JP6932342B2 - 肝臓癌を処置するための組成物および方法 - Google Patents
肝臓癌を処置するための組成物および方法 Download PDFInfo
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- JP6932342B2 JP6932342B2 JP2018539985A JP2018539985A JP6932342B2 JP 6932342 B2 JP6932342 B2 JP 6932342B2 JP 2018539985 A JP2018539985 A JP 2018539985A JP 2018539985 A JP2018539985 A JP 2018539985A JP 6932342 B2 JP6932342 B2 JP 6932342B2
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- heteroaryl
- pharmaceutically acceptable
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C225/00—Compounds containing amino groups and doubly—bound oxygen atoms bound to the same carbon skeleton, at least one of the doubly—bound oxygen atoms not being part of a —CHO group, e.g. amino ketones
- C07C225/22—Compounds containing amino groups and doubly—bound oxygen atoms bound to the same carbon skeleton, at least one of the doubly—bound oxygen atoms not being part of a —CHO group, e.g. amino ketones having amino groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C225/00—Compounds containing amino groups and doubly—bound oxygen atoms bound to the same carbon skeleton, at least one of the doubly—bound oxygen atoms not being part of a —CHO group, e.g. amino ketones
- C07C225/20—Compounds containing amino groups and doubly—bound oxygen atoms bound to the same carbon skeleton, at least one of the doubly—bound oxygen atoms not being part of a —CHO group, e.g. amino ketones having amino groups bound to carbon atoms of rings other than six-membered aromatic rings of the carbon skeleton
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/12—Ketones
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- A—HUMAN NECESSITIES
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- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/12—Ketones
- A61K31/122—Ketones having the oxygen directly attached to a ring, e.g. quinones, vitamin K1, anthralin
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C49/00—Ketones; Ketenes; Dimeric ketenes; Ketonic chelates
- C07C49/527—Unsaturated compounds containing keto groups bound to rings other than six-membered aromatic rings
- C07C49/543—Unsaturated compounds containing keto groups bound to rings other than six-membered aromatic rings to a six-membered ring
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C49/00—Ketones; Ketenes; Dimeric ketenes; Ketonic chelates
- C07C49/527—Unsaturated compounds containing keto groups bound to rings other than six-membered aromatic rings
- C07C49/557—Unsaturated compounds containing keto groups bound to rings other than six-membered aromatic rings having unsaturation outside the rings
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/04—Indoles; Hydrogenated indoles
- C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
- C07D209/14—Radicals substituted by nitrogen atoms, not forming part of a nitro radical
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
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Description
R2は、水素、C(=O)OR5、C(=O)R5、C(=O)NR5R6、あるいは1つ以上のハロゲン、アリールまたはヘテロアリールで随意に置換されたC1−C8アルキルであり、
R3は、水素、随意に置換されたメチルまたは(CH2)m−CH3であり、
R4は、H、C(=O)OR5、C(=O)R5、C(=O)NR5R6、C1−C8アルキル、C2−C8アルケニル、C2−C8アルキニルであり、
ここでC1−C8アルキル、C2−C8アルケニル、C2−C8アルキニルは、NR5R6、OR5、OC(=O)R7、C(=O)OR5、C(=O)R5、C(=O)NR5R6、C1−C8アルキル、C2−C8アルケニル、C2−C8アルキニル、C3−C8シクロアルキル、およびC1−C8ハロアルキルから選択される1つ以上の置換基で随意に置換され;
R5およびR6はそれぞれ、独立してHまたはC1−C8アルキルであり;
R7は、C1−C8アルキル、OR5またはNR5R6である。
R2は、水素、C(=O)OR5、C(=O)R5、C(=O)NR5R6、あるいは1つ以上のハロゲン、アリールまたはヘテロアリールで随意に置換されたC1−C8アルキルであり、および
R5およびR6はそれぞれ、独立してHまたはC1−C8アルキルである。
R2は、水素、C(=O)OR5、C(=O)R5、C(=O)NR5R6、あるいは1つ以上のハロゲン、NR5R6、OR5、C6−C10アリールまたはC4−C10ヘテロアリールで随意に置換されたC1−C8アルキルであり、
R3は、水素、随意に置換されたメチルまたは(CH2)m−CH3であり、
R4は、H、C(=O)OR5、C(=O)R5、C(=O)NR5R6、C1−C8アルキル、C2−C8アルケニル、C2−C8アルキニルであり、
ここでC1−C8アルキル、C2−C8アルケニル、C2−C8アルキニルは、NR5R6、OR5、OC(=O)R7、C(=O)OR5、C(=O)R5、C(=O)NR5R6、C1−C8アルキル、C2−C8アルケニル、C2−C8アルキニル、C3−C8シクロアルキル、およびC1−C8ハロアルキルから選択される1つ以上の置換基で随意に置換され;
R5およびR6はそれぞれ、独立してHまたはC1−C8アルキルであり;および
R7は、C1−C8アルキル、OR5またはNR5R6である。
本明細書で言及されるすべての公報、特許、および特許出願は、個々の公報、特許、特許出願が引用によって組み込まれるように具体的且つ個々に示される程度まで、引用によって本明細書に組み込まれる。
R2は、水素、C(=O)OR5、C(=O)R5、C(=O)NR5R6、あるいは1つ以上のハロゲン、アリールまたはヘテロアリールで随意に置換されたC1−C8アルキルであり、
R3は、水素、随意に置換されたメチルまたは(CH2)m−CH3であり、
R4は、H、C(=O)OR5、C(=O)R5、C(=O)NR5R6、C1−C8アルキル、C2−C8アルケニル、C2−C8アルキニルであり、
ここでC1−C8アルキル、C2−C8アルケニル、C2−C8アルキニルは、NR5R6、OR5、OC(=O)R7、C(=O)OR5、C(=O)R5、C(=O)NR5R6、C1−C8アルキル、C2−C8アルケニル、C2−C8アルキニル、C3−C8シクロアルキル、およびC1−C8ハロアルキルから選択される1つ以上の置換基で随意に置換され;
R5およびR6はそれぞれ、独立してHまたはC1−C8アルキルであり;および
R7は、C1−C8アルキル、OR5またはNR5R6である。
特定の実施形態では、Rは、H、またはC1−C8アルキルである。特定の実施形態では、Rは、水素、メチル、エチル、プロピル、ブチル、ペンチル、またはヘキシルである。特定の実施形態では、Rは、水素、C(=O)OR5、C(=O)R5、またはC(=O)NR5R6である。特定の実施形態では、Rは、H、C1−C8アルキル、C(=O)OR5、C(=O)R、5またはC(=O)NR5R6である。特定の実施形態では、Rは、H、またはC(=O)R5である。特定の実施形態では、Rは、H、C(=O)C3H8、C(=O)C2H5、またはC(=O)CH3である。特定の実施形態では、Rは、H、C1−C8アルキル、あるいは1つ以上のNR5R6、またはC4−C10ヘテロアリールで置換されたC1−C8アルキルである。
R2は、水素、C(=O)OR5、C(=O)R5、C(=O)NR5R6、あるいは1つ以上のハロゲン、アリールまたはヘテロアリールで随意に置換されたC1−C8アルキルであり;および
R5およびR6はそれぞれ、独立してHまたはC1−C8アルキルである。
R2の各々、およびR3は、独立して、水素、随意に置換されたメチルまたは(CH2)m−CH3であり、
R4は、H、C(=O)OR5、C(=O)R5、C(=O)NR5R6、C1−C8アルキル、C2−C8アルケニル、C2−C8アルキニルであり、
ここでC1−C8アルキル、C2−C8アルケニル、C2−C8アルキニルは、NR5R6、OR5、OC(=O)R7、C(=O)OR5、C(=O)R5、C(=O)NR5R6、C1−C8アルキル、C2−C8アルケニル、C2−C8アルキニル、C3−C8シクロアルキル、およびC1−C8ハロアルキルから選択される1つ以上の置換基で随意に置換され;
R5およびR6はそれぞれ、独立してHまたはC1−C8アルキルであり;
R7は、C1−C8アルキル、OR5またはNR5R6である。
典型的な抗癌剤を、適切なアミン試薬とともに、4−ヒドロキシ−2,3−ジメトキシ−6−メチル−5−(3,7,11−トリメチルドデカ−2,6,10−トリエニル)シクロヘキサ−2−エノン(100mg、0.256mmol)からスキーム1に従って調製した。化合物1の調製のためのより詳細な実験手順は以下に提供される。
30%の水酸化アンモニウム(NH4OH)溶液(2.6mL、66.8mmol)を、氷浴でのN2下におけるMeOH(26mL)中の4−ヒドロキシ−2,3−ジメトキシ−6−メチル−5−(3,7,11−トリメチルドデカ−2,6,10−トリエニル)シクロヘキサ−2−エノン(100mg、0.256mmol)の溶液に加えた。混合物を、16時間N2下において室温で撹拌した。過剰な水酸化アンモニウムを除去し、残留物をCH2Cl2(10mL×3)で抽出した。組み合わせた有機相を、ブライン10mLで洗浄し、Na2SO4上で乾燥し、真空内で濃縮して、生成物64mg(0.17mmol、67%)を得た。1H(600MHz;CDCl3)δ 1.14 (3H, d, J = 7.4 Hz), 1.54 (3H, s), 1.54−1.56 (br, 6H), 1.63 (3H, s), 1.89−1.98 (5H, m), 1.98−2.07 (5H, m), 2.31−2.38 (1H, m), 2.39−2.46 (1H, m), 3.59 (3H, s), 4.72 (1H, d, J = 4.4 Hz), 5.02−5.06 (2H, m), 5.10 (1H, t, J = 7.3 Hz); 13C (125 MHz; CDCl3) δ 15.9, 16.0, 16.1, 17.6, 25.6, 26.0, 26.5, 26.7, 39.6, 39.8, 42.0, 46.0, 59.0, 66.0, 122.0, 123.9, 124.3, 128.9, 131.2, 135.1, 137.8, 154.8, 192.0;
EI−MS,m/z 398[M+Na]+。
MTT(3−(4,5−ジメチルチアゾール−2−イル)−2,5−ジフェニルテトラゾリウムブロミド)細胞生存率アッセイは、比色アッセイ系であり、これは、生存細胞のミトコンドリアにおけるコハク酸塩テトラゾリウム還元酵素によるテトラゾリウム成分(MTT)の不溶性の青/紫色のホルマザン生成物への還元を測定する。複合体の吸光度は、分光測定で読み取られ、生細胞または生存細胞の数に正比例している。それ故、ホルマザン形成は、細胞の生存率を評価する且つ判定するために使用され得る。
4〜6週齢の胸腺ヌードマウス(National Laboratory Animal Center)を使用して、無菌条件下でラミナーフローキャビネットにおいて維持した。ルシフェラーゼ遺伝子を運ぶヒトHCC Mahlavu細胞(1×106細胞)を、50%のマトリゲル(BD Biosciences, MA)を含有している20μLのPBS中に再懸濁し、無菌技術(Lu et al., 2007)によって27ゲージの針を用いて無胸腺ヌードマウス(National Laboratory Animal Center)の左側肝葉に注入した。生物発光イメージングのために、動物に、0.2mLの無菌の等張生理食塩水中の150mg/kg用量のルシフェラーゼ基質D−ルシフェリンを注入した。
図1は、典型的な試験化合物で処置したTHP−1異種移植片マウスの腫瘍サイズの縮小を示す。癌を有するマウスを、4週間、1週当たり5日間の1日2回、強制経口投与によって120mg/kgのビヒクル(オリーブ油)または化合物1で処置した。腫瘍体積を週2回測定した。***ビヒクル対照と比較したP<0.005。
Claims (15)
- 式Iの化合物、またはその薬学的に許容可能な塩または溶媒和物であって、
R2は、水素またはC 1 −C 8 アルキル、あるいは1つ以上のハロゲン、アリールまたはヘテロアリールで置換されたC1−C8アルキルであり、
R3は、水素、メチル、置換されたメチルまたは(CH2)m−CH3であり、m=1−6であり、
R4は、H、C 1−C8アルキル、C2−C8アルケニル、C2−C8アルキニル、あるいはC1−C8アルキル、C2−C8アルケニル、C2−C8アルキニル、C3−C8シクロアルキル、およびC1−C8ハロアルキルから選択される1つ以上の置換基で置換された、C 1 −C 8 アルキル、C 2 −C 8 アルケニル、C 2 −C 8 アルキニルであり、
R5およびR6はそれぞれ、独立してHまたはC1−C8アルキルである、化合物、またはその薬学的に許容可能な塩または溶媒和物。 - R3はメチルであり、R4はHである、請求項1に記載の化合物、またはその薬学的に許容可能な塩または溶媒和物。
- R3が、水素、メチル、エチル、プロピル、ブチル、ペンチル、またはヘキシルである、請求項1に記載の化合物、またはその薬学的に許容可能な塩または溶媒和物。
- R4が、メチル、エチル、プロピル、ブチル、ペンチル、ヘキシル、C(=O)OR5、C(=O)R5、またはC(=O)NR5R6である、請求項1に記載の化合物、またはその薬学的に許容可能な塩または溶媒和物。
- Rの各々、およびR1が、独立して、水素、1つ以上のハロゲン、NR5R6、OR5、アリールまたはヘテロアリールで随意に置換された、メチル、エチル、プロピル、ブチル、ペンチル、ヘキシルである、請求項1に記載の化合物、またはその薬学的に許容可能な塩または溶媒和物。
- R1が、水素、1つ以上のハロゲン、NR5R6、あるいはヘテロアリールで随意に置換された、メチル、エチル、プロピル、ブチル、ペンチル、ヘキシルである、請求項5に記載の化合物、またはその薬学的に許容可能な塩または溶媒和物。
- Rが、水素、C(=O)OR5、C(=O)R5、C(=O)NR5R6、またはC1−C8アルキルである、請求項1に記載の化合物、またはその薬学的に許容可能な塩または溶媒和物。
- R1が、水素、あるいは1つ以上のハロゲン、NR5R6、OR5、アリールまたはヘテロアリールで随意に置換されたC1−C8アルキルであり、Rが、H、またはC(=O)R5である、請求項1または2に記載の化合物、またはその薬学的に許容可能な塩または溶媒和物。
- R2が、メチル、エチル、プロピル、ブチル、ペンチル、ヘキシル、C(=O)OR5、C(=O)R5、またはC(=O)NR5R6である、請求項8に記載の化合物、またはその薬学的に許容可能な塩または溶媒和物。
- 被験体の肝臓癌の処置に使用される治療学的に有効な量の請求項1または2のシクロヘキセノン化合物を含む、医薬組成物。
- 前記化合物が肝臓癌細胞を阻害する、請求項12に記載の医薬組成物。
- 前記化合物が癌腫瘍重量を減少させるか、または癌腫瘍サイズを縮小させる、請求項12に記載の医薬組成物。
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