JPWO2020090698A1 - Pharmaceutical composition - Google Patents
Pharmaceutical composition Download PDFInfo
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- JPWO2020090698A1 JPWO2020090698A1 JP2020553868A JP2020553868A JPWO2020090698A1 JP WO2020090698 A1 JPWO2020090698 A1 JP WO2020090698A1 JP 2020553868 A JP2020553868 A JP 2020553868A JP 2020553868 A JP2020553868 A JP 2020553868A JP WO2020090698 A1 JPWO2020090698 A1 JP WO2020090698A1
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- pharmaceutical composition
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- cancer
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- 239000008194 pharmaceutical composition Substances 0.000 title claims description 56
- 239000003814 drug Substances 0.000 claims abstract description 50
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- -1 CC-486 Chemical compound 0.000 claims description 32
- 239000003795 chemical substances by application Substances 0.000 claims description 28
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- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 22
- 229940124597 therapeutic agent Drugs 0.000 claims description 15
- 125000001424 substituent group Chemical group 0.000 claims description 14
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- SSDRNUPMYCFXGM-ZZHSESOFSA-N CN(C)C1CCC(CC1)[C@@]1(C)Oc2c(O1)c(C)c(cc2Cl)C(=O)NCc1c(C)cc(C)[nH]c1=O Chemical compound CN(C)C1CCC(CC1)[C@@]1(C)Oc2c(O1)c(C)c(cc2Cl)C(=O)NCc1c(C)cc(C)[nH]c1=O SSDRNUPMYCFXGM-ZZHSESOFSA-N 0.000 claims description 13
- 125000000217 alkyl group Chemical group 0.000 claims description 13
- 125000003710 aryl alkyl group Chemical group 0.000 claims description 12
- 125000003118 aryl group Chemical group 0.000 claims description 12
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- RTKIYFITIVXBLE-QEQCGCAPSA-N trichostatin A Chemical compound ONC(=O)/C=C/C(/C)=C/[C@@H](C)C(=O)C1=CC=C(N(C)C)C=C1 RTKIYFITIVXBLE-QEQCGCAPSA-N 0.000 claims description 6
- NMUSYJAQQFHJEW-KVTDHHQDSA-N 5-azacytidine Chemical compound O=C1N=C(N)N=CN1[C@H]1[C@H](O)[C@H](O)[C@@H](CO)O1 NMUSYJAQQFHJEW-KVTDHHQDSA-N 0.000 claims description 5
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- ZOIBZSZLMJDVDQ-UHFFFAOYSA-N 1-cyclopentyl-N-[(4,6-dimethyl-2-oxo-1H-pyridin-3-yl)methyl]-6-[4-(4-morpholinylmethyl)phenyl]-4-indazolecarboxamide Chemical compound O=C1NC(C)=CC(C)=C1CNC(=O)C1=CC(C=2C=CC(CN3CCOCC3)=CC=2)=CC2=C1C=NN2C1CCCC1 ZOIBZSZLMJDVDQ-UHFFFAOYSA-N 0.000 claims description 3
- 125000000094 2-phenylethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])C([H])([H])* 0.000 claims description 3
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- GUWXKKAWLCENJA-WGWHJZDNSA-N [(2r,3s,5r)-5-(2-amino-6-oxo-3h-purin-9-yl)-3-hydroxyoxolan-2-yl]methyl [(2r,3s,5r)-5-(4-amino-2-oxo-1,3,5-triazin-1-yl)-2-(hydroxymethyl)oxolan-3-yl] hydrogen phosphate Chemical compound O=C1N=C(N)N=CN1[C@@H]1O[C@H](CO)[C@@H](OP(O)(=O)OC[C@@H]2[C@H](C[C@@H](O2)N2C3=C(C(N=C(N)N3)=O)N=C2)O)C1 GUWXKKAWLCENJA-WGWHJZDNSA-N 0.000 claims description 3
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 3
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- QSYLKMKIVWJAAK-UHFFFAOYSA-N n-[4-[(2-amino-6-methylpyrimidin-4-yl)amino]phenyl]-4-(quinolin-4-ylamino)benzamide Chemical compound NC1=NC(C)=CC(NC=2C=CC(NC(=O)C=3C=CC(NC=4C5=CC=CC=C5N=CC=4)=CC=3)=CC=2)=N1 QSYLKMKIVWJAAK-UHFFFAOYSA-N 0.000 claims description 3
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- FIAFUQMPZJWCLV-UHFFFAOYSA-N suramin Chemical compound OS(=O)(=O)C1=CC(S(O)(=O)=O)=C2C(NC(=O)C3=CC=C(C(=C3)NC(=O)C=3C=C(NC(=O)NC=4C=C(C=CC=4)C(=O)NC=4C(=CC=C(C=4)C(=O)NC=4C5=C(C=C(C=C5C(=CC=4)S(O)(=O)=O)S(O)(=O)=O)S(O)(=O)=O)C)C=CC=3)C)=CC=C(S(O)(=O)=O)C2=C1 FIAFUQMPZJWCLV-UHFFFAOYSA-N 0.000 claims description 3
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- RPQZTTQVRYEKCR-WCTZXXKLSA-N zebularine Chemical compound O[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1N1C(=O)N=CC=C1 RPQZTTQVRYEKCR-WCTZXXKLSA-N 0.000 claims description 3
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Abstract
DNAメチル基転移酵素DNMTを阻害する作用を有する化合物と他の薬剤をがんの予防薬又は治療薬として提供すること。【選択図】なしTo provide a compound having an action of inhibiting the DNA methyltransferase DNMT and other drugs as a prophylactic or therapeutic drug for cancer. [Selection diagram] None
Description
本発明は、がんの予防又は治療薬に関する。 The present invention relates to a prophylactic or therapeutic agent for cancer.
血液がんは、血液、骨髄、及び/又はリンパ系を攻撃するがんの1種を意味する。この種類のがんには、白血病や多発性骨髄腫が含まれ、これらは全て、新しい、より効果的な治療法を必要とする致命的な疾患となり得る。 Blood cancer means a type of cancer that attacks the blood, bone marrow, and / or lymphatic system. This type of cancer includes leukemia and multiple myeloma, all of which can be fatal diseases that require new, more effective treatments.
ATL(Adult T-cell Leukemia/Lymphoma:成人T細胞白血病/リンパ腫)とは、1976年に高月ら(非特許文献1〜2)によって発見・命名された疾患であり、腫瘍性ウィルスHTLV−1(Human T-cell Leukemia/Lymphotropic Virus type-1)による感染を原因とする白血病もしくは悪性リンパ腫である。HTLV−1の感染者は、日本では南部(特に、九州や沖縄等)に多く、他にはカリブ海沿岸諸国、中央アフリカや南米等に局在化している。
HTLV−1の感染経路としては授乳、性交や輸血等が挙げられ、其のキャリアは全世界で500万〜1000万人(日本では約110万人)いるとされており、日本では男性キャリアのうちの6〜7%、女性の場合は2〜3%が毎年ATLを発症している。なお、HTLV−1感染からATL発症までの期間が非常に長く、結果的に高齢なキャリアにATL発症者が多いのが特徴である(非特許文献3)。ATL (Adult T-cell Leukemia / Lymphoma) is a disease discovered and named by Takatsuki et al. (Non-Patent
Breastfeeding, sexual intercourse, blood transfusion, etc. are listed as infection routes of HTLV-1, and it is said that there are 5 to 10 million carriers worldwide (about 1.1 million in Japan), and in Japan, male carriers. 6-7% of them, and 2-3% of women, develop ATL every year. The period from HTLV-1 infection to the onset of ATL is very long, and as a result, many elderly carriers develop ATL (Non-Patent Document 3).
ATLの治療はCHOP療法(非特許文献4)、modified LSG15療法(非特許文献5)、EPOCH療法(非特許文献6)やAZT−INFα療法といった化学療法が選択されるが、再発や薬剤耐性化が多く、標準的治療法が未だ確立されていないのが現状である。
最近では、新たなATL治療薬としてのケモカイン受容体CCR4抗体医薬・モガムリズマブ(Mogamulizumab、製品名:ポテリジオ)(非特許文献7)、抗ウィルス薬・アバカビル(非特許文献8)、ヒストン脱アセチル化酵素(HDAC)阻害薬・ボリノスタット(Vorinostat、製品名:ゾリンザ)(非特許文献9)やヒストンメチル化酵素EZH1/2の二重阻害剤DS―3201bの可能性が注目されている。Chemotherapy such as CHOP therapy (Non-Patent Document 4), modified LSG15 therapy (Non-Patent Document 5), EPOCH therapy (Non-Patent Document 6) and AZT-INFα therapy is selected for the treatment of ATL, but recurrence and drug resistance The current situation is that standard treatment methods have not yet been established.
Recently, a new ATL therapeutic drug, a chemokine receptor CCR4 antibody drug, mogamulizumab (product name: Poterigio) (Non-Patent Document 7), an antiviral drug, abacavir (Non-Patent Document 8), histone deacetylase (HDAC) inhibitor Vorinostat (product name: Zolinza) (Non-Patent Document 9) and the double inhibitor DS-3201b of histone methylase EZH1 / 2 are attracting attention.
DNMTsとは、DNAメチル基転移酵素群(DNA methyltransferases)の略称であり、DNA鎖中のアデニン環6位アミノ基のメチル化(Adenine N6-specific DNA-methyltransferase: EC 2.1.1.72)、シトシン環4位アミノ基のメチル化(Cytosine N4-specific DNA-methyltransferase: EC 2.1.1.113)又はシトシン環5位へのメチル化(Cytosine C5-specific DNA-methyltransferase: EC 2.1.1.37)を触媒する酵素群である。特に、発現遺伝子のプロモーター領域によく認められるCpG アイランドと称される配列部分においてシトシン環5位へのメチル化を触媒する酵素群(維持メチル基転移酵素DNMT1やde novo メチル基転移酵素DNMT3ファミリー)は、細胞の正常な発生と分化を調節する際に極めて重要な役割を果たしている(非特許文献10〜11)。DNMTs is an abbreviation for DNA methyltransferases, methylation of the amino group at the 6-position of the adenine ring in the DNA strand (Adenine N 6 -specific DNA-methyltransferase: EC 2.1.1.72), cytosine ring. An enzyme that catalyzes the methylation of the 4-position amino group (Cytosine N 4- specific DNA-methyltransferase: EC 2.1.1.113) or the methylation to the cytosine ring 5-position (Cytosine C 5- specific DNA-methyltransferase: EC 2.1.1.37). It is a group. In particular, a group of enzymes that catalyze methylation to the 5-position of the cytosine ring in the sequence portion called CpG island, which is often found in the promoter region of the expressed gene (maintenance methyl group transfer enzyme DNMT1 and de novo methyl group transfer enzyme DNMT3 family). Plays a crucial role in regulating the normal development and differentiation of cells (Non-Patent Documents 10-11).
また、DNMTsは、がんの発達においても深く関係している。即ち、全てのCpGの60〜90%はシトシン環5位がメチル化されていると考えられているが、異常なレベルのDNAメチル化は遺伝子の発現制御と深く関連しており、プロモーター領域(CpGアイランド)が高レベルにシトシン環5位メチル化されている遺伝子は、其の転写・発現がサイレンシングしていることが明らかにされている(非特許文献12〜14)。 DNMTs are also deeply involved in cancer development. That is, it is thought that 60 to 90% of all CpGs have methylation at the 5-position of the cytosine ring, but abnormal levels of DNA methylation are closely related to gene expression regulation, and the promoter region ( It has been clarified that the transcription / expression of a gene in which CpG island) is methylated at the 5-position of the cytosine ring at a high level is silenced (Non-Patent Documents 12 to 14).
一方、細胞には、新しく作られるDNA鎖においても親鎖と同じ位置のシトシン環5位へメチル基を導入する仕組みが備わっており、この「DNAメチル化の複製」を可能にしているのもDNMTsである。それ故、がん化した細胞では、がん抑制遺伝子の多くが転写・発現抑制されてサイレンシング状態になり、増殖しやすい状態になっている。 On the other hand, cells are equipped with a mechanism to introduce a methyl group into the 5-position of the cytosine ring at the same position as the parent strand in the newly created DNA strand, which enables this "replication of DNA methylation". DNAMs. Therefore, in cancerous cells, most of the tumor suppressor genes are suppressed in transcription and expression, and are in a silencing state, so that they can easily proliferate.
なお、このシトシン環5位のメチル化に関しては、DNMTの触媒活性中心にあるシステイン残基のSH基がDNA配列中のシトシン環6位を攻撃することによりシトシン環5位が活性化され、メチル基供与体S−アデノシル−L−メチオニンからのメチル基転移を促すという反応機構が提案されている。
Regarding the methylation of the cytosine ring 5 position, the SH group of the cysteine residue at the catalytically active center of DNMT attacks the
このような背景を持つDNMTsに対する選択的な酵素阻害剤として、5−アザシチジン(製品名:「ビダーザ(登録商標)」)や其の2’−デオキシ体(デシタビン、製品名:「ダコジェン(登録商標)」)が見いだされ、高リスクな骨髄異形成症候群や急性骨髄白血病の治療薬として臨床使用されている。なお、これらの薬剤はシトシンヌクレオシド類と化学構造(シトシン環5位炭素原子が窒素原子に置換された構造)が酷似しており、核酸生合成ルートを経て、2’−デオキシシチジンの代わりにDNA中へ入り込むことにより、がん抑制遺伝子プロモーター領域(CpGアイランド)におけるDNMTsによるシトシン環5位のメチル化反応を自殺的に阻害し、がん抑制遺伝子の正常な発現を可能にして治療効果を現わすとされている。
As selective enzyme inhibitors for DNMTs with such a background, 5-azacitidine (product name: "Vidaza (registered trademark)") and its 2'-deoxy compound (decitabine, product name: "Dacogen (registered trademark)") ) ”) Has been found and is clinically used as a therapeutic agent for high-risk myelodysplastic syndrome and acute myeloid leukemia. These drugs are very similar in chemical structure to cytosine nucleosides (the structure in which the carbon atom at the 5-position of the cytosine ring is replaced with a nitrogen atom), and DNA is used instead of 2'-deoxycytidine via the nucleic acid biosynthesis route. By entering the inside, it self-inhibits the methylation reaction at the 5-position of the cytosine ring by DNMTs in the cancer suppressor gene promoter region (CpG island), enabling normal expression of the cancer suppressor gene and showing a therapeutic effect. It is said to be forgotten.
しかしながら、血液がんに対して有効な医薬は未だ見出されていない。 However, no effective drug for blood cancer has been found yet.
上記事情により、臨床の現場では、血液がんを克服する医薬が要望されている。 Due to the above circumstances, there is a demand for a drug that overcomes blood cancer in clinical practice.
本発明の課題は、がん(とりわけ血液がん)の新規予防薬又は治療薬を提供することにある。 An object of the present invention is to provide a novel preventive agent or therapeutic agent for cancer (particularly blood cancer).
本発明者らは、血液がんに対する優れた予防薬又は治療薬を見出すために鋭意研究を重ねた結果、DNMT阻害剤(特に、化合物(I))と他の薬剤とを組み合わせてなる医薬組成物が、血液がんの予防又は治療のために有用であることを見出した。
本発明は、これらの知見に基づいて完成された。As a result of intensive research to find an excellent preventive or therapeutic agent for blood cancer, the present inventors have made a pharmaceutical composition obtained by combining a DNMT inhibitor (particularly, compound (I)) with another agent. It has been found that the compound is useful for the prevention or treatment of blood cancer.
The present invention has been completed based on these findings.
即ち本発明は、以下記載の発明〔1〕〜〔29〕を提供することにより上記課題を解決したものである。
〔1〕
他の薬剤と併用される、DNMT阻害剤を含む、医薬組成物。
〔2〕
DNMT阻害剤と併用される、他の薬剤を含む、医薬組成物。
〔3〕
DNMT阻害剤及び他の薬剤を含む、医薬組成物。
〔4〕
DNMT阻害剤が、式(I):
(式中、R及びR’は、それぞれOR3基、水素原子、ハロゲン原子又はアルキル基であり、R1、R2及びR3は、それぞれ水素原子又は式(II):
(式中、R4、R5及びR6は、それぞれ置換基を有していてもよいアルキル基又はアリール基又はアリールアルキル基である。)で表されるシリル基である。)で表される化合物又は其の塩、デシタビン、アザシチジン、RG108、チオグアニン、ゼブラリン、SGI−110、CC−486、SGI−1027、ロメグアトリブ又はプロカイナミド塩酸塩である、〔1〕〜〔3〕のいずれか1項に記載の医薬組成物。
〔5〕
前記R1が、式(II)で表されるシリル基であり、前記R2及びR又はR3が水素原子である、〔4〕に記載の医薬組成物。
〔6〕
前記R2が、式(II)で表されるシリル基であり、前記R1及びR又はR3が水素原子である、〔4〕に記載の医薬組成物。
〔7〕
前記R1及びR2が、それぞれ式(II)で表されるシリル基であり、前記R又はR3が水素原子である、〔4〕に記載の医薬組成物。
〔8〕
前記R1が水素原子であり、R2及びR3がそれぞれ式(II)で表されるシリル基である、〔4〕に記載の医薬組成物。
〔9〕
前記R1、R2及びR3が、それぞれ式(II)で表されるシリル基である、〔4〕に記載の医薬組成物。
〔10〕
前記R1、R2及びR3が、いずれも水素原子である、〔4〕に記載の医薬組成物。
〔11〕
前記R4、R5及びR6が、それぞれ置換基を有していてもよいC1〜C8アルキル基又はC6〜C10アリール基又はC7〜C14アリールアルキル基である、〔4〕に記載の医薬組成物。
〔12〕
前記C6〜C10アリール基がフェニル基又はナフチル基である、〔11〕に記載の医薬組成物。
〔13〕
前記C7〜C14アリールアルキル基が、ベンジル基、フェネチル基又はナフチルメチル基である、〔11〕に記載の医薬組成物。
〔14〕
他の薬剤が、酵素阻害剤である、〔1〕〜〔13〕のいずれか1項に記載の医薬組成物。
〔15〕
酵素阻害剤が、ヒストンアセチル化酵素阻害剤、ヒストン脱アセチル化酵素阻害剤、ヒストンメチル化酵素阻害剤、ヒストン脱メチル化酵素阻害剤及びリボヌクレオシド二リン酸レダクターゼ阻害剤からなる群から選択される1種以上である、〔14〕に記載の医薬組成物。
〔16〕
酵素阻害剤が、DS―3201b、HBI−8000、トリコスタチンA(TSA)、スラミン(Suramin)、EPZ005687及びAdoxからなる群から選択される1種以上である、〔14〕に記載の医薬組成物。
〔17〕
薬学上許容される担体を更に含む、〔1〕〜〔16〕のいずれか1項に記載の医薬組成物。
〔18〕
DNMT阻害剤及び他の薬剤が同時に投与される、〔1〕、〔2〕及び〔4〕〜〔17〕のいずれか1項に記載の医薬組成物。
〔19〕
DNMT阻害剤及び他の薬剤が別々に投与される、〔1〕、〔2〕及び〔4〕〜〔17〕のいずれか1項に記載の医薬組成物。
〔20〕
DNMT阻害剤が他の薬剤の投与前に投与される、〔1〕、〔2〕及び〔4〕〜〔17〕のいずれか1項に記載の医薬組成物。
〔21〕
DNMT阻害剤が他の薬剤の投与後に投与される、〔1〕、〔2〕及び〔4〕〜〔17〕のいずれか1項に記載の医薬組成物。
〔22〕
がんの予防又は治療のための、〔1〕〜〔21〕のいずれか1項に記載の医薬組成物。
〔23〕
がんが、白血病である、〔22〕に記載の医薬組成物。
〔24〕
白血病が、ATLである、〔23〕に記載の医薬組成物。
〔25〕
〔1〕〜〔21〕のいずれか1項に記載の医薬組成物を含有する、がんの予防薬又は治療薬。
〔26〕
がんが、白血病である、〔25〕に記載のがんの予防薬又は治療薬。
〔27〕
白血病が、ATLである、〔26〕に記載のがんの予防薬又は治療薬。
〔28〕
〔1〕〜〔22〕のいずれか1項に記載されるDNMT阻害剤及び他の薬剤を含む、がんを予防又は治療するためのキット。
〔29〕
哺乳動物に対して、DNMT阻害剤の有効量及び他の薬剤の有効量を投与することを特徴とする、当該哺乳動物におけるがんの予防又は治療方法。That is, the present invention solves the above-mentioned problems by providing the inventions [1] to [29] described below.
[1]
A pharmaceutical composition comprising a DNMT inhibitor used in combination with other agents.
[2]
A pharmaceutical composition comprising other agents used in combination with a DNMT inhibitor.
[3]
A pharmaceutical composition comprising a DNMT inhibitor and other agents.
[4]
The DNMT inhibitor is of formula (I):
(In the formula, R and R'are OR 3 groups, hydrogen atoms, halogen atoms or alkyl groups, respectively, and R 1 , R 2 and R 3 are hydrogen atoms or formula (II), respectively:
(In the formula, R 4 , R 5 and R 6 are alkyl groups or aryl groups or arylalkyl groups which may have substituents, respectively). ), Decitabine, azacitidine, RG108, thioguanine, zebularine, SGI-110, CC-486, SGI-1027, romeguatrib or procainamide hydrochloride, any of [1] to [3]. The pharmaceutical composition according to
[5]
The pharmaceutical composition according to [4], wherein R 1 is a silyl group represented by the formula (II), and R 2 and R or R 3 are hydrogen atoms.
[6]
The pharmaceutical composition according to [4], wherein R 2 is a silyl group represented by the formula (II), and R 1 and R or R 3 are hydrogen atoms.
[7]
The pharmaceutical composition according to [4], wherein R 1 and R 2 are silyl groups represented by the formula (II), respectively, and R or R 3 is a hydrogen atom.
[8]
The pharmaceutical composition according to [4], wherein R 1 is a hydrogen atom and R 2 and R 3 are silyl groups represented by the formula (II), respectively.
[9]
The pharmaceutical composition according to [4], wherein R 1 , R 2 and R 3 are silyl groups represented by the formula (II), respectively.
[10]
The pharmaceutical composition according to [4], wherein R 1 , R 2 and R 3 are all hydrogen atoms.
[11]
The R 4 , R 5 and R 6 are C 1 to C 8 alkyl groups or C 6 to C 10 aryl groups or C 7 to C 14 aryl alkyl groups, respectively, which may have substituents, [4]. ] The pharmaceutical composition according to.
[12]
The pharmaceutical composition according to [11], wherein the C 6 to C 10 aryl groups are phenyl groups or naphthyl groups.
[13]
The pharmaceutical composition according to [11], wherein the C 7 to C 14 arylalkyl group is a benzyl group, a phenethyl group or a naphthylmethyl group.
[14]
The pharmaceutical composition according to any one of [1] to [13], wherein the other drug is an enzyme inhibitor.
[15]
The enzyme inhibitor is selected from the group consisting of histone acetylase inhibitors, histone deacetylase inhibitors, histone methylase inhibitors, histone demethylase inhibitors and ribonucleotide reductase inhibitors. The pharmaceutical composition according to [14], which is one or more.
[16]
The pharmaceutical composition according to [14], wherein the enzyme inhibitor is at least one selected from the group consisting of DS-3201b, HBI-8000, Trichostatin A (TSA), Suramin, EPZ005687 and Adox. ..
[17]
The pharmaceutical composition according to any one of [1] to [16], further comprising a pharmaceutically acceptable carrier.
[18]
The pharmaceutical composition according to any one of [1], [2] and [4] to [17], wherein the DNMT inhibitor and other agents are administered at the same time.
[19]
The pharmaceutical composition according to any one of [1], [2] and [4] to [17], wherein the DNMT inhibitor and other agents are separately administered.
[20]
The pharmaceutical composition according to any one of [1], [2] and [4] to [17], wherein the DNMT inhibitor is administered before administration of another drug.
[21]
The pharmaceutical composition according to any one of [1], [2] and [4] to [17], wherein the DNMT inhibitor is administered after administration of another drug.
[22]
The pharmaceutical composition according to any one of [1] to [21] for the prevention or treatment of cancer.
[23]
The pharmaceutical composition according to [22], wherein the cancer is leukemia.
[24]
The pharmaceutical composition according to [23], wherein the leukemia is ATL.
[25]
A preventive or therapeutic agent for cancer, which comprises the pharmaceutical composition according to any one of [1] to [21].
[26]
The prophylactic or therapeutic agent for cancer according to [25], wherein the cancer is leukemia.
[27]
The prophylactic or therapeutic agent for cancer according to [26], wherein the leukemia is ATL.
[28]
A kit for preventing or treating cancer, which comprises the DNMT inhibitor and other agents according to any one of [1] to [22].
[29]
A method for preventing or treating cancer in a mammal, which comprises administering an effective amount of a DNMT inhibitor and an effective amount of another drug to the mammal.
本発明の医薬組成物は、DNMTによって発現が惹起されるATLのような白血病の予防薬又は治療薬として、有用である。 The pharmaceutical composition of the present invention is useful as a prophylactic or therapeutic agent for leukemia such as ATL whose expression is induced by DNMT.
特に言及しない限り、本明細書及び特許請求の範囲で用いた用語は以下に述べる意味を有する。 Unless otherwise specified, the terms used herein and in the claims have the following meanings.
DNMT阻害剤
本発明の「DNAメチル基転移酵素阻害剤」としては、特に限定されないが、例えば、下記の式(I):
(式中、R及びR’は、それぞれOR3基、水素原子、ハロゲン原子又はアルキル基であり、R1、R2及びR3は、それぞれ水素原子又は式(II):
(式中、R4、R5及びR6は、それぞれ置換基を有していてもよいアルキル基又はアリール基又はアリールアルキル基である。)で表されるシリル基である。)で表される化合物又は其の塩、デシタビン、アザチジン、RG108、チオグアニン、ゼブラリン、SGI−110、CC−486、SGI−1027、ロメグアトリブ及びプロカイナミド塩酸塩等が挙げられる。式(I)におけるR及びR’は、好ましくそれぞれOR3基、水素原子又はハロゲン原子である。DNMT Inhibitor The "DNA methyltransferase inhibitor" of the present invention is not particularly limited, but for example, the following formula (I):
(In the formula, R and R'are OR 3 groups, hydrogen atoms, halogen atoms or alkyl groups, respectively, and R 1 , R 2 and R 3 are hydrogen atoms or formula (II), respectively:
(In the formula, R 4 , R 5 and R 6 are alkyl groups or aryl groups or arylalkyl groups which may have substituents, respectively). ), Decitabine, azatidine, RG108, thioguanine, zebularine, SGI-110, CC-486, SGI-1027, romeguatrib, procainamide hydrochloride and the like. R and R'in the formula (I) are preferably OR 3 groups, a hydrogen atom or a halogen atom, respectively.
式(I)のR及びR’の好ましい組合せの例示は下記のとおりである。
(i)Rが、OR3基、水素原子、ハロゲン原子又はアルキル基であり、R’が、水素原子である。
(ii)Rが、OR3基又は水素原子であり、R’が、水素原子である。
(iii)Rが、フッ素原子であり、R’が、フッ素原子である。Examples of preferable combinations of R and R'of the formula (I) are as follows.
(i) R is an OR3 group, a hydrogen atom, a halogen atom or an alkyl group, and R'is a hydrogen atom.
(ii) R is an OR3 group or a hydrogen atom, and R'is a hydrogen atom.
(iii) R is a fluorine atom and R'is a fluorine atom.
「アルキル基」とは、特に限定しない限り、飽和脂肪族炭化水素基、例えば、炭素数が1〜8個の直鎖又は分岐鎖状又は環状のアルキル基をいい、例えば、メチル基、エチル基、プロピル基、イソプロピル基、ブチル基、sec−ブチル基、イソブチル基、tert−ブチル基、ペンチル基、ヘキシル基等のC1〜C6アルキル基、ヘプチル基、2−メチルヘキシル基、5−メチルヘキシル基、2,2−ジメチルペンチル基、4,4−ジメチルペンチル基、2−エチルペンチル基、1,1,3−トリメチルブチル基、1,2,2−トリメチルブチル基、1,3,3−トリメチルブチル基、2,2,3−トリメチルブチル基、2,3,3−トリメチルブチル基、1−プロピルブチル基、1,1,2,2−テトラメチルプロピル基、オクチル基、2−メチルヘプチル基、3−メチルヘプチル基、6−メチルヘプチル基、2−エチルヘキシル基、5,5−ジメチルヘキシル基、2,4,4−トリメチルペンチル基、1−エチル−1−メチルペンチル基、シクロプロピル、シクロブチル、シクロペンチル、シクロヘキシル、シクロヘプチル、シクロオクチル等の基を挙げることができるが、C1〜C6アルキルの基が好ましい。C1〜C6アルキルの基の好ましい例は、メチル基、エチル基及びプロピル基である。また、環状のアルキル基の好ましい例は、シクロペンチル基及びシクロヘキシル基である。Unless otherwise specified, the "alkyl group" refers to a saturated aliphatic hydrocarbon group, for example, a linear or branched or cyclic alkyl group having 1 to 8 carbon atoms, for example, a methyl group or an ethyl group. , propyl group, isopropyl group, butyl group, sec- butyl group, an isobutyl group, tert- butyl group, a pentyl group, C 1 -C 6 alkyl groups such as hexyl, heptyl, 2-methylhexyl group, 5-methyl Hexyl group, 2,2-dimethylpentyl group, 4,4-dimethylpentyl group, 2-ethylpentyl group, 1,1,3-trimethylbutyl group, 1,2,2-trimethylbutyl group, 1,3,3 -Trimethylbutyl group, 2,2,3-trimethylbutyl group, 2,3,3-trimethylbutyl group, 1-propylbutyl group, 1,1,2,2-tetramethylpropyl group, octyl group, 2-methyl Heptyl group, 3-methylheptyl group, 6-methylheptyl group, 2-ethylhexyl group, 5,5-dimethylhexyl group, 2,4,4-trimethylpentyl group, 1-ethyl-1-methylpentyl group, cyclopropyl , Cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl and the like can be mentioned, but groups of C 1 to C 6 alkyl are preferable. Preferred examples of C 1 to C 6 alkyl groups are methyl, ethyl and propyl groups. Further, preferred examples of the cyclic alkyl group are a cyclopentyl group and a cyclohexyl group.
「アリール」とは、単環式又は二環式芳香族性炭化水素をいい、好ましくは、例えばフェニル基、ナフチル基等のC6−10アリール基であり、もっと好ましくは、フェニル基である。The "aryl" refers to a monocyclic or bicyclic aromatic hydrocarbon, preferably a C 6-10 aryl group such as a phenyl group or a naphthyl group, and more preferably a phenyl group.
「アリールアルキル」とは、アリールにより置換されたアルキル基をいう。好ましくは、C7〜C14アリールアルキル基である。C7〜C14アリールアルキル基の例は、ベンジル基、フェネチル基又はナフチルメチル基等を含むが、これらに限定されるものではない。"Arylalkyl" refers to an alkyl group substituted with aryl. Preferably, a C 7 -C 14 arylalkyl group. Examples of C 7 -C 14 arylalkyl group, a benzyl group, include phenethyl or naphthylmethyl group, but is not limited thereto.
「置換基を有していてもよいアルキル基、置換基を有していてもよいアリール基又は置換基を有していてもよいアリールアルキル基」は、置換基を有していても、無置換であってもよいことを意味する。置換されている場合、置換基は前記アルキル基、アリール基又はアリールアルキル基の置換可能な位置に1ないし5個、好ましくは1〜3個有していてもよく、置換基数が2個以上の場合は各置換基は同一又は異なっていてもよい。置換基としては、アルキル基、ハロゲン原子、シアノ基、ニトロ基等が挙げられるが、好ましい置換基の例は、アルキル基又はハロゲンである。 The "alkyl group which may have a substituent, an aryl group which may have a substituent or an arylalkyl group which may have a substituent" may have a substituent or not. It means that it may be a replacement. When substituted, the substituents may have 1 to 5, preferably 1-3, at substitutable positions of the alkyl group, aryl group or arylalkyl group, and the number of substituents is 2 or more. In some cases, each substituent may be the same or different. Examples of the substituent include an alkyl group, a halogen atom, a cyano group, a nitro group and the like, and an example of a preferable substituent is an alkyl group or a halogen.
「ハロゲン原子」とは、フッ素原子、塩素原子、臭素原子、ヨウ素原子等をいい、好ましい例は、フッ素原子及び塩素原子である。 The "halogen atom" refers to a fluorine atom, a chlorine atom, a bromine atom, an iodine atom and the like, and preferred examples are a fluorine atom and a chlorine atom.
本発明の式(I)で表される化合物の塩は、薬理学的に許容される塩であれば如何なる塩であってもよい。其の塩としては、例えば、無機酸塩(例えば、塩酸塩、硫酸塩、臭化水素酸塩、リン酸塩等)、有機酸塩(例えば、酢酸塩、トリフルオロ酢酸塩、コハク酸塩、マレイン酸塩、フマル酸塩、プロピオン酸塩、クエン酸塩、酒石酸塩、乳酸塩、蓚酸塩、メタンスルホン酸塩、p−トルエンスルホン酸塩等)等の酸付加塩等が挙げられるが、これらに限定されるものではない。 The salt of the compound represented by the formula (I) of the present invention may be any salt as long as it is a pharmacologically acceptable salt. Examples of the salt include inorganic acid salts (for example, hydrochlorides, sulfates, hydrobromates, phosphates, etc.), organic acid salts (for example, acetates, trifluoroacetates, succinates, etc.). Acid addition salts such as maleate, fumarate, propionate, citrate, tartrate, lactate, oxalate, methanesulfonate, p-toluenesulfonate, etc.) can be mentioned. It is not limited to.
本発明の式(I)で表される化合物は、結晶であってもよく、結晶形が単一であっても、複数の結晶形の混合物であってもよい。結晶は、自体公知の結晶化法を適用して、結晶化することによって製造することができる。 The compound represented by the formula (I) of the present invention may be a crystal, a single crystal form, or a mixture of a plurality of crystal forms. Crystals can be produced by crystallization by applying a crystallization method known per se.
また、本発明の式(I)で表される化合物は、溶媒和物(例えば、水和物等)であってもよく、溶媒和物及び無溶媒和物(例えば、非水和物等)のいずれも式(I)で表される化合物に包含される。 Further, the compound represented by the formula (I) of the present invention may be a solvate (for example, a hydrate), and a solvate and a non-solvate (for example, a non-hydrate). All of are included in the compound represented by the formula (I).
本発明の式(I)で表される化合物の製造法
本発明に係る5−アザシチジン類糖部シリルエーテル誘導体(式(I)を参照)は、WO2017/183217で示す方法に準じ、製造することができる。 Method for Producing Compound Represented by Formula (I) of the Present Invention The 5-azacitidine sugar moiety silyl ether derivative (see formula (I)) according to the present invention shall be manufactured according to the method represented by WO2017 / 183217. Can be done.
他の薬剤
本発明の他の薬剤としては、例えば、酵素阻害剤が挙げられ、好ましくは、ヒストン脱アセチル化酵素阻害剤、ヒストンアセチル化酵素阻害剤、ヒストンメチル化酵素阻害剤、ヒストン脱メチル化酵素阻害剤及びリボヌクレオシド二リン酸レダクターゼ阻害剤からなる群から選択される酵素阻害剤の1種以上である。 Other Agents Examples of other agents of the present invention include enzyme inhibitors, preferably histone deacetylase inhibitors, histone acetylase inhibitors, histone methylase inhibitors, histone demethylation. It is one or more of enzyme inhibitors selected from the group consisting of enzyme inhibitors and ribonucleoside diphosphate reductase inhibitors.
「ヒストンアセチル化酵素阻害剤」としては、特に限定されないが、例えば、C646、MG149、Remodelin、及びAnacardic Acid等が挙げられる。 The "histone acetylase inhibitor" is not particularly limited, and examples thereof include C646, MG149, Remodelin, and Anacardic Acid.
「ヒストン脱アセチル化酵素阻害剤」としては、特に限定されないが、例えば、ボリノスタット(SAHA、MK0683)、エンチノスタット(MS−275)、パノビノスタット(LBH589)、トリコスタチンA(TSA)、モセチノスタット(MGCD0103)、BG45、BRD73954、ベリノスタット(PXD101)、ロミデプシン(FK228、デシペプチド)、4SC−202、HPOB、LMK−235、CAY10603、タスキニモド、TMP269、Nexturastat A、Rocilinostat(ACY−1215)、RGFP966、RG2833(RGFP109)、Scriptaid、ツバスタチンA、Pracinostat(SB939)、CUDC−101、M344、PCI−34051、ダシノスタット(LAQ824)、ツバスタチンA塩酸塩、アベキシノスタット(PCI−24781)、CUDC−907、AR−42、フェニル酪酸ナトリウム、レスミノスタット、ツバシン、キシノスタット(JNJ−26481585)二塩酸塩、MC1568、Givinostat(ITF2357)、Droxinostat、Chidamide(C S055、HBI−8000)、CHR−2485、CHR−3996、DAC−060、FRM−0334(EVP−0334)、MGCD−290、CXD−101(AZD−9468)、CG200745、アルギニン酪酸塩、スルフォラファン、SHP−141、CUDC−907、YM753(OBPー801)、バルプロ酸ナトリウム、アピシジン及びCI994(Tacedinaline)等が挙げられる。 The "histone deacetylase inhibitor" is not particularly limited, and is, for example, vorinostat (SAHA, MK0683), entinostat (MS-275), panobinostat (LBH589), tricostatin A (TSA), and mosetinostat (MGCD0103). ), BG45, BRD73954, Verinostat (PXD101), Romidepsin (FK228, Decipeptide), 4SC-202, HPOB, LMK-235, CAY10603, Tuskinimod, TMP269, Nexturastat A, Rocilinostat (ACY-1215) , Scriptide, Tubastatin A, Pracinostat (SB939), CUDC-101, M344, PCI-34051, Dasinostat (LAQ824), Tubastatin A hydrochloride, Abexinostat (PCI-241781), CUDC-907, AR-42, phenylbutyric acid Sodium, resminostat, tubacin, xinostat (JNJ-26481585) dihydrochloride, MC1568, Givinostat (ITF2357), Droxinostat, Chidamide (CS055, HBI-8000), CHR-2485, CHR-3996, DAC-060, FRM-0334 (EVP-0334), MGCD-290, CXD-101 (AZD-9468), CG200265, arginine butyrate, sulforaphane, SHP-141, CUDC-907, YM753 (OBP-801), sodium valproate, apicidine And CI994 (Tacedinaline) and the like.
「ヒストンメチル化酵素阻害剤」としては、特に限定されないが、例えば、DS−3201b、EPZ−6438、GSK−126、Chaetocin、BIX01294が挙げられる。 The "histone methyltransferase inhibitor" is not particularly limited, and examples thereof include DS-3201b, EPZ-6438, GSK-126, Chaetocin, and BIX01294.
「ヒストン脱メチル化酵素阻害剤」としては、特に限定されないが、例えば、GSK J4 HCl、OG−L002、JIB−04、IOX1、SP2509、ORY−1001(RG−6016)、GSK J1、ML324、GSK−LSD1 2HCl等が挙げられる。 The "histone demethylase inhibitor" is not particularly limited, and is, for example, GSK J4 HCl, OG-L002, JIB-04, IOX1, SP2509, ORY-1001 (RG-6016), GSK J1, ML324, GSK. -LSD1 2HCl and the like.
「リボヌクレオシド二リン酸レダクターゼ阻害剤」としては、特に限定されないが、例えば、ゲムシタビン、アラC、フルダラビン等が挙げられる。 The "ribonucleoside diphosphate reductase inhibitor" is not particularly limited, and examples thereof include gemcitabine, ara C, and fludarabine.
他の薬剤は、特に好ましくは、DS−3201b、HBI−8000、トリコスタチンA(TSA)、スラミン(Suramin)、EPZ005687及びAdoxからなる群から選択される1種以上である。 The other agent is particularly preferably one or more selected from the group consisting of DS-3201b, HBI-8000, Trichostatin A (TSA), Suramin, EPZ005687 and Adox.
医薬組成物は、製剤技術分野において慣用の方法、例えば、日本薬局方に記載の方法等により製造することができる。
本発明の上記医薬製剤を経口投与する場合の剤型としては、例えば、錠剤、カプセル剤、顆粒剤、散剤等の固形製剤が挙げられる。また、静脈内、皮下、筋肉内等に非経口投与する場合の剤型としては、例えば、注射剤、坐薬、舌下錠等が挙げられる。また、舌下、皮下及び筋肉内等に投与する場合の剤型としては、例えば、舌下錠、マイクロカプセル等の徐放製剤が挙げられる。The pharmaceutical composition can be produced by a method commonly used in the field of pharmaceutical technology, for example, the method described in the Japanese Pharmacopoeia.
Examples of the dosage form when the above-mentioned pharmaceutical preparation of the present invention is orally administered include solid preparations such as tablets, capsules, granules and powders. In addition, examples of dosage forms for parenteral administration such as intravenously, subcutaneously, and intramuscularly include injections, suppositories, and sublingual tablets. In addition, examples of the dosage form for administration sublingually, subcutaneously, intramuscularly, etc. include sustained-release preparations such as sublingual tablets and microcapsules.
医薬的に許容される担体としては、例えば、製剤素材として慣用の各種有機あるいは無機担体物質が用いられ、固形製剤における賦形剤、滑沢剤、結合剤、崩壊剤、増粘剤;液状製剤における溶剤、分散剤、溶解補助剤、懸濁化剤、等張化剤、緩衝剤、無痛化剤等として適宜適量配合される。また必要に応じて、常法に従い防腐剤、抗酸化剤、着色剤、甘味剤等の添加物を用いることもできる。 As the pharmaceutically acceptable carrier, for example, various conventional organic or inorganic carrier substances are used as the preparation material, and excipients, lubricants, binders, disintegrants, thickeners, and liquid preparations in solid preparations are used. An appropriate amount is appropriately blended as a solvent, a dispersant, a solubilizing agent, a suspending agent, an tonicity agent, a buffering agent, a pain-relieving agent, and the like. Further, if necessary, additives such as preservatives, antioxidants, colorants, and sweeteners can be used according to a conventional method.
賦形剤の好適な例としては、例えば乳糖、白糖、D−マンニトール、デンプン、結晶セルロース、軽質無水ケイ酸等が挙げられる。滑沢剤の好適な例としては、例えばステアリン酸マグネシウム、ステアリン酸カルシウム、タルク、コロイドシリカ等が挙げられる。結合剤の好適な例としては、例えば結晶セルロース、白糖、D−マンニトール、デキストリン、ヒドロキシプロピルセルロース、ヒドロキシプロピルメチルセルロース、ポリビニルピロリドン等が挙げられる。崩壊剤の好適な例としては、例えばデンプン、カルボキシメチルセルロース、カルボキシメチルセルロースカルシウム、クロスカルメロースナトリウム、カルボキシメチルスターチナトリウム等が挙げられる。増粘剤の好適な例としては、例えば天然ガム類、セルロース誘導体、アクリル酸重合体等が挙げられる。溶剤の好適な例としては、例えば注射用水、アルコール、プロピレングリコール、マクロゴール、ゴマ油、トウモロコシ油等が挙げられる。分散剤の好適な例としては、例えばツイーン(Tween)80、HCO 60、ポリエチレングリコール、カルボキシメチルセルロース、アルギン酸ナトリウム等が挙げられる。溶解補助剤の好適な例としては、例えばポリエチレングリコール、プロピレングリコール、D−マンニトール、安息香酸ベンジル、エタノール、トリスアミノメタン、コレステロール、トリエタノールアミン、炭酸ナトリウム、クエン酸ナトリウム等が挙げられる。懸濁化剤の好適な例としては、例えばステアリルトリエタノールアミン、ラウリル硫酸ナトリウム、ラウリルアミノプロピオン酸、レシチン、塩化ベンザルコニウム、塩化ベンゼトニウム、モノステアリン酸グリセリン等が挙げられる。界面活性剤の好適な例としては、例えばポリビニルアルコール、ポリビニルピロリドン、カルボキシメチルセルロースナトリウム、メチルセルロース、ヒドロキシメチルセルロース、ヒドロキシエチルセルロース、ヒドロキシプロピルセルロース等の親水性高分子等が挙げられる。等張化剤の好適な例としては、例えば塩化ナトリウム、グリセリン、D−マンニトール等が挙げられる。緩衝剤の好適な例としては、例えばリン酸塩、酢酸塩、炭酸塩、クエン酸塩等が挙げられる。無痛化剤の好適な例としては、例えばベンジルアルコール等が挙げられる。防腐剤の好適な例としては、例えばパラオキシ安息香酸エステル類、クロロブタノール、ベンジルアルコール、フェネチルアルコール、デヒドロ酢酸、ソルビン酸等が挙げられる。抗酸化剤の好適な例としては、例えば亜硫酸塩、アスコルビン酸等が挙げられる。 Suitable examples of excipients include, for example, lactose, sucrose, D-mannitol, starch, crystalline cellulose, light anhydrous silicic acid and the like. Preferable examples of the lubricant include magnesium stearate, calcium stearate, talc, colloidal silica and the like. Preferable examples of the binder include crystalline cellulose, sucrose, D-mannitol, dextrin, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, polyvinylpyrrolidone and the like. Preferable examples of the disintegrant include starch, carboxymethyl cellulose, calcium carboxymethyl cellulose, sodium croscarmellose, sodium carboxymethyl starch and the like. Preferable examples of the thickener include natural gums, cellulose derivatives, acrylic acid polymers and the like. Preferable examples of the solvent include, for example, water for injection, alcohol, propylene glycol, macrogol, sesame oil, corn oil and the like. Preferable examples of the dispersant include, for example, Tween 80, HCO 60, polyethylene glycol, carboxymethyl cellulose, sodium alginate and the like. Preferable examples of the solubilizing agent include polyethylene glycol, propylene glycol, D-mannitol, benzyl benzoate, ethanol, trisaminomethane, cholesterol, triethanolamine, sodium carbonate, sodium citrate and the like. Preferable examples of the suspending agent include stearyltriethanolamine, sodium lauryl sulfate, laurylaminopropionic acid, lecithin, benzalkonium chloride, benzethonium chloride, glycerin monostearate and the like. Preferable examples of the surfactant include hydrophilic polymers such as polyvinyl alcohol, polyvinylpyrrolidone, sodium carboxymethyl cellulose, methyl cellulose, hydroxymethyl cellulose, hydroxyethyl cellulose and hydroxypropyl cellulose. Preferable examples of the tonicity agent include, for example, sodium chloride, glycerin, D-mannitol and the like. Preferable examples of the buffer include, for example, phosphates, acetates, carbonates, citrates and the like. Preferable examples of the soothing agent include, for example, benzyl alcohol and the like. Preferable examples of preservatives include, for example, paraoxybenzoic acid esters, chlorobutanol, benzyl alcohol, phenethyl alcohol, dehydroacetic acid, sorbic acid and the like. Preferable examples of the antioxidant include sulfites, ascorbic acid and the like.
本発明の医薬組成物はがんの予防又は治療のために用いられる。
がんとしては、頭部及び頸部のがん、乳がん、肺がん、結腸がん、卵巣がん、前立腺がん、膠腫、神経膠芽腫、星状細胞腫、多型性神経膠芽腫、バナヤン−ゾナナ症候群、カウデン病、レルミット−ダクロス病、炎症性乳がん、ウィルムス腫瘍、ユーイング肉腫、横紋筋肉腫、上衣腫、髄芽腫、腎臓がん、肝臓がん、黒色腫、膵臓がん、肉腫、骨肉腫、骨巨細胞腫、甲状腺、リンパ芽球T細胞白血病、ATL(Adult T-cell Leukemia/Lymphoma:成人T細胞白血病/リンパ腫)、慢性骨髄性白血病、慢性リンパ球性白血病、ヘアリー細胞白血病、急性リンパ芽球性白血病、急性骨髄性白血病、AML、慢性好中球性白血病、急性リンパ芽球T細胞白血病、形質細胞腫、免疫芽球性大細胞型白血病、マントル細胞白血病、多発性骨髄腫 巨核芽球性白血病、多発性骨髄腫、急性巨核球性白血病、前骨髄球性白血病、赤白血病、悪性リンパ腫、ホジキンリンパ腫、非ホジキンリンパ腫、リンパ芽球性T細胞リンパ腫、バーキットリンパ腫、濾胞性リンパ腫、神経芽細胞腫、膀胱がん、尿路上皮がん、外陰がん、子宮頚がん、子宮体がん、腎がん、中皮腫、食道がん、唾液腺がん、肝細胞がん、胃がん、鼻咽頭がん、頬がん、口腔がん、GIST(消化管間質腫瘍)、及び精巣がん等が挙げられ、好ましくは、リンパ芽球T細胞白血病、ATL(Adult T-cell Leukemia/Lymphoma:成人T細胞白血病/リンパ腫)、慢性骨髄性白血病、慢性リンパ球性白血病、ヘアリー細胞白血病、急性リンパ芽球性白血病、急性骨髄性白血病、AML、慢性好中球性白血病、急性リンパ芽球T細胞白血病、免疫芽球性大細胞型白血病、マントル細胞白血病、巨核芽球性白血病、急性巨核球性白血病、前骨髄球性白血病、赤白血病であり、最も好ましくは、ATLであるが、これらに限定されるものではない。The pharmaceutical composition of the present invention is used for the prevention or treatment of cancer.
Cancers include head and neck cancer, breast cancer, lung cancer, colon cancer, ovarian cancer, prostate cancer, glioma, glioma, stellate cell tumor, and polymorphic glioma. , Banayan-Zonana Syndrome, Cowden's Disease, Lermit-Dachros's Disease, Inflammatory Breast Cancer, Wilms Tumor, Ewing's Memoroma, Lacterial Myoma, Topcoat, Myeloma, Kidney Cancer, Liver Cancer, Black Tumor, Pancreatic Cancer , Sarcoma, osteosarcoma, giant cell tumor of bone, thyroid gland, lymphoblastic T-cell leukemia, ATL (Adult T-cell Leukemia / Lymphoma), chronic myeloid leukemia, chronic lymphocytic leukemia, hairy Cellular leukemia, acute lymphoblastic leukemia, acute myeloid leukemia, AML, chronic neutrophil leukemia, acute lymphoblastic T-cell leukemia, plasmacytoma, immunoblastic large cell leukemia, mantle cell leukemia, multiple occurrences Myeloma macronuclear blastocytic leukemia, multiple myeloma, acute macronuclear leukemia, premyelocytic leukemia, red leukemia, malignant lymphoma, hodgkin lymphoma, non-hodgkin lymphoma, lymphoblastic T-cell lymphoma, Berkit lymphoma , Follicular lymphoma, neuroblastoma, bladder cancer, urinary tract epithelial cancer, genital cancer, cervical cancer, uterine body cancer, renal cancer, mesenteric cancer, esophageal cancer, salivary adenocarcinoma, Hepatic cell cancer, gastric cancer, nasopharyngeal cancer, cheek cancer, oral cancer, GIST (gastrointestinal stromal tumor), testicular cancer and the like, preferably lymphoblastic T-cell leukemia, ATL ( Adult T-cell Leukemia / Lymphoma), Chronic myeloid leukemia, Chronic lymphocytic leukemia, Hairy cell leukemia, Acute lymphoblastic leukemia, Acute myeloid leukemia, AML, Chronic neutrophil Leukemia, acute lymphoblastic T-cell leukemia, immunoblastic large cell leukemia, mantle cell leukemia, macronuclear leukemia, acute macronuclear leukemia, premyelocytic leukemia, red leukemia, most preferably ATL, but not limited to these.
本発明のATLの予防又は治療薬と他の薬剤とを組み合わせる場合、ATLの予防又は治療薬と他の薬剤の投与時期は限定されず、他の薬剤両者を、投与対象に対し、同時に投与してもよいし、時間差をおいて投与してもよい。ATLの予防又は治療薬と他の薬剤とは別々に製剤化されていてもよいし、両者が混合された合剤であってもよい。他の薬剤の投与量は、臨床上用いられている投与量に準ずればよく、投与対象、投与ルート、疾患、組み合わせ等により適宜選択することができる。他の薬剤の投与量は、例えば、当該他の薬剤を単剤として使用する時の投与量の3分の1から3倍量とすればよい。 When the ATL prophylactic or therapeutic drug of the present invention is combined with another drug, the administration time of the ATL prophylactic or therapeutic drug and the other drug is not limited, and both of the other drugs are simultaneously administered to the administration subject. It may be administered at a time lag. The prophylactic or therapeutic drug for ATL and other drugs may be formulated separately, or may be a mixture of both. The dose of the other drug may be based on the dose clinically used, and can be appropriately selected depending on the administration target, administration route, disease, combination and the like. The dose of the other drug may be, for example, one-third to three times the dose when the other drug is used as a single agent.
本発明のATLの予防又は治療薬と他の薬剤の投与形態は、特に限定されず、投与時に、ATLの予防又は治療薬と他の薬剤とが組み合わされていればよい。このような投与形態としては、例えば、(1)ATLの予防又は治療薬と他の薬剤とを同時に製剤化して得られる単一の製剤の投与、(2)ATLの予防又は治療薬と他の薬剤とを別々に製剤化して得られる2種の製剤の同一投与経路での同時投与、(3)ATLの予防又は治療薬と他の薬剤とを別々に製剤化して得られる2種の製剤の同一投与経路での時間差をおいての投与、(4)ATLの予防又は治療薬と他の薬剤とを別々に製剤化して得られる2種の製剤の異なる投与経路での同時投与、(5)ATLの予防又は治療薬と他の薬剤とを別々に製剤化して得られる2種の製剤の異なる投与経路での時間差をおいての投与(例えばATLの予防又は治療薬→他の薬剤の順序での投与、あるいは逆の順序での投与)等が挙げられる。 The administration form of the ATL prophylactic or therapeutic agent of the present invention and other agents is not particularly limited, and it is sufficient that the ATL prophylactic or therapeutic agent and other agents are combined at the time of administration. Such administration forms include, for example, (1) administration of a single preparation obtained by simultaneously formulating a prophylactic or therapeutic drug for ATL and another drug, and (2) prophylactic or therapeutic drug for ATL and other drugs. Simultaneous administration of two types of preparations obtained by separately formulating the drug by the same administration route, (3) Prophylactic or therapeutic drug for ATL and two types of preparations obtained by separately formulating the other drug. Administration with a time lag in the same administration route, (4) Simultaneous administration of two kinds of preparations obtained by separately formulating a prophylactic or therapeutic drug for ATL and another drug in different administration routes, (5) Prophylactic or therapeutic drug for ATL and other drug are separately formulated and two kinds of pharmaceuticals are administered at different administration routes with different administration routes (for example, ATL prophylactic or therapeutic drug → other drug in this order). Or administration in the reverse order) and the like.
本発明のATLの予防又は治療薬と他の薬剤とを組み合わせることにより、以下のような優れた効果を得ることができる。
(1)ATLの予防又は治療薬と他の薬剤を単独で投与する場合に比べて、其の投与量を軽減することができる、
(2)患者の症状(軽症、重症等)に応じて、他の薬剤の種類を選択することができる、
(3)ATLの予防又は治療薬と作用機序が異なる他の薬剤を選択することにより、治療期間を長く設定することができる、
(4)ATLの予防又は治療薬と作用機序が異なる他の薬剤を選択することにより、治療効果の持続を図ることができる、
(5)ATLの予防又は治療薬と他の薬剤とを併用することにより、相乗効果が得られる。By combining the prophylactic or therapeutic agent for ATL of the present invention with another agent, the following excellent effects can be obtained.
(1) The dose of ATL prophylactic or therapeutic drug and other drugs can be reduced as compared with the case of administration alone.
(2) The type of other drug can be selected according to the patient's symptoms (mild, severe, etc.).
(3) The treatment period can be set longer by selecting a prophylactic or therapeutic drug for ATL and another drug having a different mechanism of action.
(4) The therapeutic effect can be sustained by selecting another drug having a mechanism of action different from that of the preventive or therapeutic drug for ATL.
(5) A synergistic effect can be obtained by using a prophylactic or therapeutic drug for ATL in combination with another drug.
本発明のATLの予防又は治療薬を医薬製剤として患者に投与する場合、DNMT阻害剤(例えば、化合物(I))を単独で製剤化してもよいし、他の薬剤、薬学的に許容される担体等と混合して製剤化してもよい。医薬製剤中のDNMT阻害剤(例えば、化合物(I))の含有割合は通常0.1〜100%(w/w)である。また、医薬製剤に、他の薬剤を配合する場合、DNMT阻害剤(例えば、化合物(I))の含有割合は通常0.1〜99.9%(w/w)である。 When the prophylactic or therapeutic agent for ATL of the present invention is administered to a patient as a pharmaceutical preparation, the DNMT inhibitor (for example, compound (I)) may be formulated alone, or other medicines and pharmaceutically acceptable agents are acceptable. It may be formulated by mixing with a carrier or the like. The content ratio of the DNMT inhibitor (for example, compound (I)) in the pharmaceutical preparation is usually 0.1 to 100% (w / w). When another drug is added to the pharmaceutical product, the content ratio of the DNMT inhibitor (for example, compound (I)) is usually 0.1 to 99.9% (w / w).
医薬組成物又は剤形内の本発明のDNMT阻害剤(例えば、化合物(I))及び他の薬剤の量は、例えば、約1 mg〜約2,000 mg、約10 mg〜約2,000 mg、約20 mg〜約2,000 mg、約50 mg〜約1,000 mg、約100 mg〜約500 mg、約150 mg〜約500 mg又は約150 mg〜約250 mgの範囲であってもよい。 The amounts of the DNMT inhibitor of the invention (eg, compound (I)) and other agents in the pharmaceutical composition or dosage form are, for example, from about 1 mg to about 2,000 mg, from about 10 mg to about 2,000 mg, about 20. It may range from mg to about 2,000 mg, about 50 mg to about 1,000 mg, about 100 mg to about 500 mg, about 150 mg to about 500 mg, or about 150 mg to about 250 mg.
抗ATL活性につき、以下に示す。
実施例The anti-ATL activity is shown below.
Example
以下に、実施例を挙げて本発明を更に詳しく説明するが、これらは本発明を限定するものではない。 Hereinafter, the present invention will be described in more detail with reference to examples, but these are not intended to limit the present invention.
デシタビンとEPZ−6438をATL細胞株(HTLV−1感染細胞株)に処置した際の細胞増殖抑制効果を評価した。ATL細胞株については、MT−1株, MT−2株をJCRB細胞バンクより購入し使用した。それぞれの細胞を培養液 (10% FBSと1% Penn-Strepを含むRPMI-1640 ) 中で40,000 cells / 1 ml/ well で24 well plate へ播種し、37℃、 5% CO2下で約2時間インキュベートした。MT−1については、デシタビンの濃度は0.1、0.2、0.5、1 μM となるように、EPZ−6438の濃度は0.5、1、2.5、5 μMとなるように培養液で調整し、24 well plateへ加え、48時間インキュベートした。MT−2については、デシタビンの濃度は0.05、0.1、0.2、0.5 μM となるように、EPZ−6438の濃度は0.25、0.5、1、2.5 μMとなるように培養液で調整し、24 well plateへ加え、48時間インキュベートした。48時間後に、デシタビン又はEPZ−6438を終濃度が同じになるように再添加し、更に48時間(計96時間)インキュベートした後、100 μlの細胞培養液を96 well plate に移し、CCK-8試薬(DOJINDO、CK04)を用いて付属マニュアルに従い反応後、プレートリーダー(Varioskan Flash、サーモフィッシャーサイエンティフィック株式会社)で各wellの450 nmと620 nm (Blank)の吸収を測定した。検体無添加 wellの値を100%とした時の各検体処理 wellの値を相対値で表1及び表2に示す。
(表1)
(表2)
上記の表1から、デシタビン(DNMT阻害剤)とEPZ−6438(ヒストンメチル化酵素阻害剤)の併用処理はMT−1に対して相乗的な細胞増殖抑制効果を誘導することが判明した。
上記の表2から、デシタビンとEPZ−6438の併用処理はMT−2に対しても相乗的な細胞増殖抑制効果を誘導することが判明した。The cell proliferation inhibitory effect when decitabine and EPZ-6438 were treated on an ATL cell line (HTLV-1-infected cell line) was evaluated. As for ATL cell lines, MT-1 strain and MT-2 strain were purchased from JCRB cell bank and used. Each cell were seeded into 24 well plate culture in (RPMI-1640 containing 10% FBS and 1% Penn-Strep) in 40,000 cells / 1 ml / well, 37 ℃, 5
(Table 1)
(Table 2)
From Table 1 above, it was found that the combined treatment of decitabine (DNMT inhibitor) and EPZ-6438 (histone methyltransferase inhibitor) induces a synergistic cell proliferation inhibitory effect on MT-1.
From Table 2 above, it was found that the combined treatment of decitabine and EPZ-6438 induces a synergistic cell proliferation inhibitory effect on MT-2 as well.
ATL細胞株(HTLV−1 感染細胞株)であるMT−1株及びMT−2株についてはJCRB細胞バンクより購入した。それぞれの細胞を培養液 (10% FBSと1% Penn-Strepを含むRPMI-1640)中で0.5 x 105 cells / 0.9 ml/ well で24 well plate へ播種し、37℃、 5% CO2下で約3時間 インキュベートした。5 μM -1.6 μMとなるように培養液で希釈したOR−21単剤、DS−3201b単剤、OR−21, DS−3201b混合液を100 μlずつ24 well plateへ加え、8日間培養した (化合物終濃度500-16 nM)。この間、2日毎に新鮮な化合物を再添加した。また、培養4日後には細胞培養液を5倍希釈した。抗腫瘍効果については、細胞培養液を100 μlを96 well plateに分取し、CCK-8試薬(DOJINDO、CK04)を用いて付属マニュアルに従い反応後、プレートリーダー(Varioskan Flash、サーモフィッシャーサイエンティフィック株式会社)で各wellの450 nmと620 nm (Blank)の吸収を測定した。検体無添加 wellの値を100%とした時の各検体処理 wellの値を相対値で表し、IC50値を算出した。その結果を図1及び2に示す。OR−21は、式(I)においてR、R’、 R2は水素原子であり、R1は、トリエチルシリル基である化合物であり、OR−21の名称は 5'-O-Triethylsilyl-2'-deoxy-5-azacytidine である。
また、形態変化については化合物処理4日後に位相差顕微鏡により観察した。その結果を図2に示す。 図1から、OR−21(DNMT阻害剤)とDS−3201b(ヒストンメチル化酵素阻害剤)の6日間の併用処理はMT−1の細胞増殖を相乗的に抑制する(IC50; OR−21: 58 nM, DS−3201b: > 500 nM, 併用処理: 36 nM)ことが判明した。 図2から、OR−21とDS−3201bの4日間の併用処理はMT−2の細胞増殖を相乗的に抑制する(IC50; OR−21: 172 nM, DS−3201b: > 500 nM, 併用処理 118 nM)こと、また細胞がディッシュ底に接着・伸展しており、併用処理により、特徴的に細胞の接着性が亢進することが判明した。The MT-1 and MT-2 strains, which are ATL cell lines (HTLV-1 infected cell lines), were purchased from the JCRB cell bank. Each cell was seeded in culture medium (RPMI-1640 with 10% FBS and 1% Penn-Strep) at 0.5 x 10 5 cells / 0.9 ml / well on a 24-well plate at 37 ° C. under 5% CO 2. Incubated for about 3 hours. 100 μl of OR-21 single agent, DS-3201b single agent, OR-21, DS-3201b mixture diluted with a culture solution to 5 μM -1.6 μM was added to a 24-well plate and cultured for 8 days ( Compound final concentration 500-16 nM). During this time, fresh compounds were re-added every two days. In addition, 4 days after culturing, the cell culture solution was diluted 5-fold. For the antitumor effect, 100 μl of the cell culture solution was dispensed into a 96-well plate, reacted using the CCK-8 reagent (DOJINDO, CK04) according to the attached manual, and then a plate reader (Varioskan Flash, Thermo Fisher Scientific). (Co., Ltd.) measured the absorption of 450 nm and 620 nm (Blank) of each well. The IC 50 value was calculated by expressing the value of each sample processing well when the value of the sample-free well was set to 100% as a relative value. The results are shown in FIGS. 1 and 2. OR-21 is a compound in which R, R'and R 2 are hydrogen atoms and R 1 is a triethylsilyl group in the formula (I), and the name of OR-21 is 5'-O-Triethylsilyl-2. '-deoxy-5-azacytidine.
The morphological change was observed with a phase-
本発明によれば、DNMT阻害剤を他の薬剤と組み合わせて、がんの予防薬又は治療薬として医療現場に提供することができる。 According to the present invention, a DNMT inhibitor can be combined with other drugs and provided to medical practice as a preventive or therapeutic drug for cancer.
Claims (29)
(式中、R及びR’は、それぞれOR3基、水素原子、ハロゲン原子又はアルキル基であり、R1、R2及びR3は、それぞれ水素原子又は式(II):
(式中、R4、R5及びR6は、それぞれ置換基を有していてもよいアルキル基又はアリール基又はアリールアルキル基である。)で表されるシリル基である。)で表される化合物又は其の塩、デシタビン、アザシチジン、RG108、チオグアニン、ゼブラリン、SGI−110、CC−486、SGI−1027、ロメグアトリブ又はプロカイナミド塩酸塩である、請求項1〜3のいずれか1項に記載の医薬組成物。The DNMT inhibitor is of formula (I):
(In the formula, R and R'are OR 3 groups, hydrogen atoms, halogen atoms or alkyl groups, respectively, and R 1 , R 2 and R 3 are hydrogen atoms or formula (II), respectively:
(In the formula, R 4 , R 5 and R 6 are alkyl groups or aryl groups or arylalkyl groups which may have substituents, respectively). ), Decitabine, azacitidine, RG108, thioguanine, zebularine, SGI-110, CC-486, SGI-1027, romeguatrib or procainamide hydrochloride, any one of claims 1 to 3. The pharmaceutical composition according to the section.
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