898562-94-2

Usage

Uses

Used in Pharmaceutical Industry:
Quinoline, 2-[[4-[1-methyl-4-(4-pyridinyl)-1H-pyrazol-3-yl]phenoxy]methyl]is used as a potential pharmaceutical agent for its biological activity. Quinoline, 2-[[4-[1-methyl-4-(4-pyridinyl)-1H-pyrazol-3-yl]phenoxy]methyl]-'s specific application within the pharmaceutical industry would depend on the results of further analysis and study, which may reveal its efficacy in treating certain diseases or conditions.
Used in Research and Development:
In the field of chemical research and development, Quinoline, 2-[[4-[1-methyl-4-(4-pyridinyl)-1H-pyrazol-3-yl]phenoxy]methyl]serves as a subject for investigation. Scientists and researchers may explore its chemical properties, potential interactions with biological systems, and possible applications in drug discovery and development.

InChI:InChI=1/C25H20N4O/c1-29-16-23(18-12-14-26-15-13-18)25(28-29)20-7-10-22(11-8-20)30-17-21-9-6-19-4-2-3-5-24(19)27-21/h2-16H,17H2,1H3

Synthetic route

2-((4-(4-(pyridin-4-yl)-1H-pyrazol-5-yl)phenoxy)methyl)quinoline (871507-11-8) + methylhydrazine (60-34-4) → 2-({4-[1-methyl-4-(pyridin-4-yl)-1H-pyrazol-3-yl]phenoxy}methyl)quinoline (898562-94-2)

Conditions	Yield
With sulfuric acid In ethanol at 20℃; for 1h;	56%

3-(dimethylamino)-2-(pyridin-4-yl)-1-(4-(quinolin-2-ylmethoxy)phenyl)prop-2-en-1-one (871507-16-3) + methylhydrazine (60-34-4) → 2-({4-[1-methyl-4-(pyridin-4-yl)-1H-pyrazol-3-yl]phenoxy}methyl)quinoline (898562-94-2) + 2-((4-(1-methyl-4-(pyridin-4-yl)-1H-pyrazol-5-yl)phenoxy)methyl)quinoline

Conditions	Yield
With sulfuric acid In ethanol at 20℃; for 1h; Inert atmosphere;	A 56% B 17%

2-((4-(4-(pyridin-4-yl)-1H-pyrazol-5-yl)phenoxy)methyl)quinoline (871507-11-8) + methylhydrazine (60-34-4) → 2-({4-[1-methyl-4-(pyridin-4-yl)-1H-pyrazol-3-yl]phenoxy}methyl)quinoline (898562-94-2) + 2-((4-(1-methyl-4-(pyridin-4-yl)-1H-pyrazol-5-yl)phenoxy)methyl)quinoline

Conditions	Yield
With sulfuric acid In ethanol for 1h; Reflux;	A 51% B 23%

2-Chloromethylquinoline (4377-41-7) → 2-({4-[1-methyl-4-(pyridin-4-yl)-1H-pyrazol-3-yl]phenoxy}methyl)quinoline (898562-94-2) + 2-((4-(1-methyl-4-(pyridin-4-yl)-1H-pyrazol-5-yl)phenoxy)methyl)quinoline

Conditions

Yield

Multi-step reaction with 8 steps 1.1: potassium carbonate / acetone / 22 h / 60 °C / Inert atmosphere 2.1: water; sodium hydroxide / tetrahydrofuran; methanol; dichloromethane / 20 °C 3.1: thionyl chloride / chloroform / Inert atmosphere 4.1: triethylamine / dichloromethane 5.1: lithium diisopropyl amide / tetrahydrofuran / Cooling with ice 5.2: -78 °C 6.1: 1 h / Reflux 7.1: hydrazine hydrate / methanol / 1 h / Reflux 8.1: sulfuric acid / ethanol / 1 h / Reflux View Scheme

N-methoxy-N-methyl-4-(quinolin-2-ylmethoxy)-benzamide (871507-14-1) → 2-({4-[1-methyl-4-(pyridin-4-yl)-1H-pyrazol-3-yl]phenoxy}methyl)quinoline (898562-94-2) + 2-((4-(1-methyl-4-(pyridin-4-yl)-1H-pyrazol-5-yl)phenoxy)methyl)quinoline

Conditions	Yield
Multi-step reaction with 4 steps 1.1: lithium diisopropyl amide / tetrahydrofuran / Cooling with ice 1.2: -78 °C 2.1: 1 h / Reflux 3.1: hydrazine hydrate / methanol / 1 h / Reflux 4.1: sulfuric acid / ethanol / 1 h / Reflux View Scheme

2-(pyridin-4-yl)-1-(4-(quinolin-2-ylmethoxy)phenyl)ethanone (871507-15-2) → 2-({4-[1-methyl-4-(pyridin-4-yl)-1H-pyrazol-3-yl]phenoxy}methyl)quinoline (898562-94-2) + 2-((4-(1-methyl-4-(pyridin-4-yl)-1H-pyrazol-5-yl)phenoxy)methyl)quinoline

Conditions	Yield
Multi-step reaction with 3 steps 1: 1 h / Reflux 2: hydrazine hydrate / methanol / 1 h / Reflux 3: sulfuric acid / ethanol / 1 h / Reflux View Scheme

4-(quinolin-2-ylmethyloxy)benzoic acid (123724-16-3) → 2-({4-[1-methyl-4-(pyridin-4-yl)-1H-pyrazol-3-yl]phenoxy}methyl)quinoline (898562-94-2) + 2-((4-(1-methyl-4-(pyridin-4-yl)-1H-pyrazol-5-yl)phenoxy)methyl)quinoline

Conditions	Yield
Multi-step reaction with 6 steps 1.1: thionyl chloride / chloroform / Inert atmosphere 2.1: triethylamine / dichloromethane 3.1: lithium diisopropyl amide / tetrahydrofuran / Cooling with ice 3.2: -78 °C 4.1: 1 h / Reflux 5.1: hydrazine hydrate / methanol / 1 h / Reflux 6.1: sulfuric acid / ethanol / 1 h / Reflux View Scheme

4-(2-Quinolinylmethoxy)benzoic acid methyl ester (137426-86-9) → 2-({4-[1-methyl-4-(pyridin-4-yl)-1H-pyrazol-3-yl]phenoxy}methyl)quinoline (898562-94-2) + 2-((4-(1-methyl-4-(pyridin-4-yl)-1H-pyrazol-5-yl)phenoxy)methyl)quinoline

Conditions

Yield

Multi-step reaction with 7 steps 1.1: water; sodium hydroxide / tetrahydrofuran; methanol; dichloromethane / 20 °C 2.1: thionyl chloride / chloroform / Inert atmosphere 3.1: triethylamine / dichloromethane 4.1: lithium diisopropyl amide / tetrahydrofuran / Cooling with ice 4.2: -78 °C 5.1: 1 h / Reflux 6.1: hydrazine hydrate / methanol / 1 h / Reflux 7.1: sulfuric acid / ethanol / 1 h / Reflux View Scheme

4-(quinolin-2-ylmethyloxy)benzoyl chloride (134138-88-8) → 2-({4-[1-methyl-4-(pyridin-4-yl)-1H-pyrazol-3-yl]phenoxy}methyl)quinoline (898562-94-2) + 2-((4-(1-methyl-4-(pyridin-4-yl)-1H-pyrazol-5-yl)phenoxy)methyl)quinoline

Conditions	Yield
Multi-step reaction with 5 steps 1.1: triethylamine / dichloromethane 2.1: lithium diisopropyl amide / tetrahydrofuran / Cooling with ice 2.2: -78 °C 3.1: 1 h / Reflux 4.1: hydrazine hydrate / methanol / 1 h / Reflux 5.1: sulfuric acid / ethanol / 1 h / Reflux View Scheme

methyl 4-hydroxylbenzoate (99-76-3) → 2-({4-[1-methyl-4-(pyridin-4-yl)-1H-pyrazol-3-yl]phenoxy}methyl)quinoline (898562-94-2) + 2-((4-(1-methyl-4-(pyridin-4-yl)-1H-pyrazol-5-yl)phenoxy)methyl)quinoline

Conditions

Yield

Multi-step reaction with 8 steps 1.1: potassium carbonate / acetone / 22 h / 60 °C / Inert atmosphere 2.1: water; sodium hydroxide / tetrahydrofuran; methanol; dichloromethane / 20 °C 3.1: thionyl chloride / chloroform / Inert atmosphere 4.1: triethylamine / dichloromethane 5.1: lithium diisopropyl amide / tetrahydrofuran / Cooling with ice 5.2: -78 °C 6.1: 1 h / Reflux 7.1: hydrazine hydrate / methanol / 1 h / Reflux 8.1: sulfuric acid / ethanol / 1 h / Reflux View Scheme

2-({4-[1-methyl-4-(pyridin-4-yl)-1H-pyrazol-3-yl]phenoxy}methyl)quinoline (898562-94-2) + succinic acid (110-15-6) → MP-10 succinate (1037309-45-7)

Conditions	Yield
In ethyl acetate at 25℃; for 12h;
In ethyl acetate Inert atmosphere;

Upstream product

• 871507-11-8 2-((4-(4-(pyridin-4-yl)-1H-pyrazol-5-yl)phenoxy)methyl)quinoline 
• 60-34-4 methylhydrazine 
• 871507-16-3 3-(dimethylamino)-2-(pyridin-4-yl)-1-(4-(quinolin-2-ylmethoxy)phenyl)prop-2-en-1-one 
• 99-76-3 methyl 4-hydroxylbenzoate 
• 134138-88-8 4-(quinolin-2-ylmethyloxy)benzoyl chloride 
• 137426-86-9 4-(2-Quinolinylmethoxy)benzoic acid methyl ester 
• 123724-16-3 4-(quinolin-2-ylmethyloxy)benzoic acid 
• 871507-15-2 2-pyridin-4-yl-1-[4-(quinolin-2-ylmethoxy)-phenyl]-ethanone 
• 871507-14-1 N-methoxy-N-methyl-4-(quinolin-2-ylmethoxy)-benzamide 
• 4377-41-7 2-Chloromethylquinoline 

Downstream Products

• 1037309-45-7 MP-10 succinate 

Relevant academic research and scientific papers

METHODS FOR TREATING DISEASES OF THE RETINA

Disclosed herein is a method of treating disorders of the retina comprising administering to a patient in need of such treatment a therapeutically effective amount of a compound of Formula I as defined herein. These compounds are useful as PDE10 inhibitors.

Radiosynthesis and in vivo evaluation of [11C]MP-10 as a PET probe for imaging PDE10A in rodent and non-human primate brain

2-((4-(1-[11C]Methyl-4-(pyridin-4-yl)-1H-pyrazol-3-yl)phenoxy) methyl)-quinoline (MP-10), a specific PDE10A inhibitor (IC50 = 0.18 nM with 100-fold selectivity over other PDEs), was radiosynthesized by alkylation of the desmethyl precursor with [11C]CH3I, ～45% yield, >92% radiochemical purity, >370 GBq/μmol specific activity at end of bombardment (EOB). Evaluation in Sprague-Dawley rats revealed that [11C]MP-10 had highest brain accumulation in the PDE10A enriched-striatum, the 30 min striatum: cerebellum ratio reached 6.55. MicroPET studies of [11C]MP-10 in monkeys displayed selective uptake in striatum. However, a radiolabeled metabolite capable of penetrating the blood-brain-barrier may limit the clinical utility of [11C]MP-10 as a PDE10A PET tracer.

Discovery of a novel class of phosphodiesterase 10A inhibitors and identification of clinical candidate 2-[4-(1-methyl-4-pyridin-4-yl-1H-pyrazol-3- yl)-phenoxymethyl]-quinoline (PF-2545920) for the treatment of schizophrenia

By utilizing structure-based drug design (SBDD) knowledge, a novel class of phosphodiesterase (PDE) 10A inhibitors was identified. The structure-based drug design efforts identified a unique "selectivity pocket" for PDE10A inhibitors, and interactions within this pocket allowed the design of highly selective and potent PDE10A inhibitors. Further optimization of brain penetration and drug-like properties led to the discovery of 2-[4-(1-methyl-4-pyridin-4-yl-1H-pyrazol-3-yl)-phenoxymethyl]-quinoline (PF-2545920). This PDE10A inhibitor is the first reported clinical entry for this mechanism in the treatment of schizophrenia.

Heteroaromatic quinoline compounds

The invention pertains to heteroaromatic compounds that serve as effective phosphodiesterase (PDE) inhibitors. In particular, the invention relates to said compounds which are selective inhibitors of PDE10. The invention also relates to intermediates for preparation of said compounds; pharmaceutical compositions comprising said compounds; and the use of said compounds in a method for treating certain central nervous system (CNS) or other disorders.