Naphthalene derivatives and application thereof in drugs

Abstract

The invention provides a number of naphthalene derivatives or stereoisomers, tautomers, nitrogen oxides, metabolites, pharmaceutically acceptable salts or prodrugs thereof which are used for excitement of melatonin receptors. The invention also discloses pharmaceutical compositions containing such compounds and application thereof in treatment of central nervous system dysfunction of mammals, especially human.

Description

technical field

[0001] The invention belongs to the field of medicines, and in particular relates to a class of novel compounds that can be used for treating central nervous system dysfunction, their preparation methods, pharmaceutical compositions containing the compounds, and the role of the compounds and their pharmaceutical compositions in treating central nervous system dysfunction. applications in obstacles. More specifically, the present invention describes naphthalene compounds that can be used as melatonin receptor agonists. Background technique

[0002] Melatonin is a neuroendocrine hormone secreted by the pineal gland. Its main physiological functions are: 1. Anti-tumor effect. Melatonin can inhibit breast cancer, melanoma, prostate cancer, liver cancer, etc. The growth of cancer cells is an important physiological tumor suppressor; 2. Antioxidation, the body can produce free radicals through enzymatic and non-enzymatic reactions, such as oxygen free radicals, hy...

Examples

Embodiment 1

[0196] Example 1 N-(2-(7-methoxynaphthalene-1-yl)-2-methylpropyl)acetamide

[0197]

[0198] Step 1) Synthesis of 2-(7-methoxy-3,4-dihydronaphthalen-1-yl)acetonitrile

[0199] 7-methoxy-3,4-dihydronaphthalene-1 (2H)-one (5.00g, 28.37mmol), 2-cyanoacetic acid (3.62g, 42.56mmol), heptanoic acid (1.0mg, 7.09 mmol) and benzylamine (0.78mL, 7.09mmol) were reacted in toluene (30mL) in an oil bath at 140°C for 48h, then the reaction was stopped and cooled to 25°C. It was washed successively with saturated sodium bicarbonate solution (100 mL) and saturated brine (40 mL), and the organic phase was dried over anhydrous sodium sulfate after separation. After filtration, the filtrate was spin-dried under reduced pressure, and purified by column chromatography (petroleum ether / ethyl acetate (v / v)=50 / 1) to obtain the title compound as a yellow solid (5.44 g, 96.3%).

[0200] MS(ESI,pos.ion)m / z:200.2[M+1] + ;

[0201] 1H NMR (600MHz, CDCl 3 )δ7.12(d, J=8.4Hz, 1H), 6.77(dd, J=8.4...

Embodiment 2

[0219] Example 2 N-(2-(7-fluoronaphthalen-1-yl)-2-methylpropyl)acetamide

[0220]

[0221] Step 1) Synthesis of 2-(7-fluoro-3,4-dihydronaphthalen-1-yl)acetonitrile

[0222] The title compound of this step was prepared by referring to the method described in step 1 of Example 1, that is, 7-fluoro-3,4-dihydronaphthalene-1(2H)-one (2.00g, 12.18mmol), 2-cyanoacetic acid ( 1.55g, 18.27mmol), heptanoic acid (0.43mL, 3.05mmol) and benzylamine (0.33mL, 3.05mmol) were prepared by reacting in toluene (30mL), and the crude product was subjected to silica gel column chromatography (petroleum ether / ethyl acetate (v / v)=50 / 1), concentrated and dried to obtain the title compound as a yellow solid (1.03 g, 45.2%).

[0223] MS(ESI,pos.ion)m / z:188.2[M+1] + ;

[0224] 1H NMR (400MHz, CDCl 3 )δ7.13(dd, J=8.4,6.0Hz,1H),6.89(td,J=8.4,2.8Hz,1H),6.81(dd,J=9.6,2.8Hz,1H),6.33(t,J =4.4Hz, 1H), 3.45(dd, J=3.6, 1.6Hz, 2H), 2.76(t, J=8.0Hz, 2H), 2.36(m, 2H).

[0225] Step 2) Synthesis of 2-(7...

Embodiment 3

[0239] Example 3 N-(2-(7-methoxynaphthalen-1-yl)-2-methylpropyl)propionamide

[0240]

[0241] Step 1) Synthesis of N-(2-(7-methoxynaphthalene-1-yl)-2-methylpropyl) propanamide

[0242] The title compound of this step was prepared by referring to the method described in step 5 of Example 1, that is, 2-(7-methoxynaphth-1-yl)-2-methylpropan-1-amine (195 mg, 850 μmol), triethylamine (240μL, 1.70mmol) and propionyl chloride (90μL, 1.28mmol) were prepared by reacting in dichloromethane (15mL), and the crude product was subjected to silica gel column chromatography (petroleum ether / ethyl acetate (v / v)=2 / 1) , concentrated to dryness to obtain the title compound as a white solid (189 mg, 78.1%).

[0243] MS(ESI,pos.ion)m / z:286.3[M+1] + ;

[0244] 1 H NMR (600MHz, CDCl 3 )δ7.81(d, J=1.8Hz, 1H), 7.77(d, J=9.0Hz, 1H), 7.69(d, J=8.4Hz, 1H), 7.41(d, J=7.8Hz, 1H) ,7.30(t,J=7.8Hz,1H),7.15(dd,J=9.0,2.4Hz,1H),3.98(s,3H),3.79(d,J=5.4Hz,2H),2.27(q, J=6.0Hz, 2H), 1.55(s, 6H), 1.02...

technical field

[0001] The invention belongs to the field of medicines, and in particular relates to a class of novel compounds that can be used for treating central nervous system dysfunction, their preparation methods, pharmaceutical compositions containing the compounds, and the role of the compounds and their pharmaceutical compositions in treating central nervous system dysfunction. applications in obstacles. More specifically, the present invention describes naphthalene compounds that can be used as melatonin receptor agonists. Background technique

[0002] Melatonin is a neuroendocrine hormone secreted by the pineal gland. Its main physiological functions are: 1. Anti-tumor effect. Melatonin can inhibit breast cancer, melanoma, prostate cancer, liver cancer, etc. The growth of cancer cells is an important physiological tumor suppressor; 2. Antioxidation, the body can produce free radicals through enzymatic and non-enzymatic reactions, such as oxygen free radicals, hy...

Examples

Embodiment 1

[0196] Example 1 N-(2-(7-methoxynaphthalene-1-yl)-2-methylpropyl)acetamide

[0197]

[0198] Step 1) Synthesis of 2-(7-methoxy-3,4-dihydronaphthalen-1-yl)acetonitrile

[0199] 7-methoxy-3,4-dihydronaphthalene-1 (2H)-one (5.00g, 28.37mmol), 2-cyanoacetic acid (3.62g, 42.56mmol), heptanoic acid (1.0mg, 7.09 mmol) and benzylamine (0.78mL, 7.09mmol) were reacted in toluene (30mL) in an oil bath at 140°C for 48h, then the reaction was stopped and cooled to 25°C. It was washed successively with saturated sodium bicarbonate solution (100 mL) and saturated brine (40 mL), and the organic phase was dried over anhydrous sodium sulfate after separation. After filtration, the filtrate was spin-dried under reduced pressure, and purified by column chromatography (petroleum ether / ethyl acetate (v / v)=50 / 1) to obtain the title compound as a yellow solid (5.44 g, 96.3%).

[0200] MS(ESI,pos.ion)m / z:200.2[M+1] + ;

[0201] 1H NMR (600MHz, CDCl 3 )δ7.12(d, J=8.4Hz, 1H), 6.77(dd, J=8.4...

Embodiment 2

[0219] Example 2 N-(2-(7-fluoronaphthalen-1-yl)-2-methylpropyl)acetamide

[0220]

[0221] Step 1) Synthesis of 2-(7-fluoro-3,4-dihydronaphthalen-1-yl)acetonitrile

[0222] The title compound of this step was prepared by referring to the method described in step 1 of Example 1, that is, 7-fluoro-3,4-dihydronaphthalene-1(2H)-one (2.00g, 12.18mmol), 2-cyanoacetic acid ( 1.55g, 18.27mmol), heptanoic acid (0.43mL, 3.05mmol) and benzylamine (0.33mL, 3.05mmol) were prepared by reacting in toluene (30mL), and the crude product was subjected to silica gel column chromatography (petroleum ether / ethyl acetate (v / v)=50 / 1), concentrated and dried to obtain the title compound as a yellow solid (1.03 g, 45.2%).

[0223] MS(ESI,pos.ion)m / z:188.2[M+1] + ;

[0224] 1H NMR (400MHz, CDCl 3 )δ7.13(dd, J=8.4,6.0Hz,1H),6.89(td,J=8.4,2.8Hz,1H),6.81(dd,J=9.6,2.8Hz,1H),6.33(t,J =4.4Hz, 1H), 3.45(dd, J=3.6, 1.6Hz, 2H), 2.76(t, J=8.0Hz, 2H), 2.36(m, 2H).

[0225] Step 2) Synthesis of 2-(7...

Embodiment 3

[0239] Example 3 N-(2-(7-methoxynaphthalen-1-yl)-2-methylpropyl)propionamide

[0240]

[0241] Step 1) Synthesis of N-(2-(7-methoxynaphthalene-1-yl)-2-methylpropyl) propanamide

[0242] The title compound of this step was prepared by referring to the method described in step 5 of Example 1, that is, 2-(7-methoxynaphth-1-yl)-2-methylpropan-1-amine (195 mg, 850 μmol), triethylamine (240μL, 1.70mmol) and propionyl chloride (90μL, 1.28mmol) were prepared by reacting in dichloromethane (15mL), and the crude product was subjected to silica gel column chromatography (petroleum ether / ethyl acetate (v / v)=2 / 1) , concentrated to dryness to obtain the title compound as a white solid (189 mg, 78.1%).

[0243] MS(ESI,pos.ion)m / z:286.3[M+1] + ;

[0244] 1 H NMR (600MHz, CDCl 3 )δ7.81(d, J=1.8Hz, 1H), 7.77(d, J=9.0Hz, 1H), 7.69(d, J=8.4Hz, 1H), 7.41(d, J=7.8Hz, 1H) ,7.30(t,J=7.8Hz,1H),7.15(dd,J=9.0,2.4Hz,1H),3.98(s,3H),3.79(d,J=5.4Hz,2H),2.27(q, J=6.0Hz, 2H), 1.55(s, 6H), 1.02...

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