JPH10512266A - プレニルトランスフェラーゼの阻害剤 - Google Patents
プレニルトランスフェラーゼの阻害剤Info
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- JPH10512266A JPH10512266A JP8521884A JP52188496A JPH10512266A JP H10512266 A JPH10512266 A JP H10512266A JP 8521884 A JP8521884 A JP 8521884A JP 52188496 A JP52188496 A JP 52188496A JP H10512266 A JPH10512266 A JP H10512266A
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- 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
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Abstract
Description
Claims (1)
- 【特許請求の範囲】 1.式: CβX [式中、 Cは還元状態又は非還元状態のシステイニル部分であり; Xはアミノ酸であり; βはアミノ安息香酸又はアミノナフトエ酸の残基である] で示されるペプチド模倣体。 2.システイニル部分が還元状態である、請求項1記載のペプチド模倣体。 3.βが2−フェニル−4−アミノ安息香酸である、請求項2記載のペプチド 模倣体。 4.式: で示される、請求項1記載のペプチド模倣体。 5.βが置換4−アミノ安息香酸である、請求項1記載のペプチド模倣体。 6.Xがメチオニン又はフェニルアラニンである、請求項1記載のペプチド模 倣体。 7.請求項1記載のペプチド模倣体と、製薬的に受容されるキャリヤーとを含 む、薬剤組成物。 8.ファルネシルトランスフェラーゼが存在する宿主におけるファルネシルト ランスフェラーゼの阻害方法であって、宿主に請求項1記載のペプチド模倣体の 有効量を投与することを含む方法。 9.プロドラッグの形態である、請求項1記載のペプチド模倣体。 10.親油性のエステラーゼ感受性部分によって官能性化された1個以上の末端 アミノ、スルフヒドリル及び酸基によって定義される化合物を含む、請求項9記 載のプロドラッグ。 11.システインCの末端アミノ及びスルフヒドリル基がベンゾイルオキシカル ボニル基又は他の切断可能な親油性基によって官能性化され、末端カルボン酸基 がエステル化される、請求項9記載のプロドラッグ。 12.カルボン酸基がメチルエステルとしてエステル化される、請求項11記載 のプロドラッグ。 13.式: [式中、RはH,CH3又は任意の親油性エステラーゼ感受性部分を表し、R1は H又は置換若しくは非置換フェニル基を表す] で示される化合物。 14.R1が非置換フェニル基、又はアルコキシ−、クロロー、ブロモ−若しく はメチル−置換フェニル基である、請求項13記載の化合物。 15.R1が3,5−ジメチルフェニルラジカル、チオフェンラジカル、ナフチ ルラジカル、ピロールラジカル、ピリジルラジカル、アルキルラジカル及びアル コキシラジカルから成る群から選択される、請求項13記載の化合物。 16.式: [式中、RはH、CH3又は任意の親油性エステラーゼ感受性部分を表し、 R1はH又は置換若しくは非置換フェニル基である] で示される化合物。 17.R1が非置換フェニル基、又はアルコキシ−、クロロー、ブロモ−若しく はメチル−置換フェニル基である、請求項15記載の化合物。 18.R1が3,5−ジメチルフェニルラジカルである、請求項16記載の化合 物。 19.式: [式中、RはH、CH3又は任意の親油性エステラーゼ感受性部分である] で示される化合物。 20.式: [式中、RはH、CH3又は任意の親油性エステラーゼ感受性部分を表し、 R1はH、CH3又はOCH3を表す] で示される化合物。 21.ファルネシルトランスフェラーゼが存在する宿主におけるファルネシルト ランスフェラーゼの阻害方法であって、宿主に請求項13記載のペプチド模倣体 の有効量を投与することを含む方法。 22.癌の治療方法であって、このような治療を必要とする患者に請求項1又は 13に記載のペプチド模倣体の有効量を投与することを含む方法。 23.βがアミノ安息香酸の残基である、請求項1記載のペプチド模倣体。 24.Xがロイシン又はイソロイシンである、請求項23記載のペプチド模倣体 。 25.βが置換4−アミノ安息香酸である、請求項24記載のペプチド模倣体。 26.システイニル部分が還元状態である、請求項25記載のペプチド模倣体。 27.4−アミノ安息香酸がフェニル環の2−及び/又は3−位置においてアル キル、アルコキシ、アリール若しくはナフチル基、又は複素環若しくはヘテロ芳 香環によって置換される、請求項26記載のペプチド模倣体。 28.βが2−フェニル−4−アミノ安息香酸又は2−ナフチル−4−アミノ安 息香酸である、請求項26記載のペプチド模倣体。 29.Lがロイシンである、請求項28記載のペプチド模倣体。 30.請求項24記載のペプチド模倣体と製薬的に受容されるキャリヤーとを含 む薬剤組成物。 31.ゲラニルゲラニルトランスフェラーゼが存在する宿主におけるゲラニルゲ ラニルトランスフェラーゼの阻害方法であって、宿主に請求項24記載のペプチ ド模倣体の有効量を投与することを含む方法。 32.プロドラッグの形態である、請求項24記載のペプチド模倣体。 33.親油性のエステラーゼ感受性部分によって官能性化された1個以上の末端 アミノ、スルフヒドリル及び酸基によって定義される化合物を含む、請求項32 記載のプロドラッグ。 34.末端カルボン酸基がエステル化される、請求項33記載のプロドラッグ。 35.カルボン酸基がメチルエステルとしてエステル化される、請求項34記載 のプロドラッグ。 36.ゲラニルゲラニルトランスフェラーゼが存在する宿主におけるゲラニルゲ ラニルトランスフェラーゼの阻害方法であって、宿主に請求項35記載の化合物 の有効量を投与することを含む方法。 37.癌の治療方法であって、このような治療を必要とする患者に請求項24記 載のペプチド模倣体の有効量を投与することを含む方法。 38.癌の治療方法であって、このような治療を必要とする患者に請求項35記 載のペプチド模倣体の有効量を投与することを含む方法。 39.式: C0B [式中、C0は を表し、 AはO又は2Hを表し、 R0はSH、NH2又はCxHy−SO2−NH−(式中、CxHyは直鎖の飽和若 しくは不飽和炭化水素であり、xは1〜20であり、yは3〜41(41を包含 する)である)であり;Bは−NHR(式中、Rはアリール基である)を表す] で示される化合物。 40.Rがビフェニル基である、請求項39記載の化合物。 41.C0が3−メルカプト−2−アミノ−プロピルアミノである、請求項39 記載の化合物。 42.Rがビフェニル基である、請求項41記載の化合物。 43.Rが−COOHによって置換されたビフェニル基である、請求項42記載 の化合物。 44.Rが低級アルキル又はオキシアルキルによって置換されたビフェニル基で ある、請求項42記載の化合物。 45.低級アルキルがメチルである、請求項44記載の化合物。 46.式: [式中、AはO又は2Hであり;R1は水素又はCOOHであり;R2は水素、C OOH、COOCH3、CH3又はテトラゾリルであり;R3は水素又はCOOH であり;R4は水素、OCH3、OC3H7又はフェニル基である] で示される請求項39記載の化合物。 47.R1が水素であり;R2が水素、COOH又はCH3であり;R3が水素又は COOHであり;R3が水素であるときにR2はCOOH又はCH3であり;R4は 水素である] で示される請求項46記載の化合物。 48.R2がCOOHであり、R3が水素である、請求項47記載の化合物。 49.R1とR3がHであり;R2がCOOH又はCH3であり;R4がフェニル又 はn−オキシプロピル基である、請求項46記載の化合物。 50.R1、R3及びR4がHであり;R2がテトラゾリルである、請求項46記載 の化合物。 51.R0がCxHy−SO2−NH−であり;xが2〜16であり;yが3〜33 である、請求項40記載の化合物。 52.R0がC2H5−SO2−NH−、CH2=CH−SO2−NH−及びCH3( CH2)15−SO2−NH−から成る群から選択される、請求項51記載の化合物 。 53.R0がNH2−である、請求項40記載の化合物。 54.Rが2’−カルボキシ−ビフェニル基又は1−メトキシ−2’−カルボキ シ−ビフェニル基である、請求項53記載の化合物。 55.R0がSHであり、Bが3−アミノメチル−3’−カルボキシビフェニル である、請求項39記載の化合物。 56.p21rasファルネシルトランスフェラーゼの阻害を必要とする宿主に おけるp21rasファルネシルトランスフェラーゼの阻害方法であって、請求 項39記載の化合物の有効量を前記宿主に投与することを含む方法。 57.請求項39記載の化合物とそのための製薬的に受容されるキャリヤーとを 含む薬剤組成物。 58.p21rasファルネシルトランスフェラーゼの阻害を必要とする宿主に おけるp21rasファルネシルトランスフェラーゼの阻害方法であって、請求 項41記載の化合物の有効量を前記宿主に投与することを含む方法。 59.請求項41記載の化合物とそのための製薬的に受容されるキャリヤーとを 含む薬剤組成物。 60.式: CβX [式中、 Cはシステインを表し; Xはアミノ酸であり; βは非ペプチドアミノアルキル−若しくはアミノ−置換脂肪族若しくは芳香族 カルボン酸又は複素環モノカルボン酸である] で示されるペプチド模倣体。 61.βがアミノ安息香酸又はアミノアルカン酸である、請求項60記載のペプ チド模倣体。 62.式: C△ [式中、Cはシステインであり、△は、ペプチドアミノ酸を包含しないが、サイ ズにおいて式:CA1A2X(式中、Cはシステインであり、A1、A2及びX はペプチドアミノ酸である)のテトラペプチドと一致するアリール又は複素環式 置換基である] で示されるペプチド模倣体。 63.アミノメチル二環状アリールカルボン酸に直接結合したシステインを含む 、請求項65記載のペプチド模倣体。 64.△がビフェニル基を含む、請求項63記載の化合物。 65.△が3−アミノメチル−ビフェニル−3−カルボン酸のラジカルである、 請求項64記載の化合物。 66.式: △1C△ △1CA1A2X 又は △1C−β−X [式中、 Cはシステインであり; A1、A2及びXはペプチドアミノ酸であり; △はペプチドアミノ酸を包含しない、アリール又は複素環式置換基であり; βは非ペプチドアミノアルキル−若しくはアミノ−置換脂肪族若しくは芳香族 カルボン酸又はヘテロカルボン酸であり; △1はシステインS原子を介してCに結合したホスホネート基である] で示される化合物。 67.式: △1C−AMBA−X [式中、△1、C及びXは請求項56において定義した意味を有し、AMBAは アミノメチル安息香酸である] で示される請求項66記載の化合物。 68.AMBAが3−アミノメチル安息香酸である、請求項67記載の化合物。 69.式: β1C△ β1CA1A2X 又は β1C−β−X [式中、 Cはシステインであり;A1、A2及びXはペプチドアミノ酸であり; △はペプチドアミノ酸を包含しない、アリール又は複素環式置換基であり; βは非ペプチドアミノアルキル−若しくはアミノ−置換脂肪族若しくは芳香族 カルボン酸又はヘテロカルボン酸であり; β1はシステインS原子を介してCに結合したアリール又はアラルキル基であ る] で示される化合物。 70.式: β1C−AMBA−X [式中、C、X及びβ1は請求項70において定義した意味を有し、AMBAは アミノメチル安息香酸である] で示される請求項69記載の化合物。 71.AMBAが3−アミノメチル安息香酸である、請求項70記載の化合物。 72.式: 又は で示される化合物。 73.ペプチド又はペプチド模倣体の細胞への取り込みを改良する方法であって 、末端アミノ、スルフヒドリル及び酸基が親油性又は疎水性のエステラーゼ感受 性部分によって官能性化されるような、官能性化形のペプチドを用いることを含 む 方法。 74.宿主における腫瘍細胞増殖を阻害するための請求項73記載の方法であっ て、1個以上の末端アミノ、スルフヒドリル及びカルボン酸基が親油性又は疎水 性のエステラーゼ感受性部分によって官能性化されている、ペプチド又はペプチ ド模倣体の有効量を宿主に投与することを含む方法。 75.末端アミノ基及びスルフヒドリル基がベンジルオキシカルボニル基によっ て官能性化され、カルボン酸基がエステル化される、請求項74記載の方法。 76.式(A−L): {式中、R1'は: (i)水素; (ii)低級アルキル; (iii)アルケニル; (iv)アルコキシ; (v)チオアルコキシ; (vi)ハロ; (vii)ハロアルキル; (viii)アリール−L2−[式中、L2は存在しないか又は−CH2−、−CH2C H2−、−CH(CH3)−、−O−、−S(O)q(式中、qは0、1若しくは 2である)、−N(R’)−(式中、R’は水素若しくは低級アルキルである) 、又は−C(O)−であり、アリールはフェニル、ナフチル、テトラヒドロナフ チル、インダニル及びインデニルから成る群から選択され、アリール基は非置換 であるか又は置換されている];又は (ix)複素環−L3−[式中、L3は存在しないか又は−CH2−、−CH2CH2 −、−CH(CH3)−、−O−、−S(O)q(式中、qは0、1若しくは2で ある)、−N(R’)−(式中、R’は水素若しくは低級アルキルである)、又 は−C(O)−であり、複素環は単環状複素環(式中、複素環は非置換であるか 若しくは低級アルキル、ヒドロキシ、ヒドロキシアルキル、ハロ、ニトロ、オキ ソ(=O)、アミノ、N−保護アミノ、アルコキシ、チオアルコキシ及びハロア ルキルから成る群から独立的に選択される1、2若しくは3個の置換基によって 置換されている)である]であり; R1aは水素又は低級アルキルであり; R2'は: (i) [式中、R12aは水素、低級アルキル又は−C(O)O−R13(式中、R13は水 素若しくはカルボキシ保護基である)であり、R12bは水素又は低級アルキルで ある、但し、R12aとR12bが両方とも水素であることはない]; (ii)−C(O)NH−CH(R14)−C(O)OR15[式中、R14は、 (a)低級アルキル、 (b)シクロアルキル、 (c)シクロアルキルアルキル、 (d)アルコキシアルキル、 (e)チオアルコキシアルキル、 (f)ヒドロキシアルキル、 (g)アミノアルキル、 (h)カルボキシアルキル、 (i)アルコキシカルボニルアルキル、 (j)アリールアルキル、又は (k)アルキルスルホニルアルキルであり、 R15は水素、又はカルボキシ保護基である];又は (iii) であり; R3'は [式中、AはO又は2Hを表し、 R0はSH、NH2又はCxHy−SO2−NH−(式中、CxHyは直鎖の飽和若 しくは不飽和炭化水素であり、xは1〜20であり、yは3〜41(41を包含 する)である]であり; Bは−NHR(式中、Rはアリール基である)を表し; L1は−NH−である} で示される化合物又はその製薬的に受容される塩若しくはプロドラッグ。
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US08/451,839 US5834434A (en) | 1993-05-18 | 1995-05-30 | Inhibitors of farnesyltransferase |
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US08/582,076 US6011175A (en) | 1993-05-18 | 1996-01-02 | Inhibition of farnesyltransferase |
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Publication number | Priority date | Publication date | Assignee | Title |
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US5602098A (en) * | 1993-05-18 | 1997-02-11 | University Of Pittsburgh | Inhibition of farnesyltransferase |
-
1996
- 1996-01-11 JP JP52188496A patent/JP3929069B2/ja not_active Expired - Lifetime
- 1996-01-11 WO PCT/US1996/001559 patent/WO1996021456A1/en not_active Application Discontinuation
- 1996-01-11 EP EP96905380A patent/EP0794789A4/en not_active Withdrawn
- 1996-01-11 CA CA2207252A patent/CA2207252C/en not_active Expired - Lifetime
- 1996-01-11 AU AU49157/96A patent/AU4915796A/en not_active Abandoned
-
1997
- 1997-07-11 MX MX9705273A patent/MX9705273A/es unknown
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2006
- 2006-08-01 JP JP2006209503A patent/JP4138826B2/ja not_active Expired - Fee Related
Cited By (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP2010100619A (ja) * | 1997-05-07 | 2010-05-06 | Univ Of Pittsburgh | タンパク質イソプレニルトランスフェラーゼの阻害剤 |
JP4793692B2 (ja) * | 2004-04-26 | 2011-10-12 | 小野薬品工業株式会社 | 新規なblt2介在性疾患、blt2結合剤および化合物 |
JP2015519308A (ja) * | 2012-04-10 | 2015-07-09 | ザ・リージエンツ・オブ・ザ・ユニバーシテイー・オブ・カリフオルニア | 癌治療用組成物および方法 |
Also Published As
Publication number | Publication date |
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JP3929069B2 (ja) | 2007-06-13 |
WO1996021456A1 (en) | 1996-07-18 |
JP2007016035A (ja) | 2007-01-25 |
CA2207252A1 (en) | 1996-07-18 |
JP4138826B2 (ja) | 2008-08-27 |
AU4915796A (en) | 1996-07-31 |
EP0794789A4 (en) | 1999-05-26 |
EP0794789A1 (en) | 1997-09-17 |
CA2207252C (en) | 2014-02-25 |
MX9705273A (es) | 1998-06-30 |
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