JP2011530560A - α7ニコチン性モジュレーターとしてのサリチルアミド誘導体 - Google Patents
α7ニコチン性モジュレーターとしてのサリチルアミド誘導体 Download PDFInfo
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- JP2011530560A JP2011530560A JP2011522477A JP2011522477A JP2011530560A JP 2011530560 A JP2011530560 A JP 2011530560A JP 2011522477 A JP2011522477 A JP 2011522477A JP 2011522477 A JP2011522477 A JP 2011522477A JP 2011530560 A JP2011530560 A JP 2011530560A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C235/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms
- C07C235/42—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton
- C07C235/44—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton with carbon atoms of carboxamide groups and singly-bound oxygen atoms bound to carbon atoms of the same non-condensed six-membered aromatic ring
- C07C235/58—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton with carbon atoms of carboxamide groups and singly-bound oxygen atoms bound to carbon atoms of the same non-condensed six-membered aromatic ring with carbon atoms of carboxamide groups and singly-bound oxygen atoms, bound in ortho-position to carbon atoms of the same non-condensed six-membered aromatic ring
- C07C235/60—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton with carbon atoms of carboxamide groups and singly-bound oxygen atoms bound to carbon atoms of the same non-condensed six-membered aromatic ring with carbon atoms of carboxamide groups and singly-bound oxygen atoms, bound in ortho-position to carbon atoms of the same non-condensed six-membered aromatic ring having the nitrogen atoms of the carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/16—Amides, e.g. hydroxamic acids
- A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
- A61K31/166—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide having the carbon of a carboxamide group directly attached to the aromatic ring, e.g. procainamide, procarbazine, metoclopramide, labetalol
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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Abstract
Description
本発明は、ニコチン性アセチルコリン受容体(nAChR)、及び特にα7nAChRサブタイプに対する正のアロステリックモジュレーター、並びにこのような化合物の製造方法及び使用方法に関する。
ニコチン性アセチルコリン受容体(nAChR)は、リガンド依存性イオンチャネルファミリーのメンバーである。活性化されると、ニコチン性イオンチャネルを通るイオンのコンダクタンスが上昇する。ニコチン性α7受容体(α7nAChR)は、カルシウムカチオンに対して極めて透過性であるホモ五量体チャネルをインビトロで形成する。各α7nAChRは、M1、M2、M3、及びM4として知られている4個の膜貫通ドメインを有する。M2ドメインは、チャネルを裏打ちする壁を形成することが示唆されている。配列アラインメントにより、α7nAChRが進化中に高度に保存されていることが分かる。チャネルを裏打ちするM2ドメインは、ニワトリからヒトまでタンパク質配列が同一である。α7nAChRは、Revah et al. (1991), Nature, 353, 846-849; Galzi et al. (1992), Nature 359, 500-505; Fucile et al. (2000), PNAS 97(7), 3643-3648; Briggs et al. (1999), Eur. J. Pharmacol. 366 (2-3), 301-308;及びGopalakrishnan et al. (1995), Eur. J. Pharmacol. 290(3), 237-246に報告されている。
本出願は、式(I):
[式中、
Q1は、[CH2]qであり;
qは、0、1、又は2であり;
Q2は、[CH2]rであり;
rは、1又は2であり;
R1は、R1’又はR1”であり;
R1’は、場合によりハロゲンで置換されたフェニルであり;
R1”は、場合によりアルキニルで置換されたシクロアルキルであり;
R2は、R2’又はR2”であり;
R2’は、場合により低級アルコキシで置換されたフェニルであり;
R2”は、シクロアルキルであり;
R3は、低級アルコキシ又は低級アルキルであり;そして
nは、0、1、又は2である]で示される化合物を提供する。
式(I)の1つの実施態様において、R1はR1”である。
式(I)の1つの実施態様において、Q1はメチレンであり、そしてR1はR1”である。
式(I)の1つの実施態様において、R1”はシクロプロピルである。
式(I)の1つの実施態様において、R1”はシクロプロピルであり、そしてQ1はメチレンである。
式(I)の1つの実施態様において、Q2はメチレンである。
式(I)の1つの実施態様において、R2はフェニルである。
式(I)の1つの実施態様において、R2はフェニルであり、そしてQ2はメチレンである。
式(I)の1つの実施態様において、R2は4−メトキシ−フェニルである。
式(I)の1つの実施態様において、qは0である。
式(I)の1つの実施態様において、R1はシクロペンチルである。
式(I)の1つの実施態様において、qは0であり、そしてR1はシクロペンチルである。
式(I)の1つの実施態様において、Q2はエチレンである。
式(I)の1つの実施態様において、R2はフェニルである。
式(I)の1つの実施態様において、R2はフェニルであり、そしてQ2はエチレンである。
式(I)の1つの実施態様において、nは2である。
式(I)の1つの実施態様において、各R3は、独立にメチル又はメトキシである。
式(I)の1つの実施態様において、nは2であり、そして各R3は、独立にメチル又はメトキシである。
式(I)の1つの実施態様において、Q1はエチレンである。
式(I)の1つの実施態様において、R1はR1’である。
式(I)の1つの実施態様において、Q1はエチレンであり、そしてR1はR1’である。
式(I)の1つの実施態様において、R1’は2−フルオロ−フェニルである。
式(I)の1つの実施態様において、Q1はエチレンであり、そしてR1’は2−フルオロ−フェニルである。
式(I)の1つの実施態様において、Q2はメチレンである。
式(I)の1つの実施態様において、R2はR2’である。
式(I)の1つの実施態様において、Q2はメチレンであり、そしてR2はR2’である。
式(I)の1つの実施態様において、R2はR2”である。
式(I)の1つの実施態様において、Q2はメチレンであり、そしてR2はR2”である。
式(I)の1つの実施態様において、nは1である。
式(I)の1つの実施態様において、R3はメトキシである。
式(I)の1つの実施態様において、nは1であり、そしてR3はメトキシである。
式(I)の1つの実施態様において、nは2である。
式(I)の1つの実施態様において、各R3は、独立にメチル又はメトキシである。
式(I)の1つの実施態様において、nは2であり、そして各R3は、独立にメチル又はメトキシである。
式(I)の1つの実施態様において、R2はR2”であり、nは2であり、そして各R3は、独立にメチル又はメトキシである。
式(I)の1つの実施態様において、Q2はメチレンであり、nは2であり、そして各R3は、独立にメチル又はメトキシである。
式(I)の1つの実施態様において、R2はR2”であり、Q2はメチレンであり、nは2であり、そして各R3は、独立にメチル又はメトキシである。
式(I)の1つの実施態様において、qは0である。
式(I)の1つの実施態様において、R1はR1”である。
式(I)の1つの実施態様において、qは0であり、そしてR1はR1”である。
式(I)の1つの実施態様において、R1”は1−エチニル−シクロヘキシルである。
式(I)の1つの実施態様において、qは0であり、そしてR1”は1−エチニル−シクロヘキシルである。
式(I)の1つの実施態様において、Q2はメチレンである。
式(I)の1つの実施態様において、R2はシクロプロピルである。
式(I)の1つの実施態様において、Q2はメチレンであり、そしてR2はシクロプロピルである。
式(I)の1つの実施態様において、R2はシクロプロピルであり、nは2であり、そして各R3は、独立にメチル又はメトキシである。
式(I)の1つの実施態様において、Q2はメチレンであり、R2はシクロプロピルであり、nは2であり、そして各R3は、独立にメチル又はメトキシである。
4−ベンジルオキシ−2’−メトキシ−ビフェニル−3−カルボン酸シクロプロピルメチル−アミド;
4−ベンジルオキシ−2’−メトキシ−ビフェニル−3−カルボン酸[2−(2−フルオロ−フェニル)−エチル]−アミド;
4’−メトキシ−2’−メチル−4−フェネチルオキシ−ビフェニル−3−カルボン酸シクロペンチルアミド;
4’−メトキシ−2’−メチル−4−フェネチルオキシ−ビフェニル−3−カルボン酸[2−(2−フルオロ−フェニル)−エチル]−アミド;
4’−メトキシ−4−(4−メトキシ−ベンジルオキシ)−2’−メチル−ビフェニル−3−カルボン酸シクロプロピルメチル−アミド;
4−シクロプロピルメトキシ−4’−メトキシ−2’−メチル−ビフェニル−3−カルボン酸(1−エチニル−シクロヘキシル)−アミド;及び
4−シクロプロピルメトキシ−4’−メトキシ−2’−メチル−ビフェニル−3−カルボン酸[2−(2−フルオロ−フェニル)−エチル]−アミド
よりなる群から選択される、式(I)の化合物を提供する。
本出願は、式(I):
特に断りない限り、本出願(明細書及び特許請求の範囲を包含する)において使用される以下の用語は、後述の定義を有する。本明細書及び添付の特許請求の範囲において使用されるとき、単数形の「a」、「an」、及び「the」は、文脈に特に明記しない限り、複数形も包含することに留意しなければならない。
(i)病状を予防すること、即ち、その病状に曝露されているか又は罹りやすい素因を有するかもしれないが、その病状にまだ罹患していないか又は病状の症状を示していない被験体において、その病状の臨床症状が現れないようにすること、
(ii)病状を抑制すること、即ち、病状又は臨床症状の発現を止めること、あるいは
(iii)病状を緩和すること、即ち、病状又はその臨床症状の一時的又は永続的退縮を引き起こすこと
を包含する。
一般に、本出願に使用される命名法は、IUPAC系統的命名法の生成のためのBeilstein Instituteのコンピュータ化システムであるAUTONOM(登録商標)v.4.0に基づく。本明細書に示す化学構造は、ISIS(登録商標)バージョン2.2を使用して作成した。本明細書の構造中の炭素原子、酸素原子、硫黄原子又は窒素原子上に出現する空結合価は、水素原子の存在を示す。
本発明の化合物は、以下に示され説明される合成反応スキームの例に描かれている種々の方法により製造することができる。
本発明の化合物は、ニコチン性α7(α7nAChR)受容体に関連する疾患又は症状[精神病、神経変性疾患、及び認知障害(コリン作動系の機能不全を伴う)を包含する]の治療、並びに記憶及び/又は認知障害の症状[例えば、統合失調症、不安、躁病、鬱病、躁鬱病、トゥーレット症候群、パーキンソン病、ハンチントン病、認知障害(アルツハイマー病、レビー小体認知症、筋萎縮性側索硬化症、記憶障害、記憶喪失、認知欠損、注意欠陥、注意欠陥多動障害など)]の治療、更には他の用途[ニコチン嗜癖の治療、禁煙の誘導、疼痛の治療(即ち、鎮痛剤用途)、神経保護の提供、及び時差ボケの治療など]に有効である。本発明の化合物は、アルツハイマー病の患者、及び統合失調症、不安、躁病、鬱病、躁鬱病、トゥーレット症候群、パーキンソン病、ハンチントン病、レビー小体認知症、筋萎縮性側索硬化症、記憶障害、記憶喪失、認知欠損、注意欠陥又は注意欠陥多動障害に伴う認知障害又は認知疾患を有する患者の認知力を増強するのに有用である。
本発明は、少なくとも1種の本発明の化合物、又は個々の異性体、異性体のラセミ若しくは非ラセミ混合物、あるいはその医薬的に許容しうる塩又は溶媒和物を、少なくとも1種の薬学的に許容しうる担体と共に、そして場合により他の治療成分及び/又は予防成分と共に含む医薬組成物を包含する。
以下の調製法及び実施例は、当業者が本発明をより明瞭に理解し、かつ実施できるようにするために与えられる。これらは、本発明の範囲を限定するものではなく、本発明を単に例示し代表するものと考えるべきである。以下の略語が実施例において使用されうる。
CDI 1,1−カルボニル−ジイミダゾール
DCM ジクロロメタン/塩化メチレン
DMF N,N−ジメチルホルムアミド
DMAP 4−ジメチルアミノピリジン
EDCI 1−エチル−3−(3’−ジメチルアミノプロピル)カルボジイミド
EtOAc 酢酸エチル
EtOH エタノール
tBuOH tert−ブタノール
gc ガスクロマトグラフィー
HMPA ヘキサメチルホスホルアミド
HOAc 酢酸
HOBt N−ヒドロキシベンゾトリアゾール
hplc 高速液体クロマトグラフィー
mCPBA m−クロロ過安息香酸
MeCN アセトニトリル
MeOH メタノール
NMP N−メチルピロリジノン
TEA トリエチルアミン
TFA トリフルオロ酢酸
THF テトラヒドロフラン
LDA リチウムジイソプロピルアミン
LHMDS リチウムビス(トリメチルシリル)アミド
TBAF フッ化テトラブチルアンモニウム
TLC 薄層クロマトグラフィー
5−ヨードサリチル酸メチル(TCI、4.9g、17.5mmol)、シクロプロパンカルビノール(Aldrich、1.15g、16mmol)及びトリフェニルホスフィン(Aldrich、5.45g、21mmol)を無水トルエン(50mL)に溶解して、0℃に冷却した。この溶液にアゾジカルボン酸ジイソプロピル(Aldrich、4.1mL、21mmolを20mLのトルエンに溶解)を、15分以上かけて滴下して加えた。周囲温度で3日間撹拌後、この混合物をヘキサンで希釈して、シリカパッドに直接のせた。所望のエーテル((3)、4.63g、油状物)が、ヘキサン中酢酸エチル5〜20%勾配で溶出して、目的物質に一致する分光学的性質を示した。
エステル(6)(実施例1にしたがい調製、1.6g、4.1mmol)を、テトラヒドロフラン(60mL)及びメタノール(5mL)に溶解した。この溶液を氷浴に入れて、水酸化リチウム[(400mg、約10mmol)を水(20mL)に溶解]で処理し、周囲温度で一晩撹拌した。この混合物から揮発物を除去し、残渣を水(50mL)とエチルエーテル(2×30mL)とに分液した。水層を10%酢酸水溶液でクエンチして、酢酸エチル(3×60mL)で抽出し、次に無水硫酸ナトリウム上で保存した。濾過及び揮発物の除去後、目的の酸((7)、1.4g、融点125〜126℃、親イオンM−1のMS m/z 377)を得たが、これは候補構造に一致する分光学的性質を示した。この酸(255mg、0.67mmol)をN−メチル−2−ピロリジノン(4mL)に溶解して、カルボニルジイミダゾール(108mg、0.67mmol、一度に加える)で処理した。この溶液を周囲温度で10分間激しく撹拌した。アミノメチルシクロプロパン(0.12mL、1.4mmol)を急速に加え、生じた金色の溶液を一晩撹拌した。この混合物を水(20mL)とヘキサン:酢酸エチル(1:1、4×25mL)とに分液し、新鮮な水、食塩水で洗浄して、無水硫酸ナトリウム上で保存した。目的のアミド((8)、185mg、融点115.6〜116.5℃、親イオンM+1のMS m/z 432)をシリカゲルクロマトグラフィー(溶離液:10〜80%酢酸エチル/ヘキサン)により単離したが、分光学的性質は記載の構造に一致した。
エステル(5)(2.23g、6.8mmol)を、テトラヒドロフラン(60mL)及びメタノール(5mL)に溶解した。この溶液を氷浴に入れて、水酸化リチウム[(860mg、約20mmol)を予め水(20mL)に溶解]で処理して、周囲温度で一晩撹拌した。混合物から揮発物を除去して、残渣を水(50mL)とエチルエーテル(2×30mL)とに分液した。水層を10%酢酸水溶液でクエンチして、酢酸エチル(3×60mL)で抽出し、次に無水硫酸ナトリウム上で保存した。濾過及び揮発物の除去後、目的の酸((11)、1.66g、融点139〜140.5℃、親イオンM+1のMS m/z 313)を得たが、これは候補構造に一致する分光学的性質を示した。この酸(314mg、1.0mmol)をN−メチル−2−ピロリジノン(4mL)に溶解して、O−(7−アザベンゾトリアゾール−1−イル)ウロニウム ヘキサフルオロホスフェート(4210mg、1.1mmol)によりN2下で処理した。この溶液を直ちにトリエチルアミン(0.28mL、2.0mmol)及び1−エチニルシクロヘキシルアミン(0.28mL、2.1mmol)で処理し、周囲温度で16時間撹拌させておいた。次にこれを0.2M硫酸水素カリウム(15mL)及びヘキサン:酢酸エチル(1:1、3×40mL)に分液した。合わせた有機層を、新鮮な水、次に食塩水で洗浄して、無水硫酸ナトリウム上で保存した。抽出物の容量を減少させて残渣にし、これをシリカゲルクロマトグラフィーに付した。目的のアミド((12)、235mg、油状物、親イオンM+1のMS m/z 418)は、候補構造に一致する分光学的性質を示した。
種々の経路による送達のための医薬品製剤は、下記の表に示されるように処方する。表中に使用される「活性成分」又は「活性化合物」は、1種以上の式(I)の化合物を意味する。
約0.025〜0.5パーセントの活性化合物を含有する幾つかの水性懸濁液を、鼻腔用スプレー製剤として調製する。本製剤は、場合により、例えば、微結晶性セルロース、カルボキシメチルセルロースナトリウム、ブドウ糖などのような不活性成分を含有する。塩酸を加えることによりpHを調整してもよい。この鼻腔用スプレー製剤は、典型的には一回の作動で約50〜100マイクロリットルの製剤を送達する鼻腔用スプレー計量ポンプを介して送達することができる。典型的な投与スケジュールは、4〜12時間毎に2〜4回のスプレーである。
ニコチン性α7調節アッセイ
細胞培養
細胞培養増殖培地:F10培地(Invitrogen)、2.5%ウシ胎仔血清(FBS、Summit Biotechnology)、15%熱不活化ドナー・ウマ血清(Invitrogen)、250μg/mlヒグロマイシンB(Invitrogen);及び100nMメチルリカコナイト(Methyllicaconite)(MLA、Sigma)を、H2O中で5μMに調製したストック溶液を50倍希釈して、それぞれ新しい培養液に加える。
アッセイに使用する緩衝液は、HBSS FLIPR緩衝液(Invitrogen)、2mM CaCl2(Sigma)、10mMヘペス(Invitrogen)、2.5mMプロベネシド(Sigma)、及び0.1% BSA(Sigma)である。
α7nAChRアッセイは、ニコチン性受容体チャネルを直接活性化するか、かつ/又は本来のアゴニストのアセチルコリン(ACh、Sigma)による活性化を調節する試験化合物の作用を測定するように設計された、細胞に基づく機能の読み出し情報である。
複数濃度の試験化合物を、それぞれ96ウェルアッセイプレートで並行して調べる。試験化合物の最高FACを100μM(1.00E−4 M)にするために、10mM試験化合物ストック溶液(100% DMSO)24μlを、576μlのFLIPR緩衝液に直接加える(即ち、最高[試験化合物]濃度=0.4mM=4倍FAC)。0.4mMの試験化合物試料から開始して、試験化合物をFLIPR緩衝液で連続希釈(Biomek2000を使用)することにより、以下の試験化合物FACを得る:ビヒクル、1.00E−4 M、3.16E−5、1.00E−5 M、3.16E−6、1.00E−6 M、3.16E−7、1.00E−7 M。DMSOの最大FAC=試験化合物の最高FACの100μMに曝露した試料ウェル中1%。陰性対照は、ビヒクル添加と、これに続くACh添加により作成した。陽性対照は、1μM PNU-120596添加と、これに続くACh添加により作成した。
α7nAChRのIC50/EC50値、内因性アゴニスト活性、及び正のアロステリック調節を、ACTIVITYBASE(商標)データ解析ソフトウェアを使用して測定した。用量反応データについては、曲線の近似中点(変曲点)又は曲線が活性閾値と交差する点(典型的には対照の50%)のいずれかを使用してIC50/EC50を求めることができる。
ホルマリン疼痛アッセイ
オスのSprague Dawleyラット(180〜220g)を、個別のプレキシガラスのシリンダーに入れ、試験環境に30分間馴化させる。ビヒクル、薬剤、又は陽性対照(モルヒネ2mg/kg)を、5ml/kgで皮下投与する。投与の15分後、右の後肢の足底面に、26ゲージ針を使用してホルマリン(50μl中5%)を注射する。直ちにラットを観察チャンバーに戻す。チャンバーの周りに置いた鏡により、ホルマリン注射した足が妨害されずに観察できる。各ラットの侵害防御的行動の持続時間は、自動の行動タイマーを使用して、盲検観察者が記録する。後肢の嘗め、及び震え/足上げを5分のビン幅で別々に記録し、合計60分間とする。0〜5分の時間に嘗め又は震えに費やした時間(秒)の合計は、初期相と見なし、一方で後期相は、15〜40分の間に嘗め又は震えに費やした時間(秒)の合計をとる。血漿試料を採取する。
認知の増強
本発明の化合物の認知増強性は、動物認知モデル(新規な対象認知タスクモデル)で見ることができる。4ヶ月齢のオスのWistarラット(Charles River, The Netherlands)を使用した。化合物を毎日調製して、生理食塩水に溶解し、そして3用量で試験した。投与は常に、T1の60分前に腹腔内投与した(注射容量1ml/kg)。化合物注射の30分後に、スコポラミン臭化水素酸塩を注射した。24匹のラットの2つの同等の試験群を作成して、2つの実験により試験した。用量の試験順序はランダムに決定した。実験は、二重盲検プロトコールを使用して行った。全てのラットを各用量条件で一度試験した。対象認知試験は、Ennaceur, A., Delacour, J., 1988, A new one-trial test for neurobiological studies of memory in rats. 1: Behavioral data. Behav. Brain Res. 31, 47-59に記載されるように行った。
Claims (34)
- Q1が、メチレンである、請求項1に記載の化合物。
- R1が、R1”である、請求項2に記載の化合物。
- R1”が、シクロプロピルである、請求項3に記載の化合物。
- Q2が、メチレンである、請求項4に記載の化合物。
- R2が、フェニルである、請求項5に記載の化合物。
- R2が、4−メトキシ−フェニルである、請求項5に記載の化合物。
- qが、0である、請求項1に記載の化合物。
- R1が、シクロペンチルである、請求項8に記載の化合物。
- Q2が、エチレンである、請求項9に記載の化合物。
- R2が、フェニルである、請求項10に記載の化合物。
- nが、2である、請求項11に記載の化合物。
- 各R3が、独立にメチル又はメトキシである、請求項12に記載の化合物。
- Q1が、エチレンである、請求項1に記載の化合物。
- R1が、R1’である、請求項14に記載の化合物。
- R1’が、2−フルオロ−フェニルである、請求項15に記載の化合物。
- Q2が、メチレンである、請求項16に記載の化合物。
- R2が、R2’である、請求項17に記載の化合物。
- R2が、R2”である、請求項18に記載の化合物。
- nが、1であり、そしてR3が、メトキシである、請求項18に記載の化合物。
- nが、2であり、そして各R3が、独立にメチル又はメトキシである、請求項19に記載の化合物。
- qが、0であり、そしてR1が、R1”である、請求項1に記載の化合物。
- R1”が、1−エチニル−シクロヘキシルである、請求項22に記載の化合物。
- Q2が、メチレンであり、そしてR2が、シクロプロピルである、請求項23に記載の化合物。
- nが、2であり、そして各R3が、独立にメチル又はメトキシである、請求項24に記載の化合物。
- 4−ベンジルオキシ−2’−メトキシ−ビフェニル−3−カルボン酸シクロプロピルメチル−アミド;
4−ベンジルオキシ−2’−メトキシ−ビフェニル−3−カルボン酸[2−(2−フルオロ−フェニル)−エチル]−アミド;
4’−メトキシ−2’−メチル−4−フェネチルオキシ−ビフェニル−3−カルボン酸シクロペンチルアミド;
4’−メトキシ−2’−メチル−4−フェネチルオキシ−ビフェニル−3−カルボン酸[2−(2−フルオロ−フェニル)−エチル]−アミド;
4’−メトキシ−4−(4−メトキシ−ベンジルオキシ)−2’−メチル−ビフェニル−3−カルボン酸シクロプロピルメチル−アミド;
4−シクロプロピルメトキシ−4’−メトキシ−2’−メチル−ビフェニル−3−カルボン酸(1−エチニル−シクロヘキシル)−アミド;及び
4−シクロプロピルメトキシ−4’−メトキシ−2’−メチル−ビフェニル−3−カルボン酸[2−(2−フルオロ−フェニル)−エチル]−アミド
よりなる群から選択される、請求項1に記載の化合物。 - 必要とする被験体における認知を増強する方法であって、有効量の請求項1に記載の化合物を前記被験体に投与することを含む、方法。
- 前記被験体が、アルツハイマー病を有する、請求項27に記載の方法。
- 請求項1に記載の化合物を、少なくとも1種の薬学的に許容しうる担体、希釈剤、又は賦形剤との混合物として含む医薬組成物。
- 治療活性物質として使用するための、請求項1〜26のいずれか1項に記載の化合物。
- ニコチン性α7(α7nACh)受容体に関連する疾患の治療及び/又は予防用の治療活性物質として使用するための、請求項1〜26のいずれか1項に記載の化合物。
- ニコチン性α7(α7nACh)受容体に関連する疾患の治療的及び/又は予防的処置用の医薬の製造のための、請求項1〜26のいずれか1項に記載の化合物の使用。
- 認知増強用の医薬の製造のための、請求項1〜26のいずれか1項に記載の化合物の使用。
- 本明細書に定義される発明。
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