JP7296643B2 - ベキサロテン誘導体および癌の治療におけるその使用 - Google Patents
ベキサロテン誘導体および癌の治療におけるその使用 Download PDFInfo
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- JP7296643B2 JP7296643B2 JP2020544954A JP2020544954A JP7296643B2 JP 7296643 B2 JP7296643 B2 JP 7296643B2 JP 2020544954 A JP2020544954 A JP 2020544954A JP 2020544954 A JP2020544954 A JP 2020544954A JP 7296643 B2 JP7296643 B2 JP 7296643B2
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- Prior art keywords
- alkyl
- compound
- pharmaceutically acceptable
- haloalkyl
- carbon atom
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Classifications
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- C07C63/68—Compounds having carboxyl groups bound to a carbon atoms of six-membered aromatic rings containing halogen
- C07C63/74—Compounds having carboxyl groups bound to a carbon atoms of six-membered aromatic rings containing halogen having unsaturation outside the aromatic rings
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C13/00—Cyclic hydrocarbons containing rings other than, or in addition to, six-membered aromatic rings
- C07C13/28—Polycyclic hydrocarbons or acyclic hydrocarbon derivatives thereof
- C07C13/32—Polycyclic hydrocarbons or acyclic hydrocarbon derivatives thereof with condensed rings
- C07C13/47—Polycyclic hydrocarbons or acyclic hydrocarbon derivatives thereof with condensed rings with a bicyclo ring system containing ten carbon atoms
- C07C13/48—Completely or partially hydrogenated naphthalenes
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
- A61K31/192—Carboxylic acids, e.g. valproic acid having aromatic groups, e.g. sulindac, 2-aryl-propionic acids, ethacrynic acid
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Description
本出願は、2018年3月1日に出願された米国特許仮出願第62/637,387号の優先権の利益を主張し、その全体が参照によって組み込まれる。
癌は、腫瘍形成、ある部位から別の部位への癌性細胞の転移、および罹患した個体の死をしばしばもたらす細胞の異常または制御されない増殖である。各年、数千万例を超える新たな症例が世界中で診断される。さらに、ほとんど1千万件の癌関連死が毎年世界中で生じる。癌を治す理解および努力における大幅な進歩にも関わらず、1年あたりの癌症例数は次の20年以内にほぼ2倍になることが予想される。
2つのR基およびこれらが結合している炭素原子が=CH2またはシクロプロピル環を形成し、
R1は、-CO2H、-CO2(C1~C6アルキル)、-CO2(アリールC1~C6アルキル)、-CO2(アリール)、-CHO、-CONH2、-CONH(C1~C6アルキル)、-CON(C1~C6アルキル)2、-CONH-OH、-CONH-OCO(C1~C6アルキル)、-CONH-NH2、-N(R9)SO2R9、-SO2N(R9)2、-N(CO)NHSO2CH3、テトラゾール、イソキサゾール、ヒドロキシイソキサゾール、およびオキサゾリジンジオンからなる群から選択され、
各R9は独立して、水素、C1~C6アルキル、アリール、およびヘテロアリールからなる群から選択され、
R2は、ハロゲン、C1~C6アルキル、C1~C6ハロアルキル、ヒドロキシ(C1~C6アルキル)、アルコキシ(C1~C6アルキル)、アミノ(C1~C6アルキル)、または-CNであり、
R3は、水素、ハロゲン、C1~C6アルキル、またはC1~C6ハロアルキルであり、
R4およびR5は独立して、C1~C6アルキルまたはC1~C6ハロアルキルであるか、あるいはR4およびR5はこれらが結合している炭素原子とともに、任意に1つ以上のR8によって置換されるC3~C6シクロアルキルを形成し、
R6およびR7は独立して、C1~C6アルキルまたはC1~C6ハロアルキルであるか、あるいはR6およびR7はこれらが結合している炭素原子とともに、任意に1つ以上のR8によって置換されるC3~C6シクロアルキルを形成し、
各R8は独立して、ハロゲン、-NO2、-CN、C1~C6アルキル、C1~C6ハロアルキル、-NH2、-NH(C1~C6アルキル)、-N(C1~C6アルキル)2、-OH、C1~C6アルコキシ、およびC1~C6ハロアルコキシからなる群から選択され、
ただし、R2、R4、R5、R6、およびR7の各々が独立してメチルであるとき、R3は水素ではない。
XはCH2、O、またはNHであり、
yはCH2、O、またはNHであり、
mは整数1~4であり、
nは整数1~4であり、
R1は、-CO2H、-CO2(C1~C6アルキル)、-CO2(アリールC1~C6アルキル)、-CO2(アリール)、-CHO、-CONH2、-CONH(C1~C6アルキル)、-CON(C1~C6アルキル)2、-CONH-OH、-CONH-OCO(C1~C6アルキル)、-CONH-NH2、-N(R9)SO2R9、-SO2N(R9)2、-N(CO)NHSO2CH3、テトラゾール、イソキサゾール、ヒドロキシイソキサゾール、およびオキサゾリジンジオンからなる群から選択され、
各R9は独立して、水素、C1~C6アルキル、アリール、およびヘテロアリールからなる群から選択され、
R2は、ハロゲン、C1~C6アルキル、C1~C6ハロアルキル、ヒドロキシ(C1~C6アルキル)、アルコキシ(C1~C6アルキル)、アミノ(C1~C6アルキル)、または-CNであり、
R3は、水素、ハロゲン、C1~C6アルキル、またはC1~C6ハロアルキルであり、
R4およびR5は独立して、C1~C6アルキルまたはC1~C6ハロアルキルであるか、あるいはR4およびR5はこれらが結合している炭素原子とともに、任意に1つ以上のR8によって置換されるC3~C6シクロアルキルを形成し、
R6およびR7は独立して、C1~C6アルキルまたはC1~C6ハロアルキルであるか、あるいはR6およびR7はこれらが結合している炭素原子とともに、任意に1つ以上のR8によって置換されるC3~C6シクロアルキルを形成し、
各R8は独立して、ハロゲン、-NO2、-CN、C1~C6アルキル、C1~C6ハロアルキル、-NH2、-NH(C1~C6アルキル)、-N(C1~C6アルキル)2、-OH、C1~C6アルコキシ、およびC1~C6ハロアルコキシからなる群から選択される。
2つのR基およびこれらが結合している炭素原子が=CH2またはシクロプロピル環を形成し、
R1は、-CO2H、-CO2(C1~C6アルキル)、-CO2(アリールC1~C6アルキル)、-CO2(アリール)、-CHO、-CONH2、-CONH(C1~C6アルキル)、-CON(C1~C6アルキル)2、-CONH-OH、-CONH-OCO(C1~C6アルキル)、-CONH-NH2、-N(R9)SO2R9、-SO2N(R9)2、-N(CO)NHSO2CH3、テトラゾール、イソキサゾール、ヒドロキシイソキサゾール、およびオキサゾリジンジオンからなる群から選択され、
各R9は独立して、水素、C1~C6アルキル、アリール、およびヘテロアリールからなる群から選択され、
R2は、ハロゲン、C1~C6アルキル、C1~C6ハロアルキル、ヒドロキシ(C1~C6アルキル)、アルコキシ(C1~C6アルキル)、アミノ(C1~C6アルキル)、または-CNであり、
R3は、水素、ハロゲン、C1~C6アルキル、またはC1~C6ハロアルキルであり、
R4およびR5は独立して、C1~C6アルキルまたはC1~C6ハロアルキルであるか、あるいはR4およびR5はこれらが結合している炭素原子とともに、任意に1つ以上のR8によって置換されるC3~C6シクロアルキルを形成し、
R6およびR7は独立して、C1~C6アルキルまたはC1~C6ハロアルキルであるか、あるいはR6およびR7はこれらが結合している炭素原子とともに、任意に1つ以上のR8によって置換されるC3~C6シクロアルキルを形成し、
各R8は独立して、ハロゲン、-NO2、-CN、C1~C6アルキル、C1~C6ハロアルキル、-NH2、-NH(C1~C6アルキル)、-N(C1~C6アルキル)2、-OH、C1~C6アルコキシ、およびC1~C6ハロアルコキシからなる群から選択され、
ただし、R2、R4、R5、R6、およびR7の各々が独立してメチルであるとき、R3は水素ではない。
XはCH2、O、またはNHであり、
yはCH2、O、またはNHであり、
mは整数1~4であり、
nは整数1~4であり、
R1は、-CO2H、-CO2(C1~C6アルキル)、-CO2(アリールC1~C6アルキル)、-CO2(アリール)、-CHO、-CONH2、-CONH(C1~C6アルキル)、-CON(C1~C6アルキル)2、-CONH-OH、-CONH-OCO(C1~C6アルキル)、-CONH-NH2、-N(R9)SO2R9、-SO2N(R9)2、-N(CO)NHSO2CH3、テトラゾール、イソキサゾール、ヒドロキシイソキサゾール、およびオキサゾリジンジオンからなる群から選択され、
各R9は独立して、水素、C1~C6アルキル、アリール、およびヘテロアリールからなる群から選択され、
R2は、ハロゲン、C1~C6アルキル、C1~C6ハロアルキル、ヒドロキシ(C1~C6アルキル)、アルコキシ(C1~C6アルキル)、アミノ(C1~C6アルキル)、または-CNであり、
R3は、水素、ハロゲン、C1~C6アルキル、またはC1~C6ハロアルキルであり、
R4およびR5は独立して、C1~C6アルキルまたはC1~C6ハロアルキルであるか、あるいはR4およびR5はこれらが結合している炭素原子とともに、任意に1つ以上のR8によって置換されるC3~C6シクロアルキルを形成し、
R6およびR7は独立して、C1~C6アルキルまたはC1~C6ハロアルキルであるか、あるいはR6およびR7はこれらが結合している炭素原子とともに、任意に1つ以上のR8によって置換されるC3~C6シクロアルキルを形成し、
各R8は独立して、ハロゲン、-NO2、-CN、C1~C6アルキル、C1~C6ハロアルキル、-NH2、-NH(C1~C6アルキル)、-N(C1~C6アルキル)2、-OH、C1~C6アルコキシ、およびC1~C6ハロアルコキシからなる群から選択される。
本開示はまた、癌を治療する方法を提供する。このような方法は、このような治療を必要とする対象に、本明細書で説明される開示の1種類以上の化合物(すなわち、式(I)、(I-1)、(I-2)、(II-1)~(II-6)の化合物)、または本明細書で説明される開示の医薬組成物の有効な量を投与することを含む。
一実施形態では、本開示は前述の化合物および少なくとも1種類の医薬品として許容可能な担体、溶媒、補助剤、または希釈剤を含む医薬組成物を提供する。
本明細書全体を通して、文脈が別段に必要としない限り、用語「含む(comprise)」および「含む(include)」および変形(例えば、「含む(comprises)」、「含んでいる(comprising)」、「含む(includes)」、「含んでいる(including)」)は、記載される成分、特性、要素、またはステップ、あるいは成分、特性、要素、またはステップの群の包含を意味すると理解されるが、いかなる他の統合またはステップあるいは統合またはステップの群も除外するものではない。
開示される化合物を合成するために有用である一般的に知られている化学合成スキームおよび条件を提供する多くの全般的な参考文献が利用可能である(例えば、Smith and March,March’s Advanced Organic Chemistry:Reactions,Mechanisms,and Structure,Fifth Edition,Wiley-Interscience,2001、またはVogel,A Textbook of Practical Organic Chemistry,Including Qualitative Organic Analysis,4th Edition,New York: Longman,1978を参照されたい)。
すべての試薬は市販されており、さらに精製または乾燥することなく「そのまま」使用した。1H-NMRスペクトルは、Bruker Ultrashield 400(400MHz)装置で得た。Prep-HPLC精製は、Agela HS-1000T装置でアセトニトリル/水を用いて実施した。LC/MS分析は、SHIMADZU LCMS-2020EVでKinetex 2.6μm EVO C18 100A、50mmx3.0mm、2.6μmカラムを用いて実施した。使用した標準グラジエントは、10%ACN/H2Oから95%ACN/H2Oまでだった。水相を5mM重炭酸アンモニウムで緩衝化した。
HL60細胞をRPMI、10%ウシ胎児血清で増殖させ、細胞を0.5x106個/mLの密度で本開示の化合物、全トランスレチノイン酸(ATRA)(陽性コントロール)、またはDMSO(陰性コントロール)の存在中でプレートに24時間加えた。細胞を洗浄し、ウサギ血清でブロックしてから染色した。マウス抗ヒトCD45 BV711およびCD38 PE-Cy7をFVS510(BD Biosciences、San Jose、CA、USA)の存在下で使用して、細胞分化の指標としてCD38誘導を測定した。データはDivaソフトウェア(BD Biosciences)を用いてBD LSR IIフローサイトメーターで取得した。フロープロットは、FlowJo(V10)およびFCS Express(6.06.0014)を用いて分析した。CD38誘導は、一重項排除(FSC-H/FSC-A)と生存率(FVS510-)に関する選別後に全細胞のパーセンテージとして示される。結果を図1に示す。本開示の化合物は、HL60細胞において用量依存的なCD38発現を誘導し、白血病性芽球の初期分化を示唆する。
MV4;11細胞をRPMI、10%ウシ胎児血清で増殖させ、細胞を0.5x106個/mLの密度で本開示の化合物、全トランスレチノイン酸(ATRA)(陽性コントロール)、またはDMSO(陰性コントロール)の存在中でプレートに24時間加えた。細胞を洗浄し、ウサギ血清でブロックしてから染色した。マウス抗ヒトCD45 BV711およびCD38 PE-Cy7をFVS510(BD Biosciences,San Jose,CA,USA)の存在下で使用して、細胞分化の指標としてCD38誘導を測定した。データはDivaソフトウェア(BD Biosciences)を用いてBD LSR IIフローサイトメーターで取得した。フロープロットは、FlowJo(V10)およびFCS Express(6.06.0014)を用いて分析した。CD38誘導は、一重項排除(FSC-H/FSC-A)と生存率(FVS510-)に関する選別後に全細胞のパーセンテージとして示される。結果を図2に示す。本開示の化合物は、MV4;11細胞において用量依存的なCD38発現を誘導し、これは白血病性芽球の初期段階の分化を示唆する。
NB4細胞をRPMI、10%ウシ胎児血清で増殖させ、細胞を25000個/mLの密度で本開示の化合物、ATRA(陽性コントロール)、またはDMSO(陰性コントロール)の存在中で、プレートに4日間加えた。細胞を洗浄し、ウサギ血清でブロックしてから染色した。マウス抗ヒトCD11b PEおよびLive-Dead Aqua(BD Biosciences、San Jose,CA,USA)を使用して、細胞分化の指標としてCD11b誘導を測定した。データはDivaソフトウェア(BD Biosciences)を用いてBD LSR IIフローサイトメーターで取得した。フロープロットは、FlowJo(V10)およびFCS Express(6.06.0014)を用いて分析した。CD38誘導は、一重項排除(FSC-H/FSC-A)と生存率(FVS510-)に関する選別後に全細胞のパーセンテージとして示される。ATRA陽性コントロールを4回繰り返して実施した。結果を図3に示す。本開示の化合物およびベキサロテンは、同レベルの後期分化活性および用量反応パターンを示す。
NB4細胞またはMV4;11細胞をRPMI、10%ウシ胎児血清で増殖させ、本開示の化合物(DMSOに溶解)の存在下または非存在下で細胞25,000個/mLの密度でプレートに5日間加えた。細胞は、血球計数盤およびトリパンブルー排除を用いて光学顕微鏡で、またはCellometer Viastain AOPI染色液(Nexcelom CS2-0106)を用いてNexcelom Cellometer Auto 2000で、マニュアルによって計数した。図4は、NB4細胞が本開示の化合物またはベキサロテンとのインキュベーション後に細胞数の用量依存的な減少を示し、本開示の化合物による細胞数の減少が、同等レベルのベキサロテンで認められるよりも大きく現れる。図5は、MV4;11細胞が本開示の化合物またはATRAとともにインキュベートされたときの細胞数の用量依存的な減少を示し、本開示の化合物は、同様な用量のベキサロテンよりも大きな細胞数の減少を示す。
Claims (14)
- 式
2つのR基およびこれらが結合している炭素原子が=CH2またはシクロプロピル環を形成し、
R1は、-CO2H、-CO2(C1~C6アルキル)、-CO2(アリールC1~C6アルキル)、-CO2(アリール)、-CHO、-CONH2、-CONH(C1~C6アルキル)、-CON(C1~C6アルキル)2、-CONH-OH、-CONH-OCO(C1~C6アルキル)、-CONH-NH2、-N(R9)SO2R9、-SO2N(R9)2、-N(CO)NHSO2CH3、テトラゾール、イソキサゾール、ヒドロキシイソキサゾール、およびオキサゾリジンジオンからなる群から選択され、
各R9は独立して、水素、C1~C6アルキル、アリール、およびヘテロアリールからなる群から選択され、
R2は、ハロゲン、C1~C6アルキル、C1~C6ハロアルキル、ヒドロキシ(C1~C6アルキル)、アルコキシ(C1~C6アルキル)、アミノ(C1~C6アルキル)、または-CNであり、
R3は、ハロゲン、C1~C6アルキル、またはC1~C6ハロアルキルであり、
R4およびR5は独立して、C1~C6アルキルまたはC1~C6ハロアルキルであるか、あるいはR4およびR5はこれらが結合している炭素原子とともに、任意に1つ以上のR8によって置換されるC3~C6シクロアルキルを形成し、
R6およびR7は独立して、C1~C6アルキルまたはC1~C6ハロアルキルであるか、あるいはR6およびR7はこれらが結合している炭素原子とともに、任意に1つ以上のR8によって置換されるC3~C6シクロアルキルを形成し、
各R8は独立して、ハロゲン、-NO2、-CN、C1~C6アルキル、C1~C6ハロアルキル、-NH2、-NH(C1~C6アルキル)、-N(C1~C6アルキル)2、-OH、C1~C6アルコキシ、およびC1~C6ハロアルコキシからなる群から選択される、化合物、またはこの医薬品として許容可能な塩。 - 2つのR基およびこれらが結合している炭素原子が=CH2を形成する、請求項1に記載の化合物またはその医薬品として許容可能な塩。
- 2つのR基およびこれらが結合している炭素原子がシクロプロピル環を形成する、請求項1に記載の化合物またはその医薬品として許容可能な塩。
- R1が-CO2H、-CO2(C1~C6アルキル)、-CONH2、-CONH(C1~C6アルキル)、または-CON(C1~C6アルキル)2であるか、あるいはR1が-CO2Hまたは-CO2(C1~C6アルキル)であるか、あるいはR1が-CO2Hである、請求項1~3のいずれかに記載の化合物またはその医薬品として許容可能な塩。
- R2がハロゲン、C1~C6アルキル、またはC1~C6ハロアルキルであるか、あるいはR2がハロゲンであるか、あるいはR2がC1~C6アルキルまたはC1~C6ハロアルキルであるか、あるいはR2がC1~C6アルキルであるか、あるいはR2がメチルであるか、あるいはR2がC1~C6ハロアルキルであるか、あるいはR2がC1~C2ハロアルキルであるか、あるいはR2がC1ハロアルキルであるか、あるいはR2がジフルオロメチルである、請求項1~4のいずれかに記載の化合物またはその医薬品として許容可能な塩。
- R 3がハロゲンであるか、あるいはR3がフルオロである、請求項1~5のいずれかに記載の化合物またはその医薬品として許容可能な塩。
- R4およびR5はこれらが結合している炭素原子とともに、任意に1つ以上のR8によって置換されるC3~C6シクロアルキルを形成するか、あるいはR4およびR5がこれらが結合している炭素原子とともに、任意に1つ以上のR8によって置換されるシクロプロピルを形成するか、あるいはR4およびR5がこれらが結合している炭素原子とともに非置換シクロプロピルを形成する、請求項1~6のいずれかに記載の化合物またはその医薬品として許容可能な塩。
- R4およびR5が独立してC1~C6アルキルであるか、あるいはR4およびR5が独立してメチルである、請求項1~6のいずれかに記載の化合物またはその医薬品として許容可能な塩。
- R6およびR7がこれらが結合している炭素原子とともに、任意に1つ以上のR8によって置換されるC3~C6シクロアルキルを形成するか、あるいはR6およびR7がこれらが結合している炭素原子とともに、任意に1つ以上のR8によって置換されるシクロプロピルを形成するか、あるいはR6およびR7がこれらが結合している炭素原子とともに非置換シクロプロピルを形成する、請求項1~8のいずれかに記載の化合物またはその医薬品として許容可能な塩。
- R6およびR7が独立してC1~C6アルキルであるか、あるいはR6およびR7が独立してメチルである、請求項1~8のいずれかに記載の化合物またはその医薬品として許容可能な塩。
- R4およびR5がこれらが結合している炭素原子とともに、任意に1つ以上のR8によって置換されるC3~C6シクロアルキルを形成し、R6およびR7が独立してC1~C6アルキルまたはC1~C6ハロアルキルである、請求項1~6のいずれかに記載の化合物またはその医薬品として許容可能な塩。
- 請求項1~12のいずれかに記載の化合物またはその医薬品として許容可能な塩および医薬品として許容可能な担体を含む、医薬組成物。
- 癌、自己免疫障害および/または皮膚炎を治療するための、または末梢血球数を増加および/または免疫系機能を改善するための、請求項1~12のいずれかに記載の化合物もしくはその医薬品として許容可能な塩または請求項13に記載の医薬組成物。
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US20210363093A1 (en) | 2021-11-25 |
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EP3758694A1 (en) | 2021-01-06 |
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CA3092682A1 (en) | 2019-09-06 |
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