JP2012500253A - ピロロ[2,3−d]ピリミジン化合物 - Google Patents
ピロロ[2,3−d]ピリミジン化合物 Download PDFInfo
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- JP2012500253A JP2012500253A JP2011523467A JP2011523467A JP2012500253A JP 2012500253 A JP2012500253 A JP 2012500253A JP 2011523467 A JP2011523467 A JP 2011523467A JP 2011523467 A JP2011523467 A JP 2011523467A JP 2012500253 A JP2012500253 A JP 2012500253A
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- methyl
- compound
- pyrrolo
- trans
- jak
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Abstract
Description
薬学的に許容できる担体および式Iの化合物を含む医薬組成物、
治療有効量の式Iの化合物またはその薬学的に許容できる塩を、必要とする哺乳動物に投与することによって、臓器移植拒絶反応、狼瘡、多発性硬化症、関節リウマチ、乾癬、癌、変形性関節症、および糖尿病から選択される障害または症状を管理または治療するための方法、
治療有効量の式Iの化合物またはその薬学的に許容できる塩を、必要とする哺乳動物に投与することによって、糖尿病、癌、自己免疫性甲状腺障害、潰瘍性大腸炎、クローン病、ドライアイ、アルツハイマー病、白血病、および免疫抑制または免疫調節が望ましいであろう他の適応症から選択される障害または症状を管理または治療するための方法、
治療有効量の式Iの化合物またはその薬学的に許容できる塩を、必要とする哺乳動物に投与することによって、哺乳動物における、アレルギー性皮膚炎、湿疹、アトピー性皮膚炎、そう痒症およびその他のそう痒性症状を含むアレルギー反応ならびに腸疾患などの炎症性疾患から選択される障害または症状を管理または治療するための方法、
治療有効量の式Iの化合物またはその薬学的に許容できる塩を、必要とする哺乳動物に投与することによって、慢性または難治性喘息、遅発型喘息、気道反応性亢進、気管支炎、気管支喘息、アレルギー性喘息、内因性喘息、外因性喘息、塵埃喘息、再発性気道閉塞、および慢性閉塞性肺疾患を含む喘息およびその他の閉塞性気道疾患から選択される障害または症状を管理または治療するための方法、
治療有効量の式Iの化合物またはその薬学的に許容できる塩を、必要とする哺乳動物に投与することによって、タンパク質チロシンキナーゼまたはJAK−1、JAK−2、JAK−3および/もしくはTyk−2を阻害するための方法、
治療有効量の式Iの化合物またはその薬学的に許容できる塩を、必要とする哺乳動物に投与することによって、タンパク質チロシンキナーゼまたはJAK−1、JAK−2、JAK−3および/もしくはTyk−2を阻害するための方法、ならびに
本発明の化合物を調製するための方法
も提供する。
哺乳動物(すなわちヒトおよび動物)における障害を治療するための治療的使用では、本発明の化合物またはその医薬組成物は、経口、非経口、局所、経直腸、経粘膜、または経腸的に投与することができる。非経口投与には、全身的な効果を引き起こすための間接注射または患部への直接注射が含まれる。局所投与には、皮膚または局部適用によって容易に接近できる臓器、例えば、眼または耳の治療が含まれる。これには、全身的な効果を引き起こすための経皮送達も含まれる。直腸投与には、坐剤の形態が含まれる。好ましい投与経路は、経口および非経口である。
式Iの化合物は、その本来の形態で、または塩として使用することができる。安定な非毒性の酸性または塩基性塩を形成することが望ましい場合には、薬学的に許容できる塩としての化合物の投与が適切かもしれない。式Iの化合物の薬学的に許容できる塩には、酢酸塩、アスコルビン酸塩、アスパラギン酸塩、安息香酸塩、ベシル酸塩、重炭酸塩/炭酸塩、重硫酸塩/硫酸塩、ホウ酸塩、カンシル酸塩、クエン酸塩、エジシル酸塩、エトグルタル酸塩、エシル酸塩、ギ酸塩、フマル酸塩、グルセプト酸塩、グルコン酸塩、グルクロン酸塩、グリセロリン酸塩、ヘキサフルオロリン酸塩、ヒベンズ酸塩、塩酸塩/塩化物、臭化水素酸塩/臭化物、ヨウ化水素酸塩/ヨウ化物、イセチオン酸塩、乳酸塩、リンゴ酸塩、マレイン酸塩、マロン酸塩、メシル酸塩、メチル硫酸塩、ナフチル酸塩、2−ナプシル酸塩、ニコチン酸塩、硝酸塩、オロチン酸塩、シュウ酸塩、パルミチン酸塩、パモ酸塩、リン酸塩/リン酸水素/リン酸二水素、糖酸塩、ステアリン酸塩、コハク酸塩、酒石酸塩、トシル酸塩およびトリフルオロ酢酸塩がある。
本発明の医薬組成物は、当技術分野でよく知られているプロセスによって、例えば、従来の混合、溶解、造粒、糖衣錠作成、湿式粉砕、乳化、カプセル封入、封入(entrapping)、凍結乾燥プロセスまたは噴霧乾燥を用いて製造することができる。
本発明で使用するのに適した医薬組成物には、有効成分が使用目的、すなわち、障害または疾患の管理または治療を達成するのに十分な量で含有されている組成物が含まれている。より具体的には、治療有効量は、疾患の症候/徴候の予防、緩和もしくは寛解、または治療対象の生存の延長に有効な化合物の量を表す。
本発明の化合物は、ヤヌスキナーゼ−1(JAK−1)、ヤヌスキナーゼ−2(JAK−2)およびヤヌスキナーゼ−3(JAK−3)に対して効力があるヤヌスキナーゼ阻害剤(JAK−i)である。したがって、これらは、臓器移植、狼瘡、多発性硬化症、関節リウマチ、乾癬、I型糖尿病および糖尿病からの合併症、癌、喘息、アトピー性皮膚炎、自己免疫性甲状腺障害、潰瘍性大腸炎、クローン病、アルツハイマー病、白血病、変形性関節症、そう痒症の管理、慢性呼吸器疾患および免疫抑制/免疫調節が望ましい他の適応症のための治療薬として有用である。
関節リウマチ、若年性関節炎、および乾癬性関節炎を含む関節炎;
慢性または難治性喘息、遅発型喘息、気道反応性亢進、気管支炎、気管支喘息、アレルギー性喘息、内因性喘息、外因性喘息、塵埃喘息、再発性気道閉塞、および慢性閉塞性肺疾患を含む喘息および他の閉塞性気道疾患;
単一臓器または単一細胞型の自己免疫異常と名付けられたもの、例えば橋本甲状腺炎、自己免疫性溶血性貧血、悪性貧血の自己免疫性萎縮性胃炎、自己免疫性脳脊髄炎、自己免疫性精巣炎、グッドパスチャー病、自己免疫性血小板減少症、交感性眼炎、重症筋無力症、グレーブス病、原発性胆汁性肝硬変、慢性活動性肝炎、潰瘍性大腸炎および膜性糸球体症、全身性の自己免疫異常に関連するとして名付けられたもの、例えば全身性紅斑性狼瘡、関節リウマチ、シェーグレン症候群、ライター症候群、多発性筋炎−皮膚筋炎、全身性硬化症、結節性多発性動脈炎、多発性硬化症および水疱性類天疱瘡を含む自己免疫疾患または異常、ならびにコーガン症候群、強直性脊椎炎、ヴェグナー肉芽腫症、自己免疫性脱毛症、I型または若年型糖尿病、および甲状腺炎を含むO細胞(体液)に基づき得るまたはT細胞に基づき得る別の自己免疫疾患;
消化管/胃腸管癌、大腸癌、肝臓癌、肥満細胞腫瘍および扁平上皮癌を含む皮膚癌、***癌および乳癌、卵巣癌、前立腺癌、リンパ腫、急性骨髄性白血病および慢性骨髄性白血病を含む白血病、腎臓癌、肺癌、筋肉腫、骨肉腫、膀胱癌、脳腫瘍、口腔黒色腫および転移性黒色腫を含む黒色腫、カポジ肉腫、多発性骨髄腫を含む骨髄腫、骨髄増殖性疾患、増殖性糖尿病性網膜症、および充実性腫瘍を含む血管形成関連障害を含む癌または腫瘍;
I型糖尿病および糖尿病からの合併症を含む糖尿病;
眼の自己免疫疾患、角結膜炎、春季結膜炎、ベーチェット病に関連するブドウ膜炎および水晶体原性ブドウ膜炎を含むブドウ膜炎、角膜炎、ヘルペス性角膜炎、円錐角膜炎、角膜上皮ジストロフィー、角膜白斑、眼天疱瘡、モーレン潰瘍、強膜炎、グレーブス眼症、フォークト−小柳−原田症候群、乾性角結膜炎(ドライアイ)、フリクテン、虹彩毛様体炎、サルコイドーシス、内分泌性眼障害、交感性眼炎、アレルギー性結膜炎、および眼内血管新生を含む眼疾患、障害または症状;
クローン病および/または潰瘍性大腸炎、炎症性腸疾患、小児脂肪便症、直腸炎、好酸球性胃腸炎、および肥満細胞症を含む腸管の炎症、アレルギーまたは症状;
運動ニューロン疾患、アルツハイマー病、パーキンソン病、筋萎縮性側索硬化症、ハンチントン病、脳虚血を含む神経変性疾患、または心的外傷、ストライク、グルタミン酸神経毒性もしくは低酸素が原因である神経変性疾患;発作における虚血性/再潅流傷害、心筋虚血、腎虚血、心臓発作、心肥大、アテローム性動脈硬化症および動脈硬化症、臓器低酸素症、および血小板凝集;
アトピー性皮膚炎、湿疹、乾癬、強皮症、そう痒症および他のそう痒性症状を含む皮膚疾患、症状または障害;
ウマを含む哺乳動物におけるアレルギー性皮膚炎およびウマにおける咬傷過敏症、夏季湿疹および皮膚掻痒などのアレルギー性疾患を含むアレルギー反応;ならびに
ランゲルハンス島移植片拒絶反応、骨髄移植片拒絶反応、移植片対宿主疾患、骨髄、軟骨、角膜、心臓、椎間板、島、腎臓、肢、肝臓、肺、筋肉、筋芽細胞、神経、すい臓、皮膚、小腸、または気管、および異物移植などの臓器および細胞移植片拒絶反応を含む移植片拒絶反応などの種々の症状または疾患を治療するのに使用することができる。
1H-NMR
(d6-DMSO): 1.17 - 1.32 (2H), 1.57 - 1.73 (4H), 1.76 - 1.92 (1H),
1.93 - 2.08 (2H), 2.30 - 2.39 (3H), 2.53 - 2.62 (3H), 2.87 - 2.98 (2H), 3.07 -
3.17 (3H), 4.53 - 4.75 (1H), 6.81 - 6.94 (1H), 7.38 - 7.47 (2H), 7.56 - 7.65
(1H), 7.92 - 8.02 (2H), 8.15 - 8.27 (1H).
1H-NMR
(d6-DMSO): 1.17 - 1.32 (2H), 1.57 - 1.73 (4H), 1.76 - 1.92 (1H),
1.93 - 2.08 (2H), 2.30 - 2.39 (3H), 2.53 - 2.62 (3H), 2.87 - 2.98 (2H), 3.07 -
3.17 (3H), 4.53 - 4.75 (1H), 6.81 - 6.94 (1H), 7.38 - 7.47 (2H), 7.56 - 7.65
(1H), 7.92 - 8.02 (2H), 8.15 - 8.27 (1H)
1H-NMR
(d6-DMSO): 0.98 - 1.18 (2H), 1.55 - 1.76 (5H), 1.99 - 2.13 (2H),
2.29 - 2.39 (5H), 3.05 - 3.15 (3H), 4.47 - 4.76 (1H), 6.77 - 6.92 (1H), 7.38 -
7.48 (2H), 7.54 - 7.62 (1H), 7.91 - 8.02 (2H), 8.17 - 8.25 (1H)
1H-NMR
(d6-DMSO): 0.98 - 1.18 (2H), 1.55 - 1.76 (5H), 1.99 - 2.13 (2H),
2.29 - 2.39 (5H), 3.05 - 3.15 (3H), 4.47 - 4.76 (1H), 6.77 - 6.92 (1H), 7.38 -
7.48 (2H), 7.54 - 7.62 (1H), 7.91 - 8.02 (2H), 8.17 - 8.25 (1H)
1H-NMR
(d6-DMSO): 1.06 - 1.23 (2H), 1.39 - 1.51 (1H), 1.51 - 1.70 (4H),
1.74 - 1.88 (2H), 2.30 - 2.40 (6H), 2.73 - 2.84 (2H), 3.06 - 3.14 (3H), 4.44 -
4.76 (1H), 6.76 - 6.94 (1H), 7.36 - 7.49 (2H), 7.56 - 7.62 (1H), 7.90 - 8.02
(2H), 8.17 - 8.26 (1H)
1H-NMR
(d6-DMSO): 1.02 - 1.20 (2H), 1.53 - 1.75 (7H), 2.31 - 2.39 (3H),
2.39 - 2.47 (3H), 3.04 - 3.12 (3H), 3.80 - 3.91 (2H), 4.34 - 4.76 (1H), 6.78 -
6.93 (1H), 7.37 - 7.54 (4H), 7.54 - 7.64 (1H), 7.75 - 7.84 (2H), 7.91 - 8.01
(2H), 8.14 - 8.25 (1H)
1H-NMR
(d6-DMSO): 1.00 - 1.19 (2H), 1.30 - 1.45 (1H), 1.52 - 1.77 (4H),
1.77 - 1.91 (2H), 3.09 - 3.20 (3H), 3.20 - 3.29 (2H), 4.37 - 4.51 (1H), 6.45 -
6.57 (1H), 7.06 - 7.17 (1H), 8.01 - 8.14 (1H)
1H-NMR
(d6-DMSO):
1H-NMR
(CD3OD): 1.08 - 1.31 (4H), 1.51 - 1.64 (1H), 1.93 - 2.05 (2H), 2.10
- 2.22 (2H), 2.38 - 2.50 (1H), 2.50 - 2.54 (3H), 3.48 - 3.55 (2H)
N−メチル−1−{トランス−4−[メチル(7H−ピロロ[2,3−d]ピリミジン−4−イル)アミノ]シクロヘキシル}メタンスルホンアミドの調製
1H-NMR
(d6-DMSO): 1.20 - 1.39 (2H), 1.62 - 1.75 (4H), 1.77 - 1.91 (1H),
1.97 - 2.11 (2H), 2.54 - 2.63 (3H), 2.89 - 2.99 (2H), 3.10 - 3.21 (3H), 4.44 -
4.86 (1H), 6.43 - 6.61 (1H), 7.01 - 7.19 (1H), 7.94 - 8.16 (1H)
N−メチル−1−{トランス−4−[メチル(7H−ピロロ[2,3−d]ピリミジン−4−イル)アミノ]シクロヘキシル}メタンスルホンアミドマレイン酸塩の調製
実験MH+ 338.2;予測 338.2。
1H-NMR
(d6-DMSO): 1.24 - 1.38 (2H), 1.68 - 1.92 (5H), 2.00 - 2.11 (2H),
2.56 - 2.61 (3H), 2.91 - 3.00 (2H), 3.15 - 3.27 (3H), 4.39 - 4.70 (1H), 6.53 -
6.73 (1H), 7.16 - 7.36 (1H), 8.07 - 8.29 (1H).
N−メチル−1−{トランス−4−[メチル(7H−ピロロ[2,3−d]ピリミジン−4−イル)アミノ]シクロヘキシル}−メタンスルホンアミドマレイン酸塩(A形)の粉末X線回折の採取方法
自動サンプルチェンジャー、θ−θゴニオメーター、自動ビーム発散スリット、およびPSD Vantec−1検出器を取り付けたBruker−AXS Ltd.のD4粉末X線回折計を用いて、A形、N−メチル−1−{トランス−4−[メチル(7H−ピロロ[2,3−d]ピリミジン−4−イル)アミノ]シクロヘキシル}−メタンスルホンアミドマレイン酸塩の粉末X線回折パターンを集めた。試料を、低バックグラウンドキャビティシリコンウェーハ試験片台上に載せることによって分析の準備をした。試験片を回転させ、その間、X線管を40kV/35mAで作動させながら銅K−α1X線(波長=1.5406オングストローム)を照射した。分析は、2°〜55°の2θ範囲にわたって0.018°のステップ当たり0.2秒のカウントに設定した連続モードで実行するゴニオメーターで行った。結果を表1および表2に要約して示す。
N−シクロブチル−1−{トランス−4−[メチル(7H−ピロロ[2,3−d]ピリミジン−4−イル)アミノ]シクロヘキシル}メタンスルホンアミドの調製
実験MH+ 378.0;予測 378.2
1H-NMR
(d6-DMSO): 1.22 - 1.32 (2H), 1.47 - 1.70 (6H), 1.78 - 2.04 (5H),
2.16 - 2.24 (2H), 2.85 - 2.86 (2H), 3.15 (3H).3.68 - 3.78 (1H), 4.60 - 4.72 (1H), 6.51 - 6.54 (1H), 7.11 - 7.12
(1H), 7.44 - 7.49 (1H), 8.08 (1H), 11.60 (1H)
N−エチル−1−{トランス−4−[メチル(7H−ピロロ[2,3−d]ピリミジン−4−イル)アミノ]シクロヘキシル}メタンスルホンアミドの調製
実験MH+ 352.0;予測 352.2
1H-NMR
(CDCl3): 1.24 - 1.44 (5H), 1.64 - 1.74 (2H), 1.87 - 2.09 (3H), 2.15
- 2.21 (2H), 2.97 - 2.99 (2H), 3.18 - 3.27 (5H), 4.46 - 4.52 (1H), 4.74 - 4.86
(1H), 6.55 (1H), 7.04 (1H), 8.28 (1H)
JAK酵素アッセイ
材料:組換えJAK−2(カタログ番号PV4210)およびJAK−3(カタログ番号PV3855)は(Invitrogen Corporation、米国ウィスコンシン州Madison)から購入した。この研究で使用した組換えJAK−1(GST−JAK−1(852−1142))およびTyk−2(GST−Tyk2(870−1187、C1187S))は、Pfizer Laboratoriesで発現および精製された。アデノシン5’−三リン酸(ATP)は、Sigma Chemical Company、米国ミズーリ州St.Louisから得た。JAK−2およびJAK−3アッセイに使用したJAKtideペプチド(ペプチド配列、FITC−KGGEEEEYFELVKK(配列番号:1))とJAK−1およびTyk−2アッセイに使用したIRS−1ペプチド(ペプチド配列、5−FAM−KKSRGDYMTMQIG(配列番号:2))は、(American Peptide Company、米国カリフォルニア州Sunnyvale)から購入した。コーティング試薬3は、(Caliper Life Sciences、米国マサチューセッツ州Hopkinton)から購入した。
イヌのin vitro T細胞増殖アッセイ
T細胞活性化は、種々の炎症性障害および自己免疫異常ならびに喘息、アレルギーおよびそう痒症において重要な役割を果たす。T細胞活性化は、部分的に、JAK−STAT経路を介してシグナルを送るサイトカインによって誘発できるので、JAK阻害剤は、異常なT細胞活性化を伴うかかる疾患に対して有効な可能性がある。
ノミ関連そう痒症および皮膚炎軽減アッセイ
ノミ関連そう痒症および皮膚炎は、イヌによく見られる皮膚状態である。そう痒症は、ノミ関連皮膚炎に関連する最も重篤な臨床的症状の1つであり、連続してひっかき、顔をこすり、足を噛むことは、紅斑、浮腫、脱毛症、苔癬化、および色素沈着過度などの種々の変化を皮膚にもたらし得る。ノミ関連そう痒症および皮膚炎は、実験的に誘導することができる。これらのモデルでは、炎症性細胞およびサイトカインは、アレルゲンに対する免疫反応を媒介することがわかっている。したがって、そう痒発生性および炎症誘発性サイトカイン受容体のシグナル伝達を阻害するJAK阻害剤は、ノミ関連そう痒症および皮膚炎の阻害、軽減または最小化に有効な可能性がある。
体重が5〜35kgで年齢が1歳より大きい雄および雌の雑種犬28匹に、餌を与えていない成虫のネコノミ(Ctenocephalides felis)およそ100匹を、投与を開始する14日前に寄生させ、研究の間中、4日毎にイヌ1匹当たりノミ30匹を再寄生させた。投与の7日前に、イヌ24匹を、皮膚病変に関する視覚的アナログ尺度(VAS)スコアに基づいて、無作為に3つの異なる治療グループ、偽薬、0.5mg/kgまたは0.25mg/kgの実施例1bの化合物に分けた。治療は、経口的に28日間1日2回行い、研究中、そう痒行動ならびに紅斑および皮膚病変を評価した。ビデオ記録可能な囲いの中にイヌを入れ、4時間にわたってイヌの活動を記録することによって、そう痒行動を記録した。イヌがひっかき行動に何秒費やしたかを調べることによって、そう痒活動を定量化した。腹部、鼠径部の画像キャプチャによって皮膚病変を記録し、視覚的アナログ尺度(VAS)に従って重症度のランクを付けた。
反復測定のための混合線形モデルを用いて、ビデオキャプチャしたそう痒行動の経過時間を分析した。モデルには、治療と研究日の固定効果ならびに治療と研究日の相互作用が含まれていた。変量効果には、ブロック、ブロックと治療と誤差の相互作用が含まれていた。そう痒行動(1日目)のベースラインデータを、そう痒行動の分析で共分散として使用した。最小自乗平均を、治療平均の推定値として使用した。最小自乗平均の標準誤差を推定し、90%信頼区間を作成した。対数変換後のデータに関して最小自乗平均から幾何平均をコンピューターで計算した。ア・プリオリ対比(a priori contrast)を使用して治療を評価した。治療差を10%有意水準(P≦0.10)で評価した。
治療結果を図2および図3に示す。病変および紅斑が、0.5mg/kgグループにおいて著しく軽減した。図2は、ノミアレルギーのイヌにおける実施例1bの27日目のVASスコアを示している(最小自乗平均)。10%有意水準で偽薬と比較すると、そう痒の著しい軽減が、両グループの研究中に種々の時点で見られた(0.25mg/kgの用量が1、4および12日目、0.5mg/kgの用量が1および20日目)。図3は、ノミアレルギーのイヌにおける実施例1bの記録4時間当たりのそう痒の秒数を示している(長い幾何平均)。
細胞増殖阻害アッセイ
ネコの細胞系 MYA−1およびFETJは、ATCC(米国バージニア州Manassas)から得たネコのTリンパ芽球細胞系である。これらの細胞は、37℃で5%CO2の加湿インキュベーター内において10%FBSを補充したRPMI 1640完全培地中で培養した。
ミシガン州立大学(MSU)獣医学部で獣医学スタッフによって悪性リンパ節を切除し、輸送培地(10%ウシ胎児血清(FBS)、100U/mLペニシリン、100ug/mLストレプトマイシンおよび0.25ug/mLアンホテリシンBを補充したアドバンストRPMI 1640完全培地(Invitrogen/Gibco(登録商標))中に置いた。結節を、小さい断片に刻んで組織ふるいを通すことによって24時間以内の切除にて処理した。細胞懸濁液を200xgで回転させ、上清を除去し、細胞ペレットを室温で10分間NH4Cl中に再懸濁させた。細胞懸濁液を遠心分離によってペレットにした;NH4Clを除去し、ハンクス平衡塩類溶液(HBSS)で1回洗浄し、続いて増殖培地(アドバンストRPMI完全、1%FBS、50nM 2−メルカプトエタノール、100U/mLペニシリン、100ug/mLストレプトマイシンおよび0.25ug/mLアンホテリシンB)中に再懸濁した。次いで細胞懸濁液を100μmナイロン細胞ストレーナー(BD−Falcon)に通し、血球計算盤を用いてカウントした。増殖培地単独、0.005%Pansorbin(登録商標)(熱不活性化、ホルマリン固定黄色ブドウ球菌(Staphylococcus Aureus)細胞(SAC)、Calbiochem)、および10ng/mLイヌIL−2(R&D Systems)を補充した増殖培地、または125ng/mLコンカバリンA(Sigma)および125ng/mLリポ多糖類(LPS;Calbiochem)を補充した増殖培地のいずれかの中で細胞を培養した。
上記培地中で培養した細胞を、1×103細胞/穴(ネコ細胞系)または2×105細胞/穴(リンパ節細胞)の密度で96穴コスタープレート(Corning)に播き、37℃で5%CO2の加湿インキュベーター内において最長5日間、種々の濃度の試験化合物に曝露した。増殖に対する影響を、製造業者の使用説明書に従い、CellTiter 96(登録商標)AQueous 非放射性細胞増殖アッセイ(Promega)を用いて決定した。一般に、可溶性テトラゾリウム塩(MTS)および電子結合試薬を用いて、増殖を間接的に測定した。組織培地に可溶なホルマザン生成物へのMTS生物還元を、Softmax Pro 4.6ソフトウェア(Molecular Devices)を用いてSpectramaxプレートリーダー上で490nMにおける吸光度によってモニターした。データを、GraphPad Prism 4.00を用いてパーセントDMSO対照として図示し、IC50曲線を、S字状用量応答を含む非線形回帰モデルを用いてあてはめた。
表4は、実施例1の化合物が、増殖に関してIL−2に依存しているがIL−2独立系(FETJ)には依存していないネコのリンパ細胞系MYA−1の増殖を阻害できることを示している。式IAの化合物またはその塩も、TまたはB細胞リンパ腫と診断されたイヌから得たイヌ結節組織の増殖を阻害することができる。これらの結果は、JAK阻害剤が、イヌおよびネコのリンパ腫を治療するのに有効かもしれないことを示唆している。
Claims (19)
- R1がメチルである、請求項1に記載の化合物。
- R1がエチル、またはシクロブチルである、請求項1に記載の化合物。
- N−メチル−1−{トランス−4−[メチル(7H−ピロロ[2,3−d]ピリミジン−4−イル)アミノ]シクロヘキシル}メタンスルホンアミド、またはその薬学的に許容できる塩である、請求項1に記載の化合物。
- 請求項1に記載の化合物、またはその薬学的に許容できる塩および薬学的に許容できる担体を含む医薬組成物。
- 治療有効量の請求項1に記載の化合物を、必要とする哺乳動物に投与することを含む、哺乳動物におけるアレルギー反応、アレルギー性皮膚炎、アトピー性皮膚炎、湿疹、またはそう痒症を治療するための方法。
- 前記治療有効量が、0.01mg/kg体重/日〜100mg/kg体重/日である、請求項6に記載の方法。
- 前記治療有効量が、0.1mg/kg体重/日〜10mg/kg体重/日である、請求項6に記載の方法。
- 前記哺乳動物にコンパニオンアニマルが含まれる、請求項6に記載の方法。
- 前記コンパニオンアニマルがイヌである、請求項9に記載の方法。
- 前記哺乳動物に家畜が含まれる、請求項6に記載の方法。
- 請求項1に記載の化合物を経口、非経口、または局所的に投与する、請求項6に記載の方法。
- 治療有効量の請求項1に記載の化合物を、必要とする哺乳動物に投与することを含む、哺乳動物における神経変性疾患、角結膜炎、慢性呼吸器疾患、自己免疫疾患、炎症性腸疾患、新生物および関節炎症状を治療するための方法。
- 治療有効量の請求項1に記載の化合物を、必要とする哺乳動物に投与することを含む、哺乳動物における癌、白血病、狼瘡、多発性骨髄腫を治療するための方法。
- 結晶形AのN−メチル−1−{トランス−4−[メチル(7H−ピロロ[2,3−d]ピリミジン−4−イル)アミノ]シクロヘキシル}メタンスルホンアミドマレイン酸塩。
- およそ6.2、12.6および15.7において°2θで表される少なくとも1つの特徴的なピークを有するX線粉末回折パターンを含む、請求項15に記載の結晶形AのN−メチル−1−{トランス−4−[メチル(7H−ピロロ[2,3−d]ピリミジン−4−イル)アミノ]シクロヘキシル}メタンスルホンアミドマレイン酸塩。
- およそ6.2、12.6、15.7、18.5、27および28.38において°2θで表される特徴的なピークを有するX線粉末回折パターンを含む、請求項15に記載の結晶形AのN−メチル−1−{トランス−4−[メチル(7H−ピロロ[2,3−d]ピリミジン−4−イル)アミノ]シクロヘキシル}メタンスルホンアミドマレイン酸塩。
- およそ6.178、8.519、12.601、13.819、15.478、15.719、16.32、17.997、18.539、20.298、20.659、21.583、22.642、23.08、24.86、25.602、26.582、27.02、27.721、28.161、28.38において°2θで表される特徴的なピークを有するX線粉末回折パターンを含む、請求項15に記載の結晶形AのN−メチル−1−{トランス−4−[メチル(7H−ピロロ[2,3−d]ピリミジン−4−イル)アミノ]シクロヘキシル}メタンスルホンアミドマレイン酸塩。
- N−メチル−1−{トランス−4−[メチル(7H−ピロロ[2,3−d]ピリミジン−4−イル)アミノ]シクロヘキシル}メタンスルホンアミドとマレイン酸を反応させることを含む、N−メチル−1−{トランス−4−[メチル(7H−ピロロ[2,3−d]ピリミジン−4−イル)アミノ]シクロヘキシル}メタンスルホンアミドマレイン酸塩A形を調製するための方法。
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Cited By (8)
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JP2015522603A (ja) * | 2012-07-17 | 2015-08-06 | グラクソスミスクライン、インテレクチュアル、プロパティー、ナンバー2、リミテッドGlaxosmithkline Intellectual Property No.2 Limited | 選択的アンドロゲン受容体調節剤としてのインドールカルボニトリル類 |
JP2015522620A (ja) * | 2012-07-20 | 2015-08-06 | ゾエティス・エルエルシー | ヤヌスキナーゼ(jak)阻害剤の投与計画 |
JP2016509049A (ja) * | 2013-02-22 | 2016-03-24 | ファイザー・インク | ヤヌス関連キナーゼ(JAK)の阻害剤としてのピロロ[2,3−d]ピリミジン誘導体 |
JP2017165762A (ja) * | 2013-02-22 | 2017-09-21 | ファイザー・インク | ヤヌス関連キナーゼ(JAK)の阻害剤としてのピロロ[2,3−d]ピリミジン誘導体 |
JP2019505547A (ja) * | 2016-02-16 | 2019-02-28 | ゾエティス・サービシーズ・エルエルシー | 7H−ピロロ[2,3−d]ピリミジン化合物の調製方法 |
JP2022518821A (ja) * | 2019-01-30 | 2022-03-16 | 格格巫(珠海)生物科技有限公司 | Jak阻害剤及びその製造方法 |
JP7278649B2 (ja) | 2019-01-30 | 2023-05-22 | 格格巫(珠海)生物科技有限公司 | Jak阻害剤及びその製造方法 |
JP7278649B6 (ja) | 2019-01-30 | 2024-02-15 | 格格巫(珠海)生物科技有限公司 | Jak阻害剤及びその製造方法 |
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