JP6068451B2 - キナーゼ阻害剤 - Google Patents
キナーゼ阻害剤 Download PDFInfo
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- JP6068451B2 JP6068451B2 JP2014511503A JP2014511503A JP6068451B2 JP 6068451 B2 JP6068451 B2 JP 6068451B2 JP 2014511503 A JP2014511503 A JP 2014511503A JP 2014511503 A JP2014511503 A JP 2014511503A JP 6068451 B2 JP6068451 B2 JP 6068451B2
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- Prior art keywords
- unsubstituted
- substituted
- alkyl
- saturated
- hydrogen
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- 229940043355 kinase inhibitor Drugs 0.000 title description 137
- 239000003757 phosphotransferase inhibitor Substances 0.000 title description 135
- 125000000217 alkyl group Chemical group 0.000 claims description 381
- 150000001875 compounds Chemical class 0.000 claims description 292
- 229910052739 hydrogen Inorganic materials 0.000 claims description 284
- 239000001257 hydrogen Substances 0.000 claims description 284
- 125000001072 heteroaryl group Chemical group 0.000 claims description 205
- 125000000592 heterocycloalkyl group Chemical group 0.000 claims description 204
- 125000003118 aryl group Chemical group 0.000 claims description 178
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 162
- 125000004404 heteroalkyl group Chemical group 0.000 claims description 155
- -1 methylene compound Chemical class 0.000 claims description 151
- 150000002431 hydrogen Chemical class 0.000 claims description 143
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 139
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 129
- 229910052736 halogen Inorganic materials 0.000 claims description 128
- 150000002367 halogens Chemical group 0.000 claims description 122
- 125000001424 substituent group Chemical group 0.000 claims description 116
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- 229920006395 saturated elastomer Polymers 0.000 claims description 86
- 125000005842 heteroatom Chemical group 0.000 claims description 76
- 229910052760 oxygen Inorganic materials 0.000 claims description 67
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 65
- 229910052717 sulfur Inorganic materials 0.000 claims description 61
- 229910052799 carbon Inorganic materials 0.000 claims description 56
- 125000002950 monocyclic group Chemical group 0.000 claims description 53
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- 150000003839 salts Chemical class 0.000 claims description 46
- 125000005843 halogen group Chemical group 0.000 claims description 39
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- 208000023275 Autoimmune disease Diseases 0.000 claims description 2
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- 125000004194 piperazin-1-yl group Chemical group [H]N1C([H])([H])C([H])([H])N(*)C([H])([H])C1([H])[H] 0.000 claims description 2
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- 125000004494 ethyl ester group Chemical group 0.000 description 18
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- 239000003112 inhibitor Substances 0.000 description 17
- 238000002360 preparation method Methods 0.000 description 17
- PVEOYINWKBTPIZ-UHFFFAOYSA-N but-3-enoic acid Chemical compound OC(=O)CC=C PVEOYINWKBTPIZ-UHFFFAOYSA-N 0.000 description 16
- 230000002829 reductive effect Effects 0.000 description 16
- 125000006413 ring segment Chemical group 0.000 description 16
- 125000006568 (C4-C7) heterocycloalkyl group Chemical group 0.000 description 15
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- 239000000758 substrate Substances 0.000 description 15
- NIXOWILDQLNWCW-UHFFFAOYSA-N Acrylic acid Chemical compound OC(=O)C=C NIXOWILDQLNWCW-UHFFFAOYSA-N 0.000 description 14
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 14
- 125000003342 alkenyl group Chemical group 0.000 description 14
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- 125000003161 (C1-C6) alkylene group Chemical group 0.000 description 12
- CVFFSNDOBXFEKR-UHFFFAOYSA-N 3-(4-chlorophenyl)-2h-pyrazolo[3,4-d]pyrimidin-4-amine Chemical compound C1=2C(N)=NC=NC=2NN=C1C1=CC=C(Cl)C=C1 CVFFSNDOBXFEKR-UHFFFAOYSA-N 0.000 description 12
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- 125000004076 pyridyl group Chemical group 0.000 description 12
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- UIJXHKXIOCDSEB-MRVPVSSYSA-N tert-butyl (3r)-3-hydroxypiperidine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CCC[C@@H](O)C1 UIJXHKXIOCDSEB-MRVPVSSYSA-N 0.000 description 1
- APCBTRDHCDOPNY-SSDOTTSWSA-N tert-butyl (3r)-3-hydroxypyrrolidine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CC[C@@H](O)C1 APCBTRDHCDOPNY-SSDOTTSWSA-N 0.000 description 1
- UIJXHKXIOCDSEB-QMMMGPOBSA-N tert-butyl (3s)-3-hydroxypiperidine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CCC[C@H](O)C1 UIJXHKXIOCDSEB-QMMMGPOBSA-N 0.000 description 1
- BFFLLBPMZCIGRM-UHFFFAOYSA-N tert-butyl 2-(hydroxymethyl)pyrrolidine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CCCC1CO BFFLLBPMZCIGRM-UHFFFAOYSA-N 0.000 description 1
- APCBTRDHCDOPNY-UHFFFAOYSA-N tert-butyl 3-hydroxypyrrolidine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CCC(O)C1 APCBTRDHCDOPNY-UHFFFAOYSA-N 0.000 description 1
- DRDVJQOGFWAVLH-UHFFFAOYSA-N tert-butyl n-hydroxycarbamate Chemical compound CC(C)(C)OC(=O)NO DRDVJQOGFWAVLH-UHFFFAOYSA-N 0.000 description 1
- 201000003120 testicular cancer Diseases 0.000 description 1
- 125000004192 tetrahydrofuran-2-yl group Chemical group [H]C1([H])OC([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- 125000003831 tetrazolyl group Chemical group 0.000 description 1
- 238000011285 therapeutic regimen Methods 0.000 description 1
- 230000004797 therapeutic response Effects 0.000 description 1
- 238000004809 thin layer chromatography Methods 0.000 description 1
- 125000005505 thiomorpholino group Chemical group 0.000 description 1
- 238000000293 three-dimensional nuclear magnetic resonance spectroscopy Methods 0.000 description 1
- 201000002510 thyroid cancer Diseases 0.000 description 1
- 239000006208 topical dosage form Substances 0.000 description 1
- 231100000440 toxicity profile Toxicity 0.000 description 1
- 235000010487 tragacanth Nutrition 0.000 description 1
- 239000000196 tragacanth Substances 0.000 description 1
- 229940116362 tragacanth Drugs 0.000 description 1
- HSBSUGYTMJWPAX-HNQUOIGGSA-N trans-2-hexenedioic acid Chemical compound OC(=O)CC\C=C\C(O)=O HSBSUGYTMJWPAX-HNQUOIGGSA-N 0.000 description 1
- 238000012546 transfer Methods 0.000 description 1
- 230000009466 transformation Effects 0.000 description 1
- 238000000844 transformation Methods 0.000 description 1
- ITMCEJHCFYSIIV-UHFFFAOYSA-M triflate Chemical compound [O-]S(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-M 0.000 description 1
- 229910052722 tritium Inorganic materials 0.000 description 1
- 208000029729 tumor suppressor gene on chromosome 11 Diseases 0.000 description 1
- 229940121358 tyrosine kinase inhibitor Drugs 0.000 description 1
- 201000005112 urinary bladder cancer Diseases 0.000 description 1
- 210000004291 uterus Anatomy 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
- 229920002554 vinyl polymer Polymers 0.000 description 1
- 239000011345 viscous material Substances 0.000 description 1
- 238000001262 western blot Methods 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
Classifications
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- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
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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
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
- C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
- C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D215/48—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
- C07D215/54—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen attached in position 3
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D235/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
- C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
- C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
- C07D235/06—Benzimidazoles; Hydrogenated benzimidazoles with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 2
- C07D235/08—Radicals containing only hydrogen and carbon atoms
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
- C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
- C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
- C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
- C07D239/48—Two nitrogen atoms
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- C07D239/72—Quinazolines; Hydrogenated quinazolines
- C07D239/86—Quinazolines; Hydrogenated quinazolines with hetero atoms directly attached in position 4
- C07D239/94—Nitrogen atoms
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- 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
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- 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
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- 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
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- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
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- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
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- 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
- C07D405/02—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 two hetero rings
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- 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
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- C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
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- 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
Description
本出願は、参照により全体として全ての目的のために本明細書に組み込まれる2011年5月17日に出願された米国仮特許出願第61/487,233号明細書の利益を主張する。
特に記載のない限り、本明細書および特許請求の範囲において使用される以下の用語は、本出願の目的のために定義され、以下の意味を有する。本明細書において使用される略語は、化学および生物学分野の範囲内でのそれらの慣用の意味を有する。本明細書に記載の化学構造および化学式は、化学分野において公知の化学原子価の標準的規則に従って構築される。
第1の態様において、式Iの構造:
(i)式
(ii)式
式(I)の化合物は、当分野において一般に公知の化学合成技術を使用して調製することができる。これに関して、代表的番号の式(I)の化合物の調製におけるいくつかの指針を、スキームおよび実施例セクションに提供する。本出願に開示されるスキームおよび実施例は、説明にすぎず、本発明の化合物を調製する手法に関する排他的または限定的教示であることを意味するものではない。これらのスキームへの種々の改変を行うことができ、それは本開示および当分野において公知のものを参照する当業者に示唆される。当業者は、本明細書に提供される式がいかなる特定の立体化学に限定されないことも認識する。
L1は、−C(O)−、−N(L2R5)SO2−、−N(L2R5)C(O)−、
(i)式
(ii)式
(式中、R’およびR’’は、独立して水素または非置換飽和(C1−C6)アルキルである)から独立して選択される1もしくは3つの置換基により置換されている飽和(C1−C6)アルキルである。
別の態様において、タンパク質キナーゼを阻害する方法が提供される。本方法は、タンパク質キナーゼを有効量の本明細書に提供されるキナーゼ阻害剤と接触させることを含む。キナーゼ阻害剤は、本明細書に提供される式(または上記のその実施形態のいずれか)の構造を有し得る。一部の実施形態において、タンパク質キナーゼを阻害する方法は、細胞内で実施される。したがって、ある実施形態において,細胞内のタンパク質キナーゼを阻害する方法が提供される。本方法は、細胞を有効量の本明細書に提供されるキナーゼ阻害剤と接触させることを含む。キナーゼ阻害剤は、本明細書に提供される式(または上記のその実施形態のいずれか)の構造を有し得る。一部の実施形態において、細胞は、原核または真核である。細胞は、真核であり得る(例えば、原生動物細胞、真菌細胞、植物細胞または動物細胞)。一部の実施形態において、細胞は、哺乳動物細胞、例えばヒト細胞、ウシ細胞、ブタ細胞、ウマ細胞、イヌ細胞およびネコ細胞、マウス細胞、またはラット細胞である。一部の実施形態において、細胞は、ヒト細胞である。細胞は、器官または生物の一部を構成し得る。ある実施形態において、細胞は、器官の一部も生物の一部も構成しない。
別の態様において、キナーゼ活性に関連する疾患の治療が必要とされる対象におけるキナーゼ活性に関連する疾患を治療する方法である。本方法は、対象に有効量(例えば、治療有効量)の本明細書に提供される式の構造を有する化合物(または上記のその実施形態のいずれか)を投与することを含む。化合物は、式Iの構造を有し得る。
当分野において公知である技術および本明細書に提供される指針を使用して、候補キナーゼ阻害剤は、任意の公知のタンパク質キナーゼを阻害する阻害剤の能力について容易にアッセイすることができる。例えば、本明細書に提供される式の構造またはその実施形態を有する候補キナーゼ阻害剤は、キナーゼ活性部位結合残基および/またはキナーゼ活性部位触媒残基の間の潜在的な結合接触を評価するために、コンピュータモデリング技術を使用して最初にアッセイすることができる。このようなコンピュータモデリング技術は、インシリコ技術と称することもできる。上記考察のとおり、キナーゼ活性部位結合残基および/またはキナーゼ活性部位触媒残基は、1次アミノ酸構造が公知である任意のキナーゼについて、公知であるか、または容易に決定される。特に、コンピュータモデリング技術は、チオール付加物を形成するために、電子欠乏オレフィン炭素を用いて、キナーゼ活性部位システイン残基と反応する候補キナーゼ阻害剤の能力を評価するために用いることができる。例えば、キナーゼ阻害剤電子欠乏オレフィン炭素が、キナーゼ活性部位システインスルフヒドリルの10Å以内にある場合、キナーゼ阻害剤の効力および/または選択性を改善することができる(例えば、1000〜10000倍)。
別の態様において、本発明は、本発明のキナーゼ阻害剤化合物または薬学的に許容可能な賦形剤(例えば、担体)との組合せにおけるキナーゼ阻害剤化合物を含む、医薬組成物を提供する。
本発明のキナーゼ阻害剤は、広範な経口、非経口、および局所的剤形で調製および投与することができる。したがって、本発明の化合物は、注射(例えば、静脈内、筋肉内、皮内、皮下、十二指腸内、または腹腔内)により投与することができる。また、本明細書に記載の化合物は、吸入により、例えば、鼻内投与することができる。さらに、本発明の化合物は、経皮投与することができる。複数の投与経路(例えば、筋肉内、経口、経皮)を使用して本発明の化合物を投与することができることも想定される。したがって、本発明はまた、薬学的に許容可能な担体または賦形剤、および1つ以上の本発明の化合物を含む医薬組成物を提供する。
本発明により提供される医薬組成物には、活性成分が治療有効量、すなわち、その意図される目的を達成するために有効な量で含有される組成物が含まれる。特定の適用のために有効な実際の量は、とりわけ、治療される病態に依存する。例えば、癌を治療するための方法において投与される場合、このような組成物は、所望の結果(例えば、対象における癌細胞の数の減少)を達成するために有効な量の活性成分を含有する。
特定の化合物についての毒性と治療効果との比は、その治療指数であり、LD50(集団の50%において致死である化合物の量)とED50(集団の50%において有効である化合物の量)との比として表現することができる。高い治療指数を示す化合物が好ましい。細胞培養アッセイおよび/または動物試験から得られた治療指数データは、ヒトにおける使用のために一定範囲の投与量を処方する際に使用することができる。このような化合物の投与量は、好ましくは、毒性をほとんど有さないかまたは全く有さないED50を含む一定範囲の血漿濃度内である。投与量は、用いられる剤形および利用される投与の経路に応じてこの範囲内で変動し得る。例えば、Fingl et al.,In:Pharmacological Basis of Therapeutics,Ch.1,p.l,1975参照。正確な処方、投与の経路、および投与量は、患者の病態および化合物を使用する特定の方法の観点から個々の医師が選択することができる。
一部の実施形態において、本明細書に提供されるキナーゼ阻害剤は、他の治療剤または治療モダリティとの組合せにおいて使用することができる。一部の実施形態において、追加の治療剤は抗癌剤である。治療剤は、化学療法剤、生物製剤、ホルモン療法剤、または本明細書に提供される式(またはその実施形態)のキナーゼ阻害剤ではないキナーゼ阻害剤であり得る。追加の治療剤は、さらに、アルキル化剤、アントラサイクリン、モノクローナル抗体、サイトカイン、ヌクレオシドアナログ、プレドニゾン、タキサン、エストロゲン、プロゲステロン、ホルモンアンタゴニスト、ビンカアルカロイド、代謝拮抗物質などであり得る。
式(I)の化合物および中間体(参照)の以下の調製は、当業者がより明確に理解し、本発明を実施することができるように挙げる。これらは、本発明の範囲を限定するものとはみなすべきでなく、単にその説明および代表例にすぎない。
参照A
4−アミノ−3−(4−フェノキシフェニル)−1H−ピラゾロ[3,4−d]ピリミジンの合成
4−アミノ−3−(4−クロロフェニル)−1H−ピラゾロ[3,4−d]ピリミジンの合成
(3S)−1−ピロリジンカルボン酸、3−ヒドロキシ−,2−プロペン−1−イルエステルの合成
(R)−2−(3−(4−アミノ−3−(4−クロロフェニル)−1H−ピラゾロ[3,4−d]ピリミジン−1−イル)ピロリジン−1−カルボニル)−3−シクロプロピルアクリロニトリルの合成
2−(3−(4−アミノ−3−(4−フェノキシフェニル)−1H−ピラゾロ[3,4−d]ピリミジン−1−イル)ピペリジン−1−カルボニル)−3−フェニルアクリロニトリルの合成
2−(3−(4−アミノ−3−(4−フェノキシフェニル)−1H−ピラゾロ[3,4−d]ピリミジン−1−イル)ピペリジン−1−カルボニル)−3−(2−クロロフェニル)アクリロニトリルの合成
2−(3−(4−スミノ(smino)−3−(4−フェノキシフェニル)−1H−ピラゾロ[3,4−d]ピリミジン−1−イル)ピペリジン−1−カルボニル)−4,4−ジメチルペント−2−エンニトリルの合成
一般的手順A
ピリミジン1と第1級または第2級アルコールとの光延反応を行い、次いでBoc脱保護および2−シアノ酢酸によるアシル化を行う。
3−(4−(4−アミノ−3−(4−フェノキシフェニル)−1H−ピラゾロ[3,4−d]ピリミジン−1−イル)ピペリジン−1−イル)−3−オキソプロパンニトリルの合成
(R)−3−(3−(4−アミノ−3−(4−フェノキシフェニル)−1H−ピラゾロ[3,4−d]ピリミジン−1−イル)ピペリジン−1−イル)−3−オキソプロパンニトリルの合成
(S)−3−(3−(4−アミノ−3−(4−フェノキシフェニル)−1H−ピラゾロ[3,4−d]ピリミジン−1−イル)ピペリジン−1−イル)−3−オキソプロパンニトリルの合成
3−(4−((4−アミノ−3−(4−フェノキシフェニル)−1H−ピラゾロ[3,4−d]ピリミジン−1−イル)メチル)ピペリジン−1−イル)−3−オキソプロパンニトリルの合成
3−(3−((4−アミノ−3−(4−フェノキシフェニル)−1H−ピラゾロ[3,4−d]ピリミジン−1−イル)メチル)ピペリジン−1−イル)−3−オキソプロパンニトリルの合成
(S)−3−(3−(4−アミノ−3−(4−フェノキシフェニル)−1H−ピラゾロ[3,4−d]ピリミジン−1−イル)ピロリジン−1−イル)−3−オキソプロパンニトリルの合成
(R)−3−(2−((4−アミノ−3−(4−フェノキシフェニル)−1H−ピラゾロ[3,4−d]ピリミジン−1−イル)メチル)ピロリジン−1−イル)−3−オキソプロパンニトリルの合成
N−((1S,4S)−4−(4−アミノ−3−(4−フェノキシフェニル)−1H−ピラゾロ[3,4−d]ピリミジン−1−イル)シクロヘキシル)−2−シアノアセトアミドの合成
一般的手順B
シアノアセトアミドとシクロプロパンカルボキサルデヒドとの縮合
2−(4−(4−アミノ−3−(4−フェノキシフェニル)−1H−ピラゾロ[3,4−d]ピリミジン−1−イル)ピペリジン−1−カルボニル)−3−シクロプロピルアクリロニトリルの合成
(R)−2−(3−(4−アミノ−3−(4−フェノキシフェニル)−1H−ピラゾロ[3,4−d]ピリミジン−1−イル)ピペリジン−1−カルボニル)−3−シクロプロピルアクリロニトリルの合成
(S)−2−(3−(4−アミノ−3−(4−フェノキシフェニル)−1H−ピラゾロ[3,4−d]ピリミジン−1−イル)ピペリジン−1−カルボニル)−3−シクロプロピルアクリロニトリルの合成
2−(4−((4−アミノ−3−(4−フェノキシフェニル)−1H−ピラゾロ[3,4−d]ピリミジン−1−イル)メチル)ピペリジン−1−カルボニル)−3−シクロプロピルアクリロニトリルの合成
2−(3−((a−アミノ−3−(4−フェノキシフェニル)−1H−ピラゾロ[3,4−d]ピリミジン−1−イル)メチル)ピペリジン−1−カルボニル)−3−シクロプロピルアクリロニトリルの合成
(S)−2−(3−(4−アミノ−3−(4−フェノキシフェニル)−1H−ピラゾロ[3,4−d]ピリミジン−1−イル)ピロリジン−1−カルボニル)−3−シクロプロピルアクリロニトリルの合成
(R)−2−(2−((a−アミノ−3−(4−フェノキシフェニル)−1H−ピラゾロ[3,4−d]ピリミジン−1−イル)メチル)ピロリジン−1−カルボニル)−3−シクロプロピルアクリロニトリルの合成
N−((1S,4S)−4−(4−アミノ−3−(4−フェノキシフェニル)−1H−ピラゾロ[3,4−d]ピリミジン−1−イル)シクロヘキシル)−2−シアノ−3−シクロプロピルアクリルアミドの合成
(R)−2−(3−(4−アミノ−3−(4−フェノキシフェニル)−1H−ピラゾロ[3,4−d]ピリミジン−1−イル)ピペリジン−1−カルボニル)−4−(ジメチルアミノ)−4−メチルペント−2−エンニトリルの合成
(R)−2−(3−(4−アミノ−3−(4−フェノキシフェニル)−1H−ピラゾロ[3,4−d]ピリミジン−1−イル)ピペリジン−1−カルボニル)−5−ヒドロキシ−4,4−ジメチルペント−2−エンニトリルの合成
2−(3−(4−アミノ−3−(4−クロロフェニル)−1H−ピラゾロ[3,4−d]ピリミジン−1−イル)ピペリジン−1−カルボニル)−3−シクロプロピルアクリロニトリルの合成
N−(4−(3−ブロモフェニルアミノ)キナゾリン−6−イル)−2−シアノ−3−シクロプロピルアクリルアミドの合成
(R)−2−(3−(4−アミノ−3−(4−フェノキシフェニル)−1H−ピラゾロ[3,4−d]ピリミジン−1−イル)ピペリジン−1−カルボニル)−3−シクロプロピルアクリロニトリルの合成
2−((R)−3−(4−アミノ−3−(4−(3,4−ジクロロフェノキシ)−3−メトキシフェニル)−1H−ピラゾロ[3,4−d]ピリミジン−1−イル)ピペリジン−1−カルボニル)−3−シクロプロピルアクリロニトリルの合成
1,2−ジクロロ−4−(2−メトキシ−4−ニトロフェノキシ)ベンゼン(60g、190.40mmol、1.00当量)、Fe(53g、946.43mmol、4.97当量)および塩化アンモニウム(10g、188.68mmol、0.99当量)のテトラヒドロフラン/水(1/2)(600mL)中混合物を、窒素の不活性雰囲気下で60℃において一晩撹拌した。混合物をCeliteに通して濾過し、濾液を真空下で濃縮した。得られた溶液を3x500mLのジクロロメタンにより抽出し、有機層を合わせた。得られた混合物を3x500mLのブラインにより洗浄した。混合物を、無水硫酸マグネシウム上で乾燥させ、真空下で濃縮して40g(74%)の4−(3,4−ジクロロフェノキシ)−3−メトキシアニリンを薄灰色固体として得た。
亜硝酸ナトリウム(14.4g、208.70mmol、1.98当量)の水(500mL)中溶液を、4−(3,4−ジクロロフェノキシ)−3−メトキシアニリン(30g、105.58mmol、1.00当量)の硫酸(1000mL)中溶液中に0℃において撹拌しながら滴加し、混合物を0℃において30分間撹拌した。上記混合物を、ヨウ化カリウム(1000mL、5%)の水中溶液に50℃において撹拌しながら滴加した。反応を直ちに完了させた。反応混合物を室温に冷却し、3x500mLの酢酸エチルにより抽出し、有機層を合わせた。得られた混合物を3x500mLの飽和水性重炭酸ナトリウムおよび3x500mLのブラインにより洗浄した。混合物を無水硫酸ナトリウム上で乾燥させ、真空下で濃縮して24g(粗製物)の1,2−ジクロロ−4−(4−ヨード−2−メトキシフェノキシ)ベンゼンを赤色油状物として得た。
1,4−ジオキサン(500mL)中の1,2−ジクロロ−4−(4−ヨード−2−メトキシフェノキシ)ベンゼン(93g、235.43mmol、1.00当量)、酢酸カリウム(46g、469.39mmol、1.99当量)、4,4,5,5−テトラメチル−2−(4,4,5,5−テトラメチル−1,3,2−ジオキサボロラン−2−イル)−1,3,2−ジオキサボロラン(89g、350.39mmol、1.49当量)およびPd(dppf)Cl2(4.65g)の混合物を、窒素の不活性雰囲気下で90℃において一晩撹拌した。反応混合物を室温に冷却し、真空下で濃縮した。残留物を500mLの酢酸エチル中で溶解させ、mLの水およびブラインにより洗浄した。混合物を無水硫酸ナトリウム上で乾燥させ、真空下で濃縮した。残留物をシリカゲルカラム上にアプライし、酢酸エチル/石油エーテル(1/100)により10g(11%)の2−[4−(3,4−ジクロロフェノキシ)−3−メトキシフェニル]−4,4,5,5−テトラメチル−1,3,2−ジオキサボロランを薄黄色油状物として得た。
(R)−2−(3−(4−アミノ−3−(4−フェノキシフェニル)−1H−ピラゾロ[3,4−d]ピリミジン−1−イル)ピペリジン−1−カルボニル)−4,4−ジメチルペント−2−エンニトリルの合成
2−(2−((4−アミノ−3−(4−フェノキシフェニル)−1H−ピラゾロ[3,4−d]ピリミジン−1−イル)メチル)ピロリジン−1−カルボニル)−3−シクロプロピルアクリロニトリルの合成
2−(2−((4−アミノ−3−(4−フェノキシフェニル)−1H−ピラゾロ[3,4−d]ピリミジン−1−イル)メチル)ピロリジン−1−カルボニル)−4,4−ジメチルペント−2−エンニトリルの合成
(EZ)−N−((1r,4r)−4−(4−アミノ−3−(4−フェノキシフェニル)−1H−ピラゾロ[3,4−d]ピリミジン−1−イル)シクロヘキシル)−2−シアノ−3−シクロプロピルアクリルアミドの合成
(EZ)−N−((1r,4r)−4−(4−アミノ−3−(4−フェノキシフェニル)−1H−ピラゾロ[3,4−d]ピリミジン−1−イル)シクロヘキシル)−2−シアノ−3−シクロプロピルアクリルアミドの合成
(EZ)−2−(4−(4−アミノ−3−(4−フェノキシフェニル)−1H−ピラゾロ[3,4−d]ピリミジン−1−イル)ピペリジン−1−カルボニル)−3−シクロプロピルアクリロニトリルの合成
2−(4−(4−アミノ−3−(4−フェノキシフェニル)−1H−ピラゾロ[3,4−d]ピリミジン−1−イル)ピペリジン−1−カルボニル)−4,4−ジメチルペント−2−エンニトリルの合成
(R,EZ)−2−(3−(4−アミノ−3−(4−(3,4−ジクロロフェノキシ)−3−メトキシフェニル)−1H−ピラゾロ[3,4−d]ピリミジン−1−イル)ピペリジン−1−カルボニル)−4,4−ジメチルペント−2−エンニトリルの合成
(R)−N−(4−(4−アミノ−1−(1−(2−シアノ−3−シクロプロピルアクリロイル)ピペリジン−3−イル)−1H−ピラゾロ[3,4−d]ピリミジン−3−イル)フェニル)−4−(トリフルオロメチル)ベンズアミドの合成
(R)−N−(4−(4−アミノ−1−(1−(2−シアノ−4,4−ジメチルペント−2−エノイル)ピペリジン−3−イル)−1H−ピラゾロ[3,4−d]ピリミジン−3−イル)フェニル)−4−(トリフルオロメチル)ベンズアミドの調製
N−(3−((6−(2−クロロフェニル)−8−メチル−7−オキソ−7,8−ジヒドロピリド[2,3−d]ピリミジン−2−イル)−アミノ)フェニル)−2−シアノ−3−シクロプロピルアクリルアミドの合成
N−(3−(6−(2−クロロフェニル)−8−メチル−7−オキソ−7,8−ジヒドロピリド[2,3−d]ピリミジン−2−イルアミノ)−ベンジル)−2−シアノ−3−シクロプロピルアクリルアミドの合成
N−(3−(6−(2−クロロフェニル)−8−メチル−7−オキソ−7,8−ジヒドロピリド[2,3−d]ピリミジン−2−イルアミノ)−ベンジル)−2−シアノ−3−シクロプロピル−N−メチルアクリルアミドの合成
2−(5−(6−(2−クロロフェニル)−8−メチル−7−オキソ−7,8−ジヒドロピリド[2,3−d]−ピリミジン−2−イルアミノ)−1,2,3,4−テトラヒドロイソキノリン−2−カルボニル)−3−シクロプロピルアクリロニトリルの合成
2−シアノ−3−シクロプロピル−N−(3−(2−(4−モルホリノフェニルアミノ)−ピリミジン−4−イルアミノ)フェニル)アクリルアミドの合成
3−シクロプロピル−2−(3−(5−フルオロ−2−(6−(4−メチルピペラジン−1−イル)ピリジン−3−イルアミノ)ピリミジン−4−イルアミノ)ピペリジン−1−カルボニル)アクリロニトリルの合成
3−シクロプロピル−2−[2−({5−フルオロ−2−[6−(4−メチル−ピペラジン−1−イル)−ピリジン−3−イルアミノ]−ピリミジン−4−イルアミノ}−メチル)−ピロリジン−1−カルボニル]−アクリロニトリルの合成
3−シクロプロピル−2−(3−(5−フルオロ−2−(6−モルホリノピリジン−3−イルアミノ)ピリミジン−4−イルアミノ)−ピペリジン−1−カルボニル)アクリロニトリルの合成
3−シクロプロピル−2−(2−(((5−フルオロ−2−((6−モルホリノピリジン−3−イル)アミノ)ピリミジン−4−イル)−アミノ)メチル)ピロリジン−1−カルボニル)アクリロニトリルの合成
3−シクロプロピル−2−(3−((5−フルオロ−2−(フェニルアミノ)ピリミジン−4−イル)アミノ)ピペリジン−1−カルボニル)アクリロニトリルの合成
3−シクロプロピル−2−(2−(((5−フルオロ−2−(フェニルアミノ)ピリミジン−4−イル)アミノ)メチル)−ピロリジン−1−カルボニル)アクリロニトリルの合成
N−(3−(5−フルオロ−4−(フェニルアミノ)ピリミジン−2−イルアミノ)−4−メトキシフェニル)−2−シアノ−3−シクロプロピルアクリルアミドの合成
5−(4−(2−シアノ−3−シクロプロピルアクリルアミド)ベンジルアミノ)−7−(3,5−ジメトキシフェニルアミノ)−イミダゾ[1,2−c]ピリミジン−8−カルボキサミドの合成
5−(3−(2−シアノ−3−シクロプロピルアクリルアミド)ベンジルアミノ)−7−(3,5−ジメトキシフェニル−アミノ)イミダゾ[1,2−c]ピリミジン−8−カルボキサミドの合成
5−((1−(2−シアノ−3−シクロプロピルアクリロイル)ピペリジン−3−イル)メチルアミノ)−7−(3,5−ジメトキシフェニルアミノ)イミダゾ[1,2−c]ピリミジン−8−カルボキサミドの合成
5−((1−(2−シアノ−3−シクロプロピルアクリロイル)ピペリジン−4−イル)メチルアミノ)−7−(3,5−ジメトキシフェニルアミノ)イミダゾ[1,2−c]ピリミジン−8−カルボキサミドの合成
5−((1−(2−シアノ−3−シクロプロピルアクリロイル)アゼチジン−3−イル)メチルアミノ)−7−(3,5−ジメトキシフェニルアミノ)イミダゾ[1,2−c]ピリミジン−8−カルボキサミドの合成
5−((1−(2−シアノ−3−シクロプロピルアクリロイル)アゼチジン−3−イル)メチルアミノ)−7−(3,5−ジメトキシフェニルアミノ)イミダゾ[1,2−c]ピリミジン−8−カルボキサミドの合成
5−(3−(2−シアノ−3−シクロプロピルアクリルアミド)−2,2−ジメチルプロピルアミノ)−7−(3,5−ジメトキシフェニルアミノ)イミダゾ[1,2−c]ピリミジン−8−カルボキサミドの合成
実施例1
インビトロキナーゼ活性アッセイについての一般的手順
Btkインビトロキナーゼ活性アッセイについての一般的手順。Btk(ヒト、全長)を購入し(Invitrogen、カタログ番号PV3363)、生成物の文献から改変された手順に従って使用した。Btk(キナーゼ希釈緩衝液中150nM)をMgCl2(10mM)、ATP(100μM)、およびZn(OAc)2(10μM)の添加により予備活性化し、室温において5分間インキュベートした。続いて、BSA(0.1mg/mL)が補給されたキナーゼアッセイ緩衝液中のBtk(5nMの最終濃度)を、阻害剤(6または10種の濃度、デュプリケート、5%のDMSO最終濃度)と室温において30分間プレインキュベートした。キナーゼ反応は、0.16μCi/μLのg−32P−ATP(6000Ci/mmol、NEN)および0.2mg/mLの基質(ポリ[Glu:Tyr]、4:1のGlu:Tyr)の添加により開始させ、室温において30分間インキュベートした。キナーゼ活性は、5μLのそれぞれの反応物をホスホセルロースのシート上にスポットすることにより測定した。それぞれのブロットを10%のAcOH溶液により1回洗浄し、0.1%のH3PO4溶液により2回洗浄し、MeOHにより1回洗浄した(1回の洗浄当たり5〜10分間)。乾燥ブロットをストレージフォスファスクリーンに30分間曝露し、Typhoonイメージャー(GE Life Sciences)によりスキャンした。データを、ImageQuant(v.5.2,Molecular Dynamics)を使用して定量し、GraphPad Prism 4.0ソフトウエアを使用してプロットした。
EGFRインビトロキナーゼ活性アッセイについての一般的手順
EGFR(ErbB1)キナーゼドメイン(ヒト、GST融合物)を購入し(Invitrogen、カタログ番号PV3872)、生成物文献から改変された手順に従って使用した。BSA(0.1mg/mL)が補給されたキナーゼアッセイ緩衝液中のEGFR(4nMの最終濃度)を、阻害剤(6または10種の濃度、デュプリケート、5%のDMSO最終濃度)と室温において30分間プレインキュベートした。キナーゼ反応は、0.16μCi/μLのg−32P−ATP(6000Ci/mmol、NEN)および0.2mg/mLの基質(ポリ[Glu:Tyr]、4:1のGlu:Tyr)の添加により開始させ、室温において30分間インキュベートした。キナーゼ活性は、5μLのそれぞれの反応物をホスホセルロースのシート上にスポットすることにより測定した。それぞれのブロットを10%のAcOH溶液により1回洗浄し、0.1%のH3PO4溶液により2回洗浄し、MeOHにより1回洗浄した(1回の洗浄当たり5〜10分間)。乾燥ブロットをストレージフォスファスクリーンに30分間曝露し、Typhoonイメージャー(GE Life Sciences)によりスキャンした。データを、ImageQuant(v.5.2,Molecular Dynamics)を使用して定量し、GraphPad Prism4.0ソフトウエアを使用してプロットした。シアノアクリルアミド33は、EGFRキナーゼ活性をIC50<0.1μMで阻害した。
マウスコラーゲン誘導性関節炎の阻害
マウスコラーゲン誘導性関節炎(mCIA)の阻害は、関節リウマチについての標準的な動物疾患モデルである。従来の研究は、BTKの阻害がmCIAの遮断において有効であることを実証している(Honigberg L.A.,et.al.,Proc Natl Acad Sci USA.107:13075−80.2010参照)。0日目開始時、DBA/1マウスに完全フロイントアジュバント中II型コラーゲンのエマルションを注射する。マウスを21日後に追加免疫して疾患の発現を同調させる。軽度な疾患の発現後、動物を試験に加え、無作為化する。投与は、試験化合物または対照としてのデキサメタゾン(0.2mg/kg)による1日1回、典型的には11日間の経口である。1つの群は、ビヒクル単独を受容する。臨床評価(0〜4)は、関節炎の膨張および重症度の程度に基づく。全ての四肢についての評価を16の最大評価について追加する。抗コラーゲン抗体および総Igを、Elisaにより試験の終了時にそれぞれの動物について計測する(Bolder BioPath,Boulder,CO)。
透析時のキナーゼ活性の回復
可逆性を確認する標準的な実験方法は、当分野において公知である。タンパク質透析は、そのような1つの方法である。式Iの化合物により阻害されるタンパク質キナーゼを含有する溶液を、大規模透析に供してキナーゼ阻害剤が可逆性であるか否か確認することができる。透析の間の経時的なタンパク質キナーゼ活性の部分的または完全な回復は、可逆性の指標である。
本明細書に記載の式Iの化合物(1uM)を、20mMのHepes[pH8.0]、10mMのMgCl2、2.5mMのトリス(2−カルボキシエチル)ホスフィン(TCEP)、0.25mg/mLのBSA、および100uMのATPを含有する緩衝液中タンパク質キナーゼ(50nM、必要により予備活性化)の溶液に添加する。室温において60分後、反応物を透析カセット(0.1〜0.5mLのSlide−A−Lyzer,MWCO 10kDa,Pierce)に移し、2Lの緩衝液(20mMのHepes[pH8.0]、10mMのMgCl2、1mMのDTT)に対して4℃において透析する。透析緩衝液を2時間後に交換し、次いで実験終了まで24時間毎に交換する。アリコートを透析カセットから24時間毎に取り出し、液体窒素中でフラッシュ凍結し、続いてタンパク質キナーゼ活性についてトリプリケートで分析する。それぞれの試料についてのキナーゼ活性は、その時点についてのDMSO対照に正規化し、平均±SDとして表現する。
キナーゼ活性は、透析時に可逆性キナーゼ阻害剤による阻害から回復する。4℃または室温における大規模透析時、キナーゼ活性は、過剰(20当量、1.0uM)の可逆性キナーゼ阻害剤による阻害から時間依存的に部分的または完全に回復する。
質量スペクトル分析
式Iの化合物により阻害されるタンパク質キナーゼは、質量スペクトル分析に供して恒久的な不可逆性共有結合アダクトの形成を評価することができる。インタクトな完全タンパク質またはタンパク質キナーゼのトリプシン開裂時に生成されるペプチド断片を試験する好適な分析方法は、一般に当分野において公知である。そのような方法は、恒久的な不可逆性共有結合タンパク質アダクトを、対照試料の質量と不可逆性アダクトの質量に対応する質量ピークを観察することにより同定する。そのような2つの方法を以下に記載する。
方法
タンパク質キナーゼ(5uM)を、式Iの化合物(25uM、5当量)と室温において緩衝液(20mMのHepes[pH8.0]、100mMのNaCl、10mMのMgCl2)中で1時間インキュベートする。式Iの化合物を有さない対照試料も調製する。反応を、等容量の0.4%ギ酸の添加により停止させ、試料を液体クロマトグラフィー(Microtrap C18 Proteinカラム[Michrom Bioresources]、5%のMeCN、0.2%のギ酸、0.25mL/分;95%のMeCN、0.2%のギ酸により溶出)およびインラインESI質量分析(LCT Premier,Waters)により分析する。タンパク質キナーゼおよび任意のアダクトの分子質量は、MassLynxデコンボリューションソフトウエアにより決定することができる。
式Iの化合物により阻害されるキナーゼの高分解能インタクト質量分析は、阻害剤の不存在下でのキナーゼ(例えば、対照試料)と類似するスペクトルを示す。キナーゼの分子質量と式Iの化合物の分子質量に対応する質量スペクトルにおける新たなピークの形成は存在しない。この実験に基づくと、恒久的な不可逆性タンパク質アダクトは当業者に明らかでない。
方法
タンパク質(10〜100pmol)を、式Iの化合物(100〜1000pmol、10当量)と3時間インキュベートしてからトリプシン消化する。ヨードアセトアミドを化合物インキュベーション後にアルキル化剤として使用することができる。式Iの化合物を有さない対照試料も調製する。トリプシン消化のため、1ulのアリコート(3.3pmol)を、10ulの0.1%TFAにより希釈してから脱着マトリックスとしてのアルファシアノ−4−ヒドロキシ桂皮酸(0.1%のTFA:アセトニトリル50:50中5mg/mol)または脱着マトリックスとしてのシナピン酸(0.1%のTFA:アセトニトリル50:50中10mg/mol)を使用してマイクロC18 Zip TippingをMALDI標的上に直接行った。
式Iの化合物により阻害されるキナーゼのトリプシン断片の高分解能質量分析は、阻害剤の不存在下でのキナーゼ(例えば、対照試料)と類似のスペクトルを示す。対照試料中に存在しないいかなる改変ペプチドの証拠も存在しない。この実験に基づくと、恒久的な不可逆性タンパク質アダクトは当業者に明らかでない。
薬物−キナーゼ滞留時間の測定、薬物オフレート(off−rate)アッセイ
以下のものは、化合物がBTKからの緩慢な解離速度または解離速度の不存在を示すかどうかを区別するためのプロトコルであり、それは例えば、典型的には、共有結合が化合物と標的との間で形成される場合に行う。緩慢な解離についての読取りは、時間分解蛍光共鳴エネルギー移動(TR−FRET)を使用して検出されるキナーゼ活性部位への高親和性蛍光トレーサー分子の結合を遮断する対象化合物の能力である。この実験は、50mMのHepes pH7.5、10mMのMgCl2、0.01%のTriton X−100、および1mMのEGTAからなる緩衝液中で実施した。
以下のアプローチを、標的との不可逆性結合を形成する化合物、例えばアクリルアミド化合物を可逆的に結合する化合物から区別するために開発した。反応物は、対象化合物よりも高い濃度のタンパク質標的を用いて調製した。不可逆性化合物および可逆性化合物は両方、標的に結合し、溶液から枯渇した。次いで、反応物を、摂動、例として、5Mのグアニジン塩酸塩による変性およびトリプシンによる消化、標的の適切な折り畳みの撹乱により処理した。摂動は、標的からの解離に起因して可逆性化合物を溶液に戻す一方、不可逆性化合物は標的に結合したままであることが見出された。溶液中の化合物の濃度は、タンデム質量分析に結合した高速液体クロマトグラフィー(HPLC)を使用して摂動の前後の両方で評価した。この技術を使用して、アクリルアミド含有化合物1(以下の表に示す)は、天然状態および摂動状態の両方の溶液から枯渇する一方、可逆性化合物1および27は、折り畳まれた状態で枯渇するが標的の摂動後に溶液に戻ることが実証された(以下の表参照)。
以下のものは、式(I)の化合物を含有する代表的な医薬配合物である。
以下の成分を緊密に混合し、単一の分割錠に打錠する。
以下の成分を緊密に混合し、硬シェルゼラチンカプセル剤中にロードする。
MSAを有する脱イオン水中2%のHPMC、1%のTween80、pH2.2中の本発明の化合物(例えば、化合物1)、少なくとも20mg/mLまで適量。
Claims (12)
- 以下の構造式(XI)を有する化合物:
点線は、場合により結合であり;
yは、0から2の整数であり;
jは、0から3の整数であり;
fは、0または1であり;
Z1、Z2、およびZ3は、−N−または−CH−であり、但し、Z1、Z2、およびZ3の少なくとも1つおよび2つ以下は、同時にNであり;
Arは、単環式もしくは縮合二環式(C6−C10)アリール、N、OもしくはSから選択される1〜4つのヘテロ原子を含有する単環式もしくは縮合二環式5〜10員ヘテロアリール、単環式(C3−C10)シクロアルキルまたはN、OもしくはSから選択される1〜4つのヘテロ原子を含有する4から8員ヘテロシクロアルキルであり、上記定義の単環式アリールまたはヘテロアリールに場合により縮合しており、1または2つの−CO−基を環中に含有してよく;
R12は、水素、(C1−C6)非置換飽和アルキル、ヒドロキシ、非置換飽和(C1−C6)アルコキシ、ハロゲン、ハロ置換(C1−C6)飽和アルキル、または非置換飽和(C1−C6)ハロアルコキシであり;
R14は、水素、(C1−C6)非置換飽和アルキル、ヒドロキシ、−O(C1−C6)非置換飽和アルキル、非置換飽和(C1−C6)アルコキシ、ハロゲン、非置換飽和(C1−C6)ハロアルキル、または非置換飽和(C1−C6)ハロアルコキシであり;
L1は、−C(O)−または−SO2−であり;
L4は、結合、−O−、−NH−、またはメチレンであり;
環Aは、アゼチジン−1−イル、ピロリジン−1−イル、ピペラジン−1−イル、またはピペリジン−1−イルであり、
L11は、−O−、−CO−、−CH2−、−S−、−SO−、−SO2−、−NR15C−、−NR15CCO−、−CONR15C−、−NR15CSO2−、−SO2NR15C−、または−NR15CCONR15D−であり(式中、それぞれのR15CおよびR15Dは、独立して水素またはC1−C6非置換飽和アルキルである);
R23は、水素、(C1−C6)非置換飽和アルキル、ヒドロキシ、非置換飽和(C1−C6)アルコキシ、ハロ、非置換飽和(C1−C6)ハロアルキル、非置換飽和(C1−C6)ハロアルコキシ、カルボキシ、−COO−(C1−C6)非置換飽和アルキル、シアノ、−CONH2、または−NRxRyであり、ここでRxは、水素であり、Ryは、水素、(C1−C6)非置換飽和アルキル、非置換飽和(C3−C6)シクロアルキル、非置換飽和(C3−C6)シクロアルキル−(C1−C6)非置換飽和アルキル、−CORであり、ここでRは、(C1−C6)非置換飽和アルキル、または−SO2−(C1−C6)非置換飽和アルキルであり;
R2およびR3は、独立して(C1−C6)非置換飽和アルキル、非置換飽和(C1−C6)ハロアルコキシ、ヒドロキシル、非置換飽和(C1−C6)アルコキシ、カルボキシ、シアノ、−COO−(C1−C6)非置換飽和アルキル、−S−(C1−C6)非置換飽和アルキル、−SO2−(C1−C6)非置換飽和アルキル、ハロ、−CONRR’もしくは−NRR’(式中、それぞれのRは、水素、(C1−C6)非置換飽和アルキル、(C3−C6)非置換飽和シクロアルキル、1、2、もしくは3つのヒドロキシまたは1から3つの非置換飽和(C1−C6)アルコキシにより置換されている(C1−C6)飽和アルキルであり、R’は、水素、(C1−C6)非置換飽和アルキル、または非置換飽和(C3−C6)シクロアルキルである)から独立して選択される1、2、もしくは3つの置換基により置換されている(C1−C6)飽和アルキルまたはN、OもしくはSから選択される1〜4つのヘテロ原子を含有し、(C1−C6)非置換飽和アルキル、ヒドロキシル、非置換飽和(C1−C6)アルコキシ、−S−(C1−C6)非置換飽和アルキル、−SO2−(C1−C6)非置換飽和アルキル、もしくはハロから独立して選択される1もしくは2つの置換基により場合により置換されている4から8員ヘテロシクロアルキルであり、またはR2およびR3は、それらが付着している炭素原子と一緒に(C3−C6)非置換飽和シクロアルキルを形成しており、且つR 2 およびR 3 が、それらが付着している炭素原子と一緒に(C 3 −C 6 )非置換飽和シクロアルキルを形成する場合には、R 4 は、水素ともなり得る;
R4は、R18−置換もしくは非置換アルキル、R18−置換もしくは非置換ヘテロアルキル、R18−置換もしくは非置換シクロアルキル、R18−置換もしくは非置換ヘテロシクロアルキル、R18−置換もしくは非置換アリール、またはR18−置換もしくは非置換ヘテロアリールであり、
R18は、独立してハロゲン、−CN、−OH、−SH、−NH2、−COOH、−NO2、−CONH2、−CF3、非置換アルキル、非置換ヘテロアルキル、非置換シクロアルキル、非置換ヘテロシクロアルキル、非置換アリール、または非置換ヘテロアリールである]
を有する。]。 - 式(XI)の化合物のL11 が、−O−である、請求項1に記載の化合物。
- 式(XI)の化合物のR12 が、不存在、メチル、フルオロ、またはトリフルオロメチルである、請求項2に記載の化合物。
- R 14 が、不存在、非置換飽和(C1−C6)アルキル、非置換飽和(C1−C6)アルコキシ、シアノ、ハロ、非置換飽和(C1−C6)ハロアルキルまたは非置換飽和(C1−C6)ハロアルコキシである、請求項3に記載の化合物。
- R 23 が、不存在、非置換飽和(C1−C6)アルキル、非置換飽和(C1−C6)アルコキシ、ハロ、非置換飽和(C1−C6)ハロアルキル、非置換飽和(C1−C6)ハロアルコキシ、またはシアノである、請求項4に記載の化合物。
- L 4 が、結合、−O−、−NH−またはメチレンである、請求項5に記載の化合物。
- L 1 が、−C(O)−または−SO2−であり、環Aが、水素、メチル、もしくはフルオロにより場合により置換されているアゼチジニル、ピロリジニル、ピペリジニル、またはピペラジニルである、請求項6に記載の化合物。
- R 2およびR3 が、独立して非置換飽和C1−C6アルキルであるか、または一緒に飽和非置換シクロアルキルを形成しており、R4 が、水素、メチル、ヒドロキシメチル、ヒドロキシエチル、メチルアミノ、ジメチルアミノ、2−メチルアミノエチル、または2,2−ジメチルアミノエチルである、請求項7に記載の化合物。
- Arが、非置換フェニルであるか、またはメタ位もしくはパラ位の少なくとも一方で置換したフェニルである、請求項8に記載の化合物。
- 請求項1に記載の化合物または薬学的に許容可能なその塩、および薬学的に許容可能な賦形剤を含む、医薬組成物。
- 請求項1に記載の化合物を含有する医薬。
- 炎症疾患、自己免疫疾患、または癌の治療用の、請求項10に記載の医薬組成物。
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AU2012255759B2 (en) | 2017-08-10 |
EP2710007A2 (en) | 2014-03-26 |
HUE048834T2 (hu) | 2020-08-28 |
JP2014513729A (ja) | 2014-06-05 |
DK2710007T3 (da) | 2020-01-27 |
ES2770550T3 (es) | 2020-07-02 |
KR102052670B1 (ko) | 2019-12-06 |
PL2710007T3 (pl) | 2020-06-01 |
MX2013013415A (es) | 2014-07-09 |
CA2836449A1 (en) | 2012-11-22 |
BR112013029508A2 (pt) | 2019-12-24 |
WO2012158843A3 (en) | 2013-04-11 |
KR20140059169A (ko) | 2014-05-15 |
CA2836449C (en) | 2021-04-27 |
EP2710007A4 (en) | 2015-04-01 |
BR112013029508B1 (pt) | 2022-05-03 |
US9580427B2 (en) | 2017-02-28 |
MX355728B (es) | 2018-04-27 |
CN103717602B (zh) | 2016-11-09 |
AU2012255759A1 (en) | 2014-01-16 |
US20140323464A1 (en) | 2014-10-30 |
EP2710007B1 (en) | 2019-12-11 |
WO2012158843A2 (en) | 2012-11-22 |
CN103717602A (zh) | 2014-04-09 |
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