JP2011519956A - キナゾリン誘導体 - Google Patents
キナゾリン誘導体 Download PDFInfo
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- JP2011519956A JP2011519956A JP2011508714A JP2011508714A JP2011519956A JP 2011519956 A JP2011519956 A JP 2011519956A JP 2011508714 A JP2011508714 A JP 2011508714A JP 2011508714 A JP2011508714 A JP 2011508714A JP 2011519956 A JP2011519956 A JP 2011519956A
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- compound
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- cycloalkyl
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- 125000004193 piperazinyl group Chemical group 0.000 description 1
- 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 description 1
- 229920000053 polysorbate 80 Polymers 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 239000000651 prodrug Substances 0.000 description 1
- 229940002612 prodrug Drugs 0.000 description 1
- 125000006239 protecting group Chemical group 0.000 description 1
- 125000004076 pyridyl group Chemical group 0.000 description 1
- 125000000714 pyrimidinyl group Chemical group 0.000 description 1
- 125000000719 pyrrolidinyl group Chemical group 0.000 description 1
- 125000002943 quinolinyl group Chemical group N1=C(C=CC2=CC=CC=C12)* 0.000 description 1
- 206010039073 rheumatoid arthritis Diseases 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 235000019333 sodium laurylsulphate Nutrition 0.000 description 1
- 239000012453 solvate Substances 0.000 description 1
- 239000007921 spray Substances 0.000 description 1
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- 239000007858 starting material Substances 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 201000011549 stomach cancer Diseases 0.000 description 1
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- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 125000003718 tetrahydrofuranyl group Chemical group 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 125000000335 thiazolyl group Chemical group 0.000 description 1
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- 230000009466 transformation Effects 0.000 description 1
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- 235000015112 vegetable and seed oil Nutrition 0.000 description 1
- 235000013311 vegetables Nutrition 0.000 description 1
- 239000003981 vehicle Substances 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
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Classifications
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- 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
- C07D405/12—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 chain containing hetero atoms as chain links
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/517—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine
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- A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
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- A—HUMAN NECESSITIES
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- A61P35/00—Antineoplastic agents
- A61P35/02—Antineoplastic agents specific for leukemia
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- A—HUMAN NECESSITIES
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- A61P35/00—Antineoplastic agents
- A61P35/04—Antineoplastic agents specific for metastasis
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- A—HUMAN NECESSITIES
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- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/14—Vasoprotectives; Antihaemorrhoidals; Drugs for varicose therapy; Capillary stabilisers
Abstract
Description
本発明の1つの態様は、下式(I):
本発明の化合物の例を以下に示す。
本発明のキナゾリン化合物は、KDRと接触するとこのレセプターの活性を阻害する。したがって、有効な量の1つ以上のこれらの化合物は、血管形成を阻害し、かつ血管形成関連の障害を有する対象者を治療するために、使用することができる。
この化合物は実施例1に記載された方法と類似の方法で調製した。
試験化合物によるKDRキナーゼ活性の阻害について、Z’−LYTETM Tyr1ペプチドアッセイキット(米国カリフォルニア州カールスバード所在のインビトロジェン(Invitrogen)、カタログ番号PV3190)を使用して評価した。該アッセイを製造業者が推奨する手順に従って実施した。
発光量比=クマリン発光(445nm)/フルオレセイン発光(520nm)
%リン酸化=1−{(発光量比×F100%)−C100%}/{(C0%−C100%)+[発光量比×(F100%−F0%)]}
によって計算したが、上記式中:
C100%=100%Phos.対照の平均クマリン発光シグナル
C0%=0%Phos.対照の平均クマリン発光シグナル
F100%=100%Phos.対照の平均フルオレセイン発光シグナル
F0%=0%Phos.対照の平均フルオレセイン発光シグナル
である。阻害率は以下:
阻害%=(C2ウェルのPhos.−試験ウェルのPhos.)/(C2ウェルのPhos.)×100%
のように計算した。IC50(KDRキナーゼ活性を50%阻害するのに必要な濃度)の値は、このように得られた阻害率に基づいて計算した。
その他の実施形態
本明細書に開示された特徴はすべて任意の組み合わせに組み合わせることが可能である。本明細書に開示された特徴はそれぞれ、同一、等価であるかまたは類似の目的を提供する代替の特徴に置き換えることができる。したがって、別途明白な記載のないかぎり、開示された各特徴は、総括的な一連の等価または類似の特徴のうちの一例にすぎない。
Claims (26)
- 下式:
R1、R2、R3、R4、R5、R6、R7、R8、R9およびR10はそれぞれ独立に、H、ハロ、ニトロ、アミノ、シアノ、ヒドロキシ、アルキル、アルケニル、アルキニル、アリール、シクロアルキル、ヘテロシクロアルキル、ヘテロアリール、アルコキシ、アルキルチオ、アルキルカルボニル、カルボキシ、アルコキシカルボニル、カルボニルアミノ、スルホニルアミノ、アミノカルボニル、もしくはアミノスルホニルであるか、またはR3およびR4が、結合している炭素原子と一緒になって、N、OおよびSから選択された1〜3個のヘテロ原子を任意選択で含有している4〜7員の飽和環、不飽和環、もしくは芳香環を形成し;
XはO、SまたはNRであって、Rは、H、アルキル、アルケニル、アルキニル、アリール、シクロアルキル、ヘテロシクロアルキル、ヘテロアリール、アルキルカルボニル、アルコキシカルボニル、アミノカルボニルまたはアミノスルホニルであり;かつ、
ZはNまたはC−CNである、化合物。 - ZはNである、請求項1に記載の化合物。
- XはO、NHまたはN−CH3である、請求項1に記載の化合物。
- R7は−C(O)NRaRbであり、RaおよびRbはそれぞれ独立に、H、アルキル、アルケニル、アルキニル、アリール、シクロアルキル、ヘテロシクロアルキルもしくはヘテロアリールであるか、またはRaおよびRbが、結合している窒素原子と一緒になって、1〜3個のヘテロ原子を含有する3〜8員環をなす、請求項2に記載の化合物。
- RaおよびRbはそれぞれ独立に、H、アルキル、またはシクロアルキルである、請求項4に記載の化合物。
- R6はアルキルである、請求項5に記載の化合物。
- R6はメチルである、請求項6に記載の化合物。
- XはO、NHまたはN−CH3である、請求項6に記載の化合物。
- R6はアルキルである、請求項2に記載の化合物。
- R6はメチルである、請求項9に記載の化合物。
- R3およびR4はそれぞれアルコキシである、請求項2に記載の化合物。
- R7は−C(O)NRaRbであり、RaおよびRbはそれぞれ独立に、H、アルキル、アルケニル、アルキニル、アリール、シクロアルキル、ヘテロシクロアルキルもしくはヘテロアリールであるか、またはRaおよびRbが、結合している窒素原子と一緒になって、1〜3個のヘテロ原子を含有する3〜8員環をなす、請求項11に記載の化合物。
- RaおよびRbはそれぞれ独立に、H、アルキル、またはシクロアルキルである、請求項12に記載の化合物。
- RaはHでありRbはメチルである、請求項13に記載の化合物。
- R6はアルキルである、請求項14に記載の化合物。
- XはO、NHまたはN−CH3である、請求項13に記載の化合物。
- R3およびR4はそれぞれメトキシである、請求項13に記載の化合物。
- ZはC−CNである、請求項1に記載の化合物。
- R7は−C(O)NRaRbであり、RaおよびRbはそれぞれ独立に、H、アルキル、アルケニル、アルキニル、アリール、シクロアルキル、ヘテロシクロアルキルもしくはヘテロアリールであるか、またはRaおよびRbが、結合している窒素原子と一緒になって、1〜3個のヘテロ原子を含有する3〜8員環をなす、請求項18に記載の化合物。
- RaおよびRbはそれぞれ独立に、H、アルキル、またはシクロアルキルである、請求項19に記載の化合物。
- R6はアルキルである、請求項20に記載の化合物。
- 請求項1に記載の化合物と薬学的に許容可能な担体とを含んでなる医薬組成物。
- 血管形成関連の障害を治療する方法であって、有効な量の請求項1に記載の化合物を、投与を必要とする対象者に投与することを含んでなる方法。
- 血管形成関連の障害は、がん、加齢黄斑変性症、または慢性炎症性疾患である、請求項22に記載の方法。
- 表皮増殖因子レセプターの活性を阻害する方法であって、該レセプターを有効な量の請求項1に記載の化合物と接触させることを含んでなる方法。
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