JP2020200247A - Compound, pharmaceutical composition, kdm5c inhibitor and antidepressant - Google Patents
Compound, pharmaceutical composition, kdm5c inhibitor and antidepressant Download PDFInfo
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- JP2020200247A JP2020200247A JP2019106166A JP2019106166A JP2020200247A JP 2020200247 A JP2020200247 A JP 2020200247A JP 2019106166 A JP2019106166 A JP 2019106166A JP 2019106166 A JP2019106166 A JP 2019106166A JP 2020200247 A JP2020200247 A JP 2020200247A
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- 239000008194 pharmaceutical composition Substances 0.000 title claims description 7
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- 125000003118 aryl group Chemical group 0.000 claims description 13
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 11
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Abstract
Description
本発明は、化合物、医薬組成物、ＫＤＭ５Ｃ阻害剤及び抗うつ剤に関する。 The present invention relates to compounds, pharmaceutical compositions, KDM5C inhibitors and antidepressants.
ＫＤＭ５はがんとの関係が知られており、例えば特許文献１は、ＫＤＭ５拮抗剤ががん治療及びがんの薬剤耐性の防止に有効であることを開示する。また、特許文献２は、
ヒストン脱メチル化酵素の活性をモジュレートすることができる化合物ががんの治療に有効であることを開示している。
KDM5 is known to be related to cancer. For example, Patent Document 1 discloses that a KDM5 antagonist is effective in treating cancer and preventing drug resistance of cancer. In addition, Patent Document 2
It discloses that compounds capable of modulating the activity of histone demethylase are effective in the treatment of cancer.
本発明は、強力なＫＤＭ５Ｃ阻害作用を有する化合物、医薬組成物及び抗うつ剤を提供することを目的とする。 An object of the present invention is to provide a compound, a pharmaceutical composition and an antidepressant having a strong KDM5C inhibitory action.
本発明は、以下の化合物、医薬組成物、ＫＤＭ５Ｃ阻害剤及び抗うつ剤を提供するものである。
項１． 下記式（Ｉ）
The present invention provides the following compounds, pharmaceutical compositions, KDM5C inhibitors and antidepressants.
Item 1. The following formula (I)
（式中、Ｒ１〜Ｒ４のいずれか１つはＣＯＲ８を示し、Ｒ１〜Ｒ４の他の３つは、同一または相異なり、水素原子、ハロゲン原子、ＯＨ、ＮＯ２、ＣＮ、アルキル、シクロアルキル、アルコキシ、アルキルカルボニルアミノ、アルキルカルボニルオキシ、アリールカルボニルオキシ、カルバモイル、アリールカルボニルアミノ、アリール、アラルキル、アルキルカルボニル、ＳＨ又はアルキルチオを示す。Ｒ１とＲ２、Ｒ２とＲ３、Ｒ３とＲ４は、メチレンジオキシを表わすか、或いは、これらが結合している炭素原子と一緒になってシクロペンテン環、シクロペンタジエン環、シクロヘキセン環、シクロヘキサジエン環、ベンゼン環、或いは５員又は６員のヘテロ環を形成してもよい。
Ｒ５は、水素原子、ハロゲン原子、アルキル、アルコキシ、アリール、アラルキル、ヒドロキシアルキル又はシクロアルキルを示す。Ｒ４とＲ５は、これらが結合している炭素原子と一緒になって置換基を有していてもよいベンゼン環又は置換基を有していてもよいピリジン環を形成してもよい。
Ｒ６、Ｒ７は、同一または相異なり、水素原子、アルキル、アルコキシ、アリール、アラルキル、ヒドロキシアルキル又はシクロアルキルを示す。但し、Ｒ６とＲ７が同時に水素原子となることはない。
Ｒ８は、ＯＨ、アルコキシ、ヒドロキシアルキルオキシ、シクロアルキルオキシ、アリールオキシ又はアラルキルオキシを示す。
ＺはＮ又はＣＲ９を示す。Ｒ９は水素原子、アルキル、アリール又はアラルキルを示す。
ｎは０〜５の整数を示す。）
で表される化合物、またはその薬学的に許容される塩もしくは溶媒和物。
項２． 項１に記載の化合物またはその薬学的に許容される塩もしくは溶媒和物と薬学的に許容される賦形剤を含む医薬組成物。
項３． 項１に記載の化合物またはその薬学的に許容される塩もしくは溶媒和物を有効成分とするＫＤＭ５Ｃ阻害剤。
項４． 項１に記載の化合物またはその薬学的に許容される塩もしくは溶媒和物を有効成分とする抗うつ剤。
(Wherein one of R 1 to R 4 represents a COR 8, three other R 1 to R 4 are the same or different, a hydrogen atom, a halogen atom, OH, NO 2, CN, Alkyl, cycloalkyl, alkoxy, alkylcarbonylamino, alkylcarbonyloxy, arylcarbonyloxy, carbamoyl, arylcarbonylamino, aryl, aralkyl, alkylcarbonyl, SH or alkylthio. R 1 and R 2 , R 2 and R 3 , R 3 and R 4 represent a methylenedioxy, or together with the carbon atom to which they are attached, a cyclopentene ring, a cyclopentadiene ring, a cyclohexene ring, a cyclohexadiene ring, a benzene ring, or a 5-membered or A 6-membered heterocycle may be formed.
R 5 represents a hydrogen atom, a halogen atom, an alkyl, an alkoxy, an aryl, an aralkyl, a hydroxyalkyl or a cycloalkyl. R 4 and R 5 may be combined with the carbon atom to which they are bonded to form a benzene ring which may have a substituent or a pyridine ring which may have a substituent.
R 6 and R 7 are the same or different and represent hydrogen atom, alkyl, alkoxy, aryl, aralkyl, hydroxyalkyl or cycloalkyl. However, R 6 and R 7 do not become hydrogen atoms at the same time.
R 8 represents OH, alkoxy, hydroxyalkyloxy, cycloalkyloxy, aryloxy or aralkyloxy.
Z indicates N or CR 9 . R 9 represents a hydrogen atom, alkyl, aryl or aralkyl.
n represents an integer from 0 to 5. )
A compound represented by, or a pharmaceutically acceptable salt or solvate thereof.
Item 2. A pharmaceutical composition containing the compound according to Item 1 or a pharmaceutically acceptable salt or solvate thereof and a pharmaceutically acceptable excipient.
Item 3. A KDM5C inhibitor containing the compound according to Item 1 or a pharmaceutically acceptable salt or solvate thereof as an active ingredient.
Item 4. An antidepressant containing the compound according to Item 1 or a pharmaceutically acceptable salt or solvate thereof as an active ingredient.
本発明によれば、強力なＫＤＭ５Ｃ阻害作用を有する抗うつ剤を提供することができる。 According to the present invention, it is possible to provide an antidepressant having a strong KDM5C inhibitory action.
本発明の化合物は、下記式（Ｉ） The compound of the present invention has the following formula (I).
（式中、Ｒ１〜Ｒ７、Ｚ、ｎは、前記に定義された通りである。）
で表される化合物、またはその薬学的に許容される塩もしくは溶媒和物である。
(In the formula, R 1 to R 7 , Z, n are as defined above.)
A compound represented by, or a pharmaceutically acceptable salt or solvate thereof.
本発明の１つの好ましい実施形態において、Ｒ３はＣＯＲ８を示し、Ｒ１、Ｒ２、Ｒ４は同一または相異なり、水素原子、ハロゲン原子、ＯＨ、ＮＯ２、ＣＮ、アルキル、シクロアルキル、アルコキシ、アルキルカルボニルオキシ、アリールカルボニルオキシ、カルバモイル、アルキルカルボニルアミノ、アリール、アラルキル、アルキルカルボニル、ＳＨ又はアルキルチオを示す。Ｒ１とＲ２は、メチレンジオキシを表わすか、或いは、これらが結合している炭素原子と一緒になってシクロペンテン環、シクロペンタジエン環、シクロヘキセン環、シクロヘキサジエン環、ベンゼン環、或いは５員又は６員のヘテロ環を形成してもよい。 In one preferred embodiment of the invention, R 3 represents COR 8 and R 1 , R 2 , R 4 are the same or different, hydrogen atom, halogen atom, OH, NO 2 , CN, alkyl, cycloalkyl, Alkoxy, alkylcarbonyloxy, arylcarbonyloxy, carbamoyl, alkylcarbonylamino, aryl, aralkyl, alkylcarbonyl, SH or alkylthio. R 1 and R 2 represent methylenedioxy, or together with the carbon atom to which they are attached, cyclopentene ring, cyclopentadiene ring, cyclohexene ring, cyclohexadiene ring, benzene ring, or 5-membered or A 6-membered heterocycle may be formed.
本発明の他の１つの好ましい実施形態において、Ｒ２はＣＯＲ８を示し、Ｒ１、Ｒ３、Ｒ４は同一または相異なり、水素原子、ハロゲン原子、ＯＨ、ＮＯ２、ＣＮ、アルキル、シクロアルキル、アルコキシ、アルキルカルボニルオキシ、アリールカルボニルオキシ、カルバモイル、アルキルカルボニルアミノ、アリール、アラルキル、アルキルカルボニル、ＳＨ又はアルキルチオを示す。Ｒ３とＲ４は、メチレンジオキシを表わすか、或いは、これらが結合している炭素原子と一緒になってシクロペンテン環、シクロペンタジエン環、シクロヘキセン環、シクロヘキサジエン環、ベンゼン環、或いは５員又は６員のヘテロ環を形成してもよい。 In another preferred embodiment of the invention, R 2 represents COR 8 and R 1 , R 3 and R 4 are the same or different, hydrogen atom, halogen atom, OH, NO 2 , CN, alkyl, cyclo. Indicates alkyl, alkoxy, alkylcarbonyloxy, arylcarbonyloxy, carbamoyl, alkylcarbonylamino, aryl, aralkyl, alkylcarbonyl, SH or alkylthio. R 3 and R 4 represent methylenedioxy, or together with the carbon atom to which they are attached, cyclopentene ring, cyclopentadiene ring, cyclohexene ring, cyclohexadiene ring, benzene ring, or 5-membered or A 6-membered heterocycle may be formed.
本発明の他の１つの好ましい実施形態において、Ｒ１はＣＯＲ８を示し、Ｒ２〜Ｒ４は同一または相異なり、水素原子、ハロゲン原子、ＯＨ、ＮＯ２、ＣＮ、アルキル、シクロアルキル、アルコキシ、アルキルカルボニルオキシ、アリールカルボニルオキシ、カルバモイル、アルキルカルボニルアミノ、アリール、アラルキル、アルキルカルボニル、ＳＨ又はアルキルチオを示す。Ｒ２とＲ３、Ｒ３とＲ４は、メチレンジオキシを表わすか、或いは、これらが結合している炭素原子と一緒になってシクロペンテン環、シクロペンタジエン環、シクロヘキセン環、シクロヘキサジエン環、ベンゼン環、或いは５員又は６員のヘテロ環を形成してもよい。 In another preferred embodiment of the invention, R 1 represents COR 8 and R 2 to R 4 are the same or different, hydrogen atom, halogen atom, OH, NO 2 , CN, alkyl, cycloalkyl, alkoxy. , Alkoxycarbonyloxy, arylcarbonyloxy, carbamoyl, alkylcarbonylamino, aryl, aralkyl, alkylcarbonyl, SH or alkylthio. R 2 and R 3 , R 3 and R 4 represent methylenedioxy, or together with the carbon atom to which they are attached, cyclopentene ring, cyclopentadiene ring, cyclohexene ring, cyclohexadiene ring, benzene. A ring or a 5- or 6-membered heterocycle may be formed.
本発明の他の１つの好ましい実施形態において、Ｒ５は水素原子、フッ素原子又はアルキルである。 In another a preferred embodiment of the present invention, R 5 is hydrogen atom, a fluorine atom or an alkyl.
本発明の他の１つの好ましい実施形態において、Ｒ６、Ｒ７は、同一または相異なり、水素原子、アルキル、アラルキル、ヒドロキシアルキル又はシクロアルキルを示し、より好ましくはアルキルを示す。 In another preferred embodiment of the invention, R 6 and R 7 represent the same or different, hydrogen atom, alkyl, aralkyl, hydroxyalkyl or cycloalkyl, more preferably alkyl.
本発明の他の１つの好ましい実施形態において、Ｒ８はＯＨ、アルコキシ、アリールオキシ又はアラルキルオキシである。 In another a preferred embodiment of the present invention, R 8 is OH, alkoxy, aryloxy or aralkyloxy.
本発明の他の１つの好ましい実施形態において、Ｒ９は水素原子又はアルキルである。 In another preferred embodiment of the invention, R 9 is a hydrogen atom or alkyl.
本発明の他の１つの好ましい実施形態において、一般式（Ｉ）で表される本発明の好ましい化合物は、Ｒ３がＣＯＲ８を示し、Ｒ１、Ｒ２、Ｒ４、Ｒ５がいずれも水素原子である。 In another preferred embodiment of the present invention, in the preferred compound of the present invention represented by the general formula (I), R 3 represents COR 8 , and R 1 , R 2 , R 4 , and R 5 are all. It is a hydrogen atom.
ｎは０〜５の整数、好ましくは０〜４の整数、より好ましくは１〜３の整数、さらに好ましくは１又は２、特に好ましくは１である。 n is an integer of 0 to 5, preferably an integer of 0 to 4, more preferably an integer of 1 to 3, more preferably 1 or 2, and particularly preferably 1.
Ｚは、Ｎ(窒素原子)又はＣＲ９、より好ましくはＮである。 Z is N (nitrogen atom) or CR 9 , more preferably N.
溶媒和物を構成する溶媒としては、水、アルコール(メタノール、エタノール、ｎ−プロパノール、イソプロパノール、ブタノールなど)、アセトン、メチルエチルケトン、酢酸エチル、テトラヒドロフラン、ジエチルエーテル、ジイソプロピルエーテル、ベンゼン、トルエン、塩化メチレン、クロロホルム、アセトニトリル、ジメチルホルムアミド、ジメチルスルホキシドなどが挙げられる。 Solvents constituting the solvent include water, alcohol (methanol, ethanol, n-propanol, isopropanol, butanol, etc.), acetone, methyl ethyl ketone, ethyl acetate, tetrahydrofuran, diethyl ether, diisopropyl ether, benzene, toluene, methylene chloride, etc. Examples thereof include chloroform, acetonitrile, dimethylformamide and dimethyl sulfoxide.
薬学的に許容される塩としては、ナトリウム塩、カリウム塩、リチウム塩などのアルカリ金属塩、フッ酸塩、塩酸塩、臭化水素酸塩、ヨウ化水素酸塩、硫酸塩、硝酸塩、リン酸塩、過塩素酸塩などの無機酸塩、メタンスルホン酸塩、エタンスルホン酸塩、ベンゼンスルホン酸塩、トルエンスルホン酸塩、酢酸塩、乳酸塩、マレイン酸塩、フマル酸塩、コハク酸塩、クエン酸塩、ピルビン酸塩、安息香酸塩などの有機酸塩が挙げられる。 Pharmaceutically acceptable salts include alkali metal salts such as sodium salts, potassium salts and lithium salts, phosphates, hydrochlorides, hydrobromite, hydroiodide, sulfates, nitrates and phosphates. Inorganic acid salts such as salts and perchlorates, methane sulfonates, ethane sulfonates, benzene sulfonates, toluene sulfonates, acetates, lactates, maleates, fumarates, succinates, Examples include organic acid salts such as citrate, pyruvate and benzoate.
本明細書において、ハロゲン原子としては、フッ素原子、塩素原子、臭素原子、ヨウ素原子が挙げられ、フッ素原子、塩素原子、臭素原子が好ましく、フッ素原子、塩素原子がより好ましい。 In the present specification, examples of the halogen atom include a fluorine atom, a chlorine atom, a bromine atom and an iodine atom, preferably a fluorine atom, a chlorine atom and a bromine atom, and more preferably a fluorine atom and a chlorine atom.
アルキルとしては、メチル、エチル、ｎ−プロピル、イソプロピル、ｎ−ブチル、イソブチル、tert−ブチル、ｎ−ペンチル、イソペンチル、ヘキシル、ヘプチル、オクチル、２−エチルヘキシル、ノニル、デシル等の直鎖又は分枝を有するＣ１−１０アルキル、好ましくはＣ１−８アルキル、より好ましくはＣ１−６アルキルが挙げられる。 As alkyl, linear or branched such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, hexyl, heptyl, octyl, 2-ethylhexyl, nonyl, decyl and the like. C 1-10 alkyl having, preferably C 1-8 alkyl, more preferably C 1-6 alkyl.
アルキルチオとしては、メチルチオ、エチルチオ、ｎ−プロピルチオ、イソプロピルチオ、ｎ−ブチルチオ、イソブチルチオ、tert−ブチルチオ、ｎ−ペンチルチオ、イソペンチルチオ、ヘキシルチオ等の直鎖又は分枝を有するＣ１−６アルキルチオが挙げられる。 Examples of the alkyl thio include C 1-6 alkyl thio having a linear or branched structure such as methyl thio, ethyl thio, n-propyl thio, isopropyl thio, n-butyl thio, iso butyl thio, tert-butyl thio, n-pentyl thio, isopen til thio, and hexyl thio. Can be mentioned.
ヒドロキシアルキルとしては、ヒドロキシメチル、２−ヒドロキシエチル、３−ヒドロキシプロピル、４−ヒドロキシブチル、５−ヒドロキシペンチル、６−ヒドロキシヘキシル等のＣ１−６ヒドロキシアルキルが挙げられる。 Examples of the hydroxyalkyl include C 1-6 hydroxyalkyl such as hydroxymethyl, 2-hydroxyethyl, 3-hydroxypropyl, 4-hydroxybutyl, 5-hydroxypentyl and 6-hydroxyhexyl.
ヒドロキシアルキルオキシとしては、ヒドロキシメチルオキシ、２−ヒドロキシエチルオキシ、３−ヒドロキシプロピルオキシ、４−ヒドロキシブチルオキシ、５−ヒドロキシペンチルオキシ、６−ヒドロキシヘキシルオキシ等のＣ１−６ヒドロキシアルキルオキシが挙げられる。 Examples of hydroxyalkyloxy include C 1-6 hydroxyalkyloxy such as hydroxymethyloxy, 2-hydroxyethyloxy, 3-hydroxypropyloxy, 4-hydroxybutyloxy, 5-hydroxypentyloxy, and 6-hydroxyhexyloxy. Be done.
シクロアルキルとしては、シクロプロピル、シクロブチル、シクロペンチル、シクロヘキシル及びシクロヘプチル等のＣ３−７シクロアルキルが挙げられる。 Examples of cycloalkyl include C 3-7 cycloalkyl such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl.
シクロアルキルオキシとしては、シクロプロピルオキシ、シクロブチルオキシ、シクロペンチルオキシ、シクロヘキシルオキシ及びシクロヘプチルオキシ等のＣ３−７シクロアルキルオキシが挙げられる。 Examples of cycloalkyloxy include C 3-7 cycloalkyloxy such as cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy and cycloheptyloxy.
アルキルカルボニルアミノとしては、メチルカルボニルアミノ、エチルカルボニルアミノ、ｎ−プロピルカルボニルアミノ、イソプロピルカルボニルアミノ、ｎ−ブチルカルボニルアミノ、イソブチルカルボニルアミノ、tert−ブチルカルボニルアミノ、ｎ−ペンチルカルボニルアミノ、イソペンチルカルボニルアミノ、ヘキシルカルボニルアミノ等の直鎖又は分岐を有するＣ１−６アルキルカルボニルアミノが挙げられる。 Examples of the alkylcarbonylamino include methylcarbonylamino, ethylcarbonylamino, n-propylcarbonylamino, isopropylcarbonylamino, n-butylcarbonylamino, isobutylcarbonylamino, tert-butylcarbonylamino, n-pentylcarbonylamino and isopentylcarbonylamino. , C 1-6 alkylcarbonylamino having a linear or branched such as hexylcarbonylamino.
アルキルカルボニルとしては、メチルカルボニル、エチルカルボニル、ｎ−プロピルカルボニル、イソプロピルカルボニル、ｎ−ブチルカルボニル、イソブチルカルボニル、tert−ブチルカルボニル、ｎ−ペンチルカルボニル、イソペンチルカルボニル、ヘキシルカルボニル等の直鎖又は分岐を有するＣ１−６アルキルカルボニルが挙げられる。 As the alkylcarbonyl, linear or branched such as methylcarbonyl, ethylcarbonyl, n-propylcarbonyl, isopropylcarbonyl, n-butylcarbonyl, isobutylcarbonyl, tert-butylcarbonyl, n-pentylcarbonyl, isopentylcarbonyl, hexylcarbonyl and the like. C 1-6 alkylcarbonyl having is mentioned.
アリールとしては、５又は６員の芳香族炭化水素環からなる単環又は多環系の基を意味し、具体的には、フェニル、ナフチル、フルオレニル、アントリル、ビフェニリル、テトラヒドロナフチル、クロマニル、２，３−ジヒドロ−１，４−ジオキサナフタレニル、インダニル及びフェナントリルが挙げられる。 Aryl means a monocyclic or polycyclic group consisting of a 5- or 6-membered aromatic hydrocarbon ring, and specifically, phenyl, naphthyl, fluorenyl, anthryl, biphenylyl, tetrahydronaphthyl, chromanyl, 2, Included are 3-dihydro-1,4-dioxanaphthalenyl, indanyl and phenyl.
５員又は６員のヘテロ環としては、フラン、チオフェン、ピロール、イミダゾール、ピラゾール、オキサゾール、チアゾール、イソオキサゾール、イソチアゾール、ピリジン、ピラジン、ピリミジン、ピリダジンが挙げられる。 Examples of the 5- or 6-membered heterocycle include furan, thiophene, pyrrole, imidazole, pyrazole, oxazole, thiazole, isoxazole, isothiazole, pyridine, pyrazine, pyrimidine, and pyridazine.
アルキルカルボニルオキシの具体例としては、メチルカルボニルオキシ、エチルカルボニルオキシ、ｎ−プロピルカルボニルオキシ、イソプロピルカルボニルオキシ、ｎ−ブチルカルボニルオキシ、イソブチルカルボニルオキシ、tert−ブチルカルボニルオキシ、ｎ−ペンチルカルボニルオキシ、イソペンチルカルボニルオキシ、ヘキシルカルボニルオキシ等のＣ１−６アルキルカルボニルオキシが挙げられる。 Specific examples of alkylcarbonyloxy include methylcarbonyloxy, ethylcarbonyloxy, n-propylcarbonyloxy, isopropylcarbonyloxy, n-butylcarbonyloxy, isobutylcarbonyloxy, tert-butylcarbonyloxy, n-pentylcarbonyloxy, iso. Examples thereof include C 1-6 alkylcarbonyloxy such as pentylcarbonyloxy and hexylcarbonyloxy.
アリールカルボニルオキシの具体例としては、フェニルカルボニルオキシ、ナフチルカルボニルオキシ、フルオレニルカルボニルオキシ、アントリルカルボニルオキシ、ビフェニリルカルボニルオキシ、テトラヒドロナフチルカルボニルオキシ、クロマニルカルボニルオキシ、２，３−ジヒドロ−１，４−ジオキサナフタレニルカルボニルオキシ、インダニルカルボニルオキシ及びフェナントリルカルボニルオキシが挙げられる。 Specific examples of arylcarbonyloxy include phenylcarbonyloxy, naphthylcarbonyloxy, fluorenylcarbonyloxy, anthrylcarbonyloxy, biphenylylcarbonyloxy, tetrahydronaphthylcarbonyloxy, chromanylcarbonyloxy, 2,3-dihydro-1. , 4-Dioxanaphthalenylcarbonyloxy, indanylcarbonyloxy and phenanthrylcarbonyloxy.
アリールカルボニルアミノの具体例としては、フェニルカルボニルアミノ、ナフチルカルボニルアミノ、フルオレニルカルボニルアミノ、アントリルカルボニルアミノ、ビフェニリルカルボニルアミノ、テトラヒドロナフチルカルボニルアミノ、クロマニルカルボニルアミノ、２，３−ジヒドロ−１，４−ジオキサナフタレニルカルボニルアミノ、インダニルカルボニルアミノ及びフェナントリルカルボニルアミノが挙げられる。 Specific examples of arylcarbonylamino include phenylcarbonylamino, naphthylcarbonylamino, fluorenylcarbonylamino, anthrylcarbonylamino, biphenylylcarbonylamino, tetrahydronaphthylcarbonylamino, chromanylcarbonylamino, 2,3-dihydro-1. , 4-Dioxanaphthalenylcarbonylamino, indanylcarbonylamino and phenanthrylcarbonylamino.
アルコキシの具体例としては、メトキシ、エトキシ、ｎ−プロポキシ、イソプロポキシ、ｎ−ブトキシ、イソブトキシ、tert−ブトキシ、ｎ−ペンチルオキシ、イソペンチルオキシ、ヘキシルオキシ等の直鎖又は分岐を有するＣ１−６アルコキシが挙げられる。 Specific examples of alkoxy include C 1- having a linear or branched structure such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, n-pentyloxy, isopentyloxy, and hexyloxy. 6 Alkoxy can be mentioned.
アリールオキシの具体例としては、フェニルオキシ、ナフチルオキシ、フルオレニルオキシ、アントリルオキシ、ビフェニリルオキシ、テトラヒドロナフチルオキシ、クロマニルオキシ、２，３−ジヒドロ−１，４−ジオキサナフタレニルオキシ、インダニルオキシ及びフェナントリルオキシが挙げられる。 Specific examples of aryloxy include phenyloxy, naphthyloxy, fluorenyloxy, anthryloxy, biphenylyloxy, tetrahydronaphthyloxy, cromanyloxy, 2,3-dihydro-1,4-dioxanaphthalenyl. Examples include oxy, indanyloxy and phenanthryloxy.
アラルキルの具体例としては、ベンジル、ナフチルメチル、フルオレニルメチル、アントリルメチル、ビフェニリルメチル、テトラヒドロナフチルメチル、クロマニルメチル、２，３−ジヒドロ−１，４−ジオキサナフタレニルメチル、インダニルメチル及びフェナントリルメチル、フェネチル、ナフチルエチル、フルオレニルエチル、アントリルエチル、ビフェニリルエチル、テトラヒドロナフチルエチル、クロマニルエチル、２，３−ジヒドロ−１，４−ジオキサナフタレニルエチル、インダニルエチル及びフェナントリルエチルが挙げられる。 Specific examples of aralkyl include benzyl, naphthylmethyl, fluorenylmethyl, anthrylmethyl, biphenylylmethyl, tetrahydronaphthylmethyl, chromanylmethyl, 2,3-dihydro-1,4-dioxanaphthalenylmethyl, Indanylmethyl and phenanthrylmethyl, phenethyl, naphthylethyl, fluorenylethyl, anthrylethyl, biphenylylethyl, tetrahydronaphthylethyl, chromanylethyl, 2,3-dihydro-1,4-dioxanaphthalenyl Included are ethyl, indanyl ethyl and phenanthryl ethyl.
アラルキルオキシの具体例としては、ベンジルオキシ、ナフチルメチルオキシ、フルオレニルメチルオキシ、アントリルメチルオキシ、ビフェニリルメチルオキシ、テトラヒドロナフチルメチルオキシ、クロマニルメチルオキシ、２，３−ジヒドロ−１，４−ジオキサナフタレニルメチルオキシ、インダニルメチルオキシ及びフェナントリルメチルオキシ、フェネチルオキシ、ナフチルエチルオキシ、フルオレニルエチルオキシ、アントリルエチルオキシ、ビフェニリルエチルオキシ、テトラヒドロナフチルエチルオキシ、クロマニルエチルオキシ、２，３−ジヒドロ−１，４−ジオキサナフタレニルエチルオキシ、インダニルエチルオキシ及びフェナントリルエチルオキシが挙げられる。 Specific examples of aralkyloxy include benzyloxy, naphthylmethyloxy, fluorenylmethyloxy, anthrylmethyloxy, biphenylylmethyloxy, tetrahydronaphthylmethyloxy, chromanylmethyloxy, 2,3-dihydro-1,4. -Dioxanaphthalenylmethyloxy, indanylmethyloxy and phenanthrylmethyloxy, phenethyloxy, naphthylethyloxy, fluorenylethyloxy, anthrylethyloxy, biphenylylethyloxy, tetrahydronaphthylethyloxy, chromanyl Ethyloxy, 2,3-dihydro-1,4-dioxanaphthalenylethyloxy, indanylethyloxy and phenanthrylethyloxy can be mentioned.
置換基を有していてもよいベンゼン環又は置換基を有していてもよいピリジン環の置換基としては、ハロゲン原子、ＯＨ、ＮＯ２、ＣＮ、アルキル、シクロアルキル、アルコキシ、アルキルカルボニルオキシ、アリールカルボニルオキシ、アミノ、カルバモイル、アルキルカルボニルアミノ、アリール、アラルキル、アルキルカルボニル、ＳＨ又はアルキルチオが挙げられる。 Substituents of the benzene ring which may have a substituent or the pyridine ring which may have a substituent include halogen atom, OH, NO 2 , CN, alkyl, cycloalkyl, alkoxy, alkylcarbonyloxy, and the like. Arylcarbonyloxy, amino, carbamoyl, alkylcarbonylamino, aryl, aralkyl, alkylcarbonyl, SH or alkylthio.
本発明の化合物は、以下のスキーム１〜３に従い製造することができる。
スキーム１
The compounds of the present invention can be produced according to the following schemes 1-3.
Scheme 1
（式中、Ｒ１〜Ｒ４、Ｒ６、Ｒ７、ｎは前記に定義される通りである。）
スキーム２
(In the equation, R 1 to R 4 , R 6 , R 7 , and n are as defined above.)
Scheme 2
（式中、Ｒ１〜Ｒ７、Ｚ、ｎは前記に定義される通りである。Ｘは脱離基を示す。）
スキーム３
(In the formula, R 1 to R 7 , Z, n are as defined above. X indicates a leaving group.)
Scheme 3
（式中、Ｒ１〜Ｒ７、Ｚ、ｎは前記に定義される通りである。Ｘは脱離基を示す。）
スキーム１において、化合物（１）１モルに対し化合物（２）を１モルから過剰量、硫酸銅を１モルから過剰量、アスコルビン酸を１モルから過剰量使用し、クリックケミストリーにより溶媒の存在下に１０℃〜溶媒の沸点程度の温度下に１〜２４時間反応させることで、Ｒ５＝Ｈ、Ｚ＝Ｎである本発明の化合物（ＩＡ）を得ることができる。
(In the formula, R 1 to R 7 , Z, n are as defined above. X indicates a leaving group.)
In Scheme 1, 1 mol to excess of compound (2), 1 mol to excess of copper sulphate, 1 mol to excess of ascorbic acid was used per 1 mol of compound (1), and in the presence of a solvent by click chemistry. to 10 ° C. ~ be to 1-24 hours to a temperature of about the boiling point of the solvent, it is possible to obtain R 5 = H, the compounds of the invention which are Z = N a (IA).
スキーム２において、化合物（３）１モルに対し化合物（４）を１モルから過剰量使用し、必要に応じて塩基及び溶媒の存在下に１０℃〜溶媒の沸点程度の温度下に１〜２４時間反応させることで、本発明の一般式（Ｉ）の化合物を得ることができる。 In Scheme 2, 1 mol to 1 mol of compound (4) is used in excess of 1 mol of compound (3), and if necessary, 1 to 24 at a temperature of 10 ° C. to about the boiling point of the solvent in the presence of a base and a solvent. By reacting for a time, the compound of the general formula (I) of the present invention can be obtained.
スキーム３において、化合物（５）１モルに対し化合物（６）を１モルから過剰量使用し、必要に応じて塩基及び溶媒の存在下に１０℃〜溶媒の沸点程度の温度下に１〜２４時間反応させることで、本発明の一般式（Ｉ）の化合物を得ることができる。 In Scheme 3, 1 mol to 1 mol of compound (6) is used in excess of 1 mol of compound (5), and if necessary, 1 to 24 at a temperature of 10 ° C. to about the boiling point of the solvent in the presence of a base and a solvent. By reacting for a time, the compound of the general formula (I) of the present invention can be obtained.
スキーム１〜３の反応において、溶媒としては、塩化メチレン、１，２−ジクロロエタンなどの塩素化炭化水素、トルエン等の芳香族溶媒、酢酸エチルなどのエステル系溶媒、アセトン、メチルエチルケトンなどのケトン系溶媒、ジエチルエーテル、テトラヒドロフランなどのエーテル系溶媒が挙げられる。 In the reactions of Schemes 1 to 3, the solvent used is a chlorinated hydrocarbon such as methylene chloride and 1,2-dichloroethane, an aromatic solvent such as toluene, an ester solvent such as ethyl acetate, and a ketone solvent such as acetone and methyl ethyl ketone. , Diethyl ether, tetrahydrofuran and other ether solvents.
スキーム２〜３の反応において、塩基としては、ＤＢＵ、ピリジン、トリエチルアミン、ジイソプロピルエチルアミンなどが挙げられる。 In the reactions of Schemes 2-3, examples of the base include DBU, pyridine, triethylamine, diisopropylethylamine and the like.
脱離基としては、塩素原子、臭素原子、p-トルエンスルホニルオキシ（Ts-O）、ベンゼンスルホニルオキシ、メタンスルホニルオキシ(Ms-O)などが挙げられる。 Examples of the leaving group include a chlorine atom, a bromine atom, p-toluenesulfonyloxy (Ts-O), benzenesulfonyloxy, and methanesulfonyloxy (Ms-O).
本発明の好ましい化合物は、ＫＤＭ５Ｃ（Lysine-specific demethylase 5C）阻害剤であり、より好ましくはＫＤＭ５Ｃを選択的に阻害する。ＫＤＭ５Ｃに対するＩＣ５０は１００ｎＭ以下が好ましく、５０ｎＭ以下がより好ましく、１０ｎＭ以下がさらに好ましい。また、ＫＤＭ５Ｃに対するＩＣ５０はＫＤＭ５Ａに対するＩＣ５０よりも１０倍以上低いことが好ましく、５０倍以上低いことがより好ましく、１００倍以上低いことがさらに好ましい。 A preferred compound of the present invention is a KDM5C (Lysine-specific demethylase 5C) inhibitor, more preferably a selective inhibitor of KDM5C. The IC 50 for KDM5C is preferably 100 nM or less, more preferably 50 nM or less, and even more preferably 10 nM or less. Further, IC 50 for KDM5C it is preferably lower by 10 times or more IC 50 for KDM5A, more preferably less than 50 times, more preferably 100 times or more lower.
本発明の化合物は、ＫＤＭ５Ｃの強力な阻害作用を有し、抗うつ剤として好ましい。 The compound of the present invention has a strong inhibitory effect on KDM5C and is preferable as an antidepressant.
本発明の化合物を有効成分とする医薬は、その使用目的に合わせて投与方法、剤型、投与量を適宜決定することが可能である。例えば、本発明の化合物を有効成分とする医薬の投与形態は、経口投与でも非経口投与でも良い。剤型としては、例えば錠剤、粉剤、カプセル剤、顆粒剤、エキス剤、シロップ剤等の経口投与剤、または注射剤、点滴剤、もしくは坐剤等の非経口投与剤を挙げることができる。これらの製剤は、本発明の化合物と薬学的に許容される賦形剤を含む医薬組成物として製造することができる。本発明の化合物の抗うつ剤としての有効量は、通常、成人一日当たり経口投与の場合、0.1-1000 mg、非経口投与の場合0.01-200 mg程度が適当であり、これを一日に一回乃至複数回投与する。投与量は種々の条件で変動するので、上記投与量範囲より少ない量で充分な場合もある。 The administration method, dosage form, and dosage of the drug containing the compound of the present invention as an active ingredient can be appropriately determined according to the purpose of use. For example, the administration form of the drug containing the compound of the present invention as an active ingredient may be oral administration or parenteral administration. Examples of the dosage form include oral administrations such as tablets, powders, capsules, granules, extracts and syrups, and parenteral administrations such as injections, infusions and suppositories. These preparations can be produced as pharmaceutical compositions containing the compounds of the present invention and pharmaceutically acceptable excipients. The effective amount of the compound of the present invention as an antidepressant is usually about 0.1-1000 mg for oral administration per day for adults and 0.01-200 mg for parenteral administration, and this should be applied once a day. Administer multiple times or multiple times. Since the dose varies under various conditions, an amount smaller than the above dose range may be sufficient.
以下、実施例を参照して本発明を更に具体的に説明するが、本発明は以下の特定の実施例に限定されるものではない。 Hereinafter, the present invention will be described in more detail with reference to Examples, but the present invention is not limited to the following specific Examples.
・分析
融点はYanagimoto製融点測定装置を用いて測定した。
1H NMR(300 MHz)および13C NMR（75 MHz）はBRUKER社 AVANCE300 AV spectrometerを用いて測定した。化学シフト(δ)は内部標準であるテトラメチルシランを元にparts per million (ppm)で示した。
Electrospray ionization (ESI) マススペクトルはBRUKER社HCT plus mass spectrometerを用いた。
HPLCは島津製HPLC装置にCOSMOSIL Packed Column(5C18-AR-II, 4.6ID×150 mm, ナカライ製)を取り付け、以下の条件で測定した。溶媒：（Ａ）0.1%TFA水溶液、（Ｂ）0.1%TFAアセトニトリル溶液。流速：1.0 mL/min。測定波長：254 nm。溶媒組成：A/B 0〜20 分(90/10 〜 10/90), 20〜30 分 (10/90), 30 〜 40 (10-90 〜 90/10).
·analysis
The melting point was measured using a melting point measuring device manufactured by Yanagimoto.
1 H NMR (300 MHz) and 13 C NMR (75 MHz) were measured using a BRUKER AVANCE300 AV spectrometer. The chemical shift (δ) is shown in parts per million (ppm) based on the internal standard tetramethylsilane.
For the Electrospray ionization (ESI) mass spectrum, BRUKER's HCT plus mass spectrometer was used.
For HPLC, a COSMOSIL Packed Column (5C 18 -AR-II, 4.6 ID x 150 mm, manufactured by Nakarai) was attached to an HPLC apparatus manufactured by Shimadzu, and the measurement was performed under the following conditions. Solvent: (A) 0.1% TFA aqueous solution, (B) 0.1% TFA acetonitrile solution. Flow velocity: 1.0 mL / min. Measurement wavelength: 254 nm. Solvent composition: A / B 0 to 20 minutes (90/10 to 10/90), 20 to 30 minutes (10/90), 30 to 40 (10-90 to 90/10).
・試薬
試薬と溶媒はAldrich、東京化成工業、キシダ化学、関東化学、和光純薬、ナカライテスクの市販品をそのまま使用した。カラムクロマトグラフィーはTOYOTAKAKO SILICA GEL製 (#AP300D)シリカゲル(粒径 200-440 mesh) を用いた。
-Reagents Reagents and solvents used were commercially available products from Aldrich, Tokyo Chemical Industry, Kishida Chemical, Kanto Chemical, Wako Pure Chemical Industries, and Nacalai Tesque. For column chromatography, silica gel (particle size 200-440 mesh) manufactured by TOYO TAKAKO SILICA GEL (# AP300D) was used.
KDM5阻害剤として報告されたCPI-455は、文献（Nat Chem Biol. 2016 Jul;12(7):531-8. doi: 10.1038/nchembio.2085. Epub 2016 May 23.）に従い合成した。 CPI-455 reported as a KDM5 inhibitor was synthesized according to the literature (Nat Chem Biol. 2016 Jul; 12 (7): 531-8. Doi: 10.1038 / nchembio.2085. Epub 2016 May 23.).
KDM5阻害剤として報告されたNCDM-81aは、文献(ACS Med. Chem. Lett.2015, 6, 6, 665-670)に従い合成した。 NCDM-81a, reported as a KDM5 inhibitor, was synthesized according to the literature (ACS Med. Chem. Lett. 2015, 6, 6, 665-670).
製造例１
2-Ethynylisoniconinic acid (Alk1)
Step 1. methyl 2-bromoisonicotinate (9).
2-ブロモニコチン酸 (1.46 g, 7.23 mmol)のジクロロメタン/メタノール(10.0 mL/15.0 mL)溶液にEDCI.HCl (1.36 g, 7.20 mmol)を加え20時間室温で撹拌した。反応終了後、溶媒を留去し、残渣をシリカゲルカラムクロマトグラフィー(酢酸エチル/n-ヘキサン = 1/10)で精製した。無色粉末固体1.35 gの生成物9を得た。収率87%。 1H NMR (CDCl3, 300 MHz, δ; ppm) 8.52 (dd, 1H, J = 4.2, 0.6 Hz), 8.02 (t, 1H, J = 6.6 Hz), 7.80 (dd, 1H, J = 3.9, 0.6 Hz), 3.97 (s, 3H); 13C NMR (CDCl3, 75 MHz, δ; ppm) 151.04, 144.26, 141.19, 129.15, 123.30, 54.40; MS (ESI) m/z 215.7, 217.7 (MH+).
Manufacturing example 1
2-Ethynylisoniconinic acid (Alk1)
Step 1. methyl 2-bromoisonicotinate (9).
EDCI . HCl (1.36 g, 7.20 mmol) was added to a solution of 2-bromonicotinic acid (1.46 g, 7.23 mmol) in dichloromethane / methanol (10.0 mL / 15.0 mL), and the mixture was stirred at room temperature for 20 hours. After completion of the reaction, the solvent was evaporated and the residue was purified by silica gel column chromatography (ethyl acetate / n-hexane = 1/10). Product 9 of 1.35 g of a colorless powder solid was obtained. Yield 87%. 1 H NMR (CDCl 3 , 300 MHz, δ; ppm) 8.52 (dd, 1H, J = 4.2, 0.6 Hz), 8.02 (t, 1H, J = 6.6 Hz), 7.80 (dd, 1H, J = 3.9, 0.6 Hz), 3.97 (s, 3H); 13 C NMR (CDCl 3 , 75 MHz, δ; ppm) 151.04, 144.26, 141.19, 129.15, 123.30, 54.40; MS (ESI) m / z 215.7, 217.7 (MH +) ).
Step 2: 4-trimethylsilylethynylpyridine-2-carboxylic acid methyl ester (10)
化合物 9 (216 mg, 1.00 mmol), PdCl2(PPh3)2 (36.0 mg, 51.2 μmol)とCuI (19.0 mg, 100 μmol)のトリエチルアミン(200 μL)/アセトニトリル(2.00 mL)溶液にトリメチルシリルアセチレン(165 μL, 1.17 mmol)をアルゴン雰囲気下で加えた。反応溶液を室温、アルゴン雰囲気下で3時間撹拌した。反応終了後、溶媒を留去し、残渣にジエチルエーテルを加え、ろ過により固体を除去した。ろ液を濃縮後、残渣をシリカゲルカラムクロマトグラフィー(酢酸エチル/n-ヘキサン= 1/10)で精製し、102 mgの黄色オイル状生成物10を得た。収率70%。1H NMR (CDCl3, 300 MHz, δ; ppm) 8.68 (dd, 1H, J = 4.2, 0.6 Hz), 7.97 (s, 1H), 7.73 (dd, 1H, J = 4.2, 0.6 Hz), 3.93 (s, 3H), 0.26 (s, 9H); 13C NMR (CDCl3, 75 MHz, δ; ppm) 151.04, 144.26, 138.20, 127.06, 122.58, 103.50, 96.86, 53.35, 0.18; MS (ESI) m/z 233.8 (MH+).
Step 2: 4-trimethylsilylethynylpyridine-2-carboxylic acid methyl ester (10)
Triethylamine (200 μL) / acetonitrile (2.00 mL) solution of compound 9 (216 mg, 1.00 mmol), PdCl 2 (PPh 3 ) 2 (36.0 mg, 51.2 μmol) and CuI (19.0 mg, 100 μmol) with trimethylsilylacetylene ( 165 μL, 1.17 mmol) was added under an argon atmosphere. The reaction solution was stirred at room temperature under an atmosphere of argon for 3 hours. After completion of the reaction, the solvent was distilled off, diethyl ether was added to the residue, and the solid was removed by filtration. After concentrating the filtrate, the residue was purified by silica gel column chromatography (ethyl acetate / n-hexane = 1/10) to give 102 mg of yellow oily product 10. Yield 70%. 1 H NMR (CDCl 3 , 300 MHz, δ; ppm) 8.68 (dd, 1H, J = 4.2, 0.6 Hz), 7.97 (s, 1H), 7.73 (dd, 1H, J = 4.2, 0.6 Hz), 3.93 (s, 3H), 0.26 (s, 9H); 13 C NMR (CDCl 3 , 75 MHz, δ; ppm) 151.04, 144.26, 138.20, 127.06, 122.58, 103.50, 96.86, 53.35, 0.18; MS (ESI) m / z 233.8 (MH + ).
Step 3: 2-Ethynyisonicotinic acid (Alk1)
化合物10 (50.0 mg, 215 μmol)のメタノール(2.00 mL)溶液に2 N水酸化ナトリウム水溶液 (236 μL, 472 μmol)を0 °Cで加えた。反応溶液を室温、12時間撹拌した。反応終了後、反応溶液に飽和クエン酸水溶液を加えpHを4.0に調整した。析出した固体をろ取し、水で洗浄後、乾燥させた。粗生成物をメタノール/酢酸エチル=2/1で再結晶し、29.4 mgの白色固体Alk1を得た。収率93%。mp 203-205 °C; 1H NMR (DMSO-d6, 300 MHz, δ; ppm) 8.75 (dd, 1H, J = 5.1, 0.9 Hz), 7.87-7.88 (m, 1H), 7.81 (dd, 1H, J = 4.8, 1.5 Hz), 4.45 (s, 1H); 13C NMR (DMSO-d6, 75 MHz, δ; ppm) 164.95, 150.97, 143.43, 137.88, 126.11, 122.75, 82.64, 81.05; Anal. Calcd. for C8H5NO1 : C, 65.31; H, 3.43; N, 9.52. Found: C, 64.91; H, 3.60; N, 9.28. HRMS (EI) Calcd. for C8H5O2N 147.0320, Found 147.0310.
Step 3: 2-Ethynyisonicotinic acid (Alk1)
A 2 N aqueous sodium hydroxide solution (236 μL, 472 μmol) was added to a solution of compound 10 (50.0 mg, 215 μmol) in methanol (2.00 mL) at 0 ° C. The reaction solution was stirred at room temperature for 12 hours. After completion of the reaction, a saturated aqueous citric acid solution was added to the reaction solution to adjust the pH to 4.0. The precipitated solid was collected by filtration, washed with water, and dried. The crude product was recrystallized from methanol / ethyl acetate = 2/1 to give 29.4 mg of white solid Alk1. Yield 93%. mp 203-205 ° C; 1 H NMR (DMSO-d 6 , 300 MHz, δ; ppm) 8.75 (dd, 1H, J = 5.1, 0.9 Hz), 7.87-7.88 (m, 1H), 7.81 (dd, dd, 1H, J = 4.8, 1.5 Hz), 4.45 (s, 1H); 13 C NMR (DMSO-d 6 , 75 MHz, δ; ppm) 164.95, 150.97, 143.43, 137.88, 126.11, 122.75, 82.64, 81.05; Anal Calcd. For C 8 H 5 NO 1 : C, 65.31; H, 3.43; N, 9.52. Found: C, 64.91; H, 3.60; N, 9.28. HRMS (EI) Calcd. For C8H5O2N 147.0320, Found 147.0310.
4-[N-(methylsulfonyl)]-2-ethynylpyridinecarboxamide (Alk2)
Alk1 (147 mg, 1.00 mmol)、EDCI.HCl (388 mg, 2.00 mmol)、およびDMAP (244 mg, 2.00 mmol)のジクロロメタン(15.0 mL)溶液にmethyl sulfonamide (189 mg, 2.00 mmol)を加え、室温で24時間撹拌した。反応溶液を水で洗浄し、水層を1N塩酸で酸性にした後、ジクロロメタンで抽出した。有機層を水で洗浄し、Na2SO4で乾燥したあと、エバポレータ―で溶媒を留去した。残渣をシリカゲルカラムクロマトグラフィー(ジクロロメタン/メタノール = 10/1)で精製し、56 mgの褐色固体Alk2を得た。収率26%。 mp 141-142 °C; 1H NMR (DMSO-d6, 300 MHz, δ; ppm) 8.76 (1H, dd, J = 4.5, 0.9 Hz), 8.00 (1H, q, J = 0.9 Hz), 7.82 (1H, dd, J = 3.6, 1.5 Hz), 4.50 (1H, s), 3.38 (3H, s); 13C NMR (DMSO-d6, 75 MHz, δ; ppm) 164.62, 151.02, 142.36, 139.99, 125.40, 121.88, 82.41, 81.39, 41.16; MS (ESI) m/z 225.1 (MH+); HPLC tR=7.58 min purity 96.5%. Anal. Calcd. for C8H5NO1 : C, 65.31; H, 3.43; N, 9.52. Found: C, 64.91; H, 3.60; N, 9.28. HRMS (EI) Calcd. for C8H5O2N 147.0320, Found 147.0310.
4- [N- (methylsulfonyl)]-2-ethynylpyridine carboxamide (Alk2)
Methyl sulfonamide (189 mg, 2.00 mmol) was added to a solution of Alk1 (147 mg, 1.00 mmol), EDCI . HCl (388 mg, 2.00 mmol), and DMAP (244 mg, 2.00 mmol) in dichloromethane (15.0 mL) at room temperature. Was stirred for 24 hours. The reaction solution was washed with water, the aqueous layer was acidified with 1N hydrochloric acid, and then extracted with dichloromethane. The organic layer was washed with water, dried over Na 2 SO 4 , and then the solvent was distilled off with an evaporator. The residue was purified by silica gel column chromatography (dichloromethane / methanol = 10/1) to give 56 mg of brown solid Alk2. Yield 26%. mp 141-142 ° C; 1 H NMR (DMSO-d 6 , 300 MHz, δ; ppm) 8.76 (1H, dd, J = 4.5, 0.9 Hz), 8.00 (1H, q, J = 0.9 Hz), 7.82 (1H, dd, J = 3.6, 1.5 Hz), 4.50 (1H, s), 3.38 (3H, s); 13 C NMR (DMSO-d 6 , 75 MHz, δ; ppm) 164.62, 151.02, 142.36, 139.99 , 125.40, 121.88, 82.41, 81.39, 41.16; MS (ESI) m / z 225.1 (MH + ); HPLC t R = 7.58 min purity 96.5%. Anal. Calcd. For C 8 H 5 NO 1 : C, 65.31; H, 3.43; N, 9.52. Found: C, 64.91; H, 3.60; N, 9.28. HRMS (EI) Calcd. For C8H5O2N 147.0320, Found 147.0310.
4-(2H-tetrazol-5-yl)-pyridine (Alk3)
Step 1:4-cyano-2-[2-(trimethylsilyl) ethynyl] pyridine (12)
2-chloro-4-cyanopyridine 11 (1.40 g, 10.0 mmol)、PdCl2(PPh3)2(138 mg, 330 μmol)およびCuI (38.0 mg, 330 μmol)のトリエチルアミン(20.0 mL)/アセトニトリル(20.0 mL)溶液にトリメチルシリルアセチレン(2.20 mL, 15.0 mmol)をアルゴン雰囲気下で加え、反応溶液をアルゴン雰囲気下3時間60 °Cで加熱した。反応終了後、溶媒をエバポレーターで留去し、ジエチルエーテルを加え1 N塩酸、飽和NaHCO3水溶液、brineで有機層を洗浄、Na2SO4で乾燥させた。溶媒を留去後、残渣をカラムクロマトグラフィー(酢酸エチル/n-ヘキサン = 1/10)で精製し、1.96 gの黄白色固体12を得た。収率98%。 mp 46.0-48.0 °C 1H NMR (CDCl3, 300 MHz, δ; ppm) 8.75 (1H, dd, J = 4.2, 0.9 Hz), 7.67 (1H, q, J = 0.3 Hz), 7.44 (1H, dd, J = 3.6, 1.5 Hz), 0.30 (9H, s); 13C NMR (CDCl3, 75 MHz, δ; ppm) 151.04, 144.62, 128.74, 124.15, 121.04, 115.89, 101.82, 98.78, 0.36; MS (ESI) m/z201.1 (MH+).
4- (2H-tetrazol-5-yl) -pyridine (Alk3)
Step 1: 4-cyano-2- [2- (trimethylsilyl) ethynyl] pyridine (12)
2-chloro-4-cyanopyridine 11 (1.40 g, 10.0 mmol), PdCl 2 (PPh 3 ) 2 (138 mg, 330 μmol) and CuI (38.0 mg, 330 μmol) triethylamine (20.0 mL) / acetonitrile (20.0 mL) ) Trimethylsilylacetylene (2.20 mL, 15.0 mmol) was added to the solution under an argon atmosphere, and the reaction solution was heated at 60 ° C for 3 hours under an argon atmosphere. After completion of the reaction, the solvent was distilled off with an evaporator, diethyl ether was added, the organic layer was washed with 1 N hydrochloric acid, saturated acrylamide 3 aqueous solution, and brine, and dried with Na 2 SO 4 . After distilling off the solvent, the residue was purified by column chromatography (ethyl acetate / n-hexane = 1/10) to obtain 1.96 g of a yellowish white solid 12. Yield 98%. mp 46.0-48.0 ° C 1 H NMR (CDCl 3 , 300 MHz, δ; ppm) 8.75 (1H, dd, J = 4.2, 0.9 Hz), 7.67 (1H, q, J = 0.3 Hz), 7.44 (1H, 1H, dd, J = 3.6, 1.5 Hz), 0.30 (9H, s); 13 C NMR (CDCl 3 , 75 MHz, δ; ppm) 151.04, 144.62, 128.74, 124.15, 121.04, 115.89, 101.82, 98.78, 0.36; MS (ESI) m / z201.1 (MH + ).
Step 2: 4-cyano-2-ethynylpyridine (13)
化合物12 (1.96 g, 9.79 mmol)のジクロロメタン(25.0 mL)溶液に1 M TBAF/THF (14.0 mL, 14.0 mmol)を0 °Cで加え、反応溶液を2時間、0 °Cで撹拌した。反応終了後、酢酸エチルを加え、有機層を水で洗浄し、Na2SO4で乾燥した。溶媒を留去後、残渣をシリカゲルカラムクロマトグラフィー(酢酸エチル/n-ヘキサン = 1/3)で精製し、黄白色固体13を823 mg得た。収率66%。 mp 104-106 °C; 1H NMR (CDCl3, 300 MHz, δ; ppm) 8.76 (1H, dd, J = 4.2, 0.9 Hz), 7.68 (1H, q, J = 0.3 Hz), 7.49 (1H, dd, J = 3.6, 1.5 Hz), 3.32 (1H, s); 13C NMR (CDCl3, 75 MHz, δ; ppm) 151.11, 143.79, 128.84, 124.70, 121.08, 115.70, 81.10, 80.05; MS (ESI) m/z 129.2 (MH+).
Step 2: 4-cyano-2-ethynylpyridine (13)
1 M TBAF / THF (14.0 mL, 14.0 mmol) was added to a solution of compound 12 (1.96 g, 9.79 mmol) in dichloromethane (25.0 mL) at 0 ° C, and the reaction solution was stirred for 2 hours at 0 ° C. After completion of the reaction, ethyl acetate was added, the organic layer was washed with water, and dried over Na 2 SO 4 . After distilling off the solvent, the residue was purified by silica gel column chromatography (ethyl acetate / n-hexane = 1/3) to obtain 823 mg of a yellowish white solid 13. Yield 66%. mp 104-106 ° C; 1 H NMR (CDCl 3 , 300 MHz, δ; ppm) 8.76 (1H, dd, J = 4.2, 0.9 Hz), 7.68 (1H, q, J = 0.3 Hz), 7.49 (1H) , dd, J = 3.6, 1.5 Hz), 3.32 (1H, s); 13 C NMR (CDCl 3 , 75 MHz, δ; ppm) 151.11, 143.79, 128.84, 124.70, 121.08, 115.70, 81.10, 80.05; MS ( ESI) m / z 129.2 (MH + ).
Step 3: 4-(2H-tetrazol-5-yl)-pyridine (Alk3)
化合物13 (396 mg, 3.00 mmol)のDMF (20.0 mL)溶液にアジ化ナトリウム(195 mg, 3.00 mmol)と塩化アンモニウム(162 mg, 3.00 mmol)を窒素雰囲気下で加えた。反応溶液を窒素雰囲気下、80 °Cで12時間加熱撹拌した。反応終了後、酢酸エチルを加え、4 N塩酸で洗浄した。有機層を水、brineで洗浄し、Na2SO4で乾燥した。溶媒を留去後、残渣をシリカゲルカラムクロマトグラフィー(酢酸エチル/n-ヘキサン = 2/1)で精製し、 褐色固体Alk3を62.0 mg得た。収率12%。 mp 210-212 °C; 1H NMR (DMSO-d6, 300 MHz, δ; ppm) 8.79 (1H, dd, J = 4.2, 0.9 Hz), 8.10 (1H, q, J = 0.6 Hz), 8.00 (1H, dd, J = 3.3, 1.8 Hz), 4.51 (1H, s); 13C NMR (DMSO-d6, 75 MHz, δ; ppm) 154.74, 151.45, 142.73, 132.92, 124.12, 120.70, 82.35, 81.41; MS (ESI) m/z 172.1 (MH+); HPLC tR=7.45 min purity 96.0%. HRMS (EI) Calcd. for C8H5N5 171.0537, Found 171.0545.
Step 3: 4- (2H-tetrazol-5-yl) -pyridine (Alk3)
Sodium azide (195 mg, 3.00 mmol) and ammonium chloride (162 mg, 3.00 mmol) were added to a solution of compound 13 (396 mg, 3.00 mmol) in DMF (20.0 mL) under a nitrogen atmosphere. The reaction solution was heated and stirred at 80 ° C for 12 hours under a nitrogen atmosphere. After completion of the reaction, ethyl acetate was added and the mixture was washed with 4 N hydrochloric acid. The organic layer was washed with water and brine and dried over Na 2 SO 4 . After distilling off the solvent, the residue was purified by silica gel column chromatography (ethyl acetate / n-hexane = 2/1) to obtain 62.0 mg of brown solid Alk3. Yield 12%. mp 210-212 ° C; 1 H NMR (DMSO-d 6 , 300 MHz, δ; ppm) 8.79 (1H, dd, J = 4.2, 0.9 Hz), 8.10 (1H, q, J = 0.6 Hz), 8.00 (1H, dd, J = 3.3, 1.8 Hz), 4.51 (1H, s); 13 C NMR (DMSO-d 6 , 75 MHz, δ; ppm) 154.74, 151.45, 142.73, 132.92, 124.12, 120.70, 82.35, 81.41; MS (ESI) m / z 172.1 (MH + ); HPLC t R = 7.45 min purity 96.0%. HRMS (EI) Calcd. For C8H5N5 171.0537, Found 171.0545.
2-Ethynylisonicotinate (Alk4)
化合物10 (380 mg, 1.60 mmol)のTHF (2.00 mL)溶液に1 M TBAF/THF (2.20 mL, 2.20 mmol)を0 °Cで加え、反応溶液を0 °Cで2時間撹拌した。反応終了後、酢酸エチルを加え、水で洗浄し、有機層をNa2SO4 で乾燥させた。溶媒を留去後、残渣をシリカゲルカラムクロマトグラフィー(酢酸エチル/n-ヘキサン = 1/2)で精製した。さらに粗生成物をn-ヘキサンで再結晶することにより、無色固体Alk4を248 mg得た。収率96%。 mp 64.5-65.5 °C; 1H NMR (CDCl3, 300 MHz, δ; ppm) 8.75 (d, 1H, J = 5.1 Hz), 8.03 (q, 1H, J = 0.6 Hz), 7.81 (dd, 1H, J = 4.2, 0.9 Hz), 3.97 (s, 3H), 3.23 (s, 1H); 13C NMR (CDCl3, 75 MHz, δ; ppm) 164.95, 150.97, 143.43, 137.88, 126.78, 122.62, 82.21, 78.37, 53.00 ; MS (ESI) m/z 162.2 (MH+); HPLC tR= 11.7 min purity 99.4%
2-Ethynylisonicotinate (Alk4)
1 M TBAF / THF (2.20 mL, 2.20 mmol) was added to a solution of compound 10 (380 mg, 1.60 mmol) in THF (2.00 mL) at 0 ° C and the reaction solution was stirred at 0 ° C for 2 hours. After completion of the reaction, ethyl acetate was added, the mixture was washed with water, and the organic layer was dried over Na 2 SO 4 . After distilling off the solvent, the residue was purified by silica gel column chromatography (ethyl acetate / n-hexane = 1/2). Further, the crude product was recrystallized from n-hexane to obtain 248 mg of colorless solid Alk4. Yield 96%. mp 64.5-65.5 ° C; 1 H NMR (CDCl 3 , 300 MHz, δ; ppm) 8.75 (d, 1H, J = 5.1 Hz), 8.03 (q, 1H, J = 0.6 Hz), 7.81 (dd, 1H) , J = 4.2, 0.9 Hz), 3.97 (s, 3H), 3.23 (s, 1H); 13 C NMR (CDCl 3 , 75 MHz, δ; ppm) 164.95, 150.97, 143.43, 137.88, 126.78, 122.62, 82.21 , 78.37, 53.00; MS (ESI) m / z 162.2 (MH + ); HPLC t R = 11.7 min purity 99.4%
製造例２
アジド化合物Az1-7, YMA04-110-A, YMA04-110-Dの合成
Step 1: 2-Azidoethanol (15)
2-ブロモエタノール (581 μL, 10.0 mmol)の水溶液(5.00 mL)にアジ化ナトリウム(647 mg, 8.30 mmol)を加え、反応溶液を100 °Cで12時間加熱還流した。反応終了後、塩化ナトリウムを加え、水層をジクロロメタンで抽出した。有機層をNa2SO4で乾燥後溶媒を留去した。得られた無色の液体状粗生成物を直接次の反応に用いた。
Manufacturing example 2
Synthesis of azide compounds Az1-7, YMA04-110-A, YMA04-110-D
Step 1: 2-Azidoethanol (15)
Sodium azide (647 mg, 8.30 mmol) was added to an aqueous solution (5.00 mL) of 2-bromoethanol (581 μL, 10.0 mmol), and the reaction solution was heated to reflux at 100 ° C. for 12 hours. After completion of the reaction, sodium chloride was added and the aqueous layer was extracted with dichloromethane. The organic layer was dried over Na 2 SO 4 and the solvent was distilled off. The obtained colorless liquid crude product was directly used in the next reaction.
Step 2: 1-Mesyl-2-azidoethanol (16)
化合物15のジクロロメタン(10.0 mL)溶液にトリエチルアミン(1.74 mL, 12.5 mmol)とmethanesulfonyl chloride (967 μL, 12.5 mmol)を0 °Cで加え、反応溶液を室温で12時間撹拌した。反応終了後、反応溶液をろ過し、ろ液をエバポレータ―で濃縮した。残渣をシリカゲルカラムクロマトグラフィー(酢酸エチル/n-ヘキサン= 2/3)で精製し、無色オイル状の16を560 mg得た。収率34%。 1H NMR (CDCl3, 300 MHz, δ; ppm) 4.26 (2H, t, J = 5.7 Hz), 3.52 (2H, t, J = 4.5 Hz), 3.01 (3H, s); 13C NMR (CDCl3, 75 MHz, δ; ppm) 67.88, 49.55, 37.17.
Step 2: 1-Mesyl-2-azidoethanol (16)
Triethylamine (1.74 mL, 12.5 mmol) and methanesulfonyl chloride (967 μL, 12.5 mmol) were added to a solution of compound 15 in dichloromethane (10.0 mL) at 0 ° C, and the reaction solution was stirred at room temperature for 12 hours. After completion of the reaction, the reaction solution was filtered and the filtrate was concentrated with an evaporator. The residue was purified by silica gel column chromatography (ethyl acetate / n-hexane = 2/3) to obtain 560 mg of 16 in the form of a colorless oil. Yield 34%. 1 1 H NMR (CDCl 3 , 300 MHz, δ; ppm) 4.26 (2H, t, J = 5.7 Hz), 3.52 (2H, t, J = 4.5 Hz), 3.01 (3H, s); 13 C NMR (CDCl) 3 , 75 MHz, δ; ppm) 67.88, 49.55, 37.17.
Step 3: 2-Azido-1-ethylhexylmethylamine (Az1)
化合物16 (189 mg, 1.15 mmol)と炭酸カリウム(482 mg, 3.50 mmol)のアセトニトリル(5 mL)溶液にN-ヘキシルメチルアミン(151 μL, 1.00 mmol)を加え、12時間、90 °Cで加熱還流した。反応終了後、反応溶液をろ過し、ろ液をエバポレータ―で濃縮した。残渣をシリカゲルカラムクロマトグラフィー(酢酸エチル/n-ヘキサン = 1/3)で精製し、無色オイル状のAz1を50.0 mg得た。収率27%。1H NMR (CDCl3, 300 MHz, δ; ppm) 3.32 (2H, t, J = 6.0 Hz), 2.58 (2H, t, J = 6.0 Hz), 2.37 (2H, t, J = 7.8 Hz), 2.26 (3H, s), 1.42-1.49 (2H, m), 1.26-1.32 (6H, m), 0.89 (3H, t J= 6.6 Hz); 13C NMR (CDCl3, 75 MHz, δ; ppm) 58.14, 56.52, 49.16, 42.34, 31.91, 27.36, 27.16, 22.74, 14.14; MS (ESI) m/z 185.1 (MH+); HPLC tR=10.2 min purity 97.6%. HRMS (EI) Calcd. for C9H20N4 185.1764, Found 185.1761.
Step 3: 2-Azido-1-ethylhexylmethylamine (Az1)
N-Hexylmethylamine (151 μL, 1.00 mmol) was added to a solution of compound 16 (189 mg, 1.15 mmol) and potassium carbonate (482 mg, 3.50 mmol) in acetonitrile (5 mL) and heated at 90 ° C for 12 hours. Circulated. After completion of the reaction, the reaction solution was filtered and the filtrate was concentrated with an evaporator. The residue was purified by silica gel column chromatography (ethyl acetate / n-hexane = 1/3) to obtain 50.0 mg of Az1 in the form of a colorless oil. Yield 27%. 1 1 H NMR (CDCl 3 , 300 MHz, δ; ppm) 3.32 (2H, t, J = 6.0 Hz), 2.58 (2H, t, J = 6.0 Hz), 2.37 (2H, t, J = 7.8 Hz), 2.26 (3H, s), 1.42-1.49 (2H, m), 1.26-1.32 (6H, m), 0.89 (3H, t J = 6.6 Hz); 13 C NMR (CDCl 3 , 75 MHz, δ; ppm) 58.14, 56.52, 49.16, 42.34, 31.91, 27.36, 27.16, 22.74, 14.14; MS (ESI) m / z 185.1 (MH + ); HPLC t R = 10.2 min purity 97.6%. HRMS (EI) Calcd. For C9H20N4 185.1764 , Found 185.1761.
Azides Az2-7, YMA04-110-A, YMA04-110-DはAz1の合成法に示したものと同様の方法で合成した。
2-Azido-1-benzylmethylethylamine (Az2)
収率53%; 無色オイル 1H NMR (CDCl3, 300 MHz, δ; ppm): 7.28-7.40 (5H, m), 3.61 (2H, s), 3.36 (2H, t, J = 6.0 Hz), 2.69 (2H, t, J = 6.0 Hz), 2.31 (3H, s); 13C NMR (CDCl3, 75 MHz, δ; ppm): 138.68, 128.91, 128.34, 127.15, 62.57, 56.26, 48.90, 42.15; MS (ESI) m/z 191.2 (MH+). HPLC tR=7.87 min purity 96.2%.
Azides Az2-7, YMA04-110-A, and YMA04-110-D were synthesized by the same method as shown in the synthesis method of Az1.
2-Azido-1-benzylmethylethylamine (Az2)
Yield 53%; Colorless Oil 1 H NMR (CDCl 3 , 300 MHz, δ; ppm): 7.28-7.40 (5H, m), 3.61 (2H, s), 3.36 (2H, t, J = 6.0 Hz), 2.69 (2H, t, J = 6.0 Hz), 2.31 (3H, s); 13 C NMR (CDCl 3 , 75 MHz, δ; ppm): 138.68, 128.91, 128.34, 127.15, 62.57, 56.26, 48.90, 42.15; MS (ESI) m / z 191.2 (MH + ). HPLC t R = 7.87 min purity 96.2%.
2-Azido-1-diethylbutylamine (Az3)
収率24%; 無色オイル 1H NMR (CDCl3, 300 MHz, δ; ppm): 3.28 (2H, t, J = 6.3 Hz), 2.66 (2H, t, J = 6.3 Hz), 2.55 (2H, q, J = 6.9 Hz), 2.46 (2H, t, J = 7.8 Hz), 1.31-1.44 (4H, m), 1.04 (3H, t, J = 0.9 Hz), 0.93 (3H, t, J = 7.2 Hz); 13C NMR (CDCl3, 75 MHz, δ; ppm): 53.60, 52.85, 49.51, 47.81, 29.37, 20.55, 14.02, 11.80; MS (ESI) m/z 171.3 (MH+). HPLC tR=22.9 min purity 95.8%.
2-Azido-1-diethylbutylamine (Az3)
Yield 24%; Colorless oil 1 H NMR (CDCl 3 , 300 MHz, δ; ppm): 3.28 (2H, t, J = 6.3 Hz), 2.66 (2H, t, J = 6.3 Hz), 2.55 (2H, 2H, q, J = 6.9 Hz), 2.46 (2H, t, J = 7.8 Hz), 1.31-1.44 (4H, m), 1.04 (3H, t, J = 0.9 Hz), 0.93 (3H, t, J = 7.2) Hz); 13 C NMR (CDCl 3 , 75 MHz, δ; ppm): 53.60, 52.85, 49.51, 47.81, 29.37, 20.55, 14.02, 11.80; MS (ESI) m / z 171.3 (MH + ). HPLC t R = 22.9 min purity 95.8%.
2-Azido-1-ethylpentylmethylamine (Az4)
収率37%; 無色オイル 1H NMR (CDCl3, 300 MHz, δ; ppm): 3.32 (2H, t, J= 6.3 Hz), 2.57 (2H, t, J = 6.0 Hz), 2.36 (2H, t, J = 6.0 Hz), 2.26 (3H, s), 1.42-1.52 (2H, m), 1.28-1.32 (4H, m), 0.90 (3H, t, J = 7.2 Hz); 13C NMR (CDCl3, 75 MHz, δ; ppm): 57.95, 56.38, 49.00, 42.18, 29.52, 26.92, 22.57, 14.00; MS (ESI) m/z 171.3 (MH+). HPLC tR = 22.7 min purity 98.5%.
2-Azido-1-ethylpentylmethylamine (Az4)
Yield 37%; Colorless Oil 1 H NMR (CDCl 3 , 300 MHz, δ; ppm): 3.32 (2H, t, J = 6.3 Hz), 2.57 (2H, t, J = 6.0 Hz), 2.36 (2H, 2H, t, J = 6.0 Hz), 2.26 (3H, s), 1.42-1.52 (2H, m), 1.28-1.32 (4H, m), 0.90 (3H, t, J = 7.2 Hz); 13 C NMR (CDCl) 3 , 75 MHz, δ; ppm): 57.95, 56.38, 49.00, 42.18, 29.52, 26.92, 22.57, 14.00; MS (ESI) m / z 171.3 (MH + ). HPLC t R = 22.7 min purity 98.5%.
2-Azido-1-ethylpropylbutylamine (Az5)
収率36%; 無色オイル 1H NMR (CDCl3, 300 MHz, δ; ppm): 3.25 (2H, t, J = 6.0 Hz), 2.65 (2H, t, J = 6.3 Hz), 2.39-2.47 (4H, m), 1.30-1.50 (6H, m), 0.89 (6H, q, J = 7.2 Hz); 13C NMR (CDCl3, 75 MHz, δ; ppm): 56.49, 54.20, 53.56, 49.54, 29.38, 20.52, 20.38, 14.01, 11.76; MS (ESI) m/z 185.3 (MH+). HPLC tR = 10.2 min purity 97.6%
2-Azido-1-ethylpropylbutylamine (Az5)
36% yield; 1 H NMR of colorless oil (CDCl 3 , 300 MHz, δ; ppm): 3.25 (2H, t, J = 6.0 Hz), 2.65 (2H, t, J = 6.3 Hz), 2.39-2.47 ( 4H, m), 1.30-1.50 (6H, m), 0.89 (6H, q, J = 7.2 Hz); 13 C NMR (CDCl 3 , 75 MHz, δ; ppm): 56.49, 54.20, 53.56, 49.54, 29.38 , 20.52, 20.38, 14.01, 11.76; MS (ESI) m / z 185.3 (MH + ). HPLC t R = 10.2 min purity 97.6%
2-Azido-1-ethyldibutylamine (Az6)
収率48%; 無色オイル 1H NMR (CDCl3, 300 MHz, δ; ppm): 3.25 (2H, t, J = 6.3 Hz), 2.63 (2H, t, J = 6.3 Hz), 2.44 (4H, t, J = 7.2 Hz), 1.30-1.43 (8H, m), 0.92 (6H, t, J = 7.2 Hz); 13C NMR (CDCl3, 75 MHz, δ; ppm): 54.19, 53.52, 49.53, 29.39, 20.51, 13.99; MS (ESI) m/z 199.3 (MH+). HPLC tR = 9.15 min purity 99.9%.
2-Azido-1-ethyldibutylamine (Az6)
48% yield; 1 H NMR of colorless oil (CDCl 3 , 300 MHz, δ; ppm): 3.25 (2H, t, J = 6.3 Hz), 2.63 (2H, t, J = 6.3 Hz), 2.44 (4H, 4H, t, J = 7.2 Hz), 1.30-1.43 (8H, m), 0.92 (6H, t, J = 7.2 Hz); 13 C NMR (CDCl 3 , 75 MHz, δ; ppm): 54.19, 53.52, 49.53, 29.39, 20.51, 13.99; MS (ESI) m / z 199.3 (MH + ). HPLC t R = 9.15 min purity 99.9%.
2-Azido-1-ethylbutylbenzylamine (Az7)
収率16%; 無色オイル 1H NMR (CDCl3, 300 MHz, δ; ppm): 7.25-7.39 (5H, m), 3.65 (2H, s), 3.26 (2H, t, J = 6.0 Hz), 2.71 (2H, t, J = 6.3 Hz), 2.51 (2H, t, J = 7.2 Hz), 1.47-1.57 (2H, m), 1.29-1.41 (2H, m), 0.92 (3H, t, J = 7.2 Hz); 13C NMR (CDCl3, 75 MHz, δ; ppm): 139.49, 128.73, 128.23, 126.95, 59.09, 54.13, 53.31, 49.43, 29.29, 20.44, 14.01; MS (ESI) m/z 233.3 (MH+). HPLC tR = 11.1 min purity 96.3%
2-Azido-1-ethylbutylbenzylamine (Az7)
Yield 16%; Colorless Oil 1 H NMR (CDCl 3 , 300 MHz, δ; ppm): 7.25-7.39 (5H, m), 3.65 (2H, s), 3.26 (2H, t, J = 6.0 Hz), 2.71 (2H, t, J = 6.3 Hz), 2.51 (2H, t, J = 7.2 Hz), 1.47-1.57 (2H, m), 1.29-1.41 (2H, m), 0.92 (3H, t, J = 7.2 Hz); 13 C NMR (CDCl 3 , 75 MHz, δ; ppm): 139.49, 128.73, 128.23, 126.95, 59.09, 54.13, 53.31, 49.43, 29.29, 20.44, 14.01; MS (ESI) m / z 233.3 ( MH + ). HPLC t R = 11.1 min purity 96.3%
1-(2-Azidoethyl)piperidine (YMA04-110-A)
収率42%; 黄色オイル 1H NMR (CDCl3, 300 MHz, δ; ppm) 3.31 (2H, t, J = 6.3 Hz), 2.52 (2H, t, J = 6.3 Hz), 2.41 (4H, t, J = 5.4 Hz), 1.53-1.59 (4H, m), 1.37-1.45 (2H, m); 13C NMR (CDCl3, 75 MHz, δ; ppm) 57.92, 54.69, 49.77, 48.50, 25.98, 24.34; MS (ESI) m/z 155.0 (MH+)
1- (2-Azidoethyl) piperidine (YMA04-110-A)
Yield 42%; Yellow Oil 1 H NMR (CDCl 3 , 300 MHz, δ; ppm) 3.31 (2H, t, J = 6.3 Hz), 2.52 (2H, t, J = 6.3 Hz), 2.41 (4H, t) , J = 5.4 Hz), 1.53-1.59 (4H, m), 1.37-1.45 (2H, m); 13 C NMR (CDCl 3 , 75 MHz, δ; ppm) 57.92, 54.69, 49.77, 48.50, 25.98, 24.34 MS (ESI) m / z 155.0 (MH + )
2-Azido-N-methyl-N-(phenyl methyl)Ethan amine (YMA04-110-D)
収率43%; 黄色オイル: 1H NMR (CDCl3, 300 MHz, δ; ppm) 7.28-7.40 (5H, m), 3.61 (2H, s), 3.36 (2H, t, J = 6.0 Hz), 2.69 (2H, t, J = 6.0 Hz), 2.31 (3H, s); 13C NMR (CDCl3, 75 MHz, δ; ppm) 138.7, 128.9, 128.3, 127.2, 62.57, 56.26, 48.90, 42.15; MS (ESI) m/z 190.1 (MH+)
2-Azido-N-methyl-N- (phenyl methyl) Ethan amine (YMA04-110-D)
43% yield; Yellow oil: 1 H NMR (CDCl 3 , 300 MHz, δ; ppm) 7.28-7.40 (5H, m), 3.61 (2H, s), 3.36 (2H, t, J = 6.0 Hz), 2.69 (2H, t, J = 6.0 Hz), 2.31 (3H, s); 13 C NMR (CDCl 3 , 75 MHz, δ; ppm) 138.7, 128.9, 128.3, 127.2, 62.57, 56.26, 48.90, 42.15; MS (ESI) m / z 190.1 (MH + )
製造例３
2-Azido-1-ethylbutylhexylamine (Az8)
Step1:N-butyl-1-hexanamine (17)
BH3 .SMe2(1.00 mL, 10.0 mmol)を1-ヘキセン(5.00 mL, 40.0 mmol)に0 °C、窒素雰囲気下で滴下した。滴下終了後、反応溶液を室温、窒素雰囲気下で12時間撹拌した、Sodium hypochlorite (18.4 mL, 10.0 mmol)をN-ブチルアミン(1.00 mL, 10.0 mmol)のTHF (10.0 mL)溶液に0 °C、窒素雰囲気下で滴下した。この溶液を窒素雰囲気下0 °Cでtrialkylborane溶液に素早く加えた。この反応溶液を窒素雰囲気下、室温で3時間撹拌した。反応終了後、10% HClを加えて反応溶液をpH 1.0に調整し、ジエチルエーテルで洗浄した。水層に6 N NaOH水溶液を加えpH >13に調整後、エーテルで目的物を抽出した。有機層をNa2SO4で乾燥し、エバポレータ―で濃縮して650 mgの無色オイル状の生成物17 を得た。収率41%。 1H NMR (CDCl3, 300 MHz, δ; ppm) 2.56 (2H, t, J = 7.2 Hz), 2.56 (1H, t, J = 7.5 Hz), 1.26-1.47 (12H, m), 0.83-0.99 (6H, m); 13C NMR (CDCl3, 75 MHz, δ; ppm) 50.16, 49.81, 32.32, 31.79, 30.15, 27.09, 22.60, 20.52, 14.00; MS (ESI) m/z158.3 (MH+).
Manufacturing example 3
2-Azido-1-ethylbutylhexylamine (Az8)
Step1: N-butyl-1-hexanamine (17)
BH 3. SMe 2 (1.00 mL , 10.0 mmol) of 1-hexene (5.00 mL, 40.0 mmol) in 0 ° C, was added dropwise under a nitrogen atmosphere. After completion of the dropwise addition, the reaction solution was stirred at room temperature in a nitrogen atmosphere for 12 hours, and Sodium hypochlorite (18.4 mL, 10.0 mmol) was added to a solution of N-butylamine (1.00 mL, 10.0 mmol) in THF (10.0 mL) at 0 ° C. The solution was added dropwise in a nitrogen atmosphere. This solution was quickly added to the trialkylborane solution at 0 ° C under a nitrogen atmosphere. The reaction solution was stirred at room temperature for 3 hours under a nitrogen atmosphere. After completion of the reaction, 10% HCl was added to adjust the reaction solution to pH 1.0, and the reaction solution was washed with diethyl ether. A 6 N NaOH aqueous solution was added to the aqueous layer to adjust the pH to> 13, and then the desired product was extracted with ether. The organic layer was dried over Na 2 SO 4 and concentrated on an evaporator to give 650 mg of colorless oily product 17. Yield 41%. 1 H NMR (CDCl 3 , 300 MHz, δ; ppm) 2.56 (2H, t, J = 7.2 Hz), 2.56 (1H, t, J = 7.5 Hz), 1.26-1.47 (12H, m), 0.83-0.99 (6H, m); 13 C NMR (CDCl 3 , 75 MHz, δ; ppm) 50.16, 49.81, 32.32, 31.79, 30.15, 27.09, 22.60, 20.52, 14.00; MS (ESI) m / z158.3 (MH +) ).
Step2:2-Azido-1-ethylbutylhexylamine(Az8)
化合物16 (189 mg, 1.15 mmol) と炭酸カリウム(482 mg, 3.50 mmol) のアセトニトリル(5.00 mL)溶液に化合物17 (157 mg, 1.00 mmol)を加え、90 °Cで12時間加熱還流した。反応終了後、反応溶液をろ過し、ろ液をエバポレータ―で濃縮した。残渣をシリカゲルカラムクロマトグラフィー(酢酸エチル/n-ヘキサン= 1/3)で精製し、104 mgの無色オイル状のAz8 を得た。収率46%。 1H NMR (CDCl3, 300 MHz, δ; ppm): 3.26 (2H, t, J = 6.0 Hz), 2.64 (2H, t, J = 6.3 Hz), 2.44 (2H, t, J = 7.2 Hz), 2.44 (2H, t, J = 7.2 Hz), 1.40-1.45 (4H, m), 1.27-1.32 (8H, m), 0.87-0.94 (6H, m); 13C NMR (CDCl3, 75 MHz, δ; ppm): 54.67, 54.35, 53.64, 49.68, 31.96, 29.50, 27.29, 27.24, 22.80, 20.70, 14.19; MS (ESI) m/z 227.3 (MH+). HPLC tR = 13.3 min purity 98.3%
Step2: 2-Azido-1-ethylbutylhexylamine (Az8)
Compound 17 (157 mg, 1.00 mmol) was added to a solution of compound 16 (189 mg, 1.15 mmol) and potassium carbonate (482 mg, 3.50 mmol) in acetonitrile (5.00 mL), and the mixture was heated under reflux at 90 ° C for 12 hours. After completion of the reaction, the reaction solution was filtered and the filtrate was concentrated with an evaporator. The residue was purified by silica gel column chromatography (ethyl acetate / n-hexane = 1/3) to give 104 mg of Az8 in the form of a colorless oil. Yield 46%. 1 H NMR (CDCl 3 , 300 MHz, δ; ppm): 3.26 (2H, t, J = 6.0 Hz), 2.64 (2H, t, J = 6.3 Hz), 2.44 (2H, t, J = 7.2 Hz) , 2.44 (2H, t, J = 7.2 Hz), 1.40-1.45 (4H, m), 1.27-1.32 (8H, m), 0.87-0.94 (6H, m); 13 C NMR (CDCl 3 , 75 MHz, δ; ppm): 54.67, 54.35, 53.64, 49.68, 31.96, 29.50, 27.29, 27.24, 22.80, 20.70, 14.19; MS (ESI) m / z 227.3 (MH + ). HPLC t R = 13.3 min purity 98.3%
4-(2-Azidoethyl)morpholine (YMA04-112)
モルホリン(948 μL, 10.0 mmol)のトルエン溶液(20 mL)にブロモエタノール(349 μL, 5.00 mmol)を滴下し、反応溶液を3時間加熱還流した。反応終了後、反応溶液をろ過し、ろ液をエバポレータ―で濃縮した。残渣をジクロロメタン(8 mL)に溶かし、トリメチルアミン(1.67 mL, 12.0 mmol)を加えた。さらにmethanesulfonyl chloride (902 μL, 12.0 mmol)を0 oCで滴下した後、反応溶液を室温で3時間撹拌した。反応終了後、飽和重曹水を加えジクロロメタンで抽出した。有機層をbrineで洗浄、Na2SO4で乾燥し、溶媒をエバポレータ―で留去した。残渣にDMSO (30 mL)とアジ化ナトリウム(780 mg, 12.0 mmol)を加え、反応溶液を80 oCで2時間加熱撹拌した。反応終了後、水を加え、酢酸エチルで抽出した。有機層を水で洗浄、Na2SO4.で乾燥し、溶媒をエバポレーターで留去した。残渣をシリカゲルカラムクロマトグラフィー(酢酸エチル)で精製し、黄色オイル状の4-(2-Azidoethyl)morpholine (YMA04-112, 収率18%)を得た。 1H NMR (CDCl3, 300 MHz, δ; ppm) 3.69-3.78 (4H, m), 3.34 (2H, t, J = 6.0 Hz), 2.57 (2H, t, J = 1.5 Hz), 2.49-2.50 (4H, m); 13C NMR (CDCl3, 75 MHz, δ; ppm) 66.95, 57.67, 53.68, 48.01; MS (ESI) m/z 157.1 (MH+)
4- (2-Azidoethyl) morpholine (YMA04-112)
Bromoethanol (349 μL, 5.00 mmol) was added dropwise to a toluene solution (20 mL) of morpholin (948 μL, 10.0 mmol), and the reaction solution was heated to reflux for 3 hours. After completion of the reaction, the reaction solution was filtered and the filtrate was concentrated with an evaporator. The residue was dissolved in dichloromethane (8 mL) and trimethylamine (1.67 mL, 12.0 mmol) was added. Further, methanesulfonyl chloride (902 μL, 12.0 mmol) was added dropwise at 0 o C, and the reaction solution was stirred at room temperature for 3 hours. After completion of the reaction, saturated aqueous sodium hydrogen carbonate was added and the mixture was extracted with dichloromethane. The organic layer was washed with brine, dried over Na 2 SO 4 , and the solvent was evaporated with an evaporator. DMSO (30 mL) and sodium azide (780 mg, 12.0 mmol) were added to the residue, and the reaction solution was heated and stirred at 80 o C for 2 hours. After completion of the reaction, water was added and the mixture was extracted with ethyl acetate. The organic layer was washed with water, dried over Na 2 SO 4. and the solvent was evaporated. The residue was purified by silica gel column chromatography (ethyl acetate) to obtain a yellow oily 4- (2-Azidoethyl) morpholine (YMA04-112, yield 18%). 1 1 H NMR (CDCl 3 , 300 MHz, δ; ppm) 3.69-3.78 (4H, m), 3.34 (2H, t, J = 6.0 Hz), 2.57 (2H, t, J = 1.5 Hz), 2.49-2.50 (4H, m); 13 C NMR (CDCl 3 , 75 MHz, δ; ppm) 66.95, 57.67, 53.68, 48.01; MS (ESI) m / z 157.1 (MH + )
トリアゾール化合物NPC-3422, YMA04-115, YMA04-118, YMA04-119の合成
実施例１
5-(1-(1-ethyl hexyl methyl amine-1H-[1,2,3]triazol-5-yl)-pyridine-2-carboxylic acid (NPC-3422)
Step 1: 5-(1-(1-ethyl hexyl methyl amine-1H-[1,2,3]triazol-5-yl)-pyridine-2-carboxylate (NPC-3543)
Alk4 (16.2 mg, 100 μmol)とAz1 (18.3 mg, 100 μmol)のtert-ブチルアルコール (2.50 mL)と水(2.50 mL)溶液にCuSO4・5H2O (25.0 mg, 100 μmol)とsodium ascorbate (20.0 mg, 100 μmol)を加え、反応溶液を室温で12時間撹拌した。反応終了後、溶媒をエバポレータ―で留去し、水を加えて酢酸エチルで抽出した。有機層をbrineで洗浄し、Na2SO4で乾燥した。溶媒を留去後、残渣をシリカゲルカラムクロマトグラフィー(酢酸エチル/n-ヘキサン= 1/3 to ジクロロメタン/メタノール= 5/1)で精製し、16.2 mgのオレンジ色オイルNPC-3543 得た。収率47%。 1H NMR (CDCl3, 300 MHz, δ; ppm) 8.71-8.74 (2H, m), 8.30 (1H, s), 7.78 (1H, dd, J = 3.6, 0.6 Hz), 4.52 (2H, t, J = 6.3 Hz), 3.99 (3H, s), 2.88 (2H, t, J = 6.0 Hz), 2.40 (2H, t, J = 7.5 Hz), 2.31 (3H, s), 1.22-1.42 (8H, m), 0.83 (3H, t, J = 6.6 Hz); 13C NMR (CDCl3, 75 MHz, δ; ppm) 165.60, 151.70, 150.21, 147.54, 138.35, 123.25, 121.74, 119.50, 57.98, 57.03, 52.70, 48.57, 42.09, 31.75, 27.21, 27.02, 22.63, 14.02; MS (ESI) m/z 346.4 (MH+); HPLC tR = 12.13 min purity 95.6%
Synthesis of triazole compounds NPC-3422, YMA04-115, YMA04-118, YMA04-119 Example 1
5- (1- (1-ethyl hexyl methyl amine-1H- [1,2,3] triazol-5-yl) -pyridine-2-carboxylic acid (NPC-3422)
Step 1: 5-(1- (1-ethyl hexyl methyl amine-1H- [1,2,3] triazol-5-yl)-pyridine-2-carboxylate (NPC-3543)
Alk4 (16.2 mg, 100 μmol) and Az1 (18.3 mg, 100 μmol) in tert- butyl alcohol (2.50 mL) and water (2.50 mL) was added CuSO 4 · 5H 2 O (25.0 mg, 100 μmol) and sodium ascorbate (20.0 mg, 100 μmol) was added and the reaction solution was stirred at room temperature for 12 hours. After completion of the reaction, the solvent was distilled off with an evaporator, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine and dried over Na 2 SO 4 . After distilling off the solvent, the residue was purified by silica gel column chromatography (ethyl acetate / n-hexane = 1/3 to dichloromethane / methanol = 5/1) to obtain 16.2 mg of orange oil NPC-3543. Yield 47%. 1 1 H NMR (CDCl 3 , 300 MHz, δ; ppm) 8.71-8.74 (2H, m), 8.30 (1H, s), 7.78 (1H, dd, J = 3.6, 0.6 Hz), 4.52 (2H, t, J = 6.3 Hz), 3.99 (3H, s), 2.88 (2H, t, J = 6.0 Hz), 2.40 (2H, t, J = 7.5 Hz), 2.31 (3H, s), 1.22-1.42 (8H, m), 0.83 (3H, t, J = 6.6 Hz); 13 C NMR (CDCl 3 , 75 MHz, δ; ppm) 165.60, 151.70, 150.21, 147.54, 138.35, 123.25, 121.74, 119.50, 57.98, 57.03, 52.70 , 48.57, 42.09, 31.75, 27.21, 27.02, 22.63, 14.02; MS (ESI) m / z 346.4 (MH + ); HPLC t R = 12.13 min purity 95.6%
Step 2: 5-(1-(1-ethyl hexyl methyl amine-1H-[1,2,3]triazol-5-yl)-pyridine-2-carboxylic acid hydrochloride (NPC-3422)
NPC-3543 (16.2 mg, 47.0 μmol)をメタノール(3.00 mL)に溶かし、2.00 mLの2 N 水酸化ナトリウム水溶液を加えた。反応溶液を室温で12時間撹拌した。反応終了後、溶媒をエバポレータ―で留去し、残渣に4N HCl/ジオキサンを加えpHを1.0に調整した。溶液をろ過し、ろ液を濃縮して10.0 mgの無色固体NPC-3422(HCl塩)を得た。収率25% 1H NMR (MeOD, 300 MHz, δ; ppm) 8.79 (1H, d, J = 4.5 Hz), 8.64 (1H, s), 8.61 (1H, s), 7.89 (1H, dd, J = 3.6, 1.5 Hz), 4.99 (2H, t, J = 6.0Hz), 3.92 (2H, s), 3.30 (2H, s), 3.02 (3H, s), 1.73 (2H, quin., J = 7.8 Hz), 1.38 (6H, m), 0.93 (3H, t, J = 7.2 Hz); 13C NMR (MeOD, 75 MHz, δ; ppm) 166.00, 150.45, 150.21, 147.56, 139.83, 124.01, 122.37, 119.36, 56.67, 54.24, 44.53, 39.71, 30.92, 25.73, 23.56, 22.03, 12.79; MS (ESI) m/z 332.1(MH+); HPLC tR = 10.10 min purity 99.6% HRMS (EI) Calcd. for C17H25N5O2 331.2008, Found 331.2041.
Step 2: 5-(1- (1-ethyl hexyl methyl amine-1H- [1,2,3] triazol-5-yl) -pyridine-2-carboxylic acid hydrochloride (NPC-3422)
NPC-3543 (16.2 mg, 47.0 μmol) was dissolved in methanol (3.00 mL) and 2.00 mL of 2N aqueous sodium hydroxide solution was added. The reaction solution was stirred at room temperature for 12 hours. After completion of the reaction, the solvent was distilled off with an evaporator, and 4N HCl / dioxane was added to the residue to adjust the pH to 1.0. The solution was filtered and the filtrate was concentrated to give 10.0 mg of colorless solid NPC-3422 (HCl salt). Yield 25% 1 H NMR (MeOD, 300 MHz, δ; ppm) 8.79 (1H, d, J = 4.5 Hz), 8.64 (1H, s), 8.61 (1H, s), 7.89 (1H, dd, J) = 3.6, 1.5 Hz), 4.99 (2H, t, J = 6.0Hz), 3.92 (2H, s), 3.30 (2H, s), 3.02 (3H, s), 1.73 (2H, quin., J = 7.8 Hz), 1.38 (6H, m), 0.93 (3H, t, J = 7.2 Hz); 13 C NMR (MeOD, 75 MHz, δ; ppm) 166.00, 150.45, 150.21, 147.56, 139.83, 124.01, 122.37, 119.36 , 56.67, 54.24, 44.53, 39.71, 30.92, 25.73, 23.56, 22.03, 12.79; MS (ESI) m / z 332.1 (MH + ); HPLC t R = 10.10 min purity 99.6% HRMS (EI) Calcd. For C17H25N5O2 331.2008 , Found 331.2041.
トリアゾール化合物YMA04-115, YMA04-118およびYMA04-119は対応するアジド化合物を原料として、NPC-3422の合成と同様の方法で合成した。 The triazole compounds YMA04-115, YMA04-118 and YMA04-119 were synthesized using the corresponding azide compounds as raw materials in the same manner as in the synthesis of NPC-3422.
5-(1-(1-ethyl methyl benzyl amine-1H-[1,2,3]triazol-5-yl)-pyridine-2-carboxylic acid hydrochloride (YMA04-115)
収率66%; 黄白色固体 1H NMR (DMSO-d6, 300 MHz, δ; ppm): 8.82 (2H, s), 8.45 (1H, s), 7.78 (1H, d, J = 3.9 Hz), 7.59-7.56 (2H, m), 7.48-7.46 (3H, m), 5.01 (2H, t, J = 6.6 Hz), 4.40 (2H, s), 3.72 (2H, t, J = 3.0 Hz), 2.73 (3H, s); 13C NMR (DMSO-d6, 75 MHz, δ; ppm): 166.5, 159.1, 151.4, 147.4, 139.8, 131.9, 130.3, 130.2, 129.4, 125.1, 122.5, 118.8, 59.5, 53.9, 45.0; HRMS (EI) Calcd. for C18H19O2N5 (MH+) 338.1612, Found 338.1609(MH+). HPLC tR=11.87 min purity 96.2%.
5- (1- (1-ethyl methyl benzyl amine-1H- [1,2,3] triazol-5-yl) -pyridine-2-carboxylic acid hydrochloride (YMA04-115)
Yield 66%; Yellow-white solid 1 H NMR (DMSO-d6, 300 MHz, δ; ppm): 8.82 (2H, s), 8.45 (1H, s), 7.78 (1H, d, J = 3.9 Hz), 7.59-7.56 (2H, m), 7.48-7.46 (3H, m), 5.01 (2H, t, J = 6.6 Hz), 4.40 (2H, s), 3.72 (2H, t, J = 3.0 Hz), 2.73 (3H, s); 13 C NMR (DMSO-d6, 75 MHz, δ; ppm): 166.5, 159.1, 151.4, 147.4, 139.8, 131.9, 130.3, 130.2, 129.4, 125.1, 122.5, 118.8, 59.5, 53.9, 45.0; HRMS (EI) Calcd. For C18H19O2N5 (MH + ) 338.1612, Found 338.1609 (MH + ). HPLC t R = 11.87 min purity 96.2%.
5-(1-(piperidine-1H-[1,2,3]triazol-5-yl)-pyridine-2-carboxylic acid hydrochloride (YMA04-118)
収率 38%; 無色固体 1H NMR (DMSO-d6, 300 MHz, δ; ppm): 8.88 (1H, s), 8.80 (1H, d, J = 4.8 Hz), 8.44 (1H, s), 7.77 (1H, d, J = 3.9 Hz), 5.02 (2H, t, J = 6.6 Hz), 3.67 (2H, d, J = 4.2 Hz), 3.41 (2H, d, J = 3.9 Hz), 2.99-2.93 (2H, m), 1.84-1.35 (6H, m); 13C NMR (DMSO-d6, 75 MHz, δ; ppm): 166.3, 151.1, 151.0, 147.1, 139.9, 124.9, 122.4, 118.8, 54.5, 52.6, 44.6, 22.6, 21.6; MS (ESI) (MH+). HRMS (EI) Calcd. for C15H19O2N5 (MH+) 302.1612, Found 302.1610(MH+). HPLC tR=5.93 min purity 98.0%.
5- (1-(piperidine-1H- [1,2,3] triazol-5-yl) -pyridine-2-carboxylic acid hydrochloride (YMA04-118)
Yield 38%; Colorless solid 1 H NMR (DMSO-d6, 300 MHz, δ; ppm): 8.88 (1H, s), 8.80 (1H, d, J = 4.8 Hz), 8.44 (1H, s), 7.77 (1H, d, J = 3.9 Hz), 5.02 (2H, t, J = 6.6 Hz), 3.67 (2H, d, J = 4.2 Hz), 3.41 (2H, d, J = 3.9 Hz), 2.99-2.93 (2H, m), 1.84-1.35 (6H, m); 13 C NMR (DMSO-d6, 75 MHz, δ; ppm): 166.3, 151.1, 151.0, 147.1, 139.9, 124.9, 122.4, 118.8, 54.5, 52.6 , 44.6, 22.6, 21.6; MS (ESI) (MH + ). HRMS (EI) Calcd. For C15H19O2N5 (MH + ) 302.1612, Found 302.1610 (MH + ). HPLC t R = 5.93 min purity 98.0%.
5-(1-(1-morpholine-1H-[1,2,3]triazol-5-yl)-pyridine-2-carboxylic acid hydrochloride (YMA04-119)
収率 35%; オレンジ色固体 1H NMR (DMSO-d6, 300 MHz, δ; ppm): 8.82 (2H, s), 8.45 (1H, s), 7.78 (1H, d, J = 3.9 Hz), 7.59-7.56 (2H, m), 7.48-7.46 (3H, m), 5.01 (2H, t, J = 6.6 Hz), 4.40 (2H, s), 3.72 (2H, t, J = 3.0 Hz), 2.73 (3H, s); 13C NMR (DMSO-d6, 75 MHz, δ; ppm): 166.5, 159.1, 151.4, 147.4, 139.8, 131.9, 130.3, 130.2, 129.4, 125.1, 122.5, 118.8, 59.5, 53.9, 45.0; HRMS (EI) Calcd. for C14H17O3N5 (MH+) 304.1404, Found 304.1406 (MH+). HPLC tR=1.75 min purity 96.0%.
5- (1- (1-morpholine-1H- [1,2,3] triazol-5-yl) -pyridine-2-carboxylic acid hydrochloride (YMA04-119)
Yield 35%; Orange Solid 1 H NMR (DMSO-d6, 300 MHz, δ; ppm): 8.82 (2H, s), 8.45 (1H, s), 7.78 (1H, d, J = 3.9 Hz), 7.59-7.56 (2H, m), 7.48-7.46 (3H, m), 5.01 (2H, t, J = 6.6 Hz), 4.40 (2H, s), 3.72 (2H, t, J = 3.0 Hz), 2.73 (3H, s); 13 C NMR (DMSO-d6, 75 MHz, δ; ppm): 166.5, 159.1, 151.4, 147.4, 139.8, 131.9, 130.3, 130.2, 129.4, 125.1, 122.5, 118.8, 59.5, 53.9, 45.0; HRMS (EI) Calcd. For C14H17O3N5 (MH + ) 304.1404, Found 304.1406 (MH + ). HPLC t R = 1.75 min purity 96.0%.
5-(1-(1-ethyl hexyl methyl amine-1H-[1,2,3]triazol-5-yl)-pyridine-2-carboxylic acid (syn-T1, NPC-3422)
Step 1: 5-(1-(1-ethyl hexyl methyl amine-1H-[1,2,3]triazol-5-yl)-pyridine-2-carboxylate (syn-T4, NPC-3543)
Alk4 (123 mg, 0.760 mmol)とAz1 (210 mg, 1.14 mmol)を5.00 mLのトルエンに溶かし、100 °Cで30時間加熱還流した。反応終了後溶媒を留去し、残渣をシリカゲルカラムクロマトグラフィー(酢酸エチル/n-ヘキサン= 1/1 to 1/0)で精製し、76.0 mgの黄色オイル状のsyn-triazole (収率29%) (syn-T4)と68.0 mgのオレンジ色オイル状のanti- triazole (収率26%) (NPC-3543)をそれぞれ得た。
syn-T4: 1H NMR (CDCl3, 300 MHz, δ; ppm) 8.79 (1H, dd, J = 4.2, 0.9 Hz), 8.12 (1H, t, J = 0.9 Hz), 8.02 (1H, s), 7.80 (1H, dd, J = 3.6, 1.5 Hz), 4.97 (2H, t, J = 7.2 Hz), 3.96 (3H, s), 2.83 (2H, t, J = 7.2 Hz), 2.32 (2H, t, J= 7.2 Hz), 2.22 (3H, s), 1.15-1.29 (8H, m), 0.82 (3H, t, J = 7.2 Hz); 13C NMR (CDCl3, 75 MHz, δ; ppm) 164.94, 150.46, 148.40, 138.72, 135.30, 133.77, 122.21, 122.01, 57.75, 56.84, 53.02, 47.80, 42.34, 31.76, 27.14, 26.98, 22.64, 14.07; MS (ESI) m/z 346.4 (MH+); HPLC tR= 12.65 min purity 95.6%
NPC-3543: 1H NMR (CDCl3, 300 MHz, δ; ppm) 8.71-8.74 (2H, m), 8.30 (1H, s), 7.78 (1H, dd, J= 3.6, 0.6 Hz), 4.52 (2H, t, J = 6.3Hz), 3.99 (3H, s), 2.88 (2H, t, J = 6.0 Hz), 2.40 (2H, t, J = 7.5 Hz), 2.31 (3H, s), 1.22-1.42 (8H, m), 0.83 (3H, t, J= 6.6 Hz); 13C NMR (CDCl3, 75 MHz, δ; ppm) 165.60, 151.70, 150.21, 147.54, 138.35, 123.25, 121.74, 119.50, 57.98, 57.03, 52.70, 48.57, 42.09, 31.75, 27.21, 27.02, 22.63, 14.02; MS (ESI) m/z 346.4 (MH+); HPLC tR = 12.13 min purity 95.6%
5- (1- (1-ethyl hexyl methyl amine-1H- [1,2,3] triazol-5-yl) -pyridine-2-carboxylic acid (syn-T1, NPC-3422)
Step 1: 5-(1- (1-ethyl hexyl methyl amine-1H- [1,2,3] triazol-5-yl)-pyridine-2-carboxylate (syn-T4, NPC-3543)
Alk4 (123 mg, 0.760 mmol) and Az1 (210 mg, 1.14 mmol) were dissolved in 5.00 mL of toluene and heated to reflux at 100 ° C. for 30 hours. After completion of the reaction, the solvent was distilled off, and the residue was purified by silica gel column chromatography (ethyl acetate / n-hexane = 1/1 to 1/0), and 76.0 mg of yellow oily syn-triazole (yield 29%) was purified. ) (Syn-T4) and 68.0 mg of orange oily anti-triazole (yield 26%) (NPC-3543) were obtained, respectively.
syn-T4: 1 H NMR (CDCl 3 , 300 MHz, δ; ppm) 8.79 (1H, dd, J = 4.2, 0.9 Hz), 8.12 (1H, t, J = 0.9 Hz), 8.02 (1H, s) , 7.80 (1H, dd, J = 3.6, 1.5 Hz), 4.97 (2H, t, J = 7.2 Hz), 3.96 (3H, s), 2.83 (2H, t, J = 7.2 Hz), 2.32 (2H, 2H, t, J = 7.2 Hz), 2.22 (3H, s), 1.15-1.29 (8H, m), 0.82 (3H, t, J = 7.2 Hz); 13 C NMR (CDCl 3 , 75 MHz, δ; ppm) 164.94, 150.46, 148.40, 138.72, 135.30, 133.77, 122.21, 122.01, 57.75, 56.84, 53.02, 47.80, 42.34, 31.76, 27.14, 26.98, 22.64, 14.07; MS (ESI) m / z 346.4 (MH + ); HPLC t R = 12.65 min purity 95.6%
NPC-3543: 1 1 H NMR (CDCl 3 , 300 MHz, δ; ppm) 8.71-8.74 (2H, m), 8.30 (1H, s), 7.78 (1H, dd, J = 3.6, 0.6 Hz), 4.52 ( 2H, t, J = 6.3Hz), 3.99 (3H, s), 2.88 (2H, t, J = 6.0 Hz), 2.40 (2H, t, J = 7.5 Hz), 2.31 (3H, s), 1.22- 1.42 (8H, m), 0.83 (3H, t, J = 6.6 Hz); 13 C NMR (CDCl 3 , 75 MHz, δ; ppm) 165.60, 151.70, 150.21, 147.54, 138.35, 123.25, 121.74, 119.50, 57.98 , 57.03, 52.70, 48.57, 42.09, 31.75, 27.21, 27.02, 22.63, 14.02; MS (ESI) m / z 346.4 (MH + ); HPLC t R = 12.13 min purity 95.6%
Step 2: 5-(1-(1-ethyl hexyl methyl amine-1H-[1,2,3]triazol-5-yl)-pyridine-2-carboxylic acid (syn-T1, NPC-3422)
syn体およびanti体のトリアゾール化合物(50.0 mg, 145 μmol)のメタノール溶液(3.00 mL)に2.00 mLの2 N 水酸化ナトリウム水溶液をそれぞれ加え、反応溶液を室温、12時間撹拌した。反応終了後、溶媒を留去し、残渣に4N 塩酸/ジオキサンを加え、pH 1.0に調整した。溶液をろ過し、ろ液を濃縮して13.9 mgのsyn-T1および10.0 mgのanti-T1 を得た。(収率29%/21%).
syn-T1: 1H NMR (MeOD, 300 MHz, δ; ppm) 8.92 (1H, dd, J = 4.5, 0.6 Hz), 8.43 (1H, s), 8.40 (1H, t, J = 0.3 Hz), 7.97 (1H, dd, J = 3.6, 1.5 Hz), 5.36 (2H, t, J = 6.0 Hz), 3.92 (2H, s), 3.29 (2H, t, J = 8.4 Hz), 3.05 (3H, s), 1.75 (2H, quin., J = 8.1 Hz), 1.37 (6H, m), 0.93 (3H, t, J = 7.2 Hz); 13C NMR (MeOD, 75 MHz, δ; ppm) 166.99, 151.80, 148.47, 141.77, 137.53, 135.20, 124.35, 123.72, 58.00, 56.08, 46.15, 41.34, 32.32, 27.14, 25.03, 23.41, 14.21; MS (ESI) m/z 332.1(MH+); HPLC tR= 10.98 min purity 99.5%
NPC-3422: 1H NMR (MeOD, 300 MHz, δ; ppm) 8.79 (1H, d, J = 4.5 Hz), 8.64 (1H, s), 8.61 (1H, s), 7.89 (1H, dd, J = 3.6, 1.5 Hz), 4.99 (2H, t, J = 6.0 Hz), 3.92 (2H, s), 3.30 (2H, s), 3.02 (3H, s), 1.73 (2H, quin., J = 7.8 Hz), 1.38 (6H, m), 0.93 (3H, t, J = 7.2 Hz); 13C NMR (MeOD, 75 MHz, δ; ppm) 166.00, 150.45, 150.21, 147.56, 139.83, 124.01, 122.37, 119.36, 56.67, 54.24, 44.53, 39.71, 30.92, 25.73, 23.56, 22.03, 12.79; MS (ESI) m/z 332.1(MH+); HPLC tR = 10.10 min purity 99.6%
Step 2: 5-(1- (1-ethyl hexyl methyl amine-1H- [1,2,3] triazol-5-yl) -pyridine-2-carboxylic acid (syn-T1, NPC-3422)
A 2.00 mL aqueous solution of 2 N sodium hydroxide was added to a methanol solution (3.00 mL) of syn and anti triazole compounds (50.0 mg, 145 μmol), and the reaction solution was stirred at room temperature for 12 hours. After completion of the reaction, the solvent was distilled off, and 4N hydrochloric acid / dioxane was added to the residue to adjust the pH to 1.0. The solution was filtered and the filtrate was concentrated to give 13.9 mg syn-T1 and 10.0 mg anti-T1. (Yield 29% / 21%).
syn-T1: 1 1 H NMR (MeOD, 300 MHz, δ; ppm) 8.92 (1H, dd, J = 4.5, 0.6 Hz), 8.43 (1H, s), 8.40 (1H, t, J = 0.3 Hz), 7.97 (1H, dd, J = 3.6, 1.5 Hz), 5.36 (2H, t, J = 6.0 Hz), 3.92 (2H, s), 3.29 (2H, t, J = 8.4 Hz), 3.05 (3H, s) ), 1.75 (2H, quin., J = 8.1 Hz), 1.37 (6H, m), 0.93 (3H, t, J = 7.2 Hz); 13 C NMR (MeOD, 75 MHz, δ; ppm) 166.99, 151.80 , 148.47, 141.77, 137.53, 135.20, 124.35, 123.72, 58.00, 56.08, 46.15, 41.34, 32.32, 27.14, 25.03, 23.41, 14.21; MS (ESI) m / z 332.1 (MH + ); HPLC t R = 10.98 min purity 99.5%
NPC-3422: 1 H NMR (MeOD, 300 MHz, δ; ppm) 8.79 (1H, d, J = 4.5 Hz), 8.64 (1H, s), 8.61 (1H, s), 7.89 (1H, dd, J) = 3.6, 1.5 Hz), 4.99 (2H, t, J = 6.0 Hz), 3.92 (2H, s), 3.30 (2H, s), 3.02 (3H, s), 1.73 (2H, quin., J = 7.8 Hz), 1.38 (6H, m), 0.93 (3H, t, J = 7.2 Hz); 13 C NMR (MeOD, 75 MHz, δ; ppm) 166.00, 150.45, 150.21, 147.56, 139.83, 124.01, 122.37, 119.36 , 56.67, 54.24, 44.53, 39.71, 30.92, 25.73, 23.56, 22.03, 12.79; MS (ESI) m / z 332.1 (MH + ); HPLC t R = 10.10 min purity 99.6%
試験例１
酵素活性試験
KDM酵素の活性評価はAlpha screenアッセイシステムを用いた。評価に用いたバッファーおよび試薬を表S1に示した。2.5 μLの阻害剤溶液(3.0% DMSO/アッセイバッファー溶液)もしくはアッセイバッファー(50 mM HEPES pH 7.5, 0.1% w/v BSA, 0.01% v/v Tween-20 containing 3% DMSO、コントロールとブランク用)をOptiPlateTM-384白色プレートの各ウェルに添加した。そこに5.0 μLの酵素溶液を添加した。(ブランクのウェルには5.0 μLのアッセイバッファーを加えた)。室温で5分置いた後、2.5 μLの基質タンパク質/2-OG (50 μM)/Fe(II)(5 μM)/アスコルビン酸ナトリウム (100 μM)のバッファー溶液を各ウェルに添加した。酵素や基質タンパク質の最終濃度を表S2にまとめた。これらの反応溶液を室温で1時間もしくは2時間、おだやかに振盪撹拌した(250 rpm)。5.0 μLのアクセプタービーズのepigeneticバッファー溶液(100 μg/mL)を各ウェルに添加し、室温、1時間穏やかに振盪撹拌した(250 rpm)。最後に、10 μLのドナービーズのepigeneticバッファー溶液(50 μg/mL)を加え室温、30分間暗所で振盪撹拌した(250 rpm)。その後、AlphaシグナルをEnsight(R)readers(PerkinElmer Ltd)で検出した。(励起光波長:615 nm、発光波長: 655 nm)。酵素活性(%)は阻害剤のウェルのAlphaシグナルをコントロールのウェルのシグナルで割った値で算出した。結果を図１に示す。
Test Example 1
Enzyme activity test
The Alpha screen assay system was used to evaluate the activity of the KDM enzyme. The buffers and reagents used for the evaluation are shown in Table S1. 2.5 μL inhibitor solution (3.0% DMSO / assay buffer solution) or assay buffer (50 mM HEPES pH 7.5, 0.1% w / v BSA, 0.01% v / v Tween-20 containing 3% DMSO, for controls and blanks) Was added to each well of OptiPlate TM -384 white plate. 5.0 μL of enzyme solution was added thereto. (5.0 μL of assay buffer was added to the blank wells). After standing at room temperature for 5 minutes, a buffer solution of 2.5 μL of substrate protein / 2-OG (50 μM) / Fe (II) (5 μM) / sodium ascorbate (100 μM) was added to each well. The final concentrations of enzymes and substrate proteins are summarized in Table S2. These reaction solutions were gently shaken and stirred at room temperature for 1 or 2 hours (250 rpm). 5.0 μL of acceptor beads epigenetic buffer solution (100 μg / mL) was added to each well and gently shaken for 1 hour at room temperature (250 rpm). Finally, 10 μL of donor bead epigenetic buffer solution (50 μg / mL) was added and stirred at room temperature for 30 minutes in the dark with shaking (250 rpm). The Alpha signal was then detected by Ensight (R) readers (PerkinElmer Ltd). (Excitation wavelength: 615 nm, emission wavelength: 655 nm). Enzyme activity (%) was calculated by dividing the Alpha signal in the inhibitor well by the signal in the control well. The results are shown in FIG.
細胞培養
ヒト前立腺がん細胞PC3 (Japanese Collection of Research Bioresources; JCRB9110, Japan)を10% ウシ胎児血清アルブミン(FBS; SIGMA, #172012-500ML)、5% penicillin/streptomyc (Nacalai, #09366-44)を含むHam's F-12K (Kaighn's)培地(Gibco, #21127022)で 5% CO2雰囲気下、37 °Cで培養した。ヒト前立腺がん細胞LNCaP (American type culture collection, ATCC)およびヒト胃がん細胞MKN45(provided by RIKEN BRC cell bank; RCB1001, Japan)は10% FBS, 5% penicillin/streptomycin mixtureを含むRPMI-1640 (Sigma, R8758)培地中、5% CO2雰囲気下、37 °Cで培養した。
Cell Culture Human Prostate Cancer Cell PC3 (Japanese Collection of Research Bioresources; JCRB9110, Japan) 10% Fetal Bovine Serum Albumin (FBS; SIGMA, # 172012-500ML), 5% penicillin / streptomyc (Nacalai, # 09366-44) The cells were cultured in Ham's F-12K (Kaighn's) medium (Gibco, # 21127022) containing 5% CO 2 at 37 ° C. Human prostate cancer cells LNCaP (American type culture collection, ATCC) and human gastric cancer cells MKN45 (provided by RIKEN BRC cell bank; RCB1001, Japan) contain RPMI-1640 (Sigma, Sigma, 5% penicillin / streptomycin mixture) containing 10% FBS, 5% penicillin / streptomycin mixture. R8758) Incubated in medium at 37 ° C in a 5% CO 2 atmosphere.
ウェスタンブロッティング
PC3, LnCAP および MKN45 細胞 (5 x 105cells/2 mL/dish)にNPC-3543 を処理し、48時間培養した。その後細胞ペレットをSDSバッファーで抽出した。抽出したライセートのタンパク質濃度をBCA protein assayを用いて測定した。ライセートのタンパク濃度を揃え、5-20% SDS-polyacrylamideゲルを用いて電気泳動を行った。さらにPVDFメンブレンに転写した。メンブレンを5%スキムミルクTBS-T溶液でブロッキングを行った後、一次抗体polyclonal H3K4me3 antibody (Abcam, #ab8580) (1:5000希釈), H3K4me2 antibody (CST, #9725) (1:5000希釈), H3K4me1 antibody (Abcam, #ab8895) (1:5000希釈), H3 antibody (Abcam, #ab1791) (1:200000 希釈), KDM5A antibody (CST, #3876) (1:1000希釈), KDM5B antibody (CST, #3273) (1:1000希釈)、KDM5C antibody (CST, #5361) (1:1000希釈)、mouse monoclonal α-tubulin antibody (sigma, #T8203) (1:1000希釈)をそれぞれ5%スキムミルクTBS-T溶液で希釈し、室温で1時間振盪撹拌して反応させた。メンブレンを3回TBS-Tで洗浄後、二次抗体ECL rabbit/mouse IgG, HRP-linked whole Anti-body (GE Healthcare Life Sciences, #NA934) (1:2500希釈)を室温1時間反応させた。再び3回 TBS-Tで洗浄した。バンドは化学発光により検出し、ImmobilonTMWestern Chemiluminescent HRP Substrate (Millipore, #P90718)を検出薬として使用した。結果を図2に示す。KDM5C過剰発現細胞PC3でのみ、H3K4のメチル化が亢進していた。このことから、NPC-3543は細胞系でもKDM5Cを選択的に阻害することが明らかになった。
Western blotting
PC3, LnCAP and MKN45 cells (5 x 10 5 cells / 2 mL / dish) were treated with NPC-3543 and cultured for 48 hours. The cell pellet was then extracted with SDS buffer. The protein concentration of the extracted lysate was measured using the BCA protein assay. The protein concentrations of lysates were adjusted, and electrophoresis was performed using a 5-20% SDS-polyPAGE gel. It was further transferred to a PVDF membrane. After blocking the membrane with 5% skim milk TBS-T solution, primary antibody polyclonal H3K4me3 antibody (Abcam, # ab8580) (1: 5000 dilution), H3K4me2 antibody (CST, # 9725) (1: 5000 dilution), H3K4me1 antibody (Abcam, # ab8895) (1: 5000 dilution), H3 antibody (Abcam, # ab1791) (1: 200,000 dilution), KDM5A antibody (CST, # 3876) (1: 1000 dilution), KDM5B antibody (CST, # 3273) (1: 1000 diluted), KDM5C antibody (CST, # 5361) (1: 1000 diluted), mouse monoclonal α-tubulin antibody (sigma, # T8203) (1: 1000 diluted) 5% skim milk TBS-T respectively The antibody was diluted with the solution and stirred at room temperature for 1 hour with shaking. After washing the membrane 3 times with TBS-T, the secondary antibody ECL rabbit / mouse IgG and HRP-linked whole Anti-body (GE Healthcare Life Sciences, # NA934) (1: 2500 dilution) were reacted at room temperature for 1 hour. It was washed with TBS-T three times again. The band was detected by chemiluminescence, and Immobilon TM Western Chemiluminescent HRP Substrate (Millipore, # P90718) was used as a detection agent. The result is shown in figure 2. H3K4 methylation was enhanced only in KDM5C overexpressing cell PC3. From this, it was clarified that NPC-3543 selectively inhibits KDM5C even in the cell line.
試験例２
NPC-3543投与マウスの行動評価試験(図3-6)
8週齢の雄性DBA/2マウス（以下、DBAマウス）の内側前頭前野にカニューレを留置し、NPC-3543 (100μM)あるいは溶媒を投与し、その2時間後に社会性敗北ストレス(*1)を負荷した。これを5日間連続して行い、社会性試験(*2)を施行した。
Test Example 2
Behavioral evaluation test of NPC-3543-administered mice (Fig. 3-6)
A cannula was placed in the medial prefrontal cortex of 8-week-old male DBA / 2 mice (hereinafter referred to as DBA mice), NPC-3543 (100 μM) or a solvent was administered, and 2 hours later, social defeat stress (* 1) was applied. Loaded. This was done for 5 consecutive days, and a social test (* 2) was conducted.
*1社会性敗北ストレス
テストマウスを攻撃性の高いCD-1マウスのケージに5分間入れる。この時、CD-1マウスはテストマウスに対して一方的に攻撃を仕掛ける（肉体的ストレス負荷）。5分経過後、CD-1マウスとテストマウスを透明なアクリル板で仕切り、２４時間飼育する（心理ストレス負荷）。これを５日間連続で行った(図３)。
* 1 Social defeat stress test mice are placed in highly aggressive CD-1 mouse cages for 5 minutes. At this time, the CD-1 mouse unilaterally attacks the test mouse (physical stress load). After 5 minutes, the CD-1 mouse and the test mouse are separated by a transparent acrylic plate and bred for 24 hours (psychological stress load). This was done for 5 consecutive days (Fig. 3).
*2社会性試験
42 cm四方の箱に新奇マウスとしてCD-1マウスを置く（ターゲットエリア）。この箱の中にテストマウス（DBAマウス）を置き、３分間でターゲットエリアに滞在した時間をビデオトラッキングシステム（Any-Mazeソフトウェア）により測定した(図４)。
* 2 Social test
Place the CD-1 mouse as a novel mouse in a 42 cm square box (target area). A test mouse (DBA mouse) was placed in this box, and the time spent in the target area for 3 minutes was measured by a video tracking system (Any-Maze software) (Fig. 4).
＜スクロース嗜好性試験の方法＞
1%スクロース溶液と通常水の入ったボトルを同時に与えた。4時間でスクロース溶液と通常水を飲んだ量を計測し、スクロース水を飲んだ割合（sucrose preference）をアンヘドニアの指標とした(図５)。通常、動物は甘いスクロースを好むが、うつ病の病態の１つであるanhedonia（無感症）の状態にある動物はスクロースに対する選択性が低下する。
<Method of sucrose palatability test>
A bottle of 1% sucrose solution and normal water was given simultaneously. The amount of sucrose solution and normal water consumed was measured in 4 hours, and the ratio of sucrose water consumed (sucrose preference) was used as an index of anhedonia (Fig. 5). Animals usually prefer sweet sucrose, but animals in anhedonia (anhedonia), one of the pathologies of depression, have reduced selectivity for sucrose.
KDM5C阻害薬（NPC-3543）は、Sucrose Preference試験において、抗うつ効果を示した。このことから、KDM5C阻害剤（NPC-3543)が抗うつ薬として有効であることが示された。 The KDM5C inhibitor (NPC-3543) showed antidepressant effects in the Sucrose Preference study. This indicates that the KDM5C inhibitor (NPC-3543) is effective as an antidepressant.
＜遺伝子発現解析(図６)＞
ストレス脆弱性DBAマウスに軽度ストレスを5日間与えた。このときにNPC-3543 (100μM)又は溶媒(vehicle、水)を毎日投与し、次世代シーケンサーを用いた遺伝子発現解析（RNA-seq）を行い、主成分分析(PCA)とクラスタリング解析を行った。その結果、ストレス負荷によって生じた異常な遺伝子発現パターンがKDM5C阻害剤(NPC-3543)によって正常化することが明らかになった。
<Gene expression analysis (Fig. 6)>
Stress Vulnerability DBA mice were given mild stress for 5 days. At this time, NPC-3543 (100 μM) or solvent (vehicle, water) was administered daily, gene expression analysis (RNA-seq) was performed using a next-generation sequencer, and principal component analysis (PCA) and clustering analysis were performed. .. As a result, it was clarified that the abnormal gene expression pattern caused by stress loading was normalized by the KDM5C inhibitor (NPC-3543).
Claims (4)
Ｒ５は、水素原子、ハロゲン原子、アルキル、アルコキシ、アリール、アラルキル、ヒドロキシアルキル又はシクロアルキルを示す。Ｒ４とＲ５は、これらが結合している炭素原子と一緒になって置換基を有していてもよいベンゼン環又は置換基を有していてもよいピリジン環を形成してもよい。
Ｒ６、Ｒ７は、同一または相異なり、水素原子、アルキル、アルコキシ、アリール、アラルキル、ヒドロキシアルキル又はシクロアルキルを示す。但し、Ｒ６とＲ７が同時に水素原子となることはない。
Ｒ８は、ＯＨ、アルコキシ、ヒドロキシアルキルオキシ、シクロアルキルオキシ、アリールオキシ又はアラルキルオキシを示す。
ＺはＮ又はＣＲ９を示す。Ｒ９は水素原子、アルキル、アリール又はアラルキルを示す。
ｎは０〜５の整数を示す。）
で表される化合物、またはその薬学的に許容される塩もしくは溶媒和物。 The following formula (I)
R 5 represents a hydrogen atom, a halogen atom, an alkyl, an alkoxy, an aryl, an aralkyl, a hydroxyalkyl or a cycloalkyl. R 4 and R 5 may be combined with the carbon atom to which they are bonded to form a benzene ring which may have a substituent or a pyridine ring which may have a substituent.
R 6 and R 7 are the same or different and represent hydrogen atom, alkyl, alkoxy, aryl, aralkyl, hydroxyalkyl or cycloalkyl. However, R 6 and R 7 do not become hydrogen atoms at the same time.
R 8 represents OH, alkoxy, hydroxyalkyloxy, cycloalkyloxy, aryloxy or aralkyloxy.
Z indicates N or CR 9 . R 9 represents a hydrogen atom, alkyl, aryl or aralkyl.
n represents an integer from 0 to 5. )
A compound represented by, or a pharmaceutically acceptable salt or solvate thereof.
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