130641-38-2

Usage

Uses

Used in Pharmaceutical Industry:
Bindarit is used as an anti-inflammatory agent for its selective inhibition of a subfamily of inflammatory chemokines, reducing inflammation and modulating the NFkB pathway.
Used in Autoimmune Disease Treatment:
Bindarit is used as a therapeutic agent for autoimmune diseases, such as lupus nephritis, by delaying the onset of proteinuria and prolonging survival in mouse models when administered at a specific dose.
Used in Neurological Disorder Treatment:
Bindarit is used as a treatment for neurological disorders, such as experimental autoimmune encephalomyelitis (EAE) in mice, by reducing the incidence and severity of the condition.
Used in Inflammation and Chemotactic Protein Inhibition:
Bindarit is used as a selective inhibitor against monocyte chemotactic proteins MCP-1/CCL2, MCP-3/CCL7, and MCP-2/CCL8, exhibiting its potential in modulating immune responses and inflammation.
Used in Drug Delivery and Transport Inhibition:
Bindarit is used as a noncompetitive inhibitor of monocarboxylate transporter 4 (MCT4), selectively targeting MCT4 over MCT1, which may have implications in drug delivery and transport mechanisms.

InChI:InChI=1/C19H20N2O3/c1-19(2,18(22)23)24-13-16-15-10-6-7-11-17(15)21(20-16)12-14-8-4-3-5-9-14/h3-11H,12-13H2,1-2H3,(H,22,23)

Synthetic route

1-benzyl-3-chloromethyl-1H-indazole + ethyl 2-hydroxy-2,2-dimethylethanoate (80-55-7) → 2-((1-benzyl-1H-indazol-3-yl)methoxy)-2-methylpropanoic acid (130641-38-2)

Conditions	Yield
Stage #1: ethyl 2-hydroxy-2,2-dimethylethanoate With sodium hexamethyldisilazane In tetrahydrofuran; N,N-dimethyl-formamide at 0 - 5℃; for 1.5h; Inert atmosphere; Stage #2: 1-benzyl-3-chloromethyl-1H-indazole With tetra-(n-butyl)ammonium iodide In tetrahydrofuran; N,N-dimethyl-formamide at 0 - 25℃; for 10h; Inert atmosphere;	88.7%

benzyl bromide (100-39-0) → 2-((1-benzyl-1H-indazol-3-yl)methoxy)-2-methylpropanoic acid (130641-38-2)

Conditions	Yield
Multi-step reaction with 5 steps 1.1: potassium tert-butylate / toluene / 0.5 h / 20 °C / Inert atmosphere 1.2: 4.5 h / 20 °C 2.1: isopropylmagnesium chloride / tetrahydrofuran / 7 h / -10 °C / Inert atmosphere 2.2: 0 °C 3.1: hydrogenchloride / toluene; water / 2 h / 90 °C 4.1: sodium hydride / N,N-dimethyl-formamide; toluene / 1.5 h / Inert atmosphere 4.2: 10 h / 90 °C 5.1: sodium hydroxide / 3 h / Reflux View Scheme
Multi-step reaction with 5 steps 1.1: potassium tert-butylate / toluene / 0.5 h / 20 °C / Inert atmosphere 1.2: 4.5 h / 20 °C 2.1: isopropylmagnesium chloride / tetrahydrofuran / 7 h / -10 °C / Inert atmosphere 2.2: 2 h / 0 °C 3.1: hydrogenchloride / toluene; water / 2 h / 90 °C 4.1: sodium hydride / toluene; mineral oil / 1.5 h / Inert atmosphere 4.2: 10 h / 90 °C 5.1: sodium hydroxide / 3 h / Reflux View Scheme

3-bromo-1H-indazole (40598-94-5) → 2-((1-benzyl-1H-indazol-3-yl)methoxy)-2-methylpropanoic acid (130641-38-2)

Conditions	Yield
Multi-step reaction with 5 steps 1.1: potassium tert-butylate / toluene / 0.5 h / 20 °C / Inert atmosphere 1.2: 4.5 h / 20 °C 2.1: isopropylmagnesium chloride / tetrahydrofuran / 7 h / -10 °C / Inert atmosphere 2.2: 0 °C 3.1: hydrogenchloride / toluene; water / 2 h / 90 °C 4.1: sodium hydride / N,N-dimethyl-formamide; toluene / 1.5 h / Inert atmosphere 4.2: 10 h / 90 °C 5.1: sodium hydroxide / 3 h / Reflux View Scheme
Multi-step reaction with 5 steps 1.1: potassium tert-butylate / toluene / 0.5 h / 20 °C / Inert atmosphere 1.2: 4.5 h / 20 °C 2.1: isopropylmagnesium chloride / tetrahydrofuran / 7 h / -10 °C / Inert atmosphere 2.2: 2 h / 0 °C 3.1: hydrogenchloride / toluene; water / 2 h / 90 °C 4.1: sodium hydride / toluene; mineral oil / 1.5 h / Inert atmosphere 4.2: 10 h / 90 °C 5.1: sodium hydroxide / 3 h / Reflux View Scheme

(1-Benzyl-1H-indazol-3-yl)-methanol (131427-21-9) → 2-((1-benzyl-1H-indazol-3-yl)methoxy)-2-methylpropanoic acid (130641-38-2)

Conditions	Yield
Multi-step reaction with 3 steps 1.1: hydrogenchloride / toluene; water / 2 h / 90 °C 2.1: sodium hydride / N,N-dimethyl-formamide; toluene / 1.5 h / Inert atmosphere 2.2: 10 h / 90 °C 3.1: sodium hydroxide / 3 h / Reflux View Scheme
Multi-step reaction with 3 steps 1.1: hydrogenchloride / toluene; water / 2 h / 90 °C 2.1: sodium hydride / toluene; mineral oil / 1.5 h / Inert atmosphere 2.2: 10 h / 90 °C 3.1: sodium hydroxide / 3 h / Reflux View Scheme

1-benzyl-3-chloromethyl-1H-indazole → 2-((1-benzyl-1H-indazol-3-yl)methoxy)-2-methylpropanoic acid (130641-38-2)

Conditions	Yield
Multi-step reaction with 2 steps 1.1: sodium hydride / N,N-dimethyl-formamide; toluene / 1.5 h / Inert atmosphere 1.2: 10 h / 90 °C 2.1: sodium hydroxide / 3 h / Reflux View Scheme
Multi-step reaction with 2 steps 1.1: sodium hydride / toluene; mineral oil / 1.5 h / Inert atmosphere 1.2: 10 h / 90 °C 2.1: sodium hydroxide / 3 h / Reflux View Scheme

N-benzyl-3-iodo-1H-indazole (205643-28-3) → 2-((1-benzyl-1H-indazol-3-yl)methoxy)-2-methylpropanoic acid (130641-38-2)

Conditions	Yield
Multi-step reaction with 4 steps 1.1: isopropylmagnesium chloride / 2-methyltetrahydrofuran / 2 h / -10 °C / Inert atmosphere 1.2: 2 h / 0 °C 2.1: hydrogenchloride / toluene; water / 2 h / 90 °C 3.1: sodium hydride / N,N-dimethyl-formamide; toluene / 1.5 h / Inert atmosphere 3.2: 10 h / 90 °C 4.1: sodium hydroxide / 3 h / Reflux View Scheme
Multi-step reaction with 5 steps 1.1: isopropylmagnesium chloride / tetrahydrofuran / 2 h / -10 °C / Inert atmosphere 1.2: 0 °C 2.1: sodium bis(2-methoxyethoxy)aluminium dihydride / toluene / 0.25 h / 20 °C / Inert atmosphere 3.1: hydrogenchloride / toluene; water / 2 h / 90 °C 4.1: sodium hydride / N,N-dimethyl-formamide; toluene / 1.5 h / Inert atmosphere 4.2: 10 h / 90 °C 5.1: sodium hydroxide / 3 h / Reflux View Scheme
Multi-step reaction with 4 steps 1.1: isopropylmagnesium chloride / 2-methyltetrahydrofuran / 2 h / -10 °C / Inert atmosphere 1.2: 2 h / 0 °C 2.1: hydrogenchloride / toluene; water / 2 h / 90 °C 3.1: sodium hydride / toluene; mineral oil / 1.5 h / Inert atmosphere 3.2: 10 h / 90 °C 4.1: sodium hydroxide / 3 h / Reflux View Scheme
Multi-step reaction with 5 steps 1.1: isopropylmagnesium chloride / tetrahydrofuran / 2 h / -10 °C / Inert atmosphere 1.2: 0 °C 2.1: sodium bis(2-methoxyethoxy)aluminium dihydride / toluene / 0.25 h / 20 °C / Inert atmosphere 3.1: hydrogenchloride / toluene; water / 2 h / 90 °C 4.1: sodium hydride / toluene; mineral oil / 1.5 h / Inert atmosphere 4.2: 10 h / 90 °C 5.1: sodium hydroxide / 3 h / Reflux View Scheme

1-benzyl-1H-indazole-3-carbaldehyde (1186509-61-4) → 2-((1-benzyl-1H-indazol-3-yl)methoxy)-2-methylpropanoic acid (130641-38-2)

Conditions	Yield
Multi-step reaction with 4 steps 1.1: sodium bis(2-methoxyethoxy)aluminium dihydride / toluene / 0.25 h / 20 °C / Inert atmosphere 2.1: hydrogenchloride / toluene; water / 2 h / 90 °C 3.1: sodium hydride / N,N-dimethyl-formamide; toluene / 1.5 h / Inert atmosphere 3.2: 10 h / 90 °C 4.1: sodium hydroxide / 3 h / Reflux View Scheme
Multi-step reaction with 4 steps 1.1: sodium bis(2-methoxyethoxy)aluminium dihydride / toluene / 0.25 h / 20 °C / Inert atmosphere 2.1: hydrogenchloride / toluene; water / 2 h / 90 °C 3.1: sodium hydride / toluene; mineral oil / 1.5 h / Inert atmosphere 3.2: 10 h / 90 °C 4.1: sodium hydroxide / 3 h / Reflux View Scheme

C21H24N2O3 → 2-((1-benzyl-1H-indazol-3-yl)methoxy)-2-methylpropanoic acid (130641-38-2)

Conditions	Yield
Stage #1: C21H24N2O3 With sodium hydroxide for 3h; Reflux; Stage #2: With hydrogenchloride In water
Stage #1: C21H24N2O3 With sodium hydroxide for 3h; Reflux; Stage #2: With hydrogenchloride In water

1-benzyl-3-bromoindazole (29985-03-3) → 2-((1-benzyl-1H-indazol-3-yl)methoxy)-2-methylpropanoic acid (130641-38-2)

Conditions	Yield
Multi-step reaction with 4 steps 1.1: isopropylmagnesium chloride / tetrahydrofuran / 7 h / -10 °C / Inert atmosphere 1.2: 0 °C 2.1: hydrogenchloride / toluene; water / 2 h / 90 °C 3.1: sodium hydride / N,N-dimethyl-formamide; toluene / 1.5 h / Inert atmosphere 3.2: 10 h / 90 °C 4.1: sodium hydroxide / 3 h / Reflux View Scheme
Multi-step reaction with 4 steps 1.1: isopropylmagnesium chloride / tetrahydrofuran / 7 h / -10 °C / Inert atmosphere 1.2: 2 h / 0 °C 2.1: hydrogenchloride / toluene; water / 2 h / 90 °C 3.1: sodium hydride / toluene; mineral oil / 1.5 h / Inert atmosphere 3.2: 10 h / 90 °C 4.1: sodium hydroxide / 3 h / Reflux View Scheme

morpholine (110-91-8) + 2-((1-benzyl-1H-indazol-3-yl)methoxy)-2-methylpropanoic acid (130641-38-2) → 1-benzyl-3-[(1,1-dimethyl-2-morpholin-4-yl-2-oxyethoxy)methyl]-1H-indazole (1186580-36-8)

Conditions	Yield
Stage #1: 2-((1-benzylindazol-3-yl)methoxy)-2-methyl propionic acid With sodium methylate In methanol at 20℃; for 0.166667h; Stage #2: morpholine With thionyl chloride In toluene at 20℃;

2-((1-benzyl-1H-indazol-3-yl)methoxy)-2-methylpropanoic acid (130641-38-2) → 2-[(1-benzyl-1H-indazol-3-yl)methoxy]-2-methylpropan-1-ol (1186507-73-2)

Conditions	Yield
Stage #1: 2-((1-benzylindazol-3-yl)methoxy)-2-methyl propionic acid With lithium aluminium tetrahydride In tetrahydrofuran; diethyl ether at 20℃; Stage #2: With water; sodium hydroxide In tetrahydrofuran; diethyl ether

2-((1-benzyl-1H-indazol-3-yl)methoxy)-2-methylpropanoic acid (130641-38-2) → 2-[(1-benzyl-5-chloro-1H-indazol-3-yl)methoxy]-2-methylpropanoic acid (1186507-48-1)

Conditions	Yield
With chlorine; acetic acid at 20℃;

2-((1-benzyl-1H-indazol-3-yl)methoxy)-2-methylpropanoic acid (130641-38-2) → 2-[(1-benzyl-5-bromo-1H-indazol-3-yl)methoxy]-2-methylpropanoic acid (1186507-66-3)

Conditions	Yield
With bromine; acetic acid at 10 - 20℃;

2-((1-benzyl-1H-indazol-3-yl)methoxy)-2-methylpropanoic acid (130641-38-2) → 1-benzyl-3-[(1,1-dimethyl-2-morpholin-4-ylethoxy)methyl]-1H-indazole. (1186610-50-3)

Conditions	Yield
Multi-step reaction with 2 steps 1.1: sodium methylate / methanol / 0.17 h / 20 °C 1.2: 20 °C 2.1: lithium aluminium tetrahydride / tetrahydrofuran; diethyl ether / 20 °C / Reflux View Scheme

2-((1-benzyl-1H-indazol-3-yl)methoxy)-2-methylpropanoic acid (130641-38-2) → 1-benzyl-3-[(1,1-dimethyl-2-morpholin-4-ylethoxy)methyl]-1H-indazole maleate

Conditions	Yield
Multi-step reaction with 3 steps 1.1: sodium methylate / methanol / 0.17 h / 20 °C 1.2: 20 °C 2.1: lithium aluminium tetrahydride / tetrahydrofuran; diethyl ether / 20 °C / Reflux 3.1: ethanol / 20 °C View Scheme

Upstream product

• 100-39-0 benzyl bromide 
• 40598-94-5 3-bromo-1H-indazole 
• 131427-21-9 (1-Benzyl-1H-indazol-3-yl)-methanol 
• 131427-22-0 1-benzyl-3-chloromethyl-1H-indazole 
• 205643-28-3 N-benzyl-3-iodo-1H-indazole 
• 1186509-61-4 1-benzyl-1H-indazole-3-carbaldehyde 
• 29985-03-3 1-benzyl-3-bromoindazole 
• 80-55-7 ethyl 2-hydroxy-2,2-dimethylethanoate 

Downstream Products

• 1186610-50-3 1-benzyl-3-[(1,1-dimethyl-2-morpholin-4-ylethoxy)methyl]-1H-indazole. 
• 1186507-66-3 2-[(1-benzyl-5-bromo-1H-indazol-3-yl)methoxy]-2-methylpropanoic acid 
• 1186507-48-1 2-[(1-benzyl-5-chloro-1H-indazol-3-yl)methoxy]-2-methylpropanoic acid 
• 1186507-73-2 2-[(1-benzyl-1H-indazol-3-yl)methoxy]-2-methylpropan-1-ol 
• 1186580-36-8 1-benzyl-3-[(1,1-dimethyl-2-morpholin-4-yl-2-oxyethoxy)methyl]-1H-indazole 

Relevant academic research and scientific papers

PROCESSES OF MAKING 2-((1-BENZYL-1H-INDAZOL-3-YL)METHOXY)-2-METHYLPROPANOIC ACID AND ITS DERIVATIVES

The invention in this disclosure is related to the processes of making Bindarit or derivatives thereof. Specifically, the present invention provides, in part, new processes for making 2-((1-benzyl-1H-indazol-3-yl)methoxy)-2-methylpropanoic acid and its derivatives. By way of non-limiting example, synthesis and purification processes of 2-((1-benzyl-1H-indazol-3-yl)methoxy)-2-methylpropanoic acid are provided by the invention in this disclosure.

PROCESS FOR THE PREPARATION OF 1-BENZYL-3-HYDR0XYMETHYL-1H-INDAZ0LE AND ITS DERIVATIVES AND REQUIRED MAGNESIUM INTERMEDIATES

The present invention relates to the process for the preparation of 1-benzyl-3-hydroxymethyl-1H-indazole according to formula (II), to be used in a subsequent process for the preparation of 1-benzyl-3- hydroxymethyl-1H-indazole according to formula (I).

PROCESS FOR THE PREPARATION OF 1-BENZYL-3-HYDROXYMETHYL- 1H- INDAZOLE AND ITS DERIVATIVES AND REQUIRED MAGNESIUM INTERMEDIATES

The present invention relates to the process for the conversion of 1-benzyl-3-hydroxymethyl-1H-indazole according to formula (II), to the 1-benzyl-3-hydroxymethyl-1H-indazole according to formula (I).

NOVEL 1-BENZYL-3-HYDROXYMETHYLINDAZOLE DERIVATIVES AND USE THEREOF IN THE TREATMENT OF DISEASES BASED ON THE EXPRESSION OF MCP-1, CX3CR1 AND P40

The present invention relates to novel 1-benzyl-3-hydroxymethylindazole derivatives according to Formula (I) described in the claims, and to a pharmaceutical composition comprising them, together with a pharmaceutically acceptable vehicle. In addition, the present invention relates to the use of 1-benzyl-3-hydroxymethylindazole derivatives for the preparation of a pharmaceutical composition that is active in the treatment of diseases based on the expression of MCP-1, CX3CR1 and p40, and to their use in a method for treating or preventing diseases based on the expression of MCP-1, CX3CR1 and p40.