JP4843220B2 - Il−8受容体アンタゴニスト - Google Patents
Il−8受容体アンタゴニスト Download PDFInfo
- Publication number
- JP4843220B2 JP4843220B2 JP2004548492A JP2004548492A JP4843220B2 JP 4843220 B2 JP4843220 B2 JP 4843220B2 JP 2004548492 A JP2004548492 A JP 2004548492A JP 2004548492 A JP2004548492 A JP 2004548492A JP 4843220 B2 JP4843220 B2 JP 4843220B2
- Authority
- JP
- Japan
- Prior art keywords
- alkyl
- aryl
- heterocyclic
- heteroaryl
- chloro
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Lifetime
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- C07D295/22—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with hetero atoms directly attached to ring nitrogen atoms
- C07D295/26—Sulfur atoms
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/02—Stomatological preparations, e.g. drugs for caries, aphtae, periodontitis
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Description
本発明は、新規スルホンアミド置換ジフェニル尿素化合物、医薬組成物、その製造法およびIL−8、GROα、GROβ、GROγ、NAP−2およびENA−78介在疾患の治療におけるその使用に関する。
インターロイキン−8(IL−8)に対しては様々な名称、例えば好中球誘引/活性化タンパク質−1(NAP−1)、単球由来好中球走化性因子(MDNCF)、好中球活性化因子(NAF)およびT−細胞リンパ球走化性因子が用いられている。インターロイキン−8は、好中球、好塩基球およびT−細胞のサブセットに対する化学誘引物質である。これは、TNF、IL−1α、IL−1βまたはLPSに曝露されたマクロファージ、線維芽細胞、内皮細胞および上皮細胞を含むほとんどの有核細胞により、およびLPSまたはFMLPのような走化性因子に曝露された場合に好中球自体により産生される。M. Baggiolini et al., J. Clin. Invest. 84, 1045 (1989); J. Schroder et al, J. Immunol. 139, 3474 (1987)およびJ. Immunol. 144, 2223 (1990) ; Strieter, et al., Science 243, 1467 (1989)およびJ. Biol. Chem. 264, 10621 (1989); Cassatella et al., J. Immunol. 148, 3216 (1992)。
本発明は、ケモカインが、IL−8aまたはb受容体に結合するケモカイン介在疾患の治療方法であって、有効量の式(I)で示される化合物またはその医薬上許容される塩を投与することを含む方法を提供する。特に、ケモカインはIL−8である。
また、本発明は、IL−8のその受容体への結合の阻害が必要な哺乳類における該阻害方法であって、該哺乳類に、有効量の式(I)で示される化合物を投与することを含む方法に関する。
また、本発明は、式(I)で示される新規化合物および式(I)で示される化合物および医薬担体または希釈剤を含む医薬組成物を提供する。
Rbは、独立して、水素、NR6R7、OH、ORa、C1−5アルキル、アリール、アリールC1−4アルキル、アリールC2−4アルケニル;シクロアルキル、シクロアルキルC1−5アルキル、ヘテロアリール、ヘテロアリールC1−4アルキル、ヘテロアリールC2−4アルケニル、ヘテロサイクリック、ヘテロサイクリックC1−4アルキルまたはヘテロサイクリックC2−4アルケニル基であり、これらの基はすべて、ハロゲン;ニトロ;ハロ置換C1−4アルキル;C1−4アルキル;アミノ、モノまたはジ−C1−4アルキル置換アミン;ORa;C(O)Ra;NRaC(O)ORa;OC(O)NR6R7;ヒドロキシ;NR9C(O)Ra;S(O)m’Ra;C(O)NR6R7;C(O)OH;C(O)ORa;S(O)2NR6R7;NHS(O)2Raにより、独立して1〜3回置換されていてもよく、別に、2個のRb置換基は結合して、炭素に加えて、独立して1〜3個のNRa、O、S、SOまたはSO2基により置換されていてもよく、含有していてもよい、不飽和であってもよい3〜10員環を形成してもよく;
mは、1〜3の整数であり;
m’は、0または1または2の整数であり;
nは、1〜3の整数であり;
qは、0または1〜10の整数であり;
tは、0または1または2の整数であり;
sは、1〜3の整数であり;
R6およびR7は、独立して、水素、またはC1−4アルキル、ヘテロアリール、アリール、アルキルアリール、アルキルC1−4ヘテロアルキルであるか、あるいは、R6およびR7は、それらが結合している窒素原子と一緒になって、酸素、窒素または硫黄から選択される付加的なヘテロ原子を含有していてもよく、置換されていてもよい5〜7員環を形成してもよく;
R9は、水素またはaC1−4アルキルであり;
R10は、C1−10アルキルC(O)2R8であり;
R11は、水素、置換されていてもよいC1−4アルキル、置換されていてもよいアリール、置換されていてもよいアリールC1−4アルキル、置換されていてもよいヘテロアリール、置換されていてもよいヘテロアリールC1−4アルキル、置換されていてもよいヘテロサイクリックまたは置換されていてもよいヘテロサイクリックC1−4アルキルであり;
R13は、適当には、C1−4アルキル、アリール、アリールC1−4アルキル、ヘテロアリール、ヘテロアリールC1−4アルキル、ヘテロサイクリックまたはヘテロサイクリックC1−4アルキルである]
により示される化合物またはその医薬上許容される塩である。
また、式(I)で示される化合物は、IL−8αおよびβ受容体に結合するIL−8または他のケモカインを阻害する必要がある、ヒト以外の他の哺乳類の獣医学的治療にも関連して用いられる。哺乳類の、治療的または予防的に治療されるケモカイン介在疾患は、治療方法のセクションに記載するような病態を含む。
適当には、R9は、水素またはC1−4アルキルである。
適当には、qは、0または1〜10の整数である。
適当には、R11は、水素、C1−4アルキル、アリール、アリールC1−4アルキル、ヘテロアリール、ヘテロアリールC1−4アルキル、ヘテロサイクリックまたはヘテロサイクリックC1−4アルキルである。
適当には、R13は、C1−4アルキル、アリール、アリールアルキル、ヘテロアリール、ヘテロアリールC1−4アルキル、ヘテロサイクリックまたはヘテロサイクリックC1−4アルキルであり、すべてのアリール、ヘテロアリールおよびヘテロサイクリック含有基は、置換されていてもよい。
Yがジオキシブリッジを形成する場合、sは、好ましくは1である。Yが付加的な不飽和環を形成する場合、好ましくは、それはナフチレン環系を構成する6員環である。これらの環系は、上記と同意義の他のYに1〜3回置換されていてもよい。
適当には、Raは、アルキル、アリールC1−4アルキル、ヘテロアリール、ヘテロアリール−C1−4アルキル、ヘテロサイクリックまたはヘテロサイクリックC1−4アルキルであり、これらのすべての基は、置換されていてもよい。
Y環のいずれかの位置において置換されていてもよい場合、nは、好ましくは、1である。R1およびYの両方ともが水素でありうるが、少なくとも1つの環が、好ましくは両方の環が置換されていることが好ましい。
・「ハロ」は、すべてのハロゲン、クロロ、フルオロ、ブロモおよびヨウドである。
・「C1−10アルキル」または「アルキル」は、鎖長を特記しない限り、1〜10個の炭素原子の、直鎖または分枝鎖基を意味し、限定するものではないが、メチル、エチル、n−プロピル、iso−プロピル、n−ブチル、sec−ブチル、iso−ブチル、tert−ブチル、n−ペンチル等を含む。
・「アルケニル」は、鎖長が特記されない限り、2〜10個の炭素原子の直鎖または分枝鎖を意味するのに用いられ、限定するものではないが、エテニル、1−プロペニル、2−プロペニル、2−メチル−1−プロペニル、1−ブテニル、2−ブテニル等を含む。
・「ヘテロアリール」(単独またはいずれの組み合わせ、例えば「ヘテロアリールオキシ」または「ヘテロアリールアルキル」においても)は、1または2個の環が、N、OまたはSからなる群から選択される1または2個のヘテロ原子を含有する、5〜10員の芳香環系であり、限定するものではないが、ピロール、ピラゾール、フラン、チオフェン、キノリン、イソキノリン、キナゾリニル、ピリジン、ピリミジン、オキサゾール、テトラゾール、チアゾール、チアジアゾール、トリアゾール、イミダゾールまたはベンズイミダゾールである。
N−[4−クロロ−2−ヒドロキシ−3−(4−メチル−ピペラジン−1−スルホニル)−フェニル]−N’−(2−クロロ−3−フルオロフェニル)尿素;
N−[4−クロロ−2−ヒドロキシ−3−(4−(2−ヒドロキシエチル)−ピペラジン−1−スルホニル)フェニル]−N’−(2−クロロ−3−フルオロフェニル)尿素;
N−[4−クロロ−2−ヒドロキシ−3−(1−ピペラジニルスルホニル)フェニル]−N’−(2−クロロ−3−フルオロフェニル)尿素またはその医薬上許容される塩を含む。
式(I)で示される化合物は、下記スキーム1に説明する合成方法を用いて得ることができる。これらのスキームにおいて提供される合成方法は、本明細書に概要を記載した反応との適合性が得られるように、適当な保護された任意の置換基を用いて反応させられる、種々の異なるR、R’およびアリール(置換されていてもよい)基を有する式(I)で示される化合物の製造に用いることができる。これらの場合、続く脱保護により、一般的に開示されている性質の化合物が得られる。一旦尿素核が確立すると、これらの式で示されるさらなる化合物は、当該分野でよく知られている官能基相互変換に関する標準的な方法を用いることにより調製することができる。
1a)2−クロロ−3−フルオロ安息香酸
20mLのTHF中の3−フルオロ安息香酸(4.02g、28.71mmol)の溶液を、50mLのTHF中のTMEDA(10.00mL、66.3mmol)および1.3Mのsec−BuLi(48mL、62.4mmol)の懸濁液に、−90℃で滴下した。混合物を−90℃で35分間撹拌した。混合物を−78℃に加温し、50mLのTHF中のヘキサクロロエタン(27.0g、113.9mmol)の溶液を滴下した。20時間後、反応を水でクエンチし、ジエチルエーテルで希釈した。二層を、濃HClで約1〜2のpHに調製した。有機層を水、ブラインで洗浄し、乾燥し、濃縮して、黄褐色固体として30.4gの粗物質を得、これをヘキサンで洗浄し、3.728g(74%)の所望の生成物1aを得た(淡黄褐色固体)。MS(m/z)175.2(M+H)
25mLのオキサリルクロライド中の2−クロロ−3−フルオロ安息香酸(実施例1a)(2.704g、15.54mmol)の懸濁液を2時間加熱還流した。溶液を冷却し、濃縮して、粗酸塩化物(3.13g)を褐色液体として得、これを次の工程に直接用いた。
10mLの水中のNaN3(2.79g、43mmol)の溶液を、20mLのアセトン中の酸塩化物(3.13g)の溶液に0℃で滴下した。15分後、溶液をCH2Cl2で希釈し、水およびブラインで洗浄した。有機層を乾燥し、濃縮して、褐色液体を得、これを酢酸エチル/ヘキサン(5/95、v/v)を用いてシリカゲルにより濾過して、2.97g(96%)の1b(無色の液体)を得た。化合物をさらに生成することなく用いた。
100mLのTHF中の2−tert−ブチル−6−クロロ−ベンゾオキサゾール−7−スルホニルクロライド(10.75g、34.9mmol)の溶液を0℃に冷却して、Et3N(3.47mL、24.9mmol)、ついで、Boc−ピペラジン(5.0g、26.8mmol)を加えた。得られた混合物を20時間撹拌し、室温に加温した。混合物を水に注ぎ、EtOAcで抽出し、水で洗浄した;有機層を乾燥し、濃縮した。酢酸エチル/ヘキサン(30/70、v/v)で溶出するシリカゲルのカラムクロマトグラフィーにより精製して、11.12g(91%)の所望の生成物1cを得た。LC−MS(m/z)458.2(M+H)
ジオキサン(20mL)中の出発物質1c(11.12g)の溶液を、水(11mL)および濃H2SO4(11mL)で処理した。混合物を12時間加熱還流した。反応混合物を濃縮し、ついで、残渣を、50%のNaOH水溶液で塩基性化して約pH14にした。(Boc)2O(5.6g、1.05等量)および100mLのAcOEtを加え、得られた混合物を室温にて16時間撹拌した。混合物を分離し、水層をEtOAcで抽出し、有機層を合して、乾燥し、濃縮した。酢酸エチル/ヘキサン(30/70、v/v)で溶出するシリカゲルのカラムクロマトグラフィーにより精製して8.18g(85%)の所望の生成物1dを得た。1H NMR(CDCl3):δ6.85(m,2H),3.48(t,4H),3.25(t,4H),1.47(s,9H)
5mLのN,N−ジメチルホルムアミド中の1d(3.8g、9.7mmol)および3−クロロ−2−フルオロベンゾイルアジド(1b)(2.9g、14.5mmol)の溶液を、室温にて18時間撹拌した。混合物を酢酸エチルで希釈し、水で洗浄して、粗物質を得た。酢酸エチル/ヘキサン(20/80、v/v)で溶出してシリカゲルのカラムクロマトグラフィーに溶出して、3.6g(66%)の1eを得た。LC−MS(m/z)562.8(M+H)
ジオキサン中の20mLの4NのHCl中の3.6gBoc−生成物の溶液を、室温にて2時間撹拌し、溶媒を蒸発させた。残渣をメタノールおよび酢酸エチルから再結晶して、標題生成物(2.9g)(60%)を得た。LC−MS(m/z)463.0(M+H)
2a)tert−ブチル−6−クロロ−7−(4−(2−メトキシエチル)−ピペラジン−1−スルホニル]−ベンゾオキサゾール
実施例1cに記載の一般方法に従って、2−tert−ブチル−6−クロロ−ベンゾオキサゾール−7−スルホニルクロライドを、2−メトキシ−エチル−ピペラジンとカップリングさせて、所望の生成物2a(1.11g)(82%)を得た。LC−MS(m/z)416.2(M+H)
実施例1dに記載の一般方法に従って、tert−ブチル−6−クロロ−7−(4−2−メトキシ−エチル)−ピペラジン−1−スルホニル]−ベンゾオキサゾールを加水分解して、粗2bを得、これをさらに精製することなく次の工程に用いた。
実施例1eに記載の一般方法に従って、6−アミノ−3−クロロ−2−[4−(2−メトキシル−エチル)−ピペラジン−1−スルホニル]−フェノールおよび3−クロロ−2−フルオロベンゾイルアジドをカップリングさせ、168mg(2aから20%)の生成物2c(RP−HPLC精製によりトリフルオロ酢酸塩として単離した)を得た。LC−MS(m/z)521.2(M+H)
Ar雰囲気下、3mLのジクロロメタン中の2cトリフルオロ酢酸塩(100mg、0.16mmol)の懸濁液に、三臭化ホウ素(0.63mL、0.63mmol)を加えた。混合物を、室温にて一晩撹拌した。メタノールでクエンチした後、固体が精製した。混合物を濾過し、固体を回収した。アセトニトリル/水/0.1%のTFA(10分間で10/90、v/v〜90/10、v/v)で溶出するGilsonHPLCで精製して、66mg(76%)の標題化合物2dを得た。LC−MS(m/z)507.2(M+H)
実施例1cに記載の一般方法に従って、2−tert−ブチル−6−クロロ−ベンゾオキサゾール−7−スルホニルクロライドを、メチル−ピペラジンとカップリングさせて、所望の生成物3a(600mg)(53%)を得た。LC−MS(m/z)372.0(M+H)
実施例1dに記載の一般方法に従って、2−tert−ブチル−6−クロロ−7−(4−メチル−ピペラジン−1−スルホニル)−ベンゾオキサゾールを加水分解して、3b(441mg)(89%)を得た。LC−MS(m/z)306.2(M+H)
実施例1eに記載の一般方法に従って、6−アミノ−3−クロロ−2−(4−メチル−ピペラジン−1−スルホニル)−フェノールおよび3−クロロ−2−フルオロ−ベンゾイルアジド(1b)を、カップリングさせて、203mg(30%)の標題化合物3cを得た。LC−MS(m/z)477.0(M+H)
式(I)で示される化合物またはその医薬上許容される塩は、ヒトまたは他の哺乳類における、かかる哺乳類の細胞、例えば、限定するものではないが、単球および/またはマクロファージ、またはI型受容体もしくはII型受容体とも称されるIL−8α受容体もしくはβ受容体に結合する他のケモカインによる過剰または未制御のIL−8サイトカイン産生により悪化するかまたは引き起こされる病態の予防または治療的処置用の医薬の製造において用いることができる。
本発明の化合物のIL−8、およびGro−αケモカイン阻害効果を以下のインビトロ検定により測定した:
受容体結合検定:
比活性が2000Ci/mmolである[125I]IL−8(ヒト組換体)をイリノイ州アーリントン・ハイツのアマシャム・コーポレイション(Amersham Corp.)から入手した。Gro−αをエヌイーエヌ−ニュー・イングランド・ニュークリア(NEN-New England Nuclear)から入手した。他の薬品はすべて分析用であった。すでに開示されているようにして(Holmes et al., Science, 1991, 253, 1278)、高レベルの組換えヒトIL−8αおよびβ型受容体を、個別に、チャイニーズハムスター卵巣細胞において発現させた。すでに開示されているプロトコル(Haour et al., J. Biol. Chem., 249, pp 2195−2205 (1974))に従って、チャイニーズハムスター卵巣膜をホモジナイズした。ただし、ホモジナイゼーション緩衝液を10mMのTris−HCl、1mMのMgSO4、0.5mMのEDTA(エチレンジアミン四酢酸)、1mMのPMSF(α−トルエンスルホニルフルオリド)、0.5mg/Lのロイペプチン、pH7.5に変更した。膜タンパク質濃度を、ピアス・カンパニー(Pierce Co.)のミクロ検定キットを用いて、ウシ血清アルブミンを標準として用いて測定した。すべての検定は、96−ウェルマイクロプレートフォーマットで行った。各反応混合物は、1.2mMのMgSO4、0.1mMのEDTA、25mMのNaClおよび0.03%のCHAPSを含有する20mMのビス−トリスプロパンおよび0.4mMのTrisのHCl緩衝液(pH8.0)中125I IL−8(0.25nM)または125I Gro−αおよび0.5μg/mLのIL−8Rαまたは1.0μg/mLのIL−8Rβ膜を含有した。加えて、あらかじめDMSOに溶解させて最終濃度を0.01nM〜100uMにした目的の薬物または化合物を添加した。検定を、125I−IL−8の添加により開始した。室温で1時間後、Tomtec 96−ウェルハーベスターを用いて1%ポリエチレンイミン/0.5%のBSAでブロックしたガラス繊維フィルターマット上にてプレートを収穫し、25mMのNaCl、10mMのTrisのHCl、1mMのMgSO4、0.5mMのEDTA、0.03%のCHAPS(H7.4)で3回洗浄した。ついで、フィルターを乾燥させ、Betaplate液体シンチレーションカウンターで計数した。組換えIL−8RαまたはI型受容体は、また、本明細書において非許容受容体とも称され、組換えIL−8RβまたはII型受容体は許容受容体と称される。
Current Protocols in Immunology, vol. I, Suppl 1, Unit 6.12.3.(その開示内容は、全体として出典明示により本明細書の一部とする)に記載されているようにして好中球走化性検定法でこれらの化合物のインビトロ阻害特性を測定する。Current Protocols in Immunology Vol. I, Suppl 1 Unit 7.23.1(その開示内容は、全体として出典明示により本明細書の一部とする)に開示されているようにしてヒト血液から好中球を単離する。化学誘引物質IL−8、GRO−α、GRO−β、GRO−γおよびNAP−2を0.1〜100nMの濃度で48マルチウェルチャンバー(メリーランド州キャビン・ジョンのニューロ・プローブ(Neuro Probe))の下部チャンバーに入れる。2つのチャンバーは5μmポリカーボネートフィルターで隔てられている。本発明の化合物を試験する場合、細胞を上部チャンバーに添加する直前に、該化合物を細胞と混合する(0.001−1000nM)。インキュベーションは、5%CO2を有する加湿インキュベータ中にて約37℃で約45〜90分間行う。インキュベーション期間の最後に、ポリカーボネート膜を取り出し、最上部を洗浄し、ついで、該膜を、Diff Quick染色プロトコル(アメリカ合衆国イリノイ州マックゴー・パークのバクスター・プロダクツ(Baxter Products))を用いて染色する。ケモカインに対して走化性を示した細胞を顕微鏡を用いて目視により計数する。一般に、各サンプルについて4つのフィールドを計数し、これらの数を平均して、移動した細胞の平均数を求める。各サンプルを三重に試験し、各化合物を少なくとも4回繰り返し試験する。特定の細胞(正の対照細胞)には化合物を添加せず、これらの細胞は細胞の最大走化性応答を示す。負の対照(刺激しない)が望ましい場合には、下部チャンバーにケモカインを添加しない。正の対照と負の対照との差異は、細胞の走化性活性を表す。
ヒト好中球からのエラスターゼ放出を防止する能力について本発明の化合物を試験する。Current Protocols in Immunology Vol. I, Suppl 1 Unit 7.23.1.に記載されているようにしてヒト血液から好中球を単離する。リンゲル溶液(NaClの118、KClの4.56、NaHCO3の25、KH2PO4の1.03、グルコースの11.1、HEPESの5mM、pH7.4)中に懸濁したPMNの0.88×106細胞を、50μlの容量で96ウェルプレートの各ウェルに入れる。このプレートに、50μlの容量の試験化合物(0.001〜1000nM)、50μl(20μg/ml)の容量のシトカラシンBおよび50μlの容量のリンゲル緩衝液を添加する。これらの細胞を5分間加温(37℃、5%のCO2、95%のRH)した後、最終濃度0.01〜1000nMのIL−8、GROα、GROβ、GROγまたはNAP−2を添加した。該反応を45分間進行させた後、96ウェルプレートを遠心分離し(800×g、5分)、上清100ulを取り出した。この上清を第2の96ウェルプレートに添加し、ついで、リン酸緩衝生理食塩水に溶解した人工エラスターゼ基質(MeOSuc−Ala−Ala−Pro−Val−AMC、カリフォルニア州ラ・ジョラのノヴァ・ビオケム(Nova Biochem))を最終濃度6μg/mlになるように添加する。直ちに、プレートを蛍光96ウェルプレートリーダー(Cytofluor 2350、マサチューセッツ州ベッドフォードのミリポア(Millipore))に入れ、Nakajima et al., J. Biol Chem 254 4027 (1979) の方法に従って3分間隔でデータを集める。PMNから放出されたエラスターゼの量を、MeOSuc−Ala−Ala−Pro−Val−AMC分解速度を測定することにより計算する。
この検定は、ラットにおいて実験的に誘発した側液衝撃外傷性脳傷害(TBI)の後に起こる特定の脳領域における腫瘍壊死因子mRNAの発現を調べるために行う。成体スプレーグ−ドーリーラット(n=42)をペントバルビタールナトリウム(60mg/kg、i.p.)で麻酔し、左側頭頭頂皮質上に集中する中度の重篤度(2.4atm)の側液衝撃脳傷害(n=18)、または「擬似」処置(麻酔、および傷害を伴わない手術、n=18)を与えた。傷害の1時間後、6時間後および24時間後に動物を断頭により屠殺し、脳を取り出し、左(傷害)頭頂皮質(LC)、対側性右皮質の対応する領域(RC)、傷害頭頂皮質と隣接する皮質(LA)、右皮質における対応する隣接領域(RA)、左海馬(LH)および右海馬(RH)の組織試料を調製する。全RNAを単離し、ノーザンブロットハイブリダイゼーション処理し、TNF−α正対照RNAと比較して定量化する(マクロファージ=100%)。傷害の1時間後、損傷した半球において、TNF−α mRNA発現の著しい増加がLH(正対照の104±17%、擬似処置と比較してp<0.05)、LC(105±21%、p<0.05)およびLA(69±8%、p<0.01)にて見られる。傷害の6時間後、TNF−α mRNA発現の増加がまたLH(46±8%、p<0.05)、LC(30±3%、p<0.01)およびLA(32±3%、p<0.01)にて見られ、24時間後まで続く。対側性半球において、TNF−α mRNAの発現は、傷害の1時間後には、RH(46±2%、p<0.01)、RC(4±3%)およびRA(22±8%)において増加し、6時間後にはRH(28±11%)、RC(7±5%)およびRA(26±6%、p<0.05)において増加するが、24時間後には増加しない。擬似処置(傷害を伴わない手術)またはナイーブ動物においては、TNF−α mRNAの発現の一貫した変化は、いずれの時点でもいずれの半球における6つの脳領域のいずれにおいても見られない。これらの結果は、側矢状液衝撃脳傷害後、TNF−α mRNAの一時的発現が、損傷してない半球のものを含めて特定の脳領域において変えられることを示す。TNF−αは、神経成長因子(NGF)を誘発でき、活性化星状細胞からの他のサイトカインの放出を刺激するので、TNF−αの遺伝子発現におけるこの外傷後の変化は、CNS外傷に対する急性応答および再生性応答の両方において重要な役割を果たす。
この検定は、ラットにおいて実験的側液衝撃外傷性脳傷害(TBI)後の特定の脳領域におけるインターロイキン−1β(IL−1β)mRNAの局所的発現を特徴付ける。成体スプレーグ−ドーリーラット(n=42)をペントバルビタールナトリウム(60mg/kg、i.p.)で麻酔し、左側頭頭頂皮質上に集中する中度の重篤度(2.4 atm)の側液衝撃脳傷害(n=18)、または「擬似」処置(麻酔、および傷害を伴わない手術、n=18)を与えた。傷害の1時間後、6時間後および24時間後に動物を屠殺し、脳を取り出し、左(傷害)頭頂皮質(LC)、対側性右皮質の対応する領域(RC)、傷害頭頂皮質と隣接する皮質(LA)、右皮質における対応する隣接領域(RA)、左海馬(LH)および右海馬(RH)の組織試料を調製する。全RNAを単離し、ノーザンブロットハイブリダイゼーション処理し、脳組織IL−1β mRNAの量を、同一ゲル上に負荷したIL−1β正マクロファージRNAの相対的な放射能の%として表す。脳傷害の1時間後、損傷した半球において、IL−1β mRNAの発現の著しくかつ有意な増加がLC(正対照の20.0±0.7%、n=6、擬似処置動物と比較してp<0.05)、LH(24.5±0.9%、p<0.05)およびLA(21.5±3.1%、p<0.05)にて見られ、傷害の6時間後まで、LC(4.0±0.4%、n=6、p<0.05)およびLH(5.0±1.3%、p<0.05)にて上昇し続ける。擬似処置またはナイーブ動物においては、IL−1β mRNAの発現は、個々の脳領域のいずれにおいても見られない。これらの結果は、TBI後、IL−1β mRNAの一時的発現が特定の脳領域において局部的に刺激されることを示す。IL−1βのようなサイトカインにおけるこれらの局部的変化は、外傷後において役割を果たす。
Claims (3)
- N−[4−クロロ−2−ヒドロキシ−3−(1−ピペラジニルスルホニル)フェニル]−N’−(2−クロロ−3−フルオロフェニル)尿素またはその医薬上許容される塩。
- 医薬上許容される塩が、塩酸塩、臭化水素酸塩、硫酸塩、リン酸塩、メタンスルホン酸塩、エタンスルホン酸塩、酢酸塩、リンゴ酸塩、酒石酸塩、クエン酸塩、乳酸塩、シュウ酸塩、コハク酸塩、フマル酸塩、マレイン酸塩、安息香酸塩、サリチル酸塩、フェニル酢酸塩およびマンデル酸塩から選択される、請求項1記載の化合物。
- N−[4−クロロ−2−ヒドロキシ−3−(1−ピペラジニルスルホニル)フェニル]−N’−(2−クロロ−3−フルオロフェニル)尿素。
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- 2003-10-27 AR ARP030103917A patent/AR041834A1/es not_active Application Discontinuation
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- 2003-10-28 PT PT03781400T patent/PT1558259E/pt unknown
- 2003-10-28 JP JP2004548492A patent/JP4843220B2/ja not_active Expired - Lifetime
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- 2003-10-28 DK DK03781400.1T patent/DK1558259T3/da active
- 2003-10-28 US US10/532,956 patent/US20060040952A1/en not_active Abandoned
- 2003-10-28 AU AU2003287219A patent/AU2003287219A1/en not_active Abandoned
- 2003-10-28 EP EP11157820A patent/EP2388006A1/en not_active Withdrawn
- 2003-10-28 WO PCT/US2003/033964 patent/WO2004039775A2/en active Application Filing
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AR041834A1 (es) | 2005-06-01 |
PE20040607A1 (es) | 2004-09-18 |
EP2388006A1 (en) | 2011-11-23 |
AU2003287219A8 (en) | 2004-05-25 |
US20090093492A1 (en) | 2009-04-09 |
EP1558259A2 (en) | 2005-08-03 |
JP2006506404A (ja) | 2006-02-23 |
US7709485B2 (en) | 2010-05-04 |
PT1558259E (pt) | 2011-06-17 |
DE60336672D1 (de) | 2011-05-19 |
MY143477A (en) | 2011-05-31 |
ES2362357T3 (es) | 2011-07-04 |
SI1558259T1 (sl) | 2011-06-30 |
CY1112135T1 (el) | 2015-11-04 |
ATE504300T1 (de) | 2011-04-15 |
EP1558259A4 (en) | 2009-04-08 |
WO2004039775A3 (en) | 2004-08-26 |
WO2004039775A2 (en) | 2004-05-13 |
US20060040952A1 (en) | 2006-02-23 |
EP1558259B1 (en) | 2011-04-06 |
AU2003287219A1 (en) | 2004-05-25 |
DK1558259T3 (da) | 2011-07-11 |
TW200418812A (en) | 2004-10-01 |
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