(15ml)中の混合物に、室温でSOCl2(1ml、13.70mmol)を添加し、混合物を80℃で3時間加熱する。反応混合物を減圧下濃縮して、粗生成物を得て、それをさらに精製せずに使用する。
次に、得られた残留物(0.252g、0.625mmol)のDMSO(1.5ml)溶液に、室温で水酸化アンモニウム(0.027ml、0.688mmol)を添加する。反応物を室温で撹拌する。30分間後、LCMSは少量の所望の生成物と大量の出発物質を示したため、さらに水酸化アンモニウムを添加し、反応物を室温で一夜、反応が完了するまで撹拌する。反応物をEtOAcで抽出する。合わせた有機層をH2O、1N HCl、H2O、1N NaOHおよび塩水で洗浄し、無水硫酸ナトリウムで乾燥させ、濾過し、減圧下濃縮する。残留物をカラムクロマトグラフィー(2%〜6%EtOH/DCM)で精製して、(R)−4−ビフェニル−4−イル−3−ウレイド−酪酸エチルエステル(169mg)を得る。HPLC保持時間=1.04分(条件B);MS (m+1)=327。
これを1,2−ジメトキシエタン(40mL)に溶解し、Et3N(1.46mL、10.5mmol)およびクロロギ酸エチル(1.00mL、10.5mmol)を添加する。室温で0.5時間撹拌後、得られた沈殿を濾過により除去する。濾液にNaBH4(0.44g、11.6mmol)のH2O(5mL)溶液をゆっくり添加する。2時間撹拌後、反応混合物をEtOAcで希釈し、H2Oおよび塩水で洗浄する。有機層をNa2SO4で乾燥させ、濃縮し、フラッシュカラムクロマトグラフィー(シリカゲル、溶離剤;ヘプタン/EtOAc=100:0〜0:100)で精製して、[(R)−2−(3’−クロロ−ビフェニル−4−イル)−1−ヒドロキシメチル−エチル]−カルバミン酸tert−ブチルエステル(2.8g)を得る。HPLC保持時間=1.26分(条件A):MS (m+1-Boc)=262. 1H-NMR (400 MHz, DMSO-d6) δ ppm 1.43 (s, 9 H), 2.90 (d, 2 H, J=7.33 Hz), 3.60 (dd, 1 H, J=5.05, 10.86 Hz), 3.72 (dd, 1 H, J=3.79, 11.12 Hz), 3.91 (bs, 1 H), 4.75 (bs, 1 H), 7.29-7.34 (m, 3 H), 7.37 (t, 1 H, J=7.83 Hz), 7.44-7.48 (m, 1 H), 7.51 (d, 2 H, J=8.08 Hz), 7.57 (t, 1 H, J=1.77 Hz)。
これをMeOH(20mL)およびAcOH(0.199mL、3.47mmol)に溶解する。この溶液にKCN(0.226g、3.47mmol)のH2O(4mL)溶液をゆっくり添加する。室温で一夜撹拌後、反応混合物をEtOAcで希釈し、飽和NaHCO3水性溶液、H2Oおよび塩水で洗浄する。有機層をNa2SO4で乾燥させ、濃縮する。これをジオキサン中4M HCl溶液(20mL)およびMeOH(10mL)で室温で処理する。一夜撹拌後、反応混合物を濃縮する。残留物をMeOHに溶解し、SOCl2(0.211mL、2.89mmol)で処理する。50℃で5時間撹拌後、反応混合物を濃縮乾固する。残留物をTHF(10mL)に溶解し、飽和NaHCO3水性溶液(5mL)およびBoc2O(0.631g、2.89mmol)で処理する。室温で2時間撹拌後、反応混合物をEtOAcで希釈し、塩水で洗浄する。有機層をMgSO4で乾燥させ、濃縮する。残留物をフラッシュカラムクロマトグラフィー(シリカゲル、溶離剤;ヘプタン/EtOAc=100:0〜0:100)で精製して、(R)−3−tert−ブトキシカルボニルアミノ−4−(3’−クロロ−ビフェニル−4−イル)−2−ヒドロキシ−酪酸メチルエステル(0.61g)を得る。HPLC保持時間=1.01、1.06分(条件B):MS (m+1-Boc)=320. 1H-NMR (400 MHz, CDCl3) δ ppm 1.40 (s, 9 H), 2.77-3.05 (m, 2 H), 3.63 (s, 0.7 H), 3.77 (s, 2.3 H), 4.11 (s, 0.8 H), 4.25-4.40 (m, 1.2 H), 4.78-4.95 (m, 1 H), 7.27-7.40 (m, 4 H), 7.42-7.58 (m, 4 H)。
(R)−3−tert−ブトキシカルボニルアミノ−4−(3’−クロロ−ビフェニル−4−イル)−2−ヒドロキシ−酪酸メチルエステル(113mg、0.269mmol)をジオキサン中4M HCl溶液(2mL)で処理する。室温で1時間撹拌後、反応混合物を濃縮する。残留物を次工程にさらに精製せずに使用する。HPLC保持時間=1.22、1.29分(条件A):MS (m+1)=320。
(R)−3−tert−ブトキシカルボニルアミノ−4−(3’−クロロ−ビフェニル−4−イル)−2−メトキシ−酪酸メチルエステル(200mg、0.461mmol)をジオキサン中4M HCl溶液(3mL)で処理する。室温で1時間撹拌後、反応混合物を濃縮する。残留物を次工程にさらに精製せずに使用する。HPLC保持時間=1.26、1.33分(条件A):MS (m+1)=334。
(R)−3−tert−ブトキシカルボニルアミノ−4−(3’−クロロ−ビフェニル−4−イル)−2−フルオロ−酪酸メチルエステル(60mg、0.142mmol)をジオキサン中4M HCl溶液(1.5mL)で処理する。室温で1時間撹拌後、反応混合物を濃縮する。残留物を次工程にさらに精製せずに使用する。HPLC保持時間=0.88分(条件B):MS (m+1)=322。
次に、2−(エトキシカルボニルメチル−アミノ)−プロピオン酸ベンジルエステル(1.7g、6.41mmol)のDCM(80ml)溶液に、0℃でBOC−無水物(2.232ml、9.61mmol)およびTEA(2.68ml、19.22mmol)を添加した。反応混合物をゆっくり室温に温め、一夜撹拌した。反応を塩水でクエンチし、DCMで抽出した。合わせた有機層を塩水で洗浄し、無水硫酸ナトリウムで乾燥させ、濾過し、濃縮して、粗物質を得た。フラッシュクロマトグラフィー(シリカゲル、5〜10%アセトン/ヘプタン)により、表題化合物を油状物として得た(1.66g、71%収率)。LCMS(条件B):366 (M+1);保持時間=1.13分間。
次に、2−(tert−ブトキシカルボニル−エトキシカルボニルメチル−アミノ)−プロピオン酸ベンジルエステルのEtOAc溶液を、H2バルーン下、湿10%Pd/Cの触媒により1時間水素化した。反応物から触媒を濾別し、濃縮して、次反応のための粗物質を得た。
Claims (19)
- 式I’:
R1はH、C1−7アルキル、ヒドロキシ、C1−7アルコキシ、ハロゲン、−SH、−S−C1−7アルキルまたはNRaRbであり;
各R2は独立してC1−7アルキル、ハロ、NO2、CN、C1−7アルカノイルアミノ、C3−7シクロアルキル、ヒドロキシ、C1−7アルコキシ、ハロC1−7アルキル、−NRaRb、C6−10アリール、ヘテロアリールまたはヘテロシクリルであり;ここで、各RaおよびRbは独立してHまたはC1−7アルキルであり;
R3はA1−C(O)X1またはA2−R4であり;
R4はC6−10アリールまたはヘテロアリールであり、これらは、単環でも二環でもよく、場合によりヒドロキシ、ヒドロキシC1−7アルキル、ニトロ、−NRaRb、−C(O)C1−7アルキル、C(O)−O−C1−7アルキル、C1−7アルコキシ、ハロ、C1−7アルキル、ハロ−C1−7アルキル(akyl)、C2−7アルケニル、C6−10アリール、ヘテロアリール、−NHSO2−C1−7アルキルおよびベンジルからなる群から独立して選択される1個以上の置換基で置換されていてよく;またはR4は場合によりオキソ、ヒドロキシ、ヒドロキシC1−7アルキル、アミノ、C(O)−O−C1−7アルキル、C1−7アルコキシ、ハロ、C1−7アルキル、ハロ−C1−7アルキル(akyl)、C6−10アリール、ヘテロアリール、−NHSO2−C1−7アルキルおよびベンジルからなる群から独立して選択される1個以上の置換基で置換されていてよいヘテロシクリルであり;
R5はH、ハロ、ヒドロキシ、C1−7アルコキシ、ハロ、C1−7アルキルまたはハロ−C1−7アルキル(akyl)であり;
XおよびX1は独立してOH、−O−C1−7アルキル、−NRaRb、−NHS(O)2−C1−7アルキル、−NHS(O)2−ベンジルまたは−O−C6−10アリールであり、ここで、アルキルは場合によりC6−10アリール、ヘテロアリール、ヘテロシクリル、C(O)NH2、C(O)NH−C1−6アルキルおよびC(O)N(C1−6アルキル)2からなる群から独立して選択される1個以上の置換基で置換されていてよく;
B1は−C(O)NH−または−NHC(O)−であり;
A1は結合または直鎖もしくは分枝鎖C1−7アルキレンであり;これは、場合によりハロ、C3−7シクロアルキル、C1−7アルコキシ、ヒドロキシおよびO−アセテートからなる群から独立して選択される1個以上の置換基で置換されていてよく;ここで、2個のジェミナルアルキルは場合により一体となってC3−7シクロアルキルを形成してよく;または
A1は直鎖もしくは分枝鎖C1−7アルケニレンであるか;または
A1は直鎖C1−4アルキレンであり、ここで、1個以上の炭素原子がO、NRcから選択されるヘテロ原子で置き換えられており;そしてA1は場合によりハロおよびC1−7アルキルからなる群から独立して選択される1個以上の置換基で置換されていてよく;ここで、各Rcは、独立してH、C1−7アルキル、−C(O)−O−C1−7アルキルまたは−CH2C(O)OHであるか;または
A1はフェニルまたはヘテロアリールであり;この各々は場合によりC1−7アルキル、C3−7シクロアルキル、ハロ−C1−7アルキル、ヒドロキシ、C1−7アルコキシ、ハロ、−NRaRb、−OCH2CO2Hおよび−OCH2C(O)NH2からなる群から独立して選択される1個以上の置換基で置換されていてよく;または
A1はC3−7シクロアルキルであり;
A1は−C1−4アルキレン−C6−10−アリール−、−C1−4アルキレン−ヘテロアリール−または−C1−4アルキレン−ヘテロシクリル−であり、ここで、A1はいずれの方向でもよく;
A2は結合または直鎖もしくは分枝鎖C1−7アルキレンであり;これは、場合によりハロ、C1−7アルコキシ、ヒドロキシ、O−アセテートおよびC3−7シクロアルキルからなる群から独立して選択される1個以上の置換基で置換されていてよく;
nは0、1、2、3、4または5であり;
ここで、各ヘテロアリールは、炭素原子および1〜5個のヘテロ原子から選択される5−10環原子を含む単環または二環芳香環であり
各ヘテロシクリルは、炭素原子および1〜5個のヘテロ原子から選択を含む4−7環原子を含む単環の飽和もしくは部分的に飽和であるが、非芳香族性の基であり、ここで、ヘテロアリールまたはヘテロシクリルの各ヘテロ原子は独立してO、NおよびSから選択される。〕
の化合物またはその薬学的に許容される塩。 - 式I:
R1はHまたはC1−7アルキルであり;
各R2は独立してC1−7アルキル、ハロ、NO2、CN、C1−7アルカノイルアミノ、C3−7シクロアルキル、ヒドロキシ、C1−7アルコキシ、ハロC1−7アルキル、−NRaRb、C6−10アリール、ヘテロアリールまたはヘテロシクリルであり;ここで、各RaおよびRbは独立してHまたはC1−7アルキルであり;
R3はA1−C(O)X1またはA2−R4であり;
R4はC6−10アリールまたはヘテロアリールであり、これらは、単環でも二環でもよく、場合によりヒドロキシ、ヒドロキシC1−7アルキル、アミノ、C(O)−O−C1−7アルキル、C1−7アルコキシ、ハロ、C1−7アルキル、ハロ−C1−7アルキル(akyl)、C6−10アリール、ヘテロアリール、−NHSO2−C1−7アルキルおよびベンジルからなる群から独立して選択される1個以上の置換基で置換されていてよく;またはR4は場合によりオキソ、ヒドロキシ、ヒドロキシC1−7アルキル、アミノ、C(O)−O−C1−7アルキル、C1−7アルコキシ、ハロ、C1−7アルキル、ハロ−C1−7アルキル(akyl)、C6−10アリール、ヘテロアリール、−NHSO2−C1−7アルキルおよびベンジルからなる群から独立して選択される1個以上の置換基で置換されていてよいヘテロシクリルであり;
R5はH、ハロ、ヒドロキシ、C1−7アルコキシ、ハロ、C1−7アルキルまたはハロ−C1−7アルキル(akyl)であり;
XおよびX1は独立してOH、−O−C1−7アルキル、NRaRbまたは−O−C6−10アリールであり、ここで、アルキルは場合によりC6−10アリール、ヘテロアリール、ヘテロシクリル、C(O)NH2、C(O)NH−C1−6アルキルおよびC(O)N(C1−6アルキル)2からなる群から独立して選択される1個以上の置換基で置換されていてよく;
B1は−C(O)NH−または−NHC(O)−であり;
A1は結合または直鎖もしくは分枝鎖C1−7アルキレンであり;これは、場合によりハロ、C3−7シクロアルキル、C1−7アルコキシ、ヒドロキシおよびO−アセテートからなる群から独立して選択される1個以上の置換基で置換されていてよく;ここで、2個のジェミナルアルキルは場合により一体となってC3−7シクロアルキルを形成してよく;または
A1はフェニルまたはヘテロアリールであり;この各々は場合によりC1−7アルキル、C3−7シクロアルキル、ハロ−C1−7アルキル、ヒドロキシ、C1−7アルコキシ、ハロ、−NRaRb、−OCH2CO2Hおよび−OCH2C(O)NH2からなる群から独立して選択される1個以上の置換基で置換されていてよく;または
A1はC3−7シクロアルキルであり;
A1は−C1−4アルキレン−C6−10−アリール−、−C1−4アルキレン−ヘテロアリール−または−C1−4アルキレン−ヘテロシクリル−であり、ここで、A1はいずれの方向でもよく;
A2は結合または直鎖もしくは分枝鎖C1−7アルキレンであり;これは、場合によりハロ、C1−7アルコキシ、ヒドロキシ、O−アセテートおよびC3−7シクロアルキルからなる群から独立して選択される1個以上の置換基で置換されていてよく;
nは0、1、2、3、4または5であり;
ここで、各ヘテロアリールは、炭素原子および1〜5個のヘテロ原子から選択される5−10環原子を含む単環または二環芳香環であり
各ヘテロシクリルは、炭素原子および1〜5個のヘテロ原子から選択を含む4−7環原子を含む単環の飽和もしくは部分的に飽和であるが、非芳香族性の基であり、ここで、ヘテロアリールまたはヘテロシクリルの各ヘテロ原子は独立してO、NおよびSから選択される。〕
である、請求項1に記載のの化合物またはその薬学的に許容される塩。 - R1がHまたはC1−7アルキルであり;
各R2が独立してC1−7アルキル、ハロ、C3−7シクロアルキル、ヒドロキシ、C1−7アルコキシ、ハロC1−7アルキル、−NRaRb、C6−20アリール、ヘテロアリールまたはヘテロシクリルであり;ここで、各RaおよびRbが独立してHまたはC1−7アルキルであり;
R3がA1−C(O)X1またはA2−R4であり;
R4がC6−20アリールまたはヘテロアリールであり、その各々は単環または二環であってよく、その各々は、場合によりヒドロキシ、C1−7アルコキシ、ハロ、C1−7アルキル、ハロ−C1−7アルキル(akyl)、C6−10アリール、ヘテロアリール、−NHSO2−C1−7アルキルおよびベンジルからなる群から独立して選択される1個以上の置換基で置換されていてよく;
R5がHであり;
XおよびX1が独立してOH、−O−C1−7アルキルまたはNRaRbであり;
B1が−C(O)NH−または−NHC(O)−であり;
A1が直鎖もしくは分枝鎖C1−7アルキレンであり;これは、場合によりハロ、C3−7シクロアルキル、C1−7アルコキシ、ヒドロキシおよびO−アセテートからなる群から独立して選択される1個以上の置換基で置換されていてよく;ここで、2個のジェミナルアルキルは場合により一体となってC3−7シクロアルキルを形成してよく;または
A1がフェニルまたはヘテロアリールであり;この各々は場合によりC1−7アルキル、C3−7シクロアルキル、ハロ−C1−7アルキル、ヒドロキシ、C1−7アルコキシ、ハロ、−NRaRb、−OCH2CO2Hおよび−OCH2C(O)NH2からなる群から独立して選択される1個以上の置換基で置換されていてよく;
A2が結合または直鎖もしくは分枝鎖C1−7アルキレンであり;これは、場合によりハロ、C1−7アルコキシ、ヒドロキシ、O−アセテートおよびC3−7シクロアルキルからなる群から独立して選択される1個以上の置換基で置換されていてよく;
nが0、1、2、3、4または5であり;
ここで、各ヘテロアリールは、炭素原子および1〜5個のヘテロ原子から選択される5−10環原子を含む単環または二環芳香環であり、
各ヘテロシクリルは、炭素原子および1〜5個のヘテロ原子から選択を含む4−7環原子を含む単環の飽和もしくは部分的に飽和であるが、非芳香族性の基であり、ここで、ヘテロアリールまたはヘテロシクリルの各ヘテロ原子は独立してO、NおよびSから選択される、
請求項1または2に記載の化合物またはその薬学的に許容される塩。 - A1が場合により置換されていてよい直鎖または分枝鎖C1−7アルキレンである、
請求項1〜5のいずれかに記載の化合物またはその薬学的に許容される塩。 - A1がCH2CH2である、
請求項1〜6のいずれかに記載の化合物またはその薬学的に許容される塩。 - A1が場合により置換されていてよいフェニルまたはヘテロアリールである、
請求項1〜5のいずれかに記載の化合物またはその薬学的に許容される塩。 - A2が結合またはCH2またはCH2−CH2である、
請求項9に記載の化合物またはその薬学的に許容される塩。 - R1がHであり、R2が独立してハロ、C1−7アルコキシ、ヒドロキシ、C1−7アルキルまたはハロ−C1−7アルキルであり、nが0、1または2であり、XおよびX1が独立してOHまたは−O−C1−7アルキルである、
請求項1〜10のいずれかに記載の化合物またはその薬学的に許容される塩。 - nが1または2であり;R2がメタ−クロロまたはメタ−フルオロであり、残りの場合により存在するR2記がハロ、C1−7アルキル、ハロ−C1−7アルキル、ヒドロキシおよびC1−7アルコキシである、
請求項1〜11のいずれかに記載の化合物またはその薬学的に許容される塩。 - 請求項1〜12のいずれかに記載の化合物またはその薬学的に許容される塩および1種以上の薬学的に許容される担体を含む、医薬組成物。
- 請求項1〜12のいずれかに記載の化合物またはその薬学的に許容される塩およびHMG−Co−Aレダクターゼ阻害剤、アンギオテンシン受容体ブロッカー、アンギオテンシン変換酵素阻害剤、カルシウムチャネルブロッカー、エンドセリンアンタゴニスト、レニン阻害剤、利尿剤、ApoA−I摸倣剤、抗糖尿病剤、肥満軽減剤、アルドステロン受容体ブロッカー、エンドセリン受容体ブロッカー、アルドステロンシンターゼ阻害剤、CETP阻害剤および5型ホスホジエステラーゼ(PDE5)阻害剤から選択される1種以上の治療活性剤を含む、組合せ剤。
- 中性エンドペプチダーゼEC3.4.24.11活性を処置を必要とする対象において阻害する方法であって:該対象に治療有効量の請求項1〜12のいずれかに記載の化合物またはその薬学的に許容される塩を投与することを含む、方法。
- 障害または疾患が高血圧、肺高血圧、収縮期高血圧、抵抗性高血圧、末梢血管疾患、心不全、鬱血性心不全、左室肥大、狭心症、腎機能不全、腎不全、糖尿病性腎症、非糖尿病性腎症、ネフローゼ(nephroic)症候群、糸球体腎炎、強皮症、糸球体硬化症、原発性腎臓疾患のタンパク尿、腎血管性高血圧、糖尿病性網膜症および末期腎臓疾患(ESRD)、内皮機能不全、拡張期機能不全、肥大型心筋症、糖尿病性心筋症、上室性および心室性不整脈、心房細動(AF)、心線維症、心房粗動、有害血管リモデリング、プラーク安定化、心筋梗塞(MI)、腎臓線維症、多嚢胞性腎臓疾患(PKD)、肺動脈高血圧、腎不全、周期性浮腫、メニエール病、高アルドステロン症高カルシウム尿症、腹水、緑内障、月経障害、早産、子癇前症、子宮内膜症および生殖障害、喘息、閉塞性睡眠時無呼吸、炎症、白血病、疼痛、癲癇、情動障害、鬱病、精神病状態、認知症、老人性錯乱、肥満および消化器障害、創傷治癒、敗血症性ショック、胃酸分泌機能不全、高レニン血症、嚢胞性線維症、再狭窄、2型糖尿病、代謝症候群、糖尿病性合併症、アテローム性動脈硬化症、男女の性機能不全から選択される、請求項15に記載の方法。
- 医薬として使用するための、請求項1〜12のいずれかに記載の化合物またはその薬学的に許容される塩。
- 処置を必要とする対象における中性エンドペプチダーゼEC3.4.24.11活性と関連する障害または疾患を処置するための、請求項1〜12のいずれかに記載の化合物の使用。
- 障害または疾患が高血圧、肺高血圧、収縮期高血圧、抵抗性高血圧、末梢血管疾患、心不全、鬱血性心不全、左室肥大、狭心症、腎機能不全、腎不全、糖尿病性腎症、非糖尿病性腎症、ネフローゼ(nephroic)症候群、糸球体腎炎、強皮症、糸球体硬化症、原発性腎臓疾患のタンパク尿、腎血管性高血圧、糖尿病性網膜症および末期腎臓疾患(ESRD)、内皮機能不全、拡張期機能不全、肥大型心筋症、糖尿病性心筋症、上室性および心室性不整脈、心房細動(AF)、心線維症、心房粗動、有害血管リモデリング、プラーク安定化、心筋梗塞(MI)、腎臓線維症、多嚢胞性腎臓疾患(PKD)、肺動脈高血圧、腎不全、周期性浮腫、メニエール病、高アルドステロン症高カルシウム尿症、腹水、緑内障、月経障害、早産、子癇前症、子宮内膜症および生殖障害、喘息、閉塞性睡眠時無呼吸、炎症、白血病、疼痛、癲癇、情動障害、鬱病、精神病状態、認知症、老人性錯乱、肥満および消化器障害、創傷治癒、敗血症性ショック、胃酸分泌機能不全、高レニン血症、嚢胞性線維症、再狭窄、2型糖尿病、代謝症候群、糖尿病性合併症、アテローム性動脈硬化症、男女の性機能不全から選択される、請求項18に記載の使用。
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