JP5746388B2 - フェニルアミノピリミジン化合物およびその使用 - Google Patents
フェニルアミノピリミジン化合物およびその使用 Download PDFInfo
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- JP5746388B2 JP5746388B2 JP2014018467A JP2014018467A JP5746388B2 JP 5746388 B2 JP5746388 B2 JP 5746388B2 JP 2014018467 A JP2014018467 A JP 2014018467A JP 2014018467 A JP2014018467 A JP 2014018467A JP 5746388 B2 JP5746388 B2 JP 5746388B2
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- LSGOVYNHVSXFFJ-UHFFFAOYSA-N vanadate(3-) Chemical compound [O-][V]([O-])([O-])=O LSGOVYNHVSXFFJ-UHFFFAOYSA-N 0.000 description 1
- 229960002381 vardenafil Drugs 0.000 description 1
- 230000002792 vascular Effects 0.000 description 1
- 210000004509 vascular smooth muscle cell Anatomy 0.000 description 1
- 239000005526 vasoconstrictor agent Substances 0.000 description 1
- 229960003726 vasopressin Drugs 0.000 description 1
- 239000013598 vector Substances 0.000 description 1
- 229960001722 verapamil Drugs 0.000 description 1
- 230000035899 viability Effects 0.000 description 1
- 208000009540 villous adenoma Diseases 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
- 210000003905 vulva Anatomy 0.000 description 1
- 229960005080 warfarin Drugs 0.000 description 1
- PJVWKTKQMONHTI-UHFFFAOYSA-N warfarin Chemical compound OC=1C2=CC=CC=C2OC(=O)C=1C(CC(=O)C)C1=CC=CC=C1 PJVWKTKQMONHTI-UHFFFAOYSA-N 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
- 239000008096 xylene Substances 0.000 description 1
- 229910052725 zinc Inorganic materials 0.000 description 1
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- 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
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- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
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- A61K31/5375—1,4-Oxazines, e.g. morpholine
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Description
QおよびZは、NおよびCR1から独立に選択され;
nは、1、2または3であり;
R1は、水素、ハロゲン、R2、OR2、OH、R4、OR4、CN、CF3、(CH2)nN(R2)2、NO2、R2R4、SO2R4、NR2SO2R3、COR4、NR2COR3、CO2H、CO2R2、NR2COR4、R2CN、R2CN、R2OH、R2OR3およびOR5R4から独立に選択されるか、または2つのR1置換基が、それらが結合している炭素と一緒になって、5または6員の不飽和ヘテロシクリルを形成し;
R2は、置換もしくは非置換のC1〜4アルキル、または置換もしくは非置換のC1〜4アルキレンであり、ここで、2個までの炭素原子は、CO、NRY、CONRY、S、SO2またはOで置き換えられていてもよく;
R3は、R2、C2〜4アルケニル、または置換もしくは非置換のアリールであり;
R4は、NH2、NHR2、N(R1)2、置換または非置換のモルホリノ、置換または非置換のチオモルホリノ、置換または非置換のチオモルホリノ-1-オキシド、置換または非置換のチオモルホリノ-1,1-ジオキシド、置換または非置換のピペラジニル、置換または非置換のピペリジニル、置換または非置換のピリジニル、置換または非置換のピロリジニル、置換または非置換のピロリル、置換または非置換のオキサゾリル、置換または非置換のイミダゾリル、置換または非置換のテトラヒドロフラニル、および置換または非置換のテトラヒドロピラニルであり;
R5は、置換または非置換のC1〜4アルキレンであり;
R6〜R10は、H、RXCN、ハロゲン、置換または非置換のC1〜4アルキル、OR1、CO2R1、N(R1)2、NO2、CON(R1)2、SO2N(RY)2、N(SO2R1)2、置換または非置換のピペラジニル、N(RY)SO2R2、およびCF3から独立に選択され;
RXは、存在しないか、または置換もしくは非置換のC1〜6アルキレンであり、ここで、2個までの炭素原子は、CO、NSO2R1、NRY、CONRY、S、SO2またはOで置き換えられていてもよく;
RYは、H、または置換もしくは非置換のC1〜4アルキルであり;
R11は、H、ハロゲン、置換または非置換のC1〜4アルキル、OR2、CO2R2、CN、CON(R1)2、およびCF3から選択される。
本発明は、式I
QおよびZは、NおよびCR1から独立に選択され;
nは、1、2または3であり;
R1は、水素、ハロゲン、R2、OR2、OH、R4、OR4、CN、CF3、(CH2)nN(R2)2、NO2、R2R4、SO2R4、NR2SO2R3、COR4、NR2COR3、CO2H、CO2R2、NR2COR4、R2CN、R2CN、R2OH、R2OR3およびOR5R4から独立に選択されるか、または2つのR1置換基が、それらが結合している炭素と一緒になって、5または6員の不飽和ヘテロシクリルを形成し;
R2は、置換もしくは非置換のC1〜4アルキル、または置換もしくは非置換のC1〜4アルキレンであり、ここで、2個までの炭素原子は、CO、NRY、CONRY、S、SO2またはOで置き換えられていてもよく;
R3は、R2、C2〜4アルケニル、または置換もしくは非置換のアリールであり;
R4は、NH2、NHR2、N(R1)2、置換または非置換のモルホリノ、置換または非置換のチオモルホリノ、置換または非置換のチオモルホリノ-1-オキシド、置換または非置換のチオモルホリノ-1,1-ジオキシド、置換または非置換のピペラジニル、置換または非置換のピペリジニル、置換または非置換のピリジニル、置換または非置換のピロリジニル、置換または非置換のピロリル、置換または非置換のオキサゾリル、置換または非置換のイミダゾリル、置換または非置換のテトラヒドロフラニル、および置換または非置換のテトラヒドロピラニルであり;
R5は、置換または非置換のC1〜4アルキレンであり;
R6〜R10は、H、RXCN、ハロゲン、置換または非置換のC1〜4アルキル、OR1、CO2R1、N(R1)2、NO2、CON(R1)2、SO2N(RY)2、N(SO2R1)2、置換または非置換のピペラジニル、N(RY)SO2R2、およびCF3から独立に選択され;
RXは、存在しないか、または置換もしくは非置換のC1〜6アルキレンであり、ここで、2個までの炭素原子は、CO、NSO2R1、NRY、CONRY、S、SO2またはOで置き換えられていてもよく;
RYは、H、または置換もしくは非置換のC1〜4アルキルであり;かつ
R11は、H、ハロゲン、置換または非置換のC1〜4アルキル、OR2、CO2R2、CN、CON(R1)2、およびCF3から選択される。
QおよびZは、NおよびCR1から独立に選択され;
R1は、水素、ハロゲン、R2、OR2、OH、R4、CN、CF3、NO2、R2R4、SO2R4、NR2SO2R3、COR4、CO2H、CO2R2、NR2COR3、NR2COR4、R2CN、R2OH、R2OR3およびOR5R3から独立に選択されるか、または2つのR1置換基が、それらが結合している炭素原子と一緒になって、Nを含有する5または6員の不飽和ヘテロシクリルを形成し;
R2は、C1〜4アルキル、またはC1〜4アルキレンであり;
R3は、R2、C2〜4アルケニル、またはアリールであり;
R4は、NH2、NHR2、N(R2)2、モルホリノ、チオモルホリノ、チオモルホリノ-1-オキシド、チオモルホリノ-1,1-ジオキシド、4-カルボニルメチルピペラジニル、4-メチルピペラジニル、3-もしくは4-ヒドロキシピペリジニル、4-ヒドロキシメチルピペリジニル、4-ピロリジニルピペリジニル、4もしくは5-メチルオキサゾリル、4-ヒドロキシピリジニル、3-ヒドロキシピロリル、3-ヒドロキシピロリジニル、ピリジニルピラゾリル、またはイミダゾリルであり;
R5は、C2〜4アルキレンであり;
R6〜R9は、H、RXCN、ハロゲン、置換または非置換のC1〜4アルキル、置換または非置換のアリール、OR1、CO2R1、N(R1)2、NO2、CON(R1)2、およびCON(R1)2から独立に選択され;
RXは、置換または非置換のC1〜4アルキレンであり、ここで、2個までの炭素原子は、CO、NSO2R1、NRY、CONRY、SO、SO2またはOで置き換えられていてもよく;
RYは、H、または置換もしくは非置換のC1〜4アルキルであり;かつ
R11は、H、ハロゲン、置換または非置換のC1〜4アルキル、OR2、CO2R2、CN、CON(R1)2、およびCF3から選択される。
Zは、NおよびCHから独立に選択され;
R1は、水素、ハロゲン、OH、CONHR2、CON(R2)2、CF3、R2OR2、CN、モルホリノ、チオモルホリニル、チオモルホリノ-1,1-ジオキシド、置換もしくは非置換のピペリジニル、置換もしくは非置換のピペラジニル、イミダゾリル、置換もしくは非置換のピロリジニル、およびC1〜4アルキレンから独立に選択され、ここで、炭素原子は、NRYおよび/またはモルホリノ、チオモルホリニル、チオモルホリノ-1,1-ジオキシド、置換もしくは非置換のピペリジニル、置換もしくは非置換のピペラジニル、イミダゾリル、または置換もしくは非置換のピロリジニルで置換されたOで置き換えられていてもよく;
R2は、置換または非置換のC1〜4アルキルであり;
RYは、H、または置換もしくは非置換のC1〜4アルキルであり;
R8は、RXCNであり;
RXは、置換または非置換のC1〜4アルキレンであり、ここで、2個までの炭素原子は、CO、NSO2R1、NRY、CONRY、SO、SO2またはOで置き換えられていてもよく;
R11は、HまたはC1〜4アルキルである。
1〜4個の窒素原子を含む不飽和の5〜6員ヘテロ単環式基、例えば、ピロリル、ピロリニル、イミダゾリル、ピラゾリル、ピリジル、ピリミジニル、ピラジニル、ピリダジニル、トリアゾリルまたはテトラゾリル;
1〜2個の酸素原子および1〜3個の窒素原子を含む不飽和の5または6員へテロ単環式基、例えば、オキサゾリル、イソキサゾリルまたはオキサジアゾリル;および
1〜2個の硫黄原子および1〜3個の窒素原子を含む不飽和の5または6員へテロ単環式基、例えば、チアゾリルまたはチアジアゾリル
が含まれる。
一般式Iの化合物は、一般には、ジクロロピリミジンから調製される。
式Iの化合物は、プロテインキナーゼ、特にJAKキナーゼに対する活性を有し、最も特定的にはJAK2に対して活性である。JAK2阻害薬は、JAK2の活性を選択的に阻害する任意の化合物である。JAK2の1つの活性は、STATタンパク質をリン酸化することである。したがって、JAK2阻害薬の効果の一例が、1種または複数のSTATタンパク質のリン酸化を低下させることである。該阻害薬は、JAK2のリン酸化形態またはJAK2の非リン酸化形態を阻害できる。
本発明は、式Iの化合物の少なくとも1種および薬学上許容される担体を含む医薬組成物を提供する。担体は、「薬学上許容される」ものでなければならず、「薬学上許容される」とは、それが、該組成物中の他の成分と適合性があり、かつ対象に対して有害でないことを意味する。本発明の組成物は、後記のような他の治療薬を含むことができ、例えば、医薬製剤の技術分野で周知であるような技術に従って、従来の固体もしくは液体のビヒクルまたは希釈剤、ならびに所望される投与方式に適切なタイプの医薬添加物(例えば、賦形剤、結合剤、保存剤、安定剤、風味剤など)を採用することによって製剤することができる(例えば、Remingtonの「The Science and Practice of Pharmacy」第21版、2005年、Lippincott Williams & Wilkinsを参照されたい)。
(a)経口投与、外面塗布用に構成された組成物、例えば、水薬(例えば、水性または非水性の溶液または懸濁液);錠剤または丸薬;飼料と混合するための粉末、顆粒またはペレット;舌に塗布するためのペースト;
(b)例えば、無菌の溶液または懸濁液のような、例えば、皮下、筋肉内または静脈内注射による、あるいは(適切なら)乳頭を介して懸濁液または溶液を乳房中に導入する乳房内注射による非経口投与用に構成された組成物;
(c)例えば、皮膚に塗布されるクリーム、軟膏または噴霧剤のような、局所適用用に構成された組成物;または
(d)例えば、ペッサリー、クリームまたは泡剤のような、直腸または膣内用に構成された組成物、が含まれる。
式Iの化合物は、臓器移植を含む免疫性および炎症性疾患;癌および骨髄増殖性疾患を含む過剰増殖性疾患;ウイルス性疾患;代謝性疾患;および血管性疾患などのJAKキナーゼ関連疾患を含む、キナーゼ関連疾患の治療で使用できる。
成症候群)、ホジキン病、非ホジキンリンパ腫[悪性リンパ腫];皮膚:悪性黒色腫、基底組織癌、扁平上皮組織癌、カポジ肉腫、奇胎異形成母斑、脂肪腫、血管腫、皮膚線維腫、ケロイド、乾癬;副腎:神経芽組織腫;および骨髄増殖性疾患、例えば、真性赤血球増加症(PV)、原発性骨髄線維症、血小板血症、本態性血小板血症(ET)、特発性骨髄線維症(IMF)とも呼ばれる特発性髄様化生(AMM)、慢性骨髄性白血病(CML)、全身性肥満細胞症(SM)、慢性好中球性白血病(CNL)、骨髄異形成症候群(MDS)、および全身性肥満細胞疾患(SMCD)が含まれる。
用語「治療上有効な量」は、研究者、獣医師、医師またはその他の臨床医学者が求める、組織、系、動物またはヒトの生物学的または医学的応答を誘発する式IおよびIIの化合物の量を指す。
(化合物の合成)
本発明の化合物は、当業者に周知の方法によって、および選択した化合物に関する以下に示す合成および実験手順中に記載のように調製できる。
PyBOP ベンゾトリアゾール-1-イルオキシトリピロリジノホスホニウムヘキサフルオロホスフェート
DMF N,N-ジメチルホルムアミド
DMAP 4-ジメチルアミノピリジン
DCM ジクロロメタン
NMP 1-メチル-2-ピロリジノン
n-PrOH n-プロパノール
ACN アセトニトリル
EDC・HCl 1-エチル-3-(ジメチルアミノプロピル)カルボジイミド塩酸塩
HOBT N-ヒドロキシベンゾトリアゾール
TEA トリエチルアミン
DIPEA ジイソプロピルエチルアミン
p-TsOH p-トルエンスルホン酸
HATU o-(7-アザベンゾトリアゾール-1-イル)-N,N,N',N'-テトラメチルウロニウムヘキサフルオロホスフェート
4-エトキシカルボニルフェニルボロン酸(23.11g、119mmol)、2,4-ジクロロピリミジン(16.90g、113mmol)、トルエン(230mL)および炭酸ナトリウム水溶液(2M、56mL)の混合物を激しく撹拌し、懸濁液中に窒素を15分間吹き込んだ。テトラキス(トリフェニルホスフィン)パラジウム[0](2.61g、2.26mmol)を添加した。窒素をさらに10分間吹き込み、混合物を100℃まで加熱し、次いで75℃で一夜加熱した。混合物を冷却し、酢酸エチル(200mL)で希釈し、水(100mL)を添加し、層を分離した。水層を酢酸エチル(100mL)で抽出し、2つの有機抽出液を合わせた。有機抽出液を食塩水で洗浄し、硫酸ナトリウムを通して濾過し、濃縮し、得られた固体をメタノール(100mL)と共に磨り潰し、濾過した。固体をメタノール(2×30mL)で洗浄し、風乾した。この材料をアセトニトリル(150mL)およびジクロロメタン(200mL)に溶解し、MP.TMT Pd除去用樹脂(Agronaut部品番号800471)(7.5g)と共に2日間撹拌した。溶液を濾過し、固体をジクロロメタン(2×100mL)で洗浄し、濾液を濃縮し、類白色固体としてエチル4-(2-クロロピリミジン-4-イル)ベンゾエートを得た(17.73g、60%)。ジクロロメタンでさらに洗浄すると、さらに1.38gおよび0.5gの生成物が得られた。1H NMR (300MHz, d6-DMSO) δ 8.89 (1H, d, J=5.0Hz); 8.32 (2H, d, J=8.7Hz); 8.22 (1H, d, J=5.5Hz); 8.12 (2H, d, J=8.7Hz); 4.35 (2H, q, J=7.1Hz); 1.34 (3H, t, J=7.1Hz); LC-ESI-MS (方法B): rt 7.3分; m/z 263.0/265.0 [M+H]+。
2,4-ジクロロ-5-メチルピリミジン(244mg、1.5mmol)と2-メトキシ-4-(4,4,5,5-テトラメチル-1,3,2-ジオキサボロラン-2-イル)安息香酸メチル(210mg、1.0mmol)とのトルエン(3mL)溶液に、n-プロパノール(1mL)、重炭酸ナトリウム水溶液(2M、1.5μL)、およびテトラキス(トリフェニルホスフィン)パラジウム[0](116mg、0.1mmol)を添加した。反応物を、110℃で40時間加熱し、次いで、酢酸エチルと飽和重炭酸ナトリウム水溶液との間に分配した。水層を酢酸エチルでさらに2回抽出し、合わせた有機画分を水、食塩水で洗浄し、次いで、乾燥(硫酸ナトリウム)し、濾過し、濃縮した。溶離液として30〜60%酢酸エチル/石油スピリットを使用するシリカゲルクロマトグラフィーにより、クリーム色の固体として4-(2-クロロ-5-メチルピリミジン-4-イル)-2-メトキシ安息香酸メチルを得た(165mg、56%)。LC-ESI-MS (方法B): rt 6.2分; m/z 293.3/295.3 [M+H]+。
4-カルボキシフェニルボロン酸(5.0g、30mmol)のDMF(5mL)+ジクロロメタン(200mL)懸濁液に、0℃でオキサリルクロリド(5.9mL、66mmol)を滴加した。ガスの放出が遅くなったら、氷浴を取り外し、反応物を30分で室温に戻した。次いで、反応物を40℃で3時間加熱すると、その時間までにすべての固体が溶解した。ジクロロメタンを留去し、DMF溶液を0℃まで冷却した。次いで、アミノアセトニトリル塩酸塩(3.05g、33mmol)のDMF(80mL)+DIPEA(13mL、75mmol)溶液を滴加した。滴加が完結した後、氷浴を取り外し、溶液を室温で16時間撹拌したままにした。次いで、大部分のDMFを真空で除去し、反応物を酢酸エチルと2M塩酸水との間に分配した。水層を酢酸エチルでさらに2回抽出し、合わせた有機画分を、乾燥(Na2SO4)、濾過し、減圧下で濃縮してワックス状淡黄色固体として4-(シアノメチルカルバモイル)フェニルボロン酸を得た(5.34g、87%)。1H NMR (300MHz, d6-DMSO): 9.18 (br. t, J=5.1Hz, 1H)、7.8〜7.9 (m, 4H)、4.31 (d, J=5.4Hz, 2H); LC-ESI-MS (方法B): rt 0.9分; m/z 203.3 [M-H]-。
丸底フラスコに、4-メタンスルホニルアミノフェニルボロン酸(4.30g、20mmol)、2,4-ジクロロピリミジン(5.97g、40mmol、2当量)、トルエン(75mL)、n-プロパノール(25mL)、および炭酸ナトリウム水溶液(2M、18mL、1.8当量)を仕込んだ。反応混合物を排気し、窒素で常圧に戻すことを3回繰り返した後、テトラキス(トリフェニルホスフィン)パラジウム(0)触媒(1.02g、4.4モル%)を添加した。反応混合物を排気し窒素で常圧に戻すことを再び3回繰り返した後、窒素雰囲気下に100℃で66時間加熱した。反応混合物を、冷却し、室温で数時間撹拌すると、その間に、反応混合物から生成物が沈殿した。微細な黄色固体を、真空濾過で捕集し、メタノールで洗浄し、高真空下で乾燥した(3.45g、収率61%)。1H NMRおよびLC MSのデータにより、これが所望のN-(4-(2-クロロピリミジン-4-イル)フェニル)メタンスルホンアミドであることを確認した。1H NMR (300MHz, d6-DMSO) δ 10.26 (1H, brs); 8.75 (1H, d, J=5.5Hz); 8.17 (2H, d, J=9.1Hz); 8.05 (1H, d, J=5.5Hz); 7.35 (2H, d, J=8.7Hz); 3.10 (3H, s)。LC-ESI-MS (方法B): rt 5.5分; m/z 284.2/286.1 [M+H]+。
-5℃に保持した、5-ブロモ-2,4-ジクロロピリミジン(300mg、1.3mmol)のジクロロメタン(3mL)溶液に、冷えた57%ヨウ化水素酸水(5mL)を添加した。生じた溶液を-5℃で2時間撹拌した。固体の炭酸ナトリウムを、溶液がpH7となるまで少量ずつ添加し、5%メタ重亜硫酸ナトリウム水溶液を添加することによって混合物を脱色した。すべての固体が溶解するまで水を添加し、有機相を分離した。水相をジクロロメタンで2回抽出し、次いで、合わせた有機層を、無水硫酸ナトリウム上で乾燥し、濾過、濃縮して、白色固体として粗5-ブロモ-2,4-ジヨードピリミジンを得た(410mg)。この材料を、さらなる精製なしで次の段階に使用した。LC-ESI-MS (方法B): rt 6.8分; m/z 410.9/412.9 [M+H]+。
化合物3(10.0g)をメタノール(1L)に懸濁した。撹拌された溶液に濃硫酸(10.52g、90%w/w)を滴加した。澄明褐色溶液が生じ、そして固体塊が生じた。溶液を速やかに濾過し、次いで、3時間撹拌を継続した(数分以内に第2沈殿が生じた)。この時間後、淡黄色沈殿を濾過により捕集し、メタノール(10mL)で洗浄し、次いで、真空下で一夜乾燥して、淡黄色固体として4-(4-(4-(4-(シアノメチルカルバモイル)フェニル)ピリミジン-1-イウム-2-イルアミノ)フェニル)モルホリン-4-イウム硫酸水素塩を得た(10.20g、69%)。融点205℃。微量元素分析: C23H26N6O10S2に対して計算値C 45.24;H 4.29;N 13.76;S 10.50%、実測値C 45.18;H 4.36;N 13.84;S 10.24。1H NMR (300MHz, d6-DMSO) δ 9.85 (br. s, 1H)、9.34 (t, J=5.4Hz, 1H)、8.59 (d, J=5.2Hz, 1H)、8.27 (d, J=8.5Hz, 2H)、8.03 (d, J=8.5Hz, 2H)、7.83 (d, J=8.4Hz, 2H)、7.50 (d, J=5.2Hz, 1H)、7.34 (br. s, 2H)、4.36 (d, J=5.4Hz, 2H)、3.89 (br. s, 4H)、3.37 (br. s, 4H); 13C NMR (75.5MHz, d6-DMSO) δ 166.07、163.36、159.20、158.48、140.19、139.34、136.45、134.89、128.00、127.22、121.13、119.89、117.59、109.05、64.02、54.04、27.82。LC-ESI-MS (方法D): rt 10.0分; m/z 415.1 [M+H]+。
LC-ESI-MS (方法D): rt 10.3分; m/z 415.3 [M+H]+。
50mLの2口丸底フラスコに磁気撹拌バーおよび滴下ロートを取り付けた。NaBH4のテトラヒドロフラン懸濁液(100mg、2.4mmol/10mL)、続いて5-アミノ-2-モルホリノベンゼンカルボン酸(222mg、1.0mmol)を一度に添加した。還流コンデンサーを取り付け、反応混合物を窒素雰囲気下で0℃まで冷却した。反応混合物に、ヨウ素のテトラヒドロフラン溶液(250mg、1.0mmol/15mL)滴加した。ヨウ素の添加を完結し、ガスの発生が止まった後、反応混合物を、還流下で6時間加熱し、室温で一夜撹拌したままにした。メタノールを、混合物が澄明になるまで徐々に添加した。得られた溶液を室温で30分間撹拌し、次いで、溶媒を減圧下で除去した。残留物を、20%KOH(30mL)に溶解し、4時間撹拌し、ジクロロメタン(3×30mL)で抽出した。合わせた有機抽出液を、食塩水で洗浄し、無水Na2SO4上で乾燥し、濃縮して、灰白色固体として5-アミノ-2-モルホリノベンジルアルコールを得た(150mg、収率72%)。1H NMR (300MHz, CDCl3) δ 7.05 (d, J=8.7Hz, 1H)、6.59 (dd, J=8.4, 2.7Hz, 1H)、6.49 (d, J=2.7Hz, 1H)、5.51 (br s, 1H)、4.71 (s, 2H)、3.84 (t, J=5.1Hz, 4H)、3.60 (br s, 2H)、2.91 (t, J=5.1Hz, 4H)。LC-ESI-MS (方法B): rt 2.31分; m/z 209.2 [M+H]+。
1Hおよび13C NMRのデータは、Brucker AV-300 AVANCE NMR分光計を用いて得られた。
(全般的パラメーター)
LC-EI-MSおよびEI-MSのデータは、Waters Millenium32ソフトウェア・バージョン4.0の制御下で操作する、以下に概略を示す設定値のWaters 2996ホトダイオードアレイ検出器および統合型TMD電子衝撃質量分光計に連結されたWaters 2795 Alliance HPLCを用いて得られた。
ほぼ0.36L/分のヘリウム流量;集積モードを走査に設定;1スペクトル/秒のサンプリング速度;ソース温度200℃;ネブライザー温度80℃;膨張領域温度75℃;所望により質量範囲m/z100〜550、m/z100〜650またはm/z100〜700。
LC-MSのパラメーターは、後に概略を示す方法のそれぞれについて記載する通りとした。EI-MSのサンプルは、カラムなしで0.25mL/分の溶媒流量で注入され分析される。
溶媒グラジエント:
カラム:次のものの1つ
・Alltima HP C18、2.1×150mm、5μ
・XTerra MS C18、3.0×100mm、3.5μ
・XBridge C18、3.0×100mm、3.5μ
溶媒グラジエント
カラム:次のものの1つ
・Alltima HP C18、2.1×150mm、5μ
・XTerra MS C18、3.0×100mm、3.5μ
・XBridge C18、3.0×100mm、3.5μ
(全般的パラメーター)
LC-ESI-MSのデータは、Masslynxソフトウェア・バージョン4.1を備え、以下に概略を示す設定値の、Waters 2996ホトダイオードアレイ検出器およびエレクトロスプレーのイオン化条件下で操作するWaters ZQ質量分光計に連結されたWaters 2695Xe HPLCを用いて得られた。
質量範囲: m/z100〜650
走査時間: 0.5
中間走査遅れ: 0.1
脱溶媒ガス: 500L/hN2
コーンガス: 100L/hN2
脱溶媒温度: 400℃
ソース温度: 120℃
コーン電圧: ESI正のモードで+30v
ESI負のモードで-45v
下に概略を示す次の条件集合の1つとした。
溶媒グラジエント
カラム:XTerra MS C18、2.1×50mm、3.5μ
溶媒グラジエント
カラム:XTerra MS C18、2.1×50mm、3.5μ
溶媒グラジエント
カラム:XTerra MS C18、3.0×100mm、3.5μ
(化合物の希釈)
スクリーニングを目的とする場合には、使用前に、化合物(100%DMSO中の)を37度で少なくとも20分間温めた。まず、アッセイ緩衝液で20μMの原液(DMSOの最終濃度は0.3%であった)を製造した。次いで、該原液を、384ウェルのOptiplate(Packard)中で希釈した(化合物の最終濃度は5μMであった)。
次の手順を使用してJAKキナーゼ領域を産生した。
ヒトJAK2のキナーゼ領域は、次のプライマーを用いるポリメラーゼ連鎖反応を利用してU937mRNAから増幅した:
SALI-jk2 5'-ACG CGT CGA CGG TGC CTT TGA AGA CCG GGA T-3'[配列番号7]
jk2-NOTI 5'-ATA GTT TAG CGG CCG CTC AGA ATG AAG GTC ATT T-3'[配列番号8]。
JAK2のPCR産物を、目的ベクターpDest20 (Gibco)中にクローニングした。次いで、JAK2プラスミドをコンピテントDH10Bac組織(Gibco)中に導入して形質転換し、Sf9昆虫組織へのトランスフェクションを介して組換えバキュロウイルスを調製した。
ヒトJAK3のキナーゼ領域は、次のプライマーを用いるポリメラーゼ連鎖反応を利用してU937mRNAから増幅した:
XHOI-J3 5'-CCG CTC GAG TAT GCC TGC CAA GAC CCC ACG-3'[配列番号9]
J3-KPNI 5'-CGG GGT ACC CTA TGA AAA GGA CAG GGA GTG-3'[配列番号10]
JAK3のPCR産物を、目的発現ベクターpDest20(Gibco)中にクローニングした。次いで、JAK3プラスミドをコンピテントDH10Bac組織(Gibco)中に導入して形質転換し、Sf9昆虫組織のトランスフェクションを介して組換えバキュロウイルスを調製した。
各JAKファミリーメンバーからのバキュロウイルス調製物を、SF-900II血清不含培地(Invitrogen)中でほぼ2×106細胞/mLの細胞密度まで増殖した1リットルのSf9(Spodoptera frugiperda)細胞(Invitrogen)に感染させた。細胞を、20:1の細胞培養物対ウイルス原液比でウイルスに感染させた。感染48時間後に、細胞を回収し、溶解した。GSTタグを付けたJAKキナーゼドメインを、GSHアガロースカラム(Scientifix)でのアフィニティークロマトグラフィーで精製した。
キナーゼのアッセイは、384ウェルのOptiplate(Packard)中でAlphascreenプロテインチロシンキナーゼP100検出キットを使用して実施した。化合物を、ホスホチロシンアッセイ用緩衝液(10mM HEPES、pH7.5、100mM MgCl2、25mM NaCl、200mMバナジン酸ナトリウム、および0.1%Tween20)の存在下に親和性で精製したPTK領域と20分間プレインキュベートした。次いで、化合物を基質と共に80または625umATPの存在下で60または90分間インキュベートした。使用する基質は、ビオチン-EGPWLEEEEEAYGWMDF-NH2[配列番号13]の配列を有する基質-1(最終濃度111μM)、またはビオチン-EQEDEPEGDYFEWLEPEの配列を有する基質-2(最終濃度133μM)とした。Alphascreenホスホチロシン受容体ビーズ、続いて停止緩衝液中1/100の濃度のストレプトアビジン供与体ビーズを、各ウェルに減光の下で添加し、2〜3時間インキュベートした。Alphascreenプレートを、Packard Fusion Alpha装置で読み取った。
(化合物の希釈)
スクリーニングを目的として、化合物を、96ウェルプレート中で20μMの濃度に希釈した。アッセイを実施する前に、プレートを37℃で30分間温めた。
TELのヌクレオチドl-487を包含するコード領域を、オリゴヌクレオチド5TEL(5'-GGA GGA TCC TGA TCT CTC TCG CTG TGA GAC-3')[配列番号14]および3TEL(5'-AGGC GTC GAC TTC TTC TTC ATG GTT CTG-3')[配列番号15]、ならびに鋳型としてのU937mRNAを使用するPCRによって増幅した。5TELプライマー中にはBamH1制限部位を組み込み、3TELプライマー中にはSal1制限部位を組み込んだ。JAK2のキナーゼ領域を包含する領域(ヌクレオチド2994〜3914;JAK2F 5'-ACGC GTC GAC GGT GCC TTT GAA GAC CGG GAT-3'[配列番号16];JAK2R 5'-ATA GTT TAG CGG CCG CTC AGA ATG AAG GTC ATT T-3')[配列番号17]、およびJAK3(ヌクレオチド2520〜3469;JAK3F 5'-GAA GTC GAC TAT GCC TGC CAA GAC CCC ACG ATC TT-3')[配列番号18]を、TaqDNAポリメラーゼ(Gibco/BRL)および鋳型としてのU937mRNAを使用するPCRによって作出した。JAK2およびJAK3の順方向プライマー中にはSal1制限部位を組み込み、JAK2の逆方向プライマーにはNot1部位を組み込み、JAK3の逆方向プライマーにはXba1部位を付加した。
培養物から組織を収集することによって、組織懸濁液を調製した。(この試験で使用される組織は、高い生存能を有する後期対数増殖期にあった)。組織を、前述のような適切な増殖培地で、1.1×最終濃度(組織系に応じて50,000組織/mL〜200,000組織/mL)に希釈した。
結果を表2に示すが、+++は<1μMであり、++は<5μMであり、+は<20μMである。
(STAT5リン酸化のマルチパラメーター細胞内フローサイトメトリー解析)
ヒト赤白血球病細胞系、HEL 92.1.7(ATCC、TIB-180)を、1mMのピルビン酸ナトリウムで補足された10%FCS含有RPMI 1640中で増殖させた。蛍光体-STAT5を測定するために、HEL細胞を、RPMI 1640+1%FCS中、37℃で18時間増殖させ、アッセイ点毎に2×105個の細胞を、DMSO/試験化合物に37℃で2時間曝露した。細胞を、1300rpmで3分間遠心分離し、パラホルムアルデヒド(最終濃度2%)中、37℃で15分間固定した。遠心分離後、細胞を、90%メタノール中、4℃で30分間透過処理した。PBS-2%FCS中での3回の洗浄に続いて、BD PharMingen社のフィコエリトリン複合化マウス免疫グロブリンイソタイプ対照(カタログ番号551436)およびSTAT5(Y694)に対するフィコエリトリン複合化マウスIgG1抗体(カタログ番号612567)を使用して次のように染色を実施した。
(実験1)
(方法論)
ネズミのBリンパ球前駆細胞系BaF3を、10%FCS含有RPMI 1640培地中に常法通り維持した。実験当日に、細胞をPBS中で2回洗浄し、0.1%FCS含有RPMI 1640培地中に再懸濁した。血清欠乏の2時間後に、細胞を、所望濃度の化合物3、対照化合物、またはビヒクル(DMSO)単独とさらに2時間処理した。次いで、細胞に、マウスのIL-3を5ng/mLの最終濃度で15分間の間に添加した。次いで、細胞を、氷上に置き、氷冷PBS中で2回洗浄した。洗浄した細胞ペレットを、液体窒素中で急速凍結し、-80℃で貯蔵した。
(方法論)
ヒトの赤白血球病細胞系HEL 92.1.7を、10%FCS含有RPMI 1640培地中に常法通り維持した。実験前日に、細胞をPBS中で2回洗浄し、1%FCS含有RPMI 1640培地中に再懸濁し、一夜培養した。
(マウス血漿中の成長ホルモン-賦活化されたインスリン様成長因子-1濃度に対する化合物3の効果)
時刻0での成長ホルモン(+GH、30μg/マウス)または生理食塩水(対照)の皮下投与に先立つ、8時間および30分の経口経管栄養による化合物3(50mg/kg)、またはビヒクル単独(対照、+GH)の投与後の雌性C3/Hマウス(n=6/群)における、循環IGF-1濃度(平均±s.e.m.)。GH投与の6時間後に血液検体を捕集し、マウスのIGF-1についてELISAを使用して血漿中IGF-1濃度を測定した(R & D Systems)。異なる肩付き文字は、一元ANOVAおよび事後ボンフェローニ検定によって検知される群間の有意差(P<0.05)を意味する。
Balb/Cnu/nuマウスに、マウスのBa/F3 TelJAK2細胞(2.5×106個/マウス)を皮下接種し、化合物3(20mg/kg、10mg/kg、または5mg/kg)、あるいはビヒクル単独(5%N-メチルピロリドン、0.1M Captisol(登録商標))を経口経管栄養で1日2回、またはタキソール(登録商標)(5mg/kg静脈内、週3回、n=15マウス/群)を投与する。腫瘍(6mm3の平均腫瘍容積)を触知できたら、腫瘍細胞接種の11日目後に投与を開始した。腫瘍の寸法を週に2回測定した。14日目の投与で、平均のパーセントT/C値は、化合物3に関して、1日に2回の20mg/kgで39%、1日に2回の10mg/kgで25%、1日に5mg/kgで82%であった。投与後14日目の腫瘍容積をt-検定(マン・ホイットニーの順位和検定)で比較すると、1日2回20mg/kgおよび1日2回10mg/kgの化合物3、ならびにタキソールで処理された群では、ビヒクル対照で処理された群および5mg/kgの化合物3で処理された群(これらは、互いに差がない)に比較して、腫瘍容積がより小さいことが見出された(p<0.05)。より厳しい統計的検定(クラスカル・ウォリスの一元ANOVA)、それに続く対照群に対するダンの事後多重比較により、ビヒクル対照で処理された群と、化合物3で処理された群(1日2回の10または20mg/kg)またはタキソールで処理された群との間の有意差(p<0.05)が確認された。結果を図6に示す。
化合物は、JAK2V617F-陽性骨髄増殖性疾患(MPD)のネズミモデルでも試験することができる。
(JAK2V617F-陽性MPDの確立)
5-フルオロウラシルで治療された雄性Balb/cマウスからの骨髄を、JAK2-V617F-GFPレトロウイルスで感染し、致死的に照射された雌性受容者中に眼窩後で注射することができる。21日目から、マウスを、毎日の検査および毎週2回のGFP-陽性組織についての血球数+FACSによって観察できる。ヘマトクリットの上昇は、28日目ごろに、白血球数の上昇は40日目ごろに起こり得ると予想される。
早期介入群:治療は、経口経管栄養により与えられる化合物または担体を用い、21日目に開始する(各群12尾のマウス)。マウスを、毎日の検査および毎週2回のGFP-陽性組織についての血球数+FACSによって観察できる。60日目に最終薬物投与の8〜12時間後にマウスを屠殺する。瀕死のマウス、または白血球数が200,000/nLを超えるもしくは体重減少>20%のマウスは、より早期に屠殺できる。
肝臓および脾臓の重量を測定できる。骨髄、肝臓および脾臓からの組織切片を、HE染色によって分析できる。骨髄および脾臓は、レティキュリン線維症を評価するために銀で染色することもできる。脾臓および骨髄組織は、GFPについてのFACS、組織系譜マーカー、JAK2およびSTAT5のリン酸化によって分析できる。血液は、心穿刺によって収集され、血漿は、分離され、薬物濃度測定のため凍結され得る。群間の生存率は、カプラン-マイヤー法を用いて比較できる。
JAK2V617F突然変異を伴う、および伴わないMPD(主として骨髄線維症)患者(それぞれN=10)および5人の正常対照(市販供給業者)からの末梢血液単核組織を、密度勾配遠心分離法(Ficoll)によって単離できる。前駆組織を富化するための市販キットを使用してCD34+組織を選択できる。CD34+組織を、ウシ胎児血清およびサイトカイン(+/-EPO)で補足されたメチルセルロースに三つ組で播種できる。プレートを2週間インキュベートした後、赤血球および骨髄のコロニー形成を、倒立顕微鏡下で評価できる。
腫瘍の開始、進行および転移に対する化合物の効果は、インビボの動物効力モデルと関連させて評価できる。モデルは、ヒト腫瘍細胞系に由来する、または好ましくは原発性もしくは転移性ヒト腫瘍に由来する、免疫不全マウス中のヒト腫瘍異種移植片モデルでよい。その他のモデルは、正位部位で成長したヒト腫瘍異種移植片、播種性疾患モデル、および遺伝子導入もしくは標識化腫瘍モデルでよい。モデルには、原発性腫瘍の外科的切除および転移性疾患の評価も含めることができる。
式Iの化合物は、Gust,RおよびSchuster,D.P.の論文、Experimental Lung Research、27巻、1〜12頁、2001年に記載のように、肺高血圧のイヌモデルで試験できる。それらの化合物は、モノクロタリン誘導肺高血圧のウサギモデルでも試験できる。式Iの化合物は、肺動脈高血圧を有するヒトでも試験できる。式Iの化合物の効果は、肺動脈高血圧を有するヒトにおいて、その心肺血行動態に対する急性効果を測定することによって試験できる。化合物の右心室圧、肺動脈圧、肺血管抵抗、および心拍出量に対する化合物の効果を判定できる。6分歩行時間および最大酸素消費量に対する化合物の効果を、PAHを有するヒトで判定できる。生活の質(質問表で測定されるような)、入院、および生存率に対する化合物の効果を、PAHを有するヒトで判定できる。ヒトにおいて、PAHは、遺伝子異常(すなわち、原発性または家族性PAH)または強皮症、未修正の先天性心疾患、混合膠原病性血管障害、C型肝炎またはその他の肝疾患、HIV感染、あるいは遺伝性出血性毛細血管拡張症などの二次的原因によって引き起こされる可能性がある。化合物の効果は、ヒトの内皮組織、線維芽組織および/または平滑筋組織系に対して試験することもでき:例えば、ヒト肺動脈平滑筋組織系におけるSTAT3のリン酸化に対するIC50を測定できる。他の種、すなわちラットからの組織系も調べることができる。ヒト血管からの、または他の種、すなわちラットからの血管からの事前収縮血管輪に対する化合物の効果を調べることができる。例えば、フェニレフリン、エンドセリン、セロトニン、バソプレシン、アンジオテンシンII、またはKCLで前収縮されたラットの肺動脈輪を研究して、血管弛緩に関する化合物の用量-反応を決定できる。他の血管収縮薬も調べることができる。
JAK2小分子阻害薬の活性を評価するために、下流タンパク質STAT5のリン酸化状態を測定することによってJAK-STAT経路の活性を定量するアッセイ法が開発されている。リガンドが結合した後、造血性サイトカイン受容体は、会合したJAK2タンパク質を活性化する配座変化を受ける。活性化されたJAK2は、次いで、受容体の細胞内部分をリン酸化し、細胞内シグナル伝達タンパク質を補給するための結合部位を形成する。STAT5は、活性化されたサイトカイン受容体複合体に補給される1つのタンパク質であり、その複合体で、STAT5は、リン酸化され、次いで核内に移行し、細胞の成長および分化を介在する一組の遺伝子の発現を調節する。
骨髄は、JAK2 V617F陽性骨髄増殖性疾患を有する患者の回腸クレストから捕集した。フローサイトメトリーアッセイは、生検処置の当日に新鮮な骨髄検体で実施した。骨髄単核細胞を密度勾配遠心分離によって捕集し、次いで、0.75〜1.0×106個の細胞を、各種濃度の化合物3と共に、インディケーター不含RPMI中、37℃で1時間インキュベートした。細胞を、エリスロポエチンで10分間最大限に刺激し、次いで、培養培地に4%ホルムアルデヒドを直接添加して固定した。次いで細胞を、冷メタノールで透過処理し、次いで、最適濃度の蛍光標識化抗体を添加した。細胞表面タンパク質の発現(CD45lo、CD71hi集団)をベースにしたpYSTAT5の測定には、赤血球細胞を選択した。
化合物3を、赤血球細胞集団中、3μM〜0.0041μMの様々な濃度で試験した。最初の骨髄標本は、3μM〜0.037μMの阻害薬濃度範囲で試験した。次の2つの患者標本は、1μM〜0.0041μMの濃度範囲で試験した。
Claims (23)
- 以下の構造:
- N-(シアノメチル)-4-(2-(4-モルホリノフェニルアミノ)ピリミジン-4-イル)ベンズアミドの塩酸塩である、請求項1に記載の化合物。
- N-(シアノメチル)-4-(2-(4-モルホリノフェニルアミノ)ピリミジン-4-イル)ベンズアミドである、請求項1に記載の化合物。
- N-(シアノメチル)-4-(2-(4-(4-ヒドロキシピペリジン-1-イル)フェニルアミノ)-5-メチルピリミジン-4-イル)ベンズアミドまたはその薬学上許容される塩である化合物。
- 請求項1または2に記載の化合物および薬学上許容される担体を含む医薬組成物。
- 請求項1または2に記載の化合物を含むインプラント。
- 請求項4に記載の化合物および薬学上許容される担体を含む医薬組成物。
- 請求項4に記載の化合物を含むインプラント。
- ヤーヌスキナーゼ(JAK)関連疾患の治療のための、請求項5に記載の医薬組成物であって、前記疾患が骨髄増殖性障害である、医薬組成物。
- 骨髄増殖性障害が、真性赤血球増加症(PV)、原発性骨髄線維症、血小板血症、本態性血小板血症(ET)、特発性骨髄線維症、慢性骨髄性白血病、全身性肥満細胞症(SM)、慢性好中球性白血病(CNL)、骨髄異形成症候群(MDS)、および全身性肥満細胞疾患(SMCD)からなる群から選択される、請求項9に記載の医薬組成物。
- 骨髄増殖性障害が真性赤血球増加症(PV)である、請求項9に記載の医薬組成物。
- 骨髄増殖性障害が原発性骨髄線維症である、請求項9に記載の医薬組成物。
- 骨髄増殖性障害が本態性血小板血症(ET)である、請求項9に記載の医薬組成物。
- 錠剤、カプセル、顆粒または粉末の形態で提供される、請求項5に記載の医薬組成物。
- 50から400mgの量で前記化合物または薬学上の塩を含む、請求項5に記載の医薬組成物。
- 100、150、200または300mgの量で前記化合物または薬学上の塩を含む、請求項5に記載の医薬組成物。
- ヤーヌスキナーゼ(JAK)関連疾患の治療のための、請求項7に記載の医薬組成物であって、前記疾患が骨髄増殖性障害である、医薬組成物。
- 骨髄増殖性障害が、真性赤血球増加症(PV)、原発性骨髄線維症、血小板血症、本態性血小板血症(ET)、特発性骨髄線維症、慢性骨髄性白血病、全身性肥満細胞症(SM)、慢性好中球性白血病(CNL)、骨髄異形成症候群(MDS)、および全身性肥満細胞疾患(SMCD)からなる群から選択される、請求項17に記載の医薬組成物。
- 骨髄増殖性障害が真性赤血球増加症(PV)である、請求項17に記載の医薬組成物。
- 骨髄増殖性障害が原発性骨髄線維症である、請求項17に記載の医薬組成物。
- 骨髄増殖性障害が本態性血小板血症(ET)である、請求項17に記載の医薬組成物。
- 細胞を請求項1に記載の化合物と接触させる段階を含む、細胞中のJAKをin vitroで阻害する方法。
- 細胞を請求項4に記載の化合物と接触させる段階を含む、細胞中のJAKをin vitroで阻害する方法。
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JP2015145386A (ja) * | 2007-03-12 | 2015-08-13 | ワイエム・バイオサイエンシズ・オーストラリア・ピーティーワイ・リミテッド | フェニルアミノピリミジン化合物およびその使用 |
JP2016175934A (ja) * | 2007-03-12 | 2016-10-06 | ワイエム・バイオサイエンシズ・オーストラリア・ピーティーワイ・リミテッド | フェニルアミノピリミジン化合物およびその使用 |
USRE48285E1 (en) | 2014-06-12 | 2020-10-27 | Sierra Oncology, Inc. | N-(cyanomethyl)-4-(2-(4-morpholinophenylamino)pyrimidin-4-yl)benzamide |
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