JP2019532917A - 置換された三環式ヘテロ環化合物 - Google Patents
置換された三環式ヘテロ環化合物 Download PDFInfo
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- JP2019532917A JP2019532917A JP2019511946A JP2019511946A JP2019532917A JP 2019532917 A JP2019532917 A JP 2019532917A JP 2019511946 A JP2019511946 A JP 2019511946A JP 2019511946 A JP2019511946 A JP 2019511946A JP 2019532917 A JP2019532917 A JP 2019532917A
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- amino
- cyclopentyl
- dihydronaphtho
- thiazol
- formula
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Abstract
Description
本出願は、2016年9月2日出願の米国仮出願62/382,962の利益を主張し、これはその全体を引用により本明細書に包含させる。
本発明は、S1P1活性の調節因子として有用である式(I)、式(II)、式(III)または式(IV)の置換された三環式ヘテロ環化合物(その塩を含む)を提供する。
本発明の第1の態様は、式(I):
--- は、単結合または二重結合を表し;
R1は、−(CH2)2−3CH3、−(CH2)5−6CH3、−(CH2)1−2C(CH3)3、−NRa(CH2)3CH3、−O(CH2)3−5CH3、−S(CH2)3−4CH3、−OCH2CH2O(CH2)3CH3、メチルフェニルまたはメトキシフェニルであり;
R2は、−OHまたは−OP(O)(OH)2であり;および
Raは、Hまたは−CH3である]
の化合物またはその塩を提供する。
[式中:
R1は、−(CH2)5CH3または
であり;
Raは、−(CH2)5CH3であり;および
R2は、−OHまたは−OP(O)(OH)2である]
の化合物またはその塩を提供する。
[式中:
R1は、−(CH2)4CH3または−CF3およびフェニルで置換された−イソオキサゾリルであり;および
R2は、−OHまたは−OP(O)(OH)2である]
の化合物またはその塩を提供する。
から選択される、式(I)、式(II)または式(III)の化合物あるいはその塩を提供する。
本発明の特徴および利点は、下記の詳細な説明を読むことによって当業者にとってより簡単に理解されうる。明確にするために、別の実施態様として上記および下記に記載される本発明の一定の特徴は、組み合わされて1つの実施態様を形成することも理解されるべきである。反対に、簡潔さのために、1つの実施例として記載される本発明の様々な特徴は、そのサブコンビナーションを形成するために組み合わされうる。典型的もしくは好ましいものとして本明細書で特定される実施態様は、例示するためであり、限定することが目的とされていない。
a)The Practice of Medicinal Chemistry, Camille G. Wermuth et al., Ch 31,(Academic Press, 1996);
b)Design of Prodrugs, Bundgaard, H. ed., Elsevier (1985);
c)A Textbook of Drug Design and Development, P. Krogsgaard-Larson and H. Bundgaard, eds. Ch 5, pgs 113-191(Harwood Academic Publishers, 1991;および
d)Hydrolysis in Drug and Prodrug Metabolism, Bernard Testa and Joachim M. Mayer,(Wiley-VCH, 2003)。
ヒト免疫系は、感染、疾患または死を引き起こしうる微生物、ウイルスおよび寄生虫から体を防御するために進化してきた。複雑な調節メカニズムは、その個体に回復不能または顕著な損傷を引き起こすことなく、免疫系の様々な細胞成分が外部の物質または生物を標的とすることを可能にする。発症事象は現時点で十分に理解されていないが、自己免疫疾患の症状において、免疫系が罹っている患者の標的とする器官に応答するその炎症に関与している。様々な自己免疫疾患は、典型的に、罹患している主要もしくは最初の標的器官もしくは組織;例えば、関節リウマチの場合の関節、橋本甲状腺炎の場合の甲状腺、多発性硬化症の場合の中枢神経系、I型糖尿病の場合の膵臓、および炎症性腸疾患の場合の腸によって特徴付けられる。それゆえ、免疫系または免疫系の一定の細胞型(例えば、Bリンパ球およびTリンパ球、T細胞)に作用する治療剤は、1種類より多くの自己免疫疾患に有用性を示しうることが観察されている。
本発明の化合物は、有機合成の当業者に周知の多くの方法で製造することができる。本発明の化合を製造するための一般的な合成スキームは下記に記載される。これらのスキームは、説明を目的としており、本明細書に開示された化合物を製造するために当業者が使用し得る技術を制限することを意味しない。本発明の化合物を製造するための様々な方法は、当業者にとって明らかである。一般的なスキームに記述した方法により製造される本発明の化合物の例示は、下記に示される実施例において説明される。ホモキラルの例示の製造は、当業者には既知の技術により実施され得る。例えば、ホモキラル化合物を、キラル相分取HPLCによるラセミ体生成物またはジアステレオマーを分離することにより製造され得る。あるいは、例示化合物を、エナンチオマーを多く含む生成物またはジアステレオマーを多く含む生成物を得るために、既知方法により製造され得る。
スキーム2は、ハライド3の異なる多様な別法を示す。ハライド3は、Fe(III)触媒下において、グリニャール試薬と反応して、加水分解後にアミノアルコール5に至る(J. Am. Chem. Soc., 2002, 124, 13856-13863)。ハライドは、ヒンダード塩基の存在下において、アルコール(J. Med. Chem. 2009, 52, 3689-3702)またはチオール(Angew. Chem. Int. Ed. 1998, 37, 84-87)により置換されて、加水分解後にアミノアルコール6を提供することもできる。あるいは、ハライド3を、鈴木カップリング(J. Organometallic Chem. 1999, 576, 147-168)またはバックワルド・ハートウィッグカップリング(Acc. Chem. Res . 1998, 31, 852;Acc. Chem. Res. 1998, 31, 805)に付して、各々加水分解後にアミノ−アルコール7および8を得る。
スキーム4および5は、ヨードまたはビニル前駆体いずれかから、置換された4,5−ジヒドロナフト[2,1−d]チアゾール−7−カルボン酸の製造を介して、式(IV)の三環式カルボキサミド化合物を製造するための方法を示す。
条件A:(分析)
Waters Acquity UPLC BEH C18(2.1 x 50)mm, 1.7μm 粒子;移動相A:5:95 アセトニトリル:水(10mM 酢酸アンモニウムを含む);移動相B:95:5 アセトニトリル:水(10mM 酢酸アンモニウムを含む);温度:50℃;グラジエント:3分かけて0〜100%B、次いで0.75分間100%Bで保持;流量:1.0mL/min;検出:220nmのUV。
条件B:(分取)
Shimatzu prep HPLC, Luna(登録商標) C18 30 x 100 mm, 5 μm(Phenomenex Inc.);2mLインジェクション;移動相A=0.1%TFA/水;移動相B=0.1% TFA/MeCN;温度:25℃;グラジエント:5分かけて20〜100%B、次いで10分間100%Bで保持、流量:30mL/min;検出:220nmのUV。
条件G:Column:Waters Acquity BEH C18 2.1 x 50 mm 1.7 μm;3分かけて0〜100%溶媒Bの直線グラジエント、次いで0.75分100%Bで保持;流量:1.11mL/min;溶媒A:5:95 アセトニトリル:水(10mM 酢酸アンモニウムを含む);溶媒B:95:5 アセトニトリル:水(10mM 酢酸アンモニウムを含む);温度=50℃;生成物は220nm波長で検出した。
条件K:Column:BEH C18 2.1 x 50mm 1.7um, 1.5分かけて0〜100%溶媒Bの直線グラジエント、次いで0.7分間100%Bで保持;流量:1.11mL/min;溶媒A:5:95 アセトニトリル:水(10mM 酢酸アンモニウムを含む);溶媒B:95:5 アセトニトリル:水(10mM 酢酸アンモニウムを含む);温度=50℃;生成物は220nm波長で検出した。
(5R,7S)−7−(6−オキソ−5,6,7,8−テトラヒドロナフタレン−2−イル)−3−オキサ−1−アザスピロ[4.4]ノナン−2−オン(200mg,0.7mmol)(WO 2006/028959A1)を、スクリューキャップバイアル内でエタノール(1.4mL)に溶解した。チオウレア(187mg,2.5mmol)およびヨウ素(196mg,0.77mmol)を、次いで室温で加えた。このチューブを密封して、100℃で2時間加熱した。LCMS分析により、出発物質が完全に変換されたことが明らかとなった。チューブを開封して、反応混合物を100℃で15分間濃縮した。室温に冷却すると、目的の生成物が沈殿した。水(1mL)を加えて、更に15分間攪拌して、次いで濾過により、目的の化合物(5R,7S)−7−(2−アミノ−4,5−ジヒドロナフト[2,1−d]チアゾール−7−イル)−3−オキサ−1−アザスピロ[4.4]ノナン−2−オン,ヨウ化水素酸塩(200mg,61%)を褐色固体として得た。LCMS(M+H):342.3;LC保持時間:0.64min(分析HPLC方法A), 1H NMR(400MHz, メタノール-d4)δ 7.23(s, 1H), 7.21-7.15(m, 1H), 7.06(d, J=7.9 Hz, 1H), 4.40(d, J=8.6 Hz, 1H), 4.31(d, J=8.6 Hz, 1H), 3.17-3.03(m, 3H), 2.93-2.81(m, 2H), 2.34(dd, J=13.0, 7.3 Hz, 1H), 2.22-2.08(m, 2H), 2.04-1.76(m, 3H).
アセトニトリル(2.2mL)中の(5R,7S)−7−(2−アミノ−4,5−ジヒドロナフト[2,1−d]チアゾール−7−イル)−3−オキサ−1−アザスピロ[4.4]ノナン−2−オン,ヨウ化水素酸塩(50mg,0.1mmol)およびヨウ化銅(I)(31mg,0.16mmol)の懸濁液に、0℃で、tert−亜硝酸ブチル(20μL,0.15mmol)を加えた。LCMS分析により出発物質の完全な消費が示されたときに、反応混合物を、この温度で15分間、室温で終夜攪拌した。混合物を、EtOAcで希釈して、セライトを通して濾過した。得られる溶液を減圧濃縮した。LCMS(M+H):453.1;LC保持時間:1.01min(分析HPLC方法A).
(5R,7S)−7−(2−アミノ−4,5−ジヒドロナフト[2,1−d]チアゾール−7−イル)−3−オキサ−1−アザスピロ[4.4]ノナン−2−オン,ヨウ素酸(38mg,0.08mmol)/EtOAc(25mL)の溶液を、1N NaOH(25mL)で1回洗った。有機層を、硫酸ナトリウム上で乾燥させて、濾過した。有機溶液に、TFA(100μL)を加えて、溶液を減圧濃縮した。残留物を、アセトニトリル(1.7mL)に溶解した。この溶液に、0℃で、塩化銅(I)(12mg,0.13mmol)、次いでtert−亜硝酸ブチル(15μL,0.12mmol)を加えた。反応混合物を、この温度で15分間、室温で終夜攪拌した。LCMS分析により、出発物質の完全な消費が示された。混合物を、MeOH(2mL)で希釈して、条件Bを用いるHPLCにより精製して、(5R,7S)−7−(2−クロロ−4,5−ジヒドロナフト[2,1−d]チアゾール−7−イル)−3−オキサ−1−アザスピロ[4.4]ノナン−2−オン(12mg,0.033mmol,40%収率)を褐色固体として得た。
((1R,3S)−1−アミノ−3−(2−ヘプチル−4,5−ジヒドロナフト[2,1−d]チアゾール−7−イル)シクロペンチル)メタノール,TFA塩
THF(0.5mL)およびN−メチル−2−ピロリジノン(0.1mL)の混合物中の(5R,7S)−7−(2−クロロ−4,5−ジヒドロナフト[2,1−d]チアゾール−7−イル)−3−オキサ−1−アザスピロ[4.4]ノナン−2−オン(14mg,0.04mmol)および鉄(III)アセチルアセトナート(1.40mg,3.9μmol)の溶液に、1M ヘプチル臭化マグネシウム(0.12mL,0.12mmol)を室温で加えた。15分後にLCMSによる反応の分析により、完全な変換が示された。反応混合物を、ジエチルエーテルで希釈して、1N HClを添加してクエンチした。水層を、EtOAcで2回逆抽出した。有機層を合わせて、MgSO4で乾燥させて、減圧濃縮した。得られる油状物を、ジオキサン(1mL)に溶解して、次いでNaOH(0.56mL,0.56mmol)を添加した。溶液を100℃まで昇温させて、3時間攪拌した。LCMSにより、完全な変換が示された。溶液を、条件Bを用いてHPLCにインジェクションして、((1R,3S)−1−アミノ−3−(2−ヘプチル−4,5−ジヒドロナフト[2,1−d]チアゾール−7−イル)シクロペンチル)メタノール,TFA(3mg,5.6μmol,15%収率,2工程)を黄色固体として得た。LCMS(M+H):399.5;LC保持時間:0.94 min(分析HPLC方法A);1H NMR(400MHz, メタノール-d4)δ 7.26-7.13(m, 3H), 3.65(dd, J=14.7, 12.1 Hz, 2H), 3.26-3.12(m, 1H), 3.12-2.91(m, 4H), 2.47(dd, J=13.4, 7.0 Hz, 1H), 2.25-2.11(m, 1H), 2.08-1.91(m, 3H), 1.90-1.70(m, 2H), 1.53-1.25(m, 10H), 0.93(t, J=6.8 Hz, 3H).
((1R,3S)−1−アミノ−3−(2−(2−ブトキシエトキシ)−4,5−ジヒドロナフト[2,1−d]チアゾール−7−イル)シクロペンチル)メタノール,トリフルオロ酢酸塩
(5R,7S)−7−(2−クロロ−4,5−ジヒドロナフト[2,1−d]チアゾール−7−イル)−3−オキサ−1−アザスピロ[4.4]ノナン−2−オン(3mg,8μmol)/ジオキサン(0.5mL)の溶液に、2−ブトキシエタノール(20mg,0.17mmol)、次いでカリウム tert−ブトキシド(9mg,0.08mmol)を室温で加えた。LCMSにより、出発物質の完全な消費が示された時に、混合物を70℃で2時間攪拌した。この混合物に、室温で、1M NaOH溶液(0.5mL,0.500mmol)を加えた。混合物を、70℃に加熱して、14時間攪拌した。LCMSにより、中間体の完全な消費が示された。この溶液を、条件Bを用いてHPLCprepにインジェクションして、((1R,3S)−1−アミノ−3−(2−(2−ブトキシエトキシ)−4,5−ジヒドロナフト[2,1−d]チアゾール−7−イル)シクロペンチル)メタノール,TFA(3mg,5.5μmol,66%収率)を白色固体として得た。LCMS(M+H):4173;LC保持時間:0.87min(分析HPLC方法A), 1H NMR(400MHz, メタノール-d4)δ 7.17(s, 1H), 7.13(dd, J=7.8, 1.4 Hz, 1H), 7.03(d, J=7.9 Hz, 1H), 4.60-4.49(m, 2H), 3.87-3.77(m, 2H), 3.65(dd, J=13.2, 10.8 Hz, 2H), 3.56(t, J=6.5 Hz, 2H), 3.24-3.10(m, 1H), 3.03(t, J=7.0 Hz, 2H), 2.83(t, J=8.4 Hz, 2H), 2.51-2.41(m, 1H), 2.24-2.09(m, 1H), 2.05-1.89(m, 3H), 1.75(t, J=12.7 Hz, 1H), 1.68-1.52(m, 2H), 1.49-1.33(m, 2H), 0.95(t, J=7.4 Hz, 3H).
((1R,3S)−1−アミノ−3−(2−(ヘキシルオキシ)ナフト[2,1−d]チアゾール−7−イル)シクロペンチル)メタノール,トリフルオロ酢酸塩
((1R,3S)−1−アミノ−3−(2−(ヘキシルオキシ)−4,5−ジヒドロナフト[2,1−d]チアゾール−7−イル)シクロペンチル)メタノール,TFA(8mg,0.016mmol)/MeCN(1.6mL)の溶液に、塩化銅(II)(21mg,0.16mmol)を加えた。反応混合物を、室温で終夜攪拌して、外気にあてた。LCMSにより、完全な変換が示された。反応混合物を、MeOHで希釈して、条件Bを用いるHPLCprepにインジェクションして、((1R,3S)−1−アミノ−3−(2−(ヘキシルオキシ)ナフト[2,1−d]チアゾール-7-イル)シクロペンチル)メタノール,TFA(5mg,9.3μmol,60%収率)を得た。LCMS(M+H):399.2;LC保持時間:1.00min(分析HPLC方法A);1H NMR(400MHz, メタノール-d4)δ 7.90-7.79(m, 3H), 7.76(d, J=8.6 Hz, 1H), 7.58(dd, J=8.6, 1.8 Hz, 1H), 4.61(t, J=6.6 Hz, 2H), 3.70(dd, J=16.3, 11.9 Hz, 2H), 3.47-3.37(m, 1H), 2.58(dd, J=13.2, 6.2 Hz, 1H), 2.35-2.24(m, 1H), 2.17-1.97(m, 3H), 1.97-1.81(m, 3H), 1.62-1.49(m, 2H), 1.49-1.35(m, 4H), 0.96(t, J=7.0 Hz, 3H).
((1R,3S)−1−アミノ−3−(2−(ブチルアミノ)−4,5−ジヒドロナフト[2,1−d]チアゾール−7−イル)シクロペンチル)メタノール,トリフルオロ酢酸塩
(5R,7S)−7−(2−アミノ−4,5−ジヒドロナフト[2,1−d]チアゾール−7−イル)−3−オキサ−1−アザスピロ[4.4]ノナン−2−オン(50mg,0.15mmol)/MeOH(15mL)の溶液に、ブチルアルデヒド(53mg,0.73mmol)を加えた。反応混合物を、70℃で1時間加熱して、次いで室温まで冷却した。水素化ホウ素ナトリウム(55mg,1.5mmol)を、次いで添加して、溶液を30分間攪拌した。LCMSにより、完全な消費が示された。LCMS(M+H):398.4;LC保持時間:0.75min(分析HPLC方法A)。溶媒を、減圧除去して、EtOAcに希釈した。有機層を、1N NaOHで洗い、硫酸ナトリウム上で乾燥させて、濾過して、減圧濃縮した。得られる油状物を、ジオキサン(0.7mL)に溶解して、次いで水酸化ナトリウム(1M,150μL,0.15mmol)を加えた。溶液を100℃に温めて、2時間攪拌した。LCMSにより、完全な変換が示された。溶液を、条件Bを用いるHPLCにインジェクションして、((1R,3S)−1−アミノ−3−(2−(ブチルアミノ)−4,5−ジヒドロナフト[2,1−d]チアゾール−7−イル)シクロペンチル)メタノール,2TFA(12mg,0.019mmol)を、白色固体として得た。LCMS(M+H):372.3;LC保持時間:0.61min(分析HPLC方法A);1H NMR(400MHz, メタノール-d4)δ 7.23(s, 1H), 7.22-7.16(m, 1H), 7.08(d, J=7.7 Hz, 1H), 3.71-3.58(m, 2H), 3.47(t, J=7.2 Hz, 2H), 3.23-3.14(m, 1H), 3.11(t, J=8.1 Hz, 2H), 2.89(t, J=8.1 Hz, 2H), 2.52-2.42(m, 1H), 2.23-2.09(m, 1H), 2.05-1.91(m, 3H), 1.83-1.68(m, 3H), 1.50(dq, J=15.0, 7.5 Hz, 2H), 1.03(t, J=7.4 Hz, 3H).
((1R,3S)−1−アミノ−3−(2−(ブチル(メチル)アミノ)−4,5−ジヒドロナフト[2,1−d]チアゾール−7−イル)シクロペンチル)メタノール,トリフルオロ酢酸塩
(5R,7S)−7−(2−クロロ−4,5−ジヒドロナフト[2,1−d]チアゾール−7−イル)−3−オキサ−1−アザスピロ[4.4]ノナン−2−オン(20mg,0.055mmol)/トルエン(500μL)の懸濁液に、N−メチルブタン−1−アミン(13μL,0.11mmol)、次いでカリウム tert−ブトキシド(19mg,0.17mmol)、ジシクロヘキシル(2',4',6'−トリイソプロピル−[1,1'−ビフェニル]−2−イル)ホスフィン(5mg,0.011mmol)およびPd2(dba)3(3mg,0.003mmol)を室温で加えた。混合物を、次いで70℃に加熱して、1時間攪拌した。LCMSにより、出発物質の完全な消費が示された。混合物を、水およびEtOAcの間に分配した。水溶液を、EtOAcで2回逆抽出した。有機層を合わせて、乾燥して、減圧濃縮した。LCMS(M+H):412.3;LC保持時間:0.79min(分析HPLC方法A)。得られる油状物を、ジオキサン(0.5mL)に溶解して、NaOH(705μl,0.705mmol)を加えた。混合物を、100℃で3時間加熱した。LCMSにより、出発物質の完全な変換が示された。溶液をEtOAcおよび水を用いて後処理した。有機層を、硫酸ナトリウム上で乾燥させて、減圧濃縮した。得られる油状物を、MeOHに溶解して、条件Bを用いるHPLCprepにインジェクションして、((1R,3S)−1−アミノ−3−(2−(ブチル(メチル)アミノ)−4,5−ジヒドロナフト[2,1−d]チアゾール−7−イル)シクロペンチル)メタノール,2TFA(5mg,7.9μmol,11%収率)を白色固体として得た。LCMS(M+H):386.2;LC保持時間:0.63min(分析HPLC方法A).1H NMR(400MHz, メタノール-d4)δ 7.20(s, 1H), 7.18(d, J=7.7 Hz, 1H), 7.07(d, J=7.7 Hz, 1H), 3.73-3.57(m, 4H), 3.28(s, 3H), 3.23-3.14(m, 1H), 3.08(t, J=8.0 Hz, 2H), 2.88(t, J=8.0 Hz, 2H), 2.52-2.41(m, 1H), 2.17(br. s., 1H), 2.05-1.90(m, 3H), 1.84-1.69(m, 3H), 1.45(dd, J=15.2, 7.5 Hz, 2H), 1.03(t, J=7.4 Hz, 3H)
((1R,3S)−1−アミノ−3−(2−(p−トリル)−4,5−ジヒドロナフト[2,1−d]チアゾール−7−イル)シクロペンチル)メタノール,トリフルオロ酢酸塩
(5R,7S)−7−(2−クロロ−4,5−ジヒドロナフト[2,1−d]チアゾール−7−イル)−3−オキサ−1−アザスピロ[4.4]ノナン−2−オン(20mg,0.055mmol)/ジオキサン(550μL)の溶液に、p−トリルボロン酸(38mg,0.28mmol)および炭酸ナトリウム(55μL,0.11mmol)を加えた。反応混合物を、窒素でパージして、次いでジクロロ[1,1'−ビス(ジフェニルホスフィノ)フェロセン]パラジウム(II)(2mg,2.78μmol)を添加した。反応混合物を、100℃に加熱して、1時間後にLCMSにより完全な変換が示された。LCMS(M+H):417.1;LC保持時間:1.12min(分析HPLC方法A)。溶液を、室温に冷却して、次いでNaOH(1M,554μL,0.554mmol)を加えた。反応混合物を100℃に加熱して、6時間後にLCMSにより完全な変換が示された。溶液を、EtOAcおよび水で希釈した。水層を、EtOAcで2回逆抽出した。有機画分を合わせて、硫酸ナトリウム上で乾燥させて、濾過して、減圧濃縮した。生じる固体をMeOHに溶解して、条件Bを用いるHPLCprepで精製して、((1R,3S)−1−アミノ−3−(2−(p−トリル)−4,5−ジヒドロナフト[2,1−d]チアゾール−7−イル)シクロペンチル)メタノール,TFA(8mg,0.015mmol,27%収率)を得た。LCMS(M+H):391.2;LC保持時間:0.87min(分析HPLC方法A)。 1H NMR(400MHz, メタノール-d4)δ 7.86(d, J=8.1 Hz, 2H), 7.32(dd, J=7.8, 5.4 Hz, 3H), 7.28-7.17(m, 2H), 3.66(dd, J=15.4, 11.4 Hz, 2H), 3.14-3.01(m, 4H), 2.49(dd, J=13.3, 7.2 Hz, 1H), 2.43(s, 3H), 2.20(br. s., 1H), 2.08-1.92(m, 3H), 1.77(t, J=12.8 Hz, 1H).
DMF(611μL,7.9mmol)/DCM(2.5mL)の溶液に、PBr3(8.8mL,8.8mmol)を加えた。溶液を、室温で1時間攪拌した。この溶液に、(5R,7S)−7−(6−オキソ−5,6,7,8−テトラヒドロナフタレン−2−イル)−3−オキサ−1−アザスピロ[4.4]ノナン−2−オン(250mg,0.88mmol)/DCM(2.5mL)を加えた。反応混合物を室温で1時間攪拌し、その時点でLCMSにより出発物質の完全な完了が示された。反応混合物を、DCMで希釈して、2回NaHCO3で洗い、硫酸ナトリウム上で乾燥させて、濃縮して、2−ブロモ−6−((5R,7S)−2−オキソ−3−オキサ−1−アザスピロ[4.4]ノナン−7−イル)−3,4−ジヒドロナフタレン−1−カルバルデヒド(332mg,101%)を得た。LCMS(M+H):378.0;LC保持時間:0.93min(分析HPLC方法A).
2−ブロモ−6−((5R,7S)−2−オキソ−3−オキサ−1−アザスピロ[4.4]ノナン−7−イル)−3,4−ジヒドロナフタレン−1−カルバルデヒド(330mg,0.88mmol)およびエチル 2−メルカプトアセテート(97μL,0.88mmol)/EtOH(5.8mL)の溶液に、室温で、ナトリウムエトキシド(298mg,4.4mmol)を一度に加えた。反応混合物をこの温度で終夜攪拌した。次いで、反応混合物を70℃で1時間加熱し、その時点でLCMSにより目的の生成物が示された。反応を、1N HClでクエンチした。反応混合物をEtOAcで3回抽出した。EtOAcおよびヘキサンを用いるシリカゲルでの精製により、エチル 7−((5R,7S)−2−オキソ−3−オキサ−1−アザスピロ[4.4]ノナン−7−イル)−4,5−ジヒドロナフト[2,1−b]チオフェン−2−カルボキシレート(120mg,0.302mmol,34%収率)の単離物を得た;2工程の収率。LCMS(M+H):398.2;LC保持時間:1.01min(分析HPLC方法A);1H NMR(400MHz, クロロホルム-d)δ 8.04(s, 1H), 7.48(d, J=7.9 Hz, 1H), 7.17-7.06(m, 2H), 5.44(br. s., 1H), 4.44-4.35(m, 3H), 4.35-4.28(m, 1H), 3.17-3.06(m, 1H), 3.05-2.97(m, 4H), 2.38(dd, J=13.3, 7.4 Hz, 1H), 2.26-2.10(m, 2H), 2.05-1.93(m, 2H), 1.93-1.81(m, 1H), 1.42(t, J=7.2 Hz, 3H).
エチル 7−((5R,7S)−2−オキソ−3−オキサ−1−アザスピロ[4.4]ノナン−7−イル)−4,5−ジヒドロナフト[2,1−b]チオフェン−2−カルボキシレート(120mg,0.3mmol)/THF(3mL)の溶液に、LiBH4(2M,755μL,1.509mmol)を加えた。ガスの発生が止んだ後に、このチューブにフタをして、反応混合物を5時間70℃に加熱して、その時にLCMSにより約90%の変換が示された。反応を1N HClでクエンチした。反応混合物を、EtOAcで希釈した。水層をEtOAcで3回抽出した。有機層を合わせて、硫酸ナトリウム上で乾燥して、減圧濃縮して、(5R,7S)−7−(2−(ヒドロキシメチル)−4,5−ジヒドロナフト[2,1−b]チオフェン−7−イル)−3−オキサ−1−アザスピロ[4.4]ノナン−2−オン(100mg,0.28mmol,93%収率)を白色固体として得た。LCMS(M+H−H2O):338.1;LC保持時間:0.82min(分析HPLC方法A).
(5R,7S)−7−(2−(ヒドロキシメチル)−4,5−ジヒドロナフト[2,1−b]チオフェン−7−イル)−3−オキサ−1−アザスピロ[4.4]ノナン−2−オン(36mg,0.1mmol)/DCM(2mL)の溶液に、順に、0℃で、ヒューニッヒ塩基(87μL,0.5mmol)、DMSO(71μL,1mmol)およびSO3−ピリジン(64mg,0.4mmol)を加えた。この反応をLCMSにより追跡して、出発物質:目的の生成物を1:1の比率で確認した。反応混合物を、DCMで希釈して、水、次いで1N HClで抽出した。有機層を乾燥して、減圧濃縮して、白色固体を得た。LCMS(M+H):354.0;LC保持時間:0.89min(分析HPLC方法A).
ブロモ(ブチル)トリフェニルホスホラン(60mg,0.15mmol)/THF(2mL)の溶液に、室温で、LiHMDS(1M,0.15mL,0.15mmol)を加えた。溶液を30分間攪拌すると、黄色に変わった。この溶液に、粗製7−((5R,7S)−2−オキソ−3−オキサ−1−アザスピロ[4.4]ノナン−7−イル)−4,5−ジヒドロナフト[2,1−b]チオフェン−2−カルバルデヒド(35mg,0.1mmol)/THF(2mL)を加えて、得られる混合物を室温で1時間攪拌した。LCMSにより、目的の生成物の発生が示された。反応混合物を、DCMで希釈して、1N HClで1回洗った。有機層を乾燥して、減圧濃縮した。対応する油状物を、ISCO(グラジエント100%ヘキサン〜100%EtOAc)により得て、(5R,7S)−7−(2−(ペンタ−1−エン−1−イル)−4,5−ジヒドロナフト[2,1−b]チオフェン−7−イル)−3−オキサ−1−アザスピロ[4.4]ノナン−2−オン(3mg,7.62μmol,2工程に対して8%収率)を得た。LCMS(M+H):394.2;LC保持時間:1.21min(分析HPLC方法A)。
(5R,7S)−7−(2−(ペンタ−1−エン−1−イル)−4,5−ジヒドロナフト[2,1−b]チオフェン−7−イル)−3−オキサ−1−アザスピロ[4.4]ノナン−2−オン(3mg,7.6μmol)/EtOH(0.5mL)の溶液に、室温で、Pd−C(1mg,7.6μmol)を加えた。反応混合物を減圧下に置いて、水素で再度充填した。反応を1時間攪拌して、その時点でLCMSにより完全な変換が示された。混合物を、Celiteを通して濾過して、EtOAcで溶出した。溶媒を、減圧除去して、(5R,7S)−7−(2−ペンチル−4,5−ジヒドロナフト[2,1−b]チオフェン−7−イル)−3−オキサ−1−アザスピロ[4.4]ノナン−2−オン(2.2mg,5.6μmol,73%収率)を油状物として得た。
(5R,7S)−7−(2−ペンチル−4,5−ジヒドロナフト[2,1−b]チオフェン−7−イル)−3−オキサ−1−アザスピロ[4.4]ノナン−2−オン(2.2mg,5.6μmol)/ジオキサン(0.4mL)の溶液に、NaOH(1M,0.11mL,0.11mmol)を加えた。LCMSにより完全な変換が示された時に、溶液を100℃で2時間攪拌した。得られる混合物を濃縮して、MeOHに溶解して、条件Bを用いてHPLCにインジェクションして、((1R,3S)−1−アミノ−3−(2−ペンチル−4,5−ジヒドロナフト[2,1−b]チオフェン−7−イル)シクロペンチル)メタノール,TFA(1.5mg,3.01μmol,54%収率)を得た。LCMS(M+H):370.1;LC保持時間:1.01min(分析HPLC方法A);1H NMR(400MHz, メタノール-d4)δ 7.44-7.36(m, 1H), 7.21-7.10(m, 2H), 7.06(s, 1H), 3.73-3.57(m, 2H), 3.16(td, J=3.4, 1.9 Hz, 1H), 3.03-2.95(m, 2H), 2.93-2.85(m, 2H), 2.82(t, J=7.5 Hz, 2H), 2.50-2.39(m, 1H), 2.23-2.09(m, 1H), 2.04-1.90(m, 3H), 1.84-1.62(m, 3H), 1.51-1.32(m, 4H), 1.02-0.87(m, 3H).
((1R,3S)−1−アミノ−3−(2−(2−ブトキシエトキシ)−4,5−ジヒドロナフト[2,1−d]チアゾール−7−イル)シクロペンチル)メチル ジヒドロゲンホスフェート,トリフルオロ酢酸塩
((1R,3S)−1−アミノ−3−(2−(2−ブトキシエトキシ)−4,5−ジヒドロナフト[2,1−d]チアゾール−7−イル)シクロペンチル)メタノール(4mg,9.6μmol)/アセトニトリル(0.5mL)の溶液に、0℃で、ピロ塩化ホスホリル(0.013mL,0.096mmol)を加えた。5分後に、冷却浴を外して、反応混合物を室温まで昇温させた。反応混合物を、この温度で1.5時間攪拌した。LCMSにより、完全な変換が示された。反応を水(0.2mL)の添加によりクエンチした。反応混合物を、15分間攪拌して、次いで条件Bを用いてHPLCにインジェクションして、((1R,3S)−1−アミノ−3−(2−(2−ブトキシエトキシ)−4,5−ジヒドロナフト[2,1−d]チアゾール−7−イル)シクロペンチル)メチル ジヒドロゲンホスフェート,TFA(1.2mg,1.9μmol,19%収率)を白色固体として得た。LCMS(M+H):497.2;LC保持時間:0.82min(分析HPLC方法A)。
(3−アミノ−3−(ヒドロキシメチル)ピロリジン−1−イル)(2−(3−フェニル−4−(トリフルオロメチル)イソオキサゾール−5−イル)−4,5−ジヒドロナフト[2,1−d]チアゾール−7−イル)メタノン
7−ヨード−2−ペンチル−4,5−ジヒドロナフト[2,1−d]チアゾール(PCT Int.Appl.(2011), WO2011059784 A1 2011051)(100mg,0.261mmol)を、無水テトラヒドロフラン(5ml)に溶解した。溶液を、おおよそ−20℃に冷却した(エチレングリコール/ドライアイス−この浴は−30℃であった)。イソプロピルマグネシウムクロリド(0.248ml,0.496mmol)を滴加した。反応混合物を室温まで温めて1時間攪拌して、その後乾燥CO2ガスを反応溶液に通してバブリングした。混合物を、室温で1時間攪拌し、この時点でLC−MS分析により反応が完了したことが示された。反応混合物を、1N HClで反応をクエンチした。反応混合物を、室温で1時間攪拌した。溶媒をエバポレートした。得られた残留物を、アセトニトリル(4ml)中で超音波処理して、製造例49Aを白色固体として得た(48mg,59%収率)。HPLC 保持時間=3.93min(条件K);LC/MS M+1=302.1.
反応フラスコに、2−ペンチル−4,5−ジヒドロナフト[2,1−d]チアゾール−7−カルボン酸(46mg,0.153mmol)、(3−アミノピロリジン−3−イル)メタノール,2HCl(31.7mg,0.168mmol)、酢酸エチル(2mL)およびDMF(0.500mL)を加えた。混合物を10分間超音波処理した後に、1−プロパンホスホン酸の環状無水物(酢酸エチル中で50%)(0.109mL,0.183mmol)を滴加した。混合物を、5分間攪拌して、DIPEA(0.107mL,0.610mmol)を加えた。混合物を、室温で2時間攪拌して、この時点でLC−MSにより完全な変換が示された。反応をクエンチした(1N HClを3mL)。混合物を40分間攪拌した。得られる生成物を、逆相HPLCで精製して、ラセミ体生成物(55mg)を得た。ラセミ体生成物を、キラル分離により分離した。
(3−アミノ−3−(ヒドロキシメチル)ピロリジン−1−イル)(2−(3−フェニル−4−(トリフルオロメチル)イソオキサゾール−5−イル)−4,5−ジヒドロナフト[2,1−d]チアゾール−7−イル)メタノン
3−フェニル−4−(トリフルオロメチル)−5−(7−ビニル−4,5−ジヒドロナフト[2,1−d]チアゾール−2−イル)イソキサゾール(J. Med. Chem.2016, 59(21), 9837-9854参照)(520mg,1.225mmol)/THF(15ml)の透明な溶液に、NMO/水(0.635mL,3.06mmol)、四酸化オスミウム/水(0.449mL,0.074mmol)を、室温で順に加えた。混合物を、室温で終夜攪拌した。過ヨウ素酸ナトリウム(655mg,3.06mmol)/H2O(4mL)を、反応混合物に加えた。混合物を、窒素下において、室温で2時間攪拌して、この時点でLC−MSにより、反応が完了したことが示された。水(4mL)を加えて、白色固体を得た。固体生成物を濾過して、水(2x1 mL)で洗い、減圧乾燥して、標題化合物(450mg,0.95mmol,78%収率)を得た。HPLC Ret time=4.29min(条件K).LC/MS M+1=427.1.
2−(3−フェニル−4−(トリフルオロメチル)イソオキサゾール−5−イル)−4,5−ジヒドロナフト[2,1−d]チアゾール−7−カルバルデヒド(15mg,0.035mmol)/DMSO(1ml)の溶液に、リン酸二水素ナトリウム(10.97mg,0.091mmol)/H2O(0.3ml)を加えた。混合物を0℃に冷却して、亜塩素酸ナトリウム(9.94mg,0.088mmol)/H2O(0.4ml)をゆっくりと加えた。混合物を、室温まで昇温させて、次いで室温で4時間攪拌した。LC−MS分析により、部分的な変換が示された。追加の2等量の塩化ナトリウムを加えて、混合物を、室温にて15時間攪拌して、次いで50℃で45分間加熱して、この時点でLC−MS分析により、反応が完了したことが示された。混合物を、冷1N HCl(15mL)に注ぎ入れて、攪拌して、次いでEtOAcで抽出した。有機層を濃縮して、終夜真空下において乾燥させて、製造例51B(10mg,0.023mmol,64%収率)を得た。HPLC Ret time=4.07min(条件K);LC/MS M+1=443.2.
2−(3−フェニル−4−(トリフルオロメチル)イソオキサゾール−5−イル)−4,5−ジヒドロナフト[2,1−d]チアゾール−7−カルボン酸(50mg,0.113mmol)を、DMF(0.3mL)およびCH2Cl2(1.5mL)の共溶媒に溶解した。この溶液に、N1−((エチルイミノ)メチレン)−N3,N3−ジメチルプロパン−1,3−ジアミン塩酸塩(22.75mg,0.119mmol)およびHOBT(18.17mg,0.119mmol)の溶液を加えた。混合物を、室温で50分間攪拌した。次いで、3−((tert−ブトキシカルボニル)アミノ)ピロリジン−3−カルボン酸(26.0mg,0.113mmol)を加えた。混合物を、室温で終夜攪拌して、この時点でLC−MS分析により、反応が完了したことが示された。混合物を、CH2Cl2(40ml)に注ぎ入れて、0.5N HClで2回洗った。有機層を、Na2SO4で乾燥して、減圧下で濃縮して、製造例51C(60mg,0.09mmol,81%)を得た。HPLC Ret.Time=1.06min(条件G);LC/MS M+1=655.2.
CH2Cl2(3mL)に、3−((tert−ブトキシカルボニル)アミノ)−1−(2−(3−フェニル−4−(トリフルオロメチル)イソオキサゾール−5−イル)−4,5−ジヒドロナフト[2,1−d]チアゾール−7−カルボニル)ピロリジン−3−カルボン酸(60mg,0.092mmol)を溶解した。溶液を、氷水浴で0℃に冷却して、塩化オキサリル(8.79μl,0.101mmol)を加えて、次いで2滴のDMFを滴加した。混合物を、0℃で、5分間攪拌した。次いで、CH2Cl2を送風により蒸発させて、MeOH(3ml)を加えた。混合物を、室温で4時間攪拌して、この時点でLC−MS分析により、目的の生成物ピークが示された。MeOHを、減圧下で除去して、飽和NaHCO3水溶液(3mL)を加えた。混合物を、酢酸エチルで抽出した。有機層を、終夜、高真空下で乾燥させて、生成物(88%収率,55mg)を得た。HPLC Ret.Time=0.87min(条件G);LC/MS M+1=569.2.
メチル 3−アミノ−1−(2−(3−フェニル−4−(トリフルオロメチル)イソオキサゾール−5−イル)−4,5−ジヒドロナフト[2,1−d]チアゾール−7−カルボニル)ピロリジン−3−カルボキシレート(55mg,0.097mmol)/MeOH(3mL)の溶液に、0℃で、NaBH4(18.30mg,0.484mmol)を加えた。混合物を、0℃で、2時間攪拌して、この時点でLC−MS分析により、反応が完了していることが示された。反応を、1N HClでクエンチして、逆相HPLCにより精製した。分画物を含有する生成物を回収して、高真空下において終夜乾燥させて、生成物(29mg)をラセミ体混合物として得た。HPLC Ret.Time:3.43min(条件K),LC/MS M+1=541.2. 1H NMR(400 MHz, メタノール-d4) δ 7.73-7.44(m, 8H), 3.87-3.69(m, 6H), 3.22(s, 4H), 2.27(s, 1H), 2.16(s, 1H).
実施例51(おおよそ35mg)のラセミ混合物を、キラル分離により分離した。分画物(「PK−1」および「PK−2」)を、MeOH(0.1%ジエチルアミンを含む)中に回収した。各画分の純度は、分取クロマトグラフィーに基づいて>98%であると算出された。
分取クロマトグラフィー条件:Instrument:Berger SFC MGII(LVL−L4021 Lab);カラム:AS−H 50X3cm ID,5μm;流量:85.0mL/min;移動相:85/15 CO2/MeOH(0.1%DEAを含む);検出器波長:220nm.
実施例53:PK2:HPLC Ret time=3.08min(条件K);LC/MS M+1=541.2.1H NMR(400MHz, メタノール-d4) δ 7.73-7.49(m, 8H), 3.92-3.74(m, 3H), 3.72-3.64(m, 2H), 3.62(s, 1H), 3.25(s, 4H), 2.17-2.02(m, 1H), 1.87(d, J=13.0 Hz, 1H).
式(I)、式(II)、式(III)および式(IV)の化合物およびその塩(ここで、R2は、-OHである)は、アルコールのリン酸化を介する生物学的活性化後のその生物学的標的(例えば、S1P1)に関与し、式(I)、式(II)、式(III)および式(IV)の活性型リン酸エステル化合物またはその塩(式中、R2は−OP(O)(OH)2である)を提供する。インビトロで実施例の生物学的活性の特徴分析を、合成により製造したリン酸化化合物のサンプルに対して行なった。
化合物を、384Falcon v−ボトルプレート(11点で0.5μl/ウェル,3倍希釈)にのせた。S1Pi/CHO細胞またはEDG3−Ga15−bla HEK293T細胞(EDG3当量 S1P3)から調製した膜は、MULTIDROP(登録商標)により化合物プレート(40μl/ウェル,最終タンパク質3μg/ウェル)に添加した。[35S]GTP(1250Ci/mmol,Perkin Elmer)をアッセイ緩衝液:20mM HEPES、pH7.5、10mM MgCl2、150mM NaCl、1mM EGTA(エチレングリコール四酢酸)、1mM DTT(ジチオスレイトール)、10μM GDP、0.1% 脂肪酸不含BSAおよび10μg/ml サポニン中で0.4nMに希釈した。40μlの[35S]GTP溶液を0.2nMの最終濃度で化合物プレートに加えた。反応混合物を室温で45分間保った。インキュベーション終了後、全ての化合物プレート中の混合物は、VELOCITY11(登録商標) Vprepリキッドハンドラーによりミリポア384−ウェルFBフィルタープレートに移した。フィルタープレートは、マニホールド・エンブラ・プレートウォッシャーを用いて水で4回洗浄し、60℃で45分間乾燥させた。Packard TOPCOUNT(登録商標)でカウントするために、MicroScint 20シンチレーション液(30μl)を各ウェルに加えた。EC50は、試験した各化合物について得られたYmax(最大応答値)の50%に相当するアゴニスト濃度として定義される。
GTPγS S1P1 EC50値についてのより低い値は、GTPyS S1P1結合アッセイにおいては化合物のより高い活性を示した。GTPyS S1P3EC50値のより高い値は、GTPySS1P3結合アッセイにおいてはより低い活性を示した(表A)。
ルイスラットに、ビヒクル単独(ポリエチレングリコール300,「PEG300」)または試験化合物(ビヒクル中の溶液または懸濁液として)を経口投与した。化合物を、ビヒクル溶液またはビヒクル懸濁液として投与した(塩形態を用いる場合においては試験化合物の遊離の量を考慮して調整した)。血液を24時間後に採血して、血中リンパ球数をADVIA120血液分析器(Siemens Healthcare Diagnostics)で決定した。結果は、各測定時にビヒクルで処理した群と比較して、循環リンパ球の割合の減少として評価された。この結果は、各処理群内の全ての動物の平均的な結果を示す(n=2)。上記した血中リンパ球減少アッセイ(BLR)の結果は、表Bに示される。
本発明の化合物は、SlP1受容体のアゴニストとしての活性を有しており、血中リンパ球減少アッセイの低下をもたらし、そのため様々なSlP1受容体に関連した症状を治療、予防または治癒する際に使用され得る。驚くべき本発明の化合物の選択性は、自己免疫および炎症性疾患、例えば、多発性硬化症、関節リウマチ、炎症性腸疾患、全身性エリテマトーテス、乾癬または血管性疾患を治療、予防または治癒する際のその使用可能性を提示する。本発明の化合物の他の使用可能性は、移植された臓器の拒絶反応を最小または低減することを包含する。
Claims (16)
- 前記化合物が、(1R,3S)−1−アミノ−3−(2−ヘプチル−4,5−ジヒドロナフト[2,1−d]チアゾール−7−イル)シクロペンチル)メタノール,TFA塩(1);((1R,3S)−1−アミノ−3−(2−プロピル−4,5−ジヒドロナフト[2,1−d]チアゾール−7−イル)シクロペンチル)メタノール,トリフルオロ酢酸塩(2);((1R,3S)−1−アミノ−3−(2−(3,3−ジメチルブチル)−4,5−ジヒドロナフト[2,1−d]チアゾール−7−イル)シクロペンチル)メタノール,トリフルオロ酢酸塩(3);((1R,3S)−1−アミノ−3−(2−ネオペンチル−4,5−ジヒドロナフト[2,1−d]チアゾール−7−イル)シクロペンチル)メタノール,トリフルオロ酢酸塩(4);((1R,3S)−1−アミノ−3−(2−ヘキシル−4,5−ジヒドロナフト[2,1−d]チアゾール−7−イル)シクロペンチル)メタノール,トリフルオロ酢酸塩(5);((1R,3S)−1−アミノ−3−(2−ブチル−4,5−ジヒドロナフト[2,1−d]チアゾール−7−イル)シクロペンチル)メタノール,トリフルオロ酢酸塩(6);((1R,3S)−1−アミノ−3−(2−(2−ブトキシエトキシ)−4,5−ジヒドロナフト[2,1−d]チアゾール−7−イル)シクロペンチル)メタノール,トリフルオロ酢酸塩(7);((1R,3S)−1−アミノ−3−(2−ブトキシ−4,5−ジヒドロナフト[2,1−d]チアゾール−7−イル)シクロペンチル)メタノール,トリフルオロ酢酸塩(8);((1R,3S)−1−アミノ−3−(2−(ヘキシルオキシ)−4,5−ジヒドロナフト[2,1−d]チアゾール−7−イル)シクロペンチル)メタノール,トリフルオロ酢酸塩(9);((1R,3S)−1−アミノ−3−(2−(ブチルチオ)−4,5−ジヒドロナフト[2,1−d]チアゾール−7−イル)シクロペンチル)メタノール,トリフルオロ酢酸塩(10);((1R,3S)−1−アミノ−3−(2−(ペンチルチオ)−4,5−ジヒドロナフト[2,1−d]チアゾール−7−イル)シクロペンチル)メタノール,トリフルオロ酢酸塩(11);((1R,3S)−1−アミノ−3−(2−(ペンチルオキシ)−4,5−ジヒドロナフト[2,1−d]チアゾール−7−イル)シクロペンチル)メタノール,トリフルオロ酢酸塩(12);((1R,3S)−1−アミノ−3−(2−(ヘキシルオキシ)ナフト[2,1−d]チアゾール−7−イル)シクロペンチル)メタノール,トリフルオロ酢酸塩(13);((1R,3S)−1−アミノ−3−(2−(ブチルチオ)ナフト[2,1−d]チアゾール−7−イル)シクロペンチル)メタノール,トリフルオロ酢酸塩(14);((1R,3S)−1−アミノ−3−(2−(ペンチルオキシ)ナフト[2,1−d]チアゾール−7−イル)シクロペンチル)メタノール,トリフルオロ酢酸塩(15);((1R,3S)−1−アミノ−3−(2−ブトキシナフト[2,1−d]チアゾール−7−イル)シクロペンチル)メタノール,トリフルオロ酢酸塩(16);((1R,3S)−1−アミノ−3−(2−(ブチルアミノ)−4,5−ジヒドロナフト[2,1−d]チアゾール−7−イル)シクロペンチル)メタノール,トリフルオロ酢酸塩(17);((1R,3S)−1−アミノ−3−(2−(ブチル(メチル)アミノ)−4,5−ジヒドロナフト[2,1−d]チアゾール−7−イル)シクロペンチル)メタノール,トリフルオロ酢酸塩(18);((1R,3S)−1−アミノ−3−(2−(p−トリル)−4,5−ジヒドロナフト[2,1−d]チアゾール−7−イル)シクロペンチル)メタノール,トリフルオロ酢酸塩(19);((1R,3S)−1−アミノ−3−(2−(3−メトキシフェニル)−4,5−ジヒドロナフト[2,1−d]チアゾール−7−イル)シクロペンチル)メタノール,トリフルオロ酢酸塩(20);((1R,3S)−1−アミノ−3−(2−ペンチル−4,5−ジヒドロナフト[2,1−b]チオフェン−7−イル)シクロペンチル)メタノール,トリフルオロ酢酸塩(21);((1R,3S)−1−アミノ−3−(2−(ヘキシルオキシ)−4,5−ジヒドロナフト[2,1−d]チアゾール−7−イル)シクロペンチル)メチル ジヒドロゲンホスフェート,トリフルオロ酢酸塩(30);((1R,3S)−1−アミノ−3−(2−(ブチルチオ)−4,5−ジヒドロナフト[2,1−d]チアゾール−7−イル)シクロペンチル)メチル ジヒドロゲンホスフェート,トリフルオロ酢酸塩(31);((1R,3S)−1−アミノ−3−(2−(ブチルアミノ)−4,5−ジヒドロナフト[2,1−d]チアゾール−7−イル)シクロペンチル)メチル ジヒドロゲンホスフェート,トリフルオロ酢酸塩(32);((1R,3S)−1−アミノ−3−(2−(ペンチルチオ)−4,5−ジヒドロナフト[2,1−d]チアゾール−7−イル)シクロペンチル)メチルメチル ジヒドロゲンホスフェート,トリフルオロ酢酸塩(33);((1R,3S)−1−アミノ−3−(2−(ペンチルオキシ)−4,5−ジヒドロナフト[2,1−d]チアゾール−7−イル)シクロペンチル)メチル ジヒドロゲンホスフェート,トリフルオロ酢酸塩(34);((1R,3S)−1−アミノ−3−(2−(p−トリル)−4,5−ジヒドロナフト[2,1−d]チアゾール−7−イル)シクロペンチル)メチル ジヒドロゲンホスフェート,トリフルオロ酢酸塩(35);((1R,3S)−1−アミノ−3−(2−(3−メトキシフェニル)−4,5−ジヒドロナフト[2,1−d]チアゾール−7−イル)シクロペンチル)メチル ジヒドロゲンホスフェート,トリフルオロ酢酸塩(36);((1R,3S)−1−アミノ−3−(2−(3,3−ジメチルブチル)−4,5−ジヒドロナフト[2,1−d]チアゾール−7−イル)シクロペンチル)メチル ジヒドロゲンホスフェート,トリフルオロ酢酸塩(37);((1R,3S)−1−アミノ−3−(2−ネオペンチル−4,5−ジヒドロナフト[2,1−d]チアゾール−7−イル)シクロペンチル)メチル ジヒドロゲンホスフェート,トリフルオロ酢酸塩(38);((1R,3S)−1−アミノ−3−(2−ブチル−4,5−ジヒドロナフト[2,1−d]チアゾール−7−イル)シクロペンチル)メチル ジヒドロゲンホスフェート,トリフルオロ酢酸塩(39);((1R,3S)−1−アミノ−3−(2−ヘキシル−4,5−ジヒドロナフト[2,1−d]チアゾール−7−イル)シクロペンチル)メチル ジヒドロゲンホスフェート,トリフルオロ酢酸塩(40);((1R,3S)−1−アミノ−3−(2−ブトキシナフト[2,1−d]チアゾール−7−イル)シクロペンチル)メチル ジヒドロゲンホスフェート,TFA塩(46);((1R,3S)−1−アミノ−3−(2−(ヘキシルオキシ)ナフト[2,1−d]チアゾール−7−イル)シクロペンチル)メチル ジヒドロゲンホスフェート,TFA塩(47);および((1R,3S)−1−アミノ−3−(2−(ブチルチオ)ナフト[2,1−d]チアゾール−7−イル)シクロペンチル)メチル ジヒドロゲンホスフェート(48)、
から選択される、請求項1記載の化合物。 - 前記化合物が、(1−アミノ−3−(3−(5−ヘキシル−4−(トリフルオロメチル)イソオキサゾール−3−イル)−4,5−ジヒドロナフト[1,2−c]イソオキサゾール−7−イル)シクロペンチル)メタノール(22〜25);または(1−アミノ−3−(3−ヘキシル−4,5−ジヒドロナフト[1,2−c]イソオキサゾール−7−イル)シクロペンチル)メチル ジヒドロゲンホスフェート(41〜45)である、請求項3記載の化合物。
- 前記化合物が、(3−アミノ−3−(ヒドロキシメチル)ピロリジン−1−イル)(2−(3−フェニル−4−(トリフルオロメチル)イソオキサゾール−5−イル)−4,5−ジヒドロナフト[2,1−d]チアゾール−7−イル)メタノン(49および50);または(3−アミノ−3−(ヒドロキシメチル)ピロリジン−1−イル)(2−(3−フェニル−4−(トリフルオロメチル)イソオキサゾール−5−イル)−4,5−ジヒドロナフト[2,1−d]チアゾール−7−イル)メタノン(51〜53)である、請求項3記載の化合物。
- 請求項1に記載の化合物またはその医薬的に許容される塩;ならびに医薬的に許容される担体を包含する、医薬組成物。
- 哺乳類患者に、請求項1記載の化合物またはその医薬的に許容される塩を投与することを特徴とする、自己免疫疾患または慢性炎症疾患を治療する方法。
- 自己免疫疾患または慢性炎症疾患が、ループス(lupus)、多発性硬化症、炎症性腸疾患、シューグレン症候群および関節リウマチから選択される、請求項7記載の方法。
- 請求項3記載の化合物またはその医薬的に許容される塩;ならびに医薬的に許容される担体を含む、医薬組成物。
- 哺乳類患者に、請求項3記載の化合物またはその医薬的に許容される塩を投与することを特徴とする、自己免疫疾患または慢性炎症性疾患を治療する方法。
- 自己免疫疾患または慢性炎症疾患が、ループス、多発性硬化症、炎症性腸疾患、シューグレン症候群および関節リウマチから選択される、請求項10記載の方法。
- 請求項5記載の化合物またはその医薬的に許容される塩;ならびに医薬的に許容される担体を含む、医薬組成物。
- 哺乳類患者に、請求項5記載の化合物またはその医薬的に許容される塩を投与することを特徴とする、自己免疫疾患または慢性炎症疾患を治療する方法。
- 自己免疫疾患または慢性炎症疾患が、ループス、多発性硬化症、炎症性腸疾患、シューグレン症候群および関節リウマチから選択される、請求項13記載の方法。
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Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP2010513532A (ja) * | 2006-12-21 | 2010-04-30 | アボット・ラボラトリーズ | スフィンゴシン−1−ホスフェート受容体作働薬および拮抗薬化合物 |
JP2013509431A (ja) * | 2009-10-29 | 2013-03-14 | ブリストル−マイヤーズ スクイブ カンパニー | 三環式ヘテロ環化合物 |
WO2016028959A1 (en) * | 2014-08-20 | 2016-02-25 | Bristol-Myers Squibb Company | Substituted bicyclic compounds |
Family Cites Families (57)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JPS4722226Y1 (ja) | 1968-09-04 | 1972-07-20 | ||
GB1354098A (en) | 1970-04-24 | 1974-06-05 | Teikoku Hormone Mfg Co Ltd | 1-hydroxyiminonaphthalene derivatives |
GB1354097A (en) | 1970-04-24 | 1974-06-05 | Teikoku Hormone Mfg Co Ltd | Isoxazole derivatives |
JPS4716454Y1 (ja) | 1970-07-22 | 1972-06-09 | ||
US3843666A (en) | 1973-05-29 | 1974-10-22 | Sandoz Ag | Process for preparing substituted indeno,naphtho and cyclohepta pyrazoles |
US4200750A (en) | 1977-01-07 | 1980-04-29 | Westwood Pharmaceuticals Inc. | 4-Substituted imidazo [1,2-a]quinoxalines |
JPS62127067A (ja) | 1985-11-28 | 1987-06-09 | 日科ミクロン株式会社 | 酸素発生器 |
CA2146018A1 (en) | 1992-10-23 | 1994-05-11 | Paul David Leeson | Dopamine receptor subtype ligands |
US6069143A (en) | 1994-12-20 | 2000-05-30 | Smithkline Beecham Corporation | Fibrinogen receptor antagonists |
CA2241845C (en) | 1996-01-05 | 2002-10-01 | Hoechst Marion Roussel, Inc. | 4,5-dihydronaphth[1,2-c]isoxazoles and derivatives thereof having cns activity |
TW416953B (en) | 1996-09-25 | 2001-01-01 | Takeda Chemical Industries Ltd | Tricyclic compounds for eliciting a prostaglandin I2 receptor agonistic effect, their production and use |
PT1023063E (pt) | 1997-10-06 | 2004-02-27 | Abbott Gmbh & Co Kg | Derivados de indeno¬1,2-c|- nafto¬1,2-c|- e benzo¬6,7|ciclo-hepta¬1,2-c|pirazole |
CN1335836A (zh) | 1998-11-06 | 2002-02-13 | 巴斯福股份公司 | 三环吡唑衍生物 |
US6462036B1 (en) | 1998-11-06 | 2002-10-08 | Basf Aktiengesellschaft | Tricyclic pyrazole derivatives |
DE19908538A1 (de) | 1999-02-26 | 2000-08-31 | Aventis Pharma Gmbh | Polycyclische 2-Amino-Thiazol Systeme, Verfahren zu ihrer Herstellung und Arzneimittel enthaltend diese Verbindungen |
WO2000055158A1 (de) | 1999-03-12 | 2000-09-21 | Basf Aktiengesellschaft | Tricyclische benzoylpyrazol-derivate als herbizide |
WO2003061655A1 (en) | 2002-01-16 | 2003-07-31 | University Of Virginia Patent Foundation | 2-aminothiazole allosteric enhancers of a1 adenosine receptors |
AU2003216054B2 (en) | 2002-01-18 | 2007-01-04 | Merck & Co., Inc. | Selective S1P1/Edg1 receptor agonists |
JP4430941B2 (ja) | 2002-01-18 | 2010-03-10 | メルク エンド カムパニー インコーポレーテッド | Edg受容体作動薬 |
US7351725B2 (en) | 2002-01-18 | 2008-04-01 | Merck & Co., Inc. | N-(benzyl)aminoalkylcarboxylates, phosphinates, phosphonates and tetrazoles as Edg receptor agonists |
CA2477423A1 (en) | 2002-03-01 | 2003-09-12 | Merck & Co., Inc. | Aminoalkylphosphonates and related compounds as edg receptor agonists |
DE60326950D1 (de) | 2002-05-15 | 2009-05-14 | Janssen Pharmaceutica Nv | N-substituierte tricyclische 3-aminopyrazole als pdgf rezeptorenhemmer |
US7220764B2 (en) | 2002-06-17 | 2007-05-22 | The Pennsylvania State University Research Foundation | Sphingosine kinase inhibitors |
EP1549640A4 (en) | 2002-06-17 | 2008-08-06 | Merck & Co Inc | 1 - ((5-ARYL-1,2,4-OXADIAZOL-3-YL) BENZYL) AZETIDINE-3-CARBOXYLATE AND 1 - ((5-ARYL-1,2,4-OXADIAZOL-3-YL) BENZYL) PYRROLIDIN-3-CARBOXYLATE AS EDG RECEPTOR AGONISTS |
JP2004018489A (ja) | 2002-06-19 | 2004-01-22 | Otsuka Pharmaceut Factory Inc | Acat−1阻害剤 |
US7320986B2 (en) | 2003-03-07 | 2008-01-22 | Abbott Labortories | Fused tri and tetra-cyclic pyrazole kinase inhibitors |
AU2004251146A1 (en) | 2003-05-19 | 2005-01-06 | Irm, Llc | Immunosuppressant compounds and compositions |
WO2005058848A1 (en) | 2003-12-17 | 2005-06-30 | Merck & Co., Inc. | (3,4-disubstituted)propanoic carboxylates as s1p (edg) receptor agonists |
EP1719771A1 (en) | 2004-02-19 | 2006-11-08 | Takeda Pharmaceutical Company Limited | Pyrazoloquinolone derivative and use thereof |
TW200538433A (en) | 2004-02-24 | 2005-12-01 | Irm Llc | Immunosuppressant compounds and compositiions |
US7468371B2 (en) | 2004-03-24 | 2008-12-23 | Abbott Laboratories Inc. | Tricyclic pyrazole kinase inhibitors |
EP1793919A4 (en) | 2004-09-03 | 2009-12-23 | Imarx Therapeutics Inc | DEVICE AND METHOD FOR PRODUCING A MICROSPHERIC COMPOSITE COMPOSITION |
WO2006047195A2 (en) | 2004-10-22 | 2006-05-04 | Merck & Co., Inc. | 2-(aryl)azacyclylmethyl carboxylates, sulfonates, phosphonates, phosphinates and heterocycles as s1p receptor agonists |
CA2586156A1 (en) | 2004-11-04 | 2006-05-18 | Merck & Co., Inc. | Niacin receptor agonists, compositions containing such compounds and methods of treatment |
MX2007011672A (es) | 2005-03-23 | 2007-11-15 | Actelion Pharmaceuticals Ltd | Nuevos derivados de tiofeno como agonistas del receptor de esfingosina-1-fosfato-1. |
DE602006015297D1 (de) | 2005-04-22 | 2010-08-19 | Daiichi Sankyo Co Ltd | 3-azetidincarbonsäure-derivate zur verwendung als immunsuppressiva |
JP2008545767A (ja) | 2005-06-08 | 2008-12-18 | ノバルティス アクチエンゲゼルシャフト | 多環式オキサジアゾールまたはイソキサゾールおよびsip受容体リガンドとしてのそれらの使用 |
AU2006283175A1 (en) | 2005-08-23 | 2007-03-01 | Irm Llc | Immunosuppressant compounds and compositions |
CA2646469A1 (en) | 2006-03-21 | 2007-09-27 | Epix Delaware, Inc. | S1p receptor modulating compounds |
BRPI0709866B8 (pt) | 2006-04-03 | 2021-05-25 | Astellas Pharma Inc | compostos héteros e composição farmacêutica compreendendo ditos compostos |
JP2009269819A (ja) | 2006-08-25 | 2009-11-19 | Asahi Kasei Pharma Kk | アミン化合物 |
CA2974246C (en) | 2006-09-01 | 2020-02-25 | Senhwa Biosciences, Inc. | Tricyclic heteroaryl compounds and their use as protein modulators |
MX2009002234A (es) | 2006-09-08 | 2009-03-16 | Actelion Pharmaceuticals Ltd | Derivados de piridin-3-il como agentes inmunomoduladores. |
US8779154B2 (en) | 2006-09-26 | 2014-07-15 | Qinglin Che | Fused ring compounds for inflammation and immune-related uses |
RS20090208A (en) | 2006-10-31 | 2010-06-30 | Pfizer Products Inc. | Pyrazoline compounds as mineralocorticoid receptor antagonists |
GB0625648D0 (en) | 2006-12-21 | 2007-01-31 | Glaxo Group Ltd | Compounds |
WO2008094896A1 (en) | 2007-01-31 | 2008-08-07 | Janssen Pharmaceutica, N.V. | N-substituted tricyclic 3-aminopyrazoles as anti-mitotic tubulin polymerization inhibitors |
CN101627034B (zh) | 2007-03-16 | 2013-05-15 | 埃科特莱茵药品有限公司 | 氨基-吡啶衍生物作为s1p1/edg1受体激动剂 |
CL2008000793A1 (es) | 2007-03-23 | 2008-05-30 | Xenon Pharmaceuticals Inc | Compuestos derivados de dihidroindazol; composicion farmaceutica que comprende a dichos compuestos; y su uso para tratar un trastorno del hierro. |
JP4899161B2 (ja) | 2007-06-04 | 2012-03-21 | ギガフォトン株式会社 | エキシマレーザ装置 |
EA201070422A1 (ru) | 2007-10-04 | 2010-12-30 | Мерк Сероно С.А. | Производные оксадиазола |
KR20100092473A (ko) | 2007-11-01 | 2010-08-20 | 액테리온 파마슈티칼 리미티드 | 신규한 피리미딘 유도체 |
AU2008338965A1 (en) | 2007-12-18 | 2009-06-25 | Arena Pharmaceuticals, Inc. | Tetrahydrocyclopenta[b]indol-3-yl carboxylic acid derivatives useful in the treatment of autoimmune and inflammatory disorders |
WO2009089305A1 (en) | 2008-01-07 | 2009-07-16 | Synta Pharmaceuticals Corp. | Compounds for inflammation and immune-related uses |
KR101626996B1 (ko) | 2008-03-31 | 2016-06-02 | 제넨테크, 인크. | 벤조피란 및 벤족세핀 pi3k 저해제 화합물 및 이의 사용 방법 |
EP2326621B1 (en) | 2008-07-23 | 2016-06-08 | Arena Pharmaceuticals, Inc. | SUBSTITUTED 1,2,3,4- TETRAHYDROCYCLOPENTA[b]INDOL-3-YL) ACETIC ACID DERIVATIVES USEFUL IN THE TREATMENT OF AUTOIMMUNE AND INFLAMMATORY DISORDERS |
US9115054B2 (en) | 2013-02-21 | 2015-08-25 | Bristol-Myers Squibb Company | Tetrahydronaphthalenyl compounds useful as sipi agonists |
-
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Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP2010513532A (ja) * | 2006-12-21 | 2010-04-30 | アボット・ラボラトリーズ | スフィンゴシン−1−ホスフェート受容体作働薬および拮抗薬化合物 |
JP2013509431A (ja) * | 2009-10-29 | 2013-03-14 | ブリストル−マイヤーズ スクイブ カンパニー | 三環式ヘテロ環化合物 |
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JP7029445B2 (ja) | 2022-03-03 |
US20190218193A1 (en) | 2019-07-18 |
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CN110234633A (zh) | 2019-09-13 |
KR102482825B1 (ko) | 2022-12-29 |
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