JP7041821B2 - アミノ置換窒素含有縮合環化合物、その調製方法及び使用 - Google Patents
アミノ置換窒素含有縮合環化合物、その調製方法及び使用 Download PDFInfo
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- JP7041821B2 JP7041821B2 JP2020544089A JP2020544089A JP7041821B2 JP 7041821 B2 JP7041821 B2 JP 7041821B2 JP 2020544089 A JP2020544089 A JP 2020544089A JP 2020544089 A JP2020544089 A JP 2020544089A JP 7041821 B2 JP7041821 B2 JP 7041821B2
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Classifications
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- A—HUMAN NECESSITIES
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- 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
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
- A61K31/4375—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a six-membered ring having nitrogen as a ring heteroatom, e.g. quinolizines, naphthyridines, berberine, vincamine
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- 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
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
- A61K31/444—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone
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- A—HUMAN NECESSITIES
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- 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
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/445—Non condensed piperidines, e.g. piperocaine
- A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
- A61K31/4545—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
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- 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
- A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
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- 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
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- A—HUMAN NECESSITIES
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
- A61P35/02—Antineoplastic agents specific for leukemia
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—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
- C07D471/12—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 three hetero rings
- C07D471/14—Ortho-condensed systems
Landscapes
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Epidemiology (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Oncology (AREA)
- Hematology (AREA)
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Description
R1は、水素、ハロゲン、C1~C3アルキル、シアノから選択されるものであり、好ましくは、水素、ハロゲン、メチルから選択されるものであり;
ただし、
M1は、好ましくは、CH又はNから選択されるものであり;
R3、R4及びR5は、それぞれ独立して、水素、ハロゲン(例えば、フッ素)又はN(R9)(R10)-(CH2)p-(ここで、R9及びR10は両方ともC1-C6アルキルであり、pは0、1又は2から選択されるものである;例えば、N(R9)(R10)-(CH2)p-はジメチルアミノメチレン)から選択されるものであり;より好ましくは、R3は水素又はフッ素から選択されるものであり、且つ、R4及びR5は水素から選択されるものであり;
より好ましくは、次の構造から選択され:
a)酸又は塩基の存在下で、一般式(A)の化合物を、α-ハロカルボニル化合物又はその等価物と縮合反応させて、一般式(B)の化合物を調製する;及び
b)酸、塩基又は遷移金属触媒の存在下で、一般式(B)の化合物をアミン化合物と置換反応又はカップリング反応させて、一般式(C)の化合物を調製する;及び、
c)塩基又は縮合試薬の存在下で、一般式(C)の化合物をアクリル酸又はアクリロイルクロリド系化合物と縮合反応させて、一般式(I)の化合物を調製する。
別に定義されない限り、本明細書で使用されるすべての科学用語は、特許請求の範囲のカテゴリーが属する技術分野の当業者によって一般に理解されるものと同じ意味を有する。特に明記しない限り、本明細書全文に引用されているすべての特許、特許出願、及び公開資料は、参照によりその全体が組み込まれている。
「ヒドロキシ」とは、-OH基を指す。
「ヒドロキシアルキル」は、ヒドロキシ(-OH)基で置換された、以下に定義されるアルキル基を指す。
「カルボニル」は、-C(=O)-基を指す。
「ニトロ」は-NO2を指す。
「シアノ」は-CNを指す。
「アミノ」は-NH2を指す。
「置換アミノ」とは、例えばモノアルキルアミノ、ジアルキルアミノ、アルキルアミド、アラルキルアミノ、ヘテロアラルキルアミノなど以下に定義される1つ又は2つのアルキル、アルキルカルボニル、アラルキル、ヘテロアラルキルで置換されたアミノ基を指す。
「カルボキシ」は-COOHを指す。
(i)特に哺乳動物が疾患又は病症にかかりやすいが、疾患又は病症を有すると診断されていない場合、当該哺乳動物における疾患又は病症の発生を防ぐ;
(ii)疾患又は病症を抑制する、すなわち、その発症を抑制する;
(iii)疾患又は病症を緩和する、つまり、当該疾患又は病症の状態を退行させる;又は
(iv)疾患又は病症によって引き起こされる症状を軽減する。
中間体1:6-(2,6-ジクロロ-3,5-ジメトキシ-フェニル)-2-メチルチオ-ピリジン[2,3-d]ピリミジン-7-イルアミン
アルデヒド中間体(1 eq.)及びN-Bocジアミンを無水メタノールに溶かし、氷酢酸1滴を滴下し、室温で1時間攪拌した後、固体の水素化ホウ素ナトリウム(2 eq.)を氷冷下でバッチに加え、室温で一晩攪拌した。反応完了後、飽和塩化アンモニウム溶液を添加して反応をクエンチさせ、酢酸エチルで抽出し、有機相をそれぞれに飽和炭酸水素ナトリウム溶液及び水で洗浄し、無水硫酸ナトリウムで乾燥させ、濾過し、減圧濃縮し、カラムクロマトグラフィーにより分離し精製して標的中間体を得た。
メチルチオ中間体(1 eq.)をジクロロメタンに溶解し、m-クロロペルオキシ安息香酸(2 eq.)を氷冷下でバッチに加え、室温で一晩撹拌した。反応完了後、反応溶液をチオ硫酸ナトリウム溶液でクエンチし、有機相を分離し、飽和炭酸水素ナトリウム溶液及び水で順に洗浄し、無水硫酸ナトリウムで乾燥させ、濾過し、減圧濃縮し、カラムクロマトグラフィーにより分離し精製して、メチルスルホン化合物の中間体を得た。
メチルスルホニル中間体(1 eq.)及び原料アミン(2 eq.)を無水N、N-ジメチルホルムアミドに溶解し、マイクロ波で100℃に加熱し2時間反応させた。反応完了後、ジクロロメタンを加え抽出を行い、有機相を飽和炭酸水素ナトリウム溶液と水で順に洗浄し、無水硫酸ナトリウムで乾燥させ、濾過し、減圧濃縮し、カラムクロマトグラフィーで分離し精製して、ニトロ化合物の中間体を得た。
原料(1 eq.)をジクロロメタンに溶解し、氷浴で冷却しながら、トリフルオロ酢酸(10 eq.)を加えて2時間撹拌した。反応完了後、減圧濃縮し、残渣を精製せずに直接に次の反応に使用した。
ピペラジン中間体(1 eq.)及びDIPEA(2 eq.)を乾燥したN、N-ジメチルホルムアミドに溶解し、アクリロイルクロリド(1.2 eq.)を氷冷下でゆっくりと滴下した。添加完了後、反応を室温で一晩進行させた。反応溶液をジクロロメタン及び飽和炭酸水素ナトリウム溶液でクエンチし、有機相を分離し、それぞれに水及び飽和食塩水で洗浄し、無水硫酸ナトリウムで乾燥させ、濾過し、減圧濃縮した。残渣を分取HPLC又はBiotage Flashカラムクロマトグラフィーににより分離し生成して、標的化合物を得た。
(1)1×キナーゼバッファーの調製;(2)化合物濃度勾配の調製:試験化合物の試験濃度を10 uMから開始し、3倍勾配で10個濃度に希釈し、複製ウェルで試験し、96ウェルプレートで勾配濃度が100倍の最終試験濃度までの10個の異なる濃度の溶液に希釈した。次に、1×キナーゼバッファーを使用して、各濃度の化合物を更に5倍の最終濃度の中間希釈溶液に希釈した。(3)調製した化合物溶液をそれぞれに5μL取り、それぞれを384ウェルプレートの化合物ウェルに加え、各濃度は単一ウェルで検出された。陰性対照ウェルと陽性対照ウェルにそれぞれ5%DMSO 5μLを加えた;(4)1×キナーゼバッファーで2.5倍の最終濃度のキナーゼ溶液を準備した;(5)化合物ウェルと陽性対照ウェルにそれぞれに2.5倍の最終濃度のキナーゼ溶液10μLを加え、陰性対照ウェルに1×キナーゼバッファー10μLを追加した;(6)1000 rpmで30秒間遠心分離し、均一に混ぜるまで振とうした後、室温で10分間インキュベートした;(7)1×キナーゼバッファーで2.5倍の最終濃度のATPとキナーゼ基質22の混合溶液を準備した;(8)2.5倍の最終濃度のATPと基質の混合溶液10μLを加えて反応を開始した;(9)384ウェルプレートを1000 rpmで30秒間遠心分離し、均一に混ぜるまで振とうした後、28℃でそれぞれ対応する時間インキュベートした;(10)停止反応液30μLを添加しキナーゼ反応を停止させ、1000 rpmで30秒間遠心分離し、均一に混ぜるまで振とうした;(11)変換率をCaliper EZ ReaderIIで読み取り、濃度のlog値をX軸として、阻害率(%)をY軸として、分析ソフトウェアGraphPad Prism 5のlog(inhibitor) vs. response -Variable slopeを利用して、用量反応曲線に適合させ、それによって、酵素活性に関する各化合物のIC50値を得た。
1.試験方法:試験方法:対数増殖期にいるHep3B細胞(ATCC)を取り、適切な密度でウェルあたり100μLで96ウェル培養プレートに接種し、一晩培養した後、異なる濃度の化合物を入れ72時間作用させ、且つ溶媒対照群(陰性対照)を設定し、5%CO2下、37℃でインキュベートした。10 mM化合物ストック溶液を細胞に添加し、化合物を細胞に72時間作用した後、CellTiter-Glo(登録商標)(Promega)法を使用して化合物の細胞増殖に対する影響を検出し、30μLのCTG試薬を各ウェルに添加し、37℃のインキュベーターに入れ、2~4時間置いた後、全波長マイクロプレートリーダーEnvisionで数値を読み、検出波長が450 nmであった。次の式を使用して、腫瘍細胞増殖に対する化合物の阻害率(%)を計算した:阻害率(%)=(OD陰性対照ウェル-OD投与ウェル)/OD陰性対照ウェル×100%。IC50値は、Graphpad Prism 5ソフトウェアを採用して、4パラメータ法で回帰を行うことによって取得された。
本発明の化合物は、EGFR、VEGFR、PDGFR、FGFR、RET、MET、Src、Lyn、Syk、MEK、CDK、RAF、ROSなどの異なるキナーゼに対する阻害活性についても試験され、実施例化合物のいくつか(例えば実施例3、実施例17)は、100倍を超える選択性で、より優れたキナーゼ選択性を示している。
SRB染色法又はCCK8法を使用して、HuH-7、JHH-7、DMS114、SNU-16、KG1、UM-UC-14、HCT116、NCI-H716、MCF-7、Colo-205、KMS11、RT-112、OPM-2、NCI-H460、SNU-869、CNE、NCI-H2122、NCI-H1299、A549、MG63、Kappars-299、SK-OV-3、U87MG、BT474、LNCAP、A498、KYSE140、HUCC-T1、PANC-1などの様々な腫瘍細胞の増殖に対する阻害活性を検出し、実施例化合物のいくつか(例えば実施例3及び実施例17)が異なる細胞への増殖阻害はより強い阻害活性を示し、より良好な腫瘍活性を示し、多種腫瘍細胞に対する増殖阻害活性が100 nM未満である。
(1)代謝安定性試験:150μL肝臓ミクロソーム(最終濃度0.5 mg / mL)のシステムを使って代謝安定性インキュベーションを行い、システムにはNADPH(最終濃度1 mM)、1μM試験化合物、及び陽性対照であるミダゾラム或いは陰性対照であるアテノロールが含まれており、それぞれに0 min、5 min、10 min及び30 minでチニダゾールを含むアセトニトリルで反応を停止させ、10分間ボルテックスし、15000 rpmで10分間遠心分離し、50μLの上澄みを取り96ウェルに入れ、サンプリングした。化合物の代謝安定性は、元薬物の相対的な減少量を測定することにより計算された。
2、いくつかの実施例化合物(例えば実施例3、実施例17)は、より良好なADME特性、及びラットとマウス生体内でのより良好な吸収と代謝特性を示し、且つ、AUC / Cmaxなどの全て指標から化合物の優れたドラッガビリティー(druggability)が示された。
1、活発な成長期の腫瘍組織を取り約1.5 mm3に切断し、無菌条件下でヌードマウスの右脇下に皮下接種した。ノギスでヌードマウスに皮下移植した腫瘍の直径を測定し、平均腫瘍体積は約130 mm3であった場合、動物をランダムにグループに分けた。実施例化合物(1%Tween 80を含む注射用水で所望濃度に調製して用意する)を所定の用量で3週間連続経口投与し、溶媒対照群には同量の溶媒を投与した。実験プロセス全体において、移植腫瘍の直径を週に2回測定し、同時にマウスの体重を量った。腫瘍体積(tumor volume 、TV)の計算式は次のとおりであり:TV= 1/2×a×b2、ここで、aとbはそれぞれ長さと幅を表した。測定結果に基づいて相対腫瘍体積(relative tumor volume 、RTV)が計算され、計算式はRTV = Vt / V0であった。ここで、V0はグループ分けに投与した時(すなわちd0)に測定された腫瘍体積であり、Vtは各測定時での腫瘍体積であった。抗腫瘍活性の評価指標は1)相対腫瘍増殖率T / C(%)で、その計算式は次のとおりであり:T / C(%)=(TRTV / CRTV)×100%、ここで、TRTVは:治療群のRTV; CRTVは:陰性対照群のRTVであり; 2)腫瘍体積成長阻害率はGI%で、その計算式は次のとおりであり:GI%= [1-(TVt-TV0)/(CVt-CT0)]×100%、TVtは治療群の毎回測定される腫瘍体積であり; TV0は治療群がグループ分けに投与した時に得られる腫瘍体積であり、CVtは対照群の毎回測定される腫瘍体積であり、CV0は対照群がグループ分けに投与した時に得られる腫瘍体積であった。3)腫瘍重量抑制率、その計算式は次の通りであり:腫瘍重量阻害率%=(Wc-WT)/ Wc×100%、ここで、Wcは:対照群の腫瘍重量、WTは:治療群の腫瘍重量である。
付記
<項1>
式(I)で表される化合物、又はその薬学的に許容される塩、又はエナンチオマー、ジアステレオマー、互変異性体、溶媒和物、多結晶体又はプロドラッグ。
(ただし、
R 1 は、水素、ハロゲン、C 1 ~C 3 アルキル、シアノから選択されるものであり;
R 2 は、水素、C 1 ~C 10 アルキル、3~8員のシクロアルキル又はヘテロシクロアルキル、5~8員のアリール又はヘテロアリールから選択されるものであり;
R 3 、R 4 、及びR 5 はそれぞれ独立して、水素、ハロゲン、シアノ、アルキル、スルホン、スルホキシド、アシル、スルホニル、ニトロから選択されるものであり;
M 1 はCR 6 又はNから選択されるものであり;R 6 は、水素、ハロゲン、C 1 ~C 3 アルキルから選択されるものであり;
Arは5~6員のアリール又はヘテロアリールから選択されるものであり;
Lは、化学結合、C 1 ~C 10 アルキル、アルケニル、アルキニル、アルコキシ、アルキルチオ、アルキルアミノ、アシル、スルホニル、4~8員のシクロアルキル又はヘテロシクロアルキル、5~10員のアリール又はヘテロアリールから選択されるものであり;
Aは、4~8員のシクロアルキル又はヘテロシクロアルキル、5~10員のアリール又はヘテロアリールから選択されるものであり;
上記の基のいずれかの1つ又は複数の水素原子は、重水素、ハロゲン、ヒドロキシル、アミノ、シアノ、スルホン又はスルホキシド、C 1 ~C 8 アルキル、C 3 ~C 8 シクロアルキル、C 1 ~C 8 アルコキシ、C 1 ~C 8 アルキルアミノ、C 2 ~C 6 アルケニル、C 2 ~C 6 アルキニル、C 2 ~C 6 アシル又はスルホニル、5~8員のアリール又はヘテロアリール、4~8員の飽和シクロアルキル又はヘテロシクロアルキルからなる群から選択される置換基で置換されてもよい;ここで、前記ヘテロアリール基は、N、O、P及びSからなる群から選択される1~3個のヘテロ原子を含み;前記ヘテロシクロアルキルは、N、O、P、及びSからなる群から選択される1~3個のヘテロ原子を含む。)
<項2>
前記式(I)において、
M 1 は、CH又はNから選択されるものであり;
及び/又は、R 1 は、水素、ハロゲン、C 1 ~C 3 アルキルから選択されるものであり;
及び/又は、R 2 は、水素、C 1 ~C 6 アルキル、C 1 ~C 6 重水素化アルキル、C 1 ~C 6 ハロアルキル、5~8員のアリール又はヘテロアリール、4~6員のシクロアルキル又はヘテロシクロアルキル-(CH 2 )x-、O(R 6 )-(CH 2 )y-、N(R 7 )(R 8 )-(CH 2 )z-、N(CH 3 ) 2 C(=O)CH-、HOC(CH 3 ) 2 CH-又はCH(CH 2 OH) 2 -CH 2 -から選択されるものであり;ここで、前記5~8員のアリール又はヘテロアリールは、好ましくはピリジルであり、且つ、好ましくは一つの6員のヘテロシクロアルキルで更に置換され;前記4~6員のシクロアルキル又はヘテロシクロアルキルは、好ましくはシクロプロピル、テトラヒドロフラニル、ピペラジニル、ピペリジニル又はテトラヒドロピロリルであり、且つ、好ましくは更にC 1 ~C 6 アルキル又はアミノで置換され;R 6 、R 7 及びR 8 はそれぞれ独立して水素又はC 1 ~C 6 アルキルから選択されるものであり;x、y及びzはそれぞれ独立して0、1、2、3又は4から選択されるものであり;
及び/又は、R 3 、R 4 及びR 5 は、それぞれ独立して、水素、ハロゲン又はN(R 9 )(R 10 )-(CH 2 )p-から選択されるものであり、ここで、R 9 及びR 10 は両方ともC 1 ~C 6 アルキルであり、pは0、1又は2から選択されるものであり;より好ましくは、R 3 は水素又はフッ素から選択されるものであり、且つ、R 4 及びR 5 は水素から選択されるものであり;
及び/又は、Arは、フェニル基から選択されるものであり、且つ、更に好ましくは、前記フェニル基上の1個または複数個の水素原子がハロゲン、シアノ、C 1 ~C 8 アルキル、C 1 ~C 8 アルコキシ、アミノ、ヒドロキシ、C 2 ~C 6 アシル又はスルホニルから選択された置換基で置換されたものであり;更に好ましくは、2つのハロゲン及び2つのC 1 -C 8 アルコキシ基で置換されたものであり;
及び/又は、Lは、化学結合、-(CH 2 ) d -、-(CH 2 ) e -CH=CH-、又は-O-(CH 2 ) n -から選択されるものであり、ここでdは1、2又は3であり、eは1又は2であり、nは1、2、3又は4であり;
及び/又は、Aは、5~6員のヘテロシクロアルキル、5~6員のヘテロアリール-NH-、-Ph-(CH 2 ) o -NH-、5~6員のヘテロアリール-(CH 2 ) m -5~6員のヘテロシクロアルキル-から選択されるものであり、ここで、oは0又は1から選択され、前記5~6員のヘテロシクロアルキルは更に好ましくはピペラジニル、ピペリジニル又はテトラヒドロピロリルであり、前記5~6員のヘテロアリールは更に好ましくはピリジル、オキサゾリル又はトリアゾリルであり、mは0又は1から選択されており;且つ、Aは、好ましくはその2つの置換基がメタ又はパラ位置の置換関係であり;
その中で、Lは常にA構造のアリール基、ヘテロアリール基又は非脂肪族アミン基の一端に結合することを特徴とする<項1>に記載の式(I)で表される化合物、又はその薬学的に許容される塩、又はそのエナンチオマー、ジアステレオマー、互変異性体、溶媒和物、多結晶体又はプロドラッグ。
<項3>
前記式(I)において、
R 2 は、H、メチル、-CD 3 、-CH 2 C(CH 3 ) 2 F、N(CH 3 ) 2 C(=O)CH-、HOC(CH 3 ) 2 CH-、CH(CH 2 OH) 2 -CH 2 -、
CH 3 OCH 2 CH 2 -、
から選択されるものであり;
及び/又は、Lは、化学結合、-CH 2 -、-CH 2 CH 2 -、-CH 2 CH 2 CH 2 -、-CH 2 -CH=CH-又は-O-CH 2 CH 2 -から選択されるものであり;
及び/又は、Aは、以下の構造フラグメント:
から選択されるものであることを特徴とする<項2>に記載の式(I)で表される化合物、又はその薬学的に許容される塩、又はそのエナンチオマー、ジアステレオマー、互変異性体、溶媒和物、多結晶体又はプロドラッグ。
<項4>
前記式(I)で表される化合物が以下の構造:
を有しており、より好ましくは、次の構造:
から選択され;
ただし、nは0、1又は2から選択されるものであり、M 1 及びR 2 の定義は<項1>~<項3>のいずれか1項に記載されている通りであり;B環は、5~10員の芳香環又は芳香族複素環であり;好ましくは、ベンゼン環、ピリジン環、オキサゾール環又はトリアゾール環であることを特徴とする<項1>~<項3>のいずれか1項に記載の式(I)で表される化合物、又はその薬学的に許容される塩、又はそのエナンチオマー、ジアステレオマー、互変異性体、溶媒和物、多結晶体又はプロドラッグ。
<項5>
前記式(I)で表される化合物が以下の構造:
を有しており、
ただし、nは0、1又は2から選択されるものであり、R 2 の定義は<項1>~<項3>のいずれか1項に記載されている通りであり;
より好ましくは、次の構造から選択され:
ただし、R 2 の定義は<項1>~<項3>のいずれか1項に記載されている通りであることを特徴とする<項1>~<項3>のいずれか1項に記載の式(I)で表される化合物、又はその薬学的に許容される塩、又はそのエナンチオマー、ジアステレオマー、互変異性体、溶媒和物、多結晶体又はプロドラッグ。
<項6>
前記式(I)で表される化合物は以下化合物のいずれか一つであることを特徴とする<項1>に記載の式(I)で表される化合物、又はその薬学的に許容される塩、又はそのエナンチオマー、ジアステレオマー、互変異性体、溶媒和物、多結晶体又はプロドラッグ。
<項7>
a)酸又は塩基の存在下で、一般式(A)の化合物を、α-ハロカルボニル化合物又はその等価物と縮合反応させて、一般式(B)の化合物を調製する工程;及び
b)酸、塩基又は遷移金属触媒の存在下で、一般式(B)の化合物をアミン化合物と置換反応又はカップリング反応させて、一般式(C)の化合物を調製する工程;及び、
c)塩基又は縮合試薬の存在下で、一般式(C)の化合物をアクリル酸又はアクリロイルクロリド系化合物と縮合反応させて、一般式(I)の化合物を調製する工程;
を含む、<項1>~<項6>のいずれか1項に記載の式(I)で表される化合物の調製方法。
(ただし、各式において、LGは、ハロゲン、スルホン、スルホキシド、又はスルホネートであり、他の各基団の定義は<項1>~<項6>のいずれか1項に記載されている通りである。)
<項8>
治療有効量の<項1>~<項6>のいずれか1項に記載の式(I)で表される化合物、或いはその薬学的に許容される塩、或いはそのエナンチオマー、ジアステレオマー、互変異性体、溶媒和物、多結晶体又はプロドラッグ、及び少なくとも1つの医薬品賦形剤を含む医薬組成物。
<項9>
FGFRキナーゼ阻害剤の調製における<項1>~<項6>のいずれか1項に記載の式(I)で表される化合物、或いはその薬学的に許容される塩、或いはそのエナンチオマー、ジアステレオマー、互変異性体、溶媒和物、多結晶体又はプロドラッグ;或いは<項8>に記載の医薬組成物の使用。
<項10>
タンパク質キナーゼ、特にFGFRキナーゼの活性又は発現量に関連する疾患を予防及び/又は治療するための薬剤の調製における、特に腫瘍を予防及び/又は治療するための薬剤の調製における<項1>~<項6>のいずれか1項に記載の式(I)で表される化合物、或いはその薬学的に許容される塩、或いはそのエナンチオマー、ジアステレオマー、互変異性体、溶媒和物、多結晶体又はプロドラッグ;或いは<項8>に記載の医薬組成物の使用。
(ただし、前記腫瘍は、非小細胞肺がん、小細胞肺がん、肺腺がん、肺扁平上皮がん、乳がん、前立腺がん、肝臓がん、皮膚がん、胃がん、上皮細胞がん、胃腸道間質腫瘍、腸がん、胆管がん、胆嚢がん、結腸直腸がん、脳がん、白血病、リンパ腫、鼻咽頭がん、膀胱がん、膵がんから選択されるものであり、特に肝臓がん又は胆管がんである。)
Claims (12)
- 式(I)で表される化合物、又はその薬学的に許容される塩、又はエナンチオマー、ジアステレオマー、互変異性体、溶媒和物、又は多結晶体。
(ただし、
R1は、水素であり;
R2は、H、メチル、-CD3、-CH2C(CH3)2F、HOC(CH3)2CH-、CH(CH2OH)2-CH2-、
、CH3OCH2CH2-、
であり;
R3、R4、及びR5はそれぞれ水素であり;
M1はCH又はNであり;
Arは2つのハロゲン及び2つのC1-C8アルコキシ基で置換されたフェニル基であり;
Lは、化学結合、-CH2-、-CH2CH2-、又は-CH2CH2CH2-であり;
Aは、下記の構造フラグメントから選択されるものである。
) - 治療有効量の請求項1~6のいずれか1項に記載の化合物、或いはその薬学的に許容される塩、或いはそのエナンチオマー、ジアステレオマー、互変異性体、溶媒和物、又は多結晶体、及び少なくとも1つの医薬品賦形剤を含む医薬組成物。
- FGFRキナーゼ阻害剤として使用するための、請求項7に記載の医薬組成物。
- タンパク質キナーゼ、ここで、前記タンパク質キナーゼはFGFRキナーゼである、の活性又は発現量に関連する疾患を予防及び/又は治療するための請求項7に記載の医薬組成物。
- 腫瘍を予防及び/又は治療するための請求項7に記載の医薬組成物。
- 腫瘍、ここで前記腫瘍は非小細胞肺がん、小細胞肺がん、肺腺がん、肺扁平上皮がん、乳がん、前立腺がん、肝臓がん、皮膚がん、胃がん、上皮細胞がん、胃腸道間質腫瘍、腸がん、胆管がん、胆嚢がん、結腸直腸がん、脳がん、白血病、リンパ腫、鼻咽頭がん、膀胱がん、膵がんから選択されるものである、を予防及び/又は治療するための請求項7に記載の医薬組成物。
- 腫瘍、ここで、前記腫瘍は肝臓がん又は胆管がんである、を予防及び/又は治療するための請求項7に記載の医薬組成物。
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