JP5493870B2 - 3,8−ジアミノテトラヒドロキノリン誘導体 - Google Patents
3,8−ジアミノテトラヒドロキノリン誘導体 Download PDFInfo
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- JP5493870B2 JP5493870B2 JP2009552416A JP2009552416A JP5493870B2 JP 5493870 B2 JP5493870 B2 JP 5493870B2 JP 2009552416 A JP2009552416 A JP 2009552416A JP 2009552416 A JP2009552416 A JP 2009552416A JP 5493870 B2 JP5493870 B2 JP 5493870B2
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- Prior art keywords
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- oxo
- compound
- tetrahydroquinolin
- methyl
- Prior art date
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- BZWGZEOWKRFPRY-UHFFFAOYSA-N 1,2,3,4-tetrahydroquinoline-3,8-diamine Chemical class C1=CC=C2CC(N)CNC2=C1N BZWGZEOWKRFPRY-UHFFFAOYSA-N 0.000 title claims description 53
- 150000001875 compounds Chemical class 0.000 claims description 292
- 125000004432 carbon atom Chemical group C* 0.000 claims description 47
- 125000000217 alkyl group Chemical group 0.000 claims description 44
- 150000003839 salts Chemical class 0.000 claims description 28
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 23
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 20
- 125000005843 halogen group Chemical group 0.000 claims description 18
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 17
- 229910052757 nitrogen Inorganic materials 0.000 claims description 17
- 125000003545 alkoxy group Chemical group 0.000 claims description 16
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 14
- 125000006615 aromatic heterocyclic group Chemical group 0.000 claims description 12
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 claims description 11
- 125000001041 indolyl group Chemical group 0.000 claims description 9
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 9
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 8
- 125000001624 naphthyl group Chemical group 0.000 claims description 8
- 125000003386 piperidinyl group Chemical group 0.000 claims description 7
- 229910052717 sulfur Inorganic materials 0.000 claims description 7
- 125000002373 5 membered heterocyclic group Chemical group 0.000 claims description 6
- 125000004070 6 membered heterocyclic group Chemical group 0.000 claims description 6
- 125000000051 benzyloxy group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])O* 0.000 claims description 6
- 125000006165 cyclic alkyl group Chemical group 0.000 claims description 6
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 6
- 125000001544 thienyl group Chemical group 0.000 claims description 6
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 5
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 5
- 125000004076 pyridyl group Chemical group 0.000 claims description 5
- 125000002541 furyl group Chemical group 0.000 claims description 4
- 125000006301 indolyl methyl group Chemical group 0.000 claims description 4
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 3
- 229910052799 carbon Inorganic materials 0.000 claims description 3
- 239000003937 drug carrier Substances 0.000 claims description 3
- 125000004464 hydroxyphenyl group Chemical group 0.000 claims description 3
- 125000002816 methylsulfanyl group Chemical group [H]C([H])([H])S[*] 0.000 claims description 3
- 125000000168 pyrrolyl group Chemical group 0.000 claims description 3
- 125000004191 (C1-C6) alkoxy group Chemical group 0.000 claims description 2
- 125000003785 benzimidazolyl group Chemical group N1=C(NC2=C1C=CC=C2)* 0.000 claims description 2
- 125000004618 benzofuryl group Chemical group O1C(=CC2=C1C=CC=C2)* 0.000 claims description 2
- 125000001164 benzothiazolyl group Chemical group S1C(=NC2=C1C=CC=C2)* 0.000 claims description 2
- 125000004196 benzothienyl group Chemical group S1C(=CC2=C1C=CC=C2)* 0.000 claims description 2
- 125000002883 imidazolyl group Chemical group 0.000 claims description 2
- 125000005956 isoquinolyl group Chemical group 0.000 claims description 2
- 239000008194 pharmaceutical composition Substances 0.000 claims description 2
- 125000000714 pyrimidinyl group Chemical group 0.000 claims description 2
- 125000002294 quinazolinyl group Chemical group N1=C(N=CC2=CC=CC=C12)* 0.000 claims description 2
- 125000005493 quinolyl group Chemical group 0.000 claims description 2
- 125000000335 thiazolyl group Chemical group 0.000 claims description 2
- -1 chloropropionyl group Chemical group 0.000 description 243
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 171
- 238000005160 1H NMR spectroscopy Methods 0.000 description 119
- 238000004992 fast atom bombardment mass spectroscopy Methods 0.000 description 96
- 230000015572 biosynthetic process Effects 0.000 description 94
- 238000003786 synthesis reaction Methods 0.000 description 84
- 229910052739 hydrogen Inorganic materials 0.000 description 77
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- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 73
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 52
- 238000006243 chemical reaction Methods 0.000 description 49
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- 230000002829 reductive effect Effects 0.000 description 49
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 45
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 42
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- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 38
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 33
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 33
- 238000001816 cooling Methods 0.000 description 31
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 29
- 239000002904 solvent Substances 0.000 description 28
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 27
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- 229940124597 therapeutic agent Drugs 0.000 description 20
- 125000003277 amino group Chemical group 0.000 description 19
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 18
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 18
- 230000000694 effects Effects 0.000 description 18
- HNJBEVLQSNELDL-UHFFFAOYSA-N pyrrolidin-2-one Chemical group O=C1CCCN1 HNJBEVLQSNELDL-UHFFFAOYSA-N 0.000 description 18
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Classifications
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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- A—HUMAN NECESSITIES
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- A61P35/00—Antineoplastic agents
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- A—HUMAN NECESSITIES
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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- A—HUMAN NECESSITIES
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/04—Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/06—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
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- C—CHEMISTRY; METALLURGY
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- C—CHEMISTRY; METALLURGY
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- C07K—PEPTIDES
- C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
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- C07K5/06017—Dipeptides with the first amino acid being neutral and aliphatic
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- C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
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- C07K5/06—Dipeptides
- C07K5/06008—Dipeptides with the first amino acid being neutral
- C07K5/06017—Dipeptides with the first amino acid being neutral and aliphatic
- C07K5/0606—Dipeptides with the first amino acid being neutral and aliphatic the side chain containing heteroatoms not provided for by C07K5/06086 - C07K5/06139, e.g. Ser, Met, Cys, Thr
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- C07K5/06—Dipeptides
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- C07K5/06—Dipeptides
- C07K5/06139—Dipeptides with the first amino acid being heterocyclic
- C07K5/06156—Dipeptides with the first amino acid being heterocyclic and Trp-amino acid; Derivatives thereof
Description
グレリンは強力なGH分泌促進活性を示すことから(非特許文献5、10)、成長ホルモン欠損症である低身長症の治療薬として有用である。また、GHは成長のほかに老化に深く関与するホルモンと考えられ、GHの低下は筋肉および骨量の低下などを引き起こし、高齢者のQOLを悪化させることから、グレリンのGH分泌促進活性はこれらを改善することが期待でき、老化の防止および治療薬として有用である。
グレリンは、強力な摂食亢進作用を示す末梢投与可能な唯一の液性因子である(非特許文献11)。ヒトでは空腹期に血中グレリン濃度は高く、食後に低下することから、摂食の引き金になるホルモンと考えられており(非特許文献12)、空腹情報は胃の求心性迷走神経を経由して摂食中枢に伝達されていることが明らかにされた(非特許文献13)。この強力な摂食亢進作用は、神経性食欲不振症などの摂食障害を改善することが期待でき、その治療薬として有用である。
グレリンを皮下に連日投与すると、摂食量はほとんど変化しなかったにもかかわらず、顕著な体重の増加が見られ、脂肪組織が増大した(非特許文献14)。更に、グレリンの大量皮下投与においては呼吸商の増加が認められ、グレリンによる脂肪組織増大と体脂肪利用の抑制が示唆された(非特許文献14)。このように、グレリンは末梢で脂質代謝調節に深く関与して、エネルギー代謝調節作用を示した。
グレリンには心機能の改善作用がある(非特許文献15、16)。グレリンを慢性心不全患者に経静脈的に投与すると、心拍数を変えることなく、血圧の低下、心拍出量の増加が認められ、明らかに心機能が改善された。また、心筋梗塞後心不全モデルにおいて、グレリンは心機能改善および低栄養状態(カへキシア)の是正が示され、これらのことからグレリンの心不全治療薬としての有用性が示唆された(非特許文献17)。
グレリンは迷走神経を介して胃運動を亢進する(非特許文献18)。この作用は、術後イレウスや糖尿病性胃麻痺のような胃の運動に障害が見られる疾患の治療薬を提供する可能性がある。
従って、本発明の目的は、強いGHS−Rアゴニスト作用を有し、悪液質等の全身性消耗性疾患治療薬として有用な化合物を提供することにある。
Arは、フェニル基、ナフチル基、S、N及びOから選ばれる1個もしくは2個を含む5員環もしくは6員環の芳香族複素環式基、又はベンゼン環とS、N及びOから選ばれる1個もしくは2個を含む5員環もしくは6員環の複素環とが縮合した芳香族複素環式基(ここで、これらのフェニル、ナフチル又は芳香族複素環式基には、1〜3個のハロゲン原子、炭素数1〜6のアルキル基又は炭素数1〜6のアルコキシ基が置換していてもよい)を示し;
R1及びR2は、同一又は異なって、水素原子又はメチル基を示し;
R3は、炭素数1〜6のアルキル基(ここでアルキル基には、メチルチオ又はベンジルオキシ基が置換していてもよい)、フェニル基、フェニル−C1−4アルキル基、又はインドリルC1−4アルキル基(ここで、フェニル基又はインドリル基には炭素数1〜6のアルキル基、ハロゲン原子、水酸基又は炭素数1〜6のアルコキシ基が置換していてもよい)を示し;
nは0又は1の数を示し;
R4及びR5は、同一又は異なって、水素原子、炭素数1〜6の直鎖状、分岐状もしくは環状のアルキル基、(ここでアルキル基にはハロゲン原子、水酸基、炭素数1〜6のアルコキシ基、フェニル基、ベンジルオキシ基又はヒドロキシフェニル基が置換していてもよい)を示すか、あるいは、R4又はR5とR6又はR7が隣接する窒素原子と一緒になってピロリジン環若しくはピペリジン環(ここでピロリジン環若しくはピペリジン環には水酸基が置換してもよい)を形成してもよく;
R6及びR7は同一又は異なって、水素原子、又は炭素数1〜6のアルキル基を示す。)
で表される3,8−ジアミノテトラヒドロキノリン誘導体又はその塩を提供するものである。
また本発明は、上記3,8−ジアミノテトラヒドロキノリン誘導体(1)又はその塩、及び薬学的に許容される担体を含有する医薬組成物を提供するものである。
また、本発明は、上記3,8−ジアミノテトラヒドロキノリン誘導体(1)又はその塩の全身性消耗性疾患治療薬製造のための使用を提供するものである。
さらに本発明は、上記3,8−ジアミノテトラヒドロキノリン誘導体(1)又はその塩の有効量を投与することを特徴とする全身性消耗性疾患の治療法を提供するものである。
さらに好ましい当該複素環としては、次の構造(a)のものが挙げられる。
以下、反応工程毎に説明する。
化合物(A)又は化合物(A−1)を還元することにより、化合物(B)が得られる。Raの一般的な保護基としては例えばtert−ブトキシカルボニル基、アセチル基、ベンジルオキシカルボニル基が挙げられる。還元反応は、パラジウム、白金、ニッケル等を用いる触媒的接触還元反応が好ましい。例えばパラジウム−炭素、白金−炭素、酸化白金、ラネーニッケル等の触媒存在下に水素添加するのが好ましい。このとき、パラジウム−炭素存在下、水素源として水素ガスまたはギ酸アンモニウムを使用することがさらに好ましい。
また化合物(A)を鉄、スズ、亜鉛等の金属触媒を用いて還元すれば化合物(A−2)が得られる。さらに化合物(A−2)をパラジウム、白金、ニッケル等を用いる触媒的接触還元することにより、化合物(B)が得られる。
化合物(B)の8位アミノ基にR8及びR9の置換基を導入することにより、化合物(C)が得られる。R8及びR9がアルカノイル基等のような場合には、通常のアミド化反応により行うことができる。
同様の方法により、化合物(L)を用いることで化合物(M)が得られる。
化合物(B)又は化合物(L)に4−ハロゲノブチリルクロリド又はコハク酸無水物を反応させて化合物(B)又は化合物(L)の8位のアミノ基に4−ハロゲノブタノイル基又は3−ヒドロキシカルボニルプロパノイル基を導入し、次いで分子内アルキル化反応又はアミド結合形成反応による環化により、−N(R8)R9がピロリジン−2−オン−1−イル基又はピロリジン−2,5−ジオン−1−イル基である化合物(C)又は化合物(M)を製造することができる。さらに、この−N(R8)R9が、ピロリジン−2−オン−1−イル基である化合物を酸化することにより、−N(R8)R9が、ピロリジン−2−ヒドロキシ−5−オン−1−イル基である化合物を製造することができる。
化合物(B)にArCH2ハライド、ArCH2メタンスルホナート又はArCH2パラトルエンスルホナート等を反応させることにより化合物(D)が得られる。この反応は、アルカリ金属の水酸化物、アルカリ金属の水素化物、アルカリ金属の炭酸塩等の塩基の存在下に行うのが好ましい。または光延反応により化合物(B)とArCH2OHから化合物(D)が得られる。
同様の方法により、化合物(C)を用いることで化合物(E)が、化合物(L)を用いることで化合物(N)が、また化合物(M)を用いることで本発明化合物(1)若しくは本発明化合物(1)のアミノ基が保護された化合物が得られる。
化合物(D)の8位アミノ基にR8及びR9の置換基を導入することにより、化合物(E)が得られる。R8又はR9がアルキル基等のような場合には、通常の還元的アミノ化反応によりモノアルキル化、ジアルキル化を行うことができる。
化合物(D)にアルキルアルデヒドと還元剤(例えばシアノ水素化ほう素ナトリウム、トリアセトキシ水素化ほう素ナトリウム)を反応させて、化合物(D)の8位のアミノ基にモノアルキル基またはジアルキル基を導入することができる。モノアルキル基を導入した化合物は、次いでこれに通常のアミド化反応によりアルカノイル基を導入することができる。
同様の方法により、化合物(N)を用いることで本発明化合物(1)若しくは本発明化合物(1)のアミノ基が保護された化合物が得られる。
化合物(E)のアミノ基の保護基を一般的な脱保護反応で除去することにより、化合物(F)が得られる。ここで化合物(F)は、光学分割しておくのが好ましい。
同様の方法により、化合物(H)のアミノ基が保護された化合物を用いることで化合物(H)が、本発明化合物(1)のアミノ基が保護された化合物を用いることで本発明化合物(1)が、化合物(B)を用いることで化合物(J)が、化合物(K)のアミノ基が保護された化合物を用いることで化合物(K)が得られる。
化合物(F)にアミノ酸類(G)を縮合させることで化合物(H)のアミノ基が保護された化合物が得られる。式(G)中、Raはアミノ基の一般的な保護基を示し、カーバメイト型保護基(例えばtert−ブトキシカルボニル基、ベンジルオキシカルボニル基)が挙げられる。化合物(F)とアミノ酸類(G)の縮合反応は、一般的なカップリング試薬を用いた反応、または混合酸無水物法によるアミノ酸縮合反応を行うのが好ましい。化合物(F)が酒石酸等のジカルボン酸との塩である場合は、アルカリ金属の水酸化物等の塩基を化合物(F)に対し等モル量加え、溶解させた水溶液を縮合反応に用いることが好ましい。
同様の方法により、化合物(J)とアミノ酸類(G)を縮合することで化合物(K)のアミノ基が保護された化合物が得られる。同様の方法により、化合物(F)とアミノ酸類(G−2)(式(G−2)中、R6、R7の一方または両方がアミノ基の保護基である場合がある)を縮合させることにより本発明化合物(1)若しくは本発明化合物(1)のアミノ基が保護された化合物が得られる。
同様の方法により、化合物(K)とアミノ酸類(I)を縮合することで化合物(L)のアミノ基が保護された化合物が得られる。
特に、癌、老化、感染症および炎症性疾患による悪液質治療薬、薬剤(抗癌剤など)および放射線治療時の食欲減退を改善する治療薬として有用である。
また、これらの固形製剤をヒドロキシメチルセルロースフタレート、ヒドロキシプロピルメチルセルロースアセテートサクシネート、セルロースアセテートフタレート、メタアクリレートコーポリマーなどの被覆用基剤を用いて放出制御製剤とすることができ、さらに、液剤、懸濁剤、乳濁剤のごとき液体製剤とすることもできる。
N−(2−オキソ−1,2,3,4−テトラヒドロキノリン−3−イル)アセトアミドの合成
10%パラジウム−炭素26.1gを加え、水素置換を5回行った。内温60−85℃に保持し、5時間激しく攪拌した(化合物dの生成)。反応溶液を30℃まで冷却しセライト濾過し、N,N−ジメチルアセトアミド250mLにて洗浄した。ろ液に室温下、水3750mL、25%水酸化ナトリウム221.1gを加え、内温74℃で2時間加熱攪拌した(化合物eの生成)。内温10℃以下で1時間攪拌後、析出物を濾過した(この際2つの反応液を合わせた)。析出物を水250mLで2回掛け洗浄し、表題化合物405.9gを粉末状化合物として得た。
1H−NMR(400MHz,DMSO−d6):δ(ppm)1.15(6H,t,J=7.0Hz),1.86(3H,s),3.83(2H,s),4.04−4.17(4H,m),7.23(1H,dd,J=1.0,8.0Hz),7.48−7.55(1H,m),7.61−7.68(1H,m),7.88(1H,dd,J=1.5,8.0Hz),8.16(1H,m).
・化合物d:Ms(FAB)m/z277(M+H)+
1H−NMR(400MHz,DMSO−d6):δ(ppm)0.94(3H,t,J=7.0Hz)1.86(3H,s),3.33(1H,d,J=16.0Hz)3.41(1H,d,J=16.0Hz),3.59−4.01(2H,m),6.86(1H,d,J=8.0Hz),6.89−6.95(1H,m),7.11−7.18(2H,m),8.34(1H,s),10.54(1H,s).
・化合物e:Ms(FAB)m/z205(M+H)+
1H−NMR(400MHz,DMSO−d6):δ(ppm)1.91(3H,s),2.85(1H,t,J=14.5Hz),3.02(1H,dd,J=6.5,15.5Hz),4.40−4.49(1H,m),6.87(1H,d,J=8.0Hz),6.91−6.97(1H,m),7.13−7.22(2H,m),8.20(1H,d,J=8.0Hz),10.33(1H,s).
N−(6−ブロモ−2−オキソ−1,2,3,4−テトラヒドロキノリン−3−イル)アセトアミドの合成
この操作を2ロットで行い、析出物を濾取する際に2ロットを合わせた。得られた析出物を水(405mL×2)、エタノール(1500mL)で順次洗浄し、風乾することで表題化合物768.0gを得た。
Ms(FAB)m/z283(M+H)+
1H−NMR(400MHz,DMSO−d6):δ(ppm)1.90(3H,s),2.87(1H,t,J=14.0Hz),3.04(1H,dd,J=6.5,15.5Hz),4.40−4.41(1H,m),6.81(1H,d,J=8.5Hz),7.35(1H,dd,J=2.0,8.5Hz),7.42(1H,d,J=2.0Hz),8.19(1H,d,J=8.0Hz),10.41(1H,s).
N−(6−ブロモ−8−ニトロ−2−オキソ−1,2,3,4−テトラヒドロキノリン−3−イル)アセトアミドの合成
この操作を2ロットで行い、各反応液を50%エタノール15.9Lへ順次注ぎ込んだ。反応容器を水7.95Lで洗いこみ、20℃で1時間攪拌し濾取した。得られた析出物を水(7.95L×2)、エタノール(954mL)で順次洗浄した。60℃にて減圧乾燥し、表題化合物908.0gを得た。
Ms(FAB)m/z328(M+H)+
1H−NMR(400MHz,DMSO−d6):δ(ppm)1.91(3H,s),3.05(1H,t,J=14.0Hz),3.21(1H,dd,J=6.0,16.0Hz),4.58−4.68(1H,m),7.92(1H,d,J=1.0Hz),8.16(1H,d,J=2.0Hz),8.33(1H,d,J=8.0Hz),10.01(1H,s).
3−アミノ−6−ブロモ−8−ニトロ−3,4−ジヒドロキノリン−2(1H)−オン 塩酸塩の合成
1H−NMR(400MHz,DMSO−d6):δ(ppm)3.25(1H,t,J=15.0Hz),3.42(1H,dd,J=6.5,15.0Hz),4.33−4.45(1H,m),8.04(1H,br s),8.18(1H,d,J=2.0Hz),8.84(3H,br s),10.45(1H,s).
6−ブロモ−8−ニトロ−2−オキソ−1,2,3,4−テトラヒドロキノリン−3−イルカルバミン酸 tert−ブチルの合成
MS(FAB)m/z387(M+H)+
1H−NMR(400MHz,DMSO−d6):δ(ppm)1.41(9H,s),3.09(1H,t,J=15.5Hz),3.19(1H,dd,J=7.0,15.5Hz),4.29−4.39(1H,m),7.24(1H,d,J=8.5Hz),7.91(1H,br s),8.14(1H,d,J=2.0Hz),9.94(1H,br s).
8−アミノ−2−オキソ−1,2,3,4−テトラヒドロキノリン−3−イルカルバミン酸 tert−ブチルの合成
MS(FAB)m/z278(M+H)+
1H−NMR(400MHz,DMSO−d6):δ(ppm)1.41(9H,s),2.78−2.92(2H,m),4.03−4.14(1H,m),5.05(2H,br s),6.41(1H,d,J=7.5Hz),6.53(1H,d,J=7.5Hz),6.69(1H,t,J=7.5Hz),6.94(1H,d,J=7.5Hz),9.45(1H,br s).
2−オキソ−8−(2−オキソピロリジン−1−イル)−1−(チオフェン−3−イルメチル)−1,2,3,4−テトラヒドロキノリン−3−イルカルバミン酸 tert−ブチルの合成
・化合物(A):MS(FAB)m/z382(M+H)+
1H−NMR(400MHz,DMSO−d6):δ(ppm)1.41(9H,s),1.98−2.07(2H,m),2.46−2.56(2H,m),2.93−3.02(2H,m),3.71(2H,t,J=6.5Hz),4.07−4.18(1H,m),6.93(1H,t,J=8.0Hz),7.00−7.07(2H,m),7.31(1H,d,J=8.0Hz),9.37(1H,br s),9.58(1H,br s).
・化合物(B):MS(FAB)m/z346(M+H)+
1H−NMR(400MHz,DMSO−d6):δ(ppm)1.41(9H,s),2.08−2.18(2H,m),2.36−2.43(2H,m),2.93−3.06(2H,m),3.56−3.62(2H,m),4.08−4.19(1H,m),6.95−7.07(2H,m),7.10(1H,d,J=7.5Hz),7.16(1H,d,J=7.5Hz),9.66(1H,s).
・化合物(C):MS(FAB)m/z442(M+H)+
1H−NMR(400MHz,DMSO−d6,80℃):δ(ppm)1.41(9H,s),1.83−2.07(2H,m),2.25−2.36(2H,m),2.79−2.94(2H,m),3.13−3.40(1H,m),3.72−3.79(1H,m),4.08−4.17(1H,m),4.56(1H,d,J=15.5Hz),5.17(1H,d,J=15.5Hz),6.52−6.61(1H,m),6.79(1H,d,J=5.0Hz),7.00−7.04(1H,m),7.06−7.12(1H,m),7.13−7.18(2H,m),7.31(1H,dd,J=3.0,5.0Hz).
1−ベンジル−2−オキソ−8−(2−オキソピロリジン−1−イル)−1,2,3,4−テトラヒドロキノリン−3−イルカルバミン酸 tert−ブチルの合成
MS(FAB)m/z436(M+H)+
1H−NMR(400MHz,CDCl3):δ(ppm)1.47(9H,s),1.71−1.84(1H,m),2.10−2.42(2H,m),2.70(1H,t,J=14.5Hz),3.19−3.56(3H,m),4.37−4.46(1H,m),4.88−5.11(2H,m),5.82(1H,d,J=4.5Hz),7.06−7.30(9H,m).
8−アミノ−1−ベンジル−1,2,3,4−テトラヒドロ−2−オキソキノリン−3−イルカルバミン酸 tert−ブチルの合成
MS(FAB)m/z368(M+H)+
1H−NMR(400MHz,CDCl3):δ(ppm)1.45(9H,s),2.53(1H,t,J=14.5Hz),3.15(1H,dd,J=5.0,14.5Hz),3.50(2H,br s),4.21−4.33(1H,m),5.04(1H,d,J=15.0Hz),5.17(1H,d,J=15.0Hz),5.53−5.84(1H,m),6.62(2H,d,J=8.0Hz),6.91(1H,t,J=7.5Hz),7.17−7.28(5H,m).
1−ベンジル−8−エチルアミノ−1,2,3,4−テトラヒドロ−2−オキソキノリン−3−イルカルバミン酸 tert−ブチルの合成
MS(FAB)m/z396(M+H)+
1H−NMR(400MHz,CDCl3):δ(ppm)0.90(3H,t,J=7.0Hz),1.45(9H,s),2.58(1H,t,J=14.5Hz),2.88−3.20(4H,m),4.26−4.36(1H,m),4.80(1H,d,J=15.0Hz),5.21(1H,d,J=15.0Hz),5.75−5.86(1H,m),6.58(2H,d,J=8.0Hz),7.02(1H,t,J=8.0Hz),7.16−7.31(5H,m).
1−ベンジル−8−(N−エチルアセトアミド)−2−オキソ−1,2,3,4−テトラヒドロキノリン−3−イルカルバミン酸 tert−ブチルの合成
MS(FAB)m/z438(M+H)+
1H−NMR(400MHz,CDCl3):δ(ppm)0.91−1.00(2.4H,m),1.34(0.6H,t,J=7.0Hz),1.45(0.9H,s),1.47(8.1H,s),1.58(2.1H,s),1.75(0.9H,s),2.68−3.15(2H,m),3.24−3.43(1H,m),4.10−4.42(2H,m),4.60−4.70(0.9H,m),5.10(0.1H,d,J=16.5Hz),5.45(0.1H,d,J=16.5Hz),5.72−5.88(1.9H,m),6.87−7.32(8H,m).
3−アミノ−8−(2−オキソピロリジン−1−イル)−1−(チオフェン−3−イルメチル)−3,4−ジヒドロキノリン−2(1H)−オンの合成
MS(FAB)m/z342(M+H)+
1H−NMR(400MHz,DMSO−d6,80℃):δ(ppm)1.78−2.03(4H,m),2.22−2.39(2H,m),2.62(1H,t,J=14.5Hz),2.86(1H,dd,J=5.0,14.5Hz),3.32−3.39(1H,m),3.46(1H,dd,J=5.0,13.0Hz),3.62−3.37(1H,m),4.61(1H,d,J=15.5Hz),5.13(1H,d,J=15.5Hz),6.75−6.80(1H,m),6.96−7.14(4H,m),7.27−7.33(1H,m).
3−アミノ−1−ベンジル−8−(2−オキソピロリジン−1−イル)−3,4−ジヒドロキノリン−2(1H)−オンの合成
MS(FAB)m/z336(M+H)+
1H−NMR(400MHz,DMSO−d6):δ(ppm)1.60−2.37(6H,m),2.74(1H,t,J=15.0Hz),2.91(1H,dd,J=5.0,15.0Hz),3.10−4.09(3H,m),4.41−5.25(2H,m),7.02−7.32(8H,m).
N−(3−アミノ−1−ベンジル−1,2,3,4−テトラヒドロ−2−オキソキノリン−8−イル)−N−エチルアセトアミドの合成
MS(FAB)m/z338(M+H)+
1H−NMR(400MHz,CDCl3):δ(ppm)0.93−1.10(2.4H,m),1.27(0.6H,t,J=7.0Hz),1.50(2.1H,s),1.69(0.6H,s),1.75(0.3H,s),1.88(2H,br s),2.73−3.10(3H,m),3.49−3.80(2H,m),4.62(0.9H,d,J=16.0Hz),4.87(0.1H,d,J=16.0Hz),5.13(0.1H,d,J=16.0Hz),5.34(0.2H,d,J=16.0Hz),5.84(0.7H,d,J=16.0Hz),6.84−7.33(8H,m).
3−アミノ−8−(2−オキソピロリジン−1−イル)−1−(チオフェン−3−イルメチル)−3,4−ジヒドロキノリン−2(1H)−オン D−(‐)−酒石酸塩の合成
1H−NMR(400MHz,DMSO−d6,80℃):δ(ppm)1.79−2.06(2H,m),2.23−2.40(2H,m),2.79(1H,t,J=14.5Hz),2.95(1H,dd,J=5.0,14.5Hz),3.32−3.39(1H,m),3.67−3.78(2H,m),4.05(2H,s),4.61(1H,d,J=15.5Hz),5.16(1H,d,J=15.5Hz),6.80(1H,d,J=5.0Hz),7.00−7.04(1H,m),7.08−7.20(3H,m),7.33(1H,dd,J=3.0,5.0Hz).
3−アミノ−1−ベンジル−8−(2−オキソピロリジン−1−イル)−3,4−ジヒドロキノリン−2(1H)−オン D−(‐)−酒石酸塩の合成
1H−NMR(400MHz,DMSO−d6,80℃):δ(ppm)1.55−1.73(1H,m),1.82−1.95(1H,m),2.11−2.32(2H,m),2.83(1H,t,J=14.5Hz),2.99(1H,dd,J=5.0,14.5Hz),3.28−3.37(1H,m),3.60−3.71(1H,m),3.76(1H,dd,J=5.5,13.5Hz),4.07(2H,s),4.69(1H,d,J=15.5Hz),5.08(1H,d,J=15.5Hz),7.01−7.26(8H,m).
(−)−3−アミノ−8−(2−オキソピロリジン−1−イル)−1−(チオフェン−3−イルメチル)−3,4−ジヒドロキノリン−2(1H)−オンの合成
[α]D 25=‐6.1°(c1.0,MeOH)
MS(FAB)m/z342(M+H)+
1H−NMR(400MHz,DMSO−d6,80℃):δ(ppm)1.78−2.03(4H,m),2.22−2.39(2H,m),2.62(1H,t,J=14.5Hz),2.86(1H,dd,J=5.0,14.5Hz),3.32−3.39(1H,m),3.46(1H,dd,J=5.0,13.0Hz),3.62−3.37(1H,m),4.61(1H,d,J=15.5Hz),5.13(1H,d,J=15.5Hz),6.75−6.80(1H,m),6.96−7.14(4H,m),7.27−7.33(1H,m).
(−)−3−アミノ−1−ベンジル−8−(2−オキソピロリジン−1−イル)−3,4−ジヒドロキノリン−2(1H)−オンの合成
[α]D 25=−13.5°(c1.0,MeOH)
MS(FAB)m/z336(M+H)+
1H−NMR(400MHz,DMSO−d6):δ(ppm)1.60−2.37(6H,m),2.74(1H,t,J=15.0Hz),2.91(1H,dd,J=5.0,15.0Hz),3.10−4.09(3H,m),4.41−5.25(2H,m),7.02−7.32(8H,m).
(R)−2−(tert−ブトキシカルボニルアミノ)−3−(1−メチル−1H−インドール−3−イル)プロパン酸の合成
MS(FAB)m/z319(M+H)+
1H−NMR(400MHz,DMSO−d6):δ(ppm)1.33(9H,s),2.97(1H,dd,J=9.5,14.5Hz),3.12(1H,dd,J=4.5,14.5Hz),3.72(3H,s),4.13(1H,dt,J=4.5,9.5Hz),6.99−7.06(2H,m),7.10−7.17(2H,m),7.38(1H,d,J=8.0Hz),7.54(1H,d,J=8.0Hz),12.58(1H,br s).
(R)−2−(tert−ブトキシカルボニルアミノ)−3−(1−エチル−1H−インドール−3−イル)プロパン酸の合成
MS(FAB)m/z333(M+H)+
1H−NMR(400MHz,DMSO−d6):δ(ppm)1.32(3H,t,J=7.0Hz),1.33(9H,s),2.97(1H,dd,J=9.0,14.5Hz),3.12(1H,dd,J=5.0,14.5Hz),4.09−4.20(3H,m),6.95−7.04(2H,m),7.08−7.22(2H,m),7.41(1H,d,J=8.0Hz),7.53(1H,d,J=8.0Hz),12.50−12.70(1H,br).
(R)−2−(tert−ブトキシカルボニルアミノ)−3−[1−(2−フルオロエチル)−1H−インドール−3−イル]プロパン酸の合成
MS(FAB)m/z351(M+H)+
1H−NMR(400MHz,DMSO−d6):δ(ppm)1.33(9H,s),2.98(1H,dd,J=9.5,14.5Hz),3.13(1H,dd,J=4.5,14.5Hz),4.12−4.20(1H,m),4.38−4.50(2H,m),4.62(1H,t,J=4.5Hz),4.74(1H,t,J=4.5Hz),6.96−7.07(2H,m),7.10−7.19(2H,m),7.45(1H,d,J=9.0Hz),7.80(1H,d,J=8.0Hz),12.57(1H,br s).
(R)−2−(tert−ブトキシカルボニルアミノ)−3−(1−プロピル−1H−インドール−3−イル)プロパン酸の合成
MS(FAB)m/z347(M+H)+
1H−NMR(400MHz,DMSO−d6):δ(ppm)0.81(3H,t,J=7.5Hz),1.32(9H,s),1.67−1.78(2H,m),2.97(1H,dd,J=9.5,14.5Hz),3.12(1H,dd,J=5.0,14.5Hz),4.07(2H,t,J=7.0Hz),4.11−4.19(1H,m),6.95−7.04(2H,m),7.18−7.20(2H,m),7.41(1H,d,J=8.0Hz),7.53(1H,d,J=8.0Hz),12.56(1H,br s).
(R)−2−(tert−ブトキシカルボニルアミノ)−3−(1−イソプロピル−1H−インドール−3−イル)プロパン酸の合成
MS(FAB)m/z347(M+H)+
1H−NMR(400MHz,DMSO−d6):δ(ppm)1.33(9H,s),1.41(3H,d,J=6.5Hz),1.42(3H,d,J=6.5Hz),2.97(1H,dd,J=9.5,14.5Hz),3.13(1H,dd,J=4.5,14.5Hz),4.15−4.24(1H,m),4.63−4.77(1H,m),6.97−7.05(2H,m),7.11(1H,dt,J=1.0,8.0Hz),7.25(1H,s),7.44(1H,d,J=8.0Hz),7.52(1H,d,J=8.0Hz),12.57(1H,br s).
(2R)−4−メチル−1−オキソ−1−[2−オキソ−8−(2−オキソピロリジン−1−イル)−1−(チオフェン−3−イルメチル)−1,2,3,4−テトラヒドロキノリン−3−イルアミノ]ペンタン−2−イルカルバミン酸tert−ブチルの合成
MS(FAB)m/z555(M+H)+
1H−NMR(400MHz,DMSO−d6,80℃):δ(ppm)0.87(3H,d,J=5.0Hz),0.89(3H,d,J=5.0Hz),1.39(9H,s),1.49(2H,t,J=7.0Hz),1.58−1.70(1H,m),1.82−2.06(2H,m),2.24−2.39(2H,m),2.74(1H,t,J=14.0Hz),2.95−3.05(1H,m),3.34−3.43(1H,m),3.70−3.81(1H,m),4.00−4.08(1H,m),4.35−4.44(1H,m),4.59(1H,d,J=15.5Hz),5.17(1H,d,J=15.5Hz),6.57(1H,br s),6.80(1H,dd,J=1.0,5.0Hz),7.02−7.07(1H,m),7.09−7.14(1H,m),7.14−7.20(2H,m),7.32(1H,dd,J=3.0,5.0Hz),7.76(1H,d,J=6.5Hz).
(2R)−3−(1−メチル−1H−インドール−3−イル)−1−オキソ−1−[2−オキソ−8−(2−オキソピロリジン−1−イル)−1−(チオフェン−3−イルメチル)−1,2,3,4−テトラヒドロキノリン−3−イルアミノ]プロパン−2−イルカルバミン酸 tert−ブチルの合成
MS(FAB)m/z642(M+H)+
1H−NMR(400MHz,DMSO−d6):δ(ppm)1.15−1.19(1H,m),1.32(9H,s),1.85−2.43(4H,m),2.60−2.79(2H,m),2.88−2.99(1H,m),3.09(1H,dd,J=5.5,9.0Hz),3.30−3.38(1H,m),3.73(3H,s),4.19−4.85(3H,m),4.97−5.24(1H,m),6.80(1H,d,J=5.0Hz),6.94(1H,d,J=8.5Hz),7.01(1H,t,J=7.5Hz),7.08−7.17(6H,m),7.34−7.45(2H,m),7.61(1H,d,J=7.5Hz),8.21(1H,d,J=7.5Hz).
(2R)−3−(1−エチル−1H−インドール−3−イル)−1−オキソ−1−[2−オキソ−8−(2−オキソピロリジン−1−イル)−1−(チオフェン−3−イルメチル)−1,2,3,4−テトラヒドロキノリン−3−イルアミノ]プロパン−2−イルカルバミン酸 tert−ブチルの合成
MS(FAB)m/z656(M+H)+
1H−NMR(400MHz,DMSO−d6):δ(ppm)1.30−1.38(12H,m),1.86−2.45(5H,m),2.58−2.77(2H,m),2.93(1H,dd,J=5.5,9.0Hz),3.10(1H,dd,J=5.5,9.0Hz),3.28−3.39(1H,m),4.14(2H,q,J=7.0Hz),4.28−4.79(3H,m),5.01−5.22(1H,m),6.79(1H,d,J=5.0Hz),6.93(1H,d,J=8.5Hz),7.00(1H,t,J=7.5Hz),7.05−7.23(6H,m),7.37−7.43(2H,m),7.59(1H,d,J=8.0Hz),8.17(1H,d,J=7.0Hz).
(2R)−3−[1−(2−フルオロエチル)−1H−インドール−3−イル]−1−オキソ−1−[2−オキソ−8−(2−オキソピロリジン−1−イル)−1−(チオフェン−3−イルメチル)−1,2,3,4−テトラヒドロキノリン−3−イルアミノ]プロパン−2−イルカルバミン酸 tert−ブチルの合成
MS(FAB)m/z674(M+H)+
1H−NMR(400MHz,DMSO−d6,80℃):δ(ppm)1.32(9H,m),1.82−2.07(2H,m),2.24−2.40(2H,m),2.59(1H,t,J=14.0Hz),2.79(1H,dd,J=5.0,15.0Hz),2.94−3.05(1H,m),3.14(1H,dd,J=5.5,14.5Hz),3.32−3.42(1H,m),3.70−3.82(1H,m),4.29−4.46(4H,m),4.54−4.66(2H,m),4.75(1H,t,J=5.0Hz),5.17(1H,d,J=15.5Hz),6.44(1H,s),6.78(1H,dd,J=1.5,5.0Hz),6.98−7.06(2H,m),7.08−7.22(5H,m),7.33(1H,dd,J=3.0.5.0Hz),7.40(1H,d,J=8.0Hz),7.57(1H,d,J=8.0Hz),7.80(1H,d,J=7.0Hz).
(2R)−1−オキソ−1−[2−オキソ−8−(2−オキソピロリジン−1−イル)−1−(チオフェン−3−イルメチル)−1,2,3,4−テトラヒドロキノリン−3−イルアミノ]−3−(1−プロピル−1H−インドール−3−イル)−プロパン−2−イルカルバミン酸 tert−ブチルの合成
MS(FAB)m/z670(M+H)+
1H−NMR(400MHz,DMSO−d6,80℃):δ(ppm)0.85(3H,t,J=7.5Hz),1.31(9H,s),1.72−1.81(2H,m),1.84−2.06(2H,m),2.25−2.39(2H,m),2.59(1H,t,J=14.5Hz),2.80(1H,dd,J=5.0,15.0Hz),2.92−3.03(1H,m),3.09−3.19(1H,m),3.33−3.42(1H,m),3.70−3.81(1H,m),4.04(2H,t,J=7.0Hz),4.27−4.42(2H,m),4.58(1H,d,J=15.5Hz),5.17(1H,d,J=15.5Hz),6.41(1H,s),6.78(1H,dd,J=1.5,5.0Hz),6.95−7.04(2H,m),7.06−7.20(5H,m),7.31−7.40(2H,m),7.53−7.58(1H,m),7.80(1H,d,J=7.0Hz).
(2R)−3−(1−イソプロピル−1H−インドール−3−イル)−1−オキソ−1−[2−オキソ−8−(2−オキソピロリジン−1−イル)−1−(チオフェン−3−イルメチル)−1,2,3,4−テトラヒドロキノリン−3−イルアミノ]プロパン−2−イルカルバミン酸 tert−ブチルの合成
MS(FAB)m/z670(M+H)+
1H−NMR(400MHz,DMSO−d6,80℃):δ(ppm)1.32(9H,s),1.43(3H,d,J=6.5Hz),1.43(3H,d,J=6.5Hz),1.82−2.08(2H,m),2.24−2.40(2H,m),2.56(1H,t,J=14.5Hz),2.68−2.80(1H,m),2.90−3.15(1H,m),3.14(1H,dd,J=6.0,14.5Hz),3.30−3.42(1H,m),3.68−3.80(1H,m),4.27−4.42(2H,m),4.57(1H,d,J=15.5Hz),4.61−4.72(1H,m),5.17(1H,d,J=15.5Hz),6.36−6.50(1H,m),6.77(1H,d,J=5.0Hz),6.93−7.21(6H,m),7.26(1H,s),7.28−7.35(1H,m),7.40(1H,d,J=8.0Hz),7.55(1H,d,J=8.0Hz),7.79(1H,d,J=7.0Hz).
(2R)−2−アミノ−4−メチル−N−[2−オキソ−8−(2−オキソピロリジン−1−イル)−1−(チオフェン−3−イルメチル)−1,2,3,4−テトラヒドロキノリン−3−イル]ペンタンアミドの合成
MS(FAB)m/z455(M+H)+
1H−NMR(400MHz,DMSO−d6,80℃):δ(ppm)0.87(3H,d,J=6.5Hz),0.89(3H,d,J=6.5Hz),1.23−1.33(1H,m),1.45−1.56(1H,m),1.68−2.06(5H,m),2.25−2.39(2H,m),2.76(1H,t,J=14.0Hz),2.95−3.04(1H,m),3.28(1H,dd,J=5.0,8.5Hz),3.31−3.42(1H,m),3.68−3.80(1H,m),4.39(1H,dd,J=5.0,13.5Hz),4.59(1H,d,J=15.5Hz),5.17(1H,d,J=15.5Hz),6.76−6.82(1H,m),7.00−7.19(4H,m),7.32(1H,dd,J=3.0,5.0Hz),8.11(1H,br s).
(2R)−2−アミノ−3−(1−メチル−1H−インドール−3−イル)−N−[2−オキソ−8−(2−オキソピロリジン−1−イル)−1−(チオフェン−3−イルメチル)−1,2,3,4−テトラヒドロキノリン−3−イル]プロパンアミドの合成
MS(FAB)m/z542(M+H)+
1H−NMR(400MHz,DMSO−d6,80℃):δ(ppm)1.65−2.03(4H,m),2.24−2.39(2H,m),2.67(1H,t,J=14.5Hz),2.82(1H,dd,J=5.0,8.0Hz),2.96(1H,dd,J=5.0,10.5Hz),3.14(1H,dd,J=5.0,9.5Hz),3.36−3.40(1H,m),3.57(1H,dd,J=3.0,5.0Hz),3.72−3.75(4H,m),4.38(1H,dd,J=5.0,9.0Hz),4.59(1H,d,J=16.0Hz),5.15(1H,d,J=16.0Hz),6.79(1H,d,J=4.0Hz),6.97−7.03(2H,m),7.09−7.19(5H,m),7.30−7.36(2H,m),7.55(1H,d,J=8.0Hz),8.02(1H,br).
(2R)−2−アミノ−3−(1−エチル−1H−インドール−3−イル)−N−[2−オキソ−8−(2−オキソピロリジン−1−イル)−1−(チオフェン−3−イルメチル)−1,2,3,4−テトラヒドロキノリン−3−イル]プロパンアミドの合成
MS(FAB)m/z556(M+H)+
1H−NMR(400MHz,DMSO−d6,80℃):δ(ppm)1.33(3H,t,J=7.0Hz),1.74−2.43(7H,m),2.69−2.81(2H,m),2.89(1H,dd,J=5.0,10.0Hz),3.12(1H,dd,J=5.0,10.0Hz),3.55(1H,dd,J=3.5,5.5Hz),4.15(2H,q,J=7.0Hz),4.25−5.23(4H,m),6.80(1H,d,J=5.0Hz),7.00(1H,t,J=7.5Hz),7.06−7.21(5H,m),7.27(1H,s),7.38−7.47(2H,m),7.56(1H,d,J=8.0Hz),8.38(1H,d,J=7.0Hz).
(2R)−2−アミノ−3−[1−(2−フルオロエチル)−1H−インドール−3−イル]−N−[2−オキソ−8−(2−オキソピロリジン−1−イル)−1−(チオフェン−3−イルメチル)−1,2,3,4−テトラヒドロキノリン−3−イル]プロパンアミドの合成
MS(FAB)m/z574(M+H)+
1H−NMR(400MHz,DMSO−d6,80℃):δ(ppm)1.70−2.09(4H,m),2.21−2.39(2H,m),2.67(1H,t,J=14.5Hz),2.83(1H,dd,J=8.0,14.0Hz),2.88−2.97(1H,m),3.06−3.17(1H,m),3.30−3.41(1H,m),3.52−3.62(1H,m),3.68−3.80(1H,m),4.30−4.48(3H,m),4.52−4.68(2H,m),4.70−4.80(1H,m),5.15(1H,d,J=15.5Hz),6.79(1H,d,J=5.0Hz),6.95−7.04(2H,m),7.05−7.23(5H,m),7.27−7.34(1H,m),7.41(1H,d,J=8.0Hz),7.57(1H,d,J=8.0Hz),8.03−8.14(1H,m).
(2R)−2−アミノ−N−[2−オキソ−8−(2−オキソピロリジン−1−イル)−1−(チオフェン−3−イルメチル)−1,2,3,4−テトラヒドロキノリン−3−イル]−3−(1−プロピル−1H−インドール−3−イル)−プロパンアミドの合成
MS(FAB)m/z570(M+H)+
1H−NMR(400MHz,DMSO−d6,80℃):δ(ppm)0.85(3H,t,J=7.0Hz),1.57−2.07(6H,m),2.22−2.38(2H,m),2.60−2.71(1H,m),2.80−2.98(2H,m),3.12(1H,dd,J=5.0,14.5Hz),3.33−3.41(1H,m),3.53−3.62(1H,m),3.69−3.79(1H,m),3.98−4.08(2H,m),4.31−4.41(1H,m),4.59(1H,d,J=15.5Hz),5.15(1H,d,J=15.5Hz),6.80(1H,d,J=7.1Hz),6.99(1H,t,J=7.2Hz),7.07−7.19(5H,m),7.24(1H,s),7.38−7.43(2H,m),7.56(1H,d,J=7.7Hz),8.38(1H,J=7.1Hz).
(2R)−2−アミノ−3−(1−イソプロピル−1H−インドール−3−イル)−N−[2−オキソ−8−(2−オキソピロリジン−1−イル)−1−(チオフェン−3−イルメチル)−1,2,3,4−テトラヒドロキノリン−3−イル]プロパンアミドの合成
MS(FAB)m/z570(M+H)+
1H−NMR(400MHz,DMSO−d6,80℃):δ(ppm)1.44(3H,d,J=6.5Hz),1.44(3H,d,J=6.5Hz),1.80−2.17(4H,m),2.22−2.38(2H,m),2.64(1H,t,J=14.5Hz),2.76−2.95(2H,m),3.13(1H,dd,J=5.0,14.5Hz),3.30−3.42(1H,m),3.54−3.64(1H,m),3.68−3.80(1H,m),4.30−4.42(1H,m),4.58(1H,d,J=15.5Hz),4.62−4.72(1H,m),5.15(1H,d,J=15.5Hz),6.78(1H,d,J=5.0Hz),6.93−7.20(6H,m),7.24−7.34(2H,m),7.41(1H,d,J=8.0Hz),7.55(1H,d,J=8.0Hz),7.98−8.15(1H,m).
(2R)−2−アミノ−3−(1H−インドール−3−イル)−N−[2−オキソ−8−(2−オキソピロリジン−1−イル)−1−(チオフェン−3−イルメチル)−1,2,3,4−テトラヒドロキノリン−3−イル]プロパンアミドの合成
MS(FAB)m/z528(M+H)+
1H−NMR(400MHz,DMSO−d6,80℃):δ(ppm)1.65−2.07(4H,m),2.23−2.39(2H,m),2.67(1H,t,J=14.5Hz),2.82(1H,dd,J=8.0,14.0Hz),2.94(1H,dd,J=5.0,14.5Hz),3.14(1H,dd,J=5.0,14.5Hz),3.33−3.42(1H,m),3.59(1H,dd,J=2.0,8.0Hz),3.70−3.79(1H,m),4.38(1H,dd,J=5.0,13.5Hz),4.58(1H,d,J=15.5Hz),5.16(1H,d,J=15.5Hz),6.79(1H,dd,J=1.0,5.0Hz),6.93−7.19(7H,m),7.28−7.36(2H,m),7.54(1H,d,J=8.0Hz),8.10(1H,br s),10.58(1H,br s).
N−(8−アミノ−2−オキソ−1,2,3,4−テトラヒドロキノリン−3−イル)アセトアミドの合成
MS(FAB)m/z220(M+H)+
1H−NMR(400MHz,DMSO−d6):δ(ppm)1.90(3H,s),2.73−2.93(2H,m),4.33−4.43(1H,m),5.06(2H,s),6.42(1H,d,J=7.5Hz),6.55(1H,d,J=7.5Hz),6.70(1H,d,J=7.5Hz),8.16(1H,d,J=8.0Hz),9.54(1H,s).
3,8−ジアミノ−3,4−ジヒドロキノリン−2(1H)−オン 二塩酸塩の合成
MS(FAB)m/z178(M+H)+
1H−NMR(400MHz,DMSO−d6):δ(ppm)3.06−3.25(2H,m),4.15−4.27(1H,m),6.93−7.01(2H,m),7.03−7.11(1H,m),7.45−8.20(3H,br),8.62−8.78(3H,m),10.43(1H,s).
(2R)−2−アミノ−N−(8−アミノ−2−オキソ−1,2,3,4−テトラヒドロキノリン−3−イル)−4−メチルペンタンアミドの合成
低極性側ジアステレオマー:
MS(FAB)m/z291(M+H)+
1H−NMR(400MHz,DMSO−d6):δ(ppm)0.87(3H,d,J=6.5Hz),0.91(3H,d,J=6.5Hz),1.22−1.31(1H,m),1.43−1.52(1H,m),1.72−1.90(3H,m),2.76(1H,t,J=14.5Hz),3.00(1H,dd,J=6.0,15.0Hz),3.21(1H,dd,J=4.5,9.5Hz),4.29(1H,dt,J=6.0,15.0Hz),5.07(2H,s),6.43(1H,d,J=7.5Hz),6.55(1H,d,J=7.5Hz),6.71(1H,t,J=7.5Hz),8.34(1H,d,J=7.0Hz),9.60(1H,s).
高極性側ジアステレオマー:
MS(FAB)m/z291(M+H)+
1H−NMR(400MHz,DMSO−d6):δ(ppm)0.87(3H,d,J=6.5Hz),0.89(3H,d,J=6.5Hz),1.21−1.30(1H,m),1.43−1.51(1H,m),1.70−1.88(3H,m),2.78(1H,t,J=14.5Hz),2.99(1H,dd,J=6.0,15.0Hz),3.24(1H,dd,J=4.5,9.5Hz),4.26−4.35(1H,m),5.07(2H,s),6.43(1H,d,J=7.5Hz),6.55(1H,d,J=7.5Hz),6.70(1H,t,J=7.5Hz),8.32(1H,d,J=7.0Hz),9.60(1H,s).
(2R)−1−(8−アミノ−2−オキソ−1,2,3,4−テトラヒドロキノリン−3−イルアミノ)−4−メチル−1−オキソペンタン−2−イルカルバミン酸 tert−ブチルの合成
MS(FAB)m/z391(M+H)+
1H−NMR(400MHz,DMSO−d6):δ(ppm)0.87(3H,d,J=6.5Hz),0.88(3H,d,J=6.5Hz),1.39(9H,s),1.41−1.50(2H,m),1.56−1.68(1H,m),2.72−2.82(1H,m),2.91(1H,dd,J=6.0,15.0Hz),4.03−4.12(1H,m),4.29−4.38(1H,m),5.07(2H,s),6.42(1H,d,J=7.5Hz),6.55(1H,d,J=7.5Hz),6.70(1H,t,J=7.5Hz),6.96(1H,d,J=8.5Hz),8.05(1H,d,J=7.5Hz),9.59(1H,s).
(2R)−1−[8−(4−クロロブタンアミド)−2−オキソ−1,2,3,4−テトラヒドロキノリン−3−イルアミノ]−4−メチル−1−オキソペンタン−2−イルカルバミン酸 tert−ブチルの合成
MS(FAB)m/z496(M+H)+
1H−NMR(400MHz,DMSO−d6):δ(ppm)0.87(3H,d,J=6.5Hz),0.88(3H,d,J=6.5Hz),1.39(9H,s),1.42−1.52(2H,m),1.56−1.69(1H,m),1.98−2.08(2H,m),2.48−2.56(2H,m),2.83−2.94(1H,m),3.04(1H,dd,J=6.0,15.0Hz),3.71(2H,t,J=6.5Hz),4.04−4.14(1H,m),4.35−4.45(1H,m),6.93(1H,d,J=8.0Hz),6.95(1H,d,J=8.0Hz),7.06(1H,d,J=7.5Hz),7.33(1H,d,J=8.0Hz),8.13(1H,d,J=7.5Hz),9.37(1H,s),9.73(1H,s).
(2R)−4−メチル−1−オキソ−1−[2−オキソ−8−(2−オキソピロリジン−1−イル)−1,2,3,4−テトラヒドロキノリン−3−イルアミノ]ペンタン−2−イルカルバミン酸 tert−ブチルの合成
MS(FAB)m/z459(M+H)+
1H−NMR(400MHz,DMSO−d6):δ(ppm)0.87(3H,d,J=6.5Hz),0.88(3H,d,J=6.5Hz),1.39(9H,s),1.42−1.50(2H,m),1.56−1.70(1H,m),2.08−2.18(2H,m),2.40(2H,t,J=8.0Hz),2.90(1H,t,J=15.0Hz),3.06(1H,dd,J=6.0,15.0Hz),3.56−3.74(2H,m),4.04−4.13(1H,m),4.36−4.46(1H,m),6.92−7.03(2H,m),7.12(1H,d,J=7.5Hz),7.18(1H,d,J=7.5Hz),8.13(1H,d,J=7.5Hz),9.81(1H,s).
(2R)−4−メチル−1−オキソ−1−[2−オキソ−8−(2−オキソピロリジン−1−イル)−1−(ピリジン−2−イルメチル)−1,2,3,4−テトラヒドロキノリン−3−イルアミノ]ペンタン−2−イルカルバミン酸tert−ブチルの合成
MS(FAB)m/z550(M+H)+
1H−NMR(400MHz,DMSO−d6):δ(ppm)0.86(3H,d,J=6.5Hz),0.87(3H,d,J=6.5Hz),1.37(9H,s),1.40−1.50(2H,m),1.55−1.67(1H,m),1.72−1.86(1H,m),1.90−2.14(2H,m),2.20−2.36(1H,m),2.93−3.10(2H,m),3.20−3.52(2H,m),3.88−4.14(1H,m),4.32−5.20(3H,m),7.00(1H,d,J=8.5Hz),7.06−7.33(5H,m),7.63−7.75(1H,m),8.14(1H,d,J=7.0Hz),8.39−8.48(1H,m).
(2R)−2−アミノ−4−メチル−N−[2−オキソ−8−(2−オキソピロリジン−1−イル)−1−(ピリジン−2−イルメチル)−1,2,3,4−テトラヒドロキノリン−3−イル]ペンタンアミドの合成
MS(FAB)m/z450(M+H)+
1H−NMR(400MHz,DMSO−d6,80℃):δ(ppm)0.87(3H,d,J=6.5Hz),0.89(3H,d,J=6.5Hz),1.24−1.33(1H,m),1.46−1.56(1H,m),1.60−1.98(5H,m),2.12−2.29(2H,m),2.95−3.13(2H,m),3.22−3.44(2H,m),3.67−3.78(1H,m),4.45(1H,dd,J=6.0,13.0Hz),4.75(1H,d,J=16.5Hz),5.14(1H,d,J=16.5Hz),7.07−7.23(5H,m),7.64(1H,dt,J=2.0,7.5Hz),8.00−8.22(1H,br),8.40(1H,d,J=4.5Hz).
2−メチル−1−[(2R)−4−メチル−1−オキソ−1−[2−オキソ−8−(2−オキソピロリジン−1−イル)−1−(チオフェン−3−イルメチル)−1,2,3,4−テトラヒドロキノリン−3−イルアミノ]ペンタン−2−イルアミノ]−1−オキソプロパン−2−イルカルバミン酸 tert−ブチルの合成
MS(FAB)m/z640(M+H)+
1H−NMR(400MHz,DMSO−d6):δ(ppm)0.85(3H,d,J=6.5Hz),0.87(3H,d,J=6.5Hz),1.33(3H,s),1.35(3H,s),1.37(9H,s),1.49−1.72(3H,m),1.81−2.06(2H,m),2.23−2.39(2H,m),2.77(1H,t,J=14.5Hz),2.92(1H,dd,J=5.0,14.5Hz),3.31−3.40(1H,m),3.68−3.79(1H,m),4.30−4.45(2H,m),4.58(1H,d,J=15.5Hz),5.16(1H,d,J=15.5Hz),6.56(1H,br s),6.73−6.80(1H,m),6.98−7.19(4H,m),7.27−7.36(2H,m),7.83(1H,d,J=7.0Hz).
2−メチル−1−[(2R)−3−(1−メチル−1H−インドール−3−イル)−1−オキソ−1−[2−オキソ−8−(2−オキソピロリジン−1−イル)−1−(チオフェン−3−イルメチル)−1,2,3,4−テトラヒドロキノリン−3−イルアミノ]プロパン−2−イルアミノ]−1−オキソプロパン−2−イルカルバミン酸 tert−ブチルの合成
MS(FAB)m/z727(M+H)+
1H−NMR(400MHz,DMSO−d6):δ(ppm)1.25(6H,d,J=5.0Hz),1.31(9H,s),1.81−2.42(4H,m),2.61−2.79(2H,m),3.05−3.18(2H,m),3.22−3.55(3H,m),3.72(3H,s),4.29−5.36(4H,m),6.73−6.81(1H,m),6.98−7.21(8H,m),7.35−7.42(2H,m),7.56(1H,d,J=7.0Hz),8.18(1H,br).
1−[(2R)−3−(1−エチル−1H−インドール−3−イル)−1−オキソ−1−[2−オキソ−8−(2−オキソピロリジン−1−イル)−1−(チオフェン−3−イルメチル)−1,2,3,4−テトラヒドロキノリン−3−イルアミノ]プロパン−2−イルアミノ]−2−メチル−1−オキソプロパン−2−イルカルバミン酸 tert−ブチルの合成
MS(FAB)m/z741(M+H)+
1H−NMR(400MHz,DMSO−d6):δ(ppm)1.23(3H,s),1.25(3H,s),1.27−1.35(12H,m),1.80−2.42(4H,m),2.57−2.78(2H,m),3.05−3.16(2H,m),3.25−3.61(2H,m),4.13(2H,q,J=7.0Hz),4.32−5.29(4H,m),6.76(1H,d,J=4.0Hz),6.98−7.23(8H,m),7.37−7.43(2H,m),7.55(2H,d,J=8.0Hz),8.16(1H,br).
1−[(2R)−3−[1−(2−フルオロエチル)−1H−インドール−3−イル]−1−オキソ−1−[2−オキソ−8−(2−オキソピロリジン−1−イル)−1−(チオフェン−3−イルメチル)−1,2,3,4−テトラヒドロキノリン−3−イルアミノ]プロパン−2−イルアミノ]−2−メチル−1−オキソプロパン−2−イルカルバミン酸 tert−ブチルの合成
MS(FAB)m/z759(M+H)+
1H−NMR(400MHz,DMSO−d6,80℃):δ(ppm)1.28(3H,s),1.29(3H,s),1.32(9H,s),1.81−2.06(2H,m),2.22−2.39(2H,m),2.55−2.70(1H,m),3.06−3.20(2H,m),3.31−3.39(1H,m),3.67−3.80(1H,m),4.32−4.46(3H,m),4.51−4.67(3H,m),4.75(1H,t,J=5.0Hz),5.16(1H,d,J=15.5Hz),6.58(1H,s),6.76(1H,dd,J=1.0,5.0Hz),6.97−7.22(7H,m),7.27−7.35(2H,m),7.40(1H,d,J=8.0Hz),7.57(1H,d,J=8.0Hz),7.79(1H,d,J=7.5Hz).
2−メチル−1−オキソ−1−[(2R)−1−オキソ−1−[2−オキソ−8−(2−オキソピロリジン−1−イル)−1−(チオフェン−3−イルメチル)−1,2,3,4−テトラヒドロキノリン−3−イルアミノ]−3−(1−プロピル−1H−インドール−3−イル)プロパン−2−イルアミノ]プロパン−2−イルカルバミン酸tert−ブチルの合成
MS(FAB)m/z755(M+H)+
1H−NMR(400MHz,DMSO−d6,80℃):δ(ppm)0.85(3H,t,J=7.0Hz),1.27(3H,s),1.29(3H,s),1.33(9H,s),1.71−1.81(2H,m),1.83−2.06(2H,m),2.23−2.39(2H,m),2.55−2.70(2H,m),3.05−3.19(2H,m),3.31−3.40(1H,m),3.69−3.79(1H,m),4.04(2H,t,J=5.0Hz),4.31−4.41(1H,m),4.51−4.65(2H,m),5.16(1H,d,J=15.5Hz),6.76(1H,dd,J=1.5,5.0Hz),6.69(2H,m),7.05−7.21(5H,m),7.26−7.41(3H,m),7.55(1H,d,J=8.0Hz),7.79(1H,d,J=7.5Hz).
1−[(2R)−3−(1−イソプロピル−1H−インドール−3−イル)−1−オキソ−1−[2−オキソ−8−(2−オキソピロリジン−1−イル)−1−(チオフェン−3−イルメチル)−1,2,3,4−テトラヒドロキノリン−3−イルアミノ]プロパン−2−イルアミノ]−2−メチル−1−オキソプロパン−2−イルカルバミン酸 tert−ブチルの合成
MS(FAB)m/z755(M+H)+
1H−NMR(400MHz,DMSO−d6,80℃):δ(ppm)1.27(3H,s),1.29(3H,s),1.33(9H,s),1.43(3H,d,J=6.5Hz),1.43(3H,d,J=6.5Hz),1.80−2.06(2H,m),2.23−2.39(2H,m),2.50−2.70(2H,m),3.05−3.20(2H,m),3.31−3.40(1H,m),3.68−3.80(1H,m),4.32−4.42(1H,m),4.55(1H,d,J=15.5Hz),4.58−4.72(2H,m),5.16(1H,d,J=15.5Hz),6.59(1H,br s),6.76(1H,dd,J=1.0,5.0Hz),6.95−7.02(2H,m),7.04−7.19(4H,m),7.25−7.34(3H,m),7.40(1H,d,J=8.5Hz),7.54(1H,d,J=8.0Hz),7.79(1H,d,J=7.5Hz).
(2R)−2−メチル−1−[(2R)−3−(1−メチル−1H−インドール−3−イル)−1−オキソ−1−[2−オキソ−8−(2−オキソピロリジン−1−イル)−1−(チオフェン−3−イルメチル)−1,2,3,4−テトラヒドロキノリン−3−イルアミノ]プロパン−2−イルアミノ]−1−オキソブタン−2−イルカルバミン酸 tert−ブチルの合成
MS(FAB)m/z741(M+H)+
1H−NMR(400MHz,DMSO−d6):δ(ppm)0.48(3H,t,J=7.5Hz),1.20(3H,s),1.31(9H,s),1.55−1.73(2H,m),1.80−2.43(4H,m),2.57−2.85(3H,m),3.03−3.38(3H,m),3.72(3H,s),4.32−4.76(3H,m),4.93−5.28(1H,m),6.72−6.88(2H,m),6.98−7.23(7H,m),7.37(1H,d,J=8.0Hz),7.39−7.44(1H,m),7.58(1H,d,J=8.0Hz),7.61−7.69(1H,m),8.12−8.24(1H,m).
2−メチル−1−[(2R)−4−メチル−1−オキソ−1−[2−オキソ−8−(2−オキソピロリジン−1−イル)−1−(ピリジン−2−イルメチル)−1,2,3,4−テトラヒドロキノリン−3−イルアミノ]ペンタン−2−イルアミノ]−1−オキソプロパン−2−イルカルバミン酸 tert−ブチルの合成
MS(FAB)m/z635(M+H)+
1H−NMR(400MHz,DMSO−d6):δ(ppm)0.82(3H,d,J=6.0Hz),0.85(3H,d,J=6.0Hz),1.27(3H,s),1.30(3H,s),1.35(9H,s),1.54−2.36(7H,m),2.95(1H,dd,J=5.0,14.5Hz),3.06(1H,t,J=14.5Hz),3.19−3.48(2H,m),4.24−5.16(4H,m),6.93−7.35(6H,m),7.38−7.78(2H,m),8.07−8.18(1H,m),8.40−8.48(1H,m).
(2R)−2−(2−アミノ−2−メチルプロパンアミド)−4−メチル−N−[2−オキソ−8−(2−オキソピロリジン−1−イル)−1−(チオフェン−3−イルメチル)−1,2,3,4−テトラヒドロキノリン−3−イル]ペンタンアミドの合成
MS(FAB)m/z540(M+H)+
1H−NMR(400MHz,DMSO−d6,80℃):δ(ppm)0.87(3H,d,J=6.5Hz),0.89(3H,d,J=6.5Hz),1.21(6H,s),1.49−2.09(7H,m),2.24−2.39(2H,m),2.77(1H,t,J=14.5Hz),2.94(1H,dd,J=5.0,14.5Hz),3.35−3.44(1H,m),3.70−3.80(1H,m),4.32−4.46(2H,m),4.59(1H,d,J=15.5Hz),5.16(1H,d,J=15.5Hz),6.79(1H,dd,J=1.0,5.0Hz),7.01−7.05(1H,m),7.10(1H,dd,J=6.5,8.5Hz),7.13−7.20(3H,m),7.32(1H,dd,J=3.0,5.0Hz),7.93(1H,d,J=7.0Hz).
2−アミノ−2−メチル−N−[(2R)−3−(1−メチル−1H−インドール−3−イル)−1−オキソ−1−[2−オキソ−8−(2−オキソピロリジン−1−イル)−1−(チオフェン−3−イルメチル)−1,2,3,4−テトラヒドロキノリン−3−イルアミノ]プロパン−2−イル]プロパンアミドの合成
MS(FAB)m/z627(M+H)+
1H−NMR(400MHz,DMSO−d6):δ(ppm)1.11(3H,s),1.15(3H,s),1.82−2.45(6H,m),2.54(1H,dd,J=5.5,10.0Hz),2.58−2.78(1H,m),3.03−3.18(1H,m),3.20−3.49(3H,m),3.73(3H,s),4.32−4.81(3H,m),4.96−5.29(1H,m),6.78(1H,d,J=5.0Hz),6.99−7.23(7H,m),7.34−7.41(2H,m),7.58(1H,d,J=8.0Hz),8.20(1H,d,J=7.0Hz),8.38(1H,d,J=8.0Hz).
2−アミノ−N−[(2R)−3−(1−エチル−1H−インドール−3−イル)−1−オキソ−1−[2−オキソ−8−(2−オキソピロリジン−1−イル)−1−(チオフェン−3−イルメチル)−1,2,3,4−テトラヒドロキノリン−3−イルアミノ]プロパン−2−イル]−2−メチルプロパンアミドの合成
MS(FAB)m/z641(M+H)+
1H−NMR(400MHz,DMSO−d6):δ(ppm)1.10(3H,s),1.14(3H,s),1.32(3H,t,J=7.0Hz),1.85−2.42(6H,m),2.55−2.69(2H,m),3.00−3.13(2H,m),3.25−3.60(2H,m),4.15(2H,q,J=7.0Hz),4.28−4.81(3H,m),4.95−5.27(1H,m),6.77(1H,d,J=5.0Hz),7.00(1H,t,J=7.0Hz),7.03−7.22(6H,m),7.38−7.43(2H,m),7.58(1H,d,J=8.0Hz),8.19(1H,br),8.35(1H,d,J=8.0Hz).
2−アミノ−N−[(2R)−3−[1−(2−フルオロエチル)−1H−インドール−3−イル]−1−オキソ−1−[2−オキソ−8−(2−オキソピロリジン−1−イル)−1−(チオフェン−3−イルメチル)−1,2,3,4−テトラヒドロキノリン−3−イルアミノ]プロパン−2−イル]−2−メチルプロパンアミドの合成
MS(FAB)m/z659(M+H)+
1H−NMR(400MHz,DMSO−d6,80℃):δ(ppm)1.11(3H,s),1.16(3H,s),1.79−2.08(4H,m),2.23−2.39(2H,m),2.59(1H,t,J=14.0Hz),2.71(1H,dd,J=5.0,15.0Hz),3.03−3.20(2H,m),3.31−3.42(1H,m),3.67−3.79(1H,m),4.30−4.48(3H,m),4.50−4.67(3H,m),4.69−4.78(1H,m),5.14(1H,d,J=15.5Hz),6.72−6.80(1H,m),6.93−7.21(8H,m),7.27−7.34(1H,m),7.40(1H,d,J=8.0Hz),7.58(1H,d,J=8.0Hz),7.84(1H,d,J=7.0Hz).
2−アミノ−2−メチル−N−[(2R)−1−オキソ−1−[2−オキソ−8−(2−オキソピロリジン−1−イル)−1−(チオフェン−3−イルメチル)−1,2,3,4−テトラヒドロキノリン−3−イルアミノ]−3−(1−プロピル−1H−インドール−3−イル)プロパン−2−イル]プロパンアミドの合成
MS(FAB)m/z655(M+H)+
1H−NMR(400MHz,DMSO−d6,80℃):δ(ppm)0.84(3H,t,J=7.5Hz),1.11(3H,s),1.16(3H,s),1.71−1.81(2H,m),1.82−2.06(4H,m),2.23−2.39(2H,m),2.58(1H,t,J=14.5Hz),2.71(1H,dd,J=5.0,14.5Hz),3.05−3.18(2H,m),3.32−3.41(1H,m),3.68−3.79(1H,m),4.05(2H,t,J=7.0Hz),4.34−4.41(1H,m),4.52−4.64(2H,m),5.14(1H,d,J=16.0Hz),6.77(1H,dd,J=1.0,5.0Hz),6.94−7.03(6H,m),7.30−7.39(2H,m),7.56(1H,d,J=8.0Hz),7.85(1H,d,J=7.0Hz).
2−アミノ−N−[(2R)−3−(1−イソプロピル−1H−インドール−3−イル)−1−オキソ−1−[2−オキソ−8−(2−オキソピロリジン−1−イル)−1−(チオフェン−3−イルメチル)−1,2,3,4−テトラヒドロキノリン−3−イルアミノ]プロパン−2−イル]−2−メチルプロパンアミドの合成
MS(FAB)m/z655(M+H)+
1H−NMR(400MHz,DMSO−d6,80℃):δ(ppm)1.12(3H,s),1.17(3H,s),1.43(3H,d,J=6.5Hz),1.43(3H,d,J=6.5Hz),1.81−2.06(4H,m),2.23−2.38(3H,m),2.52−2.75(2H,m),3.11(2H,dq,J=14.5,7.5Hz),3.33−3.42(1H,m),3.69−3.80(1H,m),4.32−4.42(1H,m),4.56(1H,d,J=15.5Hz),4.60−4.72(2H,m),5.15(1H,d,J=15.5Hz),6.76(1H,dd,J=1.0,5.0Hz),6.95−7.02(2H,m),7.05−7.18(4H,m),7.25(1H,s),7.32(1H,dd,J=3.0,5.0Hz),7.40(1H,d,J=8.5Hz),7.56(1H,d,J=8.0Hz),7.86(1H,d,J=7.0Hz).
(2R)−2−アミノ−2−メチル−N−[(2R)−3−(1−メチル−1H−インドール−3−イル)−1−オキソ−1−[2−オキソ−8−(2−オキソピロリジン−1−イル)−1−(チオフェン−3−イルメチル)−1,2,3,4−テトラヒドロキノリン−3−イルアミノ]プロパン−2−イル]ブタンアミドの合成
MS(FAB)m/z641(M+H)+
1H−NMR(400MHz,DMSO−d6):δ(ppm)0.56(3H,t,J=7.5Hz),1.09(3H,s),1.22−1.35(2H,m),1.51−1.63(1H,m),1.80−2.75(9H,m),2.98−3.12(2H,m),3.72(3H,s),4.28−4.77(3H,m),4.93−5.23(1H,m),6.78(1H,d,J=5.0Hz),6.97−7.22(7H,m),7.37(1H,d,J=8.0Hz),7.39−7.44(1H,m),7.60(1H,d,J=8.0Hz),8.12−8.24(1H,m),8.37(1H,d,J=8.0Hz).
(2R)−2−((S)−2−アミノプロパンアミド)−4−メチル−N−[2−オキソ−8−(2−オキソピロリジン−1−イル)−1−(チオフェン−3−イルメチル)−1,2,3,4−テトラヒドロキノリン−3−イル]ペンタンアミドの合成
MS(FAB)m/z526(M+H)+
1H−NMR(400MHz,DMSO−d6,80℃):δ(ppm)0.88(6H,dd,J=6.5,9Hz),1.14(3H,d,J=7Hz),1.54(2H,m),1.61(2H,m),1.9−2.0(2H,m),2.30(2H,m),2.78(1H,t,J=14Hz),2.91(1H,dd,J=5,15Hz),3.31(1H,m),3.39(1H,m),3.75(1H,br s),4.39(2H,m),4.59(1H,d,J=15.5Hz),5.16(1H,d,J=15.5Hz),6.80(1H,d,J=5Hz),7.03(1H,br s),7.12(1H,dd,J=7,8.5Hz),7.17(2H,m),7.33(1H,m),7.91(1H,d,J=7Hz).
(2R)−2−((R)−2−アミノプロパンアミド)−4−メチル−N−[2−オキソ−8−(2−オキソピロリジン−1−イル)−1−(チオフェン−3−イルメチル)−1,2,3,4−テトラヒドロキノリン−3−イル]ペンタンアミドの合成
MS(FAB)m/z526(M+H)+
1H−NMR(400MHz,DMSO−d6,80℃):δ(ppm)0.88(6H,t,J=7Hz),1.15(3H,d,J=14Hz),1.53(2H,m),1.61(1H,m),1.85−2.05(2H,m),2.30(2H,m),2.78(1H,t,J=14Hz),2.94(1H,dd,J=5,15Hz),3.30(1H,m),3.39(1H,m),4.40(2H,m),4.59(1H,d,J=15.5Hz),5.15(1H,d,J=15.5Hz),6.99(1H,d,J=5Hz),7.13(1H,br s),7.10(1H,m),7.16(1H,d,J=7Hz),7.33(1H,m),7.92(1H,d,J=7Hz).
(2R)−2−((S)−2−アミノ−2−メチルブタンアミド)−4−メチル−N−[2−オキソ−8−(2−オキソピロリジン−1−イル)−1−(チオフェン−3−イルメチル)−1,2,3,4−テトラヒドロキノリン−3−イル]ペンタンアミドの合成
MS(FAB)m/z554(M+H)+
1H−NMR(400MHz,DMSO−d6,80℃):δ(ppm)0.78(3H,t,J=7Hz),0.87(6H,d,J=6.5Hz),1.15(3H,s),1.44(1H,m),1.54(2H,m),1.63(3H,m),1.85−2.05(3H,m),2.30(2H,m),2.74(1H,t,J=14Hz),2.94(1H,dd,J=5,15Hz),3.38(1H,m),3.76(1H,m),4.38(2H,m),4.58(1H,d,J=15.5Hz),5.16(1H,d,J=15.5Hz),6.78(1H,d,J=5Hz),7.03(1H,br s),7.11(1H,m),7.18(2H,m),7.33(1H,m),7.91(1H,d,J=7Hz).
(2R)−2−((R)−2−アミノ−2−メチルブタンアミド)−4−メチル−N−[2−オキソ−8−(2−オキソピロリジン−1−イル)−1−(チオフェン−3−イルメチル)−1,2,3,4−テトラヒドロキノリン−3−イル]ペンタンアミドの合成
MS(FAB)m/z554(M+H)+
1H−NMR(400MHz,DMSO−d6,80℃):δ(ppm)0.79(3H,t,J=15Hz),0.88(6H,t,J=15Hz),1.16(3H,s),1.19(1H,d,J=14Hz),1.43(1H,m),1.54(2H,m),1.64(3H,m),1.85−2.05(3H,m),2.30(2H,m),2.77(1H,t,J=14Hz),2.94(1H,m),3.39(1H,m),3.75(1H,m),4.39(2H,m),4.58(1H,d,J=16Hz),5.16(1H,d,J=16Hz),6.79(1H,d,J=5Hz),7.13(1H,br s),7.10(1H,dd,J=6,9Hz),7.17(1H,d,J=7Hz),7.33(1H,dd,J=3,5Hz),7.95(1H,d,J=7Hz).
N−[(2R)−3−(1H−インドール−3−イル)−1−オキソ−1−[2−オキソ−8−(2−オキソピロリジン−1−イル)−1−(チオフェン−3−イルメチル)−1,2,3,4−テトラヒドロキノリン−3−イルアミノ]ペンタン−2−イル]−2−アミノ−2−メチルプロパンアミドの合成
MS(FAB)m/z613(M+H)+
1H−NMR(400MHz,DMSO−d6,80℃):δ(ppm)1.10(3H,s),1.16(3H,s),1.31−2.02(4H,m),2.26−2.34(2H,m),2.59(1H,dd,J=13.0Hz),2.72(1H,dd,J=5.0,10.0Hz),3.08−3.18(2H,m),3.34−3.40(1H,m),3.73−3.74(1H,m),4.34−4.40(1H,m),4.54−4.62(2H,m),5.14(1H,d,J=15.5Hz),6.76(1H,d,J=5.0Hz),6.93−7.17(7H,m),7.31−7.33(2H,m),7.54(1H,d,J=8.0Hz),7.84(1H,d,J=7.0Hz),8.20(1H,s),10.16(1H,s).
(2R)−2−(2−アミノ−2−メチルプロパンアミド)−4−メチル−N−[2−オキソ−8−(2−オキソピロリジン−1−イル)−1−(ピリジン−2−イルメチル)−1,2,3,4−テトラヒドロキノリン−3−イル]ペンタンアミドの合成
MS(FAB)m/z535(M+H)+
1H−NMR(400MHz,DMSO−d6):δ(ppm)0.87(3H,d,J=6.5Hz),0.89(3H,d,J=6.5Hz),1.17(3H,s),1.17(3H,s),1.43−1.63(3H,m),1.70−2.34(6H,m),2.94(1H,dd,J=5.0,14.5Hz),3.07(1H,t,J=14.5Hz),3.15−3.52(2H,m),4.15−5.20(4H,m),7.03−7.35(5H,m),7.63−7.75(1H,m),7.98−8.14(1H,m),8.40−8.53(2H,m).
1−(1−(8−アミノ−2−オキソ−1,2,3,4,−テトラヒドロキノリン−3−イルアミノ)−4−メチル−1−オキソペンタン−2−イルアミノ)−2−メチル−1−オキソプロパン−2−イルカルバミン酸 tert−ブチルの合成
MS(FAB)m/z476(M+H)+
1H−NMR(400MHz,DMSO−d6):δ(ppm)0.83(3H,d,J=6.5Hz),0.86(3H,d,J=6.5Hz),1.28(3H,s),1.30(3H,s),1.36(9H,s),1.43−1.69(3H,m),2.76−2.88(2H,m),4.29−4.40(2H,m),5.05(2H,s),6.42(1H,d,J=7.0Hz),6.54(1H,d,J=7.0Hz),6.69(1H,t,J=8.0Hz),7.04(1H,br),7.61(1H,d,J=6.0Hz),8.01(1H,d,J=5.0Hz),8.31(1H,s).
1−[(2R)−1−[8−(4−クロロブタンアミド)−2−オキソ−1,2,3,4−テトラヒドロキノリン−3−イルアミノ]−4−メチル−1−オキソペンタン−2−イルアミノ]−2−メチル−1−オキソペンタン−2−イルカルバミン酸 tert−ブチルの合成
MS(FAB)m/z581(M+H)+
1H−NMR(400MHz,DMSO−d6):δ(ppm)0.83(3H,d,J=6.5Hz),0.87(3H,d,J=6.5Hz),1.29(3H,s),1.31(3H,s),1.36(9H,s),1.44−1.72(3H,m),1.98−2.08(2H,m),2.48−2.58(2H,m),2.85−3.06(2H,m),3.71(2H,t,J=6.5Hz),4.24−4.48(2H,m),6.94(1H,t,J=7.5Hz),6.98−7.15(2H,m),7.32(1H,d,J=8.0Hz),7.52−7.69(1H,m),8.02−8.20(1H,m),9.35(1H,s),9.69(1H,s).
2−メチル−1−[(2R)−4−メチル−1−オキソ−1−[2−オキソ−8−(2−オキソピロリジン−1−イル)−1,2,3,4−テトラヒドロキノリン−3−イルアミノ]ペンタン−2−イルアミノ]−1−オキソペンタン−2−イルカルバミン酸 tert−ブチルの合成
MS(FAB)m/z544(M+H)+
1H−NMR(400MHz,DMSO−d6):δ(ppm)0.83(3H,d,J=6.0Hz),0.87(3H,d,J=6.0Hz),1.28(3H,s),1.31(3H,s),1.36(9H,s),1.44−1.72(3H,m),2.08−2.19(2H,m),2.40(2H,t,J=8.0Hz),2.92(1H,t,J=15.0Hz),3.01(1H,dd,J=6.5,15.0Hz),3.55−3.74(2H,m),4.25−4.48(2H,m),6.99(1H,t,J=8.0Hz),7.06(1H,br s),7.11(1H,d,J=8.0Hz),7.18(1H,d,J=8.0Hz),7.52−7.71(1H,m),8.00−8.16(1H,m),9.77(1H,s).
2−メチル−1−[(2R)−4−メチル−1−オキソ−1−[2−オキソ−8−(2−2−オキソピロリジン−1−イル)−1−(チオフェン−2−イルメチル)−1,2,3,4−テトラヒドロキノリン−3−イルアミノ]ペンタン−2−イルアミノ]−1−オキソペンタン−2−イルカルバミン酸 tert−ブチルの合成
MS(FAB)m/z640(M+H)+
1H−NMR(400MHz,DMSO−d6):δ(ppm)0.83(3H,d,J=6.0Hz),0.86(3H,d,J=6.0Hz),1.29(3H,s),1.31(3H,s),1.35(9H,s),1.40−1.72(3H,m),1.74−2.48(4H,m),2.65−2.79(1H,m),2.82−2.88(1H,m),3.23−3.75(2H,m),4.25−4.82(3H,m),5.30−5.61(1H,m),6.77(1H,br s),6.82−6.88(1H,m),6.93−7.08(1H,br s),7.13(1H,t,J=7.5Hz),7.22(2H,t,J=7.5Hz),7.32(1H,d,J=5.0Hz),7.53−7.71(1H,m),8.10−8.25(1H,m).
(2R)−2−(2−アミノ−2−メチルプロパンアミド)−4−メチル−N−[2−オキソ−8−(2−オキソピロリジン−1−イル)−1−(チオフェン−2−イルメチル)−1,2,3,4−テトラヒドロキノリン−3−イル]ペンタンアミドの合成
MS(FAB)m/z640(M+H)+
1H−NMR(400MHz,DMSO−d6):δ(ppm)0.87(3H,d,J=6.0Hz),0.89(3H,d,J=6.0Hz),1.19(6H,s),1.43−1.67(3H,m),1.68−2.28(4H,m),2.29−2.50(2H,m),2.73(1H,t,J=14.5Hz),2.86(1H,dd,J=5.0,14.5Hz),3.20−3.80(2H,m),4.32−4.90(3H,m),5.18−5.61(1H,m),6.78(1H,br s),6.84−6.91(1H,m),7.13(1H,t,J=7.5Hz),7.17−7.29(2H,m),7.33(1H,d,J=5.0Hz),7.96−8.18(1H,br s),8.49(1H,d,J=7.5Hz).
1−((2R)−1(8−アミノ−2−オキソ−1−(ピリジン−2−イルメチル)−1,2,3,4−テトラヒドロキノリン−3−イルアミノ)−4−メチル−1−オキソペンタン−2−イルアミノ)−2−メチル−1−オキソプロパン−2−イルカルバミン酸 tert−ブチルの合成
MS(FAB)m/z567(M+H)+
1H−NMR(400MHz,DMSO−d6):δ(ppm)0.80(3H,d,J=6.5Hz),0.83(3H,d,6.5Hz),1.25(3H,s),1.28(3H,s),1.34(9H,s),1.40−1.45(1H,m),1.50−1.66(2H,m),2.72(1H,dd,J=5.0,10.0Hz),2.94(1H,t,J=14.0Hz),4.24−4.33(2H,m),4.95(1H,d,J=15.5Hz),5.06(1H,d,J=15.5Hz),5.51(2H,s),6.51(1H,d,J=7.5Hz),6.66(1H,d,J=8.0Hz),6.82(1H,t,J=8.0Hz),6.99(1H,br),7.23(1H,dd,J=2.0,5.0Hz),7.31(1H,d,J=8.0Hz),7.53−7.61(1H,m),7.71−7.75(1H,m),7.98−8.03(1H,m),8.44(1H,d,J=10.0Hz).
1−((2R)−1−(8−(エチルアミノ)−2−オキソ−1−(ピリジン−2−イルメチル)−1,2,3,4−テトラヒドロキノリン−3−イルアミノ)−4−メチル−1−オキソペンタン−2−イルアミノ)−2−メチル−1−オキソプロパン−2−イルカルバミン酸 tert−ブチルの合成
MS(FAB)m/z595(M+H)+
1H−NMR(400MHz,DMSO−d6):δ(ppm)0.79(3H,d,J=6.5Hz),0.83(3H,d,J=6.5Hz),1.10(3H,t,J=7.0Hz),1.25(3H,s),1.28(3H,s),1.35(9H,s),1.39−1.45(1H,m),1.50−1.66(2H,m),2.74(1H,dd,J=5.0,10.0Hz),2.88−3.10(3H,m),4.22−4.32(2H,m),4.89(2H,s),6.35(1H,br),6.56(1H,d,J=7.5Hz),6.61(1H,d,J=8.0Hz),6.92−7.03(2H,m),7.27(1H,dd,J=2.0,5.0Hz),7.35(1H,d,J=8.0Hz),7.55−7.62(1H,m),7.74−7.80(1H,m),7.96−8.03(1H,m),8.48(1H,d,J=4.0Hz).
(2R)−2−(2−アミノ−2−メチルプロパンアミド)−N−(8−(エチルアミノ)−2−オキソ−1−(ピリジン−2−イルメチル))−1,2,3,4−テトラヒドロキノリン−3−イル)−4−メチルペンタンアミドの合成
MS(FAB)m/z495(M+H)+
1H−NMR(400MHz,DMSO−d6):δ(ppm)0.85(3H,d,J=7.0Hz),0.87(3H,d,J=7.0Hz),1.10(3H,t,J=7.0Hz),1.15(3H,s),1.17(3H,s),1.43−1.59(3H,m),1.98−2.05(2H,m),2.74(1H,dd,J=5.0,10.0Hz),2.91−3.11(3H,m),4.29−4.42(2H,m),4.92(2H,s),6.28−6.35(1H,m),6.56(1H,d,J=7.5Hz),6.61(1H,d,J=8.0Hz),6.98(1H,t,J=7.5Hz),7.27(1H,dd,J=2.0,5.0Hz),7.37(1H,d,J=8.0Hz),7.73−7.80(1H,m),8.03(1H,br),8.32(1H,t,J=4.0Hz),8.47(1H,d,J=4.5Hz).
(2R)−2−(2−アミノ−2−メチルプロパンアミド)−4−メチル−N−[2−オキソ−8−(2−オキソピロリジン−1−イル)−1−(チオフェン−3−イルメチル)−1,2,3,4−テトラヒドロキノリン−3−イル]ペンタンアミド 塩酸塩の合成
1H−NMR(400MHz,DMSO−d6,80℃):δ(ppm)0.88(3H,d,J=6.0Hz),0.91(3H,d,J=6.0Hz),1.53−1.70(9H,m),1.90−2.06(2H,m),2.25−2.39(2H,m),2.80(1H,t,J=14.5Hz),2.94(1H,dd,J=5.0,14.5Hz),3.37−3.43(1H,m),3.77−3.79(1H,m),4.38−4.49(2H,m),4.58(1H,d,J=16.0Hz),5.17(1H,d,J=16.0Hz),6.79−6.80(1H,m),7.04−7.19(4H,m),7.32−7.34(1H,m),7.98(1H,d,J=7.0Hz),8.10−8.25(3H,m).
2−アミノ−2−メチル−N−[(2R)−3−(1−メチル−1H−インドール−3−イル)−1−オキソ−1−[2−オキソ−8−(2−オキソピロリジン−1−イル)−1−(チオフェン−3−イルメチル)−1,2,3,4−テトラヒドロキノリン−3−イルアミノ]プロパン−2−イル]プロパンアミド 塩酸塩の合成
1H−NMR(400MHz,DMSO−d6,80℃):δ(ppm)1.36(3H,s),1.51(3H,s),1.89−2.04(2H,m),2.24−2.38(2H,m),2.69(1H,t,J=14.0Hz),2.80(1H,dd,J=5.0,10.0Hz),3.10(1H,dd,J=5.0,9.0Hz),3.23(1H,dd,J=5.5,9.0Hz),3.38−3.42(1H,m),3.71(3H,s),3.76−3.78(1H,m),4.36−4.43(1H,m),4.58(1H,d,J=15.5Hz),4.65−4.71(1H,m),5.17(1H,d,J=15.5Hz),6.79(1H,d,J=5.0Hz),6.98−7.03(2H,m),7.09−7.19(5H,m),7.32−7.35(2H,m),7.64(1H,d,J=8.0Hz),8.05(1H,d,J=5.0Hz),8.15(3H,s),8.28(1H,d,J=8.0Hz).
2−アミノ−N−[(2R)−3−(1−エチル−1H−インドール−3−イル)−1−オキソ−1−[2−オキソ−8−(2−オキソピロリジン−1−イル)−1−(チオフェン−3−イルメチル)−1,2,3,4−テトラヒドロキノリン−3−イルアミノ]プロパン−2−イル]−2−メチルプロパンアミド 塩酸塩の合成
1H−NMR(400MHz,DMSO−d6):δ(ppm)1.26−1.36(6H,m),1.47(3H,s),1.82−2.41(4H,m),2.69−2.81(2H,m),3.03(1H,dd,J=10.5Hz,14.0Hz),3.18(1H,dd,J=5.0,14.0Hz),3.40−3.53(2H,m),4.09−4.20(2H,m),4.33−4.82(3H,m),5.00−5.22(1H,m),6.80(1H,d,J=4.5Hz),7.01(1H,t,J=7.5Hz),7.06−7.26(6H,m),7.40−7.46(2H,m),7.76(1H,d,J=8.0Hz),8.04(3H,s),8.50(1H,d,J=8.5Hz),8.64(1H,d,J=8.0Hz).
2−アミノ−N−[(2R)−3−[1−(2−フルオロエチル)−1H−インドール−3−イル]−1−オキソ−1−[2−オキソ−8−(2−オキソピロリジン−1−イル)−1−(チオフェン−3−イルメチル)−1,2,3,4−テトラヒドロキノリン−3−イルアミノ]プロパン−2−イル]−2−メチルプロパンアミド 塩酸塩の合成
1H−NMR(400MHz,DMSO−d6,80℃):δ(ppm)1.35(3H,s),1.49(3H,s),1.82−2.08(2H,m),2.23−2.38(2H,m),2.61−2.71(1H,m),2.79(1H,dd,J=5.0,15.0Hz),3.02−3.29(2H.m),3.34−3.58(1H,m),3.72−3.85(1H,m),4.33−4.49(3H,m),4.52−4.66(2H,m),4.67−4.78(2H,m),5.17(1H,d,J=15.5Hz),6.74−6.81(1H,m),7.03(2H,t,J=7.0Hz),7.06−7.22(5H,m),7.30−7.36(1H,m),7.41(1H,d,J=8.0Hz),7.67(1H,d,J=8.0Hz),7.92−8.09(4H,m),8.20(1H,d,J=8.0Hz).
2−アミノ−2−メチル−N−[(2R)−1−オキソ−1−[2−オキソ−8−(2−オキソピロリジン−1−イル)−1−(チオフェン−3−イルメチル)−1,2,3,4−テトラヒドロキノリン−3−イルアミノ]−3−(1−プロピル−1H−インドール−3−イル)プロパン−2−イル]プロパンアミド 塩酸塩の合成
1H−NMR(400MHz,DMSO−d6,80℃):δ(ppm)0.86(3H,t,J=7.5Hz),1.35(3H,s),1.50(3H,s),1.71−1.81(2H,m),1.83−2.09(2H,m),2.23−2.39(2H,m),2.65(1H,t,J=14.0Hz),2.78(1H,dd,J=5.0,15.0Hz),3.01−3.28(2H,m),3.33−3.45(1H,m),3.71−3.86(1H,m),4.00−4.08(2H,m),4.37−4.47(1H,m),4.57(1H,d,J=15.5Hz),4.67−4.76(1H,m),5.17(1H,d,J=15.5Hz),6.74−6.81(1H,m),6.95−7.04(2H,m),7.05−7.23(5H,m),7.29−7.40(2H,m),7.64(1H,d,J=8.0Hz),7.95−8,14(4H,m),8.21(1H,d,J=8.0Hz).
2−アミノ−N−[(2R)−3−(1−イソプロピル−1H−インドール−3−イル)−1−オキソ−1−[2−オキソ−8−(2−オキソピロリジン−1−イル)−1−(チオフェン−3−イルメチル)−1,2,3,4−テトラヒドロキノリン−3−イルアミノ]プロパン−2−イル]−2−メチルプロパンアミド 塩酸塩の合成
1H−NMR(400MHz,DMSO−d6,80℃):δ(ppm)1.33(3H,s),1.39−1.49(9H,m),1.83−2.08(2H,m),2.23−2.40(2H,m),2.56−2.69(1H,m),2.76(1H,dd,J=5.0,15.0Hz),3.04−3.14(1H,m),3.18−3.26(1H,m),3.34−3.49(1H,m),3.51−3.86(1H,m),4.35−4.47(1H,m),4.57(1H,d,J=15.5Hz),4.62−4.76(2H,m),5.17(1H,d,J=15.5Hz),6.74−6.80(1H,m),6.96−7.03(2H,m),7.06−7.22(4H,m),7.29(1H,s),7.31−7.36(1H,m),7.41(1H,d,J=8.0Hz),7.47−7.76(4H,m),8.02(1H,d,J=7.0Hz),8.06−8.27(1H,m).
(2R)−2−((R)−2−アミノプロパンアミド)−4−メチル−N−[2−オキソ−8−(2−オキソピロリジン−1−イル)−1−(チオフェン−3−イルメチル)−1,2,3,4−テトラヒドロキノリン−3−イル]ペンタンアミド 塩酸塩の合成
1H−NMR(400MHz,DMSO−d6,80℃):δ(ppm)0.90(6H,t,J=6.5Hz),1.38(3H,d,J=7Hz),1.54(2H,m),1.67(1H,m),1.9−2.0(2H,m),2.30(2H,m),2.78(1H,t,J=15Hz),2.91(1H,m),3.40(1H,m),3.77(1H,m),3.88(1H,m),4.45(2H,m),4.58(1H,d,J=15.5Hz),5.16(1H,d,J=15.5Hz),6.80(1H,d,J=5Hz),7.03(1H,br s),7.09−7.20(3H,m),7.34(1H,m),7.83−8.07(4H,m),8.29(1H,br s).
(2R)−2−((R)−2−アミノ−2−メチルブタンアミド)−4−メチル−N−[2−オキソ−8−(2−オキソピロリジン−1−イル)−1−(チオフェン−3−イルメチル)−1,2,3,4−テトラヒドロキノリン−3−イル]ペンタンアミド 塩酸塩の合成
1H−NMR(400MHz,DMSO−d6):δ(ppm)0.82−0.93(9H,m),1.47(3H,s),1.50(1H,m),1.64(2H,m),1.75(1H,m),2.05(1H,m),2.30(2H,br s),2.83(2H,m),4.50(1H,br s),4.54(2H,br s),6.80(1H,d,J=5Hz),7.09(1H,br s),7.14(1H,m),7.23(1H,m),7.42(1H,m),8.08(2H,br s),8.36(1H,d,J=8Hz),8.45(1H,d,J=6.5Hz).
(2R)−2−アミノ−2−メチル−N−[(2R)−3−(1−メチル−1H−インドール−3−イル)−1−オキソ−1−[2−オキソ−8−(2−オキソピロリジン−1−イル)−1−(チオフェン−3−イルメチル)−1,2,3,4−テトラヒドロキノリン−3−イルアミノ]プロパン−2−イル]ブタンアミド 塩酸塩の合成
1H−NMR(400MHz,DMSO−d6,80℃):δ(ppm)0.82(3H,t,J=7.5Hz),1.34(3H,s),1.76−1.83(1H,m),1.85−2.08(3H,m),2.25−2.39(2H,m),2.65(1H,t,J=14.0Hz),2.80(1H,dd,J=5.0,10.0Hz),3.09(1H,dd,J=5.0,9.0Hz),3.21(1H,dd,J=5.5,9.0Hz),3.37−3.43(1H,m),3.71(3H,s),3.73−3.82(1H,m),4.39−4.43(1H,m),4.56(1H,d,J=15.6Hz),4.65−4.75(1H,m),5.17(1H,d,J=15.5Hz),6.78(1H,d,J=5.0Hz),6.99−7.06(2H,m),7.09−7.19(5H,m),7.32−7.35(2H,m),7.65(1H,d,J=8.0Hz),7.80−7.98(3H,m),8.01(1H,d,J=7.0Hz),8.17−8.25(1H,m).
(2R)−2−(2−アミノ−2−メチルプロパンアミド)−4−メチル−N−[2−オキソ−8−(2−オキソピロリジン−1−イル)−1−(ピリジン−2−イルメチル)−1,2,3,4−テトラヒドロキノリン−3−イル]ペンタンアミド 塩酸塩の合成
1H−NMR(400MHz,DMSO−d6,80℃):δ(ppm)0.87(3H,d,J=6.5Hz),0.89(3H,d,J=6.5Hz),1.19(3H,s),1.20(3H,s),1.48−1.81(4H,m),1.85−1.98(2H,m),2.13−2.29(2H,m),2.94−3.09(4H,m),3.35−3.43(1H,m),3.66−3.79(1H,m),4.37(1H,dd,J=5.5,8.5Hz),4.43−4.53(1H,m),4.74(1H,d,J=16.5Hz),5.14(1H,d,J=16.5Hz),7.05−7.24(5H,m),7.64(1H,dt,J=2.0,7.5Hz),7.70−8.30(1H,br),7.94(1H,d,J=7.0Hz),8.39(1H,d,J=5.0Hz).
(2R)−2−(2−アミノ−2−メチルプロパンアミド)−4−メチル−N−[2−オキソ−8−(2−オキソピロリジン−1−イル)−1−(チオフェン−3−イルメチル)−1,2,3,4−テトラヒドロキノリン−3−イル]ペンタンアミド(R)−(−)−マンデル酸塩の合成
Mp:183−185℃
1H−NMR(400MHz,DMSO−d6):δ(ppm)0.87(3H,d,J=6.5Hz),0.90(3H,d,J=6.5Hz),1.36(3H,s),1.37(3H,s),1.43−1.66(4H,m),1.85−2.42(3H,m),2.70−2.95(2H,m),3.10−4.10(2H,m),4.35−4.80(3H,m),4.60(1H,s),4.98−5.27(1H,m),6.30−7.00(3H,br),6.81(1H,d,J=5.0Hz),7.05−7.28(8H,m),7.33−7.45(3H,m),8.29(1H,d,J=8.0Hz),8.48(1H,d,J=7.5Hz).
(2R)−2−(2−アミノ−2−メチルプロパンアミド)−4−メチル−N−[2−オキソ−8−(2−オキソピロリジン−1−イル)−1−(チオフェン−3−イルメチル)−1,2,3,4−テトラヒドロキノリン−3−イル]ペンタンアミド(S)−(+)−マンデル酸塩
Mp:171−173℃
1H−NMR(400MHz,DMSO−d6):δ(ppm)0.87(3H,d,J=6.0Hz),0.90(3H,d,J=6.0Hz),1.36(3H,s),1.36(3H,s),1.44−1.65(4H,m),1.85−2.05(1H,m),2.20−2.40(2H,m),2.73−2.97(2H,m),3.20−4.10(2H,m),4.35−4.80(3H,m),4.62(1H,s),5.00−5.20(1H,m),6.40−7.00(3H,br),6.80(1H,d,J=5.0Hz),7.05−7.28(8H,m),7.33−7.44(3H,m),8.28(1H,d,J=8.0Hz),8.46(1H,d,J=7.5Hz).
(2R)−2−(2−アミノ−2−メチルプロパンアミド)−4−メチル−N−[2−オキソ−8−(2−オキソピロリジン−1−イル)−1−(チオフェン−2−イルメチル)−1,2,3,4−テトラヒドロキノリン−3−イル]ペンタンアミド 塩酸塩
1H−NMR(400MHz,DMSO−d6):δ(ppm)0.87(3H,d,J=6.0Hz),0.90(3H,d,J=6.0Hz),1.43−1.77(9H,m),1.92−2.27(2H,m),2.31−2.48(2H,m),2.73(1H,t,J=14.5Hz),2.87(1H,dd,J=5.0,14.5Hz),3.28−3.75(2H,m),4.31−4.92(3H,m),5.23−5.65(1H,br s),6.75−6.89(2H,m),7.11−7.27(3H,m),7.34(1H,d,J=5.0Hz),8.30(3H,br s),8.40(1H,d,J=8.5Hz),8.51(1H,d,J=7.5Hz).
(2R)−2−(2−アミノ−2−メチルプロパンアミド)−N−[1−ベンジル−2−オキソ−8−(2−オキソピロリジン−1−イル)−1,2,3,4−テトラヒドロキノリン−3−イル]−4−メチルペンタンアミド 塩酸塩
(2R)−2−(2−アミノ−2−メチルプロパンアミド)−N−[1−ベンジル−2−オキソ−8−(2−オキソピぺリジン−1−イル)−1,2,3,4−テトラヒドロキノリン−3−イル]−4−メチルペンタンアミド 塩酸塩
(2R)−2−(2−アミノ−2−メチルプロパンアミド)−N−[1−ベンジル−8−(2,5−ジオキソピロリジン−1−イル)−2−オキソ−1,2,3,4−テトラヒドロキノリン−3−イル]−4−メチルペンタンアミド 塩酸塩
2−アミノ−N−[(2R)−1−[1−ベンジル−2−オキソ−8−(2−オキソピロリジン−1−イル)−1,2,3,4−テトラヒドロキノリン−3−イルアミノ]−3−(1H−インドール−3−イル)−1−オキソプロパン−2−イル]−2−メチルプロパンアミド 塩酸塩
(2R)−2−((R)−2−アミノ−3−(4−ヒドロキシフェニル)プロパンアミド)−N−(8−(ジエチルアミノ)−2−オキソ−1−(ピリジン−2−イルメチル)−1,2,3,4−テトラヒドロキノリン−3−イル)−4−メチルペンタンアミド 塩酸塩
1H−NMR(400MHz,DMSO−d6):δ(ppm)0.75−1.03(12H,m),1.43−1.55(2H,m),1.59−1.71(1H,m),2.70−3.09(8H,m),3.97(1H,br),4.40−4.49(1H,m),4.56(1H,dd,J=6.5,8.5Hz),5.44(1H,d,J=16.0Hz),5.86(1H,d,J=16.0Hz),6.67(2H,d,J=12.5Hz),6.92−7.36(7H,m),7.59−7.66(1H,m),8.11(3H,br),8.36(1H,d,J=4.5Hz),8.60(1H,d,J=7.5Hz),8.67(1H,d,J=8.5Hz),9.34(1H,s).
(2R)−N−(8−アセトアミド−2−オキソ−1−(ピリジン−2−イルメチル)−1,2,3,4−テトラヒドロキノリン−3−イル)−2−(2−アミノ−2−メチルプロパンアミド)−4−メチルペンタンアミド
1H−NMR(400MHz,DMSO−d6):δ(ppm)0.86(3H,d,J=6.5Hz),0.88(3H,d,J=6.5Hz),1.15(3H,s),1.16(3H,s),1.44−1.60(3H,m),1.81(3H,s),1.95−2.17(2H,m),2.88(1H,dd,J=5.0,10.5Hz),3.05(1H,t,J=14.5Hz),4.35−4.47(2H,m),4.87(1H,d,J=16.0Hz),5.02(1H,d,J=16.0Hz),7.06(1H,t,J=8.0Hz),7.12(1H,d,J=7.5Hz),7.21−7.29(2H,m),7.41(1H,d,J=7.5Hz),7.70−7.77(1H,m),8.03(1H,br),8.41(1H,d,J=8.0Hz),8.46(1H,d,J=4.0Hz),10.00(1H,s).
2−アミノ−N−((1R)−2−(8−(ジメチルアミノ)−2−オキソ−1−(ピリジン−2−イルメチル)−1,2,3,4−テトラヒドロキノリン−3−イルアミノ)−2−オキソ−1−フェニルエチル)−2−メチルプロパンアミド 塩酸塩
1H−NMR(400MHz,DMSO−d6):δ(ppm)1.50(3H,s),1.53(3H,s),2.51−2.69(6H,s),2.76(1H,dd,J=5.0,10.0Hz),3.00(1H,t,J=14.5Hz),4.48−4.58(1H,m),5.42(1H,d,J=16.0Hz),5.53(1H,d,J=16.0Hz),5.81(1H,d,J=8.0Hz),6.84−6.99(3H,m),7.10−7.18(2H,m),7.29−7.41(3H,m),7.48(2H,d,J=7.5Hz),7.61−7.68(1H,m),8.22(3H,br),8.35(1H,d,J=4.0Hz),8.82(1H,d,J=8.5Hz),8.89(1H,d,J=8.0Hz).
(2R)−2−(2−アミノ−2−メチルプロパンアミド)−N−(8−(N−エチルアセトアミド)−2−オキソ−1−(ピリジン−2−イルメチル)−1,2,3,4−テトラヒドロキノリン−3−イル)−4−メチルペンタンアミド 塩酸塩
1H−NMR(400MHz,DMSO−d6):δ(ppm)0.81−0.94(9H,m),1.08−1.75(9H,m),2.80−3.20(3H,m),3.93−4.04(1H,m),4.53−4.62(2H,m),4.69−5.68(2H,m),7.06−7.38(5H,m),7.67−7.77(1H,m),8.14(3H,br),8.30−8.58(3H,m).
(2R)−2−(2−アミノ−2−メチルプロパンアミド)−N−[8−(ジエチルアミノ)−2−オキソ−1−(ピリジン−2−イルメチル)−1,2,3,4−テトラヒドロキノリン−3−イル)−4−(メチルチオ)ブタンアミド 塩酸塩
1H−NMR(400MHz,DMSO−d6):δ(ppm)0.75−0.85(3H,m),0.93−1.03(3H,m),1.47(3H,s),1.49(3H,s),1.83−2.08(2H,m),2.06(3H,s),2.35−2.55(2H,m),2.86−3.18(6H,m),4.28−4.48(1H,m),4.54−4.63(1H,m),5.41(1H,d,J=16.0Hz),5.85(1H,d,J=16.0Hz),6.92−7.05(3H,m),7.09(1H,d,J=7.5Hz),7.12−7.22(1H,m),7.62−7.72(1H,m),8.16(3H,br s),8.37(1H,s),8.39(1H,s),8.44(1H,d,J=7.5Hz).
2−アミノ−N−[(2R)−3−(ベンジルオキシ)−1−[8−(ジエチルアミノ)−2−オキソ−1−(ピリジン−2−イルメチル)−1,2,3,4−テトラヒドロキノリン−3−イルアミノ]−1−オキソプロパン−2−イル]−2−メチルプロパンアミド 塩酸塩
1H−NMR(400MHz,DMSO−d6):δ(ppm)0.73−0.87(3H,m),0.93−1.07(3H,m),1.49(3H,s),1.49(3H,s),2.83−3.20(6H,m),3.62−3.75(2H,m),4.37−4.57(3H,m),4.82−4.91(1H,m),5.41(1H,d,J=16.0Hz),5.85(1H,d,J=16.0Hz),6.88−7.17(5H,m),7.27−7.39(5H,m),7.60−7.67(1H,m),8.15(3H,br s),8.36(1H,d,J=4.0Hz),8.49(1H,d,J=8.0Hz),8.54(1H,d,J=7.5Hz).
2−アミノ−N−[(2R)−3−(4−クロロフェニル)−1−[8−(ジメチルアミノ)−2−オキソ−1−(ピリジン−2−イルメチル)−1,2,3,4−テトラヒドロキノリン−3−イルアミノ]−1−オキソプロパン−2−イル]−2−メチルプロパンアミド 塩酸塩
1H−NMR(400MHz,DMSO−d6):δ(ppm)1.25(3H,s),1.44(3H,s),2.63(6H,br s),2.80−2.90(2H,m),2.98−3.10(2H,m),3.35−3.48(1H,m),4.46−4.56(1H,m),4.76−4.85(1H,m),5.43(1H,d,J=16.0Hz),5.54(1H,d,J=16.0Hz),6.87−7.03(3H,m),7.09−7.17(2H,m),7.30−7.40(4H,m),7.64(1H,t,J=7.5Hz),8.04(3H,br s),8.35(1H,d,J=4.5Hz),8.51(1H,d,J=9.0Hz),8.71(1H,d,J=7.5Hz).
(2R)−2−(2−アミノアセタミド)−N−[8−(ジエチルアミノ)−1−(フラン−2−イルメチル)−2−オキソ−1,2,3,4−テトラヒドロキノリン−3−イル]−4−メチルペンタンアミド 塩酸塩
1H−NMR(400MHz,DMSO−d6):δ(ppm)0.70−0.88(3H,m),0.89(3H,d,J=7.0Hz),0.90(3H,d,J=7.0Hz),1.00−1.20(3H,m),1.42−1.72(3H,m),2.70−2.80(2H,m),2.85−3.30(4H,m),3.52−3.65(2H,m),4.30−4.42(1H,m),4.50−4.63(1H,m),5.42(1H,d,J=15.5Hz),5.72(1H,d,J=15.5Hz),5.92(1H,d,J=3.0Hz),6.24(1H,dd,J=2.0,3.0Hz),6.89(1H,d,J=6.5Hz),6.97−7.07(2H,m),7.41(1H,d,J=1.0Hz),8.04(3H,br s),8.56(1H,d,J=8.0Hz),8.66(1H,d,J=8.0Hz).
(2R)−2−(2−アミノ−3−メチルブタンアミド)−N−[8−(ジエチルアミノ)−2−オキソ−1−(ピリジン−2−イルメチル)−1,2,3,4−テトラヒドロキノリン−3−イル]−4−メチルペンタンアミド 塩酸塩
1H−NMR(400MHz,DMSO−d6):δ(ppm)0.73−0.83(3H,m),0.87(3H,d,J=6.5Hz),0.90(3H,d,J=6.5Hz),0.90−1.02(3H,m),1.26(3H,s),1.26(3H,s),1.41−1.68(3H,m),2.81−3.19(6H,m),3.30−3.50(2H,m),4.38−4.55(2H,m),5.41(1H,d,J=16.5Hz),5.88(1H,d,J=16.5Hz),6.92−7.08(3H,m),7.16(1H,d,J=7.5Hz),7.27(1H,br s),7.79(1H,br s),8.05(3H,br s),8.40−8.56(2H,m).
(2R,4R)−N−[(2R)−1−[8−(ジエチルアミノ)−2−オキソ−1−(ピリジン−2−イルメチル)−1,2,3,4−テトラヒドロキノリン−3−イルアミノ]−4−メチル−1−オキソペンタン−2−イル]−4−ヒドロキシピロリジン−2−カルボキサミド塩酸塩
1H−NMR(400MHz,DMSO−d6):δ(ppm)0.75−0.84(3H,m),0.89(3H,d,J=7.0Hz),0.90(3H,d,J=7.0Hz),0.93−1.01(3H,m),1.45−1.68(3H,m),1.80−1.90(1H,m),2.83(1H,dd,J=5.0,15.0Hz),2.88−3.28(8H,m),4.16−4.26(1H,m),4.30−4.38(1H,m),4.41−4.61(2H,m),5.23−5.45(1H,br),5.41(1H,d,J=16.0Hz),5.86(1H,d,J=16.0Hz),6.92−7.05(3H,m),7.10(1H,d,J=8.0Hz),7.16−7.23(1H,m),7.63−7.75(1H,m),8.40(1H,d,J=4.5Hz),8.48−8.61(2H,m),8.65(1H,d,J=8.5Hz),9.92(1H,br s).
N−[2−オキソ−8−(2−オキソピロリジン−1−イル)−1,2,3,4−テトラヒドロキノリン−3−イル]アセタミドの合成
1H−NMR(400MHz,DMSO−d6):δ(ppm)1.91(3H,s),2.07(2H,t,J=6.7Hz),2.53(2H,t,J=7.0Hz),2.91(1H,t,J=14.4Hz),3.04(1H,dd,J=6.3,14.4Hz),3.69(2H,t,J=6.5Hz),4.41−4.45(1H,m),6.92(1H,t,J=7.7Hz),7.01(1H,d,J=7.4Hz),7.35(1H,d,J=7.4Hz),7.84(1H,d,J=7.8Hz),9.17(1H,s),9.34(1H,s).
・化合物C Ms(FAB)m/z288(M+H)+
1H−NMR(400MHz,DMSO−d6):δ(ppm)1.92(3H,s),2.07−2.19(1H,m),2.42(1H,t,J=7.8Hz),2.90(1H,t,J=15.0Hz),3.04(1H,dd,J=6.3,15.0Hz),3.58−3.71(2H,m),4.41−4.48(1H,m),6.99(1H,t,J=7.5Hz),7.11(1H,d,J=7.5Hz),7.17(1H,d,J=7.5Hz),8.25(1H,d,J=7.5Hz),9.74(1H,s).
3−(ブロモメチル)チオフェンの合成
Ms(FAB)m/z178(M+H)+
1H−NMR(400MHz,DMSO−d6):δ(ppm)4.72(2H,s),7.16(1H,dd,J=1.0,5.0Hz),7.55(1H,J=3.0,5.0Hz),7.62(1H,d,J=3.0Hz).
N−(2−オキソ−8−(2−オキソピロリジン−1−イル)−1−(チオフェン−3−イルメチル)−1,2,3,4−テトラヒドロキノリン−3−イル)アセトアミドの合成
1H−NMR(400MHz,DMSO−d6,80℃):δ(ppm)1.92(3H,s),1.95−2.07(2H,m),2.22−2.39(2H,m),2.75(1H,t,J=14.4Hz),2.93(1H,dd,J=5.1,14.4Hz),3.34−3.40(1H,m),3.72−3.79(1H,m),4.41−4.47(1H,m),4.57(1H,d,J=15.6Hz),5.17(1H,d,J=15.7Hz),6.79(1H,dd,J=1.0,4.9Hz),7.03(1H,dd,J=1.0,2.6Hz),7.10(1H,t,J=7.6Hz),7.15−7.17(2H,m),7.32(1H,dd,J=3.0,4.9Hz),7.87(1H,d,J=6.8Hz).
3−アミノ−8−(2−オキソピロリジン−1−イル)−1−(チオフェン−3−イルメチル)−3,4−ジヒドロキノリン−2(1H)−オンの合成
(2R)−4−メチル−1−オキソ−1−[2−オキソ−8−(2−オキソピロリジン−1−イル)−1−(チオフェン−3−イルメチル)−1,2,3,4−テトラヒドロキノリン−3−イルアミノ]ペンタン−2−イルカルバミン酸tert−ブチルの合成
(2R)−2−アミノ−4−メチル−N−[2−オキソ−8−(2−オキソピロリジン−1−イル)−1−(チオフェン−3−イルメチル)−1,2,3,4−テトラヒドロキノリン−3−イル]ペンタンアミドの合成
2−メチル−1−[(2R)−4−メチル−1−オキソ−1−[2−オキソ−8−(2−オキソピロリジン−1−イル)−1−(チオフェン−3−イルメチル)−1,2,3,4−テトラヒドロキノリン−3−イルアミノ]ペンタン−2−イルアミノ]−1−オキソプロパン−2−イルカルバミン酸 tert−ブチルの合成
(2R)−2−(2−アミノ−2−メチルプロパンアミド)−4−メチル−N−[2−オキソ−8−(2−オキソピロリジン−1−イル)−1−(チオフェン−3−イルメチル)−1,2,3,4−テトラヒドロキノリン−3−イル]ペンタンアミドの合成
(2R)−2−(2−アミノ−2−メチルプロパンアミド)−4−メチル−N−[2−オキソ−8−(2−オキソピロリジン−1−イル)−1−(チオフェン−3−イルメチル)−1,2,3,4−テトラヒドロキノリン−3−イル]ペンタンアミド(R)−(−)−マンデル酸塩の合成
N−(8−ニトロ−2−オキソ−1,2,3,4−テトラヒドロキノリン−3−イル)アセタミドの合成
1H−NMR(400MHz,DMSO−d6):δ(ppm)1.92(3H,s),3.04(1H,t,J=15.2Hz),3.21(1H,dd,J=5.1,15.2Hz),4.59−4.65(1H,m),7.18(1H,t,J=7.4Hz),7.66(1H,d,J=7.4Hz),8.02(1H,d,J=8.4Hz),8.34(1H,d,J=8.0Hz),9.99(1H,s).
化合物B MS(FAB)m/z250(M+H)+
1H−NMR(400MHz,DMSO−d6):δ(ppm)1.91(3H,s),2.99(1H,t,J=15.1Hz),3.21(1H,dd,J=6.5,15.1Hz),4.54−4.61(1H,m),7.03(1H,d,J=10.7Hz),8.11(1H,dd,J=2.5,8.8Hz),8.17(1H,d,J=2.5Hz),8.28(1H,d,J=8.8Hz),10.92(1H,s).
2−メチル−1−[(2R)−4−メチル−1−オキソ−1−[2−オキソ−8−(2−オキソピロリジン−1−イル)−1−(チオフェン−3−イルメチル)−1,2,3,4−テトラヒドロキノリン−3−イルアミノ]ペンタン−2−イルアミノ]−1−オキソプロパン−2−イルカルバミン酸 tert−ブチルの合成
(R)−2−(2−(tert−ブトキシカルボニルアミノ)−2−メチルプロパンアミド)−4−メチルペンタン酸 メチルエステルの合成
(R)−2−(2−(tert−ブトキシカルボニルアミノ)−2−メチルプロパンアミド)−4−メチルペンタン酸の合成
6−ブロモ−8−ニトロ−2−オキソ−1,2,3,4−テトラヒドロキノリン−3−イルカルバミン酸 tert−ブチルの合成
2−オキソ−8−(2−オキソピロリジン−1−イル)−1,2,3,4−テトラヒドロキノリン−3−イルカルバミン酸 tert−ブチルの合成
2−オキソ−8−(2−オキソピロリジン−1−イル)−1−(チオフェン−3−イルメチル)−1,2,3,4−テトラヒドロキノリン−3−イルカルバミン酸 tert−ブチルの合成
3−アミノ−8−(2−オキソピロリジンー1−イル)−1−(チオフェン−3−イルメチル)−3,4−ジヒドロキノリン−2(1H)−オンの合成
(2R)−2−(2−アミノ−2−メチルプロパンアミド)−N−(8−(2−ヒドロキシ−5−オキソピロリジン−1−イル)−2−オキソ−1−(チオフェン−3−イルメチル)−1,2,3,4−テトラヒドロキノリン−3−イル)−4−メチルペンタンアミドの合成
MS(FAB)m/z557(M+H)+
1H−NMR(400MHz,CDCl3,50℃):δ(ppm)δ(ppm)0.95(3H,d,J=6.5Hz),0.98(3H,d,J=6.5Hz),1.33(3H,s),1.35(3H,s),1.38−1.92(7H,m),2.22−2.33(1H,m),2.55−2.68(2H,m),3.22(1H,dd,J=5.0,14.5Hz),3.30−3.60(1H,m),4.42(1H,dt,J=5.5,8.5Hz),4.53(1H,dt,J=5.5,14.0Hz),4.80(1H,d,J=14.5Hz),5.05(1H,d,J=14.5Hz),5.21−5.31(1H,m),6.87(1H,dd,J=1.5,5.0Hz),7.00−7.04(1H,m),7.14−7.22(3H,m),7.24−7.38(2H,m),7.94(1H,d,J=8.5Hz).
tert−ブチル 1−((2R)−1−(8−(2,5−ジオキソピロリジン−1−イル)−2−オキソ−1−(チオフェン−3−イルメチル)−1,2,3,4−テトラヒドロキノリン−3−イルアミノ)−2−メチル−1−オキソプロパン−2−イルカルバミン酸の合成
化合物A
MS(FAB)m/z672(M+H)+
1H−NMR(400MHz,DMSO−d6):δ(ppm)0.85(d,3H,J=6.5Hz),0.88(d,3H,J=6.6Hz),1.33(s,3H),1.35(s,3H),1.37(s,9H),1.49−1.71(m,3H),2.48−2.53(m,4H),2.71(t,1H,J=14.8Hz),2.85(dd,1H,J=5.1,15.0Hz),4.28−4.38(m,2H),4.76(d,1H,J=15.5Hz),5.30(d,1H,J=15.5Hz),6.73(s,1H),6.74(dd,1H,J=1.2,5.0Hz),7.00−7.07(m,2H),7.24(dd,1H,J=3.0,6.8Hz),7.27(dd,1H,J=3.0,5.0Hz),7.33(d,1H,J=8.1Hz),7.83(d,1H,J=7.1Hz),9.43(s,1H),11.5(br s,1H).
化合物B
MS(FAB)m/z654(M+H)+
1H−NMR(400MHz,DMSO−d6):δ(ppm)0.83(d,3H,J=6.3Hz),0.87(d,3H,J=6.4Hz),1.29(s,3H),1.31(s,3H),1.35(s,9H),1.43−1.53(m,1H),1.55−1.78(m,3H),2.26−2.37(m,1H),2.42−2.50(m,1H),2.64−2.73(m,1H),2.97(m,2H),4.30−4.51(m,3H),4.78(d,1H,J=16.0Hz),6.76(dd,1H,J=1.0,4.8Hz),6.94(d,1H,J=1.5Hz),7.01(br s,1H),7.12(dd,1H,J=1.3,7.9Hz),7.22(t,1H,J=7.6Hz),7.41(d,1H,J=6.5Hz),7.47(dd,1H,J=3.0,4.9Hz),7.62(br s,1H),8.15(br s,1H).
(2R)−2−(2−アミノ−2−メチルプロパンアミド)−N−(8−(2,5−ジオキソピロリジン−1−イル)−2−オキソ−1−(チオフェン−3−イルメチル)−1,2,3,4−テトラヒドロキノリン−3−イル)−4−メチルペンタンアミドの合成
MS(FAB)m/z554(M+H)+
1H−NMR(400MHz,CDCl3,50℃):δ(ppm)0.94(d,3H,J=7.0Hz),0.96(d,3H,J=6.9Hz),1.36(s,3H),1.38(s,3H),1.48(s,2H),1.53−1.85(m,4H),2.25(ddd,1H,J=3.8,9.8,18.2Hz),2.40(ddd,1H,J=3.9,9.8,18.2Hz),2.58(ddd,1H,J=4.8,10.0,13.4Hz),2.76(t,1H,J=14.0Hz),3.48(dd,1H,J=5.3,15.1Hz),4.37(d,1H,J=16.5Hz),4.43−4.49(m,1H),4.67(dt,1H,J=5.3,13.4Hz),5.04(d,1H,J=16.3Hz),6.85(dd,1H,J=1.0,5.0Hz),6.90(d,1H,J=7.9Hz),6.93−6.97(m,1H),7.19(t,1H,J=7.7Hz),7.22(br s,1H),7.25−7.31(m,1H),7.91(d,1H,J=8.3Hz).
(2R)−2−(2−アミノ−2−メチルプロパンアミド)−N−(8−(2,5−ジオキソピロリジン−1−イル)−2−オキソ−1−(チオフェン−3−イルメチル)−1,2,3,4−テトラヒドロキノリン−3−イル)−4−メチルペンタンアミド 塩酸塩の合成
1H−NMR(400MHz,DMSO−d6):δ(ppm)0.87(d,3H,J=6.3Hz),0.91(d,3H,J=6.3Hz),1.48(s,3H),1.50(s,3H),1.52−1.82(m,4H),2.28−2.37(m,1H),2.43−2.52(m,1H),2.65−2.74(m,1H),2.98(d,2H,J=9.5Hz),4.41−4.62(m,3H),4.79(d,1H,J=16.7Hz),6.77(dd,1H,J=1.2,5.0Hz),6.95−6.98(m,1H),7.13(dd,1H,J=1.4,7.9Hz),7.23(t,1H,J=7.6Hz),7.39−7.43(m,1H),7.48(dd,1H,J=2.9,4.9Hz),8.17(br s,3H),8.38(d,1H,J=8.6Hz),8.50(d,1H,J=7.7Hz).
(2R)−2−(2−アミノ−2−メチルプロパンアミド)−4−メチル−N−[2−オキソ−8−(2−オキソピロリジン−1−イル)−1−(チオフェン−3−イルメチル)−1,2,3,4−テトラヒドロキノリン−3−イル]ペンタンアミド 塩酸塩の合成
(2R)−2−(2−アミノ−2−メチルプロパンアミド)−N−(1−ベンジル−2−オキソ−1,2,3,4−テトラヒドロキノリン−3−イル)−4−メチルペンタンアミド 塩酸塩
MS(FAB)m/z451(M+H)+
1H−NMR(400MHz,DMSO−d6):δ(ppm)0.88(3H,d,J=6.0Hz),0.91(3H,d,J=6.0Hz),1.45−1.75(9H,m),2.97−3.10(2H,m),4.53−4.68(2H,m),5.12(1H,d,J=16.5Hz),5.23(1H,d,J=16.5Hz),6.97−7.04(2H,m),7.15−7.35(7H,m),8.24(3H,br s),8.40(1H,d,J=8.5Hz),8.53(1H,d,J=7.5 Hz).
(実験方法)
ヒトGHS−R1a遺伝子をCHO−K1細胞に導入して作製したGHS−R1a安定発現細胞(hGHS−R1a/CHO)を用いて、被験化合物のアゴニスト活性を細胞内カルシウム濃度の上昇率を指標に評価した。
hGHS−R1a/CHO細胞を96ウェルプレート(Clear bottom/Black plate、Corning社)に6×104cells/wellで播種し、10%牛胎児血清を含むHam’s F12培地で37℃、5%CO2で18時間培養した。培養後、培地を除いた後、hGHS−R1a/CHO細胞をカルシウム蛍光指示薬(4μM Fluo−3AM、Dojin社)、2mM Probenecid、0.1% Pluronic F−127、0.1%BSAを含むHanks’balanced salt solution/HEPES(HBSS/HEPES、100μl)で2時間培養し、指示薬を細胞内に取り込ませた。細胞を洗浄後、2mM Probenecid、0.1%BSAを含むHBSS/HEPESを175μl/well添加し、被験化合物添加前後の蛍光強度変化をFLEXstation(Ex485nm、Em525nm、Molecular Devices社)を用いて測定した。被験化合物は、ジメチルスルホキシドで連続希釈した後、終濃度が所定の濃度になるように2mM Probenecid、0.04% Pluronic F−127、0.1%BSAを含むHBSS/HEPESで希釈し、各ウェルに25μl添加した。
アゴニスト活性は、以下の式より計算し、用量反応曲線から各被験化合物のEC50値(50%アゴニスト活性を示す化合物濃度)を求めた。
A:被験化合物添加後の蛍光強度
B:被験化合物添加前の蛍光強度
C:100nMグレリン添加後の蛍光強度
D:グレリン添加前の蛍光強度
(実験法)
雄性ラットには静脈内(1or3mg/kg)又は経口(30mg/kg)投与、雄性ビーグル犬には静脈内又は経口(3mg/kg)投与後経時的に採血して血漿を得、LC−MS/MSにて測定して得られた血漿中濃度から生物学的利用率(Bioavailability:BA)を算出した(n=3)。
(結果)
ラットにおける実施例34aの化合物のBAは35%(anamorelin hydrochlorideは21%)、イヌにおける実施例34aのBAは84%(anamorelin hydrochlorideは19%)と、anamorelin hydrochlorideと比較して優れた経口吸収性を示した。
(実験法)
雄性ラットに麻酔下薬物を静脈内投与(1〜4mg/kg)後に定速静注(14〜95μg/kg)し、定常状態に達すると思われる2時間後に全採血してから脳を摘出した。得られた脳及び血漿中薬物濃度をLC−MS/MSにて測定し、脳内濃度対血漿中濃度比(Kp値)を算出した(n=6or9)。
(結果)
実施例34aの化合物について、各薬物濃度を振った平均のKp値は0.06(anamorelin hydrochlorideは0.42)であり、anamorelin hydrochlorideに比較して中枢移行性がはるかに軽減されており、本薬物の中枢における副作用はほとんど見られない。
(実験法)
ヒト肝ミクロソームを用いたin vitro CYP3A4阻害活性についてミダゾラム水酸化活性を指標にして測定し、そのKi値を算出した。
(結果)
実施例34aの化合物について、各薬物濃度を振った平均のKi値は86μmol/L(anamorelin hydrochlorideは3μmol/L)であり、anamorelin hydrochlorideに比較してCYP3A4阻害活性が弱く、本酵素による薬物相互作用を起こしにくい。
カプセルに充填した被験物質をビーグル犬に強制経口投与し、急性毒性を検討した。
雄ビーグル犬に実施例34aの化合物30及び100mg/kgとanamorelin hydrochlorideの3、10及び30mg/kgを単回経口投与し、一般状態の観察及び血液学、血液生化学検査を実施した。
実施例34aの化合物の投与群では最高用量(100mg/kg)において軽度な嘔吐がみられたのみであったが、anamorelin hydrochloride投与群では30mg/kgで嘔吐、徐脈、振戦、歩行異常等の重篤な一般状態の異常が認められた。
実施例34aの化合物ではanamorelin hydrochlorideでみられる異常を示さず、高い安全性が確認された。
(実験方法)
IL−1βで誘発された悪液質モデルラットを用い、体重および摂餌量低下に対する被験化合物の改善作用を評価した。
SD系ラット(雄性、8週齢、270−340g、日本チャ−ルスリバー)は、1ケージ当たり1匹で飼育し、餌(CRF−1、オリエンタル酵母工業)および水は自由に摂取させた。飼育室の照明サイクルは、10:30〜22:30に消灯、22:30〜10:30に点灯するように設定した。
浸透圧ポンプ(Mini−Osmotic Pump Model 2001、ALZET社、生理的食塩水充填)を接続したカニューレを脳室内に挿入したラットを作製した。3日間飼育した後、リコンビナントマウスIL−1β(rmIL−1β)を充填した浸透圧ポンプに交換して、rmIL−1βを脳室内に持続注入(5μg/μl/hr)し、悪液質を惹起した。IL−1β注入開始2日後から0.5%メチルセルロース溶液に溶解した被験化合物を消灯直前に経口投与し、経日的に24hrの体重および摂餌量を測定した。
(結果)
実施例34aの化合物は、100mg/kgの用量でIL−1βにより誘発された体重および摂餌量低下を有意に抑制し、IL−1β誘発悪液質を改善した。
(製剤例)
日本薬局方に準じ、実施例34a粉末8g、乳糖19.8g、結晶セルロース6g、ヒドロキシプロピルセルロース2gおよびクロスポビドン4gを混合し、精製水を造粒液として造粒後、乾燥して造粒末とした。これに、ステアリン酸マグネシウムを0.2g混合して打錠末を調製した。打錠末は、適切な質量に調整し打錠し、実施例34aを40mg含む径8mm、1錠200mgの錠剤を得た。
Claims (13)
- 一般式(1a)
(式中、XはCH2、C=O、CH−OR、CH−SR又はCH−NRR’を示し;
mは1又は2の数を示し;
Arは、フェニル基、ナフチル基、S、N及びOから選ばれる1個もしくは2個を含む5員環もしくは6員環の芳香族複素環式基、又はベンゼン環とS、N及びOから選ばれる1個もしくは2個を含む5員環もしくは6員環の複素環とが縮合した芳香族複素環式基(ここで、これらのフェニル、ナフチル又は芳香族複素環式基には、1〜3個のハロゲン原子、炭素数1〜6のアルキル基又は炭素数1〜6のアルコキシ基が置換していてもよい)を示し;
R1及びR2は、同一又は異なって、水素原子又はメチル基を示し;
R3は、炭素数1〜6のアルキル基(ここでアルキル基には、メチルチオ又はベンジルオキシ基が置換していてもよい)、フェニル基、フェニル−C1−4アルキル基、又はインドリルC1−4アルキル基(ここで、フェニル基又はインドリル基には炭素数1〜6のアルキル基、ハロゲン原子又は炭素数1〜6のアルコキシ基が置換していてもよい)を示し;
nは0又は1の数を示し;
R4及びR5は、同一又は異なって、水素原子、炭素数1〜6の直鎖状、分岐状もしくは環状のアルキル基、(ここでアルキル基にはハロゲン原子、水酸基、炭素数1〜6のアルコキシ基、フェニル基、ベンジルオキシ基又はヒドロキシフェニル基が置換していてもよい)を示すか、あるいは、R4又はR5とR6又はR7が隣接する窒素原子と一緒になってピロリジン環若しくはピペリジン環(ここでピロリジン環若しくはピペリジン環には水酸基が置換してもよい)を形成してもよく;
R6及びR7は同一又は異なって、水素原子、又は炭素数1〜6のアルキル基を示し;
R及びR’は同一又は異なって、水素原子、又は炭素数1〜6の直鎖状、分岐状もしくは環状のアルキル基を示す。)
で表される3,8−ジアミノテトラヒドロキノリン誘導体又はその塩。 - mが1である請求項1記載の化合物又はその塩。
- Arがフェニル基、ナフチル基、ピリジル基、キノリル基、イソキノリル基、チエニル基、フリル基、ピロリル基、ベンゾチエニル基、ベンゾフリル基、インドリル基、チアゾリル基、ピリミジニル基、キナゾリニル基、イミダゾリル基、ベンゾイミダゾリル基又はベンゾチアゾリル基(これらの環には1〜3個のハロゲン原子、炭素数1〜6のアルキル基又は炭素数1〜6のアルコキシ基が置換していてもよい)である請求項1又は2記載の化合物又はその塩。
- Arがフェニル基、ピリジル基、チエニル基又はフリル基である請求項1又は2記載の化合物又はその塩。
- R3が炭素数1〜6のアルキル基、ベンジル基又はインドリルメチル基(インドリル基には炭素数1〜6のアルキル基が窒素原子上に置換していてもよい)である請求項1〜4のいずれか1項記載の化合物又はその塩。
- nが0である請求項1〜5のいずれか1項記載の化合物又はその塩。
- R4及びR5が、同一又は異なって、水素原子、炭素数1〜4の直鎖状、分岐状もしくは環状のアルキル基である請求項1〜6のいずれか1項記載の化合物又はその塩。
- R6及びR7が水素原子である請求項1〜7のいずれか1項記載の化合物又はその塩。
- R3が炭素数4のアルキル基である請求項1〜8のいずれか1項記載の化合物又はその塩。
- R4及びR5が、同一又は異なって、水素原子、メチル基、エチル基又はR4及びR5が一緒になってシクロブチル基である請求項1〜9のいずれか1項記載の化合物又はその塩。
- 請求項1〜10のいずれか1項記載の化合物又はその塩を含有する医薬。
- 請求項1〜10のいずれか1項記載の化合物又はその塩、及び薬学的に許容される担体を含有する医薬組成物。
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2012
- 2012-09-14 US US13/617,469 patent/US8501772B2/en active Active
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2014
- 2014-05-20 HR HRP20140449AT patent/HRP20140449T1/hr unknown
- 2014-06-03 CY CY20141100391T patent/CY1115138T1/el unknown
Patent Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JPH06172316A (ja) * | 1991-03-20 | 1994-06-21 | Merck & Co Inc | 成長ホルモン放出促進新規ベンゾ縮合ラクタム類 |
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WO2009098901A1 (ja) | 2009-08-13 |
TWI422585B (zh) | 2014-01-11 |
AU2009212645A1 (en) | 2009-08-13 |
SI2241564T1 (sl) | 2014-06-30 |
AU2009212645B2 (en) | 2012-07-19 |
US20130012537A1 (en) | 2013-01-10 |
US8501772B2 (en) | 2013-08-06 |
CA2714480A1 (en) | 2009-08-13 |
KR20100116175A (ko) | 2010-10-29 |
ZA201005346B (en) | 2011-11-30 |
EP2241564A4 (en) | 2011-07-20 |
DK2241564T3 (da) | 2014-05-19 |
PT2241564E (pt) | 2014-06-12 |
EP2241564B1 (en) | 2014-04-30 |
CN101939313A (zh) | 2011-01-05 |
CN101939313B (zh) | 2013-05-22 |
BRPI0907749A2 (pt) | 2015-07-21 |
JPWO2009098901A1 (ja) | 2011-05-26 |
MX2010008740A (es) | 2010-08-30 |
US8299255B2 (en) | 2012-10-30 |
CY1115138T1 (el) | 2016-12-14 |
HRP20140449T1 (hr) | 2014-06-20 |
ES2464342T3 (es) | 2014-06-02 |
EP2241564A1 (en) | 2010-10-20 |
KR101553725B1 (ko) | 2015-09-16 |
RU2010137336A (ru) | 2012-03-20 |
PL2241564T3 (pl) | 2014-09-30 |
RU2482117C2 (ru) | 2013-05-20 |
TW200940530A (en) | 2009-10-01 |
CA2714480C (en) | 2017-03-28 |
US20100317693A1 (en) | 2010-12-16 |
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