JP2021535112A - 補体d因子の医学的障害の治療のための医薬化合物 - Google Patents
補体d因子の医学的障害の治療のための医薬化合物 Download PDFInfo
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Classifications
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P13/00—Drugs for disorders of the urinary system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P27/00—Drugs for disorders of the senses
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
- C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D451/00—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof
- C07D451/02—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof containing not further condensed 8-azabicyclo [3.2.1] octane or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane; Cyclic acetals thereof
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
- C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
- C07D491/04—Ortho-condensed systems
- C07D491/044—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
- C07D491/052—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring the oxygen-containing ring being six-membered
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00
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- Organic Chemistry (AREA)
- Chemical & Material Sciences (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmacology & Pharmacy (AREA)
- Engineering & Computer Science (AREA)
- Animal Behavior & Ethology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Urology & Nephrology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Plural Heterocyclic Compounds (AREA)
- Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
Abstract
Description
本出願は、2018年8月20日に出願された米国出願第62/765,318号;及び2018年9月6日に出願された米国出願第62/727,847号の優先権の利益を主張し;これらの各々は、あらゆる目的のために参照により本明細書に援用される。
第US2017−0226142号;第US2017−0260219号;第US2017−0298084号;第US2017−0298085号;第US2018−0022766号;第US2018−0022767号;第US2018−0072762号;第US2018−0030075号;第US2018−0169109号;第US2018−0177761号;第US2018−0179185号;第US2018−0179186号;第US2018−0179236号;第US2018−0186782号;第US2018−0201580号;第US2019−0031692号;第US2019−0048033号;第US2019−0144473号;及び第US2019−0211033号に記載されており、これらはいずれもAchillion Pharmaceuticals,Incが所有している。
式中:
xが、0、1、または2であり;
nが、1、2、3、または4であり;
qが、0、1、2、または3であり;
R1、R1’、R2、R2’、R3、及びR3’が、それぞれ独立して、必要に応じて、及び安定した化合物をもたらす場合にのみ、水素、−C0−C4アルキルNR9R12、−C0−C4アルキルOR12、C1−C6ハロアルキル、−SO2R11、ハロゲン、ヒドロキシル、及びC1−C6アルキルから選択され;
またはR1とR2が、一緒になって3〜6員の炭素環を形成し;
またはR2とR3が、一緒になって3〜6員の炭素環を形成し;
A1が:
A2が:
A3が:
A4が:
A5が:
B1が、C1−C6アルキル、C0−C4アルキル−アリール、C0−C4アルキル−ヘテロアリール、及びC0−C4アルキル−複素環から選択され、その場合、各B1を、場合により、独立して、ハロゲン、C1−C3アルキル、C1−C3ハロアルキル、−COOH、シアノ、C2−C6アルカノイル、C1−C6アルコキシ、−C0−C4アルキルNR9R12、−C0−C4アルキルOR12、C1−C6ハロアルキル、−SO2R11、及びC1−C6ハロアルコキシから選択される1つ、2つ、3つまたは4つの基で置換することができ;
B2が:
代替の実施形態では、B2が:
Rが、水素またはC1−C4アルキルであり;
R5が、C1−C3アルキル、−NR9R10、及び−NR9OR10から選択され;
またはR5が、−C1−C3アルキル−OR9であり;
R7が、
各R8が、独立して、ハロゲン、C1−C3アルキル、C1−C3ハロアルキル、−COOH、シアノ、C2−C6アルカノイル、C1−C6アルコキシ、−C0−C4アルキルNR9R10、−C0−C4アルキルOR9、C1−C6ハロアルキル、及びC1−C6ハロアルコキシから選択され;
代替の実施形態では、R8は水素であり;
各R9及びR10が、独立して、水素及びC1−C4アルキルから選択され;
各R11が、独立して、C1−C3アルキル、−OR9、及び−NR9R10から選択され;
代替の実施形態では、R11は水素であり;
各R12が、独立して、水素、C1−C3アルキル、及び−C(O)R11から選択され;
特定の実施形態では、各R12は、独立して、水素または−C(O)R11であり;
R13が−NR9OR10であり;
X13及びX14が、独立して、N及びCR31から選択され;
R22が、−C0−C4アルキルNR9R12、−C0−C4アルキルOR12、C1−C6ハロアルキル、−SO2R11、ハロゲン、ヒドロキシル、及びC1−C6アルキルから選択され;
R23が、水素、C1−C6アルキル、−C0−C4アルキル−アリール、−C0−C4アルキル−ヘテロアリール、及び−C0−C4アルキル−複素環から選択され;
各R31が、独立して、水素、ハロゲン、C1−C6アルキル、ヒドロキシル、−C0−C4アルキルNR9R12、−C0−C4アルキルOR12、C1−C6ハロアルキル、−SO2R11、及びC1−C6ハロアルコキシから選択され;
R32が、アリール、ヘテロアリール、及び複素環から選択され、その場合、アリール、ヘテロアリール、または複素環を、場合により、独立して、ハロゲン、C1−C3アルキル、C1−C3ハロアルキル、−CO2R11、シアノ、C2−C6アルカノイル、C1−C6アルコキシ、−C0−C4アルキルNR9R12、−C0−C4アルキルOR12、C 1−C6ハロアルキル、−SO2R11、及びC1−C6ハロアルコキシから選択される1つ、2つ、または3つの基で置換することができ;
R33が、
R34が、ハロゲン、ヒドロキシル、C1−C6アルキル、−C0−C4アルキルNR9R12、−C0−C4アルキルOR12、C1−C6ハロアルキル、−SO2R11、及びC1−C6ハロアルコキシから選択される。
Qが、CHまたはNであり;
Q1が、CH2、O、NH、またはNR9であり;
wが、0、1、または2であり;
A6が:
A7が:
A8が:
B3が:
B4が:
B5が:
R35が、
各R36が、独立して、C1−C6アルキル、ハロゲン、及びC1−C6ハロアルキルから選択され;
R37が、C(O)R11、F、及びCNから選択され;
R38が、
各R39が、独立して、水素、C1−C6アルキル、ハロゲン、及びC1−C6ハロアルキルから選択され;
R40が、
R41が、
各R42が、独立して、ハロゲン、C1−C3アルキル、C1−C3ハロアルキル、−COOH、C2−C6アルカノイル、C1−C6アルコキシ、−C0−C4アルキルNR9R10、−C0−C4アルキルOR9、C1−C6ハロアルキル、及びC1−C6ハロアルコキシから選択され;そして
他のすべての変数は、本明細書中で定義するとおりである。
a.場合により薬学的に許容される組成物中の、本発明の化合物またはその薬学的に許容される塩、プロドラッグ、同位体類似体、N−オキシド、もしくは単離された異性体
b.非アルコール性脂肪性肝炎(NASH)、肝炎、肝硬変、または肝不全などの脂肪肝の発症及び脂肪肝に起因する病態;皮膚筋炎;筋萎縮性側索硬化症;生物療法(例えば、CAR T細胞療法)に応答したサイトカイン反応または炎症反応;発作性夜間ヘモグロビン尿症(PNH)、関節リウマチ、多発性硬化症、加齢性黄斑変性症(AMD)、網膜変性症、その他の眼疾患(例えば、地図状萎縮)、呼吸器疾患、心血管疾患、補体副経路(AP)関連腎症、例えばC3腎(C3G)障害、例えばC3腎炎(C3GN)もしくはデンスデポジット病(DDD)、または膜性増殖性糸球体腎炎(MPGN)障害、例えば、免疫複合体膜性増殖性糸球体腎炎(IC−MPGN)、虚血性再灌流障害もしくは脳卒中、外傷性脳損傷(TBI)及び脊髄損傷(SCI)を含むがこれらに限定されない後天性脳損傷または後天性脊髄損傷などの中枢神経系または末梢神経系の障害、アルツハイマー病(AD)、多発性硬化症、視神経脊髄炎(NMO)、筋萎縮性側索硬化症(ALS)、パーキンソン病(PD)、ハンチントン病(HD)、脱髄性髄鞘破壊性疾患、脱髄性白質萎縮性疾患、ならびに神経炎症性障害を含むがこれらに限定されない障害の治療または予防に使用するための、場合により、薬学的に許容される組成物中の、本発明の化合物またはその薬学的に許容される塩、プロドラッグ、同位体類似体、N−オキシド、もしくは単離された異性体。
c.薬学的に許容される担体中の、本発明の化合物またはその薬学的に許容される塩、プロドラッグ、同位体類似体、N−オキシド、もしくは単離された異性体の、薬学的に許容される組成物
d.補体経路、及び例えば、カスケードD因子によって媒介される障害の治療または予防に使用するための、場合により、薬学的に許容される組成物中の、本発明の化合物またはその薬学的に許容される塩、プロドラッグ、同位体類似体、N−オキシド、もしくは単離された異性体
e.非アルコール性脂肪性肝炎(NASH)、肝炎、肝硬変、肝不全などの脂肪肝の発症及び脂肪肝に起因する病態;皮膚筋炎;筋萎縮性側索硬化症;生物療法(例えば、CAR T細胞療法)に応答したサイトカイン反応または炎症反応;発作性夜間ヘモグロビン尿症(PNH)、C3腎炎、デンスデポジット病、C3腎症、関節リウマチ、多発性硬化症、加齢性黄斑変性症(AMD)、網膜変性症、その他の眼疾患(例えば、地図状萎縮)、呼吸器疾患または心血管疾患を含むがこれらに限定されない障害を治療または予防するための薬剤の製造における、場合により薬学的に許容される組成物中の、本明細書に記載の本発明の化合物、またはその薬学的に許容される塩、プロドラッグ、同位体類似体、N−オキシド、もしくは単離された異性体の使用
f.本発明の化合物または活性化合物の実施形態を製造中に使用することを特徴とする、障害を治療または予防するための、または一般的に補体カスケードD因子によって媒介される障害を治療または予防するための、治療的用途を目的とする薬剤を製造するためのプロセス
g.実質的に純粋な形態(例えば、少なくとも90、95、または98%)の本明細書に記載の本発明の化合物またはその塩
h.炎症性病態または免疫病態である医学的障害、補体カスケード(機能不全カスケードを含む)によって媒介される障害、通常の補体活性に関与もしくは応答する細胞の能力に悪影響を与える細胞の障害または異常、あるいは外科手術もしくは他の医療手技または医薬品もしくは生物医薬品の投与、輸血、または他の同種組織もしくは体液の投与などの医療処置に対する望ましくない補体媒介性応答を治療するために使用するための薬学的に許容される組成物を形成するための、場合により担体中の、本明細書に記載の本発明の化合物、またはその薬学的に許容される塩、プロドラッグ、同位体類似体、N−オキシド、もしくは単離された異性体
i.上記(a)〜(h)のそれぞれについて、または本明細書中で、部分の各集合体及びそれから作製される各活性化合物またはその使用は、そのような記載がスペースの都合上のものに過ぎず、そのような表示に対する属または亜属のみを説明することを意図するものではないことから、それらが具体的かつ個別に開示されているものとみなし、考えるものとする。
化合物は、標準的な命名法を使用して記載する。別段の定義がない限り、本明細書中で使用するすべての技術用語及び科学用語は、本発明が属する分野の当業者によって一般的に理解される意味と同じ意味を有する。
i.親薬物上のカルボン酸とヒドロキシル化プロドラッグ部分により、エステルを形成;
ii.親薬物上のカルボン酸とアミンプロドラッグにより、アミドを形成;
iii.親薬物上のアミノとカルボン酸プロドラッグ部分により、アミドを形成;
iv.親薬物上のアミノとスルホン酸により、スルホンアミドを形成;
v.親薬物上のスルホン酸とプロドラッグ部分上のアミノにより、スルホンアミドを形成;
vi.親薬物上のヒドロキシル基とプロドラッグ部分上のカルボン酸により、エステルを形成;
vii.親薬物上のヒドロキシルとヒドロキシル化プロドラッグ部分により、エーテルを形成;
viii.親薬物上のホスホネートとヒドロキシル化プロドラッグ部分により、ホスホネートエステルを形成;
ix.親薬物上のリン酸とヒドロキシル化プロドラッグ部分により、リン酸エステルを形成;
x.親薬物上のヒドロキシルとプロドラッグ上のホスホネートにより、ホスホネートエステルを形成;
xi.親薬物上のヒドロキシルとリン酸プロドラッグ部分により、リン酸エステルを形成;
xii.親薬物上のカルボン酸と構造HO−(CH2)2−O−(C2−24脂肪族基)のプロドラッグ、例えば、HO−(CH2)2−O−(C2−24アルキル基)により、エステルを形成;
xiii.親薬物上のカルボン酸と構造HO−(CH2)2−S−(C2−24脂肪族基)のプロドラッグ、例えば、HO−(CH2)2−S−(C2−24アルキル基)により、チオエステルを形成;
xiv.親薬物上のヒドロキシルと構造HO−(CH2)2−O−(C2−24脂肪族基)のプロドラッグ、例えば、HO−(CH2)2−O−(C2−24アルキル基)により、エーテルを形成;
xv.親薬物上のカルボン酸と、構造HO−(CH2)2−S−(C2−24脂肪族基)のプロドラッグ、例えば、HO−(CH2)2−S−(C2−24アルキル基)により、チオエーテルを形成;及び
xvi.親化合物上のカルボン酸、オキシム、ヒドラジド、ヒドラゾン、アミンまたはヒドロキシルと、ポリ乳酸、ポリラクチド−コ−グリコリド、ポリグリコリド、ポリエチレングリコール、ポリ無水物、ポリエステル、ポリアミドまたはペプチドを含むがこれらに限定されない生分解性ポリマーまたはオリゴマーであるプロドラッグ部分。オキシム結合の例示的な合成は、Jin et.al.の表題“Oxime Linkage: A Robust Tool for the Design of PH−Sensitive Polymeric Drug Carriers” in BioMacromolecules,2011,12(10),3460−3468に公開された論文に提供されている。
特定の実施形態では、活性化合物のいずれかを、それを必要とする患者にそのN−オキシド形態で提供することができる。一実施形態では、活性化合物または活性化合物の前駆体のN−オキシドを、製造スキームにおいて使用する。さらに別の実施形態では、N−オキシドは、本明細書中の活性化合物のうちの1つの投与の代謝産物であり、独立した活性を有し得る。N−オキシドは、目的の化合物を、酸化剤、例えば、適切なペルオキシ酸または過酸化物で処理してN−オキシド化合物を生成することによって形成することができる。例えば、ヘテロアリール基、例えばピリジル基を、穏やかな反応条件下、レニウム系触媒の存在下で過炭酸ナトリウムなどの酸化剤で処理して、N−オキシド化合物を生成することができる。当業者であれば、この化学を実施するために適切な保護基が必要である場合があることを理解するであろう。Jain,S.L.et al.,“Rhenium−Catalyzed Highly Efficient Oxidations of Tertiary Nitrogen Compounds to N−Oxides Using Sodium Percarbonate as Oxygen Source,Synlett,2261−2663,2006を参照のこと。
一実施形態では、「アルキル」は、C1−C10アルキル、C1−C9アルキル、C1−C8アルキル、C1−C7アルキル、C1−C6アルキル、C1−C5アルキル、C1−C4アルキル、C1−C3アルキル、またはC1−C2アルキルである。
sec−ヘキシルが挙げられる。
一実施形態では、「ハロアルキル」は、C1−C10ハロアルキル、C1−C9ハロアルキル、C1−C8ハロアルキル、C1−C7ハロアルキル、C1−C6ハロアルキル、C1−C5ハロアルキル、C1−C4ハロアルキル、C1−C3ハロアルキル、及びC1−C2ハロアルキルである。
一実施形態では、「アリール」は、6炭素の芳香族基(フェニル)である。
一実施形態では、「ヘテロアリール」は、1、2、または3個の窒素原子を含む5員の芳香族基である。
一実施形態では、「シクロアルキル」は、C3−C8シクロアルキル、C3−C7シクロアルキル、C3−C6シクロアルキル、C3−C5シクロアルキル、C3−C4シクロアルキル、C4−C8シクロアルキル、C5−C8シクロアルキル、またはC6−C8シクロアルキルである。
一実施形態では、「複素環」は、1つの窒素と、3、4、5、6、7、または8個の炭素原子を有する環状環を指す。
場合により薬学的に許容される担体中の、
xが、0、1、または2であり;
nが、1、2、3、または4であり;
qが、0、1、2、または3であり;
R1、R1’、R2、R2’、R3、及びR3’が、それぞれ独立して、必要に応じて、及び安定した化合物をもたらす場合にのみ、水素、−C0−C4アルキルNR9R12、−C0−C4アルキルOR12、C1−C6ハロアルキル、−SO2R11、ハロゲン、ヒドロキシル、及びC1−C6アルキルから選択され;
またはR1とR2が、一緒になって3〜6員の炭素環を形成し;
またはR2とR3が、一緒になって3〜6員の炭素環を形成し;
A1が:
A2が:
A3が:
A4が:
A5が:
特定の実施形態では、B1がC0−C4アルキル−ヘテロアリールであり、その場合、各B1を、場合により、独立して、ハロゲン、C1−C3アルキル、C1−C3ハロアルキル、−COOH、シアノ、C2−C6アルカノイル、C1−C6アルコキシ、−C0−C4アルキルNR9R12、−C0−C4アルキルOR12、C1−C6ハロアルキル、−SO2R11、及びC1−C6ハロアルコキシから選択される1つ、2つ、3つ、または4つの基で置換することができ;
特定の実施形態では、B2が:
Rが、水素またはC1−C4アルキルであり;
R5が、C1−C3アルキル、−NR9R10、−NR9OR10、及び−C1−C3アルキル−OR9から選択され;
R7が、
各R8が、独立して、ハロゲン、C1−C3アルキル、C1−C3ハロアルキル、−COOH、シアノ、C2−C6アルカノイル、C1−C6アルコキシ、−C0−C4アルキルNR9R10、−C0−C4アルキルOR9、C1−C6ハロアルキル、及びC1−C6ハロアルコキシから選択され;
各R9及びR10が、独立して、水素及びC1−C4アルキルから選択され;
各R11が、独立して、C1−C3アルキル、−OR9、及び−NR9R10から選択され;
代替の実施形態では、R11は水素であり;
各R12が、独立して、水素、C1−C3アルキル、及び−C(O)R11から選択され;
特定の実施形態では、各R12は、独立して、水素または−C(O)R11であり;
R13が−NR9OR10であり;
X13及びX14が、独立して、N及びCR31から選択され;
R22が、−C0−C4アルキルNR9R12、−C0−C4アルキルOR12、C1−C6ハロアルキル、−SO2R11、ハロゲン、ヒドロキシル、及びC1−C6アルキルから選択され;
R23が、水素、C1−C6アルキル、−C0−C4アルキル−アリール、−C0−C4アルキル−ヘテロアリール、及び−C0−C4アルキル−複素環から選択され;
代替の実施形態では、R23は、水素、C1−C6アルキル、−C0−C4アルキル−アリール、−C0−C4アルキル−ヘテロアリール、C2−C6アルキル−OR9、及び−C0−C4アルキル−複素環から選択され;
各R31が、独立して、水素、ハロゲン、C1−C6アルキル、ヒドロキシル、
−C0−C4アルキルNR9R12、−C0−C4アルキルOR12、C1−C6ハロアルキル、−SO2R11、及びC1−C6ハロアルコキシから選択され;
R32が、アリール、ヘテロアリール、及び複素環から選択され、その場合、アリール、ヘテロアリール、または複素環を、場合により、独立して、ハロゲン、C1−C3アルキル、C1−C3ハロアルキル、−CO2R11、シアノ、C2−C6アルカノイル、C1−C6アルコキシ、−C0−C4アルキルNR9R12、−C0−C4アルキルOR12、C1−C6ハロアルキル、−SO2R11、及びC1−C6ハロアルコキシから選択される1つ、2つ、または3つの基で置換することができ;
特定の実施形態では、R33は、
R34が、ハロゲン、ヒドロキシル、C1−C6アルキル、−C0−C4アルキルNR9R12、−C0−C4アルキルOR12、C1−C6ハロアルキル、−SO2R11、及びC1−C6ハロアルコキシから選択され;
代替の実施形態では、各R8は、独立して、水素、ハロゲン、C1−C3アルキル、C1−C3ハロアルキル、−COOH、シアノ、C2−C6アルカノイル、C1−C6アルコキシ、C2−C6アルケニル、C2−C6アルキニル、−C0−C4アルキルNR9R10、−C0−C4アルキルOR9、C1−C6ハロアルキル、及びC1−C6ハロアルコキシから選択され;
代替の実施形態では、各R8は、独立して、テトラゾール、ハロゲン、C1−C3アルキル、C1−C3ハロアルキル、−COOH、シアノ、C2−C6アルカノイル、C1−C6アルコキシ、C2−C6アルケニル、C2−C6アルキニル、−C0−C4アルキルNR9R10、−C0−C4アルキルOR9、C1−C6ハロアルキル、及びC1−C6ハロアルコキシから選択される)。
C(C2−C6アルキニル)、及びC(C1−C6アルキル)から選択される。
C(C2−C6アルキニル)、及びC(C1−C6アルキル)から選択される。
本発明の一態様では、式I、式II、式III、式IV、式V、式VI、式VII、式VIII、式IX、式X、式XI、式XII、式XIII、式XIV、式XV、式XVI、式XVII、式XVIII、式XIX、式XX、式XXI、式XXII、または式XXIIIの化合物を提供し、式中、単一のC−H結合は、R201基で置き換えられ、式中:
R201が、C0−C3アルキル−NR9R15、C0−C3アルキル−OR15、C0−C3アルキル−SR15;C0−C3アルキル−複素環、−脂肪族−OR15、−脂肪族−SR15、及び−脂肪族−NR9R15から選択され;その場合、R201を、場合によりR301に置換することができ、これをR201に直接連結することができ、または、アミノ、ヒドロキシル、チオ、カルボン酸、リン酸、ホスホン酸、もしくはスルホン結合を介してR201に連結することができ、式中、R201基が、場合により、独立して、ハロゲン、C1−C3アルキル、C1−C3ハロアルキル、−COOH、シアノ、C2−C6アルカノイル、C1−C6アルコキシ、−C0−C4アルキルNR9R12、−C0−C4アルキルOR12、C1−C6ハロアルキル、−SO2R11、及びC1−C6ハロアルコキシから選択される1、2、または3基で置換され;式中、他のすべての変数が、本明細書で定義されているとおりである。
−CH2−NR9−複素環から選択される。
本発明の一態様では、式I、式II、式III、式IV、式V、式VI、式VII、式VIII、式IX、式X、式XI、式XII、式XIII、式XIV、式XV、式XVI、式XVII、式XVIII、式XIX、式XX、式XXI、式XXII、または式XXIIIの化合物を提供し、式中、1つのNHまたはO−H結合が、R301基で置換され;R301が、以下から選択される:
i.脂肪酸残基。例として、3、4、または5個の脂肪族炭素を有する短鎖脂肪酸、6、7、8、9、10、11または12個の炭素の脂肪族尾部を有する中鎖脂肪酸、13、14、15、16、17、18、19、20、21または22個の炭素の脂肪族尾部を有する長鎖脂肪酸、あるいは22、23、24、25、26、27、もしくは28個またはそれ以上の脂肪族炭素を有する超長鎖脂肪酸がある。脂肪族鎖は、飽和、一不飽和、二不飽和、三不飽和、多価不飽和、またはアルキニルであり得る。不飽和脂肪酸は、シスまたはトランス配置で使用することができ、オレイン酸、リノール酸などのω6脂肪酸、α−リノレン酸などのω3脂肪酸、ドコサヘキサエン酸、ステアリドン酸、エイコサペンタエン酸、ドコサペンタエン酸、エイコサテトラエン酸、ミリストレイン酸、パルミトレン酸、サピエン酸、エライジン酸、バクセン酸、ガドレイン酸、エイコセン酸、ネルボン酸、エイコサジエン酸、ドカサジエン酸、リノレン酸、t−リノレン酸、ピノレン酸、エレオステアリン酸、β−エレオステアリン酸、ミード酸、エイコサトリエン酸、リノール酸、リノエライジン酸、α−リノレン酸、アラキドン酸、エルシン酸及びドコサヘキサエン酸が挙げられるが、これらに限定されない。本発明のプロドラッグを提供するために使用することができる飽和脂肪酸の非限定的な例は、カプリル酸、カプリン酸、ラウリン酸、ミリスチン酸、パルミチン酸、ステアリン酸、アラキジン酸、ベヘン酸、リグノセリン酸及びセロチン酸である。
ii.天然または合成であり、例えば、α、β γまたはδアミノ酸を含むアミノ酸残基。天然アミノ酸として、タンパク質中に認められるアミノ酸、例えば、グリシン、アラニン、バリン、ロイシン、イソロイシン、メチオニン、フェニルアラニン、トリプトファン、プロリン、セリン、スレオニン、システイン、チロシン、アスパラギン、グルタミン、アスパラギン酸、グルタミン酸、リジン、アルギニン及びヒスチジンが挙げられる。いくつかの実施形態では、アミノ酸は、L配置で存在する。あるいは、アミノ酸を、D配置で、またはL配置とD配置の混合物で使用することができる。あるいは、アミノ酸は、アラニル、バリニル、ロイシニル、イソロイシニル、プロリニル、フェニルアラニニル、トリプトファニル、メチオニニル、グリシニル、セリニル、スレオニニル、システイニル、チロシニル、アスパラギニル、グルタミニル、アスパルトイル、グルタロイル、リジニル、アルギニニル、ヒスチジニル、β−アラニル、β−バリニル、β−ロイシニル、β−イソロイシニル、β−プロリニル、β−フェニルアラニニル、β−トリプトファニル、β−メチオニニル、β−グリシニル、β−セリニル、β−スレオニニル、β−システイニル、β−チロシニル、β−アスパラギニル、β−グルタミニル、β−アスパルトイル、β−グルタロイル、β−リジニル、β−アルギニニルまたはβ−ヒスチジニルの誘導体であり得る。さらなるアミノ酸として、セレノシステイン、ピロリジン、N−ホルミルメチオニン、γ−アミノ酪酸(GABA)、δ−アミノレブリン酸、アミノ安息香酸(4−アミノ安息香酸を含む)、アミノイソ酪酸、デヒドロアラニン、シスタチオニン、ランチオニン、ジェンコリン酸、ジアミノピメリン酸、ノルバリン、アロイソロイシン、t−ロイシン、α−アミノヘプタン酸、ピペコール酸、α,β−ジアミノプロピオン酸、α,γ−ジアミノ酪酸、オルニチン、グルタミン酸、アロスレオニン、ホモシステイン、β−アミノ酪酸、α−アミノイソ酪酸、イソバリン、サルコシン、N−エチルグリシン、N−プロピルグリシン、N−イソプロピルグリシン、N−メチルアラニン、N−エチルアラニン、N−メチル−β−アラニン、イソセリン、ノルロイシン、ホモセリン、O−メチル−ホモセリン、O−エチルホモセリン、ホモノルロイシン、カルボキシグルタミン酸、ヒドロキシプロリン、ヒプシン、ピログルタミン酸、及びα−ヒドロキシ−γ−アミノ酪酸が挙げられる。
iii.単独で、または別のプロドラッグ部分へのリンカーとして使用することができる、アミノ基とカルボン酸との間の長さが延長された非天然アミノ酸残基。例として、所望の特性を提供するのに適切なように、アミノ酸及びカルボン酸が、例えば、3、4、5、6、7、8、9、10、11もしくは12個またはそれ以上の直鎖状、分岐状または環状の原子または部分(例えば、アルキレングリコール部分)を有する脂肪族またはヘテロ脂肪族部分、例えば、アルキル、アルケニル、アルキニル、エチレングリコール、プロピレングリコール、アルキレングリコールなどの部分によって分離されたアミノ酸(非限定的な例は、8−アミノ−3,6−ジオキサオクタン酸)が挙げられる。いくつかの実施形態では、アミノ酸は、ヘテロ脂肪鎖に、1つ以上の内部アミン、カルボニル、カルボキシ、オキソ、チオ、ホスフェートまたはホスホネート部分を有する。
iv.末端脂肪酸または水素もしくはアルキルなどのエンドキャップに結合した1つまたは一連のアミノ酸残基。非限定的な一例では、8−アミノ−3,6−ジオキサオクタン酸(1つまたは複数を順に)を、カルボン酸、スルホニル、ヒドロキシルまたはアミノ基などの官能基を介して、本発明の選択された補体D阻害剤に共有結合させる。一般的には、Lau,et al.,“Discovery of the Once−Weekly Glucagon−Like Peptide−1(GLP−1) Analog Semiglutide”,J.Med.Chem.,2015,58,7370−7380を参照のこと。8−アミノ−3,6−ジオキサオクタン酸を、C16、C18、C20脂肪酸を含むがこれらに限定されない脂肪酸、またはC8、C10、C12、C14、C16、C18もしくはC20二酸を含むがこれらに限定されないジカルボン酸に共有結合させる。選択した構成で1つ以上のアミノ酸を使用して、長さまたは官能性を追加することもできる。
式中、R302、R303、R304、R305、R306、R307、及びR308は、独立して、以下から選択される:結合、ポリエチレングリコール、天然アミノ酸、非天然アミノ酸、
n2が、それぞれ独立して、0、1、2、3、4、5、6、7、8、9、10、11、12、13、14、15、16、17、18、19、及び20から選択され;そして
X300が、結合、−NH−、−N(アルキル)−、O、−CH2−O−、−CH2−NH−、及び−CH2−N(アルキル)−から選択される。
C1−C6チオアルキルから選択される。
本明細書に記載の活性化合物は、それを必要とする宿主に、純化学物質として投与することができるが、より一般的には、そのような治療を必要とする宿主、一般的にはヒトにとって有効量の本明細書に記載の活性化合物またはその薬学的に許容される塩、プロドラッグ、同位体類似体、N−オキシド、もしく単離された異性体を含む医薬組成物として投与する。したがって、一実施形態では、本開示は、有効量の化合物またはその薬学的に許容される塩、プロドラッグ、同位体類似体、N−オキシド、もしくは単離された異性体を、本明細書に記載の使用のいずれかのための少なくとも1つの薬学的に許容される担体と共に含む医薬組成物を提供する。医薬組成物は、唯一の活性薬剤として化合物もしくは塩を、または代替の実施形態では、化合物及び少なくとも1つの追加的な活性薬剤を含み得る。
一態様では、本明細書に記載の有効量の活性化合物またはその塩もしくは組成物を使用して、炎症性または免疫性の病態である医学的障害を治療し、障害は、補体カスケード(機能不全のカスケードを含む)によって媒介され、障害には、補体D因子関連障害もしくは補体副経路関連障害を含む補体媒介性疾患もしくは障害、正常な補体活性に関与もしくは応答する細胞の能力に悪影響を与える細胞の障害もしくは異常、あるいは外科手術もしくは他の医療処置、または医薬品もしくは生物医薬品の投与、血液輸血、または他の同種組織もしくは体液の投与などの医療処置に対する望ましくない補体媒介性応答が含まれる。
硝子体炎、サルコイドーシス、梅毒、結核、またはライム病;網膜血管炎、イールズ病、結核、梅毒、またはトキソプラズマ症;神経網膜炎、ウイルス性網膜炎、または急性網膜壊死;水痘帯状疱疹ウイルス、単純ヘルペスウイルス、サイトメガロウイルス、エプスタインバーウイルス、扁平苔癬、またはデング熱関連疾患(例えば、出血性デング熱);マスカレード症候群、接触性皮膚炎、外傷誘発性炎症、UVB誘発性炎症、湿疹、環状肉芽腫、またはにきび。
いくつかの実施形態では、本明細書に記載の活性化合物またはその塩もしくは組成物を、例えば、本明細書に記載の障害を治療するために、有効量の少なくとも1つの追加の治療薬と併用して、もしくは交互に、または前に、同時に、もしくは後に提供してもよい。そのような併用療法のための第2の活性薬剤の非限定的な例を以下に提供する。
プロテアーゼ阻害剤:血漿由来C1−INH濃縮物、例えばCetor(登録商標)(Sanquin)、Berinert−P(登録商標)(CSL Behring、Lev Pharma)、及びCinryze(登録商標);組換えヒトC1阻害剤、例えば、Rhucin(登録商標);リトナビル(Norvir(登録商標)、Abbvie,Inc.);
可溶性補体調節因子:可溶性補体受容体1(TP10)(Avant Immunotherapeutics);sCR1−sLex/TP−20(Avant Immunotherapeutics);MLN−2222/CAB−2(Millenium Pharmaceuticals);ミロコセプト(Inflazyme Pharmaceuticals);治療用抗体:エクリズマブ/Soliris及びラブリズマブ/Ultomiris(Alexion Pharmaceuticals);ペキセリズマブ(Alexion Pharmaceuticals);オファツムマブ(Genmab A/S);TNX−234(Tanox);TNX−558(Tanox);TA106(Taligen Therapeutics);ニュートラズマブ(G2療法);抗プロペルジン(Novelmed Therapeutics);HuMax−CD38(Genmab A/S);
補体成分阻害剤:コンプスタチン/POT−4(Potentia Pharmaceuticals);ARC1905(Archemix);4(1MEW)APL−1、APL−2(Appelis);CP40/AMY−101、PEG−Cp40(Amyndas);
PDGF阻害剤:トシル酸ソラフェニブ;メシル酸イマチニブ(STI571);リンゴ酸スニチニブ;ポナチニブ(AP24534);アキシチニブ;イマチニブ(STI571);ニンテダニブ(BIBF1120);パゾパニブHCl(GW786034 HCl);ドビチニブ(TKI−258、CHIR−258);リニファニブ(ABT−869);クレノラニブ(CP−868596);マシチニブ(AB1010);チボザニブ(AV−951);モテサニブ二リン酸(AMG−706);アムバチニブ(MP−470);TSU−68(SU6668、オランチニブ);CP−673451;Ki8751;テラチニブ;PP121;パゾパニブ;KRN633;ドビチニブ(TKI−258)ジ乳酸;MK−2461;チルホスチン(AG1296);ドビチニブ(TKI258)乳酸;センノシドB;スニチニブ;AZD2932;及びトラピジル;抗H因子または抗B因子薬:抗FB siRNA(Alnylam);FCFD4514S(Genentech/Roche)CFB及びCFD用のSOMAmer(SomaLogic);TA106(Alexion Pharmaceuticals);5C6、及びAMY−301(Amyndas);
補体C3またはCAP C3コンバターゼ標的化分子:TT30(CR2/CFH)(Alexion);TT32(CR2/CR1)(Alexion Pharmaceuticals);ナファモスタット(FUT−175、Futhan)(Torri Pharmaceuticals);ビカシオマブ、NM9308(Novelmed);CVF、HC−1496(InCode)ALXN1102/ALXN1103(TT30)(Alexion Pharmaceuticals);rFH(Optherion);H17 C3(C3b/iC3b)(EluSys Therapeutics);Mini−CFH(Amyndas)Mirococept(APT070);sCR1(CDX−1135)(Celldex);CRIg/CFH;抗CR3、抗MASP2、抗C1s、及び抗C1n分子:Cynryze(ViroPharma/Baxter);TNT003(True North);OMS721(Omeros);OMS906(Omeros);及びImprime PGG(Biothera);
受容体アゴニスト:PMX−53(Peptech Ltd.);JPE−137(Jerini);JSM−7717(Jerini);
その他:組換えヒトMBL(rhMBL;Enzon Pharmaceuticals);サリドマイド、レナリドマイド、ポマリドマイドなどのイミド及びグルタルイミド誘導体;本明細書に記載の活性化合物またはその塩もしくは組成物と併用して、または交互に使用することができる追加の非限定的な例として、以下が挙げられる。
本明細書において、有効量のC5阻害剤を、式I、式II、式III、式IV、式V、式VI、式VII、式VIII、式IX、式X、式XI、式XII、式XIII、式XIV、式XV、式XVI、式XVII、式XVIII、式XIX、式XX、または式XXIから選択される有効量のCFD阻害剤と併用して、または交互に対象に投与することを含む、対象におけるPNHの治療方法を提供する。
いくつかの実施形態では、C5阻害剤はRG6107/SKY59である。RG6107/SKY59は、Roche Pharmaceuticalsによって開発された抗C5リサイクル抗体である。
本明細書において、有効量のC3阻害剤を、式I、式II、式III、式IV、式V、式VI、式VII、式VIII、式IX、式X、式XI、式XII、式XIII、式XIV、式XV、式XVI、式XVII、式XVIII、式XIX、式XX、式XXI、式XXII、または式XXIIIから選択される有効量のCFD阻害剤と併用して、または交互に対象に投与することを含む、対象におけるPNHの治療方法を提供する。
本明細書において、CFB阻害剤を、本発明の化合物と併用して、または交互に投与することを含む、PNHの治療方法を提供する。CFB阻害剤は当技術分野で公知である。いくつかの実施形態では、本発明の化合物を:抗FB SiRNA(Alnylam Pharmaceuticals,ケンブリッジ,MA)、TA106(モノクローナル抗体、Alexion Pharmaceuticals,ニューヘブン,CT);LNP023(小分子、Novartis,バーゼル,スイス);SOMAmer(アプタマー、SomaLogic,ボールダー,CO);ビカシオマブ(Novelmed Therapeutics,クリーブランド,OH);コンプリン(Kadam et al.,J.Immunol.2010,DOI:10.409/jimmunol.10000200を参照のこと);Ionis−FB−LRx(リガンド結合アンチセンス薬、Ionis Pharmaceuticals,カールズバッド,CA);またはそれらの組み合わせを含むがこれらに限定されないCFB阻害剤と併用することができる。別の実施形態では、本発明の化合物と併用することができるCFB阻害剤として、PCT/US17/39587に開示されている阻害剤が挙げられる。別の実施形態では、本明細書に記載の本発明の化合物と併用することができるCFB阻害剤として、PCT/US17/014458に開示されている阻害剤が挙げられる。別の実施形態では、本明細書に記載の本発明の化合物と併用することができるCFB阻害剤として、米国特許出願公開第2016/0024079;PCT出願WO2013/192345;PCT出願WO2013/164802;PCT出願WO2015/066241;PCT出願WO2015/009616(Novartis AGに譲渡)に開示されている阻害剤が挙げられる。
本明細書において、補体成分の汎阻害剤を、本発明の化合物と併用して、または交互に投与することを含む、PNHの治療方法を提供する。補体成分の汎阻害剤は当技術分野で公知である。いくつかの実施形態では、阻害剤はFUT−175である。
本発明の一態様では、本明細書に記載の障害のいずれかに関して、活性化合物またはその塩もしくは組成物を投与する前に、有効量の予防的抗細菌ワクチンを投与することを含む、それを必要とする宿主を治療するための方法を提供する。本発明の別の態様では、本明細書に記載の障害のいずれかに関して、活性化合物またはその塩もしくは組成物を投与する前に、有効量の予防的抗細菌薬、例えば医薬品を投与することを含む、それを必要とする宿主を治療するための方法を提供する。本発明の一態様では、本明細書に記載の障害のいずれかに関して、活性化合物またはその塩もしくは組成物の投与後に、有効量の抗菌ワクチンを投与することを含む、それを必要とする宿主を治療するための方法を提供する。本発明の別の態様では、本明細書に記載の障害のいずれかに関して、活性化合物またはその塩もしくは組成物を投与した後に、有効量の抗細菌薬、例えば医薬品を投与することを含む、それを必要とする宿主を治療するための方法を提供する。一実施形態では、障害は、PNH、C3G、またはaHUSである。一実施形態では、宿主は、臓器または他の組織または生体液の移植を受けている。一実施形態では、宿主にエクリズマブも投与する。
すべての非水反応は、無水溶媒を使用して、乾燥アルゴンまたは窒素ガスの雰囲気下で実施した。反応の進行と標的化合物の純度は、以下に示す2つの液体クロマトグラフィー(LC)法のうちの1つを使用して決定した。出発物質、中間体、及び最終生成物の構造を、NMR分光法及び質量分析法を含む標準的な分析技術によって確認した。
機器:Waters Acquity Ultra Performance LC
カラム:ACQUITY UPLC BEH C18 2.1 ×50mm、1.7μm
カラム温度:40℃
移動相:溶媒A:H2O+0.05%FA;溶媒B:CH3CN+0.05%FA
流速:0.8mL/分
濃度勾配:0.24分間の15%B、3.26分間の濃度勾配(15〜85%B)、次いで0.5分間の85%B。
検出:UV(PDA)、ELS、及びMS(EIモードのSQ)
機器:Shimadzu LC−2010A HT
カラム:Athena,C18−WP,50×4.6mm,5μm
カラム温度:40℃
移動相:溶媒A:H2O/CH3OH/FA=90/10/0.1;溶媒B:H2O/CH3OH/FA=10/90/0.1
流速:3mL/分
濃度勾配:0.4分間の30%B、3.4分間の濃度勾配(30〜100%B)、次いで0.8分間の100%B
検出:UV(220/254nm)
機器:DAD検出器を備えたAgilent1100/1200シリーズLCシステム
カラム:Atlantis dC18(250×4.6)mm、5μm
カラム温度:周囲温度
移動相A:水中0.1%TFA、移動相B:アセトニトリル
流速:1.0mL/分
濃度勾配:
機器:PDA検出器を備えたShimadzu LC 20ADシステム
カラム:Phenomenex Gemini NX C18(150×4.6)mm,5μm
カラム温度:周囲温度
移動相A:水中の10mM NH4OAC、移動相B:アセトニトリル
流速:1.0mL/分
濃度勾配:
以下のスキームは、本発明の化合物の作製方法の非限定的な例である。当業者であれば、類似体を作製するため、または他の方法で化合物を調製するために実施することができる様々な改変が存在することを認識するであろう。例えば、鈴木カップリングを用いる場合はいつでも、文献に記載されているようなカップリングを実施するための当技術分野で公知の他の方法が存在する(Molander,G.A.,Trice,S.L.J.,& Kennedy,S.M.(2012).Scope of the two−step,one−pot palladium−catalyzed borylation/Suzuki cross−coupling reaction utilizing bis−boronic acid.Journal of Organic Chemistry,77(19),8678−8688)。
を0℃で反応混合物に加え、混合物を室温で16時間撹拌した。反応の完了後、反応混合物を濃縮し、逆相HPLCによって直接精製して、化合物1−2を得た。
スキーム24.化合物38の合成
白色の固形物として、化合物170(1.9mg、収率7.4%)。1H−NMR (400 MHz, CD3OD)δ 9.25 (s, 2H), 8.52 (s, 1H), 7.61 (s, 1H), 7.54 (d, J = 8.0 Hz, 1H), 7.37 (d, J= 7.9 Hz, 1H), 5.97 (d, J = 17.8 Hz, 1H), 5.80 (d, J = 17.8 Hz, 1H), 4.53 (dd, J= 9.1, 5.5 Hz, 1H), 3.54 (dd, J = 5.5, 2.2 Hz, 1H), 3.34 (d, J = 7.2 Hz, 2H), 2.76(s, 3H), 2.68 (s, 3H), 2.67 − 2.61 (m, 1H), 2.30 (dd, J = 12.8, 5.8 Hz, 1H), 2.12(s, 3H), 1.41 (s, 3H), 1.24 (t, J = 7.2 Hz, 3H), 1.12 (t, J = 5.2 Hz, 1H), 0.97(dd, J = 5.4, 2.3 Hz, 1H);LC/MS (ESI) m/z: 644/646 (M+H)+.
DCM(5mL)中の化合物185−5(80mg、0.19mmol)の溶液に、−60℃でDAST(46mg、0.29mmol)を加え、混合物を−60℃で1時間撹拌した。混合物を濃縮乾固し、シリカゲルカラムクロマトグラフィー(DCM:MeOH=80:1で溶出)で精製して、化合物185−6(45mg、収率57.3%)を黄色の油状物として得た。LC/MS (ESI) m/z: 414 (M+H)+.
窒素雰囲気下、室温のDMF(10容量)中のS1(1R,3S,5R)−2−(2−(3−アセチル−7−メチル−5−(2−メチルピリミジン−5−イル)−1H−インダゾール−1−イル)アセチル)−5−メチル−2−アザビシクロ[3.1.0]ヘキサン−3−カルボン酸(1当量)の撹拌溶液に、N,N−ジイソプロピルエチルアミン(DIEA)(3当量)及び1−[ビス(ジメチルアミノ)メチレン]−1H−1,2,3−トリアゾロ[4,5−b]ピリジニウム3−オキシドヘキサフルオロホスフェート(HATU)(1.05当量)を加える。反応混合物を室温で10分間撹拌する。次に、アミン(RHNH)を反応混合物に加え、混合物を室温でさらに30分間撹拌する。反応の完了後、反応混合物をMeOHで希釈し、逆相HPLCによって直接精製して、化合物S2を得る。
(1R,3S,5R)−2−{2−[3−アセチル−7−メチル−5−(2−メチルピリミジン−5−イル)インダゾール−1−イル]アセチル}−N−(2,2−ジメチルペンチル)−5−メチル−2−アザビシクロ[3.1.0]ヘキサン−3−カルボキサミドを、一般的手順1を使用して調製した。1HNMR (400 MHz, メタノール−d4) δ 9.00 (s, 2H), 8.42 − 8.37 (m, 1H), 7.78 (t, J = 6.4 Hz,1H), 7.52 (s, 1H), 5.90 (d, J = 17.7 Hz, 1H), 5.76 (d, J = 17.7 Hz, 1H), 4.39 (dd,J = 9.1, 5.1 Hz, 1H), 3.47 (dd, J = 5.6, 2.4 Hz, 1H), 3.07 (dd, J = 13.3, 6.5 Hz,1H), 2.97 (dd, J = 13.3, 6.1 Hz, 1H), 2.76 (s, 3H), 2.73 (s, 3H), 2.68 (s, 3H),2.50 (dd, J = 13.2, 9.1 Hz, 1H), 2.10 (dd, J = 13.3, 5.1 Hz, 1H), 1.38 (s, 3H),1.34 − 1.07 (m, 5H), 0.98 − 0.81 (m, 10H).
表1は、特性データを含む例示的なD因子阻害剤を示す。実施例3のアッセイを使用して、化合物のIC50を測定した。他の標準的なD因子阻害アッセイを利用することもできる。3つの***は、IC50が1μM未満である化合物を示すために使用され;2つの**は、IC50が1μM〜10μMの化合物を示し;1つの*は、IC50が10μM超である化合物を示す。
最終濃度80nMのヒトD因子(ヒト血清から精製、Complement Technology,Inc.)を、様々な濃度の被験化合物と共に、50mM Tris、1M NaCl、pH7.5中で、室温で5分間インキュベートする。合成基質Z−L−Lys−SBzl及びDTNB(エルマン試薬)を、それぞれ100μMの最終濃度で添加する。マイクロプレート分光光度計を使用して、405nmでの吸光度(A405)を30秒間隔で30分間記録する。IC50値を、被験化合物濃度の関数としての補体D因子反応速度の非線形回帰によって計算する。
溶血アッセイは、G.Ruiz−Gomez,et al.,J.Med.Chem.(2009)52:6042−6052によって以前に記載された。アッセイの前に、ウサギ赤血球(RE)の100%溶解を達成するために必要な正常ヒト血清(NHS)の最適濃度を滴定によって決定する。アッセイでは、NHS(Complement Technology)を、GVB0緩衝液(0.1%ゼラチン、5mM Veronal、145mM NaCl、0.025%NaN3、pH7.3、Complement Technology)+10mM Mg−EGTAで希釈し、被験化合物と共に、様々な濃度で、37℃、15分間インキュベートする。新たにGVB0+10mM Mg−EGTA中に懸濁したRE(Complement Technology)を添加して、1×108細胞/mLの最終濃度とし、反応物を37℃で30分間インキュベートする。陽性対照の反応物(100%溶解)は、NHS及びREを含むが被験化合物を含まないGVB0+10mM Mg−EGTAからなり;陰性対照の反応物(0%溶解)は、REのみを含むGVB0+10mM Mg−EGTAからなる。試料を2000gで3分間遠心分離し、上清を採取する。マイクロプレート分光光度計を使用して、405nmでの吸光度(A405)を記録する。IC50値を、被験化合物濃度の関数としての溶血率からの非線形回帰によって計算する。
Claims (41)
- 式:
またはその薬学的に許容される塩であって;
式中:
xが、0、1、または2であり;
nが、1、2、3、または4であり;
qが、0、1、2、または3であり;
R1、R1’、R2、R2’、R3、及びR3’が、それぞれ独立して、水素、−C0−C4アルキルNR9R12、−C0−C4アルキルOR12、C1−C6ハロアルキル、−SO2R11、ハロゲン、ヒドロキシル、及びC1−C6アルキルから選択され;
またはR1とR2が、一緒になって3〜6員の炭素環を形成し;
またはR2とR3が、一緒になって3〜6員の炭素環を形成し;
A1が:
A2が:
A3が:
A4が:
A5が:
B1がC0−C4アルキル−ヘテロアリールであり、その場合、各B1を、場合により、独立して、ハロゲン、C1−C3アルキル、C1−C3ハロアルキル、−COOH、シアノ、C2−C6アルカノイル、C1−C6アルコキシ、−C0−C4アルキルNR9R12、−C0−C4アルキルOR12、−SO2R11、及びC1−C6ハロアルコキシから選択される1つ、2つ、3つ、または4つの基で置換することができ;
B2が:
Rが、水素またはC1−C4アルキルであり;
R5が、C1−C3アルキル、−NR9R10、−NR9OR10、及び−C1−C3アルキル−OR9から選択され;
各R8が、独立して、ハロゲン、C1−C3アルキル、C1−C3ハロアルキル、−COOH、シアノ、C2−C6アルカノイル、C1−C6アルコキシ、−C0−C4アルキルNR9R10、−C0−C4アルキルOR9、C1−C6ハロアルキル、及びC1−C6ハロアルコキシから選択され;
R7が、
各R9及びR10が、独立して、水素及びC1−C4アルキルから選択され;
各R11が、独立して、C1−C3アルキル、−OR9、及び−NR9R10から選択され;
各R12が、独立して、水素または−C(O)R11であり;
R13が−NR9OR10であり;
X13及びX14が、独立して、N及びCR31から選択され;
R22が、−C0−C4アルキルNR9R12、−C0−C4アルキルOR12、C1−C6ハロアルキル、−SO2R11、ハロゲン、ヒドロキシル、及びC1−C6アルキルから選択され;
R23が、水素、C1−C6アルキル、−C0−C4アルキル−アリール、−C0−C4アルキル−ヘテロアリール、及び−C0−C4アルキル−複素環から選択され;
各R31が、独立して、水素、ハロゲン、C1−C6アルキル、ヒドロキシル、−C0−C4アルキルNR9R12、−C0−C4アルキルOR12、C1−C6ハロアルキル、−SO2R11、及びC1−C6ハロアルコキシから選択され;
R32が、アリール、ヘテロアリール、及び複素環から選択され、その場合、前記アリール、ヘテロアリール、または複素環を、場合により、独立して、ハロゲン、C1−C3アルキル、C1−C3ハロアルキル、−CO2R11、シアノ、C2−C6アルカノイル、C1−C6アルコキシ、−C0−C4アルキルNR9R12、−C0−C4アルキルOR12、C1−C6ハロアルキル、−SO2R11、及びC1−C6ハロアルコキシから選択される1つ、2つ、または3つの基で置換することができ;
R33が、
R34が、ハロゲン、ヒドロキシル、C1−C6アルキル、−C0−C4アルキルNR9R12、−C0−C4アルキルOR12、C1−C6ハロアルキル、−SO2R11、及びC1−C6ハロアルコキシから選択される、前記化合物、またはその薬学的に許容される塩。 - 式:
またはその薬学的に許容される塩であって;
nが、1、2、3、または4であり;
qが、0、1、2、または3であり;
R1、R1’、R2、R2’、R3、及びR3’が、それぞれ独立して、水素、−C0−C4アルキルNR9R12、−C0−C4アルキルOR12、C1−C6ハロアルキル、−SO2R11、ハロゲン、ヒドロキシル、及びC1−C6アルキルから選択され;
またはR1とR2が、一緒になって3〜6員の炭素環を形成し;
またはR2とR3が、一緒になって3〜6員の炭素環を形成し;
B1が、C1−C6アルキル、C0−C4アルキル−アリール、C0−C4アルキル−ヘテロアリール、及びC0−C4アルキル−複素環から選択され、その場合、各B1を、場合により、独立して、ハロゲン、C1−C3アルキル、C1−C3ハロアルキル、−COOH、シアノ、C2−C6アルカノイル、C1−C6アルコキシ、−C0−C4アルキルNR9R12、−C0−C4アルキルOR12、−SO2R11、及びC1−C6ハロアルコキシから選択される1つ、2つ、3つまたは4つの基で置換することができ;
R5が、C1−C3アルキル、−NR9R10、−NR9OR10、及び−C1−C3アルキル−OR9から選択され;
R8が、独立して、テトラゾール、ハロゲン、C1−C3アルキル、C1−C3ハロアルキル、−COOH、シアノ、C2−C6アルカノイル、C1−C6アルコキシ、C2−C6アルケニル、C2−C6アルキニル、−C0−C4アルキルNR9R10、−C0−C4アルキルOR9、C1−C6ハロアルキル、及びC1−C6ハロアルコキシから選択される。
特定の実施形態では、R11は、水素またはC1−C3アルキルである。
各R9及びR10が、独立して、水素及びC1−C4アルキルから選択され;
各R11が、独立して、C1−C3アルキル、−OR9、及び−NR9R10から選択され;
各R12が、独立して、水素、C1−C3アルキル、及び−C(O)R11から選択され;
X13及びX14が、独立して、N及びCR31から選択され;
R22が、−C0−C4アルキルNR9R12、−C0−C4アルキルOR12、C1−C6ハロアルキル、−SO2R11、ハロゲン、ヒドロキシル、及びC1−C6アルキルから選択され;
R23が、水素、C1−C6アルキル、−C0−C4アルキル−アリール、−C0−C4アルキル−ヘテロアリール、及び−C0−C4アルキル−複素環から選択され;
各R31が、独立して、水素、ハロゲン、C1−C6アルキル、ヒドロキシル、−C0−C4アルキルNR9R12、−C0−C4アルキルOR12、C1−C6ハロアルキル、−SO2R11、及びC1−C6ハロアルコキシから選択され;
R32が、アリール、ヘテロアリール、及び複素環から選択され、その場合、前記アリール、ヘテロアリール、または複素環を、場合により、独立して、ハロゲン、C1−C3アルキル、C1−C3ハロアルキル、−CO2R11、シアノ、C2−C6アルカノイル、C1−C6アルコキシ、−C0−C4アルキルNR9R12、−C0−C4アルキルOR12、C1−C6ハロアルキル、−SO2R11、及びC1−C6ハロアルコキシから選択される1つ、2つ、または3つの基で置換することができ;
Qが、CHまたはNであり;
Q1が、CH2、O、NH、またはNR9であり;
wが、0、1、または2であり;
A1が:
A6が:
A7が:
A8が:
B3が:
B4が:
B5が:
R35が、
各R36が、独立して、C1−C6アルキル、ハロゲン、及びC1−C6ハロアルキルから選択され;
R37が、C(O)R11、F、及びCNから選択され;
R38が、
各R39が、独立して、水素、C1−C6アルキル、ハロゲン、及びC1−C6ハロアルキルから選択され;
R40が、
R41が、
各R42が、独立して、ハロゲン、C1−C3アルキル、C1−C3ハロアルキル、−COOH、C2−C6アルカノイル、C1−C6アルコキシ、−C0−C4アルキルNR9R10、−C0−C4アルキルOR9、C1−C6ハロアルキル、及びC1−C6ハロアルコキシから選択される、前記化合物、またはその薬学的に許容される塩。 - 式中、B1が、場合により、独立して、ハロゲン、C1−C3アルキル、C1−C3ハロアルキル、−COOH、シアノ、C2−C6アルカノイル、C1−C6アルコキシ、−C0−C4アルキルNR9R12、−C0−C4アルキルOR12、−SO2R11、及びC1−C6ハロアルコキシから選択される1つ、2つ、3つ、または4つの基で置換された2−ピリジンである、請求項1または2に記載の化合物。
- 式中、R32が、場合により、独立して、ハロゲン、C1−C3アルキル、C1−C3ハロアルキル、−CO2R11、シアノ、C2−C6アルカノイル、C1−C6アルコキシ、−C0−C4アルキルNR9R12、−C0−C4アルキルOR12、C1−C6ハロアルキル、−SO2R11、及びC1−C6ハロアルコキシから選択される1つ、2つ、または3つの基で置換されるヘテロアリールである、請求項1〜6のいずれか一項に記載の化合物。
- 式中、R32が、ハロゲン、C1−C3アルキル、C1−C3ハロアルキル、−CO2R11、シアノ、C2−C6アルカノイル、C1−C6アルコキシ、−C0−C4アルキルNR9R12、−C0−C4アルキルOR12、C1−C6ハロアルキル、−SO2R11、及びC1−C6ハロアルコキシから選択される1つの基で置換されるヘテロアリールである、請求項1〜6のいずれか一項に記載の化合物。
- 式中、R1及びR2が、一緒になって3員の炭素環を形成する、請求項1〜10のいずれか一項に記載の化合物。
- 式中、X13がCHであり、X14が、CH、C(C2−C6アルケニル)及びC(C2−C6アルキニル)から選択される、請求項1〜11のいずれか一項に記載の化合物。
- 式中、X13がNであり、X14が、CH、C(C2−C6アルケニル)及びC(C2−C6アルキニル)から選択される、請求項1〜11のいずれか一項に記載の化合物。
- 表1から選択される化合物またはその薬学的に許容される塩。
- 表2から選択される化合物またはその薬学的に許容される塩。
- 請求項1〜16のいずれか一項に記載の化合物またはその薬学的に許容される塩、及び薬学的に許容される担体を含む、医薬組成物。
- 請求項1〜17のいずれか一項に記載の治療有効量の化合物もしくはその医薬組成物またはその薬学的に許容される塩を、それを必要とする対象に投与することを含む、補体D因子媒介性障害の治療方法。
- 前記対象がヒトである、請求項18に記載の方法。
- 前記障害がC3腎症である、請求項19に記載の方法。
- 前記障害が眼科障害である、請求項19に記載の方法。
- 前記障害が加齢性黄斑変性症(AMD)である、請求項19に記載の方法。
- 前記障害が発作性夜間ヘモグロビン尿症(PNH)である、請求項19に記載の方法。
- 前記障害がC3腎炎である、請求項19に記載の方法。
- 前記障害がデンスデポジット病である、請求項19に記載の方法。
- 請求項1〜17のいずれか一項に記載の化合物またはその医薬組成物を、製造において使用することを特徴とする、補体D因子媒介性障害を治療する治療的用途のための薬剤の製造方法。
- 前記対象がヒトである、請求項26に記載の方法。
- 前記障害がC3腎症である、請求項27に記載の方法。
- 前記障害が眼科障害である、請求項27に記載の方法。
- 前記障害が加齢性黄斑変性症(AMD)である、請求項27に記載の方法。
- 前記障害が発作性夜間ヘモグロビン尿症(PNH)である、請求項27に記載の方法。
- 前記障害がC3腎炎である、請求項27に記載の方法。
- 前記障害がデンスデポジット病である、請求項27に記載の方法。
- 補体D因子媒介性障害を治療するための薬剤を調製するための、請求項1〜17のいずれか一項に記載の化合物またはその医薬組成物の使用。
- 前記対象がヒトである、請求項34に記載の使用。
- 前記障害がC3腎症である、請求項35に記載の使用。
- 前記障害が眼科障害である、請求項35に記載の使用。
- 前記障害が加齢性黄斑変性症(AMD)である、請求項35に記載の使用。
- 前記障害が発作性夜間ヘモグロビン尿症(PNH)である、請求項35に記載の使用。
- 前記障害がC3腎炎である、請求項35に記載の使用。
- 前記障害がデンスデポジット病である、請求項35に記載の使用。
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