Novel melatonin compounds and preparation methods thereof and applications in medicine

Abstract

The invention relates to novel melatonin compounds and preparation methods thereof and applications in medicine, and concretely relates to the novel melatonin compounds represented by a general formula (I), the preparation methods thereof, drug compositions containing the compounds, and the applications of the compounds or the drug compositions which are used as therapeutic agents for preparing drugs which treat depression or periventricular leukomalacia, wherein a definition of each substituent in the general formula (I) is same to that of claims.

Description

technical field

[0001] The invention relates to a melatonin compound and its non-toxic pharmaceutically acceptable salt, preparation method, pharmaceutical composition containing them and clinical application, especially for the treatment of depression. Background technique

[0002] Disruption of the circadian rhythm pattern has been considered as one of the etiological factors in the pathophysiology of depression, and the disturbance of this internal rhythm is the characteristic of abnormal changes in mood, so the normalization of this type of rhythm impairment has been identified as an anti-inflammatory factor. A new measure of drug efficacy for depression.

[0003] Melatonin is an endogenous neurohormone that is only secreted by the anterior pituitary gland of the pineal gland at night, and acts on melatonin receptors concentrated in the suprachiasmatic nucleus (SCN) of the hypothalamus to participate in mediation The mammalian circadian rhythm, the well-known guardian o...

Examples

Embodiment 1

[0030] Embodiment 1: Preparation of N-((2-(3-methoxypropoxy)naphthalene-8-yl)ethyl)acetamide (compound I-1)

[0031]

[0032] Compound I-1

[0033] Take 10.0 g of (2-(3-methoxypropoxy)naphthalene-8-yl)methylamine and dissolve it in 100 ml of acetonitrile. Then 6.48 g of acetic anhydride was added. Heat to reflux for 6 hours. Add 1% activated carbon in total volume to the reaction liquid, reflux for decolorization for 15 min, and filter. The filtrate was concentrated to dryness under reduced pressure, and the residue was separated by HPLC to obtain 5.6 g of compound I-1.

Embodiment 2

[0034] Example 2: Preparation of N-((2-(3-(trifluoromethyl)propoxy)naphthalene-8-yl)ethyl)acetamide (Compound I-2)

[0035]

[0036] Compound I-2

[0037] Take 10.0 g of (2-(3-(trifluoromethyl)propoxy)naphthalene-8-yl)methylamine and dissolve it in 100 ml of acetonitrile. Then 6.48 g of acetic anhydride was added. Heat to reflux for 6 hours. Add 1% activated carbon in total volume to the reaction liquid, reflux for decolorization for 15 min, and filter. The filtrate was concentrated to dryness under reduced pressure, and the residue was separated by HPLC to obtain 5.0 g of compound I-2.

Embodiment 3

[0038] Embodiment 3: Preparation of (2-(3-methoxypropoxy)naphthalene-8-yl)-N,N-dimethylethylamine (compound 1-3)

[0039]

[0040] Compound I-3

[0041] Take 10.0 g of (2-(3-methoxypropoxy)naphthalene-8-yl)methanamine, add 100 ml of acetonitrile and stir to dissolve. Then 5.7 g of dimethyl sulfate was added. Heat to reflux for 6 hours. Add 1% activated carbon in total volume to the reaction liquid, reflux for decolorization for 15 min, and filter. The filtrate was concentrated to dryness under reduced pressure, and the residue was separated by HPLC to obtain 4.5 g of compound I-3.

technical field

[0001] The invention relates to a melatonin compound and its non-toxic pharmaceutically acceptable salt, preparation method, pharmaceutical composition containing them and clinical application, especially for the treatment of depression. Background technique

[0002] Disruption of the circadian rhythm pattern has been considered as one of the etiological factors in the pathophysiology of depression, and the disturbance of this internal rhythm is the characteristic of abnormal changes in mood, so the normalization of this type of rhythm impairment has been identified as an anti-inflammatory factor. A new measure of drug efficacy for depression.

[0003] Melatonin is an endogenous neurohormone that is only secreted by the anterior pituitary gland of the pineal gland at night, and acts on melatonin receptors concentrated in the suprachiasmatic nucleus (SCN) of the hypothalamus to participate in mediation The mammalian circadian rhythm, the well-known guardian o...

Examples

Embodiment 1

[0030] Embodiment 1: Preparation of N-((2-(3-methoxypropoxy)naphthalene-8-yl)ethyl)acetamide (compound I-1)

[0031]

[0032] Compound I-1

[0033] Take 10.0 g of (2-(3-methoxypropoxy)naphthalene-8-yl)methylamine and dissolve it in 100 ml of acetonitrile. Then 6.48 g of acetic anhydride was added. Heat to reflux for 6 hours. Add 1% activated carbon in total volume to the reaction liquid, reflux for decolorization for 15 min, and filter. The filtrate was concentrated to dryness under reduced pressure, and the residue was separated by HPLC to obtain 5.6 g of compound I-1.

Embodiment 2

[0034] Example 2: Preparation of N-((2-(3-(trifluoromethyl)propoxy)naphthalene-8-yl)ethyl)acetamide (Compound I-2)

[0035]

[0036] Compound I-2

[0037] Take 10.0 g of (2-(3-(trifluoromethyl)propoxy)naphthalene-8-yl)methylamine and dissolve it in 100 ml of acetonitrile. Then 6.48 g of acetic anhydride was added. Heat to reflux for 6 hours. Add 1% activated carbon in total volume to the reaction liquid, reflux for decolorization for 15 min, and filter. The filtrate was concentrated to dryness under reduced pressure, and the residue was separated by HPLC to obtain 5.0 g of compound I-2.

Embodiment 3

[0038] Embodiment 3: Preparation of (2-(3-methoxypropoxy)naphthalene-8-yl)-N,N-dimethylethylamine (compound 1-3)

[0039]

[0040] Compound I-3

[0041] Take 10.0 g of (2-(3-methoxypropoxy)naphthalene-8-yl)methanamine, add 100 ml of acetonitrile and stir to dissolve. Then 5.7 g of dimethyl sulfate was added. Heat to reflux for 6 hours. Add 1% activated carbon in total volume to the reaction liquid, reflux for decolorization for 15 min, and filter. The filtrate was concentrated to dryness under reduced pressure, and the residue was separated by HPLC to obtain 4.5 g of compound I-3.

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