JPWO2019208805A1 - Btk阻害活性を有する化合物を有効成分として含む自己免疫疾患の予防および/または治療剤 - Google Patents
Btk阻害活性を有する化合物を有効成分として含む自己免疫疾患の予防および/または治療剤 Download PDFInfo
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- JPWO2019208805A1 JPWO2019208805A1 JP2020515621A JP2020515621A JPWO2019208805A1 JP WO2019208805 A1 JPWO2019208805 A1 JP WO2019208805A1 JP 2020515621 A JP2020515621 A JP 2020515621A JP 2020515621 A JP2020515621 A JP 2020515621A JP WO2019208805 A1 JPWO2019208805 A1 JP WO2019208805A1
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- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- MIXMJCQRHVAJIO-TZHJZOAOSA-N qk4dys664x Chemical compound O.C1([C@@H](F)C2)=CC(=O)C=C[C@]1(C)[C@@H]1[C@@H]2[C@@H]2C[C@H]3OC(C)(C)O[C@@]3(C(=O)CO)[C@@]2(C)C[C@@H]1O.C1([C@@H](F)C2)=CC(=O)C=C[C@]1(C)[C@@H]1[C@@H]2[C@@H]2C[C@H]3OC(C)(C)O[C@@]3(C(=O)CO)[C@@]2(C)C[C@@H]1O MIXMJCQRHVAJIO-TZHJZOAOSA-N 0.000 description 1
- 229960003042 quinapril hydrochloride Drugs 0.000 description 1
- IBBLRJGOOANPTQ-JKVLGAQCSA-N quinapril hydrochloride Chemical compound Cl.C([C@@H](C(=O)OCC)N[C@@H](C)C(=O)N1[C@@H](CC2=CC=CC=C2C1)C(O)=O)CC1=CC=CC=C1 IBBLRJGOOANPTQ-JKVLGAQCSA-N 0.000 description 1
- 208000023504 respiratory system disease Diseases 0.000 description 1
- 206010039073 rheumatoid arthritis Diseases 0.000 description 1
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- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
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- 235000011803 sesame oil Nutrition 0.000 description 1
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- 229910052710 silicon Inorganic materials 0.000 description 1
- 239000010703 silicon Substances 0.000 description 1
- 150000003384 small molecules Chemical class 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000007901 soft capsule Substances 0.000 description 1
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- 235000019698 starch Nutrition 0.000 description 1
- 229940012831 stearyl alcohol Drugs 0.000 description 1
- 229960005322 streptomycin Drugs 0.000 description 1
- 239000006190 sub-lingual tablet Substances 0.000 description 1
- 238000010254 subcutaneous injection Methods 0.000 description 1
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- 239000005720 sucrose Substances 0.000 description 1
- 229960001940 sulfasalazine Drugs 0.000 description 1
- NCEXYHBECQHGNR-QZQOTICOSA-N sulfasalazine Chemical compound C1=C(O)C(C(=O)O)=CC(\N=N\C=2C=CC(=CC=2)S(=O)(=O)NC=2N=CC=CC=2)=C1 NCEXYHBECQHGNR-QZQOTICOSA-N 0.000 description 1
- 150000003467 sulfuric acid derivatives Chemical class 0.000 description 1
- 229910021653 sulphate ion Inorganic materials 0.000 description 1
- 239000004094 surface-active agent Substances 0.000 description 1
- 230000004083 survival effect Effects 0.000 description 1
- 239000003765 sweetening agent Substances 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 229940095064 tartrate Drugs 0.000 description 1
- 229960005187 telmisartan Drugs 0.000 description 1
- 229960004084 temocapril Drugs 0.000 description 1
- FIQOFIRCTOWDOW-BJLQDIEVSA-N temocapril Chemical compound C([C@@H](C(=O)OCC)N[C@@H]1C(N(CC(O)=O)C[C@H](SC1)C=1SC=CC=1)=O)CC1=CC=CC=C1 FIQOFIRCTOWDOW-BJLQDIEVSA-N 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 235000019364 tetracycline Nutrition 0.000 description 1
- 229940040944 tetracyclines Drugs 0.000 description 1
- 150000003522 tetracyclines Chemical class 0.000 description 1
- TUNFSRHWOTWDNC-HKGQFRNVSA-N tetradecanoic acid Chemical compound CCCCCCCCCCCCC[14C](O)=O TUNFSRHWOTWDNC-HKGQFRNVSA-N 0.000 description 1
- KHVCOYGKHDJPBZ-WDCZJNDASA-N tetrahydrooxazine Chemical compound OC[C@H]1ONC[C@@H](O)[C@@H]1O KHVCOYGKHDJPBZ-WDCZJNDASA-N 0.000 description 1
- 125000003698 tetramethyl group Chemical group [H]C([H])([H])* 0.000 description 1
- OULAJFUGPPVRBK-UHFFFAOYSA-N tetratriacontyl alcohol Natural products CCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCO OULAJFUGPPVRBK-UHFFFAOYSA-N 0.000 description 1
- 150000003536 tetrazoles Chemical class 0.000 description 1
- ZYXWYDDFNXBTFO-UHFFFAOYSA-N tetrazolidine Chemical compound C1NNNN1 ZYXWYDDFNXBTFO-UHFFFAOYSA-N 0.000 description 1
- NYERMPLPURRVGM-UHFFFAOYSA-N thiazepine Chemical compound S1C=CC=CC=N1 NYERMPLPURRVGM-UHFFFAOYSA-N 0.000 description 1
- JWCVYQRPINPYQJ-UHFFFAOYSA-N thiepane Chemical compound C1CCCSCC1 JWCVYQRPINPYQJ-UHFFFAOYSA-N 0.000 description 1
- BISQTCXKVNCDDA-UHFFFAOYSA-N thiepine Chemical compound S1C=CC=CC=C1 BISQTCXKVNCDDA-UHFFFAOYSA-N 0.000 description 1
- 229930192474 thiophene Natural products 0.000 description 1
- IBBLKSWSCDAPIF-UHFFFAOYSA-N thiopyran Chemical compound S1C=CC=C=C1 IBBLKSWSCDAPIF-UHFFFAOYSA-N 0.000 description 1
- 229950009104 tirabrutinib Drugs 0.000 description 1
- 229960002051 trandolapril Drugs 0.000 description 1
- 229940126307 triamcinolone acetate Drugs 0.000 description 1
- YNDXUCZADRHECN-JNQJZLCISA-N triamcinolone acetonide Chemical compound C1CC2=CC(=O)C=C[C@]2(C)[C@]2(F)[C@@H]1[C@@H]1C[C@H]3OC(C)(C)O[C@@]3(C(=O)CO)[C@@]1(C)C[C@@H]2O YNDXUCZADRHECN-JNQJZLCISA-N 0.000 description 1
- 150000003852 triazoles Chemical class 0.000 description 1
- 125000004784 trichloromethoxy group Chemical group ClC(O*)(Cl)Cl 0.000 description 1
- 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 description 1
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 1
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 1
- 229960004699 valsartan Drugs 0.000 description 1
- ACWBQPMHZXGDFX-QFIPXVFZSA-N valsartan Chemical compound C1=CC(CN(C(=O)CCCC)[C@@H](C(C)C)C(O)=O)=CC=C1C1=CC=CC=C1C1=NN=NN1 ACWBQPMHZXGDFX-QFIPXVFZSA-N 0.000 description 1
- 229940099259 vaseline Drugs 0.000 description 1
- 229950007160 vecabrutinib Drugs 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
- 239000003871 white petrolatum Substances 0.000 description 1
Classifications
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- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
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Abstract
Description
[1] Btk阻害活性を有する化合物を含有する、天疱瘡、類天疱瘡、ANCA関連血管炎、IgG4関連疾患、ネフローゼ症候群および皮膚エリテマトーデスからなる群から選択される自己免疫疾患の予防および/または治療剤、
[2] 自己免疫疾患が、天疱瘡、類天疱瘡、ANCA関連血管炎またはネフローゼ症候群である前記[1]記載の剤、
[3] 自己免疫疾患が、ANCA関連血管炎である前記[1]または[2]記載の剤、
[4] ANCA関連血管炎が、顕微鏡的多発血管炎、多発血管炎性肉芽腫症(Wegener肉芽腫症)、好酸球性多発血管炎性肉芽腫症(Chug-Strauss症候群)、および腎限局型血管炎からなる群から選択される1種以上である前記[1]ないし[3]のいずれか一項に記載の剤、
[5] ANCA関連血管炎が、顕微鏡的多発血管炎、好酸球性多発血管炎性肉芽腫症(Chug-Strauss症候群)、および腎限局型血管炎からなる群から選択される1種以上である前記[1]ないし[4]のいずれか一項に記載の剤、
[6] ANCA関連血管炎が、MPO−ANCA陽性および/またはPR3−ANCA陽性のANCA関連血管炎である前記[1]ないし[5]のいずれか一項に記載の剤、
[7] Btk阻害活性を有する化合物を含有する、NETs(好中球細胞外トラップ)形成抑制剤、
[8] Btk阻害活性を有する化合物が、一般式(I)
R1は(1)ハロゲン原子、(2)C1〜4アルキル基、(3)C1〜4アルコキシ基、(4)C1〜4ハロアルキル基、または(5)C1〜4ハロアルコキシ基を表し、
ring1は(1)ハロゲン原子、(2)C1〜4アルキル基、(3)C1〜4アルコキシ基、(4)ニトリル、(5)C1〜4ハロアルキル基および(6)C1〜4ハロアルコキシ基からなる群より各々独立に選択される1〜5個の置換基で置換されていてもよい4〜7員の環状基を表し、ただし、ring1上の置換基が2個以上のとき、当該置換基はそれらが結合するring1を構成する原子と一緒になって4〜7員の環状基を形成してもよく、
ring2は1〜3個の−K−R2で置換されていてもよい4〜7員の飽和ヘテロ環を表し、
Kは(1)結合手、(2)C1〜4アルキレン、(3)−C(O)−、(4)−C(O)−CH2−、(5)−CH2−C(O)−、(6)−C(O)O−、または(7)−SO2−を表し(ただし、左側の結合手がring2と結合するものとする。)、
R2は(1)NR3R4、(2)ハロゲン原子、(3)CONR5R6、(4)CO2R7および(5)OR8からなる群より各々独立に選択される1〜5個の置換基で置換されていてもよい、(1)C1〜4アルキル、(2)C2〜4アルケニル、または(3)C2〜4アルキニル基を表し、
R3およびR4はそれぞれ独立して、(1)水素原子、または(2)OR9またはCONR10R11で置換されていてもよいC1〜4アルキル基を表し、
R3およびR4は結合する窒素原子と一緒になって、オキソ基または水酸基で置換されていてもよい4〜7員の含窒素飽和ヘテロ環を形成してもよく、
R5およびR6はそれぞれ独立して(1)水素原子、(2)C1〜4アルキル基、または(3)フェニル基を表し、
R7は(1)水素原子、または(2)C1〜4アルキル基を表し、
R8は(1)水素原子、(2)C1〜4アルキル基、(3)フェニル基、または(4)ベンゾトリアゾリル基を表し、
R9は(1)水素原子、または(2)C1〜4アルキル基を表し、
R10およびR11はそれぞれ独立して、(1)水素原子、または(2)C1〜4アルキル基を表し、
nは0〜4の整数を表し、
mは0〜2の整数を表し、
nが2以上のとき、R1は同じでも異なっていてもよい。)で示される化合物、またはその塩である前記[1]ないし[7]のいずれか一項に記載の剤、
[9] Btk阻害活性を有する化合物が、チラブルチニブ、イブルチニブ、アカラブルチニブ、エヴォブルチニブ、フェネブルチニブ/GDC−0853、ポセルチニブ/LY3337641、スペブルチニブ、ヴェカブルチニブ/SNS−062、ザヌブルチニブ/BGB−3111、PRN1008、BMS−986142、ブラネブルチニブ/BMS−986195、LOU−064、M−7583、AC−058、DTRMWXHS−12、TAS−5315、TAK−020、ARQ−531、BMS−935177、PCI−45292、PRN−2246、SHR−1459、ABBV−105、CT−1530、ICP022、LOXO−305、JNJ−64264681、HWH−486およびそれらの塩からなる群から選択される1種以上である前記[1]ないし[7]のいずれか一項に記載の剤、
[10] Btk阻害活性を有する化合物が、チラブルチニブ、イブルチニブ、スペブルチニブ、アカラブルチニブ、エヴォブルチニブ、ポセルチニブ、フェネブルチニブ、ヴェカブルチニブ、ザヌブルチニブ、PRN−1008、BMS−986142およびそれらの塩からなる群から選択される1種以上である前記[1]ないし[7]または[9]のいずれか一項に記載の剤、
[11] Btk阻害活性を有する化合物が、チラブルチニブ、イブルチニブ、アカラブルチニブ、フェネブルチニブ、BMS−986142、エヴォブルチニブ、ポセルチニブ、およびそれらの塩からなる群から選択される1種以上である前記[1]ないし[7]または[9]もしくは[10]のいずれか一項に記載の剤、
[12] Btk阻害活性を有する化合物が、チラブルチニブ、またはその塩である前記[1]ないし[11]のいずれか一項に記載の剤、
[13] 天疱瘡、類天疱瘡、ANCA関連血管炎、IgG4関連疾患、ネフローゼ症候群および皮膚エリテマトーデスからなる群から選択される自己免疫疾患の予防および/または治療剤を製造するための、Btk阻害活性を有する化合物の使用、
[14] Btk阻害活性を有する化合物の有効量を哺乳動物に投与することを特徴とする、天疱瘡、類天疱瘡、ANCA関連血管炎、IgG4関連疾患、ネフローゼ症候群および皮膚エリテマトーデスからなる群から選択される自己免疫疾患の予防および/または治療方法、
[15] 天疱瘡、類天疱瘡、ANCA関連血管炎、IgG4関連疾患、ネフローゼ症候群および皮膚エリテマトーデスからなる群から選択される自己免疫疾患の予防および/または治療における使用のための、Btk阻害活性を有する化合物、
[16] Btk阻害活性を有する化合物を含有する、特発性蕁麻疹、重症喘息、および好酸球性副鼻腔炎からなる群から選択される炎症・アレルギー性疾患の予防および/または治療剤、
等の実施態様を提供する。
本発明に用いられるBtk阻害活性を有する化合物は、一態様として低分子化合物が挙げられ、その一態様として、特許文献1(国際公開第2011/152351号パンフレット)に記載された下記一般式(I)
経口剤としての内服用固形剤は、例えば、本発明に用いられるBtk阻害活性を有する化合物を賦形剤(例えば、ラクトース、マンニトール、グルコース、微結晶セルロース、デンプン等)、結合剤(例えば、ヒドロキシプロピルセルロース、ポリビニルピロリドン、メタケイ酸アルミン酸マグネシウム等)、崩壊剤(例えば、繊維素グリコール酸カルシウム等)、滑沢剤(例えば、ステアリン酸マグネシウム等)、安定剤、溶解補助剤(グルタミン酸、アスパラギン酸等)等と混合し、常法に従って製剤化される。また、必要によりコーティング剤(例えば、白糖、ゼラチン、ヒドロキシプロピルセルロース、ヒドロキシプロピルメチルセルロースフタレート等)で被覆していてもよいし、また2以上の層で被覆していてもよい。
本発明に用いられるBtk阻害活性を有する化合物の毒性は十分に低いものであり、医薬品として安全に使用することができる。
本発明に用いられるBtk阻害活性を有する化合物は、例えば、Btk阻害活性、B細胞からの抗体産生抑制作用等を有するため、哺乳動物、特にヒトにおいて、自己免疫疾患または炎症・アレルギー性疾患の予防および/または治療剤として使用することができる。
アンジオテンシン変換酵素(ACE)阻害薬の例としては、アラセプリル、塩酸イミダプリル、塩酸キナプリル、塩酸テモカプリル、塩酸デラプリル、塩酸ベナゼプリル、カプトプリル、トランドラプリル、ペリンドプリル エルブミン、マレイン酸エナラプリル、リシノプリル水和物、シラザプリル水和物が挙げられる。
96ウェルプレートにヒト血清アルブミン(HSA)(Sigma)を固相化させた後、抗HSA抗体(Sigma)を添加して免疫複合体を形成させた。10%ウシ胎児血清(FBS)でブロッキングし、本プレートを好中球の活性化に使用した。
各被験化合物のネフローゼ症候群の治療における有効性は、抗GBM(glomerular basement membrane;糸球体基底膜)抗体を用いて惹起した腎炎モデルを用いて評価することができる。この抗GBM抗体惹起腎炎モデルは、当業者であれば明らかなように、例えば、J. Immunol., 183: 3980-3988 (2009)、J. Immunol., 191: 4540-4550 (2013)等に記載の実験方法によって作製することができる。
Claims (12)
- Btk阻害活性を有する化合物を含有する、天疱瘡、類天疱瘡、ANCA関連血管炎、IgG4関連疾患、ネフローゼ症候群および皮膚エリテマトーデスからなる群から選択される自己免疫疾患の予防および/または治療剤。
- 自己免疫疾患が、ANCA関連血管炎である請求項1記載の剤。
- ANCA関連血管炎が、顕微鏡的多発血管炎、多発血管炎性肉芽腫症(Wegener肉芽腫症)、好酸球性多発血管炎性肉芽腫症(Chug-Strauss症候群)、および腎限局型血管炎からなる群から選択される1種以上である請求項1または2に記載の剤。
- ANCA関連血管炎が、顕微鏡的多発血管炎、好酸球性多発血管炎性肉芽腫症(Chug-Strauss症候群)、および腎限局型血管炎からなる群から選択される1種以上である請求項1ないし3のいずれか一項に記載の剤。
- ANCA関連血管炎が、MPO−ANCA陽性および/またはPR3−ANCA陽性のANCA関連血管炎である請求項1ないし4のいずれか一項に記載の剤。
- Btk阻害活性を有する化合物を含有する、NETs(好中球細胞外トラップ)形成抑制剤。
- Btk阻害活性を有する化合物が、一般式(I)
R1は(1)ハロゲン原子、(2)C1〜4アルキル基、(3)C1〜4アルコキシ基、(4)C1〜4ハロアルキル基、または(5)C1〜4ハロアルコキシ基を表し、
ring1は(1)ハロゲン原子、(2)C1〜4アルキル基、(3)C1〜4アルコキシ基、(4)ニトリル、(5)C1〜4ハロアルキル基および(6)C1〜4ハロアルコキシ基からなる群より各々独立に選択される1〜5個の置換基で置換されていてもよい4〜7員の環状基を表し、ただし、ring1上の置換基が2個以上のとき、当該置換基はそれらが結合するring1を構成する原子と一緒になって4〜7員の環状基を形成してもよく、
ring2は1〜3個の−K−R2で置換されていてもよい4〜7員の飽和ヘテロ環を表し、
Kは(1)結合手、(2)C1〜4アルキレン、(3)−C(O)−、(4)−C(O)−CH2−、(5)−CH2−C(O)−、(6)−C(O)O−、または(7)−SO2−を表し(ただし、左側の結合手がring2と結合するものとする。)、
R2は(1)NR3R4、(2)ハロゲン原子、(3)CONR5R6、(4)CO2R7および(5)OR8からなる群より各々独立に選択される1〜5個の置換基で置換されていてもよい、(1)C1〜4アルキル、(2)C2〜4アルケニル、または(3)C2〜4アルキニル基を表し、
R3およびR4はそれぞれ独立して、(1)水素原子、または(2)OR9またはCONR10R11で置換されていてもよいC1〜4アルキル基を表し、
R3およびR4は結合する窒素原子と一緒になって、オキソ基または水酸基で置換されていてもよい4〜7員の含窒素飽和ヘテロ環を形成してもよく、
R5およびR6はそれぞれ独立して(1)水素原子、(2)C1〜4アルキル基、または(3)フェニル基を表し、
R7は(1)水素原子、または(2)C1〜4アルキル基を表し、
R8は(1)水素原子、(2)C1〜4アルキル基、(3)フェニル基、または(4)ベンゾトリアゾリル基を表し、
R9は(1)水素原子、または(2)C1〜4アルキル基を表し、
R10およびR11はそれぞれ独立して、(1)水素原子、または(2)C1〜4アルキル基を表し、
nは0〜4の整数を表し、
mは0〜2の整数を表し、
nが2以上のとき、R1は同じでも異なっていてもよい。)で示される化合物、またはその塩である請求項1ないし6のいずれか一項に記載の剤。 - Btk阻害活性を有する化合物が、チラブルチニブ、イブルチニブ、スペブルチニブ、アカラブルチニブ、エヴォブルチニブ、ポセルチニブ、フェネブルチニブ、ヴェカブルチニブ、ザヌブルチニブ、PRN−1008、BMS−986142およびそれらの塩からなる群から選択される1種以上である請求項1ないし6のいずれか一項に記載の剤。
- Btk阻害活性を有する化合物が、チラブルチニブ、またはその塩である請求項1ないし8のいずれか一項に記載の剤。
- 天疱瘡、類天疱瘡、ANCA関連血管炎、IgG4関連疾患、ネフローゼ症候群および皮膚エリテマトーデスからなる群から選択される自己免疫疾患の予防および/または治療剤を製造するための、Btk阻害活性を有する化合物の使用。
- Btk阻害活性を有する化合物の有効量を哺乳動物に投与することを特徴とする、天疱瘡、類天疱瘡、ANCA関連血管炎、IgG4関連疾患、ネフローゼ症候群および皮膚エリテマトーデスからなる群から選択される自己免疫疾患の予防および/または治療方法。
- 天疱瘡、類天疱瘡、ANCA関連血管炎、IgG4関連疾患、ネフローゼ症候群および皮膚エリテマトーデスからなる群から選択される自己免疫疾患の予防および/または治療における使用のための、Btk阻害活性を有する化合物。
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