JP2013504516A - 新規なジペプチジルペプチダーゼ(dp−iv)化合物 - Google Patents
新規なジペプチジルペプチダーゼ(dp−iv)化合物 Download PDFInfo
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- JP2013504516A JP2013504516A JP2011526589A JP2011526589A JP2013504516A JP 2013504516 A JP2013504516 A JP 2013504516A JP 2011526589 A JP2011526589 A JP 2011526589A JP 2011526589 A JP2011526589 A JP 2011526589A JP 2013504516 A JP2013504516 A JP 2013504516A
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- 150000001875 compounds Chemical class 0.000 title claims abstract description 116
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- C12Y—ENZYMES
- C12Y304/00—Hydrolases acting on peptide bonds, i.e. peptidases (3.4)
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Abstract
Description
・2005年にSakashitaらは、(4-置換)-L-プロリル-(2S)-2-シアノピロリジンが不飽和類似体と比較して増大したDP-IV活性阻害を示すこと、および(4β-置換)-L-プロリル-(2S)-2-シアノピロリジンが対応する4α異性体よりも20倍強い活性を示すことを開示した(Bioorg.Med.Chem.Lett.2005、15、2441頁)。
・Tsaiらは、(4βカルバモイル)-L-プロリル-(2S)-2-シアノピロリジンが増大したDP-IV阻害活性を示す一方、(5,5-gem-ジメチル)-L-プロリル-(2S)-2-シアノピロリジンが非置換類似体と比較してDP-IV阻害の500倍の減少を示すことを開示した(Bioorg.Med.Chem.Lett.2006、16、3268頁)。
・Heins,Jらは、DP-IVが、配列H-X-Pro-YまたはH-X-Ala-Y(ここで、X,Y=任意のアミノ酸、YはProではない)を有するタンパク質のN末端からのジペプチドの開裂を触媒するセリンプロテアーゼであることを開示している(Biochim.Biophys.Acta.、1988、954、161頁)。
Aはペプチドであり、
AはさらにR3-R4と定義され、ここで、R3およびR4はともにまたは独立に、1〜10の範囲のアミノ酸を有するペプチドと定義される。ペプチドを形成するためのアミノ酸は、天然由来または合成のアミノ酸類似体から選択される。好ましいペプチドは、グリシン、アラニン、バリン、ロイシン、イソロイシン、フェニルアラニン、メチオニン、トリプトファン、リジン、グルタミン、グルタミン酸、セリン、プロリン、システイン、チロシン、ヒスチジン、アルギニン、アスパラギン、アスパラギン酸、スレオニンまたはこれらのアミノ酸の混合物から選択されるアミノ酸を用いて形成される。
Bはペプチドと置換アミンとの間のペプチド結合である。
R1および/またはR2は独立に、非置換または置換アルキル;非置換または置換シクロアルキル;非置換または置換シクロアルキルアルコキシ;非置換または置換C1〜6アルキルアルコキシ;非置換または置換シクロアルコキシアルキル;C1〜6アルコキシ-C1〜6アルキル;非置換または置換フェニル;非置換または置換ベンジル;ハロゲン化C1〜6アルキル;C1〜6アルコキシ-C1〜6アルキル;シクロアルコキシ-C1〜6アルキル;非置換または置換アリール;非置換または置換ビシクロC4-C15化合物;N、SおよびOから独立に選択される1〜4個のヘテロ原子を含む飽和または不飽和でもよいヘテロサイクルであって、非置換またはオキソ、OH、ハロゲン、C1〜6アルキル、およびOC1〜6アルキルから独立に選択される1〜3個の置換基で置換されたヘテロサイクルから選択され、ここで、C1〜6アルキルおよびOC1〜6アルキルは直鎖状または分枝状で、所望によりにより1〜5個のハロゲンで置換されている。あるいは、R1およびR2はともにまたは独立に水素または
-----は式Iのペプチド結合におけるN原子の存在を示す。
nは0〜10の間の任意の数である。
R5、R6、R7、またはArは、HまたはC1〜4アルキル、-CH2CF3、-CH2CH=CH2、-CH2-CON(CH3)2、-Ph、-CH2-Ph、-CH2-(4-MeO-Ph)、-CH2-(4-Me-Ph)、-CH2-(4-CN-Ph)、-CH2-(2-CF3Ph)、-CH2-(2-F-Ph)、-CH2-(4-F-Ph)、-CH(OH)-(4-F-Ph)、-CH2-(3,5-ビスCF3-Ph)、-CH2-(2-ピリジル)、-2,4-ジクロロ-Ph、-(4-MeO-Ph)、-(4-Me-Ph)、-(4-CN-Ph)、-(2-Me-Ph)、-(2-クロロ-Ph)、-(2-クロロ-4-MeO-Ph)、-(2-クロロ―4-CN-Ph)、ナフタイル、-(2-F-Ph)、-(2,4-ジ-F-Ph)、-(2,4,5-ジ-F-Ph)の何れかである。
a、またはb、またはcは、N、S、O、Cから独立に選択される]
の新規なペプチド誘導体、およびその薬学的に許容される塩、その鏡像体、本発明による化合物の調製のための方法、それらを含む薬学的組成物、および医学的活性成分としてのそれらの使用に関する。
「アルキル」ならびにアルコキシおよびアルカノイル等の接頭辞「アルク」を有する他の基は、炭素鎖が他に定義されない限り、直鎖状または分枝状の何れでもよい炭素鎖およびそれらの組み合わせを意味する。アルキル基の例としては、メチル、エチル、プロピル、イソプロピル、ブチル、sec-およびtert-ブチル、ペンチル、ヘキシル、ヘプチル、オクチル、ノニル等が挙げられる。炭素原子の数が特定されない場合には、C1〜6が意図される。
本明細書に記述する化合物は互変異性体として存在し得る。個々の互変異性体ならびにその混合物は、本発明の化合物に包含される。
反応液を濾過してDCCの尿素誘導体を除去した。次いで濾液を真空で濃縮した。精製のためカラムクロマトグラフィーを行なう。(式14の化合物)(180mg、51%)
試薬および溶媒:
試薬、溶媒、標準および装置:
・トリフルオロ酢酸(ARグレード)
・アセトニトリル(HPLCグレード)
・MilliQ水
・DPP IV阻害剤の標準試薬としてのSitagliptin塩基
・UV検出器および自動サンプラー付きのShimadzu LC-2010
希釈剤:アセトニトリル
正確に測定したMilliQ水1000mlをビーカーに移す。トリフルオロ酢酸でpHを2.00±0.05に調整する。これを穏やかに振盪して0.45μのメンブランフィルターで濾過する。
アセトニトリル300mlを1000mlの容量フラスコに移し、pH2.00±0.05の緩衝液で標識まで体積を補う。
10mlの容量フラスコ中でSitagliptin塩基標準試薬約20mgを正確に秤量する。希釈剤5.0mlを加え、(要すれば)これを超音波処理して固体を溶解し、希釈剤で標識まで体積を補い、濃度2000ppmの標準溶液(ストック溶液)とする。
上のストック溶液をさらに希釈して、0.025μM〜100μMまで変化する種々の濃度の溶液を得た。種々の濃度について、μM単位の濃度に対するピーク面積の線形カーブをプロットした。
種々の臓器(肝、腎および膵)および血清試料から抽出試料(タンパク質性物質を除去した後)を得て、これらをHPLC系に直接注入した。
液体クロマトグラフィーには可変波長UV検出器、自動サンプラーおよびデータプロセッサーが備えられている。
カラム:ypersil BDS C8、4.6mm×250mm、5μ
検出器波長:54nm
流量:1.0ml/min
注入量:20μl
カラム温度:60℃
ブランク(希釈剤)およびブランク抽出試料を注入し、0.025μM〜100μMの種々の濃度の標準調製液を注入して、μM単位の濃度に対する曲線下面積のグラフをプロットする。試料調製液を注入してクロマトグラムを記録する。ブランクによるいかなるピークをも無視して、種々の時間間隔で集められた抽出試料から放出されたSitagliptinの濃度を計算する。
Sitagliptineの保持時間は約5.0〜6.0分である。
試料中のSitagliptinの面積を標準の線形カーブに対して外挿することによって、種々の時間間隔で集められた抽出試料からの放出Stagliptinの濃度を計算する。
SitagliptinジペプチドまたはSitagliptin塩基をヤギ血清とともに37℃でインキュベートした。0、15、30、45分、1時間、2時間、6時間および24時間の時点で試料を集め、シリカ抽出カートリッジを用いて固相抽出を行なった。両方の分子の標準をアセトニトリル+水中で調製した(抽出効率を確認するため)。試料をHPLCにかけ、「保持時間」および「曲線下面積」を評価した。化合物の保持時間は、化合物の同定のためのパラメーターとして用いる。曲線下面積は、反応液中に存在する分子の量を評価するために用いる。各化合物についてグラフをプロットする。
Claims (6)
- 式1
Aはペプチドであり、
Bはペプチドと置換アミンとの間のペプチド結合であり、
R1およびR2はここに定義された通りであり、
R1およびR2はともにまたは独立に水素または
-----は式Iのペプチド結合におけるN原子の存在を示し、
nは0〜10の間の任意の数であり、
R5、R6、R7、またはArは、HまたはC1〜4アルキル、-CH2CF3、-CH2CH=CH2、-CH2-CON(CH3)2、-Ph、-CH2-Ph、-CH2-(4-MeO-Ph)、-CH2-(4-Me-Ph)、-CH2-(4-CN-Ph)、-CH2-(2-CF3Ph)、-CH2-(2-F-Ph)、-CH2-(4-F-Ph)、-CH(OH)-(4-F-Ph)、-CH2-(3,5-ビスCF3-Ph)、-CH2-(2-ピリジル)、-2,4-ジクロロ-Ph、-(4-MeO-Ph)、-(4-Me-Ph)、-(4-CN-Ph)、-(2-Me-Ph)、-(2-クロロ-Ph)、-(2-クロロ-4-MeO-Ph)、-(2-クロロ-4-CN-Ph)、-ナフタイル、-(2-F-Ph)、-(2,4-ジ-F-Ph)、-(2,4,5-ジ-F-Ph)の何れかであり、
a、またはb、またはcは、N、S、O、Cから独立に選択される]
の化合物およびその薬学的に許容される塩、鏡像体。 - DPP IV酵素が対象の化合物を放出する、請求項1に記載の化合物。
- DPP IV酵素がDPP IV酵素の阻害剤である化合物を放出する、請求項1および2に記載の化合物。
- 請求項1に記載の化合物は安定な化合物である。
- 請求項1から4の何れかに記載の化合物は薬学的に許容される塩を含む。
- 請求項1から3に記載の化合物を投与することによる哺乳動物におけるジペプチジルペプチダーゼIV(DP-IV)酵素の阻害。
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PCT/IB2009/006807 WO2010029422A1 (en) | 2008-09-12 | 2009-09-11 | Novel dipeptidyl peptidase (dp-iv) compounds |
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WO2012017391A2 (en) * | 2010-08-03 | 2012-02-09 | Cadila Pharmaceuticals Limited | Novel compounds as dpp-iv inhibitors and process for preparation thereof |
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Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP2002518518A (ja) * | 1998-06-24 | 2002-06-25 | プロバイオドラッグ ゲゼルシャフト フュア アルツナイミッテルフォルシュンク エムベーハー | 不安定なdpiv阻害剤の化合物 |
JP2003524591A (ja) * | 1998-06-24 | 2003-08-19 | プロバイオドラッグ ゲゼルシャフト フュア アルツナイミッテルフォルシュンク エムベーハー | Dpiv阻害剤のプロドラッグ |
JP2006504732A (ja) * | 2002-10-07 | 2006-02-09 | メルク エンド カムパニー インコーポレーテッド | 抗糖尿病ベータアミノ複素環ジペプチジルペプチダーゼ阻害剤 |
JP2007509973A (ja) * | 2003-10-31 | 2007-04-19 | アルザ・コーポレーシヨン | 増強された吸収のための組成物および投与形態物 |
Family Cites Families (8)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
IL111785A0 (en) * | 1993-12-03 | 1995-01-24 | Ferring Bv | Dp-iv inhibitors and pharmaceutical compositions containing them |
US6613879B1 (en) * | 1999-05-14 | 2003-09-02 | Boehringer Ingelheim Pharma Kg | FAP-activated anti-tumour compounds |
WO2003048190A2 (en) * | 2001-12-04 | 2003-06-12 | The Curators Of The University Of Missouri | Acyclovir-peptide analogs |
CA2508947A1 (en) * | 2002-12-20 | 2004-07-15 | Merck & Co., Inc. | 3-amino-4-phenylbutanoic acid derivatives as dipeptidyl peptidase inhibitors for the treatment or prevention of diabetes |
WO2004085661A2 (en) * | 2003-03-24 | 2004-10-07 | Merck & Co., Inc | Process to chiral beta-amino acid derivatives |
GB0310593D0 (en) * | 2003-05-08 | 2003-06-11 | Leuven K U Res & Dev | Peptidic prodrugs |
JO2625B1 (en) * | 2003-06-24 | 2011-11-01 | ميرك شارب اند دوم كوربوريشن | Phosphoric acid salts of dipeptidyl betidase inhibitor 4 |
US7442682B2 (en) * | 2004-10-19 | 2008-10-28 | Nitto Denko Corporation | Transepithelial delivery of peptides with incretin hormone activities |
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- 2009-09-11 WO PCT/IB2009/006807 patent/WO2010029422A1/en active Application Filing
- 2009-09-11 EP EP09812753.3A patent/EP2343973B1/en not_active Not-in-force
- 2009-09-11 RU RU2011113690/04A patent/RU2011113690A/ru unknown
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Patent Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP2002518518A (ja) * | 1998-06-24 | 2002-06-25 | プロバイオドラッグ ゲゼルシャフト フュア アルツナイミッテルフォルシュンク エムベーハー | 不安定なdpiv阻害剤の化合物 |
JP2003524591A (ja) * | 1998-06-24 | 2003-08-19 | プロバイオドラッグ ゲゼルシャフト フュア アルツナイミッテルフォルシュンク エムベーハー | Dpiv阻害剤のプロドラッグ |
JP2006504732A (ja) * | 2002-10-07 | 2006-02-09 | メルク エンド カムパニー インコーポレーテッド | 抗糖尿病ベータアミノ複素環ジペプチジルペプチダーゼ阻害剤 |
JP2007509973A (ja) * | 2003-10-31 | 2007-04-19 | アルザ・コーポレーシヨン | 増強された吸収のための組成物および投与形態物 |
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US20140045771A1 (en) | 2014-02-13 |
US20110183919A1 (en) | 2011-07-28 |
WO2010029422A1 (en) | 2010-03-18 |
RU2011113690A (ru) | 2012-10-20 |
ES2571217T3 (es) | 2016-05-24 |
EP2343973A4 (en) | 2012-05-23 |
AU2009290531A1 (en) | 2010-03-18 |
CA2737253C (en) | 2017-08-15 |
US8563517B2 (en) | 2013-10-22 |
JP5781930B2 (ja) | 2015-09-24 |
EP2343973A1 (en) | 2011-07-20 |
ZA201102597B (en) | 2011-12-28 |
AU2009290531B2 (en) | 2014-08-21 |
CA2737253A1 (en) | 2010-03-18 |
EP2343973B1 (en) | 2016-02-17 |
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