JP2015530386A - ケモカイン受容体のアンタゴニスト - Google Patents
ケモカイン受容体のアンタゴニスト Download PDFInfo
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- JP2015530386A JP2015530386A JP2015529926A JP2015529926A JP2015530386A JP 2015530386 A JP2015530386 A JP 2015530386A JP 2015529926 A JP2015529926 A JP 2015529926A JP 2015529926 A JP2015529926 A JP 2015529926A JP 2015530386 A JP2015530386 A JP 2015530386A
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- pyrazolo
- pyridine
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- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 1
- RYFMWSXOAZQYPI-UHFFFAOYSA-K trisodium phosphate Chemical compound [Na+].[Na+].[Na+].[O-]P([O-])([O-])=O RYFMWSXOAZQYPI-UHFFFAOYSA-K 0.000 description 1
- 229910052722 tritium Inorganic materials 0.000 description 1
- 229960000281 trometamol Drugs 0.000 description 1
- 230000004614 tumor growth Effects 0.000 description 1
- 208000001072 type 2 diabetes mellitus Diseases 0.000 description 1
- 238000002255 vaccination Methods 0.000 description 1
- 238000003828 vacuum filtration Methods 0.000 description 1
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- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
- 229920002554 vinyl polymer Polymers 0.000 description 1
- 229940087652 vioxx Drugs 0.000 description 1
- 230000009385 viral infection Effects 0.000 description 1
- 150000003704 vitamin D3 derivatives Chemical class 0.000 description 1
- 229960000833 xylometazoline Drugs 0.000 description 1
- 229950007802 zidometacin Drugs 0.000 description 1
- MWLSOWXNZPKENC-SSDOTTSWSA-N zileuton Chemical compound C1=CC=C2SC([C@H](N(O)C(N)=O)C)=CC2=C1 MWLSOWXNZPKENC-SSDOTTSWSA-N 0.000 description 1
- 229960005332 zileuton Drugs 0.000 description 1
- 229910052725 zinc Inorganic materials 0.000 description 1
- 229960003414 zomepirac Drugs 0.000 description 1
- ZXVNMYWKKDOREA-UHFFFAOYSA-N zomepirac Chemical compound C1=C(CC(O)=O)N(C)C(C(=O)C=2C=CC(Cl)=CC=2)=C1C ZXVNMYWKKDOREA-UHFFFAOYSA-N 0.000 description 1
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Abstract
Description
本願は、2012年8月28日にされた米国特許出願第61/693,758号、及び2013年6月6日にされた米国特許出願第61/831,694号に基づく優先権の利益を主張し、それらの全ての開示内容は、本願において参照により援用される。
適用無し
適用無し
無し
I.略語及び定義
「アルキル」という用語は、それ自体、又は他の置換基の部分として、他に言及の無い限り、表示された数の炭素原子を有する(即ちC1−8は、1〜8個の炭素原子を意味する)直鎖又は分岐鎖の炭化水素基を意味する。アルキル基の例として、メチル、エチル、n−プロピル、イソプロピル、n−ブチル、t−ブチル、イソブチル、sec−ブチル、n−ペンチル、n−ヘキシル、n−ヘプチル、n−オクチル等が挙げられる。「アルケニル」という用語は、1つ以上の二重結合を有する不飽和アルキル基を意味する。同様に、「アルキニル」という用語は、1つ以上の三重結合を有する不飽和アルキル基を意味する。そのような不飽和アルキル基の例として、ビニル、2−プロペニル、クロチル、2−イソペンテニル、2−(ブタジエニル)、2,4−ペンタジエニル、3−(1,4−ペンタジエニル)、エチニル、1−および3−プロピニル、3−ブチニル、および高次同族体および異性体を含む。「シクロアルキル」という用語は、表示された数の炭素原子を有し(例えばC3−6シクロアルキル)、完全に飽和している、又は環の頂点の間に1つ以上の二重結合を有しない炭化水素環を意味する。また、「シクロアルキル」は、二環式、及び複素環式の炭化水素環をも意味し、例えば、ビシクロ[2.2.1]ヘプタン、ビシクロ[2.2.2]オクタン等が挙げられる。「ヘテロシクロアルキル」は、N、O及びSから選択される1〜5個のヘテロ原子を含むシクロアルキル基を意味し、窒素及び硫黄原子は任意で酸化され、窒素原子は任意で四級化される。ヘテロシクロアルキルは、単環、二環又は複素環式環であってもよい。ヘテロシクロアルキルの非限定的な例として、ピロリジン、ピペリジニル、イミダゾリジン、ピラゾリジン、ブチロラクタム、バレロラクタム、イミダゾリジノン、ヒダントイン、ジオキソラン、フタルイミド、ピペリジン、1,4−ジオキサン、モルホリン、チオモルホリン、チオモルホリン−S−オキシド、チオモルホリン−S,S−オキシド、ピペラジン、ピラン、ピリドン、3−ピロリン、チオピラン、ピロン、テトラヒドロフラン、テトラヒドロチオフェン、およびキヌクリジン基が挙げられる。ヘテロシクロアルキル基は、環炭素またはヘテロ原子を通して分子の残部に結合することができる。
各R1a及びR1bは、H, C1−8 アルキル, C1−8 ハロアルキル, C3−6 シクロアルキル, −CORa, −CO2Ra, −CONRaRb, −NRaRb, −NRaCORb, −ORa, −X1CORa, −X1CO2Ra, −X1CONRaRb, −X1NRaCORb, −X1NRaRb,及び−X1ORaからなる群から独立して選択され、ここでX1はC1−4 アルキレンからなる群から選択され、そして各Ra及びRbは、水素, C1−8 アルキル, C1−8 ハロアルキル, 及びC3−6 シクロアルキルからなる群から独立して選択され、そして任意で隣接する炭素原子上の2つのR1aは一緒になって5−, 6−又は7−員炭素環又はヘテロ炭素環を形成し;
各R2a及びR2bは、H, ヒドロキシル, C1−8 アルキル, C1−8 ハロアルキル, C1−8 アルコキシ, C1−4 アルコキシ−C1−4 アルキル, C1−8 ヒドロキシアルキル, C1−4 アルコキシ−C1−4 アルコキシ, C3−6 シクロアルキル, C3−6 シクロアルキル−C1−4 アルキル, 3〜7−員ヘテロシクロアルキル, 3〜7−員ヘテロシクロアルキル−C1−4 アルキル, −X1CO2Ra, −X1CONRaRb, −X1NRaCORb, −X1NRaRbからなる群から独立して選択され、ここでX1, Ra及びRbは上記で定義したものである。
又は、R5, R6, R7, R8及びR9の2つがAr2の環の隣接する2つの頂点に結合している場合、それらは任意で一緒に0、1又は2個のO及びNから選択されるヘテロ原子を環の構成原子とする5又は6員環を形成する。
。
下記実施例に示すように、本発明の化合物及び誘導体は、構成要素を組み立てるようにして、当業者が調製することが出来る。
上記で提供される化合物に加え、ヒト及び動物におけるCCR1活性の調節のための組成物は、典型的には医薬担体又は希釈剤を含有する。
さらに別の態様によれば、本発明は、CCR1−、CCR2−及び/又はCCR3−介在型の症状又は疾患を治療する方法であって、前記疾患又は症状を有する対象に、上記式Iの化合物の治療有効量を投与する方法を提供する。本明細書で「対象」は、哺乳類等の動物を含むものと定義され、限定するものではないが、例えば、霊長類(例えばヒト)、ウシ、ヒツジ、ヤギ、ウマ、イヌ、ネコ、ウサギ、ラット、マウス等がある。
以下の実施例は例示するために提供されるが、本発明を限定するものではない。
所望のアミン(1.2当量)及びカルボン酸を、THF (0.2 M)及びEt3N (1−2当量)中で組み合わせ、続いてHATU (1.3当量)を室温で添加した。反応終了後、混合物をEtOAcで希釈し、飽和NaHCO3及びブラインで洗浄し、Na2SO4で脱水し、濾過し、減圧下で濃縮した。
所望のカルボン酸を、CHCl3 (0.25 M)中で希釈し、DMFを2滴添加した。塩化オキサリル(1.2当量)を室温で添加し、混合物からガスを発生させた。20〜30分後、所望のアミン(1.2当量)を添加し、続いてEt3N (2.5当量)又はCHCl3と等しい体積のNaHCO3を添加した。反応終了後、混合物をEtOAcで希釈し、飽和NaHCO3及びブラインで洗浄し、Na2SO4で脱水し、濾過し、減圧下で濃縮した。
1H NMR (400 MHz, CDCl3、回転異性体の混合物) δ 8.37 (s, 0.8 H), 7.63 (s, 0.2 H), 7.42−7.46 (m, 2 H), 7.13−7.19 (m, 2 H), 5.14 (s, 0.4 H), 5.03 (s, 1.6 H), 3.90 (m, 0.4 H), 3.87 (m, 1.6 H), 2.86 (m, 2 H), 2.28 (s, 2.4 H), 2.25 (s, 0.6 H), 2.05−2.13 (m, 2 H), 1.62 (s, 6 H); MS: (ES) m/z計算C21H24ClFN5O2 [M + H]+ 432.2、発見432.1。
当該実施例は、本発明に関連する化合物(候補化合物)の生物学的活性の評価を示す。
A.細胞
1.CCR1発現細胞
a)THP−1細胞
THP−1細胞をATCC (TIB−202)から取得し、2mM L−グルタミン、1.5 g/L重炭酸ナトリウム、4.5 g/Lグルコース、10 mM HEPES、1 mMピルビン酸ナトリウム、0.05% 2−目ルカぷとエタノール及び10% FBSを添加したRPMI−1640培地中に懸濁して培養した。細胞を5%CO2/95%大気、湿度100%、温度37℃で増殖させ、週2回1:5でサブカルチャーし(細胞を密度範囲2x105〜2x106細胞/mLで培養する)、1x106細胞/mLで回収した。THP−1細胞はCCR1を発現し、CCR1結合及び機能アッセイに使用出来る。
ミルテニービーズ単離系(Miltenyi, Auburn, CA)を使用して、ヒト軟膜から単球を単離した。要するに、Ficoll勾配分離により末梢血の単核細胞を単離した後、細胞をPBSで洗浄し、標準的な手順を使用して赤血球を溶血させた。残った細胞を、磁性ビーズ(Miltenyi Biotech, Auburn, CA)を結合させた抗−CD14抗体で標識した。標識された細胞をAutoMACS (Miltenyi, Auburn, CA)に通して、陽性のフラクションを回収した。単球はCCR1を発現しており、CCR1結合及び機能アッセイに使用出来る。
1.CCR1リガンド結合の阻害
CCR1発現細胞を遠心分離し、アッセイ緩衝剤中で再懸濁した(20 mM HEPES pH 7.1, 140 mM NaCl, 1 mM CaCl2, 5 mM MgCl2、0.2%ウシ血清アルブミン添加)。濃度はTHP−1細胞において5x106 cells/mL、単球において5x105とした。結合アッセイは、以下のように用意された。前記化合物を最終濃度が2〜10μMとなるように添加したアッセイプレートに、0.1mLの細胞(THP−1細胞5x105cells/well、単球5x104)を添加して、スクリーニングを行った(又は化合物のIC50判定における用量応答の部分)。そして、最終濃度〜50 pM、ウェル当たりの収率30,000 cpmとなるようにアッセイ緩衝剤で希釈した、0.1 mLの125I標識MIP−1α(Perkin Elmer Life Sciences, Boston, MAより入手)、又は0.1mLの125I標識CCL15/ロイコタクチン(Perkin Elmer Life Sciences, Boston, MAによりカスタム放射性標識したものを入手)を添加し(125I標識MIP−1αをTHP−1細胞に、125I標識CCL15/ロイコタクチンを単球に使用した)、当該プレートを密封し、約3時間、4℃で、シェーカープラットフォーム上でインキュベーションした。反応物を、真空細胞回収器(Packard Instruments; Meriden, CT)上の、0.3%ポリエチレンイミン(PEI)溶液に予め浸漬させたGF/Bガラスフィルター上に吸収させた。各ウェルにシンチレーション液(40μl; Microscint 20, Packard Instruments)を添加し、当該ウェルを密封し、Topcountシンチレーションカウンター(Packard Instruments)中で放射活性を測定した。希釈剤のみ(合計カウント用)、又は過剰のMIP−1α又はMIP−1β (1 μg/mL、非特異的結合用)を含む対象ウェルを使用して、化合物における合計の阻害のパーセントを計算した。GraphPad, Inc. (San Diego, Ca)のPrismコンピュータープログラムを使用して、IC50値を計算した。IC50値は、標識MIP−1αの受容体への結合を50%阻害するのに要する濃度である(更なるリガンド結合及び他の機能性アッセイの記載については、Dairaghi, et al., J. Biol. Chem. 274:21569−21574 (1999), Penfold, et al., Proc. Natl. Acad. Sci. USA. 96:9839−9844 (1999), and Dairaghi, et al,. J. Biol. Chem. 272:28206−28209 (1997)を参照されたい)。
細胞内に貯留したカルシウムの放出を検出するため、細胞(THP−1又は単球)を、細胞培地中の3μMのINDO−1AM色素(Molecular Probes; Eugene, OR)と共に室温で45分間インキュベーションし、リン酸緩衝生理食塩水(PBS)で洗浄した。INDO−1AMを添加した後、細胞をフラックス緩衝剤(ハンクバランス塩溶液(HBSS)に1%FBS添加)中に再懸濁した。カルシウム動員は、励起350nm、蛍光放射を400nm及び490nmで同時に2つ記録する、Photon Technology International 分光光度計(Photon Technology International; New Jersey)を使用して測定した。相対的な細胞内のカルシウムレベルは、400 nm/490 nmの放射量の比率として表現した。実験は37℃でキュベット中で定常的に撹拌して行われ、各キュベットは、2mLフラックス緩衝剤に106細胞を含有していた。ケモカインリガンドは、1〜100nMの範囲に渡って使用され得る。前記放射比率は、時間に対してプロットされた(典型的には2〜3分)。候補リガンドブロック化合物を10秒で添加し(最大10μM)、その後ケモカイン(即ちMIP−1α; R&D Systems; Minneapolis, MN)を60秒で添加し、対照ケモカイン(即ちMIP−1α; R&D Systems; Minneapolis, MN) and control chemokine (i.e., SDF−1α; R&D Systems; Minneapolis, MN)を150秒で添加した。
96ウェルケモタキシスチャンバー(Neuroprobe; Gaithersburg, MD)中で、5μm孔ポリカーボネート、ポリビニルピロリドン被覆フィルターを使用して、ケモタキシス緩衝剤(ハンクバランス塩溶液(HBSS)及び1%FBS)を使用して、ケモタキシスアッセイを実施した。CCR1ケモカインリガンド(即ちMIP−1α、CCL15/ロイコタクチン; R&D Systems; Minneapolis, MN)を使用して、CCR1により誘導される移動の阻害を評価した。他のケモカイン(即ちSDF−1α; R&D Systems; Minneapolis, MN)は、特異性の対照として使用された。下方のチャンバーには29μlのケモカイン(即ち0.1nMのCCL15/ロイコタクチン)及び様々な量の化合物が充填されており、上方のチャンバーには、20μl中の100,000個のTHP−1又は単球が含まれている。当該チャンバーを37℃で1〜2時間インキュベーションし、下方のチャンバーに移動した細胞の数を、ウェルあたり5箇所の任意の領域の細胞数を直接カウントすることにより、又は核酸量を測定する蛍光色素を用いた手法であるCyQuantアッセイ(Molecular Probes)により、及びSpectrafluor Plus (Tecan)を用いた測定により、定量した。IC50値の計算は、Prism from GraphPad, Inc. (San Diego, Ca)を用いて行われた。IC50値は、CCR1アゴニストに対する応答が50%の細胞において阻害されるのに必要な化合物の濃度である。
a)破壊的関節炎症のウサギモデル
ウサギのLPS試験は、基本的にはPodolin, et al. J. Immunol. 169(11):6435−6444 (2002)の記載に従い実施された。雌ニュージーランドウサギ(約2キログラム)の両膝の関節にLPS(10ng)を投与した。候補化合物、例えば1.016(1%メタノール中に製剤化)、又はビヒクル(1%メタノール)を、5ml/kgの用量で2回経口投与した(上記LPS投与の2時間前及び4時間後)。LPS注射の16時間後、膝を洗浄し、細胞数カウントを実施した。処理の有益な効果は、膝関節の炎症を起こした滑液中に集合した炎症性細胞の数の減少により判定された。候補化合物による処理は、炎症性細胞の集合を顕著に低下させた。
17日間のII型コラーゲン関節炎の発症の試験は、関節炎が誘導する臨床的な足首の腫れに対する候補化合物の作用を評価するために実施された。ラットのコラーゲン関節炎は、様々な抗関節炎薬剤の前臨床試験に広く使用される、多発性関節炎の実験モデルである(Trentham, et al., J. Exp. Med. 146(3):857−868 (1977), Bendele, et al., Toxicologic Pathol. 27:134−142 (1999), Bendele, et al., Arthritis Rheum. 42:498−506 (1999))。このモデルの特徴は、頑強で容易に測定可能な多発性関節炎の確実な発症及び進行、パンヌス形成を伴う顕著な軟骨の破壊、及び穏和乃至中等度の骨再吸収、並びに骨膜骨の増殖である。
オキサゾロンにより誘導される皮膚遅延型過敏症のマウスモデルにおいて、本発明の化合物を評価することが出来る。要するに、8〜10週齢のBALB/cマウスの剃毛した腹部に、エタノールに溶解した1%オキサゾロン溶液を局所投与し、この時点を0日とした。投与後6日目、マウスにビヒクル又は漸増用量の本発明の化合物を経口投与し、その直前、及び4時間前、右耳にオキサゾロン0.5%エタノール溶液を局所投与した。翌日(7日)、キャリパー測定により耳の厚さを測定した。本発明の化合物で処理した動物は、対照のビヒクルで処理したものと比べて耳の腫れを顕著に減少させた。これは、本発明の化合物が、オキサゾロンが誘導する皮膚の過敏症の軽減を誘導したことを示唆する。
アレルギー性喘息のマウスモデルにおいて、本発明の化合物を評価することが出来る。喘息は、8〜10週齢BALB/cマウスを0及び10日目にアルムアジュバント中のOVAで感作することによって誘導された。二十日目にマウスにPBS中のOVAを経鼻投与して、気道の炎症を誘導した。ビヒクルで処理したマウス群と、漸増用量の本発明の化合物で処理したマウス群とを設け、当該処理を20日から23日まで行った。23日目に経鼻OVA処理の後、動物の気管支肺胞洗浄(BAL)中の細胞浸潤物を解析した。ビヒクルで処理したものと比べて本発明の化合物で処理したマウスにおいてBAL白血球数の顕著な減少が認められ、これは、本発明の化合物が、このモデルにおいて効果的であることを示唆する。
この実施例は、悪性細胞の治療におけるCCR1アンタゴニストの有効性を評価するための手順を記載する。通常のマウス系統に、OVAによるワクチン化に続く癌特異的抗原応答の容易な評価を可能とするためにOVAをトランスフェクションしたマウス胸腺腫EL4を含む、様々なよく特徴付けられたマウス腫瘍株を移植した。これらの腫瘍モデルのいずれかからの3種類のマウス系列において、以下のようにCCR1アンタゴニストの有効性を試験した。第一のマウス系列には、腫瘍移植直後に、その後、様々な投与スケジュールで、追加でPBS及びTween0.5%を腹腔内投与した。第二のマウス系列は、腫瘍移植直後に、その後、様々な投与スケジュールで、様々な用量のCCR1アンタゴニストを、腹腔内、静脈内、皮下、筋肉内、経口、又は他の投与様式で投与したマウスの群からなる。第三のマウス系列は陽性対照であり、腫瘍移植直後に、その後、様々な投与スケジュールで、抗IL4抗体、抗IFNg抗体、IL4又はTNFのいずれかを腹腔内投与した群からなる。有効性は、腫瘍の増殖対退縮を通じてモニターされた。OVAをトランスフェクションしたEL4胸腺腫モデルの場合、細胞溶解性OVA特異的応答が、インビトロでOVAを用いてリンパ節細胞の流出を刺激し、72時間時点での抗原特異的細胞毒性を測定することにより測定できる。
P−糖タンパク質遺伝子を欠くMDR1a−ノックアウトマウスは、特定の無病原体条件下で、大腸炎を自然に発症する。これらの動物における病理学は、ヒトの潰瘍性大腸炎に類似のTh1型T細胞媒介性炎症として特徴付けられている。疾患は通常生後8〜10週辺りで生じ始める。しかしながら、疾患が発症する齢及び最高の浸透レベルは、異なる動物施設の間で顕著に変化する。MDR1aノックアウトマウスを使用した実験において、CCR1アンタゴニストは、投与の時間に依存して、予防的に、又は治療的に評価され得る。雌マウス(n=34)に、例えば有効用量で毎日皮下投与等の適切な方法で、本発明の化合物を投与した。この実験は、IBD関連成長遅延及び肛門の滲出及び炎症の評点により評価された。肛門の滲出及び炎症を減少させ、又はIBD関連成長遅延を阻害する化合物は、この表示における化合物の有効性を示唆する。
マウスRENCA腫瘍モデルは、肺への自然な転移において成人腎細胞癌の進行を正確に模倣し、固形腫瘍のモデルとして利用される。Balb/c6〜8週齢雌マウスの腎臓被膜下に約5e5のRENCA細胞(マウス腎臓腺癌; ATCC cat# CRL−2947)を播種し、腎臓腫瘍の増殖を22日間観察し、早くて15日目には、肺への転移が観察された。動物にビヒクル又は本発明の化合物を、例えば腫瘍移植時点から毎日皮下投与して、最初の成長に対する効果をモニタリングし、又は時間が経ってから(例えば7日)、転移に対する影響をモニタリングした。原発腫瘍領域は、機械式キャリパーを使用して週2回測定された。腫瘍の体積は、v=pab2/6で計算され、ここでaは最長の直径、bは次に長いaに直交する直径を示す。腫瘍体積又は腫瘍の発生率の減少は、この表示における化合物の有効性を示唆する。
RIPDからの回復における本発明の化合物の有効性を評価するために、様々なモデルを使用出来る。例えばTokudaらは、ブレオマイシン誘導肺線維症のモデルを記載している(Tokuda et al, J Immunol. 164(5):2745−51 (2000))。あるいは、Yangらは、直接の放射線誘導疾患のモデルを記載している(Yang et al, Am J Respir Cell Mol Biol. 45(1):127−35 (2011))。要するに、麻酔した10〜12週齢の処理又は無処理マウスを不動化し、胸腔以外の全身を遮蔽し、セシウム源から、1.65 Gy/minで、14.5 Gyの単発線量の放射線照射をした。この用量で、生存率は、適切な数の動物における長期間の解析が可能となるのに充分であった。化合物の有効性は、当業者に知られる様々な方法、例えば肺の機械的評価、肺のヒドロキシプロリンレベル等により評価できる。
Claims (27)
- 以下の式:
nは0〜3の整数であり;
各R1a及びR1bは、H, C1−8 アルキル, C1−8 ハロアルキル, C3−6 シクロアルキル, −CORa, −CO2Ra, −CONRaRb, −NRaRb, −NRaCORb, −ORa, −X1CORa, −X1CO2Ra, −X1CONRaRb, −X1NRaCORb, −X1NRaRb,及び−X1ORaからなる群から独立して選択され、ここでX1はC1−4 アルキレンからなる群から選択され、そして各Ra及びRbは、水素, C1−8 アルキル, C1−8 ハロアルキル, 及びC3−6 シクロアルキルからなる群から独立して選択され、そして任意で隣接する炭素原子上の2つのR1aは一緒になって5−, 6−又は7−員炭素環又はヘテロ炭素環を形成し;
各R2a及びR2bは、H, ヒドロキシル, C1−8 アルキル, C1−8 ハロアルキル, C1−8 アルコキシ, C1−4 アルコキシ−C1−4 アルキル, C1−8 ヒドロキシアルキル, C1−4 アルコキシ−C1−4 アルコキシ, C3−6 シクロアルキル, C3−6 シクロアルキル−C1−4 アルキル, 3〜7−員ヘテロシクロアルキル, 3〜7−員ヘテロシクロアルキル−C1−4 アルキル, −X1CO2Ra, −X1CONRaRb, −X1NRaCORb, −X1NRaRbからなる群から独立して選択され、ここでX1, Ra及びRbは上記で定義したものであり ;
Ar1は、6員又は10員の単環式又は融合した二環式アリール環、及び5〜10員の単環式又は融合した二環式ヘテロアリール環からなる群から選択され;それらはそれぞれR3, R3a, R3b, R4及び R4aの1〜5個の置換基で置換され、これらの置換基は、H, ハロゲン, −ORc, −OC(O)Rc, −NRcRd, −SRc, −Re, −CN, −NO2, −CO2Rc, −CONRcRd, −C(O)Rc, −OC(O)NRcRd, −NRdC(O)Rc, −NRdC(O)2Re, −NRc−C(O)NRcRd, −NH−C(NH2)=NH, −NReC(NH2)=NH, −NH−C(NH2)=NRe, −NH−C(NHRe)=NH, −S(O)Re, −S(O)2Re, −NRcS(O)2Re, −S(O)2NRcRd, −N3, −X2ORc, −O−X2ORc, −X2OC(O)Rc, −X2NRcRd, −O−X2NRcRd, −X2SRc, −X2CN, −X2NO2, −X2CO2Rc, −O−X2CO2Rc, −X2CONRcRd, −O−X2CONRcRd, −X2C(O)Rc, −X2OC(O)NRcRd, −X2NRdC(O)Rc, −X2NRdC(O)2Re, −X2NRcC(O)NRcRd, −X2NH−C(NH2)=NH, −X2NReC(NH2)=NH, −X2NH−C(NH2)=NRe, −X2NH−C(NHRe)=NH, −X2S(O)Re, −X2S(O)2Re, −X2NRcS(O)2Re, −X2S(O)2NRcRd, −X2N3, −NRd−X2ORc, −NRd−X2NRcRd, −NRd−X2CO2Rc及び−NRd−X2CONRcRdからなる群から独立して選択され、ここで各X2 C1−4 アルキレンからなる群から独立して選択され、そして各Rc及びRdは、水素, C1−8 アルキル, C1−8 ヒドロキシアルキル, C1−8 ハロアルキル及びC3−6 シクロアルキルからなる群から独立して選択され、又は任意でRc及びRdは、同一の窒素原子と結合している場合、当該窒素原子と一緒に、0〜2個の追加のヘテロ原子を環の構成原子とする5又は6員環を形成し;そして各Reは、C1−8 アルキル, C1−8 ヒドロキシアルキル, C1−8 ハロアルキル及びC3−6 シクロアルキルからなる群から独立して選択され;
Ar2は、
6員又は10員の単環式又は融合した二環式アリール環、及び5〜10員の単環式又は融合した二環式ヘテロアリール環からなる群から選択され;それらはそれぞれR5, R6, R7, R8及びR9の1〜5個の置換基で置換され、これらの置換基は、H, ハロゲン, −ORf, −OC(O)Rf, −NRfRg, −SRf, −Rh, −CN, −NO2, −CO2Rf, −CONRfRg, −C(O)Rf, −OC(O)NRfRg, −NRgC(O)Rf, −NRgC(O)2Rh, −NRf−C(O)NRfRg, −NH−C(NH2)=NH, −NRhC(NH2)=NH, −NH−C(NH2)=NRh, −NH−C(NHRh)=NH, −S(O)Rh, −S(O)2Rh, −NRfS(O)2Rh, −S(O)2NRfRg, −NRfS(O)2NRfRg, −N3, −X3ORf, −X3OC(O)Rf, −X3NRfRg, −X3SRf, −X3CN, −X3NO2, −X3CO2Rf, −X3CONRfRg, −X3C(O)Rf, −X3OC(O)NRfRg, −X3NRgC(O)Rf, −X3NRgC(O)2Rh, −X3NRf−C(O)NRfRg, −X3NH−C(NH2)=NH, −X3NRhC(NH2)=NH, −X3NH−C(NH2)=NRh, −X3NH−C(NHRh)=NH, −X3S(O)Rh, −X3S(O)2Rh, −X3NRfS(O)2Rh, −X3S(O)2NRfRg, −Y, −X3Y, −S(O)2Y, −C(O)Y, −X3N3, −O−X3ORf, −O−X3NRfRg, −O−X3CO2Rf, −O−X3CONRfRg, −NRg−X3ORf, −NRg−X3NRfRg, −NRg−X3CO2Rf, 及び−NRg−X3CONRfRgからなる群から独立して選択され、ここでYは、5又は6員アリール、ヘテロアリール、又はヘテロ環であり、任意でハロゲン、−ORf, −OC(O)Rf, −NRfRg, −Rh, −SRf, −CN, −NO2, −CO2Rf, −CONRfRg, −C(O)Rf, −NRgC(O)Rf, −NRgC(O)2Rh, −S(O)Rh, −S(O)2Rh, −NRfS(O)2Rh, −S(O)2NRfRg, −X3ORf, X3SRf, −X3CN, −X3NO2, −X3CO2Rf, −X3CONRfRg, −X3C(O)Rf, −X3OC(O)NRfRg, −X3NRgC(O)Rf, −X3NRgC(O)2Rh, −X3NRf−C(O)NRfRg, −X3OC(O)Rf, −X3S(O)Rh, −X3S(O)2Rh, −X3NRfRg, −X3NRfS(O)2Rh, −X3S(O)2NRfRg, −O−X3ORf, −O−X3NRfRg, −O−X3CO2Rf, −O−X3CONRfRg, −NRg−X3ORf, −NRg−X3NRfRg, −NRg−X3CO2Rf, 及び −NRg−X3CONRfRgからなる群から選択される1〜3個の置換基で置換され、ここで各X3は、C1−4 アルキレンからなる群から独立して選択され、そして各Rf及びRgは、C1−8 アルキル, C1−8 ヒドロキシアルキル, C1−8 ハロアルキル及びC3−6 シクロアルキルからなる群から選択され、又はそれらが同一の窒素原子と結合している場合、当該窒素原子と一緒に、0〜2個の追加のヘテロ原子を環の構成原子とする5又は6員環を形成し、そして各Rhは、C1−8 アルキル, C2−8 アルケニル, C2−8 アルキニル, C1−8 ヒドロキシアルキル, C1−8 ハロアルキル及びC3−6 シクロアルキルからなる群から独立して選択され;
又は、R5, R6, R7, R8及びR9の2つがAr2の環の隣接する2つの頂点に結合している場合、それらは任意で一緒に0、1又は2個のO及びNから選択されるヘテロ原子を環の構成原子とする5又は6員環を形成する]
で表される化合物、又はその塩、回転異性体、若しくは光学異性体。 - Ar1が、フェニル、ナフチル、ピリジル、ピラゾリル、ピリダジニル、ピリミジニル、トリアジニル、キノリニル、キノキサリニル及びプリニルからなる群から選択され、それらのそれぞれが、任意でR3, R3a, R3b, R4及びR4aで置換される、請求項1に記載の化合物。
- Ar2が、フェニル、ピラゾリル、イミダゾリル、トリアゾリル、テトラゾリル、オキサゾリル、イソキサゾリル、オキサジアゾリル、オキサチアジアゾリル、ピロリル、チアゾリル、イソチアゾリル、ベンズイミダゾリル、ベンゾキサゾリル、ベンゾピラゾリル、ベンゾトリアゾリル、ピラゾロ[3,4−b]ピリジン、ピラゾロ[3,4−d]ピリジン、イミダゾ[4,5−b]ピリジン、イミダゾ[1,5−a]ピリジン、及びピロロ[2,3−b]ピリジンからなる群から選択され、それらのそれぞれが、任意でR5, R6及びR7で置換される、請求項1又は2のいずれか1項に記載の化合物。
- Ar1がフェニル, ナフチル及びピリジルからなる群から選択され、それらのそれぞれが、1〜5個の置換基R3, R3a, R3b, R4及びR4aで置換される、請求項1〜3のいずれか1項に記載の化合物。
- Ar2が、ピラゾリル、イミダゾリル、及びトリアゾリルからなる群から選択され、それらのそれぞれが、R5, R6及びR7で置換される、請求項1〜4のいずれか1項に記載の化合物。
- Ar1がフェニル, ナフチル及びピリジルからなる群から選択され、それらのそれぞれが、1〜5個の置換基R3, R3a, R3b, R4及びR4aで置換され;かつAr2が、ピラゾリル、イミダゾリル、及びトリアゾリルからなる群から選択され、それらのそれぞれが、R5, R6及びR7で置換される、請求項1〜3のいずれか1項に記載の化合物。
- Ar1がフェニルであり、置換基R3, R3a, R3b, R4及びR4aで置換され、かつAr2が、ピラゾリル、イミダゾリル、ベンズイミダゾリル、ベンゾピラゾリル、ピラゾロ[3,4−b]ピリジン、ピラゾロ[3,4−d]ピリジン、イミダゾ[4,5−b]ピリジン、イミダゾ[1,5−a]ピリジン、及びピロロ[2,3−b]ピリジンからなる群から選択され、それらのそれぞれが、任意でR5, R6及びR7で置換される、請求項1〜4のいずれか1項に記載の化合物。
- Ar2がヘテロアリール基である、請求項1〜8のいずれか1項に記載の化合物。
- Ar2がヘテロアリール基であり、任意で置換され、環の頂点の窒素原子を介して当該分子と結合している、請求項1〜9のいずれか1項に記載の化合物。
- Yが、ピリジル、ピリミジニル、イミダゾリル、オキサゾリル、オキサジアゾリル、トリアゾリル、チアゾリル、イミダゾリニル及びピラゾリルからなる群から選択される、請求項1〜12のいずれか1項に記載の化合物。
- 医薬として許容される賦形剤又は担体及び請求項1に記載の化合物を含有する医薬組成物。
- ステント又はステントグラフトデバイスとして形成される、請求項20に記載の医薬組成物。
- CCR−1が関与する疾患又は症状を治療する方法であって、治療有効量の請求項1〜21のいずれか1項に記載の化合物又は組成物を、当該治療を必要とする対象に投与する工程を含む、当該方法。
- 前記CCR−1が関与する疾患又は症状が、炎症性の症状である、請求項22に記載の方法。
- 前記CCR−1が関与する疾患又は症状が、免疫調節障害である、請求項22に記載の方法。
- 前記CCR−1が関与する疾患又は症状が関節リウマチ、多発性硬化症、移植による拒絶反応、皮膚炎、湿疹、蕁麻疹、血管炎、炎症性腸疾患、食物アレルギー、喘息、アルツハイマー症、パーキンソン症、乾癬、エリテマトーデス、変形性関節症、脳卒中、再狭窄、放射線誘導性肺疾患、及び脳脊髄炎からなる群から選択される、請求項22に記載の方法。
- 前記投与が、経口、非経口、直腸、経皮、舌下、経鼻、又は局所投与である、請求項22に記載の方法。
- 前記化合物が、抗炎症剤、鎮痛剤、抗増殖剤、代謝阻害剤、白血球遊走阻害剤、又は免疫調節剤と組み合わせて投与される、請求項22に記載の方法。
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