JP6898429B2 - 黄斑変性症を治療するためのエンタカポン関連化合物 - Google Patents
黄斑変性症を治療するためのエンタカポン関連化合物 Download PDFInfo
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- JP6898429B2 JP6898429B2 JP2019510788A JP2019510788A JP6898429B2 JP 6898429 B2 JP6898429 B2 JP 6898429B2 JP 2019510788 A JP2019510788 A JP 2019510788A JP 2019510788 A JP2019510788 A JP 2019510788A JP 6898429 B2 JP6898429 B2 JP 6898429B2
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- macular degeneration
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- entacapone
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- 208000002780 macular degeneration Diseases 0.000 title claims description 21
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- MIQPIUSUKVNLNT-UHFFFAOYSA-N tolcapone Chemical compound C1=CC(C)=CC=C1C(=O)C1=CC(O)=C(O)C([N+]([O-])=O)=C1 MIQPIUSUKVNLNT-UHFFFAOYSA-N 0.000 description 1
- 229960004603 tolcapone Drugs 0.000 description 1
- 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 description 1
- 125000004385 trihaloalkyl group Chemical group 0.000 description 1
- 229910052722 tritium Inorganic materials 0.000 description 1
- 239000003981 vehicle Substances 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
- 229920002554 vinyl polymer Polymers 0.000 description 1
- 230000004393 visual impairment Effects 0.000 description 1
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Description
R1及びR2は独立したH又はMeであって、
R3はH、OH又はNHRであって、Rは、H又は、置換基を有していてもよく(optionally substituted)、ヘテロ基を有していてもよく、環状のC1−C18ヒドロカルビルを有していてもよく、
R4は置換基を有していてもよく、ヘテロ基を有していてもよく、環状のC1−C18ヒドロカルビルを有していてもよい。
R4はシアノ又は2〜5個の炭素原子を有するアルキルカルボニルを表し、R5はシアノ;2〜5個の炭素原子を有するアルキルカルボニル;又は、非置換のカルバモイル又は1〜8個の炭素原子を含むアルキルで置換されたカルバモイル、若しくは、1〜8個の炭素原子を含むヒドロキシアルキルで置換されたカルバモイルを表す。
Yは硫黄又は酸素であり、
R1は下記式(II)の基、
R2はH、又は、R1と同一若しくは異なっていてもよい式IIの基であり、
R3はそれぞれ独立して(C 1 −C20)アルキル、(CR4R5)X−R6、(C 1 −C20)−アルキレン−(C 1 −C20)−アルコキシ、(C2−C20)−アルケニル、(C2−C20)−アルキニル、(C0−C20)−アルキレン−(C3−C 18)−シクロアルキル、(C0−C20)−アルキレン−(3−l8員環)−ヘテロシクロアルキル、(C 1 −C20 )−アルキレン−(C3−C18)−シクロアルケニル、(C 0 −C20)−アルキレン−(3−18員環)−ヘテロシクロアルケニル、(C 0 −C20 )−アルキレン−(C6−C 18)−アリール(C 0 −C20 )−アルキレン−(5−18員環)−ヘテロアリール、(C2−C20)−アルケニレン−(C3−C 18)−シクロアルキル、(C2−C20)−アルケニレン−(3−18員環)−ヘテロシクロアルキル、(C2−C20)−アルケニレン−(C3−C18)−シクロアルケニル、(C2−C20)−アルケニレン−(3−18員環)−ヘテロシクロアルケニル、(C2−C20)−アルケニレン−(C6−C 18)−アリール、又は(C2−C20)−アルケニレン−(5−18員環)−ヘテロアリール、であって、
R3が有する炭素原子数の合計数は30以下であり、
R4及びR5は互いにそれぞれ独立して、H、(C 1 −C20)−アルキル、(C 1 −C20)−アルキレン−ヒドロキシ、(C0−C20)−アルキレン−(C 1 −C20)−アルコキシ、OH、(C0−C20 )−アルキレン−N(R7)CO−(C 1 −C20)−アルキル、(C0−C20)−アルキレン−CON(R8)(R9)、(C0−C20)−アルキレン−COO−(C 1 −C20)−アルキル、(C0−C20)−アルキレン−N(R10)(R 11 )、SO3R17、(C0−C20)−アルキレン−(C6−C18)−アリール及び(C0−C20)−アルキレン−(5−18員環)−ヘテロアリールを含む群から選択され、
又は、
(CR4R5)と同じ群のR4及びR5、又は、(CR4R5)とは異なる群のR4及びR5は、3〜6個の原子を有する環状炭素若しくは複素環をともに形成してもよく、さらに、1以上の隣接していない(CR4R5)の群は、O、CO、OCO、COO、CON(R19)、N(R20)CO又はNR21で置換されていてもよく、
R6は独立してH、(C 1 −C20)−アルキル、(C2−C20)−アルケニル、(C2−C20)−アルキニル、OH、O−(C 1 −C8)−アルキル、O−(C0−C8)−アルキレン−(C6−C 14)−アリール、CO−O−(C 1 −C8)−アルキル、CO−N(R12)(R13)、N(R14)CO−(C 1 −C8)−アルキル、N(R15 )(R16)、SO3R18、(C0−C20)−アルキレン−(5−18員環)−ヘテロアリール又は(C0−C20)−アルキレン−(C6−C 18)−アリールであって、
R7、R14、R17、R18、R19、R20、R21は互いに独立したH又は(C 1 −C20 )−アルキルであり、
R8、R9、R10、R11、R12、R13、R15、R16は互いに独立したH又は(C 1 −C20)−アルキルであり、
R22及びR23はH及び(C 1 −C 15)−アルキルを含む群から独立して選択され、
及び、
xは1〜14であって、
アルキル基、アルケニル基、アルキニル基、シクロアルキル基、ヘテロシクロアルキル基、シクロアルケニル基、ヘテロシクロアルケニル基、アルコキシ基、アリール基、ヘテロアリール基、アルケニレン基及びアルキレン基が、非置換又はさらに置換されていてもよい。
(a)エンタカポン、エンタカポン誘導体若しくは立体異性体、水素化物、又はその薬学的に許容され得る塩を含む眼科用組成物であって、前記組成物は、レボドパ(L−DOPA)又はカルビドパのような、ドーパミン又はドーパミン誘導体を含まず;
(b)エンタカポン、エンタカポン誘導体若しくは立体異性体、水素化物、又はその薬学的に許容され得る塩を含む局所眼科用組成物;又は、
(c)黄斑変性症又は加齢性黄斑変性症を治療又は阻害するための、第2の異なる薬剤と一緒に包装若しくは一緒に処方された、エンタカポン、エンタカポン誘導体若しくは立体異性体、水素化物、又はその薬学的に許容され得る塩を含む組成物;
を含む、医薬組成物又は医薬製剤を提供する。
・組成物又は製剤は、他の抗パーキンソン病薬、神経活性剤、抗肥満薬、抗糖尿病薬及び/又は他の活性医薬成分(API)を含まない。抗パーキンソン病薬は、例えば、L−DOPA、デプレニル、チロシンヒドロキシラーゼ、アポモルヒネ、トリヘキシフェニジル(benzhexol)やオルフェナドリンなどの抗コリン薬、及び、N−フェニル−7−(ヒドロキシルイミノ)シクロプロパ[b]クロメン−1a−カルボキサミド(PHCCC)などのmGluR4増強剤などを含み;
・組成物又は製剤は、点眼剤、軟膏剤、ゲル剤又は乳剤の、局所用の形態であり;
・組成物又は製剤は、硝子体内注射製剤又は眼内インプラント製剤の形態であり;
・組成物又は製剤は、エンタカポン、エンタカポン誘導体又はその薬学的に許容され得る塩が単位剤形であり;及び/又は
・組成物又は薬剤は、第2の薬剤が、レバシズマブ(revacizumab)、ラニビズマブ、ペガプタニブ及びアフリベルセプトから選択される抗血管新生薬(例えば、VEGF阻害剤)である。
特定の実施形態及び実施例に関する以下の説明は、限定としてではなく例として提供されている。当業者は、本質的に同様の結果を得るために変更又は修正することができる様々な重要ではないパラメータを容易に認識するであろう。
−NR’−及び−S(O)2NR’における置換基R’は、水素又は非置換の(C1−C6)アルキルから選択される。
(a)
R1及びR2は独立したH又はMeであって、
R3はOH又はNHRであって、Rは、H又は置換基を有していてもよく、ヘテロ基を有していてもよく、環状のC1−C18ヒドロカルビルを有していてもよく、
R4は置換基を有していてもよく、ヘテロ基を有していてもよく、環状のC1−C18ヒドロカルビルを有していてもよい。
(b)
R1及びR2は独立したH又はMeであって、
R3はH、OH又はNHRであって、Rは、H又はC1−C4アルキルであって、
R4はCONHR5であって、
R5は置換基を有していてもよく、ヘテロ基を有していてもよく、環状のC1−C18ヒドロカルビルを有していてもよい。
(c)
R1及びR2は独立したH又はMeであって、
R3はH、OH又はNHRであって、Rは、H又はC1−C4アルキルであって、
R4はCOR5であって、
R5は置換基を有していてもよく、N、O、S及びPから独立に選択される1〜n−1個のヘテロ原子を含むn=3〜18のn員環を含む複素環のC3−C18ヒドロカルビルである。又は、
(d)
R1及びR2は独立したH又はMeであって、
R3はH、OH又はNHRであって、Rは、H又はC1−C4アルキルであって、
R4は置換基を有していてもよく、N、O、S及びPから独立に選択される1〜n−1個のヘテロ原子を含むn=3〜18のn員環を含む複素環のC3−C18ヒドロカルビルであって、特に、阻害剤から除外される化合物は、CAS番号:1364322−41−7、1150310−12−5、1150310−15−8及び143542−72−7である。
置換基を有していてもよい3員環:アジリジン、オキシラン、オキサジリジン;
置換基を有していてもよい4員環:アゼチジン、オキセタン、オキサゼチジン;
置換基を有していてもよい5員環:ピロール、1,2−ジアゾ−ル(ピラゾール)、1,3ジアゾ−ル(イミダゾール)、チアゾール、イソチアゾール、オキサゾール、イソキサゾール、フラン、ジオキソール、チオフェン;
置換基を有していてもよい6員環:ピリジン、ジアジン、トリアジン、オキサジン、チアジン、ダイオキシン、オキサチイン(oxathiine)、ジチイン(dithiine);
置換基を有していてもよい9員環:インドール、ベンゾチアゾール、ベンゾオキサゾール(benzooxazole)、ベンゾフラン、ベンゾジオキソール、ベンゾチオフェン、ベンゾジチオール;又は
置換基を有していてもよい10員環:キノリン、キノキサリン、キナゾリン、クロメン、ベンゾジオキシン、チオクロメン、ベンゾジチイン(benzodithiine)、を含む。
R3がOHであって、及び/又は
RがH又はC1−C4アルキル、特にMeである。
欧州特許出願公開第1978014号明細書に、エンタカポンの準備方法が開示されており、代表的な誘導体の合成方法は、国際公開第2016/206573号に十分に開示されているため、本明細書では繰り返さない。
我々は、低酸素誘導網膜症ゼブラフィッシュモデル(Cao et al., Hypoxia-induced retinopathy model in adult zebrafish. Nat Protoc 2010, 5 (12), 1903-10)において、エンタカポン及び代表的なエンタカポン誘導体の治療効果を測定した。
Claims (8)
- 黄斑変性症又は加齢性黄斑変性症の治療又は阻害を必要とするヒトに対する使用のための医薬組成物又は医薬製剤であって、前記組成物又は製剤は、エンタカポン又はその薬学的に許容され得る塩を含み、前記組成物又は製剤は、他の抗パーキンソン病薬、神経活性剤、抗肥満薬及び/又は抗糖尿病薬を含まないことを条件とする、医薬組成物又は医薬製剤。
- パーキンソン病、肥満、糖尿病又は糖尿病網膜症ではない前記ヒトに対する、請求項1又は2に記載の使用のための組成物又は製剤。
- 黄斑変性症又は加齢性黄斑変性症を治療又は阻害するための、第2の異なる薬剤をさらに含む、請求項1〜3のいずれか1項に記載の使用のための組成物又は製剤。
- 点眼剤、軟膏剤、ゲル剤又は乳剤の、局所用の形態の、請求項1〜4のいずれか1項に記載の使用のための組成物又は製剤。
- 硝子体内注射製剤の形態又は眼内インプラント製剤の形態の、請求項1〜4のいずれか1項に記載の使用のための組成物又は製剤。
- 前記組成物又は製剤が単位剤形である、請求項1〜4のいずれか1項に記載の使用のための組成物又は製剤。
- 前記第2の異なる薬剤が、レバシズマブ、ラニビズマブ、ペガプタニブ及びアフリベルセプトから選択される抗血管新生薬である、請求項4に記載の使用のための組成物又は製剤。
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CNPCT/CN2016/096472 | 2016-08-24 | ||
CN2016096472 | 2016-08-24 | ||
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US20060034937A1 (en) * | 1999-11-23 | 2006-02-16 | Mahesh Patel | Solid carriers for improved delivery of active ingredients in pharmaceutical compositions |
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EP1946756A1 (en) * | 2007-01-17 | 2008-07-23 | Revotar Biopharmaceuticals AG | Use of entacapone in cosmetic, dermatological and pharmaceutical compositions |
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US9827210B2 (en) * | 2007-06-29 | 2017-11-28 | Phovitreal Pty Ltd | Treatment or prophylaxis of a neurological or neuropsychiatric disorders via ocular administration |
AU2009236078B2 (en) * | 2008-04-18 | 2014-03-06 | Arizona Board Of Regents, A Body Corp. Of The State Of Arizona, Acting For And On Behalf Of The University Of Arizona | Methods and compositions for treating age-related macular degeneration |
CA2734491A1 (en) * | 2008-08-19 | 2010-02-25 | Knopp Neurosciences, Inc. | Compositions and methods of using (r)-pramipexole |
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WO2012142039A1 (en) * | 2011-04-15 | 2012-10-18 | University Of North Dakota | Combination of liver x receptor modulator and estrogen receptor modulator for the treatment of age-related diseases |
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US9951057B2 (en) * | 2015-01-30 | 2018-04-24 | Lieber Institute For Brain Development | COMT inhibiting methods and compositions |
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JP7116202B2 (ja) | 2016-08-24 | 2022-08-09 | ナショナル・インスティチュート・オブ・バイオロジカル・サイエンシズ,ベイジン | 黄斑変性症を治療するための医薬の製造におけるエンタカポン関連化合物の使用 |
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