JP2013522228A - Pde10インヒビターならびに関連する組成物および方法 - Google Patents
Pde10インヒビターならびに関連する組成物および方法 Download PDFInfo
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- JP2013522228A JP2013522228A JP2012557252A JP2012557252A JP2013522228A JP 2013522228 A JP2013522228 A JP 2013522228A JP 2012557252 A JP2012557252 A JP 2012557252A JP 2012557252 A JP2012557252 A JP 2012557252A JP 2013522228 A JP2013522228 A JP 2013522228A
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- Prior art keywords
- phenyl
- methyl
- dimethoxyphenyl
- compound
- bromo
- Prior art date
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- 238000012353 t test Methods 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
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- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- KSKISSONZRPPSZ-UHFFFAOYSA-N tert-butyl-[[4-(5-cyclopropyl-1,3,4-oxadiazol-2-yl)phenyl]methoxy]-dimethylsilane Chemical compound C1=CC(CO[Si](C)(C)C(C)(C)C)=CC=C1C1=NN=C(C2CC2)O1 KSKISSONZRPPSZ-UHFFFAOYSA-N 0.000 description 1
- JRMUNVKIHCOMHV-UHFFFAOYSA-M tetrabutylammonium bromide Chemical compound [Br-].CCCC[N+](CCCC)(CCCC)CCCC JRMUNVKIHCOMHV-UHFFFAOYSA-M 0.000 description 1
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- 239000002562 thickening agent Substances 0.000 description 1
- 125000001544 thienyl group Chemical group 0.000 description 1
- ARYHTUPFQTUBBG-UHFFFAOYSA-N thiophen-2-ylboronic acid Chemical compound OB(O)C1=CC=CS1 ARYHTUPFQTUBBG-UHFFFAOYSA-N 0.000 description 1
- 125000000464 thioxo group Chemical group S=* 0.000 description 1
- 210000001519 tissue Anatomy 0.000 description 1
- CFOAUYCPAUGDFF-UHFFFAOYSA-N tosmic Chemical compound CC1=CC=C(S(=O)(=O)C[N+]#[C-])C=C1 CFOAUYCPAUGDFF-UHFFFAOYSA-N 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000002103 transcriptional effect Effects 0.000 description 1
- 125000004306 triazinyl group Chemical group 0.000 description 1
- 125000001425 triazolyl group Chemical group 0.000 description 1
- 125000003866 trichloromethyl group Chemical group ClC(Cl)(Cl)* 0.000 description 1
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 1
- LEIMLDGFXIOXMT-UHFFFAOYSA-N trimethylsilyl cyanide Chemical compound C[Si](C)(C)C#N LEIMLDGFXIOXMT-UHFFFAOYSA-N 0.000 description 1
- 125000005580 triphenylene group Chemical group 0.000 description 1
- 229910052722 tritium Inorganic materials 0.000 description 1
- 241000701447 unidentified baculovirus Species 0.000 description 1
- 125000004417 unsaturated alkyl group Chemical group 0.000 description 1
- 230000004584 weight gain Effects 0.000 description 1
- 235000019786 weight gain Nutrition 0.000 description 1
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- MVWVFYHBGMAFLY-UHFFFAOYSA-N ziprasidone Chemical compound C1=CC=C2C(N3CCN(CC3)CCC3=CC=4CC(=O)NC=4C=C3Cl)=NSC2=C1 MVWVFYHBGMAFLY-UHFFFAOYSA-N 0.000 description 1
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Classifications
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- C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D277/22—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
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- A61K31/341—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide not condensed with another ring, e.g. ranitidine, furosemide, bufetolol, muscarine
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Abstract
Description
本出願は、2010年3月12日に出願された米国仮特許出願番号61/313,544号、および2011年1月7日に出願された米国仮特許出願番号61/430,841号の米国特許法119条(e)項の下での利益を主張し、これら米国仮特許出願は、その全容が参照によって本明細書に援用される。
(技術分野)
本発明は、一般に、PDE10インヒビターとしての活性を有する化合物、および上記化合物を含む組成物、ならびにそれを必要とする温血動物へのこのような化合物の投与によって種々の障害を処置するための方法に関する。
環式ヌクレオチドホスホジエステラーゼ(PDE)は、大きな酵素スーパーファミリーとして示されている。PDEは、カルボキシル末端の近位にある保存された触媒ドメイン、およびしばしばアミノ末端付近にある調節ドメインもしくはモチーフを有するモジュール構造を有することが公知である。上記PDEスーパーファミリーは、現在、11個のPDEファミリーに下位分類される、20個より多くの異なる遺伝子を含む(非特許文献1)。
簡潔には、本発明は、一般に、PDE10インヒビターとしての活性を有する化合物、その調製および使用のための方法、ならびに上記化合物を含む薬学的組成物に関する。
上記で言及されるように、本発明は、一般に、PDE10インヒビターとして有用な化合物、ならびにそれらの調製および使用のための方法、ならびに上記化合物を含む薬学的組成物に関する。
を有し、ここで:
Aは、
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もしくは−(CH2)nN(CH3)2であり;
R2は、(i)置換されたかもしくは置換されていないアリール、または(ii)置換されたかもしくは置換されていないヘテロシクリルであり;
R3は、置換されたかもしくは置換されていないアリールであり;
R4は、水素、C1−6アルキルもしくはC1−6ハロアルキルであり;
nは、1、2、3、4、5もしくは6であり;ならびに
mは、0、1、2、3、4、5もしくは6である。
「アミノ」とは、−NH2ラジカルをいう。
「シアノ」とは、−CNラジカルをいう。
「ヒドロキシ」もしくは「ヒドロキシル」とは、−OHラジカルをいう。
「イミノ」とは、=NH置換基をいう。
「ニトロ」とは、−NO2ラジカルをいう。
「オキソ」とは、=O置換基をいう。
「チオキソ」とは、=S置換基をいう。
1−(4−(4−ブロモ−3,5−ジメトキシフェニル)チアゾール−2−イル)−2−メトキシ−2−(4−モルホリノフェニル)エタノン
1−(4−(4−ブロモ−3,5−ジメトキシフェニル)オキサゾール−2−イル)−2−メトキシ−2−(4−モルホリノフェニル)−エタノン
2−(4−(1H−ピラゾール−1−イル)フェニル)−1−(4−(4−ブロモ−3,5−ジメトキシフェニル)チアゾール−2−イル)−2−メトキシエタノン
1−(4−(4−ブロモ−3,5−ジメトキシフェニル)−1−メチル−1H−イミダゾール−2−イル)−2−メトキシ−2−(4−モルホリノフェニル)エタノン
2−(4−(1H−ピラゾール−1−イル)フェニル)−1−(4−(4−ブロモ−3,5−ジメトキシフェニル)オキサゾール−2−イル)−2−メトキシエタノン
1−(4−(4−ブロモ−3,5−ジメトキシフェニル)オキサゾール−2−イル)−2−メトキシ−2−(4−(ピペリジン−1−イル)フェニル)エタノン
1−(4−(4−ブロモ−3,5−ジメトキシフェニル)オキサゾール−2−イル)−2−メトキシ−2−(4−(ピロリジン−1−イル)フェニル)エタノン
1−(4−(4−ブロモ−3,5−ジメトキシフェニル)オキサゾール−2−イル)−2−(4−イソプロポキシフェニル)−2−メトキシエタノン
1−(4−(4−ブロモ−3,5−ジメトキシフェニル)オキサゾール−2−イル)−2−メトキシ−2−(キノリン−5−イル)エタノン
1−(4−(4−ブロモ−3,5−ジメトキシフェニル)オキサゾール−2−イル)−2−メトキシ−2−(キノリン−3−イル)エタノン
1−(4−(4−ブロモ−3,5−ジメトキシフェニル)オキサゾール−2−イル)−2−メトキシ−2−(4−(5−メチル−1,3,4−オキサジアゾール−2−イル)フェニル)エタノン
1−(5−(4−ブロモ−3,5−ジメトキシフェニル)フラン−2−イル)−2−メトキシ−2−(4−モルホリノフェニル)エタノン
1−(5−(4−ブロモ−3,5−ジメトキシフェニル)フラン−2−イル)−2−メトキシ−2−(4−(5−メチル−1,3,4−オキサジアゾール−2−イル)フェニル)エタノン
2−(4−(1H−ピラゾール−1−イル)フェニル)−1−(5−(4−ブロモ−3,5−ジメトキシフェニル)フラン−2−イル)−2−メトキシエタノン
2−(4−(1H−ピラゾール−4−イル)フェニル)−1−(5−(4−ブロモ−3,5−ジメトキシフェニル)フラン−2−イル)−2−メトキシエタノン
1−(5−(4−ブロモ−3,5−ジメトキシフェニル)フラン−2−イル)−2−メトキシ−2−(4−(5−メチルフラン−2−イル)フェニル)エタノン
2,3−ジメトキシ−5−(5−(2−メトキシ−2−(4−(5−メチル−1,3,4−オキサジアゾール−2−イル)フェニル)アセチル)フラン−2−イル)ベンゾニトリル
1−(5−(4−ブロモ−3,5−ジメトキシフェニル)フラン−2−イル)−2−(4−(5−エチル−1,3,4−オキサジアゾール−2−イル)フェニル)−2−メトキシエタノン
1−(5−(4−ブロモ−3,5−ジメトキシフェニル)フラン−2−イル)−2−(4−(1,1−ジオキシドイソチアゾリジン−2−イル)フェニル)−2−メトキシエタノン
1−(5−(4−ブロモ−3,5−ジメトキシフェニル)フラン−2−イル)−2−メトキシ−2−(キノリン−5−イル)エタノン
1−(5−(3,5−ジメトキシ−4−メチルフェニル)フラン−2−イル)−2−メトキシ−2−(4−(5−メチル−1,3,4−オキサジアゾール−2−イル)フェニル)エタノン
1−(5−(4−ブロモ−3,5−ジメトキシフェニル)フラン−2−イル)−2−(4−(5−シクロプロピル−1,3,4−オキサジアゾール−2−イル)フェニル)−2−メトキシエタノン
1−(5−(4−ブロモ−3,5−ジメトキシフェニル)フラン−2−イル)−2−メトキシ−2−(6−(ピペリジン−1−イル)ピリジン−3−イル)エタノン
2,6−ジメトキシ−4−(5−(2−メトキシ−2−(4−モルホリノフェニル)アセチル)フラン−2−イル)フェニルベンゾエート
1−(5−(4−ブロモ−3,5−ジメトキシフェニル)フラン−2−イル)−2−メトキシ−2−(1−メチル−1H−ベンゾ[d][1,2,3]トリアゾール−5−イル)エタノン
1−(5−(4−ブロモ−3,5−ジメトキシフェニル)フラン−2−イル)−2−メトキシ−2−(4−(モルホリノメチル)フェニル)エタノン
1−(5−(3,5−ジメトキシフェニル)フラン−2−イル)−2−メトキシ−2−(4−モルホリノフェニル)エタノン
1−(5−(4−(ジフルオロメトキシ)−3,5−ジメトキシフェニル)フラン−2−イル)−2−メトキシ−2−(4−モルホリノフェニル)エタノン
1−(5−(4−エトキシ−3,5−ジメトキシフェニル)フラン−2−イル)−2−メトキシ−2−(4−モルホリノフェニル)エタノン
2−(4−(2H−1,2,3−トリアゾール−2−イル)フェニル)−1−(5−(4−ブロモ−3,5−ジメトキシフェニル)フラン−2−イル)−2−メトキシエタノン
2−(4−(1H−1,2,3−トリアゾール−1−イル)フェニル)−1−(5−(4−ブロモ−3,5−ジメトキシフェニル)フラン−2−イル)−2−メトキシエタノン
2−(4−(1H−1,2,4−トリアゾール−1−イル)フェニル)−1−(5−(4−ブロモ−3,5−ジメトキシフェニル)フラン−2−イル)−2−メトキシエタノン
1−(5−(4−ブロモ−3,5−ジメトキシフェニル)フラン−2−イル)−2−メトキシ−2−(4−(2−メチル−2H−テトラゾール−5−イル)フェニル)エタノン
1−(5−(4−ブロモ−3,5−ジメトキシフェニル)フラン−2−イル)−2−メトキシ−2−(4−(5−メチル−1,3,4−チアジアゾール−2−イル)フェニル)エタノン
1−(5−(4−ブロモ−3,5−ジメトキシフェニル)フラン−2−イル)−2−メトキシ−2−(4−(2−メチルチアゾール−4−イル)フェニル)エタノン
2−メトキシ−2−(4−(5−メチル−1,3,4−オキサジアゾール−2−イル)フェニル)−1−(5−(3,4,5−トリメトキシフェニル)フラン−2−イル)エタノン
1−(5−(4−ブロモ−3,5−ジメトキシフェニル)フラン−2−イル)−2−メトキシ−2−(4−(ピリジン−3−イル)フェニル)エタノン
1−(5−(4−ブロモ−3,5−ジメトキシフェニル)フラン−2−イル)−2−エトキシ−2−(4−モルホリノフェニル)エタノン
1−(5−(3−ブロモ−4,5−ジメトキシフェニル)フラン−2−イル)−2−メトキシ−2−(4−(5−メチル−1,3,4−オキサジアゾール−2−イル)フェニル)エタノン
1−(5−(3−クロロ−4,5−ジメトキシフェニル)フラン−2−イル)−2−メトキシ−2−(4−(5−メチル−1,3,4−オキサジアゾール−2−イル)フェニル)エタノン
1−(5−(4−ブロモ−3,5−ジメトキシフェニル)フラン−2−イル)−2−(シクロプロピルメトキシ)−2−(4−モルホリノフェニル)エタノン
1−(5−(4−ブロモ−3,5−ジメトキシフェニル)フラン−2−イル)−2−メトキシ−2−(6−メトキシピリジン−3−イル)エタノン
1−(5−(4−ブロモ−3,5−ジメトキシフェニル)フラン−2−イル)−2−(4−((ジメチルアミノ)メチル)フェニル)−2−メトキシエタノン
1−(5−(4−ブロモ−3,5−ジメトキシフェニル)フラン−2−イル)−2−メトキシ−2−(6−モルホリノピリジン−3−イル)エタノン
1−(5−(4−ブロモ−3,5−ジメトキシフェニル)フラン−2−イル)−2−メトキシ−2−(4−(ピラジン−2−イル)フェニル)エタノン
2−エトキシ−2−(4−(5−メチル−1,3,4−オキサジアゾール−2−イル)フェニル)−1−(5−(3,4,5−トリメトキシフェニル)フラン−2−イル)エタノン
1−(5−(4−ブロモ−3,5−ジメトキシフェニル)フラン−2−イル)−2−エトキシ−2−(4−(5−メチル−1,3,4−オキサジアゾール−2−イル)フェニル)エタノン
1−(5−(4−フルオロ−3,5−ジメトキシフェニル)フラン−2−イル)−2−メトキシ−2−(4−モルホリノフェニル)エタノン
1−(5−(4−クロロ−3,5−ジメトキシフェニル)フラン−2−イル)−2−メトキシ−2−(4−(5−メチル−1,3,4−チアジアゾール−2−イル)フェニル)エタノン
1−(5−(4−クロロ−3,5−ジメトキシフェニル)フラン−2−イル)−2−メトキシ−2−(4−モルホリノフェニル)エタノン
1−(3−(3,4−ジメトキシフェニル)−1H−ピラゾール−1−イル)−2−(4−フルオロフェニル)−2−メトキシエタノン
1−(3−(4−ブロモ−3,5−ジメトキシフェニル)−1H−ピラゾール−1−イル)−2−メトキシ−2−(4−モルホリノフェニル)エタノン
1−(3−(3,4−ジメトキシフェニル)−1H−ピラゾール−1−イル)−2−メトキシ−2−(4−モルホリノフェニル)エタノン
1−(5−(4−ブロモ−3,5−ジメトキシフェニル)−1,2,4−オキサジアゾール−3−イル)−2−メトキシ−2−(4−モルホリノフェニル)エタノン
1−(4−(4−ブロモ−3,5−ジメトキシフェニル)−5−メチルオキサゾール−2−イル)−2−メトキシ−2−(4−モルホリノフェニル)エタノン
1−(5−(4−ブロモ−3,5−ジメトキシフェニル)オキサゾール−2−イル)−2−メトキシ−2−(4−モルホリノフェニル)エタノン
1−(5−(4−ブロモ−3,5−ジメトキシフェニル)チオフェン−2−イル)−2−メトキシ−2−(4−(5−メチル−1,3,4−オキサジアゾール−2−イル)フェニル)エタノン
1−(4−(4−ブロモ−3,5−ジメトキシフェニル)−5−(トリフルオロメチル)オキサゾール−2−イル)−2−メトキシ−2−(4−モルホリノフェニル)エタノン
1−(5−(4−ブロモ−3,5−ジメトキシフェニル)チオフェン−2−イル)−2−メトキシ−2−(4−モルホリノフェニル)エタノン
2−(4−(5−シクロプロピル−1,3,4−オキサジアゾール−2−イル)フェニル)−2−メトキシ−1−(5−(3,4,5−トリメトキシフェニル)フラン−2−イル)エタノン
1−(5−(4−クロロ−3,5−ジメトキシフェニル)フラン−2−イル)−2−メトキシ−2−(4−(5−メチル−1,3,4−オキサジアゾール−2−イル)フェニル)エタノン
1−(5−(4−フルオロ−3,5−ジメトキシフェニル)フラン−2−イル)−2−メトキシ−2−(4−(5−メチル−1,3,4−オキサジアゾール−2−イル)フェニル)エタノン
1−(5−(4−クロロ−3,5−ジメトキシフェニル)フラン−2−イル)−2−エトキシ−2−(4−(5−メチル−1,3,4−オキサジアゾール−2−イル)フェニル)エタノン
1−(5−(4−クロロ−3,5−ジメトキシフェニル)フラン−2−イル)−2−エトキシ−2−(4−モルホリノフェニル)エタノン
さらなる代表的化合物の合成
以下の表1中の代表的化合物を、(i)適切な出発物質を選択することによって前述の手順に従って、および(ii)公知の有機合成技術に従って合成した。
化合物アッセイ
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、バキュロウイルス系において発現された組換えヒトPDE1A3、2A3、3触媒領域、4触媒領域、5触媒領域、7A、8A、9A2、10A1および11A1酵素を使用して行った。PDE活性を、96ウェルプレート形式に適合させた上記のThompsonおよびApplemanの2工程方法の改変を使用して測定した。上記PDEインヒビターの効果を、試験化合物濃度および基質濃度(Kmより低く、これにより、KiがIC50と等しくなる)の存在下で、固定量の上記酵素をアッセイすることによって決定した。最終アッセイ容積は、アッセイ緩衝液(10mM MgCl2;40mM Tris.HCl;pH7.4)を用いて110μlであった。反応を酵素によって開始し、(3H)−基質および物質とともに20分間にわたって30℃においてインキュベートした。上記反応を、上記酵素を変性させる(上記反応物を70℃へと2分間にわたって加熱する)ことによって終わらせた。次いで、上記反応物を、4℃において10分間にわたって冷却し、その後、蛇毒(Crotalus atrox, 0.2mg/ml)を10分間にわたって30℃において添加し、これによって、上記トリチウム化基質の非特異的加水分解を可能にした。残りの加水分解されていない環式ヌクレオチドの分離は、活性化したDowex(200μl)アニオン交換レジンへの上記混合物のバッチ結合によって達成した。上記アニオン交換レジンは、荷電ヌクレオチドを結合し、加水分解(3H)基質のみを可溶性画分に残した。次いで、その可溶性画分(50μl)を、microscint−20(200μl)に添加し、Top Count Plateリーダーでカウントした。放射性ユニットを、インヒビター濃度に対してプロットし、Graph Pad Prismソフトウェアを使用して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、ドパミン作動性、グルタミン酸作動性、およびセロトニン作動性の神経伝達物質の機能不全と関連した。これら3つのクラスにおける精神刺激薬、ドパミン作動性アゴニスト(例えば、アンフェタミンおよびアポモルフィン)、グルタミン作動性アンタゴニスト(例えば、フェンシクリジン(PCP)およびケタミン)、およびセロトニン作動性アゴニスト(例えば、LSDおよびMDMA)はすべて、動物における精神異常発現状態(例えば、機能亢進およびプレパルス抑制の破壊)を誘導する。これらは、ヒトにおける統合失調症の症状と非常によく似ている。公知の抗精神病薬(代表的な抗精神病薬(例えば、ハロペリドール)および典型的ではない抗精神病薬(例えば、オランザピン)の両方を含む)は、動物においてこのような精神異常発現状態を逆転させる。以下に記載される実施例67〜77は、動物行動モデルにおいて本発明の代表的化合物を評価して、得られた効果と、公知の抗精神病薬の効果との比較を可能にする。実施例67〜77において使用される方法は、以下のとおりである。
化合物1−1によるPCP誘導性機能亢進の低下
化合物1−1(実施例1)は、図1および図2に示されるように、PCP誘導性機能亢進を低下することが見いだされた。C57BL/6雄性マウスに、化合物1−1もしくはビヒクルのいずれかを、腹腔内注射(図1)もしくは経口胃管栄養法(図2)によって与えた。20分間(i.p.に関して)もしくは40分間(p.o.に関して)の後に、上記マウスに、PCP(5mg/kg,i.p.)を注射した。10分後、上記マウスを、運動チャンバの中に入れ、水平次元でのそれらの歩行活動を、20分間にわたって、赤外線ビーム遮断によってモニターした(示されるように、5回連続、4分間の区間(INT))。図1は、化合物1−1(10mg/kg)が、上記ビヒクル+PCPコントロール(p=0.0088,n=8/群,独立サンプルt検定)に対する比較によって認められるように、PCPによって誘導される機能亢進を有意に低下させることを示す。図2は、化合物1−1が、経口胃管栄養法によって与えられる場合にも有効であることを示す(p=0.0045,n=8/群,独立サンプルt検定)。
化合物2−1によるPCP誘導性機能亢進の低下
化合物2−1(実施例2)は、図3および図4に示されるように、PCP誘導性機能亢進を低下させることが見いだされた。C57BL/6雄性マウスに、化合物2−1もしくはビヒクルのいずれかを、腹腔内注射(図3)もしくは経口胃管栄養法(図4)によって与えた。20分間(i.p.に関して)もしくは40分間(p.o.に関して)の後に、上記マウスに、PCP(5mg/kg,i.p.)を注射した。10分間後、上記マウスを運動チャンバに入れ、水平次元でのそれらの歩行活動を、20分間にわたって赤外線ビーム遮断によってモニターした(示されるように、5回連続、4分間の区間(INT))。図3は、化合物2−1(10mg/kg)が、上記ビヒクル+PCPコントロール(p=0.0021,n=8/群,独立サンプルt検定)に対する比較によって認められるように、PCPによって誘導される機能亢進を有意に低下させることを示す。図4は、化合物2−1が、経口胃管栄養法によって与えられた場合にも有効であることを示す(10mg/kg用量についてはp=0.000005,n=8/群,独立サンプルt検定)。
化合物2−1による条件回避応答の低下
化合物2−1(実施例2)は、図5に示されるように、条件回避応答(CAR)を低下させることが見いだされた。C57BL/6雄性マウスを、上記有害刺激(足のショック)を予測し回避するように、上記CARパラダイムにおいて訓練したところ、各日の30回の試行あたり、約25回の回避応答のプラトーに達した。次いで、上記マウスに、ビヒクルもしくは化合物2−1のいずれかを、上記CARパラダイムにおいて30回の試行について試験する30分前に、経口胃管栄養法を介して与えた。ビヒクル処置および化合物処置を、隔日で同じ動物に与え、回避応答を低下させることにおける化合物の効果を、被験体内比較を介して分析した(ペアt検定)。ビヒクル曝露は、これら訓練した動物の回避応答を変化させない。図5は、化合物2−1(12mg/kg)が、回避応答の回数を有意に低下させることを示す(p=0.0048,n=7/群,ペアt検定)。
化合物11−1によるPCP誘導性機能亢進の低下
化合物11−1(実施例11)は、図6に示されるように、PCP誘導性機能亢進を低下させることが見いだされた。C57BL/6雄性マウスに、化合物11−1もしくはビヒクルのいずれかを腹腔内注射によって与えた。5分後、それらにPCP(5mg/kg,i.p.)を注射した。10分後、上記マウスを運動チャンバに入れ、水平次元でのそれらの歩行活動を、20分間にわたって赤外線ビーム遮断によってモニターした(示されるように、5回連続、4分間の区間(INT))。図6は、化合物11−1(10mg/kg)が、上記ビヒクル+PCPコントロールに対する比較によって認められるように、PCPによって誘導される機能亢進を有意に低下させることを示す(p=0.00040,n=8/群,独立サンプルt検定)。
化合物34−1による条件回避応答の低下
化合物34−1(実施例34)は、図7に示されるように、条件回避応答(CAR)を低下させることが見いだされた。C57BL/6雄性マウスを、上記有害刺激(足のショック)を予測し回避するように、上記CARパラダイムにおいて訓練したところ、各日に、30回の試行につき約25〜28回の回避応答のプラトー(「訓練プラトー」)に達した。次いで、上記マウスに、ビヒクルもしくは化合物のいずれかを(試験の25分前)、経口胃管栄養法を介して与え、次いで、上記CARパラダイムにおいて30回の試行について試験した。ビヒクル処置および化合物処置を、隔日で同じ動物に与え、回避応答を低下させることにおける化合物の効果を、被験体内比較を介して分析した(ペアt検定)。ビヒクル曝露(「ビヒクル」)は、これら訓練した動物の上記回避応答を変化させない。図7は、化合物34−1が、10mg/kgにおいて回避応答の回数を有意に低下させることを示す(p=0.0003,n=7/群)。
化合物36−1による条件回避応答の低下
化合物36−1(実施例36)は、図8に示されるように、条件回避応答(CAR)を低下させることを示した。C57BL/6雄性マウスを、上記有害刺激(足のショック)を予測し回避するように、上記CARパラダイムにおいて訓練したところ、各日に、30回の試行につき約25〜28回の回避応答のプラトー(「訓練プラトー」)に達した。次いで、上記マウスに、ビヒクルもしくは化合物のいずれかを(試験の25分前)、経口胃管栄養法を介して与え、次いで、上記CARパラダイムにおいて30回の試行について試験した。ビヒクル処置および化合物処置を、隔日で同じ動物に与え、回避応答を低下させることにおける化合物の効果を、被験体内比較を介して分析した(ペア−t検定)。ビヒクル曝露(「ビヒクル」)は、これら訓練した動物の回避応答を変化させない。図8は、化合物36−1が、15mg/kgにおいて回避応答の回数を有意に低下させることを示し(p=0.000014,n=5/群)、5mg/kgおよび10mg/kgにおいては、有意性に達しないという傾向を示す。
化合物47−1による条件回避応答の低下
化合物47−1(実施例47)は、図9に示されるように、条件回避応答(CAR)を低下させることが見いだされた。C57BL/6雄性マウスを、有害刺激(足のショック)を予測し回避するように、上記CARパラダイムにおいて訓練したところ、各日に、30回の試行につき約25〜28回の回避応答のプラトー(「訓練プラトー」)に達した。次いで、上記マウスに、ビヒクルもしくは化合物のいずれかを(試験の55分前)、経口胃管栄養法を介して与え、次いで、上記CARパラダイムにおいて30回の試行について試験した。ビヒクル処置および化合物処置を、隔日で同じ動物に与え、回避応答を低下させることにおける化合物の効果を、被験体内比較を介して分析した(ペアt検定)。ビヒクル曝露(「ビヒクル」)は、これら訓練した動物の回避応答を変化させない。図9は、化合物47−1は、5mg/kgおよび10mg/kgにおいて回避応答の回数を有意に低下させることを示し(それぞれ、p=0.0002およびp=3.3 E−10,n=8/群)、2mg/kgにおいて有意性に達しなかったという傾向を示す。
化合物61−1による条件回避応答の低下
化合物61−1(実施例61)は、図10に示されるように、条件回避応答(CAR)を低下させることが見いだされた。C57BL/6雄性マウスを、有害刺激(足のショック)を予測し回避するように、上記CARパラダイムにおいて訓練したところ、各日に30回の試行につき約25〜28回の回避応答のプラトー(「訓練プラトー」)に達した。次いで、上記マウスに、ビヒクルもしくは化合物のいずれかを(試験の55分前)、経口胃管栄養法を介して与え、次いで、上記CARパラダイムにおいて30回の試行について試験した。ビヒクル処置および化合物処置を、隔日で同じ動物に与え、回避応答を低下させることにおける化合物の効果を、被験体内比較を介して分析した(ペアt検定)。ビヒクル曝露(「ビヒクル」)は、これら訓練した動物の回避応答を変化させない。図10は、化合物61−1が、2mg/kg、5mg/kgおよび10mg/kgにおいて、回避応答の回数を有意に低下させることを示す(それぞれ、p=0.015、p=0.00008およびp=2.1 E−7、n=5/群)。
化合物63−1による条件回避応答の低下
化合物63−1(実施例63)は、図11に示されるように、条件回避応答(CAR)を低下させることが見いだされた。C57BL/6雄性マウスを、有害刺激(足のショック)を予測し回避するように、上記CARパラダイムにおいて訓練したところ、各日で、30回の試行につき約25〜28回の回避応答のプラトー(「訓練プラトー」)に達した。次いで、上記マウスに、ビヒクルもしくは化合物のいずれかを(試験の55分前)、経口胃管栄養法を介して与え、次いで、上記CARパラダイムにおいて30回の試行について試験した。ビヒクル処置および化合物処置を、隔日で同じ動物に与え、回避応答を低下させることにおける化合物の効果を、被験体内比較を介して分析した(ペアt検定)。ビヒクル曝露(「ビヒクル」)は、これら訓練した動物の回避応答を変化させない。図11は、化合物63−1が、2mg/kg、5mg/kgおよび10mg/kgにおいて回避応答の回数を有意に低下させることを示す(それぞれ、p=0.0099、p=0.00011およびp=6.6 E−16,n=6/群)。
化合物49−1による条件回避応答の低下
化合物49−1(実施例49)は、図12に示されるように、条件回避応答(CAR)を低下させることが見いだされた。C57BL/6雄性マウスを、有害刺激(足のショック)を予測し回避するように、上記CARパラダイムにおいて訓練したところ、各日で、30回の試行につき約25〜28回の回避応答のプラトー(「訓練プラトー」)に達した。次いで、上記マウスに、ビヒクルもしくは化合物のいずれかを(試験の55分前)、経口胃管栄養法を介して与え、次いで、上記CARパラダイムにおいて30回の試行について試験した。ビヒクル処置および化合物処置を、隔日で同じ動物に与え、回避応答を低下させることにおける化合物の効果を、被験体内比較を介して分析した(ペアt検定)。ビヒクル曝露(「ビヒクル」)は、これら訓練した動物の回避応答を変化させない。図12は、化合物49−1が、10mg/kgにおいて回避応答の回数を有意に低下させることを示す(p=5.7 E−9,n=8/群)。
化合物65−10による条件回避応答の低下
化合物65−10(実施例65,表1)は、図13に示されるように、条件回避応答(CAR)を低下させることが見いだされた。C57BL/6雄性マウスを、有害刺激(足のショック)を予測し回避するように、上記CARパラダイムにおいて訓練したところ、各日で、30回の試行につき約25〜28回の回避応答のプラトー(「訓練プラトー」)に達した。次いで、上記マウスに、ビヒクルもしくは化合物のいずれかを(試験の55分前)、経口胃管栄養法を介して与え、次いで、上記CARパラダイムにおいて30回の試行について試験した。ビヒクル処置および化合物処置を、隔日で同じ動物に与え、回避応答を低下させることにおける化合物の効果を、被験体内比較を介して分析した(ペアt検定)。ビヒクル曝露(「ビヒクル」)は、これら訓練した動物の回避応答を変化させない。図13は、化合物65−10が、5mg/kgおよび10mg/kgにおいて回避応答の回数を有意に低下させることを示す(p=0.0145およびp=0.00011;n=8/群)。
したがって本発明は以下の項目を提供する:
(項目1)
以下の構造(I):
Aは、
R 1 は、C 1−6 アルキル、C 1−6 ハロアルキル、C 1−6 アラルキル、アリール、−(CH 2 ) n O(CH 2 ) m CH 3 もしくは−(CH 2 ) n N(CH 3 ) 2 であり;
R 2 は、(i)置換されたかもしくは置換されていないアリール、または(ii)置換されたかもしくは置換されていないヘテロシクリルであり;
R 3 は、置換されたかもしくは置換されていないアリールであり;
R 4 は、水素、C 1−6 アルキルもしくはC 1−6 ハロアルキルであり;
nは、1、2、3、4、5もしくは6であり;ならびに
mは、0、1、2、3、4、5もしくは6である、
化合物。
(項目2)
以下の構造(I−A):
(項目3)
以下の構造(I−B):
(項目4)
以下の構造(I−C):
(項目5)
以下の構造(I−D):
(項目6)
以下の構造(I−E):
(項目7)
以下の構造(I−F):
(項目8)
以下の構造(I−G):
(項目9)
以下の構造(I−H):
(項目10)
以下の構造(I−I):
(項目11)
R 4 は、水素である、項目1、3または4に記載の化合物。
(項目12)
R 4 は、C 1−6 アルキルである、項目1、3または4に記載の化合物。
(項目13)
R 4 は、メチルである、項目12に記載の化合物。
(項目14)
R 1 は、C 1−6 アルキルである、項目1〜13のいずれか1項に記載の化合物。
(項目15)
R 1 は、メチルである、項目14に記載の化合物。
(項目16)
R 1 は、エチルである、項目14に記載の化合物。
(項目17)
R 3 は、置換されたかもしくは置換されていないフェニルである、項目1〜16のいずれか1項に記載の化合物。
(項目18)
R 3 は、置換されたフェニルである、項目17に記載の化合物。
(項目19)
R 3 は、4−ブロモ−3,5−ジメトキシフェニルである、項目18に記載の化合物。
(項目20)
R 3 は、4−クロロ−3,5−ジメトキシフェニルである、項目18に記載の化合物。
(項目21)
R 3 は、3,4,5−トリメトキシフェニルである、項目18に記載の化合物。
(項目22)
R 2 は、置換されたかもしくは置換されていないアリールである、項目1〜21のいずれか1項に記載の化合物。
(項目23)
R 2 は、置換されたかもしくは置換されていないフェニルである、項目22に記載の化合物。
(項目24)
R 2 は、置換されたフェニルである、項目23に記載の化合物。
(項目25)
R 2 は、C 1−6 アルコキシで置換されたフェニルである、項目24に記載の化合物。
(項目26)
R 2 は、置換されたかもしくは置換されていないヘテロシクリルで置換されたフェニルである、項目24に記載の化合物。
(項目27)
R 2 は、置換されたヘテロシクリルで置換されたフェニルである、項目26に記載の化合物。
(項目28)
R 2 は、4−(5−メチル−1,3,4−オキサジアゾール−2−イル)フェニルである、項目27に記載の化合物。
(項目29)
R 2 は、4−(5−メチル−1,3,4−チアジアゾール−2−イル)フェニルである、項目27に記載の化合物。
(項目30)
R 2 は、置換されていないヘテロシクリルで置換されたフェニルである、項目26に記載の化合物。
(項目31)
R 2 は、4−モルホリノフェニルである、項目30に記載の化合物。
(項目32)
R 2 は、置換されたかもしくは置換されていないヘテロシクリルである、項目1〜21のいずれか1項に記載の化合物。
(項目33)
1−(5−(4−ブロモ−3,5−ジメトキシフェニル)フラン−2−イル)−2−メトキシ−2−(4−(5−メチル−1,3,4−チアジアゾール−2−イル)フェニル)エタノン;
2−メトキシ−2−(4−(5−メチル−1,3,4−オキサジアゾール−2−イル)フェニル)−1−(5−(3,4,5−トリメトキシフェニル)フラン−2−イル)エタノン;
1−(5−(4−ブロモ−3,5−ジメトキシフェニル)フラン−2−イル)−2−エトキシ−2−(4−(5−メチル−1,3,4−オキサジアゾール−2−イル)フェニル)エタノン;
1−(5−(4−クロロ−3,5−ジメトキシフェニル)フラン−2−イル)−2−メトキシ−2−(4−(5−メチル−1,3,4−オキサジアゾール−2−イル)フェニル)エタノン;
1−(5−(4−クロロ−3,5−ジメトキシフェニル)フラン−2−イル)−2−エトキシ−2−(4−(5−メチル−1,3,4−オキサジアゾール−2−イル)フェニル)エタノン;
1−(5−(4−クロロ−3,5−ジメトキシフェニル)フラン−2−イル)−2−メトキシ−2−(4−(5−メチル−1,3,4−チアジアゾール−2−イル)フェニル)エタノン;もしくは1−(5−(4−クロロ−3,5−ジメトキシフェニル)フラン−2−イル)−2−エトキシ−2−(4−(5−メチル−1,3,4−チアジアゾール−2−イル)フェニル)エタノンである、項目1に記載の化合物。
(項目34)
項目1〜33のいずれか1項に記載の化合物、および薬学的に受容可能なキャリアもしくは希釈剤を含む、薬学的組成物。
(項目35)
温血動物においてPDE10を阻害するための方法であって、該方法は、項目1〜33のいずれか1項に記載の化合物もしくは項目34に記載の薬学的組成物の有効量を、該動物に投与する工程を含む、方法。
(項目36)
神経障害を処置するための方法を必要とする温血動物において、神経障害を処置するための方法であって、該方法は、項目1〜33のいずれか1項に記載の化合物もしくは項目34に記載の薬学的組成物の有効量を、該動物に投与する工程を含む、方法。
(項目37)
上記神経障害は、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、癲癇、失語症、ベル麻痺、脳性麻痺、睡眠障害、疼痛、ツレット症候群、統合失調症、妄想性障害、双極性障害、外傷後ストレス障害、薬物誘導性精神病、パニック障害、強迫性障害、注意欠陥障害、破壊的行動障害、自閉症、うつ病、認知症、認知障害、癲癇、不眠症および多発性硬化症のような精神障害、不安障害、運動障害および/もしくは神経障害からなる群より選択される、項目36に記載の方法。
(項目38)
上記神経障害は、統合失調症である、項目37に記載の方法。
(項目39)
上記神経障害は、外傷後ストレス障害である、項目37に記載の方法。
Claims (39)
- 以下の構造(I):
Aは、
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もしくは−(CH2)nN(CH3)2であり;
R2は、(i)置換されたかもしくは置換されていないアリール、または(ii)置換されたかもしくは置換されていないヘテロシクリルであり;
R3は、置換されたかもしくは置換されていないアリールであり;
R4は、水素、C1−6アルキルもしくはC1−6ハロアルキルであり;
nは、1、2、3、4、5もしくは6であり;ならびに
mは、0、1、2、3、4、5もしくは6である、
化合物。 - 以下の構造(I−A):
- 以下の構造(I−B):
- 以下の構造(I−C):
- 以下の構造(I−D):
- 以下の構造(I−E):
- 以下の構造(I−F):
- 以下の構造(I−G):
- 以下の構造(I−H):
- 以下の構造(I−I):
- R4は、水素である、請求項1、3または4に記載の化合物。
- R4は、C1−6アルキルである、請求項1、3または4に記載の化合物。
- R4は、メチルである、請求項12に記載の化合物。
- R1は、C1−6アルキルである、請求項1〜13のいずれか1項に記載の化合物。
- R1は、メチルである、請求項14に記載の化合物。
- R1は、エチルである、請求項14に記載の化合物。
- R3は、置換されたかもしくは置換されていないフェニルである、請求項1〜16のいずれか1項に記載の化合物。
- R3は、置換されたフェニルである、請求項17に記載の化合物。
- R3は、4−ブロモ−3,5−ジメトキシフェニルである、請求項18に記載の化合物。
- R3は、4−クロロ−3,5−ジメトキシフェニルである、請求項18に記載の化合物。
- R3は、3,4,5−トリメトキシフェニルである、請求項18に記載の化合物。
- R2は、置換されたかもしくは置換されていないアリールである、請求項1〜21のいずれか1項に記載の化合物。
- R2は、置換されたかもしくは置換されていないフェニルである、請求項22に記載の化合物。
- R2は、置換されたフェニルである、請求項23に記載の化合物。
- R2は、C1−6アルコキシで置換されたフェニルである、請求項24に記載の化合物。
- R2は、置換されたかもしくは置換されていないヘテロシクリルで置換されたフェニルである、請求項24に記載の化合物。
- R2は、置換されたヘテロシクリルで置換されたフェニルである、請求項26に記載の化合物。
- R2は、4−(5−メチル−1,3,4−オキサジアゾール−2−イル)フェニルである、請求項27に記載の化合物。
- R2は、4−(5−メチル−1,3,4−チアジアゾール−2−イル)フェニルである、請求項27に記載の化合物。
- R2は、置換されていないヘテロシクリルで置換されたフェニルである、請求項26に記載の化合物。
- R2は、4−モルホリノフェニルである、請求項30に記載の化合物。
- R2は、置換されたかもしくは置換されていないヘテロシクリルである、請求項1〜21のいずれか1項に記載の化合物。
- 1−(5−(4−ブロモ−3,5−ジメトキシフェニル)フラン−2−イル)−2−メトキシ−2−(4−(5−メチル−1,3,4−チアジアゾール−2−イル)フェニル)エタノン;
2−メトキシ−2−(4−(5−メチル−1,3,4−オキサジアゾール−2−イル)フェニル)−1−(5−(3,4,5−トリメトキシフェニル)フラン−2−イル)エタノン;
1−(5−(4−ブロモ−3,5−ジメトキシフェニル)フラン−2−イル)−2−エトキシ−2−(4−(5−メチル−1,3,4−オキサジアゾール−2−イル)フェニル)エタノン;
1−(5−(4−クロロ−3,5−ジメトキシフェニル)フラン−2−イル)−2−メトキシ−2−(4−(5−メチル−1,3,4−オキサジアゾール−2−イル)フェニル)エタノン;
1−(5−(4−クロロ−3,5−ジメトキシフェニル)フラン−2−イル)−2−エトキシ−2−(4−(5−メチル−1,3,4−オキサジアゾール−2−イル)フェニル)エタノン;
1−(5−(4−クロロ−3,5−ジメトキシフェニル)フラン−2−イル)−2−メトキシ−2−(4−(5−メチル−1,3,4−チアジアゾール−2−イル)フェニル)エタノン;もしくは1−(5−(4−クロロ−3,5−ジメトキシフェニル)フラン−2−イル)−2−エトキシ−2−(4−(5−メチル−1,3,4−チアジアゾール−2−イル)フェニル)エタノンである、請求項1に記載の化合物。 - 請求項1〜33のいずれか1項に記載の化合物、および薬学的に受容可能なキャリアもしくは希釈剤を含む、薬学的組成物。
- 温血動物においてPDE10を阻害するための方法であって、該方法は、請求項1〜33のいずれか1項に記載の化合物もしくは請求項34に記載の薬学的組成物の有効量を、該動物に投与する工程を含む、方法。
- 神経障害を処置するための方法を必要とする温血動物において、神経障害を処置するための方法であって、該方法は、請求項1〜33のいずれか1項に記載の化合物もしくは請求項34に記載の薬学的組成物の有効量を、該動物に投与する工程を含む、方法。
- 前記神経障害は、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、癲癇、失語症、ベル麻痺、脳性麻痺、睡眠障害、疼痛、ツレット症候群、統合失調症、妄想性障害、双極性障害、外傷後ストレス障害、薬物誘導性精神病、パニック障害、強迫性障害、注意欠陥障害、破壊的行動障害、自閉症、うつ病、認知症、認知障害、癲癇、不眠症および多発性硬化症のような精神障害、不安障害、運動障害および/もしくは神経障害からなる群より選択される、請求項36に記載の方法。
- 前記神経障害は、統合失調症である、請求項37に記載の方法。
- 前記神経障害は、外傷後ストレス障害である、請求項37に記載の方法。
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