JP5116666B2 - 細胞質ホスホリパーゼa2阻害剤 - Google Patents
細胞質ホスホリパーゼa2阻害剤 Download PDFInfo
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- JP5116666B2 JP5116666B2 JP2008513819A JP2008513819A JP5116666B2 JP 5116666 B2 JP5116666 B2 JP 5116666B2 JP 2008513819 A JP2008513819 A JP 2008513819A JP 2008513819 A JP2008513819 A JP 2008513819A JP 5116666 B2 JP5116666 B2 JP 5116666B2
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- UCFGDBYHRUNTLO-QHCPKHFHSA-N topotecan Chemical compound C1=C(O)C(CN(C)C)=C2C=C(CN3C4=CC5=C(C3=O)COC(=O)[C@]5(O)CC)C4=NC2=C1 UCFGDBYHRUNTLO-QHCPKHFHSA-N 0.000 description 1
- 229960000303 topotecan Drugs 0.000 description 1
- 229940019127 toradol Drugs 0.000 description 1
- XFCLJVABOIYOMF-QPLCGJKRSA-N toremifene Chemical compound C1=CC(OCCN(C)C)=CC=C1C(\C=1C=CC=CC=1)=C(\CCCl)C1=CC=CC=C1 XFCLJVABOIYOMF-QPLCGJKRSA-N 0.000 description 1
- 229960005026 toremifene Drugs 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 239000002341 toxic gas Substances 0.000 description 1
- NZHGWWWHIYHZNX-CSKARUKUSA-N tranilast Chemical compound C1=C(OC)C(OC)=CC=C1\C=C\C(=O)NC1=CC=CC=C1C(O)=O NZHGWWWHIYHZNX-CSKARUKUSA-N 0.000 description 1
- 229960005342 tranilast Drugs 0.000 description 1
- 230000009466 transformation Effects 0.000 description 1
- 238000000844 transformation Methods 0.000 description 1
- 229960001727 tretinoin Drugs 0.000 description 1
- 150000003626 triacylglycerols Chemical class 0.000 description 1
- 229960005294 triamcinolone Drugs 0.000 description 1
- GFNANZIMVAIWHM-OBYCQNJPSA-N triamcinolone Chemical compound O=C1C=C[C@]2(C)[C@@]3(F)[C@@H](O)C[C@](C)([C@@]([C@H](O)C4)(O)C(=O)CO)[C@@H]4[C@@H]3CCC2=C1 GFNANZIMVAIWHM-OBYCQNJPSA-N 0.000 description 1
- 229960002117 triamcinolone acetonide Drugs 0.000 description 1
- YNDXUCZADRHECN-JNQJZLCISA-N triamcinolone acetonide Chemical compound C1CC2=CC(=O)C=C[C@]2(C)[C@]2(F)[C@@H]1[C@@H]1C[C@H]3OC(C)(C)O[C@@]3(C(=O)CO)[C@@]1(C)C[C@@H]2O YNDXUCZADRHECN-JNQJZLCISA-N 0.000 description 1
- IMFACGCPASFAPR-UHFFFAOYSA-N tributylamine Chemical group CCCCN(CCCC)CCCC IMFACGCPASFAPR-UHFFFAOYSA-N 0.000 description 1
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 1
- 238000001665 trituration Methods 0.000 description 1
- 229940072651 tylenol Drugs 0.000 description 1
- IUCCYQIEZNQWRS-DWWHXVEHSA-N ularitide Chemical compound C([C@H]1C(=O)NCC(=O)NCC(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@H](C(NCC(=O)N[C@@H](C)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CO)C(=O)NCC(=O)N[C@@H](CC(C)C)C(=O)NCC(=O)N[C@@H](CSSC[C@@H](C(=O)N1)NC(=O)[C@H](CO)NC(=O)[C@H](CO)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CO)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H]1N(CCC1)C(=O)[C@H](C)NC(=O)[C@@H](N)[C@@H](C)O)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CO)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(O)=O)=O)[C@@H](C)CC)C1=CC=CC=C1 IUCCYQIEZNQWRS-DWWHXVEHSA-N 0.000 description 1
- 210000002700 urine Anatomy 0.000 description 1
- RUDATBOHQWOJDD-UZVSRGJWSA-N ursodeoxycholic acid Chemical compound C([C@H]1C[C@@H]2O)[C@H](O)CC[C@]1(C)[C@@H]1[C@@H]2[C@@H]2CC[C@H]([C@@H](CCC(O)=O)C)[C@@]2(C)CC1 RUDATBOHQWOJDD-UZVSRGJWSA-N 0.000 description 1
- 229960001661 ursodiol Drugs 0.000 description 1
- 239000002966 varnish Substances 0.000 description 1
- 210000005167 vascular cell Anatomy 0.000 description 1
- 235000013311 vegetables Nutrition 0.000 description 1
- 230000002861 ventricular Effects 0.000 description 1
- 229960003048 vinblastine Drugs 0.000 description 1
- JXLYSJRDGCGARV-XQKSVPLYSA-N vincaleukoblastine Chemical compound C([C@@H](C[C@]1(C(=O)OC)C=2C(=CC3=C([C@]45[C@H]([C@@]([C@H](OC(C)=O)[C@]6(CC)C=CCN([C@H]56)CC4)(O)C(=O)OC)N3C)C=2)OC)C[C@@](C2)(O)CC)N2CCC2=C1NC1=CC=CC=C21 JXLYSJRDGCGARV-XQKSVPLYSA-N 0.000 description 1
- OGWKCGZFUXNPDA-XQKSVPLYSA-N vincristine Chemical compound C([N@]1C[C@@H](C[C@]2(C(=O)OC)C=3C(=CC4=C([C@]56[C@H]([C@@]([C@H](OC(C)=O)[C@]7(CC)C=CCN([C@H]67)CC5)(O)C(=O)OC)N4C=O)C=3)OC)C[C@@](C1)(O)CC)CC1=C2NC2=CC=CC=C12 OGWKCGZFUXNPDA-XQKSVPLYSA-N 0.000 description 1
- 229960004528 vincristine Drugs 0.000 description 1
- OGWKCGZFUXNPDA-UHFFFAOYSA-N vincristine Natural products C1C(CC)(O)CC(CC2(C(=O)OC)C=3C(=CC4=C(C56C(C(C(OC(C)=O)C7(CC)C=CCN(C67)CC5)(O)C(=O)OC)N4C=O)C=3)OC)CN1CCC1=C2NC2=CC=CC=C12 OGWKCGZFUXNPDA-UHFFFAOYSA-N 0.000 description 1
- GBABOYUKABKIAF-GHYRFKGUSA-N vinorelbine Chemical compound C1N(CC=2C3=CC=CC=C3NC=22)CC(CC)=C[C@H]1C[C@]2(C(=O)OC)C1=CC([C@]23[C@H]([C@]([C@H](OC(C)=O)[C@]4(CC)C=CCN([C@H]34)CC2)(O)C(=O)OC)N2C)=C2C=C1OC GBABOYUKABKIAF-GHYRFKGUSA-N 0.000 description 1
- 229960002066 vinorelbine Drugs 0.000 description 1
- 229940087652 vioxx Drugs 0.000 description 1
- 230000009385 viral infection Effects 0.000 description 1
- 230000000007 visual effect Effects 0.000 description 1
- 229940045860 white wax Drugs 0.000 description 1
- 239000002023 wood Substances 0.000 description 1
- BPICBUSOMSTKRF-UHFFFAOYSA-N xylazine Chemical compound CC1=CC=CC(C)=C1NC1=NCCCS1 BPICBUSOMSTKRF-UHFFFAOYSA-N 0.000 description 1
- 229960001600 xylazine Drugs 0.000 description 1
- 239000008096 xylene Substances 0.000 description 1
- 229960004764 zafirlukast Drugs 0.000 description 1
- MWLSOWXNZPKENC-UHFFFAOYSA-N zileuton Chemical compound C1=CC=C2SC(C(N(O)C(N)=O)C)=CC2=C1 MWLSOWXNZPKENC-UHFFFAOYSA-N 0.000 description 1
- 229940052267 zyflo Drugs 0.000 description 1
Images
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- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/04—Indoles; Hydrogenated indoles
- C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
- C07D209/14—Radicals substituted by nitrogen atoms, not forming part of a nitro radical
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- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- 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
- A61K31/404—Indoles, e.g. pindolol
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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- A—HUMAN NECESSITIES
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- A61P25/00—Drugs for disorders of the nervous system
- A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
- A61P25/16—Anti-Parkinson drugs
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- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/04—Indoles; Hydrogenated indoles
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- Indole Compounds (AREA)
Description
式中、
n1は、1または2であり、
n2は、1または2であり、
n3は、1または2であり、
n5は、0、1または2であり、
X2は、結合、O、−CH2−またはSO2であり、
各R5は独立に、HまたはC1〜3アルキルであり、
R6は、HまたはC1〜6アルキルであり、
R7は、1〜3個の独立に選択されたR30基により所望により置換されていてもよいOH、ベンジルオキシ、CH3、CF3、OCF3、C1〜3アルコキシ、ハロゲン、COH、CO(C1〜3アルキル)、CO(OC1〜3アルキル)、キノリン−5−イル、キノリン−8−イル、3,5−ジメチルイソオキサゾール−4−イル、チオフェン−3−イル、ピリジン−4−イル、ピリジン−3−イル、−CH2−Q、およびフェニルからなる群から選択され、
R8は、1〜3個の独立に選択されたR30基により置換されているH、OH、NO2、CF3、OCF3、C1〜3アルコキシ、ハロゲン、CO(C1〜3アルキル)、CO(OC1〜3アルキル)、キノリン−5−イル、キノリン−8−イル、3,5−ジメチルイソオキサゾール−4−イル、チオフェン−3−イル、−CH2−Q、およびフェニルからなる群から選択され、
Qは、OH、ジアルキルアミノ、
R20は、H、C1〜3アルキルおよびCO(C1〜3アルキル)からなる群から選択され、ならびに
R30は、ジアルキルアミノ、CNおよびOCF3からなる群から選択される(ただし、
a)各々R5がH、R6がH、n5が0、およびR8がHの場合は、R7は塩素とはなれず、
b)各々R5がH、R6がH、n5が0、X2がOまたは−CH2−、およびR8がHの場合は、R7はCH3とはなれず、
c)各々R5がH、およびR6がHの場合は、R7およびR8の両方はフッ素とはなれず、
d)各々R5がH、R6がH、およびX2がOの場合は、R7およびR8の両方は塩素とはなれず、
e)各々R5がH、R6がH、X2がO、およびR8がNO2の場合は、R7はフッ素とはなれず、ならびに
f)各々R5がH、R6がH、X2がSO2、およびR8がHの場合は、R7はフッ素または塩素とはなれない)。
式中、
Xは、結合またはOであり、
n1は、1または2であり、
n2は、1または2であり、
n6は、1または2であり、
R5は、HまたはCH3であり、
R6は、HまたはC1〜6アルキルであり、ならびに
R8は、H、OH、NO2、CF3、OCF3、OCH3、ハロゲン、COCH3、COOCH3、ジメチルアミノ、ジエチルアミノおよびCNからなる群から選択される。
式中、
n1は、1または2であり、
n2は、1または2であり、
n3は、1または2であり、
n5は、0、1または2であり、
X2は、結合、O、−CH2−またはSO2であり、
各R5は独立に、HまたはC1〜3アルキルであり、
R6は、HまたはC1〜6アルキルであり、
R7は、1〜3個の独立に選択されたR30基により所望により置換されていてもよいOH、ベンジルオキシ、CH3、CF3、OCF3、C1〜3アルコキシ、ハロゲン、COH、CO(C1〜3アルキル)、CO(OC1〜3アルキル)、キノリン−5−イル、キノリン−8−イル、3,5−ジメチルイソオキサゾール−4−イル、チオフェン−3−イル、ピリジン−4−イル、ピリジン−3−イル、−CH2−Q、およびフェニルからなる群から選択され、
R8は、1〜3個の独立に選択されたR30基により置換されているH、OH、NO2、CF3、OCF3、C1〜3アルコキシ、ハロゲン、CO(C1〜3アルキル)、CO(OC1〜3アルキル)、キノリン−5−イル、キノリン−8−イル、3,5−ジメチルイソオキサゾール−4−イル、チオフェン−3−イル、−CH2−Q、およびフェニルからなる群から選択され、
Qは、OH、アルキルアミノ、
R20は、H、C1〜3アルキルおよびCO(C1〜3アルキル)からなる群から選択され、ならびに
R30は、ジアルキルアミノ、CNおよびOCF3からなる群から選択される(ただし、
a)各々R5がH、R6がH、n5が0、およびR8がHの場合は、R7は塩素とはなれず、
b)各々R5がH、R6がH、n5が0、X2がOまたは−CH2−、およびR8がHの場合は、R7はCH3とはなれず、
c)各々R5がH、およびR6がHの場合は、R7およびR8の両方はフッ素とはなれず、
d)各々R5がH、R6がH、およびX2がOの場合は、R7およびR8の両方は塩素とはなれず、
e)各々R5がH、R6がH、X2がO、およびR8がNO2の場合は、R7はフッ素とはなれず、ならびに
f)各々R5がH、R6がH、X2がSO2、およびR8がHの場合は、R7はフッ素または塩素とはなれない)。
式中、
Xは、結合またはOであり、
n1は、1または2であり、
n2は、1または2であり、
n6は、1または2であり、
R5は、HまたはCH3であり、
R6は、HまたはC1〜6アルキルであり、ならびに
R8は、H、OH、NO2、CF3、OCF3、OCH3、ハロゲン、COCH3、COOCH3、ジメチルアミノ、ジエチルアミノおよびCNからなる群から選択される。
下記は、本発明の代表的な化合物の調製を詳細に説明する。下記の実施例は、例示的な目的のために提示し、どのような形でも本発明を制限することは意図しない。当業者であれば、変化させまたは修飾しても本質的に同じ結果をもたらすことができる種々の重要ではないパラメーターを容易に認識するであろう。
本発明の化合物は、下記に示す方法A〜Eの手順によって調製することができる。
4−{2−[2−[2−({[2−(ベンジルオキシ)ベンジル]スルホニル}アミノ)エチル]−5−クロロ−1−(ジフェニルメチル)−1H−インドール−3−イル]エトキシ}安息香酸
工程1:DMF(0.83M)中の4−ヒドロキシ−安息香酸メチルエステル(1.0当量)に、K2CO3(2.0当量)、次いで2−ブロモ−1,1−ジエトキシ−エタンを加え、反応混合物を110℃にて2日間撹拌した。TLCは、新しいスポットを示した。反応混合物を酢酸エチルで希釈し、1NのNaOH、水、およびブラインで洗浄し、硫酸ナトリウム上で乾燥させ、溶媒を除去し、所望の生成物を収率84%で得た。この物質を次の工程でさらに精製せずに使用した。
4−{2−[5−クロロ−1−(ジフェニルメチル)−2−(2−{[(2−ヒドロキシベンジル)スルホニル]アミノ}エチル)−1H−インドール−3−イル]エトキシ}安息香酸
工程1:4−{2−[2−[2−({[2−(ベンジルオキシ)ベンジル]スルホニル}アミノ)エチル]−5−クロロ−1−(ジフェニルメチル)−1H−インドール−3−イル]エトキシ}安息香酸(実施例1の工程9、109mg、0.14mmol)に、THFおよびMeOHを加えた。10%のPd/C(11mg)を加えた。混合物を室温にてH2(1atm)下で一晩撹拌し、セライトを通して濾過し、濃縮し、カラムクロマトグラフィー(35%EtOAc/hex)にかけ、4−(2−{1−ベンズヒドリル−5−クロロ−2−[2−(2−ヒドロキシ−フェニルメタンスルホニルアミノ)エチル]−1H−インドール−3−イル}エトキシ)安息香酸メチルエステル(74mg、76%)をオフホワイトの固体として得た。
4−{2−[5−クロロ−2−(2−{[(2,6−ジブロモベンジル)スルホニル]アミノ}エチル)−1−(ジフェニルメチル)−1H−インドール−3−イル]エトキシ}安息香酸
工程1:2,6−ジブロモトルエン(5.38g、21.53mmol)をベンゼン(1.54M)に溶かした溶液に、N−ブロモスクシンイミド(4.21g、23.68mmol)および過酸化ベンゾイル(0.52g、2.15mmol)を加えた。次いで、混合物を一晩加熱還流した。混合物を室温に冷却し、H2Oで希釈し、EtOAcで抽出した。混合した有機相をブラインで洗浄し、MgSO4上で乾燥し、濃縮して、臭化ベンジル7.65gを茶色の固体として得た。1H NMR(400MHz,CDCl3)δ 4.83(s,2H)、7.01(t,J=8.0Hz,1H)、7.55(d,J=8.1Hz,2H)。
4−(2−{1−ベンズヒドリル−5−クロロ−2−[2−メチル−6−ニトロ−フェニルメタンスルホニルアミノ)エチル−1−H−インドール−3−イル}エトキシ)安息香酸
工程1:2−メチル−6−ニトロフェニル安息香酸(3.02g、16.67mmol)を塩化チオニル(0.56M)に溶かした溶液に、DMF(触媒)を加え、混合物を5.5時間加熱還流した。次いで、混合物を室温に冷却し、濃縮した。次いで、残渣をTHF(30mL)で溶解し、ゆっくりと20分かけてTHF(30mL)中のNaBH4のスラリーに加え、これを0℃に予冷した。混合物を室温にて2時間撹拌し、次いでH2Oを、続いて4MのHClを加えることによってクエンチした。混合物をEtOAcで抽出した。混合した有機相を飽和NaHCO3およびブラインで洗浄し、MgSO4上で乾燥し、濃縮し、ベンジルアルコール2.52g(90%)をオレンジ色の固体として得た。1H NMR(400MHz,CDCl3)δ 2.55(s,3H)、4.70(s,2H)、7.35(t,J=7.8Hz,1H)、7.48(d,J=7.6Hz,1H)、7.70(d,J=8.3Hz,1H)。
4−(2−{5−クロロ−1−(ジフェニルメチル)−2−[2−({[2−(トリフルオロメチル)ベンジル]スルホニル}アミノ)エチル]−1H−インドール−3−イル}エトキシ)安息香酸
工程1:2−(トリフルオロメチル)ベンジルブロミド(25g、0.14mol)、亜硫酸ナトリウム(19.1g、0.15mol)、ヨウ化テトラブチルアンモニウム(0.224g、0.6mmol)およびH2O(930mL)の混合物を、2日間加熱還流した。混合物を室温に冷却し、水相を油状残渣からデカントし、ロータリーエバポレーター上で乾燥するまで濃縮し、所望のナトリウム塩(22.2g、60%)を白色固体として得て、さらなる精製をせずに使用した。
4−(2−{5−クロロ−1−(ジフェニルメチル)−2−[2−({[2−フルオロ−6−(トリフルオロメチル)ベンジル]スルホニル}アミノ)エチル]−1H−インドール−3−イル}エトキシ)安息香酸
工程1:実施例5の工程1に記載した手順を使用して、2−フルオロ−6−(トリフルオロメチルフェニル)ベンジルブロミド(15g、61mmol)から、2−フルオロ−6−(トリフルオロメチルフェニル)メタンスルホン酸ナトリウム塩(15g、89%)を白色固体として得た。1HNMR(400MHz,DMSO−d6)δ 4.02(s,2H)、7.26〜7.66(m,3H)。
4−{3−[5−クロロ−2−(2−{[(2,6−ジブロモベンジル)スルホニル]アミノ}エチル)−1−(ジフェニルメチル)−1H−インドール−3−イル]プロピル}安息香酸
工程1:無水DMF(69mL)中のメチル−4−ヨード安息香酸(5.3g、20.2mmol)、アリルアルコール(1.78g、30.3mmol)、NaHCO3(4.24g、50.5mmol)、Pd(OAc)2(0.14g、0.60mmol)、(n−Bu)4NBr(6.55g、20.2mmol)および4−A分子ふるい(4.1g)の混合物を、室温にて4日間撹拌した。セライトを通して反応混合物を濾過し、濾液を水に注ぎ、EtOAcで抽出した。有機層をブラインで洗浄し、乾燥し(Na2SO4)、真空下で濃縮した。フラッシュクロマトグラフィー(シリカゲル、10〜20%EtOAc−ヘキサン)により、所望の4−(3−オキソ−プロピル)安息香酸メチルエステル2.11gを透明な油として得た(回収した出発物質に基づいて85%)。
4−{3−[5−クロロ−2−(2−{[(2,6−ジクロロベンジル)スルホニル]アミノ}エチル)−1−(ジフェニルメチル)−1H−インドール−3−イル]プロピル}安息香酸
工程1:実施例3の工程1における条件を用いて、2,6−ジクロロベンジルブロミド(3.32g、13.84mmol)を、チオ酢酸カリウムと反応させ、チオ酢酸ベンジル2.92g(90%)を得た。
4−(3−{1−ベンズヒドリル−5−クロロ−2−[2−(2−メチル−6−ニトロ−フェニルメタンスルホニルアミノ)エチル−1H−インドール−3−イル}プロピル)安息香酸
工程1:実施例1の工程9で概説したように、4−{3−[2−(2−アミノエチル)−1−ベンズヒドリル−5−クロロ−1H−インドール−3−イル]プロピル}安息香酸メチル(実施例7の工程6、255mg、0.47mmol)を、2−メチル−6−ニトロ−フェニル−メタンスルホニルクロリド(実施例4の工程4)と反応させ、スルホンアミド180mgを黄色の固体として収率51%で得た。
4−(3−{5−クロロ−1−(ジフェニルメチル)−2−[2−({[2−(トリフルオロメチル)ベンジル]スルホニル}アミノ)エチル]−1H−インドール−3−イル}プロピル)安息香酸
工程1:(参照により本明細書中にその全体が組み込まれている米国特許第6797708(B2)号に記載されているように調製された)4−{3−[2−(2−アミノエチル)−1−ベンズヒドリル−5−クロロ−1H−インドール−3−イル]プロピル}安息香酸(10.0g、19mmol)をCH3CN(100mL)およびMeOH(25mL)に懸濁させた懸濁液に、(トリメチルシリル)ジアゾメタン(ヘキサン溶液中2.0M、9.6mL、19mmol)を加えた。16時間後に、混合物を濾過、濃縮し、メチルエステル(8.8g、約86%)をオレンジ色の泡として得て、これを精製せずに使用した。
1H NMR(400MHz,DMSO−d6)δ 1.81〜1.97(m,2H)、2.66〜2.79(m,4H)、2.95(s,4H)、4.41(s,2H)、6.45(d,J=8.8Hz,1H)、6.78(dd,J=8.8,2.0Hz,1H)、7.01〜7.14(m,5H)、7.24〜7.42(m,8H)、7.46(d,J=2.0Hz,1H)、7.50〜7.66(m,4H)、7.73(d,J=7.8Hz,1H)、7.85(d,J=8.3Hz,2H)、12.77(s,1H);HRMS:C41H36ClF3N2O4S+H+の計算値、745.21092;実測値(ESI−FTMS,[M+H]1+)、745.2132;元素分析C41H36ClF3N2O4Sの計算値:C,66.08;H,4.87;N3.76。実測値:C,66.07;H,4.57;N,3.67。
4−(3−{5−クロロ−1−(ジフェニルメチル)−2−[2−(メチル{[2−(トリフルオロメチル)ベンジル]スルホニル}アミノ)エチル]−1H−インドール−3−イル}プロピル)安息香酸
工程1:実施例1の工程10の手順を使用して、副生物(0.66g、0.85mmol)として実施例10の工程2から単離したN−Meスルホンアミドエステルを加水分解して、表題生成物0.30g(46%)を、薄黄色の粉末として得た。1H NMR(400MHz,DMSO−d6)δ 1.76〜1.93(m,2H)、2.63〜2.81(m,9H)、3.31(s,2H)、4.46(s,2H)、6.46(d,J=8.8Hz,1H)、6.78(dd,J=8.8,2.3Hz,1H)、6.98〜7.13(m,5H)、7.23〜7.43(m,8H)、7.46(d,J=2.0Hz,1H)、7.51〜7.66(m,3H)、7.72(d,J=7.8Hz,1H)、7.86(d,J=8.3Hz,2H)、12.75(br s,1H);HRMS:C42H38ClF3N2O4S+H+の計算値、759.22657;実測値(ESI−FTMS,[M+H]1+)、759.2269;HPLC純度:H2O/CH3CN:96.2%,H2O/MeOH:95.7%。
4−{3−[2−[2−({[2,6−ビス(トリフルオロメチル)ベンジル]スルホニル}アミノ)エチル]−5−クロロ−1−(ジフェニルメチル)−1H−インドール−3−イル]プロピル}安息香酸
工程1:2,6−ビス(トリフルオロメチル)ベンゾイルフルオリド。W.DmowskiおよびK.Piasecka−MaciejewskaによるTetrahedron Lett.1998,54,6781〜6792(参照により本明細書中にその全体が組み込まれている)に記載されている手順を使用して、2,6−ビス(トリフルオロメチル)安息香酸7.0gを、オレンジ色の固体の酸フッ化物(7.0g、100%)に変換した。1H NMR(400MHz,DMSO−d6)δ 8.17(t,J=8.0Hz,1H)、8.40(d,J=8.0Hz,2H)。
4−(3−{5−クロロ−1−(ジフェニルメチル)−2−[2−({[2−(メトキシカルボニル)ベンジル]スルホニル}アミノ)エチル]−1H−インドール−3−イル}プロピル)安息香酸
工程1:2−メチル安息香酸メチル(5.0g、0.033mmol)とN−ブロモスクシンイミド(5.9g、0.033mmol)とをCCl4(50mL)中で混合した混合物に、過酸化ベンゾイル(0.04g、0.00016mmol)を加えた。混合物を1.5時間加熱還流し、室温に冷却し、セライトを通して濾過し、濃縮して2−(ブロモメチル)安息香酸メチル(7.2g、約94%の塊を回収)を得た。これには約14%の未反応出発物質が混入しており、精製せずに使用した。
4−(3−{5−クロロ−1−(ジフェニルメチル)−2−[2−({[2−フルオロ−6−(トリフルオロメチル)ベンジル]スルホニル}アミノ)エチル]−1H−インドール−3−イル}プロピル)安息香酸
工程1:実施例5の工程1に記載した手順を使用して、2−フルオロ−6−(トリフルオロメチルフェニル)ベンジルブロミド(15g、61mmol)から、2−フルオロ−6−(トリフルオロメチルフェニル)メタンスルホン酸ナトリウム塩(15g、89%)を白色固体として得た。1HNMR(400MHz,DMSO−d6)δ 4.02(s,2H)、7.26〜7.66(m,3H)。
4−[3−(5−クロロ−1−(ジフェニルメチル)−2−{2−[({2−[2−(トリフルオロメチル)フェニル]エチル}スルホニル)アミノ]エチル}−1H−インドール−3−イル)プロピル]安息香酸
工程1:2−(トリフルオロメチル)フェネチルアルコール(5.0g、26mmol)を、実施例12の工程3におけるようにCBr4で処理し、臭化物(6.6g、100%)を得て、これを精製せずに使用した。
4−{3−[5−クロロ−1−(ジフェニルメチル)−2−(2−{[(2−ホルミルベンジル)スルホニル]アミノ}エチル)−1H−インドール−3−イル]プロピル}安息香酸
工程1:CH2Cl2中のα−ブロモ−o−トルニトリル(10g、51mmol)に、0℃にてDIBAL−H(ヘキサン中1M、55mL、55mmol)を加え、反応混合物を同じ温度で3.5時間撹拌し、次いで冷たい5%HBr溶液に0℃にて注いだ。混合物を15分間撹拌し、次いで層を分離し、水層をCH2Cl2で抽出し、混合した有機層をNaHCO3および水で洗浄し、MgSO4上で乾燥し、蒸発させ、色が濃い液体(9.4g)を得た。この物質を次の工程においてさらに精製せずに直接使用した。
4−(3−{5−クロロ−1−(ジフェニルメチル)−2−[2−({[2−(モルホリン−4−イルメチル)ベンジル]スルホニル}アミノ)エチル]−1H−インドール−3−イル}プロピル)安息香酸
工程1:DCE(2mL)中の4−{3−[5−クロロ−1−(ジフェニルメチル)−2−(2−{[(2−ホルミルベンジル)スルホニル]アミノ}エチル)−1H−インドール−3−イル]プロピル}安息香酸メチル(実施例16の工程5、58mg、0.081mmol)に、0℃にてモルホリン(0.0092mL、0.105mmol)およびNaBH(OAc)3(27mg、0.13mmol)を加え、反応混合物を室温に一晩温めた。反応物を飽和NaHCO3でクエンチし、EtOAcで抽出し、MgSO4上で乾燥した。シリカゲルクロマトグラフィー(35%〜50%EtOAc/ヘキサン)による精製によって、所望の生成物を白色固体(41mg、64%)として得た。
4−{3−[5−クロロ−2−{2−[({2−[(ジエチルアミノ)メチル]ベンジル}スルホニル)アミノ]エチル}−1−(ジフェニルメチル)−1H−インドール−3−イル]プロピル}安息香酸
工程1:実施例17の工程1において概説したように、4−{3−[5−クロロ−1−(ジフェニルメチル)−2−(2−{[(2−ホルミルベンジル)スルホニル]アミノ}エチル)−1H−インドール−3−イル]プロピル}安息香酸メチル(実施例16の工程5、58mg、0.081mmol)を、DCE(2mL)中のHNEt2(0.022mL、0.21mmol)およびNaBH(OAc)3(56mg、0.26mmol)と反応させ、4−{3−[5−クロロ−2−{2−[({2−[(ジエチルアミノ)メチル]ベンジル}スルホニル)アミノ]エチル}−1−(ジフェニルメチル)−1H−インドール−3−イル]プロピル}安息香酸メチル(26mg、41%)と、副生物である4−(3−{5−クロロ−1−(ジフェニルメチル)−2−[2−({[2−(ヒドロキシメチル)ベンジル]スルホニル}アミノ)エチル]−1H−インドール−3−イル}プロピル)安息香酸メチル(8.6mg、15%)とを両方とも白色固体として得た。
4−(3−{5−クロロ−1−(ジフェニルメチル)−2−[2−({[2−(ヒドロキシメチル)ベンジル]スルホニル}アミノ)エチル]−1H−インドール−3−イル}プロピル)安息香酸
工程1:実施例1の工程10における手順を用いて、実施例18の工程1からの副生物である4−(3−{5−クロロ−1−(ジフェニルメチル)−2−[2−({[2−(ヒドロキシメチル)ベンジル]スルホニル}アミノ)エチル]−1H−インドール−3−イル}プロピル)安息香酸メチル(8.4mg、0.0012mmol)を加水分解して、表題生成物5.0mg(61%)を白色固体として得た。
4−(3−{5−クロロ−1−(ジフェニルメチル)−2−[2−({[2−(ピペラジン−1−イルメチル)ベンジル]スルホニル}アミノ)エチル]−1H−インドール−3−イル}プロピル)安息香酸、および実施例21の4−{3−[2−{2−[({2−[(4−アセチルピペラジン−1−イル)メチル]ベンジル}スルホニル)アミノ]エチル}−5−クロロ−1−(ジフェニルメチル)−1H−インドール−3−イル]プロピル}安息香酸
工程1:実施例17の工程1において概説したように、4−{3−[5−クロロ−1−(ジフェニルメチル)−2−(2−{[(2−ホルミルベンジル)スルホニル]アミノ}エチル)−1H−インドール−3−イル]プロピル}安息香酸メチル(実施例16の工程5、45mg、0.063mmol)を、DCE(3mL)中の1−アセチルピペラジン(28mg、0.22mmol)およびNaBH(OAc)3(26mg、0.12mmol)と反応させて、スルホンアミド(39mg、75%)を白色の泡として得た。
4−[3−(5−クロロ−1−(ジフェニルメチル)−2−{2−[({2−[(4−メチルピペラジン−1−イル)メチル]ベンジル}スルホニル)アミノ]エチル}−1H−インドール−3−イル)プロピル]安息香酸
工程1:実施例17の工程1において概説したように、4−{3−[5−クロロ−1−(ジフェニルメチル)−2−(2−{[(2−ホルミルベンジル)スルホニル]アミノ}エチル)−1H−インドール−3−イル]プロピル}安息香酸メチル(実施例16の工程5、44mg、0.061mmol)を、DCE(3mL)中の1−メチルピペラジン(0.026mL、0.23mmol)およびNaBH(OAc)3(34mg、0.16mmol)と反応させ、スルホンアミド(41mg、84%)を白色固体として得た。
4−[3−(5−クロロ−1−(ジフェニルメチル)−2−{2−[({1−[2−(トリフルオロメチル)フェニル]エチル}スルホニル)アミノ]エチル}−1H−インドール−3−イル)プロピル]安息香酸
工程1:実施例3の工程2において概説した手順に従って、DMF(50mL)中のα−メチル−2−トリフルオロメチルベンジルブロミド(10.0g、39.5mmol)に、チオ酢酸カリウム(8.1g、71.1mmol)を加えた。これにより、チオ酢酸をオレンジ色の油(10.49g、91%)として得た。
1H NMR(400MHz,CDCl3)δ 1.68(d,J=7.1Hz,3H)1.93(t,J=5.4Hz,2H)2.02〜2.08(m,1H)2.63〜2.77(m,6H)2.86(t,J=7.6Hz,2H)6.47(d,J=8.8Hz,1H)7.01〜7.07(m,4H)7.24〜7.40(m,12H)7.44(t,J=7.5Hz,1H)7.60(d,J=7.6Hz,1H)7.85(d,J=8.1Hz,1H)8.00(d,J=8.1Hz,2H)
4−{3−[2−(2−{[(2−ブロモベンジル)スルホニル]アミノ}エチル)−5−クロロ−1−(ジフェニルメチル)−1H−インドール−3−イル]プロピル}安息香酸
工程1:実施例1の工程9における手順を用いて、4−{3−[2−(2−アミノエチル)−1−ベンズヒドリル−5−クロロ−1H−インドール−3−イル]プロピル}安息香酸メチル(実施例7の工程6、1.51g、2.81mmol)を、2−ブロモフェニルメタンスルホニルクロリドと反応させて、スルホンアミド1.06gを白色固体として収率49%で得た。
4−(3−{5−クロロ−1−(ジフェニルメチル)−2−[2−({[2−(トリフルオロメトキシ)ベンジル]スルホニル}アミノ)エチル]−1H−インドール−3−イル}プロピル)安息香酸
工程1:実施例1の工程9における手順を用いて、4−{3−[2−(2−アミノエチル)−1−ベンズヒドリル−5−クロロ−1H−インドール−3−イル]プロピル}安息香酸メチル(実施例7の工程6、164mg、0.305mmol)を、2−トリフルオロメトキシフェニルメタンスルホニルクロリドと反応させ、スルホンアミド109mgを白色固体として収率46%で得た。
4−{3−[5−クロロ−2−(2−{[(3−クロロ−6−フルオロ−2−メチルベンジル)スルホニル]アミノ}エチル)−1−(ジフェニルメチル)−1H−インドール−3−イル]プロピル}安息香酸
工程1:2,6−ジフルオロ−N−(2−ヒドロキシ−1,1−ジメチル−エチル)ベンズアミド。窒素下の2−アミノ−2−メチルプロパノール(10.1g、113.3mmol)をCH2Cl2(75mL)に溶かした0℃溶液に、2,6−ジフルオロベンゾイルクロリド(10.0g、56.6mmol)をCH2Cl2(50mL)に溶かした溶液を滴下した。次いで、反応混合物を室温に温め、一晩撹拌した。反応混合物をH2Oで希釈し、水相をCH2Cl2で抽出し、乾燥し(MgSO4)、濃縮した。ヘキサンと共に粉砕することによる精製によって、アミド12.05g(93%)を白色固体として得た。1H NMR(400MHz,CDCl3)δ 1.41(s,6H)、3.66〜3.75(m,2H)、3.77〜3.87(m,1H)、5.94(s,1H)、6.90〜6.99(m,2H)、7.31〜7.41(m,1H)。
4−(3−{5−クロロ−1−(ジフェニルメチル)−2−[2−({[2−ニトロ−6−(トリフルオロメチル)ベンジル]スルホニル}アミノ)エチル]−1H−インドール−3−イル}プロピル)安息香酸
工程1:2−ブロモメチル−1−ニトロ−3−トリフルオロメチル−ベンゼン。2−メチル−1−ニトロ−3−トリフルオロメチルベンゼン(5.0g、24.4mmol)をCCl4(300mL)に溶かした溶液に、N−ブロモスクシンイミド(4.35g、24.4mmol)および過酸化ベンゾイル(0.11g、0.45mmol)を加えた。混合物を加熱還流し、光(300W)に20時間曝した。混合物を室温に冷却し、濾過、濃縮した。カラムクロマトグラフィー(EtOAc−ヘキサン)による精製により、臭化ベンジル3.03g(44%)を黄色の油として得た。1H NMR(400MHz,CDCl3)δ 4.93(s,2H)、7.63(t,J=8.1Hz,1H)、7.94(d,J=7.8Hz,1H)、8.06(d,J=8.1Hz,1H)。
4−{3−[5−クロロ−1−(ジフェニルメチル)−2−(2−{[(2−フルオロベンジル)スルホニル]アミノ}エチル)−1H−インドール−3−イル]プロピル}安息香酸
工程1:実施例1の工程9における手順を用いて、4−{3−[2−(2−アミノエチル)−1−ベンズヒドリル−5−クロロ−1H−インドール−3−イル]プロピル}安息香酸メチル(実施例7の工程6、163mg、0.303mmol)を、(2−ニトロ−6−トリフルオロメチル−フェニル)−メタンスルホニルクロリドと反応させて、スルホンアミド15mgを白色固体として収率7%で得た。
4−{3−[2−(2−{[(ビフェニル−2−イルメチル)スルホニル]アミノ}エチル)−5−クロロ−1−(ジフェニルメチル)−1H−インドール−3−イル]プロピル}安息香酸
工程1:実施例24の工程1からの臭化物(83mg、0.108mmol)を、フェニルボロン酸(19.8mg、0.162mmol)、KF(9.4mg、0.162mmol)、Pd(OAc)2(3.4mg、0.015mmol)およびPPh3(11.8mg、0.045mmol)と共にマイクロ波反応容器に入れた。DME(0.12M)、MeOH(0.42M)、H2O(0.42M)をその容器に加え、混合物をアルゴン流下で脱気し、ふたをして、Smith Creatorマイクロ波中で120℃にて1時間加熱した。反応混合物を室温に冷却し、(EtOAcで洗浄した)セライトを通して濾過し、H2Oで希釈した。水層をEtOAcで抽出した。混合した有機相を、H2Oおよびブラインで洗浄し、MgSO4上で乾燥し、濃縮した。粗生成物のカラムクロマトグラフィー(EtOAc−Hex)による精製によって、鈴木生成物75mg(91%)を黄色の固体として得た。
4−{3−[5−クロロ−1−(ジフェニルメチル)−2−(2−{[(2−ピリジン−4−イルベンジル)スルホニル]アミノ}エチル)−1H−インドール−3−イル]プロピル}安息香酸
工程1:実施例29の工程1の手順に従って、実施例24の工程1からの臭化物(77mg、0.10mmol)をピリジン−4−ボロン酸と反応させ、鈴木生成物33mg(43%)を白色固体として得た。
4−{3−[5−クロロ−1−(ジフェニルメチル)−2−(2−{[(2−ピリジン−3−イルベンジル)スルホニル]アミノ}エチル)−1H−インドール−3−イル]プロピル}安息香酸
工程1:実施例29の工程1の手順に従って、実施例24の工程1からの臭化物(77mg、0.10mmol)を、ピリジン−3−ボロン酸と反応させ、鈴木生成物59mg(77%)を黄色の固体として得た。
4−(3−{5−クロロ−1−(ジフェニルメチル)−2−[2−({[2−(3−チエニル)ベンジル]スルホニル}アミノ)エチル]−1H−インドール−3−イル}プロピル)安息香酸
工程1:実施例29の工程1の手順に従って、実施例24の工程1からの臭化物(77mg、0.10mmol)を、チオフェン−3−ボロン酸と反応させ、鈴木生成物67mg(87%)を黄色の固体として得た。
4−{3−[5−クロロ−2−[2−({[2−(3,5−ジメチルイソオキサゾール−4−イル)ベンジル]スルホニル}アミノ)エチル]−1−(ジフェニルメチル)−1H−インドール−3−イル]プロピル}安息香酸
工程1:実施例29の工程1の手順に従って、実施例24の工程1からの臭化物(77mg、0.10mmol)を3,5−ジメチルイソオキサゾール−4−ボロン酸と反応させ、鈴木生成物36mg(46%)を黄色の固体として得た。
4−{3−[5−クロロ−1−(ジフェニルメチル)−2−(2−{[(2−キノリン−8−イルベンジル)スルホニル]アミノ}エチル)−1H−インドール−3−イル]プロピル}安息香酸
工程1:実施例29の工程1の手順に従って、実施例24の工程1からの臭化物(77mg、0.10mmol)を、8−キノリンボロン酸と反応させ、鈴木生成物67mg(82%)を白色固体として得た。
4−{3−[5−クロロ−2−{2−[({[4’−(ジメチルアミノ)ビフェニル−2−イル]メチル}スルホニル)アミノ]エチル}−1−(ジフェニルメチル)−1H−インドール−3−イル]プロピル}安息香酸
工程1:実施例29の工程1の手順に従って、実施例24の工程1からの臭化物(77mg、0.10mmol)を4−(ジメチルアミノ)−フェニルボロン酸と反応させ、鈴木生成物51mg(約52%)を白色固体として得た。
4−[3−(5−クロロ−1−(ジフェニルメチル)−2−{2−[({[2’−(トリフルオロメトキシ)ビフェニル−2−イル]メチル}スルホニル)アミノ]エチル}−1H−インドール−3−イル)プロピル]安息香酸
工程1:実施例29の工程1の手順に従って、実施例24の工程1からの臭化物(77mg、0.10mmol)を、2−(トリフルオロメトキシ)フェニルボロン酸と反応させ、鈴木生成物36mg(約36%)を白色固体として得た。
4−{3−[5−クロロ−2−[2−({[(2’−シアノビフェニル−2−イル)メチル]スルホニル}アミノ)エチル]−1−(ジフェニルメチル)−1H−インドール−3−イル]プロピル}安息香酸
工程1:実施例24の工程1からの臭化物(73mg、0.095mmol)を、2−シアノフェニルボロン酸と反応させて、鈴木生成物23mg(30%)を黄色の固体として得た。
3−{4−[(2−{5−クロロ−1−(ジフェニルメチル)−2−[2−({[2−(トリフルオロメチル)ベンジル]スルホニル}アミノ)エチル]−1H−インドール−3−イル}エチル)スルホニル]フェニル}プロパン酸
工程1:2−ブロモ−4−クロロアニリン(1.0当量)をCH2Cl2(0.25M)に溶解し、次いでトリエチルアミンおよびトリフルオロアセチル無水物(各々1.1当量)を加えた。得られた混合物を、室温にて1時間撹拌した。溶媒を蒸発させ、溶離液としてCH2Cl2を用いたフラッシュクロマトグラフィーで残渣を精製し、収率97%でアミドを得た。m/z(M−H)−300.0
3−(4−{[2−(5−クロロ−1−(ジフェニルメチル)−2−{2−[({1−[2−(トリフルオロメチル)フェニル]エチル}スルホニル)アミノ]エチル}−1H−インドール−3−イル)エチル]スルホニル}フェニル)プロパン酸
工程1:実施例1の工程9における手順を用いて、エチル3−[4−({2−[2−(2−アミノエチル)−5−クロロ−1−(ジフェニルメチル)−1H−インドール−3−イル]エチル}スルホニル)フェニル]プロパノアート(実施例38の工程14)を、1−(2−トリフルオロメチルフェニル)エタンスルホニルクロリド(0.13g、0.46mmol)と反応させて、3−{4−[2−(1−ベンズヒドリル−5−クロロ−2−{2−[1−(2−トリフルオロメチルフェニル)エタンスルホニルアミノ]−エチル}−1H−インドール−3−イル)エタンスルホニル]フェニル}プロピオン酸エチルエステル(0.110g、40%)を得た。
1H NMR(400MHz,CDCl3)δ 1.67(d,J=6.8Hz,3H)2.57〜2.72(m,4H)2.80(t,J=6.8Hz,2H)2.84〜2.94(m,2H)3.03(t,J=6.4Hz,2H)3.20〜3.31(m,2H)5.82〜5.88(m,1H)6.37(s,1H)6.73〜6.81(m,2H)6.98(d,J=4.4Hz,2H)7.05(d,J=5.4Hz,2H)7.24〜7.49(m,11H)7.63(d,J=7.8Hz,1H)7.80(d,J=7.8Hz,1H)7.88(d,J=8.6Hz,2H)。
4−{3−[5−クロロ−1−(ジフェニルメチル)−2−(2−{[(2−ヒドロキシベンジル)スルホニル]アミノ}エチル)−1H−インドール−3−イル]プロピル}安息香酸
工程1:実施例5の工程1に記載した手順を使用して、2−ベンジルオキシベンジルブロミド(参照、J.Med.Chem.2006,49,31〜34,R.V.Somuら)(32.2g、116mmol)から(2−ベンジルオキシフェニル)メタンスルホン酸ナトリウム塩(30g、86%)を白色固体として得た。1H NMR(400MHz,DMSO−d6)δ 3.82(s,2H)5.09(s,2H)6.81〜6.91(m,1H)6.96(d,J=7.58Hz,1H)7.08〜7.18(m,1H)7.26〜7.34(m,1H)7.34〜7.41(m,2H)7.45(dd,J=1.77Hz,1H)7.52(d,J=7.07Hz,2H)。
4−{3−[5−クロロ−1−(ジフェニルメチル)−2−(2−{[(2−キノリン−5−イルベンジル)スルホニル]アミノ}エチル)−1H−インドール−3−イル]プロピル}安息香酸
工程1:実施例29の工程1の手順に従って、実施例24の工程1からの臭化物を、5−キノリンボロン酸と反応させ、鈴木生成物を得た。
GLUミセルアッセイ
アッセイは、355nM励起フィルターおよび460nMエミッションフィルターを備えた蛍光プレートリーダーを使用した96ウェルフォーマットで行った(Lab Systems社製FluoroscanII、Helsinki、Finland)。アッセイ緩衝液は、940μMのTriton X−100、50mMのHepes(pH7.4)、0.3mMのEDTA、1mMのCaCl2および300mMのKClを含有した。DTPC(1,2−O−テトラデシル−sn−グリセロ−3−ホスホコリン、Avanti社製)を120μMの最終濃度で実験の日に加え、GLU(7−ヒドロキシクマリニル−γ−リノレネート、Biomol Research Lab、Inc.社製)を90μMの最終濃度で各アッセイの直前に加えた。
阻害率=[1−(阻害剤を伴う勾配−負の対照の勾配)/(正の対照の勾配−負の対照の勾配)]×100
雄性Sprague−Dawleyラットの心臓穿刺によりヘパリン処理済チューブ内に新鮮な血液を回収した。血液の一定分量(0.6mL)を、溶媒(DMSO)6μLまたは様々な濃度の試験化合物6μLと共に15分間37℃にてインキュベーションした。続いて血液を、DMSO中で希釈したカルシウムイオノフォアA23187(Sigma社製C−7522)6μLと共に10分間37℃でインキュベーションした。A23187の最終濃度は5μMであった。DMSO(6μL)を非刺激の対照中に加えた。冷たいEDTA60μLを混合することにより反応を終わらせて、20mMの最終濃度とした。血液を6,500rpmで10分間微量遠心機によって遠心分離し、血漿を得た。タンパク質沈殿のために70μLの分量の血漿を冷たいメタノール400μLと混合した。−80℃にて30分間インキュベーションした後に、6,500rpmで10分間遠心分離することにより上清を得て、メーカーの手順(Assay Designs, Inc.社製ELISAキット#900−002)に従って、TXB2のためにアッセイした。
血栓症モデルにおけるcPLA2阻害剤投与の効果を、下記の手順によって決定した。
血小板機能分析器(PFA−100(登録商標))を使用して、ヒトの血小板凝集を研究した。ヒト血液を、直近の2週間に亘り血小板阻害剤を摂取したことを否定したボランティアから回収した。3.2%クエン酸ナトリウムのヴァキュテーナー管(Becton Dickinson社製)中に血液を回収した。管を5回反転させ、血液を15mLポリプロピレン円錐管内中に移した。100%DMSOに溶解した各々の阻害剤(4−(3−{5−クロロ−1−(ジフェニルメチル)−2−[2−({[2−フルオロ−6−(トリフルオロメチル)ベンジル]スルホニル}アミノ)エチル]−1H−インドール−3−イル}プロピル)安息香酸(実施例14)、4−(3−{5−クロロ−1−(ジフェニルメチル)−2−[2−({[2−(トリフルオロメトキシ)ベンジル]スルホニル}アミノ)エチル]−1H−インドール−3−イル}プロピル)安息香酸(実施例25)、4−{3−[1−ベンズヒドリル−5−クロロ−2−(2−{[(3,4−ジクロロベンジル)スルホニル]アミノ}エチル)−1H−インドール−3−イル]プロピル}安息香酸(化合物C))5μlを、ヒト全血1mL分量に加え、各々の阻害剤濃度とDMSO最終濃度0.5%とした。PFA−100中での操作の前に、管を10回反転して混合し、室温にて10分間静置した。コラーゲン/エピネフリンカートリッジを使用してPFA−100用のメーカーのプロトコルに従った(全血中0.5%のDMSO単独は、125+/−13.9秒の閉鎖時間となった)。メーカーによって設定された最大閉鎖時間は300秒である。
血管障害誘導の2時間前に、Sprague−Dawley異系交配ラット(体重80〜100グラム)は、経口胃管栄養法によって25mg/kgの用量で4−(3−{5−クロロ−1−(ジフェニルメチル)−2−[2−({[2−フルオロ−6−(トリフルオロメチル)ベンジル]スルホニル}アミノ)エチル]−1H−インドール−3−イル}プロピル)安息香酸(実施例14)または4−(3−{5−クロロ−1−(ジフェニルメチル)−2−[2−({[2−(トリフルオロメトキシ)ベンジル]スルホニル}アミノ)エチル]−1H−インドール−3−イル}プロピル)安息香酸(実施例25)を与えられた。胃管栄養法の総容量は、0.5mLであった。対照群の動物は、ビヒクルのみで処置された。血管障害の15分前に、ラットにケタミン/キシラジン混合物の筋肉内注射により麻酔した。麻酔後に、左頸動脈を切断し、さらなる測定を行った。プロトロンビン傷害の誘導のために、10%FeCl3溶液に浸した丸い濾紙(直径2mm)を、露出した血管壁に貼った。5分後に、濾紙を取り除き、1PRB血管周囲Dopplerフロープローブ(Transonic Systems Inc.社製)を、頸動脈の周りに固定し、血流を測定した。Transonic社製流量計(モデルTS420、Transonic Systems Inc.社製)およびWindaqデータ収集ソフトウェアを使用して、全部で30分間血流を記録した。
ビヒクル、実施例14の化合物、または実施例25の化合物を投与したラットから血液を回収し、上記の塩化第二鉄による障害プロトコルの対象とした。血液を大静脈から回収し、37℃にて血液凝固を1時間起こさせた。次いで、血清を単離し、血清トロンボキサンB2濃度をELISAによって決定した。
多発性硬化症の動物モデルにおけるcPLA2阻害剤投与の効果を下記の手順によって決定した。
0−EAEの臨床的症状を示さない(麻痺なし)
1−尾部麻痺
2−尾部麻痺および部分的な後足麻痺
3−尾部麻痺および完全な後足麻痺
4−尾部麻痺、完全な後足麻痺および部分的な前足麻痺
5−瀕死の動物(四肢全ての麻痺、反応なし、これらのマウスは直ちに安楽死させた。)
アテローム性動脈硬化症のアポリポタンパク質E(ApoE)ノックアウトマウスモデルにおけるcPLA2阻害剤の投与効果を、下記の手順によって決定した。
ApoE遺伝子を破壊するため胚性幹細胞の遺伝子ターゲティングによって、アポリポタンパク質E(ApoE)ノックアウトマウスを作製した。ApoEは、肝臓によるカイロミクロンおよびVLDL粒子の取込みに関与し、したがって血流中のコレステロールに富んだレムナントの蓄積を予防する糖タンパク質である。ApoE遺伝子のホモ接合性不活性化の結果として、ApoE KOマウスは、高コレステロール値を示し、これが、動脈系に沿った特異領域、特に高度な血行障害が著しい大動脈洞において、および大動脈に沿った分枝部位において、アテローム動脈硬化性プラークの形成を誘導する。
細胞質ホスホリパーゼA2(cPLA2)は、細胞活性化に伴い、選択的にアラキドン酸の放出を媒介する。アラキドン酸の代謝物であるエイコサノイドは、炎症過程の重要なモジュレーターであると認識されている。炎症誘発性エイコサノイドの生合成の減少は、ヒトおよびマウスにおけるアテローム性動脈硬化症の病変進行の抑制を示し、したがってアテローム性動脈硬化症におけるcPLA2の潜在的な役割を示唆している(RankeらによるCirculation1993;87(6)1873〜1879;PaulらによるLife Sciences2000;68(4):457〜465;CyrusらによるCirculation2002;106(10)1282〜1287;PraticoらによるPNAS2001;98(6):3358〜3363;BurleighらによるCirculation2002;105(15):1816〜1823;CayatteらによるATVB2000;20(7):1724〜1728;AielloらによるATVB2002;22(3):443〜449;SubbanagounderらによるCirc.Res.1999;85(4):311〜318を参照されたい)。さらに、cPLA2発現はヒトのアテローム性動脈硬化症の動脈には検出されてきたが、通常の健康なヒトの動脈では検出されていない(Schafer ElinderらによるATVB1997;17(10):2257〜2263を参照のこと)。
6週齢の雄性ApoE KOマウスを、4−{3−[1−ベンズヒドリル−5−クロロ−2−(2−{[(3,4−ジクロロベンジル)スルホニル]アミノ}エチル)−1H−インドール−3−イル]プロピル}安息香酸(化合物C)で処置した。マウスに、1.3mg/gおよび3.3mg/gの化合物C(各々、〜250ng/mLおよび〜500ng/mLの最大の薬物曝露となった)、またはビヒクルを補充した通常の固形飼料の食餌を20週間与えた。下記の表に示す通り、対照動物と比較した場合、処置の9週間および20週間後に、血清トロンボキサンB2値は、有意に減少した。
ApoE KOマウスに、3.3mg/g(固形飼料もしくはビヒクル)の化合物Cまたは実施例10の化合物を補充した通常の固形飼料の食餌を2日間与えた。後眼窩洞から血液を回収し、37°にて1時間凝固させた。次いで、血清を単離し、ELISAによってトロンボキサンB2をアッセイした。トロンボキサン濃度(ng/mL)は、ビヒクル:76.1±17.3;化合物C(3.3mg/g):33.5±11.6;実施例10の化合物:(3.3mg/g):1.4±0.7であることが見出された。
脳卒中モデルにおけるcPLA2阻害剤投与の効果を下記の手順によって決定した。
初代小脳顆粒ニューロンを、P5−8ラットの子から単離した。簡潔に言うと、小脳を回収し、Ca2+およびMg2+を含有しない氷冷のリン酸緩衝生理食塩水(PBS)中にプールした。組織を細かく刻み、アール平衡塩類溶液中にパパイン20IU/ml(Worthington Biochemical社製、Freehold、NJ)を含有する酵素的解離培地に移し、30分間37℃にてインキュベーションした。酵素的解離後に、パパイン溶液を吸引し、DNアーゼ2,000IU/mlおよびオボムコイドプロテアーゼ阻害剤10mg/mlを含有する完全培地[B−27サプリメント(Gibco社製、Grand Island、NY)、ペニシリン/ストレプトマイシン、アフィディコリン、グルタメート、塩化カリウムを有するNeurobasal培地]中で、先端熱加工したパスツールピペットを用いて組織を機械的に粉砕した。完全培地中の単細胞懸濁液を、5.0×105細胞/ウェルの密度で、プレコーティングしたポリ−L−オルニチン/ラミニン24−ウェルプレート(Becton−Dickinson社製、Bedford、MA)上に蒔いた。実験前に細胞を2週間保持した。
培養物を、OGDの60分前に様々な濃度の化合物Aで処理した。嫌気チャンバー(80%窒素、10%水素、10%二酸化炭素のガス混合物)内で培地を除去し、脱酸素緩衝液と交換した。新鮮な化合物A、実施例34または実施例41の化合物を培養物に加え、嫌気チャンバー内に2時間保持した。インキュベーションの終わりに、新鮮な培地に交換し、新鮮な化合物Aを加えた。培養物をさらに24時間正常酸素圧のインキュベーター中に保持した。24時間後に培地への乳酸デヒドロゲナーゼ放出を測定することにより、細胞死を決定した(Roche Biochemicals社製)。下記の表において、対照、OGD、様々な濃度の化合物A、および正の対照のNMDA受容体アンタゴニストであるMK801の値を示す。
パーキンソン病モデルにおけるcPLA2阻害剤投与の効果を、下記の手順によって決定した。
Pong K.らによる(1997)J.Neurochem.69 986〜994に記載されているように、初代ドーパミンニューロンを、E15ラット胚から単離した。簡潔に言うと、腹側中脳を単離し、Ca2+およびMg2+を含有しない氷冷のリン酸緩衝生理食塩水(PBS)中に組織をプールした。組織をアール平衡塩類溶液中にパパイン20IU/ml(Worthington Biochemical社製、Freehold、NJ)を含有する酵素的解離培地に移し、30分間37℃にてインキュベーションした。酵素的解離後に、パパイン溶液を吸引し、DNアーゼ2,000IU/mlおよびオボムコイドプロテアーゼ阻害剤10mg/mlを含有する完全培地[B−27サプリメント(Gibco社製、Grand Island、NY)、ペニシリン/ストレプトマイシン、アフィディコリン、グルタメートを有するNeurobasal培地]中で、先端熱加工したパスツールピペットを用いて組織を機械的に粉砕した。完全培地中の単細胞懸濁液を、5.0×105細胞/ウェルの密度で、プレコーティングしたポリ−L−オルニチン/ラミニン24−ウェルプレート(Becton−Dickinson社製、Bedford、MA)上に蒔いた。実験前に細胞を1週間保持した。
MPTPの有毒代謝物である神経毒MPP+への曝露の数時間前に、培養物を様々な濃度の化合物A、化合物B、化合物CおよびGDNF(グリア細胞由来神経栄養因子、正の対照)で処理した。培養物を10μMのMPP+に60分間曝した。曝露後に、新鮮な培地に交換し、新鮮な化合物を加えた。Pongらにより1997(上述)に記載されたように、3H−ドーパミン取込みを測定することによって、ドーパミンニューロン生存率を24時間後に決定した。結果を下記の表に示す。
実施例10の化合物を使用したin vivoの薬理学研究を行い、カラギーナン足浮腫モデル(Winter,C.A.らによるProc Soc Exp Biol Med1962;111:544〜547を参照されたい)、コラーゲン誘導関節炎モデル(Trentham,D.E.らによるJ Exp.Med146;828〜833を参照されたい)、および痛覚過敏の完全フロイントアジュバント(CFA)誘導モデル(Stein CらによるPharmacology Biochemistry & Behavior,1988;31:445〜451を参照されたい)を含めた炎症および末梢性疼痛のモデルにおける経口投与の有効性を示した。プロスタグランジンおよびロイコトリエンのin vivo阻害も、痛覚過敏モデルにおけるCFA攻撃誘発された足で測定した。
カラギーナン足浮腫アッセイは、プロスタグランジンの生成をもたらす化合物のin vivo評価のために特に有用な炎症の急性モデルである。特に、NSAIDは、このモデルにおいて独特に用量反応的に浮腫を抑制し、このモデルにおけるNSAID活性はヒトにおいて観察される活性とよく一致する(Mukherjee AらによるInflamm Res.1996;45:531〜540を参照されたい)。したがって、実施例10の化合物をカラギーナン足浮腫モデルにおいて試験した。このモデルに、カラギーナンの足蹠内注射の2時間前に、化合物を経口投与し、その後3時間に亘り足腫脹の抑制を決定した。足浮腫は、3mg/kgの低さの用量で統計的に有意に減少し、おおよその(最大阻害の50%に基づいた)ED50は、7.5mg/kgであると決定した。
実施例10の化合物を、ヒト慢性関節リウマチとの多くの免疫的および病理的類似性を有する、マウスCIAモデルにおいて試験した(Trentham,D.E.らによる上記を参照されたい)。ウシII型コラーゲンおよびCFAのエマルジョンの皮内注射と、当初の免疫化の21日後の不完全フロイントアジュバント中に乳化したウシII型コラーゲン皮内注射による追加免疫によって、DBA/1LacJマウスにおいて関節炎を誘導した。動物の10%が病徴を示すときに開始する準治療的投与計画において、化合物の有効性を評価した。その時点で、動物を投与群に無作為に割振り、実施例10の化合物(100mg/kg)PO BIDを28日間投与した。対照群はセレコキシブ、ビヒクル単独を与えられるか、または無処置で放置された。全ての動物は、毎日盲検法で病徴の視覚的兆候を点数付けされた。
末梢感覚ニューロンが侵害刺激および非侵害刺激の両方に反応し、慢性疼痛をもたらすように、末梢感覚ニューロンの感受性を高めることができる(Julius,D.らによるNature.2001;413:203;Woolf,C.J.らによるScience.200;288:1765を参照されたい)。炎症および組織の損傷部位のプロスタグランジンおよびロイコトリエンは、この疼痛反応の増強に部分的に関与している。プロスタグランジンは、イオンチャネルのリン酸化反応を促進し、興奮性を増加させ、感覚ニューロン疼痛閾値を下げる。同じように、ロイコトリエンB4および関連する12−LOのアラキドン酸代謝物は、熱および低pHに反応するニューロン上のカプサイシン受容体(またはVR1)イオンチャネルに結合し活性化する(Piomelli D.によるTRENDS in Pharmacological Sciences,January2001;22(1):17〜29を参照されたい)。実施例10の化合物の効果を、CFA誘導痛覚過敏モデルにおいて測定し、末梢および中心部位での脂質メディエーター生成を測定した。
喘息は、多くの細胞および細胞成分が関与している気道の慢性炎症性疾患として定義されてきた。感受性の高い個体において、この炎症は、特に夜または早朝に、喘鳴、息切れ、胸苦しさおよび咳嗽の反復性または持続性のエピソードをもたらす。これらのエピソードは通常、広範に亘るが可変性の気道閉塞と関連し、これは自発的または治療によって解消する場合が多い。この炎症はまた、種々の刺激に対する既往の気管支過敏性の関連する増大ももたらす。喘息の前臨床モデルは、疾患の病態の発症機序への洞察をもたらし、喘息治療の発達に役立ってきた。特に、アレルゲン誘発性肺炎症のげっ歯類モデルは、アレルギー性喘息と関連する炎症を阻害する化合物のin vivo評価に有用であり、グルココルチコイド、ロイコトリエン受容体アンタゴニスト、5−L0阻害剤、およびホスホジエステラーゼ4阻害剤の有効性を評価するために広範囲に使用されてきた(Kumar,R.K.らによるJ Pharmacol Exp Ther.2003;307:349〜355;Wu,A.Y.らによるClin Exp Allergy.2003;33:359〜366;Bell,R.L.らによるJ Pharmacol Exp Ther1997;280:1366〜1373;およびHenderson,W.R.,Jr.らによるJ Exp Med.1996;184:1483〜1494を参照されたい)。
Brown Norwayラットモデルにおいて実施例10の化合物の有効性を評価した(オボアルブミン(OVA)感作動物は、1日目および2日目に気道を介してオボアルブミンの(OVA)エアロゾルを攻撃誘発された)。OVA感作ラットは、エアロゾルを介して1日目および2日目に攻撃誘発を受けた。実施例10の化合物を、2日間の攻撃誘発期間に亘り攻撃誘発の1時間前および攻撃誘発の10時間後に30mg/kg PO BIDで投与した。1日目および2日目の攻撃誘発1時間前に、デキサメタゾンを3mg/kg IPで投与した。3日目に動物を屠殺し、細胞流入の分析のために気管支肺胞腔を洗浄した。2日間に亘る攻撃誘発期間における30mg/kgの経口BID投与は、8回の独立した研究において8回とも気管支肺胞洗浄液(BALF)の好酸球流入を統計的に有意に阻害した。実施例10の化合物はまた、試験した用量でBALF内の炎症細胞の総数を統計的に有意に減少させたが、このモデルにおいてリンパ球または好中球流入には有意な効果を及ぼさなかった。
アレルゲン誘発性可逆的気道狭窄およびAHRは、喘息のヒツジモデルにおいてin vivoで調べることのできるアレルギー性喘息の2つの顕著な特徴である。この動物モデルにおいて行われる研究は、アラキドン酸代謝物の放出は抗原攻撃誘発に対する気管支遅延反応の発生において重要な役割を果たしているという有力な証拠を提供する(Abraham,W.M.らによるRespiration.1989;56:48〜56を参照されたい)。回虫抗原の吸入後の急性気管支収縮の間のLO経路によるロイコトリエンの放出は、後発事象、すなわち遅発型反応および気管支過敏性の開始の主要因を表す。5−LO阻害剤ジレウトンは、このモデルにおいて抗原誘発性の気道の遅発型反応、炎症、およびAHRを阻止し、一方選択的LTD4受容体アンタゴニストであるモンテルカストの静脈への連続IV注入は、即時型および遅発型喘息反応の両方を減少させる(Abraham,W.M.らによるEur J Pharmacol1992;217:119〜126;Jones,T.R.らによるCan J Physiol Pharmacol.1995;73:191〜201を参照されたい)。さらに、デュアルLTD4/TXB2阻害剤の経口投与は、即時型および遅発型反応の両方、ならびにカルバコールおよびヒスタミンへのAHRを阻害することができる(Abraham,W.M.らによるJ Pharmacol Exp Ther.1988;247:1004〜1011を参照されたい)。PAFはまた、このモデルにおける遅発型反応に結び付けられてきており、cPLA2αアンタゴニストによる脂質メディエーターのより完全な遮断は、現在の抗ロイコトリエンと比較して臨床的により有効であり得るという概念をさらに支持する(Abraham,W.M.らによるJ Appl Physiol.1989;66:2351〜2357を参照されたい)。
Claims (34)
- 3−{4−[(2−{5−クロロ−1−(ジフェニルメチル)−2−[2−({[2−(トリフルオロメチル)ベンジル]スルホニル}アミノ)エチル]−1H−インドール−3−イル}エチル)スルホニル]フェニル}プロパン酸である化合物またはその医薬上許容される塩。
- 請求項1記載の化合物またはその医薬上許容される塩および医薬上許容される担体を含む医薬組成物。
- プロスタグランジン、ロイコトリエンまたは血小板活性化因子により引き起こされるか、あるいは進行する炎症を治療するための、請求項1記載の化合物またはその医薬上許容される塩を含む医薬組成物。
- プロスタグランジン、ロイコトリエンまたは血小板活性化因子により引き起こされるか、あるいは進行する痛みを治療するための、請求項1記載の化合物またはその医薬上許容される塩を含む医薬組成物。
- 喘息を治療するための、請求項1記載の化合物またはその医薬上許容される塩を含む医薬組成物。
- 関節障害およびリウマチ障害を治療するための、請求項1記載の化合物またはその医薬上許容される塩を含む医薬組成物。
- 障害が関節リウマチである請求項6記載の医薬組成物。
- 障害が変形性関節症である請求項6記載の医薬組成物。
- 障害が若年性関節炎である請求項6記載の医薬組成物。
- 疾患または障害の治療または予防、あるいはかかる疾患または障害の兆候の進行を防止するための、請求項1記載の化合物またはその医薬上許容される塩を含む医薬組成物であって、該疾患または障害が、卒中、アテローム性動脈硬化症、多発性硬化症、パーキンソン、卒中による中枢神経系損傷、虚血による中枢神経系損傷および傷害による中枢神経系損傷から選択される組成物。
- 疾患または障害が卒中である請求項10記載の医薬組成物。
- 疾患または障害がアテローム性動脈硬化症である請求項10記載の医薬組成物。
- 疾患または障害が多発性硬化症である請求項10記載の医薬組成物。
- 疾患または障害がパーキンソン病である請求項10記載の医薬組成物。
- 疾患または障害が、卒中、虚血または傷害による中枢神経系損傷である請求項10記載の医薬組成物。
- 静脈または動脈血血栓症の治療または予防、あるいはかかる血栓症の兆候の進行を防止するための、請求項1記載の化合物またはその医薬上許容される塩を含む医薬組成物。
- 血栓症がアテローム性血栓症である請求項16記載の医薬組成物。
- さらに抗炎症剤を含む請求項2記載の医薬組成物。
- さらに抗喘息剤を含む請求項2記載の医薬組成物。
- 哺乳動物においてプロスタグランジン、ロイコトリエンまたは血小板活性化因子により引き起こされるか、あるいは進行する炎症を治療するための医薬の製造における、請求項1記載の化合物またはその医薬上許容される塩の使用。
- 哺乳動物においてプロスタグランジン、ロイコトリエンまたは血小板活性化因子により引き起こされるか、あるいは進行する痛みを治療するための医薬の製造における、請求項1記載の化合物またはその医薬上許容される塩の使用。
- 哺乳動物において喘息を治療するための医薬の製造における、請求項1記載の化合物またはその医薬上許容される塩の使用。
- 哺乳動物において関節障害およびリウマチ障害を治療するための医薬の製造における、請求項1記載の化合物またはその医薬上許容される塩の使用。
- 障害が関節リウマチである請求項23記載の使用。
- 障害が変形性関節症である請求項23記載の使用。
- 障害が若年性関節炎である請求項23記載の使用。
- 哺乳動物における疾患または障害の治療または予防、あるいはかかる疾患または障害の兆候の進行を防止するための医薬の製造における請求項1記載の化合物またはその医薬上許容される塩の使用であって、該疾患または障害が、卒中、アテローム性動脈硬化症、多発性硬化症、パーキンソン、卒中による中枢神経系損傷、虚血による中枢神経系損傷および傷害による中枢神経系損傷から選択される使用。
- 疾患または障害が卒中である請求項27記載の使用。
- 疾患または障害がアテローム性動脈硬化症である請求項27記載の使用。
- 疾患または障害が多発性硬化症である請求項27記載の使用。
- 疾患または障害がパーキンソン病である請求項27記載の使用。
- 疾患または障害が、卒中、虚血または傷害による中枢神経系損傷である請求項27記載の使用。
- 哺乳動物における静脈または動脈血血栓症の治療または予防、あるいはかかる血栓症の兆候の進行を防止するための医薬の製造における請求項1記載の化合物またはその医薬上許容される塩の使用。
- 血栓症がアテローム性血栓症である請求項33記載の使用。
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JP7365706B2 (ja) | 2018-02-16 | 2023-10-20 | ワジンスキ,パヴェル | 形状変化が可能な二輪自転車 |
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