JP6749234B2 - 皮膚修復のための化合物及び方法 - Google Patents
皮膚修復のための化合物及び方法 Download PDFInfo
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- JP6749234B2 JP6749234B2 JP2016517557A JP2016517557A JP6749234B2 JP 6749234 B2 JP6749234 B2 JP 6749234B2 JP 2016517557 A JP2016517557 A JP 2016517557A JP 2016517557 A JP2016517557 A JP 2016517557A JP 6749234 B2 JP6749234 B2 JP 6749234B2
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- ethyl
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- methyl
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- UGOMMVLRQDMAQQ-UHFFFAOYSA-N xphos Chemical compound CC(C)C1=CC(C(C)C)=CC(C(C)C)=C1C1=CC=CC=C1P(C1CCCCC1)C1CCCCC1 UGOMMVLRQDMAQQ-UHFFFAOYSA-N 0.000 description 1
- 239000011787 zinc oxide Substances 0.000 description 1
- 235000014692 zinc oxide Nutrition 0.000 description 1
- CPYIZQLXMGRKSW-UHFFFAOYSA-N zinc;iron(3+);oxygen(2-) Chemical compound [O-2].[O-2].[O-2].[O-2].[Fe+3].[Fe+3].[Zn+2] CPYIZQLXMGRKSW-UHFFFAOYSA-N 0.000 description 1
- 239000002076 α-tocopherol Substances 0.000 description 1
- 235000004835 α-tocopherol Nutrition 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
- C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
- C07D409/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
- A61P17/02—Drugs for dermatological disorders for treating wounds, ulcers, burns, scars, keloids, or the like
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C65/00—Compounds having carboxyl groups bound to carbon atoms of six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups
- C07C65/21—Compounds having carboxyl groups bound to carbon atoms of six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups containing ether groups, groups, groups, or groups
- C07C65/24—Compounds having carboxyl groups bound to carbon atoms of six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups containing ether groups, groups, groups, or groups polycyclic
- C07C65/26—Compounds having carboxyl groups bound to carbon atoms of six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups containing ether groups, groups, groups, or groups polycyclic containing rings other than six-membered aromatic rings
-
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- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C65/00—Compounds having carboxyl groups bound to carbon atoms of six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups
- C07C65/21—Compounds having carboxyl groups bound to carbon atoms of six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups containing ether groups, groups, groups, or groups
- C07C65/28—Compounds having carboxyl groups bound to carbon atoms of six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups containing ether groups, groups, groups, or groups having unsaturation outside the aromatic rings
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- 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
- C07D209/08—Indoles; Hydrogenated indoles with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached to carbon atoms of the hetero ring
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- 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
- C07D209/12—Radicals substituted by oxygen atoms
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- 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
- C07D209/18—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- 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
- C07D209/18—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D209/22—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals with an aralkyl radical attached to the ring nitrogen atom
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- 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
- C07D209/18—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D209/26—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals with an acyl radical attached to the ring nitrogen atom
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- 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
- C07D209/44—Iso-indoles; Hydrogenated iso-indoles
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
- C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
- C07D215/04—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached to the ring carbon atoms
- C07D215/06—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached to the ring carbon atoms having only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, attached to the ring nitrogen atom
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
- C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
- C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D215/48—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
-
- 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
Description
式中、
点線は、任意の結合を表すが、但し、E1との1つの任意の結合のみが存在することを条件とし、
E1及びE2は、それぞれ独立して、CまたはNであり、
L1は、結合、C1〜C4アルキレン、C2〜C4アルケニレン、または
C2〜C4アルキニレンであり、
L2は、結合、C1〜C4アルキレン、
であり、
Ar1及びAr2は、それぞれ独立して、アリールまたはヘテロアリールであり、
R1、R2、及びR3は、それぞれ独立して、−CO2H、ハロゲン、−CF3、アルコキシ、ベンジルオキシ、C1〜C4アルキル、−OH、−OCH2CO2H、−CH=CHCO2H、またはNRaRbであり、式中、Ra及びRbは、それぞれ独立して、Hまたは低級アルキルであり、
nは、1または2であり、
m及びpは、それぞれ独立して、1〜5であり、
qは、0〜3である。
式中、
点線は、任意の結合を表し、
E1及びE2は、それぞれ独立して、CまたはNであり、
L1は、C1〜C4アルキレン、アルケニレン、またはアルキニレンであり、
L2は、C0〜C4アルキレン、
であり、
Ar1及びAr2は、それぞれ独立して、アリールまたはヘテロアリールであり、
R1、R2、及びR3は、それぞれ独立して、−CO2H、ハロゲン、−CF3、アルコキシ、ベンジルオキシ、C1〜C4アルキル、−OH、またはNRaRbであり、式中、Ra及びRbは、それぞれ独立して、Hまたは低級アルキルであり、
nは、1または2であり、
m及びpは、それぞれ独立して、1〜5であり、
qは、0〜3である。
式中、
点線は、任意の結合を表すが、但し、E1との1つの任意の結合のみが存在することを条件とし、
E1及びE2は、それぞれ独立して、CまたはNであり、
L1は、結合、C1〜C4アルキレン、C2〜C4アルケニレン、またはC2〜C4アルキニレンであり、
L2は、結合、C1〜C4アルキレン、
であり、
Ar1及びAr2は、それぞれ独立して、アリールまたはヘテロアリールであり、
R1、R2、及びR3は、それぞれ独立して、−CO2H、ハロゲン、−CF3、アルコキシ、ベンジルオキシ、C1〜C4アルキル、−OH、−OCH2CO2H、−CH=CHCO2H、またはNRaRbであり、式中、Ra及びRbは、それぞれ独立して、Hまたは低級アルキルであり、
nは、1または2であり、
m及びpは、それぞれ独立して、1〜5であり、
qは、0〜3である、化合物が提供される。
上記の式(I)の化合物が、本明細書で提供される。
式中、
点線は、任意の結合を表し、
E1及びE2は、それぞれ独立して、CまたはNであり、
L1は、C1〜C4アルキレン、アルケニレン、またはアルキニレンであり、
L2は、C0〜C4アルキレン、
であり、
Ar1及びAr2は、それぞれ独立して、アリールまたはヘテロアリールであり、
R1、R2、及びR3は、それぞれ独立して、−CO2H、ハロゲン、−CF3、アルコキシ、ベンジルオキシ、C1〜C4アルキル、−OH、またはNRaRbであり、式中、Ra及びRbは、それぞれ独立して、Hまたは低級アルキルであり、
nは、1または2であり、
m及びpは、それぞれ独立して、1〜5であり、
qは、0〜3である、化合物が提供される。
式中、
点線は、任意の結合を表すが、但し、1つの任意の結合のみが存在することを条件とし、
L1は、結合、C1〜C2アルキレン、C2アルケニレン、C2アルキニレン、または−OCH2−であり、
L2は、CH2であり、
Ar1及びAr2は、それぞれ、フェニルであり、
R1は、−CO2H、−OCH2CO2H、または−CH=CHCO2Hであり、
各R2は、独立して、ハロゲン、−CF3、C1〜C4アルキル、またはC1〜C4アルコキシであり、
R3は、H、ハロゲン、またはC1〜C4アルコキシであり、
p及びvは、それぞれ独立して、1または2である、化合物が提供される。
メチル4−(2−(インドリン−7−イル)エチル)ベンゾエート。THF(10mL)中のメチル4−ビニルベンゾエート(536mg、3.33mmol)及び9−BBNダイマー(812mg、3.33mmol)の溶液を室温で19時間攪拌し、次いで0.5mLのH2Oを添加した。30分後、溶液を10mLのDMF中の7−ブロモインドリン(527mg、2.66mmol)及びPdCl2(dppf)(448mg、0.55mmol)の混合物へ、カニューレで移した。K3PO4溶液(1.4mL、3M)を5分後に添加し、この濃い色の混合物を、室温で一晩攪拌した。次いで、混合物を50mLの酢酸エチルと50mLのH2Oとの間で分配し、酢酸エチル溶液をH2O(3×50mL)でさらに洗浄した。次いで、溶液を乾燥させ(Na2SO4)、濾過し、蒸発させた。Teledyne IscoのCombiflash装置を用いて、シリカゲル上でのフラッシュクロマトグラフィー(0%酢酸エチル/ヘキサン→40%)と、続いて別のフラッシュクロマトグラフィー(0%酢酸エチル/CH2Cl2→10%)による残渣の精製で、表題の化合物(320mg、33%)を得た。
tert−ブチル3,4−ジヒドロキノリン−1(2H)−カルボン酸。二炭酸ジ−tert−ブチル(1.181g、5.4mmol)を、CH3CN(15mL)中1,2,3,4−テトラヒドロキノリン(626mg、4.7mmol)、トリエチルアミン(1.3mL、9.3mmol)、及びDMAP(112mg、0.19mmol)の溶液に添加した。反応を室温で1.5時間攪拌し、次いで55℃で一晩加熱した。溶液を、室温まで冷まし、次いで蒸発させた。残渣を25mLの酢酸エチルと25mLの1M HClとの間で分配した。酢酸エチル溶液を、1M HCl(2×25mL)及び25mLのブラインでさらに洗浄し、次いで乾燥させ(Na2SO4)、濾過し、蒸発させた。Teledyne IscoのCombiflash装置を用いて、シリカゲル上でのフラッシュクロマトグラフィー(0%酢酸エチル/ヘキサン→40%)による残渣の精製で、表題の化合物(139mg、13%)を得た。
メチル4−(2−(1,2,3,4−(テトラヒドロキノリン−8−イル)エチル)ベンゾエート。上述のメチル4−(2−(インドリン−7−イル)エチル)ベンゾエートについての手順を使用し、8−ヨード−1,2,3,4−テトラヒドロキノリン(57mg、0.22mmol)及びメチル4−ビニルベンゾエート(46mg、0.29mmol)で開始し、これで、表題の化合物(31mg、0.10mmol、48%)を得た。
4−ブロモ−2−(3−メトキシベンジル)イソインドリン。2mLのアセトン中4−ブロモイソインドリン(98mg、0.49mmol)、3−メトキシベンジルブロミド(69μL、0.49mmol)、及びK2CO3(66mg、0.48mmol)の混合物を、室温で攪拌した。一晩の攪拌後、混合物を25mLのH2O/25mLのCH2Cl2の間で分配した。水層をCH2Cl2(25mL)でさらに抽出し、混合有機溶液を乾燥させ(Na2SO4)、濾過し、蒸発させた。Teledyne IscoのCombiflash装置を用いて、シリカゲル上でのフラッシュクロマトグラフィー(0%酢酸エチル/ヘキサン→40%)による残渣の精製で、表題の化合物(32mg、20%)を得た。
メチル4−(2−(イソインドリン−4−イル)エチル)ベンゾエート。メチル4−(2−(インドリン−7−イル)エチル)ベンゾエートについての上述の手順を使用し、4−ブロモイソインドリン(252mg、0.1.27mmol)及びメチル4−ビニルベンゾエート(246mg、1.53mmol)で開始した。シリカゲル上でのフラッシュクロマトグラフィーによる粗生成物の精製(2%メタノール/CH2Cl2(0.5%トリエチルアミン)→4%)で、表題の化合物(155mg、43%)を得た。
メチル5−ブロモチオフェン−2−カルボン酸。30mLのCH3OH中5−ブロモチオフェン−2−カルボン酸(4.995g、24.1mmol)/8mLの塩化アセチルの溶液を、65℃で加熱した。22時間後、反応を、室温まで冷まし、次いで、蒸発させた。残渣を100mLの飽和NaHCO3溶液/75mLの酢酸エチルの間で分配した。酢酸エチル層を飽和NaHCO3溶液(75mL)でさらに洗浄し、次いで乾燥させ(Na2SO4)、濾過し、蒸発させ、表題の化合物(4.921g、22.3mmol、93%)を得た。
この中間体を、スキーム1で示されるもの及び上述の類似の手順を用いて、最終化合物の特質を持たせた。
7−ヨード−1−(3−メトキシベンジル)−1H−インドール。NaH(鉱油中54mg、1.3mmol、60%)を7−ヨード−1H−インドール(273mg、1.1mmol)の溶液に添加した。15分後、3−メトキシベンジルブロミド(169μL、1.2mmol)を添加し、混合物を室温で攪拌した。20時間後、反応を30mLの酢酸エチル/25mLのH2Oの間で分配した。有機層を、H2O(3×25mL)でさらに洗浄し、次いで乾燥させ(Na2SO4)、濾過し、蒸発させた。Teledyne IscoのCombiflash装置を用いて、シリカゲル上でのフラッシュクロマトグラフィー(0%酢酸エチル/ヘキサン→40%)による残渣の精製で、表題の化合物(314mg、79%)を得た。
1−(7−ブロモインドリン−1−イル)−2−(3−メトキシフェニル)エタノン。2mLのCH2Cl2中2−(3−メトキシフェニル)酢酸(124mg、0.75mmol)を7−ブロモインドリン(137mg、0.69mmol)及びN−(3−ジメチルアミノプロピル)−N’−エチルカルボジイミド(EDCI、191mg、1.0mmol)の混合物に添加した。23時間後、10mLの飽和NaHCO3溶液を添加し、得られた混合物をCH2Cl2(2×20mL)で抽出した。有機層を乾燥させ(Na2SO4)、濾過し、蒸発させた。Teledyne IscoのCombiflash装置を用いて、シリカゲル上でのフラッシュクロマトグラフィー(0%酢酸エチル/ヘキサン→60%)による残渣の精製で、表題の化合物(177mg、51%)を得た。
メチル4−(2−(1−(3,5−ジメトキシベンゾイル)インドリン−7−イル)エチル)ベンゾエート。トリエチルアミン(18μL、0.13mmol)をCH2Cl2(0.75mL)中メチル4−(2−(インドリン−7−イル)エチル)ベンゾエート(19mg、0.066mmol)及び3,5−ジメトキシベンゾイルクロリド(13mg、0.065mmol)の溶液に添加した。3時間後、10mLの1M HCl溶液を添加し、得られた混合物を、CH2Cl2(2×20mL)で抽出した。混合有機溶液を乾燥させ(Na2SO4)、濾過し、蒸発させた。Teledyne IscoのCombiflash装置を用いて、シリカゲル上でのフラッシュクロマトグラフィー(0%酢酸エチル/ヘキサン→20%)による残渣の精製で、表題の化合物(26mg、90%)を得た。
メチル4−(2−(1−((3−メトキシフェニル)スルホニル)インドリン−7−イル)エチル)ベンゾエート。ピリジン(26μL、0.32mmol)を、THF(0.5mL)中メチル4−(2−(インドリン−7−イル)エチル)ベンゾエート(23mg、0.080mmol)及び3−メトキシベンゼン−1−塩化スルホニル(12μL、0.085mmol)の溶液に添加した。22時間後、15mLの1M HCl溶液を添加し、得られた混合物を酢酸エチル(20mL)で抽出した。次いで、有機溶液を乾燥させ(Na2SO4)、濾過し、蒸発させた。Teledyne IscoのCombiflash装置を用いて、シリカゲル上でのフラッシュクロマトグラフィー(0%酢酸エチル/ヘキサン→40%)による残渣の精製で、表題の化合物(32mg、89%)を得た。
4−(2−(1−((3,5−ジメトキシフェニル)スルホニル)インドリン−7−イル)エチル)安息香酸。4−(2−(1−(3−フルオロベンジル)インドリン−7−イル)エチル)安息香酸についての上述の手順を、80℃の代わりに60℃での加熱を用いて使用した。
7−ブロモ−1−(3−メトキシベンジル)インドリン。1.2mLのDMF中7−ブロモインドリン(152mg、0.77mmol)、3−メトキシベンジルブロミド(107μL、0.76mmol)、及びK2CO3(170mg、1.2mmol)の混合物を室温で3時間、及び50℃で20時間攪拌した。次いで、混合物を室温まで冷まし、25mLの酢酸エチルと25mLのH2Oとの間で分配した。有機層をH2O(3×25mL)でさらに洗浄し、次いで乾燥させ(Na2SO4)、濾過し、蒸発させ、次の工程で直接使用する表題の化合物を得た。
tert−ブチル5−フルオロインドリン−1−カルボン酸。Iwao,M.;Kuraishi,T.Heterocycles 1992,34,1031に記載されるものと同様の手順を使用した。2mLのTHF中5−フルオロインドリン(100mg、0.73mmol)及び二炭酸ジ−tert−ブチル(188mg、0.86mmol)の溶液を、室温で一晩攪拌した。この時に、20mLの飽和NaHCO3溶液を添加し、混合物を酢酸エチル(20mL)で抽出した。次いで、酢酸エチル溶液を、乾燥し(Na2SO4)、濾過し、蒸発させた。Teledyne IscoのCombiflash装置を用いて、シリカゲル上でのフラッシュクロマトグラフィー(0%酢酸エチル/ヘキサン→20%)による残渣の精製で、表題の化合物(140mg、81%)を得た。
7−ブロモ−1−(3,5−ジメトキシベンジル)−2,3−ジヒドロ−1H−インデン−1−オール。0.5mLのTHF中7−ブロモ−2,3−ジヒドロ−1H−インデン−1−オン(102mg、0.48mmol)の溶液を、3,5−ジメトキシベンジルマグネシウムブロミド(3.8mL、0.95mmol、0.25M/2−メチルテトラヒドロフラン、Novel Chemical Solutionsから)の0℃溶液にカニューレによって滴加し、0.5mLのTHFですすいだ。反応を、0℃で30分間攪拌し、次いで室温まで温めた。2時間後、30mLの飽和NH4Cl溶液を添加し、得られた混合物を、酢酸エチル(3×20mL)で抽出した。混合酢酸エチル溶液を乾燥させ(Na2SO4)、濾過し、蒸発させた。Teledyne IscoのCombiflash装置を用いて、シリカゲル上でのフラッシュクロマトグラフィー(酢酸エチル/ヘキサン)による残渣の精製で、表題の化合物(145mg、83%)を得た。
競合結合実験を、Hankの平衡塩類溶液、ヘペス20mM、pH7.3、細胞膜(〜60μgタンパク質)またはヒトEP2受容体を安定的に発現するHEK293細胞からの2×105の細胞、[3H]PGE2(10nM)、及び300μlの総体積の様々な濃度の試験化合物を含有する媒体で実施した。反応混合物を、23℃で60分間培養し、真空下、Whatman GF/Bフィルター上で濾過した。フィルターを、50mMのTris/HCl(pH7.3)を含有する5mLの氷のように冷たい緩衝液で3回洗浄した。不特定の結合を、過剰未標識PGE2(10μM)の存在下で推定した。結合データは、非線形回帰分析を用いて、結合部位の単一のクラスの結合モデルに適合させた。これによって得られたIC50値を、[L]が、PGE2濃度(10nM)を表し、KDが、ヒトEP2受容体の[3H]PGE2の解離定数(40nM)を表す、Ki=(IC50/(1+[L]/KD)の方程式を用いて、Kiに転換した。
放射リガンド結合
ヒトもしくはネコFP受容体、またはEP1受容体、EP2受容体、もしくはEP4受容体を安定的に発現するHEK−293細胞を、TME緩衝液で洗浄し、フラスコの底部から削り取り、Brinkman PT10/35ポリトロンを用いて30秒間均質にした。遠心管内に最終的な40mLの体積を達成するために、TME緩衝液を添加した。(TMEの組成物は、100mM TRIS系、20mM MgCl2、2M EDTA;7.4のpHを達成するために10N HClを添加する)。
(a)細胞培養
組み換えヒトプロスタグランジン受容体(プロスタグランジン受容体は、hDP/Gqs5、hEP1、hEP2/Gqs5、hEP3A/Gqi5、hEP4/Gqs5、hFP、hIP、hTPを発現した)の一タイプまたはサブタイプを安定的に発現するHEK−293(EBNA)細胞を、100mm培養皿で、10%ウシ胎仔血清、2mMのL−グルタミン、選択マーカーとして250g/mlのジェネテシン(G418)及び200mg/mlのハイグロマイシンB、ならびに100単位/mlのペニシリンG、100g/mlのストレプトマイシン、及び0.25mg/mlのアムホテリシンBを含有する高グルコースDMEM媒体中で培養した。
細胞を、1ウェル当たり5×104細胞の密度でBiocoat(登録商標)ポリ−D−リジンでコーティングされた黒壁で明澄な底部の96ウェルプレート(Becton−Dickinson)に播種し、培養器内、37℃で一晩付着させた。次いで、細胞を、Denley Cellwashプレート洗浄機(Labsystems)を用いて、HBSS−HEPES緩衝液(重炭酸及びフェノールレッドを含まないHanks平衡塩類溶液、20mM HEPES、pH7.4)で2回洗浄した。カルシウム感受性染料Fluo−4AMを用いて、2mMの最終濃度での暗中における染料充填の45分後、プレートをHBSS−HEPES緩衝液で4回洗浄、過剰染料を除去し、各ウェルに100mL残した。プレートを、数分間37℃に再平衡化した。
式中、
点線は、任意の結合を表すが、但し、E1との1つの任意の結合のみが存在することを条件とし、
E1及びE2は、それぞれ独立して、CまたはNであり、
L1は、結合、C1〜C4アルキレン、C2〜C4アルケニレン、またはC2〜C4アルキニレンであり、
L2は、結合、C1〜C4アルキレン、
であり、
Ar1及びAr2は、それぞれ独立して、アリールまたはヘテロアリールであり、
R1、R2、及びR3は、それぞれ独立して、−CO2H、ハロゲン、−CF3、アルコキシ、ベンジルオキシ、C1〜C4アルキル、−OH、−OCH2CO2H、−CH=CHCO2H、またはNRaRbであり、式中、Ra及びRbは、それぞれ独立して、Hまたは低級アルキルであり、
nは、1または2であり、
m及びpは、それぞれ独立して、1〜5であり、
qは、0〜3である、化合物。
式中、
点線は、任意の結合を表し、
E1及びE2は、それぞれ独立して、CまたはNであり、
L1は、C1〜C4アルキレン、C2〜C4アルケニレン、またはC2〜C4アルキニレンであり、
L2は、C0〜C4アルキレン、
であり、
Ar1及びAr2は、それぞれ独立して、アリールまたはヘテロアリールであり、
R1、R2、及びR3は、それぞれ独立して、−CO2H、ハロゲン、−CF3、アルコキシ、ベンジルオキシ、C1〜C4アルキル、−OH、またはNRaRbであり、式中、Ra及びRbは、それぞれ独立して、Hまたは低級アルキルであり、
nは、1または2であり、
m及びpは、それぞれ独立して、1〜5であり、
qは、0〜3である、化合物。
式中、
点線は、任意の結合を表すが、但し、1つの任意の結合のみが存在することを条件とし、
L1は、結合、C1〜C2アルキレン、C2アルケニレン、C2アルキニレン、または−OCH2−であり、
L2は、CH2であり、
Ar1及びAr2は、それぞれフェニルであり、
R1は、−CO2H、−OCH2CO2H、または−CH=CHCO2Hであり、
各R2は、独立して、ハロゲン、−CF3、C1〜C4アルキル、またはC1〜C4アルコキシであり、
R3は、H、ハロゲン、またはC1〜C4アルコキシであり、
p及びvは、それぞれ独立して、1または2である、化合物。
Claims (27)
- 式(I)の化合物であって、
式中、
点線は、任意の結合を表すが、但し、E1との1つの任意の結合のみが存在することを条件とし、
E1及びE2は、それぞれ独立して、CまたはNであり、
L1は、−OCH2 −、C2アルキレン、C2アルケニレン、またはC2アルキニレンであり、
L2は、C1〜C4アルキレン、
であり、
Ar1及びAr2は、それぞれ独立して、アリールまたはヘテロアリールであり、
R1は−CO2Hであり、
R2、及びR3は、それぞれ独立して、−CO2H、ハロゲン、−CF3、アルコキシ、ベンジルオキシ、C1〜C4アルキル、−OH、−OCH2CO2H、−CH=CHCO2H、またはNRaRbであり、式中、Ra及びRbは、それぞれ独立して、HまたはC1〜C6アルキルであり、
nは、1であり、
m及びpは、それぞれ独立して、1または2であり、
qは、0〜3である、前記化合物。 - L1は、C2アルキレンである、請求項1に記載の前記化合物。
- L2は、C1〜C4アルキレンである、請求項1に記載の前記化合物。
- L2は、C1アルキレンである、請求項3に記載の前記化合物。
- Ar1は、アリールである、請求項1に記載の前記化合物。
- Ar1は、フェニルまたはナフチルである、請求項5に記載の前記化合物。
- Ar1は、フラニル、チエニル、オキサゾリル、アクリジニル、フェナジニル、ベンズイミダゾリル、ベンゾフラニル、ベンゾオキサゾリル、ベンゾチアゾリル、ベンゾチアジアゾリル、ベンゾチオフェニル、ベンゾオキサジアゾリル、ベンゾトリアゾリル、イミダゾリル、インドリル、イソオキサゾリル、イソキノリニル、インドリジニル、イソチアゾリル、イソインドリルオキサジアゾリル、インダゾリル、ピリジル、ピリダジル、ピリミジル、ピラジニル、ピロリル、ピラジニル、ピラゾリル、プリニル、フタラジニル、プテリジニル、キノリニル、キナゾリニル、キノキサリニル、トリアゾリル、テトラゾリル、チアゾリル、トリアジニル、チアジアゾリル、及びチオフェニル、から選択されるヘテロアリールである、請求項1に記載の前記化合物。
- Ar1は、チオフェニルである、請求項7に記載の前記化合物。
- Ar2は、フェニル及びナフチルから選択されるアリールである、請求項1に記載の前記化合物。
- Ar2は、ベンゾ[d][1,3]ジオキソリル、フラニル、チエニル、オキサゾリル、アクリジニル、フェナジニル、ベンズイミダゾリル、ベンゾフラニル、ベンゾオキサゾリル、ベンゾチアゾリル、ベンゾチアジアゾリル、ベンゾチオフェニル、ベンゾオキサジアゾリル、ベンゾトリアゾリル、イミダゾリル、インドリル、イソオキサゾリル、イソキノリニル、インドリジニル、イソチアゾリル、イソインドリルオキサジアゾリル、インダゾリル、ピリジル、ピリダジル、ピリミジル、ピラジニル、ピロリル、ピラジニル、ピラゾリル、プリニル、フタラジニル、プテリジニル、キノリニル、キナゾリニル、キノキサリニル、トリアゾリル、テトラゾリル、チアゾリル、トリアジニル、チアジアゾリル、及びチオフェニル、から選択されるヘテロアリールである、請求項1に記載の前記化合物。
- Ar2は、ベンゾ[d][1,3]ジオキソリルである、請求項10に記載の前記化合物。
- R2は、ハロゲンである、請求項1に記載の前記化合物。
- R2は、Fである、請求項12に記載の前記化合物。
- R2は、アルコキシである、請求項1に記載の前記化合物。
- R2は、メトキシである、請求項14に記載の前記化合物。
- 式(III)の請求項1に記載の前記化合物であって、
式中、
点線は、任意の結合を表すが、但し、ただ1つの任意の結合が存在し、それがインデン環内に存在することを条件とし、
L1は、C2アルキレン、C2アルケニレン、C2アルキニレン、または−OCH2−であり、
L2は、-CH2であり、
Ar1及びAr2は、それぞれフェニルであり、
R1は、−CO2Hであり、
各R2は、独立して、ハロゲン、−CF3、C1〜C4アルキル、またはC1〜C4アルコキシであり、
R3は、H、ハロゲン、またはC1〜C4アルコキシであり、
pは、1または2であり、vは1である、前記化合物。 - L1は、C2アルキレンであり、R1は、−CO2Hであり、各R2は、ハロゲン、メチル、またはメトキシであり、及び、R3は、Hである、請求項16に記載の前記化合物。
- L1は、C2アルキレンであり、R1は、−CO2Hであり、各R2は、ハロゲン、メチル、またはメトキシであり、R3は、Hであり、及び、pは、2である、請求項16に記載の前記化合物。
- L1は、C2アルキレンであり、R1は、−CO2Hであり、各R2は、メトキシであり、及び、R3は、Hである、請求項16に記載の前記化合物。
- 以下の構造のうちのいずれか1つを有する化合物
- 請求項1〜20のいずれか一項に記載の少なくとも1つの化合物と、それらのための薬学的に許容される担体とを含む、医薬的組成物。
- 請求項1〜20のいずれか一項に記載の化合物を含む、皮膚の欠陥の治療用医薬組成物。
- 肥厚性瘢痕、陥凹瘢痕、皮膚線条、及びこれらの組み合わせからなる群から選択される種類の瘢痕の形成を減少させる、請求項22に記載の医薬組成物。
- 前記皮膚の欠陥は、しわである、請求項22に記載の医薬組成物。
- 顔、首、腕、胴体、背中、脚、及びこれらの組み合わせからなる群から選択される領域に投与される、請求項22に記載の医薬組成物。
- 外科的切開前、手術中、手術後、及びこれらの組み合わせからなる群から選択される時点で投与される、請求項22に記載の医薬組成物。
- 瘢痕形成を最小化、瘢痕形成を予防、しわ形成を予防、及び/または既存のしわの出現を減少させる、請求項22に記載の医薬組成物。
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WO2014151798A2 (en) * | 2013-03-15 | 2014-09-25 | Sony Computer Entertainment Inc. | User-generated recordings of skeletal animations |
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AU2014324650B2 (en) | 2018-12-06 |
CA2924843A1 (en) | 2015-04-02 |
JP2020196731A (ja) | 2020-12-10 |
US9546162B2 (en) | 2017-01-17 |
CN105579438B (zh) | 2019-12-06 |
EP3049392A1 (en) | 2016-08-03 |
US20150094330A1 (en) | 2015-04-02 |
CN105579438A (zh) | 2016-05-11 |
EP3049392B1 (en) | 2019-02-27 |
KR20160058945A (ko) | 2016-05-25 |
JP2016537308A (ja) | 2016-12-01 |
KR102291753B1 (ko) | 2021-08-20 |
AU2014324650A1 (en) | 2016-04-07 |
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