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NZ779170B2 - Novel substituted benzimidazole derivatives as D-amino acid oxidase (DAAO) inhibitors - Google Patents
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NZ779170B2 - Novel substituted benzimidazole derivatives as D-amino acid oxidase (DAAO) inhibitors - Google Patents

Novel substituted benzimidazole derivatives as D-amino acid oxidase (DAAO) inhibitors

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Publication number
NZ779170B2
NZ779170B2 NZ779170A NZ77917017A NZ779170B2 NZ 779170 B2 NZ779170 B2 NZ 779170B2 NZ 779170 A NZ779170 A NZ 779170A NZ 77917017 A NZ77917017 A NZ 77917017A NZ 779170 B2 NZ779170 B2 NZ 779170B2
Authority
NZ
New Zealand
Prior art keywords
thio
methyl
compound
linear
branched
Prior art date
Application number
NZ779170A
Other versions
NZ779170A (en
Inventor
Hai Gwo Hwu
Wen Sung Lai
Chih Min Liu
Yu Li Liu
Chung Ming Sun
Yufeng Jane Tseng
Original Assignee
National Health Research Institutes
National Taiwan University
National Yang Ming Chiao Tung University
Yufeng Jane Tseng
Filing date
Publication date
Application filed by National Health Research Institutes, National Taiwan University, National Yang Ming Chiao Tung University, Yufeng Jane Tseng filed Critical National Health Research Institutes
Priority to NZ792401A priority Critical patent/NZ792401B2/en
Publication of NZ779170A publication Critical patent/NZ779170A/en
Publication of NZ779170B2 publication Critical patent/NZ779170B2/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • A61K31/4184—1,3-Diazoles condensed with carbocyclic rings, e.g. benzimidazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/04—Centrally acting analgesics, e.g. opioids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A61P25/16—Anti-Parkinson drugs
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/24—Antidepressants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D235/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
    • C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
    • C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
    • C07D235/24—Benzimidazoles; Hydrogenated benzimidazoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached in position 2
    • C07D235/28—Sulfur atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic Table
    • C07F7/02—Silicon compounds
    • C07F7/08—Compounds having one or more C—Si linkages
    • C07F7/18—Compounds having one or more C—Si linkages as well as one or more C—O—Si linkages
    • C07F7/1804—Compounds having Si-O-C linkages
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/6558—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing at least two different or differently substituted hetero rings neither condensed among themselves nor condensed with a common carbocyclic ring or ring system
    • C07F9/65583—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing at least two different or differently substituted hetero rings neither condensed among themselves nor condensed with a common carbocyclic ring or ring system each of the hetero rings containing nitrogen as ring hetero atom
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Abstract

The present invention provides novel substituted benzimidazole derivatives used as DAAO inhibitors and for treatment and/or prevention of neurological disorders.

Claims (13)

WE CLAIM:
1. A compound of formula (I), wherein n is 0 or 1, X is –S–; A is N; Ra is –C(=O)ORa1; wherein Ra1 is H or linear or branched C1-15alkyl; Rb is H, linear or branched C1-15alkyl, linear or branched C2-15alkenyl, C1-3alkoxy-C1-15alkyl-, -T'-C3-10cycloalkyl, -T'-C3-10cycloalkenyl, -10 aryl or -T'-C5-10heteroaryl; Rc each is independently linear or branched C1-15alkyl, linear or branched C1-15alkoxyl, hydroxyl group, or –C1-10alkylene-Y-C6-10heteroaryl wherein -Y- is -CH2-, -NH-, -O- or -S-; m is an integer from 0 to 4; -T- is absent, C1-3alkylene or kenylene; -T'- is C1-3alkylene or C2-3alkenylene; and n the heteroaryl ns at least one heteroatom, each heteroatom being independently S, N or O; wherein the alkyl, alkenyl, alkoxy, cycloalkyl, aryl, heteroaryl, alkylene and alkenylene are each independently unsubstituted or substituted with at least one substituent; wherein the substituent is each independently a halogen, amino, nitro, nitroso, linear or branched C1-15 alkyl, or linear or branched C1-15 alkoxy or C3-10cycloalkyl; and when Rb is H, the tautomers are included, or a pharmaceutically able salt thereof, provided that the compound is not 5-carbethoxy[[(3,4-dimethoxypyridinyl)methyl]thio]-1H-benzimidazole, 5-carbmethoxy[[(4,5-dimethylpyridinyl)methyl]thio]-1H-benzimidazole, 5-carbmethoxy[[(3,5-dimethylpyridinyl)methyl]thio]-1H-benzimidazole, 5-carbmethoxy[[(3,5-dimethylmethoxypyridinyl)methyl]thio]-1H-benzimidazole, ethoxy[[(3,5-dimethylmethoxypyridinyl)methyl]thio]-1H-benzimidazole, 2-[2-pyridylmethylthio]-(5-carbethoxy)benzimidazole, ethyl 1-ethyl[(2-pyridinylmethyl)thio]-1H-benzimidazolecarboxylate, or 2-[(2-pyridinylmethyl)thio]-1H-benzimidazolecarboxylic acid.
2. The compound of Claim 1, wherein n is 0.
3. The compound of Claim 1 or Claim 2, wherein m is an integer from 0 to 3.
4. The compound of any one of Claims 1 to 3, wherein Ra is –C(=O)OH, or –C(=O)OC1- 4alkyl.
5. The compound of any one of Claims 1 to 4, wherein Rc each is independently halogen, linear or ed C1-6alkyl, linear or branched C1-6alkoxyl, or –C1-10alkenylene-Y-C6- 10heteroaryl; wherein Y is S and C6-10heteroaryl is unsubstituted or substituted by C1-15alkyl, C2- 15alkenyl, C1-15alkoxy, -OH, -NH2, -NO2 or n.
6. The compound of Claim 1 or Claim 2, which is selected from the group ting of: 12082: Methyl 1-(2-(cyclohexenyl)ethyl)(((4-methoxy-3,5-dimethylpyridin yl)methyl)thio)-1H-benzo[d]imidazolecarboxylate 12083: 1-(2-(cyclohexenyl)ethyl)(((4-methoxy-3,5-dimethylpyridin yl)methyl)thio)-1H-benzo[d]imidazolecarboxylic acid, and 12088: methyl 2-(((4-methoxy-3,5-dimethylpyridinyl)methyl)thio)octyl-1H- benzo[d]imidazolecarboxylate, or a pharmaceutically acceptable salt thereof.
7. A pharmaceutical composition, comprising a compound of any one of Claims 1 to 6 or a pharmaceutically acceptable salt thereof.
8. A n in vitro method of inhibiting a DAAO, comprising ting a cell with a compound of any one of Claims 1 to 6 or a pharmaceutically acceptable salt thereof.
9. Use of a compound according to any one of Claims 1 to 6 or a pharmaceutically acceptable salt thereof in the cture of a medicament for treating or preventing a disease associated with DAAO inhibition in a subject.
10. The use of Claim 9, wherein the disease is symptom domains of schizophrenia and schizoaffective disorder, depression, Tourette Syndrome, Post-traumatic stress disorder (PTSD), Obsessive-compulsive disorder (OCD), analgesics, loss of memory and/or ion associated with neurodegenerative diseases or loss of neuronal function characteristic of neurodegenerative diseases.
11. The use of Claim 10, wherein the symptom domains of schizophrenia and schizoaffective disorder include negative, cognitive, depressive, ve and general psychopathology symptom domains.
12. The use of Claim 9, wherein the disease is mild cognitive impairment (MCI), Alzheimer's disease, son's disease or schizophrenia.
13. The use of Claim 9, wherein the disease associated with DAAO inhibition is pain, ataxia or convulsion. Yufeng Jane Tseng National Taiwan University National Chiao Tung University National Health ch utes By the Attorneys for the Applicant SPRUSON & FERGUSON :ras?ua de?e? W WW8{WWWWWWWQWWW W! WWWWWWWWWWWWWWW {52% m WWWWW? WWW WWWWWWWWWWW}: hyp?ria?am?an _////////////////////////} WWW W WWW“ WWWWWWW cha?g %‘%<~3£3§ .g g?f???iage an :?" affgzzi
NZ779170A 2017-09-14 Novel substituted benzimidazole derivatives as D-amino acid oxidase (DAAO) inhibitors NZ779170B2 (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
NZ792401A NZ792401B2 (en) 2017-09-14 Novel substituted benzimidazole derivatives as D-amino acid oxidase (DAAO) inhibitors

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US201662394479P 2016-09-14 2016-09-14
NZ751050A NZ751050B2 (en) 2016-09-14 2017-09-14 Novel substituted benzimidazole derivatives as d-amino acid oxidase (daao) inhibitors

Publications (2)

Publication Number Publication Date
NZ779170A NZ779170A (en) 2025-08-29
NZ779170B2 true NZ779170B2 (en) 2025-12-02

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