JP2008208086A - 3-amino-2-indolylbutyrolactam derivative, method for producing the same and medicine containing the derivative as active component - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a medicine to suppress cell death and effective as a preventing and treating agent for the progress of the symptoms of various diseases in which the cell death is participated in the progress and exacerbation of the diseases. <P>SOLUTION: The invention provides a compound expressed by general formula (1) and its pharmaceutically allowable salt, and the use of the compound relating to the cell death suppressing activity. <P>COPYRIGHT: (C)2008,JPO&INPIT

Description

  The present invention relates to a novel 3-amino-2-indolylbutyrolactam derivative having a cell death-inhibiting action, a process for producing the same, and a pharmaceutical comprising the same as an active ingredient.

  In multicellular organisms, cell death is a physiologically essential phenomenon, and cells that should be removed under strict control are directed to death themselves. This active cell death is called apoptosis, and the molecular mechanism has been elucidated in detail with the identification of the central execution factor caspase and the development of its inhibitor. On the other hand, in recent years, it has been found that cell death not involving caspase is observed in diseases such as neurodegenerative diseases and ischemic heart diseases, and research on the cell death mechanism and control factors has been actively conducted.

  Against this backdrop, Sodeoka et al. Have already confirmed that caspases are not affected by bisindolylmaleimide derivatives, bisindolylpyrrole derivatives, indolylmaleimide derivatives, and indolylpyrrole derivatives by an assay system using primary cultured cells. They have found that they suppress cell death induced by oxidative stress and have filed patent applications (Patent Documents 1 to 4).

  Diseases involving oxidative stress include cerebral ischemia (Non-patent document 1) and ischemic heart disease (Non-patent document 2), as well as ischemia reperfusion injury in various organs (Non-patent document 3), Alzheimer's disease Neurodegenerative diseases such as (Non-patent Document 4) are known. In fact, compounds that suppress cell death induced by oxidative stress (hydrogen peroxide, nitric oxide, etc.) in vitro suppress ischemia-reperfusion injury even in vivo (Non-Patent Documents 5 to 7) In addition, it has been reported that a therapeutic effect is reported in models of neurodegenerative diseases such as Parkinson's disease and amyotrophic lateral sclerosis (Non-patent Document 8), thereby suppressing cell death induced by oxidative stress. This compound can be said to be effective as a therapeutic agent for these diseases.

  Therefore, Sodeoka et al. Developed an assay system using the cultured cell line HL60, and reported that the search for cell death inhibitors can be performed more efficiently (Non-patent Document 9). We investigated the structure-activity relationship of drill maleimide derivatives, and reported the mono-indolyl maleimide derivative IM-54, which is not toxic at 10 μM, whereas the bis-indolyl maleimide derivative is toxic at 10 μM (non-patent literature) Ten). However, as a result of further investigation, it was found that IM-54 was also toxic at 30 μM. Therefore, a compound having low toxicity at a higher concentration and excellent cell death inhibiting activity at a lower concentration was sought. .

  On the other hand, from indolylmaleimide derivatives to 3-amino-4-hydroxy-2-indolylbutyrolactam derivatives, 4-alkoxy-3-amino-2-indolylbutyrolactam derivatives, 4-alkylthio-3-amino-2 None of the methods for producing -indolylbutyrolactam derivatives and 4-alkyl-3-amino-2-indolylbutyrolactam derivatives have been reported.

WO 99/42100 WO 00/47575 WO 01/13916 WO 01/74807 G. Fiskum, R. E. Rosenthal, V. Vereczki, E. Martin, G. E. Hoffman, C. Chinopoulos, and A. Kowaltowski, J. Bioenerg. Biomembr. 36, 347-352 (2004). L. G. Kevin, E. Novalija, and D. F. Stowe, Anesth. Analg. 101, 1275-1287 (2005). D. Galaris, A. Barbouti, and P. Korantzopoulos, Curr. Pharm. Des. 12, 2875-2890 (2006). Y. Gilgun-Sherki, E. Melamed, and D. Offen, Neuropharmacology 40, 959-975 (2001). H. Yoshida, H. Yanai, Y. Namiki, K. Fukatsu-Sasaki, N. Furutani, and N. Tada, CNS Drug Reviews 12, 9-20 (2006). V. J. Adlam, J. C. Harrison, C. M. Porteous, A. M. James, R. A. J. Smith, M. P. Murphy, and I. A. Sammut, FASEB J. 19, 1088-1095 (2005). OR Kunduzova, G. Escourrou, F. de la Farge, R. Salvayre, MH Seguelas, N. Leducq, F. Bono, JM Herbert, and A. Parini, J. Am. Soc. Nephrol. 15, 2152-2160 ( 2004). H. H. Szeto, AAPS J. 8, E521-E531 (2006). M. Katoh, K. Dodo, M. Fujita, and M. Sodeoka, Bioorg. Med. Chem. Lett., 15, 3109-3113 (2005). K. Dodo, M. Katoh, T. Shimizu, M. Takahashi, and M. Sodeoka, Bioorg. Med. Chem. Lett., 15, 3114-3118 (2005).

  An object of the present invention is to provide a drug that suppresses cell death, which is effective as a preventive and therapeutic agent for the progression of symptoms of various diseases in which cell death is involved in its progression.

  As a result of intensive studies, the present inventors have found that a 3-amino-2-indolylbutyrolactam derivative represented by the following general formula (1) has a cell death inhibitory action, and completes the present invention. It came.

(式中、
Xは、水素原子、置換基を有していてもよいアルキル基、置換基を有していてもよいアルケニル基、置換基を有していてもよいアルキニル基、置換基を有していてもよいアリール基、置換基を有していてもよいアラルキル基、ヒドロキシル基、置換基を有していてもよいアルコキシル基、置換基を有していてもよいアルケニル、アルキニル、アリール若しくはアラルキルオキシ基、チオール基、置換基を有していてもよいアルキル、アルケニル、アルキニル、アリール若しくはアラルキルチオ基、置換基を有していてもよいアルキル、アルケニル、アルキニル、アリール若しくはアラルキルスルホニル基、置換基を有していてもよいアルキル、アルケニル、アルキニル、アリール若しくはアラルキルスルフィニル基、シアノ基、置換基を有していてもよいアミノ基、又はハロゲン原子を表し、
R¹は、置換基を有していてもよいアルキル基、置換基を有していてもよいアルケニル基、置換基を有していてもよいアルキニル基、置換基を有していてもよいアリール基、置換基を有していてもよいアラルキル基、置換基を有していてもよいアシル基、置換基を有していてもよいアシルオキシ基、置換基を有していてもよいアルキル、アルケニル、アルキニル、アリール若しくはアラルキルオキシカルボニル基、置換基を有していてもよいアルキル、アルケニル、アルキニル、アリール若しくはアラルキルチオカルボニル基、置換基を有していてもよいアミノカルボニル基、置換基を有していてもよいアミノカルボニルオキシ基、置換基を有していてもよいアルキル、アルケニル、アルキニル、アリール若しくはアラルキルスルホニル基、置換基を有していてもよいアルコキシル基、置換基を有していてもよいアルケニル、アルキニル、アリール若しくはアラルキルオキシ基、置換基を有していてもよいアミノ基、又はヒドロキシル基を表し、
R²及びR³は、互いに独立に、水素原子、置換基を有していてもよいアルキル基、置換基を有していてもよいアルケニル基、置換基を有していてもよいアルキニル基、置換基を有していてもよいアリール基、置換基を有していてもよいアラルキル基、置換基を有していてもよいアシル基、置換基を有していてもよいアシルオキシ基、置換基を有していてもよいアルキル、アルケニル、アルキニル、アリール若しくはアラルキルオキシカルボニル基、置換基を有していてもよいアルキル、アルケニル、アルキニル、アリール若しくはアラルキルチオカルボニル基、置換基を有していてもよいアミノカルボニル基、置換基を有していてもよいアミノカルボニルオキシ基、置換基を有していてもよいアルキル、アルケニル、アルキニル、アリール若しくはアラルキルスルホニル基、置換基を有していてもよいアルコキシル基、置換基を有していてもよいアルケニル、アルキニル、アリール若しくはアラルキルオキシ基、置換基を有していてもよいアミノ基、又はヒドロキシル基を表し、
又はR²及びR³は、それらが結合する窒素原子と一体になって、更なるヘテロ原子を含んでもよく、置換基を有していてもよい、飽和若しくは不飽和の環構造を形成していてもよく、
R⁴はインドール環の位置番号で2, 4, 5, 6又は7位あるいはその複数の位置についた基を表し、nは1〜5の数であり、nが2以上である場合はR⁴の種類は同じでも異なっていてもよく、水素原子、ハロゲン原子、置換基を有していてもよいアルキル基、置換基を有していてもよいアルケニル基、置換基を有していてもよいアルキニル基、置換基を有していてもよいアリール基、置換基を有していてもよいアラルキル基、置換基を有していてもよいアルコキシル基、置換基を有していてもよいアルケニル、アルキニル、アリール若しくはアラルキルオキシ基、置換基を有していてもよいアルキル、アルケニル、アルキニル、アリール若しくはアラルキルオキシカルボニル基、置換基を有していてもよいアルキル、アルケニル、アルキニル、アリール若しくはアラルキルオキシカルボニルオキシ基、置換基を有していてもよいアルキル、アルケニル、アルキニル、アリール若しくはアラルキルチオカルボニル基、置換基を有していてもよいアルキル、アルケニル、アルキニル、アリール若しくはアラルキルチオカルボニルオキシ基、置換基を有していてもよいアミノカルボニル基、置換基を有していてもよいアミノカルボニルオキシ基、置換基を有していてもよいアルキル、アルケニル、アルキニル、アリール若しくはアラルキルスルホニル基、アルキル、アルケニル、アルキニル、アリール若しくはアラルキルスルフィニル基、置換基を有していてもよいアルキル、アルケニル、アルキニル、アリール若しくはアラルキルチオ基、ヒドロキシル基、カルボキシル基、オキシスルホニル基、シアノ基、ニトロ基、又は置換基を有していてもよいアミノ基を表し、
R⁵は、置換基を有していてもよいアルキル基、置換基を有していてもよいアルケニル基、置換基を有していてもよいアルキニル基、置換基を有していてもよいアリール基、置換基を有していてもよいアラルキル基、水素原子、置換基を有していてもよいアシル基、置換基を有していてもよいアシルオキシ基、置換基を有していてもよいアルキル、アルケニル、アルキニル、アリール若しくはアラルキルオキシカルボニル基、置換基を有していてもよいアルキル、アルケニル、アルキニル、アリール若しくはアラルキルチオカルボニル基、置換基を有していてもよいアミノカルボニル基、置換基を有していてもよいアミノカルボニルオキシ基、置換基を有していてもよいアルキル、アルケニル、アルキニル、アリール若しくはアラルキルスルホニル基、置換基を有していてもよいアルコキシル基、置換基を有していてもよいアルケニル、アルキニル、アリール若しくはアラルキルオキシ基、置換基を有していてもよいアミノ基、又はヒドロキシル基を表す)
で表される3-アミノ-2-インドリルブチロラクタム誘導体又はその塩に関する。 The present invention relates to a general formula (1):

(Where
X may be a hydrogen atom, an alkyl group that may have a substituent, an alkenyl group that may have a substituent, an alkynyl group that may have a substituent, or a substituent. A good aryl group, an optionally substituted aralkyl group, a hydroxyl group, an optionally substituted alkoxyl group, an optionally substituted alkenyl, alkynyl, aryl or aralkyloxy group, A thiol group, an optionally substituted alkyl, alkenyl, alkynyl, aryl or aralkylthio group, an optionally substituted alkyl, alkenyl, alkynyl, aryl or aralkylsulfonyl group, having a substituent Optionally having alkyl, alkenyl, alkynyl, aryl or aralkylsulfinyl group, cyano group, substituent Represents an amino group or a halogen atom,
R ¹ represents an alkyl group which may have a substituent, an alkenyl group which may have a substituent, an alkynyl group which may have a substituent, and an aryl which may have a substituent. Group, an aralkyl group which may have a substituent, an acyl group which may have a substituent, an acyloxy group which may have a substituent, an alkyl or alkenyl which may have a substituent , Alkynyl, aryl or aralkyloxycarbonyl group, optionally substituted alkyl, alkenyl, alkynyl, aryl or aralkylthiocarbonyl group, optionally substituted aminocarbonyl group, substituted An optionally substituted aminocarbonyloxy group, an optionally substituted alkyl, alkenyl, alkynyl, aryl or aralkylsulfonyl group, It represents optionally an alkoxyl group which may have a group, alkenyl which may have a substituent, alkynyl, aryl or aralkyl group, optionally substituted amino group, or a hydroxyl group,
R ² and R ³ are each independently a hydrogen atom, an alkyl group which may have a substituent, an alkenyl group which may have a substituent, an alkynyl group which may have a substituent, An aryl group which may have a substituent, an aralkyl group which may have a substituent, an acyl group which may have a substituent, an acyloxy group which may have a substituent, a substituent May have an alkyl, alkenyl, alkynyl, aryl or aralkyloxycarbonyl group, may have a substituent, may have an alkyl, alkenyl, alkynyl, aryl or aralkylthiocarbonyl group, may have a substituent A good aminocarbonyl group, an optionally substituted aminocarbonyloxy group, an optionally substituted alkyl, alkenyl, alkynyl, aryl Is an aralkylsulfonyl group, an optionally substituted alkoxyl group, an optionally substituted alkenyl, an alkynyl, aryl or aralkyloxy group, an optionally substituted amino group, or a hydroxyl group Represents a group,
Or R ² and R ³ together with the nitrogen atom to which they are attached form a saturated or unsaturated ring structure that may contain further heteroatoms and may have a substituent. You can,
R ⁴ is a position number of the indole ring and represents a group attached to the 2, 4, 5, 6 or 7 position or a plurality of positions thereof, n is a number from 1 to 5, and when n is 2 or more, R ⁴ These may be the same or different, and may have a hydrogen atom, a halogen atom, an alkyl group which may have a substituent, an alkenyl group which may have a substituent, or a substituent. An alkynyl group, an aryl group which may have a substituent, an aralkyl group which may have a substituent, an alkoxyl group which may have a substituent, an alkenyl which may have a substituent, Alkynyl, aryl or aralkyloxy group, optionally substituted alkyl, alkenyl, alkynyl, aryl or aralkyloxycarbonyl group, optionally substituted alkyl, alkenyl, alkynyl, aryl Is an aralkyloxycarbonyloxy group, an optionally substituted alkyl, alkenyl, alkynyl, aryl or aralkylthiocarbonyl group, an optionally substituted alkyl, alkenyl, alkynyl, aryl or aralkylthiocarbonyloxy A group, an optionally substituted aminocarbonyl group, an optionally substituted aminocarbonyloxy group, an optionally substituted alkyl, alkenyl, alkynyl, aryl or aralkylsulfonyl group, Alkyl, alkenyl, alkynyl, aryl or aralkylsulfinyl group, optionally substituted alkyl, alkenyl, alkynyl, aryl or aralkylthio group, hydroxyl group, carboxyl group, oxysulfonyl group, cyano , A nitro group, or an amino group which may have a substituent,
R ⁵ represents an alkyl group which may have a substituent, an alkenyl group which may have a substituent, an alkynyl group which may have a substituent, or an aryl which may have a substituent. A group, an aralkyl group which may have a substituent, a hydrogen atom, an acyl group which may have a substituent, an acyloxy group which may have a substituent, or a substituent. Alkyl, alkenyl, alkynyl, aryl or aralkyloxycarbonyl group, optionally substituted alkyl, alkenyl, alkynyl, aryl or aralkylthiocarbonyl group, optionally substituted aminocarbonyl group, substituent An aminocarbonyloxy group which may have a substituent, alkyl, alkenyl, alkynyl, aryl or aralkylsulfo which may have a substituent An alkoxyl group which may have a substituent, an alkenyl which may have a substituent, an alkynyl, aryl or aralkyloxy group, an amino group which may have a substituent, or a hydroxyl group To express)
The 3-amino-2-indolyl butyrolactam derivative represented by these, or its salt.

  The present invention also relates to a method for producing the compound.

  The present invention also relates to a cell death inhibitor containing the compound or a pharmaceutically acceptable salt thereof as an active ingredient.

  The present invention also relates to a medicament containing the compound or a pharmaceutically acceptable salt thereof as an active ingredient. The medicament is useful as a prophylactic or therapeutic agent for various diseases or symptoms in which cell death is associated with its progressive deterioration.

  The present invention also relates to a preservative for organs, tissues and cells, containing the compound or a pharmaceutically acceptable salt thereof as an active ingredient.

  The present invention also relates to a biological research reagent containing the compound or a salt thereof.

  The compound of the present invention or a salt thereof can suppress cell death. Prevention of the disease or symptom by administering the compound of the present invention or a salt thereof to a mammal such as a human in need of prevention or treatment of various diseases or symptoms in which cell death is involved in the progression of the disease Or it can be treated.

  In the present specification, the alkyl group in the “optionally substituted alkyl group” may be linear, branched or cyclic, for example, an alkyl group having 1 to 30 carbon atoms. Are methyl, ethyl, propyl, isopropyl, butyl, isobutyl, s-butyl, t-butyl, pentyl, isopentyl, neopentyl, hexyl, heptyl, octyl, nonyl Decyl group, cyclopropyl group, cyclobutyl group, cyclopentyl group, cyclohexyl group, cycloheptyl group, undecyl group, dodecyl group, tridecyl group, tetradecyl group, pentadecyl group, hexadecyl group, 14-methylpentadecyl group, 6-methylpentadecyl group Examples thereof include a decyl group, an octadecyl group, an icosyl group, and a tetracosyl group.

  In the present specification, the alkenyl group in “optionally substituted alkenyl group” may be linear, branched or cyclic, for example, an alkenyl group having 2 to 30 carbon atoms. Are allyl, vinyl, crotyl, 1-penten-1-yl, 2-penten-1-yl, 3-penten-1-yl, 1-hexen-1-yl, 2-hexene Examples include a 1-yl group, a 3-hexen-1-yl group, a 2-cyclohexenyl group, and a 2-cyclopentenyl group.

  In the present specification, the alkynyl group in the “optionally substituted alkynyl group” may be linear, branched or cyclic, for example, an alkynyl group having 2 to 30 carbon atoms, more preferably carbon. A alkynyl group of 2 to 10, specifically, ethynyl group, propargyl group, 1-pentyn-1-yl group, 2-pentyn-1-yl group, 3-pentyn-1-yl group, 1-octyne Examples include a 1-yl group and an 8-heptadecin-1-yl group.

  In the present specification, the aryl group in the “aryl group optionally having substituent (s)” may contain a heteroatom, and the number of carbons (the total number of heteroatoms and carbon atoms when a heteroatom is contained) Is, for example, 5 to 30, more preferably 5 to 20, specifically phenyl group, naphthyl group, anthranyl group, pyrenyl group, biphenyl group, 4-pyridyl group, 2-pyridyl group, pyrimidinyl group, pyrazinyl group, Examples include pyridanidyl group, piperazinyl group, pyrazolyl group, imidazolyl group, quinylyl group, pyrrolyl group, indolyl group, and furyl group.

  In the present specification, the aralkyl group in the “aralkyl group optionally having substituent (s)” may contain a heteroatom, and the number of carbons (in the case of containing a heteroatom, the total of the heteroatom and the carbon atom) The number) is, for example, 6 to 30, more preferably 7 to 15, and specific examples include benzyl, phenethyl, naphthylmethyl, and the like.

  In the present specification, an alkoxyl group in “optionally substituted alkoxyl group”, or an alkenyloxy group, “alkynyloxy” in “optionally substituted alkenyl, alkynyl, aryl or aralkyloxy group” Group, aryloxy group or aralkyloxy group may be linear, branched or cyclic, and has, for example, 30 or less, more preferably 10 or less, specifically methoxy, ethoxy or propyl. Examples thereof include an oxy group, a t-butoxy group, an allyloxy group, a cyclopentyloxy group, a cyclohexyloxy group, a benzyloxy group, and a phenoxy group.

  In the present specification, in the “optionally substituted alkyl, alkenyl, alkynyl, aryl or aralkylthio group”, the alkylthio group, alkenylthio group, alkynylthio group, arylthio group or aralkylthio group is a straight chain. The number of carbon atoms is, for example, 30 or less, more preferably 10 or less, specifically, methylthio group, ethylthio group, propylthio group, t-butylthio group, allylthio group, cyclopentylthio group. Cyclohexylthio group, benzylthio group, phenylthio group and the like.

  In the present specification, the acyl group in the “acyl group optionally having substituent (s)” or the “acyloxy group optionally having substituent (s)” is linear, branched, cyclic, saturated, unsaturated. Either saturated aliphatic or aromatic, for example, an acyl group having 2 to 30 carbon atoms, specifically acetyl group, propionyl group, isopropionyl group, pivaloyl group, oleoyl group, cyclohexylcarbonyl group, acroyl group, Examples include a crotonoyl group, a benzoyl group, a naphthoyl group, and a nicotinoyl group.

  In the present specification, “optionally substituted alkyl, alkenyl, alkynyl, aryl or aralkyloxycarbonyl group” or “optionally substituted alkyl, alkenyl, alkynyl, aryl or aralkyloxycarbonyl group” The alkyloxycarboxyl group, alkenyloxycarboxyl group, alkynyloxycarboxyl group, aryloxycarboxyl group or aralkyloxycarboxyl group in the “oxy group” may be linear, branched or cyclic, and has a carbon number. Is, for example, 30 or less, more preferably 10 or less, specifically methoxycarbonyl group, ethoxycarbonyl group, propyloxycarbonyl group, isopropyloxycarbonyl group, butoxycarbonyl group, s-butoxycarbonyl group, t-butoxycarbonyl group. , Black pentyloxycarbonyl group, a cyclohexyl group, benzyloxycarbonyl group, allyloxycarbonyl group, phenyloxycarbonyl group, groups such as pyridyloxy carbonyl group.

  In the present specification, “optionally substituted alkyl, alkenyl, alkynyl, aryl or aralkylthiocarbonyl group” or “optionally substituted alkyl, alkenyl, alkynyl, aryl or aralkylthiocarbonyl group” The alkylthiocarbonyl group, alkenylthiocarbonyl group, alkynylthiocarbonyl group, arylthiocarbonyl group or aralkylthiocarbonyl group in the “oxy group” may be linear, branched or cyclic, and the number of carbon atoms is, for example, 30 or less. Preferably it is 10 or less, specifically, methylthiocarbonyl group, ethylthiocarbonyl group, propylthiocarbonyl group, isopropylthiocarbonyl group, butylthiocarbonyl group, t-butylthiocarbonyl group, cyclopentyloxythiocarbonyl , Cyclohexyloxy thiocarbonyl group, a benzyl thio group, phenylthio group, groups such as pyridylthiocarbonyl group.

  In the present specification, the “optionally substituted aminocarbonyl group” in the “optionally substituted aminocarbonyl group” or the “optionally substituted aminocarbonyloxy group”. ”Has an unsubstituted carbamoyl group, an alkyl group which may have a substituent, an alkenyl group which may have a substituent, an alkynyl group which may have a substituent, or a substituent. A carbamoyl group substituted with an aromatic group which may be optionally substituted, a hydroxyl group, an alkoxyl group which may have a substituent, an amino group which may have a substituent, etc. More preferably, it is 10 or less, specifically, carbamoyl group, ethylaminocarbonyl group, propylaminocarbonyl group, isopropylaminocarbonyl group, butylaminocarbonyl group, t-butylaminocarbonyl. Group, cyclopentylamino group, cyclohexylamino group, benzylamino group, phenylaminocarbonyl group, pyridylaminocarbonyl group, groups such as benzyloxycarbonyl amino group and the like.

  In this specification, the alkylsulfonyl group, alkenylsulfonyl group, alkynylsulfonyl group, arylsulfonyl group or aralkylsulfonyl group in the “optionally substituted alkyl, alkenyl, alkynyl, aryl or aralkylsulfonyl group” is The chain may be any of chain, branched and cyclic, and the number of carbons is, for example, 30 or less, more preferably 10 or less. Specifically, methanesulfonyl group, ethanesulfonyl group, benzenesulfonyl group, cyclohexanesulfonyl group, naphthalenesulfonyl group And the like.

  In the present specification, the alkylsulfinyl group, alkenylsulfinyl group, alkynylsulfinyl group, arylsulfinyl group or aralkylsulfinyl group in the “optionally substituted alkyl, alkenyl, alkynyl, aryl or aralkylsulfinyl group” is The chain may be any of chain, branched and cyclic, and the number of carbon atoms is, for example, 30 or less, more preferably 10 or less. Specifically, methanesulfinyl group, ethanesulfinyl group, benzenesulfinyl group, cyclohexanesulfinyl group, naphthalenesulfinyl group And the like.

  In the present specification, the “optionally substituted amino group” is substituted with an unsubstituted amino group, or an alkyl group, alkenyl group, alkynyl group, aryl group, aralkyl group, acyl group, sulfonyl group, or the like. The number of carbon atoms is, for example, 30 or less, more preferably 10 or less, specifically, an ethylamino group, a propylamino group, an isopropylamino group, a butylamino group, a t-butylamino group, a benzylamino group. , Phenylamino group, pyridylamino group, piperazinyl group, indolinyl group, acetylamino group, benzoylamino group, benzenesulfonyl group, methanesulfonylamino group and the like.

  In the present specification, examples of the “halogen atom” include a fluorine atom, a chlorine atom, a bromine atom and an iodine atom.

  In the present specification, the “substituent” means, for example, an alkyl group, an alkenyl group, an alkynyl group, an aryl group, an acyl group, an acyloxy group, an alkyl, an alkenyl, an alkynyl, an aryl or an aralkyloxycarbonyl group, an alkyl, an alkenyl, an alkynyl, Aryl or aralkyloxycarbonyloxy group, alkyl, alkenyl, alkynyl, aryl or aralkylthiocarbonyl group, alkyl, alkenyl, alkynyl, aryl or aralkylthiocarbonyloxy group, aminocarbonyl group, aminocarbonyloxy group, alkoxyl group, alkenyl, alkynyl Aryl, aralkyloxy, alkyl, alkenyl, alkynyl, aryl or aralkylthio, alkyl, alkenyl, alkynyl, a Lumpur or aralkyl sulfonyl group, alkyl, alkenyl, can be mentioned alkynyl, aryl or aralkyl sulfinyl group, these specific examples are the same as described above. Other substituents include halogen group, nitro group, amino group (acyl group, alkyl, alkenyl, alkynyl, aryl or aralkylthiocarbonyloxy group, carbamoyl group, substituted sulfonyl group, alkyl group, cycloalkyl group, aryl group, etc. And a group such as a cyano group, a hydroxyl group, a carboxyl group, an oxysulfonyl group, and an epoxy group, and an aralkyl group such as a benzyl group, a phenethyl group, and a naphthylmethyl group.

  Preferred examples of X include a hydrogen atom, an optionally substituted alkyl group, an optionally substituted alkenyl group, an optionally substituted alkynyl group, and a substituent. An optionally substituted aryl group, an optionally substituted aralkyl group, a hydroxyl group, an optionally substituted alkoxyl group, an optionally substituted alkenyl, alkynyl, aryl or Aralkyloxy group, thiol group, and optionally substituted alkyl, alkenyl, alkynyl, aryl or aralkylthio group can be mentioned, and particularly preferred groups are hydrogen atom, unsubstituted alkyl group, hydroxyl group , An unsubstituted alkylthio group, and an unsubstituted arylthio group. As the unsubstituted alkyl group, an alkyl group having 1 to 10 carbon atoms is particularly preferable. As the unsubstituted alkylthio group, those having 1 to 10 carbon atoms are particularly preferable. As the unsubstituted arylthio group, those having 5 to 10 carbon atoms are particularly preferable. Particularly preferred groups for X are a hydrogen atom, a methyl group, a hydroxyl group, a phenylthio group, or a propylthio group.

R ¹ is preferably an alkyl group which may have a substituent, an alkenyl group which may have a substituent, an alkynyl group which may have a substituent, or a substituent. An aryl group which may be substituted and an aralkyl group which may have a substituent are mentioned, and particularly preferred groups include an unsubstituted alkyl group and an unsubstituted aralkyl group. As the unsubstituted alkyl group, an alkyl group having 1 to 10 carbon atoms is particularly preferable. The unsubstituted aralkyl group is preferably one having 6 to 10 carbon atoms. Particularly preferred as R ¹ is a methyl group, i-propyl group, or benzyl group.

R ² is preferably a hydrogen atom, an alkyl group which may have a substituent, an alkenyl group which may have a substituent, an alkynyl group which may have a substituent, or a substituent. The aryl group which may have and the aralkyl group which may have a substituent are mentioned, As the particularly preferable group, an alkyl group which may have a substituent and an unsubstituted aralkyl group are mentioned. Can be mentioned. The alkyl group which may have a substituent is preferably an alkyl group having 1 to 10 carbon atoms. The unsubstituted aralkyl group is preferably one having 6 to 10 carbon atoms. Particularly preferred as R ² is a pentyl group, a cyclopentyl group, or a benzyl group.

R ³ is preferably a hydrogen atom, an alkyl group which may have a substituent, an alkenyl group which may have a substituent, an alkynyl group which may have a substituent, or a substituent. The aryl group which may have and the aralkyl group which may have a substituent are mentioned, A particularly preferable group is a hydrogen atom.

When R ² and R ³ together with the nitrogen atom to which they are attached form a saturated or unsaturated ring structure that may contain further heteroatoms and may have a substituent, The ring may be an aromatic ring or an aliphatic ring, and the number of ring members is, for example, 5 to 7.

Preferred as R ⁴ are a hydrogen atom, a halogen atom, an alkyl group which may have a substituent, an alkenyl group which may have a substituent, an alkynyl group which may have a substituent, An aryl group which may have a substituent, an aralkyl group which may have a substituent, an alkoxyl group which may have a substituent, and an alkenyl, alkynyl which may have a substituent, An aryl or aralkyloxy group is mentioned, As a particularly preferable group, a hydrogen atom and a halogen atom are mentioned. n is preferably 1, and the substitution position is preferably the 5-position of the indole ring. As the halogen atom, Br or Cl is preferable. Particularly preferred as R ⁴ is a hydrogen atom or Br or Cl bonded to the 5-position of the indole ring.

R ⁵ preferably has an alkyl group which may have a substituent, an alkenyl group which may have a substituent, an alkynyl group which may have a substituent, or a substituent. An aryl group which may be substituted and an aralkyl group which may have a substituent are mentioned, and an unsubstituted alkyl group is particularly preferred. The unsubstituted alkyl group preferably has 1 to 10 carbon atoms. A particularly preferred group as R ⁵ is a methyl group.

  The compound of the present invention or a salt thereof may be in the form of a hydrate with water or a solvate with a lower alcohol or the like. The hydrate or solvate form thereof is also included in the scope of the compound according to the present invention or a salt thereof.

  As a pharmaceutically acceptable salt of the compound of the present invention, for a compound having an acid site, a salt with an inorganic base or an organic base, for example, an alkali metal salt such as sodium salt or potassium salt, an alkali such as calcium salt or magnesium salt, etc. Earth metal salt, ammonium salt, triethylamine salt, ethanolamine salt, lysine salt, arginine salt, quinoline salt, aliphatic or heterocyclic aromatic amine salt such as pyridine salt, quaternary ammonium salt such as tetramethylammonium salt, etc. Alternatively, for compounds having a base moiety, salts with inorganic or organic acids such as hydrochloride, bromate, iodate, sulfate, nitrate, phosphate, citrate, tartrate, malic acid, lactic acid Salt, salicylate, malonate, fumarate, succinate, oxalic acid, ascorbate and the like can be mentioned.

  The compounds of the present invention can be prepared based on the methods described in the Examples.

(式中、R¹〜R⁵及びnは一般式(1)について定義したとおりである)
で表される3-アミノ-2-インドリルマレイミド誘導体を水素化試薬と反応させて、前記誘導体中の4位のカルボニル基を選択的に-OH基に還元する工程を含む方法により製造することができる。水素化試薬としては、LiAlH₄等が使用できる。本工程はTHF中で行うことが好ましい。出発物質となる3-アミノ-2-インドリルマレイミド誘導体は、公知の化合物であり、例えば Bioorg. Med. Chem. Lett. 2005, 15, 3114-3117記載の方法により調製することが可能である。 The compound in which X is a hydroxyl group in the general formula (1)
formula:

(Wherein R ^{1 to} R ⁵ and n are as defined for general formula (1))
A 3-amino-2-indolylmaleimide derivative represented by the formula (1) is reacted with a hydrogenating reagent to selectively reduce a carbonyl group at the 4-position in the derivative to an —OH group. Can do. As the hydrogenation reagent, LiAlH ₄ or the like can be used. This step is preferably performed in THF. The starting 3-amino-2-indolylmaleimide derivative is a known compound and can be prepared, for example, by the method described in Bioorg. Med. Chem. Lett. 2005, 15, 3114-3117.

In general formula (1), X is an optionally substituted alkyl, alkenyl, alkynyl, aryl, or aralkylthio group. butyrolactam derivatives with R ⁶ -SH (wherein R ⁶ is an alkyl group optionally having a substituent, alkenyl group, alkynyl group, aryl group, or aralkyl group shows a) a thiol compound represented by It can be produced by a method including a step of reacting in the presence of 10-camphorsulfonic acid to replace the —OH group at the 4-position in the derivative with a —SR ⁶ group. This step is preferably performed in dichloromethane.

In the general formula (1), the compound in which X is an alkoxyl group which may have a substituent, or an alkenyl, alkynyl, aryl or aralkyloxy group which may have a substituent was obtained by the above method. 3-amino-4-hydroxy-2-indolylbutyrolactam derivative and R ⁷ —OH (wherein R ⁷ is an optionally substituted alkyl group, alkenyl group, alkynyl group, aryl group, or aralkyl group) In the presence of 10-camphorsulfonic acid and replacing the —OH group at the 4-position in the derivative with an —OR ⁷ group. be able to. In this step, an organic solvent can be appropriately selected and used. When R ⁷ —OH is liquid, it is preferable to carry out this step using R ⁷ —OH as a solvent.

In the general formula (1), a compound in which X is a hydrogen atom is obtained by the above method, and in the general formula (1), X is a —SR ⁶ group (wherein R ⁶ is an alkyl which may have a substituent). And a compound comprising a group, an alkenyl group, an alkynyl group, an aryl group, or an aralkyl group) is reacted with hydrogen to reduce a —SR ⁶ group in the compound to —H. . This step is preferably performed in the presence of a Raney nickel catalyst. This step is preferably performed in ethanol.

In the general formula (1), X has an alkyl group which may have a substituent, an alkenyl group which may have a substituent, an alkynyl group which may have a substituent, and a substituent. The compound which is an aryl group which may be substituted, or an aralkyl group which may have a substituent, is obtained by the above method, wherein X is an —OR ⁷ group (wherein R ⁷ is a substituent) A compound which is an alkyl group, an alkenyl group, an alkynyl group, an aryl group or an aralkyl group, which may have (R ⁸ ) ₃ Al (wherein R ⁸ may have a substituent) An alkyl group, an alkenyl group which may have a substituent, an alkynyl group which may have a substituent, an aryl group which may have a substituent, or an aralkyl which may have a substituent -OR in the derivative is reacted with an organoaluminum compound represented by It can be produced by a method in which ⁷ groups are substituted with -R ⁸ groups. An example of the organoaluminum compound used in this step is trimethylaluminum. This step is preferably performed in dichloromethane.

In general formula (I), X may have a substituent alkyl, alkenyl, alkynyl, aryl or aralkylsulfonyl group, or may have a substituent alkyl, alkenyl, alkynyl, aryl or aralkylsulfinyl group. Is obtained by oxidizing the compound obtained by the above method, wherein X is a —SR ⁶ group in the general formula (1). As a method of oxidizing the —SR ⁶ group to convert it to the corresponding —S (═O) ₂ R ⁶ group (sulfonyl group), methods known to those skilled in the art can be employed. Similarly, methods known to those skilled in the art can be employed for the method of converting the —SR ⁶ group to the corresponding —S (═O) R ⁶ group (sulfinyl group).

  The compound in which X is a cyano group in the general formula (I) is obtained by the above method. In the compound in which X is a hydroxyl group in the general formula (1), the hydroxyl group is converted to a cyano group by a method known to those skilled in the art. Can be obtained by substituting

  The compound in which X is an amino group which may have a substituent in the general formula (I) is obtained by the above method, and the compound in which X is a hydroxyl group in the general formula (1) It can be obtained by substitution with a desired amino group by a method known to those skilled in the art.

  The compound in which X is a halogen atom in the general formula (I) is obtained by the above method. In the compound in which X is a hydroxyl group in the general formula (1), the hydroxyl group is obtained by a method known to those skilled in the art. It can be obtained by substitution with a halogen atom.

  The compound of the present invention has high cell death inhibitory activity. Cell death that can be suppressed by the compounds of the present invention typically includes cell death induced by oxidative stress. As described in the background section, known diseases that involve cell death due to oxidative stress include ischemic reperfusion disorders such as cerebral ischemia and ischemic heart disease, and neurodegenerative diseases such as Alzheimer's disease. ing. Compounds that suppress cell death induced by oxidative stress (such as hydrogen peroxide and nitric oxide) in vitro can also prevent ischemia / reperfusion injury in the brain and heart in vivo, It has been reported that it exhibits therapeutic effects in neurodegenerative disease models such as Alzheimer's disease and amyotrophic lateral sclerosis. Therefore, it can be said that the present compound that suppresses cell death induced by oxidative stress is effective as a preventive or therapeutic agent for these diseases. The compounds of the present invention are also effective as preservatives for organs, tissues and cells.

  The present invention requires an effective amount of a compound of the present invention for the prevention or treatment of various diseases or conditions in which cell death (especially cell death induced by oxidative stress) is involved in its progression. The present invention relates to a method for preventing or treating the disease or symptom by administration to a mammal such as a human. According to the present invention, Alzheimer's disease, spinal muscular artophy (SMA), amyotrophic lateral sclerosis (ALS), Parkinson's disease, Huntington's disease, retinitis pigmentosa, glaucoma, cerebellar degeneration, etc. Neurodegenerative diseases can be prevented or treated by suppressing neuronal cell death. According to the present invention, cerebral ischemia or subsequent delayed neuronal cell death (DND) can be prevented or treated by suppressing neuronal cell death. According to the present invention, ischemic heart disease can be prevented or treated by suppressing the death of cardiomyocytes. According to the present invention, ischemia reperfusion injury in various organs such as the liver and kidney can be prevented or treated by suppressing cell death due to oxidative stress. According to the present invention, it is possible to prevent dysfunction during preservation of organs, tissues or cells.

  Various forms can be selected as dosage forms when the compound according to the present invention is used as a medicine, for example, oral preparations such as tablets, capsules, powders, granules or liquids, injections, rectal administration agents, and external preparations for skin. And parenteral administration agents such as inhalants.

  The solid preparation can be produced as it is in the form of tablets, capsules, granules or powders, but can also be produced using appropriate additives. Examples of such additives include sugars such as lactose or glucose, starches, fatty acids such as stearic acid, inorganic salts such as magnesium aluminate metasilicate or anhydrous calcium phosphate such as polyvinylpyrrolidone or polyalkylene glycol, etc. Polymers such as fatty acid salts such as calcium stearate or magnesium stearate, alcohols such as stearyl alcohol or benzyl alcohol, synthetic cellulose derivatives such as methylcellulose, ethylcellulose, carboxymethylcellulose or hydroxypropylmethylcellulose, others, water, gelatin, talc , Vegetable oil, gum arabic, and other commonly used additives.

  Liquid preparations use appropriate additives usually used in liquid preparations such as water, alcohols or plant-derived oils such as soybean oil, peanut oil or sesame oil, and are in the form of suspensions, syrups, injections, etc. Manufactured as.

  In particular, suitable solvents for administration as injections include, for example, distilled water for injection, aqueous lidocaine hydrochloride, physiological saline, aqueous glucose solution, ethanol, and liquid for intravenous injection (eg, aqueous solutions such as citric acid and sodium citrate). ), An electrolyte solution, or a mixed solution thereof. These injections may be pre-dissolved, or may be in the form of a powder or a suitable additive added upon use.

  To produce a rectal dosage form, the active ingredient and cacao butter, fatty acid tri-, di- and monoglycerides, suppository bases such as polyethylene glycol are heated and melted and poured into a mold and cooled, or the active ingredient May be dissolved in polyethylene glycol, soybean oil or the like and then coated with a gelatin film.

  In order to produce an external preparation for skin, the active ingredient is added to petrolatum, beeswax, liquid paraffin, polyethylene glycol, etc., if necessary, heated and kneaded to make an ointment, or rosin, alkyl acrylate polymer After kneading with an adhesive such as polyethylene, it is spread on a nonwoven fabric such as polyethylene to obtain a tape.

  In order to produce an inhalant, the active ingredient is dissolved or dispersed in a propellant such as Freon gas and filled in a pressure resistant container to form an aerosol agent.

  Actually preferred dosages of the compounds of the invention will vary depending on the type of composition formulated, frequency of application and disease to be treated, as well as the age, weight and condition of the patient, but usually about 1-1000 mg per day, preferably It is 5 to 500 mg, and it is desirable to administer it once or several times.

  As used herein, “organ” includes any organ, such as heart, lung, liver, kidney, pancreas, intestine and the like.

  The “tissue” in the present specification includes all tissues, and examples thereof include skin, cornea, bone marrow, blood vessel, bone and the like.

  In this specification, all cells (normal cells, immortalized cell lines, cancerous cells, therapeutic or research purposes) are expected to have an effect on the maintenance or preservation of cell functions by transplantation. And the like, and examples thereof include blood cells, pancreatic Langerhans islet cells, epithelial cells, nervous system cells, fetal stem cells, and the like.

  In addition, various administration forms can be selected when the compound according to the present invention is used as a preservative for organs, tissues, or cells. For example, the compound can be used in a culture solution or a preservation solution containing appropriate salts and nutrients. Alternatively, a pharmaceutically acceptable salt thereof can be added, and in the case of organ transplantation, it can be administered to a donor before organ excision by internal perfusion, intravenous administration, or the like.

  The compound of the present invention or a salt thereof can also be used as a reagent for biological test studies relating to cell death (particularly cell death induced by oxidative stress). In this application, the compound of the present invention or a salt thereof may be provided as a kit together with other reagents, buffers, and other elements necessary for test studies.

  EXAMPLES Hereinafter, although an Example demonstrates this invention in detail, it cannot be overemphasized that this invention is not limited to these.

  In this example, a compound group represented by the formula (1) was synthesized.

¹ H NMR and ¹³ C NMR spectra were measured using JEOL AL-400, AL-300 and AL-270 manufactured by JASCO Corporation. Chemical shift values are expressed in ppm. Mass spectra (FAB-MS (Pos.)) Were measured using JEOL MStation JMS-700.

  In this example, a compound having an asymmetric carbon means a racemic mixture unless otherwise specified.

Production reaction 1
Synthesis of 5-hydroxy-1-methyl-3- (1-methyl-1H-indol-3-yl) -4- (pentylamino) -1H-pyrrol-2 (5H) -one (IHL-5)

IM-54 (51.0 mg, 0.191 mmol) synthesized according to a known method (Bioorg. Med. Chem. Lett. 2005, 15, 3114-3117) was dissolved in THF (2 mL), and lithium aluminum hydride was added under ice cooling. (72 mg, 1.91 mmol) was added. After stirring for 5 minutes, saturated aqueous sodium potassium tartrate solution was added, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated, and the obtained solid was washed with ethyl acetate to obtain IHL-5 (55.4 mg, 88%) as a white solid.
Molecular weight: 327.42
Molecular formula: C ₁₉ H ₂₅ N ₃ O ₂
¹ H-NMR (300 MHz, CD ₃ OD): δ0.75 (t, J = 7.3 Hz, 3H), 0.89-1.20 (m, 4H), 1.21-1.50 (m, 2H), 2.93 (s, 3H ), 3.10 (t, J = 7.0 Hz, 2H), 3.80 (s, 3H), 4.50-4.74 (br, 1H), 5.24 (s, 1H), 5.87-5.95 (br, 1H), 7.03 (dd, J = 7.3 and 7.6 Hz, 1H), 7.07 (s, 1H), 7.16 (dd, J = 7.3 and 7.8 Hz, 1H), 7.35 (d, J = 7.8 Hz, 1H), 7.45 (d, J = 7.6 Hz, 1H).
¹³ C-NMR (75.5 MHz, CD ₃ OD): δ 14.29, 23.22, 26.54, 29.85, 31.35, 32.86, 44.84, 82.98, 92.45, 106.5, 110.2, 120.0, 121.1, 122.5, 130.0, 130.2, 138.2, 160.1, 175.6.
FAB-MS (m-nitrobenzyl alcohol) m / z 327 (M ⁺ ).

IHL derivatives
It was synthesized from the corresponding indolylmaleimide derivative in the same manner as IHL-5.

4- (Benzylamino) -5-hydroxy-1-methyl-3- (1-methyl-1H-indol-3-yl) -1H-pyrrol-2 (5H) -one (IHL-1)
Yield: 99%
Molecular weight: 347.41
Molecular formula: C ₂₁ H ₂₁ N ₃ O ₂
¹ H-NMR (400 MHz, CDCl ₃ ): δ 2.88 (s, 3H), 3.69 (s, 3H), 4.20-4.70 (br, 1H), 4.34 (d, J = 14.5 Hz, 1H), 4.43 ( d, J = 14.5 Hz, 1H), 4.91 (br s, 1H), 5.18 (s, 1H), 7.05 (dd, J = 7.6 and 7.6 Hz, 1H), 7.10 (s, 1H), 7.12-7.18 ( m, 2H), 7.21 (dd, J = 7.6 and 7.6 Hz, 1H), 7.24-7.35 (m, 4H), 7.49 (d, J = 7.6 Hz, 1H).
¹³ C-NMR (100 MHz, CDCl ₃ ): δ 26.53, 32.81, 48.03, 81.76, 95.19, 104.5, 109.3, 119.1, 120.1, 121.3, 127.2, 127.2 (2C), 127.3 (2C), 128.4, 128.7, 136.4 , 138.6, 155.7, 172.3.
FAB-MS (m-nitrobenzyl alcohol) m / z 347 (M ⁺ ).

4- (3- (Dimethylamino) propylamino) -5-hydroxy-1-isopropyl-3- (1-methyl-1H-indol-3-yl) -1H-pyrrol-2 (5H) -one (IHL- 2)
Yield: 88%
Molecular weight: 370.49
Molecular formula: C ₂₁ H ₃₀ N ₄ O ₂
¹ H-NMR (400 MHz, CDCl ₃ ): δ 1.33 (d, J = 6.8 Hz, 3H), 1.37 (d, J = 6.8 Hz, 3H), 1.46-1.66 (m, 2H), 2.05-2.27 ( m, 7H, involving singlet at 2.14), 3.20-3.53 (m, 2H), 3.80 (s, 3H), 4.32 (qq, J = 6.8 and 6.8 Hz, 1H), 4.72 (t, J = 6.0 Hz, 1H ), 5.51 (s, 1H), 7.09 (dd, J = 7.6 and 7.8 Hz, 1H), 7.20 (dd, J = 7.6 and 8.0 Hz, 1H), 7.25 (s, 1H), 7.30 (d, J = 8.0 Hz, 1H), 7.52 (d, J = 7.8 Hz, 1H).
FAB-MS (m-nitrobenzyl alcohol) m / z 370 (M ⁺ ).

4- (Cyclopentylamino) -5-hydroxy-1-methyl-3- (1-methyl-1H-indol-3-yl) -1H-pyrrol-2 (5H) -one (IHL-3)
Yield: 92%
Molecular weight: 325.40
Molecular formula: C ₁₉ H ₂₃ N ₃ O ₂
¹ H-NMR (400 MHz, CD ₃ OD): δ 1.31-1.95 (m, 8H), 2.97 (s, 3H), 3.84 (s, 3H), 3.98 (quintet, J = 6.0 Hz, 1H), 5.30 (s, 1H), 7.06 (dd, J = 7.6 and 8.0 Hz, 1H), 7.11 (s, 1H), 7.19 (dd, J = 7.6 and 8.0 Hz, 1H), 7.30 (d, J = 8.0 Hz, 1H), 7.52 (d, J = 8.0 Hz, 1H).
FAB-MS (m-nitrobenzyl alcohol) m / z 325 (M ⁺ ).

4- (Benzylamino) -3- (5-bromo-1-methyl-1H-indol-3-yl) -5-hydroxy-1-methyl-1H-pyrrol-2 (5H) -one (IHL-4)
Yield: 90%
Molecular weight: 426.31
Molecular formula: C ₂₁ H ₂₀ BrN ₃ O ₂
¹ H-NMR (300 MHz, CD ₃ OD): δ 2.96 (s, 3H), 3.75 (s, 3H), 4.30 (dd, J = 6.2 and 15.4 Hz, 1H), 4.42 (dd, J = 6.2 and 15.4 Hz, 1H), 5.31 (s, 1H), 6.63 (t, J = 6.2 Hz, 1H), 6.89 (s, 1H), 7.06 (d, J = 7.0 Hz, 2H), 7.13-7.36 (m, 5H), 7.57 (d, J = 1.5 Hz, 1H).
¹³ C-NMR (75.5 MHz, CD ₃ OD): δ 26.47, 32.99, 48.14, 83.10, 92.87, 105.92, 111.98, 113.40, 123.64, 125.10, 127.76 (2C), 127.88, 129.35 (2C), 131.79, 131.94, 136.73, 140.62, 160.08, 175.23.
FAB-MS (m-nitrobenzyl alcohol) m / z 425 (M ⁺ ).

4- (3- (Dimethylamino) propylamino) -5-hydroxy-1-methyl-3- (1-methyl-1H-indol-3-yl) -1H-pyrrol-2 (5H) -one (IHL- 6)
Yield: 89%
Molecular weight: 342.44
Molecular formula: C ₁₉ H ₂₆ N ₄ O ₂
¹ H-NMR (400 MHz, CDCl ₃ ): δ 1.40-1.68 (m, 2H), 2.11 (s, 6H), 2.18 (ddd, J = 5.6, 5.8 and 12.3 Hz, 1H), 2.40 (ddd, J = 6.0, 8.4 and 12.3 Hz, 1H), 2.97 (s, 3H), 3.17-3.33 (m, 1H), 3.34-3.51 (m, 1H), 3.78 (s, 3H), 4.80 (t, J = 6.0 Hz, 1H), 5.25 (s, 1H), 7.07 (dd, J = 7.7 and 7.9 Hz, 1H), 7.19 (dd, J = 7.9 and 8.2 Hz, 1H), 7.20 (s, 1H), 7.30 (d , J = 8.2 Hz, 1H), 7.48 (d, J = 7.7 Hz, 1H).
¹³ C-NMR (100 MHz, CDCl ₃ ): δ 26.47, 27.30, 32.91, 42.27 44.64 (2C), 56.09, 81.34, 95.63, 104.96, 109.29, 118.99, 120.04, 121.25, 127.11, 128.43, 136.54, 156.26, 171.49 .
FAB-MS (m-nitrobenzyl alcohol) m / z 342 (M ⁺ ).

4- (Benzylamino) -3- (5-chloro-1-methyl-1H-indol-3-yl) 5-hydroxy-1-methyl-1H-pyrrol-2 (5H) -one (IHL-7)
Yield: 88%
Molecular weight: 381.86
Molecular formula: C ₂₁ H ₂₀ ClN ₃ O ₂
¹ H-NMR (400 MHz, CDCl ₃ ): δ 2.91 (s, 3H), 3.67 (s, 3H), 4.37 (d, J = 6.0 Hz, 2H), 4.83 (t, J = 6.0 Hz, 1H) , 5.20 (s, 1H), 7.03-7.45 (m, 8H), 7.57 (d, J = 1.7 Hz, 1H).
¹³ C-NMR (100 MHz, CDCl ₃ ): δ 26.66, 33.06, 48.16, 81.94, 94.71, 104.26, 110.41, 119.43, 121.70, 124.94, 127.24 (4C), 127.44, 128.61, 130.02, 134.27, 155.75, 171.99.
FAB-MS (m-nitrobenzyl alcohol) m / z 381 (M ⁺ ).

1-Benzyl-5-hydroxy-3- (1-methyl-1H-indol-3-yl) -4- (pentylamino) -1H-pyrrol-2 (5H) -one (IHL-8)
Yield: 100%
Molecular weight: 403.52
Molecular formula: C ₂₅ H ₂₉ N ₃ O ₂
¹ H-NMR (300 MHz, CDCl ₃ ): δ 0.80 (t, J = 7.0 Hz, 3H), 1.05-1.48 (m, 6H), 3.13 (dddd, J = 6.0, 6.3, 6.3 and 12.3 Hz, 1H ), 3.23 (dddd, J = 6.0, 6.3, 6.3 and 12.3 Hz, 1H), 3.75 (s, 3H), 4.07 (d, J = 15.0 Hz, 1H), 4.53 (t, J = 6.0 Hz, 1H) , 4.97 (d, J = 15.0 Hz, 1H), 5.17 (s, 1H), 7.04 (dd, J = 7.5 and 7.8 Hz, 1H), 7.12-7.29 (m, 7H), 7.32 (d, J = 7.8 Hz, 1H), 7.47 (d, J = 7.5 Hz, 1H).
¹³ C-NMR (75.5 MHz, CDCl ₃ ): δ 13.83, 22.21, 28.74, 30.40, 32.77, 42.60, 44.22, 79.04, 93.97, 104.77, 109.46, 119.10, 120.23, 121.37, 126.71, 127.00, 128.15 (2C), 128.43 (2C), 128.72, 136.64, 138.09, 156.56, 172.19.
FAB-MS (m-nitrobenzyl alcohol) m / z 403 (M ⁺ ).

5-Hydroxy-1-isopropyl-3- (1-methyl-1H-indol-3-yl) -4- (pentylamino) -1H-pyrrol-2 (5H) -one (IHL-9)
Yield: 68%
Molecular weight: 355.47
Molecular formula: C ₂₁ H ₂₉ N ₃ O ₂
¹ H-NMR (300 MHz, CDCl ₃ ): δ 0.84 (t, J = 6.9 Hz, 3H), 1.08-1.25 (m, 4H), 1.26 (d, J = 6.9 Hz, 3H), 1.31 (d, J = 6.9 Hz, 3H), 1.35-1.48 (m, 2H), 3.15 (dddd, J = 6.0, 6.8, 6.8 and 12.9 Hz, 1H), 3.26 (dddd, J = 6.0, 6.8, 6.8 and 12.9 Hz, 1H), 3.76 (s, 3H), 4.30 (qq, J = 6.9 and 6.9 Hz, 1H), 4.53 (t, J = 6.0 Hz, 1H), 5.43 (s, 1H), 7.07 (dd, J = 7.8 and 8.1 Hz, 1H), 7.19 (s, 1H), 7.20 (dd, J = 7.8 and 8.1 Hz, 1H), 7.31 (d, J = 8.1 Hz, 1H), 7.47 (d, J = 8.1 Hz, 1H ).
¹³ C-NMR (75.5 MHz, CDCl ₃ ): δ 13.89, 20.04, 22.23 (2C), 28.75, 30.44, 32.73, 43.13, 44.14, 78.84, 94.42, 104.81, 109.36, 118.98, 120.12, 121.31, 127.14, 128.70, 136.60, 156.07, 171.99.
FAB-MS (m-nitrobenzyl alcohol) m / z 355 (M ⁺ ).

Production reaction 2
Synthesis of 1-methyl-3- (1-methyl-1H-indol-3-yl) -4- (pentylamino) -5- (propylthio) -1H-pyrrole-2,5-dione (ISL-5)

IHL-5 (62.0 mg, 0.156 mmol) was dissolved in dichloromethane (0.75 mL), and 1-propanethiol (21 μL, 0.235 mmol) and 10-camphorsulfonic acid (4 mg, 0.016 mmol) were added at room temperature. After stirring for 1 hour, saturated aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated, and the resulting crude product was purified by silica gel column chromatography (hexane / ethyl acetate = 2/1) to give ISL-5 (55.6 mg, 92%) lightly. Obtained as a yellow oil.
Molecular weight: 385.57
Molecular formula: C ₂₂ H ₃₁ N ₃ OS
¹ H-NMR (300 MHz, CDCl ₃ ): δ 0.83 (t, J = 7.0 Hz, 3H), 0.97 (t, J = 7.3 Hz, 3H), 1.10-1.28 (m, 4H), 1.43 (tt, J = 7.0 and 7.0 Hz, 2H), 1.60 (tq, J = 7.3 and 7.3 Hz, 2H), 2.31 (td, J = 7.3 and 12.1 Hz, 1H), 2.40 (td, J = 7.3 and 12.1 Hz, 1H ), 3.02 (s, 3H), 3.12 (dtd, J = 6.3, 7.0 and 13.0 Hz, 1H), 3.34 (dtd, J = 6.3, 7.0 and 13.0 Hz, 1H), 3.80 (s, 3H), 4.50 ( t, J = 6.3 Hz, 1H), 4.89 (s, 1H), 7.10 (ddd, J = 1.1, 7.0 and 7.5 Hz, 1H), 7.21 (ddd, J = 1.1, 7.0 and 7.5 Hz, 1H), 7.22 (s, 1H), 7.32 (dd, J = 1.1 and 7.5 Hz, 1H), 7.46 (dd, J = 1.1 and 7.5 Hz, 1H).
¹³ C-NMR (75.5 MHz, CDCl ₃ ): δ 13.71, 13.84, 22.19, 22.64, 26.60, 27.79, 28.71, 30.20, 32.82, 44.17, 64.06, 97.32, 105.07, 109.37, 119.12, 120.01, 121.26, 127.57, 128.71 , 136.63, 154.49, 171.72.
FAB-MS (m-nitrobenzyl alcohol) m / z 385 (M ⁺ ).

ISL derivatives
It was synthesized from the corresponding IHL derivative in the same manner as ISL-5.

4- (Benzylamino) -3- (1-methyl-1H-indol-3-yl) -5- (phenylthio) -1H-pyrrole-2,5-dione (ISL-1)
Yield: 86%
Molecular weight: 439.57
Molecular formula: C ₂₇ H ₂₅ N ₃ OS
¹ H-NMR (400 MHz, CDCl ₃ ): δ 3.16 (s, 3H), 3.70 (s, 3H), 4.48 (br s, 2H), 4.76 (br s, 1H), 5.07 (s, 1H), 6.90 (s, 1H), 6.91-7.05 (m, 2H), 7.06-7.35 (m, 10H), 7.40-7.50 (m, 2H).
¹³ C-NMR (100 MHz, CDCl ₃ ): δ 27.04, 32.84, 48.20, 67.20, 99.31, 104.40, 109.09, 118.82, 120.17, 121.22, 127.21 (2C), 127.34, 127.42, 128.00, 128.46, 128.58 (2C) , 128.80 (2C), 129.22, 135.26 (2C), 136.34, 138.43, 152.93, 171.26.
FAB-MS (m-nitrobenzyl alcohol) m / z 439 (M ⁺ ).

4- (Benzylamino) -1-methyl-3- (1-methyl-1H-indol-3-yl) -5- (propylthio) -1H-pyrrole-2,5-dione (ISL-2)
Yield: 95%
Molecular weight: 405.56
Molecular formula: C ₂₄ H ₂₇ N ₃ OS
¹ H-NMR (300 MHz, CDCl ₃ ): δ 0.96 (t, J = 7.3 Hz, 3H), 1.59 (tq, J = 7.0 and 7.3 Hz, 2H), 2.30 (td, J = 7.0 and 12.1 Hz, 1H), 2.37 (td, J = 7.0 and 12.1 Hz, 1H), 3.00 (s, 3H), 3.76 (s, 3H), 4.37 (d, J = 15.4 Hz, 1H), 4.46 (d, J = 15.4 Hz, 1H), 4.86 (s, 1H), 7.00-7.35 (m, 9H), 7.49 (d, J = 7.5 Hz, 1H).
¹³ C-NMR (75.5 MHz, CDCl ₃ ): δ 13.75, 22.64, 26.65, 27.80, 32.85, 48.06, 64.24, 98.77, 104.79, 109.41, 119.30, 120.05, 121.46, 127.31 (2C), 127.46, 127.79, 128.59 ( 2C), 128.93, 136.62, 138.65, 153.81, 171.61
FAB-MS (m-nitrobenzyl alcohol) m / z 405 (M ⁺ ).

4- (Benzylamino) -3- (5-bromo-1-methyl-1H-indol-3-yl) -5- (propylthio) -1H-pyrrole-2,5-dione (ISL-3)
Yield: 85%
Molecular weight: 484.45
Molecular formula: C ₂₄ H ₂₆ BrN ₃ OS
¹ H-NMR (300 MHz, CDCl ₃ ): δ 1.00 (t, J = 7.3 Hz, 3H), 1.61 (tq, J = 7.0 and 7.3 Hz, 2H), 2.30 (td, J = 7.0 and 12.5 Hz, 1H), 2.37 (td, J = 7.0 and 12.5 Hz, 1H), 3.02 (s, 3H), 3.76 (s, 3H), 4.33 (d, J = 14.7 Hz, 1H), 4.45 (d, J = 14.7 Hz, 1H), 4.88 (br s, 1H), 7.10-7.20 (m, 4H), 7.21-7.36 (m, 4H), 7.64 (d, J = 1.8 Hz, 1H).
¹³ C-NMR (75.5 MHz, CDCl ₃ ): δ 13.80, 22.72, 26.73, 27.87, 33.06, 48.16, 64.51, 97.84, 104.62, 110.95, 112.79, 122.58, 124.40, 127.38 (2C), 127.59, 128.72 (2C) , 129.69, 130.18, 135.29, 138.40, 154.24, 171.50.
FAB-MS (m-nitrobenzyl alcohol) m / z 484 (M ⁺ ).

4- (Cyclopentylamino) -3- (1-methyl-1H-indol-3-yl) -5- (propylthio) -1H-pyrrole-2,5-dione (ISL-4)
Yield: 99%
Molecular weight: 383.55
Molecular formula: C ₂₂ H ₂₉ N ₃ OS
¹ H-NMR (300 MHz, CDCl ₃ ): δ 0.97 (t, J = 7.3 Hz, 3H), 1.19-2.01 (m, 10H), 2.31 (td, J = 7.0 and 12.3 Hz, 1H), 2.38 ( td, J = 7.0 and 12.3 Hz, 1H), 3.03 (s, 3H), 3.81 (s, 3H), 4.10-4.15 (br, 1H), 4.48 (d, J = 7.0 Hz, 1H), 7.11 (dd , J = 7.5 and 7.8 Hz, 1H), 7.22 (dd, J = 7.5 and 8.1 Hz, 1H), 7.23 (s, 1H), 7.33 (d, J = 8.1 Hz, 1H), 7.46 (d, J = (7.8 Hz, 1H).
¹³ C-NMR (75.5 MHz, CDCl ₃ ): δ 13.75, 22.62, 23.54, 23.78, 26.63, 27.77, 32.84, 34.18, 34.35, 55.18, 64.15, 97.41, 105.09, 109.40, 119.08, 120.05, 121.32, 127.48, 128.73 , 136.65, 153.75, 171.70.
FAB-MS (m-nitrobenzyl alcohol) m / z 383 (M ⁺ ).

4- (3- (Dimethylamino) propylamino) -3- (1-methyl-1H-indol-3-yl) -5- (propylthio) -1H-pyrrole-2,5-dione (ISL-6)
Yield: 84%
Molecular weight: 400.58
Molecular formula: C ₂₂ H ₃₂ N ₄ OS
¹ H-NMR (300 MHz, CDCl ₃ ): δ 0.97 (t, J = 7.3 Hz, 3H), 1.56 (tt, J = 6.6 and 6.6 Hz, 1H), 1.61 (tq, J = 7.0 and 7.3 Hz, 2H), 2.17 (td, J = 6.6 and 12.1 Hz, 1H), 2.27 (td, J = 6.6 and 12.1 Hz, 1H), 2.32 (td, J = 7.0 and 12.3 Hz, 1H), 2.41 (td, J = 7.0 and 12.3 Hz, 1H), 3.02 (s, 3H), 3.18 (dtd, J = 6.0, 6.6 and 12.5 Hz, 1H), 3.42 (dtd, J = 6.0, 6.6 and 12.5 Hz, 1H), 3.80 ( s, 3H), 4.91 (s, 1H), 5.64 (t, J = 6.0 Hz, 1H), 7.11 (ddd, J = 1.1, 7.0 and 7.8 Hz, 1H), 7.19 (s, 1H), 7.20 (ddd , J = 1.1, 7.0 and 8.1 Hz, 1H), 7.31 (d, J = 8.1 Hz, 1H), 7.46 (d, J = 7.8 Hz, 1H).
¹³ C-NMR (75.5 MHz, CDCl ₃ ): δ 13.80, 22.75, 26.65, 27.36, 27.86, 32.82, 32.87, 43.75, 45.14, 57.81, 64.03, 96.90, 105.36, 109.24, 119.09, 120.28, 121.32, 127.82, 128.63 , 136.65, 155.08, 171.94
FAB-MS (m-nitrobenzyl alcohol) m / z 400 (M ⁺ ).

4- (Benzylamino) -3- (5-chloro-1-methyl-1H-indol-3-yl) -5- (propylthio) -1H-pyrrole-2,5-dione (ISL-7)
Yield: 98%
Molecular weight: 440.00
Molecular formula: C ₂₄ H ₂₆ ClN ₃ OS
¹ H-NMR (300 MHz, CDCl ₃ ): δ 0.99 (t, J = 7.3 Hz, 3H), 1.61 (tq, J = 7.0 and 7.3 Hz, 2H), 2.30 (td, J = 7.0 and 12.3 Hz, 1H), 2.37 (td, J = 7.0 and 12.3 Hz, 1H), 3.01 (s, 3H), 3.76 (s, 3H), 4.33 (dd, J = 5.9 and 14.7 Hz, 1H), 4.44 (dd, J = 6.3 and 14.7 Hz, 1H), 4.83 (dd, J = 5.9 and 6.3 Hz, 1H), 4.87 (s, 1H), 5.64 (t, J = 6.0 Hz, 1H), 7.05-7.36 (m, 8H) , 7.47 (d, J = 1.1 Hz, 1H) ..
¹³ C-NMR (75.5 MHz, CDCl ₃ ): δ 13.80, 22.68, 26.69, 27.83, 33.08, 48.12, 64.51, 97.85, 104.67, 110.48, 119.46, 121.83, 125.18, 127.33 (2C), 127.55, 128.67 (2C) , 129.01, 130.31, 135.01, 138.43, 154.18, 171.51.
FAB-MS (m-nitrobenzyl alcohol) m / z 439 (M ⁺ ).

1-Benzyl-3- (1-methyl-1H-indol-3-yl) -4- (pentylamino) -5- (propylthio) -1H-pyrrole-2,5-dione (ISL-8)
Yield: 94%
Molecular weight: 461.66
Molecular formula: C ₂₈ H ₃₅ N ₃ OS
¹ H-NMR (300 MHz, CDCl ₃ ): δ 0.78 (t, J = 6.9 Hz, 3H), 0.95 (t, J = 7.3 Hz, 3H), 1.04-1.47 (m, 6H), 1.58 (tq, J = 7.0 and 7.3 Hz, 2H), 2.30 (td, J = 7.0 and 12.3 Hz, 1H), 2.38 (td, J = 7.0 and 12.3 Hz, 1H), 3.02 (dtd, J = 6.0, 6.6 and 12.3 Hz , 1H), 3.30 (dtd, J = 6.0, 6.6 and 12.3 Hz, 1H), 3.79 (s, 3H), 4.21 (d, J = 15.0 Hz, 1H), 4.47 (t, J = 6.0 Hz, 1H) , 4.77 (s, 1H), 5.23 (d, J = 15.0 Hz, 1H), 7.08 (dd, J = 7.1 and 7.8 Hz, 1H), 7.11-7.39 (m, 8H), 7.44 (d, J = 7.8 Hz, 1H).
¹³ C-NMR (75.5 MHz, CDCl ₃ ): δ 13.76, 13.82, 22.18, 22.52, 27.76, 28.69, 30.14, 32.83, 42.58, 44.18, 61.28, 96.94, 104.97, 109.42, 119.16, 120.06, 121.41, 127.18, 127.49 , 128.46 (2C), 128.55 (2C), 128.82, 136.67, 137.98, 154.88, 171.39.
FAB-MS (m-nitrobenzyl alcohol) m / z 461 (M ⁺ ).

1-isopropyl-3- (1-methyl-1H-indol-3-yl) -4- (pentylamino) -5- (propylthio) -1H-pyrrole-2,5-dione (ISL-9)
Yield: 80%
Molecular weight: 413.62
Molecular formula: C ₂₄ H ₃₅ N ₃ OS
¹ H-NMR (300 MHz, CDCl ₃ ): δ 0.79 (t, J = 6.9 Hz, 3H), 0.94 (t, J = 7.3 Hz, 3H), 1.21-1.30 (m, 4H), 1.30-1.50 ( m, 4H), 1.59 (tq, J = 7.0 and 7.3 Hz, 2H), 2.36 (td, J = 7.0 and 12.3 Hz, 1H), 2.45 (td, J = 7.0 and 12.3 Hz, 1H), 3.06 (dtd , J = 6.0, 6.6 and 12.4 Hz, 1H), 3.28 (dtd, J = 6.0, 6.6 and 12.3 Hz, 1H), 3.76 (s, 3H), 4.20 (qq, J = 7.0 and 7.0 Hz, 1H), 4.49 (t, J = 6.0 Hz, 1H), 4.95 (s, 1H), 7.06 (ddd, J = 1.1, 7.0 and 7.8 Hz, 1H), 7.17 (ddd, J = 1.1, 7.0 and 8.1 Hz, 1H) , 7.22 (s, 1H), 7.27 (dd, J = 1.1 and 8.1 Hz, 1H), 7.43 (dd, J = 1.1 and 7.8 Hz, 1H).
¹³ C-NMR (75.5 MHz, CDCl ₃ ): δ 13.80, 13.84, 20.21, 21.23, 22.23, 22.50, 27.66, 28.76, 30.25, 32.79, 44.27, 44.61, 61.56, 97.98, 105.10, 109.32, 119.10, 120.13, 121.31 , 127.76, 128.85, 136.61, 154.08, 171.85.
FAB-MS (m-nitrobenzyl alcohol) m / z 413 (M ⁺ ).

Production reaction 3
Synthesis of 1-methyl-3- (1-methyl-1H-indol-3-yl) -4- (pentylamino) -1H-pyrrol-2 (5H) -one (IL-3)

ISL-5 (35.8 mg, 0.093 mmol) was dissolved in ethanol (0.93 mL), 50% Raney nickel suspension (0.1 mL) was added at room temperature, and the mixture was stirred for 1 hour under a hydrogen stream. Insoluble matter was removed by Celite filtration, and the filtrate was washed with water and concentrated under reduced pressure. The resulting crude product was purified by silica gel column chromatography (hexane / ethyl acetate = 2 / 1-1 / 1-1 / 2) to obtain IL-3 (25.0 mg, 87%) as a pale yellow oily compound. Obtained.
Molecular weight: 311.42
Molecular formula: C ₁₉ H ₂₅ N ₃ O
¹ H-NMR (300 MHz, CDCl ₃ ): δ 0.90 (t, J = 7.0 Hz, 3H), 1.18-1.42 (m, 4H), 1.45-1.63 (m, 2H), 3.06 (s, 3H), 3.09 (dt, J = 6.0 and 7.3 Hz, 2H), 3.80 (s, 3H), 3.98 (s, 2H), 4.51 (t, J = 6.0 Hz, 1H), 7.10 (dd, J = 7.0 and 7.8 Hz , 1H), 7.22 (dd, J = 7.0 and 8.1 Hz, 1H), 7.26 (s, 1H), 7.33 (d, J = 8.1 Hz, 1H), 7.49 (d, J = 7.8 Hz, 1H).
¹³ C-NMR (75.5 MHz, CDCl ₃ ): δ 13.89, 22.27, 28.90, 29.25, 30.20, 32.81, 44.16, 50.18, 96.28, 105.29, 109.47, 118.92, 119.97, 121.25, 126.39, 128.21, 136.74, 154.51, 173.27 .
FAB-MS (m-nitrobenzyl alcohol) m / z 311 (M ⁺ ).

IL derivatives
It was synthesized from the corresponding ISL derivative in the same manner as IL-3.

4- (Benzylamino) -1-methyl-3- (1-methyl-1H-indol-3-yl) -1H-pyrrol-2 (5H) -one (IL-1)
Yield: 57%
Molecular weight: 331.41
Molecular formula: C ₂₁ H ₂₁ N ₃ O
¹ H-NMR (270 MHz, CDCl ₃ ): δ 3.03 (s, 3H), 3.80 (s, 3H), 3.96 (s, 2H), 4.33 (s, 2H), 4.59-5.32 (br, 1H), 7.09 (ddd, J = 1.2, 7.1 and 7.8 Hz, 1H), 7.16-7.44 (m, 8H), 7.49 (d, J = 7.8 Hz, 1H).
¹³ C-NMR (67.8 MHz, CDCl ₃ ): δ 29.35, 32.94, 48.11, 50.29, 97.68, 105.02, 109.46, 119.02, 119.99, 121.29, 126.42, 126.82 (2C), 127.61, 128.30, 128.77 (2C), 136.69 , 138.12, 153.99, 172.85.
FAB-MS (m-nitrobenzyl alcohol) m / z 331 (M ⁺ ).

4- (Cyclopentylamino) -1-methyl-3- (1-methyl-1H-indol-3-yl) -1H-pyrrol-2 (5H) -one (IL-2)
Yield: 86%
Molecular weight: 309.41
Molecular formula: C ₁₉ H ₂₃ N ₃ O
¹ H-NMR (300 MHz, CDCl ₃ ): δ 1.33-1.49 (m, 2H), 1.50-1.80 (m, 4H), 1.88-2.07 (m, 2H), 3.07 (s, 3H), 3.69 (ttd , J = 6.6, 6.6 and 8.4 Hz, 1H), 3.81 (s, 3H), 4.03 (s, 2H), 4.54 (d, J = 8.4 Hz, 1H), 7.10 (ddd, J = 1.1, 7.1 and 7.8 Hz, 1H), 7.22 (ddd, J = 1.1, 7.1 and 8.1 Hz, 1H), 7.28 (s, 1H), 7.33 (dd, J = 1.1 and 8.1 Hz, 1H), 7.47 (dd, J = 1.1 and (7.8 Hz, 1H).
¹³ C-NMR (75.5 MHz, CDCl ₃ ): δ 23.70 (2C), 29.29, 32.85, 34.23 (2C), 50.44, 55.60, 96.52, 105.31, 109.55, 118.94, 119.95, 121.26, 126.32, 128.27, 136.79, 153.88 , 173.22.
FAB-MS m / z 309 (M ⁺ ).

4- (3- (Dimethylamino) propylamino) -1-methyl-3- (1-methyl-1H-indol-3-yl) -1H-pyrrol-2 (5H) -one (IL-4)
Yield: 96%
Molecular weight: 326.44
Molecular formula: C ₁₉ H ₂₆ N ₄ O
¹ H-NMR (300 MHz, CDCl ₃ ): δ 1.66 (tt, J = 6.3 and 6.6 Hz, 2H), 2.06 (s, 6H), 2.30 (t, J = 6.6 Hz, 2H), 3.05 (s, 3H), 3.18 (dt, J = 6.0 and 6.3 Hz, 2H), 3.79 (s, 3H), 3.98 (s, 2H), 5.32 (t, J = 6.0 Hz, 1H), 7.08 (ddd, J = 1.2 , 7.1 and 7.8 Hz, 1H), 7.20 (ddd, J = 1.2, 7.1 and 8.1 Hz, 1H), 7.23 (s, 1H), 7.31 (d, J = 8.1 Hz, 1H), 7.52 (d, J = (7.8 Hz, 1H).
¹³ C-NMR (75.5 MHz, CDCl ₃ ): δ 27.62, 29.26, 32.78, 43.15, 45.25, 45.28, 50.24, 50.45, 96.22, 105.57, 109.27, 118.88, 120.33, 121.19, 126.61, 127.99, 136.76, 154.87, 173.86 .
FAB-MS m / z 326 (M ⁺ ).

1-Benzyl-3- (1-methyl-1H-indol-3-yl) -4- (3- (pentylamino) -1H-pyrrol-2 (5H) -one (IL-5)
Yield: 73%
Molecular weight: 387.52
Molecular formula: C ₂₅ H ₂₉ N ₃ O
¹ H-NMR (300 MHz, CDCl ₃ ): δ 0.88 (t, J = 6.6 Hz, 3H), 1.14-1.39 (m, 4H), 1.40-1.58 (m, 2H), 3.04 (dt, J = 6.3 and 6.9 Hz, 2H), 3.83 (s, 3H), 3.89 (s, 2H), 4.56 (t, J = 6.3 Hz, 1H), 4.70 (s, 1H), 7.12 (ddd, J = 1.1, 7.1 and 7.8 Hz, 1H), 7.24 (ddd, J = 1.1, 7.1 and 8.1 Hz, 1H), 7.25-7.40 (m, 1H), 7.52 (dd, J = 1.1 and 7.8 Hz, 1H).
¹³ C-NMR (75.5 MHz, CDCl ₃ ): δ 13.84, 22.26 (2C), 28.89, 30.11, 32.83, 44.17, 46.14, 47.64, 95.92, 105.23, 109.54, 118.98, 120.05, 121.32, 126.37, 127.19, 128.04 ( 2C), 128.31, 128.59 (2C), 136.81, 138.29, 173.03.
FAB-MS m / z 387 (M ⁺ ).

1-Isopropyl-3- (1-methyl-1H-indol-3-yl) -4- (3- (pentylamino) -1H-pyrrol-2 (5H) -one (IL-6)
Yield: 94%
Molecular weight: 339.47
Molecular formula: C ₂₁ H ₂₉ N ₃ O
¹ H-NMR (300 MHz, CDCl ₃ ): δ 0.91 (t, J = 7.2 Hz, 3H), 1.24 (d, J = 6.9 Hz, 6H), 1.29-1.40 (m, 4H), 1.41-1.60 ( m, 2H), 3.14 (dt, J = 5.7 and 6.6 Hz, 2H), 3.81 (s, 3H), 3.95 (s, 2H), 4.54 (t, J = 5.7 Hz, 1H), 4.58 (qq, J = 5.7 and 6.6 Hz, 1H), 7.11 (ddd, J = 1.1, 7.1 and 7.8 Hz, 1H), 7.22 (ddd, J = 1.1, 7.1 and 8.1 Hz, 1H), 7.31 (s, 1H), 7.33 ( dd, J = 1.1 and 8.1 Hz, 1H), 7.51 (dd, J = 1.1 and 7.8 Hz, 1H).
¹³ C-NMR (75.5 MHz, CDCl ₃ ): δ 13.91, 20.75, 22.31, 28.98, 30.21, 32.81, 32.87, 41.87, 43.22, 44.22, 96.79, 105.28, 109.49, 118.89, 120.08, 121.22, 126.39, 128.30, 136.78 , 154.45, 172.34.
FAB-MS m / z 339 (M ⁺ ).

4- (Benzylamino) -3- (5-bromo-1-methyl-1H-indol-3-yl) 1-methyl-1H-pyrrol-2 (5H) -one (IL-7)
Yield: 37%
Molecular weight: 410.31
Molecular formula: C ₂₁ H ₂₀ BrN ₃ O
¹ H-NMR (300 MHz, CDCl ₃ ): δ 3.02 (s, 3H), 3.76 (s, 3H), 3.97 (s, 2H), 4.32 (d, J = 6.3 Hz, 2H), 4.87 (t, J = 6.3 Hz, 1H), 7.17 (d, J = 9.8 Hz, 1H), 7.22-7.44 (m, 7H), 7.70 (s, 1H).
¹³ C-NMR (75.5 MHz, CDCl ₃ ): δ 29.21, 33.16, 48.10, 50.24, 96.94, 104.85, 110.99, 112.48, 122.63, 124.21, 127.08 (2C), 127.80, 128.16, 128.97 (2C), 129.54, 135.44 , 137.98, 154.31, 172.76.
FAB-MS m / z 410 (M ⁺ ).

Production reaction 4
Synthesis of 4- (benzylamino) -1,5-dimethyl-3- (1-methyl-1H-indol-3-yl) -1H-pyrrol-2 (5H) -one (IML-1)

IHL-1 (28.9 mg, 0.084 mmol) was dissolved in ethanol (0.84 mL), and 10-camphorsulfonic acid (2 mg, 0.0084 mmol) was added at room temperature. After stirring for 3 hours, saturated aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated, and the obtained solid was washed with diethyl ether to give compound A (28.4 mg, 91%) as a white solid.
Molecular weight: 375.46
Molecular formula: C ₂₃ H ₂₅ N ₃ O ₂
¹ H-NMR (300 MHz, CDCl ₃ ): δ 1.26 (t, J = 7.2 Hz, 3H), 2.96 (s, 3H), 3.49 (q, J = 7.2 Hz, 2H), 3.78 (s, 3H) , 4.41 (dd, J = 6.3 and 14.7 Hz, 1H), 4.51 (dd, J = 6.3 and 14.7 Hz, 1H), 4.85 (t, J = 6.3 Hz, 1H), 5.36 (s, 1H), 7.09 ( ddd, J = 1.1, 7.1 and 7.8 Hz, 1H), 7.15-7.39 (m, 8H), 7.47 (dd, J = 1.1 and 7.8 Hz, 1H).

Compound A (31.9 mg, 0.085 mmol) was dissolved in dichloromethane (0.85 mL), and 1.02 M trimethylaluminum-hexane solution (0.17 mL, 0.17 mmol) was added under ice cooling. After stirring at room temperature for 2 hours, dichloroethane (1 mL) and 1.02 M trimethylaluminum-hexane solution (1.7 mL, 1.7 mmol) were added. After stirring at 60 ° C for 12 hours, saturated aqueous sodium potassium tartrate was added, and the mixture was extracted with ethyl acetate. did. The organic layer was dried over anhydrous sodium sulfate and concentrated, and the resulting crude product was purified by silica gel column chromatography (hexane / ethyl acetate = 1/4) and gel permeation chromatography to obtain IML-1 (9.8 mg, 33%) was obtained as a white solid.
Molecular weight: 345.44
Molecular formula: C ₂₂ H ₂₃ N ₃ O
¹ H-NMR (300 MHz, CDCl ₃ ): δ 1.49 (d, J = 6.6 Hz, 3H), 3.00 (s, 3H), 3.79 (s, 3H), 4.06 (q, J = 6.6 Hz, 1H) , 4.31 (s, 2H), 4.44-4.75 (m, 1H), 7.07 (ddd, J = 1.1, 7.1 and 7.8 Hz, 1H), 7.15-7.35 (m, 8H), 7.47 (d, J = 7.8 Hz , 1H).
¹³ C-NMR (75.5 MHz, CDCl ₃ ): δ 17.74, 26.87, 32.87, 48.83, 55.84, 98.22, 105.00, 109.39, 119.12, 120.01, 121.36, 127.08 (2C), 127.25, 127.59, 128.72, 128.81 (2C) , 136.72, 138.65, 159.33, 171.90.
FAB-MS m / z 345 (M ⁺ )

Test Example Cell death inhibitory activity and cytotoxicity were evaluated using human leukemia cell HL60 (performed in the same manner as in Non-Patent Document 3).

Test Example 1 (Cell death inhibitory activity test)
HL60 cells cultured in RPMI1640 medium containing 5% fetal calf serum (FCS) were suspended in new medium to 4x10 ⁵ cells / ml, then seeded 95.5 μl each in a 96-well plate, and cultured for 2 hours . Subsequently, DMSO (compound-free group) or DMSO solution of each compound (final concentration 0.5 μM) was added 0.5 μl at a time, and further cultured for 1 hour. Thereafter, 4 μl of hydrogen peroxide diluted with a medium was added to each well to a final concentration of 100 μM to induce cell death. At this time, water diluted with a medium was added to the compound-free group that did not induce cell death (control group). After culturing for 3 hours, 10 μl of alamarBlue (trademark) (Biosource) was added as a viable cell number indicator, and the fluorescence immediately after the addition and after standing for 3 to 4 hours in a 37 ° C. 5% CO ₂ incubator [ Excitation wavelength (Ex.): 560 nm, radiation wavelength (Em.): 590 nm] were measured with Spectra Max Gemini XS (Molecular Devices), and the fluctuation value was determined. Then, the relative value of the fluorescence fluctuation value of each group when the fluorescence fluctuation value of the control group was taken as 100% was calculated, and this was taken as the cell viability. At this time, the cell death inhibitory activity is based on the difference in cell viability between the group without addition of the compound and the group with addition of the compound in the group treated with hydrogen peroxide. The results are shown in Table 1.
Cell viability (%) = (fluorescence fluctuation value of each group / fluorescence fluctuation value of control group) x 100
Cell death inhibitory activity (%) = (cell survival rate of compound addition / hydrogen peroxide treatment group)-(cell survival rate of compound non-addition / hydrogen peroxide treatment group)

Test Example 2 (Cytotoxicity test)
HL60 cells cultured in RPMI1640 medium containing 5% fetal calf serum (FCS) were suspended in fresh medium to 3x10 ⁵ cells / ml, then seeded at 99.5 μl each in a 96-well plate and cultured for 2 hours . Next, DMSO (compound-free group) or DMSO solution of each compound (final concentration 30 μM) was added in an amount of 0.5 μl each, and further cultured for 16 hours. Then, add 10 μl of alamarBlue (trademark) (Biosource) as a viable cell number indicator to each well, and add fluorescence [excitation immediately after addition and after standing in a 5% CO ₂ incubator at 37 ° C for 2-3 hours. Wavelength (Ex.): 560 nm, radiation wavelength (Em.): 590 nm] were measured with Spectra Max Gemini XS (Molecular Devices), and the fluctuation value was determined. Then, the relative value of the fluorescence fluctuation value of the compound addition group was calculated when the fluorescence fluctuation value of the compound addition group was taken as 100%. Based on this, cytotoxicity was determined. The results are shown in Table 2 below.
Cytotoxicity (%) = 100-(Fluorescence fluctuation value when compound is added / Fluorescence fluctuation value in group without compound) x 100

Test Example 3 (Concentration dependence of cell death inhibitory activity)
HL60 cells cultured in RPMI1640 medium containing 5% fetal calf serum (FCS) were suspended in fresh medium to 4x10 ⁵ cells / ml, seeded in 99.5 μl each in a 96-well plate, and cultured for 2 hours . Subsequently, DMSO (compound-free group) or DMSO solution of each compound was added in an amount of 0.5 μl, followed by further incubation for 1 hour. Thereafter, 4 μl of hydrogen peroxide solution diluted with a medium was added to each well and diluted with a medium to a final concentration of 100 μM to induce cell death. At this time, water diluted with a medium was added to the compound-free group that did not induce cell death (control group). After culturing for 3 hours, 10 μl of alamarBlue (trademark) (Biosource) was added as a viable cell number indicator, and the fluorescence immediately after the addition and after standing for 3 to 4 hours in a 37 ° C. 5% CO ₂ incubator [ Excitation wavelength (Ex.): 560 nm, radiation wavelength (Em.): 590 nm] were measured with Spectra Max Gemini XS (Molecular Devices), and the fluctuation value was determined. Then, the relative value of the fluorescence fluctuation value of each group when the fluorescence fluctuation value of the control group was taken as 100% was calculated, and this was taken as the cell viability. At this time, the cell death inhibitory activity is based on the difference in cell viability between the group without addition of the compound and the group with addition of the compound in the group treated with hydrogen peroxide. The results are shown in Table 2 and FIG.
Cell viability (%) = (fluorescence fluctuation value of each group / fluorescence fluctuation value of control group) x 100
Cell death inhibitory activity (%) = (cell survival rate of compound addition / hydrogen peroxide treatment group)-(cell survival rate of compound non-addition / hydrogen peroxide treatment group)

  In FIG. 1, the activity of a derivative having a similar substituent (aminopentyl group) and different mother nucleus is compared with the known compound IM-54. As a result, it was found that high activity was exhibited at a lower concentration, and it was revealed that the novel skeleton developed in the present invention greatly contributed to the activity improvement.

FIG. 1 is a graph showing the relationship between the concentration of the compound of the present invention and a conventionally known compound added to HL60 cells and the cell viability.

Claims (14)

General formula (1):

(Where
X may be a hydrogen atom, an alkyl group that may have a substituent, an alkenyl group that may have a substituent, an alkynyl group that may have a substituent, or a substituent. A good aryl group, an optionally substituted aralkyl group, a hydroxyl group, an optionally substituted alkoxyl group, an optionally substituted alkenyl, alkynyl, aryl or aralkyloxy group, A thiol group, an optionally substituted alkyl, alkenyl, alkynyl, aryl or aralkylthio group, an optionally substituted alkyl, alkenyl, alkynyl, aryl or aralkylsulfonyl group, having a substituent Optionally having alkyl, alkenyl, alkynyl, aryl or aralkylsulfinyl group, cyano group, substituent Represents an amino group or a halogen atom,
R ¹ represents an alkyl group which may have a substituent, an alkenyl group which may have a substituent, an alkynyl group which may have a substituent, and an aryl which may have a substituent. Group, an aralkyl group which may have a substituent, an acyl group which may have a substituent, an acyloxy group which may have a substituent, an alkyl or alkenyl which may have a substituent , Alkynyl, aryl or aralkyloxycarbonyl group, optionally substituted alkyl, alkenyl, alkynyl, aryl or aralkylthiocarbonyl group, optionally substituted aminocarbonyl group, substituted An optionally substituted aminocarbonyloxy group, an optionally substituted alkyl, alkenyl, alkynyl, aryl or aralkylsulfonyl group, It represents optionally an alkoxyl group which may have a group, alkenyl which may have a substituent, alkynyl, aryl or aralkyl group, optionally substituted amino group, or a hydroxyl group,
R ² and R ³ are each independently a hydrogen atom, an alkyl group which may have a substituent, an alkenyl group which may have a substituent, an alkynyl group which may have a substituent, An aryl group which may have a substituent, an aralkyl group which may have a substituent, an acyl group which may have a substituent, an acyloxy group which may have a substituent, a substituent May have an alkyl, alkenyl, alkynyl, aryl or aralkyloxycarbonyl group, may have a substituent, may have an alkyl, alkenyl, alkynyl, aryl or aralkylthiocarbonyl group, may have a substituent A good aminocarbonyl group, an optionally substituted aminocarbonyloxy group, an optionally substituted alkyl, alkenyl, alkynyl, aryl Is an aralkylsulfonyl group, an optionally substituted alkoxyl group, an optionally substituted alkenyl, an alkynyl, aryl or aralkyloxy group, an optionally substituted amino group, or a hydroxyl group Represents a group,
Or R ² and R ³ together with the nitrogen atom to which they are attached form a saturated or unsaturated ring structure that may contain further heteroatoms and may have a substituent. You can,
R ⁴ is a position number of the indole ring and represents a group attached to the 2, 4, 5, 6 or 7 position or a plurality of positions thereof, n is a number from 1 to 5, and when n is 2 or more, R ⁴ These may be the same or different, and may have a hydrogen atom, a halogen atom, an alkyl group which may have a substituent, an alkenyl group which may have a substituent, or a substituent. An alkynyl group, an aryl group which may have a substituent, an aralkyl group which may have a substituent, an alkoxyl group which may have a substituent, an alkenyl which may have a substituent, Alkynyl, aryl or aralkyloxy group, optionally substituted alkyl, alkenyl, alkynyl, aryl or aralkyloxycarbonyl group, optionally substituted alkyl, alkenyl, alkynyl, aryl Is an aralkyloxycarbonyloxy group, an optionally substituted alkyl, alkenyl, alkynyl, aryl or aralkylthiocarbonyl group, an optionally substituted alkyl, alkenyl, alkynyl, aryl or aralkylthiocarbonyloxy A group, an optionally substituted aminocarbonyl group, an optionally substituted aminocarbonyloxy group, an optionally substituted alkyl, alkenyl, alkynyl, aryl or aralkylsulfonyl group, Alkyl, alkenyl, alkynyl, aryl or aralkylsulfinyl group, optionally substituted alkyl, alkenyl, alkynyl, aryl or aralkylthio group, hydroxyl group, carboxyl group, oxysulfonyl group, cyano , A nitro group, or an amino group which may have a substituent,
R ⁵ represents an alkyl group which may have a substituent, an alkenyl group which may have a substituent, an alkynyl group which may have a substituent, or an aryl which may have a substituent. A group, an aralkyl group which may have a substituent, a hydrogen atom, an acyl group which may have a substituent, an acyloxy group which may have a substituent, or a substituent. Alkyl, alkenyl, alkynyl, aryl or aralkyloxycarbonyl group, optionally substituted alkyl, alkenyl, alkynyl, aryl or aralkylthiocarbonyl group, optionally substituted aminocarbonyl group, substituent An aminocarbonyloxy group which may have a substituent, alkyl, alkenyl, alkynyl, aryl or aralkylsulfo which may have a substituent An alkoxyl group which may have a substituent, an alkenyl which may have a substituent, an alkynyl, aryl or aralkyloxy group, an amino group which may have a substituent, or a hydroxyl group To express)
A 3-amino-2-indolylbutyrolactam derivative represented by the formula:   2. A cell death inhibitor comprising the compound according to claim 1 or a pharmaceutically acceptable salt thereof as an active ingredient.   The compound according to claim 1 or a pharmaceutically acceptable salt thereof as an active ingredient, Alzheimer's disease, spinal muscular artophy (SMA), amyotrophic lateral sclerosis (ALS), Parkinson's disease A preventive or therapeutic agent for a neurodegenerative disease selected from the group consisting of Huntington's disease, retinitis pigmentosa, glaucoma, and cerebellar degeneration.   A prophylactic or therapeutic agent for cerebral ischemia or subsequent delayed neuronal death (DND), comprising the compound according to claim 1 or a pharmaceutically acceptable salt thereof as an active ingredient.   A prophylactic or therapeutic agent for ischemic heart disease comprising the compound according to claim 1 or a pharmaceutically acceptable salt thereof as an active ingredient.   A preventive or therapeutic agent for ischemia reperfusion injury in an organ, comprising the compound according to claim 1 or a pharmaceutically acceptable salt thereof as an active ingredient.   7. A preservative for organs, tissues and cells, comprising the compound according to claim 1 or a pharmaceutically acceptable salt thereof as an active ingredient.   A medicament comprising the compound according to claim 1 or a pharmaceutically acceptable salt thereof as an active ingredient.   A biological research reagent comprising the compound according to claim 1 or a salt thereof. A method for producing a compound wherein X is a hydroxyl group in the general formula (1) according to claim 1,
formula:

(Wherein R ^{1 to} R ⁵ and n are as defined for general formula (1))
The method comprising the step of reacting a 3-amino-2-indolylmaleimide derivative represented by formula (1) with a hydrogenating reagent to reduce a carbonyl group at the 4-position in the derivative to an —OH group. A method for producing a compound in which, in the general formula (1) according to claim 1, X is an optionally substituted alkyl, alkenyl, alkynyl, aryl, or aralkylthio group,
A 3-amino-4-hydroxy-2-indolylbutyrolactam derivative obtained by the method according to claim 10 and R ⁶ -SH (wherein R ⁶ is an optionally substituted alkyl group, alkenyl Group, an alkynyl group, an aryl group, or an aralkyl group) is reacted in the presence of 10-camphorsulfonic acid to convert a 4-OH group in the derivative to a -SR ⁶ group. The method comprising the step of substituting A method for producing a compound in which, in the general formula (1) according to claim 1, X is an optionally substituted alkoxyl group, or an optionally substituted alkenyl, alkynyl, aryl or aralkyloxy group Because
A 3-amino-4-hydroxy-2-indolylbutyrolactam derivative obtained by the method according to claim 10 and R ⁷ -OH (wherein R ⁷ is an optionally substituted alkyl group, alkenyl An alkynyl group, an aryl group, or an aralkyl group) in the presence of 10-camphorsulfonic acid, the 4-OH group in the derivative is converted to an -OR ⁷ group. The method comprising the step of substituting A method for producing a compound wherein X is a hydrogen atom in the general formula (1) according to claim 1,
In the general formula (1) according to claim 1, obtained by the method according to claim 11, X is a -SR ⁶ group (wherein R ⁶ is an optionally substituted alkyl group, alkenyl group, alkynyl). And a method of reducing a —SR ⁶ group in the compound to —H by reacting a compound that is a group, an aryl group, or an aralkyl group) with hydrogen. In the general formula (1) according to claim 1, X is an optionally substituted alkyl group, an optionally substituted alkenyl group, an optionally substituted alkynyl group, a substituted group. A method for producing a compound which is an aryl group which may have a group, or an aralkyl group which may have a substituent,
In the general formula (1) according to claim 1, obtained by the method according to claim 12, wherein X is an -OR ⁷ group (wherein R ⁷ is an optionally substituted alkyl group, alkenyl group, alkynyl). A compound which represents a group, an aryl group, or an aralkyl group) and (R ⁸ ) ₃ Al (wherein R ⁸ is an alkyl group which may have a substituent, an alkenyl group which may have a substituent) , An alkynyl group which may have a substituent, an aryl group which may have a substituent, or an aralkyl group which may have a substituent. And the step of substituting —R ⁷ group in the derivative with —R ⁸ group.

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