JP2014515758A - ピラゾロピリダジンおよび網膜変性疾患およびアッシャー症候群に伴う聴覚損失を治療するための方法 - Google Patents
ピラゾロピリダジンおよび網膜変性疾患およびアッシャー症候群に伴う聴覚損失を治療するための方法 Download PDFInfo
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- JP2014515758A JP2014515758A JP2014508507A JP2014508507A JP2014515758A JP 2014515758 A JP2014515758 A JP 2014515758A JP 2014508507 A JP2014508507 A JP 2014508507A JP 2014508507 A JP2014508507 A JP 2014508507A JP 2014515758 A JP2014515758 A JP 2014515758A
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- alkyl
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- alkylene
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- 238000000034 method Methods 0.000 title claims abstract description 93
- 208000014769 Usher Syndromes Diseases 0.000 title claims abstract description 32
- 206010011878 Deafness Diseases 0.000 title claims abstract description 21
- 230000002207 retinal effect Effects 0.000 title claims abstract description 21
- 230000010370 hearing loss Effects 0.000 title claims abstract description 20
- 231100000888 hearing loss Toxicity 0.000 title claims abstract description 20
- 208000016354 hearing loss disease Diseases 0.000 title claims abstract description 20
- 208000015122 neurodegenerative disease Diseases 0.000 title claims abstract description 19
- NMEPLWZDUIIAAC-UHFFFAOYSA-N 1h-pyrazolo[4,3-c]pyridazine Chemical compound C1=NN=C2C=NNC2=C1 NMEPLWZDUIIAAC-UHFFFAOYSA-N 0.000 title description 12
- 150000001875 compounds Chemical class 0.000 claims abstract description 172
- 239000000203 mixture Substances 0.000 claims abstract description 74
- 208000007014 Retinitis pigmentosa Diseases 0.000 claims abstract description 6
- 206010007747 Cataract congenital Diseases 0.000 claims abstract description 4
- 201000007737 Retinal degeneration Diseases 0.000 claims abstract description 4
- 206010064930 age-related macular degeneration Diseases 0.000 claims abstract description 4
- 208000002780 macular degeneration Diseases 0.000 claims abstract description 4
- 230000004258 retinal degeneration Effects 0.000 claims abstract description 4
- 150000003839 salts Chemical class 0.000 claims description 66
- 125000003161 (C1-C6) alkylene group Chemical group 0.000 claims description 54
- 125000001309 chloro group Chemical group Cl* 0.000 claims description 30
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 28
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- 102000004169 proteins and genes Human genes 0.000 claims description 18
- 208000011580 syndromic disease Diseases 0.000 claims description 16
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- 239000007787 solid Substances 0.000 description 87
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- 239000000243 solution Substances 0.000 description 76
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- PYRKKGOKRMZEIT-UHFFFAOYSA-N 2-[6-(2-cyclopropylethoxy)-9-(2-hydroxy-2-methylpropyl)-1h-phenanthro[9,10-d]imidazol-2-yl]-5-fluorobenzene-1,3-dicarbonitrile Chemical compound C1=C2C3=CC(CC(C)(O)C)=CC=C3C=3NC(C=4C(=CC(F)=CC=4C#N)C#N)=NC=3C2=CC=C1OCCC1CC1 PYRKKGOKRMZEIT-UHFFFAOYSA-N 0.000 description 13
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Classifications
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- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- 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
- A61K31/50—Pyridazines; Hydrogenated pyridazines
- A61K31/5025—Pyridazines; Hydrogenated pyridazines ortho- or peri-condensed with heterocyclic ring systems
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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- A61K31/167—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide having the nitrogen of a carboxamide group directly attached to the aromatic ring, e.g. lidocaine, paracetamol
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- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
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Abstract
Description
本発明は、式I
(式中、Halは、−Cl、−F、−I、または−Brであり、
xは、0から5の範囲の整数であり、
各R1は、独立して、−Cl、−F、−I、−Br、−C1−C3アルキル、−O−C1−C3アルキル、−CN、−CF3、−C(O)NH(CH3)、または−C≡CCH2OHであり、
yは、0から5の範囲の整数であり、
各R2は、独立して、−Cl、−F、−Br、−C1−C3アルキル、−O−C1−C3アルキル、−CN、−CF3、−C(O)NH(CH3)、または−C≡CCH2OHであり、
R3は、−H、−C1−C6アルキル、−(C1−C6アルキレン)−OH、−(C1−C6アルキレン)−フェニル、−(C1−C6アルキレン)−O−(C1−C6アルキル)、−C2−C6アルケニル、−(C1−C6アルキレン)−C(O)R4、−(C1−C6アルキレン)−R5、
R4は、−OH、−O−(C1−C6アルキル)、−NH2、−NH(C1−C6アルキル)、−NH((C1−C6アルキレン)−OH)、−NH((C1−C6アルキレン)N(C1−C6アルキル)2)、N(C1−C6アルキル)((C1−C6アルキレン)−CN)、−N(C1−C6アルキル)((C1−C6アルキレン)N(C1−C6アルキル)2)、−NH(C1−C6アルキレン)−O−(C1−C6アルキル)、
(式中、Halは、−Cl、−F、−I、または−Brであり、
xは、0から5の範囲の整数であり、
各R1は、独立して、−Cl、−F、−I、−Br、−C1−C3アルキル、−O−C1−C3アルキル、−CN、−CF3、−C(O)NH(CH3)、または−C≡CCH2OHであり、
R3は、−H、−C1−C6アルキル、−(C1−C6アルキレン)−OH、−(C1−C6アルキレン)−フェニル、−(C1−C6アルキレン)−O(C1−C6アルキル)、−C2−C6アルケニル、−(C1−C6アルキレン)−C(O)R4、−(C1−C6アルキレン)−R5、
R4は、−OH、−O−(C1−C6アルキル)、−NH2、−NH(C1−C6アルキル)、−NH((C1−C6アルキレン)−OH)、−NH((C1−C6アルキレン)N(C1−C6アルキル)2)、N(C1−C6アルキル)((C1−C6アルキレン)−CN)、−N(C1−C6アルキル)((C1−C6アルキレン)N(C1−C6アルキル)2)、−NH(C1−C6アルキレン)−O−(C1−C6アルキル)、
5および47−97、または医薬として許容される該化合物の塩(「ピラゾロピリダジン化
合物」)のそれぞれは、アッシャー症候群に伴う網膜変性疾患または聴覚損失を治療するのに有用である。
「アルキル」という用語は、直鎖または分枝の飽和した炭化水素基を指す。例示的アルキル基として、−CH3、−CH2CH3、−CH2CH2CH3、−CH(CH3)2、−CH2CH2CH2CH3、−CH(CH3)CH2CH3、−CH2CH(CH3)2、−C(CH3)3、−CH2CH2CH2CH2CH3、−CH(CH3)CH2CH2CH3、−CH2CH2CH(CH3)2、−CH2C(CH3)3、−CH2CH2CH2CH2CH3、−CH(CH3)CH2CH2CH3、−CH2CH2CH(CH3)2および−CH(CH3)C(CH3)3基が挙げられる。
APCI 大気圧化学イオン化
DAPI 4’,6−ジアミジノ−2−フェニルインドール
DIPEA ジイソプロピルエチルアミン
DMEM Dulbecco変法イーグル培地
DMF ジメチルホルムアミド
DMSO ジメチルスルホキシド
EDAC 1−(3−ジメチルアミノプロピル)−3−エチルカルボジイミド塩酸塩
ESI エレクトロスプレーイオン化
ESI−TOF エレクトロスプレーイオン化−飛行時間
HATU 2−(7−アザ−1H−ベンゾトリアゾール−1−イル)−1,1,3,3−テトラメチルウロニウムヘキサフルオロホスフェート
HOPO 2−ヒドロキシピリジン−N−オキシド
HPLC 高速液体クロマトグラフィー
LCMS 液体クロマトグラフィー−質量分析法
LDA リチウムジイソプロピルアミド
m/z 質量電荷比
MALDI−TOF マトリックス支援レーザー脱離イオン化法−飛行時間
MS 質量分析法
PBS リン酸緩衝食塩水
Rt 保持時間
SDS ドデシル硫酸ナトリウム
THF テトラヒドロフラン
一実施形態において、ピラゾロピリダジン化合物は、式I
(式中、Rは、フルオロ、クロロ、ヨード、メチル、メトキシ、シアノ、トリフルオロメチル、または−(CO)NH(CH3)である。)。一実施形態において、式IのRは、ピラゾロピリダジノ環系に対してパラ位にある。一実施形態において、式IのRは、ピラゾロピリダジノ環系に対してメタ位にある。一実施形態において、式IのRは、ピラゾロピリダジノ環系に対してオルト位にある。
本発明はまた、式II
(式中、Halは、−Cl、−F、−I、または−Brであり、
xは、0から5の範囲の整数であり、
各R1は、独立して、−Cl、−F、−I、−Br、−C1−C3アルキル、−O−C1−C3アルキル、−CN、−CF3、−C(O)NH(CH3)、または−C≡CCH2OHであり、
yは、0から5の範囲の整数であり、
各R2は、独立して、−Cl、−F、−Br、−C1−C3アルキル、−O−C1−C3アルキル、−CN、−CF3、−C(O)NH(CH3)、または−C≡CCH2OHであり、
R3は、−H、−C1−C6アルキル、−(C1−C6アルキレン)−OH、−(C1−C6アルキレン)−フェニル、−(C1−C6アルキレン)−O−(C1−C6アルキル)、−C2−C6アルケニル、−(C1−C6アルキレン)−C(O)R4、−(C1−C6アルキレン)−R5、
R4は、−OH、−O−(C1−C6アルキル)、−NH2、−NH(C1−C6アルキル)、−NH((C1−C6アルキレン)−OH)、−NH((C1−C6アルキレン)N(C1−C6アルキル)2)、N(C1−C6アルキル)((C1−C6アルキレン)−CN)、−N(C1−C6アルキル)((C1−C6アルキレン)N(C1−C6アルキル)2)、−NH(C1−C6アルキレン)−O−(C1−C6アルキル)、
本発明はさらに、式III
(式中、Halは、−Cl、−F、−I、または−Brであり、
xは、0から5の範囲の整数であり、
各R1は、独立して、−Cl、−F、−I、−Br、−C1−C3アルキル、−O−C1−C3アルキル、−CN、−CF3、−C(O)NH(CH3)、または−C≡CCH2OHであり、
R3は、−H、−C1−C6アルキル、−(C1−C6アルキレン)−OH、−(C1−C6アルキレン)−フェニル、−(C1−C6アルキレン)−O(C1−C6アルキル)、−C2−C6アルケニル、−(C1−C6アルキレン)−C(O)R4、−(C1−C6アルキレン)−R5、
R4は、−OH、−O−(C1−C6アルキル)、−NH2、−NH(C1−C6アルキル)、−NH((C1−C6アルキレン)−OH)、−NH((C1−C6アルキレン)N(C1−C6アルキル)2)、N(C1−C6アルキル)((C1−C6アルキレン)−CN)、−N(C1−C6アルキル)((C1−C6アルキレン)N(C1−C6アルキル)2)、−NH(C1−C6アルキレン)−O−(C1−C6アルキル)、
特定のピラゾロピリダジン化合物の非限定的例として、
本発明はさらに、式IV
ピラゾロピリダジン化合物を合成するのに有用な合成スキーム(schema)の非限定的例として、以下が挙げられる。
本発明の化合物は、治療を必要とする対象に、網膜変性疾患の治療のために投与することができる。網膜変性疾患の非限定的例として以下が挙げられる:網膜色素変性症、レーバー先天性黒内障、症候性網膜変性症、湿性および乾性加齢黄斑変性を含めた加齢黄斑変性、ならびにアッシャー症候群。一部の実施形態において、アッシャー症候群はアッシャー症候群のサブタイプである。一部の実施形態において、サブタイプはアッシャーIである。一部の実施形態において、サブタイプはアッシャーIIである。一部の実施形態において、サブタイプはアッシャーIIIである。
ステップ2:N−(3−(2−クロロフェニル)−1−メチル−1H−ピラゾール−5−イル)アセトアミド
ステップ3:N−(3−(2−クロロフェニル)−4−ヨード−1−メチル−1H−ピラゾール−5−イル)アセトアミド
ステップ4:N−(3−(2−クロロフェニル)−1−メチル−4−(フェニルエチニル)−1H−ピラゾール−5−イル)アセトアミド
ステップ5:3−(2−クロロフェニル)−1−メチル−4−(フェニルエチニル)−1H−ピラゾール−5−アミン
ステップ6:4−クロロ−3−(2−クロロフェニル)−1−メチル−5−フェニル−1H−ピラゾロ[3,4−c]ピリダジン(化合物37)
94.61%純度。
ステップ2:(3,5−ジクロロ−6−フェニルピリダジン−4−イル)(フェニル)メタノン
ステップ3:4−クロロ−3,5−ジフェニル−1H−ピラゾロ[3,4−c]ピリダジン(化合物9)
4−クロロ−3−(4−ヨードフェニル)−1−メチル−5−フェニル−1H−ピラゾロ[3,4−c]ピリダジン(化合物43)
97.4%純度。
ステップ2:エチル2−(5−アセトアミド−3−(4−フルオロフェニル)−1H−ピラゾール−1−イル)アセテート
ステップ3:エチル2−(5−アセトアミド−3−(4−フルオロフェニル)−4−ヨード−1H−ピラゾール−1−イル)アセテート
ステップ4:エチル2−(5−アセトアミド−3−(4−フルオロフェニル)−4−(フェニルエチニル)−1H−ピラゾール−1−イル)アセテート
ステップ5:2−(5−アミノ−3−(4−フルオロフェニル)−4−(フェニルエチニル)−1H−ピラゾール−1−イル)酢酸
ステップ6:2−(4−クロロ−3−(4−フルオロフェニル)−5−フェニル−1H−ピラゾロ[3,4−c]ピリダジン−1−イル)酢酸
ステップ7:2−(4−クロロ−3−(4−フルオロフェニル)−5−フェニル−1H−ピラゾロ[3,4−c]ピリダジン−1−イル)−1−モルホリノエタノン
ステップ1:N−(3−(4−フルオロフェニル)−1−(2−ヒドロキシエチル)−4−(フェニルエチニル)−1H−ピラゾール−5−イル)アセトアミド
ステップ2:2−(5−アミノ−3−(4−フルオロフェニル)−4−(フェニルエチニル)−1H−ピラゾール−1−イル)エタノール
ステップ3:2−(4−クロロ−3−(4−フルオロフェニル)−5−フェニル−1H−ピラゾロ[3,4−c]ピリダジン−1−イル)エタノール
ステップ1:N−(3−(4−フルオロフェニル)−1−(2−モルホリノエチル)−4−(フェニルエチニル)−1H−ピラゾール−5−イル)アセトアミド
ステップ2:3−(4−フルオロフェニル)−1−(2−モルホリノエチル)−4−(フェニルエチニル)−1H−ピラゾール−5−アミン
ステップ3:3−(4−フルオロフェニル)−1−(2−モルホリノエチル)−5−フェニル−1H−ピラゾロ[3,4−c]ピリダジン−4−オール
ステップ4:4−(2−(4−クロロ−3−(4−フルオロフェニル)−5−フェニル−1H−ピラゾロ[3,4−c]ピリダジン−1−イル)エチル)モルホリン(化合物78)
ステップ1:4−クロロ−1−(2−ヨードエチル)−3,5−ジフェニル−1H−ピラゾロ[3,4−c]ピリダジン
ステップ2:4−クロロ−3,5−ジフェニル−1−ビニル−1H−ピラゾロ[3,4−c]ピリダジン(化合物82)
ステップ2:1−(5−アミノ−3−フェニル−4−(フェニルエチニル)−1H−ピラゾール−1−イル)−2−メチルプロパン−2−オール
ステップ3:1−(4−クロロ−3,5−ジフェニル−1H−ピラゾロ[3,4−c]ピリダジン−1−イル)−2−メチルプロパン−2−オール
ステップ2:1−(4−クロロ−3,5−ジフェニル−1H−ピラゾロ[3,4−c]ピリダジン−1−イル)プロパン−2−オール(化合物91)
ステップ2:1−(4−クロロ−3,5−ジフェニル−1H−ピラゾロ[3,4−c]ピリダジン−1−イル)プロパン−2−オール(化合物92)
ステップ1:2−(5−アミノ−3−(3−フルオロフェニル)−4−(フェニルエチニル)−1H−ピラゾール−1−イル)エタノール
ステップ2:2−(4−クロロ−3−(3−フルオロフェニル)−5−フェニル−1H−ピラゾロ[3,4−c]ピリダジン−1−イル)エタノール
3−(3,5−ジフルオロフェニル)−3−オキソプロパンニトリルの合成
ステップ2:2−(4−クロロ−3,5−ジフェニル−1H−ピラゾロ[3,4−c]ピリダジン−1−イル)プロパン−1−オール(化合物96)
本発明のピラゾロピリジジン(pyrazolopyridizine)化合物に対するLC−MS条件
(a)標準的酸性LC−MS条件:(10cm_ESI_ギ酸または10cm_ESCI_ギ酸)
0.1%(V/V)ギ酸を有するアセトニトリル(遠UV等級):0.1%ギ酸勾配を有する水(PureLab Optionユニットによる高純度)を使用するPhenomenex Luna 5μm C18(2)、100×4.6mm(プラスガードカートリッジ)カラムを使用した。流速は2mL/分であった。Watersダイオードアレイ検出器(開始範囲210nm、終了範囲400nm、範囲間隔4nm)を使用してUV検出を行った。質量検出を単一の四重極(quadrapole)LC−MS装置を介して実施した。イオン化は、化合物の種類に応じて、ESIまたはAPCIのいずれかである。使用した勾配は、0.00分の時点での水性溶媒95%から、3.50分の時点での水性溶媒5%までとした。次いでこのパーセンテージをさらに2分間保持した。
(b)標準的塩基性LC−MS条件:(10cm_ESCI_Bicarb_または10cm_ESI_Bicarb):
アセトニトリル(遠UV等級):10mM炭酸水素アンモニウム(アンモニウム水素炭酸塩)勾配を有する水(PureLab Optionユニットによる高純度)を使用するWaters Xterra MS 5μm CI8、100×4.6mm(プラスガードカートリッジ)を使用した。流速は2mL/分であった。Watersダイオードアレイ検出器(開始範囲210nm、終了範囲400nm、範囲間隔4nm)を使用してUV検出を実施した。質量検出は、単一の四重極(quadrapole)LC−MS装置を介して実施した。イオン化は、化合物の種類に応じてESIまたはAPCIのいずれかである。使用された勾配は、0.00分の時点での水性溶媒95%から4.0分の時点での水性溶媒5%までとした。次いでこのパーセンテージをさらに1.5分間保持した。
(c)標準的酸性HPLC条件:(15cm_ギ酸_ASCENTIS_HPLC)
0.1%(V/V)ギ酸を有するアセトニトリル(遠UV等級):0.1%ギ酸勾配を有する水(PureLab Optionユニットによる高純度)を使用するSupelco Ascentis(登録商標)Express C18またはHichrom Halo C18、2.7μm C18、150×4.6mmカラムを使用した。流速は1mL/分であった。Agilentダイオードアレイ検出器(300nm、帯域幅200nm;ref.450nm、帯域幅100nm)を使用してUV検出を行った。使用した勾配は、0.00分の時点での水性溶媒96%から、9.00分の時点での水性溶媒0%までとした。次いでこのパーセンテージをさらに4.5分間保持した。
(d)標準的塩基性HPLC条件:(15cm_Bicarb_GeminiNX_HPLC)
アセトニトリル(遠UV等級):10mM炭酸水素アンモニウム勾配を有する水(PureLab Optionユニットによる高純度)を使用する、Phenomenex Gemini NX、3μm C18、150×4.6mmカラムを使用した。流速は1mL/分であった。Agilentダイオードアレイ検出器(300nm、帯域幅200nm;ref.450nm、帯域幅100nm)を使用してUV検出を行った。使用した勾配は、0.00分の時点での水性溶媒95.5%から、9.00分の時点での水性溶媒0%までとした。次いでこのパーセンテージをさらに4.5分間保持した。
(e)標準的酸性HPLC条件:(10cm_ギ酸_ACE3 C18 AR_HPLC_CH3CN)
0.1%(V/V)ギ酸を有するアセトニトリル(遠UV等級):0.1%ギ酸勾配を有する水(PureLab Optionユニットによる高純度)を使用する、Hichrom ACE3 C18−AR ミックスモード100×4.6mmカラムを使用した。流速は1mL/分であった。Agilentダイオードアレイ検出器(300nm、帯域幅200nm;ref.450nm、帯域幅100nm)を使用してUV検出を行った。使用した勾配は、0.00分から3.00分の時点での水性溶媒98%から、12.00分の時点での水性溶媒100%のまでとした。次いでこのパーセンテージをさらに2.4分間保持した。
クラリン−1は、アッシャーIII症候群において変異した遺伝子によりコードされているタンパク質である(Adatoら、2002年)。北アメリカにおいて、最も広がっているクラリン−1の変異はN48Kであり、このN48Kは、グリコシル化の損失およびトラフィッキングの欠陥を引き起こすことが報告されている(Tianら、2009年)。その結果、N48Kタンパク質は原形質膜に到達せず、プロテアソームにより分解される。したがって、N48Kクラリン−1の細胞表面へのトラフィッキングを修復することによって、アッシャーIII症候群への介入手段が得られると考えられている。
本発明の例示的ピラゾロピリミジン化合物の活性に対するIC50値を実施例92のアッセイ法に従い得た。化合物1−35、37−39、42、44、45および47−97に対するIC50値は、10マイクロモル以下である。化合物1−9、10、11、13−34、37−39、44、45、47−97に対するIC50値はすべて5マイクロモル以下である。化合物1、2、4−9、13、14、17、19、28、32、38、39、45、48−61、63−74、76、77、79、81、83、85−97に対するIC50値はすべて1マイクロモル以下である。
化合物44は、ピラゾロピリミジン部分およびビオチン基を含み、ピラゾロピリミジン部分に結合するタンパク質を特定するためのプローブとして有用である。タンパク質は、以下の通り特定される:HEK293−クラリン−1 N48K−HA D9細胞は、コラーゲンコーティングされた96−ウェルプレートに、1ウェル当たり細胞20,000個の細胞密度で、10%ウシ胎児血清を含有するDulbecco変法イーグル培地(DMEM)内、加湿したインキュベーター内で、37℃、5%CO2で播種する。終夜のインキュベーション後、24時間インキュベーションするために、化合物44を10マイクロモル以下の濃度で各ウェルに加える。インキュベーションは、場合によって3回重複して実施する。化合物44を用いた24時間のインキュベーション後、細胞をリン酸緩衝食塩水(PBS)で3回洗浄し、細胞可溶化物に変換する。次いで、化合物44に結合したタンパク質を分離し、当技術分野で公知の任意の適切な方法を使用して特定する。例えば、細胞可溶化物をストレプトアビジンコーティングしたビーズに塗布し、ドデシル硫酸ナトリウム(SDS)などの洗浄剤を含有する緩衝液でビーズを洗浄することによって、任意の非特異的結合タンパク質を除去する。次いで、例えば、8Mグアニジン・HCl、pH1.5を使用して、SDS−PAGE(−ポリアクリルアミドゲル電気泳動)緩衝液中でビーズを沸騰させることによって、またはビーズのトリプシン消化により結合したタンパク質をビーズから溶離する。次いで放出されたペプチドの質量を、質量分析器、例えば、マトリックス支援レーザー脱離イオン化法−飛行時間(MALDI−TOF)またはエレクトロスプレーイオン化−飛行時間(ESI−TOF)などを用いて測定することができる。次いでこれらの質量を、公知のタンパク質配列を含有するデータベースのものと比較することによって、タンパク質を特定する。化合物44に結合しているペプチドフラグメントもまた特定される。これは、ペプチドフラグメントの分子量が化合物44の分子量によって増加するからである。
Claims (25)
- 式II
(式中、Halは、−Cl、−F、−I、または−Brであり、
xは、0から5の範囲の整数であり、
各R1は、独立して、−Cl、−F、−I、−Br、−C1−C3アルキル、−O−C1−C3アルキル、−CN、−CF3、−C(O)NH(CH3)、または−C≡CCH2OHであり、
yは、0から5の範囲の整数であり、
各R2は、独立して、−Cl、−F、−Br、−C1−C3アルキル、−O−C1−C3アルキル、−CN、−CF3、−C(O)NH(CH3)、または−C≡CCH2OHであり、
R3は、−H、−C1−C6アルキル、−(C1−C6アルキレン)−OH、−(C1−C6アルキレン)−フェニル、−(C1−C6アルキレン)−O−(C1−C6アルキル)、−C2−C6アルケニル、−(C1−C6アルキレン)−C(O)R4、−(C1−C6アルキレン)−R5、
R4は、−OH、−O−(C1−C6アルキル)、−NH2、−NH(C1−C6アルキル)、−NH((C1−C6アルキレン)−OH)、−NH((C1−C6アルキレン)N(C1−C6アルキル)2)、N(C1−C6アルキル)((C1−C6アルキレン)−CN)、−N(C1−C6アルキル)((C1−C6アルキレン)N(C1−C6アルキル)2)、−NH(C1−C6アルキレン)−O−(C1−C6アルキル)、
aは、0から10の範囲の整数であり、
bは、0から8の範囲の整数であり、
cは、0から6の範囲の整数であり、ならびに
R5は、
- 式III
(式中、Halは、−Cl、−F、−I、または−Brであり、
xは、0から5の範囲の整数であり、
各R1は、独立して、−Cl、−F、−I、−Br、−C1−C3アルキル、−O−C1−C3アルキル、−CN、−CF3、−C(O)NH(CH3)、または−C≡CCH2OHであり、
R3は、−H、−C1−C6アルキル、−(C1−C6アルキレン)−OH、−(C1−C6アルキレン)−フェニル、−(C1−C6アルキレン)−O(C1−C6アルキル)、−C2−C6アルケニル、−(C1−C6アルキレン)−C(O)R4、−(C1−C6アルキレン)−R5、
R4は、−OH、−O−(C1−C6アルキル)、−NH2、−NH(C1−C6アルキル)、−NH((C1−C6アルキレン)−OH)、−NH((C1−C6アルキレン)N(C1−C6アルキル)2)、N(C1−C6アルキル)((C1−C6アルキレン)−CN)、−N(C1−C6アルキル)((C1−C6アルキレン)N(C1−C6アルキル)2)、−NH(C1−C6アルキレン)−O−(C1−C6アルキル)、
aは、0から10の範囲の整数であり、
bは、0から8の範囲の整数であり、
cは、0から6の範囲の整数であり、
R5は、
各R6およびR7は、独立して、−Hまたは−Iであり、R6およびR7のうちの少なくとも1つは−Iであり、ならびに
R3が−C1−C3アルキルである場合、R7は−Hである。)。 - 請求項1もしくは2に記載の化合物または該化合物の医薬として許容される塩および医薬として許容される担体またはビヒクルを含む組成物。
- 網膜変性疾患を治療するための方法であって、治療を必要とする対象に、有効量の請求項1もしくは2に記載の化合物または該化合物の医薬として許容される塩を投与することを含む方法。
- 網膜変性疾患が、網膜色素変性症、レーバー先天性黒内障、症候性網膜変性症、加齢黄斑変性、またはアッシャー症候群である、請求項5に記載の方法。
- アッシャー症候群がアッシャーI、アッシャーIIまたはアッシャーIII症候群である、請求項6に記載の方法。
- 網膜変性疾患がアッシャーIII症候群である、請求項5に記載の方法。
- アッシャー症候群に伴う聴覚損失を治療するための方法であって、治療を必要とする対象に有効量の請求項1もしくは2に記載の化合物または該化合物の医薬として許容される塩を投与することを含む方法。
- アッシャー症候群がアッシャーI、アッシャーIIまたはアッシャーIII症候群である、請求項9に記載の方法。
- アッシャー症候群がアッシャーIII症候群である、請求項9に記載の方法。
- 請求項12に記載の化合物または該化合物の塩に結合することが可能なタンパク質を特定するための方法であって、
a.前記タンパク質を前記化合物または該化合物の塩に結合させるために効果的な条件下で、HEK293−クラリン−1 N48K−HA D9細胞を前記化合物または該化合物の塩と接触させること、
b.前記細胞を細胞可溶化物に変換すること、
c.前記細胞可溶化物をストレプトアビジンコーティングしたビーズに塗布すること、
d.前記ビーズを洗浄すること、
e.前記ビーズから、結合したタンパク質を溶離させること、および
f.前記溶離したタンパク質の質量を測定すること
を含む方法。 - タンパク質および請求項12に記載の化合物または該化合物の塩の複合物。
- 請求項17に記載の化合物または該化合物の医薬として許容される塩および医薬として許容される担体またはビヒクルを含む組成物。
- 網膜変性疾患を治療するための方法であって、治療を必要とする対象に、有効量の請求項17に記載の化合物または該化合物の医薬として許容される塩を投与することを含む方法。
- 網膜変性疾患が、網膜色素変性症、レーバー先天性黒内障、症候性網膜変性症、加齢黄斑変性、またはアッシャー症候群である、請求項19に記載の方法。
- アッシャー症候群が、アッシャーI、アッシャーIIまたはアッシャーIII症候群である、請求項20に記載の方法。
- 網膜変性疾患がアッシャーIII症候群である、請求項19に記載の方法。
- アッシャー症候群に伴う聴覚損失を治療するための方法であって、治療を必要とする対象に、有効量の請求項17に記載の化合物または該化合物の医薬として許容される塩を投与することを含む方法。
- アッシャー症候群が、アッシャーI、アッシャーIIまたはアッシャーIII症候群である、請求項23に記載の方法。
- アッシャー症候群がアッシャーIII症候群である、請求項24に記載の方法。
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AU2012249801B2 (en) | 2016-05-19 |
CA2834049A1 (en) | 2012-11-01 |
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CA2834049C (en) | 2018-05-22 |
EP2701510A1 (en) | 2014-03-05 |
PL2701510T3 (pl) | 2017-07-31 |
IL229023A0 (en) | 2013-12-31 |
HUE032820T2 (en) | 2017-11-28 |
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US20130252936A1 (en) | 2013-09-26 |
WO2012148994A1 (en) | 2012-11-01 |
ZA201307961B (en) | 2015-12-23 |
US10307422B2 (en) | 2019-06-04 |
JP5902293B2 (ja) | 2016-04-13 |
ES2625534T3 (es) | 2017-07-19 |
US20150266812A1 (en) | 2015-09-24 |
US20180207159A1 (en) | 2018-07-26 |
IL229023A (en) | 2017-07-31 |
US20160158172A1 (en) | 2016-06-09 |
US9549910B2 (en) | 2017-01-24 |
EP2701510A4 (en) | 2014-06-11 |
EP2701510B1 (en) | 2017-02-15 |
US9260381B2 (en) | 2016-02-16 |
JP2016193884A (ja) | 2016-11-17 |
US9079909B2 (en) | 2015-07-14 |
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