JP2004051594A - Vascularization inhibitor - Google Patents
Vascularization inhibitor Download PDFInfo
- Publication number
- JP2004051594A JP2004051594A JP2002214423A JP2002214423A JP2004051594A JP 2004051594 A JP2004051594 A JP 2004051594A JP 2002214423 A JP2002214423 A JP 2002214423A JP 2002214423 A JP2002214423 A JP 2002214423A JP 2004051594 A JP2004051594 A JP 2004051594A
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- Prior art keywords
- angiogenesis
- hydrate
- solvate
- compound
- ring
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Abstract
Description
【０００１】
【発明の属する技術分野】
本発明は、病的な血管新生を伴う疾患、例えば、糖尿病性網膜症、加齢黄班変性症、又は癌等の治療に有用な血管増殖抑制剤に関する。
【０００２】
【従来の技術】
血管新生は血管が新たに増生する現象であり、脊椎動物の胎生期における循環器系の形成や、組織形成に関与するばかりでなく、成熟個体の性周期における黄体形成、胎盤形成などに関与する。一方、これら正常の血管新生以外に、慢性炎症、糖尿病性網膜症、又は加齢黄斑変性症等視力を奪う重大な疾患や固形腫瘍の増殖、慢性関節リューマチの特に関節腔内におけるパンヌス形成、又は関節症における滑膜の増殖時に病的血管新生が認められ、疾患の進展に深く関与している。従って、これらの病的な血管新生を阻害することが、これらの疾患の治療につながる可能性がある。血管腔の内腔を被覆する細胞を血管内皮細胞と呼んでいるが、血管内皮細胞が成長因子や生理活性物質または物理的損傷などの刺激を受けて、増殖することによって、血管新生が行われる。直接又は間接的に血管内皮細胞の増殖を刺激する成長因子として、血管内皮細胞増殖因子（ＶＥＧＦ）や線維芽細胞増殖因子（ＦＧＦ）等多くの因子が知られている。血管新生阻害剤としてフマギリンおよびその誘導体ＴＮＰ−４７０、抗ＶＥＧＦ抗体、ある種のＶＥＧＦ受容体キナーゼ阻害剤、エンドスタチン等の数多くの化合物が研究開発され、ヒトでの臨床試験が進んでいる（文献：細胞 ３２：１０８−１１２， ２０００）。これらの中でもフマギリンおよびその誘導体ＴＮＰ−４７０の血管内皮細胞増殖阻止作用は強いとされているが、血管内皮細胞特異性は未だ充分とはいえないため、満足できる血管新生抑制剤とはいえない。
【０００３】
【発明が解決しようとする課題】
本発明の課題は、病的血管新生の関与する疾患、例えば、慢性関節リューマチ、糖尿病性網膜症、固形癌、又は慢性炎症などの疾患の予防薬あるいは治療薬として有用で、副作用の少ない血管新生阻害剤を見出すことである。
本発明者等は、血管新生を阻害する化合物につき、多くの化合物をスクリーニングした結果、特定のイミダゾピリミジン誘導体中に、血管内皮細胞の増殖、遊走、管腔形成を阻害する作用を示す化合物を見出し、血管新生を伴う疾患の予防若しくは治療剤として本発明を完成したものである。
【０００４】
【課題を解決するための手段】
即ち、本発明は、以下に述べる（１）〜（１２）に関するものである。
（１） 式（Ｉ）で表されるイミダゾピリミジン誘導体、その薬学的に許容し得る塩、又はそれらの水和物若しくは溶媒和物を有効成分とする病的な血管新生の抑制に有効な血管新生抑制剤、
【化８】
（２） Ａ環が、置換基を有するベンゼン環であって、下記式（ＩＩ）で表されるイミダゾピリミジン誘導体、その薬学的に許容し得る塩、又はそれらの水和物若しくは溶媒和物を有効成分とする病的な血管新生の抑制に有効な、上記（１）記載の血管新生抑制剤、
【化９】
Ｒ２は、水素原子、ハロゲン原子、低級アルキル基、又は低級アルキルアミン基を意味し、
Ｒ３は、水素原子、ハロゲン原子、低級アルキル基、１‐ピペリジニル基、ベンジルメチルアミノ基、α―ヒドロキシイミノベンジル基、テトラヒドロピリジン環、次式（▲１▼）若しくは（▲２▼）で表される基、低級アルキルアミン、低級ジアルキルアミン、又はＲ２とＲ３が一緒になって形成する炭素原子が硫黄原子に置換されていてもよい環状アルキレン鎖あるいはテトラヒドロピリジン環を意味する。）
【化１０】
【化１１】
（４） 次式（ａ）から（ｍ）で表される化合物から選ばれるいずれかの化合物、その塩、又はそれらの水和物若しくは溶媒和物を有効成分とする病的な血管新生の抑制に有効な、上記（２）に記載の血管新生抑制剤、
【化１２】
【化１３】
【化１４】
（８） 病的な血管新生が、糖尿性網膜症又は加齢黄班変性症における血管新生である、上記（１）から（６）のいずれかに記載の血管新生抑制剤、
（９） 病的な血管新生が、関節リウマチ、又は関節症における血管新生である上記（１）から（６）のいずれかに記載の血管新生抑制剤、
（１０） 上記（１）から（６）のいずれかに記載される化合物を有効成分として含む血管内皮細胞増殖抑制剤、
（１１） 上記（４）又は（５）に記載されるいずれかの化合物を有効成分とする血管内皮細胞増殖抑制剤、及び
（１２） 上記（４）又は（５）に記載されるいずれかの化合物を有効成分とする管腔形成阻害剤。
【０００５】
【発明の実施の形態】
以下に、本発明を詳細に説明する。
本発明の血管新生抑制剤は、一般式（Ｉ）で表されるイミダゾピリミジン誘導体、その塩、又はそれらの水和物若しくは溶媒和物を有効成分とする。一般式（Ｉ）において、Ｒ１の低級アルキル基は、炭素数１から６程度が好ましく、炭素数１のメチル基がより好ましい。
一般式（Ｉ）におけるＡ環には１〜２の基が置換でき、１〜２の置換基は各々独立して、ハロゲン原子、低級アルキル基、低級アルキルアミノ基、低級ジアルキルアミノ基、１−ピペリジニル基、ベンジルメチルアミノ基、α−ヒドロキシイミノペンジル基、テトラヒドロピリジン基もしくは次式（▲１▼）もしくは（▲２▼）である。あるいは２つの置換基が一緒になって、炭素原子が硫黄原子に置換されていてもよい環状アルキレン鎖、又はテトラヒドロピリジン環を形成してもよい。
Ａ環上の２つの置換基、Ｒ２とＲ３あるいはＲ４とＲ５が一緒になって環状アルキレン鎖を形成する時、環状アルキレン鎖の炭素原子の一部は硫黄原子に置換していても良く、そのとき、炭素原子一個が硫黄原子一個に置換されていることが好ましく、具体的には、より好ましい例としてジヒドロチオピラン環又はシクロヘキサン環を挙げることができる。
ハロゲン原子としては、フッ素原子、塩素原子、臭素原子およびヨウ素原子を挙げることができ、好ましくは塩素原子もしくは臭素原子であり、塩素原子がより好ましい。
低級アルキル基は、直鎖状、分枝状若しくは環状の炭素数１から３のアルキル基を意味し、例えば、メチル基、エチル基、プロピル基、イソプロピル基、又はシクロプロピル基等を挙げることができ、好ましくはメチル基又はエチル基であり、より好ましくはメチル基である。
低級アルキルアミノ基は直鎖状、分枝状又は環状の炭素数１から３のアルキル基１つとアミノ基とで構成する基を意味し、低級アルキルアミノ基としてはメチルアミノ基、及びエチルアミノ基等を挙げることができる。
低級ジアルキルアミノ基は、直鎖状、分枝状又は環状の炭素数１から３のアルキル基２つとアミノ基とで構成する基を意味し、低級ジアルキルアミノ基としてはジメチルアミノ基、及びジエチルアミノ基等を挙げることができる。
一般式（Ｉ）の代表的な化合物であって、ベンゼン環を有するものとしては、［化５］に示す１３個の化合物を挙げることができ、また、チオフェンを有するものとしては、［化６］に示す６個の化合物を挙げることができるが、これらに限定されるものではない。
【０００６】
また、［化５］及び［化６］で表される化合物が異性体を含むとき、本発明に
おける血管新生抑制を示す化合物には、それらの異性体を含むものとし、例えば、Ｅ体およびＺ体、及びそれらの混合物をも含むものとする。
【０００７】
これらの化合物は、フリーの形で用いることもできるし、塩、又はそれらの水和物若しくは溶媒和物で用いることもできる。
発明化合物（１）の塩としては、医薬的に許容し得る塩であれば特に限定されないが、具体的には、塩酸塩、臭化水素酸塩、ヨウ化水素酸塩、燐酸塩、硝酸塩、硫酸塩等の鉱酸塩類；メタンスルホン酸塩、２−ヒドロキシエタンスルホン酸塩、ｐ−トルエンスルホン酸塩等の有機スルホン酸塩類；並びに酢酸塩、プロパン酸塩、シュウ酸塩、マロン酸塩、コハク酸塩、グルタル酸塩、アジピン酸塩、酒石酸塩、マレイン酸塩、リンゴ酸塩、及びマンデル酸塩等の有機カルボン酸塩類が挙げられる。薬理学的に許容される種々の塩、例えば塩酸塩、トシル酸塩、メタンスルフォン酸塩、及びクエン酸塩等があげられる。
【０００８】
本発明に係る代表的な化合物は、殆どが公知の化合物である。従ってそれらの化合物は市販品として入手できるか、あるいは以下に挙げる公報に基づき当業者なら容易に製造することができる。
本発明に含まれる代表的な化合物の製造方法は、例えば、以下の公報に開示されている。化合物（ａ）、（ｅ）及び（ｉ）は特開昭５４−４１８９４号に、化合物（ｂ）は特開昭和５９−０５３４８７号に、化合物（ｃ）は特開昭５９−５１２８５号に、化合物（ｄ）は特開昭６０−００４１８６号に、化合物（ｆ）は特開昭５４−１３５７９号及び特開平０２−０２２２７６号に、化合物（ｇ）は特開昭４８−０８６８９４号に、化合物（ｈ）はＵＳＰ第３９３２４０７号に、化合物（ｋ）及び（ｊ）は特開平０３−０６３２７７号に、化合物（ｍ）は特開昭５７−１２３１８４号に、化合物（ｌ）は特開昭５９−１５５３８３号に、各々、記載されている。また、チオフェン環を有する化合物（ｎ）、（ｏ）、（ｐ）、（ｑ）、（ｒ）及び（ｓ）については特開昭５５−２７１０５号に開示されている。
【０００９】
本発明の血管新生抑制剤は、血管内皮細胞に対して極めて特異的な増殖抑制効果と血管内皮細胞の管腔形成抑制作用を示した。このことから、これらのイミダゾピリミジン誘導体は、経口的経路で、また、非経口的経路、すなわち、静脈内、動脈内、皮下、直腸内、粘膜内等、あるいは患部局所内、すなわち関節腔内、眼球内、固形腫瘍内、乾癬病変等に投与することができる。人体にこれらの経路で投与することにより、病的な血管新生が認められる慢性炎症、糖尿病性網膜症、加齢黄斑変性症、固形腫瘍の増殖、慢性関節リューマチの特に関節腔内におけるパンヌス形成、関節症における滑膜増殖時等の疾患の治療薬としての利用が期待できる。
【００１０】
次に、本発明で用いたイミダゾピリミジン誘導体あるいはその薬理的に許容される塩、又は／及び水和物（以下、本発明の化合物と略す。）の製剤について説明する。
本発明の血管新生抑制剤の剤型としては、有効成分を医学的に許容される担体、賦形剤、滑沢剤、結合剤等の添加物を含有する種々の形態、例えば水または各種の輸液用製剤に溶解させた液剤、散剤、顆粒剤、錠剤、注射剤、坐剤、又は外用製剤等が、公知の製剤技術により製造できる。本発明化合物を人体用の医薬として使用する場合にその投与量は、一般的には、成人の経口一日量として０．１−１００ ｍｇ、通常０．１−１０ ｍｇが適当で、漸減していくのが好ましいことがある。注射による投与の場合は通常経口の１／５量が適当であるが、必要に応じて漸減あるいは漸増することができる。また、病巣局所に投与する場合、例えば関節腔内、又は眼球内等に投与する場合はさらに投与量を減ずることができ、全身に対する作用を減弱させ、有効に用いることが可能である。またその投与量は患者の症状、年齢、又は体重等により適宜増減してもよい。
【００１１】
本発明で用いたイミダゾピリミジン誘導体を注射で投与する場合、水性注射剤、水性懸濁注射剤、脂肪乳剤、又はリポソーム注射剤等が好ましい。水性注射剤、又は水性懸濁注射剤においては、本発明に係るイミダゾピリミジン誘導体あるいはその薬理的に許容される塩を、精製水と混合し、必要に応じて水溶性あるいは水膨潤性高分子、ｐＨ調整剤、界面活性剤、浸透圧調整剤、防腐剤、又は保存剤などを加え、混合して、必要に応じて加熱しながら溶解乃至懸濁させ、滅菌して注射剤容器に充填密封し、水性注射剤、又は水性懸濁注射剤とする。水性注射剤は、静脈内、皮下、筋肉内、皮内、又は関節腔内等に投与することができる。また、水性懸濁注射剤は皮下、筋肉内、皮内、又は関節腔内等に服用することができる。また経口でも投与することができる。
【００１２】
水溶性あるいは水膨潤性高分子としては、ゼラチン、セルロース誘導体、アクリル酸誘導体、ポビドン、マクロゴール、ポリアミノ酸誘導体、又は多糖体類が好ましく、ゼラチン類では精製ゼラチンが好ましく、セルロース誘導体では、メチルセルロース、ヒドロキシプロピルメチルセルロース２９１０、ヒドロキシプロピルメチルセルロース２２０８、ヒドロキシプロピルメチルセルロース２９０６、ヒドロキシプロピルセルロース、低置換度ヒドロキシプロピルセルロース、カルメロースナトリウム、アクリル酸誘導体として、アミノアクリルメタアクリレートコポリマー、メタアクリル酸コポリマー、ポリアミノ酸誘導体としては、ポリリジン、ポリグルタミン酸が好ましい。多糖体としては、ヒアルロン酸、デキストラン、又はデキストリンが特に好ましい。水溶性あるいは水膨潤性高分子の添加量は、エスクレチン、その誘導体、あるいはその薬理的に許容される塩の性質、量、並びに水溶性あるいは水膨潤性高分子の性質、分子量、適用部位によって異なるが概ね製剤全量に対し、０．０１％乃至１０％の範囲で使用可能である。
【００１３】
ｐＨ調整剤には、人体に無害な酸あるいはアルカリが用いられ、界面活性剤には、非イオン性界面活性剤、陰イオン性界面活性剤、両性界面活性剤が用いられる。また、浸透圧調整剤には、塩化ナトリウム、ブドウ糖等が、防腐剤にはパラベン類が、保存剤にはアスコルビン酸や亜硫酸塩類が例示される。これらの使用量は、特に限定はないが、その作用がそれぞれ発揮できる範囲で用いることができる。また、必要に応じ塩酸プロカイン等の局所麻酔剤、ベンジルアルコール等の無痛化剤、キレート剤、緩衝剤、あるいは水溶性有機溶剤等を加えてもよい。
【００１４】
脂肪乳剤は適当な油脂に乳化剤とイミダゾピリミジン誘導体、あるいはその薬理的に許容される塩を配合し、精製水を加えて、必要に応じて水溶性あるいは水膨潤性高分子、ｐＨ調整剤、界面活性剤、浸透圧調整剤、防腐剤、又は保存剤などを加え、適当な乳化装置で乳化し、滅菌して注射剤容器に充填密封することによって調製される。
【００１５】
本発明化合物からなる経口用製剤としては本発明化合物を主剤とする剤型としては例えば錠剤、散剤、 顆粒剤、カプセル剤や、溶液剤、シロップ剤、エリキシル剤、又は油性ないし水性の懸濁液等を投与法に応じ適当な製剤を選択し、通常の賦形剤、滑沢剤、結合剤等の添加物と共に、公知の製剤技術により製造できる。
固形製剤としては活性化合物とともに製剤学上許容されている添加物を含み、例えば充填剤類や増量剤類、結合剤類、崩壊剤類、溶解促進剤類、湿潤剤類、又は潤滑剤類等を必要に応じて選択して混合し、製剤化することができる。
また外用製剤として溶液剤、懸濁液、乳濁液、軟膏、ゲル、クリーム、ローション、及びスプレー等を例示できる。
【００１６】
本発明の血管新生抑制剤としの代表化合物である化合物（ｆ）（アナグレライド、ａｎａｇｒｅｌｉｄｅ）は、血漿板増多症の治療薬として米国等の諸外国で臨床使用実績のある医薬品であり、その面からヒトに投与できる安全性の高い化合物である。
アナグレライドを０．５ ｍｇ もしくは１ ｍｇ服用したヒトで見られる最も多い副作用は頭痛などが報告されているにすぎない（出典ＮＤＡ ２０−３３３／Ｓ−００２）。
また、本発明の血管新生抑制剤の別の代表的化合物である化合物（ｄ）は、ラット、サルにそれぞれ１０ｍｇ／ｋｇ、４ｍｇ／ｋｇを４週間静脈内投与しても、症状、解剖所見、心電図変化とも認められず、毒性学的無影響量と推定された。また、抗原性、変異原性は認められず、生殖試験においても悪影響は及ぼさなかった。ラベル体を用いた試験でも残留傾向は認められず、組織内移行は高くなかった。また、化合物（ｄ）を、ヒトに対して静脈内に１分、３０分、１２０分間点滴持続静注し、最高血中濃度約８０ − １００ ｎｇ／ｍＬに達する用量を２−３回／日連続投与した場合に一部に、軽微な頭重感、一過性の拍動感があったのみであり重篤な毒性はみとめられなかった。
このようにヒト血管内皮細胞の増殖抑制作用を発現する数ｎｇ／ｍＬよりも１０倍以上の血中濃度で治療薬もしくは治験薬としてのヒトにおける安全性が充分確保されている。また、関節腔内投与、又は眼球内投与の場合は病巣局所濃度に比較し、血中濃度が極めて低いと考えられ、全身に与える影響はさらに軽微である。
【００１７】
以下、実施例を挙げて本発明を更に詳細に説明するが、本発明はこれらによって限定されるものではない。
【実施例１】
［増殖阻止試験方法］
この試験で用いた表１に示す化合物は、すべてが公知の化合物である。従って、前記に示した公報に記載の方法に基づき合成したものを用いた。また、血管新生抑制作用を有する公知の化合物として用いたフマギリンは、シグマ社製のものを用いた（その構造を［化１５］に示す。）。ヒト血管内皮細胞としてヒト臍帯静脈血管内皮細胞（ＨＵＶＥＣ）の培養には、接着因子溶液（ Ｉ 型コラーゲン含有溶液）をコートした１００ ｍｍ 径組織培養用ディッシュを用い、成長因子溶液（日水製薬、東京）を添加した血管内皮細胞用血清含有培地（５％牛胎児血清含有ＭＣＤＢ１０４培地、日水製薬）中で、３７℃、５％ ＣＯ２、継代維持した。 ヒト気管支平滑筋細胞を平滑筋細胞基礎培地中で３７℃、５％ ＣＯ２下で培養し、試験に供した。各細胞を各々の増殖因子非添加培地で調整し、９６−ウェルマイクロプレートに播種した。約６時間培養後、各種濃度の化合物および増殖因子（ｂＦＧＦ， ＶＥＧＦ）を添加した。４日間培養後、ＭＴＴ ａｓｓａｙにより細胞数を判定した。
【００１８】
【化１５】
〔試験結果〕 各検体の５０％増殖阻止濃度を表に示した。表に代表的な化合物の活性値を示す。 陽性対照薬フマギリンと同様にこれら化合物はいずれもヒト臍帯静脈血管内皮細胞ＨＵＶＥＣに対し、陽性対照薬フマギリンと同様に、強い増殖阻止活性を示し、その５０％増殖阻止濃度は約０．１ から ２５０ ｎｇ／ｍＬであった（表１）。
一方、ヒト肺がん細胞ＰＣ−６、ヒト気管支平滑筋細胞、マウス白血病Ｐ３８８の増殖には最高濃度の１０，００００ ｎｇ／ｍＬでも影響せず， ５０％増殖阻止濃度を求めることはできなかった。すなわち、これらの化合物は血管内皮細胞増殖阻止濃度の２０００倍から５０００倍以上の濃度でも他の細胞（肺がん細胞、平滑筋細胞、白血病細胞）に対して増殖阻止作用は示さず、極めて選択的に血管内皮細胞に対してのみ阻止効果を示した。一方、対照薬フマギリンは、１から４００倍濃度でこれら他の細胞の増殖を阻止した。以上により本発明化合物は血管内皮細胞に極めて選択的に阻止作用を示すことが実証された。
【００２０】
【実施例２】
〔管腔形成阻止試験〕
９６−ウェルマイクロプレートの各ウェルにマウスＥＨＳ肉腫由来のマトリゲルを５０ ｍＬ 添加し、３７℃でゲル化させた。ゲルの上にＨＵＶＥＣ細胞および種種の化合物を加えた２０％ＦＢＳ含有Ｍ１９９培地を加え、細胞を播種した。培養開始１８時間後にマトリゲル上に形成された内皮細胞の管腔ネットワーク長を測定し、各化合物の抑制作用を５０％阻止濃度で表した。イミダゾピリミジン誘導体は血管内皮細胞の増殖阻止作用に加え、管腔形成阻止作用も示すことがあきらかになった。
【００２１】
【表１】
以下には、化合物（ｄ）を用いて、本発明の製剤の処方例を示す。
＜処方例１（注射剤１）＞
凍結乾燥製剤
１バイアル中に、化合物（ｄ）フリー体として５ｍｇ、マルトース１水和物１０ ０ｍｇおよび適量の水酸化ナトリウムを含有。
添付溶解液
１アンプル中、乳酸４．５ｍｇ、Ｄ−ソルビトール２７０ｍｇ、適量の水酸化ナトリウ ムおよび注射用水を含有する（全量５ｍＬ，ｐＨ４．０）。
処方（凍結乾燥製剤）
化合物（ｄ）（フリー体） ５ｍｇ
マルトース１水和物 １００ｍｇ
水酸化ナトリウム 適量 ｐＨ３．５
注射用水 （全量２ｍｌ）
添付溶解液
乳酸 ４．５ｍｇ
Ｄ−ソルビトール ２７０ｍｇ
水酸化ナトリウム 適量 ｐＨ４．３
注射用水 ５ｍｌ
【００２３】
＜処方例２（注射剤２）＞
凍結乾燥製剤
１バイアル中に、化合物（ｄ）フリー体として５ｍｇ、マルトース１水和物１０ ０ｍｇおよび適量の水酸化ナトリウムを含有。
添付溶解液
１アンプル中、Ｄ−ソルビトール２７０ｍｇおよび注射用水を含有する（全量５ｍＬ，ｐＨ４．０）。
処方（凍結乾燥製剤）
化合物（ｄ）（フリー体） ５ｍｇ
マルトース１水和物 １００ｍｇ
水酸化ナトリウム 適量 ｐＨ３．５
注射用水 （全量２ｍｌ）
添付溶解液
Ｄ−ソルビトール ２７０ｍｇ
注射用水 ５ｍｌ
【００２４】
＜処方例３（注射剤３）＞
凍結乾燥製剤
１バイアル中に、化合物（ｄ）フリー体として５ｍｇ、マルトース１水和物１０ ０ｍｇおよび適量の水酸化ナトリウムを含有
添付溶解液
注射用水 ２ｍＬ。
処方（凍結乾燥製剤）
化合物（ｄ）（フリー体） ５ｍｇ
マルトース１水和物 １００ｍｇ
水酸化ナトリウム 適量 ｐＨ３．５
注射用水 （全量２ｍｌ）
添付溶解液
注射用水 ２ｍｌ
【００２５】
＜処方例４（経口製剤１）＞
カプセル剤 １ｍｇ 製剤
５号ゼラチンカプセルに化合物（ｄ）フリー体として１．０ｍｇ、マンニトール５５ ．９ｍｇ、結晶セルロース２５．０ｍｇ、クロスポビドン２．５ｍｇ、軽質無水ケイ酸０．２ｍｇ およびステアリン酸マグネシウム０．４ｍｇを含有する。
処方
化合物（ｄ）（フリー体） １．０ｍｇ
マンニトール ５５．９ｍｇ
結晶セルロース ２５．０ｍｇ
クロスポビドン ２．５ｍｇ
軽質無水ケイ酸 ０．２ｍｇ
ステアリン酸マグネシウム ０．４ｍｇ
全量 ８５ｍｇ
【００２６】
＜処方例５（経口製剤１）＞
カプセル剤 ５ｍｇ 製剤
５号ゼラチンカプセルに化合物（ｄ）フリー体として５．０ｍｇ、マンニトール５１ ．９ｍｇ、結晶セルロース２５．０ｍｇ、クロスポビドン２．５ｍｇ、軽質無水ケイ酸０．２ｍｇ およびステアリン酸マグネシウム０．４ｍｇを含有する。
処方
化合物（ｄ）（フリー体） ５．０ｍｇ
マンニトール ５１．９ｍｇ
結晶セルロース ２５．０ｍｇ
クロスポビドン ２．５ｍｇ
軽質無水ケイ酸 ０．２ｍｇ
ステアリン酸マグネシウム ０．４ｍｇ
全量 ８５ｍｇ
【００２７】
【発明の効果】
本発明の血管新生抑制剤は、血管内皮細胞に対して特異的に増殖抑制効果と血管内皮細胞の管腔形成抑制作用を示した。このことから、これらの本発明の医薬であるイミダゾピリミジン誘導体は、糖尿病性網膜症、又は加齢黄斑変性症による視力低下および失明、固形腫瘍の増殖、慢性関節リューマチの特に関節腔内におけるパンヌス形成、関節症における滑膜の増殖等の疾患、又は乾癬等病的血管新生を伴う疾患に対する治療薬としての利用が期待できる。[0001]
TECHNICAL FIELD OF THE INVENTION
The present invention relates to a vascular growth inhibitor useful for treating diseases associated with pathological angiogenesis, such as diabetic retinopathy, age-related macular degeneration, and cancer.
[0002]
[Prior art]
Angiogenesis is a phenomenon in which blood vessels newly grow and are involved not only in circulatory system formation and tissue formation in the vertebrate embryo, but also in luteal formation and placenta formation in the estrous cycle of mature individuals. . On the other hand, in addition to these normal angiogenesis, chronic inflammation, diabetic retinopathy, or growth of solid tumors such as age-related macular degeneration or solid tumors that deprive vision, pannus formation especially in the joint cavity of rheumatoid arthritis, or Pathological angiogenesis is observed during synovial proliferation in arthropathy, and is deeply involved in disease progression. Thus, inhibiting these pathological angiogenesis may lead to the treatment of these diseases. The cells that cover the lumen of the vascular lumen are called vascular endothelial cells, and angiogenesis is performed by proliferating and proliferating vascular endothelial cells when stimulated by growth factors, bioactive substances, or physical damage. . As growth factors that directly or indirectly stimulate the proliferation of vascular endothelial cells, many factors such as vascular endothelial cell growth factor (VEGF) and fibroblast growth factor (FGF) are known. Numerous compounds such as fumagillin and its derivative TNP-470, anti-VEGF antibody, certain VEGF receptor kinase inhibitors, and endostatin have been researched and developed as angiogenesis inhibitors, and human clinical trials are in progress (Literature) : Cells 32: 108-112, 2000). Among these, fumagillin and its derivative TNP-470 are said to have a strong inhibitory effect on the proliferation of vascular endothelial cells, but they cannot be said to be satisfactory angiogenesis inhibitors because their vascular endothelial cell specificity is not yet sufficient.
[0003]
[Problems to be solved by the invention]
An object of the present invention is to provide angiogenesis that is useful as a preventive or therapeutic agent for diseases involving pathological angiogenesis, such as rheumatoid arthritis, diabetic retinopathy, solid cancer, or chronic inflammation, and has few side effects. Is to find inhibitors.
The present inventors have screened a large number of compounds that inhibit angiogenesis, and as a result, have found, among specific imidazopyrimidine derivatives, a compound exhibiting an action of inhibiting proliferation, migration, and tube formation of vascular endothelial cells. The present invention has been completed as a prophylactic or therapeutic agent for diseases associated with angiogenesis.
[0004]
[Means for Solving the Problems]
That is, the present invention relates to (1) to (12) described below.
(1) An imidazopyrimidine derivative represented by the formula (I), a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof, which is a blood vessel effective for inhibiting pathological angiogenesis. Newborn inhibitors,
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(2) Ring A is a substituted benzene ring, and represents an imidazopyrimidine derivative represented by the following formula (II), a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof. An angiogenesis inhibitor according to the above (1), which is effective for suppressing pathological angiogenesis as an active ingredient.
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R2 represents a hydrogen atom, a halogen atom, a lower alkyl group, or a lower alkylamine group,
R3 is a hydrogen atom, a halogen atom, a lower alkyl group, a 1-piperidinyl group, a benzylmethylamino group, an α-hydroxyiminobenzyl group, a tetrahydropyridine ring, represented by the following formula (1) or (2). A lower alkylamine, a lower dialkylamine, or a cyclic alkylene chain or a tetrahydropyridine ring in which a carbon atom formed by R2 and R3 together may be substituted with a sulfur atom. )
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(4) Inhibition of pathological angiogenesis using any compound selected from the compounds represented by the following formulas (a) to (m), a salt thereof, or a hydrate or solvate thereof as an active ingredient: An angiogenesis inhibitor according to the above (2), which is effective for:
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(8) The angiogenesis inhibitor according to any of (1) to (6) above, wherein the pathological angiogenesis is angiogenesis in diabetic retinopathy or age-related macular degeneration,
(9) The angiogenesis inhibitor according to any of (1) to (6) above, wherein the pathological angiogenesis is angiogenesis in rheumatoid arthritis or arthropathy,
(10) A vascular endothelial cell growth inhibitor comprising the compound according to any of (1) to (6) as an active ingredient,
(11) A vascular endothelial cell growth inhibitor comprising the compound described in (4) or (5) as an active ingredient, and (12) any of the compounds described in (4) or (5) above. A tube formation inhibitor comprising a compound as an active ingredient.
[0005]
BEST MODE FOR CARRYING OUT THE INVENTION
Hereinafter, the present invention will be described in detail.
The angiogenesis inhibitor of the present invention contains an imidazopyrimidine derivative represented by the general formula (I), a salt thereof, or a hydrate or solvate thereof as an active ingredient. In the general formula (I), the lower alkyl group for R1 preferably has about 1 to 6 carbon atoms, and more preferably a methyl group having 1 carbon atom.
Ring A in formula (I) may be substituted with 1 to 2 groups, and the 1 to 2 substituents are each independently a halogen atom, a lower alkyl group, a lower alkylamino group, a lower dialkylamino group, A piperidinyl group, a benzylmethylamino group, an α-hydroxyiminopendyl group, a tetrahydropyridine group, or the following formula (1) or (2). Alternatively, two substituents may be taken together to form a cyclic alkylene chain in which a carbon atom may be substituted by a sulfur atom, or a tetrahydropyridine ring.
When two substituents on ring A, R2 and R3 or R4 and R5, together form a cyclic alkylene chain, some of the carbon atoms of the cyclic alkylene chain may be substituted with sulfur atoms. At this time, it is preferable that one carbon atom is substituted by one sulfur atom, and specific examples include a dihydrothiopyran ring and a cyclohexane ring.
Examples of the halogen atom include a fluorine atom, a chlorine atom, a bromine atom and an iodine atom, preferably a chlorine atom or a bromine atom, and more preferably a chlorine atom.
The lower alkyl group means a linear, branched or cyclic alkyl group having 1 to 3 carbon atoms, and examples thereof include a methyl group, an ethyl group, a propyl group, an isopropyl group, and a cyclopropyl group. And preferably a methyl group or an ethyl group, and more preferably a methyl group.
The lower alkylamino group means a linear, branched or cyclic alkyl group having 1 to 3 carbon atoms and an amino group, and the lower alkylamino group includes a methylamino group and an ethylamino group. And the like.
The lower dialkylamino group means a group composed of two linear, branched or cyclic alkyl groups having 1 to 3 carbon atoms and an amino group, and the lower dialkylamino group includes a dimethylamino group and a diethylamino group. And the like.
As typical compounds of the general formula (I), those having a benzene ring include 13 compounds represented by [Chemical Formula 5], and those having a thiophene include [Chemical Formula 6] ], But is not limited thereto.
[0006]
When the compounds represented by [Chemical Formula 5] and [Chemical Formula 6] include isomers, the compound showing angiogenesis inhibition in the present invention includes those isomers. For example, E-form and Z-form , And mixtures thereof.
[0007]
These compounds can be used in a free form or as a salt or a hydrate or solvate thereof.
The salt of the invention compound (1) is not particularly limited as long as it is a pharmaceutically acceptable salt. Specifically, hydrochloride, hydrobromide, hydroiodide, phosphate, nitrate, Mineral salts such as sulfates; organic sulfonates such as methanesulfonate, 2-hydroxyethanesulfonate and p-toluenesulfonate; and acetates, propanoates, oxalates, malonates, Organic carboxylate salts such as succinate, glutarate, adipate, tartrate, maleate, malate, and mandelate. Various pharmacologically acceptable salts, for example, hydrochloride, tosylate, methanesulfonate, citrate and the like can be mentioned.
[0008]
Most of the typical compounds according to the present invention are known compounds. Therefore, those compounds are commercially available or can be easily prepared by those skilled in the art based on the following gazettes.
Methods for producing typical compounds included in the present invention are disclosed, for example, in the following publications. Compounds (a), (e) and (i) are described in JP-A-54-41894, compound (b) is described in JP-A-59-053487, compound (c) is described in JP-A-59-51285, Compound (d) is described in JP-A-60-004186, compound (f) is described in JP-A-54-13579 and JP-A-02-022276, compound (g) is described in JP-A-48-086894, (H) is described in US Pat. No. 3,932,407, compounds (k) and (j) are described in JP-A-03-063277, compound (m) is described in JP-A-57-123184, and compound (l) is described in JP-A-59-123184. No. 155383, respectively. Compounds (n), (o), (p), (q), (r) and (s) having a thiophene ring are disclosed in JP-A-55-27105.
[0009]
The angiogenesis inhibitor of the present invention exhibited an extremely specific growth inhibitory effect on vascular endothelial cells and an inhibitory effect on tube formation of vascular endothelial cells. From this, these imidazopyrimidine derivatives can be administered by the oral route and the parenteral route, i.e., intravenous, intraarterial, subcutaneous, rectal, intramucosal, etc., or within the affected area, i.e., in the joint cavity, It can be administered intraocularly, in solid tumors, psoriatic lesions and the like. By administering to the human body by these routes, chronic inflammation in which pathological angiogenesis is observed, diabetic retinopathy, age-related macular degeneration, growth of solid tumors, pannus formation especially in the joint cavity of rheumatoid arthritis, It can be expected to be used as a therapeutic drug for diseases such as synovial proliferation in arthrosis.
[0010]
Next, the preparation of the imidazopyrimidine derivative or a pharmaceutically acceptable salt and / or hydrate thereof (hereinafter, abbreviated as the compound of the present invention) used in the present invention will be described.
As the dosage form of the angiogenesis inhibitor of the present invention, various forms containing additives such as a carrier, an excipient, a lubricant, and a binder which are medically acceptable as the active ingredient, for example, water or various Liquid preparations, powders, granules, tablets, injections, suppositories, or external preparations dissolved in a preparation for infusion can be produced by known preparation techniques. When the compound of the present invention is used as a medicament for human body, its dosage is generally 0.1 to 100 mg, usually 0.1 to 10 mg, as an oral daily dose for adults, and is gradually reduced. May be preferred. In the case of administration by injection, usually 1/5 of the oral dose is appropriate, but it can be gradually reduced or increased as needed. In addition, when administered locally to a lesion, for example, when administered into a joint cavity or an eyeball, the dose can be further reduced, the effect on the whole body is reduced, and it can be used effectively. Further, the dose may be appropriately increased or decreased depending on the condition, age, weight, or the like of the patient.
[0011]
When the imidazopyrimidine derivative used in the present invention is administered by injection, an aqueous injection, an aqueous suspension injection, a fat emulsion, or a liposome injection is preferred. In an aqueous injection, or an aqueous suspension injection, the imidazopyrimidine derivative or a pharmaceutically acceptable salt thereof according to the present invention is mixed with purified water, and if necessary, a water-soluble or water-swellable polymer, Add a pH adjusting agent, a surfactant, an osmotic pressure adjusting agent, a preservative, or a preservative, mix, dissolve or suspend under heating if necessary, sterilize, fill in an injection container and seal. , An aqueous injection, or an aqueous suspension injection. Aqueous injections can be administered intravenously, subcutaneously, intramuscularly, intradermally, or intraarticularly. Further, the aqueous suspension injection can be taken subcutaneously, intramuscularly, intradermally, or intraarticularly. It can also be administered orally.
[0012]
As the water-soluble or water-swellable polymer, gelatin, cellulose derivatives, acrylic acid derivatives, povidone, macrogol, polyamino acid derivatives, or polysaccharides are preferable, purified gelatin is preferable for gelatins, and methylcellulose is used for cellulose derivatives. Hydroxypropylmethylcellulose 2910, hydroxypropylmethylcellulose 2208, hydroxypropylmethylcellulose 2906, hydroxypropylcellulose, low-substituted hydroxypropylcellulose, carmellose sodium, acrylic acid derivative, aminoacryl methacrylate copolymer, methacrylic acid copolymer, polyamino acid derivative Is preferably polylysine or polyglutamic acid. As the polysaccharide, hyaluronic acid, dextran, or dextrin is particularly preferred. The amount of the water-soluble or water-swellable polymer varies depending on the nature and amount of esculetin, its derivative, or its pharmaceutically acceptable salt, and the nature, molecular weight, and application site of the water-soluble or water-swellable polymer. Can be used in the range of 0.01% to 10%, based on the total amount of the preparation.
[0013]
Acids or alkalis harmless to the human body are used as the pH adjuster, and nonionic surfactants, anionic surfactants, and amphoteric surfactants are used as the surfactant. In addition, examples of the osmotic pressure adjusting agent include sodium chloride and glucose, examples of the preservative include parabens, and examples of the preservative include ascorbic acid and sulfites. The amount of these used is not particularly limited, but can be used in a range in which the respective effects can be exhibited. If necessary, a local anesthetic such as procaine hydrochloride, a soothing agent such as benzyl alcohol, a chelating agent, a buffer, or a water-soluble organic solvent may be added.
[0014]
A fat emulsion is prepared by mixing an emulsifier and an imidazopyrimidine derivative or a pharmaceutically acceptable salt thereof with an appropriate fat or oil, adding purified water, and adding a water-soluble or water-swellable polymer, a pH adjuster, It is prepared by adding an active agent, an osmotic pressure adjusting agent, a preservative or a preservative, emulsifying with a suitable emulsifying device, sterilizing, filling and sealing an injection container.
[0015]
Examples of oral preparations comprising the compound of the present invention include, as tablets, powders, granules, capsules, solutions, syrups, elixirs, or oily or aqueous suspensions containing the compound of the present invention as a main component A suitable formulation can be selected according to the administration method, and can be produced by a known formulation technique together with usual excipients, lubricants, additives such as a binder and the like.
Solid preparations include pharmaceutically acceptable additives together with the active compound, such as fillers, extenders, binders, disintegrants, dissolution enhancers, wetting agents, lubricants, etc. Can be selected and mixed as needed to form a formulation.
Examples of the external preparation include solutions, suspensions, emulsions, ointments, gels, creams, lotions, and sprays.
[0016]
Compound (f) (anagrelide), which is a representative compound as an angiogenesis inhibitor of the present invention, is a drug that has been used clinically in foreign countries such as the United States as a therapeutic agent for plasmacytosis, and Is a highly safe compound that can be administered to humans.
The most common side effect observed in humans taking 0.5 mg or 1 mg of anagrelide is only headache or the like reported (Source: NDA 20-333 / S-002).
In addition, compound (d), which is another representative compound of the angiogenesis inhibitor of the present invention, was administered to rats and monkeys at 10 mg / kg and 4 mg / kg intravenously for 4 weeks, respectively. Neither electrocardiographic changes were observed, and it was estimated to be a toxicologically no-effect level. No antigenicity or mutagenicity was observed, and no adverse effects were observed in reproductive tests. In the test using the labeled body, no residual tendency was observed, and the translocation into the tissue was not high. The compound (d) is intravenously intravenously administered to a human for 1 minute, 30 minutes, and 120 minutes for 1 minute, 30 minutes, and 120 minutes, and the dose that reaches the maximum blood concentration of about 80-100 ng / mL is 2-3 times / day. In the case of continuous administration, only a slight feeling of heavy head and transient pulsation were observed in some parts, and no serious toxicity was observed.
Thus, human safety as a therapeutic drug or an investigational drug is sufficiently ensured at a blood concentration of 10 times or more than several ng / mL that exhibits the inhibitory action of human vascular endothelial cells. In the case of intra-articular administration or intraocular administration, the blood concentration is considered to be extremely lower than the local concentration of the lesion, and the effect on the whole body is further slight.
[0017]
Hereinafter, the present invention will be described in more detail with reference to Examples, but the present invention is not limited thereto.
Embodiment 1
[Proliferation inhibition test method]
The compounds shown in Table 1 used in this test are all known compounds. Therefore, what was synthesized based on the method described in the above-mentioned publication was used. Fumagillin used as a known compound having an angiogenesis inhibitory action was manufactured by Sigma (the structure is shown in [Formula 15]). For culturing human umbilical vein vascular endothelial cells (HUVEC) as human vascular endothelial cells, a 100 mm diameter tissue culture dish coated with an adhesive factor solution (solution containing type I collagen) was used. The cells were maintained in a serum-containing medium for vascular endothelial cells (MCDB104 medium containing 5% fetal calf serum, Nissui Pharmaceutical) supplemented with 37% of 5% CO 2 for 5 hours. Human bronchial smooth muscle cells were cultured in a smooth muscle cell basal medium at 37 ° C. under 5% CO 2 and subjected to a test. Each cell was prepared with each growth factor-free medium and seeded in a 96-well microplate. After culturing for about 6 hours, various concentrations of compounds and growth factors (bFGF, VEGF) were added. After culturing for 4 days, the number of cells was determined by MTT assay.
[0018]
Embedded image
[Test Results] The 50% growth inhibitory concentration of each sample is shown in the table. The table shows the activity values of representative compounds. Like the positive control drug fumagillin, all of these compounds show a strong growth inhibitory activity against human umbilical vein vascular endothelial cells HUVEC, similar to the positive control drug fumagillin, and have a 50% growth inhibitory concentration of about 0.1 to 250%. ng / mL (Table 1).
On the other hand, the growth of human lung cancer cells PC-6, human bronchial smooth muscle cells, and mouse leukemia P388 was not affected by the maximum concentration of 10,000 ng / mL, and a 50% growth inhibitory concentration could not be determined. In other words, these compounds do not show a growth inhibitory effect on other cells (lung cancer cells, smooth muscle cells, leukemia cells) even at a concentration of 2,000 to 5,000 times or more the vascular endothelial cell growth inhibitory concentration, and are very selectively. It showed an inhibitory effect only on vascular endothelial cells. On the other hand, the control drug fumagillin inhibited the growth of these other cells at 1- to 400-fold concentration. As described above, it was demonstrated that the compound of the present invention has a very selective inhibitory effect on vascular endothelial cells.
[0020]
Embodiment 2
(Lumen formation inhibition test)
50 mL of Matrigel derived from mouse EHS sarcoma was added to each well of a 96-well microplate, and gelled at 37 ° C. On the gel, HUVEC cells and M199 medium containing 20% FBS supplemented with various compounds were added, and the cells were seeded. Eighteen hours after the start of the culture, the luminal network length of endothelial cells formed on Matrigel was measured, and the inhibitory action of each compound was expressed as a 50% inhibitory concentration. It has been clarified that the imidazopyrimidine derivative has an inhibitory action on the formation of a lumen as well as an inhibitory action on the proliferation of vascular endothelial cells.
[0021]
[Table 1]
Hereinafter, formulation examples of the formulation of the present invention using compound (d) will be shown.
<Prescription example 1 (injection 1)>
One vial of the freeze-dried preparation contains 5 mg of compound (d) as a free form, 100 mg of maltose monohydrate and an appropriate amount of sodium hydroxide.
One ampoule of the attached solution contains 4.5 mg of lactic acid, 270 mg of D-sorbitol, an appropriate amount of sodium hydroxide and water for injection (total amount 5 mL, pH 4.0).
Formulation (lyophilized formulation)
Compound (d) (free form) 5mg
Maltose monohydrate 100mg
Sodium hydroxide suitable amount pH3.5
Water for injection (2 ml in total)
Dissolved solution 4.5mg lactic acid
D-sorbitol 270mg
Sodium hydroxide suitable amount pH 4.3
5 ml of water for injection
[0023]
<Prescription example 2 (injection 2)>
One vial of the freeze-dried preparation contains 5 mg of compound (d) as a free form, 100 mg of maltose monohydrate and an appropriate amount of sodium hydroxide.
One ampoule of the attached lysis solution contains 270 mg of D-sorbitol and water for injection (total volume 5 mL, pH 4.0).
Formulation (lyophilized formulation)
Compound (d) (free form) 5mg
Maltose monohydrate 100mg
Sodium hydroxide suitable amount pH3.5
Water for injection (2 ml in total)
Dissolved solution D-sorbitol 270mg
5 ml of water for injection
[0024]
<Prescription example 3 (injection 3)>
One vial of freeze-dried preparation contains 5 mg of compound (d) as a free form, 100 mg of maltose monohydrate and an appropriate amount of sodium hydroxide
Attached lysis solution 2 mL of water for injection.
Formulation (lyophilized formulation)
Compound (d) (free form) 5mg
Maltose monohydrate 100mg
Sodium hydroxide suitable amount pH3.5
Water for injection (2 ml in total)
Attached lysate 2ml water for injection
[0025]
<Prescription example 4 (oral preparation 1)>
Capsule 1 mg Preparation 1.0 mg as a free form of compound (d) in gelatin capsule No. 5, mannitol 55. Contains 9 mg, crystalline cellulose 25.0 mg, crospovidone 2.5 mg, light anhydrous silicic acid 0.2 mg and magnesium stearate 0.4 mg.
Formulation Compound (d) (free form) 1.0 mg
Mannitol 55.9mg
Crystalline cellulose 25.0mg
Crospovidone 2.5mg
Light silicic anhydride 0.2mg
0.4 mg of magnesium stearate
85mg
[0026]
<Prescription example 5 (oral preparation 1)>
Capsule 5 mg Formulation No. 5 Gelatin capsules, 5.0 mg as compound (d) free form, mannitol 51. Contains 9 mg, crystalline cellulose 25.0 mg, crospovidone 2.5 mg, light anhydrous silicic acid 0.2 mg and magnesium stearate 0.4 mg.
Formulation Compound (d) (free form) 5.0 mg
51.9 mg of mannitol
Crystalline cellulose 25.0mg
Crospovidone 2.5mg
Light silicic anhydride 0.2mg
0.4 mg of magnesium stearate
85mg
[0027]
【The invention's effect】
The angiogenesis inhibitor of the present invention specifically exhibited a growth inhibitory effect on vascular endothelial cells and an inhibitory effect on tube formation of vascular endothelial cells. From these facts, these medicines of the present invention, imidazopyrimidine derivatives, diminished vision and blindness due to diabetic retinopathy or age-related macular degeneration, growth of solid tumors, pannus formation especially in the joint cavity of rheumatoid arthritis It can be expected to be used as a therapeutic agent for diseases such as synovial proliferation in arthropathy or diseases accompanied by pathological angiogenesis such as psoriasis.
Claims (12)
容し得る塩、又はそれらの水和物若しくは溶媒和物を有効成分とする病的な血管新生の抑制に有効な血管新生抑制剤。
されるイミダゾピリミジン誘導体、その薬学的に許容し得る塩、又はそれらの水和物若しくは溶媒和物を有効成分とする病的な血管新生の抑制に有効な、請求項１記載の血管新生抑制剤。
Ｒ２は、水素原子、ハロゲン原子、低級アルキル基、又は低級アルキルアミン基を意味し、
Ｒ３は、水素原子、ハロゲン原子、低級アルキル基、１‐ピペリジニル基、ベンジルメチルアミノ基、α―ヒドロキシイミノベンジル基、テトラヒドロピリジン環、次式（▲１▼）若しくは（▲２▼）で表される基、低級アルキルアミン、低級ジアルキルアミン、又はＲ２とＲ３が一緒になって形成する炭素原子が硫黄原子に置換されていてもよい環状アルキレン鎖若しくはテトラヒドロピリジン環を意味する。）
R2 represents a hydrogen atom, a halogen atom, a lower alkyl group, or a lower alkylamine group,
R3 is a hydrogen atom, a halogen atom, a lower alkyl group, a 1-piperidinyl group, a benzylmethylamino group, an α-hydroxyiminobenzyl group, a tetrahydropyridine ring, represented by the following formula (1) or (2). A lower alkylamine, a lower dialkylamine, or a cyclic alkylene chain or a tetrahydropyridine ring in which a carbon atom formed by R2 and R3 together may be substituted with a sulfur atom. )
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2009138796A3 (en) * | 2008-05-16 | 2010-01-07 | Shire Llc | Imidazo [2,1-b] quinazolin-2-one derivatives and their use as platelet anti-aggregative agents |
| US8304420B2 (en) | 2006-11-28 | 2012-11-06 | Shire Llc | Substituted quinazolines for reducing platelet count |
| WO2014183673A1 (en) * | 2013-05-16 | 2014-11-20 | 中国科学院上海药物研究所 | Anti-tumor use of anagrelide and derivatives thereof |
| WO2022199627A1 (en) * | 2021-03-23 | 2022-09-29 | National Institute Of Biological Sciences, Beijing | Polycyclic compounds and uses thereof |
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2002
- 2002-07-23 JP JP2002214423A patent/JP2004051594A/en active Pending
Cited By (10)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US8304420B2 (en) | 2006-11-28 | 2012-11-06 | Shire Llc | Substituted quinazolines for reducing platelet count |
| WO2009138796A3 (en) * | 2008-05-16 | 2010-01-07 | Shire Llc | Imidazo [2,1-b] quinazolin-2-one derivatives and their use as platelet anti-aggregative agents |
| US20110152298A1 (en) * | 2008-05-16 | 2011-06-23 | Shire Llc | Imidazo [2,1-b] quinazolin-2-one derivatives and their use as platelet anti-aggregative agents |
| JP2011521910A (en) * | 2008-05-16 | 2011-07-28 | シャイア エルエルシー | Substituted quinazoline |
| WO2014183673A1 (en) * | 2013-05-16 | 2014-11-20 | 中国科学院上海药物研究所 | Anti-tumor use of anagrelide and derivatives thereof |
| CN104161759A (en) * | 2013-05-16 | 2014-11-26 | 中国科学院上海药物研究所 | Antitumor use of Anagrelide and its derivatives |
| US10105362B2 (en) | 2013-05-16 | 2018-10-23 | Zhejiang Bossan Pharmaceutical Co., Ltd. | Anti-tumor use of anagrelide and derivatives thereof |
| CN104161759B (en) * | 2013-05-16 | 2019-10-08 | 中国科学院上海药物研究所 | The anticancer usage of anagrelide and its derivative |
| WO2022199627A1 (en) * | 2021-03-23 | 2022-09-29 | National Institute Of Biological Sciences, Beijing | Polycyclic compounds and uses thereof |
| CN117062819A (en) * | 2021-03-23 | 2023-11-14 | 北京生命科学研究所 | Polycyclic compounds and their uses |
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