JP5759893B2 - Pde10阻害剤ならびに関連する組成物および方法 - Google Patents
Pde10阻害剤ならびに関連する組成物および方法 Download PDFInfo
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- JP5759893B2 JP5759893B2 JP2011522195A JP2011522195A JP5759893B2 JP 5759893 B2 JP5759893 B2 JP 5759893B2 JP 2011522195 A JP2011522195 A JP 2011522195A JP 2011522195 A JP2011522195 A JP 2011522195A JP 5759893 B2 JP5759893 B2 JP 5759893B2
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- C07C255/63—Carboxylic acid nitriles containing cyano groups and nitrogen atoms further bound to other hetero atoms, other than oxygen atoms of nitro or nitroso groups, bound to the same carbon skeleton
- C07C255/65—Carboxylic acid nitriles containing cyano groups and nitrogen atoms further bound to other hetero atoms, other than oxygen atoms of nitro or nitroso groups, bound to the same carbon skeleton with the nitrogen atoms further bound to nitrogen atoms
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- C07D317/48—Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes, unsubstituted on the hetero ring
- C07D317/62—Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes, unsubstituted on the hetero ring with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to atoms of the carbocyclic ring
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Description
を有し、その製薬上許容される塩、立体異性体、溶媒和物およびプロドラッグを含む。
を有し、その製薬上許容される塩、立体異性体、溶媒和物およびプロドラッグを含む。
上記の通り、本発明は、一般に、PDE10阻害剤として有用な化合物、ならびにそれらの調製および使用、ならびに前記化合物を含有する医薬組成物に関する。
Xは、-O-または-S-であり;
R1は、C1-6アルキル、C1-6ハロアルキル、C1-6アラルキル、アリール、-(CH2)nO(CH2)mCH3または-(CH2)nN(CH3)2であり;
R2およびR3は同一であるか異なっており、独立して置換もしくは無置換ヘテロシクリル、または置換もしくは無置換アリールであり;
R4およびR5は同一であるか異なっており、独立して水素、C1-6アルキルまたはC1-6ハロアルキルであり;
nは、1、2、3、4、5または6であり;かつ
mは、0、1、2、3、4、5または6である]
を有し、またはその製薬上許容される塩、立体異性体、溶媒和物またはプロドラッグである。
R1は、水素、C1-6アルキル、C1-6ハロアルキル、C1-6アラルキル、アリール、-(CH2)nO(CH2)mCH3または-(CH2)nN(CH3)2であり;
R2は、置換または無置換アリールであり;
R3は、置換もしくは無置換ヘテロシクリル、または置換もしくは無置換アリールであり;かつ
R4およびR5は同一であるか異なっており、独立して水素、C1-6アルキルまたはC1-6ハロアルキルであり;
nは、1、2、3、4、5または6であり;かつ
mは、0、1、2、3、4、5または6である]
を有し、またはその製薬上許容される塩、立体異性体、溶媒和物またはプロドラッグである。
R1は、C1-6アルキル、C1-6ハロアルキル、C1-6アラルキル、アリール、-(CH2)nO(CH2)mCH3または-(CH2)nN(CH3)2であり;
R2は、置換もしくは無置換ヘテロシクリル、置換フェニル、または置換もしくは無置換ナフチルであり;
R3は、置換もしくは無置換ヘテロシクリル、または置換もしくは無置換アリールであり;かつ
R4およびR5は同一であるか異なっており、独立して水素、C1-6アルキルまたはC1-6ハロアルキルであり;
nは、1、2、3、4、5または6であり;かつ
mは、0、1、2、3、4、5または6である。
R1は、C1-6アルキル、C1-6ハロアルキル、-(CH2)nO(CH2)mCH3または-(CH2)nN(CH3)2であり;
R2およびR3は同一であるか異なっており、独立して置換もしくは無置換ヘテロシクリル、または置換もしくは無置換アリールであり;かつ
R4およびR5は同一であるか異なっており、独立して水素、C1-6アルキルまたはC1-6ハロアルキルであり;
nは、1、2、3、4、5または6であり;かつ
mは、0、1、2、3、4、5または6である。
R1は、水素、C1-6アルキル、C1-6ハロアルキル、C1-6アラルキル、アリール、-(CH2)nO(CH2)mCH3または-(CH2)nN(CH3)2であり;
R2は、
R2aは、-N(R2bR2c)または少なくとも1個のN環原子を有する複素環であり、かつ
R2bおよびR2cは同一であるか異なっており、独立して水素、C1-6アルキル、C1-6ハロアルキル、C1-6アラルキルまたはアリールである]
であり;
R3は、
R3aは-C1-6アルコキシであり、
R3bはハロゲンであり、かつ
R3cは-C1-6アルコキシである]
であり;
R4およびR5は同一であるか異なっており、独立して水素、C1-6アルキルまたはC1-6ハロアルキルであり;
nは、1、2、3、4、5または6であり;かつ
mは、0、1、2、3、4、5または6である。
R1は、水素、C1-6アルキル、C1-6ハロアルキル、C1-6アラルキル、アリール、-(CH2)nO(CH2)mCH3または-(CH2)nN(CH3)2であり;
R2は、
R2aは、-N(R2bR2c)または少なくとも1個のN環原子を有する複素環であり、ただし、R2aは1H-テトラゾール-1-イルではなく、かつ
R2bおよびR2cは同一であるか異なっており、独立して水素、C1-6アルキル、C1-6ハロアルキル、C1-6アラルキルまたはアリールである]
であり;
R3は、
R3aは-C1-6アルコキシであり、かつ
R3cは-C1-6アルコキシである]
であり;
R4およびR5は同一であるか異なっており、独立して水素、C1-6アルキルまたはC1-6ハロアルキルであり;
nは、1、2、3、4、5または6であり;かつ
mは、0、1、2、3、4、5または6である。
構造(I-A)および(IV-A)のエノールプロドラッグは、それぞれ構造(I)または構造(IV)の化合物を、溶媒(例えばジクロロメタン)中で塩基(例えばトリエチルアミン)により処理した後、求電子試薬(例えば塩化アセチル)を加えることにより調製することができる。構造(I-B)および(IV-B)のN-アシル化プロドラッグは、それぞれ構造(I-A)または(IV-A)のプロドラッグを溶媒(例えばトルエン)中で加熱することによる熱転位により調製することができる。例えば、Carpinoら, J. Org. Chem., 53, 6047-6053 (1988); Geitaら, Zhurnal Organicheskoi Khimii, 13(7), 1461-1465 (1977) (Institute of Organic Synthesis, Academy of Sciences of the Latvian SSR, 1346-1350より翻訳が入手可能); Maroulisら, J. Heterocyclic Chem., 21, 1653-1656 (1984); Mongeら, J. Heterocyclic Chem., 21, 397-400 (1984);およびSinghら, Tetrahedron Letters, 29, 2711-2714 (1973)を参照されたい。
(E)-2-(2,3-ジヒドロベンゾ[b][1,4]ジオキシン-6-イル)-2-メトキシ-N'-(3,4,5-トリメトキシベンジリデン)アセトヒドラジドの合成
2-(2,3-ジヒドロベンゾ[b][1,4]ジオキシン-6-イル)-2-メトキシ酢酸
Bio-Organic Chemistry (1972-1999); 1997; 835-844)に従って合成することができる。
(E)-2-(4-(1H-ピラゾール-1-イル)フェニル)-N'-(4-ブロモ-3,5-ジメトキシベンジリデン)-2-メトキシ-N-(2,2,2-トリフルオロエチル)アセトヒドラジドの合成
さらなる代表的な化合物の合成
下記の表1に示す通りの代表的な化合物を、(i)適切な出発物質を選択することにより前記方法に従って合成し(例えば、4-フルオロマンデル酸誘導体(例えば、実施例12-1および12-3)を市販の4-フルオロマンデル酸を使用して合成した)、また、(ii)公知の有機合成技術に従って合成した(例えば、市販のα-フェニル酢酸メチルエステルをエタノール中、加熱しながらヒドラジン水和物により処理することにより、フェニル-酢酸ヒドラジドが得られ(例えば、Pandeye, S. N.; Manjula, H.; Stables, J. P.; Pharmazie; 2001, 56, 121-124を参照されたい)、フェニル酢酸ヒドラジドを触媒量の酢酸の存在下、エタノール中で加熱しながら置換ベンズアルデヒドにより処理することにより、対応する置換フェニル-酢酸ベンジリデンヒドラジドが得られる(例えば、Stephanidou-Stephanatou, J.; Lefkopoulou, S; Journal of Heterocyclic Chemistry; 1982; 19; 705-711.0を参照されたい))。
化合物のアッセイ
PDE10生化学アッセイ
ホスホジエステラーゼ(PDE)アッセイを、Sf9細胞を使用してバキュロウイルス発現系に発現した組換えヒトPDE 1A3、2A3、3触媒領域、4触媒領域、5触媒領域、7A、8A、9A2、10A1および11A1酵素を用いて実施した。PDE活性を、96ウェルプレートフォーマットに適合するように修正した上記のThompsonおよびApplemanの二段階法を使用して測定した。PDE阻害剤の効果を、KiがIC50に等しくなるようなKmである、下記の試験化合物濃度および基質濃度の存在下で一定量の酵素をアッセイすることにより測定した。最終アッセイ体積は、アッセイ緩衝液(10mM MgCl2;40mM Tris.HCl;pH 7.4)を加えて110μlとした。酵素により反応を開始し、(3H)-基質および物質と共に30℃で20分間インキュベートした。酵素を変性させることにより反応を終結した(反応液を70℃に2分間加熱した)。次に,反応液を4℃に10分間冷却した後、ヘビ毒(Crotalus atrox、0.2 mg/ml)を30℃で10分間加えて、トリチウム化された基質の非特異的加水分解をおこなった。残った加水分解されていない環状ヌクレオチドの分離を、活性化されたDowex(200μl)アニオン交換樹脂への混合物のバッチ結合により達成した。アニオン交換樹脂は荷電したヌクレオチドに結合し、加水分解された(3H)基質のみが可溶性分画に残った。次に可溶性分画(50μl)をmicroscint-20 (200μl)に加えて、Top Countプレートリーダーによりカウントした。Graph Pad Prismソフトウェアを用いて放射能単位を阻害剤濃度に対してプロットし、IC50値を得た。
行動モデルにおける代表的化合物の評価
統合失調症は、ドーパミン、グルタミン酸およびセロトニン神経伝達の機能不全と関連づけられてきた。これら3つのクラスの精神刺激薬、ドーパミン作動薬(例えばアンフェタミンおよびアポモルフィン)、グルタミン酸拮抗薬(例えば、PCPおよびケタミン)、およびセロトニン作動薬(例えば、LSDおよびMDMA)はすべて、動物においてヒトの統合失調症の症状に極めて類似した精神異常発現状態(例えば、活動亢進およびプレパルス抑制の障害)を誘導する。公知の抗精神病薬は、定型抗精神病薬(例えば、ハロペリドール)および非定型抗精神病薬(例えば、オランザピン)のどちらも、動物におけるこのような精神異常発現状態を回復させる。下記の実施例14〜15において、本発明の代表的な化合物を動物行動モデルにおいて評価して、公知の抗精神病薬のそれに対する効果と比較する。実施例14〜15において使用した方法は、以下の通りである。
PCP誘導性活動亢進の抑制
本発明の化合物12-63、12-55および12-60(実施例12の表1に定義されるもの)を、PCP誘導性活動亢進を有意におよび実質的に抑制する能力について評価した。C57BL/6雄マウスに化合物(10 mg/kg)またはビヒクルのいずれかを腹腔内注射した。10分後、マウスにPCP(5 mg/kg)を腹腔内注射した。PCP注射の10分後にマウスを活動室に入れ、それらの自発運動活性を20分間赤外線ビームの切断によりモニターした。図1は、化合物12-63が、PCPにより誘発される活動亢進をビヒクルと比較して有意に抑制したことを示している(p<0.0001、群あたりn=8、反復測定ANOVA)。図2は、化合物12-55(10 mg/kg、腹腔内)も実質的に活動亢進を抑制することを示しており(ビヒクルと比較してp=0.0008、群あたりn=8、反復測定ANOVA)、図3は、化合物12-60に関して同様の結果を示している(ビヒクルと比較してp<0.0001、群あたりn=8、反復測定ANOVA)。
条件回避反応の抑制
本発明の化合物12-44(実施例12の表1に定義されるもの)を、経口投与後に条件回避反応を抑制する能力について評価し、結果を図4に示した。C57BL/6雄マウスを、CARパラダイムにおいて不快な刺激を予測し回避するように訓練し、1日30回の試験あたり約20〜25回の回避反応のプラトーに達した(「トレーニングプラトー」)。次に、マウスに化合物またはビヒクルのいずれかを腹腔内注射して、20分後にそれらをCARパラダイムにより30回試験した。同じ動物に対してビヒクル処理および化合物処理を1日おきに実施し、回避反応の抑制における化合物の効果を個体内比較により分析した(2標本t検定)。ビヒクル曝露(「ビヒクル」)はこれらの訓練された動物の回避反応を変化させない。図4は、化合物12-44が、10 mg/kg(p=0.01、群あたりn=6、2標本t検定)および30 mg/kg(p=0.001、群あたりn=6、2標本t検定)の両方の経口投与で回避反応の数を有意に減少させることを示している。後者の用量では、回避の数は28から7に大幅に減少する。
化合物12-63によるPCP誘導性活動亢進の抑制
図5Aに示す通り、化合物12-63(実施例12の表1に定義されるもの)がPCP誘導性活動亢進を抑制することが見出された。C57BL/6雄マウスに化合物またはビヒクルのいずれかを強制経口投与した。15分後、マウスにPCP(5 mg/kg)を腹腔内経路で注射した。PCP注射の10分後にマウスを活動室に入れ、それらの水平方向における自発運動活性を赤外線ビームの切断により20分間モニターした(指示された通りの5回の連続した4分間隔(INT))。図5Aは、化合物12-63(4および10 mg/kg)が、ビヒクル+PCP対照群と比較して、PCPにより誘導された活動亢進を減少または消失させることを示している(用量10 mg/kgに対してp = 0.00003、群あたりn=8、2標本t検定)。
化合物12-63による条件回避反応の抑制
図5Bに示す通り、化合物12-63(実施例12の表1に定義されるもの)が条件回避反応(CAR)を抑制することが見出された。C57BL/6雄マウスを、CARパラダイムにおいて不快な刺激(足のショック)を予測し回避するように訓練し、30回の試験あたり約25回の回避反応のプラトーに達した(「トレーニングプラトー」)。次に、マウスにビヒクル(試験の15分前)または化合物(試験の25分前)のいずれかを強制経口投与し、CARパラダイムにより30回試験した。同じ動物に対してビヒクル処理および化合物処理を1日おきに実施し、回避反応の抑制における化合物の効果を個体内比較により分析した(2標本t検定)。ビヒクル曝露(「ビヒクル」)はこれらの訓練された動物の回避反応を変化させない。図5Bは、化合物12-63(10 mg/kg)が、回避反応の数を有意に減少させることを示している(p = 0.007、群あたりn=6)。これらすべてのケースにおいて、逃避反応の数は対応して増加し、2つの室の間の移動の総数は変化しなかった(データは示さない)。これは、運動機能不全のためでなく、CARの特異的抑制であることを示している。
化合物12-104によるPCP誘導性活動亢進の抑制
図6Aに示す通り、化合物12-104(実施例12の表1に定義されるもの)がPCP誘導性活動亢進を抑制することが見出された。C57BL/6雄マウスに化合物またはビヒクルのいずれかを強制経口投与した。25分後、マウスにPCP(5 mg/kg)を腹腔内経路で注射した。PCP注射の10分後にマウスを活動室に入れ、それらの水平方向における自発運動活性を赤外線ビームの切断により20分間モニターした(指示された通りの5回の連続した4分間隔(INT))。図6Aは、化合物12-104(3および6 mg/kg)が、ビヒクル+PCP対照との比較によりわかる通り、PCPにより誘導された活動亢進を減少または消失させることを示している(p = 0.0189、群あたりn=8、独立標本t検定)。
化合物12-104による条件回避反応の抑制
図6Bに示す通り、化合物12-104(実施例12の表1に定義されるもの)が条件回避反応(CAR)を抑制することが見出された。C57BL/6雄マウスを、CARパラダイムにおいて不快な刺激(足のショック)を予測し回避するように訓練し、1日30回の試験あたり約25回の回避反応のプラトーに達した。次に、マウスにビヒクル(試験の15分前)または化合物(試験の25分前)のいずれかを強制経口投与し、次いでCARパラダイムにより30回試験した。同じ動物に対してビヒクル処理および化合物処理を1日おきに実施し、回避反応の抑制における化合物の効果を個体内比較により分析した(2標本t検定)。ビヒクル曝露(「ビヒクル」)はこれらの訓練された動物の回避反応を変化させない。図6Bは、化合物12-104(10および30 mg/kg)が、回避反応の数を有意に減少させることを示している(p = 0.0159、群あたりn=7)。
化合物12-114によるPCP誘導性活動亢進の抑制
図7Aに示す通り、化合物12-114(実施例12の表1に定義されるもの)がPCP誘導性活動亢進を抑制することが見出された。C57BL/6雄マウスに化合物またはビヒクルのいずれかを強制経口投与した。25分後、それらにPCP(5 mg/kg、腹腔内)を注射した。10分後、マウスを活動室に入れ、それらの水平方向における自発運動活性を赤外線ビームの切断により20分間モニターした(指示された通りの5回の連続した4分間隔(INT))。図7Aは、化合物12-114(10 mg/kg)が、ビヒクル+PCP対照との比較によりわかる通り、PCPにより誘導された活動亢進を完全に消失させることを示している(p < 0.0000001、群あたりn=8、独立標本t検定)。
化合物12-114による条件回避反応の抑制
図7Bに示す通り、化合物12-114(実施例12の表1に定義されるもの)が条件回避反応(CAR)を抑制することが見出された。C57BL/6雄マウスを、CARパラダイムにおいて不快な刺激(足のショック)を予測し回避するように訓練し、1日30回の試験あたり約25回の回避反応のプラトーに達した。次に、マウスにビヒクル(試験の15分前)または化合物(試験の25分前)のいずれかを強制経口投与し、次いでCARパラダイムにより30回試験した。同じ動物に対してビヒクル処理および化合物処理を1日おきに実施し、回避反応の抑制における化合物の効果を個体内比較により分析した(2標本t検定)。ビヒクル曝露(「ビヒクル」)はこれらの訓練された動物の回避反応を変化させない。図7Bは、化合物12-114(10 mg/kg)が、回避反応の数を有意に減少させることを示している(p = 0.0003、群あたりn=7、2標本t検定)。
化合物12-132によるPCP誘導性活動亢進の抑制
図8Aに示す通り、化合物12-132(実施例12の表1に定義されるもの)がPCP誘導性活動亢進を抑制することが見出された。C57BL/6雄マウスにPCP(5 mg/kg)および化合物またはビヒクルのいずれかを腹腔内経路により同時注射した。10分後、マウスを活動室に入れ、それらの水平方向における自発運動活性を赤外線ビームの切断により20分間モニターした(指示された通りの5回の連続した4分間隔(INT))。図8Aは、化合物12-132(10 mg/kg)が、ビヒクル+PCP対照との比較によりわかる通り、PCPにより誘導された活動亢進を実質的に減少させることを示している(p < 0.0000001、群あたりn=8、2標本t検定)。
化合物12-132による条件回避反応の抑制
図8Bに示す通り、化合物12-132(実施例12の表1に定義されるもの)が条件回避反応(CAR)を抑制することが見出された。C57BL/6雄マウスを、CARパラダイムにおいて不快な刺激(足のショック)を予測し回避するように訓練し、30回の試験あたり約25回の回避反応のプラトーに達した(「トレーニングプラトー」)。次に、マウスにビヒクル(試験の15分前)または化合物(試験の25分前)のいずれかを強制経口投与し、次いでCARパラダイムにより30回試験した。同じ動物に対してビヒクル処理および化合物処理を1日おきに実施し、回避反応の抑制における化合物の効果を個体内比較により分析した(2標本t検定)。ビヒクル曝露(「ビヒクル」)はこれらの訓練された動物の回避反応を変化させない。図8Bは、化合物12-132(10 mg/kg)が、回避反応の数を有意に減少させることを示している(p = 0.044、群あたりn=7)。これらすべてのケースにおいて、逃避反応の数は対応して増加し、2つの室の間の移動の総数は変化しなかった(データは示さない)。これは、運動機能不全のためでなく、CARの特異的抑制であることを示している。
化合物12-134によるPCP誘導性活動亢進の抑制
図9Aに示す通り、化合物12-134(実施例12の表1に定義されるもの)がPCP誘導性活動亢進を抑制することが見出された。C57BL/6雄マウスに化合物またはビヒクルのいずれかを強制経口投与した。25分後、マウスにPCP(5 mg/kg)を腹腔内経路で注射した。PCP注射の10分後にマウスを活動室に入れ、それらの水平方向における自発運動活性を赤外線ビームの切断により20分間モニターした(指示された通りの5回の連続した4分間隔(INT))。図9Aは、化合物12-134(4、6および10 mg/kg)が、ビヒクル+PCP対照との比較によりわかる通り、PCPにより誘導された活動亢進を減少または消失させることを示している(それぞれp = 0.0033、0.0012、および0.00001、群あたりn=8、独立標本t検定)。
化合物12-134による条件回避反応の抑制
図9Bに示す通り、化合物12-134(実施例12の表1に定義されるもの)が条件回避反応(CAR)を抑制することが見出された。C57BL/6雄マウスを、CARパラダイムにおいて不快な刺激(足のショック)を予測し回避するように訓練し、1日30回の試験あたり約25回の回避反応のプラトーに達した。次に、マウスにビヒクル(試験の15分前)または化合物(試験の25分前)のいずれかを強制経口投与し、次いでCARパラダイムにより30回試験した。同じ動物に対してビヒクル処理および化合物処理を1日おきに実施し、回避反応の抑制における化合物の効果を個体内比較により分析した(2標本t検定)。ビヒクル曝露(「ビヒクル」)はこれらの訓練された動物の回避反応を変化させない。図9Bは、化合物12-134(3、6および10 mg/kg)が、回避反応の数を有意に減少させることを示している(それぞれp = 0.0117、0.0043、および8E-9、群あたりn=7)。
化合物12-115によるPCP誘導性活動亢進の抑制
図10Aに示す通り、化合物12-115(実施例12の表1に定義されるもの)がPCP誘導性活動亢進を抑制することが見出された。C57BL/6雄マウスに化合物またはビヒクルのいずれかを強制経口投与した。25分後、マウスにPCP(5 mg/kg)を腹腔内経路で注射した。注射の10分後にマウスを活動室に入れ、それらの水平方向における自発運動活性を赤外線ビームの切断により20分間モニターした(指示された通りの5回の連続した4分間隔(INT))。図10Aは、化合物12-115が、2および5 mg/kgの経口投与で活動亢進を有意に抑制し(それぞれp = 0.02および0.001)、10 mg/kgの経口投与において活動亢進を消失させること(p = 1.5 E-5、群あたりn=8、独立標本t検定)を示している。
化合物12-115による条件回避反応の抑制
図10Bに示す通り、化合物12-115(実施例12の表1に定義されるもの)が条件回避反応(CAR)を抑制することが見出された。C57BL/6雄マウスを、CARパラダイムにおいて不快な刺激(足のショック)を予測し回避するように訓練し、1日30回の試験あたり約25回の回避反応のプラトーに達した。次に、マウスにビヒクル(試験の15分前)または化合物(試験の25分前)のいずれかを強制経口投与し、CARパラダイムにより30回試験した。同じ動物に対してビヒクル処理および化合物処理を1日おきに実施し、回避反応の抑制における化合物の効果を個体内比較により分析した(2標本t検定)。ビヒクル曝露(「ビヒクル」)はこれらの訓練された動物の回避反応を変化させない。図10Bは、化合物12-115(10 mg/kg、経口)が、回避反応の数を有意に減少させることを示している(p = 1.2 E-5、群あたりn=7、2標本t検定)。
化合物12-140によるPCP誘導性活動亢進の抑制
図11Aに示す通り、化合物12-140(実施例12の表1に定義されるもの)がPCP誘導性活動亢進を抑制することが見出された。C57BL/6雄マウスに化合物またはビヒクルのいずれかを強制経口投与した。25分後、マウスにPCP(5 mg/kg)を腹腔内経路で注射した。PCP注射の10分後にマウスを活動室に入れ、それらの水平方向における自発運動活性を赤外線ビームの切断により20分間モニターした(指示された通りの5回の連続した4分間隔(INT))。図11Aは、化合物12-140が、4および8 mg/kgの経口投与で活動亢進を有意に減少または消失させることを示している(それぞれp = 0.004および5.9 E-8、群あたりn=8、独立標本t検定)。
化合物12-140による条件回避反応の抑制
図11Bに示す通り、化合物12-140(実施例12の表1に定義されるもの)が条件回避反応(CAR)を抑制することが見出された。C57BL/6雄マウスを、CARパラダイムにおいて不快な刺激(足のショック)を予測し回避するように訓練し、1日30回の試験あたり約25回の回避反応のプラトーに達した。次に、マウスにビヒクル(試験の15分前)または化合物(試験の25分前)のいずれかを強制経口投与し、CARパラダイムにより30回試験した。同じ動物に対してビヒクル処理および化合物処理を1日おきに実施し、回避反応の抑制における化合物の効果を個体内比較により分析した(2標本t検定)。ビヒクル曝露(「ビヒクル」)はこれらの訓練された動物の回避反応を変化させない。図11Bは、化合物12-140が、6および10 mg/kgの用量で回避反応の数を有意に減少させることを示している(それぞれp = 0.00053および3.1 E-12、群あたりn=7、2標本t検定)。
化合物12-142によるPCP誘導性活動亢進の抑制
図12Aに示す通り、化合物12-142(実施例12の表1に定義されるもの)がPCP誘導性活動亢進を抑制することが見出された。C57BL/6雄マウスに化合物またはビヒクルのいずれかを強制経口投与した。25分後、マウスにPCP(5 mg/kg)を腹腔内経路で注射した。PCP注射の10分後にマウスを活動室に入れ、それらの水平方向における自発運動活性を赤外線ビームの切断により20分間モニターした(指示された通りの5回の連続した4分間隔(INT))。図12Aは、化合物12-142が、8 mg/kgの経口投与で活動亢進を基本的に消失させることを示している(p = 5.9 E-6、群あたりn=8、独立標本t検定)。
化合物12-142による条件回避反応の抑制
図11Bに示す通り、化合物12-142(実施例12の表1に定義されるもの)が条件回避反応(CAR)を抑制することが見出された。C57BL/6雄マウスを、CARパラダイムにおいて不快な刺激(足のショック)を予測し回避するように訓練し、1日30回の試験あたり約25回の回避反応のプラトーに達した。次に、マウスにビヒクル(試験の15分前)または化合物(試験の25分前)のいずれかを強制経口投与し、CARパラダイムにより30回試験した。同じ動物に対してビヒクル処理および化合物処理を1日おきに実施し、回避反応の抑制における化合物の効果を個体内比較により分析した(2標本t検定)。ビヒクル曝露(「ビヒクル」)はこれらの訓練された動物の回避反応を変化させない。図11Bは、化合物12-142が、5 mg/kgの用量で回避反応の数を有意に減少させることを示している(それぞれp = 0.033、群あたりn=7、2標本t検定)。
Claims (23)
- 温血動物においてPDE10を阻害するための医薬の製造における、下記の構造(I):
Xは、-O-または-S-であり;
R1は、C1-6アルキル、C1-6ハロアルキル、C1-6アラルキル、アリール、-(CH2)nO(CH2)mCH3または-(CH2)nN(CH3)2であり;
R2 は、置換もしくは無置換フェニル、置換もしくは無置換ピリジル、置換もしくは無置換チオフェニル、置換もしくは無置換イミダゾリル、またはそれらの縮合二環系であり、R3は、置換もしくは無置換フェニル、または置換もしくは無置換ピラゾリルであり;
R4およびR5は同一であるか異なっており、独立して水素、C1-6アルキルまたはC1-6ハロアルキルであり;
nは、1、2、3、4、5または6であり;かつ
mは、0、1、2、3、4、5または6である]
を有する化合物、またはその製薬上許容される塩、立体異性体、もしくは溶媒和物の使用。 - 神経障害の治療を必要とする温血動物における神経障害を治療するための医薬の製造における、下記の構造(I):
Xは、-O-または-S-であり;
R1は、C1-6アルキル、C1-6ハロアルキル、C1-6アラルキル、アリール、-(CH2)nO(CH2)mCH3または-(CH2)nN(CH3)2であり;
R2 は、置換もしくは無置換フェニル、置換もしくは無置換ピリジル、置換もしくは無置換チオフェニル、置換もしくは無置換イミダゾリル、またはそれらの縮合二環系であり、R3は、置換もしくは無置換フェニル、または置換もしくは無置換ピラゾリルであり;かつ
R4およびR5は同一であるか異なっており、独立して水素、C1-6アルキルまたはC1-6ハロアルキルであり;
nは、1、2、3、4、5または6であり;かつ
mは、0、1、2、3、4、5または6である]
を有する化合物、またはその製薬上許容される塩、立体異性体、もしくは溶媒和物の使用。 - 神経障害が、精神障害、不安障害、運動障害および/または神経障害(例えば、パーキンソン病、ハンチントン病、アルツハイマー病、脳炎、恐怖症、てんかん、失語症、ベル麻痺、脳性麻痺、睡眠障害、疼痛、トゥレット症候群、統合失調症、妄想障害、双極性障害、心的外傷後ストレス障害、薬剤性精神病、パニック障害、強迫性障害、注意欠陥障害、崩壊性行動障害、自閉症、鬱病、認知症、認知障害、てんかん、不眠症および多発性硬化症)からなる群より選択される、請求項2に記載の使用。
- R4およびR5が水素である、請求項4に記載の使用。
- R1がC1-6アルキルである、請求項4または5に記載の使用。
- R1がメチルである、請求項6に記載の使用。
- R1がエチルである、請求項6に記載の使用。
- R1がイソプロピルである、請求項6に記載の使用。
- R3が置換フェニルである、請求項4〜9のいずれか1項に記載の使用。
- R3が4-ブロモ-3,5-ジメトキシフェニルである、請求項10に記載の使用。
- R2が置換または無置換フェニルである、請求項4〜11のいずれか1項に記載の使用。
- R2が置換または無置換ピリジル、置換もしくは無置換チオフェニル、または置換もしくは無置換イミダゾリルである、請求項4〜11のいずれか1項に記載の使用。
- 下記の構造(II):
R1は、C1-6アルキルであり;
R2は、置換もしくは無置換ピリジル、置換もしくは無置換チオフェニル、置換もしくは無置換イミダゾリル、またはそれらの縮合二環系、置換フェニル、または置換もしくは無置換ナフチルであり;
R3は、置換もしくは無置換ピラゾリル、または置換もしくは無置換フェニルであり;かつ
R4およびR5は同一であるか異なっており、独立して水素、C1-6アルキルまたはC1-6ハロアルキルであり;
nは、1、2、3、4、5または6であり;かつ
mは、0、1、2、3、4、5または6である]
を有する化合物、またはその製薬上許容される塩、立体異性体、もしくは溶媒和物。 - R4およびR5が水素である、請求項14に記載の化合物。
- R1がメチルである、請求項14または15に記載の化合物。
- R1がエチルである、請求項14または15に記載の化合物。
- R1がイソプロピルである、請求項14または15に記載の化合物。
- R3が置換フェニルである、請求項14〜18のいずれか1項に記載の化合物。
- R3が4-ブロモ-3,5-ジメトキシフェニルである、請求項19に記載の化合物。
- R2が置換フェニルである、請求項14〜20のいずれか1項に記載の化合物。
- R2が置換または無置換ピリジル、置換もしくは無置換チオフェニル、または置換もしくは無置換イミダゾリルである、請求項14〜20のいずれか1項に記載の化合物。
- 請求項14〜22のいずれか1項に記載の化合物および製薬上許容される担体または希釈剤を含む医薬組成物。
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US7786139B2 (en) * | 2006-11-21 | 2010-08-31 | Omeros Corporation | PDE10 inhibitors and related compositions and methods |
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FR2936784B1 (fr) | 2008-10-08 | 2010-10-08 | Gaztransp Et Technigaz | Cuve a membrane ondulee renforcee |
RU2545456C2 (ru) * | 2010-03-12 | 2015-03-27 | Омерос Корпорейшн | Pde10 ингибиторы и содержащие их композиции и способы |
US9132136B2 (en) | 2010-08-02 | 2015-09-15 | Hoffmann-La Roche Inc. | Pharmaceutical combination |
CA2824047C (en) | 2011-01-11 | 2019-06-18 | Sunovion Pharmaceuticals Inc. | Heteroaryl compounds and methods of use thereof |
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WO2014071044A1 (en) | 2012-11-01 | 2014-05-08 | Allergan, Inc. | Substituted 6,7-dialkoxy-3-isoquinoline derivatives as inhibitors of phosphodiesterase 10 (pde10a) |
WO2015006689A1 (en) | 2013-07-12 | 2015-01-15 | University Of South Alabama | Treatment and diagnosis of cancer and precancerous conditions using pde10a inhibitors and methods to measure pde10a expression |
US9200016B2 (en) | 2013-12-05 | 2015-12-01 | Allergan, Inc. | Substituted 6, 7-dialkoxy-3-isoquinoline derivatives as inhibitors of phosphodiesterase 10 (PDE 10A) |
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