JP5087171B2 - 5−ヒドロキシトリプタミン−6リガンドとしての1−(アリールスルホニル)−4−(ピペラジン−1−イル)−1h−ベンズイミダゾール類 - Google Patents
5−ヒドロキシトリプタミン−6リガンドとしての1−(アリールスルホニル)−4−(ピペラジン−1−イル)−1h−ベンズイミダゾール類 Download PDFInfo
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- JP5087171B2 JP5087171B2 JP2011536412A JP2011536412A JP5087171B2 JP 5087171 B2 JP5087171 B2 JP 5087171B2 JP 2011536412 A JP2011536412 A JP 2011536412A JP 2011536412 A JP2011536412 A JP 2011536412A JP 5087171 B2 JP5087171 B2 JP 5087171B2
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- Prior art keywords
- benzimidazole
- alkyl
- compound
- sulfonyl
- piperazin
- Prior art date
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- 230000004039 social cognition Effects 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
- 239000012321 sodium triacetoxyborohydride Substances 0.000 description 1
- ABBQHOQBGMUPJH-UHFFFAOYSA-N sodium;2-hydroxybenzoic acid Chemical compound [Na+].OC(=O)C1=CC=CC=C1O ABBQHOQBGMUPJH-UHFFFAOYSA-N 0.000 description 1
- 230000003595 spectral effect Effects 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 239000008223 sterile water Substances 0.000 description 1
- 239000012258 stirred mixture Substances 0.000 description 1
- 238000003860 storage Methods 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 201000009032 substance abuse Diseases 0.000 description 1
- 231100000736 substance abuse Toxicity 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 description 1
- 238000000967 suction filtration Methods 0.000 description 1
- 150000003457 sulfones Chemical class 0.000 description 1
- 229910052717 sulfur Inorganic materials 0.000 description 1
- 239000011593 sulfur Substances 0.000 description 1
- 230000016978 synaptic transmission, cholinergic Effects 0.000 description 1
- 238000001308 synthesis method Methods 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 229940095064 tartrate Drugs 0.000 description 1
- 229950002757 teoclate Drugs 0.000 description 1
- BCNZYOJHNLTNEZ-UHFFFAOYSA-N tert-butyldimethylsilyl chloride Chemical compound CC(C)(C)[Si](C)(C)Cl BCNZYOJHNLTNEZ-UHFFFAOYSA-N 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- 125000001712 tetrahydronaphthyl group Chemical group C1(CCCC2=CC=CC=C12)* 0.000 description 1
- 125000000383 tetramethylene group Chemical group [H]C([H])([*:1])C([H])([H])C([H])([H])C([H])([H])[*:2] 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 150000003568 thioethers Chemical group 0.000 description 1
- 210000001578 tight junction Anatomy 0.000 description 1
- 238000007070 tosylation reaction Methods 0.000 description 1
- 229940066528 trichloroacetate Drugs 0.000 description 1
- YNJBWRMUSHSURL-UHFFFAOYSA-N trichloroacetic acid Chemical compound OC(=O)C(Cl)(Cl)Cl YNJBWRMUSHSURL-UHFFFAOYSA-N 0.000 description 1
- UORVGPXVDQYIDP-UHFFFAOYSA-N trihydridoboron Substances B UORVGPXVDQYIDP-UHFFFAOYSA-N 0.000 description 1
- 239000005051 trimethylchlorosilane Substances 0.000 description 1
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 1
- 229910052722 tritium Inorganic materials 0.000 description 1
- 229960000281 trometamol Drugs 0.000 description 1
- 230000031836 visual learning Effects 0.000 description 1
- RYBOXBBYCVOYNO-UHFFFAOYSA-N way-181,187 Chemical compound C1=CC=C2C(CCN)=CN(S(=O)(=O)C=3N4C=CSC4=NC=3Cl)C2=C1 RYBOXBBYCVOYNO-UHFFFAOYSA-N 0.000 description 1
- 230000003936 working memory Effects 0.000 description 1
- 150000003751 zinc Chemical class 0.000 description 1
Classifications
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Description
本発明の別の観点は、式IIの化合物を提供する:
本発明の別の観点は、式IIIの化合物を提供する:
本発明の別の観点は、式IVの化合物を提供する:
別の観点において、本発明は本発明の化合物を含む組成物、および本発明の化合物を作るための方法を提供する。さらなる観点において、本発明は対象において5−HT6を調節するための方法、およびそれを必要とする哺乳類において5−HT6に関連する障害を処置するための方法を提供する。
R1aおよびR1bはそれぞれ独立してHまたはC1−C6アルキル、C2−C6アルケニル、またはC2−C6アルキニルであり、それぞれがC1−C4アルキル、C3−C6シクロアルキル、C3−C6シクロアルケニル、C2−C6アルケニル、C2−C6アルキニル、ハロ、ニトロ、シアノ、ヒドロキシ、−N(Ra)2、−C(O)Rb、−ORc、および−S(O)pRdからなるグループから独立して選択される0〜4個の置換基で置換されており;
あるいは、R1aおよびR1bは一緒になって−(CH2)n−を形成しており;
R2はH、C1−C4アルキル、−CHOまたは−C(O)(C1−C4アルキル)であり;
R3はそれぞれの出現において独立してハロ、ニトロ、シアノ、ヒドロキシ、−N(Ra)2、C1−C6アルキル、C2−C6アルケニル、C2−C6アルキニル、C1−C6アシル、またはC1−C6アルコキシであり、ここでそれぞれのC1−C6アルキル、C1−C6アルキル、C2−C6アルケニル、C1−C6アシルまたはC1−C6アルコキシは、C1−C4アルキル、C3−C6シクロアルキル、C3−C6シクロアケニル(akenyl)、C2−C6アルケニル、C2−C6アルキニル、ハロ、ニトロ、シアノ、ヒドロキシ、−N(Ra)2、−C(O)Rb、−ORcおよび−S(O)pRdからなるグループから独立して選択される0〜4個の置換基で置換されており;
R4はH、ヒドロキシ、C1−C6アルキル、C2−C6アルケニル、C2−C6アルキニル、C1−C6アシル、C3−C6シクロアルキル、またはC3−C6シクロアルケニルであり、ここでそれぞれのC1−C6アルキル、C2−C6アルケニル、C2−C6アルキニル、C1−C6アシル、C3−C6シクロアルキル、またはC3−C6シクロアルケニルは、C1−C4アルキル、C3−C6シクロアルキル、C3−C6シクロアケニル(akenyl)、ハロ、ニトロ、シアノ、ヒドロキシ、−N(Ra)2、−C(O)Rb、−ORcおよび−S(O)pRdからなるグループから独立して選択される0〜4個の置換基で置換されており;
R5、R6、R7、R8、およびR9はそれぞれ独立してH、ハロ、ニトロ、シアノ、ヒドロキシ、S(O)pRd、−N(Ra)2、C1−C6アルキル、C1−C6アシル、C1−C6アルコキシ、C3−C6シクロアルキル、またはC3−C6シクロアルケニルであり、ここでそれぞれのC1−C6アルキル、C1−C6アシル、C1−C6アルコキシ、C3−C6シクロアルキル、またはC3−C6シクロアルケニルは、C1−C4アルキル、C3−C6シクロアルキル、C3−C6シクロアケニル(akenyl)、C2−C6アルケニル、C2−C6アルキニル、ハロ、ニトロ、シアノ、ヒドロキシ、−N(Ra)2、−C(O)Rb、−ORcおよび−S(O)pRdからなるグループから独立して選択される0〜4個の置換基で置換されており;
あるいは、R5およびR6またはR6およびR7の一方はそれらが結合している炭素原子と一緒になって0〜3個のR10基で置換された縮合したフェニル、C3−C6シクロアルキル、またはC3−C6シクロアルケニル環を形成しており;
R10はハロ、ニトロ、シアノ、ヒドロキシ、S(O)pRd、−N(Ra)2、C1−C6アルキル、C1−C6アシル、C1−C6アルコキシ、C3−C6シクロアルキル、またはC3−C6シクロアルケニルであり、ここでそれぞれのC1−C6アルキル、C1−C6アシル、C1−C6アルコキシ、C3−C6シクロアルキル、またはC3−C6シクロアルケニルは、C1−C4アルキル、C3−C6シクロアルキル、C3−C6シクロアルケニル、C2−C6アルケニル、C2−C6アルキニル、ハロ、ニトロ、シアノ、ヒドロキシ、フェニル、−N(Ra)2、−C(O)Rb、−ORc、および−S(O)pRdからなるグループから独立して選択される0〜4個の置換基で置換されており;
それぞれのRaは、独立してH、−CHO、−C(O)(C1−C4アルキル)、−CO2(C1−C4アルキル)、またはC1−C4アルキルであり、それは場合によりハロで置換されており;
それぞれのRbは、独立してH、−OH、C1−C4アルコキシ−、−NH2、−NH(C1−C4アルキル)、−N(C1−C4アルキル)2、またはC1−C4アルキルであり、それは場合によりハロで置換されており;
それぞれのRcは、独立してH、−C(O)(C1−C4アルキル)、またはC1−C4アルキルであり、それは場合によりハロで置換されており;
それぞれのRdは、独立してヒドロキシまたはC1−C4アルキルであり、それは場合によりハロで置換されており;
それぞれのpは、独立して0、1、または2であり、
mは0、1または2であり;そして
nは1または2である。
本発明の別の観点は、式IIIの化合物を提供する:
本発明の別の観点は、式IVの化合物を提供する:
1態様において:
R1aおよびR1bはそれぞれ独立してHまたはC1−C6アルキルであり;
あるいは、R1aおよびR1bは一緒になって−(CH2)n−を形成しており;
R2はHまたはC1−C4アルキルであり;
R3はそれぞれの出現において独立してヒドロキシルまたはハロであり;
R4はH、ヒドロキシ、またはC1−C6アルキルであり;
R5、R6、R7、R8、およびR9はそれぞれ独立してH、ハロ、ヒドロキシ、C1−C6アルキル、またはC1−C6アルコキシであり、ここでそれぞれのC1−C6アルキルまたはC1−C6アルコキシは0〜3個のハロで置換されており;
あるいは、R5およびR6またはR6およびR7の一方はそれらが結合している炭素原子と一緒になって0〜3個のR10基で置換された縮合したフェニル、C3−C6シクロアルキル、またはC3−C6シクロアルケニル環を形成しており;
それぞれのR10は、独立してハロ、ヒドロキシ、C1−C6アルキル、またはC1−C6アルコキシであり、ここでそれぞれのC1−C6アルキルまたはC1−C6アルコキシは0〜3個のハロで置換されており;
mは0、1または2であり;そして
nは1または2である。
1態様において、R2はHである。
1態様において、R4はC1−C6アルキルである。
1態様において、R4はメチル、エチル、プロピル、またはブチルである。
1態様において、R4はHである。
1態様において、R3はハロである。
1態様において、R1aおよびR1bは独立してHまたはC1−C4アルキルである。
1態様において、R1aおよびR1bは共にHである。
1態様において、R1aはHであり、R1bは−CH3である。
1態様において、R5はHまたはハロである。
1態様において、R5はクロロである。
1態様において、R5は場合によりハロで置換されたC1−C4アルキルである。
1態様において、R6はH、ハロ、場合によりハロで置換されたC1−C4アルキル、または場合によりハロで置換されたC1−C4アルコキシである。
1態様において、R5、R6、R7、R8、およびR9の1個は場合によりハロで置換されたC1−C4アルキルであり、R5、R6、R7、R8、およびR9の1個はハロであり、R5、R6、R7、R8、およびR9の残りの3個はHである。
1態様において、R6はフルオロである。
1態様において、R7はフルオロである。
1態様において、R7はそれぞれ場合によりハロで置換されたC1−C4アルコキシまたはC1−C4アルキルである。
1態様において、R5、R6、R7、R8、およびR9の2個はハロであり、R5、R6、R7、R8、およびR9の残りの3個はHである。
1態様において、R5およびR6はそれらが結合している炭素原子と一緒になって、それぞれ場合によりR10で置換された縮合したフェニル、C3−C6シクロアルキル、またはC3−C6シクロアルケニル環を形成している。
1態様において、R5およびR6はHである。
1態様において、R6およびR7はそれらが結合している炭素原子と一緒になって、場合によりハロで置換された縮合したフェニル、C1−C6シクロアルキル、またはC1−C6シクロアルケニル環を形成している。
1態様において、R6はOC1−C4アルキル、R8はC1−C4アルキル、およびR9はハロである。
1態様において、R6はFである。
1態様において、R7、R8、およびR9はそれぞれHである。
1態様において、式Iの化合物は1−[(3−フルオロフェニル)スルホニル]−4−(1−ピペラジニル)−1H−ベンズイミダゾール、1−[(2−フルオロフェニル)スルホニル]−4−(1−ピペラジニル)−1H−ベンズイミダゾール、1−[(3−クロロフェニル)スルホニル]−4−(1−ピペラジニル)−1H−ベンズイミダゾール、1−(1−ナフタレニルスルホニル)−4−(1−ピペラジニル)−1H−ベンズイミダゾール、および1−[(2,5−ジクロロフェニル)スルホニル]−4−(1−ピペラジニル)−1H−ベンズイミダゾールを除外する。
4−(4−メチルピペラジン−1−イル)−1−(ナフタレン−1−イルスルホニル)−1H−ベンゾ[d]イミダゾール;
1−(ナフタレン−1−イルスルホニル)−4−(ピペラジン−1−イル)−1H−ベンゾ[d]イミダゾール;
1−(フェニルスルホニル)−4−(ピペラジン−1−イル)−1H−ベンゾ[d]イミダゾール;
2−メチル−1−(1−ナフチルスルホニル)−4−ピペラジン−1−イル−1H−ベンズイミダゾール;
2−メチル−1−(フェニルスルホニル)−4−ピペラジン−1−イル−1H−ベンズイミダゾール;
2−エチル−1−(フェニルスルホニル)−4−ピペラジン−1−イル−1H−ベンズイミダゾール;
4−(4−エチルピペラジン−1−イル)−1−(フェニルスルホニル)−1H−ベンズイミダゾール;
2−ブチル−1−(フェニルスルホニル)−4−ピペラジン−1−イル−1H−ベンズイミダゾール;
2−メチル−4−(4−メチルピペラジン−1−イル)−1−(1−ナフチルスルホニル)−1H−ベンズイミダゾール;
1−[(4−クロロフェニル)スルホニル]−4−ピペラジン−1−イル−1H−ベンズイミダゾール;
1−[(2−クロロフェニル)スルホニル]−4−ピペラジン−1−イル−1H−ベンズイミダゾール;
4−(4−メチルピペラジン−1−イル)−1−(フェニルスルホニル)−1H−ベンズイミダゾール;
1−[(4−メトキシフェニル)スルホニル]−2−メチル−4−ピペラジン−1−イル−1H−ベンズイミダゾール;
2−メチル−4−ピペラジン−1−イル−1−{[3−(トリフルオロメトキシ)フェニル]スルホニル}−1H−ベンズイミダゾール;
1−[(2−クロロフェニル)スルホニル]−2−メチル−4−ピペラジン−1−イル−1H−ベンズイミダゾール;
1−[(3−クロロフェニル)スルホニル]−2−メチル−4−ピペラジン−1−イル−1H−ベンズイミダゾール;
1−[(4−クロロフェニル)スルホニル]−2−メチル−4−ピペラジン−1−イル−1H−ベンズイミダゾール;
2−メチル−1−[(3−メチルフェニル)スルホニル]−4−ピペラジン−1−イル−1H−ベンズイミダゾール;
1−[(3−クロロフェニル)スルホニル]−4−ピペラジン−1−イル−1H−ベンズイミダゾール;
1−[(4−フルオロフェニル)スルホニル]−4−ピペラジン−1−イル−1H−ベンズイミダゾール;
1−[(2−フルオロフェニル)スルホニル]−4−ピペラジン−1−イル−1H−ベンズイミダゾール;
1−[(3−フルオロフェニル)スルホニル]−4−ピペラジン−1−イル−1H−ベンズイミダゾール;
1−(2−ナフチルスルホニル)−4−ピペラジン−1−イル−1H−ベンズイミダゾール;
1−[(4−メトキシフェニル)スルホニル]−4−ピペラジン−1−イル−1H−ベンズイミダゾール;
4−ピペラジン−1−イル−1−{[4−(トリフルオロメトキシ)フェニル]スルホニル}−1H−ベンズイミダゾール;
1−[(3−フルオロフェニル)スルホニル]−2−メチル−4−ピペラジン−1−イル−1H−ベンズイミダゾール;
1−[(4−メチルフェニル)スルホニル]−4−ピペラジン−1−イル−1H−ベンズイミダゾール;
4−ピペラジン−1−イル−1−{[3−(トリフルオロメトキシ)フェニル]スルホニル}−1H−ベンズイミダゾール;
1−[(3−クロロ−4−フルオロフェニル)スルホニル]−4−ピペラジン−1−イル−1H−ベンズイミダゾール;
2−メチル−4−ピペラジン−1−イル−1−{[4−(トリフルオロメトキシ)フェニル]スルホニル}−1H−ベンズイミダゾール;
2−メチル−1−[(4−メチルフェニル)スルホニル]−4−ピペラジン−1−イル−1H−ベンズイミダゾール;
1−[(2−フルオロフェニル)スルホニル]−2−メチル−4−ピペラジン−1−イル−1H−ベンズイミダゾール;
4−ピペラジン−1−イル−1−{[2−(トリフルオロメトキシ)フェニル]スルホニル}−1H−ベンズイミダゾール;
1−[(3−メトキシフェニル)スルホニル]−4−ピペラジン−1−イル−1H−ベンズイミダゾール;
1−[(4−メチル−1−ナフチル)スルホニル]−4−ピペラジン−1−イル−1H−ベンズイミダゾール;
1−[(3−メチルフェニル)スルホニル]−4−ピペラジン−1−イル−1H−ベンズイミダゾール;
1−[(3−クロロ−2−メチルフェニル)スルホニル]−4−ピペラジン−1−イル−1H−ベンズイミダゾール;
1−[(4−フルオロフェニル)スルホニル]−2−メチル−4−ピペラジン−1−イル−1H−ベンズイミダゾール;
1−[(2−メチルフェニル)スルホニル]−4−ピペラジン−1−イル−1H−ベンズイミダゾール;
4−ピペラジン−1−イル−1−{[4−(トリフルオロメチル)フェニル]スルホニル}−1H−ベンズイミダゾール;
4−ピペラジン−1−イル−1−{[2−(トリフルオロメチル)フェニル]スルホニル}−1H−ベンズイミダゾール;
4−ピペラジン−1−イル−1−{[3−(トリフルオロメチル)フェニル]スルホニル}−1H−ベンズイミダゾール;
2−メチル−1−(2−ナフチルスルホニル)−4−ピペラジン−1−イル−1H−ベンズイミダゾール;
1−[(2−メトキシフェニル)スルホニル]−4−ピペラジン−1−イル−1H−ベンズイミダゾール;
1−[(3−メトキシフェニル)スルホニル]−2−メチル−4−ピペラジン−1−イル−1H−ベンズイミダゾール;
2−メチル−4−ピペラジン−1−イル−1−{[2−(トリフルオロメトキシ)フェニル]スルホニル}−1H−ベンズイミダゾール;
2−メチル−1−[(2−メチルフェニル)スルホニル]−4−ピペラジン−1−イル−1H−ベンズイミダゾール;
2−メチル−4−ピペラジン−1−イル−1−{[2−(トリフルオロメチル)フェニル]スルホニル}−1H−ベンズイミダゾール;
2−メチル−4−ピペラジン−1−イル−1−{[3−(トリフルオロメチル)フェニル]スルホニル}−1H−ベンズイミダゾール;
1−[(5−クロロ−1−ナフチル)スルホニル]−4−ピペラジン−1−イル−1H−ベンズイミダゾール;
2−メチル−1−[(4−メチル−1−ナフチル)スルホニル]−4−ピペラジン−1−イル−1H−ベンズイミダゾール;
1−[(2−メトキシフェニル)スルホニル]−2−メチル−4−ピペラジン−1−イル−1H−ベンズイミダゾール;
1−[(2−クロロフェニル)スルホニル]−4−(3−メチルピペラジン−1−イル)−1H−ベンズイミダゾール;
1−[(3−クロロフェニル)スルホニル]−4−(3−メチルピペラジン−1−イル)−1H−ベンズイミダゾール;
1−[(3−メチルフェニル)スルホニル]−4−(3−メチルピペラジン−1−イル)−1H−ベンズイミダゾール;
1−[(2−メトキシフェニル)スルホニル]−4−(3−メチルピペラジン−1−イル)−1H−ベンズイミダゾール;
4−(3−メチルピペラジン−1−イル)−1−{[2−(トリフルオロメトキシ)フェニル]スルホニル}−1H−ベンズイミダゾール;
1−[(3−クロロ−2−メチルフェニル)スルホニル]−4−(3−メチルピペラジン−1−イル)−1H−ベンズイミダゾール;
1−[(2−クロロフェニル)スルホニル]−2−(1−メチルエチル)−4−ピペラジン−1−イル−1H−ベンズイミダゾール;
1−[(3−クロロフェニル)スルホニル]−2−(1−メチルエチル)−4−ピペラジン−1−イル−1H−ベンズイミダゾール;
2−(1−メチルエチル)−1−(ナフタレン−1−イルスルホニル)−4−ピペラジン−1−イル−1H−ベンズイミダゾール;
1−[(5−クロロナフタレン−1−イル)スルホニル]−2−(1−メチルエチル)−4−ピペラジン−1−イル−1H−ベンズイミダゾール;
2−(1−メチルエチル)−4−ピペラジン−1−イル−1−{[2−(トリフルオロメトキシ)フェニル]スルホニル}−1H−ベンズイミダゾール;
2−(1−メチルエチル)−1−[(4−メチルナフタレン−1−イル)スルホニル]−4−ピペラジン−1−イル−1H−ベンズイミダゾール;
1−[(5−クロロ−2−メトキシフェニル)スルホニル]−4−ピペラジン−1−イル−1H−ベンズイミダゾール;
1−[(5−ブロモ−2−メトキシフェニル)スルホニル]−4−ピペラジン−1−イル−1H−ベンズイミダゾール;
1−[(2,5−ジメトキシフェニル)スルホニル]−4−ピペラジン−1−イル−1H−ベンズイミダゾール;
1−[(2−メトキシ−5−メチルフェニル)スルホニル]−4−ピペラジン−1−イル−1H−ベンズイミダゾール;
1−[(2−メトキシ−4−メチルフェニル)スルホニル]−4−ピペラジン−1−イル−1H−ベンズイミダゾール;
1−[(2−クロロ−6−メチルフェニル)スルホニル]−4−ピペラジン−1−イル−1H−ベンズイミダゾール;
1−{[2−クロロ−5−(トリフルオロメチル)フェニル]スルホニル}−4−ピペラジン−1−イル−1H−ベンズイミダゾール;
1−[(2−フルオロ−5−メチルフェニル)スルホニル]−4−ピペラジン−1−イル−1H−ベンズイミダゾール;
1−[(2−フルオロ−3−メチルフェニル)スルホニル]−4−ピペラジン−1−イル−1H−ベンズイミダゾール;
1−[(3−フルオロ−2−メトキシフェニル)スルホニル]−4−ピペラジン−1−イル−1H−ベンズイミダゾール;
1−[(2−クロロフェニル)スルホニル]−4−[(3R)−3−メチルピペラジン−1−イル]−1H−ベンズイミダゾール;
1−[(3−クロロフェニル)スルホニル]−4−[(3R)−3−メチルピペラジン−1−イル]−1H−ベンズイミダゾール;
1−[(3−クロロ−2−メチルフェニル)スルホニル]−4−[(3R)−3−メチルピペラジン−1−イル]−1H−ベンズイミダゾール;
4−[(3R)−3−メチルピペラジン−1−イル]−1−(ナフタレン−1−イルスルホニル)−1H−ベンズイミダゾール;
1−[(2−クロロフェニル)スルホニル]−4−[(3S)−3−メチルピペラジン−1−イル]−1H−ベンズイミダゾール;
1−[(3−クロロフェニル)スルホニル]−4−[(3S)−3−メチルピペラジン−1−イル]−1H−ベンズイミダゾール;
4−[(3S)−3−メチルピペラジン−1−イル]−1−(ナフタレン−1−イルスルホニル)−1H−ベンズイミダゾール;
1−[(3−クロロ−2−メチルフェニル)スルホニル]−4−[(3S)−3−メチルピペラジン−1−イル]−1H−ベンズイミダゾール;
1−[(2,3−ジフルオロフェニル)スルホニル]−4−ピペラジン−1−イル−1H−ベンズイミダゾール;
1−[(2,5−ジフルオロフェニル)スルホニル]−4−ピペラジン−1−イル−1H−ベンズイミダゾール;
1−[(2−クロロ−5−フルオロフェニル)スルホニル]−4−ピペラジン−1−イル−1H−ベンズイミダゾール;
1−[(2,6−ジクロロフェニル)スルホニル]−4−ピペラジン−1−イル−1H−ベンズイミダゾール;
1−[(3−フルオロ−2−メチルフェニル)スルホニル]−4−ピペラジン−1−イル−1H−ベンズイミダゾール;
1−[(3−クロロ−5−フルオロフェニル)スルホニル]−4−ピペラジン−1−イル−1H−ベンズイミダゾール;
1−[(2−エトキシフェニル)スルホニル]−2−メチル−4−ピペラジン−1−イル−1H−ベンズイミダゾール;
1−[(5−クロロ−2−メトキシ−4−メチルフェニル)スルホニル]−4−ピペラジン−1−イル−1H−ベンズイミダゾール;
2−メチル−4−(3−メチルピペラジン−1−イル)−1−(フェニルスルホニル)−1H−ベンズイミダゾール;
2−メチル−4−(3−メチルピペラジン−1−イル)−1−(ナフタレン−1−イルスルホニル)−1H−ベンズイミダゾール;
1−[(2−クロロフェニル)スルホニル]−2−メチル−4−(3−メチルピペラジン−1−イル)−1H−ベンズイミダゾール;
1−[(3−フルオロフェニル)スルホニル]−2−メチル−4−(3−メチルピペラジン−1−イル)−1H−ベンズイミダゾール;
1−[(3−クロロ−2−メチルフェニル)スルホニル]−2−メチル−4−(3−メチルピペラジン−1−イル)−1H−ベンズイミダゾール;
4−[(3R,5S)−3,5−ジメチルピペラジン−1−イル]−2−メチル−1−(フェニルスルホニル)−1H−ベンズイミダゾール;
4−[(3R,5S)−3,5−ジメチルピペラジン−1−イル]−2−メチル−1−(ナフタレン−1−イルスルホニル)−1H−ベンズイミダゾール;
1−[(2−クロロフェニル)スルホニル]−4−[(3R,5S)−3,5−ジメチルピペラジン−1−イル]−2−メチル−1H−ベンズイミダゾール;
4−[(3R,5S)−3,5−ジメチルピペラジン−1−イル]−1−[(3−フルオロフェニル)スルホニル]−2−メチル−1H−ベンズイミダゾール;
1−[(3−クロロ−2−メチルフェニル)スルホニル]−4−[(3R,5S)−3,5−ジメチルピペラジン−1−イル]−2−メチル−1H−ベンズイミダゾール;
6−フルオロ−1−(ナフタレン−1−イルスルホニル)−4−ピペラジン−1−イル−1H−ベンズイミダゾール;
1−[(2−クロロフェニル)スルホニル]−6−フルオロ−4−ピペラジン−1−イル−1H−ベンズイミダゾール;
6−フルオロ−1−(フェニルスルホニル)−4−ピペラジン−1−イル−1H−ベンズイミダゾール;
4−[(1S,4S)−2,5−ジアザビシクロ[2.2.1]ヘプタ−2−イル]−1−(フェニルスルホニル)−1H−ベンズイミダゾール;
4−[(1S,4S)−2,5−ジアザビシクロ[2.2.1]ヘプタ−2−イル]−1−(ナフタレン−1−イルスルホニル)−1H−ベンズイミダゾール;
1−[(2−クロロフェニル)スルホニル]−4−[(1S,4S)−2,5−ジアザビシクロ[2.2.1]ヘプタ−2−イル]−1H−ベンズイミダゾール;
4−[(1S,4S)−2,5−ジアザビシクロ[2.2.1]ヘプタ−2−イル]−1−[(3−フルオロフェニル)スルホニル]−1H−ベンズイミダゾール;
1−[(3−クロロ−2−メチルフェニル)スルホニル]−4−[(1S,4S)−2,5−ジアザビシクロ[2.2.1]ヘプタ−2−イル]−1H−ベンズイミダゾール;
4−[(1S,4S)−2,5−ジアザビシクロ[2.2.1]ヘプタ−2−イル]−2−メチル−1−(フェニルスルホニル)−1H−ベンズイミダゾール;
4−[(1S,4S)−2,5−ジアザビシクロ[2.2.1]ヘプタ−2−イル]−2−メチル−1−(ナフタレン−1−イルスルホニル)−1H−ベンズイミダゾール;
1−[(2−クロロフェニル)スルホニル]−4−[(1S,4S)−2,5−ジアザビシクロ[2.2.1]ヘプタ−2−イル]−2−メチル−1H−ベンズイミダゾール;
4−[(1S,4S)−2,5−ジアザビシクロ[2.2.1]ヘプタ−2−イル]−1−[(3−フルオロフェニル)スルホニル]−2−メチル−1H−ベンズイミダゾール;
1−[(3−クロロ−2−メチルフェニル)スルホニル]−4−[(1S,4S)−2,5−ジアザビシクロ[2.2.1]ヘプタ−2−イル]−2−メチル−1H−ベンズイミダゾール;
2−メチル−4−[(3R)−3−メチルピペラジン−1−イル]−1−(フェニルスルホニル)−1H−ベンズイミダゾール;
2−メチル−4−[(3R)−3−メチルピペラジン−1−イル]−1−(1−ナフチルスルホニル)−1H−ベンズイミダゾール;
2−メチル−4−[(3S)−3−メチルピペラジン−1−イル]−1−(フェニルスルホニル)−1H−ベンズイミダゾール;
2−メチル−4−[(3S)−3−メチルピペラジン−1−イル]−1−(1−ナフチルスルホニル)−1H−ベンズイミダゾール;
4−(3−エチルピペラジン−1−イル)−1−(1−ナフチルスルホニル)−1H−ベンズイミダゾール;
4−(3−エチルピペラジン−1−イル)−1−(フェニルスルホニル)−1H−ベンズイミダゾール;
4−(3−イソプロピルピペラジン−1−イル)−1−(フェニルスルホニル)−1H−ベンズイミダゾール;
4−(3−イソプロピルピペラジン−1−イル)−1−(1−ナフチルスルホニル)−1H−ベンズイミダゾール;
1−[(2−クロロフェニル)スルホニル]−4−(3−イソプロピルピペラジン−1−イル)−1H−ベンズイミダゾール;
4−(3−イソブチルピペラジン−1−イル)−1−(フェニルスルホニル)−1H−ベンズイミダゾール;
4−(3−イソブチルピペラジン−1−イル)−1−(1−ナフチルスルホニル)−1H−ベンズイミダゾール;
1−[(2−クロロフェニル)スルホニル]−4−(3−イソブチルピペラジン−1−イル)−1H−ベンズイミダゾール;
1−[(5−クロロ−1−ナフチル)スルホニル]−2−メチル−4−[(3S)−3−メチルピペラジン−1−イル]−1H−ベンズイミダゾール;
1−[(5−クロロ−1−ナフチル)スルホニル]−2−メチル−4−[(3R)−3−メチルピペラジン−1−イル]−1H−ベンズイミダゾール;
4−(3−メチルピペラジン−1−イル)−1−(フェニルスルホニル)−1H−ベンズイミダゾール;および
4−(3−メチルピペラジン−1−イル)−1−(1−ナフチルスルホニル)−1H−ベンズイミダゾール;またはそれらの互変異性体、立体異性体、もしくは医薬的に許容できる塩。
他の観点において、本発明は経口投与に適した医薬的に許容できるキャリヤーを提供し、その組成物は経口剤形を含む。
本発明の別の態様は、対象に式I〜IVの化合物を投与することを含む、対象における5−HT6受容体活性を調節する方法を提供し、ここで、対象において5−HT6受容体活性が調節される。
a)式IAの化合物:
と反応させ、
式ICの化合物:
ここで、R1a、R1b、およびR2〜R9は式Iにおいて定義された通りであり;
XがR2であるならば、式Iの化合物が形成され;または
Xが保護基であるならば、そのプロセスはさらに、以下を含む:
b)式ICの化合物を脱保護して脱保護された化合物を形成する;
ここで、R2がHであるならば、式Iの化合物が形成され;または
R2がH以外であるならば、そのプロセスはさらに、以下を含む:
c)GA−R2またはGA=R2をその脱保護された化合物と反応させる;
ここで、GAは活性化基であり;
ここで、式Iの化合物が形成される。
1態様において、その塩基は水素化ナトリウム(NaH)である。
1態様において、GAはハロ、トシレート、メシレート、トリフレート、またはオキソである。
本発明の別の観点において、そのプロセスはさらに、以下:
a)式IDの化合物:
と反応させる、
ここで、式IBの化合物が形成される;により式IBの化合物を調製することを含む。
1態様において、その塩基は炭酸水素ナトリウム(NaHCO3)であり、その反応工程は約100℃より上で行われる。
1態様において、R4−C(OEt)3を式IFの化合物と反応させる工程は、モンモリロナイト(montmorillonite)KSFおよびトルエンの存在下で行われる。
1態様において、その水素化の工程はH2および炭素上パラジウム(H2/Pd−C)の存在下で行われる。
(a)2,3−ジニトロアニリンを硝酸ナトリウム(NaNO2)と反応させて(2,3−ジニトロフェニル)ジアゾニウム化合物を形成する;および
(b)そのジニトロフェニル)ジアゾニウム化合物を式IHの化合物と接触させる:
1態様において、2,3−ジニトロアニリンを硝酸ナトリウム(NaNO2)と反応させる工程は、酢酸(AcOH)および臭化銅(CuBr)の存在下で行われる。
(a)アジ化ナトリウムを1,3−ジフルオロ−2−ニトロベンゼンと反応させて1−アジド−3−フルオロ−2−ニトロベンゼンを形成する;および
(b)1−アジド−3−フルオロ−2−ニトロベンゼンを式IHの化合物と接触させる:
1態様において、その接触させる工程は、N,N−ジイソプロピルエチルアミン(DIPEA)の存在下で行われる。
別の態様において、前記のプロセスの工程のいずれかは、液体クロマトグラフィー(LC)、質量分析(MS)、液体クロマトグラフィー/質量分析(LC/MS)、ガスクロマトグラフィー(GC)、ガスクロマトグラフィー/質量分析(GC/MS)、核磁気共鳴(NMR)、薄層クロマトグラフィー(TLC)、融点(MP)分析、旋光度(OR)または元素分析を含む分析工程を含む。
定義
下記の定義は、文脈が別途示さない限り本発明の化合物と関連して用いられる。一般に、所与の基の中に存在する炭素原子の数は“Cx−Cy”と指定され、ここでxおよびyはそれぞれ下限および上限である。例えば、“C1−C6”と指定される基は1から6個までの炭素原子を含む。本明細書における定義において用いられる炭素数は炭素バックボーンおよび炭素分枝を指すが、置換基、例えばアルコキシ置換基および同様のものの炭素原子は含まない。別途示さない限り、本明細書において明確に定義されていない置換基の命名法は、官能性(functionality)の末端部分を、続いて隣接する官能性を、結合の点へと向かって左から右へ名付けることにより達成される。例えば、置換基“アリールアルキルオキシカルボニル”は、基(C6−C14アリール)−(C1−C6アルキル)−O−C(O)−を指す。上記の定義は許容できない置換パターン(例えば5個のフルオロ基で置換されたメチル、単一の炭素原子上の2個のヒドロキシル基、非芳香族二重結合上のヒドロキシル基)を含むことを意図していないことは理解されている。そのような許容できない置換パターンは当業者には周知である。下記の基のそれぞれにおいて、亜群(subgroup)が多数回出現するように指定されている場合、それぞれの出現は独立に選択される。例えば、ジ(C1−C6アルキル)アミノ−、例えば(C1−C6アルキル)2N−、において、そのC1−C6アルキル基は同じまたは異なっていることができる。
アリール−は芳香族炭化水素基を指す。C6−C14アリール−基の例には、フェニル、1−ナフチル、2−ナフチル、3−ビフェン−1−イル、アントリル、テトラヒドロナフチル、フルオレニル、インダニル、ビフェニレニル、およびアセナフテニルが含まれるが、それらに限定されない。アリール基は、少なくとも1個の環が芳香族であり、結合の点が芳香族炭素原子における限り、単環式または多環式であることができる。アリール基は置換されていない、または1個以上の以下の基で置換されていることができる:C1−C6アルキル−、ハロゲン、ハロアルキル−、ヒドロキシル、ヒドロキシル(C1−C6アルキル)−、H2N−、アミノアルキル−、ジ(C1−C6アルキル)アミノ−、HO2C−、(C1−C6アルコキシ)カルボニル−、(C1−C6アルキル)カルボキシ−、ジ(C1−C6アルキル)アミド−、H2NC(O)−、(C1−C6アルキル)アミド−、またはO2N−。
“ハロアルキル−”は上記で定義されたようなアルキル基を指し、ここで水素原子の1個以上が−F、−Cl、−Br、または−Iで置き換えられている。それぞれの置換は独立に選択されることができる。C1−C6ハロアルキル−基の代表的な例には、−CH2F、−CCl3、−CF3、CH2CF3、−CH2Cl、−CH2CH2Br、−CH2CH2I、−CH2CH2CH2F、−CH2CH2CH2Cl、−CH2CH2CH2CH2Br、−CH2CH2CH2CH2I、−CH2CH2CH2CH2CH2Br、−CH2CH2CH2CH2CH2I、−CH2CH(Br)CH3、−CH2CH(Cl)CH2CH3、−CH(F)CH2CH3および−C(CH3)2(CH2Cl)が含まれるが、それらに限定されない。
“ヒドロキシ”または“ヒドロキシル”は、基HO−を指す。
“5−HT6受容体活性を調節する”は、5−HT6受容体と関係するプロセスまたはシグナル伝達事象に影響を及ぼすこと(すなわち、阻害または刺激)を指す。具体的には、5−HT6の阻害は脳におけるアセチルコリンおよびグルタメートのレベルを増大させ、一方で5−HT6受容体の作動(agonism)または刺激は結果として増大した細胞性cAMPをもたらす。
“オキソ”は原子(=O)を指す。活性化基として、‘オキソ’基は求核性アミン基による還元的アミノ化を受けてアルキルアミノまたはアミノアルキル置換基を形成することができる。好ましくは、その還元的アミノ化の段階はホウ素を含む還元剤の存在下で起こる。
対象における疾患の“処置すること”または“処置”は、その疾患を抑制することまたはその発現を止めること;その疾患の症状を改善すること;またはその疾患の後退を引き起こすことを指す。従って、本明細書で用いられる“アルツハイマー病の処置”は、アルツハイマー病と関係する症状の改善、例えばアルツハイマー病に関連する痴呆の改善またはアルツハイマー病と関係する認知機能不全の処置を含む。従って、“精神分裂病の処置”は、認知機能の向上または安定化および精神分裂病と関係する認知欠陥を改善することを含む。
療法的使用のため、式I〜IVのいずれかの薬理学的に有効な化合物は、通常はその(またはある)必須の有効成分として少なくとも1種類のそのような化合物を固体または液体の医薬的に許容できるキャリヤーと共に、ならびに場合により医薬的に許容できる補助剤(adjutants)および賦形剤と共に含む医薬組成物として、標準的および一般的に用いられる技法を用いて投与されるであろう。
1態様において、有効量の本発明の化合物またはその医薬的に許容できる塩および有効量の別の療法薬を同じ組成物内に含む組成物を投与することができる。
スキーム1は、式Iの化合物およびその中間体の調製を記述する。
下記の方法のそれぞれは上記で示したスキーム1に対応しており、ここでR1はHであり、mは0であり、GPはBocである。その化合物および/または中間体は、Onyx Monolithic C18カラム(100×3.0mm)を有するAgilent HPLCおよびHewlett-Packard質量分析計:溶媒系:水中10〜100%アセトニトリル、流速:1.8mL/分、分子量範囲200〜700において行われたLC質量分析により特性づけられた。その化合物において、400MHz Varian NMR装置(カリフォルニア州パロアルト)を用いて核磁気共鳴(NMR)分析を行った。スペクトルの基準は、TMSまたは溶媒の既知の化学シフトのどちらかである。一部の化合物試料は、試料の可溶性の増大を促進するために高温(例えば75℃)で流される。
2,3−ジニトロアニリンはN−(2,3−ジニトロフェニル)アセトアミドから調製することができ、それは今度は市販の材料である3−ニトロアセトアミドから下記のスキームで記述されているように調製される:
−3℃で冷却された濃硫酸(216mL)および90%(発煙)硝酸(216mL)の攪拌混合物に、3−ニトロアセトアニリド(12.0g)を一部ずつ20分間かけて添加した。その混合物を−10℃で30分間攪拌した。次いでその反応物を1時間かけて室温まで温まらせ、砕いた氷(600mL)の上に注ぐと黄色固体が得られた。結果として得られた沈殿物を吸引により集めた。得られた固体を沸騰しているエタノール(125mL)中で溶解させ、この溶液を2時間放置した。得られた薄黄色の針状物質を濾過し、エタノールで洗浄して空気乾燥させると望まれる生成物(3.1g,21%)が得られた。Arnold T. Nielsen, Ronald L. Atkins, William P. Norris, Clifford L. Coon, Michael E. Sitzmann J. Org. Chem.; 1980; 45(12); 2341-2347(本明細書に援用する)を参照。化学式:C8H7N3O5 分子量:225.16;MS(ES) m/z226。
メタノール(200mL)中のN−(2,3−ジニトロフェニル)アセトアミド(3.0 g)の溶液に、ナトリウムメトキシド(72mg)を添加した。その攪拌溶液を還流状態で3時間加熱した。その溶液に水を添加し(300mL)、黄色固体の沈殿物を集めて乾燥させると望まれる生成物(2.27g,93%)が得られた。化学式:C6H5N3O4 分子量:183.12;MS(ES) m/z184。
化合物3は下記のスキームに従って調製することができる:
35 mLの氷酢酸中の2,3−ジニトロアニリン(2.27g,12.4mmol)の溶液を、濃硫酸(7mL)中の亜硝酸ナトリウム(0.95g,13.8mmol)の攪拌および冷却された溶液に、反応物の温度を15〜20℃に保ちながら滴加した。次いで得られたジアゾニウム溶液を、5分間の期間をかけて、75℃〜80℃で加熱したHBr(48%)(10mL)および水(10mL)の混合物中の臭化銅(1.85g,12.9mmol)の攪拌溶液に添加した。添加の後、その混合物を室温まで冷却し、水(500mL)に添加した。その溶液から薄緑色の粉末を濾過し、室温において真空中で乾燥させると、望まれる生成物である1−ブロモ−2,3−ジニトロベンゼン(3.0g,99%)が得られた。この生成物をそれ以上精製せずにその後の反応において用いた。Donald L. Vivian J. Org. Chem. 1956, 21, 1188を参照。
1−ブロモ−2,3−ジニトロベンゼン(1.0g,4.05mmol)、N−Boc−ピペラジン(0.90g,4.86mmol)、炭酸セシウム(1.58g,4.86mmol)、BINAP(0.113g,0.182mmol)、およびトリス(ジベンジリデンアセトン)ジパラジウム(0.111g,0.121mmol)のトルエン(12.0mL)中における混合物を、還流状態で4時間加熱した。トルエンを蒸発させ、残留物をジクロロメタン(100mL)中で溶解させ、水で洗浄し、硫酸ナトリウムで乾燥させ、濾過した。ジクロロメタンを蒸発させ、残留物をシリカゲル上でヘキサン/酢酸エチル(30−70% EtOAc)を用いてクロマトグラフィー処理すると、望まれる生成物3(0.37g,26%)が得られた。MS(ES) m/z353。Shashank Shekhar, Per Ryberg, John F. Hartwig, Jinu S. Mathew, Donna G. Blackmond, Eric R. Strieter, and Stephen L. Buchwald J. Am. Chem. Soc. 2006 128, 3584-3591(本明細書に援用する)を参照。
tert−ブチル 4−(2,3−ジニトロフェニル)ピペラジン−1−カルボキシレート(3)をエタノール(8.0mL)中で溶解させ、これに10% Pd−C(30mg)を添加する。この混合物の水素化を、Parr装置(Parr apparatus)上で、33psiにおいて一夜かけて完了させた。混合物をCELITE(商標)を通して濾過し、シリカゲルカラム上でジクロロメタンおよび酢酸エチル(15〜50% EtOAc)を用いてクロマトグラフィー処理すると、望まれる生成物が薄茶色の非晶質の固体として得られる(0.129g,79%); MS(ES) m/z293。
1−アジド−3−フルオロ−2−ニトロベンゼン(0.35g;1.9mmol)のDMSO(2.0mL)中における溶液に、Boc−ピペラジン(0.40mL;1.2当量)およびN−Boc−ピペラジン(1.2当量)を添加した。その溶液を60℃で6時間加熱した。その反応が完了した際、溶液を水(50mL)の中に注ぎ、酢酸エチルの中に抽出した。その有機溶液をNa2SO4で乾燥させ、濾過し、減圧下で蒸発させた。残留物をシリカ上でジクロロメタン/メタノールを用いてクロマトグラフィー処理する。精製された生成物5をジエチルエーテルおよびヘキサンから結晶化する; MS(ES) m/z348.2;
化合物(5)からの化合物tert−ブチル 4−(2,3−ジアミノフェニル)ピペラジン−1−カルボキシレート(6)の調製(方法B):
式Iの化合物は、あるいは化合物8の調製に関して記述した一般的手順に従って中間体10から調製することができる。
4−アミノベンズイミダゾール、ビス(クロロエチル)アルキルアミンの混合物を、炭酸水素ナトリウム(3.0当量)と共に25mLの1−ブタノール中で攪拌する。その混合物を還流温度(115℃の油浴)で一夜加熱した。その混合物を冷却し、Celite(商標)のパッドを通して濾過し、濾液を真空下で濃縮した。その粗製の残留物をシリカゲルのカラム上で精製すると、望まれる生成物が得られた。WO 2006/009734; Villemin et al., Synthetic Communications 1996 26 (15), 2895-2899;およびMarcos et al., Tetrahedron 1991 47(35), 7459-64(本明細書に援用する)において提供されている合成方法論も参照。
実施例1:4−(4−メチルピペラジン−1−イル)−1−(ナフタレン−1−イルスルホニル)−1H−ベンゾ[d]イミダゾール
生物学的アッセイ:
5−HT 6 結合アッセイ
10細胞スタック(10-cell stacks)で接着して成長した、セロトニン5−HT6受容体亜型を発現するCHO-Dukx-A2細胞(クローン50−7)を、5mM EDTAを含むPBS緩衝液中で一般に用いられる細胞回収プロトコルを用いて剥がして回収し、続いて2000rpmで10分間遠心分離し(上清を廃棄する)、またはそれはApplied Cell Sciences (メリーランド州ロックビル)により湿細胞ペレットとして提供される。そのペレットを、MgCl2およびCaCl2を含む十分なPBS緩衝液(GIBCO 14040-133)で穏やかに再懸濁して、約40×106細胞/mlの最終濃度を得る。その細胞懸濁液を微量遠心チューブの中に小分けにし、2000rpmで10分間遠心分離し、上清を廃棄し、乾燥ペレットとして−80℃で保管する。200μlの希釈したブラッドフォード試薬と混合した5μlの溶解液において、ウシ血漿ガンマグロブリンを標準として用いてタンパク質を測定する。
{(結合−NSB)/(総計−NSB)}×100=%総計
10種類の濃度からの%結合データの回帰分析を、GraphPad Prism、XL Fitまたは均等なソフトウェアで行う。4パラメーターロジスティック曲線当てはめモデルを用いてIC50値を計算し、下記のチェン−プルソフ(Cheng-Prusoff)方程式によりKi値を計算する:
Ki=IC50/(1+L/Kd)
ここで、Lは用いた放射活性リガンドのnM濃度であり、Kdはそのリガンドのその受容体に関する解離定数である。SPA結合形式での[3H]−LSDに関するKdは約3 nMである。
Claims (8)
- 2−メチル−1−(フェニルスルホニル)−4−ピペラジン−1−イル−1H−ベンズイミダゾール、またはその医薬的に許容できる塩である化合物。
- 請求項1に記載の化合物および医薬的に許容できるキャリヤーを含む組成物。
- 対象における5−HT6受容体機能の調節における使用のための、請求項2に記載の組成物。
- 薬物としての使用のための、請求項2に記載の組成物。
- 5−HT 6 に関連する障害の処置における使用ための組成物であって、5−HT6に関連する障害が中枢神経系(CNS)疾患または障害である、請求項2に記載の組成物。
- 5−HT6に関連する障害が、精神病、不安、抑うつ、てんかん、強迫性障害、片頭痛、認知障害、睡眠障害、摂食障害、食欲不振、肥満、大食、過食障害、パニック発作、薬物乱用からの離脱の結果もたらされる障害、精神分裂病と関係する認知欠陥、胃腸障害、過敏性腸症候群、記憶障害、アルツハイマー病、パーキンソン病、ハンチントン舞踏病、精神分裂病、注意欠陥多動性障害、欠陥的神経成長により特徴付けられる神経変性疾患、および疼痛から選択される、請求項5に記載の組成物。
- 5−HT6に関連する障害が、抑うつ、認知障害、精神分裂病と関係する認知欠陥、記憶障害、アルツハイマー病と関係する認知機能不全、および疼痛から選択される、請求項6に記載の組成物。
- 5−HT6に関連する障害が、アルツハイマー病と関係する認知機能不全である、請求項6に記載の組成物。
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BRPI0515489A (pt) * | 2004-09-20 | 2008-07-29 | Xenon Pharmaceuticals Inc | derivados heterocìclicos e sua utilização como inibidores de estearoil-coa desaturase |
CA2580781A1 (en) * | 2004-09-20 | 2006-03-30 | Xenon Pharmaceuticals Inc. | Bicyclic heterocyclic derivatives and their use as inhibitors of stearoyl-coa-desaturase (scd) |
EP1799668A1 (en) * | 2004-09-20 | 2007-06-27 | Xenon Pharmaceuticals Inc. | Heterocyclic derivatives and their use as mediators of stearoyl-coa desaturase |
AU2005329423A1 (en) * | 2004-09-20 | 2006-09-28 | Xenon Pharmaceuticals Inc. | Heterocyclic derivatives and their use as stearoyl-CoA desaturase inhibitors |
CN104557726B (zh) * | 2013-10-19 | 2019-05-24 | 广东东阳光药业有限公司 | 芳杂环类衍生物及其在药物上的应用 |
WO2016004882A1 (en) | 2014-07-08 | 2016-01-14 | Sunshine Lake Pharma Co., Ltd. | Aromatic heterocyclic derivatives and pharmaceutical applications thereof |
WO2017052394A1 (en) | 2015-09-23 | 2017-03-30 | Uniwersytet Jagielloński | Imidazopyridine compounds and their use as 5-ht6 receptor ligands |
EP3530651A1 (en) | 2018-02-21 | 2019-08-28 | Adamed sp. z o.o. | Indole and benzimidazole derivatives as dual 5-ht2a and 5-ht6 receptor antagonists |
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JP3155008B2 (ja) | 1994-07-26 | 2001-04-09 | ファイザー・インコーポレーテッド | セロトニンアゴニストおよびアンタゴニストとしての4−インドール誘導体 |
US5849759A (en) | 1995-12-08 | 1998-12-15 | Berlex Laboratories, Inc. | Naphthyl-substituted benzimidazole derivatives as anti-coagulants |
DZ2376A1 (fr) | 1996-12-19 | 2002-12-28 | Smithkline Beecham Plc | Dérivés de sulfonamides nouveaux procédé pour leurpréparation et compositions pharmaceutiques les c ontenant. |
ATE296811T1 (de) | 1997-07-11 | 2005-06-15 | Smithkline Beecham Plc | Sulfonamid-derivate als 5-ht6 receptor antagonisten und verfahren zu ihrer herstellung |
GB9716656D0 (en) | 1997-08-07 | 1997-10-15 | Zeneca Ltd | Chemical compounds |
DE69906397T2 (de) | 1998-01-16 | 2004-02-19 | F. Hoffmann-La Roche Ag | Benzosulfonderivate |
US6251893B1 (en) | 1998-06-15 | 2001-06-26 | Nps Allelix Corp. | Bicyclic piperidine and piperazine compounds having 5-HT6 receptor affinity |
CA2338311C (en) | 1998-08-10 | 2007-01-23 | Michael E. Garst | Prodrugs of the pyridyl methyl sulfinyl benzimidazoles |
GB9818916D0 (en) | 1998-08-28 | 1998-10-21 | Smithkline Beecham Plc | Use |
SE0002754D0 (sv) | 2000-07-21 | 2000-07-21 | Pharmacia & Upjohn Ab | New pharmaceutical combination formulation and method of treatment with the combination |
SE0003810D0 (sv) * | 2000-10-20 | 2000-10-20 | Pharmacia Ab | Novel compounds their use and preparations |
PL361887A1 (en) | 2000-10-20 | 2004-10-04 | Biovitrum Ab | 2-, 3-, 4-, or 5-substituted-n1-(benzensulfonyl)indoles and their use in therapy |
NZ525592A (en) * | 2000-11-02 | 2004-07-30 | Wyeth Corp | 1-Aryl- or 1-alkylsufonyl-heterocyclylbenzazoles as 5-hydroxytryptamine-6 ligands |
US7034029B2 (en) | 2000-11-02 | 2006-04-25 | Wyeth | 1-aryl- or 1-alkylsulfonyl-heterocyclylbenzazoles as 5-hydroxytryptamine-6 ligands |
BR0210411A (pt) * | 2001-06-15 | 2004-08-17 | Hoffmann La Roche | Derivados 4-piperazinilindol com afinidade para o receptor 5-ht6 |
CN1321110C (zh) * | 2001-06-15 | 2007-06-13 | 弗·哈夫曼-拉罗切有限公司 | 具有5-ht6受体亲和力的4-哌嗪基吲哚衍生物 |
WO2003026665A1 (en) | 2001-09-26 | 2003-04-03 | Bayer Pharmaceuticals Corporation | 2-phenylamino-4-(5-pyrazolylamino)-pyrimidine derivatives as kinase inhibitors, in particular, src kinase inhibitors |
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JP4926943B2 (ja) | 2004-04-13 | 2012-05-09 | シンタ ファーマシューティカルズ コーポレーション | Il−12産生を阻害する二塩 |
AU2005267798A1 (en) | 2004-07-28 | 2006-02-09 | Irm Llc | Compounds and compositions as modulators of steroid hormone nuclear receptors |
US7713954B2 (en) | 2004-09-30 | 2010-05-11 | Roche Palo Alto Llc | Compositions and methods for treating cognitive disorders |
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