JP5844354B2 - ヒドロキシピリドン誘導体、その医薬組成物、及び増殖性疾患治療のためのその治療的使用 - Google Patents
ヒドロキシピリドン誘導体、その医薬組成物、及び増殖性疾患治療のためのその治療的使用 Download PDFInfo
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- JP5844354B2 JP5844354B2 JP2013513287A JP2013513287A JP5844354B2 JP 5844354 B2 JP5844354 B2 JP 5844354B2 JP 2013513287 A JP2013513287 A JP 2013513287A JP 2013513287 A JP2013513287 A JP 2013513287A JP 5844354 B2 JP5844354 B2 JP 5844354B2
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/89—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members with hetero atoms directly attached to the ring nitrogen atom
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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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
- A61P35/02—Antineoplastic agents specific for leukemia
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
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- Hematology (AREA)
- Oncology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Pyridine Compounds (AREA)
- Medicinal Preparation (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Description
本出願は、2010年6月1日に出願された米国特許仮出願第61/350,431号の優先権を主張するものであり、この出願の開示はその全体が引用により本明細書中に組み込まれている。
ヒドロキシピリドン誘導体、及びそれらの医薬組成物が、本明細書において提供される。同じく増殖性疾患の1つ以上の症状を治療、予防又は改善する方法も、本明細書において提供される。
血液悪性疾患又は造血器悪性疾患は、白血病及びリンパ腫を含む血液又は骨髄の癌である。白血病は、血液細胞の制御できない蓄積により特徴付けられ、これは4型に分類される:急性リンパ性白血病(ALL)、急性骨髄性白血病(AML)、慢性リンパ性白血病(CLL)、及び慢性骨髄性白血病(CML)。急性白血病は、急激に進行する疾患であり、結果的に骨髄及び血液中に未熟な無機能の細胞の蓄積を生じる。この骨髄は多くの場合、十分な正常な赤血球、白血球及び血小板の形成を停止する。他方で、慢性白血病は、より緩徐に進行し、且つより多数のより成熟した機能細胞の形成を可能にする。慢性白血病は、急性白血病よりも11%多い症例を占める。
本明細書において、式Iの化合物、又はそれらの鏡像異性体、鏡像異性体の混合物、2種以上のジアステレオマーの混合物、互変異性体、2種以上の互変異性体の混合物、若しくは同位体変種;又は、それらの医薬として許容し得る塩、溶媒和物、水和物、若しくはプロドラッグが提供される:
Zは、結合、-O-、-S-、-S(O)-、-S(O2)-、又は-N(R8)-であり;
R1は、水素又は-C(O)R2であり;
R2は、(a)水素又は重水素;(b)C1-6アルキル、C2-6アルケニル、C2-6アルキニル、C3-7シクロアルキル、C6-14アリール、C7-15アラルキル、ヘテロアリール、又はヘテロシクリル;或いは、(c)-OR1a、-NR1bR1c、-NR1aC(O)R1d、-NR1aC(O)OR1d、-NR1aC(O)NR1bR1c、-NR1aC(=NR1d)NR1bR1c、-NR1aS(O)R1d、-NR1aS(O)2R1d、-NR1aS(O)NR1bR1c、又は-NR1aS(O)2NR1bR1cであり;
R3及びR5は、各々独立して水素、重水素、又はフルオロであり;
R4は、-COOH、-CH2R4a、-CH(R4a)2、又は-C(R4a)3であり;ここで、R4aは、水素、重水素、フルオロ、又はヒドロキシルであり;
R6は、水素、重水素、フルオロ、又はヒドロキシルであり;
各R7は独立して、(a)重水素、ハロ、シアノ、ニトロ、又はグアニジン;(b)C1-6アルキル、C2-6アルケニル、C2-6アルキニル、C3-7シクロアルキル、C6-14アリール、C7-15アラルキル、ヘテロアリール、又はヘテロシクリル;或いは、(c)-C(O)R1a、-C(O)OR1a、-C(O)NR1bR1c、-C(NR1a)NR1bR1c、-OR1a、-OC(O)R1a、-OC(O)OR1a、-OC(O)NR1bR1c、-OC(=NR1a)NR1bR1c、-OS(O)R1a、-OS(O)2R1a、-OS(O)NR1bR1c、-OS(O)2NR1bR1c、-NR1bR1c、-NR1aC(O)R1d、-NR1aC(O)OR1d、-NR1aC(O)NR1bR1c、-NR1aC(=NR1d)NR1bR1c、-NR1aS(O)R1d、-NR1aS(O)2R1d、-NR1aS(O)NR1bR1c、-NR1aS(O)2NR1bR1c、-SR1a、-S(O)R1a、-S(O)2R1a、-S(O)NR1bR1c、又は-S(O)2NR1bR1cであるか;又は
2つのR7は、一緒に連結され、結合、-O-、-NR8-、-S-、C1-6アルキレン、C1-6ヘテロアルキレン、C2-6アルケニレン、又はC2-6ヘテロアルケニレンを形成し;
R8は独立して、(a)水素又は重水素;(b)C1-6アルキル、C2-6アルケニル、C2-6アルキニル、C3-7シクロアルキル、C6-14アリール、C7-15アラルキル、ヘテロアリール、又はヘテロシクリル;或いは、(c)-C(O)R1a、-C(O)OR1a、-C(O)NR1bR1c、-C(NR1a)NR1bR1c、-OR1a、-OC(O)R1a、-OC(O)OR1a、-OC(O)NR1bR1c、-OC(=NR1a)NR1bR1c、-OS(O)R1a、-OS(O)2R1a、-OS(O)NR1bR1c、-OS(O)2NR1bR1c、-NR1bR1c、-NR1aC(O)R1d、-NR1aC(O)OR1d、-NR1aC(O)NR1bR1c、-NR1aC(=NR1d)NR1bR1c、-NR1aS(O)R1d、-NR1aS(O)2R1d、-NR1aS(O)NR1bR1c、-NR1aS(O)2NR1bR1c、-S(O)R1a、-S(O)2R1a、-S(O)NR1bR1c、又は-S(O)2NR1bR1cであり;
各R1a、R1b、R1c、及びR1dは独立して、水素、重水素、C1-6アルキル、C2-6アルケニル、C2-6アルキニル、C3-7シクロアルキル、C6-14アリール、C7-15アラルキル、ヘテロアリール、又はヘテロシクリルであるか;或いは、R1a及びR1cは、それらが結合したC及びN原子と一緒に、ヘテロシクリルを形成するか;或いは、R1b及びR1cは、それらが結合したN原子と一緒に、ヘテロシクリルを形成し;
mは、1、2、3、又は4の整数であり;並びに
nは、0、1、2、3、4、5、6、又は7の整数であり;
但し、R1、R3、R5、R6、R7、及びR4aの少なくとも1つは、水素ではないことを条件とし、
ここでアルキル、アルキレン、ヘテロアルキレン、アルケニル、アルケニレン、ヘテロアルケニレン、アルキニル、シクロアルキル、アリール、アラルキル、ヘテロアリール、及びヘテロシクリルの各々は、1個以上の置換基Qにより任意に置換され、ここで各Qは、(a)重水素、シアノ、ハロ、及びニトロ;(b)C1-6アルキル、C2-6アルケニル、C2-6アルキニル、C3-7シクロアルキル、C6-14アリール、C7-15アラルキル、ヘテロアリール、及びヘテロシクリルであり、その各々は更に1個以上の、一実施態様においては1、2、3又は4個の置換基Qaにより任意に置換されたもの;並びに、(c)-C(O)Ra、-C(O)ORa、-C(O)NRbRc、-C(NRa)NRbRc、-ORa、-OC(O)Ra、-OC(O)ORa、-OC(O)NRbRc、-OC(=NRa)NRbRc、-OS(O)Ra、-OS(O)2Ra、-OS(O)NRbRc、-OS(O)2NRbRc、-NRbRc、-NRaC(O)Rd、-NRaC(O)ORd、-NRaC(O)NRbRc、-NRaC(=NRd)NRbRc、-NRaS(O)Rd、-NRaS(O)2Rd、-NRaS(O)NRbRc、-NRaS(O)2NRbRc、-SRa、-S(O)Ra、-S(O)2Ra、-S(O)NRbRc、及び-S(O)2NRbRcであり、ここで各Ra、Rb、Rc、及びRdは、独立して、(i)水素又は重水素;(ii)C1-6アルキル、C2-6アルケニル、C2-6アルキニル、C3-7シクロアルキル、C6-14アリール、C7-15アラルキル、ヘテロアリール、又はヘテロシクリルであって、各々が1個以上の、一実施態様においては1、2、3又は4個の置換基Qaにより任意に置換されたもの;又は、(iii)Rb及びRcが、それらが結合したN原子と一緒に、1個以上の、一実施態様においては1、2、3又は4個の置換基Qaにより任意に置換されたヘテロシクリルを形成しているもの:から独立して選択され;
ここで各Qaは独立して、(a)重水素、シアノ、ハロ、及びニトロ;(b)C1-6アルキル、C2-6アルケニル、C2-6アルキニル、C3-7シクロアルキル、C6-14アリール、C7-15アラルキル、ヘテロアリール、及びヘテロシクリル;並びに、(c)-C(O)Re、-C(O)ORe、-C(O)NRfRg、-C(NRe)NRfRg、-ORe、-OC(O)Re、-OC(O)ORe、-OC(O)NRfRg、-OC(=NRe)NRfRg、-OS(O)Re、-OS(O)2Re、-OS(O)NRfRg、-OS(O)2NRfRg、-NRfRg、-NReC(O)Rh、-NReC(O)ORf、-NReC(O)NRfRg、-NReC(=NRh)NRfRg、-NReS(O)Rh、-NReS(O)2Rh、-NReS(O)NRfRg、-NReS(O)2NRfRg、-SRe、-S(O)Re、-S(O)2Re、-S(O)NRfRg、及び-S(O)2NRfRgであり;ここで各Re、Rf、Rg、及びRhは独立して、(i)水素又は重水素;(ii)C1-6アルキル、C2-6アルケニル、C2-6アルキニル、C3-7シクロアルキル、C6-14アリール、C7-15アラルキル、ヘテロアリール、若しくはヘテロシクリル;又は、(iii)Rf及びRgがそれらが結合したN原子と一緒にヘテロシクリルを形成しているもの:からなる群から選択される。)。
本明細書に記した開示の理解を促進するために、多くの用語を以下に定義する。
」立体配置又はそれらの混合物、或いは「Z」又は「E」立体配置又はそれらの混合物を有するラジカルを包含している。例えば、C2-6アルケニルとは、炭素原子2〜6個の直鎖の不飽和の一価の炭化水素ラジカル、又は炭素原子3〜6個の分岐状の不飽和の一価の炭化水素ラジカルをいう。いくつかの実施態様において、アルケニルは、炭素原子2〜20個(C2-20)、2〜15個(C2-15)、2〜10個(C2-10)、又は2〜6個(C2-6)の直鎖の一価の炭化水素ラジカル、又は炭素原子3〜20個(C3-20)、3〜15個(C3-15)、3〜10個(C3-10)、又は3〜6個(C3-6)の分岐状の一価の炭化水素ラジカルである。アルケニル基の例は、エテニル、プロペン-1-イル、プロペン-2-イル、アリル、ブテニル、及び4-メチルブテニルを含むが、これらに限定されるものではない。
本明細書において、ヒドロキシピリドン誘導体、及びそれらの医薬組成物が提供される。また本明細書において、増殖性疾患の1つ以上の症状を治療、予防、又は改善する方法が提供される。
Zは、結合、-O-、-S-、-S(O)-、-S(O2)-、又は-N(R8)-であり;
R1は、水素又は-C(O)R2であり;
R2は、(a)水素又は重水素;(b)C1-6アルキル、C2-6アルケニル、C2-6アルキニル、C3-7シクロアルキル、C6-14アリール、C7-15アラルキル、ヘテロアリール、又はヘテロシクリル;或いは、(c)-OR1a、-NR1bR1c、-NR1aC(O)R1d、-NR1aC(O)OR1d、-NR1aC(O)NR1bR1c、-NR1aC(=NR1d)NR1bR1c、-NR1aS(O)R1d、-NR1aS(O)2R1d、-NR1aS(O)NR1bR1c、又は-NR1aS(O)2NR1bR1cであり;
R3及びR5は、各々独立して水素、重水素、又はフルオロであり;
R4は、-COOH、-CH2R4a、-CH(R4a)2、又は-C(R4a)3であり;ここで、R4aは、水素、重水素、フルオロ、又はヒドロキシルであり;
R6は、水素、重水素、フルオロ、又はヒドロキシルであり;
各R7は独立して、(a)重水素、ハロ、シアノ、ニトロ、又はグアニジン;(b)C1-6アルキル、C2-6アルケニル、C2-6アルキニル、C3-7シクロアルキル、C6-14アリール、C7-15アラルキル、ヘテロアリール、又はヘテロシクリル;或いは、(c)-C(O)R1a、-C(O)OR1a、-C(O)NR1bR1c、-C(NR1a)NR1bR1c、-OR1a、-OC(O)R1a、-OC(O)OR1a、-OC(O)NR1bR1c、-OC(=NR1a)NR1bR1c、-OS(O)R1a、-OS(O)2R1a、-OS(O)NR1bR1c、-OS(O)2NR1bR1c、-NR1bR1c、-NR1aC(O)R1d、-NR1aC(O)OR1d、-NR1aC(O)NR1bR1c、-NR1aC(=NR1d)NR1bR1c、-NR1aS(O)R1d、-NR1aS(O)2R1d、-NR1aS(O)NR1bR1c、-NR1aS(O)2NR1bR1c、-SR1a、-S(O)R1a、-S(O)2R1a、-S(O)NR1bR1c、又は-S(O)2NR1bR1cであるか;又は
2つのR7は、一緒に連結され、結合、-O-、-NR8-、-S-、C1-6アルキレン、C1-6ヘテロアルキレン、C2-6アルケニレン、又はC2-6ヘテロアルケニレンを形成し;
R8は独立して、(a)水素又は重水素;(b)C1-6アルキル、C2-6アルケニル、C2-6アルキニル、C3-7シクロアルキル、C6-14アリール、C7-15アラルキル、ヘテロアリール、又はヘテロシクリル;或いは、(c)-C(O)R1a、-C(O)OR1a、-C(O)NR1bR1c、-C(NR1a)NR1bR1c、-OR1a、-OC(O)R1a、-OC(O)OR1a、-OC(O)NR1bR1c、-OC(=NR1a)NR1bR1c、-OS(O)R1a、-OS(O)2R1a、-OS(O)NR1bR1c、-OS(O)2NR1bR1c、-NR1bR1c、-NR1aC(O)R1d、-NR1aC(O)OR1d、-NR1aC(O)NR1bR1c、-NR1aC(=NR1d)NR1bR1c、-NR1aS(O)R1d、-NR1aS(O)2R1d、-NR1aS(O)NR1bR1c、-NR1aS(O)2NR1bR1c、-S(O)R1a、-S(O)2R1a、-S(O)NR1bR1c、又は-S(O)2NR1bR1cであり;
各R1a、R1b、R1c、及びR1dは独立して、水素、重水素、C1-6アルキル、C2-6アルケニル、C2-6アルキニル、C3-7シクロアルキル、C6-14アリール、C7-15アラルキル、ヘテロアリール、又はヘテロシクリルであるか;或いは、R1a及びR1cは、それらが結合したC及びN原子と一緒に、ヘテロシクリルを形成するか;或いは、R1b及びR1cは、それらが結合したN原子と一緒に、ヘテロシクリルを形成し;
mは、1、2、3、又は4の整数であり;並びに
nは、0、1、2、3、4、5、6、又は7の整数であり;
但し、R1、R3、R5、R6、R7、及びR4aの少なくとも1つは、水素ではないことを条件とし、
ここでアルキル、アルキレン、ヘテロアルキレン、アルケニル、アルケニレン、ヘテロアルケニレン、アルキニル、シクロアルキル、アリール、アラルキル、ヘテロアリール、及びヘテロシクリルの各々は、1個以上の置換基Qにより任意に置換され、ここで各Qは、(a)重水素、シアノ、ハロ、及びニトロ;(b)C1-6アルキル、C2-6アルケニル、C2-6アルキニル、C3-7シクロアルキル、C6-14アリール、C7-15アラルキル、ヘテロアリール、及びヘテロシクリルであり、その各々は更に1個以上の、一実施態様においては1、2、3又は4個の置換基Qaにより任意に置換されたもの;並びに、(c)-C(O)Ra、-C(O)ORa、-C(O)NRbRc、-C(NRa)NRbRc、-ORa、-OC(O)Ra、-OC(O)ORa、-OC(O)NRbRc、-OC(=NRa)NRbRc、-OS(O)Ra、-OS(O)2Ra、-OS(O)NRbRc、-OS(O)2NRbRc、-NRbRc、-NRaC(O)Rd、-NRaC(O)ORd、-NRaC(O)NRbRc、-NRaC(=NRd)NRbRc、-NRaS(O)Rd、-NRaS(O)2Rd、-NRaS(O)NRbRc、-NRaS(O)2NRbRc、-SRa、-S(O)Ra、-S(O)2Ra、-S(O)NRbRc、及び-S(O)2NRbRcであり、ここで各Ra、Rb、Rc、及びRdは、独立して、(i)水素又は重水素;(ii)C1-6アルキル、C2-6アルケニル、C2-6アルキニル、C3-7シクロアルキル、C6-14アリール、C7-15アラルキル、ヘテロアリール、又はヘテロシクリルであって、各々が1個以上の、一実施態様においては1、2、3又は4個の置換基Qaにより任意に置換されたもの;又は、(iii)Rb及びRcがそれらが結合したN原子と一緒に、1個以上の、一実施態様においては1、2、3又は4個の置換基Qaにより任意に置換されたヘテロシクリルを形成しているもの:から独立して選択され;
ここで各Qaは独立して、(a)重水素、シアノ、ハロ、及びニトロ;(b)C1-6アルキル、C2-6アルケニル、C2-6アルキニル、C3-7シクロアルキル、C6-14アリール、C7-15アラルキル、ヘテロアリール、及びヘテロシクリル;並びに、(c)-C(O)Re、-C(O)ORe、-C(O)NRfRg、-C(NRe)NRfRg、-ORe、-OC(O)Re、-OC(O)ORe、-OC(O)NRfRg、-OC(=NRe)NRfRg、-OS(O)Re、-OS(O)2Re、-OS(O)NRfRg、-OS(O)2NRfRg、-NRfRg、-NReC(O)Rh、-NReC(O)ORf、-NReC(O)NRfRg、-NReC(=NRh)NRfRg、-NReS(O)Rh、-NReS(O)2Rh、-NReS(O)NRfRg、-NReS(O)2NRfRg、-SRe、-S(O)Re、-S(O)2Re、-S(O)NRfRg、及び-S(O)2NRfRgであり;ここで各Re、Rf、Rg、及びRhは独立して、(i)水素又は重水素;(ii)C1-6アルキル、C2-6アルケニル、C2-6アルキニル、C3-7シクロアルキル、C6-14アリール、C7-15アラルキル、ヘテロアリール、若しくはヘテロシクリル;又は、(iii)Rf及びRgがそれらが結合したN原子と一緒にヘテロシクリルを形成しているもの:からなる群から選択される。)。
本明細書に提供される化合物は、当業者に公知の任意の方法により、調製、単離又は入手することができる。例えば、式Iの化合物は、各々の開示がその全体で引用により本明細書中に組み込まれている、米国特許第3,883,545号及び第3,972,888号に説明された方法に従い調製することができる。
一実施態様において、活性成分として、本明細書に提供される化合物、例えば式Iの化合物であり、その鏡像異性体、鏡像異性体の混合物、2種以上のジアステレオマーの混合物、互変異性体、2種以上の互変異性体の混合物、若しくは同位体変種;又は、それらの医薬として許容し得る塩、溶媒和物、水和物、若しくはプロドラッグを含むもの;を、医薬として許容し得る媒体、担体、希釈剤、賦形剤、又はそれらの混合物と組合せて含有する医薬組成物が本明細書において提供される。
経口投与のための本明細書に提供される医薬組成物は、経口投与のための固体、半固体、又は液体の剤形で提供されることができる。本明細書において使用されるように、経口投与は、頬側、舌側、及び舌下投与も含む。好適な経口剤形は、錠剤、ファストメルト(fastmelts)、咀嚼錠、カプセル剤、丸剤、ストリップ、トローチ剤、舐剤、香錠、カシェ剤、ペレット、医療用チューインガム、バルク散剤、発泡性若しくは非発泡性散剤若しくは顆粒剤、経口ミスト、液剤、乳剤、懸濁剤、ウェファー、散粉剤(sprinkles)、エリキシル剤、及びシロップ剤を含むが、これらに限定されるものではない。本医薬組成物は、活性成分に加えて、非限定的に、結合剤、充填剤、希釈剤、崩壊剤、湿潤剤、滑沢剤、流動促進剤、着色剤、色移り防止剤、甘味剤、香味剤、乳化剤、懸濁化剤及び分散剤、保存剤、溶媒、非水性液体、有機酸、並びに二酸化炭素給源を含む、1種以上の医薬として許容し得る担体又は賦形剤を含有することができる。
本明細書に提供される医薬組成物は、局所投与又は全身投与のために、注射、注入、又は埋め込みによって非経口的に投与することができる。本明細書において使用される非経口投与は、静脈内投与、動脈内投与、腹腔内投与、髄腔内投与、脳室内投与、尿管内投与、胸骨内投与、頭蓋内投与、筋肉内投与、滑液嚢内投与、膀胱内投与及び皮下投与を含む。
本明細書に提供される医薬組成物は、皮膚、開口部、又は粘膜へ局所的に投与することができる。本明細書に使用される局所投与は、皮膚(内)、結膜、角膜内、眼球内、眼内、耳内、経真皮、鼻腔、膣、尿道、呼吸器、及び直腸の投与を含む。
本明細書に提供される医薬組成物は、改変された放出剤形として製剤することができる。本明細書において使用される用語「改変された放出」とは、活性成分の放出の速度又は場所が、同じ経路で投与された場合に、即時型剤形のものとは異なる剤形をいう。改変された放出剤形は、遅延放出、拡大放出、延長放出、持続放出、パルス放出、制御放出、加速放出及び迅速放出、標的指向放出、及びプログラムされた放出、並びに胃内滞留剤形を含むが、これらに限定されるものではない。改変された放出剤形である医薬組成物は、マトリックス制御放出装置、浸透圧制御放出装置、多粒子制御放出装置、イオン交換樹脂、腸溶性コーティング、多層コーティング、ミクロスフェア、リポソーム、及びそれらの組合せを含むが、これらに限定されるものではない当業者に公知の様々な改変された放出の装置及び方法を用いて調製することができる。活性成分の放出速度は、活性成分の粒子サイズ及び多形性が変動することにより改変することもできる。
改変された放出剤形で本明細書に提供される医薬組成物は、当業者に公知のマトリックス制御放出装置を用いて製造することができる(Takadaらの文献、「制御された薬物送達のエンサイクロペディア(Encyclopedia of Controlled Drug Delivery)」、第2巻、Mathiowitz編集、Wiley社、1999年を参照されたい)。
改変された放出剤形において本明細書に提供される医薬組成物は、1-チャンバーシステム、2-チャンバーシステム、非対称メンブレン技術(AMT)、及び押出コアシステム(ECS)を含むが、これらに限定されるものではない、浸透圧制御放出装置を使用し、製造することができる。概して、そのような装置は、少なくとも2つの構成要素を有する:(a)活性成分を含むコア;及び、(b)該コアを封入している少なくとも1つの送達ポートを有する半透膜。半透膜は、送達ポートを通る押出により薬物放出を引き起こすように、使用する水性環境からコアへの水の流入を制御する。
改変された放出剤形中の本明細書に提供される医薬組成物は、直径が約10μm〜約3mm、約50μm〜約2.5mm、又は約100μm〜約1mmの範囲である、多数の粒子、顆粒、又はペレットを含有する、多粒子制御放出装置として作製することができる。そのような多粒子は、湿式-及び乾式-造粒、押出/球形化、ローラー圧縮、溶融-凝固、及びシードコアのスプレー-コーティングを含む、当業者に公知のプロセスにより製造することができる。例えば、「多粒子経口薬物送達(Multiparticulate Oral Drug Delivery);Marcel Dekker:1994年;及び、「医薬品ペレット化技術(Pharmaceutical Pelletization Technology)」;Marcel Dekker:1989年を参照されたい。
本明細書に提供される医薬組成物はまた、リポソーム-、再封された赤血球-、及び抗体-ベースの送達システムを含む、治療される対象の体の特定の組織、受容体、又は他の領域を標的指向するように製剤することもできる。例としては、下記の特許に開示されたものを含むが、これらに限定されるものではない:
一実施態様において、本明細書に提供される化合物、例えば式Iの化合物であり、その鏡像異性体、鏡像異性体の混合物、2種以上のジアステレオマーの混合物、互変異性体、2種以上の互変異性体の混合物、若しくは同位体変種;又は、それらの医薬として許容し得る塩、溶媒和物、水和物、若しくはプロドラッグを含むものの治療有効量を対象へ投与することを含む、対象における増殖性疾患の治療方法が、本明細書において提供される。
本明細書において使用されるこれらのプロセス、スキーム及び実施例において使用される記号及び規約は、特定の略語が具体的に定義されるかどうかに関わらず、例えばJournal of the American Chemical Society又はJournal of Biological Chemistryなどの現代の科学文献において使用されるものと一致している。具体的には、しかし非限定的に、下記の略語を、実施例において及び本明細書を通じて使用することができる:g(グラム);mg(ミリグラム);mL(ミリリットル);μL(マイクロリットル);mM(ミリモル);μM(マイクロモル);Hz(ヘルツ);MHz(メガヘルツ);mmol(ミリモル);hr又はhrs(時間);min(分);MS(質量分析);ESI(エレクトロスプレーイオン化);TLC(薄層クロマトグラフィー);HPLC(高速液体クロマトグラフィー);THF(テトラヒドロフラン);CDCl3(重水素化クロロホルム);DMSO(ジメチルスルホキシド);DMSO-d6(重水素化ジメチルスルホキシド);EtOAc(酢酸エチル);及び、MeOH(メタノール)。
(全般的生物学的方法)
(細胞培養)
白血病細胞又は細胞株(HL-60、RSV411、k562、Jurkat、U937)、リンパ腫細胞又は細胞株(MDAY-D2)、固形腫瘍細胞又は細胞株(PPC-1、HeLa、OVCAR-3、DU-145、HT-29)、並びにGM05757ヒト肺線維芽細胞を、RPMI 1640培地において培養した。HepG2ヘパトーマ細胞及びMRC5ヒト肺線維芽細胞は、ダルベッコ改変イーグル培地において増殖した。OCI-M2、OCI-AML2、及びNB4白血病細胞株並びにOPM2、KMS11、LP1、UTMC2、KSM18、及びOCIMy5骨髄腫細胞株は、Iscove改変ダルベッコ培地において維持した。LF1ヒト肺線維芽細胞は、HAM培地において維持した。全ての培地は、10%ウシ胎仔血清、ペニシリン100μg/mL、及びストレプトマイシン100単位/mLを補充した(全てHyclone社、ローガン、UTより入手)。これらの細胞は、5%CO2を補充した加湿大気内で、37℃でインキュベーションした。
細胞は、収集し、冷PBSで洗浄し、70%冷エタノール中に再度浮遊させ、且つ-20℃で一晩インキュベーションした。その後細胞を、DNase-非含有RNase(Invitrogen社、カールスバッド、CA)100ng/mLにより37℃で30分間処理し、冷PBSで洗浄し、プロテアーゼ阻害剤(Sigma社)50μg/mLを含むPBS中に再度浮遊させた。DNA含量は、フローサイトメトリー(FACSCalibur;BD Biosciences社、サンノゼ、CA)により分析した。
(抗癌活性に関するルシフェラーゼアッセイ)
化合物の抗癌活性を、本明細書に記載のようなルシフェラーゼアッセイを用いて決定した。
(HeLa細胞におけるサバイビンmRNA及びタンパク質発現レベルの決定)
化合物で処理した野生型HeLa細胞におけるサバイビンmRNA及びタンパク質発現のレベルを、定量的リアルタイムポリメラーゼ連鎖反応(QRT-PCR)及び免疫ブロット法を用いて測定し、その抗癌活性を決定した。
等量のcDNAを、調製したマスター混合物(SYBR Green PCRマスターミックス;Applied Biosystems社、フォスターシティ、CA)へ添加した。QRT-PCRを、ABI Prism 7700配列検出システム(Applied Biosystems社、フォスターシティ、CA)において行った。転写物の相対存在量を、増幅の閾値サイクル(CT)により表し、これは標的RNA/増幅される第一鎖cDNAの量に逆相関した。等量の後者に関して正規化するために、推定ハウスキーピング遺伝子GAPDHの転写物レベルをアッセイした。
(白血病幹細胞)
本明細書に提供される化合物を、TEX細胞及びM9-ENL1細胞の生存度を低下するそれらの能力について試験した。TEX細胞及びM9-ENL1細胞は、各々TLS-ERG又はMLL-ENL癌遺伝子により形質導入された分化系列欠損(lineage-depleted)ヒト臍帯血細胞(Lin-CB)に由来し、階層的分化及び骨髄再増殖などの白血病幹細胞に類似した特性を示す。TEX細胞及びM9-ENL1細胞を、本明細書に提供される化合物により最終濃度1μM又は5μMで処理した。インキュベーション後72時間で、細胞生存度をAlamar Blueアッセイにより測定した。
(マウス異種移植モデル)
マウス異種移植モデルを使用し、化合物のインビボ抗癌活性を評価した。
(細胞増殖アッセイ及びIC50の決定)
(接着細胞)
0日目に、細胞を、96-ウェル組織培養プレートの個々のウェルへ、培地100μL中に20,000個細胞/ウェルで播種した。翌日、化合物を、培地100μL中に希釈し、合計200μLとした。化合物の各濃度を、DMSO中に1000倍濃度で調製した(例えば、アッセイにおける最終濃度20μMに関して、化合物を100%DMSO中に20mMで調製した)。その後化合物を培地中に1:500で希釈し、各ウェルに100μLの量を添加し、0.1%DMSOで最終濃度1:1000とした。化合物の各濃度は、3つ組で試験した。細胞を37℃、5%CO2でインキュベーションした。72時間後、CellTiter 96 Aqueous One Solution細胞増殖アッセイ(Promega社)の20μLを、各ウェルに添加した。細胞を、インキュベーター内に戻し、490nmでの吸光度を2〜3時間後に測定した。代謝活性のある細胞の数を50%だけ減少する化合物の濃度を決定し、IC50として報告した。「生存率(%)」は、平均バックグラウンド値(培地のみ)を減算することにより決定し、DMSOのみで処置した細胞から得られた平均値に対する比として表現した。
浮遊細胞によるアッセイは、40,000〜60,000個の細胞を各ウェルに添加し、且つ化合物を細胞播種後ただちに添加したこと以外は、同様であった。
Claims (66)
- 式Iの化合物、又はそれらの鏡像異性体、鏡像異性体の混合物、2種以上のジアステレオマーの混合物、互変異性体、2種以上の互変異性体の混合物、若しくは同位体変種;又は、それらの医薬として許容し得る塩、溶媒和物、若しくは水和物:
Zは、結合、-O-、-S-、-S(O)-、-S(O2)-、又は-N(R8)-であり;
R1は、-C(O)R2であり;
R2は、(a)水素又は重水素;又は(b)C1-6アルキル、C2-6アルケニル、C2-6アルキニル、C3-7シクロアルキル、C6-14アリール、C7-15アラルキル、ヘテロアリール、又はヘテロシクリルであり;
R3及びR5は、各々独立して水素、重水素、又はフルオロであり;
R4は、-COOH、-CH2R4a、-CH(R4a)2、又は-C(R4a)3であり;ここで、R4aは、水素、重水素、フルオロ、又はヒドロキシルであり;
R6は、水素、重水素、フルオロ、又はヒドロキシルであり;
各R7は独立して、(a)重水素、ハロ、シアノ、ニトロ、又はグアニジン;(b)C1-6アルキル、C2-6アルケニル、C2-6アルキニル、C3-7シクロアルキル、C6-14アリール、C7-15アラルキル、ヘテロアリール、又はヘテロシクリル;或いは、(c)-C(O)R1a、-C(O)OR1a、-C(O)NR1bR1c、-C(NR1a)NR1bR1c、-OR1a、-OC(O)R1a、-OC(O)OR1a、-OC(O)NR1bR1c、-OC(=NR1a)NR1bR1c、-OS(O)R1a、-OS(O)2R1a、-OS(O)NR1bR1c、-OS(O)2NR1bR1c、-NR1bR1c、-NR1aC(O)R1d、-NR1aC(O)OR1d、-NR1aC(O)NR1bR1c、-NR1aC(=NR1d)NR1bR1c、-NR1aS(O)R1d、-NR1aS(O)2R1d、-NR1aS(O)NR1bR1c、-NR1aS(O)2NR1bR1c、-SR1a、-S(O)R1a、-S(O)2R1a、-S(O)NR1bR1c、又は-S(O)2NR1bR1cであるか;又は
2つのR7は、一緒に連結され、結合、-O-、-NR8-、-S-、C1-6アルキレン、C1-6ヘテロアルキレン、C2-6アルケニレン、又はC2-6ヘテロアルケニレンを形成し;
R8は独立して、(a)水素又は重水素;(b)C1-6アルキル、C2-6アルケニル、C2-6アルキニル、C3-7シクロアルキル、C6-14アリール、C7-15アラルキル、ヘテロアリール、又はヘテロシクリル;或いは、(c)-C(O)R1a、-C(O)OR1a、-C(O)NR1bR1c、-C(NR1a)NR1bR1c、-OR1a、-OC(O)R1a、-OC(O)OR1a、-OC(O)NR1bR1c、-OC(=NR1a)NR1bR1c、-OS(O)R1a、-OS(O)2R1a、-OS(O)NR1bR1c、-OS(O)2NR1bR1c、-NR1bR1c、-NR1aC(O)R1d、-NR1aC(O)OR1d、-NR1aC(O)NR1bR1c、-NR1aC(=NR1d)NR1bR1c、-NR1aS(O)R1d、-NR1aS(O)2R1d、-NR1aS(O)NR1bR1c、-NR1aS(O)2NR1bR1c、-S(O)R1a、-S(O)2R1a、-S(O)NR1bR1c、又は-S(O)2NR1bR1cであり;
各R1a、R1b、R1c、及びR1dは独立して、水素、重水素、C1-6アルキル、C2-6アルケニル、C2-6アルキニル、C3-7シクロアルキル、C6-14アリール、C7-15アラルキル、ヘテロアリール、又はヘテロシクリルであるか;或いは、R1a及びR1cは、それらが結合したC及びN原子と一緒に、ヘテロシクリルを形成するか;或いは、R1b及びR1cは、それらが結合したN原子と一緒に、ヘテロシクリルを形成し;
mは、1、2、3、又は4の整数であり;並びに
nは、0、1、2、3、4、5、6、又は7の整数であり;
ここでアルキル、アルキレン、ヘテロアルキレン、アルケニル、アルケニレン、ヘテロアルケニレン、アルキニル、シクロアルキル、アリール、アラルキル、ヘテロアリール、及びヘテロシクリルの各々は、1個以上の置換基Qにより任意に置換され、ここで各Qは、(a)重水素、シアノ、ハロ、及びニトロ;(b)C1-6アルキル、C2-6アルケニル、C2-6アルキニル、C3-7シクロアルキル、C6-14アリール、C7-15アラルキル、ヘテロアリール、及びヘテロシクリルであり、その各々は更に1個以上の置換基Qaにより任意に置換されたもの;並びに、(c)-C(O)Ra、-C(O)ORa、-C(O)NRbRc、-C(NRa)NRbRc、-ORa、-OC(O)Ra、-OC(O)ORa、-OC(O)NRbRc、-OC(=NRa)NRbRc、-OS(O)Ra、-OS(O)2Ra、-OS(O)NRbRc、-OS(O)2NRbRc、-NRbRc、-NRaC(O)Rd、-NRaC(O)ORd、-NRaC(O)NRbRc、-NRaC(=NRd)NRbRc、-NRaS(O)Rd、-NRaS(O)2Rd、-NRaS(O)NRbRc、-NRaS(O)2NRbRc、-SRa、-S(O)Ra、-S(O)2Ra、-S(O)NRbRc、及び-S(O)2NRbRcであり、ここで各Ra、Rb、Rc、及びRdは、独立して、(i)水素又は重水素;(ii)C1-6アルキル、C2-6アルケニル、C2-6アルキニル、C3-7シクロアルキル、C6-14アリール、C7-15アラルキル、ヘテロアリール、又はヘテロシクリルであって、各々が1個以上の置換基Qaにより任意に置換されたもの;又は、(iii)Rb及びRcが、それらが結合したN原子と一緒に、1個以上の置換基Qaにより任意に置換されたヘテロシクリルを形成しているもの:から独立して選択され;
ここで各Qaは独立して、(a)重水素、シアノ、ハロ、及びニトロ;(b)C1-6アルキル、C2-6アルケニル、C2-6アルキニル、C3-7シクロアルキル、C6-14アリール、C7-15アラルキル、ヘテロアリール、及びヘテロシクリル;並びに、(c)-C(O)Re、-C(O)ORe、-C(O)NRfRg、-C(NRe)NRfRg、-ORe、-OC(O)Re、-OC(O)ORe、-OC(O)NRfRg、-OC(=NRe)NRfRg、-OS(O)Re、-OS(O)2Re、-OS(O)NRfRg、-OS(O)2NRfRg、-NRfRg、-NReC(O)Rh、-NReC(O)ORf、-NReC(O)NRfRg、-NReC(=NRh)NRfRg、-NReS(O)Rh、-NReS(O)2Rh、-NReS(O)NRfRg、-NReS(O)2NRfRg、-SRe、-S(O)Re、-S(O)2Re、-S(O)NRfRg、及び-S(O)2NRfRgであり;ここで各Re、Rf、Rg、及びRhは独立して、(i)水素又は重水素;(ii)C1-6アルキル、C2-6アルケニル、C2-6アルキニル、C3-7シクロアルキル、C6-14アリール、C7-15アラルキル、ヘテロアリール、若しくはヘテロシクリル;又は、(iii)Rf及びRgがそれらが結合したN原子と一緒にヘテロシクリルを形成しているもの:からなる群から選択される。)。 - 前記Zが結合である、請求項1記載の化合物。
- 前記mが2である、請求項1又は2記載の化合物。
- 前記nが0である、請求項1〜3のいずれか一項記載の化合物。
- 前記nが2である、請求項1〜3のいずれか一項記載の化合物。
- 前記2つのR7が一緒に連結され、-O-、-S-、メチレン、又はエチレンを形成する、請求項5記載の化合物。
- 前記R2がC1-6アルキルである、請求項1記載の化合物。
- 前記R2がC6-14アリールである、請求項1記載の化合物。
- 前記R2がフェニルである、請求項9記載の化合物。
- 前記R3が水素である、請求項1〜10のいずれか一項記載の化合物。
- 前記R3が重水素である、請求項1〜10のいずれか一項記載の化合物。
- 前記R3がフルオロである、請求項1〜10のいずれか一項記載の化合物。
- 前記R5が水素である、請求項1〜13のいずれか一項記載の化合物。
- 前記R5が重水素である、請求項1〜13のいずれか一項記載の化合物。
- 前記R5がフルオロである、請求項1〜13のいずれか一項記載の化合物。
- 前記R4が-CH2R4aである、請求項1〜16のいずれか一項記載の化合物。
- 前記R4が-CH(R4a)2である、請求項1〜16のいずれか一項記載の化合物。
- 前記R4が-C(R4a)3である、請求項1〜16のいずれか一項記載の化合物。
- 前記R4aが水素である、請求項1〜17のいずれか一項記載の化合物。
- 前記R4aが重水素である、請求項1〜19のいずれか一項記載の化合物。
- 前記R4aがフルオロである、請求項1〜19のいずれか一項記載の化合物。
- 前記R4aがヒドロキシルである、請求項17記載の化合物。
- 前記R4が、メチル又はトリフルオロメチルである、請求項1〜16のいずれか一項記載の化合物。
- 前記R6が水素である、請求項1〜24のいずれか一項記載の化合物。
- 前記R6が重水素である、請求項1〜24のいずれか一項記載の化合物。
- 前記R6がフルオロである、請求項1〜24のいずれか一項記載の化合物。
- 前記R6がヒドロキシルである、請求項1〜24のいずれか一項記載の化合物。
- 前記化合物が、濃縮された重水素である、請求項1〜28のいずれか一項記載の化合物。
- 同位体濃縮されたとして特定された原子の少なくとも1つが、約5%以上同位体濃縮を有する、請求項1〜29のいずれか一項記載の化合物。
- 前記R1が、-C(O)-C6-14アリールであり;R3、R5、及びR6が、水素であり;R4が、C1-6アルキルであり;mが2であり;且つ、nが0であり;ここで、該アルキル及びアリールが、1個以上の置換基Qにより任意に置換されている、請求項1記載の化合物。
- 前記R1が、ベンゾイルであり;R3、R5、及びR6が、水素であり;R4が、メチルであり;mが2であり;且つ、nが0であり;ここで、該メチル及びベンゾイルが、1個以上の置換基Qにより任意に置換されている、請求項1記載の化合物。
- 前記R1が、ベンゾイルであり;R3、R5、及びR6が、水素であり;R4が、メチル又はトリフルオロメチルであり;mが2であり;且つ、nが0である、請求項1記載の化合物。
- 請求項1〜34のいずれか一項記載の化合物、又はそれらの鏡像異性体、鏡像異性体の混合物、2種以上のジアステレオマーの混合物、互変異性体、2種以上の互変異性体の混合物、若しくは同位体変種;又は、それらの医薬として許容し得る塩、溶媒和物、若しくは水和物を含む、医薬組成物。
- 第二の治療薬を更に含む、請求項35記載の医薬組成物。
- 前記組成物が、単回投与量の投与のために製剤されている、請求項35又は36記載の医薬組成物。
- 前記組成物が、経口、非経口、又は静脈内剤形として製剤されている、請求項37記載の医薬組成物。
- 前記経口剤形が、錠剤、カプセル剤、又は液剤である、請求項38記載の医薬組成物。
- 対象において増殖性疾患の1つ以上の症状を治療、予防又は改善するための、請求項35〜39のいずれか一項記載の医薬組成物。
- 前記増殖性疾患が、血液悪性疾患である、請求項40記載の医薬組成物。
- 前記増殖性疾患が、白血病である、請求項41記載の医薬組成物。
- 前記増殖性疾患が、急性白血病である、請求項42記載の医薬組成物。
- 前記増殖性疾患が、ALL又はAMLである、請求項43記載の医薬組成物。
- 前記増殖性疾患が、慢性白血病である、請求項42記載の医薬組成物。
- 前記増殖性疾患が、CLL又はCMLである、請求項45記載の医薬組成物。
- 前記増殖性疾患が、薬物抵抗性である、請求項40〜46のいずれか一項記載の医薬組成物。
- 前記増殖性疾患が、Bcr-Ablキナーゼ阻害薬抵抗性である、請求項47記載の医薬組成物。
- 前記増殖性疾患が、イマチニブ-、ダサチニブ-、ニラチニブ-、又はボスチニブ-抵抗性である、請求項48記載の医薬組成物。
- 前記増殖性疾患が、シタラビン-抵抗性である、請求項47記載の医薬組成物。
- 前記化合物が、経口、非経口、又は局所的に投与されるように用いられることを特徴とする、請求項40〜50のいずれか一項記載の医薬組成物。
- 前記化合物が、第二の治療薬と組合せて投与されるように用いられることを特徴とする、請求項40〜51のいずれか一項記載の医薬組成物。
- 前記第二の治療薬が、イマチニブ、ダサチニブ、ニラチニブ、ボスチニブ、又はシタラビンである、請求項52記載の医薬組成物。
- 前記増殖性疾患が、白血病、成人T細胞白血病、前骨髄球性白血病、前駆B細胞白血病、リンパ腫、マントル細胞リンパ腫、乳癌、膵臓癌、前立腺癌、頭頸部癌、卵巣癌、メラノーマ、神経膠腫、肝臓癌、腎臓癌、結腸直腸癌、横紋筋肉腫、舌癌、胃癌、多発性骨髄腫、膀胱癌、甲状腺癌、類表皮癌、肺癌、NSC肺癌、及び大細胞肺癌から選択される、請求項40〜53のいずれか一項記載の医薬組成物。
- 細胞の成長を阻害するための、請求項35〜39のいずれか一項記載の医薬組成物。
- 前記細胞が、血液悪性疾患細胞である、請求項55記載の医薬組成物。
- 前記細胞が、白血病細胞である、請求項55記載の医薬組成物。
- 前記細胞が、急性白血病細胞である、請求項57記載の医薬組成物。
- 前記細胞が、ALL又はAML細胞である、請求項58記載の医薬組成物。
- 前記細胞が、慢性白血病細胞である、請求項57記載の医薬組成物。
- 前記細胞が、CLL又はCML細胞である、請求項57記載の医薬組成物。
- 前記細胞が、薬物抵抗性である、請求項55〜61のいずれか一項記載の医薬組成物。
- 前記細胞が、Bcr-Ablキナーゼ阻害薬抵抗性である、請求項62記載の医薬組成物。
- 前記細胞が、イマチニブ-、ダサチニブ-、ニラチニブ-、又はボスチニブ-抵抗性である、請求項63記載の医薬組成物。
- 前記細胞が、シタラビン-抵抗性である、請求項62記載の医薬組成物。
- 前記細胞が、白血病、成人T細胞白血病、前骨髄球性白血病、前駆B細胞白血病、リンパ腫、マントル細胞リンパ腫、乳癌、膵臓癌、前立腺癌、頭頸部癌、卵巣癌、メラノーマ、神経膠腫、肝臓癌、腎臓癌、結腸直腸癌、横紋筋肉腫、舌癌、胃癌、多発性骨髄腫、膀胱癌、甲状腺癌、類表皮癌、肺癌、NSC肺癌、及び大細胞肺癌の細胞から選択される、請求項55〜65のいずれか一項記載の医薬組成物。
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PCT/US2011/038700 WO2011153197A1 (en) | 2010-06-01 | 2011-06-01 | Hydroxypyridone derivatives, pharmaceutical compositions thereof, and their therapeutic use for treating proliferative diseases |
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EP (1) | EP2576513A1 (ja) |
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GB201420348D0 (en) * | 2014-11-17 | 2014-12-31 | Univ Northumbria Newcastle | Compounds for treating neurodegenerative diseases |
AU2020256166A1 (en) | 2019-04-02 | 2021-10-14 | Aligos Therapeutics, Inc. | Compounds targeting PRMT5 |
CN110354121B (zh) * | 2019-07-08 | 2023-05-02 | 温州医科大学 | 环吡酮胺在制备治疗肿瘤药物中的应用和包含环吡酮胺的组合药物及用途 |
CN113603640A (zh) * | 2021-08-06 | 2021-11-05 | 成都化润药业有限公司 | 一种羟吡酮乙胺盐的合成方法 |
CN113588852A (zh) * | 2021-08-16 | 2021-11-02 | 浙江鼎泰药业股份有限公司 | 一种高活性透皮贴膏中挥发性成分含量的测定方法 |
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2011
- 2011-06-01 MX MX2012013879A patent/MX2012013879A/es active IP Right Grant
- 2011-06-01 CN CN2011800377765A patent/CN103038216A/zh active Pending
- 2011-06-01 EP EP11731574.7A patent/EP2576513A1/en not_active Withdrawn
- 2011-06-01 CN CN201510258042.XA patent/CN104945318A/zh active Pending
- 2011-06-01 AU AU2011261499A patent/AU2011261499B2/en not_active Ceased
- 2011-06-01 CA CA2801001A patent/CA2801001A1/en not_active Abandoned
- 2011-06-01 CN CN201510258095.1A patent/CN104926722A/zh active Pending
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CN104945318A (zh) | 2015-09-30 |
CN104926722A (zh) | 2015-09-23 |
CN103038216A (zh) | 2013-04-10 |
MX2012013879A (es) | 2013-04-03 |
WO2011153197A1 (en) | 2011-12-08 |
EP2576513A1 (en) | 2013-04-10 |
AU2011261499A1 (en) | 2013-01-10 |
US8334307B2 (en) | 2012-12-18 |
JP2013528619A (ja) | 2013-07-11 |
US9273005B2 (en) | 2016-03-01 |
US20130072526A1 (en) | 2013-03-21 |
CA2801001A1 (en) | 2011-12-08 |
AU2011261499B2 (en) | 2015-07-16 |
US20120022115A1 (en) | 2012-01-26 |
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