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CN-121986087-A - Neuroprotective agents

CN121986087ACN 121986087 ACN121986087 ACN 121986087ACN-121986087-A

Abstract

The present invention provides novel compounds useful for the treatment of diseases that can be prevented, alleviated, and/or treated by inhibiting axonal degeneration, and pharmaceutical compositions containing the same. The present invention relates to a compound represented by the general formula (I) [ wherein R a 、R b 、X 1 、R 1 、L 1 、L 2 and R 2 are as described in the specification and claims ] or a pharmaceutically acceptable salt thereof, and a pharmaceutical composition containing the same.

Inventors

  • ARAKI TOSHIYUKI
  • Nan Xiangwen
  • Noronaga Shinji
  • FUNAKOSHI MASASHI
  • Itou Kuo
  • KAWAMOTO YUICHIRO
  • ABE HIDETOSHI
  • YAMADA ATSUSHI
  • ISHIDA NATSUKI
  • NOMOTO MASAHIRO

Assignees

  • 国立研究开发法人国立精神·神经医疗研究中心
  • 学校法人东京药科大学

Dates

Publication Date
20260505
Application Date
20241011
Priority Date
20231013

Claims (16)

  1. 1. A compound represented by the following general formula (I) or a pharmaceutically acceptable salt thereof, In the formula, R a and R b are independently a hydrogen atom, halogen, nitro, cyano, amino, hydroxy, C 1～6 alkyl, halo C 1～6 alkyl, amino C 1～6 alkyl, hydroxy C 1～6 alkyl, C 1～6 alkoxy, halo C 1～6 alkoxy, C 1～6 alkoxy C 1～6 alkoxy, C 1～6 alkoxycarbonyl, C 2～6 alkenyl, C 2～6 alkenyloxy, C 2～6 alkynyl or C 2～6 alkynyloxy, or R a and R b present on adjacent carbon atoms optionally form together with the carbon atom to which they are bonded a fused, substituted or unsubstituted carbocyclic or heterocyclic ring with a pyridine ring, X 1 is a direct bond, -CR 11 =CR 11 -, or- (CONR 11 ) m CH 2 -, R 1 is a hydrogen atom or a C 1～6 alkyl group, L 1 is C 1～10 alkylene, arylene, C 1～10 alkylene-arylene, arylene-C 1～10 alkylene, C 1～10 alkylene-arylene-C 1～10 alkylene, arylene-C 1～10 alkylene-arylene, heterocyclylene, C 1～10 alkylene-heterocyclylene, heterocyclylene-C 1～10 alkylene or C 1～10 alkylene-heterocyclylene-C 1～10 alkylene, where the alkylene, arylene or heterocyclylene moiety is optionally substituted by halogen, -COOR 12 、-CONHR 12 or oxo, L 2 is a direct bond, -O-, -NR 13 -、-NR 13 SO 2 -, or- (OCH 2 CH 2 ) n O-, R 2 is a hydrogen atom, an azido group, a substituted or unsubstituted C 1～6 alkyl group, a substituted or unsubstituted C 2～6 alkenyl group, a substituted or unsubstituted C 2～6 alkynyl group, -COR 14 , a substituted or unsubstituted aryl group, or a substituted or unsubstituted heterocyclic group, Here the number of the elements is the number, M is 0 or 1 and the number of the groups, N is 1 to 6, and the number of the n is, R 11 is independently a hydrogen atom or a C 1～6 alkyl group, R 12 is a hydrogen atom or a C 1～6 alkyl group, R 13 is a hydrogen atom, a C 1～6 alkyl group or-COR 14 , R 14 is substituted or unsubstituted C 1～6 alkyl, substituted or unsubstituted C 2～6 alkenyl, substituted or unsubstituted C 2～6 alkynyl, substituted or unsubstituted C 3～10 cycloalkyl, substituted or unsubstituted C 3～10 cycloalkenyl, substituted or unsubstituted aryl, or substituted or unsubstituted heterocyclyl, Wherein, the compound is not included, L 1 is arylene, C 1～3 alkylene-arylene, arylene-C 1～3 alkylene or C 1～3 alkylene-arylene-C 1～3 alkylene, L 2 is directly bonded, L 1 is C 1～3 alkylene-arylene, L 2 is-O-, and L 1 is C 1～3 alkylene, L 2 is-NH-, and R 2 is-CO-5 membered heterocyclyl.
  2. 2. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein the compound is a compound represented by the following general formula (Ia): In the formula, X 1 is a direct bond, -CR 11 =CR 11 -or-CONR 11 CH 2 -, R 1 is a hydrogen atom or a C 1～6 alkyl group, L 1 is C 1～10 alkylene, arylene, C 1～3 alkylene-arylene, arylene-C 1～3 alkylene, C 1～3 alkylene-arylene-C 1～3 alkylene, heterocyclylene, C 1～3 alkylene-heterocyclylene, heterocyclylene-C 1～3 alkylene or C 1～3 alkylene-heterocyclylene-C 1～3 alkylene, where the alkylene moiety is optionally substituted by-COOR 12 or-CONHR 12 , L 2 is a direct bond, -O-, -NR 13 -、-NR 13 SO 2 -, or- (OCH 2 CH 2 ) n O-, R 2 is a hydrogen atom, an azido group, a substituted or unsubstituted C 1～6 alkyl group, a substituted or unsubstituted C 2～6 alkenyl group, a substituted or unsubstituted C 2～6 alkynyl group, -COR 14 , a substituted or unsubstituted aryl group, or a substituted or unsubstituted heterocyclic group, Here the number of the elements is the number, N is 1 to 6, and the number of the n is, R 11 is independently a hydrogen atom or a C 1～6 alkyl group, R 12 is a hydrogen atom or a C 1～6 alkyl group, R 13 is a hydrogen atom, a C 1～6 alkyl group or-COR 14 , R 14 is substituted or unsubstituted C 1～6 alkyl, substituted or unsubstituted C 2～6 alkenyl, substituted or unsubstituted aryl, or substituted or unsubstituted heterocyclyl, Wherein, the compound is not included, L 1 is arylene, C 1～3 alkylene-arylene, arylene-C 1～3 alkylene or C 1～3 alkylene-arylene-C 1～3 alkylene, L 2 is directly bonded, L 1 is C 1～3 alkylene-arylene, L 2 is-O-, and L 1 is C 1～3 alkylene, L 2 is-NH-, and R 2 is-CO-5 membered heterocyclyl.
  3. 3. A compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein L 2 is-O-or-NH-.
  4. 4. A compound according to claim 3, or a pharmaceutically acceptable salt thereof, wherein the compound is represented by the following formula (II): In the formula, X 11 is a direct bond, -CR 11 =CR 11 -or-CONR 11 CH 2 -, X 12 is a direct bond, C 1～3 alkylene, -CR 11 =CR 11 -or-CH 2 NR 11 CO-, L 11 is C 1～10 alkylene, arylene, C 1～3 alkylene-arylene, arylene-C 1～3 alkylene, C 1～3 alkylene-arylene-C 1～3 alkylene, heterocyclylene, C 1～3 alkylene-heterocyclylene, heterocyclylene-C 1～3 alkylene or C 1～3 alkylene-heterocyclylene-C 1～3 alkylene, L 21 is-O-or-NH-, Y 1 is N or CH, and the total number of the N or CH, R 11 is independently a hydrogen atom or a C 1～6 alkyl group, R 12 is a hydrogen atom or a C 1～6 alkyl group, R 21 is independently selected from the group consisting of halogen, nitro, cyano, amino, hydroxy, C 1～6 alkyl, halo C 1～6 alkyl, hydroxy C 1～6 alkyl, C 1～6 alkoxy, halo C 1～6 alkoxy, C 1～6 alkoxy C 1～6 alkoxy, C 1～6 alkoxycarbonyl, C 2～6 alkenyl, C 2～6 alkenyloxy, C 2～6 alkynyl and C 2～6 alkynyloxy.
  5. 5. The compound of claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein L 2 is a direct bond or- (OCH 2 CH 2 ) n O-.
  6. 6. The compound of claim 5, or a pharmaceutically acceptable salt thereof, wherein R 2 is a hydrogen atom, a substituted or unsubstituted C 1～6 alkyl group, a substituted or unsubstituted C 2～6 alkenyl group, a substituted or unsubstituted C 2～6 alkynyl group, a substituted or unsubstituted aryl group, or a substituted or unsubstituted heterocyclyl group.
  7. 7. The compound of claim 1, or a pharmaceutically acceptable salt thereof, which is a compound of: 。
  8. 8. A pharmaceutical composition comprising a compound of claim 1 or a pharmaceutically acceptable salt thereof and comprising at least 1 pharmaceutically acceptable additive.
  9. 9. The pharmaceutical composition according to claim 8 for use in the treatment of a disease that can be prevented, ameliorated and/or treated by the inhibition of axonal degeneration.
  10. 10. The pharmaceutical composition of claim 9, wherein the disease is a neurodegenerative disease.
  11. 11. Use of a compound of claim 1, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of a disease that can be prevented, ameliorated and/or treated by inhibition of axonal degeneration.
  12. 12. A method of treating a disease capable of being prevented, ameliorated and/or treated by the inhibition of axonal degeneration, comprising administering to a patient in need thereof a therapeutically effective amount of a compound of claim 1 or a pharmaceutically acceptable salt thereof.
  13. 13. The pharmaceutical composition of claim 8 for use in the treatment of a disease that can be prevented, ameliorated and/or treated by inhibiting SARM 1.
  14. 14. The pharmaceutical composition of claim 13, wherein the disease is a neurodegenerative disease.
  15. 15. Use of a compound of claim 1, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of a disease that can be prevented, ameliorated and/or treated by the inhibition of SARM 1.
  16. 16. A method of treating a disease that is prevented, ameliorated and/or treated by the inhibition of SARM1, comprising administering to a patient in need thereof a therapeutically effective amount of a compound of claim 1 or a pharmaceutically acceptable salt thereof.

Description

Neuroprotective agents Technical Field The present invention relates to nicotinamide derivatives and pharmaceutical compositions containing the same, and in particular to nicotinamide derivatives and pharmaceutical compositions containing the same for the treatment of diseases that can be prevented, alleviated and/or treated by inhibiting axonal degeneration. Background Axonal degeneration is known to occur in many neurodegenerative diseases (Axon Degeneration). The lack of protein 1 (STERILE ALPHA AND TIR Motif-containing 1, SARM 1) containing the sterile alpha and TIR motifs reportedly significantly attenuated axonal degeneration in some models, suggesting that SARM1 modulates axonal degeneration by its enzymatic activity. Accordingly, a compound capable of inhibiting SARM1 has been attracting attention (for example, refer to patent document 1). In addition, in recent studies, it has been suggested that the active state of SARM1 is regulated by the abundance ratio of nicotinamide adenine dinucleotide (Nicotinamide Adenine Dinucleotide (NAD)) and substrates and intermediates of the NAD biosynthetic pathway (for example, refer to non-patent document 1). In addition, nicotinamide ribosyltransferase (Nicotinamide Phosphoribosyl Transferase (NAMPT)) is considered to be a rate-limiting enzyme in the NAD biosynthetic pathway, and thus compounds that do not inhibit NAMPT and are capable of inhibiting SARM1 involved in NAD decomposition are desired. Prior art literature Patent literature Patent document 1 Japanese patent application laid-open No. 2023-501969 Non-patent literature Non-patent document 1: li et al eLife 2021;10: e67381 Disclosure of Invention Problems to be solved by the invention The present invention provides novel compounds useful for the treatment of diseases that can be prevented, alleviated, and/or treated by inhibiting axonal degeneration, and pharmaceutical compositions containing the same. Solution for solving the problem As a result of intensive studies on compounds having a SARM1 inhibitory activity, the present inventors have found that a series of derivatives having a nicotinamide structure or salts thereof have a SARM1 inhibitory activity and/or a NAMPT inhibitory activity weak, and are useful for treating diseases, particularly neurodegenerative diseases, which can be prevented, alleviated and/or treated by inhibiting axonal degeneration mediated by these compounds, and have completed the present invention. The present invention is as follows. [1] A compound represented by the following general formula (I) or a pharmaceutically acceptable salt thereof, [ In the above-mentioned, a method for producing a semiconductor device, R a and R b are independently a hydrogen atom, halogen, nitro, cyano, amino, hydroxy, C 1～6 alkyl, halo C 1～6 alkyl, amino C 1～6 alkyl, hydroxy C 1～6 alkyl, C 1～6 alkoxy, halo C 1～6 alkoxy, C 1～6 alkoxy C 1～6 alkoxy, C 1～6 alkoxycarbonyl, C 2～6 alkenyl, C 2～6 alkenyloxy, C 2～6 alkynyl or C 2～6 alkynyloxy, or R a and R b present on adjacent carbon atoms optionally form together with the carbon atom to which they are bonded a fused, substituted or unsubstituted carbocyclic or heterocyclic ring with a pyridine ring, X 1 is a direct bond, -CR 11=CR11 -, or- (CONR 11)mCH2 -, R 1 is a hydrogen atom or a C 1～6 alkyl group, L 1 is C 1～10 alkylene, arylene, C 1～10 alkylene-arylene, arylene-C 1～10 alkylene, C 1～10 alkylene-arylene-C 1～10 alkylene, arylene-C 1～10 alkylene-arylene, heterocyclylene, C 1～10 alkylene-heterocyclylene, heterocyclylene-C 1～10 alkylene or C 1～10 alkylene-heterocyclylene-C 1～10 alkylene, where the foregoing alkylene, arylene or heterocyclylene moieties are optionally substituted by halogen, -COOR 12、-CONHR12 or oxo, L 2 is a direct bond, -O-, -NR 13-、-NR13SO2 -, or- (OCH 2CH2)n O-, R 2 is a hydrogen atom, an azido group, a substituted or unsubstituted C 1～6 alkyl group, a substituted or unsubstituted C 2～6 alkenyl group, a substituted or unsubstituted C 2～6 alkynyl group, -COR 14, a substituted or unsubstituted aryl group, or a substituted or unsubstituted heterocyclic group, Here the number of the elements is the number, M is 0 or 1 and the number of the groups, N is 1 to 6, and the number of the n is, R 11 is independently a hydrogen atom or a C 1～6 alkyl group, R 12 is a hydrogen atom or a C 1～6 alkyl group, R 13 is a hydrogen atom, a C 1～6 alkyl group or-COR 14, R 14 is substituted or unsubstituted C 1～6 alkyl, substituted or unsubstituted C 2～6 alkenyl, substituted or unsubstituted C 2～6 alkynyl, substituted or unsubstituted C 3～10 cycloalkyl, substituted or unsubstituted C 3～10 cycloalkenyl, substituted or unsubstituted aryl, or substituted or unsubstituted heterocyclyl ]. (Wherein, excluding compounds wherein L 1 is arylene, C 1～3 alkylene-arylene, arylene-C 1～3 alkylene or C 1～3 alkylene-arylene-C 1～3 alkylene, L 2 is a direct bond; a compound wherein L 1 is C 1～3 alkylene-arylene and L 2 is-O-; and compounds wherein L 1 is C 1～3 alkylene, L 2