JP7287951B2 - アデノシン受容体アンタゴニストとしてのキノキサリン誘導体 - Google Patents
アデノシン受容体アンタゴニストとしてのキノキサリン誘導体 Download PDFInfo
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- GBABOYUKABKIAF-GHYRFKGUSA-N vinorelbine Chemical compound C1N(CC=2C3=CC=CC=C3NC=22)CC(CC)=C[C@H]1C[C@]2(C(=O)OC)C1=CC([C@]23[C@H]([C@]([C@H](OC(C)=O)[C@]4(CC)C=CCN([C@H]34)CC2)(O)C(=O)OC)N2C)=C2C=C1OC GBABOYUKABKIAF-GHYRFKGUSA-N 0.000 description 1
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Classifications
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- A—HUMAN NECESSITIES
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- 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
- A61K31/4965—Non-condensed pyrazines
- A61K31/497—Non-condensed pyrazines containing further heterocyclic rings
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- 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
- A61K31/498—Pyrazines or piperazines ortho- and peri-condensed with carbocyclic ring systems, e.g. quinoxaline, phenazine
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- A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
- A61K31/5375—1,4-Oxazines, e.g. morpholine
- A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
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- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
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- A—HUMAN NECESSITIES
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- C07D241/36—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings condensed with carbocyclic rings or ring systems
- C07D241/38—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings condensed with carbocyclic rings or ring systems with only hydrogen or carbon atoms directly attached to the ring nitrogen atoms
- C07D241/40—Benzopyrazines
- C07D241/44—Benzopyrazines 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 carbon atoms of the hetero ring
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- C07D417/00—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
- 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
- C07D417/12—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 linked by a chain containing hetero atoms as chain links
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- C07D417/14—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 three or more 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
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- C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
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Description
アデノシンは、無数の生理学的活性がある、具体的には心臓血管系、神経系、および免疫系内の普遍的なモジュレーターである。アデノシンは、生物活性ヌクレオチドであるアデノシン三リン酸(ATP)、アデノシン二リン酸(ADP)、アデノシン一リン酸(AMP)、および環状アデノシン一リン酸(cAMP)に構造的にも代謝的にも、生化学的メチル化剤であるS-アデノシル-L-メチオニン(SAM)に、ならびに補酵素であるNAD、FAD、および補酵素Aに構造的に、ならびにRNAに、関する。
アデノシン受容体は、生理学的「STOP」(終止機構)(これは免疫応答を限定し得、これによって種々の疾患の発症の間の過剰な免疫損傷から正常な組織を保護する)として作用することにより、in vivoでの炎症の下方調節において必須的役割(non-redundant role)を果たすことが本明細書に開示されている。
驚くべきことに、本発明に従うキノキサリン誘導体は、A2Aアデノシン受容体またはA2AおよびA2B両アデノシン受容体の有効性の高いインヒビターであり、同時にA1およびA3アデノシン受容体に対して高選択性を有し、よって本発明の化合物は、がんならびに感染性の疾患および障害などの、過剰増殖性の疾患および障害の処置のために使用され得ることが見出された。
Hal、または、
1~10個のC原子を有する直線状もしくは分枝状のアルキル、これらは、非置換であるか、またはR4によって単置換、二置換、もしくは三置換されており、かつ、1~4個のC原子は、相互に独立して、O、S、SO、SO2、NH、NCH3、-OCO-、-NHCONH-、-NHCO-、-NR5SO2R6-、-COO-、-CONH-、-NCH3CO-、-CONCH3-、-C≡C-基、および/または-CH=CH-基によって置き換えられていてもよいし、および/または、加えて、1~10個のH原子は、Fおよび/またはClによって置き換えられていてもよく、または、
3~7個のC原子を有する単環式もしくは二環式の環状アルキル、これらは、非置換であるか、またはR4によって単置換、二置換、もしくは三置換されており、かつ前記環状アルキル中、1~4個のC原子は、相互に独立して、O、S、SO、SO2、NH、NCH3、-OCO-、-NHCONH-、-NHCO-、-NR5SO2R6-、-COO-、-CONH-、-NCH3CO-、-CONCH3-、-C≡C-基、および/または-CH=CH-基によって置き換えられていてもよいし、および/または、加えて、1~10個のH原子は、Fおよび/またはClによって置き換えられていてもよく、または、
3~14個の炭素原子と0~4個のヘテロ原子(独立して、N、O、およびSから選択される)とを含有する単環式もしくは二環式のヘテロアリール、ヘテロシクリル、アリール、または環状アルキルアリール(これらは、非置換であるか、またはR4によって単置換、二置換、もしくは三置換されている)であり、
1~10個のC原子を有する直線状または分枝状のアルキルであって、これらは、非置換であるか、またはR4によって単置換、二置換、もしくは三置換されており、かつ前記アルキル中、1~4個のC原子は、相互に独立して、O、S、SO、SO2、NH、NCH3、-OCO-、-NHCONH-、-NHCO-、-NR5SO2R6-、-COO-、-CONH-、-NCH3CO-、-CONCH3-、-C≡C-基、および/または-CH=CH-基によって置き換えられていてもよいし、および/または、加えて、1~10個のH原子は、Fおよび/またはClによって置き換えられていてもよく、または、
3~7個のC原子を有する環状アルキルによって置き換えられていてもよく、前記環状アルキルは、非置換であるか、またはR4によって単置換、二置換、もしくは三置換されており、かつ前記環状アルキル中、1~4個のC原子は、相互に独立して、O、S、SO、SO2、NH、NCH3、-OCO-、-NHCONH-、-NHCO-、-NR5SO2R6-、-COO-、-CONH-、-NCH3CO-、-CONCH3-、-C≡C-基、および/または-CH=CH-基によって置き換えられていてもよいし、および/または、加えて、1~10個のH原子は、Fおよび/またはClによって置き換えられていてもよく、または、
3~14個の炭素原子と0~4個のヘテロ原子(独立して、N、O、およびSから選択される)とを含有する単環式もしくは二環式のヘテロアリール、ヘテロシクリル、アリール、または環状アルキルアリール(これらは、非置換であるか、またはR4によって単置換、二置換、もしくは三置換されている)であり、
H、R5、=S、=NR5、=O、OH、COOH、Hal、NH2、SO2CH3、SO2NH2、CN、CONH2、NHCOCH3、NHCONH2、NO2、または1~10個のC原子を有する直線状もしくは分枝状のアルキルであって、前記アルキルは、非置換であるか、またはR5によって単置換、二置換、もしくは三置換されており、かつ前記アルキル中、1~4個のC原子は、相互に独立して、O、S、SO、SO2、NH、NCH3、-OCO-、-NHCONH-、-NHCO-、-NR5SO2R6-、-COO-、-CONH-、-NCH3CO-、-CONCH3-、-C≡C-基、および/または-CH=CH-基によって置き換えられていてもよいし、および/または、加えて、1~10個のH原子は、Fおよび/またはClによって置き換えられていてもよく、または、
3~7個のC原子を有する単環式もしくは二環式の環状アルキルによって置き換えられていてもよく、前記環状アルキルは、非置換であるか、またはR5によって単置換、二置換、もしくは三置換されており、かつ前記環状アルキル中、1~4個のC原子は、相互に独立して、O、S、SO、SO2、NH、NCH3、-OCO-、-NHCONH-、-NHCO-、-NRSO2R4-、-COO-、-CONH-、-NCH3CO-、-CONCH3-、-C≡C-基、および/または-CH=CH-基によって置き換えられていてもよいし、および/または、加えて、1~10個のH原子は、Fおよび/またはClによって置き換えられていてもよく、または、
3~14個の炭素原子と0~4個のヘテロ原子(独立して、N、O、およびSから選択される)とを含有する単環式もしくは二環式のヘテロアリール、ヘテロシクリル、アリール、または環状アルキルアリール(これらは、非置換であるか、またはR5によって単置換、二置換、もしくは三置換されている)であり、
Halは、F、Cl、Br、またはIであり、
で表されるキノキサリン誘導体、ならびにその生理学的に許容し得る塩、誘導体、溶媒和物、プロドラッグ、および立体異性体、ならびにあらゆる比率におけるそれらの混合物に関する。
R1 は、
1~10個のC原子を有する直線状または分枝状のアルキルであり、ここで、非置換であるか、またはR4によって単置換、二置換、もしくは三置換されており、かつ前記アルキル中、1~4個のC原子は、相互に独立して、O、S、SO、SO2、NH、NCH3、-OCO-、-NHCONH-、-NHCO-、-NR5SO2R6-、-COO-、-CONH-、-NCH3CO-、-CONCH3-、-C≡C-基、および/または-CH=CH-基によって置き換えられていてもよいし、および/または、加えて、1~10個のH原子は、Fおよび/またはClによって置き換えられていてもよい、または、
以下の構造体:
かつ式中Q、Y、R2、R3、R4、R5、およびR6は、上に開示されたとおりの意味を有する、
で表される化合物に関する。
Qは、CHまたはNであり、
Yは、CHであり、
かつ式中R1、R2、R3、R4、R5、およびR6は、請求項1に開示されたとおりの意味を有する、
で表される化合物、ならびにその生理学的に許容し得る塩、誘導体、溶媒和物、プロドラッグ、および立体異性体、ならびにあらゆる比率におけるそれらの混合物に関する。
の1つであり、前記構造体は、非置換であるか、またはR5で単置換、二置換、もしくは三置換されており、
かつ式中Q、Y、R2、R3、R4、R5、およびR6は、上に開示されたとおりの意味を有する、
で表される化合物に関する。
R3は、非置換であるか、またはFで単置換、二置換、もしくは三置換されている、1~6個のC原子を有するO-アルキルであり、
かつQ、Y、R1、R2、R4、R5、およびR6は、上に開示されたとおりの意味を有する、
で表される化合物に関する。
R3は、OMeであり、
かつQ、Y、R1、R2、R4、R5、およびR6は、上に開示されたとおりの意味を有する、
で表される化合物に関する。
O-アルキルまたはOAは、1~6個のC原子を有する直線状または分枝状のアルコキシルを示し、好ましくはメトキシルであり、さらにまた、例としてエトキシル、n-プロポキシル、イソプロポキシル、n-ブトキシル、イソブトキシル、sec-ブトキシル、またはtert-ブトキシルでもある。
アルキルカルボニルは、直鎖または分枝の鎖アルキルおよびカルボン酸基を指す。
などにおいて置き換えられていてもよい。
Boc ter-ブトキシカルボニル
CBZ ベンズイルオキシカルボニル
DNP 2,4-ジニトロフェニル
FMOC 9-フルオレニルメトキシカルボニル
imi-DNP イミダゾール環の1位における2,4-ジニトロフェニル
OMe メチルエステル
POA フェノキシアセチル
DCCI ジシクロヘキシルカルボジイミド
HOBt 1-ヒドロキシベンゾトリアゾール
加えて、本発明は、少なくとも1種のさらなる医薬活性化合物を含む、本発明に従う上の医薬調製物に関する。
一般式Iで表される化合物は、一般式Iで表される化合物のすべての立体異性体、鏡像異性体、ジアステレオマー等々もまた、本発明においてクレームされるように、1以上のキラル中心を含有していてもよい。
e)式Iで表される化合物の酸は、塩基での処置によって変換されて、その塩の1つになること
を特徴とする、式Iで表される化合物の調製のためのプロセスに関する。
出発材料または出発化合物は、一般に知られている。それらが新規である場合、それらは、それ自体知られている方法で調製され得る。
出発材料として使用されるべき式Iで表される化合物の官能性誘導体は、例えば当該標準的な著作物および特許出願に記載されるとおり、アミノ酸およびペプチド合成の知られている方法によって調製され得る。
A2AおよびA2Bなどのアデノシン受容体が、炎症の間に免疫応答を下方調節し、かつ免疫損傷から組織を保護することが示されたところ、アデノシン受容体を通したシグナリングの阻害は、免疫応答を強めかつ延ばすために使用され得る。
用語「医薬製剤」および「医薬調製物」は、本発明の目的上、同義語として使用される。
a)有効量の、式Iで表される化合物、および/またはその薬学的に使用可能な塩、誘導体、溶媒和物、プロドラッグ、および立体異性体、ならびにあらゆる比率におけるそれらの混合物と、
b)有効量のさらなる医薬活性化合物と
の個別のパックからなる、セット(キット)に関する。
(vii)アンチセンス治療、例えばISIS 2503、抗Rasアンチセンスなどの、上に言及された標的に向けられたもの;
AUC 血漿薬物濃度-時間曲線下免疫
Cmax 最大血漿濃度
CL クリアランス
CV 変動係数
CYP シトクロムP450
DMSO ジメチルスルホキシド
F バイオアベイラビリティ
fa 吸収率
iv 静脈内
LC-MS/MS 液体クロマトグラフィータンデム質量分析
LLOQ 定量下限
NC 計算されていない
ND 決定されていない
PEG ポリエチレングリコール
Pgp 透過性(Permeability)糖タンパク質
PK 薬物動態の(または薬物動態)
po Per os(経口の)
t1/2 半減期
tmax 薬物の最大血漿濃度に達した時間
UPLC 超高性能液体クロマトグラフィー
Vss 分布容積(定常状態での)
v/v 体積に対する体積
本発明はとくに、表2の化合物、ならびにその生理学的に許容し得る塩、誘導体、溶媒和物、プロドラッグ、および立体異性体、ならびにあらゆる比率におけるそれらの混合物に関する。
使用されたすべての溶媒は市販されており、さらなる精製はせずに使用した。反応は典型的には、窒素の不活性雰囲気下で無水溶媒を使用して行った。フラッシュカラムクロマトグラフィーは一般に、Silica gel 60(0.035~0.070mm粒子サイズ)を使用して実行した。
a. 1-ブロモ-4-メトキシ-2,3-ジニトロ-ベンゼン
250mL三ツ口丸底フラスコ中へ、硫酸(100ml)中1-ブロモ-4-メトキシ-2-ニトロベンゼン(50.0g、205mmol)を入れた。硝酸(24ml、530mmol)を0℃にて撹拌しながら滴加した。溶液を室温にて1h撹拌し、1000mlの氷水でクエンチした。溶液を1000mlの酢酸エチルで2度抽出し、合わせた有機層を無水硫酸ナトリウム上で乾燥、濃縮乾固させた。粗材料を酢酸エチル/ヘキサン(2:3)から再結晶させることで、20.0g(32%)の1-ブロモ-4-メトキシ-2,3-ジニトロベンゼンが黄色固体としてもたらされた。融点:150~153℃。1H NMR (400 MHz, DMSO-d6) ppm = 8.19 (d, J = 9.3 Hz, 1H), 7.70 (d, J = 9.3 Hz, 1H), 4.02 (s, 3H)。HPLC/MS(純度) 91%。Rt 1.73min(方法A)。[M+H]+ 276.8、278.9。
b. 4-(4-メトキシ-2,3-ジニトロ-フェニル)-3,6-ジヒドロ-2H-ピラン
アルゴンの不活性雰囲気でパージかつ維持された350mL圧力タンク反応器中へ、1-ブロモ-4-メトキシ-2,3-ジニトロベンゼン、91%(15.7g、51.4mmol)、2-(3,6-ジヒドロ-2H-ピラン-4-イル)-4,4,5,5-テトラメチル-1,3,2-ジオキサボロラン、95%(13.7g、61.7mmol)、Pd(dppf)Cl2ジクロロメタン錯体、95%(4.42g、5.14mmol)、炭酸カリウム(8.53g、61.7mmol、水(12ml)に溶解されている)、エタノール(31.6ml)、およびトルエン(316ml)を入れた。混合物を100℃にて1h撹拌し、室温まで冷却して、真空下で濃縮乾固させた。残渣をカラムクロマトグラフィー(酢酸エチル/石油エーテル:1/1)によって精製することで、13.0g(86%)の4-(4-メトキシ-2,3-ジニトロフェニル)-3,6-ジヒドロ-2H-ピランがオレンジ色固体として生産された。HPLC/MS(純度) 95%。Rt 1.17min(方法B)。[M+あH]+ 281.2。
250ml丸底フラスコ中へ、パラジウム/炭素、10%(4.00g、3.76mmol)、メタノール(100ml)、および4-(4-メトキシ-2,3-ジニトロフェニル)-3,6-ジヒドロ-2H-ピラン、95%(10.5g、33.9mmol)を入れた。混合物を水素雰囲気下35℃にて15h撹拌した。固体を濾別して捨てた。濾過物を蒸発乾固させ、残渣をカラムクロマトグラフィー(酢酸エチル/ヘキサン、70/30)によって精製することで、4.51g(58%)の3-メトキシ-6-(オキサン-4-イル)ベンゼン-1,2-ジアミンが黄色固体として生産された。融点:116~117℃。1H NMR (400 MHz, クロロホルム-d) 6.67 (d, J = 8.5 Hz, 1H), 6.45 (d, J = 8.5 Hz, 1H), 4.18 -4.09 (m, 2H), 3.86 (s, 3H), 3.65 -3.53 (m, 2H), 3.46(s, 4H), 2.82 -2.64 (m, 1H), 1.93 -1.73 (m, 4H)。HPLC/MS(純度) 97%。Rt 1.01min(方法C)。[M+H]+ 223.1。
d. 8-メトキシ-5-(テトラヒドロ-ピラン-4-イル)-1H-キノリン-2-オン
3-メトキシ-6-(テトラヒドロ-ピラン-4-イル)-ベンゼン-1,2-ジアミン、97%(3.41g、15.8mmol)をメタノール(80ml)中に溶解し、グリオキシル酸エチル、トルエン中50%溶液(9.64ml、94.7mmol)を加えて、混合物を80℃にて2h撹拌した。反応混合物を蒸発乾固させ、粗材料を酢酸エチルで粉砕した。形成された固体を濾別してフラッシュクロマトグラフィー(酢酸エチル/シクロヘキサン、勾配)によって精製することで、1.62g(31%)の無色固体が生産された。HPLC/MS(純度) 80%。Rt 1.79min(方法D)。[M+H]+ 261.1。
e. 2-クロロ-8-メトキシ-5-(テトラヒドロ-ピラン-4-イル)-キノキサリン
8-メトキシ-5-(テトラヒドロ-ピラン-4-イル)-1H-キノリン-2-オン、80%(1.62g、4.98mmol)を室温にて塩化ホスホリル(27.1g、177mmol)に溶解し、混合物を105℃にて3h撹拌した。室温まで冷却後、混合物を飽和水性NaHCO3溶液とジクロロメタンとの間で分配して、RTにてもう1h撹拌した。有機層を分離し、水性相をジクロロメタンで3回抽出した。合わせた有機層を硫酸ナトリウム上で乾燥させて濾過し、濾過物を蒸発乾固させることで、1.74g(100%)の標題化合物が黄色固体として与えられた。HPLC/MS(純度) 80%。Rt 2.36min(方法D)。[M+H]+ 279.1。
f. 8-メトキシ-5-(テトラヒドロ-ピラン-4-イル)-キノリン-2-イルアミン
高圧チューブ(high-pressure tube)中、2-クロロ-8-メトキシ-5-(テトラヒドロ-ピラン-4-イル)-キノキサリン、80%(1.74g、4.98mmol)をTHF(20ml)に溶解した。この混合物へ、水中アンモニア溶液、32%(60ml)およびヨウ化銅(I)(500mg、2.62mmol)を加え、管(vessel)に封をして、混合物を140℃にて4h撹拌した(max.21bar圧)。室温まで冷却後、混合物を蒸発乾固させてフラッシュクロマトグラフィー(酢酸エチル/シクロヘキサン、勾配)によって精製することで、1.00g(60%)の無色固体が生産された。HPLC/MS(純度) 79%。Rt 1.71min(方法D)。[M+H]+ 260.1。
g. N-[8-メトキシ-5-(オキサン-4-イル)キノリン-2-イル]-1-(2-メトキシエチル)-1H-ピラゾール-4-カルボキサミド
8-メトキシ-5-(テトラヒドロ-ピラン-4-イル)-キノリン-2-イルアミン、79%(100mg、0.305mmol)、1-(2-メトキシエチル)-1H-ピラゾール-4-カルボン酸(67.4mg、0.396mmol)、N-(3-ジメチルアミノプロピル)-N’-エチルカルボジイミド塩酸塩(75.9mg、0.396mmol、1-ヒドロキシベンゾトリアゾール水和物(53.5mg、0.396mmol)をN,N-ジメチルホルムアミド(5.00ml)に溶解した。N-エチルジイソプロピルアミン(0.13ml、0.762mmol)を室温にて加え、混合物を室温にて3日間撹拌した。反応混合物を蒸発乾固させ、アセトニトリル/水でのフラッシュクロマトグラフィーによって精製し、事前精製された画分をジクロロメタン/水でのフラッシュクロマトグラフィーによって再度精製することで、6.00mg(5%)の標題化合物がライトベージュ色固として生産された。1H NMR (500 MHz, DMSO-d6) ppm = 11.20 (s, 1H), 9.65 (s, 1H), 8.58 - 8.57 (m, 1H), 8.24 - 8.23 (m, 1H), 7.51 (d, J = 8.2 Hz, 1H), 7.24 (d, J = 8.2 Hz, 1H), 4.33 (t, J = 5.2 Hz, 2H), 4.02 - 3.97 (m, 2H), 3.96 (s, 3H), 3.96 - 3.90 (m, 1H), 3.72 (t, J = 5.2 Hz, 2H), 3.56 (td, J = 11.5, 2.5 Hz, 2H), 3.26 (s, 3H), 1.87 - 1.73 (m, 4H)。HPLC/MS(純度) 100%。Rt 2.26min(方法D)。[M+H]+ 272.1
h. 4-(4-メトキシ-2,3-ジニトロ-フェニル)ピリジン
アルゴンの不活性雰囲気でパージかつ維持された350mL圧力タンク反応器中へ、1-ブロモ-4-メトキシ-2,3-ジニトロベンゼン、95%(5.00g、17.2mmol)、4-(テトラメチル-1,3,2-ジオキサボロラン-2-イル)ピリジン、95%(4.44g、20.6mmol)、Pd(dppf)Cl2ジクロロメタン錯体、90%(1.56g、1.72mmol)、炭酸カリウム(2.99g、20.6mmol、水(2ml)に溶解されている)、エタノール(10ml)、およびトルエン(100ml)を入れた。混合物を100℃にて15h撹拌し、冷却後に蒸発乾固させた。残渣をカラムクロマトグラフィー(酢酸エチル/ヘキサン、80/20)によって精製することで、4.01g(81%)の4-(4-メトキシ-2,3-ジニトロフェニル)ピリジンが黄色固体として生産された。HPLC/MS(純度) 95%。Rt 0.90min(方法E)。[M+H]+ 276.1。
i. 3-メトキシ-6-ピリジン-4-イル-ベンゼン-1,2-ジアミン
250ml丸底フラスコ中へ、パラジウム/炭素、10%(2.13g、19.9mmol)、メタノール(60ml)、および4-(4-メトキシ-2,3-ジニトロフェニル)ピリジン、95%(4.00g、13.8mmol)を入れた。混合物を水素雰囲気下RTにて15h撹拌した。固体を濾別して捨てた。濾過物を蒸発乾固させ、残渣をカラムクロマトグラフィー(酢酸エチル/MeOH、95/5)によって精製することで、2.0g(52%)の3-メトキシ-6-(ピリジン-4-イル)ベンゼン-1,2-ジアミンが黄色固体として生産された。1H NMR (400 MHz, DMSO-d6) 8.57 (d, J = 1.7 Hz, 2H), 7.42 (d, J = 1.7 Hz, 2H), 6.46 (d, J = 8.4 Hz, 2H), 4.33 (s, 4H), 3.78 (s, 3H)。融点:165~166℃。HPLC/MS(純度) 91%。Rt 0.64min(方法A)。[M+H]+ 216.0。
3-メトキシ-6-ピリジン-4-イル-ベンゼン-1,2-ジアミン、91%(1.77g、7.48mmol)、および3-メトキシ-6-ピリジン-4-イル-ベンゼン-1,2-ジアミン、93%(2.00g、8.64mmol)をメタノール(80ml)に溶解させ、次いでグリオキシル酸エチル、トルエン中50%溶液(9.85mL、96.7mmol)を室温にて加え、反応混合物を80℃にて3h撹拌した。混合物を蒸発乾固させ、残渣を酢酸エチルで粉砕することで沈殿物が与えられ、これを濾過後、フラッシュクロマトグラフィー(ジクロロメタン/エタノール、勾配)によってさらに精製することで、1.80g(44%)の標題化合物が無色固体として生産された。HPLC/MS(純度) 100%。Rt 1.43min(方法D)。[M+H]+ 254.1。
8-メトキシ-5-ピリジン-4-イル-1H-キノリン-2-オン(1,800g、7,107mmol)を室温にて塩化ホスホリル(32.7g、213mmol)に溶解し、混合物を105℃にて3h撹拌した。室温まで冷却後、混合物を飽和水性NaHCO3溶液とジクロロメタンとの間で分配し、RTにてもう1h撹拌した。沈殿物を濾別することで、870mg(34%)の標題化合物が黄色固体として与えられた。HPLC/MS(純度) 75%。Rt 1.89min(方法D)。[M+H]+ 254.1。
高圧チューブ中、2-クロロ-8-メトキシ-5-ピリジン-4-イル-キノキサリン、75%(870mg、2.40mmol)をTHF(20ml)に溶解した。この混合物へ、水中アンモニア溶液、32%(50ml)、およびヨウ化銅(I)(229mg、1.20mmol)を加え、管に封をし、混合物を140℃にて5h撹拌した(max.21bar圧)。室温まで冷却後、混合物を蒸発乾固させ、フラッシュクロマトグラフィー(酢酸エチル/シクロヘキサン、勾配)によって精製することで、140mg(23%)の無色固体が生産された。HPLC/MS(純度) 100%。Rt 1.33min(方法D)。[M+H]+ 253.1。
m. 4-ヒドロキシ-N-[8-メトキシ-5-(ピリジン-4-イル)キノリン-2-イル]-4-メチルピペリジン-1-カルボキサミド
8-メトキシ-5-ピリジン-4-イル-キノリン-2-イルアミン(140mg、0.555mmol)および1,1’-カルボニルdiイミダゾール(117mg、0.721mmol)をジクロロメタン(4ml)に懸濁し、70℃にて20h撹拌した。次いで4-メチルピペリジン-4-オール(83.1mg、0.721mmol)を70℃に手加え、混合物を70℃にてもう3h撹拌した。反応混合物を蒸発乾固させ、フラッシュクロマトグラフィー(水/アセトニトリル、勾配)によって直接精製した。数滴の1N HCl溶液を、生成物を含有するウェルへ加えることで、蒸発乾固後の21.0mg(9%)の塩酸塩の塩の標題化合物が黄色固体として生産された。1H NMR (500 MHz, DMSO-d6) ppm = 10.14 (s, 1H), 9.30 (s, 1H), 8.97 - 8.94 (m, 2H), 8.42 - 8.39 (m, 2H), 7.97 (d, J = 8.3 Hz, 1H), 7.43 (d, J = 8.4 Hz, 1H), 4.06 (s, 3H), 3.82 (dt, J = 13.4, 4.3 Hz, 2H), 3.34 - 3.26 (m, 2H), 1.54 - 1.44 (m, 4H), 1.16 (s, 3H)。HPLC/MS(純度) 100%。Rt 1.76min(方法D)。[M+H]+ 394.2。
n. 5-ブロモ-2-メトキシ-3-ニトロピリジン-4-アミン
発煙硝酸(109ml)と濃硫酸(160mL)との混合物を、0℃にて撹拌しながら、5-ブロモ-2-メトキシピリジン-4-アミン(36.00g、177mmol)を含有する丸底フラスコへ滴加した。混合物を室温にて12h撹拌し、氷水(400ml)でクエンチした。混合物をDCMで抽出した(4回、各500mlで)。有機相を合わせてブラインで洗浄し、無水Na2SO4上で乾燥させて濾過した。濾過物を減圧下で濃縮し、残渣をフラッシュクロマトグラフィー(EtOAc/石油エーテル、勾配)によって精製することで、5-ブロモ-2-メトキシ-3-ニトロピリジン-4-アミンが黄色固体(5.54g、13%)として生産された。MS: m/z = 249.8 [M+H]+。1H NMR (300 MHz, DMSO-d6) δ 8.11 (s, 1 H), 7.14 (s, 1 H), 3.88 (s, 3 H)。
ジオキサン(174ml)中5-ブロモ-2-メトキシ-3-ニトロピリジン-4-アミン(4.95g、20.0mmol)の溶液へ、フェニルボロン酸(2.48g、20.4mmol)、Pd(dppf)Cl2CH2Cl2(652mg、0.80mmol)、炭酸カリウム(5.92g、42.9mmol)、および水(37ml)を室温にて加えた。窒素を混合物中へ5分間通気させた後、混合物を80℃にて16h撹拌した。固体を濾別した。濾過物を減圧下で濃縮し、残渣をフラッシュクロマトグラフィー(EtOAc/石油エーテル、勾配)によって精製することで、2-メトキシ-3-ニトロ-5-フェニルピリジン-4-アミンが黄色固体(3.96g、81%)として生産された。MS: m/z = 246.3 [M+H]+。
MeOH(138ml)中2-メトキシ-3-ニトロ-5-フェニルピリジン-4-アミン(3.96g、16.2mmol)の溶液へ、パラジウム/炭素、10%(515mg、4.84mmol)を入れた。混合物をH2雰囲気下で室温にて16h撹拌した。反応が終わったとき、固体を濾別した。濾過物を真空下で濃縮することで、2-メトキシ-5-フェニルピリジン-3,4-ジアミンが黄色固体(3.37g、97%)として生産された。MS: m/z = 216.3 [M+H]+。
メタノール(181ml)中2-メトキシ-5-フェニルピリジン-3,4-ジアミン(3.37g、15.6mmol)の溶液へ、2-オキソ酢酸エチル(10.86g、106mmol)を室温にて加えた。混合物を80℃にて3h撹拌した。室温まで冷却後それを減圧下で濃縮し、残渣をフラッシュクロマトグラフィー(EtOAc/石油エーテル、勾配)によって精製した。2つの位置異性体を回収し、第1画分を黄色固体としての5-メトキシ-8-フェニルピリド[3,4-b]ピラジン-3-オール(750mg、19%)として同定した。MS: m/z = 254.0 [M+H]+。
ジクロロメタン(24ml)中5-メトキシ-8-フェニルピリド[3,4-b]ピラジン-3-オール(750mg、2.97mmol)の溶液へ、4-メチルベンゼン-1-スルホニル塩化物(616mg、3.25mmol)、4-ジメチルアミノピリジン(39mg、0.28mmol)、およびトリエチルアミン(414mg、4.14mmol)を室温にて加えた。溶液を室温にて2h撹拌し、次いで水(50ml)でクエンチした。混合物をジクロロメタンで抽出し(150mlで3回)、有機相を合わせてブラインで洗浄し、無水Na2SO4上で乾燥させた。溶媒を減圧下で除去し、残渣をフラッシュクロマトグラフィー(EtOAc/石油エーテル、勾配)によって精製することで、5-メトキシ-8-フェニルピリド[3,4-b]ピラジン-3-イル4-メチルベンゼン-1-スルホナートが緑色固体(806mg、67%)として生産された。MS: m/z = 408.2 [M+H]+。
ジオキサン(85ml)中5-メトキシ-8-フェニルピリド[3,4-b]ピラジン-3-イル4-メチルベンゼン-1-スルホナート(806mg、1.97mmol)の溶液へ、カルバミン酸tert-ブチル(463mg、3.94mmol)、Pd(OAc)2(47mg、0.2mmol)、XPhos(198mg、0.39mmol)、およびCs2CO3(966mg、2.97mmol)を加えた。窒素を混合物中へ5分間通気させた後、混合物を100℃にて16h撹拌した。反応が終わったとき、固体を濾別した。濾過物を減圧下で濃縮し、残渣をフラッシュクロマトグラフィー(EtOAc/石油エーテル、勾配)によって精製することで、5-メトキシ-8-フェニルピリド[3,4-b]ピラジン-3-アミンが黒色固体(185mg、37%)として生産された。MS: m/z = 253.3 [M+H]+。
THF(50ml)中5-メトキシ-8-フェニルピリド[3,4-b]ピラジン-3-アミン(120mg、0.48mmol)の溶液へ、炭酸ナトリウム(252mg、2.38mmol)、クロロギ酸フェニル(744mg、4.76mmol)、およびピリジン(188mg、2.38mmol)を室温にて加えた。混合物を50℃にて6h撹拌した。反応が終わったとき、固体を濾別した。濾過物を減圧下で濃縮することで、フェニルN-[5-メトキシ-8-フェニルピリド[3,4-b]ピラジン-3-イル]カルバマートが白色固体(300mg、粗)として生産された。MS: m/z = 373.2 [M+H]+。
THF(10ml)中フェニルN-[5-メトキシ-8-フェニルピリド[3,4-b]ピラジン-3-イル]カルバマート(100mg、粗)の溶液へ、4-メチルピペリジン-4-オール(31mg、0.27mmol)、およびジイソプロピルエチルアミン(34.0mg、0.27mmol)を室温にて加えた。溶液を60℃にて12h撹拌した。室温まで冷却後、反応を水(20ml)の添加によってクエンチした。混合物をDCMで抽出した(50mlで3回)。有機相を合わせてブラインで洗浄し、無水Na2SO4上で乾燥させて濾過した。濾過物を減圧下で濃縮し、残渣を以下:カラム、XBridge Prep C18 OBDカラム、19 x 150mm 5um;8minまでに水中MeCN(10mmol/l NH4HCO3+0.1% NH3.H2Oをもつ)、30%~50%勾配;検出器、UV254/220nmの条件下、分取HPLCによって精製することで、4-ヒドロキシ-N-[5-メトキシ-8-フェニルピリド[3,4-b]ピラジン-3-イル]-4-メチルピペリジン-1-カルボキサミドが黄色固体(30.0mg、2ステップで47%)として生産された。HPLC:99.3%純度、室温=4.14min。MS: m/z = 394.3 [M+H]+。1H NMR (400 MHz, DMSO-d6) δ 10.22 (s, 1 H), 9.38 (s, 1 H), 8.19 (s, 1 H), 7.68-7.60 (m, 2 H), 7.54-7.38 (m, 3 H), 4.37 (s, 1 H), 4.10 (s, 3 H), 3.87-3.76 (m, 2 H), 3.34-3.24 (m, 2 H), 1.56-1.42 (m, 4 H), 1.16 (s, 3 H)。
方法A:
Shimadzu LCMS-2020;カラム:Poroshell HPH-C18、3.0x50 mm、2.7 μm;移動相A:水/5mM NH4HCO3、移動相B:アセトニトリル;流速:1.0mL/min;勾配:2.2分までに10% B~95% B、1.0分保つ;波長:254nm
Shimadzu LCMS-2020;カラム:Poroshell HPH-C18、3.0x50 mm、2.7 μm;移動相A:水/5mM NH4HCO3、移動相B:アセトニトリル;流速:1.3mL/min;勾配:2.1分までに10% B~95% B、0.6分保つ;波長:254nm
Shimadzu LCMS-2020;カラム:Shim-pack XR-ODS、3.0x50 mm、2.2 μm;移動相A:水/0.05% TFA、移動相B:アセトニトリル/0.05% TFA;流速:1.2mL/min;勾配:2.2分までに5% B~100% B、1.0分保つ;波長:254nm
Agilent Technologies 1200シリーズ;カラム:Chromolith Performance RP18e;100 x 3 mm;移動相AA:水/0.1% TFA、移動相B:アセトニトリル/0.1% TFA;勾配:0.2分間1% B、3.8分までに1% B~100% B、0.4分保つ;流速:2mL/min、波長:220nm
Shimadzu LCMS-2020;カラム:Shim-pack XR-ODS、3.0x50 mm、2.2 μm;移動相A:水/0.05% TFA、移動相B:アセトニトリル/0.05% TFA;流速:1.2mL/min;勾配:2.0分までに5% B~100% B、0.5分保つ;波長254nm
ヒトA2A、A2B、A1、およびA3受容体の機能活性を、アデノシン受容体の第2メッセンジャーであるcAMPの定量化によって決定した。
この目的のために、ヒトA2AまたはA2B受容体(ともにGs共役)のいずれかを発現する組み換えHEK293細胞を394ウェルマイクロタイタープレート中へ播種し、試験化合物およびアゴニスト(NECA)を加えた。15minのインキュベーション後、HTRF試薬(cAMP dynamic 2、Cis Bio)を加え、細胞cAMPレベルを、ENVISION(Perkin Elmer)プレートリーダーを使用して決定した。
細胞を384ウェルプレート中へ播種し、フォルスコリン、試験化合物、およびアゴニスト(A1受容体にはCPA、A3受容体にはIB-MECA)を加えた。30minのインキュベーション後、HTRF試薬(cAMP dynamic 2、Cis Bio)を加え、細胞cAMPレベルをENVISION(Perkin Elmer)プレートリーダーを使用して決定した。
得られた生データをインヒビター対照および中性対照(DMSO)に対して正規化し、正規化データを、GeneDataソフトウェアを使用してフィッティングした。
内在性のGs共役ヒトA2A受容体の機能的活性を、この受容体が高度に発現されているT細胞において測定した。受容体活性の決定を、アデノシン受容体の第2メッセンジャーであるcAMPの定量化によって行った。
本研究の目的は、本発明の化合物の単回の静脈内および経口投与後のメスのウィスター系ラット/マウスにおける薬物動態特性に関する情報を得ることであった。
動物実験(生存相(In-life phase))
メスのウィスター系ラット/マウス(n=6)には、試験化合物の単回の静脈内(ボーラス)注射または経口投与(強制飼養による)のいずれかを受けさせた。0.2および10mg/kg(化合物あたり)の用量を夫々、静脈内および経口(per os)で、iv投与にはDMSO(0.2%)/PEG 200(40%)/水の溶液として、経口投薬には水中Methocel(0.5%)/Tween 20(0.25%)の懸濁液として、与えた。連続的な血液試料を、0.1(ivのみ)、0.25(poのみ)、0.5、1、2、4、6、および24h後、投与ルートあたり3匹の動物の舌下からイソフルレン吸入下で採取し、さらに処理することで血漿が得られた。また、投与ルートあたり3匹のラットの尿および糞試料も0~24hの時間間隔にわたり収集し、分析のためにプールした。
血漿、糞中の化合物濃度を、「Institute of Drug Metabolism and Pharmacokinetics」にて先に開発されたタンデム質量分析検出(LC-MS/MS)とともにUPLC方法を使用して定量化した。LC-MS/MS系は、AB Sciex質量分析計API 5500 Q-trapと連動されたWaters Acquity UPLCからなった。UPLC分離を、溶離液として0.1% ギ酸およびアセトニトリルをもつ移動相の勾配を使用する逆相カラム(HSS T3、1.8μM、2.1×50mm)上で実行した。化合物の検出を、陽イオン化モードにおける複数の反応モニタリングを使用して実施した。血漿試料を内部標準(20μl)でスパイクし(spiked)、アナライトを、三級ブチルメチルエーテル(tBME)を使用してマトリックスから抽出した。有機相を窒素流の下で蒸発乾固させた。残渣をLC-MS/MS分析のためにアセトニトリル/0.1% ギ酸に溶解させた。糞試料をその4倍体積のエタノール/水混合物(4:1、v/v)でホモジナイズした。水性エタノール抽出物のアリコートを内部標準でスパイクし、アセトニトリル/水(1:1、v/v)で希釈し、LC-MS/MS系中へ直接注入した。
薬物動態パラメータCmaxおよびtmaxを得られたデータから取得した。曲線下面積(AUC)、クリアランス(CL)、体積(V)、半減期(t1/2)、F、およびすべての用量-正規化値を、特注のソフトウェア「DDS-TOX」を使用して算出した。「DDS-TOX」値を数種の化合物について評価し、確証がある(validated)ソフトウェアWinNonLinによって与えられた値と匹敵することが示された。AUC値を、線形アップ/対数ダウン(linear up/log down)方法を使用する非コンパートメント分析によって算出した。平均血漿濃度および誘導された薬物動態パラメータの数値データを、提示用に有効数字3桁に丸めた。経口バイオアベイラビリティおよび排出データ-用量の%として表現される-は、有効数字2桁を使用して表示する。
背景:
腫瘍微小環境中のアデノシン(Ado)は、A2A受容体を通したシグナリングによってT細胞活性を阻害し得、かつT細胞によるサイトカイン分泌を抑制し得る。CGS-21680等のA2A特異的アゴニストも、T細胞サイトカイン分泌のin vitroおよびin vivoでの阻害という同じような働きをする。強力な潜在的A2AアンタゴニストまたはA2A/A2B二重アンタゴニストは、この阻害からT細胞をレスキューし得る。本明細書中、我々は、マウス脾臓からの汎T細胞を使用して潜在的なA2AアンタゴニストまたはA2A/A2B二重アンタゴニストをこれらの活性に関しスクリーニングするという我々が確立したin vitro系を記載する。記載された方法は、T細胞サイトカイン産生の増強作用を評価するために、潜在的なA2AまたはA2A/A2B二重アンタゴニストと共にA2Aアゴニストを添加することと組み合わせて、マウス脾細胞から精製された汎T細胞を刺激する、CD3/CD28が予めコーティングされたビーズの使用を伴う。
簡潔には、マウス汎T細胞を、製造業者のプロトコルに従い汎T細胞単離キットMouse II(MACS Miltenyi biotech Cat# Order no. 130-095-130)を使用して、BALB/cマウスの脾臓から精製する。精製されたT細胞を、10%加熱不活性化ウシ胎仔血清をもつRPMI培地中、Nunc(商標)96ウェルポリスチレン丸底マイクロウェルプレートに播種する。細胞を、CD3/CD28で予めコーティングされたビーズ(Dynabeads(商標)Mouse T-Activator CD3/CD28;Cat# 11456D)で活性化する前に37℃にて1h休ませる。30min後、細胞を、試験アンタゴニスト(単数または複数)の用量を変動させて処置する。細胞を、A2AアゴニストであるCGS-21680(1μM)または中性対照(DMSO)で処置する前に、37℃にて30min追加してインキュベートする。24hインキュベーション後に上清中のIL-2レベルを、48hインキュベーション後に上清中のIFN-γレベルを、製造業者のプロトコルに従いELISA(R&D systems Cat# DY402 (IL-2);DY485 (IFN-γ))によって測定する。濃度を算出したら、DMSO対照とアゴニスト単独対照とのサイトカイン濃度の差を算出し(Δと呼ぶ)、各濃度のアンタゴニストによるレスキューのパーセンテージを、Microsoft Excelを使用することによって算出する。アンタゴニストの用量依存的なサイトカインレスキューのこれらパーセンテージをGraphPad PrismソフトウェアでプロットしてIC50を算出する。
2回蒸留(bidistilled)した水中100gの本発明の化合物および5gのリン酸水素二ナトリウムの溶液を、2N 塩酸を使用してpH6.5へ調整し、滅菌条件下で濾過し、注射バイアル中へ移し、滅菌条件下で凍結乾燥させて、滅菌条件下で密封する。各注射バイアルは5mgの本発明の化合物を含有する。
溶液を、940mlの2回蒸留した水中1gの本発明の化合物、9.38gのNaH2PO4・2H2O、28.48gのNa2HPO4・12H2O、および0.1gの塩化ベンザルコニウムから調製する。pHを6.8へ調整し、溶液を最大1lにし、放射線によって滅菌する。
60lの2回蒸留した水中1kgの本発明の化合物の溶液を、滅菌条件下で濾過し、アンプル中へ移し、滅菌条件下で凍結乾燥させて、滅菌条件下で密封する。各アンプルは10mgの本発明の化合物を含有する。
Claims (16)
- 式I、
Qは、CHまたはNであり、
Yは、CHであり、
R1は、以下の構造体:
前記構造体は、非置換であるか、またはR 4 で単置換、二置換、もしくは三置換されており、
R2は、以下の構造体:
前記構造体は、非置換であるか、またはR 5 で単置換、二置換、もしくは三置換されており、
R3は、以下の構造体:
R4は、
H、R5、=S、=NR5、=O、OH、COOH、Hal、NH2、SO2CH3、SO2NH2、CN、CONH2、NHCOCH3、NHCONH2、NO2、または1~10個のC原子を有する直線状もしくは分枝状のアルキルであって、前記アルキルは、非置換であるか、またはR5によって単置換、二置換、もしくは三置換されており、かつ前記アルキル中、1~4個のC原子は、相互に独立して、O、S、SO、SO2、NH、NCH3、-OCO-、-NHCONH-、-NHCO-、-NR5SO2R6-、-COO-、-CONH-、-NCH3CO-、-CONCH3-、-C≡C-基、および/または-CH=CH-基によって置き換えられていてもよいし、および/または、加えて、1~10個のH原子は、Fおよび/またはClによって置き換えられていてもよく、または、
3~7個のC原子を有する単環式もしくは二環式の環状アルキルによって置き換えられていてもよく、前記環状アルキルは、非置換であるか、またはR5によって単置換、二置換、もしくは三置換されており、かつ前記環状アルキル中、1~4個のC原子は、相互に独立して、O、S、SO、SO2、NH、NCH3、-OCO-、-NHCONH-、-NHCO-、-NRSO2R4-、-COO-、-CONH-、-NCH3CO-、-CONCH3-、-C≡C-基、および/または-CH=CH-基によって置き換えられていてもよいし、および/または、加えて、1~10個のH原子は、Fおよび/またはClによって置き換えられていてもよく、または、
3~14個の炭素原子と0~4個のヘテロ原子(独立して、N、O、およびSから選択される)とを含有する単環式もしくは二環式のヘテロアリール、ヘテロシクリル、アリール、または環状アルキルアリール(これらは、非置換であるか、またはR5によって単置換、二置換、もしくは三置換されている)であり、
R5、R6は、相互に独立して、H、=S、=NH、=O、OH、COOH、Hal、NH2、SO2CH3、SO2NH2、CN、CONH2、NHCOCH3、NHCONH2、NO2、および1~10個のC原子を有する直線状または分枝状のアルキルからなる群から選択されるが、前記アルキル中、1~4個のC原子は、相互に独立して、O、S、SO、SO2、NH、NCH3、-OCO-、-NHCONH-、-NHCO-、-COO-、-CONH-、-NCH3CO-、-CONCH3-、-C≡C-基、および/または-CH=CH-基によって置き換えられていてもよいし、および/または、加えて、1~10個のH原子は、Fおよび/またはClによって置き換えられていてもよく、
Halは、F、Cl、Br、またはIである、
で表される化合物、ならびにその生理学的に許容し得る塩、溶媒和物、および立体異性体、ならびにあらゆる比率におけるそれらの混合物。 - 式中R3が、OMeであり、
かつQ、Y、R1、R2、R4、R5、およびR6が、請求項1に開示されたとおりの意味を有する、
請求項1に記載の化合物、ならびにその生理学的に許容し得る塩、溶媒和物、および立体異性体、ならびにあらゆる比率におけるそれらの混合物。 -
d)式Iで表される化合物の塩基が、酸での処置によって変換されて、その塩の1つになること、あるいは
e)式Iで表される化合物の酸が、塩基での処置によって変換されて、その塩の1つになること
を特徴とする、請求項1に記載の式Iで表される化合物の調製のためのプロセス。 - アデノシンA2Aおよび/またはA2B受容体インヒビターとしての、請求項1~3のいずれか一項に記載の化合物、ならびにその生理学的に許容し得る塩、溶媒和物、および立体異性体、ならびにあらゆる比率におけるそれらの混合物。
- 請求項1~3のいずれか一項に記載の少なくとも1つの化合物、および/またはその生理学的に許容し得る塩、溶媒和物、および立体異性体、ならびにあらゆる比率におけるそれらの混合物を含む、医薬調製物。
- 賦形剤および/またはアジュバントをさらに含む、請求項6に記載の医薬調製物。
- 請求項1~3のいずれか一項に記載の少なくとも1つの化合物、および/またはその生理学的に許容し得る塩、溶媒和物、および立体異性体、ならびにあらゆる比率におけるそれらの混合物と、および少なくとも1つのさらなる医薬活性化合物とを含む、医薬調製物。
- 請求項1~3のいずれか一項に記載の化合物、および/またはその生理学的に許容し得る塩、溶媒和物、および立体異性体の1つ、ならびにあらゆる比率におけるそれらの混合物が、固体、液体、もしくは半液体の賦形剤またはアジュバントと一緒に好適な剤形にさせられることを特徴とする、医薬調製物の調製のためのプロセス。
- 請求項1~3のいずれか一項に記載の少なくとも1つの化合物、および/またはその生理学的に許容し得る塩、溶媒和物、および立体異性体の1つ、ならびにあらゆる比率におけるそれらの混合物を含む、生理学的および/または病態生理学的状態の処置および/または予防法における使用のための医薬。
- 請求項1~3のいずれか一項に記載の少なくとも1つの化合物、および/またはその生理学的に許容し得る塩、溶媒和物、および立体異性体の1つ、ならびにあらゆる比率におけるそれらの混合物を含む、過剰増殖性および感染性の疾患および障害からなる群から選択される生理学的および/または病態生理学的状態の処置および/または予防法における使用のための医薬。
- 過剰増殖性の疾患または障害が、がんである、請求項11に記載の医薬。
- がんが、急性および慢性リンパ球性白血病、急性顆粒球性白血病、副腎皮質がん、膀胱がん、脳がん、乳房がん、子宮頸がん、子宮頸部過形成、子宮頸がん、絨毛がん、慢性顆粒球性白血病、慢性リンパ球性白血病、大腸がん、子宮内膜がん、食道がん、本態性血小板増加症、泌尿生殖器癌、神経膠腫、膠芽腫、有毛細胞白血病、頭頸部癌、ホジキン病、カポジ肉腫、肺癌、リンパ腫、悪性カルチノイド癌、悪性高カルシウム血症、悪性黒色腫、悪性膵臓インスリノーマ、甲状腺髄様癌、黒色腫、多発性骨髄腫、菌状息肉種、骨髄性およびリンパ球性白血病、神経芽細胞腫、非ホジキンリンパ腫、非小細胞肺がん、骨肉腫、卵巣癌、膵臓癌、真性赤血球増加症、原発性脳腫瘍、原発性マクログロブリン血症、前立腺がん、腎細胞がん、横紋筋肉腫、皮膚がん、小細胞肺がん、軟部組織の肉腫、扁平上皮細胞がん、胃がん、精巣がん、甲状腺がん、ならびにウィルムス腫瘍からなる群から選択される、請求項12に記載の医薬。
- 過剰増殖性の疾患または障害が、加齢性黄斑変性症、クローン病、肝硬変、慢性炎症に関する障害、増殖性糖尿病網膜症、増殖性硝子体網膜症、未熟児網膜症、肉芽腫症、器官または組織の移植に関連する免疫過剰増殖、および免疫増殖性の疾患または障害(炎症性腸疾患、乾癬、リウマチ性関節炎、全身性エリテマトーデス(SLE)、網膜低酸素状態に続発する血管過剰増殖、および血管炎からなる群から選択される)からなる群から選択される、請求項11に記載の医薬。
- 感染性の疾患または障害が、
a)レトロウイルス、ヘパドナウイルス、ヘルペスウイルス、フラビウイルス科、および/またはアデノウイルスによって引き起こされるウイルス誘導性の感染性疾患、ここでレトロウイルスが、レンチウイルスまたはオンコレトロウイルスから選択され、ここでレンチウイルスが、HIV-1、HIV-2、FIV、BIV、SIVs、SHIV、CAEV、VMV、およびEIAVからなる群から選択され、ならびにオンコレトロウイルスが、HTLV-I、HTLV-II、およびBLVからなる群から選択され、ヘパドナウイルスが、HBV、GSHV、およびWHVからなる群から選択され、ヘルペスウイルスが、HSV I、HSV II、EBV、VZV、HCMV、またはHHV8からなる群から選択され、ならびにフラビウイルス科が、HCV、西ナイル、および黄熱病からなる群から選択され、
b)グラム陽性細菌によって引き起こされる細菌感染症、ここでグラム陽性細菌が、メチシリン感受性およびメチシリン耐性ブドウ球菌(Staphylococcus aureus、Staphylococcus epidermidis、Staphylococcus haemolyticus、Staphylococcus hominis、Staphylococcus saprophyticus、およびコアグラーゼ陰性ブドウ球菌を包含する)、糖ペプチド低感受性Staphylococcus aureus(GISA)、ペニシリン感受性およびペニシリン耐性連鎖球菌(Streptococcus pneumoniae、Streptococcus pyogenes、Streptococcus agalactiae、Streptococcus avium、Streptococcus bovis、Streptococcus lactis、Streptococcus sanguis、ならびにC群連鎖球菌(GCS)、G群連鎖球菌(GGS)、およびビリダンス連鎖球菌を包含する)、腸球菌(Enterococcus faecalisおよびEnterococcus faeciumなどのバンコマイシン感受性およびバンコマイシン耐性株)、Clostridium difficile、Iisteria monocytogenes、Corynebacterium jeikeium、Chlamydia spp(C. pneumoniaeを包含する)、ならびにMycobacterium tuberculosisからなる群から選択され、
c)グラム陰性細菌によって引き起こされる細菌感染症、ここでグラム陰性細菌が、Escherichia spp.(Escherichia coliを包含する)を包含する腸内細菌属、Klebsiella spp.、Enterobacter spp.、Citrobacter spp.、Serratia spp.、Proteus spp.、Providencia spp.、Salmonella spp.、Shigella spp.、シュードモナス属(P. aeruginosaを包含する)、Moraxella spp.(M. catarrhalisを包含する)、Haemophilus spp.、およびNeisseria spp.からなる群から選択され、
d)phylum Apicomplexa、またはSarcomastigophora(Trypanosoma、Plasmodia、Leishmania、Babesia、もしくはTheileriaを包含する)、Cryptosporidia、Sacrocystida、Amoebia、Coccidia、およびTrichomonadiaからなる群から選択される、細胞内のアクティブな寄生体によって誘導される感染性疾患
からなる群から選択される、請求項11に記載の医薬。 - a)有効量の、請求項1~3のいずれか一項に記載の化合物、および/またはその生理学的に許容し得る塩、溶媒和物、および立体異性体、ならびにあらゆる比率におけるそれらの混合物、ならびに
b)有効量のさらなる医薬活性化合物
の個別のパックからなる、セット(キット)。
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