JP2009533343A - ヒスタミンh4受容体のモジュレーターとしてのインドールおよびベンゾイミダゾール - Google Patents
ヒスタミンh4受容体のモジュレーターとしてのインドールおよびベンゾイミダゾール Download PDFInfo
- Publication number
- JP2009533343A JP2009533343A JP2009504253A JP2009504253A JP2009533343A JP 2009533343 A JP2009533343 A JP 2009533343A JP 2009504253 A JP2009504253 A JP 2009504253A JP 2009504253 A JP2009504253 A JP 2009504253A JP 2009533343 A JP2009533343 A JP 2009533343A
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- JP
- Japan
- Prior art keywords
- methanone
- indol
- pyrrolidin
- methylamino
- methyl
- 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.)
- Granted
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- SIKJAQJRHWYJAI-UHFFFAOYSA-N Indole Chemical compound C1=CC=C2NC=CC2=C1 SIKJAQJRHWYJAI-UHFFFAOYSA-N 0.000 title description 8
- PZOUSPYUWWUPPK-UHFFFAOYSA-N indole Natural products CC1=CC=CC2=C1C=CN2 PZOUSPYUWWUPPK-UHFFFAOYSA-N 0.000 title description 4
- RKJUIXBNRJVNHR-UHFFFAOYSA-N indolenine Natural products C1=CC=C2CC=NC2=C1 RKJUIXBNRJVNHR-UHFFFAOYSA-N 0.000 title description 4
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- AEPVGIPVZCQCFW-GFCCVEGCSA-N [(3r)-3-(methylamino)pyrrolidin-1-yl]-(7-methyl-1h-indol-2-yl)methanone Chemical compound C1[C@H](NC)CCN1C(=O)C1=CC2=CC=CC(C)=C2N1 AEPVGIPVZCQCFW-GFCCVEGCSA-N 0.000 claims description 5
- DOCRCNTVCILACW-LBPRGKRZSA-N [(3s)-3-(methylamino)pyrrolidin-1-yl]-(5-methyl-1h-indol-2-yl)methanone Chemical compound C1[C@@H](NC)CCN1C(=O)C1=CC2=CC(C)=CC=C2N1 DOCRCNTVCILACW-LBPRGKRZSA-N 0.000 claims description 5
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- C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings
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Abstract
Description
で処置すると細胞表面に発現する接着分子CD11b/CD18(LFA−1)およびCD54(ICAM−1)の量が増加する(非特許文献10)。そのような増加はH4受容体の拮抗薬によって阻止されるが、H1受容体拮抗薬によってもH2受容体拮抗薬によってもH3受容体拮抗薬によっても阻止されない。
ここに、特定のインドールおよびベンゾイミダゾール誘導体がヒスタミンH4受容体をモジュレートする活性を有することを見いだした。
AはCHまたはNであり;
各R1は独立してCl、Br、メチル、エチル、NO2またはCF3であり;
mは0、1または2であり;
R2はHであり;
R3はH、メチルまたはエチルであり;そして
1)R4がH、メチルまたはエチルであり;R5およびR6の中の一方がH、メチルまたはエチルでありそしてもう一方がHであるか;或は
2)R4とR5が一緒になって−(CH2)3−を形成しており;そしてR6がHであるか;或は
3)R4とR6が一緒になって−CH2−を形成しており;そしてR5がHである]
で表される化合物に関する。
以下に行う用語解説および最後の実施例を包含する以下の説明を参照することで本発明をより詳細に理解することができるであろう。簡潔さの目的で、本明細書に示す特許を包含する出版物の開示は引用することによって本明細書に組み入れられる。
を指す。典型的なアルキル基にはメチル(Me、これをまた構造的に記号“/”で表すこともあり得る)、エチル(Et)、n−プロピル、イソプロピル、ブチル、イソブチル、s−ブチル、t−ブチル(tBu)、ペンチル、イソペンチル、t−ペンチル、ヘキシル、イソヘキシルおよび当技術分野の通常の技術および本明細書に示す教示に照らしてこの上に示した例のいずれか1つに相当すると見なされるであろう基が含まれる。
き形態も表すことを意図する。同位体標識付き化合物は、1個以上の原子が選択した原子質量もしくは質量数を有する原子に置き換わっている以外は本明細書に示す式で表される構造を有する。本発明の化合物に取り込ませることができる同位体の例には、水素、炭素、窒素、酸素、燐、フッ素、塩素およびヨウ素の同位体、例えばそれぞれ2H、3H、11C、13C、14C、15N、18O、17O、31P、32P、35S、18F、36Cl、125Iなどが含まれる。そのような同位体標識付き化合物は代謝検定(好適には14Cを用いた)、反応速度検定(例えば2Hまたは3Hを用いた)、検出もしくは造影技術[例えば陽電子放出断層撮影(PET)または単光子放出コンピュータ断層撮影(SPECT)](薬剤または基質組織分布検定を包含)または患者の放射線治療で用いるに有用である。特に、18Fまたは11C標識付き化合物がPETまたはSPECT検定に特に好適であり得る。更に、重質同位体、例えば重水素(即ち2H)などによる置換を行うと代謝安定性がより高くなる、例えば生体内半減期が長くなるか或は必要な投薬量が少なくなることなどで結果として特定の治療的利点が得られる可能性もある。本発明の同位体標識付き化合物およびこれらのプロドラッグの調製は、一般に、容易に入手可能な同位体標識付き反応体を同位体標識が付いていない反応体の代わりに用いて本スキームまたは本実施例に開示する手順および以下に記述する調製を行うことで実施可能である。
がR1−6、Aおよびmおよび本明細書で用いる他のいずれかの一般的置換基記号などの如き員に適用可能な場合、それらにも拡大適用する。
も包含する。
どから生じさせた有機塩、およびナトリウム、カルシウム、カリウム、マグネシウム、マンガン、鉄、銅、亜鉛、アルミニウムおよびリチウムから生じさせた無機塩が含まれる。
効な代謝産物の測定は当技術分野で公知または利用可能な常規技術を用いて実施可能である。例えばBertolini他、J.Med.Chem.1997、40、2011−2016;Shan他、J.Pharm.Sci.1997、86(7)、765−767;Bagshawe、Drug Dev.Res.1995、34、220−230;Bodor、Adv.Drug Res.1984、13、224−331;Bundgaard、Design of Prodrugs(Elsevier Press、1985);およびLarsen、Design and Application of
Prodrugs、Drug Design and Development(Krogsgaard−Larsen他編集、Harwood Academic Publishers、1991)を参照のこと。
する目的で投与する。
学的に許容される賦形剤、例えば懸濁剤(例えばソルビトール、メチルセルロース、アルギン酸ナトリウム、ゼラチン、ヒドロキシエチルセルロース、カルボキシメチルセルロース、ステアリン酸アルミニウムゲルなど);非水性媒体、例えば油(例えばアーモンド油または分別ヤシ油)、プロピレングリコール、エチルアルコールまたは水;防腐剤(例えばp−ヒドロキシ安息香酸メチルまたはプロピルまたはソルビン酸);湿潤剤、例えばレシチンなど;および必要ならば香味または着色剤を含有させてもよい。
、酸(V)に活性化を混合無水物もしくは酸クロライドとして受けさせた後、アミン(VI)とのカップリングを適切な塩基、例えばトリエチルアミン(TEA)、iPr2NEt、ピリジン、イミダゾールなどの存在下で起こさせる。適切なアミノ保護基をR3および/またはR4の代わりに用いてもよくそしてそれをカップリング後に除去してもよい。
化学:
以下の実施例に記述する化合物および相当する分析データを得ようとする時、特に明記しない限り、以下の実験および分析プロトコルに従った。
gilentシリーズ1100MSDを特に明記しない限り正モードで用いることで得た。計算した質量は正確な質量に相当する。
、7.01−6.97(m、1H)、5.49(s、1H)、5.41−5.02(m、1H)、4.58(s、1H)、4.28−3.39(m、4H)、3.33−3.29(m、1H)、2.32−2.21(m、1H)、2.13−2.04(m、1H).
)させた後、濃縮した。その残留物をFCCで精製することで表題の化合物(565mg、69%)を得た。 MS(ESI):下記として計算した質量:C19H25N3O3、343.19;m/z 測定値:344[M+H]+.1H NMR(CDCl3:9.73(s、1H)、7.67(d、J=8.0、1H)、7.46(dd、J=8.3、0.8、1H)、7.29(t、J=8.2、1H)、6.89(d、J=1.3、1H)、4.89(br s、1H)、4.26−3.49(m、4H)、2.85(s、3H)、2.36−1.96(m、2H)、1.76(s、1H)、1.49(s、9H).下記として計算した分析値:C19H25N3O3:C、66.45;H、7.34;N、12.24.測定値:C、66.42;H、7.55;N、12.10.
3H)、2.67−2.08(m、2H).
MS(ESI):下記として計算した質量:C16H18ClN3O、303.11;m/z 測定値:304.4[M+H]+.1H NMR(回転異性体の混合物;DMSO):7.68−7.59(m、1H)、7.47−7.41(m、1H)、7.24−7.17(m、1H)、7.07(s、0.5H)、6.96(s、0.5H)、4.34−4.23(m、0.5H)、4.21−4.11(m、1H)、4.05−3.83(m、3H)、3.72−3.61(m、0.5H)、3.41−3.33(m、1H)
、3.25−3.15(m、0.6H)、3.13−2.98(m、1.4H)、2.96−2.76(m、1H)、2.00−1.76(m、4H).
MS(ESI):下記として計算した質量:C16H18ClN3O、303.11;m/z 測定値:304.4[M+H]+.1H NMR(回転異性体の混合物;DMSO):7.68−7.59(m、1H)、7.47−7.41(m、1H)、7.24−7.17(m、1H)、7.07(s、0.5H)、6.96(s、0.5H)、4.34−4.23(m、0.5H)、4.21−4.11(m、1H)、4.05−3.83(m、3H)、3.72−3.61(m、0.5H)、3.41−3.33(m、1H)、3.25−3.15(m、0.6H)、3.13−2.98(m、1.4H)、2.96−2.76(m、1H)、2.00−1.76(m、4H).
表題の化合物の調製を市販の(S,S)−オクタヒドロ−ピロロ[3,4−b]ピリジン(Haorui Pharma−Chem、Inc.、Batch #050312、95%ee)を用いて実施例6に記述したようにして実施した。
17(m、1H)、2.46−2.31(m、6H)、2.25−2.04(m、1H)、1.97−1.84(m、0.5H)、1.83−1.71(m、0.5H).
.
−b]ピリジン−6−イル)−メタノンの塩酸塩.
95−1.80(m、1H).
組換え型ヒトヒスタミンH 4 受容体を用いた結合検定
SK−N−MC細胞またはCOS7細胞にpH4Rを用いた一過性トランスフェクションを受けさせた後、それを150cm2の組織培養皿内で増殖させた。細胞を生理的食塩水溶液で洗浄し、細胞掻器で掻き落とした後、遠心分離(1000rpm、5分)で集めた。その細胞沈澱物を20mMのTris−HClに入れてポリトロン組織ホモジナイザー(polytron tissue homogenizer)を高速で用いて10秒間均一にすることで細胞膜を調製した。ホモジネートを1000rpmの遠心分離に4℃で5分間かけた。次に、その上澄み液を集めた後、20,000 x gの遠心分離に4℃で25分間かけた。最終的な沈澱物を50mMのTris−HClに入れて再び懸濁させた。細胞膜を3H−ヒスタミン(5−70nM)と一緒に過剰量のヒスタミン(10,000nM)の存在有り無しでインキュベートした。インキュベーションを室温で45分間実施した。膜をWhatman GF/Cフィルターを用いた迅速濾過により得た後、氷で冷却しておいた50mMのTris HClで4回洗浄した。次に、フィルターを乾燥させ、シンチラント(scintillant)と混合した後、放射能の計数を実施した。ヒトヒスタミンH4受容体を発現するSK−N−MCまたはCOS7細胞を用いて、上述した反応物をいろいろな濃度の阻害剤または試験すべき化合物の存在下でインキュベートすることを通して、他の化合物が示す結合親和性および結合している3H−リガンドを追い出す能力を測定した。3H−ヒスタミンを用いた競合結合検定では、Ki値の計算を実験的に測定した5nMのKD値および5nMのリガンド濃度を基にしてY.−C.ChengおよびW.H.Prusoff(Biochem.Pharmacol.1973、22(23):3099−3108):Ki=(IC50)/(1+([L]/(KD))に従うことで行った。この検定試験を受けさせた化合物が示した結果を得た結果の平均(平均値)として表1に示す。活性が特定の値より大きい(>)として示す場合、その値は当該化合物が検定用培地中で示す溶解度限界またはこの検定で試験を実施した最大濃度である。
Claims (26)
- 式(I):
AはCHまたはNであり;
各R1は独立してCl、Br、メチル、エチル、NO2またはCF3であり;
mは0、1または2であり;
R2はHであり;
R3はH、メチルまたはエチルであり;そして
1)R4がH、メチルまたはエチルであり;R5およびR6の中の一方がH、メチルまたはエチルでありそしてもう一方がHであるか;或は
2)R4とR5が一緒になって−(CH2)3−を形成しており;そしてR6がHであるか;或は
3)R4とR6が一緒になって−CH2−を形成しており;そしてR5がHである]
で表される化合物、式(I)で表される化合物の製薬学的に許容される塩、式(I)で表される化合物の製薬学的に許容されるプロドラッグまたは式(I)で表される化合物の製薬学的に活性な代謝産物である化学物質。 - AがCHである請求項1記載の化学物質。
- AがNである請求項1記載の化学物質。
- R1がClである請求項1記載の化学物質。
- mが0または1である請求項1記載の化学物質。
- R3がHまたはメチルである請求項1記載の化学物質。
- R4がメチルであり、R5がHでありそしてR6がHである請求項1記載の化学物質。
- R4とR5が一緒になって−(CH2)3−を形成しておりそしてR6がHである請求項1記載の化学物質。
- R4とR6が一緒になって−CH2−を形成しておりそしてR5がHである請求項1記載の化学物質。
- 下記:
(S,S)−(2,5−ジアザ−ビシクロ[2.2.1]ヘプト−2−イル)−(1H−インドール−2−イル)−メタノン;
(S,S)−(1H−インドール−2−イル)−(5−メチル−2,5−ジアザ−ビシクロ[2.2.1]ヘプト−2−イル)−メタノン;
(1H−インドール−2−イル)−(3−メチルアミノ−ピロリジン−1−イル)−メタノン;
(R)−(1H−インドール−2−イル)−(3−メチルアミノ−ピロリジン−1−イル)−メタノン;
シス−(1H−インドール−2−イル)−(オクタヒドロ−ピロロ[3,4−b]ピリジン−6−イル)−メタノン;
(S,S)−(1H−インドール−2−イル)−(オクタヒドロ−ピロロ[3,4−b]ピリジン−6−イル)−メタノン;
シス−(5−クロロ−1H−ベンゾイミダゾール−2−イル)−(オクタヒドロ−ピロロ[3,4−b]ピリジン−6−イル)−メタノン;
(R)−(5−クロロ−1H−インドール−2−イル)−(3−メチルアミノ−ピロリジン−1−イル)−メタノン;
(S)−(5−クロロ−1H−インドール−2−イル)−(3−メチルアミノ−ピロリジン−1−イル)−メタノン;
シス−(5−クロロ−1H−インドール−2−イル)−(オクタヒドロ−ピロロ[3,4−b]ピリジン−6−イル)−メタノン;
(R,R)−(5−クロロ−1H−インドール−2−イル)−(オクタヒドロ−ピロロ[3,4−b]ピリジン−6−イル)−メタノン;
(S,S)−(5−クロロ−1H−インドール−2−イル)−(オクタヒドロ−ピロロ[3,4−b]ピリジン−6−イル)−メタノン;
シス−(5−フルオロ−1H−インドール−2−イル)−(オクタヒドロ−ピロロ[3,4−b]ピリジン−6−イル)−メタノン;
シス−(7−ニトロ−1H−インドール−2−イル)−(オクタヒドロ−ピロロ[3,4−b]ピリジン−6−イル)−メタノン;
シス−(4,6−ジフルオロ−1H−インドール−2−イル)−(オクタヒドロ−ピロロ[3,4−b]ピリジン−6−イル)−メタノン;
(S)−(5−フルオロ−1H−インドール−2−イル)−(3−メチルアミノ−ピロリジン−1−イル)−メタノン;
(R)−(5−フルオロ−1H−インドール−2−イル)−(3−メチルアミノ−ピロリジン−1−イル)−メタノン;
(S)−(3−メチルアミノ−ピロリジン−1−イル)−(7−メチル−1H−インドール−2−イル)−メタノン;
(R)−(3−メチルアミノ−ピロリジン−1−イル)−(7−メチル−1H−インドール−2−イル)−メタノン;
(S)−(3−メチルアミノ−ピロリジン−1−イル)−(5−メチル−1H−インドール−2−イル)−メタノン;
(R)−(3−メチルアミノ−ピロリジン−1−イル)−(5−メチル−1H−インドール−2−イル)−メタノン;
(S)−(4,6−ジフルオロ−1H−インドール−2−イル)−(3−メチルアミノ−ピロリジン−1−イル)−メタノン;
(R)−(4,6−ジフルオロ−1H−インドール−2−イル)−(3−メチルアミノ−ピロリジン−1−イル)−メタノン;
(3−アミノ−ピロリジン−1−イル)−(5−クロロ−1H−インドール−2−イル)−メタノン;
(5−クロロ−1H−インドール−2−イル)−(3−ジメチルアミノ−ピロリジン−1−イル)−メタノン;
(3−ジメチルアミノ−ピロリジン−1−イル)−(1H−インドール−2−イル)−メタノン;
シス−(1H−インドール−2−イル)−(1−メチル−オクタヒドロ−ピロロ[3,4−b]ピリジン−6−イル)−メタノン;
シス−(5−クロロ−1H−インドール−2−イル)−(1−メチル−オクタヒドロ−ピロロ[3,4−b]ピリジン−6−イル)−メタノン;
シス−(5−メチル−1H−インドール−2−イル)−(オクタヒドロ−ピロロ[3,4−b]ピリジン−6−イル)−メタノン;
(1H−ベンゾイミダゾール−2−イル)−(3−メチルアミノ−ピロリジン−1−イル)−メタノン;
(1H−ベンゾイミダゾール−2−イル)−(3−ジメチルアミノ−ピロリジン−1−イル)−メタノン;および
これらの製薬学的に許容される塩、
から選択される化学物質。 - 式(I)で表される化合物または前記式(I)で表される化合物の製薬学的に許容される塩である請求項1記載の化学物質。
- 式(II)で表される化合物または前記式(II)で表される化合物の製薬学的に許容される塩である請求項10記載の化学物質。
- ヒスタミンH4受容体の活性が媒介する病気、障害または病状を治療するための製薬学的組成物であって、式(I);
AはCHまたはNであり;
各R1は独立してCl、Br、メチル、エチル、NO2またはCF3であり;
mは0、1または2であり;
R2はHであり;
R3はH、メチルまたはエチルであり;そして
1)R4がH、メチルまたはエチルであり;R5およびR6の中の一方がH、メチルまたはエチルでありそしてもう一方がHであるか;或は
2)R4とR5が一緒になって−(CH2)3−を形成しており;そしてR6がHであるか;或は
3)R4とR6が一緒になって−CH2−を形成しており;そしてR5がHである]
で表される化合物、式(I)で表される化合物の製薬学的に許容される塩、式(I)で表される化合物の製薬学的に許容されるプロドラッグおよび式(I)で表される化合物の製薬学的に活性な代謝産物から選択される少なくとも1種の薬剤を有効な量で含有して成る製薬学的組成物。 - 前記式(I)が式(II)である請求項14記載の製薬学的組成物。
- 前記薬剤が下記:
(S,S)−(2,5−ジアザ−ビシクロ[2.2.1]ヘプト−2−イル)−(1H−インドール−2−イル)−メタノン;
(S,S)−(1H−インドール−2−イル)−(5−メチル−2,5−ジアザ−ビシクロ[2.2.1]ヘプト−2−イル)−メタノン;
(1H−インドール−2−イル)−(3−メチルアミノ−ピロリジン−1−イル)−メタノン;
(R)−(1H−インドール−2−イル)−(3−メチルアミノ−ピロリジン−1−イル)−メタノン;
シス−(1H−インドール−2−イル)−(オクタヒドロ−ピロロ[3,4−b]ピリジン−6−イル)−メタノン;
(S,S)−(1H−インドール−2−イル)−(オクタヒドロ−ピロロ[3,4−b]ピリジン−6−イル)−メタノン;
シス−(5−クロロ−1H−ベンゾイミダゾール−2−イル)−(オクタヒドロ−ピロロ[3,4−b]ピリジン−6−イル)−メタノン;
(R)−(5−クロロ−1H−インドール−2−イル)−(3−メチルアミノ−ピロリジン−1−イル)−メタノン;
(S)−(5−クロロ−1H−インドール−2−イル)−(3−メチルアミノ−ピロリジン−1−イル)−メタノン;
シス−(5−クロロ−1H−インドール−2−イル)−(オクタヒドロ−ピロロ[3,4−b]ピリジン−6−イル)−メタノン;
(R,R)−(5−クロロ−1H−インドール−2−イル)−(オクタヒドロ−ピロロ[3,4−b]ピリジン−6−イル)−メタノン;
(S,S)−(5−クロロ−1H−インドール−2−イル)−(オクタヒドロ−ピロロ[3,4−b]ピリジン−6−イル)−メタノン;
シス−(5−フルオロ−1H−インドール−2−イル)−(オクタヒドロ−ピロロ[3,4−b]ピリジン−6−イル)−メタノン;
シス−(7−ニトロ−1H−インドール−2−イル)−(オクタヒドロ−ピロロ[3,4−b]ピリジン−6−イル)−メタノン;
シス−(4,6−ジフルオロ−1H−インドール−2−イル)−(オクタヒドロ−ピロロ[3,4−b]ピリジン−6−イル)−メタノン;
(S)−(5−フルオロ−1H−インドール−2−イル)−(3−メチルアミノ−ピロリジン−1−イル)−メタノン;
(R)−(5−フルオロ−1H−インドール−2−イル)−(3−メチルアミノ−ピロリジン−1−イル)−メタノン;
(S)−(3−メチルアミノ−ピロリジン−1−イル)−(7−メチル−1H−インドール−2−イル)−メタノン;
(R)−(3−メチルアミノ−ピロリジン−1−イル)−(7−メチル−1H−インドール−2−イル)−メタノン;
(S)−(3−メチルアミノ−ピロリジン−1−イル)−(5−メチル−1H−インドール−2−イル)−メタノン;
(R)−(3−メチルアミノ−ピロリジン−1−イル)−(5−メチル−1H−インドー
ル−2−イル)−メタノン;
(S)−(4,6−ジフルオロ−1H−インドール−2−イル)−(3−メチルアミノ−ピロリジン−1−イル)−メタノン;
(R)−(4,6−ジフルオロ−1H−インドール−2−イル)−(3−メチルアミノ−ピロリジン−1−イル)−メタノン;
(3−アミノ−ピロリジン−1−イル)−(5−クロロ−1H−インドール−2−イル)−メタノン;
(5−クロロ−1H−インドール−2−イル)−(3−ジメチルアミノ−ピロリジン−1−イル)−メタノン;
(3−ジメチルアミノ−ピロリジン−1−イル)−(1H−インドール−2−イル)−メタノン;
シス−(1H−インドール−2−イル)−(1−メチル−オクタヒドロ−ピロロ[3,4−b]ピリジン−6−イル)−メタノン;
シス−(5−クロロ−1H−インドール−2−イル)−(1−メチル−オクタヒドロ−ピロロ[3,4−b]ピリジン−6−イル)−メタノン;
シス−(5−メチル−1H−インドール−2−イル)−(オクタヒドロ−ピロロ[3,4−b]ピリジン−6−イル)−メタノン;
(1H−ベンゾイミダゾール−2−イル)−(3−メチルアミノ−ピロリジン−1−イル)−メタノン;
(1H−ベンゾイミダゾール−2−イル)−(3−ジメチルアミノ−ピロリジン−1−イル)−メタノン;および
これらの製薬学的に許容される塩、
から選択される請求項14記載の製薬学的組成物。 - ヒスタミンH4受容体の活性が媒介する病気、障害または病状に苦しんでいるか或はそうであると診断された被験体を治療する方法であって、前記治療を必要としている被験体に式(I):
AはCHまたはNであり;
各R1は独立してCl、Br、メチル、エチル、NO2またはCF3であり;
mは0、1または2であり;
R2はHであり;
R3はH、メチルまたはエチルであり;そして
1)R4がH、メチルまたはエチルであり;R5およびR6の中の一方がH、メチルまたはエチルでありそしてもう一方がHであるか;或は
2)R4とR5が一緒になって−(CH2)3−を形成しており;そしてR6がHであるか;或は
3)R4とR6が一緒になって−CH2−を形成しており;そしてR5がHである]
で表される化合物、式(I)で表される化合物の製薬学的に許容される塩、式(I)で表される化合物の製薬学的に許容されるプロドラッグおよび式(I)で表される化合物の製薬学的に活性な代謝産物から選択した少なくとも1種の薬剤を有効な量で投与することを含んで成る方法。 - 前記式(I)が式(II)である請求項17記載の方法。
- 前記薬剤を下記:
(S,S)−(2,5−ジアザ−ビシクロ[2.2.1]ヘプト−2−イル)−(1H−インドール−2−イル)−メタノン;
(S,S)−(1H−インドール−2−イル)−(5−メチル−2,5−ジアザ−ビシクロ[2.2.1]ヘプト−2−イル)−メタノン;
(1H−インドール−2−イル)−(3−メチルアミノ−ピロリジン−1−イル)−メタノン;
(R)−(1H−インドール−2−イル)−(3−メチルアミノ−ピロリジン−1−イル)−メタノン;
シス−(1H−インドール−2−イル)−(オクタヒドロ−ピロロ[3,4−b]ピリジン−6−イル)−メタノン;
(S,S)−(1H−インドール−2−イル)−(オクタヒドロ−ピロロ[3,4−b]ピリジン−6−イル)−メタノン;
シス−(5−クロロ−1H−ベンゾイミダゾール−2−イル)−(オクタヒドロ−ピロロ[3,4−b]ピリジン−6−イル)−メタノン;
(R)−(5−クロロ−1H−インドール−2−イル)−(3−メチルアミノ−ピロリジン−1−イル)−メタノン;
(S)−(5−クロロ−1H−インドール−2−イル)−(3−メチルアミノ−ピロリジン−1−イル)−メタノン;
シス−(5−クロロ−1H−インドール−2−イル)−(オクタヒドロ−ピロロ[3,4−b]ピリジン−6−イル)−メタノン;
(R,R)−(5−クロロ−1H−インドール−2−イル)−(オクタヒドロ−ピロロ[3,4−b]ピリジン−6−イル)−メタノン;
(S,S)−(5−クロロ−1H−インドール−2−イル)−(オクタヒドロ−ピロロ[3,4−b]ピリジン−6−イル)−メタノン;
シス−(5−フルオロ−1H−インドール−2−イル)−(オクタヒドロ−ピロロ[3,4−b]ピリジン−6−イル)−メタノン;
シス−(7−ニトロ−1H−インドール−2−イル)−(オクタヒドロ−ピロロ[3,4−b]ピリジン−6−イル)−メタノン;
シス−(4,6−ジフルオロ−1H−インドール−2−イル)−(オクタヒドロ−ピロロ[3,4−b]ピリジン−6−イル)−メタノン;
(S)−(5−フルオロ−1H−インドール−2−イル)−(3−メチルアミノ−ピロリジン−1−イル)−メタノン;
(R)−(5−フルオロ−1H−インドール−2−イル)−(3−メチルアミノ−ピロリジン−1−イル)−メタノン;
(S)−(3−メチルアミノ−ピロリジン−1−イル)−(7−メチル−1H−インドール−2−イル)−メタノン;
(R)−(3−メチルアミノ−ピロリジン−1−イル)−(7−メチル−1H−インドール−2−イル)−メタノン;
(S)−(3−メチルアミノ−ピロリジン−1−イル)−(5−メチル−1H−インドール−2−イル)−メタノン;
(R)−(3−メチルアミノ−ピロリジン−1−イル)−(5−メチル−1H−インドール−2−イル)−メタノン;
(S)−(4,6−ジフルオロ−1H−インドール−2−イル)−(3−メチルアミノ−ピロリジン−1−イル)−メタノン;
(R)−(4,6−ジフルオロ−1H−インドール−2−イル)−(3−メチルアミノ−ピロリジン−1−イル)−メタノン;
(3−アミノ−ピロリジン−1−イル)−(5−クロロ−1H−インドール−2−イル)
−メタノン;
(5−クロロ−1H−インドール−2−イル)−(3−ジメチルアミノ−ピロリジン−1−イル)−メタノン;
(3−ジメチルアミノ−ピロリジン−1−イル)−(1H−インドール−2−イル)−メタノン;
シス−(1H−インドール−2−イル)−(1−メチル−オクタヒドロ−ピロロ[3,4−b]ピリジン−6−イル)−メタノン;
シス−(5−クロロ−1H−インドール−2−イル)−(1−メチル−オクタヒドロ−ピロロ[3,4−b]ピリジン−6−イル)−メタノン;
シス−(5−メチル−1H−インドール−2−イル)−(オクタヒドロ−ピロロ[3,4−b]ピリジン−6−イル)−メタノン;
(1H−ベンゾイミダゾール−2−イル)−(3−メチルアミノ−ピロリジン−1−イル)−メタノン;
(1H−ベンゾイミダゾール−2−イル)−(3−ジメチルアミノ−ピロリジン−1−イル)−メタノン;および
これらの製薬学的に許容される塩、
から選択する請求項17記載の方法。 - 前記病気、障害または病状が炎症である請求項17記載の方法。
- 前記病気、障害または病状が炎症性疾患、アレルギー性疾患、皮膚疾患、自己免疫病、リンパ系疾患および免疫不全疾患から成る群より選択される請求項17記載の方法。
- 前記病気、障害または病状がアレルギー、喘息、慢性閉塞性肺疾患(COPD)、アテローム性動脈硬化症、関節リウマチ、多発性硬化症、炎症性腸疾患、大腸炎、クローン病、潰瘍性大腸炎、乾癬、掻痒、皮膚の痒み、アトピー性皮膚炎、皮膚の掻痒、蕁麻疹、眼の炎症、結膜炎、鼻ポリープ、アレルギー性鼻炎、鼻の痒み、強皮症、自己免疫性甲状腺疾患、免疫介在性糖尿病、狼瘡、重症筋無力症、自己免疫性神経障害、ギラン・バレー、自己免疫性ブドウ膜炎、自己免疫性溶血性貧血、悪性貧血、自己免疫性血小板減少症、側頭動脈炎、抗リン脂質症候群、血管炎、ヴェーゲナー肉芽腫症、ベーチェット病、疱疹状皮膚炎、尋常性天疱瘡、白斑、原発性胆汁性肝硬変、自己免疫性肝炎、自己免疫性卵巣炎、自己免疫性精巣炎、副腎の自己免疫病、多発性筋炎、皮膚筋炎、脊椎関節症、強直性脊椎炎およびシェーグレン症候群から選択される請求項17記載の方法。
- 前記病気、障害または病状がアレルギー、喘息、自己免疫病および掻痒から選択される請求項17記載の方法。
- ヒスタミンH4受容体の活性をモジュレートする方法であって、ヒスタミンH4受容体を、有効な量の式(I):
AはCHまたはNであり;
各R1は独立してCl、Br、メチル、エチル、NO2またはCF3であり;
mは0、1または2であり;
R2はHであり;
R3はH、メチルまたはエチルであり;そして
1)R4がH、メチルまたはエチルであり;R5およびR6の中の一方がH、メチルまたはエチルでありそしてもう一方がHであるか;或は
2)R4とR5が一緒になって−(CH2)3−を形成しており;そしてR6がHであるか;或は
3)R4とR6が一緒になって−CH2−を形成しており;そしてR5がHである]
で表される化合物および式(I)で表される化合物の塩から選択した少なくとも1種の薬剤と接触させることを含んで成る方法。 - 前記式(I)が式(II)である請求項24記載の方法。
- 前記少なくとも1種の薬剤が下記:
(S,S)−(2,5−ジアザ−ビシクロ[2.2.1]ヘプト−2−イル)−(1H−インドール−2−イル)−メタノン;
(S,S)−(1H−インドール−2−イル)−(5−メチル−2,5−ジアザ−ビシクロ[2.2.1]ヘプト−2−イル)−メタノン;
(1H−インドール−2−イル)−(3−メチルアミノ−ピロリジン−1−イル)−メタノン;
(R)−(1H−インドール−2−イル)−(3−メチルアミノ−ピロリジン−1−イル)−メタノン;
シス−(1H−インドール−2−イル)−(オクタヒドロ−ピロロ[3,4−b]ピリジン−6−イル)−メタノン;
(S,S)−(1H−インドール−2−イル)−(オクタヒドロ−ピロロ[3,4−b]ピリジン−6−イル)−メタノン;
シス−(5−クロロ−1H−ベンゾイミダゾール−2−イル)−(オクタヒドロ−ピロロ[3,4−b]ピリジン−6−イル)−メタノン;
(R)−(5−クロロ−1H−インドール−2−イル)−(3−メチルアミノ−ピロリジン−1−イル)−メタノン;
(S)−(5−クロロ−1H−インドール−2−イル)−(3−メチルアミノ−ピロリジン−1−イル)−メタノン;
シス−(5−クロロ−1H−インドール−2−イル)−(オクタヒドロ−ピロロ[3,4−b]ピリジン−6−イル)−メタノン;
(R,R)−(5−クロロ−1H−インドール−2−イル)−(オクタヒドロ−ピロロ[3,4−b]ピリジン−6−イル)−メタノン;
(S,S)−(5−クロロ−1H−インドール−2−イル)−(オクタヒドロ−ピロロ[3,4−b]ピリジン−6−イル)−メタノン;
シス−(5−フルオロ−1H−インドール−2−イル)−(オクタヒドロ−ピロロ[3,4−b]ピリジン−6−イル)−メタノン;
シス−(7−ニトロ−1H−インドール−2−イル)−(オクタヒドロ−ピロロ[3,4−b]ピリジン−6−イル)−メタノン;
シス−(4,6−ジフルオロ−1H−インドール−2−イル)−(オクタヒドロ−ピロロ[3,4−b]ピリジン−6−イル)−メタノン;
(S)−(5−フルオロ−1H−インドール−2−イル)−(3−メチルアミノ−ピロリジン−1−イル)−メタノン;
(R)−(5−フルオロ−1H−インドール−2−イル)−(3−メチルアミノ−ピロリジン−1−イル)−メタノン;
(S)−(3−メチルアミノ−ピロリジン−1−イル)−(7−メチル−1H−インドール−2−イル)−メタノン;
(R)−(3−メチルアミノ−ピロリジン−1−イル)−(7−メチル−1H−インドー
ル−2−イル)−メタノン;
(S)−(3−メチルアミノ−ピロリジン−1−イル)−(5−メチル−1H−インドール−2−イル)−メタノン;
(R)−(3−メチルアミノ−ピロリジン−1−イル)−(5−メチル−1H−インドール−2−イル)−メタノン;
(S)−(4,6−ジフルオロ−1H−インドール−2−イル)−(3−メチルアミノ−ピロリジン−1−イル)−メタノン;
(R)−(4,6−ジフルオロ−1H−インドール−2−イル)−(3−メチルアミノ−ピロリジン−1−イル)−メタノン;
(3−アミノ−ピロリジン−1−イル)−(5−クロロ−1H−インドール−2−イル)−メタノン;
(5−クロロ−1H−インドール−2−イル)−(3−ジメチルアミノ−ピロリジン−1−イル)−メタノン;
(3−ジメチルアミノ−ピロリジン−1−イル)−(1H−インドール−2−イル)−メタノン;
シス−(1H−インドール−2−イル)−(1−メチル−オクタヒドロ−ピロロ[3,4−b]ピリジン−6−イル)−メタノン;
シス−(5−クロロ−1H−インドール−2−イル)−(1−メチル−オクタヒドロ−ピロロ[3,4−b]ピリジン−6−イル)−メタノン;
シス−(5−メチル−1H−インドール−2−イル)−(オクタヒドロ−ピロロ[3,4−b]ピリジン−6−イル)−メタノン;
(1H−ベンゾイミダゾール−2−イル)−(3−メチルアミノ−ピロリジン−1−イル)−メタノン;
(1H−ベンゾイミダゾール−2−イル)−(3−ジメチルアミノ−ピロリジン−1−イル)−メタノン;および
これらの塩、
の中の少なくとも1種である請求項24記載の方法。
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US60/790,421 | 2006-04-07 | ||
PCT/US2007/008218 WO2007117401A2 (en) | 2006-04-07 | 2007-03-30 | Indoles and benzoimidazoles as modulators of the histamine h4 receptor |
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NZ571691A (en) | 2006-03-31 | 2011-07-29 | Janssen Pharmaceutica Nv | Benzoimidazol-2-yl pyrimidines and pyrazines as modulators of the histamine H4 receptor |
US20090069343A1 (en) * | 2006-04-10 | 2009-03-12 | Dunford Paul J | Combination Histamine H1R and H4R Antagonist Therapy for Treating Pruritus |
CA2671378C (en) | 2006-12-19 | 2015-10-20 | F. Hoffmann-La Roche Ag | Heteroaryl pyrrolidinyl and piperidinyl ketone derivatives |
EP2187883A2 (en) * | 2007-08-10 | 2010-05-26 | Genelabs Technologies, Inc. | Nitrogen containing bicyclic chemical entities for treating viral infections |
BRPI0915526A2 (pt) | 2008-06-12 | 2016-01-26 | Janssen Pharmaceutica Nv | uso de um antagonista da histamina h4 para o tratamento de aderências pós-operatórias |
US9371311B2 (en) | 2008-06-30 | 2016-06-21 | Janssen Pharmaceutica Nv | Benzoimidazol-2-yl pyrimidine derivatives |
US8436008B2 (en) | 2008-12-22 | 2013-05-07 | Incyte Corporation | Substituted heterocyclic compounds |
EP2201982A1 (en) | 2008-12-24 | 2010-06-30 | INSERM (Institut National de la Santé et de la Recherche Médicale) | Histamine H4 receptor antagonists for the treatment of vestibular disorders |
US8349852B2 (en) | 2009-01-13 | 2013-01-08 | Novartis Ag | Quinazolinone derivatives useful as vanilloid antagonists |
WO2010108059A1 (en) | 2009-03-20 | 2010-09-23 | Incyte Corporation | Substituted pyrimidine derivatives as antagonists of the histamine h4 receptor |
JPWO2011013752A1 (ja) * | 2009-07-31 | 2013-01-10 | 塩野義製薬株式会社 | 縮合へテロ環誘導体を含有する医薬組成物 |
EP2531510B1 (en) | 2010-02-01 | 2014-07-23 | Novartis AG | Pyrazolo[5,1b]oxazole derivatives as crf-1 receptor antagonists |
WO2011092293A2 (en) | 2010-02-01 | 2011-08-04 | Novartis Ag | Cyclohexyl amide derivatives as crf receptor antagonists |
US8835444B2 (en) | 2010-02-02 | 2014-09-16 | Novartis Ag | Cyclohexyl amide derivatives as CRF receptor antagonists |
JP6185574B2 (ja) | 2012-06-08 | 2017-08-23 | センソリオン | 耳鳴りを治療するためのh4受容体阻害剤 |
AR092211A1 (es) * | 2012-09-24 | 2015-04-08 | Merck Patent Ges Mit Beschränkter Haftung | Derivados de hidropirrolopirrol |
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Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP2004520434A (ja) * | 2001-03-09 | 2004-07-08 | オーソ−マクニール・フアーマシユーチカル・インコーポレーテツド | 複素環化合物 |
WO2005014556A1 (en) * | 2003-08-05 | 2005-02-17 | Bayer Healthcare Ag | 2-aminopyrimidine derivatives |
WO2005054239A1 (en) * | 2003-12-05 | 2005-06-16 | Bayer Healthcare Ag | 2-aminopyrimidine derivatives |
JP2006500390A (ja) * | 2002-09-06 | 2006-01-05 | ジヤンセン・フアーマシユーチカ・ナームローゼ・フエンノートシヤツプ | 複素環式化合物 |
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US20060111416A1 (en) | 2004-11-24 | 2006-05-25 | Lane Charlotte A L | Octahydropyrrolo[3,4-C]pyrrole derivatives |
GT200600005A (es) | 2005-01-12 | 2006-08-16 | Un derivado de 2-(aminocarbonilo ciclico)-indolina y una composicion farmaceutica que lo contiene | |
PE20081897A1 (es) * | 2007-03-29 | 2009-02-09 | Novartis Ag | 3-imidazolil-indoles para el tratamiento de enfermedades proliferativas |
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Patent Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP2004520434A (ja) * | 2001-03-09 | 2004-07-08 | オーソ−マクニール・フアーマシユーチカル・インコーポレーテツド | 複素環化合物 |
JP2006500390A (ja) * | 2002-09-06 | 2006-01-05 | ジヤンセン・フアーマシユーチカ・ナームローゼ・フエンノートシヤツプ | 複素環式化合物 |
WO2005014556A1 (en) * | 2003-08-05 | 2005-02-17 | Bayer Healthcare Ag | 2-aminopyrimidine derivatives |
WO2005054239A1 (en) * | 2003-12-05 | 2005-06-16 | Bayer Healthcare Ag | 2-aminopyrimidine derivatives |
Non-Patent Citations (2)
Title |
---|
JPN6012045087; VENABLE,J.D. et al: Journal of Medicinal Chemistry Vol.48, No.26, 2005, p.8289-8298 * |
JPN6012045088; TERZIOGLU,N. et al: Bioorganic & Medicinal Chemistry Letters Vol.14, No.21, 2004, p.5251-5256 * |
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WO2007117401A3 (en) | 2008-06-26 |
HK1125034A1 (en) | 2009-07-31 |
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AU2007235578B2 (en) | 2011-07-14 |
US7544698B2 (en) | 2009-06-09 |
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US20070238771A1 (en) | 2007-10-11 |
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