Indanone derivatives, pharmaceutically acceptable salts or optical isomers thereof, preparation method for same, and pharmaceutical compositions containing same as active ingredient for preventing or treating viral diseases

Patent metadata

Field	Value
Publication number	US-2016297789-A1
Application number	US-201615189771-A
Country	US
Kind code	A1
Filing date	Jun 22, 2016
Priority date	Jun 16, 2011
Publication date	Oct 13, 2016
Grant date	—

Abstract

Disclosed are novel indanone derivatives, pharmaceutically acceptable salts thereof or enantiomers, a preparation method thereof, and a pharmaceutical composition for the prevention or treatment of viral diseases, comprising the same as an active ingredient. The indanone derivatives have excellent inhibitory activity against picornaviruses including coxsackie-, entero-, echo-, Polio-, and rhinoviruses, as well as exhibiting low cytotoxicity, so that they can be useful as an active ingredient of a pharmaceutical composition for the prevention or treatment of viral diseases including poliomyelitis, paralysis, acute hemorrhagic conjunctivitis, viral meningitis, hand-foot-and-mouth disease, vesicular disease, hepatitis A, myositis, myocarditis, pancreatitis, diabetes, epidemic myalgia, encephalitis, cold, herpangina, foot-and-mouth disease, asthma, chronic obstructive pulmonary disease, pneumonia, sinusitis or otitis media.

First claim

1 . An indanone derivative represented by the following Chemical Formula 1, a pharmaceutically acceptable salt thereof, or an enantiomer thereof:

wherein,
A 1 , A 2 , A 3 , and A 4 are, independently or optionally, selected from the group consisting of —H, halogen, —OH, —CN, —N 3 , alkoxy of C 1 ˜C 10 , linear or branched alkyl of C 1 ˜C 10 , 5-˜7-membered heterocycloalkyl unsubstituted or substituted with —OH or methoxyphenylalkyl, aryl of C 6 ˜C 12 , —O(C═O)R 1 , —(C═O)R 1 , —(C═O)OR 1 , —O(C═O)OR 1 , —O(C═O)NR 1 R 2 , —NO 2 , —NR 1 R 2 , —NR 1 (C═O)R 2 , —NR 1 (C═S)R 2 , —NR 1 (C═O)OR 2 , —NR 1 (C═O)—NR 2 R 3 , —NR 1 (SO 2 )R 2 , and —NR 1 (C═S)—NR 2 R 3 , with a proviso that at least two of A 1 , A 2 , A 3 and A 4 may form a ring together if they are adjacent to each other;
D is —OH, halogen, linear or branched alkyl of C 1 ˜C 10 , alkoxy of C 1 ˜C 10 unsubstituted or substituted with phenyl, —O(CH 2 ) n OH, —O(C═O)R 1 , —(C═O)R 1 , —(C═O)OR 1 , —O(C═O)OR 1 , —O(C═O)NR 1 R 2 , —NO 2 , —NR 1 R 2 , —NR 1 (O)R 2 , —NR 1 (C═O)R 2 , —NR 1 (C═S)R 2 , —NR 1 (C═O)OR 2 , —NR 1 (C═O)—NR 1 R 2 , or —NR 1 (C═S)—NR 1 R 2 ;
E is halogen, —OH, —CN, —N═C═O, —N 3 , alkoxy of C 1 ˜C 10 , —O(C═O)R 1 , —(C═O)R 1 , —(C═O)OR 1 , —O(C═O)OR 1 , —O(C═O)NR 1 R 2 , —NO 2 , —NR 1 R 2 , —NR 1 (C═O)R 2 , —NR 1 (C═S)R 2 , —NR 1 (C═O)OR 2 , —NR 1 (C═O)—NR 1 R 2 , —NR 1 (C═O)NR 20 OR 3 , —NR(SO 2 )R 2 , —NR 1 (C═S)—NR 1 R 2 , —NR 1 (P═O)(OR 2 ) 2 , or

G 1 , G 2 , G 3 , and G 4 are independently or optionally selected from the group consisting of —H, halogen, —OH, CN, alkoxy of C 1 ˜C 10 , linear or branched alkyl of C 1 ˜C 20 , aryl of C 6 ˜C 12 , —O(C═O)R 1 , —(C═O)R 1 , —(C═O)OR 1 , —(CH 2 ) n —(C═O)OR 1 , —O(C═O)OR 1 , —O(C═O)NR 1 R 2 , —NO 2 , —NR 1 R 2 , —NR 1 (C═O)R 2 , —NR 1 (C═S)R 2 , —NR 1 (C═O)OR 2 , —NR 1 (C═O)—NR 2 R 3 , and —NR 1 (C═S)—NR 2 R 3 , with a proviso that at least two of G 1 , G 2 , G 3 , and G 4 may form a ring together if they are adjacent to each other;
X is hydrogen, oxygen, sulfur, hydroxy, linear or branched alkyl of C 1 ˜C 10 , linear or branched alkylene of C 1 ˜C 10 , ═N—NR 1 R 2 , —NR 1 —OR 2 , or ═N—OR 1 ;
Y is —O—, —CH 2 —, —NH—, or —(NR 5 )—;
R 5 is —(C═O)H, —(C═O)OH, —(C═O)R 1 , —(C═S)R 1 , or —(C═O)OR 1 ;
Z is C or N;
R 1 , R 2 , R 3 , and R 4 are independently hydrogen, linear or branched alkyl of C 1 ˜C 10 , linear or branched alkylene of C 1 ˜C 10 unsubstituted or substituted with phenyl, cycloalkyl of C 3 ˜C 7 , heterocycloalkyl of C 3 ˜C 7 , aryl of C 6 ˜C 12 , or 5-˜14-membered heteroaryl;
wherein the heterocycloalkyl may be substituted with at least one oxygen atom via a double bond,
the aryl is mono- or bicyclic and may have at least one substituent selected from the group consisting of halogen, —CN, phenyl, linear or branched alkyl of C 1 ˜C 6 , R 5 , and alkoxy of C 1 ˜C 6 ,
the heteroaryl is mono-, bi- or tricyclic, and may have at least one substituent selected from the group consisting of halogen, —OH, —NO 2 , —NH 2 , —CN, ═O or —O − , linear or branched alkyl of C 1 ˜C 10 , linear or branched alkoxy of C 1 ˜C 10 , and phenyl,
the linear or branched alkyl may be unsubstituted or substituted with at least one substituent selected from the group consisting of phenyl, halogen, 5-˜7-membered heteroaryl, and —NHBoc,
the phenyl may be substituted with at least one selected from the group consisting of halogen, phenyl, or phenyl-substituted alkoxy of C 1 ˜C 6 ,
the hetetrocycloalkyl or heteroaryl contains at least one heteroatom selected from the group consisting of N, O, and S,
the halogen is F, Cl, Br, or I,
n is an integer of 1˜10, and
represents a single or double bond.

2 . The indanone derivative, pharmaceutically acceptable salt, or enantiomer of claim 1 , wherein
A 1 , A 2 , A 3 , and A 4 are, independently or optionally, selected from the group consisting of —H, alkoxy of C 1 ˜C 5 , linear or branched alkyl of C 1 ˜C 5 , 5-˜7-membered heterocycloalkyl unsubstituted or substituted with —OH or methoxyphenylalkyl, aryl of C 6 ˜C 12 , —NO 2 , and —NR 1 R 2 ; D is —OH, halogen, linear or branched alkyl of C 1 ˜C 5 , or alkoxy of C 1 ˜C 5 unsubstituted or substituted with phenyl; E is halogen, —OH, or alkoxy of C 1 ˜C 5 ; E is halogen, —OH, alkoxy of C 1 ˜C 5 , —NR 1 (C═O)R 2 , —NR 1 (C═O)OR 2 , or —NR 1 (C═O)—NR 1 R 2 ; G 1 , G 2 , G 3 , and G 4 are, independently or optionally, selected from the group consisting of —H, alkoxy of C 1 ˜C 5 , and linear or branched alkyl of C 1 ˜C 6 ; X is oxygen, hydroxyl, or linear or branched alkyl of C 1 ˜C 5 ; Y is —O— or —CH 2 —; Z is C or N; R 1 , R 2 , R 3 , and R 4 are independently hydrogen, linear or branched alkyl of C 1 ˜C 7 , heterocycloalkyl of C 3 ˜C 7 , aryl of C 6 ˜C 12 , or 5-˜14-membered heteroaryl; wherein the heterocycloalkyl may be substituted with at least one oxygen atom via a double bond, the aryl is mono- or bicyclic and may have at least one substituent selected from the group consisting of halogen, phenyl, linear or branched alkyl of C 1 ˜C 3 , and alkoxy of C 1 ˜C 3 , the heteroaryl is mono-, bi- or tricyclic, and may have at least one substituent selected from the group consisting of halogen, —OH, —NO 2 , —NH 2 , —CN, ═O or —O − , linear or branched alkyl of C 1 ˜C 10 , linear or branched alkoxy of C 1 ˜C 10 , and phenyl, the linear or branched alkyl may be unsubstituted or substituted with at least one substituent selected from the group consisting of phenyl, halogen, and 5-˜7-membered heteroaryl, the phenyl may be substituted with at least one selected from the group consisting of halogen, and phenyl, the hetetrocycloalkyl or heteroaryl contains at least one heteroatom selected from the group consisting of N, O, and S, the halogen is F, or Cl, and represents a single or double bond.

3 . The indanone derivative, pharmaceutically acceptable salt, or enantiomer of claim 1 , wherein
A 1 , A 2 , A 3 , and A 4 are, independently or optionally, selected from the group consisting of —H and —NR 1 R 2 ; D is —OH; E is —OH or —NR 1 (C═O)R 2 ; G 1 , G 2 , G 3 , and G 4 are, independently or optionally, linear or branched alkyl of C 1 ˜C 15 ; X is oxygen; Y is —O—; Z is C; R 1 , R 2 , R 3 , and R 4 are, independently, hydrogen or 5-˜14-membered heteroaryl; wherein, the 5-˜14-membered heteroaryl is monocyclic, bicyclic, or tricyclic, and may be substituted with a substituent selected from the group consisting of halogen, —OH, —NO 2 , —NH 2 , —CN, ═O or —O—, linear or branched alkyl of C 1 ˜C 10 , linear or branched alkoxy of C 1 ˜C 10 , and phenyl, the phenyl may be substituted with at least one selected form the group consisting of halogen and phenyl, the heteroaryl contains a heteroatom selected from the group consisting of N, O, and S, and the halogen is F or Cl, and represents a single or double bond.

4 . The indanone derivative, pharmaceutically acceptable salt, or enantiomer of claim 1 , wherein
A 1 , A 2 , and A 3 are —H, and A 4 is —NH 2 ; D is —OH; E is —NR 1 (C═O)R 2 ; G 1 , G 3 and G 4 are —H, and G 2 is isopropyl; X is oxygen; Y is —O—; Z is C; R 1 is hydrogen and R 2 is 5-˜14-membered heteroaryl; wherein the heteroaryl is furane, benzofurane, pyridine, pyrazolopyridine, pyrimidine, pyrazolopyrimidine, pyrazine, thiopene, quinoline, isoquinoline, triazole, thiazole, indole, pyrazole, indazole, tetrazole, benzotriazole, chromene, pyrane, pyrrole, benzopyrazole, isoxazole, xanthene, cinnoline, imidazole

Assignees

• Korea Res Inst Chemical Tech
• Katholieke Univ Leuven K U Leuven R & D

Inventors

• Jung Young Sik
• Lee Chong Kgo
• Kim Hae Soo
• Jeong Hee Chun
• Kim Pil Ho
• Han Soo Bong
• Shin Jin Soo
• Neyts Johan
• Thibaut Hendrik Jan

Classifications

• A61P9/00

  Drugs for disorders of the cardiovascular system · CPC title

• A61P3/10

  for hyperglycaemia, e.g. antidiabetics · CPC title

• A61P31/00

  Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics · CPC title

• A61P31/16

  for influenza or rhinoviruses · CPC title

• A61P31/14

  for RNA viruses · CPC title