JP7197244B2 - 免疫応答調節剤として使用するための分岐鎖連結基を有するアミド置換イミダゾ[4,5-c]キノリン化合物 - Google Patents
免疫応答調節剤として使用するための分岐鎖連結基を有するアミド置換イミダゾ[4,5-c]キノリン化合物 Download PDFInfo
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- WPLOVIFNBMNBPD-ATHMIXSHSA-N subtilin Chemical compound CC1SCC(NC2=O)C(=O)NC(CC(N)=O)C(=O)NC(C(=O)NC(CCCCN)C(=O)NC(C(C)CC)C(=O)NC(=C)C(=O)NC(CCCCN)C(O)=O)CSC(C)C2NC(=O)C(CC(C)C)NC(=O)C1NC(=O)C(CCC(N)=O)NC(=O)C(CC(C)C)NC(=O)C(NC(=O)C1NC(=O)C(=C/C)/NC(=O)C(CCC(N)=O)NC(=O)C(CC(C)C)NC(=O)C(C)NC(=O)CNC(=O)C(NC(=O)C(NC(=O)C2NC(=O)CNC(=O)C3CCCN3C(=O)C(NC(=O)C3NC(=O)C(CC(C)C)NC(=O)C(=C)NC(=O)C(CCC(O)=O)NC(=O)C(NC(=O)C(CCCCN)NC(=O)C(N)CC=4C5=CC=CC=C5NC=4)CSC3)C(C)SC2)C(C)C)C(C)SC1)CC1=CC=CC=C1 WPLOVIFNBMNBPD-ATHMIXSHSA-N 0.000 description 1
- 239000013589 supplement Substances 0.000 description 1
- 230000001629 suppression Effects 0.000 description 1
- 239000000375 suspending agent Substances 0.000 description 1
- 208000011580 syndromic disease Diseases 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- MEQRKUOHHVBSMX-HNNXBMFYSA-N tert-butyl N-[(4S)-4-[(3-aminoquinolin-4-yl)amino]-5-ethoxypentyl]carbamate Chemical compound NC=1C=NC2=CC=CC=C2C=1N[C@@H](CCCNC(OC(C)(C)C)=O)COCC MEQRKUOHHVBSMX-HNNXBMFYSA-N 0.000 description 1
- NHRZYMHFDYWMHU-ZDUSSCGKSA-N tert-butyl N-[(4S)-4-[(3-aminoquinolin-4-yl)amino]-5-hydroxypentyl]carbamate Chemical compound NC=1C=NC2=CC=CC=C2C=1N[C@@H](CCCNC(OC(C)(C)C)=O)CO NHRZYMHFDYWMHU-ZDUSSCGKSA-N 0.000 description 1
- VMSNAGJCAFKZOF-JTQLQIEISA-N tert-butyl N-[(4S)-4-amino-5-ethoxypentyl]carbamate Chemical compound N[C@@H](CCCNC(OC(C)(C)C)=O)COCC VMSNAGJCAFKZOF-JTQLQIEISA-N 0.000 description 1
- FIALLEIYGSKKSC-HNNXBMFYSA-N tert-butyl N-[(4S)-5-ethoxy-4-[(3-nitroquinolin-4-yl)amino]pentyl]carbamate Chemical compound C(C)OC[C@H](CCCNC(OC(C)(C)C)=O)NC1=C(C=NC2=CC=CC=C12)[N+](=O)[O-] FIALLEIYGSKKSC-HNNXBMFYSA-N 0.000 description 1
- LFVHTDROVHZSPI-INIZCTEOSA-N tert-butyl N-[(4S)-5-ethoxy-4-imidazo[4,5-c]quinolin-1-ylpentyl]carbamate Chemical compound C(C)OC[C@H](CCCNC(OC(C)(C)C)=O)N1C=NC=2C=NC=3C=CC=CC=3C=21 LFVHTDROVHZSPI-INIZCTEOSA-N 0.000 description 1
- QXYLCTPEAXTKCA-AWEZNQCLSA-N tert-butyl N-[(4S)-5-hydroxy-4-imidazo[4,5-c]quinolin-1-ylpentyl]carbamate Chemical compound OC[C@H](CCCNC(OC(C)(C)C)=O)N1C=NC=2C=NC=3C=CC=CC=3C=21 QXYLCTPEAXTKCA-AWEZNQCLSA-N 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- 229960002766 tetanus vaccines Drugs 0.000 description 1
- 229940124597 therapeutic agent Drugs 0.000 description 1
- 229940021747 therapeutic vaccine Drugs 0.000 description 1
- 238000004809 thin layer chromatography Methods 0.000 description 1
- 150000007970 thio esters Chemical class 0.000 description 1
- 210000001519 tissue Anatomy 0.000 description 1
- 239000003053 toxin Substances 0.000 description 1
- 231100000765 toxin Toxicity 0.000 description 1
- 108700012359 toxins Proteins 0.000 description 1
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 1
- 238000011269 treatment regimen Methods 0.000 description 1
- 229960002109 tuberculosis vaccine Drugs 0.000 description 1
- 210000004881 tumor cell Anatomy 0.000 description 1
- 201000008297 typhoid fever Diseases 0.000 description 1
- 241000701161 unidentified adenovirus Species 0.000 description 1
- 241001529453 unidentified herpesvirus Species 0.000 description 1
- 241000712461 unidentified influenza virus Species 0.000 description 1
- 241001430294 unidentified retrovirus Species 0.000 description 1
- 208000007089 vaccinia Diseases 0.000 description 1
- 229940021648 varicella vaccine Drugs 0.000 description 1
- 239000003981 vehicle Substances 0.000 description 1
- 230000029663 wound healing Effects 0.000 description 1
- 230000037314 wound repair Effects 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K39/39—Medicinal preparations containing antigens or antibodies characterised by the immunostimulating additives, e.g. chemical adjuvants
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
Description
本出願は、2017年12月20日に出願された米国特許仮出願第62/608334号の優先権を主張するものであり、その開示の全体が参照により本明細書に組み込まれる。
いくつかの薬剤化合物は、免疫システムの特定の重要な側面を刺激することによって、及び特定の他の側面を抑制することによって、作用する(例えば、米国特許第6,039,969号(Tomai et al.)、及び同第6,200,592号(Tomai et al.))。これらの化合物は、時として、免疫応答調節剤(immune response modifier、IRM)と呼ばれる。いくつかのIRM化合物は、ウイルス性疾患、腫瘍形成、及びTH2-媒介性疾患を処置するのに有用である。いくつかのIRM化合物は、ワクチンアジュバントとして有用である。
Rは、ハロゲン、ヒドロキシ、アルキル、アルコキシ、及び-C(O)-O-アルキルからなる群から選択され、
nは、0又は1の整数であり、
Xはアルキレンであり、このアルキレン基は、1つ以上の-O-基により任意に介在されていてもよく、
R1は、C1-5アルキル及び-C1-3アルキレン-O-C1-3アルキルからなる群から選択され、
R2は、水素、メチル、エチル、n-プロピル、n-ブチル、-CH2OCH3、-CH2OCH2CH3、及び-CH2CH2OCH3からなる群から選択され、
R3はアルキルであり、このアルキル基は、1つ以上の-O-基により任意に介在されていてもよく、
R4は、水素、メチル、エチル、n-プロピル、及びイソプロピルからなる群から選択される。
本開示の医薬組成物も想到される。本開示の医薬組成物は、本開示(本明細書に記載)の化合物又は塩の治療有効量を、製薬上許容される担体と組み合わせて含有する。
ウイルス性疾患、例えば、アデノウイルス、ヘルペスウイルス(例えば、HSV-I、HSV-II、CMV、若しくはVZV)、ポックスウイルス(例えば、天然痘若しくはワクシニアなどのオルソポックスウイルス、又は伝染性軟属腫)、ピコルナウイルス(例えば、ライノウイルス若しくはエンテロウイルス)、オルソミクソウイルス(例えば、インフルエンザウイルス、鳥インフルエンザ)、パラミクソウイルス(例えば、パラインフルエンザウイルス、ムンプスウイルス、麻疹ウイルス、及び呼吸器合胞体ウイルス(respiratory syncytial virus、RSV)、コロナウイルス(例えば、SARS)、パポバウイルス(例えば、性器疣贅、尋常性疣贅、又は足底疣贅を引き起こすものなどのパピローマウイルス)、ヘパドナウイルス(例えば、B型肝炎ウイルス)、フラビウイルス(例えば、C型肝炎ウイルス若しくはデングウイルス)、又はレトロウイルス(例えば、HIVなどのレンチウイルス)、エボラウイルスによる感染によって引き起こされる疾患。
アトピー性皮膚炎又は湿疹、好酸球増加、喘息、アレルギー、アレルギー性鼻炎、及びオメン症候群などのTH2媒介性アトピー性疾患;
創傷修復に関連する疾患、例えば、ケロイド形成及び他のタイプの瘢痕化の阻害(例えば、慢性創傷を含めた創傷治療の促進)など;
マラリア、リーシュマニア症、クリプトスポリジア症、トキソプラズマ症、及びトリパノソーマ感染症を含むがこれらに限定されない寄生生物性疾患が挙げられる。
実施形態1は、式(I)
nは、0又は1の整数であり、
Rは、ハロゲン、ヒドロキシ、アルキル、アルコキシ、及び-C(O)-O-アルキルからなる群から選択され、
Xはアルキレンであり、このアルキレン基は、1つ以上の-O-基により任意に介在されていてもよく、
R1は、C1-5アルキル及び-C1-3アルキレン-O-C1-3アルキルからなる群から選択され、
R2は、水素、メチル、エチル、n-プロピル、n-ブチル、-CH2OCH3、-CH2OCH2CH3、及び-CH2CH2OCH3からなる群から選択され、
R3はアルキルであり、このアルキル基は、1つ以上の-O-基により任意に介在されていてもよく、
R4は、水素、メチル、エチル、n-プロピル、及びイソプロピルからなる群から選択される]の化合物、又は製薬上許容されるその塩である。
N-[(4S)-4-(4-アミノイミダゾ[4,5-c]キノリン-1-イル)-5-エトキシ-ペンチル]アセトアミド、
N-[(4S)-4-(4-アミノイミダゾ[4,5-c]キノリン-1-イル)-5-エトキシ-ペンチル]プロパンアミド、
N-[(4S)-4-(4-アミノイミダゾ[4,5-c]キノリン-1-イル)-5-エトキシ-ペンチル]-2-メチルプロパンアミド、
N-[(4S)-4-(4-アミノイミダゾ[4,5-c]キノリン-1-イル)-5-エトキシ-ペンチル]ブタンアミド、
N-[(4S)-4-(4-アミノイミダゾ[4,5-c]キノリン-1-イル)-5-エトキシ-ペンチル]-3-メチルブタンアミド、
N-[(4S)-4-(4-アミノイミダゾ[4,5-c]キノリン-1-イル)-5-エトキシ-ペンチル]ペンタンアミド、
N-[(4S)-4-(4-アミノイミダゾ[4,5-c]キノリン-1-イル)-5-エトキシ-ペンチル]ヘキサンアミド、
N-[(4S)-4-(4-アミノイミダゾ[4,5-c]キノリン-1-イル)-5-エトキシ-ペンチル]オクタンアミド、
N-[(4S)-4-(4-アミノイミダゾ[4,5-c]キノリン-1-イル)-5-エトキシ-ペンチル]ノナンアミド、
N-[(4S)-4-(4-アミノイミダゾ[4,5-c]キノリン-1-イル)-5-エトキシ-ペンチル]デカンアミドからなる群から選択される化合物、又は製薬上許容されるその塩である。
N-[(4S)-4-(4-アミノイミダゾ[4,5-c]キノリン-1-イル)-5-エトキシ-ペンチル]ドデカンアミド、
N-[(4S)-4-(4-アミノイミダゾ[4,5-c]キノリン-1-イル)-5-エトキシ-ペンチル]テトラデカンアミド、
N-[(4S)-4-(4-アミノイミダゾ[4,5-c]キノリン-1-イル)-5-エトキシ-ペンチル]ヘキサデカンアミドからなる群から選択される化合物、又は製薬上許容されるその塩である。
N-[(4S)-4-(4-アミノイミダゾ[4,5-c]キノリン-1-イル)-5-エトキシ-ペンチル]オクタデカンアミド、
N-[(4S)-4-(4-アミノイミダゾ[4,5-c]キノリン-1-イル)-5-エトキシ-ペンチル]エイコサンアミド
からなる群から選択される化合物、又は製薬上許容されるその塩である。
nは、0又は1の整数であり、
Rは、ハロゲン、ヒドロキシ、アルキル、アルコキシ、及び-C(O)-O-アルキルからなる群から選択され、
Xはアルキレンであり、このアルキレン基は、1つ以上の-O-基により任意に介在されていてもよく、
R1は、C1-5アルキル及び-C1-3アルキレン-O-C1-3アルキルからなる群から選択され、
R2は、水素、メチル、エチル、n-プロピル、及びn-ブチル、-CH2OCH3、-CH2OCH2CH3、及び-CH2CH2OCH3からなる群から選択され、
R3はアルキルであり、このアルキル基は、1つ以上の-O-基により任意に介在されていてもよく、
R4は、水素、メチル、エチル、n-プロピル、及びイソプロピルからなる群から選択される]の化合物、又は製薬上許容されるその塩である。
N-[4-(4-アミノイミダゾ[4,5-c]キノリン-1-イル)-5-エトキシ-ペンチル]アセトアミド、
N-[4-(4-アミノイミダゾ[4,5-c]キノリン-1-イル)-5-エトキシ-ペンチル]プロパンアミド、
N-[4-(4-アミノイミダゾ[4,5-c]キノリン-1-イル)-5-エトキシ-ペンチル]-2-メチルプロパンアミド、
N-[4-(4-アミノイミダゾ[4,5-c]キノリン-1-イル)-5-エトキシ-ペンチル]ブタンアミド、
N-[4-(4-アミノイミダゾ[4,5-c]キノリン-1-イル)-5-エトキシ-ペンチル]-3-メチルブタンアミド、
N-[4-(4-アミノイミダゾ[4,5-c]キノリン-1-イル)-5-エトキシ-ペンチル]ペンタンアミド、
N-[4-(4-アミノイミダゾ[4,5-c]キノリン-1-イル)-5-エトキシ-ペンチル]ヘキサンアミド、
N-[4-(4-アミノイミダゾ[4,5-c]キノリン-1-イル)-5-エトキシ-ペンチル]オクタンアミド、
N-[4-(4-アミノイミダゾ[4,5-c]キノリン-1-イル)-5-エトキシ-ペンチル]ノナンアミド、
N-[4-(4-アミノイミダゾ[4,5-c]キノリン-1-イル)-5-エトキシ-ペンチル]デカンアミドからなる群から選択される化合物、又は製薬上許容されるその塩である。
N-[4-(4-アミノイミダゾ[4,5-c]キノリン-1-イル)-5-エトキシ-ペンチル]ドデカンアミド、
N-[4-(4-アミノイミダゾ[4,5-c]キノリン-1-イル)-5-エトキシ-ペンチル]テトラデカンアミド、
N-[4-(4-アミノイミダゾ[4,5-c]キノリン-1-イル)-5-エトキシ-ペンチル]ヘキサデカンアミドからなる群から選択される化合物、又は製薬上許容されるその塩である。
N-[4-(4-アミノイミダゾ[4,5-c]キノリン-1-イル)-5-エトキシ-ペンチル]オクタデカンアミド、
N-[4-(4-アミノイミダゾ[4,5-c]キノリン-1-イル)-5-エトキシ-ペンチル]エイコサンアミド
からなる群から選択される化合物、又は製薬上許容されるその塩である。
15mLの無水テトラヒドロフラン(tetrahydrofuran、THF)に溶解させたN-δ-BOC-N-α-CBZ-L-オルニチン(4.71g、12.9mmol)の撹拌溶液を、氷/メタノール浴において-15℃に冷却した。この溶液をN-メチルモルホリン(1.42mL、12.9mmol)と組み合わせ、続いてエチルクロロホルメート(1.23mL、12.9mmol)を添加した。5分間撹拌した後、反応混合物を濾過し、少量のTHFですすぎ、N-メチルモルホリン塩酸塩を除去した。得られた濾液を冷浴に戻し、7mLの水中、1.00gのNaBH4の溶液を注意深く添加した。20分間撹拌した後、反応混合物を100mLの水と組み合わせ、続いて75mLの酢酸エチルを添加した。この層を分離し、有機部分を水及び飽和食塩水で洗浄し、Na2SO4で乾燥させ、濾過し、濃縮して無色のシロップを得た。シロップをヘプタンから濃縮して、白色固体として、3.62gのtert-ブチルN-[(4S)-4-(ベンジルオキシカルボニルアミノ)-5-ヒドロキシ-ペンチル]カルバメートをもたらした。
20mLのトルエンに溶解させたN-[(4S)-4-(ベンジルオキシカルボニルアミノ)-5-ヒドロキシ-ペンチル]カルバメート(3.62g、10.3mmol)の撹拌溶液を、1.15gの50%NaOH溶液及びジエチルサルフェート(1.61mL、12.3mmol)と組み合わせた。次いで、テトラブチルアンモニウムクロリド水和物(200mg)を、反応混合物に添加した。2時間撹拌した後、反応混合物を10mLの飽和NH4OH溶液でクエンチし、更に75分間撹拌した。次いで、反応物を水と組み合わせ、層同士を分離した。有機層を水(2×)及び飽和食塩水で連続的に洗浄し、Na2SO4で乾燥させ、濾過し、減圧下で濃縮して、無色のシロップを得た。カラムクロマトグラフィー(SiO2、20%酢酸エチル/ヘキサンから50%酢酸エチル)による精製は、白色結晶固体として、0.37gのtert-ブチルN-[(4S)-4-(ベンジルオキシカルボニルアミノ)-5-エトキシ-ペンチル]カルバメートをもたらした。
メタノール中のtert-ブチルN-[(4S)-4-(ベンジルオキシカルボニルアミノ)-5-エトキシ-ペンチル]カルバメート(0.37g、0.97mmol)の溶液を圧力ボトルに入れ、40mgの炭素担持10%パラジウムを添加した。次いで、水素(40PSI)雰囲気下、ボトルを終夜振盪した。反応混合物をセライトのパッドを通して濾過し、メタノールですすぎ、減圧下で濾液を濃縮して、無色のシロップとして、197mgのtert-ブチルN-[(4S)-4-アミノ-5-エトキシ-ペンチル]カルバメートを得た。
15mLのジクロロメタンに溶解させたtert-ブチルN-[(4S)-4-アミノ-5-エトキシ-ペンチル]カルバメート(197mg、0.801mmol)の溶液を、4-クロロ-3-ニトロキノリン(166mg、0.801mmol)及びトリエチルアミン(223μL、1.60mmol)と組み合わせ、反応混合物を窒素雰囲気下で終夜撹拌した。反応混合物を濃縮し、黄色固体を得た。この固体を、20mLの酢酸エチルに溶解させ、水(3×)及び飽和食塩水で洗浄した。有機部分をNa2SO4で乾燥させ、濾過し、濃縮して、黄色固体を得た。カラムクロマトグラフィー(SiO2、20%酢酸エチル/ヘキサンから50%酢酸エチル)による精製は、黄色固体として、283mgのtert-ブチルN-[(4S)-5-エトキシ-4-[(3-ニトロ-4-キノリル)アミノ]ペンチル]カルバメートをもたらした。
15mLのアセトニトリル中のtert-ブチルN-[(4S)-5-エトキシ-4-[(3-ニトロ-4-キノリル)アミノ]ペンチル]カルバメート(283mg、0.677mmol)の懸濁液を圧力ボトルに入れ、次いで、80mgの炭素担持3%白金を添加した。次いで、水素(40PSI)雰囲気下、ボトルを90分間振盪した。反応混合物をセライトのパッドを通して濾過し、アセトニトリルですすぎ、減圧下で濾液を濃縮して、橙色の泡として、262mgのtert-ブチルN-[(4S)-4-[(3-アミノ-4-キノリル)アミノ]-5-エトキシ-ペンチル]カルバメートを得た。
10mLの酢酸n-プロピル中に溶解させたtert-ブチルN-[(4S)-4-[(3-アミノ-4-キノリル)アミノ]-5-エトキシ-ペンチル]カルバメート(262mg、0.67mmol)の溶液を、トリエチルオルトホルメート(0.32mL、1.92mmol)及び50mgのピリジン塩酸塩と組み合わせ、混合物を105℃に終夜加熱した。冷却した反応混合物を25mLの酢酸エチルで希釈し、飽和NaHCO3溶液、水、及び飽和食塩水で連続的に洗浄した。有機部分をNa2SO4で乾燥させ、濾過し、濃縮して、淡褐色のシロップを得た。カラムクロマトグラフィー(SiO2、2.5%メタノール/クロロホルムから5%メタノール/クロロホルム)による精製は、淡琥珀色のシロップとして、200mgのtert-ブチルN-[(4S)-5-エトキシ-4-イミダゾ[4,5-c]キノリン-1-イル-ペンチル]カルバメートをもたらした。
5mLのジクロロメタンに溶解させたtert-ブチルN-[(4S)-5-エトキシ-4-イミダゾ[4,5-c]キノリン-1-イル-ペンチル]カルバメート(200mg、0.497mmol)の溶液を、3-クロロ過安息香酸(150mg、57~86%)と組み合わせ、反応物を45分間撹拌した。反応混合物を、1mLの濃NH4OH溶液及びp-トルエンスルホニルクロリド(104mg、0.547mmol)と組み合わせた。45分間撹拌した後、反応混合物を10mLのジクロロメタンで希釈し、水(3×)及び飽和食塩水で洗浄した。有機部分をNa2SO4で乾燥させ、濾過し、減圧下で濃縮した。カラムクロマトグラフィー(SiO2、33%CMA/クロロホルムから50%CMA)による精製によって、淡褐色のシロップを得た。このシロップを、30mLのジクロロメタンに溶解させ、1N NaOH溶液(2×)、水、及び飽和食塩水で連続的に洗浄した。有機部分をNa2SO4で乾燥させ、濾過し、減圧下で濃縮した。カラムクロマトグラフィー(SiO2、2.5%メタノール/クロロホルムから10%メタノール/クロロホルム)による更なる精製は、71mgのtert-ブチルN-[(4S)-4-(4-アミノイミダゾ[4,5-c]キノリン-1-イル)-5-エトキシ-ペンチル]カルバメートの淡褐色のシロップをもたらした。
5mLのエタノールに溶解させたtert-ブチルN-[(4S)-4-(4-アミノイミダゾ[4,5-c]キノリン-1-イル)-5-エトキシ-ペンチル]カルバメート(71mg、0.172mmol)の溶液を、0.5mLの濃塩酸溶液と組み合わせた。混合物を90℃に60分間加熱し、次いで、減圧下で濃縮した。得られたシロップをエタノールから濃縮して、硬い白色の泡として、62mgの1-[(1S)-4-アミノ-1-(エトキシメチル)ブチル]イミダゾ[4,5-c]キノリン-4-アミン二塩酸塩を得た。
1.2mLの無水N,N-ジメチルホルムアミド(dimethylformamide、DMF)に溶解させた1-[(1S)-4-アミノ-1-(エトキシメチル)ブチル]イミダゾ[4,5-c]キノリン-4-アミン二塩酸塩(62mg、0.16mmol)の溶液を、トリエチルアミン(67μL、0.48mmol)及びステアロイルクロリド(50mg、0.16mmol)と組み合わせた。90分間撹拌した後、反応混合物を2mLのジクロロメタンと組み合わせ、撹拌を90分間継続した。反応混合物を、20mLのジクロロメタン及び水で希釈した。少量のメタノールを添加し、得られたエマルションを分解した。層同士を分離し、有機部分を水(2×)及び飽和食塩水で洗浄した。有機部分をNa2SO4で乾燥させ、濾過し、減圧下で濃縮した。カラムクロマトグラフィー(SiO2、2.5%メタノール/クロロホルムから10%メタノール/クロロホルム)による精製によって、46mgの固体を得た。2mLの高温アセトニトリルからの結晶化は、白色粉末として、38mgのN-[(4S)-4-(4-アミノイミダゾ[4,5-c]キノリン-1-イル)-5-エトキシ-ペンチル]オクタデカンアミドをもたらした。1H NMR(CD3OD,500MHz)δ8.41(s,1H),8.27(d,J=8.2Hz,1H),7.74(d,J=8.3Hz,1H),7.54(t,J=7.7Hz,1H),7.38(t,J=7.6Hz,1H),5.39(m,1H),4.01(dd,J=5.8,10.4Hz,1H),3.93(dd,J=3.8,10.4Hz,1H),3.52(q,J=7.0Hz,2H),3.22(m,2H),2.19(m,2H),2.14(t,J=7.4Hz,2H),1.63-1.51(m,4H),1.32-1.23(m,24H),1.12(t,J=7.0Hz,3H),0.92(t,J=7.0Hz,3H)。
15mLの無水THF中に溶解させたN-δ-BOC-N-α-CBZ-L-オルニチン(4.71g、12.9mmol)の撹拌溶液を、氷/メタノール浴において-15℃に冷却した。溶液にN-メチルモルホリン(1.43mL、13.0mmol)を添加し、続いてイソブチルクロロホルメート(1.69mL、13.0mmol)を添加した。5分間撹拌した後、反応混合物を濾過し、少量のTHFですすぎ、N-メチルモルホリン塩酸塩を除去した。得られた濾液を冷浴に戻し、7mLのH2O中、1.00gのNaBH4の溶液を注意深く添加した。20分間撹拌した後、反応混合物を100mLの水と組み合わせ、続いて100mLの酢酸エチルを添加した。層同士を分離し、追加の25mLの酢酸エチルで水性部分を抽出した。組み合わせた有機部分を水及び飽和食塩水で洗浄し、Na2SO4で乾燥させ、濾過し、濃縮して無色のシロップを得た。シロップをエタノールから濃縮して、白色固体として、4.22gのtert-ブチルN-[(4S)-4-(ベンジルオキシカルボニルアミノ)-5-ヒドロキシ-ペンチル]カルバメートをもたらした。
50mLのメタノール中のtert-ブチルN-[(4S)-4-(ベンジルオキシカルボニルアミノ)-5-ヒドロキシ-ペンチル]カルバメート(4.22g、12.0mmol)の溶液を圧力ボトルに入れ、300mgの炭素担持10%パラジウムを添加した。次いで、水素(40PSI)雰囲気下、ボトルを終夜振盪した。反応混合物をセライトのパッドを通して濾過し、MeOHですすぎ、減圧下で濾液を濃縮して、無色のシロップとして、2.61gのtert-ブチルN-[(4S)-4-アミノ-5-ヒドロキシ-ペンチル]カルバメートを得た。
50mLのジクロロメタンに溶解させたtert-ブチルN-[(4S)-4-アミノ-5-ヒドロキシ-ペンチル]カルバメート(2.61g、12.0mmol)の溶液を、4-クロロ-3-ニトロキノリン(2.49g、12.0mmol)及びトリエチルアミン(3.33mL、23.9mmol)と組み合わせ、反応混合物を窒素雰囲気下で終夜撹拌した。反応混合物を濃縮し、黄色固体を得た。この固体を、125mLの酢酸エチルに溶解させ、水(3×)及び飽和食塩水で洗浄した。有機部分をNa2SO4で乾燥させ、濾過し、濃縮して、黄色固体として、4.23gのtert-ブチルN-[(4S)-5-ヒドロキシ-4-[(3-ニトロ-4-キノリル)アミノ]ペンチル]カルバメートを得た。
125mLのアセトニトリル中のtert-ブチルN-[(4S)-5-ヒドロキシ-4-[(3-ニトロ-4-キノリル)アミノ]ペンチル]カルバメート(4.23g、10.8mmol)の懸濁液を圧力ボトルに入れ、200mgの炭素担持3%白金を添加した。次いで、水素(40PSI)雰囲気下、ボトルを4時間振盪した。反応混合物をセライトのパッドを通して濾過し、アセトニトリルですすぎ、減圧下で濾液を濃縮して、橙色の泡として、3.80gのtert-ブチルN-[(4S)-4-[(3-アミノ-4-キノリル)アミノ]-5-ヒドロキシ-ペンチル]カルバメートを得た。
40mLの酢酸n-プロピル中に溶解させたtert-ブチルN-[(4S)-4-[(3-アミノ-4-キノリル)アミノ]-5-ヒドロキシ-ペンチル]カルバメート(3.80g、10.6mmol)の溶液を、トリエチルオルトホルメート(3.50mL、21.1mmol)及び300mgのピリジン塩酸塩と組み合わせ、混合物を105℃に2日間加熱した。冷却した反応混合物を50mLの酢酸エチルで希釈し、飽和NaHCO3溶液、水、及び飽和食塩水で連続的に洗浄した。有機部分をNa2SO4で乾燥させ、濾過し、濃縮して、淡褐色のシロップを得た。カラムクロマトグラフィー(SiO2、1%メタノール/クロロホルムから10%メタノール/クロロホルム)による精製は、白色の泡として、2.40gのtert-ブチルN-[(4S)-5-ヒドロキシ-4-イミダゾ[4,5-c]キノリン-1-イル-ペンチル]カルバメートをもたらした。
200mLの丸底(bound bottom)フラスコに、1.04gの50%NaOH水溶液、及び150mgのテトラブチルアンモニウムクロリド水和物を投入した。40mLの高温トルエンに溶解させたtert-ブチルN-[(4S)-5-ヒドロキシ-4-イミダゾ[4,5-c]キノリン-1-イル-ペンチル]カルバメート(2.00g、5.40mmol)の溶液を添加し、反応混合物を85℃に加熱した。ジエチルサルフェート(886μL、6.77mmol)を添加し、混合物を4時間撹拌した。反応混合物を冷却し、10mLの飽和NH4OH溶液でクエンチした。75分間撹拌した後、反応物を水及びトルエンと組み合わせ、層同士を分離した。有機層をH2O(2×)及び飽和食塩水で連続的に洗浄し、Na2SO4で乾燥させ、濾過し、減圧下で濃縮して、無色のシロップを得た。カラムクロマトグラフィー(SiO2、20%酢酸エチル/ヘキサンから50%酢酸エチル)による精製は、金色のシロップとして、888mgのtert-ブチルN-[(4S)-5-エトキシ-4-イミダゾ[4,5-c]キノリン-1-イル-ペンチル]カルバメートをもたらした。
実施例1のG及びH剤の手順に従って、321mg(0.832mmol)の1-[(1S)-4-アミノ-1-(エトキシメチル)ブチル]イミダゾ[4,5-c]キノリン-4-アミン二塩酸塩をもたらした。この化合物を5mLの無水DMFに溶解させ、トリエチルアミン(347μL、2.50mmol)及びミリストイルクロリド(226μL、0.832mmol)と組み合わせた。終夜撹拌した後、25mLの水を反応混合物に添加した。得られた固体を濾過によって単離し、水ですすぎ、10%メタノール/クロロホルムに溶解させ、次いで減圧下で濃縮し、ワックス状固体を得た。カラムクロマトグラフィー(SiO2、2%メタノール/クロロホルムから15%メタノール/クロロホルム)による精製によって、淡褐色固体を得た。アセトニトリルからの結晶化は、淡褐色固体として、30mgのN-[(4S)-4-(4-アミノイミダゾ[4,5-c]キノリン-1-イル)-5-エトキシ-ペンチル]テトラデカンアミドをもたらした。1H NMR(CD3OD,500MHz)δ8.42(s,1H),8.29(d,J=8.1Hz,1H),7.75(d,J=8.3Hz,1H),7.56(t,J=7.7Hz,1H),7.40(t,J=7.6Hz,1H),5.40(m,1H),4.01(dd,J=5.4,10.0Hz,1H),3.93(dd,J=3.0,10.2Hz,1H),3.52(q,J=6.9Hz,2H),3.22(m,2H),2.27-2.08(m,4H),1.64-1.50(m,4H),1.39-1.21(m,20H),1.11(t,J=7.0Hz,3H),0.91(t,J=6.8Hz,3H)。
健康なヒト供与者からの全血を、静脈穿刺によって、EDTAが入ったバキュテイナー管又はシリンジに採取した。密度勾配遠心分離により、ヒト末梢血単核球(peripheral blood mononuclear cell、PBMC)を全血から精製した。Histopaque 1077(15mL、Sigma(St.Louis,MO))を、6×50mL滅菌ポリプロピレンコニカルチューブに移した。Histopaqueに、ハンクス平衡塩溶液(Hank’s Balanced Salts Solution、HBSS)(Gibco,Life Technology(Grand Island NY))で1:2に希釈した15~25mLの血液を重層した。次いで、このチューブを、1370rpm、30分間、20℃で、中断なく遠心分離した(400×g、GH 3.8A Rotor)。
Claims (10)
- 式(I)
nは、0又は1の整数であり、
Rは、ハロゲン、ヒドロキシ、アルキル、アルコキシ、及び-C(O)-O-アルキルからなる群から選択され、
Xはアルキレンであり、前記アルキレン基は、1つ以上の-O-基により任意に介在されていてもよく、
R1は、C1-5アルキル及び-C1-3アルキレン-O-C1-3アルキルからなる群から選択され、
R2は、水素、メチル、エチル、n-プロピル、n-ブチル、-CH2OCH3、-CH2OCH2CH3、及び-CH2CH2OCH3からなる群から選択され、
R3はアルキルであり、前記アルキル基は、1つ以上の-O-基により任意に介在されていてもよく、
R4は、水素、メチル、エチル、n-プロピル、及びイソプロピルからなる群から選択される]
の化合物、又は製薬上許容されるその塩。 - XがC1-8アルキレンである、請求項1に記載の化合物又は塩。
- R1が、-CH2OCH3又は-CH2OCH2CH3である、請求項1に記載の化合物又は塩。
- R2が、水素、メチル、及びエチルからなる群から選択される、請求項1に記載の化合物又は塩。
- R3がC5-19アルキルである、請求項1に記載の化合物又は塩。
- Rが、ヒドロキシ、F、及びClからなる群から選択される、請求項1に記載の化合物又は塩。
- nが0である、請求項1に記載の化合物又は塩。
- R4が水素である、請求項1に記載の化合物又は塩。
- ワクチンアジュバントとして使用するための、請求項1に記載の化合物又は塩。
- 請求項1に記載の化合物又は塩の治療有効量を、製薬上許容される担体と組み合わせて含む、医薬組成物。
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CN111511740A (zh) | 2020-08-07 |
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