JP2021530451A - セレブロン(crbn)に対するリガンド - Google Patents
セレブロン(crbn)に対するリガンド Download PDFInfo
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- JP2021530451A JP2021530451A JP2020571833A JP2020571833A JP2021530451A JP 2021530451 A JP2021530451 A JP 2021530451A JP 2020571833 A JP2020571833 A JP 2020571833A JP 2020571833 A JP2020571833 A JP 2020571833A JP 2021530451 A JP2021530451 A JP 2021530451A
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- VLLMWSRANPNYQX-UHFFFAOYSA-N thiadiazole Chemical compound C1=CSN=N1.C1=CSN=N1 VLLMWSRANPNYQX-UHFFFAOYSA-N 0.000 description 1
- 125000005307 thiatriazolyl group Chemical group S1N=NN=C1* 0.000 description 1
- 125000005308 thiazepinyl group Chemical group S1N=C(C=CC=C1)* 0.000 description 1
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- JOXIMZWYDAKGHI-UHFFFAOYSA-M toluene-4-sulfonate Chemical compound CC1=CC=C(S([O-])(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-M 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 1
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- BWHDROKFUHTORW-UHFFFAOYSA-O tritert-butylphosphanium Chemical compound CC(C)(C)[PH+](C(C)(C)C)C(C)(C)C BWHDROKFUHTORW-UHFFFAOYSA-O 0.000 description 1
- 210000004881 tumor cell Anatomy 0.000 description 1
- 230000006663 ubiquitin-proteasome pathway Effects 0.000 description 1
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- 125000002948 undecyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
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- 208000013139 vaginal neoplasm Diseases 0.000 description 1
- 229920002554 vinyl polymer Polymers 0.000 description 1
- 230000000007 visual effect Effects 0.000 description 1
- 235000019165 vitamin E Nutrition 0.000 description 1
- 229940046009 vitamin E Drugs 0.000 description 1
- 239000011709 vitamin E Substances 0.000 description 1
- 239000001993 wax Substances 0.000 description 1
- 238000009736 wetting Methods 0.000 description 1
- 239000011787 zinc oxide Substances 0.000 description 1
- 229960001296 zinc oxide Drugs 0.000 description 1
- 235000014692 zinc oxide Nutrition 0.000 description 1
- GVJHHUAWPYXKBD-IEOSBIPESA-N α-tocopherol Chemical compound OC1=C(C)C(C)=C2O[C@@](CCC[C@H](C)CCC[C@H](C)CCCC(C)C)(C)CCC2=C1C GVJHHUAWPYXKBD-IEOSBIPESA-N 0.000 description 1
Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- 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
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- 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
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
- A61K31/52—Purines, e.g. adenine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D473/00—Heterocyclic compounds containing purine ring systems
- C07D473/02—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6
- C07D473/16—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6 two nitrogen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D473/00—Heterocyclic compounds containing purine ring systems
- C07D473/26—Heterocyclic compounds containing purine ring systems with an oxygen, sulphur, or nitrogen atom directly attached in position 2 or 6, but not in both
- C07D473/32—Nitrogen atom
- C07D473/34—Nitrogen atom attached in position 6, e.g. adenine
Abstract
Description
本出願は、2018年6月29日に出願された米国仮出願第62/692,167号に対する35U.S.C.§119(e)の下での優先権の利益を主張し、該仮出願は参照により全体が本明細書に組み込まれる。
本発明は、米国国立衛生研究所により授与された助成金番号R01CA214608の下での政府の支援により為された。政府は本発明においてある特定の権利を有する。
複素環という用語はまたヘテロシクリルアルコキシ基を包含し、これは、本明細書において使用される場合、式−−O−−Rc−ヘテロシクリル(式中、Rcはアルキレン鎖である)の酸素原子を通じて結合したラジカルを指す。
別の態様では、本発明は、本発明の化合物、またはその薬学的に許容される塩もしくは立体異性体を製造する方法を対象とする。概括的に言えば、本発明の化合物またはその薬学的に許容される塩もしくは立体異性体は、化学的に関連する化合物の調製に応用可能であることが公知の任意の方法により調製されてもよい。本発明の化合物は、様々な実施例において記載され、かつ本発明の化合物を調製することができる非限定的な方法を説明する合成スキームと組み合わせてより良好に理解されるであろう。
本発明の別の態様は、治療有効量の式(I)の化合物、またはその薬学的に許容される塩もしくは立体異性体、および薬学的に許容される担体を含む医薬組成物を対象とする。「薬学的に許容される担体」という用語は、当該技術分野において公知のように、哺乳動物に本発明の化合物を投与するために好適な、薬学的に許容される材料、組成物または溶媒を指す。好適な担体としては、例えば、化合物を1つの臓器、または身体の部分から別の臓器、または身体の部分に運ぶまたは輸送するように機能する、液体(水性および同様に非水性の両方、およびその組合せ)、固体、被包材料、気体、ならびにその組合せ(例えば、半固体)、ならびに気体を挙げることができる。担体は、配合物の他の成分に対して生理学的に不活性であり、かつそれと適合性であり、かつ対象または患者に対して毒性でないという意味において「許容される」ものである。配合物の種類に依存して、組成物は1つまたはより多くの薬学的に許容される賦形剤を含んでもよい。
投与量
本明細書において使用される場合、「治療有効量」という用語は、カゼインキナーゼ1アルファ(CK1α)、配列類似性83ファミリーメンバーF(FAM83F)、DTWドメイン含有1(DTWD1)、ジンクフィンガータンパク質91ホモログ(ZFP91)、ZFP62、ZFP36リングフィンガータンパク質様(ZFP36L2)、リングフィンガータンパク質166(RNF166)、イカロスファミリージンクフィンガータンパク質1(IKZF1)、IKZF2、IKZF3、IKZF4、IKZF5、Ras関連タンパク質Rab−28(RAB28)、グルタチオンS−トランスフェラーゼパイ1(GSTP1)、GSPT2、ミトコンドリアインポート内膜トランスロカーゼサブユニットTim10(TIMM10)、GDNF誘導性ジンクフィンガータンパク質1(GZF1)、初期増殖応答1(EGR1)−、がん過剰メチル化1(HIC1)−、HIC2−、インスリノーマ関連タンパク質2(INSM2)−、odd−skipped関連転写因子2(OSR2)、タンパク質ポリブロモ−1(PB1)、PRドメインジンクフィンガータンパク質15(PRD15)、スパルト様転写因子1(SALL1)、SALL3、SALL4、WIZ、ジンクフィンガーおよびBTBドメイン含有タンパク質17(ZBT17)、ZBT41、ZBT49、ZBT7A、ZBT7B、ZBTB2、ZBTB39、Kタンパク質と相互作用するジンクフィンガータンパク質1(ZIK1)、ジンクフィンガータンパク質3(ZNF3)、ZNF217、ZNF276、ZNF316、ZNF324B、ZNF335、ZNF397、ZNF407、ZNF408、ZNF462、ZNF483、SNF517、ZNF526、ZNF581、ZNF587、ZNF589、ZNF618、ZNF644、ZNF646、ZNF653、ZNF654、ZNF692、ZNF724、ZNF771、ZNF782、ZNF784、ZNF814、ジンクフィンガーおよびSCANドメイン含有10(ZSC10)、ZSC22、ZC827、ならびにUFM1特異的ペプチダーゼドメイン含有ジンクフィンガー(ZUFSP)からなる群から選択されるタンパク質の異常な活性により特徴付けられまたは媒介される疾患または障害を患う具体的な患者において所望の治療応答を生じさせるのに効果的な本発明の化合物またはその薬学的に許容される塩もしくは立体異性体の量を指す。一部の実施形態では、疾患または障害は、IKZF2の異常な活性により特徴付けられまたは媒介される。「治療有効量」という用語は、投与された場合に、治療すべき疾患もしくは障害における肯定的な修飾(例えば、軽快)を誘導し、または疾患もしくは障害の発症もしくは進行を予防するために十分な、または対象において治療されている疾患もしくは障害の症状の1つもしくはより多くを何らかの程度まで緩和し、または単純に疾患(例えば、がん)細胞を殺傷しもしくはその増殖を阻害する、本発明の化合物またはその薬学的に許容される塩もしくは立体異性体の量を含む。
一部の態様では、本発明の化合物は、セレブロンによる分解のために標的化され得る、疾患または障害の発端、1つまたはより多くの症状またはマーカーの顕在化、重篤度または進行に参加するタンパク質の異常な活性により特徴付けられ、かつ標的化されたタンパク質の分解が治療的利益を付与することがある、疾患および障害の治療において有用であり得る。疾患または障害は、上記に開示されるように、非病的状態と比較して上昇したタンパク質レベルを伴うことがある異常なタンパク質活性により特徴付けられまたは媒介されると言われることがある。「疾患」は、動物がホメオスタシスを維持できず、かつ疾患が寛解されない場合に、動物の健康状態が増悪し続ける動物の健康状態として一般にみなされる。対照的に、動物における「障害」は、動物がホメオスタシスを維持できるが、動物の健康状態が障害の非存在下におけるよりも好都合なものではない健康状態である。治療されないままの場合、障害は、動物の健康状態のさらなる減少を必ずしも引き起こさない。一部の実施形態では、本出願の化合物は、増殖性疾患および障害(例えば、がんまたは良性新生物)の治療において有用であり得る。本明細書において使用される場合、「細胞増殖性疾患または障害」という用語は、非がん性状態、前がん性状態、およびがんを含む、制御されないまたは異常な細胞増殖、または両方により特徴付けられる状態を指す。
本発明の化合物は、疾患および障害の治療において、少なくとも1つの他の活性剤、例えば、抗がん剤またはレジメンと組み合わせて使用されてもよい。この文脈における「組み合わせて」という用語は、剤が併用投与されることを意味し、これは、同じもしくは別々の投与形態による実質的に同期間の投与、または逐次的、例えば、同じ治療レジメンの部分としてもしくは連続的な治療レジメンによる投与を含む。そのため、逐次的に与えられる場合、第2の化合物の投与の開始時に、2つの化合物のうちの1つ目は、一部の場合には、治療の部位において効果的な濃度で依然として検出可能である。順序および時間間隔は、それらが(例えば、それらがそれ以外に投与された場合よりも増加した利益を提供するように相乗的に)一緒に作用できるように決定されてもよい。例えば、治療剤は、異なる時点において任意の順序において同時または逐次的に投与されてもよいが、同時に投与されない場合、それらは、相乗的な様式であり得る所望の治療効果を提供するように時間的に十分に近く投与されてもよい。そのため、該用語は、正確に同じ時点での活性剤の投与に限定されない。
本発明の組成物はキットまたは薬学的システムに集められてもよい。本発明のこの態様によるキットまたは薬学的システムは、本発明の化合物またはその医薬組成物を含有する1つまたはより多くの容器、例えば、バイアル、チューブ、アンプル、またはボトルをその中に緊密に閉じ込めて有するキャリアまたはパッケージ、例えば、箱、カートン、またはチューブなどを含む。本発明のキットまたは薬学的システムはまた、化合物および組成物を使用するための印刷された説明書を含んでもよい。
Claims (31)
- 式(I):
- R3がアリールまたは置換されたアリールを表し、かつ式(Ia1)の前記化合物が、式(Ia1a):
- R3が、置換されていてもよいC6〜C14のアリール、または置換されていてもよいC6〜14のヘテロアリール基を表す、請求項1に記載の化合物。
- R3が、置換されていてもよいC5〜14の炭素環または置換されていてもよいC5〜14の複素環式基を表す、請求項1に記載の化合物。
- R4が、置換されていてもよいC6〜14のアリール、または置換されていてもよいC6〜14のヘテロアリール基を表す、請求項1に記載の化合物。
- R4が、置換されていてもよいC5〜14の炭素環または置換されていてもよいC5〜14の複素環式基を表す、請求項1に記載の化合物。
- R3またはR4が、置換されていてもよいC6〜14のアリール基または置換されたC6〜14のヘテロアリール基である、請求項1に記載の化合物。
- R3またはR4が置換されていてもよいフェニル基である、請求項1に記載の化合物。
- ZがCH2である、請求項1に記載の化合物。
- 治療有効量の請求項1に記載の化合物、またはその薬学的に許容される塩もしくは立体異性体、および薬学的に許容される担体を含む、医薬組成物。
- カプセルまたは錠剤の形態である、請求項27に記載の薬学的に組成物。
- 溶液または懸濁液である、請求項27に記載の医薬組成物。
- 治療有効量の請求項1に記載の化合物、またはその薬学的に許容される塩もしくは立体異性体をそれを必要とする対象に投与することを含む、カゼインキナーゼ1アルファ(CK1α)、配列類似性83ファミリーメンバーF(FAM83F)、DTWドメイン含有1(DTWD1)、ジンクフィンガータンパク質91ホモログ(ZFP91)、ZFP62、ZFP36リングフィンガータンパク質様(ZFP36L2)、リングフィンガータンパク質166(RNF166)、イカロスファミリージンクフィンガータンパク質1(IKZF1)、IKZF2、IKZF3、IKZF4、IKZF5、Ras関連タンパク質Rab−28(RAB28)、グルタチオンS−トランスフェラーゼパイ1(GSTP1)、GSPT2、ミトコンドリアインポート内膜トランスロカーゼサブユニットTim10(TIMM10)、GDNF誘導性ジンクフィンガータンパク質1(GZF1)、初期増殖応答1(EGR1)、がん過剰メチル化1(HIC1)、HIC2、インスリノーマ関連タンパク質2(INSM2)、odd−skipped関連転写因子2(OSR2)、タンパク質ポリブロモ−1(PB1)、PRドメインジンクフィンガータンパク質15(PRD15)、スパルト様転写因子1(SALL1)、SALL3、SALL4、WIZ、ジンクフィンガーおよびBTBドメイン含有タンパク質17(ZBT17)、ZBT41、ZBT49、ZBT7A、ZBT7B、ZBTB2、ZBTB39、Kタンパク質と相互作用するジンクフィンガータンパク質1(ZIK1)、ジンクフィンガータンパク質3(ZNF3)、ZNF217、ZNF276、ZNF316、ZNF324B、ZNF335、ZNF397、ZNF407、ZNF408、ZNF462、ZNF483、SNF517、ZNF526、ZNF581、ZNF587、ZNF589、ZNF618、ZNF644、ZNF646、ZNF653、ZNF654、ZNF692、ZNF724、ZNF771、ZNF782、ZNF784、ZNF814、ジンクフィンガーおよびSCANドメイン含有10(ZSC10)、ZSC22、ZC827、ならびにUFM1特異的ペプチダーゼドメイン含有ジンクフィンガー(ZUFSP)からなる群から選択されるタンパク質の異常な活性により特徴付けられまたは媒介される疾患または障害を治療する方法。
- IKZF2の異常な活性により特徴付けられまたは媒介される前記疾患または障害である、請求項30に記載の方法。
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US20230242508A1 (en) * | 2021-12-22 | 2023-08-03 | Gilead Sciences, Inc. | Ikaros zinc finger family degraders and uses thereof |
KR20230127844A (ko) | 2022-02-25 | 2023-09-01 | 계명대학교 산학협력단 | 항암 활성을 갖는 신규 화합물 및 이의 용도 |
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