JP2021533164A - イミダゾテトラジン化合物 - Google Patents
イミダゾテトラジン化合物 Download PDFInfo
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- JP2021533164A JP2021533164A JP2021506472A JP2021506472A JP2021533164A JP 2021533164 A JP2021533164 A JP 2021533164A JP 2021506472 A JP2021506472 A JP 2021506472A JP 2021506472 A JP2021506472 A JP 2021506472A JP 2021533164 A JP2021533164 A JP 2021533164A
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- tmz
- compound
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- -1 Imidazotetrazine compound Chemical class 0.000 title claims description 58
- 150000001875 compounds Chemical class 0.000 claims abstract description 179
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- 125000001424 substituent group Chemical group 0.000 claims description 34
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 22
- 201000011510 cancer Diseases 0.000 claims description 21
- QXYCTGXCOQXVRU-UHFFFAOYSA-N 8-acetyl-3-methylimidazo[5,1-d][1,2,3,5]tetrazin-4-one Chemical compound N1=NN(C)C(=O)N2C1=C(C(=O)C)N=C2 QXYCTGXCOQXVRU-UHFFFAOYSA-N 0.000 claims description 20
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims description 19
- 150000003839 salts Chemical class 0.000 claims description 15
- 125000000217 alkyl group Chemical group 0.000 claims description 14
- 125000000623 heterocyclic group Chemical group 0.000 claims description 13
- 229910052757 nitrogen Inorganic materials 0.000 claims description 13
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- 125000001494 2-propynyl group Chemical group [H]C#CC([H])([H])* 0.000 claims description 11
- 229910052717 sulfur Inorganic materials 0.000 claims description 10
- 125000003545 alkoxy group Chemical group 0.000 claims description 5
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- 125000001475 halogen functional group Chemical group 0.000 claims 6
- SHKSWTUELIHTPG-UHFFFAOYSA-N 1h-imidazole;tetrazine Chemical group C1=CNC=N1.C1=CN=NN=N1 SHKSWTUELIHTPG-UHFFFAOYSA-N 0.000 abstract description 34
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- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 8
- LXCFILQKKLGQFO-UHFFFAOYSA-N methylparaben Chemical compound COC(=O)C1=CC=C(O)C=C1 LXCFILQKKLGQFO-UHFFFAOYSA-N 0.000 description 8
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- LYHRBIAPWZFXBG-UHFFFAOYSA-N 7h-imidazo[4,5-e]tetrazine Chemical compound N1=NNC2=NC=NC2=N1 LYHRBIAPWZFXBG-UHFFFAOYSA-N 0.000 description 6
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical group [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 6
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- ZQPPMHVWECSIRJ-KTKRTIGZSA-N oleic acid Chemical compound CCCCCCCC\C=C/CCCCCCCC(O)=O ZQPPMHVWECSIRJ-KTKRTIGZSA-N 0.000 description 1
- 238000005457 optimization Methods 0.000 description 1
- 238000003305 oral gavage Methods 0.000 description 1
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- 125000002971 oxazolyl group Chemical group 0.000 description 1
- 230000001590 oxidative effect Effects 0.000 description 1
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- 201000002528 pancreatic cancer Diseases 0.000 description 1
- 208000008443 pancreatic carcinoma Diseases 0.000 description 1
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- 125000003538 pentan-3-yl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 1
- 125000005327 perimidinyl group Chemical group N1C(=NC2=CC=CC3=CC=CC1=C23)* 0.000 description 1
- 230000002572 peristaltic effect Effects 0.000 description 1
- 150000002978 peroxides Chemical class 0.000 description 1
- 230000002085 persistent effect Effects 0.000 description 1
- CVXGFPPAIUELDV-UHFFFAOYSA-N phenacylazanium;chloride Chemical compound [Cl-].[NH3+]CC(=O)C1=CC=CC=C1 CVXGFPPAIUELDV-UHFFFAOYSA-N 0.000 description 1
- 125000004934 phenanthridinyl group Chemical group C1(=CC=CC2=NC=C3C=CC=CC3=C12)* 0.000 description 1
- 125000004625 phenanthrolinyl group Chemical group N1=C(C=CC2=CC=C3C=CC=NC3=C12)* 0.000 description 1
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- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
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- HWCKGOZZJDHMNC-UHFFFAOYSA-M tetraethylammonium bromide Chemical compound [Br-].CC[N+](CC)(CC)CC HWCKGOZZJDHMNC-UHFFFAOYSA-M 0.000 description 1
- 125000003718 tetrahydrofuranyl group Chemical group 0.000 description 1
- 125000001412 tetrahydropyranyl group Chemical group 0.000 description 1
- 125000000383 tetramethylene group Chemical group [H]C([H])([*:1])C([H])([H])C([H])([H])C([H])([H])[*:2] 0.000 description 1
- 125000003831 tetrazolyl group Chemical group 0.000 description 1
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- RTKIYNMVFMVABJ-UHFFFAOYSA-L thimerosal Chemical compound [Na+].CC[Hg]SC1=CC=CC=C1C([O-])=O RTKIYNMVFMVABJ-UHFFFAOYSA-L 0.000 description 1
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- 125000004933 β-carbolinyl group Chemical group C1(=NC=CC=2C3=CC=CC=C3NC12)* 0.000 description 1
Images
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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
本出願は、2018年8月9日に出願された米国仮特許出願第62/716,390号、2018年12月12日に出願された同第62/778,750号、及び2019年7月12日に出願された同第62/873,669号に対する35U.S.C.§119(e)の下での優先権を主張するものであり、これらのそれぞれは、その全体が参照により本明細書に組み込まれる。
本発明は、国立衛生研究所(National Institutes of Health)によって授与された助成金番号R21−CA195149の下で政府の支援を受けてなされた。政府は本発明に一定の権利を有する。
式中、
XはO又はSであり;
R1は、ハロ、−CN、−NO2、−(C1−C6)アルキル、−C(=O)Ra、フェニル、又は5員もしくは6員の複素環であり、ここで、Raは、H、ハロ、−(C1−C6)アルキル、−(C3−C6)シクロアルキル、ORb、SRb、又はNRbRcであり;ここで、
Rbは、H、−(C1−C6)アルキル、又は(C3−C6)シクロアルキルであり;
Rcは、H、−(C1−C6)アルキル、又は(C3−C6)シクロアルキルであるか;又は
Raが−NRbRcである場合、RbとRcは一緒になって複素環を形成してもよく;
R2は、−(C1−C6)アルキル、−(C3−C6)シクロアルキル、プロパルギル、フェニル、又は5員もしくは6員の複素環であり;ならびに
R3は、H、−(C1−C6)アルキル、又は(C3−C6)シクロアルキルであり;
ここで、各−(C1−C6)アルキル、−(C3−C6)シクロアルキル、プロパルギル、フェニル、及び5員又は6員の複素環は1つ以上の置換基で置換されていてもよく、各−(C1−C6)アルキルは分岐していないか又は分岐していてもよい、
の化合物又はその塩を提供する。
以下の定義は、本明細書及び特許請求の範囲の明確で一貫した理解を提供するために含まれる。本明細書で使用される場合、列挙される用語は以下の意味を有する。本明細書で使用される他のすべての用語及び語句は、当業者が理解するそれらの通常の意味を有する。そのような通常の意味は、R.J.Lewis,John Wiley&Sons,New York,N.Y.,2001によるHawley’s Condensed Chemical Dictionary 14th Editionなどの専門用語辞典を参照することによって得られ得る。
本開示は、式I:
式中、
XはO又はSであり;
R1は、ハロ、−CN、−NO2、−(C1−C6)アルキル、−C(=O)Ra、フェニル、又は5員もしくは6員の複素環であり、ここで、Raは、H、ハロ、−(C1−C6)アルキル、−(C3−C6)シクロアルキル、ORb、SRb、又はNRbRcであり;ここで
Rbは、H、−(C1−C6)アルキル、又は(C3−C6)シクロアルキルであり;
Rcは、H、−(C1−C6)アルキル、又は(C3−C6)シクロアルキルであるか;又は
Raが−NRbRcである場合、RbとRcは一緒になって複素環を形成してもよく;
R2は、−(C1−C6)アルキル、−(C3−C6)シクロアルキル、プロパルギル、フェニル、又は5員もしくは6員の複素環であり;ならびに
R3は、H、−(C1−C6)アルキル、又は(C3−C6)シクロアルキルであり;
ここで、各−(C1−C6)アルキル、−(C3−C6)シクロアルキル、プロパルギル、フェニル、及び5員又は6員の複素環は1つ以上の置換基で置換されていてもよく、各−(C1−C6)アルキルは分岐していないか又は分岐していてもよい、
の化合物又はその塩を提供する。
式中、
WはO、S、又はNRdであり;ここで、RdはH、−(C1−C6)アルキル、又は(C3−C6)シクロアルキルであり;
VはN又はCRxであり、ここで、RxはH、−(C1−C6)アルキル、又は(C3−C6)シクロアルキルであり;
YはN又はCRyであり、ここで、RyはH、−(C1−C6)アルキル、又は(C3−C6)シクロアルキルであり;及び
ZはN又はCHである、
の部分である。
のうちの1つであり、
ここで、5員複素環部分R1は置換されていてもよい(炭素原子CHのいずれか一方で、それによりその炭素をC置換基に修飾し、置換基は本明細書で定義される置換基である)。
式中、G1は、ハロ、アルキル、アルコキシ、フェノキシ、又はジアルキルアミンである、
の化合物である。いくつかの実施形態では、G1は、OCH3、OCH2CH3、OPh、又はN(CH3)2である。
である。
式中、RzはH、ハロ、−(C1−C6)アルキル、又は(C3−C6)シクロアルキルである、
の化合物である。他の実施形態では、RzはCH3又はCH2CH3である。さらに他の実施形態では、化合物は、
である。
C8置換イミダゾテトラジンの構築。TMZのC8位にアミドが含まれているのは、主にイミダゾトリアゼン及びイミダゾテトラジンの最初の合成のアーティファクトである。ダカルバジンとTMZはどちらも、前駆体である4−ジアゾイミダゾール−5−カルボキサミド(1、スキーム1b)から誘導される。報告によれば室温で2.5年超22というこのジアゾ種の顕著な安定性は、他のジアゾイミダゾール種(4−ジアゾイミダゾール(2)など)が単純に分解する探索化学のための使用を可能にした23。したがって、1962年のダカルバジン及び1984年のTMZの最初の合成には、それぞれジメチルアミンによる1のクエンチング24、又はイソシアン酸メチルによる1の環化25が含まれ、第一級アミド部分が残存した。時が経つと共に、このアミドは抗癌活性に重要であることが示唆されてきた。そのような主張は、C8の水素結合ドナーが活性に必要であることを示唆する理論的研究によって裏付けられたが2,16、状況を分かりにくくさせているのは、非CNS癌モデルにおける関連化合物(ミトゾロミド)の誘導体から採用された矛盾する構造−活性相関(SAR)である26。C8位で新規誘導体を構築するために使用できる一般的な合成経路を確立することにはかなりの課題がある;これらの合成上の課題は新しいイミダゾテトラジンの開発を妨げており、新しい化合物及び生物学的データがないため、時代遅れのSARが存続している。
C8アミドを置き換えることの課題には、水性感受性;塩基感受性;ジアゾイミダゾール分解;及びCH3NCOの不良な代用物が含まれる。
1984年以来公知であり、FDAは1999年から承認し、2009年には売上高が10億ドルに達したにもかかわらず、TMZは依然として唯一の承認されたイミダゾテトラジン抗癌剤である;これはおそらく、従来の医薬品化学キャンペーンを妨げるこのクラスの化合物の一般化された合成の欠如に起因する。本明細書では、以前にはアクセスできなかった新規C8置換イミダゾテトラジンの構築を可能にする新しい合成方法を報告する。体系的な直接アッセイでこれらの化合物を評価することにより、C8アミドは抗癌活性に必要ではなく、実際に、C8でH結合ドナー又はアクセプタ(又は両方)を欠く化合物は、培養下の癌細胞に対してTMZに匹敵する活性を依然として保持できるという最終的な結論に至った。C8でのアミドの必要性から解放されたので、この位置を変化させてイミダゾテトラジンのパネルを合成した。驚くべきことに、C8の置換基の電子特性は、これまで定義されていなかった現象である、対応するプロドラッグの活性化に劇的な影響を及ぼす。イミダゾテトラジンの加水分解安定性とC8の電子との間の本明細書で導き出された関係は、容易にアクセスできるσp値を使用してプロドラッグの安定性を調整できるようにし、インビボで同様の安定性を有するTMZ誘導体の合理的な設計を可能にし、イミダゾテトラジンプロドラッグ活性化の最適なタイミングの検討を促進する。
本発明はまた、本発明の化合物及び組成物を製造する方法に関する。化合物及び組成物は、有機合成の適用可能な技術のいずれか、例えば本明細書に記載される技術によって調製することができる。多くのそのような技術は当技術分野で周知である。ただし、公知の技術の多くは、Compendium of Organic Synthetic Methods(John Wiley&Sons,New York),Vol.1,Ian T.Harrison and Shuyen Harrison,1971;Vol.2,Ian T.Harrison and Shuyen Harrison,1974;Vol.3,Louis S.Hegedus and Leroy Wade,1977;Vol.4,Leroy G.Wade,Jr.,1980;Vol.5,Leroy G.Wade,Jr.,1984;and Vol.6,Michael B.Smith、ならびにMarch’s Advanced Organic Chemistry:Reactions,Mechanisms,and Structure,5th Ed.by M.B.Smith and J.March(John Wiley&Sons,New York,2001);Comprehensive Organic Synthesis;Selectivity,Strategy&Efficiency in Modern Organic Chemistry,in 9 Volumes,Barry M.Trost,Ed.−in−Chief(Pergamon Press,New York,1993 printing));Advanced Organic Chemistry,Part B:Reactions and Synthesis,Second Edition,Cary and Sundberg(1983);Protecting Groups in Organic Synthesis,Second Edition,Greene,T.W.,and Wutz,P.G.M.,John Wiley&Sons,New York;及びComprehensive Organic Transformations,Larock,R.C.,Second Edition,John Wiley&Sons,New York(1999)などの標準有機参照テキストに詳述されている。
本明細書に記載の化合物は、例えば化合物を薬学的に許容される希釈剤、賦形剤、又は担体と組み合わせることによって、治療用医薬組成物を調製するために使用することができる。化合物は、塩又は溶媒和物の形態で担体に添加し得る。例えば、化合物が安定な非毒性の酸又は塩基塩を形成するのに十分に塩基性又は酸性である場合、塩としての化合物の投与が適切であり得る。薬学的に許容される塩の例は、生理学的に許容される陰イオンを形成する酸で形成される有機酸付加塩、例えばトシル酸塩、メタンスルホン酸塩、酢酸塩、クエン酸塩、マロン酸塩、酒石酸塩、コハク酸塩、安息香酸塩、アスコルビン酸塩、α−ケトグルタル酸塩、及びβ−グリセロリン酸塩である。塩酸塩、ハロゲン化物、硫酸塩、硝酸塩、重炭酸塩、及び炭酸塩を含む適切な無機塩も形成され得る。
細胞培養及び試薬。すべての細胞株を、37℃、5%CO2、加湿環境において、1%ペニシリン/ストレプトマイシンを含む培地で増殖させた。細胞培養条件は次の通りである:従来の細胞株U87及びT98Gは、10%FBSを含むEMEMで増殖させた。従来の細胞株D54及びU118MGは、10%FBSを含むDMEMで増殖させた。HGCC患者由来の細胞株U3054MG1は、無血清幹細胞条件下で培養した(1:1のneurobasal培地:B27、N2、hEGF、及びhFGFを添加したDMEM/F12培地)。GBM腫瘍球(oncosphere)細胞株Br23c2は、0.0002%ヘパリン、hEGF、及びhFGFを添加したNeuroCult NS−A増殖キット(Stem Cell Technologies)で培養した。テモゾロミド(TMZ)はAK Scientificから購入した。TMZ類似体は下記で説明するように合成した。細胞培養試験のために、化合物をDMSO(最終濃度1%、Fisher Chemical)に溶解した。
材料及び方法。化学試薬は商業的供給源から購入し、さらに精製することなく使用した。フラッシュクロマトグラフィはシリカゲル(230〜400メッシュ)を使用して行った。無水溶媒は、窒素の陽圧下で活性アルミナが充填されたカラムに通した後、乾燥させた。特に断りのない限り、すべての反応は、窒素雰囲気下で磁気撹拌しながらオーブンで乾燥させたガラス器具で実施した。1H及び13C NMRスペクトルは、Bruker 500(500MHz、1H;125MHz、13C)又はVarian Unity Inova 500(500MHz、1H)MHz分光計で記録した。スペクトルは、残留クロロホルム(δ=7.26ppm、1H;77.16ppm、13C)又はジメチルスルホキシド(δ=2.50ppm、1H;39.52ppm、13C)を基準とする。多重度は、s(シングレット)、d(ダブレット)、t(トリプレット)、q(カルテット)、m(マルチプレット)、及びbr(広幅)で示す。結合定数Jはヘルツ(Hz)で報告する。高分解能質量分析(HRMS)は、エレクトロスプレーイオン化(ESI)又は電子衝撃イオン化(EI)を備えたWaters Q−Tof Ultima又はWaters Synapt G2−Si機器で実施した。
4〜10の調製のための一般的な手順。オーブンで乾燥させた25mLの丸底フラスコ中で、塩化アシル29(148.6mg、0.70mmol、1当量)を無水THF(2.8mL、0.25M)に溶解した。次にメチルアミン(エタノール中33%w/w、0.09mL、0.73mL、1.05当量)を添加し、反応物を室温で3時間撹拌した。完了したら、反応を停止し、溶媒を蒸発させた。粗固体をフラッシュシリカゲルクロマトグラフィ(100%酢酸エチル)によって精製して、98.3mg(68%)の純粋な4を白色固体として得た。
手順。15mLの丸底フラスコに、4−メチル−1H−イミダゾール−5−アミン二塩酸塩12(44.2mg、0.3mmol、1当量)を添加し、1M HCl(0.4mL、0.65M)に溶解した後、水(0.4mL、0.65M)中の亜硝酸ナトリウム(26.2mg、0.4mmol、1.5当量)を暗所にて0℃で添加した。溶液を30分間撹拌し、次に濃縮し、トルエンで2回共沸して、粗ジアゾ13を得た。酢酸エチル(1.3mL、0.2M)に懸濁した粗ジアゾに、無水トリエチルアミン(0.08mL、0.6mmol、2.2当量)及びメチルカルバミン酸クロリド(79mg、0.8mmol、3.2当量)を暗所で添加した。反応物を一晩撹拌した後、フラッシュシリカゲルクロマトグラフィ(4:1のヘキサン:酢酸エチル)によって精製して、2.4mg(6%)の14を淡黄色固体として得た。注:粗ジアゾ種の分解を最小限に抑えるために、濃縮は、(加熱せずに)暗所でできるだけ早く行った。
手順。オーブンで乾燥させた25mLの丸底フラスコに、16(186mg、0.89mmol、1当量)及びN−スクシンイミジルN−メチルカルバマート(321mg、1.86mmol、2.1当量)を添加し、無水アセトニトリル(1.5mL、0.6M)に懸濁した。次に、窒素下で、乾燥トリエチルアミン(0.34mL、2.4mmol、2.7当量)を緩やかに添加し、溶液を室温で一晩撹拌した。完了したら、混合物を濃縮し、シリカゲルフラッシュクロマトグラフィ(100%ジクロロメタンから4:1のジクロロメタン:メタノール)によって精製して、106mg(66%)の中間体16aを金色固体として得た。
手順。無水CH3CN(2.6mL、0.2M)中のデス−マーチンペルヨージナン(477mg、1.12mmol、2.2当量)の撹拌懸濁液に、臭化テトラエチルアンモニウム(240mg、1.12mmol、2.2当量)を添加した。反応物を室温で5分間撹拌した後、3(100mg、0.51mmol、1当量)を添加した。得られた反応混合物を50℃で2時間加熱した。完了したら、溶媒を減圧下で濃縮して粗生成物を得、これをフラッシュシリカゲルクロマトグラフィ(9:1のヘキサン:酢酸エチル)によって精製して、73mg(58%)の18を白色固体として得た。
手順。無水CH3CN(2.6mL、0.2M)中のデス−マーチンペルヨージナン(477mg、1,12mmol、2.2当量)の撹拌懸濁液に、塩化テトラメチルアンモニウム(123mg、1.12mmol、2.2当量)を添加した。反応物を室温で5分間撹拌した後、3(100mg、0.51mmol、1当量)を添加した。得られた反応混合物を50℃で2時間加熱した。完了したら、溶媒を減圧下で濃縮して粗生成物を得、これをフラッシュシリカクロマトグラフィ(9:1のヘキサン:酢酸エチル)によって精製して、43mg(45%)の19を白色固体として得た。
23〜26の調製のための一般的な手順。(a)鈴木カップリング。窒素下で、4−ブロモ−5−ニトロ−1H−イミダゾール20(400mg、2.08mmol、1当量)、フェニルボロン酸(507mg、4.17mmol、2当量)、XPhosPdG1(164mg、0.2mmol、0.1当量)及びK3PO4(1.32g、6.24mmol、3当量)の混合物を、脱気した1:1のH2O:ジオキサン(16mL、0.13M)に懸濁した。得られた混合物を110℃で16時間撹拌した。反応物を室温に冷却し、H2Oを添加した。水層を酢酸エチルで3回抽出し、合わせた有機層をNa2SO4で乾燥し、濃縮した。得られた残留物をフラッシュシリカゲルクロマトグラフィ(100%酢酸エチル)によって精製して粗生成物21を得、これをさらに精製することなく次の工程に使用した。
一般的な手順を使用して生成物を得た。黄色固体、収率5%(4工程)。
手順。29(447mg、2.09mmol、1当量)及び2−アミノアセトフェノン塩酸塩(229mg、2.09mmol、1当量)に、DMF(4.4mL、0.47M)及びピリジン(0.9mL)を添加した。反応混合物を室温で16時間撹拌した。水を添加し、水層を酢酸エチルで5回抽出した。合わせた有機層をNa2SO4で乾燥し、濃縮した。得られた残留物をフラッシュシリカゲルクロマトグラフィ(100%酢酸エチル)によって精製して、266mg(51%)の32を橙色固体として得た。
手順:中間体32(266mg、1.06mmol、1当量)を塩化ホスホリル(6.5mL、0.16M)に添加し、撹拌した混合物を110℃で3時間加熱した。完了したら、氷水を添加し、水層を酢酸エチルで4回抽出した。合わせた有機層をNa2SO4で乾燥し、濃縮した。得られた残留物をフラッシュシリカゲルクロマトグラフィ(100%酢酸エチル)によって精製して、80mg(32%)の生成物27を黄色固体として得た。
手順。アセトニトリル(40mL、0.07M)中の33(550mg、2.6mmol、1当量)の溶液にα−ブロモアセトン(220μL、2.6mmol、1当量)を添加し、この溶液を室温で18時間撹拌した。完了したら、反応を停止し、沈殿物を濾過し、フラッシュシリカゲルクロマトグラフィ(4:6のヘキサン:酢酸エチル)によって精製して、167mg(26%)の所望の生成物28を黄色固体として得た。
アレーン及びプロパルギル置換イミダゾテトラジンは、以下のように調製することができる。
ここで、G1は、OCH3、OCH2CH3、OPh、N(CH3)2、プロパルギル、又は本明細書で定義される置換基である。
以下の製剤は、本明細書に記載の式の化合物、本明細書に具体的に開示される化合物、又はその薬学的に許容される塩もしくは溶媒和物(以下「化合物X」と称する)の治療的又は予防的投与のために使用し得る代表的な医薬剤形を例示する:
(i)錠剤1 mg/錠
「化合物X」 100.0
ラクトース 77.5
ポビドン 15.0
クロスカルメロースナトリウム 12.0
微結晶セルロース 92.5
ステアリン酸マグネシウム 3.0
300.0
(ii)錠剤2 mg/錠
「化合物X」 20.0
微結晶セルロース 410.0
デンプン 50.0
デンプングリコール酸ナトリウム 15.0
ステアリン酸マグネシウム 5.0
500.0
(iii)カプセル mg/カプセル
「化合物X」 10.0
コロイド状二酸化ケイ素 1.5
ラクトース 465.5
アルファ化デンプン 120.0
ステアリン酸マグネシウム 3.0
600.0
(iv)注射剤1(1mg/mL) mg/mL
「化合物X」(遊離酸型) 1.0
二塩基性リン酸ナトリウム 12.0
一塩基性リン酸ナトリウム 0.7
塩化ナトリウム 4.5
1.0N水酸化ナトリウム溶液 適量
(pHを7.0〜7.5に調整)
注射用水 1mLにするための十分量
(v)注射剤2(10mg/mL) mg/mL
「化合物X」(遊離酸型) 10.0
一塩基性リン酸ナトリウム 0.3
二塩基性リン酸ナトリウム 1.1
ポリエチレングリコール400 200.0
0.1N水酸化ナトリウム溶液 適量
(pHを7.0〜7.5に調整)
注射用水 1mLにするための十分量
(vi)エアロゾル mg/缶
「化合物X」 20
オレイン酸 10
トリクロロモノフルオロメタン 5,000
ジクロロジフルオロメタン 10,000
ジクロロテトラフルオロエタン 5,000
(vii)局所ゲル1 重量%
「化合物X」 5%
カルボマー934 1.25%
トリエタノールアミン 適量
(pHを5〜7に調整)
メチルパラベン 0.2%
精製水 100gにするための適量
(viii)局所ゲル2 重量%
「化合物X」 5%
メチルセルロース 2%
メチルパラベン 0.2%
プロピルパラベン 0.02%
精製水 100gにするための適量
(ix)局所軟膏 重量%
「化合物X」 5%
プロピレングリコール 1%
無水軟膏基剤 40%
ポリソルベート80 2%
メチルパラベン 0.2%
精製水 100gにするための適量
(x)局所クリーム1 重量%
「化合物X」 5%
白色蜜ろう 10%
流動パラフィン 30%
ベンジルアルコール 5%
精製水 100gにするための適量
(xi)局所クリーム2 重量%
「化合物X」 5%
ステアリン酸 10%
モノステアリン酸グリセリル 3%
ポリオキシエチレンステアリルエーテル 3%
ソルビトール 5%
パルミチン酸イソプロピル 2%
メチルパラベン 0.2%
精製水 100gにするための適量
Claims (25)
- 式I:
式中、
XはO又はSであり;
R1は、ハロ、−CN、−NO2、−(C1−C6)アルキル、−C(=O)Ra、フェニル、又は5員もしくは6員の複素環であり、ここで、Raは、H、ハロ、−(C1−C6)アルキル、−(C3−C6)シクロアルキル、ORb、SRb、又はNRbRcであり;ここで
Rbは、H、−(C1−C6)アルキル、又は(C3−C6)シクロアルキルであり;
Rcは、H、−(C1−C6)アルキル、又は(C3−C6)シクロアルキルであるか;又は
Raが−NRbRcである場合、RbとRcは一緒になって複素環を形成してもよく;
R2は、−(C1−C6)アルキル、−(C3−C6)シクロアルキル、プロパルギル、フェニル、又は5員もしくは6員の複素環であり;ならびに
R3は、H、−(C1−C6)アルキル、又は(C3−C6)シクロアルキルであり;
ここで、各−(C1−C6)アルキル、−(C3−C6)シクロアルキル、プロパルギル、フェニル、及び5員又は6員の複素環は1つ以上の置換基で置換されていてもよく、各−(C1−C6)アルキルは分岐していないか又は分岐していてもよい、
の化合物又はその塩。 - R1がハロ、−(C1−C6)アルキル、又は(C3−C6)シクロアルキルである、請求項1に記載の化合物。
- R1が−C(=O)−(C1−C6)アルキル、−C(=O)−NH(C1−C6)アルキル、又はC(=O)−N[(C1−C6)アルキル]2である、請求項1に記載の化合物。
- R1がパラ置換フェニルである、請求項1に記載の化合物。
- パラ置換基がハロ、−CN、−CF3、−CF2CF3、又は(C1−C6)アルキルである、請求項6に記載の化合物。
- XがOであり、R3がHであり、及びR1が−C(=O)−(C1−C6)アルキル、−C(=O)−NH(C1−C6)アルキル、又はC(=O)−N[(C1−C6)アルキル]2である、請求項1に記載の化合物。
- XがOであり、及びR1が−C(=O)−(C1−C6)アルキルである、請求項1に記載の化合物。
- XがOであり、R2が−(C1−C6)アルキルであり、及びR3がHである、請求項1に記載の化合物。
- R2が−(C1−C6)アルキルであり、及びR3がHである、請求項1に記載の化合物。
- R2がプロパルギル又は置換フェニルである、請求項1に記載の化合物。
- 置換フェニルが、ハロ、アルキル、アルコキシ、フェノキシ、ジアルキルアミン、又はそれらの組合せで置換されている、請求項12に記載の化合物。
- R2が−(C1−C6)アルキルであり、及びR3がHである、請求項16に記載の化合物。
- Raが、CH3、CH2CH3、NHCH3、NHCH2CH3、N(CH3)2、N(CH2CH3)2、N(CH2CH2CH3)2、N(CH2CH2CH2CH3)2、N(CH2CH2)2、N[(CH2CH2)2O]、OCH3、OCH2CH3、SCH3、又はSCH2CH3である、請求項16に記載の化合物。
- RzがCH3又はCH2CH3である、請求項21に記載の化合物。
- 癌を治療する方法であって、それを必要とする対象に、治療有効量の請求項1〜23のいずれか一項に記載の化合物を投与することを含み、それによって癌が治療される、上記方法。
- 癌が膠芽腫(GBM)である、請求項20に記載の方法。
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