JP7386536B2 - アルキル鎖修飾イミダゾキノリンtlr7/8アゴニスト化合物およびその使用 - Google Patents
アルキル鎖修飾イミダゾキノリンtlr7/8アゴニスト化合物およびその使用 Download PDFInfo
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- JP7386536B2 JP7386536B2 JP2020511364A JP2020511364A JP7386536B2 JP 7386536 B2 JP7386536 B2 JP 7386536B2 JP 2020511364 A JP2020511364 A JP 2020511364A JP 2020511364 A JP2020511364 A JP 2020511364A JP 7386536 B2 JP7386536 B2 JP 7386536B2
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- KKCQWEAKAPLUIE-UHFFFAOYSA-N tert-butyl n-[[4-[[(3-amino-2-chloroquinolin-4-yl)amino]methyl]phenyl]methyl]carbamate Chemical compound C1=CC(CNC(=O)OC(C)(C)C)=CC=C1CNC1=C(N)C(Cl)=NC2=CC=CC=C12 KKCQWEAKAPLUIE-UHFFFAOYSA-N 0.000 description 1
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- BCNZYOJHNLTNEZ-UHFFFAOYSA-N tert-butyldimethylsilyl chloride Chemical compound CC(C)(C)[Si](C)(C)Cl BCNZYOJHNLTNEZ-UHFFFAOYSA-N 0.000 description 1
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- IMFACGCPASFAPR-UHFFFAOYSA-N tributylamine Chemical compound CCCCN(CCCC)CCCC IMFACGCPASFAPR-UHFFFAOYSA-N 0.000 description 1
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- 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 description 1
- UFTFJSFQGQCHQW-UHFFFAOYSA-N triformin Chemical compound O=COCC(OC=O)COC=O UFTFJSFQGQCHQW-UHFFFAOYSA-N 0.000 description 1
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Images
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
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
Description
本出願は、2017年8月22日に出願の米国特許仮出願第62/548,848号(その開示全体が本明細書中で参考として援用される)の優先権および利益を主張する。
本開示は、免疫応答を増大させるためのアルキル鎖修飾イミダゾキノリンTLR7/8アゴニスト化合物に関する。本開示はまた、アルキル鎖修飾イミダゾキノリン化合物を含む薬学的組成物、その調製方法、免疫応答を刺激する方法、ならびに被験体の疾患(例えば、感染症およびがん)の処置における薬学的組成物の使用に関する。
Toll様レセプター(TLR)は、病原体関連分子パターンと呼ばれる病原体に由来し、かつ病原体に固有の構造が保存された分子を認識する膜貫通タンパク質のファミリーである。こうして、TLRは、哺乳動物免疫系において侵入する病原体の存在を検出する病原体関連分子パターンの最前線のセンサーとして機能する(Takeuchi and Akira 2010 Cell 140:805-820)。センチネル免疫細胞におけるTLRの会合により、選択されたサイトカイン(例えば、タイプIインターフェロン)の生合成、共刺激分子の誘導、および抗原提示能力の向上を引き起こす。これらは、自然免疫応答および獲得免疫応答を活性化する重要な分子機序である。したがって、TLRのアゴニストおよびアンタゴニストは、免疫応答の調節で用いられる。TLRアゴニストは、典型的には、免疫応答を刺激するために使用されるのに対して、TLRアンタゴニストは、典型的には、免疫応答を阻害するために用いられる(Gosu et al 2012 Molecules 17:13503-13529)。
しかし、皮下投与、腫瘍内投与、または筋肉内投与後の可溶性1H-イミダゾ[4,5-c]キノリンベースのTLR7/8アゴニストが全身に急速に分布することが、患者に非常に有毒であることが実証されている(例えば、Vasilakos et al 2013 Expert Rev Vaccines 12:809-819;Savage et al 1996 Br J Cancer 74:1482-1486;Pockros et al 2007 J Hepatol 47:174-182を参照のこと)。脾臓および肝臓の細胞におけるTLRの活性化によって全身免疫系が活性化すると血清炎症促進性サイトカインレベルが増加し、それによりインフルエンザ様症状および他の有害事象が引き起こされることが、これらの化合物のヒト治療薬としての使用を局所投与経路に制限させている。したがって、強力かつバランスの取れたTLR7/8アゴニスト活性を有し、かつ薬学的組成物が注射部位での化合物の保持を促進することが可能な生理化学的性質も有する小分子治療剤が依然として必要である。
R0は、1~4個のハロゲン原子により必要に応じて置換されたC4~C21ヒドロカルビルであり;
Xは、-NH-または-NH(C=O)-であり;
R1は、C3~C6アルキル、-(CH2)pOR1a、-(CH2)pNHR1b、または-(CH2)pR1cであり;ここで、R1aおよびR1bは、独立して、C1~C3アルキルであり;R1cはC3~C4シクロアルキルであり;pは1または2であり;
R2はNHR2aであり;ここで、R2aは、H、OH、NH2、またはメチルであり;
各R3は、独立して、ハロゲン、C1~C8アルキル、-(C1~C7アルキレン)-NH2、または-CH2-フェニレン-CH2NH2であり;
qは、0、1、2、3、または4であり;
R4aおよびR4bは、独立して、HまたはC1~C8アルキルである]の化合物またはその塩であって、
但し、前記化合物が、2-ブチル-1-(4-((ヘキサデシルアミノ)メチル)ベンジル)-1H-イミダゾ[4,5-c]キノリン-4-アミン(化合物番号63-32);N-(4-((4-アミノ-2-ブチル-1H-イミダゾ[4,5-c]キノリン-1-イル)メチル)ベンジル)パルミトアミド(化合物番号63-31);またはN-(4-((4-アミノ-2-ブチル-1H-イミダゾ[4,5-c]キノリン-1-イル)メチル)ベンジル)ペンタ-4-インアミド(化合物番号63-37)以外である、化合物またはその塩が提供される。
いくつかの実施形態において、R0はC4~C14ヒドロカルビルである。
nは、4~21の整数であり;
Xは、-NH-または-NH(C=O)-であり;
R1は、C3~C6アルキル、-(CH2)pOR1a、-(CH2)pNHR1b、または-(CH2)pR1cであり;ここで、R1aおよびR1bは、独立して、C1~C3アルキルであり;R1cはC3~C4シクロアルキルであり;pは1または2であり;
R2はNHR2aであり;ここで、R2aは、H、OH、NH2、またはメチルであり;
各R3は、独立して、ハロゲン、C1~C8アルキル、-(C1~C7アルキレン)-NH2、または-CH2-フェニレン-CH2NH2であり;
qは、0、1、2、3、または4であり;
R4aおよびR4bは、独立して、HまたはC1~C8アルキルである]の化合物またはその塩であって、
但し、前記化合物が、2-ブチル-1-(4-((ヘキサデシルアミノ)メチル)ベンジル)-1H-イミダゾ[4,5-c]キノリン-4-アミン(化合物番号63-32)またはN-(4-((4-アミノ-2-ブチル-1H-イミダゾ[4,5-c]キノリン-1-イル)メチル)ベンジル)パルミトアミド(化合物番号63-31)以外である、化合物またはその塩が提供される。
I.一般的な方法および定義
II.化合物
R0は、1~4個のハロゲン原子により必要に応じて置換されたC4~C21ヒドロカルビルであり;
Xは、-NH-または-NH(C=O)-であり;
R1は、C3~C6アルキル、-(CH2)pOR1a、-(CH2)pNHR1b、または-(CH2)pR1cであり;ここで、R1aおよびR1bは、独立して、C1~C3アルキルであり;R1cはC3~C4シクロアルキルであり;pは1または2であり;
R2はNHR2aであり;ここで、R2aは、H、OH、NH2、またはメチルであり;
各R3は、独立して、ハロゲン、C1~C8アルキル、-(C1~C7アルキレン)-NH2、または-CH2-フェニレン-CH2NH2であり;
qは、0、1、2、3、または4であり;
R4aおよびR4bは、独立して、HまたはC1~C8アルキルである]の化合物またはその塩であって、
但し、前記化合物が、2-ブチル-1-(4-((ヘキサデシルアミノ)メチル)ベンジル)-1H-イミダゾ[4,5-c]キノリン-4-アミン(化合物番号63-32);N-(4-((4-アミノ-2-ブチル-1H-イミダゾ[4,5-c]キノリン-1-イル)メチル)ベンジル)パルミトアミド(化合物番号63-31);またはN-(4-((4-アミノ-2-ブチル-1H-イミダゾ[4,5-c]キノリン-1-イル)メチル)ベンジル)ペンタ-4-インアミド(化合物番号63-37)以外である、化合物またはその塩が提供される。
nは、4~21の整数であり;
Xは、-NH-または-NH(C=O)-であり;
R1は、C3~C6アルキル、-(CH2)pOR1a、-(CH2)pNHR1b、または-(CH2)pR1cであり;ここで、R1aおよびR1bは、独立して、C1~C3アルキルであり;R1cはC3~C4シクロアルキルであり;pは1または2であり;
R2はNHR2aであり;ここで、R2aは、H、OH、NH2、またはメチルであり;
各R3は、独立して、ハロゲン、C1~C8アルキル、-(C1~C7アルキレン)-NH2、または-CH2-フェニレン-CH2NH2であり;
qは、0、1、2、3、または4であり;
R4aおよびR4bは、独立して、HまたはC1~C8アルキルである]の化合物またはその塩であって、
但し、前記化合物が、2-ブチル-1-(4-((ヘキサデシルアミノ)メチル)ベンジル)-1H-イミダゾ[4,5-c]キノリン-4-アミン(化合物番号63-32)またはN-(4-((4-アミノ-2-ブチル-1H-イミダゾ[4,5-c]キノリン-1-イル)メチル)ベンジル)パルミトアミド(化合物番号63-31)以外である、化合物またはその塩が提供される。
スキーム1
スキーム1-2
スキーム2
スキーム3
スキーム4
III.薬学的組成物
賦形剤
抗原
IV.使用方法
投与量および投与様式
免疫応答の刺激
疾患の処置
V.実施例
合成例
実施例S1:N-(4-((4-アミノ-2-ブチル-1H-イミダゾ[4,5-c]キノリン-1-イル)メチル)ベンジル)テトラデカンアミド(化合物番号63-10)の合成
実施例S2:2-ブチル-1-(4-((ペンチルアミノ)メチル)ベンジル)-1H-イミダゾ[4,5-c]キノリン-4-アミン(化合物番号63-17)の合成
実施例S3:2-ブチル-1-(4-(((2-シクロプロピルエチル)アミノ)メチル)ベンジル)-1H-イミダゾ[4,5-c]キノリン-4-アミン(化合物番号63-33)の合成
実施例S4:他の例示的な化合物の合成
実施例S5:2-ブチル-1-(4-(((シクロプロピルメチル)アミノ)メチル)ベンジル)-1H-イミダゾ[4,5-c]キノリン-4-アミン(化合物番号63-38)の合成。
実施例S6:2-ブチル-1-(4-((((1-メチルシクロブチル)メチル)アミノ)メチル)ベンジル)-1H-イミダゾ[4,5-c]キノリン-4-アミン(化合物番号63-45)の合成。
実施例S7:2-ブチル-1-(4-(((シクロブチルメチル)アミノ)メチル)ベンジル)-1H-イミダゾ[4,5-c]キノリン-4-アミン(化合物番号63-44)の合成。
実施例S8:2-ブチル-1-(4-(((2-シクロブチル-2-メチルプロピル)アミノ)メチル)ベンジル)-1H-イミダゾ[4,5-c]キノリン-4-アミン(化合物番号63-47)の合成。
パートB。化合物番号63-00(60mg、0.17mmol)を、(2,3,4,5,6-ペンタフルオロフェニル)-2-シクロブチル-2-メチル-プロパノアート(54mg、0.18mmol)を含むジクロロメタン(3mL)の溶液に、トリエチルアミン(34mg、0.34mmol)の存在下で添加し、還流状態で3日間撹拌した。次いで、反応混合物を室温に冷却し、減圧下で濃縮し、残渣を5%酢酸エチル/ヘキサンで洗浄した。洗浄した残渣をジクロロメタン(15mL)に溶解し、1M HClで洗浄後に水(20mL)で洗浄し、硫酸マグネシウムで乾燥させ、濾過し、減圧下で濃縮して、67mgのN-(4-((4-アミノ-2-ブチル-1H-イミダゾ[4,5-c]キノリン-1-イル)メチル)ベンジル)-2-シクロブチル-2-メチルプロパンアミドをオフホワイトの固体として得た。
実施例S9:2-ブチル-1-(4-(((2-シクロプロピル-2-メチルプロピル)アミノ)メチル)ベンジル)-1H-イミダゾ[4,5-c]キノリン-4-アミン(化合物番号63-41)の合成。
実施例S10:2-ブチル-1-(4-((シクロヘキシルアミノ)メチル)ベンジル)-1H-イミダゾ[4,5-c]キノリン-4-アミン(化合物番号63-49)の合成。
実施例S11:式(J-2)の例示的なN-アシル化合物の合成
実施例S12:式(K)の例示的な化合物の合成
実施例S14:式(K-2)のさらなる例示的なN-アシル化合物の合成
生物学的実施例
実施例B1。インビトロ生物学的アッセイおよび結果
方法
結果
油相を形成するために、DOPC(175.6mg)を、4mLガラスバイアル中のスクアレンオイル(1.4mL)に添加した。次いで、混合物を、脂質が溶解するまで15分毎に短時間ボルテックスしながら超音波水浴中で70℃で45分間インキュベートした。示した化合物(13.7mg)をスクアレン/DOPC溶液に添加し、1分間強くボルテックスした。次いで、この溶液を、超音波水浴中にて10分毎に短時間ボルテックスしながら70℃で30分間インキュベートした。必要に応じて透明な溶液を作製するために、混合物を90℃の水浴中で15分毎に短時間ボルテックスしながら2時間さらにインキュベートした。別で水相を形成するために、Tween(登録商標)80(70mg)およびグリセロール(315mg)を、50mLポリプロピレンチューブ中で100mMクエン酸ナトリウム(pH6.5)溶液(3.5mL)および水(29.8mL)と混合した。
実施例B3。インビボ全身免疫活性化アッセイ
実施例B4。CT26結腸癌保有野生型マウスにおけるアルキル鎖修飾TLR7/8アゴニストの抗腫瘍有効性
実施例B5。2つの側腹部にCT26結腸癌を保有する野生型マウスにおける腫瘍関連抗原を共投与したアルキル鎖修飾TLR7/8アゴニストの抗腫瘍有効性
実施例B6。両側腹部にCT26結腸癌を保有する野生型マウスにおける免疫チェックポイント阻害と組み合わせたアルキル鎖修飾TLR7/8アゴニストの抗腫瘍有効性
一実施形態において、例えば、以下の項目が提供される。
(項目1)
式(J):
R 0 は、1~4個のハロゲン原子により必要に応じて置換されたC 4 ~C 21 ヒドロカルビルであり;
Xは、-NH-または-NH(C=O)-であり;
R 1 は、C 3 ~C 6 アルキル、-(CH 2 ) p OR 1a 、-(CH 2 ) p NHR 1b 、または-(CH 2 ) p R 1c であり;ここで、R 1a およびR 1b は、独立して、C 1 ~C 3 アルキルであり;R 1c はC 3 ~C 4 シクロアルキルであり;pは1または2であり;
R 2 はNHR 2a であり;ここで、R 2a は、H、OH、NH 2 、またはメチルであり;
各R 3 は、独立して、ハロゲン、C 1 ~C 8 アルキル、-(C 1 ~C 7 アルキレン)-NH 2 、または-CH 2 -フェニレン-CH 2 NH 2 であり;
qは、0、1、2、3、または4であり;
R 4a およびR 4b は、独立して、HまたはC 1 ~C 8 アルキルである]の化合物またはその塩であって、
但し、前記化合物が、2-ブチル-1-(4-((ヘキサデシルアミノ)メチル)ベンジル)-1H-イミダゾ[4,5-c]キノリン-4-アミン;N-(4-((4-アミノ-2-ブチル-1H-イミダゾ[4,5-c]キノリン-1-イル)メチル)ベンジル)パルミトアミド;またはN-(4-((4-アミノ-2-ブチル-1H-イミダゾ[4,5-c]キノリン-1-イル)メチル)ベンジル)ペンタ-4-インアミド以外である、化合物またはその塩。
(項目2)
R 0 がC 4 ~C 14 ヒドロカルビルである、項目1に記載の化合物またはその塩。
(項目3)
Xが-NH(C=O)-である、項目1または2に記載の化合物またはその塩。
(項目4)
Xが-NH-である、項目1または2に記載の化合物またはその塩。
(項目5)
R 0 は、分枝C 4 ~C 14 アルキル、-(CH 2 ) z (C(CH 3 ) 2 )R A 、または-(CH 2 ) m R A であり;mは、0、1、2、または3であり;zは、1または2であり;R A は、C 1 ~C 4 アルキル、C 1 ~C 4 アルキレン、およびハロゲンからなる群より独立して選択される1~4個の基により必要に応じて置換されたC 3 ~C 8 シクロアルキルである、項目1~4のいずれか1項に記載の化合物またはその塩。
(項目6)
R 0 が分枝C 4 ~C 14 アルキルである、項目1~5のいずれか1項に記載の化合物またはその塩。
(項目7)
R 0 が-(CH 2 ) m R A である、項目1~5のいずれか1項に記載の化合物またはその塩。
(項目8)
mが2である、項目7に記載の化合物またはその塩。
(項目9)
R 0 が-(CH 2 ) z (C(CH 3 ) 2 )R A である、項目1~5のいずれか1項に記載の化合物またはその塩。
(項目10)
zが1である、項目9に記載の化合物またはその塩。
(項目11)
R A が、シクロプロピル、シクロブチル、またはシクロペンチルである、項目7~10のいずれか1項に記載の化合物またはその塩。
(項目12)
R A が、メチル、メチレン、およびハロゲンからなる群より独立して選択される1~3個の基により必要に応じて置換されたC 3 ~C 6 シクロアルキルである、項目7~10のいずれか1項に記載の化合物またはその塩。
(項目13)
mが1または2である、項目5に記載の化合物またはその塩。
(項目14)
R A がC 3 ~C 8 シクロアルキルである、項目13に記載の化合物またはその塩。
(項目15)
R A が、メチルおよびメチレンからなる群より独立して選択される1~3個の基により必要に応じて置換されたシクロプロピルである、項目13または14に記載の化合物またはその塩。
(項目16)
mが0であり、R A が、メチルおよびメチレンからなる群より独立して選択される1~3個の基により必要に応じて置換されたシクロヘキシルである、項目5に記載の化合物またはその塩。
(項目17)
R 0 が、
(項目18)
前記化合物が、表1中の化合物番号63-33~63-36および63-38~63-49からなる群より選択される、項目1に記載の化合物またはその塩。
(項目19)
式(K):
nは、4~21の整数であり;
Xは、-NH-または-NH(C=O)-であり;
R 1 は、C 3 ~C 6 アルキル、-(CH 2 ) p OR 1a 、-(CH 2 ) p NHR 1b 、または-(CH 2 ) p R 1c であり;ここで、R 1a およびR 1b は、独立して、C 1 ~C 3 アルキルであり;R 1c はC 3 ~C 4 シクロアルキルであり;pは1または2であり;
R 2 はNHR 2a であり;ここで、R 2a は、H、OH、NH 2 、またはメチルであり;
各R 3 は、独立して、ハロゲン、C 1 ~C 8 アルキル、-(C 1 ~C 7 アルキレン)-NH 2 、または-CH 2 -フェニレン-CH 2 NH 2 であり;
qは、0、1、2、3、または4であり;
R 4a およびR 4b は、独立して、HまたはC 1 ~C 8 アルキルである]の化合物またはその塩であって、
但し、前記化合物が、2-ブチル-1-(4-((ヘキサデシルアミノ)メチル)ベンジル)-1H-イミダゾ[4,5-c]キノリン-4-アミンまたはN-(4-((4-アミノ-2-ブチル-1H-イミダゾ[4,5-c]キノリン-1-イル)メチル)ベンジル)パルミトアミド以外である、化合物またはその塩。
(項目20)
Xが-NH-である、項目19に記載の化合物またはその塩。
(項目21)
nは、4~15の整数である、項目19または20に記載の化合物またはその塩。
(項目22)
nが、4、5、6、または7である、項目19~21のいずれか1項に記載の化合物またはその塩。
(項目23)
Xが-NH(C=O)-である、項目19に記載の化合物またはその塩。
(項目24)
nが、11、12、13、または14である、項目23に記載の化合物またはその塩。
(項目25)
R 1 がC 3 ~C 6 アルキルである、項目19~24のいずれか1項に記載の化合物またはその塩。
(項目26)
R 1 がn-ブチルである、項目25に記載の化合物。
(項目27)
R 1 が-(CH 2 ) p OR 1a である、項目19~24のいずれか1項に記載の化合物またはその塩。
(項目28)
R 1 が-(CH 2 ) p NHR 1b である、項目19~24のいずれか1項に記載の化合物またはその塩。
(項目29)
R 1 が-(CH 2 ) p R 1c である、項目19~24のいずれか1項に記載の化合物またはその塩。
(項目30)
R 2 がNH 2 である、項目19~29のいずれか1項に記載の化合物またはその塩。
(項目31)
qが0である、項目19~30のいずれか1項に記載の化合物またはその塩。
(項目32)
qが1であり、R 3 がC 1 ~C 8 アルキルである、項目19~30のいずれか1項に記載の化合物またはその塩。
(項目33)
R 4a およびR 4b の各々がHである、項目19~32のいずれか1項に記載の化合物またはその塩。
(項目34)
前記化合物が、表1中の化合物番号63-01~63-30からなる群より選択される、項目19に記載の化合物またはその塩。
(項目35)
(i)項目1~34のいずれか1項に記載の化合物またはその塩;および(ii)薬学的に許容され得る賦形剤を含む薬学的組成物。
(項目36)
抗原をさらに含む、項目35に記載の薬学的組成物。
(項目37)
前記薬学的に許容され得る賦形剤が油を含む、項目35または36に記載の薬学的組成物。
(項目38)
前記薬学的組成物がスクアレンベースの水中油型ナノエマルジョンである、項目35~37のいずれか1項に記載の薬学的組成物。
(項目39)
前記薬学的組成物がリポソーム製剤である、項目35または36に記載の薬学的組成物。
(項目40)
免疫応答の刺激を必要とする哺乳動物被験体において免疫応答を刺激する方法であって、前記哺乳動物被験体に、前記哺乳動物被験体における前記免疫応答を刺激するのに十分な量の項目35~39のいずれか1項に記載の薬学的組成物を投与する工程を含む、方法。
(項目41)
抗原特異的抗体応答の誘導を必要とする哺乳動物被験体において抗原特異的抗体応答を誘導する方法であって、前記哺乳動物被験体に、前記哺乳動物被験体における前記抗原特異的抗体応答および/または抗原特異的T細胞応答を誘導するのに十分な量の項目35~39のいずれか1項に記載の薬学的組成物を投与する工程を含む、方法。
(項目42)
感染症の処置を必要とする哺乳動物被験体において感染症を処置する方法であって、前記哺乳動物被験体に、前記哺乳動物被験体における前記感染症を処置するのに十分な量の項目35~39のいずれか1項に記載の薬学的組成物を投与する工程を含む、方法。
(項目43)
感染症の予防を必要とする哺乳動物被験体において感染症を予防する方法であって、前記哺乳動物被験体に、前記哺乳動物被験体における前記感染症を予防するのに十分な量の項目35~39のいずれか1項に記載の薬学的組成物を投与する工程を含む、方法。
(項目44)
IgE関連障害の処置を必要とする哺乳動物被験体においてIgE関連障害を処置する方法であって、前記哺乳動物被験体に、前記哺乳動物被験体における前記IgE関連障害を処置するのに十分な量の項目35~39のいずれか1項に記載の薬学的組成物を投与する工程を含む、方法。
(項目45)
IgE関連障害の予防を必要とする哺乳動物被験体においてIgE関連障害を予防する方法であって、前記哺乳動物被験体に、前記哺乳動物被験体における前記IgE関連障害を予防するのに十分な量の項目35~39のいずれか1項に記載の薬学的組成物を投与する工程を含む、方法。
(項目46)
がんの処置を必要とする哺乳動物被験体においてがんを処置する方法であって、前記哺乳動物被験体に、前記哺乳動物被験体におけるがんを処置するのに十分な量の項目35~39のいずれか1項に記載の薬学的組成物を投与する工程を含む、方法。
(項目47)
前記薬学的組成物が腫瘍内注射によって投与される、項目46に記載の方法。
(項目48)
有効量の第2の治療剤を前記被験体に投与する工程をさらに含む、項目46または47に記載の方法。
(項目49)
前記第2の治療剤が化学療法剤である、項目48に記載の方法。
(項目50)
前記第2の治療剤が、阻害性免疫チェックポイント分子のアンタゴニストである、項目48に記載の方法。
(項目51)
前記第2の治療剤がエピジェネティック調節剤である、項目48に記載の方法。
(項目52)
前記第2の治療剤が免疫原性細胞死の誘導物質である、項目48に記載の方法。
(項目53)
前記阻害性免疫チェックポイント分子が、PD-1、PD-L1、PD-L2、CTLA-4(CD152)、LAG-3、TIM-3、TIGIT、IL-10、およびTGF-ベータからなる群より選択される、項目50に記載の方法。
Claims (34)
- 式(J):
[式中、
R0は、-(CH2)mRAまたは-(CH2)z(C(CH3)2)RAであり;mは、0、1、2、または3であり;zは、1または2であり;RAは、C1~C4アルキル、C1~C4アルキレン、およびハロゲンからなる群より独立して選択される1~4個の基により必要に応じて置換されたC3~C8シクロアルキルであり;
Xは、-NH-であり;
R1は、C3~C6アルキル、-(CH2)pOR1a、-(CH2)pNHR1b、または-(CH2)pR1cであり;ここで、R1aおよびR1bは、独立して、C1~C3アルキルであり;R1cはC3~C4シクロアルキルであり;pは1または2であり;
R2はNHR2aであり;ここで、R2aは、H、OH、NH2、またはメチルであり;
各R3は、独立して、ハロゲン、C1~C8アルキル、-(C1~C7アルキレン)-NH2、または-CH2-フェニレン-CH2NH2であり;
qは、0、1、2、3、または4であり;
R4aおよびR4bは、独立して、HまたはC1~C8アルキルである]の化合物またはその塩。 - R0が-(CH2)mRAである、請求項1に記載の化合物またはその塩。
- mが2である、請求項2に記載の化合物またはその塩。
- R0が-(CH2)z(C(CH3)2)RAである、請求項1に記載の化合物またはその塩。
- zが1である、請求項4に記載の化合物またはその塩。
- RAが、シクロプロピル、シクロブチル、またはシクロペンチルである、請求項2~5のいずれか1項に記載の化合物またはその塩。
- RAが、メチル、メチレン、およびハロゲンからなる群より独立して選択される1~3個の基により必要に応じて置換されたC3~C6シクロアルキルである、請求項2~5のいずれか1項に記載の化合物またはその塩。
- mが1または2である、請求項1または2に記載の化合物またはその塩。
- RAがC3~C8シクロアルキルである、請求項8に記載の化合物またはその塩。
- RAが、メチルおよびメチレンからなる群より独立して選択される1~3個の基により必要に応じて置換されたシクロプロピルである、請求項8または9に記載の化合物またはその塩。
- mが0であり、RAが、メチルおよびメチレンからなる群より独立して選択される1~3個の基により必要に応じて置換されたシクロヘキシルである、請求項1または2に記載の化合物またはその塩。
- R0が、
からなる群より選択される、請求項1に記載の化合物またはその塩。 - 前記化合物が、表1中の化合物番号63-33、63-35、63-36および63-38~63-49:
からなる群より選択される、請求項1に記載の化合物またはその塩。 - (i)請求項1~13のいずれか1項に記載の化合物またはその塩;および(ii)薬学的に許容され得る賦形剤を含む薬学的組成物。
- 抗原をさらに含む、請求項14に記載の薬学的組成物。
- 前記薬学的に許容され得る賦形剤が油を含む、請求項14または15に記載の薬学的組成物。
- 前記薬学的組成物がスクアレンベースの水中油型ナノエマルジョンである、請求項14~16のいずれか1項に記載の薬学的組成物。
- 前記薬学的組成物がリポソーム製剤である、請求項14または15に記載の薬学的組成物。
- 免疫応答の刺激を必要とする哺乳動物被験体において免疫応答を刺激するための、請求項14~18のいずれか1項に記載の薬学的組成物。
- 抗原特異的抗体応答および/または抗原特異的T細胞応答の誘導を必要とする哺乳動物被験体において抗原特異的抗体応答および/または抗原特異的T細胞応答を誘導するための、請求項14~18のいずれか1項に記載の薬学的組成物。
- 感染症の処置を必要とする哺乳動物被験体において感染症を処置するための、請求項14~18のいずれか1項に記載の薬学的組成物。
- 感染症の予防を必要とする哺乳動物被験体において感染症を予防するための、請求項14~18のいずれか1項に記載の薬学的組成物。
- IgE関連障害の処置を必要とする哺乳動物被験体においてIgE関連障害を処置するための、請求項14~18のいずれか1項に記載の薬学的組成物。
- IgE関連障害の予防を必要とする哺乳動物被験体においてIgE関連障害を予防するための、請求項14~18のいずれか1項に記載の薬学的組成物。
- がんの処置を必要とする哺乳動物被験体においてがんを処置するための、請求項14~18のいずれか1項に記載の薬学的組成物。
- 前記薬学的組成物が腫瘍内注射によって投与される、請求項25に記載の薬学的組成物。
- 前記薬学的組成物が第2の治療剤と組み合わせて前記被験体に投与されることを特徴とする、請求項25または26に記載の薬学的組成物。
- 前記第2の治療剤が化学療法剤である、請求項27に記載の薬学的組成物。
- 前記第2の治療剤が、阻害性免疫チェックポイント分子のアンタゴニストである、請求項27に記載の薬学的組成物。
- 前記第2の治療剤がエピジェネティック調節剤である、請求項27に記載の薬学的組成物。
- 前記第2の治療剤が免疫原性細胞死の誘導物質である、請求項27に記載の薬学的組成物。
- 前記阻害性免疫チェックポイント分子が、PD-1、PD-L1、PD-L2、CTLA-4(CD152)、LAG-3、TIM-3、TIGIT、IL-10、TGF-ベータ、インドールアミン2,3-ジオキシゲナーゼ(IDO)、およびP-セレクチン糖たんぱく質リガンド-1(PSGL-1)からなる群より選択される、請求項29に記載の薬学的組成物。
- 前記第2の治療剤が、免疫刺激分子のアゴニストである、請求項27に記載の薬学的組成物。
- 前記免疫刺激分子が、CD27、CD40、OX40(CD134)、GITR、4-1BB(CD137)、CD28およびICOS(CD278)からなる群より選択される、請求項33に記載の薬学的組成物。
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WO2019099412A1 (en) | 2017-11-14 | 2019-05-23 | Dynavax Technologies Corporation | Cleavable conjugates of tlr7/8 agonist compounds, methods for preparation, and uses thereof |
JP7287708B2 (ja) | 2019-02-08 | 2023-06-06 | プロジェニア インコーポレイテッド | Toll-like受容体7または8アゴニストとコレステロールの結合体およびその用途 |
AU2020372832A1 (en) * | 2019-10-29 | 2022-05-12 | Prime Reach Trading Limited | 4-Amino-imidazoquinoline compounds and use thereof |
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Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20120294885A1 (en) | 2011-05-18 | 2012-11-22 | The University Of Kansas | Toll-like receptor-7 and -8 modulatory 1h imidazoquinoline derived compounds |
JP2013512859A (ja) | 2009-12-03 | 2013-04-18 | 大日本住友製薬株式会社 | トール様受容体(tlr)を介して作用するイミダゾキノリン |
WO2017058996A1 (en) | 2015-09-29 | 2017-04-06 | The University Of Chicago | Polymer conjugate vaccines |
JP2020532571A (ja) | 2017-09-06 | 2020-11-12 | バイオエヌテック エスエーBiontech Se | Tlr7のアゴニストとしての置換イミダゾキノリン |
JP2021503005A (ja) | 2017-11-14 | 2021-02-04 | ダイナバックス テクノロジーズ コーポレイション | Tlr7/8アゴニスト化合物の切断可能なコンジュゲート、その調製方法および使用 |
Family Cites Families (37)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
IL73534A (en) | 1983-11-18 | 1990-12-23 | Riker Laboratories Inc | 1h-imidazo(4,5-c)quinoline-4-amines,their preparation and pharmaceutical compositions containing certain such compounds |
WO1995002597A1 (en) | 1993-07-15 | 1995-01-26 | Minnesota Mining And Manufacturing Company | IMIDAZO[4,5-c]PYRIDIN-4-AMINES |
JPH1180156A (ja) | 1997-09-04 | 1999-03-26 | Hokuriku Seiyaku Co Ltd | 1−(置換アリール)アルキル−1h−イミダゾピリジン−4−アミン誘導体 |
UA67760C2 (uk) | 1997-12-11 | 2004-07-15 | Міннесота Майнінг Енд Мануфакчурінг Компані | Імідазонафтиридин та тетрагідроімідазонафтиридин, фармацевтична композиція, спосіб індукування біосинтезу цитокінів та спосіб лікування вірусної інфекції, проміжні сполуки |
US6180095B1 (en) | 1997-12-17 | 2001-01-30 | Enzon, Inc. | Polymeric prodrugs of amino- and hydroxyl-containing bioactive agents |
US6110929A (en) | 1998-07-28 | 2000-08-29 | 3M Innovative Properties Company | Oxazolo, thiazolo and selenazolo [4,5-c]-quinolin-4-amines and analogs thereof |
US7238368B2 (en) | 1999-04-23 | 2007-07-03 | Alza Corporation | Releasable linkage and compositions containing same |
EP1880736A1 (en) | 1999-04-23 | 2008-01-23 | Alza Corporation | Releasable linkage and composition containing same |
US6677349B1 (en) | 2001-12-21 | 2004-01-13 | 3M Innovative Properties Company | Sulfonamide and sulfamide substituted imidazoquinolines |
DE60335010D1 (de) | 2002-08-15 | 2010-12-30 | 3M Innovative Properties Co | Immunstimulatorische zusammensetzungen und verfahren zur stimulierung einer immunantwort |
JP2006503068A (ja) | 2002-09-26 | 2006-01-26 | スリーエム イノベイティブ プロパティズ カンパニー | 1h−イミダゾダイマー |
AU2003301052A1 (en) | 2002-12-20 | 2004-07-22 | 3M Innovative Properties Company | Aryl / hetaryl substituted imidazoquinolines |
JP2006512391A (ja) | 2002-12-30 | 2006-04-13 | スリーエム イノベイティブ プロパティズ カンパニー | 組み合わせ免疫賦活薬 |
JP2006517974A (ja) | 2003-02-13 | 2006-08-03 | スリーエム イノベイティブ プロパティズ カンパニー | Irm化合物およびトル様受容体8に関する方法および組成物 |
US20040265351A1 (en) | 2003-04-10 | 2004-12-30 | Miller Richard L. | Methods and compositions for enhancing immune response |
US7923560B2 (en) | 2003-04-10 | 2011-04-12 | 3M Innovative Properties Company | Delivery of immune response modifier compounds |
WO2005018555A2 (en) | 2003-08-14 | 2005-03-03 | 3M Innovative Properties Company | Lipid-modified immune response modifiers |
ATE400573T1 (de) | 2003-11-21 | 2008-07-15 | Novartis Pharma Gmbh | 1h-imidazochinolinderivate als proteinkinaseinhibitoren |
WO2006028545A2 (en) | 2004-06-18 | 2006-03-16 | 3M Innovative Properties Company | Substituted imidazoquinolines, imidazopyridines, and imidazonaphthyridines |
WO2007079086A1 (en) | 2005-12-28 | 2007-07-12 | Coley Pharmaceutical Group, Inc. | Pyrazoloalkyl substituted imidazo ring compounds and methods |
WO2007100634A2 (en) | 2006-02-22 | 2007-09-07 | 3M Innovative Properties Company | Immune response modifier conjugates |
US9556167B2 (en) | 2012-05-02 | 2017-01-31 | Yale University | TLR-agonist-conjugated antibody recruiting molecules (TLR-ARMs) |
EP2674170B1 (en) | 2012-06-15 | 2014-11-19 | Invivogen | Novel compositions of TLR7 and/or TLR8 agonists conjugated to lipids |
EP2732825B1 (en) | 2012-11-19 | 2015-07-01 | Invivogen | Conjugates of a TLR7 and/or TLR8 agonist and a TLR2 agonist |
WO2014113634A1 (en) | 2013-01-17 | 2014-07-24 | University Of Kansas | Toll-like receptor 2-agonistic lipopeptides, and method of making the same |
EP2769738B1 (en) | 2013-02-22 | 2016-07-20 | Invivogen | Conjugated TLR7 and/or TLR8 and TLR2 polycationic agonists |
WO2015023958A1 (en) | 2013-08-15 | 2015-02-19 | The University Of Kansas | Toll-like receptor agonists |
GB201321242D0 (en) | 2013-12-02 | 2014-01-15 | Immune Targeting Systems Its Ltd | Immunogenic compound |
SG11201605455YA (en) | 2014-01-10 | 2016-08-30 | Birdie Biopharmaceuticals Inc | Compounds and compositions for treating egfr expressing tumors |
MX2016014308A (es) | 2014-05-01 | 2017-01-27 | Novartis Ag | Compuestos y composiciones como agonistas del receptor tipo toll 7. |
GB201418004D0 (en) | 2014-10-10 | 2014-11-26 | Isis Innovation | Polymer adjuvant |
US10799580B2 (en) | 2015-09-09 | 2020-10-13 | The United States Of America, As Represented By The Secretary, Department Of Health And Human Services | Expression vector delivery system and use thereof for inducing an immune response |
MA44334A (fr) | 2015-10-29 | 2018-09-05 | Novartis Ag | Conjugués d'anticorps comprenant un agoniste du récepteur de type toll |
EP3554550A1 (en) | 2016-12-13 | 2019-10-23 | Bolt Biotherapeutics, Inc. | Antibody adjuvant conjugates |
AR111651A1 (es) | 2017-04-28 | 2019-08-07 | Novartis Ag | Conjugados de anticuerpos que comprenden agonistas del receptor de tipo toll y terapias de combinación |
US20180311334A1 (en) | 2017-04-29 | 2018-11-01 | Yale University | Compositions and Methods for Inducing an Immune Response |
EP4257198A3 (en) | 2017-08-22 | 2023-10-18 | Dynavax Technologies Corporation | Alkyl chain modified imidazoquinoline derivatives as tlr7/8 agonists and uses thereof |
-
2018
- 2018-08-21 EP EP23177052.0A patent/EP4257198A3/en active Pending
- 2018-08-21 JP JP2020511364A patent/JP7386536B2/ja active Active
- 2018-08-21 EP EP18773000.7A patent/EP3672969B1/en active Active
- 2018-08-21 US US16/107,605 patent/US10618896B2/en active Active
- 2018-08-21 ES ES18773000T patent/ES2951817T3/es active Active
- 2018-08-21 WO PCT/US2018/047323 patent/WO2019040491A1/en unknown
-
2020
- 2020-03-02 US US16/806,733 patent/US11124510B2/en active Active
-
2021
- 2021-08-16 US US17/403,312 patent/US20220033400A1/en active Pending
-
2023
- 2023-07-26 JP JP2023121658A patent/JP2023129623A/ja active Pending
Patent Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP2013512859A (ja) | 2009-12-03 | 2013-04-18 | 大日本住友製薬株式会社 | トール様受容体(tlr)を介して作用するイミダゾキノリン |
US20120294885A1 (en) | 2011-05-18 | 2012-11-22 | The University Of Kansas | Toll-like receptor-7 and -8 modulatory 1h imidazoquinoline derived compounds |
WO2017058996A1 (en) | 2015-09-29 | 2017-04-06 | The University Of Chicago | Polymer conjugate vaccines |
JP2020532571A (ja) | 2017-09-06 | 2020-11-12 | バイオエヌテック エスエーBiontech Se | Tlr7のアゴニストとしての置換イミダゾキノリン |
JP2021503005A (ja) | 2017-11-14 | 2021-02-04 | ダイナバックス テクノロジーズ コーポレイション | Tlr7/8アゴニスト化合物の切断可能なコンジュゲート、その調製方法および使用 |
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