JP2020536941A - 疼痛及び疼痛に関連する状態を治療するためのプロパンアミン誘導体 - Google Patents
疼痛及び疼痛に関連する状態を治療するためのプロパンアミン誘導体 Download PDFInfo
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- JP2020536941A JP2020536941A JP2020521287A JP2020521287A JP2020536941A JP 2020536941 A JP2020536941 A JP 2020536941A JP 2020521287 A JP2020521287 A JP 2020521287A JP 2020521287 A JP2020521287 A JP 2020521287A JP 2020536941 A JP2020536941 A JP 2020536941A
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- Prior art keywords
- methyl
- methylamino
- phenyl
- phenylpropoxy
- radical
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- 125000004213 tert-butoxy group Chemical group [H]C([H])([H])C(O*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- VKZADARPOUVUIA-UHFFFAOYSA-N tert-butyl n-(3-hydroxy-3-phenylpropyl)-n-methylcarbamate Chemical compound CC(C)(C)OC(=O)N(C)CCC(O)C1=CC=CC=C1 VKZADARPOUVUIA-UHFFFAOYSA-N 0.000 description 1
- 125000001973 tert-pentyl group Chemical group [H]C([H])([H])C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
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- TUQOTMZNTHZOKS-UHFFFAOYSA-N tributylphosphine Chemical compound CCCCP(CCCC)CCCC TUQOTMZNTHZOKS-UHFFFAOYSA-N 0.000 description 1
- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 description 1
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
- C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
- C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
- C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
- C07D239/48—Two nitrogen atoms
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- A—HUMAN NECESSITIES
- 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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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C217/00—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton
- C07C217/76—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having amino groups bound to carbon atoms of six-membered aromatic rings and etherified hydroxy groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C233/00—Carboxylic acid amides
- C07C233/01—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
- C07C233/16—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms
- C07C233/24—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by a carbon atom of a six-membered aromatic ring
- C07C233/25—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by a carbon atom of a six-membered aromatic ring having the carbon atom of the carboxamide group bound to a hydrogen atom or to a carbon atom of an acyclic saturated carbon skeleton
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C233/00—Carboxylic acid amides
- C07C233/64—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings
- C07C233/67—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C233/00—Carboxylic acid amides
- C07C233/64—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings
- C07C233/76—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by doubly-bound oxygen atoms
-
- 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
- C07C235/46—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 having the nitrogen atoms of the carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
-
- 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
- C07C235/50—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 having the nitrogen atom of at least one of the carboxamide groups bound to an acyclic carbon atom of a hydrocarbon radical substituted by nitrogen atoms not being part of nitro or nitroso groups
-
- 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
- C07C235/56—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 having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a six-membered aromatic ring
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C237/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups
- C07C237/02—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton
- C07C237/04—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being acyclic and saturated
- C07C237/06—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being acyclic and saturated having the nitrogen atoms of the carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C237/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups
- C07C237/28—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atom of at least one of the carboxamide groups bound to a carbon atom of a non-condensed six-membered aromatic ring of the carbon skeleton
- C07C237/40—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atom of at least one of the carboxamide groups bound to a carbon atom of a non-condensed six-membered aromatic ring of the carbon skeleton having the nitrogen atom of the carboxamide group bound to a carbon atom of a six-membered aromatic ring
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members 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 ring carbon atoms
- C07D211/56—Nitrogen atoms
- C07D211/58—Nitrogen atoms attached in position 4
-
- C—CHEMISTRY; METALLURGY
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Abstract
Description
1)前臨床調査は、ガバペンチノイドが、下行性のノルアドレナリン作動性系の脊髄上位の活性化により、疼痛が関連する挙動を減弱させたことを示してきた(Tanabe et al.;J.Neuroosci.Res.;2008;Hayashida,K.;Eur.J.Pharmacol.;2008;598;21−26)。その結果、脊髄のα2−アドレナリン作動性受容体のNAによって誘発される活性化によって媒介されるα2δ−1が関連する痛覚消失は、NETの阻害によって可能とすることができる。神経因性疼痛の前臨床モデルにおける組合せ研究からのいくつかの証拠が存在する。ガバペンチンを伴う経口デュロキセチンは、ラットにおける神経傷害によって誘発される過敏性を低減させる添加物であった(Hayashida;2008)。ガバペンチン及びノルトリプチリン薬の組合せは、口腔顔面疼痛及び末梢神経傷害モデルに供されたマウスにおいて相乗的であった(Miranda,H.F.et al.;J.Orofac.Pain;2013;27;361−366;Pharmacology;2015;95;59−64)。
2)NET及びα2δ−1の薬物モジュレーションは、それぞれ抗うつ効果及び抗不安効果を生じさせることが示されてきた(Frampton,J.E.;CNS Drugs;2014;28;835−854;Hajos,M.et al.;CNS Drug Rev.;2004;10;23−44)。その結果、VGCCのNET及びα2δ−1サブユニットを阻害した二重薬物は、身体的疼痛及び気分の変容の可能性の両方に対して直接作用することにより、疼痛が関連する気分の障害も安定化させ得る。
(式中、
R1及びR’1は、水素原子及び分岐状若しくは非分岐状C1〜6アルキルラジカルから独立に選択され、
R2は、ハロゲン原子で任意に置換されている6員アリールラジカル、分岐状若しくは非分岐状C1〜6−アルキルラジカル、分岐状若しくは非分岐状C1〜6−アルコキシラジカル、C1〜6−ハロアルコキシラジカル、C1〜6−ハロアルキルラジカル又はヒドロキシルラジカル;又はN、O及びSから選択される少なくとも1個のヘテロ原子を有する置換若しくは非置換の5員若しくは6員ヘテロアリールラジカルであり、
nは、1であり、
mは、0又は1であり、
Wは、−(CH2)p−;−C(O)−;又は結合であり、
pは、1又は2であり、
Zは、NR3R4であり、
R3は、水素原子;分岐状若しくは非分岐状C1〜6アルキルラジカル;ベンジルラジカル;又はフェニルラジカルであり、
R4は、ハロゲン原子で任意に置換されている分岐状若しくは非分岐状C1〜6アルキルラジカル、ヒドロキシルラジカル、分岐状若しくは非分岐状C1〜6アルコキシラジカル、又は−NR4aR4bラジカル;−(CH2)s−ヘテロアリールラジカルであって、ヘテロアリール基が、−NR4cR4dラジカルで任意に置換されている、ヘテロ原子として少なくとも1個の窒素原子を有する5員若しくは6員環であり、sは、0、1若しくは2である、−(CH2)s−ヘテロアリールラジカル;R4eで任意に置換されているヘテロシクロアルキルラジカル;−(CH2)r−アリールラジカルであって、アリール基が、少なくとも1個のR5ラジカルで任意に置換されている6員環であり、rは、0、1若しくは2である、−(CH2)r−アリールラジカル;又は−C(O)R6ラジカルであり、
R4a、R4b、R4c、R4d及びR4eは、水素原子及び分岐状若しくは非分岐状C1〜6アルキルラジカルから独立に選択され、
R5は、水素原子;ヒドロキシルラジカル;分岐状若しくは非分岐状C1〜6−アルコキシラジカル;−(CH2)j−NR5aR5bラジカル;−NR5cR5dラジカル;又はR5eで任意に置換されている、ヘテロ原子として1個若しくは複数のN及び/若しくはOを含有する5員ヘテロ芳香族環であり、
R5a、R5b、R5c、R5d及びR5eは独立に、水素原子又は分岐状若しくは非分岐状C1〜6アルキルラジカルであり、
jは、0又は1であり、
R6は、分岐状若しくは非分岐状C1〜6アルキルラジカル;−(CH2)q−NR6aR6bラジカル;又はO及びNから選択される少なくとも1個のさらなるヘテロ原子を任意に含有し、且つ少なくとも1個のR7で任意に置換されている、5員若しくは6員窒素含有ヘテロアリール環;又は少なくとも1個のR8で任意に置換されている6員アリール環であり、
R6a及びR6bは、水素原子及び分岐状若しくは非分岐状C1〜6アルキルラジカルから独立に選択され、
qは、0、1、2、3又は4であり、
R7は、水素原子、分岐状若しくは非分岐状C1〜6−アルコキシラジカル、分岐状若しくは非分岐状C1〜6−アルキルチオラジカル;−NR7aR7bラジカル;並びにO、N及びSから選択される少なくとも1個のヘテロ原子を有する置換若しくは非置換の5員ヘテロシクロアルキル環から選択され、
R7a及びR7bは、水素原子及び分岐状若しくは非分岐状C1〜6アルキルラジカルから独立に選択され、
R8は、水素原子、ハロゲン原子、分岐状若しくは非分岐状C1〜6−アルキルラジカル又は−(CH2)t−NR8aR8bラジカルであり、
tは、0又は1であり、
R8a及びR8bは、水素原子及び分岐状若しくは非分岐状C1〜6アルキルラジカルから独立に選択される)
の化合物又はその薬学的に許容される塩、異性体、プロドラッグ若しくは溶媒和物に関する。
(式中、
R1及びR’1は、水素原子及び分岐状若しくは非分岐状C1〜6アルキルラジカルから独立に選択され、
R2は、ハロゲン原子で任意に置換されている6員アリールラジカル、分岐状若しくは非分岐状C1〜6−アルキルラジカル、分岐状若しくは非分岐状C1〜6−アルコキシラジカル、C1〜6−ハロアルコキシラジカル、C1〜6−ハロアルキルラジカル又はヒドロキシルラジカル;又はN、O及びSから選択される少なくとも1個のヘテロ原子を有する置換若しくは非置換の5員若しくは6員ヘテロアリールラジカルであり、
nは、1であり、
mは、0又は1であり、
Wは、−(CH2)p−;−C(O)−;又は結合であり、
pは、1又は2であり、
Zは、NR3R4であり、
R3は、水素原子;分岐状若しくは非分岐状C1〜6アルキルラジカル;ベンジルラジカル;又はフェニルラジカルであり、
R4は、ハロゲン原子で任意に置換されている分岐状若しくは非分岐状C1〜6アルキルラジカル、ヒドロキシルラジカル、分岐状若しくは非分岐状C1〜6アルコキシラジカル、又は−NR4aR4bラジカル;−(CH2)s−ヘテロアリールラジカルであって、ヘテロアリール基が、−NR4cR4dラジカルで任意に置換されている、ヘテロ原子として少なくとも1個の窒素原子を有する5員若しくは6員環であり、sが、0、1若しくは2である、−(CH2)s−ヘテロアリールラジカル;R4eで任意に置換されているヘテロシクロアルキルラジカル;−(CH2)r−アリールラジカルであって、アリール基が、少なくとも1個のR5ラジカルで任意に置換されている6員環であり、rは、0、1若しくは2である、−(CH2)r−アリールラジカル;又は−C(O)R6ラジカルであり、
R4a、R4b、R4c、R4d及びR4eは、水素原子及び分岐状若しくは非分岐状C1〜6アルキルラジカルから独立に選択され、
R5は、水素原子;ヒドロキシルラジカル;分岐状若しくは非分岐状C1〜6−アルコキシラジカル;−(CH2)j−NR5aR5bラジカル;−NR5cR5dラジカル;又はR5eで任意に置換されている、ヘテロ原子として1個若しくは複数のN及び/若しくはOを含有する5員ヘテロ芳香族環であり、
R5a、R5b、R5c、R5d及びR5eは独立に、水素原子又は分岐状若しくは非分岐状C1〜6アルキルラジカルであり、
jは、0又は1であり、
R6は、分岐状若しくは非分岐状C1〜6アルキルラジカル;−(CH2)q−NR6aR6bラジカル;又はO及びNから選択される少なくとも1個のさらなるヘテロ原子を任意に含有し、且つ少なくとも1個のR7で任意に置換されている、5員若しくは6員窒素含有ヘテロアリール環;又は少なくとも1個のR8で任意に置換されている6員アリール環であり、
R6a及びR6bは、水素原子及び分岐状若しくは非分岐状C1〜6アルキルラジカルから独立に選択され、
qは、0、1、2、3又は4であり、
R7は、水素原子、分岐状若しくは非分岐状C1〜6−アルコキシラジカル、分岐状若しくは非分岐状C1〜6−アルキルチオラジカル;−NR7aR7bラジカル;並びにO、N及びSから選択される少なくとも1個のヘテロ原子を有する置換若しくは非置換の5員ヘテロシクロアルキル環から選択され、
R7a及びR7bは、水素原子及び分岐状若しくは非分岐状C1〜6−アルキルラジカルから独立に選択され、
R8は、水素原子、ハロゲン原子、分岐状若しくは非分岐状C1〜6−アルキルラジカル又は−(CH2)t−NR8aR8bラジカルであり、
tは、0又は1であり、
R8a及びR8bは、水素原子及び分岐状若しくは非分岐状C1〜6−アルキルラジカルから独立に選択される)、
の化合物又はその薬学的に許容される塩、異性体、プロドラッグ若しくは溶媒和物に関する。
・−NR4aR4bラジカルで任意に置換されているC1〜6アルキルラジカル、好ましくは、メチル又はエチル;
・
・ラジカル:
・−C(O)R6ラジカルであり、
式中、R4a、R4b、R4c、R4d、R4e、R5及びR6は、上記で定義した通りである。
R1及びR’1は、水素原子及び分岐状若しくは非分岐状C1〜6アルキルラジカルから独立に選択され、
R2は、ハロゲン原子で任意に置換されているフェニルラジカル、分岐状若しくは非分岐状C1〜6−アルキルラジカル、分岐状若しくは非分岐状C1〜6−アルコキシラジカル、C1〜6−ハロアルコキシラジカル、C1〜6−ハロアルキルラジカル又はヒドロキシルラジカル;又は置換若しくは非置換のチオフェンラジカルであり、
nは、1であり、
mは、0又は1であり、
Wは、−(CH2)p−;−C(O)−;又は結合であり、
pは、1又は2であり、
Zは、NR3R4であり、
R3は、水素原子;分岐状若しくは非分岐状C1〜6アルキルラジカル;ベンジルラジカル;又はフェニルラジカルであり、
R4は、
・−NR4aR4bラジカルで任意に置換されている分岐状若しくは非分岐状C1〜6アルキルラジカル、好ましくは、メチル又はエチル;
・
・ラジカル:
・−C(O)R6ラジカルであり、
R4a、R4b、R4c、R4d及びR4eは、水素原子及び分岐状若しくは非分岐状C1〜6アルキルラジカルから独立に選択され、
R5は、水素原子;分岐状若しくは非分岐状C1〜6アルコキシラジカル;−(CH2)j−NR5aR5bラジカル、−NR5cR5dラジカル及び基:
R5a、R5b、R5c、R5d及びR5eは独立に、水素原子又は分岐状若しくは非分岐状C1〜6アルキルラジカルであり、
jは、0又は1であり、
R6は、分岐状若しくは非分岐状C1〜6アルキルラジカル、好ましくは、メチル、エチル又はプロピル;−(CH2)q−NR6aR6bラジカル及び:
R6a及びR6bは、H及びC1〜6アルキルから独立に選択され、
qは、0、1、2、3又は4であり、
R7は、水素原子、メトキシラジカル;メチルチオラジカル、−NR7aR7bラジカル及び下記の基:
R7a及びR7bは、H及びC1〜6アルキルラジカルから独立に選択され、
R8は、水素原子、ハロゲン原子、好ましくは、F、Cl若しくはBr;又は−(CH2)t−NR8aR8bラジカルであり、
tは、0又は1であり、
R8a及びR8bは、H及びC1〜6アルキルから独立に選択される)
の化合物又はその薬学的に許容される塩、異性体、プロドラッグ若しくは溶媒和物によって表される。
[1]3−(3−((ベンジル(エチル)アミノ)メチル)フェノキシ)−N−メチル−3−(チオフェン−2−イル)プロパン−1−アミン、
[2]3−(3−((ベンジルアミノ)メチル)フェノキシ)−N−メチル−3−(チオフェン−2−イル)プロパン−1−アミン、
[3]N−メチル−3−(3−((メチルアミノ)メチル)フェノキシ)−3−(チオフェン−2−イル)プロパン−1−アミン、
[4]3−(3−((ジメチルアミノ)メチル)フェノキシ)−N−メチル−3−(チオフェン−2−イル)プロパン−1−アミン、
[5]3−(3−((エチルアミノ)メチル)フェノキシ)−N−メチル−3−(チオフェン−2−イル)プロパン−1−アミン、
[6]3−(3−((ベンジル(メチル)アミノ)メチル)フェノキシ)−N−メチル−3−(チオフェン−2−イル)プロパン−1−アミン、
[7]3−(3−(メチルアミノ)−1−(チオフェン−2−イル)プロポキシ)−N−(ピリジン−2−イルメチル)ベンズアミド、
[8]3−(3−(メチルアミノ)−1−(チオフェン−2−イル)プロポキシ)−N−(ピリジン−3−イル)ベンズアミド、
[9]N−(3−(5−メチル−1,3,4−オキサジアゾール−2−イル)フェニル)−3−(3−(メチルアミノ)−1−(チオフェン−2−イル)プロポキシ)ベンズアミド、
[10]N−ベンジル−3−(3−(メチルアミノ)−1−(チオフェン−2−イル)プロポキシ)ベンズアミド、
[11]N−(2−((ジメチルアミノ)メチル)フェニル)−3−(3−(メチルアミノ)−1−(チオフェン−2−イル)プロポキシ)ベンズアミド、
[12]N−(2−(ジメチルアミノ)フェニル)−3−(3−(メチルアミノ)−1−(チオフェン−2−イル)プロポキシ)ベンズアミド、
[13]3−(3−(メチルアミノ)−1−フェニルプロポキシ)−N−フェニルベンズアミド、
[14]N−(3−(5−メチル−1,3,4−オキサジアゾール−2−イル)フェニル)−3−(3−(メチルアミノ)−1−フェニルプロポキシ)ベンズアミド、
[15]3−(3−(メチルアミノ)−1−フェニルプロポキシ)−N−(ピリジン−3−イル)ベンズアミド、
[16]N−メチル−3−(3−(メチルアミノ)−1−フェニルプロポキシ)ベンズアミド、
[17]N−ベンジル−3−(3−(メチルアミノ)−1−フェニルプロポキシ)ベンズアミド、
[18]3−(3−(メチルアミノ)−1−フェニルプロポキシ)−N−(ピリジン−2−イルメチル)ベンズアミド、
[19]N−エチル−3−(3−(メチルアミノ)−1−フェニルプロポキシ)ベンズアミド、
[20]3−(3−(メチルアミノ)−1−フェニルプロポキシ)−N−(2−(メチルアミノ)エチル)ベンズアミド、
[21]N−(6−(エチルアミノ)ピリジン−3−イル)−3−(3−(メチルアミノ)−1−フェニルプロポキシ)ベンズアミド、
[22]3−(3−(メチルアミノ)−1−フェニルプロポキシ)−N−(1−メチルピペリジン−4−イル)ベンズアミド、
[23]N−メチル−N−(3−(3−(メチルアミノ)−1−フェニルプロポキシ)フェニル)ベンズアミド、
[24]N−メチル−N−(3−(3−(メチルアミノ)−1−フェニルプロポキシ)フェニル)アセトアミド、
[25]N−メチル−N−(3−(3−(メチルアミノ)−1−フェニルプロポキシ)フェニル)ブチルアミド、
[26]N−メチル−N−(3−(3−(メチルアミノ)−1−フェニルプロポキシ)フェニル)ニコチンアミド、
[27]3−(アミノメチル)−N−メチル−N−(3−(3−(メチルアミノ)−1−フェニルプロポキシ)フェニル)ベンズアミド、
[28]4−アミノ−N−メチル−N−(3−(3−(メチルアミノ)−1−フェニルプロポキシ)フェニル)ブタンアミド、
[29]2−(エチルアミノ)−N−メチル−N−(3−(3−(メチルアミノ)−1−フェニルプロポキシ)フェニル)−4−(ピロリジン−1−イル)ピリミジン−5−カルボキサミド、
[30]2−(エチルアミノ)−N−メチル−N−(3−(3−(メチルアミノ)−1−(チオフェン−2−イル)プロポキシ)フェニル)−4−(ピロリジン−1−イル)ピリミジン−5−カルボキサミド、
[31]N−メチル−N−(3−((3−(メチルアミノ)−1−フェニルプロポキシ)メチル)フェニル)ベンズアミド、
[32]N−メチル−N−(3−((3−(メチルアミノ)−1−フェニルプロポキシ)メチル)フェニル)ニコチンアミド、
[33]2−メトキシ−N−メチル−N−(3−((3−(メチルアミノ)−1−フェニルプロポキシ)メチル)フェニル)ピリミジン−5−カルボキサミド、
[34]N−メチル−N−(3−((3−(メチルアミノ)−1−フェニルプロポキシ)メチル)フェニル)ピリミジン−5−カルボキサミド、
[35]N−メチル−N−(3−((3−(メチルアミノ)−1−フェニルプロポキシ)メチル)フェニル)−2−(メチルチオ)ピリミジン−5−カルボキサミド、
[36]N−メチル−N−(3−((3−(メチルアミノ)−1−フェニルプロポキシ)メチル)フェニル)ピコリンアミド、
[37]2−(エチルアミノ)−N−メチル−N−(3−((3−(メチルアミノ)−1−フェニルプロポキシ)メチル)フェニル)−4−(ピロリジン−1−イル)ピリミジン−5−カルボキサミド、
[38]2−(エチルアミノ)−N−メチル−N−(3−((3−(メチルアミノ)−1−(チオフェン−2−イル)プロポキシ)メチル)フェニル)−4−(ピロリジン−1−イル)ピリミジン−5−カルボキサミド、
[39]N−(3−((3−(メチルアミノ)−1−フェニルプロポキシ)メチル)フェニル)ベンズアミド、
[40]N−(3−((3−(メチルアミノ)−1−フェニルプロポキシ)メチル)フェニル)ニコチンアミド、
[41]2−メトキシ−N−(3−((3−(メチルアミノ)−1−フェニルプロポキシ)メチル)フェニル)ピリミジン−5−カルボキサミド、
[42]N−(3−((3−(メチルアミノ)−1−フェニルプロポキシ)メチル)フェニル)ピリミジン−5−カルボキサミド、
[43]N−(3−((3−(メチルアミノ)−1−フェニルプロポキシ)メチル)フェニル)ピコリンアミド、
[44]N−(3−((3−(メチルアミノ)−1−フェニルプロポキシ)メチル)フェニル)−2−(メチルチオ)ピリミジン−5−カルボキサミド、
[45]2−(エチルアミノ)−N−(3−((3−(メチルアミノ)−1−フェニルプロポキシ)メチル)フェニル)−4−(ピロリジン−1−イル)ピリミジン−5−カルボキサミド、
[46]N−(3−((3−(メチルアミノ)−1−(チオフェン−2−イル)プロポキシ)メチル)フェニル)ベンズアミド、
[47]2−(ジメチルアミノ)−N−(3−((3−(メチルアミノ)−1−(チオフェン−2−イル)プロポキシ)メチル)フェニル)ベンズアミド、
[48]2−フルオロ−N−(3−((3−(メチルアミノ)−1−(チオフェン−2−イル)プロポキシ)メチル)フェニル)ベンズアミド、
[49]2−(エチルアミノ)−N−(3−((3−(メチルアミノ)−1−(チオフェン−2−イル)プロポキシ)メチル)フェニル)−4−(ピロリジン−1−イル)ピリミジン−5−カルボキサミド、
[50]2−(エチルアミノ)−N−(3−(3−(メチルアミノ)−1−フェニルプロポキシ)フェニル)−4−(ピロリジン−1−イル)ピリミジン−5−カルボキサミド、
[51]2−(エチルアミノ)−N−(3−(3−(メチルアミノ)−1−(チオフェン−2−イル)プロポキシ)フェニル)−4−(ピロリジン−1−イル)ピリミジン−5−カルボキサミド、
[52]N−ベンジル−3−((3−(メチルアミノ)−1−フェニルプロポキシ)メチル)アニリン、
[53]3−((3−(メチルアミノ)−1−フェニルプロポキシ)メチル)−N−(ピリミジン−5−イルメチル)アニリン、
[54]N−(3−((3−(ジメチルアミノ)−1−(チオフェン−2−イル)プロポキシ)メチル)フェニル)ベンズアミド、
[55]2−(ジメチルアミノ)−N−(3−((3−(ジメチルアミノ)−1−(チオフェン−2−イル)プロポキシ)メチル)フェニル)ベンズアミド、
[56]N−エチル−N−(3−(3−(メチルアミノ)−1−(チオフェン−2−イル)プロポキシ)ベンジル)ベンズアミド、
[57]N−ベンジル−N−(3−((3−(メチルアミノ)−1−フェニルプロポキシ)メチル)フェニル)アセトアミド、
[58]3−((3−(メチルアミノ)−1−フェニルプロポキシ)メチル)−N−フェニルアニリン、
[59]N−(3−((3−(メチルアミノ)−1−フェニルプロポキシ)メチル)フェニル)ピリミジン−2−アミン、
[60]2−(エチルアミノ)−N−メチル−N−(3−(3−(メチルアミノ)−1−フェニルプロポキシ)フェニル)ピリミジン−5−カルボキサミド、
[61]N−(3−((3−(メチルアミノ)−1−フェニルプロポキシ)メチル)フェニル)−N−フェニルアセトアミド、
[62]N−メチル−N−(3−(3−(メチルアミノ)−1−(チオフェン−2−イル)プロポキシ)フェニル)アセトアミド、
[63]N−メチル−N−(3−(3−(メチルアミノ)−1−(チオフェン−2−イル)プロポキシ)フェニル)ベンズアミド、
[64]N−メチル−N−(3−(3−(メチルアミノ)−1−(チオフェン−2−イル)プロポキシ)フェニル)ブチルアミド、
[65]N−メチル−N−(3−(3−(メチルアミノ)−1−(チオフェン−2−イル)プロポキシ)フェニル)ニコチンアミド、
[66]N−(3−(3−(メチルアミノ)−1−(チオフェン−2−イル)プロポキシ)フェニル)ベンズアミド、
[67]N−メチル−N−(3−(3−(メチルアミノ)−1−(チオフェン−2−イル)プロポキシ)フェニル)ベンズアミド、
[68]N−メチル−N−(3−(3−(メチルアミノ)−1−フェニルプロポキシ)フェニル)ニコチンアミド及び
[69]N−メチル−N−(3−(3−(メチルアミノ)−1−フェニルプロポキシ)フェニル)ベンズアミド;
又はその薬学的に許容される塩、異性体、プロドラッグ若しくは溶媒和物。
[2]3−(3−((ベンジルアミノ)メチル)フェノキシ)−N−メチル−3−(チオフェン−2−イル)プロパン−1−アミン、
[6]3−(3−((ベンジル(メチル)アミノ)メチル)フェノキシ)−N−メチル−3−(チオフェン−2−イル)プロパン−1−アミン、
[13]3−(3−(メチルアミノ)−1−フェニルプロポキシ)−N−フェニルベンズアミド、
[14]N−(3−(5−メチル−1,3,4−オキサジアゾール−2−イル)フェニル)−3−(3−(メチルアミノ)−1−フェニルプロポキシ)ベンズアミド、
[15]3−(3−(メチルアミノ)−1−フェニルプロポキシ)−N−(ピリジン−3−イル)ベンズアミド、
[17]N−ベンジル−3−(3−(メチルアミノ)−1−フェニルプロポキシ)ベンズアミド、
[18]3−(3−(メチルアミノ)−1−フェニルプロポキシ)−N−(ピリジン−2−イルメチル)ベンズアミド、
[20]3−(3−(メチルアミノ)−1−フェニルプロポキシ)−N−(2−(メチルアミノ)エチル)ベンズアミド、
[22]3−(3−(メチルアミノ)−1−フェニルプロポキシ)−N−(1−メチルピペリジン−4−イル)ベンズアミド、
[27]3−(アミノメチル)−N−メチル−N−(3−(3−(メチルアミノ)−1−フェニルプロポキシ)フェニル)ベンズアミド、
[28]4−アミノ−N−メチル−N−(3−(3−(メチルアミノ)−1−フェニルプロポキシ)フェニル)ブタンアミド、
[38]2−(エチルアミノ)−N−メチル−N−(3−((3−(メチルアミノ)−1−(チオフェン−2−イル)プロポキシ)メチル)フェニル)−4−(ピロリジン−1−イル)ピリミジン−5−カルボキサミド、
[39]N−(3−((3−(メチルアミノ)−1−フェニルプロポキシ)メチル)フェニル)ベンズアミド、
[41]2−メトキシ−N−(3−((3−(メチルアミノ)−1−フェニルプロポキシ)メチル)フェニル)ピリミジン−5−カルボキサミド、
[43]N−(3−((3−(メチルアミノ)−1−フェニルプロポキシ)メチル)フェニル)ピコリンアミド、
[46]N−(3−((3−(メチルアミノ)−1−(チオフェン−2−イル)プロポキシ)メチル)フェニル)ベンズアミド、
[48]2−フルオロ−N−(3−((3−(メチルアミノ)−1−(チオフェン−2−イル)プロポキシ)メチル)フェニル)ベンズアミド、
[50]2−(エチルアミノ)−N−(3−(3−(メチルアミノ)−1−フェニルプロポキシ)フェニル)−4−(ピロリジン−1−イル)ピリミジン−5−カルボキサミド及び
[58]3−((3−(メチルアミノ)−1−フェニルプロポキシ)メチル)−N−フェニルアニリン;
又はその薬学的に許容される塩、異性体、プロドラッグ若しくは溶媒和物から選択される。
[70]3−(4−((ベンジル(メチル)アミノ)メチル)−3−フルオロフェノキシ)−N−メチル−3−(チオフェン−2−イル)プロパン−1−アミン及び
[71]3−(4−((ベンジルアミノ)メチル)−3−フルオロフェノキシ)−N−メチル−3−(チオフェン−2−イル)プロパン−1−アミン;
又はその薬学的に許容される塩、異性体、プロドラッグ若しくは溶媒和物から選択される。
方法Aは、一般式(I)による化合物を合成するための第1の方法を表す。方法Aは、一般式(Ia)の化合物、すなわち、式(I)の化合物(式中、mは、0である)の製造を可能とする。式(Ia)の化合物を得るための2つの方法、すなわち、方法A1及びA2について記載する。
この意味で、方法は、一般式(Ia):
の化合物の製造であって、式(IIa):
の化合物と、式(IIIa)又は(IIIb):
一般式(Ia)の化合物の製造のためのさらなる代替の方法は、式(IV−LG):
の化合物と、式(VI):
HNR1R’1
(VI)
の化合物との反応を含み、式中、R1、R’1、R2、W、Z及びnは、上記で定義した通りであり、LGは、適切な脱離基、例えば、クロロ、ブロモ、ヨード、メシレート、トシレート、ノシラート又はトリフレートを表す。
方法Bは、一般式(Ib)による化合物、すなわち、一般式(I)の化合物(式中、mは、1である)を合成するための方法を表す。式(Ib)の化合物を得るための2つの方法、すなわち、方法B1及びB2について記載する。
この意味で、第1の方法は、一般式(Ib):
の化合物の製造であって、
式(IIa):
の化合物と、式(IIIc):
の化合物との間の反応を含む製造について説明し、
式中、R1、R’1、R2、W、Z及びnは、上記で定義した通りであり、LGは、適切な脱離基、例えば、クロロ、ブロモ、ヨード、メシレート、トシレート、ノシラート又はトリフレートを表す。
式(Ib)の化合物を製造するための第2の方法は、式(V−P):
の化合物の脱保護を含み、式中、R1、R’1、R2、W、Z及びnは、上記で定義した通りであり、Pは、保護基、例えば、例えば、Boc(tert−ブトキシカルボニル)又はTeoc(2−(トリメチルシリル)エトキシカルボニル)を表す。
方法Cは、一般式(I)による化合物を合成するための第3の方法を表す。
の化合物の製造のための方法を提供し、式(VII):
の化合物から出発し、式中、R1、R’1、R2、W、Z、m及びnは、上記で定義した通りであり、Aは、アルデヒド、カルボン酸、ニトロ基又は適切な脱離基又は−(CH2)p−LGを表してもよく、LGは、適切な脱離基を表し、pは、1又は2であり、反応は、A及びWの性質によって決まり、反応は、
−Aが、アルデヒドであり、Wが、−(CH2)p−であるとき、還元剤の存在下での還元的アミノ化反応;
−Aが、カルボン酸であり、Wが、−C(O)−基であるとき、カルボン酸活性化試薬の存在下での反応;
−Aが、良好な脱離基であり、Wが、結合であるとき、金属触媒の存在下でのカップリング反応;
−Aが、ニトロ基であり、Wが、結合であるとき、還元反応;又は
−Aが、−(CH2)p−LG基であり、Wが、−(CH2)p−基であるとき、塩基の存在下での反応
を含むことをもたらす。
−Aが、アルデヒドであり、Wが、−(CH2)p−であるとき、還元試薬、好ましくは、トリアセトキシ水素化ホウ素ナトリウムの存在下で、塩基、好ましくは、ジイソプロピルエチルアミン(DIPEA)又はトリエチルアミン(TEA)の存在下で、有機溶媒、好ましくは、1,2−ジクロロエタン(DCE)中の、還元的アミノ化反応による。
−Aが、カルボン酸であり、Wが、−C(O)−であるとき、カルボン酸活性化試薬、好ましくは、HATU(2−(7−アザ−1H−ベンゾトリアゾール−1−イル)−1,1,3,3−テトラメチルウロニウム)又はEDCI(N−(3−ジメチルアミノプロピル)−N’−エチルカルボジイミド塩酸塩)の存在下で、塩基、好ましくは、DIPEA(N,N−ジイソプロピルエチルアミン)又はTEAの存在下で、有機溶媒、好ましくは、ジクロロメタン(DCM)中。代わりに、任意の適切な方法を使用した酸塩化物中間体への変換による。
−Aが、ハロゲン原子として良好な脱離基であり、Wが、結合であるとき、例えば、触媒として銅塩、好ましくは、CuI、適当なリガンド、好ましくは、N1,N2−ジメチルエタン−1,2−ジアミン又はプロリン、及び有機溶媒、好ましくは、1,4−ジオキサン、N,N−ジメチルホルムアミド(DMF)又はDMSO中の無機塩基、好ましくは、K3PO4又はK2CO3の存在下で、80〜130℃の温度範囲にて、金属触媒カップリングを使用する。代わりに、銅粉の存在下で、極性溶媒、好ましくは、水中、80℃及び還流温度の温度範囲にて。代わりに、Pd触媒、好ましくは、Pd2(dba)3及び適切なリガンド、好ましくは、2−ジシクロヘキシルホスフィノ−2’,4’,6’−トリイソプロピルビフェニル(Xphos)の存在下で、塩基、好ましくは、NaOtBuの存在下で、有機溶媒、好ましくは、トルエン又は1,4−ジオキサン中、50〜150℃の温度範囲にて
−Aが、ニトロ基であり、Wが、結合であるとき、任意の適切な方法を使用して、好ましくは、極性溶媒、好ましくは、EtOH中の鉄粉を使用して、添加物としてNH4Clの存在下で、好ましくは、室温から還流温度の間に含まれる適切な温度での還元反応による、それに続くさらなる誘導体化反応、例えば、還元的アミノ化による、又は標準的な実験条件下でのカルボン酸、酸塩化物若しくはカルボン酸無水物との反応による。
−Aが、−(CH2)p−LG基(式中、LGは、ハロゲン原子又はスルホネートとして良好な脱離基である)であり、Wが、(CH2)pであるとき、反応は、塩基、好ましくは、NaH、DIPEA又はTEAの存在下で、有機溶媒、好ましくは、DMF又はTHF中、好ましくは、0〜100℃の範囲の適切な温度にて行い得る。代わりに、ヨウ化テトラブチルアンモニウム(TBAI)の存在下で。
ACN:アセトニトリル
Anh:無水
Aq:水性
Conc:濃縮された
CH:シクロヘキサン
DCM:ジクロロメタン
DCE:1,2−ジクロロエタン
DEA:ジエチルアミン
DIAD:アゾジカルボン酸ジイソプロピル
DIBAL:ジイソブチルアルミニウムヒドリド
DIPEA:N,N−ジイソプロピルエチルアミン
DMA:N,N−ジメチルアセトアミド
DMSO:ジメチルスルホキシド
EtOAc:酢酸エチル
EtOH:エタノール
Ex:実施例
h:時間
HATU:2−(7−アザ−1H−ベンゾトリアゾール−1−イル)−1,1,3,3−テトラメチルウロニウム
Hex:ヘキサン
HPLC:高速液体クロマトグラフィー
INT:中間体
IPA:イソプロパノール
MeOH:メタノール
MS:質量分析法
Min:分
PPh3:トリフェニルホスフィン
Quant:定量的
Ret:保持
rt:室温
Sat:飽和
TBAF:フッ化テトラブチルアンモニウム
TBAI:ヨウ化テトラブチルアンモニウム
TEA:Et3N、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
XPhos:2−ジシクロヘキシルホスフィノ−2’,4’,6’−トリイソプロピルビフェニル
Wt:重量
方法A:カラムEclipse XDB−C18、4.6×150mm、5μm;流量1mL/分;A:H2O(0.05%TFA);B:ACN;勾配:7分で5%から95%B、均一濃度95%B、5分。
方法B:カラムZorbax SB−C18、2.1×50mm、1.8μm;流量0.5mL/分;A:H2O(0.1%ギ酸);B:ACN(0.1%ギ酸);勾配:4分で5%から95%B、均一濃度95%B、4分。
実施例1:3−(3−((ベンジル(エチル)アミノ)メチル)フェノキシ)−N−メチル−3−(チオフェン−2−イル)プロパン−1−アミン
3−(3−(メチルアミノ)−1−(チオフェン−2−イル)プロポキシ)−N−(ピリジン−2−イルメチル)ベンズアミド
実施例1ステップaにおいて得た化合物を、実施例1ステップbにおいて使用した条件にてエチルアミンで処理し、表題化合物(91%収率)を得た。HPLC(方法B):Ret、4.01分;ESI+−MS m/z、310.1(M+H)。
Cav2.2カルシウムチャネルのヒトα2δ−1サブユニットへの結合アッセイ
ヒトα2δ−1が濃縮されている膜(2.5μg)を、Hepes−KOH、10mM、pH7.4を含有するアッセイ緩衝液中の15nMの放射性標識された[3H]−ガバペンチンと共にインキュベートした。
ヒトノルエピネフリン輸送体(NET)が濃縮されている膜(5μg)を、50mMのTris−HCl、120mMのNaCl、5mMのKCl、pH7.4を含油するアッセイ緩衝液中で5nMの放射性標識された[3H]−ニソキセチンと共にインキュベートした。
+ Ki−α2δ−1≧3000nM
++ 500nM<Ki−α2δ−1<3000nM
+++ 100nM<Ki−α2δ−1<500nM
++++ Ki−α2δ−1<100nM
+ Ki−NET≧1000nM
++ 500nM<Ki−NET<1000nM
+++ 100nM<Ki−NET<500nM
++++ Ki−NET<100nM
Claims (19)
- 一般式(I):
(式中、
R1及びR’1は、水素原子及び分岐状若しくは非分岐状C1〜6アルキルラジカルから独立に選択され、
R2は、ハロゲン原子で任意に置換されている6員アリール、分岐状若しくは非分岐状C1〜6−アルキルラジカル、又は分岐状若しくは非分岐状C1〜6−アルコキシラジカル、C1〜6−ハロアルコキシラジカル、C1〜6−ハロアルキルラジカル又はヒドロキシルラジカル;又はN、O及びSから選択される少なくとも1個のヘテロ原子を有する置換若しくは非置換の5員若しくは6員ヘテロアリールであり、
nは、1であり、
mは、0又は1であり、
Wは、−(CH2)p−;−C(O)−;又は結合であり、
pは、1又は2であり、
Zは、NR3R4であり、
R3は、水素原子;分岐状若しくは非分岐状C1〜6アルキルラジカル;ベンジルラジカル;又はフェニルラジカルであり、
R4は、ハロゲン原子で任意に置換されている分岐状若しくは非分岐状C1〜6アルキルラジカル、ヒドロキシルラジカル、分岐状若しくは非分岐状C1〜6アルコキシラジカル又は−NR4aR4bラジカル;−(CH2)s−ヘテロアリールラジカルであって、前記ヘテロアリール基が、−NR4cR4dラジカルで任意に置換されている、ヘテロ原子として少なくとも1個の窒素原子を有する5員若しくは6員環であり、sは、0、1若しくは2である、−(CH2)s−ヘテロアリールラジカル;R4eで任意に置換されているヘテロシクロアルキルラジカル;−(CH2)r−アリールラジカルであって、前記アリール基が、少なくとも1個のR5ラジカルで任意に置換されている6員環であり、rは、0、1若しくは2である、−(CH2)r−アリールラジカル;又は−C(O)R6ラジカルであり、
R4a、R4b、R4c、R4d及びR4eは、水素原子及び分岐状若しくは非分岐状C1〜6アルキルラジカルから独立に選択され、
R5は、水素原子;ヒドロキシルラジカル;分岐状若しくは非分岐状C1〜6−アルコキシラジカル;−(CH2)j−NR5aR5bラジカル;−NR5cR5dラジカル;又はR5eで任意に置換されている、ヘテロ原子として1個若しくは複数のN及び/若しくはOを含有する5員ヘテロ芳香族環であり、
R5a、R5b、R5c、R5d及びR5eは独立に、水素原子又は分岐状若しくは非分岐状C1〜6アルキルラジカルであり、
jは、0又は1であり
R6は、分岐状若しくは非分岐状C1〜6アルキルラジカル;−(CH2)q−NR6aR6bラジカル;又はO及びNから選択される少なくとも1個のさらなるヘテロ原子を任意に含有し、且つ少なくとも1個のR7で任意に置換されている、5員若しくは6員窒素含有ヘテロアリール環;又は少なくとも1個のR8で任意に置換されている6員アリールであり、
R6a及びR6bは、水素原子及びC1〜6アルキルから独立に選択され、
qは、0、1、2、3又は4であり、
R7は、水素原子、分岐状若しくは非分岐状C1〜6−アルコキシラジカル、分岐状若しくは非分岐状C1〜6−アルキルチオラジカル;−NR7aR7bラジカル;並びにO、N及びSから選択される少なくとも1個のヘテロ原子を有する5員ヘテロシクロアルキル環から選択され、
R7a及びR7bは、H及びC1〜6アルキルから独立に選択され、
R8は、水素原子、ハロゲン原子、分岐状若しくは非分岐状C1〜6−アルキルラジカル又は−(CH2)t−NR8aR8bラジカルであり、
tは、0又は1であり、
R8a及びR8bは、水素原子及び分岐状若しくは非分岐状C1〜6アルキルラジカルから独立に選択される);
の化合物又はその薬学的に許容される塩、異性体、若しくは溶媒和物。 - R2は、ハロゲン原子で任意に置換されているフェニルラジカル、分岐状若しくは非分岐状C1〜6−アルキルラジカル、分岐状若しくは非分岐状C1〜6−アルコキシラジカル、C1〜6−ハロアルコキシラジカル、C1〜6−ハロアルキルラジカル又はヒドロキシルラジカル;又は置換若しくは非置換のチオフェン基である、請求項1に記載の化合物。
- R4は、
・−NR4aR4bラジカルで任意に置換されている分岐状若しくは非分岐状C1〜6アルキルラジカル;
・
・ラジカル:
・−C(O)R6ラジカルであり、式中、R4a、R4b、R4c、R4d、R4e、R5及びR6は、請求項1に定義される通りである、請求項1に記載の化合物。 - R5は、水素原子;分岐状若しくは非分岐状C1〜6アルコキシラジカル;−(CH2)j−NR5aR5bラジカル、−NR5cR5dラジカル及びラジカル
- R6は、分岐状若しくは非分岐状C1〜6アルキルラジカル;−(CH2)q−NR6aR6bラジカル及び
式中、R6a、R6b、R7、R8及びqは、請求項1に定義される通りである、請求項1若しくは3のいずれかに記載の化合物。 - R7は、水素原子、メトキシラジカル;メチルチオラジカル、−NR7aR7bラジカル又はラジカル
式中、R7a及びR7bは、請求項1に定義される通りである、請求項1若しくは5のいずれかに記載の化合物。 - R8は、水素原子、ハロゲン原子又は−(CH2)t−NR8aR8bラジカルであり、式中、R8a、R8b及びtは、請求項1に定義される通りである、請求項1若しくは5のいずれかに記載の化合物。
- 下記の式:
- 下記のリスト:
[1]3−(3−((ベンジル(エチル)アミノ)メチル)フェノキシ)−N−メチル−3−(チオフェン−2−イル)プロパン−1−アミン、
[2]3−(3−((ベンジルアミノ)メチル)フェノキシ)−N−メチル−3−(チオフェン−2−イル)プロパン−1−アミン、
[3]N−メチル−3−(3−((メチルアミノ)メチル)フェノキシ)−3−(チオフェン−2−イル)プロパン−1−アミン、
[4]3−(3−((ジメチルアミノ)メチル)フェノキシ)−N−メチル−3−(チオフェン−2−イル)プロパン−1−アミン、
[5]3−(3−((エチルアミノ)メチル)フェノキシ)−N−メチル−3−(チオフェン−2−イル)プロパン−1−アミン、
[6]3−(3−((ベンジル(メチル)アミノ)メチル)フェノキシ)−N−メチル−3−(チオフェン−2−イル)プロパン−1−アミン、
[7]3−(3−(メチルアミノ)−1−(チオフェン−2−イル)プロポキシ)−N−(ピリジン−2−イルメチル)ベンズアミド、
[8]3−(3−(メチルアミノ)−1−(チオフェン−2−イル)プロポキシ)−N−(ピリジン−3−イル)ベンズアミド、
[9]N−(3−(5−メチル−1,3,4−オキサジアゾール−2−イル)フェニル)−3−(3−(メチルアミノ)−1−(チオフェン−2−イル)プロポキシ)ベンズアミド、
[10]N−ベンジル−3−(3−(メチルアミノ)−1−(チオフェン−2−イル)プロポキシ)ベンズアミド、
[11]N−(2−((ジメチルアミノ)メチル)フェニル)−3−(3−(メチルアミノ)−1−(チオフェン−2−イル)プロポキシ)ベンズアミド、
[12]N−(2−(ジメチルアミノ)フェニル)−3−(3−(メチルアミノ)−1−(チオフェン−2−イル)プロポキシ)ベンズアミド、
[13]3−(3−(メチルアミノ)−1−フェニルプロポキシ)−N−フェニルベンズアミド、
[14]N−(3−(5−メチル−1,3,4−オキサジアゾール−2−イル)フェニル)−3−(3−(メチルアミノ)−1−フェニルプロポキシ)ベンズアミド、
[15]3−(3−(メチルアミノ)−1−フェニルプロポキシ)−N−(ピリジン−3−イル)ベンズアミド、
[16]N−メチル−3−(3−(メチルアミノ)−1−フェニルプロポキシ)ベンズアミド、
[17]N−ベンジル−3−(3−(メチルアミノ)−1−フェニルプロポキシ)ベンズアミド、
[18]3−(3−(メチルアミノ)−1−フェニルプロポキシ)−N−(ピリジン−2−イルメチル)ベンズアミド、
[19]N−エチル−3−(3−(メチルアミノ)−1−フェニルプロポキシ)ベンズアミド、
[20]3−(3−(メチルアミノ)−1−フェニルプロポキシ)−N−(2−(メチルアミノ)エチル)ベンズアミド、
[21]N−(6−(エチルアミノ)ピリジン−3−イル)−3−(3−(メチルアミノ)−1−フェニルプロポキシ)ベンズアミド、
[22]3−(3−(メチルアミノ)−1−フェニルプロポキシ)−N−(1−メチルピペリジン−4−イル)ベンズアミド、
[23]N−メチル−N−(3−(3−(メチルアミノ)−1−フェニルプロポキシ)フェニル)ベンズアミド、
[24]N−メチル−N−(3−(3−(メチルアミノ)−1−フェニルプロポキシ)フェニル)アセトアミド、
[25]N−メチル−N−(3−(3−(メチルアミノ)−1−フェニルプロポキシ)フェニル)ブチルアミド、
[26]N−メチル−N−(3−(3−(メチルアミノ)−1−フェニルプロポキシ)フェニル)ニコチンアミド、
[27]3−(アミノメチル)−N−メチル−N−(3−(3−(メチルアミノ)−1−フェニルプロポキシ)フェニル)ベンズアミド、
[28]4−アミノ−N−メチル−N−(3−(3−(メチルアミノ)−1−フェニルプロポキシ)フェニル)ブタンアミド、
[29]2−(エチルアミノ)−N−メチル−N−(3−(3−(メチルアミノ)−1−フェニルプロポキシ)フェニル)−4−(ピロリジン−1−イル)ピリミジン−5−カルボキサミド、
[30]2−(エチルアミノ)−N−メチル−N−(3−(3−(メチルアミノ)−1−(チオフェン−2−イル)プロポキシ)フェニル)−4−(ピロリジン−1−イル)ピリミジン−5−カルボキサミド、
[31]N−メチル−N−(3−((3−(メチルアミノ)−1−フェニルプロポキシ)メチル)フェニル)ベンズアミド、
[32]N−メチル−N−(3−((3−(メチルアミノ)−1−フェニルプロポキシ)メチル)フェニル)ニコチンアミド、
[33]2−メトキシ−N−メチル−N−(3−((3−(メチルアミノ)−1−フェニルプロポキシ)メチル)フェニル)ピリミジン−5−カルボキサミド、
[34]N−メチル−N−(3−((3−(メチルアミノ)−1−フェニルプロポキシ)メチル)フェニル)ピリミジン−5−カルボキサミド、
[35]N−メチル−N−(3−((3−(メチルアミノ)−1−フェニルプロポキシ)メチル)フェニル)−2−(メチルチオ)ピリミジン−5−カルボキサミド、
[36]N−メチル−N−(3−((3−(メチルアミノ)−1−フェニルプロポキシ)メチル)フェニル)ピコリンアミド、
[37]2−(エチルアミノ)−N−メチル−N−(3−((3−(メチルアミノ)−1−フェニルプロポキシ)メチル)フェニル)−4−(ピロリジン−1−イル)ピリミジン−5−カルボキサミド、
[38]2−(エチルアミノ)−N−メチル−N−(3−((3−(メチルアミノ)−1−(チオフェン−2−イル)プロポキシ)メチル)フェニル)−4−(ピロリジン−1−イル)ピリミジン−5−カルボキサミド、
[39]N−(3−((3−(メチルアミノ)−1−フェニルプロポキシ)メチル)フェニル)ベンズアミド、
[40]N−(3−((3−(メチルアミノ)−1−フェニルプロポキシ)メチル)フェニル)ニコチンアミド、
[41]2−メトキシ−N−(3−((3−(メチルアミノ)−1−フェニルプロポキシ)メチル)フェニル)ピリミジン−5−カルボキサミド、
[42]N−(3−((3−(メチルアミノ)−1−フェニルプロポキシ)メチル)フェニル)ピリミジン−5−カルボキサミド、
[43]N−(3−((3−(メチルアミノ)−1−フェニルプロポキシ)メチル)フェニル)ピコリンアミド、
[44]N−(3−((3−(メチルアミノ)−1−フェニルプロポキシ)メチル)フェニル)−2−(メチルチオ)ピリミジン−5−カルボキサミド、
[45]2−(エチルアミノ)−N−(3−((3−(メチルアミノ)−1−フェニルプロポキシ)メチル)フェニル)−4−(ピロリジン−1−イル)ピリミジン−5−カルボキサミド、
[46]N−(3−((3−(メチルアミノ)−1−(チオフェン−2−イル)プロポキシ)メチル)フェニル)ベンズアミド、
[47]2−(ジメチルアミノ)−N−(3−((3−(メチルアミノ)−1−(チオフェン−2−イル)プロポキシ)メチル)フェニル)ベンズアミド、
[48]2−フルオロ−N−(3−((3−(メチルアミノ)−1−(チオフェン−2−イル)プロポキシ)メチル)フェニル)ベンズアミド、
[49]2−(エチルアミノ)−N−(3−((3−(メチルアミノ)−1−(チオフェン−2−イル)プロポキシ)メチル)フェニル)−4−(ピロリジン−1−イル)ピリミジン−5−カルボキサミド、
[50]2−(エチルアミノ)−N−(3−(3−(メチルアミノ)−1−フェニルプロポキシ)フェニル)−4−(ピロリジン−1−イル)ピリミジン−5−カルボキサミド、
[51]2−(エチルアミノ)−N−(3−(3−(メチルアミノ)−1−(チオフェン−2−イル)プロポキシ)フェニル)−4−(ピロリジン−1−イル)ピリミジン−5−カルボキサミド、
[52]N−ベンジル−3−((3−(メチルアミノ)−1−フェニルプロポキシ)メチル)アニリン、
[53]3−((3−(メチルアミノ)−1−フェニルプロポキシ)メチル)−N−(ピリミジン−5−イルメチル)アニリン、
[54]N−(3−((3−(ジメチルアミノ)−1−(チオフェン−2−イル)プロポキシ)メチル)フェニル)ベンズアミド、
[55]2−(ジメチルアミノ)−N−(3−((3−(ジメチルアミノ)−1−(チオフェン−2−イル)プロポキシ)メチル)フェニル)ベンズアミド、
[56]N−エチル−N−(3−(3−(メチルアミノ)−1−(チオフェン−2−イル)プロポキシ)ベンジル)ベンズアミド、
[57]N−ベンジル−N−(3−((3−(メチルアミノ)−1−フェニルプロポキシ)メチル)フェニル)アセトアミド、
[58]3−((3−(メチルアミノ)−1−フェニルプロポキシ)メチル)−N−フェニルアニリン、
[59]N−(3−((3−(メチルアミノ)−1−フェニルプロポキシ)メチル)フェニル)ピリミジン−2−アミン、
[60]2−(エチルアミノ)−N−メチル−N−(3−(3−(メチルアミノ)−1−フェニルプロポキシ)フェニル)ピリミジン−5−カルボキサミド、
[61]N−(3−((3−(メチルアミノ)−1−フェニルプロポキシ)メチル)フェニル)−N−フェニルアセトアミド、
[62]N−メチル−N−(3−(3−(メチルアミノ)−1−(チオフェン−2−イル)プロポキシ)フェニル)アセトアミド、
[63]N−メチル−N−(3−(3−(メチルアミノ)−1−(チオフェン−2−イル)プロポキシ)フェニル)ベンズアミド、
[64]N−メチル−N−(3−(3−(メチルアミノ)−1−(チオフェン−2−イル)プロポキシ)フェニル)ブチルアミド、
[65]N−メチル−N−(3−(3−(メチルアミノ)−1−(チオフェン−2−イル)プロポキシ)フェニル)ニコチンアミド、
[66]N−(3−(3−(メチルアミノ)−1−(チオフェン−2−イル)プロポキシ)フェニル)ベンズアミド、
[67]N−メチル−N−(3−(3−(メチルアミノ)−1−(チオフェン−2−イル)プロポキシ)フェニル)ベンズアミド、
[68]N−メチル−N−(3−(3−(メチルアミノ)−1−フェニルプロポキシ)フェニル)ニコチンアミド及び
[69]N−メチル−N−(3−(3−(メチルアミノ)−1−フェニルプロポキシ)フェニル)ベンズアミド;
から選択される請求項1に記載の化合物、又はその薬学的に許容される塩、異性体若しくは溶媒和物。 - 下記の式:
- 下記の基:
[2]3−(3−((ベンジルアミノ)メチル)フェノキシ)−N−メチル−3−(チオフェン−2−イル)プロパン−1−アミン、
[6]3−(3−((ベンジル(メチル)アミノ)メチル)フェノキシ)−N−メチル−3−(チオフェン−2−イル)プロパン−1−アミン、
[13]3−(3−(メチルアミノ)−1−フェニルプロポキシ)−N−フェニルベンズアミド、
[14]N−(3−(5−メチル−1,3,4−オキサジアゾール−2−イル)フェニル)−3−(3−(メチルアミノ)−1−フェニルプロポキシ)ベンズアミド、
[15]3−(3−(メチルアミノ)−1−フェニルプロポキシ)−N−(ピリジン−3−イル)ベンズアミド、
[17]N−ベンジル−3−(3−(メチルアミノ)−1−フェニルプロポキシ)ベンズアミド、
[18]3−(3−(メチルアミノ)−1−フェニルプロポキシ)−N−(ピリジン−2−イルメチル)ベンズアミド、
[20]3−(3−(メチルアミノ)−1−フェニルプロポキシ)−N−(2−(メチルアミノ)エチル)ベンズアミド、
[22]3−(3−(メチルアミノ)−1−フェニルプロポキシ)−N−(1−メチルピペリジン−4−イル)ベンズアミド、
[27]3−(アミノメチル)−N−メチル−N−(3−(3−(メチルアミノ)−1−フェニルプロポキシ)フェニル)ベンズアミド、
[28]4−アミノ−N−メチル−N−(3−(3−(メチルアミノ)−1−フェニルプロポキシ)フェニル)ブタンアミド、
[38]2−(エチルアミノ)−N−メチル−N−(3−((3−(メチルアミノ)−1−(チオフェン−2−イル)プロポキシ)メチル)フェニル)−4−(ピロリジン−1−イル)ピリミジン−5−カルボキサミド、
[39]N−(3−((3−(メチルアミノ)−1−フェニルプロポキシ)メチル)フェニル)ベンズアミド、
[41]2−メトキシ−N−(3−((3−(メチルアミノ)−1−フェニルプロポキシ)メチル)フェニル)ピリミジン−5−カルボキサミド、
[43]N−(3−((3−(メチルアミノ)−1−フェニルプロポキシ)メチル)フェニル)ピコリンアミド、
[46]N−(3−((3−(メチルアミノ)−1−(チオフェン−2−イル)プロポキシ)メチル)フェニル)ベンズアミド、
[48]2−フルオロ−N−(3−((3−(メチルアミノ)−1−(チオフェン−2−イル)プロポキシ)メチル)フェニル)ベンズアミド、
[50]2−(エチルアミノ)−N−(3−(3−(メチルアミノ)−1−フェニルプロポキシ)フェニル)−4−(ピロリジン−1−イル)ピリミジン−5−カルボキサミド及び
[58]3−((3−(メチルアミノ)−1−フェニルプロポキシ)メチル)−N−フェニルアニリン
から選択される、請求項1若しくは9に記載の化合物、又はその薬学的に許容される塩、異性体若しくは溶媒和物。 - [70]3−(4−((ベンジル(メチル)アミノ)メチル)−3−フルオロフェノキシ)−N−メチル−3−(チオフェン−2−イル)プロパン−1−アミン及び
[71]3−(4−((ベンジルアミノ)メチル)−3−フルオロフェノキシ)−N−メチル−3−(チオフェン−2−イル)プロパン−1−アミン
から選択される化合物、又はその薬学的に許容される塩、異性体若しくは溶媒和物。 - 一般式(Ia):
の化合物の製造のための方法であって、
a)式(IIa):
の化合物と、式(IIIa)又は(IIIb):
b)式(IV−LG):
の化合物と、式(VI):
HNR1R’1
(VI)
の化合物との反応を含み、式中、R1、R’1、R2、W、Z及びnは、請求項1に定義される通りであり、LGは、脱離基を表す、方法。 - 一般式(Ib):
の化合物の製造のための方法であって、
a)式(IIa):
の化合物と、式(IIIc):
の化合物との反応、又は;
b)式(V−P):
の化合物の脱保護を含み、式中、R1、R’1、R2、W、Z及びnは、請求項1に定義される通りであり、LGは、脱離基を表し、Pは、保護基を表す、方法。 - 一般式(I):
の化合物の製造のための方法であって、
式(VII):
の化合物から出発し、式中、R1、R’1、R2、W、Z、m及びnは、請求項1に定義される通りであり、Aは、アルデヒド、カルボン酸、ニトロ基又は脱離基又は−(CH2)p−LGを表してもよく、LGは、脱離基を表し、pは、1又は2であり、反応は、A及びWの性質によって決まり、前記反応は、
−Aが、アルデヒドであり、Wが、−(CH2)p−であるとき、還元剤の存在下での還元的アミノ化反応;
−Aが、カルボン酸であり、Wが、−C(O)−基であるとき、カルボン酸活性化試薬の存在下での反応;
−Aが、脱離基であり、Wが、結合であるとき、金属触媒の存在下でのカップリング反応;
−Aが、ニトロ基であり、Wが、結合であるとき、還元反応;又は
−Aが、−(CH2)p−LG基であり、Wが、−(CH2)p−基であるとき、塩基の存在下での反応
を含むことをもたらす、方法。 - 医薬として使用するための、請求項1〜12のいずれかに記載の化合物。
- 電位作動型カルシウムチャネルのサブユニットα2δ、特に、α2δ−1サブユニット及び/又はノルアドレナリン輸送体(NET)によって媒介される疾患及び/又は障害の治療及び/又は予防において使用するための、請求項1〜12のいずれかに記載の化合物。
- 前記疾患又は障害が、中程度から重度の疼痛、内臓痛、慢性疼痛、がん疼痛、片頭痛、炎症性疼痛、急性疼痛又は神経因性疼痛、又はアロディニアを伴う他の疼痛状態、及び/又は痛覚過敏、うつ、不安及び注意欠陥障害/多動性障害である、請求項17に記載の使用のための化合物。
- 請求項1〜12のいずれかに記載の化合物、又はその薬学的に許容される塩、異性体、プロドラッグ若しくは溶媒和物、及び少なくとも薬学的に許容される担体、添加物、アジュバント又はビヒクルを含む、医薬組成物。
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