JP4452969B2 - Indole compound, its production method and use - Google Patents
Indole compound, its production method and use Download PDFInfo
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- JP4452969B2 JP4452969B2 JP2001517524A JP2001517524A JP4452969B2 JP 4452969 B2 JP4452969 B2 JP 4452969B2 JP 2001517524 A JP2001517524 A JP 2001517524A JP 2001517524 A JP2001517524 A JP 2001517524A JP 4452969 B2 JP4452969 B2 JP 4452969B2
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- 0 CCC1=CC#CC2C1NCC2c1c(*C)nc(*)[o]1 Chemical compound CCC1=CC#CC2C1NCC2c1c(*C)nc(*)[o]1 0.000 description 2
- SVFWRYPOWIOYDM-UHFFFAOYSA-N CCCCCC(N(CC(c1c[n](C)c2ccccc12)=O)I)=O Chemical compound CCCCCC(N(CC(c1c[n](C)c2ccccc12)=O)I)=O SVFWRYPOWIOYDM-UHFFFAOYSA-N 0.000 description 1
- OJKSVRZREDMTSW-UHFFFAOYSA-N CCCCCc1ncc(-c(c2c3)c[nH]c2ccc3OC)[s]1 Chemical compound CCCCCc1ncc(-c(c2c3)c[nH]c2ccc3OC)[s]1 OJKSVRZREDMTSW-UHFFFAOYSA-N 0.000 description 1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
- C07D413/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
- C07D417/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
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Description
本発明は、新規インドール化合物、該化合物の製造方法および該化合物の用途に関する。
従来の技術
コノハノリ科に属する海藻アヤニシキ(Martensia fragilis Harvey)の抽出物から単離された下記式で表されるインドール化合物(マルテフラジンA)は公知である〔日本薬学会第116年会 講演要旨集2,215頁(1996年)〕。
そして、上記インドール化合物は、抗酸化作用を有し、医薬品等の用途を有することが知られている。WO99/12923では下記化合物(1)またはその塩とその製造方法および用途を開示している。
{式中、Yは基
〔式中、X′は、炭素原子数が1乃至5のアルキル基(該アルキル基は、ヒドロキシル基、カルボキシル基、アミノ基、メチルチオ基、メルカプト基、グワニジル基、イミダゾリル基またはベンジル基により置換されていてもよい。)を表し、R1′およびR2′は、それぞれ独立して、水素原子、アルキル基、アルアルキル基、シクロアルキル基またはアリール基を表す。〕
R′は、水素原子、アルキル基、アルアルキル基、シクロアルキル基、アリール基、一価の金属原子、アミンまたはアンモニウムを表し;*は不斉炭素原子の位置を示す。}。
本願発明者らは鋭意研究の後、上記化合物より優れた脂質過酸化抑制作用を有する新規インドール化合物を見出した。
発明の開示
本発明は下式Iで表されるインドール化合物に関する。
〔式中、Xは酸素原子または硫黄原子を表し、R1は水素原子、未置換のもしくはハロゲン原子で置換された炭素原子数1ないし4のアルキル基または未置換のもしくはハロゲン原子で置換された炭素原子数1ないし4のアルコキシ基を表し、R2は炭素原子数1ないし20のアルキル基を表す。〕
炭素原子数1ないし4のアルキル基である基R1は、例えばメチル基、エチル基、プロピル基、n−ブチル基、イソブチル基、第三ブチル基を表す。
また、炭素原子数1ないし4のアルコキシ基である基R1は例えばメトキシ基、エトキシ基、プロポキシ基、n−ブトキシ基、イソブトキシ基、第三ブトキシ基を表す。
R1がハロゲン置換されたアルキル基またはアルコキシ基の場合に置換基のハロゲン原子は、フッ素原子、塩素原子、臭素原子またはヨウ素原子である。
R2は直鎖または枝分かれした炭素原子数1ないし20のアルキル基であってよく、例えば、炭素原子数5ないし15のアルキル基である。ペンチル基が好ましい。
上記式Iで表される化合物のうち、Xが酸素原子または硫黄原子を表し、R1が水素原子または炭素原子数1ないし4のアルコキシ基である化合物が好ましい。さらに好ましい本発明の化合物は上記式I中、Xは酸素原子または硫黄原子を表し、R1が水素原子またはメトキシ基を表し、R2がペンチル基であるものが好ましい。
下記、MF−15,MF−17,MF−20およびMF−21で表される化合物は好ましい本願発明の式Iで表される化合物である。
本発明はまた、次式IV
で表される化合物を酸化して次式V
で表される化合物を得、次いで該化合物を環化させることからなる式I
で表されるインドール化合物を製造する方法に関する。
〔式中、Xは酸素原子または硫黄原子を表し、R1は水素原子、未置換のもしくはハロゲン原子で置換された炭素原子数1ないし4のアルキル基または未置換のもしくはハロゲン原子で置換された炭素原子数1ないし4のアルコキシ基を表し、R2は炭素原子数1ないし20のアルキル基を表す。〕
上記、式IVで表される化合物は、トリプタミンまたは置換トリプタミンとカルボン酸ハライドとの縮合により得ることができる。
従って、本発明は下記するようにトリプタミンまたは置換トリプタミンとカルボン酸ハライドを出発原料とする式Iで表される化合物の製造方法にも関する。即ち、次式II
で表される化合物を、次式III
で表されるカルボン酸ハライドと縮合させ、次式IV
で表される化合物を得、該式IVの化合物を酸化して次式V
で表される化合物とし、さらにこれを環化させて次式I
で表される上記式Iで表されるインドール化合物を製造する。
〔式中、Xは酸素原子または硫黄原子を表し、R1は水素原子、未置換のもしくはハロゲン原子で置換された炭素原子数1ないし4のアルキル基または未置換のもしくはハロゲン原子で置換された炭素原子数1ないし4のアルコキシ基を表し、R2は炭素原子数1ないし20のアルキル基を表し、Halはハロゲン置換基を表す。〕
上記、カルボン酸ハライドのハロゲン置換基部分は、フッ素原子、塩素原子、臭素原子、ヨウ素原子のいずれでもよい。しかし塩素原子が最も好ましい。
カルボン酸ハライドの炭素原子数1ないし20のアルキル部分は好ましくは炭素原子数5ないし15のアルキルであり、最も好ましくはペンチル基である。
式IVで表される化合物の酸化は特に、2,3−ジクロロ−5,6−ジシアノベンゾキノン(DDQ)の存在下で行うのが好ましい。
本発明の式Iで表される化合物のうち、Xが酸素原子を表す化合物は、▲1▼ 式IIで表されるトリプタミンまたは置換トリプタミンと、カルボン酸ハライドとのアシル化によりアミド体を形成し、ついで、▲2▼ 該アミド体を例えば、DDQの存在下で酸化してケト体とし、最後に▲3▼該ケト体を、例えばオキシ塩化リンとともに加熱還流して環化させることによりオキサゾール環を構築して製造することができる。
本発明の式Iで表される化合物のうち、Xが硫黄原子を表す化合物は、▲1▼ 式IIで表されるトリプタミンまたは置換トリプタミンと、カルボン酸ハライドとのアシル化によりアミド体を形成し、ついで、▲2▼ 該アミド体を例えば、DDQの存在下で酸化してケト体とし、最後に▲3▼該ケト体を例えばクロロホルムの存在下、五硫化二リンとともに加熱還流して環化させることによりチアゾール環を構築して製造することができる。
本発明の新規インドール化合物は、インドール環と、オキサゾール環もしくはチアゾール環を有するアルカロイドであり、脂質過酸化抑制活性を有し、動脈硬化、高血圧、血栓症等の循環器障害、腎炎等の炎症、アルコール性肝炎等の肝障害、胃潰瘍等の消化器障害、糖尿病、発癌及び老化、その他紫外線障害等の予防薬及び治療薬として、また紫外線障害予防薬として化粧品材料等に利用できるものである。
従って、本発明は更に、前記式Iで表されるインドール化合物を有効成分とする脂質過酸化抑制剤に関する。
発明を実施するための最良の形態
以下に本発明のインドール化合物の製造実施例、ならびに生物学的実施例を示す。なおこの実施例は本発明を限定することを意図するものではない。
I.インドール化合物の製造実施例
〔実施例1〕 RがHである場合の式Iで表される化合物の合成
以下の合成スキーム1に従って製造する。
1.トリプタミンのアシル化
300mLの3頸フラスコ中にトリプタミン(1)1g(6.24mmol)および塩化メチレン75mLを加え、0℃に冷却した。続いて塩化メチレン5mL中に溶解したヘキサン酸クロリド(2)1.05mL(8.11mmol,1.3eq)と、5%水酸化ナトリウム水溶液6mL(8.11mmol,1.3eq)を滴下漏斗にて同時に加えた。0℃で30分、室温で1時間攪拌後、塩化メチレンで抽出し、飽和重曹水、5%塩酸水溶液、飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥し、溶媒を減圧留去した。残さをカラムクロマトグラフィー(SiO245g,n−ヘキサン:酢酸エチル1:1)で精製すると、目的とするアミド体(3)を1.24g(77%)得た。これを酢酸エチル、n−ヘキサンで再結晶を行い、無色粉末を得た。
mp.93−94℃(AcOEt/n−Hex).
IR(KBr):ν3398,3256,3084,2933,2850,1631,1560,1458,741cm−1.
1H−NMR(400MHz,CDCl3):δ8.05(1H,broad,N1−H),7.62(1H,td,J=7.1,1.0Hz,C7−H),7.38(1H,td,J=7.1,1.0Hz,C4−H),7.22(1H,td,J=7.1,1.2Hz,C5−H),7.13(1H,td,J=7.1,1.0Hz,C6−H),7.04(1H,d,J=2.5Hz,C2−H),5.48(1H,broad,3’N−H),3.61(2H,q,J=6.4Hz,C2’−H),2.98(2H,t,J=6.1Hz,C1’−H),2.09(2H,t,J=7.6Hz,C2”−H),1.64−1.50(2H,m,C3”−H),1.36−1.28(2H,m,C4”−H),1.28−1.20(2H,m,C5”−H),0.87(3H,t,J=7.5Hz,C6”−H).
13C−NMR(100MHz,CDCl3):δ173.12(C1”),136.41(C7a),127.36(C3),122.19(C5),121.99(C2),119.47(C6),118.72(C7),113.08(C3a),111.23(C4),39.63(C2’),36.85(C2”),31.43(C5”),25.40(C1’),25.36(C3”),22.36(C4”),13.91(C6”).
LRFABMS m/z(%): 259(M+ +H,80),143(100).
2.アシルトリプタミンのDDQ酸化
300mLナス型フラスコにアミド体(3)1g(3.87mmol)および水−THF(10:90)100mLを加え溶解した後、DDQ1.76g(7.74mmol,2eq)を加え室温で2時間攪拌する。飽和チオ硫酸ナトリウム水溶液を加えて反応を終了させた後、減圧下テトラヒドロフランを除去する。酢酸エチルで抽出し、飽和重曹水、飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥し、溶媒を減圧留去した。残さをメタノールにて再結晶を行い、無色結晶を得た(収量1.03g,収率96%)。
mp.223℃(MeOH).
IR(KBr):ν3459,3329,3207,2951,2925,2860,1655,1623,1543,1518,1458,1437,1018,926,769,744cm−1.
1H−NMR(400MHz,DMSO−D6):δ8.35(1H,s,C2−H),8.16(1H,dd,J=7.7,1.5Hz,C7−H),7.93(1H,broad,N3’−H),7.48(1H,dd,J=7.8,1.5Hz,C4−H),7.22(1H,td,J=7.1,1.5Hz,C5−H),7.18(1H,td,J=7.1,1.5Hz,C6−H),4.44(2H,d,J=5.6Hz,C2’−H),2.19(2H,t,J=7.4Hz,C2”−H),1.61−1.50(2H,m,C3”−H),1.36−1.29(2H,m,C4”−H),1.29−1.23(2H,m,C5”−H),0.88(3H,t,J=7.1Hz,C6”−H).
13C−NMR(100MHz,DMSO−D6):δ190.15(C1”),172.17(C1’),136.26(C7a),133.04(C2),125.23(C3),122.53(C5),121.48(C6),120.93(C7),114.00(C3a),111.86(C4),45.55(C2’),35.05(C3”),30.65(C2”),24.70(C4”),21.57(C5”),13.51(C6”).
LRFABMS m/z(%): 273(M+ +H,70),154(100).
3.MF−15の合成
還流冷却器、塩カル管を装着した25mLナス型フラスコにケト体(4)804mg(2.95mmol)およびオキシ塩化リン8mLを加えて1.5時間加熱還流した。反応溶液を室温まで冷却し、水の入ったビーカーに反応溶液を流し込み、水層が塩基性になるまでアンモニア水を加えた。その後、酢酸エチルで抽出し、有機層を水で洗浄し、無水硫酸ナトリウムで乾燥し、溶媒を減圧留去した。残さをカラムクロマトグラフィー(SiO220g,n−ヘキサン:酢酸エチル1:1)で精製して目的とする環化体MF−15を638.9mg(85.2%)で得た。その後、酢酸エチル/n−ヘキサンにて再結晶を行い、無色結晶を得た。
mp.130.5−131.5℃(AcOEt/n−Hex).
IR(KBr):ν3134,2935,2856,1637,1570,1456,1348,1248,1182,1122,1012,916,768,737cm−1.
UV(MeOH):λmax 298.6,281.0,266.8,225.0nm.
1H−NMR(400MHz,CDCl3):δ8.38(1H,broad,N1−H),7.84(1H,dd,J=7.7,0.98Hz,C7−H),7.51(1H,d,J=2.7Hz,C2−H),7.43(1H,dd,J=7.3,1.2Hz,C4−H),7.28(1H,td,J=7.7,1.2Hz,C5−H),7.24(1H,td,J=7.7,1.2Hz,C6−H),7.15(1H,s,C4’−H),2.84(2H,t,J=7.7Hz,C1”−H),1.85(2H,f,J=7.6Hz,C2”−H),1.47−1.40(2H,m,C3”−H),1.40−1.38(2H,m,C4”−H),0.92(3H,t,J=7.0Hz,C5”−H).
13C−NMR(100MHz,CDCl3):δ162.97(C2’),147.07(C5’),136.24(C7a),124.14(C3),122.97(C5),121.46(C2),120.81(C6),120.00(C7),119.88(C4’),111.47(C4),106.12(C3a),31.35(C3”),28.18(C1”),26.86(C2”),22.32(C4”),13.93(C5”).
Anal.Calcd for C16H18N2O: C 75.76;H 7.13;N 11.01,
Found: C 75.46;H 7.15;N 10.97.
4.MF−17の合成
還流冷却器、塩カル管を装着した25mLナス型フラスコにケト体(4)150mg(0.55mmol)、クロロホルム7mLおよび五硫化二リン122mg(0.55mmol,1eq)を加えて20時間加熱還流した。反応溶液を0℃に冷却した後、10%水酸化カリウム水溶液を加えクロロホルムで抽出した。有機層を水で洗浄し、無水硫酸ナトリウムで乾燥し、溶媒を減圧留去した。
これをカラムクロマトグラフィー(SiO28g,n−ヘキサン:酢酸エチル2:1)で精製して目的とする環化体MF−17を109.4mg(73.4%)で得た。その後、酢酸エチル/n−ヘキサンにて再結晶を行い、無色結晶を得た。
mp.102−103℃(AcOEt/n−Hex).
IR(KBr):ν3136,3093,2956,2925,2870,1562,1508,1498,1446,1377,1342,1281,1248,1188,1153,1134,1090,1011,906,874,812,775,739,677cm−1.
UV(MeOH): λmax 309.0,220.6nm.
1H−NMR(400MHz,CDCl3):δ8.74(1H,broad,N1−H),7.88(1H,d,J=7.6Hz,C7−H),7.82(1H,d,J=0.98Hz,C4’−H),7.40(1H,dd,J=8.1,0.98Hz,C4−H),7.38(1H,d,J=2.4Hz,C2−H),7.27(1H,td,J=7.1,1.2Hz,C5−H),7.22(1H,td,J=7.1,1.2Hz,C6−H),3.03(2H,t,J=7.7Hz,C1”−H),1.85(2H,dt,J=14.6,7.5Hz,C2”−H),1.49−1.38(2H,m,C3”−H),1.38−1.23(2H,m,C4”−H),0.92(3H,t,J=7.1Hz,C5”−H).
13C−NMR(100MHz,CDCl3):δ169.78(C2’),137.43(C4’),137.10(C5’),132.21(C7a),126.13(C3),123.51(C6),123.19(C2),121.31(C5),120.22(C7),112.10(C4),108.89(C3a),33.60(C1”),31.43(C3”),29.90(C2”),22.48(C4”),14.00(C5”).
LRFABMS m/z(%): 271(M+ +H,100).
HRFABMS Calcd for C16H18N2S+H: 271.1269;Found: 271.1275.
〔実施例2〕 Rが−OCH3である場合の式Iで表される化合物の合成
以下の合成スキーム2に従って製造する。
1.トリプタミンのアシル化
300mLの3頸フラスコ中に5−メトキシトリプタミン(5)1g(5.25mmol)および塩化メチレン75mLを加え、0℃に冷却した。続いて塩化メチレン5mL中に溶解したヘキサン酸クロリド(2)0.95mL(6.83mmol,1.3eq)と、5%水酸化ナトリウム水溶液5.4mL(6.83mmol,1.3eq)を滴下漏斗にて同時に加えた。0℃で30分、室温で30分攪拌後、塩化メチレンで抽出し、飽和重曹水、5%塩酸水溶液、飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥し、溶媒を減圧留去した。残さをカラムクロマトグラフィー(SiO245g,n−ヘキサン:酢酸エチル1:1)で精製すると、目的とする縮合体(6)を0.93g(62%)得た。
IR(neat):ν3292,3074,2929,1726,1653,1549,1487,1373,1217,1174,1103,1072,1038,924,829,796cm−1.
1H−NMR(400MHz,CDCl3):δ8.32(1H,broad,N1−H),7.25(1H,d,J=8.8Hz,C4−H),7.03(1H,d,J=2.2Hz,C2−H),6.98(1H,d,J=2.2Hz,C7−H),3.85(3H,s,−OCH3),3.59(2H,q,J=6.6Hz,C2’−H),2.93(2H,t,J=6.6Hz,C1’−H),2.10(2H,t,J=7.7Hz,C2”−H),1.58(2H,ddd,J=29.8,14.9,7.3Hz,C3”−H),1.34−1.26(2H,m,C4”−H),1.26−1.20(2H,m,C5”−H),0.86(3H,t,J=6.8Hz,C6”−H).
13C−NMR(100MHz,CDCl3):δ173.22(C1”),153.98(C5),131.58(C7a),127.70(C3),122.82(C2),112.56(C3a),112.29(C6),112.00(C7),100.47(C4),55.90(−OCH3),39.54(C2’),36.82(C2”),31.39(C5”),25.40(C1’),25.32(C3”),22.32(C4”),13.86(C6”).
LRFABMS m/z(%): 289(M+ +H,80),173(100).
HRFABMS Calcd for C17H24N2O2 +H: 289.1916;Found 289.1916.
2.アシルトリプタミンのDDQ酸化
200mLナス型フラスコにアシル体(6)500mg(1.73mmol)および水−THF(90:10)溶液50mLを加え攪拌した後、DDQ787mg(3.47mmol,2eq)を加え室温で0.9時間攪拌した。チオ硫酸ナトリウム水溶液を加えて反応を終了させた後、減圧留去にてテトラヒドロフランを除去した。酢酸エチルで抽出し、飽和重曹水、飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥し、溶媒を減圧留去した。粗生成物を酢酸エチルにて再結晶し、無色結晶482.6mg(92%)を得た。
mp.194−195℃(MeOH).
IR(KBr):ν3327,3222,2925,2854,2825,1655,1618,1543,1514,1473,1437,1323,1269,1215,1080,1036,939,918,843,805,762cm−1.
1H−NMR(400MHz,CDCl3):δ9.43(1H,broad,N1−H),7.89(1H,d,J=3.0Hz,C2−H),7.81(1H,d,J=2.4Hz,C7−H),7.33(1H,d,J=8.8Hz,C4−H),6.94(1H,dd,J=8.8,2.5Hz,C6−H),6.72(1H,broad,N3’−H),4.62(2H,d,J=4.1Hz,C2’−H),3.89(3H,s,−OCH3),2.34(2H,t,J=7.7Hz,C2”−H),1.72(2H,ddd,J=30.0,15.1,7.5Hz,C3”−H),1.41−1.36(2H,m,C4”−H),1.36−1.32(2H,m,C5”−H),0.91(3H,t,J=7.0Hz,C6”−H).
13C−NMR(100MHz,CDCl3):δ190.4(C1”),174.51(C1’),157.50(C5),132.03(C2),131.75(C7a),126.84(C3),115.23(C6),113.07(C7),113.02(C3a),103.79(C4),56.03(−OCH3),46.35(C2’),36.83(C3”),31.64(C2”),25.57(C4”),22.51(C5”),14.00(C6”).
LRFABMS m/z(%)303(M+ +H,100).
HRFABMS Calcd for C17H22N2O3 +H:303.1709; Found 303.1706.
3.MF−20の合成
還流冷却器、塩カル管を装着した25mLナス型フラスコにケト体(7)150mg(0.50mmol)およびオキシ塩化リン2.5mLを加えて40分加熱還流した。反応溶液を室温まで冷却し、水の入ったビーカーに反応溶液を流し込み、水層が塩基性になるまでアンモニア水を加えた。その後、酢酸エチルで抽出し、水で洗浄し、無水硫酸ナトリウムで乾燥し、溶媒を減圧留去した。残さをカラムクロマトグラフィー(SiO25g,n−ヘキサン:酢酸エチル1:1)で精製して目的とする環化体MF−20を135mg(95%)得た。その後、酢酸エチル/n−ヘキサンにて再結晶を行い、無色結晶を得た。
mp.121−122℃(AcOEt/n−Hex).
IR(KBr):ν3128,3037,2918,1641,1587,1475,1213,1149,1124,1032,939,908,822,766,733,671cm−1.
UV(MeOH): λmax 307.6,270.2,223.4nm.
1H−NMR(400MHz,CDCl3):δ8.60(1H,broad,N1−H),7.47(1H,d,J=2.4Hz,C2−H),7.30(1H,d,J=8.8Hz,C7−H),7.26(1H,d,J=2.7Hz,C4−H),7.11(1H,s,C4’−H),6.93(1H,dd,J=8.8,2.2Hz,C6−H),3.90(3H,s,−OCH3),2.84(2H,t,J=7.6Hz,C1”−H),1.84(2H,dt,J=14.7,7.6,7.1Hz,C2”−H),1.47−1.33(2H,m,C3”−H),1.32−1.23(2H,m,C4”−H),0.91(3H,t,J=6.8Hz,C5”−H).
13C−NMR(100MHz,CDCl3):δ162.90(C2’),154.92(C5),147.19(C5’),131.34(C7a),124.67(C3),122.25(C2),119.51(C4’),113.04(C6),112.23(C7),105.75(C3a),101.87(C4),55.89(−OCH3),31.32(C3”),28.17(C1”),26.87(C2”),22.31(C4”),13.91(C5”).
LRFABMS m/z(%): 284(M+ ,100).
HRFABMS:Calcd for C17H20N2O2 +H 285.1603;Found 285.1611.
4.MF−21の合成
還流冷却器、塩カル管を装着した25mLナス型フラスコにケト体(7)150mg(0.50mmol)、クロロホルム6mLおよび五硫化二リン111mg(0.50mmol,1eq)を加えて14時間加熱還流した。反応溶液を0℃に冷却した後、10%水酸化カリウム水溶液を加えクロロホルムで抽出した。有機層を水で洗浄し、無水硫酸ナトリウムで乾燥し、溶媒を減圧留去した。これをカラムクロマトグラフィー(SiO25g,n−ヘキサン:酢酸エチル1:1)で精製して目的とする環化体MF−21を138.6mg(92.4%)得た。その後、酢酸エチル/n−ヘキサンにて再結晶を行い、無色結晶を得た。
m.p.93−94℃(AcOEt,/n−Hex).
IR(KBr):ν3153,3049,2954,2918,2858,1637,1566,1475,1350,1309,1254,1209,1128,1036,928,901,837,787cm−1.
UV(MeOH): λmax 309.4,284.0,218.6nm.
1H−NMR(400MHz,CDCl3):δ8.86(1H,broad,N1−H),7.79(1H,s,C4’−H),7.35(1H,d,J=2.6Hz,C2−H),7.30(1H,d,J=2.5Hz,C4−H),7.28(1H,d,J=9.0Hz,C7−H),6.92(1H,dd,J=8.8,2.2Hz,C6−H),3.88(3H,s,−OCH3),3.03(2H,t,J=7.7Hz,C1”−H),1.85(2H,dt,J=14.8,7.7,7.3Hz,C2”−H),1.48−1.42(2H,m,C3”−H),1.42−1.33(2H,m,C4”−H),0.92(3H,t,J=7.1Hz,C5”−H).
13C−NMR(100MHz,CDCl3):δ169.69(C2’),155.57(C5),137.15(C2),132.41(C5’),132.17(C7a),126.57(C3),123.99(C4’),113.68(C6),112.88(C7),108.46(C3a),101.79(C4),56.16(−OCH3),33.56(C3”),31.41(C1”),29.87(C2”),22.46(C4”),13.97(C5”).
LRFABMS m/z(%): 301(M+ +H,100).
HRFABMS:Calcd for C17H20N2SO +H 301.1375; FOund 301.1371.
II.インドール化合物の生物学的作用
〔実施例3〕 ラット肝臓ミクロソームの脂質過酸化に対するインドール化合物の効果
(1)過酸化脂質の測定
14mM MgCl2を含む0.1Mトリス塩酸緩衝液(pH7.5)0.5mlにラット肝臓より調製したミクロソーム画分(タンパク濃度30〜50mg/ml)10μl及び下記表の被験化合物のエタノール溶液10μlを加え混和し、37℃で5分間プレインキュベートした。次に、0.2Mアデノシンニリン酸10μl,12mM FeSO410μl,NADPH再生系40μlおよび蒸留水を加えて1mlとし、混和後、37℃で10分間反応させた。反応後、0.375%チオバルビツール酸(TBA),0.25N塩酸を含む15%トリクロロ酢酸溶液2mlを添加して沸騰水浴中で15分間反応させ、この反応により生成するマロンジアルデヒドをはじめとするチオバルビツール酸反応性物質の量を波長535nmでの吸光度を測定して求めた。この値をもとに、脂質過酸化を50%抑制する値(IC50値)を求めた。
(2)試験結果
上記製造実施例で製造されたマルテフラジン誘導体MF−15、MF−17、MF−20およびMF−21並びに天然型と同一構造をもつ合成(1″S,3″S)マルテフラジンA〔前記式(1A)の化合物の(1″S,3″S)体〕の各インドール化合物の脂質過酸化抑制活性を比較検討した。その結果、下記の表に示すようにマルテフラジン誘導体MF−15、MF−17、MF−20およびMF−21のIC50値はそれぞれ0.59,0.29,0.38および0.48μg/mlでありおよび合成(1″S,3″S)マルテフラジンAのIC50値は1.35μg/mlであり本発明に係る各誘導体の方がより強い活性を示した。
発明の効果
本発明によって、未置換または置換トリプタミンとカルボン酸ハライドとの縮合によりアミド体を形成し、次いでそれを酸化した後、環化させることによってオキサゾール環またはチアゾール環を構築する新規合成法による新規なインドール化合物を得ることが可能となった。本発明のインドール環と、オキサゾール環もしくはチアゾール環を有するアルカロイドは、脂質過酸化抑制活性等の生理活性を有し、医薬品及び化粧品材料等に利用できるものである。The present invention relates to a novel indole compound, a method for producing the compound, and use of the compound.
Conventional technology
An indole compound (maltephrazine A) represented by the following formula isolated from an extract of the marine alga (Martensia fragilis Harvey), which belongs to the family Aceraceae, is known [Abstracts of the 116th Annual Meeting of the Pharmaceutical Society of Japan, page 2,215. (1996)].
And it is known that the said indole compound has an antioxidant action and has uses, such as a pharmaceutical. WO99 / 12923 discloses the following compound (1) or a salt thereof, and a production method and use thereof.
{Where Y is a group
[Wherein X ′ represents an alkyl group having 1 to 5 carbon atoms (the alkyl group is substituted with a hydroxyl group, a carboxyl group, an amino group, a methylthio group, a mercapto group, a guanidyl group, an imidazolyl group or a benzyl group). And R1′ And R2Each independently represents a hydrogen atom, an alkyl group, an aralkyl group, a cycloalkyl group or an aryl group. ]
R ′ represents a hydrogen atom, an alkyl group, an aralkyl group, a cycloalkyl group, an aryl group, a monovalent metal atom, an amine or ammonium; * represents the position of an asymmetric carbon atom. }.
The inventors of the present application have found a novel indole compound having a lipid peroxidation inhibitory action superior to that of the above compound after intensive studies.
Disclosure of the invention
The present invention relates to an indole compound represented by Formula I below.
[In the formula, X represents an oxygen atom or a sulfur atom;1Represents a hydrogen atom, an unsubstituted or substituted alkyl group having 1 to 4 carbon atoms, or an unsubstituted or substituted alkoxy group having 1 to 4 carbon atoms, R2Represents an alkyl group having 1 to 20 carbon atoms. ]
A group R which is an alkyl group of 1 to 4 carbon atoms1Represents, for example, a methyl group, an ethyl group, a propyl group, an n-butyl group, an isobutyl group, or a tertiary butyl group.
And a group R which is an alkoxy group having 1 to 4 carbon atoms.1Represents, for example, a methoxy group, an ethoxy group, a propoxy group, an n-butoxy group, an isobutoxy group, or a tertiary butoxy group.
R1In the case where is a halogen-substituted alkyl group or alkoxy group, the halogen atom of the substituent is a fluorine atom, a chlorine atom, a bromine atom or an iodine atom.
R2May be a straight chain or branched alkyl group having 1 to 20 carbon atoms, for example, an alkyl group having 5 to 15 carbon atoms. A pentyl group is preferred.
Among the compounds represented by the above formula I, X represents an oxygen atom or a sulfur atom, and R1Are preferably a hydrogen atom or an alkoxy group having 1 to 4 carbon atoms. Further preferred compounds of the present invention are those in the above formula I, wherein X represents an oxygen atom or a sulfur atom, and R1Represents a hydrogen atom or a methoxy group, R2Is preferably a pentyl group.
The following compounds represented by MF-15, MF-17, MF-20 and MF-21 are preferred compounds represented by formula I of the present invention.
The present invention also provides the following formula IV
Oxidizing the compound represented by formula V
And then cyclizing the compound
In an indole compound represented by the formula:
[In the formula, X represents an oxygen atom or a sulfur atom;1Represents a hydrogen atom, an unsubstituted or substituted alkyl group having 1 to 4 carbon atoms, or an unsubstituted or substituted alkoxy group having 1 to 4 carbon atoms, R2Represents an alkyl group having 1 to 20 carbon atoms. ]
The compound represented by the formula IV can be obtained by condensation of tryptamine or substituted tryptamine with a carboxylic acid halide.
Accordingly, the present invention also relates to a process for producing a compound represented by formula I using tryptamine or substituted tryptamine and a carboxylic acid halide as starting materials as described below. That is, the following formula II
A compound represented by the following formula III
Is condensed with a carboxylic acid halide represented by the formula IV
And the compound of formula IV is oxidized to give the following formula V
And is further cyclized to give a compound of the following formula I
An indole compound represented by the above formula I represented by
[In the formula, X represents an oxygen atom or a sulfur atom;1Represents a hydrogen atom, an unsubstituted or substituted alkyl group having 1 to 4 carbon atoms, or an unsubstituted or substituted alkoxy group having 1 to 4 carbon atoms, R2Represents an alkyl group having 1 to 20 carbon atoms, and Hal represents a halogen substituent. ]
The halogen substituent portion of the carboxylic acid halide may be any of a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom. However, a chlorine atom is most preferred.
The alkyl moiety having 1 to 20 carbon atoms of the carboxylic acid halide is preferably an alkyl having 5 to 15 carbon atoms, and most preferably a pentyl group.
The oxidation of the compound represented by formula IV is particularly preferably carried out in the presence of 2,3-dichloro-5,6-dicyanobenzoquinone (DDQ).
Among the compounds represented by the formula I of the present invention, the compound in which X represents an oxygen atom, (1) forms an amide by acylation of tryptamine or substituted tryptamine represented by the formula II and a carboxylic acid halide. Then, (2) the amide form is oxidized in the presence of DDQ to form a keto form, and finally (3) the keto form is heated and refluxed with, for example, phosphorus oxychloride to cyclize the oxazole ring. Can be built and manufactured.
Among the compounds represented by the formula I of the present invention, the compound in which X represents a sulfur atom (1) forms an amide by acylation of tryptamine or substituted tryptamine represented by the formula II and a carboxylic acid halide. Then, (2) the amide is oxidized to form a keto in the presence of DDQ, and finally (3) the keto is heated to reflux with diphosphorus pentasulfide in the presence of chloroform, for example. Thus, a thiazole ring can be constructed and produced.
The novel indole compound of the present invention is an alkaloid having an indole ring and an oxazole ring or thiazole ring, has lipid peroxidation inhibitory activity, cardiovascular disorders such as arteriosclerosis, hypertension, thrombosis, inflammation such as nephritis, It can be used as a prophylactic and therapeutic agent for liver disorders such as alcoholic hepatitis, gastrointestinal disorders such as gastric ulcers, diabetes, carcinogenesis and aging, and other UV disorders, and as a UV disorder preventive and cosmetic material.
Therefore, the present invention further relates to a lipid peroxidation inhibitor comprising the indole compound represented by the formula I as an active ingredient.
BEST MODE FOR CARRYING OUT THE INVENTION
The production examples and biological examples of the indole compounds of the present invention are shown below. This example is not intended to limit the invention.
I. Examples of production of indole compounds
Example 1 Synthesis of a compound of formula I when R is H
Prepared according to Synthesis Scheme 1 below.
1. Acylation of tryptamine
In a 300 mL three-necked flask, 1 g (6.24 mmol) of tryptamine (1) and 75 mL of methylene chloride were added and cooled to 0 ° C. Subsequently, 1.05 mL (8.11 mmol, 1.3 eq) of hexanoic acid chloride (2) dissolved in 5 mL of methylene chloride and 6 mL (8.11 mmol, 1.3 eq) of 5% aqueous sodium hydroxide solution were added using a dropping funnel. Added at the same time. After stirring at 0 ° C. for 30 minutes and at room temperature for 1 hour, the mixture was extracted with methylene chloride, washed with saturated aqueous sodium hydrogen carbonate, 5% aqueous hydrochloric acid and saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue is subjected to column chromatography (SiO 22Purification by 45 g, n-hexane: ethyl acetate 1: 1) yielded 1.24 g (77%) of the desired amide (3). This was recrystallized from ethyl acetate and n-hexane to obtain a colorless powder.
mp. 93-94 ° C (AcOEt / n-Hex).
IR (KBr): ν 3398, 3256, 3084, 2933, 2850, 1631, 1560, 1458, 741 cm-1.
1H-NMR (400 MHz, CDCl3): Δ 8.05 (1H, broadcast, N1-H), 7.62 (1H, td, J = 7.1, 1.0 Hz, C7-H), 7.38 (1H, td, J = 7. 1,1.0 Hz, C4-H), 7.22 (1H, td, J = 7.1, 1.2 Hz, C5-H), 7.13 (1H, td, J = 7.1, 1.. 0 Hz, C6-H), 7.04 (1H, d, J = 2.5 Hz, C2-H), 5.48 (1H, broadcast, 3'N-H), 3.61 (2H, q, J = 6.4 Hz, C2′−H), 2.98 (2H, t, J = 6.1 Hz, C1′−H), 2.09 (2H, t, J = 7.6 Hz, C2 ″ −H) , 1.64-1.50 (2H, m, C3 ″ -H), 1.36-1.28 (2H, m, C4 ″ -H), 1.28-1.20 (2H, m, C5) "-H), 0.87 (3H, , J = 7.5Hz, C6 "-H).
13C-NMR (100 MHz, CDCl3): Δ 173.12 (C1 ″), 136.41 (C7a), 127.36 (C3), 122.19 (C5), 121.99 (C2), 119.47 (C6), 118.72 (C7) ), 113.08 (C3a), 111.23 (C4), 39.63 (C2 ′), 36.85 (C2 ″), 31.43 (C5 ″), 25.40 (C1 ′), 25. 36 (C3 ″), 22.36 (C4 ″), 13.91 (C6 ″).
LRFABMS m / z (%): 259 (M+ + H, 80), 143 (100).
2. DDQ oxidation of acyltryptamine
In a 300 mL eggplant-shaped flask, 1 g (3.87 mmol) of amide compound (3) and 100 mL of water-THF (10:90) are added and dissolved. . A saturated aqueous sodium thiosulfate solution is added to terminate the reaction, and then tetrahydrofuran is removed under reduced pressure. The mixture was extracted with ethyl acetate, washed with saturated aqueous sodium hydrogen carbonate and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was recrystallized from methanol to obtain colorless crystals (yield 1.03 g, yield 96%).
mp. 223 ° C (MeOH).
IR (KBr): ν 3459, 3329, 3207, 2951, 925, 2860, 1655, 1623, 1543, 1518, 1458, 1437, 1018, 926, 769, 744 cm-1.
1H-NMR (400 MHz, DMSO-D6): Δ 8.35 (1H, s, C2-H), 8.16 (1H, dd, J = 7.7, 1.5 Hz, C7-H), 7.93 (1H, broadcast, N3′-H) ), 7.48 (1H, dd, J = 7.8, 1.5 Hz, C4-H), 7.22 (1H, td, J = 7.1, 1.5 Hz, C5-H), 7. 18 (1H, td, J = 7.1, 1.5 Hz, C6-H), 4.44 (2H, d, J = 5.6 Hz, C2′-H), 2.19 (2H, t, J = 7.4 Hz, C2 "-H), 1.61-1.50 (2H, m, C3" -H), 1.36-1.29 (2H, m, C4 "-H), 1.29 -1.23 (2H, m, C5 "-H), 0.88 (3H, t, J = 7.1 Hz, C6" -H).
13C-NMR (100 MHz, DMSO-D6): Δ190.15 (C1 ″), 172.17 (C1 ′), 136.26 (C7a), 133.04 (C2), 125.23 (C3), 122.53 (C5), 121.48 ( C6), 120.93 (C7), 114.00 (C3a), 111.86 (C4), 45.55 (C2 ′), 35.05 (C3 ″), 30.65 (C2 ″), 24. 70 (C4 ″), 21.57 (C5 ″), 13.51 (C6 ″).
LRFABMS m / z (%): 273 (M+ + H, 70), 154 (100).
3. Synthesis of MF-15
To a 25 mL eggplant-shaped flask equipped with a reflux condenser and a salt tube, keto body (4) (804 mg, 2.95 mmol) and phosphorus oxychloride (8 mL) were added and heated to reflux for 1.5 hours. The reaction solution was cooled to room temperature, poured into a beaker containing water, and aqueous ammonia was added until the aqueous layer became basic. Thereafter, the mixture was extracted with ethyl acetate, the organic layer was washed with water and dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue is subjected to column chromatography (SiO 2220 g, n-hexane: ethyl acetate 1: 1) to obtain 638.9 mg (85.2%) of the intended cyclized product MF-15. Thereafter, recrystallization was performed with ethyl acetate / n-hexane to obtain colorless crystals.
mp. 130.5-131.5 ° C. (AcOEt / n-Hex).
IR (KBr): ν3134, 2935, 2856, 1637, 1570, 1456, 1348, 1248, 1182, 1122, 1012, 916, 768, 737 cm-1.
UV (MeOH): λmax 298.6, 281.0, 266.8, 225.0 nm.
1H-NMR (400 MHz, CDCl3): Δ 8.38 (1H, broadcast, N1-H), 7.84 (1H, dd, J = 7.7, 0.98 Hz, C7-H), 7.51 (1H, d, J = 2. 7 Hz, C2-H), 7.43 (1H, dd, J = 7.3, 1.2 Hz, C4-H), 7.28 (1H, td, J = 7.7, 1.2 Hz, C5- H), 7.24 (1H, td, J = 7.7, 1.2 Hz, C6-H), 7.15 (1H, s, C4′-H), 2.84 (2H, t, J = 7.7 Hz, C1 ″ -H), 1.85 (2H, f, J = 7.6 Hz, C2 ″ -H), 1.47-1.40 (2H, m, C3 ″ -H), 1. 40-1.38 (2H, m, C4 ″ -H), 0.92 (3H, t, J = 7.0 Hz, C5 ″ -H).
13C-NMR (100 MHz, CDCl3): Δ 162.97 (C2 ′), 147.07 (C5 ′), 136.24 (C7a), 124.14 (C3), 122.97 (C5), 121.46 (C2), 120.81 ( C6), 120.00 (C7), 119.88 (C4 ′), 111.47 (C4), 106.12 (C3a), 31.35 (C3 ″), 28.18 (C1 ″), 26. 86 (C2 ″), 22.32 (C4 ″), 13.93 (C5 ″).
Anal. Calcd for C16H18N2O: C 75.76; H 7.13; N 11.01
Found: C 75.46; H 7.15; N 10.97.
4). Synthesis of MF-17
To a 25 mL eggplant-shaped flask equipped with a reflux condenser and a salt-cal tube, keto (4) 150 mg (0.55 mmol), chloroform 7 mL and diphosphorus pentasulfide 122 mg (0.55 mmol, 1 eq) were added and heated to reflux for 20 hours. . The reaction solution was cooled to 0 ° C., 10% aqueous potassium hydroxide solution was added, and the mixture was extracted with chloroform. The organic layer was washed with water and dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure.
This is column chromatography (SiO28 g, n-hexane: ethyl acetate 2: 1) to obtain 109.4 mg (73.4%) of the intended cyclized product MF-17. Thereafter, recrystallization was performed with ethyl acetate / n-hexane to obtain colorless crystals.
mp. 102-103 <0> C (AcOEt / n-Hex).
IR (KBr): ν 3136, 3093, 2956, 2925, 2870, 1562, 1508, 1498, 1446, 1377, 1342, 1281, 1248, 1188, 1153, 1134, 1090, 1011, 906, 874, 812, 775, 739 , 677cm-1.
UV (MeOH): λmax 309.0, 220.6 nm.
1H-NMR (400 MHz, CDCl3): Δ 8.74 (1H, broadcast, N1-H), 7.88 (1H, d, J = 7.6 Hz, C7-H), 7.82 (1H, d, J = 0.98 Hz, C4 ′) -H), 7.40 (1H, dd, J = 8.1, 0.98 Hz, C4-H), 7.38 (1H, d, J = 2.4 Hz, C2-H), 7.27 ( 1H, td, J = 7.1, 1.2 Hz, C5-H), 7.22 (1H, td, J = 7.1, 1.2 Hz, C6-H), 3.03 (2H, t, J = 7.7 Hz, C1 ″ -H), 1.85 (2H, dt, J = 14.6, 7.5 Hz, C2 ″ -H), 1.49-1.38 (2H, m, C3 ″) -H), 1.38-1.23 (2H, m, C4 "-H), 0.92 (3H, t, J = 7.1 Hz, C5" -H).
13C-NMR (100 MHz, CDCl3): Δ 169.78 (C2 ′), 137.43 (C4 ′), 137.10 (C5 ′), 132.21 (C7a), 126.13 (C3), 123.51 (C6), 123.19 (C2), 121.31 (C5), 120.22 (C7), 112.10 (C4), 108.89 (C3a), 33.60 (C1 "), 31.43 (C3"), 29. 90 (C2 ″), 22.48 (C4 ″), 14.00 (C5 ″).
LRFABMS m / z (%): 271 (M+ + H, 100).
HRABMS Calcd for C16H18N2S + H: 271.1269; Found: 271.1275.
Example 2 R is —OCH3Synthesis of compounds of formula I when
Prepared according to Synthesis Scheme 2 below.
1. Acylation of tryptamine
In a 300 mL three-necked flask, 1 g (5.25 mmol) of 5-methoxytryptamine (5) and 75 mL of methylene chloride were added and cooled to 0 ° C. Subsequently, 0.95 mL (6.83 mmol, 1.3 eq) of hexanoic acid chloride (2) dissolved in 5 mL of methylene chloride and 5.4 mL (6.83 mmol, 1.3 eq) of 5% aqueous sodium hydroxide solution were added to the dropping funnel. At the same time. After stirring at 0 ° C. for 30 minutes and at room temperature for 30 minutes, the mixture was extracted with methylene chloride, washed with saturated aqueous sodium hydrogen carbonate, 5% aqueous hydrochloric acid and saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue is subjected to column chromatography (SiO 22Purification by 45 g, n-hexane: ethyl acetate 1: 1) gave 0.93 g (62%) of the desired condensate (6).
IR (neat): ν3292, 3074, 2929, 1726, 1653, 1549, 1487, 1373, 1217, 1174, 1103, 1072, 1038, 924, 829, 796 cm-1.
1H-NMR (400 MHz, CDCl3): Δ 8.32 (1H, broadcast, N1-H), 7.25 (1H, d, J = 8.8 Hz, C4-H), 7.03 (1H, d, J = 2.2 Hz, C2−) H), 6.98 (1H, d, J = 2.2 Hz, C7-H), 3.85 (3H, s, -OCH3), 3.59 (2H, q, J = 6.6 Hz, C2′-H), 2.93 (2H, t, J = 6.6 Hz, C1′-H), 2.10 (2H, t, J = 7.7 Hz, C2 ″ -H), 1.58 (2H, ddd, J = 29.8, 14.9, 7.3 Hz, C3 ″ -H), 1.34-1.26 (2H, m, C4 "-H), 1.26-1.20 (2H, m, C5" -H), 0.86 (3H, t, J = 6.8 Hz, C6 "-H).
13C-NMR (100 MHz, CDCl3): Δ 173.22 (C1 ″), 153.98 (C5), 131.58 (C7a), 127.70 (C3), 122.82 (C2), 112.56 (C3a), 112.29 (C6) ), 112.00 (C7), 100.47 (C4), 55.90 (-OCH3), 39.54 (C2 ′), 36.82 (C2 ″), 31.39 (C5 ″), 25.40 (C1 ′), 25.32 (C3 ″), 22.32 (C4 ″), 13.86 (C6 ″).
LRFABMS m / z (%): 289 (M+ + H, 80), 173 (100).
HRABMS Calcd for C17H24N2O2 + H: 289.1916; Found 2899.116.
2. DDQ oxidation of acyltryptamine
To a 200 mL eggplant-shaped flask, 500 mg (1.73 mmol) of acyl (6) and 50 mL of water-THF (90:10) solution were added and stirred, and then 787 mg (3.47 mmol, 2 eq) of DDQ was added and stirred at room temperature for 0.9 hours. did. After completion of the reaction by adding an aqueous sodium thiosulfate solution, tetrahydrofuran was removed by distillation under reduced pressure. The mixture was extracted with ethyl acetate, washed with saturated aqueous sodium hydrogen carbonate and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The crude product was recrystallized from ethyl acetate to obtain 482.6 mg (92%) of colorless crystals.
mp. 194-195 ° C (MeOH).
IR (KBr): ν 3327, 3222, 2925, 2854, 2825, 1655, 1618, 1543, 1514, 1473, 1437, 1323, 1233, 1215, 1080, 1036, 939, 918, 843, 805, 762 cm-1.
1H-NMR (400 MHz, CDCl3): Δ 9.43 (1H, broadcast, N1-H), 7.89 (1H, d, J = 3.0 Hz, C2-H), 7.81 (1H, d, J = 2.4 Hz, C7−) H), 7.33 (1H, d, J = 8.8 Hz, C4-H), 6.94 (1H, dd, J = 8.8, 2.5 Hz, C6-H), 6.72 (1H , Broadcast, N3′-H), 4.62 (2H, d, J = 4.1 Hz, C2′-H), 3.89 (3H, s, —OCH)3), 2.34 (2H, t, J = 7.7 Hz, C2 ″ −H), 1.72 (2H, ddd, J = 30.0, 15.1, 7.5 Hz, C3 ″ −H), 1.41-1.36 (2H, m, C4 ″ -H), 1.36-1.32 (2H, m, C5 ″ -H), 0.91 (3H, t, J = 7.0 Hz, C6 "-H).
13C-NMR (100 MHz, CDCl3): Δ 190.4 (C1 ″), 174.51 (C1 ′), 157.50 (C5), 132.03 (C2), 131.75 (C7a), 126.84 (C3), 115.23 ( C6), 113.07 (C7), 113.02 (C3a), 103.79 (C4), 56.03 (-OCH3), 46.35 (C2 '), 36.83 (C3 "), 31.64 (C2"), 25.57 (C4 "), 22.51 (C5"), 14.00 (C6 ").
LRFABMS m / z (%) 303 (M+ + H, 100).
HRABMS Calcd for C17H22N2O3 + H: 303.1709; Found 303.1706.
3. Synthesis of MF-20
To a 25 mL eggplant-shaped flask equipped with a reflux condenser and a salt-cal tube, 150 mg (0.50 mmol) of keto (7) and 2.5 mL of phosphorus oxychloride were added and heated to reflux for 40 minutes. The reaction solution was cooled to room temperature, poured into a beaker containing water, and aqueous ammonia was added until the aqueous layer became basic. Thereafter, the mixture was extracted with ethyl acetate, washed with water, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The residue is subjected to column chromatography (SiO 22Purification by 5 g, n-hexane: ethyl acetate 1: 1) gave 135 mg (95%) of the desired cyclized product MF-20. Thereafter, recrystallization was performed with ethyl acetate / n-hexane to obtain colorless crystals.
mp. 121-122 ° C (AcOEt / n-Hex).
IR (KBr): ν 3128, 3037, 2918, 1641, 1587, 1475, 1213, 1149, 1124, 1032, 939, 908, 822, 766, 733, 671 cm-1.
UV (MeOH): λmax 307.6, 270.2, 223.4 nm.
1H-NMR (400 MHz, CDCl3): Δ 8.60 (1H, broadcast, N1-H), 7.47 (1H, d, J = 2.4 Hz, C2-H), 7.30 (1H, d, J = 8.8 Hz, C7−) H), 7.26 (1H, d, J = 2.7 Hz, C4-H), 7.11 (1H, s, C4′-H), 6.93 (1H, dd, J = 8.8, 2.2 Hz, C6-H), 3.90 (3H, s, -OCH3), 2.84 (2H, t, J = 7.6 Hz, C1 ″ −H), 1.84 (2H, dt, J = 14.7, 7.6, 7.1 Hz, C2 ″ −H), 1.47-1.33 (2H, m, C3 ″ -H), 1.32-1.23 (2H, m, C4 ″ -H), 0.91 (3H, t, J = 6.8 Hz, C5 "-H).
13C-NMR (100 MHz, CDCl3): Δ 162.90 (C2 ′), 154.92 (C5), 147.19 (C5 ′), 131.34 (C7a), 124.67 (C3), 122.25 (C2), 119.51 ( C4 ′), 113.04 (C6), 112.23 (C7), 105.75 (C3a), 101.87 (C4), 55.89 (—OCH3), 31.32 (C3 ″), 28.17 (C1 ″), 26.87 (C2 ″), 22.31 (C4 ″), 13.91 (C5 ″).
LRFABMS m / z (%): 284 (M+ , 100).
HRABMS: Calcd for C17H20N2O2 + H 285.1603; Found 285.1611.
4). Synthesis of MF-21
To a 25 mL eggplant-shaped flask equipped with a reflux condenser and a salt tube, keto (7) 150 mg (0.50 mmol), chloroform 6 mL and diphosphorus pentasulfide 111 mg (0.50 mmol, 1 eq) were added and heated to reflux for 14 hours. . The reaction solution was cooled to 0 ° C., 10% aqueous potassium hydroxide solution was added, and the mixture was extracted with chloroform. The organic layer was washed with water and dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. This is column chromatography (SiO25g, n-hexane: ethyl acetate 1: 1) to obtain 138.6 mg (92.4%) of the intended cyclized product MF-21. Thereafter, recrystallization was performed with ethyl acetate / n-hexane to obtain colorless crystals.
m. p. 93-94 ° C (AcOEt, / n-Hex).
IR (KBr): ν 3153, 3049, 2954, 2918, 2858, 1637, 1566, 1475, 1350, 1309, 1254, 1209, 1128, 1036, 928, 901, 837, 787 cm-1.
UV (MeOH): λmax 309.4, 284.0, 218.6 nm.
1H-NMR (400 MHz, CDCl3): Δ 8.86 (1H, broadcast, N1-H), 7.79 (1H, s, C4′-H), 7.35 (1H, d, J = 2.6 Hz, C2-H), 7. 30 (1H, d, J = 2.5 Hz, C4-H), 7.28 (1H, d, J = 9.0 Hz, C7-H), 6.92 (1H, dd, J = 8.8, 2.2 Hz, C6-H), 3.88 (3H, s, -OCH3), 3.03 (2H, t, J = 7.7 Hz, C1 ″ -H), 1.85 (2H, dt, J = 14.8, 7.7, 7.3 Hz, C2 ″ −H), 1.48-1.42 (2H, m, C3 ″ -H), 1.42-1.33 (2H, m, C4 ″ -H), 0.92 (3H, t, J = 7.1 Hz, C5 "-H).
13C-NMR (100 MHz, CDCl3): Δ 169.69 (C2 ′), 155.57 (C5), 137.15 (C2), 132.41 (C5 ′), 132.17 (C7a), 126.57 (C3), 123.99 ( C4 ′), 113.68 (C6), 112.88 (C7), 108.46 (C3a), 101.79 (C4), 56.16 (—OCH3), 33.56 (C3 ″), 31.41 (C1 ″), 29.87 (C2 ″), 22.46 (C4 ″), 13.97 (C5 ″).
LRFABMS m / z (%): 301 (M+ + H, 100).
HRABMS: Calcd for C17H20N2SO + H 301.1375; FOUND 301.1371.
II. Biological action of indole compounds
Example 3 Effect of Indole Compound on Rat Liver Microsomal Lipid Peroxidation
(1) Measurement of lipid peroxide
14 mM MgCl210 μl of a microsomal fraction (protein concentration 30-50 mg / ml) prepared from rat liver and 10 μl of an ethanol solution of the test compound shown in the table below are mixed with 0.5 ml of 0.1 M Tris-HCl buffer (pH 7.5) containing And preincubation for 5 minutes at 37 ° C. Next, 0.2 M adenosine diphosphate 10 μl, 12 mM FeSO410 μl, NADPH regeneration system 40 μl and distilled water were added to make 1 ml. After mixing, the mixture was reacted at 37 ° C. for 10 minutes. After the reaction, 2 ml of a 15% trichloroacetic acid solution containing 0.375% thiobarbituric acid (TBA) and 0.25N hydrochloric acid was added and reacted for 15 minutes in a boiling water bath. The amount of the thiobarbituric acid-reactive substance is determined by measuring the absorbance at a wavelength of 535 nm. Based on this value, a value that inhibits lipid peroxidation by 50% (IC50Value).
(2) Test results
The martefradine derivatives MF-15, MF-17, MF-20 and MF-21 produced in the above production examples and the synthetic (1 ″ S, 3 ″ S) martefradine A having the same structure as the natural type [formula (1A The lipid peroxidation inhibitory activity of each indole compound of the (1 "S, 3" S form) of the compound of) was compared. As a result, as shown in the following table, ICs of the martefradine derivatives MF-15, MF-17, MF-20 and MF-2150The values are 0.59, 0.29, 0.38 and 0.48 μg / ml, respectively, and the synthetic (1 ″ S, 3 ″ S) Martefradine A IC50The value was 1.35 μg / ml, and each derivative according to the present invention showed stronger activity.
The invention's effect
According to the present invention, a novel indole by a novel synthetic method in which an amide is formed by condensation of an unsubstituted or substituted tryptamine with a carboxylic acid halide, which is then oxidized and then cyclized to construct an oxazole or thiazole ring It became possible to obtain a compound. Alkaloids having an indole ring and an oxazole ring or thiazole ring of the present invention have physiological activities such as lipid peroxidation inhibitory activity and can be used for pharmaceuticals and cosmetic materials.
Claims (6)
コキシ基を表す、請求項1記載のインドール化合物。The indole compound according to claim 1 , wherein in the formula I, X represents a sulfur atom, and R 1 represents a hydrogen atom or an alkoxy group having 1 to 4 carbon atoms.
〔式中、Xは硫黄原子を表し、R1は水素原子、未置換のもしくはハロゲン原子で置換された炭素原子数1ないし4のアルキル基または未置換のもしくはハロゲン原子で置換された炭素原子数1ないし4のアルコキシ基を表し、R2は炭素原子数1ないし20のアルキル基を表す。〕Formula IV
[Wherein X represents a sulfur atom, R 1 represents a hydrogen atom, an alkyl group having 1 to 4 carbon atoms which is unsubstituted or substituted with a halogen atom, or the number of carbon atoms which is unsubstituted or substituted with a halogen atom. R 1 represents an alkyl group having 1 to 4 carbon atoms, and R 2 represents an alkyl group having 1 to 20 carbon atoms. ]
〔式中、Xは硫黄原子を表し、R1は水素原子、未置換のもしくはハロゲン原子で置換された炭素原子数1ないし4のアルキル基または未置換のもしくはハロゲン原子で置換された炭素原子数1ないし4のアルコキシ基を表し、R2は炭素原子数1ないし20のアルキル基を表し、Halはハロゲン原子を表す。〕。Formula II
[Wherein X represents a sulfur atom, R 1 represents a hydrogen atom, an alkyl group having 1 to 4 carbon atoms which is unsubstituted or substituted with a halogen atom, or the number of carbon atoms which is unsubstituted or substituted with a halogen atom. Represents an alkoxy group having 1 to 4; R 2 represents an alkyl group having 1 to 20 carbon atoms; and Hal represents a halogen atom. ].
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