JP6302906B2 - ウイルス感染および他の疾患を治療するためのアルキルピリミジン誘導体 - Google Patents
ウイルス感染および他の疾患を治療するためのアルキルピリミジン誘導体 Download PDFInfo
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- JP6302906B2 JP6302906B2 JP2015525892A JP2015525892A JP6302906B2 JP 6302906 B2 JP6302906 B2 JP 6302906B2 JP 2015525892 A JP2015525892 A JP 2015525892A JP 2015525892 A JP2015525892 A JP 2015525892A JP 6302906 B2 JP6302906 B2 JP 6302906B2
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- C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
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- C—CHEMISTRY; METALLURGY
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- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
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- C07D409/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
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- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
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Description
の化合物、またはその薬学的に許容される塩、溶媒和物もしくは多形が提供され、式中、
R1は、水素、フッ素、ヒドロキシル、アミン、C1〜6アルキル、C1〜6アルキルアミノ、C1〜6アルコキシ、C3〜7シクロアルキル、C4〜7複素環、アリール、二環式複素環、アリールアルキル、ヘテロアリール、ヘテロアリールアルキル、アリールオキシ、ヘテロアリールオキシ、カルボン酸、カルボン酸エステル、カルボン酸アミドであり、これらはそれぞれ、ハロゲン、ヒドロキシル、アミノ、C1〜6アルキル、ジ(C1〜6)アルキルアミノ、(C1〜4)アルコキシ−(C1〜4)アルキル、C1〜6アルキルアミノ、C1〜6アルキル、C1〜6アルコキシ、C3〜6シクロアルキル、カルボン酸、カルボン酸エステル、カルボン酸アミド、複素環、アリール、アルケニル、アルキニル、アリールアルキル、ヘテロアリール、ヘテロアリールアルキル、またはニトリルから独立して選択される1個以上の置換基で任意選択により置換されており、
R2は、C1〜6アルキルであり、これはそれぞれ、ハロゲン、ヒドロキシル、アミノ、ニトリル、カルボン酸、カルボン酸エステル、カルボン酸アミド、C1〜3アルキル、C1〜3アルコキシまたはC3〜6シクロアルキル、スルホン、スルホキシド、またはニトリルから独立して選択される1個以上の置換基で任意選択により置換されており、
但し、N−(2−アミノ−5−フェネチルピリミジン−4−イル)−N−ペンチルアミンは除外される。
式(I)の化合物はスキーム1に従って製造される。
スキーム1
N2雰囲気下、−78℃で、CH3PPh3Br(27.91g、78.1mmol、1.5当量)をTHF(70mL)に懸濁し、撹拌した。n−ブチルリチウム(30mL、75mmol、1.44当量、2.5Mヘキサン溶液)を20分間かけて滴下し、さらに0.5時間撹拌した後、2−アミノ−4,6−ジクロロ−5−ホルミルピリミジン[5604−46−6](10.0g、52mmol、1.0当量)をTHF(180mL)懸濁液として添加した。冷却浴を取り外し、混合物を室温で2時間撹拌した。反応を−78℃に冷却した後、NH4Cl(飽和水溶液)をゆっくり添加した。冷却浴を取り外し、混合物を1.5時間撹拌した。有機層を分離し、水で洗浄し、乾燥し(Na2SO4)、固体を濾過により除去し、濾液の溶媒を減圧留去した。石油エーテルから酢酸エチルへの勾配を用いるシリカカラムクロマトグラフィーにより粗製物を精製し、無色油状物、A−1(1.2g)を得た。
1H NMR(400MHz,クロロホルム−d)δ ppm 5.30(br.s.,2H),5.65(d,1H),5.82(d,1H),6.58(q,1H)
A−1(1.0g、5.26mmol)、n−ブチルアミン(0.39g、5.26mmol)およびEt3N(0.53g、5.26mmol、1.0当量)のエタノール(10mL)溶液を12時間還流した。溶媒を減圧留去した。石油エーテルから酢酸エチルへの勾配を用いるシリカゲルカラムクロマトグラフィーにより粗製物を精製した。最良の画分をプールし、減圧濃縮して、B−1(300mg)を得た。
LC−MS m/z=227(M+H)
1H NMR(400MHz,クロロホルム−d)δ ppm 0.95(t,J=7.3Hz,3H),1.38(dq,J=14.9,7.4Hz,2H),1.55(quin,J=7.4Hz,2H),3.38(q,J=7.3Hz,2H),4.75(br.s.,2H),5.39(br.s.,1H),5.5(m,2H),6.55(m,1H)
B−1(200mg、0.88mmol、1.0当量)のメタノール(5mL)溶液に、10%Pd/C(20mg)を添加し、H2ガス(50Psi)と50℃で17時間混合した。分取高速液体クロマトグラフィー(C18カラム、溶離液:CH3CN/H2O、10/90〜95/5、0.05%HCl)により粗生成物を精製した。所望の画分をプールし、減圧濃縮して、1(74mg)を得た。
LC−MS m/z=195(M+H)
1H NMR(400MHz,クロロホルム−d)δ ppm 0.95(t,J=7.3Hz,3H),1.20(t,J=7.3Hz,3H),1.38(dq,J=14.9,7.4Hz,2H),1.62(quin,J=7.4Hz,2H),1.93(br.s.,1H),2.37(q,J=7.3Hz,2H),3.40−3.63(m,2H),6.18(br.s.,1H),7.24(br.s.,1H),13.43(br.s.,1H)
方法1.陽イオンモードのAgilent 1100 LC−MSは、50℃に保たれるYMC−PACK ODS−AQ、50×2.0mm、5μmカラムを備えた。次の移動相および勾配を10分間の総分析時間(total run time)にわたり0.8mL/分で使用し、220nmで監視した。
生物学的アッセイの説明
TLR7およびTLR8活性の評価
TLR7またはTLR8発現ベクターおよびNFκB−lucレポーター構築物で一過性トランスフェクションを行ったHEK293細胞を使用する細胞レポーターアッセイで、化合物のヒトTLR7(hTLR7)および/またはTLR8(hTLR8)活性化能力を評価した。一例では、TLR発現構築物は、各野生型配列、またはTLRの第2のロイシンリッチリピートに欠失がある突然変異体配列を発現する。このような突然変異TLRタンパク質は、アゴニスト活性化をより受け易いことが以前示された(米国特許第7498409号明細書)。
本発明は、以下の態様を包含し得る。
[1]
式(I)
(式中、
R 1 は、水素、フッ素、ヒドロキシル、アミン、C 1〜6 アルキル、C 1〜6 アルキルアミノ、C 1〜6 アルコキシ、C 3〜7 シクロアルキル、C 4〜7 複素環、アリール、二環式複素環、アリールアルキル、ヘテロアリール、ヘテロアリールアルキル、アリールオキシ、ヘテロアリールオキシ、カルボン酸、カルボン酸エステル、カルボン酸アミドであり、これらはそれぞれ、ハロゲン、ヒドロキシル、アミノ、C 1〜6 アルキル、ジ(C 1〜6 )アルキルアミノ、(C 1〜4 )アルコキシ−(C 1〜4 )アルキル、C 1〜6 アルキルアミノ、C 1〜6 アルキル、C 1〜6 アルコキシ、C 3〜6 シクロアルキル、カルボン酸、カルボン酸エステル、カルボン酸アミド、複素環、アリール、アルケニル、アルキニル、アリールアルキル、ヘテロアリール、ヘテロアリールアルキル、またはニトリルから独立して選択される1個以上の置換基で任意選択により置換されており、
R 2 は、C 1〜6 アルキルであり、これはそれぞれ、ハロゲン、ヒドロキシル、アミノ、ニトリル、カルボン酸、カルボン酸エステル、カルボン酸アミド、C 1〜3 アルキル、C 1〜3 アルコキシまたはC 3〜6 シクロアルキル、スルホン、スルホキシド、またはニトリルから独立して選択される1個以上の置換基で任意選択により置換されており、
但し、N−(2−アミノ−5−フェネチルピリミジン−4−イル)−N−ペンチルアミンは除外される)
の化合物、またはその薬学的に許容される塩、溶媒和物もしくは多形。
[2]
R 1 が複素環であり、R 2 がヒドロキシル基で置換されたC 1〜6 アルキルである、上記[1]に記載の化合物。
[3]
R 1 が水素であり、R 2 がC 1〜6 アルキルであり、これがそれぞれ、ハロゲン、ヒドロキシル、アミノ、ニトリル、カルボン酸、カルボン酸エステル、カルボン酸アミド、C 1〜3 アルキル、C 1〜3 アルコキシまたはC 3〜6 シクロアルキル、スルホン、スルホキシド、またはニトリルから独立して選択される1個以上の置換基で任意選択により置換されている、上記[1]に記載の化合物。
[4]
上記[1]〜[3]のいずれか一項に記載の式(I)の化合物またはその薬学的に許容される塩、溶媒和物もしくは多形を、1種以上の薬学的に許容される医薬品添加物、賦形剤または担体と一緒に含む医薬組成物。
[5]
医薬として使用される、上記[1]〜[3]のいずれか一項に記載の式(I)の化合物、もしくはその薬学的に許容される塩、溶媒和物もしくは多形、または上記[4]に記載の医薬組成物。
[6]
TLR7の調節および/またはTLR8の調節が関与する障害の治療に使用される、上記[1]〜[3]のいずれか一項に記載の式(I)の化合物、もしくはその薬学的に許容される塩、溶媒和物もしくは多形、または上記[4]に記載の医薬組成物。
Claims (7)
- 式(I)
(式中、
R1は、水素、フッ素、ヒドロキシル、アミン、C1〜6アルキル、C1〜6アルキルアミノ、C1〜6アルコキシ、C3〜7シクロアルキル、C4〜7複素環、アリール、二環式複素環、アリールアルキル、ヘテロアリール、ヘテロアリールアルキル、アリールオキシ、またはヘテロアリールオキシであり、これらはそれぞれ、ハロゲン、ヒドロキシル、アミノ、C1〜6アルキル、ジ(C1〜6)アルキルアミノ、(C1〜4)アルコキシ−(C1〜4)アルキル、C1〜6アルキルアミノ、C1〜6アルキル、C1〜6アルコキシ、C3〜6シクロアルキル、複素環、アリール、アルケニル、アルキニル、アリールアルキル、ヘテロアリール、ヘテロアリールアルキル、またはニトリルから独立して選択される1個以上の置換基で任意選択により置換されており、
R2は、C1〜6アルキルであり、これはそれぞれ、ハロゲン、ヒドロキシル、アミノ、ニトリル、C 1〜3アルキル、C1〜3アルコキシ、C3〜6シクロアルキル、またはスルホンから独立して選択される1個以上の置換基で任意選択により置換されており、
但し、N−(2−アミノ−5−フェネチルピリミジン−4−イル)−N−ペンチルアミンは除外される)
の化合物、またはその薬学的に許容される塩、溶媒和物もしくは多形。 - R1がC 4〜7 複素環であり、R2がヒドロキシル基で置換されたC1〜6アルキルである、請求項1に記載の化合物またはその薬学的に許容される塩、溶媒和物もしくは多形。
- R1が水素であり、R2がC1〜6アルキルであり、これがそれぞれ、ハロゲン、ヒドロキシル、アミノ、ニトリル、C 1〜3アルキル、C1〜3アルコキシ、C3〜6シクロアルキル、またはスルホンから独立して選択される1個以上の置換基で任意選択により置換されている、請求項1に記載の化合物またはその薬学的に許容される塩、溶媒和物もしくは多形。
- 以下:
およびその薬学的に許容される塩、溶媒和物もしくは多形から選択される、請求項1に記載の化合物またはその薬学的に許容される塩、溶媒和物もしくは多形。 - 請求項1〜4のいずれか一項に記載の式(I)の化合物またはその薬学的に許容される塩、溶媒和物もしくは多形を、1種以上の薬学的に許容される医薬品添加物、賦形剤または担体と一緒に含む医薬組成物。
- 医薬として使用される、請求項1〜4のいずれか一項に記載の式(I)の化合物、もしくはその薬学的に許容される塩、溶媒和物もしくは多形、または請求項5に記載の医薬組成物。
- TLR7の調節および/またはTLR8の調節が関与する障害を治療するための、請求項1〜4のいずれか一項に記載の式(I)の化合物、もしくはその薬学的に許容される塩、溶媒和物もしくは多形、または請求項5に記載の医薬組成物。
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