JP5951843B2 - シクロプロピル縮合ピロリジン骨格を有するジペプチジルペプチダーゼivの阻害剤及び方法 - Google Patents
シクロプロピル縮合ピロリジン骨格を有するジペプチジルペプチダーゼivの阻害剤及び方法 Download PDFInfo
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- JP5951843B2 JP5951843B2 JP2015092196A JP2015092196A JP5951843B2 JP 5951843 B2 JP5951843 B2 JP 5951843B2 JP 2015092196 A JP2015092196 A JP 2015092196A JP 2015092196 A JP2015092196 A JP 2015092196A JP 5951843 B2 JP5951843 B2 JP 5951843B2
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- 0 CCC(C)C(*)C(N(C(C1)C1C1)[C@]1C(N)=O)O Chemical compound CCC(C)C(*)C(N(C(C1)C1C1)[C@]1C(N)=O)O 0.000 description 14
- BANFFHFECRGFRZ-UTCJRWHESA-N C/C=N\N=C/NC Chemical compound C/C=N\N=C/NC BANFFHFECRGFRZ-UTCJRWHESA-N 0.000 description 1
- PMYZJKUEIPRTDH-UHFFFAOYSA-N C1OC2=CC=[I]CC=C2O1 Chemical compound C1OC2=CC=[I]CC=C2O1 PMYZJKUEIPRTDH-UHFFFAOYSA-N 0.000 description 1
- UOAARZNSKLWKCF-UHFFFAOYSA-N C=C(C1(CC(C(N(C2CC3C2)C3C#N)=O)N)CCCC1)F Chemical compound C=C(C1(CC(C(N(C2CC3C2)C3C#N)=O)N)CCCC1)F UOAARZNSKLWKCF-UHFFFAOYSA-N 0.000 description 1
- VFMWYELGTJWGDQ-GHNGPNRHSA-N C=C(C1(CCC1)C(C(N(C(C1)C1C1)[C@@H]1C#N)=O)N)F Chemical compound C=C(C1(CCC1)C(C(N(C(C1)C1C1)[C@@H]1C#N)=O)N)F VFMWYELGTJWGDQ-GHNGPNRHSA-N 0.000 description 1
- VFMWYELGTJWGDQ-YECOWLKZSA-N C=C(C1(CCC1)C(C(N([C@@H](C1)C1C1)[C@@H]1C#N)=O)N)F Chemical compound C=C(C1(CCC1)C(C(N([C@@H](C1)C1C1)[C@@H]1C#N)=O)N)F VFMWYELGTJWGDQ-YECOWLKZSA-N 0.000 description 1
- VLAGXRRGXCNITB-JECWYVHBSA-N CC(C)(C)OC(N(C(C1)[C@H]1C1)C1C(N)=O)=O Chemical compound CC(C)(C)OC(N(C(C1)[C@H]1C1)C1C(N)=O)=O VLAGXRRGXCNITB-JECWYVHBSA-N 0.000 description 1
- MPUOLMPEDWOCRL-UHFFFAOYSA-N CC(C)(C)OC(NC(C1(CCC1)C=C)C(N(C(C1)C1C1)C1C#N)=O)=O Chemical compound CC(C)(C)OC(NC(C1(CCC1)C=C)C(N(C(C1)C1C1)C1C#N)=O)=O MPUOLMPEDWOCRL-UHFFFAOYSA-N 0.000 description 1
- NPFZERARSGQOBH-UDXKHGJESA-N CC(C)(C)OC(NC(C1(CO)CCC1)C(N(C(C1)C1C1)[C@@H]1C#N)=O)=O Chemical compound CC(C)(C)OC(NC(C1(CO)CCC1)C(N(C(C1)C1C1)[C@@H]1C#N)=O)=O NPFZERARSGQOBH-UDXKHGJESA-N 0.000 description 1
- IMQHQMKMENWYOK-UHFFFAOYSA-N CC(C)(C)OC(NC(CC1(CCC1)C(F)=C)C(O)=O)=O Chemical compound CC(C)(C)OC(NC(CC1(CCC1)C(F)=C)C(O)=O)=O IMQHQMKMENWYOK-UHFFFAOYSA-N 0.000 description 1
- WDKXBSGYEZZGLN-AYKNFASUSA-N CC(C)(C)OC(N[C@@H](C(CC(C1)C2)(CC1C1)CC21F)C(N(C(C1)C1C1)[C@@H]1C(N)=O)=O)=O Chemical compound CC(C)(C)OC(N[C@@H](C(CC(C1)C2)(CC1C1)CC21F)C(N(C(C1)C1C1)[C@@H]1C(N)=O)=O)=O WDKXBSGYEZZGLN-AYKNFASUSA-N 0.000 description 1
- BPLGYSBKVUGLIL-WFBLGPOFSA-N CC(C)(C)S(C[C@@H](C(N(C1CC2C1)[C@@H]2C#N)=O)N)(=O)=O Chemical compound CC(C)(C)S(C[C@@H](C(N(C1CC2C1)[C@@H]2C#N)=O)N)(=O)=O BPLGYSBKVUGLIL-WFBLGPOFSA-N 0.000 description 1
- RDFIYANGSUATST-MWJCJQSMSA-N CC(C)(CO)C(C(N([C@@H](CC1)C1C1)C1C#N)=O)N Chemical compound CC(C)(CO)C(C(N([C@@H](CC1)C1C1)C1C#N)=O)N RDFIYANGSUATST-MWJCJQSMSA-N 0.000 description 1
- RAKAYBHFZSTBFR-UHFFFAOYSA-N CC(CC1C2C1)N2C(C(C1(CCCC1)C(F)=C)N)=O Chemical compound CC(CC1C2C1)N2C(C(C1(CCCC1)C(F)=C)N)=O RAKAYBHFZSTBFR-UHFFFAOYSA-N 0.000 description 1
- XSDICDSCVREANX-UHFFFAOYSA-N CC1C=C[N]#CC1 Chemical compound CC1C=C[N]#CC1 XSDICDSCVREANX-UHFFFAOYSA-N 0.000 description 1
- QMBLWFTYQDTVHY-PYJARURNSA-N CCC(C)C(C(N(C(C1)[C@H]1CC1)[C@@H]1C#N)=O)NC(OC(C)(C)C)=O Chemical compound CCC(C)C(C(N(C(C1)[C@H]1CC1)[C@@H]1C#N)=O)NC(OC(C)(C)C)=O QMBLWFTYQDTVHY-PYJARURNSA-N 0.000 description 1
- DJZSYOVDOCJIGD-WVMKXHBISA-N CCC(C)[C@@H](C(N1C[C@H](C2)[C@H]2C1)=O)NC(OC(C)(C)C)=O Chemical compound CCC(C)[C@@H](C(N1C[C@H](C2)[C@H]2C1)=O)NC(OC(C)(C)C)=O DJZSYOVDOCJIGD-WVMKXHBISA-N 0.000 description 1
- YQHPZMVJXYDEJL-UHFFFAOYSA-N CCOC(C(C1(C)CCCCC1)NC(OC(C)(C)C)=O)=O Chemical compound CCOC(C(C1(C)CCCCC1)NC(OC(C)(C)C)=O)=O YQHPZMVJXYDEJL-UHFFFAOYSA-N 0.000 description 1
- ICBCULSDMSBNNZ-UHFFFAOYSA-N COC(C1(CC2)CC2CC1)=O Chemical compound COC(C1(CC2)CC2CC1)=O ICBCULSDMSBNNZ-UHFFFAOYSA-N 0.000 description 1
- KJSZBKDMHLKDNG-IYXRBSQSSA-N C[C@H](CCC1C#N)N1C(C(C1(CCCC1)C(C)=C)N)=O Chemical compound C[C@H](CCC1C#N)N1C(C(C1(CCCC1)C(C)=C)N)=O KJSZBKDMHLKDNG-IYXRBSQSSA-N 0.000 description 1
- HERBTDLLYZOHBP-UHFFFAOYSA-N NC(C(N1C(C2)=C2CC1C#N)O)C1(CO)CCC1 Chemical compound NC(C(N1C(C2)=C2CC1C#N)O)C1(CO)CCC1 HERBTDLLYZOHBP-UHFFFAOYSA-N 0.000 description 1
- CMKYSPWIUMHMJR-UHFFFAOYSA-N NC(C1(CO)CCC1)C(N(C(C1)C1C1)C1C#N)=O Chemical compound NC(C1(CO)CCC1)C(N(C(C1)C1C1)C1C#N)=O CMKYSPWIUMHMJR-UHFFFAOYSA-N 0.000 description 1
- WJQRXWVSKOAFPJ-UHFFFAOYSA-N NC(C1(CO)CCCC1)C(N(C(C1)C1C1)C1C#N)=O Chemical compound NC(C1(CO)CCCC1)C(N(C(C1)C1C1)C1C#N)=O WJQRXWVSKOAFPJ-UHFFFAOYSA-N 0.000 description 1
- QSKQRLCATLZUSY-QBWABLMJSA-N NC(C1CCOCC1)C(N(C(C1)[C@@H]1C1)C1C#N)=O Chemical compound NC(C1CCOCC1)C(N(C(C1)[C@@H]1C1)C1C#N)=O QSKQRLCATLZUSY-QBWABLMJSA-N 0.000 description 1
- NPIJSEYBEGRQEP-UHFFFAOYSA-N NC(Cc(cc1)ccc1O)C([N]1(C2C1C2C1)C1C#N)=O Chemical compound NC(Cc(cc1)ccc1O)C([N]1(C2C1C2C1)C1C#N)=O NPIJSEYBEGRQEP-UHFFFAOYSA-N 0.000 description 1
- HVFWWHXMGYZKKH-TXTOARCRSA-N N[C@@H](C(CC(C1)C2)(CC1C1)CC21F)C(N([C@@H](C1)C1C1)[C@@H]1C#N)=O Chemical compound N[C@@H](C(CC(C1)C2)(CC1C1)CC21F)C(N([C@@H](C1)C1C1)[C@@H]1C#N)=O HVFWWHXMGYZKKH-TXTOARCRSA-N 0.000 description 1
- QGJUIPDUBHWZPV-YFBHERNLSA-N N[C@@H](C(CC(C1)C2)(CC1C1)CC21O)C(N(C(C1)C1C1)[C@@H]1C#N)=O Chemical compound N[C@@H](C(CC(C1)C2)(CC1C1)CC21O)C(N(C(C1)C1C1)[C@@H]1C#N)=O QGJUIPDUBHWZPV-YFBHERNLSA-N 0.000 description 1
- CNEBXOWFQASQAR-XLHMZOHDSA-N N[C@@H](C1(CC(C2)C3)CC3CC2C1)C(N(C(C1)C1C1)[C@@H]1C#N)=O Chemical compound N[C@@H](C1(CC(C2)C3)CC3CC2C1)C(N(C(C1)C1C1)[C@@H]1C#N)=O CNEBXOWFQASQAR-XLHMZOHDSA-N 0.000 description 1
- JUJWROOIHBZHMG-UHFFFAOYSA-N c1ccncc1 Chemical compound c1ccncc1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 1
- KYQCOXFCLRTKLS-UHFFFAOYSA-N c1cnccn1 Chemical compound c1cnccn1 KYQCOXFCLRTKLS-UHFFFAOYSA-N 0.000 description 1
- CZPWVGJYEJSRLH-UHFFFAOYSA-N c1cncnc1 Chemical compound c1cncnc1 CZPWVGJYEJSRLH-UHFFFAOYSA-N 0.000 description 1
- FYADHXFMURLYQI-UHFFFAOYSA-N c1ncnnc1 Chemical compound c1ncnnc1 FYADHXFMURLYQI-UHFFFAOYSA-N 0.000 description 1
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- C07C271/00—Derivatives of carbamic acids, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
- C07C271/06—Esters of carbamic acids
- C07C271/08—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms
- C07C271/10—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms
- C07C271/22—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms to carbon atoms of hydrocarbon radicals substituted by carboxyl groups
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- A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
- A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
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- C07C2603/70—Ring systems containing bridged rings containing three rings containing only six-membered rings
- C07C2603/74—Adamantanes
Description
本発明によれば、シクロプロピル縮合ピロリジン骨格を有する化合物は、DP−4を阻害し、式:
xは0又は1であり、yは0又は1であるが、
yが0のときxは1であり、
yが1のときxは0であり;
nは0又は1であり;
Xは水素又はCN(すなわち、シアノ基)であり;
R1、R2、R3及びR4は、同一又は異なって、水素原子、アルキル、アルケニル、アルキニル、シクロアルキル、シクロアルキルアルキル、ビシクロアルキル、 トリシクロアルキル、アルキルシクロアルキル、ヒドロキシアルキル、ヒドロキシアルキルシクロアルキル、ヒドロキシシクロアルキル、ヒドロキシビシクロアルキル、ヒドロキシトリシクロアルキル、ビシクロアルキルアルキル、アルキルチオアルキル、アリールアルキルチオアルキル、シクロアルケニル、アリール、アラルキル、ヘテロアリール, ヘテロアリールアルキル, シクロヘテロアルキル又はシクロヘテロアルキルアルキルの中から独立して選択されるものであり、これらすべての基は、適宜、有効な炭素原子に、水素原子、ハロ、アルキル、ポリハロアルキル、アルコキシ、ハロアルコキシ、ポリハロアルコキシ、アルコキシカルボニル、アルケニル、アルキニル、シクロアルキル、シクロアルキルアルキル、ポリシクロアルキル、ヘテロアリールアミノ、アリールアミノ、シクロヘテロアルキル、シクロヘテロアルキルアルキル、 ヒドロキシ、ヒドロキシアルキル、ニトロ、シアノ、アミノ、置換されたアミノ、アルキルアミノ、ジアルキルアミノ、チオール、アルキルチオ、アルキルカルボニル、アシル、アルコキシカルボニル、アミノカルボニル、アルキニルアミノカルボニル、アルキルアミノカルボニル、アルケニルアミノカルボニル、アルキルカルボニルオキシ、アルキルカルボニルアミノ、アリールカルボニルアミノ、アルキルスルホニルアミノ、アルキルアミノカルボニルアミノ、アルコキシカルボニルアミノ、アルキルスルホニル、アミノスルホニル、アルキルスルフィニル、スルホンアミド又はスルホニルの中から選択される1、2、3、4又は5基で置換されていてもよく;
R1及びR3は一緒になって−(CR5R6)m−を形成していてもよく、ここでmは2〜6、R5及びR6は、同一又は異なって、ヒドロキシ、アルコキシ、シアノ、水素原子、アルキル、アルケニル、アルキニル、シクロアルキル、シクロアルキルアルキル、シクロアルケニル、アリール、アリールアルキル、ヘテロアリール、ヘテロアリールアルキル、シクロヘテロアルキル、ハロ、アミノ、置換されたアミノ、シクロヘテロアルキルアルキル, アルキルカルボニルアミノ、アリールカルボニルアミノ、アルコキシカルボニルアミノ、アリールオキシカルボニルアミノ、アルコキシカルボニル、アリールオキシカルボニル又はアルキルアミノカルボニルアミノの中から独立して選択されるものである。また、R1及びR4は一緒になって−(CR7R8)p−を形成していてもよく、ここでpは2〜6、R7及びR8は、同一又は異なって、ヒドロキシ、アルコキシ、シアノ、水素元素、アルキル、アルケニル、アルキニル、シクロアルキル、シクロアルキルアルキル、シクロアルケニル、アリール, アリールアルキル、ヘテロアリール、ヘテロアリールアルキル、シクロヘテロアルキル、ハロ、アミノ、置換されたアミノ、シクロヘテロアルキルアルキル、アルキルカルボニルアミノ, アリールカルボニルアミノ, アルコキシカルボニルアミノ、アリールオキシカルボニルアミノ、アルコキシカルボニル、アリールオキシカルボニル又はアルキルアミノカルボニルアミノの中から独立して選択されるものである。また、R1及びR3は
また、R1及びR3は
の構造を持つ化合物で、医薬的に許容できるそれらの塩、又はそのプロドラッグエステル、及びその全立体異性体を含む。
R3は水素又はアルキルであり;
R1は水素、アルキル、シクロアルキル、ビシクロアルキル、トリシクロアルキル、アルキルシクロアルキル、ヒドロキシアルキル、ヒドロキシトリシクロアルキル、ヒドロキシシクロアルキル、ヒドロキシビシクロアルキル、又はヒドロキシアルキルシクロアルキルであり;
R2は水素又はアルキルであり;
nは0であり;
Xはシアノであり;
xは0又は1であり;
yは0又は1である、
化合物である。
[式中、
R1はアルキル、シクロアルキル、ビシクロアルキル、トリシクロアルキル、アルキルシクロアルキル、ヒドロキシアルキル、ヒドロキシシクロアルキル、ヒドロキシアルキルシクロアルキル、ヒドロキシビシクロアルキル、又はヒドロキシトリシクロアルキル];
[式中、
R1はアルキル、シクロアルキル、ビシクロアルキル、トリシクロアルキル、ヒドロキシビシクロアルキル、ヒドロキシトリシクロアルキル、アルキルシクロアルキル、ヒドロキシアルキル、ヒドロキシシクロアルキル、又はヒドロキシアルキルシクロアルキル];
並びに、下記式:
反応式1
反応式2
ブタの酵素は、いくらかの改良を加えつつ、あらかじめ引用文献(1)に記載してあるように精製した。腎臓を15〜20頭から取り、皮部を取り除き、−80℃で凍結した。凍結組織(2000〜2500 g)を0.25Mのショ糖12 Lでワーリングブレンダーを用いてホモジナイズした。それから、そのホモジネートを37℃で18時間放置することで、細胞膜からDP−4の切断を容易にした。切断工程後、ホモジネートを遠心分離(7000×g、20分、4℃)して浄化し、上清を集めた。固形の硫酸アンモニウムを60%飽和液に加え、遠心分離(10,000×g)で沈殿物を集め、除去した。追加の硫酸アンモニウムを上清に加えて80%飽和液にし、80%ペレットを集めて、20 mMのNa2HPO4(pH 7.4)に溶かした。
酵素は、以下の改良を加えつつ、基質としてgly−pro−p−ニトロアニリドを用いて、あらかじめ引用文献(2)に記載してある安定状態の条件下定量した。反応液は最終的な量が100 μlで、100 mMのAces、52 mMのTRIS、52 mMのエタノールアミン、500 μMのgly−pro−p−ニトロアニリド、0.2%のDMSO及び4.5 nMの酵素が25℃、pH 7.4で含まれていた。10 μMのテスト化合物での単回の定量にあたっては、緩衝液、化合物及び酵素を96穴のミクロタイタープレートに加え、室温で5分間インキュベートした。反応は基質の添加によって開始した。p−ニトロアニリンの連続的な生成を、モレキュラデバイスTmaxプレートリーダー(Molecular Devices Tmax plate reader)を用いて、15分間405 nMで、9秒毎に読み取って測定した。p−ニトロアニリン生成の直線的速度は、各プログラム曲線の直線的部分を通して得た。p−ニトロアニリン吸収の標準的曲線は、各実験の初期段階に得られ、p−ニトロアニリンの生成を触媒化する酵素を、標準曲線から定量した。50%よりおおきな阻害があった化合物は更なる分析するのに選別した。
Ph=フェニル
Bn=ベンジル
i−Bu=イソブチル
Me=メチル
Et=エチル
Pr=プロピル
Bu=ブチル
TMS=トリメチルシリル
FMOC=フルオレニルメトキシカルボニル
Boc又はBOC=tert−ブトキシカルボニル
Cbz=カルボベンジルオキシ又はカルボベンゾキシ又はベンジルオキシカルボニル
HOAc又はAcOH=酢酸
DMF=N,N−ジメチルホルムアミド
EtOAc=酢酸エチル
THF=テトラヒドロフラン
TFA=トリフルオロ酢酸
Et2NH=ジエチルアミン
NMM=N−メチルモルホリン
n−BuLi=n−ブチルリチウム
Pd/C=パラジウム炭素
PtO2=酸化白金(IV)
TEA=トリエチルアミン
EDAC=3−エチル−3’−(ジメチルアミノ)プロピル−カルボジイミド塩酸塩(又は1−[(3−(ジメチル)アミノ)プロピル])−3−エチルカルボジイミド塩酸塩)
HOBT又はHOBT・H2O=1−ヒドロキシベンゾトリアゾール一水和物
HOAT=1−ヒドロキシ−7−アザベンゾトリアゾール
PyBOP試薬=ベンゾトリアゾール−1−イルオキシ-トリピロリジノ ホスホニウム 6フッ化リン酸塩
min=分
h又はhr=時
L=リットル
mL=ミリリットル
μL=マイクロリットル
g=グラム
mg=ミリグラム
mol=モル
mmol=ミリモル
meq=ミリ当量
rt=室温
sat又はsat’d=飽和の
aq.=水性の
TLC=薄層クロマトグラフィー
HPLC=高速液体クロマトグラフィー
LC/MS=高速液体クロマトグラフィー/マススペクトロメトリー
MS又はMass Spec=マススペクトロメトリー
NMR=核磁気共鳴
mp=融点
一般法A:
商業的に有用なアミノ酸から阻害剤を調製のためのパラレルアレイ(Parallel array)合成方法。反応式3に示すように、実施例1工程1に記載したエステル11は、THF/水中の水酸化リチウムにより酸性物質にけん化され、クロロギ酸イソブチル/NMMによる処理、それに続くジオキサン中のアンモニアの処理により、アミド12へと変換した。Boc保護基は塩化メチレン中TFAによる酸性条件下除去されて、13を得た。そのTFA塩はEDAC/HOBT/DMF又はEDAC/DMAP/CH2Cl2のいずれかを用いてBoc−t−ブチルグリシンと結合し、14を得た。そのアミド体はオキシ塩化リン/イミダゾールを用いて−20℃ピリジン中ニトリル体15へと脱水反応し、最後に周囲温度で塩化メチレン中TFAで脱保護して標的化合物16を得た。
反応式3 一般法A(実施例6−27)
Bocで保護されたアミノ酸へのクライゼン(Claisen)転位の経路。
反応式4 一般法B(実施例30−47)
シクロペンチリデン酢酸エチルエステル
火炎乾燥した500 mL容の丸底フラスコに、120 mLの無水THFに水素化ナトリウム(鉱油に60%分散した5.10 g、128 mmol、1.10当量)を投入し、0℃アルゴン雰囲気下ホスホノ酢酸トリエチル(25.6 mL、128 mmol、1.10当量)を滴下ロートを用いて滴下して加えた。反応混合物を更に1時間攪拌しながら、室温まで加温した。10 mLの無水THFに溶かしたシクロペンタノン(10.3 mL、116 mmol)溶液を、滴下ロートを用いて20分間かけて滴下して加え、反応混合物を室温で2.5時間攪拌した。その後エーテル(200 mL)と水(100 mL)を加え、液層を分離した。有機相を水(100 mL)、食塩水(100 mL)で連続して洗浄し、乾燥し(無水硫酸ナトリウム)、減圧濃縮して、無色の油状物として目的のエステル体を得た(17.5 g、98%)。
2−シクロペンチリデンエタノール
火炎乾燥した500 mL容の丸底フラスコに、100 mLの無水トルエンにシクロペンチリデン酢酸エチルエステル(17.5 g、113 mmol)を投入し、−78℃アルゴン雰囲気下DIBAL−H(1.5Mのトルエン溶液の189 mL、284 mmol、2.50当量)を滴下ロートを用いて30分間掛けて滴下して加え、その後反応混合物を18時間攪拌しつつ、室温まで加温した。その後反応混合物を−78℃まで再冷却し、無水メタノール30 mLを注意深く加えてクエンチした。室温まで昇温して、1Nのロッシェル塩(Rochelle’s salt)(100 mL)を加えて、反応混合物を90分間攪拌した。その後二相の反応混合物をエーテル(200 mL)で分液ロートに希釈し、分液した。有機層を食塩水(100 mL)で洗浄し、乾燥し(無水硫酸ナトリウム)、減圧濃縮した。フラッシュカラムクロマトグラフィー(シリカゲル、塩化メチレン/酢酸エチル、10:1)で精製し、無色油状物として目的のアリル型アルコールを得た(11.6 g、92%)。
N−(tert−ブチルオキシカルボニル)グリシン−(2−シクロペンチリデンエチル)
N−(tert−ブチルオキシカルボニル)(1’ビニルシクロペンチル)−グリシン
一般法C:
4,5−メタノ−プロリンアミドへのペプチド結合、アミド体の脱水反応及び最終的な脱保護。
反応式5 一般法C
一般法D:
オゾン分解によるビニル置換基の酸化的開裂。保護されたシクロペンチルビニルニトリル体22をオゾンによる6〜8分の処理して、水素化ホウ素ナトリウムによる還元的なクエンチをして、直接的にヒドロキシメチル類似体24を得た。この化合物を、0℃でTFAの塩化メチレン溶液による酸性条件下脱保護して、目的化合物25を得た。
反応式6 一般法D(実施例44,46,48)
一般法E:
四酸化オスミウム−過ヨウ素酸ナトリウムによるビニル置換基の酸化開裂、これに続く水素化ホウ素ナトリウムによるアルコールへの還元。シクロブチルオレフィン体26はTHF:水(1:1)の混液中四酸化オスミウムと過ヨウ素酸ナトリウムで処理して、中間体のアルデヒドを粗生成物として単離し、すぐに水素化ホウ素ナトリウムで還元し、収率56%で27を得た。TFAを用いた標準的な脱保護条件で目的化合物28を得た。
反応式7 一般法E(実施例45,47)
50 mL容のフラスコに、ジヒドロ−4,4−ジメチル−2,3−フランジオン(5.0 g、39.0 mmol)、酢酸(10 mL)、酢酸ナトリウム(3.82 g、39.0 mmol)及びヒドロキシルアミン塩酸塩(2.71 g、39.0 mmol)を投入した。反応混合物を室温で2時間攪拌し、減圧濃縮して、ほとんどの酢酸を留去した。残留物を水(100 mL)に注ぎ、水相を酢酸エチル(40 mL、3回)で抽出した。有機相は無水硫酸ナトリウムで乾燥し、濃縮することで、置いておくと凝固する無色の油状物を得た。
200 mL容の丸底フラスコにパートAの固形物(39 mmol)を投入し、エタノール80 mLと2N塩酸39 mL(78 mmol)で希釈した。反応混合物を5%パラジウム炭素1.0 gで処理し、反応混合物を脱気した。フラスコを水素雰囲気下8時間置いた。反応混合物をセライトでろ過し、ろ液を濃縮して灰白色の固形物を得た。
250 mL容の丸底フラスコにパートBの固形物を投入し、THF(50 mL)と水(15 mL)で希釈した。ジ炭酸ジ−tert−ブチル(12.7 g、117 mmol)と重炭酸ナトリウム(10.0 g、117 mmol)で反応混合物を処理した。4時間攪拌後、反応混合物をエーテル50 mLと水50 mLで希釈した。分液し、有機分画を硫酸マグネシウムで乾燥し、濃縮した。残渣を30%酢酸エチル−ヘキサン溶液によるシリカゲルのフラッシュカラムクロマトグラフィーで精製し、白色固形物として工程1の化合物を得た(2.00 g、全体で22%)。
ビニル置換基の接触還元。反応式8に示すように、保護されているビニル基が置換されたアミノ酸20を、常圧下10%パラジウム炭素と水素を用いた接触還元により、相当する飽和類似体29へ変換した。
反応式8 一般法F(実施例50〜56)
N−(tert−ブチルオキシカルボニル)(1’ビニルシクロペンチル)グリシン(2.23 g、8.30 mmol)をメタノール50 mLに溶かし、アルゴンでパージした水素添加用の容器に投入した。この混合物に10%パラジウム炭素(224 mg、10% w/w)を加え、反応液を1気圧の水素雰囲気下、室温で12時間攪拌した。反応液をセライトでろ過して、濃縮し、メタノール:塩化メチレン(1:9)の混液によるシリカゲルのフラッシュカラムクロマトグラフィーで精製し、ガラス状物として工程1の化合物を得た。(FAB MH+272)
非対称なストレッカー(Strecker)反応により合成されたL−アミノ酸。商業上利用価値の高いアダマンチルカルボン酸を、メタノール中塩酸で還流するか、エーテル/メタノール中トリメチルシリルジアゾメタンを用いるかでエステル化して、30を得た。そのエステル体を、THF中LAHを用いてアルコール31へと還元し、その後スワン(Swern)酸化して、アルデヒド体32を得た。アルデヒド体32は、シアン化カリウム、亜硫酸水素ナトリウム及びR−(−)−2−フェニルグリシノールを用いて、非対称なストレッカー(Strecker)条件下33へ変換された。33のニトリル体を、酢酸中12Mの塩酸を用いた強い酸性条件下加水分解し、34を得た。キラル補助剤を、50 psiの水素下酸性メタノール中パールマン触媒(Pearlman's catalyst)を用いて接触還元して除いて、35を得た。そして生じたアミノ基をカルバミン酸t−ブチルとして保護し、36を得た。
反応式9 一般法G(実施例59〜64)
ラセミ体アミノ酸のストレッカー(Strecker)合成
反応式10 一般法H(実施例65〜66)
N−(ベンジルオキシカルボニル)コハク酸イミド(5.6 g、22.4 mmol)を塩化メチレン(25 mL)に溶かし、その溶液をアミノマロン酸ジエチル塩酸塩(5.0 g、23.6 mmol)とトリエチルアミン(13.4 mL、95 mmol)の冷却し(0℃)、攪拌した塩化メチレン(125 mL)溶液に加えた。生じた溶液を0℃で10分間攪拌し、続いて室温で1時間攪拌した。反応液を10%クエン酸(50 mL、2回)、10%炭酸水素ナトリウム(50 mL、2回)及び水(50 mL)で洗浄して、乾燥し(無水硫酸ナトリウム)、蒸発させて無色の油状物として、N−ベンジルオキシカルボニルアミノマロン酸ジエチルを得て、0℃で放置して結晶化させた(6.3 g)。(LC/Mass +イオン):310(M+H)
反応式11 一般法I
文献[Tetrahedron Lett. 1988,29, 2983]に従い、カルバミン酸ベンジルのエタノール溶液をトリエチルシラン(2当量)、ジ炭酸ジ−t−ブチル(1.1当量)、触媒量の酢酸パラジウム及びトリエチルアミン(0.3当量)で処理して、「ワンポット」法でBOC保護されたアミン体を得ることができる。
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JP2010006181A Expired - Lifetime JP5427047B2 (ja) | 2000-03-10 | 2010-01-14 | シクロプロピル縮合ピロリジン骨格を有するジペプチジルペプチダーゼivの阻害剤及び方法 |
JP2012263345A Pending JP2013040219A (ja) | 2000-03-10 | 2012-11-30 | シクロプロピル縮合ピロリジン骨格を有するジペプチジルペプチダーゼivの阻害剤及び方法 |
JP2013249334A Expired - Lifetime JP5953292B2 (ja) | 2000-03-10 | 2013-12-02 | シクロプロピル縮合ピロリジン骨格を有するジペプチジルペプチダーゼivの阻害剤及び方法 |
JP2015092196A Expired - Lifetime JP5951843B2 (ja) | 2000-03-10 | 2015-04-28 | シクロプロピル縮合ピロリジン骨格を有するジペプチジルペプチダーゼivの阻害剤及び方法 |
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JP2010006181A Expired - Lifetime JP5427047B2 (ja) | 2000-03-10 | 2010-01-14 | シクロプロピル縮合ピロリジン骨格を有するジペプチジルペプチダーゼivの阻害剤及び方法 |
JP2012263345A Pending JP2013040219A (ja) | 2000-03-10 | 2012-11-30 | シクロプロピル縮合ピロリジン骨格を有するジペプチジルペプチダーゼivの阻害剤及び方法 |
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