JP5837549B2 - 新規の置換イミダゾキノリン - Google Patents
新規の置換イミダゾキノリン Download PDFInfo
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- JP5837549B2 JP5837549B2 JP2013240978A JP2013240978A JP5837549B2 JP 5837549 B2 JP5837549 B2 JP 5837549B2 JP 2013240978 A JP2013240978 A JP 2013240978A JP 2013240978 A JP2013240978 A JP 2013240978A JP 5837549 B2 JP5837549 B2 JP 5837549B2
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- Prior art keywords
- alkyl
- aryl
- compound
- heterocyclyl
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- RHKWIGHJGOEUSM-UHFFFAOYSA-N 3h-imidazo[4,5-h]quinoline Chemical class C1=CN=C2C(N=CN3)=C3C=CC2=C1 RHKWIGHJGOEUSM-UHFFFAOYSA-N 0.000 title description 5
- 150000001875 compounds Chemical class 0.000 claims description 148
- -1 -N 3 Chemical group 0.000 claims description 52
- 125000000217 alkyl group Chemical group 0.000 claims description 50
- 150000003839 salts Chemical class 0.000 claims description 46
- 125000003118 aryl group Chemical group 0.000 claims description 35
- 125000000623 heterocyclic group Chemical group 0.000 claims description 34
- 206010028980 Neoplasm Diseases 0.000 claims description 32
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 30
- 125000001072 heteroaryl group Chemical group 0.000 claims description 28
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- DLFVBJFMPXGRIB-UHFFFAOYSA-N Acetamide Chemical compound CC(N)=O DLFVBJFMPXGRIB-UHFFFAOYSA-N 0.000 claims description 24
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- 125000001424 substituent group Chemical group 0.000 claims description 20
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- 201000011510 cancer Diseases 0.000 claims description 18
- 201000010099 disease Diseases 0.000 claims description 15
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 15
- 125000003545 alkoxy group Chemical group 0.000 claims description 14
- 125000000304 alkynyl group Chemical group 0.000 claims description 14
- 230000004913 activation Effects 0.000 claims description 12
- 125000003342 alkenyl group Chemical group 0.000 claims description 11
- 229910052736 halogen Inorganic materials 0.000 claims description 11
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- 125000004432 carbon atom Chemical group C* 0.000 claims description 10
- 238000004519 manufacturing process Methods 0.000 claims description 10
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 9
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- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 5
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 4
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 4
- 230000001613 neoplastic effect Effects 0.000 claims description 4
- 125000003107 substituted aryl group Chemical group 0.000 claims description 4
- 125000005842 heteroatom Chemical group 0.000 claims description 3
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 3
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 3
- 125000004430 oxygen atom Chemical group O* 0.000 claims description 3
- 125000003386 piperidinyl group Chemical group 0.000 claims description 3
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- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims 2
- 125000000218 acetic acid group Chemical group C(C)(=O)* 0.000 claims 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims 1
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- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 22
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- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 10
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- SQQXRXKYTKFFSM-UHFFFAOYSA-N chembl1992147 Chemical compound OC1=C(OC)C(OC)=CC=C1C1=C(C)C(C(O)=O)=NC(C=2N=C3C4=NC(C)(C)N=C4C(OC)=C(O)C3=CC=2)=C1N SQQXRXKYTKFFSM-UHFFFAOYSA-N 0.000 description 8
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- DOUYETYNHWVLEO-UHFFFAOYSA-N imiquimod Chemical compound C1=CC=CC2=C3N(CC(C)C)C=NC3=C(N)N=C21 DOUYETYNHWVLEO-UHFFFAOYSA-N 0.000 description 6
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- TZYVRXZQAWPIAB-FCLHUMLKSA-N 5-amino-3-[(2r,3r,4s,5r)-3,4-dihydroxy-5-(hydroxymethyl)oxolan-2-yl]-4h-[1,3]thiazolo[4,5-d]pyrimidine-2,7-dione Chemical compound O=C1SC=2C(=O)NC(N)=NC=2N1[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O TZYVRXZQAWPIAB-FCLHUMLKSA-N 0.000 description 5
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 5
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 5
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- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 5
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Description
本発明は、イミダゾキノリン誘導体、及び、イミダゾキノリン誘導体を含む医薬組成物に関する。イミダゾキノリン誘導体はトール様レセプターアゴニスト/TLR7アクティベータとして有用である。
異なる特異性を有する10種類のレセプターの遺伝子ファミリーを現在含んでいるトール様レセプター(TLR)は細胞病原体パターン認識系の一部をなし、様々な感染(細菌、ウイルス、真菌)に対する防御のために進化している。TLRの活性化はサイトカイン応答を導き、たとえば、インターフェロンを開放しそして特定の免疫細胞を活性化させる。組織内で選択されるTLRの機能発現は非常に様々である。レセプターの一部は細胞表面にあり、たとえば、TLR4は、たとえば、上皮細胞上で(大腸菌リポ多糖(LPS)により刺激される)、又は、TLR3、7、8及び9は特定の免疫細胞においてエンドソーム膜にある。後者はすべて核酸によって活性化されるが、その様々なタイプを認識する。たとえば、TLR9はCpGサブシーケンスを含む一本鎖DNAによって活性化され、TLR7及び8は一本鎖RNAによって活性化され、そしてTLR3は二本鎖RNAによって活性化される。
小分子、特に、イミダゾキノリン−4−アミン誘導体は高い効力のTLR7のためのアクティベータであることが判った。これらのイミダゾキノリン誘導体は好ましい物理化学的及び薬物動態学的性質を有する。したがって、本発明は、TLR7のためのアクティベータであることが判った化合物であって、一般構造式I
本発明は、さらに、式Iの化合物を有効量で含む医薬組成物を提供する。
さらに、式Iの化合物を合成する方法を記載する。
下記においてより詳細に記載するイミダゾイミダゾキノール誘導体が有効なTLR7アクティベータであり、そして、驚くべきかつ特に有利な特性を有することが判った。
アルキル、アルキニル、アリール、アルコキシ、ヘテロシクリル又はヘテロアリールは1つ以上の基によって場合により置換されていてよく、その基は、たとえば、−H、−OH、ハロゲン、−CO−N(R4)2、−N(R4)2、−CO−C1−10アルキル、−CO−O−C1−10アルキル、−N3、場合により置換されているアリール、ヘテロシクリル又は−CO−アリールからなる群より選ばれ、
各R4は−H、−C1−10アルキル、−C1−10アルキル−アリール、アリールからなる群より独立に選ばれ、
AはC1−C6アルキルであり、
Bは−N(R2)(R3)であり、
R2は水素又は−(CO)−R5であり、
R5は、アルキル、アルキニル、アリール、ヘテロシクリル及びヘテロアリールからなる群より選ばれ、ここで、その各々は1つ以上の基によって場合により置換されていてよく、その基は、たとえば、−H、−OH、ハロゲン、−CN、−NO2、−COOH、−SH、−CO−C1−6アルキル、−CO−O−C1−6アルキル、−N3、場合により置換されているアリール、ヘテロシクリル、−CO−アリール又は−CO−ヘテロサイクルからなる群より選ばれ、
R3は、−H、アルキル、アルケニル、アリール、ヘテロアリール、シクロアルキル及びヘテロシクリルからなる群より選ばれ、ここで、
アルキル、アルケニル、アリール、ヘテロアリール、シクロアルキル又はヘテロシクリルは未置換であっても又は1つ以上の置換基によって置換されていてもよく、その基は、たとえば、−H、アルキル、アルケニル、アルコキシ、ハロゲン、−OH、−N3、トリフルオロメチル、−アルキル−アリール、−O−アルキル−アリール、−CO−アリール、アリール、ヘテロシクリル、ヘテロアリール、−CO−ヘテロアリール、−CO−置換アリール、−CO−置換ヘテロアリール、−CO−O−アルキル、−CO−N−アルキル、−CO−N−アリールからなる群より選ばれる)の化合物、又は、その医薬上許容される溶媒和物、塩、N−オキシドもしくは立体異性体、又はそれらの組み合わせを提供する。
さらに、用語「アリール」としては、本明細書中で使用される際に、炭素同素環の芳香環もしくは環系が挙げられる。アリール基の例としては、フェニル、ナフチル、ビフェニル、フルオレニル及びインデニルが挙げられる。特に、用語「アリール」はフェニル又はナフタレンを指す。好ましい実施形態において、アリールはフェニルである。置換アリールは上記のとおりである。
N−[4−(4−アミノ−2−エチル−1H−イミダゾ[4,5−c]キノリン−1−イル)ブチル]−N−(1,1−ジオキシドテトラヒドロ−3−チエニル)アセトアミド、
N−[4−(4−アミノ−2−エチル−1H−イミダゾ[4,5−c]キノリン−1−イル)ブチル]−N−(1−メチル−1−オキシドピペリジン−4−イル)アセトアミド、
3−{アセチル[4−(4−アミノ−2−エチル−1H−イミダゾ[4,5−c]キノリン−1−イル)ブチル]アミノ}−2,5−アンヒドロ−1,3,4−トリデオキシペンチトール、
N−[4−(4−アミノ−2−エチル−1H−イミダゾ[4,5−c]キノリン−1−イル)ブチル]−N−(1−ベンジル−2−メチル−1−オキシドピロリジン−3−イル)アセトアミド、
2−エチル−1−[4−テトラヒドロ−2H−ピラン−4−イルアミノ)ブチル]−1H−イミダゾ[4,5−c]キノリン−4−アミン、
1−[4−(1−アザビシクロ[2.2.2]オクト−3−イルアミノ)ブチル]−2−エチル−1H−イミダゾ[4,5−c]キノリン−4−アミン、又は、
1−{4−[(1,1−ジオキシド−3,4−ジヒドロ−2H−チオクロメン−4−イル)アミノ]ブチル}−2−エチル−1H−イミダゾ[4,5−c]キノリン−4−アミン、
から選ばれる式Iの化合物、又は、その医薬上許容される溶媒和物、塩、N−オキシドもしくは立体異性体、又は、それらの組み合わせに関する。
工程−I:3−ニトロ−キノリン−4−オール
プロピオン酸中のキノリン−4−オール(1当量)の混合物を攪拌しながら125℃に加熱した。硝酸(2.2当量)を攪拌されている溶液に滴下して加え、その間、反応混合物の温度を125℃に維持した。反応物を125℃で15分間攪拌し、そして周囲温度に冷却した。反応物をエタノールで希釈し、そして固形分を減圧ろ過により回収した。固形分を順次、エタノール、水及びエタノールで洗浄した。得られた黄色の固形分を還流エタノール中で加熱し、そして熱混合物からろ過して、純粋な3−ニトロ−キノリン−4−オールを提供した。
N,N−ジメチルホルムアミド中の工程1で得られた式1の化合物のサスペンションをよく攪拌したものに、オキシ塩化リン(1.2当量)をゆっくりと添加した。30分間攪拌しながら、反応混合物をさらに50℃に加熱した。得られた溶液を周囲温度に冷却し、そして氷/水混合物中に注いだ。固形分をろ過により回収し、そして乾燥して、4−クロロ−3−ニトロ−キノリンを提供した。
(4−アミノ−ブチル)−カルバミン酸tert-ブチルエステル(1.2当量)及びトリエチルアミン(1.5当量)のエタノール中の溶液に、式2の化合物(1当量)を添加した。その後、反応混合物を15分間還流し、その後、水で希釈して、不純物生成物を沈殿させ、それをろ過により分離した。飽和水酸化アンモニウム溶液をろ液に添加し、そして沈殿した固形分を減圧ろ過により回収し、そして乾燥して、式3のtert-ブチル{4−[(3−ニトロキノリン−4−イル)アミノ]ブチル}カルバメートを生じた。
式3の化合物(1当量)、炭素上5%パラジウム(2%wt)及び硫酸マグネシウムの酢酸エチル中のサスペンションをパール装置(parr apparatus)で50psiの水素ガスで4時間水素化した。その後、得られた反応混合物をろ過し、そしてろ液を減圧下に濃縮し、未精製固形分を生じ、それをシリカゲルカラムクロマトグラフィーにより精製し、式4のtert-ブチル{4−[(3−アミノキノリン−4−イル)アミノ]ブチル}カルバメートを提供した。
式4の化合物(1当量)のトルエン中の溶液に、トリエチルオルトプロピオネート(2当量)を添加し、得られた反応混合物を80〜90℃で5時間加熱した。その後、反応混合物を冷却し、そして溶剤を蒸発させて、トルエンを50%除去した。残りの反応混合物に、氷−水を添加し、そして生成物を白色固形分として沈殿させ、それを、その後、減圧ろ過により分離させ、乾燥して、式5のtert-ブチル[4−(2−エチル−1H−イミダゾ[4,5−c]キノリン−1−イル)ブチル]カルバメートを提供した。
工程Vで得られた式5の [4−(2−エチル−イミダゾ[4,5−c]キノリン−1−イル)−ブチル]カルバミン酸tert-ブチルエステルのトリフルオロ酢酸中の溶液を40℃で4時間攪拌した。その後、反応混合物を氷−水混合物上に注ぎ、クロロホルムで抽出した。有機層を硫酸ナトリウム上で乾燥させ、そして減圧下に濃縮して、式6の4−(2−エチル−1H−イミダゾ[4,5−c]キノリン−1−イル)ブタン−1−アミンを提供した。
工程I:N−[4−(2−エチル−1H−イミダゾ[4,5−c]キノリン−1−イル)ブチル]テトラヒドロチオフェン−3−アミン
工程VIで得られた4−(2−エチル−イミダゾ[4,5−c]キノリン−1−イル)ブチルアミンのテトラヒドロフラン中のサスペンションに、酢酸(1当量)及びジヒドロチオフェン−3−オン(1.1当量)を添加した。得られた反応混合物を10分間攪拌した。ナトリウムトリアセトキシボロハイドライド(2.2当量)を反応混合物に1時間にわたって添加し、そして得られたサスペンションを、その後、4〜5時間攪拌した。その後、反応をメタノールでクエンチし、乾燥まで濃縮した。反応混合物を水酸化ナトリウム水溶液を用いて塩基性化し、そしてクロロホルムで抽出した。有機層を硫酸ナトリウム上で乾燥させ、減圧下に濃縮し、粘性固形分を生じた。その後、生成物をシリカゲルカラムクロマトグラフィーによって精製し、[4−(2−エチル−イミダゾ[4,5−c]キノリン−1−イル)−ブチル]−(テトラヒドロチオフェン−3−イル)−アミンを提供した。
[4−(2−エチル−イミダゾ[4,5−c]キノリン−1−イル)−ブチル]−(テトラヒドロ−チオフェン−3−イル)−アミンのジクロロメタン中の溶液に、トリエチルアミン(1.5当量)及び無水酢酸(1.5当量)を添加し、そして周囲温度で4時間攪拌した。その後、反応混合物をジクロロメタン中で希釈し、そして重炭酸ナトリウム飽和溶液で洗浄した。有機層を硫酸ナトリウム上で乾燥させ、そして減圧下に濃縮し、N−[4−(2−エチル−1H−イミダゾ[4,5−c]キノリン−1−イル)ブチル]−N−(テトラヒドロ−3−チエニル)アセトアミドを提供した。
N−[4−(2−エチル−イミダゾ[4,5−c]キノリン−1−イル)ブチル]−N−(テトラヒドロチオフェン−3−イル)−アセトアミドのクロロホルム中の溶液に、m−クロロ過安息香酸(4当量)を添加し、周囲温度で2時間攪拌した。その後、反応混合物をクロロホルムで希釈し、そして重炭酸ナトリウム飽和溶液で洗浄した。有機層を硫酸ナトリウム上で乾燥させ、そして減圧下に濃縮して、粘性塊を生じた。その後、シリカゲルカラムクロマトグラフィーを用いて生成物を精製し、N−[(1,1−ジオキシドテトラヒドロ−3−チエニル)−N−[4−(2−エチル−5−オキシド−1H−イミダゾ[4,5−c]キノリン−1−イル)ブチル]アセトアミドを提供した。
(1,1−ジオキソ−テトラヒドロ−1λ*6*−チオフェン−3−イル)−N−[4−(2−エチル−5−オキシ−イミダゾ[4,5−c]キノリン−1−イル)−ブチル]−アセトアミドのクロロホルム中の溶液に、p−トルエンスルホニルクロリド(1.2当量)を添加し、次いで、水酸化アンモニウム水溶液を添加した。得られた反応混合物を室温で一晩攪拌した。その後、反応混合物をクロロホルムにより希釈し、そして重炭酸ナトリウム飽和溶液で洗浄した。有機層を硫酸ナトリウム上で乾燥させ、そして減圧下に濃縮し、粘性固形分を提供し、その後、それをシリカゲルカラムクロマトグラフィーを用いて精製し、題記の化合物を提供した。
1H NMR (300 MHz, CDCl3) δ (ppm): 8.29(dd, 1H, J=8,4&J=3.OHz), 8.21(dd, 1H, J=8.4Hz, J=3.0Hz), 7.65(m, 2H), 5.49(s, 2H), 4.58(t, 2H), 3.78(t, 2H), 3.3(t, 2H), 3.02(q, 2H), 2.34(d, 2H), 2.2(t, 1H), 2.1(s, 3H), 2.09(m, 2H), 1.9(m, 2H), 1.79(m, 2H), 1.55(t, 3H)
例2〜4も例1の手順に従って調製した。
1H NMR (300 MHz, CDCl3) δ (ppm): 8.24(dd, 1H, J=8.4&J=3.0Hz), 8.19(dd, 1H, J=8.4&J=3.0Hz), 7.60(m, 2H), 5.60(s, 2H), 4.52(t, 2H), 3.75(t, 2H), 3.4(m, 1H), 3.2(m, 4H), 3.12(q, 2H), 2.16(s, 3H), 2.01(m, 2H), 1.99(m, 4H), 1.70(m, 2H), 1.51(t, 3H)
1H NMR (300 MHz, CDCl3) δ (ppm):8.35(dd, 1H, J=8.4&J=3.OHz), 8.29(dd, 1H, J=8.4&J=3.0Hz), 7.63(m, 2H), 5.56(s, 2H), 4.50(t, 2H), 4.42(m, 1H), 3.70(t, 2H), 3.62(m, 1H), 3.35(t,2H), 3.12(q, 2H), 2.15(s,3H), 2.05(m, 2H),1.92(d, 3H),1.8(t, 2H) 1.70(m, 2H), 1.51(t, 3H)
1H NMR (300 MHz, CDCl3) δ (ppm): 8.31(dd, 1H, J=8.4&J=3.0Hz), 8.15(dd, 1H, J=8.4Hz, J=3.0Hz), 7.62(m, 2H), 7.55(m, 5H), 5.59(s, 2H), 4.50(t, 2H), 3.71(t, 2H),3.35(t, 2H), 3.23(s, 2H), 3.21(q, 2H),2.19(d, 2H), 2.15(t, 1H), 2.10(s, 3H), 2.09(m, 2H), 1.9(m, 2H),1.79(m, 2H), 1.55(t, 3H)
工程−I:N−[4−(2−エチル−1H−イミダゾ [4,5−c]キノリン−1−イル)ブチル]テトラヒドロ−2H−ピラン−4−アミン
例Iの工程IVで得られた4−(2−エチル−1H−イミダゾ[4,5−c]キノリン−1−イル)ブタン−1−アミンのテトラヒドロフラン中のサスペンションに、酢酸(1当量)及びテトラヒドロピラン−4−オン(1.1当量)を添加した。得られた反応混合物を10分間攪拌した。ナトリウムトリアセトキシボロハイドライド(2.2当量)を反応混合物に1時間にわたって添加し、その後、得られたサスペンションを4〜5時間攪拌した。その後、メタノールで反応をクエンチし、乾燥まで濃縮した。反応混合物を水酸化ナトリウム水溶液を用いて塩基性化し、そしてクロロホルムで抽出した。有機層を硫酸ナトリウム上で乾燥させ、そして減圧下に濃縮し、粘性固形分を提供した。その後、生成物をシリカゲルカラムクロマトグラフィーによって精製し、N−[4−(2−エチル−1H−イミダゾ [4,5−c]キノリン−1−イル)ブチル]テトラヒドロ−2H−ピラン−4−アミンを提供した。
N−[4−(2−エチル−1H−イミダゾ [4,5−c]キノリン−1−イル)ブチル]テトラヒドロ−2H−ピラン−4−アミンのジクロロメタン中の溶液に、トリエチルアミン(1.5当量)を添加し、次いで、ジ−tert-ブチル−ジカーボネート(1.5当量)を添加し、そして得られた反応混合物を周囲温度で4時間攪拌した。その後、反応混合物を完全に蒸発させ、ジクロロメタン中に溶解させ、水で洗浄し、そして有機層を硫酸ナトリウム上で乾燥させ、減圧下に濃縮し、tert-ブチル[4−(2−エチル−1H−イミダゾ[4,5−c]キノリン−1−イル)ブチル]テトラヒドロ−2H−ピラン−4−イルカルバメートを提供した。
tert-ブチル[4−(2−エチル−1H−イミダゾ[4,5−c]キノリン−1−イル)ブチル]テトラヒドロ−2H−ピラン−4−イルカルバメートのクロロホルム中の溶液に、m−クロロ過安息香酸(4当量)を添加し、そして周囲温度で2時間攪拌した。その後、反応混合物をクロロホルムで希釈し、そして重炭酸ナトリウム飽和溶液で洗浄した。有機層を硫酸ナトリウム上で乾燥させ、減圧下に濃縮し、粘性塊を生じた。その後、生成物をシリカゲルカラムクロマトグラフィーを用いて精製し、tert-ブチル[4−(2−エチル−5−オキシド−1H−イミダゾ[4,5−c]キノリン−1−イル)ブチル]テトラヒドロ−2H−ピラン−4−イルカルバメートを提供した。
tert-ブチル[4−(2−エチル−5−オキシド−1H−イミダゾ[4,5−c]キノリン−1−イル)ブチル]テトラヒドロ−2H−ピラン−4−イルカルバメートのクロロホルム中の溶液に、p−トルエンスルホニルクロリド(1.2当量)を添加し、次いで、水酸化アンモニウム水溶液を添加した。得られた反応混合物を室温で一晩攪拌した。反応混合物を重炭酸ナトリウム飽和溶液で洗浄した。有機層を分離し、無水硫酸ナトリウム上で乾燥させ、そして減圧下に濃縮し、粘性塊を生じさせ、それを、その後、シリカゲルカラムクロマトグラフィーを用いて精製し、tert-ブチル[4−(4−アミノ−2−エチル−1H−イミダゾ[4,5−c]キノリン−1−イル)ブチル]テトラヒドロ−2H−ピラン−4−イルカルバメートを提供した。
tert-ブチル[4−(4−アミノ−2−エチル−1H−イミダゾ[4,5−c]キノリン−1−イル)ブチル]テトラヒドロ−2H−ピラン−4−イルカルバメートのトリフルオロ酢酸中の溶液を40℃で4時間攪拌した。その後、反応混合物を氷−水混合物上に注ぎ、そしてクロロホルムで抽出した。有機層を硫酸ナトリウム上で乾燥させ、そして減圧下に濃縮し、題記の化合物を提供した。
1H NMR (300 MHz,MeOD) δ (ppm):8.2(d, 1H, J=8.1Hz), 7.75(m, 2H), 7.6(dt, 1H, J=1.5 & 7.2Hz),4.69(t, 2H), 4.01(d, 1H), 3.98(d, 1H), 3.4(m, 3H), 3.2(m, 2H), 3.1(m, 2H), 2.0(m, 4H), 1.9(m, 4H), 1.5(t, 3H)
例6〜7も例5の手順に従って調製した。
1H NMR (300 MHz, MeOD) δ (ppm): 8.01(d, 1H, J=8.4Hz), 7.67(dd, 1H, J=1.2 & 8.4 Hz), 7.4(dt, 1H, J=1.5 & 7.8Hz), 7.33(dt, 1H, J=1.2 & 7.5Hz), 4.5 (m, 2H), 4.2(m, 2H), 3.6(m, 1H), 3.4(m, 1H), 3.1(m, 2H), 3.0(q, 2H), 2.7(m, 2H), 1.9(m, 3H), 1.7(m, 2H), 1.5(t, 3H), 1.4(m, 2H), 1.3(m, 3H)
1H NMR (300 MHz5 MeOD) δ (ppm);8.2(d, 1H, J=8.1Hz), 7.80(dt, 1H, J=1.5 & 6.3Hz), 7,73(d, 1H, J=7.5Hz), 7.64(dt, 1H, J=1.5 & 7.5Hz), 7.5(m, 4H), 4.59(t, 2H), 3.97(t, 1H), 3.70(m, 1H), 3.02(q, 2H), 2.71(m, 3H), 2.50(m, 2H), 1.99(m, 2H), 1.69(m, 2H), 1.48(t, 3H)
TLR7を活性化する化合物を試験するためにヒト癌細胞ライン(PCIR−1)又はヒトPBMCフラクションを用いて細胞アッセイを確立する。
PCIR−1におけるTLRmRNA発現(TaqMan PCR分析)
TLR1++,TLR2(+),TLR3+,TLR4++,TLR5(+),TLR6++,TLR7++,TLR8−,TLR9+++,TLR10−
以下において、参照化合物及び本発明に係る化合物を用いた研究をLeja A, Hofmann HP, Maier T, Drache D, Grebe C, Fischer S, Gimmnich P, Sanders K, Gekeler Vに記載された腎がん細胞の肺転移(Renca lung metastasis)モデルで示す。Balb/cマウスの腎がん細胞の肺への転移はTLR9又はTLR7アゴニストによって強く抑制される。Abstract 3552, Proc Am Cancer Res 48, 2007。
Claims (22)
- 式I
アルキル、アルキニル、アリール、アルコキシ、ヘテロシクリル又はヘテロアリールは未置換であっても、又は、1つ以上の置換基によって置換されていてもよく、
AはC1−C6アルキルであり、
Bは−N(R2)(R3)であり、
R2は−(CO)−R5であり、
R5は、アルキル、アルキニル、アリール、ヘテロシクリル及びヘテロアリールからなる群より選ばれ、ここで、アルキル、アルキニル、アリール、ヘテロシクリル及びヘテロアリールは未置換であっても、又は、1つ以上の置換基によって置換されていてもよく、
R3は、アリール、ヘテロアリール、シクロアルキル及びヘテロシクリルからなる群より選ばれ、ここで、アリール、ヘテロアリール、シクロアルキル及びヘテロシクリルは未置換であっても、又は、1つ以上の置換基によって置換されていてもよい)
の化合物、又は、その医薬上許容される溶媒和物、塩、N−オキシドもしくは立体異性体、又はそれらの混合物。 - R3は、アリール、ヘテロアリール、シクロアルキル及びヘテロシクリルからなる群より選ばれ、ここで、アリール、ヘテロアリール、シクロアルキル及びヘテロシクリルの各々は未置換であっても、又は、1つ以上の置換基によって置換されていてもよく、その置換基は、−H、アルキル、アルケニル、アルコキシ、ハロゲン、−OH、−N3、トリフルオロメチル、−アルキル−アリール、O−アルキル−アリール、−CO−アリール、アリール、ヘテロシクリル、ヘテロアリール、−CO−ヘテロアリール、−CO−置換アリール、−CO−置換ヘテロアリール、−CO−O−アルキル、−CO−N−アルキル、−CO−N−アリールからなる群より選ばれる、請求項1記載の式Iの化合物。
- R1は、アルキル、アルキニル、アリール、アルコキシ、ヘテロシクリル及びヘテロアリールからなる群より選ばれ、ここで、アルキル、アルキニル、アリール、アルコキシ、ヘテロシクリル及びヘテロアリールは1つ以上の置換基によって場合により置換されていてよく、その置換基の各々は、−H、−OH、ハロゲン、−CO−N(R4)2、−N(R4)2、−CO−C1−10アルキル、−CO−O−C1−10アルキル、−N3、場合により置換されているアリール、ヘテロシクリル又は−CO−アリールからなる群より選ばれ、
各R4は−H、−C1−10アルキル、−C1−10アルキル−アリール又はアリールからなる群より独立に選ばれる、請求項1又は2記載の式Iの化合物。 - R5は1つ以上の置換基によって置換されており、その置換基は、−H、−OH、ハロゲン、−CN、−NO2、−COOH、−SH、−CO−C1−6アルキル、−CO−O−C1−6アルキル、−N3、場合により置換されているアリール、ヘテロシクリル、−CO−アリール及び−CO−ヘテロシクリルからなる群より選ばれる、請求項1〜3のいずれか1項記載の式Iの化合物。
- R1はアルキニル又はアルコキシである、請求項1〜4のいずれか1項記載の式Iの化合物。
- R3はヘテロシクリルであり、それは未置換であっても、又は、1つ以上の置換基によって置換されていてもよく、その置換基は、−H、アルキル、アルケニル、ハロゲン及び−OHからなる群より選ばれる、請求項1〜5のいずれか1項記載の式Iの化合物。
- R3はジオキソ−テトラヒドロチオフェニル、ピペリジニル、テトラヒドロフラニル、ピロリジン、テトラヒドロピラニル及びアザビシクロオクタニルからなる群より選ばれ、ジオキソ−テトラヒドロチオフェニル、ピペリジニル、テトラヒドロフラニル、ピロリジン、テトラヒドロピラニル及びアザビシクロオクタニルの各々は1つ以上の基によって場合により置換されていてよい、請求項1〜6のいずれか1項記載の式Iの化合物。
- R1はアルキルである、請求項1〜7のいずれか1項記載の式Iの化合物。
- R 1 はエチルである、請求項8項記載の式Iの化合物。
- R5はアルキルである、請求項1〜9のいずれか1項記載の式Iの化合物。
- R 5 はメチルである、請求項10記載の式Iの化合物。
- R 1 は、1つ以上の置換基−N(R 4 ) 2 によって置換されていてもよい、C 1−4 アルキルであり、各R 4 は−H、及び−C 1−4 アルキルからなる群から選ばれる、請求項1記載の化合物。
- R 3 はヘテロシクリルであり、該ヘテロシクリルは、酸素原子、窒素原子及びSOxから選ばれる1つの環ヘテロ原子(xは2である)を含む非芳香環の単環系であり、該ヘテロシクリルは、未置換であっても、又は、−H、及び−C 1−4 アルキルからなる群から選ばれる1つ以上の置換基によって置換されていてもよく、
R 1 は、1つ以上の置換基−N(R 4 ) 2 によって置換されていてもよい、C 1−4 アルキルであり、各R 4 は−H、及び−C 1−4 アルキルからなる群より選ばれ、
該アルキルは、1〜4個の炭素原子を有する直鎖又は枝分かれ鎖アルキル基である、請求項1記載の化合物。 - Aがブチルであり;
R 3 が、ヘテロアリール及びヘテロシクリルからなる群より選択され、ここで、ヘテロシクリルは、酸素原子、窒素原子又はSO x (xは0、1又は2である)を含む非芳香族環であり、ヘテロアリールは、少なくとも1つの酸素原子、窒素原子又は硫黄原子を含む芳香族環であり、ヘテロアリール又はヘテロシクリルは、未置換、又は−H、C 1−4 アルキル、C 2−4 アルケニル、C 1−4 アルコキシ、ハロゲン、−OH、−N 3 、及びトリフルオロメチル、からなる群より選ばれる1以上の基によって置換されていてもよい、請求項1記載の化合物。 - N−[4−(4−アミノ−2−エチル−1H−イミダゾ[4,5−c]キノリン−1−イル)ブチル]−N−(1,1−ジオキシドテトラヒドロ−3−チエニル)アセトアミド、
N−[4−(4−アミノ−2−エチル−1H−イミダゾ[4,5−c]キノリン−1−イル)ブチル]−N−(1−メチル−1−オキシドピペリジン−4−イル)アセトアミド、
3−{アセチル[4−(4−アミノ−2−エチル−1H−イミダゾ[4,5−c]キノリン−1−イル)ブチル]アミノ}−2,5−アンヒドロ−1,3,4−トリデオキシペンチトール、又は
N−[4−(4−アミノ−2−エチル−1H−イミダゾ[4,5−c]キノリン−1−イル)ブチル]−N−(1−ベンジル−2−メチル−1−オキシドピロリジン−3−イル)アセトアミド
である、請求項1記載の化合物、又は、その医薬上許容される溶媒和物、塩、N−オキシドもしくは立体異性体、又はそれらの混合物。 - 医薬上許容される担体と一緒に、請求項1〜15のいずれか1項記載の式Iの化合物を治療に有効な量で含む、医薬組成物。
- 対象に対して100ng/kg〜50mg/kgの化合物という投与量を提供するのに十分な量の式Iの化合物、又は、その医薬上許容される溶媒和物、塩、N−オキシドもしくは立体異性体、又はそれらの混合物を含む、請求項16記載の医薬組成物。
- 前記投与量が10μg/kg〜5mg/kgである、請求項17記載の医薬組成物。
- TLR7活性化に感受性であるウイルス性もしくは腫瘍性疾患又は癌の治療のための、請求項16又は17記載の医薬組成物。
- 請求項1〜15のいずれか1項記載の化合物、又は、請求項16又は17記載の医薬組成物のTLR7の活性化のための医薬の製造のための使用。
- 請求項1〜15のいずれか1項記載の化合物、又は、請求項16又は17記載の医薬組成物のウイルス性もしくは腫瘍性疾患の治療のための医薬の製造のための使用。
- 請求項1〜15のいずれか1項記載の化合物、又は、請求項16又は17記載の医薬組成物のTLR7の活性化に感受性である癌の治療のための医薬の製造のための使用。
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